| Abstract|| |
To evaluate the effect of levamisole therapy combined with corticosteroid in children with nephrotic syndrome and frequent relapses (FR) or steroid dependence (SD), we studied retrospectively 24 children (18 boys and six girls) with a mean age of 32 months. Eleven (46%) patients had FR and 13 (54%) had SD. Levamisole was used for a mean period of 8.5 months. The relapse rate decreased from a mean of 4 relapses/year during steroid therapy alone to 1.3 relapses/ year during the combined therapy in 17 (71%) of the patients. Remission was sustained, after discontinuing levamisole, for more than six months in 11 of the 17 responders (65%), and six patients relapsed after discontinuing levamisole. Seven of the 24 study patients (29%) had no response to levamisole.
The seven patients who failed to respond to levamisole and the six initial responders who could not maintain remission after discontinuing the drug were treated with cyclophosphamide for 12 weeks. Eight of these patients (61.5%) had remission sustained for a mean duration of 10 months. The FR patients sustained remission for a longer period of time than SD patients in both groups. Levamisole was more effective than cyclophosphamide in patients with the age of onset of the disease above 2 years (10 patients out of 11 (91%). The side effects of levamisole and cyclophosphamide in our patients were transient and manageable. We conclude that levamisole is a safe and effective drug if combined with corticosteroid therapy in children with nephrotic syndrome. Further studies may be required.
Keywords: Nephrotic syndrome, Steroid-sensitive, Levamisole, Cyclophosphamide
|How to cite this article:|
Al-Ibrahim AA, Al-Kharraz SM, Al-Sadoon DM, Al -Madani AJ, Al-Musallam SA. Levamisole Therapy as a Second-line Immunosuppressive Agent in Corticosteroid-sensitive Nephrotic Syndrome in Children. Saudi J Kidney Dis Transpl 2003;14:153-7
|How to cite this URL:|
Al-Ibrahim AA, Al-Kharraz SM, Al-Sadoon DM, Al -Madani AJ, Al-Musallam SA. Levamisole Therapy as a Second-line Immunosuppressive Agent in Corticosteroid-sensitive Nephrotic Syndrome in Children. Saudi J Kidney Dis Transpl [serial online] 2003 [cited 2020 Feb 21];14:153-7. Available from: http://www.sjkdt.org/text.asp?2003/14/2/153/33024
| Introduction|| |
Children with steroid-sensitive nephrotic syndrome have a good long-term prognosis. However, about half of the patients usually experience frequent relapses that affect their quality of life and cause difficult problems in their management.
Prolonged or repeated use of corticosteroids often results in serious side effects, such as hypertension, growth failure and cushingoid obesity. In order to minimize the side effects of steroids, different immunosuppressive agents in frequently relapsing children have been used such as cyclophosphamide, levamisole and cyclosporine. ,,
Currently, there is no consensus on the most appropriate non-steroidal immunosuppressive agent. There have been several reports of successful treatment of steroid-responsive nephrotic syndrome with levamisole (1-tetramisole). ,,,,,,,,,,
In this study, we report our experience with the efficacy and safety of levamisole and cyclophosphamide as non-steroidal immunosuppressive agents in frequently relapsing and steroid dependent nephrotic children.
| Patients and Methods|| |
We reviewed the records of nephrotic children who had follow-up at our center, from January 1997 to December 2001. The patients included in the study had either steroid dependent (SD) or frequently relapsing (FR) nephrotic syndrome.
Relapses were defined as the presence of 3+ protein in the urine dip stick test (Albustix) on three consecutive days in children supposedly in remission. Complete remission was defined as finding no proteinuria by Albustix for three consecutive days, while partial response was defined as a trace to 1+ proteinuria by Albustix but without edema. Late resistance was defined as the initial response of the nephrotic syndrome to steroids followed by subsequent failure during a new attack of the disease. The child's parents undertook daily urinalysis with Albustix on the first morning specimen and recorded the result in addition to administered doses of the drugs.
SD was defined as the occurrence of two consecutive relapses of nephrotic syndrome while on maintenance therapy with prednisolone of 0.5 mg/kg on alternate day or within 14 days of discontinuation of the drug. FR was defined as two or more relapses within six months of the initial response.
The SD and FR nephrotic patients were treated with prednisolone dose of 2 mg/kg/ day until remission, and then the dose was reduced to 1.5 mg/kg/ alternate days for four weeks. Afterwards, Levamisole was added in a single dose of 2.5 mg/kg to the modified prednisolone dose administered on the same day. After 14 days of stating Levamisole, the dose of prednisolone was reduced further in steps of 0.25 mg/kg/ alternate days every 14 days. When the dose of prednisolone reached 0.25 mg/kg/ alternate days, it was fixed for 3-6 months. Levamisole and prednisolone were continued for a minimum of eight months, and then they were discontinued together.
If the patients showed no response after 6 months of treatment with levamisole or relapsed after discontinuing this therapy, cyclophosphamide was then used in a dose of 2.5 mg/kg/day for 12 weeks.
Full blood count was obtained every two weeks for one month, then every month for two months, then every two months. Prothrombin time (PT), Partial thrombin time (PTT), serum protein, albumin, urea, creatinine, calcium, phosphorus, alkaline phosphatase, liver function tests were obtained every two months. Complete urinalysis was performed during each visit.
Side effects of levamisole were recorded. If any patient develops leucopenia, leukocyte count less than 4000/cm³, the drug was discontinued and leukocytes count was checked weekly until it returned back to normal, then the medication would be resumed.
| Results|| |
There were 24 children who had adequate data for analysis (18 boys and six girls). Their ages at the time of diagnosis ranged between 18 months and 9 ½ years with a mean of 32 months; 14 (58%) patients were two years of age or below, and 10 (42%) patients more than two 2 years. The follow-up period ranged between 18 months to 5 years. There were 13 (54%) SD patients and 11 (46%) FR; all received levamisole and prednisolone.
Levamisole was used for a period ranged between 8 and 12 months with a mean of 8.5 months. The FR patients had a mean duration of levamisole therapy of 6.9 months Vs 9.5 months in the SD patients.
The relapse rate before levamisole therapy ranged between 3.5-5/year with a mean of four/year, which decreased to 0-2/year with a mean of 1.3/year in 17(71%) patients; seven out of 17 (41%) had no relapses during levamisole therapy. Seven (29%) patients had no response to levamisole.
Out of the 24 patients treated with levamisole, 11 (46%) sustained remission after discontinuing levamisole therapy for a period ranged from 6-40 months and a mean of 19.4 months; 64% of the patients who sustained remission where SD patients. The FR patients had a mean duration of sustained remission of 19.5 months Vs 8.5 months in the SD patients.
The seven patients who failed to respond to levamisole and the six initial responders who could not maintain remission after discontinuing the drug were treated with cyclophosphamide for 12 weeks. Eight of these 13 patients (61.5%) had remission sustained for a mean duration of 10 months. The FR patients had a mean duration of sustained remission of 24.8 months Vs 14 months in the SD patients [Table - 1].
There were five out of twenty-four (20.8%) patients who did not respond to levamisole or cyclophosphamide. Three of them showed initial complete remission while on cyclophosphamide therapy, but relapsed within 23 months thereafter; two patients had mesangioproliferative glomerulonephrities (MPGN) and one had minimal change disease.
Two patients developed mild transient rash while on levamisole therapy and two patients developed mild GI symptoms which did not require discontinuation of the drug. One out of the 24 (4%) study patients developed transient leucopenia; the leukocytes count was less than 3000/cm³, which normalized after one week of holding levamisole. Three out of 13 (23%) patients on cyclophosphamide developed leucopenia while on therapy; the leukocytes counts were less than 4000/cm³, which also returned back to normal after one week of holding therapy.
| Discussion|| |
Several studies suggested levamisole as the first choice of non-steroidal immunosuppressive agents in patients to achieve less frequent relapses and more sustained remission in children with frequently relapsing or steroid dependant nephrotic syndrome in addition to the decrease of the side effects of steroids. ,
Some studies favored levamisole to cyclophosphamide due to comparable effectiveness and fewer side effects. ,, However, the effect was not sustained for a long period in many studies; ,, the duration of sustained remission was 8-12 months in the study of Bagga et al in 1997 and three months in the study of the British association for pediatric nephrology on 1991. ,
In our study, we used levamisole as a first choice non-steroidal immunosuppressive agent combined with prednisolone and found less relapse rate during levamisole therapy as was reported by other studies. ,,,
Sustained remission for a minimum of six months after discontinuing levamisole therapy and corticosteroids was shown in 46% and was in a higher percentage of the SD nephrotic children than the FR ones. Nevertheless, the duration of the sustained remission after discontinuing the treatment was longer in FR patients than the SD patients, though they were treated for a shorter period. Our findings were different from those reported by Kemper et al, where the response was better in the FR than SD. This may be because the patients in their study were older (3.5-22 years and a mean of 10 years) compared to the ages in our patients, since the older the patients have the fewer the relapses. 
In our study, the duration of the sustained remission was longer in a higher percentage of the patients treated with cyclophosphamide compared to those treated with levamisole.
This was reported before in other studies. ,,,
We also found that there was a relationship between the duration of sustained remission and the age of onset of the disease. Levamisole was more effective in patients first diagnosed at age of two years or more and cyclophosphamide was more effective in patients diagnosed at two years of age or less. This relationship was found by some,  but not by others.  These differences may be due to the different age groups in those studies.
The percentage of the non-responders to either levamisole or cyclophosphamide was high when the age of onset of the disease was less than two years.
In our study, leucopenia was the most serious side effect encountered in the treatment with cyclophosphamide or levamisole but it was transient in both.
In conclusion, this study suggests that levamisole is a safe and effective drug and can induce sustained remission if given combined with corticosteroid therapy in both frequent relapses and steroid dependant nephrotic syndrome children. However, levamisole can be effective as a first choice second-line treatment in children above two years of age, while cyclophosphamide may be more effective in the younger age group. Further studies are needed to confirm this observation.
| References|| |
|1.||Durkan A, Hodson EM, Willis NS, Craig JC. Immunosuppressive agents in childhood nephrotic syndrome in children (Cochrane review). Cocchrane Data Base System 2001;4: CD002290. |
|2.||Durkan AM, Hodson EM, Willis NS, Craig JC. Immunosuppressive agent in childhood nephrotic syndrome: a meta-analysis of randomized controlled trials. Kidney Int 2001;59(5):1919-27. |
|3.||Bagga A, Sharma A, Srivastiva RN. Levamisole therapy in corticosteroiddependent nephrotic syndrome. Pediatric Nephrol 1997;11:415-7. |
|4.||Tanphaichitr P, Tanphaichitr D, Sureeratanan D, Chatasing S. Treatment of nephrotic syndrome with levamisole. J Pediatrics 1996;96(3)490-3. |
|5.||Ksiazek J, Krynski J. Evaluation of the efficacy of levamisole in corticosteroiddependant nephrotic syndrome in children. Pediatric Pol 1995;70(12): 1037-42. |
|6.||Mehta KP, Ali U, Kutty M, Kolhatkar. Immunore gulatory treatment for minimal change nephrotic syndrome. Arch Dis Child 1986;61(2):153-8. |
|7.||La Manna A, Politoc C, Del Gado R, Foglia AC. Levamisole in children's idiopathic nephrotic syndrome. Child Nephrol Ural 1988-89;9(4)200-2. |
|8.||AlSaran K, Grisaru S, Stephens D, Arbus G. Levamisole vs. cyclophosphamide for frequently replacing steroid-dependent nephrotic syndrome. Clin Nephrol 2001; 56(4):289-94. |
|9.||Niaudet P, Drachman R, Gagnadoux MF, Broyer M. Treatment of idiopathic nephrotic syndrome with levamisole. Acta Pediatr Scand 1984;73(5):637-41. |
|10.||Kemper MJ, Amon O, Timmermann-K, Altrogge H, Muller-Wiefel DE. The treatment with levamisole of frequently recurring steroid-sensitive idiopathic nephrotic syndrome in children. Dtsch Med Wochenschr 1998; 123(9):239-43. |
|11.||Fu LS, Chi CS. Levamisole in steroidsensitive nephrotic syndrome children with steroid-dependency and/or frequent relapses. Acta Pediatr Taiwan 2000;41(2):80-4. |
|12.||Tenbrock K, Muller-Berghaus J, Fuchshuber A, Michalk D, Querfeld U. Levamisole treatment in steroid-sensitive and steroidresistant nephrotic syndrome. Pediatri Nephrol 1998;12:459-62. |
|13.||Takeda A, Ohgushi H, Niimura F, Matsutani H. Long-term effects of immunosuppressants in steroid-dependent nephrotic syndrome. Pediatr Nephrol 1998;12:746-50. [PUBMED] [FULLTEXT]|
|14.||British Association for Pediatric Nephrology. Levamisole for corticosteroid-dependent nephrotic syndrome in childhood. Lancet 1991;337:1555-7 |
|15.||Cameron JS, Chantler C, Ogg CS, White RH. Long-term stability of remission in nephrotic syndrome after treatment with cyclophosphamide. Br Med J 1974;4:7-11. [PUBMED] [FULLTEXT]|
|16.||McDonald J, Murphy AV, Arniel GC. Long-term assessment of cyclophosphamid therapy for nephrosis in children. Lancet 1974;2:980-2. |
|17.||Arbeitsgemeinschaft for paediatrische nephrology. Effect of cytotoxic drugs in frequently relapsing nephrotic syndrome with or without steroid dependence. N Engl J Med 1982;306:451-4. |
|18.||Kabuki N, Okugawa T, Hayakawa H, et al. Influence of age at onset on the outcome of steroid-sensitive nephrotic syndrome. Pediatr Nephrol 1998;12:467:70. [PUBMED] [FULLTEXT]|
Alia Abulrahim Al-Ibrahim
Consultant Pediatric Nephrologist, Suliemania Children's Hospital, P.O. Box 59046. Riyadh 11525
[Table - 1]