Mineralocorticoid receptor blockade with spironolactone has no direct effect on plasma IL-17A and injury markers in urine from kidney transplant patients

Abstract

Kidney transplantation is associated with increased risk of cardiovascular morbidity. Interleukin (IL)-17A mediates kidney injury. Aldosterone promotes T helper 17 lymphocyte differentiation and IL-17A production through the mineralocorticoid receptor. In this exploratory, post hoc substudy, it was hypothesized that a 1-yr intervention with the mineralocorticoid receptor antagonist spironolactone lowers IL-17A and related cytokines and reduces epithelial injury in kidney transplant recipients. Plasma and urine samples were obtained from kidney transplant recipients from a double-blind randomized clinical trial testing spironolactone (n = 39) versus placebo (n = 41). Plasma concentrations of cytokines interferon-γ, IL-17A, tumor necrosis factor-α, IL-6, IL-1β, and IL-10 were determined before and after 1-yr treatment. Urine calbindin-to-creatinine, clusterin-to-creatinine, kidney injury molecule-1-to-creatinine, osteoactivin-to-creatinine, trefoil factor 3 (TFF3)-to-creatinine, and VEGF-to-creatinine ratios were analyzed. Blood pressure and plasma aldosterone concentration at inclusion did not relate to plasma cytokines and injury markers expect for urine TFF3-to-creatinine ratios that correlated positively to blood pressure. None of the cytokines changed in plasma after spironolactone intervention. Plasma IL-17A increased in the placebo-treated group. Spironolactone induced an increase in plasma K⁺ (0.4 ± 0.4 mmol/L). This increase did not correlate with plasma IL-17A or urine calbindin and TFF3 changes. Ongoing treatment at inclusion with angiotensin-converting enzyme inhibitor and/or ANG II receptor blockers was not associated with changed levels of IL-17A and injury markers and had no effect on the response to spironolactone. Urinary calbindin and TFF3 decreased in the spironolactone-treated group with no difference in between-group analyses. In conclusion, irrespective of ongoing ANG II inhibition, spironolactone has no effect on plasma IL-17A and related cytokines or urinary injury markers in kidney transplant recipients.NEW & NOTEWORTHY The mineralocorticoid receptor antagonist spironolactone had no direct anti-inflammatory effects on prohypertensive interleukin-17A or distal nephron epithelial injury markers in kidney transplant recipients.

Keywords: aldosterone; calcineurin; cytokine; hypertension; interleukins.