We describe the case of a 51-year-old woman with HCV-associated cryoglobulinemic glomerulonephritis (GN). She presented mild deterioration of kidney function, non-nephrotic proteinuria, and active ...urinary sediment. Kidney biopsy showed features of membranoproliferative changes with some sclerosis. Sustained viral response (SVR) was obtained by 6 months of antiviral therapy (peg-IFN-α2a plus ribavirin). SVR was linked with improvement of kidney function and remission of proteinuria. Clinical and virological remission persists over a 25-month follow-up. This case report emphasizes efficacy and safety of antiviral treatment of HCV-associated glomerulonephritis – preliminary but encouraging results exist. We identified by systematic review of the literature 9 studies (156 unique patients); the pooled estimate of frequency of sustained virological response after IFN-based therapy was 0.49 (95% confidence interval, CI: 0.21, 0.77; p < 0.0005; random effects model). Heterogeneity was found (I2 = 98.9%, p < 0.0001). Two possible regimens should be considered for the treatment of HCV-associated cryoglobulinemic GN according to the clinical presentation. Immunosuppressive therapy is recommended for HCV-related kidney disease having aggressive course, and recent evidence supports rituximab (RTX) use with a reduced exposure to corticosteroids. We identified six studies (66 unique patients) on RTX therapy for HCV-associated kidney disease; at the end of RTX therapy, the pooled estimate of the mean decrease in proteinuria was 1.4 g/24 h (95% CI: 0.75, 2.05, p < 0.001); The p test for heterogeneity gave a value of 0.94 (I2 = 0). Several questions related to RTX use remain. HCV-induced GN is uncommon among CKD patients of developed countries, and this clearly hampers prospective controlled clinical trials aimed to evaluate efficacy and safety of antiviral or immunosuppressive therapy in this population.
Idiopathic membranous nephropathy (IMN) may have a variable course, with some patients entering spontaneous remission and others slowly progressing to renal failure. The disease is treatable, but the ...available treatments are not devoid of potential morbidity. We review the studies dedicated to finding prognostic markers. Although a number of clinical and histologic markers are associated with an increased risk of progression to renal failure, in many cases it is still impossible to recognize at presentation what will be the long-term outcome for a patient with IMN. More reliable are time-dependent predictors, such as the amount of proteinuria over time and complete or partial remission. However, this means that a physician should wait for months or even years before taking therapeutic decisions, with the risk of starting after renal or extrarenal complications have already developed. How to proceed will have to be dictated by a careful evaluation of the patient: Taking into consideration not only the risk of renal progression but also the possible extrarenal complications, we suggest starting a "specific" treatment for patients presenting with full-blown nephrotic syndrome or with increasing levels of serum creatinine, while specific treatment is not necessary for asymptomatic patients with subnephrotic proteinuria.
: Background: The relative role of IgA anomalies and genetic factors in IgA nephropathy (IgAN) recurrence after transplantation has never been investigated in a single cohort.
Methods: Sixty‐one ...transplanted patients who had IgAN as an original disease (30 with biopsy‐proved early recurrence, median 2.9 yr post‐transplant), and 120 controls, were investigated for aberrantly glycosylated IgA1, IgA binding to mesangial matrix, macromolecular IgA (IgA/fibronectin and uteroglobulin/IgA/fibronectin complexes), and polymorphisms of cytokines tumor necrosis factor alpha (TNFα), interleukin 10 (IL‐10), IL‐6, interferon gamma and transforming growth factor beta 1 and renin‐angiotensin system (angiotensinogen converting enzyme, angiotensin II receptor 1, and angiotensinogen) genes.
Results: At multivariate logistic regression analysis, recurrence showed a border‐line association with aberrantly glycosylated IgA1 odds ratio (OR) 8.172, p = 0.077, and was significantly less frequent in carriers of ‐308 AG/AA TNF‐α“high producer” genotype (OR 0.125, p = 0.036) and ‐1082, ‐819, ‐592 ACC/ATA IL‐10 “low producer” (OR 0.038, p = 0.009) genotypes.
Conclusion: High levels of aberrantly glycosylated IgA1 do not appear to play a strong crucial role in recurrence of IgAN. Polymorphisms of TNFα and IL‐10 known to condition Th1 prevalence were associated with protection from early recurrence of IgAN.
Importance of the field: Idiopathic membranous nephropathy (IMN) can have a variable natural course. Treatments able to induce remission can improve the long-term prognosis. However, the optimal ...therapy for IMN remains controversial.
Area covered in this review: We reviewed the historical and current literature from 1979 to 2010 regarding the natural course of IMN and the possible treatments giving special emphasis to randomized controlled trials and to more recent approaches.
What the reader will gain: The reader will gain a comprehensive review of the available treatments of IMN. A personal therapeutic algorithm for nephrotic patients with IMN is also provided.
Take home message: At least five different treatments showed efficacy in many (but not all) patients with IMN.
Depletion of clusterin in renal diseases causing nephrotic syndrome.
Clusterin is a lipoprotein that has anti-complement effects in membranous nephropathy (MN). In focal segmental glomerulosclerosis ...(FSGS), it inhibits permeability plasma factor activity and could influence proteinuria. Moreover, with aging, knockout mice for clusterin develop a progressive glomerulopathy with sclerosis.
Since little is known about clusterin metabolism in humans, we determined clusterin levels and composition in the sera and urine of 23 patients with MN, 25 with FSGS and 23 with steroid-responsive nephrotic syndrome (NS). Renal localization was evaluated by immunofluorescence and morphometry.
Serum clusterin was markedly reduced in active MN, in FSGS and in children with NS compared to controls; after stable remission of proteinuria, nearly normal levels were restored. Among various biochemical variables, serum clusterin was inversely correlated with hypercholesterolemia. Urinary clusterin, representing a 0.01 fraction of serum, was higher in the urine from normal subjects and FSGS patients in remission with proteinuric MN, FSGS and idiopathic NS; clusterin was inversely correlated with proteinuria. In all cases, urinary and serum clusterin was composed of the same 80 kD isoforms. Finally, a decrease in focal segmental or global clusterin staining was found in FSGS glomeruli, especially in areas of sclerosis. Instead, in MN an overall increment of staining was observed that ranged from mild/focal to very intense/diffuse.
The overall pool of clusterin is reduced in glomerular diseases causing nephrotic syndrome, with hypercholesterolemia appearing as the unifying feature. Depletion of clusterin should negatively affect the clinical outcome in nephrotic patients and efforts should be aimed at normalizing clusterin overall pool.
It is still unknown whether it is better to administer cyclosporine (CsA) once or twice a day to renal-transplant patients.
Fifty-four patients were randomized to receive CsA once a day (OD group, 28 ...patients) or twice a day (BD group, 26 patients). Clinical parameters and pharmacokinetic studies were regularly monitored over the first year.
Two patients lost their grafts because of renal vascular thrombosis. A patient in the BD group died. The other 51 patients were alive with graft functioning after a minimum follow-up of 1 year. Five patients per group had reversible acute rejection. There was a not significant trend toward a lower mean serum creatinine in OD than in BD (1.38 +/- 0.38 and 1.7 +/- 0.80 mg/dL at 1 year posttransplant, respectively). In 47 patients, 319 pharmacokinetic studies were performed. We measured the area under the concentration-time curve during the first 4 hours (AUC0-4) and CsA blood levels at 0, 2, and 4 hours after dosing. C0 was significantly lower in OD than in BD (P=0.0011), whereas C2 (P<0.0001) and C4 (P<0.0001) were significantly higher in OD than in BD. In OD, the AUC was higher than in BD (P<0.0001). OD allows us to reach high levels of C2 and AUC for several hours after dosing, whereas BD showed persistently high levels throughout the whole day.
No difference in survival and rejection rates were observed between OD and BD groups.
Background:
The evidence in the medical literature on the treatment of hepatitis C virus–associated glomerular disease is extremely limited. The advent of nonconventional immunosuppressive agents and ...direct-acting antivirals promises high efficacy and safety.
Aims:
We conducted an open-label, single-arm clinical study to examine the efficacy and safety of a combined approach for hepatitis C virus–associated glomerular disease.
Methods:
In the first phase of the study, patients with hepatitis C virus–associated glomerular disease received interferon-based antiviral therapy and immunosuppressive agents; since 2013, interferon-free antiviral therapy was adopted and novel immunosuppressants (including B-cell depleting agents and mycophenolate mofetil) or immunomodulators (ribavirin) were choiced. Virological and clinical responses were evaluated over a long observation period (median follow-up of 60 weeks and 46.5 months after the end of treatment with interferon and direct-acting antiviral agents, respectively).
Results:
We enrolled 25 consecutive patients with hepatitis C virus–associated glomerular disease, 8 being liver transplant recipients for hepatitis C. A total of 13 patients received therapy with direct-acting antivirals and experienced sustained viral response (serum hepatitis C virus RNA <12 IU/mL, 12 weeks after treatment ended, sustained viral response12). The mean (±standard deviation) proteinuria decreased from 2.61 ± 1.01 at baseline to 1.71 ± 1.43 (g/day) at sustained viral response 48, p = 0.031; microscopic hematuria and serum cryoglobulins disappeared in six (50%) and seven (64%) patients, respectively, after sustained viral response by direct-acting antivirals. Adverse events occurred in 69% (9/13) of patients and were mild, with four cases of ribavirin-related anemia requiring blood transfusions (no drop-outs). After sustained viral response by direct-acting antivirals, immunosuppressive and immunomodulatory agents were initiated in clinical relapsers (n = 2) and nonresponders (n = 3) with some benefit. Among patients on interferon-based regimens (n = 12), viral response (sustained viral response 24) and dropout rates were 58% (7/12) and 33% (4/12), respectively. After sustained viral response by interferon-based therapy, clinical relapsers (n = 3) were successfully managed with immunosuppressive agents in two patients.
Conclusion:
Treatment with direct-acting antivirals provides excellent rates of viral response and safety in patients with hepatitis C virus–related glomerular disease; viral response was frequently accompanied by clinical improvement. The absence of hepatitis C virus RNA from serum allowed immunosuppressive and immunomodulatory therapies with benefits for glomerular abnormalities and no concern on hepatitis C virus replication.
Background. Little information is available about the long-term outcome of renal transplanted patients with idiopathic membranous nephropathy (MN). Methods. The outcomes of 35 first renal transplants ...performed between 1975 and 2008 in patients with MN were compared with those of 70 controls transplanted in the same period and matched for sex, age and source of donors. Results. The mean post-transplant follow-up was 117 ± 86 months for MN patients and 123 ± 83 months for controls. At 15 years, patient survival was 96% in patients with MN and 88% in the controls (P = ns), while graft survival rates were respectively 40% and 69% (P = 0.06). MN recurred in 12 patients (34%), namely in 4/8 (50%) patients who received the kidney from related living donors and in 8/27 (29.6%) who received the kidney from a deceased donor. Recurrence led to graft failure in six patients, all deceased donor kidney recipients, within 54 ± 33 months. The other six grafts are functioning 134 ± 73 months after transplantation. Patients with recurrence were more frequently females (42% vs 4.3%, P = 0.02). The recurrence occurred earlier (4.8 ± 3.0 vs 45.6 ± 46.9 months, P = 0.05), and there was a trend to develop a higher proteinuria (7.1 ± 5.5 vs 3.67 ± 2.6 g/24 h, P = 0.1) in grafts eventually lost because of recurrence. Conclusions. The long-term patient survival was similar in renal transplant recipients with MN and in controls. The graft survival was lower in MN patients than in controls, although the difference was at borderline significance. Recurrence occurred in one-third of the patients and caused graft loss in half of them.
We conducted a controlled trial to investigate the long-term effects of treatment with methylprednisolone and chlorambucil in patients with idiopathic membranous nephropathy. We have previously ...reported that after a mean of 31 months, treated patients did better. We now report the results of a longer follow-up. Eighty-one patients with proteinuria (greater than or equal to 3.5 g per day) and biopsy-proved membranous nephropathy were randomly assigned to receive either supportive therapy alone or a six-month course of corticosteroids alternated with chlorambucil (0.2 mg per kilogram of body weight per day) every other month. Methylprednisolone was first given intravenously in three pulses (1 g per day) and was then given orally (0.4 mg per kilogram per day) for 27 days. The patients were followed for 2 to 11 years (median, 5). Two patients in the control group and one in the treatment group died. At the last follow-up visit, 9 of 39 patients assigned to the control group (23 percent) and 28 of 42 patients assigned to the treatment group (67 percent) did not have the nephrotic syndrome. At five years there were more remissions of the nephrotic syndrome in treated patients than in controls (22 of 30 vs. 10 of 25; P = 0.026). Compared with base-line values, the mean reciprocal of the plasma creatinine level declined significantly in the control group (33 percent; P = 0.0002) but not in the treatment group (6 percent; P not significant). Plasma creatinine increased by 50 percent or more in 19 controls (49 percent) and in 4 treated patients (10 percent). We conclude that a six-month course of methylprednisolone and chlorambucil can bring about sustained remission of the nephrotic syndrome and help to preserve renal function in patients with idiopathic membranous nephropathy.
In renal allograft recipients, most cases of liver dysfunction are caused by hepatitis B virus and hepatitis C virus (HCV). The natural history of hepatitis C and B was studied in 286 renal allograft ...recipients who received a kidney allograft between 1972 and 1989 when tests for anti-HCV became available.
In all patients, hepatitis B (HB) surface (s) antigen (Ag) was tested before and anti-HCV (by enzyme-linked immunosorbent assay II) after transplantation.
At enrollment in 1989 (5.5+/-4 years after transplantation), 209 patients were anti-HCV positive (C+), 42 patients were HBsAg-positive (B+), and 35 patients were both B+ and C+ (C+B+). One hundred four patients were receiving azathioprine (AZA) and 182 were on cyclosporine A (CsA). Since transplantation, the median follow-up was 18 years in AZA-treated and 13 years in CsA-treated patients. Liver biopsy showed chronic hepatitis in 73 patients, cirrhosis in 20 patients, and fibrosing cholestatic hepatitis in 2 patients. In 34 patients, liver biopsy was repeated, and progression of fibrosis was observed in 24 patients. The 12-year patient survival rate was similar in B+, C+, and B+C+ patients (67%, 78%, and 71%, respectively; P=not significant). Liver-related death was the first cause of death in B+ and B+C+ infected patients (58% and 72%, respectively), whereas cardiovascular disease was the leading cause of death in C+ patients (40%). Multivariate analysis showed that older age (>40 years) (relative risk RR, 2.8), B+ status (RR, 2.36), and C+ status (RR, 1.65) were independently associated with a worse patient survival.
In the long term, B+ patients had a higher risk of death related to liver disease than C+ patients, and co-infection did not worsen patient survival.
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