Genetic Markers Among the Israeli Druze Minority Population With End-Stage Kidney Disease.

RATIONALE & OBJECTIVE: Genetic etiologies have been identified among approximately 10% of adults with chronic kidney disease (CKD). However, data are lacking regarding the prevalence of monogenic etiologies especially among members of minority groups. This study characterized the genetic markers among members of an Israeli minority group with end-stage kidney disease (ESKD). STUDY DESIGN: A national-multicenter cross-sectional study of Israeli Druze patients (an Arabic-speaking Near-Eastern transnational population isolate) who are receiving maintenance dialysis for ESKD. All study participants underwent exome sequencing. SETTING & PARTICIPANTS: We recruited 94 adults with ESKD, comprising 97% of the total 97 Druze individuals throughout Israel being treated with dialysis during the study period. PREDICTORS: Demographics and clinical characteristics of kidney disease. OUTCOME: Genetic markers. ANALYTICAL APPROACH: Whole-exome sequencing and the relationship of markers to clinical phenotypes. RESULTS: We identified genetic etiologies in 17 of 94 participants (18%). None had a previous molecular diagnosis. A novel, population-specific, WDR19 homozygous pathogenic variant (p.Cys293Tyr) was the most common genetic finding. Other monogenic etiologies included PKD1, PKD2, type IV collagen mutations, and monogenic forms of noncommunicable diseases. The pre-exome clinical diagnosis corresponded to the final molecular diagnosis in fewer than half of the participants. LIMITATIONS: This study was limited to Druze individuals, so its generalizability may be limited. CONCLUSIONS: Exome sequencing identified a genetic diagnosis in approximately 18% of Druze individuals with ESKD. These results support conducting genetic analyses in minority populations with high rates of CKD and for whom phenotypic disease specificity may be low. PLAIN-LANGUAGE SUMMARY: Chronic kidney disease (CKD) affects many people worldwide and has multiple genetic causes. However, there is limited information on the prevalence of genetic etiologies, especially among minority populations. Our national-multicenter study focused on Israeli Druze patients. Using exome-sequencing, we identified previously undetected genetic causes in nearly 20% of patients, including a new and population-specific WDR19 homozygous pathogenic variant. This mutation has not been previously described; it is extremely rare globally but is common among the Druze, which highlights the importance of studying minority populations with high rates of CKD. Our findings provide insights into the genetic basis of end-stage kidney disease in the Israeli Druze, expand the WDR19 phenotypic spectrum, and emphasize the potential value of genetic testing in such populations.

Interest and perceived capability of self-care in haemodialysis units.

AIMS: To (a) assess patients' interest and perceived capability of participating in haemodialysis; (b) assess nurses' perceptions of patients' interest and perceived capability of participating in haemodialysis; and (c) examine associations between patient characteristics and interest and perceived capability of performing haemodialysis self-care. DESIGN: Cross-sectional, questionnaire-based study. METHODS: Data were collected from dialysis patients and their nurses between October 2018-May 2019. Patients' interest and perceived capability of participation were assessed by a 10-item Likert-type scale developed and tested for this study, with responses ranging from 1 (not interested/no perceived capability) to 5 (already doing task independently). Multivariate linear regression was used to assess the relationship between patient characteristics, including age, sex, education level and severity of illness to ratings of activation level and haemodialysis self-care scale scores. The STROBE checklist was used as a guideline for this study. RESULTS: Ninety-one patients and 31 nurses participated. Overall, patients expressed interest (2.43 ± 0.93) and perceived themselves capable (2.34 ± 0.9) of participating in various haemodialysis-related tasks. Nurses assessed lower interest (2.19 ± 0.77) than patients, but similar average capability (2.31 ± 0.8). Both greater interest and perceived capability were correlated with more years of education and higher patient activation; additionally, interest was associated with disease severity and perceived capability was associated with age. CONCLUSION: Haemodialysis patients are interested and perceive themselves capable of participating in the tasks involved in dialysis care. Nurses underestimate patient interest in participation. RELEVANCE TO CLINICAL PRACTICE: Self-care behaviours among haemodialysis patients are important, as they may affect quality of life and survival. Determining interest and perceived capability of participation is a first step towards evaluating the feasibility of self-care in a supervised haemodialysis setting.

Comparison of the Functional Outcomes of Lower Limb Amputees with or without End-Stage Renal Disease.

BACKGROUND: The potential for full rehabilitation following amputation among end-stage renal disease patients is poor. OBJECTIVES: To evaluate the functional outcomes and survival among amputees treated with hemodialysis at the end of the rehabilitation procedure. METHODS: We recruited 46 patients after lower limb amputation. Of these individuals, 19 (41.3%) were treated with dialysis and 27 (58.7%) were non-dialysis-dependent patients (NDDP). Both groups were divided into three sub-groups according to their independence with regard to activities of daily living (ADL) and their ability to walk with prostheses. RESULTS: The survival of lower limb amputees treated with dialysis was shorter compared to NDDP. Survival after amputation among the NDDP who were fully or partially independent in ADL and with regard to mobility, was longer compared to the non-mobile amputees as with the patients treated with dialysis. CONCLUSIONS: Survival was significantly longer in lower limb amputees NDDP and shorter in patients who did not achieve a certain level of functioning.

Unexpected Normal Colloid Osmotic Pressure in Clinical States with Low Serum Albumin.

BACKGROUND: In clinical states associated with systemic oxidative stress (OS) and inflammation such as chronic kidney disease (CKD), oxidative modifications of serum albumin impair its quantification, resulting in apparent hypoalbuminemia. As the maintenance of oncotic pressure/colloid osmotic pressure (COP) is a major function of albumin, this study examined the impact of albumin oxidation on COP, both in-vivo and in-vitro. METHODS: Patients with proteinuria and patients on chronic hemodialysis (HD) with systemic inflammation and OS were enrolled. Blood samples were collected from 134 subjects: 32 healthy controls (HC), proteinuric patients with high (n = 17) and low (n = 31) systemic inflammation and from 54 patients on chronic hemodialysis (HD) with the highest levels of OS and inflammation. RESULTS: In-vitro oxidized albumin showed significantly higher COP values than non-oxidized albumin at identical albumin levels. In vivo, in hypoalbuminemic HD patients with the highest OS and inflammation, COP values were also higher than expected for the low albumin levels. The contribution to COP by other prevalent plasma proteins, such as fibrinogen and immunoglobulins was negligible. We imply that the calculation of COP based on albumin levels should be revisited in face of OS and inflammation. Hence, in hypoalbuminemic proteinuric patients with systemic OS and inflammation the assumption of low COP should be verified by its measurements.

Does Pomegranate intake attenuate cardiovascular risk factors in hemodialysis patients?

BACKGROUND: Atherosclerotic cardiovascular disease (CVD) is the most common cause of morbidity and mortality among hemodialysis (HD) patients. It has been attributed, among other causes, to hypertension and dyslipidemia. The aim of the present study was to investigate the effect of a year-long consumption of Pomegranate juice (PJ), on two traditional cardiovascular (CV) risk factors: hypertension and lipid profile, as well as on cardiovascular events. METHODS: 101 HD patients were randomized to receive 100 cc of PJ (0.7 mM polyphenols) or matching placebo juice, three times a week for one year. The primary endpoints were traditional CV risk factors; blood pressure and lipid profile. Systolic, diastolic and pulse pressure, plasma levels of triglycerides (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and total cholesterol were monitored quarterly during the study year. Secondary endpoint was incidence of cardiovascular events. RESULTS: PJ consumption yielded a significant time response improvement in systolic blood pressure, pulse pressure, triglycerides and HDL level; an improvement that was not observed in the placebo intake group. These beneficial outcomes were more pronounced among patients with hypertension, high level of triglycerides and low levels of HDL. CONCLUSION: Regular PJ consumption by HD patients reduced systolic blood pressure and improved lipid profile. These favorable changes may reduce the accelerated atherosclerosis and high incidence of CVD among HD patients. TRIAL REGISTRATION: ClinicalTrials.gov registry, Identifier number: NCT00727519.

Pomegranate juice intake attenuates the increase in oxidative stress induced by intravenous iron during hemodialysis.

The hemodialysis (HD) procedure induces oxidative stress (OS), which is further aggravated by intravenous (IV) iron administration, aimed at correcting anemia of patients with HD. We have recently shown that 1 year of pomegranate juice (PJ) intake attenuated OS and inflammation in patients with HD. In the current study, we hypothesized that a single dose of PJ can attenuate the enhanced OS and inflammation induced by both the dialysis procedure and IV iron administration during HD session. Twenty-seven patients with HD were randomized to receive PJ or placebo during 1 dialysis session with IV iron. Blood samples were drawn before and after the session to asses OS biomarkers such as advanced oxidation protein products and myeloperoxidase (MPO), whereas polymorphonuclear leukocyte (PMNL) counts served as an indirect measure of inflammation. At the end of the dialysis session, an increase in advanced oxidation protein products and MPO levels as well as a decrease in PMNLs counts were observed in the placebo group, whereas no significant changes occurred in the PJ group. The postdialysis increase in MPO levels in the placebo group is a direct result of PMNL degranulation, associated with postdialysis decrease in PMNL counts. Degranulation of PMNLs leads to the release of other cell moieties, such as inflammatory mediators and proteases that enhance inflammation. We conclude that PJ intake attenuated the increase in systemic OS and inflammation induced by IV iron administration during the dialysis session. These beneficial effects illuminate the previously observed attenuation in OS and inflammation in patients with HD on prolonged PJ intake.

Albumin oxidation leads to neutrophil activation in vitro and inaccurate measurement of serum albumin in patients with diabetic nephropathy.

Previous studies suggest that oxidative modifications of serum albumin lead to underestimation of albumin concentrations using conventional assays. In addition, oxidation of serum albumin may cause neutrophil activation and further oxidation of albumin, which may result in a series of reciprocal cyclical processes. Because hypoalbuminemia, systemic inflammation, and oxidative stress are common in diabetic nephropathy patients, the aim of this study was to show that albumin modifications and neutrophil activation underlie these reciprocal systemic processes. Blood samples from a cohort of 19 patients with diabetic nephropathy and 15 healthy controls were used for albumin separation. An oxidation-dependent "albumin detection index," representing the detection efficacy of the universal bromocresol green assay, was determined for each subject. This index was correlated with serum albumin levels, various markers of oxidative stress or inflammation, and kidney function. Activation of separated neutrophils by glycoxidized albumin was assessed by the release of neutrophil gelatinase-associated lipocalin (NGAL) and myeloperoxidase (MPO). The albumin detection index of diabetic nephropathy patients was significantly lower compared to that of controls, correlating positively with serum levels of albumin and kidney function and negatively with albumin glycoxidation and inflammatory markers. Glycoxidized albumin had a direct role in neutrophil activation, resulting in NGAL and MPO release. The hypoalbuminemia observed in patients with diabetic nephropathy partially results from underestimation of modified/oxidized albumin using the bromocresol green assay. However, modified or oxidized albumin may lead to a cycle of accelerated oxidative stress and inflammation involving neutrophil activation. We suggest that the albumin detection index, a new marker of oxidative stress, may also serve as a biomarker of diabetic nephropathy severity and its progression.

One year of pomegranate juice intake decreases oxidative stress, inflammation, and incidence of infections in hemodialysis patients: a randomized placebo-controlled trial.

Increased systemic inflammation and oxidative stress are well established as nontraditional key players in the pathogenesis of atherosclerosis and are also involved in the innate immunity dysregulation in hemodialysis (HD) patients. The study aim was to investigate the effect of 1-year intake of pomegranate juice, an antioxidant source, on oxidative stress, inflammation, and long-term clinical outcomes. A randomized placebo controlled double-blind trial was designed, enrolling 101 chronic HD patients to receive during each dialysis 100 cc of pomegranate juice, or matching placebo, three times a week for 1 year. The primary endpoints were levels of oxidative stress and inflammation biomarkers. Secondary endpoints were hospitalization due to infections and the progression of atherosclerotic process based on a composite of variables of the carotid arteries: intima media thickness (IMT), number, and structure of plaques. Pomegranate juice intake yielded a significant time response reduction in polymorphonuclear leukocyte priming, protein oxidation, lipid oxidation, and inflammation biomarkers levels. These beneficial effects were abolished 3 months postintervention. Pomegranate juice intake resulted in a significantly lower incidence rate of the second hospitalization due to infections. Furthermore, 25% of the patients in the pomegranate juice group had improvement and only 5% progression in the atherosclerotic process, while more than 50% of patients in the placebo group showed progression and none showed any improvement. Prolonged pomegranate juice intake improves nontraditional CV risk factors, attenuates the progression of the atherosclerotic process, strengthens the innate immunity, and thus reduces morbidity among HD patients.

Is anemia at hospital admission associated with in-hospital acute kidney injury occurrence?

BACKGROUND: The effect of acute kidney injury (AKI) on anemia has been well-documented. However, the effect of 'preexisting' anemia on AKI has been less addressed. The aims of the present study were to investigate (1) the association between anemia at hospital admission and AKI occurrence, and (2) the effect of 'preexisting' anemia on the clinical outcomes of AKI. METHODS: A retrospective cohort study was undertaken among patients aged > or =17 years who were admitted to our hospital during the year 2006 (n = 34,802). Anemia at hospital admission and AKI occurrences were determined using the WHO definition and the RIFLE criteria, respectively. A subgroup of patients with an estimated glomerular filtration rate > or =60 ml/min/1.73 m(2) was analyzed separately to control for the effect of chronic kidney disease on anemia. RESULTS: The cumulative incidence of AKI was 11.2% in anemic patients at hospital admission, compared to 5.5% in nonanemic subjects. The association between anemia at admission and AKI occurrence remained statistically significant after controlling for potential confounders (odds ratio 1.5, 95% CI 1.4-1.6). In addition, an association between anemia at hospital admission and clinical outcomes of AKI was observed. CONCLUSION: Anemia at hospital admission should be recognized as a potential risk factor for in-hospital AKI occurrence.

Contrast-induced nephropathy among Israeli hospitalized patients: incidence, risk factors, length of stay and mortality.

BACKGROUND: Radiological procedures utilizing intravascular contrast media are being widely applied for both diagnostic and therapeutic purposes. This has resulted in the increasing incidence of procedure-related contrast-induced nephropathy. In Israel, data on the incidence of CIN and its consequences are lacking. OBJECTIVES: To describe the epidemiology of CIN among hospitalized patients in the Western Galilee Hospital, Nahariya (northern Israel), and to explore the impact of CIN on mortality and length of stay. METHODS: The study group was a historical cohort of 1111 patients hospitalized during the year 2006 who underwent contrast procedure and whose serum creatinine level was measured before and after the procedure. Data were electronically extracted from different computerized medical databases and merged into a uniform platform using visual basic application. RESULTS: The occurrence of CIN among hospitalized patients was 4.6%. Different CIN rates were noticed among various high risk subgroups such as patients with renal insufficiency and diabetes mellitus (14.1%-44%). Average in-hospital length of stay was almost twice as long among patients with CIN compared to subjects without this condition. Furthermore, the in-hospital death rate among CIN patients was 10 times higher. A direct association was observed between severity of CIN based on the RIFLE classification and risk of mortality. CONCLUSIONS: Low CIN occurrence was demonstrated in general hospitalized patients (4.6%), and high rates (44%) in selected high risk subgroups of patients (with renal insufficiency or diabetes mellitus). Furthermore, prolonged length of stay and high in-hospital mortality were directly related to CIN severity.

Hospital-acquired acute kidney injury in Israel.

BACKGROUND: Acute kidney injury remains a common significant clinical problem. Yet there are scant data in Israel on the incidence of hospital-acquired AKI and on diagnosis validity. OBJECTIVES: To describe the epidemiology of AKI among hospitalized patients in the Western Galilee Hospital, Nahariya, compare discharge summaries to laboratory diagnosis, and investigate the impact of AKI on mortality and length of stay. METHODS: Computerized medical and laboratory data of 34,802 hospitalized subjects were collected. AKI was diagnosed according to three different definitions. We calculated the sensitivity and specificity of AKI based on ICD-9 diagnosis compared to patient's laboratory data as the gold standard. RESULTS: The overall AKI annual incidence rate was 1-5.1%, depending on the AKI definition used. The incidence of AKI based on ICD-9 diagnosis was significantly lower compared to the laboratory-based diagnosis. Average in-hospital length of stay was 2.4 times longer among patients with AKI compared to subjects without this condition. Furthermore, the in-hospital death rate among AKI patients was 14 times higher than among non-AKI hospitalized subjects, with a positive association between AKI severity and risk of death. CONCLUSIONS: Using AKI laboratory diagnosis as the gold standard revealed ICD-9 diagnosis to be 9.1% sensitive and 99.4% specific. Hospital-acquired AKI is a major contributor to prolonged length of stay and high mortality rates; therefore, interventions to reduce in-hospital disease incidence are required.

Polymorphonuclear leucocyte priming in long intermittent nocturnal haemodialysis patients--is melatonin a player?

BACKGROUND: The relationships between sleep quality, melatonin circadian rhythm and polymorphonuclear leucocyte (PMNL) priming during the night of dialysis treatment compared with a night without dialysis were studied in a group of nocturnal haemodialysis (HD) patients. METHODS: Twenty-eight long intermittent nocturnal HD patients were included. Sleep quality was assessed by a questionnaire and wrist actigraphy. Plasma melatonin levels were assayed every 2 h, from 9 p.m. to 5 a.m. PMNL priming was assessed by the rate of superoxide release from separated PMNLs at 9 p.m. and 5 a.m., on a night of dialysis and a night with sleepover in the dialysis unit without being dialysed. RESULTS: Melatonin levels increased similarly during a night with and without dialysis, reaching peak level at 5 a.m. Most (73%) of the patients had severe sleep disturbances. A significant negative correlation was found between the sleep quality score, the rate of superoxide release from separated PMNLs and melatonin levels. While during a night without dialysis a significant reduction of the rate of superoxide release was found at 5 a.m. (compared with 9 p.m.), no significant reduction was observed when the patients were dialysed. Patients with flat melatonin curves, with <10 pg/ml, showed a faster rate of superoxide release than those with higher levels. CONCLUSIONS: The nocturnal HD process does not affect plasma melatonin levels or rhythms, suggesting that melatonin is not dialysed. Higher endogenous melatonin levels are associated with better sleep and lower PMNL priming. The lower PMNL priming in patients with higher plasma melatonin levels suggests that melatonin overrides the oxidative burden induced by the dialysis process.

[Catheter lock solution--taurolock for prevention of catheter-related bacteremia in hemodialysis patients].

BACKGROUND: Bacteremia and thrombosis are the major complications of tunneled cuff central vein catheters (TCC) used for haemodialysis. Bacterial biofilm is the source of catheter related bacteremia (CRB). Instillation of catheter lock solution (CLS) containing antibiotic-anticoagulant solution can cure and prevent CRB. The aim of this publication is to report our experience with the use of CLS - TauroLock (Taurolidine and 4% citrate) in the prevention of catheter related bacteremia in hemodialysis patients. METHODS: Thirteen patients with TCC on chronic hemodialysis were included in the study. Group A: 5 patients with previous inserted catheters and history of at least one bacteremia episode before the study. Group B: 8 patients with new catheters. At the end of each dialysis the catheters were locked with TauroLock until the next dialysis session. RESULTS: In Group A, the catheter related bacteremia (CRB) was reduced from 9.5-episodes\1000 patients days prior to the study to 1.15 episodes\1000 patients days through 867 days of treatment. In Group B, there were not any CRB during 1179 treatment days in the 8 patients. Due to catheter patency problems, 2500 IU of heparin was added to the TauroLock solution in 3 patients (60%) of group A and in 7 patients (87.5%) of group B and Urokinase instillation in 1 and 3 patients of group A and B respectively. CONCLUSION: The catheter lock solution TauroLock significantly decreased the rate of CRB in HD patients with TCC, to complete prevention in new TCC. Addition of heparin to the TauroLock solution should be considered to maintain catheter patency.

Primed peripheral polymorphonuclear leukocyte: a culprit underlying chronic low-grade inflammation and systemic oxidative stress in chronic kidney disease.

This study characterizes the causal relationship between peripheral polymorphonuclear leukocyte (PMNL) priming, systemic oxidative stress (OS), and inflammation in patients with varying degrees of renal insufficiency (chronic kidney disease [CKD] not on renal replacement therapy [RRT]: continuous ambulatory peritoneal dialysis or hemodialysis [HD]) and healthy control subjects. Rate of superoxide release was measured after stimulation of PMNL with phorbol 12-myristate 13-acetate or zymosan. Priming was estimated by the rate of superoxide release after phorbol 12-myristate 13-acetate stimulation. Systemic OS was related to PMNL priming and intracellular myeloperoxidase activity. Inflammation was linked to peripheral white blood cells and PMNL counts, PMNL apoptosis, and PMNL ex vivo survival in autologous and heterologous sera. PMNL priming and counts were related to the severity of renal failure in CKD not on RRT. Compared with control subjects, PMNL from all CKD patients showed increased priming, highest in HD, with a significant decrease in their response to zymosan. PMNL myeloperoxidase activity and apoptosis were increased in all renal failure patients. Decreased ex vivo cell survival and elevated leukocyte counts were found in all patients, highest in HD. Both PMNL priming and counts correlated negatively with the GFR. A positive significant correlation was shown between PMNL counts and their priming in all groups, suggesting that the increased PMNL count in peripheral blood is an adaptive response to PMNL priming. Hence, PMNL priming is a key mediator of low-grade inflammation and OS associated with renal failure, occurring before the onset of RRT and further augmented in chronic HD.

A rare lung manifestation with rapidly progressive glomerulonephritis (RPGN).

In this unusual case, we report the history of a patient who was hospitalized with pulmonary manifestations presenting as broncholitis obliterance organizing pneumonia (BOOP) associated with ANCA-negative pauci-immune glomerulonephritis. Other known causes for the occurrence of BOOP were excluded. Immediate diagnosis and treatment with a combination of steroids and cytotoxic therapy resulted in a complete remission and prevented eventual dialysis.

Interaction between erythropoietin and peripheral polymorphonuclear leukocytes in continuous ambulatory dialysis patients.

The effect of erythropoietin (EPO) on the oxidative stress (OS) and inflammation caused by polymorphonuclear leukocytes (PMNLs) in end-stage renal failure patients undergoing continuous ambulatory peritoneal dialysis (CAPD) was investigated in vivo and in vitro. The studies were performed on isolated PMNLs from peripheral blood of CAPD patients before and following 6 weeks of EPO treatment and from healthy controls. OS was expressed by the rate of superoxide release from phorbol 12-myristate 13-acetate (PMA) stimulated isolated PMNLs and the inflammatory state was evaluated by PMNL counts of the enrolled subjects. Following 6 weeks of EPO treatment in CAPD patients, both the rate of superoxide release from PMNLs and PMNL counts fell significantly when compared with the pretreatment values. In vitro incubation of PMNLs from CAPD patients with increasing amounts of EPO displayed a significant reduction in their rates of superoxide release. EPO, by direct interaction with PMNLs, attenuated their primed state, causing reduction in oxidative stress and inflammation.