Asian Journal of Pediatric Nephrology

: 2021  |  Volume : 4  |  Issue : 1  |  Page : 1--2

Judicious selection of oral cyclophosphamide in childhood nephrotic syndrome

Gurdeep Singh Dhooria 
 Department of Pediatrics, Dayanand Medical College and Hospital, Ludhiana, Punjab, India

Correspondence Address:
Gurdeep Singh Dhooria
Department of Pediatrics, Dayanand Medical College and Hospital, Ludhiana - 141 012, Punjab

How to cite this article:
Dhooria GS. Judicious selection of oral cyclophosphamide in childhood nephrotic syndrome.Asian J Pediatr Nephrol 2021;4:1-2

How to cite this URL:
Dhooria GS. Judicious selection of oral cyclophosphamide in childhood nephrotic syndrome. Asian J Pediatr Nephrol [serial online] 2021 [cited 2022 Oct 7 ];4:1-2
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Oral cyclophosphamide is one of the most commonly used steroid-sparing agents in patients with steroid-sensitive nephrotic syndrome. This is an alkylating medication, which exerts immunosuppressive activity by causing cytotoxic effects on proliferating lymphocytes. Cyclophosphamide has been used in patients with frequent relapses as well as in steroid dependence, to reduce the frequency of relapses and achieve long-term remission.[1],[2]

With availability and access to other agents, the use of cyclophosphamide for patients with nephrotic syndrome has declined. However, the medication continues to be preferred by many parents and physicians because of its lower cost and brief duration of therapy, compared to other steroid-sparing agents. Therapy with the latter, including levamisole, mycophenolate mofetil, and calcineurin inhibitors, is usually required for prolonged periods, usually 1–2 years or longer. Apart from cost, this might result in increased risk of noncompliance. Prolonged therapy with these agents also has risk of long-term toxicities, including antineutrophil cytoplasmic antibody-associated small-vessel vasculitis, neutropenia, and increased risk of systemic infections. Treatment with calcineurin inhibitors (cyclosporine and tacrolimus) may be associated with cosmetic and metabolic adverse effects, and variable toxicity involving the brain and the kidneys. There is increasing evidence, from case series as well as few randomized studies, regarding the beneficial role of rituximab in patients with steroid-sensitive nephrotic syndrome. While therapy with this agent seems promising, there are concerns with cost of therapy as well as risk of significant toxicities.

The latest guidelines of the Indian Society of Pediatric Nephrology[3] recommend the use of cyclophosphamide as a steroid-sparing agent, chiefly in patients who continue to show relapses despite treatment with levamisole or mycophenolate mofetil. However, cyclophosphamide may be considered for use as the initial steroid-sparing strategy in patients older than 7 years, especially those having significant steroid toxicity and/or complicated relapses. Therapy with cyclophosphamide is given for 12 weeks, along with alternate-day prednisolone. The guidelines do not recommend a second course of treatment with this agent.

We recently reported, in the Pediatric Nephrology, our experience with oral cyclophosphamide in 100 patients (75 boys), including 19 and 81 patients with frequent relapses and steroid dependence, respectively. The median (interquartile range) age at onset of nephrotic syndrome was 3 (2.0–5.2) years and at administration of cyclophosphamide was 5.7 (3.7–7.9) years. We found that treatment with this medication was beneficial, with 50% patients in sustained remission at 6 months, 31% at 1 year, and 11% at 2 years. An older age at initiation of cyclophosphamide (>5-years) independently predicted satisfactory response (odds ratio: 2.9, 95% confidence interval: 1.0–8.2; P = 0.044).[4] The precise reasons for better efficacy of cyclophosphamide in older children are not clear, but could relate to higher clearance of the medication in the young. Therefore, calculations using body surface area-adjusted dose may achieve comparable effect. Younger children might also be more sensitive to the triggers for relapses, and at risk of frequent viral infections.

Recent use of cyclophosphamide has also been limited due to concerns regarding its toxicity. A systematic review, published almost two decades ago, showed that the chief side effects of therapy were leukopenia (32.4%), alopecia (17%), hemorrhagic cystitis (2.2%), and severe bacterial infections (1.5%). Patients receiving prolonged and unsupervised therapy were at risk of malignancies. The risk of gonadal toxicity in females was very low. Males showed an increased risk of oligo- or azoospermia, especially if receiving a cumulative cyclophosphamide dose exceeding 200 mg/kg.[5] Most guidelines including those by the Indian Society of Pediatric Nephrology, therefore, advise that the medication be given at a dose of 2 mg/kg/day for 12 weeks, corresponding to a cumulative dose of 168 mg/kg.[3] Most guidelines also recommend that complete blood counts be monitored in patients every 2 weeks to detect reversible leukopenia. If total leukocyte count is below 4000 cells/cu mm, the medication is discontinued, and restarted when counts increase beyond 4000 cells/cu mm. Liberal water intake is advised to reduce the risk of hemorrhagic cystitis.

Based on the literature, we prefer to avoid the use of cyclophosphamide in young children (<5–7 years old), and would prefer its one-time use in older children. Thus, the first choice of steroid-sparing therapy for younger children should be mycophenolate mofetil or levamisole. If required, oral cyclophosphamide may be administered later in the course of disease, and before considering therapy with calcineurin inhibitors or rituximab. While cyclophosphamide continues to be an important medication for patients with frequently relapsing nephrotic syndrome, physicians should be aware of its benefits and toxicity, and use it judiciously.


1Ponticelli C, Escoli R, Moroni G. Does cyclophosphamide still play a role in glomerular diseases? Autoimmun Rev 2018;17:1022-7.
2Larkins NG, Liu ID, Willis NS, Craig JC, Hodson EM. Non-corticosteroidimmunosuppressive medications for steroid-sensitive nephrotic syndrome inchildren. Cochrane Database Syst Rev 2020;4:CD002290.
3Sinha A, Bagga A, Banerjee S, Mishra K, Mehta A, Agarwal I, et al. Expert Group of Indian Society of Pediatric Nephrology. Steroid Sensitive Nephrotic Syndrome: Revised Guidelines. Indian Pediatr. 2021;58:461-481.
4Sandhu J, Bhat D, Dhooria GS, Pooni PA, Bhargava S, Kakkar S, et al. Oral cyclophosphamide therapy in 100 children with steroid-sensitive nephrotic syndrome: experience from a developing country. Pediatr Nephrol 2021. Epub ahead of print.
5Latta K, von Schnakenburg C, Ehrich JH. A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children. Pediatr Nephrol 2001;16:271-82.