Tacrolimus may be an effective alternative to high-dose steroids as first-line treatment for adults with minimal change nephrotic syndrome (MCNS), according to investigators.
A 24-week open-label study of 144 adults, found that tacrolimus plus low-dose steroids was noninferior to high-dose steroid therapy for achieving complete remission at 8 weeks, Sang Koo Lee, MD, of Asan Medical Center at the University of Ulsan in Seoul, South Korea, and colleagues reported in the Journal of American Society of Nephrology. Treatment with a maintenance dose of tacrolimus during steroid tapering reduced the relapse rate and appeared to result in no clinically-relevant safety differences.
“The efficacy and safety of combined tacrolimus and low-dose steroid has not been known well,” Dr Lee said.
The investigators randomly assigned 144 patients with primary biopsy-confirmed MCNS (initial or relapsed) MCNS to receive tacrolimus, a calcineurin inhibitor (CNI) 0.05 mg/kg twice daily plus prednisolone 0.5 mg/kg once daily or once-daily 1 mg/kg prednisolone alone for up to 8 weeks or until complete remission is achieved. Once patients achieved complete remission, the steroid was tapered to a maintenance dose of 5.0 to 7.5 mg/d in both groups until 24 weeks after study drug initiation. The patients ranged in age from 16 to 79 years. A total of 113 patients completed the study.
Results showed that 79.1% of patients in the tacrolimus plus low-dose steroid group achieved complete remission within 8 weeks compared with 76.8% receiving high-dose steroid therapy, a finding that the investigators said demonstrated that tacrolimus was noninferior to high-dose steroids for MCNS.
“Combined tacrolimus and low-dose steroid represent an important therapeutic option to limit exposure to steroids, especially for patients with contraindications or intolerance to standard high-dose steroid treatment,” Dr Lee said.
Significantly fewer patients relapsed on maintenance tacrolimus (3-8 ng/mL) plus tapered steroid (5.7%) compared with tapered steroids alone (22.6%). In terms of safety, the investigators observed no significant differences between the study arms. Most adverse events (AEs) were classified as mild or moderate. Two cases of severe AEs occurred in each of the groups.
The investigators said that, to their knowledge, their study is the first randomized controlled trial to directly compare these 2 protocols in adult patients with MCNS. “Future comparative studies should further taper or discontinue tacrolimus, and extend the follow-up period beyond 24 weeks, to determine if there is a true reduction in relapse or if the combined tacrolimus and low-dose steroid treatment only delays the time to relapse versus standard treatment,” they wrote.
With respect to study limitations, the authors acknowledged that open-label trials can be limited by reporting bias due to lack of allocation concealment and blinding. Other limitations included a relatively short follow-up duration and a study population made up of patients of a single ethnicity (Korean).
Renu Regunathan-Shenk, MD, assistant professor of medicine at the George Washington University School of Medicine and Health Sciences in Washington, DC, praised the study for its clinical relevance. “While the current KDIGO [Kidney Disease: Improving Global Outcomes] guidelines recommend high-dose steroid as first-line treatment for minimal change disease, in practice many adults cannot tolerate this treatment as it may cause or exacerbate conditions such as diabetes, obesity, and psychiatric disease,” Dr Regunathan-Shenk said.
Many patients also discontinue steroids due to cosmetic side effects such as weight gain, acne, and facial puffiness, she said. The addition of a CNI to low-dose steroids may help minimize these side effects and reduce relapse rates, which are higher in the adult population.
“I am surprised that the time to remission did not differ between the 2 groups, as in my practice I often see patients respond to calcineurin inhibitors faster than they do to steroid treatment,” said Dr. Regunathan-Shenk.
While CNIs often are well tolerated, they require therapeutic drug monitoring due to the potential for long-term toxicity. Subsequently, patients must be carefully managed. More follow-up is warranted to determine the long-term safety of using calcineurin inhibitors for this patient population, she said.
“Studies like these are important to provide clinicians with more options to treat minimal change disease in adults,” Dr Regunathan-Shenk added. “Most data on minimal change disease comes from the pediatric literature; however, adults with minimal change disease are more likely to have steroid resistance or dependence, as well as frequent relapse, making them more difficult to treat.”
Abdallah Geara, MD, an assistant professor of clinical medicine at Penn Medicine in Philadelphia, Pennsylvannia, said the majority of patients with MCNS do not end up with significant kidney dysfunction long term, but the side effects of high-dose steroids have a major long-term impact. “This study does prove that we can safely and efficiently treat minimal change disease with much lower doses of steroids when combining them with tacrolimus,” Dr Geara said. “This is a step in the right direction. In general, these results are not surprising. Over the last few years we have seen different studies confirming that we are using way too much steroid in glomerular disease in general.”
The current study, she said, is impressive due to its design and inclusion of a large number of patients for this rare disease. “This study will help us build a roadmap for our patients in the future to use.”
Syeda B. Ahmad, MD, a nephrologist at the University of Pittsburgh Medical Center Kidney Disease Center in Pittsburgh, Pennsylvania, agrees, noting that the clinical relevance of the new study will help change the current treatment to a reduced-dose steroid regimen.
“This study provides clinicians with a blueprint on how to combine low-dose steroids with CNI and tapering regimen, which is currently not established in the nephrology community,” said Dr Geara. “Calcineurin inhibitors are an important class of medications in the treatment of glomerular diseases due to their effect on podocyte stabilization and favorable side effect profile. They are less toxic than cyclophosphamide and can be used for a longer time interval.”
Chin HJ, Chae DW, Kim YC, et al. Comparison of the efficacy and safety of tacrolimus and low-dose corticosteroid with high-dose corticosteroid for minimal change nephrotic syndrome in adults. Published online November 9, 2020. J Am Soc Nephrol. doi:10.1681/ASN.2019050546