Obidike, EO

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108Nigerian Journal of Clinical PracticeMarch 2009 Vol 12(1):108-112CONCURRENT USE OF CYCLOPHOSPHAMIDE AND PREDNISOLONE INCHILDHOOD NEPHROTIC SYNDROME IN SOUTH-EAST NIGERIA; AREPORT OF 5 CASESEO ObidikeABSTRACTIntroduction:Objective:Methods:Results:Conclusion:Department of Paediatrics, University of Nigeria Teaching Hospital, Enugu, Nigeria.Nephrotic syndrome is a chronic renal disease that can lead to end stage renal disease. There aredifferent histological types with global variations in frequency. Literatures reviewed showed that the Africanvariant is less likely to be minimal change variant. No clear treatment protocol for it has been most beneficial.This paper aims to evaluate the outcome of a treatment protocol using cyclophosphamide andprednisolone concurrently.A low dose and short duration concurrent use of cyclophosphamide and prednisolone was used fortreating children with nephrotic syndrome who had not developed derangements of their renal function. Thecase files of those that were treated and followed up over a 10 year period or until they were above 18years ofage were analysed for their clinical parameters.Five cases were treated and all have been in clinical remission for more than 4 years as at the time ofthe review, though 2 of them relapsed twice initially. They were all aged above 6 years and had microscopichematuria. The 3 cases whose ESRs were done had high levels. Two cases that presented 1 yr after the onset oftheir symptoms resolved without relapse while 2 out of the remaining 3 in whom this interval was less than 6months relapsed.This treatment protocol appears beneficial to childhood nephrotics in this environment andshould be used.Key Words : Cyclophosphamide, Prednisolone, Childhood, Nephrotic Syndrome, Nigeria.INTRODUCTIONNephrotic syndrome is a clinical condition ofoedema and proteinuria (>1gm/M /24hrs or40mg/M /hr) in which the renal histology (lightmicroscopy) demonstrates fatty degeneration of thetubules associated with normal appearing glomeruli.The oedema in this chronic renal disease follows thehypoproteinaemia (serum albumin level of <2.5g/dl)that results from the massive proteinuria. Thedifferent renal histological findings include theminimal change nephrotic syndrome (MCNS)which constitutes about 84.5% of cases; focalsegmental glomerulosclerosis, (FSGS) 9.5%;membranoproliferative glomerulonephritis( M P G N ) , 2 . 5 % a n d m e m b r a n o u sglomerulonephritis (MGN), the remainingpercentage. African children with nephroticsyndrome rarely show the minimal change lesion.22123Correspondence: Dr E O ObidikeIn a study of nephrotic syndrome in children aged 316 years in Ilorin, Nigeria, out of the 8 biopsies thatwere done, focal mesangial proliferativeglomerulonephritis was seen in 63% while minimalchange, membranoproliferative and mesangialproliferative glomerulonephritis were equallydistributed amongst the remaining.The diagnosis which is both clinical and laboratory isbased on the presence of oedema, hypoproteinemiaand massive proteinuria. Uncomplicated cases havenormal serum urea, electrolytes and creatine levels,though some may have hematuria. Though thehypoproteinemia in this condition is not the onlycause of the oedema that makes most of them topresent, however the loss of oncotic pressuresubsequent on the hypoproteinemia initiates all thebodily responses 24 culminating in the oedema.Without intervention, persistent proteinuria of themagnitude in nephrotic syndrome is expected toultimately lead to oedema.Though a chronic disease, spontaneous remission,especially with the minimal change histological type,4109is speculated to often occur, whilst a few willprogress to end-stage renal disease.Drug treatment has offered the best chance ofreversing the renal process and resolving thebiochemical derangements and clinical features.Steroids were initially found to be very useful, andalthough more than 80% of patients with MCNSresponded to the steroids steroid responders,unfortunately, 50-60% of these steroid respondersdeveloped frequent relapses or became steroiddependent. The prolonged use of steroids in thefrequent relapsers and steroid dependents also madethem to suffer from the adverse effects of steroidtherapy. The other histological types on the otherhand were poorly responsive to steroids. Thesesetbacks led to the discovery of the cytotoxics, andthe alkylating agents cyclophosphamide andchloroambucil were found beneficial whensteroids failed. Due to the initial favourableresponse of the commoner MCNS to steroids, themainstay of treatment or the first line drug for thetreatment of nephrotic syndrome became thesteroids. The need to improve treatment outcomeresulted in the use of the effective drugs singlyor as a combination; sequentially andconcurrently. There appears to be a consensus thatthe combination therapy gave better results thansingle drug therapy. Combination treatment havebeen found useful in other chronic ailments e.g.tuberculosis, HIV/AIDS and hypertension andnephrotic syndrome, a chronic ailment may not bemuch different.Many factors however affect the outcome of drugtreatment in nephrotic syndrome and include; thehistological type, first presentation or relapse, ageof the child at the onset, duration oftreatment, type of drug, type of response tosteroid therapy, dose of the drug, the renalfunction status and the patient's race.Long remission periods have been associated withthe use of cyclophosphamide either sequential to orin combination with steroids. A comparativeanalysis studying the effect of a low dose(2.5mg/kg/day) and a high dose (5mg/kg/day)cyclophosphamide over a period showed that lowdose used long enough was capable of giving goodresults while at the same time avoiding the toxic orside effects of a high dose. A study, using a dose of3mg/kg/day for 8 weeks, showed beneficial resultsand concluded that a lower dose may work and thatfor children, shorter durations may even beeffective.McCrory et al had commented that there is noagreement regarding the most desirable program oftherapy for children with nephrotic syndrome. Theyrecommended the evolution of a new and safer but5678910,11129,11,13,141 5,161718 1913,1715,20,21 2122 2014,15 3,415161516effective therapy to control or prevent relapses. Tuneet al shared the same view when they suggested thatthe present conservative approach to the managemento f s t e r o i d r e s i s t a n t f o c a l s e g m e n t a lglomerulosclerosis should be changed since thiscondition is more likely to progress to end-stage renaldisease.There is therefore the need to work out treatmentmodality or modalities that will be most beneficial tothese patients especially for those in this environmentthat are not likely to be the MCNS type.This study therefore tried to look at the outcome ofchildren presenting with nephritic syndrome whowere treated with a low dose short course ofcyclophosphamide and prednisolone.All the children that presented with oedema,hypoproteinemia and massive proteinuria butwithout deranged serum urea, electrolyte andcreatine values seen over a ten year period (Nov 1994Oct 2004) in a children's specialist hospital atOnitsha, Southeast Nigeria were enrolled afterexplanation.Information to be obtained included their ages, sexes,blood pressures, complete blood count anderythrocyte sedimentation rates, serum urea,electrolytes and creatine, serum proteins, 24hrurinary protein, urine stripe test for protein and rbcsusing Combur . Abdominal ultrasound was donewhen abnormal masses were palpated par abdomen.Patients were followed up and their blood pressures,serum proteins and urinalysis were monitored.A concurrent use of low dose and short durationprotocol using cyclophosphamide and prednisolonewas used in treating the children. It consisited of:Cyclophosphamide in a dose of 2 2.5mg/kg/day to the approximate total doseobtainable from the available tablet strength of100mg/tablet. This was given once daily for atotal of 8 weeks. The dosage was adjusted as thepatient's weight changed with loss of oedema.Prednisolone was given in a dose of 1.5mg/kg/day to achieve an approximate totaldaily dose divisible by 5 since the tablets are in5mgs strength. It was given in two divideddoses and for a total of 12 weeks, with doseadjustment according to changes in the patient'sbody weight. After 10 weeks, the dose wastapered off at the rate of 0.5 mg/wk.Adjunctive therapy of furosemide in a dose of 24 mg/kg/day in two divided doses was given tothose with discomforting oedema or anarsaca.Other clinical problems e.g. infections that werepresent were treated appropriately.Relapses during follow up were documented andgiven the same course of treatment.2310METHODOLOGYNigerian Journal of Clinical Practice March 2009, Vol.12(1) Concurrent Use of Cyclophosphamide Obidikehowever had deranged renal functions and were nottreated here but were referred while another twoobjected to the treatment. The 5 remaining case fileswere then evaluated.Table 1 shows the epidemiological features of thepatients, any other problems detected, additionaltreatment given and duration of remission.Table 2 shows the laboratory results before institutionof treatment.No renal biopsies were done on them.practice and since a pattern seemed to have beenobserved with these 5 cases, it was thoughtworthwhile to communicate a preliminary report onthe evolving pattern.Finally, no clear different protocol was used for therelapsed cases. It is pertinent to also mention thatnone relapsed within less than 6 months period.The clinical feature, oedema, which the patientsrelated to was used as the determinant of theirclinical state i.e. remitted or relapsed.They were followed up to the time of the report or, upto the age 18 years if they attain that age before thetime of the report.Nine case files were identified as cases of nephroticsyndrome seen over the 10 year period. TwoThe 1st three attained 18 years and stopped comingfor consultation.yrs - years, mths - months,wks - week, pres. - presentationTable 2:Pt id = patient identity, Alb = Albumin, Glo =GlobulinUnfortunately, time, distance and costs constraintsmade the necessary blood and urinary biochemicalmonitoring difficult.Secondly, 5 cases are inadequate for statisticalconclusions but nephrotic syndrome is not a verycommonly seen condition in any particular privateRESULTSLaboratory Results.DISCUSSION110Nigerian Journal of Clinical Practice March 2009, Vol.12(1) Concurrent Use of Cyclophosphamide Obidike111In this review, there were 4 males and one femalewhich is in keeping with involvement of more malesthan females in nephrotic syndrome.Though two cases relapsed, all of them ultimatelywent into clinical remission, with the least havingbeen in remission for 48 months now. On the otherhand, when only steroids were used, the percentageof steroid responders reduced with time. Though allthe cases had hematuria, which could also be foundin MCNS, the presence of a high ESR in thosemonitored would suggest that these nephrotics weresecondary in origin. That would have meant poorresponse to treatment as found by some workers. Inthis review however, two of the initial 3 respondershad high ESRs.Considering the impact of age, they were all above 6years of age and this may have improved theirchances of going into remission since it is knownthat if the age is less than 6 years, they tended torelapse into adulthood.Additionally, some other workers have shown thatthe shorter the time of onset to treatment, the betterthe response to treatment. This review has findingsat variance with this view because the two cases thatlasted for more than 12 months before the onset oftreatment resolved with the first course while 2 outof the 3 cases that were less than 6 months relapsed 2times over.This review also showed that the second relapsetook a shorter time than the first to manifest which isthe finding in other studies. The subsequent relapseamongst the relapsed cases tends to reinforce theview that a history of relapse increases the frequencyof subsequent relapses.This low dose short duration concurrent use ofcyclophosphamide and prednisolone in thetreatment of nephrotics seems to offer good resultsthat may be comparative to others. Generally, whilstlow dose cyclophosphamide and short durationprednisolone were associated with relapses, thisconcurrent use of both drugs in this manner seemedto have had a synergistic action of both drugs on thedisease process. Other studies seem to support thisview.From the foregone therefore, it is probable that theconcurrent use of cyclophosphamide andprednisolone in the treatment of nephrotics in thisenvironment maybe a type of the non-conservativemanagement of secondary nephrotics that wasadvocated for by Tune et al.These findings could result in the childhoodnephrotics in our environment enjoying fewerhospital consultations consequent upon fewerrelapses, better health without the otherwiselaborious medication schedules and the consequentpositive impact of these on their socio-economicwell being if this protocol is utilized.82523262728281523ACKNOWLEDGEMENTI wish to express my profound gratitude to the staffand management of Prime Concept Consultants,Children Specialist Hospital located at 36 Obosi road,Nkpor who handled these patients and patients whobenefited from it. Their cooperation made thiscommunication possible.My gratitude also goes to my wife, Dr (Mrs.) N.D.Obidike, and Dr Gideon Anigbo for finding time toproof read the manuscript.REFERENCES1. Travis L. Finberg L,Konop R, SpitzerA, Trachtman H, LangmanC . B .2.3.4. Adedoyin O.T, Gbelee H.O.D and Adeniyi A.5. Gulati S, Pokhariyal S, Sharma R. K,Elhence R, Kher V, Pandey C. M and GuptaA.6. McEnery P.T and Strife F.C.7. Arneil G.C.8. Churg J, Habib R, White R. H. R.9. Arneil G. C and Lam C.N.In Nephrotic Syndrome.( E d s ) e M e d i c i n eSpecialties>Paediatrics>Nephrology. 2005International Study of Kidney Disease inChildren: Primary nephrotic syndrome inc h i l d r e n : c l i n i c a l s i g n i f i c a n c e o fhistopathologic variants of minimal change anddiffuse mesangial hypercellularity. A report ofthe International Study of Kidney Disease inChildren. 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Concurrent use of cyclophosphamide and prednisolone in childhood nephrotic syndrome in South-Easr Nigeria, A report of 5 cases

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Concurrent use of cyclophosphamide and prednisolone in childhood nephrotic syndrome in South-Easr Nigeria, A report of 5 cases

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