Disease In End-stage Renal Disease Patients Research Articles

Understanding the Korean Dialysis Cohort for Mineral, Vascular Calcification, and Fracture (ORCHESTRA) Study: Design, Method, and Baseline Characteristics

Introduction: End-stage renal disease (ESRD) is a growing disease worldwide, including Korea. This is an important condition that affects patient outcome. To provide optimal management for mineral disturbance, vascular calcification, and bone disease in ESRD patients, the Korean dialysis cohort for mineral, vascular calcification, and fracture (ORCHESTRA) study was conducted by enrolling Korean dialysis patients. Methods: Sixteen university-affiliated hospitals and one Veterans’ Health Service Medical Center participated in this study. This prospective cohort study enrolled approximately 900 consecutive patients on dialysis between May 2019 and January 2021. Enrolled subjects were evaluated at baseline for demographic information, laboratory tests, radiologic imaging, and bone mineral densitometry (BMD) scans. After enrollment, regular assessments of the patients were performed, and their biospecimens were collected according to the study protocol. The primary outcomes were the occurrence of major adverse cardiovascular events, invasive treatment for peripheral artery disease, and osteoporotic fractures. The secondary outcomes were hospitalization for cerebrovascular disease or progression of abdominal aortic calcification. Participants will be assessed for up to 3 years to determine whether primary or secondary outcomes occur. Results: Between May 2019 and January 2021, all participating centers recruited 900 consecutive dialysis patients, including 786 undergoing hemodialysis (HD) and 114 undergoing peritoneal dialysis (PD). The mean age of the subjects was 60.4 ± 12.3 years. Males accounted for 57.7% of the total population. The mean dialysis vintage was 6.1 ± 6.0 years. The HD group was significantly older, had a longer dialysis vintage, and more comorbidities. Overall, the severity of vascular calcification was higher and the level of BMD was lower in the HD group than in the PD group. Conclusion: This nationwide, multicenter, prospective cohort study focused on chronic kidney disease-mineral and bone disorder and aimed to provide clinical evidence to establish optimal treatment guidelines for Asian dialysis patients.

Prevalence of oral mucosal and periodontal disease amongst patients receiving dialysis

End-stage renal disease (ESRD) requires renal replacement therapy (RRT), namely a renal transplant or renal dialysis or both. Dialysis corrects the electrolyte imbalance and reduces circulating urea and creatinine levels. ESRD patients may present with oral complications and disease due to impaired renal functions, associated comorbidities, or the pharmacological management thereof.To determine the prevalence of periodontal- and oral mucosal disease in ESRD patients undergoing dialysis. Recommendations will be made regarding dental treatment needs and dental management. Cross-sectional study. Fifty-three ESRD patients were evaluated for mucosal lesions and periodontal disease. Patient's age, race, gender, comorbidities, dialysis duration and medicationwere recorded. Treatment urgency was determined, and patients referred accordingly for appropriate dental treatment. Mean age of patients was 42,9 ±10,4 years with a median time on dialysis of 30 months. Majority of patients were hypertensive (94.34%). No oral mucosal lesions was found. PSR score of 3 was mostly found (36.58%). Sixty-two percent of patients had a moderate treatment urgency.A relationship between chronic kidney disease and periodontitis exists. ESRD patients should thus be enrolled into a periodontal screening and treatment program and all dental treatmen

Gut-derived uremic toxin trimethylamine-N-oxide in cardiovascular disease under end-stage renal disease: an injury mechanism and therapeutic target

The main cause of death in patients with end-stage renal disease (ESRD) is cardiovascular disease, and trimethylamine-N-oxide (TMAO) has been found to be one of the specific risk factors in the pathogenic process in recent years. TMAO is derived from intestinal bacterial metabolism of dietary choline, carnitine and other substances and subsequently catalyzed by flavin monooxygenase enzymes in the liver. The changes of intestinal bacteria in ESRD patients have contributed to the accumulation of gut-derived uremic toxins such as TMAO, indoxyl sulfate and indole-3-acetic acid. While elevated TMAO concentration accelerates atherosclerosis through mechanisms such as inflammation, increased scavenger receptor expression, and inhibition of reverse cholesterol transport. In this review, this research introduces the biological function, metabolic processes of TMAO and mechanisms by which TMAO promotes the progression of cardiovascular disease in ESRD patients and summarizes current interventions that may be used to reverse gut microbiota disturbances, such as activated carbon, fecal microbial transplantation, dietary improvement, probiotic and probiotic introduction. It also focuses on exploring intervention targets to reduce the gut-derived uremic toxin TMAO in order to explore the possibility of more cardiovascular disease treatments for ESRD patients.

Galectin 3 (LGALS3) Gene Polymorphisms Are Associated with Biochemical Parameters and Primary Disease in Patients with End-Stage Renal Disease in Serbian Population.

Galectin 3 plays a significant role in the development of chronic renal failure, particularly end-stage renal disease (ESRD). The aim of our study was to investigate the association between Gal-3 and biochemical parameters and primary disease in ESRD patients, by exploring the polymorphisms LGALS3 rs4644, rs4652, and rs11125. A total of 108 ESRD patients and 38 healthy controls were enrolled in the study. Genotyping of LGALS3 gene rs4644, rs4652, and rs11125 polymorphisms was performed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). By multivariate logistic regression analysis, we found that LGALS3 rs4644 CC and rs4652 AA genotypes were significantly associated with a higher risk for lower hemoglobin, higher level of parathyroid hormone, and also occurrence of diabetes mellitus and arterial hypertension. The CAA haplotype was significantly more common in patients with diabetes, low hemoglobin level, and normal PTH level. It has been observed as well that the ACT haplotype was more common in patients with low glomerular filtration, low PTH, and normal hemoglobin level. We found that the LGALS3 rs4644 and rs4652 gene polymorphism may be involved in the pathogenesis and appearance of complications in ESRD patients and thus could be considered a new genetic risk factor in this population.

Pole Test and Ankle-Brachial Index by Using Doppler Ultrasound for Peripheral Arterial Disease in End-Stage Renal Disease Patients.

Peripheral arterial disease (PAD) causes great disability in end-stage renal disease (ESRD). Pole test is a simplified test utilizing the basis of Doppler ultrasound invented to correct false elevation in ankle-brachial index (ABI) in diabetic patients with severe calcification of the tibial artery. However, the role of pole test in ESRD patients is still unclear. The aim of this study was to explore the sensitivity, specificity, and overall utility of pole tests in such patients. One hundred and four patients were recruited and examined with 3 tests: pole test, ABI, and toe-brachial index, the latter serving as the gold standard. Receiver operating characteristic analysis was performed using SPSS version 22.0. The sensitivity, specificity, and other diagnostic values of ABI and pole tests were calculated. There were 104 ESRD patients enrolled. Pole tests showed to have low probability to provide accurate results (area under the curve = 0.505, standard error = 0.042). Low sensitivity of ABI (34.96%) can be observed in ESRD patients. Specificity, positive predictive value, and negative predictive value of ABI in all cases were, respectively, 85.91%, 81.13%, and 43.26%. It is concluded that pole test accuracy seemed to be limited in ESRD patients. ABI was found to be confounded by medial arterial calcification, resulting in low sensitivity as well. The results of this study permit the observation that an optimal tool for screening peripheral arterial disease in ESRD patients remains to be discovered.

Prevalence and Outcomes of Pericardial Effusion in Kidney Transplant Candidates

Pericardial disease is a recognized manifestation of cardiovascular disease in the end-stage renal disease (ESRD) population, and can manifest as pericardial effusion, though the prognosis of pericardial disease in ESRD patients is unclear. In the modern era of renal replacement therapy, little is known about the prevalence and the implications of pericardial effusion in ESRD patients, its echocardiographic characteristics, and risk factors. We conducted a retrospective chart review on subjects > than 18 years of age with known ESRD who were undergoing outpatient evaluation for renal transplantation at Mayo Clinic Arizona between January 2001 and December 2015 and had baseline echocardiogram completed within 3 months of their initial evaluation. Patients with moderate sized pericardial effusions or larger were identified. The pericardial effusion cohort was age and gender matched with a cohort of patients with ESRD without pericardial effusion in a 1:2 fashion. 54 patients with moderate or greater sized pericardial effusion out of 2,820 patients that fit our inclusion criteria, corresponding to a prevalence of 1.9%. A total of 41 patients or 75.9%, had a moderate sized effusion. A total of 13 patients, or 24.1% had a large sized effusion, 7 of whom had tamponade physiology on echocardiography. The presence and size of the effusion was not predictive for worse outcomes. Hemodialysis duration was protective, but no other factors were predictive or protective in the development of moderate sized or larger pericardial effusions, including echocardiographic parameters.

Vitamin K for the Treatment of Cardiovascular Disease in End-Stage Renal Disease Patients: Is there Hope?

In Chronic Kidney Disease, vascular calcification (VC) is highly prevalent even at early stages and is gradually enhanced, along with disease progression to End-Stage Renal Disease (ESRD). The calcification pattern in uremia includes all types of mineralization and contributes to the heavy cardiovascular (CV) burden that is common in these patients. Ectopic mineralization is the result of the imbalance between inhibitors and promoters of vascular calcification, with the latter overwhelming the former. The most powerful, natural inhibitor of calcification is Matrix Gla Protein (MGP), a small vitamin K dependent protein, secreted by chondrocytes and vascular smooth muscle cells. In uremia, MGP was reported as the only molecule able to reverse VC by "sweeping" calcium and hydroxyapatite crystals away from the arterial wall. To become biologically active, this protein needs to undergo carboxylation and phosphorylation, reactions highly dependent on vitamin K status. The inactive form of MGP reflects the deficiency of vitamin K and has been associated with CV events and mortality in ESRD patients. During the past decade, vitamin K status has emerged as a novel risk factor for vascular calcification and CV disease in various populations, including dialysis patients. This review presents evidence regarding the association between vitamin K and CV disease in ESRD patients, which are prone to atherosclerosis and atheromatosis.

MON-056 Leucine-Rich a-2-Glycoprotein 1 increased Peripheral arterial occlusive disease risk in end-stage renal disease

Plasma Leucine-Rich a-2-Glycoprotein 1(LRG1) as a novel serum biomarker for inflammation and angiogenetic diseases. Patients with end-stage renal disease (ESRD) are associated with several health-related adverse outcomes including inflammation, atherosclerosis and premature mortality in individuals. Whether level of Plasma Leucine-Rich a-2-Glycoprotein 1 may associate with the clinical status of hemodialysis patients is unknown. The immunity in ESRD study (iESRD) recruited 169 hemodialysis patients from southern Taiwan. By history taking and detailed chart reviews, baseline co-morbidities were recorded. Peripheral blood was sampled before hemodialysis session and processed immediately. Plasma levels of LRG1 and high-sensitivity C reactive protein were determined by ELISA. Peripheral blood monocyte and T cell differentiation subsets 1 may by multicolor flow cytometry. Among these patients, 100% were LRG-1-seropositive. In a multivariate-adjusted logistic regression model, higher LRG1 tertile was significantly associated with Peripheral arterial occlusive disease(PAOD) (odds ratio = 3.49)after adjusting for gender, hemoglobin, DM, hypertension, and the level hs-CRP. LRG1 exhibit lower TCM percentages of CD4+ and CD8+ T cells but also lower TNAIVE percentages of CD8+ T cells. Similar trends were observed when the absolute cell number of each T cell subsets was analyzed. Level of LRG-1 positively correlated with both IL-6, CRP and WBC, indicating the accumulation of these cytokines participate in the progression of atherosclerosis. LRG-1positively correlates with the existence of the Peripheral arterial occlusive disease in ESRD patients. Role of LRG-1 and the associated inflammation response should the in the pathogenesis of atherosclerosis in this patient population.

Evaluation of left ventricular mechanical dyssynchrony with phase analysis in end-stage renal disease patients with normal gated SPECT-MPI.

Phase analysis using gated single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) is a relatively new tool for the assessment of ventricular synchrony. Hypertension, diabetes, renal diseases, and dyslipidemia may affect the phase parameters though their impact is not well understood. The present study aimed to evaluate the incidence of the left ventricular mechanical dyssynchrony (LVMD) in end-stage renal disease (ESRD) patients with normal gated SPECT-MPI and QRS duration (<120 ms) on electrocardiogram. Data of 129 patients (86 males) referred for gated SPECT-MPI for their pretransplant evaluation with normal gated stress SPECT-MPI (SSS <3 and ejection fraction ≥50%) were included in the study analysis. Documented clinical history along with confounding factors such as hypertension, dyslipidemia, smoking, and alcoholism were evaluated. Left ventricle functional (end-diastolic, end-systolic, and LV myocardial volume) and phase parameters (phase standard deviation [PSD], phase bandwidth [PBW] and entropy) were calculated using the QPS-QGS program. LVMD was noted in 36 (28%) of ESRD patients with normal QRS duration and gated SPECT-MPI. The mean attenuated corrected LV myocardial volume, ejection fraction, mean PSD, and PBW values were 84.3 ± 38.1 ml, 65.3 ± 13.5%, 9.8° ± 3.9°, and 61.4° ± 24.7°, respectively. The LV myocardial volume shows statistically significant correlation with the phase parameters (r = 0.31–0.47; P < 0.001). LVMD is present in a significant number of ESRD patients, and its extent is more with increase in LV myocardial volume. It may have an additional role in risk-stratification for cardiovascular disease in ESRD patients.

Anti-cytomegalovirus IgG antibody titer is positively associated with advanced T cell differentiation and coronary artery disease in end-stage renal disease

BackgroundAccumulating evidence indicates that persistent human cytomegalovirus (HCMV) infection is associated with several health-related adverse outcomes including atherosclerosis and premature mortality in individuals with normal renal function. Patients with end-stage renal disease (ESRD) exhibit impaired immune function and thus may face higher risk of HCMV-related adverse outcomes. Whether the level of anti-HCMV immune response may be associated with the prognosis of hemodialysis patients is unknown.ResultsAmong 412 of the immunity in ESRD study (iESRD study) participants, 408 were HCMV seropositive and were analyzed. Compared to 57 healthy individuals, ESRD patients had higher levels of anti-HCMV IgG. In a multivariate-adjusted logistic regression model, the log level of anti-HCMV IgG was independently associated with prevalent coronary artery disease (OR = 1.93, 95% CI = 1.2~ 3.2, p = 0.01) after adjusting for age, sex, hemoglobin, diabetes, calcium phosphate product and high sensitivity C-reactive protein. Levels of anti-HCMV IgG also positively correlated with both the percentage and absolute number of terminally differentiated CD8+ and CD4+ CD45RA+ CCR7- TEMRA cells, indicating that immunosenescence may participate in the development of coronary artery disease.ConclusionThis is the first study showing that the magnitude of anti-HCMV humoral immune response positively correlates with T cell immunosenescence and coronary artery disease in ESRD patients. The impact of persistent HCMV infection should be further investigated in this special patient population.

Abstract 690: Endothelial-Specific Krüppel-Like Factor 2 Inactivation Promotes Endothelial Dysfunction in the Setting of Uremia

Background: Uremic solutes that accumulate in end-stage renal disease (ESRD) contribute to endothelial dysfunction and subsequent cardiovascular disease in ESRD patients. However, the specific mechanisms which mediate uremia-induced endothelial dysfunction in ESRD are not understood. Kruppel-like factors (KLFs) are important regulators of endothelial homeostasis which may be affected by the uremic milieu. In this study, we examined the role and regulation of endothelial KLF2 in mediating endothelial dysfunction in the setting of uremia. Methods and Results: First, we assessed the impact of the uremic milieu on endothelial gene expression utilizing serum from uremic and non-uremic pigs with chronic renal insufficiency. We demonstrate that KLF2 expression was dose-dependently decreased with uremic serum in human umbilical vein endothelial cells (HUVECS) versus normal serum which was reversed by prolonged serum dialysis or the application of laminar shear stress. Carboxymethyl-lysine (CML) modified albumin, a uremic advanced glycation end-product (AGE), also inhibited KLF2 expression. This effect was completely abrogated by receptor for AGE (RAGE) siRNA, as well as by a constitutively active form of IκBα, implicating a role for RAGE activation and the NF-κB signaling pathway. KLF2 suppression also promoted endothelial dysfunction in vitro, as adenoviral overexpression of KLF2 inhibited reactive oxygen species production and leukocyte adhesion in HUVECs treated with uremic serum or CML-AGE. For in vivo translation, we utilized high-frequency ultrasound and quantified flow-mediated dilation of the femoral artery in endothelial-specific KLF2 conditional knockout (cKO) mice after 5 minutes of hindlimb ischemia and demonstrated a 50% reduction in vasodilation in KLF2 cKO mice compared to controls. The lack of femoral artery vasodilation in KLF2 cKO mice was also accompanied by attenuated return of wall shear stress to baseline independent of blood velocity. Conclusions: Collectively, these observations implicate loss of endothelial KLF2 as mediator of endothelial dysfunction in the setting of uremia and suggest that elevating KLF2 expression may be a novel strategy for prevention and treatment of cardiovascular disease in ESRD.

Abstract 715: Peripheral Artery Disease in Patients with End Stage Renal Disease: Nationwide Trends in Management and Outcomes

Background: Patients with end stage renal disease (ESRD) are at high risk for peripheral artery disease (PAD). We sought to determine the national prevalence of PAD, trends in management and outcomes among this high risk population. Methods: We queried the 2003-2014 National Inpatient Sample databases to identify PAD related admissions (claudication and critical limb ischemia) among patients with ESRD using ICD-9 codes. Temporal trends in treatment options, and in-hospital mortality were analyzed. Multivariate logistic regression was used to assess predictors of major amputation. Results: Among 9 million ESRD patient admissions, 357,949 (3.9%) had PAD related diagnosis. Patients were mainly white (39%), men (58%), with mean age of 65.6 years. The prevalence of PAD slightly decreased from 4.3% in 2003 to 3.9% in 2014 (P trend &lt; 0.001). Utilization of percutaneous transluminal angioplasty (PTA) increased by 142% (10.6% to 25.7%), whereas, open bypass use decreased by 51% (14.1% to 6.9%) during the study period (P trend &lt; 0.001). Moreover, the total number of major amputations was 65,669. There was a notable decline in its usage from 25.9% to 15.3% (adjusted odds ratio [OR] per year: 0.96; 95% confidence interval: 0.95-0.98, P&lt;0.001). Revascularization appeared to reduce the risk of amputation (OR 0.49, P&lt;0.001). On the contrary, hypertension (OR 2.5, P&lt;0.001), heart failure (OR 1.5, P&lt;0.001), and black race (OR 1.5, P&lt;0.001) were independent predictors of amputation. Overall in-hospital mortality rate was 6.3%, with no statistically significant trend throughout the years. Conclusion: PAD is a common disease in ESRD patients. Among therapeutic options, a significant increase in less invasive endovascular revascularization methods and a decline in open bypass surgeries were noted. Despite the significant drop in amputation rates, racial disparities persist, with black patients having higher odds of major amputation.

Association between early Helicobacter pylori eradication and a lower risk of recurrent complicated peptic ulcers in end-stage renal disease patients.

End-stage renal disease (ESRD) patients exhibit an increased incidence of peptic ulcer disease. Helicobacter pylori plays a central role in the development of peptic ulcers. The effect of early H pylori eradication on the recurrence of complicated peptic ulcer disease in ESRD patients remains unclear. The aim of the present study was to explore whether early H pylori eradication therapy in ESRD patients can reduce the risk of recurrent complicated peptic ulcers.We conducted a population-based cohort study and recruited patients with ESRD who had developed peptic ulcers. We categorized patients into early (time lag ≦120 days after peptic ulcer diagnosis) and late H pylori eradication therapy groups. The Cox proportional hazards model was used. The endpoint was based on hospitalization for complicated recurrent peptic ulcers.The early and late H pylori eradication therapy groups consisted of 2406 and 1356 ESRD patients, respectively, in a time lag of 120 days. After adjusting for possible confounders, the early eradication group exhibited a lower rate of complicated recurrent peptic ulcer disease (hazard ratio [HR] = 0.76, 95% confidence interval [CI] = 0.64–0.91, P = 0.003) in a time lag of ≦120 days, but a similar rate of complicated recurrent peptic ulcer disease in time lags of ≦1 year (HR = 0.97, 95% CI 0.79–1.19, P = 0.758) and 2 years (HR = 1.11, 95% CI 0.86–1.44, P = 0.433) compared with the late eradication group.We recommend administering H pylori eradication within 120 days after peptic ulcer diagnosis to H pylori infected ESRD patients who have developed peptic ulcers.

Apoprotein(A) Isoforms Risk Factors for Atherogenesis in Esrd Patients on Haemodialysis

Abstract Introduction. End-stage renal disease (ESRD) patients undergoing hemodialysis are at an increased risk of arteriosclerotic vascular disease (ASVD). The increased risk is commonly attributed to the traditional risk factors related to ESRD. However, interest for more recent risk factors for ASVD, such as the level of lipoprotein(a) and its specific apoprotein(a) has been promoted. The aim of this paper is to determine whether apo(a) phenotype is a risk factor for arteriosclerotic vascular disease in ESRD patients who are on hemodialysis. Methods. Apo(a) phenotypisation was performed by using the Western Blot Technique of blood samples from 96 end-stage renal disease patients who were undergoing hemodialysis, and from 100 healthy individuals. Results. Frequency distribution of the basic apo(a) isoforms calculated by means of the χ2-test has shown that there was no significant statistical difference in distribution among patients on hemodialysis, and healthy carriers (χ2-0.36, p&lt;0.548-for carriers of single apo(a) isoforms, (χ2-0.10, p&lt;0.7545-for carriers of double apo(a) isoforms). The calculated relative risks have demonstrated that apo(a) phenotype was not a risk factor for ASVD in HD patients. Conclusion. Based on the results obtained, it can be concluded that the apo(a) phenotype is not a risk factor for arteriosclerotic vascular disease in patients undergoing hemodialysis.

Evaluation of dialysis in patients with end-stage renal disease by salivary urea, creatinine and uric acid

To explore the changes of saliva urea, creatinine (Cr), and uric acid (UA) before and after hemodialysis in patients with end-stage renal disease (ESRD), and to evaluate the clearing effect of Urea, Cr, and UA. Saliva and serum (2 mL) were collected from the dialysis patients. The concentrations of Urea, Cr, and UA in both samples were measured by biochemical analyzer. The concentrations of Urea, Cr, and UA in the saliva and the serum, and their correlation were analyzed. Before and after the hemodialysis, the reduction ratio (RR) of Urea, Cr, and UA in the saliva and the serum was calculated. In ESRD dialysis patients, the levels of Urea, Cr, and UA in the saliva and the serum were highly correlated (correlation coefficients were 0.979, 0.973, and 0.948, respectively). The concentrations of Urea, Cr, and UA in the saliva and the serum before the dialysis were lower than those after the dialysis, with significant difference (P<0.05). The RR of Urea, Cr, and UA in the saliva and the serum did not differ statistically (P>0.05). The clearing effect of salivar Urea, Cr, and UA is similar to that of the serum. Saliva is expected to replace the serum to evaluate hemodialysis efficacy and monitor the renal disease in ESRD patients.

Cardiovascular disease in end-stage renal disease

The number of end-stage renal disease (ESRD) patients is progressively growing with more than 60,000 ESRD patients on renal replacement therapy in Korea. The mortality risk in ESRD patients is approximately 10 to 20-fold higher compared to the general population, which is mainly attributed to prevalent cardiovascular disease in these patients. However, the risk factors for cardiovascular disease in ESRD patients are different from the general population, and useful biomarkers for predicting cardiovascular mortality are not completely defined. The nationwide multicenter Clinical Research Center (CRC) for ESRD program was initiated in Korea not only to elucidate the incidence and prevalence of cardiovascular disease in ESRD patients but also to identify potential risk factors including various biomarkers for cardiovascular disease. A prospective cohort of 864 incident hemodialysis patients, from 34 dialysis centers of the CRC for ESRD in Korea, was followed up for 36 months, and the clinical outcome of these patients was reviewed. This article presents the recent data from the CRC for ESRD program, and, in addition, brief reviews on key risk factors and potential biomarkers for cardiovascular disease in ESRD patients.

Myocardial microvascular disease and major adverse cardiovascular events in patients with end-stage renal disease: rationale and design of the MICROCARD study

Myocardial ischaemia, a consequence of coronary artery disease, is a major cause of death in patients with end-stage renal disease (ESRD). The pathophysiology and clinical presentation of coronary artery disease in ESRD patients seem to differ from non-ESRD patients with higher implication of myocardial microvascular disease (MMD), higher mortality, fewer myocardial infarctions, less significant coronary stenosis and low efficacy of well-established drugs such as statin and angiotensin-converting enzyme inhibitors. No study has investigated the presence of MMD and its clinical impact in ESRD patients. We designed an observational prospective cohort study to investigate the prevalence of MMD and its association with major adverse cardiovascular events (MACE) in ESRD patients with a positive non-invasive test for myocardial ischaemia. Patients eligible for inclusion are those>18 years old receiving dialysis and/or undergoing investigation for kidney transplantation, who are referred to our renal clinic and meet all the inclusion criteria but none of the exclusion criteria. Patients with a positive test for myocardial ischaemia will be enrolled in the 'invasive group'. They will be further examined to detect simultaneously epicardial coronary stenosis by coronary angiography and MMD using pressure wire measurement of fractional flow reserve and coronary flow reserve followed by calculation of the index of microcirculatory resistance. Patients with a negative test for myocardial ischaemia will be enrolled in a 'control group' designed to verify whether the invasive group is indeed at high risk for MACE. Both groups will be followed up for 2 years to compare the incidence of MACE. The MICROCARD study will phenotype MMD and will investigate its relation with the incidence of MACE in ESRD patients with myocardial ischaemia. Clinicaltrial.gov NCT01291771.

Circulating pro-inflammatory CD4posCD28null T cells are independently associated with cardiovascular disease in ESRD patients

Cytomegalovirus seropositivity is associated with an increased risk for cardiovascular disease in end-stage renal disease (ESRD) patients. Circulating pro-inflammatory CD4posCD28null T cells are expanded in cytomegalovirus-seropositive ESRD patients and potentially could mediate atherosclerotic plaque instability and rupture. In this study, we tested the hypothesis that increased numbers of circulating CD4posCD28null T cells may represent a risk factor for cardiovascular disease in ESRD patients. Prospectively collected data from 240 cytomegalovirus-seropositive stable ESRD patients were analysed. Traditional cardiovascular risk factors (age, smoking, hypercholesterolaemia and diabetes mellitus) and the percentage and absolute number of CD4posCD28null T cells were significantly associated with the presence of atherosclerotic disease, after univariate and multivariate statistical analysis. An ~2-3-fold increase in the prevalence of atherosclerotic disease was noted between patients with the highest and lowest number of CD4posCD28null cells. CD8posCD28null T-cell populations were also significantly expanded in cytomegalovirus-seropositive ESRD patients and closely correlated with the number of CD4posCD28null T cells. However, this cell population was not related to an increased prevalence of cardiovascular disease. Cytomegalovirus-seropositive ESRD patients may have substantially increased numbers of circulating pro-inflammatory CD4posCD28null T cells that are independently associated with the presence of atherosclerotic disease. The expansion of these cells may therefore represent a novel non-traditional cardiovascular risk factor for ESRD patients.

Heterogeneity of carboxyl-terminal parathyroid hormone circulating forms in patients with hyperparathyroidism due to end stage renal disease

To study carboxyl-terminal (COOH) parathyroid hormone (PTH) circulating forms in patients with hyperparathyroidism due to end stage renal disease (ESRD). An immunometric assay that recognizes both intact and COOH PTH forms was developed. The assay, in conjunction with an intact assay, was used to measure PTH in serum samples obtained from 25 patients with hyperparathyroidism due to ESRD. Samples were also submitted to gel filtration chromatography in a Superdex((R)) 30 1.6 x 60 cm column, and the PTH content in the elution tubes, measured using both assays. Values from 39.000 to 232.300 ng/mL (mean +/- sd = 101.680 +/- 45.330 ng/mL) were found using the COOH assay (PTH 39-84 was used as standard). Values obtained by the intact PTH assay ranged from 318 to 3.307 ng/mL (1.769 +/- 693 ng/mL) with a correlation between assays of 0.462 (p = 0.02). The elution profile obtained using the COOH assay showed a preponderance of forms with MW ranging from 8.500 to 4.500 daltons. The profiles obtained from the 25 patients were very similar. In patients with hyperparathyroidism due to ESRD circulating PTH levels contain a broad range of molecular forms including COOH with MW ranging from 8.500 to 4.500 daltons. These forms are not recognized by the standard intact PTH assays. The correlation of these findings to the clinical aspects of bone disease in ESRD patients remains to be studied.

Association of angiotensin-converting enzyme and endothelial Nitric Oxide synthase gene polymorphisms with vascular disease in ESRD patients in a Chinese population

The effect of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and endothelial Nitric Oxide synthase (eNOS) gene G894 --> T on vascular disease in end-stage renal disease (ESRD) patients was rarely studied previously. We investigated such effect in a Chinese population. A total of 153 ESRD patients with vascular disease (88 men and 65 women; mean age +/- SD: 54.0 +/- 13.2) were recruited. Polymerase chain reaction was used to classify the ACE genotypes as II, ID and DD and the eNOS genotypes as GG, GT, and TT. Analyses were performed in ESRD patients with vascular disease (n = 153) and the age-matched controls (n = 148). The frequencies of ACE DD and eNOS TT genotypes and ACE D and eNOS T alleles in ESRD patients with vascular disease were significantly higher than those in the controls (P < 0.05). There was a significant interaction between ACE I/D alleles and eNOS G894 --> T polymorphism: adjusted odds ratio 2.128 (95%CI 1.022-4.434, P = 0.017). These results indicated that the etiology of vascular disease in ESRD patients is associated with ACE and eNOS (G894 --> T) gene polymorphisms. Our data also suggest that an interaction effect may exist between ACE (I/D) and eNOS (G894 --> T) polymorphism in increasing the risk of vascular complications in ESRD patients.