George A. Kaysen

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 0. 0001) and age (chi-square = 6.38; P = 0.012) also superceded albumin level (chi-square = 0.45; P = 0.51) in predicting cardiovascular mortality.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.

Serum albumin: relationship to inflammation and nutrition.

Hypoalbuminemia is the result of the combined effects of inflammation and inadequate protein and caloric intake in patients with chronic disease such as chronic renal failure. Inflammation and malnutrition both reduce albumin concentration by decreasing its rate of synthesis, while inflammation alone is associated with a greater fractional catabolic rate (FCR) and, when extreme, increased transfer of albumin out of the vascular compartment. A vicious cascade of events ensues in which inflammation induces anorexia and reduces the effective use of dietary protein and energy intake and augments catabolism of the key somatic protein, albumin. Hypoalbuminemia is a powerful predictor of mortality in patients with chronic renal failure, and the major cause of death in this population is due to cardiovascular events. Inflammation is associated with vascular disease and likely causes injury to the vascular endothelium, and hypoalbuminemia as two separate expressions of the inflammatory process. Albumin has a myriad of important physiologic effects that are essential for normal health. However, simply administering albumin to critically ill patients with hypoalbuminemia has not been shown to improve survival or reduce morbidity. Thus the inference from these clinical studies suggests that the cause of hypoalbuminemia, rather than low albumin levels specifically, is responsible for morbidity and mortality.

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.

Determinants of albumin concentration in hemodialysis patients

Hypoalbuminemia predicts mortality in hemodialysis patients with end-stage renal disease and is assumed to result from malnutrition. To investigate a possible alternative cause, we evaluated the relationships between serum albumin (Salb) and serum levels of two positive acute-phase proteins: C-reactive protein (CRP) and serum amyloid A (SAA). We also examined the relationship between Salb and dialysis dose delivered (Kt/V) and normalized protein catabolic rate (PCRn) measured during 3 consecutive months in a group of 115 patients. Serum albumin was measured monthly for 5 months. SAA levels were not increased in the majority of patients, despite its low molecular weight (8 kd), and predialysis concentrations were independent of residual renal function, compatible with a nonrenal site of metabolism. Both CRP and SAA levels correlated negatively with Salb both by linear regression and by multiple regression analysis (P < 0.001). CRP correlated with fibrinogen (P < 0.005). Salb also correlated positively with PCRn (P = 0.001), but not with Kt/V. The Kt/V did not correlate with PCRn. While CRP and SAA correlated with one another, neither variable correlated with PCRn. When either SAA or CRP was high, Salb was low regardless of PCRn. Thus, there are two separate independent factors predicting Salb--markers of inflammation and protein intake--but high concentrations of acute-phase proteins have a greater impact on Salb than does low PCRn. Activity of the acute-phase response is an important predictor of low Salb in hemodialysis patients independently of nutritional factors.

Etiology of the Protein-Energy Wasting Syndrome in Chronic Kidney Disease: A Consensus Statement From the International Society of Renal Nutrition and Metabolism (ISRNM)

Protein-energy wasting (PEW), a term proposed by the International Society of Renal Nutrition and Metabolism (ISRNM), refers to the multiple nutritional and catabolic alterations that occur in chronic kidney disease (CKD) and associate with morbidity and mortality. To increase awareness, identify research needs, and provide the basis for future work to understand therapies and consequences of PEW, ISRNM provides this consensus statement of current knowledge on the etiology of PEW syndrome in CKD. Although insufficient food intake (true undernutrition) due to poor appetite and dietary restrictions contribute, other highly prevalent factors are required for the full syndrome to develop. These include uremia-induced alterations such as increased energy expenditure, persistent inflammation, acidosis, and multiple endocrine disorders that render a state of hypermetabolism leading to excess catabolism of muscle and fat. In addition, comorbid conditions associated with CKD, poor physical activity, frailty, and the dialysis procedure per se further contribute to PEW.

POOR NUTRITIONAL STATUS AND INFLAMMATION: Serum Albumin: Relationship to Inflammation and Nutrition

Hypoalbuminemia is the result of the combined effects of inflammation and inadequate protein and caloric intake in patients with chronic disease such as chronic renal failure. Inflammation and malnutrition both reduce albumin concentration by decreasing its rate of synthesis, while inflammation alone is associated with a greater fractional catabolic rate (FCR) and, when extreme, increased transfer of albumin out of the vascular compartment. A vicious cascade of events ensues in which inflammation induces anorexia and reduces the effective use of dietary protein and energy intake and augments catabolism of the key somatic protein, albumin. Hypoalbuminemia is a powerful predictor of mortality in patients with chronic renal failure, and the major cause of death in this population is due to cardiovascular events. Inflammation is associated with vascular disease and likely causes injury to the vascular endothelium, and hypoalbuminemia as two separate expressions of the inflammatory process. Albumin has a myriad of important physiologic effects that are essential for normal health. However, simply administering albumin to critically ill patients with hypoalbuminemia has not been shown to improve survival or reduce morbidity. Thus the inference from these clinical studies suggests that the cause of hypoalbuminemia, rather than low albumin levels specifically, is responsible for morbidity and mortality.

Impact of Dialysis Dose and Membrane on Infection-Related Hospitalization and Death: Results of the HEMO Study

Infection is the second most common cause of death among hemodialysis patients. A predefined secondary aim of the HEMO study was to determine if dialysis dose or flux reduced infection-related deaths or hospitalizations. The effects of dialysis dose, dialysis membrane, and other clinical parameters on infection-related deaths and first infection-related hospitalizations were analyzed using Cox regression analysis. Among the 1846 randomized patients (mean age, 58 yr; 56% female; 63% black; 45% with diabetes), there were 871 deaths, of which 201 (23%) were due to infection. There were 1698 infection-related hospitalizations, yielding a 35% annual rate. The likelihood of infection-related death did not differ between patients randomized to a high or standard dose (relative risk [RR], 0.99 [0.75 to 1.31]) or between patients randomized to high-flux or low-flux membranes (RR, 0.85 [0.64 to 1.13]). The relative risk of infection-related death was associated (P < 0.001 for each variable) with age (RR, 1.47 [1.29 to 1.68] per 10 yr); co-morbidity score (RR, 1.46 [1.21 to 1.76]), and serum albumin (RR, 0.19 [0.09 to 0.41] per g/dl). The first infection-related hospitalization was related to the vascular access in 21% of the cases, and non-access-related in 79%. Catheters were present in 32% of all study patients admitted with access-related infection, even though catheters represented only 7.6% of vascular accesses in the study. In conclusion, infection accounted for almost one fourth of deaths. Infection-related deaths were not reduced by higher dose or by high flux dialyzers. In this prospective study, most infection-related hospitalizations were not attributed to vascular access. However, the frequency of access-related, infection-related hospitalizations was disproportionately higher among patients with catheters compared with grafts or fistulas.

Long-term renal function in kidney donors. Sustained compensatory hyperfiltration with no adverse effects.

Twenty patients who underwent uninephrectomy for kidney donation between 1964 and 1968 participated in a long-term study of the function of the solitary kidney. Mean follow up after uninephrectomy was 15.8 +/- .3 years. One patient with a strong family history of essential hypertension developed de novo mild hypertension. The current creatinine clearance of the donors was 80 +/- 4 ml/min. The 1-week, 3-6 months and 14-18 years postuninephrectomy percentages of predonation creatinine clearance were 72 +/- 3%, 76 +/- 3% and 78 +/- 2%, respectively. The 24-hr urine protein excretion in kidney donors was significantly higher than in controls (141 +/- 20 mg vs. 74 +/- 3 mg, respectively, P less than .0005). Except for one donor who may have developed glomerulonephritis, the donors had normal urinary albumin excretion. The cause of the slightly elevated nonalbumin proteinuria is not known. However, this long-term study of kidney donors shows no adverse effects on the blood pressure and renal function after many years of compensatory hyperfiltration.

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.