Randomized Intervention Studies in Human Polycystic Kidney and Liver Disease

Abstract

Autosomal dominant polycystic disease (ADPKD) is the most common life-threatening genetic disease in the United States. ADPKD is more common than Huntington disease, hemophilia, cystic fibrosis, sickle cell disease, Down syndrome, and myotonic dystrophy combined .1 The increase in kidney cyst volume over time correlates with hypertension and progressive renal dysfunction, yet, to date, there is no established intervention to slow or prevent the renal cyst growth. Increased proliferation accompanies renal cyst growth, and recent research in nonorthologous experimental animals and patients with ADPKD suggests aberrant activation of the Ser/Thr kinase mammalian target of rapamycin (mTOR), which modulates cell growth and proliferation.2–5 Recently, rapamycin was shown to have dramatic effects on liver cyst volumes in humans6 and in an orthologous rodent model with conditional inactivation of the PKD1 gene.7 The results demonstrate that mTOR inhibition with rapamycin decreases cyst growth, fibrosis, and proliferation and improves renal function. Of interest, there was regression of cyst burden, which may have been due to increased apoptosis among the cystic epithelium. Perico et al. 8 in this issue of JASN performed a renal safety and efficacy study to examine further this potential pathogenetic ADPKD pathway in humans. This randomized crossover study examined the effect of sirolimus (rapamycin) over 6 months on progression of ADPKD compared with conventional therapy. The main efficacy variable was the effect on total kidney volume, but renal cyst and parenchymal volumes were also measured. The effect of sirolimus on GFR was also examined relative to kidney volume and structure …