Background: Cardiac dysfunction and arrhythmia are common and onerous cardiovascular events in end-stage renal disease (ESRD) patients, especially those on dialysis. Fibroblast growth factor (FGF)-23 is a phosphate-regulating hormone whose levels dramatically increase as renal function declines. Beyond its role in phosphorus homeostasis, FGF-23 may elicit a direct effect on the heart. Whether FGF-23 modulates ventricular cardiac rhythm is unknown, prompting us to study its role on excitation–contraction (EC) coupling. Methods: We examined FGF-23 in vitro actions on EC coupling in adult rat native ventricular cardiomyocytes using patch clamp and confocal microscopy and in vivo actions on cardiac rhythm using electrocardiogram. Results: Compared with vehicle treatment, FGF-23 induced a significant decrease in rat cardiomyocyte contraction, L-type Ca2+ current, systolic Ca2+ transients and sarcoplasmic reticulum (SR) load and SR Ca2+-adenosine triphosphatase 2a pump activity. FGF-23 induced pro-arrhythmogenic activity in vitro and in vivo as automatic cardiomyocyte extracontractions and premature ventricular contractions. Diastolic spontaneous Ca2+ leak (sparks and waves) was significantly increased by FGF-23 via the calmodulin kinase type II (CaMKII)-dependent pathway related to hyperphosphorylation of ryanodine receptors at the CaMKII site Ser2814. Both contraction dysfunction and spontaneous pro-arrhythmic Ca2+ events induced by FGF-23 were blocked by soluble Klotho (sKlotho). Conclusions: Our results show that FGF-23 reduces contractility and enhances arrhythmogenicity through intracellular Ca2+ mishandling. Blocking its actions on the heart by improving sKlotho bioavailability may enhance cardiac function and reduce arrhythmic events frequently observed in ESRD.

Hemodialysis patients experience high oxidative stress because of systemic inflammation and depletion of antioxidants. Little is known about the global oxidative status during dialysis or whether it is linked to the type of dialysis. We investigated the oxidative status before (pre-) and after (post-) one dialysis session in patients subjected to high-flux dialysis (HFD) or on-line hemodiafiltration (OL-HDF). We analyzed carbonyls, oxidized LDL (oxLDL), 8-hydroxy-2′-deoxyguanosine, and xanthine oxidase (XOD) activity as oxidative markers, and total antioxidant capacity (TAC), catalase, and superoxide dismutase activities as measures of antioxidant defense. Indices of oxidative damage (OxyScore) and antioxidant defense (AntioxyScore) were computed and combined into a global DialysisOxyScore. Both dialysis modalities cleared all markers (p < 0.01) except carbonyls, which were unchanged, and oxLDL, which increased post-dialysis (p < 0.01). OxyScore increased post-dialysis (p < 0.001), whereas AntioxyScore decreased (p < 0.001). XOD and catalase activities decreased post-dialysis after OL-HDF (p < 0.01), and catalase activity was higher after OL-HDF than after HFD (p < 0.05). TAC decreased in both dialysis modalities (p < 0.01), but remained higher in OL-HDF than in HFD post-dialysis (p < 0.05), resulting in a lower overall DialysisOxyScore (p < 0.05). Thus, patients on OL-HDF maintain higher levels of antioxidant defense, which might balance the elevated oxidative stress during dialysis, although further longitudinal studies are needed.

Resistant hypertension (RH) is a concept that currently goes beyond the classical definition of blood pressure ≥140/90 mmHg in subjects receiving three or more drugs of different classes at maximally tolerated doses. Here, we review the clinical relevance of RH and the different types of RH-associated phenotypes, namely refractory hypertension, controlled resistant hypertension, and masked uncontrolled hypertension. We also discuss current drug strategies and future treatments for these high-risk phenotypes.

Background: Acute renal failure (ARF) following renal ischemia-reperfusion (I/R) injury is considered a relevant risk factor for cardiac damage, but the underlying mechanisms, particularly those triggered at cardiomyocyte level, are unknown. Methods: We examined intracellular Ca²⁺ dynamics in adult ventricular cardiomyocytes isolated from C57BL/6 mice 7 or 15 days following unilateral renal I/R. Results: After 7 days of I/R, the cell contraction was significantly lower in cardiomyocytes compared to sham-treated mice. It was accompanied by a significant decrease in both systolic Ca²⁺ transients and sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA_2a) activity measured as Ca²⁺ transients decay. Moreover, the incidence of pro-arrhythmic events, measured as the number of Ca²⁺ sparks, waves or automatic Ca²⁺ transients, was greater in cardiomyocytes from mice 7 days after I/R than from sham-treated mice. Ca²⁺ mishandling related to systolic Ca²⁺ transients and contraction were recovered to sham values 15 days after I/R, but Ca²⁺ sparks frequency and arrhythmic events remained elevated. Conclusions: Renal I/R injury causes a cardiomyocyte Ca²⁺ cycle dysfunction at medium (contraction-relaxation dysfunction) and long term (Ca²⁺ leak), after 7 and 15 days of renal reperfusion, respectively.

Matrix metalloproteinases (MMPs) are involved in deleterious tissue remodeling associated with target organ damage in renal disease. The aim of this study was to study the association between renal dysfunction and activity of the inflammatory metalloproteinase MMP-9 in hypertensive patients with mild-moderate chronic kidney disease (CKD). Plasmatic active MMP-9, total MMP-9, tissue inhibitor of MMP-9 (TIMP-1), MMP-9/TIMP-1 ratio and MMP-9-TIMP-1 interaction were analyzed in 37 hypertensive patients distributed by estimated glomerular filtration rate (eGFR) in 3 groups:>90, 90-60 y 60-30mL/min/1.73 m2. Total MMP-9 was not different as eGFR declines. TIMP-1 was significantly increased in hypertensive patients with eGFR 60-30mL/min/1.73 m2 (P<.01 versus>90mL/min/1.73 m2). This relates to the significant decrease in the interaction between MMP-9-TIMP-1 observed in patients with eGFR 60-30mL/min/1.73 m2 (P<.01 versus>90mL/min/1.73 m2). Despite the systemic elevation of TIMP-1, active MMP-9 was significantly increased in hypertensive patients with eGFR 60-30mL/min/1.73 m2 (P<.05 and P90 and 90-60mL/min/1.73 m2, respectively). TIMP-1, active MMP-9 and MMP-9-TIMP-1 interaction significantly correlate with the decline in renal function, which was not observed with total MMP-9. The progression of CKD, even in stages where the decline of renal function is still moderate, is associated with an increase in MMP-9 activity, which could be considered as a potential therapeutic target.