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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 56-61

Therapies for steroid-sensitive nephrotic syndrome


Department of Paediatrics, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka

Date of Web Publication27-Dec-2018

Correspondence Address:
Dr A S Abeyagunawardena
Department of Paediatrics, Faculty of Medicine, University of Peradeniya, Peradeniya
Sri Lanka
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJPN.AJPN_35_18

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  Abstract 


Nephrotic syndrome (NS), a common childhood kidney disease, is associated with significant morbidity and mortality due to disease complications. Most patients who respond to corticosteroids show a relapsing course that requires repeated courses of therapy, and frequent relapses or steroid dependence are common. Most children with steroid-sensitive relapses show minimal change disease upon biopsy. Focal segmental glomerulosclerosis is the predominant histology in patients with steroid-resistant NS where renal biopsy is recommended, and a complicated disease course is anticipated. Patients with frequent relapses are at risk of severe infections, thrombosis, and hypovolemia and receive repeated and prolonged courses of prednisolone that often result in corticosteroid toxicity. These challenges have led to the use of numerous corticosteroid-sparing agents or regimens to reduce the risk of relapses as well as cumulative corticosteroid burden. This review discusses therapy-related aspects of steroid-sensitive NS and compares different regimens of corticosteroid and other immunosuppressive medications that are used in managing this condition.

Keywords: Immunosuppression, minimal change disease, noncorticosteroid, prednisone, prednisolone, steroid sparing


How to cite this article:
Thalgahagoda R S, M. Jayaweera A H, Karunadasa U I, Abeyagunawardena A S. Therapies for steroid-sensitive nephrotic syndrome. Asian J Pediatr Nephrol 2018;1:56-61

How to cite this URL:
Thalgahagoda R S, M. Jayaweera A H, Karunadasa U I, Abeyagunawardena A S. Therapies for steroid-sensitive nephrotic syndrome. Asian J Pediatr Nephrol [serial online] 2018 [cited 2019 May 21];1:56-61. Available from: http://www.ajpn-online.org/text.asp?2018/1/2/56/248646




  Introduction Top


Childhood nephrotic syndrome (NS), characterized by heavy proteinuria, edema, hypoalbuminemia, and hyperlipidemia, is the most common childhood glomerular disease worldwide. With an estimated incidence of 1–7/100,000 children per year and a prevalence of 16/100,000 children in the USA and Europe,[1],[2] it is a common cause for referral to pediatric nephrology services. Moreover, it is associated with significant morbidity, and even mortality, due to hypovolemia, thrombosis, and serious infections. While 10%–30% of patients have only a single episode and enter permanent remission thereafter, 60%–90% of patients have a relapsing illness, and about one-tenth develop steroid resistance. Fortunately, the vast majority of patients achieve spontaneous sustained remission by the end of the second decade of life. [Table 1] provides important definitions for childhood NS.[3]
Table 1: Definitions related to childhood nephrotic syndrome (adapted from Thalgahagoda et al[3]

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While NS is usually idiopathic, a small proportion of cases may be secondary or congenital.[4] NS may be the presenting feature of systemic lupus erythematosus, membranoproliferative glomerulonephritis, membranous nephropathy, immunoglobulin A nephropathy, or Henoch–Schönlein purpura.[5] Rare conditions that may present with NS include Alport syndrome and, rarely, diabetes mellitus. Congenital NS, referring to disease with onset before the age of 3 months, is chiefly caused by homozygous mutations in the NPHS1 gene that encodes the podocyte slit-diaphragm protein nephrin, and is often called the Finnish type, based on the country where it was first described and is most commonly reported from. Mutations in other genes such as NPHS2 and WT1 (diffuse mesangial sclerosis, Denys–Drash, and WAGR syndromes) are less common. Congenital NS may also follow congenital infections such as syphilis, toxoplasmosis, cytomegalovirus, and HIV.[4]

Idiopathic NS accounts for ≥90% of patients with onset between 1 and 10 years of age.[1] Based on the response to corticosteroid therapy, the condition is categorized as steroid-sensitive and steroid-resistant disease. Clinical response to corticosteroids has more prognostic value than the findings on kidney biopsy, which usually shows minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or diffuse mesangial proliferation. MCD, accounting for over 80% of cases, is characterized by steroid sensitivity in the vast majority, leading to the terms MCD and steroid-sensitive disease being used interchangeably; however, a proportion of patients have steroid resistance. FSGS, seen in around 15% of patients, is associated with steroid sensitivity in about one-third of cases.[4] Diffuse mesangial proliferation accounts for the remaining 5% of cases and is steroid responsive in about 50% of cases.

More than 90% of children with steroid-sensitive NS show MCD on biopsy. However, disease relapses lead to morbidity and decreased quality of life.[6],[7],[8] The occurrence of frequent relapses, often accompanied by steroid dependence, in about 20%–60% patients,[9] is associated with risks of complications of disease, such as severe infections, thrombosis, hypovolemic acute kidney injury, dyslipidemia, and malnutrition[10] or therapy-related adverse effects such as obesity, hirsutism, striae, hypertension, diabetes mellitus, avascular necrosis of the head of femur, and behavioral changes.[11] These concerns have resulted in the use of various corticosteroid-sparing strategies to reduce the frequency of relapses, as discussed below.


  Treatment of the Initial Episode Top


Prednisolone is the agent of choice when treating the initial episode of NS, as it is associated with remission in ≥80% of cases.[12] In 1981, the International Study of Kidney Diseases in Children (ISKDC) recommended treating the initial episode with prednisolone at 60 mg/m2 daily for 4 weeks, followed by 40 mg/m2 of prednisolone, given on 3 consecutive days out of 7 days, for 4 weeks.[6] Subsequently, intermittent prednisolone was advised to be given on alternate or every other day (EOD), referred to as modified ISKDC, or standard regimen, in managing the initial episode. In 1994, the British Association for Paediatric Nephrology and Research Unit suggested administering a dose of 60 mg/m2 every day until remission, followed by 40 mg/m2 EOD for another 4 weeks.[13] In 1988, the German Arbeitsgemeinschaft für Pädiatrische Nephrologie (APN) reported that the an 8-week regimen for the initial episode of NS was superior to a shorter regimen of prednisolone as it was associated with less severe disease course on the long term.[14]

A series of controlled studies have subsequently examined the impact of the intensity of therapy of the initial episode, in terms of total dose and/or duration of prednisolone therapy, on the severity of subsequent disease course, as assessed by the frequency of subsequent disease relapses. A controlled, prospective, multicenter study involving 71 patients showed that the frequency of relapses and the proportion with relapse at 6-month follow-up was higher with standard ISKDC regimen as compared to a 12-week regimen (60 mg/m2 daily for 6 weeks, followed by 40 mg/m2 EOD for 6 weeks), despite having a slightly lower rate of side effects.[15] However, a recent study that compared the same two regimens found no beneficial effect of prolonged treatment on the outcome in the subsequent year.[16] A study from India that compared the standard regimen with therapy for 16 weeks (2 mg/kg daily, 1.5 mg/kg daily, 1.5 mg/kg EOD, and 1 mg/kg EOD, each for 4 weeks) demonstrated an insignificant postponement of the first relapse with prolonged therapy. However, prolonged therapy was associated with a higher cumulative dose, significant steroid toxicity, and no change in the subsequent relapse rates.[17] The systematic review and meta-analysis of these and other studies suggested that extended duration of initial corticosteroid therapy reduces relapse frequency.[18]

However, recent, large, well-designed, multicentric studies with low risk of bias, conducted in the Netherlands, Japan, and India, have demonstrated no difference in key outcomes when initial therapy with predniso (lo) ne for 8–12 weeks was compared to that given for 16–26 weeks. A nationwide randomized, double-blind, placebo-controlled trial from the Netherlands showed that extending initial prednisolone treatment from 3 to 6 months while providing the same total prednisolone dose does not reduce the risk of frequent relapses.[9] An open-label multicentric study from Japan, enrolling 255 patients, found that therapy with prednisolone for 2 months was not inferior to therapy for 6 months.[19] Similarly, an Indian multicenter, placebo-controlled trial enrolling 183 patients found similar rates of sustained remission, frequent relapses, and steroid-related adverse effects in patients treated with 3 versus 6 months of steroids.[20] A recent meta-analysis including these studies indicates that outcomes are similar for therapies of 2–3 months' duration or longer than 3–4 months; it is likely that previous studies with high risk of bias had overestimated the effect of prolonged therapy compared to more recent, less-biased trials.[18]

Another concern with the standard ISKDC regimen has been the abrupt drop in corticosteroid dose from 60 mg/m2 daily to 40 mg/m2 EOD or, subsequently, its abrupt cessation that may precipitate a relapse in some patients.[21],[22] Hence, studies have compared standard 8-week therapy to slow tapering over 5–7 months, with inclusion of an EOD dose of 60 mg/m2 for 2–4 weeks after daily therapy at the same dose, and use of lower doses of EOD prednisolone beyond 40 mg/m2 EOD.[23],[24],[25] Three such studies, including one from Sri Lanka, have shown that prolonged slow tapering was associated with significantly lower proportions of patients with relapses and frequent relapses or steroid dependence, significantly lower mean relapse rates, and significantly delayed first relapse (22.8 vs. 12.5 months).[23],[24],[25] This approach overcame the abrupt drop explained previously.

A few studies suggest that the time taken to attain remission in the first episode may reflect the severity of subsequent disease; patients remitting beyond 10–14 days of therapy are more likely to be steroid dependent than that those who respond promptly.[21],[22] It is suggested that delayed time to remission might identify a category of patients that would benefit from extended initial corticosteroid therapy. Further, infections are more common in developing Asian countries and are known to trigger disease relapses.

Based on the evidence as well as concerns listed above, the authors recommend that therapy for the initial episode with prednisolone should be given at 60 mg/m2 daily for 4–6 weeks, followed by 60 mg/m2 EOD and tapering prednisolone over a period of 6–8 weeks.


  Therapy and Prevention of Relapses Top


In their studies, Choonara et al. showed successful induction of remission with short duration and lower dose regimens.[26] However, further evidence is needed to change the practice of using 60 mg/m2 of prednisolone to induce remission. The authors, therefore, recommended that a relapse should be treated with prednisolone at 60 mg/m2 daily until remission, followed by 60 mg/m2 on alternate days for 2 weeks tapering over a variable period of time determined by the frequency of relapses, i.e., more frequent relapses require longer duration of tapering. This recommendation is due to the fact that early induction with optimal doses of prednisolone will shorten the duration of relapse, thus minimizing the complications associated with a relapse.

Viral upper respiratory tract infections (URTIs) commonly precipitate relapses of NS.[27] A small, short-term increase in the usual steroid dose at the beginning of an URTI in patients with steroid-dependent NS (SDNS) has shown a reduced relapse frequency.[27],[28],[29] In patients who are off steroids, a 5-day course of 0.5 mg/kg/day prednisolone during an URTI can reduce the risk of subsequence relapse.[30]


  Comparison of Immunosuppressive Therapies Top


Cyclophosphamide

The alkylating agent, cyclophosphamide, may be administered either orally or intravenously. It is given orally at a dose of 2–3 mg/kg/day for 8–12 weeks, with a tapering steroid regimen over a variable period. Intravenously, it is administered as monthly pulses of 600 mg/m2 for 6 months. The intravenous route, while being as efficacious as the oral route, has the advantage of having fewer adverse effects. The small cumulative dose also enables a second course of intravenous cyclophosphamide, if required.[31] However, due to the long-term risk of malignancy and gonadal toxicity, especially in boys, repeated courses of the agent are best avoided. Although a study by APN reported that a 12-week course of oral cyclophosphamide resulted in a higher proportion of sustained remission than the standard 8-week regimen,[32] a subsequent controlled study showed no such difference.[33] Kemper et al. suggested that the 12-week regimen yields unfavorable results, with a majority of children with SDNS relapsing early and requiring more alternative therapies.[34] Children on cyclophosphamide therapy should be monitored for bone marrow suppression with weekly leukocyte counts, and the medication is discontinued if the count falls below 4000/mm3. The drug may be restarted with caution upon recovery of the leukocyte counts. While cyclophosphamide has been used for the treatment of NS for ≥30 years, poor outcomes in recent studies and the emergence of new, more efficacious, alternative therapies with fewer adverse effects, have resulted in decline in its usage.[35]

Levamisole

Levamisole, which has been used as a steroid-sparing agent in NS, has antihelminthic and immunomodulatory properties. Since its first description in the management of childhood NS by Tanphaichitr et al. in 1980,[36] the agents have been shown to be useful in patients with mild disease. Levamisole does not induce remission of proteinuria. It is usually administered following remission, at a dose of 2–2.5 mg/kg on alternate days, and can be given for prolonged periods as it has few adverse effects. The dose of prednisolone is tapered and often continued; however, levamisole has been shown to maintain remission even as monotherapy in children with SDNS.[37] In recent literature, daily levamisole is described as being more efficacious than alternate-day dosing, suggesting that daily therapy may be considered if response to levamisole given EOD is unsatisfactory. Abeyagunawardena et al. described significantly reduced rates of relapse with no major adverse events in children with SDNS administered levamisole daily for a year along with EOD prednisolone.[38]

Levamisole remains an effective mode of therapy for patients with frequent relapses and mild steroid dependence. While the efficacy of levamisole in patients with severe steroid dependence is limited, therapy with the agent could be considered, given its safety and recent success with daily dosing regimens. Leukopenia, the most common adverse effect associated with therapy, requires monitoring of total leukocyte counts every 12–16 weeks.[39] Hepatotoxicity and vasculitis are rare.

Cyclosporine A

The calcineurin inhibitor cyclosporine A (CsA) has been shown to be an effective steroid-sparing agent in patients with SDNS and induces remission in a high proportion of patients with steroid-resistant NS. Indeed, it is the recommended first choice of therapy for steroid-resistant NS. CsA acts by downregulating interleukin 2 production and activation of T lymphocytes. CsA is also thought to stabilize the podocyte cytoskeleton, thus reducing proteinuria independent of its immunosuppressive action. CsA is usually administered at a dose of 5–6 mg/kg/day in two divided doses and is titrated to maintain 12-h trough levels of 50–150 ng/ml. Beyond the first 3 months of therapy when trough levels should be maintained in the upper half of the target range, dose reduction may be attempted if the patient is stable. Steroids may need to be continued along with CsA, but remission can be maintained with much lower doses.

The use of CsA in SDNS is limited, chiefly by its nephrotoxicity, to use in patients with very strong steroid dependence and refractoriness to therapy with other steroid-sparing drugs. Renal function should be monitored every 1–3 months. Protocol biopsies are recommended every 2–3 years to ascertain the presence and extent of therapy-related tubulointerstitial lesions. Further, patients tend to relapse once therapy with CsA is discontinued, thus developing a state of CsA dependence, similar to the steroid dependence that necessitated its commencement. Hulton et al. reported that patients in whom CsA was discontinued following stable remission had high relapse rates and a poor response even following its recommencement.

CsA induces partial or complete remission in the majority of patients with steroid resistance. In two studies, CsA induced complete remission of proteinuria in 42% and 50% of patients and partial remission in 6% and 30% of patients, respectively;[40],[41] however, over half of the patients in the French prospective study did not respond.[42] Patients who achieved complete remission with CsA may demonstrate a steroid-sensitive disease course afterward. Such “secondary steroid sensitivity” has been observed by the authors as well. The practice guidelines by the Kidney Disease Improving Global Outcomes expert group suggest that a calcineurin inhibitor (CsA or tacrolimus) should be commenced as initial therapy for steroid resistance and continued for at least 6 months; therapy is discontinued if partial or complete remission is not achieved.

The principal adverse effect of CsA therapy is acute and chronic nephrotoxicity. Other adverse effects include hypertension, hyperkalemia, hypomagnesemia, hypertrichosis, and gum hypertrophy. The risk of gum hypertrophy is significantly reduced if good oral hygiene is maintained.

Tacrolimus

Tacrolimus is another calcineurin inhibitor that is shown to be effective in both steroid-dependent NS and steroid-resistant NS. Compared to CsA, tacrolimus appears to have similar, rather than superior, efficacy in maintaining remission of SDNS. Loeffler et al. reported excellent efficacy in steroid-resistant NS, with complete and partial remission in 81% and 13% patients, respectively. Apart from nephrotoxicity, another significant adverse effect of tacrolimus is the risk of development of insulin-dependent diabetes mellitus, which often resolves with cessation of therapy. A significant advantage of tacrolimus over CsA is the absence of cosmetic adverse effects.

Mycophenolate mofetil

Mycophenolate mofetil (MMF) is an inhibitor of purine synthesis, that thus suppresses the proliferation of both T and B lymphocytes. It is administered at a dose of 600–1200 mg/m2 daily in two divided doses, along with tapering doses of prednisolone, for 12–24 months.[39] Several small studies have shown that the agent is quite effective in maintaining remission, particularly in children with steroid dependence. Bagga et al. reported 50% or greater reduction of relapse rates and pronounced steroid sparing in 14 out of 19 patients who had failed cyclophosphamide and/or levamisole and were administered MMF along with tapering prednisolone for a mean period of 1 year. While adverse effects were uncommon, most (68.4%) patients experienced increase in relapse frequency once MMF was discontinued.[42] Hogg et al. observed sustained remission in 75% of patients administered MMF at 600 mg/m2 twice daily for 6 months or longer along with tapering doses of prednisolone during the initial 16 weeks; the remission was often sustained even after discontinuation of MMF.[43]

In a multicenter, randomized, controlled trial with a crossover design in patients with steroid dependence, MMF was found to be inferior to CsA in preventing relapses but was associated with significantly improved glomerular filtration rate.[44] Others have reported satisfactory remission when therapy with CsA was converted to MMF,[45],[46] a strategy that is particularly useful in children with nephrotoxicity due to long-term use of CsA. MMF has the advantage of improved outcomes while being associated with only mild adverse events. The efficacy of MMF requires evaluation in adequately powered randomized controlled studies.

Rituximab

Rituximab is a chimeric monoclonal anti-CD20 antibody that induces B-cell apoptosis, which in turn may interfere with T cell function, considered important in the pathogenesis of NS. Rituximab is postulated to affect the podocyte cytoskeleton, leading to a reduction of proteinuria beyond an immunosuppressive effect. Gulati et al. reported sustained remission for 1 year or longer in 83% of patients with steroid dependence treated with rituximab. In their experience, rituximab was effective in inducing complete or partial remission in 27% and 21% patients, respectively, with steroid-resistant NS. In contrast, Magnasco et al. failed to demonstrate benefit from adding rituximab to therapy with CNI for steroid-resistant NS.

A recent open-label, unicentric, randomized controlled trial from India suggested that rituximab is useful as a first-line corticosteroid-sparing therapy. The authors reported significantly higher rates of 12-month relapse-free survival, longer median time to first relapse, lower cumulative corticosteroid use, and fewer adverse effects in patients treated with rituximab compared to those given oral tacrolimus.[47] Recent studies report that maintaining depletion of B-cells in patients with SDNS by administering repeated courses of rituximab is a useful strategy that reduces relapse rates and helps sustain remission while reducing the need for other immunosuppressants.[48],[49],[50] While adverse effects are rare, rituximab may rarely induce severe hypogammaglobulinemia, leading to need for intravenous immunoglobulin infusions.[51]


  Conclusion Top


We conclude that levamisole may be considered as the first choice of alternative therapy for patients with frequent relapses and mild steroid dependence as it has few adverse effects. Patients who are unresponsive to levamisole with EOD prednisolone warrant therapy with MMF or cyclophosphamide. The use of CsA or tacrolimus is reserved for patients with severe steroid dependence, often present from the onset of disease, and for those refractory to therapy with other second-line agents. Patients receiving prolonged therapy with CsA/tacrolimus and those with CsA-induced nephrotoxicity may be successfully managed with MMF or rituximab. Calcineurin inhibitors (CsA or tacrolimus) are the agents of choice in managing patients with steroid resistance. Empiric options for therapy in refractory cases include MMF, cyclophosphamide, and rituximab. [Figure 1] summarizes the sequence of therapeutic options.
Figure 1: A general guide for selecting corticosteroid-sparing drugs in the course of managing patients with frequently relapsing or steroid-dependent nephrotic syndrome (adapted from Thalgahagoda et al.)[3]

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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