Urine Klotho Is Lower in Critically Ill Patients With Versus Without Acute Kidney Injury and Associates With Major Adverse Kidney Events

Abstract

Objectives: Klotho and fibroblast growth factor-23 were recently postulated as candidate biomarkers and/or therapeutic targets in acute kidney injury. We examined whether urine Klotho and serum intact fibroblast growth factor-23 levels were differentially and independently associated with major adverse kidney events in critically ill patients with and without acute kidney injury. Design: Single-center, prospective, case-control study. Setting: ICU in a tertiary medical center. Patients: Fifty-four acute kidney injury patients and 52 controls without acute kidney injury admitted to the ICU. Interventions: None. Measurements and Main Results: Acute kidney injury was defined by Kidney Disease: Improving Global Outcomes criteria and included only acute kidney injury stage greater than or equal to 2. Controls were matched by age, gender, and baseline estimated glomerular filtration rate. Paired serum and urine samples were obtained 24–48 hours after acute kidney injury diagnosis (cases) or ICU admission (controls). The primary outcome was 90-day major adverse kidney events, which was the composite of all-cause death, dependence on renal replacement therapy, or a 50% or higher decrease in estimated glomerular filtration rate from baseline. Major adverse kidney events, which was the composite of all-cause death, dependence on renal replacement therapy, or a 50% or higher decrease in estimated glomerular filtration rate from baseline. Major adverse kidney events developed in 44 patients (41.5%). Patients in whom major adverse kidney events developed had more comorbidity, higher acuity of illness scores, and more prevalent acute kidney injury. Levels of urine Klotho adjusted by creatinine were lower, and serum intact fibroblast growth factor-23 levels were higher in acute kidney injury patients versus ICU controls. In adjusted models, the highest versus lowest tertile of urine Klotho/creatinine was independently associated with an overall 95% lower risk of major adverse kidney events (81% lower risk in patients with acute kidney injury). The highest versus lowest tertile of serum intact fibroblast growth factor-23 was associated with more than 300% higher risk of major adverse kidney events. Conclusions: Urine Klotho/creatinine levels were significantly lower and serum intact fibroblast growth factor-23 levels were significantly higher in critically ill patients with acute kidney injury versus matched controls without acute kidney injury. When measured in the first 48 hours of ICU admission or acute kidney injury diagnosis, urine Klotho/creatinine independently associated with major adverse kidney events, particularly in patients with acute kidney injury. These results show promise for testing these biomarkers—individually or in combination—as part of novel risk prediction models of renal outcomes in the ICU.

Kidney Biomarkers and Major Adverse Kidney Events in Critically Ill Patients

“…This was a secondary analysis of the AKI biobank from the “Klotho and Acute Kidney Injury” (KLAKI) Study Group. 7 In brief, this single center, prospective study enrolled adult patients ≥ 18 years old over a one year period admitted to the ICU with stage ≥ 2 AKI per Kidney Disease: Improving Global Outcomes (KDIGO) criteria and matched controls based on age, gender, and baseline estimated glomerular filtration rate (eGFR). 8 Patients must have had a baseline eGFR ≥ 60 mL/min/1.73 m 2 .…”

“…Patients were excluded if they had end-stage kidney disease (ESKD), a kidney or any other solid organ transplant, evidence of AKI prior to ICU admission, or uroepithelial tumors. 7…”

Fibroblast Growth Factor 23 and αKlotho in Acute Kidney Injury: Current Status in Diagnostic and Therapeutic Applications

“…The first human AKI study showed significantly lower urine αKlotho at the time of AKI diagnosis when compared with healthy controls [38]. A larger prospective ICU study showed that AKI patients had lower urinary αKlotho within 48 h of AKI diagnosis when compared with ICU controls [39]. Urine αKlotho concentration and urine αKlotho-to-Cr ratio inversely correlated with hospital and mechanical ventilation days.…”

“…Urine αKlotho concentration and urine αKlotho-to-Cr ratio inversely correlated with hospital and mechanical ventilation days. Each 1-fold higher urine αKlotho/Cr was associated with an 83% lower risk of major adverse kidney events at 90 days [39].…”

Serum Klotho in Living Kidney Donors and Kidney Transplant Recipients: A Meta-Analysis

“…Klotho-deficient mice develop premature aging, hyperphosphatemia, vascular calcification and endothelial dysfunction, and have shorter lifespans, while klotho overexpressing mice have 20–30% longer lifespans than wild type mice [ 2 , 24 , 39 ]. Since klotho expression is the most abundant in the kidney [ 40 ], patients with kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), are found to have a significant reduction in klotho expression and soluble levels [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Studies have demonstrated that serum klotho declines in progressive human CKD with the lowest serum klotho levels among patients with end-stage kidney disease (ESKD) on dialysis [ 41 , 48 ].…”