Dissecting the histological features of lupus nephritis highlights new common patterns of injury in class III/IV.

OBJECTIVE: The International Society of Nephrology/Renal Pathology Society classification is the gold standard for the characterisation of lupus nephritis (LN) on renal biopsy, with therapeutic repercussions. Its recent revision simplified the current class subdivisions, eliminating the S/G forms of class IV, although data on a possible pathogenetic/clinical value of this subdivision are still contradictory. METHODS: 353 renal biopsies from Belimumab International Study in LN were assessed through central pathology review. Univariate logistic models and a decision tree were performed on 314 adequate biopsies to evaluate the impact of histological features on focal/diffuse classes. Removing class I/II (n=6) and 'pure' class V (n=34), principal component analysis (PCA) and heatmap were used to explore similarities among III, IVS and IVG biopsies either incorporating or not the mixed classes (+V, n=274). Finally, a method aimed at partitioning the cases into k clusters based on their similarity (KMeans), was used to study features from the cohort of 'pure' class III/IVS/IVG cases (n=214) to determine alternative subdivisions based on phenotypic data. RESULTS: Segmental endocapillary hypercellularity (EH) was prevalent in class III, global EH, wire loops, hyaline thrombi and double contours were hallmarks of class IVG, with IVS cases showing intermediate characteristics. Heatmap and PCA confirmed the segregation of these features among classes, showing better segregation for focal/diffuse LN as compared with the mixed classes (+V). KMeans revealed the presence of two main clusters, membranoproliferative-like (n=83) or vasculitis-like (n=131). CONCLUSIONS: This study reveals new phenotypic forms of LN surpassing the traditional classes as determined by the current classification. Future validation and confirmation are required to confirm these findings.

Developments in the Histopathological Classification of ANCA-Associated Glomerulonephritis.

BACKGROUND AND OBJECTIVES: The histopathologic classification for ANCA-associated GN distinguishes four classes on the basis of patterns of injury. In the original validation study, these classes were ordered by severity of kidney function loss as follows: focal, crescentic, mixed, and sclerotic. Subsequent validation studies disagreed on outcomes in the crescentic and mixed classes. This study, driven by the original investigators, provides several analyses in order to determine the current position of the histopathologic classification of ANCA-associated GN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A validation study was performed with newly collected data from 145 patients from ten centers worldwide, including an analysis of interobserver agreement on the histopathologic evaluation of the kidney biopsies. This study also included a meta-analysis on previous validation studies and a validation of the recently proposed ANCA kidney risk score. RESULTS: The validation study showed that kidney failure at 10-year follow-up was significantly different between the histopathologic classes (P<0.001). Kidney failure at 10-year follow-up was 14% in the crescentic class versus 20% in the mixed class (P=0.98). In the meta-analysis, no significant difference in kidney failure was also observed when crescentic class was compared with mixed class (relative risk, 1.15; 95% confidence interval, 0.94 to 1.41). When we applied the ANCA kidney risk score to our cohort, kidney survival at 3 years was 100%, 96%, and 77% in the low-, medium-, and high-risk groups, respectively (P<0.001). These survival percentages are higher compared with the percentages in the original study. CONCLUSIONS: The crescentic and mixed classes seem to have a similar prognosis, also after adjusting for differences in patient populations, treatment, and interobserver agreement. However, at this stage, we are not inclined to merge the crescentic and mixed classes because the reported confidence intervals do not exclude important differences in prognosis and because an important histopathologic distinction would be lost.

Development and validation of a peripheral blood mRNA assay for the assessment of antibody-mediated kidney allograft rejection: A multicentre, prospective study.

BACKGROUND: Antibody-mediated rejection, a leading cause of renal allograft graft failure, is diagnosed by histological assessment of invasive allograft biopsies. Accurate non-invasive biomarkers are not available. METHODS: In the multicentre, prospective BIOMARGIN study, blood samples were prospectively collected at time of renal allograft biopsies between June 2011 and August 2016 and analyzed in three phases. The discovery and derivation phases of the study (N = 117 and N = 183 respectively) followed a case-control design and included whole genome transcriptomics and targeted mRNA expression analysis to construct and lock a multigene model. The primary end point was the diagnostic accuracy of the locked multigene assay for antibody-mediated rejection in a third validation cohort of serially collected blood samples (N = 387). This trial is registered with ClinicalTrials.gov, number NCT02832661. FINDINGS: We identified and locked an 8-gene assay (CXCL10, FCGR1A, FCGR1B, GBP1, GBP4, IL15, KLRC1, TIMP1) in blood samples from the discovery and derivation phases for discrimination between cases with (N = 49) and without (N = 134) antibody-mediated rejection. In the validation cohort, this 8-gene assay discriminated between cases with (N = 41) and without antibody-mediated rejection (N = 346) with good diagnostic accuracy (ROC AUC 79·9%; 95% CI 72·6 to 87·2, p < 0·0001). The diagnostic accuracy of the 8-gene assay was retained both at time of stable graft function and of graft dysfunction, within the first year and also later after transplantation. The 8-gene assay is correlated with microvascular inflammation and transplant glomerulopathy, but not with the histological lesions of T-cell mediated rejection. INTERPRETATION: We identified and validated a novel 8-gene expression assay that can be used for non-invasive diagnosis of antibody-mediated rejection. FUNDING: The Seventh Framework Programme (FP7) of the European Commission.

Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation.

Despite partial elucidation of the pathophysiology of antibody-mediated rejection (ABMR) after kidney transplantation, it remains largely unclear which of the involved immune cell types determine disease activity and outcome. We used microarray transcriptomic data from a case-control study (n=95) to identify genes that are differentially expressed in ABMR. Given the co-occurrence of ABMR and T-cell-mediated rejection (TCMR), we built a bioinformatics pipeline to distinguish ABMR-specific mRNA markers. Differential expression of 503 unique genes was identified in ABMR, with significant enrichment of natural killer (NK) cell pathways. CIBERSORT (Cell type Identification By Estimating Relative Subsets Of known RNA Transcripts) deconvolution analysis was performed to elucidate the corresponding cell subtypes and showed increased NK cell infiltration in ABMR in comparison to TCMR and normal biopsies. Other leukocyte types (including monocytes/macrophages, CD4 and CD8 T cells, and dendritic cells) were increased in rejection, but could not discriminate ABMR from TCMR. Deconvolution-based estimation of NK cell infiltration was validated using computerized morphometry, and specifically associated with glomerulitis and peritubular capillaritis. In an external data set of kidney transplant biopsies, activated NK cell infiltration best predicted graft failure amongst all immune cell subtypes and even outperformed a histologic diagnosis of acute rejection. These data suggest that NK cells play a central role in the pathophysiology of ABMR and graft failure after kidney transplantation.

Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices.

We present a consensus report pertaining to the improved clarity of definitions and classification of glomerular lesions in lupus nephritis that derived from a meeting of 18 members of an international nephropathology working group in Leiden, Netherlands, in 2016. Here we report detailed recommendations on issues for which we can propose adjustments based on existing evidence and current consensus opinion (phase 1). New definitions are provided for mesangial hypercellularity and for cellular, fibrocellular, and fibrous crescents. The term "endocapillary proliferation" is eliminated and the definition of endocapillary hypercellularity considered in some detail. We also eliminate the class IV-S and IV-G subdivisions of class IV lupus nephritis. The active and chronic designations for class III/IV lesions are replaced by a proposal for activity and chronicity indices that should be applied to all classes. In the activity index, we include fibrinoid necrosis as a specific descriptor. We also make recommendations on issues for which there are limited data at present and that can best be addressed in future studies (phase 2). We propose to proceed to these investigations, with clinicopathologic studies and tests of interobserver reproducibility to evaluate the applications of the proposed definitions and to classify lupus nephritis lesions.

The clinicopathologic characteristics of kidney diseases related to monotypic IgA deposits.

Monoclonal gammopathy of renal significance (MGRS) regroups renal disorders caused by a monoclonal immunoglobulin without overt hematological malignancy. MGRS includes tubular disorders, glomerular disorders with organized deposits, and glomerular disorders with non-organized deposits, such as proliferative glomerulonephritis with monoclonal IgG deposits. Since glomerular involvement related to monotypic IgA deposits is poorly described we performed retrospective analysis and defined clinico-biological characteristics, renal pathology, and outcome in 19 referred patients. This analysis allowed distinction between 2 types of glomerulopathies, α-heavy chain deposition disease (5 patients) and glomerulonephritis with monotypic IgA deposits (14 patients) suggestive of IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits in 12 cases. Clinicopathologic characteristics of α-heavy chain deposition disease resemble those of the γ-heavy chain disease, except for a higher frequency of extra-capillary proliferation and extra-renal involvement. IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits should be differentiated from diseases with polytypic IgA deposits, given distinct clinical, histological, and pathophysiological features. Similarly to IgG-proliferative glomerulonephritis with monoclonal immunoglobulin deposits, overt hematological malignancy was infrequent, but sensitive serum and bone marrow studies revealed a subtle plasma cell proliferation in most patients with IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Anti-myeloma agents appeared to favorably influence renal prognosis. Thus, potential progression towards symptomatic IgA multiple myeloma suggests that careful hematological follow-up is mandatory. This series expands the spectrum of renal disease in MGRS.

ANCA-Associated Glomerulonephritis: Risk Factors for Renal Relapse.

Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild-moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8-14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different.

Case report and literature review: Glomerular and neurologic thrombotic microangiopathy as a primary manifestation of multicentric castleman disease.

INTRODUCTION: We report the case of a multicentric Castleman disease (MCD) with initial renal involvement. Although the renal involvement in this case was typical of MCD, it constitutes a rare presentation of the disease, and in our case the renal manifestations led to the haematological diagnosis. CLINICAL FINDINGS/PATIENT CONCERNS: The patient was admitted for fever, diarrhea, anasarca, lymphadenopathies and acute renal failure. Despite intravenous rehydration using saline and albumin, renal function worsened and the patient required dialysis. While diagnostic investigations were performed, right hemiplegia occurred. There was no anemia or thrombocytopenia. DIAGNOSES: Kidney biopsy was consistent with glomerular thrombotic microangiopathy (TMA). Lymph node histology was consistent with hyalin-vascular variant of Castleman disease. OUTCOMES: Given the renal and neurological manifestations of this MCD-associated TMA, the patient was treated with plasma exchange during one month, and six courses of rituximab, cyclophosphamide and dexamethasone. The evolution was favorable. CONCLUSION: Although rare, this diagnosis is worth knowing, as specific treatment has to be started as soon as possible and proved to be efficient in our case as well as in other reports in the literature.

Renal safety of high-dose, sucrose-free intravenous immunoglobulin in kidney transplant recipients: an observational study.

High-dose intravenous immunoglobulin (IVIg) is commonly used during kidney transplantation. Its nephrotoxicity has been attributed to sucrose stabilizers. We evaluated the renal safety of newer formulations of sucrose-free IVIg. We retrospectively studied clinical and histological data from 75 kidney recipients receiving high-dose, sucrose-free IVIg courses. This group was compared with 75 matched kidney recipients not treated with IVIg. Sucrose-free IVIg treatment was not associated with any acute kidney injury episode at 3 months, but an increased frequency of tubular macrovacuoles (28% vs. 2.8%, P < 0.001) was observed. Among IVIg-treated patients, the presence of macrovacuoles at 3 months was associated with increased IF/TA scores at 3 months (1.7 ± 1 vs. 1 ± 1, P = 0.005) and was more often observed in kidneys with higher IF/TA scores on day 0 (0.6 ± 0.9 vs. 0.3 ± 0.8, P = 0.03) at 3 months. Finally, patients treated with amino-acid-stabilized formulations developed fewer macrovacuoles at 3 months (12% vs. 60%; P < 0.001) than those treated with carbohydrate-stabilized IVIg. Our study shows that high-dose, sucrose-free IVIg use in early kidney recipients is clinically well tolerated. Among sucrose-free IVIg, amino-acid-stabilized formulations are associated with less tubular toxicity than carbohydrate-stabilized IVIg.

Loss of tubular creatinine secretion as the only sign of tubular proximal cell dysfunction in light chain proximal tubulopathy: A case report.

Light chain proximal tubulopathy (LCPT) is a rare disease, characterized by cytoplasmic inclusions of light chain (usually kappa) immunoglobulins. Clinical presentation is usually a Fanconi syndrome. The proximal tubular dysfunction can be incomplete, and exceptional cases of LCPT without any tubular dysfunction have even been described. Here, we report a case of LCPT in which the only sign of proximal tubulopathy is the absence of secretion of creatinine, as assessed by the simultaneous measurement of renal clearance of creatinine and CrEDTA. The loss of tubular creatinine secretion as a sign of tubular proximal cell dysfunction ought to be identified in patients with light chain proximal tubulopathy as it leads to a clinically relevant underestimation of GFR by the creatinine-derived equations. The prevalence and prognostic significance of this particular proximal tubular damage in LCPT remain to be determined.

Long-term CD4 lymphopenia is associated with accelerated decline of kidney allograft function.

BACKGROUND: Persistent CD4 T-cell lymphopenia after kidney transplantation has been associated with an increased occurrence of opportunistic infections, malignancies and even mortality, but studies have focussed only on the first few years after kidney transplantation. In this study, we investigated the risk factors and clinical significance of long-term profound CD4 lymphopenia detected ≥10 years after renal transplantation. METHODS: Between 2007 and 2010, 6206 CD4 T-cell counts, including 1507 counts <300/mm(3), were identified in an active cohort of 1876 kidney transplant patients. We identified 27 HIV-negative lymphopenic kidney transplant recipients out of 513 patients with graft survival over 10 years. We compared this cohort to 54 non-lymphopenic controls matched for the date of kidney transplantation. RESULTS: The prevalence of CD4 lymphopenia 10 years after transplantation was 5.3%. CD4 T-cell lymphopenia was associated with significantly lower thymic output and with B-cell lymphopenia (P < 0.05). The duration of pre-transplant dialysis, but not the use of lymphopenic induction or recipient age, was significantly associated with a persistent CD4 lymphopenia (6.1 versus 3.0 years, P = 0.008). CD4 lymphopenia was associated with a higher frequency of cancer (50 versus 29.6%, P = 0.047). Most strikingly, long-term lymphopenia was significantly and independently associated with an accelerated decline in renal allograft function (P = 0.005), despite a similar rate of biopsy-proven acute rejection and comparable immunosuppression. CONCLUSIONS: Our study shows an association between long-term CD4 T-cell lymphopenia in kidney recipients and malignancy and an accelerated decline of kidney allograft function.

Spectrum and Prognosis of Noninfectious Renal Mixed Cryoglobulinemic GN.

Noninfectious mixed cryoglobulinemic GN (MCGN) has been poorly investigated. We analyzed presentation and outcome of 80 patients with biopsy-proven MCGN, which were identified in the retrospective French CryoVas survey. MCGN was related to primary Sjögren's syndrome in 22.5% of patients and to lymphoproliferative disorders in 28.7% of patients, and was defined as essential in 48.8% of patients. At presentation, hematuria, proteinuria ≥1 g/d, hypertension, and renal failure were observed in 97.4%, 84.8%, 85.3%, and 82.3% of cases, respectively. Mean±eGFR was 39.5±20.4 ml/min per 1.73 m(2) Membranoproliferative GN was the predominant histologic pattern, observed in 89.6% of cases. Renal interstitium inflammatory infiltrates were observed in 50% of cases. First-line treatment consisted of steroids alone (27.6%) or in association with rituximab (21.1%), alkylating agents (36.8%) or a combination of cyclophosphamide and rituximab (10.5%). After a mean follow-up of 49.9±45.5 months, 42.7% of patients relapsed with a renal flare in 75% of cases. At last follow-up, mean eGFR was 50.2±26.1 ml/min per 1.73 m(2)with 9% of patients having reached ESRD; 59% and 50% of patients achieved complete clinical and renal remission, respectively. A rituximab+steroids regimen prevented relapses more effectively than steroids alone or a cyclophosphamide+steroids combination did, but was associated with a higher rate of early death when used as first-line therapy. Severe infections and new-onset B-cell lymphoma occurred in 29.1% and 8.9% of cases, respectively; 24% of patients died. In conclusion, noninfectious MCGN has a poor long-term outcome with severe infections as the main cause of death.

The Revisited Classification of GN in SLE at 10 Years: Time to Re-Evaluate Histopathologic Lesions.

Over 10 years have passed since the latest revision of the histopathologic classification of lupus nephritis. This revision was a significant improvement compared with the previous version, mainly because of clearer and more concise definitions and the elimination of mixed subclasses. Despite these improvements, there are still some difficulties in the classification for lupus nephritis, many of which are in the definitions provided. In this review, we focus on the difficulties surrounding the evaluation of classes III and IV lesions, particularly the definitions of endocapillary and extracapillary proliferation, the use of the terms endocapillary proliferation and hypercellularity, the clinical relevance of segmental and global subdivision in class IV, and the value of distinguishing lesions that indicate activity and chronicity. Vascular and tubulointerstitial lesions are also discussed. Furthermore, we give an overview of the history of the classification to provide background on the origin and development of the definitions in lupus nephritis. The issues raised in this review as well as the suggestions for improvements may assist with a revision of the lupus nephritis classification in the near future.

[Diagnostic value of IgG subtypes in membranous nephropathy: A case report]. / Place de l'étude des sous-classes d'IgG dans les glomérulonéphrites extramembraneuses : à propos d'un cas.

The study of immunoglobulin G subtypes constituting immune deposits present in membranous nephropathy is useful to guide diagnosis. IgG4 deposits are more often seen in primitive forms of membranous nephropathy due to autoantibody (anti-phospholipase A2 receptor in a majority of cases). These deposits are polytypic. In secondary forms, deposits are constituted of IgG1, IgG2 and IgG3. We report the case of a 52-year-old woman whose renal biopsy, done for glomerular proteinuria, shows membranous nephropathy with monotypic IgG4 deposits with no overt hematologic malignancy and no anti-PLA2R antibodies.

Light and heavy chain deposition disease associated with CH1 deletion.

Light and heavy chain deposition disease (LHCDD) is a rare complication of monoclonal gammopathy. In all documented cases, LHCDD is the association of deposits of a monoclonal light chain with a normal heavy chain, especially in the kidneys. We describe here a 78-year-old woman whose renal biopsy showed nodular glomerulosclerosis, initially diagnosed as diabetic nephropathy. Detailed kidney biopsy immunofluorescence study corrected the diagnosis to γ1-κ-LHCDD. Advanced immunoblot analysis showed deletion of CH1 in the both blood and kidney heavy chain. We report here, to our knowledge, the first case of γ1 LHCDD associated with a deletion of CH1.

Twenty-five years of RENHIS: a history of histopathological studies within EUVAS.

In the early 1990s, an international working group of experienced renal pathologists, the Renal Histology group, set up a scoring system for biopsies with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis. This scoring system subdivided glomerular, interstitial and vascular lesions and served as a tool for the evaluation of all renal biopsies from studies of the European Vasculitis Study Group (EUVAS). Histopathological studies gave new insights into the prediction of renal outcome in patients with ANCA-associated glomerulonephritis. Percentage of normal glomeruli and a selected number of interstitial parameters were reliable predictors of long-term follow-up glomerular filtration rate in all studies. Out of these results, a histopathological classification distinguishing focal, crescentic, mixed and sclerotic classes of ANCA-associated glomerulonephritis was developed. Until today, 13 studies have validated this classification system. Future studies will try to determine if and how renal histology could be helpful in guiding treatment of ANCA-associated glomerulonephritis.

Crystalline light chain proximal tubulopathy with chronic renal failure and silicone gel breast implants: 1 case report.

A 39-year-old female patient was admitted to explore chronic renal failure. Clinical history included silicone breast implants. Clinical examination was normal. Urinalysis revealed tubular proteinuria with Bence-Jones κ protein. Monoclonal immunoglobulin G κ and free monoclonal κ-light chains (LCs) were revealed by serum protein immunoelectrophoresis. Bone marrow aspiration with karyotype analysis and skeletal radiologic survey were normal. Kidney biopsy revealed a peculiar pattern of proximal tubular cells with hypertrophy and clarification initially diagnosed as an osmotic nephrosis. Immunofluorescence study, including immunoglobulin LCs conjugates was normal. Immunoelectron microscopy finally revealed a crystalline LC proximal tubulopathy κ. Our case presents some peculiarities: the absence of hematologic malignancy sign and the young patient's age. The silicone breast implants have been reported to be involved in the generation of monoclonal gammopathy.

Renal function and ear, nose, throat involvement in anti-neutrophil cytoplasmic antibody-associated vasculitis: prospective data from the European Vasculitis Society clinical trials.

OBJECTIVE: We investigated whether ENT involvement is associated with renal biopsy findings and renal function in patients with ANCA-associated vasculitis (AAV). METHODS: Newly diagnosed AAV patients derived from three international, multicentre trials were included. To investigate an association between ENT involvement and estimated glomerular filtration rate (eGFR) at diagnosis and 5-year follow-up, we performed multivariable regression analyses including clinical and histopathological parameters. To investigate whether our findings are specific to ENT involvement, we performed comparable analyses between eGFR and other early disease manifestations (arthralgia/arthritis, cutaneous and lung involvement). RESULTS: One hundred and eighty-five of the 414 patients had ENT involvement. The mean presenting eGFR of patients with and without ENT involvement was 39.16 and 23.88 ml/min/1.73 m(2), respectively (P < 0.001). Mean eGFR increased by 6.76 ml/min/1.73 m(2) with each added ENT symptom (P = 0.007). Patients with ENT involvement had less interstitial fibrosis and tubular atrophy and a prognostically more favourable histopathological class on renal biopsy examination. Multivariable regression analyses correcting for clinical and histopathological parameters showed that ENT involvement is associated with both baseline and 5-year follow-up eGFR. There were no associations between baseline and 5-year follow-up eGFR and arthralgia/arthritis, cutaneous or lung involvement, suggesting that our findings are specific to ENT involvement. CONCLUSION: The presence of ENT involvement in AAV patients is associated with prognostically favourable renal biopsy findings and better renal function. These results indicate that there may be different phenotypes of AAV defined by ENT involvement.

Interobserver agreement on histopathological lesions in class III or IV lupus nephritis.

BACKGROUND AND OBJECTIVES: To treat lupus nephritis effectively, proper identification of the histologic class is essential. Although the classification system for lupus nephritis is nearly 40 years old, remarkably few studies have investigated interobserver agreement. Interobserver agreement among nephropathologists was studied, particularly with respect to the recognition of class III/IV lupus nephritis lesions, and possible causes of disagreement were determined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A link to a survey containing pictures of 30 glomeruli was provided to all 360 members of the Renal Pathology Society; 34 responses were received from 12 countries (a response rate of 9.4%). The nephropathologist was asked whether glomerular lesions were present that would categorize the biopsy as class III/IV. If so, additional parameters were scored. To determine the interobserver agreement among the participants, κ or intraclass correlation values were calculated. The intraclass correlation or κ-value was also calculated for two separate levels of experience (specifically, nephropathologists who were new to the field or moderately experienced [less experienced] and nephropathologists who were highly experienced). RESULTS: Intraclass correlation for the presence of a class III/IV lesion was 0.39 (poor). The κ/intraclass correlation values for the additional parameters were as follows: active, chronic, or both: 0.36; segmental versus global: 0.39; endocapillary proliferation: 0.46; influx of inflammatory cells: 0.32; swelling of endothelial cells: 0.46; extracapillary proliferation: 0.57; type of crescent: 0.46; and wire loops: 0.35. The highly experienced nephropathologists had significantly less interobserver variability compared with the less experienced nephropathologists (P=0.004). CONCLUSIONS: There is generally poor agreement in terms of recognizing class III/IV lesions. Because experience clearly increases interobserver agreement, this agreement may be improved by training nephropathologists. These results also underscore the importance of a central review by experienced nephropathologists in clinical trials.