The Role of Cortisol and Aldosterone in Hypertensive Nephropathy.

introductionHypertensive nephropathy is a key cause of chronic kidney disease, with both aldosterone and cortisol potentially contributing to its progression. This study investigated the independent and combined effects of baseline and longitudinal changes in serum cortisol and aldosterone levels on the risk and progression of hypertensive nephropathy in patients with essential hypertension. METHODOLOGY: A prospective cohort study was conducted at Khyber Teaching Hospital, Peshawar, from January 2022 to December 2023, enrolling 190 adults (30-70 years) with essential hypertension and preserved renal function (estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m², no macroproteinuria). Patients with diabetes, autoimmune disease, chronic infection, adrenal/pituitary disorders, corticosteroid or mineralocorticoid receptor antagonist use, or secondary hypertension were excluded. Fasting blood samples were collected at baseline, 12, and 24 months (8-9 AM) to measure cortisol and aldosterone using chemiluminescent immunoassay (CLIA), with participants avoiding caffeine, smoking, and stress 12 hours prior. Renal function was monitored via serum creatinine, eGFR (CKD-EPI), and urine protein-to-creatinine ratio; hypertensive nephropathy was defined per Kidney Disease: Improving Global Outcomes (KDIGO) as eGFR <60 mL/min/1.73 m² and/or proteinuria >150 mg/day for three or more months. Additional data included blood pressure, BMI, sodium intake, antihypertensive use, smoking, and psychosocial stress. Analyses were performed in SPSS v26.0 (IBM Corp., Armonk, NY, USA) using Kaplan-Meier curves and Cox models (adjusted for confounders). Hormonal interactions were assessed with multiplicative/additive terms, while repeated-measures ANOVA and regression evaluated hormone trajectories.

resultsOver a median follow-up of 24 months, 43 patients (22.6%) developed hypertensive nephropathy. The absolute risk of nephropathy was substantially higher among those in the highest tertiles of both cortisol and aldosterone (34.4%) compared to those in the lowest tertiles (11.2%). Elevated baseline cortisol levels were independently associated with increased risk of nephropathy (hazard ratio [HR]: 2.31; 95% confidence interval [CI]: 1.29-4.13; p=0.005). Similarly, elevated aldosterone levels were independently associated with risk (HR: 1.97; 95% CI: 1.11-3.50; p=0.021). There was a significant interaction between cortisol and aldosterone levels (p for interaction = 0.038), indicating a synergistic effect on the risk of nephropathy. Patients who developed nephropathy also exhibited increasing hormone levels over time (p < 0.05 by repeated-measures ANOVA). Sensitivity analyses excluding cases occurring within the first six months and stratified by baseline renal status confirmed the robustness of these associations.

conclusionBoth elevated and increasing serum cortisol and aldosterone levels independently and synergistically predict the development of hypertensive nephropathy. It is suggested that incorporating hormonal profiling into early risk stratification models may enhance identification of hypertensive patients at risk for kidney damage. Future multi-center studies are warranted to validate these findings across diverse populations and to explore whether interventions targeting these hormonal pathways can reduce renal risk.