Single versus dual blockade of the renin-angiotensin system in patients with IgA nephropathy

Abstract

Background Inhibitors of the renin-angiotensin system (RAS) are cornerstones of supportive therapy in patients with IgA nephropathy (IgAN). We analyzed the effects of single versus dual RAS blockaQueryde during our randomized STOP-IgAN trial. Methods STOP-IgAN participants with available successive information on their RAS treatment regimen and renal outcomes during the randomized 3-year trial phase were stratified post hoc into two groups, i.e. patients under continuous single or dual RAS blocker therapy over the entire 3 years of the trial phase. Primary and secondary STOP-IgAN trial endpoints, i.e. frequencies of full clinical remission, eGFR-loss ≥ 15 and ≥ 30 ml/min/1.73 m 2 and ESRD onset, were analyzed by logistic regression and linear mixed effects models. Results Among the 112 patients included in the present analysis, 82 (73%) were maintained on single and 30 (27%) on dual RAS inhibitor therapy throughout the trial. Neither RAS blocker strategy significantly affected full clinical remission, eGFR-loss rates, onset of ESRD. Proteinuria moderately increased in patients under dual RAS blockade by 0.1 g/g creatinine during the 3-year trial phase. This was particularly evident in patients without additional immunosuppression during the randomized trial phase, where proteinuria increased by 0.2 g/g creatinine in the dual RAS blockade group. In contrast, proteinuria decreased in patients under single RAS blocker therapy by 0.3 g/g creatinine. The course of eGFR remained stable and did not differ between the RAS treatment strategies. Conclusion In the STOP-IgAN cohort, neither RAS blocker regimen altered renal outcomes. Patients on dual RAS blockade even exhibited higher proteinuria over the 3-year trial phase.

Comparative efficacy of different renin angiotensin system blockade therapies in patients with IgA nephropathy: a Bayesian network meta-analysis of 17 RCTs

“…Recently, Lennartz et al based on the results of the 3-year trial STOP-IgAN, found no obvious difference in blood pressure between treatment groups, but patients on dual RAS blockade had a slightly higher level of proteinuria. In addition, there was no significant difference between groups regarding the loss of kidney function during the trial (Lennartz et al, 2020). The results of this article differ from our analysis mainly because of the differences in the methods.…”

KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases

“…A post hoc analysis of the STOP-IgAN trial demonstrated no additional benefit with dual blockade. 89 In the judgment of the Work Group, a strong recommendation is warranted because of the consistency of the benefits for treatment of hypertension and proteinuria observed across the spectrum of kidney diseases, the generally low risk of harm for hypertension and antiproteinuric treatment, and the lack of rationale for a different recommendation for IgAN specifically.…”

“…A post hoc analysis of the STOP-IgAN trial demonstrated no additional benefit with dual blockade. 89 Recommendation 2.3.2: We recommend that all patients with proteinuria >0.5 g/d, irrespective of whether they have hypertension, be treated with either an ACEi or ARB (1B). independent of changes in BP control, is associated with improved kidney outcome.…”

“…A post hoc analysis of the STOP-IgAN trial demonstrated no additional benefit with dual blockade. 89 It is uncertain, however, whether RAS blockade will lead to better outcomes in IgAN with moderately increased albuminuria (30-300 mg/d) and normal BP, given the absence of RCTs addressing this question. In view of the current uncertainty over the safety and efficacy of existing immunosuppressive treatment choices, all patients who remain at high risk of progressive CKD despite maximal supportive care should be offered the opportunity to take part in a clinical trial.…”

Current treatment of IgA nephropathy

“…However, recent findings from our STOP-IgAN cohort argue against such a dual RAS blocker regimen. Unexpectedly, proteinuria at the end of the randomized, 3-year trial phase was even higher in our patients on dual RAS blocker therapy whereas overall renal outcomes were comparable between trial participants under single and those dual RAS blocker therapy [ 11 ]. Another RAS-blocking therapy, the direct renin inhibitor aliskiren, has been shown to reduce proteinuria at 6 months by a further 26% and suppress serum IL-6 and TGF-β levels when given to IgAN patients with proteinuria > 1 g/day despite optimized ARB treatment [ 12 ].…”