Is There a Functional Role of Mitochondrial Dysfunction in the Pathogenesis of ARPKD?

Abstract

Polycystic kidney diseases (PKD) form a group of severe genetic kidney diseases that are characterized by fibrocystic changes of the kidneys and the liver. The main forms of PKD are autosomal dominant and autosomal recessive polycystic kidney disease (ADPKD, ARPKD). In general, cystic kidney diseases are the most common genetic cause of chronic kidney failure in both children and adults (1). ARPKD is a disorder that typically is diagnosed very early in life or even prenatally. Typically, the kidneys show bilateral massive enlargement although they keep their reniform shape. Kidney disease results in a need for kidney replacement therapy (KRT) in around 50% of patients in the first two decades of life (2, 3). Liver involvement is obligatory in ARPKD, typically presenting with congenital hepatic fibrosis and portal hypertension or with dilated bile ducts. Both are considered to be a consequence of a defect during development of the bile ducts (“ductal plate malformation”) (4). Adult patients with ARPKD have been described with variable disease manifestations. Hepatic disease may be the leading clinical issue in adults with ARPKD (5). In ADPKD renal cystogenesis starts early in life or even before birth but does not present with obvious clinical symptoms until adulthood in most patients (1, 6, 7). Liver involvement is typically characterized by liver cysts. Additional extrarenal symptoms in ADPKD include for example intracranial aneurysms, cardiac valve anomalies like mitral prolapse or abdominal wall diverticula in a subset of patients (1, 7). Extrarenal manifestations may be very helpful for clinical differential diagnosis and to distinguish ADPKD from ARPKD. ADPKD is mainly caused by variants in the genes PKD1 and PKD2 with the large majority of patients carrying PKD1 variants (1). Variants in other genes e.g., with atypical forms of ADPKD have been identified (7). Variants in PKHD1 are the main cause of ARPKD with phenotypical overlay e.g., of kidney disease in patients with other underlying genetic changes (1, 8), including biallelic hypomorphic PKD1 variants. Genotype-phenotype correlations in ADPKD show more rapid progression of kidney disease in patients with PKD1 variants and especially in those patients carrying variants resulting in protein truncation (7, 9). For ARPKD it was shown by various groups that biallelic truncating variants are associated with severe phenotypes. A recent study extended the findings and revealed that for missense variants the affected region in PKHD1 also seems to be important (10). In a study on 304 children with the clinical diagnosis of ARPKD and detected PKHD1 variants it was found that patients with either two missense variants affecting the amino acids 709–1837 or a null variant and a missense variant in this region less frequently showed progression to chronic kidney failure when being compared during their follow-up when compared to patients with variants affecting other regions of PKHD1. On the other hand patients with variants affecting the amino acids 2625–4074 showed less favorable hepatic outcome (10). The underlying molecular mechanisms of these associations remain to be explored.