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

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.

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