Modification of elastin by pentosidine is associated with the calcification of aortic media in patients with end-stage renal disease.

BACKGROUND: Calcification of the media of arteries is common in patients with end-stage renal disease (ESRD) undergoing haemodialysis and is a major cause of arteriosclerosis. The aim of this study was to clarify the role of glycoxidative modification of elastin in the calcification of aortic media in this group of patients. METHODS: Samples of tunica media were obtained from non-atherosclerotic areas of the aortas of cadavers of seven non-diabetic patients with ESRD (age 65.5 +/- 10.6 years) and 10 age-matched controls (age 61.1 +/- 10.3 years). The localization of pentosidine, a major glycoxidation product, and calcium deposits in the media were examined using immunohistochemical and von Kossa staining, followed by orcein staining for elastin fibres. Tissue levels of pentosidine and calcium were measured in elastase-digested media using reversed high-performance liquid chromatography and atomic absorption spectrophotometry, respectively. RESULTS: In aortic media, but not intima, immunostained pentosidine was observed along elastin fibres or in the extracellular spaces between them. Early calcification was manifest as small punctate calcified deposits along elastin fibres in the media. Advanced calcification was found as large, confluent calcified deposits in extracellular spaces between elastin fibres. Double staining showed co-localization of pentosidine and calcified deposits in the media. Both the staining density of pentosidine and calcification were more prominent in ESRD patients than in controls. The mean medial contents of both elastin-associated pentosidine and calcium were significantly higher in ESRD patients than in controls. In ESRD patients, the level of calcium in elastase-digested media correlated significantly with pentosidine levels, which increased in parallel with the duration of haemodialysis. CONCLUSIONS: Our results indicate that glycoxidative modification of elastin in aortic media may be involved in the enhancement of medial calcification in ESRD patients on haemodialysis.     

Angiographic progression of coronary artery disease in patients with end-stage renal disease.

BACKGROUND: Patients with end-stage renal disease have an increased risk of developing coronary artery disease (CAD). The cardiovascular mortality of dialysis patients is 10-15 times higher compared with the general population. The aim of our study was to evaluate the morphological progression of coronary arteriosclerosis in this cardiovascular high-risk group by visual assessment and quantitative coronary angiography. Methods and results. In 26 patients with chronic renal failure (age, 47+/-11 years; 15 male; duration of dialysis, 23+/-25 months) the severity of CAD and degree of coronary stenoses were assessed in two coronary angiograms after a mean follow-up interval of 30+/-15 months (12-60). Baseline angiography revealed CAD in 13/22 patients (59%). The second angiography was performed as screening procedure prior to renal transplantation (n=20) and/or as follow-up angiography after coronary angioplasty (n=10). Visual assessment showed a progression defined by the development of haemodynamically relevant stenosis of >50% luminal diameter in 13 patients. Quantitative angiographic evaluation was performed in a total of 45 segments showing >25% narrowing at the second angiogram. A progression (>15% luminal reduction) was found in 17 of 45 segments, a new lesion (initial luminal diameter <20%) was detected in nine segments, resulting in progression or new lesion in 16 patients (62%). Patients with or without progression did not differ in age, duration of dialysis treatment, number of cardiovascular risk factors, or serum total cholesterol and fibrinogen levels. After percutaneous transluminal coronary angioplasty (PTCA) a restenosis was seen in seven of 16 primarily successfully dilated segments. After the second angiography, myocardial revascularization was performed in eight patients (1 PTCA, 7 coronary artery bypass graft). CONCLUSIONS: Patients with end-stage renal disease have a high prevalence of CAD. In line with the clinical course, CAD patients on maintenance dialysis undergo rapid angiographic progression of CAD, which results in a high rate of subsequent myocardial revascularizations.     

Predictors of cardiovascular events in patients with end-stage renal disease: an analysis from the Fosinopril in dialysis study.

BACKGROUND: Cardiovascular events (CVE) are a major cause of morbidity and mortality in end-stage renal disease (ESRD) patients. These patients are often excluded from CV clinical trials, and the prognostic factors associated with CVE in patients with ESRD have not been fully explored. A risk prediction model was created from the FOSIDIAL trial to identify factors predictive of CVE and to evaluate the relative strength of known predictors when considered together in a multivariate model. METHODS: FOSIDIAL was a prospective, randomized, double-blind study with 2-year follow-up and CVE adjudication. The study enrolled 397 patients with ESRD and left ventricular hypertrophy (LVH). CVE included cardiovascular death, non-fatal myocardial infarction, unstable angina, stroke, revascularization, heart failure hospitalization, resuscitated cardiac arrest and confirmed stroke. The model was built using a forward selection of all baseline variables. A structural equation model (SEM) was used to identify factors with an indirect association with CVE. RESULTS: CV history was the most important prognostic factor, followed by C-reactive protein (CRP), left ventricular mass index, diabetes and age. Smoking, low HDL, female gender and Kt/V were indirectly associated with CVE. CONCLUSION: Prior CV disease, elevated CRP, LVH, diabetes or advanced age identifies patients at the highest risk for CVE. These data may be useful to detect high risk patients, to define potential targets for pharmacologic intervention, and to plan future studies in ESRD. Further research is needed to identify effective approaches that reduce the rate of CVE in these patients.     

The dilemmas of patient treatment for end-stage renal disease

In past years, physicians responsible for the treatment of chronic uremia have faced dilemmas that have been methodologic and economic while attempting to provide good patient care. These have been overcome, but in the course of time a larger one has developed. The current dilemma is one of high costs for end-stage renal disease (ESRD) management and the failure of current treatment programs to adequately rehabilitate the ESRD patient. In spite of widespread concern about this dilemma, few current data and even fewer projections exist about the eventual costs for their care. Existing data demonstrate several problems that are the basis of this dilemma: (1) the projections of incidence and prevalence of ESRD patients have been too low; (2) renal transplantation has failed to develop into a dominant (and least costly) form of ESRD therapy; (3) home dialysis programs have failed to offset the rapidly expanding in-center dialysis population; and (4) prevalence of and costs for chronic hemodialysis have increased far beyond expected levels. Using current data for the US population as to the incidence and overall mortality rate of ESRD patients, it is apparent that the dialysis population is only 39% of the way toward a steady state-corresponding to only the 4th year of a calculated 25-year growth curve. Although the current costs for maintenance of ESRD patients exceeds $1.3 billion, based upon such projections with the current distribution of patient treatment modalities, the overall annual cost will be in excess of $3.3 billion before a steady state is achieved. Improvement in mortality rates or increases in the incidence of patients will increase the steady state prevalence and the overall costs. Renal transplantation, unless kidney survival rate is increased so that it approximates patient survival, is unlikely to offset the rapidly increasing costs. New technology that would reduce the costs for center-based chronic hemodialysis has not been identified. Emphasis upon home dialysis modalities as a method of increasing patient rehabilitation and reducing costs appears to be a short-term necessity. Increased research and development in prevention of ESRD and in achieving better transplant kidney survival appear to be extremely important as long-term goals.     

Oxalate removal by hemodialysis in end-stage renal disease

Because of mounting evidence of precipitation of calcium oxalate in the soft tissues of patients with end-stage renal disease (ESRD) on maintenance hemodialysis, the plasma oxalate concentrations and calculated dialysis removal of oxalate were studied in seven patients without evidence of either primary or absorption hyperoxaluria prior to ESRD. A reversed-phase high-pressure liquid chromatographic method was developed to quantitate serum oxalate. Mean value +/- SE in four healthy controls was 28 +/- 5 mumol/L, and in the seven patients it was 187 +/- 15 mumol/L predialysis and 89 +/- 11 mumol/L postdialysis. Oxalate deposition in the soft tissues of ESRD patients is the consequence of sustained hyperoxalemia. Oxalate removal by dialysis was calculated from the four-hour oxalate clearance. Since the ionic radii of phosphate and oxalate are similar, total oxalate clearance was calculated midpoint of dialysis. Mean oxalate removal/dialysis was 3.01 +/- 0.283 mmol. On a daily basis this value was 1.645 +/- 0.155 mmol, which is about threefold the normal oxalate excretion rate. It is not significantly different from the excretion rate in absorption oxalurias but is less than that in primary hyperoxaluria. Therefore, it is concluded that hyperoxalemia in ESRD results from loss of renal excretion, failure of hemodialysis to remove enough oxalate to maintain a normal serum concentration, and increased intestinal absorption of oxalate and/or increased endogenous production.     

Unilateral renal cell carcinoma with coexistent renal disease: a rare cause of end-stage renal disease.

BACKGROUND: Renal cell carcinoma (RCC) is a disorder encompassing a wide spectrum of pathological renal lesions. Coexistence of unilateral RCC and associated pathology in the contralateral kidney is an unusual and challenging therapeutic dilemma that can result in renal failure. So far, data on unilateral RCC with chronic renal failure necessitating renal replacement therapy have not been published. The aim of the present study was to evaluate the incidence of end-stage renal disease (ESRD) from unilateral RCC, and to assess the associated pathology and possible pathogenic factors. METHODS: In 1999, a survey of the 350 patients treated by chronic dialysis in Asturias, Spain, was carried out to identify and collect clinical information on patients with primary unilateral RCC whilst on their renal replacement programme. RESULTS: Seven patients were identified as having ESRD and unilateral RCC, giving an incidence of 2% of patients treated by dialysis. There was a wide spectrum of associated disease and clinical presentation. All patients underwent radical or partial nephrectomy and were free of recurrence 6--64 months after surgery. Six patients were alive and free of malignancy recurrence for 6--30 months after the onset of haemodialysis. CONCLUSION: ESRD is rare in association with unilateral RCC, but does contribute to significant morbidity. However, the data presented here are encouraging and suggest that cancer-free survival with renal replacement therapy can be achieved in such patients.     

National survey of palliative care in end-stage renal disease in the UK.

BACKGROUND: Palliative care for patients with end-stage renal disease (ESRD) is a neglected aspect of nephrology. We carried out this survey to establish the current pattern of provision of palliative care for ESRD in the UK. METHODS: An anonymous but numbered questionnaire concerning local palliative care provision was sent to clinical directors of all 69 UK renal units. RESULTS: All the questionnaires were returned. Only 27 (39%) units employ nursing or Professions Allied to Medicine (PAM) staff with palliative care for ESRD patients as a specified part of their role. In 19 of these units, staff spend <4 h per week concerned with palliative care and only five units have staff working for >12 h a week in this role. Fifty-five (80%) units do not have a written protocol for palliative care. Anaemic ESRD patients with an expected survival of >3 months receive blood transfusion in 59 (86%) units, intravenous iron in 61 (88%) units and erythropoietin in 63 (91%) units. Only 37 (54%) units kept a record of patients seen by the unit staff but deemed not suitable for dialysis. CONCLUSION: There is a significant variation in provision of palliative care services across the UK. In some areas, access to palliative care is restricted to patients with malignant disease, and ESRD patients are excluded.     

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.     

Soluble adhesion molecules in end-stage renal disease: a predictor of outcome.

BACKGROUND: Inflammation is thought to contribute to initiation and aggravation of atherosclerosis through a process predominantly mediated by adhesion molecules. The aims of this study were to investigate the association between the concentrations of circulating soluble intercellular (sICAM-1) and vascular cellular (sVCAM-1) adhesion molecules and clinical outcome, and to evaluate the effect of antihypertensive drugs on sICAM-1 and sVCAM-1 concentrations in end-stage renal disease (ESRD) patients. METHODS: We prospectively investigated 310 (191 males) incident ESRD patients, 53+/-12 years old, shortly before the start of renal replacement therapy. Glomerular filtration rate (GFR) was 6.4 (range 0.8-16.5) ml/min/1.73 m(2). Plasma sICAM-1 and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) kits. Survival was determined from the day of examination, with a mean follow-up period of 39 (range 1-123) months. RESULTS: In non-adjusted analysis, high sICAM-1 and sVCAM-1 levels were associated with all-cause and cardiovascular (P<0.001) mortality. After adjusting for age, gender, diabetes mellitus, serum cholesterol, C-reactive protein (CRP), subjective global assessment and angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), the association between high sICAM-1 and mortality remained significant for all-cause (HR 1.9; CI 1.2-2.9, P = 0.004) and cardiovascular (HR 1.8; CI 1.1-3.1, P = 0.02) mortality, and a high sVCAM-1 was associated with all-cause mortality (HR 1.7; CI 1.04-2.7, P = 0.03). Furthermore, the concentration of sICAM-1, but not sVCAM-1, was lower in patients receiving ACEI/ARB (254+/-83 vs 275+/-92 ng/ml; P<0.05) or patients receiving calcium channel blockers (CCB, 251+/-75 vs 273+/-95 ng/ml; P<0.05) than in non-users. CONCLUSIONS: In ESRD patients, sICAM-1 and sVCAM-1 are independent predictors of all cause and cardiovascular death. The use of ACEI/ARB or CCB was associated with decreased concentrations of soluble adhesion molecules.     

Cardiovascular complications in pediatric end-stage renal disease

Mortality from end-stage renal disease (ESRD) is often due to cardiac causes. Although cardiovascular complications of ESRD have long been recognized, only recently has the presence of traditional cardiovascular risk factors been associated with late cardiovascular complications. This review presents a history of cardiac involvement in ESRD, the pathophysiology of accelerated atherosclerosis and left ventricular hypertrophy, and a summary of the literature on cardiovascular risk assessment in children. Techniques for non-invasive assessment of cardiac end-organ injury are also discussed. Recommendations for monitoring of risk factors and treatment in the pediatric ESRD population are presented.     

Removal of clodronate by haemodialysis in end-stage renal disease patients

BACKGROUND: Clodronate is a potent calcium-lowering drug. The effect ofhaemodialysis on clodronate pharm-acokinetics is unknown. METHODS: The removal of clodronate by haemodialysis was determined in10 end-stage renal disease patients (ESRD). A 2-h infusion of300 mg of clodronate was followed immediately by a 4-h haemodialysis.Vascular access was by AV fistula. A 1.5-m² cuprophane hollow-fibredialyser was applied. Blood flow was 205±15ml/min, dialysateflow 523±29 ml/min. Clodronate was determined by high-performanceliquid chromatography in total collected dialysate, and in bloodbefore and after the dialyser at initiation, 2 h, and 4 h ofHD. RESULTS: The initial predialyser serum concentration of clodronate was13.6 ± 4 ug/ml. It decreased to 4.9 ± 0.5 ug/mland 2.6 ± 0.5 ug/ml at 2h and 4h respectively. The clearanceof clodronate (86 ± 10 ml/min) remained unchanged duringHD. Clodronate in total collected dialysate per single 4-h HDwas 105 ± 16 mg (35% of injected dose). CONCLUSIONS: We conclude that clodronate is effectively removed from plasmaby HD. The present data together with information provided byprevious studies suggest that 300 mg of clodronate given asan 2-h infusion immediately prior to haemodialysis is an adequatedosage for ESRD patients.     

Heart valve calcifications in patients with end-stage renal disease: analysis for risk factors

BACKGROUND: The prevalence of valve calcification (VC) in end-stage renal disease patients is high and information regarding risk factors is scarce. Our aims were to determine the prevalence of VC in our maintenance haemodialysis (HD) population and to examine some possible aetiologic factors for its occurrence. METHODS: We studied 90 patients (47 women) on maintenance HD for more than 12 months. An M-mode two-dimensional echocardiogram was carried out to evaluate mitral, aortic VC and ventricular geometry. We calculated mean daily calcium intake for the phosphate intestinal chelaing in the previous year to echocardiogram date and also mean values from previous year of Ca, PO4, Ca x PO4, parathyroid hormone, lipide profile, nutritional and inflammatory marquers. Finally consumption of calcium and alfacalcidol was also noted. RESULTS: Thirty-six patients (40%) presented with VC. Patients with VC were older and showed higher levels of serum calcium (92.00 +/- 7.54 vs 89.27 +/- 6.86 mg/L, P = 0.04), phosphorus (69.70 +/- 18.33 vs 44.90 +/- 12.43 mg/L, P < 0.0001), Ca x P product (6164.97 +/- 1797.64 vs 4024.70 +/- 1066.40 mg(2)/L(2), P < 0.0001) and poor ventricular geometry, as compared with patients without VC. Moreover, they required higher doses of alfacalcidol for treating secondary hyperparathyroidism (0.43 +/- 0.60 vs 0.11 +/- 0.46 microg/day, P < 0.0001). CONCLUSION: Findings of the present study are consistent with a role of altered calcium and phosphate metabolism in the pathogenesis of VC in HD patients.     

Patterns of end-stage renal disease in US African-Americans

Summary: Although African-Americans constitute only about 12.4% of the population of the United States of America (USA), they comprise over 30% of the end-stage renal disease (ESRD) patient population. Diabetes mellitus (predominantly type 2) is the most frequently reported cause of ESRD in all racial and ethnic groups in the USA. However, hypertensive renal disease is reported as the dominant cause of ESRD in African-Americans. In general, all racial and ethnic minority groups in the USA have greater incidence and prevalence rates of ESRD than Caucasians. However, survival probabilities in all ESRD patients, dialysis patients, and cadaveric renal allograft recipients are greater in African-Americans than in Caucasians. the suggested reasons for these racial and ethnic disparities are discussed.     

Anterior urethral valve as a cause of end-stage renal disease

Although posterior urethral valves are predominant as a cause of obstructive uropathy in children, anterior urethral valves may also appear as the underlying etiologic factor in end-stage renal disease that results from obstruction. Two cases are presented of anterior urethral valve patients that were admitted with end-stage renal disease. The first case was successfully treated with diverticulectomy and urethral reconstruction in preparation for renal transplantation. The second case, however, had been on cystostomy drainage for 6 years and also had a contracted bladder. A more extensive lower urinary tract reconstruction was delayed. Children with poor stream and recurrent infections should be evaluated carefully and anterior urethral valve or diverticula should be considered in differential diagnosis of obstructive lesions.     

Measurement of vascular calcification using CT fistulograms.

BACKGROUND: Vascular calcification (VC), precipitated by calcium and phosphate imbalance, is a major contributor to cardiovascular disease (CVD) in chronic kidney disease (CKD). Electron-beam computed tomography (EBCT) quantitatively assesses coronary artery calcification (CAC), with VC scores predictive of atherosclerosis and cardiac events in the general and CKD population. EBCT is not readily available but spiral CT can also provide quantitative assessment of the extent of VC. CT fistulograms can be used as initial investigation for arterio-venous fistula (AVF) problems in haemodialysis (HD). The images obtained include thoracic aorta, brachio-cephalic, subclavian and common carotid arteries which allow assessment of the extent of VC in these vessels. No study to date has combined the CT fistulogram with concurrent determination of VC. METHODS: We hypothesize that a single investigation for AVF management may also provide information on VC. We retrospectively analysed CT fistulograms on 28 HD patients determining VC scores (in Hounsfield units) in AVF, subclavian and carotid arteries and aorta. We correlated these scores with patient demographics, serum markers of mineral metabolism (time averaged for the period 6 months prior to CT) and calcium-based phosphate binders. RESULTS: Patients (60.7% male) had a median age of 59 years and 46.4% were diabetic. The mean duration of dialysis was 17.5 months. CT fistulograms showed predominantly aortic (75% of patients) and subclavian (75%) calcifications, with only 21.4% having carotid VC and minimal VC at the level of AVF. Median VC scores were 619.8 (0-1481.4) for aorta and 521.7 (0-1139.6) for subclavian (scores of >400 indicate severe atherosclerotic disease), but there was no significant correlation with serum markers or duration of HD. Increasing age correlated significantly with greater VC in aortic (R = 0.53, P = 0.003) and subclavian (R = 0.40, P = 0.03) vessels, as well as with the number of VC sites involved. CAC was present in most patients (89.3%) but CAC scores were not able to be determined because of cardiac movement. CONCLUSION: Concurrent determination of the degree of calcification in certain vessels may be possible from CT studies assessing AVF structure. VC scores provided by CT fistulograms could contribute to HD patient CVD risk assessment but studies with larger patient numbers are required to determine their relevance.     

Seropositivity for cytomegalovirus in patients with end-stage renal disease is strongly associated with atherosclerotic disease.

BACKGROUND: Infection with cytomegalovirus (CMV) is considered a risk factor for progression of atherosclerotic disease. Patients with end-stage renal disease (ESRD) display signs of frequent CMV re-activation, which may be caused by the uraemia-associated defect in cellular immunity. The possible contribution of CMV seropositivity to the hugely increased risk for cardiovascular disease in patients with ESRD is not clear. METHODS: In a retrospective study we analysed the clinical data of patients with ESRD that were evaluated for renal transplantation from January 2002 to March 2006. Classical cardiovascular risk factors and CMV seropositivity were related to the prevalence of atherosclerotic disease. RESULTS: A total of 408 patients were evaluated with a median age of 52 years (range 18-81 years). Multivariate logistic regression identified age (odds ratio; OR 2.7 per decade), smoking (OR 2.2), hypertension (OR 1.9), C-reactive protein (CRP) (OR 2.6) and CMV seropositivity (OR 2.7) as independent variables that were significantly associated with a positive medical history of atherosclerotic disease. The average titre for anti-CMV immunoglobulin G was higher in patients with atherosclerotic disease (100 AU/ml vs 71 AU/ml, P < 0.05). CMV seropositivity was independently associated with an elevated CRP. In addition, patients with the combination of a high CRP and CMV seropositivity showed the highest prevalence of atherosclerotic disease. CONCLUSION: CMV seropositivity is significantly associated with atherosclerotic disease in ESRD patients. Our data suggest that the risk for progressive atherosclerosis is specifically increased in patients with an inflammatory response to CMV.