Pathophysiology of Uric Acid Nephrolithiasis

The study will use a combination of cell culture, animal, and human studies employing some of
the latest technologies in magnetic resonance spectroscopy and single-photon emission
computed tomography, combined with classical physiology, biochemistry, and molecular biology
to test four interrelated hypotheses. There is increased uptake of free fatty acids into the
kidney as a result of higher circulating levels as well as preferential transport by the
proximal tubule as part of a "conditioning" effect. The increased provision of free fatty
acid supplies metabolic substrate for ATP generation hence reducing the consumption of other
substrates such as glutamine, which is the principal source of ammoniagenesis by the proximal
tubule. This substrate competition, or metabolic switch, can lower the formation of the major
urinary buffer ammonia, even in the absence of injury to the proximal tubule. With sustained
lipid loading of the proximal tubule that exceeds its oxidative capacity, lipid storage is
first activated but with time, toxic lipid metabolites may build up. We have evidence that
excess saturated fat, which is prevalent in the Western diet, leads to proximal tubule
lipotoxicity manifested as endoplasmic reticulum (ER) leakage/stress, and we propose that
defective ammoniagenesis is part of a broader lipotoxic phenotype. We further propose that
accumulation of a specific lipid species may be responsible for the toxicity. To test whether
proximal tubule steatosis and lipotoxicity in humans have a functional consequence, we will
study uric acid stone formers. Having previously shown that thiazolidinediones (TZD) reduce
renal steatosis and lipotoxicity and improve ammonium excretion in animals, we have initiated
a randomized intervention trial with TZD or placebo in human uric acid stone formers. The
interim analysis showed that after 6 months of TZD therapy, stone formers had improved
urinary biochemical parameters and reduced propensity for uric acid precipitation. We will
continue this trial but add a novel highly sensitive method to non-invasively measure renal
fat, testing whether improvement in urinary biochemistry associates with reduction of renal
fat. This proposal addresses fundamental concepts of renal tubular lipid biology and
lipotoxicity, and clinically will shift the paradigm of uric acid stone therapy from empiric
urinary alkalinization to specific reduction in renal fat. We will also introduce
cutting-edge human imaging studies for kidney research.

Inclusion Criteria:

- Subjects with uric acid kidney stone disease

- Age > 21 years

Exclusion Criteria:

- Body weight> 350 lb

- Chronic alcohol use

- Chronic liver disease

- Chronic renal disease

- Anemia

- Contraindication to pioglitazone use:

- history of congestive heart failure NYHA class III or IV

- significant pedal edema

- liver failure

- not willing to practice an effective contraception for the duration of the study

- Thiazolidinedione use in the preceding 18 months