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Ana I. Sánchez Fructuoso, Maria L. Maestro, Isabel Pérez-Flores, Rosalía Valero, Sara Rafael, Silvia Veganzones, Natividad Calvo, Virginia De la Orden, Jose C. De la Flor, Francisco Valga, Marta Vidaurreta, Cristina Fernández-Pérez, Alberto Barrientos, Serum level of fibroblast growth factor 23 in maintenance renal transplant patients, Nephrology Dialysis Transplantation, Volume 27, Issue 11, November 2012, Pages 4227–4235, https://doi.org/10.1093/ndt/gfs409
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Abstract
The discovery of fibroblast growth factor 23 (FGF23) provides a new conceptual framework that improves our understanding of the pathogenesis of post-transplant bone disease. Excess FGF23 is produced in the early post-transplant period; levels return to normal in the months following transplant. However, few manuscripts discuss FGF23 levels in stable long-term renal transplant recipients.
We performed a cross-sectional observational study of 279 maintenance kidney recipients with chronic kidney disease (CKD) Stages 1–4 and stable allograft function who had received their transplant at least 12 months previously. We calculated the estimated GFR (eGFR) using the MDRD4 equation.
FGF23, parathyroid hormone (PTH) and phosphorus values were higher in more advanced stages, while the serum calcitriol levels and the phosphate reabsorption rate were lower. A significant inverse correlation was found between eGFR and FGF23 (r = − 0.487; P < 0.001), PTH (r = − 0.444; P < 0.001), serum phosphate levels (r = − 0.315; P < 0.001) and fractional excretion of magnesium (r = − 0.503; P < 0.001). Multivariable analysis showed that increased time on corticosteroids (P < 0.001), PTH (P < 0.001), serum phosphate (P = 0.003), decreased serum calcitriol (P = 0.049) and estimated glomerular filtration (P = 0.003) rate were associated with high FGF23 levels. In contrast with pre-transplant patients and first year post-transplant patients, higher FGF23 values were not correlated with increased phosphate excretion. An elevated phosphate reabsorption rate was associated with decreased PTH (P < 0.001) and calciuria (P = 0.028) and increased serum calcitriol (P = 0.009), plasma bicarbonate (P = 0.024) and estimated glomerular filtration (P = 0.003).
Serum FGF23 concentrations remain increased in long-term kidney graft recipients, even in the early stages of CKD. It remains to be seen whether measures aimed at reducing serum levels of PTH and phosphate and/or corticosteroid doses might help to lower serum FGF23 and whether this will improve kidney recipient outcomes.
Comments
Dear Editor, In our previous article about FGF23 in renal transplant patients, we concluded that FGF23 levels remained increased in these patients even in the early stages of chronic kidney diseases (CKD). In a recent letter, Blekestad et al noticed a typing error in our paper. As we reported in our study in the methods section, the units used to measure circulating C-terminal FGF23 using a second-generation enzyme-linked immunosorbent assay (Immutopics Inc., San Clemente, CA) were RU/ml, not pg/ml as mentioned in the table. We apologize for this unfortunate error and we thank Dr Blekestad for his commentary. To answer the aforementioned letter, we have measured FGF23 in 108 not transplanted volunteers (78 subjects with stage 1 CKD and 30 with stage 2). The median values of FGF23 in control patients were 16.8 RU/ml (interquartile range 8.0-2910) vs 76.4 RU/ml (54.0-95.8) in renal transplant patients (p<0.001). When we stratified patients according to the stage of CKD, FGF23 levels in stage 1 were 11.8 RU/ml (interquartile range 7.0-23.1) in control patients vs 94.2 RU/ml (interquartile range 57.8-149.2; p=<0.001) in renal transplant patients. In subjects with CKD stage 2, these values were 31.8 RU/ml (interquartile range 27.7-42.5) in controls vs 73.5 RU/ml (interquartile range 52.0-90.3) in transplanted patients (p<0.001). In conclusion, we apologize for the typo and maintain our conclusion that FGF23 levels remained increased in renal transplant patients even in the early stages of chronic kidney diseases.
Conflict of Interest:
None declared
We read with great interest the paper by Sanchez Fructuoso et al. but have some major concerns regarding the methodology and their conclusion (1).
Data on markers of mineral and bone disorder in long-term kidney transplant patients are scarce. Controversies exist whether FGF23 levels return to normal during the first year post-transplant (2) or stays elevated for several years. This issue was addressed by two studies published in 2012 with conflicting results (1, 3). Sanchez Fructuoso et al. concluded that FGF23 concentrations remained increased in long-term kidney graft recipients, even in the early stages of CKD while Sirilak et al. found that the FGF23 levels were lower or comparable with normal subjects.
Sanchez Fructuoso et al. states in the methods section that circulating C-terminal FGF23 (cFGF23) was measured using a second-generation enzyme-linked immunosorbent assay (Immutopics Inc., San Clemente, CA). They refer however to Immutopics ELISA kit for intact FGF23 (iFGF23) and their results are given in pg/ml (reference nr 38: www.immutopics.com/pdf/directional-insert/60-6500.pdf). The cFGF23 assay gives cFGF23 levels in RU/ml and the iFGF23 assay in pg/ml. These values are not interchangeable and reference intervals for cFGF23 and iFGF23 are not identical (4, 5). The reference value was in Sanchez Fructuosa et al.'s paper set to < 100 RU/ml in accordance with the results from Isakova et al. (6). Smith ER et al. published 95% reference limits for iFGF23 and cFGF23 assays from Immutopics recently to be 11.7 - 48.6 pg/ml, and 21.6 - 91.0 RU/ml, respectively (7).
If Sanchez Fructuoso et al. have analyzed cFGF23 in RU/ml and not iFGF23 in pg/ml, then their conclusion is not supported by the data presented. They state that the FGF23 levels are higher than a reference with an upper limit of 100 RU/ml even in the early stages of CKD. In table 2 the results for CKD stages 1 and 2 are reported as a median of 76 (IQR 54 - 96). The majority, 75% of these patients, have levels below 96.
Conclusion: There are several commercially available assays of FGF23. They have different limitations and do not provide interchangeable results. The article from Sanchez Fructuosa et al., although addressing an interesting research question, is as it reads now difficult to interpret. We would therefore like to ask the authors which assay they used to determine FGF23.
Inger H Bleskestad MD and Lasse G Goransson MD, PhD Department of Internal Medicine, Stavanger University Hospital Stavanger, Norway
References 1. Sanchez Fructuoso AI, Maestro ML, Perez-Flores I et al. Serum level of fibroblast growth factor 23 in maintenance renal transplant patients. Nephrol Dial Transplant 2012; 27: 4227-4235 2. Evenepoel 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: 1829-1836 3. Sirilak S, Chatsrisak K, Ingsathit A et al. Renal phosphate loss in long-term kidney transplantation. Clin J Am Soc Nephrol 2012; 7: 323-331 4. Heijboer AC, Levitus M, Vervloet MG et al. Determination of fibroblast growth factor 23. Ann Clin Biochem 2009; 46: 338-340 5. Smith 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: 1971-1981 6. Isakova T, Wahl P, Vargas GS et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 2011; 79: 1370-1378 7. Smith ER, Cai MM, McMahon LP, Holt SG. Biological variability of plasma intact and C-terminal FGF23 measurements. J Clin Endocrinol Metab 2012; 97: 3357-3365
Conflict of Interest:
None declared