Klotho and chronic kidney disease

Abstract

Through alternative splicing, Klotho protein exists both as a secreted and a membrane form whose extracellular domain could be shed from the cell surface by secretases and released into the circulation to act as endocrine factor. Unlike membrane Klotho which functions as a coreceptor for fibroblast growth factor-23 (FGF23) to modulate FGF23 signal transduction, soluble Klotho is a multifunction protein present in the biological fluids including blood, urine and cerebrospinal fluid and plays important roles in antiaging, energy metabolism, inhibition of Wnt signaling, antioxidation, modulation of ion transport, control of parathyroid hormone and 1,25(OH)2VD3 production, and antagonism of renin-angiotensin-aldosterone system. Emerging evidence from clinical and basic studies reveal that chronic kidney disease is a state of endocrine and renal Klotho deficiency, which may serve as an early biomarker and a pathogenic contributor to chronic progression and complications in chronic kidney disease including vascular calcification, cardiac hypertrophy, and secondary hyperparathyroidism. Supplementation of exogenous Klotho and/or upregulation of endogenous Klotho production by using rennin angiotensin system inhibitors, HMG CoA reductase inhibitors, vitamin D analogues, peroxisome proliferator-activated receptors-gamma agonists, or anti-oxidants may confer renoprotection from oxidation and suppression of renal fibrosis, and also on prevention or alleviation of complications in chronic kidney disease. Therefore, Klotho is a highly promising candidate on the horizon as an early biomarker, and as a novel therapeutic agent for chronic kidney disease.

Figure 1. Mechanisms and pathophysiological influences of Klotho deficiency in CKD

A. Putative mechanism of downregulation of Klotho expression in CKD: In CDK/ESRD, multiple potential factors including loss of renal mass, over production of proinflammatory cytokines such as tumor necrosis factor (TNF) and interferon (IFN), dyslipidemia and hyperglycemia, elevation of uremic toxin such as indoxyl sulfate, and oxidative stress, all downregulate renal Klotho and consequently blood Klotho. There are several positive loops. Klotho deficiency stimulates FGF23 synthesis which is also enhanced by elevation of blood Pi. High blood FGF23 suppresses 1,25-(OH)₂VD₃ synthesis and worsens VD deficiency, which further inhibits Klotho. Low blood 1,25-(OH)₂VD₃ not only reduces Klotho expression, but also stimulates renin angiotensin system which further suppresses Klotho production. Downregulation of Klotho in the kidney and the circulation further activates renin angiotensin system and decreases renal Klotho expression. On the other hand, low Klotho expression aggravates phosphate retention by decreasing urinary Pi excretion. High Pi per se also decreases renal Klotho expression. B. Pathogenic role of Klotho deficiency and interaction with other mineral metabolism disturbances in chronic kidney diseases: In the uremic parathyroid gland, FGFR1 and Klotho expression are downregulated which renders parathyroid gland resistant to the suppressive effect of FGF23 which triggers and promotes secondary hyperparathyroidism. The high blood phosphate and FGF23, activated renin-angiotensin system activation, and low blood vitamin D in concert contribute to cardiomyopathy. Whether Klotho plays a direct role in cardiac hypertrophy remains to be clarified (dash line). High phosphate induces vascular smooth muscle cells reprogramming to osteoblast/chondrocytes, low blood Klotho contributes to failure of suppression of high phosphate-induced calcification. The direct effect of FGF23 on vascular calcification remains to be explored (dash line). Low blood vitamin D accelerates vascular calcification. Low blood and renal Klotho facilitate renal fibrogenesis, impair tissue regeneration, and consequently promote chronic progression of CKD. Whether and how high FGF23 and phosphate in blood induces renal fibrosis is still unknown (dash line).

Figure 1. Mechanisms and pathophysiological influences of Klotho deficiency in CKD

A. Putative mechanism of downregulation of Klotho expression in CKD: In CDK/ESRD, multiple potential factors including loss of renal mass, over production of proinflammatory cytokines such as tumor necrosis factor (TNF) and interferon (IFN), dyslipidemia and hyperglycemia, elevation of uremic toxin such as indoxyl sulfate, and oxidative stress, all downregulate renal Klotho and consequently blood Klotho. There are several positive loops. Klotho deficiency stimulates FGF23 synthesis which is also enhanced by elevation of blood Pi. High blood FGF23 suppresses 1,25-(OH)₂VD₃ synthesis and worsens VD deficiency, which further inhibits Klotho. Low blood 1,25-(OH)₂VD₃ not only reduces Klotho expression, but also stimulates renin angiotensin system which further suppresses Klotho production. Downregulation of Klotho in the kidney and the circulation further activates renin angiotensin system and decreases renal Klotho expression. On the other hand, low Klotho expression aggravates phosphate retention by decreasing urinary Pi excretion. High Pi per se also decreases renal Klotho expression. B. Pathogenic role of Klotho deficiency and interaction with other mineral metabolism disturbances in chronic kidney diseases: In the uremic parathyroid gland, FGFR1 and Klotho expression are downregulated which renders parathyroid gland resistant to the suppressive effect of FGF23 which triggers and promotes secondary hyperparathyroidism. The high blood phosphate and FGF23, activated renin-angiotensin system activation, and low blood vitamin D in concert contribute to cardiomyopathy. Whether Klotho plays a direct role in cardiac hypertrophy remains to be clarified (dash line). High phosphate induces vascular smooth muscle cells reprogramming to osteoblast/chondrocytes, low blood Klotho contributes to failure of suppression of high phosphate-induced calcification. The direct effect of FGF23 on vascular calcification remains to be explored (dash line). Low blood vitamin D accelerates vascular calcification. Low blood and renal Klotho facilitate renal fibrogenesis, impair tissue regeneration, and consequently promote chronic progression of CKD. Whether and how high FGF23 and phosphate in blood induces renal fibrosis is still unknown (dash line).

Figure 2. Proposed therapeutic strategies in CKD

Five principal mineral disturbances in CKD: Klotho deficiency, excess FGF23, secondary hyperparathyroidism, vitamin D deficiency, and phosphate retention are shown as interacting and self-amplifying setting off a vortex of downhill spiral. Shown in italics are means to interrupt these pathways at specific points. Each maneuver has the potential of breaking the spiral. In a given patient, a particular combination of prescriptions can be tailored to best suit that individual. The prescription will also not be static in the sense that it has to be constantly readjusted with time as the patient’s pathophysiology evolves and responds to therapy. Vit D: vitamin D