Combination of immunosuppressive agents in treatment of steroid-resistant minimal change disease and primary focal segmental glomerulosclerosis.
BACKGROUND
Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most prevalent histopathological lesions in idiopathic nephrotic syndrome (INS). The latter is associated with high morbidity and mortality due to symptomatic anasarca, bacterial infections, venous and arterial thromboembolism, and potential progression to end-stage renal disease in the case of FSGS. Traditionally, most patients are treated with corticosteroids, cyclophosphamide (CTX) or calcineurin-inhibitors (C-I). Unfortunately, many patients become steroid or C-I dependent, with the inherent risk of long-term side effects, or are resistant to both. The aim of this paper is to report on our experience with a new protocol of a combination of immunosuppressive agents added sequentially to improve the response of steroid and C-I refractory or resistant-INS and to minimize the long-term side-effects of single-agent treatment.


METHODS
Twenty-one patients with corticosteroid-resistant and C-I refractory INS (6 with MCD and 15 with FSGS) were treated prospectively over 6 and a half years. Our protocol consisted of an initial regimen of C-I followed by the addition of mycophenolate mofetil (MMF) and then by monthly intravenous CTX for 3 consecutive months. Dose reduction of C-I or/and MMF was attempted afterwards at 4-months intervals. Patients who remained refractory to the previously mentioned protocol were treated with an additional course of pulse Solu-Medrol given for 3 days followed by oral corticosteroids tapered over 6 months in addition to a second course of intravenous CTX given for 3 consecutive months.


RESULTS
With the initial regimen, two patients with MCD, remained in complete remission (CR) without any therapy after the course of CTX. Fifteen patients had variable response to C-I and MMF, but they achieved CR after CTX and their initial dosage of C-I and MMF were reduced to nearly one half. The remaining four patients had refractory form of FSGS even after the initial regimen, yet responded with CR to the additional course of steroid/CTX. However, no success with dose-reduction, in C-I and MMF, was achieved in the latter four patients.


CONCLUSIONS
Our study represents the first clinical trial with prospective and adequate follow-up of combination therapy of immunosuppressive agents in INS. This method is effective and safe for treatment of patients who are refractory to the conventional single-agent therapy.
El-Reshaid
Kamel
K
Department of Medicine, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait. waelalbader@yahoo.com
El-Reshaid
Wael
W
Madda
John
J
D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage*; D016572:Cyclosporine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007677:Kidney Function Tests; D008297:Male; D011446:Prospective Studies; D012720:Severity of Illness Index; D016559:Tacrolimus / Q000008:administration & dosage*; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003520:Cyclophosphamide; D016559:Tacrolimus