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Introduction: QTc interval prolongation is increasingly frequent as chronic kidney disease (CKD) advances and predicts death in dialysis. However, predictors and mortality risk in predialysis CKD are understudied. FGF23 induces left ventricular hypertrophy (LVH) which is associated with QTc interval prolongation and death, suggesting a possible pathway from FGF23 to death that entails LVH and QTc prolongation. We looked for links between FGF23 and prolonged QTc intervals mediated by LVH and for deaths associated with QTc prolongation in a prospective observational cohort of patients with predialysis CKD., Methods: Participants underwent protocolized baseline and semiannual FGF23 testing, baseline and study end echocardiograms, and baseline and annual electrocardiograms over 3 years., Results: A total of 2,254 participants (34.1% female; mean age: 68.7 years; mean glomerular filtration: rate 41.4 mL/min/m2) enrolled in the study. Baseline LVH (left ventricular mass index >131 g/m2 [>100 g/m2 if female]) was present in 10.8% and prolonged QTc intervals (≥500 ms) in 1.5% of participants. One hundred thirty-eight (6.1%) participants died during the study. In generalized mixed-effects regression, each unit increase in the natural log of FGF23 - but not LVH - predicted an odds ratio of 1.76 (1.15, 2.70, p = 0.009) for prolonged QTc intervals independently of 15 other covariates. Mediation analysis showed that only 13% of FGF23's total effect on prolonged QTc intervals was mediated by LVH. Patients with prolonged QTc intervals had higher unadjusted (log rank p < 0.001) and adjusted (hazard ratio: 2.06 [1.08, 3.92, p = 0.028]) mortality rates than those with QTc intervals <500 ms., Discussion: QTc interval prolongation ≥500 ms was prospectively associated with FGF23 independently of LVH and with increased mortality risk in patients with predialysis CKD., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Pediatric obesity and diabetes has increased over the last several decades. While the role of common adipokines on metabolic parameters has been well studied in adults, the relationship of novel adipokines and hepatokines in pediatric type 1 (T1D) and type 2 diabetes (T2D) is not well understood. This study assessed novel adipokines C1q/TNF-related proteins (CTRP1 and CTRP9), and hepatokine fibroblast growth factor 21 (FGF21) in youth with T1D and T2D diabetes., Methods: Participants (n = 80) with T1D (n = 40) enrolled in the Pediatric Diabetes Consortium (PDC) T1D NeOn registry, and T2D (n = 40) from the PDC T2D registry. Cross-sectional analysis compared adipokines (CTRP1, CTRP9, FGF21) between T1D and T2D, and regression models assessed adipokine relationship with clinical characteristics., Results: The mean age of the participants was 14.9 ± 2 years, and 50% were female. T2D participants had a shorter diabetes duration (p = 0.0009), higher weight (p < 0.0001), and BMI (p < 0.0001) than T1D participants. CTRP9 levels were higher in T1D (13,903.6 vs. 3,608.5 pg/mL, p = 0.04) than T2D, and FGF21 levels were higher in T2D (113.1 vs. 70.6 pg/mL, p = 0.03) than T1D, with no differences in CTRP1. In regression analysis of T1D, CTRP9 was positively associated with C-peptide (p = 0.006), and FGF21 was positively associated with hemoglobin A1c (p = 0.04). In T2D, CTRP1 was positively associated with HbA1c (p < 0.001) and glucose (p = 0.004), even after controlling for age, sex, and BMI., Conclusions: CTRP9 levels are higher in youth with T1D compared to T2D, and FGF21 levels are higher in youth with T2D than T1D. Novel adipokines are related to metabolic homeostasis in the inflammatory milieu of pediatric diabetes., (© 2022 S. Karger AG, Basel.)

Background: Fibroblast growth factor 23 (FGF-23) and α-Klotho protein appear to have an important role in the pathogenesis of CKD-mineral and bone disorders. The aim of this study was to investigate the association of FGF-23 and α-Klotho levels with adverse clinical outcomes in patients with non-dialysis CKD., Materials and Methods: We conducted a prospective cohort study, enrolling participants with non-dialysis CKD from a single center in Greece. At enrollment, glomerular filtration rate (GFR) was measured (mGFR) and plasma levels of carboxyl terminal FGF-23 (cFGF-23) and soluble α-Klotho (sKlotho) were determined by enzyme-linked immunoassay. Participants were followed for up to 5 years or until the occurrence of the primary endpoint of initiation of renal replacement therapy or death. Multivariate regression tree analysis was used to identify informative baseline parameters in order to categorize participants. Also, using median values of cFGF-23 and sKlotho, participants were categorized into 4 groups, in whom survival was compared using Kaplan-Meier and Cox regression analysis., Results: 128 participants were enrolled with a median mGFR of 41.5 mL/min/1.73 m2 (IQR = 28.2). Baseline mGFR correlated with cFGF-23 and sKlotho (r = -0.54 and r = 0.49, respectively; p < 0.0001 for both). cFGF-23 and sKlotho levels correlated negatively (r = -0.24, p = 0.006). Multivariate regression tree analysis resulted in 3 groups defined by cutoff values of mGFR (60.9 mL/min/1.73 m2) and phosphate (3.7 mg/dL). These groups correlated with CKD stage, cFGF-23, and sKlotho (p < 0.0001 for all). During a median follow-up of 36 months (IQR = 22), 40 (31.2%) participants reached the primary endpoint (31 initiated renal replacement therapy, 9 died). Survival to primary endpoint differed among the 4 groups formed using median values of both biomarkers, with the low FGF-23/high Klotho and high FGF-23/low Klotho having the longest and shortest survival, respectively. High FGF-23/low Klotho group, compared to the opposite one, had a significantly elevated risk of the primary outcome (HR, 6.8; 95% CI, 2.3-19.6; p = 0.0004)., Conclusions: In patients with CKD stages 1-5, the combination of higher cFGF-23 and lower sKlotho levels along with mGFR and serum phosphate was associated with adverse clinical outcomes. The utility of combinations of traditional and novel biomarkers to predict outcomes warrants further study., (© 2020 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Control of hyperphosphatemia in patients on dialysis remains a major challenge., Objective: This study evaluated predictors of serum phosphorus (sP) control among dialysis patients treated with noncalcium, oral phosphate binder therapy in a phase 3 clinical trial., Methods: Post hoc analyses were performed using data for patients with hyperphosphatemia who received 52 weeks of treatment with sucroferric oxyhydroxide (SFOH) or sevelamer carbonate (sevelamer). Patients were categorized into those who achieved sP control (n = 302; defined as sP ≤ 5.5 mg/dL at week 52), and those with uncontrolled sP (n = 195; sP >5.5 mg/dL at week 52). Because SFOH and sevelamer have previously demonstrated similar effects on chronic kidney disease-mineral-bone disorder parameters in this study, the treatment groups were pooled., Results: Average age at baseline was higher among sP-controlled versus sP-uncontrolled patients (56.9 vs. 53.4 years; p = 0.005). Baseline sP levels were significantly lower among sP-controlled versus sP-uncontrolled patients (7.30 vs. 7.85 mg/dL; p < 0.001), and sP reductions from baseline were significantly greater in the sP-controlled group (-2.89 vs. -0.99 mg/dL at week 52; p < 0.001). Logistic regression analysis identified higher baseline sP levels (odds ratio [OR] = 0.86, 95% confidence interval [CI]: 0.765-0.960), no concomitant active vitamin D therapy use (OR = 0.51, 95% CI: 0.328-0.804), and higher body mass index at baseline (OR = 0.96, 95% CI: 0.937-0.992) as significant predictors of uncontrolled sP., Conclusion: This analysis indicates that sP control may be more challenging in younger patients with high sP levels. Closer monitoring and management of serum phosphorus levels may be required in this population., (The Author(s). Published by S. Karger AG, Basel.)

Background: Chronic kidney disease (CKD) is the result of a reduced number of nephrons, in which adipose tissue and its metabolites play a significant role. Fibroblast growth factors, FGF19 and FGF21, are involved in lipid and carbohydrate metabolism. The aim of the study was to examine the concentrations of FGF19 and FGF21 in patients with CKD, as well as the correlation between FGF19 and FGF21 and selected biochemical parameters., Materials and Methods: The study included 178 subjects: 52 patients with CKD in stages 2-4, without haemodialysis (CKD), 47 haemodialysed patients with CKD (HD), 56 patients with CKD after a renal transplantation (Tx) and 23 healthy subjects as the control group (C)., Results: The highest FGF19 serum concentrations were observed in CKD patients and the lowest were observed in the Tx group. Patients in the CKD group had significantly higher serum FGF21 concentrations. There were negative correlations between FGF19 and glomerular filtration rate (GFR), as well as high-density lipoprotein cholesterol levels in patients after kidney transplantation. Negative correlations were also found between serum FGF21 concentrations and GFR in patients after Tx, while positive correlations were observed between FGF21 concentrations and lean body mass in the CKD group, body mass index and total cholesterol in the HD group., Conclusions: Our results suggest that increased concentrations of FGF19 and FGF21 in patients with CKD may be associated with the metabolism of lipids and carbohydrates. Our results also indicate that haemodialysis and transplantation results in the reduction of FGF19 and FGF21 concentrations in patients with CKD., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background: In the majority of patients with advanced chronic kidney disease (CKD), values of parathyroid hormone (PTH1-84) and fibroblast growth factor 23 (FGF-23) exceed the normal reference range, potentially as an appropriate adaptation to reduced glomerular filtration rate (GFR). We tested whether GFR-specific cutoffs for PTH1-84 and FGF-23 could better identify patients with inappropriately high PTH1-84 and FGF-23 for their degree of CKD and thereby improve prognostication of clinical outcomes compared to a uniform threshold., Methods: Prospective pan-Canadian cohort of 1,812 patients with mean estimated GFR (eGFR) 28.9 mL/min/1.73 m2 followed for a median of 52 months. Repeated log-rank tests were used to identify optimal cutoffs for PTH1-84 and FGF-23 within eGFR strata (<20, 20-29 and ≥30 mL/min/1.73 m2) that maximally differentiated high- and low-risk populations for (1) cardiovascular (CV) events (fatal or nonfatal myocardial infarction, coronary revascularization, stroke, heart failure) and (2) renal events (initiation of chronic renal replacement therapy). In multivariable models, we examined the association between -GFR-specific cutoffs and outcomes and compared their added prognostic value to existing uniform thresholds., Results: Risk-based cutoffs for PTH1-84 and FGF-23 increased in a graded fashion with decreasing eGFR. Among patients with eGFR <20 mL/min/1.73 m2, CV risk-based cutoffs for PTH1-84 and FGF-23 were 3.4 and 5.5 times the upper limit of normal, respectively, and reclassified 31.9 and 35.1% of patients when added to a multivariable base model for CV events. In contrast, the addition of PTH1-84 and FGF-23 to the base model using uniform cutoffs failed to reclassify such patients. Similar findings were demonstrated for renal outcomes., Conclusion: GFR-specific risk-based cutoffs for PTH1-84 and FGF-23 may facilitate more meaningful risk stratification in advanced CKD than current GFR-agnostic reference ranges derived from healthy adults. This may be most applicable in those with severely reduced GFR., (© 2019 S. Karger AG, Basel.)

Introduction: Arterial calcification (AC) is a common complication in chronic kidney disease (CKD) patients that starts to develop before these patients need renal replacement therapy. In these patients, calcification can involve tunica intima or tunica media. This study has looked for the prevalence, severity, and distribution of arterial wall calcification in incident hemodialysis patients through intraoperative arterial biopsy obtained during creation of arteriovenous vascular access for hemodialysis., Methodology: One hundred and seventy-two stage 5 CKD adults (98 male and 74 female) were included. Beside histopathology of the obtained arterial samples, all these cases were tested for serum calcium (Ca), phosphorus (P), alkaline phosphatase, uric acid, parathormone (PTH), fibroblast growth factor 23 (FGF23), and 25 hydroxy vitamin D., Results: Eighty six (50%) of the cases had AC (group I); 29 (17%) as intimal (subgroup Ii), 36 (21%) as medial (subgroup Im), while 21 (12%) had both intimal and medial calcification (subgroup Iim). Eighty-six patients (50%) were devoid of calcification (group II). Apart from the significantly higher serum level of PTH in group I, statistical analysis failed to disclose significant difference in any of the other studied parameters between the 2 groups. On the other hand, there were significant differences in serum P, Ca × P product, serum PTH, and FGF23 between patients according to intensity of calcification., Conclusion: Half of incident hemodialysis CKD patients have developed AC mainly in tunica media. Discrepancy in serum P can have an impact on calcification intensity., (© 2019 S. Karger AG, Basel.)

Introduction and Objective: Fibroblast growth factor (FGF-23) and matrix extracellular phosphoglycoprotein (MEPE) are bone-related factors and their role in physiologic conditions and in different life stages are unknown. We aimed to evaluate age- and pregnancy-related changes in MEPE and FGF-23 levels and their correlations with calcium (Ca)-phosphate (PO4) metabolism., Methods: The study population included 96 healthy children (50 females) and 31 women (11 healthy, 10 pregnant, and 10 lactating). Intact FGF-23 (iFGF-23), MEPE, ferritin, parathyroid hormone (PTH), 25-OH vitamin D, alkaline phosphatase (ALP), IGF-I, IGFBP-3 and, Ca, PO4 and creatine (Cre) in serum (S) and urine (U) samples were determined. The renal phosphate threshold (TmPO4/GFR) and z-scores for the parameters that show age-related changes were calculated., Results: Serum iFGF-23 concentrations showed nonsignificant changes with age; however, MEPE decreased with age, reaching the lowest levels after 7 years. Additionally, higher serum MEPE concentrations were observed during pregnancy. Other than ALP, all other examined parameters demonstrated age-related changes. ALP, BUN, S-Cre, and U-Ca/Cre showed puerperal and pregnancy related changes together with MEPE. iFGF-23 was positively correlated with S-PO4 and TmPO4/GFR. MEPE was positively correlated with S-Ca, S-PO4 and TmPO4/GFR and negatively correlated with PTH, IGF-1, and IGFBP-3., Conclusion: Not iFGF-23 but MEPE showed age-dependent changes and was affected by pregnancy. Although, MEPE and iFGF-23 did not correlate with each other, they seem to affect serum and urinary phosphate in the same direction. Additionally, we found evidence that ferritin and growth factors might have a role in serum calcium and phosphate regulation., (© 2020 S. Karger AG, Basel.)

Background: Hyperphosphatemia is a major accelerator of complications in chronic kidney disease and dialysis, and phosphate (Pi) binders have been shown to regulate extracellular Pi levels. Research on hyperphosphatemia in mouse models is scarce, and few models display hyperphosphatemia induced by glomerular injury, despite its relevance to human glomerular disease conditions. In this study, we investigated the involvement of hyperphosphatemia in kidney disease progression using a mouse model in which hyperphosphatemia is induced by focal segmental glomerulosclerosis (FSGS)., Methods: We established the NEP25 mouse model in which FSGS-hyperphosphatemia is induced by podocyte injury and evaluated the effect of a Pi binder, sevelamer., Results: After disease induction, we confirmed a gradual increase in serum Pi accompanied by reduced renal function and observed increases in serum FGF23 and PTH. Treatment with sevelamer significantly reduced serum Pi and urinary Pi fractional excretion and suppressed increases in serum FGF23 and PTH. A high dose improved serum creatinine and tubular injury markers, and pathological analysis confirmed amelioration of glomerular and tubular damage. Gene expression and marker analysis suggested protective effects on tubular epithelial cells in the diseased kidney. Compared to disease control, NEP25 mice treated with sevelamer retained their mRNA expression of Klotho, a known FGF23 co-receptor and renoprotective factor., Conclusions: Hyperphosphatemia caused by renal function decline was observed in a FSGS-induced NEP25 mouse model. Studies using this model showed that Pi regulation had a positive impact on kidney disease progression, and notably on tubular epithelial cell injury, which indicates the importance of Pi regulation in the treatment of kidney disease progression., (© 2019 S. Karger AG, Basel.)

Background: Various epidemiological studies linked high fibroblast growth factor 23 (FGF23) levels with cardiovascular events in chronic kidney disease (CKD). It remains enigmatic whether high FGF23 exerts adverse cardiovascular effects, or whether it reflects detrimental effects of residual confounders. Earlier studies adjusted for CKD-mineral bone disease (CKD-MBD) regulators of FGF23 rather than for recently discovered non-CKD-MBD regulators, among which iron deficiency and heart failure are of particular importance. Moreover, they used c-terminal FGF23 (cFGF23) assays rather than more specific intact FGF23 (iFGF23) assays., Methods: The CARE FOR HOMe study analyzed plasma ferritin, iFGF23, cFGF23 and N-terminal proBNP (NT-proBNP) along with conventional risk factors, among 575 CKD G2-G4 patients to determine the interaction between FGF23, its non-CKD-MBD regulators, and incident cardiovascular events in CKD patients. The participants were followed up for 5.1 ± 2.1 years for the occurrence of atherosclerotic events and hospitalization for acute decompensated heart failure., Results: cFGF23 correlated strongly with high iFGF23 (r = 0.607), fairly with high NT-proBNP (r = 0.453) and weakly with low ferritin (r = -0.207); correlation coefficients of iFGF23 with NT-proBNP and ferritin were numerically lower. In Kaplan-Meier analyses, both endpoints were predicted by cFGF23 and iFGF23. In Cox regression models, cFGF23 remained an outcome predictor after adjustment for conventional risk factors and ferritin. This prediction was largely eliminated when further adjusting for NT-proBNP. iFGF23 was less consistently associated with adverse outcome in partly adjusted models, and failed to predict outcome in fully adjusted models., Conclusion: In summary, iron deficiency and heart failure affect plasma FGF23. As adjustment for NT-proBNP virtually eliminates the association between plasma FGF23 and predefined outcome, we speculate that high FGF23, rather than exerting detrimental cardiovascular effects, mirrors prevalent heart disease., (© 2019 S. Karger AG, Basel.)

Background: Long-term patterns of fibroblast growth factor 23 (FGF23) are poorly characterized among dialysis patients., Objectives: To identify different FGF23 trajectories and determine clinical factors that predict distinct FGF23 trajectories and whether FGF23 trajectories differ in regard to their associations with all-cause mortality among prevalent hemodialysis patients., Methods: The HEMO study was a randomized multicenter study evaluating the effects of high-dose vs. standard-dose and high-flux vs. low-flux hemodialysis on mortality. We measured intact FGF23 levels in stored serum samples at baseline and annually among 919 HEMO participants and identified FGF23 trajectories using group-based modeling. Logistic regression determined predictors of trajectories. Cox regression models evaluated the association between trajectory and all-cause mortality., Results: We identified 5 distinct FGF23 trajectory groups during the initial 24 months: low stable, low increasing, elevated increasing, elevated decreasing, and elevated stable. In multivariable models, diabetes, high dose dialysis, no venous catheter, low serum calcium, phosphorus, and interleukin-6, no vitamin D analog use, and greater residual kidney function were associated with the low stable trajectory group compared to the elevated stable group. High flux dialysis, no venous catheter, and low serum phosphorus and 25-hydroxyvitamin D were associated with the elevated decreasing trajectory group compared to the elevated stable group. After full adjustment, the low stable trajectory group was associated with reduced mortality (hazard ratio [HR] 0.61; 95% CI -0.41-0.91) compared to the elevated stable trajectory group., Conclusions: We identified 5 distinct FGF23 trajectories over 24 months among HEMO study participants including a decreasing trajectory. The low stable FGF23 trajectory was associated with a reduced HR of all-cause mortality., (© 2019 S. Karger AG, Basel.)

Background: Serum phosphate and vitamin D receptor activator regulate fibroblast growth factor 23 (FGF23), and iron may modulate FGF23 metabolism. The aim of the present study was to elucidate the effects of ferric citrate hydrate and lanthanum carbohydrate on serum FGF23 levels in hemodialysis patients., Methods: This prospective, open-label, multicenter study enrolled 60 patients on hemodialysis treated with lanthanum carbonate. Patients were randomly assigned to 2 groups: those switching from lanthanum carbonate to ferric citrate hydrate (ferric citrate group, n = 30) or those continuing lanthanum carbonate (control group, n = 30). Patients were monitored for 24 weeks. Endpoints included changes in FGF23, phosphate, and the dose of erythropoiesis stimulating agent (ESA), erythropoietin responsiveness index (ERI), and adverse events., Results: FGF-23 levels were significantly lower in the ferric citrate group compared with the levels in the control group (change from baseline -6,160 vs. -1,118 pg/mL; p = 0.026). There were no significant changes in serum calcium, phosphate, and intact parathyroid hormone levels in either group. The ferric citrate group had significantly increased serum iron, ferritin, and transferrin saturation. Hemoglobin levels were significantly elevated, and the dose of ESA was significantly decreased in the ferric citrate group but not in the control group. ERI and the dose of intravenous saccharated ferric oxide were significantly lower in the ferric citrate group compared with those of the control group (p = 0.015 and p = 0.002)., Conclusion: In patients on hemodialysis, 24-week treatment with ferric citrate hydrate resulted in significant reduction in FGF23 and ERI independently of serum phosphate level., (© 2018 S. Karger AG, Basel.)

Background: The serum phosphorus concentration ([P]s) is the sum of EP/Ccr and TRP/Ccr, where Ccr is creatinine clearance and EP and TRP are rates of excretion and reabsorption of phosphate. In chronic kidney disease (CKD), parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) mediate reduction of TRP/Ccr, and [PTH] and [FGF23] are linear functions of EP/Ccr. If controls and patients with CKD are considered together, TRP/Ccr is a hyperbolic function of EP/Ccr. Given these observations, we hypothesized that hyperbolas would describe relationships of phosphate reabsorption to [PTH] and [FGF23]., Methods: We studied 30 patients and 28 controls with mean eGFR of 29.5 and 86.0 mL/min/1.73 m2, respectively. All analyses combined both subsets. We measured fasting [PTH] 1-84 and intact [FGF23], and determined contemporaneous EP/Ccr, TRP/Ccr, fractional excretion of phosphorus (FEP), and phosphate tubular maximum per volume of filtrate (TmP/GFR). We examined linear regressions of TRP/Ccr and TmP/GFR on 100/[PTH] and 100/[FGF23]; from linear equations we derived hyperbolic equations relating reabsorptive parameters to hormone concentrations., Results: TRP/Ccr and TmP/GFR were linear functions of 100/[PTH] and 100/[FGF23] and hyperbolic functions of [PTH] and [FGF23]. TRP/Ccr and TmP/GFR fell minimally over the ranges of EP/Ccr, [PTH], and [FGF23] seen in CKD. FEP rose with EP/Ccr despite stable phosphate reabsorption., Conclusions: Hyperbolas describe relationships of TRP/Ccr and TmP/GFR to [PTH] and [FGF23] if subjects with normal and reduced GFR are analyzed together. Although FEP rises with [PTH] and [FGF23] as GFR falls, the simultaneous increments do not signify hormonally mediated reductions in phosphate reabsorption., (Published by S. Karger AG, Basel.)

Fibroblast growth factor 23 (FGF23) is a regulator of phosphate and vitamin D homeostasis that carries out primary bone- and mineral-related physiological functions to increase renal phosphate excretion and reduce 1α-hydroxylation of 25-hydroxyvitamin D. In a negative endocrine feedback loop, 1,25-dihydroxyvitamin D also stimulates FGF23 secretion. Previous studies have assessed the correlation between vitamin D receptor activator therapy and FGF23 concentrations, and to our knowledge, none has assessed the correlation between intravenous (i.v.) maxacalcitol therapy and FGF23 concentration in hemodialysis patients. Subjects included 148 patients on maintenance hemodialysis. Serum FGF23 concentrations were measured. The correlations among serum FGF23 concentrations with i.v. maxacalcitol therapy and other clinical parameters and medications were analyzed. Mean serum log FGF23 was 3.7 ± 0.8 pg/mL. After division into two equal groups based on median serum log FGF23 level, the percentages of patients administered i.v. maxacalcitol (60/74 [81.1%] vs. 45/74 [60.8%], p < 0.01) were significantly higher in the high log FGF23 group. The amounts of serum FGF23 concentrations had been significantly higher to the amounts of i.v. maxacalcitol per week dependency. Multivariate regression analysis showed that treatment with i.v. maxacalcitol was an independent predictor of serum FGF23 levels, regardless of phosphate or calcium concentrations. i.v. maxacalcitol correlates with serum FGF23 concentration in hemodialysis patients, independent of serum phosphate or calcium concentrations., (© 2018 S. Karger AG, Basel.)

Background: The use of L-carnitine has been proposed in haemodialysis (HD) when deficiency is present to improve anaemia resistant to erythropoietin stimulating agent, intradialytic hypotension or cardiac failure. We tested the effects of L-carnitine supplementation on parameters of chronic kidney disease-mineral bone disorder., Methods: CARNIDIAL was a randomized, double-blinded trial having included 92 incident HD subjects for a 1-year period to receive L-carnitine versus placebo. Determinant factors of C-terminal fibroblast growth factor 23 (cFGF23) and intact FGF23 were studied including Klotho level. The L-carnitine effect on mineral metabolism was analyzed between groups by mixed linear models for repeated measurements., Results: Klotho was below the lower limit of quantification (LLOQ) in 55% of the 163 samples. In multivariate analysis, cFGF23 was positively correlated with calcium and phosphate and was higher in subjects having Klotho > LLOQ. No correlation existed between Klotho and phosphate and phosphate was even higher in subjects having Klotho > LLOQ (p < 0.001). Both forms of FGF23 were not related to iron markers nor to IV iron dose. No L-carnitine effect was detected on parathyroid hormone (PTH) or FGF23 during the study period where PTH slightly decreased over time, whereas FGF23 increased. But calcium and phosphate increased more in the L-carnitine group., Conclusion: L-carnitine supplementation increased calcium and phosphate plasma concentrations with no detected downregulation effect on PTH and FGF23. (Clinical Trial 00322322, May 5, 2006)., (© 2018 S. Karger AG, Basel.)

Background: Patients with chronic kidney disease (CKD) show elevated levels of inflammatory markers and have an increased risk of infections as well as cardiovascular morbidity. Recent studies have implied effects of fibroblast growth factor 23 (FGF23) on inflammation in CKD. We analyzed potential correlations between levels of FGF23 with pro-inflammatory chemokines and markers of leukocyte transmigration in CKD patients., Methods: One hundred three patients with CKD 2-5ND and 54 healthy controls, had biochemical markers in blood and urine analyzed according to routine protocol. Pro-inflammatory cytokines were analyzed by Milliplex technique and leukocyte CD11b adhesion molecule expression was measured by flow cytometry. FGF23 levels were measured with ELISA technique. Treatment of leukocytes from healthy blood donors with FGF23 was performed in vitro and effects analyzed by flow cytometry., Results: Tumor necrosis factor-alpha, RANTES and interleukin (IL)-12 levels were significantly higher (p = 0.001, p < 0.001, and p < 0.001) in patients with CKD. Elevated FGF23 levels in the CKD group correlated to glomerular filtration rate, parathyroid hormone, urinary albumin excretion and phosphate as well as to IL-12 and RANTES. CD11b expression on resting granulocytes and monocytes, and on activated monocytes, was associated with FGF23. In vitro treatment of leukocytes with FGF23 reduced CD11b expression in resting as well as in formyl-methyinoyl-leucyl-phenylalanine-stimulated granulocytes (p = 0.03)., Conclusion: FGF23 levels are associated with various inflammatory markers such as pro-inflammatory cytokines and adhesion molecules on innate immune cells. However, further studies are warranted to define the direct role of FGF23 in modulation of the innate immune system in CKD., (© 2018 S. Karger AG, Basel.)

Background: Fibroblast growth factor 23 (FGF-23) is a hormone that regulates phosphorus levels and vitamin D metabolism. Previous studies have shown FGF-23 to be a risk factor for incident end-stage renal disease; however, there are less data on the association of FGF-23 with earlier kidney-related outcomes., Methods: Serum FGF-23 was assayed using an intact ELISA assay in 2,496 participants of the Healthy Aging and Body Composition Study, a cohort of well-functioning older adults. Kidney function was estimated by assaying cystatin C at baseline and years 3 and 10. The associations between FGF-23 and decline in kidney function (defined by estimated glomerular filtration rate (eGFR) decline ≥30% or ≥3 mL/min/year) and incident chronic kidney disease (CKD; incident eGFR <60 mL/min/1.73 m2 and ≥1 mL/min/year decline) were evaluated. Models were adjusted for demographics, baseline eGFR, urine albumin/creatinine ratio, comorbidity, and serum calcium, phosphorus, 25(OH) vitamin D and parathyroid hormone., Results: The mean (SD) age was 75 (3) years, with 52% female and 38% black. There were 405 persons with 30% decline, 702 with >3 mL/min/year decline, and 536 with incident CKD. In fully adjusted continuous models, doubling of FGF-23 concentrations was not associated with kidney function decline (OR [95% CI] = 0.98 [0.82-1.19] for ≥30% decline and OR 1.17 [95% CI 1.00-1.37] for ≥3 mL/min/year decline), or incident CKD (incident rate ratio [IRR] 1.05 [95% CI 0.91-1.22]). In adjusted quartile analysis, the highest quartile of FGF-23 was significantly associated with incident CKD (IRR 1.27 [95% CI 1.02-1.58] for highest vs. lowest quartile)., Conclusion: Higher FGF-23 concentrations were not consistently associated with decline in kidney function or incident CKD in community-dwelling older adults., (© 2018 S. Karger AG, Basel.)

Background: After parathyroidectomy (PTX), hungry bone syndrome leads to hypocalcemia due to bone remineralization. The aim of this pilot study was to analyze changes in markers of bone metabolism in patients with secondary hyperparathyroidism (sHPT) after PTX and to correlate these markers with bone pain measured with a validated questionnaire., Materials and Methods: All patients who underwent PTX for sHPT between March 2010 and February 2012 at out institution were included in this prospective observational pilot study. At the day before surgery and on the 3rd day thereafter, levels of parathyroid hormone (PTH), calcium, osteocalcin, alkaline phosphatase (AP), bone-specific AP (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), osteoprotegerin (OPG), sclerostin, fibroblast growth factor 23, and Klotho were measured. Additionally, all patients were requested to answer the Brief Pain Inventory preoperatively and on the 5th postoperative day., Results: A total of 35 patients with a mean age of 49.8 years were analyzed. A significant difference between the pre- and postoperative values could be detected in PTH, calcium, BAP, TRAP5b, and sclerostin. The highest correlation of laboratory markers with bone pain was found for preoperative PTH (r = 0.3), postoperative OPG (r = 0.4), postoperative BAP (r = -0.4), and postoperative Klotho (r = -0.4)., Conclusions: The present study revealed significant perioperative changes in PTH, BAP, sclerostin, and TRAP5b after PTX. These markers may serve as laboratory markers to monitor bone metabolism in patients with sHPT. PTH, OPG, and sclerostin were the parameters with the closest correlation to bone pain. However, larger prospective trials with a longer follow-up are required to confirm these results., (© 2018 S. Karger AG, Basel.)

Background/aims: In patients with autosomal dominant polycystic kidney disease (ADPKD), cardiovascular events are the most frequent cause of mortality and morbidity. The aim of our study is to investigate the association between serum fibroblast growth factor-23 (FGF-23) and arterial stiffness (AS) as determined with brachial-ankle pulse wave velocity (baPWV) and atherosclerosis development as determined with carotid artery intima-media thickness (CA- IMT)., Methods: This cross-sectional study was conducted with totally 86 ADPKD patients, 50 (58.1%) female and 36 (41.9%) male, with a mean age of 49.5 ± 13.9 years. Patients were compared with healthy control group with similar distribution of age and gender. AS was assessed with baPWW, and atherosclerosis development was assessed with CA-IMT. CA-IMT > 9 mm was considered as increased atherosclerosis. Serum FGF-23 and soluble klotho (s-KL) levels were measured with enzyme-linked immunosorbent assay. Due to skewed distribution of variables, statistical calculations of FGF-23 and s-KL were performed with log10., Results: According to the CKD stages, 46 (53.5%) patients had stage 1-2, 32 (37.2%) had stage 3-4, and 8 (9.3%) had predialysis stage 5 disease. Mean log10FGF-23 was 2.43 ± 0.41 pg/mL, and mean log10s-KL was 1.28 ± 0.09 ng/mL. Mean baPWV was 7.48 ± 1.68 m/sec, and mean CA-IMT was 0.63 ± 0.14 mm. Among patients at various stages of CKD, systolic blood pressure (SBP) (p = 0.003), diastolic blood pressure (DBP) (p = 0.002), creatinine, 1.25hydroxy(OH)2VitaminD3, log10FGF-23, baPWV, CA-IMT were higher (p < 0.001)andlog10s-KL were lower (p < 0.001) in comparison to healthy individuals. FGF-23 was positively correlated with creatinine, 1.25(OH)2VitD3 (p < 0.001), baPWV (p = 0.002) and CA-IMT (p = 0.005), and negatively correlated with eGFR (p < 0.001)., Conclusion: In patients with ADPKD, as the disease stage advanced, serum FGF-23 levels increased while s-KL decreased. In ADPKD patients, AS and atherosclerosis development increased as compared to healthy subjects, and as CKD advanced. In ADPKD patients, the effect of serum FGF-23 on the development of AS and atherosclerosis in peripheral vessels is independent of s-KL., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Background/aims: Both iron deficiency and chronic inflammation are highly prevalent in patients with chronic kidney disease (CKD). The effect of intravenous iron infusion on mineral metabolism in CKD may be modified by inflammation. Intravenous iron theraphy may reduce peripheral degradation, secretion, clearence of iFGF23 and lead to hypophosphatemia. The aim of the study was to evaluate the effect of intravenous iron on mineral metabolism in CKD patients., Methods: 35 non-dialysis patients with CKD stages 3-5. received 100 mg/24h of ferric oxide saccharated solution for 5 days. Serum calcium (Ca), phosphorus (P), parathormone (PTH), intact-FGF23 (iFGF23), C-terminal-FGF23 (cFGF23), bone alkaline phosphatase (BAP) and high-sensitive CRP were assessed on day 1 and 3 at baseline and 2 hours after each dose administration and once on day 6. Plasma iFGF23 and cFGF23, as well as serum BAP were measured with ELISA and other parameters with standard automated laboratory methods., Results: Serum iFGF23 increased after iv iron on day 1 and 6 (from 268.9±446.5 to 326.3±529.9 on day 1; p=0.05 and to 451.4±601 pg/mL on day 6; p=0.03). cFGF23 was reduced only on day 1 (from 654.3±441.3 to 473.6±414 RU/mL; p=0.016). P concentration decreased significantly two hours after the first iron infusion (from 1.69±0.5 to 1.54±0.35 mmol/l; p=0.003). In following days the changes of cFGF23, P and of other calcium-phosphate metabolism were not significant. Serum CRP correlated neither with iFGF-23 nor cFGF-23., Conclusion: Intravenous iron supplementation may only transiently affect the production and degradation of FGF23 resulting in hypophosphatemia at the commencement of iron therapy. Chronic low-grade inflammation does not seem to play a role in that mechanism., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Objectives: To investigate whether serum fibroblast growth factor 21 (FGF21) levels can be used to predict the future development of major adverse cardiovascular events (MACEs)., Methods: This study included 253 patients who received subsequent follow-up, and complete data were collected for 234 patients. Independent predictors of MACEs were identified by using the Cox proportional-hazards regression analysis. The prognostic value of FGF21 levels for MACEs was evaluated by Kaplan-Meier survival analysis., Results: Of 229 patients finally enrolled in the analysis, 27/60 without coronary artery disease (CAD) at baseline experienced a MACE, and 132/169 patients with CAD at baseline experienced a MACE. Among patients with CAD at baseline, serum FGF21 levels were significantly higher in patients with MACEs (p < 0.05) than in patients without MACEs. Kaplan-Meier survival analysis showed patients with a higher serum FGF21 had a significantly lower event-free survival (p = 0.001) than those with a lower level. Further Cox proportional-hazards regression analysis, including the traditional risk factors for cardiovascular disease, showed that serum FGF21 was an independent predictor of MACE occurrence., Conclusions: In patients with CAD at baseline, an elevated serum FGF21 level was associated with the development of a MACE in the future., (© 2018 S. Karger AG, Basel.)

Background/aims: Aortic arch calcification (AoAC) is frequently detected in maintenance hemodialysis (MHD) patients and is associated with cardiovascular and all-cause mortality. We investigated the factors associated with AoAC and analyzed the relationship between the factors including bone-derived biomarkers and AoAC., Methods: We enrolled 389 stable MHD patients. AoAC was assessed using chest-X ray examination. Demographic data was collected in addition to serum levels of biochemical and bone-derived biomarkers, including sclerostin and fibroblast growth factor-23 (FGF-23)., Results: Two hundred sixteen patients (55.5%) had AoAC. Patients with AoAC score ≥ 4 were older, with a higher percentage being male, and exhibited lower serum levels of albumin and triglyceride. Serum FGF-23 levels were inversely associated with AoAC severity, and FGF-23was directly related to vascular calcification. Age, gender, and dialysis vintage were independent predictors of AoAC., Conclusion: MHD patients have a high prevalence of AoAC. The grade of AoAC was dependent on older age in association with longer dialysis vintage. Levels of circulating FGF-23 but not sclerostin were related to AoAC severity. Serum FGF-23 levels were independently associated with AoAC., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Objective: This study investigated the effects of sucroferric oxyhydroxide on fibroblast growth factor (FGF)-23 and dose reduction of erythropoiesis-stimulating agents (ESA) and intravenous saccharated ferric oxide in hemodialysis patients., Methods: In this prospective, open-label, parallel-group, multicenter trial involving patients receiving lanthanum carbonate hydrate, eligible patients were randomized to a sucroferric oxyhydroxide group or a control group. Hemoglobin, serum phosphate, FGF-23, iron, and ferritin levels, as well as transferrin saturation, doses of intravenous saccharated ferric oxide and ESA administered, and the erythropoietin responsiveness index (ERI) were monitored for 24 weeks., Results: Sixty-eight eligible patients were allocated to receive sucroferric oxyhydroxide (n = 34) or serve as controls (n = 34). Data for 31 patients in the sucroferric oxyhydroxide group and 32 in the control group were analyzed. Serum phosphate was equally well controlled in both groups. In the sucroferric oxyhydroxide group, intact FGF-23 levels decreased significantly from baseline at the end of the study (p = 0.01) and there was a significant difference compared with the control group (p = 0.035). Required doses of ESA and ERI were significantly reduced in the sucroferric oxyhydroxide group decreased significantly. The dose of intravenous saccharated ferric oxide required in the sucroferric oxyhydroxide group was significantly lower than that at baseline (p = 0.006) and in the control group (p = 0.003)., Conclusions: Treatment of hyperphosphatemia with sucroferric oxyhydroxide was effective in patients on hemodialysis, resulting in decreased serum FGF-23 levels and a reduction in the required dose of saccharated ferric oxide., (© 2018 S. Karger AG, Basel.)

Aims: In children with chronic kidney disease (CKD), fetuin-A and fibroblast growth factor-23 (FGF-23) have been implicated in the mechanism and progression of several cardiac changes. This study aimed to determine the types and rates of cardiac changes in children with CKD and their association with fetuin-A, FGF-23, and other cardiovascular risk factors (CVRFs)., Methods: This comparative cross-sectional study recruited 88 children (5-18 years): 27 CKD I with a glomerular filtration rate (GFR) >90 mL/min/1.73 m2 and 61 with a GFR of <90 mL/min/1.73 m2 (29 CKD II-IV, 32 CKD V-dialysis). Each patient had a short demographic and clinical history taken along with a physical examination. Blood was taken and sent for routine tests and for fetuin-A and FGF-23 assay. All patients had an echocardiogram to evaluate cardiac structure and function., Results: The distribution of left atrial diameter (LAD) and left ventricular (LV) mass differed significantly (p < 0.05) across the different CKD groups. Abnormal LAD was seen in 10% of patients; LV hypertrophy (LVH) in 27%; LV systolic dysfunction in 6% and diastolic dysfunction in 1 patient. Fetuin-A was the only independent predictor for abnormal LAD; mean arterial pressure was independently associated with concentric LVH, and age and hypoalbuminemia with eccentric LVH. Overall, the dialysis group had the highest rate of cardiac changes and associated risk factors., Conclusion: Though not common, the importance of left atrial changes in children with CKD is highlighted along with the need to address modifiable CVRFs such as hypertension and hypoalbuminemia., (© 2017 S. Karger AG, Basel.)

Background: Quantitative dose-response associations between fibroblast growth factor 23 (FGF23) and risks of mortality, cardiovascular disease (CVD), and renal events in chronic kidney disease (CKD) are not known. This study aimed to summarize and quantify the predictive effects of FGF23 among the pre-dialysis CKD stages 1-5 population., Methods: Data sources included PubMed, EMBASE, and Web of Science. Prospective cohort studies assessing the associations between FGF23 and all-cause mortality, CVD, and renal events in CKD patients were selected. Summary risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. The composite higher or the highest level in FGF23 categories of each study was considered the high level. The reference level was regarded as the low level in the overall analysis. The restricted cubic spline model was used to estimate dose-response associations., Results: Fifteen prospective cohort studies centered around 15,355 subjects were analyzed. A high FGF23 level was associated with increased risks of all-cause mortality (RR 1.46, 95% CI 1.38-1.55, p < 0.001), CVD (RR 1.37, 95% CI 1.15-1.63, p < 0.001), and renal events (RR 1.31, 95% CI 1.07-1.59, p = 0.008), respectively. There was a positive, nonlinear, dose-response relationship between FGF23 and all-cause mortality. The reference level in dose-response analysis was defined as 51 RU/mL of c-terminal FGF23. We then calculated RRs for increments of 20 RU/mL, which was associated with increased risks of mortality (RR 1.04, 95% CI 1.00-1.07, p = 0.038), CVD (RR 1.02, p < 0.001), and renal events (RR 1.01, p < 0.001), respectively., Conclusions: There may be positive dose-response predictive effects of FGF23 on all-cause mortality, CVD, and renal events in patients with CKD., (© 2017 S. Karger AG, Basel.)

Background/aims: The release of fibroblast growth factor FGF23, a powerful regulator of 1,25(OH)2D3 formation and mineral metabolism, is stimulated by store-operated Ca2+ entry (SOCE), which is accomplished by the pore forming Ca2+ release activated channel protein Orai1. Regulators of Orai1 and thus FGF23 release include serum & glucocorticoid inducible kinase SGK1, a kinase up-regulated by glucocorticosteroids. Some effects of glucocorticoids require the presence of annexin A7, such as suppression of prostaglandin E2 in gastric glands. The present study thus explored whether annexin A7 impacts on FGF23 plasma levels., Methods: Comparisons were made between gene targeted mice lacking functional annexin A7 (Anx7-/-) and their wild type littermates (Anx7+/+). Serum C-terminal-FGF23, intact FGF23, 1,25(OH)2D3 and PTH concentrations were measured by ELISA or EIA. The serum and urinary phosphate concentrations were measured by colorimetry, the serum Ca2+ concentration and the urinary Ca2+ concentration by flame photometry., Results: Serum C-terminal FGF23 levels and corticosterone levels were significantly higher and serum 1,25(OH)2 D3 and PTH levels were significantly lower in Anx7-/- than in Anx7+/+ mice. Water intake was slightly but significantly higher in Anx7-/- mice than in Anx7+/+ mice. No significant difference was observed between Anx7-/- and Anx7+/+ mice in urinary fluid excretion, plasma Ca2+ concentration, plasma phosphate concentration and urinary Ca2+ output. The urinary phosphate output was significantly lower in Anx7-/- mice than in Anx7+/+ mice., Conclusion: Annexin A7 deficiency upregulates FGF23 plasma levels, an effect paralleled by increased corticosterone plasma levels, as well as decreased 1,25(OH)2 D3 and PTH plasma levels., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Background: The role of fibroblast growth factor 23 (FGF23) in the regulation of mineral homeostasis in early life is inadequately understood. We aimed to explore the effects of vitamin D supplementation on serum FGF23 and to elucidate longitudinal changes in FGF23, in addition to studying its association with mineral metabolism in early infancy., Methods: Altogether 113 healthy infants received vitamin D3 10, 30 or 40 µg/day from age 0.5 to 3.0 months. Cord blood at birth and capillary blood samples at 3 months were analyzed for serum 25-hydroxyvitamin D, parathyroid hormone, phosphate, calcium and intact and C-terminal FGF23., Results: In repeated-measures ANCOVA, intact FGF23 concentration increased with time (p < 0.001) and C-terminal FGF23 decreased (p < 0.001). At 3 months, girls had a higher concentration of intact FGF23 (51 vs. 26 pg/ml, p < 0.001) and a greater increase over time (x0394;FGF23 intact 45 vs. 16 pg/ml, p = 0.001) than boys. Vitamin D did not affect serum intact or C-terminal FGF23 concentrations. Girls showed a positive correlation between phosphate and intact FGF23 (p = 0.004), whereas in boys phosphate and C-terminal FGF23 correlated inversely (p = 0.006)., Conclusions: A substantial sex-related difference in intact FGF23 concentration exists during early infancy, possibly related to differences in skeletal growth between boys and girls., (© 2016 S. Karger AG, Basel.)

Background: Increased levels of phosphate and fibroblast growth factor-23 (FGF23) are strong predictors of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Preliminary data suggest that interventions lowering gastro-intestinal phosphate uptake lowers serum FGF23 concentrations and improves cardiovascular risk and subsequently survival. However, data are lacking about the magnitude of effects, the effect in different stages of CKD and whether there is a dose-effect relationship., Methods: Therefore, the Sevelamer on FGF23 Trial (SoFT) is designed as an open-label, single-arm, clinical pilot study aiming to demonstrate the feasibility of a phosphate-restricted diet in combination with the phosphate binder sevelamer to induce an effective, predictable and sustained decrease in FGF23 level in patients with an estimated glomerular filtration rate (eGFR) of 15-90 or >90 ml/min/1.73 m2 with proteinuria >1.0 g in 24 h urine collection, despite optimally dosed RAAS blockade, without inducing hypophosphatemia using a forced uptitration treatment regimen aimed at restricting phosphate uptake., (© 2016 S. Karger AG, Basel.)

Background/aims: Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23., Methods: Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks., Results: ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events., Conclusion: Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD., (© 2016 S. Karger AG, Basel.)

Background: Bone disorders are next to cardiovascular problems in frequency in renal transplant (RT) recipients. Reduction in 1,25-dihydroxycholecalciferol (1,25D) levels is among the reasons causing bone loss in these patients. Klotho (KL) serves as a co-receptor for fibroblast growth factor 23 (FGF23), and functions in vitamin D metabolism. KL polymorphisms have been identified in several studies, and phenylalanine to valine substitution at amino acid position 352 seemed to be important to KL function. We investigated KL F352V polymorphism and its relation with 1,25D levels in RT recipients., Methods: The study included 25 RT recipients (8 female, 17 male) and 26 (14 female, 12 male) healthy control subjects who were wild (FF) phenotypes in terms of KL F352V polymorphism. RT recipients with (FV, n = 11) and without (FF, n = 14) a heterozygote polymorphism were determined with high resolution DNA melting analysis of KL F352V polymorphism. Serum 1,25D levels were measured using the RIA method., Results: RT recipients with FV phenotype had significantly lower 1,25D levels (17.58 ± 18.38 pg/ml) compared to recipients with FF phenotype (44.91 ± 24.68 pg/ml) and control subjects (28.24 ± 12.13 pg/ml). 1,25D levels in RT recipients with FF phenotype were significantly higher than control subjects., Conclusions: KL F352V polymorphism may increase the expression of FGF23 co-receptor, KL protein and thus may decrease renal expression of 1α-hydroxylase, and/or stimulate 24-hydroxylase in RT recipients. The resultant decrease 1,25D levels may participate in bone loss in these patients.

Background: Abnormalities in mineral homeostasis are ubiquitous in patients on dialysis, and influenced by race. In this study, we determine the race-specific relationship between mineral parameters and mortality in patients initiating hemodialysis., Methods: We measured the levels of fibroblast growth factor 23 (FGF23) and 25-hydroxyvitamin D (25 D) in 184 African American and 327 non-African American hemodialysis patients who enrolled between 1995 and 1998 in the Choices for Healthy Outcomes in Caring for ESRD Study. Serum calcium, phosphorus, parathyroid hormone (PTH) and total alkaline phosphatase levels were averaged from clinical measurements during the first 4.5 months of dialysis. We evaluated the associated prospective risk of mortality using multivariable Cox proportional hazards models stratified by race., Results: PTH and total alkaline phosphatase levels were higher, whereas calcium, phosphorus, FGF23 and 25 D levels were lower in African Americans compared to those of non-African Americans. Higher serum phosphorus and FGF23 levels were associated with greater mortality risk overall; however, phosphorus was only associated with risk among African Americans (HR 5.38, 95% CI 2.14-13.55 for quartile 4 vs. 1), but not among non-African Americans (p-interaction = 0.04). FGF23 was associated with mortality in both groups, but more strongly in African Americans (HR 3.91, 95% CI 1.74-8.82 for quartiles 4 vs. 1; p-interaction = 0.09). Serum calcium, PTH, and 25 D levels were not consistently associated with mortality. The lowest and highest quartiles of total alkaline phosphatase were associated with higher mortality risk, but this did not differ by race (p-interaction = 0.97)., Conclusions: Aberrant phosphorus homeostasis, reflected by higher phosphorus and FGF23, may be a risk factor for mortality in patients initiating hemodialysis, particularly among African Americans., (© 2015 S. Karger AG, Basel.)

FGF23 and Klotho synergize to regulate phosphate homeostasis by promoting renal phosphate excretion. Chronic kidney disease (CKD) may be viewed as a state of FGF23 resistance caused by Klotho deficiency. This viewpoint explains several observations on phosphate metabolism in CKD that lack mechanistic insights. Our objectives were to correlate serum klotho and FGF-23 with other variables that regulate phosphate metabolism. We studied 40 patients with CKD on conservative treatment (group A), 44 patients with end-stage renal disease (ESRD) on regular hemodialysis (group B), 40 kidney transplant recipients (KTR) (group C) and 40 healthy controls for measuring serum klotho and FGF-23. Blood samples were withdrawn for measuring the levels of serum Calcium (Ca), Phosphorus (P), alkaline phosphatase (ALP), 1,25 (OH)2 D3, intact parathyroid hormone (PTH), FGF-23 and α klotho. The mean levels of FGF-23 and α klotho in control group were 225.78 ± 111.05 pg/ml (range: 102.4, 418.5) and 6.78 ± 1.90 ng/ml (range: 4, 11), respectively. The mean levels of FGF-23 in the 3 studied groups were 1,034.2 ± 84.6, 1,288.7 ± 131.4 and 1,008.7 ± 117.6 pg/ml, respectively. The median levels of s-klotho in the 3 studied groups were 3.15, 2.3 and 2.95, respectively. It was found that FGF-23 was significantly increased and α klotho was significantly decreased in all patients when compared with those in the control group (p < 0.001, <0.001, respectively). We found that there was a significant inverse correlation between serum Ca and α klotho in the studied groups. There was no significant correlation between FGF-23 and α klotho in the studied groups (p > 0.05). We have shown that circulating s-klotho was not related to FGF-23 in CKD, dialysis and KTR patients. In addition, we demonstrated a novel association between serum Ca and s-klotho that needs to be further studied., (© 2015 S. Karger AG, Basel.)

Background/aim: Dietary phosphate intake and vitamin D receptor activator (VDRA) regulate fibroblast growth factor 23 (FGF23); iron may modulate FGF23 metabolism. We aimed to determine whether oral iron supplementation influences serum FGF23 concentration in hemodialysis (HD) patients, while excluding the effect of dietary phosphate intake., Methods: This prospective study enrolled 27 maintenance HD patients with iron deficiency and hyperphosphatemia treated with sevelamer-HCl. The phosphate binder was changed from sevelamer-HCl to ferric citrate hydrate (FCH) to maintain constant phosphate levels. VDRA, other phosphate binders, and cinacalcet HCl were not changed. Serum intact FGF23, C-terminal FGF23 (C-term FGF23), intact parathyroid hormone (PTH), 1,25(OH)2D and other parameters were monitored for 12 weeks., Results: Serum phosphate levels (5.89 ± 1.45 mg/dl at baseline, 5.54 ± 1.35 mg/dl at 12 weeks) and 1,25(OH)2D levels were unchanged. Serum ferritin levels increased from 25.6 ± 24.3 ng/ml at baseline to 55.8 ± 33.5 ng/ml at 12 weeks with FCH administration. Serum intact FGF23 and C-term FGF23 levels significantly decreased at 12 weeks compared with baseline (2,000 (1,300.0-3,471.4) to 1,771.4 (1,142.9-2,342.9) pg/ml, p = 0.01, and 1,608.7 (634.8-2,308.7) to 1,165.2 (626.1-1,547.8) RU/ml, p = 0.007, respectively); serum intact PTH levels significantly increased (96 (65-125) to 173 (114-283) pg/ml, p < 0.001)., Conclusions: Oral FCH administration decreased serum intact FGF23 and C-term FGF23 levels and increased intact PTH levels; phosphate and 1,25(OH)2D levels were unchanged. Oral FCH administration to treat iron deficiency is a possible strategy for reducing serum FGF23 levels independent of phosphate and VDRA., (© 2015 The Author(s) Published by S. Karger AG, Basel.)

The removal characteristics of on-line pre-dilution hemodiafiltration (HDF) were compared with those of hemodialysis using so-called 'super high-flux' or 'class V' dialyzers. A strong correlation between the reduction rate (RR) of α1-microglobulin (MG) and relief of clinical symptoms was found. The treatment conditions, including flow rates as well as selection of diafilter performance, were determined in consideration of the target symptoms to be removed and the target RR of α1-MG or, alternately, the albumin loss. An RR of β2-MG >80% corresponded to that of α1-MG being >35% in both modalities, and these numbers were more easily achieved by employing on-line pre-dilution HDF, rather than hemodialysis with super high-flux dialyzers. In some situations, however, albumin loss of 6 g or more may be admissible when a patient shows severe clinical symptoms, such as restless legs syndrome. HDF with a large amount of fluid exchange and a large amount of albumin loss is worth trying, as long as the albumin loss is controlled in a measured manner., (© 2015 S. Karger AG, Basel.)

Background: We previously reported that vascular calcification (VC) score was associated with mortality in patients on haemodialysis (HD) and that a high serum level of parathyroid hormone (PTH) and fibroblast growth factor (FGF)-23 were the only factors associated with VC progression., Aim: To assess the impact of VC progression on HD patient survival., Methods: The study cohort including 85 HD patients studied between 2006 and 2007 and between 2009 and 2010 was divided into patients with VC progression (PG+, n = 38) and no-progression (PG-, n = 47), based on VC scores measured twice at 3-year intervals (VC1 and VC2). Patients were followed during 3 additional years., Results: Kaplan-Meier analysis determined that PG+ displayed increased mortality (hazard ratio (HR): 2.4; 95% confidence interval (CI): 1.12-4.8; p = 0.03). This result was confirmed using a Cox proportional hazards model adjusted for age, dialysis duration, the VC1 score, and the mean FGF-23 and iPTH serum levels (HR: 2.7; 95% CI: 1.12-6.6; p = 0.02)., Conclusion: VC progression is associated with poor survival in patients on HD, irrespective of a patient's baseline VC score., (2015 S. Karger AG, Basel.)

In end-stage renal disease patients, various abnormalities of bone mineral metabolism adversely affect mortality. Hyperphosphatemia is known to adversely affect mortality and quality of life in chronic kidney disease patients and has been shown to be involved not only in the onset and progression of secondary hyperparathyroidism but also in vascular calcification. Thus, hyperphosphatemia is the main treatment target indicated in several guidelines for chronic kidney disease-mineral and bone disorder treatment. Phosphate binders are typically required for the management of hyperphosphatemia because dietary phosphorus restriction and phosphorus removal by hemodialysis alone are insufficient. We are able to prescribe five phosphate binders (calcium carbonate, sevelamer HCl, lanthanum carbonate (LaC), bixalomer, and ferric citrate) to Japanese hemodialysis patients. LaC is the most powerful noncalcium-containing phosphate binder for the treatment of hyperphosphatemia. In this chapter, we discuss the efficacy and safety of LaC, the safety of which has been under debate. In particular, we consider its toxic effects on the skeletal system. LaC is effective for hyperphosphatemia treatment in end-stage renal failure patients. It has been shown to be able to decrease serum fibroblast growth factor-23 levels. This result suggests that it may have beneficial effects on the cardiovascular system in patients undergoing renal replacement therapy. However, the effects of LaC remain obscure. Further investigations are required. No negative effects of LaC on bone metabolism or bone morphometry have been reported, but long-term clinical data are needed., (© 2015 S. Karger AG, Basel.)

Background: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in disorders of serum phosphorus concentration and vitamin D. The role of FGF23 in vascular calcification remains controversial., Methods: Relationships between FGF23 and coronary artery calcified atherosclerotic plaque (CAC), aortoiliac calcified plaque (CP), carotid artery CP, volumetric bone mineral density (vBMD), albuminuria, and estimated glomerular filtration rate (eGFR) were determined in 545 African Americans with type 2 diabetes (T2D) and preserved kidney function in African American-Diabetes Heart Study participants. Generalized linear models were fitted to test associations between FGF23 and cardiovascular, bone, and renal phenotypes, and change in measurements over time, adjusting for age, gender, African ancestry proportion, body mass index, diabetes duration, hemoglobin A1c, blood pressure, renin-angiotensin-system inhibitors, statins, calcium supplements, serum calcium, and serum phosphate., Results: The sample was 56.7% female with a mean (SD) age of 55.6 (9.6) years, diabetes duration of 10.3 (8.2) years, eGFR 90.9 (22.1) ml/min/1.73 m2, urine albumin:creatinine ratio (UACR) 151 (588) (median 13) mg/g, plasma FGF23 161 (157) RU/ml, and CAC 637 (1,179) mg. In fully adjusted models, FGF23 was negatively associated with eGFR (p < 0.0001) and positively associated with UACR (p < 0.0001) and CAC (p = 0.0006), but not with carotid CP or aortic CP. Baseline FGF23 concentration did not associate with changes in vBMD or CAC after a mean of 5.1 years follow-up., Conclusions: Plasma FGF23 concentrations were independently associated with subclinical coronary artery disease, albuminuria, and kidney function in the understudied African American population with T2D. Findings support relationships between FGF23 and vascular calcification, but not between FGF23 and bone mineral density, in African Americans lacking advanced nephropathy., (© 2016 S. Karger AG, Basel.)

Background/aims: Vitamin D-deficient rickets (DR) has recently re-emerged among developed countries. Vitamin D deficiency can influence biochemical results of patients with fibroblast growth factor 23 (FGF23)-related hereditary hypophosphatemic rickets (HR), making differential diagnosis difficult. In the present study we evaluated the utility of serum FGF23 levels in the diagnosis of DR and during its treatment., Methods: The study group comprised 24 children with DR and 8 children with HR. Serum FGF23 levels and bone metabolism-related measurements were assessed., Results: Serum FGF23 levels in patients with DR were less than 19 pg/ml, while those in patients with HR were more than 57 pg/ml. There were significant differences in serum levels of calcium, phosphate, parathyroid hormone, and 1,25-dihydroxyvitamin D, as well as tubular maximum phosphate reabsorption per glomerular filtration rate between patients with DR and HR, but these values were not fully mutually exclusive. In addition, serum FGF23 and phosphate levels were increased following treatment., Conclusion: Serum FGF23 level is the most critical biochemical marker for distinguishing DR from HR and might be a good indicator of biochemical response to the intervention. Serum FGF23 levels show utility for the diagnosis of DR and in the assessment of its response to treatment.

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that regulates phosphate and 1,25-hydroxyvitamin D [1,25(OH)2D] metabolism. FGF23 binds to FGF receptor 1 with its coreceptor Klotho and maintains serum phosphate levels within the normal range by increasing renal phosphate excretion. In addition, FGF23 reduces the synthesis and accelerates the degradation of 1,25(OH)2D to reduce intestinal phosphate absorption. Moreover, FGF23 acts at the parathyroid gland to decrease parathyroid hormone synthesis and secretion. In chronic kidney disease (CKD), serum FGF23 levels rise exponentially as renal function declines long before a significant increase in serum phosphate concentration occurs. Although there is room for argument, FGF23 and Klotho are recently reported contributors to vascular calcification. Finally, prospective observational studies have shown that serum FGF23 concentrations predict mortality not only among dialysis patients but among predialysis CKD patients. In addition to being a coreceptor for FGF23, Klotho circulates as an endocrine substance and exerts a multitude of effects. This review describes recent advances in research on the FGF23-Klotho axis in CKD. © 2014 S. Karger AG, Basel.

Background: Fibroblast growth factor 21 (FGF21) is a hormone involved in the metabolism of carbohydrates and lipids. Increased circulating FGF21 levels are closely associated with nonalcoholic fatty liver disease (NAFLD). However, the association between genetic variations of FGF21 and NAFLD remains unknown. In our study, we aimed to investigate the association of these genetic variations with serum FGF21 levels and NAFLD., Methods: We genotyped four single nucleotide polymorphisms (SNPs) in FGF21 and its flanking region in 340 nondiabetic subjects. NAFLD was defined as the presence of a specific abdominal ultrasonographic pattern. Serum FGF21 concentrations were measured using an enzyme-linked immunosorbent assay kit., Results: We found significant evidence of an association with NAFLD for rs499765 (p = 0.039). After adjusting for age and sex, the effect of rs499765 on NAFLD remained significant (p = 0.045). However, after adjusting for multiple comparisons, no association was found. Moreover, rs499765 was associated with serum FGF21 levels (p = 0.030). In addition, both rs2071699 and rs838136 showed an association with serum aspartate aminotransferase levels (p = 0.049 and p = 0.047, respectively). The SNP rs838136 also showed a correlation with serum alanine aminotransferase concentrations after adjustment for body mass index (p = 0.034). We also combined the minor group with the heterozygous genotype and observed that rs499765 had an effect on FGF21 (p = 0.031)., Conclusion: The variant rs499765 adjacent to FGF21 is associated with serum FGF21 levels and NAFLD in a Chinese nondiabetic population., (© 2014 S. Karger AG, Basel.)

Background: Fibroblast growth factor 21 (FGF21) is a metabolic and growth regulator., Aim: To investigate the role of FGF21 during growth in infancy., Methods: Blood samples for FGF21, leptin, insulin and glucose were collected from cord blood obtained from 95 preterm and term newborns (cross-sectional group), and at 6 and 12 months of life in 80 preterm and term infants (longitudinal group). Length and weight were measured at birth, 6 months, and 12 months., Results: From birth through 12 months of age, preterm infants' linear growth and weight gain were larger than those of term infants, irrespective of birth weight SDS. At birth and at 12 months, there was no difference in FGF21 levels between preterm and term infants; in contrast, at 6 months, serum FGF21 in term infants was significantly higher than that of preterm ones. In the 0-6-month period, in the whole longitudinal group, serum FGF21 was inversely correlated to the length change SDS, and such a significant inverse correlation persisted in the preterm-AGA group in the 6-12-month period. In addition, term infants who experienced length catch-up in the first 6 months of life exhibited lower serum FGF21 levels at 6 months, and those with length catch-up growth between 6 and 12 months had a greater decrease of serum FGF21 level in the same time period., Conclusions: Our results indicate that FGF21 in infancy is inversely correlated with linear growth rate, thus suggesting that FGF21 is a negative regulator of human growth., (2014 S. Karger AG, Basel)

Background/aims: Progressive chronic kidney disease (CKD) is associated with worsening cardiovascular (CV) risk not explained by traditional risk factors. Left ventricular (LV) hypertrophy (LVH) is an important CV risk factor, but its progression has not been documented in early CKD. We explored whether progression of LVH in early CKD would occur despite stable kidney function., Methods: We conducted a post hoc analysis of a 12-month study of lanthanum carbonate in stage 3 CKD, which included longitudinal assessments of CV biomarkers. Primary outcome for the analysis was the change in LV mass (LVM) indexed to height in meters(2.7) (LVM/Ht(2.7)). Secondary outcomes were changes in blood pressure (BP), pulse-wave velocity, LV systolic/diastolic function, fibroblast growth factor 23 (FGF23), klotho, and estimated glomerular filtration rate (eGFR)., Results: Thirty-one of 38 original subjects had sufficient data for analysis. LVM/Ht(2.7) increased (47 ± 13 vs. 53 ± 13 g/m(2.7), p = 0.006) over 12 months despite stable BP, stable eGFR and normal LV systolic function. Vascular stiffness and LV diastolic dysfunction persisted throughout the study. Klotho levels decreased (748 ± 289 to 536 ± 410 pg/ml, p = 0.03) but were unrelated to changes in LVM/Ht(2.7). The change in FGF23/klotho ratio was strongly correlated with changes in LVM/Ht(2.7) (r2 = 0.582, p = 0.03)., Conclusion: Subjects with stage 3 CKD exhibited increasing LVM, persistent LV diastolic dysfunction and vascular stiffness despite stable kidney function, BP and LV systolic function. Abnormal FGF23 signaling due to reduced klotho expression may be associated with increasing LVM.

Background/aims: Ramipril attenuates renal Fibroblast growth factor-23 (FGF-23) expression, ameliorates proteinuria and normalizes serum phosphate in the diabetic Zucker rat with progressive renal disease suggesting that the renoprotective effect by this drug may be in part due to a FGF-23-lowering effect of angiotensin-converting enzyme (ACE) inhibition., Methods: In this nonrandomized study, we tested whether ACE-inhibition reduces circulating FGF-23 in type-2 diabetics with stage-1 chronic kidney disease (CKD) and proteinuria. Intact FGF-23, the eGFR, proteinuria and the endothelium-dependent flow-mediated (FMD) response to ischemia and other parameters were measured at baseline and after 12-weeks of treatment with ramipril (n = 68) or amlodipine (n = 32)., Results: Blood Pressure (BP) fell to a similar extent (p < 0.001) in the two groups. However, 24 h proteinuria and the FMD improved more (both p < 0.01) in ramipril-treated patients than in amlodipine-treated patients. Changes in proteinuria (r = 0.47) and in FMD (r = -0.49) by ramipril were closely associated (p < 0.001) with simultaneous changes in FGF-23 and this link was confirmed in multiple regression analyses. In these analyses, the relationship between FMD and proteinuria changes attained statistical significance (p < 0.01) only in a model excluding FGF-23 suggesting that endothelial dysfunction and FGF-23 share a common pathway conducive to renal damage., Conclusion: Findings in this study contribute to generate the hypothesis that FGF-23 may be implicated in proteinuria and in endothelial dysfunction in diabetic nephropathy (clinicaltrials.gov (NCT01738945)).

Background: Chronic Kidney Disease (CKD) is associated with alterations in phosphorus excretion, and increases in fibroblast growth factor (FGF23) and parathyroid hormone (PTH). Plant protein-based phytate-bound phosphorus, is less bioavailable than that from animal sources. Our one-week study that was conducted previously showed that a nearly 100% plant protein-based diet benefits mineral metabolism in CKD; however, this diet may not be acceptable to patients. Here we hypothesize that a diet containing 70% protein from plants has similar efficacy and is tolerated by CKD patients., Methods: Thirteen subjects with CKD 3-4 received an omnivorous diet containing 70% protein from plants for 4 weeks. The primary outcome was change in 24 h urine phosphorus. Secondary outcomes were changes in serum phosphorus, FGF23, PTH, urine sodium excretion, grip strength and fat free mass. Repeated measures analysis of variance (ANOVA) was used to test differences in parameters over the 4 weeks., Results: Mean age of subjects was 54.8 years. Median eGFR was 26 (IQR 14.7) ml/min/1.73 m(2). Over the 4-week period, urine phosphorus significantly decreased by 215 ± 232 mg/day (p < 0.001). No significant changes in serum FGF23, phosphorus or PTH were noted. Urine sodium and titratable acid decreased significantly on the diet. Hand grip strength and fat-free mass did not change. There were two hyperkalemia events both 5.8 mEq/l, corrected by food substitutions. No other adverse events were observed., Conclusions: A 70% plant protein diet is safe, tolerated, and efficacious in lowering urine phosphorus excretion and may be an alternative to phosphate binders., (© 2015 S. Karger AG, Basel.)

Background: Elevated fibroblast growth factor 23 (FGF23) levels are associated with progression of chronic kidney disease (CKD) and increased mortality. Studies in individuals without CKD suggest that FGF23 levels are regulated by dietary phosphorus; however, the effect of pharmacologic phosphorus restriction on FGF23 in CKD patients is uncertain., Methods: We performed a prospective cohort study examining the effect of phosphorus reduction with sevelamer carbonate on FGF23 levels in CKD patients. Adults with an estimated glomerular filtration rate <60 ml/min/1.73 m(2) according to MDRD (Modification of Diet in Renal Disease) and hyperphosphatemia were enrolled. Subjects were started on sevelamer carbonate 800 mg by mouth with meals and the dose was titrated to achieve a serum phosphorus between 2.7 and 4.6 mg/dl for those with CKD stages III and IV, and between 3.5 and 5.5 mg/dl for CKD stage V. FGF23 levels were measured at baseline and 3 months. Results were analyzed as percent change from baseline., Results: 40 patients completed the study. Mean estimated glomerular filtration rate by MDRD at entry was 21.2 ± 10.5, serum phosphorus 4.8 ± 0.8, and FGF23 level 602.3 ± 1,074.6. Mean serum phosphorus and FGF23 levels after 3 months were 4.4 ± 0.9 and 599.2 ± 720.9, respectively. No significant difference was seen in FGF23 (p = 0.76) despite a significant difference in phosphorus (p = 0.001)., Conclusion: The patients treated with sevelamer carbonate did not have a significant change in plasma FGF23 levels despite a significant reduction in phosphorus. It is possible that once overt hyperphosphatemia develops, FGF23 levels may not be reduced by phosphorus reduction alone in CKD patients., (Copyright © 2013 S. Karger AG, Basel.)

Background: The aim of the study was to assess the relationship between fibroblast growth factor-23 (FGF-23) and vascular calcifications (VC) in peritoneal dialysis (PD) patients., Methods: A cross-sectional study was performed in 55 PD patients who underwent pelvic X-ray to assess for VC. Patients with and without linear calcifications were recorded., Results: Fifteen patients (27.3%) had linear calcifications on pelvic X-ray. FGF-23 levels were higher in patients with VC (299.5 (30.4-2,410.0) vs. 74.4 (14.8-1,030) pg/ml, p < 0.01). Diabetic patients had lower FGF-23 values (43.2 (14.9-134.0) vs. 103.5 (14.8-2,410) pg/ml, p < 0.01). Patients with residual renal function (RRF) had lower FGF-23 levels (70.6 (14.8-513) vs. 179.5 (30.4-2,410) pg/ml, p = 0.06); however, this did not reach statistical significance. FGF-23 levels, age, creatinine, Ca, dialysis duration and HbA1c were positively correlated with VC, whereas RRF, Ca intake and ALP were negatively associated. Multivariate logistic analysis confirmed FGF-23 levels, age, dialysis duration and RRF to be associated with VC., Conclusions: FGF-23 levels are associated with VC in PD patients. Further studies are needed to clarify whether it is simply a marker or a potential factor. It may prove to be an important therapeutic target for VC management., (© 2013 S. Karger AG, Basel.)

Deregulated phosphate homeostasis can lead to a wide range of disorders, including myopathy, cardiac dysfunction, and skeletal abnormalities. Therefore, characterization of the molecular regulation of phosphate metabolism is of pathophysiological and clinical significance. Hyp mouse is the model for human X-linked hypophosphatemia which is due to mutations that inactivate the endopeptidases of the X chromosome (PHEX). PHEX inactivation leads to increased serum levels of fibroblast growth factor 23 (FGF23), a phosphaturic hormone that induces excessive renal phosphate excretion and severe hypophosphatemia. The expression of WNT signaling components is increased in Hyp mice. To determine the potential role of WNT signaling in FGF23-mediated hypophosphatemia, we cross-bred Hyp mice with mice deficient in the WNT coreceptor low-density lipoprotein receptor-related protein 6 (Lrp6) to generate Hyp and Lrp6 double mutant mice (Hyp/Lrp6). Like Hyp mice, Hyp/Lrp6 double mutants maintained high serum levels of FGF23, and accordingly exhibited hypophosphatemia to the same degree as the Hyp mice did, indicating that genetically reducing WNT signaling does not impact FGF23-induced phosphaturia. Moreover, similar to Hyp mice, the Hyp/Lrp6 double mutants also exhibited reduced mineralization of the bone, further supporting that reduced WNT signaling does not affect the chronic phosphate wasting caused by excess FGF23 in these mice. In further support of our finding, injection of bioactive FGF23 protein into Lrp6 mutant mice reduced serum phosphate levels to a similar degree as FGF23 injection into wild-type mice. Our in vivo studies provide genetic and pharmacological evidence for a WNT-independent function of FGF23 in the regulation of phosphate homeostasis., (Copyright © 2013 S. Karger AG, Basel.)

Living donor kidneys have been associated with better graft and overall survival in kidney transplant recipients. Although a living kidney donation is generally considered safe in carefully selected living donors, concerns of possible adverse effects related to kidney donation remain, especially in younger and high-risk donors. In this study, we examined the changes in a panel of traditional and novel serum biomarkers linked with cardiovascular conditions in a cohort of 34 healthy living kidney donors with a mean age ± SD of 40 ± 10 years and estimated predonation glomerular filtration rate (GFR) of 86 ± 10 ml/min/1.73 m(2). At 6 months after donation, there were no significant changes in the clinical parameters including body mass index and blood pressure despite a significant decline in the mean estimated GFR to 60 ml/min/1.73 m(2). Among the panel of markers, the levels of symmetric dimethylarginine and fibroblast growth factor 23 increased significantly compared to baseline, suggesting that living kidney donation may result in changes in biomarkers that are associated with cardiovascular risk in other cohorts., (Copyright © 2013 S. Karger AG, Basel.)