Eliezer Golan

Calcitriol blunts the deleterious impact of advanced glycation end products on endothelial cells

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-kappaB 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-kappaB-p65 DNA binding activity was enhanced and associated with a decrease in inhibitor kappaBalpha (IkappaBalpha) and an increase in phosphorylated (p)-IkappaBalpha levels. Addition of calcitriol blunted the AGEs-induced elevation of NF-kappaB-p65 DNA binding activity, a phenomenon related to an increased expression of IkappaBalpha. This increase was correlated to declined p-IkappaBalpha 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.

Persistent Asymptomatic Isolated Microscopic Hematuria in Israeli Adolescents and Young Adults and Risk for End-Stage Renal Disease

CONTEXT Few data are available on long-term outcomes among adolescents and young adults with persistent asymptomatic isolated microscopic hematuria. OBJECTIVE To evaluate the risk of end-stage renal disease (ESRD) in adolescents and young adults with persistent asymptomatic isolated microscopic hematuria. DESIGN, SETTING, AND PARTICIPANTS Nationwide, population-based, retrospective cohort study using medical data from 1,203,626 persons aged 16 through 25 years (60% male) examined for fitness for military service between 1975 and 1997 were linked to the Israeli treated ESRD registry. Incident cases of treated ESRD from January 1, 1980, to May 31, 2010, were included. Cox proportional hazards models were used to estimate the hazard ratio (HR) of treated ESRD among those diagnosed as having persistent asymptomatic isolated microscopic hematuria. MAIN OUTCOME MEASURES Treated ESRD onset, defined as the date of initiation of dialysis treatment or the date of renal transplantation, whichever came first. RESULTS Persistent asymptomatic isolated microscopic hematuria was diagnosed in 3690 of 1,203,626 eligible individuals (0.3%). During 21.88 (SD, 6.74) years of follow-up, treated ESRD developed in 26 individuals (0.70%) with and 539 (0.045%) without persistent asymptomatic isolated microscopic hematuria, yielding incidence rates of 34.0 and 2.05 per 100,000 person-years, respectively, and a crude HR of 19.5 (95% confidence interval [CI], 13.1-28.9). A multivariate model adjusted for age, sex, paternal country of origin, year of enrollment, body mass index, and blood pressure at baseline did not substantially alter the risk associated with persistent asymptomatic isolated microscopic hematuria (HR, 18.5 [95% CI, 12.4-27.6]). A substantially increased risk for treated ESRD attributed to primary glomerular disease was found for individuals with persistent asymptomatic isolated microscopic hematuria compared with those without the condition (incidence rates, 19.6 vs 0.55 per 100,000 person-years, respectively; HR, 32.4 [95% CI, 18.9-55.7]). The fraction of treated ESRD attributed to microscopic hematuria was 4.3% (95% CI, 2.9%-6.4%). CONCLUSION Presence of persistent asymptomatic isolated microscopic hematuria in persons aged 16 through 25 years was associated with significantly increased risk of treated ESRD for a period of 22 years, although the incidence and absolute risk remain quite low.

Mortality risk factors associated with familial Mediterranean fever among a cohort of 1.25 million adolescents

Objective There are limited data on long-term comorbidities and mortality among patients with familial Mediterranean fever (FMF). Our objective was to evaluate comorbidities and death rates among individuals with FMF. Methods We studied a nationwide, population-based, retrospective cohort of 1225 individuals with FMF (59% men) in a database of 1 244 350 adolescents (16–20 years of age) medically evaluated for military service between 1973 and 1997. This cohort was linked with the national mortality, cancer and end-stage renal disease (ESRD) registries in Israel. Study outcomes were all-cause mortality, occurrence of ESRD and malignancy by the age of 50 years. Results During 30 years of follow-up, death rates were 8.73/104 versus 4.32/104 person-years in the FMF and control groups, respectively (p=0.002). In a multivariable analysis adjusted for age, birth year, socio-economic status, education, ethnicity and body mass index, FMF was associated with increased mortality in men (HR=1.705 (95% CI 1.059 to 2.745), p=0.028) and women (HR=2.48 (1.032 to 5.992), p=0.042). Renal amyloidosis accounted for 35% and 60% of deaths in men and women, respectively. FMF was not associated with an increased incidence of cancer. Conclusions FMF is associated with increased all-cause mortality that is likely attributed to reduced colchicine compliance or responsiveness. Individuals with FMF do not have an increased incidence of cancer. These results support the awareness among medical community to decrease the higher than average mortality rate among participants with FMF.

Survival disparities within American and Israeli dialysis populations: learning from similarities and distinctions across race and ethnicity.

There are counterintuitive but consistent observations that African American maintenance dialysis patients have greater survival despite their less favorable socioeconomic status, high burden of cardiovascular risks including hypertension and diabetes, and excessively high chronic kidney disease prevalence. The fact that such individuals have a number of risk factors for lower survival and yet live longer when undergoing dialysis treatment is puzzling. Similar findings have been made among Israeli maintenance dialysis patients, in that those who are ethnically Arab have higher end‐stage renal disease but exhibit greater survival than Jewish Israelis. The juxtaposition of these two situations may provide valuable insights into racial/ethnic‐based mechanisms of survival in chronic diseases. Survival advantages of African American dialysis patients may be explained by differences in nutritional status, inflammatory profile, dietary intake habits, body composition, bone and mineral disorders, mental health and coping status, dialysis treatment differences, and genetic differences among other factors. Prospective studies are needed to examine similar models in other countries and to investigate the potential causes of these paradoxes in these societies. Better understanding the roots of racial/ethnic survival differences may help improve outcomes in both patients with chronic kidney disease and other individuals with chronic disease states.

Vitamin D receptor activation in a diabetic-like environment: potential role in the activity of the endothelial pro-inflammatory and thioredoxin pathways.

High blood and tissue concentrations of glucose and advanced glycation end products (AGEs) are thought to play an important role in the development of diabetic vascular complications. Thioredoxin interacting protein (TXNIP) is up-regulated in response to high levels of glucose and is an endogenous inhibitor of thioredoxin (TRX), and may play a contributory role in the occurrence of diabetic-related vascular diseases. Vitamin D inhibits endothelial proliferation and is a cardiovascular protective agent. The present study evaluated the impact of paricalcitol and calcitriol on the endothelial inflammatory and TXNIP pathways in cultured endothelial cells exposed to a diabetic-like environment. Fresh human umbilical vein cord endothelial cells (HUVEC) were treated for 24h with 200 μg/ml AGE-HSA and 250 mg/dl glucose concentrations, with paricalcitol or calcitriol. IL6, IL8, NFκB (p50/p65), receptor of AGE (RAGE), TXNIP, and TRX expressions were evaluated at the levels of mRNA, protein, and TRX activity. Calcitriol and paricalcitol significantly down-regulated the markers involved in the inflammatory responses. Only paricalcitol induced a significant decrease in TXNIP mRNA and protein expressions. Neither paricalcitol nor calcitriol affected TRX reductase activity or TRX mRNA and protein expressions. Our findings indicate that in an endothelial diabetic-like environment, paricalcitol and calcitriol significantly decreased the expression of genes involved in the inflammatory pathway. In this in vitro study, it seems that the TRX antioxidant system was not involved. The different effects found between paricalcitol and calcitriol might reflect the selectivity of vitamin D receptor (VDR) activation.

Frequent involvement of the internal cuff segment in CAPD peritonitis and exit-site infection—an ultrasound study

BACKGROUND The extent of involvement of the subcutaneous Tenckhoff catheter tract in CAPD peritonitis and catheter-related infections is of major therapeutic importance. By definition, both peritonitis and exit-site infections do not involve the catheter tract. However, diagnosis of these infections as well as the more sinister tunnel infection is based mainly on clinical signs. METHODS We examined the usefulness of ultrasound examination (US) of the catheter tract in delineating catheter-related (exit-site and tunnel) infections, and their relationship to each other and to peritonitis. CAPD patients with no evidence of peritonitis or catheter-related infections for 6 months prior to examination served as controls. US were performed by one of two experienced radiologists using the Acuson 128XP/10 scanner with a 7-MHz linear transducer. A positive US was defined as an area of hypoechogenicity (indicative of fluid collection) >2 mm in width along any portion of the catheter tract. Findings were localized into segments(S) as follows: S1, limited to external cuff; S2, intercuff segment adjacent to the external cuff; S3, intercuff segment adjacent to the internal cuff; S4, limited to the internal cuff; and S5, involvement extending throughout the catheter tract. RESULTS Between March 1993 and January 1995, 39 CAPD patients, all with a double-cuff straight Tenckhoff catheter with the exit site situated above the point of entry into the peritoneum were studied. A total of 56 US were performed divided among 26 episodes of peritonitis, four tunnel infections, 13 exit-site infections,and 13 controls. There were 30 positive US distributed among 16 peritonitis, four tunnel, eight exit site infections and two control patients. The two positive controls went on to develop peritonitis within 1 month of the US. The majority of the US findings (13/16 in episodes of peritonitis and 5/8 exit site infections were localized to segment 4, that is, to the internal cuff region. Apart from a significant increase in width in all infected segments versus a normal tunnel, no differences in size were seen between peritonitis, exit-site, or tunnel infections, nor were there any differences in size and localization in these infections when comparing the offending organism (Gram-positive, negative, or culture negative). CONCLUSIONS We conclude that peritonitis and exit-site infections are frequently accompanied by involvement of the catheter tract. The localization of infection to the internal cuff region in cases of exit-site infection probably occurred as a result of downward migration along the catheter tract. This supports the notion that ideally the exit site should be pointing caudally or that the peritoneal catheter have a swan-neck configuration. With regard to peritonitis, infection within the peritoneal cavity appears to extend and involve the internal cuff region. Thus both the internal and external cuffs do not seem to pose an effective barrier against the spread of infection.. Based on our data, we recommend that US be performed as a routine investigation in all cases of exit-site infection and in cases of refractory or relapsing peritonitis.

Calcium, Parathyroid Hormone, and Vitamin D: Major Determinants of Chronic Pain in Hemodialysis Patients

BACKGROUND AND OBJECTIVES Pain is a frequent complaint of hemodialysis (HD) patients, yet information regarding its causes and frequency is relatively scarce. The aim of this study was to evaluate the frequency and possible causes of chronic pain in patients who are on long-term HD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We prospectively enrolled 100 patients who were undergoing maintenance HD for at least 3 mo. Pain was evaluated using the Brief Pain Inventory. Data collected on each participant included age, gender, ethnic origin, body mass index, smoking habits, time on dialysis, type of blood access, comorbidities, and biochemical and hematologic parameters. RESULTS The average age was 64.5 yr; the average time on dialysis 40.4 mo. Forty-five patients were male. Thirty-one participants were of Arabic origin. Fifty-three patients had diabetes, 36 of whom had diabetic retinopathy. Although 51 patients experienced chronic pain, only 19.6% described the pain as severe. Musculoskeletal pain, neuropathic pain, and headache were the most prevalent forms of pain. The presence of diabetic retinopathy and neuropathy (but not diabetes per se) and levels of intact parathyroid hormone, calcium, and calcitriol (but not 25-hydroxyvitamin D(3)) differed significantly between those who experienced chronic pain and those who did not. On a logistic regression model, higher serum calcium levels and intact parathyroid hormone levels >250 pg/ml were independently associated with chronic pain, as well as the presence of diabetic retinopathy. Calcitriol had a marginal effect. CONCLUSIONS Disturbed mineral metabolism is strongly associated with chronic pain in long-term HD patients, along with microangiopathy.

Increased prevalence of HCV antibodies in dialyzed Ashkenazi Jews—a possible ethnic predisposition

BACKGROUND The prevalence of hepatitis C (HCV) antibodies in dialysis patients is considerably higher than that found among healthy blood donors. This increased seroprevalence has been correlated to increased duration of dialysis, mode of dialysis and to the number of blood transfusions administered. However, factors other than nosocomial ones also seem to play a part in disease transmission. The role of the patients ethnic origin, possibly reflecting on his/her genetic makeup has received scant attention. In this study, HCV seroprevalence in our dialysis population, which consists of three major ethnic subgroups (Ashkenazi Jews, Sephardi Jews and Arabs), was examined. METHODS AND RESULTS Altogether HCV seropositivity was determined in 120 dialysed patients--65 males/55 females (76 hemodialysis, 44 CAPD), using second generation ELISA confirmed by RIBA-2. Mean age was 59.7 +/- 15.7 (range 16-86 years). Patients had to have been on dialysis for a minimum of 3 months (mean duration 45.2 +/- 44.5 months). Patients whose end-stage renal disease was due to diabetic nephropathy (DN) or those who had previously been transplanted (TP) were considered as separate groups and compared to the group as a whole. Of the 120 patients, there were 49 Ashkenazi Jews (40.8%), 57 Sephardi Jews (47.5%) and 14 Arabs (11.7%). Overall HCV prevalence was 21.7% (26/120) with a significantly greater prevalence in HD compared to CAPD (30.3 vs. 6.8%, P < 0.01). Respective values for Ashkenazi Jews, Sephardi Jews and Arabs were 30.6, 15.8, and 14.3% (P < 0.01, Ashkenazi Jews vs. Sephardi Jews and Arabs). DN had a lower 3.7% while TP had a higher 46.1% prevalence compared to the group as a whole (P < 0.01). In general, the increased frequency of anti HCV antibodies was significantly correlated to the duration of dialysis and the number of blood transfusions administered. This, however, was not the case in the greater prevalence of HCV found in Ashkenazi Jews compared to Sephardi Jews and Arabs which was independent of the above factors and the mode of dialysis. CONCLUSION Our results showing increased HCV seropositivity in Ashkenazi Jews compared to Sephardi Jews and Arabs, suggest that ethnic factors might predispose to HCV transmission and infectivity.

Prehypertension among 2.19 million adolescents and future risk for end-stage renal disease

Objective: Persistent hypertension in adulthood is a leading cause of end-stage renal disease (ESRD). Whether lower blood pressure (BP) values, in the range of prehypertension, are also associated with future occurrence of ESRD is unclear. Even less clear is the potential risk of early prehypertension appearing in adolescence. To address this question, we examined whether BP measurements in the prehypertensive range at age 16–19 years predict adult ESRD. Methods: Medical data on 2194 635 16–19-year-old adolescents examined for medical fitness prior to military service from 1977 to 2013 were linked to the Israeli ESRD registry in this nationwide population-based cohort study. Incident cases of ESRD were recorded. Survival models were applied. Results: During 35 007 506 person-years of follow-up (median follow-up 16.8 years), there were 690 ESRD cases, with an overall incidence rate of 1.97 cases per 100 000 person-years. Examinees with elevated BP readings in the prehypertensive range (BP between the 90th and 95th percentiles or between 120 and 139/80–89 mmHg) had increased incidence of ESRD with a hazard ratio of 1.32 (95% confidence interval, 1.11–1.58) adjusted for year of birth, age at examination, sex, BMI, education, socioeconomic status, and country of origin. Hypertension (BP above the 95th percentile or above 140/90 mmHg) was associated with a hazard ratio of 1.44 (95% confidence interval, 1.17–1.79). A spline model demonstrated a nadir of risk at SBP values as low as 94 mmHg. Conclusion: Asymptomatic, healthy adolescents with prehypertension have a 32% increased risk for subsequent ESRD, compared with adolescents with optimal BP.

Comparison of Intact PTH and Bio-Intact PTH Assays Among Non-Dialysis Dependent Chronic Kidney Disease Patients

Background The third-generation bio-intact parathyroid hormone (PTH) (1–84) assay was designed to overcome problems associated with the detection of C-terminal fragments by the second-generation intact PTH assay. The two assays have been compared primarily among dialysis populations. The present study evaluated the correlations and differences between these two PTH assays among patients with chronic kidney disease (CKD) stages 3 to 5 not yet on dialysis. Methods Blood samples were collected from 98 patients with CKD stages 3 to 5. PTH concentrations were measured simultaneously by using the second-generation - PTH intact-STAT and third-generation bio-intact 1–84 PTH assays. Other serum biomarkers of bone mineral disorders were also assessed. CKD stage was calculated by using the CKD-Epidemiology Collaboration (EPI) formula. Results Serum bio-intact PTH concentrations were strongly correlated but significantly lower than the intact PTH concentrations (r=0.963, P<0.0001). This finding was consistent among CKD stages 3 to 5. PTH concentrations by both assays (intact and bio-intact PTH) positively correlated with urea (r=0.523, r=0.504; P=0.002, respectively), phosphorus (r=0.532, r=0.521; P<0.0001, respectively) and negatively correlated with blood calcium (r=−0.435, r=−0.476; P<0.0001, respectively), 25(OH) vitamin D, (r=−0.319, r=−0.353; respectively, P<0.0001) and the estimated glomerular filtration rate (r=−0.717, r=−0.688; P<0.0001, respectively). Conclusions Among patients with CKD stages 3 to 5 not on dialysis, the bio-intact PTH assay detected significantly lower PTH concentrations compared with intact PTH assay. Additional studies that correlate the diagnosis and management of CKD mineral and bone disorders with bone histomorphometric findings are needed to determine whether bio-intact PTH assay results are better surrogate markers in these early stages of CKD.