PKD: Diabetes Drug Promising in Model of Kidney Disease

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PKD: Diabetes Drug Promising in Model of Kidney Disease
   
   By Crystal Phend, Senior Staff Writer, MedPage Today
November 15, 2010
   
      
   MedPage Today Action Points

    * Explain that pioglitazone, a PPAR-gamma agonist, reduced the burden of renal and liver cysts in a rat model of polycystic kidney disease.


    * Note that there was also a trend toward reduced fibrosis, but the investigators cautioned that further work is needed before the drug should be tried in humans.

   
   Review

The diabetes drug pioglitazone (Actos) shows potential to suppress renal and hepatic cyst growth and fibrosis in an animal model of polycystic kidney disease.

Rats with the genetic disorder showed significantly reduced renal cyst burden with standard and low-dose pioglitazone, and some effects on hepatic cyst burden as well, Bonnie L. Blazer-Yost, PhD, of Indiana University-Purdue University at Indianapolis, and colleagues reported online in PPAR Research.

Pioglitazone is a peroxisome proliferator activator receptor gamma (PPAR-gamma) agonist.

"Currently, the clinical management of polycystic kidney disease is limited to cyst aspiration, surgical resection, or organ transplantation," they wrote in the paper.

However, "it's too early to be trying it in patients" despite the drug's availability on the market for other indications, Blazer-Yost cautioned in an interview. Further animal studies are needed to make sure pioglitazone is safe for this patient population, she explained.

"I think we need to be very careful of liver enzymes because we know that a previous PPAR-gamma agonist was taken off the market for liver toxicity," she told MedPage Today. "In a patient population that may have some compromised liver function, we want to be very careful about testing the effect on the liver before doing patient studies."

Ironically, pioglitazone's well-known risk of fluid retention led to the discovery, the researchers noted.

Animal models suggested that the side effect arises from alterations in electrolyte and fluid transport in the kidney's distal nephrons, which is a pathway implicated in the development of slow-growing fluid-filled cysts in polycystic kidney disease as well.

The researchers used a rat model that simulates human autosomal dominant polycystic kidney disease and, after weaning, added pioglitazone to their food to approximate concentrations of 4 or 20 mg/kg per day.

This protocol was followed independently at the Mayo Clinic over seven weeks with both male and female rats, and at Indiana University-Purdue University Indianapolis over 14 weeks with female rats only.

Compared with a control group fed normal chow without pioglitazone, rats fed the 20-mg/kg dose of pioglitazone showed a significant decrease in renal cyst burden in the male animals after only seven weeks of pioglitazone treatment (0.31 versus 0.72 mL, P=0.04). The female rats showed a similar trend after seven weeks of feeding (P=0.06) and a significant decrease in renal cyst volume after 14 weeks (0.42 versus 0.66 mL among controls, P=0.035).

Hepatic cyst burden was also lowered with pioglitazone, at 20 mg/kg in the female rats at both seven and 14 weeks, but showed no detectable effect after seven weeks on the milder liver cystic disease observed in the males.

The lower 4-mg/kg dose of pioglitazone appeared just as effective as the higher dose in reducing the renal cyst burden in both female and male animals over seven weeks (P=0.016 and P=0.007 versus controls).

Low-dose pioglitazone also decreased liver weight as a percentage of body weight in both female (5.24% versus 5.59%, P=0.043) and male animals (4.42% versus 4.83%, P=0.022).

Pioglitazone also showed trends for reduced renal and hepatic fibrosis, although not consistently across dose, duration, and sex groups, which Blazer-Yost's group called not surprising given the mild fibrosis present in early stages of disease progression in this rat model.

"Possibly because fibrosis is mild at early stages of the disease in this animal model, the antifibrotic effect of pioglitazone was not consistently observed and reached statistical significance in only certain groups," the researchers suggested.

After the animals were sacrificed, imaging showed that the lower cyst burden was predominantly due to smaller cyst size rather than fewer cysts, which the researchers speculated was due to slower cyst growth while on pioglitazone.

The gender differences may have been due to subtle, earlier gender differences in disease progression, they suggested.

The researchers cautioned that the studies differed in methods, particularly with regard to duration of pioglitazone feeding, since they were combined retrospectively.

The study was supported by funds from an IUPUI Research Support Fund Grant and developmental funds from the Department of Pathology and Laboratory Medicine. The research at the Mayo Clinic was supported by funds from Takeda Pharmaceuticals North America.

Blazer-Yost reported being named on a pending patent for use of PPAR-gamma drugs in the treatment of polycystic kidney disease.
Primary source: PPAR Research
Source reference:
Blazer-Yost BL, et al "Pioglitazone attenuates cystic burden in the PCK rodent model of polycystic kidney disease" PPAR Res 2010; DOI: 10.1155/2010/274376.
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