Pathophysiology Of Chronic Kidney Disease Research Articles

Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients. We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb). Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT (β=-0.31, p=0.044) and U-Alb (β=-0.25, p=0.025) only at night. Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.

Hypertension in Chronic Kidney Disease.

Hypertension, a global public health problem, is currently the leading factor in the global burden of disease. It is the major modifiable risk factor for heart disease, stroke and kidney failure. Chronic kidney disease (CKD) is both a common cause of hypertension and CKD is also a complication of uncontrolled hypertension. The interaction between hypertension and CKD is complex and increases the risk of adverse cardiovascular and cerebrovascular outcomes. This is particularly significant in the setting of resistant hypertension commonly seen in patient with CKD. The pathophysiology of CKD associated hypertension is multi-factorial with different mechanisms contributing to hypertension. These pathogenic mechanisms include sodium dysregulation, increased sympathetic nervous system and alterations in renin angiotensin aldosterone system activity. Standardized blood pressure (BP) measurement is essential in establishing the diagnosis and management of hypertension in CKD. Use of ambulatory blood pressure monitoring provides an additional assessment of diurnal variation in BP commonly seen in CKD patients. The optimal BP target in the treatment of hypertension in general and CKD population remains a matter of debate and controversial despite recent guidelines and clinical trial data. Medical therapy of patients with CKD associated hypertension can be difficult and challenging. Additional evaluation by a hypertension specialist may be required in the setting of treatment resistant hypertension by excluding pseudo-resistance and treatable secondary causes. Treatment with a combination of antihypertensive drugs, including appropriate diuretic choice, based on estimated glomerular filtration rate, is a key component of hypertension management in CKD patients. In addition to drug treatment non-pharmacological approaches including life style modification, most important of which is dietary salt restriction, should be included in the management of hypertension in CKD patients.

Abstract 14830: Cellular Iron Transport Protein, Transferrin Receptor 1 Plays an Important Role in the Pathophysiology of Chronic Kidney Disease

Background: Cellular iron transport protein, transferrin receptor 1 (TfR1) is required for the uptake of transferrin-bound iron into the cells. Several reports have shown that iron accumulation is associated with the pathophysiology of chronic kidney disease (CKD); however, the role of TfR1 in the pathophysiology of CKD remains unknown. Herein, we investigate TfR1 in the experimental models of CKD. Methods and Results: CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. CKD rats showed proteinuria and tubular dilatation. Of note, TfR1 expression is increased in the remnant kidney along with increased iron accumulation, as compared with controls. To investigate the functional importance of TfR1 in the pathophysiology of CKD, we subjected to 5/6 nephrectomy in TfR1 hetero knockout mice. At 8weeks after 5/6 nephrectomy, systolic blood pressure was similar in TfR1 hetero knockout mice and wild-type (WT) littermates. In contrast, urinary albumin excretion, serum BUN, and creatinine levels were increased to a lesser extent in TfR1 hetero knockout mice compared with WT littermates. In addition, renal fibrosis was observed in the remnant kidney in WT mice, while the extent was attenuated in TfR1 hetero knockout mice. Consistent with these findings, increased renal gene expression of collagen type I and collagen type III were attenuated in TfR1 hetero knockout mice compared with WT littermates. Conclusions: These results indicate that TfR1 plays a role in the pathophysiology of CKD. Understanding the role of TfR1 in the pathophysiology of CKD may lead to a novel therapeutic approach for CKD.

Interactions between HIF-1α and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease

Renal hypoxia contributes to chronic kidney disease (CKD) progression, as validated in experimental and human CKD. In the early stages, increased oxygen consumption causes oxygen demand/supply mismatch, leading to hypoxia. Hence, early targeting of the determinants and regulators of oxygen consumption in CKD may alter the disease course before permanent damage ensues. Here, we focus on hypoxia inducible factor-1α (HIF-1α) and AMP-activated protein kinase (AMPK) and on the mechanisms by which they may facilitate cellular hypoxia adaptation. We found that HIF-1α activation in the subtotal nephrectomy (STN) model of CKD limits protein synthesis, inhibits apoptosis, and activates autophagy, presumably for improved cell survival. AMPK activation was diminished in the STN kidney and was remarkably restored by HIF-1α activation, demonstrating a novel role for HIF-1α in the regulation of AMPK activity. We also investigated the independent and combined effects of HIF-1α and AMPK on cell survival and death pathways by utilizing pharmacological and knockdown approaches in cell culture models. We found that the effect of HIF-1α activation on autophagy is independent of AMPK, but on apoptosis it is partially AMPK dependent. The effects of HIF-1α and AMPK activation on inhibiting protein synthesis via the mTOR pathway appear to be additive. These various effects were also observed under hypoxic conditions. In conclusion, HIF-1α and AMPK appear to be linked at a molecular level and may act as components of a concerted cellular response to hypoxic stress in the pathophysiology of CKD.

The Pivotal Role of a Novel Biomarker of Reactive Oxygen Species in Chronic Kidney Disease.

Risk stratification of chronic kidney disease (CKD) is clinically important because such patients are at high risk of cardiovascular events. Although reactive oxygen species (ROS) are reported to be closely associated with the pathophysiology of CKD, there are few useful ROS biomarkers known for CKD patients. Hence, our objectives in this study were to investigate whether serum derivatives of reactive oxygen metabolites (DROM), a novel biomarker of ROS, is involved in the pathophysiology of CKD (case-control study), and is a significant predictor of future cardiovascular events in CKD patients (follow-up study).Patients with suspected coronary artery disease (CAD) were enrolled and underwent coronary angiography. Patients with CKD (estimated glomerular filtration ratio <60 mL/min/1.73 m2 and/or proteinuria, n = 324) were compared with those without CKD (non-CKD). Serum DROM was measured at stable conditions. A case-control study of the 324 CKD patients and 263 non-CKD patients was conducted after matching risk factors, and a follow-up study of the 324 CKD patients was performed. CKD patients were divided into low- and high-DROM groups using their median value (348 unit; called the Carratelli unit [U.CARR]), and followed until the occurrence of cardiovascular events.DROM levels were significantly higher in risk factors-matched CKD patients than in risk factors-matched non-CKD patients (347.0 [301.8–391.8] U.CARR vs. 338.5 [299.8–384.3] U.CARR, P = 0.03). During mean 23 ± 14 months follow-up of 324 CKD patients, 83 cardiovascular events were recorded. Kaplan–Meier analysis demonstrated a higher probability of cardiovascular events in CKD patients with high DROM than in those with low DROM (P < 0.001, log-rank test). Multivariate Cox hazard analysis including significant predictors in simple Cox hazard analysis demonstrated that high DROM was a significant and independent predictor of cardiovascular events in CKD patients (hazard ratio: 1.76, 95% confidence interval: 1.10–2.82, P = 0.02).In conclusion, serum DROM values were significant and independent predictors of cardiovascular events in CKD patients, indicating that the measurements of DROM might provide clinical benefits for risk stratification of CKD patients.

Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease.

Iron accumulation is associated with the pathophysiology of chronic kidney disease (CKD). Renal fibrosis is a final common feature that contributes to the progression of CKD; however, little is known about the association between renal iron accumulation and renal interstitial fibrosis in CKD. Here we investigate the effects of iron chelation on renal interstitial fibrosis in a rat model of CKD. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. At 8 weeks after operation, 5/6 nephrectomized rats were administered an oral iron chelator, deferasirox (DFX), in chow for 8 weeks. Other CKD rats were given a normal diet. Sham-operative rats given a normal diet served as a control. CKD rats exhibited hypertension, glomerulosclerosis and renal interstitial fibrosis. Iron chelation with DFX did not change hypertension and glomerulosclerosis; however, renal interstitial fibrosis was attenuated in CKD rats. Consistent with these findings, renal gene expression of collagen type III and transforming growth factor-β was increased in CKD rats compared with the controls, while iron chelation suppressed these increments. In addition, a decrease in vimentin along an increase in E-cadherin in renal gene expression was observed in CKD rats with iron chelation. CKD rats also showed increased CD68-positive cells in the kidney, whereas its increase was attenuated by iron deprivation. Similarly, increased renal gene expression of CD68, tumor necrosis factor-α and monocyte chemoattractant protein-1 was suppressed in CKD rats with iron chelation. Renal iron accumulation seems to be associated with renal interstitial fibrosis in a rat model of CKD.

Pathophysiology of chronic kidney disease

This series of four articles explores the pathophysiology and treatment of chronic kidney disease (CKD) and acute kidney injury (AKI). We review the causes of CKD and AKI, treatment options and secondary complications. CKD and AKI are both relatively common in general practice and early identification and appropriate management may improve the outcome of patients with these conditions. This first article focuses on the pathophysiology of CKD and possible complications.

Participação do óxido nítrico na fisiopatologia da doença renal crônica

Nitric oxide (NO) is a free radical gas, inorganic, which has seven electrons of nitrogen and oxygen eight, possessing an unpaired electron. This radical is produced from L-arginine by a reaction mediated by the enzyme NO synthase. NO it is about a radical of who acts abundant on a variety of biological processes, particularly when produced by endothelial cells plays a significant role in cardiovascular control, as a modulator of peripheral vascular resistance and platelet aggregation. This free radical has also a neurotransmitter and mediator of the immune system. NO kidney function has been considered in many physiological functions such as: (a) regulation of hemodynamics and glomerular function tubuloglomerular, (b) participation in pressure natriuresis (c) maintaining medullar perfusion (d) inhibiting sodium reabsorption tubular, and (e) acting as a modulator of the activity of the sympathetic nervous system. Given these functions, the occurrence of its deficiency is associated with chronic kidney disease (CKD) in vasoconstriction and consequently glomerular hypertension, high blood pressure (HBP), proteinuria and progression of renal dysfunction. This work has the scope to describe the role of NO in renal physiology and pathophysiology of CKD.

Role of hypoxia in progressive chronic kidney disease and implications for therapy

Chronic hypoxia in the tubulointerstitium has been recognized as a final common pathway that leads to the development of end-stage renal disease. Hypoxia-inducible factor (HIF), a master regulator of the adaptive response against hypoxia, is involved in the pathogenesis of chronic kidney disease (CKD). This review focuses on HIF and novel therapeutic strategies targeting HIF. Although HIF upregulation is beneficial against hypoxic kidney injury, it may be harmful under certain pathological conditions. Recent advances in epigenetic changes provide an additional layer of complexity to our understanding of gene regulation in response to hypoxia, which is most likely involved in the progression of CKD. On the basis of this novel knowledge, the pharmacological activation and modulation of HIF is emerging as a novel therapeutic target. HIF plays a crucial role in the pathophysiology of CKD. The underlying molecular mechanisms, including epigenetics, have been thoroughly investigated. On the basis of the experimental data available to date, the pharmacological activation of HIF is likely a novel promising therapy for CKD.

The inflammation–lipocalin 2 axis may contribute to the development of chronic kidney disease

Chronic kidney disease (CKD) is an important risk factor for coronary heart disease, and previous studies indicated the involvement of low-grade inflammation in the pathogenesis of CKD. The study was designed to (i) identify and confirm genes and their products upregulated in mesangial cells cocultured with endotoxin-stimulated macrophages and (ii) determine the clinical relevance of genes and proteins upregulated in mesangial cells under inflammatory conditions by an epidemiological approach. DNA microarray analysis revealed upregulated expression of many genes and their products including several cytokines and chemokines, as well as the inflammatory marker, lipocalin 2 gene. The gene expression and protein upregulation of lipocalin 2 were synergistically affected by endotoxin and tumor necrosis factor (TNF)-α stimulation. In human studies, lipocalin 2 level was significantly associated with creatinine (r = 0.419, P < 0.001) and negatively associated with eGFR (r = -0.365, P < 0.001). Multiple logistic regression analysis revealed a significant association between lipocalin 2 and soluble tumor necrosis factor receptor 2 (sTNF-R2), eGFR and uric acid in general subjects attending regular annual medical check-up (n = 420). When subjects with diabetes were excluded from the analysis, lipocalin 2 remained associated with sTNF-R2, eGFR and uric acid. Since an activated TNF system, as demonstrated by elevated sTNF-R2, and elevated uric acid were recently implicated in an elevated CKD risk, we conclude that inflammation could play an important role in the pathogenesis of CKD, and that lipocalin 2 is a potential universal marker for impaired kidney function. Furthermore, the results obtained by the current microarray analysis could improve the understanding of gene profiles associated with the pathophysiology of CKD under inflammatory conditions.

Novel insights from genetic and epigenetic studies in understanding the complex uraemic phenotype

Like in many other common complex disorders, studies of chronic kidney disease (CKD) can now make use of the increasing knowledge of the human genome, its variations and impact on disease susceptibility, initiation, progression and complications. Such studies are facilitated by novel readily available high through-put genotyping methods and sophisticated analytical approaches to scan the genome for DNA variations and epigenetic modifications. Here, we review some of the recent discoveries that have emerged from these studies and expanded our knowledge of genetic risk loci and epigenetic markers in CKD pathophysiology. Obstacles and practical issues in this field are discussed.

Feline CKD: Pathophysiology and risk factors--what do we know?

Chronic kidney disease (CKD) is one of the most frequently encountered disorders in cats, having increased in prevalence in recent decades. Although the underlying cause is rarely identified, the common final outcome of feline CKD is tubulointerstitial fibrosis. Knowledge of CKD pathophysiology is necessary for optimal individualised patient management, especially with regard to diagnosis and treatment of extrarenal complications. CKD is most common in senior and geriatric cats, but should be considered in any feline patient with ureterolithiasis, hyperthyroidism, retrovirus infection, systemic hypertension, cardiovascular disease or urinary tract infection. Most of our knowledge of the pathogenesis of CKD is extrapolated from human nephrology and experimental animal studies. There is, therefore, a need for further studies in cats. The prevalence of clinical signs in feline CKD is well documented. Several concurrent diseases associated with CKD have also been reported in cats, especially in the geriatric population, but there is no or only limited published evidence demonstrating a cause-and-effect relationship between most of these conditions and CKD. Studies performed over the past 15 years have nevertheless allowed identification of major risk factors (proteinuria, plasma phosphate and plasma creatinine) influencing the progression of feline CKD. Clinical signs occur in the late stages of renal disease, so populations at higher risk of CKD should be screened routinely. CKD-associated complications (systemic hypertension, secondary renal hyperparathyroidism, hypokalaemia, anaemia, metabolic acidosis) must not be overlooked as they may affect the progression of disease. Disease progression is itself unpredictable and renal function may remain stable for extended periods. Most cats with early CKD do not progress to end-stage CKD before they die. General practitioners play a major role in screening feline patients at risk of development or progression of CKD.

Chronic kidney disease: a new look at pathogenetic mechanisms and treatment options

The concept of renoprotection has evolved significantly, driven by improved understanding of the pathophysiology of chronic kidney disease (CKD) and the advent of novel treatment options. Glomerular hyperfiltration, hypertension and proteinuria represent key mediators of CKD progression. It is increasingly recognized that proteinuria may actually be pathological and etiological in CKD progression and not just symptomatic. It initiates a sequence of events involving activation of proinflammatory and profibrotic signaling pathways in proximal tubular epithelial cells with transmission of the disease to the tubulointerstitium and progression to end-stage kidney disease (ESKD). Although the etiology and epidemiology of pediatric CKD differs to that in adults, studies in the various animal models of kidney disease, from obstructive uropathy to glomerulonephritis, have revealed that many common proinflammatory and profibrotic pathways are induced in progressive proteinuric CKD, irrespective of the primary disease. This pathomechanistic overlap therefore translates into the potential for common treatment targets for a wide spectrum of kidney diseases. In this review we therefore discuss the experimental and clinical evidence for an array of prospective future drug treatments of CKD progression. While conceptually promising, clear definitive evidence beyond preclinical data does not exist for many of these treatments, and others are limited by serious adverse effects. More studies are needed before general recommendations can be given.

The role of phosphorus in the pathophysiology of chronic kidney disease

To review the human and veterinary literature on the role of phosphorus in the pathophysiology of chronic kidney disease (CKD) and to explore why control of plasma phosphorus concentration is an important goal in the management of patients with this disease. Human and veterinary studies, reviews, clinical reports, textbooks, and recent research findings focused on phosphate homeostasis and CKD patient management. Recent studies using rodent models and human patients with CKD have focused on trying to elucidate the role of the phosphatonins, predominantly fibroblast growth factor-23, in phosphate homeostasis and the pathophysiology of secondary renal hyperparathyroidism (SRHP). Fibroblast growth factor-23 is now considered to be a key regulator of plasma phosphorus concentration in people but has only recently been investigated in companion animal species. Cross-sectional studies of naturally occurring CKD in dogs and cats have shown hyperphosphatemia and SRHP to be highly prevalent and associated with increased morbidity and mortality in these patients. Experimental studies of surgically induced renal impairment in the dog and cat, and cases of naturally occurring CKD have emphasized the ability of renal care diets to modify plasma phosphorus and parathyroid hormone concentrations. Evidence from these studies indicates that maintaining plasma phosphorus concentrations to within the International Renal Interest Society targets for CKD patients improves survival time and reduces clinical manifestations of hyperphosphatemia and SRHP. The maintenance of plasma phosphorus concentrations in to within the International Renal Interest Society targets is recommended in management of CKD patients. The discovery of the phosphatonins has improved understanding of the mechanisms involved in phosphorus homeostasis and SRHP and may lead to improved ability to monitor and manage these patients.

Renal pathophysiology: lessons learned from the canine remnant kidney model

To review the pathophysiology of chronic kidney disease (CKD) in dogs and the contributions of the canine remnant kidney model to our understanding of this disease. Original studies in the human and veterinary medical fields. Three of the fundamental principles of modern nephrology-the intact nephron hypothesis, the trade-off hypothesis, and the hyperfiltration theory were developed directly as a result of studies of the remnant kidney model. Most of the pivotal early studies were conducted in dogs. As a result, our understanding of CKD, and of the renal and systemic adaptations to CKD, is largely based on studies of this model. Studies of the remnant kidney model have advanced our understanding of the pathophysiology of CKD. Nearly every therapeutic intervention used in CKD, by veterinarians and physicians alike, has its basis in studies of the remnant kidney model or in knowledge that was derived from studies of this model. A great debt is owed to the canine participants in these studies and to a small number of key scientists who conducted this important and insightful research.

The influence of the pleiotropic action of erythropoietin and its derivatives on nephroprotection.

Erythropoietin (EPO) is traditionally described as a hematopoietic cytokine or growth hormone regulating proliferation, differentiation, and survival of erythroid progenitors. The use of EPO in patients with chronic kidney disease (CKD) was a milestone achievement in the treatment of anemia. However, EPO involves some degree of risk, which increases with increasing hemoglobin levels. A growing number of studies have assessed the renoprotective effects of EPO in acute kidney injury (AKI) or CKD. Analysis of the biological effects of erythropoietin and pathophysiology of CKD in these studies suggests that treatment with erythropoiesis-stimulating agents (ESAs) may exert renoprotection by pleiotropic actions on several targets and directly or indirectly slow the progression of CKD. By reducing ischemia and oxidative stress or strengthening anti-apoptotic processes, EPO may prevent the development of interstitial fibrosis and the destruction of tubular cells. Furthermore, it could have a direct protective impact on the integrity of the interstitial capillary network through its effects on endothelial cells and promotion of vascular repair, or modulate inflammation response. Thus, it is biologically plausible to suggest that correcting anemia with ESAs could slow the progression of CKD.The aim of this article is to discuss these possible renoprotection mechanisms and provide a comprehensive overview of erythropoietin and its derivatives.

Epigenetic markers of renal function in african americans.

Chronic kidney disease (CKD) is an increasing concern in the United States due to its rapidly rising prevalence, particularly among African Americans. Epigenetic DNA methylation markers are becoming important biomarkers of chronic diseases such as CKD. To better understand how these methylation markers play a role in kidney function, we measured 26,428 DNA methylation sites in 972 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We then evaluated (1) whether epigenetic markers are associated with estimated glomerular filtration rate (eGFR), (2) whether the significantly associated markers are also associated with traditional risk factors and/or novel biomarkers for eGFR, and (3) how much additional variation in eGFR is explained by epigenetic markers beyond established risk factors and biomarkers. The majority of methylation markers most significantly associated with eGFR (24 out of the top 30) appeared to function, at least in part, through pathways related to aging, inflammation, or cholesterol. However, six epigenetic markers were still able to significantly predict eGFR after adjustment for other risk factors. This work shows that epigenetic markers may offer valuable new insight into the complex pathophysiology of CKD in African Americans.

Ghrelin and leptin pathophysiology in chronic kidney disease

Ghrelin is an orexigenic hormone with additional effects on the regulation of inflammation and the cardiovascular system. It may play an important role in the pathogenesis of cachexia/protein-energy wasting (PEW), inflammation and cardiovascular complications in chronic kidney disease (CKD). There are three circulating gene products of ghrelin, namely, acyl ghrelin, des-acyl ghrelin and obestatin, each with individual distinct functions. Perturbations of these circulating ghrelin proteins impact the overall milieu of CKD. Leptin is an anorexigenic hormone which is secreted from the adipocytes and interacts with ghrelin and other appetite-regulating hormones. Leptin also plays a role in regulating inflammation and the cardiovascular system. Indeed, ghrelin and leptin may play yin-and-yang roles in CKD pathophysiology. Clinical trials involving the use of the mimetics or antagonists of these hormones are limited to short-term phase I/II studies. Further understanding of their interactions in CKD pathophysiology is needed for potential large-scale clinical trials, which may impact the quality of life and survival of patients with CKD.

Biomarkers in native and transplant kidneys

Predicting the outcomes of patients with chronic kidney disease (CKD) is important from both patient and healthcare system perspectives. This review examines the current state of conventional and nonconventional biomarkers as noninvasive tools to improve risk-stratification and outcome prediction in CKD. Conventional biomarkers (serum creatinine, urine albumin, and clinical variables such as sex, age, and diabetes) have been the cornerstone of most prediction models for CKD progression to end-stage renal disease (ESRD), and adverse cardiovascular outcomes including death. With better understanding of the pathophysiology of CKD and the evolution of molecular diagnostics, numerous novel or nonconventional markers have emerged. They have been examined individually and in combination to predict specific outcomes. We highlight these markers and studies, conducted primarily in patients with native kidneys. In those with transplant kidneys, markers of both acute and chronic kidney dysfunction have been examined, although to a lesser extent. Similarities and differences in knowledge derived from these two populations are highlighted. Improving prediction of outcomes in CKD patients with either native or transplant kidneys remains an important goal. Increasingly sophisticated biomarkers may potentially identify targets for clinical research, improve the nature and timing of therapeutic interventions, and guide resource allocation.

Klotho in health and disease

The klotho gene was originally identified as a putative aging-suppressor gene in mice that extended life span when overexpressed and induced a premature aging syndrome when disrupted. Subsequently, it became clear that the Klotho family of membrane proteins function as obligate co-receptors for endocrine fibroblast growth factors (FGFs) that regulate various metabolic processes. This review focuses on the Klotho-FGF23 endocrine system that maintains phosphate (Pi) homeostasis, and discusses the mechanism of action and the potential contribution of Klotho deficiency to acute kidney injury (AKI), chronic kidney disease (CKD) and cancer. Klotho functions as a receptor for the phosphaturic hormone FGF23. Klotho deficiency induces resistance to FGF23 and predisposition to Pi retention, which represents a critical feature of pathophysiology of CKD. The extracellular domain of Klotho protein is subject to ectodomain shedding and released into the blood and urine. Secreted Klotho functions as a humoral factor that inhibits AKI, vascular calcification, renal fibrosis, and cancer metastasis in an FGF23-independent manner. Various factors that affect Klotho expression have been identified. Prevention of Klotho decline and supplementation of Klotho can be a novel therapeutic strategy for many age-related diseases.