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1. Editorial

Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 2010;20(2):66-67.

doi:10.1053/j.jrn.2010.01.039

PMCID: PMC3548574 PMID: 20185070

2. Use of a DNA Biobank Linked to Electronic Medical Records to Characterize Pharmacogenomic Predictors of Tacrolimus Dose Requirement in Kidney Transplant Recipients

Pharmacogenetics and genomics 2012;22(1):32-42.

Objective

Tacrolimus, an immunosuppressive drug widely prescribed in kidney transplantation, requires therapeutic drug monitoring due to its marked interindividual pharmacokinetic variability and narrow therapeutic index. Previous studies have established that CYP3A5 rs776746 is associated with tacrolimus clearance, blood concentration, and dose requirement. The importance of other drug absorption, distribution, metabolism, and elimination (ADME) gene variants has not been well characterized.

Methods

We used novel DNA biobank and electronic medical record resources to identify ADME variants associated with tacrolimus dose requirement. Broad ADME genotyping was performed on 446 kidney transplant recipients who had been dosed to steady state with tacrolimus. The cohort was obtained from Vanderbilt's DNA biobank, BioVU, which contains linked, de-identified electronic medical record data. Genotyping included Affymetrix DMET Plus (1936 polymorphisms), custom Sequenom MassARRAY iPLEX Gold assay (95 polymorphisms), and ancestry-informative markers. The primary outcome was tacrolimus dose requirement defined as blood concentration-to-dose ratio.

Results

In analyses that adjusted for race and other clinical factors, we replicated the association of tacrolimus blood concentration-to-dose ratio with CYP3A5 rs776746 (p = 7.15 × 10−29), and identified associations with nine variants in linkage disequilibrium with rs776746, including eight CYP3A4 variants. No NR1/2 variants were significantly associated. Age, weight, and hemoglobin were also significantly associated with the outcome. In final models, rs776746 explained 39% of variability in dose requirement, and 46% was explained by the model containing clinical covariates.

Conclusion

This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.

doi:10.1097/FPC.0b013e32834e1641

PMCID: PMC3237759 PMID: 22108237

pharmacogenomics; pharmacokinetics; calcineurin inhibitor; tacrolimus; electronic medical records; kidney transplant; cytochrome P4503A5; genetic polymorphism; dosing

3. Incidence and Predictors of End Stage Renal Disease among Low-Income Blacks and Whites

PLoS ONE 2012;7(10):e48407.

We evaluated whether black race is associated with higher incidence of End Stage Renal Disease (ESRD) among a cohort of blacks and whites of similar, generally low socioeconomic status, and whether risk factor patterns differ among blacks and whites and explain the poorly understood racial disparity in ESRD. Incident diagnoses of ESRD among 79,943 black and white participants in the Southern Community Cohort Study (SCCS) were ascertained by linkage with the United States Renal Data System (USRDS) from 2002 through 2009. Person-years of follow up were calculated from date of entry into the SCCS until date of ESRD diagnosis, date of death, or September 1, 2009, whichever occurred first. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for incident ESRD among black and white participants in relation to baseline characteristics. After 329,003 person-years of follow-up, 687 incident cases of ESRD were identified in the cohort. The age-adjusted ESRD incidence rate was 273 (per 100,000) among blacks, 3.5-fold higher than the rate of 78 among whites. Risk factors for ESRD included male sex (HR = 1.6; 95% CI 1.4–1.9), low income (HR = 1.5; 95% CI 1.2–1.8 for income below vs. above $15,000), smoking (HR = 1.2; 95% CI 1.02–1.4) and histories of diabetes (HRs increasing to 9.4 (95% CI 7.4–11.9) among those with ≥20 years diabetes duration) and hypertension (HR = 2.9; 95% CI 2.3–3.7). Patterns and magnitudes of association were virtually identical among blacks and whites. After adjustment for these risk factors, blacks continued to have a higher risk for ESRD (HR = 2.4; 95% CI = 1.9–3.0) relative to whites. The black-white disparity in risk of ESRD was attenuated but not eliminated after control for known risk factors in a closely socioeconomically matched cohort. Further research characterizing biomedical factors, including CKD progression, in ESRD occurrence in these two racial groups is needed.

doi:10.1371/journal.pone.0048407

PMCID: PMC3480508 PMID: 23110237

4. Outpatient versus Inpatient Observation after Percutaneous Native Kidney Biopsy: A Cost Minimization Study

Maripuri, Saugar | Penson, David F. | Ikizler, T. Alp | Cavanaugh, Kerri L.

American Journal of Nephrology 2011;34(1):64-70.

Background/Aims

Percutaneous kidney biopsy (PKB) is the primary diagnostic tool for kidney disease. Outpatient ‘day surgery’ (ODS) following PKB in low-risk patients has previously been described as a safe alternative to inpatient observation (IO). This study aims to determine if ODS is less costly compared to IO while accounting for all institutional costs (IC) associated with post-PKB complications, including death.

Methods

A cost minimization study was performed using decision analysis methodology which models relative costs in relation to outcome probabilities yielding an optimum decision. The potential outcomes included major complications (bleeding requiring blood transfusion or advanced intervention), minor complications (bleeding or pain requiring additional observation), and death. Probabilities were obtained from the published literature and a base case was selected. IC were obtained for all complications from institutional activity-based cost estimates. The base case assumed a complication rate of 10% with major bleeding occurring in 2.5% of patients (for both arms) and death in 0.1 and 0.15% of IO and ODS patients, respectively.

Results

ODS costs USD 1,394 per biopsy compared to USD 1,800 for IO inclusive of all complications. IC for ODS remain less when overall complications <20%, major complications <5.5%, and IC per death

Conclusion

Outpatient management after PKB for low-risk patients costs less from the institutional perspective compared to IO, inclusive of complications and death. ODS should be considered for low-risk patients undergoing native kidney biopsy.

doi:10.1159/000328901

PMCID: PMC3123742 PMID: 21677428

Kidney biopsy; Decision analysis; Institutional costs

5. Effects of Combination Tocopherols and Alpha Lipoic Acid Therapy on Oxidative Stress and Inflammatory Biomarkers in Chronic Kidney Disease

Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 2010;21(3):211-218.

Increased oxidative stress and inflammation are highly prevalent in chronic kidney disease (CKD), yet few studies have investigated whether oral antioxidant therapy can alter markers of inflammation or oxidative stress in CKD. The purpose of this study was to investigate whether a combination of mixed tocopherols and alpha lipoic acid (ALA) would alter biomarkers of oxidative stress and inflammation in subjects with Stage 3–4 CKD.

Methods

This was a prospective, randomized, double-blind, placebo-controlled pilot trial. 62 subjects were enrolled, and were randomly assigned to receive the combination of mixed tocopherols 666 IU/day plus ALA 600mg/day or their matching placebos for a total of 8 weeks. Plasma F2-isoprostane and protein thiol concentration were measured as biomarkers of oxidative stress, and C-reactive protein (CRP) and interleukin-6 (IL-6) concentration as biomarkers of systemic inflammation.

Results

There were no significant differences in demographics, diabetic status, or estimated glomerular filtration rate (eGFR) between study treatment and placebo groups at baseline. 58 of 62 randomized subjects (93%) completed the study protocol. After two months of treatment, there were no significant changes in F2-isoprostanes, protein thiols, CRP and IL-6 concentrations with mixed tocopherols and ALA treatment compared to matching placebos, whether analyzed as intention to treat or as treated. Diabetic status and baseline body mass index did not influence the results.

Conclusions

Combination oral mixed tocopherols and ALA treatment for 2 months does not influence biomarkers of oxidative stress and inflammation in Stage 3–4 CKD patients.

doi:10.1053/j.jrn.2010.08.003

PMCID: PMC3078529 PMID: 21185738

6. Development and Results of a Kidney Disease Knowledge Survey Given to Patients With CKD

Wright, Julie A. | Wallston, Kenneth A. | Elasy, Tom A. | Ikizler, T. Alp | Cavanaugh, Kerri L.

American journal of kidney diseases : the official journal of the National Kidney Foundation 2010;57(3):387-395.

Background

Little is known about disease specific knowledge in patients with chronic kidney disease (CKD). We developed and examined the results of a survey to characterize kidney disease knowledge.

Design

Survey about kidney disease knowledge, with questions developed by experts. Setting and Participants: 401 adult patients with CKD (Stages 1–5) attending a nephrology clinic from April to October 2009.

Outcomes & Measurements

We calculated survey reliability using the Kuder-Richardson-20 coefficient, and established construct validity by testing a priori hypotheses of associations between the survey and patient characteristics. We descriptively analyzed survey responses and applied linear regression analyses to evaluate associations with patient characteristics. Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine.

Results

Participants median age was 58 (25th-75th percentile, 46–68) years, 83% were White, 18% had limited literacy, and 77% had CKD Stages 3–5. The 28 question knowledge survey had good reliability (KR-20=0.72), and mean (SD) knowledge score was 66% (15%). In support of construct validity of our knowledge survey, bivariate analysis shows that scores are associated with age (β, −0.01 per ten years; 95% CI, −0.02–−0.005; p=0.003), formal education (β, 0.09; 95% CI, 0.03–0.15; p=0.004), health literacy (β, 0.06; 95% CI, 0.03–0.10; p=0.001), kidney education class participation (β, 0.05; 95% CI, 0.01–0.09; p=0.009), knowing someone else with CKD (β, 0.05; 95% CI, 0.02–0.08; p=0.001), and awareness of one’s own CKD diagnosis (β, 0.07; 95% CI, 0.04–0.10; p<0.001). Findings were similar in adjusted analyses.

Limitations

Recruitment from one clinic limits generalizabilty of findings.

Conclusions

For patients with CKD, this kidney disease knowledge survey (KiKS) is reliable and valid, and identifies areas of and risk factors for poor kidney knowledge. Further study is needed to determine the impact of CKD knowledge on self-care behaviors and clinical outcomes.

doi:10.1053/j.ajkd.2010.09.018

PMCID: PMC3053083 PMID: 21168943

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

Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 2010;21(2):149-159.

Objective

We tested the hypothesis that long-term resistance exercise combined with intradialytic oral nutrition (IDON) supplementation will improve markers of muscle mass and strength further compared to IDON alone in chronic hemodialysis (CHD) patients.

Design

Randomized controlled trial.

Setting

Outpatient Dialysis Unit at an academic center.

Main outcome measure

Lean body mass (LBM). Muscle strength and other nutritional parameters were measured as secondary outcomes.

Patients

Thirty-two participants (age 43±13 yrs, 21 male) on CHD

Design

Subjects 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 prior to each dialysis session in the NS+EX arm.

Results

22 out of 32 participants completed the 6-month intervention. There were no statistically significant differences between the study interventions with respect to changes in LBM 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=0.02) and 1-Repetition Maximum (468±148 lb, 535±144 lb, 552±142 lb, respectively, P=0.001) 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.

doi:10.1053/j.jrn.2010.03.004

PMCID: PMC2947559 PMID: 20580251

hemodialysis; protein-energy wasting; resistance exercise; nutrition supplementation

8. Exercise as an Anabolic Intervention in ESRD Patients

Ikizler, T. Alp

Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 2011;21(1):52-56.

Muscle wasting and accompanying structural derangements leading to abnormalities in muscle function, exercise performance, and physical activity are common in end-stage renal disease (ESRD) patients. Accordingly a number of studies have been performed examining the effects of exercise in this patient population. Most of the studies have assessed the effects of cardiopulmonary fitness training and a few have examined the role of resistance (i.e. strength) training. Despite the proven efficacy of resistance exercise as an anabolic intervention in otherwise healthy elderly and certain chronic disease states, recent studies in maintenance hemodialysis patients have not been encouraging in terms of long-term improvements in markers of muscle mass. Preliminary studies indicated that a combination of simultaneous exercise and nutritional supplementation could augment the anabolic effects of exercise, at least in the acute setting. However, a recent randomized clinical trial failed to show further benefits of additional resistance exercise on long-term somatic protein accretion above and beyond nutritional supplementation alone. Further research is necessary to both understand the observed lack of obvious benefits and strategies to improve the exercise regimens in ESRD patients.

doi:10.1053/j.jrn.2010.10.012

PMCID: PMC3061820 PMID: 21195920

9. Patient Perspectives on Fluid Management in Chronic Hemodialysis

Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 2009;20(5):334-341.

Objective

To describe the perspectives and experiences of chronic hemodialysis (CHD) patients regarding self-care and adherence to fluid restrictions.

Design

Semi-structured focus groups.

Setting

Two outpatient hemodialysis centers.

Participants

19 patients on chronic hemodialysis.

Intervention

Patients were asked a series of open-ended questions to encourage discussion about the management of fluid restriction within the broad categories of general knowledge, knowledge sources or barriers, beliefs and attitudes, self-efficacy, emotion, and self-care skills.

Main outcome measure

We analyzed session transcripts using the theoretical framework of content analysis to identify themes generated by the patients.

Results

Patients discussed both facilitators and barriers to fluid restriction which we categorized into 6 themes: knowledge, self-assessment, psychological factors, social, physical, and environmental. Psychological factors were the most common barriers to fluid restriction adherence, predominantly involving lack of motivation. Knowledge was the most discussed facilitator with accurate self-assessment, positive psychological factors, and supportive social contacts also playing a role. Dialysis providers were most commonly described as the source of dialysis information (54%), but learning through personal experience was also frequently noted (28%).

Conclusion

Interventions to improve fluid restriction adherence of chronic hemodialysis patients should target motivational issues, assess and improve patient knowledge, augment social support, and facilitate accurate self-assessment of fluid status.

doi:10.1053/j.jrn.2009.09.001

PMCID: PMC2888683 PMID: 19913443

hemodialysis; interdialytic weight gain; focus group; quality of life; qualitative research

10. Association of Socioeconomic Status and CKD among African Americans: The Jackson Heart Study

American journal of kidney diseases : the official journal of the National Kidney Foundation 2010;55(6):1001-1008.

Background

Socioeconomic status (SES) is recognized as a key social environmental factor because it has implications for access to resources that help individuals care for themselves and others. Few studies have examined the association of SES with CKD in high-risk populations.

Study Design

Single-site longitudinal population-based cohort

Setting and Participants

The data for this study were drawn from the baseline examination of the Jackson Heart Study. The analytic cohort consisted of 3,430 African American men and women living in the tri-county area of the Jackson, Mississippi metropolitan areas with complete data to determine CKD status.

Predictor

High SES (defined as having a family income at least 3.5 times the poverty level or having at least one undergraduate degree)

Outcomes and Measurements

CKD (defined as the presence of albuminuria or reduced estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2). Associations were explored through bivariable analyses and multivariable logistic regression analyses adjusting for CKD and cardiovascular disease risk factors as well as demographic factors.

Results

The prevalence of CKD in the Jackson Heart Study was 20% (865/3430 participants). The proportion of the Jackson Heart Study cohort with albuminuria and decreased eGFR was 12.5% (429/3430 participants) and 10.1% (347/3430 participants) respectively. High SES was inversely associated with CKD. The odds of having CKD were 41% lower for affluent participants than their less affluent counterparts. There were no statistically significant interactions between sex and education or income although subgroup analysis showed that high income was associated with CKD among male (OR 0.47, CI 0.23–0.97) but not female (OR 0.64, CI 0.40–1.03) participants.

Limitations

Models were estimated using cross-sectional data.

Conclusion

CKD is associated with SES. Additional research is needed to elucidate the impact of wealth and social contexts in which individuals are embedded, and the mediating effects of sociocultural factors.

doi:10.1053/j.ajkd.2010.01.016

PMCID: PMC2876216 PMID: 20381223

11. CRP polymorphisms and chronic kidney disease in the third national health and nutrition examination survey

BMC Medical Genetics 2011;12:65.

Background

CRP gene polymorphisms are associated with serum C-reactive protein concentrations and may play a role in chronic kidney disease (CKD) progression. We recently reported an association between the gene variant rs2808630 and CKD progression in African Americans with hypertensive kidney disease. This association has not been studied in other ethnic groups.

Methods

We used data from 5955 participants from Phase 2 of The Third National Health and Nutrition Examination Survey (1991-1994) to study the association between CRP polymorphisms and CKD prevalence in a population-based sample. The primary outcome was CKD defined as estimated glomerular filtration rate (eGFR) <60 ml/min or the presence of albuminuria. Secondary outcomes were the presence of albuminuria (any degree) and continuous eGFR. Six single nucleotide polymorphisms (SNPs) from the CRP gene, rs2808630, rs1205, rs3093066, rs1417938, rs3093058, and rs1800947, were evaluated.

Results

CRP rs2808630 AG compared to the referent AA genotype was associated with CKD in non-Hispanic blacks (n = 1649, 293 of whom had CKD) with an adjusted odds ratio (OR) of 3.09 (95% CI 1.65-5.8; p = 0.001). For the secondary outcomes, rs2808630 AG compared to the referent AA genotype was associated with albuminuria with an adjusted OR of 3.07 (95% CI 1.59-5.94; p = 0.002), however not with eGFR. There was no association between the SNPs and CKD, albuminuria or eGFR in non-Hispanic whites or Mexicans Americans.

Conclusions

In this cross-sectional study, the 3' flanking CRP gene variant rs2808630 was associated with CKD, mainly through its association with albuminuria in the non-Hispanic blacks. Despite not finding an association with eGFR, our results support our previous study demonstrating an association between CRP gene variant rs2808630 and CKD progression in a longitudinal cohort of African American with hypertensive kidney disease.

doi:10.1186/1471-2350-12-65

PMCID: PMC3119179 PMID: 21569369

12. Erratum to: Wasting in chronic kidney disease

Journal of Cachexia, Sarcopenia and Muscle 2011;2(2):119.

doi:10.1007/s13539-011-0026-6

PMCID: PMC3117998 PMID: 22477651

13. Erratum to: Wasting in chronic kidney disease

Journal of Cachexia, Sarcopenia and Muscle 2011;2(2):119.

doi:10.1007/s13539-011-0026-6

PMCID: PMC3117998 PMID: 22477651

14. Wasting in chronic kidney disease

Journal of Cachexia, Sarcopenia and Muscle 2011;2(1):9-25.

Wasting/cachexia is prevalent among patients with chronic kidney disease (CKD). It is to be distinguished from malnutrition, which is defined as the consequence of insufficient food intake or an improper diet. Malnutrition is characterized by hunger, which is an adaptive response, whereas anorexia is prevalent in patients with wasting/cachexia. Energy expenditure decreases as a protective mechanism in malnutrition whereas it remains inappropriately high in cachexia/wasting. In malnutrition, fat mass is preferentially lost and lean body mass and muscle mass is preserved. In cachexia/wasting, muscle is wasted and fat is relatively underutilized. Restoring adequate food intake or altering the composition of the diet reverses malnutrition. Nutrition supplementation does not totally reverse cachexia/wasting. The diagnostic criteria of cachexia/protein–energy wasting in CKD are considered. The association of wasting surrogates, such as serum albumin and prealbumin, with mortality is strong making them robust outcome predictors. At the patient level, longevity has consistently been observed in patients with CKD who have more muscle and/or fat, who report better appetite and who eat more. Although inadequate nutritional intake may contribute to wasting or cachexia, recent evidence indicates that other factors, including systemic inflammation, perturbations of appetite-controlling hormones from reduced renal clearance, aberrant neuropeptide signaling, insulin and insulin-like growth factor resistance, and metabolic acidosis, may be important in the pathogenesis of CKD-associated wasting. A number of novel therapeutic approaches, such as ghrelin agonists and melanocortin receptor antagonists are currently at the experimental level and await confirmation by randomized controlled clinical trials in patients with CKD-associated cachexia/wasting syndrome.

doi:10.1007/s13539-011-0019-5

PMCID: PMC3063874 PMID: 21475675

Wasting; Chronic; Kidney disease

15. Wasting in chronic kidney disease

Journal of Cachexia, Sarcopenia and Muscle 2011;2(1):9-25.

doi:10.1007/s13539-011-0019-5

PMCID: PMC3063874 PMID: 21475675

Wasting; Chronic; Kidney disease

16. Roux-en-Y gastric bypass reverses renal glomerular but not tubular abnormalities in excessively obese diabetics

Surgery 2009;147(2):282.

Background

Obesity and type 2 diabetes are associated with renal dysfunction which improves after roux-en-Y gastric bypass (RYGB) surgery. We prospectively studied, during a 12-month follow-up period, changes in glomerular and tubular functions that occurred in excessively obese diabetic and non-diabetic subjects after RYGB.

Methods

The cohort included 35 patients, 54% of them with type 2 diabetes. Glomerular filtration rate (GFR) was estimated using creatinine clearance. Tubular function was studied by measuring the ratio of urinary cystatin C to urinary creatinine (UCC ratio).

Results

Baseline renal parameters, anthropometric characteristics as well as changes in body mass index following the surgical procedures were similar between the two cohorts. Creatinine clearance decreased 15% in diabetics (p = 0.02) and 21% in non-diabetics (p = 0.03), 12 months after RYGB. A significant change in GFR was seen earlier in the non-diabetics (−29% after 6 months, p = 0.003). UCC ratio underwent a significant increase at both 6 and 12 months follow-ups (p = 0.03 and 0.003, respectively) only in the diabetic group.

Conclusion

RYGB improved GFR 12 months after surgery with non-diabetics showing a higher propensity. Tubular function remained unchanged in the non-diabetic but worsening occurred in diabetic subjects. These results underscore the importance of reversal of excessive obesity prior to the onset of frank diabetes.

doi:10.1016/j.surg.2009.09.017

PMCID: PMC2813906 PMID: 20004430

17. Sepsis as a cause and consequence of acute kidney injury: Program to Improve Care in Acute Renal Disease

Intensive Care Medicine 2010;37(2):241-248.

Purpose

Sepsis commonly contributes to acute kidney injury (AKI); however, the frequency with which sepsis develops as a complication of AKI and the clinical consequences of this sepsis are unknown. This study examined the incidence of, and outcomes associated with, sepsis developing after AKI.

Methods

We analyzed data from 618 critically ill patients enrolled in a multicenter observational study of AKI (PICARD). Patients were stratified according to their sepsis status and timing of incident sepsis relative to AKI diagnosis.

Results

We determined the associations among sepsis, clinical characteristics, provision of dialysis, in-hospital mortality, and length of stay (LOS), comparing outcomes among patients according to their sepsis status. Among the 611 patients with data on sepsis status, 174 (28%) had sepsis before AKI, 194 (32%) remained sepsis-free, and 243 (40%) developed sepsis a median of 5 days after AKI. Mortality rates for patients with sepsis developing after AKI were higher than in sepsis-free patients (44 vs. 21%; p < 0.0001) and similar to patients with sepsis preceding AKI (48 vs. 44%; p = 0.41). Compared with sepsis-free patients, those with sepsis developing after AKI were also more likely to be dialyzed (70 vs. 50%; p < 0.001) and had longer LOS (37 vs. 27 days; p < 0.001). Oliguria, higher fluid accumulation and severity of illness scores, non-surgical procedures after AKI, and provision of dialysis were predictors of sepsis after AKI.

Conclusions

Sepsis frequently develops after AKI and portends a poor prognosis, with high mortality rates and relatively long LOS. Future studies should evaluate techniques to monitor for and manage this complication to improve overall prognosis.

doi:10.1007/s00134-010-2089-9

PMCID: PMC3028102 PMID: 21152901

Acute kidney injury; Dialysis; Intensive care unit; Outcomes; Sepsis; Severity of illness

18. New Insights into the Role of Anabolic Interventions in Dialysis Patients with Protein Energy Wasting

Dong, Jie | Ikizler, T. Alp

Current opinion in nephrology and hypertension 2009;18(6):469-475.

Purpose of review

Patients on maintenance dialysis commonly develop protein-energy wasting (PEW), which is associated with poor survival. There have been several advances in anabolic interventions aimed at improving PEW in these patients in recent years.

Recent findings

Oral or parenteral nutritional supplementation, especially if administered during dialysis, improves net protein anabolism in chronic hemodialysis (CHD) patients. These beneficial effects have been extended to long-term benefits in recent clinical trials. Resistance exercise, alone or combined with intradialytic oral nutrition supplementation also improves net protein balance in the acute setting although recent studies indicated a limited beneficial effect of long-term exercise alone on muscle protein accretion in CHD patients. Anabolic agents such as growth hormone and androgens have been shown to exert significant benefits on visceral protein stores, muscle mass and strength. Ghrelin, a hormone with combined orexigenic and anti-inflammatory effects, is a potential new nutritional intervention in maintenance dialysis patients.

Summary

Existing anabolic therapeutic strategies have proven to be effective in improving PEW in maintenance dialysis patients. Combined anabolic interventions and several new and established anabolic hormones represent as further promising nutritional interventions. Large-scale randomized controlled trials examining the effects of anabolic interventions on mortality and morbidity are still lacking.

doi:10.1097/MNH.0b013e328331489d

PMCID: PMC2891019 PMID: 19713839

Dialysis; protein-energy wasting; nutritional supplementation; exercise; anabolic agents

19. Oral Protein Supplementation Alone Improves Anabolism in a Dose-Dependent Manner in Chronic Hemodialysis Patients

Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 2009;19(5):412-421.

Objective

We examined the protein anabolic effects of Pro-Stat 64, a high nitrogen-containing, enzyme-hydrolyzed, tryptophan-fortified, collagen protein supplement administrated during hemodialysis, at two different dosing regimens.

Design

This was a randomized, controlled, prospective study with 3 different groups: control, single dose of supplementation, and double dose of supplementation.

Setting

This study was performed at a clinical research center.

Patients

Six prevalent chronic hemodialysis (HD) patients were enrolled: 5 males, 1 female, 4 African Americans, and 2 Caucasians. Their mean age was 45 ± 11 years. Two patients were diabetic.

Methods

Protein turnover studies were performed using amino-acid (AA) balance and primed constant infusion of L-(1-13C) leucine.

Main Outcome Measure

Whole-body protein balance was determined according to substrate kinetics.

Results

There were no statistically significant difference at any time point between protocols for blood chemistries and hormonal markers, except for minor variations in plasma glucose. All plasma AA groups displayed decreases during control. Compared with the control group, plasma nonessential AA and total AA concentrations were statistically significantly higher during HD after both single and double doses of supplementation. The forearm arteriovenous AA balance was statistically significantly better for essential, nonessential, and total AA uptake after both single-dose and double-dose supplementation compared with the control group, except for nonessential AA, which was significantly better only after a double dose. Whole-body protein breakdown and net protein balance were statistically significantly better during HD with a double-dose administration in a dose-dependent manner, compared with the control and single-dose groups.

Conclusions

Oral AA supplementation alone improves whole-body and skeletal muscle protein anabolism in a dose-dependent manner in chronic HD patients. These data should be taken into account during clinical decision-making or when designing clinical trials of nutritional supplementation.

doi:10.1053/j.jrn.2009.01.019

PMCID: PMC2758490 PMID: 19500999

20. Commonly Used Surrogates for Baseline Renal Function Can Impact Acute Kidney Injury Classification and Prognosis

Kidney international 2009;77(6):536-542.

Studies of acute kidney injury (AKI) commonly lack data on pre-admission renal function, often substituting an inpatient or imputed serum creatinine (SCr) as an estimate for “baseline” renal function. We examined the error introduced when applying methods to estimate “baseline” on AKI classification and mortality. Within a cohort of 4863 adults with a known outpatient baseline admitted to Vanderbilt University Hospital between 10/07 and 10/08, the following surrogates were studied: (1) an eGFR of 75 ml/min/1.73m2 as suggested by the Acute Dialysis Quality Initiative (ADQI), (2) a minimum inpatient SCr, and (3) the first admission SCr. We calculated AKI incidence and mortality rates using each surrogate, and assessed their ability to correctly classify AKI incidence and mortality compared to the most recent outpatient SCr between 7-365 days before admission. Using both imputed and minimum baseline SCr values inflated AKI incidence (38.3% and 35.9% vs. 25.5%; p<0.001), reflecting low specificities of 77% and 80%, respectively. In contrast, using an admission SCr baseline underestimated AKI incidence (13.7% vs. 25.5%, p<0.001), demonstrating a low sensitivity of 39%. Using any surrogate led to frequent misclassification of patient deaths as following AKI and differences for both in-hospital and 60-day mortality rates. In summary, commonly used surrogates for baseline SCr result in bi-directional misclassification of AKI incidence and prognosis in a hospitalized setting.

doi:10.1038/ki.2009.479

PMCID: PMC2929703 PMID: 20042998

21. The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods

BMC Nephrology 2010;11:22.

Background

The incidence of acute kidney injury (AKI) has been increasing over time and is associated with a high risk of short-term death. Previous studies on hospital-acquired AKI have important methodological limitations, especially their retrospective study designs and limited ability to control for potential confounding factors.

Methods

The Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study was established to examine how a hospitalized episode of AKI independently affects the risk of chronic kidney disease development and progression, cardiovascular events, death, and other important patient-centered outcomes. This prospective study will enroll a cohort of 1100 adult participants with a broad range of AKI and matched hospitalized participants without AKI at three Clinical Research Centers, as well as 100 children undergoing cardiac surgery at three Clinical Research Centers. Participants will be followed for up to four years, and will undergo serial evaluation during the index hospitalization, at three months post-hospitalization, and at annual clinic visits, with telephone interviews occurring during the intervening six-month intervals. Biospecimens will be collected at each visit, along with information on lifestyle behaviors, quality of life and functional status, cognitive function, receipt of therapies, interim renal and cardiovascular events, electrocardiography and urinalysis.

Conclusions

ASSESS-AKI will characterize the short-term and long-term natural history of AKI, evaluate the incremental utility of novel blood and urine biomarkers to refine the diagnosis and prognosis of AKI, and identify a subset of high-risk patients who could be targeted for future clinical trials to improve outcomes after AKI.

doi:10.1186/1471-2369-11-22

PMCID: PMC2944247 PMID: 20799966

22. Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients

Critical Care 2010;14(3):R82.

Introduction

Serum creatinine concentration (sCr) is the marker used for diagnosing and staging acute kidney injury (AKI) in the RIFLE and AKIN classification systems, but is influenced by several factors including its volume of distribution. We evaluated the effect of fluid accumulation on sCr to estimate severity of AKI.

Methods

In 253 patients recruited from a prospective observational study of critically-ill patients with AKI, we calculated cumulative fluid balance and computed a fluid-adjusted sCr concentration reflecting the effect of volume of distribution during the development phase of AKI. The time to reach a relative 50% increase from the reference sCr using the crude and adjusted sCr was compared. We defined late recognition to estimate severity of AKI when this time interval to reach 50% relative increase between the crude and adjusted sCr exceeded 24 hours.

Results

The median cumulative fluid balance increased from 2.7 liters on day 2 to 6.5 liters on day 7. The difference between adjusted and crude sCr was significantly higher at each time point and progressively increased from a median difference of 0.09 mg/dL to 0.65 mg/dL after six days. Sixty-four (25%) patients met criteria for a late recognition to estimate severity progression of AKI. This group of patients had a lower urine output and a higher daily and cumulative fluid balance during the development phase of AKI. They were more likely to need dialysis but showed no difference in mortality compared to patients who did not meet the criteria for late recognition of severity progression.

Conclusions

In critically-ill patients, the dilution of sCr by fluid accumulation may lead to underestimation of the severity of AKI and increases the time required to identify a 50% relative increase in sCr. A simple formula to correct sCr for fluid balance can improve staging of AKI and provide a better parameter for earlier recognition of severity progression.

doi:10.1186/cc9004

PMCID: PMC2911707 PMID: 20459609

23. Thiazolidinedione use is associated with better survival in hemodialysis patients with non-insulin dependent diabetes

Brunelli, Steven M. | Thadhani, Ravi | Ikizler, T. Alp | Feldman, Harold I.

Kidney international 2009;75(9):961-968.

Cardiovascular mortality is especially high among dialysis patients with diabetes, as is morbidity due to protein energy wasting. Given that both of these factors may be decreased by thiazolidinedione treatment, we studied the effect of thiazolidinedione use on survival among chronic dialysis patients in a national cohort of 5290 incident dialysis patients with diabetes. Thiazolidinedione use was assessed according to prescription data, and the analyses were stratified based on insulin use due to observed interaction. In the primary analysis, thiazolidinedione treatment was associated with significantly lower all-cause mortality among insulin-free but not insulin-requiring subjects, with adjusted hazards ratios of 0.53 (0.31–0.89) and 0.82 (0.46–1.47) respectively. Sensitivity analyses found the findings to be robust with respect to confounding by indication, severity of the diabetes, potential reverse causality, and time varying exposure patterns. The mechanism of this decline in all-cause mortality will need to be examined after these studies are confirmed.

doi:10.1038/ki.2009.4

PMCID: PMC2864092 PMID: 19190679

diabetes; dialysis; epidemiology; mortality; survival thiazolidinediones

24. BODY COMPOSITION AND PHYSICAL ACTIVITY IN END STAGE RENAL DISEASE

Majchrzak, Karen M. | Pupim, Lara B. | Sundell, Mary | Ikizler, T. Alp

Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 2007;17(3):196-204.

Objective

To examine the relationship between visceral and somatic protein stores and physical activity in ESRD.

Design

A cross-sectional single center study.

Setting

Vanderbilt University Outpatient Dialysis Unit.

Patients

Fifty-five prevalent chronic hemodialysis patients (CHD): 33 males, 22 females, 45 African Americans, 9 Caucasians, 1 Asian. Mean age – 47.0 ± 1.6 years, height – 166.4 ± 13.9 cm, and weight – 83.1 ± 2.6 kgs.

Methods

Body composition (body weight, body fat mass, lean body mass (LBM), percentage of fat (%FM), and body mass index (BMI)) was measured by duel energy x-ray absorptiometry. Minute-by-minute physical activity was assessed over a seven-day period utilizing a tri-axial accelerometer. Participants were interviewed by a trained registered dietitian for two 24-hour diet recalls (one from a hemodialysis day; one from a non-hemodialysis day). Laboratory values for serum concentrations of albumin, prealbumin, C-reactive protein (CRP), and creatinine were also collected.

Main Outcome Measure

Predictors of somatic protein stores.

Results

Serum albumin was negatively and significantly correlated with %FM (p= 0.016) and fat mass (p = 0.044). CRP was positively and significantly correlated with body weight (p = 0.006), %FM (p = 0.017), fat mass (p = 0.006), and BMI (p = 0.004). Physical activity and total daily protein intake were the strongest independent predictors of amount of LBM.

Conclusion

The association between somatic protein and visceral protein stores are weak in CHD patients. Whereas increased levels of physical activity and total daily protein intake are associated with higher LBM in CHD patients, higher adiposity is associated with higher CRP and lower albumin values.

doi:10.1053/j.jrn.2007.01.003

PMCID: PMC2746570 PMID: 17462552

Body composition; chronic dialysis patients; dietary intake; physical activity

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

Journal of Clinical Investigation 2002;110(4):483-492.

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-(1-13C) leucine and L-(ring-2H5) 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.

doi:10.1172/JCI0215449

PMCID: PMC150418 PMID: 12189242

Results 1-25 (26)

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