Showing papers in "Nephrology Dialysis Transplantation in 2003"

Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality

Abstract: Background Cross-sectional and follow-up studies on end-stage renal disease patients showed that arterial calcifications are associated with cardiovascular (CV) morbidity and are an independent predictor of all-cause and CV mortality. However, these studies did not examine the impact on prognosis according to the type of calcification, i.e. intimal vs medial. Arterial media calcification (AMC), a non-occlusive condition, affects haemodynamics differently from arterial intima calcification (AIC), which occurs in atherosclerotic plaques. The aim of this study was to investigate the prognostic value of AMC in relationship to all-cause or CV mortality for stable haemodialysis (HD) patients. Methods We included 202 such patients in the present study. At baseline, soft-tissue native radiograms of the pelvis and the thigh were analysed for the presence and type (AMC vs AIC) of arterial calcifications. All patients underwent B-mode ultrasonography of the common carotid artery to determine the presence of atherosclerotic calcified plaques, measurement of aortic pulse wave velocity and echocardiography. Results AIC was usually observed in older patients with a clinical history of atherosclerosis before starting HD treatment and typical risk factors associated with atherosclerotic disease. AMC was observed in young and middle-aged patients without conventional atherosclerotic risk factors. AMC was closely associated with the duration of HD and calcium-phosphate disorders, including the oral dose of elemental calcium prescribed as phosphate binder (CaCO(3)). Compared to patients with AIC, patients with AMC had a longer survival, but in turn their survival was significantly shorter than that of patients without calcifications. Conclusions AMC is a strong prognostic marker of all-cause and CV mortality in HD patients, independently of classical atherogenic factors. The principal effect of AMC on arterial function is increased arterial stiffness.

Oxidative stress in end‐stage renal disease: an emerging threat to patient outcome

Abstract: Introduction Patients affected by end-stage renal disease (ESRD) experience an excess of morbidity and mortality due to cardiovascular disease (CVD), which cannot be fully explained by the classical CVD risk factors Among emerging CVD risk factors, oxidative stress is currently being given emphasis Methods We achieved a consensus on key points relating to oxidative stress in ESRD patients Results ESRD patients are subjected to enhanced oxidative stress, as a result of reduced anti-oxidant systems (vitamin C and selenium deficiency, reduced intracellular levels of vitamin E, reduced activity of the glutathione system) and increased pro-oxidant activity (advanced age, high frequency of diabetes, chronic inflammatory state, uraemic syndrome, bioincompatibility of dialysis membranes and solutions) Oxidative stress and inflammation are deeply interrelated, as different oxidant free radicals are generated by phagocytic cells in response to inflammatory stimuli: both are related to endothelial dysfunction, as the endothelium is a source and a target of oxidants and participates in the inflammatory response There is growing evidence, from experimental and clinical studies, that oxidative stress may be implicated in the pathogenesis of atherosclerosis and other complications of ESRD, namely dialysis-related amyloidosis, malnutrition and anaemia Given that free radicals have very short half-lives (seconds), the clinical assessment of oxidative stress is based on the measurement of different stable oxidized compounds (such as lipid peroxidation products, advanced glycation and oxidation lipid and protein products, nucleic acid oxidation derivatives) or antibodies directed against oxidized epitopes (such as anti-oxidized low-density lipoprotein antibodies) At the same time, both enzymatic anti-oxidants (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic antioxidants (glutathione, vitamin C, vitamin E, negative inflammatory proteins) can be evaluated However, many laboratory methods assessing various oxidative stress components still have to be standardized Moreover, it is still uncertain whether it is better measuring plasma anduor intracellular concentrations or activities of these components The possibility of improving patient outcome by therapeutic interventions aimed at reducing oxidative stress, eg by vitamin C or vitamin E supplementation, currently is to the fore, but results so far have remained inconclusive Conclusions It is important to consider oxidative stress as a potentially important source of patient morbidity and mortality, although this knowledge is not yet immediately applicable in the clinical arena Further well-designed, randomized controlled clinical trials with anti-oxidants (eg vitamin E, vitamin C, N-acetyl cysteine, L-arginine) are required to establish evidence-based recommendations for clinical practice

A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate

Abstract: Background. In clinical practice, the glomerular filtration rate (GFR) is often estimated from plasma creatinine. Several studies have shown cystatin C (cys C) to be a better parameter for the diagnosis of impaired renal function. No data are available, however, on the performance of cys C in follow-up of patients, compared with creatinine. Also, comparisons of cys C with the Cockcroft and Gault (CG P ¼ 0.006). Bland and Altman analysis showed that the simple formula GFR ¼ –4.32 þ 80.35 � 1/cys C, derived from our data, gave more accurate (P < 0.0001) and more precise (P ¼ 0.024) GFR estimates than obtained with the C&G formula. The day-to-day variation (biological þ analytical) for cys C was small (3.1%, SD 2.51%) in diabetic patients. In the follow-up study in diabetic patients, cys C was the parameter which had the best correlation (r ¼ 0.66) with changes in GFR. Conclusions. Cys C shows a high correlation with GFR. With a very simple formula, cys C gives a good estimate of GFR, more accurate and precise than C&G. Because biological variation is low, cys C gives also a good assessment of GFR changes during follow-up. Cys C is the preferred endogenous parameter for GFR.

Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit

Abstract: Background. Early detection of acute tubular necrosis (ATN) could permit implementation of salvage therapies and improve patient outcomes in acute renal failure (ARF). The utility of single and combined measurements of urinary tubular enzymes in predicting ARF in critically ill patients has not been evaluated using thereceiver-operatingcharacteristic(ROC)plot method. Methods. In this prospective pilot study, 26 consecutive critically ill adult patients admitted to the intensive-care unit were studied. Urine samples were collected twice daily for up to 7 days. ARF was defined as an increase in plasma creatinine of P50% and P0.15 mmolul. ROC plot analysis was applied to the tubular marker data to derive optimum cut-offs for ARF. Results. Four of the 26 study subjects (15.4%) developed ARF. Indexed to urinary creatinine concentration, c glutamyl transpeptidase (cGT), alkaline phosphatase (AP), N-acetyl-glucosaminidase (NAG), and a -a ndp-glutathione S-transferase (a -a ndp-GST) but not lactate dehydrogenase (LDH) were higher in the ARF group on admission (P-0.05). cGT, and a- and p-GST remained elevated at 24 h. The onset of ARF based on changes in plasma creatinine varied from 12 h to 4 days (median 36 h). ROC plot analysis showed that cGT, p-GST, a-GST, AP and NAG had excellent discriminating power for ARF (AUC 0.950, 0.929, 0.893, 0.863 and 0.845, respectively). The discriminating strength of creatinine clearance, while lower, was still significant (AUC 0.796). Positive and negative predictive values for ARF on admission were 67u100% for cGT, 67u90% for AP, 60u95% for a-GST, and 67u100% for p-GST indices. Positive and negative predictive values for ARF for creatinine clearance O23 mlumin were 50 and 91%, respectively. Creatinine clearances tended to be lower in ARF than in nonARF patients on admission (Ps0.06) and were significantly lower (Ps0.008) after 12 h. Plasma urea and fractional sodium excretion were unhelpful. Conclusions. Tubular enzymuria on admission to the ICU is useful in predicting ARF. The cheapness and wide availability of automated assays for cGT and AP suggests that estimation of these enzymes in random urine samples may be particularly useful for identifying patients at high risk of ARF.

Quality of sleep and health‐related quality of life in haemodialysis patients

Abstract: Background. Sleep complaints are common in haemodialysis patients. In the general population, insomnia impacts negatively on health-related quality of life (HRQoL). The objective of this study was to examine the association between quality of sleep and HRQoL in haemodialysis patients independent of known predictors of HRQoL. Methods. Quality of sleep was measured using the Pittsburgh Sleep Quality Index (PSQI) and HRQoL was measured using the Medical Outcomes Study 36-item Short Form (SF-36) in 89 haemodialysis patients. Results. Sixty-three (71%) subjects were ‘poor sleepers’ (global PSQI )5). The SF-36 mental component summary (MCS) and physical component summary (PCS) correlated inversely with the global PSQI score (MCS, rs0.28, P-0.01; PCS, rs0.45, P-0.01). The PCS score also correlated with age (rs0.24, Ps0.02), haemoglobin (rs0.21, Ps0.048) and comorbidity (rs0.40, P-0.01), and mean PCS was lower in depressed subjects (26.2 vs 35.9, Ps 0.02). Subjects with global PSQI )5 had a higher prevalence of depression, lower haemoglobin and lower HRQoL in all SF-36 domains. The global PSQI score was a significant independent predictor of the MCS and PCS after controlling for age, sex, haemoglobin, serum albumin, comorbidity and depression in multivariate analysis. Conclusions. Poor sleep is common in dialysis patients and is associated with lower HRQoL. We hypothesize that end-stage renal disease directly influences quality of sleep, which in turn impacts on HRQoL.

The effect of correction of anaemia in diabetics and non‐diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron

Abstract: Background. A mild anaemia is often found in patients with congestive heart failure (CHF), but its significance is uncertain. In an open uncontrolled study we investigated the effect of correcting this anaemia [haemoglobin (Hb) 9.5‐11.5 g%] with subcutaneous (s.c.) erythropoietin (Epo) and intravenous (i.v.) iron (Fe) in 179 patients, 84 type II diabetics and 95 non-diabetics, with moderate to severe CHF which was resistant to maximally tolerated doses of standard CHF medications. Methods. Epo, s.c., was given every 1‐3 weeks to achieve and maintain the Hb at 12.5 g%. Fe (Fe sucrose-Venofer) was added i.v. as necessary to maintain the Fe stores. Duration of treatment was 11.8q8.2 months. Results. With the Epo-Fe treatment the Hb increased from 10.41"1.0 to 13.1"1.3 g% in diabetics and from 10.5"1.0 to 12.9"1.2 g% in non-diabetics. Comparing the diabetics and non-diabetics, the New York Heart Association functional class improved by 34.8 and 32.4%, respectively. breathlessness anduor fatigue, as measured by a self-administered Visual Analogue Scale, improved by 69.7 and 67.4%, and the left ventricular ejection fraction improved by 7.4 and 11.5%, respectively. The number of hospitalizations fell by 96.4 and 95.3%, respectively, compared with the pre-treatment period. Although the glomerular filtration rate (GFR) was falling at a rate of ; 1m luminumonth before the study in both groups, neither the mean serum creatinine nor the GFR changed significantly during the study period. The mean dose of Epo needed, measured in IUuweekukg body weight, was similar in the two groups. Conclusion. The correction of the mild anaemia that was found in diabetics and non-diabetics with resistant CHF and mild to moderate chronic renal failure improved the cardiac function and patient functional status, stabilized the renal function and markedly reduced the need for hospitalization.

Trends in the incidence of renal replacement therapy for end-stage renal disease in Europe, 1990-1999.

Abstract: Background. The epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) varies considerably worldwide, but we have lacked reliable quantitative estimates of trends in the incidence by age, sex and cause in Europe over the last decade. Methods. We analysed data from nine countries participating in the ERA-EDTA registry: Austria, Belgium, Denmark, Finland, Greece, The Netherlands, Norway, Spain and UK (Scotland). Adjusted incidence rates for age and sex were studied for 2 year periods between 1990 and 1999. Average annual changes (%) were estimated by Poisson regression. Results. The adjusted incidence rate of RRT increased from 79.4 per million population (pmp) (range: 58.4-101.0) in 1990-1991 to 117.1 pmp (91.6-144.8) in 1998-1999, i.e. 4.8% (3.1-6.4%) each year. This increase did not flatten out at the end of the decade, except in The Netherlands, and was greater in men than women, 5.2 vs 4.0%/year. In most countries, the incidence rate remained stable for those younger than 45 years; it rose by 2.2%/year on average in the 45-64 year age group and by 7.0% among those 65-74 years; it tripled over the decade in those 75 years or older, and by 1998-1999 it ranged from 140.9 to 540.4pmp between countries. The incidence of ESRD due to diabetes, hypertension and renal vascular disease nearly doubled over 10 years; in 1998-1999, it varied between countries from 10.2 to 39.3 pmp for diabetes, from 5.8 to 21.0 for hypertension, and from 1.0 to 15.5 for renal vascular disease. Conclusion. RRT incidence continues to rise but at various rates in the European countries studied, tending to widen the gap between them. This mainly results from enlarging differences in incidence in the elderly and, to a lesser extent, in that due to diabetes, hypertension and renal vascular disease.

A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients

Abstract: Background. Partial correction of renal anaemia with erythropoietin improves quality of life (QoL). We aimed to examine if normalization of haemoglobin with epoetin alfa in pre-dialysis and dialysis patients further improves QoL and is safe. Methods. 416 Scandinavian patients with renal anaemia [pre-dialysis, haemodialysis (HD) and peritoneal dialysis patients] were randomized to reach a normal haemoglobin of 135-160 g/l (n = 216) or a subnormal haemoglobin of 90-120 g/l (n = 200) with or without epoetin alfa. Study duration was 48-76 weeks. QoL was measured using Kidney Disease Questionnaires in 253 Swedish dialysis patients. Safety was examined in all patients. Results. QoL improved, measured as a decrease in physical symptoms (P = 0.02), fatigue (P = 0.05), depression (P = 0.01) and frustration (P = 0.05) in the Swedish dialysis patients when haemoglobin was normalized. In pre-dialysis patients, diastolic blood pressure was higher in the normal compared with the subnormal haemoglobin group after 48 weeks. However, the progression rate of chronic renal failure was comparable. In the normal haemoglobin group (N-Hb), 51% had at least one serious adverse event compared with 49% in the subnormal haemoglobin group (S-Hb) (P = 0.32). The incidence of thrombovascular events and vascular access thrombosis in HD patients did not differ. The mortality rate was 13.4% in the N-Hb group and 13.5% in the S-Hb group (P = 0.98). Mortality decreased with increasing mean haemoglobin in both groups. Conclusions. Normalization of haemoglobin improved QoL in the subgroup of dialysis patients, appears to be safe and can be considered in many patients with end-stage renal disease. (Less)

Incidence of polyomavirus‐nephropathy in renal allografts: influence of modern immunosuppressive drugs

Abstract: BACKGROUND In recent years an increasing number of cases with polyomavirus (PV)-nephropathy after renal transplantation were reported from several transplant centres. New, highly potent immunosuppressive drugs like tacrolimus or mycophenolate mofetil were accused as risk factors for this increase. However, data about the incidence of PV-nephropathy in correlation to different immunosuppressive therapy concepts are lacking. METHODS All renal transplant biopsies performed at Hannover Medical School between 1999 and 2001 (n=1276) were immunohistochemically screened for the presence of PV-specific proteins. The results were correlated to the different immunosuppressive therapy protocols and patients with PV-nephropathy were compared with a matched control group. RESULTS PV-nephropathy was found in <1% of all investigated allograft biopsies (11/1276) and in approximately 1% of all patients (7/638), respectively. All patients being immunohistochemically positive for PV-specific proteins also showed the typical morphological changes of PV-nephropathy. Four out of seven patients with PV-nephropathy were under triple immunosuppression comprising tacrolimus and mycophenolate mofetil. Under this immunosuppressive therapy protocol an eight times higher incidence and a 13 times higher risk (multivariate odds ratio 12.7) of PV-nephropathy was observed in our patients compared with the control group. CONCLUSIONS PV-nephropathy is a rare but serious complication after renal transplantation. A small group of patients under intensive immunosuppression comprising tacrolimus in combination with mycophenolate mofetil has a significantly increased risk of acquiring this deleterious complication.

Non‐dipping is a potent predictor of cardiovascular mortality and is associated with autonomic dysfunction in haemodialysis patients

Abstract: Background. Lack of nocturnal blood pressure (BP) fall (non-dipping) is common among haemodialysis (HD) patients, but much less is known regarding its association with cardiovascular (CV) disease morbidity and mortality. Methods. Eighty HD patients initially underwent 24 h ambulatory BP monitoring (ABPM), and then they were defined as either ‘dippers’ (ns24, nocturnal BP fall P10%) or ‘non-dippers’ (ns56, fall -10%). Coronary angiography was performed in the patients who had signs anduor symptoms of coronary artery disease (CAD). Twenty-four hour ambulatory ECG was recorded in 20 dippers and 20 non-dipper HD patients, and in 20 normal subjects. All patients were followed for up to 5.8 years (33.0"19.1 months). The outcome events studied were the hospitalisations due to CV diseases and CV death. Results. Compared with dippers, non-dippers initially had a higher incidence of coronary artery stenosis (P-0.05) along with left ventricular asynergy (both Ps-0.01). The circadian rhythm of autonomic function was impaired in non-dippers. The incidences of CV events and CV deaths were 3.5 and 9 times higher in non-dippers than in dippers. The cumulative CV event-free survival and CV survival rates were lower in non-dippers than in dippers (Ps0.02 and Ps0.005, respectively). Based on Cox analysis, non-dipping was associated positively with CV events and CV mortality [hazard ratio (HR) 2.46, 95% CI 1.02‐5.92, Ps0.038 and HR 9.62, 95% CI 1.23‐75.42, Ps0.031, respectively]. Meanwhile, nocturnal systolic BP fall, diurnal systolic BP and diurnal pulse pressure were negatively associated with CV eventudeath. The clinic BP was not associated with CV eventudeath. Conclusions. The non-dipping phenomenon is closely related to a high incidence of CV diseases, a poor long-term survival and profound autonomic dysfunction. ABPM is useful in predicting long-term CV prognosis in HD patients.

Symptom burden, quality of life, advance care planning and the potential value of palliative care in severely ill haemodialysis patients

Abstract: Background There has been little research on the potential value of palliative care for dialysis patients. In this pilot study, we sought (i) to identify symptom burden, health-related quality of life (HRQoL) and advance directives in extremely ill haemodialysis patients to determine their suitability for palliative care and (ii) to determine the acceptability of palliative care to patients and nephrologists. Methods Nineteen haemodialysis patients with modified Charlson co-morbidity scores of > or =8 were recruited. Each completed surveys to assess symptom burden, HRQoL and prior advance care planning. Palliative care specialists then visited patients twice and generated recommendations. Patients again completed the surveys, and dialysis charts were reviewed to assess nephrologists' (i) compliance with recommendations and (ii) documentation of symptoms reported by patients on the symptom assessment survey. Patients and nephrologists then completed surveys assessing their satisfaction with palliative care. Results Patients reported 10.5 symptoms, 40% of which were noted by nephrologists in patients' charts. HRQoL was significantly impaired. Thirty-two percent of patients had living wills. No differences were observed in symptoms, HRQoL or number of patients establishing advance directives as a result of the intervention. Sixty-eight percent of patients and 76% of nephrologists rated the intervention worthwhile. Conclusions Extremely ill dialysis patients have marked symptom burden, considerably impaired HRQoL and frequently lack advance directives, making them appropriate candidates for palliative care. Patients and nephrologists perceive palliative care favourably despite its lack of effect in this study. A more sustained palliative care intervention with a larger sample size should be attempted to determine its effect on the care of this population.

Prospective evaluation of failure modes in autogenous radiocephalic wrist access for haemodialysis

Abstract: Introduction Radiocephalic wrist arteriovenous fistulae (RCAVF) are the primary and best option for vascular access for haemodialysis treatment However, 10‐24% of these AVFs fail due directly to thrombosis and non-maturation In a prospective study, the failure modes of radiocephalic AVFs and the impact of surgical and interventional treatment on fistula outcome were investigated Methods The rate of thrombosis and non-maturation was evaluated in 43 RCAVFs The selection of RCAVF creation was made on preoperatively determined duplex parameters Fistula function was evaluated post-operatively by clinical examination and non-invasively measured AVF blood flow A policy of a liberal use of radiological anduor surgical revision of non-functioning RCAVFs was made on the basis of duplex measured blood flow and angiographically detected vessel stenosis Results Primary fistula function was achieved in 26 of 43 patients (60%) Non-maturation and thrombosis occurred in 14 (33%) and three (7%) patients, respectively A total of 12 interventions (PTA 6; surgery 6) were needed, resulting in salvage of eight RCAVFs (47%) The blood flow in functioning AVFs was significantly higher compared to non-functioning AVFs at 1 (754 vs 440 ccumin), 7 (799 vs 524 ccumin) and 42 days (946 vs 532 ccumin) post-operatively At the end, 34 RCAVFs (79%) became functional as vascular access for haemodialysis treatment Conclusion Primary RCAVFs have a high rate of failure An aggressive approach towards early interventional treatment of these non-functional AVFs is worthwhile and leads to a considerable salvage rate Early post-operative AVF flow measurement indicates the chance of successful maturation of RCAVF

Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity

Abstract: Background Studies of proliferative lupus nephritis (PLN) suggest that African-Americans have a poorer prognosis than Whites. However, no study has simultaneously examined socio-economic status. We studied rates of progression of PLN among a tri-ethnic population with respect to socio-economic status and race/ethnicity. Methods A retrospective cohort study was carried out using individual and census-based neighbourhood data. Consecutive patients in urban tertiary care centres with biopsy-proven PLN were studied. The main outcome was time to doubling of serum creatinine. Results Among 128 patients with PLN, the percentage of patients who did not double their serum creatinine at 5 years was 67.0% (+/-4.8%) and at 10 years was 58.9% (+/-5.7%). In bivariate analyses, residence in a poor neighbourhood was positively associated with progression (P = 0.03), as was African-American and Hispanic race/ethnicity (P = 0.01). Residence in a poor neighbourhood remained associated with progression of disease after adjustment for age, sex, creatinine, hypertension, cyclophosphamide treatment and race/ethnicity [relative risk (RR) 3.5, 95% confidence interval (CI) 1.2-11, P = 0.03]. After adjustment for poverty and insurance, the RR for African-American race/ethnicity was reduced from 3.5 to 2.7 and was not statistically associated with progression of disease in the full model (P = 0.10). A similar reduction in RR from 5.5 to 3.6 was seen for Hispanic race/ethnicity, but this retained statistical significance (P = 0.03). Conclusions Poverty is an important risk factor for progression of PLN, independent of race/ethnicity. Hispanics have an elevated risk similar to or greater than African-Americans. Given these findings, some of the poorer prognosis of African-American patients with PLN may result from socio-economic rather than biological or genetic factors.

Impaired renal function is associated with markers of endothelial dysfunction and increased inflammatory activity

Abstract: Background. Patients with end-stage renal disease (ESRD) as well as those with mild renal insufficiency are at increased risk for the development of cardiovascular disease, which cannot be attributed entirely to traditional risk factors. Endothelial dysfunction and chronic inflammatory activity, two important phenomena in atherogenesis, can be found in ESRD. At present, it is unclear whether endothelial dysfunction and chronic inflammatory activity are related to renal function in the pre-dialysis stage. Methods. In a cross-sectional, single-centre study, four groups of 20 subjects with renal function ranging from a normal, calculated creatinine clearance ( > 90 ml/min) to a pre-dialysis situation (<31 ml/min) were investigated. We measured markers of endothelial function [von Willebrand factor (vWf), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor- 1 (PAI-1) and E-selectin (ES)], and markers of inflammatory activity [secretory phospholipase A 2 (sPLA 2 ) and C-reactive protein (CRP)]. Using these markers, composite endothelial function and inflammatory activity scores were constructed. Results. Creatinine clearance correlated with the endothelial function score (r= -0.43, P < 0.001), the inflammatory activity score (r = -0.53, P < 0.05), vWf (r = - 0.54, P < 0.001), sVCAM-1 (r= -0.50, P < 0.001), sPLA 2 (r = -0.28, P < 0.05), homocysteine (r = -0.61, P < 0.001), age (r= -0.54, P < 0.001) and blood pressure (r= -0.44, P < 0.001). In multivariate analyses, creatinine clearance was an independent determinant of the endothelial function score (β= -0.34. P=0.006), plasma vWf (β= -0.37, P=0.022) and sICAM-1 (β= -0.33, P=0.012). The relationship of creatinine clearance with sVCAM-1 and endothelial function score was not significant when plasma homocysteine was added to the model. Creatinine clearance was also a determinant of the inflammatory activity score (β= -0.31, P=0.025) and sPLA 2 (β= -0.32, P = 0.024), although this was no longer significant after correction for systolic blood pressure. Conclusions. Renal dysfunction is associated with markers of endothelial dysfunction and inflammatory activity. Plasma homocysteine may be an intermediate factor in the relationship between endothelial dysfunction and renal function, while blood pressure may modulate the association between inflammatory activity and renal function.

White blood cells as a novel mortality predictor in haemodialysis patients

Abstract: Background. Many conventional cardiovascular risk factors in the general population are not as predictive in end-stage renal disease (ESRD). As absolute neutrophil count and total white blood cell (WBC) count are associated with adverse cardiovascular outcomes and all-cause mortality, this analysis was undertaken to explore the associations of WBC variables with mortality risk in ESRD. Methods. Of a total study population of 44 114 ESRD patients receiving haemodialysis during 1998 at facilities operated by Fresenius Medical Care, North America, 25 661 patients who underwent differential white cell count and had complete follow-up were included. Information on case mix (age, gender, race), clinical (diabetes, body mass index), and laboratory variables (haematocrit, albumin, creatinine, potassium, calcium, phosphorus, bicarbonate, ferritin, transferrin saturation and differential WBC count) was obtained. Associations between lymphocyte count, neutrophil count and demographic and clinical variables were examined using linear regression. Associations between WBC variables and survival were estimated using Cox proportional hazard regression. Results. A higher lymphocyte count was associated with higher serum albumin and creatinine, lower age and black race. High neutrophil count was associated with lower serum albumin and creatinine, younger age and white race (all Ps -0.0001). Cox proportional hazard regression showed an increased lymphocyte count was associated with reduced mortality risk [HR 0.86 (0.83–0.89) per 500uml increase in lymphocyte count] and an increased neutrophil count was associated with increased mortality risk [HR 1.08 (1.06–1.09) per 1000uml increase in neutrophil count]. Conclusions. An increased neutrophil count is strongly associated with, and reduced lymphocyte count associated less strongly with, many surrogates of both malnutrition and inflammation. An increased neutrophil count and reduced lymphocyte count are independent predictors of increased mortality risk in haemodialysis patients.

A tricontinental view of IgA nephropathy.

Abstract: Background. The purpose of this retrospective study was to analyse patients from four centres in three continents to determine if differences in long-term outcome of IgA nephropathy (IgAN) are explained by clinical and laboratory features at presentation. Methods. The study included 711 adults with biopsyproven IgAN from Glasgow, UK (n ¼ 112), Helsinki, Finland (n ¼ 204), Sydney, Australia (n ¼ 121) and Toronto, Canada (n ¼ 274). Data collected from time of presentation to a nephrologist were age, gender, 24-h urine protein excretion (UP0), mean arterial pressure (MAP0) and creatinine clearance (CrCl0). Outcomes were slope of creatinine clearance (CrCl) and renal survival. Results. At presentation there was significant variability in baseline clinical features with patients from Helsinki havingthe lowest median UP 0, lowest MAP0 and highest CrCl0, all suggesting milder disease. There was significant variability in renal survival between centres with 10-year actuarial survival of 95.7, 87.0, 63.9 and 61.6% in Helsinki, Sydney, Glasgow and Toronto, respectively (P < 0.0001; log rank). Cox proportional hazards model revealed lower age0 and lower CrCl0 were significant independent predictors of reduced renal survival. In addition, patients from Helsinki and Sydney but not Glasgow had significantly longer renal survival than patients from Toronto. Median slope of CrCl varied by region from –1.24 ml/min/year in Helsinki, to –3.99 ml/min/ year in Toronto (Kruskal–Wallis H test P < 0.0001). By multivariate analysis older age0, higher CrCl0 and lower UP0 were independently associated with slower progression. Subjects from Helsinki had a significantly slower deterioration independent of the other clinical parameters at presentation. When the 269 patients presentingwith CrCl 0 <75 ml/min were analysed separately there was no independent centre effect. Conclusions. The findings are consistent with the hypothesis that geographical variability in long-term outcome of IgAN is explained by lead-time bias and inclusion of milder cases in centres with apparent good outcome, but do not exclude the possibility that some of the variability is due to other factors such as genetics, diet or treatment.

Immunogenicity of therapeutic proteins

Abstract: The use of proteins for medical applications has revolutionized therapies of many diseases/disorders that were often incurable with small-molecule medicines. However, since the first use of proteins as medicines, their immunogenicity has been a major problem. Over the years the quality and safety of therapeutic protein products have improved dramatically. Nevertheless, even the protein medicines of the newest generation may still cause adverse immunological events, posing a safety risk for patients and/or compromising their efficacy. Immunogenicity of therapeutic proteins is a complex, multifactorial phenomenon. In this chapter we summarize the current knowledge about immune mechanisms underlying the immunogenicity of therapeutic proteins and discuss influencing factors and clinical consequences of protein immunogenicity as well as strategies for immunogenicity assessment and mitigation.

Kidney transplants, antibodies and rejection: is C4d a magic marker?

Abstract: The immunohistochemical detection of the complement degradation product C4d in renal allograft biopsies has gained considerable clinical interest in recent years. The accumulation of C4d along peritubular capillaries is generally regarded as a marker for an antibody-mediated allo-response and is associated with poor graft survival. The aim of this review is to discuss histological findings associated with the deposition of C4d. Emphasis is placed on diagnostic and therapeutic implications. Unanswered questions regarding C4d and graft injury are highlighted.

The effect of frequent or occasional dialysis-associated hypotension on survival of patients on maintenance haemodialysis

Abstract: Background. While frequent or occasional symptomatic intradialytic hypotension (IDH) may influence patient well-being, its effects on survival—independent of comorbidities—has not previously been investigated. In this study, therefore, our objective was to assess the effect of frequent IDH (f-IDH) or occasional IDH (o-IDH) on survival. Methods. During a 10 month run-in period in 1998, 77 patients with f-IDH (� 10 hypotensive events/10 months, responding only to medical intervention) and 101 patients with o-IDH (1 or 2 events/10 months) were identified among all 958 patients of a dialysis network. Eighty-five patients who had no hypotensive episodes (no-IDH) during this run-in phase served as controls. Patients were followed for a median of 27 months (range: 0.3–37) and survival of patients in the three groups was compared by log-rank test. Independent association of f-IDH and o-IDH with survival, compared with no-IDH, was assessed by a proportional hazards model that included patient demographics, laboratory data and antihypertensive medication as well as comorbidity. Results. Forty-five patients (58%) with f-IDH, 47 (47%) with o-IDH and 33 (39%) with no-IDH died during the follow-up. Mortality rates (deaths/100 patient years) were 37 (log-rank P ¼ 0.013 vs noIDH), 26 (log-rank P ¼ 0.375 vs no-IDH) and 21 in the three groups, respectively. This indicates significantly decreased survival in patients with f-IDH as compared to those with no-IDH. In multivariate proportional hazards regression, however, where age, sex, time spent on dialysis, presence of coronary heart disease, diabetes, Kt/V, albumin level and use of -blockers, calcium-channel blockers and long-acting nitrates has been adjusted for, neither f-IDH nor o-IDH was associated with survival. Conclusions. Mortality in patients with f-IDH is significantly higher than in those without such events. After adjustments for covariates, however, there is no independent effect of frequent or occasional episodes of IDH on mortality.

Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation.

Abstract: Background. Tacrolimus is an immunosuppressive drug that is a substrate of cytochrome P450 3A (CYP3A) enzymes and P-glycoprotein (P-gp). After transplantation, many pharmacological interactions have been described. Corticosteroids induce both CYP3A and P-gp activity. This study was designed to investigate the presence of a clinically significant interaction between steroids and tacrolimus after renal transplantation. Methods. We studied 83 renal transplant recipients receiving tacrolimus after transplantation. Patients were divided into three groups, according to steroid dose (low: 0–0.15 mg/kg/day; intermediate: 0.16– 0.25 mg/kg/day; and high: >0.25 mg/kg/day). All other medications, including those known to interact with CYP3A and/or P-gp, were recorded. Steroid dosage, tacrolimus dosage, tacrolimus trough concentration (C0) and tacrolimus concentration/dose ratio [C0 divided by the 24 h dosage (mg/kg)] were assessed for each dosage group after 1 and 3 months of tacrolimus treatment. Results. The three groups were not different as regards the use of non-immunosuppressive treatments or clinical events. At 1 and 3 months, the tacrolimus doses and concentration/dose ratios differed significantly in the three steroid dosage groups. With the higher doses, higher tacrolimus doses were needed to achieve the blood tacrolimus targeted trough level. Conclusions. We demonstrated that pharmacokinetic interaction occurs between steroids and tacrolimus in renal transplant patients. The higher the steroid dosage, the higher the dosage of tacrolimus needed to achieve target trough levels in these patients. The most likely interaction mechanism is specific enzymatic induction of CYP3A and/or P-gp. Interaction is present, even when the steroid dosage is low. The clinical events liable to occur during steroid sparing or tapering must be taken into account because it may be associated with episodes of tacrolimus-related nephrotoxicity.

Impact of St John's wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients

Abstract: Background This study investigated the effect of St John's wort (SJW) extract on the pharmacokinetics of the immunosuppressants tacrolimus (TAC) and mycophenolic acid (MPA) Methods Ten stable renal transplant patients received 600 mg SJW extract for 14 days in addition to their regular regimen of TAC and mycophenolate mofetil Results Dose-corrected AUC (0 12) of TAC decreased significantly from 180 ng/ml/hh at baseline to 759 ng/ml/h after 2 weeks of SJW treatment To maintain therapeutic TAC concentrations, dose adjustments from a median 45mg/day at baseline to 80 mg/day under SJW treatment were required Two weeks after discontinuation of SJW, TAC doses were reduced to a median of 65 mg/day MPA pharmacokinetics remained unaffected by comedication with hypericum extract Conclusions Administration of SJW extract to patients receiving TAC treatment can result in a serious drug interaction leading to markedly reduced TAC blood concentrations associated with the risk of organ rejection

Assessment of vascular calcification in ESRD patients using spiral CT

Abstract: Background. Dialysis patients have increased vascularcalcification of the coronary arteries and aorta byelectron beam CT scan. The purpose of the presentstudy was to utilize an alternative machine, spiral CT,to assess calcification in end-stage renal disease (ESRD)patients.Methods. Two groups of patients with ESRD wereevaluated: group 1, those receiving a renal transplant(ns38); and group 2, those remaining on dialysis(ns33). All patients underwent quad-slice spiral CTwith retrospective gating to evaluate coronary arteryand aorta calcification scores. Both area (Agatstonmethod) and volume calculations were utilized, withretrospective gating in all but 16 subjects. Laboratorytests, medications and clinical characteristics wereanalysed.Results. Using spiral CT, the intra-reader variabilityfor coronary artery calcification (after correctionfor very low scores) was 0.9% mean u 0% medianusing the area (Agatston method) and 2.9% mean u 0%median using volume calculations. Group 1 patientswere younger, more likely to be Caucasian and on peri-toneal dialysis, had lower serum calcium and higherC-reactive protein levels than group 2. In patientswithout vs those with coronary artery calcification,only longer duration of dialysis (34"64 vs 55"50 months, Ps0.004; rs0.39, Ps0.005) and increa-sing age (39"13 vs 54"10 years, P-0.001; rs0.29,Ps0.039) were associated, whereas only increasing agewas associated with aorta calcification.Conclusion. In ESRD patients, the factors correlatingwith coronary calcification were duration of dialysisand advancing age, whereas only age correlated withaorta calcification. Spiral CT offers an alternativetechnique for the assessment of these changes.Keywords: coronary artery disease; dialysis; spiral CT;transplant; vascular calcification

Prognostic value of heart rate variability in patients with end‐stage renal disease on chronic haemodialysis

Abstract: Background. Although decreased heart rate variability (HRV) is an independent predictor of death in various populations, its prognostic value in patients with end-stage renal disease on chronic haemodialysis is unknown. Methods. We prospectively studied 120 chronic haemodialysis patients (age 61"11 years; males 51%; diabetics 38%; duration of haemodialysis therapy 50" 114 months) who underwent 24 h electrocardiography at baseline for analysis of time- and frequency-domain HRV. Results. All HRV measures in the patients were significantly reduced compared with those obtained from 62 age-matched healthy subjects. During a follow-up period of 26"10 months, 21 patients died (17.5%); 10 from cardiac causes and 11 from non-cardiac causes (seven fatal strokes and four other causes). A Cox proportional hazards model revealed that, of the HRV measures, decreases in the triangular index (TI), very-low-frequency (0.0033‐0.04 Hz) power, ultra-lowfrequency (-0.0033 Hz) power (ULF) and the ratio of low-frequency (0.04‐0.15 Hz) power to highfrequency (0.15‐0.4 Hz) power had significant predictive value for cardiac death. None of the HRV measures, however, had predictive value for noncardiac death, including stroke death. Even after adjustment for other univariate predictors including age, diabetes, serum albumin and coronary artery disease, the predictive value of decreased TI and ULF remained significant—adjusted relative risk (95% confidence interval) per 1 SD decrement of TI and ULF, 3.28 (1.08‐9.95) and 1.92 (1.01‐3.67), respectively. Conclusions. Decreases in some HRV measures, particularly those reflecting long-term variability, are independent predictors of cardiac death in chronic haemodialysis patients.

Fluid status in CAPD patients is related to peritoneal transport and residual renal function: evidence from a longitudinal study

Abstract: Background. Both peritoneal transport characteristics as well as residual renal function are related to outcome in patients treated with continuous ambulatory peritoneal dialysis (CAPD). It has been suggested that part of this relationship might be explained by an effect of both parameters on the fluid state in CAPD patients or by the relationship between inflammation and peritoneal transport. Methods. In the present study, the relationship between fluid state [extracellular water (ECW) (sodium bromide); total body water (TBW) (deuterium oxide)] with peritoneal transport characteristics (2.27% glucose dialysateuplasma creatinine [DuP (creat)] ratio), residual renal function (residual glomerular filtration rate [rGFR] by urine collection) and C-reactive protein (CRP) was assessed in 37 CAPD patients in a crosssectional and longitudinal design, with 25 patients completing the study. Results. In the cross-sectional part ECW, corrected for height (ECW:height), was inversely related to rGFR (rs0.40, Ps0.016), whereas during the longitudinal part, DuP[creat] was related to the change in ECW (rs0.40, Ps0.05). Neither DuP[creat] nor rGFR were related to CRP, whereas a significant relationship was observed between ECW:height and CRP (rs0.58, Ps0.0001). Patients were dichotomized according to rGFR (- 2o r) 2m lumin). Despite a higher daily peritoneal glucose prescription (216.3"60.0 vs 156.5"53.0 gu24 h; Ps0.004) and peritoneal ultrafiltration volume (1856"644 vs 658"781 mlu24 h, respectively; Ps0.0001), the patients with a rGFR - 2m lumin showed a higher ECW:height compared with the group with rGFR ) 2m lumin (12.5"3.8 vs 9.2"2.2 lum, respectively; Ps0.003). Results for TBW were comparable. Conclusion. Fluid state was significantly related to peritoneal transport characteristics and rGFR. The larger ECW:height in CAPD patients with a negligible rGFR existed despite a higher peritoneal ultrafiltration volume and higher peritoneal glucose prescription. These findings raise doubts as to whether fluid state in CAPD patients with a diminished rGFR can be adequately controlled on standard glucose solutions without an additional sodium and fluid restriction. The preliminary finding of a relationship between CRP and fluid state might suggest a relationship between overhydration and inflammation.

Primary hyperoxaluria type 1 in The Netherlands: prevalence and outcome

Abstract: Background. Primary hyperoxaluria type 1 (PH1) is a phenotypically heterogeneous disease. To date the relationship between biochemical parameters and outcome is unclear. We therefore undertook a national cohort study on biochemical and clinical parameters and outcome in PH1. Methods. Review of medical charts of all Dutch PH1 patients, who were identified by sending questionnaires to all Dutch nephrologists for children and adults. Results. Fifty-seven patients were identified. The prevalence and incidence rates were 2.9u10 6 and 0.15u10 6 uyear, respectively. Median age at diagnosis was 7.3 years (range 0–57). Seventeen (30%) patients were older than 18 years at time of diagnosis, of whom 10 (59%) presented with end-stage renal disease (ESRD), in contrast to only nine (23%) of those aged under 18 years. Median age at initial symptoms was 6.0 years (range 0–50). In four of nine patients with infantile PH1, normal renal function was preserved after a median follow-up of 7.7 years (range 0.1–16). Progression to renal insufficiency was associated with the presence of nephrocalcinosis, as assessed by ultrasound (relative risks1.8; 95% CI, 1.0–3.4) and with pyridoxine-unresponsiveness (relative risks2.2; 95% CI, 1.1–4.2) but not with age at presentation, the extent of hyperoxaluria, or AGT activity. No apparent nephrocalcinosis was found in five of the 19 patients who presented with ESRD. Conclusions. Although more than one-half of the PH1 patients have symptoms under the age of 10 years, PH1 can present at any age. In adults, PH1 presents predominantly with ESRD, which may be due to misinterpretation of early symptoms. Although nephrocalcinosis is correlated with development of renal insufficiency, the latter can occur even in the absence of nephrocalcinosis. Pyridoxine sensitivity is associated with better outcome in PH1.

Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency

Abstract: Background. Hepatitis C virus (HCV) infection is associated with renal manifestations, such as membranoproliferative glomerulonephritis (MPGN) with or without cryoglobulinaemia, membranous glomerulonephritis (MGN) and focal segmental glomerulosclerosis (FSGS). Standard treatment for HCV is interferon and ribavirin, but in renal insufficiency ribavirin has been contraindicated due to fear of side effects. Methods. Seven patients, two with cryoglobulinaemia, vasculitic manifestations and glomerulonephritis (GN), four with MPGN and one with FSGS were treated with a combination of interferon and ribavirin. Two patients were given pegylated interferon and ribavirin. All patients had at presentation renal insufficiency, with a glomerular filtration rate (GFR) between 10 and 65 ml/min. One patient had HCV genotype 1, the remainder 2 and 3. Duration of therapy was accordingto g (6–12 months). Ribavirin in plasma was monitored by highperformance liquid chromatography (HPLC) to avoid over-dosing, aiming at a target concentration of 10–15mmol/l. The main side effect of ribavirin, haemolytic anaemia, was monitored closely with haemoglobin controls. Results. Six of seven patients became HCV-RNAPCR negative and four of seven have maintained both virological and renal remission. One of seven has maintained virological and partial renal remission. One patient did not tolerate interferon, but is in renal remission with low-dose ribavirin. One vasculitis patient responded with complete remission, but relapsed virologically and had a minor vasculitic flare after 9 months. Only one patient with vasculitis had low-dose immunosuppression in addition to antiviral therapy. Average daily ribavirin dose was 200–800 mg. Ribavirin-induced anaemia was managed in five of seven patients with low-dose iron and erythropoietin between 4000 and 20 000 IU/week. Conclusions. Interferon and ribavirin can with reasonable safety be used in HCV-related vasculitis and GN irrespective of renal function.

HMG‐CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats

Abstract: Background. An inflammatory process may be one of the critical factors that contribute to the development of diabetic nephropathy (DN). We reported previously that intercellular adhesion molecule-1 (ICAM-1) is up-regulated and promotes macrophage infiltration in the glomeruli of diabetic rats. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have recently been emphasized to have anti-inflammatory effects; inhibition of leukocyte adhesion and migration, independent of the cholesterol-lowering effect. The present study was designed to test the hypothesis that statins prevent the development of DN by pleiotropic effects. Methods. Streptozotocin-induced diabetic rats were treated with cerivastatin (0.5 mgukg body weight) or vehicle for 4 weeks. We analysed glomerular macrophage infiltration and ICAM-1 expression. We also evaluated major regulators of ICAM-1, activation of nuclear factor-kappa B (NF-kB) using electrophoretic mobility shift assay, and oxidative stress. Results. Statin treatment reduced urinary albumin excretion (UAE) (2.96"0.18 vs 2.38"0.06; log10 UAE, P-0.05), glomerular size (12 150"329 vs 9963" 307 mm 2 , P-0.05), and lowered blood pressure, compared with untreated diabetic rats. Immunohistochemistry revealed that macrophage infiltration and ICAM-1 expression in glomeruli were increased in diabetic rats and were inhibited by statin treatment. Renal NF-kB activity, urinary excretion and renal deposition of 8-OHdG were increased in diabetic rats, and reduced by statin treatment. Conclusion. Statin treatment prevented glomerular injury, independent of the cholesterol-lowering effects. Our findings suggest that the beneficial effect might be mediated by pleiotropic effects including an antiinflammatory action through a reduction of oxidative stress, NF-kB activation, ICAM-1 expression and macrophage infiltration in the early phase of DN.

Association between residual renal function, inflammation and patient survival in new peritoneal dialysis patients

Abstract: Background. The recent ADEMEX study (Paniagua R, Amato D, Vonesh E et al. J Am Soc Nephrol 2002; 13: 1307–1320) indicates that peritoneal small solute clearance is not as critical for the survival of peritoneal dialysis (PD) patients as thought previously. On the other hand, low residual renal function (RRF), inflammation and an increased peritoneal transport rate (PTR) as evaluated by the peritoneal equilibration test (PET) are reported to be associated with increased mortality in PD patients, but the relationships between these factors and their separate and combined impact on the survival of PD patients are not clear. In this retrospective analysis, we evaluated possible relationships between RRF, inflammation and initial PTR in patients starting PD and the impact of these factors on patient survival. Methods. A total of 117 patients with initial assessments for RRF, serum C-reactive protein (CRP) and PET at a mean period of 0.4"0.2 months (range 0.1– 1.0 months) after start of PD were included in this study. Based on RRF (cut-off point, 4 mluminu1.73 m 2 ), serum CRP (cut-off point, 10 mgul), and the dialysate to plasma creatinine ratio at 4-h of dwell (mean q1SD), the patients were divided into different groups: low RRF and high RRF group, high CRP and normal CRP group and high PTR and other PTR group, respectively. Results. Of 117 patients, 54 patients (46%) were in low RRF (- 4m luminu1.73 m 2 ) group, 36 patients (31%) were in high serum CRP (P10 mgul) group and 17 patients (15%) were in high PTR group. Forty-nine patients (42%) had one of these characteristics, 26 patients (22%) had two of these characteristics, two patients (2%) had three, and 40 patients (34%) had none of these characteristics. Patients with low RRF were older and had a higher prevalence of high CRP, lower normalized protein equivalent of total nitrogen appearance (nPNA), lower total KtuVurea and lower total creatinine clearance (CCr) whereas patients with high CRP were older and had a higher proportion of men, lower serum albumin, lower nPNA, lower RRF and lower total CCr. Patients with high PTR had lower serum albumin, higher RRF and higher total CCr compared with patients with other PTR. Upon logistic multiple regression analysis, age and RRF were identified as factors affecting inflammation. Overall patient survival was significantly lower in the patients with low RRF, with high CRP, and in patients with more than two of the following: low RRF, high CRP and high PTR. In contrast, in patients with none of the discriminators low RRF, high CRP and high PTR, the 5-year survival was 100%. A high PTR was associated with decreased survival during the initial year on PD, but not thereafter. Patients who died during the follow-up period had a higher prevalence of high CRP and lower serum albumin, lower RRF, lower KtuVurea and lower total CCr. Upon Cox proportional hazards multivariate analysis, age and RRF were predictors of mortality. Conclusions. These results indicate that in patients starting PD, low initial RRF is associated with inflammation, and low RRF and inflammation are both associated with high overall mortality. A high PTR was associated with higher mortality, but only during the initial year on PD, whereas KtuVurea did not predict mortality. These results indicate the importance of RRF and inflammation as predictors of mortality in PD patients whereas the predictive power of PTR as such may lose its significance if these two parameters are taken into consideration.

The pathophysiology and treatment of hyponatraemic encephalopathy: an update

Abstract: Hyponatraemia is a common disorder that occurs in both the out-patient and in-patient setting. Hyponatraemic encephalopathy can be difficult to recognize, as the most frequent symptoms are nonspecific and can easily be incorrectly attributed to other causes. The patient usually presents with headache, nausea, vomiting and confusion, but can present with seizures, respiratory arrest and non-cardiogenic pulmonary oedema [1]. Over the past two decades, risk factors other than changes in the serum sodium level have been found to play a major role in the development of hyponatraemic encephalopathy, such as age, gender and hypoxia.

Carotid atherosclerosis is associated with inflammation and endothelial cell adhesion molecules in chronic haemodialysis patients

Abstract: Background. Recently emerging evidence suggests that endothelial adhesion molecules may participate in atherogenesis. The aim of the present report was to investigate the probable association of circulating ICAM-1, VCAM-1 and E-selectin with atherosclerotic disease in chronic haemodialysis (HD) patients. Methods. One hundred and twelve HD patients and 50 age- and sex-matched healthy normotensive controls participated in the study. Atherosclerotic disease in both groups was assessed by measuring intima– media thickness (IMT) and plaque score of the common carotid arteries using an ultrasound scanner. In addition, in a follow-up study, the survival of 81 patients after a mean period of 26 months was analysed in relation to ICAM-1 and VCAM-1 levels. Results. IMT and plaque score were significantly higher in HD patients compared with control subjects (P-0.001 and P-0.0001, respectively). The above ultrasonographic indices were correlated with age both in controls (Ps0.0001 and Ps0.002, respectively) and HD patients (Ps0.0001 and Ps0.0001, respectively). A significant relationship was observed between IMT and systolic blood pressure (BP) both in controls and in HD patients (Ps0.002 and Ps0.01, respectively). In HD patients, plaque score was also correlated with systolic BP (Ps0.02). In HD patients, IMT and plaque score were correlated significantly with log CRP values (Ps0.01 and Ps0.01, respectively). Multivariate analysis showed that log CRP values were a strong independent contributor to plaque score (Ps0.01). IMT was significantly correlated with ICAM-1 and VCAM-1 concentrations (Ps0.0001 and Ps0.003, respectively). Multivariate analysis showed that ICAM-1 concentrations were a strong independent correlate of IMT (Ps0.001). E-selectin concentrations did not show any relation with IMT or plaque score. During the follow-up period, 13 of the 81 patients died. Survival analyses showed that patients with increased ICAM-1 had a shorter survival than patients with normal ICAM-1 values and that serum ICAM-1 levels were a strong predictor of death. Conclusions. In HD patients, carotid atherosclerosis is associated with inflammation and circulating levels of soluble adhesion molecules ICAM-1 and VCAM-1. The correlations between serum ICAM-1 and IMT and ICAM-1 and survival may indicate that this molecule could be a marker of a process that contributes to the high mortality of HD patients.