Abstract

Aims: A few studies have shown disturbances in the hypothalamic-pituitary-adrenal (HPA) axis in chronic-kidney-disease (CKD), of unknown extent and clinical implications. We aimed to study the HPA axis in patients with CKD and its association with kidney impairment and metabolic disturbances. Methods: Cross-sectional controlled study. Patients with CKD stages I-II (estimated glomerular filtration rate [eGFR] through CKD-EPI equation >60), stage III (eGFR 30-60) and stage IV (eGFR 15-30) CKD with preserved diuresis (n=16, 15 and 15, respectively) were included and paired with 17 healthy controls by age, sex and body mass index (BMI). Exclusion criteria were: active glucocorticoid, immunosuppressive or anti-inflammatory treatment, diabetes mellitus, morbid obesity, drugs interfering with the HPA axis or pseudo-Cushing states. Subjects underwent clinical and analytical assessment of metabolic comorbidities, body composition analysis using DEXA and a thorough evaluation of the HPA axis. Results: We included 63 subjects (age 53±12years, 52% women, BMI 26±4kg/m2). A stepped increase in hypertension and dyslipidaemia prevalence as well as increasing levels of glucose, triglycerides and 24h-urinary protein excretion were observed with worsening kidney function (P<0.05 for all). Both plasmatic insulin levels (7.3mIU/L in stages I-II, 11.3 in stage III, 11.4 in stage-IV-CKD, 6.3 in controls; P<0.001) and visceral adipose tissue volume measured using DEXA (663 cm3 in stages I-II, 1042 in stage III, 1347 in stage-IV-CKD, 458 in controls; P<0.001) increased with worsening kidney function. A higher ACTH (23 vs. 17pg/ml, P=0.048) and less cortisol supression after 1 mg dexamethasone-suppression-test (DST) (1.2 vs. 0.9μg/dL, P<0.001) were seen in patients with CKD compared to controls. No differences in ACTH were observed according to CKD stage. 24h-urinary-free-cortisol was decreased in stages III-IV compared to CKD stages I-II and controls (P<0.001). Of all, 11 (24%) patients with CKD had a post-DST cortisol >2 mg/dL (2 [14%] in CKD stage III and 9 [60%] in the stage-IV-group); 45% of them persisted with cortisol >2 mg/dL after a low-dose 2-day-DST (2 mg/6h), all with stage IV (P<0.001 for all). No differences were observed in basal cortisol or cortisol-binding-globulin levels. In the whole cohort, cortisol after DST was lineally inversely correlated with eGFR (β -19.8, P<0.001). Cortisol after DST (OR 11.9, 95%CI 1.5-97, P=0.021) and glucose (OR 1.3, 95%CI 1.1-1.5, P=0.003) were independently associated with an eGFR <30 ml/min/m2. Conclusions: Negative feedback of the HPA axis is impaired in patients with CKD and correlates with disease stage. This should be taken into account when hypercortisolism is suspected and explored in this context.