Strength of Fibroblast Growth Factor 23 as a Cardiovascular Risk Predictor in Chronic Kidney Disease Weaken by ProBNP Adjustment.

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.

Do plasma neprilysin activity and plasma neprilysin concentration predict cardiac events in chronic kidney disease patients?

Background: Since the introduction of sacubitril/valsartan in clinical cardiology, neprilysin has become a major target for heart failure treatment. Plasma neprilysin concentration has been discussed as a novel biomarker that predicts cardiac events. Natriuretic peptides may inhibit plasma neprilysin. As they accumulate in chronic kidney disease (CKD), we hypothesized that high plasma neprilysin loses its predictive role in CKD patients. Methods: We measured plasma levels of neprilysin concentration, neprilysin activity and brain natriuretic peptide (BNP) in 542 CKD G2-G4 patients within the CARE FOR HOMe study. Patients were followed for predefined endpoints of hospitalization for acute decompensated heart failure and incident atherosclerotic cardiovascular events. Results: During 5.1 ± 2.1 years, 63 patients had acute decompensated heart failure and 125 patients had incident atherosclerotic cardiovascular events. In both Kaplan-Meier and multivariate Cox regression analyses, high plasma BNP and low, rather than elevated, neprilysin activity predicted future hospitalization for acute decompensated heart failure; neprilysin concentration was not predictive. Furthermore, only BNP was an independent predictor of incident atherosclerotic cardiovascular events. Conclusions: In line with experimental studies, high natriuretic peptides may inhibit neprilysin activity in CKD. Therefore, high neprilysin activity and concentrations are not predictors of adverse cardiovascular outcome in CKD patients. Thus neprilysin inhibitors should be implemented with caution in patients with advanced CKD.

Does a rise in plasma erythropoietin after high-altitude exposure affect FGF23 in healthy volunteers on a normal or low-phosphorus diet?

BACKGROUND AND AIMS: Data of experimental rodent models suggest that hypoxia with subsequent increase in erythropoietin stimulates the expression of the phosphaturic hormone fibroblast growth factor 23 (FGF23). METHODS AND RESULTS: To translate the findings of animal studies into human physiology, herein we exposed eight healthy volunteers to high altitude (2656 m above sea level) for four days. The volunteers were randomized on a low-phosphorous diet (n = 4) or a normal phosphorus diet (n = 4). Although high-altitude exposure caused a significant increase in plasma erythropoietin (EPO) (before high-altitude exposure: low phosphorus: median EPO 6.6 mIU/ml [interquartile range (IQR) 6.0; 8.2], normal phosphorus: median EPO 9.0 mIU/ml [IQR 7.9; 11.5]; at day 2: low phosphorus: median EPO 21.3 mIU/ml [IQR 19.5; 23.8], normal phosphorus: median EPO 19.4 mIU/ml [IQR 18.0; 20.8]), there was no consistent increase in plasma c-terminal FGF23 or plasma intact FGF23. We observed only a single, intermittent peak in c-terminal FGF23 levels after 5 h of maximal aerobic exercise. CONCLUSION: These data do not support a substantial effect of moderate hypoxia alone on the expression of FGF23, but they suggest that combined exercise and high-altitude exposure may temporarily induce FGF23 expression.

HDL functionality and cardiovascular outcome among nondialysis chronic kidney disease patients.

CVD remains the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). CKD profoundly affects HDL composition and functionality, but whether abnormal HDL independently contributes to cardiovascular events in CKD patients remains elusive. In the present study, we assessed whether compositional and functional properties of HDL predict cardiovascular outcome among 526 nondialysis CKD patients who participate in the CARE FOR HOMe study. We measured HDL cholesterol, the content of HDL-associated proinflammatory serum amyloid A (SAA), and activities of the HDL enzymes paraoxonase and lipoprotein-associated phospholipase A2 (Lp-PLA2). In addition, we assessed the antioxidative activity of apoB-depleted serum. During a mean follow-up of 5.1 ± 2.1 years, 153 patients reached the predefined primary endpoint, a composite of atherosclerotic cardiovascular events including cardiovascular mortality and death of any cause. In univariate Cox regression analyses, lower HDL-cholesterol levels, higher HDL-associated SAA content, and lower paraoxonase activity predicted cardiovascular outcome, while Lp-PLA2 activity and antioxidative capacity did not. HDL-cholesterol and HDL-paraoxonase activity lost their association with cardiovascular outcome after adjustment for traditional cardiovascular and renal risk factors, while SAA lost its association after further adjustment for C-reactive protein. In conclusion, our data suggest that neither HDL quantity nor HDL composition or function independently predict cardiovascular outcome among nondialysis CKD patients.

Validation of echocardiographic criteria for the clinical diagnosis of heart failure in chronic kidney disease.

Background: The Acute Dialysis Quality Initiative (ADQI) XI Workgroup has suggested defining heart failure (HF) in patients with end-stage renal disease by the presence of at least one out of eight predefined echocardiographic criteria. Given the high prevalence of echocardiographic alterations in chronic kidney disease (CKD) patients, we hypothesized that application of echocardiographic ADQI criteria will result in overdiagnosis of HF, without providing substantial prognostic information. Methods: Among 472 CKD stage G2-G4 patients recruited in the CARE FOR HOMe study, we assessed the presence of left-ventricular (LV) hypertrophy, valvular dysfunction, high left-atrial volume index (LAVI), systolic and diastolic LV dysfunction, enlarged LV diameter, and altered regional LV wall contractility. According to the ADQI proposal, presence of one or more of these alterations defined HF. We followed all patients for the occurrence of cardiac decompensation, defined as hospital admission for decompensated HF. Results: A total of 313 (66%) out of 472 patients fulfilled at least one ADQI echocardiographic criterion for HF. Echocardiographic alterations were more common in advanced (G3b/G4: 80%) than in milder (G2/G3a: 56%) CKD. Within subcategories of echocardiographic criteria, an increased LAVI (50%) and diastolic dysfunction (30%) were the most frequent findings. During follow-up of 4.3 ± 2.0 years, the majority (87%) of all 313 patients who fulfilled ADQI echocardiographic criteria were not hospitalized for cardiac decompensation. Conclusions: Echocardiographic criteria proposed by ADQI as a precondition for the clinical staging of HF are virtually omnipresent among CKD patients. By labelling a majority of CKD patients as having HF, application of ADQI criteria fails to specifically identify patients at high risk for future cardiac events.

Best Albuminuria Measurement to Predict Cardiovascular and Renal Events.

BACKGROUND: Kidney Disease Improving Global Outcomes (KDIGO) guidelines encourage clinicians to estimate 24-hour albuminuria as albumin to creatinine ratio (ACR) from spot urine samples. However, ACR underestimates 24-hour albumin excretion in muscular individuals. Equations that adjust ACR for surrogates of muscle mass to yield an estimated albumin excretion rate (eAER) were developed. We hypothesised that eAER is a better predictor of cardiovascular and renal outcomes than ACR. METHODS: We determined ACR and eAER among 443 patients with chronic kidney disease G2-G4 recruited into the CARE FOR HOMe study. Patients were classified into KDIGO albuminuria categories, and followed for cardiovascular and renal events. The primary analysis was the net reclassification improvement (NRI) for those with and without events within 3 years of follow-up. RESULTS: Eighty five patients experienced cardiovascular events during 3 years of follow-up, 13 of whom were reclassified to a more advanced albuminuria category, and 1 patient to a less advanced category by eAER compared to ACR (NRIevent: 14.1% (95% CI 5.8-22.4)). Among 358 patients without a cardiovascular event, 17 patients were reclassified to a more advanced albuminuria category, and 2 patients to a less advanced category by eAER (NRIno event: -4.2%, 95% CI -8.5 to -1.8). Sixty patients went through renal events, and 383 patients had event-free 3-year follow-up. NRIevent was 6.7% (95% CI -1.2 to 14.5), and NRIno event was -6.0% (95% CI -10.6 to 3.4) for renal events. CONCLUSION: Compared to ACR albuminuria categories, eAER categories are better associated with future cardiovascular events, but not with renal events.

Comparison of two different strategies for human monocyte subsets gating within the large-scale prospective CARE FOR HOMe Study.

Monocytes are heterogeneous cells consisting of (at least) three subsets: classical, intermediate, and nonclassical monocytes. Correct enumeration of cell counts necessitates well-defined gating strategies, which are essentially based upon CD14 and CD16 expression. For the delineation of intermediate from nonclassical monocytes, a "rectangular gating (RG) strategy" and a "trapezoid gating (TG) strategy" have been proposed. We compared the two gating strategies in a well-defined clinical cohort of patients with chronic kidney disease (CKD). Within the ongoing CARE FOR HOMe study, monocyte subsets were reanalyzed in 416 CKD patients, who were followed 3.6 ± 1.6 years for the occurrence of a cardiovascular event. Gating was performed by either RG or TG. We analyzed the expression of surface markers, and compared the predictive role of cell counts of monocyte subsets, as defined by RG and TG, respectively. With both gating strategies, higher intermediate monocyte counts predicted the cardiovascular endpoint in Kaplan-Meier analyses (P < 0.001 with RG; P < 0.001 with TG). After correction for confounders, intermediate monocyte counts remained independent predictors in Cox-Regression analyses (HR = 1.013 [95% CI: 1.006-1.020; P < 0.001] with RG; HR = 1.015 [95% CI: 1.006-1.024; P = 0.001] with TG). NRI was 3.9% when reclassifying patients from quartiles of intermediate monocyte counts with RG strategy toward quartiles of intermediate monocytes counts with TG strategy. In expression analysis, those monocytes which are defined as intermediate monocytes by the RG strategy and as nonclassical monocytes by the TG strategy share characteristics of both subsets. In conclusion, intermediate monocytes were independent predictors of cardiovascular outcome irrespective of the applied gating strategy. Future studies should aim to identify markers that allow for an unequivocal definition of intermediate monocytes, which may further improve their power to predict cardiovascular events.

NT-proBNP and Echocardiographic Parameters for Prediction of Cardiovascular Outcomes in Patients with CKD Stages G2-G4.

BACKGROUND AND OBJECTIVES: Natriuretic peptides and echocardiographic parameters both predict cardiovascular events in patients with CKD. However, it is unknown whether simultaneous assessment of amino-terminal probrain natriuretic peptide (NT-proBNP) and echocardiographic parameters provides complementary or redundant predictive information; in the latter case, one of these two might be dispensable. We aimed to analyze the implications of using NT-proBNP alone, echocardiographic parameters alone, or a combination of both for prediction of adverse cardiovascular outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Within the longitudinal Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg Evaluation Study, we prospectively studied 496 patients with CKD stages G2-G4, in whom we measured NT-proBNP. Left ventricular mass index, left atrial volume index, diastolic left ventricular function, and systolic left ventricular function were assessed echocardiographically. During 4.5±2.0 years of follow-up, the occurrence of (1) decompensated heart failure or all-cause mortality and (2) atherosclerotic events or all-cause mortality was recorded. We assessed the association of NT-proBNP and echocardiographic parameters with outcome (using Cox models) and evaluated the increased discriminative value associated with the addition of echocardiographic parameters and NT-proBNP (using integrated discrimination improvement and net reclassification improvement). RESULTS: During follow-up, 104 patients suffered decompensated heart failure or all-cause mortality, and 127 patents had atherosclerotic events or all-cause mortality. In univariable analyses, NT-proBNP and echocardiographic parameters predicted cardiovascular events. NT-proBNP remained an independent predictor for both end points in multivariate analysis, whereas left ventricular mass index, left atrial volume index, and diastolic left ventricular function did not. The addition of NT-proBNP on top of clinical and various echocardiographic variables was associated with improvements in reclassification for decompensated heart failure or all-cause mortality (integrated discrimination improvement =6.5%-8.3%; net reclassification improvement =23.1%-27.0%; all P≤0.03). Adding echocardiographic variables on top of clinical variables and NT-proBNP was not associated with significant net reclassification improvement (all P>0.05). CONCLUSIONS: Our data confirm NT-proBNP is an independent predictor of adverse outcomes in patients with CKD. The additional use of echocardiography for improvement of risk stratification is not supported by our results.

External Validation of the Kidney Failure Risk Equation and Re-Calibration with Addition of Ultrasound Parameters.

BACKGROUND AND OBJECTIVES: Progression of CKD toward ESRD is heterogeneous. The Kidney Failure Risk Equation (KFRE) was developed to identify CKD patients at high risk of ESRD. We aimed to externally validate KFRE and to test whether the addition of predefined Duplex ultrasound markers - renal resistive index (RRI) or difference of resistive indices in spleen and kidney (DI-RISK) - improved ESRD prediction. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The prospective Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg evaluation (CARE FOR HOMe) study recruits CKD stage G2-G4 patients referred to a tertiary referral center for nephrologic care. Four hundred three CARE FOR HOMe participants enrolled between 2008 and 2012 had available RRI measurements at study inclusion; they were subsequently followed for a mean of 4.4±1.6 years. This subcohort was used to validate KFRE and to assess the added value of the ultrasound markers (new models KFRE+RRI and KFRE+DI-RISK). Model performance was assessed by log-likelihood ratio test, c-statistic, integrated discrimination improvement metrics (for study participants without subsequent ESRD [IDI No ESRD] and for patients with ESRD [IDI ESRD]), and calibration plots. If either new model improved on KFRE, we determined to validate it in an independent cohort of 162 CKD patients. RESULTS: KFRE predicted ESRD in CARE FOR HOMe participants with a c-statistic of 0.91 (95% confidence interval, 0.83 to 0.99). Adding RRI improved the KFRE model (P<0.001), and the KFRE+RRI model was well calibrated; however, the c-statistic (0.91 [0.83-1.00]) was similar, and overall sensitivity (IDI No ESRD=0.05 [0.00-0.10]) or overall specificity (IDI ESRD=0.00 [0.00-0.01]) did not improve. Adding DI-RISK did not improve the KRFE model. In the external validation cohort, we confirmed that the KFRE+RRI model did not outperform KFRE. CONCLUSIONS: Routine Duplex examinations among CKD patients did not improve risk prediction for progression to ESRD beyond a validated equation.