Millions of people worldwide are affected by chronic kidney disease (CKD), putting them at an increased risk for kidney failure and the need for dialysis or kidney transplantation. Kidney transplantation offers significant advantages over dialysis, including improved survival rates, lower healthcare costs, enhanced quality of life, and the ability to return to a productive life.
Mineralocorticoid receptor antagonists (MRAs) protect kidney function among patients with CKD by lowering blood pressure, limiting cardiac remodeling, and reducing inflammation and fibrosis. However, few data are available regarding the role of MRAs in the treatment of kidney transplant recipients. The need for robust clinical trial data is associated with the lack of definitive guidelines, specifically endorsing the use of MRAs in the kidney transplant population.
Paula Dibo, MD, and colleagues recently conducted a meta-analysis designed to determine the efficacy of MRAs among kidney transplant recipients. The researchers aimed to provide an up-to-date literature review incorporating novel studies conducted since the last review in 2020.
The literature search included PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to June 2024. The search terms used were kidney transplant, renal transplant, kidney allograft, post-transplant, mineralocorticoid receptor blockers, aldosterone antagonists, spironolactone, finerenone, eplerenone, canrenone, and mexrenone.
The primary outcomes of interest were serum creatinine (sCR), glomerular filtration rate (GFR), hyperkalemia, systolic BP, diastolic BP, albuminuria, proteinuria, and interstitial fibrosis and tubular atrophy (IFTA) scores.
The initial search produced 1,501 results. After duplicate records and ineligible studies had been removed, 25 studies were fully reviewed based on inclusion criteria. Of those, five were included in the qualitative and quantitative review. The five studies represented 293 kidney transplant recipients; of those, 48.5% (n=142) received treatment with MRAs. Three of the five studies included spironolactone as part of the MRA regimen; the remaining two studies used eplerenone.
The mean age of participants in the MRA group was 42.5 years, and the mean age of those in the placebo group was 41.1 years. Overall, approximately two-thirds of the participants were male and had received dialysis before kidney transplant.
No statistically significant differences were observed between the placebo and MRA groups in GFR (mean difference [MD]9.04 mL/min/1.73 m2; 95% CI, –2.76 to 20.85; P=0.13). The two groups were also similar in sCR (MD, –0.21 mg/dL; 95% CI, –0.62 to 0.20; P=0.32).
No statistically significant differences were observed between those treated with MRAs and those without MRA treatment in systolic BP (MD, 0.69 mm Hg; 95% CI, –0.69 to 2.08; P=0.33) or diastolic BP (MD, 0.45 mm Hg; 95% CI, –0.69 to 1.59; P=0.44).
Patients treated with MRAs had a significantly higher risk for hyperkalemia compared with patients without MRA treatment (risk ratio [RR]4.06; 95% CI, 1.46-11.28; P=0.007). The groups were similar in IFTA scores (mild IFTA: RR, 1.21; 95% CI, 0.83-1.74; P=0.32; moderate IFTA: RR, 0.82; 95% CI, 0.45-1.50; P=0.51; severe IFTA: RR, 0.64; 95% CI, 0.24-1.76; P=0.39).
No differences were noted between the group treated with MRAs and the group without MRA treatment in the severity of albuminuria (MD, –0.06 mg/g; 95% CI, –0.37 to 0.25; P=0.71) or in severity of proteinuria (MD, –0.13 g/d; 95% CI, –0.67 to 0.41; P=0.18).
Researchers performed a series of sensitivity analyses to determine the elevated heterogeneity seen in the outcomes of GFR, systolic BP, and diastolic BP. Glomerular filtration rate had the highest heterogeneity (I2=97.3%), followed by systolic BP (I2=90.3%) and diastolic BP (I2=86.7%). In the leave-one-out analysis for GFR, the exclusion of the SPIREN study reduced heterogeneity from I2=97.3% to 89.2%; however, the pooled effect size remained stable.
Results of study quality assessment using the Cochrane RoB 2 quality assessment tool revealed that most of the studies were rated as having a low risk of bias or some concerns. In four of the five studies, patients and investigators were blinded. The fifth study was not blinded to the clinical researchers and was rated as having a high risk of bias in the measurement of outcome domain. Two studies had a rating of some concerns in the randomization domain.
Using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool, the certainty of evidence for the outcome of hyperkalemia was rated as high. Because of concerns about risk of bias from one study with unblinded outcome assessment, the outcomes of sCR and IFTA scores were rated as moderate certainty. Because of serious concerns related to the risk of bias, inconsistency, and imprecision, the certainty of evidence for GFR and systolic BP was rated as very low.
The authors included the variability of study design, the substantial heterogeneity among the included studies, the variation in follow-up periods among the studies, and the possibility that some outcomes may be underpowered for a definitive conclusion on the absence of an effect as limitations of their study.
In conclusion, the researchers wrote, “In this meta-analysis of patients who underwent KT [kidney transplantation]we found no adverse effect of steroidal MRA use on sCR levels and no beneficial impact on IFTA scores, albuminuria, or proteinuria compared to placebo. However, steroidal MRAs led to a significantly higher risk of hyperkalemia.”
