| Abstract: | Background and objectives: Renal function and imaging findings have not been comprehensively and prospectively characterized in a broad age range of patients with molecularly confirmed autosomal recessive polycystic kidney disease (ARPKD).Design, setting, participants, & measurements: Ninety potential ARPKD patients were examined at the National Institutes of Health Clinical Center. Seventy-three fulfilled clinical diagnostic criteria, had at least one PKHD1 mutation, and were prospectively evaluated using magnetic resonance imaging (MRI), high-resolution ultrasonography (HR-USG), and measures of glomerular and tubular function.Results: Among 31 perinatally symptomatic patients, 25% required renal replacement therapy by age 11 years; among 42 patients who became symptomatic beyond 1 month (nonperinatal), 25% required kidney transplantation by age 32 years. Creatinine clearance (CrCl) for nonperinatal patients (103 ± 54 ml/min/1.73 m2) was greater than for perinatal patients (62 ± 33) (P = 0.002). Corticomedullary involvement on HR-USG was associated with a significantly worse mean CrCl (61 ± 32) in comparison with medullary involvement only (131 ± 46) (P < 0.0001). Among children with enlarged kidneys, volume correlated inversely with function, although with wide variability. Severity of PKHD1 mutations did not determine kidney size or function. In 35% of patients with medullary-only abnormalities, standard ultrasound was normal and the pathology was detectable with HR-USG.Conclusions: In ARPKD, perinatal presentation and corticomedullary involvement are associated with faster progression of kidney disease. Mild ARPKD is best detected by HR-USG. Considerable variability occurs that is not explained by the type of PKHD1 mutation.Autosomal recessive polycystic kidney disease (ARPKD) occurs in 1 in 20,000 births and is the most common hepatorenal fibrocystic disease of childhood (1–7). It is caused by mutations in PKHD1, which encodes fibrocystin/polyductin (8,9), a protein localized to the primary cilium, an organelle functioning as the cell''s “sensory antenna” (10). Proteins defective in other diseases having fibrocystic pathology, such as autosomal dominant polycystic kidney disease, nephronophthisis, Bardet–Biedl, Meckel, and Joubert syndromes, also localize to the primary cilium; these disorders, along with ARPKD, comprise the “ciliopathies” (10–12).Individuals with ARPKD have nonobstructive fusiform dilations of the renal collecting ducts, leading to progressive renal insufficiency. All ARPKD patients manifest some degree of congenital hepatic fibrosis (CHF) caused by ductal plate malformation of the developing portobiliary system; some patients also have macroscopic dilations of the intrahepatic bile ducts, a combination termed Caroli''s syndrome (7,13,14). Portal hypertension complicates CHF and often results in esophageal varices and hypersplenism (15–18). Early-onset severe hypertension, often requiring multiagent therapy, occurs in most ARPKD patients (5).Most ARPKD patients present perinatally with oligohydramnios and massively enlarged, diffusely microcystic kidneys. Many such newborns subsequently succumb to pulmonary hypoplasia. Characterization of the clinical phenotype of ARPKD has been based primarily upon this subtype (i.e., perinatally symptomatic patients) (1,4,5). Documentation of the kidney disease in patients presenting late in childhood or adulthood has been more limited (3,19,20). In this paper, we detail the clinical, biochemical, imaging, and molecular characteristics of 73 children and adults with PKHD1 mutations and a spectrum of clinical presentations. Our data document the extent of renal glomerular and tubular dysfunction; correlate molecular, functional, and imaging findings; and provide prognostic information. |
