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

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ClinicalTrials.gov Identifier: NCT02502071
Recruitment Status : Completed
First Posted : July 20, 2015
Results First Posted : November 20, 2018
Last Update Posted : November 20, 2018
Sponsor:
Information provided by (Responsible Party):
Petter Bjornstad, University of Colorado Denver School of Medicine Barbara Davis Center

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
Type 1 Diabetes Diabetic Nephropathy Diabetic Kidney Disease 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 45 participants
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 : January 2017
Actual Primary Completion Date : July 2017
Actual Study Completion Date : August 2017

Resource links provided by the National Library of Medicine


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 Name: NaHCO3




Primary Outcome Measures :
  1. Change in Urine Uric Acid Concentration (Increased Solubility) by Assay [ Time Frame: Day 1 (pre-therapy) and Day 2 (post-therapy) ]
  2. Change in Number of Participants With Urine Uric Acid Precipitation by Polarized Microscopy [ Time Frame: Day 1 (pre-therapy) and Day 2 (post-therapy) ]


Information from the National Library of Medicine

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

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02502071


Locations
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United States, Colorado
Barbara Davis Center for Diabetes
Aurora, Colorado, United States, 80045
Sponsors and Collaborators
University of Colorado Denver School of Medicine Barbara Davis Center
  Study Documents (Full-Text)

Documents provided by Petter Bjornstad, University of Colorado Denver School of Medicine Barbara Davis Center:

Publications:

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Responsible Party: Petter Bjornstad, Fellow, University of Colorado Denver School of Medicine Barbara Davis Center
ClinicalTrials.gov Identifier: NCT02502071     History of Changes
Other Study ID Numbers: 15-0541
First Posted: July 20, 2015    Key Record Dates
Results First Posted: November 20, 2018
Last Update Posted: November 20, 2018
Last Verified: November 2018

Additional relevant MeSH terms:
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Kidney Diseases
Diabetes Mellitus, Type 1
Diabetic Nephropathies
Urologic Diseases
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Diabetes Complications
Uric Acid
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs