Abdul Rashid Qureshi

Muscle atrophy, inflammation and clinical outcome in incident and prevalent dialysis patients

BACKGROUND & AIMS Muscle wasting is considered the best marker of protein-energy wasting in end-stage renal disease (ESRD). We tested the usefulness of a simple observer subjective muscle atrophy (MA) grading in relation to morbidity and mortality in ESRD patients. METHODS In two different ESRD cohorts (265 incident patients starting dialysis and 221 prevalent hemodialysis patients), each patients degree of MA was visually graded by a trained nurse on a scale from 1 to 4 as part of the subjective global assessment. This score was confronted with inflammatory and nutritional indexes as well as objective measurements of muscle atrophy. Patients were then prospectively followed for up to four or six years, depending on the cohort. RESULTS Thirty percent of the incident and 39% of the prevalent patients presented signs of MA. Across worsening MA scale, nutritional and anthropometric markers of muscle loss were incrementally poorer. Inflammation markers as well as the proportion of women became progressively higher. Female sex, presence of cardiovascular disease, inflammation and low insulin-like growth factor-1 levels were associated with increased significant odd ratios of MA in each cohort. After adjustment for age, sex, inflammation, diabetes, cardiovascular disease, glomerular filtration rate and/or time on hemodialysis, the hazard ratio of death for moderate/severe MA was 2.62 (95% CI: 1.34, 5.13; p=0.001) and 3.04 (95% CI: 1.61, 5.71; p=0.0001) in the incident and prevalent cohorts respectively. CONCLUSION Increased MA is more common in female dialysis patients and associated with inflammation, poor nutritional and anthropometric status, as well as a 3-fold increased 4-6 year mortality. Our data support the use of frequent MA and/or nutritional assessments in the clinical practice.

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

Abstract.  Carrero JJ, Qureshi AR, Axelsson J, Yilmaz MI, Rehnmark S, Witt MR, Bárány P, Heimbürger O, Suliman ME, Alvestrand A, Lindholm B, Stenvinkel P (Karolinska Institutet, Stockholm; and Karo Bio AB, Novum, Huddinge; Sweden). Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med 2007; 262: 690–701.

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.

Abdominal fat deposition is associated with increased inflammation, protein–energy wasting and worse outcome in patients undergoing haemodialysis

OBJECTIVE The role of obesity in promoting or preventing the complications of haemodialysis patients remains unclear, with several studies suggesting that obesity may even be beneficial. We tested the hypothesis that abdominal fat deposition in HD patients is a risk factor associated with both increased inflammation and protein-energy wasting (PEW), as well as elevated mortality risk. METHODS A cross-sectional study with mortality follow-up [median 41 (interquartile range 25-47) months] of haemodialysis patients [n = 173, 100 men, aged 65 (51-74) years]. Abdominal fat deposition was assessed by means of a conicity index (Ci), which estimates fat accumulation in the abdomen as the deviation of body shape from a cylindrical towards a double-cone shape (i.e. two cones with a common base at the waist level). The Ci was studied with regard to baseline inflammatory, anthropometric and nutritional markers, including subjective global assessment (SGA). RESULTS Across increasing tertiles of the Ci, patients were older, fatter and more inflamed (P < 0.01 for all). At the same time, they presented a higher prevalence of PEW (SGA >1), reduced handgrip strength and lower S-creatinine (P < 0.01 for all). An increased abdominal fat deposition was associated with worse outcome independently of age, sex, comorbidities and dialysis vintage [Cox HR 1.93 (95% CI = 1.06-3.49)], but the predictive value disappeared following adjustment for interleukin-6 (IL-6) and PEW. CONCLUSION Abdominal fat deposition in haemodialysis patients is linked to both inflammation and PEW, resulting in an increased mortality risk. Our results support the idea that regional differences in adiposity accumulation may have diverse implications on patient outcome.

Endothelial dysfunction in type-2 diabetics with early diabetic nephropathy is associated with low circulating adiponectin

BACKGROUND Type-2 diabetes and diabetic kidney disease have additive effects on cardiovascular risk. Furthermore, the degree of proteinuria is an independent predictor of mortality in this patient group. We hypothesized that altered kidney clearance and/or metabolism of vasoactive peptides occurring during proteinuria could link early diabetic nephropathy to cardio vascular disease (CVD). METHODS We performed a cross-sectional study of 85 incident patients (51 +/- 5 years, 49 males) with type-2 diabetes and 38 age- and sex-matched controls. We further divided patients by the presence of minor (<500 mg/day; n = 40) or severe (>/=500 mg/day; n = 45) proteinuria. Clinical and anthropometric data, along with ultrasonographic flow-mediated dilatation (FMD) of the brachial artery and carotid intima-media thicknesses (CIMT), were recorded in each group. Circulating NAMPT/visfatin, adiponectin (normalized to BMI), AHSG/fetuin-A and hsCRP levels were also measured using commercial ELISA. RESULTS Plasma NAMPT/visfatin, CIMT, HOMA index and hsCRP levels were all significantly higher in diabetics than in control subjects, and all but CIMT correlated with proteinuria (rho = 0.46; P < 0.001, rho = 0.54; P > 0.05, rho = 0.32; P = 0.003, rho = 0.76; P < 0.001, respectively). FMD, adiponectin and AHSG/fetuin-A levels were significantly lower, and negatively correlated with proteinuria (rho = -0.54; P < 0.001, rho = -0.56; P < 0.001, rho = -0.48; P < 0.001, respectively). In a multivariate regression analysis, the degrees of proteinuria (r(2) = -0.32, P = 0.04) and plasma levels of NAMPT/visfatin (r(2) = -0.33, P = 0.006) were independently related to FMD. CONCLUSIONS The present study suggests that the presence of proteinuria, regardless of the degree of renal function impairment, is an important predictor of endothelial dysfunction in early diabetic nephropathy and that it is associated with altered circulating levels of NAMPT/visfatin and adiponectin.

Comorbidity and Acute Clinical Events as Determinants of C-Reactive Protein Variation in Hemodialysis Patients: Implications for Patient Survival

BACKGROUND Patients with chronic kidney disease stage 5 have high comorbidity and are prone to inflammation that may contribute to the high cardiovascular mortality risk. STUDY DESIGN Three-month observational cohort study of prevalent hemodialysis patients. SETTINGS & PARTICIPANTS 228 hemodialysis patients (44% women) were included, median age of 66 years, median time on dialysis therapy of 29 months. PREDICTORS & OUTCOMES In part 1, comorbidity and intercurrent illness were predictors and C-reactive protein (CRP) level was the outcome. In part 2, serial CRP values were predictors and survival was the outcome. MEASUREMENTS High-sensitivity CRP was measured weekly and interleukin 6 (IL-6), tumor necrosis factor alpha, and IL-10 were measured monthly. Data for comorbidity were collected from patient records to calculate Davies comorbidity score, and self-reported clinical events were recorded weekly. RESULTS Median baseline CRP level was 6.7 mg/L (25th to 75th percentiles, 2.5 to 21 mg/L). Baseline CRP level correlated with time-averaged CRP (Spearman rho = 0.76) and individual median of serial CRP values (rho = 0.78; both P < 0.001). Part 1: comorbidity score was significantly associated with greater CRP and IL-6 levels. Age, sex, comorbidity, and 7 of 12 clinical events had significant effects on CRP level variation. Part 2: during a mean follow-up of 29 months, 38% of patients died. Median and mean serial CRP levels were associated with a greater hazard ratio for death (1.013; 95% confidence interval, 1.004 to 1.022) and 1.012 (95% confidence interval, 1.004 to 1.020) than baseline, maximum, and minimum CRP values during the study. Other significant covariates were age, Davies risk group, dialysis vintage, and albumin level. LIMITATIONS The study is based on observational data for prevalent dialysis patients. CONCLUSIONS Comorbidity and clinical events are strongly associated with inflammation in hemodialysis patients. Despite variability over time, inflammation assessed by using CRP level is a strong predictor of mortality. Serial measurements provide additional information compared with a single measurement.

Serum Albumin as Predictor of Nutritional Status in Patients with ESRD

BACKGROUND AND OBJECTIVES Serum albumin is a widely used biomarker of nutritional status in patients with CKD; however, its usefulness is debated. This study investigated serum albumin and its correlation with several markers of nutritional status in incident and prevalent dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a cross sectional study, serum albumin (bromocresol purple), and other biochemical (serum creatinine), clinical (subjective global assessment [SGA]), anthropometric (handgrip strength, skinfold thicknesses), and densitometric (dual energy x-ray absorptiometry) markers of nutritional status were assessed in 458 incident (61% male; mean age 54 +/- 13 years; GFR, 6.6 +/-2.3 ml/min per 1.73 m(2); recruited 1994–2010) and 383 prevalent (56% male; mean age 62 +/- 14 years; recruited 1989–2004) dialysis patients. RESULTS In incident patients: serum albumin was correlated with sex (beta = -0.13; P = 0.02), diabetes mellitus (beta = -0.18; P = 0.004), and urinary albumin excretion (beta = -0.42; P = 0.001) but less so with poor nutritional status (SGA score >1; beta = -0.19; P = 0.001). In prevalent patients, serum albumin was correlated with age (beta = -0.14; P = 0.05), high-sensitivity C-reactive protein (beta = -0.34; P = 0.001), diabetes mellitus (beta = -0.11; P = 0.04), and SGA score >1 (beta = -0.14; P = 0.003). In predicting nutritional status assessed by SGA and other markers, adding serum albumin to models that included age, sex, diabetes, and cardiovascular disease did not significantly increase explanatory power. CONCLUSIONS In incident and prevalent dialysis patients,serum albumin correlates poorly with several markers of nutritional status. Thus, its value as a reliable marker of nutritional status in patients with ESRD is limited. In addition, the following inconsistencies between the main text and Tables 1 and 3 are also corrected as follows. (1) In Table 1, the GFR initially written as 6 +/- 3 ml/min per 1.73(2) should be corrected to 6.6 +/- 2.3 ml/min per 1.73(2). (2) On line 11 of page 1448, under the Clinical Correlates of Serum Albumin Concentration section describing the multiple regression models (Table 3), the P value was initially written as“serum albumin was associated with age (beta = -0.14; P = 0.05).” The P value should be corrected to have the same value as that given in Table 3 (beta = -0.14; P = 0.005. [corrected].

Whole blood cytokine attenuation by cholinergic agonists ex vivo and relationship to vagus nerve activity in rheumatoid arthritis

Abstract.  Bruchfeld A, Goldstein RS, Chavan S, Patel NB, Rosas‐Ballina M, Kohn N, Qureshi AR, Tracey KJ. (Karolinska Institute, Stockholm, Sweden; The Feinstein Institute for Medical Research, North Shore University Hospital‐LIJ Health System, Manhasset, NY, USA; and Karolinska Institute, Stockholm, Sweden) Whole blood cytokine attenuation by cholinergic agonists ex vivo and relationship to vagus nerve activity in rheumatoid arthritis. J Intern Med 2010; 268:94–101.

Soluble CD14 Levels, Interleukin-6, and Mortality Among Prevalent Hemodialysis Patients

BACKGROUND CD14 is a pattern-recognition receptor that has a central immunomodulatory role in proinflammatory signaling in response to a variety of ligands, including endotoxin. CD14 protein is present in 2 forms: soluble (sCD14) and membrane bound. Here, we studied the implications of increased sCD14 levels in hemodialysis patients. We hypothesized that sCD14 level increase may link to cytokine activation and protein-energy wasting, predisposing to increased mortality risk. STUDY DESIGN Prospective observational study of prevalent hemodialysis patients. SETTING & PARTICIPANTS 211 prevalent hemodialysis patients, median age of 65 years, with 29 months of vintage dialysis time followed up for mortality for a median of 31 months. PREDICTORS Tertiles of baseline circulating sCD14 levels corresponding to less than 2.84, 2.85 to 3.62, and greater than 3.63 microg/mL. OUTCOME The major outcome of interest was all-cause mortality. MEASUREMENTS sCD14 and endotoxin, together with other markers of inflammation and protein-energy wasting. RESULTS Median sCD14 level was 3.2 microg/mL (25th to 75th percentile, 2.7 to 3.9). sCD14 level correlated positively with C-reactive protein, interleukin 6, endotoxin, and pentraxin 3 levels and negatively with serum albumin level, muscle mass, and handgrip strength. Patients with increased sCD14 levels had lower body mass index and increased prevalence of muscle atrophy. Patients within the highest sCD14 tertile had a crude morality hazard ratio of 1.94 (95% confidence interval, 1.13 to 3.32) that persisted after adjustment for multiple confounders (hazard ratio, 3.11; 95% confidence interval, 1.49 to 6.46). In patients with persistent inflammation, the presence of a concurrent sCD14 level increase gradually increased mortality risk, but this effect was less than multiplicative and failed to show a statistical interaction. LIMITATIONS Those inherent to an observational study. CONCLUSIONS sCD14 level is associated with inflammation and protein-energy wasting in hemodialysis patients. It is a strong and independent predictor of mortality that warrants further assessment in the clinical setting regarding its usefulness as a complementary prognosticator to other general inflammatory markers.

CCR5 Deletion Protects Against Inflammation-Associated Mortality in Dialysis Patients

The CC-chemokine receptor 5 (CCR5) is a receptor for various proinflammatory chemokines, and a deletion variant of the CCR5 gene (CCR5 Delta 32) leads to deficiency of the receptor. We hypothesized that CCR5 Delta 32 modulates inflammation-driven mortality in patients with ESRD. We studied the interaction between CCR5 genotype and levels of high-sensitivity C-reactive protein (hsCRP) in 603 incident dialysis patients from the multicenter, prospective NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort. CCR5 genotype and hsCRP levels were both available for 413 patients. During 5 yr of follow-up, 170 patients died; 87 from cardiovascular causes. Compared with the reference group of patients who had the wild-type CCR5 genotype and hsCRP <or= 10 mg/L (n = 225), those carrying the deletion allele with hsCRP <or= 10 mg/L (n = 55) had similar mortality, and those carrying the wild-type genotype with hsCRP > 10 mg/L (n = 108) had an increased risk for mortality (HR: 1.82; 95% CI: 1.29 to 2.58). However, those carrying the deletion allele with hsCRP > 10 mg/L (n = 25) had a mortality rate similar to the reference group; this seemingly protective effect of the CCR5 deletion was even more pronounced for cardiovascular mortality. We replicated these findings in an independent Swedish cohort of 302 ESRD patients. In conclusion, the CCR5 Delta 32 polymorphism attenuates the adverse effects of inflammation on overall and cardiovascular mortality in ESRD.