Proenkephalin predicts kidney function and major adverse kidney events in CKD

BACKGROUND AND HYPOTHESIS: The endogenous opioid proenkephalin (PENK) has been identified as an independent risk marker for acute cardiovascular diseases and acute kidney injury. However, its regulation, its association with other cardiometabolic markers and its prognostic role in patients with chronic kidney disease (CKD) have not been thoroughly investigated. METHODS: PENK serum levels were cross-sectionally related to renal and cardiometabolic markers across three large cohorts (total N = 4722), including the Leipzig-CKD cohort (N = 581), as well as the population-based LIFE-Adult (N = 3093) and Sorbs (N = 1048) cohort. Furthermore, a longitudinal analysis was performed in the Leipzig-CKD cohort to assess the association between circulating PENK levels at baseline and a composite 4-point major adverse renal events (4P-MAKE) endpoint comprising incident or worsening kidney disease, development of kidney failure (KF) requiring kidney replacement therapy or kidney transplantation, and renal deaths. RESULTS: In the entire cross-sectional cohort (N = 4722), PENK levels were strongly and inversely correlated with markers of renal function, i.e. estimated glomerular filtration rate (eGFR), creatinine and urinary albumin-creatinine ratio. In multivariable analysis, eGFR was the strongest, independent and inverse predictor of circulating PENK levels after adjustment for age and sex, as well as markers of obesity, glucose intolerance, dyslipidemia and inflammation. Multivariable Cox regression analysis revealed that baseline circulating PENK levels were strongly associated with an increased risk of the 4P-MAKE over a median follow-up of 8.7 years. Each doubling of PENK levels was associated with a >2-fold increase in the risk of developing 4P-MAKE, even after adjusting for various clinical and metabolic variables. PENK provided added value for predicting adverse renal outcomes. CONCLUSIONS: PENK levels are strongly, independently, and inversely associated with renal function in cross-sectional analysis. Furthermore, baseline circulating PENK levels are predictive of a 4P-MAKE in patients and added independent, prognostic value for identification of patients at risk for adverse renal outcomes.