In IUAN patients, the investigator will compare 1. PPAR activation; 2. weight loss; or 3.
combination; on urine acid-base parameters relevant to UA stone risk. The investigator
will assess the effect of these interventions on fat distribution, insulin sensitivity,
and serum adiponectin, and correlate these changes with urine chemistry.
Hypothesis: Weight loss + TZD independently result in durable changes in urine chemistry.
Significance: Epidemiology of uric acid nephrolithiasis: Nephrolithiasis is an
increasingly prevalent condition that leads to significant pain1, work productivity
loss2, reduced quality of life3, urinary tract infection4, chronic kidney disease5,6 and
end-stage renal disease7. In the U.S., nephrolithiasis prevalence doubled in the past 30
years to a level similar to diabetes, and is the most expensive non-malignant urologic
condition (2006 U.S. annual cost: $10 billion)8. Compared with other stone types, uric
acid stones recur at a higher rate9, lead to more CKD10, and comprise a rising fraction
of stones11,12 , in part due to the growing prevalence of obesity and diabetes13-18. The
single most important pathogenic factor in human IUAN is an overly acidic urine,
promoting protonation of urate to the insoluble UA16,19. In previously completed
NIH-supported studies, the Investigator identified increased net acid excretion and
blunted ammoniagenesis to be the principal metabolic defects underlying aciduria in
humans IUAN and in rodent models of IUAN risk16,18,20-23. Treatment has been empirical
urinary alkalinization24 which is efficacious but has not changed since 1986. Limitations
include frequent dosing25, need for high dose in obese patients26, medication
intolerance27, and need for periodic urine collections disliked by patients. Therapy that
targets the underlying pathophysiologic defect rather than urinary chemistry is directly
needed. The Investigator showed that the thiazolidinedione (TZD) pioglitazone that
activates PPAR, improves systemic and urinary abnormalities in IUAN including impaired
excessive acid excretion and ammoniagenesis, and results in a rise in UpH. TZD treatment
of rodent IUAN model shows similar improvements28. The Investigator may have a therapy
targeting the underlying pathobiology.
The translational potential of our regimen is extremely high and immediate. If combined
TZD and weight loss (Aim) are efficacious in reducing stone risk, one can move straight
to a clinical trial using hard outcomes such as stone events, and stone count by imaging
to test this regimen. None of these maneuvers requires FDA approval to initiate. Patients
will then have instant control of urinary chemistry with empiric alkali therapy (existing
therapy), but also a chance to achieve more lasting improvement with TZD and weight loss,
which reverses the pathophysiology. Separately, adiponectin (APN) receptor agonists are
being developed as potential pharmacological agents for the management of metabolic
syndrome complications including diabetes and dyslipidemia29,30. If approved, such agents
could be tested as therapy for aciduria in the metabolic syndrome if adiponectin mediates
the impact of TZD on renal ammoniagenesis.
UA nephrolithiasis is the clinically palpable sentinel of some complex underlying
systemic pathophysiology; hence the impact of these studies extends beyond UA stones. The
Investigator is examining a novel multi-organ paradigm of increased acid production from
the gut that escapes hepatic metabolism, and ending up as an acid load imposed on the
kidney. When compounded with renal ammoniagenesis defect, this leads to aciduria and UA
lithogenesis. The Investigator will address some fundamental pathobiologic mechanisms of
the metabolic syndrome. Due to the time and budget limits, the Investigator will
concentrate our efforts to yield informative data; hence the renal focus. Our long-term
goal is to use this as a portal to study multiple aspects of the gut, hepatic, and
adipose pathophysiology of the metabolic syndrome.