Cardiorenal Syndrome and Depressive Symptoms: Exploring the Mood-Kidney Link With Heart Failure Risk in a Post-hoc Analysis of SPRINT

Rationale & Objective Depression is a potential pathophysiologic pathway in type 4 cardiorenal syndrome, ie chronic kidney disease (CKD) resulting in chronic heart failure (HF). We investigated whether depressive symptoms and CKD are independent predictors of HF and whether they augment HF risk when they present together. Study Design A post-hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) Setting & Participants Participants with baseline Patient Health Questionnaire-9 (PHQ-9) data and without baseline HF (N =8,930) Predictors Depressive symptom severity (baseline PHQ-9 0, 1-4, and 5-27) and CKD (estimated glomerular filtration rate of < 60 mL/min/1.73m 2 ) Outcome Incident HF events (pre-specified adjudicated secondary SPRINT outcome) Analytical Approach Multivariable Cox proportional hazards regression models and generalized linear models related PHQ-9 and CKD status to HF events on relative and absolute scales. Results PHQ-9 scores of 0, 1-4, and ≥ 5 were present in 3,086 (34.6%), 3,775 (42.3%), and 2,069 (23.2%) participants, respectively and baseline CKD in 2,155 (24%). There were 177 HF events over 33,358 person-years. In a multivariable Cox regression model, both CKD (HR 1.60; 95% CI, 1.13-2.28) and PHQ-9 ≥ 5 (HR vs PHQ-9 = 0: 1.92; 95% CI, 1.24-2.98) were independent HF risk factors. In another Cox model, compared to those with PHQ-9 = 0 and no CKD, those with both CKD and PHQ-9 ≥5 had 3.45 times the hazard of HF (HR 3.45, 95% CI 1.70, 7.03) with other subgroups in between. There was no evidence of a synergistic interaction, but they appeared to be additive. Results were largely consistent on the absolute risk scale. Limitations Bias from post-hoc observational use of data, clinical trial selection bias Conclusions Both CKD and depressive symptoms are independent and additive risk factors for HF. Patients with both CKD and a higher burden of depressive symptoms are at greater risk of HF. Plain-Language Summary This is a post-hoc analysis of the Systolic Blood Pressure Intervention Trial that asked whether chronic kidney disease and depressive symptoms were associated with a particularly high risk of heart failure when present together. Depressive symptom severity was measured with a validated questionnaire. We found that chronic kidney disease and depressive symptoms were both independent heart failure risk factors and are additive but not synergistic for the risk of heart failure. These findings add to our understanding of cardiorenal pathophysiology.