Effect of statin therapy on disease progression in pediatric ADPKD: Design and baseline characteristics of participants

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney condition and is associated with important renal and cardiovascular manifestations in childhood. Renal cystic disease can be documented in some cases as early as in utero. Early intervention is critical if the long-term complications of this condition, including end-stage renal disease, are to be ameliorated. Here we describe our ongoing randomized double-blind placebo-controlled phase III clinical trial to assess the effect of pravastatin treatment on renal and cardiovascular disease progression in 107 children and young adults age 8–22 years with ADPKD who are receiving the angiotensin converting enzyme inhibitor lisinopril. Baseline demographic and laboratory data are provided. Results of this study could markedly impact the standard of care for evaluation and treatment of ADPKD in this population.

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting 1 in 400 to 1000 individuals [1]. It is responsible for approximately 4% of end-stage renal disease (ESRD) in the United States and 8–10% in Europe [1]. ADPKD is caused by mutations in the genes PKD1 or PKD2, which encode polycystin 1 or polycystin 2, respectively. These proteins localize to the primary cilia and appear to interact to detect fluid flow within the renal tubule [2], [3], [4]. While tubular flow in the normal kidney results in bending of cilia and activation of the polycystin flow sensor that allows Ca²⁺ influx into the cell [5], inactivation of the polycystin complex due to PKD1 or PKD2 mutations is believed to result in altered Ca²⁺ homeostasis, thus allowing increased proliferation and apoptosis, altered polarity, and altered secretory properties in ADPKD cells [6]. These abnormalities lead to tubular cyst formation. ADPKD is characterized clinically by the progressive development of kidney cysts with renal enlargement and associated loss of renal function, such that approximately half of patients with PKD1 develop ESRD by 60 years of age [1].

Hypertension is a common feature in ADPKD, affecting up to 60–80% of patients. Hypertension occurs prior to the onset of renal insufficiency and is associated with faster progression to ESRD [7], [8], [9]. There is significant evidence that the renin–angiotensin–aldosterone system (RAAS) is a major contributor to hypertension and cyst growth in both animals and humans with ADPKD [10]. Recent studies have focused on the role of 3-hydroxy-3-methylglutaryl coenzyme A (HMG coA) reductase inhibitors (statins) in the amelioration of both progressive nephropathy and cardiovascular disease, and there are data to suggest that statins may have modulatory effects on the RAAS (reviewed in [11]). In this randomized double-blind placebo-controlled phase III clinical trial, we are investigating the effects of pravastatin treatment on renal and cardiovascular disease progression in children and young adults with ADPKD who are concurrently treated with the angiotensin converting enzyme (ACE) inhibitor lisinopril. Disease progression will be assessed with a combined primary endpoint of changes in renal volume, left ventricular mass index, and microalbuminuria over the three-year study period. Here we discuss the rationale, study design, and baseline characteristics of study participants.