Review

Klotho in Clinical Nephrology

Diagnostic and Therapeutic Implications

Javier A. Neyra, Ming Chang Hu and Orson W. Moe
CJASN January 2021, 16 (1) 162-176; DOI: https://doi.org/10.2215/CJN.02840320

Abstract

αKlotho (called Klotho here) is a membrane protein that serves as the coreceptor for the circulating hormone fibroblast growth factor 23 (FGF23). Klotho is also cleaved and released as a circulating substance originating primarily from the kidney and exerts a myriad of housekeeping functions in just about every organ. The vital role of Klotho is shown by the multiorgan failure with genetic deletion in rodents, with certain features reminiscent of human disease. The most common causes of systemic Klotho deficiency are AKI and CKD. Preclinical data on Klotho biology have advanced considerably and demonstrated its potential diagnostic and therapeutic value; however, multiple knowledge gaps exist in the regulation of Klotho expression, release, and metabolism; its target organs; and mechanisms of action. In the translational and clinical fronts, progress has been more modest. Nonetheless, Klotho has potential clinical applications in the diagnosis of AKI and CKD, in prognosis of progression and extrarenal complications, and finally, as replacement therapy for systemic Klotho deficiency. The overall effect of Klotho in clinical nephrology requires further technical advances and additional large prospective human studies.

Introduction

αKlotho (referred here as Klotho) was serendipitously discovered in 1997 by Kuro-o et al. (1) as a gene linked to aging. This gene was named Klotho after the goddess who spins the thread of life to govern human lifespan, working with two other goddesses of fate, Lachesis who measures the spun thread from Klotho’s spindle and Atropos who ends the life by cutting the thread (2). Kuro-o et al. (1) observed that Klotho hypomorphic mice exhibited a multiorgan failure syndrome resembling premature aging, including short lifespan, disturbed mineral metabolism, and multiple organ degeneration or failure, such as infertility, arteriosclerosis, cardiomyopathy, ectopic calcification, skin atrophy, osteoporosis, and emphysema. Later, both human (3) and rat (4) Klotho genes were cloned with high homology in amino acid sequences with the mouse. Subsequently, two paralogous genes were discovered and termed βKlotho (5) and γKlotho (6) to distinguish them from the first Klotho gene, which was renamed αKlotho. The α- and βKlotho proteins have known biologic roles, but the function of γKlotho is still elusive (7,8). In this manuscript, we only focus on αKlotho (Klotho).

Klotho is mostly expressed in the kidney as a transmembrane protein. In membrane-bound form, Klotho serves as a coreceptor for fibroblast growth factor 23 (FGF23) in conjunction with fibroblast growth factor receptors (FGFRs) (9) (Figure 1). The extracellular domain of transmembrane Klotho is also cleaved by proteases and released from the kidney into circulation, both as a full-length protein or as Kl1 and Kl2 fragments (10,11). These circulating forms of Klotho protein are collectively called “soluble” Klotho (Figure 1). Soluble Klotho protein is also detected in cerebrospinal fluid and urine.

Figure 1.
Figure 1.

Overview of Klotho protein. (A) Fibroblast growth factor 23 (FGF23) engages the fibroblast growth factor receptor (FGFR)-Klotho coreceptor complex that triggers cellular signaling. (B) Transmembrane Klotho with its Kl1 and Kl2 domains and the generation of soluble circulating Klotho by secretases (ADAM10 and ADAM17). (C) Structure of FGFR1c, Klotho, and FGF23 (one molecule each) as determined by Chen et al. (12). RXXR motif, proteolytic cleavage motif.

Klotho is a pleiotropic protein with multifaceted functions relevant to distinct biology and pathobiology in multiple organs and tissues. Klotho is an inhibitor of apoptosis, fibrosis, and cell senescence and is an inducer of autophagy (13⇓⇓–16). In this review, we discuss its potential clinical application in nephrology, with emphasis on diagnostic and therapeutic utility.

Physiology of Klotho

Klotho Expression and Metabolism

Klotho is highly expressed in the kidney, specifically in the distal tubules and, to a lesser extent, in the proximal tubules (17). Klotho is expressed in other organs, such as the brain, pancreas, and parathyroid glands (1). The Klotho gene encodes a single-pass 130-kD transmembrane protein that consists of two extracellular domains (Kl1 and Kl2), a transmembrane domain, and a short cytoplasmic tail (Figure 1). The extracellular domain of transmembrane Klotho is cleaved at the juxtamembrane region and between Kl1 and Kl2 by proteases (18⇓–20). A secreted form of Klotho from an alternatively spliced transcript has been proposed, but the data are not conclusive (3,21). The spliced Klotho transcript possibly undergoes nonsense-mediated mRNA decay and is not translated to protein (22). The cleaved Klotho is released into the circulation and is known as soluble Klotho (17,22). Soluble Klotho acts as an endocrine or paracrine factor affecting multiple organs, such as the kidney, bone, brain, heart, lungs, and endothelium (23⇓⇓⇓⇓⇓–29). Soluble Klotho suppresses FGF23 production in physiologic concentrations (Figure 2), but it can increase FGF23 expression in the bone (28) or act as a nonenzymatic scaffold protein that enhances FGF23 signaling on the basis of in vitro data in very high, nonphysiologic concentrations (12). Soluble Klotho is not filtered at the glomerulus, but it translocates across the kidney tubules, from the basolateral to the luminal side, and is excreted in the urine (17). Klotho expression is downregulated during acute kidney disease and CKD.

Figure 2.
Figure 2.

Physiologic and pathophysiologic role of Klotho in mineral metabolism with preserved and decreased kidney function. The dashed line indicates putative action on the basis of experimental or clinical data; no evidence supports direct effect yet. PTH, parathyroid hormone.

Klotho and Mineral Metabolism

Klotho decreases kidney phosphate reabsorption by acting as a coreceptor for FGF23 binding to FGFR1 (30) (Figure 1). Soluble Klotho also directly promotes the internalization and degradation of the NaPi2a cotransporter in the kidney proximal tubules contributing to phosphate excretion (31). Klotho may also be a suppressor of vitamin D and FGF23 production (32) because Klotho-deficient mice exhibit higher CYP27B1 gene (33) and FGF23 production (1) (Figure 2).

Klotho in Disease States

CKD

Klotho expression in the kidney and soluble Klotho in the blood and urine are decreased in animals and humans with CKD from a variety of etiologies, including glomerular and tubulointerstitial diseases (32). Because the kidneys are the primary source of soluble Klotho, circulating soluble Klotho expectedly declines as CKD progresses (Figure 3). Decreased Klotho expression in CKD is not simply due to loss of viable tissue but can be attributable to hyperphosphatemia (34) and hypermethylation or deacetylation of the Klotho gene promoter by inflammatory cytokines or uremic toxins, such as indoxyl sulfate (35,36). Similarities of clinical features, including short lifespan, cardiac remodeling, vascular calcification, bone disease, muscle wasting, and hyperphosphatemia, exist in the context of Klotho deficiency and in CKD (37).

Figure 3.
Figure 3.

Changes in circulating soluble Klotho according to eGFR decline and its relationship to other mineral metabolism parameters. 1,25(OH)2D3, 1,25-dihydroxyvitamin D.

Klotho is also expressed in the choroid plexus of the brain (1). Klotho-deficient mice display central nervous system lesions including hypomyelination, synaptic loss, and behavioral impairments such as dementia and cognitive deficits (38). Klotho deficiency in the brain impairs blood barrier and promotes immune-mediated central nervous system disorders (39). CKD is associated with depression and cognitive impairment (40). Low Klotho in cerebrospinal fluid was confirmed in Alzheimer disease (41). Low soluble Klotho in CKD may conceivably contribute to central nervous system dysfunction, although there is no evidence to date of Klotho deficiency in cerebrospinal fluid or brain in CKD.

Cardiovascular Disease

A novel risk factor of cardiovascular disease in CKD is soluble Klotho deficiency (42,43). Hyperphosphatemia and low soluble Klotho associate with more severe cardiac hypertrophy and fibrosis. Interestingly, elevated levels of FGF23 were associated with pathologic cardiac remodeling only if Klotho deficiency was also present (34). However, exogenous FGF23, independent of Klotho, induced cardiac hypertrophy through FGFR4-mediated PLC-γ signaling activation in cardiac myocytes (43,44). Klotho, independent of FGF23, was postulated to protect the heart against cardiac hypertrophy through inhibition of transient receptor potential channel-6 activity in cardiomyocytes (45). Klotho supplementation also protects against indoxyl sulfate–mediated cardiac hypertrophy in mice (46).

AKI

AKI is a syndrome with a myriad of inflammatory cytokines such as TNF-α and TNF-like weak inducer of apoptosis, which downregulate Klotho expression in the kidney through NF-kB activation in murine AKI (47). Similarly, in other inflammatory conditions such as inflammatory bowel disease, TNF-α and IFN-γ reduced Klotho expression in murine kidney (48). The reduced kidney Klotho is partly mediated by an increase in inducible nitric oxide synthase, nitric oxide production, and oxidative stress, but the precise mechanisms of how inflammation downregulates Klotho in AKI are unknown (48,49). A differential transcriptional splicing resulting in decay of Klotho mRNA has been postulated as a potential mechanism of Klotho downregulation in settings of acute illness (22).

Current experimental data support that low Klotho is not just a biomarker but pathogenic. Klotho-deficient mice have lower kidney and circulatory soluble Klotho, and they have more severe kidney damage and fibrosis and higher risk of AKI-to-CKD transition compared with wild-type mice after exposure to distinct kidney insults (14,16,23,50,51), indicating that Klotho deficiency renders the kidney more susceptible to acute insults.

Potential Mechanisms of Klotho-Mediated Kidney and Cardiovascular Protection

Preclinical data strongly suggest a pathogenic role of Klotho acting through multiple mechanisms in contributing to AKI development, AKI-to-CKD transition, progression of CKD, and development of extrarenal complications of CKD (Figure 4, Table 1).

Figure 4.
Figure 4.

Role of Klotho in kidney and cardiovascular protection. AKI occurs after exposure to kidney insults. If the insult is strong or long enough, kidney recovery is impaired, and AKI progresses to CKD. With CKD progression, kidney Klotho is decreased followed by increase in circulating FGF23 levels, low 1,25-dihydroxyvitamin D3, high blood phosphate, and increase in PTH. Abnormal mineral hormones individually and synergistically exacerbate each other in the manner of a vortex of downhill spiral (dashed line: putative action) and contribute to end organ complications, including CKD-MBD, uremic cardiomyopathy, and vascular calcification. Klotho replacement provides beneficial effects from protection of kidney against acute injury, promotion of kidney regeneration, retardation of CKD progression, and amelioration of extrarenal complications. Klotho also improves mineral metabolism disturbances and directly or indirectly lessens end organ dysfunction or abnormalities of advanced CKD. CKD-MBD, CKD-mineral and bone disorder; Ca, calcium; 1,25-D3, 1,25-dihydroxyvitamin D; Pi, phosphate.

View this table:
Table 1.

Potential mechanisms of beneficial effects of Klotho in kidney disease

Klotho Renders the Kidney More Resistant to Injury

Inhibition of Cell Senescence.

Cell senescence is a complex process in normal aging (52) and in kidney disease (53). Klotho deficiency induces and Klotho overexpression suppresses cell senescence through increased Wnt signaling activity (54,55). Intracellular Klotho also suppresses cell senescence by inhibiting expression of IL-6 and -8 (56,57).

Inhibition of Cell Apoptosis.

Klotho deficiency increases apoptosis in cultured cells (58,59) and in the kidney (23,49,50,60). Increasing Klotho decreases apoptotic cell number and improves kidney function and morphology after acute and chronic kidney damage (50,60,61).

Antioxidation.

The kl/kl mice (low Klotho expression) have higher levels and Tg-Kl mice (Klotho overexpressing) have lower levels of oxidative markers and oxidation-induced cell damage than normal mice (62,63). Klotho exerts its antioxidation effect through stimulating the FOXO family, manganese SOD (55,62), and phosphatidylinositol 3-kinase/AKT/Nrf2/heme oxygenase-1 pathways (64).

Induction of Autophagy.

Autophagy is a conserved process to degrade defective and unwanted cytoplasmic and organelle components and reuse the constituents (65). Either extremely high or low autophagy activity is associated with kidney damage (16,66). Klotho upregulates autophagy activity, protects kidney against ischemic injury, and, consequently, mitigates the progression of AKI to CKD (16).

Klotho Promotes Kidney Recovery

When recombinant Klotho protein is injected right after ischemic injury, mice had similar acute kidney damage but recovered much faster than vehicle injection (16). Intravenous administration of urinary extracellular vesicles carrying Klotho restores kidney Klotho levels in injured kidney and promotes kidney function recovery after glycerol injection (67).

Preservation of Stem Cells.

Klotho deficiency is associated with stem cell depletion (15,68) via augmentation of Wnt signaling and more cell senescence, which were rescued by Klotho protein overexpression (54).

Maintenance of Endothelial Function and Angiogenesis.

Swift and complete recovery of endothelium structure and function promotes kidney regeneration after ischemic injury (69). Klotho exerts proangiogenic actions (70) and maintains endothelial integrity (71).

Klotho Suppresses Kidney Fibrosis

Klotho suppresses kidney fibrosis in several animal models (14,72,73) via suppression of TGF-β1 activity, TGF-receptor II (14,73), and Wnt signaling activity (72). Supplementation of Klotho in rodents inhibits kidney fibrosis and retards CKD progression.

Klotho Ameliorates Disordered Mineral Metabolism in CKD

CKD is a state of Klotho deficiency, hyperphosphatemia, high FGF23 levels, and low 1,25-dihydroxyvitamin D3 (Figure 3). Klotho deficiency participates in CKD development and progression and contributes to extrarenal complications of CKD directly and indirectly through disturbed mineral metabolism (Figures 2 and 4) (29,34,74,⇓–76).

Reduction of Serum Phosphate.

Klotho deficiency impairs phosphaturia (31,77) and, consequently, accelerates phosphate accumulation in CKD. Administration of Klotho protein or enhancement of native Klotho is an effective strategy for the correction of hyperphosphatemia in experimental CKD (75).

Control of Fibroblast Growth Factor 23 Activity.

FGF23 participates in systemic phosphate balance by its triple action on intestine, bone, and kidneys through interplay with Klotho (8), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D3 (8,12,31,77,⇓–79) (Figures 2 and 4). High serum FGF23 may serve as a diagnostic biomarker and pathogenic intermediate for higher risk of cardiovascular disease and mortality in both patients with AKI (80) and patients with CKD (81). The fact that high FGF23 correlates with cardiac adverse effect only with concomitant low Klotho in animals suggests that Klotho may modulate the toxic effects of FGF23 (34).

Modulation of 1,25-Dihydroxyvitamin D3 Production.

Low 1,25-dihydroxyvitamin D3 is attributed to bone mineralization defects and secondary hyperparathyroidism in CKD (82). Vitamin D treatment attenuates cardiac FGF23/FGFR4 signaling and hypertrophy (83) and vascular calcification in uremic rats (84) in part through upregulation of circulating Klotho.

Control of Parathyroid Hormone Production.

Secondary hyperparathyroidism is associated with cardiovascular morbidity and mortality in CKD (85,86). In CKD, parathyroid gland loses its response to inhibitory signaling from FGF23 possibly due to lower Klotho and FGFR1 in the parathyroid gland (Figure 2) (87⇓–89). Correction of Klotho to improve mineral homeostasis does not only benefit bone and mineral metabolism but also may attenuate cardiovascular disease and improve the quality of life of patients with CKD (75).

Klotho Reduces Blood Pressure

Hypertension is a complication of CKD and contributes to progression of CKD and cardiovascular disease. Klotho-deficient mice develop salt-sensitive hypertension after high sodium challenge (90) and increased arterial stiffness (91). Klotho single-nucleotide polymorphism (KL rs9536314) associates with salt-sensitive hypertension in adults with newly diagnosed hypertension (92).

Biomarker Candidacy in Human Kidney Disease

Klotho in Human CKD

Kidney Klotho mRNA was significantly lower in patients with CKD versus healthy controls and positively correlated with eGFR (93,94). In CKD stages 1–5D with available kidney biopsies, Klotho mRNA levels positively correlated with eGFR, after adjustment for age and other mineral parameters (95). To date, many studies have shown a positive correlation between Klotho levels (serum and urine) and eGFR in adults with CKD (74,96⇓⇓–99). Soluble Klotho levels correlate with markers of oxidative stress (8-isoprostane) and inflammation (IL-6), although some of these associations dissipated after multivariable analyses (100). In a recent larger study, serum Klotho levels associated with kidney function decline in a cohort of well-functioning older adults aged 70–79 with mean eGFR of 73 ml/min per 1.73 m2 (101). With each doubling of serum Klotho, there was an associated 20% decreased odds of significant decline in kidney function over 10 years, which persisted after adjustment for demographics, cardiovascular risk factors, and mineral metabolism parameters, including FGF23 (101). The decline of soluble Klotho levels in adults with mild CKD (e.g., stages ≤2) antedates elevation in FGF23, PTH, and phosphate, and therefore, it may represent an early marker of CKD and CKD-MBD (Figure 3, Table 2) (96,102⇓–104). A recent meta-analysis concluded that there is a significant positive correlation between soluble Klotho and eGFR in patients with CKD (105).

View this table:
Table 2.

Human studies of soluble Klotho in CKD

In a cohort study of adult patients with CKD (stages 1–5), serum Klotho levels independently associated with the composite outcome of doubling serum creatinine, kidney failure, or death, after adjustment for age, diabetes, mean arterial pressure, eGFR, proteinuria, and PTH (96). Note that high-risk patients such as those with acute coronary syndrome, ischemic stroke, or progressive CKD within 3 months prior to the study enrollment were excluded.

Klotho and Cardiovascular Disease in Human CKD

Serum Klotho is associated with arterial stiffness measured by pulse wave velocity in patients with early CKD (97). In contrast, a different study in patients with CKD stages 2–4 showed that plasma Klotho levels were not associated with atherosclerosis, acute heart failure, or death at 2.6 years (109). Serum Klotho levels were lower in patients with primary hypertension compared with healthy volunteers, adjusted for eGFR (111). A post hoc analysis of the Effect of Strict BP Control and ACE Inhibition on the Progression of CRF in Pediatric Patients trial in children with CKD showed that ramipril therapy significantly increased serum Klotho levels without any changes in serum calcium or phosphate (113). In another study including adults with acute cerebral infarction, plasma Klotho levels were negatively associated with the presence, burden, and progression of small vessel disease (115). A recent study showed that low plasma Klotho is associated with mortality and cardiovascular events in patients on hemodialysis (114). The association between Klotho levels and cardiovascular disease has been observed only in small studies in humans mostly using surrogate markers of cardiovascular health rather than hard outcomes, such as cardiovascular events or death. Larger prospective studies with well-defined outcomes are needed to examine if Klotho is a prognostic marker of cardiovascular disease in CKD.

Klotho in AKI

In critically ill patients, urinary Klotho levels were lower in patients with AKI (Kidney Disease Improving Global Outcomes stage ≥2; within 48 hours of diagnosis) compared with well-matched intensive care unit controls (by age, sex, and baseline eGFR; within 48 hours of intensive care unit admission) (116). In a study of patients with acute tubular necrosis or acute tubulointerstitial nephritis by kidney biopsy, lower kidney Klotho protein levels associated with higher peak serum creatinine and more frequent KRT (117). In the kidney transplant population, donor kidney Klotho protein levels decreased following transplantation in those with delayed graft function (118). In postmortem kidney biopsies of critically ill patients who died of sepsis and AKI, there was lower kidney Klotho mRNA and protein in sepsis-associated AKI biopsies when compared with biopsies from control subjects undergoing nephrectomy for kidney cancer (119). Not all human studies in AKI have shown an inverse relationship between Klotho measurements and kidney function (Table 3).

View this table:
Table 3.

Human studies of soluble Klotho in AKI

In a cohort of 35 adults undergoing cardiac surgery, there was no difference in preoperative serum Klotho levels in those with (n=19) versus without (n=16) postoperative AKI. However, postoperative serum Klotho levels obtained immediately and 4 hours following cardiac surgery were both lower in patients with versus without AKI (120). Klotho levels increased soon in patients with AKI such that they were no longer different between groups by postoperative day 1 (120). In another study of 60 adults undergoing cardiac surgery or coronary angiography (50% developed postprocedure AKI), urinary Klotho levels were not different in patients with versus without AKI when measured 12 hours after the procedure (121). Neyra et al. (116) found significantly lower levels of urinary Klotho in critically ill patients who developed major adverse kidney events (death, dependence on KRT, or decrease in eGFR≥50% from baseline) within 90 days of enrollment than in those who did not. Each one-fold higher urinary Klotho level was associated with an adjusted 83% lower risk of developing the outcome (Table 3).

Collectively, current clinical data show great promise for soluble Klotho levels as not merely a diagnostic marker but as part of novel risk prediction tools of kidney-related outcomes in high-risk patients with CKD or AKI.

Measurement of Soluble Klotho in Humans

Human studies of measuring circulating soluble Klotho in serum, plasma, or urine have shown that acute or chronic kidney dysfunction is accompanied by lower soluble Klotho (102,103,116), but some studies have reported no change or even higher soluble Klotho depending on level of kidney function (16,97,99,106,109,123⇓–125). These discordant findings may largely be due to problems with performance and reproducibility of current commercially available assays (126⇓–128). An unfortunate fact is that variance in sample type, quality, collection and processing methods, vintage and conditions of storage, and number of freeze-thaw cycles can all drastically affect assay performance and yield widely disparate results (Table 4); however, precautions were not usually made to account for these confounders.

View this table:
Table 4.

Considerations for soluble Klotho measurements in human samples

Barker et al. (102) showed that a commercial ELISA yielded different results in fresh versus stored serum samples and experienced a drop in capture of exogenous soluble Klotho in patients with advanced CKD as well as when samples have undergone freeze-thaw cycles. Heijboer et al. (126) showed poor interassay and intra-assay agreement between three different commercial Klotho ELISAs, suggesting that problems exist beyond just one ELISA. Measurement of soluble Klotho using commercial ELISA was highly unstable in human urine even when stored at –80°C (129). An alternative method of Klotho assay using immunoprecipitation-immunoblot uses a synthetic anti-Klotho antibody (high affinity for Kl2 domain of Klotho) for pull down and an anti-Kl1 rat mAb (now commercially available KM2076; TransGenic Inc., Kobe, Japan) (10) for detection by immunoblot (102). This assay showed progressive decline of serum Klotho levels with increasing stages of CKD in a small single-center study using fresh samples (102).

A recent study evaluated two methods of measuring serum Klotho in patients with different strata of kidney disease (130). The authors concluded that immunoprecipitation-immunoblot, compared with ELISA, exhibited a stronger direct correlation with eGFR, better recovery (capture) of added exogenous Klotho, less susceptibility to variability from sample additives (protease inhibitors), and much better differentiation across different kidney disease groups, including AKI and CKD, in reference to healthy volunteers. The immunoprecipitation-immunoblot assay performance also declined after multiple freeze-thaw cycles, favoring the use of never-thawed samples when measuring soluble Klotho.

Development of high-throughput Klotho assays and standardized processing and storage conditions will greatly benefit the field because suboptimal assays are populating the human database, continuously rendering the unification of data interpretation very difficult.

Klotho-Focused Therapies

Counteracting the decrease in Klotho that occurs in kidney disease represents a promising strategy to prevent, ameliorate, and reverse kidney disease and its extrarenal complications (Figure 4).

One successful strategy in the laboratory is the use of viral delivery of Klotho cDNA in rodent AKI (60). In murine models, Klotho cDNA plasmids can be directly injected or delivered via a viral carrier (nonpathogenic adeno-associated virus) to rescue many phenotypes of Klotho deficiency (131⇓⇓–134), although its safety in humans is not established. Experimental data revealed attenuation of kidney disease in hypertensive rats (131,135), improvement of kidney function in AKI (60), amelioration of angiotensin II–induced kidney injury (132), improvement of endothelial function (134), and protection from uremic cardiomyopathy in CKD models (45). Another method is by the minicircle DNA vectors, which allows sustained in vivo Klotho gene expression without risk of immunogenicity and confers kidney protection in models of ischemia reperfusion injury and unilateral ureteral obstruction (136).

Another approach is to increase endogenous Klotho production by overcoming the mechanisms that suppress Klotho expression and/or release in kidney disease. In a CKD model, the vitamin D receptor agonist, paricalcitol, increased serum Klotho and reduced serum phosphate and FGF23. The source of increased soluble Klotho levels was not determined to be from the kidneys (84). Experimental upregulation of Klotho expression by 1,25-dihydroxyvitamin D3 was also described in other studies (137,138). One recent study showed that sevelamer carbonate increased serum Klotho in CKD (139). Other agents that can potentially increase endogenous Klotho expression are angiotensin II receptor antagonists, PPAR-γ agonists, androgen, and statins (Figure 5) (140⇓⇓⇓⇓–145). Thus far, the efficacy of these agents has only been demonstrated in preclinical studies, except for the use of valsartan, which was shown to increase plasma Klotho levels in patients with diabetic nephropathy following 24 weeks of therapy (143). Off-label use of already approved drugs to pharmacologically manipulate endogenous Klotho remains a viable option. It is important to recognize that pharmacologic interventions have not been tested in clinical trials of kidney disease as the primary outcome. A major hurdle is that the mechanism of how Klotho expression is upregulated needs to be defined. Whether these drugs can stimulate endogenous Klotho production/release in CKD where the Klotho-generating cells are extensively destroyed is unknown.

Figure 5.
Figure 5.

Klotho-centric therapies in kidney disease, including increase in endogenous production or administration of exogenous Klotho protein or cDNA. miRNA, microRNA; PPAR-r, peroxisome proliferator-activated receptor gamma.

Another strategy is to target epigenetic modulation of endogenous Klotho expression. Although theoretically feasible, modulation of methylation and acetylation of the Klotho gene promoter needs further confirmation for its application in the management of human kidney disease.

Alternatively, administration of exogenous recombinant Klotho protein has dual effects: restoring soluble Klotho levels and promoting endogenous production of kidney Klotho. This dual action is particularly important in kidney failure, a status in which endogenous capacity is amputated. In a murine model, soluble Klotho injected 30 or 60 minutes after ischemic injury attenuated increase in serum creatinine postinjury and improved kidney histology (50). Further, repeated administration of Klotho starting 1 day after ischemic injury led to reduced fibrosis and improved recovery from AKI (16). Klotho replacement therapy remains the only practical method to control precise levels. Although recombinant Klotho replacement has been successful in many animal models, its application in humans still faces many hurdles.

Summary and Call for Action

Preclinical, translational, and clinical studies have advanced our understanding of Klotho biology, pathobiology, and potential clinical applications. Despite this accomplishment, the translation to clinical application has been slow. Klotho is an evolutionarily conserved housekeeping protein with a myriad of functions on many organs, which can serve as a biomarker for early diagnosis and/or risk stratification of patients with acute kidney disease or CKD. Because of its universal presence and panoply of function, specificity remains an issue (e.g., circulating Klotho levels may change in many diseases with or without kidney involvement).

Despite the emergence of promising human biomarker data of Klotho, additional large-scale and multicenter validation is needed. One difficulty to surpass before one can generate large reliable human databases is the standardization of methodology for soluble Klotho measurements. Given the imperfection of assays, one should exercise caution in interpretation of multiple small studies where kidney disease occurs under diverse clinical conditions and conclusions are made on the basis of variable sample conditions using different commercial reagents, most of which lack vigorous validation. Further, other factors known to influence soluble Klotho measurements, such as age, sex, inflammation, high-phosphate diet, FGF23, vitamin D supplementation, and certain medications, need to be carefully addressed in future prospective studies testing the biomarker candidacy of Klotho. Finally, there is a critical need to distinguish and characterize the subtypes of circulating Klotho protein because current assays do not differentiate between full-length soluble Klotho formed from cleavage of the transmembrane form (18⇓–20), subsequent cleaved Kl1 and Kl2 Klotho fragments, and Klotho complexes with other circulating proteins. Therefore, with lack of knowledge as to which form of Klotho is most biologically relevant and/or captured with current assays, associations drawn between measured soluble Klotho levels and clinical outcomes should be circumspectly interpreted.

To date, no studies of Klotho protein administration in humans have been reported. However, ample animal studies have provided proof of concept that systemic Klotho protein administration is effective with seemingly good safety profiles. Because Klotho deficiency, regardless of etiology, could cause or accelerate dysfunction or degeneration in multiple systems or organs, Klotho is a valuable treatment modality of not just kidney disease but also its complications, in particular cardiovascular disease (Figure 4). The evolution of precision medicine leveraging clinical informatics along with genomic, proteomic, and metabolomic data will help the identification of high-risk patients to be targeted in Klotho-based therapeutic trials. The ongoing development of Klotho therapies and the evolution of more accurate and precise Klotho assays make these clinical trials foreseeable and no longer utopic in the near future. Clearly, bench and bedside interactive collaborative research is critically needed to develop and validate novel Klotho assays, examine its biomarker potential in diagnosis and prognosis, and identify effective therapeutic windows for Klotho administration in acute kidney disease and CKD. Pragmatic therapeutic trials in selected populations that are most likely to benefit from Klotho administration or modulation should be designed (Figure 6).

Figure 6.
Figure 6.

Potential diagnostic, prognostic, and therapeutic applications of Klotho in clinical nephrology. Dx, diagnosis.

Disclosures

All authors have nothing to disclose.

Funding

M.C. Hu and O.W. Moe are supported by National Institutes of Health grants R01-DK091392 and R01-DK092461, the Charles and Jane Pak Center Innovative Research Support, and Endowed Professor Collaborative Research Support. O.W. Moe is supported by George O’Brien Kidney Research Center grant P30-DK-07938. J.A. Neyra is a recipient of National Center for Advancing Translational Sciences Early Career Pilot Grant UL1TR001998.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

References

  1. ↵
    1. Kuro-o M,
    2. Matsumura Y,
    3. Aizawa H,
    4. Kawaguchi H,
    5. Suga T,
    6. Utsugi T,
    7. Ohyama Y,
    8. Kurabayashi M,
    9. Kaname T,
    10. Kume E,
    11. Iwasaki H,
    12. Iida A,
    13. Shiraki-Iida T,
    14. Nishikawa S,
    15. Nagai R,
    16. Nabeshima YI
    : Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390: 45–51, 1997 pmid:9363890
    OpenUrlCrossRefPubMed
  2. ↵
    1. Ellidag HY,
    2. Yilmaz N,
    3. Kurtulus F,
    4. Aydin O,
    5. Eren E,
    6. Inci A,
    7. Dolu S,
    8. Ince FDA,
    9. Giray Ö,
    10. Yaman A
    : The three sisters of fate in multiple sclerosis: Klotho (Clotho), fibroblast growth factor-23 (Lachesis), and vitamin D (Atropos). Ann Neurosci 23: 155–161, 2016 pmid:27721584
    OpenUrlPubMed
  3. ↵
    1. Matsumura Y,
    2. Aizawa H,
    3. Shiraki-Iida T,
    4. Nagai R,
    5. Kuro-o M,
    6. Nabeshima Y
    : Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 242: 626–630, 1998 pmid:9464267
    OpenUrlCrossRefPubMed
  4. ↵
    1. Ohyama Y,
    2. Kurabayashi M,
    3. Masuda H,
    4. Nakamura T,
    5. Aihara Y,
    6. Kaname T,
    7. Suga T,
    8. Arai M,
    9. Aizawa H,
    10. Matsumura Y,
    11. Kuro-o M,
    12. Nabeshima Y,
    13. Nagail R
    : Molecular cloning of rat klotho cDNA: Markedly decreased expression of klotho by acute inflammatory stress. Biochem Biophys Res Commun 251: 920–925, 1998 pmid:9791011
    OpenUrlCrossRefPubMed
  5. ↵
    1. Ito S,
    2. Kinoshita S,
    3. Shiraishi N,
    4. Nakagawa S,
    5. Sekine S,
    6. Fujimori T,
    7. Nabeshima YI
    : Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein. Mech Dev 98: 115–119, 2000 pmid:11044614
    OpenUrlCrossRefPubMed
  6. ↵
    1. Ito S,
    2. Fujimori T,
    3. Hayashizaki Y,
    4. Nabeshima Y
    : Identification of a novel mouse membrane-bound family 1 glycosidase-like protein, which carries an atypical active site structure. Biochim Biophys Acta 1576: 341–345, 2002
    OpenUrlPubMed
  7. ↵
    1. Lee S,
    2. Choi J,
    3. Mohanty J,
    4. Sousa LP,
    5. Tome F,
    6. Pardon E,
    7. Steyaert J,
    8. Lemmon MA,
    9. Lax I,
    10. Schlessinger J
    : Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling. Nature 553: 501–505, 2018 pmid:29342135
    OpenUrlCrossRefPubMed
  8. ↵
    1. Hu MC,
    2. Shiizaki K,
    3. Kuro-o M,
    4. Moe OW
    : Fibroblast growth factor 23 and Klotho: Physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 75: 503–533, 2013 pmid:23398153
    OpenUrlCrossRefPubMed
  9. ↵
    1. Kurosu H,
    2. Ogawa Y,
    3. Miyoshi M,
    4. Yamamoto M,
    5. Nandi A,
    6. Rosenblatt KP,
    7. Baum MG,
    8. Schiavi S,
    9. Hu MC,
    10. Moe OW,
    11. Kuro-o M
    : Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281: 6120–6123, 2006 pmid:16436388
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Kato Y,
    2. Arakawa E,
    3. Kinoshita S,
    4. Shirai A,
    5. Furuya A,
    6. Yamano K,
    7. Nakamura K,
    8. Iida A,
    9. Anazawa H,
    10. Koh N,
    11. Iwano A,
    12. Imura A,
    13. Fujimori T,
    14. Kuro-o M,
    15. Hanai N,
    16. Takeshige K,
    17. Nabeshima Y
    : Establishment of the anti-Klotho monoclonal antibodies and detection of Klotho protein in kidneys. Biochem Biophys Res Commun 267: 597–602, 2000 pmid:10631108
    OpenUrlCrossRefPubMed
  11. ↵
    1. Imura A,
    2. Iwano A,
    3. Tohyama O,
    4. Tsuji Y,
    5. Nozaki K,
    6. Hashimoto N,
    7. Fujimori T,
    8. Nabeshima Y
    : Secreted Klotho protein in sera and CSF: Implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 565: 143–147, 2004 pmid:15135068
    OpenUrlCrossRefPubMed
  12. ↵
    1. Chen G,
    2. Liu Y,
    3. Goetz R,
    4. Fu L,
    5. Jayaraman S,
    6. Hu MC,
    7. Moe OW,
    8. Liang G,
    9. Li X,
    10. Mohammadi M
    : α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 553: 461–466, 2018 pmid:29342138
    OpenUrlCrossRefPubMed
  13. ↵
    1. Sugiura H,
    2. Yoshida T,
    3. Shiohira S,
    4. Kohei J,
    5. Mitobe M,
    6. Kurosu H,
    7. Kuro-o M,
    8. Nitta K,
    9. Tsuchiya K
    : Reduced Klotho expression level in kidney aggravates renal interstitial fibrosis. Am J Physiol Renal Physiol 302: F1252–F1264, 2012 pmid:22338084
    OpenUrlCrossRefPubMed
  14. ↵
    1. Doi S,
    2. Zou Y,
    3. Togao O,
    4. Pastor JV,
    5. John GB,
    6. Wang L,
    7. Shiizaki K,
    8. Gotschall R,
    9. Schiavi S,
    10. Yorioka N,
    11. Takahashi M,
    12. Boothman DA,
    13. Kuro-o M
    : Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem 286: 8655–8665, 2011 pmid:21209102
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Bian A,
    2. Neyra JA,
    3. Zhan M,
    4. Hu MC
    : Klotho, stem cells, and aging. Clin Interv Aging 10: 1233–1243, 2015 pmid:26346243
    OpenUrlPubMed
  16. ↵
    1. Shi M,
    2. Flores B,
    3. Gillings N,
    4. Bian A,
    5. Cho HJ,
    6. Yan S,
    7. Liu Y,
    8. Levine B,
    9. Moe OW,
    10. Hu MC
    : αKlotho mitigates progression of AKI to CKD through activation of autophagy. J Am Soc Nephrol 27: 2331–2345, 2016 pmid:26701976
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Hu MC,
    2. Shi M,
    3. Zhang J,
    4. Addo T,
    5. Cho HJ,
    6. Barker SL,
    7. Ravikumar P,
    8. Gillings N,
    9. Bian A,
    10. Sidhu SS,
    11. Kuro-o M,
    12. Moe OW
    : Renal production, uptake, and handling of circulating αKlotho. J Am Soc Nephrol 27: 79–90, 2016 pmid:25977312
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Bloch L,
    2. Sineshchekova O,
    3. Reichenbach D,
    4. Reiss K,
    5. Saftig P,
    6. Kuro-o M,
    7. Kaether C
    : Klotho is a substrate for alpha-, beta- and gamma-secretase. FEBS Lett 583: 3221–3224, 2009 pmid:19737556
    OpenUrlCrossRefPubMed
  19. ↵
    1. Chen CD,
    2. Podvin S,
    3. Gillespie E,
    4. Leeman SE,
    5. Abraham CR
    : Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A 104: 19796–19801, 2007 pmid:18056631
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Chen CD,
    2. Tung TY,
    3. Liang J,
    4. Zeldich E,
    5. Tucker Zhou TB,
    6. Turk BE,
    7. Abraham CR
    : Identification of cleavage sites leading to the shed form of the anti-aging protein klotho. Biochemistry 53: 5579–5587, 2014 pmid:25110992
    OpenUrlCrossRefPubMed
  21. ↵
    1. Shiraki-Iida T,
    2. Aizawa H,
    3. Matsumura Y,
    4. Sekine S,
    5. Iida A,
    6. Anazawa H,
    7. Nagai R,
    8. Kuro-o M,
    9. Nabeshima Y
    : Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett 424: 6–10, 1998 pmid:9537505
    OpenUrlCrossRefPubMed
  22. ↵
    1. Mencke R,
    2. Harms G,
    3. Moser J,
    4. van Meurs M,
    5. Diepstra A,
    6. Leuvenink HG,
    7. Hillebrands JL
    : Human alternative Klotho mRNA is a nonsense-mediated mRNA decay target inefficiently spliced in renal disease. JCI Insight 2: e94375, 2017 pmid:29046474
    OpenUrlPubMed
  23. ↵
    1. Panesso MC,
    2. Shi M,
    3. Cho HJ,
    4. Paek J,
    5. Ye J,
    6. Moe OW,
    7. Hu MC
    : Klotho has dual protective effects on cisplatin-induced acute kidney injury. Kidney Int 85: 855–870, 2014 pmid:24304882
    OpenUrlCrossRefPubMed
  24. ↵
    1. Cheng MF,
    2. Chen LJ,
    3. Niu HS,
    4. Yang TT,
    5. Lin KC,
    6. Cheng JT
    : Signals mediating Klotho-induced neuroprotection in hippocampal neuronal cells. Acta Neurobiol Exp (Warsz) 75: 60–71, 2015 pmid:25856523
    OpenUrlPubMed
  25. ↵
    1. Sun S,
    2. Cheng B,
    3. Sun PG,
    4. Wu XH,
    5. Wu QQ,
    6. He P
    : RTEF-1 protects against oxidative damage induced by H2O2 in human umbilical vein endothelial cells through Klotho activation. Exp Biol Med (Maywood) 240: 1606–1613, 2015 pmid:26041389
    OpenUrlCrossRefPubMed
  26. ↵
    1. Ravikumar P,
    2. Ye J,
    3. Zhang J,
    4. Pinch SN,
    5. Hu MC,
    6. Kuro-o M,
    7. Hsia CC,
    8. Moe OW
    : α-Klotho protects against oxidative damage in pulmonary epithelia. Am J Physiol Lung Cell Mol Physiol 307: L566–L575, 2014 pmid:25063799
    OpenUrlCrossRefPubMed
  27. ↵
    1. Wang Y,
    2. Chen L,
    3. Huang G,
    4. He D,
    5. He J,
    6. Xu W,
    7. Zou C,
    8. Zong F,
    9. Li Y,
    10. Chen B,
    11. Wu S,
    12. Zhao W,
    13. Wu J
    : Klotho sensitizes human lung cancer cell line to cisplatin via PI3k/Akt pathway. PLoS One 8: e57391, 2013 pmid:23437382
    OpenUrlCrossRefPubMed
  28. ↵
    1. Smith RC,
    2. O’Bryan LM,
    3. Farrow EG,
    4. Summers LJ,
    5. Clinkenbeard EL,
    6. Roberts JL,
    7. Cass TA,
    8. Saha J,
    9. Broderick C,
    10. Ma YL,
    11. Zeng QQ,
    12. Kharitonenkov A,
    13. Wilson JM,
    14. Guo Q,
    15. Sun H,
    16. Allen MR,
    17. Burr DB,
    18. Breyer MD,
    19. White KE
    : Circulating αKlotho influences phosphate handling by controlling FGF23 production. J Clin Invest 122: 4710–4715, 2012 pmid:23187128
    OpenUrlCrossRefPubMed
  29. ↵
    1. Hu MC,
    2. Shi M,
    3. Gillings N,
    4. Flores B,
    5. Takahashi M,
    6. Kuro-O M,
    7. Moe OW
    : Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int 91: 1104–1114, 2017 pmid:28131398
    OpenUrlCrossRefPubMed
  30. ↵
    1. Urakawa I,
    2. Yamazaki Y,
    3. Shimada T,
    4. Iijima K,
    5. Hasegawa H,
    6. Okawa K,
    7. Fujita T,
    8. Fukumoto S,
    9. Yamashita T
    : Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770–774, 2006 pmid:17086194
    OpenUrlCrossRefPubMed
  31. ↵
    1. Hu MC,
    2. Shi M,
    3. Zhang J,
    4. Pastor J,
    5. Nakatani T,
    6. Lanske B,
    7. Razzaque MS,
    8. Rosenblatt KP,
    9. Baum MG,
    10. Kuro-o M,
    11. Moe OW
    : Klotho: A novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 24: 3438–3450, 2010 pmid:20466874
    OpenUrlCrossRefPubMed
  32. ↵
    1. Neyra JA,
    2. Hu MC
    : αKlotho and chronic kidney disease. Vitam Horm 101: 257–310, 2016 pmid:27125746
    OpenUrlPubMed
  33. ↵
    1. Ohnishi M,
    2. Nakatani T,
    3. Lanske B,
    4. Razzaque MS
    : Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase. Kidney Int 75: 1166–1172, 2009 pmid:19225558
    OpenUrlCrossRefPubMed
  34. ↵
    1. Hu MC,
    2. Shi M,
    3. Cho HJ,
    4. Adams-Huet B,
    5. Paek J,
    6. Hill K,
    7. Shelton J,
    8. Amaral AP,
    9. Faul C,
    10. Taniguchi M,
    11. Wolf M,
    12. Brand M,
    13. Takahashi M,
    14. Kuro-O M,
    15. Hill JA,
    16. Moe OW
    : Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 26: 1290–1302, 2015 pmid:25326585
    OpenUrlAbstract/FREE Full Text
  35. ↵
    1. Young GH,
    2. Wu VC
    : KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int 81: 611–612, 2012 pmid:22419041
    OpenUrlCrossRefPubMed
  36. ↵
    1. Sun CY,
    2. Chang SC,
    3. Wu MS
    : Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int 81: 640–650, 2012 pmid:22237753
    OpenUrlCrossRefPubMed
  37. ↵
    1. Kooman JP,
    2. Kotanko P,
    3. Schols AM,
    4. Shiels PG,
    5. Stenvinkel P
    : Chronic kidney disease and premature ageing. Nat Rev Nephrol 10: 732–742, 2014 pmid:25287433
    OpenUrlCrossRefPubMed
  38. ↵
    1. Chen CD,
    2. Sloane JA,
    3. Li H,
    4. Aytan N,
    5. Giannaris EL,
    6. Zeldich E,
    7. Hinman JD,
    8. Dedeoglu A,
    9. Rosene DL,
    10. Bansal R,
    11. Luebke JI,
    12. Kuro-o M,
    13. Abraham CR
    : The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci 33: 1927–1939, 2013 pmid:23365232
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Zhu L,
    2. Stein LR,
    3. Kim D,
    4. Ho K,
    5. Yu GQ,
    6. Zhan L,
    7. Larsson TE,
    8. Mucke L
    : Klotho controls the brain-immune system interface in the choroid plexus. Proc Natl Acad Sci U S A 115: E11388–E11396, 2018 pmid:30413620
    OpenUrlAbstract/FREE Full Text
  40. ↵
    1. Tanaka S,
    2. Okusa MD
    : Crosstalk between the nervous system and the kidney. Kidney Int 97: 466–476, 2020 pmid:32001065
    OpenUrlPubMed
  41. ↵
    1. Semba RD,
    2. Moghekar AR,
    3. Hu J,
    4. Sun K,
    5. Turner R,
    6. Ferrucci L,
    7. O’Brien R
    : Klotho in the cerebrospinal fluid of adults with and without Alzheimer’s disease. Neurosci Lett 558: 37–40, 2014 pmid:24211693
    OpenUrlCrossRefPubMed
  42. ↵
    1. Faul C,
    2. Amaral AP,
    3. Oskouei B,
    4. Hu MC,
    5. Sloan A,
    6. Isakova T,
    7. Gutiérrez OM,
    8. Aguillon-Prada R,
    9. Lincoln J,
    10. Hare JM,
    11. Mundel P,
    12. Morales A,
    13. Scialla J,
    14. Fischer M,
    15. Soliman EZ,
    16. Chen J,
    17. Go AS,
    18. Rosas SE,
    19. Nessel L,
    20. Townsend RR,
    21. Feldman HI,
    22. St John Sutton M,
    23. Ojo A,
    24. Gadegbeku C,
    25. Di Marco GS,
    26. Reuter S,
    27. Kentrup D,
    28. Tiemann K,
    29. Brand M,
    30. Hill JA,
    31. Moe OW,
    32. Kuro-O M,
    33. Kusek JW,
    34. Keane MG,
    35. Wolf M
    : FGF23 induces left ventricular hypertrophy. J Clin Invest 121: 4393–4408, 2011 pmid:21985788
    OpenUrlCrossRefPubMed
  43. ↵
    1. Grabner A,
    2. Amaral AP,
    3. Schramm K,
    4. Singh S,
    5. Sloan A,
    6. Yanucil C,
    7. Li J,
    8. Shehadeh LA,
    9. Hare JM,
    10. David V,
    11. Martin A,
    12. Fornoni A,
    13. Di Marco GS,
    14. Kentrup D,
    15. Reuter S,
    16. Mayer AB,
    17. Pavenstädt H,
    18. Stypmann J,
    19. Kuhn C,
    20. Hille S,
    21. Frey N,
    22. Leifheit-Nestler M,
    23. Richter B,
    24. Haffner D,
    25. Abraham R,
    26. Bange J,
    27. Sperl B,
    28. Ullrich A,
    29. Brand M,
    30. Wolf M,
    31. Faul C
    : Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab 22: 1020–1032, 2015 pmid:26437603
    OpenUrlCrossRefPubMed
  44. ↵
    1. Han X,
    2. Cai C,
    3. Xiao Z,
    4. Quarles LD
    : FGF23 induced left ventricular hypertrophy mediated by FGFR4 signaling in the myocardium is attenuated by soluble Klotho in mice. J Mol Cell Cardiol 138: 66–74, 2020 pmid:31758962
    OpenUrlCrossRefPubMed
  45. ↵
    1. Xie J,
    2. Yoon J,
    3. An SW,
    4. Kuro-o M,
    5. Huang CL
    : Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. J Am Soc Nephrol 26: 1150–1160, 2015 pmid:25475745
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Yang K,
    2. Wang C,
    3. Nie L,
    4. Zhao X,
    5. Gu J,
    6. Guan X,
    7. Wang S,
    8. Xiao T,
    9. Xu X,
    10. He T,
    11. Xia X,
    12. Wang J,
    13. Zhao J
    : Klotho protects against indoxyl sulphate-induced myocardial hypertrophy. J Am Soc Nephrol 26: 2434–2446, 2015 pmid:25804281
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Moreno JA,
    2. Izquierdo MC,
    3. Sanchez-Niño MD,
    4. Suárez-Alvarez B,
    5. Lopez-Larrea C,
    6. Jakubowski A,
    7. Blanco J,
    8. Ramirez R,
    9. Selgas R,
    10. Ruiz-Ortega M,
    11. Egido J,
    12. Ortiz A,
    13. Sanz AB
    : The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB. J Am Soc Nephrol 22: 1315–1325, 2011 pmid:21719790
    OpenUrlAbstract/FREE Full Text
  48. ↵
    1. Thurston RD,
    2. Larmonier CB,
    3. Majewski PM,
    4. Ramalingam R,
    5. Midura-Kiela M,
    6. Laubitz D,
    7. Vandewalle A,
    8. Besselsen DG,
    9. Muhlbauer M,
    10. Jobin C,
    11. Kiela PR,
    12. Ghishan FK
    : Tumor necrosis factor and interferon-gamma down-regulate Klotho in mice with colitis. Gastroenterology 138: 1384–1394, 2010
    OpenUrlCrossRefPubMed
  49. ↵
    1. Mitobe M,
    2. Yoshida T,
    3. Sugiura H,
    4. Shirota S,
    5. Tsuchiya K,
    6. Nihei H
    : Oxidative stress decreases klotho expression in a mouse kidney cell line. Nephron, Exp Nephrol 101: e67–e74, 2005 pmid:15976510
    OpenUrlCrossRefPubMed
  50. ↵
    1. Hu MC,
    2. Shi M,
    3. Zhang J,
    4. Quiñones H,
    5. Kuro-o M,
    6. Moe OW
    : Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective. Kidney Int 78: 1240–1251, 2010 pmid:20861825
    OpenUrlCrossRefPubMed
  51. ↵
    1. Jorge LB,
    2. Coelho FO,
    3. Sanches TR,
    4. Malheiros DMAC,
    5. Ezaquiel de Souza L,
    6. Dos Santos F,
    7. de Sá Lima L,
    8. Scavone C,
    9. Irigoyen M,
    10. Kuro-O M,
    11. Andrade L
    : Klotho deficiency aggravates sepsis-related multiple organ dysfunction. Am J Physiol Renal Physiol 316: F438–F448, 2019 pmid:30516423
    OpenUrlPubMed
  52. ↵
    1. Ferrucci L,
    2. Gonzalez-Freire M,
    3. Fabbri E,
    4. Simonsick E,
    5. Tanaka T,
    6. Moore Z,
    7. Salimi S,
    8. Sierra F,
    9. de Cabo R
    : Measuring biological aging in humans: A quest. Aging Cell 19: e13080, 2020 pmid:31833194
    OpenUrlCrossRefPubMed
  53. ↵
    1. Knoppert SN,
    2. Valentijn FA,
    3. Nguyen TQ,
    4. Goldschmeding R,
    5. Falke LL
    : Cellular senescence and the kidney: Potential therapeutic targets and tools. Front Pharmacol 10: 770, 2019 pmid:31354486
    OpenUrlPubMed
  54. ↵
    1. Liu H,
    2. Fergusson MM,
    3. Castilho RM,
    4. Liu J,
    5. Cao L,
    6. Chen J,
    7. Malide D,
    8. Rovira II,
    9. Schimel D,
    10. Kuo CJ,
    11. Gutkind JS,
    12. Hwang PM,
    13. Finkel T
    : Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317: 803–806, 2007 pmid:17690294
    OpenUrlAbstract/FREE Full Text
  55. ↵
    1. Kuro-o M
    : Klotho as a regulator of oxidative stress and senescence. Biol Chem 389: 233–241, 2008 pmid:18177265
    OpenUrlCrossRefPubMed
  56. ↵
    1. Liu F,
    2. Wu S,
    3. Ren H,
    4. Gu J
    : Klotho suppresses RIG-I-mediated senescence-associated inflammation. Nat Cell Biol 13: 254–262, 2011 pmid:21336305
    OpenUrlCrossRefPubMed
  57. ↵
    1. Zeng Y,
    2. Wang PH,
    3. Zhang M,
    4. Du JR
    : Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice. Aging Clin Exp Res 28: 69–76, 2016 pmid:25986237
    OpenUrlCrossRefPubMed
  58. ↵
    1. Ikushima M,
    2. Rakugi H,
    3. Ishikawa K,
    4. Maekawa Y,
    5. Yamamoto K,
    6. Ohta J,
    7. Chihara Y,
    8. Kida I,
    9. Ogihara T
    : Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Biochem Biophys Res Commun 339: 827–832, 2006 pmid:16325773
    OpenUrlCrossRefPubMed
  59. ↵
    1. Maekawa Y,
    2. Ohishi M,
    3. Ikushima M,
    4. Yamamoto K,
    5. Yasuda O,
    6. Oguro R,
    7. Yamamoto-Hanasaki H,
    8. Tatara Y,
    9. Takeya Y,
    10. Rakugi H
    : Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway. Geriatr Gerontol Int 11: 510–516, 2011 pmid:21518171
    OpenUrlCrossRefPubMed
  60. ↵
    1. Sugiura H,
    2. Yoshida T,
    3. Tsuchiya K,
    4. Mitobe M,
    5. Nishimura S,
    6. Shirota S,
    7. Akiba T,
    8. Nihei H
    : Klotho reduces apoptosis in experimental ischaemic acute renal failure. Nephrol Dial Transplant 20: 2636–2645, 2005 pmid:16204278
    OpenUrlCrossRefPubMed
  61. ↵
    1. Haruna Y,
    2. Kashihara N,
    3. Satoh M,
    4. Tomita N,
    5. Namikoshi T,
    6. Sasaki T,
    7. Fujimori T,
    8. Xie P,
    9. Kanwar YS
    : Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc Natl Acad Sci U S A 104: 2331–2336, 2007 pmid:17287345
    OpenUrlAbstract/FREE Full Text
  62. ↵
    1. Yamamoto M,
    2. Clark JD,
    3. Pastor JV,
    4. Gurnani P,
    5. Nandi A,
    6. Kurosu H,
    7. Miyoshi M,
    8. Ogawa Y,
    9. Castrillon DH,
    10. Rosenblatt KP,
    11. Kuro-o M
    : Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem 280: 38029–38034, 2005 pmid:16186101
    OpenUrlAbstract/FREE Full Text
  63. ↵
    1. Rakugi H,
    2. Matsukawa N,
    3. Ishikawa K,
    4. Yang J,
    5. Imai M,
    6. Ikushima M,
    7. Maekawa Y,
    8. Kida I,
    9. Miyazaki J,
    10. Ogihara T
    : Anti-oxidative effect of Klotho on endothelial cells through cAMP activation. Endocrine 31: 82–87, 2007 pmid:17709902
    OpenUrlCrossRefPubMed
  64. ↵
    1. Cui W,
    2. Leng B,
    3. Wang G
    : Klotho protein inhibits H2O2-induced oxidative injury in endothelial cells via regulation of PI3K/AKT/Nrf2/HO-1 pathways. Can J Physiol Pharmacol 97: 370–376, 2019 pmid:30576222
    OpenUrlPubMed
  65. ↵
    1. Feng Y,
    2. He D,
    3. Yao Z,
    4. Klionsky DJ
    : The machinery of macroautophagy. Cell Res 24: 24–41, 2014 pmid:24366339
    OpenUrlCrossRefPubMed
  66. ↵
    1. Li P,
    2. Shi M,
    3. Maique J,
    4. Shaffer J,
    5. Yan S,
    6. Moe OW,
    7. Hu MC
    : Beclin 1/Bcl-2 complex-dependent autophagy activity modulates renal susceptibility to ischemia-reperfusion injury and mediates renoprotection by Klotho. Am J Physiol Renal Physiol 318: F772–F792, 2020 pmid:31984794
    OpenUrlPubMed
  67. ↵
    1. Grange C,
    2. Papadimitriou E,
    3. Dimuccio V,
    4. Pastorino C,
    5. Molina J,
    6. O’Kelly R,
    7. Niedernhofer LJ,
    8. Robbins PD,
    9. Camussi G,
    10. Bussolati B
    : Urinary extracellular vesicles carrying Klotho improve the recovery of renal function in an acute tubular injury model. Mol Ther 28: 490–502, 2019
    OpenUrl
  68. ↵
    1. Sato S,
    2. Kawamata Y,
    3. Takahashi A,
    4. Imai Y,
    5. Hanyu A,
    6. Okuma A,
    7. Takasugi M,
    8. Yamakoshi K,
    9. Sorimachi H,
    10. Kanda H,
    11. Ishikawa Y,
    12. Sone S,
    13. Nishioka Y,
    14. Ohtani N,
    15. Hara E
    : Ablation of the p16(INK4a) tumour suppressor reverses ageing phenotypes of klotho mice. Nat Commun 6: 7035, 2015 pmid:25923845
    OpenUrlCrossRefPubMed
  69. ↵
    1. Polichnowski AJ
    : Microvascular rarefaction and hypertension in the impaired recovery and progression of kidney disease following AKI in preexisting CKD states. Am J Physiol Renal Physiol 315: F1513–F1518, 2018 pmid:30256130
    OpenUrlPubMed
  70. ↵
    1. Mazzotta C,
    2. Manetti M,
    3. Rosa I,
    4. Romano E,
    5. Blagojevic J,
    6. Bellando-Randone S,
    7. Bruni C,
    8. Lepri G,
    9. Guiducci S,
    10. Ibba-Manneschi L,
    11. Matucci-Cerinic M
    : Proangiogenic effects of soluble α-Klotho on systemic sclerosis dermal microvascular endothelial cells. Arthritis Res Ther 19: 27, 2017 pmid:28183357
    OpenUrlPubMed
  71. ↵
    1. Kusaba T,
    2. Okigaki M,
    3. Matui A,
    4. Murakami M,
    5. Ishikawa K,
    6. Kimura T,
    7. Sonomura K,
    8. Adachi Y,
    9. Shibuya M,
    10. Shirayama T,
    11. Tanda S,
    12. Hatta T,
    13. Sasaki S,
    14. Mori Y,
    15. Matsubara H
    : Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity. Proc Natl Acad Sci U S A 107: 19308–19313, 2010 pmid:20966350
    OpenUrlAbstract/FREE Full Text
  72. ↵
    1. Zhou L,
    2. Li Y,
    3. Zhou D,
    4. Tan RJ,
    5. Liu Y
    : Loss of Klotho contributes to kidney injury by derepression of Wnt/β-catenin signaling. J Am Soc Nephrol 24: 771–785, 2013 pmid:23559584
    OpenUrlAbstract/FREE Full Text
  73. ↵
    1. Li S,
    2. Yu L,
    3. He A,
    4. Liu Q
    : Klotho inhibits unilateral ureteral obstruction-induced endothelial-to-mesenchymal transition via TGF-β1/Smad2/Snail1 signaling in mice. Front Pharmacol 10: 348, 2019 pmid:31024315
    OpenUrlPubMed
  74. ↵
    1. Hu MC,
    2. Shi M,
    3. Zhang J,
    4. Quiñones H,
    5. Griffith C,
    6. Kuro-o M,
    7. Moe OW
    : Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22: 124–136, 2011 pmid:21115613
    OpenUrlAbstract/FREE Full Text
  75. ↵
    1. Neyra JA,
    2. Hu MC
    : Potential application of klotho in human chronic kidney disease. Bone 100: 41–49, 2017 pmid:28115282
    OpenUrlPubMed
  76. ↵
    1. Lu X,
    2. Hu MC
    : Klotho/FGF23 axis in chronic kidney disease and cardiovascular disease. Kidney Dis 3: 15–23, 2017 pmid:28785560
    OpenUrlCrossRefPubMed
  77. ↵
    1. Hu MC,
    2. Shi M,
    3. Moe OW
    : Role of αKlotho and FGF23 in regulation of type II Na-dependent phosphate co-transporters. Pflugers Arch 471: 99–108, 2019 pmid:30506274
    OpenUrlPubMed
  78. ↵
    1. Goetz R,
    2. Nakada Y,
    3. Hu MC,
    4. Kurosu H,
    5. Wang L,
    6. Nakatani T,
    7. Shi M,
    8. Eliseenkova AV,
    9. Razzaque MS,
    10. Moe OW,
    11. Kuro-o M,
    12. Mohammadi M
    : Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci U S A 107: 407–412, 2010 pmid:19966287
    OpenUrlAbstract/FREE Full Text
  79. ↵
    1. Ide N,
    2. Ye R,
    3. Courbebaisse M,
    4. Olauson H,
    5. Densmore MJ,
    6. Larsson TE,
    7. Hanai JI,
    8. Lanske B
    : In vivo evidence for an interplay of FGF23/Klotho/PTH axis on the phosphate handling in renal proximal tubules. Am J Physiol Renal Physiol 315: F1261–F1270, 2018 pmid:29993278
    OpenUrlPubMed
  80. ↵
    1. Leaf DE,
    2. Siew ED,
    3. Eisenga MF,
    4. Singh K,
    5. Mc Causland FR,
    6. Srivastava A,
    7. Ikizler TA,
    8. Ware LB,
    9. Ginde AA,
    10. Kellum JA,
    11. Palevsky PM,
    12. Wolf M,
    13. Waikar SS
    : Fibroblast growth factor 23 associates with death in critically ill patients. Clin J Am Soc Nephrol 13: 531–541, 2018 pmid:29519954
    OpenUrlAbstract/FREE Full Text
  81. ↵
    1. Rodelo-Haad C,
    2. Santamaria R,
    3. Muñoz-Castañeda JR,
    4. Pendón-Ruiz de Mier MV,
    5. Martin-Malo A,
    6. Rodriguez M
    : FGF23, biomarker or target? Toxins (Basel) 11: 175, 2019 pmid:30909513
    OpenUrlPubMed
  82. ↵
    1. Gutiérrez OM
    : Fibroblast growth factor 23 and disordered vitamin D metabolism in chronic kidney disease: Updating the “trade-off” hypothesis. Clin J Am Soc Nephrol 5: 1710–1716, 2010 pmid:20507957
    OpenUrlAbstract/FREE Full Text
  83. ↵
    1. Leifheit-Nestler M,
    2. Grabner A,
    3. Hermann L,
    4. Richter B,
    5. Schmitz K,
    6. Fischer DC,
    7. Yanucil C,
    8. Faul C,
    9. Haffner D
    : Vitamin D treatment attenuates cardiac FGF23/FGFR4 signaling and hypertrophy in uremic rats. Nephrol Dial Transplant 32: 1493–1503, 2017 pmid:28339837
    OpenUrlCrossRefPubMed
  84. ↵
    1. Lau WL,
    2. Leaf EM,
    3. Hu MC,
    4. Takeno MM,
    5. Kuro-o M,
    6. Moe OW,
    7. Giachelli CM
    : Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int 82: 1261–1270, 2012 pmid:22932118
    OpenUrlCrossRefPubMed
  85. ↵
    1. Carrillo-López N,
    2. Panizo S,
    3. Alonso-Montes C,
    4. Martínez-Arias L,
    5. Avello N,
    6. Sosa P,
    7. Dusso AS,
    8. Cannata-Andía JB,
    9. Naves-Díaz M
    : High-serum phosphate and parathyroid hormone distinctly regulate bone loss and vascular calcification in experimental chronic kidney disease. Nephrol Dial Transplant 34: 934–941, 2019 pmid:30189026
    OpenUrlPubMed
  86. ↵
    1. Isakova T,
    2. Cai X,
    3. Lee J,
    4. Mehta R,
    5. Zhang X,
    6. Yang W,
    7. Nessel L,
    8. Anderson AH,
    9. Lo J,
    10. Porter A,
    11. Nunes JW,
    12. Negrea L,
    13. Hamm L,
    14. Horwitz E,
    15. Chen J,
    16. Scialla JJ,
    17. de Boer IH,
    18. Leonard MB,
    19. Feldman HI,
    20. Wolf M; CRIC Study Investigators
    : Longitudinal evolution of markers of mineral metabolism in patients with CKD: The chronic renal insufficiency cohort (CRIC) study. Am J Kidney Dis 75: 235–244, 2020 pmid:31668375
    OpenUrlPubMed
  87. ↵
    1. Galitzer H,
    2. Ben-Dov IZ,
    3. Silver J,
    4. Naveh-Many T
    : Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int 77: 211–218, 2010 pmid:20016468
    OpenUrlCrossRefPubMed
  88. ↵
    1. Kuro-O M
    : Klotho and endocrine fibroblast growth factors: Markers of chronic kidney disease progression and cardiovascular complications? Nephrol Dial Transplant 34: 15–21, 2019 pmid:29800324
    OpenUrlPubMed
  89. ↵
    1. Patel S,
    2. Barron JL,
    3. Mirzazedeh M,
    4. Gallagher H,
    5. Hyer S,
    6. Cantor T,
    7. Fraser WD
    : Changes in bone mineral parameters, vitamin D metabolites, and PTH measurements with varying chronic kidney disease stages. J Bone Miner Metab 29: 71–79, 2011 pmid:20521154
    OpenUrlCrossRefPubMed
  90. ↵
    1. Zhou X,
    2. Chen K,
    3. Lei H,
    4. Sun Z
    : Klotho gene deficiency causes salt-sensitive hypertension via monocyte chemotactic protein-1/CC chemokine receptor 2-mediated inflammation. J Am Soc Nephrol 26: 121–132, 2015 pmid:24904083
    OpenUrlAbstract/FREE Full Text
  91. ↵
    1. Gao D,
    2. Zuo Z,
    3. Tian J,
    4. Ali Q,
    5. Lin Y,
    6. Lei H,
    7. Sun Z
    : Activation of SIRT1 attenuates klotho deficiency-induced arterial stiffness and hypertension by enhancing AMP-activated protein kinase activity. Hypertension 68: 1191–1199, 2016 pmid:27620389
    OpenUrlAbstract/FREE Full Text
  92. ↵
    1. Citterio L,
    2. Delli Carpini S,
    3. Lupoli S,
    4. Brioni E,
    5. Simonini M,
    6. Fontana S,
    7. Zagato L,
    8. Messaggio E,
    9. Barlassina C,
    10. Cusi D,
    11. Manunta P,
    12. Lanzani C
    : Klotho gene in human salt-sensitive hypertension. Clin J Am Soc Nephrol 15: 375–383, 2020 pmid:31992575
    OpenUrlAbstract/FREE Full Text
  93. ↵
    1. Asai O,
    2. Nakatani K,
    3. Tanaka T,
    4. Sakan H,
    5. Imura A,
    6. Yoshimoto S,
    7. Samejima K,
    8. Yamaguchi Y,
    9. Matsui M,
    10. Akai Y,
    11. Konishi N,
    12. Iwano M,
    13. Nabeshima Y,
    14. Saito Y
    : Decreased renal α-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion. Kidney Int 81: 539–547, 2012 pmid:22217880
    OpenUrlCrossRefPubMed
  94. ↵
    1. Koh N,
    2. Fujimori T,
    3. Nishiguchi S,
    4. Tamori A,
    5. Shiomi S,
    6. Nakatani T,
    7. Sugimura K,
    8. Kishimoto T,
    9. Kinoshita S,
    10. Kuroki T,
    11. Nabeshima Y
    : Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 280: 1015–1020, 2001 pmid:11162628
    OpenUrlCrossRefPubMed
  95. ↵
    1. Sakan H,
    2. Nakatani K,
    3. Asai O,
    4. Imura A,
    5. Tanaka T,
    6. Yoshimoto S,
    7. Iwamoto N,
    8. Kurumatani N,
    9. Iwano M,
    10. Nabeshima Y,
    11. Konishi N,
    12. Saito Y
    : Reduced renal α-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism. PLoS One 9: e86301, 2014 pmid:24466013
    OpenUrlCrossRefPubMed
  96. ↵
    1. Kim HR,
    2. Nam BY,
    3. Kim DW,
    4. Kang MW,
    5. Han JH,
    6. Lee MJ,
    7. Shin DH,
    8. Doh FM,
    9. Koo HM,
    10. Ko KI,
    11. Kim CH,
    12. Oh HJ,
    13. Yoo TH,
    14. Kang SW,
    15. Han DS,
    16. Han SH
    : Circulating α-klotho levels in CKD and relationship to progression. Am J Kidney Dis 61: 899–909, 2013 pmid:23540260
    OpenUrlCrossRefPubMed
  97. ↵
    1. Kitagawa M,
    2. Sugiyama H,
    3. Morinaga H,
    4. Inoue T,
    5. Takiue K,
    6. Ogawa A,
    7. Yamanari T,
    8. Kikumoto Y,
    9. Uchida HA,
    10. Kitamura S,
    11. Maeshima Y,
    12. Nakamura K,
    13. Ito H,
    14. Makino H
    : A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One 8: e56695, 2013 pmid:23431388
    OpenUrlCrossRefPubMed
  98. ↵
    1. Ozeki M,
    2. Fujita S,
    3. Kizawa S,
    4. Morita H,
    5. Sohmiya K,
    6. Hoshiga M,
    7. Ishizaka N
    : Association of serum levels of FGF23 and α-Klotho with glomerular filtration rate and proteinuria among cardiac patients. BMC Nephrol 15: 147, 2014 pmid:25200959
    OpenUrlPubMed
  99. ↵
    1. Akimoto T,
    2. Yoshizawa H,
    3. Watanabe Y,
    4. Numata A,
    5. Yamazaki T,
    6. Takeshima E,
    7. Iwazu K,
    8. Komada T,
    9. Otani N,
    10. Morishita Y,
    11. Ito C,
    12. Shiizaki K,
    13. Ando Y,
    14. Muto S,
    15. Kuro-o M,
    16. Kusano E
    : Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease. BMC Nephrol 13: 155, 2012 pmid:23176706
    OpenUrlCrossRefPubMed
  100. ↵
    1. Oh HJ,
    2. Nam BY,
    3. Lee MJ,
    4. Kim CH,
    5. Koo HM,
    6. Doh FM,
    7. Han JH,
    8. Kim EJ,
    9. Han JS,
    10. Park JT,
    11. Yoo TH,
    12. Kang SW,
    13. Han DS,
    14. Han SH
    : Decreased circulating klotho levels in patients undergoing dialysis and relationship to oxidative stress and inflammation. Perit Dial Int 35: 43–51, 2015 pmid:24497597
    OpenUrlAbstract/FREE Full Text
  101. ↵
    1. Drew DA,
    2. Katz R,
    3. Kritchevsky S,
    4. Ix J,
    5. Shlipak M,
    6. Gutiérrez OM,
    7. Newman A,
    8. Hoofnagle A,
    9. Fried L,
    10. Semba RD,
    11. Sarnak M
    : Association between soluble klotho and change in kidney function: The health aging and body composition study. J Am Soc Nephrol 28: 1859–1866, 2017 pmid:28104822
    OpenUrlAbstract/FREE Full Text
  102. ↵
    1. Barker SL,
    2. Pastor J,
    3. Carranza D,
    4. Quiñones H,
    5. Griffith C,
    6. Goetz R,
    7. Mohammadi M,
    8. Ye J,
    9. Zhang J,
    10. Hu MC,
    11. Kuro-o M,
    12. Moe OW,
    13. Sidhu SS
    : The demonstration of αKlotho deficiency in human chronic kidney disease with a novel synthetic antibody. Nephrol Dial Transplant 30: 223–233, 2015 pmid:25324355
    OpenUrlCrossRefPubMed
  103. ↵
    1. Shimamura Y,
    2. Hamada K,
    3. Inoue K,
    4. Ogata K,
    5. Ishihara M,
    6. Kagawa T,
    7. Inoue M,
    8. Fujimoto S,
    9. Ikebe M,
    10. Yuasa K,
    11. Yamanaka S,
    12. Sugiura T,
    13. Terada Y
    : Serum levels of soluble secreted α-Klotho are decreased in the early stages of chronic kidney disease, making it a probable novel biomarker for early diagnosis. Clin Exp Nephrol 16: 722–729, 2012 pmid:22457086
    OpenUrlCrossRefPubMed
  104. ↵
    1. Rotondi S,
    2. Pasquali M,
    3. Tartaglione L,
    4. Muci ML,
    5. Mandanici G,
    6. Leonangeli C,
    7. Sales S,
    8. Farcomeni A,
    9. Mazzaferro S
    : Soluble α -klotho serum levels in chronic kidney disease. Int J Endocrinol 2015: 872193, 2015 pmid:25873958
    OpenUrlPubMed
  105. ↵
    1. Wang Q,
    2. Su W,
    3. Shen Z,
    4. Wang R
    : Correlation between soluble α-Klotho and renal function in patients with chronic kidney disease: A review and meta-analysis. BioMed Res Int 2018: 9481475, 2018 pmid:30159331
    OpenUrlPubMed
  106. ↵
    1. Pavik I,
    2. Jaeger P,
    3. Ebner L,
    4. Wagner CA,
    5. Petzold K,
    6. Spichtig D,
    7. Poster D,
    8. Wüthrich RP,
    9. Russmann S,
    10. Serra AL
    : Secreted klotho and FGF23 in chronic kidney disease stage 1 to 5: A sequence suggested from a cross-sectional study. Nephrol Dial Transplant 28: 352–359, 2013 pmid:23129826
    OpenUrlCrossRefPubMed
    1. Wan M,
    2. Smith C,
    3. Shah V,
    4. Gullet A,
    5. Wells D,
    6. Rees L,
    7. Shroff R
    : Fibroblast growth factor 23 and soluble klotho in children with chronic kidney disease. Nephrol Dial Transplant 28: 153–161, 2013 pmid:23180879
    OpenUrlCrossRefPubMed
    1. Seiler S,
    2. Wen M,
    3. Roth HJ,
    4. Fehrenz M,
    5. Flügge F,
    6. Herath E,
    7. Weihrauch A,
    8. Fliser D,
    9. Heine GH
    : Plasma Klotho is not related to kidney function and does not predict adverse outcome in patients with chronic kidney disease. Kidney Int 83: 121–128, 2013 pmid:22895520
    OpenUrlCrossRefPubMed
  109. ↵
    1. Seiler S,
    2. Rogacev KS,
    3. Roth HJ,
    4. Shafein P,
    5. Emrich I,
    6. Neuhaus S,
    7. Floege J,
    8. Fliser D,
    9. Heine GH
    : Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4. Clin J Am Soc Nephrol 9: 1049–1058, 2014 pmid:24677555
    OpenUrlAbstract/FREE Full Text
    1. Cano FJ,
    2. Freundlich M,
    3. Ceballos ML,
    4. Rojo AP,
    5. Azocar MA,
    6. Delgado IO,
    7. Ibacache MJ,
    8. Delucchi MA,
    9. Lillo AM,
    10. Irarrázabal CE,
    11. Ugarte MF
    : Longitudinal FGF23 and Klotho axis characterization in children treated with chronic peritoneal dialysis. Clin Kidney J 7: 457–463, 2014 pmid:25878777
    OpenUrlCrossRefPubMed
  111. ↵
    1. Park MY,
    2. Herrmann SM,
    3. Saad A,
    4. Eirin A,
    5. Tang H,
    6. Lerman A,
    7. Textor SC,
    8. Lerman LO
    : Biomarkers of kidney injury and klotho in patients with atherosclerotic renovascular disease. Clin J Am Soc Nephrol 10: 443–451, 2015 pmid:25542906
    OpenUrlAbstract/FREE Full Text
    1. Sawires HK,
    2. Essam RM,
    3. Morgan MF,
    4. Mahmoud RA
    : Serum klotho: Relation to fibroblast growth factor-23 and other regulators of phosphate metabolism in children with chronic kidney disease. Nephron 129: 293–299, 2015 pmid:25766835
    OpenUrlPubMed
  113. ↵
    1. Shroff R,
    2. Aitkenhead H,
    3. Costa N,
    4. Trivelli A,
    5. Litwin M,
    6. Picca S,
    7. Anarat A,
    8. Sallay P,
    9. Ozaltin F,
    10. Zurowska A,
    11. Jankauskiene A,
    12. Montini G,
    13. Charbit M,
    14. Schaefer F,
    15. Wühl E; ESCAPE Trial Group
    : Normal 25-hydroxyvitamin D levels are associated with less proteinuria and attenuate renal failure progression in children with CKD. J Am Soc Nephrol 27: 314–322, 2016 pmid:26069294
    OpenUrlAbstract/FREE Full Text
  114. ↵
    1. Memmos E,
    2. Sarafidis P,
    3. Pateinakis P,
    4. Tsiantoulas A,
    5. Faitatzidou D,
    6. Giamalis P,
    7. Vasilikos V,
    8. Papagianni A
    : Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis. BMC Nephrol 20: 217, 2019 pmid:31185930
    OpenUrlPubMed
  115. ↵
    1. Woo HG,
    2. Chang Y,
    3. Ryu DR,
    4. Song TJ
    : Plasma Klotho concentration is associated with the presence, burden and progression of cerebral small vessel disease in patients with acute ischaemic stroke. PLoS One 14: e0220796, 2019 pmid:31398214
    OpenUrlPubMed
  116. ↵
    1. Neyra JA,
    2. Li X,
    3. Mescia F,
    4. Ortiz-Soriano V,
    5. Adams-Huet B,
    6. Pastor J,
    7. Hu M-C,
    8. Toto RD,
    9. Moe OW
    : Urine klotho is lower in critically ill patients with versus without acute kidney injury and associates with major adverse kidney events. Crit Care Explor 1: e0016, 2019
    OpenUrl
  117. ↵
    1. Seo MY,
    2. Yang J,
    3. Lee JY,
    4. Kim K,
    5. Kim SC,
    6. Chang H,
    7. Won NH,
    8. Kim MG,
    9. Jo SK,
    10. Cho W,
    11. Kim HK
    : Renal Klotho expression in patients with acute kidney injury is associated with the severity of the injury. Korean J Intern Med (Korean Assoc Intern Med) 30: 489–495, 2015 pmid:26161015
    OpenUrlCrossRefPubMed
  118. ↵
    1. Castellano G,
    2. Intini A,
    3. Stasi A,
    4. Divella C,
    5. Gigante M,
    6. Pontrelli P,
    7. Franzin R,
    8. Accetturo M,
    9. Zito A,
    10. Fiorentino M,
    11. Montinaro V,
    12. Lucarelli G,
    13. Ditonno P,
    14. Battaglia M,
    15. Crovace A,
    16. Staffieri F,
    17. Oortwijn B,
    18. van Amersfoort E,
    19. Pertosa G,
    20. Grandaliano G,
    21. Gesualdo L
    : Complement modulation of anti-aging factor klotho in ischemia/reperfusion injury and delayed graft function. Am J Transplant 16: 325–333, 2016 pmid:26280899
    OpenUrlCrossRefPubMed
  119. ↵
    1. Jou-Valencia D,
    2. Molema G,
    3. Popa E,
    4. Aslan A,
    5. van Dijk F,
    6. Mencke R,
    7. Hillebrands JL,
    8. Heeringa P,
    9. Hoenderop JG,
    10. Zijlstra JG,
    11. van Meurs M,
    12. Moser J
    : Renal klotho is reduced in septic patients and pretreatment with recombinant klotho attenuates organ injury in lipopolysaccharide-challenged mice. Crit Care Med 46: e1196–e1203, 2018 pmid:30239382
    OpenUrlPubMed
  120. ↵
    1. Liu YJ,
    2. Sun HD,
    3. Chen J,
    4. Chen MY,
    5. Ouyang B,
    6. Guan XD
    : Klotho: A novel and early biomarker of acute kidney injury after cardiac valve replacement surgery in adults. Int J Clin Exp Med 8: 7351–7358, 2015 pmid:26221275
    OpenUrlPubMed
  121. ↵
    1. Torregrosa I,
    2. Montoliu C,
    3. Urios A,
    4. Giménez-Garzó C,
    5. Tomás P,
    6. Solís MA,
    7. Ramos C,
    8. Juan I,
    9. Puchades MJ,
    10. Saez G,
    11. Blasco ML,
    12. Miguel A
    : Urinary Klotho measured by ELISA as an early biomarker of acute kidney injury in patients after cardiac surgery or coronary angiography. Nefrologia 35: 172–178, 2015 pmid:26300511
    OpenUrlPubMed
    1. Kim AJ,
    2. Ro H,
    3. Kim H,
    4. Chang JH,
    5. Lee HH,
    6. Chung W,
    7. Jung JY
    : Klotho and S100a8/A9 as discriminative markers between pre-renal and intrinsic acute kidney injury. PLoS One 11: e0147255, 2016 pmid:26799323
    OpenUrlPubMed
  123. ↵
    1. Seibert E,
    2. Radler D,
    3. Ulrich C,
    4. Hanika S,
    5. Fiedler R,
    6. Girndt M
    : Serum klotho levels in acute kidney injury. Clin Nephrol 87: 173–179, 2017
    OpenUrl
  124. ↵
    1. Devaraj S,
    2. Syed B,
    3. Chien A,
    4. Jialal I
    : Validation of an immunoassay for soluble klotho protein: Decreased levels in diabetes and increased levels in chronic kidney disease. Am J Clin Pathol 137: 479–485, 2012 pmid:22338062
    OpenUrlCrossRefPubMed
  125. ↵
    1. Kim Y,
    2. Kim JH,
    3. Nam YJ,
    4. Kong M,
    5. Kim YJ,
    6. Yu KH,
    7. Lee BC,
    8. Lee C
    : Klotho is a genetic risk factor for ischemic stroke caused by cardioembolism in Korean females. Neurosci Lett 407: 189–194, 2006 pmid:16973281
    OpenUrlCrossRefPubMed
  126. ↵
    1. Heijboer AC,
    2. Blankenstein MA,
    3. Hoenderop J,
    4. de Borst MH,
    5. Vervloet MG; NIGRAM consortium
    : Laboratory aspects of circulating α-Klotho. Nephrol Dial Transplant 28: 2283–2287, 2013 pmid:23787542
    OpenUrlCrossRefPubMed
  127. ↵
    1. Pedersen L,
    2. Pedersen SM,
    3. Brasen CL,
    4. Rasmussen LM
    : Soluble serum Klotho levels in healthy subjects. Comparison of two different immunoassays. Clin Biochem 46: 1079–1083, 2013 pmid:23707222
    OpenUrlCrossRefPubMed
  128. ↵
    1. Yamazaki Y,
    2. Imura A,
    3. Urakawa I,
    4. Shimada T,
    5. Murakami J,
    6. Aono Y,
    7. Hasegawa H,
    8. Yamashita T,
    9. Nakatani K,
    10. Saito Y,
    11. Okamoto N,
    12. Kurumatani N,
    13. Namba N,
    14. Kitaoka T,
    15. Ozono K,
    16. Sakai T,
    17. Hataya H,
    18. Ichikawa S,
    19. Imel EA,
    20. Econs MJ,
    21. Nabeshima Y
    : Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem Biophys Res Commun 398: 513–518, 2010 pmid:20599764
    OpenUrlCrossRefPubMed
  129. ↵
    1. Adema AY,
    2. Vervloet MG,
    3. Blankenstein MA,
    4. Heijboer AC
    : α-Klotho is unstable in human urine. Kidney Int 88: 1442–1444, 2015 pmid:26244922
    OpenUrlPubMed
  130. ↵
    1. Neyra JA,
    2. Moe OW,
    3. Pastor J,
    4. Gianella F,
    5. Sidhu SS,
    6. Sarnak MJ,
    7. Ix JH,
    8. Drew DA
    : Performance of soluble Klotho assays in clinical samples of kidney disease. Clin Kidney J 13: 235–244, 2019 pmid:32297879
    OpenUrlPubMed
  131. ↵
    1. Wang Y,
    2. Sun Z
    : Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage. Hypertension 54: 810–817, 2009 pmid:19635988
    OpenUrlAbstract/FREE Full Text
  132. ↵
    1. Mitani H,
    2. Ishizaka N,
    3. Aizawa T,
    4. Ohno M,
    5. Usui S,
    6. Suzuki T,
    7. Amaki T,
    8. Mori I,
    9. Nakamura Y,
    10. Sato M,
    11. Nangaku M,
    12. Hirata Y,
    13. Nagai R
    : In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension 39: 838–843, 2002 pmid:11967236
    OpenUrlAbstract/FREE Full Text
  133. ↵
    1. Shiraki-Iida T,
    2. Iida A,
    3. Nabeshima Y,
    4. Anazawa H,
    5. Nishikawa S,
    6. Noda M,
    7. Kuro-o M,
    8. Nabeshima Y
    : Improvement of multiple pathophysiological phenotypes of klotho (kl/kl) mice by adenovirus-mediated expression of the klotho gene. J Gene Med 2: 233–242, 2000 pmid:10953914
    OpenUrlCrossRefPubMed
  134. ↵
    1. Saito Y,
    2. Nakamura T,
    3. Ohyama Y,
    4. Suzuki T,
    5. Iida A,
    6. Shiraki-Iida T,
    7. Kuro-o M,
    8. Nabeshima Y,
    9. Kurabayashi M,
    10. Nagai R
    : In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome. Biochem Biophys Res Commun 276: 767–772, 2000 pmid:11027545
    OpenUrlCrossRefPubMed
  135. ↵
    1. Wang Y,
    2. Sun Z
    : Antiaging gene Klotho regulates endothelin-1 levels and endothelin receptor subtype B expression in kidneys of spontaneously hypertensive rats. J Hypertens 32: 1629–1636, 2014 pmid:24979306
    OpenUrlCrossRefPubMed
  136. ↵
    1. Shin YJ,
    2. Luo K,
    3. Quan Y,
    4. Ko EJ,
    5. Chung BH,
    6. Lim SW,
    7. Yang CW
    : Therapeutic challenge of minicircle vector encoding klotho in animal model. Am J Nephrol 49: 413–424, 2019 pmid:30982029
    OpenUrlPubMed
  137. ↵
    1. Muñoz-Castañeda JR,
    2. Herencia C,
    3. Pendón-Ruiz de Mier MV,
    4. Rodriguez-Ortiz ME,
    5. Diaz-Tocados JM,
    6. Vergara N,
    7. Martínez-Moreno JM,
    8. Salmerón MD,
    9. Richards WG,
    10. Felsenfeld A,
    11. Kuro-O M,
    12. Almadén Y,
    13. Rodríguez M
    : Differential regulation of renal Klotho and FGFR1 in normal and uremic rats. FASEB J 31: 3858–3867, 2017 pmid:28515153
    OpenUrlCrossRefPubMed
  138. ↵
    1. Takenaka T,
    2. Inoue T,
    3. Ohno Y,
    4. Miyazaki T,
    5. Nishiyama A,
    6. Ishii N,
    7. Suzuki H
    : Calcitriol supplementation improves endothelium-dependent vasodilation in rat hypertensive renal injury. Kidney Blood Press Res 39: 17–27, 2014 pmid:24821359
    OpenUrlPubMed
  139. ↵
    1. Liabeuf S,
    2. Ryckelynck JP,
    3. El Esper N,
    4. Ureña P,
    5. Combe C,
    6. Dussol B,
    7. Fouque D,
    8. Vanhille P,
    9. Frimat L,
    10. Thervet E,
    11. Mentaverri R,
    12. Prié D,
    13. Choukroun G; FRENCH Study collaborators
    : Randomized clinical trial of sevelamer carbonate on serum klotho and fibroblast growth factor 23 in CKD. Clin J Am Soc Nephrol 12: 1930–1940, 2017 pmid:29074818
    OpenUrlAbstract/FREE Full Text
  140. ↵
    1. Zhang H,
    2. Li Y,
    3. Fan Y,
    4. Wu J,
    5. Zhao B,
    6. Guan Y,
    7. Chien S,
    8. Wang N
    : Klotho is a target gene of PPAR-gamma. Kidney Int 74: 732–739, 2008 pmid:18547997
    OpenUrlCrossRefPubMed
  141. ↵
    1. Yang HC,
    2. Deleuze S,
    3. Zuo Y,
    4. Potthoff SA,
    5. Ma LJ,
    6. Fogo AB
    : The PPARgamma agonist pioglitazone ameliorates aging-related progressive renal injury. J Am Soc Nephrol 20: 2380–2388, 2009 pmid:19797472
    OpenUrlAbstract/FREE Full Text
  142. ↵
    1. Narumiya H,
    2. Sasaki S,
    3. Kuwahara N,
    4. Irie H,
    5. Kusaba T,
    6. Kameyama H,
    7. Tamagaki K,
    8. Hatta T,
    9. Takeda K,
    10. Matsubara H
    : HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells. Cardiovasc Res 64: 331–336, 2004 pmid:15485693
    OpenUrlCrossRefPubMed
  143. ↵
    1. Karalliedde J,
    2. Maltese G,
    3. Hill B,
    4. Viberti G,
    5. Gnudi L
    : Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria. Clin J Am Soc Nephrol 8: 1899–1905, 2013 pmid:23929932
    OpenUrlAbstract/FREE Full Text
  144. ↵
    1. Yoon HE,
    2. Ghee JY,
    3. Piao S,
    4. Song JH,
    5. Han DH,
    6. Kim S,
    7. Ohashi N,
    8. Kobori H,
    9. Kuro-o M,
    10. Yang CW
    : Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrol Dial Transplant 26: 800–813, 2011 pmid:20813770
    OpenUrlCrossRefPubMed
  145. ↵
    1. Hsu SC,
    2. Huang SM,
    3. Lin SH,
    4. Ka SM,
    5. Chen A,
    6. Shih MF,
    7. Hsu YJ
    : Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway. Biochem J 464: 221–229, 2014 pmid:25163025
    OpenUrlAbstract/FREE Full Text
Back to top

In this issue

View Selected Citations (0)
Print
Download PDF
Email Article
Citation Tools
Request Permissions
Klotho in Clinical Nephrology
Javier A. Neyra, Ming Chang Hu, Orson W. Moe
CJASN Jan 2021, 16 (1) 162-176; DOI: 10.2215/CJN.02840320
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo

Jump to section

Keywords