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Alk-UA: Effect of Urinary Alkalinization on Urine Uric Acid Precipitation and Crystallization in Adults With Type 1 Diabetes

Sponsor
University of Colorado, Denver (Other)
Overall Status
Completed
CT.gov ID
NCT02502071
Collaborator
(none)
45
Enrollment
1
Location
1
Arm
7
Duration (Months)
6.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether alkalinization of urine uric acid by 2 doses of sodium bicarbonate (1950mg) over 24-hours reduces precipitation and crystallization of urine uric acid over in adults with type 1 diabetes.

Condition or Disease Intervention/Treatment Phase
  • Drug: sodium bicarbonate
 Phase 4

Detailed Description

Diabetic nephropathy is characterized not only by glomerular disease but also tubulointerstitial injury. The tubular changes associated with diabetic nephropathy, include basement membrane thickening, tubular hypertrophy, epithelial-mesenchymal transition, glycogen accumulation and interstitial inflammation. Although glomerular changes has received significantly more attention from researchers and clinicians than tubulointerstitial changes in diabetes, tubular injury is known to associate better with renal function than glomerular injury. In fact, tubular proteinuria may precede microalbuminuria with type 1 diabetes, suggesting that tubular damage may be induced earlier than glomerular injury in the course of diabetic nephropathy.

Serum uric acid (SUA) is lower in adolescents and adults with type 1 diabetes compared to non-diabetic peers. Despite lower levels SUA remains an important risk factor for diabetic nephropathy in type 1 diabetes, with a large clinical trial underway examining the ability of allopurinol to prevent early renal loss. Several mechanisms have been proposed to explain the lower levels of SUA in type 1 diabetes including glucosuria induced uricosuria leading to spilling of urine uric acid (UUA) and lowering of SUA, and the notion that intracellular uric acid (IUA) and/ or UUA rather than SUA may be responsible for the development of complications. Animal studies have demonstrated that blocking uric acid production protects the kidney from tubulointerstitial injury, which suggests a causal role for uric acid in the development of diabetic tubular injury. Relative dehydration, secondary to glucosuria, exercise or inadequate liquid intake, may lead to concentrated and acidic urine, which may cause UUA to precipitate and crystallize in type 1 diabetes. The UUA precipitation and crystallization is thought to induce inflammation and injury of the tubules with possible retrograde glomerular injury. Moreover, it was recently shown that UUA promoted apoptosis in human proximal tubular cells by oxidative stress and activation of NADPH Oxidase NOX 4.

Oral alkali replacements are readily available, safe and include the following formulations sodium bicarbonate, BiCitra (sodium citrate and citric acid), PolyCitra (citric acid, sodium citrate, and potassium citrate), polycitra-K (potassium citrate and citric acid). In contrast to sodium bicarbonate, citrate is converted to bicarbonate in the liver and thus this conversion is affected by liver disease. Usual adult doses for urinary alkalinization are 325 to 2000 mg orally 1 to 4 times a day. One gram provides 12 mEq (mmoL) each of sodium and bicarbonate, and is titrated to a goal of urine pH of 8.0. In a prospective open-label trial 4 g of sodium bicarbonate was administered orally 3 times daily to 9 healthy volunteers for 24 hours, and after 10 hours all participants had a urine pH ≥ 7 and after 20 hours all participants had urine pH ≥ 8. No adverse effects or abnormal blood results were documented during the 24-hour follow-up. Urinary alkalinization should solubilize UUA thereby increasing the concentration of uric acid in urine and decreasing precipitation and crystallization of UUA. It is unknown whether alkalinization of urine reduces UUA precipitation and crystallization in type 1 diabetes.

With diabetic nephropathy being the leading cause of end-stage renal disease in the Western world, it is critical to develop a better understanding of the determinants of risk and progression of early diabetic nephropathy, to improve outcomes in patients with type 1 diabetes. UUA is a particularly attractive therapeutic target due to the potential to reduce tubular injury with sodium bicarbonate. Accordingly, the investigators propose a pilot experimental study examining the effect of urine alkalinization with oral sodium bicarbonate on UUA precipitation and crystallization in adults with type 1 diabetes.

Study Design

Study Type:
Interventional
Actual Enrollment :
45 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Effect of Urinary Alkalinization on Urine Uric Acid Precipitation and Crystallization in Adults With Type 1 DiabetesL a Open-label Trial
Study Start Date :
Jan 1, 2017
Actual Primary Completion Date :
Jul 1, 2017
Actual Study Completion Date :
Aug 1, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Sodium Bicarbonate

All participants will receive 2 doses of 1950mg Sodium Bicarbonate

Drug: sodium bicarbonate
All participants will receive 2 doses of 1950mg sodium bicarbonate
Other Names:
  • NaHCO3

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Change in Urine Uric Acid Concentration (Increased Solubility) by Assay [Day 1 (pre-therapy) and Day 2 (post-therapy)]

      Urine uric acid were evaluated using a QuantiChrom UA kit assay (DIUA-250) with quantitative colorimetric UA determination at 590 nm (BioAssay System, California, USA).

    2. Change in Number of Participants With Urine Uric Acid Precipitation by Polarized Microscopy [Day 1 (pre-therapy) and Day 2 (post-therapy)]

      Urine uric acid crystals were identified by polarized microscopy (Polarized light imaging Zeiss Axiovert 135; 0.3NA objective), and pictures were captured from each urine sample. UA crystals were defined dichotomously as being present or absent.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 45 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Adults (aged 18-45 years) with type 1 diabetes

    • Participants must be able to be fasting prior to study visit and give informed consent.

    Exclusion Criteria:

    • Non-type 1 diabetes

    • History of eGFR <60 ml/min/1.73m2 or microalbuminuria or greater

    • History of hypocalcemia or at risk of hypocalcemia

    • Taking allopurinol or uric acid altering medications

    • Ketogenic diet

    • Ketonuria

    • Taking phosphorus binders (e.g. sevelamer)

    • Pregnant or breastfeeding

    • Taking the following medications which may interact with sodium bicarbonate (e.g. phentermine, pseudoephedrine, antifungal medication, cephalosporin antibiotics [e.g. Keflex], tetracycline antibiotics [e.g. doxycycline], steroids or lithium)

    • Taking SGLT-2 inhibitors

    • Taking blood pressure medications

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Barbara Davis Center for Diabetes Aurora Colorado United States 80045

    Sponsors and Collaborators

    • University of Colorado, Denver

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    University of Colorado, Denver
    ClinicalTrials.gov Identifier:
    NCT02502071
    Other Study ID Numbers:
    • 15-0541
    First Posted:
    Jul 20, 2015
    Last Update Posted:
    Jan 24, 2022
    Last Verified:
    Jan 1, 2022
    Additional relevant MeSH terms:
    Kidney Diseases
    Diabetic Nephropathies
    Diabetes Mellitus, Type 1

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Sodium Bicarbonate
    Arm/Group Description All participants will receive 2 doses of 1950mg Sodium Bicarbonate sodium bicarbonate: All participants will receive 2 doses of 1950mg sodium bicarbonate
    Period Title: Overall Study
    STARTED 45
    COMPLETED 45
    NOT COMPLETED 0

    Baseline Characteristics

    Arm/Group Title Sodium Bicarbonate
    Arm/Group Description All participants will receive 2 doses of 1950mg Sodium Bicarbonate sodium bicarbonate: All participants will receive 2 doses of 1950mg sodium bicarbonate
    Overall Participants 45
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    33.6
    (8.5)
    Sex: Female, Male (Count of Participants)
    Female
    27
    60%
    Male
    18
    40%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    Not Hispanic or Latino
    45
    100%
    Unknown or Not Reported
    0
    0%
    Type 1 Diabetes Duration (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    20.2
    (9.3)

    Outcome Measures

    1. Primary Outcome
    Title Change in Urine Uric Acid Concentration (Increased Solubility) by Assay
    Description Urine uric acid were evaluated using a QuantiChrom UA kit assay (DIUA-250) with quantitative colorimetric UA determination at 590 nm (BioAssay System, California, USA).
    Time Frame Day 1 (pre-therapy) and Day 2 (post-therapy)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sodium Bicarbonate
    Arm/Group Description All participants will receive 2 doses of 1950mg Sodium Bicarbonate sodium bicarbonate: All participants will receive 2 doses of 1950mg sodium bicarbonate
    Measure Participants 45
    Day 1 (pre-therapy)
    23.81
    Day 2 (post-therapy)
    22.30
    2. Primary Outcome
    Title Change in Number of Participants With Urine Uric Acid Precipitation by Polarized Microscopy
    Description Urine uric acid crystals were identified by polarized microscopy (Polarized light imaging Zeiss Axiovert 135; 0.3NA objective), and pictures were captured from each urine sample. UA crystals were defined dichotomously as being present or absent.
    Time Frame Day 1 (pre-therapy) and Day 2 (post-therapy)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sodium Bicarbonate
    Arm/Group Description All participants will receive 2 doses of 1950mg Sodium Bicarbonate sodium bicarbonate: All participants will receive 2 doses of 1950mg sodium bicarbonate
    Measure Participants 45
    Day 1 (pre-therapy)
    14
    31.1%
    Day 2 (post-therapy)
    3
    6.7%

    Adverse Events

    Time Frame Adverse events were collected while the participant was in the trial (24-36 hours)
    Adverse Event Reporting Description
    Arm/Group Title Sodium Bicarbonate
    Arm/Group Description All participants will receive 2 doses of 1950mg Sodium Bicarbonate sodium bicarbonate: All participants will receive 2 doses of 1950mg sodium bicarbonate
    All Cause Mortality
    Sodium Bicarbonate
    Affected / at Risk (%) # Events
    Total 0/45 (0%)
    Serious Adverse Events
    Sodium Bicarbonate
    Affected / at Risk (%) # Events
    Total 0/45 (0%)
    Other (Not Including Serious) Adverse Events
    Sodium Bicarbonate
    Affected / at Risk (%) # Events
    Total 1/45 (2.2%)
    Endocrine disorders
    Hypoglycemia 1/45 (2.2%) 1

    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.

    Results Point of Contact

    Name/Title Dr. Petter Bjornstad, Assistant Professor
    Organization University of Colorado School of Medicine
    Phone 7207774659
    Email petter.bjornstad@childrenscolorado.org
    Responsible Party:
    University of Colorado, Denver
    ClinicalTrials.gov Identifier:
    NCT02502071
    Other Study ID Numbers:
    • 15-0541
    First Posted:
    Jul 20, 2015
    Last Update Posted:
    Jan 24, 2022
    Last Verified:
    Jan 1, 2022