Pathophysiology of Uric Acid Nephrolithiasis

Study ID
00000125 - 856

Cancer Related
No

Healthy Volunteers
Yes

Study Sites

  • UT Southwestern-Clinical Translational Research Center (CTRC)
  • Dallas Veteran's Affairs Medical Center
  • UT Southwestern Ambulatory Services
  • Zale Lipshy University Hospital
  • Parkland Health & Hospital System

Contact
Sudeepa Bhattacharya
214/648-0395
sudeepa.bhattacharya@utsouthwestern.edu

Principal Investigator
Khashayar Sakhaee, M.D.

Official Title

Pathophysiology of Uric Acid Nephrolithiasis

Brief Overview


This study has two aims:

Aim 1: To determine the presence of accumulation of fat within cells and the functional
consequences of this in the kidney by correlating kidney fat content with urine test
results.

Aim 2: The investigators will evaluate the effect of thiazolidinedione (pioglitazone) on
excess fatty acid accumulation in kidney tissue and its correlation with uric acid stone
formation in subjects with uric acid stones.

Summary


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.

Participant Eligibility


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