The natural course of idiopathic membranous nephropathy is variable, with some patients slowly progressing to renal failure while others maintain normal renal function over the entire time. Whether to treat this disease or not is controversial due to the lack of controlled data about the long-term effects of treatment. We updated at 10 years the results of a controlled trial in which 81 patients with idiopathic membraneous nephropathy and nephrotic syndrome were randomly assigned to receive symptomatic therapy (39 patients) or a treatment of six months with methylprednisolone and chlorambucil (42 patients). The probability of surviving without developing end-stage renal disease at 10 years was 92% in patients given methylprednisolone and chlorambucil versus 60% in controls (P = 0.0038). The slope of the reciprocal of plasma creatinine up to 10 years was significantly better in treated patients than in controls (P = 0.035). The probability of having a complete or partial remission of the nephrotic syndrome was significantly higher in treated patients (P = 0.000). Patients assigned to therapy spent significantly longer time without nephrotic syndrome than untreated patients (P = 0.0001). Four patients had to stop treatment because of reversible side-effects. In the long-term one treated patient developed diabetes and another one became obese. In conclusion, a six-month therapy with methylprednisolone and chlorambucil increases the probability of remission of proteinuria and protects from renal function deterioration even in the long-term. This treatment may avoid dialysis or death within 10 years to about one third of nephrotic patients with membranous nephropathy.

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Summary Gastrointestinal complications are frequent in renal transplant recipients and can include oral lesions, esophagitis, peptic ulcer, diarrhea, colon disorders and malignancy. Oral lesions may be caused by drugs such as cyclosporine and sirolimus, by virus or fungal infections. Leukoplakia may develop in patients with Epstein–Barr virus (EBV) infection. The commonest esophageal disorder is represented by fungal esophagitis usually caused by candida. A number of patients may suffer from nausea, vomiting and gastric discomfort. These disorders are more frequent in patients treated with mycophenolate mofetil (MMF). Peptic ulcer is more rare than in the past. Patients with a history of peptic ulcer are particularly prone to this complication. Other gastroduodenal disorders are caused by cytomegalovirus (CMV) and herpes simplex infection. Diarrhea is a frequent disorder which may be caused by pathogen microorganisms or by immunosuppressive agents. The differential diagnosis may be difficult. Colon disorders mainly consist of hemorrhage, usually sustained by CMV infection, or perforation which may be caused by diverticulitis or intestinal ischemia. Colon cancer, anal carcinoma, and EBV‐associated lymphoproliferative disorders are particularly frequent in transplant recipients. A particular gastric lymphoma called mucosa‐associated lymphoid tissue (MALT) lymphoma may develop in renal transplant patients. It usually responds to the eradication of Helicobacter pylori.

Although a number of factors have consistently correlated with progression to chronic renal insufficiency (CRI) in idiopathic membranous glomerulonephropathy (IMGN), they appear late, are not quantitative in nature and have not been validated. We have determined that the highest sustained six-month period of proteinuria is an important predictor of progression. Using multiple logistic modelling, the only additional prognostic variables of importance in 184 Canadian patients were the initial creatinine clearance and the rate of change in function over this six-month interval. Independent data from Italy (101 patients) and Finland (78 patients) were obtained for comparison. Sensitivity, specificity, negative and positive predictive values and overall accuracy, as well as Pearson's goodness-of-fit and Harrell's "C" statistic were used to assess the fits of the model. Accuracy of prediction was > or = 85% in all three countries. Pearson's Chi-square goodness-of-fit showed good agreement across the spectrum and Harrell's "C" statistic was > or = 90%. Therefore, a predictive, semiquantitative algorithm in IMGN has been validated. Its relevance in patient management and in clinical trials is illustrated.

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.

BackgroundA cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking.MethodsWe randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events.ResultsAt 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen.ConclusionsThis pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial.Clinical Trial registry name and registration number:Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535

Sixty-seven adults with idiopathic membranous nephropathy and the nephrotic syndrome were randomly assigned to symptomatic treatment only or to a six-month course of methylprednisolone alternated with chlorambucil every other month. Patients were followed for one to seven years. At the end of follow-up (mean of 31.4 +/- 18.2 months for the treated group and 37.0 +/- 22.0 for the control group) 23 of 32 treated patients were in complete or partial remission, as compared with 9 of 30 control patients (P = 0.001). Twelve of the treated patients were in complete remission, as compared with only two of the controls. In the treated group there were no changes in renal function during follow-up, whereas in the control group the reciprocal of the plasma creatinin level, which is proportional to the creatinine clearance, decreased significantly (P = 0.00017) after two years of follow-up. Side effects were minimal in all treated patients except two, who were dropped from the study because of peptic ulcer and gastric intolerance to chlorambucil. We conclude that steroid and chlorambucil treatment for six months favors remission of the nephrotic syndrome in adults with idiopathic membranous nephropathy and can preserve renal function for at least some years.