Evaluation of Coffee Therapy for Improvement of Renal Oxygenation (COFFEE)

• ClinicalTrials.gov Identifier: NCT03878277
• Recruitment Status: Completed
• First Posted: March 18, 2019
• Results First Posted: August 31, 2021
• Last Update Posted: February 15, 2022
• Sponsor: University of Colorado, Denver
• Collaborator: Johns Hopkins University
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

Brief Summary:

Over 1.25 million Americans have Type 1 Diabetes (T1D), increasing risk for early death from cardiovascular disease (CVD). Despite advances in glycemic and blood pressure control, a child diagnosed with T1D is expected to live up to 17 years less than non-diabetic peers. The strongest risk factor for CVD and mortality in T1D is diabetic kidney disease (DKD). Current treatments, such as control of hyperglycemia and hypertension, are beneficial, but only partially protect against DKD. This limited progress may relate to a narrow focus on clinical manifestations of disease, rather than on the initial metabolic derangements underlying the initiation of DKD. Renal hypoxia, stemming from a potential metabolic mismatch between increased renal energy expenditure and impaired substrate utilization, is increasingly proposed as a unifying early pathway in the development of DKD. T1D is impacted by several mechanisms which increase renal adenosine triphosphate (ATP) consumption and decrease ATP generation.

Caffeine, a methylxanthine, is known to alter kidney function by several mechanisms including natriuresis, hemodynamics and renin-angiotensin-aldosterone system. In contrast, to other natriuretic agents, caffeine is thought to fully inhibit the local tubuloglomerular feedback (TGF) response to increased distal sodium delivery. This observation has broad-ranging implications as caffeine can reduce renal oxygen (O2) consumption without impairing effective renal plasma flow (ERPF) and glomerular filtration rate (GFR).

There are also data suggesting that chemicals in coffee besides caffeine may provide important cardio-renal protection. Yet, there are no data examining the impact of coffee-induced natriuresis on intrarenal hemodynamic function and renal energetics in youth-onset T1D. Our overarching hypothesis in the proposed pilot and feasibility trial is that coffee drinking improves renal oxygenation by reducing renal O2 consumption without impairing GFR and ERPF. To address these hypotheses, we will measure GFR, ERPF, renal perfusion and oxygenation in response to 7 days of cold brew coffee (one Starbucks® Cold brew 325ml bottle daily [205mg caffeine]) in an open-label pilot and feasibility trial in 10 adolescents with T1D already enrolled in the CASPER Study (PI: Bjornstad).

Condition or disease	Intervention/treatment	Phase
Type1diabetes; Type1 Diabetes Mellitus; Diabetic Kidney Disease; Juvenile Diabetes; Diabetic Nephropathies; Diabetes Complications; Diabetes, Autoimmune	Drug: Starbucks® Cold brew - 325ml bottle	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Coffee, Renal Oxygenation, Blood Flow and Glomerular Filtration Rate in Early Diabetic Kidney Disease.
• Actual Study Start Date: July 1, 2019
• Actual Primary Completion Date: January 21, 2020
• Actual Study Completion Date: September 30, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cold Brew Coffee; 6 days of drinking 1 bottle of Starbucks® Cold brew 325ml [205 mg caffeine] every morning between 6am-9am.	Drug: Starbucks® Cold brew - 325ml bottle; Starbucks® Cold brew 325ml bottles daily [205mg caffeine] will be provided to the participants. Participants will be instructed to drink 1 bottle every morning between 6 and 9 am for 6 days prior to the post-intervention visit. The 7th day is the post-intervention visit, and participants will be asked to drink 1 bottle the morning of the study visit

Outcome Measures

Primary Outcome Measures :

1. Renal Oxygenation [ Time Frame: 1 hour ]

   Measured by blood oxygen level dependent (BOLD MRI), before and after Lasix injection;Regions of interest (ROI) analysis for BOLD MRI will be performed on a Leonardo Workstation (Siemens Medical Systems, Germany). Typically, 1 to 3 regions in each, cortex and medulla, per kidney per slice will be defined leading to a total of about 10 ROIs per region (cortex and medulla) per subject. The mean and standard deviation of these 10 measurements will be used a R2* measurement for the region, for the subject and for that time point. Additionally, two (delta) R2*s will be calculated as defined below:

   (delta) R2*(medulla, furosemide) = R2* (medulla, pre-furosemide) - R2* (medulla, post-furosemide); (delta) R2*(cortex, medulla) = Baseline R2* (medulla) - Baseline R2* (cortex).

2. Renal Perfusion [ Time Frame: 1 hour ]
   Measured by pseudocontinuous arterial spin labeling (pCASL) MRI; ROI analysis will be used to estimate (delta) M (difference in signal intensity between non-selective and selective inversion images). Using the same ROI, M0 will be estimated from the proton density image. T1 measurements from the same ROI will be obtained by fitting the signal intensity vs. inversion time data as described previously (104) using XLFit (ID Business Solutions Ltd., UK) or T1 maps created using MRI Mapper (Beth Israel Deaconess Medical Center, Boston). Partition coefficient will be assumed to be 0.8 ml/gm (105, 106). These values will then be used to estimate regional blood flow.

Secondary Outcome Measures :

1. Glomerular Filtration Rate [ Time Frame: 4 hours ]
   Measured by Iohexol clearance; An intravenous (IV) line was placed, and participants were asked to empty their bladders. Spot plasma and urine samples were collected prior to iohexol infusion. Iohexol was administered through bolus IV injection (5 mL of 300 mg/mL; Omnipaque 300, GE Healthcare). An equilibration period of 120 min was used and blood collections for iohexol plasma disappearance were drawn at +120, +150, +180, +210, +240 min (11). Because the Brøchner-Mortensen equation underestimates high values of GFR, the Jødal-Brøchner-Mortensen equation was used to calculate the GFR (12). We report absolute GFR (mL/min) and RPF (mL/min) in the main analyses because the practice of indexing GFR and RPF for body surface underestimates hyperfiltration and hyperperfusion (14), and body surface area (BSA) calculations introduce noise into the clearance measurements.
2. Effective Renal Plasma Flow [ Time Frame: 4 hours ]
   Measured by para-aminohippurate (PAH) clearance; An intravenous (IV) line was placed, and participants were asked to empty their bladders. Spot plasma and urine samples were collected prior PAH infusion. PAH (2 g/10 mL, prepared at the University of Minnesota, with a dose of [weight in kg]/75 × 4.2 mL; IND #140129) was given slowly over 5 min followed by a continuous infusion of 8 mL of PAH and 42 mL of normal saline at a rate of 24 mL/h for 2 h. After an equilibration period, blood was drawn at 90 and 120 min, and RPF was calculated as PAH clearance divided by the estimated extraction ratio of PAH, which varies by the level of GFR (13). We report absolute GFR (mL/min) and RPF (mL/min) in the main analyses because the practice of indexing GFR and RPF for body surface underestimates hyperfiltration and hyperperfusion (14), and body surface area (BSA) calculations introduce noise into the clearance measurements.
3. Tubular Injury Markers [ Time Frame: 4 hours ]
   Measured by markers of kidney injury in plasma; Cystatin C (mg/L) was measured by immunoturbidimetric method (Kamiya Biomedical) by our Clinical Translational Research Center Core Laboratory.

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Youth with T1D (antibody +) with <10 year duration
• Age 12-21 years
• Weight >57 lbs and <350 lbs
• BMI >5th %ile
• HbA1c <12%
• Previous exposure to caffeine

Exclusion Criteria:

• Anemia
• Allergy to shellfish or iodine
• Severe illness, recent diabetic ketoacidosis (DKA)
• Tachyarrhythmias, Attention-deficit/hyperactivity disorder (ADHD), tremors, tics, Tourette's, arrythmias, insomnia, overactive bladder
• Estimated Glomerular Filtration Rate (eGFR) <60 ml/min/1.73 m2 or creatinine > 1.5 mg/dl or history of albumin-to-creatinine ratio (ACR) >300 mg/g
• MRI Scanning contraindications (claustrophobia, implantable metal devices that are non-MRI compatible, >350 lbs)
• Pregnancy or nursing
• (Angiotensin-converting enzyme) ACE inhibitors, angiotensin receptor blockers (ARBs), diuretics, sodium-glucose co-transport (SGLT) 2 or 1 blockers, daily NSAIDs or aspirin, sulfonamides, thiazolsulfone or probenecid, atypical antipsychotics, steroids

Contacts and Locations

Locations

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

Sponsors and Collaborators

University of Colorado, Denver

Johns Hopkins University

Investigators

• Principal Investigator: Petter Bjornstad, MD; University of Colorado Denver | Anschutz

  Study Documents (Full-Text)

Documents provided by University of Colorado, Denver:

Study Protocol and Statistical Analysis Plan  [PDF] February 3, 2019

More Information

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT03878277
• Other Study ID Numbers: 18-1874
• First Posted: March 18, 2019
• Results First Posted: August 31, 2021
• Last Update Posted: February 15, 2022
• Last Verified: January 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Kidney Diseases; Diabetic Nephropathies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Complications; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Urologic Diseases; Autoimmune Diseases; Immune System Diseases