Direct-acting antiviral therapy improves kidney survival in hepatitis C virus-associated cryoglobulinaemia: the RENALCRYOGLOBULINEMIC study

Background: Direct-acting antiviral agents (DAAs) have shown high rates of sustained virological response in chronic hepatitis C virus (HCV) infection. However, the influence of DAAs on the course of kidney involvement in HCV-associated mixed cryoglobulinaemia (HCV-MC) has been little studied. The aim of this study was to analyse the effects of antiviral treatment on kidney prognosis and evolution in patients diagnosed with HCV-MC. Methods: The RENALCRYOGLOBULINEMIC study is an observational multicentre cohort study of 139 patients with HCV-MC from 14 Spanish centres. Clinical and laboratory parameters were measured before and after antiviral treatment. Primary endpoints were kidney survival and mortality after HCV-MC diagnosis. Secondary endpoints were clinical, immunological and virological responses after antiviral treatment. Results: Patients were divided into three groups based on the treatment received: treatment with DAAs (n = 100) treatment with interferon (IFN) and ribavirin (RBV) (n = 24) and no treatment (n = 15). Patients were followed up for a median duration of 138 months (interquartile range 70-251. DAA treatment reduced overall mortality {hazard ratio [HR] 0.12 [95% confidence interval (CI) 0.04-0.40]; P < 0.001} and improved kidney survival [HR 0.10 ( 95% CI 0.04-0.33); P < 0.001]. Conclusions: Results from the RENALCRYOGLOBULINEMIC study indicated that DAA treatment in patients with HCV-MC improves kidney survival and reduces mortality

The anti-aging factor Klotho protects against acquired long QT syndrome induced by uremia and promoted by fibroblast growth factor 23

[Background]: Chronic kidney disease (CKD) is associated with increased propensity for arrhythmias. In this context, ventricular repolarization alterations have been shown to predispose to fatal arrhythmias and sudden cardiac death. Between mineral bone disturbances in CKD patients, increased fibroblast growth factor (FGF) 23 and decreased Klotho are emerging as important effectors of cardiovascular disease. However, the relationship between imbalanced FGF23-Klotho axis and the development of cardiac arrhythmias in CKD remains unknown. [Methods]: We carried out a translational approach to study the relationship between the FGF23–Klotho signaling axis and acquired long QT syndrome in CKD-associated uremia. FGF23 levels and cardiac repolarization dynamics were analyzed in patients with dialysis-dependent CKD and in uremic mouse models of 5/6 nephrectomy (Nfx) and Klotho deficiency (hypomorphism), which show very high systemic FGF23 levels. [Results]: Patients in the top quartile of FGF23 levels had a higher occurrence of very long QT intervals (> 490 ms) than peers in the lowest quartile. Experimentally, FGF23 induced QT prolongation in healthy mice. Similarly, alterations in cardiac repolarization and QT prolongation were observed in Nfx mice and in Klotho hypomorphic mice. QT prolongation in Nfx mice was explained by a significant decrease in the fast transient outward potassium (K+) current (Itof), caused by the downregulation of K+ channel 4.2 subunit (Kv4.2) expression. Kv4.2 expression was also significantly reduced in ventricular cardiomyocytes exposed to FGF23. Enhancing Klotho availability prevented both long QT prolongation and reduced Itof current. Likewise, administration of recombinant Klotho blocked the downregulation of Kv4.2 expression in Nfx mice and in FGF23-exposed cardiomyocytes. [Conclusion]: The FGF23–Klotho axis emerges as a new therapeutic target to prevent acquired long QT syndrome in uremia by minimizing the predisposition to potentially fatal ventricular arrhythmias and sudden cardiac death in patients with CKD.This work was supported by projects from the Instituto de Salud Carlos III, Ministry of Economy, Industry and Competitiveness (PI17/01093, PI17/01193, PI20/00763, CP15/00129, F18/00261, CPII20/00022, SAF2017-84777-R, PID2020-113238RB-I00), from the Sociedad Española de Cardiología (SEC), and from the Fundación Renal Íñigo Alvarez de Toledo (FRIAT), co-funded by the European Regional Development Fund (Fondos FEDER)

Use of tocilizumab in kidney transplant recipients with COVID-1

Acute respiratory distress syndrome associated with coronavirus infection is related to a cytokine storm with large interleukin-6 (IL-6) release. The IL-6-receptor blocker tocilizumab may control the aberrant host immune response in patients with coronavirus disease 2019 (COVID-19) . In this pandemic, kidney transplant (KT) recipients are a high-risk population for severe infection and showed poor outcomes. We present a multicenter cohort study of 80 KT patients with severe COVID-19 treated with tocilizumab during hospital admission. High mortality rate was identified (32.5%), related with older age (hazard ratio [HR] 3.12 for those older than 60 years, P = .039). IL-6 and other inflammatory markers, including lactic acid dehydrogenase, ferritin, and D-dimer increased early after tocilizumab administration and their values were higher in nonsurvivors. Instead, C-reactive protein (CRP) levels decreased after tocilizumab, and this decrease positively correlated with survival (mean 12.3 mg/L in survivors vs. 33 mg/L in nonsurvivors). Each mg/L of CRP soon after tocilizumab increased the risk of death by 1% (HR 1.01 [confidence interval 1.004-1.024], P = .003). Although patients who died presented with worse respiratory situation at admission, this was not significantly different at tocilizumab administration and did not have an impact on outcome in the multivariate analysis. Tocilizumab may be effective in controlling cytokine storm in COVID-19 but randomized trials are needed

Direct-acting antiviral therapy improves kidney survival in hepatitis C virus-associated cryoglobulinaemia: the RENALCRYOGLOBULINEMIC study

Crioglobulinèmia; Agents antivirals d’acció directa; Virus de l'hepatitis CCrioglobulinemia; Agentes antivirales de acción directa; Virus de la hepatitis CCryoglobulinaemia; Direct-acting antiviral agents; Hepatitis C virusBackground Direct-acting antiviral agents (DAAs) have shown high rates of sustained virological response in chronic hepatitis C virus (HCV) infection. However, the influence of DAAs on the course of kidney involvement in HCV-associated mixed cryoglobulinaemia (HCV-MC) has been little studied. The aim of this study was to analyse the effects of antiviral treatment on kidney prognosis and evolution in patients diagnosed with HCV-MC. Methods The RENALCRYOGLOBULINEMIC study is an observational multicentre cohort study of 139 patients with HCV-MC from 14 Spanish centres. Clinical and laboratory parameters were measured before and after antiviral treatment. Primary endpoints were kidney survival and mortality after HCV-MC diagnosis. Secondary endpoints were clinical, immunological and virological responses after antiviral treatment. Results Patients were divided into three groups based on the treatment received: treatment with DAAs (n = 100) treatment with interferon (IFN) and ribavirin (RBV) (n = 24) and no treatment (n = 15). Patients were followed up for a median duration of 138 months (interquartile range 70–251. DAA treatment reduced overall mortality {hazard ratio [HR] 0.12 [95% confidence interval (CI) 0.04–0.40]; P < 0.001} and improved kidney survival [HR 0.10 ( 95% CI 0.04–0.33); P < 0.001]. Conclusions Results from the RENALCRYOGLOBULINEMIC study indicated that DAA treatment in patients with HCV-MC improves kidney survival and reduces mortality

FGF-23 a novel pro-arrhythmogenic factor: clinical approach in dialysis patients and experimental approach in the adult isolated cardiomyocyte

Trabajo presentado al XLVIII Congreso Nacinal de la Sociedad Española de Nefrología y al IX Congreso Iberoamericano de Nefrología, celebrados en Madrid (España) del 16 al 19 del noviembre de 2018.Peer Reviewe

Papel del factor de crecimiento de fibroblasto (FGF)-23 en la función contráctil del cardiomiocito adulto: nuevo factor pro-arritmogénic

Trabajo presentado al XLVII Congreso Nacional de la Sociedad Española de Nefrología, celebrado en Burgos del 6 al 9 de octubre de 2017.[Objetivo]: La enfermedad cardiovascular y renal tienen a menudo orígenes similares y comparten factores de riesgo comunes. El factor de crecimiento de fibroblastos 23 (FGF-23) se está empezando a considerar en la actualidad como uno de los nuevos factores de riesgo no convencionales para el desarrollo de estas patologías. Sin embargo, es totalmente desconocido si FGF-23 puede o no ejercer un papel relevante sobre la función contráctil del corazón. El objetivo de este estudio es determinar si FGF-23 tiene algún efecto sobre la capacidad funcional de los cardiomiocitos. [Métodología]: Los cardiomiocitos adultos se obtuvieron de corazones de ratas machos Wistar (n=9), mediante disociación enzimática con colagenasa tipo II. Los cardiomiocitos aislados fueron perfundidos con 100 ng/mL de FGF-23 durante 2 minutos. El estudio del manejo del Ca2+ se realizó mediante tinción con el fluoróforo Fluo-3AM y utilizando la microscopía confoca así como técnicas de PatchClamp. Para estudiar la/s vía/s intracelular/es implicada/s en el efecto de FGF-23, los cardiomiocitos fueron preincubados con el bloqueante del receptor de FGF-23 PD173074 o con klotho soluble s-klotho. [Resultados]: Los cardiomiocitos perfundidos con 100 ng/mL FGF-23 presentan un empeoramiento significativo de la contracción (p<0.01) y reducción de las velocidades de contracción y de relajación (p<0.05). Esta alteración viene asociada a una disminución acusada de los transitorios de Ca2+, y por tanto del Ca2+ sistólico. Esta reducción se debe tanto a una disminución de la corriente de entrada Ca2+ (ICaL) en los cardiomiocitos (p<0.001) como a un enlentecimiento de la recaptación del Ca2+ citosólico al interior al retículo sarcoplásmico por la bomba ATPasa SERCA (p<0.01). Además, cuando a los cardiomiocitos perfundidos con FGF-23 se les aplicaba un protocolo de diferentes estimulaciones eléctricas, éstos presentaban alteraciones pro-arritmogénicas caracterizadas por un incremento de la presencia de actividad desencadenada (p<0.01) y un incremento de la liberación espontánea de Ca2+ a través de los denominados sparks y olas de Ca2+ en comparación con los cardiomiocitos perfundidos con vehículo (p<0.01). Estas alteraciones fueron revertidas tanto por PD173074 como por s-klotho (p<0.01). [Conclusión]: FGF-23 altera de forma muy relevante el manejo del Ca2+ intracelular en el cardiomiocito adulto provocando una importante alteración en su función contráctil lo que les predispone a tener un fenotipo pro- arritmogénico, el cual se ve prevenido en presencia de s-Klotho. Estos efectos provocados por FGF-23 sobre el cardiomiocito podrían explicar las alteraciones funcionales cardiacas que presentan los pacientes con enfermedad renal, especialmente aquello que se encuentran en diálisis.Financiación: ISCIII (CP15/00129), Fundación SENEFRO yFONDOS FEDER.Peer Reviewe

Oxidative Status before and after Renal Replacement Therapy: Differences between Conventional High Flux Hemodialysis and on-Line Hemodiafiltration

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.Sin financiación4.546 JCR (2019) Q1, 17/89 Nutrition & Dietetics1.329 SJR (2019) Q1, 25/327 Food Science, 19/128 Nutrition and DieteticsNo data IDR 2019UE

Variations in Circulating Active MMP-9 Levels during Renal Replacement Therapy

Renal replacement therapy (RRT) is complicated by a chronic state of inflammation and a high mortality risk. However, different RRT modalities can have a selective impact on markers of inflammation and oxidative stress. We evaluated the levels of active matrix metalloproteinase (MMP)-9 in patients undergoing two types of dialysis (high-flux dialysis (HFD) and on-line hemodiafiltration (OL-HDF)) and in kidney transplantation (KT) recipients. Active MMP-9 was measured by zymography and ELISA before (pre-) and after (post-) one dialysis session, and at baseline and follow-up (7 and 14 days, and 1, 3, 6, and 12 months) after KT. Active MMP-9 decreased post-dialysis only in HFD patients, while the levels in OL-HDF patients were already lower before dialysis. Active MMP-9 increased at 7 and 14 days post-KT and was restored to baseline levels three months post-KT, coinciding with an improvement in renal function and plasma creatinine. Active MMP-9 correlated with pulse pressure as an indicator of arterial stiffness both in dialysis patients and KT recipients. In conclusion, active MMP-9 is better controlled in OL-HDF than in HFD and is restored to baseline levels along with stabilization of renal parameters after KT. Active MMP-9 might act as a biomarker of arterial stiffness in RRT.Sin financiación4.879 JCR (2020) Q2, 96/295 Biochemistry & Molecular Biology1.125 SJR (2020) Q2, 127/438 BiochemistryNo data IDR 2020UE

The anti-aging factor Klotho protects against acquired long QT syndrome induced by uremia and promoted by fibroblast growth factor 23

Background: Chronic kidney disease (CKD) is associated with increased propensity for arrhythmias. In this context, ventricular repolarization alterations have been shown to predispose to fatal arrhythmias and sudden cardiac death. Between mineral bone disturbances in CKD patients, increased fibroblast growth factor (FGF) 23 and decreased Klotho are emerging as important effectors of cardiovascular disease. However, the relationship between imbalanced FGF23-Klotho axis and the development of cardiac arrhythmias in CKD remains unknown. Methods: We carried out a translational approach to study the relationship between the FGF23-Klotho signaling axis and acquired long QT syndrome in CKD-associated uremia. FGF23 levels and cardiac repolarization dynamics were analyzed in patients with dialysis-dependent CKD and in uremic mouse models of 5/6 nephrectomy (Nfx) and Klotho deficiency (hypomorphism), which show very high systemic FGF23 levels. Results: Patients in the top quartile of FGF23 levels had a higher occurrence of very long QT intervals (> 490 ms) than peers in the lowest quartile. Experimentally, FGF23 induced QT prolongation in healthy mice. Similarly, alterations in cardiac repolarization and QT prolongation were observed in Nfx mice and in Klotho hypomorphic mice. QT prolongation in Nfx mice was explained by a significant decrease in the fast transient outward potassium (K+) current (Itof), caused by the downregulation of K+ channel 4.2 subunit (Kv4.2) expression. Kv4.2 expression was also significantly reduced in ventricular cardiomyocytes exposed to FGF23. Enhancing Klotho availability prevented both long QT prolongation and reduced Itof current. Likewise, administration of recombinant Klotho blocked the downregulation of Kv4.2 expression in Nfx mice and in FGF23-exposed cardiomyocytes. Conclusion: The FGF23-Klotho axis emerges as a new therapeutic target to prevent acquired long QT syndrome in uremia by minimizing the predisposition to potentially fatal ventricular arrhythmias and sudden cardiac death in patients with CKD.Instituto de Salud Carlos III, Ministry of Economy, Industry and Competitiveness (PI17/01093, PI17/01193, PI20/00763, CP15/00129, F18/00261, CPII20/00022, SAF2017-84777-R, PID2020-113238RB-I00)Sociedad Española de Cardiología (SEC), and Fundación Renal Íñigo Álvarez de Toledo (FRIAT), co-funded by the European Regional Development Fund (Fondos FEDER)8.775 JCR (2020) Q1, 13/167 Medicine, General & Internal3.463 SJR (2020) Q1, 61/2446 Medicine (miscellaneous)No data IDR 2020UE

Fibroblast growth factor (FGF)-23 induces ventricular arrhytmogenesis through Ca2+ handling dysregulation

Resumen del trabajo presentado al European Society of Cardiology (ESC) Congress, celebrado en Barcelona (España) del 26 al 30 de agosto de 2017.[Introduction] Fibroblast growth factor (FGF)-23 is a hormone synthesized in bones in response of an increase in circulating phosphate levels. It is known that patients with chronic kidney disease (CKD) show high serum levels of FGF-23 and this increment is gradual as CKD progresses. Despite of FGF-23 has been classically associated to renal dysfunction, during the last years is also considered as a non-conventional risk factor of cardiovascular (CV) disease. However, it is completely unknown whether FGF-23 might alter cardiac contractile function, especially in advanced stages of renal disease in which circulating FGF-23 levels are strongly increased.[Purpose] 1) Analyze whether FGF-23 impairs calcium (Ca2+) handling, a key regulator of contractile function and consequently the ventricular rhythm. 2) Analyze the circulating levels of FGF-23 in dialysis patients and its relationship with the ventricular rhythm.[Methods] Enzymatically isolated adult rat ventricular myocytes (n=9) were perfused firstly with a vehicle solution and subsequently with a FGF-23 solution (100 ng/mL). L-type Ca2+ current (ICaL) was recorded by the whole-cell patch-clamp technique. Ca2+ handling and contractile function were analyzed using confocal microscopy. To determinate FGF-23-dependent pathways, cardiomyocytes were pre-incubated with the FGF-receptors inhibitor PD173074 (10 μmol/mL) or soluble klotho (s-klotho) (100 ng/mL). In addition, FGF-23 serum levels were measured by the FGF-23 (C-term) ELISA-kit in samples from patients under dialysis (n=52).[Results] FGF-23 induced a significant decline of ICaL (p1000 RU/mL of FGF-23 in 68% of total dialysis patients.[Conclusion] Our study uncovers FGF-23 as new target in the intracellular Ca2+ handling, able to impair contractile function and induce a pro-arrhythmogenic phenotype in adult cardiomyocytes.[Future perspectives] Alterations evoked by FGF-23 in cardiomyocytes could explain the CV events observed in patients with CKD, especially those in dialysis. The next step will be to analyze in CKD patients whether high FGF-23 levels impair cardiac function and heart rhythm.This work was supported by grants CP15/00129 from ISCIII, Fundaciόn SENEFRO and Fondos FEDER.Peer reviewe