Diabetes is the most common cause of end-stage renal disease (ESRD) in the US. In patients with type 2 diabetes mellitus (T2DM), persistent inflammation underpins the progression of chronic kidney disease (CKD) to ESRD and the associated cardiovascular disease. Linagliptin is an oral anti-hyperglycemic agent that has anti-inflammatory, anti-proteinuric, and cardio-renal protective properties. The human gut harbors 1014 bacteria, and gut microbial imbalance has been linked to inflammation, insulin resistance, and atheroscleroisis. Prebiotic oligofructose enriched inulin (p-inulin) has been shown to restore gut microbial balance, thereby reducing endotoxin generation and attenuating inflammation. In a two-by-two factorial clinical trial we will randomize 120 T2DM-CKD patients to receive linagliptin/p-inulin/placebo daily for 12 months. First, we will demonstrate the feasibility of recruitment, randomization, and retention of study participants to record endpoints in at least 90 percent of participants. Secondly, we will establish the efficacy of linagliptin and p-inulin in reducing systemic inflammation. We will study the change in plasma levels of endotoxin and selected markers of inflammation with treatment. Alterations in gut microbial flora will be determined using quantitative real time-PCR. Thirdly, we propose to evaluate the effect of treatment with linagliptin and p-inulin on selected exploratory clinical end- points. We will evaluate the rate of decline of kidney function using the slope of estimated glomerular filtration rate and plasma cystatin level. The change in proteinuria will also be quantitated. Progression/regression of atherosclerosis will be studied using state of art phase-sensitive dual inversion recovery magnetic resonance spectroscopy (MR) imaging. We will determine left ventricular mass and function using a highly innovative MR imaging technique. This novel pilot study will prove the concept, establish feasibility, and generate preliminary data to justify the launching of a full-clinical trial.

Public Health Relevance

Toxins produced by the intestinal bacteria may be an important cause for inflammation in patients with type 2 diabetes mellitus and chronic kidney disease. We propose that treatment with the diabetic medication, linagliptin and prebiotic inulin will decrease inflammation and slow the progression of chronic kidney disease as well as lower cardiovascular disease in patients with diabetic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK099924-02
Application #
8733681
Study Section
Special Emphasis Panel (ZDK1-GRB-N (M6))
Program Officer
Flessner, Michael Francis
Project Start
2013-09-16
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$366,407
Indirect Cost
$117,863
Name
George Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
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Ramezani, Ali; Massy, Ziad A; Meijers, Björn et al. (2016) Role of the Gut Microbiome in Uremia: A Potential Therapeutic Target. Am J Kidney Dis 67:483-98
Barrows, Ian R; Ramezani, Ali; Raj, Dominic S (2015) Gut Feeling in AKI: The Long Arm of Short-Chain Fatty Acids. J Am Soc Nephrol 26:1755-7
Ramezani, Ali; Barrows, Ian R; Raj, Dominic S (2015) Electroacupuncture therapy for muscle atrophy in CKD: is there a needle in the haystack? J Am Soc Nephrol 26:510-2
Velasquez, Manuel T; Ramezani, Ali; Raj, Dominic S (2015) Urea and protein carbamylation in ESRD: surrogate markers or partners in crime? Kidney Int 87:1092-4
Jose, Pedro A; Raj, Dominic (2015) Gut microbiota in hypertension. Curr Opin Nephrol Hypertens 24:403-9
Isakova, Tamara; Ix, Joachim H; Sprague, Stuart M et al. (2015) Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD. J Am Soc Nephrol 26:2328-39
Gupta, Jayanta; Dominic, Elizabeth A; Fink, Jeffrey C et al. (2015) Association between Inflammation and Cardiac Geometry in Chronic Kidney Disease: Findings from the CRIC Study. PLoS One 10:e0124772
Poesen, Ruben; Ramezani, Ali; Claes, Kathleen et al. (2015) Associations of Soluble CD14 and Endotoxin with Mortality, Cardiovascular Disease, and Progression of Kidney Disease among Patients with CKD. Clin J Am Soc Nephrol 10:1525-33
Ramezani, Ali; Devaney, Joseph M; Cohen, Scott et al. (2015) Circulating and urinary microRNA profile in focal segmental glomerulosclerosis: a pilot study. Eur J Clin Invest 45:394-404

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