Kidney biopsy in patients with glomerulonephritis: is the earlier the better?
© Haider et al.; licensee BioMed Central Ltd. 2012
Received: 28 September 2011
Accepted: 10 May 2012
Published: 8 June 2012
Interventional diagnostic procedures are established for several diseases in medicine. Despite the KDOQI guideline recommendation for histological diagnosis of kidney disease to enable risk stratification, its optimal time point has not been evaluated. We have therefore analyzed whether histological diagnosis of glomerulonephritis (GN) at an early stage of chronic kidney disease (CKD) is associated with different outcome compared to diagnosis at a more advanced stage.
A cohort of 424 consecutive patients with histological diagnosis of GN were included in a retrospective data analysis. Kidney function was assessed by glomerular filtration rate (GFR) estimation at the time point of kidney biopsy and after consecutive immunosuppressive therapy. Censored events were death, initiation of dialysis or kidney transplantation, or progression of disease, defined as deterioration of CKD stage ≥1 from kidney biopsy to last available kidney function measurement.
Occurrence of death, dialysis/transplantation or progression of disease were associated with GFR and CKD stage at the time of kidney biopsy (p < 0.001 for all). Patients with CKD stage 1 and 2 at kidney biopsy had fewer endpoints compared to patients with a GFR of <60 ml/min (p < 0.001).
Kidney function at the time point of histological GN diagnosis is associated with clinical outcome, likely due to early initiation of specific drug treatment. This suggests that selection of therapy yields greatest benefit before renal function is impaired in GN.
The time points when interventions should be recommended have been investigated and established in multiple fields of medicine. For patients with renal disease kidney biopsy can be necessary for diagnosis and treatment selection. Technical advances (e.g. real-time ultrasound and automated biopsy needles) improved the general implementation of this procedure . Major complications occur in less than <0.1% of kidney biopsies [1–4].
The incidence of chronic kidney disease (CKD) is increasing in the western communities and outcomes are poor. The number of patients with CKD undergoing maintenance hemodialysis is expected to rise further . Complications of decreased kidney function or concomitant cardiovascular disease (CVD) may be preventable by early diagnosis and treatment . However, CKD is frequently underdiagnosed and undertreated [7–9].
There is insufficient evidence to conclude best timing of invasive diagnostic procedures in patients with several kidney diseases. An early kidney biopsy may be of particular interest for those patients where disease classification is based on histological diagnosis and where the disease progression can be mitigated by treatment. While current guidelines have established the medical management of glomerulonephritis (GN) including the necessity of histological analysis and administration of immunosuppressive therapies, it is yet unclear if early diagnosis may result in prevention of CKD development in this heterogeneous group of patients.
We therefore performed a retrospective analysis to address the question if diagnosis of GN from an early kidney biopsy before kidney function impairment, as classified by glomerular filtration rate (GFR) and CKD stage, is associated with different outcome compared to diagnosis of GN at a later CKD stage.
Patients were characterized by CKD-stages according to their kidney function prior to biopsy and during follow up. Glomerular filtration rate (GFR) estimation was calculated via the MDRD formula . Primary outcome variables were progression of disease, dialysis/kidney transplantation or death. Progression of kidney disease was defined as deterioration of CKD stage ≥1 from the time of kidney biopsy to last kidney function measurement. Stable disease was regarded as constant or improved CKD stage from the time of kidney biopsy to last available kidney function measurement, without an episode of dialysis or kidney transplantation. After kidney biopsy patients received induction therapy with cortisone with or without cyclophosphamide as immunosuppressive therapy according to their histological diagnosis and adjusted to their body weight. Systolic blood pressure was set at ≤130 mmHG. The amount of patients with the respective antihypertensive therapy: ACE-inhibitors/AT2-blockers: 190/96 (withdrawal because of systolic BP < 110 mmHg); ß-Blocker: 77; Ca-channel-blockers:106; alpha-blockers:53.
Baseline characteristics and co-morbidities in patients with GN ( n = 424)
Primary Focal Segmental Glomerulosclerosis
Minimal Change GN
Systemic Lupus Erythematosus
Diabetes Mellitus Type 1
Diabetes Mellitus Type 2
Coronary Heart Disease
Peripheral Vascular Disease
Chronic Obstructive Pulmonary Disease
For data description results are presented as median and 25–75% interquartile range or mean and standard deviation as appropriate. For univariate analysis the Mann Whitney U test or the chi-squared test were used as appropriate. The Kaplan-Meier method was used to determine event-free survival and the log rank test was used to compare survival between subgroups. Univariate and multivariate regression analysis were performed using the Cox proportional hazard regression model to determine the effect of various variables on survival. Potential predictors were defined a priori or based on associations in the univariate analysis at a conservative threshold (p < 0.10). The Hosmer-Lemeshow test was used to assess goodness of model fit. We used SPSS Statistics for data management and calculations. A two sided p-value less than 0.05 was considered statistically significant. The authors performing the data analysis (D.G.H. and V.F.) were masked and were not involved in the data acquisition.
The median observation time was 4.0 years (interquartile range, IQR: 1.3;8.4 years). Overall, 106 (25%) patients had CKD stage 1, 65 (15%) patients had CKD stage 2, 109 (26%) patients had CKD stage 3, 70 (17%) patients had CKD stage 4, and 74 (17%) patients had CKD stage 5 before kidney biopsy. Estimated GFR slightly improved in pooled analysis during the observation period from 45 ml/min (IQR: 23–80) to 51 ml/min (IQR: 25–83) after 1 month and to 52 ml/min (IQR: 29–76) at the end of the observation period (P < 0.05 vs baseline). In subgroup analysis significant improvements in GFR were seen after one month for patients with vasculitis, IgA-Nephropathy and Systemic Lupus Erythematosus (SLE) (all p < 0.05), and at study end for patients with membranous GN, IgA-Nephropathy and vasculitis (all p < 0.05).
Data of quantitative proteinuria one month after initiation of immunosuppressive therapy was accessible in 174 patients. Of these 42 patients (24%) had proteinuria of >3.5 g/d. Univariate regression analysis including underlying diseases, age, sex and GFR identified membranous GN and vasculitis as predictors for progression/persistence of proteinuria (for both p < 0.01). Multivariate regression analysis detected membranous GN as an independent predictor for progression/persistence of proteinuria (p < 0.01).
Multivariate Cox-Regression for mortality (A), for dialysis/transplantation (B) and for progression of chronic kidney disease (C)
Systemic Lupus Erythematosus
Minimal Change GN
Minimal Change GN
Systemic Lupus Erythematosus
In this large sample of patients with different etiology of GN an early time point of kidney biopsy was associated with smaller declines in kidney function, a less frequent incidence of dialysis/transplantation, and death. Preserved kidney function at the time point of biopsy was a strong predictor of salutary outcome in patients with CKD.
Overall, immunotherapy prevented deterioration of kidney function in approximately half of the cohort of patients with GN. This treatment response is comparable with that shown across the groups of subjects with different histological diagnoses of GN in other studies [11–17]. When patients were in CKD stage 1 or 2 progression of disease was less likely during therapy indicating that early specific drug treatment is essential for clinical benefit, independent of the underlying classification of GN. However, this effect was not consistent and the patients with membranoproliferative GN had the worse outcome. This is in accordance with other data .
The association of CKD stages with mortality is comparable with data obtained in the general population [18, 19]. Our data demonstrates that early biopsy-guided initiation of therapy might result in a profound advantage for patients to preserve kidney function. Patients at CKD stage 1 and 2 had a significantly better outcome compared with other patients. This is also in good agreement with studies in patients with high cardiovascular risk [20, 21].
Our analysis revealed strong associations of mortality with age. This is in accordance with other data regarding the progression of disease . Kidney biopsy has demonstrated a clear benefit also for elderly patients with acute kidney failure in an observational study . These findings are extended by our results in patients with GN. Therefore, kidney biopsy should be considered independent of age in all patients with suspected GN. Current indications for kidney biopsy are derived from surveys and expert opinions [24, 25]. This study adds important evidence based on a large cohort analysis.
A limitation of the analysis of efficiency of drug treatment is the fact that response rates have improved over time by the availability of refined dosing schemes and new drugs. However, this does not limit the principal finding of this observational study, because no therapy was withheld and all patients had access to optimized medical treatment provided by the national sickness fund during the observation period. This study has not compared individual treatments within groups of patients with different GN entities and numbers within subgroups are too small for such analysis. While this is a large study, the median follow-up is 4 years, which may not be long enough to observe clinically relevant outcome or progression in diseases such as IgA nephropathy or membranous nephropathy. A further limitation of our study is that only a controlled interventional trial may demonstrate if baseline differences may be accounted for the results seen. However, ethical concerns prevent conduct of such a trial.
In summary, kidney biopsy at CKD stages 1 or 2 and consecutive therapy preserves kidney function and prevents disease progression through early initiation of therapy. The present observational data clearly supports the concept of early kidney biopsy in patients with suspected GN.
- Korbet SM: Percutaneous renal biopsy. Semin Nephrol. 2002, 22: 254-267. 10.1053/snep.2002.31713.View ArticlePubMedGoogle Scholar
- Burstein DM, Schwartz MM, Korbet SM: Percutaneous renal biopsy with the use of real-time ultrasound. Am J Nephrol. 1991, 11: 195-200. 10.1159/000168303.View ArticlePubMedGoogle Scholar
- Marwah DS, Korbet SM: Timing of complications in percutaneous renal biopsy: What is the optimal period of observation?. Am J Kidney Dis. 1996, 28: 47-52. 10.1016/S0272-6386(96)90129-8.View ArticlePubMedGoogle Scholar
- Mendelssohn DC, Cole EH: Outcomes of percutaneous kidney biopsy, including those of solitary native kidneys. Am J Kidney Dis. 1995, 26: 580-585. 10.1016/0272-6386(95)90592-8.View ArticlePubMedGoogle Scholar
- Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Johansen K, Kasiske B, Kutner N, Liu J, St Peter W, Guo H, Gustafson S, Heubner B, Lamb K, Li S, Li S, Peng Y, Qiu Y, Roberts T, Skeans M, Snyder J, Solid C, Thompson B, Wang C, Weinhandl E, Zaun D, Arko C, Chen SC, Daniels F, Ebben J, Frazier E, Hanzlik C, Johnson R, Sheets D, Wang X, Forrest B, Constantini E, Everson S, Eggers P, Agodoa L: United States Renal Data System 2011 Annual Data Report: Atlas of chronic kidney disease & end-stage renal disease in the United States. Am J Kidney Dis. 2012, 59 (1 Suppl 1): A7, e1-420-PubMedGoogle Scholar
- Remuzzi G, Ruggenenti P, Perico N: Chronic renal diseases: renoprotective benefits of renin-angiotensin system inhibition. Ann Intern Med. 2002, 136: 604-615.View ArticlePubMedGoogle Scholar
- McClellan WM, Knight DF, Karp H, Brown WW: Early detection and treatment of renal disease in hospitalized diabetic and hypertensive patients: important differences between practice and published guidelines. Am J Kidney Dis. 1997, 29: 368-375. 10.1016/S0272-6386(97)90197-9.View ArticlePubMedGoogle Scholar
- Obrador GT, Ruthazer R, Arora P, Kausz AT, Pereira BJ: Prevalence of and factors associated with suboptimal care before initiation of dialysis in the United States. J Am Soc Nephrol. 1999, 10: 1793-1800.PubMedGoogle Scholar
- Coresh J, Wei GL, McQuillan G, Brancati FL, Levey AS, Jones C, Klag MJ: Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med. 2001, 161: 1207-1216. 10.1001/archinte.161.9.1207.View ArticlePubMedGoogle Scholar
- Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: Modification of Diet in Renal Disease Study Group. A more accurate method to estimate glomerular filtration rate from serum creatinine. Ann Intern Med. 1999, 130: 461-470.View ArticlePubMedGoogle Scholar
- Waldman M, Crew RJ, Valeri A, Busch J, Stokes B, Markowitz G, D’Agati V, Appel G: Adult minimal-change disease: clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol. 2007, 2: 445-453. 10.2215/CJN.03531006.View ArticlePubMedGoogle Scholar
- Shiiki H, Dohi K: Primary focal segmental glomerulosclerosis: clinical course, predictors of renal outcome and treatment. Intern Med. 2000, 39: 606-611. 10.2169/internalmedicine.39.606.View ArticlePubMedGoogle Scholar
- Hofstra JM, Branten AJ, Wirtz JJ, Noordzij TC, du Buf-Vereijken PW, Wetzels JF: Early versus late start of immunosuppressive therapy in idiopathic membranous nephropathy: a randomized controlled trial. Nephrol Dial Transplant. 2010, 25: 129-136. 10.1093/ndt/gfp390.View ArticlePubMedGoogle Scholar
- Tumlin JA, Madaio MP, Hennigar R: Idiopathic IgA nephropathy: pathogenesis, histopathology, and therapeutic options. Clin J Am Soc Nephrol. 2007, 2: 1054-1061. 10.2215/CJN.04351206.View ArticlePubMedGoogle Scholar
- Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR: European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010, 363: 211-220. 10.1056/NEJMoa0909169.View ArticlePubMedGoogle Scholar
- Salama AD, Levy JB, Lightstone L, Pusey CD: Goodpasture’s disease. Lancet. 2001, 358: 917-920. 10.1016/S0140-6736(01)06077-9.View ArticlePubMedGoogle Scholar
- Renal Disease Subcommittee of the American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Response Criteria: The American college of rheumatology response criteria for proliferative and membranous renal disease in systemic lupus erythematosus clinical trials. Arthritis Rheum. 2006, 54: 421-432.View ArticleGoogle Scholar
- Alchi B, Jayne D: Membranoproliferative glomerulonephritis. Pediatr Nephrol. 2010, 25: 1409-1418. 10.1007/s00467-009-1322-7.View ArticlePubMedGoogle Scholar
- Peralta CA, Shlipak MG, Judd S, Cushman M, McClellan W, Zakai NA, Safford MM, Zhang X, Muntner P, Warnock D: Detection of Chronic Kidney Disease With Creatinine, Cystatin C, and Urine Albumin-to-Creatinine Ratio and Association With Progression to End-Stage Renal Disease and Mortality. JAMA. 2011, 305: 1545-1552. 10.1001/jama.2011.468.View ArticlePubMedPubMed CentralGoogle Scholar
- Debella YT, Giduma HD, Light RP, Agarwal R: Chronic Kidney Disease as a Coronary Disease Equivalent–a Comparison with Diabetes over a Decade. Clin J Am Soc Nephrol. 2011, 6: 1385-1392. 10.2215/CJN.10271110.View ArticlePubMedPubMed CentralGoogle Scholar
- Inrig JK, Patel UD, Briley LP, She L, Gillespie BS, Easton JD, Topol EJ, Szczech LA: Mortality, kidney disease and cardiac procedures following acute coronary syndrome. Nephrol Dial Transplant. 2008, 23: 934-940.View ArticlePubMedGoogle Scholar
- Eriksen BO, Ingebretsen OC: The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age. Kidney Int. 2006, 69: 375-382. 10.1038/sj.ki.5000058.View ArticlePubMedGoogle Scholar
- López-Gómez JM, Rivera F: Spanish Registry of Glomerulonephritis. Renal biopsy findings in acute renal failure in the cohort of patients in the Spanish Registry of Glomerulonephritis. Clin J Am Soc Nephrol. 2008, 3: 674-681. 10.2215/CJN.04441007.View ArticlePubMedPubMed CentralGoogle Scholar
- Reisman L, Dikman S, Churg J, Kupfer S: Renal biopsy: why and when. Mt Sinai J Med. 1996, 63: 178-190.PubMedGoogle Scholar
- Fuiano G, Mazza G, Comi N, Caglioti A, De Nicola L, Iodice C, Andreucci M, Andreucci VE: Current indications for renal biopsy: a questionnaire-based survey. Am J Kidney Dis. 2000, 3: 448-457.View ArticleGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/13/34/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.