Mineral adaptations following kidney transplantation
Corresponding Author
Sven-Jean Tan
Department of Nephrology, The Royal Melbourne Hospital, Parkville, Vic., Australia
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Correspondence
Dr. Sven-Jean Tan, Department of Nephrology, The Royal Melbourne Hospital, Grattan Street, Parkville, Vic. 3052, Australia.
Tel.: +613 9342 7058;
fax: +613 9347 1420;
e-mail: [email protected]
Search for more papers by this authorAmy Crosthwaite
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Department of Nephrology, Austin Hospital, Heidelberg, Vic., Australia
Search for more papers by this authorDavid Langsford
Department of Nephrology, Northern Hospital, Epping, Vic., Australia
Search for more papers by this authorVaruni Obeysekere
Department of Endocrinology, St Vincent's Hospital Melbourne, Fitzroy, Vic., Australia
Search for more papers by this authorFrank L. Ierino
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Department of Nephrology, St Vincent's Hospital Melbourne, Fitzroy, Vic., Australia
Victorian Kidney Transplantation Collaborative, Melbourne, Vic., Australia
Search for more papers by this authorMatthew A. Roberts
Victorian Kidney Transplantation Collaborative, Melbourne, Vic., Australia
Eastern Health Clinical School, Monash University, Box Hill, Vic., Australia
Search for more papers by this authorPeter D. Hughes
Department of Nephrology, The Royal Melbourne Hospital, Parkville, Vic., Australia
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Search for more papers by this authorTim D. Hewitson
Department of Nephrology, The Royal Melbourne Hospital, Parkville, Vic., Australia
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Search for more papers by this authorKaren M. Dwyer
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Department of Nephrology, St Vincent's Hospital Melbourne, Fitzroy, Vic., Australia
Victorian Kidney Transplantation Collaborative, Melbourne, Vic., Australia
School of Medicine, Deakin University, Geelong, Vic., Australia
Search for more papers by this authorNigel D. Toussaint
Department of Nephrology, The Royal Melbourne Hospital, Parkville, Vic., Australia
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Search for more papers by this authorCorresponding Author
Sven-Jean Tan
Department of Nephrology, The Royal Melbourne Hospital, Parkville, Vic., Australia
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Correspondence
Dr. Sven-Jean Tan, Department of Nephrology, The Royal Melbourne Hospital, Grattan Street, Parkville, Vic. 3052, Australia.
Tel.: +613 9342 7058;
fax: +613 9347 1420;
e-mail: [email protected]
Search for more papers by this authorAmy Crosthwaite
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Department of Nephrology, Austin Hospital, Heidelberg, Vic., Australia
Search for more papers by this authorDavid Langsford
Department of Nephrology, Northern Hospital, Epping, Vic., Australia
Search for more papers by this authorVaruni Obeysekere
Department of Endocrinology, St Vincent's Hospital Melbourne, Fitzroy, Vic., Australia
Search for more papers by this authorFrank L. Ierino
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Department of Nephrology, St Vincent's Hospital Melbourne, Fitzroy, Vic., Australia
Victorian Kidney Transplantation Collaborative, Melbourne, Vic., Australia
Search for more papers by this authorMatthew A. Roberts
Victorian Kidney Transplantation Collaborative, Melbourne, Vic., Australia
Eastern Health Clinical School, Monash University, Box Hill, Vic., Australia
Search for more papers by this authorPeter D. Hughes
Department of Nephrology, The Royal Melbourne Hospital, Parkville, Vic., Australia
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Search for more papers by this authorTim D. Hewitson
Department of Nephrology, The Royal Melbourne Hospital, Parkville, Vic., Australia
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Search for more papers by this authorKaren M. Dwyer
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Department of Nephrology, St Vincent's Hospital Melbourne, Fitzroy, Vic., Australia
Victorian Kidney Transplantation Collaborative, Melbourne, Vic., Australia
School of Medicine, Deakin University, Geelong, Vic., Australia
Search for more papers by this authorNigel D. Toussaint
Department of Nephrology, The Royal Melbourne Hospital, Parkville, Vic., Australia
Department of Medicine, The University of Melbourne, Parkville, Vic., Australia
Search for more papers by this authorSummary
Klotho is predominantly expressed in the kidney and reported to have antioxidant and antifibrotic properties. Soluble Klotho (sKl), the circulating protein cleaved from membrane-bound Klotho, is reduced significantly with kidney disease and inversely associated with mortality. sKl has not been thoroughly evaluated prospectively after kidney transplantation. Incident kidney transplant recipients (KTRs) were prospectively evaluated pretransplantation, 1, 12 and 52 weeks post-transplantation. Basic biochemistry, sKl and intact FGF23 were measured. Within-subject comparisons were evaluated using repeat-measure anova or Friedman's analysis. Effects of immunosuppression and biochemical parameters on sKl and FGF-23 over time were analysed using mixed-effects modelling. Median serum creatinine (sCr) at 1 week was 116 (92–142) μmol/l, and at 52 weeks, all 29 KTRs had a functioning graft with median sCr of 111 (97–131) μmol/l. Compared with baseline, sKl was increased at 52 weeks following an initial decline at 1 week (P < 0.005 and P < 0.01, respectively), while FGF23 was considerably reduced at 52 weeks (P < 0.001). In a mixed-effects model, an increased sKl was not associated with reduction in immunosuppression or evaluated biochemical parameters. Modest increase in sKl is observed one-year postkidney transplantation with excellent early graft function suggesting factors beyond renal capacity may influence circulating sKl. FGF23 normalization was observed. Longer term evaluation in transplantation, specifically addressing the effects of immunosuppression, is required to understand the pathophysiology of the sKl/FGF23 axis and potential for modification.
References
- 1Tonelli M, Wiebe N, Knoll G, et al. Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes. Am J Transplant 2011; 11: 2093.
- 2Evenepoel P. Recovery versus persistence of disordered mineral metabolism in kidney transplant recipients. Semin Nephrol 2013; 33: 191.
- 3Moe SM, Drueke T, Lameire N, Eknoyan G. Chronic kidney disease-mineral-bone disorder: a new paradigm. Adv Chronic Kidney Dis 2007; 14: 3.
- 4Smith ER, McMahon LP, Holt SG. Fibroblast growth factor 23. Ann Clin Biochem 2014; 51(Pt 2): 203.
- 5Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008; 359: 584.
- 6Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 2011; 305: 2432.
- 7Kendrick J, Cheung AK, Kaufman JS, et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol 2011; 22: 1913.
- 8Nakano C, Hamano T, Fujii N, et al. Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis. Bone 2012; 50: 1266.
- 9Tan SJ, Smith ER, Hewitson TD, Holt SG, Toussaint ND. The importance of klotho in phosphate metabolism and kidney disease. Nephrology 2014; 19: 439.
- 10Semba RD, Cappola AR, Sun K, et al. Plasma klotho and mortality risk in older community-dwelling adults. J Gerontol A Biol Sci Med Sci 2011; 66: 794.
- 11Evenepoel P, Meijers BK, de Jonge H, et al. Recovery of hyperphosphatoninism and renal phosphorus wasting one year after successful renal transplantation. Clin J Am Soc Nephrol 2008; 3: 1829.
- 12Evenepoel P, Naesens M, Claes K, Kuypers D, Vanrenterghem Y. Tertiary ‘hyperphosphatoninism’ accentuates hypophosphatemia and suppresses calcitriol levels in renal transplant recipients. Am J Transplant 2007; 7: 1193.
- 13Wesseling-Perry K, Pereira RC, Tsai E, Ettenger R, Juppner H, Salusky IB. FGF23 and mineral metabolism in the early post-renal transplantation period. Pediatr Nephrol 2013; 28: 2207.
- 14Wolf M, Weir MR, Kopyt N, et al. A prospective cohort study of mineral metabolism after kidney transplantation. Transplantation 2016; 100: 184.
- 15Akimoto T, Kimura T, Watanabe Y, et al. The impact of nephrectomy and renal transplantation on serum levels of soluble Klotho protein. Transplant Proc 2013; 45: 134.
- 16Malyszko J, Koc-Zorawska E, Matuszkiewicz-Rowinska J, Malyszko J. FGF23 and Klotho in relation to markers of endothelial dysfunction in kidney transplant recipients. Transplant Proc 2014; 46: 2647.
- 17Bleskestad IH, Thorsen IS, Jonsson G, Skadberg O, Bergrem H, Goransson LG. Soluble Klotho and intact fibroblast growth factor 23 in long-term kidney transplant patients. Eur J Endocrinol 2015; 172: 343.
- 18Leone F, Lofaro D, Gigliotti P, et al. Soluble Klotho levels in adult renal transplant recipients are modulated by recombinant human erythropoietin. J Nephrol 2014; 27: 577.
- 19Hu MC, Kuro-o M, Moe OW. Secreted Klotho and chronic kidney disease. Adv Exp Med Biol 2012; 728: 126.
- 20Hu MC, Shi M, Zhang J, et al. Renal production, uptake, and handling of circulating alphaKlotho. J Am Soc Nephrol 2016; 27: 79.
- 21Hu MC, Moe OW. Klotho as a potential biomarker and therapy for acute kidney injury. Nat Rev Nephrol 2012; 8: 423.
- 22Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Internal Med 2009; 150: 604.
- 23Sakan H, Nakatani K, Asai O, et al. Reduced renal alpha-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism. PLoS One 2014; 9: e86301.
- 24Colley CM, Fleck A, Goode AW, Muller BR, Myers MA. Early time course of the acute phase protein response in man. J Clin Pathol 1983; 36: 203.
- 25Norlen BJ, Engberg A, Kallskog O, Wolgast M. Nephron function of the transplanted rat kidney. Kidney Int 1978; 14: 10.
- 26Alstrup K, Graugaard-Jensen C, Rittig S, Jorgensen KA. Abnormal diurnal rhythm of urine output following renal transplantation: the impact of blood pressure and diuretics. Transplant Proc 2010; 42: 3529.
- 27Yoon HE, Lim SW, Piao SG, Song JH, Kim J, Yang CW. Statin upregulates the expression of klotho, an anti-aging gene, in experimental cyclosporine nephropathy. Nephron Exp Nephrol 2012; 120: e123.
- 28Han DH, Piao SG, Song JH, et al. Effect of sirolimus on calcineurin inhibitor-induced nephrotoxicity using renal expression of KLOTHO, an antiaging gene. Transplantation 2010; 90: 135.
- 29Yoon HE, Ghee JY, Piao S, et al. Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrol Dial Transplant 2011; 26: 800.
- 30Berthier CC, Pally C, Weckbecker G, et al. Experimental heart transplantation: effect of cyclosporine on expression and activity of metzincins. Swiss Med Wkly 2009; 139: 233.
- 31Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci USA 2007; 104: 19796.
- 32Smith ER, McMahon LP, Holt SG. Method-specific differences in plasma fibroblast growth factor 23 measurement using four commercial ELISAs. Clin Chem Lab Med 2013; 51: 1971.
- 33Smith ER. The use of fibroblast growth factor 23 testing in patients with kidney disease. Clin J Am Soc Nephrol 2014; 9: 1283.
- 34Heijboer AC, Blankenstein MA, Hoenderop J, de Borst MH, Vervloet MG, consortium N. Laboratory aspects of circulating alpha-Klotho. Nephrol Dial Transplant 2013; 28: 2283.
