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Volume: 16 Issue: 3 June 2018

FULL TEXT

REVIEW
Klotho: A Promising Biomarker Closely Related to Kidney Transplant

Organ shortage has long been an obstacle to transplant procedures. As acceptance of aging kidneys from expanded criteria donors increases, the long-term outcomes of renal allografts could be unsatisfactory. The klotho gene, which is known as an antiaging gene that is highly expressed in kidneys, is closely associated with chronic kidney disease and acute kidney injury. Results from existing literature have shown a tendency to support Klotho as a renal protective protein owing to its pleiotropic effects. However, few data are available on Klotho in renal transplant. Whether Klotho serves the same purposes in the renal allograft is still a matter of controversy. This review summarizes new findings from clinical and animal studies reflecting associations between

Klotho and renal transplant. A better understanding of the potential effects of Klotho on renal transplant may offer novel insights into ameliorating renal allograft injury.


Key words : Aging, Klotho protein, Renal transplantation

Introduction

Clotho (Klotho) was one of the Moirai who controlled the destiny of humans in ancient Greek mythology. Interestingly, in 1997, Kuro-o and associates identified an antiaging gene in mice. Similar to Clotho, the gene played a critical role in animal life span and was thereby named klotho. They discovered that mutation of the mouse klotho gene causes many premature aging-like phenotypes and shortens life spans. However, overexpression of this gene suppresses aging and extends the life span.1

As a novel aging suppressor gene, klotho encodes a single-pass transmembrane protein containing 3 members: α-Klotho, β-Klotho, and Klotho-related protein.2 The vast majority of Klotho is expressed in distal convoluted tubule cells, with relatively less in proximal convoluted tubule cells in kidney.3,4 Some were found in the choroid plexus epithelial cells in the brain.5,6 In addition, small amounts of α-Klotho were found in the pituitary gland, placenta, skeletal muscle, urinary bladder, aorta, ovary, colon, thyroid gland, pancreas, and testis.7,8

There are 2 forms of Klotho protein: a secreted form and a membrane form. The secreted form originates either from proteolytic cleavage of extracellular domain of full-length α-Klotho or from alternative mRNA splicing.2 Both forms demonstrate biologic effects such as regulating excretion of phosphate and synthesis of active vitamin D in the kidney as well as antiaging activity.9 The secreted form contributes far more than the membrane form.10

In humans after 40 years old, serum levels of α-Klotho, the major form of circulating Klotho, decrease with age.11,12 A decrease in Klotho may result in aging-related diseases, including hypertension,13,14 diabetes,15 chronic kidney disease (CKD),16,17 neuro­logic disorders,18,19 and cardiovascular diseases.20 However, research on the role of Klotho in the field of kidney transplant is so far insufficient. Recent studies have revealed that Klotho showed high relevance in ischemia/reperfusion injury and renal allograft function,21,22 suggesting that further studies about Klotho are of importance and beneficial in understanding kidney transplant. In this review, we will concisely introduce and review the research progress of Klotho in kidney transplant and discuss its potential role in the renal allograft.

Klotho Biology
The klotho gene locus is located on chromosome 13 in humans, and there are 5 exons and 4 introns in the coding region. The gene has been reported to encode α-Klotho, β-Klotho, and Klotho-related protein.

α-Klotho, the dominantly present one of the 3, is expressed in distal convoluted tubule cells. The membrane form of α-Klotho regulates phosphate absorption and 1,25(OH)2D3 activity. The secreted form directly affects tissue and cell activity not expressing Klotho, such as vascular endothelial cells and smooth muscle cells.23 In contrast, β-Klotho is predominantly expressed in liver and white adipose tissue. Its functions are related to metabolism regulation, glucose uptake, bile acid synthesis, and fatty acid metabolism. The Klotho-related protein binds to fibroblast growth factor receptor 1b, growth factor receptor 1c, and growth factor receptor 2c. However, its function remains unknown.2

Many organs express Klotho protein, including kidney, brain, liver, and parathyroid gland. The kidney is the main source of Klotho and the principal organ mediating Klotho’s effects.24 In the transmembrane form, the functional role of Klotho in kidneys has been proposed as a coreceptor for fibroblast growth factor 23 (FGF-23).2 In proximal and distal renal tubules, membrane-bound Klotho and FGF-23 form a complex in the basolateral membrane. In proximal renal tubules, Klotho independently activates extracellular signal-regulated kinase 1/2 and serum/glucocorticoid-regulated kinase 1, leading to phosphorylation of the scaffolding protein sodium/hydrogen exchange regulatory cofactor 1 and subsequent internalization and degradation of sodium-phosphate cotransporters, thereby resulting in suppression of phosphate reabsorption by FGF-23. In distal renal tubules, Klotho independently activates with-no-lysine kinase 4 (WNK4), after which FGF-23 augments calcium and sodium reabsorption by increasing the apical membrane expression of the epithelial calcium channel transient receptor potential vanilloid (TRPV5) and of the sodium-chloride cotransporter. Through the above mechanisms, Klotho shows renal protective effects on proximal tubular phosphate reuptake, proximal tubular vitamin D hormone synthesis, and distal tubular calcium and sodium transport.25 The contribution of extrarenal Klotho to renal protection remains to be confirmed (Figure 1).

Klotho and Renal Aging
Aging is the age-related deterioration of physiologic functions necessary for the survival and fertility of an organism. Aging cells are characterized by permanent and irreversible growth arrest. They lose their capacity for cell proliferation and cell repair. In the human kidney, glomerular filtration declines and the renal physiologic reserve decreases with age due to the epigenetic effect, mitochondria damage, oxidative damage, telomere shortening, DNA impairment, and activation of aging genes.26 Kidney aging results in structural changes, such as decreased kidney weight and volume, glomerulosclerosis, deposition of hyaline in the glomerular basement membrane, interstitial fibrosis, tubular atrophy, intrarenal arteriosclerosis, and thickened intima. Functional changes in the aging kidney include decreased glomerular filtration rate; increased filtration fraction; impaired water, electrolyte, and glucose handling; decreased diluting and concentrating capacity; decreased plasma renin activity and aldosterone; increased angiotensin II and endothelin; and decreased vasodilator activity of prostacyclin.27 Klotho bears antiaging properties, functions as an aging suppressor that ameliorates aging, and extends the life span when overexpressed.28 In an animal study, Zuo and associates proved that aging-related kidney damage is associated with a decrease in Klotho expression.29 As an aging-related factor in a cross-sectional study, Klotho decreased with progression of pathologic grade in renal biopsy specimens of 71 patients with immunoglobulin A nephrology. In addition, Klotho was independently correlated with interstitial fibrosis in patients with immunoglobulin A nephrology.30

Fibroblast growth factor 23 is regarded as a bone-derived hormone that acts on the kidney to promote phosphate excretion to urine.31 Klotho functions as a coreceptor with FGF-23, together exerting their activity in a common endocrine system that regulates phosphate metabolism. In Klotho-deficient mice, phosphate retention was observed, suggesting that it was associated with accelerated aging.32 Mechanisms involved in the antiaging properties included those related to insulin-like growth factor 1 (IGF-1) and Wnt. Klotho was shown to modulate IGF-1 and Wnt signaling pathways and to play a critical role in antiaging and antifibrosis.33

Klotho Status in Acute Kidney Injury and Chronic Kidney Disease
Because Klotho mainly originates from the kidney, changes may be found in those who have kidney diseases. A number of studies have revealed that Klotho is associated with acute kidney injury (AKI) and CKD. In a cross-sectional case control study conducted by Seibert and colleagues, serum Klotho levels were diverse among patients with AKI and CKD (stage 1-5) and adults with normal kidney function. Their data showed that serum Klotho levels were higher in AKI patients and lower in patients with end-stage renal disease versus levels shown in healthy adults and patients with moderate CKD.34 In addition, Seo and associates showed that renal Klotho expression decreased significantly according to AKI severity in humans, regardless of cause, and that low expression was associated with poor short-term outcomes.35

Chronic kidney disease, which results in progressive deterioration of renal function, is viewed as a state of continuous Klotho deficiency.36,37 In an observational cross-sectional study, serum Klotho levels in patients with early-stage CKD were significantly lower than in healthy controls as well as in patients with more advanced-stage CKD.38 In addition, serum Klotho levels were shown to be independently associated with estimated glomerular filtration rate (eGFR), with a positive correlation shown between Klotho levels (serum and urine) and eGFR in adult CKD patients. Klotho mRNA expression levels in kidneys of CKD patients were also lower than levels in healthy controls and positively correlated with eGFR.39

Clinical Data for Klotho in Kidney Transplantation
In general, Klotho shows pleiotropic effects on kidney diseases in clinic, especially in regard to AKI and CKD, 2 renal diseases closely related to kidney transplant. Accordingly, some recent studies have implied that Klotho was associated with kidney transplant, an optimal therapy for patients with end-stage renal disease. Nevertheless, long-term allograft survival is limited by both immune and nonimmune mechanisms, as well as factors related to donors and recipients.40 Because of organ shortages, more aging kidneys have been accepted from older donors. However, aging increases AKI susceptibility and reduces tissue regenerative capability. In addition to the immune and nonimmune factors described above, the use of older kidneys contributes to renal graft deterioration and histologic lesions.41 In a study of 15 patients from Kimura and associates, urinary Klotho levels in renal transplant recipients on postoperative day 2 were significantly higher than baseline values.42 In a similar study, Akimoto and colleagues reported significantly decreased levels of soluble serum Klotho in renal transplant recipients on postoperative day 2 and day 5, but no statistically significant change was found.43

Regarding long-term renal transplant results concerning Klotho, Bleskestad and associates reported reduced soluble Klotho levels compared with levels in healthy volunteers, although the result was not significant, and a trend toward lower levels of serum Klotho compared with levels shown in a control group matched for eGFR.22 These data support results from animal studies that the kidneys are a major resource of soluble Klotho. Both short-term and long-term renal transplant recipients exhibited lower serum Klotho levels compared with controls. Although reasons are not clear, these changes could be due to AKI and immuno­suppressant toxicity. Further studies are required to better elucidate the associations between serum Klotho levels and renal graft outcomes.

Delayed graft function is a common complication after renal transplant that results in impaired graft function.44 In renal allograft biopsies, patients with delayed graft function showed a dramatic and significant reduction in Klotho expression compared with pretransplant biopsies from the same donors.21

Considering the critical role of Klotho in preventing cellular senescence, Klotho expression may play a central role in prolonging renal allograft survival. However, this hypothesis remains to be illuminated. Factors modulating Klotho expression in renal transplant are not fully understood in clinical practice. So far, few studies have been conducted to clarify this unknown in the area of renal transplantation. Paricalcitol, a commonly used drug for CKD patients with hyperparathyroidism, was found to elevate serum Klotho concentrations in renal transplant recipients with secondary hyperparathyroidism with an increment in klotho expression in peripheral blood mononuclear cells.45 Similar effects were observed with recombinant human erythropoietin both in vitro and in vivo. Leone and colleagues verified that recombinant human erythropoietin pretreatment mitigated Klotho downregulation in HK-2 cells induced by cyclosporine treatment and modulated a trend toward higher serum Klotho levels compared with healthy individuals.46 Rapamycin, which is used to prevent graft rejection after renal transplant, induced increased klotho gene and protein expression levels via mTORC2 activation both in vitro and in vivo.47 These potential factors modulating Klotho expression need further investigation to verify their potential role in prolonging renal allograft survival.

Preclinical Data for Klotho Associated With Kidney Allograft
Recently, a commentary48 raised an unanswered question: will intervention via the FGF-23/Klotho axis improve kidney transplant outcomes? Klotho has been shown to participate in several intracellular signaling pathways. The FGF-23/Klotho signaling pathway is involved in mineral homeostasis, vitamin D synthesis, cell proliferation, and cell apoptosis in the kidney. Klotho also protects renal tubular cells from oxidative damage by inhibiting the insulin/IGF-1 signaling pathway and inhibits transforming growth factor β1 for decreasing renal fibrosis. Activation of the protein kinase C signaling pathway by Klotho results in suppression of the 25-hydroxyvitamin D3 1α-hydroxylase gene in renal cells. Klotho is also involved in Wnt signaling pathways involved in renal fibrosis10 (Figure 2).

In the kidney transplant setting, a Klotho-related signaling pathway has not been confirmed. Theoretically, the antiaging properties and pleiotropic effects of Klotho could delay renal allograft aging and ameliorate immune and nonimmune injury. Indeed, in an animal study investigating how to switch the Klotho effect to clinical utility for prolonging renal allograft survival, Doi and colleagues confirmed that administration of secreted Klotho protein suppressed mouse renal fibrosis. The group also showed that secreted Klotho protein directly binds to the type II transforming growth factor (TGF)-β receptor and inhibits TGF-β1 binding to cell surface receptors, thereby inhibiting TGF-β1 signaling.49 In rats, administration of cyclosporine reduced renal and serum Klotho expression levels. However, Klotho downregulation was prevented by valsartan, a renal protective drug, thereby alleviating cyclosporine-induced nephrotoxicity.50 Similar results were shown by Piao and associates, in which N-acetylcysteine preserved Klotho expression and relieved chronic cyclosporine nephropathy via the phospho-AKT/phospho-FoxO1 pathway in mice.51 So far, the effects of Klotho in a renal allograft animal model has not been shown, and it remains to be confirmed whether Klotho plays a critical role in prolonging renal allograft survival in animals (Table 1).

Conclusions

Because of organ shortages, the use of aging kidneys from expanded criteria donors is on the rise. Interventions to prolong renal allograft survival have long been pursued. Because of its antiaging properties and other physiologic effects, Klotho could be a potential candidate to ameliorate renal allograft impairment. Although Klotho has been shown to be a potential good diagnostic marker and a possible therapeutic choice for some kidney diseases, few studies have investigated its role in renal transplant. Further research is needed to shed light on the intricate mechanisms of Klotho in the field of renal transplant for diagnostic and therapeutic purposes. Additionally, clinical studies containing large samples are required to confirm the long-term effects of Klotho in outcomes of renal allografts.


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Volume : 16
Issue : 3
Pages : 253 - 258
DOI : 10.6002/ect.2017.0329


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From the Department of Organ Transplantation, Guangdong Second Provincial General Hospital, Guangzhou, China
Acknowledgements: There are no sources of funding for this study, and the authors have no conflicts of interest to declare.
Corresponding author: Dong Liu, Department of Organ Transplantation, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Guangzhou, 510317, China
Phone: +86 20 89168095
E-mail: Ld177@163.com