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Renal biopsy in patients aged 80 years and older: a single-center experience in Japan

Ayumi Omokawa, Atsushi Komatsuda, Mizuho Nara, Takashi Fujiwara, Ryuta Sato, Masaru Togashi, Shin Okuyama, Ken-ichi Sawada, and Hideki Wakui

Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan

Running head: Renal biopsy in the very elderly

Correspondence to: Ayumi Omokawa, MD, Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita City, Akita 010-8543, Japan

Tel: +81-18-884-6116

Fax: +81-18-836-2613

E-mail: aomokawa@doc.med.akita-u.ac.jp

Abstract. Background: There are only three reports focusing on renal biopsy in a large number of the very elderly (age ≥80 years) in the United States. Methods: Clinicopathological features in 73 patients aged ≥80 years were evaluated and compared with control groups of 172 patients aged 60-61 years and 128 patients aged 70-71 years. Results: The common indications for biopsy in the very elderly were nephrotic syndrome (NS), followed by proteinuria without NS and/or hematuria, and acute kidney injury (AKI). Histological diagnoses were considered to potentially modify treatment in 57 cases (78.1%): the most frequent diagnosis was membranous nephropathy, followed by minimal change disease, and other various diseases. There were no biopsy procedure-related serious complications. Clinical assessment of treatments was evaluated in 38 of 54 patients with AKI and/or NS. Improvement of renal dysfunction or NS was observed in 24 of 30 patients who received immunosuppressive therapy. There were differences in the disease spectrum between the very elderly and control groups, and between the very elderly in our series and the United States series. Conclusions: This is the first report of renal biopsy findings in a relatively large number of Japanese very elderly. Histological observations are useful aids in estimating the prognosis and therapy selection for renal disorders even in the very elderly.

Key words

clinicopathological features - renal biopsy - very elderly

Introduction

As life expectancy increases, the number of elderly patients with manifestations of renal disease is increasing. However, nephrologists are often reluctant to perform renal biopsy in elderly patients, considering structural and functional changes which occur in the aging kidney [1] and complicating geriatric diseases.

Several studies, including our previous study, have indicated that renal biopsies can be performed as safely in elderly patients as in younger adults, and that histological examinations are essential for the accurate diagnosis and determination of the appropriate treatments even in elderly patients [2-10]. However, most of these studies considered elderly patients in the age groups of over 60 or 65 years. To our knowledge, there are only three reports focusing on renal biopsy findings in a large number of very elderly patients aged ≥80 years in the United States [11-13].

The aim of this study was to examine renal biopsy findings in a relatively large number of Japanese patients aged ≥80 years and to compare them with those in control groups of patients aged 60-61 and 70-71 years.

Patients and methods

Patients

This study was based on the renal histological records (from September 1979 to December 2010) of 5104 patients (excluding pediatric patients and transplant patients) studied at Akita University Hospital and its affiliated hospitals. For percutaneous renal biopsy, the Silverman needle was used until around 2000 in these hospitals. Thereafter, the automated biopsy needle was used under real-time ultrasound guidance.

There were 73 patients (44 male and 29 female) aged ≥80 years (1.4%). To determine whether the incidence of various renal biopsy diagnoses was unique to this age group, control groups were created by reviewing renal histological records over the same period (from January 1986, when the first patient aged ≥80 years underwent renal biopsy, to December 2010). There were 172 patients (95 male and 77 female) aged 60-61 years (3.4%) and 128 patients (68 male and 60 female) aged 70-71 years (2.5%). All patients evaluated in this study were Japanese.

To determine clinicopathological features in each case aged ≥80 years, the application form for renal biopsy which contained clinical information provided by the referring nephrologists and the renal histological report were reviewed. An indication for biopsy was determined according to the following clinical categories, essentially as outlined by Moutzouris et al. [12]:

(1) Acute kidney injury (AKI): Patients were categorized in this group, if the biopsy indication by the nephrologists was AKI, acute renal failure (ARF), or rapidly progressive glomerulonephritis (RPGN).

(2) Nephrotic syndrome (NS): NS was defined as massive proteinuria (≥3.5 g/day) and hypoproteinemia (serum total protein ≤6.0 g/dl or serum albumin ≤3.0 g/dl), with or without hematuria, and without AKI. If sufficient data were not available, the clinical diagnosis of NS described by the referring nephrologists was adopted.

(3) AKI and NS (AKI&NS): Patients with AKI and NS were classified separately in this group.

(4) Chronic-progressive kidney injury (CKI): Patients were included in this group, when the decline in renal function was less severe and/or less abrupt than defined for AKI. The presence of proteinuria and/or hematuria was not considered. Patients with NS and CKI were categorized under NS.

(5) Proteinuria without NS (UP): Patients were included in this category, if the prime renal manifestation was proteinuria without NS. All patients in this group were without significant decline in renal function.

(6) Hematuria (Hem): Patients presenting hematuria without proteinuria or significant decline in renal function were included in this category.

(7) Proteinuria and Hematuria (UP&Hem): This category was defined as proteinuria as described above plus the presence of hematuria, without significant decline in renal function.

(8) Non-classified category: Patients were included in this group, if there were reasons other than those described above.

Contribution of renal biopsy for determination of therapeutic interventions and the following prognosis

For each biopsy diagnosis, the potential effect on medical management was assessed to determine whether the renal biopsy diagnosis was likely to alter therapy, as described by Moutzouris et al. [12]. Biopsy diagnoses that were considered to potentially modify treatment included minimal change disease (MCD), primary or secondary glomerulonephritides, vasculitides, dysproteinemia-related renal disease, and acute tubulointerstitial nephritis. Biopsy results that were considered unlikely to lead specific modifications of therapy included hypertensive nephrosclerosis, focal segmental glomerulosclerosis secondary to hypertension / aging, diabetic glomerulosclerosis, acute tubular necrosis, cholesterol embolism, and end stage kidney.

To determine the outcome in each patient after renal biopsy, follow-up laboratory data of urinalysis and blood chemistry were collected via the questionnaire. When data were available, clinical assessment of treatments was evaluated by changes in proteinuria and renal function as previously described [13, 14]. With respect to AKI, improvement was defined as renal function with serum creatinine returning to no greater than 1.5 times pre-morbid creatinine level. With respect to NS, complete remission was defined as absence of proteinuria and normalized serum albumin concentration. Incomplete remission was defined as resolution of nephrotic syndrome but continuing proteinuria. No response was defined as presence of NS.

Complications of renal biopsy

To identify the presence of renal biopsy procedure-related complications, the clinical record of each patient was reviewed by referring nephrologists. “Severe complication” was defined as a death directly led by renal biopsy, massive hematoma or hematuria required blood transfusion, or need of any kind of invasive or surgical treatment.

Results

Distribution of very elderly patients

Figure 1 shows the distribution of very elderly patients who underwent renal biopsy by age and gender.

Renal Biopsy indications in very elderly patients

Figure 2 shows indications for renal biopsy in the very elderly. The most common indication was NS, followed by UP and/or Hem, AKI, AKI & NS, CKI, and others.

Renal biopsy diagnoses in very elderly patients

In each case of the very elderly, the most responsible biopsy diagnosis was determined by reviewing the renal biopsy histological report. Table 1 shows all the renal biopsy diagnoses by clinical presentation. The most common primary biopsy diagnosis was membranous nephropathy (MN), followed by MCD, membranoproliferative glomerulonephritis (MPGN) / MPGN-like lesion, and other various diseases (Figure 3).

Contribution of renal biopsy for determination of therapeutic interventions and the following prognosis in very elderly patients

Follow-up data were available for 67 patients of 73 very elderly patients. Duration of follow-up ranged from 9 days to 102 months, as patients were followed until death or their last clinical encounter. Median follow-up time for all patients was 24 months. During the final follow-up period, 9 patients died of kidney diseases, and 19 patients died of other diseases. Hemodialysis was introduced in 4 patients.

As shown in Table 1, renal biopsy diagnoses were considered to potentially modify treatment in 57 of 73 very elderly patients (78.1%). Clinical assessment of treatments could be evaluated in 38 of 54 patients with AKI and/or NS (70.4%): 8 of 10 patients with AKI, 23 of 35 patients with NS, and 7 of 9 patients with AKI&NS. Among these 38 patients, 30 patients (78.9%) were treated with immunosuppressive agents. Improvement of renal dysfunction or NS was observed in 24 of 30 patients who received immunosuppressive therapy (80.0%). On the other hand, there was an apparent infectious complication related to immunosuppression in one patient.

More detailed outcomes were previously described elsewhere in 4 very elderly patients in our series: a patient with massive glomerular deposition of monoclonal IgM-κ [15], a patient with malignancy-associated MN [16], a patient with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis [17], and a patient with proliferative glomerulonephritis with monoclonal IgG deposits [18].

Renal biopsy indications and biopsy diagnoses comparing very elderly and control patients

Renal biopsy indications and biopsy diagnoses in 73 patients aged ≥80 years were compared with those in control groups of 172 patients aged 60-61 years and 128 patients aged 70-71 years biopsied over the same period (Figures 2 and 3). The biopsy indications of NS and NS&AKI were more frequent in patients aged ≥80 years than in patients aged 60-61 and 70-71 years. The biopsy indications of UP and/or Hem were less frequent in patients aged ≥80 years than in patients aged 60-61 and 70-71 years. The biopsy diagnoses of MCD, MPGN / MPGN-like lesion, Henoch-Schönlein purpura nephritis (HSPN), and anti-glomerular basement membrane (GBM) antibody-mediated glomerulonephritis were more frequent in patients aged ≥80 years than in patients aged 60-61 and 70-71 years. The diagnoses of IgA nephropathy and diabetic glomerulosclerosis were less frequent in patients aged ≥80 years than in patients aged 60-61 and 70-71 years.

Discussion

To our knowledge, this retrospective study constitutes the largest renal biopsy series of Japanese very elderly patients aged ≥80 years. In approximately 80% of cases, various histological diagnoses were considered to potentially modify treatment. Indeed, improvement of renal dysfunction or NS was observed in 80% of patients with AKI and/or NS who received immunosuppressive therapy.

This study shows several clinicopathological characteristics in Japanese very elderly patients as compared with very elderly patients in the United States [11, 12] (Figures 4 and 5). In our series, NS was the most frequent indication for renal biopsy followed by proteinuria without NS and/or hematuria, and AKI. MN was the most frequent diagnosis, but pauci-immune glomerulonephritis was less frequent. On the contrary, in Moutzouris’s series [12], AKI was the most frequent indication for renal biopsy, and pauci-immune glomerulonephritis was the most frequent diagnosis. In Nair’s series [11], acute nephritis syndrome, ARF, and RPGN were classified separately. If these groups were classifies as AKI as in Moutzouris’s study [12], AKI was the most common indication for renal biopsy. The most frequent diagnosis was benign nephrosclerosis, followed by pauci-immune glomerulonephritis.

In very elderly patients with NS who underwent renal biopsy in our series, MN and MCD were major causes. These diagnoses would have led to considerable changes in the clinical management of these patients. Our results were consistent with those in Moutzouris’s series [12], except that amyloidosis was less frequent in our series.

In very elderly patients in our series, there was only one case of CKI, while there were more CKI (chronic renal failure) cases in Nair’s series [11] and Moutzouris’s series [12]. This difference might reflect selection bias based on indication for renal biopsy: our study includes cases of 1986-2010, while the previous two studies included cases of 2001-2003 [11] and 2005-2008 [12]. For percutaneous renal biopsy, the Silverman needle was used until around 2000 in our hospital and affiliated hospitals. Considering biopsy procedure-related complications, nephrologists performed renal biopsy in selected very elder patients with clear clinical manifestations such as AKI and/or NS, rather than more subclinical and chronic manifestations such as CKI.

In Moutzouris’s series [12], renal biopsy diagnoses in their very elderly patients aged ≥80 years were compared with those of a control group of patients aged 60-61 years. The higher incidence of pauci-immune glomerulonephritis and the lower incidence of diabetic glomerulosclerosis were found in the very elderly group compared with the control group. In our series, differences in the disease spectrum were also found between very elderly patients aged ≥80 years and control groups of patients aged 60-61 and 70-71 years. The higher incidence of MCD, MPGN / MPGN-like lesion, HSPN, and anti-GBM antibody-mediated glomerulonephritis, and the lower incidence of IgA nephropathy and diabetic glomerulosclerosis were found in the very elderly group compared with the control groups. These results suggest the different clinical contexts in the very elderly group. In addition, it is known that the incidence of anti-GBM antibody-mediated glomerulonephritis is higher in elder patients than in young adult patients in Japan [19].

In order to determine the efficacy of renal biopsy in our series, we assessed whether the biopsy contributed to determination of disease-specific therapeutic interventions. Clinical assessment of treatments could be evaluated in approximately 70% of patients with AKI and/or NS: improvement of renal dysfunction or NS was observed in 80% of patients who received immunosuppressive therapy. An apparent infectious complication related to immunosuppression was observed in one patient. Therefore, prompt disease-specific therapeutic interventions following the histological diagnosis certainly contributed to improvement of renal diseases even in the very elderly.

In our very elder patients, no serious renal biopsy procedure-related complications had occurred. Older age has been considered a risk factor for bleeding after renal biopsy in some studies, but not in others, possibly due to age-associated factors such as smaller kidney size, cortical thinning, and impaired thrombostasis and wound healing [20]. Since the introduction of the automated biopsy needles under real-time ultrasound guidance, the majority of percutaneous renal biopsies are free of significant complication [21]. Previous studies [11, 12] and our study indicate that the diagnostic benefits of renal biopsy overweigh the risks in many cases even in the very elderly patients.

In conclusion, this study confirms that histological observations are useful aids in estimating the prognosis and therapy selection for renal disorders even in very elderly patients, particularly in patients with AKI and/or NS.

Acknowledgements

The authors are grateful to all doctors in our affiliated hospitals for referring patients. This work was supported in part by the Global COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

References

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[2] Preston RA, Stemmer CL, Materson BJ, Perez-Stable E, Pardo V. Renal biopsy in patients 65 years of age or older. An analysis of the results of 334 biopsies. J Am Geriatr Soc 1990; 38: 669-674

[3] Modesto-Segonds A, Ah-Soune MF, Durand D, Suc JM. Renal biopsy in the elderly. Am J Nephrol 1993; 13: 27-34

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[8] Rivera F, López-Gómez JM, Pérez-García R. Clinicopathologic correlations of renal pathology in Spain. Kidney Int 2004; 66: 898-904

[9] Ferro G, Dattolo P, Nigrelli S, Michelassi S, Pizzarelli F. Clinical pathological correlates of renal biopsy in elderly patients. Clin Nephrol 2006; 65: 243-247

[10] Uezono S, Hara S, Sato Y et al. Renal biopsy in elderly patients: a clinicopathological analysis. Ren Fail 2006; 28: 549-555

[11] Nair R, Bell JM, Walker PD. Renal biopsy in patients aged 80 years and older. Am J Kidney Dis 2004; 44: 618-626

[12] Moutzouris D-A, Herlitz L, Appel GB et al. Renal biopsy in the very elderly. Clin J Am Soc Nephrol 2009; 4:1073-1082

[13] Bomback AS, Appel GB, Radhakrishnan J et al. ANCA-associated glomerulonephritis in the very elderly. Kidney Int 2011; 79: 757-764

[14] Shiiki H, Saito T, Nishitani Y et al. Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan. Kidney Int 2004; 65: 1400-1407

[15] Oyama Y, Komatsuda A, Ohtani H et al. Extensive intraglomerular thrombi of monoclonal IgM-κ in a patient with malignant lymphoma. Am J Kidney Dis 2000; 35: E11

[16] Ohtani H, Wakui H, Komatsuda A et al. Distribution of glomerular IgG subclass deposits in malignancy-associated membranous nephropathy. Nephrol Dial Transplant 2004; 19: 574-579

[17] Ohtani H, Wakui H, Komatsuda A et al. Differences between myeloperoxidase-specific and -nonspecific P-ANCA-associated renal disease. Ren Fail 2007; 29: 183-187

[18] Masai R, Wakui H, Komatsuda A et al. Characteristics of proliferative glomerulonephritis with monoclonal IgG deposits associated with membranoproliferative features. Clin Nephrol 2009; 72: 46-54

[19] Wakui H, Chubachi A, Asakura K et al. Goodpasture’s syndrome: a report of an autopsy case and a review of Japanese cases. Intern Med 1992; 31: 102-107

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Figure legends

Figure. 1. Distribution of very elderly patients who underwent renal biopsy by age and gender.

Figure 2. Comparison of renal biopsy indications between very elderly and control patients. AKI = acute kidney injury; CKI = chronic-progressive kidney injury; etc = non-classified; Hem = hematuria; NS = nephrotic syndrome; UP = proteinuria.

Figire 3. Major renal biopsy diagnoses in very elderly and control patients. Anti-GBM = anti-glomerular basement membrane antibody-mediated glomerulonephritis; ATN = acute tubular necrosis; DGS = diabetic glomerulosclerosis; DRRD = dysproteinemia-related renal disease; ESK = end stage kidney; FSGS = focal segmental glomerulosclerosis; HSPN = Henoch-Schönlein purpura nephritis; HTN = hypertensive nephrosclerosis; IgAN = IgA nephropathy; MCD = minimal change disease; MN = membranous nephropathy, MPGN = membranoproliferative glomerulonephritis / MPGN-like lesion; Pi GN = pauci-immune glomerulonephritis; TIN = tubulointerstitial nephritis.

Figure 4. Renal Biopsy indications in the very elderly in our series compared with two previously reported series in the United States [11, 12]. AKI = acute kidney injury; CKI = chronic-progressive kidney injury; Hem = hematuria; NS = nephrotic syndrome; UP = proteinuria. Acute nephritic syndrome and rapidly progressive glomerulonephritis in Nair’s series [11] are classified as AKI as in Moutzouris’s series [12]. Chronic renal failure in Nair’s series [11] are classified as CKI as in Moutzouris’s series [12].

Figure 5. Renal Biopsy diagnoses in the very elderly in our series compared with two previously reported series in the United States [11, 12]. Anti-GBM = anti-glomerular basement membrane antibody-mediated glomerulonephritis; ATN = acute tubular necrosis; DGS = diabetic glomerulosclerosis; DRRD = dysproteinemia-related renal disease; ESK = end stage kidney; FSGS = focal segmental glomerulosclerosis; HSPN = Henoch-Schönlein purpura nephritis; HTN = hypertensive nephrosclerosis; IgAN = IgA nephropathy; MCD = minimal change disease; MN = membranous nephropathy, MPGN = membranoproliferative glomerulonephritis / MPGN-like lesion; Pi GN = pauci-immune glomerulonephritis; TIN = tubulointerstitial nephritis. Benign nephrosclerosis in Nair’s series [11] is classified as HTN as in Moutzouris’s series [12].

*Among 235 patients in Moutzouris’s series [12], 24 patients with multiple diagnoses and 2 patients having inadequate biopsies were excluded.

Table1. Renal biopsy diagnosis by biopsy indications and clinical assessment of treatments in the very elderly

|Clinical |Renal biopsy diagnosis |Case |Outcome |

|presentation | | |available |

|CKI |Cholesterol embolism |1 | |

|(1 case) | | | |

| | | | |

| | | | |

|UP |HTN |2 | |

|(4 cases) |FSGS (secondary to HT / aging) |1 | |

| |MCD |1 | |

| | | | |

| | | | |

|Hem |ESK |1 | |

|(1 case) | | | |

| | | | |

| | | | |

|UP & Hem |HSPN |3 | |

|(10 cases) |IgAN |2 | |

| |MPGN |1 | |

| |MPGN-like lesion |1 | |

| |MN (malignancy-associated) |1 | |

| |DGS |1 | |

| |HTN |1 | |

| | | | |

| | | | |

|Others |Pi GN |1 | |

|(3 cases) |HTN |1 | |

|　 |No evidence of involvement of WG |1 | |

| | | | | | | | | | |AKI = acute kidney injury; AL = amyloid light chain; ANCA = anti-neutrophil cytoplasmic antibody; Anti-GBM = anti-glomerular basement membrane antibody-mediated glomerulonephritis; BPI = bacterial/permeability-increasing protein; CKI = chronic-progressive kidney injury; CR = complete remission; DGS = diabetic glomerulosclerosis; ECPGN = endocapillary proliferative glomerulonephritis; ESK = end stage kidney; FSGS = focal segmental glomerulosclerosis; HCV = hepatitis C virus; Hem = hematuria; HSPN = Henoch-Schönlein purpura nephritis; HT = hypertension; HTN = hypertensive nephrosclerosis; ICR = incomplete remission; IgAN = IgA nephropathy; Imp = improvement; MCD = minimal change disease; MN = membranous nephropathy; MPGN = membranoproliferative glomerulonephritis; MPO = myeloperoxidase; MSSA = methicillin-sensitive Staphylococcus aureus; Non-IgA = non-IgA mesangial proliferative glomerulonephritis; NR = no response; NS = nephrotic syndrome; PGNMID = proliferative glomerulonephritis with monoclonal IgG deposits; Pi GN = pauci-immune glomerulonephritis; TIN = tubulointerstitial nephritis; UP = proteinuria; WG = Wegener’s granulomatosis.

Tx*: immunosuppressive therapy.

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