Effect of Urinary Alkalinization on Urine Uric Acid Precipitation and Crystallization in Adults With Type 1 Diabetes
Condition: Type 1 Diabetes; Diabetic Nephropathy; Diabetic Kidney Disease
MeSH terms: Kidney Diseases; Diabetic Nephropathies; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): sodium bicarbonate
Intervention type(s): Drug
Intervention description(s): All participants will receive 2 doses of 1950mg sodium bicarbonate
Other intervention name(s): NaHCO3
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment