End-stage Renal Disease Disease Research Articles

"THE RISK FACTORS RESPONSIBLE FOR THE OCCURRENCE OF PNEUMOCYSTIS PNEUMONIA: NARRATIVE REVIEW"

"Introduction: Pneumocystis jirovecii is a fungal pathogen that causes a serious infection called Pneumocystis pneumonia - abbreviated PCP - in people with an immunosuppression condition (e.g.: HIV infection, cancer, organ transplant, inflammatory or autoimmune diseases, treatment with immunosuppressants like corticosteroids), with a high mortality rate. Methods: We searched the PubMed database for publications describing risk factors responsible for the occurrence of Pneumocystis pneumonia, without restrictions of country or English language. The following search terms were used: ((""Pneumocystis""[Mesh]) AND ""Pneumonia, Pneumocystis""[Mesh]) AND ""Risk Factors""[Mesh], for a period of six years, between 2017 and 2022. Data on the type of study and clinical characteristics of the infection caused by Pneumocystis jirovecii in immunodepressed and immunocompetent patients have been extracted. We identified 41 articles, of which 11 have been considered as relevant and are the basis of the present analysis according to our inclusion criteria. Conclusions: The review of the literature to this end shows that patients who have been exposed to the risk factors such as: advanced age with a preponderance in men, nosocomial transmission via human contamination, those with an immunocompromised immune system due to the deficiency of Mannose-binding lectin (MBL) expression and end-stage renal disease disease (ESRD) who do CCRTx, concurrent chemoradiotherapy or RTx, radiotherapy and are treated with immunosuppressive drugs such as: prednisolone (PSL), calcineurin inhibitor, tumor necrosis factor anti-TNF-α, thioprine, mycophenolate mofetil (MMF) and rituximab there is suspicion to developing Pneumocystis pneumonia, should be carefully diagnosed and managed through an appropriate early prophylaxis. In conclusion, in our opinion more deep studies are necessary in this regard."

Bleeding Outcomes Using Novel Oral Anticoagulants (NOACs) in End-Stage Renal Disease (ESRD) Versus Coumadin

Background:Patients with end-stage renal disease (ESRD) have been excluded from pivotal clinical trials with novel oral anticoagulants (NOACs). These patients are both at increased risk of venous and arterial thromboembolism and the risk of bleeding is also elevated, thus making treating such patients a challenge. Patients with ESRD and atrial fibrillation (AF) additionally have an increased risk of stroke, compared with less severe renal impairment. The risk of venous thromboembolism (VTE) is also positively correlated with CKD, suggesting ESRD is a hypercoagulable stage.Vitamin K antagonists (VKAs) such as warfarin are the mainstay of treatment as prevention or treatment of thromboembolic disease in ESRD, although the use is highly debated. Randomized controlled trials (RCTs) evaluating DOACs in AF all demonstrated non-inferiority for stroke or side effects, however these studies excluded patients on hemodialysis (HD) and those with creatinine clearance less than 25-30. There appears to be a dearth of high-quality evidence regarding use of DOACs in patients with ESRD. This retrospective analysis aims to evaluate whether use of NOACS causes increased bleeding rates compared to warfarin in the specific population of ESRD patients.Methods:Our study was a retrospective analysis of data using chart review of patients from an urban community medical center between the years 2017-2020. Retrospective data was entered into an electronic data form. Patients required a documented diagnosis of ESRD on hemodialysis and must have received at least one dose of anticoagulation to be included in analysis. Retrospective data pertaining to bleeding events were extracted for this analysis, including GI bleeding, intracranial bleeding, or any other major bleeding. Major bleeding events were defined as those requiring hospitalization or blood transfusion, or any other specific medical intervention. Demographics and clinical variables were presented using frequency and percentages. Patients were stratified into two groups, NOAC use and warfarin use. Continuous variables were analyzed using independent T test while chi square test was used for categorical variables. A p value <0.05 was considered statistically significant.Results:A total sample of 208 patients with ESRD on dialysis who had received anticoagulation were included in this analysis. 51% of patients were male and the majority were African American (79%). The mean age was 67. 43% of patients were on NOACs while 57% were on warfarin. Several other clinical factors were also recorded, with 38% of patients being obese, 92% with hypertension, 58% with diabetes, 45% with coronary artery disease, and 67% with atrial fibrillation. Bleeding outcomes were recorded for both patients who had received a NOAC or warfarin. 24 bleeding events were noted in NOAC group versus 44 events in the warfarin group. There was a higher rate of any major bleeding in the warfarin group versus NOAC group (37% vs 27%), however this not statistically significant (p=0.138)Limitations:More data will need to be collected to gain statistical significance of primary endpoint findings, and we have estimated that a total of approximately 680 patient outcomes would need to be analyzed to gain statistical significance. This data collection is currently underway. Other limitations include the retrospective nature of this study, with heavy reliance on review of patient charts for proper documentation of clinically relevant bleeding while on anticoagulation. Ideally, a prospective study would be better able to standardize data.Conclusions:Based on current data analysis, there is a trend towards warfarin having higher rates of bleeding compared to DOACs in ESRD patients on dialysis, 37% versus 27%, although this is only approaching statistical significance. These findings may shift current lines of thought that warfarin is a more acceptable choice of anticoagulation in ESRD patients given long term experience with this drug. Further studies are needed to make more definite conclusions. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Coronary microvascular dysfunction is associated with degree of anaemia in end\u2010stage renal disease

BackgroundCoronary microvascular dysfunction (CMD) is common in end-stage renal disease (ESRD) and is an adverse prognostic marker. Coronary flow velocity reserve (CFVR) is a measure of coronary microvascular function and can be assessed using Doppler echocardiography. Reduced CFVR in ESRD has been attributed to factors such as diabetes, hypertension and left ventricular hypertrophy. The contributory role of other mediators important in the development of cardiovascular disease in ESRD has not been studied. The aim of this study was to examine the prevalence of CMD in a cohort of kidney transplant candidates and to look for associations of CMD with markers of anaemia, bone mineral metabolism and chronic inflammation.Methods Twenty-two kidney transplant candidates with ESRD were studied with myocardial contrast echocardiography, Doppler CFVR assessment and serum multiplex immunoassay analysis. Individuals with diabetes, uncontrolled hypertension or ischaemic heart disease were excluded.Results7/22 subjects had CMD (defined as CFVR < 2). Demographic, laboratory and echocardiographic parameters and serum biomarkers were similar between subjects with and without CMD. Subjects with CMD had significantly lower haemoglobin than subjects without CMD (102 g/L ± 12 vs. 117 g/L ± 11, p = 0.008). There was a positive correlation between haemoglobin and CFVR (r = 0.7, p = 0.001). Similar results were seen for haematocrit. In regression analyses, haemoglobin was an independent predictor of CFVR (β = 0.041 95% confidence interval 0.012–0.071, p = 0.009) and of CFVR < 2 (odds ratio 0.85 95% confidence interval 0.74–0.98, p = 0.022).ConclusionsAmong kidney transplant candidates with ESRD, there is a high prevalence of CMD, despite the absence of traditional risk factors. Anaemia may be a potential driver of microvascular dysfunction in this population and requires further investigation.

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.

Relationship between serum apelin and cardiac parameters in hemodialysis patients

Objectives The aim of this work was to study the apelin level in hemodialysis (HD) patients and assess its association with cardiac parameters among these patients. Background Mortality in end-stage renal disease (ESRD) patients on maintenance HD is higher by several folds compared with that in the general population, and up to 50% of deaths in these patients are caused by cardiovascular diseases. Apelin, which is a recently discovered active peptide, has a broad range of physiological and pathological actions. Patients and methods A total of 80 nondiabetic end-stage renal failure patients on regular HD, in addition to 20 apparently healthy individuals as the control group, were studied. Lipid profile, serum apelin level, and echocardiography were measured in all patients. Results Serum apelin is highly significantly lower in ESRD patients on maintenance HD compared with that in the control group (P ≤ 0.001). Serum apelin was significantly positively correlated with left ventricular end-systolic dimension (r = 0.290, P = 0.038), left ventricular end-diastolic dimension (r = 0.30, P = 0.021), interventricular septum (r = 0.295, P = 0.036), right ventricle (r = 0.271, P = 0.042), left atrium (r = 0.357, P = 0.014), and aorta (r = 0.339, P = 0.023) in ESRD patients. Conclusion The apelin level was highly significantly lower in HD patients and it was significantly positively correlated with echocardiographic parameters. Thus it might be involved in the pathophysiology of cardiovascular disease in ESRD.

Anticoagulant and antiplatelet therapy in patients with chronic kidney disease

Atrial fibrillation and cardiovascular death are increased in end-stage renal disease (ESRD) patients compared to the general population. The effect of anticoagulant and antiplatelet medications for these indications in ESRD is unclear. However, both classes of medications have been used for the preservation of vascular access. This review explores the risks and benefits of anticoagulant and antiplatelet medications in ESRD. ESRD patients with atrial fibrillation have a two and three-fold greater risk of death and stroke, respectively, than ESRD patients without atrial fibrillation. Warfarin does not appear to decrease this risk, and increases the risk of bleeding and vascular calcification. Warfarin also does not appear to be effective for vascular access preservation. In a few large observational studies, antiplatelet agents did not decrease the risk of cardiovascular death, but confounding by indication is likely. Antiplatelet agents do appear to prolong unassisted arteriovenous graft patency, but the effect is modest. The role of anticoagulant and antiplatelet agents for atrial fibrillation and cardiovascular disease in ESRD remains unclear. Well designed randomized controlled trials to determine the role of anticoagulation in ESRD patients with atrial fibrillation, and anticoagulant and antiplatelet medications in the preservation of central venous catheter function are required.

Near Normalization of Metabolic and Functional Features of the Central Nervous System in Type 1 Diabetic Patients With End-Stage Renal Disease After Kidney-Pancreas Transplantation

OBJECTIVEThe pathogenesis of brain disorders in type 1 diabetes (T1D) is multifactorial and involves the adverse effects of chronic hyperglycemia and of recurrent hypoglycemia. Kidney-pancreas (KP), but not kidney alone (KD), transplantation is associated with sustained normoglycemia, improvement in quality of life, and reduction of morbidity/mortality in diabetic patients with end-stage renal disease (ESRD).RESEARCH DESIGN AND METHODSThe aim of our study was to evaluate with magnetic resonance imaging and nuclear magnetic resonance spectroscopy (1H MRS) the cerebral morphology and metabolism of 15 ESRD plus T1D patients, 23 patients with ESRD plus T1D after KD (n = 9) and KP (n = 14) transplantation, and 8 age-matched control subjects.RESULTSMagnetic resonance imaging showed a higher prevalence of cerebrovascular disease in ESRD plus T1D patients (53% [95% CI 36–69]) compared with healthy subjects (25% [3–6], P = 0.04). Brain 1H MRS showed lower levels of N-acetyl aspartate (NAA)-to-choline ratio in ESRD plus T1D, KD, and KP patients compared with control subjects (control subjects vs. all, P < 0.05) and of NAA-to-creatine ratio in ESRD plus T1D compared with KP and control subjects (ESRD plus T1D vs. control and KP subjects, P ≤ 0.01). The evaluation of the most common scores of psychological and neuropsychological function showed a generally better intellectual profile in control and KP subjects compared with ESRD plus T1D and KD patients.CONCLUSIONSDiabetes and ESRD are associated with a precocious form of brain impairment, chronic cerebrovascular disease, and cognitive decline. In KP-transplanted patients, most of these features appeared to be near normalized after a 5-year follow-up period of sustained normoglycemia.

ENOS and Caveolin-1 Gene Polymorphisms Interaction and Intima Media Thickness: A Proof of Concept Study in ESRD Patients

Caveolae are a prominent microdomain in endothelial cells and appropriate localization in caveolae is fundamental for endothelial nitric oxide synthase (eNOS) activity. Since the Glu298Asp variant in the eNOS gene alters caveolar localization of the corresponding enzyme, we tested the interaction between this variant and the rs4730751 polymorphism of the caveolin-1 (CAV-1) gene as related to arterial remodeling in end-stage renal disease (ESRD) patients. One hundred and thirty-three ethnically homogeneous ESRD patients underwent carotid ultrasonographic studies to measure intima-media thickness (IMT) and carotid cross-sectional area (CSA). Genotyping was performed by high-throughput allelic discrimination assays on real-time PCR. Arterial remodeling was associated to the number of G alleles of CAV-1 polymorphism, GG homozygotes displaying an IMT and a CSA that were, respectively, 16% and 21% higher than those in patients without the risk allele (P < 0.012). In multiple linear regression analyses including the CAV-1 and the eNOS polymorphisms and adjusting for classical risk factors and risk factors peculiar to ESRD both polymorphisms were independent correlates of IMT (CAV-1: β = 0.20, P = 0.01; eNOS β = 0.25, P = 0.001) and CSA (CAV-1: β = 0.20, P = 0.01: eNOS β = 0.13, P = 0.09). Furthermore, strong interactions emerged between the two polymorphisms for explaining the variability in IMT (P = 0.001) and in CSA (P = 0.038) in these patients. Overall these findings form preliminary evidence that disturbed interaction between CAV-1 and eNOS may be of relevance for arterial disease in ESRD and perhaps in other human diseases.

Endogenous Secretory Receptor for Advanced Glycation End-Products and Cardiovascular Disease in End-Stage Renal Disease

The receptor for advanced glycation end-products (RAGE) is involved in microvascular and macrovascular complications in diabetes. The expression of RAGE is up-regulated in atherosclerotic plaques of diabetic animals, and the augmentation of atherosclerosis in diabetic mice is inhibited by the competition of RAGE. An endogenous secretory RAGE (esRAGE) was identified as a novel splice variant carrying all of the extracellular domains, but devoid of the transmembrane and intracytoplasmic domains. The esRAGE is released from the cells, to bind advanced glycation end-products, and this is capable of neutralizing the actions of advanced glycation end-products on endothelial cells in culture. The adenoviral overexpression of esRAGE restores the impairment of vascular dysfunction in diabetes, suggesting that esRAGE may be an important inhibitor of RAGE signaling in vivo, and may be useful for the prevention of diabetic vascular complications. In 203 age-matched and sex-matched type 2 diabetic and 134 nondiabetic subjects, plasma esRAGE levels were inversely associated with carotid or femoral atherosclerosis. In patients with end-stage renal disease (ESRD), plasma esRAGE levels are higher than in those without ESRD. In a cohort of 206 patients (including 171 nondiabetic patients) with chronic renal failure who were followed for a median of 111 months, the cumulative incidence of cardiovascular death by Kaplan-Meier estimation was significantly higher in subjects in the lowest tertile of plasma esRAGE than in those in the middle or highest tertile. Compared with the lowest tertile of plasma esRAGE, the hazards ratios for the highest and middle tertile were 0.40 (95% confidence interval, 0.18 to 0.89) and 0.26 (95% confidence interval, 0.10 to 0.66), respectively. The higher risk at the lower level of esRAGE was still significant even after adjustment for body mass index, hypertension, dyslipidemia, and vascular complications, and was confounded only by age and diabetes. Thus, we postulate that plasma esRAGE is a potential protective factor and a novel biomarker against the occurrence of cardiovascular disease in ESRD.

Negative outcome studies in end-stage renal disease: how dark are the storm clouds?

The end-stage renal disease (ESRD) population treated by dialysis has grown remorselessly over the last five decades, in all continents. This growth is already a major burden to the healthcare economies of wealthy countries, and is thus a challenge for policy makers, health care providers and financial planners [1]. Fortunately, recent data (just published in NDT) suggest a stabilization/decline in the incidence of ESRD in some developed countries, possibly related to the successful implementation of renoprotective strategies in pre-dialysis chronic kidney disease (CKD) [2,3]. Dialysis patients have an impressive and worrying mortality, comparable to or worse than that seen in many cancers, e.g. 20–25% annualized mortality in some systems [4]. Around 50% of this increased mortality is due to cardiovascular (CV) disease. This is explicable, as at the start of dialysis, up to 80% of subjects already have at least subclinical CV disease. Despite significant progress in many branches of medicine over the last decades—for example, significant reductions in myocardial infarction and stroke rates in the general population [5,6]—mortality rates for dialysis patients remain practically unchanged [4,7] over the same time period. This is first explained by more liberal criteria for inclusion in renal replacement therapy (RRT) programmes, with more elderly, diabetic and CV-diseased patients treated by dialysis in recent years. Second, CV disease in ESRD is often underinvestigated and undertreated, compared to CV disease in non-renal cohorts [8]. Third, therapeutic interventions in dialysis patients aimed at reducing CV morbidity and mortality may be either ‘too little, too late’ or inadequate, as most traditional and uraemia-specific [9] risk

Acute effects of haemodialysis on biochemical modulators of endothelial function

To assess the acute effects of haemodialysis (HD) on biochemical factors modulating endothelial function. Academic medical centre. Forty patients (age 63.5 +/- 2.2 years, mean +/- SEM) undergoing HD. Folic acid (F), homocysteine (tHcy), asymmetric dimethylarginine (ADMA), high-sensitivity C-reactive protein (CRP) and malondialdehyde (MDA) were measured pre-HD, 1 h after commencing HD and within the last hour of HD (end-HD). Endothelium-dependent and -independent vasodilatation were measured by applanation tonometry (changes in augmentation index, AIx, postinhaled salbutamol and postsublingual nitroglycerin) in conjunction with biochemical measurements. Marked reductions in serum F (616 +/- 73 vs. 273 +/- 30 nmol L(-1), P < 0.001), tHcy (16.3 +/- 0.7 vs. 11.2 +/- 0.5 micromol L(-1), P < 0.001) and ADMA (0.64 +/- 0.02 vs. 0.47 +/- 0.02 micromol L(-1), P < 0.001) occurred end-HD, whereas CRP and MDA levels did not significantly change. There was no significant change in endothelium-dependent vasodilatation, whereas endothelium-independent vasodilatation improved end-HD (-23.1 +/- 1.9 vs. -17.3 +/- 1.3%, P = 0.018). Regression analysis showed that both higher ADMA (P = 0.029) and lower F levels (P = 0.040) end-HD were determinants of reduced endothelium-dependent vasodilatation end-HD (R(2) = 0.23). HD is associated with significant reductions in F, tHcy and ADMA serum concentrations. The lack of significant effects of HD on endothelium-dependent vasodilatation could be secondary to the concomitant loss of factors either enhancing (F) or impairing (ADMA) endothelial function.

Prognostic value of the New York Heart Association classification in end-stage renal disease

The New York Heart Association (NYHA) classification is a strong predictor of mortality and an established instrument for risk stratification in patients with heart disease but data on the validity of this classification in end-stage renal disease (ESRD) are sparse. In this study, we tested the predictive value of the NYHA in patients with ESRD and compared it with that of two established indexes of disease severity, i.e. the Khan index and the renal disease severity score (RDSS). The study cohort was composed of 1322 incident patients in a dialysis registry (772 male and 550 female, age 61+/-16 years). During the follow-up period (41+/-27 months) 551 patients died. A multivariate COX model including the NYHA classification explained 39% of the variation in mortality, a figure almost identical to that of a model based on the RDSS (37%) and superior (P<0.001) to that provided by the Khan index-based model (32%). The area under the receiver operating characteristic curve of NYHA classification, as related to all-cause mortality, was 0.74 (95% CI: 0.71-0.77, P<0.001). Again, RDSS had a predictive value for mortality (0.74, 95% CI: 0.72-0.77) identical to that of NYHA and higher than that of the Khan index (0.70, 95% CI: 0.67-0.72). The NYHA is a powerful predictor of mortality in ESRD and provides prognostic information equal or superior to that given by other established indexes of disease severity. Given the pervasive nature of cardiovascular disease in ESRD, this classification may be recommended for risk stratification in this population.

CHAPTER 5

CHAPTER 5

The role of vitamin D in left ventricular hypertrophy and cardiac function

The role of vitamin D in left ventricular hypertrophy and cardiac function. Cardiovascular disease is the leading cause of death among patients with end-stage renal disease (ESRD). Traditional cardiac risk factors, as well as other factors specific to the ESRD population such as hyperphosphatemia, elevated calcium and phosphate product, abnormal lipid metabolism, hyperhomocysteinemia, and chronic inflammation play a role in the excessive risk of cardiovascular death in this population. Left ventricular disorders are proven risk factors for cardiac mortality in hemodialysis patients. These disorders are present in incident ESRD patients at rates far above the general population. There is an accumulating body of evidence that suggests that vitamin D plays a role in cardiovascular disease. Abnormal vitamin metabolism, through deficiency of the active form of 1,25-dihydroxyvitamin D(3), and acquired vitamin D resistance through the uremic state, have been shown to be important in ESRD. Vitamin D deficiency has long been known to affect cardiac contractility, vascular tone, cardiac collagen content, and cardiac tissue maturation. Recent studies using vitamin D receptor deficient mice as a model demonstrate a crucial role of vitamin D in regulation of the renin-angiotensin system. Additionally, there is emerging evidence linking treatment with vitamin D to improved survival on hemodialysis and improvement in cardiac function. The emergence of this data is focusing attention on the previously underappreciated nonmineral homeostatic effects of vitamin D that very likely play an important role in the pathogenesis of cardiac disease in ESRD.

Differential management of cardiovascular disease in ESRD by nephrologists and cardiologists

Background: Mortality and morbidity from cardiovascular disease are high in patients with end-stage renal disease (ESRD). The cardiovascular profile of patients with ESRD may differ from that of the general population. We examined how nephrologists and cardiologists differ in managing hypertension and cardiovascular disease in patients with ESRD. Methods: Seven cases incorporating relevant clinical and echocardiographic findings common to this population were developed based on a chart review of an ESRD population. Each ESRD case incorporated a clinical presentation designed to test for a specific dichotomous response to a common and important clinical problem. Nine nephrology and 7 cardiology faculty members, each paired with a senior clinical fellow from the discipline, were surveyed. Results: Nephrologists were less likely than cardiologists to initiate β-blockade in patients with echocardiographic evidence of regional wall motion abnormalities if there was no history of coronary artery disease (CAD; P < 0.01). In patients with known CAD, cardiologists were more likely than nephrologists to intensify antihypertensive therapy, even in the setting of a history of fractures associated with orthostatic hypotension (P < 0.02). Decision making did not differ between subspecialists in the management of left ventricular hypertrophy, congestive heart failure, or diastolic dysfunction. Conclusion: Nephrologists and cardiologists differ in their management of hypertension in the presence of ischemic heart disease in the ESRD population. Only limited data specific to the ESRD population are available to assess which approach is superior. The discipline-driven differential management approaches observed emphasize the need for better evidence-based management strategies for this population.

Effect of erythropoietin on cardiovascular prognosis parameters in hemodialysis patients

Renal anemia is an important determinant for left ventricular hypertrophy in dialysis patients and an independent prognosis parameter for the cardiovascular survival in dialysis patients. In addition, an autonomic dysfunction is associated with the uremic state and influences the cardiovascular risk in patients with end-stage renal disease (ESRD). We investigated in this prospective longitudinal study the effect of hemoglobin normalization by a chronic treatment with recombinant human erythropoietin (rhEPO) on cardiovascular prognosis parameters in 23 patients on chronic hemodialysis with renal anemia (hemoglobin concentration < or =10.5 g/dL) and echocardiographically proven left ventricular hypertrophy. We studied muscle sympathetic nerve activity measured by microneurography; cardiopulmonary baroreflex activity by lower-body negative pressure (LBNP-) testing; left ventricular structure and mass index (LVMI) by echocardiography; blood pressure by 24-hour readings; peripheral blood flow and vascular resistance by plethysmography before (U1) and after 7 months of chronic rhEPO treatment (U2). In the anemic state, mean (+/- SD) muscle sympathetic nerve activity in ESRD was elevated (U1 rest, 34 +/- 13 bursts per minute) and cardiopulmonary baroreflex response during LBNP markedly lacking (U1 -15 mm Hg, 34 +/- 13 bursts per minute) reflecting a severely impaired autonomic function. Normalization of the hemoglobin concentration by chronic rhEPO treatment (U1, 10.5 +/- 0.9 g/dL versus U2, 13.4 +/- 3.1 g/dL, P <0.001) did not influence sympathetic nerve activity (U2, 34 +/- 15 bursts per minute, NS) and cardiopulmonary baroreflex sensitivity did not change (U2 -15 mm Hg, 37 +/- 16 bursts per minute, NS). LVMI decreased significantly after chronic treatment with rhEPO (U1, 134 +/- 26 g/m2 versus U2, 97 +/- 25 g/m2, P < 0.001) and left ventricular geometry developed from an asymmetric to a symmetric configuration (U1, relative wall thickness 0.58 versus U2, 0.43, P < 0.001). Under treatment with rhEPO, 24-hour systolic and diastolic blood pressure did not increase (systolic U1, 132 +/- 4 mm Hg versus U2, 128 +/- 3 mm Hg, NS, and diastolic U1, 76 +/- 2 mm Hg versus U2, 73 +/- 2 mm Hg, NS). Peripheral blood flow (U1, 6.1 +/- 3.3 mL/100 mL/min versus U2, 6.2 +/- 0.6 mL/100 mL/min, NS) as well as forearm vascular resistance (U1, 15.7 +/- 3.3 mm Hg/mL/100 mL versus U2, 14.9 +/- 3.1 mm Hg/mL/100 mL, NS) did not change by chronic rhEPO treatment. Normalization of hemoglobin by chronic rhEPO treatment in dialysis patients has beneficial cardiovascular effects with regression of left ventricular hypertrophy and improvement of left ventricular geometry. However, a reduction of sympathetic overactivity or a resetting of baroreceptor sensitivity by a rhEPO treatment in dialysis patients in the medium-term could not be demonstrated. The reason for this may be the complex and multifactorial pathomechanism of autonomic dysfunction and cardiovascular disease in ESRD.

Opportunities for improvement in the cardiovascular care of patients with end-stage renal disease

Cardiovascular disease accounts for the majority of morbidity and mortality in patients with end-stage renal disease (ESRD). Studies have identified several explanations for this observation, such as high rates of cardiovascular risk factors, lesser use of cardioprotective strategies, adverse outcomes with cardiovascular drugs and procedures, and accelerated atherosclerosis and myocardial disease in ESRD. Based on these findings, this article addresses the critical opportunities for improvement in cardiovascular outcomes in patients with ESRD. These improvements include prevention of cardiovascular events, management of acute coronary syndromes and heart failure, and the prevention of sudden death.

Hyperhomocysteinemia and its relationship to cardiovascular disease in ESRD: Influence of hypoalbuminemia, malnutrition, inflammation, and diabetes mellitus

Background: In the general population, a mildly elevated plasma total homocysteine (tHcy) level is an independent and graded risk factor for cardiovascular disease (CVD). In patients with end-stage renal disease (ESRD), CVD is highly prevalent and a major cause of premature mortality, and plasma tHcy levels are as much as three to four times greater than in the general population. Several other risk factors, such as diabetes mellitus (DM), inflammation, and malnutrition, also are prevalent and contribute to CVD in patients with ESRD, and there are strong associations between inflammation, malnutrition, and hypoalbuminemia in these patients. Several investigations in patients with ESRD have shown the important role of vitamin status for plasma tHcy, but little attention has been given to the influence of nutritional status. However, it is obvious that hypoalbuminemia is of interest because a substantial fraction of tHcy (>70%) is protein bound, mainly to albumin. Results: In studies of patients with ESRD in whom the prevalence of hyperhomocysteinemia was very high (>90%), tHcy level was strongly related to serum albumin level, and patients with malnutrition had lower levels of both tHcy and serum albumin than those with normal nutritional status. Furthermore, inflammation, DM, and CVD are associated with hypoalbuminemia and therefore a lower degree of hyperhomocysteinemia. In our studies, in different groups of patients with ESRD, we showed that greater tHcy levels were associated with lower CVD mortality. However, this apparently paradoxical association between lower CVD mortality and lower plasma tHcy levels (although still abnormally high) does not refute the concept that hyperhomocysteinemia is a risk factor for CVD because almost all patients may have had long-standing elevated plasma tHcy levels within a range that makes them prone to develop atherosclerosis. Instead, a potentially detrimental effect of hyperhomocysteinemia on CVD in patients with ESRD may be obscured by the influence of hypoalbuminemia, whatever the cause, because hypoalbuminemia and its causes are strong predictors of mortality. Conclusion: Our findings imply that nutritional status and serum albumin level, as well as the presence of inflammation and DM, should be taken into consideration when evaluating tHcy as a risk factor for CVD in patients with ESRD. Am J Kidney Dis 41(S1):S89-S95. © 2003 by the National Kidney Foundation, Inc.

A Fully Integrated Clinical Information System to Support Management of End-Stage Renal Disease

End-stage renal disease (ESRD) is relatively rare, but very costly. The ESRD population in the US is elderly, over 40% have diabetes mellitus, and most have additional comorbid conditions. Concerns about the quality and cost of care for people with ESRD in the US prompted the Healthcare Financing Administration (HCFA) to launch a demonstration project to determine whether disease management might improve care at reduced cost. It also stimulated health plans in the private sector to begin contracting with newly formed ESRD disease management organizations (DMOs). We describe the clinical information system developed by one such organization, RMS Disease Management, an affiliate of Baxter Healthcare Corporation. The system was designed to function within disparate medical care delivery systems and regions, without adding work for providers or health plans. A point-of-care system was implemented using a client server configuration. Data were entered on laptops and uploaded over high-speed lines to a central site. The system was developed over 14 months and implemented in 12 regions in 1998 under a contract with Humana, a national health plan. Highly experienced, locally recruited nephrology nurses co-ordinated care and entered data. The data included standard quality indicators, performance measures and key outcomes, along with data on patient assessment, care management, and comorbid conditions. We have compiled 35 000 months of patient care experience in the past three years, and entered 4000 patients with ESRD into the program. The system has provided comparisons of data at the regional and national levels, an independent reference for auditing claims, rapid turn-around of data to drive outcomes management, and the ability to link all components of care management. The system configuration is scalable and has functioned well across multiple sites of care while maintaining the privacy and security of patient data. Future plans include migration to an internet-based platform, adoption of handheld devices for data entry, and development of an Internet site where patients, their caregivers and their providers can interact. The system is designed to accomodate the evolving scope of disease management for ESRD, broadening to embrace multiple comorbid conditions and increasing its focus on prevention Wellness.

Cardiac Disease in Chronic Uremia: Management

Heart disease is a common cause of morbidity in end-stage renal disease (ESRD) patients. The management of heart disease in these patients requires a multidimensional approach to the management of heart failure, coronary disease, and arrhythmias, and to risk factors such as hypertension, anemia, secondary hyperparathyroidism, and electrolyte/acid-base disturbances. Coronary artery disease management includes use of antianginal drugs and revascularization of coronary arteries with angioplasty +/- stent placement or coronary artery bypass grafting. The long-term outcomes of these procedures need to be assessed and improved. Hypertension occupies a major role in the pathogenesis of heart disease in ESRD, and early and adequate control of hypertension is likely to have a major impact on the progression of cardiac disease. This entails the achievement of optimal volume status, combined with the appropriate use of antihypertensive agents such as calcium channel blockers, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, vasodilators, alpha-blockers, and central sympatholytic drugs. In ESRD patients, specific dialysis-related complications such as intradialytic hypotension and pericardial effusion may have additional effects on cardiac function and require attention. The choice of dialysate composition and membrane may influence clinical outcomes with specific effects on cardiac performance.