Immunosuppressive therapy of childhood idiopathic nephrotic syndrome

Review

2002 © Ashley Publications Ltd ISSN 1465-6566 513

Ashley Publicationswww.ashley-pub.com

1. Introduction

2. Goals of therapy

3. Available compounds

4. Conclusion

Monthly Focus: Cardiovascular, Renal, Endocrine & Metabolic

Immunosuppressive therapy of childhood idiopathic nephrotic syndromeA Abeyagunawardena, PA Brogan†, RS Trompeter & MJ DillonNephro-Urology Unit, Institute of Child Health, London, UK

Childhood nephrotic syndrome (NS) is a distressing chronic renal disorderwith potentially life threatening complications. Over 80% of cases in childrenare due to minimal change disease and the majority will respond to corticos-teroid therapy. Steroid-sensitive NS is considered a relatively benign condi-tion, since progression to end stage renal failure (ESRF) is extremely rare and> 80% will enter spontaneous long-term remission in later childhood. How-ever, the disease is characterised by a relapsing course, placing the child atrisk of acute complications, such as infection, hypovolaemia and thrombosis.Frequent relapses can result in a not inconsequential corticosteroid burden orprescription of cytotoxic immunosupressive therapy to control the disease. Incontrast, steroid-resistant and -refractory NS has an unfavourable outcomewith a propensity to progress to ESRF. While these clinical entities have anunpredictable response to cytotoxic immunosupressive therapy, the favoura-ble long-term renal survival associated with children who enter sustainedremission has revived the enthusiasm to treat steroid-resistant NS with moreaggressive immunosuppressive regimens.

Keywords: end-stage renal failure, nephrotic syndrome, steroid-dependent, steroid-resistant, steroid-sensitive

Expert Opin. Pharmacother. (2002) 3(5):513-519

1. Introduction

Nephrotic syndrome (NS) is characterised by heavy proteinuria, hypoalbuminae-mia, oedema and hyperlipidaemia. It is a relatively uncommon disorder with anannual incidence of 2 – 4 per 100,000 children in the UK. There is racial varia-tion in the susceptibility with a reported incidence of 9 – 16 per 100,000 BritishAsian children [1].

The syndrome can be subclassified into congenital, primary and secondaryforms. The majority of children with primary disease have minimal changes in theglomeruli on histology and 90 – 95% will respond to corticosteroid therapy [1].Since there is a close correlation between steroid sensitivity and minimal changedisease [2], a renal biopsy is not generally recommended in the absence of risk fac-tors for the other forms of NS. Thus, on the whole, most children with NS aretreated empirically with corticosteroids in the absence of a histological diagnosis.However, a minority of children with underlying focal segmental glomerulosclero-sis and diffuse mesangial proliferation will also respond to corticosteroid therapy.Consequently, a clinically useful classification of NS is that of steroid-sensitive NS(SSNS), steroid-resistant NS (SRNS) or steroid-dependent NS (SDNS). SSNS hasa favourable outcome, with high probability of long-term remission in later child-hood with preserved renal function, while the prognosis of SRNS is moreguarded, with significant progression to end stage renal failure (ESRF) [1].

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Immunosuppressive therapy of childhood idiopathic nephrotic syndrome

514 Expert Opin. Pharmacother. (2002) 3(5)

2. Goals of therapy

In the preantibiotic era, children with NS often died, usuallyfrom overwhelming infections arising as a result of poornutrition and the immunosuppression which is an inherentfeature of the disease. With the introduction of antibioticsand later the use of corticosteroid therapy, the mortality ratehas fallen dramatically.

Prednisolone was first prescribed for children with NS in1956, when Arneil described four children (aged 2 – 8 years)who responded to prednisolone at a dose of 60 mg/day [3].However, the mechanism of this beneficial effect is stillunclear. Subsequently, a dose of 60 mg/m2/day has beenaccepted as standard treatment for inducing NS remission [4].Although the majority of children will respond to corticoster-oid therapy, it is not curative and many children subsequentlyrelapse. Each relapse is associated with an increased risk ofmorbidity from infection, thromboembolism and hypovolae-mic shock [5,6]. The occurrence of relapse necessitates cleartherapeutic strategies in order to maintain remission. Despitea paucity of knowledge regarding the underlying pathologicalmolecular mechanisms responsible for NS and NS relapse,numerous therapeutic regimens have been proposed to reducethe relapse rate and minimise steroid toxicity based both onthe results of clinical trials and on personal clinical experience.

This article reviews the current approach to the therapy ofNS in childhood, with particular emphasis on the use of corti-costeroid and immunosupressive agents, based on publishedevidence from the last few decades.

3. Available compounds

3.1 CorticosteroidsCorticosteroids remain the drugs of choice for induction ofremission in childhood NS in the absence of risk factors forother forms (persistent hypertension, macroscopic haematuriaand renal impairment after correction of hypovolaemia).Unfortunately, there are no controlled trials examining differ-ent corticosteroids in children with NS and it is therefore dif-ficult to compare the efficacy of prednisone with that ofprednisolone or with other corticosteroids, such as deflazacort[7]. However, prednisone is rapidly metabolised into its activecompound prednisolone and there is little to choose betweenthe two preparations. In addition, low-dose alternate-dayprednisolone is effective in maintaining remission in childrenwith frequently relapsing disease [1].

3.1.1 Induction of remissionThe treatment protocol, prednisolone 60 mg/m2 (maximumdose 80 mg) daily in divided doses for 4 weeks followed by40 mg/m2/day prednisolone for three consecutive days of aweek (intermittent therapy) for the next 4 weeks for child-hood NS, was designed by International Study of KidneyDisease in Children (ISKDC) > 30 years ago and was empiri-cal [4]. Most paediatric nephrologists recommend alternate-

day therapy in the second month of treatment in preferenceto intermittent therapy because it reduces the relapse ratemore effectively [8]. In the past 20 years there has been consid-erable debate regarding the optimisation of the initial corti-costeroid protocol. Several controlled studies have examinedthe effect of the duration of prednisolone therapy in relationto long-term outcome and most have compared test regimensagainst the ISKDC regimen. Shorter prednisolone courses areassociated with a higher rate of relapse [9]. In contrast, signifi-cantly greater sustained remission was achieved by intensify-ing the initial steroid therapy. Using data from several multi-centre studies, it has been recommended that the total dura-tion of corticosteroid therapy should exceed that used inISKDC regimen [10,11] and the currently recommended ther-apy is an initial course of prednisone of at least 3 months [10].In a meta-analysis, the relative risk of relapse at 12 – 24months was shown to fall by 0.133 (13%) for every addi-tional month of corticosteroid therapy for 7 months [10].However, it is unclear whether this is a clinically useful reduc-tion in terms of reducing the incidence of SDNS and in theuse of second-line immunosuppressive agents, such as cyclo-phosphamide (CYC) and cyclosporin (CYA). The studiesincluded in this meta-analysis were generally poor, with onlyone of the five studies included demonstrating adequate allo-cation concealment. Furthermore, the studies all reportedsomewhat different side effects, making interpretation of theimpact of increased duration of steroid therapy on side effectprofile difficult to ascertain. In the light of this, there is nonational or international consensus regarding the ideal steroidregimen at disease presentation.

There are no firm clinical or laboratory data that predictthe risk of future relapse in individual patients after the initialepisode. However, the number of relapses within the first6 months of presentation is highly predictive of the subse-quent course [12]. There are recent tissue-type studies in chil-dren with NS suggesting that particular human leukocyteantigen (HLA) types are associated with an unfavourablecourse in SSNS [13]. However, the practical value of this obser-vation currently remains unclear. A history of intrauterinegrowth retardation [14] as well as younger age at onset of NS(< 4 years) have been reported as risk factors for frequentlyrelapsing disease [15].

The optimal initial dose and the duration of corticosteroidtherapy that is most beneficial for the induction of sustainedremission with minimal side effects remains controversial.

3.1.2 Treatment of relapsesA cardinal feature of SSNS is the tendency to relapse. Induc-tion of remission is achieved with prednisolone 60 mg/m2/dayuntil urinary remission (negative or trace on protein dip stickfor 3 consecutive days) followed by alternate-day prednisolonefor a further 4 weeks [1]. Unlike the initial treatment regimen,more intensive treatment of relapses with higher doses orlonger duration of prednisolone may have little or no effect onthe subsequent relapse rate [16]. Although induction of remis-

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Expert Opin. Pharmacother. (2002) 3(5) 515

sion has been successfully achieved in one study with lowerdoses of prednisolone (30 mg/m2/day), the duration of remis-sion in this retrospective study was difficult to analyse [17].Such therapy is not currently recommended, as it couldpotentially lead to more relapses and difficulties in definingchildren who develop secondary steroid resistance.

Children with frequently relapsing disease (two or morerelapses during the first 6 months from the initial response orfour or more relapses within any 12-month period) or SDNS(two consecutive relapses occurring during or within 2 weeksof stopping prednisolone therapy) need individualised treat-ment. Although there is no data on the merits of long-termmaintenance prednisolone as opposed to repeated standardrelapse treatment, most favour the former approach [1]. Thedose of prednisolone should be titrated to the lowest that issufficient to maintain remission in order to minimise steroidtoxicity. Most school age children can tolerate 0.5 – 0.6 mg/kgon alternate days, while pre-school children may tolerate up to1 mg/kg on alternate days. The duration of alternate-day pred-nisolone therapy should be 3 – 6 months minimum, althoughsome children may benefit from longer-term treatment [1].

3.1.3 Steroid toxicitySteroid toxicity is of major concern to children with NS andtheir families. There is a positive correlation between toxicityand cumulative steroid dose in children with SSNS [18]. Obes-ity, hirsutism, hypertension and psychological and behav-ioural disturbances are usually reversible after cessation ofsteroid therapy [18]. However, striae and cataracts are irreversi-ble [18]. Growth failure is observed in children with prolongeddaily steroid therapy and administration of alternate-day ster-oid is usually not associated with significant growth impair-ment (although may still cause impairment of growth athigher alternate-day doses) [19,20]. In order to minimise toxic-ity, patients on long-term corticosteroid therapy should bereviewed every 3 months for measurement of blood pressureand assessment of growth [1]. Screening for cataracts should beperformed at least annually [1].

3.2 Cytotoxic therapyThe importance of immune dysregulation in the pathogenesisof childhood NS was first suggested in 1974 [21]. Subsequentreports have attributed the observed suppression of immuneresponsiveness in the disease to an abnormality of T lym-phocyte number or function, thereby implicating T lym-phocytes in the pathogenesis of NS [22-24]. Humoral andcellular immune mechanisms mediated by cytokines and lym-phokines are thought to be involved in the generation of NS[25]. Both SSNS and SRNS can apparently arise through T celldysfunction that leads to the synthesis of a still-unidentifiedcirculating factor which compromises the glomerular permea-bility barrier. However, in a subset of SRNS, the disease is dueto a primary defect in the glomerular filtration barrier. Thepotential interactions between the immune dysfunction andaltered structural properties of the glomerular epithelium

remain highly speculative, although these observations repre-sent the scientific rationale for the use of cytotoxic and immu-nosuppressive drugs in childhood NS.

SSNS represents the milder spectrum of childhood NS andthe majority of affected children are successfully treated withcorticosteroid therapy alone [26,27]. Children with frequentlyrelapsing or SDNS (where significant steroid toxicity limitsthe use of corticosteroid as monotherapy) are candidates fortreatment with cytotoxic or other immunosuppressive drugs[28]. In contrast, SRNS represents a more heterogeneous groupinclusive of rare disorders, such as focal and segmentalglomerulosclerosis (FSGS), with variable response to immu-nosuppressive therapy and often progressing to ESRF [1].

3.2.1 CyclophosphamideOver the past 30 years the alkylating agent CYC has beenused for the treatment childhood NS with a reasonable degreeof success. It can be effective in inducing sustained remissionin SSNS, SRNS (particularly those forms with minimalchanges in histology) and SDNS [29,30]. CYC can induce somedegree of steroid sensitivity in previously SRNS [31].

In one study of SSNS, CYC given orally at 3 mg/kg/day for8 weeks induced sustained remission in 69% at 1 year and44% at 5 years [32]. Younger children [32] and SDNS patientsfared less well [33]. Although it was reported that CYC 2 mg/kg/day p.o. for 12 weeks achieved a higher proportion of sus-tained remission than 3 mg/kg/day for 8 weeks [34], a subse-quent controlled study failed to confirm this finding [35].Therapy with CYC for 2 weeks is associated with a higherrelapse rate [36]. Relapses following CYC are generally treatedwith steroids [1] and although a second course of CYC is effec-tive for the induction of long-term remission [29], highercumulative doses of CYC are associated with an unquantifiedlong-term risk of malignancy and infertility, with obviousadverse implications for children [29,37]. Thus, multiplecourses of CYC should be reserved for selected individuals.

Response to CYC in SRNS is unpredictable, with limitedpublished data available. SRNS with minimal change on his-tology usually responds to CYC therapy and subsequentrelapses may become steroid-responsive [31]. The outlook forSRNS due to FSGS is less favourable [38].

Intravenous pulsed CYC may offer a safe and effectivealternative to oral CYC in children in whom compliance maybe an issue [39].

3.2.2 ChlorambucilChlorambucil (CHL) can induce a prolonged steroid-freeremission in children with SRNS or SDNS. The efficacy ofCHL is similar to that of CYC [40]. As with CYC, concernsregarding long-term risk of malignancy and infertility limit itsprolonged or continuous use. The dose used in publishedstudies averages ~ 0.2 – 0.3 mg/kg/day p.o. for 8 – 12 weeks[41]. There is a suspicion that the risk of haematological malig-nancy is greater with chlorambucil than with CYC [28] and itshould therefore be used with discretion in selected patients.

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3.2.3 CyclosporinIn SSNS, CYA is generally reserved for children who demon-strate steroid dependence following a course of CYC. CYA isnow increasingly used in preference to CYC in childrenapproaching puberty (especially boys who are more vulnerableto gonadal toxicity from CYC than girls [11]), in whom thedisease may be nearing the end of its natural history, obviatingthe need for prolonged immunosuppression. The usual doseof CYA is 3 – 5 mg/kg/day to achieve a 12 h trough bloodlevel of 50 – 150 µg/l [27,41], usually for up to 1 year. However,the optimal duration of CYA therapy is unclear. Unlike CYCor CHL, relapse rates are high when the drug is discontinued[42]. Sustained remissions have been achieved with continuousCYA therapy for 5 years [43] but the use of CYA necessitatesregular and frequent monitoring of blood levels (at least tri-monthly when stable [1]), regular estimation of glomerular fil-tration rate because of its potential nephrotoxicity, and somewould recommend surveillance renal biopsies every 2 years toscreen for toxicity. Moreover, prolonged therapy with CYAmay be associated with a long-term risk of lymphoma [44,45]

and thus should be considered only for selected patients withSSNS who are difficult to control.

In contrast, CYA has successfully induced remission in chil-dren with SRNS due to FSGS, in whom previous attempts tocontrol the disease with alkylating agents had failed [46].Increasingly, CYA has been used as second-line treatment forcorticosteroid-resistant FSGS, with supportive evidence fromrandomised controlled trials in adults but uncontrolled stud-ies in children [38]. A higher proportion of sustained remis-sions have been achieved with CYA administered inconjunction with alternate-day corticosteroids than CYAalone [38]. However, many children relapse following discon-tinuation of CYA therapy, making them CYA-dependant. Inconclusion, it remains unclear whether CYA therapy improveslong-term renal survival despite the encouraging short-termsuccess in induction of remission in SRNS due to FSGS.

3.2.4 Other immunosuppressive drugsThe observation of relentless progression to ESRF in SRNSand refractory NS has led to more aggressive therapeutic trialsof immunosuppression, including combination regimens withvariable outcomes. Nitrogen mustard, tacrolimus, mycophe-nolate mofetil and vincristine have been tried with variablesuccess [47-50] but have not gained a great deal of popularity asa result of the relatively successful results with CYA. Com-bined therapy with high dose methyl prednisolone and CYCor CHL has been advocated by some and although some pae-diatric nephrologists recommend protocols such as thatdescribed by Mendoza et al. [51], no controlled data support-ing this approach exist.

3.3 Immunomodulatory drugsLevamisole (LEV) is an antihelminthic drug with immu-nomodulatory effects and steroid-sparing properties [1]. It hasbeen successfully used at a dose of 2.5 mg/kg on alternate

days, alone or in conjunction with alternate-day prednisolonefor frequently relapsing and SDNS [1,27,52]. The major advan-tage of LEV is its steroid-sparing effect with minimal toxicity,although vasculitic rash, liver toxicity and reversible leucope-nia have been reported infrequently [53-55]. LEV is less effectivewhen used alone than in combination with corticosteroids [55].No literature-based firm recommendations can be made onhow prednisolone should be withdrawn during LEV therapyin order to minimise the risk of relapse. Although a controlledtrial has questioned the therapeutic value of LEV therapy [56],a recent report demonstrated that prolonged therapy withLEV (2 – 3 years) reduced the average number of relapses perpatient from 5.2 – 0.65 in the first year and 0.69 in the sec-ond year of follow-up [57]. Therefore, LEV remains an attrac-tive alternative to corticosteroids in frequently relapsing NSand SDNS. The efficacy of LEV in SRNS is not clear andLEV is not routinely recommended for SRNS.

3.4 Toxicity of cytotoxic and immunosuppressive drugs: a paediatric perspectiveThe toxicity of cytotoxic drugs, such as CYC and CHL, havebeen well documented for many years and include short- andlong-term toxicity. Bone marrow suppression with leucope-nia, anaemia and thrombocytopenia, alopecia, nausea,abdominal pain and haemorrhagic cystitis (for CYC), consti-tute the most important short-term side effects. Arterialhypertension, hypertrichosis, gingival hyperplasia, hypomag-nesaemia, hyperuricaemia and nephrotoxicity may also beencountered during CYA therapy.

Infection is a universal concern in patients receiving cyto-toxic or immunosuppressive therapy. Concomitant glucocor-ticoid therapy adds to this problem and should beadministered as an alternate-day regimen wherever possible. Adetailed account of the plethora of opportunistic infectionsthat can occur is beyond the scope of this article; however, therisk of infection with cytomegalovirus, Pneumocystis cariniiand Varicella zoster remains ever-present [58].

Of particular concern regarding the use of cytotoxic drugsis the long-term cancer risk, although this has not been quan-tified in children [28,41]. There is generally a lack of dataregarding cumulative dose toxicity for the various agents men-tioned above but this is an important factor to bear in mindand should be discussed with both parents and children beforethe onset of therapy. Other potential medium and long-termside effects, such as teratogenicity and infertility, are alsoimportant considerations. Males appear to be more prone toCYC-induced gonadal toxicity than females [29,59], althoughin reality this rarely becomes a major concern at the doses anddurations of cytotoxic immunosuppression employed in thetreatment of childhood NS [29]. Cytotoxins and immunosup-pressive drugs undoubtedly play an important role in thetreatment of certain forms of childhood NS, although thesedrugs in themselves are associated with significant morbidityand even mortality. It is therefore of particular importancethat the benefits and risks of these agents are weighed when

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considering their use in the treatment of nonmalignant dis-eases such as NS. This point is worthy of emphasis since themajority of children with SSNS will outgrow the disease bypuberty irrespective of therapy [5].

Within certain populations a proportion of individualswith sporadic SRNS with FSGS on histology will have muta-tions in the gene NPHS2, which codes for the glomerularpodocytic protein podocin [60,61]. Such individuals are unre-sponsive to any form of immunosuppressive therapy and ithas been suggested that all cases of sporadic SRNS be testedfor NPHS2 mutations in an attempt to avoid unnecessaryimmunosuppression in some children. Whilst in the nearfuture this will be possible, genetic mutational analysis forNPHS2 is not yet widely available and thus currently thisapproach is not widely utilised in routine clinical practice.

4. Conclusion

4.1 Treatment of SSNSThe ideal corticosteroid regimen to treat an initial episode ofNS should rapidly induce remission of the nephrotic state,reduce the subsequent relapse rate and have minimal corticos-teroid toxicity. Most children receive an adequate dose of ster-oid to induce and consolidate remission with a prescription ofdaily steroid for 28 days. Thus, remission can be induced withprednisolone 60 mg/m2/day as a single morning dose for 4weeks followed by a tapering regimen of alternate-day pred-nisolone for a further 6 – 12 weeks in order to achieve sus-tained remission.

Children with frequently relapsing or steroid-dependentdisease who develop steroid toxicity will benefit from sec-ond-line treatment, either with LEV for 12 – 24 months(2.5 mg/kg alternate days) or an 8-week course of oral CYC(2 – 3 mg/kg/day). CYA is generally recommended for post-CYC steroid dependency.

4.2 Treatment of SRNSA child with SRNS should undergo renal biopsy. A significantproportion of children with SRNS and minimal change dis-ease on histology will respond to an 8-week course of CYC orprolonged therapy (≥ 1 year) with CYA.

SRNS due to FSGS poses a greater therapeutic challengefor the paediatric nephrologist and there is currently debateregarding the optimal therapy for such patients, the best avail-able evidence supporting the use of CYA. However, relapse iscommon when CYA is stopped and prolonged treatment isnecessary. Despite such endeavours, a significant proportionwill progress to ESRF. The benefits of immunosuppressivetherapy in SRNS should be meticulously balanced againsttoxicity, remembering that refractory NS only results in renaldeath and renal transplantation in these patients may offer abetter long-term outcome than that associated with excessiveimmunosuppression [62].

Recent advances in the understanding of the genetics andmolecular biology of SRNS have now enabled the identifica-tion of some patients who will not respond immunosuppres-sion and in the near future this will become crucial to themanagement of children with SRNS.

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AffiliationA Abeyagunawardena MD*, PA Brogan MD*†, RS Trompeter MD & MJ Dillon MD*These authors contributed equally to the preparation of this manuscript†Author for correspondenceNephro-Urology Unit, Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UKTel: +44 207 905 2651; Fax: +44 207 916 0011;E mail: [email protected]

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Immunosuppressive therapy of childhood idiopathic nephrotic syndrome