Clinical Trials in Pediatric Autosomal Dominant Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and is associated with concerning long-term implications for kidney function and cardiovascular health. Early intervention is needed in order to mitigate these long-term complications. Herein, we review important findings from recent clinical trials in ADPKD and their relevance to affected children and young adults and consider future directions for intervention. Recent clinical trials support aggressive control of blood pressure with blockade of the renin-angiotensin-aldosterone system as well as potential benefit of pravastatin therapy in children and young adults with ADPKD. There are several other candidate therapies, some of which have shown benefit in adult ADPKD, which require further investigation in affected children.

Prevalence of Hypertension in Children with Early-Stage ADPKD

“…Although hypertension can develop early in the course of the disease, its prevalence during childhood is not clearly established (2)(3)(4)(5)(6)(7)9,28,29). This study shows that a significant proportion of children with ADPKD has high BP, particularly at night.…”

“…Systematic screening was not recommended until recently (34). However, recent studies suggest the efficacy of targeted therapies in slowing disease progression (19,29), providing the rationale for early diagnosis. Theoretically, these treatments could be more efficient if started during childhood, in particular in patients who are at risk of being fast progressors (28), if side effects are acceptable.…”

Unmet needs and challenges for follow-up and treatment of autosomal dominant polycystic kidney disease: the paediatric perspective

“…Whereas early intervention is increasingly considered in order to attenuate both long-term renal and cardiovascular complications [27], only two interventional trials have been performed to date in children with ADPKD [28, 29], and another one is currently ongoing [30, 31] (discussed below).…”

“…Currently, pravastatin is approved for use in children from the age of 8 years with heterozygous familial hypercholesterolaemia by the FDA [80], but not by the EMA. The underlying mechanism of how pravastatin leads to potential positive effects in ADPKD remains to be fully elucidated, but statins have been shown to enhance renal blood flow and therefore glomerular filtration, to attenuate inflammation through vascular and glomerular nitric oxide production and may lower cAMP through downregulation of Gαs protein, leading to decreased cell proliferation [27]. Also, in in vitro experiments on proliferating murine tubular cells, simvastatin induced apoptosis in a time- and dose-dependent manner via down-regulation of Bcl-xL expression [81].…”

Is Autosomal Dominant Polycystic Kidney Disease Becoming a Pediatric Disorder?

“…Apart from this, there is one case report, describing the off-label use of tolvaptan in a severely affected neonate with ADPKD ( 94 ). Other coming exciting therapies, such as the AMPK activator metformin, are currently tested in adult patients, and will be tested in pediatric ADPKD depending on the results in adults ( 95 ). A general remark on (future) studies including children with ADPKD is that the subjects often are performed in tertiary and specialist centers.…”