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Background:Infections with B.1.1.529 (Omicron) variants of SARS-CoV-2 became predominant worldwide since late 2021, replacing the previously dominant B.1.617.2 variant (Delta). While those variants are highly transmissible and can evade vaccine protection, population studies suggested that outcomes from infection with Omicron variants are better compared with Delta. Data regarding prognosis of maintenance hemodialysis (MHD) patients infected with Omicron versus Delta variants, however, are scarce. Methods:This retrospective cohort study includes all patients with end-stage kidney disease treated with MHD in Meir Medical Center, Kfar-Saba, Israel, that were diagnosed with SARS-CoV-2 infection between June 2021 and May 2022. Results:Twenty-six subjects were diagnosed with the Delta variant and 71 with Omicron. Despite comparable age between groups and higher mean vaccine doses prior to the infection among the Omicron group (p< 0.001), SARS-CoV-2 infection severity was significantly worse among MHD infected with the Delta variant: 50% developed severe or critical COVID-19 versus 5% in the Omicron group (p< 0.001). Over half of MHD infected with Omicron (57%) were asymptomatic during their illness. The 30-day mortality rate for the whole cohort was 5.2%. It was significantly higher among MHD in the Delta group than in the Omicron group (5/26, 19.2% vs. 0/71, p< 0.001), as was the 90-day mortality rate (5/26, 19.2% vs. 3/71, 4.2%, p= 0.02). Conclusions:Infection with the SARS-CoV-2 Delta variant was associated with worse outcomes compared with Omicron, among subjects on MHD. However, despite mild disease among vaccinated MHD patients, infection with Omicron variant was still associated with the significant 90-day mortality rate.

Introduction: The hemodialysis population is aging, worldwide. In Israel, more than half of the dialysis population is older than 68 years. The policy for vascular access among this population is still a matter of debate, with several studies demonstrating conflicting results. This study compared vascular access outcomes across age groups (<65, 65–75, >75 years) in a single hemodialysis center in Israel.Methods: This was a retrospective, single center analysis of all vascular accesses created in adult hemodialysis patients in our institution, from January 1, 2006, through December 31, 2012. Patient characteristics, primary and secondary access failure, and complications were collected from electronic medical records. Follow-up was until death or up to 5 years.Results: A total of 612 vascular accesses created among maintenance hemodialysis patients were included, of which 196 were in patients >75 years, 184 in patients 65–75 years, and 232 in patients <65 years. Mean age of the >75 years group was 80.5 ± 4.3 years and 60.7% were men. Vascular access site was the most important predicator for primary access failure (odds ratio for primary failure of radiocephalic arteriovenous fistula was 3.5 (95% CI 2.1–6), whereas age did not affect the primary failure rate (odds ratio 1.5, p= 0.648). Radiocephalic fistulas were more prone to secondary failure than other vascular access sites were. Complications were slightly more common in the oldest group. Eight percent of the patients >75 years died before access was used.Conclusions: In our cohort, age did not affect vascular outcomes, whereas VA site seemed to be the most important parameter in primary and secondary VA failures. Our results support considering VA on an individual basis and supply valuable information regarding complication and failure rates of VA among patients >75 years.

Background and objectives: Highly effective vaccines against severe acute respiratory syndrome virus 2 have been developed and administered worldwide. However, protection from coronavirus disease 2019 is not absolute and an optimal vaccination regimen needs to be established. This study assessed the clinical efficacy of the coronavirus disease 2019 vaccine among dialysis patients receiving 3 or 4 doses of vaccine. Design, setting, participants, and measurements: This retrospective study was conducted using the electronic database of Clalit Health Maintenance Organization in Israel. Chronic dialysis patients treated with either hemodialysis or peritoneal dialysis during the coronavirus disease 2019 pandemic were included. We compared clinical outcomes of patients who had received three or four doses of the severe acute respiratory syndrome virus 2 vaccine. Results: This study included 1,030 patients on chronic dialysis, with a mean age of 68 ± 13 years. Among them, 502 patients had received 3 doses of the vaccine and 528 received 4 doses. Severe acute respiratory syndrome virus 2 infection rates, severe COVID-19 that resulted in hospitalizations, COVID-19–related mortality and all-cause mortality rates were lower among chronic dialysis patients who received a fourth dose of vaccine as compared to those who received only 3 doses (after controlling for age, sex and comorbidities). Despite lower mortality rates observed with the Omicron variant, the fourth dose was significantly associated with reduced COVID-19-related mortality (1.7% vs. 3.8%, p= 0.04). Odds ratio for COVID-19-related mortality was 0.44 with 95% CI 0.2–0.98. Conclusions: As seen in the general population and with previous vaccine boosters, the fourth dose of the BNT162b2 vaccine reduced rates of severe COVID-19-related hospitalization and mortality among chronic dialysis patients. Further studies are needed to establish the optimal regimens of vaccination for patients on chronic dialysis. Graphical abstract:

Introduction: Breakthrough COVID-19 may occur in vaccinated people, and may result from declining vaccine effectiveness or highly transmittable SARS-CoV-2 variants, such as the B.167.2 (delta) variant. We investigated risk factors and outcomes for infection with the delta variant among vaccinated hemodialysis patients. Methods: Patients on maintenance hemodialysis who received two doses of the BNT162b2 (Pfizer-BioNTech) vaccine were analysed according to having developed COVID-19 (study group) or not (control group), in a retrospective, observational, comparative study. We compared risk-factors for developing breakthrough COVID-19 and assessed clinical outcomes, including 30-day mortality rates. Results: Twenty-four cases of breakthrough SARS-CoV-2 infection were compared to 91 controls without infection. Breakthrough infection was associated with chronic immunosuppressive treatment, hematological malignancies, and low antibody levels against SARS-CoV-2 spike protein. All COVID-19 cases occurred at least 5 months after vaccination, and most were caused by the B.1.617.2 variant (at least 23/24 cases). COVID-19 was categorized as severe or critical disease in 11/24 patients (46%), and 54% required hospitalization and COVID-19-directed treatment. The source of infection was nosocomial in 6/24 cases (25%), and healthcare-related in 3/24 (12.5%). Mortality rate was 21%. Overall mortality was significantly higher in patients who developed COVID-19 than in controls (odds ratio for all-cause mortality 7.6, 95% CI 1.4–41, p = 0.002). Conclusions: Breakthrough COVID-19 with the B.1.617.2 variant can occur in vaccinated hemodialysis patients and is associated with immunosuppression and weaker humoral response to vaccination. Infections may be nosocomial and result in significant morbidity and mortality. Graphical abstract:

Background: As the geriatric population is growing rapidly, so is the prevalence of chronic kidney disease (CKD). Suitable rehabilitation programs are needed to decrease disability and improve functionality to maintain independence in activities of daily life. Aims: To assess the impact of CKD on the efficacy of rehabilitation in the geriatric population. Methods: Retrospective single-center cohort study, demographic and clinical data of 190 elderly, non-dialysis dependent CKD patients, who underwent rehabilitation, during 2016–2020 were analyzed. Results: Early CKD patients had longer duration of rehabilitation as compared with advanced CKD (32.6 ± 19.5 vs. 25.1 ± 17.6 days, p= 0.011) and tended to be more independent at discharge (37.2% vs. 27.9%, respectively; p&lt; 0.001). Duration of rehabilitation, Mini-Mental State Examination (MMSE), Functional Independence Measurement (FIM) admission and estimated GFR were important predictors of FIM at discharge. Age was negatively correlated with admission FIM, eGFR, MMSE, and discharge FIM. The odds ratio for mortality among patients with advanced as compared to early CKD was 2.197 (CI 95% 1.159–4.166, p= 0.015). Discussion: Existing rehabilitation programs raise questions of suitability for the consistently aging population, play an indispensable part in the goal of achieving functional independence in the elderly and should promote further investigation of the efficacy of rehabilitation for CKD patients. Conclusions: Advanced CKD was associated with lower FIM at admission and discharge, shorter duration of rehabilitation and more dependence at discharge, as compared to patients with early CKD. Implementing a multidisciplinary team, focused on the specific needs of geriatric CKD patients, with clear, objective parameters and goals may lead to better rehabilitative outcomes, with decreased public and private costs of ongoing care.

Background/Aims:Contrast induced nephropathy (CIN) is associated with adverse clinical outcomes in patients undergoing coronary interventions, particularly in patients with advanced chronic kidney. The study was aimed to assess the real-life feasibility and safety of ultra-low volume coronary procedures in patients with advanced chronic kidney disease. Methods:A prospective study that included patients with an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2) was conducted. Coronary procedures were performed using an ultra-low contrast volume technique. Results:The 30 patients had a mean eGFR of 31.8(±8) mL/min/1.73 m2. Indications for coronary angiography were non-ST elevation myocardial infarction (63.3%), unstable (20%), and stable angina pectoris (16.7%). Median contrast volume for diagnostic coronary angiography was 13 mL (interquartile ranges [IQR] 12–14.9), and an additional 13 mL (IQR 8.8–14.3) for percutaneous coronary intervention (PCI). In 3 patients (10%), a ≥25% increase was demonstrated in serum cystatin C levels 48 h following the procedure. None of the patients demonstrated a ≥25% increase in serum creatinine levels at 48 h. Following 6 months, no patient required renal replacement therapy or unplanned coronary intervention. Conclusions:In patients with advanced chronic kidney disease, the ultra-low contrast technique is feasible and effective and can be used safely without a significant deterioration in renal function. This technique may increase the utilization of PCI in high-risk coronary patients with chronic kidney disease.

Parathyroid hormone (PTH), which is elevated in patients with chronic renal failure, has been shown to participate in the development of vascular calcification. Previous studies have demonstrated that PTH may promote endothelial expressions of proinflammatory parameters. On the basis of these data, we evaluated whether PTH may have an impact on endothelial osteoprotegerin (OPG), a vascular-protective factor which may control vascular calcification. Endothelial cells were stimulated with 10−12to 10−10mol/l PTH. PKC and PKA are the main cellular pathways of PTH. Inhibitors and activators of PKC or PKA were used to determine whether these signaling pathways are involved in the control of endothelial OPG. PTH induced a decrease in OPG secretion and mRNA expression. Treatment of PTH-stimulated cells by calphostin C (PKC inhibitor) induced a further decrease in OPG secretion, while Rp-cAMP (PKA inhibitor) had no additional effect. In nonstimulated cells, a PKC activator significantly stimulated OPG secretion, while a PKA activator was associated with a decline. These effects were blunted in the presence of calphostin C and Rp-cAMP, respectively. An increase in OPG secretion induced by a PKC activator indicates that the basal OPG secretion is mediated through PKC. The decrease induced by a PKA activator, which is similar to the decrease observed with PTH, suggests that the action of PTH on OPG secretion and mRNA expression may be due to the PKA pathway.

Advanced glycation end products (AGEs), which are elevated in diabetic and uremic patients, may induce vascular dysfunctions, and calcitriol may improve the cardiovascular complications. Therefore, we examined whether calcitriol may modify the endothelial response to AGEs stimulation. Knowing the importance of nuclear factor-κB in endothelial inflammatory responses, the effect of AGEs and calcitriol on this pathway was also studied. Calcitriol was added to endothelial cells previously incubated with AGE-human serum albumin (HSA). AGE-HSA induced a decrease in endothelial nitric oxide synthase (eNOS) mRNA expression and enzyme activity. Addition of calcitriol to AGE-HSA-treated endothelial cells improved the decreased action of AGEs on the eNOS system. AGE-HSA increased the AGEs receptor mRNA and protein, which were both blunted by calcitriol. The parallel elevation of interleukin-6 mRNA in the presence of AGE-HSA was also blunted by calcitriol. The NF-κB-p65 DNA binding activity was enhanced and associated with a decrease in inhibitor κBα (IκBα) and an increase in phosphorylated (p)-IκBα levels. Addition of calcitriol blunted the AGEs-induced elevation of NF-κB-p65 DNA binding activity, a phenomenon related to an increased expression of IκBα. This increase was correlated to declined p-IκBα levels. The present results support the concept that calcitriol may act as a vascular protective agent counteracting the probable deleterious actions of AGEs on endothelial cell activities.

Parathyroid hormone (PTH), the major systemic calcium-regulating hormone, has been linked to uremic vascular changes. Considering the possible deleterious action of PTH on vascular structures, it seemed logical to evaluate the impact of PTH on the receptor of advanced glycation end products (RAGE) and interleukin 6 (IL-6) mRNA and protein expression, taking into account that such parameters might be involved in the pathogenesis of vascular calcification, atherosclerosis, and/or arteriolosclerosis. Human umbilical vein cord endothelial cells (HUVEC) were stimulated for 24 h with 10−12–10−10mol/l PTH. The mRNA expression of RAGE and IL-6 was established by reverse transcriptase/PCR techniques. RAGE protein levels were determined by Western blot and IL-6 secretion was measured by ELISA. The pathways by which PTH may have an effect on HUVEC functions were evaluated. PTH (10−11–10−10mol/l) significantly increased RAGE mRNA and protein expression. PTH also significantly increased IL-6 mRNA expression without changes at protein levels. The addition of protein kinase (PKC or PKA) inhibitors or nitric oxide (NO) synthase inhibitors significantly reduced the RAGE and IL-6 mRNA expression and the RAGE protein expression. PTH stimulates the mRNA expressions of RAGE and IL-6 and the protein expression of RAGE. These stimulatory effects are probably through PKC and PKA pathways and are also NO dependent. Such data may explain the possible impact of PTH on the atherosclerotic and arteriosclerotic progression.

Background:Pregnancy-induced hypertension is characterized by an increased sympathetic activity and probably by a decreased synthesis/activity of nitric oxide. The aim of the present study is to evaluate whether the beneficial action of the sympathetic antagonist methyldopa (a first-choice hypotensive agent in the treatment of PIH) may be associated to changes in nitric-oxide synthesis. Methods:Forty pregnant Wistar rats received L-NAME (NO synthase inhibitor, 9–10 mg/kg/day) from mid-pregnancy (day 11) through to term. Some rats were treated with daltroban (TxA receptor antagonist, 60 mg/kg/day), diltiazem (calcium channel blocker, 30 mg/kg/day), methyldopa (central adrenergic antagonist, 400 mg/kg/day) or L-arginine (260 mg/kg/day) from mid-pregnancy. The effect of the different treatments on systolic blood pressure (SBP), creatinine clearance (CCR), urine protein excretion (UP) and urinary nitrate excretion (UNO3, representing urine NO metabolite) were evaluated and the results compared with those found in normal pregnancy. Normal pregnant rats receiving similar treatment were used as controls. Results:In normal pregnant (P) rats, SBP values decreased from 94 ± 2 to 83 ± 3 mm Hg at the end of pregnancy (p < 0.01) and CCR augmented significantly. Drug treatment had no significant effect. In NAME-treated rats, at the same period, the SBP augmented from 92 ± 1 to 129 ± 1.8 mm Hg (p < 0.01). At the end of pregnancy, NAME rats had significantly lower CCR values and higher UP excretion when compared with P rats. UNO3 increased significantly in P and in P rats treated with methyldopa. As expected, in NAME rats UNO3 excretion was significantly reduced. Treatment with methyldopa normalized SBP, improved CCR and proteinuria and was associated with an increase in UNO3. Similar results were obtained with L-arginine treatment. Diltiazem lowered SBP significantly but had no effect on renal function or UNO3 and daltroban had no effect. Conclusion:The increased UNO3 found in NAME rats treated with methyldopa suggests that the vasoconstriction secondary to chronic NO inhibition may be partially related to an increased sympathetic activity. The efficient action of the sympathetic antagonist methyldopa may be due not only to its antihypertensive effects but also by its stimulating effect on NO synthesis leading also to an improvement of renal function.

1. In previous studies we have shown that, after the administration of adriamycin, hypertension developed in rats who became pregnant (adriamycin-pregnant rats), whereas virgin animals remained normotensive. Subsequently, we showed that this hypertension was prevented by administration of l-arginine, suggesting that deficient synthesis of nitric oxide may be pathogenetic in this model. 2. To further assess the role of nitric oxide in this model, we measured mean arterial blood pressure after administration of l-arginine to adriamycin-pregnant rats or of NG-nitro-l-arginine-methyl ester (l-NAME) to normal pregnant rats. In other experiments, we assessed the response of isolated perfused arterial mesenteric vessels, precontracted with noradrenaline, to acetylcholine, l-arginine or l-NAME. 3. Blood pressure was decreased in normal pregnant rats, whereas it was elevated in adriamycin-pregnant rats. l-NAME treatment increased blood pressure in normal pregnant rats and l-arginine decreased it in adriamycin-pregnant rats. 4. Mesenteric vessels of adriamycin-pregnant rats exibited an exaggerated vasoconstrictory response to noradrenaline, when compared with the blunted response observed in normal pregnancy. The addition of l-NAME in vitro induced a further contraction, significantly greater in normal pregnant rats. The vasodilatory response to acetylcholine and l-arginine was greater in vessels from adriamycin-pregnant rats. In contrast, responses to either nitroprusside or diazoxide were similar in all groups. 5. The results suggest a state of reduced nitric oxide synthesis in rats with adriamycin nephropathy, leading to vascular maladaption and hypertension in pregnancy.

Background and Aims: Idiopathic pulmonary fibrosis (IPF) is a common and severe form of pulmonary fibrosis. Nintedanib, a triple angiokinase inhibitor, is approved for treating IPF. Galectin 3 (Gal-3) activates a variety of profibrotic processes. Currently, the Gal-3 inhibitor TD139 is being tested in phase II clinical trials. Since this treatment is given ‘on top’ of nintedanib, it is important to estimate its effect on Gal-3 levels. Therefore, we evaluated the impact of nintedanib on Gal-3 expression using both in vitroand in vivomodels, in addition to serum samples from patients with IPF.Methods: Gal-3 levels were evaluated in IPF and control tissue samples, primary human lung fibroblasts (HLFs) following nintedanib treatment (10–100 nM, quantitative polymerase chain reaction), and in a silica-induced fibrosis mouse model with/without nintedanib (0.021–0.21 mg/kg) by immunohistochemistry. In addition, Gal-3 levels were analyzed in serum samples from 41 patients with interstitial lung disease patients with/without nintedanib treatment by ELISA.Results: Nintedanib addition to HLFs resulted in significant elevations in Gal-3, phospho-signal transducer and activator of transcription 3 (pSTAT3), as well as IL-8 mRNA levels (p< 0.05). Gal-3 expression was higher in samples from IPF patients compared with non-IPF controls at the protein and mRNA levels (p< 0.05). In the in vivomouse model, Gal-3 levels were increased following fibrosis induction and even further increased with the addition of nintedanib, mostly in macrophages (p< 0.05). Patients receiving nintedanib presented with higher Gal-3 serum levels compared with those who did not receive nintedanib (p< 0.05).Conclusion: Nintedanib elevates Gal-3 levels in both experimental models, along with patient samples. These findings highlight the possibility of using combined inhibition therapy for patients with IPF.