Novel cardiovascular risk factors in end-stage renal disease

Traditional risk factors only in part explain the risk differential between the general population and the population of patients with chronic nephropathies. Uncontrolled hyperphosphatemia and high calcium phosphate product constitute risk factors for cardiovascular calcifications, cardiac ischemia, and adverse cardiovascular outcomes, yet inflammation may be an even more important trigger of vascular calcification than these metabolic derangements. Homocysteine predicts cardiovascular events in ESRD, but evidence that this sulfur amino acid is directly implicated in the high cardiovascular mortality of uremic patients is still lacking. It seems unlikely that Chlamydia pneumoniae is a major risk factor in dialysis patients because the association between anti-Chlamydia antibodies and incident cardiovascular events seems to depend largely on the confounding effect of some traditional risk factors. Oxidative stress and raised plasma concentration of asymmetric dimethylarginine (ADMA) are pervasive in ESRD, and high ADMA in these patients may be at least in part the expression of the high rate of generation of oxidants. ADMA per se seems responsible for a 52% increase in the risk of death and for a 34% increase in the risk of cardiovascular events in dialysis patients.     

Hip fractures in end-stage renal disease patients: incidence, risk factors, and prevention

Hip fractures are an important problem for end-stage renal disease (ESRD) patients treated with dialysis. The incidence of hip fractures in the dialysis population is approximately four times that of the general population. Even more concerning is the associated 1 year mortality, which is twice that of other dialysis patients. Management of this problem is complicated by the heterogeneous nature of renal osteodystrophy and the inadequate methods of diagnosis currently available. Fall prevention has been shown to reduce the incidence of hip fracture and associated decline in functional ability in the general population. Because falls occur frequently in the dialysis population, simple fall prevention may be one important way of protecting dialysis patients from the morbidity and mortality of hip fracture.     

Traditional and emerging cardiovascular risk factors in end-stage renal disease

Patients with end-stage renal disease face a particularly high risk of cardiovascular disease and total mortality. Part of their increased risk is due to a higher prevalence of established risk factors, such as arterial hypertension, diabetes, smoking, and anemia. Hypertension and diabetes have a very high prevalence in dialysis patients and play a major role in their high mortality and morbidity. Hyperparathyroidism, hyperhomocysteinemia and disordered lipid metabolism represent factors that are peculiarly altered by the uremic state. Inflammatory processes, high sympathetic activity, and the accumulation of an endogenous inhibitor of NO synthase (ADMA), have recently emerged as cardiovascular risk factors of paramount importance. Sleep apnea has been linked with nocturnal hypertension and could be implicated in the high prevalence of concentric hypertrophy of the left ventricle in these patients. Hypertension control, as well as appropriate treatment of anemia and cessation of smoking, constitutes a fundamental area of intervention in dialysis patients. It appears possible that, in the near future, control of chronic inflammatory processes of high sympathetic activity and endothelial dysfunction will further help to curb the exceedingly high cardiovascular mortality of patients on chronic dialysis treatment.     

The challenge of cardiovascular risk factors in end-stage renal disease

Due to the impressive cardiovascular (CV) morbidity and mortality in uremic patients, assessment of CV risk factors in the dialysis population is a crucial challenge in nephrology. Cardiovascular risk factors in dialysis patients may have a different significance in ESRD patients compared to the general population. The Framingham risk equation seems not to be valid in chronic uremia. Furthermore, new powerful outcome predictors have emerged in recent years: pulse pressure, dipping status, pulse wave velocity, augmentation index. The concept of "U"-shaped association between blood pressure (as well as cholesterolemia) and mortality are extensively discussed. The authors are focusing on the value of office and ambulatory blood pressure measurements in the uremic population. An extensive evaluation of blood pressure and vascular compliance in dialysis patients is proposed. Efficient dialysis, ACE-inhibitors and beta-blockers, statins, antiplatelet treatment and adequate control of calcium-phosphorus metabolism should be the mainstay of therapy in the ESRD patients with several CV risk factors.     

Relationship between chronic kidney disease prevalence and end-stage renal disease risk

PURPOSE OF REVIEW: Incidence of end-stage renal disease has increased dramatically during the last 30 years and screening for early stages of chronic kidney disease is often suggested as a preventive measure. The relationship between chronic kidney disease and end-stage renal disease is complex, however, and recent studies have given some insights into this relationship. The review will summarize these studies and briefly discuss the clinical implications. RECENT FINDINGS: While the prevalence of chronic kidney disease is high in most Western countries, the incidence of end-stage renal disease differs substantially. The general increase in the incidence of end-stage renal disease seen in recent years may be partially explained by a lower cardiovascular mortality, allowing more patients with chronic kidney disease to develop end-stage renal disease, and widening of entrance criteria for renal replacement therapy. Data do not, however, support these factors as explanatory for the existing international differences. These differences are better explained by different prevalences of diabetes and obesity as well as by differences in rate of progression from early chronic kidney disease stages to end-stage renal disease. Rate of progression seems to be affected by race, socioeconomic status and predialytic care. SUMMARY: Several mechanisms influence the relationship between chronic kidney disease and risk of end-stage renal disease. Decreased cardiovascular mortality and improved treatment availability may explain parts of the increase in the incidence of end-stage renal disease, and there are also large international differences in rates of progression from chronic kidney disease to end-stage renal disease that may be amendable by public health and predialytic care interventions.     

Genetic factors in end-stage renal disease

Despite more aggressive treatment of diabetes, hypertension, and hyperlipidemia, the incidence and prevalence rates of end-stage renal disease (ESRD) continue to increase worldwide. The likelihood of developing chronic kidney disease in an individual is determined by interactions between genes and the environment. Familial clustering of nephropathy has repeatedly been observed in all population groups studied and for multiple etiologies of kidney disease. A three- to nine-fold greater risk of ESRD is observed in individuals with a family history of ESRD. Marked racial variation in the familial aggregation of kidney disease exists, with high rates in African American, Native American, and Hispanic American families. Disparate etiologies of nephropathy aggregate within African American families, as well. These data have led several investigators to search for genes linked to diabetic and other forms of nephropathy. Evidence for linkage to kidney disease has been detected and replicated at several loci on chromosomes 3q (types 1 and 2 diabetic nephropathy), 10q (diabetic and nondiabetic kidney disease), and 18q (type 2 diabetic nephropathy). Multicenter consortia are currently recruiting large numbers of multiplex diabetic families with index cases having nephropathy for linkage and association analyses. In addition, large-scale screening studies are underway, with the goals of better defining the overall prevalence of chronic kidney disease, as well as educating the population about risk factors for nephropathy, including family history. Given the overwhelming burden of kidney disease worldwide, it is imperative that we develop a clearer understanding of the pathogenesis of nephropathy so that individuals at risk can be identified and treated at earlier, potentially reversible, stages of their illness.     

Risk factors and mortality associated with calciphylaxis in end-stage renal disease.

BACKGROUND: We conducted a case control study to determine risk factors and mortality associated with calciphylaxis in end-stage renal disease. METHODS: Cases of calciphylaxis diagnosed between December 1989 and January 2000 were identified. Three controls were identified for each hemodialysis patient, with calciphylaxis matched to the date of initiation of hemodialysis. Laboratory data and medication doses were recorded during the 12 months prior to the date of diagnosis and at the time of diagnosis of calciphylaxis. Conditional logistic regression was used to identify risk factors for calciphylaxis. Cox proportional hazards models were used to estimate the risk of death associated with calciphylaxis. RESULTS: Nineteen cases and 54 controls were identified. Eighteen patients were hemodialysis patients, and one had a functioning renal allograft. Diagnosis was confirmed by skin biopsy in 16 cases. Women were at a sixfold higher risk of developing calciphylaxis (OR = 6.04, 95% CI 1.62 to 22.6, P = 0.007). There was a 21% lower risk of calciphylaxis associated with each 0.1 g/dL increase in the mean serum albumin during the year prior to diagnosis and at the time of diagnosis of calciphylaxis (OR = 0.79, 95% CI, 0.64 to 0.99, P = 0.037, and OR = 0.80, 95% CI, 0.67 to 0.96, P = 0.019, respectively). There was a 3.51-fold increase in the risk of calciphylaxis associated with each mg/dL increase in the mean serum phosphate during the year prior to diagnosis (95% CI, 0.99 to 12.5, P = 0.052). At the time of diagnosis of calciphylaxis, for each 10 IU/L increment in alkaline phosphatase, the risk of calciphylaxis increased by 19% (OR = 1.19, 95% CI, 1.00 to 1.40, P = 0.045). Body mass index, diabetes, blood pressure, aluminum, and higher dosage of erythropoietin and iron dextran were not independent predictors of calciphylaxis. Calciphylaxis independently increased the risk of death by eightfold (OR = 8.58, 95% CI, 3.26 to 22.6, P < 0.001). CONCLUSIONS: Female gender, hyperphosphatemia, high alkaline phosphatase, and low serum albumin are risk factors for calciphylaxis. Calciphylaxis is associated with a very high mortality.     

Non-traditional cardiovascular disease risk factors in end-stage renal disease: oxidate stress and hyperhomocysteinemia

Studies in experimental animals have shown that oxidative stress and hyperhomocyst(e)inemia culminate in abnormal vascular and endothelial regulation, functional nitric oxide deficiency, vascular hypertrophy, and atherosclerosis. Oxidative stress is accompanied by increased advanced glycation endproducts and oxidized low density lipoproteins. Studies of patients with end-stage renal disease provide extensive indirect, evidence of increased oxidative stress and more than ninety percent are hyperhomocyt(e)inemic. Presently, only uncontrolled or observational studies are available to assess the effects of anti-oxidant therapy for oxidative stress or folate therapy for hyperhomocyst(e)inemia in these patients. Promising developments include the reports of beneficial effects of a vitamin E coated dialyzer, and the reduction in homocyst(e)ine levels in patients with end-stage renal disease given an intravenous folate metabolite. However, there is presently no therapy available to reverse fully oxidative stress or hyperhomocyst(e)inemia. Therefore, the causative role of these nontraditional risk factors of cardiovascular disease remains untested.     

Ascites associated with end-stage renal disease

Patient characteristics, clinical outcomes, and proposed pathophysiologic mechanisms are reviewed in 138 patients reported in the literature to have had ascites associated with end-stage renal disease. Contributing mechanisms may include fluid overload, peritoneal membrane changes (not necessarily related to peritoneal dialysis), hypoproteinemia, and lymphatic drainage disturbances. In 15% of cases, extensive evaluations may reveal an underlying disease. The most effective therapy may be kidney transplantation.     

Traditional and non-traditional risk factors as contributors to atherosclerotic cardiovascular disease in end-stage renal disease

Cardiovascular disease (CVD) remains the main cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Although traditional risk factors, such as diabetes mellitus, hypertension, dyslipidemia and advanced age, are prevalent in ESRD patients they may not be sufficient by themselves to account for the high prevalence of CVD in patients with this condition. Thus, the search for other, non-traditional, risk factors that may be involved in the pathogenesis of uremic CVD has been an area of intense study. Data suggest that the accelerated atherosclerotic process of ESRD may involve several interrelated processes, such as oxidative stress, endothelial dysfunction and vascular calcification, in a milieu of constant low-grade inflammation. The cause(s) of inflammation in ESRD are multifactorial and, while it may reflect underlying CVD, an acute-phase reaction may also be a direct cause of vascular injury via several pathogenetic mechanisms. Available data suggest that pro-inflammatory cytokines play a central role in the genesis of both malnutrition and CVD in ESRD. Thus, it could be speculated that suppression of the vicious cycle of malnutrition, inflammation and atherosclerosis (MIA syndrome) would improve survival in dialysis patients. Recent evidence has demonstrated strong associations between inflammation and both increased oxidative stress and endothelial dysfunction in ESRD patients. As there is not yet any recognized, or even proposed, treatment for ESRD patients with chronic inflammation it would be of obvious interest to study the long-term effect of various anti-inflammatory treatment strategies on the nutritional and cardiovascular status as well as outcome of these patients.     

Proteinuria and the risk of developing end-stage renal disease

BACKGROUND: Dipstick urinalysis for proteinuria and hematuria has been used to screen renal disease, but evidence of the clinical impact of this test on development of end-stage renal disease (ESRD) is lacking. METHODS: We assessed development of ESRD through 2000 in 106,177 screened patients (50,584 men and 55,593 women), 20 to 98 years old, in Okinawa, Japan, who participated in community-based mass screening between April 1983 and March 1984. We used data from the Okinawa Dialysis Study Registry to identify ESRD patients. Multivariate logistic analyses were performed to calculate adjusted odds ratio and 95% confidence interval (95% CI) for the significance of proteinuria and hematuria on the risk of developing ESRD with confounding variables such as age, gender, blood pressure, and body mass index. A similar analysis was repeated in a subgroup of screened patients in whom serum creatinine data existed. RESULTS: During 17 years of follow-up, 420 screened persons (246 men and 174 women) entered the ESRD program. We identified a strong, graded relationship between ESRD and dipstick urinalysis positive for proteinuria; adjusted odds ratio (95% CI) was 2.71 (2.51 to 2.92, P < 0.001). Similar trends were observed after adding serum creatinine data. Compared with dipstick-negative proteinuria, adjusted odds ratio (95% CI) of proteinuria (1+) was 1.93 (1.53 to 2.41, P < 0.001) in men and 2.42 (1.91 to 3.06, P < 0.001) in women. CONCLUSION: Proteinuria was a strong, independent predictor of ESRD in a mass screening setting. Even a slight increase in proteinuria was an independent risk factor for ESRD. Therefore, asymptomatic proteinuria warrants further work-up and intervention.     

Geographic variation in the incidence of treated end-stage renal disease.

To facilitate identification of geographic clusters of areas with high or low incidence of treated end-stage renal disease, the 1983 to 1988 incidence by county was studied among whites and nonwhites less than 60 yr of age in the United States. End-stage renal disease incidence counts for 1983 to 1988 were obtained from the United States Renal Data System data base and linked to the 1985 county population obtained from U.S. Census data. Maps were smoothed by the method adopted by the National Cancer Institute that smooths only according to variability of the local rates, ignoring geographic information on clustering of events. In addition to identifying specific counties with exceptionally high or low incidence, geographic patterns were observed with many similarities across whites and nonwhites: notably high rates of disease in areas of the Southwest, the Southeast and in counties with Native American reservations and low rates in the West and Northwest. On the basis of these findings, several hypotheses are presented to explain the observed variation in treated end-stage renal disease incidence rates.     

Neutrophil dysfunction and infection risk in end-stage renal disease

Infections are still a major cause of morbidity and mortality in end-stage renal disease (ESRD) patients. The susceptibility of ESRD patients to infections is typically ascribed to the immunodeficient state associated with uremia. A central role in the host defense against bacterial infections is played by phagocytic polymorphonuclear white blood cells, which are characterized by the capacity to ingest and subsequently destroy bacteria. Disorders in polymorphonuclear cell function are exacerbated by the dialysis procedure and numerous factors including uremic toxins, iron overload, anemia of renal disease, and dialyzer bioincompatibility. It is concluded that the phagocytic defect observed in ESRD is multifactorial, and each factor should be managed individually with specific therapeutic approaches.     

Relationship between dyslipidemia and the risk of developing end-stage renal disease in a screened cohort

Background Disturbances in lipid metabolism are often observed in patients with renal failure and could be a risk factor for end-stage renal disease (ESRD). However, few studies have examined abnormal lipid metabolism as a risk factor for the development of ESRD in the general population.Methods We examined the cumulative incidence of ESRD based on the results of a community-based mass screening in Okinawa, Japan, which was conducted in 1993 by the Okinawa General Health Maintenance Association. Screenees who developed ESRD by the end of 2000 were identified through the Okinawa Dialysis Study registry.Results Total cholesterol (TC) data were available for 133338 (92.6%) of the total 143948 screenees) and triglyceride (TG) data were available for 132094 (91.8%). Dyslipidemia was defined as TC 220mg/dl or TG 150mg/dl. The cumulative incidences of ESRD, per 1000 screenees, were 1.12 for those without dyslipidemia and 2.53 for those with dyslipidemia. The adjusted hazard ratio (95% confidence interval) for dyslipidemia was 0.856 (0.484–1.516) for men and 1.260 (0.661–2.400) for women; neither was significant when adjustment was made for age, systolic blood pressure, diastolic blood pressure, body mass index, creatinine clearance, diabetes mellitus, and proteinuria.Conclusions The present study showed dyslipidemia to be an insignificant predictor of development of ESRD in the general Okinawa population.     

Lipid abnormalities associated with end-stage renal disease

Patients undergoing chronic renal replacement therapy have a high incidence of dyslipidemia. In general, there are increased concentrations of triglyceride-rich apolipoprotein B-containing particles. These elevations lead to increased levels of non-high-density lipoprotein (HDL) levels. This pattern is further modified by the method of dialysis (peritoneal versus hemodialysis) and comorbidities such as diabetes. End-stage renal disease patients also demonstrate increased levels of lipoprotein(a) (Lp(a)) and oxidized low-density lipoprotein (LDL)both of which are highly atherogenic. This review focuses on the pathogenesis of these lipid abnormalities and their role in the atherosclerotic process.     

Haematocrit and the risk of developing end-stage renal disease.

BACKGROUND: Anaemia is common in patients with renal failure; however, it is not known whether haematocrit level in the general population is a predictor for developing end-stage renal disease (ESRD). METHODS: A retrospective analysis was conducted to assess the development of ESRD within a population of 71 802 subjects (37 190 men and 34 612 women), 20-99 years, in Okinawa, Japan. Haematocrit data were collected between April 1983 and March 1984 and the subjects were followed forward to the year 2000 whether they were identified in the Okinawa Dialysis Study registry for identification of ESRD. Multivariate logistic analyses were performed to analyse the influence of haematocrit on the development of ESRD after adjusting for age, sex, blood pressure, body mass index, proteinuria and haematuria. In a subgroup of the cohort, similar analyses were repeated adjusting for estimated creatinine clearance by the method of Cockcroft and Gault. RESULTS: The mean (SD) level of haematocrit at the time of screening was 45.3% (3.3%) for men and 38.8% (3.2%) for women. During the 17-year follow-up, 269 patients (171 men and 98 women) were identified with ESRD. The mean time to onset of ESRD was 130.4 (53.6) months. The adjusted odds ratio and 95% confidence interval (CI) for the influence of haematocrit (%) on the development of ESRD was 0.991 and 0.988-0.995 (P<0.0001), suggesting that the lower haematocrit, the greater was the risk of developing ESRD. This finding was repeated in the subgroup analysis that included calculated creatinine clearance (adjusted odds ratio 0.991 and 95% CI 0.984-0.997, P=0.0057). In women, the adjusted odds ratio for haematocrits of 20.0-34.9% was 3.086 (CI 1.770-5.376, P<0.0001) when compared with the reference haematocrits of 35.0-39.9%. In men, the adjusted odds ratio for haematocrits of 25.0-39.9% was 1.927 (CI 1.418-2.625, P<0.0001) when compared with the reference haematocrits of 45.0-49.9%. CONCLUSIONS: Subjects with low haematocrits, <40% for men and <35% for women, have a significantly increased risk of ESRD.     

Increasing incidence of proteinuria and declining incidence of end-stage renal disease in diabetic Pima Indians

The introduction of more efficacious treatments for diabetic kidney disease may slow its progression, but evidence for their effectiveness in populations is sparse. We examined trends in the incidence of clinical proteinuria, defined as a urinary protein-to-creatinine ratio >0.5 g/g, and diabetic end-stage renal disease (ESRD), defined as death from diabetic nephropathy or onset of dialysis, in Pima Indians with type 2 diabetes between 1967 and 2002. The study included 2189 diabetic subjects >/=25 years old. During follow-up, 366 incident cases of proteinuria occurred in the subset of 1715 subjects without proteinuria at baseline. The age-sex-adjusted incidence rate of proteinuria increased from 24.3 cases/1000 person-years (pyrs) (95% confidence interval (CI) 18.7-30.0) in 1967-1978 to 35.4 cases/1000 pyrs (95% CI 28.1-42.8) in 1979-1990 and 38.9 cases/1000 pyrs (95% CI 31.2-46.5) in 1991-2002 (P(trend)<0.0002). In each period, the age-sex-adjusted incidence of proteinuria increased with diabetes duration, but diabetes duration-specific incidence was stable throughout the study period (P=0.8). The age-sex-adjusted incidence of ESRD increased between 1967 and 1990 and declined thereafter. The incidence of proteinuria increased over 36 years in Pima Indians as the proportion of people with diabetes of long duration increased. On the other hand, the incidence of ESRD declined after 1990, coinciding with improved control of blood pressure, hyperglycemia, and perhaps other risk factors.