We should limit extrapolating these data to patients undergoing nephrectomy for tumors. Kidney donors are selected for absence of kidney disease and kidney disease risk factors (description of the donors below). Patients undergoing partial nephrectomy don't look like this.

Thank you to @kidneyomicsamps and @MagdalenaRiedlK for the thoughtful editorial on our paper functionalizing 𝘗𝘒𝘋1 variants and implications for polycystic kidney disease (ADPKD) genetic testing and treatment. DOI: 10.1681/ASN.0000001174 journals.lww.com/jasn/fullte…

We are constantly thinking about how to integrate human genetics and better experimental models to identify the mechanisms of human disease @UCSFNephrology, @IHG_at_UCSF, @UCSFDOM . Funding for the next generation of medicine from @NIH. Critiques and feedback welcome!

@BrandesNadav, Fnu Ritu, @yimmieg @ReiterLab @willowcoyote. journals.lww.com/jasn/abstra…

Thank you to many incredible coauthors including Daji Ha (now Assistant Pofessor at @PittTweet), Meyeon Park who runs the UCSF PKD Center of Excellence, and @MarkusDellingSF @UCSFPhysiology, Mohona Gupta, Yukako Akiyama, Jillian Argiris, Aide Pinedo, Christine Haewon

Campaigns to identify and advance small molecules that improve PKD1-PKD2 channel function should be next.

Our results suggest that similarly small molecules that improve the trafficking and channel function of PKD1 could treat polycystic kidney disease. Even prior to our manuscript, campaigns to advance small molecules that improve PKD1 trafficking were underway within biotech/pharma

Our results are reminiscent of cystic fibrosis. Cystic fibrosis is also a monogenic disease caused by mutations in an ion channel. Distinct small molecule medicines rescue the trafficking and channel function of CFTR dramatically improving many lives.

We also found that a subset of pathogenic variants that did not traffic to the primary cilium could be rescued by culture at low temperature. A subset of these temperature sensitive variants had normal ion channel function upon rescue.

Surprisingly all pathogenic variants disrupted either trafficking of PKD1 to the primary cilium or function of a PKD1-PKD2 heteromeric ion channel. This human genetic evidence supports a model in which PKD1-PKD2 ion channel function at the primary cilia prevents cysts.

We reasoned that we could use human genetic variation in PKD1 to learn how PKD1 prevents cysts. PKD1 pathogenic variants but not benign variants must disrupt molecular functions that restrain cystogenesis. We studied 29 nontruncating pathogenic and benign variants in PKD1.

Polycystic kidney disease is the most common monogenic cause of kidney failure and affects over 10 million individuals. We've known most PKD is caused by mutations in PKD1 for over 30 years. But how PKD1 prevents disease has remained mysterious, limiting effective therapy.

Thank you @ASNKidney! Our lab is very grateful to receive the 2025 Carl W. Gottschalk Research Scholar Grant. Read more about the work here: kidneycure.org/pages/qa.aspx….

Grateful for the chance to learn from @ksusztak, @parkercwilson, and others @Penn and @PennKidney. So much science to be excited about.

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