Kidney Week

Abstract: FR-PO0070

Allele-Dependent Mechanisms Drive Phenotypic Heterogeneity and Reveal Therapeutic Modalities in HNF1B-Associated Cystic Kidney Disease

Session Information

• ADPKD and Cystic Kidney Disease - 2
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Kolvenbach, Caroline Maria, Boston Children's Hospital, Boston, Massachusetts, United States

Caroline Maria Kolvenbach, MD, DrMed, PhD

• Saida, Ken, Boston Children's Hospital, Boston, Massachusetts, United States

Ken Saida, MD, PhD

• Zion, Elena, Boston Children's Hospital, Boston, Massachusetts, United States

Elena Zion, MD

• Hölzel, Selina, Boston Children's Hospital, Boston, Massachusetts, United States

Selina Hölzel

• Elmubarak, Izzeldin, Boston Children's Hospital, Boston, Massachusetts, United States

Izzeldin Elmubarak, MD

• Kalkar, Gina S., Boston Children's Hospital, Boston, Massachusetts, United States

Gina S. Kalkar

• Lemberg, Katharina, Boston Children's Hospital, Boston, Massachusetts, United States

Katharina Lemberg, MD

• Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States

Shirlee Shril

• Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Friedhelm Hildebrandt, MD

Background

Heterozygous HNF1B variants are a common monogenic cause of developmental kidney disease, characterized by marked phenotypic heterogeneity ranging from isolated renal anomalies to multisystem renal cyst and diabetes (RCAD) syndrome, suggesting allele-dependent disease mechanisms. The mechanistic basis for this variability and its therapeutic implications remain poorly defined. HNF1B, a key transcriptional regulator of renal epithelial differentiation, operates upstream of cystogenic gene networks, with convergence on autosomal dominant polycystic kidney disease (ADPKD)-associated signaling pathways suggesting shared, druggable downstream targets.

Methods

We analyzed 509 pathogenic/likely pathogenic intragenic HNF1B variants, stratified by variant class and associated clinical phenotypes (kidney-only, RCAD, diabetes-only). Genotype-phenotype correlations were assessed to identify allele-specific effects. To investigate therapeutic susceptibility, we utilized a conditional Hnf1b knockout mouse model of cystic kidney disease. Mice were treated with pharmacologic modulators targeting cystogenic pathways implicated in ADPKD, including inhibition of CFTR-mediated chloride transport and vasopressin-cAMP signaling. Primary outcomes included histological analysis and renal function.

Results

Phenotypic expression differed significantly by variant class. Loss-of-function variants were enriched for kidney involvement, whereas missense variants were more frequently associated with diabetes phenotypes (p<0.01), supporting distinct disease mechanisms. Individual alleles demonstrated heterogeneous and, in some cases, restricted phenotypic spectra, indicating allele-specific effects beyond uniform haploinsufficiency. Despite this upstream heterogeneity, cystogenesis converged on shared downstream pathways. Pharmacologic modulation of CFTR transport and vasopressin signaling significantly reduced cystic burden in vivo, although renal function was not improved. These findings indicate that while disease mechanisms differ by variant, they converge on common pathways that can be therapeutically targeted.

Conclusion

Allele-dependent mechanisms define phenotypic heterogeneity in HNF1B-associated disease but converge on shared, druggable pathways, establishing a framework for mechanism-guided and genotype-stratified therapeutic intervention.