title: Sirolimus induced phosphaturia is not caused by inhibition of renal apical sodium phosphate cotransporters.
abstract: The vast majority of glomerular filtrated phosphate is reabsorbed in the proximal tubule. Posttransplant phosphaturia is common and aggravated by sirolimus immunosuppression. The cause of sirolimus induced phosphaturia however remains elusive. Male Wistar rats received sirolimus or vehicle for 2 or 7 days (1.5mg/kg). The urine phosphate/creatinine ratio was higher and serum phosphate was lower in sirolimus treated rats, fractional excretion of phosphate was elevated and renal tubular phosphate reabsorption was reduced suggesting a renal cause for hypophosphatemia. PTH was lower in sirolimus treated rats. FGF 23 levels were unchanged at day 2 but lower in sirolimus treated rats after 7 days. Brush border membrane vesicle phosphate uptake was not altered in sirolimus treated groups or by direct incubation with sirolimus. mRNA, protein abundance, and subcellular transporter distribution of NaPi-IIa, Pit-2 and NHE3 were not different between groups but NaPi-IIc mRNA expression was lower at day 7. Transcriptome analyses revealed candidate genes that could be involved in the phosphaturic response. Sirolimus caused a selective renal phosphate leakage, which was not mediated by NaPi-IIa or NaPi-IIc regulation or localization. We hypothesize that another mechanism such as a basolateral phosphate transporter may be responsible for the sirolimus induced phosphaturia.
authors.affiliation: Department of Nephrology, Medical University of Vienna, Vienna, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Haller
authors.forename: Stefan
authors.initials: S
authors.lastname: Amatschek
authors.forename: Julia
authors.initials: J
authors.lastname: Wilflingseder
authors.forename: Alexander
authors.initials: A
authors.lastname: Kainz
authors.forename: Bernd
authors.initials: B
authors.lastname: Bielesz
authors.forename: Ivana
authors.initials: I
authors.lastname: Pavik
authors.forename: Andreas
authors.initials: A
authors.lastname: Serra
authors.forename: Nilufar
authors.initials: N
authors.lastname: Mohebbi
authors.forename: Jürg
authors.initials: J
authors.lastname: Biber
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.forename: Rainer
authors.initials: R
authors.lastname: Oberbauer
mesh_terms: D000818:Animals; D003404:Creatinine / Q000097:blood / Q000652:urine; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis; D007015:Hypophosphatemia, Familial / Q000097:blood / Q000139:chemically induced* / Q000652:urine; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D010710:Phosphates / Q000097:blood / Q000652:urine; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000009:adverse effects / Q000494:pharmacology*; D050608:Sodium-Phosphate Cotransporter Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D010710:Phosphates; D050608:Sodium-Phosphate Cotransporter Proteins; D003404:Creatinine; D020123:Sirolimus