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JAMA Pediatr. 2025 May 12:e250765. doi: 10.1001/jamapediatrics.2025.0765. Online ahead of print.
Tacrolimus or Mycophenolate Mofetil for Frequently Relapsing or Steroid-Dependent Nephrotic Syndrome: A Randomized Clinical Trial
Jingjing Wang, Fei Liu, Weili Yan, Jianhua Zhou, Yu Zhang, Liping Rong, Xiaoyun Jiang, Fei Zhao, Chunhua Zhu, Xiaochuan Wu, Xiaoyan Li, Shuzhen Sun, Jing Wang, Mo Wang, Qin Yang, Hong Xu, Jing Chen, Cuihua Liu, Ming Tian, Shipin Feng, Qinwei Duan, Xuhui Zhong, Yun Zhu, Xiaozhong Li , Haidong Fu, Lingfei Huang, Daqing Ma, Jie Ding, Qing Ye, Jianhua Mao
PMID: 40354041
PMCID: PMC12070277
Introduction
Pediatric nephrologists, when faced with a child with nephrotic syndrome, rarely rely on kidney biopsies to direct initial therapy. Idiopathic nephrotic syndrome is the most frequent pediatric glomerular disease, affecting ~17 per 100,000 children per year globally. Nearly ¾ of children, 1-12 years of age, with idiopathic nephrotic syndrome will have minimal change disease (MCD). Approximately 85–90% of patients attain complete remission of proteinuria within 4–6 weeks of treatment with glucocorticoids (prednisone or prednisolone), and therefore, have steroid-sensitive nephrotic syndrome (SSNS) and no need for logistically difficult (especially if sedation is required), invasive kidney biopsies. However, among those patients with SSNS, 70–80% will have at least one relapse during follow-up, and up to 50% of these patients will experience frequent relapsing (FRNS) or steroid dependent nephrotic syndrome (SDNS) (Trautmann A, et al. Pediatric Nephrology, 2022). In fact, the prognosis for children with nephrotic syndrome is best predicted by the patient’s initial response to steroid treatment and the frequency of relapses during the first year following remission. The ideal dose and duration of steroid treatment, to prolong time between relapses, remains a subject of much debate. The current study focuses on patients with FRNS and SDNS, rather than steroid resistant patients who fail to achieve remission (a distinct category unto itself).
Children with frequent relapses are exposed to a lot of steroids leading to short stature, hypertension, obesity, and behavioral problems, thus alternate therapies to keep children in remission are needed. Various steroid-sparing immunosuppressive drugs have been used in clinical practice for FRNS and SDNS, but there remains marked variation in the selection and timing of these alternative immunosuppressive medications. If you were blinded to the specific pathology of a patient with nephrotic syndrome, how would you choose a second-line treatment? Perhaps you would choose what is most familiar, what has the most favorable side-effect profile, cost, or dosing schedule, or even patient and guardian preference. The International Pediatric Nephrology Association (IPNA) recommends calcineurin inhibitors (CNIs), cyclophosphamide, levamisole and mycophenolate mofetil (MMF), but without a specific preference for one agent over others (grade A) in patients who have FRNS or SDNS. Rituximab has also been suggested for patients who have failed a trial one or more of the above agents. In 2025, KDIGO came out with guidelines for management of nephrotic syndrome in children. KDIGO places a higher value on the data suggesting that CNIs are more likely to induce remission than cyclophosphamide, MMF, or rituximab in the treatment of children with relapsing disease, but only grades this as a 1C recommendation (KDIGO 2025). Conversely, KDIGO places a lower value on evidence suggesting that prolonged CNI use leads to nephrotoxicity. This leads us to our current discussion: a randomized control study of tacrolimus versus MMF in pediatric patients with nephrotic syndrome. When treating FRNS or SDNS in children, which medication will get the STAMP of approval? Let’s press on (pun intended).
Figure 3. Glucocorticoid alternative choices. KDIGO 2025
The Study
Methods
This trial compares tacrolimus to MMF in pediatric patients with frequently relapsing nephrotic syndrome (FRNS) or steroid dependent nephrotic syndrome (SDNS). The STAMP trial was a prospective, multicenter, open-label, parallel-arm randomized clinical trial.
Patients 2-18 years with FRNS or SDNS were recruited from 12 Chinese pediatric nephrology centers. The definitions used for the onset, remission, and relapse of nephrotic syndrome are delineated in Table 1, and are standard pediatric definitions. The inclusion criteria included an eGFR greater than 90 mL/min/1.73 m2, a disease remission period, and no use of tacrolimus, MMF, cyclosporine A, rituximab, or cyclophosphamide within the 2-year period prior to enrollment. The exclusion criteria were any secondary form of nephrotic syndrome and/or the presence of an active infection.
Table 1. Definitions. Wang J, et al. JAMA Pediatr, 2025.
Eligible children were randomized 1:1 to receive tacrolimus or MMF along with a prednisolone taper over a 12-month period. Computer-generated random codes were used to assign treatment groups. The trial was open-label, meaning that neither the patients nor the study staff were blinded to the treatment allocation.
Intervention
Monthly blood samples were collected for drug concentration measurements. Tacrolimus was administered at 0.025 to 0.050 mg/kg twice daily. The target blood concentration was 5 to 10 ng/mL for 6 months, after which it was maintained at less than 5 ng/mL. MMF was administered at a dose of 10 to 15 mg/kg twice daily. The target for mycophenolic acid area under the curve (MPA-AUC) was 30 to 50 μg·h/mL for 6 months, and subsequently maintained at 40 or less μg·h/mL. Patients were monitored for 1 year, with visits at weeks 1, 4, and 8, then every 8 weeks until 40 weeks, with a final visit at 52 weeks. Medication compliance was monitored by counting returned pills. Treatment was stopped for withdrawal criteria, including lack of efficacy.
Outcomes
The primary outcome was 1-year relapse-free survival. The secondary outcomes included relapse frequency, the first relapse time, the relapse-free survival rate in the first 6 months, cumulative steroid dosage, blood pressure, height, body weight, blood cholesterol, serum albumin concentration, and eGFR. Treatment safety was also assessed with respect to respiration and heart rate, liver function, blood glucose, and adverse reactions.
Statistical Analysis
Sample size was calculated based on a prior study showing 1-year relapse-free survival rates of 56% for the MMF group and 70% for the tacrolimus group. With α = .05 (2-sided), 80% power, and 1:1 enrollment, it was estimated 114 patients prescribed MMF and 115 prescribed tacrolimus were needed. Accounting for 15% loss to follow-up, 270 patients (135 per group) were enrolled. Comparisons between groups were made using the χ2 test or Fisher exact test, with P values only reported. Intention-to-treat analysis was followed, with censored data for incomplete visits. Kaplan-Meier curves plotted 1-year survival rates. Mixed models for repeated measures assessed eGFR changes, reporting least-square means, least-square mean differences, and 95% confidence intervals. Annualized eGFR slopes were compared using a linear mixed-effects model.
Results
A total of 292 patients from 12 care centers were assessed for eligibility from November 2019 to May 2022, and 270 patients were randomized to receive either tacrolimus (n = 135) or MMF (n = 135). Median (IQR) age was 7 (4-10) years, and 26% were female. Study follow-up ended in July 2023. A total of 243 patients completed a 1-year trial, with 27 dropouts (6 from the tacrolimus group and 21 from the MMF group). Dropout was due to active withdrawal (from frequent relapses and side-effects), inability to achieve the target drug concentrations, AEs, and loss to follow-up. Similar baseline characteristics were observed between treatment groups. Diary reviews and returned pill counts suggested good treatment adherence in both groups.
Figure 1. Trial Flow. Wang J, et al. JAMA Pediatr, 2025.
Table 2. Baseline Characteristics. Wang J, et al. JAMA Pediatr, 2025.
In the full analysis set (FAS), the 1-year relapse-free survival rate in the tacrolimus group was 1.86 fold higher (HR, 2.86; 95% CI, 1.79-4.76). In addition, the 1-year relapse-free survival rate in the per-protocol set, the tacrolimus group increased by 1.78 fold with significantly lower relapse rates (18%) compared to the MMF group (42%). Unadjusted and adjusted Cox regression analyses consistently demonstrated HRs of 0.35 to 0.36 for tacrolimus versus MMF (95% CI, 0.21-0.59). During the 1-year treatment, a total of 43 relapse events in 24 patients were recorded among the 135 patients in the TAC group; in contrast, in the MMF group, 105 relapse events in 56 patients were noted. The mean (SD) time to first relapse was significantly longer in the tacrolimus group (324 days) compared to the MMF group (263 days). The relapse rates for toddlers (<4 years old), preschool age (4-7 years), and school-aged varied slightly, but always favored tacrolimus over MMF. Finally, during the study period, the tacrolimus group had lower mean daily steroid use per unit body weight than the MMF group (0.22 mg/kg/day vs 0.34 mg/kg/day).
Figure 2. One-year relapse free survival. Wang J, et al. JAMA Pediatr, 2025.
Table 3. Primary and secondary endpoints. Wang J, et al. JAMA Pediatr, 2025
Safety
Adverse events (AEs) were reported in 95% of the tacrolimus group and 93% of the MMF group, with 34% and 36% of AEs attributed to the study medication, respectively. Serious adverse events (SAEs) occurred in 9% of the tacrolimus group and 10% of MMF group participants. Infections were the most common SAE, affecting 8 of 12 tacrolimus patients with SAEs and 10 of 14 MMF patients with SAEs. SAEs led to withdrawal in <1% of the TAC group and in no participants in the MMF group. Acute kidney disease, defined as an eGFR less than 60 ml/min/1.73 m2, a decrease in eGFR of ≥35%, or an increase in serum creatinine of more than 50% within 3 months, was only observed in 1 patient in each group. All SAEs were resolved or relieved by symptom treatment. Serum creatinine, BUN and cystatin C levels remained within the normal range during the duration of the study in both groups. However, a more negative eGFR slope was seen in the tacrolimus group (−7.0 vs −1.9, p= 0.18).
Discussion
This study is the first large-scale, multicenter, prospective, randomized clinical trial to directly compare the therapeutic benefits and safety profiles of tacrolimus and MMF in children with FRNS or SDNS. Prior non-randomized, smaller studies suggested the efficacy of tacrolimus was comparable or superior to that of MMF. The present STAMP trial further demonstrates the superiority of tacrolimus over MMF in the maintenance of remission among patients with FRNS or SDNS. At the end of the 1-year treatment period, the tacrolimus group had a significantly higher relapse-free survival rate (82%) relative to the MMF cohort (59%). Furthermore, the incidence of relapses in the tacrolimus group was substantially lower, with 18% of patients reporting 43 relapses, whereas 41% of patients in the MMF group reported 105 relapses. The tacrolimus cohort also benefited from a reduced cumulative dosage of steroids, which may be clinically relevant in limiting side effects of therapy. Of concern was the more pronounced decline in eGFR slope observed in the tacrolimus group (though not statistically significant) suggesting the potential for subclinical nephrotoxicity. This aligns with the known mechanisms of CNIs, which can induce progressive dysfunction through kidney vasoconstriction and tubulointerstitial damage, even in the absence of overt acute kidney injury.
The one year safety profile of tacrolimus and MMF revealed that most AEs were mild, with infections (unsurprisingly) representing the most frequent SAE. It is recommended that drug level should be monitored during tacrolimus treatment, and that the lowest effective dose should be used to limit toxicity. IPNA recommends a kidney biopsy if CNIs have to be continued more than 2-3 years in children, to exclude toxicity. (Trautmann A, et al. Pediatric Nephrology, 2022) Results of studies with CNIs are accepted en bloc regardless of which agent is used (tacrolimus or cyclosporine). Side-effect profiles may drive medication choice as gingival hyperplasia and hypertrichosis are more prevalent with cyclosporine, and glucose intolerance occurs more frequently with tacrolimus. Conversely, MMF use does not require monitoring of levels (although mycophenolic acid (MPA) levels can be monitored to determine adequate therapeutic dosing and adherence). A prior study in children with nephrotic syndrome showed that patients with MMF AUC < 50 were more likely to relapse than those with AUC > 50, thus the MMF arm in this study may have been underdosed. (Gellerman J, et al. J Am Soc Nephol, 2013) For small children, or those with needle phobias, avoiding repeat phlebotomy may be preferred but may lead to underdosing. MMF is generally well tolerated and side effects are predominantly GI related (nausea, diarrhea and weight loss), and may be relieved by enteric coated formulations. Ultimately, patient factors and preference based upon information related to risks and benefits, should also be considered when choosing immunosuppressive therapies.
Immunosuppression treatment of glomerular disease is not a “one size fits all” scenario. There is limited head-to-head data in specific diseases, let alone in patients who do not have a kidney biopsy or a specific pathologic diagnosis. Perhaps in the future, improved serologic markers will help better define glomerular diseases in pediatric populations (I’m looking at you anti-nephrin) when studying therapeutics. KDIGO’s most recent guidance on this subject suggests that oral cyclophosphamide and levamisole may be preferable glucocorticoid-sparing therapies in FRNS. On the other hand MMF, rituximab, CNIs, and, to a lesser extent, oral cyclophosphamide may be preferable glucocorticoid-sparing therapies in children with SDNS (practice point 1.3.3.6, KDIGO 2025). However, this recommendation is only a practice point (ungraded) and lacks rigorous data to support its use. The current study did not distinguish between these two subgroups of pediatric nephrotic patients (FRNS vs SDNS), and therefore no additional guidance can be gleaned. Perhaps most importantly, identical pathology with different patterns of disease may warrant different treatment. As we continue to strive for greater precision in medicine, genetics may play an even greater role in determining effective treatment. In fact, a few mutations have already been identified to be associated with treatment responsiveness. For example, patients with WT1 and PLCE1 mutations have been found to have variable steroid responsiveness and increased responsiveness to low-dose CNIs. (Gellerman J, et al. Pediatr Nephrol, 2010)
Limitations
Duration of treatment was limited to 12 months, unclear if risk/benefit ratio would shift if longer duration of CNI treatment was needed, with nephrotoxicity emerging with time.
Analysis was limited to relapse-free survival during active treatment.
Homogenous Chinese population, needs to be validated in other cohorts.
Lack of kidney biopsy information. Also, no kidney pathology reports after tacrolimus use, though this is not routine with 12 months of usage.
No evaluation of treatment on quality of life.
Unblinded (open-labeled), could lead to bias.
Based upon AUC, MMF arm may have been underdosed.
Conclusion
Over 1-year of active treatment, tacrolimus was associated with a significantly greater relapse-free survival period as well as a reduced requirement for corticosteroids compared with MMF in frequently relapsing or steroid dependent children with steroid sensitive nephrotic syndrome.