Jane Y. Yeun

C-reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients

Hypoalbuminemia predicts death in dialysis patients. Although hypoalbuminemia has been attributed to malnutrition, evidence of inflammation (C-reactive protein [CRP] and cytokine levels) has recently been recognized to predict albumin concentration in dialysis patients. We measured CRP and albumin levels in October 1995 in 91 hemodialysis (HD) patients. During a 34-month follow-up period, we determined the incidence and cause of death. Patients were divided into four groups based on serum albumin levels (<3.5 [lowest quartile], 3.5 to 3.8, 3.9 to 4.0, and >4.0 g/dL [highest quartile]). Survival differed among the four groups (P = 0.0063). Patients with albumin levels greater than 4.0 g/dL had the greatest survival. Kaplan-Meier survival estimates of patients from varying CRP quartiles (<2.6, 2.6 to 5.2, 5.3 to 11.5, and >11.5 microg/mL) differed among the four groups (P < 0.0001). The group with the greatest CRP level (>11.5 microg/mL) had the lowest survival. Multivariate analysis using the Cox proportional hazards model showed that only CRP level (chi-square = 21.11; P < 0.0001) and age (chi-square = 5.44; P = 0.020) predicted death. Albumin level (chi-square = 0.16; P = 0.69) was not predictive. Only when CRP was excluded from the model did low serum albumin level (chi-square = 12. 04; P = 0.0004) predict death. CRP level (chi-square = 16.79; P < 0. 0001) and age (chi-square = 6.38; P = 0.012) also superceded albumin level (chi-square = 0.45; P = 0.51) in predicting cardiovascular mortality. Although values for blood urea nitrogen, creatinine, and normalized protein catabolic rate were significantly less among patients who died, these parameters, as well as cholesterol level and diabetes, were not important predictors of death in multivariate analysis. The acute-phase response or the cause of the acute-phase response is largely responsible for the effect of hypoalbuminemia on mortality in HD patients.

Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients★

We defined erythropoietin (EPO) resistance by the ratio of the weekly EPO dose to hematocrit (Hct), yielding a continuously distributed variable (EPO/Hct). EPO resistance is usually attributed to iron or vitamin deficiency, hyperparathyroidism, aluminum toxicity, or inflammation. Activation of the acute-phase response, assessed by the level of the acute-phase C-reactive protein (CRP), correlates strongly with hypoalbuminemia and mortality in both hemodialysis (HD) and peritoneal dialysis (PD) patients. In this cross-sectional study of 92 HD and 36 PD patients, we examined the contribution of parathyroid hormone (PTH) levels, iron indices, aluminum levels, nutritional parameters (normalized protein catabolic rate [PCRn]), dialysis adequacy (Kt/V), and CRP to EPO/Hct. Albumin level serves as a measure of both nutrition and inflammation and was used as another independent variable. Serum albumin level (deltaR2 = 0.129; P < 0.001) and age (deltaR2 = 0.040; P = 0.040) were the best predictors of EPO/Hct in HD patients, and serum albumin (deltaR2 = 0.205; P = 0.002) and ferritin levels (deltaR2 = 0.132; P = 0.015) in PD patients. When albumin was excluded from the analysis, the best predictors of EPO/Hct were CRP (deltaR2 = 0.105; P = 0.003) and ferritin levels (deltaR2 = 0.051; P = 0.023) in HD patients and CRP level (deltaR2 = 0.141; P = 0.024) in PD patients. When both albumin and CRP were excluded from analysis in HD patients, low transferrin levels predicted high EPO/Hct (deltaR2 = 0.070; P = 0.011). EPO/Hct was independent of PTH and aluminum levels, PCRn, and Kt/V. High EPO/Hct occurred in the context of high ferritin and low transferrin levels, the pattern expected in the acute-phase response, not in iron deficiency. In well-dialyzed patients who were iron replete, the acute-phase response was the most important predictor of EPO resistance.

Acute phase proteins and peritoneal dialysate albumin loss are the main determinants of serum albumin in peritoneal dialysis patients

Hypoalbuminemia predicts mortality in dialysis patients. It has been postulated that hypoalbuminemia in the dialysis population is a consequence of poor protein intake resulting from inadequate dialysis. To establish the cause of hypoalbuminemia in a group of 27 patients on peritoneal dialysis (PD), we determined the relationship between serum albumin concentration and a group of parameters including dialysis dose delivered (Kt/V), normalized protein catabolic rate (PCRn), transperitoneal and urinary albumin losses, and the serum concentration of two acute-phase proteins, C-reactive protein (CRP), and serum amyloid A (SAA). Serum albumin concentration could be predicted by a combination of transperitoneal albumin loss and either the serum concentration of CRP or of SAA. There was no relationship between weekly Kt/V or PCRn and serum albumin concentration. CRP and SAA significantly correlated with one another, but neither correlated with transperitoneal albumin losses. Hypoalbuminemia in PD patients is a consequence of transperitoneal albumin losses and of the acute phase response.

Factors influencing serum albumin in dialysis patients

Hypoalbuminemia is a major risk factor for morbidity and mortality in dialysis patients. The proximate cause of hypoalbuminemia is probably responsible for these events, and not the hypoalbuminemia itself. Because protein-calorie malnutrition decreases albumin synthesis, hypoalbuminemia has been attributed to poor nutritional intake resulting from underdialysis. However, serum albumin (Salb) level is determined by several other factors: plasma volume expansion, albumin redistribution, exogenous loss, increased fractional catabolic rate (FCR), and decreased synthesis. Decreased albumin synthesis is primarily responsible for hypoalbuminemia in hemodialysis (HD) patients. Studies of a smaller number of peritoneal dialysis (PD) patients suggest exogenous albumin loss and volume expansion as contributing mechanisms. However, both malnutrition and inflammation suppress albumin synthesis. As the adequacy of dialysis has improved, recent studies are unable to show any relation between dialysis adequacy and Salb level. Further, Salb level appears to be a poor marker of nutritional status in dialysis patients when compared with other measures of nutrition, such as subjective global assessment score, anthropometry, and dietary intake. Instead, cytokines and positive acute-phase reactants, produced in response to inflammation, have been identified as important contributors to hypoalbuminemia in dialysis patients. These markers correlate with hypoalbuminemia and supercede Salb level in predicting mortality. Multivariate analysis identifies markers of inflammation and nutritional status as independent predictors of hypoalbuminemia in HD patients and markers of inflammation and peritoneal albumin loss as independent predictors in PD patients. However, the acute-phase response and malnutrition are closely interrelated, because inflammatory mediators also suppress appetite, increase muscle catabolism, and result in progressive cachexia. Future studies should focus on elucidating the inflammatory stimuli and the complex interaction between the acute-phase response and nutritional status.

C-reactive protein, oxidative stress, homocysteine, and troponin as inflammatory and metabolic predictors of atherosclerosis in ESRD.

Mortality in patients with end-stage renal disease remains high, with cardiovascular disease accounting for half of these deaths. Novel risk factors such as inflammation, oxidative stress, hyperhomocysteinemia, and high troponin levels are associated with cardiovascular risk in the general population. While there are substantial epidemiologic data confirming that these novel risk factors are associated with cardiovascular risk in end-stage renal disease patients, a causal relationship has not been established. Inflammation is readily identified by the presence of high levels of C-reactive protein, while studies of oxidative stress are hampered by the lack of a standardized test. The cause of both is unknown. Hyperhomocysteinemia results from decreased remethylation to methionine, although vitamin supplementation only partially corrects the defect, suggesting that uremic inhibition of the enzymatic process may be important. The most promising strategies for correcting oxidative stress and hyperhomocysteinemia are vitamin E and folinic acid therapy, respectively. Troponin I appears to be a more specific marker of myocardial injury than Troponin T, but troponin T retains its ability to predict cardiovascular mortality as well as all-cause mortality. Sorting out the role of each of these risk factors may be difficult since the factors may influence each other, may increase oxidative stress, and may mediate atherosclerosis through oxidative modification of lipids.

Severity of Chronic Kidney Disease as a Risk Factor for Operative Mortality in Nonemergent Patients in the California Coronary Artery Bypass Graft Surgery Outcomes Reporting Program

Guidelines published by the National Kidney Foundation in 2002 categorize renal failure into 5 stages of increasing severity. The relation of this classification to risk stratification for operative mortality in patients with nonemergent coronary artery bypass grafting (CABG) has not been clarified. We examined the effect of chronic kidney disease (CKD) severity on CABG operative mortality in patients with nonemergent CABG. Data reporting to the California CABG outcomes reporting program is mandated in California. Data from 121 hospitals on patients undergoing CABG in 2003 and 2004 were analyzed, including clinical characteristics, CKD stage, and operative mortality. CKD stage 1 and 2 were combined to form the reference group because data on urinary markers of renal failure were not available. Excluding patients with emergent or salvage acuity for CABG, 37,735 isolated CABGs were performed. Of these, 27,132 patients (71.9%) had glomerular filtration rate (GFR)>or=60 ml/min/1.73 m2; 8,861 (23.5%) had stage 3 CKD (GFR 30 to 59); 669 (1.8%) had stage 4 CKD (GFR 15 to 29); and 1,073 (2.8%) had stage 5 CKD (GFR<15 or on dialysis). In separate multivariate analyses, GFR and CKD stage were each significantly and independently associated with operative mortality (both p<0.0001). Operative mortality increased significantly with each stage of CKD (all p<0.01). Compared with the reference group, stage 3, (odds ratio [OR] 1.18, p=0.0374), stage 4 (OR 2.23, p<0.0001), and stage 5 (OR 4.39, p<0.0001) had increasingly higher operative mortality. In conclusion, CKD stage based on National Kidney Foundation guidelines is an important predictor in risk stratification for operative mortality in patients undergoing nonemergent CABG.

The Role of Homocysteine in End‐Stage Renal Disease

Homocysteine (Hcy) has been demonstrated in several large prospective clinical studies to be an independent risk factor for cardiovascular disease in the general population (1-5). Since cardiovascular disease is a major cause of morbidity and mortality in the end-stage renal disease (ESRD) population (6), Hcy has come under increased scrutiny in this patient population. This review will address Hcy metabolism and available data for Hcy as a cardiovascular risk in the general population as well as in ESRD patients. The role of factors that modify Hcy levels, potential treatment strategies for hyperhomocysteinemia, and research efforts in elucidating the pathogenesis will also be discussed.

Development, Implementation, and Results of the ASN In-Training Examination for Fellows

The American Society of Nephrology and the fellowship training program directors in conjunction with the National Board of Medical Examiners developed a comprehensive assessment of medical knowledge for nephrology fellows in-training. This in-training examination (ITE) consisted of 150 multiple-choice items covering 11 broad content areas in a blueprint similar to the American Board of Internal Medicine certifying examination for nephrology. Questions consisted of case vignettes to simulate real-life clinical experience. The first examination was given in April 2009 to 682 fellows and six training program directors. Examinees felt that the examination was well structured and relevant to their training experience Longitudinal performance on the examination will be helpful in allowing training programs to utilize results from content areas in identifying deficits in medical knowledge as well as assessing the results of any curriculum changes.

Urea Kinetics, Efficiency, and Adequacy of Hemodialysis and Other Intermittent Treatments

Abstract In the setting of renal failure, hemodialysis is an extremely effective therapy that has an impressive potential for preserving life despite total loss of a vital organ. It is clear that the average intensive care unit patient treated with intermittent hemodialysis three times weekly receives less hemodialysis than the average outpatient, despite the need for more dialysis to manage the high rates of catabolism often found in critically ill patients. This chapter focuses on hemodialysis: more specifically, on the dose of dialysis and its adequacy in critically ill patients requiring intensive care. It reviews various methods to measure and improve the adequacy of renal replacement therapy in the intensive care unit. The primary responsibility of clinicians managing the patient with acute kidney injury is to ensure adequate removal of toxic small solutes. Each patient is different, so the clinician must tailor renal replacement therapy to the individual patients needs, making adjustments in the timing, frequency, duration, flow rates, and other parameters to fit. Increasing the frequency of intermittent renal replacement therapy theoretically raises its ceiling of effectiveness, and extending treatment time may add further benefit. It is possible that differences in the dialysis modality (intermittent hemodialysis vs. continuous renal replacement therapy) as well as variations in the timing of initiation and/or dosing may affect renal recovery and survival, but all major trials fail to show that. The good news is that in acute kidney injury recovery is possible and that near-normal kidney function after recovery is a strong possibility.