| Abstract|| |
Fibroblast growth factor 23 (FGF-23) is a recently discovered regulator of phosphate and mineral metabolism and has been associated with both progression of CKD and mortality in dialysis patients. To evaluate the association between serum FGF-23 levels and echocardiographic measurements in long-term HD (HD) patients without cardiac symptoms, we studied 90 consecutive patients treated in a single HD center (51 males, 39 females; mean age 41.5 ± 14.2 years, mean HD duration 71.2 ± 14.2 months). Comprehensive echocardiography was performed after HD and blood samples were obtained before HD. The serum FGF-23 level in dialysis patients was 95.7 ± 88.4 pg/mL. In univariate analysis, serum calcium levels (r = 0.33, P <0.05), serum creatinine (r = 0.34, P <0.05), serum albumin (r = 0.35, P <0.05) and left ventricular mass index (LVMI) (r = 0.33, P <0.001) were correlated weakly with the FGF-23 levels. Neither s. phosphorus nor calcium x phosphorus product correlated with FGF-23. In univariate regression analysis, only LVMI [β = 0.42, P <0.05, confidence interval (CI) 0.3-4.3], serum calcium (β= 0.87, P <0.001, CI 0.8-7.3), serum albumin (β= 0.87, P < 0.001, CI 0.8-7.3) and serum creatinine (β= 0.67, P <0.05, CI 0.5-6.5) significantly correlated with FGF-23. FGF-23 was identified as a factor that is weakly associated with LVMI. Thus, FGF-23 alone may not be a parameter that can be used for evaluation of the cardiac status in HD patients.
|How to cite this article:|
Sany D, Elsawy AE, Aziz A, Elshahawy Y, Ahmed H, Aref H, El Rahman MA. The value of serum FGF-23 as a cardiovascular marker in HD patients. Saudi J Kidney Dis Transpl 2014;25:44-52
|How to cite this URL:|
Sany D, Elsawy AE, Aziz A, Elshahawy Y, Ahmed H, Aref H, El Rahman MA. The value of serum FGF-23 as a cardiovascular marker in HD patients. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2020 Jul 9];25:44-52. Available from: http://www.sjkdt.org/text.asp?2014/25/1/44/124483
| Introduction|| |
Cardiovascular disease is common in end-stage renal disease (ESRD) patients.  The majority of deaths in dialysis patients are cardiovascular deaths, followed by infection and stroke. ,,, Left ventricular hypertrophy (LVH) is one of the most common cardiovascular disorders in dialysis patients. ,, In addition, LVH is an independent risk factor for cardiovascular death in patients who have received maintenance hemodialysis (HD). , The causes of LVH onset and progression in dialysis patients are complicated. Possible pathogenic factors include volume overload, pressure overload, anemia, arteriovenous fistulae as blood accesses, coronary artery disease, hypertension, diabetes and other factors. ,, However, for dialysis patients, aggressive control of blood pressure and anemia does not prevent LVH.  Thus, it seems likely that other factors play a role in the formation of uremia-related LVH.
Hyperphosphatemia is common in many HD patients,  and control of serum phosphate levels in these patients correlates with a reduction in left ventricle mass index (LVMI).  It has been suggested that among HD patients, a novel mechanism may be responsible for the association of elevated serum phosphate and LVH and the subsequent deleterious effect on cardiovascular outcomes. However, the exact mechanism is still unknown. Fibroblast growth factor 23 (FGF-23) is a recently discovered phosphate-regulating hormone largely produced by the bone. Genetic and biochemical evidence indicates that FGF-23 reduces the serum phosphate concentration. The serum concentration of FGF-23 increases as kidney function declines,  and its levels are extremely high in HD patients. , Recent studies demonstrated that increased FGF-23 levels are independently associated with mortality among patients undergoing HD. ,
Given that a major target organ of FGF-23 is the kidney, the association between FGF-23 levels and clinical outcome in HD patients suggests that FGF-23 may play a role in conferring a cardiovascular risk on HD patients, independent of its role in the renal reabsorption of inorganic phosphate. The previous research suggests that elevation of FGF-23 levels may be related to the development of LVH and clinical outcome for dialysis patients. The aim of this study was to evaluate the role of FGF-23 in long-term HD patients by examining the associations between serum FGF-23 levels and LVMI.
| Materials and Methods|| |
We studied 60 healthy volunteers and 90 maintenance HD patients (39 women and 51 men, mean age 41.5 ± 14.2 years, mean HD time 71.2 ± 14.2 months). The patients suffered from ESRD due to diabetic nephropathy (n = 35), hypertensive nephrosclerosis (n = 30), chronic glomerulonephritis (n = 10) or chronic pyelonephritis (n = 5); the renal diagnosis was unknown in ten patients. The patients were prescribed treatments including CaCO 3 (35%), Ca acetate (45%), alfa calcidol (65%) and erythropoietin (50%). All patients were receiving conventional 4-h HD schedule for at least six months with polysulphone dialysers F6HPS and F7HPS (Fresenius AG, Bad Homburg, Germany) thrice a week, with bicarbonate dialysate and unfractionated heparin using a standard regimen, a 2000 unit initial bolus followed by infusion of 1000 U/h for standard anticoagulation. The mean blood flow rate was 300 mL/min during the HD session (range 250-340 mL/min). Dialysate fluid composition included sodium 140 mmol/L, potassium 1-3 mmol/L, calcium 1.5 mmol/L and bicarbonate 33 mmol/L. Dry weight was considered optimal when the patients had no residual symptoms of orthopnea, dyspnea and edema during the interdialytic period. Blood pressure (BP) of the patients was measured with a conventional mercury manometer prior to each HD session.
Hypertension was defined as a systolic BP of 140 mmHg or above and diastolic BP of 90 mmHg or above;  the average values of systolic and diastolic BP obtained in the first three weeks of the study were used in the statistical analysis. The patients were considered diabetic if they met the 1997 American Diabetes Association criteria.
Data on demographic characteristics, medical history, medication (statins, angiotensin-converting enzyme inhibitors, calcium channel-blockers, β-blockers, activated vitamin D) and blood samples were collected in all subjects at the time of enrollment.
The patients were on antihypertensive medications: Angiotensin-converting enzyme inhibitors (n = 20), β-blockers (n = 30) and calcium channel blockers (n = 8); no patient was on statin therapy. All the patients signed informed consents in accordance with the guidelines of the Human Clinical Study Committee of Ain Shams University Hospital before participating in the study.
Venous blood samples were drawn after an overnight fast. The blood samples were obtained directly through an arterio-venous fistula or central catheter on a mid-week dialysis day. Serum total cholesterol and triglycerides were quantified by commercial colorimetrical assay methods (GPO-PAP and CHOD-PAP; Boehringer-Mannheim, Mannheim, Germany). Serum biochemical parameters (creatinine, blood urea nitrogen, glucose, electrolytes, albumin and complete blood count) and intact parathormone levels were studied by means of a computerized auto-analyzer (Hitachi 717; Boehringer-Mannheim) and the HCV antibodies by ELISA. The Human Intact FGF-23 was measured by two-site enzyme-linked immunosorbent assay (ELISA) (DRG® FGF-23; EIA-4737 International Inc., USA) and measurement of the intact FGF-23 concentration was done using EDTA plasma. A morning, 12-h fasting sample was drawn. Samples were assayed immediately or stored frozen at -20°C or below. Intra-assay and inter-assay variations were 5% and 6.4%, respectively. Echocardiographic examination was performed using a Philips medical systems ultrasound Sonos7500 (Koninklijke Philips Electronics N.V., the Netherlands) with a 1.6/3.2-MHz transducer. M-mode and 2-dimensional measurements were performed in accordance with the methods recommended by the American Society of Echocardiography. Echocardiograms were obtained with the patients in semi-recumbent and left lateral positions, with the echocardiographic window located at the third or fourth intercostal space at the left sternal border. The ventricular volume and ejection volume were calculated by the Doppler technique, according to a previously published protocol.  Left ventricular mass was calculated according to a formula derived by Devereux and Reichek  and indexed for body surface area to define the LVMI. The patients were considered to have LVH if the LVMI was greater than 134 g/m 2 for men and greater than 110 g/m 2 for women.  Cardiac mass was calculated from a formula derived by Devereux and Reichek  : Left ventricle mass (g) = 1.04 × [(LVEDD + IVST + LVPWT) 3 - (LVESD) 3 ] -13.6. LVMI (g/m 2 ) = left ventricle mass (LVM)/body surface area, where LVPWT is left ventricular posterior wall thickness, IVST is interventricular septum thickness, LVEDD is left ventricular end-diastolic diameter and LVESD is left ventricular end-systolic diameter.
| Statistical Analysis|| |
Baseline characteristics were assessed with standard descriptive statistics. Whether the distributions of continuous variables were normal or not was determined by using the Shapiro Wilk test. Data were shown as mean, standard deviation, median and interquartile range. Chi-square test was used to compare qualitative variables between groups. The Fisher exact test was used instead of the chi-square test when one expected a value less than or equal to 5. Unpaired t-test was used to compare two groups with regard to quantitative variables in parametric data SD <50% of the mean. The Mann-Whitney test was used instead of the t-test for non-parametric data (SD >50% mean). Degrees of associations between continuous variables were calculated by the Spearman's correlation co-efficient. The associations between FGF-23 levels, LVMI and baseline demographic, clinical and laboratory variables were assessed by the determination of the Pearson product-moment correlation coefficient. Linear regression was used to examine the association between FGF-23, LVMI and laboratory variables. All analyses were conducted using statistical software (SPSS, version 12.0.0; SPSS, Chicago, IL, USA) and P-values less than 0.05 were considered to be statistically significant.
| Results|| |
The serum FGF-23 levels in 90 dialysis patients were significantly higher than those of 60 healthy volunteers (95.7 ± 88.4 pg/mL vs 1.12 ± 44, P <0.001). All the patients received echocardiography and were examined for LVMI. [Table 1] and [Table 2] show the comparison of demographic and biochemical profiles between diabetic and non-diabetic HD patients. Diabetic patients (n = 45) were older than those in the non-DM group (n = 45). There were no significant differences in age, sex, BMI, HD duration, hemoglobin or serum levels of creatinine, BUN, serum albumin, serum Ca, serum P, Ca x P product, iPTH, cholesterol or triglycerides levels between the HD patients with and without DM. In addition, there were no significant differences in plasma FGF-23 levels among diabetic [median 55, interquartile range (25-135) pg/mL] and non-diabetic [median 95, interquartile range (50-125) pg/mL] patients (P >0.05). There was a significant difference in LVMI of the diabetic versus the non-diabetic patients (mean ± SD = 110.4 + 28 g/m 2 vs 89.2 + 29 g/m 2 ) (P <0.001) [Figure 1], [Table 2]. There was a significant difference in the prevalence of HCV infection among the diabetic versus the non-diabetic patients (57.8% vs 35.6%) (P <0.05). Among the biomarkers examined, correlation analysis showed that serum creatinine (r = 0.34, P <0.05), serum calcium (r = 0.33, P <0.05) and serum albumin (r = 0.35, P <0.05) were significantly associated with FGF-23 levels [Table 3]. In addition, only LVMI among the echocardiographic data determined was significantly correlated with FGF-23 levels (r = 0.33, P <0.01) [Figure 2]. In univariate linear regression analysis that included all the aforementioned parameters, serum calcium [β= 0.87, P <0.001, confidence interval (CI) 0.8-7.3], serum albumin (β= 0.87, P <0.001, CI 0.8-7.3) and serum creatinine (β= 0.67, P <0.05, CI 0.5-6.5) correlated with FGF-23 [Table 4], [Figure 3] and [Figure 4].
|Figure 1: Left ventricular mass index in diabetic versus non-diabetic patients.|
Click here to view
|Table 1: Laboratory characteristics of diabetic and non-diabetic patients.|
Click here to view
|Table 2: FGF-23 and LV mass index among diabetic and non-diabetic patients.|
Click here to view
|Table 3: Correlation between FGF-23 versus demographic and laboratory data among the studied group.|
Click here to view
|Table 4: Correlation between FGF-23 levels versus laboratory data by using linear regression analysis.|
Click here to view
LVMI only correlated with FGF-23 (r = 0.33, P <0.001) [Table 4]. In univariate linear regression analysis, LVMI was significantly associated with FGF-23 (β= 0.42, P <0.05, CI 0.3-4.3). R  of FGF-23 = 0.78%, every one unit increase in FGF-23 resulted in a 78% increase in LVMI.
| Discussion|| |
A previous study found that ESRD patients maintained on HD had high levels of FGF-23 as well as hyperphosphatemia and hyperparathyroidism.  FGF-23 is primarily produced in bone tissue by osteocytes,  and its principal actions are inhibition of sodium-dependent α- hydroxylase activity in the proximal tubule of the kidney, causing phosphaturia and suppression of circulating 1,25(OH)2D levels.  When renal function declines (which is often associated with phosphate imbalance), the serum FGF-23 level increases along with an increase of phosphate and a decrease of 1,25(OH)2D levels. In ESRD, phosphate excretion does not increase even with high levels of FGF-23,  and this is in agreement with the higher FGF-23 levels in HD patients than that in healthy volunteers in our study (P <0.001). FGF-23 activation of target tissues requires the co-expression of FGF receptors and Klotho (a 130-kDa single-pass β-transmembrane glucuronidase).  Other members of the FGF family, such as FGF1 and FGF2, have been linked to growth and repair of cardiovascular system. Thus, it is reasonable to suppose that FGF-23 plays a role in the pathogenesis of hyperphosphatemia that occurs in HD patients with LVH.
The present study provides two major findings. First, we found that elevated serum FGF-23 levels were weakly correlated with LVMI, serum calcium levels, serum albumin levels and serum creatinine levels; second, FGF-23 was weakly associated with LVMI, irrespective of serum phosphate and calcium levels.
It has been consistently shown that LVH is a powerful predictor for cardiovascular outcomes in dialysis patients including congestive heart failure, cardiac ischemia and arrhythmias, and stroke.  Gutierrez et al have recently reported that FGF-23 is associated with LVMI in asymptomatic patients with chronic kidney disease (CKD).  Unlike our study, the recruited subjects in that study were CKD patients not yet requiring HD. Thus, the link between elevated FGF-23 levels and LVMI appears to be consistent in patients with CKD from moderate stage to end stage. Our finding that FGF-23 levels were weakly associated with LVMI may provide the clue to clarify the pathogenesis of cardiovascular disease in HD patients. Recently, Gutierrez et al demonstrated that elevated FGF-23 concentrations at the initiation of HD are independently associated with increased 1-year mortality in a prospective cohort of 10,055 patients.  Importantly, a linear dose-response relationship was observed between FGF-23 levels and mortality, even after multivariable adjustment including serum phosphate, calcium, log parathyroid hormone and other confounders recorded in a clinical database. In addition, FGF-23 levels were most informative when serum phosphate was relatively normal; thus, FGF-23 may represent a novel risk biomarker for death in HD patients.  Jean et al have recently reported similar findings in long-term HD patients.  Our present study suggests that patients with increased FGF-23 levels are likely to have LVH, which may be a risk factor driving the high rate of cardiovascular mortality in HD patients. In addition, we emphasize that FGF-23 levels were weakly associated with LVMI, irrespective of serum phosphate in our study. This finding is also consistent with the report by Gutierrez et al and Jean et al, who showed that increased mortality in patients with elevated levels of FGF-23 was independent of the serum phosphate levels. ,
It is interesting to note that serum FGF-23 levels were positively associated with serum calcium levels, which is consistent with the report by Jean et al, who showed that the highest FGF-23 quartile was associated with hypercalcemia.  However, no correlation has been observed in patients who are starting HD treatment.  We did not vigorously explore the precise mechanisms underlying the positive relationship between serum FGF-23 and serum calcium. Further studies will be required to understand the mechanism of the association between FGF-23 and calcium in HD patients.
Our study did not show a correlation between FGF-23 and serum phosphorus levels. Animal studies have demonstrated a linear association between FGF-23 and phosphate; however, human trials have reported a variable rise in FGF-23 levels following phosphate loading,  which highlights the complexity of phosphate regulation in humans. It is likely that FGF-23 is not the only mediator of increasing phosphate excretion and that other phosphatonins (frizzled-related protein-4, fibroblast growth factor-7, matrix extracellular phosphoglyco-protein) play a currently poorly understood role.  The stimulation of FGF-23 depends on the dose and the duration of exposure to phosphate and bone-derived co-factors besides the severity and the chronicity of CKD. It is unclear whether serum or local phosphate concentrations provide the primary stimulus for FGF-23 secretion. FGF-23 has an inhibitory effect on PTH secretion; however, FGF-23 secretion may also occur in response to PTH levels. It is not known whether this occurs through a negative feedback loop mechanism or is conferred by the effects of PTH on calcitriol and serum phosphate.  The interaction between FGF-23 and Klotho may be necessary for normal phosphate metabolism. However, it is possible that high levels of FGF-23, as seen in CKD patients, can exert a Klotho-independent effect and bind to FGF-R with low affinity. This is supported by decreased expression of Klotho in renal biopsies from CKD patients.  The expression of Klotho occurs predominantly in the distal tubules, and the signaling sequence that leads to decreased phosphate absorption in the proximal tubules remains unclear. 
In our study, the sample size was relatively small. In addition, there are potential limitations to LVMI measurement using the formula of Deveraux, because echocardiographic measurement of LV mass relies upon geometric assumptions derived from normal hearts and tends to overestimate the volume, although the measurement still correlates well with LVMI by magnetic resonance imaging. This warrants 3-dimensional echocardiographic measurement of LVMI in HD patients in the future.
We conclude that serum FGF-23 is weakly associated with LVMI among HD patients. Thus, FGF-23 is not a good marker for evaluation of the cardiac status in this population. Further studies are needed to confirm the association of elevated FGF-23 and LV mass in HD patients.
| References|| |
|1.||Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32(5 Suppl 3):S112-9. |
|2.||Collins AJ, Kasiske B, Herzog C, et al. Excerpts from the United States Renal Data System 2003 Annual Data Report: Atlas of end-stage renal disease in the United States. Am J Kidney Dis 2003;42(6 Suppl 5):A5-7,S1-230. |
|3.||Agodoa LY, Eggers PW. Renal replacement therapy in the United States: Data from the United States Renal Data System. Am J Kidney Dis 1995;25:119-33. |
|4.||Iseki K, Fukiyama K. Predictors of stroke in patients receiving chronic HD. Kidney Int 1996;50:1672-5. |
|5.||Iseki K, Kinjo K, Kimura Y, Osawa A, Fukiyama K. Evidence for high risk of cerebra hemorrhage in chronic dialysis patients. Kidney Int 1993;44:1086-90. |
|6.||Foley RN, Parfrey PS, Harnett JD, et al. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 1995;47:186-92. |
|7.||London GM, Pannier B, Guerin AP, et al. Alterations of left ventricular hypertrophy in and survival of patients receiving HD: Follow-up of an interventional study. J Am Soc Nephrol 2001;12:2759-67. |
|8.||Silberberg JS, Barre PE, Prichard SS, Sniderman AD. Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int 1989;36:286-90. |
|9.||Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barré PE. The prognostic importance of left ventricular geometry in uremic cardiomyopathy. J Am Soc Nephrol 1995;5: 2024-31. |
|10.||Foley RN. Clinical epidemiology of cardiac disease in dialysis patients: Left ventricular hypertrophy, ischemic heart disease, and cardiac failure. Semin Dial 2003;16:111-7. |
|11.||Meeus F, Kourilsky O, Guerin AP, Gaudry C, Marchais SJ, London GM. Pathophysiology of cardiovascular disease in HD patients. Kidney Int Suppl 2000;76:S140-7. |
|12.||Ayus JC, Go AS, Valderrabano F, et al. Effects of erythropoietin on left ventricular hypertrophy in adults with severe chronic renal failure and hemoglobin 10 g/dL. Kidney Int 2005;68:788-95. |
|13.||Ayus JC, Mizani MR, Achinger SG, Thadhani R, Go AS, Lee S. Effects of short daily versus conventional HD on left ventricular hypertrophy and inflammatory markers: A prospective, controlled study. J Am Soc Nephrol 2005;16:2778-88. |
|14.||Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004; 15:2208-18. |
|15.||Imanishi Y, Inaba M, Nakatsuka K, et al. FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int 2004;65:1943-6. |
|16.||Larsson T, Nisbeth U, Ljunggren O, Jüppner H, Jonsson KB. 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. Kidney Int 2003;64:2272-9. |
|17.||Gutiérrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008;359:584-92. |
|18.||Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant 2009;24:2792-6. |
|19.||Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-52. |
|20.||Lewis JF, Kuo LC, Nelson JG, Limacher MC, Quinones MA. Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: Clinical validation of two new methods using the apical window. Circulation 1984;70:425-31. |
|21.||Devereux RB, Reichek N. Echocardiographic determination of left- ventricular mass in man. Anatomic validation of the method. Circulation 1977;55:613-8. |
|22.||Liu S, Gupta A, Quarles LD. Emerging role of fibroblast growth factor 23 in a bone-kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization. Curr Opin Nephrol Hypertens 2007;16:329-35. |
|23.||Sitara D, Razzaque MS, St-Arnaud R, et al. Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals. Am J Pathol 2006;169:2161-70. |
|24.||Imanishi Y, Inaba M, Nakatsuka K, et al. FGF-23 in patients with end-stage renal disease on HD. Kidney Int 2004;65:1943-6. |
|25.||Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004;113:561-8. |
|26.||Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281:6120-3. |
|27.||Silberberg JS, Barre PE, Prichard SS, Sniderman AD. Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int 1989;36:286-90. |
|28.||Gutiérrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 2009; 119:2545-52. |
|29.||Isakova T, Gutierrez O, Shah A, et al. Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol 2008;19:615-23. |
|30.||Shirley DG, Faria NJ, Unwin RJ, Dobbie H. Direct micropuncture evidence that matrix extracellular phosphoglycoprotein inhibits proximal tubular phosphate reabsorption. Nephrol Dial Transplant 2010;25:3191-5. |
|31.||Larsson TE. The role of FGF-23 in CKD-MBD and cardiovascular disease: Friend or foe? Nephrol Dial Transplant 2010;25:1376-81. |
|32.|| Koh N, Fujimori T, Nishiguchi S, et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 2001;280:1015-20. |
|33.||Farrow EG, Davis SI, Summers LJ, White KE. Initial FGF23- mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol 2009;20:955-60. |
Division of Nephrology, University of Ain-Shams, Cairo
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]