Urinary Dickkopf-3 and Acute Kidney Injury

Study Questions:

Can urinary dickkopf-3 (DKK3) levels identify patients at high risk of post-cardiac surgery acute kidney injury (AKI)?

Methods:

This is an observational study in which the authors measured urinary DKK3 levels in two cohorts of patients undergoing cardiac surgery; a derivation cohort (n = 733) and a validation cohort (n = 216). The validation cohort was a subset of the RenalRIP trial, which assessed the impact of presurgical ischemic preconditioning on long-term kidney function. They examined the association between DKK3 and AKI, persistent renal dysfunction, and the need for dialysis. In the validation cohort, they identified a cut-off of 471 pg/ml for DKK3 levels using the lowest Akaike information criterion in their multivariable modeling.

Results:

The validation cohort consisted of 69% men, 19% diabetics, mean age of 64 years, of whom 38% underwent coronary artery bypass grafting and 71% underwent valvular surgery. The mean baseline estimated glomerular filtration rate (eGFR) was 89 ml/min/1.73 m2, and DKK3 level was 387 pg/mg of creatinine. AKI occurred in 193 (26%) patients. Urinary DKK3 >471 pg/ml was associated with an odds ratio of 1.65 (95% confidence interval [CI], 1.10-2.47; p = 0.015) in the derivation cohort and 1.94 (95% CI, 1.08-3.47; p = 0.026) in the validation cohort. The association did not differ according to baseline eGFR. Adding DKK3 to a model including age, sex, body mass index, hypertension, diabetes mellitus, and eGFR improved the integrated discrimination index (0.24; 95% CI, 0.20-0.27) and net reclassification index (0.32; 95% CI, 23-0.42) for AKI. Similar findings were reported for persistent renal dysfunction and need for dialysis at 90 days. In the RenalRIP substudy, there was a significant interaction between urinary DKK3 levels and ischemic preconditioning, with the association between urinary DKK3 and renal dysfunction noted solely in the group that did not receive ischemic preconditioning.

Conclusions:

Preoperative urinary DKK3 is an independent predictor for postoperative AKI, persistent kidney dysfunction, and dialysis at 90 days.

Perspective:

Urinary DKK3 is an indicator of renal tubular stress, and when measured preoperatively, appears to predict postoperative AKI. DKK3 thus identifies patients who prior to surgery likely have subclinical signs of tubular dysfunction. Other markers of tubular dysfunction such as NGAL and KIM-1 have performed poorly as preintervention markers of AKI risk, as they typically increase early in AKI rather than prior to the insult. The authors argue that urinary DKK3 levels could be used to identify patients that would benefit from ischemic preconditioning. The findings of the study should however be interpreted cautiously, as they are the result of post hoc analyses in small sample sizes, and are without a clear pathophysiologic rationale. Nevertheless, the most important aspect of biomarker research is in deriving potential clinical applications; and this study takes us one small step closer to new strategies for mitigating postoperative AKI.

Clinical Topics: Cardiac Surgery, Diabetes and Cardiometabolic Disease, Invasive Cardiovascular Angiography and Intervention, Prevention, Cardiac Surgery and Arrhythmias, Hypertension

Keywords: Acute Kidney Injury, Biological Markers, Body Mass Index, Cardiac Surgical Procedures, Coronary Artery Bypass, Creatinine, Diabetes Mellitus, Glomerular Filtration Rate, Hypertension, Ischemic Preconditioning, Metabolic Syndrome X, Primary Prevention, Renal Dialysis


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