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Principal Investigator: TALAT Alp IKIZLER
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2024
Funding agency: Veterans Affairs
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. Our 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. Our 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. Our 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. We 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.
We 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 Aim 1: To test the hypothesis that excessive Na accumulation in the skeletal muscle and
skin leads to local and systemic inflammation that result in resistance to metabolic effects of insulin in MHD
patients. We will achieve this aim by examining tissue Na content and net protein balance (primary outcome),
markers of inflammation and macronutrient (glucose and amino acid) disposal rates and in 60 MHD patients
and 30 frequency matched age, gender, race and body mass index controls without kidney disease. Specific
Aim 2: To test the hypothesis that removal of tissue sodium by modulating hemodialysis prescription would
improve metabolic milieu and protein energy wasting in MHD patients. We 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. Our primary outcomes will be markers of net protein balance, inflammation, and
macronutrient disposal rates. If successful, our 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.
Terms: <Abscission><Acceleration><Age><Amino Acids><BMI><BMI percentile><BMI z-score><Body Tissues><Body mass index><Catabolism><Chronic><Clinical><D-Glucose><Data><Death Rate><Development><Dextrose><Diabetes Mellitus><Dialysis><Dialysis patients><Dialysis procedure><Diet><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Enrollment><Equilibrium><Excision><Extirpation><Frequencies><Future><Gender><Glucose><Goals><Healthcare><Hemodialyses><Hemodialysis><Hour><Humulin R><Hydrogen Oxide><Immune><Immune Cell Activation><Immune system><Immunes><Inflammation><Inflammatory><Inflammatory Response><Insulin><Insulin Resistance><Intake><Intervention><Intervention Strategies><Kidney Diseases><Lead><Link><MR Imaging><MR Tomography><MRI><MRIs><Macronutrients><Macronutrients Nutrition><Magnetic Resonance Imaging><Maintenance><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Metabolic><Mission><Morbidity><Morbidity - disease rate><Muscle><Muscle Tissue><NMR Imaging><NMR Tomography><Na element><Nephropathy><Novolin R><Nuclear Magnetic Resonance Imaging><Nutritional><Obesity><Outcome><Pathogenesis><Pathway interactions><Patients><Pb element><Peripheral><Persons><Pilot Projects><Play><Population><Progress Reports><Proteins><Protocol><Protocols documentation><Quetelet index><Race><Races><Regular Insulin><Removal><Renal Disease><Reporting><Research><Resistance><Risk><Role><Skeletal Muscle><Skin><Skin Tissue><Sodium><Surgical Removal><Testing><Tissues><Transplantation><United States><United States Department of Veterans Affairs><United States Veterans Administration><Veterans><Veterans Administration><Veterans Affairs><Voluntary Muscle><Water><Zeugmatography><adiposity><ages><aminoacid><balance><balance function><clinical practice><cohort><corpulence><cutaneous tissue><developmental><diabetes><dialysis therapy><diets><enroll><health care><heavy metal Pb><heavy metal lead><hospitalization rates><immune activation><improved><inflammation marker><inflammatory marker><innovate><innovation><innovative><insulin resistant><insulin sensitivity><insulin tolerance><interventional strategy><kidney disorder><mortality><mortality rate><mortality ratio><muscular><nutrition><nutritious><pathway><patient population><pharmacologic><pilot study><prevent><preventing><primary outcome><protein metabolism><racial><racial background><racial origin><randomized, clinical trials><renal disorder><resection><resistant><response><social role><systemic inflammation><systemic inflammatory response><transplant><wasting>