Intravenous methylprednisolone in idiopathic childhood nephrotic syndrome

Abstract

The aim of our study was to determine the clinical course of children with idiopathic childhood nephrotic syndrome (ICNS) who received intravenous methylprednisolone (ivMP) following failure to achieve remission with standard oral prednisolone therapy. This study was designed as a retrospective case record review from 1993 to 2007. Sixteen children received ivMP over the 15-year study period, of whom ten responded, achieving clinical remission. The remaining six children with steroid resistant nephrotic syndrome (SRNS) underwent biopsy [four focal segmental glomerulosclerosis (FSGS), two minimal change disease (MCD)]. Three responders developed late secondary steroid resistance (two FSGS, one MCD). At the latest follow-up (mean 6.7 years), three of the ten ivMP responders and none (0/6) of the children with SRNS had heavy proteinuria and chronic kidney disease (CKD) stage 3-5. The remaining 13 children demonstrated significant steroid dependency but had achieved stable remission following cyclophosphamide and/or ciclosporin therapy. The majority of children with ICNS who do not respond to 4 weeks of daily prednisolone therapy will enter remission following three to five doses of ivMP, thus avoiding a renal biopsy at initial presentation. These children are likely to develop steroid dependency, and the majority will require treatment with alkylating agents and/ or ciclosporin to maintain remission. The requirement for ivMP in this setting appears to be associated with a risk of developing CKD in the longer term.

Introduction

Steroid responsiveness is the single most important factor determining the prognosis of idiopathic childhood nephrotic syndrome (ICNS) [1, 2]. Despite its prognostic importance, significant variation exists in the definition of steroid responsiveness and its corollary, steroid resistance or nonresponsiveness. The International Study of Kidney Disease in Children (ISKDC) defined non-responders as those children who failed to achieve remission following 8 weeks of the standard ISKDC oral prednisone regimen (60 mg/m2 daily for 4 weeks followed by 40 mg/m2 on alternate days for 4 weeks) [2]. Other reported definitions include failure to achieve remission following 4 weeks of daily oral prednisone at a dose of 60 mg/m2 [3] and 4 weeks of daily oral prednisone at a dose of 60 mg/m2 followed by three doses of intravenous methylprednisolone (ivMP) [4]. While good data exist regarding long-term outcomes following the ISKDC and other standard oral prednisone and prednisolone regimens, there are currently little long-term outcome data following regimens where additional ivMP is administered. One recent French study has reported an increased prevalence of steroid dependency and requirement for ciclosporin in children administered three doses of ivMP following failure to respond to 30 days of oral prednisone compared with those who responded to this initial course of oral therapy [5].

In our tertiary nephrology centre, children with newly presenting ICNS and no atypical features [6] are initially treated with 4 weeks of daily prednisolone at a dose of 60 mg/m2 (maximum dose 80 mg). Those in whom nephrotic range proteinuria persists after 4 weeks are then treated with ivMP 15 mg/kg for 3–5 consecutive days, with a renal biopsy being reserved for those who fail to respond to this additional therapy.

The aim of this study was to determine the clinical course and long-term outcome of those children treated using this regimen over the 15-year period from 1993 to 2007, in particular to ascertain whether this population has a high rate of adverse clinical outcomes.

Methods

All children with a diagnosis of ICNS were identified from our comprehensive departmental database. Those who received ivMP following failure to achieve remission after 4 weeks of oral prednisolone were identified, and a detailed review of their case records was undertaken.

Methylprednisolone was administered intravenously at a dose of 15 mg/kg daily. The drug was diluted in 0.9% saline to a total volume of 50 ml and administered over 4 h. Children underwent cardiac monitoring for the duration of the infusion, and nursing observations (pulse, blood pressure and respiratory rate) were recorded every 30 min throughout the course of the infusion and for 1 h following its completion.

Results

A total of 16 children (12 males) were treated with ivMP following failure to respond to 4 weeks of daily oral prednisolone between 1993 and 2007 (Fig. 1). Their median age at presentation was 3.8 years (range 1.6– 11.9 years). Eleven were of white UK origin, four were of Asian origin and one was Afro-Caribbean. Six of the children received daily ivMP for 3 days, and the remaining ten children were given daily ivMP for 5 days. Apart from transient hypertension during the infusion in three children, no immediate adverse-effects were noted.

Fig. 1.

Clinical course of 16 children who were treated with intravenous methylprednisolone (ivMP) following failure to achieve remission with 4 weeks of standard oral prednisolone treatment. FSGS Focal segmental glomerulosclerosis, MCD minimal change disease, CKD chronic kidney disease, SDNS steroid-dependent nephrotic syndrome, MMF mycophenolate mofetil, ACEi angiotensin converting enzyme inhibitor, CSA ciclosporin

Following ivMP treatment, ten children achieved remission. The remaining six who failed to respond were classed as having SRNS and underwent a renal biopsy. A histopathological diagnosis of focal segmental glomerulosclerosis (FSGS) was made in four and two had histological features consistent with minimal change disease (MCD). In all six of these children who failed to respond to ivMP, clinical remission was achieved following the addition of further immunosuppressive agents to the therapeutic regimen — cyclophosphamide in three, ciclosporin in two and tacrolimus in one child.

All 16 children demonstrated a frequently relapsing course of nephrotic syndrome, necessitating treatment with additional agents (Table 1). The initial steroid sparing agent administered was cyclophosphamide in 14 children and levamisole and tacrolimus in one child each. Ten of the children who were initially treated with cyclophosphamide subsequently required ciclosporin to reduce relapse frequency and steroid dependency. Four of these ciclosporin-treated children went on to receive mycophenolate mofetil (MMF) because of evidence of ciclosporin-induced nephrotoxicity on routine surveillance biopsies.

Table 1. Clinical parameters, therapeutic regimens, and outcomes of the 16 children with ICNS enrolled in our study.

Patient no.	Sex	Ethnie origina	Age at presentation (years)	ivMP (days)	Response to ivMP	Treatment received after ivMPb			Biopsyc	Follow-up duration (years)	Clinical status at last reviewb, c
						CYC courses (n)	CSA	MMF
1	F	C	7.8	5	✔	1	×	×	None	3.3	Remission following CYC
2	F	C	6.1	5	✔	1	×	×	None	1.9	Remission following CYC
3	M	As	4.8	5	✔	×	×	×	None	6.3	Remission following levamisole for 24 months
4	M	As	2.6	5	✔	2	✔	✔	MCD	6.3	SDNS, CNI toxicity, did not tolerate MMF, on CSA
5	M	C	4.5	3	✔	1	✔	×	MCD	5.8	Remission on CSA
6	M	C	2.1	3	✔	1	✔	✔	MCD	11.1	Remission, CNI toxicity, on MMF
7	M	C	2.1	3	✔	1	✔	×	MCD	2.5	Remission on CSA
8	M	A-C	2.3	5	✔	2	✔	✔	MCD	8.8	CKD 5, late SRNS, NPHS2 mutation -ve
9	M	C	3.1	5	✔	2	✔	×	FSGS	14.0	CKD 3, proteinuria 2 g/day, Cr 152 μmol/1, on ACEi
10	M	As	2.0	5	✔	2	✔	×	FSGS	12.2	CKD 5, late SRNS, NPHS2 mutation-ve
11	M	C	1.6	5	×	2	×	×	MCD	11.7	Remission following second course of CYC
12	M	C	2.2	3	×	1	✔	✔	MCD	4.5	SDNS, on prednisolone and CSA
13	M	C	5.0	3	×	1	✔	×	FSGS	1.6	Remission, on ACEi
14	F	с	11.9	5	×	1	×	×	FSGS	3.0	Remission following CYC
15	M	As	4.7	5	×	2	✔	×	FSGS	12.3	Remission on CSA
16	F	C	5.1	3	×	×	×	×	FSGS	2.6	Remission, initial tacrolimus for 18 months, then ACEi

ICNS, Idiopathic childhood nephrotic syndrome; ivMP, intravenous methylprednisolone; M, male; F, female

^aC, Caucasian; As, Asian; A-C, Afro-Caribbean

^bCYC, Cyclophosphamide; CSA, ciclosporin; MMF, mycophenolate mofetil

^cCNI, calcineurin inhibitor; ACEi, angiotensin converting enzyme inhibitor; MCD, minimal change disease; FSGS, focal segmental glomerulosclerosis; SDNS, steroid-dependent nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome; CKD, chronic kidney disease; Cr, creatinine; NPHS2, podocin gene

At their most recent review after a mean follow-up of 6.7 years (range 1.6–14 years), three of the ten children who achieved remission with ivMP have heavy proteinuria and chronic kidney disease (CKD) stage 3-5. All of these children had developed late steroid resistance at 3, 31 and 66 months, respectively, following their initial presentation, and all underwent renal biopsy: two had FSGS and the third child had MCD. Mutations in the gene encoding podocin, NPHS2, were absent in all three patients.

All of the remaining seven children achieved stable remission: two following 8 weeks of oral cyclophosphamide, one with levamisole and the remaining four following ciclosporin therapy. Two of the latter group were among the four who developed histological evidence of ciclosporin toxicity and received MMF.

Of the six children with initial SRNS, two achieved stable remission following 8 weeks of oral cyclophosphamide treatment and are now off all treatment. Two with a histological diagnosis of FSGS, treated with an angiotensin converting enzyme inhibitor following failure to achieve remission with cyclophosphamide and ciclosporin, have evidence of mild ongoing proteinuria, and a further two continue in stable remission on ciclosporin and alternate-day prednisolone. All six patients had normal renal function at the latest follow-up.

Discussion

In this retrospective study we report the clinical course of 16 children with ICNS who continued to demonstrate heavy proteinuria following 4 weeks of standard prednisolone treatment and proceeded to receive daily ivMP for 3–5 days. At follow-up, all demonstrated a frequently relapsing pattern of nephrotic syndrome, and 15 required cyclophosphamide and/or ciclosporin to maintain remission. Three children, all of whom achieved initial remission following ivMP, developed late steroid resistance and have progressed to CKD stage 3-5. Secondary steroid resistance is known to occur in up to 20% of children with ICNS and is a recognized risk factor for poor long-term outcome [7]. Six children with either initial or late SRNS had a histopathological diagnosis of FSGS. It is therefore clear that those children who require the administration of ivMP clinically behave very differently from those who respond to standard oral prednisolone therapy [8].

Although steroid responsiveness is the single most important factor in determining the clinical course and prognosis of ICNS [1], the definition of SRNS remains variable. The ISKDC study defined SRNS as a lack of response to 8 weeks of standard prednisone therapy [2]. One can argue that using this definition may lead to a delay in diagnosis and result in unnecessarily prolonged exposure to high-dose steroids in those who are predestined to be steroid-unresponsive. Since the vast majority of children with ICNS achieve remission following 2– 3 weeks (and 94% by the end of the first month of prednisone therapy [9]), others have recommended that children exhibiting persistent proteinuria following 4 weeks of treatment should be labeled as having SRNS and undergo a biopsy [10]. While there are some merits in following this recommendation, it will result in a larger number of biopsies being performed.

While the original ISKDC protocol, along with more current protocols in many countries, recommends the use of prednisone, it has been standard practice in the UK to prescribe oral prednisolone to children with ICNS. Prednisone is assumed to be inactive and is converted to the bioactive moiety prednisolone predominantly by the liver enzyme 11-β-hydroxydehydrogenase. In the absence of significant liver disease, this conversion is usually rapid and extensive. Although head-to-head studies comparing prednisone and prednisolone are lacking in children with ICNS, studies in adults following renal transplantation have demonstrated that no difference exists in the systemic bioavailability of prednisolone when oral prednisolone and prednisone are compared. Similarly, there appears to be no difference in post-absorption prednisolone pharmacokinetics following the administration of the two drugs [11]. We are, however, aware of anecdotal reports of patients who were unresponsive to prednisolone responding promptly to prednisone and stable remission being maintained on lower doses of prednisone than prednisolone, perhaps suggesting a different bioavailability of these drugs in children with nephrotic syndrome. We cannot, therefore, confidently exclude the fact that some of our patients might have responded to prednisone.

We believe our practice of administering ivMP for 3- 5 days following non-response to four weeks of oral prednisolone, which is similar to the policy adopted by a majority of French Paediatric Nephrologists [4, 5], has a number of advantages. It will help achieve remission in those children who require a higher dose of steroid to enter remission and also in those where adherence with initial oral therapy has been poor. The rate of biopsy is also reduced - only 6/16 (37.5%) of our patients with ICNS underwent a renal biopsy following failure to achieve remission after four weeks of oral prednisolone. Whilst generally considered to be a safe procedure in experienced hands, the risks of renal biopsy and the associated risks of sedation and/or general anesthesia are greater in the small, immunosuppressed, edematous child [12]. Finally, in achieving earlier remission there is the potential to reduce complications associated with nephrotic state, including thrombosis and infection [4].

Our approach will assist the counseling of families in terms of their child’s likely clinical course and prognosis. We have shown that children with ICNS who require ivMP following non-response to 4 weeks of oral prednisolone are likely to demonstrate strong steroid dependency and a requirement for steroid-sparing agents, such as cyclophosphamide and ciclosporin [4, 5]. Children who receive ivMP in this setting are also more likely to belong to the small group of patients with ICNS who develop CKD.

Although none of our patients developed any serious adverse effects, ivMP therapy has been reported to be associated with a number of complications, including hypertension, hyperglycemia and behavioral problems [13]. Cardiac arrhythmias, including atrial fibrillation, have been reported in adults. However, in children receiving ivMP treatment, self-limiting sinus bradycardia appears to be the predominant rhythm disorder [14].

On the basis of these observations, we recommend the administration of ivMP to all children with ICNS who fail to respond to 4 weeks of oral prednisolone. Those receiving this therapy should remain under intensive surveillance, and the family should be counseled on the increased likelihood of requirement for intensive immunosuppressive therapy and adverse long-term outcomes.