The impact of calcineurin inhibitors on neutrophil gelatinase-associated lipocalin and fibroblast growth factor 23 in long-term kidney transplant patients.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL), a protein with bacteriostatic functions rapidly excreted from stimulated or damaged epithelial cells, is elevated in acute and chronic kidney disease. A calcineurin dependent signaling pathway for fibroblast growth factor 23 (FGF23) has been revealed, but the effect of calcineurin inhibitors (CNIs) on the levels of NGAL and markers of mineral metabolism in long-term kidney transplant patients has not been explored. METHODS: In a cross-sectional study, 39 patients who received a first kidney transplant more than 10 years ago were split into two groups based on whether (n=28) or not (n=11) they used CNIs. Only patients with well-functioning grafts defined as an estimated glomerular filtration rate ≥45 mL/min per 1.73 m2 were included. RESULTS: The median levels of NGAL, intact parathyroid hormone (iPTH), and iFGF23 were significantly higher in CNI users vs CNI nonusers, 167.0 (134.0-235.0) ng/mL vs 105.0 (91.3-117.0) ng/mL, P<.001, 13.8 (10.0-17.3) pmol/L vs 8.4 (6.4-9.9) pmol/L, P=.003, and 81.6 (56.4-116.5) pg/mL vs 61.8 (43.3-72.1) pg/mL, P=.04 respectively. CONCLUSIONS: The median levels of iFGF23 were higher in CNI users compared to CNI nonusers giving support to the notion of a CNI induced FGF23 resistance in the parathyroid. The net result of CNIs side effects needs to be further explored.

Klotho and Fibroblast Growth Factor 23 Are Independent of Vitamin D, and Unlike Vitamin D, Are Not Associated With Graft- and Patient Survival After Kidney Transplantation.

Short-term survival after kidney transplantation is excellent but long-term survival remains suboptimal. The aim of the study was to explore the relationship between soluble α-Klotho (sKlotho) and intact fibroblast growth factor 23 (iFGF23) measured 8 wk and 1 y posttransplant with long-term graft- and patient survival in a cohort of kidney transplant recipients with deficient and nondeficient vitamin D (25[OH]D) levels. Methods: Vitamin D, sKlotho, and iFGF23 were measured 8 wk and 1 y posttransplant in 132 recipients transplanted between November 2012 and October 2013. Results: Of the 132 kidney transplant recipients, 49 had deficient vitamin D levels (<30 nmol/L) and 83 had nondeficient vitamin D levels (≥30 nmol/L) at 8 wk posttransplant. The mean age was 51 y and the median follow-up was 7.4 y. At 1 y posttransplant, vitamin D increased significantly. There were no significant differences in sKlotho or iFGF23 levels between the 2 vitamin D groups neither at 8 wk nor 1 y. sKlotho increased significantly and iFGF23 decreased significantly in the whole cohort. During the follow-up, there were 36 graft losses (27%) and 27 deaths (20%). Ninety-four percent of the transplant recipients with nondeficient vitamin D levels were alive with a well-functioning graft after 5 y using Kaplan-Meier survival estimates, compared with 84% of the patients with deficient vitamin D levels (P = 0.014). Klotho and FGF23 levels did not influence graft- and patient survival. Conclusions: In this nationwide cohort of kidney transplant recipients, long-term graft- and patient survival were significantly better in patients with vitamin D ≥30 nmol/L 8 wk posttransplant compared with those with vitamin D <30 nmol/L. sKlotho levels increased and iFGF23 levels decreased from 8 wk to 1 y posttransplant. Klotho and FGF23 levels were not associated with graft- and patient survival.

The relationship between Fibroblast Growth Factor 23 (FGF23) and cardiac MRI findings following primary PCI in patients with acute first time STEMI.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a regulator of mineral metabolism, that has been linked to myocardial remodeling including development of left ventricular (LV) hypertrophy and myocardial fibrosis. The aim of this study was to investigate the relationship between intact FGF23 (iFGF23), myocardial infarct size and LV remodeling following a first acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Forty-two consecutive patients with first-time STEMI, single vessel disease, successfully treated with primary percutaneous coronary intervention were included. Cardiac magnetic resonance (CMR) imaging was performed at day 2, 1 week, 2 months and 1 year post MI, and blood samples were drawn at admittance and at the same time points as the CMRs. The cohort was divided according to the presence or not of heart failure post MI. In the total cohort, iFGF23 (mean ± SD) was significantly lower at day 0 (33.7 ± 20.6 pg/ml) and day 2 (31.5 ± 23.4 pg/ml) compared with a reference interval based on 8 healthy adults (43.9 pg/ml ± 19.0 pg/ml). iFGF23 increased to normal levels (55.8 ± 23.4 pg/ml) seven days post MI. In the subset of patients with signs of acute heart failure, FGF23 was higher at all measured timepoints, reaching significantly higher FGF23 levels at 2 months and 1 year following revascularization. CONCLUSION: There was a reduction in iFGF23 levels during the acute phase of MI, with a normalization at seven days following revascularization. During one-year follow-up, there was a gradual increase in iFGF23 levels in patients with heart failure.

Neutrophil Gelatinase-Associated Lipocalin, Fibroblast Growth Factor 23, and Soluble Klotho in Long-Term Kidney Donors.

BACKGROUND: The best treatment for end-stage renal disease (ESRD) is kidney transplantation. Twenty-seven percent of transplantations in Norway are from living donors. Recent studies have shown an increased risk of ESRD and increased mortality in donors. The aim of this study was to determine if the levels of the new biomarkers neutrophil gelatinase-associated lipocalin (NGAL), soluble Klotho (sKlotho), and fibroblast growth factor 23 (FGF23) are changed in kidney donors with normal kidney function defined as an estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m2 compared to patients with chronic kidney disease (CKD) stages 3-5 and healthy controls. METHODS: This is a cross-sectional, observational, single-center study including 35 kidney donors with an eGFR ≥60 ml/min/1.73 m2 5 years after donation, 22 patients with CKD stage 3 (eGFR 30-59 ml/min/1.73 m2), 18 patients with CKD stage 4 (eGFR 15-29 ml/min/1.73 m2), 20 patients with CKD stage 5 (eGFR <15 ml/min/1.73 m2), and 35 controls comparing levels of biomarkers in long-term kidney donors with those in CKD patients and healthy controls. RESULTS: The level of log NGAL was significantly higher in donors than in healthy controls (2.02 ± 0.10 vs. 1.89 ± 0.10 ng/ml; p < 0.001), and the level increased with declining kidney function. The log FGF23 level was nonsignificantly higher in donors than in controls, but it significantly increased with declining kidney function. The log sKlotho levels were significantly lower in patients with CKD stages 4 and 5 than in controls, but no difference was revealed between controls and donors. CONCLUSION: Kidney donors have significantly higher levels of NGAL than healthy controls after a median of 15 years (range 5-38). NGAL could be a valuable diagnostic marker in the future. FGF23 and sKlotho were not significantly different between donors and controls.

Soluble Klotho and intact fibroblast growth factor 23 in long-term kidney transplant patients.

BACKGROUND: Controversies exist whether disturbances in mineral and bone disorder (MBD) normalise or persist after kidney transplantation. We assessed markers of MBD in patients with well-functioning kidney transplants to minimise confounding by reduced transplant function. METHODS: In this cross-sectional study, 40 patients aged ≥18 years who received a first kidney transplant more than 10 years ago were included. A well-functioning transplant was defined as an estimated glomerular filtration rate (eGFR) ≥45 ml/min per 1.73 m(2). RESULTS: Median time since transplantation was 18.3 years (inter quartile range (IQR) 12.2-26.2). Albumin-corrected serum calcium levels were above upper limit of normal in 15% of the transplanted patients, and serum phosphate levels below lower limit of normal in 31%. The median levels of intact parathyroid hormone (iPTH) and intact fibroblast growth factor 23 (iFGF23) were significantly higher than that in a group of healthy volunteers (11.3 pmol/l (IQR: 8.7-16.2) vs 4.4 pmol/l (IQR: 3.8-5.9), P<0.001 and 75.0 pg/ml (IQR: 53.3-108.0) vs 51.3 pg/ml (IQR: 36.3-67.6), P=0.004 respectively). There was a non-significant reduction in soluble Klotho (sKlotho) levels (605 pg/ml (IQR: 506-784) vs 692 pg/ml (IQR: 618-866)). When compared with a control group matched for eGFR, levels of iPTH were significantly higher (P<0.001), iFGF23 had a non-significant trend towards higher levels and sKlotho towards lower levels. CONCLUSIONS: In long-term kidney transplant patients with well-functioning kidney transplants, we found inappropriately high levels of iPTH and iFGF23 consistent with a state of persistent hyperparathyroidism. We speculate that the primary defect, FGF23 resistance, has evolved in the parathyroid gland before transplantation, and persists due to long half-life of the parathyroid cells.