Vaidyanathapuram S. Balakrishnan

Urinary N-Acetyl-β-(D)-Glucosaminidase Activity and Kidney Injury Molecule-1 Level Are Associated with Adverse Outcomes in Acute Renal Failure

The role of urinary biomarkers of kidney injury in the prediction of adverse clinical outcomes in acute renal failure (ARF) has not been well described. The relationship between urinary N-acetyl-beta-(D)-glucosaminidase activity (NAG) and kidney injury molecule-1 (KIM-1) level and adverse clinical outcomes was evaluated prospectively in a cohort of 201 hospitalized patients with ARF. NAG was measured by spectrophotometry, and KIM-1 was measured by a microsphere-based Luminex technology. Mean Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score was 16, 43% had sepsis, 39% required dialysis, and hospital mortality was 24%. Urinary NAG and KIM-1 increased in tandem with APACHE II and Multiple Organ Failure scores. Compared with patients in the lowest quartile of NAG, the second, third, and fourth quartile groups had 3.0-fold (95% confidence interval [CI] 1.3 to 7.2), 3.7-fold (95% CI 1.6 to 8.8), and 9.1-fold (95% CI 3.7 to 22.7) higher odds, respectively, for dialysis requirement or hospital death (P < 0.001). This association persisted after adjustment for APACHE II, Multiple Organ Failure score, or the combined covariates cirrhosis, sepsis, oliguria, and mechanical ventilation. Compared with patients in the lowest quartile of KIM-1, the second, third, and fourth quartile groups had 1.4-fold (95% CI 0.6 to 3.0), 1.4-fold (95% CI 0.6 to 3.0), and 3.2-fold (95% CI 1.4 to 7.4) higher odds, respectively, for dialysis requirement or hospital death (P = 0.034). NAG or KIM-1 in combination with the covariates cirrhosis, sepsis, oliguria, and mechanical ventilation yielded an area under the receiver operator characteristic curve of 0.78 (95% CI 0.71 to 0.84) in predicting the composite outcome. Urinary markers of kidney injury such as NAG and KIM-1 can predict adverse clinical outcomes in patients with ARF.

Adiponectin and Mortality in Patients with Chronic Kidney Disease

Adiponectin is presumed to possess antiatherogenic and cardioprotective properties. Limited data exist on the relationship between adiponectin and mortality in the earlier stages of chronic kidney disease. The Modification of Diet in Renal Disease study was a randomized, controlled trial that was conducted between 1989 and 1993. Adiponectin was measured in frozen samples that were obtained at baseline (N = 820). Survival status and cause of death, up to December 31, 2000, were obtained from the National Death Index. Multivariable Cox models were used to examine the relationship of adiponectin with all-cause and cardiovascular mortality. Mean +/- SD age was 52 +/- 12 yr, and mean +/- SD glomerular filtration rate (GFR) rate was 33 +/- 12 ml/min per 1.73 m2. Eighty-five percent of participants were white, and 60% were male. Mean +/- SD adiponectin was 12.8 +/- 8.0 mug/ml. Triglycerides, insulin resistance, glucose, body mass index, GFR, C-reactive protein, and albumin were inversely related and proteinuria and HDL cholesterol were directly related to adiponectin. During the 10-year follow-up period, 201 (25%) participants died of any cause, and 122 (15%) from cardiovascular disease. In multivariable adjusted Cox models, a 1-mug/ml increase in adiponectin was associated with a 3% (hazard ratio 1.03; 95% confidence interval 1.01 to 1.05; P = 0.02) increased risk for all-cause and 6% (hazard ratio 1.06; 95% confidence interval 1.03 to 1.09; P < 0.001) increased risk for cardiovascular mortality. High, rather than low, adiponectin is associated with increased mortality in this cohort of patients with chronic kidney disease stages 3 to 4. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms.

NADPH Oxidase p22phox and Catalase Gene Variants Are Associated with Biomarkers of Oxidative Stress and Adverse Outcomes in Acute Renal Failure

Reactive oxygen species are important mediators of injury in acute renal failure (ARF). Although polymorphisms that affect key pro- and antioxidant enzymes might alter the susceptibility to oxidative stress-mediated injury, the use of genetic epidemiology for the study of oxidative stress-related genes has received little attention in ARF. The relationship of single-nucleotide polymorphisms in the coding region (C to T substitution at position +242) of the pro-oxidant enzyme NADPH oxidase p22phox subunit gene and in the promoter region (C to T substitution at position -262) of the antioxidant enzyme catalase gene to adverse clinical outcomes was evaluated prospectively in a cohort of 200 hospitalized patients with established ARF of mixed cause and severity. Genomic DNA was extracted from peripheral blood leukocytes and analyzed with a restriction fragment length polymorphism PCR method. Genotype-phenotype associations were characterized by measuring circulating nitrotyrosine and catalase activity. Observed and expected genotype frequencies were not significantly different, and overall baseline characteristics were not significantly different according to the various genotype groups. A genotype-phenotype association was demonstrable between the NADPH oxidase p22phox genotypes and plasma nitrotyrosine level (P = 0.06), as well as between the catalase genotypes and whole-blood catalase activity (P < 0.001). Compared with the NADPH oxidase p22phox CC genotype group, the T-allele group had a higher cumulative probability of remaining hospitalized (P = 0.03). Compared with the NADPH oxidase p22phox CC genotype, the T-allele carrier state was associated with 2.1-fold higher odds for dialysis requirement or hospital death (P = 0.01). This association persisted with 2.0- to 2.2-fold higher odds for this composite outcome after adjustment for race; gender; age; and the Acute Physiology and Chronic Health Evaluation II score (P = 0.03), the Multiple Organ Failure score (P = 0.01), or presence of sepsis (P = 0.02). The polymorphism in the gene that encodes the NADPH oxidase p22phox subunit at position +242 is associated with dialysis requirement or hospital death among patients with ARF. Larger studies are needed to confirm these relationships.

Iron Storage Indices: Novel Predictors of Bacteremia in Hemodialysis Patients Initiating Intravenous Iron Therapy

Bacterial sepsis is the second leading cause of death among hemodialysis (HD) patients. Iron overload and intravenous iron therapy are linked to bacterial infection. This study examined iron stores, intravenous iron dosing, and bacteremic risk in HD patients. Retrospectively, 132 HD patients receiving their first course of intravenous iron were studied. Baseline laboratory values, including transferrin saturation (TSAT) value and ferritin level, were measured before initiating intravenous iron therapy. Patients were followed for up to 1 year after the initiation of iron therapy for the outcome of bacteremia by Cox proportional hazards regression analysis. Iron-replete patients (those with a TSAT value > or =20% and a ferritin level > or =100 ng/mL) had a significantly higher risk of bacteremia (hazard ratio [HR], 2.5). Venous catheter users (HR, 4.9) and those with diabetes mellitus (HR, 2.2) were also at increased risk. Modest iron storage levels may increase the risk of bacteremia among HD patients initiating intravenous iron therapy. Additional studies are needed to confirm these relationships.

Physicochemical properties of ferumoxytol, a new intravenous iron preparation

Background  Intravenous iron is a critical component of anaemia management. However, currently available preparations have been associated with the release of free iron, a promoter of bacterial growth and oxidative stress.

The kidney disease wasting: inflammation, oxidative stress, and diet-gene interaction.

The 350,000 maintenance hemodialysis (MHD) patients in the United States have an unacceptably high mortality rate of >20%/year. Almost half of all deaths are assumed to be cardiovascular. Markers of kidney disease wasting (KDW) such as hypoalbuminemia, anorexia, body weight and fat loss, rather than traditional cardiovascular risk factors, appear to be the strongest predictors of early death in these patients. The KDW is closely related to oxidative stress (SOX). Such SOX markers as serum myeloperoxidase are associated with pro‐inflammatory cytokines and poor survival in MHD patients. Identifying the conditions that modulate the KDW/SOX‐axis may be the key to improving outcomes in MHD patients. Dysfunctional lipoproteins such as a higher ratio of the high‐density lipoprotein inflammatory index (HII) may engender or aggravate the KDW, whereas functionally intact or larger lipoprotein pools, as in hypercholesterolemia and obesity, may mitigate the KDW in MHD patients. Hence, a reverse epidemiology or “bad‐gone‐good” phenomenon may be observed. Diet and gene and their complex interaction may lead to higher proportions of pro‐inflammatory or oxidative lipoproteins such as HII, resulting in the aggravation of the SOX and inflammatory processes, endothelial dysfunction, and subsequent atherosclerotic cardiovascular disease and death in MHD patients. Understanding the factors that modulate the KDW/SOX complex and their associations with genetic polymorphism, nutrition, and outcomes in MHD patients may lead to developing more effective strategies to improve outcomes in this and the 20 to 30 million Americans with chronic disease states such as individuals with chronic heart failure, advanced age, malignancies, AIDS, or cachexia.

C5a delays apoptosis of human neutrophils via an extracellular signal-regulated kinase and Bad-mediated signalling pathway.

Aims  We recently demonstrated that complement fragment C5a delays apoptosis of human neutrophils via induction of the phosphatidylinositol‐3 kinase (PI 3‐K) pathway. In the present study, we examined whether C5a modulates neutrophil survival through the extracellular signal‐regulated kinase (ERK) and Bad‐mediated signalling pathway.

MANAGING ERYTHROPOIETIN HYPORESPONSIVENESS

The anemia of chronic kidney disease is associated with cardiovascular disease, decreased quality of life, and mortality. The introduction of recombinant human erythropoietin (rHuEPO) has transformed the management of this condition. However, a significant proportion of patients fail to respond to even high doses of rHuEPO. Several factors have been implicated in the hyporesponsiveness to rHuEPO. Iron deficiency, whether absolute or functional, is considered the most important, and maintenance of adequate iron stores reduces rHuEPO requirements among patients on hemodialysis. However, traditional indices of iron that are currently utilized may not reflect iron stores accurately, and there is also increasing concern regarding the potential long‐term toxicity of parenteral iron therapy. Infection and inflammation also influence the response to rHuEPO, both by disruption of iron metabolism and by eliciting the release of cytokines that inhibit erythropoiesis. Oxidative stress may contribute to rHuEPO hyporesponsiveness directly by promoting lipid peroxidation in cell membranes, leading to increased erythrocyte fragility and reduced life span and also through its strong association with inflammation. Severe hyperparathyroidism can lead to a reduced number of erythroid progenitor cells. Inadequate dialysis dose, aluminum overload, nutritional factors such as deficiencies of carnitine, vitamin B12, folic acid, and vitamin C can also reduce the efficacy of rHuEPO therapy. Hyporesponsiveness to rHuEPO presents a challenge to both diagnosis and management in an era where optimizing response to rHuEPO is critical both in limiting the burgeoning costs of anemia management and improving clinical outcomes in the dialysis population.

Inflammation and Progression of CKD: The CRIC Study

BACKGROUND AND OBJECTIVES CKD is a global public health problem with significant mortality and morbidity. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants. RESULTS Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of ≥50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-α and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P<0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P<0.01), and TNF-α (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P<0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P<0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P<0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P<0.001), and TNF-α (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P<0.001) with outcome were attenuated but remained significant. CONCLUSIONS Elevated plasma levels of fibrinogen and TNF-α and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD.

Mitochondrial DNA Injury and Mortality in Hemodialysis Patients

The role of mitochondrial injury in the pathogenesis of complications of uremia is incompletely defined, although diminished bioenergetic capacity and the accumulation of mitochondrial DNA (mtDNA) mutations have been reported. This study was undertaken to evaluate the prevalence of mtDNA injury in 180 patients who had ESRD and were enrolled into the baseline phase of the HEMO study and to relate these markers to all-cause mortality. The mitochondrial injury markers studied in peripheral blood mononuclear cells were the mtDNA copy number per cell, measured by quantitative PCR, and the presence of the mtDNA(4977) mutation. After frequency-matching healthy control subjects for age, mtDNA copy number was lower among older dialysis patients compared with older healthy subjects (P = 0.01). A one-log increase in mtDNA copy number was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.64; 95% confidence interval 0.46 to 0.89). The mtDNA(4977) deletion was present in 48 (31%) patients and was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.33; 95% confidence interval 0.19 to 0.56). In summary, the mtDNA(4977) seems to predict survival in ESRD, but a reduced mitochondrial copy number seems to predict a poor outcome. Although further exploration of these associations is needed, evaluation of mitochondrial DNA copy number and somatic mtDNA mutations may provide simple genomic biomarkers to predict clinical outcomes among patients with ESRD.