UPDATES IN HARRISON 18TH EDITION



UPDATES IN HARRISON 18TH EDITION

UPDATES IN NEPHROLOGY

|Table 277-1 Inherited Disorders Affecting Renal Tubular Ion and Solute Transport |

| |

|Disease or Syndrome |

|Gene |

|OMIM* |

| |

|Disorders Involving the Proximal Tubule  |

| |

|Proximal renal tubular acidosis |

|Sodium bicarbonate cotransporter |

|(SLC4A4, 4q21) |

|604278 |

| |

|Fanconi-Bickel syndrome |

|Glucose transporter, GLUT2 |

|(SLC2A2, 3q26.2) |

|227810 |

| |

|Isolated renal glycosuria |

|Sodium glucose cotransporter |

|(SLC5A2, 16p11.2) |

|233100 |

| |

|Cystinuria |

|  |

|  |

| |

|  Type I |

|Cystine, dibasic and neutral amino acid transporter |

|(SLC3A1, 2p16.3) |

|220100 |

| |

|  Nontype I |

|Amino acid transporter, light subunit |

|(SLC7A9, 19q13.1) |

|600918 |

| |

|Lysinuric protein intolerance |

|Amino acid transporter (SLC7A7, 4q11.2)  |

|222700 |

| |

|Hartnup disorder |

|Neutral amino acid transporter |

|(SLC6A19, 5p15.33) |

|34500 |

| |

|Hereditary hypophosphatemic rickets with hypercalcemia |

|Sodium phosphate cotransporter |

|(SLC34A3, 9q34) |

|241530 |

| |

|Renal hypouricemia |

|  |

|  |

| |

|  Type 1 |

|Urate-anion exchanger |

|(SLC22A12, 11q13) |

|220150 |

| |

|  Type 2 |

|Urate transporter, GLUT9 |

|(SLC2A9, 4p16.1) |

|612076 |

| |

|Dent's disease |

|Chloride channel, ClC-5 |

|(CLCN5, Xp11.22) |

|300009 |

| |

|X-linked recessive nephrolithiasis with renal failure |

|Chloride channel, ClC-5 |

|(CLCN5, Xp11.22) |

|310468 |

| |

|X-linked recessive hypophosphatemic rickets |

|Chloride channel, ClC-5 |

|(CLCN5, Xp11.22) |

|307800 |

| |

|Disorders Involving the Loop of Henle  |

| |

|Bartter's syndrome |

|  |

|  |

| |

|  Type 1 |

|Sodium, potassium chloride cotransporter |

|(SLC12A1, 15q21.1) |

|241200 |

| |

|  Type 2 |

|Potassium channel, ROMK |

|(KCNJ1, 11q24) |

|601678 |

| |

|  Type 3 |

|Chloride channel, ClC-Kb |

|(CLCNKB, 1p36) |

|602023 |

| |

|with sensorineural deafness |

|Chloride channel accessory subunit, Barttin |

|(BSND, 1p31) |

|602522 |

| |

|Autosomal dominant hypocalcemia with Bartter-like syndrome |

|Calcium-sensing receptor |

|(CASR, 3q13.33)) |

|601199 |

| |

|Familial hypocalciuric hypercalcemia |

|Calcium-sensing receptor |

|(CASR, 3q13.33) |

|145980 |

| |

|Primary hypomagnesemia |

|Claudin-16 or paracellin-1 |

|(CLDN16 or PCLN1, 3q27) |

|248250 |

| |

|Isolated renal magnesium loss |

|Sodium potassium ATPase, 1-subunit |

|(ATP1G1, 11q23) |

|154020 |

| |

|Disorders Involving the Distal Tubule and Collecting Duct  |

| |

|Gitelman's syndrome |

|Sodium chloride cotransporter |

|(SLC12A3, 16q13) |

|263800 |

| |

|Primary hypomagnesemia with secondary hypocalcemia |

|Melastatin-related transient receptor potential cation channel 6 |

|(TRPM6, 9q22) |

|602014 |

| |

|Pseudoaldosteronism (Liddle's syndrome) |

|Epithelial sodium channel and subunits |

|(SCNN1B, SCNN1G, 16p12.1) |

|177200 |

| |

|Recessive pseudohypoaldosteronism Type 1 |

|Epithelial sodium channel, , , and subunits |

|(SCNN1A, 12p13; SCNN1B, SCNN1G, 16pp12.1) |

|264350 |

| |

|Pseudohypoaldosteronism Type 2 (Gordon's hyperkalemia-hypertension syndrome) |

|Kinases WNK-1, WNK-4 |

|(WNK1, 12p13; WNK4, 17q21.31) |

|145260 |

| |

|X-linked nephrogenic diabetes insipidus |

|Vasopressin V2 receptor (AVPR2, Xq28) |

|304800 |

| |

|Nephrogenic diabetes insipidus (autosomal) |

|Water channel, aquaporin-2 |

|(AQP2, 12q13) |

|125800 |

| |

|Distal renal tubular acidosis |

|  |

|  |

| |

|  autosomal dominant |

|Anion exchanger-1 |

|(SLC4A1, 17q21.31) |

|179800 |

| |

|  autosomal recessive |

|Anion exchanger-1 |

|(SLC4A1, 17q21.31) |

|602722 |

| |

|  with neural deafness |

|Proton ATPase, 1 subunit |

|(ATP6V1B1, 2p13.3) |

|192132 |

| |

|  with normal hearing |

|Proton ATPase, 116-kD subunit |

|(ATP6V0A4, 7q34) |

|602722 |

| |

|*Online Mendelian Inheritance in Man database (). |

|Table 279-2 Biomarkers of Acute Kidney Injury |

| |

|Biomarker |

|Comments |

|Detection |

|Species |

| |

|Alanine aminopeptidase (AAP) |

|1. Proximal tubule brush border enzyme |

|2. Instability may limit clinical utility |

|Colorimetry |

|Rat, dog, human |

| |

|Alkaline phosphatase (AP) |

|1. Proximal tubule brush border enzyme. Human intestinal alkaline phosphatase is specific for proximal tubular S3 segment; human |

|tissue nonspecific alkaline phosphatase is specific for S1 and S2 segments |

|2. Levels may not correlate with extent of functional injury |

|3. Instability may limit clinical utility |

|Colorimetry |

|Rat, human |

| |

|Alpha -Glutathione-S-transferase (alpha-GST)  |

|1. Proximal tubule cytosolic enzyme |

|2. Requires stabilization buffer for specimen storage and processing |

|3. Upregulated in AKI and renal cell carcinoma |

|ELISA |

|Mouse, rat, human |

| |

|Gamma -Glutamyl transpeptidase ( gamma GT) |

|1. Proximal tubule brush border enzyme |

|2. Instability requires samples to be analyzed quickly after collection, limiting clinical utility |

|Colorimetry |

|Rat, human |

| |

|N-Acetyl-beta -(D) glucosaminidase (NAG)  |

|1. Proximal tubule lysosomal enzyme |

|2. More stable than other urinary enzymes |

|3. Extensive preclinical and clinical data in a variety of conditions (nephrotoxicant exposure, cardiopulmonary bypass, delayed renal |

|allograft function, etc.) |

|4. Endogenous urea may inhibit activity |

|Colorimetry |

|Mouse, rat, human |

| |

|Beta 2-Microglobulin |

|  |

|1. Light chain of the MHC I molecule expressed on the cell surface of all nucleated cells |

|2. Monomeric form is filtered by the glomerulus and reabsorbed by the proximal tubule cells |

|3. Early marker of tubular dysfunction in a variety of conditions |

|4. Instability in acidic urine limits clinical utility |

|ELISA |

|Nephelometry |

|Mouse, rat, human |

| |

|Alpha 1-Microglobulin |

|  |

|1. Synthesized by the liver |

|2. Filtered by the glomerulus and reabsorbed by proximal tubule cells |

|3. Early marker of tubular dysfunction; high levels may predict poorer outcome |

|4. Stable across physiologic urinary pH |

|ELISA |

|Nephelometry |

|Mouse, rat, human |

| |

|Retinol-binding protein |

|1. Synthesized by liver, involved in vitamin A transport |

|2. Filtered by glomerulus and reabsorbed by proximal tubule cells |

|3. Early marker of tubular dysfunction |

|4. Increased stability in acidic urine when compared to [pic]2-microglobulin |

|ELISA |

|Nephelometry |

|Mouse, rat, human |

| |

|Cystatin C |

|1. Important extracellular inhibitor of cysteineproteases |

|2. Filtered by the glomerulus and reabsorbed by proximal tubule cells |

|3. Elevated urinary levels reflect tubular dysfunction; high levels may predict poorer outcome |

|ELISA |

|Nephelometry |

|Mouse, rat, human |

| |

|Microalbumin |

|1. Established marker for monitoring progression of chronic kidney disease |

|2. Elevated urinary levels may be indicative of proximal tubular damage |

|3. Lack of specificity for AKI may limit its utility |

|ELISA |

|Immunoturbidimetry |

|Mouse, rat, dog, monkey, human |

| |

|Kidney injury molecule-1 (KIM-1) |

|1. Type-1 cell membrane glycoprotein upregulated in dedifferentiated proximal tubule epithelial cells |

|2. Ectodomain is shed and can be quantitated in urine following AKI in preclinical and clinical studies |

|3. Elevated urinary levels are highly sensitive and specific for AKI |

|4. Upregulated following various models of preclinical and clinical AKI, fibrosis, renal cell carcinoma, and polycystic kidney disease|

|ELISA, Luminex®-based assay |

|  |

|Zebrafish, mouse, rat, dog, monkey, human |

| |

|Clusterin |

|1. Expressed on dedifferentiated proximal tubular epithelial cells |

|2. Elevated kidney and urinary levels are very sensitive for AKI in preclinical models |

|3. Upregulated in various rodent models of AKI, fibrosis, renal cell carcinoma, and polycystic kidney disease |

|4. No clinical study demonstrating its use |

|ELISA |

|Mouse, rat, dog, monkey, human |

| |

|Neutrophil gelatinase associated lipocalin (NGAL) |

|1. Initially identified bound to gelatinase in specific granules of the neutrophils, but also may be induced in epithelial cells in |

|the setting of inflammation or malignancy |

|2. Expression upregulated in kidney proximal tubule cells and urine following ischemic or cisplatin induced renal injury |

|3. Found to be an early indicator of AKI following cardiopulmonary bypass |

|4. Specificity for AKI in setting of sepsis and pyuria need to be further established |

|ELISA |

|Luminex®-based assay |

|Mouse, rat, human |

| |

|Interleukin-18 (IL-18) |

|1. Cytokine with broad immunomodulatory properties, particularly in setting of ischemic injury |

|2. Constitutively expressed in distal tubules; strong immunoreactivity in proximal tubules with transplant rejection |

|3. Elevated urinary levels found to be early marker of AKI and independent predictor of mortality in critically ill patients |

|ELISA |

|Luminex®-based assay |

|Mouse, rat, human |

| |

|Cysteine-rich protein (CYR-61) |

|1. Induced in proximal straight tubules of kidney and secreted in the urine within 3–6 h following ischemic kidney injury |

|2. Urinary levels decrease rapidly in spite of progression of injury indicating stability issue |

|3. No clinical study demonstrating its use |

|4. No quantitative method established |

|Western blot |

|Mouse, rat, human |

| |

|Osteopontin |

|1. Upregulated in various rodent models of AKI |

|2. The induction correlates with inflammation and tubulointerstitial fibrosis |

|3. No clinical study demonstrating its use |

|ELISA |

|Mouse, rat, monkey, human |

| |

|Liver fatty acid–binding protein (L-FABP) |

|1. Expressed in proximal tubule epithelial cells |

|2. Current evidence suggests clinical utility as a biomarker in CKD and diabetic nephropathy |

|3. Additional studies necessary to determine utility in setting of preclinical and clinical AKI |

|ELISA |

|Mouse, rat, human |

| |

|Sodium/hydrogen exchanger isoform (NHE3) |

|1. Most abundant sodium transporter in the renal tubule |

|2. Urinary levels found to discriminate between prerenal azotemia and AKI in ICU patients |

|3. Samples require considerable processing, limiting assay throughput |

|Immunoblotting |

|Mouse, rat, human |

| |

|Exosomal fetuin-A |

|1. Acute phase protein synthesized in the liver and secreted into the circulation |

|2. Levels in proximal tubule cell cytoplasm correspond to degree of injury |

|3. Urinary levels found to be much higher in ICU patients with AKI compared to ICU patients without AKI and healthy volunteers |

|4. Samples require considerable processing, limiting assay throughput |

|5. Additional studies necessary to determine utility in setting of preclinical and clinical AKI |

|Immunoblotting |

|Rat, human |

| |

|Abbreviations: AKI, acute kidney injury; ELISA, enzyme-linked immunosorbent assay; ICU, intensive care unit; RCC, renal cell |

|carcinoma. |

3.ALSO KNOW THE EXPANDED DONOR CRITERIA UPDATED IN 18TH EDITION HARRISON

|Table 282-1 Definition of an Expanded Criteria Donor (ECD) and a Non-Heart-Beating Donor [Donation after Cardiac Death (DCD)] |

| |

|Expanded Criteria Donor (ECD)  |

| |

|Deceased donor >60 years |

|Deceased donor >50 years and hypertension and creatinine >1.5 mg/dL |

|Deceased donor >50 years and hypertension and death caused by cerebrovascular accident (CVA) |

|Deceased donor >50 years and death caused by CVA and creatinine >1.5 mg/dL |

| |

|Donation after Cardiac Deatha (DCD)  |

| |

|I Brought in dead |

|II Unsuccessful resuscitation |

|III Awaiting cardiac arrest |

|IV Cardiac arrest after brainstem death |

|V Cardiac arrest in a hospital patient |

| |

|aKidneys can be used for transplantation from categories II–V but are commonly only used from categories III and IV. The survival of |

|these kidneys has not been shown to be inferior to that of deceased-donor kidneys. |

|Note: Kidneys can be bought ECD and DCD. ECD kidneys have been shown to have a poorer survival, and there is a separate shorter |

|waiting list for ECD kidneys. They are generally utilized for patients for whom the benefits of being transplanted earlier outweigh |

|the associated risks of using an ECD kidney. |

4. ALSO KNOW THE INFECTIONS IN RENAL TRANSPLANT RECIEPIENTS

|Table 282-5 The Most Common Opportunistic Infections in Renal Transplant Recipients |

| |

|Peritransplant (6 months) |

|    Aspergillus Nocardia |

|    BK virus (polyoma) |

|    Herpes zoster |

|    Hepatitis B |

|    Hepatitis C |

| |

| |

5. INDICATIONS FOR IMMUNOSUPRESSIVES HAVE BEEN ADDED IN THE 18TH EDITION.JUST GO THROUGH IT QUICKLY.

|Table 285-2 Indications for Corticosteroids and Immunosuppressives in Interstitial Nephritis |

| |

|Absolute Indications  |

| |

| Sjögren's syndrome |

| |

| Sarcoidosis |

| |

|SLE interstitial nephritis |

| |

|Adults with TINU |

| |

| Idiopathic and other granulomatous interstitial nephritis |

| |

|Relative Indications  |

| |

|Drug-induced or idiopathic AIN with: |

|    Rapid progression of renal failure |

|emsp;  Diffuse infiltrates on biopsy |

|emsp;  Impending need for dialysis |

|emsp;  Delayed recovery |

|Children with TINU |

| |

|Postinfectious AIN with delayed recovery (?) |

| |

|Abbreviations: AIN, acute interstitial nephritis; SLE, systemic lupus erythematosus; TINU, tubulointerstitial nephritis with uveitis. |

|Source: Modified from S Reddy, DJ Salant: Ren Fail 20:829, 1998. |

6.RENAL ARTERY STENOSIS EVALUATION

|Table 286-1 Summary of Imaging Modalities for Evaluating the Kidney Vasculature |

| |

|Perfusion Studies to Assess Differential Renal Blood Flow  |

| |

|Captopril renography with technetium 99mTc mertiatide (99mTc MAG3) |

|  |

|Captopril-mediated fall in filtration pressure amplifies differences in renal perfusion |

|Normal study excludes renovascularhypertension |

|Multiple limitations in patients with advanced atherosclerosis or creatinine >;2.0 mg/dL (177 [pic]mol/L) |

| |

|Nuclear imaging with technetium mertiatide or technetium-labeled pentetic acid (DTPA) to estimate fractional flow to each kidney |

|Estimates fractional flow to each kidney |

|Allows calculation of single-kidney glomerular filtration rate |

|Results may be influenced by other conditions, e.g., obstructive uropathy |

| |

|Vascular Studies to Evaluate the Renal Arteries  |

| |

|Duplex ultrasonography |

|Shows the renal arteries and measures flow velocity as a means of assessing the severity of stenosis |

|Inexpensive; widely available |

|Heavily dependent on operator's experience; less useful than invasive angiography for the diagnosis of fibromuscular dysplasia and |

|abnormalities in accessory renal arteries |

| |

|Magnetic resonance angiography |

|Shows the renal arteries and perirenal aorta |

|Not nephrotoxic, but concerns for gadolinium toxicity exclude use in GFR ;4% schistocytes in the blood |

|RBC fragmentation and at least 2 schistocytes per high-power field |

| |

|De novo, prolonged, or progressive thrombocytopenia |

|Concurrent increase in LDH above baseline |

| |

|A sudden and persistent increase in LDH |

|Negative direct and indirect Coombs test |

| |

|Decrease in hemoglobin or increased RBC transfusion requirement |

|Concurrent renal and/or neurologic dysfunction without other explanations |

| |

|Decrease in haptoglobin concentration |

|  |

| |

|Note: These features underscore the need to identify pathways of hemolysis and thrombocytopenia that accompany deterioration of kidney|

|function. |

|Abbreviations: LDH, lactate dehydrogenase; RBC, red blood cell. |

HIV-RELATED TMA

• TMA is mainly a complication encountered before widespread use of highly active retroviral therapy for HIV.

• It is seen in patients with advanced AIDS and low CD4 count, although it occasionally can be the first manifestation of HIV infection.

• The presence of MAHA thrombocytopenia and renal failure are suggestive, but renal biopsy is required to establish the diagnosis since HIV is associated with several other renal diseases.

• The median platelet count is 77,000/L with a range of 10,000 to 160,000/L, which may prohibit a renal biopsy in some patients.

• Cytomegalovirus (CMV) coinfection may also be a risk factor. The mechanism of injury is unclear, but HIV may induce apoptosis in endothelial cells.

• Plasma exchange is effective and is recommended in conjunction with antiviral therapy.

UPDATES IN RHEUMATOLOGY

1.BELIMUMAB IN SLE:

• Recent trials of anti-BLyS (belimumab, directed against the ligand of the BLyS/BAFF receptor on B cells that promotes B cell survival and differentiation to plasmablasts) showed a small, but statistically significant, better suppression of disease activity in comparison to placebo, when added to standard combhnation therapies.

• The US FDA has approved belimumab for treatment of SLE: it has not been studied in active nephritis or central nervous system lupus.

2.CLINICAL FEATURES OF ANTIPHOSPHOLIPID ANTIBODY SYNDROME

|Table 320-2 Clinical Features of Antiphospholipid Antibody Syndrome |

| |

|Manifestation |

|% |

| |

|Venous Thrombosis and Related Consequences |

| |

|Deep vein thrombosis |

|39 |

| |

|Livedo reticularis |

|24 |

| |

|Pulmonary embolism |

|14 |

| |

|Superficial thrombophlebitis |

|12 |

| |

|Thrombosis in various other sites |

|11 |

| |

|Arterial Thrombosis and Related Consequences |

| |

| |

|Stroke |

|20 |

| |

|Cardiac valve thickening/dysfunction and/or Libman-Sacks vegetations |

|14 |

| |

|Transient ischemic attack |

|11 |

| |

|Myocardial ischemia (infarction or angina) and coronary bypass thrombosis |

|10 |

| |

|Leg ulcers and/or digital gangrene |

|9 |

| |

|Arterial thrombosis in the extremities |

|7 |

| |

|Retinal artery thrombosis/amaurosis fugax |

|7 |

| |

|Ischemia of visceral organs or avascular necrosis of bone |

|6 |

| |

|Multi-infarct dementia |

|3 |

| |

|Neurologic Manifestations of Uncertain Etiology |

| |

| |

|Migraine |

|20 |

| |

|Epilepsy |

|7 |

| |

|Chorea |

|1 |

| |

|Cerebellar ataxia |

|1 |

| |

|Transverse myelopathy |

|0.5 |

| |

|Renal Manifestations Due to Various Reasons (Renal Artery/Renal Vein/Glomerular Thrombosis, Fibrous Intima Hyperplasia) |

|3 |

| |

|Osteoarticular Manifestations |

| |

| |

|Arthralgia |

|39 |

| |

|Arthritis |

|27 |

| |

|Obstetric Manifestations (Referred to the Number of Pregnancies) |

| |

| |

|Preeclampsia |

|10 |

| |

|Eclampsia |

|4 |

| |

|Fetal Manifestations (Referred to the Number of Pregnancies) |

| |

| |

|Early fetal loss (10 joints (at least 1 small joint) |

|5 |

| |

|Serology |

|Negative RF and negative ACPA |

|0 |

| |

|  |

|Low-positive RF or low-positive anti-CCP antibodies ([pic]3 times ULN) |

|2 |

| |

|  |

|High-positive RF or high-positive anti-CCP antibodies (>3 times ULN) |

|3 |

| |

|Acute-phase reactants |

|Normal CRP and normal ESR |

|0 |

| |

|  |

|Abnormal CRP or abnormal ESR |

|1 |

| |

|Duration of symptoms |

|2 other SpA features |

| |

|Sacroiliitis on imaging |

|SpA features |

| |

|--Active (acute) inflammation on MRI highly suggestive of SpA-associated sacroiliitisb |

|and/or |

|--Definite radiographic sacroiliitis according to modified New York criteriac |

|[pic]Inflammatory back paind |

|[pic]Arthritise |

|[pic]Enthesitis (heel)f |

|[pic]Anterior uveitisg |

|[pic] Dactylitise |

|[pic]Psoriasise |

|[pic]Crohn's disease or ulcerative colitise |

|[pic]Good response to NSAIDsh |

|[pic]Family history of SpAi |

|[pic] HLA-B27 |

|[pic]Elevated CRPj |

| |

|aSensitivity 83%, specificity 84%. The imaging arm (sacroiliitis) alone has a sensitivity of 66% and a specificity of 97%. |

|bBone marrow edema and/or osteitis on short tau inversion recovery (STIR) or gadolinium-enhanced T1 image. |

|cBilateral grade =2 or unilateral grade 3 or 4. |

|d See text for criteria. |

|ePast or present, diagnosed by a physician. |

|f Past or present pain or tenderness on examination at calcaneus insertion of Achilles tendon or plantar fascia. |

|g Past or present, confirmed by an ophthalmologist. |

|h Substantial relief of back pain at 24–48 h after a full dose of NSAID. |

|i First- or second-degree relatives with ankylosing spondylitis (AS), psoriasis, uveitis, reactive arthritis (ReA), or inflammatory |

|bowel disease (IBD). |

|j After exclusion of other causes of elevated CRP. |

|Abbreviations: ASAS, Assessment of Spondyloarthritis International Society; CRP, C-reactive protein; NSAIDs, nonsteroidal |

|anti-inflammatorydrugs; SpA, spondyloarthritis. |

|Source: From M Rudwaleit et al: Ann Rheum Dis 68:777, 2009. Copyright 2009, with permission from BMJ Publishing Group Ltd. |

Also know the caspar criteria for psoriatic arthritis.

|Table 325-2 The Caspar (C Lassification Criteria for Psoriatic Arthritis) Criteriaa |

| |

|To meet the CASPAR criteria, a patient must have inflammatory articular disease (joint, spine, or entheseal) with [pic]3 points from |

|any of the following five categories: |

|Evidence of current psoriasis,b, c a personal history of psoriasis, or a family history of psoriasisd |

|Typical psoriatic nail dystrophye observed on current physical examination |

|A negative test result for rheumatoid factor |

|Either current dactylitisf or a history of dactylitis recorded by a rheumatologist |

|Radiographic evidence of juxtaarticular new bone formationg in the hand or foot |

| |

|aSpecificity of 99% and sensitivity of 91%. |

|bCurrent psoriasis is assigned 2 points; all other features are assigned 1 point. |

|c Psoriatic skin or scalp disease present at the time of examination, as judged by a rheumatologist or dermatologist. |

|d History of psoriasis in a first- or second-degree relative. |

|e Onycholysis, pitting, or hyperkeratosis. |

|f Swelling of an entire digit. |

|g Ill-defined ossification near joint margins, excluding osteophyte formation. |

|Source: From W Taylor et al. |

GRANULOMATOSIS WITH POLYANGIITIS IS THE NEWER NAME FOR WEGENER’S GRANULOMATOSIS.

ENDOCRINOLOGY

1. CRITERIA FOR DIAGNOSIS OF DIABETES MELLITUS

|Table 344-2 Criteria for the Diagnosis of Diabetes Mellitus |

| |

|Symptoms of diabetes plus random blood glucose concentration 11.1 mmol/L (200 mg/dL)aor  |

|  |

| |

|Fasting plasma glucose 7.0 mmol/L (126 mg/dL)bor  |

|  |

| |

|A1C > 6.5%cor  |

|  |

| |

|Two-hour plasma glucose 11.1 mmol/L (200 mg/dL) during an oral glucose tolerance testd |

|  |

| |

|aRandom is defined as without regard to time since the last meal. bFasting is defined as no caloric intake for at least 8 h. cThe test|

|should be performed in laboratory certified according to A1C standards of the Diabetes Control and Complications Trial. dThe test |

|should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water, not recommended for |

|routine clinical use. Note: In the absence of unequivocal hyperglycemia and acute metabolic decompensation, these criteria should be |

|confirmed by repeat testing on a different day. Source: American Diabetes Association, 2011. |

2. New therapies under development for type 2 diabetes include

• Inhibitor of the sodium-glucose co- transporter in the kidney,

• Activators of glucokinase,

• An inhibitor of 11 -hydroxysteroid dehydrogenase-1

• Salsalate.

• Liraglutide – GLP-1 AGONIST

• Saxagliptin, Vildagliptin -- Dipeptidyl Peptidase-4 Inhibitors

• PANCREATIC ISLET TRANSPLANTATION:

Pancreatic islet transplantation has been plagued by limitations in

← pancreatic islet supply and

← graft survival.

Other Therapies for Type 2 Diabetes:

BILE ACID–BINDING RESINS.

← Bile acid metabolism is abnormal type 2 diabetes.

← The bile acid–binding resin colesevelam has been approved for the treatment of type 2 diabetes (already approved for treatment of hypercholesterolemia).

Emerging evidence indicates that bile acids, by signaling through nuclear receptors, may have a role in metabolism.

COLESEVELAM

← Colesevelam (available as a powder for oral solution and as 625-mg tablets) is prescribed as 3–6 tablets prior to meals.

← The most common side effects are gastrointestinal (constipation, abdominal pain, and nausea).

← Bile acid–binding resins can increase plasma triglycerides and should be used cautiously in patients with a tendency to hypertriglyceridemia.

Bromocriptine.

← A formulation of the dopamine receptor agonist bromocriptine (Cycloset), has been approved by the FDA for the treatment of type 2 diabetes (approved in 2009).

CARDIOLOGY

KNOW THE CARDIOMYOPATHIES ASSOCIATED WITH VARIOUS METABOLIC PATHWAY ABNORMALITIES.

|Table 238-4 Examples of Inherited Defects in Metabolic Pathways Associated With Cardiomyopathy, Usually Restrictive or |

|Pseudohypertrophic Phenotype |

| |

|Glycogen Storage Diseases |

|II—Pompe's (alpha 1,4 glucosidase) |

|III—Forbes: de-branching enzyme (amylo 1,6 glucosidase) |

| |

|Glucose Metabolism (Defective PRKAG2a)  |

| |

|Fatty acid metabolism |

|Carnitine transport defect |

|Medium chain Acyl-CoA dehydrogenase |

|Long chain Acyl-CoA dehydrogenase |

| |

|Sphingolipidoses |

|Fabry's disease (alpha galactosidase A) |

|Gaucher disease (beta-glucocerebroside) |

| |

|Disorders of lysosomal function |

|Danon's disease—(lysosome-associated membrane protein, LAMP2) |

| |

|Miscellaneous |

|Hemochromatosis—Fe metabolism |

|Familial amyloidosis—abnormal transthyretin |

|Barth syndrome—tafazzin defect affecting cardiolipin |

|Friedreich's ataxia—frataxin |

| |

|aGamma-2 regulatory subunit of the AMP-activated protein kinase important for glucose metabolism. |

|Drug Class |Examples |Usual Total Daily Dose* (Dosing |Other Indications |Contraindications/Cautions |

| | |Frequency/Day) | | |

| | |  | | |

| | | | | |

|Renin inhibitors |Aliskiren |150–300 mg (1) |Diabetic nephropathy |Pregnancy |

ENDOTHELIN RECEPTOR ANTAGONISTS

• The endothelin receptor antagonists bosentan and ambrisentan are approved treatments of PAH.

• In randomized clinical trials, both improved exercise tolerance as measured by an increase in 6-min walking distance.

• Therapy with bosentan is initiated at 62.5 mg bid for the first month and increased to 125 mg bid thereafter. Ambrisentan is initiated as 5 mg once daily and can be increased to 10 mg daily.

• Because of the high frequency of abnormal hepatic function tests associated with these drugs, primarily an increase in transaminases, it is recommended that liver function be monitored monthly throughout the duration of use.

• Bosentan is contraindicated in patients who are on cyclosporine or glyburide concurrently.

UPDATES:

Respiratory system

FUTURE THERAPIES IN ASTHMA

There is a need for the development of new therapies for patients with refractory asthma who have side effects with systemic corticosteroids.

Antagonists of specific mediators have little or no benefit in asthma, apart from antileukotrienes, which have rather weak effects, presumably reflecting the fact that multiple mediators are involved.

Blocking antibodies against IL-5 mepolizumab, reslizumab may reduce exacerbations in highly selected patients who have sputum eosinophils despite high doses of corticosteroids.

anti-TNF-alpha antibodies are not effective in severe asthma.

Novel anti-inflammatory treatments that are in clinical development include inhibitors of phosphodiesterase-4, NF-kappa B and p38 MAP kinase.

However, these drugs, which act on signal transduction pathways common to many cells, are likely to have troublesome side effects, necessitating their delivery by inhalation. Safer and more effective immunotherapy using T-cell peptide fragments of allergens or DNA vaccination are also being investigated.

Bacterial products, such as CpG oligonucleotides that stimulate TH1 immunity or regulatory T cells, are also currently under evaluation.

DEEP VEIN THROMBOSIS:

|Table 262-1 Clinical Decision Rules |

| |

|Low Clinical Likelihood of DVT if Point Score Is Zero or Less; Moderate-Likelihood Score Is 1 to 2; High-Likelihood Score Is 3 or |

|Greater  |

| |

|Clinical Variable |

|Score |

| |

|Active cancer |

|1 |

| |

|Paralysis, paresis, or recent cast |

|1 |

| |

|Bedridden for >3 days; major surgery 3 cm |

|1 |

| |

|Pitting edema |

|1 |

| |

|Collateral superficial nonvaricose veins |

|1 |

| |

|Alternative diagnosis at least as likely as DVT |

|–2 |

| |

|High Clinical Likelihood of PE if Point Score Exceeds 4  |

| |

|Clinical Variable |

|Score |

| |

|Signs and symptoms of DVT |

|3.0 |

| |

|Alternative diagnosis less likely than PE |

|3.0 |

| |

|Heart rate >100/min |

|1.5 |

| |

|Immobilization >3 days; surgery within 4 weeks |

|1.5 |

| |

|Prior PE or DVT |

|1.5 |

| |

|Hemoptysis |

|1.0 |

| |

|Cancer |

|1.0 |

| |

| |

- POINT SCORE METHOD FOR D.V.T.

USG of deep leg veins:

|Table 262-3 Ultrasonography of the Deep Leg Veins |

| |

|Criteria for Establishing the Diagnosis of Acute DVT  |

| |

|Lack of vein compressibility (principal criterion) |

|Vein does not "wink" when gently compressed in cross-section |

|Failure to appose walls of vein due to passive distention |

| |

|Direct Visualization of Thrombus  |

| |

|Homogeneous |

|Low echogenicity |

| |

|Abnormal Doppler Flow Dynamics  |

| |

|Normal response: calf compression augments Doppler flow signal and confirms vein patency proximal and distal to Doppler |

|Abnormal response: flow blunted rather than augmented with calf compression |

| |

Warfarin dosing in pulmonary embolism:

CYP2C9 variant alleles impair the hydroxylation of S-warfarin, thereby lowering the dose requirement. Variants in the gene encoding the vitamin K epoxide reductase complex 1 (VKORC1) can predict whether patients require low, moderate, or high warfarin doses.

NOVEL ANTICOAGULANTS:

Rivaroxaban, a factor Xa inhibitor, and dabigatran, a direct thrombin inhibitor, are approved in Canada and Europe for prevention of VTE after total hip and total knee replacement. In a large-scale trial of acute VTE treatment, dabigatran was as effective as warfarin and had less nonmajor bleeding. Because of these drugs' rapid onset of action and relatively short half-life compared with warfarin, "bridging" with a parenteral anticoagulant is not required.

DISEASE-SPECIFIC GUIDELINES FOR REFERRAL AND TRANSPLANTATION-

|Table 266-1 Disease-Specific Guidelines for Referral and Transplantation |

| |

|Chronic Obstructive Pulmonary Disease  |

| |

|Referral |

|    BODE index >5 |

| |

|Transplantation |

|    BODE index 7–10 |

|    or |

|    any of the following criteria: |

|        Hospitalization for exacerbation, with PaCO2 >50 mmHg |

|        Pulmonary hypertension or cor pulmonale despite oxygen therapy |

|        FEV1 ................
................

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