Low-Dose Spironolactone Safe, Effective for Proteinuria Reduction in IgA Nephropathy

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Findings from a recent study are providing evidence of the safety and efficacy of mineralocorticoid receptor antagonists for reducing urine protein excretion in patients with IgA nephropathy (IgAN).¹

Results confirm the beneficial effects of spironolactone for proteinuria reduction within 2 months of treatment, complementing the effects of renin-angiotensin-aldosterone system (RAAS) blockers and glucocorticoids. Of note, response varied among patients, with those showing endocapillary proliferation in renal biopsies having poor spironolactone responsiveness.¹

“Recent advances in nonsteroidal, selective mineralocorticoid receptor antagonists have demonstrated a reduction in the urinary albumin-to-creatinine ratio in diabetic patients treated with a RAAS blocker,” Lingyun Lai, PhD, of the department of nephrology at Huashan Hospital in China, and colleagues wrote.¹ “Research on the potential of mineralocorticoid receptor antagonists to reduce protein in IgAN is lacking. Although a small subset of IgAN patients were involved in CKD research, the specific effects on IgAN have not been thoroughly examined.”

Mineralocorticoid receptor antagonists, also known as aldosterone antagonists, block the action of aldosterone to help release excess water and salt without losing potassium.2 Although they are frequently used to decrease albumin excretion in chronic kidney disease, less is known about their potential impact on proteinuria in IgAN.¹

To assess the effectiveness of mineralocorticoid receptor antagonists for the treatment of proteinuria in patients with IgAN, investigators conducted an observational, retrospective cohort study of adult patients treated with spironolactone at Huashan Hospital Fudan University in China from December 2010 to July 2020. Investigators examined a 6-month regimen of spironolactone in IgAN patients who were also receiving optimal RAAS inhibitor, steroid, or hydroxychloroquine therapy and yet continued to have ≥ 0.3 g of proteinuria over a 24-h period.¹

A total of 90 IgA nephropathy patients were prescribed spironolactone during the study period. However, 2 patients were excluded from the study because they discontinued treatment in the first 2 months due to recurrent hyperkalemia and pregnancy intentions. Thus, a total of 88 patients were then included in the final analysis. Among the cohort, 60% of patients were male and the average glomerular filtration rate (GFR) was 81.1 ± 28.4 mL/min/1.73 m2 with a median 24 h proteinuria of 1.50 (Interquartile range [IQR], 1.03-2.32) g at renal biopsy.¹

Investigators noted all patients had RAAS inhibitors added, except 2 with low levels of renal function. Among the 88 patients, 26.1% received prednisone or immunosuppressants, with 12 patients undergoing prednisone therapy also being prescribed spironolactone due to proteinuria levels averaging 0.95 (IQR, 0.68-1.36) g/day after > 3 months of prednisone treatment.¹

After 2 months of spironolactone, the median 24-h proteinuria was significantly reduced from 0.93 to 0.70 g (P <.001), accompanied by a reduction in eGFR from 75.7 ± 28.6 to 73.9 ± 29.8 (P = .033) and diastolic blood pressure (DBP) from 80.0 ± 11.1 to 78.2 ± 9.8 (P = .041). Although spironolactone showed a trend toward reducing systolic blood pressure (SBP) (P = .119), it did not affect hematuria and serum potassium in the overall patient population.¹

To further analyze the characteristics of patients with better response to spironolactone, investigators divided the cohort into 2 groups, the effective and ineffective groups, based on whether 24 h-proteinuria decreased by > 20% (the mean rate of proteinuria change) after 2 months of treatment with spironolactone compared to the baseline.¹

The effective group comprised 47 patients after 2 months of treatment. The median 24 h-proteinuria decreased from 1.05 (IQR, 0.68-1.56) g to 0.50 (IQR, 0.33-0.83) g (P <.001). SBP decreased from 125.7 ± 15.9 to 121.1 ± 14.7 mm Hg (P = .041), and a reduction in eGFR was also observed after spironolactone treatment (71.0 ± 26.3 v. 66.8 ± 28 mL/min/1.73 m2; P = .035).¹

Among the 41 patients who responded less effectively to spironolactone, the median 24-h proteinuria increased from 0.83 g (IQR 0.55-1.31) to 1.04 g (IQR 0.67-1.66) (P = .003), with no differences observed in hematuria, eGFR, SBP, or DBP. Investigators noted the ineffective group had a greater proportion of glomerular endocapillary proliferation in renal biopsy findings (31.7% vs 13.3%; P = .040).¹

Investigators also pointed out patients in the effective group were generally in poorer condition compared to those in the ineffective group, as evidenced by the effective group’s trend toward a higher percentage of GCs history (45.5% vs 29.3%; P = .124), more severe proteinuria (1.05g vs 0.83g; P = .085), and poorer renal function (eGFR 71.0 vs 81.0; P = .102) with spironolactone treatment.¹

After 6 months of treatment, in the effective group, eGFR (66.8 vs 66.9 mL/min/1.73 m2; P = .480) and proteinuria (0.50 g vs 0.50 g per day; P = .347) remained stable when compared to the measurements taken after 2 months of treatment. In the ineffective group, 23 patients experienced slight reductions in proteinuria, going from 0.76 g (IQR, 0.53-1.03) to 0.75 g (IQR, 0.53-1.11) after 2 months. However, the effect on proteinuria improved after 6 months of spironolactone use, decreasing to 0.57 g (IQR, 0.31-0.76; P = .001).¹

Investigators acknowledged potential limitations to these findings, including the single center, retrospective study design without a placebo control, as well as the lack of a unified clinical standard for the use of spironolactone in patients, which may result in inconsistent treatment effects and decrease reliability.¹

“The findings of this study suggest that MR antagonists can reduce proteinuria in patients with IgAN, complementing the effects of RAS blockers or even glucocorticoids,” investigators concluded.¹ “Nevertheless, to definitively prove the beneficial effects of aldosterone antagonists on the progression of CKD, more extensive prospective randomized studies of longer duration are required.”

References

1. ^{Shang D, Guan Y, Liu S, et al. Effectiveness and Safety of Spironolactone in the Treatment of IgA Nephropathy: A Retrospective Self-Controlled Study. Kidney Blood Press. https://doi.org/10.1159/000540283}
2. ^{Cleveland Clinic. Aldosterone Antagonists. Treatments & Procedures. April 29, 2022. https://my.clevelandclinic.org/health/treatments/22917-aldosterone-antagonists}