|Year : 2018 | Volume
| Issue : 2 | Page : 46-56
Serum changes in fibroblast growth factor-23 and in parameters of phosphorus metabolism after renal transplantation
Effat A.E. Tony1, Mohamad A Sobh1, Madleen Adel A Abdou2, Mohamad F Ali1
1 Department of Internal Medicine, Faculty of Medicine, Assiut University, Assuit, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assuit, Egypt
|Date of Submission||02-Feb-2018|
|Date of Acceptance||14-May-2018|
|Date of Web Publication||4-Sep-2018|
Effat A.E. Tony
Department of Internal Medicine, Nephrology Unit, Faculty of Medicine, Assuit University, Assuit 71515
Source of Support: None, Conflict of Interest: None
Background Kidney transplantation is the preferred treatment for chronic kidney disease, but its effect on disordered mineral metabolism is incompletely understood. Post-transplant mineral bone disease (MBD) is an important complication, although its etiology and course vary. Fibroblast growth factor (FGF23) controls phosphate and vitamin D metabolism, and its assessment increases our understanding the pathogenesis of post-transplant bone disease.
Aim To determine the regulation of serum FGF23 in relation to other biochemical parameters in our post-transplant participants with preserved renal function.
Materials and methods A case–control study conducted on 48 kidney transplant recipients, with age ≥ 18 years old and an estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73m2, from the different transplantation centers during their follow-up from 2015 to 2016. They classified in equal number according to their post-transplant follow-up period into: group A; early 6 months, and group B; late 6 months. In addition, 20 healthy persons were enrolled in the study as controls. Patients with graft rejection at the time of enrollment, those with infections and neoplasms or taking medications were excluded. Participants subjected to full history taking and clinical examination. Peripheral hemogram, blood glucose, lipid profile, liver function, kidney function, urine analysis, calcium, phosphorus, parathyroid hormone (PTH), 25-hydroxyvitamin D, FGF23, and 24-h urinary phosphorus were done.
Results Significantly high levels of FGF23, PTH, and urinary phosphorous (108.6±92.7 pg/ml, 150.7±51 pg/ ml, and 1170.5±331.1 mg/day with P<0.001 for each) with significant low levels of serum phosphorus and vitamin D3 (2.5±0.9 mg/dl and 21.1±11.4 ng/ml with P<0.001 for each) in early 6-month post-transplant period were found in our patients. However, Nearly equal non-significant levels of corrected serum calcium were found throughout the study. Multivariate linear regression analysis showed significant associations of FGF23 with eGFR and other mineral bone indices in patients groups, with P˂0.05. Receiver operating characteristic curve showed that PTH of high sensitivity and specificity (95.83 and 83.33%, respectively) and phosphaturia of high sensitivity but low specificity (91.67 and 58.33%, respectively) not FGF23 (had low sensitivity and specificity (54.17 and 33.33%, respectively) could be considered as independent markers to regulate MBD in the early post-transplant period.
Conclusion FGF23 may play a role in the pathogenesis of MBD in post-transplanted patients. Although, significant associations of FGF23 with other conventional bone mineral indices in early 6-month post-transplant period were confirmed, it could not be considered as an independent marker to regulate MBD in the early post-transplant period. Future prospective studies with larger numbers of transplant recipients are required to establish its direct relationship with development or severity of MBD.
Keywords: chronic kidney disease, estimated glomerular filtration rate and 25-hydroxyvitamin D, fibroblast growth factor-23, mineral bone disease, parathyroid hormone
|How to cite this article:|
Tony EA, Sobh MA, Abdou MA, Ali MF. Serum changes in fibroblast growth factor-23 and in parameters of phosphorus metabolism after renal transplantation. J Egypt Soc Nephrol Transplant 2018;18:46-56
|How to cite this URL:|
Tony EA, Sobh MA, Abdou MA, Ali MF. Serum changes in fibroblast growth factor-23 and in parameters of phosphorus metabolism after renal transplantation. J Egypt Soc Nephrol Transplant [serial online] 2018 [cited 2018 Sep 21];18:46-56. Available from: http://www.jesnt.eg.net/text.asp?2018/18/2/46/240585
| Introduction|| |
Kidney transplantation (KT) is the preferred treatment for end-stage renal disease, because it reverses many complications of chronic kidney disease (CKD), improves recipients’ quality of life, and prolongs survival. Advances in immune suppression, which vastly enhanced short-term allograft outcomes, have enabled the transplant community to focus more attention on managing the nonimmune aspects of the post-transplant period to optimize recipients’ long-term health . Post-transplant bone disease is an important complication in a substantial proportion of patients, although its etiology and course vary. KT corrects or improves many complications of CKD, but its effect on disordered mineral metabolism is incompletely understood ,. The discovery of fibroblast growth factor-23 (FGF23) provides a new conceptual framework, increasing our understanding of the pathogenesis of post-transplant bone disease . The levels of FGF23, a new phosphaturic hormone that has recently been implicated in the development of secondary hyperparathyroidism in patients with CKD , could be increased in kidney transplant recipients. The residual FGF23 activity may also contribute to early post-transplant hypophosphatemia , which could in turn play a role in the pathogenesis of post-transplant bone disease. Controversy exists over whether these losses in phosphorus persist in the long term. Patients often undergo transplantation with pre-existing bone mineral disease; in addition, after transplantation, other potentially deleterious factors can appear, such as persistent hyperparathyroidism, hypophosphatemia, hypercalcemia, vitamin D deficiency, hypomagnesaemia, bone loss, vascular calcification, FGF 23 and immunosuppressive therapy and impaired kidney function . After transplant, elevated parathyroid hormone (PTH) level is responsible for an increase in serum calcium, a decrease in serum phosphate, and an increase in fractional excretion of phosphorus, suggesting that the secretion of PTH is not entirely under the normal feedback control , high bone turnover state, loss of bone mass, nephrocalcinosis, and reduced kidney graft function . Risk factors for the persistent hyperparathyroidism include high level of pretransplant PTH, high calcium levels and alkaline phosphatase, low levels of 25-hydroxyvitamin D [25(OH)D] and 1,25(OH)2D, prolonged duration of dialysis therapy, and reduced expression of receptors for vitamin D, calcium sensing, and FGF23 in the hyperplastic parathyroid gland . FGF23 levels at 3 months after transplantation are independently associated with fractional excretion of phosphate, decreased calcitriol levels, and pretransplant FGF23 levels. FGF23 normally returns to baseline ∼1 year after transplantation. After successful KT, as kidney function resumes, urinary phosphate excretion is normally exaggerated by the relatively high FGF23 concentration, resulting in renal phosphate wasting and hypophosphatemia in some patients. Despite the rapid reduction of FGF23 during the first 3 months after transplantation, the average FGF23 level is still higher than normal, resulting in almost 90% of patients with functioning graft experiencing hypophosphatemia at some point ,. Immediately after successful KT, serum calcium decreases secondary to the discontinuation of calcium and active vitamin D. The rapid decline in PTH results in the movement of calcium back into the bone and the loss of calcium in the urine . Thereafter, serum calcium gradually increases and becomes stabilized after 3–6 months. Owing to the high prevalence of persistent hyperparathyroidism as mentioned earlier, hypercalcemia usually develops in 10–15% of kidney transplant recipients . Pretransplant calcium and PTH levels are the significant determinants of hypercalcemia after transplantation . Increased serum calcium may also occur in association with low PTH levels. Persistently high serum calcium level is associated with interstitial microcalcification and poorer long-term graft outcomes . 25-Hydroxyvitamin D (25-OH-D) deficiency is commonly observed in KT recipients. Alterations in the vitamin D system in renal transplants show peculiarities related to post-transplant-specific derangement of the PTH-FGF23 axis, immunosuppressive regimen, and environmental factors . Recovery of graft function, inappropriately high PTH levels, and hypophosphatemia accelerate the conversion of 25(OH)D into 1,25(OH)2D3 after renal transplantation. Conversely, high FGF23 levels during the first months after transplant could inhibit 1-α-hydroxylase and enhance 24-α-hydroxylase, thereby reducing 1,25(OH)2D3 and 25(OH)D levels, respectively . Persistent vitamin D deficiency leads to hypocalcaemia and abnormal bone mineralization . Furthermore, vitamin D deficiency may be associated with poor graft outcomes, including an increased risk of acute cellular rejection possibly through the immunomodulatory effect of vitamin D on the immune system, which may be mediated through direct effects on T cells and also indirectly via modification of dendritic cell function ,.
| Materials and methods|| |
This case–control observational prospective study was conducted on 48 participants of transplanted kidneys enrolled from different renal transplantation centers and university hospitals and had reviewed for post-transplant follow-up at El-Helal Health Insurance Hospital in Sohag Government, Egypt, within the period of January 2015 to January 2017. Their ages were of more than 18 years with an estimated glomerular filtration rate (eGFR) exceeding 60 ml/min/1.73 m2, at the different renal transplantation centers and University Hospitals in Egypt who were reviewed for post-transplant follow-up at El-Helal Health Insurance Hospital in Sohag Government, Egypt, through the period between January 2015 and January 2017. The patients were classified according to their post-transplant follow-up period into two groups: group A included 24 patients in the early 6-month period and group B included 24 patients in the late 6-month period. The eGFR was calculated by the modification of diet in renal disease equation . The most common causes of CKD were hypertension, diabetes mellitus, chronic glomerulonephritis (GN), chronic pyelonephritis, lupus nephritis, polycystic kidney disease (PCKD), and unknown causes. In addition, 20 apparently healthy persons were enrolled in the study as a control group. All patient groups were matched for sex and age. The study was approved by the Ethical Committee of Faculty of Medicine, Assiut University, Egypt, and a written informed consent was obtained from each participant. Patients who had KT rejection at the time of enrollment; had infections, apparent autoimmune disease, and neoplasms; taking medications such as intravenous iron, antiviral drugs, anticancer therapy, vitamin D analog, cinacalcet and calcium supplementation; and post-transplant patients on regular hemodialysis were excluded. All participants were subjected to full history taking and thorough clinical examination. After centrifugation to yield platelet-poor plasma from samples on anticoagulant (3.8% sodium citrate) and serum from clotted blood samples, serum and plasma samples were stored in aliquots at −20°C until assay. Complete blood count was performed on whole blood samples on EDTA (Beckman Coulter Hmx, Brea, CA, USA). Random blood glucose evaluation, HbA1c determination, liver function tests, kidney function tests, complete urine analysis, and 24-h urinary phosphorus excretion were measured by the Immulite analyzer (Roche). Lipid profile tests were carried out using standard laboratory methods with Hitachi 911 autoanalyser (Roche). Serum levels of total calcium and Phosphorus measured by automated analyzer COBAS INTEGRA 400 (Boehringer Mannheim, Germany), serum levels of PTH using MAGLUMI Intact PTH Ref.13330211001M (Sandwich immuneluminometric assay), serum levels of 25(OH) Vit D3 using ELISA from CABIOTECH (CA , USA) Catalog No.: VD220 and Fibroblast growth factor 23 by ELISA using ELISA from Elabscience (China), Catalog No.: E-EL-H1116.
Collected data were fed in the computer using ‘Microsoft Office Excel Software’ program (2010) for Windows (Microsoft Corporation) and was transferred to SPSS (Statistical Package for the Social Sciences Software Program; SPSS Inc., Chicago, Illinois) version 21 to be statistically analyzed. Data were summarized using mean and SD for quantitative variables and frequency and percentage for qualitative ones. Comparison between the groups was carried out using the independent sample t-test or one-way analysis of variance for quantitative variables, and the χ2-test or Fisher’s exact test for qualitative ones. Multivariate linear regression analysis was performed. We used receiver operating characteristic analysis to examine the diagnostic performance of FGF23, PTH, serum phosphorous, vitamin D, corrected calcium, and phosphaturia. P values less than 0.05 were considered statistically significant, and less than 0.01 were considered highly significant
| Results|| |
The basic clinical and laboratory characteristics of our studied patients and controls are summarized in [Table 1].
|Table 1 The Basic clinical and laboratory characteristics of our studied patients and controls|
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The different mineral bone parameters of our studied groups are shown in [Table 2].
Multivariate linear regression analysis showed the significant association between FGF23 and phosphaturia in patients groups in early and late 6-month post-transplant periods (β-coefficients 0.45, 0.354 with P≤0.009 and 0.041, respectively). However, the significant inverse associations of FGF23 with other bone mineral indices [β-coefficients −1.210, −0.175 with P≤0.037 and 0.035 for phosphorus; β-coefficients −0.164, −0.563; P≤0.038 and P≤0.025 for PTH; and β-coefficients −0.48; −0.404; P≤0.006 and P≤0.037 for 25(OH)D3, respectively] and eGFR (β-coefficients −0.297; −2.657; P≤0.042 and ≤0.012, respectively) in patients groups in early and late 6-month post-transplant periods were found in patient groups, as shown in [Table 3].
|Table 3 Multivariate regression analysis using fibroblast growth factor-23 as dependent variable in studied groups|
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In our studied group A, PTH with cutoff value of less than or equal to 101.4 pg/ml was able to diagnose patients with BMD with high sensitivity (95.83%) and specificity (83.33%), with its high ability to detect their prognosis, as it had 85.2% positive predictive value (PPV) with P less than or equal to 0.001. The serum phosphorus with a cutoff value of greater than 2.7 mg/ml was able to diagnose patients with MBD with sensitivity of 91.67% and specificity of 79.17%, having an ability to detect their prognosis; it had 81.5% PPV and 90.5% negative predictive value (NPV), with P less than or equal to 0.001. However, FGF23 with a cutoff value of less than or equal to 102.3 pg/ml was able to diagnose patients with MBD with sensitivity of 54.17% and specificity of 33.33%, but it did not have an ability to detect their prognosis; it had nearly equal predictive values (44.8% PPV with 42.1% NPV), with P value equal to 0.004. Similarly, phosphaturia at a cutoff value of less than or equal to 1200 mg/day was able to diagnose patients with BMD with high sensitivity (91.67%) but with low specificity (58.33%), with no ability to detect their prognosis, as it had nearly equal high predictive values (85.2% PPV with 95.2% NPV) with P less than or equal to 0.004. Notably, eGFR with a cutoff value of greater than 77 ml/min/1.732 was able to diagnose patients with BMD with sensitivity of 79.17% and specificity of 75%, with no ability to detect their prognosis, as it had nearly equal high predictive values (76% PPV with 78.3% NPV), with P less than or equal to 0.03 as shown in [Table 4] and [Figure 1]a–c. Therefore, FGF23 level, although not alone, is strongly associated, together with phosphaturia, PTH and eGFR, in prediction of occurrence of MBD in early post-transplant period.
|Table 4 The Values of FGF-23 and Bone mineral Parameters for diagnosis and prognosis of BMD in our studied group A patients|
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|Figure 1 (a) ROC curve of FGF23 and PTH in group A, (b) ROC curve of FGF23 and eGFR in group A. (c) ROC curve of FGF23 and phosphaturia in group A. eGFR, estimated glomerular filtration rate; FGF23, fibroblast growth factor-23; PTH, parathyroid hormone; ROC curve, receiver operating characteristic curve.|
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In our studied group B, the level of PTH with cutoff value of greater than 67 pg/ml was able to diagnose BMD with high sensitivity (81.25%) and specificity (100%), with its high ability to detect its prognosis, as it had 100% PPV, with P less than or equal to 0.001. Similarly, the level of serum 25(OH)D3 with cutoff value of less than or equal to 14.8 ng/ml was able to diagnose patients with BMD with high specificity (100%) but low sensitivity (20.83%), having an ability to detect their prognosis, as it had high PPVs (100%) with P less than or equal to 0.004. However, the level of FGF23 with cutoff value of greater than 66 pg/ml was able to diagnose patients with BMD with moderate sensitivity (68.75%) and specificity (70%), with its high ability to detect their prognosis; it had 84.6% PPVs, with P less than or equal to 0.004. Similarly, the level of phosphaturia with cutoff value of greater than 695 mg/day was able to diagnose patients with BMD with high specificity (100%) but of low sensitivity (79.17%) with its ability to detect their prognosis, as it had high PPVs (100%) with P less than or equal to 0.004. Notably, eGFR with cutoff value of less than or equal to 84 ml/min/1.732 was able to diagnose patients with BMD with high specificity (95%) but low sensitivity (68.75%), with no ability to detect their prognosis, as it had high NPVs (97.1%), with P less than or equal to 0.031, as shown in [Table 5] and [Figure 2]a–c. Therefore, FGF23 level was strongly associated, together with phosphaturia, 25(OH)D3, PTH, and eGFR in prediction of occurrence of mineral bone disease in the late post-transplant period.
|Table 5 The values of FGF-23 and Bone mineral Parameters for diagnosis and prognosis of BMD in our studied group B patients|
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|Figure 2 (a) ROC curve of FGF23 and phosphaturia in group B; (b) ROC curve of FGF23 and PTH in group B; (c) ROC curve of FGF23 and eGFR in group B. eGFR, estimated glomerular filtration rate; FGF23, fibroblast growth factor-23; PTH, parathyroid hormone; ROC curve, receiver operating characteristic curve|
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| Discussion|| |
KT is the preferred treatment for end-stage renal disease because it reverses many complications of CKD, improves recipients’ quality of life, and prolongs survival. Advances in immune suppression, which vastly enhanced short-term allograft outcomes, have enabled the transplant community to focus more attention on managing the nonimmune aspects of the post-transplant period to optimize recipients’ long-term health . Post-transplant bone disease is an important complication in a substantial proportion of patients, although its etiology and course vary. Patients often undergo transplantation with pre-existing bone mineral disease. In addition, after transplantation, other potentially deleterious factors can appear, such as immunosuppressive therapy and impaired kidney function . KT corrects or improves many complications of CKD, but its effect on disordered mineral metabolism is incompletely understood ,. The discovery of FGF23 provides a new conceptual framework through which we can increase our understanding of the pathogenesis of post-transplant bone disease . The levels of FGF23, a new phosphaturic hormone that has recently been implicated in the development of secondary hyperparathyroidism in patients with CKD , could be increased in kidney recipients. The residual FGF23 activity may also contribute to early post-transplant hypophosphatemia , which could in turn play a role in the pathogenesis of post-transplant bone disease. Controversy exists over whether these losses in phosphorus persist in the long term.
In the current study, we sought to determine the regulation of serum FGF23 in relation to other biochemical parameters in post-transplant participants with preserved renal function. Our study on FGF23 in renal transplant patients evaluated in the early post-transplant period (range: 6–12 months) reported a marked increase in FGF23 levels. This could be explained by that the uremic bone may develop resistance to feedback inhibition of FGF23 probably caused by the preceding chronic phosphate retention in the pretransplant period. This finding agreed with Krocker et al.  who stated that the patients with chronic renal failure who had undergone renal transplantation produced greater quantities of FGF23 early after transplantation, until osteoblasts become inactive and bone metabolism is suppressed; moreover, high-dose corticosteroids, calcineurin inhibitors, and mechanistic target of rapamycin inhibitors stimulate FGF23 production. However, our results were in contrast to Bhan et al. , Evenepoel et al. , and Taweesedt and Disthabanchong  who stated that despite a decline in FGF23 levels 3 months after transplantation, they were still higher than normal, with further reductions in FGF23 levels repeatedly observed over longer follow-up, approximating normal levels 1–3 years after transplantation, and the authors explained that the pretransplant FGF23 levels emerged as the most important predictor of the FGF23 level in the early months after renal transplant. Interestingly, over the time, the mean values start to decrease and become at the end of follow-up very close to normal, as our study reported that the mean levels of FGF23 in group B patients were significantly lower than that in group A patients, and this finding could be explained by the improvement of renal function as determined by significant increase in eGFR, and it was proposed that GFR could be considered as a major determinant of FGF23 serum levels in the first year after renal transplant. Our result matched with Evenepoel et al.  who showed that FGF23 levels at early 6 months were higher when compared with that at the end of the first year after transplantation and attributed that to improved GFR. In parallel, multivariate analysis revealed that eGFR was statistically significantly negatively associated with FGF23 at end of the first year after renal transplant, supporting that GFR is an independent determinant of serum FGF23 at later post-transplant period. This inverse correlation between GFR and FGF23 levels may be partly attributable to poorer kidney function in early postrenal transplant period. This finding was agreed with Sánchez Fructuoso et al. , Evenepoel et al. , and Danilo et al.  who stated that the gradual improvement of eGFR levels at later post-transplant period is associated with the decrease in renal clearance of FGF23. Notably, this finding has also been corroborated by Wolf et al. . It is possible that kidney recipients could develop abnormal FGF23 production because of previous chronic phosphate retention, stimulating the secretion of FGF23. In addition, bone abnormalities before transplant may have led to reduced production of FGF23 in the osteocytes of recipients. In fact, the association between bone turnover and serum FGF23 can vary, as shown in several mouse models, where bone turnover was altered by a variety of exogenous and endogenous factors. Finally, the factors such as immunosuppressive drugs, which can affect bone turnover, should also be considered.
In the current study, we found that the mean level of serum phosphorous was lower in group A when compared with group B, and the mean level of phosphorous was nearly equal in group B and controls with no statistical difference. This finding was in agreement with Westerberg et al.  who deduced that increased FGF23 levels at early postrenal transplant period decrease renal phosphorous reabsorption, and subsequently serum phosphorous levels, by reducing the apical expression of the sodium-dependent Pi co-transporter IIa in the brush-border membrane of the renal proximal tubules. Moreover, Wolf et al. , Economidou et al. , and Prasad et al.  observed that serum phosphorous levels were low in the early months after transplant, with improvement at the end of the first year owing to high FGF23 levels in early post-transplant period with gradual decrease by time to near normal at the end of first year after transplant. This is in contrast with Kawarazaki et al.  who stated that the pathogenesis of hypophosphatemia at 12 months may be due largely to persistent HPT rather than because of high FGF23 level. Consequently, our study showed that FGF23 was significantly inversely correlated with serum phosphorous level in both patient groups, suggesting that phosphorous was the most significant predictor of log FGF23 in post-transplant period. Our data favor the idea that an increase in FGF23 is detected at a critical point where manifest hyperphosphatemia occurs, and that hyperphosphatemia is one major stimulus to elevate FGF23 levels in post-transplant period. This finding was in concordance with Wolf et al.  and Economidou et al. , where they found that FGF23 was negatively correlated with serum phosphorous level in early post-transplant period and found that higher FGF23 levels were associated with lower serum phosphate during the first 3 months after transplantation. This is consistent with the known physiological effects of FGF23 of hypophosphatemia owing to renal phosphate wasting and 1, 25-dihydroxyvitamin D deficiency during the early post-transplant period. It was also noteworthy that Wolf et al.  deduced FGF23 decreased despite persistently elevated PTH, which stimulates FGF23 production. Perhaps subtle but protracted PTH-mediated renal phosphate wasting in transplant recipients induces negative phosphate balance that is appropriately sensed by osteocytes, which reduce FGF23 production in an effort to conserve phosphate, despite the stimulatory effects of high PTH. In contrast to our results, El-Khatib et al.  reported that no significant correlation was found between FGF23 level and phosphorous level at 3 and 6 months after transplant and attributed it to that not only the high FGF23 levels was a contributing factor to hypophosphatemia during the early postrenal transplant period but also persistent secondary hyperparathyroidism played a role.
In the current study, the urinary phosphorous excretion was significantly increased in group A and B patients. We explained these findings by the higher mean levels of FGF23 and PTH in patients. This observation was supported by Evenepoel et al.  and Prasad et al.  who stated that FGF23 and PTH may act synergistically to cause phosphaturia. Moreover, our results showed that the mean level of FGF23 was positively correlated with phosphaturia in both patient groups. This observation was in concordance with Evenepoel et al.  who stated that high FGF23 correlated with phosphate urinary excretion in early transplant period. This is in contrast to Trombetti et al.  who stated that an inappropriate urinary phosphate wasting occurred despite low levels of PTH and suggested that FGF23 seemed to be more significantly correlated with urinary phosphorous loss than was PTH in early transplant period. Indeed, FGF23 inhibits renal tubular phosphorous reabsorption by suppressing the expression of luminal sodium co-transporters 2a and 2c, and this phosphaturic effect is independent of PTH .
In this prospective observational study, we demonstrated rates of persistent hyperparathyroidism in excess of 85% throughout the first year after KT, despite the recipients’ healthy allograft function. Even when considering a higher PTH threshold greater than 65 pg/ml, more than 70% of participants demonstrated persistent hyperparathyroidism throughout the first year. These data demonstrated that secondary hyperparathyroidism owing to CKD is only partially corrected by KT and that rates of persistent hyperparathyroidism remain extremely high during the first year after transplantation. These results were in concordance with Wolf et al.  who reported persistent hyperparathyroidism throughout the first year after KT, despite the recipients’ healthy allograft function. In addition, Evenepoel et al.  reported that the serum PTH levels remained significantly higher 1 year after renal transplantation as compared with their CKD counterparts and explained that persistent elevation of PTH throughout first year after transplant to long lifespan of parathyroid cells (∼20 years) with a cell renewal rate of ∼5% per year contributes to the very slow involution of the gland after renal transplantation, long duration of dialysis, increased parathyroid gland size, and development of nodular and/or monoclonal hyperplasia of parathyroid glands. Moreover, we found that mean value of PTH in group A was significantly higher when compared with group B patients. This is in agreement with Wolf et al.  and Prasad et al.  who reported that the early 6-month PTH levels were higher than in the next 6 months, and this could be attributed to gradual improvement of parathyroid function after 3 and 6 months after transplant owing to a reduction of the parathyroid functional mass. These results suggest that clinical surveillance for persistent hyperparathyroidism should not be reserved exclusively for individuals with high pretransplant PTH levels. Furthermore, our results showed a highly statistically significant inverse correlation between GFR and PTH in studied patient groups, suggesting that hyperparathyroidism is considered as one of the earliest manifestations of renal dysfunction after renal transplantation. This in agreement with Chowdary et al.  who reported that hyperparathyroidism is one of the earliest manifestations of impaired renal function. Progressive increases of PTH should be avoided, and marked changes in PTH levels should trigger interventions with relatively simple treatments that have the potential to prevent adverse outcomes. We also observed reductions in markers of bone turnover in the early post-transplant period, especially among recipients with high pretransplant PTH levels. Although this may suggest improved bone health in response to transplantation, the clinical implications of these changes in bone biomarkers in KT recipients require further study.
The relationship between PTH and FGF23 is complex and must be fully elucidated. Our results showed a statistically significant inverse correlation between FGF 23 and PTH in both studied groups. We could attribute this observation to the finding that FGF23 and PTH are both phosphaturic factors, decreasing renal phosphorus reabsorption in the kidney proximal tubules. Importantly, a mild hyperphosphatemia may be a stronger stimulus for PTH expression than for FGF23. The phosphaturic potency of PTH in vivo may also be stronger than that of FGF23. Furthermore, an early increase in PTH may be more beneficial in postrenal transplantation because it promotes renal phosphorus secretion and protects systemic calcium levels by increasing circulating serum calcitriol. This finding was in agreement with Kubat et al.  and Olauson et al.  who suggested that FGF23 suppresses PTH synthesis and secretion by a Klotho-independent pathway involving calcineurin. Moreover, Cianciolo and Cozzolino  attributed this finding to that the PTH-related renal phosphate wasting in KT recipients induces a negative phosphate balance that is appropriately sensed by osteocytes, thus decreasing FGF23 production in an effort to conserve phosphate. This is in contrast with Wesseling-Perry et al.  who demonstrated that serum levels of PTH and FGF23 were not correlated in early post-transplant period, and they were also unable to rule out a potential suppressive effect of FGF23 on PTH after transplantation; however, the increasing values of 1,25(OH)2D in participants with lower FGF23 values may have obscured the suppressive effect of FGF23 on PTH. However, Sánchez Fructuoso et al.  stated that in transplant recipients, the increased PTH in the setting of normal FGF23 levels was more frequent than an isolated increase in FGF23. They attributed these findings to that in pretransplant CKD with a stimulated PTH, and a certain degree of hyperplasia in the parathyroid glands could account for the more pronounced effect of this hormone. Another possible explanation could be that bone abnormalities before transplant may have led to reduced production of FGF23. Notably, Liu et al.  stated that the PTH levels were elevated in hypophosphatemic disorders caused by elevated FGF23 levels, which support the hypothesis that FGF23 is involved in the pathogenesis of hyperparathyroidism. Moreover, Saddadi et al.  and Nakanishi et al.  supposed that in dialysis patients elevated circulating FGF23 levels directly correlate with PTH levels and can be a significant predictor of refractory hyperparathyroidism. Evenepoel et al.  found that FGF23 was independently associated with PTH both 3 and 12 months after transplantation. On the contrary, Stubbs et al. , Emmett , and Rhee et al.  stated that because FGF23 gene expression is upregulated by PTH receptor activation in osteocytes, recipients with high pretransplant levels of serum PTH are more prone to persistently high FGF23 levels and to develop hypophosphatemia during the early period after transplantation. Thus, an increase in FGF23 levels may be favored by an elevated level of serum PTH before and after transplantation and by the accompanying increase in bone resorption.
Accordingly, it seems that the level of FGF23 can be considered as a prognostic factor for assessing renal function in regulating components of phosphate and vitamin D hemostasis. In the current study, the mean levels of 25(OH)D3 were significantly lower in studied patients when compared with controls, and these levels were lowest in the early transplant period. In the current study, the mean levels of 25(OH) D3 were significantly lower in studied patients when compared with controls, and these levels were lowest in the early transplant period. We could explain that by in the first 3 months post-transplant, our patients had the higher FGF23 levels with low serum phosphate and vitamin 1, 25(OH) D levels consistent with the known physiological effects of FGF23, the high-dose corticosteroids which enhance the catabolism of 25(OH)D3, and lastly it might be related to nutritional deficiency. These results align with Sánchez Fructuoso et al.  who showed that elevated serum levels of FGF23 could explain the deficiency of calcitriol and elevated renal phosphorus wasting in the early post-transplant period. Accordingly, the study by Wolf et al.  implicated persistently elevated FGF23 levels as a contributing cause of hypophosphatemia owing to renal phosphate wasting and 1,25-(OH)D deficiency during the early post-transplant period. An another study by Querings et al.  demonstrated that renal transplant recipients are at high risk for vitamin D deficiency and had significantly lower serum 25(OH)D3 levels. Interestingly, Evenepoel et al.  and Evenepoel et al.  reported that 25(OH)D3 levels decreased significantly during the first 3 months after successful renal transplantation. The underlying cause for the low 25(OH)D levels in transplant recipients is multifactorial. First, the immunosuppressant medications, including glucocorticoids, enhance the catabolism of 25(OH)D3. Second, recipients were advised to wear sun protection before going outdoors which reduces the skin’s production of vitamin D. Notably, in this study, there was a significant inverse correlation between FGF23 and 25(OH)D3 levels in both groups. This observation is supported by Hasegawa et al.  who reported that higher FGF23 levels reduce 25(OH)D production. Moreover, Quarles  and Mehrotra et al.  stated that FGF23 leads to a decrease in both 25(OH)D and 1,25(OH)2D through increasing expression of 24-hydroxylase (CYP24A1), which results in the production of the inactive metabolite 24,25-(OH)D. In contrary to this, Wesseling-Perry et al.  stated that 25(OH)D3 values were not related to FGF23 concentrations, suggesting that marked upregulation of 24-hydroxylase, the enzyme responsible for the degradation of both 1,25(OH)2D and 25(OH)D, may not be responsible for the lower 25(OH)D3 values in patients with higher concentrations of FGF23. In addition, the return of 25(OH)D values close to preoperative concentrations after the sixth month after transplantation likely reflects improved nutritional intake.Our results showed that there is no statistically significant difference in mean levels of calcium (which were within normal range) in studied patients and controls. This may be attributed to the high level of FGF23 and PTH after transplantation. This finding agreed with Economidou et al. , Saddadi et al. , Ibrahim et al. , and Monnic and Rocha  who stated that serum calcium levels increased in the first 2 months after KT, but remained within the normal range. High level of FGF23 is an important marker for secretion of phosphorus from kidneys, emphasizing the central role of FGF23 marker to regulate calcium and phosphorus metabolism after a successful renal transplantation. In addition, our results revealed no significant correlation between FGF23 and serum calcium levels. This observation is supported by El-Khatib et al. , Hasegawa et al. , and Barros et al.  who reported that higher FGF23 levels reduce 25(OH)D production leading to hypocalcemia. However, our finding disagreed with Kawarazaki et al. , Evenepoel et al. , and Trombetti et al.  who reported that hypercalcemia, which is a risk factor for calciphylaxis and renal dysfunction, is a very common complication after KTx, and persistent hyperparathyroidism has been reported to be the most plausible cause. Moreover, Wolf et al.  stated that high post-transplant PTH levels were accompanied by high rates of hypercalcemia and hypophosphatemia. These data demonstrate that secondary hyperparathyroidism owing to CKD is only partially corrected by KT and that rates of persistent hyperparathyroidism remain extremely high during the first year after transplantation.
Our study suggested that postrenal transplant period may be considered a unique phase in the natural history of disordered mineral metabolism associated with CKD that requires dedicated investigation. FGF23 levels decrease significantly after successful renal transplantation and remain within normal limits with stable graft function. The role of FGF23 in phosphorus homeostasis is more prominent in the early period after transplantation. PTH levels decrease significantly after successful transplantation, but hyperparathyroidism can persist in some recipients for a longer duration.
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| References|| |
Wolf M, Weir M, Kopyt N, Mannon R, von Visger J, Deng H et al.
A prospective cohort study of mineral metabolism after kidney transplantation. Transplantation 2016; 100: 184–193.
Cianciolo G, Cozzolino M. FGF23 in kidney transplant: the strange case of Doctor Jekyll and Mister Hyde. Clin Kidney J 2016; 9:665–668.
Sánchez Fructuoso AI, Maestro ML, Calvo N, Orden DV, Pérez Flores I, Vidaurreta M et al.
Role of fibroblast growth factor 23 (FGF23) in the metabolism of phosphorus and calcium immediately after kidney transplantation. Transplant Proc 2012; 44:2551–2554.
Isakova T, Xie H, Yang W, Xie D, Anderson AH. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 2011; 305:2432–2439.
Kawarazaki H, Shibagaki Y, Fukumoto S, Kido R, Nakajima I, Fuchinoue S et al.
The relative role of fibroblast growth factor 23 and parathyroid hormone in predicting future hypophosphatemia and hypercalcemia after living donor kidney transplantation: a 1-year prospective observational study. Nephrol Dial Transplant 2011; 26:2691–2695.
Hirukawa T, Kakuta T, Nakamura M, Fukagawa M. Mineral and bone disorders in kidney transplant recipients: reversible, irreversible, and de novo abnormalities. Clin Exp Nephrol 2015; 19:543–555.
Sirilak S, Chatsrisak K, Ingsathit A, Kantachuvesiri S, Sumethkul V, Stitchantrakul W et al.
Renal phosphate loss in long-term kidney transplantation. Clin J Am Soc Nephrol 2012; 7:323–331.
Heaf J, Tvedegaard E, Kanstrup IL, Fogh-Andersen N. Hyperparathyroidism and long-term bone loss after renal transplantation. Clin Transplant 2003; 17:268–274.
Jeona H, Kimb H, Yang J. Bone disease in post-transplant patients. Curr Opin Endocrinol Diabetes Obes 2015; 22:452–458.
Bhan I, Shah A, Holmes J, Isakova T, Gutierrez O, Burnett SM et al.
Post-transplant hypophosphatemia: tertiary ‘hyper-phosphatoninism’. Kidney Int 2006; 70:1486–1494.
Evenepoel 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: 1193–1200.
Nobata H, Tominaga Y, Imai H, Uchida K. Hypocalcemia immediately after renal transplantation. Clin Transplant 2013; 27:E644–E648.
Muirhead N, Zaltman JS, Gill JS, Churchill DN, Mann V, Cole EH. Hypercalcemia in renal transplant patients: prevalence and management in Canadian transplant practice. ClinTransplant 2014; 28:161–165.
Malluche HH, Monier-Faugere MC, Herberth J. Bone disease after renal transplantation. Nat Rev Nephrol 2010; 6:32–40.
Keyzer CA, Riphagen IJ, Joosten MM, Navis G, Muller K. Associations of 25(OH) and 1,25(OH)2 vitamin D with long-term outcomes in stable renal transplant recipients. J Clin Endocrinol Metab 2015; 100:81–89.
McGregor R, Li G, Penny H, Lombardi G, Afzali B, Goldsmith DJ. Vitamin D in renal transplantation − from biological mechanisms to clinical benefits. Am J Transplant 2014; 14:1259–1270.
Lee JR, Dadhania D, August P, Lee JB, Suthanthiran M, Muthukumar T. Circulating levels of 25-hydroxyvitamin D and acute cellular rejection in kidney allograft recipients. Transplantation 2014; 98:292–299.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in Renal Disease Study Group. Ann Intern Med 1999; 130:461–470.
Krocker D, Perka C, Tuischer J, Funk J, Tohtz S, Buttgereit F et al.
Effects of tacrolimus, cyclosporin A and sirolimus on MG63 cells. Transpl Int 2006; 19:563–569.
Evenepoel P, Viaene L, Meijers B. PTH, FGF23, and calcium: it takes three to tango? Kidney Int 2011; 80:1377.
Taweesedt P, Disthabanchong S. Mineral and bone disorder after kidney transplantation. World J Transplant 2015; 5:231–242.
Evenepoel P, Meijers BK, de Jonge H, Naesens M, Bammens B, Claes K et al.
Recovery of hyperphosphatoninism and renal phosphorus wasting one year after successful renal transplantation. Clin J Am Soc Nephrol 2008; 3:1829–1836.
Danilo F, Barbara K, Ulrich N, Donna P, Lhotta K, Lingenhel A et al.
Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the mild to moderate kidney disease (MMKD) study. J Am Soc Nephrol 2007; 18:2601–2608.
Westerberg P, Linde T, Wikstrom B, Stridsberg M. Regulation of fibroblast growth factor-23 in chronic kidney disease. Nephrol Dial Transplant 2007; 22:3202–3207.
Economidou D, Dovas S, Papagianni A. FGF23 before and after renal transplantation. J Transplant 2009; 10:1–5.
Prasad N, Jaiswal A, Agarwal V, Kumar S, Saurabh S, Yadav S et al.
FGF23 is associated with early post-transplant hypophosphataemia and normalizes faster than iPTH in living donor renal transplant recipients: a longitudinal follow-up study. Clin Kidney J 2016; 9:669–676.
El-Khatib MM, El-Shahaby AR, EEl-Khashab SO, Mohamed EE, Shaker AM. Fibroblast growth factor 23 levels before and after renal transplantation. Egypt J Int Med 2016; 28:52–59.
Trombetti A, Richert L, Hadaya K, Graf JD, Herrmann FR, Serge L et al.
Early post-transplantation hypophosphatemia is associated with elevated FGF-23 levels. Eur J Endocrinol 2011; 164:839–847.
Saito H, Kusano K, Kinosaki M, Ito H, Hirata M, Segawa H et al.
Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production. J Biol Chem 2003; 278:2206–2211.
Chowdary D, Rohini N, Prasad K. Relationship between parathyroid hormone and serum creatinine levels in chronic kidney disease patients. J Med Sci Res 2015; 3:17–21.
Kubat AU, Serpil S, Aysegul T, Harika B, Refik T, Faruk A et al.
Effects of vitamin D replacement therapy on serum FGF23 concentrations in vitamin D-deficient women in short term. Eur J Endocrinol 2010; 163: 825–831.
Olauson H, Lindberg K, Amin R, Tobias E. Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet 2013; 9:e1003975.
Wesseling-Perry K, Renata C, Tsai1 E, Ettenger R, Jüppner H, Isidro B. FGF23 and mineral metabolism in the early post-renal transplantation period. Pediatr Nephrol 2013; 28:2207–2215.
Liu S, Brown TA, Zhou J, Xiao ZS, Awad H, Guilak F. Role of matrix extracellular phosphoglycoprotein in the pathogenesis of X-linked hypophosphatemia. J Am Soc Nephrol 2005; 16:1645–1653.
Saddadi F, Rasoolzadeh A, Mohammadreza G, Maryam M. Impact of FGF23 level on calcium and phosphorus levels in post-renal transplantation. J Renal Inj Prev 2017; 6:99–102.
Nakanishi S, Kazama JJ, Nii-Kono T, Omori K, Yamashita T, Fukumoto S et al.
Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients. Kidney Int 2005; 67:1171–1178.
Stubbs J, Liu S, Quarles D. Role of fibroblast growth factor 23 in phosphate homeostasis and pathogenesis of disordered mineral metabolism in chronic kidney disease. Semin Dial 2007; 20:302–308.
Emmett M. What does serum fibroblast growth factor 23 do in hemodialysis patients? Kidney Int 2008; 73:3–5.
Rhee Y, Farrow E, Lee R, Bivi N, Lezcano V, Plotkin L et al.
Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. J Bone 2011; 49:636–643.
Querings K, Girndt M, Geisel J, Georg T, Tilgen W, Reichrath J. 25-Hydroxyvitamin D deficiency in renal transplant recipients. J Clin Endocrinol Metab 2006; 91:526–529.
Hasegawa H, Nagano N, Urakawa I, Yamazaki Y, Iijima K, Fujita T et al.
Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with earlystage chronic kidney disease. Kidney Int 2010; 78:975–980.
Quarles LD. Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res 2012; 318:1040–1048.
Mehrotra S, Raj K, Manas R, Prasad N, Kaul A. Fibroblast growth factor-23, vitamin D and mineral metabolism in renal transplant recipients. Ind J Transplant 2016; 10:1–4.
Ibrahim OA, Modawe GA, AbdElkarim AA. Assessment of calcium phosphorus and parathyroid hormone in sudanese patient with renal transplantation. J Med Biol Sci Res 2016; 2:1–4.
Monnic ML, Rocha AA. Aspects of the blood chemistry of kidney transplant patients. J Bras Patol Med Lab 2015; 51:284–290.
Barros X, Torregrosa JV, Casals G, Paschoalin R, Durán CE, Campistol JM et al.
Earlier decrease of FGF-23 and less hypophosphatemia in preemptive kidney transplant recipients. Transplantation 2012; 94:830–836.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]