Lara B. Pupim

Intradialytic parenteral nutrition improves protein and energy homeostasis in chronic hemodialysis patients

Decreased dietary protein intake and hemodialysis-associated protein catabolism are among several factors that predispose chronic hemodialysis (CHD) patients to protein calorie malnutrition. Since attempts to increase protein intake by dietary counseling are usually ineffective, intradialytic parenteral nutrition (IDPN) has been proposed as a potential therapeutic approach in malnourished CHD patients. In this study, we examined protein and energy homeostasis during hemodialysis in seven CHD patients at two separate hemodialysis sessions, with and without IDPN administration. Patients were studied 2 hours before, during, and 2 hours following a hemodialysis session, using a primed constant infusion of L-(1-(13)C) leucine and L-(ring-(2)H(5)) phenylalanine. Our results showed that IPDN promoted a large increase in whole-body protein synthesis and a significant decrease in whole-body proteolysis, along with a significant increase in forearm muscle protein synthesis. The net result was a change from an essentially catabolic state to a highly positive protein balance, both in whole-body and forearm muscle compartments. We conclude that the provision of calories and amino acids during hemodialysis with IDPN acutely reverses the net negative whole-body and forearm muscle protein balances, demonstrating a need for long-term clinical trials evaluating IDPN in malnourished CHD patients.

Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): Rationale and Design Overview

BACKGROUND AND OBJECTIVES The dramatically high rates of mortality and cardiovascular morbidity observed among dialysis patients highlights the importance of identifying and implementing strategies to lower cardiovascular risk in this population. Results from clinical trials undertaken thus far, including trials on lipid reduction, normalization of hematocrit, and increased dialysis dosage, have been unsuccessful. Available data indicate that abnormalities in calcium and phosphorus metabolism, as a result of either secondary hyperparathyroidism alone or the therapeutic measures used to manage secondary hyperparathyroidism, are associated with an increased risk for death and cardiovascular events. However, no prospective trials have evaluated whether interventions that modify these laboratory parameters result in a reduction in adverse cardiovascular outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events is a global, phase 3, double-blind, randomized, placebo-controlled trial evaluating the effects of cinacalcet on mortality and cardiovascular events in hemodialysis patients with secondary hyperparathyroidism. Approximately 3800 patients from 22 countries will be randomly assigned to cinacalcet or placebo. Flexible use of traditional therapies will be permitted. The primary end point is the composite of time to all-cause mortality or first nonfatal cardiovascular event (myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular disease, including lower extremity revascularization and nontraumatic amputation). RESULTS The study will be event driven (terminated at 1882 events) with an anticipated duration of approximately 4 yr. CONCLUSIONS Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events will determine whether management of secondary hyperparathyroidism with cinacalcet reduces the risk for mortality and cardiovascular events in hemodialysis patients.

Oxidative Stress Is Increased in Critically Ill Patients with Acute Renal Failure

Patients with acute renal failure (ARF) experience a high mortality rate. Dysregulated inflammation and altered metabolism may increase oxidative stress in ARF patients. Thirty-eight patients who met the Program to Improve Care in Acute Renal Disease (PICARD) Study inclusion criteria underwent plasma protein oxidation and plasma cytokine measurements. For comparison, similar measurements were also performed in 21 critically ill patients without ARF, 28 patients with ESRD, and 49 healthy subjects. Plasma protein thiol oxidation was measured by spectrophotometry. Plasma protein carbonyl content and cytokine concentrations were measured by ELISA. Plasma protein thiol oxidation and carbonyl content were markedly different in ARF patients compared with healthy subjects, ESRD patients, and critically ill patients (P < 0.001 in all cases). There were significant but less marked differences in plasma protein oxidation between ESRD patients and critically ill patients compared with healthy subjects. Plasma protein thiol oxidation in ARF patients improved with dialysis (P < 0.001); however, there was significant plasma oxidant reaccumulation during the interdialytic period (P < 0.001) not due to rebound equilibration of compartmentalized solutes. Plasma proinflammatory cytokine levels were significantly higher (P < 0.05) in ARF patients and critically ill patients than in healthy subjects. Plasma protein oxidation is markedly increased in ARF patients compared with healthy subjects, ESRD patients, and critically ill patients. Increased oxidative stress may be an important target for nutritional and pharmacologic therapy in ARF patients.

Linkage of hypoalbuminemia, inflammation, and oxidative stress in patients receiving maintenance hemodialysis therapy

BACKGROUND Hypoalbuminemia is a powerful predictor of cardiovascular mortality in maintenance hemodialysis patients. Increased biomarkers of acute-phase inflammation and oxidative stress are highly prevalent and also correlate with cardiovascular morbidity and mortality. The extent to which hypoalbuminemia, biomarkers of inflammation, and biomarkers of oxidative stress are linked in this patient population is unknown. We hypothesized that a high proportion of hypoalbuminemic hemodialysis patients also would manifest increased levels of biomarkers of inflammation and oxidative stress. METHODS We surveyed 600 maintenance hemodialysis patients and identified 18 severely hypoalbuminemic patients (serum albumin level < 3.2 g/dL [32 g/L]) without recent infection or hospitalization. We then identified 18 age-, race-, sex-, and diabetes-matched normoalbuminemic hemodialysis patients, as well as 18 age-, race-, sex-, and diabetes-matched healthy subjects, for cohort comparison. Measurements of plasma interleukin-6 (IL-6) levels, plasma protein reduced thiol content, plasma protein carbonyl content, and plasma free F2-isoprostane levels, as well as serum concentrations of C-reactive protein (CRP) and prealbumin, were performed for study purposes. RESULTS Levels of serum CRP, IL-6, plasma protein thiol oxidation, and protein carbonyl formation were significantly elevated in both hypoalbuminemic and normoalbuminemic hemodialysis patients compared with healthy subjects and also were significantly different in hypoalbuminemic maintenance dialysis patients compared with normoalbuminemic hemodialysis patients. Prealbumin levels were significantly lower in hypoalbuminemic hemodialysis patients than in other groups. CONCLUSION There is a high prevalence of inflammation and oxidative stress in the maintenance hemodialysis population. Levels of inflammatory and oxidative stress biomarkers are increased further in hypoalbuminemic compared with normoalbuminemic dialysis patients. Hypoalbuminemia, acute-phase inflammation, and oxidative stress may act synergistically to increase cardiovascular morbidity and mortality risk in maintenance hemodialysis patients.

Intradialytic Oral Nutrition Improves Protein Homeostasis in Chronic Hemodialysis Patients with Deranged Nutritional Status

Decreased dietary protein intake and hemodialysis (HD)-associated protein catabolism predispose chronic HD (CHD) patients to deranged nutritional status, which is associated with poor clinical outcome in this population. Intradialytic parenteral nutrition (IDPN) reverses the net negative whole-body and skeletal muscle protein balance during HD. IDPN is costly and restricted by Medicare and other payers. Oral supplementation (PO) is a more promising, physiologic, and affordable intervention in CHD patients. Protein turnover studies were performed by primed-constant infusion of L-(1-(13)C) leucine and L-(ring-(2)H(5)) phenylalanine in eight CHD patients with deranged nutritional status before, during, and after HD on three separate occasions: (1) with IDPN infusion, (2) with PO administration, and (3) with no intervention (control). Results showed highly positive whole-body net balance during HD for both IDPN and PO (4.43 +/- 0.7 and 5.71 +/- 1.2 mg/kg fat-free mass per min, respectively), compared with a neutral balance with control (0.25 +/- 0.5 mg/kg fat-free mass per min; P = 0.002 and <0.001 for IDPN versus control and PO versus control, respectively). Skeletal muscle protein homeostasis during HD also improved with both IDPN and PO (50 +/- 19 and 42 +/- 17 microg/100 ml per min) versus control (-27 +/- 13 microg/100 ml per min; P = 0.005 and 0.009 for IDPN versus control and PO versus control, respectively). PO resulted in persistent anabolic benefits in the post-HD phase for muscle protein metabolism, when anabolic benefits of IDPN dissipated (-53 +/- 25 microg/100 ml per min for control, 47 +/- 41 microg/100 ml per min for PO [P = 0.039 versus control], and -53 +/- 24 microg/100 ml per min for IDPN [P = 1.000 versus control and 0.039 versus PO]). Long-term studies using intradialytic oral supplementation are needed for CHD patients with deranged nutritional status.

Angiotensin-Converting Enzyme Inhibitors as a Risk Factor for Contrast-Induced Nephropathy

Background/Aims: The aim of the present study was to assess the influence of chronic angiotensin-converting enzyme (ACE) inhibitor administration on the development of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography. Methods: A total of 230 patients with renal insufficiency and age ≧65 years were divided into two groups according to prior use of ACE inhibitors (ACE inhibitor group, n = 109; control group, n = 121). CIN was defined as an increase of ≧25% in creatinine over the baseline value within 48 h of angiography. Results: CIN occurred in 17 patients (15.6%) in the ACE inhibitor group and 7 patients (5.8%) in the control group (p = 0.015). Serum creatinine level increased from 1.34 ± 0.20 to 1.53 ± 0.27 mg/dl in the ACE inhibitor group and from 1.33 ± 0.18 to 1.45 ± 0.19 mg/dl in the control group (p < 0.001). Chronic ACE inhibitor administration was a risk indicator of CIN [odds ratio 3.37; 95% confidence interval 1.14–9.94; p = 0.028]. Multi-vessel coronary involvement (p = 0.001), hypoalbuminemia (p = 0.005), diabetes mellitus (p = 0.006), GFR ≤40 ml/min (p = 0.010), and congestive heart failure (p = 0.024) were other risk indicators of CIN. Conclusion: Chronic ACE inhibitor administration is a risk for developing CIN in elderly patients with renal insufficiency.

Nutritional Supplementation Acutely Increases Albumin Fractional Synthetic Rate in Chronic Hemodialysis Patients

Uremic malnutrition is associated with increased risk of hospitalization and death in chronic hemodialysis (CHD) patients. Most nutritional intervention studies in CHD patients traditionally have used concentrations of serum albumin as the primary outcome measure and showed slight or no significant improvements. A recent study showed that intradialytic parenteral nutrition (IDPN) improves whole-body protein synthesis in CHD patients. On the basis of this observation, it was hypothesized that the anabolic effects of IDPN are associated with increases in the fractional synthetic rate of albumin, a direct estimate of acute changes in hepatic albumin synthesis. Seven CHD patients were studied during two hemodialysis (HD) sessions, with and without IDPN, using primed-constant infusion of (13C) leucine 2 h before, during, and 2 h after HD. Plasma enrichments of (13C) leucine and (13C) ketoisocaproate were examined to determine the fractional synthetic rate of albumin. The results indicate that administration of IDPN significantly improves the fractional synthetic rate of albumin during HD (16.2 +/- 1.5%/d versus 12.8 +/- 1.7%/d; P < 0.05) in CHD patients in parallel with significant improvements in whole-body protein synthesis (5.05 +/- 1.3 mg/kg fat-free mass/min versus 3.22 +/- 0.3 mg/kg fat-free mass/min; P < 0.05). IDPN is protein anabolic in the acute setting in CHD patients, as evidenced by significant concomitant increases in the fractional synthetic rate of albumin and whole-body protein synthesis.

Early Intervention Improves Mortality and Hospitalization Rates in Incident Hemodialysis Patients: RightStart Program

BACKGROUND AND OBJECTIVES Annualized mortality rates of chronic hemodialysis (CHD) patients in their first 90 d of treatment range from 24 to 50%. Limited studies also show high hospitalization rates. It was hypothesized that a structured quality improvement program (RightStart), focused on medical needs and patient education and support, would improve outcomes for incident CHD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 918 CHD incident patients were prospectively enrolled in a multicenter RightStart Program, and compared with a time-concurrent group of 1020 control patients from non-RightStart clinics. RightStart patients received 3 mo of intervention in management of anemia, dosage of dialysis, nutrition, and dialysis access and a comprehensive educational program. Outcomes were tracked for up to 12 mo. RESULTS At 3 mo, RightStart patients had higher albumin and hematocrit values. Dose of dialysis and permanent access placement were not statistically significantly different from control subjects. Compared with baseline, Mental Composite Score for RightStart patients improved significantly. Mean hospitalization days per patient year were reduced with RightStart versus control subjects. Mortality rates at 3, 6, and 12 mo were 20, 18, and 17 for RightStart patients versus 39, 33, and 30 deaths per 100 patient-years for control subjects, respectively. CONCLUSIONS A structured program of prompt medical and educational strategies in incident CHD patients results in improved morbidity and mortality that last up to 1 yr.

The Effect of Resistance Exercise to Augment Long-term Benefits of Intradialytic Oral Nutritional Supplementation in Chronic Hemodialysis Patients

BACKGROUND Resistance exercise combined with intradialytic oral nutrition (IDON) supplementation improves net protein balance in the acute setting in chronic hemodialysis patients. We hypothesized that combination of long-term resistance exercise and IDON would improve markers of muscle mass and strength further compared with IDON alone. METHODS Thirty-two participants (21 male; mean age, 43 ± 13 years) on chronic hemodialysis were randomly assigned to IDON plus resistance exercise (NS + EX), or IDON (NS) alone for 6 months. IDON consisted of a lactose-free formula consisting of protein, carbohydrate, and fat. Three sets of 12 repetitions of leg-press were completed before each dialysis session in the NS + EX arm. Primary outcome measurement was lean body mass. Muscle strength and other nutritional parameters were measured as secondary outcomes. RESULTS Of 32 participants, 22 completed the 6-month intervention. There were no statistically significant differences between the study interventions with respect to changes in lean body mass and body weight, when comparing NS + EX to NS. There were also no statistically significant differences in any of the secondary outcomes measured in the study. Body weight (80.3 ± 16.6 kg, 81.1 ± 17.5 kg, and 80.9 ± 18.2 kg at baseline, month 3, and month 6, respectively; P = .02) and 1-repetition maximum (468 ± 148 lb, 535 ± 144 lb, and 552 ± 142 lb, respectively; P = .001) increased statistically significantly during the study for all patients combined. CONCLUSION This study did not show further benefits of additional resistance exercise on long-term somatic protein accretion above and beyond nutritional supplementation alone. When both treatments groups were combined, body weight and muscle strength improved during the study.

Intradialytic serial vascular access flow measurements

Hemodialysis vascular access failure represents a major source of morbidity and mortality in chronic hemodialysis (CHD) patients. Serial vascular access blood flow (VABF) measurements are being used as a screening method at an increasing rate. There are limited data on the changes in VABF throughout the hemodialysis session, which may potentially affect the validity of VABF measurement. This study is performed to evaluate the trend in VABF during a given hemodialysis session by serial VABF measurements, along with potential factors that may affect VABF. Thirty-two CHD patients had serial VABF measurements performed during a hemodialysis session. Each patient had three serial VABF measurements during a hemodiaysis treatment (within 30, 90, and 150 minutes from the start of hemodialysis). Mean arterial blood pressure (MAP), ultrafiltration rate, and patient symptoms were recorded simultaneously. The mean VABF was 1,344 +/- 486 mL/min within 30 minutes of hemodialysis and decreased to 1,308 +/- 532 and 1,250 +/- 552 mL/min after 90 and 150 minutes, respectively. This trend was statistically significant (P = 0.03). There was a strong correlation between VABF measurements and MAP, which was more pronounced after 90 minutes of initiation of hemodialysis (r = 0.68; P < 0.001). Using multivariate analysis, it can be predicted that after 90 minutes of hemodialysis, each 10% decrease in MAP would result in an expected decrease of 8% in VABF. There was no effect of type of vascular access, baseline VABF, or amount of ultrafiltration on VABF changes. In conclusion, VABF measurements can be performed up to 2 to 2(1/2) hours from the start of hemodialysis in the majority of patients. The major determinant of VABF changes is MAP. In a subset of patients with a decrease MAP greater than 15%, it is advisable to perform VABF measurement either at the first 90 minutes of hemodialysis or postpone it to another treatment session, when MAP is more stable.