The Oxford Classification of IgA nephropathy (IgAN) includes the following four histologic components: mesangial (M) and endocapillary (E) hypercellularity, segmental sclerosis (S) and interstitial fibrosis/tubular atrophy (T). These combine to form the MEST score and are independently associated with renal outcome. Current prediction and risk stratification in IgAN requires clinical data over 2 years of follow-up. Using modern prediction tools, we examined whether combining MEST with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than current best methods that use 2 years of follow-up data. We used a cohort of 901 adults with IgAN from the Oxford derivation and North American validation studies and the VALIGA study followed for a median of 5.6 years to analyze the primary outcome (50% decrease in eGFR or ESRD) using Cox regression models. Covariates of clinical data at biopsy (eGFR, proteinuria, MAP) with or without MEST, and then 2-year clinical data alone (2-year average of proteinuria/MAP, eGFR at biopsy) were considered. There was significant improvement in prediction by adding MEST to clinical data at biopsy. The combination predicted the outcome as well as the 2-year clinical data alone, with comparable calibration curves. This effect did not change in subgroups treated or not with RAS blockade or immunosuppression. Thus, combining the MEST score with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than our current best methods.

SummaryBackground and objectives The discovery of different podocyte autoantibodies in membranous nephropathy (MN) raises questions about their pathogenetic and clinical meaning. This study sought to define antibody isotypes and correlations; to compare levels in MN, other glomerulonephritides, and controls; and to determine their association with clinical outcomes.Design, setting, participants, & measurements Serum IgG 1 , IgG 3 , and IgG 4 against aldose reductase (AR), SOD2, and a-enolase (aENO) were measured at diagnosis in 186 consecutive MN patients, in 96 proteinuric controls (36 with FSGS, and 60 with IgA nephropathy), and in 92 healthy people recruited in four Italian nephrology units. Anti-phospholipase A2 receptor (PLA2r) and anti-neutral endopeptidase (NEP) IgG 4 were titrated in the same specimens. Association with 1-year follow-up clinical parameters was studied in 120 patients.Results IgG 4 was the most common isotype for all antibodies; IgG 1 and IgG 3 were nearly negligible. IgG 4 levels were positive in a significant proportion of MN patients (AR, 34%; SOD2, 28%; aENO, 43%). Antibody titers were higher in MN than in healthy and pathologic controls (P,0.005). Anti-NEP IgG 4 did not differ from normal controls (P=0.12). Anti-PLA2r IgG 4 was detected in 60% of patients and correlated with anti-AR, anti-SOD2, and anti-aENO IgG 4 (P,0.001). In MN patients negative for the whole antibody panel (20%), 1-year proteinuria was lower compared with patients with at least one antibody positivity (P,0.05).Conclusions Our data suggest that IgG 4 is the prevalent isotype for antibodies against cytoplasmic antigens of podocytes (AR, SOD2, aENO). Their levels were higher than in other proteinuric glomerulonephritides and in normal controls and were correlated with anti-PLA2r. Only baseline negativity for all known antibodies predicted lower 1-year proteinuria.

This study demonstrates that a tight regulation of the intrarenal RAS exists in IgAN and that it follows the general rules disclosed in animal models. Moreover, the RAS seems to be activated early in the diseased kidney and it appears that such activation drives inflammation and a parallel stimulation of the TGF-beta fibrogenic loop, particularly at the tubulointerstitial level.

OBJECTIVEChronic renal insufficiency and/or proteinuria in type 2 diabetes may stem from chronic renal diseases (CKD) other than classic diabetic nephropathy in more than one-third of patients. We interrogated urine proteomic profiles generated by surface-enhanced laser desorption/ionization-time of flight/mass spectrometry with the aim of isolating a set of biomarkers able to reliably identify biopsy-proven diabetic nephropathy and to establish a stringent correlation with the different patterns of renal injury.RESEARCH DESIGN AND METHODSTen micrograms of urine proteins from 190 subjects (20 healthy subjects, 20 normoalbuminuric, and 18 microalbuminuric diabetic patients and 132 patients with biopsy-proven nephropathy: 65 diabetic nephropathy, 10 diabetic with nondiabetic CKD [nd-CKD], and 57 nondiabetic with CKD) were run using a CM10 ProteinChip array and analyzed by supervised learning methods (Classification and Regression Tree analysis).RESULTSThe classification model correctly identified 75% of patients with normoalbuminuria, 87.5% of those with microalbuminuria, and 87.5% of those with diabetic nephropathy when applied to a blinded testing set. Most importantly, it was able to reliably differentiate diabetic nephropathy from nd-CKD in both diabetic and nondiabetic patients. Among the best predictors of the classification model, we identified and validated two proteins, ubiquitin and β2-microglobulin.CONCLUSIONSOur data suggest the presence of a specific urine proteomic signature able to reliably identify type 2 diabetic patients with diabetic glomerulosclerosis.

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Background and objectivesADPKD is erroneously perceived as a not rare condition, which is mainly due to the repeated citation of a mistaken interpretation of old epidemiological data, as reported in the Dalgaard's work (1957). Even if ADPKD is not a common condition, the correct prevalence of ADPKD in the general population is uncertain, with a wide range of estimations reported by different authors. In this work, we have performed a meta-analysis of available epidemiological data in the European literature. Furthermore we collected the diagnosis and clinical data of ADPKD in a province in the north of Italy (Modena). We describe the point and predicted prevalence of ADPKD, as well as the main clinical characteristics of ADPKD in this region.MethodsWe looked at the epidemiological data according to specific parameters and criteria in the Pubmed, CINAHL, Scopus and Web of Science databases. Data were summarized using linear regression analysis. We collected patients’ diagnoses in the Province of Modena according to accepted clinical criteria and/or molecular analysis. Predicted prevalence has been calculated through a logistic regression prediction applied to the at-risk population.ResultsThe average prevalence of ADPKD, as obtained from 8 epidemiological studies of sufficient quality, is 2.7: 10,000 (CI95 = 0.73–4.67). The point prevalence of ADPKD in the province of Modena is 3.63: 10,000 (CI95 = 3.010–3.758). On the basis of the collected pedigrees and identification of the at-risk subjects, the predicted prevalence in the Province of Modena is 4.76: 10,000 (CI 95% = 4.109–4.918).ConclusionAs identified in our study, point prevalence is comparable with the majority of the studies of literature, while predicted prevalence (4.76: 10,000) generally appears higher than in the previous estimates of the literature, with a few exceptions. Thus, this could suggest that undiagnosed ADPKD subjects, as predicted by our approach, could be relevant and will most likely require more clinical attention. Nevertheless, our estimation, in addition to the averaged ones derived from literature, not exceeding the limit of 5:10,000 inhabitants, are compatible with the definition of rare disease adopted by the European Medicines Agency and Food and Drug Administration.

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Background The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. Results All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). Conclusion We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.