COFFEE: Evaluation of Coffee Therapy for Improvement of Renal Oxygenation

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT03878277
• Collaborator: Johns Hopkins University (Other)
• Enrollment: 10
• Location: 1
• Arm: 1
• Actual Duration (Months): 27
• Patients Per Site Per Month: 0.4

Study Details

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
• 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: Jul 1, 2019
• Actual Primary Completion Date: Jan 21, 2020
• Actual Study Completion Date: Sep 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 [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 [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 [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 [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 [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

Criteria

• Ages Eligible for Study: 12 Years to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	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)

• Study Protocol and Statistical Analysis Plan - Feb 3, 2019

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT03878277
• Other Study ID Numbers: 18-1874
• First Posted: Mar 18, 2019
• Last Update Posted: Feb 15, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• 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

Study Results

Participant Flow

Arm/Group Title	Cold Brew Coffee
Arm/Group Description	6 days of drinking 1 bottle of Starbucks® Cold brew 325ml [205 mg caffeine] every morning between 6am-9am. 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
Period Title: Overall Study
STARTED	10
COMPLETED	10
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Cold Brew Coffee
Arm/Group Description	6 days of drinking 1 bottle of Starbucks® Cold brew 325ml [205 mg caffeine] every morning between 6am-9am. 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
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	18.5 (2.6)
Sex: Female, Male (Count of Participants)
Female	4 40%
Male	6 60%
Race/Ethnicity, Customized (Count of Participants)
White non-Hispanic	10 100%

Outcome Measures

1. Primary Outcome

Title	Renal Oxygenation
Description	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).
Time Frame	1 hour

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cold Brew Coffee
Arm/Group Description	6 days of drinking 1 bottle of Starbucks® Cold brew 325ml [205 mg caffeine] every morning between 6am-9am. 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
Measure Participants	10
Before cold brew	22.4 (1.5)
After cold brew	22.5 (2.1)

2. Primary Outcome

Title	Renal Perfusion
Description	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.
Time Frame	1 hour

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cold Brew Coffee
Arm/Group Description	6 days of drinking 1 bottle of Starbucks® Cold brew 325ml [205 mg caffeine] every morning between 6am-9am. 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
Measure Participants	10
Before cold brew (Right kidney ASL)	3.02 (0.67)
After cold brew (Right kidney ASL)	3.03 (0.62)
Before cold brew (Left kidney ASL)	3.15 (0.50)
After cold brew (Left kidney ASL)	3.03 (0.72)

3. Secondary Outcome

Title	Glomerular Filtration Rate
Description	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.
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cold Brew Coffee
Arm/Group Description	6 days of drinking 1 bottle of Starbucks® Cold brew 325ml [205 mg caffeine] every morning between 6am-9am. 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
Measure Participants	10
Before cold brew	3.25 (0.47)
After cold brew	3.27 (0.80)

4. Secondary Outcome

Title	Effective Renal Plasma Flow
Description	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.
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cold Brew Coffee
Arm/Group Description	6 days of drinking 1 bottle of Starbucks® Cold brew 325ml [205 mg caffeine] every morning between 6am-9am. 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
Measure Participants	10
Before cold brew	13.08 (1.58)
After cold brew	13.02 (0.67)

5. Secondary Outcome

Title	Tubular Injury Markers
Description	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.
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cold Brew Coffee
Arm/Group Description	6 days of drinking 1 bottle of Starbucks® Cold brew 325ml [205 mg caffeine] every morning between 6am-9am. 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
Measure Participants	10
Before cold brew (cystatin C)	0.82 (0.18)
After cold brew (cystatin C)	0.84 (0.19)

Adverse Events

Time Frame	During the duration of trial with cold brew (7 days) as well as 24 hours after the last study visit.
Arm/Group Title	Cold Brew Coffee
Arm/Group Description	6 days of drinking 1 bottle of Starbucks® Cold brew 325ml [205 mg caffeine] every morning between 6am-9am. 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
All Cause Mortality
	Cold Brew Coffee
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Serious Adverse Events
	Cold Brew Coffee
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Other (Not Including Serious) Adverse Events
	Cold Brew Coffee
	Affected / at Risk (%)	# Events
Total	1/10 (10%)
Vascular disorders
Vasovagal syncope	1/10 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.