Clinical and pre-clinical studies of renal disease in tuberous sclerosis

Thamann, Anna Hellmann 2014. Clinical and pre-clinical studies of renal disease in tuberous sclerosis. MPhil Thesis, Cardiff University. Item availability restricted.

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Abstract

Tuberous Sclerosis Complex (TSC) is a rare autosomal dominant disease characterized by benign hamartomatous growths in a variety of organs. Renal involvement with angiomyolipomas and/or cysts is common. A subset of patients develops severe polycystic kidney disease in association with contiguous deletion of the TSC2 and PKD1 genes. Little is known about the natural history of the renal disease in this group. The present study had dual aims. The first was to further characterize the TSC2/PKD1 contiguous gene deletion syndrome and to compare renal function and its change over time in these patients with those having mutations affecting TSC2alone. Clinical and renal function data were assimilated on 44 patients with TSC2/PKD1 deletion and 69 patients with TSC2 mutations. Additional genetic analyses were used to more fully characterize the genomic extent and mosaicism of TSC2/PKD1 deletions. In comparison to patients with TSC2 mutations, those with TSC2/PKD1 deletion presented significantly earlier with significantly more advanced chronic kidney disease and lower estimated glomerular function rate and they were more likely to progress to end stage renal disease (P = 0.007). The second aim was to investigate the efficacy of rapamycin, sunitinib, and nelfinavir in the treatment of renal lesions in a Tsc1+/‐ mouse model in which spontaneous renal cysts arise and progress to papillary cyst‐adenomas and to solid adenomas and carcinomas. Compared to controls, rapamycin alone or in combination with sunitinib reduced significantly the number and size of papillary and solid lesions while sunitinib or nelfinivir treatment alone led to a lesser reduction in numbers of solid lesions but no change in overall lesion numbers. Rapamycin, a highly specific inhibitor on mTORC1, appears to hold more promise than the other agents for the treatment of TSC‐associated renal disease.

Item Type:	Thesis (MPhil)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Date of First Compliant Deposit:	30 March 2016
Last Modified:	10 Jan 2024 10:58
URI:	https://orca.cardiff.ac.uk/id/eprint/75110

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