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Pediatr Nephrol (2003) 18:1143–1146DOI 10.1007/s00467-003-1279-x Hammad O. Alshaya · Jaudah A. Al-Maghrabi
Jameela A. Kari
Intravenous pulse cyclophosphamide—is it effective in children with steroid-resistant nephrotic syndrome? Received: 3 March 2003 / Revised: 9 July 2003 / Accepted: 10 July 2003 / Published online: 17 September 2003 IPNA 2003 Abstract Treatment of steroid-resistant nephrotic syn-
drome (SRNS) remains a challenge to pediatric nephrol-ogists. Recently, intravenous cyclophosphamide (IV- Steroid-resistant nephrotic syndrome (SRNS) represents CPM) infusion was shown to be effective, safe, and eco- around 20% of primary nephrotic syndrome in children nomical for the treatment of SRNS, particularly minimal [1] and its management remains a problem for pediatric change disease (MCD), as it results in more sustained re- nephrologists [2]. It is mostly caused by non-minimal missions, longer periods without proteinuria, and fewer change histopathology [1]. The probability of having fo- significant side effects at a lower cumulative dose. A cal segmental glomerulosclerosis (FSGS) or membrano- prospective study was conducted to evaluate IV-CPM in- proliferative glomerulonephritis (MPGN) as the underly- fusions in the management of children with SRNS sec- ing cause of SRNS is higher with increasing age, where- ondary to MCD or IgM nephropathy. Five patients with as the risk of having minimal change disease (MCD) is SRNS (4 IgM nephropathy and 1 MCD) received six more likely with younger age at presentation [3, 4]. Opti- monthly IV-CPM infusions at a dose of 500 mg/m2. No mal treatment of SRNS has been hampered by a lack of patient achieved complete or sustained remission. Three patients attained partial remission, which was not sus- In the last 2 decades cyclosporin A (CsA) in combina- tained for more than 1 month post therapy. One patient tion with prednisolone has been shown to be effective in progressed rapidly to end-stage renal disease during inducing complete remission in some children with idio- treatment. Side effects included vomiting in four patients pathic SRNS [5]. There is an increasing trend to use CsA and alopecia in one patient. Conclusion: IV-CPM pulse in SRNS, particularly with FSGS [6], and its use has therapy at a dose of 500 mg/m2 is unsuccessful in obtain- been recommended by many authors [7, 8]. Alkylating ing complete or sustained remission in children with and antimetabolic agents have been used in SRNS since SRNS secondary to IGM nephropathy or MCD. Further the 1960s [9], without sustained benefit. Oral cyclophos- randomized controlled studies with higher doses are re- phamide (CPM) was used particularly with SRNS caused by MCD [10], with variable success. Intravenous(IV) CPM has been reported to be superior to oral CPM Keywords Intravenous cyclophosphamide ·
in inducing remission in steroid-resistant MCD [11, 12].
Steroid-resistant nephrotic syndrome · Minimal change We report the disappointing results of a prospective pilot study of IV-CPM in children with SRNS secondaryto MCD with or without diffuse mesangial hypercellular-ity (DMH) or IgM nephropathy.
Department of Pediatrics,King Abdul Aziz University Hospital, All patients presenting to our unit over the first half of 2002 with a diagnosis of SRNS were recruited. Only those with a renal biopsy showing MCD with or without DMH or IgM nephropathy were in- cluded in the study. Children with SRNS secondary to FSGS or MPGN were excluded from the study. SRNS was defined as a fail- ure to achieve remission after 4 weeks of enteral prednisolone at a dose of 60 mg/m2 per day, plus three intravenous doses of methyl- prednisolone (600 mg/m2 per day or 30 mg/kg per day) on alter- nate days [13]. We have seen 26 patients with nephrotic syndromeover a 6-month period, 20 patients had steroid-sensitive nephrotic syndrome (SSNS) and 1 patient with SRNS was excluded as hehad FSGS. Five children fulfilled the criteria, four females andone male. The ratio of SRNS to SSNS is biased and does not re- flect the actual ratio, as we represent a referal center for difficult nephrology cases. The mean±SD age at presentation was2.2±1.2 years. All except one patient was Arab in origin. (Patient3 was Pakistani.) Four children were primary non-responders andone was a secondary non-responder (patient 2 had steroid-depen- dent NS initially). None was positive for hepatitis B surface anti- gen or antinuclear antibody. All children had a low serum albuminat the initiation of IV-CPM pulse therapy, with mean±SD of 13.8±0.9 (range 11–16) g/l (normal 35–50). Complement compo- nents were normal, C3 1.4±0.2 g/l (normal 0.75–1.65), C4 0.3±0.04 g/l (normal 0.2–0.6), and kidney function was normal,with a mean creatinine of 21.6±7.4 µmol/l (Table 1). We used thesame dose of IV-CPM as Elhence et al. [12], of 500 mg/m2 permonth for six doses. All patients were continued on oral predniso- lone 40 mg/m2 on alternate days and enalapril (0.1–0.5 mg/kg) throughout the 6-month treatment period. The response was evalu-ated in terms of complete remission (proteinuria <1+ on urinalysisand serum albumin >35 g/l) and non-remission (proteinuria >3+ on urinalysis and serum albumin <25 g/l). Partial remission was defined as serum albumin of 25–35 g/l. The duration of remission,serum albumin and creatinine, urinary protein, and side effects were all monitored throughout the treatment and for 2 months af- ter. Glomerular filtration rate was calculated in all patients at the end of treatment by diethyenteriamine pentacetic acid (OTPA)scan. Unfortunately none of the cohort had a second renal biopsy,as the parents were very reluctant to give their consent.
The histopathology of biopsies from two patients (3 and 5) showed a mild increase in mesangial matrix and no in- crease in cellularity. Light microscopy of biopsies fromthe other patients (1, 2, and 4) also showed a mild in-crease in mesangial cellularity. No sclerosis, crescents, or membrane thickening was seen in any of the speci-mens. Direct immunofluorescence (IF) of four biopsies showed diffuse mesangial IgM (+2) and no staining forIgG, IgA, C4, and fibrinogen. IF of the fifth biopsy (pa-tient 3) was negative for all antibodies. Electron micros- copy showed mild mesangial matrix expansion in allcases. Focal or diffuse effacement of foot processes was seen in all cases. A few small deposits in the mesangiumwere observed in four cases. Overall assessment indicat- ed that four cases should be diagnosed as IgM nephropa- thy and one as minimal change glomerulonephritis.
No patient achieved complete remission. Three pa- tients (1, 2, and 3) attained partial remission (Table 1), which was not sustained for more than 1 month posttherapy. The other two patients remained non-responsiveand one of them (patient 5) progressed rapidly to end- stage renal disease during the treatment course and need-ed dialysis. Side effects observed were vomiting in fourpatients and alopecia in one patient. None of the patients had leukopenia or hemorrhagic cystitis.
Laboratory data before, during, and after cyclophosphamide therapy in individual patients ( for poor response or the need for a higher dose of cyclo-phosphamide is the ethnic and therefore the genetic In this pilot study we report our disappointing results background of our cohort, as all except one were Arab using IV-CPM in five children with SRNS secondary to MCD or IgM nephropathy. None of our patients We conclude that IV-CPM pulse therapy at a dose of achieved a complete or sustained remission. This is at 500 mg/m2 was unsuccessful in achieving complete or variance with the previous report by Elhence et al. [12].
sustained remission in children with SRNS secondary to All seven children who received IV-CPM in their study IgM nephropathy or MCD. Further randomized con- went into complete remission (100%), which was sus- trolled studies with higher doses are required.
tained in four patients. The remaining three patientssubsequently became steroid sensitive, while one offour patients who received oral cyclophosphamide re- sponded (25%) and the other three children continued 1. The International Study of Kidney Disease in Children (1981) to remain steroid resistant [12]. The poor response in The primary nephrotic syndrome in children. Identification of our patients compared with the previous study could be patients with minimal change nephrotic syndrome from initial explained by the difference in histopathology. Four of response to prednisone. J Pediatr 98:561–564 our cohort had IgM nephropathy, while all the patients 2. McBryde KD, Kershaw DB, Smoyer WE (2001) Pediatric ste- in the previous study had MCD. Some investigators roid-resistant nephrotic syndrome. Curr Probl Pediatr AdolescHealth Care 31:280–307 consider IgM nephropathy as a variant of MCD and 3. International Study of Kidney Disease in Children (1978) they are indistinguishable clinically or in their laborato- Nephrotic syndrome in children: prediction of histopathology ry characteristics [14, 15, 16]. Others think that, al- from clinical and laboratory characteristics at time of diagno- though IgM nephropathy is a variant of MCD and 4. Sorof JM, Hawkins EP, Brewer ED, Boydstun II, Kale AS, DMH, a significant percentage will develop impaired Powell DR (1998) Age and ethnicity affect the risk and out- renal function, due to the evolution of FSGS [17]. Fur- come of focal segmental glomerulosclerosis. Pediatr Nephrol thermore, it was reported that subepithelial deposits, in- flammatory cells, and the percentage of interstitium 5. Niaudet P (1994) Treatment of childhood steroid-resistant id- iopathic nephrosis with a combination of cyclosporine and IgM, IgG, and C3 deposition in MCD is univariately correlated with a poor prognosis and progression to end 6. Vehaskari VM (1999) Treatment practices of FSGS among stage renal failure [18]. IgM nephropathy was also North American pediatric nephrologists. Pediatr Nephrol thought to be an entity separate from focal glomerulo- 7. Burgess E (1999) Management of focal segmental glomerulo- sclerosis: evidence-based recommendations. Kidney Int [Suppl IV-CPM therapy was reported to be a safe, effective, and economical therapeutic modality in steroid-resistant 8. Lieberman KV, Tejani A (1996) A randomized double-blind children with idiopathic FSGS [11]. Recently, Gulati placebo-controlled trial of cyclosporine in steroid-resistant id- and Kher [11] from India reported complete remission iopathic focal segmental glomerulosclerosis in children. J AmSoc Nephrol 7:56–63 in 65% of 20 children with FSGS who were treated with 9. Grupe WE, Heymann W (1966) Cytotoxic drugs in steroid-re- IV-CPM, with the mean duration of remission following sistant renal disease. Alkylating and antimetabolic agents in last dose of IV-CPM of 12.5 months. They used month- the treatment of nephrotic syndrome, lupus nephritis, chronic ly infusions of IV-CPM at a dose of 500–750 mg/m2, in glomerulonephritis, and purpura nephritis in children. Am JDis Child 112:448–458 addition to adjunctive prednisolone [11]. Similarly, 10. Bargman JM (1999) Management of minimal lesion glomeru- Bajpai et al. [21] reported their use of IV-CPM at a dose lonephritis: evidence-based recommendations. Kidney Int of 750 mg/m2 in addition to alternate-day prednisolone in 24 patients with heterogeneous histopathology (MCD in 11. Gulati S, Kher V (2000) Intravenous pulse cyclophosphamide- 11, FSGS in 9, and MPGN in 4). At the end of 6 months -a new regime for steroid resistant focal segmental glomerulo-sclerosis. Indian Pediatr 37:141–148 of treatment, 7 (29.2%) patients each had complete re- 12. Elhence R, Gulati S, Kher V, Gupta A, Sharma RK (1994) In- mission and partial remission, while 10 (41.6%) patients travenous pulse cyclophosphamide—a new regime for steroid- showed no response to therapy. However, a higher pro- resistant minimal change nephrotic syndrome. Pediatr Nephrol portion with MCD (45.5%) achieved complete remis- 13. Niaudet P, Gagnadoux MF, Broyer M (1998) Treatment of sion compared with FSGS (22.2%) and MPGN. They childhood steroid-resistant idiopathic nephrotic syndrome.
concluded that therapy with IV-CPM has limited effica- cy in inducing sustained remission in patients with ini- 14. Al-Eisa A, Carter JE, Lirenman DS, Magil AB (1996) Child- tial corticosteroid resistance. However, sustained remis- hood IgM nephropathy: comparison with minimal change dis-ease. Nephron 72:37–43 sion is likely to occur in a significant proportion of pa- 15. Donia AF, Sobh MA, Moustafa FE, Bakr MA, Foda MA tients with late resistance and those with absence of sig- (2000) Clinical significance and long-term evolution of mini- nificant tubulointerstitial changes on renal histology mal change histopathologic variants and of IGM nephropathy [21]. This raises the possibility of achieving remission with higher IV-CPM doses in non-MCD SRNS. All our 16. Abdurrahman MB, Elidrissy AT, Mahmoud K, Rasheed S al, Mugeirin M al (1993) Failure of clinical and laboratory char- patients received a dose of 500 mg/m2 and we did not acteristics to differentiate mesangial proliferative from mini- observe neutropenia in any patient. Another explanation mal-change nephrotic syndrome. Acta Paediatr 82:579–581 17. Zeis PM, Kavazarakis E, Nakopoulou L, Moustaki M, 20. Garcia DM, Gomez-Morales M, Cortes V, Aguayo ML, Messaritaki A, Zeis MP, Nicolaidou P (2001) Glomerulopathy Gigosos RL, Lardelli P, Navas A, Aneiros J, Aguilar D (1993) with mesangial IgM deposits: long-term follow up of 64 chil- Mononuclear cell subsets in IgM mesangial proliferative glo- merulonephritis. A comparative study with minimal change 18. Kirpekar R, Yorgin PD, Tune BM, Kim MK, Sibley RK nephrotic syndrome and immunonegative mesangial prolifera- (2002) Clinicopathologic correlates predict the outcome in tive glomerulonephritis. Nephron 65:215–221 children with steroid-resistant idiopathic nephrotic syndrome 21. Bajpai A, Bagga A, Hari P, Dinda A, Srivastava RN (2003) In- treated with pulse methylprednisolone therapy. Am J Kidney travenous cyclophosphamide in steroid-resistant nephrotic 19. Kopolovic J, Shvil Y, Pomeranz A, Ron N, Rubinger D, Oren R (1987) IgM nephropathy: morphological study related toclinical findings. Am J Nephrol 7:275–280

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