**1. Introduction**

α-Klotho (klotho) is a membrane protein that is highly expressed in the kidney, especially in the distal tubular epithelial cells [1–10]. Membrane-bound klotho regulates phosphate homeostasis by acting as a co-factor of fibroblast growth factor 23 (FGF23) [11–14]. FGF23-Klotho signaling promotes urinary phosphate excretion and suppresses the expression of renal <sup>1</sup>α-hydroxylase, resulting in reduced vitamin D-dependent intestinal absorption of calcium and phosphate [11,15]. Altogether, FGF23-Klotho signaling regulates phosphate metabolism and prevents phosphate retention [16–20]. Soluble klotho can be detected in the circulation in two forms: (1) cleaved klotho, which is derived from cleavage of the extracellular domain of membrane klotho, and potentially (2) secreted klotho, which is derived from an alternatively spliced klotho mRNA transcript [21,22].

Soluble klotho displays diverse physiological effects and hormonal functions, including the reduction of oxidative stress and the inhibition of intracellular insulin and insulin-like growth factor 1 (IGF-1) signaling [15,23–28]. Klotho protects the kidney by suppression of apoptosis [29,30] and cell senescence [31,32], suppression of fibrosis [33–37], and upregulation of autophagy [3,38] in renal tubular cells. 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 [41–51]. 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]. Low serum klotho is associated with increased mortality and cardiovascular events among patients with ESKD [52].

When compared to treatment with chronic dialysis, kidney transplantation (KTx) is the best therapeutic option for patients with ESKD and is associated with increased survival and better quality of life [53–56]. In addition, living donor KTx provides greater allograft longevity than those transplanted from a deceased donor [57]. However, changes in serum klotho levels and the impact of klotho on outcomes among KTx recipients and kidney donors remain unclear [58–75]. Thus, we conducted this systematic review and meta-analysis to assess serum klotho levels and the impact of klotho on outcomes among KTx recipients and kidney donors.
