Nocturnal hypoxemia: a neglected cardiovascular risk factor in end-stage renal disease?

Its is well established that sleep apnea (SA) is a health problem of paramount importance because it disrupts sleep and quality of life and may induce serious neuroendocrine and cardiovascular complications. There is little doubt that chronic renal failure is an independent cause of SA. The hypothesis that SA may depend on the accumulation of endogenous opioids still remains to be tested. Cytokines, particularly TNF-alpha and IL-6 which are much elevated in end-stage renal disease (ESRD), may also be implicated in the pathogenesis of SA. Nocturnal hypoxemia is an independent predictor of cardiovascular events in ESRD and the prediction power of this parameter remains strong and substantially unmodified after statistical adjustment for established cardiovascular risk factors in the dialysis population. Left ventricular hypertrophy and dysautonomia appear to be most likely intermediate mechanisms mediating the adverse cardiovascular effects of SA in ESRD.     

Hypertension as a cardiovascular risk factor in end-stage renal failure

There is a paucity of high quality studies on the prognostic importance of arterial pressure in end-stage renal disease. Furthermore, the optimal timing for blood pressure (BP) measurements (pre- or postdialysis), and the prognostic value of 24-hour ambulatory BP monitoring in these patients remain to be established. In end-stage renal disease patients without diabetes and heart failure, predialysis systolic, diastolic, and pulse pressure are strongly and independently related to left ventricular mass, and the strength of these relationships is higher than that between the corresponding postdialysis values and left ventricular mass. Average predialysis systolic pressure (monthly average) is associated with left ventricular mass as strongly as 24-hour systolic BP, which suggests that the average routine predialysis BP taken over 1 month may be equally representative of the “true” BP (the integrated BP load) than 24-hour ambulatory BP monitoring. Mortality is U shaped in large hemodialysis databases. In the only prospective study that adequately controlled for cardiac function at baseline, it was shown that hypertension is associated with a higher risk of developing congestive heart failure, and that patients with left ventricular hypertrophy or chronic heart failure are at a much higher risk of mortality than patients without these complications. The role of arterial stiffening (pulse pressure) as a cardiovascular risk factor has been firmly established in an analysis of a very large dialysis database in the United States, and by recent studies based on direct measurements of pulse wave velocity.     

Asymmetric dimethylarginine (ADMA): a cardiovascular and renal risk factor on the move

The endogenous inhibitor of the nitric oxide synthase, asymmetric dimethylarginine (ADMA), by reducing nitric oxide (NO) availability, may trigger pro-atherogenic effects. A high plasma concentration of this substance has been associated to intima-media thickening, left ventricular hypertrophy and all-cause and cardiovascular mortality in patients with end-stage renal disease, and to coronary events in males in the general population. Recent studies show that ADMA predicts renal disease progression and death in patients with moderate to severe renal insufficiency. ADMA may be at the crossroad of the atherosclerosis process and may represent an important factor in the high risk associated with renal insufficiency.     

Primary renal disease as a cardiovascular risk factor

Cardiovascular disease (CVD) is the No. 1 cause of death in patients with end-stage renal disease (ESRD) and is approximately 3 to 5 times that of non-uremic control subjects. Moreover, higher rates of CVD are seen in patients with moderate and even mild renal dysfunction, particularly if the patient has hypertension or diabetes. Recent studies have indicated that even modest elevations in serum creatinine and urinary albumin excretion are associated with increased CVD risk, not only in persons with diabetes or hypertension but also in the general population. In addition, recent studies have suggested that targeting the kidney and/or kidney specific endpoints (via the renin-angiotensin-aldosterone-kinin system) in the treatment of hypertension, diabetes, and heart failure slows progression of renal disease and reduces the risk of extra-renal micro- and macrovascular complications. We conclude that it is important to screen for renal disease in those with hypertension, diabetes, and other CVD risk factors because it predicts those who are at high risk for major CVD events.     

Circulating E-selectin as a risk marker in patients with end-stage renal disease

BACKGROUND: E-selectin is a key adhesion molecule which plays a fundamental role in endothelial progenitor cell-dependent reparative mechanisms in experimental ischaemia and it serves to anchor leucocytes to the endothelium in inflammatory processes. Inflammation is one of the strongest risk factors for death and cardiovascular (CV) events in end-stage renal disease (ESRD). OBJECTIVE: The objective of the current study was to evaluate whether E-selectin is a useful biomarker of clinical outcome in ESRD patients. We tested the prediction power of circulating E-selectin for mortality and CV events in a cohort of 265 ESRD patients. RESULTS: During the follow-up, 59 patients died and 58 had CV events. All-cause mortality was inversely related to serum E-selectin, the risk of death being the lowest in patients in the third E-selectin tertile (HR: 1, reference group), intermediate in those in the second tertile (HR: 1.30) and the highest in patients in the first tertile (HR: 2.02, P = 0.01). Similarly, the risk of fatal and nonfatal CV events followed an inverse pattern being lowest in the third tertile (reference group) and highest in the first tertile (HR: 1.73, P = 0.03). The prediction power of E-selectin for death and CV events was confirmed in a Cox regression analysis where E-selectin emerged as an inverse predictor of these outcomes, particularly so in patients with severe inflammation. CONCLUSIONS: These data are in keeping with the hypothesis that in systemic inflammation altered E-selectin shedding may play a role in arterial damage and implicates this adhesion molecule in atherosclerotic complications in a high-risk condition like ESRD.     

Cardiovascular risk in diabetic end-stage renal disease patients

Diabetes mellitus is the leading cause of end-stage renal disease (ESRD), accounting for 54% of all incident cases according to the US Renal Data System. These patients suffer an extremely high mortality rate due to the very high incidence of cardiovascular disease. A significant proportion of these patients already has established cardiovascular disease at the time of initiation of dialysis treatment. More importantly, as these patients develop progressive kidney dysfunction, they are not only subjected to traditional Framingham risk factors, but, more importantly, to a whole host of "kidney disease-related risk factors" that further accelerate the progression of cardiovascular disease and thus contribute to adverse cardiovascular outcomes. The present article provides an updated view on the multitude of traditional Framingham risk factors and kidney disease-related risk factors that diabetic ESRD patients are subjected to. A better understanding of the different cardiovascular risk factors will be fundamental to institute early detection programs, as well as to provide aggressive cardiovascular management of these patients.     

Elevated heart rate: a major risk factor for cardiovascular disease

Mounting evidence shows that elevated heart rate is associated with a greater risk of developing hypertension and atherosclerosis and that it is a potent predictor of cardiovascular morbidity and mortality. These relationships have been shown not only in general populations but also among hypertensive individuals, with important implications for the treatment of hypertension. In spite of this evidence heart rate has been overlooked as a risk factor, but the fact that in most studies the risk related to fast heart rate remained highly significant after controlling for major risk factors for atherosclerosis suggests that it plays a direct role in the induction of the risk. The clustering of several risk factors for coronary artery disease in subjects with fast heart rate suggests that sympathetic overactivity accounts for the increased cardiovascular morbidity in subjects with tachycardia. In fact, experimental studies have shown that a heightened sympathetic tone can cause obesity, hyperinsulinemia, and insulin resistance which in the long run can promote the development of atherosclerosis. Moreover, experimental studies in the animal suggest that the heamodynamic disturbances related to high heart rate have a direct impact on the arterial wall promoting the development of atherosclerotic plaques. Preliminary results in the experimental animal and pooled data from intervention studies in patients with myocardial infarction or congestive heart failure suggest that drug-induced reduction of heart rate may be beneficial in several clinical conditions.     

Thallium stress testing does not predict cardiovascular risk in diabetic patients with end-stage renal disease undergoing cadaveric renal transplantation

PURPOSE: This study assessed the usefulness of thallium stress testing as a predictor of perioperative cardiovascular risk in diabetic patients with end-stage renal disease undergoing cadaveric renal transplantation. Demographic factors influencing the exercise performance in these patients were also examined. PATIENTS AND METHODS: The medical records of 189 consecutive patients with diabetic nephropathy who were evaluated for cadaveric renal transplantation were reviewed. Thallium stress testing was the initial examination of cardiovascular status in 141 patients. An adequate examination was one in which at least 70% of maximum heart rate was achieved. A thallium stress test was normal if there were no ST segment depressions on the electrocardiogram and no perfusion abnormalities on the thallium scan. Forty-four patients underwent cardiac catheterization as the initial evaluation (Group C) and four patients underwent transplantation without a formal cardiovascular evaluation (Group D). RESULTS: Sixty-four of the 141 patients undergoing thallium stress testing had an adequate and normal examination (Group A). The incidence of perioperative cardiac events in this group was 2%. Seventy-seven patients (Group B) had an abnormal (n = 41) or an inadequate (n = 36) thallium stress test and most (n = 61) then underwent coronary angiography. The use of beta-blockers was the only predictor of an abnormal or inadequate thallium stress test (10 of 64 versus 27 of 77, chi 2 = 6.66, p less than or equal to 0.025). Forty-three percent (26 of 61 in Group B) of patients with inadequate or abnormal thallium stress tests had significant coronary artery disease on cardiac catheterization. The perioperative risk of cardiac events was not different in Group A versus Groups B, C, and D combined. Survival of Group A and B patients was not different but was significantly longer than that of Group C patients (p less than 0.001). Thallium stress testing was less expensive than cardiac catheterization ($1,000 versus $4,000 to $5,000). CONCLUSIONS: Thallium stress testing allowed 45% of patients to avoid cardiac catheterization before renal transplantation. Discontinuing beta-blockers before thallium stress tests may improve exercise performance. The risk of perioperative cardiac events after transplantation was low and not different among patient groups. The relatively low predictive value of thallium stress testing for significant coronary artery disease and perioperative cardiac events in diabetic patients with end-stage renal disease suggests the need for the development of a more cost-effective, noninvasive screening test for this patient population.     

Endothelial damage,asymmetric dimethylarginine and cardiovascular risk in end-stage renal disease

To be appropriately labelled as a 'risk factor' any putative risk factor should increase the prediction power of standard statistical models based on 'traditional' (Framingham) risk factors. In end-stage renal disease (ESRD), Framingham risk factors do not fully explain the cardiovascular burden of these patients. Inflammation, hyperhomocysteinemia and anemia contribute to the high cardiovascular risk of ESRD, but knowledge is still incomplete. We suspected that asymmetric dimethylarginine (ADMA) is an important cardiovascular risk factor in dialysis patients. This substance inhibits nitric oxide synthase thus triggering a series of pathophysiological events leading to atherosclerosis. To test this hypothesis, we studied the relationship between ADMA and intima media thickness (IMT) in the carotid artery. ADMA was found to be strongly and independently related to IMT. More importantly we found that patients with relatively higher plasma ADMA had shorter survival and a higher rate of incident cardiovascular complications in comparison to those with a relatively lower plasma concentration. These data represent a sound basis for intervention studies aimed at modifying the plasma ADMA concentration in ESRD patients.     

Inflammatory arthritis as a novel risk factor for cardiovascular disease

Cardiovascular disease (CVD) comorbidity is a significant issue for the inflammatory arthritides (IA). There is a wealth of mortality studies showing increased cardiovascular mortality in rheumatoid arthritis (RA) and the evidence suggests that the same is likely to be true of psoriatic arthritis (PsA) and ankylosing spondylitis (AS). CVD co-morbidity is due to ischaemic pathologies driven by accelerated atherosclerosis and relates to the increased prevalence and clustering of classical risk factors, which may also be affected by treatments for IA, and their interplay with novel risk factors, namely systemic inflammation. Currently we are unable to quantify the contribution that classical and novel risk factors make to an individuals' CVD risk and specific algorithms need to be developed and validated in RA, PsA and AS to facilitate clinical management. Furthermore, large clinical trials are required to assess the effect of lifestyle modifications, primary prevention strategies and effective immunosuppression on hard CVD endpoints. However, in the meantime, a pragmatic approach should be adopted towards CVD risk management. Consensus opinion has generated guidelines for the management of CVD risk in IA and we discuss the importance of assessing each individual for CVD risk and establishing a system for routine risk factor identification alongside a commitment to treat identified risk factors to specific targets.     

Improved survival rate in patients with diabetes and end-stage renal disease in Denmark

Aims/hypothesis We investigated the survival rate of Danish diabetic patients with end-stage renal disease (ESRD) between 1990 and 2005 and evaluated possible predictors of survival rate. Materials and methods Data were obtained from the Danish National Register on Dialysis and Transplantation and from the Scandiatransplant database. Survival rates in different patient groups and association with age, sex, calendar time, waiting-list status and renal transplantation were evaluated using a multivariate Cox regression model. Results During the study period 8,421 patients (13% type 1 diabetic, 9% type 2 diabetic and 78% non-diabetic) started renal replacement therapy. The overall survival rate improved by 15% per five calendar years (hazard ratio [HR]=0.85, 95% CI: 0.81–0.88). The percentage of patients within each group who received renal transplantation was: type 1 diabetic: 26%, type 2 diabetic: 5%, non-diabetic: 24%. The survival rate of transplanted patients with diabetes mellitus (types 1 and 2) compared with non-diabetic patients at 1 year was: 95 vs 93%, at 5 years: 80 vs 85% and at 10 years: 52 vs 71%. Among diabetic patients survival rate was better in transplanted than in waiting-list patients (HR = 0.21, 95% CI 0.13–0.34), whereas the survival rate in waiting-list patients seemed to be superior to the survival rate among non-transplantation candidates (HR = 0.75, 95% CI 0.53–0.1.02, p = 0.07). Conclusions/interpretation The survival rate of diabetic patients with ESRD has improved during the last 15 years. Although some selection bias may exist, significantly improved survival rate was observed among transplanted patients compared with dialysis patients on the waiting-list for transplantation. Renal transplantation should therefore be offered to diabetic patients with ESRD whenever possible.     

Tuberculosis in patients with end-stage renal disease

Ten patients with proved disease caused by Myocobacterium tuberculosis were identified over a 10 year period in a population of 172 adult patients undergoing long-term dialysis. The incidence of tuberculosis was 12 times greater than that prevailing in the general community during the period of the study and could not be accounted for solely by demographic factors. Diagnosis was obscured because the symptoms were nonspecific and attributable to uremia, intermediate strength (5 TU) tuberculin tests were often negative, the roentgenographic appearance of pulmonary disease was often atypical, and there was more frequent extrapulmonary involvement. Impaired cellular immunity due to advanced renal failure may predispose to the increased incidence of tuberculosis and the greater frequency of extrapulmonary disease observed. Treatment was safe and effective in these patients using 300 mg of isoniazid and 8 to 10 mg/kg of ethambutol daily. Eight patients survived longer than one year following the diagnosis of tuberculosis, and all were clinically cured. No deaths were directly attributed to tuberculosis. A high index of suspicion and aggressive evaluation may be necessary to diminish the significant mortality described previously in association with disseminated disease.     

HCV in patients with end-stage renal disease

Chronic hepatitis C virus (HCV) infection remains an important cause of liver disease in patients with end-stage renal disease (ESRD) and conversely, renal failure has a significant impact on morbidity and mortality throughout the natural history of chronic HCV and its treatment. With improved awareness within dialysis units of the potential for spread and the institution of preventative measures, the prevalence of HCV infection in the hemodialysis-dependent population has continued to decline since 1995. Use of HCV (+) donor kidneys is associated with an increase in the prevalence of liver disease, but when compared with continued hemodialysis, transplantation using these kidneys is associated with improved survival. Overall, survival in patients with chronic HCV infection appears to be better after renal transplantation when compared with maintenance hemodialysis, and transplant should be considered for these patients. Data support the use of interferon and the improved efficacy of pegylated interferon formulations for treatment of chronic HCV infection in ESRD patients, although tolerability continues to be troublesome. The newest and most promising data regarding the treatment of HCV in ESRD involve the combination of reduced dose ribavirin with interferon or pegylated interferon suggesting similar enhancements in sustained virologic response (SVR) as seen in non-ESRD patients, but caution is advised, as all studies to date used ribavirin plasma concentration monitoring in patient with ESRD. Finally, with regard to postrenal transplant treatment of HCV infection, there is no evidence to support treatment with interferon-based therapy and pretransplant treatment remains the best option whenever possible.     

Increased end-stage renal disease risk in patients with inflammatory bowel disease:A nationwide populationbased study

AIM To estimate the risk of end-stage renal disease(ESRD)in patients with inflammatory bowel disease(IBD).METHODS From January 2010 to December 2013, patients with Crohn's disease(CD) and ulcerative colitis(UC) were identified, based on both the International Classification of Diseases, 10 th revision(ICD-10) and the rare,intractable disease registration program codes from the National Health Insurance(NHI) database in South Korea. We compared 38812 patients with IBD to ageand sex-matched non-IBD controls with a ratio of 1:3.Patients newly diagnosed with ESRD were identified with the ICD-10 code.RESULTS During a mean follow-up of 4.9 years, ESRD was detected in 79(0.2%) patients with IBD and 166(0.1%)controls. The incidence of ESRD in patients with IBD was0.42 per 1000 person-years. Patients with IBD had a significantly higher risk of ESRD than controls [adjusted hazard ratio(HR) = 3.03; 95% confidence interval(CI):1.77-5.20; P 0.001]. The incidences(per 1000 personyears)of ESRD were 0.51 in patients with CD and 0.13 in controls, respectively(adjusted HR = 6.33; 95%CI:2.75-14.56; P 0.001). In contrast, the incidence of ESRD was similar between the UC and control groups(0.37 vs 0.37 per 1000 person-years; adjusted HR = 2.01;95%CI: 0.90-4.51; P = 0.089).CONCLUSION The risk of ESRD was elevated in patients with CD, but not UC. Patients with CD should be monitored carefully for signs of renal insufficiency.     

Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease

To test the predictive values of and independent contributions to cardiovascular and all-cause mortality of various arterial parameters exploring characteristics of the arterial wall at different sites, we studied prospectively 110 stable end-stage renal disease patients on hemodialysis. These parameters involved carotid diameter, carotid intima-media thickness, carotid compliance, carotid distensibility, carotid incremental elastic modulus, aortic diameter, aortic pulse wave velocity, and the presence of arterial calcifications measured at the sites of the carotid artery, abdominal aorta, iliofemoral axis, and legs. The presence of calcifications was analyzed semiquantitatively as a score (0 to 4) according to the number of arterial sites with calcifications. During a follow-up of 53+/-21 months (mean+/-SD), 25 cardiovascular and 14 noncardiovascular deaths occurred. In univariate analysis, the carotid incremental elastic modulus was the most closely related to prognosis. Risk of death increased with the number of vascular sites involved by calcifications. Moreover, information (in terms of prediction) given by carotid elastic incremental modulus was additive to the presence and extent of vascular calcification-related prediction value. Adjusted hazard ratios of all-cause and cardiovascular mortality for an increase of 1 unit in calcification score were 1.9 (95% confidence interval [CI], 1.4 to 2.6) and 2.6 (95% CI, 1.5 to 4.4), respectively (P<0.001 for both). Adjusted hazard ratios of all-cause and cardiovascular mortality for a 1-SD increase in carotid incremental elastic modulus were 1.6 (95% CI, 1.2 to 2.2) and 1.7 (95% CI, 1.2 to 2.4), respectively (P<0.01 for both). The results of this study showed that the presence and extent of vascular calcifications were strong predictors of cardiovascular and all-cause mortality. Carotid incremental elastic modulus gave additional predictive value.