Cytotoxic Drugs in Steroid-Resistant Renal Disease

Abstract

THE USE of cytotoxic agents in the treatment of renal diseases was first reported in 1949 by Chasis 1,2 using nitrogen mustard (mechlorethamine) in adults with chronic glomerulonephritis. Shortly thereafter, Kel-ley and Panos3 confirmed improvement in children with nephrosis, and Taylor4 in adults with chronic glomerulonephritis, using the same approach. These reports were followed by others,5-9 but as the therapeutic value of steroids became more widely accepted, cytotoxic drugs were displaced as therapeutic agents. Interest was renewed in 1963 by Coldbeck,10 Kellum and Haserick,11 and Goodman and Wolff.12 There has been further encouragement in the use of these agents in the treatment of other nonneoplastic diseases 12-15 as well as in renal diseases.15-22 This report will review 3\m=1/2\years' experience in 25 children with cytotoxic drugs in addition to corticosteroids in the treatment of chronic renal diseases. Patients and MethodsThe agents used in this study were cyclophosphamide (Cytoxan), azathioprine (Imuran), and chlorambucil (Leukeran). A total of 37 courses have been given to 25 children with idiopathic nephrotic syn¬ drome, systemic lupus erythematosus, chronic glo¬ merulonephritis, or anaphylactoid purpura nephritis. The children were 6 to 17y¿ years old at the time of treatment and had had renal disease for three months to 14 years.Corticosteroids were administered to the 16 pa-tients with idiopathic nephrosis * as described ear¬ lier.23 In essence the children received 40 to 60 mg of prednisone (or its equivalent) daily. In the 12 children whose proteinuria persisted, daily steroid was continued for two to six months, as tolerated, when an intermittent maintenance regimen was be¬ gun which consisted of 80 mg of prednisone on three consecutive days of each week. In only two children was continuous steroid therapy given for more than ten months. There were four patients whose proteinuria disappeared on daily therapy. For these, daily corticosteroid was continued until the urine had remained free of protein for two weeks. Then the intermittent regimen described above was instituted for an additional two months of proteinfree urine, followed by a gradual reduction in dosage until discontinued four to six weeks later. Either sulfisoxazole (Gantrisin) or a broad spectrum anti¬ biotic during periods of anasarca was administered daily to all children during the course of steroid therapy. The six patients with lupus erythematosus were treated essentially as described above. For several patients the daily dose of corticosteroid was reduced to a minimum sustaining level for prolonged periods rather than the intermittent therapy. Only two chil¬ dren received continuous steroid therapy for more than ten months. The cytotoxic agents were administered according to the following criteria. (1) Nephrotic syndrome, where treatment with steroids might have been ef¬ fective but where problems with hypercorticism en¬ dangered the patient, or where steroids in high doses were required for six months or longer in ord...

Paired Trial of Cyclophosphamide and Prednisone in Children with Nephrosis

“…The present study shows that, contrary to the conclusion of Grupe and Heymann (1966), cyclophosphamide is effective when it is used alone without steroids. The short-term effects of cyclophosphamide and prednisone on children with nephrosis were very similar.…”

“…In the past decade there has been a new upsurge of interest in the use of such 'immunosuppressive agents' in the nephrotic syndrome (Coldbeck, 1963; Received 31 December 1970. Grupe and Heymann, 1966;West, Hong, and Holland, 1966;Etteldorf et al, 1967;and Moncrieff et al, 1969) and better results have been achieved.…”

The Effect of Treatment with Prednisone and Nitrogen Mustard on the Renal Lesions and Life Span of Patients with Lupus Glomerulonephritis

“…In addition to HN2 [4,13,24,26,43], corticosteroids have been used in combination with other drugs (table IV); thioguanine [10,12], 6-mercaptopurine [31,45], azathioprine [2,8,12,22,29,32,35,46,47,50], cyclophospha mide [5,9,22,48,51], methotrexate [9], thiomycetin [49] or chlorambucil [4,22]. Bariety et al [4] deliberately used LDS with a combination of an alkalyting agent (HN2 or chlorambucil) and an antimetabolite (cyclophosphamide or 6-mercaptopurine).…”

“…yes HDS CYC no 5 3 unchanged; 2 doubtful or partial response Cruchaud et a i [9] yes HDS CYC or METH yes 6 3 improved Cameron et a i [5] yes HDS CYC yes 6 3 improved ; 2 unchanged ; 1 died Steinbert et a i [48] yes LDS CYC yes 9 greater improvement than placebo Svec et a i [49] yes NG TC yes 5 4 improved Grupe and Heymann [22] yes HDS CHL no 2 1 remission; 1 unchanged Bariéty et a i [4] yes LDS HN 2 or CHL and 6MP or CYC yes 9 2 remissions; 3 partial remissions; 4 with no remission 1 LDS = Low dose of corticosteroids ; HDS = high dose of corticosteroids; NG = dose of corticosteroids not given. !…”

Comparison of Azathioprine, Prednisone, and Heparin Alone or Combined in Treating Lupus nephritis

“…20. 31, 35, 40], occur in most patients with systemic lupus erythematosus (SLE) [17,18,34] and constitute the most common cause of death in patients with that disease [11,18,30,35].…”