Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

The Klotho gene encodes a 130-kDa single-pass transmembrane protein with a short cytoplasmic domain (10 amino acids) and is expressed predominantly in the kidney. Mice carrying a loss-of-function mutation in the Klotho gene develop a syndrome resembling human aging, including shortened life span, skin atrophy, muscle atrophy, osteoporosis, arteriosclerosis, and pulmonary emphysema (1). Conversely, overexpression of the Klotho gene extends the life span and increases resistance to oxidative stress in mice (2-4). These observations suggest that the Klotho gene functions as an aging suppressor gene. The extracellular domain of Klotho protein is shed and secreted in the blood (2, 5), potentially functioning as a humoral factor that signals suppression of intracellular insulin/IGF1 signaling, which partly contributes to its anti-aging properties (2). However, a signaling pathway(s) directly activated by Klotho protein, including the identity of the Klotho receptor, has not been determined. The function of the transmembrane form of Klotho protein also remains to be determined.Fibroblast growth factor-23 (FGF23) 2 was originally identified as a gene mutated in patients with autosomal dominant hypophosphatemic rickets (6), where mutations in the FGF23 gene conferred resistance to inactivation by protease cleavage, resulting in elevated serum levels of FGF23 (7-12). FGF23 inhibits phosphate transport in renal proximal tubular cells and in proximal tubules perfused in vitro (13). Consistent with these findings, mice defective in FGF23 expression show increased renal phosphate reabsorption and hyperphosphatemia (14). Although FGF23 binds to multiple FGF receptors (FGFRs) (15), it has modest receptor affinity (K D ϭ 200 -700 nM) and often requires cofactors such as heparin or glycosaminoglycan (15, 16) to activate FGF signaling in cultured cells and to inhibit phosphate transport in proximal tubules perfused in vitro (13).Klotho-deficient mice (Klotho Ϫ/Ϫ mice) and FGF23 deficient mice (Fgf23 Ϫ/Ϫ mice) develop many common phenotypes, including shortened life span, growth retardation, infertility, muscle atrophy, hypoglycemia, and vascular calcification in the kidneys. Notably, they both have increased serum levels of phosphate (14, 17). These observations have led us to the hypothesis that Klotho and FGF23 may function via a common signal transduction pathway. In this report we show that Klotho binds to multiple FGFRs and functions as a cofactor necessary for FGF signaling activation by FGF23. MATERIALS AND METHODSExpression Vectors-Complementary DNA containing the mouse FGFRs coding region (IMAGE Clone, Invitrogen, supplemental Fig. 1) were cloned into pcDNA3.1(ϩ) expression vector (Invitrogen). Before subcloning, a V5-epitope tag was added to the C terminus and appropriate restriction enzyme sites to the both ends using synthetic oligonucleotides and polymerase chain reaction. Expression vectors for the mouse FGF23 resistant to proteolytic inactivation (R179Q) (18), the transmembrane form of mouse Klotho, and the extracel...

Soft-tissue calcification is a prominent feature in both chronic kidney disease (CKD) and experimental Klotho deficiency, but whether Klotho deficiency is responsible for the calcification in CKD is unknown. Here, wild-type mice with CKD had very low renal, plasma, and urinary levels of Klotho. In humans, we observed a graded reduction in urinary Klotho starting at an early stage of CKD and progressing with loss of renal function. Despite induction of CKD, transgenic mice that overexpressed Klotho had preserved levels of Klotho, enhanced phosphaturia, better renal function, and much less calcification compared with wild-type mice with CKD. Conversely, Klotho-haploinsufficient mice with CKD had undetectable levels of Klotho, worse renal function, and severe calcification. The beneficial effect of Klotho on vascular calcification was a result of more than its effect on renal function and phosphatemia, suggesting a direct effect of Klotho on the vasculature. In vitro, Klotho suppressed Na ϩ -dependent uptake of phosphate and mineralization induced by high phosphate and preserved differentiation in vascular smooth muscle cells. In summary, Klotho is an early biomarker for CKD, and Klotho deficiency contributes to soft-tissue calcification in CKD. Klotho ameliorates vascular calcification by enhancing phosphaturia, preserving glomerular filtration, and directly inhibiting phosphate uptake by vascular smooth muscle. Replacement of Klotho may have therapeutic potential for CKD.

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The global nephrology community recognises the need for a cohesive plan to address the problem of chronic kidney disease (CKD). In July, 2016, the International Society of Nephrology hosted a CKD summit of more than 85 people with diverse expertise and professional backgrounds from around the globe. The purpose was to identify and prioritise key activities for the next 5-10 years in the domains of clinical care, research, and advocacy and to create an action plan and performance framework based on ten themes: strengthen CKD surveillance; tackle major risk factors for CKD; reduce acute kidney injury-a special risk factor for CKD; enhance understanding of the genetic causes of CKD; establish better diagnostic methods in CKD; improve understanding of the natural course of CKD; assess and implement established treatment options in patients with CKD; improve management of symptoms and complications of CKD; develop novel therapeutic interventions to slow CKD progression and reduce CKD complications; and increase the quantity and quality of clinical trials in CKD. Each group produced a prioritised list of goals, activities, and a set of key deliverable objectives for each of the themes. The intended users of this action plan are clinicians, patients, scientists, industry partners, governments, and advocacy organisations. Implementation of this integrated comprehensive plan will benefit people who are at risk for or affected by CKD worldwide.