C3 deposits worsens the prognosis in type iii extracapillary glomerulonephritis. / El depósito de C3 en la glomerulonefritis extracapilar de tipo iii condiciona un mal pronóstico.

INTRODUCTION: Type iii extracapillary glomerulonephritis (PEGN) is a common cause of rapidly progressive glomerulonephritis and it is usually associated with circulating anti-neutrophil cytoplasmic antibodies (ANCAs). Recent evidence points to complement activation as an important factor in the pathogenesis of PEGN. The aim of the present study was to assess the value of C3 deposits in the prognosis of PEGN. METHODS: All patients diagnosed of PEGN from 1995 to 2015 (n=72) were included in this study. Progression of renal disease in patients with positive staining for C3 by immunofluorescence was compared with those with negative staining. Mean follow up was 73 months. Progression to end-stage renal disease in relation to clinical and histological variables was analyzed. RESULTS: Positive staining for C3 was observed in 22 out of the 72 patients (30.5%). At the time of diagnosis, patients with C3 deposits had higher serum creatinine concentration than those without C3 staining (5.00 vs. 3.85mg/dl, P=0.050). Renal survival at 10 years was 36.9% in patients with positive C3 staining vs. 64.4% in patients with negative staining (P=0.005). Mortality at 10 years was higher in patients with C3 deposits than in patients without deposits (77 vs. 49.3%). CONCLUSIONS: Thus, our study shows that PEGN with deposits of C3 is associated with worse renal prognosis and greater mortality. These results would support the hypothesis that activation of the alternative pathway complement may play an important role in the generation of renal injury associated with PEGN.

C4d as a diagnostic tool in membranous nephropathy.

INTRODUCTION: membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. The diagnosis is based on typical findings observed using electron microscope (EM) and immunofluorescence (IF) studies. On some occasions, tissues are only available for analysis using an optical microscope (OM); in these cases, it can be difficult to differentiate between MN and minimal change disease (MCD). Recently, the use of C4d immunohistochemical staining has spread. Very little information is available regarding C4d deposits in MN. Our study consisted of analysing whether C4d staining of samples embedded in paraffin could be useful for diagnosing MN. MATERIAL AND METHOD: Ours was a retrospective study including all patients diagnosed with MN by renal biopsy in our unit between January 2001 and October 2008. We only included adult patients with a definitive diagnosis of MN or idiopathic MCD by OM, IF, and ME studies. In October 2008, 3µm sections of renal tissue fixed in formaldehyde were removed from paraffin and rehydrated. The samples were then stained for C4d immunohistochemical analysis using anti-human polyclonal antibodies obtained from rabbits. RESULTS: Our study included a final sample of 19 patients with MCD and 21 with MN. No C4d deposits were observed in any of the glomeruli in patients with MCD, and 100% of these patients were classified as negative. However, C4d deposits were detected in 100% of patients with MN, and were observable in all glomeruli with a uniform granular distribution, demarcating all capillary loops. CONCLUSIONS: C4d immunohistochemical staining is a very useful tool for diagnosing MN.

Significance of preimplantation analysis of kidney biopsies from expanded criteria donors in long-term outcome.

BACKGROUND: The shortage of organs has led to expanding the criteria for donors. Histologic evaluations before transplantation may enable the identification of organs unsuitable for single implantation. The aim of this study was to evaluate the histologic findings as prognostic factors of allograft survival from expanded criteria donors (ECDs). METHODS: We included a cohort of 136 single transplantations with kidneys from ECD and correlated the preimplantation pathologic findings with graft failure. Renal structures from ECD older (n=104) or younger (n=32) than 60 years were evaluated histologically for renal senescence and rated with a total histologic score. A multivariate Cox analysis was performed to identify predictors of graft failure. RESULTS: Glomerulosclerosis was the most prevalent lesion in biopsies from donors older and younger than 60 years (P=0.002); interstitial fibrosis was more severe in biopsies from older donors (P=0.001); older donors showed a higher prevalence of tubular atrophy (P=0.022), and vascular compartment showed no significant differences. Kidney biopsy-based scoring system ranged from 0 to 15 points, indicating the presence of changes in the renal parenchyma. Biopsies with total histologic scores less than or equal to 5 showed significantly better 5-year graft survival than those with scores more than 5 (P<0.001). A preimplantation score more than 5 points remained an independent predictor of graft failure (hazard ratio 6.95; 95% confidence interval 1.57-30). CONCLUSIONS: Histologic analysis of kidney biopsies before transplantation is a valuable tool for facilitating the selection of viable grafts from ECD donors. When the total score is more than 5, single kidney transplantation from ECD should not be recommended for patients similar to this study population.

Darbepoetin-α treatment enhances glomerular regenerative process in the Thy-1 glomerulonephritis model.

Recent studies have demonstrated that erythropoietin (EPO) and its analogs induce cytoprotective effects on many nonerythroid cells. In this study, we examined whether darbepoetin-α might prevent glomerular lesions in the Thy-1.1 model of glomerulonephritis (Thy-1-GN). GN was induced in Wistar rats by a single injection of monoclonal anti-Thy-1.1 antibody. Rats were killed at 24 h, 72 h, 7 days, 10 days, or 15 days after antibody injection. Kidneys were removed for histological analysis, and proteinuria was measured. Because at day 7 the maximal degree of renal damage and proteinuria was found, the effect of darbepoetin-α was tested at day 7 and two different protocols of administration were used; After anti-Thy-1.1 injection, rats received two doses of darbepoetin-α or vehicle at days 0 and 4 or at days 4 and 6. At day 7, proteinuria, plasma creatinine concentration, and renal morphology analysis were performed. Also, α-actin, desmin, caspase-3, and Ki67 protein expression were evaluated by immunohistochemistry. Our results showed that in both protocols of administration, darbepoetin-α treatment decreased proteinuria in Thy-1-GN rats and this effect correlated with the improvement in renal morphology. Glomerular lesions, α-actin, and caspase-3 protein expression, observed in most glomeruli of Thy-1-GN rats, were significantly reduced in darbepoetin-α-treated rats, while cell proliferation was significantly enhanced. The results indicate that darbepoetin-α treatment promotes glomerular recovery.

Mesangial C4d deposition: a new prognostic factor in IgA nephropathy.

BACKGROUND: It has been shown that patients with IgA nephropathy can be divided into two groups on the basis of the pattern of complement activation. Activation of the lectin pathway of complement is associated with more severe renal disease. Glomerular deposition of C4d is a marker of activation of the lectin pathway of complement. The aim of our study was to determine whether C4d staining at the time of the renal biopsy could identify patients with a different long-term prognosis in IgA nephropathy. METHODS: This retrospective cohort study included all patients with IgA nephropathy who underwent renal biopsy at our centre from January 1992 to December 2006. We evaluated baseline age, sex, presence of macroscopic haematuria, hypertension, serum creatinine and glomerular filtration rate (GFR), urine protein, mesangial C4d staining, glomerulosclerosis, interstitial fibrosis and extracapillary proliferation. Kaplan-Meier survival and Cox proportional hazards analyses were performed, with end-stage renal disease (ESRD) being defined as onset of dialysis or transplantation. RESULTS: Nineteen patients (32.2%) were C4d positive and 40 patients (67.8%) C4d negative. Age, hypertension, absence of macroscopic haematuria, serum creatinine levels, GFR, glomerular sclerosis, interstitial fibrosis and C4d-positive staining were all univariately associated with evolution to ESRD. Renal survival at 10 years was 43.9% in C4d-positive patients versus 90.9% in C4d-negative patients (log-rank, P = 0.0005). CONCLUSION: Negative mesangial C4d staining in glomeruli in patients with IgA nephropathy helps to identify patients with a good long-term prognostic for whom aggressive treatments are not justified.