What is the issue?
Nephrotic syndrome is a condition where the kidneys leak protein from the blood into the urine. Minimal change disease defined on kidney biopsy is the third most common primary kidney disease in adults with unexplained nephrotic syndrome (10% to 15%). The most effective treatment regimens have not been determined.
What did we do?
We identified all randomised controlled trials (RCTs), which investigated the treatment of adults with nephrotic syndrome due to minimal change disease. We searched for RCTs evaluating steroid therapy and those evaluating other agents with/without steroid therapy.
What did we find?
We found 15 studies randomising 769 participants, whose results could be evaluated. Calcineurin inhibitors (tacrolimus, cyclosporin) with/without low-dose prednisolone were as effective as prednisolone alone in achieving remission with no differences in the numbers who were resistant or who relapsed (eight studies) but with reduced side effects of obesity and acne. Enteric-coated mycophenolate sodium was as effective as prednisolone alone in achieving remission with no differences found in side effects. We found that it was unclear whether prednisolone compared to no treatment or intravenous methylprednisolone influences the number of participants with remission or subsequent relapse because the certainty of the evidence was very low. In a single small study, no differences in the number with remission or relapse were identified with levamisole compared with prednisolone. We did not find any completed studies evaluating rituximab but two studies are in progress.
We found that data included in this updated review indicate that calcineurin inhibitors and enteric-coated mycophenolate sodium may be effective in achieving remission in adults with nephrotic syndrome due to MCD with some reduction in the side effects of high dose prednisolone therapy. Studies of these therapies in relapsing disease and in MCD resistant to prednisolone therapy are required.
This updated review has identified evidence for the efficacy and adverse effects of CNIs and EC-MPS with or without reduced-dose prednisolone compared with prednisolone alone for the induction of remission in adults with MCD and nephrotic syndrome with some reductions in steroid-associated adverse events. RCT data on the efficacy and adverse effects of rituximab in adults with MCD are awaited. Further, adequately powered RCTs are required to determine the relative efficacies of CNIs and EC-MPS and to evaluate these medications in patients with relapsing or steroid-resistant disease.
Steroids have been used widely since the early 1970s for the treatment of adult-onset minimal change disease (MCD). Recently, newer agents have been used in adult MCD aiming to reduce the risk of adverse effects. The response rates to immunosuppressive agents in adult MCD are more variable than in children. The optimal agent, dose, and duration of treatment for the first episode of nephrotic syndrome, or for disease relapse(s) have not been determined. This is an update of a review first published in 2008.
We aimed to 1) evaluate the benefits and harms of different agents, including both immunosuppressive and non-immunosuppressive agents, in adults with MCD causing the nephrotic syndrome; and 2) evaluate the efficacy of interventions on 'time-to-remission' of nephrotic syndrome, in adults with MCD causing the nephrotic syndrome.
We searched the Cochrane Kidney and Transplant Register of Studies up to 21 July 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Randomised controlled trials (RCTs) and quasi-RCTs of any intervention for MCD with nephrotic syndrome in adults over 18 years were included. Studies comparing different types, routes, frequencies, and duration of immunosuppressive agents and non-immunosuppressive agents were assessed.
Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random-effects model and results were expressed as a risk ratio (RR) for dichotomous outcomes, or mean difference (MD) for continuous data with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Fifteen RCTs (769 randomised participants) were identified; four studies evaluated different prednisolone regimens, eight studies evaluated the calcineurin inhibitors (CNIs) (tacrolimus or cyclosporin), two studies evaluated enteric-coated mycophenolate sodium (EC-MPS) and one study evaluated levamisole. In all but two studies of non-corticosteroid agents, reduced-dose prednisolone was given with the treatment agent and the comparator was high-dose prednisolone. In the risk of bias assessment, 11 and seven studies were at low risk of bias for sequence generation and allocation concealment, respectively. No studies were at low risk of performance bias and eight studies were at low risk of detection bias. Thirteen, 10 and six studies were at low risk of attrition bias, reporting bias and other bias, respectively.
Compared with no specific treatment, it is uncertain whether prednisolone increases the number with complete remission (1 study, 28 participants: RR 1.44, 95% CI 0.95 to 2.19), complete or partial remission (1 study, 28 participants: RR 1.38, 95% CI 0.98 to 1.95), subsequent relapse (1 study, 28 participants: RR 0.75, 95% CI 0.48 to 1.17), or reduces the adverse effects because the certainty of the evidence is very low. Compared with oral prednisolone alone, it is uncertain whether intravenous methylprednisolone and prednisolone increase the number with complete remission (2 studies, 35 participants: RR 1.76, 95% CI 0.17 to 18.32; I² = 90%), relapse (two studies, 19 participants. RR 1.18, 95% CI 0.65 to 2.15; I² = 0%) or adverse events because the certainty of the evidence is very low.
Compared with prednisolone alone, CNIs with reduced-dose prednisolone or without prednisolone probably make little or no difference to the number achieving complete remission (8 studies; 492 participants: RR 0.99, 95% CI 0.93 to 1.05; I² = 0%), complete or partial remission (4 studies, 269 participants: RR 1.01, 95% CI 0.96 to 1.05; I² = 0%), or relapse (7 studies; 422 participants: RR 0.73, 95% CI 0.51 to 1.03; I² = 0%) (moderate certainty evidence), may reduce the risk of obesity or Cushing's Syndrome (5 studies; 388 participants: RR 0.11, 95% CI 0.02 to 0.59; I² = 45%) and the risk of acne (4 studies; 270 participants: RR 0.15, 95% CI 0.03 to 0.67; I² = 0%) (low certainty evidence); and had uncertain effects on diabetes or hyperglycaemia, hypertension, and acute kidney injury (AKI) (low certainty evidence).
Compared with prednisolone alone, EC-MPS with reduced-dose prednisolone probably make little or no difference to the number undergoing complete remission at 4 weeks (1 study, 114 participants: RR 1.12, 95% CI 0.84 to 1.50), and at 24 weeks probably make little or no difference to the number undergoing complete remission (2 studies, 134 participants: RR 1.12, 95% CI 0.84 to 1.38; I² = 0%) (moderate certainty evidence), complete or partial remission (2 studies 134 participants: RR 0.92, 95% CI 0.75 to 1.12; I² = 0%), relapse (2 studies, 83 participants: RR 0.50, 95% CI 0.07 to 3.74; I² = 56%) (low certainty evidence); or to the adverse events of new-onset glucose intolerance, death, or AKI (low certainty evidence).
One study (24 participants) compared levamisole and prednisolone with prednisolone in patients with relapsing disease. The authors identified no differences in mean relapse rate or adverse effects but no standard deviations were provided.