Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease

Hyperphosphatemia, calcitriol deficiency, and secondary hyperparathyroidism (SHPT) are common complications of chronic kidney disease (CKD). Fibroblast growth factor-23 (FGF-23) is a novel phosphaturic hormone that also inhibits renal 1alpha-hydroxylase activity and thus may be involved in the pathogenesis of SHPT. Several hypotheses were tested: that FGF-23 increases as renal function declines; is linearly associated with serum phosphate levels; is associated with increased phosphaturia independent of parathyroid hormone (PTH); and is associated with decreased calcitriol levels independent of renal function, hyperphosphatemia, and vitamin D stores. FGF-23, PTH, 25(OH)D3, calcitriol, calcium, phosphate, and urinary fractional excretion of phosphate (Fe(PO4)) were measured in 80 CKD patients. Multiple linear regression was used to test the hypotheses. FGF-23 and PTH were inversely associated with estimated GFR (eGFR), whereas calcitriol levels were linearly associated with eGFR. Hyperphosphatemia and hypocalcemia were present in only 12 and 6% of patients, respectively, all of whose eGFR was <30. Increased Fe(PO4) was associated with decreased eGFR, and both increased FGF-23 and PTH were independently associated with increased Fe(PO4). Increased FGF-23 and decreased 25(OH)D3 were independent predictors of decreased calcitriol, but the effects on calcitriol levels of renal function itself and hyperphosphatemia were completely extinguished by adjusting for FGF-23. It is concluded that FGF-23 levels increase early in CKD before the development of serum mineral abnormalities and are independently associated with serum phosphate, Fe(PO4), and calcitriol deficiency. Increased FGF-23 may contribute to maintaining normal serum phosphate levels in the face of advancing CKD but may worsen calcitriol deficiency and thus may be a central factor in the early pathogenesis of SHPT.     

Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers

BACKGROUND: Hyperphosphatemia is a risk factor for the development of several different complications of chronic kidney disease (CKD), including secondary hyperparathyroidism and cardiovascular complications, due to the formation of calcium-phosphate deposits. Fibroblast growth factor-23 (FGF-23) is a recently discovered protein that is mutated in autosomal-dominant hypophosphatemic rickets, an inherited phosphate wasting disorder, and it may represent a novel hormonal regulator of phosphate homeostasis. We therefore hypothesized that FGF-23 levels may be altered in hyperphosphatemia associated with renal failure and that its concentration changes in response to different levels of phosphate intake. METHODS: Using a two-site enzyme-linked immunosorbent assay (ELISA) detecting the C-terminal portion of FGF-23, serum concentration was measured in 20 patients with different stages of renal failure (creatinine range 155 to 724 micromol/L), in 33 patients with end-stage renal disease (ESRD) on dialysis treatment, and in 30 patients with functioning renal grafts. Furthermore, six healthy males were given oral phosphate binders in combination with low dietary phosphate intake for 2 days followed by 3 days of repletion with inorganic phosphate. FGF-23 levels were determined at multiple time points. RESULTS: FGF-23 serum levels were significantly elevated in CKD with a strong correlation between serum creatinine and FGF-23 concentration. Independent correlations were also seen between FGF-23 and phosphate, calcium, parathyroid hormone (PTH), and 1,25(OH)2D3. No changes in serum FGF-23 levels were observed in volunteers following ingestion of oral phosphate binders/low dietary phosphate intake, which led to a decline in phosphate excretion or during the subsequent repletion with inorganic phosphate through oral phosphate and a normal diet. CONCLUSION: Circulating FGF-23 was significantly elevated in patients with CKD and its concentration correlated with renal creatinine clearance. In healthy volunteers, FGF-23 levels did not change after phosphate deprivation or phosphate loading.     

FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.

We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism. INTRODUCTION: The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes. MATERIALS AND METHODS: To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals. RESULTS: An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1alpha-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h. CONCLUSIONS: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis.     

The CKD-MBD Syndrome: Hysteresis in PTH Involvement and PTH Administration for Its Management

Chronic kidney disease (CKD) disturbs mineral homeostasis, leading to mineral and bone disorders (MBD). CKD-MBD is a significant problem and currently available treatment options have important limitations. Phosphate retention is thought to be the initial cause of CKD-MBD but serum phosphate remains normal until the late stages of CKD, due to elevated levels of the phosphaturic hormone fibroblast growth factor-23 (FGF-23), and parathyroid hormone (PTH). Reduction of 1,25-dihydroxy-vitamin D (1,25[OH]₂D) concentration is the next event in the adaptive response of the homeostatic system. We argue, and provide the rationale, that calcium retention which takes place concurrently with phosphate retention, could be the reason behind the hysteresis in the response of PTH. If indeed this is the case, intermittent administration of PTH in early CKD could prevent the hysteresis, which arguably leads to the development of secondary hyperparathyroidism, and provide the platform for an effective management of CKD-MBD. © 2020 American Society for Bone and Mineral Research (ASBMR).     

IL-1β Drives Production of FGF-23 at the Onset of Chronic Kidney Disease in Mice

FGF-23 has arisen as an early biomarker of renal dysfunction, but at the onset of chronic kidney disease (CKD), data suggest that FGF-23 may be produced independently of the parathyroid hormone (PTH), 1,25(OH)₂-vitamin D₃ signaling axis. Iron status is inversely correlated to the level of circulating FGF-23, and improvement in iron bioavailability within patients correlates with a decrease in FGF-23. Alternately, recent evidence also supports a regulatory role of inflammatory cytokines in the modulation of FGF-23 expression. To determine the identity of the signal from the kidney-inducing upregulation of osteocytic FGF-23 at the onset of CKD, we utilized a mouse model of congenital CKD that fails to properly mature the glomerular capillary tuft. We profiled the sequential presentation of indicators of renal dysfunction, phosphate imbalance, and iron bioavailability and transport to identify the events that initiate osteocytic production of FGF-23 during the onset of CKD. We report here that elevations in circulating intact-FGF-23 coincide with the earliest indicators of renal dysfunction (P14), and precede changes in serum phosphate or iron homeostasis. Serum PTH was also not changed within the first month. Instead, production of the inflammatory protein IL-1β from the kidney and systemic elevation of it in the circulation matched the induction of FGF-23. IL-1β's ability to induce FGF-23 was confirmed on bone chips in culture and within mice in vivo. Furthermore, neutralizing antibody to IL-1β blocked FGF-23 expression in both our congenital model of CKD and a second nephrotoxic serum-mediated model. We conclude that early CKD resembles a situation of primary FGF-23 excess mediated by inflammation. These findings do not preclude that altered mineral availability or anemia can later modulate FGF-23 levels but find that in early CKD they are not the driving stimulus for the initial upregulation of FGF-23. © 2020 American Society for Bone and Mineral Research.     

慢性肾脏病患者血浆成纤维细胞生长因子23水平与骨矿物质代谢的相关性分析

目的观察分析血浆成纤维细胞生长因子23(FGF-23)水平与慢性肾脏病(CKD)患者骨矿物质代谢的相关性。方法选择2015年1月至2017年6月经实验室、影像学等检查确诊为CKD的患者105例作为CKD组,按照肾小球滤过率估计值(eGFR)分为1~5期;选择同期就诊于体检中心且性别、年龄相当的健康体检者30例作为健康组。比较分析两组血红蛋白(Hb)、血浆白蛋白(ALB)、血浆FGF-23、肾小球滤过率(GFR)情况及不同CKD分期患者间血钙、血磷、碱性磷酸酶(ALP)、甲状旁腺激素(PTH)水平,利用Spearman相关分析探讨CKD患者血浆FGF-23水平与血钙、血磷、ALP等指标之间的关系。结果 CKD组的FGF-23显著高于健康组(P<0.05),而Hb、GFR显著低于健康组(P<0.05),并且存在钙磷代谢紊乱、低白蛋白血症。不同CKD分期患者间血磷及血清ALP水平随肾功能的下降有增高趋势,但差异无统计学意义(P>0.05);血钙随GFR下降有下降趋势,但差异无明显统计学意义(P>0.05);PTH水平随CKD分期增高而增高,FGF-23水平随肾功能的降低而增加(P<0.05)。以FGF-23为因变量,以血钙、血磷、ALP、PTH为自变量进行Spearman相关分析。结果显示,FGF-23与血钙(r=-0.77,P<0.05)呈负相关,FGF-23与血磷(r=0.21,P<0.05)、ALP(r=0.85,P<0.01)、PTH(r=0.675,P<0.05)呈正相关。结论 CKD患者外周血FGF-23水平与骨矿物质代谢有一定的相关性。血清FGF-23与血清中钙、磷、PTH具有一定的关系。正常人的血液循环中有FGF-23表达不高,但在高磷饮食、使用活性维生素D过程中,患者血清FGF-23水平也明显升高。FGF-23的调控可能是维生素D、钙、磷、iPTH等多种因素共同作用的结果。通过早期检测血清中FGF-23与钙、磷、ALP的水平,可为患者赢取更多的治疗时间,为患者获益。     

Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D

Background Hypovitaminosis D is common in chronic kidney disease (CKD). Effects of 25-hydroxyvitamin D replenishment in CKD are not well described. Methods An 8-week randomized, placebo-controlled, double-blind parallel intervention study was conducted in haemodialysis (HD) and non-HD CKD patients. Treatment consisted of 40 000 IU of cholecalciferol orally per week. Plasma 25-hydroxyvitamin D (25-OHD), plasma 1,25-dihydroxyvitamin D (1,25-diOHD), plasma parathyroid hormone (PTH), serum phosphate, ionized serum calcium and serum fibroblast growth factor 23 (FGF-23) were analysed. We also investigated biomarkers related to cardiovascular disease (plasma D-dimer, plasma fibrinogen, plasma von Willebrand factor antigen and activity, plasma interleukin 6, plasma C-reactive protein, blood pressure, aortic augmentation index, aortic pulse wave velocity and 24-h urinary protein loss). Objective and subjective health variables were assessed (muscle function tests, visual analogue scores and Health Assessment Questionnaire). Results Fifty-two CKD patients with 25-OHD <50 nmol/L at screening were included. Cholecalciferol supplementation led to a significant increase to a median of 155 nmol/L 25-OHD (interquartile range 137-173 nmol/L) in treated patients (n = 25, P < 0.001). In non-HD patients, we saw a significant increase in 1,25-diOHD (n = 13, P < 0.01) and a lowering of PTH (n = 13, P < 0.001). This was not observed in HD patients. Cholecalciferol supplementation caused a significant increase in serum calcium and FGF-23. Conclusions 25-OHD replenishment was effectively obtained with the employed cholecalciferol dosing. In non-HD patients, it had favourable effects on 1,25-diOHD and PTH. Vitamin D-supplemented patients must be monitored for hypercalcaemia. The present study could not identify significant pleiotropic effects of 25-OHD replenishment.     

FGF23: its role in renal bone disease

Fibroblast growth factor 23 (FGF23) is a recently characterized peptide hormone produced mainly in the bone. It is secreted in response to dietary phosphorus load, and its main function is the promotion of urinary phosphate excretion and the suppression of active vitamin D (1,25D) production in the kidney. As such, FGF23 plays an important role in the maintenance of systemic phosphate homeostasis. In the advanced stages of chronic kidney disease (CKD), the kidney cannot excrete a phosphate load even in the presence of high levels of FGF23. This results in both hyperphosphatemia and a low level of 1,25D that stimulates the secretion of parathyroid hormone (PTH), leading to the development of secondary hyperparathyroidism. In chronic dialysis patients without residual renal function, FGF23 levels become extremely high due to stimulation by vitamin D therapy as well as by high levels of serum phosphate and PTH. Recent investigations have demonstrated that serum FGF23 level can be a useful marker for the prediction of the future development of refractory hyperparathyroidism and the response to vitamin D therapy in dialysis patients. In addition, putative protective roles of FGF23 against calcification have also been speculated on. Further elucidation of the mechanisms of FGF23 action will be needed to understand the various roles of FGF23 in CKD-Mineral and Bone Disorder (CKD-MBD).     

Regulation of fibroblast growth factor-23 in chronic kidney disease.

BACKGROUND: Fibroblast growth factor-23 (FGF23) is a circulating factor that regulates the renal reabsorption of inorganic phosphate (Pi) and is increased in chronic kidney disease (CKD). The aim of the current investigation was to study the regulation of FGF23 in CKD subjects with various degree of renal function. As such, we analysed the relationship between FGF23, Pi, calcium, parathyriod hormone (PTH), 25(OH) vitamin D3(25(OH)D3), 1,25(OH)2 vitamin D3(1,25(OH)2D3) and estimated glomerular filtration rate (eGFR). METHODS: Intact FGF23 and other biochemical variables were analysed in 72 consecutive adult out-patients with various stages of CKD (eGFR ranging from 4-96 ml/min.) Association studies were performed using linear univariate and multivariate analysis. RESULTS: FGF23 was significantly elevated at CKD stage 4 (266 +/- 315 pg/ml, P < 0.001) and 5 (702 +/- 489 pg/ml, P < 0.001) compared with CKD 1-2 (46 +/- 43 pg/ml). In CKD 4-5 an independent association between log FGF23 and Pi (P < 0.001), 25(OH)D3 (P < 0.05) as well as eGFR (P < 0.01) was observed. In contrast, in CKD 1-3 log PTH (P < 0.05) was the only independent predictor of log FGF23 in multivariate analysis. In CKD 1-5, Pi (P < 0.00001) and log PTH (P < 0.01) were explanatory variables for log FGF23 in multivariate analysis. CONCLUSIONS: We conclude that serum FGF23 increases in CKD 4-5, in parallel with the emerging hyperphosphataemia. Serum Pi is the most important predictor of FGF23 when GFR is less than 30 ml/min. In contrast, our data suggest that Pi may not be an important determinant of FGF23 in normophosphataemic CKD subjects. Finally, the association between FGF23 and PTH in CKD may suggest a co-regulation that remains to be further elucidated.     

慢性肾脏病患者血管钙化与成纤维细胞生长因子23-Klotho轴的关系

目的 阐明成纤维细胞生长因子FGF23-Klotho轴与慢性肾脏病(chronic kidneydisease,CKD)患者血管钙化之间的关系,以及CKD患者成纤维细胞生长因子-23 (FGF-23)、Klotho的检测及差异.方法 应用酶联免疫分析(ELISA)法检测65例CKD 3～5期未透析患者与15名健康对照组全段FGF-23、Klotho和1,25二羟基维生素D3[1,25(OH)2-VitD3]的水平,同时测定血清肌酐(creatinine,CREA)、钙(calcium,Ca)、磷(phosphate,P)、碱性磷酸酶(alkaline phosphatese,ALP)、尿酸(uric acid,UA)、全段甲状旁腺激素(parathyroid hormone,iPTH)等指标,分析FGF-23与各指标的关系.结果 CKD患者血清FGF-23水平随肾功能下降而逐渐升高,CKD各期与对照组相比、各期组间相比差异存在统计学意义(P＜0.05).Klotho与FGF-23存在显著正相关,1,25(OH)2-VitD3随肾功能损害的程度加重而下降.相关分析结果显示:CKD 3～5期患者血清FGF-23与血清Klotho、CREA、P、Ca×P、iPrH存在显著正相关(r分别为0.338、0.542、0.402、0.423、0.342,均P＜0.01),与eGFR存在显著负相关(r为-0.627,P＜0.01).多元回归分析显示:CREA、eGFR、P、Ca×P、iPTH、Klotho是血清FGF-23水平的独立影响因素.Ca、CREA、iPTH、Klotho、1,25(OH)2-VitD3、eGFR等指标无明显差异(P＞0.05).无血管钙化组和血管钙化组比较,患者的FGF-23、年龄、Ca×P、P、ALP水平有显著性差异(P＜0.05).血管钙化的危险因素采用多因素Logistic回归分析:年龄、P可能是发生血管钙化的主要危险因素(r值分别为-1.446、-1.454,P值分别为0.011、0.029).结论 CKD 3～5期患者血清FGF-23显著升高,CREA、eGFR、P、Ca×P、iPTH、Klotho可能是血清FGF-23水平的影响因素.年龄、P可能为血管钙化的危险因素.     

Role of fibroblast growth factor 23 in phosphate homeostasis and pathogenesis of disordered mineral metabolism in chronic kidney disease

The discovery of fibroblast growth factor 23 (FGF23), a novel bone-derived hormone that inhibits phosphate reabsorption and calcitriol production by the kidney, has uncovered primary regulatory pathways and new systems biology governing bone mineralization, vitamin D metabolism, parathyroid gland function and renal phosphate handling. This phosphaturic hormone, which is made predominately by osteocytes in bone, appears to have a physiologic role as a counter-regulatory hormone for vitamin D. Evidence has also emerged to support the existence of a bone-kidney axis to coordinate the mineralization of bone with renal handling of phosphate. Pathologically, high circulating levels of FGF23 result in hypophosphatemia, decreased production of 1,25(OH)(2)D, elevated parathyroid hormone and rickets/osteomalacia in patients with functioning kidneys, whereas low levels are associated with tumoral calcinosis, hyperphosphatemia and elevated 1,25(OH)(2)D. In addition, patients with chronic kidney disease (CKD) exhibit marked elevations of circulating FGF23. While the significance of increased FGF23 levels in CKD remains to be defined, it might contribute to phosphate excretion and suppression of 1,25(OH)(2)D levels in CKD stages 3 and 4, as well as potentially contribute to secondary hyperparathyroidism through direct actions on the parathyroid gland in more advanced renal failure. As our knowledge expands regarding the regulation and functions of FGF23, the assessment of FGF23 will become an important diagnostic marker as well as a therapeutic target for management of disordered mineral metabolism in a variety of acquired and hereditary disorders.     

Fibroblast growth factor-23 is regulated by 1alpha,25-dihydroxyvitamin D.

Serum FGF-23 regulation was studied in patients with hypoparathyroidism or pseudohypoparathyroidism treated with calcitriol. Serum FGF-23 levels changed in parallel in response to changes in serum 1,25-D, suggesting that FGF-23 may be regulated by 1,25-D. In addition, the phosphaturic effect of FGF-23 may be diminished in the absence of PTH action on the kidney. INTRODUCTION: Fibroblast growth factor (FGF)-23 is a recently described hormone that has been shown to be involved in the regulation of phosphate and vitamin D metabolism. The physiologic role of FGF-23 in mineral metabolism and how serum FGF-23 levels are regulated have yet to be elucidated. Three patients with mineral metabolism defects that allowed for the investigation of the regulation of FGF-23 were studied. MATERIALS AND METHODS: Patient 1 had postsurgical hypoparathyroidism and Munchausen's syndrome and consumed a pharmacologic dose of calcitriol. Patient 2 had postsurgical hypoparathyroidism and fibrous dysplasia of bone. She was treated with increasing doses of calcitriol followed by synthetic PTH(1-34). Patient 3 had pseudohypoparathyroidism type 1B and tertiary hyperparathyroidism. She underwent parathyroidectomy, which was followed by the development of hungry bone syndrome and hypocalcemia, requiring treatment with calcitriol. Serum FGF-23 and serum and urine levels of mineral metabolites were measured in all three patients. RESULTS: Patient 1 had an acute and marked increase in serum FGF-23 (70 to 670 RU/ml; normal range, 18-108 RU/ml) within 24 h in response to high-dose calcitriol administration. Patient 2 showed stepwise increases in serum FGF-23 from 117 to 824 RU/ml in response to increasing serum levels of 1alpha,25-dihydroxyvitamin D (1,25-D). Finally, before parathyroidectomy, while hypercalcemic, euphosphatemic, with low levels of 1,25-D (10 pg/ml; normal range, 22-67 pg/ml), and with very high serum PTH (863.7 pg/ml; normal range, 6.0-40.0 pg/ml), patient 3 had high serum FGF-23 levels (217 RU/ml). After surgery, while hypocalcemic, euphosphatemic, and with high serum levels of serum 1,25-D (140 pg/ml), FGF-23 levels were higher than preoperative levels (305 RU/ml). It seemed that the phosphaturic effect of FGF-23 was diminished in the absence of PTH or a PTH effect. CONCLUSIONS: Serum FGF-23 may be regulated by serum 1,25-D, and its phosphaturic effect may be less in the absence of PTH.     

Altered divalent ion metabolism in early renal failure: role of 1,25(OH)2D

The present study evaluates the role of 1,25(OH)2D in the pathogenesis of abnormal mineral metabolism in patients with early renal failure (ERF). This was accomplished by examining the calcemic response to PTH and the handling of an oral phosphate load both before and after 6 weeks of therapy with 1,25(OH)2D. Twelve patients with ERF and six normal volunteers were studied. Patients with ERF as compared with normal subjects have low serum phosphate, low urinary calcium, low serum 1,25(OH)2D, and high plasma PTH and urinary cyclic AMP (cAMP). With EDTA infusion, an impaired calcemic response to PTH is observed in patients with ERF. The phosphate load test shows that these patients have an increased ability to excrete phosphate. After 1,25(OH)2D therapy a significant increase in serum phosphate, urinary calcium, and a decrease in urinary cAMP is observed only in ERF patients. In addition, the impaired calcemic response to PTH improves significantly, the renal handling of phosphate becomes normal, and the low baseline level of 1,25(OH)2D increases to normal. A significant correlation between levels of 1,25(OH)2D and creatinine clearance is observed in both patients and normals. In summary, the present data suggest that a mild deficiency of 1,25(OH)2D is present in ERF patients. The pathophysiological consequence of such a deficiency in patients with ERF may be important.     

慢性肾脏病患者血清FGF-23及Klotho水平与肾功能进展的关系

目的 观察慢性肾脏病(CKD)患者血清FGF-23及Klotho水平与肾功能进展的关系.方法 选取本院门诊30例健康体检者(对照组)及90例CKD1～5期的患者(CKD组),其中CKD组根据肾功能下降情况分为肾功能恶化组及肾功能稳定组;采用EHSA法测定血清FGF-23及Klotho水平,分析FGF-23及Klotho水平变化与肾功能进展的关系.结果 CKD组血清FGF-23明显高于对照组,血清Klotho明显低于对照组,且随着肾功能进展,这种变化越明显;肾功能恶化组FGF-23明显高于肾功能稳定组,而血清Klotho明显低于肾功能稳定组;相关分析显示,FGF-23与Klotho之间呈负相关.结论 CKD患者血清FGF-23水平明显升高,血清KLotho明显降低,与肾功能进展有关,可作为CKD患者肾功能恶化及不良预后的指标.     

Effects of oral phosphorus supplementation on mineral metabolism of renal transplant recipients

Background. Persistent hyperparathyroidism (HPT) is frequently observed in kidney transplant recipients. Hypophosphataemia is a common biochemical consequence of HPT. Theoretically, oral phosphorus administration may induce negative effects on the control of HPT, though this point has never been demonstrated in kidney-transplant recipients. This study was designed to evaluate the effects of oral phosphorus supplementation on the mineral metabolism of successful kidney transplant recipients. Methods. Thirty-two kidney transplant recipients with serum creatinine <2 mg/dl and serum phosphate levels <3.5 mg/dl were included in the study. After a wash-out period in which oral phosphorus supplementation was discontinued, the following parameters were determined (F0 period): serum calcium, phosphate, alkaline phosphatase, uric acid, bicarbonate, PTH, 1,25-dihydroxyvitamin D3 (1,25(OH)2D) and 25-hydroxyvitamin D3 (250HD). Creatinine clearance, calcium, and phosphate excretion were determined from a 24-h urine sample. The same determinations were repeated (F1 period) after all patients received 1.5 g of oral phosphorus for 15 days. For data analysis, patients were divided into two subgroups (optimal and suboptimal) according to allograft function (Ccr>or<70 ml/min/1.73 m²). Results. In the F0 period, only nine of 32 patients had PTH levels within the normal range (<65 pg/ml). The mean concentrations of PTH, 1,25(OH)2D and 25OHD were 132±97 pg/ml, 40.5+16 pg/ml and 12.5±8.2 ng/ml respectively. Phosphorus supplementation led to significant reductions in serum calcium and 1,25(OH)2D concentrations, as well as in urinary calcium excretion in the whole group. On the contrary, serum phosphate, PTH, and urinary phosphate excretion increased significantly. The percentage increase in PTH concentrations after phosphorus supplementation were similar in patients with optimal and suboptimal allograft function (33 vs 36%). The reduction of 1,25(OH)2D concentrations after phosphorus supplementation was observed mainly in the subgroup with optimal allograft function (21% reduction with respect to baseline values), while the mean 1,25(OH)2D concentrations in patients with suboptimal allograft function scarcely changed (1.4% increase). Changes in 1,25(OH)2D concentrations after phosphorus supplementation, expressed as a percentage of the initial concentrations, correlated positively with the percentage changes in PTH concentrations for the whole group, as well as for each subgroup. The best determinants for the percentage and the absolute increase in PTH concentration after phosphorus supplementation was the final serum phosphate concentration (F=4.84, r=0.37, P=0.035) and the increase in serum phosphate (F=7.69, r=0.45, P=0.009) respectively. Conclusions. Oral phosphorus supplementation led to a significant increase in the PTH concentration of kidney transplant recipients. The mean 1,25(OH)2D concentration decreased mainly in recipients with optimal allograft function. The counterbalance effect of PTH on 1,25(OH)2D production may account for the relative preservation of 1,25(OH)2D levels in recipients with suboptimal allograft function.     

Vitamin D insufficiency and hyperparathyroidism in children with chronic kidney disease

Chronic kidney disease (CKD) is associated with altered calcium-phosphate homeostasis and hyperparathyroidism due to decreased activity of 1alpha-hydroxylase and impaired activation of 25-hydroxyvitamin D3 [25(OH)D3]. In some patients these problems start earlier because of vitamin D deficiency. A retrospective review of patients followed in the chronic renal insufficiency clinic at Children's Hospital of Michigan assessed the prevalence of vitamin D deficiency in CKD stages 2-4 and evaluated the effect of treatment with ergocalciferol on serum parathormone (PTH). Blood levels of 1,25 dihydroxyvitamin D3, 25(OH)D3, and parathormone (PTH) were examined in 57 children (40 boys; mean age 10.6 years). Of 57 subjects, 44 (77.2%) had 25(OH)D3 levels 30 ng/ml was 67.84 +/- 29.09 ng/ml and in the remaining patients was elevated, at 120.36 +/- 86.42 ng/ml (p = 0.05). Following ergocalciferol treatment (22), PTH decreased from 122.13 +/- 82.94 ng/ml to 80.14 +/- 59.24 ng/ml (p < 0.001) over a period of 3 months. We conclude that vitamin D deficiency is common in children with CKD stages 2-4 and is associated with hyperparathyroidism in the presence of normal 1,25 dihydroxyvitamin D3. Its occurrence before significant renal impairment is noteworthy. Early diagnosis and appropriate treatment is emphasized.     

Elevated fibroblast growth factor 23 levels as a cause of early post-renal transplantation hypophosphatemia

Background

Hypophosphatemia is a common complication after renal transplantation. Hyperparathyroidism has long been thought to be the cause, but hypophosphatemia can persist after high parathyroid hormone (PTH) levels normalize. Furthermore, calcitriol levels remain inappropriately low after transplantation, suggesting that mechanisms other than PTH contribute. Fibroblast growth factor 23 (FGF-23) induces phosphaturia, inhibits calcitriol synthesis, and accumulates in chronic kidney disease. We performed prospective study to investigate if FGF-23 early after renal transplantation contributes to hypophosphatemia.

Methods

We measured FGF-23 levels before and at 1, 2, 4, and 12 weeks after transplantation in 20 renal transplant recipients. Serum creatinine, calcium (Ca), phosphate (Pi), intact PTH (PTH), and 1,25-dihydroxy vitamin D (1,25(OH)₂VitD) were measured at the same time.

Results

FGF-23 levels decreased by 97% at 4 weeks after renal transplantation (PRT) (7,471 ± 11,746 vs 225 ± 295 pg/mL; P < .05) but were still above normal. PTH and Pi levels also decreased significantly after renal transplantation, and Ca and 1,25(OH)₂VitD slightly increased. PRT hypophosphatemia of <2.5 mg/dL developed in 15 (75%) and 12 (60%) patients at 4 weeks and 12 weeks respectively. Compared with nonhypophosphatemic patients, the levels of FGF-23 of hypophosphatemic patients were higher (303 ± 311 vs 10 ± 6.9 pg/mL; P = .02) at 4 weeks PRT. FGF-23 levels were inversely correlated with Pi (r² = 0.406; P = .011); PTH was not independently associated with Pi (r² = 0.132; P = .151).

Conclusions

FGF-23 levels decrease dramatically after renal transplantation. During the early PRT period, Pi rapidly decreased, suggesting that FGF-23 is cleared by the kidney, but residual FGF-23 may contribute to the PRT hypophosphatemia. FGF-23, but not PTH levels, was independently associated with PRT hypophosphatemia.     

Fibroblast growth factor 23: associations with cardiovascular disease and mortality in chronic kidney disease

Fibroblast growth factor-23 (FGF-23) has emerged as an important hormone involved in phosphorus and vitamin D homeostasis. Chronic kidney disease (CKD) is the most common clinical condition in which FGF-23 levels are persistently and markedly elevated. Abnormal phosphate homeostasis and high circulating levels of FGF-23 are early complications of CKD. Although increases in FGF-23 levels may help maintain serum phosphate levels in the normal range in CKD, the long-term effects of its sustained elevated levels are unclear. Patients with CKD have high risks of developing end-stage renal disease (ESRD), cardiovascular disease, and premature death. Recent prospective studies in populations with predialysis CKD, ESRD on hemodialysis, and kidney transplant recipients demonstrate that elevated FGF-23 levels are independently associated with cardiovascular events and mortality. It was originally thought that FGF-23 was only a biomarker of disturbed phosphate balance; however, recent studies have shown that FGF-23 can have a direct effect on the heart, inducing left ventricular hypertrophy. This suggests that elevated FGF-23 levels may be a novel mechanism that explains the poor cardiovascular outcomes in CKD patients. Interventional studies are required in order to clarify the relation of causality between FGF-23 and cardiovascular mortality in this population.