ABSTRACT
Pulsed low-dose cyclophosphamide (CTX) therapy has become a very effective approach in improving the clinical outcomes of lupus nephritis (LN) patients. However, variations of CTX therapeutic outcomes in LN patients are incompletely understood. We investigated the contributions of known allelic variants to CTX therapy outcomes in 77 LN patients. Then, 22 out of the 77 patients were randomly enrolled to evaluate the pharmacokinetic profiles. LN patients with a GSTA1*A mutation (CT heterozygous) had more risk of non-remission (44% vs. 20%, P=0.005). Pharmacokinetic data indicated that patients with a GSTA1*A heterozygous variant had a lower exposure to 4-hydroxycyclophosphamide (4OHCTX) compared to wild-type patients (AUC4OHCTX: 12.8 (9.8, 19.5) vs. 27.5 (18.1, 32.8) h mg/l, P=0.023). Clinical remission was significantly related to higher exposure of 4OHCTX (P=0.038). In conclusion, LN patients with GSTA1*A heterozygous genotypes had poor CTX treatment remission due to less exposure to activated metabolites of CTX.
Subject(s)
Cyclophosphamide/therapeutic use , Glutathione Transferase/genetics , Immunosuppressive Agents/therapeutic use , Lupus Nephritis/drug therapy , Adult , Aged , Cyclophosphamide/analogs & derivatives , Cyclophosphamide/metabolism , Cyclophosphamide/pharmacokinetics , Female , Glutathione Transferase/metabolism , Heterozygote , Humans , Immunosuppressive Agents/pharmacokinetics , Lupus Nephritis/genetics , Male , Middle Aged , Pharmacogenetics , Polymorphism, Genetic , Remission Induction , Treatment Outcome , Young AdultABSTRACT
The role of metabolic acidosis in the progression of chronic kidney disease (CKD) remains unclear. The aim of the present study was to investigate the direct effects of acid loading on the proliferation of rat glomerular mesangial cells (GMCs) in vitro and the possible role of sodium-hydrogen ion exchanger isoform 1 (NHE1). Rat GMCs were treated with acidic medium as acid loading. Growth and proliferation of GMCs was studied by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, thymidine ((3)H-TdR) incorporation, and flow cytometry. NHE1 protein expression and activity were quantified by Western blot and dual wavelength epifluorescent illumination with 2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein, respectively. 5-(N,N-dimethyl) amiloride hydrochloride (DMA), a specific inhibitor of NHE1, was used to investigate the possible involvement of NHE1 in the proliferation of GMCs. The MTT assay, (3)H-TdR incorporation, and cell cycle distribution analysis indicated that acid loading stimulated the proliferation of GMCs. Acid loading increased NHE1 activity, but had no effects on NHE1 expression at the protein level. The effects of acid loading on the proliferation of GMCs were inhibited by DMA. Acid loading induced GMC proliferation through NHE1-dependent pathways. Our findings may contribute to the understanding of metabolic acidosis in the progression of CKD.
Subject(s)
Acidosis/physiopathology , Mesangial Cells/metabolism , Renal Insufficiency, Chronic/physiopathology , Sodium-Hydrogen Exchangers/metabolism , Amiloride/analogs & derivatives , Amiloride/pharmacology , Animals , Blotting, Western , Cell Cycle/physiology , Cell Proliferation , Disease Progression , Flow Cytometry , Fluoresceins/chemistry , Hydrogen-Ion Concentration , Rats , Sodium-Hydrogen Exchanger 1 , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Staining and Labeling , Tetrazolium Salts/metabolism , Thiazoles/metabolismABSTRACT
Peritonitis in peritoneal dialysis (PD) patients is characterized by abdominal pain and dialysate leukocytosis. Abdominal abscesses have been reported in PD patients with relapsing peritonitis. We report here 3 cases of lesser sac infection in PD patients who had severe abdominal pain but not generalized or diffuse peritonitis.
