University of Manchester



Major Adverse Cardiovascular Events following Simultaneous Pancreas and Kidney Transplantation in the United KingdomPetros Yiannoullou1,2, Angela Summers1,2, Shu C Goh2, Catherine Fullwood3, Hussein Khambalia1,2, Zia Moinuddin1,2, Iestyn M Shapey1,2, Josephine Naish4,5, Christopher Miller4,5,6,, Titus Augustine1,2, Martin K Rutter2,7*, David van Dellen1,2 **Equal contribution 1Department of Renal and Pancreatic Transplantation, Manchester University NHS Foundation Trust, Oxford Road, Manchester M13 9WL, UK2Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester UK3Centre for Biostatistics, Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Research and Innovation, Manchester University NHS Foundation Trust, Grafton St, M13 9WU4Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PL5Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology & Regenerative Medicine, School of Biology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT6North West Heart Centre, Manchester University NHS Foundation Trust, Southmoor Road, Wythenshawe, Manchester, M23 9LT7Manchester Diabetes Centre, 193 Hathersage Rd, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Oxford Road, Manchester, M13 0JE, UKRunning title:Cardiovascular events following SPKT in the UKKeywords: mortality; cardiovascular, pancreas; kidney; transplantationAbstract word count: 2334Manuscript word count: 3840Table count: 4References: 40Corresponding author: Petros Yiannoullou, Department of Renal and Pancreatic Transplantation, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UKTel: +447590332010Email: petros.yiann@Funding: NoneAbbreviationsAUC – Area under the curveBMI – Body mass indexCI – Confidence intervalCIT – Cold ischaemia timeCVA – Cerebrovascular accidentCVD – Cardiovascular diseaseDBD – Donation after brainstem deathDCD – Donation after cardiac deathECD – Expanded criteria donorESRD – End-stage renal diseaseHDL – High density lipoproteinHLA – Human leukocyte antigenHR – Hazard ratioHTN - HypertensionICD – International classification of diseasesIQR – Interquartile rangeLDKT – living donor kidney transplantMACE – Major adverse cardiovascular eventMI – Myocardial infarctionNHSBT – National Health Service Blood and TransplantNHS – National Health ServiceONS – Office for National Statisticsp.a – per annumROC – Receiver operating characteristicsRR – Relative riskRRT – Renal replacement therapySsBP – Systolic blood pressureSCD – Standard criteria donorSPKT – Simultaneous Pancreas and Kidney TransplantationUK – United KingdomUKTR – United Kingdom transplant registryUSA – United States of AmericaAbstractBackground: People with tType- 1 diabetesics with and kidney failure have an increased risk for major adverse cardiovascular events (MACE). Simultaneous pancreas and kidney transplantation (SPKT) improves survival, but the long-term risk for MACE is uncertain. Methods: We assessed the frequency and risk factors for MACE (defined as fatal cardiovascular disease and non-fatal myocardial infarction or stroke), and related non-fatal MACE to allograft failure in all type-1 diabetic SPKT recipients with type-1 diabetes transplanted between 2001-2015 in the United Kingdom. In a subgroup, we related a pre-transplant cardiovascular risk score to MACE. Results: During 5 years of follow up, 133/1699 type-1 diabetic SPKT recipients (7.8%) experienced a MACE. Age (Hazard Ratio [95% CI]: 1.04 [1.01-1.07] per year), prior MI (2.6 [1.3-5.0]), stroke (2.3 [1.2-4.7]), amputation (2.0 [1.023-3.78]), donor history of hypertension (1.8 [1.054-3.2]), and waiting time (1.02 [1.001-1.04] per month) were significant predictors. Non-fatal MACEs predicted subsequent allograft failure (renal: 1.6 [1.06-2.6]; pancreas: 1.7 [1.09-2.6]). In the subgroup, the pre-transplant cardiovascular risk score predicted MACE (1.04 [1.02-1.06] per 1% increment). Conclusions: We report a high rate of MACE in SPKT recipients. There are a number of variables that predict MACE whilst non-fatal MACE increases the risk of subsequent allograft failure. It may be beneficial that organs from hypertensive donors are matched to recipients with lower cardiovascular risk. Pre-transplant cardiovascular risk scoring may help identify patients who would benefit from risk factor optimisation or alternative transplant therapies, and warrants validation nationally.1 – IntroductionType-1 diabetes mellitus affects approximately 400,000 people in the United Kingdom (UK) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s11245-009-9073-4","ISBN":"2940240701","ISSN":"01677411","URL":"","abstract":"This article covers the current data with regard to diabetes in the UK.","accessed":{"date-parts":[["2018","1","19"]]},"author":[{"dropping-particle":"","family":"Diabetes UK","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Facts and stats","id":"ITEM-1","issue":"October 2016","issued":{"date-parts":[["2016"]]},"page":"2","title":"Prevalence of diabetes","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(1)","plainTextFormattedCitation":"(1)","previouslyFormattedCitation":"¹"},"properties":{"noteIndex":0},"schema":""}(1). Type-1 diabetes significantly reduces life expectancy predominantly due to cardiovascular disease (CVD) complications ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00125-015-3857-4","ISBN":"1432-0428 (Electronic) 0012-186X (Linking)","ISSN":"14320428","PMID":"26796634","abstract":"AIMS/HYPOTHESIS: There is limited information about the impact of type 1 diabetes on life expectancy in a contemporary population. We examined the life expectancy of type 1 diabetic patients and explored the contribution of mortality at different ages and of different causes of death to years of life lost (YLL) compared with the general population.\\n\\nMETHODS: We derived mortality rates of Australians with type 1 diabetes listed on the National Diabetes Services Scheme (NDSS) between 1997 and 2010 (n = 85,547) by linking the NDSS to the National Death Index. The Chiang method was used to estimate life expectancy and Arriaga's method was used to estimate the contributions of age-specific and cause-specific mortality to the YLL.\\n\\nRESULTS: A total of 5,981 deaths were identified during the 902,136 person-years of follow up. Type 1 diabetic patients had an estimated life expectancy at birth of 68.6 years (95% CI 68.1, 69.1), which was 12.2 years (95% CI 11.8, 12.7) less than that in the general population. The improvement in life expectancy at birth in 2004-2010 compared with 1997-2003 was similar for both type 1 diabetic patients (men, 1.9 years [95% CI 0.4, 3.3]; women, 1.5 years [95% CI 0.0, 3.2]) and the general population (men, 2.2 years; women, 1.4 years). Deaths at age <60 years accounted for 60% of the YLL from type 1 diabetes for men and 45% for women. The major contribution to YLL was mortality from endocrine and metabolic disease at age 10-39 years (men, 39-59%; women, 35-50%) and from circulatory disease at age ≥40 years (men, 43-75%; women, 34-75%).\\n\\nCONCLUSIONS/INTERPRETATION: Data from 1997 to 2010 showed that Australian type 1 diabetic patients had an estimated loss in life expectancy at birth of 12.2 years compared with the general population.","author":[{"dropping-particle":"","family":"Huo","given":"Lili","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Harding","given":"Jessica L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peeters","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shaw","given":"Jonathan E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Magliano","given":"Dianna J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetologia","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2016"]]},"page":"1177-1185","publisher":"Diabetologia","title":"Life expectancy of type 1 diabetic patients during 1997–2010: a national Australian registry-based cohort study","type":"article-journal","volume":"59"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1007/s00125-016-3914-7","ISSN":"14320428","author":[{"dropping-particle":"","family":"Petrie","given":"Dennis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lung","given":"Tom W.C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rawshani","given":"Aidin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Palmer","given":"Andrew J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svensson","given":"Ann Marie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eliasson","given":"Bj?rn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clarke","given":"Philip","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetologia","id":"ITEM-2","issue":"6","issued":{"date-parts":[["2016"]]},"page":"1167-1176","title":"Recent trends in life expectancy for people with type 1 diabetes in Sweden","type":"article-journal","volume":"59"},"uris":[""]}],"mendeley":{"formattedCitation":"(2,3)","plainTextFormattedCitation":"(2,3)","previouslyFormattedCitation":"^2,3"},"properties":{"noteIndex":0},"schema":""}(2,3). The addition of chronic kidney disease further increases CVD risk ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00125-010-1860-3.In","ISBN":"1432-0428","abstract":"AIMS/HYPOTHESIS: The FinnDiane Study has reported that mortality in type 1 diabetes is not increased over a 7year follow-up in the absence of renal disease (RD). Using the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study population (n=658) of childhood-onset type 1 diabetes (age <17years), the present study sought to replicate and expand these findings to a 20year follow-up (as of 1 January 2008) and examine cause of death by renal status., METHODS: At baseline (1986-1988), mean age and duration of diabetes were 28 and 19years, respectively. RD was defined as an albumin excretion rate >=20ug/min from multiple samples and grouped as microalbuminuria (MA; 20-200ug/min), overt nephropathy (ON; >200ug/min), or end stage renal disease (ESRD; dialysis or renal transplantation)., RESULTS: At baseline, 311 (47.3%) individuals had RD (MA 21.3%, ON 22.2% and ESRD 3.8%). During a median 20year follow-up, there were 152 deaths (23.1%). Mortality was 6.2 (95% CI 5.2-7.2) times higher than expected, with standardised mortality ratios of 2.0 (1.2-2.8) for normoalbuminuria (NA); 6.4 (4.4-8.4) for MA; 12.5 (9.5-15.4) for ON; and 29.8 (16.8-42.9) for ESRD. Excluding those (n=64) with NA who later progressed to RD, no significant excess mortality was observed in the remaining NA group (1.2, 0.5-1.9), whose deaths were largely unrelated to diabetes., CONCLUSIONS/INTERPRETATION: These data confirm the importance of RD, including persistent microalbuminuria, as a marker of mortality risk and suggest that type 1 diabetes patients without renal disease achieve long-term survival comparable to the general population.","author":[{"dropping-particle":"","family":"Orchard","given":"T J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Secrest","given":"A M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"R G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Costacou","given":"T","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issue":"e93, 0006777","issued":{"date-parts":[["2010"]]},"page":"2312-2319","title":"In the absence of renal disease, 20year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study","type":"article-journal","volume":"53"},"uris":[""]}],"mendeley":{"formattedCitation":"(4)","plainTextFormattedCitation":"(4)","previouslyFormattedCitation":"⁴"},"properties":{"noteIndex":0},"schema":""}(4). We have shown that simultaneous pancreas and kidney transplantation (SPKT) improves survival compared to those on the waiting list ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/ndt/gfs613","ISBN":"1460-2385 (Electronic)\\r0931-0509 (Linking)","ISSN":"0931-0509","PMID":"23512107","abstract":"BACKGROUND: Pancreas transplantation in complicated type 1 (insulin dependent) diabetes mellitus improves the quality of life, increases longevity and stabilizes diabetic complications. There may be clinician reticence due to perceived poor outcomes with published associated mortality rates of 5-8% due to significant co-morbidities, particularly cardiovascular impairment.\\n\\nMETHODS: Retrospective analysis was performed on patients undergoing pancreas transplantation in a single centre since the programme's initiation [simultaneous pancreas kidney (SPK) = 148, pancreas after kidney (PAK) = 33 and pancreas transplant alone (PTA) = 11] compared with a control group accepted contemporaneously onto the waiting list. The primary endpoint was patient mortality. The risk factors including medical and diabetic history, demographics, transplant type and waiting time were analysed.\\n\\nRESULTS: The waiting list mortality was 30% (35 of 120) compared with a mortality of 9% (20 of 193) post-transplantation (P < 0.001). Deaths on the waiting list compared with transplantation up to 1 year had a relative risk of 2.67 (95% CI: 0.81-3.51; P = 0.19), whilst those surviving >1 year had a relative risk of 5.89 of dying on the waiting list (95% CI: 1.70-3.20; P < 0.0005). There were no differences in terms of cardiovascular or renal-associated risk factors, nor in other potential confounding factors other than duration of diabetes (P = 0.02). Median survival from listing was shorter in younger patients (<50; P < 0.0001).\\n\\nCONCLUSIONS: Type 1 diabetics with renal failure listed for pancreas transplantation are at a significant risk of mortality even without surgery. Transplantation offers considerable survival benefits, despite associated surgical and immunosuppressive risks. In selected patients, pancreas transplantation remains the benchmark treatment for type 1 diabetes mellitus.","author":[{"dropping-particle":"","family":"Dellen","given":"David","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Worthington","given":"Judith","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mitu-Pretorian","given":"Otilia M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ghazanfar","given":"Abbas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Forgacs","given":"Bence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pararajasingam","given":"Ravi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Campbell","given":"Babatunde","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parrott","given":"Neil R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Augustine","given":"Titus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tavakoli","given":"Afshin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nephrology Dialysis Transplantation","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2013"]]},"page":"1315-1322","title":"Mortality in diabetes: pancreas transplantation is associated with significant survival benefit","type":"article-journal","volume":"28"},"uris":[""]}],"mendeley":{"formattedCitation":"(5)","plainTextFormattedCitation":"(5)","previouslyFormattedCitation":"⁵"},"properties":{"noteIndex":0},"schema":""}(5). However, there is limited data on the long-term risk for major adverse cardiovascular events (MACE) in contemporary SPKT cohorts ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.amjcard.2017.05.038","ISSN":"00029149","PMID":"28683901","abstract":"Large database studies detailing the risk of perioperative cardiovascular complications after pancreas transplant has been limited, perhaps because these outcomes are not captured by transplant registries. Greater data on the incidence and risks of such outcomes could provide additional insight for referring physicians and inform potential recipients of their risk. We performed a serial, cross-sectional analysis of the National Inpatient Sample, the largest publicly available inpatient database in the United States, to assess for the risk of cardiovascular complications after pancreas transplants in the United States from 2003 to 2012 (n = 13,399). Using multivariable logistic regression models, the risk of cardiovascular outcomes after simultaneous pancreas-kidney transplants (SPK) was compared with solitary pancreas transplants (pancreas after kidney and pancreas transplant alone [PAK + PTA]). The unadjusted prevalence of in-hospital cardiovascular complications was higher in SPK than PAK + PTA (5.5% vs 3.7%, p <0.001). After multivariable adjustment, SPK remained associated with significantly higher odds of any cardiovascular complication (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.21 to 1.80, p = 0.01), and particularly stroke (OR 13.41, 95% CI 4.78 to 37.63, p <0.001), compared with PAK + PTA. However, there was no difference in perioperative mortality (OR 0.78, 95% CI 0.54 to 1.12, p = 0.18). In conclusion, these findings highlight the association between uremia and stroke in pancreas transplant patients, as well as the need for improved preoperative cardiac risk assessment and perioperative management, especially in those who underwent SPK.","author":[{"dropping-particle":"","family":"Kim","given":"Jim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schulman-Marcus","given":"Joshua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watkins","given":"Anthony C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feldman","given":"Dmitriy N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swaminathan","given":"Rajesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Jun B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Muthukumar","given":"Thangamani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Serur","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Luke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartono","given":"Choli","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American Journal of Cardiology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017"]]},"page":"682-687","publisher":"Elsevier Inc.","title":"In-Hospital Cardiovascular Complications After Pancreas Transplantation in the United States from 2003 to 2012","type":"article-journal","volume":"120"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1007/s00125-015-3853-8","ISSN":"1432-0428 (Electronic)","PMID":"26713324","abstract":"AIMS/HYPOTHESIS: Mortality due to cardiovascular disease (CVD), particularly coronary artery disease (CAD), is high in type 1 diabetic patients with end-stage renal disease (ESRD). We aimed to determine whether normoglycaemia, as achieved by successful simultaneous pancreas and kidney (SPK) transplantation, could improve long-term outcomes compared with living donor kidney-alone (LDK) transplantation. METHODS: We studied 486 type 1 diabetic patients with ESRD who underwent a first SPK (n = 256) or LDK (n = 230) transplant between 1983 and 2012 and were followed to the end of 2014. Data were retrieved from the Norwegian Renal Registry and hospital records. Kaplan-Meier plots and multivariate Cox regression, with correction for recipient, donor and transplant factors, were used to examine potential associations between transplant type and all-cause and CVD- and CAD-related mortality. RESULTS: Median follow-up time was 7.9 years (interquartile range 4.3, 12.9). The adjusted HR for CVD-related deaths in SPK recipients compared with LDK recipients was 0.63 (95% CI 0.40, 0.99; p = 0.047), while the HRs for all-cause and CAD-related mortality were 0.81 (95% CI 0.57, 1.16; p = 0.25) and 0.63 (95% CI 0.36, 1.12; p = 0.12), respectively. Compared with the LDK group, SPK recipients were younger and received grafts from younger donors. Cardiovascular mortality was higher in patients transplanted between 1983 and 1999 compared with those who received their grafts in subsequent years. CONCLUSIONS/INTERPRETATION: In patients with type 1 diabetes and ESRD, SPK transplantation was associated with reduced long-term cardiovascular mortality compared with LDK transplantation.","author":[{"dropping-particle":"","family":"Lindahl","given":"Jorn P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartmann","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aakhus","given":"Svend","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Endresen","given":"Knut","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Midtvedt","given":"Karsten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holdaas","given":"Hallvard","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leivestad","given":"Torbjorn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horneland","given":"Rune","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oyen","given":"Ole","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jenssen","given":"Trond","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetologia","id":"ITEM-2","issue":"4","issued":{"date-parts":[["2016"]]},"page":"844-852","title":"Long-term cardiovascular outcomes in type 1 diabetic patients after simultaneous pancreas and kidney transplantation compared with living donor kidney transplantation.","type":"article-journal","volume":"59"},"uris":[""]}],"mendeley":{"formattedCitation":"(6,7)","plainTextFormattedCitation":"(6,7)","previouslyFormattedCitation":"^6,7"},"properties":{"noteIndex":0},"schema":""}(6,7). Cardiovascular death with a functioning graft (DWFG) accounts for a large proportion of allograft loss in transplant populations ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/00007890-200101150-00014","ISBN":"0041-1337 (Print)\\r0041-1337 (Linking)","ISSN":"0041-1337","PMID":"11211201","abstract":"BACKGROUND: Simultaneous pancreas-kidney transplantation (SPK) ameliorates the progression of microvascular diabetic complications but the procedure is associated with excess initial morbidity and an uncertain effect on patient survival when compared with solitary cadaveric or living donor renal transplantation. We evaluated mortality risks associated with SPK, solitary renal transplantation, and dialysis treatment in a national cohort of type 1 diabetics with end-stage nephropathy. METHODS: A total of 13,467 adult-type 1 diabetics enrolled on the renal and renal-pancreas transplant waiting list between 10/01/88 and 06/30/97 were followed until 06/30/98. Time-dependent mortality risks and life expectancy were calculated according to the treatment received subsequent to wait-list registration: SPK; cadaveric kidney only (CAD); living donor kidney only (LKD) transplantation; and dialysis [wait-listed, maintenance dialysis treatment (WLD)]. RESULTS: Adjusted 10-year patient survival was 67% for SPK vs. 65% for LKD recipients (P=0.19) and 46% for CAD recipients (P<0.001). The excess initial mortality normally associated with renal transplantation and the risk of early infectious death was 2-fold higher in SPK recipients. The time to achieve equal proportion of survivors as the WLD patients was 170, 95, and 72 days for SPK, CAD, and LKD recipients, respectively (P<0.001). However, the adjusted 5-year morality risk (RR) using WLD as the reference and the expected remaining life years were 0.40, 0.45, and 0.75 and 23.4, 20.9, and 12.6 years for SPK, LKD, and CAD, respectively. There was no survival benefit in SPK recipients > or =50 years old (RR=1.38, P=0.81). CONCLUSIONS: Among patients with type 1 DM with end-stage nephropathy, SPK transplantation before the age of 50 years was associated with long-term improvement in survival compared to solitary cadaveric renal transplantation or dialysis.","author":[{"dropping-particle":"","family":"Ojo","given":"a O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meier-Kriesche","given":"H U","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanson","given":"J a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leichtman","given":"a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Magee","given":"J C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cibrik","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolfe","given":"R a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Port","given":"F K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Agodoa","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"D B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaplan","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplantation","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2001"]]},"page":"82-90","title":"The impact of simultaneous pancreas-kidney transplantation on long-term patient survival.","type":"article-journal","volume":"71"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1097/SLA.0b013e3181b76d2b","ISBN":"1528-1140 (Electronic)\\r0003-4932 (Linking)","ISSN":"00034932","PMID":"19730242","abstract":"OBJECTIVE: Simultaneous pancreas-kidney transplantation (SPK) is a procedure which frees the diabetic patient with end-stage nephropathy from dialysis and daily insulin injections. The purpose of this study is to report long-term outcomes of this procedure, and describe surgical and medical complications. METHODS: The analysis includes 1000 consecutive SPKs performed between 1985 and 2007. Bladder drainage was used in 390 patients and enteric drainage in 610 patients. In 362 patients, SPK transplantation was performed before initiation of dialysis. RESULTS: Patient survival at 1, 10, and 20 years is 97%, 80%, and 58%; kidney survival is 91%, 63%, and 38%; and pancreas survival is 88%, 63%, and 36%, respectively. There was no difference (P > 0.19) for patient, kidney, and pancreas survival between bladder and enteric drainage. Major surgical complications for bladder-drained patients were anastomotic leaks, urological complications, and infections. For enteric-drained patients, major surgical complications were infection, bleeding, and enzyme leak. Principal causes of death were myocardial infarction (n = 23), cerebrovascular accident (n = 18), and renal failure (n = 15). Graft failure for the kidney was due to acute rejection (n = 48), chronic rejection (n = 146), and death with a functioning graft (n = 99). Graft failure for the pancreas was caused by chronic graft loss (n = 44), thrombosis (n = 31), rejection (n = 80), and death with a functioning graft (n = 125). A total of 113 patients were retransplanted with either living related or unrelated donor kidneys (n = 64) or deceased donor kidneys (n = 42). Survival for retransplanted kidneys is 84% at 1 year and 68% at 5 years. Surviving bladder-drained patients underwent enteric conversion (>50%) for severe recalcitrant metabolic or urologic complications, most commonly enzyme leaks, hematuria, and recurrent urinary tract infection. CONCLUSIONS: Diabetic patients with end-stage renal failure have a poor prognosis without transplantation. Transplantation with SPK provides a marked extension of the patient's life and freedom from insulin injections. Enteric drainage is currently the surgical technique of choice. SPK transplantation should be considered the treatment of choice in this patient population.","author":[{"dropping-particle":"","family":"Sollinger","given":"Hans W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Odorico","given":"Jon S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Becker","given":"Yolanda T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Alessandro","given":"Anthony M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pirsch","given":"John D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Surgery","id":"ITEM-2","issue":"4","issued":{"date-parts":[["2009"]]},"page":"618-629","title":"One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up","type":"article-journal","volume":"250"},"uris":[""]}],"mendeley":{"formattedCitation":"(8,9)","plainTextFormattedCitation":"(8,9)","previouslyFormattedCitation":"^8,9"},"properties":{"noteIndex":0},"schema":""}(8,9). However, the relationship between non-fatal cardiovascular events and subsequent allograft loss in SPKT recipients is unknown.The QRISK2? calculator was developed within the UK general population to estimate an individual’s 10-year risk of CVD, without modification of risk factors. The QRISK2? variables include modifiable and non-modifiable factors, ethnicity, and level of social deprivation estimated from an individual’s UK postal code (supplemental table 1) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/bmj.39609.449676.25","ISBN":"0959-8146","ISSN":"0959-8138","PMID":"18573856","abstract":"OBJECTIVE: To develop and validate version two of the QRISK cardiovascular disease risk algorithm (QRISK2) to provide accurate estimates of cardiovascular risk in patients from different ethnic groups in England and Wales and to compare its performance with the modified version of Framingham score recommended by the National Institute for Health and Clinical Excellence (NICE). DESIGN: Prospective open cohort study with routinely collected data from general practice, 1 January 1993 to 31 March 2008. SETTING: 531 practices in England and Wales contributing to the national QRESEARCH database. PARTICIPANTS: 2.3 million patients aged 35-74 (over 16 million person years) with 140,000 cardiovascular events. Overall population (derivation and validation cohorts) comprised 2.22 million people who were white or whose ethnic group was not recorded, 22,013 south Asian, 11,595 black African, 10,402 black Caribbean, and 19,792 from Chinese or other Asian or other ethnic groups. MAIN OUTCOME MEASURES: First (incident) diagnosis of cardiovascular disease (coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records or linked Office for National Statistics death certificates. Risk factors included self assigned ethnicity, age, sex, smoking status, systolic blood pressure, ratio of total serum cholesterol:high density lipoprotein cholesterol, body mass index, family history of coronary heart disease in first degree relative under 60 years, Townsend deprivation score, treated hypertension, type 2 diabetes, renal disease, atrial fibrillation, and rheumatoid arthritis. RESULTS: The validation statistics indicated that QRISK2 had improved discrimination and calibration compared with the modified Framingham score. The QRISK2 algorithm explained 43% of the variation in women and 38% in men compared with 39% and 35%, respectively, by the modified Framingham score. Of the 112,156 patients classified as high risk (that is, >or=20% risk over 10 years) by the modified Framingham score, 46,094 (41.1%) would be reclassified at low risk with QRISK2. The 10 year observed risk among these reclassified patients was 16.6% (95% confidence interval 16.1% to 17.0%)-that is, below the 20% treatment threshold. Of the 78 024 patients classified at high risk on QRISK2, 11,962 (15.3%) would be reclassified at low risk by the modified Framingham score. The 10 year observed risk among these patients was 23.3% (22.2% to 24.4%)-that is, above the 20% threshold.…","author":[{"dropping-particle":"","family":"Hippisley-Cox","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Coupland","given":"Carol","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vinogradova","given":"Yana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robson","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Minhas","given":"Rubin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sheikh","given":"Aziz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brindle","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Bmj","id":"ITEM-1","issue":"7659","issued":{"date-parts":[["2008"]]},"page":"1475-1482","title":"Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2.","type":"article-journal","volume":"336"},"uris":[""]}],"mendeley":{"formattedCitation":"(10)","plainTextFormattedCitation":"(10)","previouslyFormattedCitation":"¹⁰"},"properties":{"noteIndex":0},"schema":""}(10). A score ≥10% is the current threshold for statin therapy; a score ≥20% is considered severe risk ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/bmj.39609.449676.25","ISBN":"0959-8146","ISSN":"0959-8138","PMID":"18573856","abstract":"OBJECTIVE: To develop and validate version two of the QRISK cardiovascular disease risk algorithm (QRISK2) to provide accurate estimates of cardiovascular risk in patients from different ethnic groups in England and Wales and to compare its performance with the modified version of Framingham score recommended by the National Institute for Health and Clinical Excellence (NICE). DESIGN: Prospective open cohort study with routinely collected data from general practice, 1 January 1993 to 31 March 2008. SETTING: 531 practices in England and Wales contributing to the national QRESEARCH database. PARTICIPANTS: 2.3 million patients aged 35-74 (over 16 million person years) with 140,000 cardiovascular events. Overall population (derivation and validation cohorts) comprised 2.22 million people who were white or whose ethnic group was not recorded, 22,013 south Asian, 11,595 black African, 10,402 black Caribbean, and 19,792 from Chinese or other Asian or other ethnic groups. MAIN OUTCOME MEASURES: First (incident) diagnosis of cardiovascular disease (coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records or linked Office for National Statistics death certificates. Risk factors included self assigned ethnicity, age, sex, smoking status, systolic blood pressure, ratio of total serum cholesterol:high density lipoprotein cholesterol, body mass index, family history of coronary heart disease in first degree relative under 60 years, Townsend deprivation score, treated hypertension, type 2 diabetes, renal disease, atrial fibrillation, and rheumatoid arthritis. RESULTS: The validation statistics indicated that QRISK2 had improved discrimination and calibration compared with the modified Framingham score. The QRISK2 algorithm explained 43% of the variation in women and 38% in men compared with 39% and 35%, respectively, by the modified Framingham score. Of the 112,156 patients classified as high risk (that is, >or=20% risk over 10 years) by the modified Framingham score, 46,094 (41.1%) would be reclassified at low risk with QRISK2. The 10 year observed risk among these reclassified patients was 16.6% (95% confidence interval 16.1% to 17.0%)-that is, below the 20% treatment threshold. Of the 78 024 patients classified at high risk on QRISK2, 11,962 (15.3%) would be reclassified at low risk by the modified Framingham score. The 10 year observed risk among these patients was 23.3% (22.2% to 24.4%)-that is, above the 20% threshold.…","author":[{"dropping-particle":"","family":"Hippisley-Cox","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Coupland","given":"Carol","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vinogradova","given":"Yana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robson","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Minhas","given":"Rubin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sheikh","given":"Aziz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brindle","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Bmj","id":"ITEM-1","issue":"7659","issued":{"date-parts":[["2008"]]},"page":"1475-1482","title":"Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2.","type":"article-journal","volume":"336"},"uris":[""]}],"mendeley":{"formattedCitation":"(10)","plainTextFormattedCitation":"(10)","previouslyFormattedCitation":"¹⁰"},"properties":{"noteIndex":0},"schema":""}(10). Its ability to predict MACE in SPKT recipients has never been assessed. We aimed to assess the long-term risk for MACE and identify associated risk factors, in the full UK cohort of SPKT recipients. We also aimed to relate post-transplant non-fatal MACE to subsequent allograft loss. In a Manchester-based subgroup, we aimed to relate a pre-transplant QRISK2? score to MACE.2 – Materials and Methods2.1Cohort, exposures and covariatesThe National Health Service Blood and Transplant (NHSBT) prospectively records recipient and donor data, from all UK centres, into the United Kingdom Transplant Registry (UKTR) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2018","9","4"]]},"author":[{"dropping-particle":"","family":"National Health Service Blood and Transplant","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"Annual Reports on Pancreas and Islet Transplantation","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(11)","plainTextFormattedCitation":"(11)","previouslyFormattedCitation":"¹¹"},"properties":{"noteIndex":0},"schema":""}(11). All type-1 diabetic SPKT recipients with type-1 diabetes aged ≥ 18years old and, transplanted between 2001 (the first year of robust national data) and 2015 were included.Type-1 diabetes was confirmed using C-peptide measurement in the majority of cases; however, some centres used clinical parameters such as age of onset. Surgical technique and immunosuppressive regimens were not standardised. To obtain more detailed patient and cardiovascular risk factor data, Further datafurther information for a subset of the total population were collated from the electronic patient records and case notes at a single UK transplant centre. Cardiovascular risk was calculated from pre-transplant variables using the QRISK?2-2017 calculator available at . Current or ex tobacco smokers were defined as having a history of tobacco smoke exposure. We defined unemployed as being able to work, but not working or unable to work due to disease. Amputation was defined as limb or digit amputation. For the local cohort, retinopathy was defined as pre-proliferative or proliferative changes, or maculopathy. An ankle-brachial pressure index ≤0.9 or the presence of flow limiting arterial stenosis on angiography, were used to identify patients with peripheral arterial disease (PAD). Patients were excluded if they had received any prior transplant.All cases were closed for analysis on the 27th April 2017. 2.2OutcomesThe primary outcome measure was the first recorded MACE following transplantation. MACE was defined as fatal cardiovascular disease (International Classification of Diseases [ICD] version 10 codes: I11 – hypertensive heart disease, I20-25 – ischaemic heart diseases, I42 + I43 – cardiomyopathies [excluding infectious, familial, alcohol, and drug related cardiomyopathies], I44 + I45 – conduction disorders, I46.1 – sudden cardiac death, I50 – heart failure, I51 – complications of heart disease [excluding myocarditis], and I61 – I69 [cerebrovascular diseases excluding sub-arachnoid haemorrhage]) or non-fatal myocardial infarction (MI), and/or non-fatal stroke. The General Register Office of the UK Government records the details of all UK deaths into the Register of Births, Deaths and Marriages from death certificates. The Office for National Statistics (ONS) is the recognised national statistical institute of the UK. It quality assures mortality data and provides data reports. To improve the completeness and accuracy of outcome data, cause of death data were obtained from the ONS and linked at patient level by NHSBT.Non-fatal MACE is recorded into the UKTR using forms that are completed annually by clinicians or transplant coordinators. The event time for non-fatal events was taken as the mid-point between annual follow up appointments. We analysed a secondary outcome of fatal cardiovascular disease.A tertiary outcome of allograft loss was included for analysis. The definition of pancreas allograft failure varies between centres, some use C-peptide measurement, whilst others use a return to exogenous insulin use. NHSBT records pancreas survival to the earlier of those definitions or death. Kidney allograft survival is determined to the earlier of return to dialysis or death.2.3Statistical methodsParameters are expressed as mean (standard deviation [SD]) or median (interquartile range [IQR]) as appropriate. Continuous variables were compared using either the student-t-test or Mann-Whitney U test. Categorical variables were compared using Pearson’s Chi-Square or Fisher’s exact tests. Survival analyses were visualised using Kaplan-Meier plots.Cox regression models were used to relate covariates to MACE and cardiovascular mortality. Covariates were tested for co-linearity using the Pearson correlation coefficient or Chi Square tests, and included in multivariable models if they were considered clinically important or if univariable p-values were ≤ 0.1.Immortal-time bias (ITB) can arise from inappropriate handling of the time interval between the start of follow up and an exposure (supplemental figure S1) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/aje/kwm324","ISBN":"1476-6256","ISSN":"00029262","PMID":"18056625","abstract":"Immortal time is a span of cohort follow-up during which, because of exposure definition, the outcome under study could not occur. Bias from immortal time was first identified in the 1970s in epidemiology in the context of cohort studies of the survival benefit of heart transplantation. It recently resurfaced in pharmaco-epidemiology, with several observational studies reporting that various medications can be extremely effective at reducing morbidity and mortality. These studies, while using different cohort designs, all involved some form of immortal time and the corresponding bias. In this paper, the author describes various cohort study designs leading to this bias, quantifies its magnitude under different survival distributions, and illustrates it by using data from a cohort of lung cancer patients. The author shows that for time-based, event-based, and exposure-based cohort definitions, the bias in the rate ratio resulting from misclassified or excluded immortal time increases proportionately to the duration of immortal time. The bias is more pronounced with a decreasing hazard function for the outcome event, as illustrated with the Weibull distribution compared with a constant hazard from the exponential distribution. In conclusion, observational studies of drug benefit in which computerized databases are used must be designed and analyzed properly to avoid immortal time bias.","author":[{"dropping-particle":"","family":"Suissa","given":"Samy","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Epidemiology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2008"]]},"page":"492-499","title":"Immortal time bias in pharmacoepidemiology","type":"article-journal","volume":"167"},"uris":[""]}],"mendeley":{"formattedCitation":"(12)","plainTextFormattedCitation":"(12)","previouslyFormattedCitation":"¹²"},"properties":{"noteIndex":0},"schema":""}(12). To overcome ITB when exploring the relationship with subsequent allograft loss, we used an extended Cox model with a time-dependent definition for non-fatal MACE ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/aje/kwm324","ISBN":"1476-6256","ISSN":"00029262","PMID":"18056625","abstract":"Immortal time is a span of cohort follow-up during which, because of exposure definition, the outcome under study could not occur. Bias from immortal time was first identified in the 1970s in epidemiology in the context of cohort studies of the survival benefit of heart transplantation. It recently resurfaced in pharmaco-epidemiology, with several observational studies reporting that various medications can be extremely effective at reducing morbidity and mortality. These studies, while using different cohort designs, all involved some form of immortal time and the corresponding bias. In this paper, the author describes various cohort study designs leading to this bias, quantifies its magnitude under different survival distributions, and illustrates it by using data from a cohort of lung cancer patients. The author shows that for time-based, event-based, and exposure-based cohort definitions, the bias in the rate ratio resulting from misclassified or excluded immortal time increases proportionately to the duration of immortal time. The bias is more pronounced with a decreasing hazard function for the outcome event, as illustrated with the Weibull distribution compared with a constant hazard from the exponential distribution. In conclusion, observational studies of drug benefit in which computerized databases are used must be designed and analyzed properly to avoid immortal time bias.","author":[{"dropping-particle":"","family":"Suissa","given":"Samy","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Epidemiology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2008"]]},"page":"492-499","title":"Immortal time bias in pharmacoepidemiology","type":"article-journal","volume":"167"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1186/s12874-017-0405-6","ISSN":"14712288","abstract":"? 2017 The Author(s). Background: Aspirin has been considered to be beneficial in preventing cardiovascular diseases and cancer. Several pharmaco-epidemiology cohort studies have shown protective effects of aspirin on diseases using various statistical methods, with the Cox regression model being the most commonly used approach. However, there are some inherent limitations to the conventional Cox regression approach such as guarantee-time bias, resulting in an overestimation of the drug effect. To overcome such limitations, alternative approaches, such as the time-dependent Cox model and landmark methods have been proposed. This study aimed to compare the performance of three methods: Cox regression, time-dependent Cox model and landmark method with different landmark times in order to address the problem of guarantee-time bias. Methods: Through statistical modeling and simulation studies, the performance of the above three methods were assessed in terms of type I error, bias, power, and mean squared error (MSE). In add ition, the three statistical approaches were applied to a real data example from the Korean National Health Insurance Database. Effect of cumulative rosiglitazone dose on the risk of hepatocellular carcinoma was used as an example for illustration. Results: In the simulated data, time-dependent Cox regression outperformed the landmark method in terms of bias and mean squared error but the type I error rates were similar. The results from real-data example showed the same patterns as the simulation findings. Conclusions: While both time-dependent Cox regression model and landmark analysis are useful in resolving the problem of guarantee-time bias, time-dependent Cox regression is the most appropriate method for analyzing cumulative dose effects in pharmaco-epidemiological studies.","author":[{"dropping-particle":"","family":"Cho","given":"In Sung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chae","given":"Ye Rin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Ji Hyeon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoo","given":"Hae Rin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jang","given":"Suk Yong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Gyu Ri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nam","given":"Chung Mo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMC Medical Research Methodology","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2017"]]},"page":"1-7","publisher":"BMC Medical Research Methodology","title":"Statistical methods for elimination of guarantee-time bias in cohort studies: A simulation study","type":"article-journal","volume":"17"},"uris":[""]}],"mendeley":{"formattedCitation":"(12,13)","plainTextFormattedCitation":"(12,13)","previouslyFormattedCitation":"^12,13"},"properties":{"noteIndex":0},"schema":""}(12,13). All analyses were performed using SPSS (version 22, New York, United States of America [USA]). A 2-tailed p-value of ≤ 0.05 was considered to be statistically significant.2.4Missing valuesAside from BMI (26.4%) and employment status (24.9%), patient-level data were missing in <5% of individuals. For the local cohort, patient level data were missing in ≤4%. All missing values were considered missing at random and complete case analyses were performed. 3 – ResultsWe identified 1699 patients with type-1 diabetes who received their first SPKT between 2001-2015 (mean [SD] age: 41.6 [8.3] years; 59% male; 6.3% with prior MI or stroke) with a median (IQR) follow-up of 5.0 (2.7-8.4) years. During the observation period, the use of alemtuzumab induction immunosuppression increased from 12.1% of recipients in 2001-5 to 68.7% in 2011-15 while the use of other agents decreased. Furthermore, the use of maintenance immunosuppression regimens containing prednisolone decreased (supplemental table 2).MACE occurred in 133 (7.8%) individuals in the total UKTR cohort (1.4% per annum [p.a.]). Cardiovascular disease accounted for 31.2% (74/237) of deaths (4.4% overall; 0.8% p.a.). Ischaemic heart disease accounted for the majority of MACE (56.4%) (supplemental table 3). The median (IQR) time to MACE was 913 (138-1606) days. The peak frequency of events occurred 133 days following transplantation. A second peak occurred 866 days post-transplant (supplemental figure S2). There was no significant difference in the types of events experienced at each time point (peak 1 vs. peak 2: p=0.391).Table 1 summarises shows the recipient and donor characteristics by MACE outcome. Within In the UKTR cohort, the UKTR cohort, those experiencing a MACE were older (43.1 [8.4] vs. 41.5 [8.3] years, p=0.034) and more likely to have had a history of MI (9.8% vs. 2.9%, p<0.001) or stroke (6.8% vs. 3.2%, p=0.043). They had an earlier year of transplant (2006 vs. 2010, p<0.001), longer pancreas cold ischaemia time (CIT), (12.6 vs. 11.6 hours, p=0.002) and more had received organs from hypertensive donors (13.5% vs. 7.9%, p=0.033). A smaller proportion received alemtuzumab induction immunosuppression while more received maintenance immunosuppressive regimens containing prednisolone. Furthermore, less had received organs donated after cardiac death (DCD) and expanded criteria kidneys (ECD).Recipients of DCD and ECD organs had a more recent year of transplant compared to recipients of organs from donors with brainstem death (DBD) and standard criteria donors (SCD) (DCD vs. DBD - 2012 [2010-14] vs. 2009 [2006-12], p<0.001; ECD vs. SCD – 2015[2015-15] vs. 2009 [2007-2012], p<0.001)..Within the Manchester subgroup (n=306), 23 (7.5%) experienced a MACE of which 8 (34.7%) were fatal. The median (IQR) time to a MACE was 905 (116-2000) days. Patients were followed for a median of 5.7 years. Those experiencing a MACE were more likely to be older (47.5 [7.8] vs. 41.0 [9.0] years, p=0.008), on antihypertensive and antiplatelet medications, , haved an earlier year of transplant (2005 vs. 2010, p<0.001), more had a history of MI (34.8% vs. 10.6%, p=0.001), and a higher QRISK2? score; and have received prednisolone based maintenance immunosuppression. They were less likely to have received alemtuzumab induction immunotherapy (35.2 vs. 24.4, p=0.001;( table 1). The QRISK2? score was ≥ 20 in 205 (67.0%) of the Manchester cohort, of which 85 (41.5%) were receiving antiplatelet medications, 110 (53.7%) lipid lowering treatment, and 171 (83.7%) antihypertensives. In patients with a systolic blood pressure (SBP) ≥ 130mmHg, 74.0% (94/127) were receiving antihypertensive treatment.In the full UKTR cohort, the univariable predictors of MACE were recipient age (hazard ratio [HR] [95% CI]: 1.03 [1.01-1.05] per year, p=0.004), prior MI (3.5 [2.0-6.1], p<0.001), prior stroke (2.4 [1.2-4.7], p=0.012), prior amputation (2.04 [1.1-3.7], p=0.019), donor history of hypertension (2.0 [1.2-3.2], p=0.008), and pancreas CIT; (1.06 [1.002-1.1] per hour, p=0.042) and prednisolone based maintenance immunosuppression. Advancing year of transplant was associated with a 10% lower risk for MACE per year (0.9 [0.8-0.9], p<0.001), table 2. Tobacco smoking (1.3 [0.8-2.0], p=0.248), sex (female vs. male – 1.0 [0.7-1.4], p=0.994), and ethnicity (non-white vs. white 0.9 [0.4-1.4], p=0.669) were not significant. DCD and ECD were not included in the Cox regression models as they were highly correlated with the year of transplant (Pearson correlation coefficient = 0.992 and 0.991 respectively, p<0.001). In the multivariable model, waiting time became a significant hazard (2% increase in risk per month) (1.02 [1.001-1.03], p=0.040, per month), while pancreas CIT and prednisolone lost significance, table 3. The predictors of fatal CVD were, recipient age (1.06 [1.03-1.09], p<0.001), prior history of MI (4.9 [2.5-9.6], p<0.001), stroke (3.2 [1.4-7.5], p=0.006) and amputation (3.1 [1.6-6.3], p=0.001). In the multivariable model, unemployment (1.8 [1.03-3.2], p=0.041) and a donor history of hypertension (2.2 [1.2-4.2], p=0.012) remained significant hazards, while blindness (1.9 [1.02-3.6], p=0.042) became a significant factor. Prednisolone was not related to fatal CVD (table 4).Pancreas allograft loss was recorded in 507 (29.8%) patients, of which 155 were due to death with a functioning graft (DWFG). Kidney allograft loss was recorded in 371 (21.8%) patients (149 DWFG). A non-fatal MACE conferred an additional 60% risk for subsequent all-cause kidney allograft failure (1.6 [1.06-2.6], p=0.027) and 70% for all-cause pancreas allograft failure (1.7 [1.09-2.6], p=0.018).Table 2 shows the univariable predictors for MACE in the local Manchester subgroup (n=306). Again, rRecipient age (1.07 [1.02-1.1], p=0.005), prior MI,I (4.0 [1.7-9.4], p=0.002), and year of transplant were significant factors. Aantihypertensive therapy (8.3 [1.1-62.5], p=0.041), prior history of peritoneal dialysis was associated with a five-fold increase in MACE risk, while receiving antiplatelet therapy was associated with four times the risk. Alemtuzumab reduced MACE risk by 80%, while prednisolone based maintenance immunosuppression was associated with three times the risk(5.2 [1.2-22.7], p=0.029). , Each one percent increase in the pre-transplant QRISK2? score was associated with a four percent increase in post-transplant MACE risk(1.04 [1.02-1.06], p<0.001) and year of transplant (0.8 [0.7-0.9], p=0.004) were all significant factors. A QRISK2? score above 20% conferred an eleven-fold increased risk (table 2, supplemental figure S3) (11.4 [1.5-84.6], p=0.017). In age-adjusted models a history of MI (3.5 [1.5-8.3], p=0.005), peritoneal dialysis, antiplatelet therapy, alemtuzumab, prednisolone, (5.8 [1.3-25.5], p=0.020) and year of transplant (0.8 [0.7-0.9], p=0.002) remained significant. The hazard ratio for total cholesterol/HDL ratio (1.3 [0.998-1.7], p=0.052) approached significance (supplemental table 42). Alemtuzumab and prednisolone became insignificant factors in models adjusting for the year of transplant (0.6 [0.1-3.2], p=0.534; 1.3 [0.3-6.0], p=774 respectively).The QRISK2? score demonstrated acceptable discrimination for MACE with an area under the receiver operating characteristics (ROC) curve of 0.715 (95%CI: 0.616-0.815), p=0.001.4 – Discussion4.1Prior studies of event rates in relation to the National cohortVery few studies have assessed the long-term risks for cardiovascular events in SPKT recipients ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.transproceed.2016.01.082","ISSN":"18732623","abstract":"Background Kidney transplantation (KTx) markedly reduces mortality in patients with end-stage kidney disease (ESKD) caused by type 1 diabetes mellitus (T1DM). The outstanding issue is whether transplantation should be limited only to KTx, with further insulinotherapy, or combined with pancreas transplantation in patients with ESKD/T1DM. The goal of this study was to compare the results of simultaneous pancreas–kidney transplantation (SPKTx) and deceased donor KTx and to identify factors affecting patient and kidney graft survival in patients with ESKD/T1DM. Methods Eighty-seven deceased donor KTx and 66 SPKTx operated on in the Silesia region of Poland between 1998 and 2013 were included in the retrospective analysis. Results During the mean 6.7 ± 3.6 years of follow-up, fewer cardiovascular episodes were observed in SPKTx recipients than in KTx recipients (1.5% vs 12.6%; P?< .05). Five-year patient survival (80.7% in SPKTx vs 77.5% in KTx) and kidney graft survival (66.1% in SPKTx vs 70.4% in KTx) did not differ between study groups. There were no differences in patient survival (log-rank test, P?= .99) or kidney graft survival (P?= .99) based on Kaplan-Meier curves. Multivariable Cox proportional hazard analysis failed to identify factors explaining patient and kidney graft survival. Five-year pancreas graft survival was 58.9%. SPKTx recipients had significantly higher estimated glomerular filtration rates during the 7-year posttransplant period and less frequently developed proteinuria (6.1% vs 23%; P?< .01). Conclusions Pancreas transplantation reduced cardiovascular risk and prevented the development of proteinuria but did not improve patient and kidney graft survival in recipients with T1DM in the 7-year follow-up period.","author":[{"dropping-particle":"","family":"Ziaja","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolonko","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kamińska","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chudek","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Owczarek","given":"A. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kujawa-Szewieczek","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuriata-Kordek","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Krzy?owska","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Badura","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Czerwiński","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"J?rdusik","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Król","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klinger","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wi?cek","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cierpka","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplantation Proceedings","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2016"]]},"page":"1681-1686","title":"Long-Term Outcomes of Kidney and Simultaneous Pancreas–Kidney Transplantation in Recipients With Type 1 Diabetes Mellitus: Silesian Experience","type":"article-journal","volume":"48"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.transproceed.2010.07.046","ISSN":"00411345","PMID":"20970588","abstract":"Objective To retrospectively evaluate the incidence of cardiovascular events after functioning simultaneous pancreas-kidney transplantation (SPKT). Patients and Methods Cardiovascular events after 89 SPKT procedures performed at our institution from March 1995 to March 2009 were investigated. Study criteria included normal functioning of both grafts. Patients included 36 women and 53 men, with mean (range) age of 37.7 (2566) years. Duration of diabetes mellitus was 23.6 (1048) years, and of dialysis therapy was 19.8 (070) months. The exocrine pancreatic secretions were drained to the bladder in 41 patients, and enterically in 45 patients. Mean (SD) follow-up was 58.62 (34.74) months. Results During follow-up after SPKT, 9 patients (10.1%) experienced cardiovascular events including cerebrovascular accident in 4 patients, myocardial infarction (MI) in 3, and episodes of angina pectoris without evidence of coronary artery disease in 2 patients. Nevertheless, these two patients had sustained an MI that required coronary angioplasty before SPKT. Moreover, coronary angioplasty was required in 2 patients before they were enrolled in the transplantation program because of silent coronary artery disease. Four of 9 cardiovascular events occurred in the perioperative period. No deaths occurred due to cardiovascular events. Patient survival rate was 100%, with both grafts functioning in 87 (97.8%). Conclusion Cardiovascular events occur relatively frequently in patients undergoing SPKT. In the present study, most events occurred in the perioperative period, but did not result in death. ? 2010 Elsevier Inc.","author":[{"dropping-particle":"","family":"Medina-Polo","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Domínguez-Esteban","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morales","given":"J. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pamplona","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andres","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jimenez","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manrique","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moreno","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Díaz","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplantation Proceedings","id":"ITEM-2","issue":"8","issued":{"date-parts":[["2010"]]},"page":"2981-2983","publisher":"Elsevier Inc.","title":"Cardiovascular events after simultaneous pancreas-kidney transplantation","type":"article-journal","volume":"42"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.transproceed.2013.02.087","ISBN":"0041-1345","ISSN":"00411345","PMID":"23622626","abstract":"Cardiovascular and cerebrovascular disease (CCVD) are major causes of morbidity and mortality among patients with diabetes. Strict control of treatable risk factors that contribute to atherosclerosis is important to reduce the risk of stroke, myocardial infarction, and peripheral arterial disease. Simultaneous pancreas-kidney transplantation (SPKT) may significantly improve these risk factors in patients with type 1 diabetes. We studied 103 SPKT from our center with both organs functioning for metabolic and hypertensive control; body mass index (BMI); immunosuppression; and CCVD events. The 53 females/50 males showed a mean age of 35 ± 6 years, diabetes for 24 ± 6 years, and on dialysis for 31 ± 23 months. The follow-up ranged from 6-142 months. Mean value of last creatinine clearance was 76 ± 24 mL/min, all 103 SPKT were insulin-independent with mean glycemia = 81 ± 10 mg/dL and hemoglobin A1c (HbA1c) = 5.3% ± 0.4%. All of them were under tacrolimus treatment; 9.7% also with sirolimus but 67% steroid-free. According to the National Cholesterol Education Program Adult Treatment Panel 3 criteria, 4 patients showed a fasting glucose > 100 mg/dL; only one, HbA1c > 5.6%. Hypertension was recorded in 38.5%; low high-density lipoprotein cholesterol in 19.4%; hypertriglyceridemia in 7.8%; BMI > 30% in only 2 patients; 21.4% were prescribed statins. We registered cardiovascular events in 7 patients (6.8%). Patients with steroid treatment showed higher triglycerides (122 ± 53 vs 90 ± 36 mg/dL; P =.001) and more often tended to be hypertensive (41.2% vs 37.7%, P =.073) compared with those free of these drugs. Hypertension was associated with an higher BMI (24.1 ± 2.8 vs 22.3 ± 2.9 kg/m2, P =.002). BMI > 25% was associated with higher total cholesterol (195 ± 47 vs 169 ± 28 mg/dL, P =.015) and low-density lipoprotein cholesterol (116 ± 40 vs 96 ± 27 mg/dL, P =.003). Among our SPKT the prevalences of CCVD and metabolic syndrome were low. Hypertension was the most frequent single factor. Obesity was rare. In patients on steroids, hypertriglyceridemia was more prevalent and hypertension tended to be more frequent. Hypertensive patients showed a higher BMI, which correlated with a worse lipid profile. Steroid withdrawal, whenever possible, may be important to achieve metabolic goals and minimize cardiovascular risk. ? 2013 Elsevier Inc.","author":[{"dropping-particle":"","family":"Martins","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fonseca","given":"I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dias","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Malheiro","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rocha","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Azevedo","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silva","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Almeida","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henriques","given":"A. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davide","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cabrita","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplantation Proceedings","id":"ITEM-3","issue":"3","issued":{"date-parts":[["2013"]]},"page":"1063-1065","publisher":"Elsevier Inc.","title":"Cardiovascular risk factors and events in pancreas-kidney transplants","type":"article-journal","volume":"45"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1016/j.amjcard.2017.05.038","ISSN":"00029149","PMID":"28683901","abstract":"Large database studies detailing the risk of perioperative cardiovascular complications after pancreas transplant has been limited, perhaps because these outcomes are not captured by transplant registries. Greater data on the incidence and risks of such outcomes could provide additional insight for referring physicians and inform potential recipients of their risk. We performed a serial, cross-sectional analysis of the National Inpatient Sample, the largest publicly available inpatient database in the United States, to assess for the risk of cardiovascular complications after pancreas transplants in the United States from 2003 to 2012 (n = 13,399). Using multivariable logistic regression models, the risk of cardiovascular outcomes after simultaneous pancreas-kidney transplants (SPK) was compared with solitary pancreas transplants (pancreas after kidney and pancreas transplant alone [PAK + PTA]). The unadjusted prevalence of in-hospital cardiovascular complications was higher in SPK than PAK + PTA (5.5% vs 3.7%, p <0.001). After multivariable adjustment, SPK remained associated with significantly higher odds of any cardiovascular complication (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.21 to 1.80, p = 0.01), and particularly stroke (OR 13.41, 95% CI 4.78 to 37.63, p <0.001), compared with PAK + PTA. However, there was no difference in perioperative mortality (OR 0.78, 95% CI 0.54 to 1.12, p = 0.18). In conclusion, these findings highlight the association between uremia and stroke in pancreas transplant patients, as well as the need for improved preoperative cardiac risk assessment and perioperative management, especially in those who underwent SPK.","author":[{"dropping-particle":"","family":"Kim","given":"Jim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schulman-Marcus","given":"Joshua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watkins","given":"Anthony C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feldman","given":"Dmitriy N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swaminathan","given":"Rajesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Jun B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Muthukumar","given":"Thangamani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Serur","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Luke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartono","given":"Choli","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American Journal of Cardiology","id":"ITEM-4","issue":"4","issued":{"date-parts":[["2017"]]},"page":"682-687","publisher":"Elsevier Inc.","title":"In-Hospital Cardiovascular Complications After Pancreas Transplantation in the United States from 2003 to 2012","type":"article-journal","volume":"120"},"uris":[""]}],"mendeley":{"formattedCitation":"(6,14–16)","plainTextFormattedCitation":"(6,14–16)","previouslyFormattedCitation":"^6,14–16"},"properties":{"noteIndex":0},"schema":""}(6,14–16). We report the largest study of long-term CVD risk in this cohort, and demonstrate a large residual risk for CVD events following SPKT. This is particularly relevant because it occurs despite the young age and careful selection of recipients. It also occurs in the context of potential CVD benefits from SPKT ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.transproceed.2006.01.029","ISBN":"0041-1345 (Print)\\r0041-1345 (Linking)","ISSN":"00411345","PMID":"16647461","abstract":"The main cause of death for diabetic patients and patients on dialysis is coronary artery disease (CAD). The most common cause of graft loss following simultaneous pancreas and kidney transplantation (SPK) is death with a functioning graft due to CAD. Therefore, careful pretransplantation evaluation of CAD is mandatory. In our series, every patient undergoes a noninvasive cardiac function test like dobutamine stress echocardiography (DSE) or myocardial thallium scintigraphy using adenosine to induce medical stress. Thirty patients were evaluated for SPK: 15 patients with myocardial scintigraphy and 8 with DSE. Seven investigations showed pathological findings and we performed coronary angiograms, none of which showed coronary artery stenosis. Seven primary coronary angiograms were performed: four due to a history of CAD and three as a primary diagnostic. Following SPK one patient died at 21 days after transplantation due to myocardial infarction. He had a history of CAD with angioplasty and stent implantation. Noninvasive cardiac function tests like DSE or myocardial scintigraphy are reliable methods to evaluate CAD in patients with diabetic nephropathy awaiting SPK. In case of a suspicious finding or a history of CAD, a coronary angiogram should be performed to assess the need for revascularization. Following this algorithm we may further reduce the mortality of SPK. ? 2006 Elsevier Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Woeste","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wullstein","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zapletal","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hauser","given":"I. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gossmann","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Geiger","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bechstein","given":"W. O.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplantation Proceedings","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2006"]]},"page":"747-750","title":"Evaluation of Type 1 Diabetics for Simultaneous Pancreas-Kidney Transplantation With Regard to Cardiovascular Risk","type":"article-journal","volume":"38"},"uris":[""]}],"mendeley":{"formattedCitation":"(17)","plainTextFormattedCitation":"(17)","previouslyFormattedCitation":"¹⁷"},"properties":{"noteIndex":0},"schema":""}(17). Prior studies in patients with type-1 diabetes and renal failure have shown that SPKT improves several CVD risk factors including glucose, blood pressure and lipid levels when compared to kidney transplant alone ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.transproceed.2005.09.156","ISBN":"0041-1345 (Print)\\r0041-1345 (Linking)","ISSN":"00411345","PMID":"16386603","abstract":"Introduction. The prognosis of patients with type 1 diabetes mellitus and chronic renal failure improves after simultaneous pancreas-kidney (SPK) transplantation. Good control of glycemia and other cardiovascular risk factors may positively influence prognosis. The objective of this study was to evaluate changes in cardiovascular risk factors after SKP. Patients and methods. We studied 13 patients (aged 36 ± 8 years, 7 women) before and 12 months after SPK transplantation. All were treated with thymoglobulin, prednisone, tacrolimus, and mycophenolate mofetil. We compared the following pre- and post-SPK parameters: glycemia, HbA1c, total cholesterol, HDL, LDL, triglycerides, systolic (sBP), diastolic blood pressure (dBP), and body mass index (BMI). Results. Twelve months after SPK transplantation, glycemia, HbA1c and triglycerides significantly decreased (P < .001; P < .001, and P < .002, respectively), as did sBP (P < .002) and dBP (P < .001). No changes were found for BMI or total, HDL and LDL cholesterol values. The number of patients requiring antihypertensive therapy fell (13 versus 3; P < .002), as did the number of drugs (2.3 ± 0.8 versus 0.4 ± 0.7; P < .001). The number of patients requiring statins also fell (11 versus 3; P < .002). At 12 months, all patients had normal renal function (creatinine clearance 85 ± 10 mL/min) and required no insulin; four had microalbuminuria. Conclusion. These interim results show an improved cardiovascular risk profile 12 months after SPK transplantation, which lays the basis for a more favorable long-term prognosis. ? 2005 by Elsevier Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Pérez Tamajón","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marrero Miranda","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Caballero Figueroa","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hernández Marrero","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laynez Cerde?a","given":"I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bravo Gutiérrez","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meneses Fernández","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alarcó Hernández","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morcillo Herrera","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"González-Posada Delgado","given":"J. M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplantation Proceedings","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2005"]]},"page":"3979-3980","title":"Improved cardiovascular risk profile of patients with type 1 diabetes mellitus and renal failure after simultaneous pancreas-kidney transplantation","type":"article-journal","volume":"37"},"uris":[""]}],"mendeley":{"formattedCitation":"(18)","plainTextFormattedCitation":"(18)","previouslyFormattedCitation":"¹⁸"},"properties":{"noteIndex":0},"schema":""}(18). In our study, MACE occurred in 7.8% over 5 years. This compares favourably to the rate in diabetic kidney transplant recipients with diabetes in Japan (n=1614; 19.6% over 6 years), and a single USA centre (n=212; 26.9% over 3.4 years) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s10157-017-1500-z","ISSN":"14377799","abstract":"? 2017 Japanese Society of Nephrology Background: The number of kidney transplant recipients (KTRs) from diabetic nephropathy (DN) and with cardiovascular disease (CVD) history has increased worldwide. Nevertheless, epidemiologic evidence of CVD in KTRs remains limited. Methods: We investigated post-transplant CVD in 1614 adult KTRs between 1990 and 2014. CVD was defined according to the international classification of diseases (ICD-10). All-cause mortality was also investigated. Final follow-up was performed in March 2016. The KTRs were categorized into four groups according to DN and CVD at surgery. Results: During the follow-up period, 309 KTRs experienced CVDs and 124 KTRs died. The 15-year cumulative CVDs rate was 87% in KTRs with both DN and CVD history, and the rate in KTRs without those was 22.3%. DN and CVD were associated with increased risk of post-transplant CVD [hazard ratio (HR), 3.44; 95% confidence interval (CI), 2.03–5.82; P < 0.001], and the impact marked increased after 7.5 years follow-up period (HR, 16.56; 95% CI, 6.56–41.8; P < 0.001). DN and CVD in KTRs were associated with mortality (HR, 3.32; 95% CI, 1.34–8.22; P = 0.009), and post-transplant CVD was the leading cause (35.5%) of overall death. However, DN and CVD were not associated with increased graft failure rate. Conclusions: The risk of post-transplant CVDs incidence in KTRs with DN and CVD history is high, and it increases during the late transplant period. Appropriate routine cardiovascular screening and evaluation are needed to reduce late-onset CVD incidence.","author":[{"dropping-particle":"","family":"Okumi","given":"Masayoshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kakuta","given":"Yoichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Unagami","given":"Kohei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maenosono","given":"Ryoichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyake","given":"Katsunori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iizuka","given":"Junpei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takagi","given":"Toshio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ishida","given":"Hideki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tanabe","given":"Kazunari","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tanabe","given":"Kazunari","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Unagami","given":"Kohei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Toma","given":"Hiroshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Omoto","given":"Kazuya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shirakawa","given":"Hiroki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Furusawa","given":"Miyuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fujiwara","given":"Makiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kusubayashi","given":"Kayo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shimada","given":"Katsunori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okumi","given":"Masayoshi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical and Experimental Nephrology","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-8","title":"Cardiovascular disease in kidney transplant recipients: Japan Academic Consortium of Kidney Transplantation (JACK) cohort study","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1111/j.1600-6143.2007.02101.x","ISBN":"1600-6143","ISSN":"16006135","PMID":"18294155","abstract":"An increasing proportion of kidney recipients have diabetes mellitus (DM). Herein, we assessed the impact of DM on morbidity and mortality. The study included 933 recipients of first transplants. DM was present in 212 (23%). Compared to non-diabetics (NoDM), DM were older, heavier and had more pretransplant cardiovascular (CV) disease (16% vs. 48%, p < 0.0001). DM had reduced survival (5 years, 93% vs. 70%, p < 0.0001) and higher incidence of CV events (9% vs. 37%, p < 0.0001). CV disease was the most common cause of death in DM (61%) but not in NoDM (26%). Mortality from infections was also higher in DM (p = 0.001). In NoDM, survival related to recipient age (hazard ratio (HR) = 1.07, p < 0.0001) and dialysis pretransplant HR = 2.21, p = 0.01, while in DM, survival related to dialysis (HR = 2.89, p = 0.01) and pretransplant CV disease (HR = 2.79, p = 0.007). In NoDM, the incidence of posttransplant CV events was related to traditional CV risk factors, while in DM only the pretransplant CV history related to this outcome. In conclusion, survival differs between NoDM and DM recipients quantitatively, by cause of death and by risk factors. In NoDM, survival is excellent, and the main threat to survival relates to immunosuppression. In DM, survival is inferior primarily due to CV disease generally present prior to transplantation.","author":[{"dropping-particle":"","family":"Cosio","given":"F. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hickson","given":"L. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Griffin","given":"M. D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stegall","given":"M. D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kudva","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Transplantation","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2008"]]},"page":"593-599","title":"Patient survival and cardiovascular risk after kidney transplantation: The challenge of diabetes","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"(19,20)","plainTextFormattedCitation":"(19,20)","previouslyFormattedCitation":"^19,20"},"properties":{"noteIndex":0},"schema":""}(19,20). However, direct comparison with these studies is limited as they also included people with type-2 diabetesic patients. Also the selection criteria for kidney alone transplantation are different to those for SPKT. The UKTR rate is higher than other SPKT cohorts. Kim and colleagues reported events in 5.5% in the USA, but their study was limited to perioperative cardiovascular complications ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.amjcard.2017.05.038","ISSN":"00029149","PMID":"28683901","abstract":"Large database studies detailing the risk of perioperative cardiovascular complications after pancreas transplant has been limited, perhaps because these outcomes are not captured by transplant registries. Greater data on the incidence and risks of such outcomes could provide additional insight for referring physicians and inform potential recipients of their risk. We performed a serial, cross-sectional analysis of the National Inpatient Sample, the largest publicly available inpatient database in the United States, to assess for the risk of cardiovascular complications after pancreas transplants in the United States from 2003 to 2012 (n = 13,399). Using multivariable logistic regression models, the risk of cardiovascular outcomes after simultaneous pancreas-kidney transplants (SPK) was compared with solitary pancreas transplants (pancreas after kidney and pancreas transplant alone [PAK + PTA]). The unadjusted prevalence of in-hospital cardiovascular complications was higher in SPK than PAK + PTA (5.5% vs 3.7%, p <0.001). After multivariable adjustment, SPK remained associated with significantly higher odds of any cardiovascular complication (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.21 to 1.80, p = 0.01), and particularly stroke (OR 13.41, 95% CI 4.78 to 37.63, p <0.001), compared with PAK + PTA. However, there was no difference in perioperative mortality (OR 0.78, 95% CI 0.54 to 1.12, p = 0.18). In conclusion, these findings highlight the association between uremia and stroke in pancreas transplant patients, as well as the need for improved preoperative cardiac risk assessment and perioperative management, especially in those who underwent SPK.","author":[{"dropping-particle":"","family":"Kim","given":"Jim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schulman-Marcus","given":"Joshua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watkins","given":"Anthony C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feldman","given":"Dmitriy N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swaminathan","given":"Rajesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Jun B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Muthukumar","given":"Thangamani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Serur","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Luke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartono","given":"Choli","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American Journal of Cardiology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017"]]},"page":"682-687","publisher":"Elsevier Inc.","title":"In-Hospital Cardiovascular Complications After Pancreas Transplantation in the United States from 2003 to 2012","type":"article-journal","volume":"120"},"uris":[""]}],"mendeley":{"formattedCitation":"(6)","plainTextFormattedCitation":"(6)","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}(6). The CVD event rate in our study also contrasts with findings reported on SPKT recipients in Poland (n=66; 0.2% p.a. over 6.7 years) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.transproceed.2016.01.082","ISSN":"18732623","abstract":"Background Kidney transplantation (KTx) markedly reduces mortality in patients with end-stage kidney disease (ESKD) caused by type 1 diabetes mellitus (T1DM). The outstanding issue is whether transplantation should be limited only to KTx, with further insulinotherapy, or combined with pancreas transplantation in patients with ESKD/T1DM. The goal of this study was to compare the results of simultaneous pancreas–kidney transplantation (SPKTx) and deceased donor KTx and to identify factors affecting patient and kidney graft survival in patients with ESKD/T1DM. Methods Eighty-seven deceased donor KTx and 66 SPKTx operated on in the Silesia region of Poland between 1998 and 2013 were included in the retrospective analysis. Results During the mean 6.7 ± 3.6 years of follow-up, fewer cardiovascular episodes were observed in SPKTx recipients than in KTx recipients (1.5% vs 12.6%; P?< .05). Five-year patient survival (80.7% in SPKTx vs 77.5% in KTx) and kidney graft survival (66.1% in SPKTx vs 70.4% in KTx) did not differ between study groups. There were no differences in patient survival (log-rank test, P?= .99) or kidney graft survival (P?= .99) based on Kaplan-Meier curves. Multivariable Cox proportional hazard analysis failed to identify factors explaining patient and kidney graft survival. Five-year pancreas graft survival was 58.9%. SPKTx recipients had significantly higher estimated glomerular filtration rates during the 7-year posttransplant period and less frequently developed proteinuria (6.1% vs 23%; P?< .01). Conclusions Pancreas transplantation reduced cardiovascular risk and prevented the development of proteinuria but did not improve patient and kidney graft survival in recipients with T1DM in the 7-year follow-up period.","author":[{"dropping-particle":"","family":"Ziaja","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolonko","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kamińska","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chudek","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Owczarek","given":"A. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kujawa-Szewieczek","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuriata-Kordek","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Krzy?owska","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Badura","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Czerwiński","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"J?rdusik","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Król","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klinger","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wi?cek","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cierpka","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplantation Proceedings","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2016"]]},"page":"1681-1686","title":"Long-Term Outcomes of Kidney and Simultaneous Pancreas–Kidney Transplantation in Recipients With Type 1 Diabetes Mellitus: Silesian Experience","type":"article-journal","volume":"48"},"uris":[""]}],"mendeley":{"formattedCitation":"(14)","plainTextFormattedCitation":"(14)","previouslyFormattedCitation":"¹⁴"},"properties":{"noteIndex":0},"schema":""}(14). These findings may have been influenced by sample size and being a single-centre study, with specific patient selection criteria/management.The proportion experiencing fatal CVD in our study also compares favourably to that reported in living donor kidney transplant recipients with type-1 diabetes in the UK (6.2% over 3.9 years) and in Norway (34.3% over 7.9 years) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"09340874","PMID":"28319322","abstract":"Transplant options for patients with type 1 diabetes and end-stage renal disease (ESRD) include deceased donor kidney, live donor kidney (LDK) and simultaneous pancreas-kidney (SPK) transplantation. The aim of this study was to compare outcomes between LDK and SPK for patients with type 1 diabetes and ESRD in the UK. Data on all SPK (n = 1739) and LDK (n = 385) transplants performed between January 2001 and December 2014 were obtained from the UK Transplant Registry. Unadjusted patient and kidney graft survival were calculated using the Kaplan-Meier method. Multivariate analysis of kidney graft and patient survival was performed using Cox proportional hazards regression. There was no significant difference in patient (P = 0.435) or kidney graft survival (P = 0.204) on univariate analysis. On multivariate analysis there was no association between LDK/SPK and patient survival [HR 0.71 (0.47-1.06), P = 0.095]. However, LDK was associated with an overall lower risk for kidney graft failure [HR 0.60 (0.38-0.94), P = 0.025]. SPK recipients with a functioning pancreas graft had significantly better kidney graft and patient survival than LDK recipients or those with a failed pancreas graft. SPK transplantation does not confer an overall survival advantage compared to LDK. However, those SPK recipients with a functioning pancreas have significantly better outcomes.","author":[{"dropping-particle":"","family":"Barlow","given":"Adam D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saeb-Parsy","given":"Kourosh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watson","given":"Christopher J. E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplant International","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2017"]]},"page":"884-892","title":"An analysis of the survival outcomes of simultaneous pancreas and kidney transplantation compared to live donor kidney transplantation in patients with type 1 diabetes: a UK Transplant Registry study","type":"article-journal","volume":"30"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1007/s00125-015-3853-8","ISSN":"1432-0428 (Electronic)","PMID":"26713324","abstract":"AIMS/HYPOTHESIS: Mortality due to cardiovascular disease (CVD), particularly coronary artery disease (CAD), is high in type 1 diabetic patients with end-stage renal disease (ESRD). We aimed to determine whether normoglycaemia, as achieved by successful simultaneous pancreas and kidney (SPK) transplantation, could improve long-term outcomes compared with living donor kidney-alone (LDK) transplantation. METHODS: We studied 486 type 1 diabetic patients with ESRD who underwent a first SPK (n = 256) or LDK (n = 230) transplant between 1983 and 2012 and were followed to the end of 2014. Data were retrieved from the Norwegian Renal Registry and hospital records. Kaplan-Meier plots and multivariate Cox regression, with correction for recipient, donor and transplant factors, were used to examine potential associations between transplant type and all-cause and CVD- and CAD-related mortality. RESULTS: Median follow-up time was 7.9 years (interquartile range 4.3, 12.9). The adjusted HR for CVD-related deaths in SPK recipients compared with LDK recipients was 0.63 (95% CI 0.40, 0.99; p = 0.047), while the HRs for all-cause and CAD-related mortality were 0.81 (95% CI 0.57, 1.16; p = 0.25) and 0.63 (95% CI 0.36, 1.12; p = 0.12), respectively. Compared with the LDK group, SPK recipients were younger and received grafts from younger donors. Cardiovascular mortality was higher in patients transplanted between 1983 and 1999 compared with those who received their grafts in subsequent years. CONCLUSIONS/INTERPRETATION: In patients with type 1 diabetes and ESRD, SPK transplantation was associated with reduced long-term cardiovascular mortality compared with LDK transplantation.","author":[{"dropping-particle":"","family":"Lindahl","given":"Jorn P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartmann","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aakhus","given":"Svend","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Endresen","given":"Knut","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Midtvedt","given":"Karsten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holdaas","given":"Hallvard","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leivestad","given":"Torbjorn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horneland","given":"Rune","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oyen","given":"Ole","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jenssen","given":"Trond","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetologia","id":"ITEM-2","issue":"4","issued":{"date-parts":[["2016"]]},"page":"844-852","title":"Long-term cardiovascular outcomes in type 1 diabetic patients after simultaneous pancreas and kidney transplantation compared with living donor kidney transplantation.","type":"article-journal","volume":"59"},"uris":[""]}],"mendeley":{"formattedCitation":"(7,21)","plainTextFormattedCitation":"(7,21)","previouslyFormattedCitation":"^7,21"},"properties":{"noteIndex":0},"schema":""}(7,21). While differences between recipient/donor characteristics and selection criteria for SPKT and LDKT may account for this, the benefits of a functioning pancreas allograft might also contribute to these findings.A consistent finding in our analyses was that CVD outcomes improved over time. This observation is consistent with trends in the general population and a Norwegian cohort of SPKT recipients ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00125-015-3853-8","ISSN":"1432-0428 (Electronic)","PMID":"26713324","abstract":"AIMS/HYPOTHESIS: Mortality due to cardiovascular disease (CVD), particularly coronary artery disease (CAD), is high in type 1 diabetic patients with end-stage renal disease (ESRD). We aimed to determine whether normoglycaemia, as achieved by successful simultaneous pancreas and kidney (SPK) transplantation, could improve long-term outcomes compared with living donor kidney-alone (LDK) transplantation. METHODS: We studied 486 type 1 diabetic patients with ESRD who underwent a first SPK (n = 256) or LDK (n = 230) transplant between 1983 and 2012 and were followed to the end of 2014. Data were retrieved from the Norwegian Renal Registry and hospital records. Kaplan-Meier plots and multivariate Cox regression, with correction for recipient, donor and transplant factors, were used to examine potential associations between transplant type and all-cause and CVD- and CAD-related mortality. RESULTS: Median follow-up time was 7.9 years (interquartile range 4.3, 12.9). The adjusted HR for CVD-related deaths in SPK recipients compared with LDK recipients was 0.63 (95% CI 0.40, 0.99; p = 0.047), while the HRs for all-cause and CAD-related mortality were 0.81 (95% CI 0.57, 1.16; p = 0.25) and 0.63 (95% CI 0.36, 1.12; p = 0.12), respectively. Compared with the LDK group, SPK recipients were younger and received grafts from younger donors. Cardiovascular mortality was higher in patients transplanted between 1983 and 1999 compared with those who received their grafts in subsequent years. CONCLUSIONS/INTERPRETATION: In patients with type 1 diabetes and ESRD, SPK transplantation was associated with reduced long-term cardiovascular mortality compared with LDK transplantation.","author":[{"dropping-particle":"","family":"Lindahl","given":"Jorn P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartmann","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aakhus","given":"Svend","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Endresen","given":"Knut","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Midtvedt","given":"Karsten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holdaas","given":"Hallvard","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leivestad","given":"Torbjorn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horneland","given":"Rune","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oyen","given":"Ole","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jenssen","given":"Trond","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetologia","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2016"]]},"page":"844-852","title":"Long-term cardiovascular outcomes in type 1 diabetic patients after simultaneous pancreas and kidney transplantation compared with living donor kidney transplantation.","type":"article-journal","volume":"59"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1007/s00125-016-3914-7","ISSN":"14320428","author":[{"dropping-particle":"","family":"Petrie","given":"Dennis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lung","given":"Tom W.C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rawshani","given":"Aidin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Palmer","given":"Andrew J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svensson","given":"Ann Marie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eliasson","given":"Bj?rn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clarke","given":"Philip","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetologia","id":"ITEM-2","issue":"6","issued":{"date-parts":[["2016"]]},"page":"1167-1176","title":"Recent trends in life expectancy for people with type 1 diabetes in Sweden","type":"article-journal","volume":"59"},"uris":[""]}],"mendeley":{"formattedCitation":"(3,7)","plainTextFormattedCitation":"(3,7)","previouslyFormattedCitation":"^3,7"},"properties":{"noteIndex":0},"schema":""}(3,7). This likely arises from improved recipient/donor selection, operative technique, perioperative care and immunosuppression as our national programme has matured; in addition to improvements in population health and the management of CVD risk factors ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISBN":"9781783868551","author":[{"dropping-particle":"","family":"NHS Digital","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issue":"November","issued":{"date-parts":[["2016"]]},"number-of-pages":"1-43","title":"Quality and Outcomes Framework – Prevalence, Achievements and Exceptions Report 2015/16","type":"book"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1056/NEJMoa1608664","ISBN":"0954-6111","ISSN":"0028-4793","PMID":"19863361","abstract":"BackgroundLong-term trends in excess risk of death and cardiovascular outcomes have not been extensively studied in persons with type 1 diabetes or type 2 diabetes. MethodsWe included patients registered in the Swedish National Diabetes Register from 1998 through 2012 and followed them through 2014. Trends in deaths and cardiovascular events were estimated with Cox regression and standardized incidence rates. For each patient, controls who were matched for age, sex, and county were randomly selected from the general population. ResultsAmong patients with type 1 diabetes, absolute changes during the study period in the incidence rates of sentinel outcomes per 10,000 person-years were as follows: death from any cause, ?31.4 (95% confidence interval [CI], ?56.1 to ?6.7); death from cardiovascular disease, ?26.0 (95% CI, ?42.6 to ?9.4); death from coronary heart disease, ?21.7 (95% CI, ?37.1 to ?6.4); and hospitalization for cardiovascular disease, ?45.7 (95% CI, ?71.4 to ?20.1). Absolute changes per 10,000 p...","author":[{"dropping-particle":"","family":"Rawshani","given":"Aidin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rawshani","given":"Araz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Franzén","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eliasson","given":"Bj?rn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svensson","given":"Ann-Marie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miftaraj","given":"Mervete","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGuire","given":"Darren K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sattar","given":"Naveed","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosengren","given":"Annika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gudbj?rnsdottir","given":"Soffia","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-2","issue":"15","issued":{"date-parts":[["2017"]]},"page":"1407-1418","title":"Mortality and Cardiovascular Disease in Type 1 and Type 2 Diabetes","type":"article-journal","volume":"376"},"uris":[""]}],"mendeley":{"formattedCitation":"(22,23)","plainTextFormattedCitation":"(22,23)","previouslyFormattedCitation":"^22,23"},"properties":{"noteIndex":0},"schema":""}(22,23).4.2Prior studies of CVD risk factors in relation to the national cohortOur study adds to the work by Kim and co-workers (2017). They reported significant relationships with age, non-white ethnicity, male sex, previous cardiac surgery or coronary intervention, valvular disease, pulmonary circulatory disorder and anaemia ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.amjcard.2017.05.038","ISSN":"00029149","PMID":"28683901","abstract":"Large database studies detailing the risk of perioperative cardiovascular complications after pancreas transplant has been limited, perhaps because these outcomes are not captured by transplant registries. Greater data on the incidence and risks of such outcomes could provide additional insight for referring physicians and inform potential recipients of their risk. We performed a serial, cross-sectional analysis of the National Inpatient Sample, the largest publicly available inpatient database in the United States, to assess for the risk of cardiovascular complications after pancreas transplants in the United States from 2003 to 2012 (n = 13,399). Using multivariable logistic regression models, the risk of cardiovascular outcomes after simultaneous pancreas-kidney transplants (SPK) was compared with solitary pancreas transplants (pancreas after kidney and pancreas transplant alone [PAK + PTA]). The unadjusted prevalence of in-hospital cardiovascular complications was higher in SPK than PAK + PTA (5.5% vs 3.7%, p <0.001). After multivariable adjustment, SPK remained associated with significantly higher odds of any cardiovascular complication (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.21 to 1.80, p = 0.01), and particularly stroke (OR 13.41, 95% CI 4.78 to 37.63, p <0.001), compared with PAK + PTA. However, there was no difference in perioperative mortality (OR 0.78, 95% CI 0.54 to 1.12, p = 0.18). In conclusion, these findings highlight the association between uremia and stroke in pancreas transplant patients, as well as the need for improved preoperative cardiac risk assessment and perioperative management, especially in those who underwent SPK.","author":[{"dropping-particle":"","family":"Kim","given":"Jim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schulman-Marcus","given":"Joshua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watkins","given":"Anthony C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feldman","given":"Dmitriy N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swaminathan","given":"Rajesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Jun B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Muthukumar","given":"Thangamani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Serur","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Luke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartono","given":"Choli","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American Journal of Cardiology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017"]]},"page":"682-687","publisher":"Elsevier Inc.","title":"In-Hospital Cardiovascular Complications After Pancreas Transplantation in the United States from 2003 to 2012","type":"article-journal","volume":"120"},"uris":[""]}],"mendeley":{"formattedCitation":"(6)","plainTextFormattedCitation":"(6)","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}(6). Our study focused on longer-term follow-up and supported some of these findings. Differences in results could be explained by differences in timeframes of observation, and recipient and donor characteristics especially since they reported on all pancreas transplant recipients whereas ours focused on SPKT recipients ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.amjcard.2017.05.038","ISSN":"00029149","PMID":"28683901","abstract":"Large database studies detailing the risk of perioperative cardiovascular complications after pancreas transplant has been limited, perhaps because these outcomes are not captured by transplant registries. Greater data on the incidence and risks of such outcomes could provide additional insight for referring physicians and inform potential recipients of their risk. We performed a serial, cross-sectional analysis of the National Inpatient Sample, the largest publicly available inpatient database in the United States, to assess for the risk of cardiovascular complications after pancreas transplants in the United States from 2003 to 2012 (n = 13,399). Using multivariable logistic regression models, the risk of cardiovascular outcomes after simultaneous pancreas-kidney transplants (SPK) was compared with solitary pancreas transplants (pancreas after kidney and pancreas transplant alone [PAK + PTA]). The unadjusted prevalence of in-hospital cardiovascular complications was higher in SPK than PAK + PTA (5.5% vs 3.7%, p <0.001). After multivariable adjustment, SPK remained associated with significantly higher odds of any cardiovascular complication (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.21 to 1.80, p = 0.01), and particularly stroke (OR 13.41, 95% CI 4.78 to 37.63, p <0.001), compared with PAK + PTA. However, there was no difference in perioperative mortality (OR 0.78, 95% CI 0.54 to 1.12, p = 0.18). In conclusion, these findings highlight the association between uremia and stroke in pancreas transplant patients, as well as the need for improved preoperative cardiac risk assessment and perioperative management, especially in those who underwent SPK.","author":[{"dropping-particle":"","family":"Kim","given":"Jim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schulman-Marcus","given":"Joshua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watkins","given":"Anthony C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feldman","given":"Dmitriy N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swaminathan","given":"Rajesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Jun B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Muthukumar","given":"Thangamani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Serur","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Luke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartono","given":"Choli","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The American Journal of Cardiology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017"]]},"page":"682-687","publisher":"Elsevier Inc.","title":"In-Hospital Cardiovascular Complications After Pancreas Transplantation in the United States from 2003 to 2012","type":"article-journal","volume":"120"},"uris":[""]}],"mendeley":{"formattedCitation":"(6)","plainTextFormattedCitation":"(6)","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}(6).We show an adverse effect of advancing age on CVD risk. This is unsurprising as atherosclerosis and plaque rupture are age-related processes ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fgene.2017.00216","ISSN":"16648021","PMID":"29312440","abstract":"A considerable volume of research over the last decade has focused on understanding the fundamental mechanisms for the progression of atherosclerosis-the underlying cause for the vast majority of all cardiovascular (CVD)-related complications. Aging is the dominant risk factor for clinically significant atherosclerotic lesion formation, yet the heightened impact of aging on the disease is not accounted for by changes in traditional risk factors, such as lack of physical activity, smoking, hypertension, hyperlipidemia, or diabetes mellitus. This review will examine the pathological and biochemical processes of atherosclerotic plaque formation and growth, with particular focus on the aging risk vis-a-vis arterial homeostasis. Particular focus will be placed on the impact of a number of important contributors to arterial homeostasis including bone marrow (BM)-derived vascular progenitor cells, differential monocyte subpopulations, and the role of cellular senescence. Finally, this review will explore many critical observations in the way the disease process has been reassessed both by clinicians and researchers, and will highlight recent advances in this field that have provided a greater understanding of this aging-driven disease.","author":[{"dropping-particle":"","family":"Head","given":"Trajen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Daunert","given":"Sylvia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldschmidt-Clermont","given":"Pascal J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Genetics","id":"ITEM-1","issue":"DEC","issued":{"date-parts":[["2017"]]},"page":"1-11","title":"The aging risk and atherosclerosis: A fresh look at arterial homeostasis","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"(24)","plainTextFormattedCitation":"(24)","previouslyFormattedCitation":"²⁴"},"properties":{"noteIndex":0},"schema":""}(24). We demonstrate strong relationships between the presence of known CVD prior to transplant (myocardial infarction and stroke), amputation and the risk for subsequent MACE or fatal CVD. In a previous mortality study involving 78 German SPKT recipients, prior MI (relative risk [RR]: 5.1) and amputation (RR: 3.7) were strongly associated with a reduced patient survival ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/01.TP.0000147789.06043.A6","ISBN":"0041-1337 (Print)\\r0041-1337 (Linking)","ISSN":"00411337","PMID":"15614154","abstract":"BACKGROUND: The objective of this study was to determine the long-term results after simultaneous pancreas-kidney transplantation (SPK) at a single-center institution in Europe. PATIENTS AND METHODS: Seventy-eight consecutive patients with insulin-dependent diabetes mellitus and end-stage nephropathy were followed for a median of 7 years after SPK. Immunosuppressive protocol consisted of cyclosporine A, azathioprine, prednisone, and antithymocyte globulin. Multivariate Cox proportional hazard model was used to investigate the impact of different putative risk factors on long-term patient survival. Health-related quality of life was assessed by a validated questionnaire (SF-36). RESULTS: Patient survival at 5 and 10 years was 81% and 67%, respectively. Pancreas function rate was 73% and 60% and kidney function 67% and 44%, respectively. In multivariate analysis, preexisting myocardial infarction (relative risk [RR] 5.1, 95% confidence interval [CI] 1.5-16.6) and amputation (RR 3.7, 95% CI 1.1-12.9) were strongly associated with a diminished long-term patient survival. Analysis of patients with long-term functioning pancreas and kidney grafts revealed excellent results for quality of life posttransplant that were comparable with average scores of the normal German population. CONCLUSIONS: This series representing the largest experience with long-term follow-up in Europe confirms an excellent long-term survival and an exceptional quality of life after SPK","author":[{"dropping-particle":"","family":"Drognitz","given":"Oliver","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benz","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pfeffer","given":"Frank","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fischer","given":"Christoph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Makowiec","given":"Frank","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schareck","given":"Wolfgang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hopt","given":"Ulrich Theodor","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplantation","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2004"]]},"page":"1802-1808","title":"Long-term follow-up of 78 simultaneous pancreas-kidney transplants at a single-center institution in Europe","type":"article-journal","volume":"78"},"uris":[""]}],"mendeley":{"formattedCitation":"(25)","plainTextFormattedCitation":"(25)","previouslyFormattedCitation":"²⁵"},"properties":{"noteIndex":0},"schema":""}(25). These risk factors are surrogates for prevalent vascular disease and are considered markers of ‘diabetes severity’. They have been shown to be potent risk factors for CVD events in other clinical contexts ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJM199006143222403","ISSN":"0028-4793 (Print)","PMID":"2342536","abstract":"To determine the associations of total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol with mortality from coronary heart disease and cardiovascular disease, we studied 2541 white men who were 40 to 69 years old at base line and followed them for an average of 10.1 years. Seventeen percent had some manifestation of cardiovascular disease at base line, whereas the others did not. Among the men who had cardiovascular disease at base line, we found, after multivariate adjustment, that those with \"high\" blood cholesterol levels (above 6.19 mmol per liter) had a risk of death from cardiovascular disease, including coronary heart disease, that was 3.45 times higher (95 percent confidence interval, 1.63 to 7.33) than that for men with \"desirable\" blood cholesterol levels (below 5.16 mmol per liter). The corresponding hazard ratios were 5.92 (95 percent confidence interval, 2.59 to 13.51) for LDL cholesterol levels above 4.13 mmol per liter as compared with those below 3.35 mmol per liter, and 6.02 (95 percent confidence interval, 2.73 to 13.28) for HDL cholesterol levels below 0.90 mmol per liter as compared with those above 1.16 mmol per liter. All three lipid levels were also significant predictors of death from coronary heart disease alone (P less than 0.005). Total cholesterol and LDL cholesterol levels were also significant predictors of death from cardiovascular and coronary heart disease in men without preexisting cardiovascular disease, although at a lower level of absolute risk of death. Thus, the 10-year risk of death from cardiovascular disease for a man with preexisting cardiovascular disease increased from 3.8 percent to almost 19.6 percent with increasing levels of total cholesterol from \"desirable\" to \"high,\" whereas the corresponding risk for a man who was free of cardiovascular disease at base line increased from 1.7 percent to 4.9 percent. Our findings suggest that total, LDL, and HDL cholesterol levels predict subsequent mortality in men 40 to 69 years of age, especially those with preexisting cardiovascular disease.","author":[{"dropping-particle":"","family":"Pekkanen","given":"Juha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Linn","given":"Shai","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heiss","given":"G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suchindran","given":"C.M M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leon","given":"Arthur","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rifkind","given":"B.M M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tyroler","given":"H.A A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gerrardo-Heiss","given":"P.H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suchindran","given":"C.M M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leon","given":"Arthur","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rifkind","given":"B.M M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tyroler","given":"H.A A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The New England Journal of Medicine","id":"ITEM-1","issue":"21","issued":{"date-parts":[["1990","6"]]},"language":"eng","page":"1700-1707","publisher-place":"United States","title":"Ten-year Mortality from Cardiovascular Disease in Relation to Cholesterol Level Among Men With and Without Preexisting Cardiovascular Disease","type":"article-journal","volume":"322"},"uris":[""]},{"id":"ITEM-2","itemData":{"abstract":"Background 99mTc sestamibi is a recently developed radioisotope that has been used to measure myocardium at risk and infarct size. The relation between these measurements and subsequent patient outcome has not yet been demonstrated. Methods and Results Two hundred seventy-four consecutive patients with acute myocardial infarction underwent tomographic 99mTc sestamibi imaging on arrival at the hospital (to measure myocardium at risk before reperfusion therapy) and at hospital discharge (to measure the amount of salvaged myocardium and final infarct size). Defect size on the sestamibi images was quantified using a threshold value of 60% of peak counts from the circumferential count profile curves generated for five representative slices of the left ventricle. Patients were followed after hospital discharge to evaluate the association between final infarct size and subsequent mortality. The median defect size measured was 27% of the left ventricle at presentation to the hospital (range, 0% to 77%) and was 12% of the left ventricle at hospital discharge (range, 0% to 68%). Almost one half of the patients had a final infarct size of ≤10%. The median amount of myocardium salvaged was 9% (range, ?31% to 75%). During a median duration of follow-up of 12 months, there were 10 deaths (7 cardiac and 3 noncardiac) and 1 resuscitated out-of-hospital cardiac arrest. There was a significant association between infarct size and overall mortality (χ2=8.66, P=.003) and cardiac mortality (χ2=11.89, P&amp;lt;.001). Two-year mortality was 7% for patients whose infarct size was ≥12% versus 0% for patients whose infarct size was &amp;lt;12%. There also was a significant association between myocardium at risk and cardiac mortality (χ2=6.87, P=.009). There was no association between myocardium at risk and overall mortality or between amount of myocardium salvaged and either overall mortality or cardiac mortality. Conclusions Larger infarct size measured by 99mTc sestamibi imaging after acute myocardial infarction is associated with increased mortality risk during short-term follow-up.","author":[{"dropping-particle":"","family":"Miller","given":"Todd D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christian","given":"Timothy F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hopfenspirger","given":"Mona R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hodge","given":"David O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gersh","given":"Bernard J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gibbons","given":"Raymond J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Circulation","id":"ITEM-2","issue":"3","issued":{"date-parts":[["1995","8","1"]]},"page":"334 LP - 341","title":"Infarct Size After Acute Myocardial Infarction Measured by Quantitative Tomographic 99mTc Sestamibi Imaging Predicts Subsequent Mortality","type":"article-journal","volume":"92"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1186/s12933-015-0322-0","ISSN":"14752840","PMID":"26743116","abstract":"BACKGROUND We evaluated the risks of renal and cardiovascular complications, and mortality associated with lower extremity amputation (LEA) in patients with type 1 diabetes. METHODS We studied two cohorts of people with long standing type 1 diabetes: GENEDIAB (n = 456) and GENESIS (n = 611). Subsets of the cohorts (n = 260, n = 544) were followed for 9 and 5 years, respectively. Outcomes were the incidence of end stage renal disease (ESRD), myocardial infarction, stroke and mortality during follow-up. Analyses were performed in pooled cohorts. RESULTS The prevalence of LEA at baseline was 9.3 % (n = 99). A positive history of LEA was associated with the baseline prevalence of established (OR 4.50, 95 % CI 2.33-8.91, p < 0.0001) and advanced diabetic nephropathy (OR 5.50, 95 % CI 2.89-10.78, p < 0.0001), ESRD (OR 2.86, 95 % CI 1.43-5.50, p = 0.004), myocardial infarction (OR 3.25, 95 % CI 1.68-6.15, p = 0.0006) and stroke (OR 3.88, 95 % CI 1.67-8.72, p = 0.002, adjusted for sex, age, and cohort membership). A positive history of LEA at baseline was associated with the incidence during follow-up of ESRD (HR 2.69, 95 % CI 1.17-6.20, p = 0.02), and myocardial infarction (HR 3.53, 95 % CI 1.79-6.97, p = 0.0001). History of LEA was also associated with increased risk for all-cause (HR 3.55, 95 % CI 2.05-6.16, p < 0.0001), cardiovascular (HR 3.30, 95 % CI 1.36-8.02, p = 0.008), infectious disease (HR 5.18, 95 % CI 1.13-23.84, p = 0.03) and other-cause mortality (HR 2.81, 95 % CI 1.09-7.26, p = 0.03). History of LEA at baseline was associated with a 40 % reduction in the duration of survival in the subset of patients who died during follow-up. Population attributable risk of the history of LEA at baseline for total mortality during follow-up was 0.31. CONCLUSIONS Patients with LEA have a higher risk of ESRD, myocardial infarction and cardiovascular and non-cardiovascular mortality. Our results highlight the importance of LEA as a key-predictor for major vascular events and premature death in type 1 diabetic patients.","author":[{"dropping-particle":"","family":"Mohammedi","given":"Kamel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Potier","given":"Louis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Belhatem","given":"Narimène","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matallah","given":"Nadia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hadjadj","given":"Samy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roussel","given":"Ronan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marre","given":"Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Velho","given":"Gilberto","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cardiovascular Diabetology","id":"ITEM-3","issue":"1","issued":{"date-parts":[["2016"]]},"page":"1-9","publisher":"BioMed Central","title":"Lower-extremity amputation as a marker for renal and cardiovascular events and mortality in patients with long standing type 1 diabetes","type":"article-journal","volume":"15"},"uris":[""]},{"id":"ITEM-4","itemData":{"ISSN":"0003-4819","abstract":"? Objective: To investigate whether abnormalities in blood viscosity predict a poor prognosis for subsequent cardiovascular events in stroke survivors.? Design: Nested case-control study among a cohort of survivors of a first stroke, followed for an average of 2 years. Patients with a second stroke, myocardial infarction, or cardiovascular death were matched with patients who did not have such events (control patients).? Setting: Buchberg-Klinik, Bad T?lz, Germany, a specialized center for stroke rehabilitation.? Patients: A total of 625 consecutive patients. Twenty-one patients (3.5%) were lost to follow-up. Sixty pairs were matched.? Measurements: Native and hematocrit-standardized blood viscosity at three shear rates, hematocrit, plasma viscosity, fibrinogen, erythrocyte sedimentation rate, total leukocyte count, and the matching variables.? Results: Eighty-five patients had a second stroke, myocardial infarction, or died due to a cardiovascular event. Patients with re-events had higher blood viscosity and fibrinogen levels than the control patients. In the 60 matched pairs, the mean of the paired differences between patients with re-events and control patients was 5.03 mPa · s (95% Cl, 1.262 to 8.941; P = 0.01) for native blood viscosity at shear rate 0.7 s-1, for plasma viscosity, 0.044 mPa · s (Cl, 0.006 to 0.083; P &gt; 0.02), and for fibrinogen, 0.056 g/L (Cl, 0.010 to 0.101; P &gt; 0.02). Odds ratios were significantly increased only for plasma viscosity (odds ratio, 2.86; Cl, 1.06 to 8.43) and fibrinogen (odds ratio, 3.67; Cl, 1.31 to 11.69).? Conclusions: Hyperfibrinogenemia is an independent risk factor for cardiovascular events in stroke survivors. Intervention trials with fibrinogen lowering measures may be warranted.","author":[{"dropping-particle":"","family":"Resch","given":"KL","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ernst","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matrai","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paulsen","given":"HF","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Internal Medicine","id":"ITEM-4","issue":"5","issued":{"date-parts":[["1992","9","1"]]},"note":"10.7326/0003-4819-117-5-371","page":"371-375","title":"FIbrinogen and viscosity as risk factors for subsequent cardiovascular events in stroke survivors","type":"article-journal","volume":"117"},"uris":[""]}],"mendeley":{"formattedCitation":"(26–29)","plainTextFormattedCitation":"(26–29)","previouslyFormattedCitation":"^26–29"},"properties":{"noteIndex":0},"schema":""}(26–29). The relationship between BMI and CVD outcomes was not significant in our study, which is contrary to large population based studies ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/bmj.39609.449676.25","ISBN":"0959-8146","ISSN":"0959-8138","PMID":"18573856","abstract":"OBJECTIVE: To develop and validate version two of the QRISK cardiovascular disease risk algorithm (QRISK2) to provide accurate estimates of cardiovascular risk in patients from different ethnic groups in England and Wales and to compare its performance with the modified version of Framingham score recommended by the National Institute for Health and Clinical Excellence (NICE). DESIGN: Prospective open cohort study with routinely collected data from general practice, 1 January 1993 to 31 March 2008. SETTING: 531 practices in England and Wales contributing to the national QRESEARCH database. PARTICIPANTS: 2.3 million patients aged 35-74 (over 16 million person years) with 140,000 cardiovascular events. Overall population (derivation and validation cohorts) comprised 2.22 million people who were white or whose ethnic group was not recorded, 22,013 south Asian, 11,595 black African, 10,402 black Caribbean, and 19,792 from Chinese or other Asian or other ethnic groups. MAIN OUTCOME MEASURES: First (incident) diagnosis of cardiovascular disease (coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records or linked Office for National Statistics death certificates. Risk factors included self assigned ethnicity, age, sex, smoking status, systolic blood pressure, ratio of total serum cholesterol:high density lipoprotein cholesterol, body mass index, family history of coronary heart disease in first degree relative under 60 years, Townsend deprivation score, treated hypertension, type 2 diabetes, renal disease, atrial fibrillation, and rheumatoid arthritis. RESULTS: The validation statistics indicated that QRISK2 had improved discrimination and calibration compared with the modified Framingham score. The QRISK2 algorithm explained 43% of the variation in women and 38% in men compared with 39% and 35%, respectively, by the modified Framingham score. Of the 112,156 patients classified as high risk (that is, >or=20% risk over 10 years) by the modified Framingham score, 46,094 (41.1%) would be reclassified at low risk with QRISK2. The 10 year observed risk among these reclassified patients was 16.6% (95% confidence interval 16.1% to 17.0%)-that is, below the 20% treatment threshold. Of the 78 024 patients classified at high risk on QRISK2, 11,962 (15.3%) would be reclassified at low risk by the modified Framingham score. The 10 year observed risk among these patients was 23.3% (22.2% to 24.4%)-that is, above the 20% threshold.…","author":[{"dropping-particle":"","family":"Hippisley-Cox","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Coupland","given":"Carol","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vinogradova","given":"Yana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robson","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Minhas","given":"Rubin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sheikh","given":"Aziz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brindle","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Bmj","id":"ITEM-1","issue":"7659","issued":{"date-parts":[["2008"]]},"page":"1475-1482","title":"Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2.","type":"article-journal","volume":"336"},"uris":[""]}],"mendeley":{"formattedCitation":"(10)","plainTextFormattedCitation":"(10)","previouslyFormattedCitation":"¹⁰"},"properties":{"noteIndex":0},"schema":""}(10). This may be explained in part by the UK selection criteria for SPKT in type-1 diabetics, which list BMI≥30 as a relative contraindication, and cohort studies studies of diabetic cohorts that report non-linear relationships between BMI and CVD in people with diabetes, which could be missed using conventional Cox models ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00125-014-3473-8","ISBN":"0012-186X\\r1432-0428","ISSN":"14320428","PMID":"25512005","abstract":"Aims/hypothesis We aimed to describe the shape of observed relationships between risk factor levels and clinically impor- tant outcomes in type 2 diabetes after adjusting for multiple confounders. Methods We used retrospective longitudinal data on 246,544 adults with type 2 diabetes from 600 practices in the Clinical Practice Research Datalink, 2006–2012. Proportional hazards regression models quantified the risks of mortality and micro- vascular or macrovascular events associated with four modifiable biological variables (HbA1c, systolic BP, diastolic BP and total cholesterol), while controlling for important patient and practice covariates. Results U-shaped relationships were observed between all- cause mortality and levels of the four biometric risk factors. Lowest risks were associated with HbA1c 7.25–7.75% (56– 61 mmol/mol), total cholesterol 3.5–4.5 mmol/l, systolic BP 135–145 mmHg and diastolic BP 82.5–87.5 mmHg. Coronary and stroke mortality related to the four risk factors in a positive, curvilinear way, with the exception of systolic BP, which related to deaths in a U-shape. Macrovascular events showed a positive and curvilinear relationship with HbA1c but a U-shaped relationship with total cholesterol and systolic BP. Microvascular events related to the four risk factors in a curvilinear way: positive for HbA1c and systolic BP but negative for cholesterol and diastolic BP. Conclusions/interpretation We identified several relation- ships that support a call for major changes to clinical practice. Most importantly, our results support trial data indicating that normalisation of glucose and BP can lead to poorer outcomes. This makes a strong case for target ranges for these risk factors rather than target levels.","author":[{"dropping-particle":"","family":"Kontopantelis","given":"Evangelos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Springate","given":"David A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reeves","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ashcroft","given":"Darren M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rutter","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buchan","given":"Iain","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Doran","given":"Tim","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetologia","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2014"]]},"page":"505-518","title":"Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study","type":"article-journal","volume":"58"},"uris":[""]},{"id":"ITEM-2","itemData":{"abstract":"The aim of this document is to provide a policy for the selection of adult and paediatric patients on to the UK national transplant list and, where necessary, criteria for their de-selection. These criteria apply to all proposed recipients of organs from deceased donors and all centres should work to the same selection criteria. Non-compliance to these guidelines will be handled directly by NHSBT, in accordance with the Non Compliance with Selection and Allocation Policies It is acknowledged that these guidelines will require regular review and refreshment. Where they do not cover specific individual cases, mechanisms are in place for selection of exceptional cases. 1. Conditions that are considered for transplantation Patients who are considered for pancreas or islet transplantation fall into three categories: ? Pancreas transplant alone / islet transplant alone o Patients with severe hypoglycaemic unawareness but normal or near-normal renal function ? Simultaneous pancreas and kidney transplant / Simultaneous islet and kidney transplant o Patients with renal failure and insulin-dependent diabetes ? Pancreas after kidney transplant / islet after kidney transplant o Patients with functioning kidney transplants and diabetes The majority of patients who are considered have type 1 diabetes but a minority of insulin-dependent type 2 diabetic patients may also be suitable candidates for pancreas transplant. POLICY POL185/4 Pancreas transplantation: Patient selection This copy is uncontrolled unless printed on 'Controlled' paper (Template Version 07/10/08) Author(s): Kathy Zalewska Page 2 of 6 2. Assessment of patients There are three stages of assessment: ? Pre-transplant assessment ? Decision ? Transplant list 2.1 Pre-transplant assessment The assessment should be completed within 18 weeks of referral although this may be delayed if medical issues that require intervention prior to listing for transplantation are identified. At the end of assessment, the decision will be made as to whether the patient should be listed for a transplant and this decision communicated to the referring doctor and the patient's general practitioner. The importance of the multidisciplinary involvement in the assessment of the patient and care received is paramount. The assessment may involve a whole spectrum of healthcare professionals, including physicians, surgeons, radiologists, nurses, transpl…","author":[{"dropping-particle":"","family":"Zalewska","given":"Kathy","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-2","issued":{"date-parts":[["2016"]]},"number-of-pages":"6-11","title":"POLICY POL185/4 Pancreas transplantation: Patient selection","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"(30,31)","plainTextFormattedCitation":"(30,31)","previouslyFormattedCitation":"^30,31"},"properties":{"noteIndex":0},"schema":""}(30,31).The results of our unadjusted model for MACE suggest a significant adverse effect of increasing pancreas CIT. Pancreas CIT is related to adverse allograft outcomes ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0041-1337 (Print)","PMID":"15502718","abstract":"BACKGROUND: Technical failure (TF) rates remain high after pancreas transplants; while rates have decreased over the last decade, more than 10% of all pancreas grafts continue to be lost due to technical reasons. We performed a multivariate analysis to determine causes and risk factors for TF of pancreas grafts. RESULTS: Between 1994 and 2003, 937 pancreas transplants were performed at our center in the following transplant categories: simultaneous pancreas-kidney (SPK) (n=327), pancreas after kidney (PAK) (n=399), and pancreas transplant alone (PTA) (n=211). Of these, 123 (13.1%) grafts were lost due to technical reasons (thrombosis, leaks, infections). TF rates were higher for SPK (15.3%) versus PAK (12.2%) or PTA (11.4%), though this was not statistically significant. Thrombosis accounted for 52.0% of all TFs. Other causes were infections (18.7%), pancreatitis (20.3%), leaks (6.5%), and bleeding (2.4%). Thrombosis was the most common cause for TF in all three transplant categories. By multivariate analysis, the following were significant risk factors for TF of the graft: recipient body mass index (BMI) >30 kg/m (relative risk [RR]=2.42, P=0.0003), preservation time >24 hr (1.87, P=0.04), cause of donor death other than trauma (RR=1.58, P=0.04), enteric versus bladder drainage (1.68, P=0.06), and donor BMI >30 kg/m (1.66, P=0.06). Not significant were donor or recipient age, a retransplant, and the category of transplant. CONCLUSIONS: TFs remain significant after pancreas transplants. In SPK recipients, TF represents the most common cause of pancreas graft loss. For isolated pancreas transplants, TF is second only to rejection as a cause of graft loss. Increased preservation times and donor or recipient obesity seem to be risk factors. Minimizing these risks factors would be important to try to decrease TF.","author":[{"dropping-particle":"","family":"Humar","given":"Abhinav","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramcharan","given":"Thigarajan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kandaswamy","given":"Raja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gruessner","given":"Rainer W G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gruessner","given":"Angelika C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sutherland","given":"David E R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplantation","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2004","10"]]},"language":"eng","page":"1188-1192","publisher-place":"United States","title":"Technical failures after pancreas transplants: why grafts fail and the risk factors--a multivariate analysis.","type":"article-journal","volume":"78"},"uris":[""]}],"mendeley":{"formattedCitation":"(32)","plainTextFormattedCitation":"(32)","previouslyFormattedCitation":"³²"},"properties":{"noteIndex":0},"schema":""}(32). It is possible that this relationship reflects the effect that adverse allograft outcomes may have on MACE. However, one must also consider that longer pancreas CIT may arise from differences in recipient and donor selection, transplant volume, logistics, and surgical technique between transplant centres. In addition, the UK average pancreas CIT has been declining over the study period, potentially confounding our unadjusted results ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2018","9","4"]]},"author":[{"dropping-particle":"","family":"National Health Service Blood and Transplant","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"Annual Reports on Pancreas and Islet Transplantation","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(11)","plainTextFormattedCitation":"(11)","previouslyFormattedCitation":"¹¹"},"properties":{"noteIndex":0},"schema":""}(11). This is supported by the loss of significance in adjusted models. Our results also suggest that prednisolone immunosuppression is adversely related to MACE in unadjusted models. We also show that there has been a decline in the use of prednisolone containing immunosuppression regimens over time, possibly due to increased use of T-cell depleting agents at induction such as alemtuzumab (supplemental table 2). It is possible that our unadjusted results may reflect the effect of an earlier year of transplantation. Whilst this is supported by the loss of significance in adjusted models, a previous large population based study from the Netherlands reported that oral glucocorticoids were adversely related to cardiovascular outcomes ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/hrt.2003.020180","ISBN":"1468-201X (Electronic)\\r1355-6037 (Linking)","ISSN":"13556037","PMID":"15253953","abstract":"OBJECTIVE: To assess whether use of oral glucocorticoids is associated with cardiovascular and cerebrovascular morbidity. DESIGN AND SETTING: Nested case-control study within a cohort of patients (> or = 50 years old) with at least one prescription for oral or non-systemic glucocorticoids. Data were from the general practice research database. PATIENTS: 50 656 patients were identified with a first record for ischaemic heart disease (International classification of diseases, ninth revision (ICD-9) codes 410, 411, 413, and 414), ischaemic stroke or transient ischaemic attack (ICD-9 codes 430-436), or heart failure (ICD-9 code 428) between 1988 and 1998. One control was matched to each case by sex, age, general practice, underlying disease, and calendar time. MAIN OUTCOME MEASURE: Odds ratio (OR) of cardiovascular or cerebrovascular events in patients using oral glucocorticoids compared with non-users. RESULTS: There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome (adjusted OR 1.25, 95% confidence interval (CI) 1.21 to 1.29). The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest ORs were observed in the group with the highest average daily dose, although the dose-response relation was not continuous. Current use was associated with an increased risk of heart failure (adjusted OR 2.66, 95% CI 2.46 to 2.87), which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease (OR 1.20, 95% CI 1.11 to 1.29). CONCLUSIONS: Oral glucocorticoid use was identified as a risk factor for heart failure. However, the evidence remains observational and only a randomised controlled trial of glucocorticoid treatment versus other disease modifying agents is likely to distinguish the importance of the underlying disease activity from its treatment in predicting cardiovascular outcomes","author":[{"dropping-particle":"","family":"Souverein","given":"P. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berard","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Staa","given":"T. P.","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Egberts","given":"A. C G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leufkens","given":"H. G M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"B. R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Heart","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2004"]]},"page":"859-865","title":"Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study","type":"article-journal","volume":"90"},"uris":[""]}],"mendeley":{"formattedCitation":"(33)","plainTextFormattedCitation":"(33)","previouslyFormattedCitation":"³³"},"properties":{"noteIndex":0},"schema":""}(33). Taken together, these results suggest that efforts to avoid glucocorticoid immunosuppression in SPKT recipients should be continued.The relationship between increasing waiting time and MACE is unsurprising. Patients waiting longer have prolonged dialysis exposure, which increases the risk of all-cause and cardiovascular mortality ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1001/jama.2009.1488","ISSN":"1538-3598 (Electronic)","PMID":"19861670","abstract":"CONTEXT: Cardiovascular mortality is considered the main cause of death in patients receiving dialysis and is 10 to 20 times higher in such patients than in the general population. OBJECTIVE: To evaluate if high overall mortality in patients starting dialysis is a consequence of increased cardiovascular mortality risk only or whether noncardiovascular mortality is equally increased. DESIGN, SETTING, AND PATIENTS: Using data from between January 1, 1994, and January 1, 2007, age-stratified mortality in a European cohort of adults starting dialysis and receiving follow-up for a mean of 1.8 (SD, 1.1) years (European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] Registry [N = 123,407]) was compared with the European general population (Eurostat). MAIN OUTCOME MEASURES: Cause of death was recorded by ERA-EDTA codes in patients and matching International Statistical Classification of Diseases, 10th Revision codes in the general population. Standardized cardiovascular and noncardiovascular mortality rates, their ratio, difference, and relative excess of cardiovascular over noncardiovascular mortality were calculated. RESULTS: Overall all-cause mortality rates in patients and the general population were 192 per 1000 person-years (95% confidence interval [CI], 190-193) and 12.055 per 1000 person-years (95% CI, 12.05-12.06), respectively. Cause of death was known for 90% of the patients and 99% of the general population. In patients, 16,654 deaths (39%) were cardiovascular and 21,654 (51%) were noncardiovascular. In the general population, 7,041,747 deaths (40%) were cardiovascular and 10,183,322 (58%) were noncardiovascular. Cardiovascular and noncardiovascular mortality rates in patients were respectively 38.1 per 1000 person-years (95% CI, 37.2-39.0) and 50.1 per 1000 person-years (95% CI, 48.9-51.2) higher than in the general population. On a relative scale, standardized cardiovascular and noncardiovascular mortality were respectively 8.8 (95% CI, 8.6-9.0) and 8.1 (95% CI, 7.9-8.3) times higher than in the general population. The ratio of these rates, ie, relative excess of cardiovascular over noncardiovascular mortality in patients starting dialysis compared with the general population, was 1.09 (95% CI, 1.06-1.12). Relative excess in a sensitivity analysis in which unknown/missing causes of death were regarded either as noncardiovascular or cardiovascular varied between 0.90 (95% CI, 0.88-0.93) and 1.39 (95% CI, 1.35-1.43). CONCL…","author":[{"dropping-particle":"","family":"Jager","given":"Dinanda J","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grootendorst","given":"Diana C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jager","given":"Kitty J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dijk","given":"Paul C","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tomas","given":"Lonneke M J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ansell","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Collart","given":"Frederic","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Finne","given":"Patrik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heaf","given":"James G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meester","given":"Johan","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wetzels","given":"Jack F M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosendaal","given":"Frits R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dekker","given":"Friedo W","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"JAMA","id":"ITEM-1","issue":"16","issued":{"date-parts":[["2009","10"]]},"language":"eng","page":"1782-1789","publisher-place":"United States","title":"Cardiovascular and noncardiovascular mortality among patients starting dialysis.","type":"article-journal","volume":"302"},"uris":[""]}],"mendeley":{"formattedCitation":"(34)","plainTextFormattedCitation":"(34)","previouslyFormattedCitation":"³⁴"},"properties":{"noteIndex":0},"schema":""}(34). Over the observation period, we observed a gradual increase in the use of organs from DCD and ECD donors. A lower proportion of MACE patients received DCD and ECD donor organs, suggesting a protective relationship; however, we identified strong correlations between donor type and the year of transplant, leading us to exclude donor type from regression models. Receiving organs from a donor with a history of hypertension conferred a 2-fold higher risk of MACE and fatal CVD. It is known that recipients of a kidney from a hypertensive donor have a 10-fold higher risk of developing hypertension ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"1046-6673 (Print)","PMID":"8866403","abstract":"In several genetic hypertensive rat strains, transplantation studies have established that the kidney carries at least a portion of the genetic message for hypertension. In man it has, of course, been more difficult to obtain clearcut results. This historical prospective observational study, double-blinded for knowledge of donors' and recipients' family history for hypertension, concerns 85 transplanted patients, not treated with cyclosporine and with stable renal function, followed up for an average of 8 yr. Both the donors' and the recipients' families were carefully characterized for presence or absence of hypertension. After transplantation, in recipients without hypertension in their own families, a kidney coming from a \"hypertensive\" family determines less withdrawal and more introduction of antihypertensive therapy (AHT) than a kidney from a \"normotensive\" family (odds ratio for AHT introduction 5.0, confidence interval, 1.4 to 17.8; P = 0.017). In recipients with familial hypertension, the origin of the kidney does not influence the prevalence of hypertension after transplantation. More detailed analyses show that, in recipients without familial hypertension, the transplantation of a \"hypertensive\" kidney determines a tenfold larger increase in the requirement of antihypertensive therapy than the transplantation of a \"normotensive\" kidney, to obtain a similar blood pressure control (P = 0.003). This results is confirmed by the analysis of time-profile trends for antihypertensive therapy, adjusted for missing data, in the most clinically stable period (2nd to 10th yr after transplantation). The transmission of familial hypertension with the kidney is thus seen only in recipients coming from \"normotensive\" families, because a familial tendency for hypertension blunts the effect of receiving a \"hypertensive\" kidney.","author":[{"dropping-particle":"","family":"Guidi","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Menghetti","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Milani","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Montagnino","given":"G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Palazzi","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bianchi","given":"G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American Society of Nephrology : JASN","id":"ITEM-1","issue":"8","issued":{"date-parts":[["1996","8"]]},"language":"eng","page":"1131-1138","publisher-place":"United States","title":"Hypertension may be transplanted with the kidney in humans: a long-term historical prospective follow-up of recipients grafted with kidneys coming from donors with or without hypertension in their families.","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"(35)","plainTextFormattedCitation":"(35)","previouslyFormattedCitation":"³⁵"},"properties":{"noteIndex":0},"schema":""}(35). Donor hypertension also relates to adverse renal allograft outcomes ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/ajt.13432","ISBN":"1600-6135","ISSN":"16006143","PMID":"26361242","abstract":"Donation after cardiac death is an important source of transplantable organs, but evidence suggests donor warm ischemia contributes to inferior outcomes. Attempts to predict recipient outcome using donor hemodynamic measurements have not yielded statistically significant results. We evaluated novel measures of donor hemodynamics as predictors of delayed graft function and graft failure in a cohort of 1050 kidneys from 566 donors. Hemodynamics were described using regression line slopes, areas under the curve, and time beyond thresholds for systolic blood pressure, oxygen saturation, and shock index (heart rate divided by systolic blood pressure). A logistic generalized estimation equation model showed that area under the curve for systolic blood pressure was predictive of delayed graft function (above median: odds ratio 1.42, 95% confidence interval [CI] 1.06-1.90). Multivariable Cox regression demonstrated that slope of oxygen saturation during the first 10 minutes after extubation was associated with graft failure (below median: hazard ratio 1.30, 95% CI 1.03-1.64), with 5-year graft survival of 70.0% (95%CI 64.5%-74.8%) for donors above the median versus 61.4% (95%CI 55.5%-66.7%) for those below the median. Among older donors, increased shock index slope was associated with increased hazard of graft failure. Validation of these findings is necessary to determine the utility of characterizing donor warm ischemia to predict recipient outcome.","author":[{"dropping-particle":"","family":"Allen","given":"M. B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Billig","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reese","given":"P. P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shults","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hasz","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"West","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abt","given":"P. L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Transplantation","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"page":"181-193","title":"Donor hemodynamics as a predictor of outcomes after kidney transplantation from donors after cardiac death","type":"article-journal","volume":"16"},"uris":[""]}],"mendeley":{"formattedCitation":"(36)","plainTextFormattedCitation":"(36)","previouslyFormattedCitation":"³⁶"},"properties":{"noteIndex":0},"schema":""}(36). We speculate that inducing or exacerbating recipient hypertension and adverse renal allograft survival may contribute to our findings. Unemployment was a significant hazard for fatal CVD. Previous population based studies have reported associations between voluntary or involuntary unemployment and cardiovascular disease in general populations ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0113495","ISBN":"1932-6203","ISSN":"19326203","PMID":"25409032","abstract":"BACKGROUND: The aim of this research was to investigate the association between job loss and the development of stroke or cardiovascular disease among middle-aged to older individuals in Korea. We also examined how this relationship was modified by gender and the nature of the job loss.\\n\\nMETHODS: This study used samples from the first- to fourth-wave datasets from the Korean Longitudinal Study of Aging (KLoSA), which were collected in 2006, 2008, 2010, and 2012. The study collected data from a total of 10,254 subjects aged ≥ 45 years at baseline. After applying exclusion criteria, the final sample size for analysis consisted of 4,000 individuals. Information about employment status, development of stroke or cardiovascular disease, and covariates (age, income level, and behavioral factors) was obtained. Cox proportional hazards models were used to evaluate the association between voluntary/involuntary job loss and the development of stroke or cardiovascular disease. We performed these analyses separately according to disease, gender, and the nature of the job loss.\\n\\nRESULTS: Involuntary job loss significantly increased the risk of stroke or cardiovascular disease among males (adjusted hazard ratio [HR]? = 3.560, 95% confidence interval [CI]? = 2.055-6.168). Voluntary retirement also increased the risk of cardiovascular disease or stroke among males (adjusted HR = 2.879, 95% CI = 1.533-5.409). Job loss was more closely associated with stroke than with cardiovascular disease (stroke, adjusted HR = 6.208, 95% CI = 2.417-15.943; cardiovascular disease, adjusted HR = 2.768, 95% CI = 1.402-5.465).\\n\\nCONCLUSION: Our findings suggest that both voluntary retirement and involuntary job loss increase the risk for stroke or cardiovascular disease in middle-aged to older individuals, especially males.","author":[{"dropping-particle":"","family":"Kang","given":"Mo Yeol","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Hyoung Ryoul","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2014"]]},"title":"Association between voluntary/involuntary job loss and the development of stroke or cardiovascular disease: A prospective study of middle-aged to older workers in a rapidly developing asian country","type":"article-journal","volume":"9"},"uris":[""]}],"mendeley":{"formattedCitation":"(37)","plainTextFormattedCitation":"(37)","previouslyFormattedCitation":"³⁷"},"properties":{"noteIndex":0},"schema":""}(37). Due to the definition we used for unemployment, it is likely that our findings indicate disease severity. However, it is important to consider other factors associated with unemployment that may influence cardiovascular outcomes, such as deprivation and psychological factors.A high proportion of recipients were current or ex-smokers (39.5%). Whilst this was not a significant hazard in our analyses, it may have contributed toward the CVD event rate as it is a strong CVD risk factor in large population based studies ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/bmj.39609.449676.25","ISBN":"0959-8146","ISSN":"0959-8138","PMID":"18573856","abstract":"OBJECTIVE: To develop and validate version two of the QRISK cardiovascular disease risk algorithm (QRISK2) to provide accurate estimates of cardiovascular risk in patients from different ethnic groups in England and Wales and to compare its performance with the modified version of Framingham score recommended by the National Institute for Health and Clinical Excellence (NICE). DESIGN: Prospective open cohort study with routinely collected data from general practice, 1 January 1993 to 31 March 2008. SETTING: 531 practices in England and Wales contributing to the national QRESEARCH database. PARTICIPANTS: 2.3 million patients aged 35-74 (over 16 million person years) with 140,000 cardiovascular events. Overall population (derivation and validation cohorts) comprised 2.22 million people who were white or whose ethnic group was not recorded, 22,013 south Asian, 11,595 black African, 10,402 black Caribbean, and 19,792 from Chinese or other Asian or other ethnic groups. MAIN OUTCOME MEASURES: First (incident) diagnosis of cardiovascular disease (coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records or linked Office for National Statistics death certificates. Risk factors included self assigned ethnicity, age, sex, smoking status, systolic blood pressure, ratio of total serum cholesterol:high density lipoprotein cholesterol, body mass index, family history of coronary heart disease in first degree relative under 60 years, Townsend deprivation score, treated hypertension, type 2 diabetes, renal disease, atrial fibrillation, and rheumatoid arthritis. RESULTS: The validation statistics indicated that QRISK2 had improved discrimination and calibration compared with the modified Framingham score. The QRISK2 algorithm explained 43% of the variation in women and 38% in men compared with 39% and 35%, respectively, by the modified Framingham score. Of the 112,156 patients classified as high risk (that is, >or=20% risk over 10 years) by the modified Framingham score, 46,094 (41.1%) would be reclassified at low risk with QRISK2. The 10 year observed risk among these reclassified patients was 16.6% (95% confidence interval 16.1% to 17.0%)-that is, below the 20% treatment threshold. Of the 78 024 patients classified at high risk on QRISK2, 11,962 (15.3%) would be reclassified at low risk by the modified Framingham score. The 10 year observed risk among these patients was 23.3% (22.2% to 24.4%)-that is, above the 20% threshold.…","author":[{"dropping-particle":"","family":"Hippisley-Cox","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Coupland","given":"Carol","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vinogradova","given":"Yana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robson","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Minhas","given":"Rubin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sheikh","given":"Aziz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brindle","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Bmj","id":"ITEM-1","issue":"7659","issued":{"date-parts":[["2008"]]},"page":"1475-1482","title":"Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2.","type":"article-journal","volume":"336"},"uris":[""]}],"mendeley":{"formattedCitation":"(10)","plainTextFormattedCitation":"(10)","previouslyFormattedCitation":"¹⁰"},"properties":{"noteIndex":0},"schema":""}(10). 4.3Prior studies of allograft failure following non-fatal CVD eventsWe are the first to report an association between non-fatal MACEs and subsequent allograft loss in SPKT recipients. Previous studies of renal and SPKT recipients have focused upon DWFG secondary to fatal CVD ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/00007890-200101150-00014","ISBN":"0041-1337 (Print)\\r0041-1337 (Linking)","ISSN":"0041-1337","PMID":"11211201","abstract":"BACKGROUND: Simultaneous pancreas-kidney transplantation (SPK) ameliorates the progression of microvascular diabetic complications but the procedure is associated with excess initial morbidity and an uncertain effect on patient survival when compared with solitary cadaveric or living donor renal transplantation. We evaluated mortality risks associated with SPK, solitary renal transplantation, and dialysis treatment in a national cohort of type 1 diabetics with end-stage nephropathy. METHODS: A total of 13,467 adult-type 1 diabetics enrolled on the renal and renal-pancreas transplant waiting list between 10/01/88 and 06/30/97 were followed until 06/30/98. Time-dependent mortality risks and life expectancy were calculated according to the treatment received subsequent to wait-list registration: SPK; cadaveric kidney only (CAD); living donor kidney only (LKD) transplantation; and dialysis [wait-listed, maintenance dialysis treatment (WLD)]. RESULTS: Adjusted 10-year patient survival was 67% for SPK vs. 65% for LKD recipients (P=0.19) and 46% for CAD recipients (P<0.001). The excess initial mortality normally associated with renal transplantation and the risk of early infectious death was 2-fold higher in SPK recipients. The time to achieve equal proportion of survivors as the WLD patients was 170, 95, and 72 days for SPK, CAD, and LKD recipients, respectively (P<0.001). However, the adjusted 5-year morality risk (RR) using WLD as the reference and the expected remaining life years were 0.40, 0.45, and 0.75 and 23.4, 20.9, and 12.6 years for SPK, LKD, and CAD, respectively. There was no survival benefit in SPK recipients > or =50 years old (RR=1.38, P=0.81). CONCLUSIONS: Among patients with type 1 DM with end-stage nephropathy, SPK transplantation before the age of 50 years was associated with long-term improvement in survival compared to solitary cadaveric renal transplantation or dialysis.","author":[{"dropping-particle":"","family":"Ojo","given":"a O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meier-Kriesche","given":"H U","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanson","given":"J a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leichtman","given":"a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Magee","given":"J C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cibrik","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolfe","given":"R a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Port","given":"F K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Agodoa","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"D B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaplan","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplantation","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2001"]]},"page":"82-90","title":"The impact of simultaneous pancreas-kidney transplantation on long-term patient survival.","type":"article-journal","volume":"71"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1097/SLA.0b013e3181b76d2b","ISBN":"1528-1140 (Electronic)\\r0003-4932 (Linking)","ISSN":"00034932","PMID":"19730242","abstract":"OBJECTIVE: Simultaneous pancreas-kidney transplantation (SPK) is a procedure which frees the diabetic patient with end-stage nephropathy from dialysis and daily insulin injections. The purpose of this study is to report long-term outcomes of this procedure, and describe surgical and medical complications. METHODS: The analysis includes 1000 consecutive SPKs performed between 1985 and 2007. Bladder drainage was used in 390 patients and enteric drainage in 610 patients. In 362 patients, SPK transplantation was performed before initiation of dialysis. RESULTS: Patient survival at 1, 10, and 20 years is 97%, 80%, and 58%; kidney survival is 91%, 63%, and 38%; and pancreas survival is 88%, 63%, and 36%, respectively. There was no difference (P > 0.19) for patient, kidney, and pancreas survival between bladder and enteric drainage. Major surgical complications for bladder-drained patients were anastomotic leaks, urological complications, and infections. For enteric-drained patients, major surgical complications were infection, bleeding, and enzyme leak. Principal causes of death were myocardial infarction (n = 23), cerebrovascular accident (n = 18), and renal failure (n = 15). Graft failure for the kidney was due to acute rejection (n = 48), chronic rejection (n = 146), and death with a functioning graft (n = 99). Graft failure for the pancreas was caused by chronic graft loss (n = 44), thrombosis (n = 31), rejection (n = 80), and death with a functioning graft (n = 125). A total of 113 patients were retransplanted with either living related or unrelated donor kidneys (n = 64) or deceased donor kidneys (n = 42). Survival for retransplanted kidneys is 84% at 1 year and 68% at 5 years. Surviving bladder-drained patients underwent enteric conversion (>50%) for severe recalcitrant metabolic or urologic complications, most commonly enzyme leaks, hematuria, and recurrent urinary tract infection. CONCLUSIONS: Diabetic patients with end-stage renal failure have a poor prognosis without transplantation. Transplantation with SPK provides a marked extension of the patient's life and freedom from insulin injections. Enteric drainage is currently the surgical technique of choice. SPK transplantation should be considered the treatment of choice in this patient population.","author":[{"dropping-particle":"","family":"Sollinger","given":"Hans W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Odorico","given":"Jon S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Becker","given":"Yolanda T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Alessandro","given":"Anthony M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pirsch","given":"John D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Surgery","id":"ITEM-2","issue":"4","issued":{"date-parts":[["2009"]]},"page":"618-629","title":"One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up","type":"article-journal","volume":"250"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1111/tri.12218","ISBN":"0934-0874","ISSN":"09340874","PMID":"24138318","abstract":"The risk of death within the first year postkidney transplantation is not well described in the contemporary era. We extracted data on all kidney transplant procedures performed in England between April 2001 and March 2012. Data linkage analysis was performed between Hospital Episode Statistics and the Office for National Statistics to identify all deaths. Cox proportional hazard models were performed to identify factors associated with 1-year mortality. 566 deaths (3.0%) occurred within the first year post-transplant (from 19 103 kidney transplant procedures analysed). Infection, cardiovascular events and malignancy were classified in 21.6%, 18.3% and 7.4% of death certificates, respectively. Among recipients with prior myocardial infarct history who died within the first year, 38.8% of deaths were attributed to a cardiac-related event. Malignancy-related death was responsible for 61.5% of 1-year mortality for allograft recipients with pretransplant cancer history. 22.1% of deaths included kidney failure as a contributory factor on the death certificate (3.3% specifically stated allograft failure). Variables associated with 1-year mortality included deceased-donor kidney, increasing age, residence in socioeconomically deprived area and history of select medical comorbidities pre-operatively. We conclude 1-year mortality postkidney transplantation is low, but in select allograft recipients, the risk of death increases considerably.","author":[{"dropping-particle":"","family":"Farrugia","given":"Daniela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cheshire","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Begaj","given":"Irena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khosla","given":"Sajan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ray","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sharif","given":"Adnan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplant International","id":"ITEM-3","issue":"3","issued":{"date-parts":[["2014"]]},"page":"262-270","title":"Death within the first year after kidney transplantation - An observational cohort study","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"(8,9,38)","plainTextFormattedCitation":"(8,9,38)","previouslyFormattedCitation":"^8,9,38"},"properties":{"noteIndex":0},"schema":""}(8,9,38). Non-fatal MACEs increase mortality risk and this is likely to be reflected in our findings given that we included DWFG in our analyses ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1399-0012.2004.00173.x","ISSN":"09020063","PMID":"15233812","abstract":"The objective of this study was to evaluate the outcome of simultaneous pancreas and kidney transplantation (SPK) with focus on cardiovascular mortality and morbidity in relation to graft function. From January 1985 through 1999, 87 SPK were performed in the unit. Sixty recipients were males, median age at diabetes onset 13 yr (1-40) and age at transplantation 39 yr (29-54). No case was lost to follow-up. Morbidity and mortality during median 8 yr of follow-up (range 1-15 yr) were recorded. Major macrovascular disease (MVD) was defined as myocardial infarction or sudden death (AMI), stroke or peripheral gangrene requiring amputation of leg, foot or fingers. At the evaluation, 26 of 87 patients (30%) had died, 19 after loss of the pancreas graft and 20 after loss of the kidney. MVD was the dominant cause of death. Non-lethal MVD had previously been recorded in 62%. Of the 61 patients alive, 22 had lost their pancreas graft and 12 the concomitant kidney. MVD had occurred in 32%. Whereas 89% of the concomitant kidneys functioned when the pancreas graft did so, only 37% of the kidneys functioned if the pancreas had been lost, p < 0.0001. The mortality rate was significantly higher among patients who lost both grafts (16/26 than in those who lost only the pancreas graft (3/15), p = 0.01. Progressive MVD is a major clinical problem for SPK transplant patients, particularly if the kidney fails. Blackwell Munksgaard, 2004","author":[{"dropping-particle":"","family":"Nordén","given":"Gunnela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carlstr?m","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wramner","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nyberg","given":"Gudrun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Norden","given":"Gunnela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carlstrom","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wramner","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nyberg","given":"Gudrun","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Transplantation","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2004","8"]]},"language":"eng","page":"372-376","publisher-place":"Denmark","title":"Macrovascular disease after simultaneous pancreas and kidney transplantation","type":"article-journal","volume":"18"},"uris":[""]}],"mendeley":{"formattedCitation":"(39)","plainTextFormattedCitation":"(39)","previouslyFormattedCitation":"(39)"},"properties":{"noteIndex":0},"schema":""}(39). However, SPKT recipients experiencing events are likely to have abnormal levels of modifiable CVD risk factors, such as blood pressure and lipid profile, which may also influence allograft outcomes ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.transproceed.2013.02.087","ISBN":"0041-1345","ISSN":"00411345","PMID":"23622626","abstract":"Cardiovascular and cerebrovascular disease (CCVD) are major causes of morbidity and mortality among patients with diabetes. Strict control of treatable risk factors that contribute to atherosclerosis is important to reduce the risk of stroke, myocardial infarction, and peripheral arterial disease. Simultaneous pancreas-kidney transplantation (SPKT) may significantly improve these risk factors in patients with type 1 diabetes. We studied 103 SPKT from our center with both organs functioning for metabolic and hypertensive control; body mass index (BMI); immunosuppression; and CCVD events. The 53 females/50 males showed a mean age of 35 ± 6 years, diabetes for 24 ± 6 years, and on dialysis for 31 ± 23 months. The follow-up ranged from 6-142 months. Mean value of last creatinine clearance was 76 ± 24 mL/min, all 103 SPKT were insulin-independent with mean glycemia = 81 ± 10 mg/dL and hemoglobin A1c (HbA1c) = 5.3% ± 0.4%. All of them were under tacrolimus treatment; 9.7% also with sirolimus but 67% steroid-free. According to the National Cholesterol Education Program Adult Treatment Panel 3 criteria, 4 patients showed a fasting glucose > 100 mg/dL; only one, HbA1c > 5.6%. Hypertension was recorded in 38.5%; low high-density lipoprotein cholesterol in 19.4%; hypertriglyceridemia in 7.8%; BMI > 30% in only 2 patients; 21.4% were prescribed statins. We registered cardiovascular events in 7 patients (6.8%). Patients with steroid treatment showed higher triglycerides (122 ± 53 vs 90 ± 36 mg/dL; P =.001) and more often tended to be hypertensive (41.2% vs 37.7%, P =.073) compared with those free of these drugs. Hypertension was associated with an higher BMI (24.1 ± 2.8 vs 22.3 ± 2.9 kg/m2, P =.002). BMI > 25% was associated with higher total cholesterol (195 ± 47 vs 169 ± 28 mg/dL, P =.015) and low-density lipoprotein cholesterol (116 ± 40 vs 96 ± 27 mg/dL, P =.003). Among our SPKT the prevalences of CCVD and metabolic syndrome were low. Hypertension was the most frequent single factor. Obesity was rare. In patients on steroids, hypertriglyceridemia was more prevalent and hypertension tended to be more frequent. Hypertensive patients showed a higher BMI, which correlated with a worse lipid profile. Steroid withdrawal, whenever possible, may be important to achieve metabolic goals and minimize cardiovascular risk. ? 2013 Elsevier Inc.","author":[{"dropping-particle":"","family":"Martins","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fonseca","given":"I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dias","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Malheiro","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rocha","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Azevedo","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silva","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Almeida","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henriques","given":"A. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davide","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cabrita","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Transplantation Proceedings","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2013"]]},"page":"1063-1065","publisher":"Elsevier Inc.","title":"Cardiovascular risk factors and events in pancreas-kidney transplants","type":"article-journal","volume":"45"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1371/journal.pone.0160607","ISSN":"19326203","PMID":"27501048","author":[{"dropping-particle":"","family":"An","given":"Jung Nam","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahn","given":"Song Vogue","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Jung Pyo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bae","given":"Eunjin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kang","given":"Eunjeong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Hack Lyoung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Yong Jin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oh","given":"Yun Kyu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Yon Su","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Young Hoon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"Chun Soo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-2","issue":"8","issued":{"date-parts":[["2016"]]},"page":"1-12","title":"Pre-transplant cardiovascular risk factors affect kidney allograft survival: A multi-center study in Korea","type":"article-journal","volume":"11"},"uris":[""]}],"mendeley":{"formattedCitation":"(16,39)","plainTextFormattedCitation":"(16,39)","previouslyFormattedCitation":"^16,39"},"properties":{"noteIndex":0},"schema":""}(16,39). The relationship we report is important as CVD risk is modifiable and continued efforts should be made to minimise this following transplantation. In our local experience, CVD events in SPKT recipients are often managed in non-transplant centres. This is likely the case across the UK as pancreas transplantation takes place in a small number of centres. We suggest that SPKT recipients experiencing events are transferred to transplant centres to receive joint cardiology and transplant team treatment; ensuring transplant factors such as immunosuppression are optimised during the CVD episode.4.4Prior studies in relation to the local cohortWe demonstrate a relationship between renal replacement therapy (RRT) and worse MACE outcomes. However, the relationship between RRT and MACE was not observed in the national dataset, which is likely to be the more robust analysis considering the relative sample sizes. We did not observe significant relationships between individual modifiable CVD risk factors and outcome events, with only the HR for total cholesterol/HDL ratio approaching significance. We speculate that the modest sample size accounts for this, as these factors are validated predictors of CVD outcomes in large cohort studies ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/bmj.39609.449676.25","ISBN":"0959-8146","ISSN":"0959-8138","PMID":"18573856","abstract":"OBJECTIVE: To develop and validate version two of the QRISK cardiovascular disease risk algorithm (QRISK2) to provide accurate estimates of cardiovascular risk in patients from different ethnic groups in England and Wales and to compare its performance with the modified version of Framingham score recommended by the National Institute for Health and Clinical Excellence (NICE). DESIGN: Prospective open cohort study with routinely collected data from general practice, 1 January 1993 to 31 March 2008. SETTING: 531 practices in England and Wales contributing to the national QRESEARCH database. PARTICIPANTS: 2.3 million patients aged 35-74 (over 16 million person years) with 140,000 cardiovascular events. Overall population (derivation and validation cohorts) comprised 2.22 million people who were white or whose ethnic group was not recorded, 22,013 south Asian, 11,595 black African, 10,402 black Caribbean, and 19,792 from Chinese or other Asian or other ethnic groups. MAIN OUTCOME MEASURES: First (incident) diagnosis of cardiovascular disease (coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records or linked Office for National Statistics death certificates. Risk factors included self assigned ethnicity, age, sex, smoking status, systolic blood pressure, ratio of total serum cholesterol:high density lipoprotein cholesterol, body mass index, family history of coronary heart disease in first degree relative under 60 years, Townsend deprivation score, treated hypertension, type 2 diabetes, renal disease, atrial fibrillation, and rheumatoid arthritis. RESULTS: The validation statistics indicated that QRISK2 had improved discrimination and calibration compared with the modified Framingham score. The QRISK2 algorithm explained 43% of the variation in women and 38% in men compared with 39% and 35%, respectively, by the modified Framingham score. Of the 112,156 patients classified as high risk (that is, >or=20% risk over 10 years) by the modified Framingham score, 46,094 (41.1%) would be reclassified at low risk with QRISK2. The 10 year observed risk among these reclassified patients was 16.6% (95% confidence interval 16.1% to 17.0%)-that is, below the 20% treatment threshold. Of the 78 024 patients classified at high risk on QRISK2, 11,962 (15.3%) would be reclassified at low risk by the modified Framingham score. The 10 year observed risk among these patients was 23.3% (22.2% to 24.4%)-that is, above the 20% threshold.…","author":[{"dropping-particle":"","family":"Hippisley-Cox","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Coupland","given":"Carol","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vinogradova","given":"Yana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robson","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Minhas","given":"Rubin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sheikh","given":"Aziz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brindle","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Bmj","id":"ITEM-1","issue":"7659","issued":{"date-parts":[["2008"]]},"page":"1475-1482","title":"Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2.","type":"article-journal","volume":"336"},"uris":[""]}],"mendeley":{"formattedCitation":"(10)","plainTextFormattedCitation":"(10)","previouslyFormattedCitation":"¹⁰"},"properties":{"noteIndex":0},"schema":""}(10).Each 1% increment in the QRISK2? score conferred an additional 4% increase in the risk for MACE following SPKT, and demonstrated acceptable discrimination (AUC = 0.715). However, 64.6% had a QRISK2? ≥20%, but did not experience a MACE, raising concerns about the specificity of using a 20% threshold in this cohort. Our follow-up period was 5.7 years, whereas QRISK2? was designed to predict 10-year CVD risk partly explaining this finding. We suggest that the QRISK2? score is validated in the national cohort to determine a better threshold. We believe that QRISK2? may facilitate the identification of individuals that might benefit from enhanced cardiovascular investigation prior to listing, risk factor modification, or alternative transplant pathways such as LDKT or simultaneous islet and kidney transplantation.We observed that only 74.0% of patients meeting National Institute for Health and Care Excellence (NICE) criteria for antihypertensive treatment (SBP≥130mmHg) were receiving any ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISBN":"978-1-4731-1389-3","abstract":"The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The application of the recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian. Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties. Type 1 diabetes in adults: diagnosis and management (NG17)","author":[{"dropping-particle":"","family":"National Institute for Health and Care Excellence (NICE)","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Type 1 diabetes in adults: diagnosis and management","id":"ITEM-1","issue":"August","issued":{"date-parts":[["2015"]]},"page":"1-86","title":"Type 1 diabetes in adults : diagnosis and management","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(40)","plainTextFormattedCitation":"(40)","previouslyFormattedCitation":"⁴⁰"},"properties":{"noteIndex":0},"schema":""}(40). Furthermore, only 49.3% of those meeting NICE criteria for lipid management and only 53.7% of those with a QRISK2? score ≥ 20% were receiving lipid lowering treatment. Our findings suggest that local SPKT recipients are receiving sub-optimal risk factor management whilst awaiting transplantation, and this needs urgent attention for patient benefit.4.5Strengths and limitationsThis study has several strengths based on the comprehensive nature of the data. It augments the national transplant registry with ONS mortality data. As with most registry data sets, there are some limitations, which include the absence of markers of cardiac function, and modifiable CVD risk factor data in the national cohort. The frequency of annual follow up data returned to NHSBT varies from 90-100%/year, and only allograft failure and death are separately validated ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2018","9","4"]]},"author":[{"dropping-particle":"","family":"National Health Service Blood and Transplant","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"Annual Reports on Pancreas and Islet Transplantation","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(11)","plainTextFormattedCitation":"(11)","previouslyFormattedCitation":"¹¹"},"properties":{"noteIndex":0},"schema":""}(11). Therefore, our report likely underestimates the rate of non-fatal MACEs. When compared with outcome data for the local Manchester subgroup, the UKTR outcomes were accurate in 92% of cases. The local subgroup had a modest sample size/event number, which limited the ability to perform multivariable modelling. While the subgroup had similar age, ethnicity and gender to the entire national cohort; a larger proportion had history of MI and were receiving dialysis at baseline, and may not be representative of the full UKTR cohort. Due to the UK selection criteria for SPKT, we had a limited range of BMIs. It is unlikely that this affected the performance of QRISK2? in our cohort, as QRISK2? was developed using BMI as a continuous variable ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/bmj.39609.449676.25","ISBN":"0959-8146","ISSN":"0959-8138","PMID":"18573856","abstract":"OBJECTIVE: To develop and validate version two of the QRISK cardiovascular disease risk algorithm (QRISK2) to provide accurate estimates of cardiovascular risk in patients from different ethnic groups in England and Wales and to compare its performance with the modified version of Framingham score recommended by the National Institute for Health and Clinical Excellence (NICE). DESIGN: Prospective open cohort study with routinely collected data from general practice, 1 January 1993 to 31 March 2008. SETTING: 531 practices in England and Wales contributing to the national QRESEARCH database. PARTICIPANTS: 2.3 million patients aged 35-74 (over 16 million person years) with 140,000 cardiovascular events. Overall population (derivation and validation cohorts) comprised 2.22 million people who were white or whose ethnic group was not recorded, 22,013 south Asian, 11,595 black African, 10,402 black Caribbean, and 19,792 from Chinese or other Asian or other ethnic groups. MAIN OUTCOME MEASURES: First (incident) diagnosis of cardiovascular disease (coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records or linked Office for National Statistics death certificates. Risk factors included self assigned ethnicity, age, sex, smoking status, systolic blood pressure, ratio of total serum cholesterol:high density lipoprotein cholesterol, body mass index, family history of coronary heart disease in first degree relative under 60 years, Townsend deprivation score, treated hypertension, type 2 diabetes, renal disease, atrial fibrillation, and rheumatoid arthritis. RESULTS: The validation statistics indicated that QRISK2 had improved discrimination and calibration compared with the modified Framingham score. The QRISK2 algorithm explained 43% of the variation in women and 38% in men compared with 39% and 35%, respectively, by the modified Framingham score. Of the 112,156 patients classified as high risk (that is, >or=20% risk over 10 years) by the modified Framingham score, 46,094 (41.1%) would be reclassified at low risk with QRISK2. The 10 year observed risk among these reclassified patients was 16.6% (95% confidence interval 16.1% to 17.0%)-that is, below the 20% treatment threshold. Of the 78 024 patients classified at high risk on QRISK2, 11,962 (15.3%) would be reclassified at low risk by the modified Framingham score. The 10 year observed risk among these patients was 23.3% (22.2% to 24.4%)-that is, above the 20% threshold.…","author":[{"dropping-particle":"","family":"Hippisley-Cox","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Coupland","given":"Carol","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vinogradova","given":"Yana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robson","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Minhas","given":"Rubin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sheikh","given":"Aziz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brindle","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Bmj","id":"ITEM-1","issue":"7659","issued":{"date-parts":[["2008"]]},"page":"1475-1482","title":"Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2.","type":"article-journal","volume":"336"},"uris":[""]}],"mendeley":{"formattedCitation":"(10)","plainTextFormattedCitation":"(10)","previouslyFormattedCitation":"¹⁰"},"properties":{"noteIndex":0},"schema":""}(10). Finally, the UK SPKT population is unique and our findings may not apply to other populations.4.6Clinical implicationsThis study has several clinical implications, including that these patients have a high risk for fatal and non-fatal CVD events. A non-fatal cardiovascular event following transplantation significantly increases the risk of subsequent allograft failure, suggesting that those experiencing events should be jointly managed by cardiology and transplant teams, preferably at transplant centres. In so doing, allograft factors can be optimised whilst receiving CVD investigations or treatment. In Data on modifiable risk factors are not recorded into the UKTR. However, in our local cohort we report that the QRISK2? score predicted MACE, suggesting that it may be of clinical use to identify potential SPKT recipients who might benefit especially from more active management of CVD risk factors or who could be offered alternative innovative treatment pathways such as simultaneous islet and kidney transplantation. These findings also highlight an opportunity to expand the national dataset to include information on modifiable CVD risk factors, as currently these data are not collected and some patients may not have adequate risk factor control, as we report in our local cohort. Efforts to further reduce the use of prednisolone based maintenance immunosuppression should be continued. Finally, it may be beneficial that organs from hypertensive donors are matched to recipients with lower risk of hypertension to minimise future CVD risk.AcknowledgementsClaire Counter and Joanna Bunnett, Department of Statistics, NHS Blood and Transplant.Dr Miller is funded by a Clinician Scientist Award (CS-2015-15-003) from the National Institute for Health Research, UK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, NHSBT, the Office for National Statistics, the National Institute for Health Research or the Department of Health.Author contributions and transparency statementThe study was designed by PY, AS, JN, MKR and DvD. PY, SCG, HK, ZM and IS participated in acquisition of data for the national and local cohorts. PY, AS and CF analysed the data. PY, AS, MKR, TA, CM and DvD interpreted the data. PY wrote the manuscript and all co-authors reviewed and edited the manuscript, before approving its submission. PY is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.As guarantor of this work PY affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.DisclosuresThe authors of this manuscript have the following conflicts of interest to declare:MKR has acted as a consultant for GSK, Novo Nordisk, Roche Diabetes Care and MSD, and also participated in advisory board meetings on their behalf. MKR has received lecture fees from MSD and grant support from Novo Nordisk, MSD and GSK. MKR owns stocks in GSK. All of the aforementioned relationships are unrelated to this study and manuscript.CM has received a research grant from Guerbet and research support from Roche. These relationships are unrelated to this study and manuscript.The following authors have no conflicts of interest to declare:PY, AS, SCG, CF, HK, ZM, IS, JN, TA and DVD have not received any support from any organisation for the submitted work; have no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could have influenced the submitted work.Ethical approvalNo ethical approval was required for this study as only restricted data were requested in accordance with NHSBT data access policy available at per the NHS Code of Practice on Confidentiality and in accordance with the Declaration of Helsinki (), NHSBT prospectively obtain informed consent from transplant candidates for inclusion of their data in the United Kingdom Transplant Registry database. Informed consent is also obtained by NHSBT for the use of restricted data (non-identifiable data) by third parties for the purpose of transplant related research.PY is an approved researcher with the Office for National Statistics:Approved researcher number: ONSF20308Valid until 23/6/22Data sharing statementThe data presented herewith were provided by NHSBT and the ONS. Individuals wishing to access the raw data would require proof of permission from NHSBT and the ONS. Data sharing will only take place upon receipt of verified permission from NHSBT and the ONS. Patient and public involvementThis research was done without patient involvement. Patients were not invited to comment on the study design and were not consulted to develop patient relevant outcomes or interpret the results. Patients were not invited to contribute to the writing or editing of this document for readability or accuracy.Previous communicationsPresented in abstract form at the American Transplant Congress June 2018, Seattle, Washington, United States of America.Licence statementThe Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from the Contribution to third party material where-ever it may be located; and, vi) licence any third party to do any or all of the above. 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POLICY POL185/4 Pancreas Transplantation: Patient Selection.; 2016. . Humar A, Ramcharan T, Kandaswamy R, Gruessner RWG, Gruessner AC, Sutherland DER. Technical failures after pancreas transplants: why grafts fail and the risk factors--a multivariate analysis. Transplantation. 2004;78(8):1188-1192.33. Souverein PC, Berard A, Van Staa TP, et al. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study. Heart. 2004;90(8):859-865. doi:10.1136/hrt.2003.020180.34. de Jager DJ, Grootendorst DC, Jager KJ, et al. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA. 2009;302(16):1782-1789. doi:10.1001/jama.2009.1488.35. Guidi E, Menghetti D, Milani S, Montagnino G, Palazzi P, Bianchi G. Hypertension may be transplanted with the kidney in humans: a long-term historical prospective follow-up of recipients grafted with kidneys coming from donors with or without hypertension in their families. 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Type 1 diabetes in adults?: diagnosis and management. Type 1 diabetes adults diagnosis Manag. 2015;(August):1-86.All UKTR SPKT recipientsManchester SPKT subgroupn=1699n=306CharacteristicMACE No MACE P-valueMACE No MACE P-value(133 [7.8%])(1566 [92.2%])(23 [7.5%])(283 [92.5%])Recipient factorsAge at transplant, years (SD)43.1 (8.4)41.5 (8.3)0.03447.5 (7.8)41.0 (9.2)0.008Male79 (59.4%)920 (58.7%)0.88412 (52.2%)172 (60.8%)0.418Non-white ethnicity8 (6.0%)117 (7.5%)0.6334 (17.4%)19 (6.7%)0.082Body mass index, kg/m225.0 (22.3-27.4)24.6 (22.1-27.2)0.92026.2 (22-27)24.8 (22-27)0.491Tobacco smoke exposure57 (42.8%)615 (39.3%)0.5613 (13.0%)34 (12.0%)0.748Unemployed64 (48.1%)675 (43.1%)0.371NANARegistered blind18 (13.5%)136 (8.7%)0.0653 (13.0%)36 (12.7%)1.000RetinopathyNANA20 (87.0%)238 (84.1%)1.000Myocardial Infarction13 (9.8%)44 (2.9%)<0.0018 (34.8%)30 (10.6%)0.001Stroke9 (6.8%)49 (3.2%)0.0432 (8.7%)13 (4.6%)0.313Amputation12 (9.0%)81 (5.2%)0.0723 (13.0%)15 (5.3%)0.136Peripheral vascular diseaseNANA3 (13.0%)32 (11.3%)0.736Peripheral neuropathyNANA14 (60.9%)139 (49.1%)0.386Autonomic neuropathyNANA10 (43.5%)95 (33.5%)0.365Antihypertensive treatmentNANA2119 (91.382.6%)2024 (712.41%)0.04974Systolic blood pressure, mmHgNANA154 (120-163)143 (123-158)0.901Total cholesterol/HDL ratioNANA3.0 (2.3-4.9)2.8 (2.1-4.0)0.217Lipid lowering treatmentNANA10 (43.5%)141 (49.8%)0.069Antiplatelet treatmentNANA12 (52.2%)97 (34.3%)0.006Duration of diabetes, years (SD)NANA25.5 (8.2)25.8 (8.3)0.869Number receiving dialysis at listing67 (50.4%)893 (57.0%)0.38317 (73.9%)176 (62.3%)0.369Number receiving dialysis at transplant82 (61.6%)1087 (69.4%)0.28621 (91.3%)207 (73.1%)0.078-Haemodialysis48 (36.1%)628 (40.1%)6 (26.1%)109 (38.5%)-Peritoneal dialysis33 (24.8%)456 (29.1%)0.53115 (65.2%)98 (34.6%)0.011QRISK2? score, %NANA35.2 (28-48)24.4 (16-36)0.001QRISK2? ≥ 20%NANA22 (95.7%)183 (64.6%)0.002Donor factorsAge35 (23-44)36 (23-45)0.87134 (24-42)34 (21-43)0.989Donation after cardiac death6 (4.5%)222 (14.2%)0.0020 (0.0%)29 (10.2%)0.144Expanded criteria kidney1 (0.8%)73 (4.7%)0.0260 (0.0%)10 (3.5%)1.000Hypertension18 (13.5%)123 (7.9%)0.0330 (0.0%)8 (2.8%)1.000Transplant factorsWaiting time, months10.0 (3.8-25.1)12.5 (4.8-20.8)0.84910.0 (6.6-23.6)15.5 (4.4-20.8)0.138Year of transplant2006 (2004-2010)2010 (2007-2013)<0.0012005 (2004-2008)2010 (2007-2012)<0.001Cold ischaemia time, hours12.6 (10.5-15.0)11.6 (9.7-13.8)0.00214.0 (12.8-15.7)13.0 (10.3-15.1)0.102HLA mismatch group 4**80 (60.2%)968 (61.8%)0.51310 (43.5%)79 (27.9%)0.696ImmunosuppressionAlemtuzumab 52 (39.1%)842 (53.8%)0.0033 (13.0%)147 (51.9%)<0.001Basiliximab56 (42.1%)555 (35.4%)0.05620 (87.0%)136 (48.1%)<0.001Prednisolone85 (63.9%)691 (44.1%)<0.00119 (82.6%)129 (45.6%)0.001Table 1 – Recipient and donor characteristics in United Kingdom Transplant Registry SPKT recipients and the Manchester subgroup by MACE outcome.NA = not available*Human leukocyte antigen (HLA) mismatch group 4 = (1DR + 2B) or (2DR) mismatchesAll UKTR SPKT recipients Manchester SPKT subgroup (n=1699)(n=306)PredictorHR (95% CI)p-valueHR (95%CI)p-valueRecipientAge1.03 (1.01-1.05)0.0041.07 (1.02-1.1)0.005Body mass index, kg/m21.0 (0.9-1.1)0.7991.03 (0.9-1.2)0.645Prior myocardial infarction3.5 (2.0-6.1)<0.0014.0 (1.7-9.4)0.002Prior stroke2.4 (1.2-4.7)0.0122.4 (0.6-10.4)0.229Prior amputation2.0 (1.1-3.7)0.0192.8 (0.8-9.4)0.104Prior peripheral artery disease-0.99 (0.3-3.3)0.986Registered blind1.5 (0.9-2.5)0.0911.09 (0.3-3.7)0.892Retinopathy-1.2 (0.4-4.1)0.747Antihypertensive treatment-3.88.3 (0.9-16.11.1-62.5)0.07341Systolic blood pressure, mmHg-0.99 (0.98-1.02)0.799Total cholesterol/HDL ratio-1.3 (0.99-1.6)0.053Lipid lowering treatment-1.2 (0.5-3.4)0.668Antiplatelet treatment-4.4 (1.4-13.7)0.010Total cholesterol/HDL ratio > 4-2.4 (0.97-6.0)0.059Renal replacement therapy0.9 (0.6-1.3)0.4573.9 (0.9-16.6)0.067Haemodialysis*1.0 (0.6-1.4)0.8072.4 (0.5-11.8)0.289Peritoneal dialysis*0.8 (0.5-1.2)0.2575.2 (1.2-22.7)0.029Duration of diabetes, years-1.0 (0.95-1.05)0.995QRISK2? score, %-1.04 (1.02-1.06)<0.001QRISK2? ≥ 20%-11.4 (1.5-84.6)0.017TransplantWaiting time, months1.01 (0.999-1.02)0.0760.99 (0.96-1.02)0.537HLA group1.0 (0.7-1.2)0.7231.2 (0.5-2.9)0.655Cold ischaemia time, hours1.06 (1.002-1.1)0.0421.1 (0.9-1.2)0.288Year of transplant, year0.9 (0.8-0.9)<0.0010.8 (0.7-0.9)0.004Donor history of hypertension2.0 (1.2-3.2)0.0084.6 (0-4713)0.668ImmunosuppressionAlemtuzumab0.7 (0.5-1.1)0.1080.2 (0.1-0.8)0.024Prednisolone1.8 (1.2-2.5)0.0023.4 (1.1-10.2)0.032Table 2 - Univariable hazard ratios (95% CI) for predictors of MACE in the United Kingdom Transplant Registry SPKT recipients and the Manchester-based subgroup of SPKT recipients using variables at measured at baseline. The QRISK2 score assesses the ten-year risk of a cardiovascular event based on several cardiovascular risk factors measured at baseline; a risk >10% is considered high-risk and a risk >20% is considered to be very high-risk. Data are HR (95%CI) from Cox regression. *Predialysis as reference categoryPredictorHR (95% CI)p-valueRecipientAge, years1.04 (1.01-1.07)0.0022Prior myocardial infarction2.6 (1.3-5.0)0.006Prior stroke2.3 (1.2-4.7)0.018Prior amputation2.0 (1.023-3.78)0.0442Registered blind1.5 (0.9-2.56)0.13621TransplantWaiting time, months1.02 (1.0001-1.03)0.0460Donor history of hypertension1.8 (1.054-3.2)0.0345Cold ischaemia time, hours1.0 (0.956-1.067)0.847711Year of transplant, year0.9 (0.8-0.9)<0.001Prednisolone1.1 (0.7-1.8)0.544Table 3 – Multivariable-adjusted hazard ratios (95% CI) for predictors of MACE in United Kingdom Transplant Registry SPKT recipients at baseline. Data are HR (95%CI) from Cox regressionPredictorUnivariable HR (95% CI)p-valueAdjusted HR*(95% CI)p-valueAge, years1.06 (1.03-1.09)<0.001-Prior myocardial infarction4.9(2.5-9.6)<0.001-Prior stroke3.2 (1.4-7.5)0.006-Prior amputation3.1 (1.6-6.3)0.001-Unemployed 1.4 (1.06-6.3)0.0201.8 (1.03-3.2)0.041Donor history of hypertension2.4 (1.3-4.5)0.0062.2 (1.2-4.2)0.012Registered blind1.8 (0.98-3.3)0.0561.9 (1.02-3.6)0.042Year of transplant, year0.99 (0.91-1.07)0.729-Prednisolone1.3 (0.8-2.0)0.3611.3 (0.8-2.1)0.358Table 4 – Univariable and multivariable-adjusted hazard ratios (95% CI) for predictors of cardiovascular death in United Kingdom Transplant Registry SPKT recipients. Data are HR (95%CI) from Cox regression*Adjusting for age, prior MI, stroke and amputationENDS ................
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