title: Maximum tolerable dose of cyclophosphamide and azathioprine in Pakistani patients with primary renal disease.
abstract: OBJECTIVE
  The immunosuppressive regimens, at present, mainly rely on western guidelines that were derived from studies conducted in western populations. No such study exists for South Asian population, which is home to almost two billion people different in both genetics and environment from west. Locally derived thresholds for side effects markedly different from western figures may warrant re-adjustment of current local immunosuppressive regimens that are at present based largely on western guidelines. In order to define optimum dose for Cyclophosphamide (CYC) and Azathioprine (AZA) based immunosuppressive therapy, we conducted this study to find out maximum tolerable doses of azathioprine (AZA) and cyclophosphamide (CYC) beyond which neutropenia and thrombocytepenia are most likely to occur in patients with primary renal pathology.
  
  
  METHODS
  Patients with systemic vasculitis and idiopathic glomerulonephritis who were on CYC and AZA were identified through review of medical records at a tertiary care hospital in Pakistan (The Aga Khan University Hospital, Karachi). Patients were categorized under three principal diagnosis i.e. systemic lupus erythematosus (SLE), primary (idiopathic) glomerulonephritis (GN) and Wegener's granulomatosis (WG). The Receiver Operating Curve (ROC) was used to calculate the maximum tolerable dose for both CYC and AZA.
  
  
  RESULTS
  We identified 94 patients aged 6-82 years (median 44.5 years) with primary renal disease (Wegener's granulomatosis n=13, Systemic lupus erythematosis n=62 and idiopathic glomerulonephritis n=19) who received CYC or AZA. Of these 94 patients, 36.2% (n=34) received CYC and 63.8% (n=60) received AZA. The mean dose of CYC was 1.54 +/- 0.50 mg/kg of body weight (range: 0.77-2.93). The mean dose of AZA was 1.64 +/- 0.59 mg/kg of body weight (range: 0.47-2.97). The maximum tolerable doses calculated for CYC and AZA were 1.25 mg/kg and 1.30 mg/kg of body weight respectively. The maximum tolerable dose for CYC and AZA among males could not be calculated, because of insufficient number of patients who developed neutropenia and thrombocytopenia. The maximum tolerable doses for CYC and AZA among females were 1.34 mg/kg and 1.03 mg/kg of body weight respectively. Also we found out that AZA was relatively more likely to cause neutropenia and thrombocytopenia (p=0.07).
  
  
  CONCLUSIONS
  We thereby recommend that CYC should be initiated at a dose no more than 1 mg/kg of body weight and AZA at an initial dose of 0.75-1.0 mg/kg of body weight. The dose may be adjusted later on the basis of clinical response and laboratory reports.
authors.affiliation: Department of Medicine, The Aga Khan University Hospital, Karachi.
authors.forename: S S
authors.initials: SS
authors.lastname: Ali
authors.forename: M A
authors.initials: MA
authors.lastname: Rabbani
authors.forename: S S M
authors.initials: SS
authors.lastname: Moinuddin
authors.forename: S
authors.initials: S
authors.lastname: Virani
authors.forename: F
authors.initials: F
authors.lastname: Farooque
authors.forename: A
authors.initials: A
authors.lastname: Salam
authors.forename: A
authors.initials: A
authors.lastname: Ahmad
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000008:administration & dosage*; D016009:Chi-Square Distribution; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage*; D005260:Female; D005921:Glomerulonephritis / Q000188:drug therapy*; D014890:Granulomatosis with Polyangiitis / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010154:Pakistan; D012372:ROC Curve; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D001379:Azathioprine