Patricia Wahl

Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease

Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100 RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.

Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.

CONTEXT A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease. OBJECTIVE To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease. DESIGN, SETTING, AND PARTICIPANTS A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. MAIN OUTCOME MEASURES All-cause mortality and end-stage renal disease. RESULTS At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2). CONCLUSION Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease.

Fibroblast growth factor 23 is not associated with and does not induce arterial calcification

Elevated fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease. As a potential mediating mechanism, FGF23 induces left ventricular hypertrophy; however, its role in arterial calcification is less clear. In order to study this we quantified coronary artery and thoracic aorta calcium by computed tomography in 1501 patients from the Chronic Renal Insufficiency Cohort (CRIC) study within a median of 376 days (interquartile range 331 to 420 days) of baseline. Baseline plasma FGF23 was not associated with prevalence or severity of coronary artery calcium after multivariable adjustment. In contrast, higher serum phosphate levels were associated with prevalence and severity of coronary artery calcium, even after adjustment for FGF23. Neither FGF23 nor serum phosphate were consistently associated with thoracic aorta calcium. We could not detect mRNA expression of FGF23 or its co-receptor, klotho, in human or mouse vascular smooth muscle cells, or normal or calcified mouse aorta. Whereas elevated phosphate concentrations induced calcification in vitro, FGF23 had no effect on phosphate uptake or phosphate-induced calcification regardless of phosphate concentration or even in the presence of soluble klotho. Thus, in contrast to serum phosphate, FGF23 is not associated with arterial calcification and does not promote calcification experimentally. Hence, phosphate and FGF23 promote cardiovascular disease through distinct mechanisms.

Effects of Dietary Phosphate Restriction and Phosphate Binders on FGF23 Levels in CKD

BACKGROUND Elevated levels of fibroblast growth factor 23 (FGF23) are associated with increased risk of adverse outcomes in patients with CKD. Reducing dietary phosphate intake or absorption may decrease FGF23 levels, but data on the combined effects of dietary phosphate restriction and phosphate binders in CKD are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this 2×2 factorial, single-blinded, placebo-controlled, 3-month study, conducted between July 2009 and March 2012, 39 patients with CKD stages 3 or 4 and normal serum phosphate levels were randomly assigned to one of four groups: ad libitum diet plus lanthanum carbonate (LC) placebo (n=10), 900-mg phosphate diet plus LC placebo (n=10), ad libitum diet plus LC (n=11), or 900-mg phosphate diet plus LC (n=8). The dose of LC was 1000 mg three times daily with meals. Dietary restriction was accomplished with outpatient counseling. The primary end point was change in FGF23 levels from baseline. RESULTS Compared with ad libitum diet, the 900-mg phosphate diet did not significantly reduce FGF23 levels (diet × time interaction, P=0.05). Compared with placebo, LC alone also did not significantly reduce FGF23 levels (LC × time interaction, P=0.21). However, the dual intervention significantly decreased FGF23 levels throughout the study period (diet × LC × time interaction, P=0.02), resulting in a 35% (95% confidence interval, 8%-62%) reduction by study end. CONCLUSION The combination of LC plus counseling for a phosphate-restricted diet decreased FGF23 levels in patients with CKD stages 3-4 and normal serum phosphate levels.

Fibroblast Growth Factor 23 in Patients Undergoing Peritoneal Dialysis

BACKGROUND AND OBJECTIVES Fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality in patients with ESRD. Before FGF23 testing can be integrated into clinical practice of ESRD, further understanding of its determinants is needed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a study of 67 adults undergoing peritoneal dialysis, we tested the hypothesis that longer dialysis vintage and lower residual renal function and renal phosphate clearance are associated with higher FGF23. We also compared the monthly variability of FGF23 versus parathyroid hormone (PTH) and serum phosphate. RESULTS In unadjusted analyses, FGF23 correlated with serum phosphate (r = 0.66, P < 0.001), residual renal function (r = -0.37, P = 0.002), dialysis vintage (r = 0.31, P = 0.01), and renal phosphate clearance (r = -0.38, P = 0.008). In adjusted analyses, absence of residual renal function and greater dialysis vintage associated with higher FGF23, independent of demographics, laboratory values, peritoneal dialysis modality and adequacy, and treatment with vitamin D analogs and phosphate binders. Urinary and dialysate FGF23 clearances were minimal. In three serial monthly measurements, within-subject variability accounted for only 10% of total FGF23 variability compared with 50% for PTH and 60% for serum phosphate. CONCLUSIONS Increased serum phosphate, loss of residual renal function, longer dialysis vintage, and lower renal phosphate clearance are associated with elevated FGF23 levels in ESRD patients undergoing peritoneal dialysis. FGF23 may be a more stable marker of phosphate metabolism in ESRD than PTH or serum phosphate.

FGF23 in Chronic Kidney Disease

Chronic kidney disease (CKD) is a growing public health epidemic that is associated with a markedly increased risk of cardiovascular mortality. Disordered mineral metabolism and particularly, disordered phosphorus metabolism appears to be a contributing factor. Fibroblast growth factor 23 (FGF23) regulates phosphorus and vitamin D metabolism. Its levels increase progressively beginning in early CKD, presumably as a physiological adaptation to maintain normal serum phosphate levels or normal phosphorus balance. FGF23 promotes phosphaturia and decreases production of calcitriol. Recent studies suggest that increased FGF23 is associated with mortality, left ventricular hypertrophy, endothelial dysfunction and progression of CKD. These results were consistently independent of serum phosphate levels. At the very least, FGF23 is emerging as a novel biomarker that may help identify which CKD patients might benefit most from aggressive management of disordered phosphorus metabolism. It is also possible that markedly increased FGF23 levels in CKD could contribute directly to tissue injury in the heart, vessels and kidneys, an exciting question that is sure to be the topic of intense investigation in the near future.

Earlier Onset and Greater Severity of Disordered Mineral Metabolism in Diabetic Patients With Chronic Kidney Disease

OBJECTIVE Disordered mineral metabolism is a common complication of chronic kidney disease (CKD) and a novel risk factor for CKD progression, cardiovascular disease, and mortality. Although diabetes is the leading cause of CKD and is associated with worse clinical outcomes than other etiologies, few studies have evaluated mineral metabolism in CKD according to diabetes status. RESEARCH DESIGN AND METHODS Using the Chronic Renal Insufficiency Cohort Study, we tested the hypothesis that diabetes is independently associated with lower serum calcium and higher serum phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23). RESULTS Compared with participants without diabetes (n = 1,936), those with diabetes (n = 1,820) were more likely to have lower estimated glomerular filtration rate (eGFR), lower serum albumin, and higher urinary protein excretion (all P < 0.001). Unadjusted serum phosphate, PTH, and FGF23 levels were higher and calcium was lower among those with compared with those without diabetes (all P < 0.001). After multivariate adjustment, diabetes remained a significant predictor of serum phosphate, PTH, and FGF23 but not calcium. The eGFR cut point at which 50% of participants met criteria for secondary hyperparathyroidism or elevated FGF23 was higher in participants with diabetes compared with those without (PTH: eGFR 30–39 vs. 20–29, P < 0.001; FGF23: eGFR 50–59 vs. 40–49, P < 0.001). CONCLUSIONS Disordered mineral metabolism begins earlier in the course of CKD and is more severe among CKD patients with compared with those without diabetes. Future studies should explore mechanisms for these differences and whether they contribute to excess risks of adverse clinical outcomes among diabetic patients with CKD.

Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury

High levels of circulating TNF and its receptors, TNFR1 and TNFR2, predict the progression of diabetic kidney disease (DKD), but their contribution to organ damage in DKD remains largely unknown. Here, we investigated the function of local and systemic TNF in podocyte injury. We cultured human podocytes with sera collected from DKD patients, who displayed elevated TNF levels, and focal segmental glomerulosclerosis (FSGS) patients, whose TNF levels resembled those of healthy patients. Exogenous TNF administration or local TNF expression was equally sufficient to cause free cholesterol-dependent apoptosis in podocytes by acting through a dual mechanism that required a reduction in ATP-binding cassette transporter A1-mediated (ABCA1-mediated) cholesterol efflux and reduced cholesterol esterification by sterol-O-acyltransferase 1 (SOAT1). TNF-induced albuminuria was aggravated in mice with podocyte-specific ABCA1 deficiency and was partially prevented by cholesterol depletion with cyclodextrin. TNF-stimulated free cholesterol-dependent apoptosis in podocytes was mediated by nuclear factor of activated T cells 1 (NFATc1). ABCA1 overexpression or cholesterol depletion was sufficient to reduce albuminuria in mice with podocyte-specific NFATc1 activation. Our data implicate an NFATc1/ABCA1-dependent mechanism in which local TNF is sufficient to cause free cholesterol-dependent podocyte injury irrespective of TNF, TNFR1, or TNFR2 serum levels.

Fibroblast Growth Factor 23 and Incident CKD in Type 2 Diabetes

BACKGROUND AND OBJECTIVES High levels of fibroblast growth factor 23 are associated with accelerated progression of CKD. Whether high fibroblast growth factor 23 levels also predict incident CKD is uncertain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A prospective case-cohort study was conducted within the Action to Control Cardiovascular Risk in Diabetes Trial. The analytic sample consisted of a random subcohort of 590 patients with type 2 diabetes without prevalent CKD at baseline, 124 of whom developed incident CKD during follow-up, and 520 additional patients with incident CKD outside the random subcohort. The association between serum intact fibroblast growth factor 23 and incident CKD, defined as the new onset of eGFR<60 ml/min per 1.73 m(2) that represented a ≥25% decrease from baseline in an individual with eGFR≥60 ml/min per 1.73 m(2) and no microalbuminuria (<30 mg/g creatinine) at baseline, was tested. RESULTS The mean baseline eGFR in the random subcohort was 90.9±22.7 ml/min per 1.73 m(2). During a median follow-up of 4.7 years, there was a total of 644 patients with incident CKD. The median baseline fibroblast growth factor 23 level was modestly higher among patients with incident CKD versus controls (43.5, interquartile range=34.7-55.1 versus 39.8, interquartile range=31.9-49.5 pg/ml; P<0.001). Higher baseline fibroblast growth factor 23 levels were associated with higher risk of incident CKD in unadjusted and demographics-adjusted models, but the effect was attenuated after additional adjustment for clinical risk factors and baseline eGFR (hazard ratio per SD of natural log fibroblast growth factor 23, 1.09; 95% confidence interval, 0.94 to 1.27), which was the strongest predictor of incident CKD. Consistent with the results of primary analyses, baseline fibroblast growth factor 23 was not associated with eGFR slope. CONCLUSIONS Higher fibroblast growth factor 23 levels are not independently associated with higher risk of incident CKD in patients with type 2 diabetes.

Systemic and renal lipids in kidney disease development and progression

Altered lipid metabolism characterizes proteinuria and chronic kidney diseases. While it is thought that dyslipidemia is a consequence of kidney disease, a large body of clinical and experimental studies support that altered lipid metabolism may contribute to the pathogenesis and progression of kidney disease. In fact, accumulation of renal lipids has been observed in several conditions of genetic and nongenetic origins, linking local fat to the pathogenesis of kidney disease. Statins, which target cholesterol synthesis, have not been proven beneficial to slow the progression of chronic kidney disease. Therefore, other therapeutic strategies to reduce cholesterol accumulation in peripheral organs, such as the kidney, warrant further investigation. Recent advances in the understanding of the biology of high-density lipoprotein (HDL) have revealed that functional HDL, rather than total HDL per se, may protect from both cardiovascular and kidney diseases, strongly supporting a role for altered cholesterol efflux in the pathogenesis of kidney disease. Although the underlying pathophysiological mechanisms responsible for lipid-induced renal damage have yet to be uncovered, several studies suggest novel mechanisms by which cholesterol, free fatty acids, and sphingolipids may affect glomerular and tubular cell function. This review will focus on the clinical and experimental evidence supporting a causative role of lipids in the pathogenesis of proteinuria and kidney disease, with a primary focus on podocytes.