Graduation Year

2025

Document Type

Thesis

Degree

M.S.B.E.

Degree Name

MS in Biomedical Engineering (M.S.B.E.)

Degree Granting Department

Biomedical Engineering

Major Professor

Richard Heller, Ph.D.

Co-Major Professor

Christine Klemens, Ph.D.

Committee Member

Robert Frisina, Ph.D.

Abstract

Polycystic kidney disease (PKD) is the most common genetic disorder affecting kidneys and the fourth leading cause of kidney failure. It occurs in two major forms, autosomal dominant PKD (ADPKD), and autosomal recessive PKD (ARPKD). ADPKD is typically adult-onset and caused by mutations in the PKD1 and PKD2 genes, and ARPKD generally manifests in utero and is caused by mutations in the PKHD1 gene. Despite the severity of the disease, only one FDA-approved drug, tolvaptan, is currently available for ADPKD and remains under clinical investigation for ARPKD. However, its use is limited by adverse side effects including polyuria, polydipsia, and hepatotoxicity.

In the first aim we analysed the biochemical and metabolic composition of human ADPKD and benign renal cyst fluid. Specifically, we measured electrolyte concentrations and osmolarities. We found 3 distal cysts (2 male and 1 female) with high potassium and low sodium. Distal cysts also had higher phosphate concentrations compared to proximal cysts. Benign cysts had highly variable electrolyte concentrations. All the cysts osmolarities ranged from 250 to 361 mOsms. Untargeted metabolomics of cyst fluid and serum from ADPKD patients and benign controls also had numerous differences in their metabolite profiles. Further analysis revealed several pathways of interest, including purine metabolism, vitamin B metabolism, and amino acid metabolism. Sex differences were also observed in the ADPKD cyst fluid. Lastly, proximal cysts had consistent amino acid concentrations between patients, while no noticeable patterns were observed in the benign cysts. Taurine concentrations were also measured in age-matched healthy and ADPKD plasma and urine, with no significant differences observed.

The second aim evaluated the dietary effects of taurine in an ARPKD rat model. Taurine supplementation influenced multiple physiological parameters, including increased water intake and urine output in both sexes, higher liver weights in females, and increased kidney weights and liver cystic burden in males. Taurine also appeared to accumulate within the cyst fluid. Together, these findings provide insights into the composition of human ADPKD cyst fluid and assess the role of taurine in PKD pathophysiology.

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