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Observational Study
. 2025 Jun;38(5):1445-1456.
doi: 10.1007/s40620-024-02184-3. Epub 2025 Jan 30.

Phenotypic outcomes of PKD1 compared with non-PKD1 genetically confirmed autosomal dominant polycystic kidney disease

Elhussein A E Elhassan #  1   2 , Darragh O'Donoghue #  3 , Sophia Heneghan  4 , Omri Teltsh  4 , Sahin Sarihan  4 , Shohdan M Osman  3   5 , Michelle Clince  3 , David Synnott  3 , Sophie Craig  3 , Amy Hudson  3 , Brendan Doyle  6   7 , David Lappin  8 , Donal J Sexton  9   10 , Liam Casserly  11 , John Holian  12 , Colm Magee  3 , Mark Denton  3 , Clodagh Sweeney  13 , Atif Awan  5   13 , Emma McCann  14 , Gianpiero L Cavalleri  4   15 , Katherine A Benson  4 , Peter J Conlon  3   5
Affiliations
Observational Study

Phenotypic outcomes of PKD1 compared with non-PKD1 genetically confirmed autosomal dominant polycystic kidney disease

Elhussein A E Elhassan et al. J Nephrol. 2025 Jun.

Abstract

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) represents the most common monogenic cause of kidney failure. While identifying genetic variants predicts disease progression, characterization of recently described ADPKD-like variants is limited. We explored disease progression and genetic spectrum of genetically-confirmed ADPKD families with PKD1 and non-PKD1 variants.

Methods: In this observational study, we evaluated the clinical (ADPKD-related complications, estimated glomerular filtration rate (eGFR) decline, and progression to kidney failure), radiological (height-adjusted total kidney volume (ht-TKV)), and genetic characteristics of ADPKD families referred to the Irish Kidney Gene Project. Logistic regression and Kaplan-Meier analyses examined relationships between genetic variants and disease progression.

Results: Genomic sequencing was performed on 261 ADPKD families, and 75.8% (198/261 families, comprising 391 individuals) were identified to harbor pathogenic/likely pathogenic variants; 74.2% (147/198) PKD1 families and 23.2% (46/198) non-PKD1 families, which include PKD2 (n = 29 families), IFT140 variants (n = 4), ALG5, DNAJB11 and NEK8 (n = 3 each), ALG8 and ALG9 variants (n = 2 each). The remaining 2.6% (5/198) accounted for non-ADPKD variants. Compared to PKD1, non-PKD1 families were characterized by a milder phenotype; milder eGFR decline (- 1.4 mL/min/1.73m2/year vs. - 3.2; p < 0.001), smaller ht-TKV (449.7 mL/m vs. 1769; p 0.002) and a delayed progression towards kidney failure (73 vs. 52 years; HR: 0.12, p < 0.001 [95% CI: 0.07-0.19]). ADPKD-NEK8 heterozygotes demonstrated earlier progression to kidney failure (average age 8 vs. 49 years for PKD1; Bonferroni-corrected p 0.017).

Conclusion: Non-PKD1 variants have heterogeneous phenotypic and genotypic attributes resulting in milder disease, although ADPKD-NEK8 is an important exception with early progression.

Keywords: PKD1; ADPKD; Copy number variants; Endoplasmic reticulum and NEK8.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no conflicts of interest. Ethical approval: Approval for the conduct of the study was obtained from the ethics committee of Beaumont Hospital, Dublin, Ireland (REC 19/28). Informed consent to participate: Written informed consent was obtained from patients before enrollment.

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