Renal cyst growth is attenuated by a combination treatment of tolvaptan and pioglitazone, while pioglitazone treatment alone is not effective

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common monogenic disorders, characterized by the progressive formation of fluid-filled cysts. Tolvaptan is an approved drug for ADPKD patients, but is also associated with multiple side effects. The peroxisome proliferator-activator receptor gamma (PPAR gamma) agonist pioglitazone slows disease progression in the PCK rat model for PKD. Here, we tested whether a combination treatment of relevant doses of tolvaptan and pioglitazone leads to improved efficacy in an adult-onset PKD mouse model. Tolvaptan indeed slowed PKD progression, but the combination treatment was not more effective than tolvaptan alone. In addition, although pioglitazone raised plasma levels of its surrogate drug marker adiponectin, the drug unexpectedly failed to slow PKD progression. The pioglitazone target PPAR. was expressed at surprisingly low levels in mouse, rat and human kidneys. Other pioglitazone targets were more abundantly expressed, but this pattern was comparable across various species. The data suggest that several potential pharmacokinetic and pharmacodynamic (PK/PD) differences between different species may underlie whether or not pioglitazone is able to slow PKD progression. The ongoing phase II clinical trial with low-dose pioglitazone treatment (NCT02697617) will show whether pioglitazone is a suitable drug candidate for ADPKD treatment.Functional Genomics of Systemic Disorder

Preclinical evaluation of tolvaptan and salsalate combination therapy in a Pkd1-mouse model

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder and an important cause of end stage renal disease (ESRD). Tolvaptan (a V2R antagonist) is the first disease modifier drug for treatment of ADPKD, but also causes severe polyuria. AMPK activators have been shown to attenuate cystic kidney disease.Methods: In this study, we tested the efficacy of the combined administration of salsalate (a direct AMPK activator) and tolvaptan using clinically relevant doses in an adult-onset conditional Pkd1 knock-out (KO) mouse model.Results: Compared to untreated Pkd1 mutant mice, the therapeutic effects of salsalate were similar to that of tolvaptan. The combined treatment tended to be more effective than individual drugs used alone, and was associated with improved kidney survival (p < 0.0001) and reduced kidney weight to body weight ratio (p < 0.0001), cystic index (p < 0.001) and blood urea levels (p < 0.001) compared to untreated animals, although the difference between combination and single treatments was not statistically significant. Gene expression profiling and protein expression and phosphorylation analyses support the mild beneficial effects of co-treatment, and showed that tolvaptan and salsalate cooperatively attenuated kidney injury, cell proliferation, cell cycle progression, inflammation and fibrosis, and improving mitochondrial health, and cellular antioxidant response.Conclusion: These data suggest that salsalate-tolvaptan combination, if confirmed in clinical testing, might represent a promising therapeutic strategy in the treatment of ADPKD.Functional Genomics of Systemic Disorder

Effects of immunisation against Theileria parva on beef cattle productivity and economics of control options

Over 500 cattle of all age groups on 2 farms in Zimbabwe were immunised against theileriosis using the "infection and treatment" method and disease prevalence and their productivity assessed during a period of 18 months. The immunising stock, Theileria parva (Boleni) was isolated in Zimbabwe. None of the immunised cattle suffered from theileriosis upon natural exposure whereas 22 unimmunised cattle died of theileriosis and a further 48 required treatment for theileriosis. In the first year, some immunised cattle were maintained with minimal threshold dipping (once or twice during the rainy season). During periods of very high tick challenge of 100 to 1,000 Rhipicephalus appendiculatus per animal from January to March, a transient decrease in liveweight gain was observed particularly in cows. However, by the end of the period of observation, the weights had recovered so that intensively dipped and immunised and threshold or strategically dipped groups of cattle showed no significant differences. From the results it w as estimated that each engorging female R. appendiculatus caused a temporary depression in weight gain of 8 grams. In young stock the weight loss was excerbated by the presence of screw worm (Chrysomya bezziana) infestation. It was then possible to define an economically attrative integrated tick and theileriosis control strategy based on these findings, whereby immunised cattle were dipped 6 times between mid-December and mid-March. In this regimen, no weight loss occurred and no cases of screw worm were observed. For each of 3 herd sizes of 250.000 and 1,000 cattle, comparisons were made of the costs of 4 different control options: 1. Intensive dipping (40 times/year). 2. Intensive pour-on acaricide treatments (18 times/year). 3. Theileria immunisation with strategic dipping (6 times/year). 4. Theileria immunisation with pour-on treatment (4 times/year). It is concluded from these studies that, on farms where theileriosis is a serious problem, immunisation coupled with a strategic dipping programme is economically very attractive. In the year in which immunisation is carried out, costs will be higher than for intensive dipping, but from the second year on, the costs are decreased to approximately 50 percent of those for intensive dipping