Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 has been proposed as an early biomarker of disordered phosphorus metabolism in earlier stages of chronic kidney disease (CKD), but data from large, well-characterized CKD cohorts are lacking. We measured FGF23 in baseline samples from 3,879 participants in the Chronic Renal Insufficiency Cohort study, a nationally representative, diverse CKD cohort with mean (± sd) estimated glomerular filtration rate (eGFR) of 42.8 ± 13.5 ml/min/1.73m2. Serum phosphate (3.7 ± 0.7 mg/dl) and parathyroid hormone (PTH; median 54, interquartile range [IQR] 35 – 89 pg/ml) levels were in the normal range, but FGF23 (median 145, IQR 96 – 239 RU/ml) was markedly greater than in healthy populations and increased significantly with decreasing eGFR. FGF23 excess, defined as ≥ 100 RU/ml, was more common than secondary hyperparathyroidism (≥ 65 pg/ml) and hyperphosphatemia (≥ 4.6 mg/dl) in all strata of eGFR, and the eGFR threshold at which the slope of FGF23 increased (57.8; 95%CI: 55.4 – 60.8 ml/min/1.73m2) was higher than the corresponding threshold for PTH (46.9; 95%CI: 45.5 – 51.4 ml/min/1.73m2). Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increases in phosphate or PTH. These findings provide additional support for use of FGF23 as a sensitive early screening test to identify disordered phosphorus metabolism in CKD patients with normal serum phosphate levels.

Background and objectives: The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factorsfor the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with CKD. We examined baseline demographic and clinical characteristics.Design, setting, participants, & measurements: Seven clinical centers recruited adults who were aged 21 to 74 yr and had CKD using age-based estimated GFR (eGFR) inclusion criteria. At baseline, blood and urine specimens were collected and information regarding health behaviors, diet, quality of life, and functional status was obtained. GFR was measured using radiolabeled iothalamate in one third of participants.Results: A total of 3612 participants were enrolled with mean age ؎ SD of 58.2 ؎ 11.0 yr; 46% were women, and 47% had diabetes. Overall, 45% were non-Hispanic white, 46% were non-Hispanic black, and 5% were Hispanic. Eighty-six percent reported hypertension, 22% coronary disease, and 10% heart failure. Mean body mass index was 32.1 ؎ 7.9 kg/m 2 , and 47% had a BP >130/80 mmHg. Mean eGFR was 43.4 ؎ 13.5 ml/min per 1.73 m 2 , and median (interquartile range) protein excretion was 0.17 g/24 h (0.07 to 0.81 g/24 h). Lower eGFR was associated with older age, lower socioeconomic and educational level, cigarette smoking, self-reported CVD, peripheral arterial disease, and elevated BP.Conclusions: Lower level of eGFR was associated with a greater burden of CVD as well as lower socioeconomic and educational status. Long-term follow-up of participants will provide critical insights into the epidemiology of CKD and its relationship to adverse outcomes.

Chronic kidney disease (CKD) affects 8 to 16% people worldwide, with an increasing incidence and prevalence of end-stage kidney disease (ESKD). The effective management of CKD is confounded by the inability to identify patients at high risk of progression while in early stages of CKD. To address this challenge, a renal biopsy transcriptome-driven approach was applied to develop noninvasive prognostic biomarkers for CKD progression. Expression of intrarenal transcripts was correlated with the baseline estimated glomerular filtration rate (eGFR) in 261 patients. Proteins encoded by eGFR-associated transcripts were tested in urine for association with renal tissue injury and baseline eGFR. The ability to predict CKD progression, defined as the composite of ESKD or 40% reduction of baseline eGFR, was then determined in three independent CKD cohorts. A panel of intrarenal transcripts, including epidermal growth factor (EGF), a tubule-specific protein critical for cell differentiation and regeneration, predicted eGFR. The amount of EGF protein in urine (uEGF) showed significant correlation (P < 0.001) with intrarenal EGF mRNA, interstitial fibrosis/tubular atrophy, eGFR, and rate of eGFR loss. Prediction of the composite renal end point by age, gender, eGFR, and albuminuria was significantly (P < 0.001) improved by addition of uEGF, with an increase of the C-statistic from 0.75 to 0.87. Outcome predictions were replicated in two independent CKD cohorts. Our approach identified uEGF as an independent risk predictor of CKD progression. Addition of uEGF to standard clinical parameters improved the prediction of disease events in diverse CKD populations with a wide spectrum of causes and stages.