A 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.
We 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.
At 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.
This 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.
Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.
Primary membranous nephropathy (MN) is a frequent cause of nephrotic syndrome (NS) in adults. In untreated patients, the outcome is variable, with one-third of the patients entering remission while ...the remaining ones show persisting proteinuria or progression to end-stage renal disease. Randomized clinical trials reported the efficacy of a 6-month regimen alternating intravenous and oral glucocorticoids with an alkylating agent every other month. The potential side effects of this regimen were limited by the fact that the use of glucocorticoids and alkylating agent did not exceed 3 months each. Two randomized trials with follow-ups (FU) up to 10 years provided assurance about the long-term efficacy and safety of this cyclical therapy. Calcineurin inhibitors have also been used successfully. However, in most responders, NS relapsed after the drug was withdrawn. Conflicting results have been reported with mycophenolate salts and adrenocorticotropic hormone. Observational studies reported good results with rituximab (RTX). Two controlled trials demonstrated the superiority of RTX over antiproteinuric therapy alone and cyclosporine. However, the FUs were relatively short and no randomized trial has been published against cyclical therapy. The available results, together with the discovery that most patients with MN have circulating antibodies against the phospholipase A2 receptor 1, support the use of cytotoxic drugs or RTX in MN. It is difficult to choose between these two different treatments. RTX is easier to use, but the FUs of the available studies are short, thus doubts remain about the long-term risk of relapses and the safety of repeated administrations of RTX.
Primary membranous nephropathy (MN) is a frequent cause of NS in adults. In native kidneys the disease may progress to ESRD in the long term, in some 40-50% of untreated patients. The identification ...of the pathogenic role of anti-podocyte autoantibodies and the development of new therapeutic options has achieved an amelioration in the prognosis of this disease. MN may also develop in renal allograft as a recurrent or a
disease. Since the
MN may have some different pathogenetic and morphologic features compared to recurrent MN, in the present paper we will deal only with the recurrent disease. The true incidence of the recurrent form is difficult to assess. This is mainly due to the variable graft biopsy policies in kidney transplantation, among the different transplant centers. Anti-phospholipase A2 receptor (PLA2R) autoantibodies are detected in 70-80% of patients. The knowledge of anti-PLA2R status before transplant is useful in predicting the risk of recurrence. In addition, the serial survey of the anti-PLA2R titers is important to assess the rate of disease progression and the response to treatment. Currently, there are no established guidelines for prevention and treatment of recurrent MN. Symptomatic therapy may help to reduce the signs and symptoms related to the nephrotic syndrome. Anecdotal cases of response to cyclical therapy with steroids and cyclophosphamide have been published. Promising results have been reported with rituximab in both prophylaxis and treatment of recurrence. However, these results are based on observational data, and prospective controlled trials are still missing.
West Nile virus infection is more frequently associated with neuroinvasive disease and high morbidity and mortality in immunocompromised hosts. Here, we describe a 47-year-old Egyptian kidney ...transplant recipient who was admitted to our department in 2016 for persistent fever, altered mental status, and upper limb tremors. In addition, renal impairment, signs of acute thrombotic microangiopathy, pancreatitis, and slightly altered inflammatory indices were present. The patient was treated with antibacterial and antiviral therapy, and reduced immunosuppressive therapy was prescribed. After several biochemical and instrumental examinations, only slight blood positivity for West Nile virus immunoglobulin M in the absence of immunoglobulin G was found, whereas immunoglobulins M and G on cerebrospinal fluid and West Nile virus polymerase chain reaction were negative. Serology evaluated after 23 days of hospitalization confirmed immunoglobulin M positivity and detected weak immunoglobulin G positivity; however, according to the US Centers for Disease Control and Prevention diagnostic criteria, it was not sufficient to confirm diagnosis. During hospitalization, clinical recovery was observed, but severe renal insufficiency persisted. Renal biopsy performed after clinical recovery demonstrated chronic antibody-mediated rejection with advanced chronic lesions, without viral cytopathic signs. Four months later, we received confirmation of West Nile virus infection by plaque reduction neutralization test. The current case described severe West Nile virus infection with clinical neurologic involvement, thrombotic microangiopathy, and pancreatitis, resulting in irreversible loss of kidney function. Delayed diagnosis, based on US Centers for Disease Control and Prevention criteria, was due to absence of both characteristic radiologic features and sensitive and promptly available laboratory tests. This case stresses the need for accurate diagnostic tests and/or a partial revision of the diagnostic criteria. In fact, with an earlier diagnosis, we would have avoided diagnostic and therapeutic procedures that may have contributed to the loss of graft function in the described case.
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.
Background:
We conducted a pilot trial to compare the effectiveness and safety of 2 different treatments in patients with membranous nephropathy and nephrotic syndrome.
Methods:
To validate the ...hypothesis that the 2 treatments were equivalent, patients with biopsy-proven membranous nephropathy and nephrotic syndrome were randomly assigned to methylprednisolone alternated with a cytotoxic drug every other month for 6 months (group A) or to intramuscular synthetic adrenocorticotropic hormone administered twice a week for 1 year (group B).
Results:
The primary outcome measure is cumulative number of remissions as a first event. Fifteen of 16 patients in group A and 14 of 16 patients in group B entered complete or partial remission as a first event. After a median follow-up of 24 months (interquartile range, 15 to 25 months), there were 4 complete remissions and 8 partial remissions in group A versus 8 complete remissions and 6 partial remissions in group B. Median proteinuria decreased from protein of 5.1 g/d (interquartile range, 4.0 to 7.3 g/d) to 2.1 g/d (interquartile range, 0.4 to 3.8 g/d;
P = 0.004) in group A and 6.0 g/d (interquartile range, 4.4 to 8.5 g/d) to 0.3 g/d (interquartile range, 0.2 to 1.9 g/d;
P = 0.049) in group B. Two patients from each group interrupted treatment because of side effects or inefficacy.
Conclusion:
Most nephrotic patients with membranous nephropathy responded to either treatment. Proteinuria was significantly decreased with both methylprednisolone and cytotoxic agents or prolonged administration of synthetic adrenocorticotropic hormone, without significant differences between these 2 therapies.
The research of novel markers in urinary samples, for the description of renal damage, is of high interest, and several works demonstrated the value of urinary mRNA quantification for the search of ...events related to renal disease or affecting the outcome of transplant kidneys. In the present pilot study, a comparison of the urine mRNA expression of specific podocyte markers among patients who had undergone clinical indication to renal transplanted (RTx, n = 20) and native (N, n = 18) renal biopsy was performed. The aim of this work was to identify genes involved in podocytes signaling and cytoskeletal regulation (NPHS1, NPHS2, SYNPO, WT1, TRPC6, GRM1, and NEUROD) in respect to glomerular pathology. We considered some genes relevant for podocytes signaling and for the function of the glomerular filter applying an alternative normalization approach. Our results demonstrate the WT1 urinary mRNA increases in both groups and it is helpful for podocyte normalization. Furthermore, an increase in the expression of TRPC6 after all kinds of normalizations was observed. According to our data, WT1 normalization might be considered an alternative approach to correct the expression of urinary mRNA. In addition, our study underlines the importance of slit diaphragm proteins involved in calcium disequilibrium, such as TRPC6.
The management of hepatitis C virus (HCV)-induced glomerular disease remains unsatisfactory despite novel advances in antiviral and immunosuppressive therapy. Recent evidence highlighted the role of ...ribavirin, a drug provided with immunomodulatory properties, in the treatment of glomerular diseases associated with chronic HCV. We administered low-dose ribavirin (200 mg/day or 200 mg twice a week or 200 mg thrice weekly) in a prospective fashion to a group of patients with HCV-associated glomerular disease (n = 7). Ribavirin monotherapy was given in most (n = 6) patients and was accompanied by erythropoietin therapy in all. The primary endpoint was reduction of 24-h proteinuria after treatment ended; the secondary end-points were decrease in serum creatinine and amelioration of urinary abnormalities. We collected data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities. Many patients (n = 6) had inactive HCV infection as they had shown HCV RNA clearance from serum after antiviral therapy with direct-acting antivirals. Some patients (n = 4) had membranoproliferative glomerulo- nephritis, the diagnosis being confirmed by kidney histology in three cases; others (n = 2) received diagnosis of diabetic glomerulosclerosis, confirmed in one by kidney biopsy. We observed consistent reduction of 24-h proteinuria in two individuals after ribavirin therapy; another patient reported disappearance of microscopic hematuria. We found severe AE (hemolytic anemia) in three patients which required discontinuation of ribavirin treatment in two patients, one required hospitalization. Other AEs were cutaneous rash (n = 1), dyspepsia (n = 1), and fatigue (n = 1). Low-dose ribavirin was able to give consistent reduction of 24-h proteinuria in two patients; tolerance to ribavirin was unsatisfactory. We need further studies aimed to expand our knowledge on ribavirin therapy of HCV-associated glomerular disease. The low incidence of the disease hampers the conduction of clinical trials on this aim.
Background/Aims: Interferon treatment of malignant or viral diseases can be accompanied by various side-effects including nephro-toxicity. Methods: We report on a 68-year-old Caucasian male who ...received dual therapy with pegylated interferon 2a plus ribavirin for chronic hepatitis C. Results: After three months of antiviral therapy, the patient developed acute kidney failure (serum creatinine up to 6 mg/dL) with mild proteinuria (500 mg daily) and haematuria. Immediate immunosuppressive therapy with high-dose intravenous steroids did not improve kidney function. Kidney biopsy was consistent with acute tubular necrosis without glomerular abnormalities. He started long-term peritoneal dialysis (four regular exchanges) to provide both dialysis adequacy and ascites removal. Kidney function gradually improved over the following months (serum creatinine around 2 mg/dL) and peritoneal dialysis was continued with two exchanges daily. The temporal relationship between the administration of the drug and the occurrence of nephro-toxicity, and the absence of other obvious reasons for acute tubular necrosis support a causative role for pegylated interferon; benefit on kidney disease was noted after withdrawal of antiviral agents. An extensive review of the literature on acute tubular necrosis associated with interferon-based therapy, based on in vitro data and earlier case-reports, has been made. The proposed pathogenic mechanisms are reviewed. Conclusions: Our case emphasizes the importance of monitoring renal function during treatment of chronic hepatitis C with antiviral combination therapy as treatment may precipitate kidney damage at tubular level.
Validation of a predictive model of idiopathic membranous nephropathy: Its clinical and research implications. 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 > 85% in all three countries. Pearson's Chi-square goodness-of-fit showed good agreement across the spectrum and Harrell's “C” statistic was ≥ 90%. Therefore, a predictive, semiquantitative algorithm in IMGN has been validated. Its relevance in patient management and in clinical trials is illustrated.
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