Resistance to Erythropoiesis-Stimulating Agents among Patients on Hemodialysis Is Typically Transient.

INTRODUCTION: This study examines factors associated with erythropoiesis-stimulating agent (ESA) hyporesponsiveness, the duration of ESA hyporesponsiveness, the frequency of new episodes, and variation across countries. METHODS: We used international Dialysis Outcomes and Practice Patterns Study data from 2015 to 2018 (N = 26,656) to investigate changes in ESA Resistance Index (ERI), calculated as epoetin dose divided by [hemoglobin × body weight] in patients on hemodialysis. We illustrated the proportion of patients who moved to other ERI quintiles over 12 months, and we studied the incidence and duration of ESA resistance. We examined case-mix factors associated with quintiles of ERI. RESULTS: Most patients migrated out of their original ERI quintile within 4 months. Only 22% of patients in the top quintile of ERI at baseline (4.4% of all patients) remained in the top quintile during all 12 months of follow-up. A total of 42% of patients manifested an upper-quintile ERI during at least 1 month. Median duration of a new episode of ESA resistance was 2 months. Catheter hemoaccess, elevated C-reactive protein, lower transferrin saturation, lower serum albumin concentration, and recent hospitalization occurred more frequently among patients in the highest ERI quintile at baseline. ERI values were highest in the USA, Italy, and Mideastern nations and lowest in Russia and Japan. DISCUSSION/CONCLUSION: It is a misconception to envision a sizable, fixed segment of the population with permanent resistance to ESA - resistance fluctuates frequently. The implications of these findings for prescription of ESAs and of hypoxia-inducible factor-prolyl hydroxylase inhibitors are discussed.

Medical Director Practice of Advising Increased Dietary Protein Intake in Hemodialysis Patients With Hyperphosphatemia: Associations With Mortality in the Dialysis Outcomes and Practice Patterns Study.

OBJECTIVES: Patients undergoing hemodialysis (HD) may have poor nutritional status and hyperphosphatemia. Nephrologists sometimes manage hyperphosphatemia by prescribing phosphate binders and/or recommending restriction of dietary phosphate including protein-rich foods; the later may, however, adversely affect nutritional status. DESIGN AND METHODS: The analysis includes 8805 HD patients on dialysis ≥ 120 days in 12 countries in Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 4 (2009-2011), from 248 facilities. The primary exposure variable was response to the following question: "For patients with serum albumin 3.0 g/dL and phosphate 6.0 mg/dL, do you recommend to (A) increase or (B) decrease/no change in dietary protein intake (DPI)?". The association between medical director's practice of recommending an increase in DPI and all-cause mortality was analyzed with Cox regression adjusted for potential confounders. Linear and logistic regressions were used to model the cross-sectional associations between DPI advice practice and intermediate markers of patient nutrition. RESULTS: Median follow-up was 1.6 years. In the case scenario, 91% of medical directors in North America had a practice of recommending DPI increase compared to 58% in Europe (range = 36%-83% across 7 countries) and 56% in Japan. The practice of advising DPI increase was weakly associated with lower mortality [HR (95% CI): 0.88 (0.76-1.02)]. The association tended to be stronger in patients with age 70+ years [HR (95% CI): 0.82 (0.69-0.97), P = .12 for interaction]. The practice of advising DPI increase was associated with 0.276 mg/dL higher serum creatinine levels (95% CI: 0.033-0.520) after adjustment for case mix. CONCLUSIONS: Medical director's practice of recommending an increase in DPI for HD patients with low albumin and high phosphate levels was associated with higher serum creatinine levels and potentially lower all-cause mortality. To recommend protein intake liberalization in parallel with phosphate management by physicians may be a critical practice for better nutritional status and outcomes in HD patients.

Effect of comorbidities on survival in patients >80 years of age at onset of renal replacement therapy: data from the ERA-EDTA Registry.

BACKGROUND: The number of elderly patients on renal replacement therapy (RRT) is increasing. The survival and quality of life of these patients may be lower if they have multiple comorbidities at the onset of RRT. The aim of this study was to explore whether the effect of comorbidities on survival is similar in elderly RRT patients compared with younger ones. METHODS: Included were 9333 patients ≥80 years of age and 48 352 patients 20-79 years of age starting RRT between 2010 and 2015 from 15 national or regional registries submitting data to the European Renal Association-European Dialysis and Transplantation Association Registry. Patients were followed until death or the end of 2016. Survival was assessed by Kaplan-Meier curves and the relative risk of death associated with comorbidities was assessed by Cox regression analysis. RESULTS: Patients ≥80 years of age had a greater comorbidity burden than younger patients. However, relative risks of death associated with all studied comorbidities (diabetes, ischaemic heart disease, chronic heart failure, cerebrovascular disease, peripheral vascular disease and malignancy) were significantly lower in elderly patients compared with younger patients. Also, the increase in absolute mortality rates associated with an increasing number of comorbidities was smaller in elderly patients. CONCLUSIONS: Comorbidities are common in elderly patients who enter RRT, but the risk of death associated with comorbidities is less than in younger patients. This should be taken into account when assessing the prognosis of elderly RRT patients.

Apixaban Downregulates Endothelial Inflammatory and Prothrombotic Phenotype in an In Vitro Model of Endothelial Dysfunction in Uremia.

PURPOSE: Chronic kidney disease (CKD) associates with inflammatory and prothrombotic phenotypes, resulting in higher cardiovascular risk. Factor Xa displays functions beyond coagulation, exhibiting proinflammatory effects. The aim of the present study was to investigate whether a direct FXa inhibitor protects from the endothelial dysfunction (ED) caused by uremia. METHODS: Macro (HUVEC) and microvascular (HMEC) endothelial cells (ECs) were exposed to serum from uremic patients or healthy donors, in absence and presence of apixaban (60 ng/ml). We evaluated changes in surface VCAM-1 and ICAM-1, intracellular eNOS, reactive oxygen species (ROS), and von Willebrand Factor (VWF) production by immunofluorescence, reactivity of the extracellular matrix (ECM) towards platelets, and intracellular signaling. RESULTS: ECs exposed to uremic serum triggered dysregulation of all the parameters. Presence of apixaban resulted in decreased expression of VCAM-1 (178 ± 14 to 89 ± 2% on HMEC and 324 ± 71 to 142 ± 25% on HUVEC) and ICAM-1 (388 ± 60 to 111 ± 10% on HMEC and 148 ± 9% to 90 ± 7% on HUVEC); increased eNOS (72 ± 8% to 95 ± 10% on HMEC); normalization of ROS levels (173 ± 21 to 114 ± 13% on HMEC and 165 ± 14 to 127 ± 7% on HUVEC); lower production of VWF (168 ± 14 to 92 ± 4% on HMEC and 151 ± 22 to 99 ± 11% on HUVEC); and decreased platelet adhesion onto ECM (134 ± 22 to 93 ± 23% on HMEC and 161 ± 14 to 117 ± 7% on HUVEC). Apixaban inhibited p38MAPK and p42/44 activation in HUVEC (139 ± 15 to 48 ± 15% and 411 ± 66 to 177 ± 57%, respectively) (p < 0.05 vs control for all parameters). CONCLUSION: Anti-FXa strategies, such as apixaban, prevented ED caused by the uremic milieu, exhibiting anti-inflammatory and antioxidant properties and modulating the reactivity of the ECM.

SARS-CoV-2 Infection in a Spanish Cohort of CKD-5D Patients: Prevalence, Clinical Presentation, Outcomes, and De-Isolation Results.

INTRODUCTION: COVID-19 is a highly contagious disease that has easily spread worldwide. Outpatient maintenance hemodialysis seems to entail an increased risk of contagion, and previous reports inform of increased mortality among this population. METHODS: We retrospectively analyzed clinical and laboratory parameters, outcomes, and management once discharged of CKD-5D patients infected with SARS-CoV-2 from our health area. RESULTS: Out of the 429 CKD-5D population, 36 were diagnosed with SARS-CoV-2 infection (8%): 34 on in-center hemodialysis and 2 on peritoneal dialysis. Five were asymptomatic. The most common symptom was fever (70%), followed by dyspnea and cough. History of cardiovascular disease and elevation of LDH and C-reactive protein during admission were associated with higher mortality. Thirteen patients died (36%), 8 patients were admitted to an ICU, and survival was low (38%) among the latter. The mean time to death was 12 days. Most discharged patients got negative rRT-PCR in nasopharyngeal swabs within 26 days of diagnosis. However, there is a portion of cured patients that continue to have positive results even more than 2 months after the initial presentation. CONCLUSIONS: Patients on dialysis have an increased mortality risk if infected with SARS-CoV-2. Preventive measures have proven useful. Thus, proper ones, such as universal screening of the population and isolation when required, need to be generalized. Better de-isolation criteria are necessary to ensure an appropriate use of public health resources.

Up-regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide.

Endothelial dysfunction is an earlier contributor to the development of atherosclerosis in chronic kidney disease (CKD), in which the role of epigenetic triggers cannot be ruled out. Endothelial protective strategies, such as defibrotide (DF), may be useful in this scenario. We evaluated changes induced by CKD on endothelial cell proteome and explored the effect of DF and the mechanisms involved. Human umbilical cord vein endothelial cells were exposed to sera from healthy donors (n = 20) and patients with end-stage renal disease on haemodialysis (n = 20). Differential protein expression was investigated by using a proteomic approach, Western blot and immunofluorescence. HDAC1 and HDAC2 overexpression was detected. Increased HDAC1 expression occurred at both cytoplasm and nucleus. These effects were dose-dependently inhibited by DF. Both the HDACs inhibitor trichostatin A and DF prevented the up-regulation of the endothelial dysfunction markers induced by the uraemic milieu: intercellular adhesion molecule-1, surface Toll-like receptor-4, von Willebrand Factor and reactive oxygen species. Moreover, DF down-regulated HDACs expression through the PI3/AKT signalling pathway. HDACs appear as key modulators of the CKD-induced endothelial dysfunction as specific blockade by trichostatin A or by DF prevents endothelial dysfunction responses to the CKD insult. Moreover, DF exerts its endothelial protective effect by inhibiting HDAC up-regulation likely through PI3K/AKT.

Data from the ERA-EDTA Registry were examined for trends in excess mortality in European adults on kidney replacement therapy.

The objective of this study was to investigate whether the improvement in survival seen in patients on kidney replacement therapy reflects the enhanced survival of the general population. Patient and general population statistics were obtained from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry and the World Health Organization databases, respectively. Relative survival models were composed to examine trends over time in all-cause and cause-specific excess mortality, stratified by age and modality of kidney replacement therapy, and adjusted for sex, primary kidney disease and country. In total, 280,075 adult patients started kidney replacement therapy between 2002 and 2015. The excess mortality risk in these patients decreased by 16% per five years (relative excess mortality risk (RER) 0.84; 95% confidence interval 0.83-0.84). This reflected a 14% risk reduction in dialysis patients (RER 0.86; 0.85-0.86), and a 16% increase in kidney transplant recipients (RER 1.16; 1.07-1.26). Patients on dialysis showed a decrease in excess mortality risk of 28% per five years for atheromatous cardiovascular disease as the cause of death (RER 0.72; 0.70-0.74), 10% for non-atheromatous cardiovascular disease (RER 0.90; 0.88-0.92) and 10% for infections (RER 0.90; 0.87-0.92). Kidney transplant recipients showed stable excess mortality risks for most causes of death, although it did worsen in some subgroups. Thus, the increase in survival in patients on kidney replacement therapy is not only due to enhanced survival in the general population, but also due to improved survival in the patient population, primarily in dialysis patients.

Survival of patients treated with extended-hours haemodialysis in Europe: an analysis of the ERA-EDTA Registry.

BACKGROUND: Previous US studies have indicated that haemodialysis with ≥6-h sessions [extended-hours haemodialysis (EHD)] may improve patient survival. However, patient characteristics and treatment practices vary between the USA and Europe. We therefore investigated the effect of EHD three times weekly on survival compared with conventional haemodialysis (CHD) among European patients. METHODS: We included patients who were treated with haemodialysis between 2010 and 2017 from eight countries providing data to the European Renal Association-European Dialysis and Transplant Association Registry. Haemodialysis session duration and frequency were recorded once every year or at every change of haemodialysis prescription and were categorized into three groups: CHD (three times weekly, 3.5-4 h/treatment), EHD (three times weekly, ≥6 h/treatment) or other. In the primary analyses we attributed death to the treatment at the time of death and in secondary analyses to EHD if ever initiated. We compared mortality risk for EHD to CHD with causal inference from marginal structural models, using Cox proportional hazards models weighted for the inverse probability of treatment and censoring and adjusted for potential confounders. RESULTS: From a total of 142 460 patients, 1338 patients were ever treated with EHD (three times, 7.1 ± 0.8 h/week) and 89 819 patients were treated exclusively with CHD (three times, 3.9 ± 0.2 h/week). Crude mortality rates were 6.0 and 13.5/100 person-years. In the primary analyses, patients treated with EHD had an adjusted hazard ratio (HR) of 0.73 [95% confidence interval (CI) 0.62-0.85] compared with patients treated with CHD. When we attributed all deaths to EHD after initiation, the HR for EHD was comparable to the primary analyses [HR 0.80 (95% CI 0.71-0.90)]. CONCLUSIONS: EHD is associated with better survival in European patients treated with haemodialysis three times weekly.

Percutaneous left atrial appendage closure, a safe alternative to anticoagulation for patients with nonvalvular atrial fibrillation and end-stage renal disease on hemodialysis: A single center experience.

The evidence about the effectiveness and safety of oral anticoagulation in patients on hemodialysis is conflicting and scarce. Percutaneous left atrial appendage occlusion (LAAO) has demonstrated to be a valid alternative therapeutic option for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). The aim of this study is to present the outcomes of percutaneous LAAO in patients with end-stage renal disease (ESRD) on hemodialysis and NVAF in our center. We conducted a retrospective review of clinical records, demographics, LAAO procedure, complications, and outcomes of patients with NVAF and ESRD on hemodialysis who underwent a percutaneous LAAO in our center between January 2017 and January 2019. In the period of the study, eight patients with ESRD on hemodialysis underwent a percutaneous LAAO in our center. The overall mean age was 67.5 years (range 56-81; SD ± 7.2). All patients had permanent NVAF. The total mean dialysis duration was 8.49 years (range 0.83-14.8; SD ± 6.2). The mean CHA2DS2-VASc and HAS-BLED scores were high (4.75 [SD ± 1.16] and 4.62 [SD ± 0.91], respectively). All patients had history of a major hemorrhagic event (BARC Score ≥3). Most patients (n = 6) showed left ventricular hypertrophy, and the average LVEF was 54% (SD ± 6.5). All devices were implanted successfully. Postprocedural antithrombotic regimen prescribed was based on antiplatelet therapy. No deaths, cardioembolic events, or major bleeding (according to the BARC scale) were reported during a mean follow-up of 14.24 months (SD ± 9.44). Percutaneous LAAO could be of particular interest in patients with NVAF and CKD in hemodialysis. Further studies will be necessary to confirm this hypothesis.

Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease.

BACKGROUND/AIMS: Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by endothelial dysfunction (ED), which exhibits a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. In this study, the effect of several compounds with anti-inflammatory and/or antioxidant properties on uremia-induced endothelial dysfunction has been evaluated in an in vitro model. METHODS: Endothelial cells (ECs) were exposed to sera from uremic patients in the absence and presence of the flavonoids apigenin, genistein and quercetin, the antioxidant enzyme mimetics (AEM) ebselen (glutathione peroxidase mimetic), EUK-134 and EUK-118 (both superoxide dismutase mimetics), and the pharmacological drug N-acetylcysteine (NAC). We explored changes in the expression of adhesion receptors on the cell surface, by immunofluorescence, the production of radical oxygen species (ROS), by fluorescence detection, and the activation of signaling proteins related to inflammation, by both a phosphospecific antibody cell-based ELISA and immunoblotting techniques. RESULTS: Uremic media induced a significantly increased expression of ICAM-1, overproduction of radical oxygen species (ROS) and activation of p38 mitogen activated protein kinase (p38MAPK) and Nuclear Factor kB (NFkB) in ECs. Quercetin, the AEM and NAC showed a significant inhibitory effect on both ICAM-1 expression and ROS generation (p<0.05). All the compounds reduced p38MAPK activation, but only the AEM, especially ebselen, and NAC, both potentiating the glutathione peroxidase pathway, also inhibited NFkB activation. These two compounds were capable of increasing endothelial glutathione levels, especially in response to uremia. CONCLUSION: Our results indicate that the potentiation of the antioxidant pathways can be an effective strategy to improve endothelial dysfunction in uremia and a potential target to reduce the cardiovascular risk in this population.