The controversy of klotho as a potential biomarker in chronic kidney disease

Abstract

Klotho is an identified longevity gene with beneficial pleiotropic effects on the kidney. Evidence shows that a decline in serum Klotho level occurs in early chronic kidney disease (CKD) and continues as CKD progresses. Klotho deficiency is associated with poor clinical outcomes and CKD mineral bone disorders (CKD-MBD). Klotho has been postulated as a candidate biomarker in the evaluation of CKD. However, the evidence for the clinical significance of the relationship between Klotho and kidney function, CKD stage, adverse kidney and/or non-kidney outcomes, and CKD-MBD remains inconsistent and in some areas, contradictory. Therefore, there is uncertainty as to whether Klotho is a potential biomarker in CKD; a general consensus regarding the clinical significance of Klotho in CKD has not been reached, and there is limited evidence synthesis in this area. To address this, we have systematically assessed the areas of controversy, focusing on the inconsistencies in the evidence base. We used a PICOM strategy to search for relevant studies and the Newcastle–Ottawa Scale scoring to evaluate included publications. We reviewed the inconsistent clinical findings based on the relationship of Klotho with CKD stage, kidney and/or non-kidney adverse outcomes, and CKD-MBD in human studies. Subsequently, we assessed the underlying sources of the controversies and highlighted future directions to resolve these inconsistencies and clarify whether Klotho has a role as a biomarker in clinical practice in CKD.

Serum and Urinary Soluble α-Klotho as Markers of Kidney and Vascular Impairment

“…Cleavage of transmembrane Klotho results in the soluble form of the protein (sKlotho), which can be found in serum, urine and cerebrospinal fluid. It has been reported [ 9 , 35 ] that sKlotho levels decrease during the progression of CKD, though the value of sKlotho as an early and reliable biomarker of kidney α-Klotho production and CKD progression is still a matter of debate [ 36 , 37 , 38 ].…”

Klotho exerts protection in chronic kidney disease associated with regulating inflammatory response and lipid metabolism

“…Controversy exists regarding using Klotho as a potential biomarker in CKD [ 30 ]. A key contributing factor to this controversy is the absence of standardized techniques for assessing soluble Klotho [ 63 ].…”

Role of Klotho and AGE/RAGE-Wnt/β-Catenin Signalling Pathway on the Development of Cardiac and Renal Fibrosis in Diabetes

“…These results suggest that in the early phases of the diabetic kidney disease, with preserved GFR, urine sKlotho may be an earlier marker of kidney damage than serum sKlotho. However, the role of sKlotho in CKD is very complex and its possible use as an urinary marker of renal function has been poorly studied [ 23 ].…”

“…Furthermore, Klotho has been postulated as a biomarker of progression of heart and kidney damage [ 17 , 18 , 19 ]. The studies of Klotho in diabetes, mainly in type 1 diabetes mellitus (T1DM), are scarce, showing controversial results [ 20 , 21 , 22 , 23 ]. In addition, the relationship between Klotho and the AGE/RAGE pathway has not been studied in animal models of diabetes.…”