title: Dimethylthetin treatment causes diffuse alveolar lung damage: a pilot study in a sheep model of Continuous Ambulatory Peritoneal Dialysis (CAPD).
abstract: Total plasma homocysteine (Hcy) concentration correlates with risk of vascular disease. Over 80% of chronic renal failure patients have elevated plasma Hcy and a 10-20 times higher incidence of vascular disease. Glycine betaine lowers plasma Hcy through methylation catalysed by betaine-homocysteine methyltransferase (BHMT). Dimethylthetin (DMT), a synthetic glycine betaine analogue, is a more effective BHMT substrate. DMT is therefore a potential therapeutic agent for reducing plasma Hcy in humans and may be particularly useful in renal failure patients receiving dialysis because of chronic betaine depletion as a result of treatment. We aimed to determine whether the addition of DMT to dialysis fluid lowered plasma Hcy concentrations in a Continuous Ambulatory Peritoneal Dialysis sheep model using animals that were either in acute renal failure (n=3) or had normal renal function (n=1). Sub-acute exposure to DMT was toxic to all four animals, which died with total lung consolidation and collapse and Diffuse Alveolar Damage within 48 h of beginning treatment. Adverse side effects were observed after 4-8 doses. DMT was not detected in pre-dialysis plasma samples and the final concentration at death was 0.5-7.8 mmol/L, depending on the number of doses each animal was exposed to. Abnormalities were not observed in animals supplied standard dialysis fluid, or fluid with added glycine betaine. Toxicity associated with DMT treatment raises concerns for its use in further studies. However, sub-acute administration of DMT to sheep may provide a useful model of acute alveolar damage.
authors.affiliation: Biochemistry Unit, Canterbury Health Laboratories, P.O. Box 151, Christchurch, New Zealand. sandy.slow@cdhb.govt.nz
authors.forename: Sandy
authors.initials: S
authors.lastname: Slow
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Vasudevamurthy
authors.forename: Robin
authors.initials: R
authors.lastname: Fraser
authors.forename: Christopher
authors.initials: C
authors.lastname: McEntyre
authors.forename: Michael
authors.initials: M
authors.lastname: Lever
authors.forename: Stephen
authors.initials: S
authors.lastname: Chambers
authors.forename: Peter
authors.initials: P
authors.lastname: George
mesh_terms: D000818:Animals; D001622:Betaine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D050940:Betaine-Homocysteine S-Methyltransferase / Q000378:metabolism; D015314:Dialysis Solutions / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000097:blood / Q000517:prevention & control; D009392:Nephrectomy; D010531:Peritoneal Dialysis, Continuous Ambulatory / Q000009:adverse effects; D010865:Pilot Projects; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000473:pathology; D051437:Renal Insufficiency / Q000097:blood / Q000628:therapy; D012756:Sheep; D013379:Substrate Specificity
chemical_list: D015314:Dialysis Solutions; C521378:dimethylthetin; D006710:Homocysteine; D001622:Betaine; D050940:Betaine-Homocysteine S-Methyltransferase; D005998:Glycine