Reproducibility of the Oxford classification of immunoglobulin A nephropathy, impact of biopsy scoring on treatment allocation and clinical relevance of disagreements: evidence from the VALidation of IGA study cohort.

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.

Outcome of fibrillary glomerulonephritis.

QUESTIONS UNDER STUDY: We assessed the long-term follow up of all the patients with fibrillary glomerulonephritis diagnosed since 1992 at our centre of reference for renal pathology in Basel. METHODS: We performed a retrospective surveillance study with mail questionnaire based follow-up of all patients with the diagnosis of fibrillary glomerulonephritis found in the database of the department of renal pathology in Basel from 1992 to 2007. The outcome was assessed in terms of endstage renal disease (ESRD), death, reduction of proteinuria and improvement of estimated glomerular filtration rate (eGFR). RESULTS: We obtained sufficient follow up data from 16 out of 20 identified patients. The mean follow up time was 35 months (1-115.1). Six patients died (37.5%), three without having ESRD. Six patients (37.5%) reached ESRD, five of them went on hemodialysis. Thirteen patients (81.3%) received an immunosuppressive therapy with steroids, five of them in combination with cyclophosphamide. The group without immunosuppressive therapy was too small to compare the two groups. In relation to the histological pattern membranous glomerulonephritis (MGN) had a better outcome as compared to the other histological patterns. CONCLUSIONS: FGN is a heterogeneous disease associated with significant risk of ESRD and mortality. The histological type of the glomerulonephritis may influence the course of the disease.

ACE inhibitors and angiotensin II receptor blockers in IgA nephropathy with mild proteinuria: the ACEARB study.

Few studies have investigated IgA nephropathy patients presenting with 'favorable' clinical features at onset, such as normal renal function, proteinuria<1 g/24 hours and the absence of hypertension, and no controlled clinical trials have tested the effects of treatment in such patients who may nevertheless develop end-stage renal disease. It is therefore important to find a well-tolerated and economic therapy capable of decreasing their risk of high proteinuria and blood pressure levels. The aim of this multicenter open-label randomized clinical trial is to test whether blocking the renin-angiotensin system (RAS) decreases the risk of progression in patients aged 3-60 years with biopsy-proven benign IgA glomerulonephritis, proteinuria levels of 0.3-0.9 g/24 hours, and normal renal function and blood pressure. The RAS is blocked by first using a single drug class (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker), and then combining the 2 classes as soon as the 1-drug blockade has become ineffective. We plan to enroll 378 patients over the next 3 years and randomize them to receive ramipril 5 mg/day (3 mg/m2 in children) (group A), irbesartan 300 mg/day (175 mg/m 2 in children) (group B) or supportive therapy (group C); if an increase in proteinuria of at least 50% from baseline is detected after 6 months of treatment, the other RAS inhibitor will be added. The observation period will be at least 5 years (except in the case of the development of the primary end point).

Glomerular monocyte-macrophage features in ANCA-positive renal vasculitis and cryoglobulinemic nephritis.

Although it is widely known that many macrophages are present in glomeruli of antineutrophil cytoplasmic antibody (ANCA)-positive renal vasculitis (ANCA + RV) and are believed to contribute to necrotizing extracapillary damage, their precise role is not yet completely understood, especially in humans. The goal of this study was to provide evidence of glomerular macrophage properties in human vasculitis. Twenty-five renal biopsies of ANCA + RV and 18 cases of cryoglobulinemic glomerulonephritis (cryoGN), a disease characterized by massive glomerular macrophage infiltration but absence of necrotizing extracapillary lesions, were selected, and macrophage number, adhesion, acute activation, proliferation, and apoptosis were analyzed by immunohistochemistry and in situ hybridization. Accumulation of macrophages in ANCA + RV was found in areas of glomerular active lesions, whereas in cryoGN, they homogeneously occupied the entire glomerular tuft. Considering the areas of accumulation, comparable macrophage numbers were detected in both diseases. Glomerular vascular cell adhesion molecule-1 was found only in ANCA + RV and only in areas of active lesions. Acute macrophage activation (HLA class II, 27E10) and proinflammatory cytokine production (tumor necrosis factor-alpha, interleukin-1alpha) were prominent in ANCA + RV, whereas in cryoGN, 30% of glomerular macrophages seemed activated and cytokine expression was limited to a few glomerular cells (P: = 0.01). Moreover, only in ANCA + RV proliferative markers were shown on glomerular macrophages and apoptotic macrophages were found. From the data, it seems that ANCA + RV and cryoGN differ profoundly in macrophage properties, namely adhesion, proliferation, and apoptotic clearance. Moreover, acute activation and cytokine production seem to be present in a greater number of macrophages in ANCA + RV, giving this disease a stronger severity that could be taken into account for therapeutic strategies.