Randomized Controlled Trial of Mineralocorticoid Receptor Blockade in Children with Chronic Kidney Allograft Nephropathy

Abstract

Background and objectives: We showed that mineralocorticoid receptor blockade (MRB) prevented acute and chronic cyclosporine nephropathy (CsA-Nx) in the rat. The aim of this translational study was to investigate the effect of long-term eplerenone administration on renal allograft function in children with biopsy-proven chronic allograft nephropathy (CAN).

Design, setting, participants, & measurements: Renal transplant children <18 years, biopsy-proven CAN, and a GFR>40 ml/min per 1.73 m² were included. Patients with BK virus active nephritis, recurrence of renal disease, GFR decline in previous 3 months, or treated with calcium antagonists or antifungal drugs were excluded. They were randomized to receive placebo (n=10) or eplerenone 25 mg/d for 24 months (n=13). Visits were scheduled at baseline, 6, 12, and 24 months. At each period, a complete clinical examination was performed and blood and urine samples were taken. Urine creatinine, 8-hydroxylated-guanosine, heat shock protein 72 (HSP72), and kidney injury molecule (KIM-1) levels were also assessed. In kidney biopsy samples, the tubulo-interstitial area affected by fibrosis (TIF) and glomerulosclerosis were measured at baseline and after 24 months.

Results: The baseline eGFR was 80±6 in the placebo and 86±6 ml/min per 1.73 m² in the eplerenone group; at 24 months it was 66±8 and 81±7 ml/min per 1.73 m², respectively (P=0.33; 95% confidence intervals, -18 to 33 at baseline, and -11 to 40 after 24 months). The albumin-to-creatinine ratio was 110±74 in the placebo, and 265±140 mg/g in the eplerenone group; and after 24 months it was 276±140 and 228±88 mg/g, respectively (P=0.15; 95% confidence intervals, -283 to 593, and -485 to 391, respectively). In addition, the placebo exhibited a greater TIF, glomerulosclerosis, and urinary HSP72 compared with the eplerenone group.

Conclusions: Although this study was underpowered to provide definitive evidence that long-term eplerenone administration attenuates the progression of CAN in pediatric transplant patients, it encourages testing the potential benefit of MRB in this pediatric population.

Graphical abstract

Figure 1.

Study flow diagram. Twenty-four renal transplant children fulfilling the inclusion criteria from 131 studied renal graft biopsy samples. The children were randomized to receive placebo (n=11) or eplerenone (n=13) for 24 months. Only one patient from the placebo group discontinued the study treatment.

Figure 2.

Effect of long-term eplerenone administration on BP, serum potassium, and aldosterone levels in placebo- (○) or eplerenone-treated patients (■). (A) Systolic BP, (B) diastolic BP, (C) serum potassium levels, and (D) serum aldosterone levels. The data are expressed as mean±SD.

Figure 3.

Long-term eplerenone administration effect on renal function and tubulo-interstitial fibrosis. (A) Serum creatinine, (B) eGFR by the Zappitelli formula, (C) urinary albumin-to-creatinine ratio, and (D) percentage of tubulo-interstitial fibrosis assessed by morphometry analysis in placebo- (○) or eplerenone-treated patients (■). The data are expressed as mean±SD, except for urinary albumin-to-creatinine ratio expressed as median and 25th–75th percentiles. Alb/Cr, albumine/creatinine ratio; Ep0, eplerenone month 0; Ep6, eplerenone month 6; Ep12, eplerenone month 12; Ep24, eplerenone month 24; P0, placebo month 0; P6, placebo month 6; P12, placebo month 12; P24, placebo month 24.

Figure 4.

Effect of long-term eplerenone treatment on glomerular injury. Glomerulosclerosis percentage was quantified in renal biopsy samples from placebo- or eplerenone-treated groups at 0 and 24 months. (A) FSGS, (B) global glomerulosclerosis, and (C) total glomerulosclerosis in placebo 0 (white bars), placebo 24 (squared bars), eplerenone 0 (gray bars), and eplerenone 24 (black bars). The data are expressed as mean±SD, *P<0.05 versus placebo 0 group. Ep0, eplerenone month 0; Ep24, eplerenone month 24; GS, glomerulosclerosis; P0, placebo month 0; P24, placebo month 24.

Figure 5.

Long-term eplerenone administration on oxidative stress and urinary renal injury biomarkers. (A) 8-Hydroxylated guanosine (white bars) in placebo 24 (squared bars), eplerenone 0 (gray bars), and eplerenone 24 (black bars). (B) Percentage of change in urinary HSP72 compared with baseline in placebo (white bars) and eplerenone 24 (black bars). (C) Urinary KIM-1 in placebo- (○) or eplerenone-treated pediatric patients (■). (D) TGF-β1 at baseline and 12 months of treatment. The data are expressed as mean±SD. Cr, creatinine; Ep0, eplerenone month 0; Ep24, eplerenone month 24; P0, placebo month 0; P24, placebo month 24.