Mario Espinosa

Spontaneous Remission of Nephrotic Syndrome in Idiopathic Membranous Nephropathy

Spontaneous remission is a well known characteristic of idiopathic membranous nephropathy, but contemporary studies describing predictors of remission and long-term outcomes are lacking. We conducted a retrospective, multicenter cohort study of 328 patients with nephrotic syndrome resulting from idiopathic membranous nephropathy that initially received conservative therapy. Spontaneous remission occurred in 104 (32%) patients: proteinuria progressively declined after diagnosis until remission of disease at 14.7 +/- 11.4 months. Although spontaneous remission was more frequent with lower levels of baseline proteinuria, it also frequently occurred in patients with massive proteinuria: 26% among those with baseline proteinuria 8 to 12 g/24 h and 22% among those with proteinuria >12 g/24 h. Baseline serum creatinine and proteinuria, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, and a >50% decline of proteinuria from baseline during the first year of follow-up were significant independent predictors for spontaneous remission. Only six patients (5.7%) experienced a relapse of nephrotic syndrome. The incidence of death and ESRD were significantly lower among patients with spontaneous remission. In conclusion, spontaneous remission is common among patients with nephrotic syndrome resulting from membranous nephropathy and carries a favorable long-term outcome with a low incidence of relapse. A decrease in proteinuria >50% from baseline during the first year predicts spontaneous remission.

An update for atypical haemolytic uraemic syndrome: diagnosis and treatment: A consensus document

Haemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Atypical HUS (aHUS) is a sub-type of HUS in which the TMA phenomena are the consequence of decreased regulation of the alternative complement pathway on cell surfaces due to a genetic cause. aHUS is an extremely rare disease that, despite the administration of standard treatment with plasma therapy, often progresses to terminal chronic renal failure with a high associated rate of mortality. In recent years, research has established the key role that the complement system plays in the induction of endothelial damage in patients with aHUS, through the characterisation of multiple mutations and polymorphisms in the genes that code for certain complement factors. Eculizumab is a monoclonal antibody that inhibits the terminal fraction of the complement protein, blocking the formation of a cell membrane attack complex. In prospective studies in patients with aHUS, administering eculizumab produces a rapid and sustained interruption in the TMA process, with significant improvements in long-term renal function and an important decrease in the need for dialysis or plasma therapy. In this document, we review and bring up to date the important aspects of this disease, with special emphasis on how recent advancements in diagnostic and therapeutic processes can modify the treatment of patients with aHUS.

Occult Hepatitis C Virus Infection among Hemodialysis Patients

Occult hepatitis C virus (HCV) infection (i.e., detectable HCV-RNA in the liver or peripheral blood mononuclear cells) in the absence of both serum HCV-RNA and anti-HCV antibodies has not been investigated in hemodialysis patients. In this study, real-time PCR and in situ hybridization was used to test for the presence of genomic and antigenomic HCV-RNA in peripheral blood mononuclear cells of 109 hemodialysis patients with abnormal levels of liver enzymes. Occult HCV infection, determined by the presence of genomic HCV-RNA, was found in 45% of the patients; 53% of these patients had ongoing HCV replication, indicated by the presence of antigenomic HCV-RNA. Patients with occult HCV infection had spent a significantly longer time on hemodialysis and had significantly higher mean alanine aminotransferase levels during the 6 mo before study entry. Logistic regression analysis revealed that mortality was associated with age >60 yr (odds ratio 3.30; 95% confidence interval 1.05 to 10.33) and the presence of occult HCV infection (odds ratio 3.84; 95% confidence interval 1.29 to 11.43). In conclusion, the prevalence of occult HCV infection is high among hemodialysis patients with persistently abnormal values of liver enzymes of unknown cause. The clinical significance of occult HCV infection in these patients requires further study.

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.

Association of C4d Deposition with Clinical Outcomes in IgA Nephropathy

BACKGROUND AND OBJECTIVES Several studies have suggested that activation of the complement system is a contributing pathogenic mechanism in IgA nephropathy (IgAN). C4d staining is an inexpensive and easy-to-perform method for the analysis of renal biopsies. This study aimed to assess the clinical and prognostic implications of C4d staining in IgAN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This retrospective cohort study included 283 patients with IgAN in 11 hospitals in Spain who underwent a renal biopsy between 1979 and 2010. The primary predictor was mesangial C4d staining. Secondary predictors included demographic, clinical, and laboratory characteristics, and Oxford pathologic classification criteria. The primary end point was the cumulative percentage of patients who developed ESRD, defined as onset of chronic dialysis or renal transplantation. C4d was analyzed by immunohistochemical staining using a polyclonal antibody. Kaplan-Meier and Cox proportional hazards analyses were performed to evaluate the effect of C4d staining on renal survival. RESULTS There were 109 patients (38.5%) and 174 patients (61.5%) who were classified as C4d positive and C4d negative, respectively. Renal survival at 20 years was 28% in C4d-positive patients versus 85% in C4d-negative patients (P<0.001). Independent risk factors associated with ESRD were as follows: proteinuria (hazard ratio [HR] per every 1 g/d increase. 1.16; 95% confidence interval [95% CI], 1.03 to 1.31; P=0.01), eGFR (HR per every 1 ml/min per 1.73 m(2) increase, 0.96; 95% CI, 0.94 to 0.97; P<0.001), T2 Oxford classification (tubular atrophy/interstitial fibrosis, >50%; HR, 4.42; 95% CI, 1.40 to 13.88; P=0.01), and C4d-positive staining (HR, 2.45; 95% CI, 1.30 to 4.64; P=0.01). CONCLUSIONS C4d-positive staining is an independent risk factor for the development of ESRD in IgAN. This finding is consistent with the possibility that complement activation is involved in the pathogenesis of this disease.

Actualización en síndrome hemolítico urémico atípico: diagnóstico y tratamiento. Documento de consenso

Haemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Different causes can induce the TMA process that characterizes HUS. In this document we consider atypical HUS (aHUS) a sub-type of HUS in which the TMA phenomena are the consequence of the endotelial damage in the microvasculature of the kidneys and other organs due to a disregulation of the activity of the complement system. In recent years, a variety of aHUs-related mutations have been identified in genes of the the complement system, which can explain approximately 60% of the aHUS cases, and a number of mutations and polymorphisms have been functionally characterized. These findings have stablished that aHUS is a consequence of the insufficient regulation of the activiation of the complement on cell surfaces, leading to endotelial damage mediated by C5 and the complement terminal pathway. Eculizumab is a monoclonal antibody that inhibits the activation of C5 and blocks the generation of the pro-inflammatory molecule C5a and the formation of the cell membrane attack complex. In prospective studies in patients with aHUS, the use of Eculizumab has shown a fast and sustained interruption of the TMA process and it has been associated with significative long-term improvements in renal function, the interruption of plasma therapy and important reductions in the need of dialysis. According to the existing literature and the accumulated clinical experience, the Spanish aHUS Group published a consensus document with recommendations for the treatment of aHUs (Nefrologia 2013;33[1]:27-45). In the current online version of this document, we update the aetiological classification of TMAs, the pathophysiology of aHUS, its differential diagnosis and its therapeutic management.

Natural history of acute HCV infection in hemodialysis patients.

AIMS Chronic liver disease develops in the majority of non-uremic patients with hepatitis C virus (HCV) infection. The aim of this study was to analyze the evolution towards chronic hepatopathy in 19 cases of acute hepatitis C observed in hemodialysis patients from 1990 to 2001. METHODS A prospective follow-up study on HCV infection was conducted in 3 HD units from April 1990 to June 2001 to study clinical outcomes after acute hepatitis C. A total of 781 patients were tested monthly for alanine aminotransferase and anti-HCV in serum. In this period, 19 patients suffered from acute hepatitis C. Evolution to chronic liver disease in the follow-up was evaluated by means of biochemical (increased ALT) and virological criteria (HCV-RNA+). The transmission mechanism, the apparition of anti-HCV, clinical manifestations and mortality were also investigated. RESULTS In 15 (78.9%) of the 19 patients, the viremia remained positive (chronic viremia) and 11 patients (57.8%) evolved to chronic liver disease (chronic viremia and high transaminase levels) with a median follow-up of 3 years (range 1 - 6). Five of them who underwent liver biopsies had histologic signs of chronic active hepatitis. One of them (5.2%) evolved to liver cirrhosis in the follow-up. In 4 out of 19 patients (21%) the HCV infection resolved. Although 7 (36.8%) of them died in the follow-up, acute hepatitis C infection was not a short-term independent risk factor of death. CONCLUSIONS Three years after acute hepatitis C, 87.5% of the hemodialysis patients remained HCV-RNA positive and 56.2% evolved to chronic liver disease. It is important to stress that HCV infection spontaneously cleared in 4 out of 19 patients (21%).

Effectiveness of mycophenolate mofetil in C3 glomerulonephritis

C3 glomerulonephritis is a clinicopathologic entity defined by the presence of isolated or dominant deposits of C3 on immunofluorescence. To explore the effect of immunosuppression on C3 glomerulonephritis, we studied a series of 60 patients in whom a complete registry of treatments was available over a median follow-up of 47 months. Twenty patients had not received immunosuppressive treatments. In the remaining 40 patients, 22 had been treated with corticosteroids plus mycophenolate mofetil while 18 were treated with other immunosuppressive regimens (corticosteroids alone or corticosteroids plus cyclophosphamide). The number of patients developing end-stage renal disease was significantly lower among treated compared with untreated patients (3 vs. 7 patients, respectively). No patient in the corticosteroids plus mycophenolate mofetil group doubled serum creatinine nor developed end-stage renal disease, as compared with 7 (significant) and 3 (not significant), respectively, in patients treated with other immunosuppressive regimens. Renal survival (100, 80, and 72% at 5 years) and the number of patients achieving clinical remission (86, 50, and 25%) were significantly higher in patients treated with corticosteroids plus mycophenolate mofetil as compared with patients treated with other immunosuppressive regimens and untreated patients, respectively. Thus, immunosuppressive treatments, particularly corticosteroids plus mycophenolate mofetil, can be beneficial in C3 glomerulonephritis.

Predictors of response and relapse in patients with idiopathic membranous nephropathy treated with tacrolimus

BACKGROUND Although tacrolimus is recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis for the treatment of idiopathic membranous nephropathy (MN), little is known about factors that influence response and relapse of the disease after tacrolimus therapy. METHODS Multicentre study that collected 122 MN patients with nephrotic syndrome and stable renal function treated with tacrolimus. Duration of treatment was 17.6 ± 7.2 months, including a full-dose and a tapering period. RESULTS The percentage of remission was 60, 78 and 84% after 6, 12 and 18 months of treatment, respectively. The amount of proteinuria at baseline significantly predicted remission, the lower the baseline proteinuria the higher the probability of remission. Only 10 patients (8%) received concomitantly corticosteroids, and their rate of remission was similar (80% at 18 months). Among responders, 42% achieved complete remission (CR) and 58% partial remission (PR). Almost half (44%) of the responder patients relapsed. The amount of proteinuria at the onset of tacrolimus tapering was significantly higher in relapsing patients. By multivariable analysis, the presence of a PR versus CR at the onset of tacrolimus tapering and a shorter duration of the tapering period significantly predicted relapses. Tolerance was good and the number of adverse events low. CONCLUSIONS Tacrolimus monotherapy is an effective and safe option for the treatment of MN with stable renal function. Relapses are frequent in patients with PR and can be partially prevented by a longer tapering period.

Elevated factor H–related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy

IgA nephropathy (IgAN), a frequent cause of chronic kidney disease worldwide, is characterized by mesangial deposition of galactose-deficient IgA1-containing immune complexes. Complement involvement in IgAN pathogenesis is suggested by the glomerular deposition of complement components and the strong protection from IgAN development conferred by the deletion of the CFHR3 and CFHR1 genes (ΔCFHR3-CFHR1). Here we searched for correlations between clinical progression and levels of factor H (FH) and FH-related protein 1 (FHR-1) using well-characterized patient cohorts consisting of 112 patients with IgAN, 46 with non-complement-related autosomal dominant polycystic kidney disease (ADPKD), and 76 control individuals. Patients with either IgAN or ADPKD presented normal FH but abnormally elevated FHR-1 levels and FHR-1/FH ratios compared to control individuals. Highest FHR-1 levels and FHR-1/FH ratios are found in patients with IgAN with disease progression and in patients with ADPKD who have reached chronic kidney disease, suggesting that renal function impairment elevates the FHR-1/FH ratio, which may increase FHR-1/FH competition for activated C3 fragments. Interestingly, ΔCFHR3-CFHR1 homozygotes are protected from IgAN, but not from ADPKD, and we found five IgAN patients with low FH carrying CFH or CFI pathogenic variants. These data support a decreased FH activity in IgAN due to increased FHR-1/FH competition or pathogenic CFH variants. They also suggest that alternative pathway complement activation in patients with IgAN, initially triggered by galactose-deficient IgA1-containing immune complexes, may exacerbate in a vicious circle as renal function deterioration increase FHR-1 levels. Thus, a role of FHR-1 in IgAN pathogenesis is to compete with complement regulation by FH.