Phenotypic features of vascular calcification in chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease stage 5 (CKD5) are predisposed to vascular calcification (VC), but the combined effect of factors associated with VC was sparsely investigated. We applied the relaxed linear separability (RLS) feature selection model to identify features that concomitantly associate with VC in CKD5 patients. METHODS: Epigastric arteries collected during surgery from living donor kidney transplant recipients were examined to score the histological extent of medial VC. Sixty-two phenotypic features in 152 patients were entered into RLS model to differentiate between no-minimal VC (n = 93; score 0-1) and moderate-extensive VC (n = 59; score 2-3). The subset of features associated with VC was selected on the basis of cross-validation procedure. The strength of association of the selected features with VC was expressed by the absolute value of 'RLS factor'. RESULTS: Among 62 features, a subset of 17 features provided optimal prediction of VC with 89% of patients correctly classified into their groups. The 17 features included traditional risk factors (diabetes, age, cholesterol, BMI and male sex) and markers of bone metabolism, endothelial function, metabolites, serum antibodies and mitochondrial-derived peptide. Positive RLS factors range from 1.26 to 4.05 indicating features associated with increased risk of VC, and negative RLS factors range from -0.95 to -1.83 indicating features associated with reduced risk of VC. CONCLUSION: The RLS model identified 17 features including novel biomarkers and traditional risk factors that together concomitantly associated with medial VC. These results may inform further investigations of factors promoting VC in CKD5 patients.

Association between levels of pentraxin 3 and incidence of chronic kidney disease in the elderly.

OBJECTIVE: Higher levels of the novel inflammatory marker pentraxin 3 (PTX3) predict cardiovascular mortality in patients with chronic kidney disease (CKD). Yet, whether PTX3 predicts worsening of kidney function has been less well studied. We therefore investigated the associations between PTX3 levels, kidney disease measures and CKD incidence. METHODS: Cross-sectional associations between serum PTX3 levels, urinary albumin/creatinine ratio (ACR) and cystatin C-estimated glomerular filtration rate (GFR) were assessed in two independent community-based cohorts of elderly subjects: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 768, 51% women, mean age 75 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 651, mean age 77 years). The longitudinal association between PTX3 level at baseline and incident CKD (GFR <60 mL(-1) min(-1) 1.73 m(-2) was also analysed (number of events/number at risk: PIVUS 229/746, ULSAM 206/315). RESULTS: PTX3 levels were inversely associated with GFR [PIVUS: B-coefficient per 1 SD increase -0.16, 95% confidence interval (CI) -0.23 to -0.10, P < 0.001; ULSAM: B-coefficient per 1 SD increase -0.09, 95% CI -0.16 to -0.01, P < 0.05], but not ACR, after adjusting for age, gender, C-reactive protein and prevalent cardiovascular disease in cross-sectional analyses. In longitudinal analyses, PTX3 levels predicted incident CKD after 5 years in both cohorts [PIVUS: multivariable odds ratio (OR) 1.21, 95% CI 1.01-1.45, P < 0.05; ULSAM: multivariable OR 1.37, 95% CI 1.07-1.77, P < 0.05]. CONCLUSIONS: Higher PTX3 levels are associated with lower GFR and independently predict incident CKD in elderly men and women. Our data confirm and extend previous evidence suggesting that inflammatory processes are activated in the early stages of CKD and drive impairment of kidney function. Circulating PTX3 appears to be a promising biomarker of kidney disease.

Clinical determinants and mortality predictability of stearoyl-CoA desaturase-1 activity indices in dialysis patients.

BACKGROUND: Stearoyl-CoA desaturase-1 (SCD-1) converts dietary saturated fatty acids to monounsaturated fatty acids. Elevated SCD-1 activity thus signifies impaired fatty acid metabolism and excess saturated fat intake. In the general population, increased SCD-1 activity is associated with cardiovascular disease and mortality. The determinants and implications of SCD-1 activity in dialysis patients are unknown. SUBJECTS: A total of 222 dialysis patients (39% women) with prospective follow-up, median age of 57 years and an average of 12 months of dialysis. DESIGN: Fatty acid compositions in plasma phospholipids and free fatty acids (FFAs) were assessed by gas-liquid chromatography. SCD-1 activity indices were calculated as the product-to-precursor fatty acid ratio (palmitoleic acid/palmitic acid) in each fraction to reflect SCD-1 activities in the liver and adipose tissue. RESULTS: Median hepatic and adipose tissue SCD-1 activity indices were 0.016 and 0.150, respectively. In multivariate analyses, SCD-1 was positively associated with age, female sex and serum interleukin-6 level. During 18.4 (interquartile range 5.5-37.3) months of follow-up, there were 61 deaths and 115 kidney transplants. The cut-off level for high SCD-1 indices was determined by receiver operating characteristic curve analyses. In fully adjusted competing risk models, patients with high SCD-1 indices in both phospholipids and FFAs had more than twofold increased mortality risk before kidney transplantation [hazard ratio (HR) 2.29, 95% confidence interval (CI) 1.28-4.11 and HR 2.36, 95% CI 1.38-4.03, respectively], compared with patients with low SCD-1 indices. CONCLUSIONS: Both hepatic and adipose tissue SCD-1 activity indices independently predict mortality in dialysis patients. Further studies are warranted to determine whether reducing SCD-1 activity by dietary intervention (limiting saturated fat) could improve survival in dialysis patients.

Immunoglobulin (Ig)M antibodies against oxidized cardiolipin but not native cardiolipin are novel biomarkers in haemodialysis patients, associated negatively with mortality.

The risk of premature death is high in haemodialysis (HD) patients. Antibodies against cardiolipin (anti-CL) are thrombogenic in diseases such as systemic lupus erythematosus (SLE). CL is easily oxidized (Ox) and plays a role in apoptosis. In this work we studied immunoglobulin (Ig)M anti-CL and anti-OxCL in HD-patients. We conducted an observational study with a prospective follow-up examining the relationship between anti-CL, anti-OxCL and mortality risk in a well-characterized cohort of 221 prevalent HD patients [56% men, median age 66 (interquartile range 51-74) years, vintage time 29 (15-58) months] with a mean follow-up period of 41 (20-48 months). According to the receiver operator characteristic (ROC) analysis, anti-OxCL [area under the curve (AUC) 0·62, P < 0·01], but not anti-CL (AUC 0·52, P = 0·2), is associated with mortality. In crude and adjusted Cox analysis, every log increase in anti-OxCL inversely predicted all-cause [adjusted hazard ratios (HR) 0·62 (0·43-0·89)] and CVD-related [adjusted HR 0·56 (0·32-0·98)] mortality. Patients with anti-OxCL levels below median also had increased all-cause and cardiovascular disease (CVD)-related mortality. Although anti-OxCL and anti-phosphorylcholine (PC) were related positively to each other (ρ = 0·57, P < 0·01), patients with one or two of these autoantibody levels below the median were associated with an incrementally increased death risk. Anti-OxCL were co-factor ß2-GPI-independent; anti-CL from patients with anti-phospholipid antibody syndrome were ß2-GPI-dependent, while sera from HD-patients less so. Sera from healthy donors was not ß2-GPI-dependent. Anti-OxCL IgM is ß2-glycoprotein 1 (GPI)-independent and a novel biomarker; low levels are associated with death among HD patients (and high levels with decreased risk). Combination with anti-PC increases this association. Putative therapeutic implications warrant further investigation.

Acute renal failure in dense deposit disease: complete recovery after combination therapy with immunosuppressant and plasma exchange.

We describe the clinical course of a female adolescent who was followed because of isolated microhematuria and hypocomplementemia before admission to hospital with a sudden onset of acute renal failure. At presentation, she exhibited complement consumption through the complement alternative pathway (AP) while other serologic tests were negative. Renal biopsy revealed dense deposit disease (DDD) with a crescentic pattern. Intravenous methylprednisolone, followed by plasma exchange (PE), and intravenous cyclophosphamide pulses were started shortly after admission. C3NeF and anti-factor H antibody tests were negative. Serum factor H and I levels were normal as well as factor H activity. Screening for mutation in the factor H gene revealed the H402 allele variant. Clinical remission, defined as normalization in renal function and in the activity levels of the complement AP, was noted at one month post-presentation and throughout the follow-up. A repeat renal biopsy showed the disappearance of crescent formation, whereas electron microscopy revealed no regression in dense transformation of the lamina densa. In summary, our patient was successfully treated with immunosuppressant and PE. The absence of known factors associated with DDD suggests that, in this particular case, other regulatory mechanisms of complement AP might have been involved in the disease process.

Temporal discrepancies in the association between the apoB/apoA-I ratio and mortality in incident dialysis patients.

BACKGROUND: In the general population, a high apoB/apoA-I ratio is a strong risk factor for cardiovascular disease and mortality. However, whether this is the case in chronic kidney disease (CKD) patients is currently unknown. STUDY DESIGN: The apoB/apoA-I ratio was evaluated in 391 incident CKD stage 5 patients examined close to dialysis initiation, and again after 1 year of dialysis in a subgroup of 182 patients, subsequently followed for up to 3 years. RESULTS: Baseline values of the apoB/apoA-I ratio as well as changes in the ratio during the first year of dialysis correlated with body mass index (BMI) and fat mass. The baseline apoB/apoA-I ratio showed no association with 4-year mortality. However, after adjustment for confounders, a high apoB/apoA-I ratio (>0.9) predicted short-term (first year) survival [hazard ratio (HR): 0.35; 95% confidence interval (CI): 0.13-0.85)] and long-term (next 3 years) mortality (HR: 1.72; 95% CI: 1.01-2.96). An increase in the apoB/apoA-I ratio during the first year of dialysis was linked to a survival advantage thereafter (HR: 0.48; 95% CI: 0.22-0.98). However, this association lost its significance (HR: 0.62; 95% CI: 0.26-1.36) after adjustment for indices of protein-energy wasting. CONCLUSIONS: A high apoB/apoA-I ratio and an increase in this ratio during the first year on dialysis were associated with short-term survival advantage in CKD patients. This paradoxical relationship represents an example of the so-called reverse epidemiology phenomenon in CKD patients and suggests that the apoB/apoA-I ratio should always be interpreted with caution in this patient population.

Intercurrent events and comorbid conditions influence hemoglobin level variability in dialysis patients.

BACKGROUND: To help identify factors contributing to intra-patient Hb variability, pooled records were analyzed from 5,592 patients undergoing hemodialysis (HD) in European, multicenter, open-label, single-arm Phase 3b trials. PATIENTS AND METHODS: Patients previously treated with recombinant human erythropoietin (rHuEPO) were switched to darbepoietin-alpha administered once a week (QW) or once every 2 weeks (Q2W), maintaining the same dosing schedule and route of ESA administration (intravenous or subcutaneous) up to and through the evaluation period. Patients were treated with darbepoietin-alpha to maintain Hb levels between 10 and 13 g/dl. Intrapatient variability was calculated using the SD model, taking all of an individual patient's Hb values during the evaluation period (Weeks 21 - 24 after conversion) and calculating the SD of these Hb values. Adverse events (AE) of infection or inflammation were recorded. RESULTS: Smaller variability was seen for patients 65 years of age or older compared with younger patients (p = 0.0044) and greater variability for patients less than 40 years of age compared with older patients (p < 0.01). Little difference in variability was seen in relation to sex overall or to the presence or absence of diabetes. Intra-patient Hb variability was greater in the presence of intercurrent conditions, including infection or inflammation (p = 0.0032), blood transfusion (p < 0.0001), hospitalization (p < 0.0001), or hospitalization for cardiovascular (CV) causes (p = 0.0012), than in their absence. Iron status differences had little detectable effect on intra-patient Hb variability. A larger number of changes made to the ESA dose during the evaluation period was also associated with greater Hb variability compared with fewer dose changes, but this association could not be proved as being causative. Although p values were calculated for some comparisons, statistical significance might not indicate clinical significance because of the large sample size. Multivariable analysis to assess the association between AE status and intra-patient Hb variability, adjusting for age, sex, diabetes status, number of dose changes and iron status showed that AE status was significantly associated with Hb variability. CONCLUSION: Additional studies would be needed to further investigate causes and effects of Hb variability and intercurrent events.

Telomere attrition is associated with inflammation, low fetuin-A levels and high mortality in prevalent haemodialysis patients.

INTRODUCTION: Chronic kidney disease (CKD) predisposes to a 10- to 20-fold increased cardiovascular risk. Patients undergo accelerated atherogenesis and vascular ageing. We investigated whether telomere attrition, a marker of cell senescence, contributes to this increased mortality risk. METHODS: This is a cross-sectional study in prevalent haemodialysis patients [n = 175; 98 Males; median (range) age: 66 (23-86) years]. Biochemical markers of oxidative stress and inflammatory status were measured in relation to the patient's leucocyte telomere length. Overall mortality was assessed after a median of 31 (range 2-42) months. RESULTS: Telomere length was shorter in CKD men, despite women being older (average +/- SD 6.41 +/- 1.23 vs. 6.96 +/- 1.48 kb, P = 0.002). Telomere length was associated with age (rho = -0.18, P = 0.01), fetuin-A (rho = 0.26, P = 0.0004), high-sensitivity C-reactive protein (rho = -0.21, P = 0.005) and IL-6 (rho = -0.17, P = 0.02). In a multivariate logistic regression (pseudo r(2) = 0.14), telomere length was associated with age >65 years (odds ratio: 2.11; 95% CI: 1.10, 4.06), sex (2.01; 1.05, 3.86), fetuin-A (1.85; 0.97, 3.50) and white blood cell count (2.04; 1.02, 4.09). Receiver operating characteristic curves identified a telomere length < 6.28 kb as a fair predictor of mortality. Finally, reduced telomere length was associated with increased mortality, independently of age, gender and inflammation (likelihood ratio 41.6, P < 0.0001), but dependently on fetuin-A levels. CONCLUSION: Age and male gender seem to be important contributors to reduced telomere length in CKD patients, possibly via persistent inflammation. Reduced telomere length also contributes to the mortality risk of these patients through pathways that could involve circulating levels of fetuin-A.

Low serum fetuin-A concentration predicts poor outcome only in the presence of inflammation in prevalent haemodialysis patients.

BACKGROUND: Fetuin-A, a negative acute phase protein that inhibits vascular calcification, has a controversial association with mortality in chronic kidney disease (CKD) patients. Chronic inflammation, which is common in CKD, may promote vascular calcification. MATERIALS AND METHODS: We investigated the impact of inflammation on the relationship between serum fetuin-A and mortality (42 months) in 222 prevalent haemodialysis (HD) patients. RESULTS: Serum fetuin correlated negatively with comorbidity score (assessed by Davies score) and circulating inflammatory markers. Patients with low fetuin-A levels (< median) had higher mortality (Hazard ratio 'HR' 2.2; CI 1.4-3.5, P < 0.001), but this association was lost after adjustment for age, gender, comorbidities score, dialysis vintage and inflammation (CRP > median). In inflamed patients with low fetuin a significantly independent association with mortality (HR 2.3; CI 1.2-4.5, P = 0.01) was observed compared to non-inflamed patients with high fetuin-A, after adjusting for the same variables. Non-inflamed patients with low fetuin-A and inflamed patients with high fetuin-A did not have increased mortality compared to non-inflamed patients with high fetuin-A. CONCLUSIONS: The results show that low levels of serum fetuin-A are associated with increased mortality in HD patients only in the presence of inflammation. This suggests that coexistence of a low serum fetuin-A level and low-grade inflammation exerts an additive effect on the risk of death in HD patients.

Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease.

OBJECTIVES: In this study, we explore the associations of decreased thyroid hormone levels with inflammation, wasting and survival in biochemically euthyroid patients with end-stage renal disease (ESRD). DESIGN: After exclusion of 23 patients with thyroid-stimulating hormone (TSH) values outside the normal range (0.1-4.5 mIU L(-1)), 187 clinically and biochemically euthyroid incident ESRD stage 5 patients starting dialysis were followed for a median of 20 (range 1-60) months. Measurements of total and free forms of thyroid hormones, s-albumin, hs-CRP, interleukin (IL)-6, vascular adhesion molecule (VCAM)-1 and insulin-like growth factor 1 (IGF-1) were performed at baseline. RESULTS: In this population, 17 out of 210 patients (8%) were defined as subclinically hypothyroid. Multivariate analysis, according to receiver operating characteristic (ROC) curves, showed that mortality was best predicted by total triiodothyronine (T3). When using the cut-off levels derived from ROC, low T3 levels were associated with increased inflammation (higher hs-CRP, IL-6 and VCAM-1) and lower concentration of both s-albumin and IGF-1. Finally, low T3 but not low free triiodothyronine was associated with worse all-cause (Likelihood ratio = 45.4; P < 0.0001) and cardiovascular mortality (Likelihood ratio = 47.8; P < 0.0001) after adjustment for confounding factors. CONCLUSION: This study showed that low T3 levels are independent predictors of all-cause and also cardiovascular disease mortality in biochemically euthyroid patients, perhaps due to an intimate association with inflammation. Based on these results, the use of T3 levels in studies assessing the relationship between thyroid dysfunction and mortality risk is recommended.

Are insulin-like growth factor and its binding proteins 1 and 3 clinically useful as markers of malnutrition, sarcopenia and inflammation in end-stage renal disease?

INTRODUCTION: Malnutrition is common in end-stage renal disease (ESRD) and affects both morbidity and mortality. The growth hormone-dependent insulin-like growth factor (IGF)-I may be a good marker of malnutrition because of its short half-life. In the present study, we investigate the influence of decreasing residual renal function as well as of chronic inflammation on the IGF system to assess its usefulness in this patient group. PATIENTS AND METHODS: Cross-sectional analysis of 220 ESRD patients (140 males) with a mean age of 52+/-1 years. Biochemical analyses of insulin, IGF-I, IGFBP-1, IGFBP-3, IL-6, high sensitivity (hs)-CRP and other routine markers. Malnutrition status was recorded using subjective global assessment (SGA), body mass index, estimated protein intake from nitrogen appearance (nPNA), handgrip strength (HGS) and insulin resistance (HOMA-IR). Dual energy X-ray absorptiometry was used to assess body composition. RESULTS: Both IGF-I and IGFBP-1 showed significant and opposite correlations with most markers of nutritional status, including SGA (rho=-0.29 and 0.27; P<0.001), nPNA (rho=0.18 and -0.22; P<0.05), S-creatinine (rho=0.19 and -0.19; P<0.01) and HGS (rho=0.21 and -0.25; P<0.01). IFG-I was strongly correlated with IGFBP-3 (rho=0.62; P<0.001) and inversely correlated with IGFBP-1 (rho=0.44; P<0.001). Both IGF-I and IGFBP-3, but not IGFBP-1, were significantly correlated with age (rho=-0.25 for IGF-I and -0.35 for IGFBP-3; P<0.001) and hsCRP (rho=-0.21 and -0.32; P<0.01). In multivariate analysis, SGA and s-albumin were independent predictors of both IGF-I and IGFBP-1. CONCLUSION: Both IGF-I and IGFBP-1 appear to correlate well with markers of protein-energy malnutrition and sarcopenia. However, IGF-I is also influenced by age, whereas IGFBP-1 is influenced by glucose metabolism. IGFBP-3 does not correlate with nutritional status in ESRD, perhaps because of a strong association with inflammation.

Plasma pentosidine and total homocysteine levels in relation to change in common carotid intima-media area in the first year of dialysis therapy.

BACKGROUND: Homocysteine and advanced glycation end-products (AGEs), which accumulate in chronic kidney disease (CKD), are recently proposed cardiovascular risk factors. In this study, we evaluated the association between changes in calculated intima media (cIM) area of the common carotid artery during the first year of dialysis therapy and plasma total homocysteine (tHcy) level as well as circulating AGEs such as plasma pentosidine level. METHODS: We studied 63 CKD patients (38 males) aged 52 +/- 12 years at a time-point close to start of dialysis treatment and after 12 months of dialysis treatment (41 on peritoneal and 22 on hemodialysis). The tHcy and plasma pentosidine levels were measured by HPLC. Change in cIM area was evaluated by non-invasive B mode ultrasonography. Malnutrition was assessed by subjective global assessment (SGA). RESULTS: At basal, 70% of the patients had carotid plaques, 32% had symptomatic CVD, 38% had malnutrition, 30% had inflammation (CRP > or = 1 mg/dl) and 23% had diabetes mellitus, respectively. At baseline, the mean plasma pentosidine levels were similar in the patients with and without carotid plaques (36 +/- 21 vs 36 +/- 19 pmol/mg albumin, respectively), whereas the median plasma tHcy was significantly lower in the patients with carotid plaques than in the patients without carotid plaques (32 +/- 21 vs 52 +/- 42 pmol/l, p < 0.01, respectively). The prevalence of hyperhomocysteinemia (tHcy level > 13.7 micromol/l) was 95%. In univariate analysis, the change in cIM area during the first year of dialysis was significantly correlated with basal plasma pentosidine level (p = 0.31, p = 0.01), but not with basal tHcy (p = -0.11). However, neither pentosidine nor tHcy levels were correlated with cIM area at basal or at 12 months. In a stepwise multiple regression model, age and plasma pentosidine content, but not the tHcy level, associated with changes in the cIM area. CONCLUSION: Progression of atherosclerosis, as indicated by changes in carotid intima-media area during the course of dialysis treatment, was associated with pentosidine, but not with tHcy, levels at baseline in these CKD patients. This suggests that the accumulation of AGEs in CKD patients may have a role in the pathogenesis of CVD in these patients. Since almost all CKD patients have hyperhomocysteinemia, this finding, however, does not exclude a role ofhomocysteine as a risk factor for CVD in CKD patients.

Peroxisome proliferator-activated receptor gamma polymorphisms affect systemic inflammation and survival in end-stage renal disease patients starting renal replacement therapy.

BACKGROUND: Inflammation may contribute to the markedly increased cardiovascular morbidity and mortality in end-stage renal disease (ESRD). However, the prevalence of inflammation varies in different ESRD populations. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is an important nuclear signaling protein that may regulate inflammatory response, and recent studies have revealed genetic polymorphisms that have significant effect on PPAR-gamma signaling. The aim of this study was to clarify whether the PPAR-gamma 161C/T and PPAR-gamma2 Pro12Ala single-nucleotide polymorphisms (SNPs) influence the inter-individual variance of inflammation and mortality in ESRD patients. METHODS: The present prospective study included 229 incident Caucasian ESRD patients (62% males) just prior to starting renal replacement therapy and 207 healthy controls (62% males). Blood samples were taken for measuring systemic inflammatory (CRP, TNF-alpha, IL-6) and nutritional (S-albumin) parameters. The presence of diabetes mellitus, malnutrition (subjective global assessment (SGA)) and cardiovascular disease (CVD) were also assessed. Genotyping of the two PPAR-gamma SNPs was performed using Pyrosequencing. During follow-up (1621+/-63 days), both all-cause and CVD-mortality were investigated. RESULTS: ESRD patients had a higher prevalence of both the PPAR-gamma 161 CC and PPAR-gamma2 Pro12Pro genotypes than the general population (p<0.01). Whereas the Pro12Pro genotype was associated with higher median serum levels of both hs-CRP (p<0.05) and TNF-alpha (p<0.01) the 161CC genotype was associated with a significantly higher (6.6 mg/L versus 3.3 mg/L; p<0.01) median hs-CRP level. Following adjustment for age, gender, SGA and CVD a significantly higher mortality rate was observed in patients with the Pro12Pro genotype. CONCLUSION: This study demonstrates significant differences in PPAR-gamma genotype distribution between ESRD patients and healthy controls. Furthermore, as the PPAR-gamma2 Pro12Pro genotype was associated with both higher levels of biomarkers of inflammation as well as shorter survival, genetic polymorphisms seem to play a role in determining systemic inflammatory status and outcome in this patient group.

Long-term effects on lymphocytotoxic antibodies and immune reactivity in hemodialysis patients treated with recombinant human erythropoietin.

Twenty-six hemodialysis patients were given human recombinant erythropoietin to correct anemia. Eighteen patients had previously received multiple transfusions and 18 had been transfused within the preceding six months. Ten patients had lymphocytotoxic antibodies (panel reactive antibodies, PRA), measured as percent positive reactions against a panel of lymphocytes from 22 lymphocyte donors before the start of erythropoietin treatment. There was a significant decrease in mean PRA activity from 60% to 35% (p less than 0.05) during 6-18 months of treatment. Three of 26 patients received blood transfusions after the start of erythropoietin treatment, because of intercurrent disease or blood loss. Kidney transplantation was performed in four of the PRA-positive patients and in eight of the PRA-negative patients. Nine kidney transplants are currently functioning. The three graft losses were due to rejections. The lymphocyte immune reactivity measured after stimulation in MLC (mixed lymphocyte culture) against pooled lymphocytes and after PHA (phytohemagglutinin) and Con A (Concanavalin A) stimulation, was significantly lower in the hemodialysis patients than in the healthy controls (p less than 0.05). The responses did not change after correction of anemia. The number of OKM1 (Ortho's monoclonal antibody against M1 cells [monocytes])-positive cells among peripheral blood lymphocytes were significantly higher (p less than 0.001) in uremic patients than in healthy controls. After 12-18 months of treatment with erythropoietin this difference disappeared.(ABSTRACT TRUNCATED AT 250 WORDS)

Clostridium difficile infection--a poor prognostic sign in uremic patients?

Uremia has been reported as a risk factor for the occurrence of infection with Clostridium difficile. During the two-year period 1984-86, 110 episodes of Clostridium difficile infection were encountered in 70 patients on a nephrology ward. Sixty-two patients had chronic renal failure and eight had acute renal failure. Sixty-seven of the patients were uremic and were treated with hemodialysis (n = 35), CAPD (n = 21), intermittent peritoneal dialysis (n = 6) or conservatively with a low protein diet (n = 5). Most of the patients were female (n = 41) and elderly (64 +/- 2 years). Malnutrition was common as indicated by low serum albumin concentrations (26 +/- 1 g/l) prior to the Clostridium difficile infection. Clostridium difficile infection was confirmed by stool culture and/or cytotoxin assay. Asymptomatic infections were found in eight patients. The highest relative risks of subsequent Clostridium difficile infection were calculated for patients treated with cephalosporins and isoxazolyl penicillins. All patients were treated with vancomycin, which often resulted in a dramatic improvement. One to six relapses of Clostridium difficile infection were observed in 22 of the patients. Sixty of the original 70 patients died during the five-year follow-up period. Thirty-four patients died during the first year of follow-up. Seven patients were transplanted, two are still on CAPD treatment and one has only moderate chronic renal failure (serum creatinine 200 mumol/l). Elderly debilitated uremic patients are especially susceptible to infection with Clostridium difficile which may be a poor prognostic sign in chronic renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Nutritional assessment in anemic hemodialysis patients treated with recombinant human erythropoietin.

Nutritional status was assessed in 25 anemic hemodialysis patients before and during erythropoietin treatment. Nutritional assessment included regular blood chemistry determinations, anthropometric measurements, analysis of protein content in skeletal muscle, and estimation of daily protein intake from protein catabolic rate determinations (using urea kinetic modelling) and dialysis efficiency for urea. These measurements were done immediately prior to erythropoietin treatment, after anemia correction and after one year of maintenance erythropoietin treatment. Both relative body weights and subcutaneous fat stores were low at the start, but increased significantly (p less than 0.05) during the study. Sixteen of the 25 patients gained weight and eight patients lost weight. The patients with weight gain had at the start of the study low weight indices (body weight 89.9 +/- 7.6% of ideal body weight, body mass index 20.6 +/- 1.6), significantly (p less than 0.005) lower than the patients with weight loss. Although protein malnutrition was not obvious from arm anthropometrics, alkali soluble protein/DNA ratio or from serum albumin determinations, ASP/DNA ratio, increased in three of five patients investigated after one year on erythropoietin treatment. Neither protein catabolic rate nor dialysis efficiency changed significantly during the study. We conclude that anemia correction with erythropoietin has a positive effect on malnutrition in hemodialysis patients. In patients with underweight, an adjustment of fat stores was initially observed, followed possibly by an improvement in muscle protein content.

Daily subcutaneous administration of recombinant human erythropoietin (rhEPO) in peritoneal dialysis patients: a European dose-response study.

In a prospective randomized open multicenter study, 107 anemic (Hct < = 28%) peritoneal dialysis (PD) patients were treated with s.c. rhEPO daily. The mean observation period was 299 days (range 14-479 days). Patients were randomly assigned to 3 groups with different initial doses: 5 U/kg (G5), 10 U/kg (G10), 20 U/kg (G20). Initial doses were maintained for at least 8 weeks unless the target Hct (30-35%) was achieved earlier. The weekly increase of Hct was significantly (p < 0.05) dose-dependent: 0.19% in G5, 0.5% in G10 and 0.94% in G20. In case of insufficient response (< 0.5% per week), the dose was doubled every 4 weeks. Final doses on achieving the target Hct ranged from 5 to 40 U/kg (median 20 U/kg). The dose was then reduced to 50% and adjusted individually. The median maintenance dose was 9.9 U/kg/day. No tendency towards higher blood pressure or intensification of antihypertensive treatment was observed. When rhEPO is administered daily, 10 U/kg/day (70 U/kg weekly) is the recommended starting dose. The need for higher doses used in unsatisfactory response, should lead to further examination to rule out iron deficiency and other reasons for non-response. The median maintenance dose reported here is the lowest published in the literature for PD patients and seems to be linked to the daily injections.

Management of iron deficiency in renal anemia: guidelines for the optimal therapeutic approach in erythropoietin-treated patients.

Much progress has been made in recent years in the management of anemia associated with chronic and renal failure with recombinant human erythropoietin (r-Hu EPO). However, there remains much debate surrounding the diagnosis and treatment of iron deficiency. To ensure that full benefit from erythropoietin therapy is received, most patients require iron supplement during treatment. There are, however, few guidelines for the use of iron therapy. Iron deficiency results in an inadequate response to r-Hu EPO and is the main cause of resistance to this treatment. Oral iron therapy is of limited value in patients receiving r-Hu EPO. Thus, intravenous iron supplementation should be administered only in patients who do not tolerate available intravenous iron preparations or who are on continuous ambulatory peritoneal dialysis with no evidence of functional iron deficiency. This article provides guidelines for the diagnosis of absolute or functional iron deficiency in patients with renal anemia and suggests treatment schedules for intravenous iron supplementation. We hope that all dialysis patients will be able on this basis to achieve a satisfactory iron status and benefit fully from r-Hu EPO therapy.

Subcutaneous epoetin beta in renal anemia: an open multicenter dose titration study of patients on continuous peritoneal dialysis.

OBJECTIVE: To establish dose requirements (target hemoglobin > 100 g/L) and safety of subcutaneously administered epoetin beta. DESIGN: Open multicenter study. PATIENTS: Forty-five anemic patients (21 female, 24 male; mean age 55 years; range 20-79 years) who had been on continuous peritoneal dialysis for 1-157 months (mean 24 months). Thirty patients required blood transfusions during the year prior to the study. Mean hemoglobin concentration pretreatment was 75 g/L (range 57-89 g/L). INTERVENTION: After a pretreatment period of two weeks, 60 IU kg-1 week-1 divided into three weekly doses of epoetin beta was administered subcutaneously. The dose was increased by 60 IU kg-1 week-1 after ten weeks, and when necessary, every fourth week in patients with hemoglobin levels below 100 g/L. MAIN OUTCOME MEASURES: Hemoglobin concentration. Analysis of factors affecting the response to epoetin beta. Safety of epoetin beta. RESULTS: Thirty-eight of the 45 patients completed six months and 21 patients completed one year in the study. Twenty-six patients reached hemoglobin 100 g/L within six months and 8 patients did later on. The mean hemoglobin concentration after three months was 93 g/L (range 64-144 g/L) and after six months was 99 g/L (range 59-130 g/L; mean epoetin beta dose 122 IU kg-1 week-1). During the second six-month period of the study, hemoglobin levels were stable in most patients. After one year, the mean hemoglobin was 110 g/L (range 84-153 g/L) and the mean epoetin beta dose was 107 IU kg-1 week-1. Prolonged correction time and impaired response to epoetin were observed in patients with infections or hemorrhages and in patients with low hemoglobin concentration before starting epoetin treatment. Iron deficiency was controlled by iron supplementation, either orally or, in 10 patients, intravenously. Increased blood pressure, requiring intensified antihypertensive treatment, was observed in 13 patients. CONCLUSIONS: Continuous peritoneal dialysis patients with moderate anemia (Hb 75-90 g/L) and without complicating disorders can be managed with subcutaneous doses of epoetin < 120 IU kg-1 week-1. The epoetin beta dose should be adjusted after the first month of treatment since most patients required higher doses than the initial 60 IU kg-1 week-1.

An educational programme for persistent life-style changes in patients with chronic renal disease.

The aim of this study was to produce positive life-style changes in patients with chronic renal disease through a residential education programme about the medical aspects of chronic renal failure and the various treatment options in order to increase their physical capacity, emotional stability and general well-being. The programme was available to all categories of patients with chronic renal disease irrespective of treatment modality. Comparison of data pre and post course demonstrated improvements in physical activity, mental well-being and nutritional awareness.