Autosomal Recessive PKD: Not Just for Kids, Long-Term Outcomes in Early vs. Late-Onset Disease

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Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy usually caused by biallelic PKHD1 variants. It is typically diagnosed in early childhood, though late-onset ARPKD are increasingly recognized with broader molecular testing, but long-term outcomes data is lacking. Methods: This retrospective study compared early- and late-onset ARPKD in patients with biallelic PKHD1 pathogenic variants, using clinical and imaging data from 1961 to 2022 to evaluate long-term outcomes and phenotypic differences. Results: Among 50 genetically confirmed ARPKD-PKHD1 patients, 27 had early-onset [median diagnosis age 0 yrs (IQR 0–2)] and 23 had late-onset disease [31 yrs (20–42)]; median follow-up was 22 yrs (8–32) vs. 15 yrs (6–25) (p = 0.46). Figure 1A illustrates that late-onset ARPKD presented with fewer renal and more hepatobiliary symptoms. Nephromegaly at diagnosis was less common, and over time, these patients had a lower lifetime incidence of hypertension and kidney failure (p < 0.05), but higher rates of ascending cholangitis and urinary stone disease (p < 0.05). Interestingly, the distribution of two non-truncating (2NT) versus non-truncating/truncating (NT/T) variants was similar between early- and late-onset cases (p = 0.15). In late-onset patients with serial imaging, height adjusted total kidney and liver volumes, and cyst counts showed variable progression, while eGFR decline was common; 11 of 14 (79%) had a final eGFR <60 ml/min/1.73m^2(Figure 1B–F). Conclusion: Late-onset ARPKD often presents with hepatobiliary-dominant features, urinary stone disease, variable organ progression, and despite limited nephromegaly, gradual kidney function decline with risk of CKD ≥3 was common. These findings support recognizing late-onset ARPKD as a meaningful clinical subset, warranting long-term monitoring and broader diagnosis in adolescents and adults with unexplained hepatobiliary disease. Funding: NIDDK Support

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