- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02502071
Effect of Urinary Alkalinization on Urine Uric Acid Precipitation and Crystallization in Adults With Type 1 Diabetes (Alk-UA)
Effect of Urinary Alkalinization on Urine Uric Acid Precipitation and Crystallization in Adults With Type 1 DiabetesL a Open-label Trial
Study Overview
Status
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
Colorado
-
Aurora, Colorado, United States, 80045
- Barbara Davis Center for Diabetes
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Sodium Bicarbonate
All participants will receive 2 doses of 1950mg Sodium Bicarbonate
|
All participants will receive 2 doses of 1950mg sodium bicarbonate
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Urine Uric Acid Concentration (Increased Solubility) by Assay
Time Frame: 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).
|
Day 1 (pre-therapy) and Day 2 (post-therapy)
|
Change in Number of Participants With Urine Uric Acid Precipitation by Polarized Microscopy
Time Frame: 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.
|
Day 1 (pre-therapy) and Day 2 (post-therapy)
|
Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- Drummond K, Mauer M; International Diabetic Nephropathy Study Group. The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. Diabetes. 2002 May;51(5):1580-7. doi: 10.2337/diabetes.51.5.1580.
- Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury? Kidney Int. 1999 Nov;56(5):1627-37. doi: 10.1046/j.1523-1755.1999.00721.x.
- Ginevri F, Piccotti E, Alinovi R, DeToni T, Biagini C, Chiggeri GM, Gusmano R. Reversible tubular proteinuria precedes microalbuminuria and correlates with the metabolic status in diabetic children. Pediatr Nephrol. 1993 Feb;7(1):23-6. doi: 10.1007/BF00861555.
- Bjornstad P, Snell-Bergeon JK, McFann K, Wadwa RP, Rewers M, Rivard CJ, Jalal D, Chonchol MB, Johnson RJ, Maahs DM. Serum uric acid and insulin sensitivity in adolescents and adults with and without type 1 diabetes. J Diabetes Complications. 2014 May-Jun;28(3):298-304. doi: 10.1016/j.jdiacomp.2013.12.007. Epub 2013 Dec 27.
- Bjornstad P, Lanaspa MA, Ishimoto T, Kosugi T, Kume S, Jalal D, Maahs DM, Snell-Bergeon JK, Johnson RJ, Nakagawa T. Fructose and uric acid in diabetic nephropathy. Diabetologia. 2015 Sep;58(9):1993-2002. doi: 10.1007/s00125-015-3650-4. Epub 2015 Jun 7.
- Bjornstad P, Maahs DM, Rivard CJ, Pyle L, Rewers M, Johnson RJ, Snell-Bergeon JK. Serum uric acid predicts vascular complications in adults with type 1 diabetes: the coronary artery calcification in type 1 diabetes study. Acta Diabetol. 2014 Oct;51(5):783-91. doi: 10.1007/s00592-014-0611-1. Epub 2014 Jun 15.
- Maahs DM, Caramori L, Cherney DZ, Galecki AT, Gao C, Jalal D, Perkins BA, Pop-Busui R, Rossing P, Mauer M, Doria A; PERL Consortium. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diab Rep. 2013 Aug;13(4):550-9. doi: 10.1007/s11892-013-0381-0.
- Lytvyn Y, Skrtic M, Yang GK, Yip PM, Perkins BA, Cherney DZ. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol. 2015 Jan 15;308(2):F77-83. doi: 10.1152/ajprenal.00555.2014. Epub 2014 Nov 5.
- Schepers MS, van Ballegooijen ES, Bangma CH, Verkoelen CF. Crystals cause acute necrotic cell death in renal proximal tubule cells, but not in collecting tubule cells. Kidney Int. 2005 Oct;68(4):1543-53. doi: 10.1111/j.1523-1755.2005.00566.x.
- Ryu ES, Kim MJ, Shin HS, Jang YH, Choi HS, Jo I, Johnson RJ, Kang DH. Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease. Am J Physiol Renal Physiol. 2013 Mar 1;304(5):F471-80. doi: 10.1152/ajprenal.00560.2012. Epub 2013 Jan 2.
- Verzola D, Ratto E, Villaggio B, Parodi EL, Pontremoli R, Garibotto G, Viazzi F. Uric acid promotes apoptosis in human proximal tubule cells by oxidative stress and the activation of NADPH oxidase NOX 4. PLoS One. 2014 Dec 16;9(12):e115210. doi: 10.1371/journal.pone.0115210. eCollection 2014.
- Cohen B, Laish I, Brosh-Nissimov T, Hoffman A, Katz LH, Braunstein R, Sagi R, Michael G. Efficacy of urine alkalinization by oral administration of sodium bicarbonate: a prospective open-label trial. Am J Emerg Med. 2013 Dec;31(12):1703-6. doi: 10.1016/j.ajem.2013.08.031. Epub 2013 Sep 20.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 15-0541
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Type 1 Diabetes
-
Poznan University of Medical SciencesUnknownDiabetes Mellitus Type 1 | Remission of Type 1 Diabetes | Chronic Complications of DiabetesPoland
-
Eledon PharmaceuticalsWithdrawnBrittle Type 1 Diabetes MellitusUnited States
-
National Institute of Allergy and Infectious Diseases...PPD; Rho Federal Systems Division, Inc.; Immune Tolerance Network (ITN)CompletedType 1 Diabetes Mellitus | T1DM | T1D | New-onset Type 1 Diabetes MellitusUnited States, Australia
-
Hoffmann-La RocheCompletedType 2 Diabetes, Type 1 DiabetesAustria, United Kingdom
-
Shanghai Changzheng HospitalRecruitingBrittle Type 1 Diabetes MellitusChina
-
Capillary Biomedical, Inc.TerminatedType 1 Diabetes | Type 1 Diabetes Mellitus | Diabetes Mellitus, Type I | Diabetes Mellitus, Insulin-Dependent, 1 | IDDMAustria
-
Capillary Biomedical, Inc.CompletedDiabetes Mellitus, Type 1 | Type 1 Diabetes | Type 1 Diabetes Mellitus | Diabetes Mellitus, Insulin-Dependent, 1Australia
-
AstraZenecaCompletedType 2 Diabetes Mellitus | Type 1 Diabetes MellitusUnited States
-
NYU Langone HealthNational Heart, Lung, and Blood Institute (NHLBI)Recruiting
-
Rabin Medical CenterDreaMed DiabetesTerminated
Clinical Trials on sodium bicarbonate
-
Sheba Medical CenterUnknownExtravasation | InfiltrationIsrael
-
GlaxoSmithKlineCompleted
-
Guy's and St Thomas' NHS Foundation TrustUniversity of PittsburghNot yet recruitingCovid19 | Acute Kidney Injury
-
Prim. Priv. Doz. Dr. Daniel CejkaMedice Arzneimittel Pütter GmbH & Co KGWithdrawnKidney Transplant; ComplicationsAustria
-
Jennifer Gassman, PhDNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); The...CompletedChronic Kidney DiseaseUnited States
-
Lars Wiuff AndersenUniversity of AarhusRecruiting
-
University of UtahThe University of Utah Center on AgingTerminatedChronic Kidney DiseaseUnited States
-
Kaiser PermanenteCompletedKidney Diseases | Contrast Induced NephropathyUnited States
-
Instituto Nacional de Cardiologia Ignacio ChavezUnknownAcute Kidney FailureMexico
-
Wake Forest University Health SciencesCompletedRenal Replacement Therapy | Kidney Failure, AcuteUnited States