Nutrition, Inflammation and Insulin Resistance in End-Stage Renal Disease (SummerMRI)

By 2030 an estimated 2 million people in the US will need dialysis or transplantation. Insulin resistance and chronic inflammation are common in dialysis patients and have been linked to protein-energy wasting, the most important determinant of clinical outcome in this patient population. The investigators hypothesize that the skin and muscle tissue sodium accumulation is a critical mechanism by which chronic inflammatory response and insulin resistance, alone or in combination lead to protein energy wasting in hemodialysis patients. The investigators will test this hypothesis by studying dialysis patients and matched controls without kidney disease by examining tissue Na content, markers of inflammation and protein metabolism.

Study Overview

• Status: Active, not recruiting
• Conditions: End-stage Renal Disease
• Intervention / Treatment: Other: high dialysate sodium concentration (138 mEq/L); Other: Low dialysate sodium concentration

Detailed Description

There are more than 420,000 patients receiving maintenance hemodialysis therapy in the United States, which is estimated to rise to over 500,000 patients by 2020. There are an estimated 45,500 Veterans receiving hemodialysis, of which over 3,000 enrolled Veterans were receiving dialysis at VA facilities in FY 2013. Over the last decade, there have been no therapies proven to significantly lower the mortality and morbidity risk for these patients. One of the most important determinants of this poor clinical outcome is protein energy wasting, a highly prevalent nutritional and metabolic abnormality characterized by increased protein breakdown in the skeletal muscle compartment. The investigators' group has shown that two well-recognized and interrelated metabolic abnormalities, insulin resistance and persistent inflammation, are likely to play a critical role in the pathogenesis of protein energy wasting and related nutritional and metabolic abnormalities. The investigators' preliminary data show that in maintenance hemodialysis (MHD) patients 1) There is an inadequate response to protein anabolic actions of insulin; 2) Persistent systemic inflammation is strongly and independently associated with skeletal muscle net protein balance; and 3) Pharmacological modulation of systemic inflammation and insulin resistance partially, but not fully, reverse net protein catabolism. It was demonstrated that non-osmotic sodium (Na) is stored in skin and muscle without commensurate water retention, which leads to local immune-cell activation and accelerated pro-inflammatory status. The investigators' preliminary data show that the skin and muscle Na+ contents, derived by 23Na magnetic resonance imaging (MRI) are substantially higher in MHD patients compared to matched healthy controls. The investigators also showed that increased skin and muscle Na concentrations are significantly associated with increased inflammatory response and decreased peripheral insulin sensitivity, in patients on MHD. These data suggest that tissue Na content, immune pathways and insulin resistance are closely linked and could lead to increased risk for protein energy wasting in MHD patients. It was reported that standard 4-hour conventional hemodialysis provides significant Na removal from muscle and skin suggesting that tissue Na and water content could be modulated by modulating hemodialysis prescription. The overall goal of this application is to elucidate the mechanisms by which tissue sodium accumulation, persistent immune system activation and insulin resistance influence the development of protein energy wasting in MHD patients. The investigators hypothesize that the skin and muscle tissue sodium accumulation is a critical mechanism by which chronic inflammatory response and insulin resistance, alone or in combination, lead to protein energy wasting in MHD patients. Specific Aims: To test the hypothesis that removal of tissue sodium by modulating hemodialysis prescription would improve metabolic milieu and protein energy wasting in MHD patients. The investigators will achieve this goal through a cross-over randomized clinical trial whereby dialysate sodium concentrations will be modulated (138 mEq/L versus 132 mEq/L, 4 weeks each) to remove 10% of baseline skeletal muscle Na content in the setting of stable sodium intake by diet. The primary outcomes will be markers of net protein balance, inflammation, and macronutrient disposal rates. If successful, the proposed studies will have great potential to influence clinical practices in MHD patients because the proposed intervention protocol would be easily accessible and could ultimately lead to improvements in the hospitalization and death rates with great impact on Veterans' Health Care and make important contributions to the research mission of the Department of Veterans Administration.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: William Lawson, MD; Phone Number: (615) 322-3412; Email: william.lawson@vumc.org
• Study Contact Backup: Name: Talat A Ikizler, MD; Phone Number: (615) 327-4751; Email: Talat.Ikizler@va.gov

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37212-2637
      • Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• On MHD for more than 6 months
• Have acceptable dialysis adequacy (eKt/V > 1.2) for a minimum of 3 months and a patent, well-functioning, hemodialysis AV access
• Ability to give informed consent

Exclusion Criteria:

• Pregnancy
• Intolerance to the medication in metabolic studies)
• Presence of a metal object in the body that might interfere with MRI
• Severe, unstable, active, or chronic inflammatory disease (active infection, active connective tissue disorder, active cancer or cancer history in the prior 5 years, HIV, liver disease, active chronic hepatitis B or C)
• Type 1 Diabetes on insulin therapy; Hospitalization within 1 month prior to the study
• Receiving steroids (including inhaled steroid and high potency topical, with the exception of over the counter hydrocortisone cream
• Prednisone > 5 mg/day) and/or other immunosuppressive agents
• Residual renal function > 5ml/min or urine output > 400 ml/day

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High Dialysate Na; high dialysate sodium concentration (138 mEq/L)	Other: high dialysate sodium concentration (138 mEq/L); high dialysate sodium concentration (138 mEq/L)
Active Comparator: Low Dialysate Na; Low dialysate sodium concentration (132 mEq/L)	Other: Low dialysate sodium concentration; low dialysate sodium concentration (132 mEq/L)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Net whole-body muscle protein balance measured by stable isotope technique reported as mg/kg.fat free mass/min	Net whole-body muscle protein balance measured by stable isotope technique reported as mg/kg.fat free mass/min. This reflects the balance between endogenous leucine appearance rate (protein synthesis), the leucine oxidation rate, and the non-oxidative leucine disappearance rate (protein breakdown).	4 weeks
Net skeletal muscle protein balance measured by stable isotope technique reported as g/100 ml/min	Net skeletal muscle protein balance measured by stable isotope technique reported as g/100 ml/min. This reflects the dilution and enrichment of phenylalanine across the forearm. Because phenylalanine is neither synthesized nor metabolized by skeletal muscle, rate of appearance (Ra) of unlabeled phenylalanine reflects muscle protein breakdown, whereas the rate of disappearance (Rd) of labeled phenylalanine estimates muscle protein synthesis. the difference between synthesis and breakdown provides net skeletal muscle protein balance at a given rate of blood flow.	4 weeks
Muscle sodium content	Muscle sodoium content measured by NAMRI before and after intervention	4 weeks
Skin sodium content	Skin sodium content measured by NAMRI before and after intervention	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Handgrip strength measured by dynamometer	Handgrip strength (HGS) will be measured on the non stula side before dialysis session using a Jamar hydraulic dynamometer.	4 weeks
Recovery time	Patients will be asked how long it took them to recover completely from the preceding session	4 weeks
Pulse Wave Velocity	Pulse Wave Velocity will be measured by Sphygmocor.	4 weeks
Interleukin 6	proinflammatory cytokine IL6 will be measured as a inflammatory marker	4 weeks
Sit to stand test	measurement of how many sit to stands can be accomplished at a given time period to assess physical function	4 weeks
Short Physical Performance Battery	Balance, gait speed and chair speed tests will be scored to provide a complete score to assess physical function	4 weeks
6-minute walk	measurement of how long can a patient walk within 6 minutes to assess physical function	4 weeks
hsCRP	hsCRP will be measured as a marker of systemic inflammation	4 weeks
Interleukin 1	Proinflammatory cytokine Interleukin 1 (IL1) will be measured as a inflammatory marker	4 weeks

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Talat A Ikizler, MD, Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2022
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): June 28, 2024

Study Registration Dates

• First Submitted: August 19, 2019
• First Submitted That Met QC Criteria: August 22, 2019
• First Posted (Actual): August 26, 2019

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: MRI; dialysis; ESRD; hemodialysis
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Disease Attributes; Renal Insufficiency; Hyperinsulinism; Renal Insufficiency, Chronic; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Inflammation; Kidney Failure, Chronic; Insulin Resistance; Pharmaceutical Solutions; Dialysis Solutions
• Other Study ID Numbers: NEPH-010-18F

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No