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Table of Contents
CLINICAL PRACTICE GUIDELINES
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 48-66

Steroid sensitive nephrotic syndrome: Revised guidelines

Aditi Sinha1, Arvind Bagga1, Sushmita Banerjee2, Kirtisudha Mishra3, Amarjeet Mehta4, Indira Agarwal5, Susan Uthup6, Abhijeet Saha7, Om Prakash Mishra8
1 Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
2 Department of Pediatrics, Institute of Child Health, Kolkata, India
3 Department of Pediatrics, Chacha Nehru Bal Chikitsalaya, Delhi, India
4 Department of Pediatrics, Sawai Man Singh Medical College, Jaipur, India
5 Department of Pediatrics, Christian Medical College, Vellore, India
6 Department of Pediatrics, Trivandrum Medical College, Thiruvananthapuram, India
7 Department of Pediatrics, Lady Hardinge Medical College, New Delhi, India
8 Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

Date of Submission10-Sep-2021
Date of Decision11-Sep-2021
Date of Acceptance13-Oct-2021
Date of Web Publication28-Dec-2021

Correspondence Address:
Arvind Bagga
Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ajpn.ajpn_34_21

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  Abstract 


Justification: Steroid-sensitive nephrotic syndrome (SSNS) is one of the most common chronic kidney diseases in children. These guidelines update the existing Indian Society of Pediatric Nephrology recommendations on its management. Objective: To frame revised guidelines on diagnosis, evaluation, management, and supportive care of patients with the illness. Process: The guidelines combine evidence-based recommendations and expert opinion. Formulation of key questions was followed by review of literature and evaluation of evidence by experts in two face-to-face meetings. Recommendations: The initial statements provide advice for evaluation at onset and follow-up and indications for kidney biopsy. Subsequent statements provide recommendations for the management of the first episode of illness and of disease relapses. Recommendations on the use of immunosuppressive strategies in patients with frequent relapses and steroid dependence are accompanied by suggestions for step-wise approach and plan of monitoring. Guidance is also provided regarding the management of common complications including edema, hypovolemia, and serious infections. Advice on immunization and transition of care is given. The revised guideline is intended to improve the management and outcomes of patients with SSNS and provide directions for future research.

Keywords: Calcineurin inhibitors, frequent relapses, levamisole, minimal change nephrotic syndrome, mycophenolate mofetil, rituximab, steroid dependence


How to cite this article:
Sinha A, Bagga A, Banerjee S, Mishra K, Mehta A, Agarwal I, Uthup S, Saha A, Mishra OP. Steroid sensitive nephrotic syndrome: Revised guidelines. Asian J Pediatr Nephrol 2021;4:48-66

How to cite this URL:
Sinha A, Bagga A, Banerjee S, Mishra K, Mehta A, Agarwal I, Uthup S, Saha A, Mishra OP. Steroid sensitive nephrotic syndrome: Revised guidelines. Asian J Pediatr Nephrol [serial online] 2021 [cited 2023 May 27];4:48-66. Available from: https://www.ajpn-online.org/text.asp?2021/4/2/48/334036



Nephrotic syndrome, characterized by edema, heavy proteinuria (>1 g/m2 daily; >40 mg/m2/hr), and hypoalbuminemia (serum albumin <3 g/dL), is one among the most common kidney diseases in childhood. The condition has an annual incidence ranging from 1.2 to 16.9 per 100,000 children.[1],[2] While nephrotic syndrome is usually primary or idiopathic, evaluation might reveal an underlying systemic illness in 5%–10% of patients. Kidney biopsy reveals minimal change disease in ~80% of patients and focal segmental glomerulosclerosis (FSGS) and mesangioproliferative glomerulonephritis (GN) in 7%–8% each. Therapy with prednisolone results in complete remission of proteinuria in 85%–90% of patients, termed steroid-sensitive nephrotic syndrome (SSNS). While the outcome in patients with SSNS is satisfactory, approximately 50% show frequent relapses or steroid dependence, and 3%–10% show late steroid resistance.[3],[4],[5]


  Objective Top


Guidelines on the management of SSNS, by the Indian Society of Pediatric Nephrology, were first published in 2001[6] and updated in 2008.[7] With increasing availability of evidence on various therapies, these guidelines have been revised. Guidance is based on the strength and quality of evidence using the GRADE model proposed by the American Academy of Pediatrics.[8] Ungraded statements (indicated by X) are like practice points, not supported by sufficient evidence. [Table 1] highlights key changes in present guidelines compared to 2008[7] and those recently proposed by the Kidney Disease Improving Global Outcomes.[9]
Table 1: Comparison between present and 2008 Guidelines of the Indian Society of Pediatric Nephrology, and Kidney Disease Improving Global Outcomes 2021[9]

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  Process Top


Workgroups were constituted to address key issues, including (i) evaluation at baseline and follow-up, role of biopsy, genetic testing, and differential diagnosis; (ii) management of the initial episode and subsequent relapses; (iii) management of frequent relapses; and (iv) supportive care and outcomes. Separate workgroups have addressed guidelines on the definition and management of steroid-resistant nephrotic syndrome.[10] The workgroups identified gaps in knowledge, formulated questions, and developed consensus statements before the meeting in New Delhi on April 5, 2019, when the evidence was discussed through alternating breakout and plenary sessions. Research studies were rated from A to D using standard criteria, and each consensus statement was assigned one of two levels of recommendation, based on the assessment of relative benefit versus harm, and relevance in context of availability and cost, and the feasibility of monitoring [Supplementary Table 1].[11] Draft guidelines were again discussed in Pune on December 21, 2019. The final manuscript was circulated to all participants for approval.


  Definitions Top


Criteria for defining the course of nephrotic syndrome are shown in [Box 1].[12],[13],[14] For purpose of this guidelines, unless stated, the term “frequent relapses”' includes patients with “steroid dependence,” and prednisolone and prednisone are used interchangeably. The management of initial and late resistance, defined as lack of remission following 6-week prednisolone therapy [Box 1], is discussed separately.[10]



Patients with frequently relapsing and steroid-resistant nephrotic syndrome are at high risk of complications, due to the illness and toxicity of medications. We advise that these patients, and those younger than 1 year, be managed by pediatric nephrologists.

Guideline 1: Evaluation

1.1 In a patient presenting with recent onset of edema, we recommend the following investigations to confirm the diagnosis of nephrotic syndrome: (i) urinalysis and (ii) blood levels of urea, creatinine, albumin and total cholesterol [Box 2] (X)



1.2 We suggest additional evaluation in selected patients [Box 2] (X)

1.3 We recommend that parents be taught to maintain a record of proteinuria (by dipstick or boiling), infections and medications received. (X)

Rationale

Children with the first episode of nephrotic syndrome require evaluation to confirm the diagnosis and screen for an underlying cause and complications. Family history of nephrotic syndrome, asthma and allergies, and renal diseases are asked for. Features including fever, abdominal pain, rash, arthralgia, oliguria, hematuria, and history of drugs or infections suggest an underlying cause, e.g., systemic lupus erythematosus and IgA vasculitis. Height, weight, and blood pressure should be recorded; weight monitoring helps in the assessment for edema.

Investigations advised at the initial episode are listed in [Box 2]. The diagnosis is based on the presence of nephrotic range proteinuria, hypoalbuminemia, and edema. Majority of the patients show total cholesterol levels exceeding 200 mg/dL. Nephrotic range proteinuria is present if in an early morning urine sample protein is 3–4+ (dipstick/boiling test), spot protein to creatinine ratio is >2 mg/dL, or the protein excretion is >40 mg/m2 per hr on a timed sample. Precise estimation of 24-hr protein excretion is cumbersome and is seldom necessary. Urine microscopy is normal, except for hyaline or granular casts; occasional microscopic hematuria is not uncommon. Persistent microscopic hematuria or red cell casts suggest disease other than minimal change nephrotic syndrome, such as infection-related GN, C3 glomerulopathy, systemic lupus, or vasculitis.[1] Additional investigations are required for their diagnosis. Since patients with nephrotic syndrome do not have increased prevalence of urinary tract infections, routine urine cultures are not necessary.

With an estimated prevalence of bacteriologically positive pulmonary tuberculosis of 296 per 100,000 population in India, the risk of latent tuberculosis infection in childhood is high.[15],[16] Tuberculin test is suggested before the first course of steroid treatment, especially with history of contact.[16] Chest radiography is done in patients with positive tuberculin test; those with features of tuberculosis require appropriate therapy. Patients with positive tuberculin reaction, but no radiological or bacteriological evidence of tuberculosis, should receive isoniazid prophylaxis for 6 months.[16] The prevalence of hepatitis B in nontribal Indian populations is low (2.4%; 95% confidence interval [CI], 2.2%–2.7%),[17] and routine screening is not required.

Genome-wide association studies have identified variants in multiple MHC class II molecules as risk factors for SSNS.[18] The diagnostic and prognostic utility of various biomarkers of minimal change disease is limited.[19] There is, currently, no role for biomarkers or genetic studies in these patients.

Subsequent evaluation

Parents are instructed to monitor the child's urine at home, using dipstick or boiling test, and are explained the features of a relapse. During remission, they are advised to screen for proteinuria 2–3 times a week; the child is also examined every day during infections, or if edema is present. Frequent assessment of biochemistry is not necessary. Evaluation of patients during relapses also includes screening for complications [Box 2].

Guideline 2: Kidney biopsy

2.1 We recommend kidney biopsy in nephrotic syndrome, in the presence of (i) persistent microscopic hematuria, gross hematuria, or acute kidney injury not attributed to hypovolemia; (ii) systemic features: fever, rash, arthralgia, and low complement C3; (iii) initial or late corticosteroid resistance; and (iv) prolonged (>30–36 months) therapy with calcineurin inhibitors (CNIs), or reduced kidney function during their use (1B)

2.2 We suggest performing kidney biopsy before initiating therapy with CNIs (X)

2.3 We recommend light microscopy and immunofluorescence examination on all kidney biopsies. Electron microscopy is required in patients with gross or persistent microscopic hematuria, low C3, and suspected disorders of glomerular basement membrane. (X)

Rationale

Clinicopathological studies show that kidney biopsy is not routinely required in children with idiopathic nephrotic syndrome before therapy with corticosteroids.[20],[21],[22] Remission of proteinuria following steroid therapy is the most important predictor of long-term outcome.[3],[23] The chief indication of kidney biopsy is in patients who fail to show complete remission of proteinuria, despite 6-week daily therapy with prednisolone (steroid-resistant illness).[10],[24] A biopsy is indicated in patients with gross hematuria or persistent microscopic hematuria at the onset (≥5 red cells per high-power field, on 3 or more occasions, in urine centrifuged at 400 g for 4–5 min) or extrarenal features of a systemic disease.[20],[21],[22],[23],[25]

An age of onset of more than 12 years is often cited as an indication for performing a kidney biopsy. Review of literature in adolescent-onset nephrotic syndrome suggests that a combination of features, including persistent microscopic hematuria, low C3, and steroid resistance, detects all patients with membranous nephropathy or proliferative GN.[20],[21],[22],[26],[27] This might obviate the need for a kidney biopsy in adolescents presenting with typical nephrotic syndrome that is steroid sensitive. Since infants (<12-month-olds), including those with congenital nephrotic syndrome, are likely to show histological features other than minimal change disease or an underlying genetic change, we advise next-generation sequencing in these patients.[10] Patients with onset of idiopathic nephrotic syndrome beyond infancy should receive therapy with prednisolone and are advised to undergo kidney biopsy if they show steroid resistance.

The large majority of patients with SSNS show minimal change disease, and less commonly, FSGS or mesangioproliferative GN.[20],[21],[22],[28] More than 90% of children with minimal change disease, 50% with mesangioproliferative GN, and 30% with FSGS have steroid-sensitive disease. Patients with frequent relapses do not require a biopsy before initiating therapy with steroid-sparing agents such as levamisole, cyclophosphamide, mycophenolate mofetil (MMF), or rituximab.[29] The exception is before the use of CNI.

While there is limited guidance to support kidney biopsy in patients with SSNS before the therapy with CNIs,[9],[30] information on the extent of tubular atrophy and interstitial fibrosis is useful when planning therapy. Therapy with CNI might result in acute nephrotoxicity, manifested as acute tubular injury and isometric tubular epithelial vacuolization.[31],[32] Chronic nephrotoxicity, characterized by striped tubulointerstitial fibrosis, has been reported in 25%–43% of biopsies following therapy (for 2.5–3.5 years) with cyclosporine or tacrolimus.[33],[34],[35] While a recent report found low risk of nephrotoxicity despite prolonged use of tacrolimus,[36] most reports suggest similar risk with both medications.[34],[37] We therefore suggest considering kidney biopsy before initiating therapy with CNIs, particularly in patients with prolonged disease and unclear course, and informing the clinician regarding baseline histological changes and allowing appropriate counseling. In view of long-term risks of nephrotoxicity, kidney biopsy should be performed following prolonged therapy with CNI, or if the therapy is associated with decline in eGFR that persists despite reduction in CNI dose.[9],[38]

An adequate biopsy specimen should preferably include the corticomedullary junction and approximately 20 glomeruli to exclude the diagnosis of FSGS.[39] Apart from renal histology, the biopsy provides information on extent and morphology of glomerulosclerosis and associated tubulointerstitial changes. The diagnosis of IgA nephropathy, C3 glomerulopathy, and early membranous nephropathy is suggested by immunofluorescence studies. While kidney biopsies from all patients with nephrotic syndrome should be examined by electron microscopy, the facility is often not available. Ultrastructural examination helps confirm the diagnosis of minimal change disease (effacement of podocyte foot processes; no electron dense deposits), differentiate primary from secondary FSGS (diffuse versus focal foot process effacement), categorize membranous nephropathy and C3 glomerulopathy, and identify disorders of glomerular basement membrane.[40]

Guideline 3: Therapy for the first episode of nephrotic syndrome

  • We recommend that therapy for the initial episode should comprise prednisolone at a dose of 60 mg/m2/day (2 mg/kg/day, maximum 60 mg in 1–2 divided doses) for 6 weeks, followed by 40 mg/m2 (1.5 mg/kg, maximum 40 mg as single morning dose) on alternate days for the next 6 weeks, and then discontinued. (1A)


Rationale

In 1981, the International Study of Kidney Disease in Children (ISKDC) proposed that the first episode of nephrotic syndrome be treated with daily prednisone for 4 weeks, followed by intermittent therapy for the next 4 weeks, and then discontinued.[41] Later, a randomized controlled trial (RCT) by the Arbeitsgemeinschaft für Pädiatrische Nephrologie showed that therapy with prednisolone for 6 weeks daily and 6 weeks alternate day was better in terms of reduced incidence of relapses over the next 12–24 months.[42] In efforts to define optimal therapy for the initial episode, several RCTs have investigated the duration and dose of prednisolone, based on which, a meta-analysis, in 2007, concluded that prolonging therapy for 6 months was associated with reduced risk of relapses and of frequent relapses (relative risk [RR] 0.55; 95% CI 0.39–0.80).[43] However, most studies included in this analysis had methodological flaws, resulting in a high risk of bias.

Four large multicenter RCTs published in the last 7 years have challenged the previous results [Supplementary Table 2]. These studies, representing outcomes in over 800 patients across the Netherlands, UK, Japan, and India, show that extending initial therapy beyond 8–12 weeks does not influence either the time to first relapse or the risk of frequent relapses at 1–2 years' follow-up. These studies had low risk of bias; three were placebo-controlled. A meta-analysis that included three of these studies showed that the risk of frequent relapses at 1–2 years' follow-up was lower for 3-months' therapy or longer versus 2-months' therapy (RR 0.68; 95% CI 0.47–1.0), but not for 5-months' therapy or longer versus 3-months' therapy (RR 0.78; 95% CI 0.50–1.22).[44] Subgroup analysis, limited to studies at low risk of bias, indicated similar risk for frequent relapses in patients treated for 2–3 months versus 3–6 months. These findings are confirmed with inclusion of the PREDNOS study [Supplementary Figure 1].[45] While post-hoc analyses in two studies suggest a trend for benefit with prolonged therapy in young children, this finding requires confirmation.[45],[46]

Based on pharmacokinetics and variations by age, prednisolone is preferably dosed by body surface area in children.[47] However, estimation of body surface area involves complex formulae with variable results.[48] Calculation using body weight is convenient but results in relative underdosing, particularly in young children.[47],[49] Underdosing, using weight-based calculations, was associated with increased risk of frequent relapses in some,[50],[51] but not in all studies.[52],[53] Experts therefore prefer to administer prednisolone based on body surface area for young children.[47]

Daily prednisolone is administered in single or divided doses, with similar time to remission.[54] There is no evidence to support therapy with preparations other than prednisone or its active metabolite, prednisolone.[55] Use of deflazacort, betamethasone, dexamethasone, or methylprednisolone is not advised. Prednisolone is best given following food; therapy with antacids, ranitidine, or proton pump inhibitors is not routinely required.

Guideline 4: Therapy of relapses

  • We recommend that relapses be treated with prednisolone at 60 mg/m2/day (2 mg/kg/day; maximum 60 mg) in single or divided doses until remission (protein trace/nil for 3 consecutive days), followed by 40 mg/m2 (1.5 mg/kg, maximum 40 mg) on alternate days for 4 weeks. (1C)


Rationale

Almost one-half of the relapses are precipitated by minor infections, usually of the upper respiratory tract. Treatment of infection may rarely induce remission, avoiding the need for corticosteroid therapy. A relapse has conventionally, albeit empirically, been treated as outlined above, but guidelines vary in the duration of therapy. Remission is achieved by 7–10 days, and daily therapy is seldom necessary beyond 2 weeks. In case of persistent proteinuria, daily therapy with prednisolone may be extended, to maximum of 6 weeks. Lack of remission despite treatment with 6 weeks' daily prednisolone indicates late steroid resistance that requires specific evaluation and management.[10]

Dose based on body surface area and weight is associated with similar time to remission and frequency of subsequent relapses.[52],[53] Retrospective studies and small RCTs suggest that reduced dose or abbreviated duration of therapy with prednisolone is effective in inducing and maintaining remission [Supplementary Table 3]. Well-powered studies are required to evaluate the optimal dose and duration of prednisolone for relapses.

Guideline 5: Management of frequent relapses and steroid dependence

Definition

Frequent relapses are defined by the ISKDC as occurrence of two or more relapses in the first 6 months after initial response or four or more relapses in a year.[3] These patients are at risk of morbidity associated with multiple relapses and corticosteroid toxicity. The term has been used for over 40 years, with minor modifications. In addition, we propose that patients with three or more relapses in any 6 months be also classified as frequent relapsers [Box 1]. Steroid dependence, as previously defined, includes patients with two consecutive relapses, while receiving or within 2 weeks of discontinuing prednisolone.[3],[6]

The occurrence of two or more relapses in the first 6 months is usually associated with high frequency of relapses in the subsequent 12–24 months.[3] Patients experiencing four relapses annually receive ~165–200 mg/kg (4.6–5.6 g/m2) prednisolone, corresponding to 0.45–0.55 mg/kg (12.5–15.5 mg/m2) daily. As 12-week prednisolone therapy for the initial episode (~115 mg/kg; ~3.4 g/m2) might be associated with adverse effects,[55],[56] the risk of steroid toxicity in patients with three relapses in any 6 months or four relapses annually is considerable.[57]

Two additional situations might suggest the need for steroid-sparing therapy. The first is a patient with significant steroid toxicity [Box 1] and fewer relapses (3 relapses/year; 2 relapses in 6 months). The second is the occurrence of two relapses in 6 months during long-term therapy with corticosteroids or steroid-sparing agents. In both instances, it is rational to manage the patients as frequent relapsers, even if they do not satisfy standard definitions. While stable remission (sustained remission or infrequent relapses, i.e. up to one relapse in 6 months) during therapy with steroid-sparing agents is acceptable, the definition of failure of therapy depends on the medication, interval between relapses, and need for concomitant corticosteroids.

Choice of therapy

We recommend that the choice of immunosuppressive strategy for patients with frequent relapses be based on considerations of its efficacy and adverse effects, patient age, steroid threshold, severity of relapses, and features of steroid toxicity [Figure 1]. (X)
Figure 1: Management of frequently relapsing or steroid-dependent nephrotic syndrome. The initial strategy is to administer prednisolone at a dose of 0.5–0.7 mg/kg on alternate days. In patients with stable remission (sustained remission or infrequent relapses), therapy may be tapered to 0.2–0.3 mg/kg on alternate days for 6–12 months. Daily therapy at the same dose for 5–7 days, during minor infections, prevents infection-associated relapses. Patients who relapse at steroid threshold >0.7 mg/kg or show steroid toxicity require therapy with steroid-sparing medications [Table 2]. The choice of agents is based on disease severity, adverse effects, patient age, cost of therapy, and parental preference. Levamisole or mycophenolate mofetil are preferred medications for mild disease. Patients with high steroid threshold (>1 mg/kg on alternate days), complicated relapses and those with significant steroid toxicity [Box 1] may be treated with mycophenolate mofetil at higher doses (1000–1200 mg/m2/day) or cyclophosphamide. The use of cyclophosphamide is avoided in children <5–7 years and in peri-pubertal boys due to reduced efficacy and risk of gonadal toxicity, respectively. Patients who relapse despite therapy with two or more steroid-sparing agents (difficult-to treat steroid sensitive disease) are considered for therapy with calcineurin inhibitors, and failing that, rituximab. The use of rituximab is avoided in young children due to the risk of hypogammaglobulinemia.

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Rationale

In patients with frequent relapses, guidelines recommend that corticosteroid therapy for the relapse be prolonged and tapered over 3 months or longer.[9],[30],[58] The dose at which relapses occur (steroid threshold) is a marker of disease severity. Prolonged therapy with alternate-day prednisolone might maintain remission in patients with low threshold relapses (<0.7 mg/kg on alternate days).

Steroid-sparing interventions are necessary in patients who continue to relapse frequently or show evidence of steroid toxicity while on alternate-day prednisolone [Figure 1]. There are limited data on relative efficacy of various steroid-sparing agents, and the choice of immunosuppressive strategy is guided by its efficacy, safety, cost and availability, patient age, disease severity, and parental preference [Table 2]. Potent medications are preferred in patients with high threshold (>1 mg/kg on alternate day) relapses, relapses associated with life-threatening complications, or relapses with significant steroid toxicity [Box 1] and [Table 2]. Occurrence of stable remission (up to one relapse in 6 months) during such therapy is acceptable, and except in severe steroid dependence, prednisolone is tapered and discontinued over few months. Therapy may be modified in patients with frequent relapses or significant adverse effects.
Table 2: Immunosuppressive medications for frequent relapses

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A proportion of patients with SSNS show disease characterized by multiple relapses despite therapy with steroid-sparing agents and/or medication-associated toxicity. We propose defining difficult-to-treat nephrotic syndrome as patients with (i) frequent relapses or infrequent relapses with significant steroid toxicity; and (ii) failure of two or more steroid sparing agents: levamisole, cyclophosphamide, or MMF. These patients might merit therapy with agents such as CNI and rituximab.

While the approach to management indicated in [Figure 1] suffices in most instances, individual situations may require different preference. Patients diagnosed either with steroid dependence soon after initial therapy, or with significant steroid toxicity at diagnosis of frequent relapses, may be considered directly for steroid-sparing therapies. Therapy with oral cyclophosphamide is avoided in young patients and in pubertal or postpubertal boys. Therapy with CNI may be preferred to MMF in very young patients with significant steroid toxicity, even though the definition of difficult-to-treat SSNS is not met.

Long-term corticosteroids

  • In patients with frequent relapses, we suggest tapering prednisolone to a dose of 0.5–0.7 mg/kg on alternate days, for 6–12 months (2B)
  • In patients receiving long-term alternate-day prednisolone, we recommend administering the same dose daily for 5–7 days during fever or respiratory tract infection. (1B)


Rationale

Therapy with alternate-day prednisolone is the initial strategy for managing patients with frequent relapses.[6],[58] Alternate-day prednisolone, often used as the control limb in RCTs, showed satisfactory response in 43%–82.5% of patients [Supplementary Table 4]. A balance of benefit over harm is lacking, and there are risks of corticosteroid toxicity. Therefore, in patients in remission at prednisolone dose of 0.5–0.7 mg/kg for a few months, the medication may be tapered to ~0.2–0.3 mg/kg on alternate days. The duration of therapy is at physician discretion, based on its efficacy and assessment of toxicity through monitoring of weight, height, blood pressure, ocular toxicity, and hyperglycemia [Table 2].


  Daily prednisolone during infections Top


More than one-half of relapses in SSNS occur following upper respiratory tract infections. Evidence from three studies [Supplementary Table 5] indicates that, beginning with the onset of infection, switching therapy from alternate-day to daily administration of prednisolone for 5–7 days prevents the occurrence of relapses. One cross-over trial also supports the use of low-dose daily prednisolone in preventing infection-associated relapses in patients off corticosteroids.[59] Results of the PREDNOS2 trial will clarify the role of these strategies in preventing infection-associated relapses (ISRCTN10900733).


  Daily prednisolone in low-dose Top


Data from an open-label RCT[60] and a case series[61] suggest that low-dose (0.2–0.3 mg/kg) daily prednisolone is associated with fewer relapses than twice the dose (0.5–0.7 mg/kg) on alternate days. The strategy led to lower steroid requirement and was not associated with toxicity.[60] These findings require confirmation in studies with longer follow-up that are powered to examine adverse effects, including suppression of the hypothalamo–pituitary–adrenal axis.[62]

Noncorticosteroid therapies

  • We recommend use of a steroid-sparing agent in patients failing therapy with alternate-day prednisolone, steroid toxicity, or complicated relapses [Figure 1] (1B)
  • In patients failing alternate-day prednisolone, we recommend therapy with either levamisole or MMF for 12–24 months (1B)
  • We recommend MMF or cyclophosphamide in patients with significant steroid toxicity, high steroid threshold, complicated relapses, of failure of therapy with levamisole. (1C)


Rationale

Levamisole

Levamisole has been used for almost four decades, mainly in Asia and Europe, as a steroid-sparing agent for frequent-relapsing nephrotic syndrome.[63] A meta-analysis [8 studies, 462 patients; [Supplementary Table 6]], suggests 35% reduction in the risk of relapses following 6–12 months' therapy with levamisole (RR 0.65; 95% CI 0.48–0.88).[64] The medication is more useful in patients with frequent relapses than in steroid dependence.[65] Comparative studies indicate that the risk of relapse in patients receiving levamisole is similar to cyclophosphamide (2 studies, 97 children; RR 2.14; 95% CI 0.22–20.95) or MMF (one study, 149 patients; RR 1.11; 95% CI 0.86–1.43).[64] Given the efficacy and safety, the agent is being examined in two RCTs when administered at onset of the disease (LEARNS, EudraCT 2017-001025-41; NEPHROVIR3, NCT02818738).

Levamisole is given at the dose of 2–2.5 mg/kg on alternate days [Table 2]. While few retrospective studies report its efficacy when administered daily [Supplementary Table 7], the safety of this strategy should be examined in controlled studies with close monitoring for adverse effects, including neutropenia, raised transaminases, anti-neutrophil cytoplasmic antibodies, and/or small-vessel vasculitis.[63],[66],[67]


  Mycophenolate mofetil Top


The use of MMF in frequently relapsing nephrotic syndrome is recent.[68] A review of 7 prospective and 6 retrospective series (508 patients) showed that therapy with MMF for 6–19 months lowered relapse rates and reduced requirement of prednisolone and/or CNI [Supplementary Table 8].[68] While placebo-controlled, blinded RCTs are lacking, MMF was found to be comparable to levamisole but inferior to cyclosporine in maintaining satisfactory remission or reducing the frequency of relapses in three open-label RCTs [Supplementary Table 9].[64] Likewise, MMF had efficacy similar or inferior to tacrolimus in a nonrandomized comparison [Supplementary Table 9]. MMF is perhaps more efficacious in young children[69] and more effective than levamisole in patients with steroid dependence.[70]

Therapy with MMF is given in two divided doses, 600–1200 mg/m2 (20–30 mg/kg) daily.[68] Dose-related adverse effects include leukopenia, abdominal pain, and diarrhea. Data from one RCT suggest that patients with higher blood levels of MMF (determined by area under the curve [AUC]) show efficacy similar to cyclosporine.[71] Others emphasize the need to achieve mycophenolic acid AUC levels exceeding 45–60 μg*h/mL[72],[73],[74] or trough levels >2–3 μg/mL.[75],[76],[77],[78] While pharmacokinetics of MMF is variable, adequate levels are achieved with high doses.[76],[77],[78] In the absence of facilities for therapeutic drug monitoring, we propose initiating therapy at the lower end of dose range and escalating as tolerated, to 1000–1200 mg/m2, if the patient continues to relapse.


  Cyclophosphamide Top


Oral cyclophosphamide, at 2–2.5 mg/kg daily for 8–12 weeks, is the most commonly used steroid-sparing agent in SSNS. Its use finds basis in evidence of efficacy and overall safety, as summarized in a systematic review (38 prospective and retrospective studies, 1504 patients) of patients administered cyclophosphamide or chlorambucil.[79] A recent meta-analysis shows reduced risk of relapse at 6–12 months (6 studies, 202 patients; RR 0.44; 95% CI 0.32–0.60) and 12–24 months (4 studies, 59 patients; RR 0.20; 95% CI 0.09–0.46) following therapy with alkylating agents.[64] In comparative studies, the risk of relapse at 12–24 months following cyclophosphamide therapy was similar to levamisole (1 study, 40 patients; RR 1.12; 95% CI 0.86–1.16) but lower than cyclosporine (2 studies, 95 patients; RR 0.51; 95% CI 0.35–0.74).[64] A Bayesian network analysis (7 reports, 391 patients) showed the lowest relapse rates with cyclophosphamide, compared to other medications.[80] Cyclophosphamide is more effective in patients with frequent relapses than in steroid dependence and in patients older than 5–7 years [Supplementary Table 10].

Therapy with cyclophosphamide is initiated during remission. Prednisolone is given at a dose of ~1 mg/kg on alternate days during therapy with cyclophosphamide; the medication may subsequently be stopped after 1–2 months. Leukopenia is the chief adverse effect, reported in one-third of patients; other concerns are alopecia and the risk of infections [Table 2]. Leukocyte count is monitored every 2 weeks, and therapy withheld if the count falls below 4000/mm3. Increased fluid intake and frequent voiding prevents hemorrhagic cystitis which, along with nausea and vomiting, is common with intravenous (IV) dosing. The risk of gonadal toxicity is proportionate to the cumulative dose and appears to be high in pubertal and postpubertal boys (Tanner stage 2 or more) and lower in girls.[30],[79],[81] Therapy with chlorambucil is associated with risk of seizures and is not recommended.

Given concerns of gonadal toxicity and malignancy, therapy with cyclophosphamide is usually administered after failure of levamisole or MMF and is limited to one 12-week course (cumulative ~168 mg/kg). Occasionally, cyclophosphamide may be the preferred initial steroid-sparing therapy in patients older than 7 years, particularly in the presence of significant steroid toxicity and/or complicated relapses. Limited evidence indicates that cyclophosphamide (500 mg/m2 monthly IV pulse; 6 doses) is as effective as 12-week oral therapy[64] and may be considered in patients with likely noncompliance to oral therapy.

Difficult-to-treat steroid-sensitive nephrotic syndrome

  • We recommend therapy with CNI, either cyclosporine or tacrolimus, in patients with difficult-to-treat SSNS (1B)
  • We recommend therapy with rituximab in patients who have either failed CNI or have received these agents for a prolonged duration (1C)
  • We suggest that therapy with rituximab be administered during disease remission after ruling out acute and chronic infections and should target B cell depletion. (2B).


Rationale

Calcineurin inhibitors

Observational studies indicate that CNIs (cyclosporine 4–6 mg/kg/day, tacrolimus 0.1–0.2 mg/kg/day, in two divided doses) maintain remission and enable steroid sparing in 60%–90% of patients with frequent relapses or steroid dependence who have failed treatment with alkylating agents.[82],[83],[84] These agents have not been compared to placebo or to each other in controlled studies for SSNS. While one RCT each found that cyclosporine was associated with reduced risk of relapse as compared to prednisolone (104 children; RR 0.33; 95% CI 0.13–0.83) or MMF (see above), patients relapsed when the therapy was discontinued.[64] In view of the efficacy and significant steroid sparing, CNIs are preferred for patients with high threshold relapses or significant corticosteroid toxicity. While therapy with CNI is usually restricted to patients with difficult-to-treat SSNS [Box 1], these agents may be considered before MMF or cyclophosphamide in young children with severe steroid dependence and/or significant steroid toxicity. The choice of the medication should follow discussion with parents about potential toxicities and the need for monitoring.

Chief adverse effects of CNIs include acute and chronic nephrotoxicity (with both agents), hirsutism, gum hypertrophy, hypertension and hyperlipidemia (with cyclosporine), and hyperglycemia or seizures (with tacrolimus).[82],[83] While tacrolimus is preferred to cyclosporine due to lack of cosmetic effects, only the latter is available as an oral suspension for young children. Therapy should be administered for at least 12 months, with monitoring of drug levels [Table 2]. Lower target trough levels and once-daily dosing are acceptable during sustained remission.[85],[86] The role of protocol biopsies, before initiating therapy with CNI and following their prolonged use, is discussed in Guideline 2.

Rituximab

B cell depletion has emerged as an effective strategy for sustaining remission in patients with steroid- and/or CNI-dependent nephrotic syndrome. Therapy with rituximab (375 mg/m2 IV once a week for 1–4 doses) in 13 prospective and retrospective series (n = 159) led to sustained remission in 25%–71% of patients, postponement of relapse by (median) 5–11 months, and withdrawal of other therapies.[87] A systematic review confirmed similar efficacy in 86 adults administered rituximab for frequent relapses.[88] In nonrandomized comparisons, the efficacy of rituximab was superior to cyclophosphamide (2 studies, 148 patients) and comparable to tacrolimus (1 study, 23 patients) [Supplementary Table 11]. In a prospective study, therapy with 2–3 doses of rituximab in 101 patients was associated with over two-third reduction in relapses, postponement of relapse by median 16 months, and reduced steroid requirement.[89]

Data from seven RCTs in patients with frequent relapses and steroid/CNI dependence indicate superior efficacy of rituximab as compared to placebo (2 studies, 71 patients), or no additional therapy (2 studies, 91 patients); the efficacy was similar or superior to CNI in one study each (174 patients) [Supplementary Table 11]. A Cochrane meta-analysis concluded that therapy with rituximab, in combination with CNI and prednisolone, versus the latter alone, reduced the risk of relapse at 6 months (5 studies, 269 patients; RR 0.23, 95% CI 0.12–0.43) and 12 months (3 studies, 198 patients; RR 0.63, 95% CI 0.42–0.93).[64]

Experts advise administering rituximab at a dose of 375 mg/m2 IV, using B cell depletion (CD19+ cells <1% of CD45+ cells, or <5 cells/μL) as a marker for adequacy of dosing. While B cell depletion is usual after even one dose,[87] a maximum of four infusions have been given. Since administration of rituximab during relapse is associated with its urinary excretion and reduced half-life, therapy is preferred during remission.[90] B cell recovery usually occurs by 6–9 months and is associated with risk of relapses.[87],[88],[90] Studies comparing response to rituximab in relation to the number of doses and use of maintenance immunosuppression are summarized in [Supplementary Table 12]. An international cohort on 511 patients with frequent relapses or steroid dependence showed that relapse-free survival was significantly shorter for patients given a single dose of rituximab (8.5 months) compared to those given two (12.7 months) or more doses (14.3 months).[91] Additional immunosuppression was useful in sustaining remission following therapy with a single dose of rituximab. In patients with difficult-to-treat SSNS with satisfactory response to rituximab, repeated doses of the medication, following relapses or repopulation of B cells, are suggested as a strategy to sustain remission [Supplementary Table 12]. Given the concerns discussed below, the optimal strategy is still not clear.

Systematic reviews show that therapy with rituximab is associated with infusion reactions (4 studies, 252 children; RR 5.8, 95% CI 1.3–25.3),[64] delayed adverse events, and infections.[87],[88] A German registry of autoimmune diseases (370 patients) reported serious infections in 5.3 cases per 100 patient-years.[92] Patients with lymphoma treated with rituximab show reactivation of hepatitis B virus infection in 9% (95% CI 5%–15%) patients.[93] In contrast to the reports of normal IgG in adult patients receiving multiple doses of rituximab [Supplementary Table 12], hypogammaglobulinemia is not uncommon in children with nephrotic syndrome and autoimmune diseases. The risk of hypogammaglobulinemia correlates inversely with age and positively with the number of rituximab doses.[94],[95],[96]

We recommend that rituximab be used in patients with difficult-to-treat disease, under the supervision of a pediatric nephrologist. Its use should be avoided in young children (<5–7 years) and restricted to patients failing other steroid-sparing agents. Active acute infections and chronic viral infections should be ruled out before therapy. We recommend administering two doses of rituximab during disease remission, at 375 mg/m2 1-week apart, followed by confirmation of B cell depletion, 2–7 days after the second dose. Vigilance for infections and monitoring for leukopenia and hypogammaglobulinemia are essential during follow-up. Further doses of rituximab should be avoided in patients with severe infusion-related adverse events, severe infections, or hypogammaglobulinemia. Prophylactic antibiotics are not routinely recommended. We suggest administering co-trimoxazole (150 mg/m2 or 5 mg/kg of trimethoprim on alternate days) in patients receiving additional immunosuppression, such as those receiving maintenance treatment with CNI or MMF following therapy with rituximab.


  Supportive Care Top


Patients with nephrotic syndrome are at risk of complications of the disease and side effects of its medications. Principles of management of hypertension, thromboembolism, growth retardation, obesity, dyslipidemia, and hypothyroidism are discussed in the guidelines on steroid-resistant nephrotic syndrome.[10] We emphasize that patients who have received oral steroids for more than 2 weeks within the past 1 year should receive additional corticosteroids during conditions associated with physiological stress such as systemic infections, inadequate oral intake, lethargy, dehydration, invasive or dental surgery, trauma, and large burns.[10] Conditions such as uncomplicated viral infections, acute otitis media, and fever, following immunization, do not require stress dosing with steroids.

Guideline 6: Management of hypovolemia and edema

Edema, a cardinal feature of nephrotic syndrome, often requires specific therapy. We propose that edema be empirically classified based on appearance and percentage weight gain from baseline, as mild (≤7% increase), moderate (8%–15%), and severe (>15% increase).[97] If urine protein is monitored regularly, the occurrence of more than mild edema is unusual. Patients with severe edema have marked hypoalbuminemia (serum albumin <1.5 g/dL), along with ascites and anasarca that interferes with daily activities.[97],[98] Intravascular volume depletion is common in patients with moderate or severe edema[99],[100] and should be assessed before instituting therapy with diuretics.

Hypovolemia

  • We recommend that patients with moderate-to-severe edema be assessed for intravascular volume status before initiating therapy with diuretics [Figure 2] (X)
  • We recommend the use of normal saline and IV albumin in patients with disease relapse and hypovolemia. (1C)
Figure 2: Management of edema in nephrotic syndrome. Edema is empirically defined, based on increase in body weight, as mild, moderate, and severe (>15% increase). Patients with mild edema are managed with salt restriction alone; prednisolone therapy is associated with spontaneous diuresis within a few days. Hypovolemia should be excluded [Box 3] before considering therapy with diuretics. Oral furosemide is the diuretic of choice; patients receiving therapy with furosemide for >48 hr should additionally receive a potassium-sparing diuretic. Edema refractory to furosemide therapy may be treated with additional thiazide diuretics or intravenous furosemide, as bolus and/or infusion. Combination therapy with intravenous albumin (20%) and furosemide enables diuresis in patients refractory to the above measures. intravenous albumin carries the risk of fluid overload and pulmonary edema in patients with renal dysfunction. Patients with features of hypovolemia require bolus (es) of normal saline if hypotensive, followed by oral and intravenous hydration, and intravenous albumin (20%) infused over 2–4 h

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Rationale

A combination of clinical and biochemical features helps estimate intravascular volume [Box 3] and [Figure 2].[97],[101] Patients with hypovolemia often have abdominal pain, nausea, vomiting, dizziness, and lethargy. Examination shows tachycardia, pallor, cold peripheries, delayed capillary refill and postural hypotension, and rarely shock.[97],[101],[102] On the other hand, patients with hypervolemia have refractory anasarca, hypertension, and dyspnea.[99],[100] Two urinary indices may help assess intravascular volume: fractional excretion of sodium (FENa) and potassium index.[103],[104] While both underfill and overfill states are associated with sodium retention,[105],[106],[107] FENa <0.5% and potassium index >0.6 indicate high aldosterone activity, a characteristic of hypovolemia.[104],[105],[108] The indices are not reliable with recent diuretic therapy and while receiving IV fluids. Other parameters of volume status include changes in hematocrit, urea to creatinine ratio,[105] inferior vena cava diameter and collapsibility, and bioimpedance analysis.[97],[99],[100],[101],[109],[110]



Hypovolemia may occur at disease onset or relapse, particularly in a setting of diarrhea, vomiting or unsupervised diuretic therapy. Therapy with diuretics should be discontinued. Hypotensive patients should receive 1–2 boluses of isotonic saline (10–20 ml/kg infused over 20–30 min) and/or 5% albumin (10–15 ml/kg over 30–60 min) [Figure 2]. Subsequently, patients are managed with IV and oral hydration and IV albumin (20%; 0.5–1 g/kg over 3–4 h).[97],[99],[101]

Edema

  • We recommend oral furosemide as first-line therapy for patients with moderate edema without hypovolemia [Figure 2] (1C)
  • We suggest that patients with furosemide-refractory edema be managed as follows: (i) combination of loop diuretics with thiazide; (ii) co-administration of human albumin with IV furosemide. (X)


Rationale

Patients with mild edema do not require diuretic therapy. Corticosteroid therapy for relapse results in diuresis within 1 week, enabling loss of retained extracellular fluid.[97],[101] Patients are advised to limit sodium intake (1–2 mEq/kg/day; 15–35 mg/kg salt). Foods rich in salt (>10 mEq/100 g; e.g., bread, cornflakes, processed cheese, sauces, potato chips, salted nuts, papad, and pickles) and preserved foods (canned vegetables, soups, and meat) are avoided in the presence of significant edema.[97],[101]

Diuretics are the initial therapy for patients who are volume replete. Patients with moderate edema without hypovolemia are managed with furosemide (2–4 mg/kg/day) that acts on the ascending limb of Henle.[101],[105] Sequential nephron blockade, with additional use of hydrochlorothiazide (2–4 mg/kg/day) or metolazone (0.1–0.2 mg/kg q12–24 h), augments diuresis by reducing distal sodium reabsorption.[97],[101] Monitoring for hypovolemia, hypokalemia, and alkalosis is essential. Spironolactone has limited diuretic efficacy but is an effective potassium-sparing agent in patients receiving high-dose furosemide.[97],[101] Use of acetazolamide or amiloride is not advised.

Patients with severe edema may fail to respond to maximal doses of furosemide and thiazide diuretics (diuretic resistance).[98] Factors contributing to diuretic resistance are poor adherence to salt restriction, reduced bioavailability of furosemide, hypoalbuminemia, hypovolemia, and compensatory salt reabsorption in the distal tubule. The bioavailability of oral furosemide is 20%–60% and is impaired by gut edema in nephrotic syndrome.[98] In patients unresponsive to oral furosemide, assessed as the absence of diuresis within 2–4 h of its administration, switching to IV therapy may elicit a response. IV furosemide, given either as 1–2 mg/kg q 8–12 h, or bolus of 1 mg/kg followed by infusion of 0.1–0.4 mg/kg/hr, is effective.[97],[98],[101] While torsemide has better efficacy and bioavailability than furosemide in adults with heart failure,[111] information in nephrotic syndrome is lacking.

Furosemide, tightly bound to blood albumin, is actively secreted via organic acid pumps in the ascending limb of Henle. Tubular secretion is impaired in patients with severe hypoalbuminemia, resulting in diuretic resistance.[101] The combination of 20% albumin (0.5–1 g/kg infused over 3–4 h) and furosemide (1–2 mg/kg at end of infusion) enhances drug delivery to tubules, with increased efficacy in terms of urine output and weight loss.[110],[112],[113] A meta-analysis confirmed that combination therapy results in diuresis and natriuresis, which declines by 24 hr.[101],[114] Therapy with IV albumin may be associated with risk of worsening hypertension, respiratory distress, and heart failure and is therefore avoided in patients with impaired kidney function.[97],[98],[99],[101],[112]

Patients with severe edema who are refractory to the above therapies are likely to have fluid overload, usually in the presence of steroid resistance or kidney dysfunction. These patients might require ultrafiltration or kidney replacement therapy. An approach to evaluation and management of edema is shown in [Figure 2].

Guideline 7: Infections and immunization

Bacterial infections

We suggest that serious bacterial infections associated with nephrotic syndrome be managed as indicated in [Table 3]. (X)
Table 3: Management of serious infections

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Rationale

Infections are the chief complication in patients with SSNS, accounting for 19%–44% of hospitalizations.[115],[116],[117],[118],[119],[120] Contributing factors include the use of immunosuppressive agents, anasarca, and urinary losses of IgG and complement factors that predisposes to infection with encapsulated organisms.[121] Peritonitis is the most common severe infection, followed by pneumonia and cellulitis.[115],[116],[117],[118],[119] Chief pathogens causing peritonitis are pneumococci and Escherichia coli; those causing pneumonia include pneumococci, Haemophilus influenzae, and Staphylococcus aureus; and those responsible for cellulitis are staphylococci, group A streptococci, and H. influenzae.[115],[116],[117],[118],[119] The diagnosis and treatment of severe infections should follow standard guidelines[122],[123],[124] [Table 3]. Apart from vaccines, there is no evidence of efficacy of other interventions for preventing bacterial infections in patients with nephrotic syndrome.[125]

Viral infections

Several viruses, including rhinovirus, adenovirus, influenza, parainfluenza, enterovirus, and respiratory syncytial and Epstein–Barr viruses, might trigger disease relapses.[126],[127] Infections such as varicella, zoster, and influenza might be associated with significant morbidity and merit specific prevention and management.[128],[129],[130]

Severe acute respiratory syndrome coronavirus-2 infection

Infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiological agent of coronavirus disease (COVID-19) poses challenges in the management of patients with nephrotic syndrome.[131] While children show mild disease, patients on immunosuppression constitute a high-risk group that is predisposed to adverse outcomes. Affected patients are at risk of AKI, particularly if associated with hypovolemia or aggressive use of diuretics. In the absence of specific therapy for SARS-CoV-2 infection, most expert groups advise reduction of immunosuppression to acceptable levels, balancing the risk of disease relapses against infection.[131],[132] Other considerations include advice through teleconsultation; low threshold for inpatient monitoring of infected patients; and limiting the use of biological agents and antimetabolites.[131],[132] Steroid dosing during SARS-CoV-2 infection should follow standard practices regarding stress dosing;[10] relapses may be treated with a lower dose of prednisolone.

Immunization

We suggest that patients with nephrotic syndrome receive: (i) age-appropriate killed, subunit or inactivated vaccines; (ii) live vaccines following principles outlined in [Table 4]; (iii) vaccines against pneumococcus, varicella, influenza, and hepatitis B [Table 5]. (X)
Table 4: Principles of immunization with live vaccines in patients with nephrotic syndrome

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Table 5: Specific vaccines for patients with nephrotic syndromea

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Rationale

Children with nephrotic syndrome should receive vaccines as appropriate for age.[133],[134] Killed, inactivated, or subunit vaccines are not contraindicated but may have reduced efficacy during immunosuppression.[133],[134],[135],[136] Principles of immunization with live vaccines in immunocompromised children and their household contacts are listed in [Table 4].[124],[134],[137] The schedule for administration of specific vaccines that are relevant to patients with nephrotic syndrome is summarized in [Table 5].[133],[134],[138] The risk of relapse following vaccination is negligible.[135],[139]

Pneumococcal vaccine

The availability of safe and immunogenic vaccines has reduced the risk of pneumococcal infections in patients with relapsing nephrotic syndrome.[140] Two categories of vaccines are available. The polysaccharide vaccine (PPSV23) is poorly immunogenic in patients younger than 2 years and does not induce immunological memory. Conjugate vaccines (PCV7-, 10-and 13-valent) induce superior and sustained antibody responses and immune memory even in young infants, with pooled efficacy of 58% (95% CI 29%–75%) against invasive disease caused by any pneumococcal serotype.[135],[141] The efficacy of PPSV23 and PCV vaccines in patients with SSNS is variable. Information is lacking on the precise impact of vaccination on rates of peritonitis, cellulitis, and pneumonia.

Both PCV7/10/13 and PPSV23 elicit satisfactory serological response, even when given during relapse or while on immunosuppressive agents.[135] Nevertheless, we suggest that the vaccine be preferably given during remission and while on low or no immunosuppression. Antibody responses are ill-sustained in patients with recurrent relapses, justifying re-dosing with PPVS23 after 5 years if the disease remains active; more than two doses of PPSV23 are not recommended.[134],[135]

Varicella vaccine

In view of the risk of severe disease in immunocompromised patients, we recommend that patients with nephrotic syndrome receive two doses of the varicella vaccine, 4–8 weeks apart [Table 5].[134],[138] Two doses result in seroconversion in ~95% of vaccines; breakthrough varicella might occur in 2.2%–7.3% of children.[142] The vaccine was safe and immunogenic in 109 patients with nephrotic syndrome, including those receiving low-dose corticosteroids, in two prospective series[143],[144] and in an open-label RCT.[145]

Severe varicella might follow infection in at-risk individuals exposed to persons with either varicella or herpes zoster. Multiple strategies for postexposure prophylaxis are used to prevent viral transmission [Table 6].[124],[133],[134],[138],[146],[147],[148],[149] Unimmunized patients with nephrotic syndrome who are not immunosuppressed should receive the vaccine within 5 days of exposure.[124] The risk of postexposure varicella was reduced to one-third in children who were vaccinated following exposure, compared to those unimmunized (3 studies; n = 110; 23% vs. 78%).[147] Healthy household contacts should also receive the vaccine to minimize the risk of infecting the patient. In patients in whom vaccination is contraindicated, the Centers for Disease Control recommends administration of varicella zoster immunoglobulin (VARIZIG) within 10 days of exposure.[148] VARIZIG administration was associated with varicella in <10% of 507 high-risk participants, including 231 immunosuppressed children.[149] In view of the low and variable titer of anti-VZV antibodies,[150] IV immunoglobulin is not recommended.[124],[134] If VARIZIG is not available, similar to the guidelines from the American Academy of Pediatrics[124] and French Society of Pediatric Nephrology,[138] we recommend administering oral acyclovir or valacyclovir for 7 days, starting 6–10 days after exposure, corresponding to the period of secondary viremia [Table 6].
Table 6: Postexposure management of unimmunized patients with nephrotic syndrome exposed to varicellaa

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Influenza vaccine

Influenza accounts for 13% of all pneumonia and 7% of severe pneumonia in children <5 years.[150],[151] Approximately 1 in 5 unvaccinated children is annually infected by influenza, of which one-half are symptomatic.[152] Given the risk of morbidity in immunosuppressed individuals, annual administration of the inactivated influenza vaccine is recommended for patients with nephrotic syndrome [Table 5] and their household contacts.[124],[130],[138]

Hepatitis B vaccine

Hepatitis B vaccination coverage rates in India are unsatisfactory, and 45% of 1–6-year-old children are not vaccinated.[153] Compared to healthy children, fewer patients with nephrotic syndrome show seroprotective (≥10 mIU/mL) antibody titers;[154] one-half of these patients seroconvert after vaccination.[136],[155] Seroprotection was lower in patients with steroid resistance and those on nonsteroid therapies.[136],[154],[155] To overcome vaccine failure, we advise an accelerated schedule using twice the age-appropriate dose and assessment of serological response to administer booster dose (s) [Table 5].[156]

Guideline 8: Transition of care

We recommend that patients with nephrotic syndrome who continue to have relapses in adolescence be transitioned into care by adult physicians. (X)

Rationale

SSNS is a self-limiting illness, with the majority of patients outgrowing the illness by puberty. Review of information from multiple cohorts, with median follow-up of 4–30 years, indicates that the frequency of relapses declines with age.[3],[4],[157],[158],[159] However, 5%–42% patients may continue to have active disease in adulthood. Risk factors for illness persisting beyond 18 years of age include early age at onset and frequently relapsing or steroid-dependent course.[3],[4],[157],[158]

Major infections, associated with relapses and intense immunosuppression, are the chief causes of hospitalization and mortality (0%–8%).[3],[157],[158] Kidney failure is uncommon (≤1%) in patients with SSNS. There is significant risk of short stature (15%), obesity (10%), hypertension (6%–46%), metabolic bone disease (9%–63%), diabetes mellitus (2%), ocular complications (10%), infertility, and malignancies.[157],[158],[160] Psychosocial concerns, including school dropout, unemployment, and unstable relationships are common.[161]

Given the risk of disease persistence and prevalence of complications, it is advised to transfer the care of adolescents with relapsing disease to “adult”' nephrologists by 18 years of age. National and international guidelines advocate for smooth transition, with emphasis on shared clinics and consideration of patient and parent perspectives.[162]


  Conclusions Top


The present guidelines, based on the best available evidence and expert guidance, provide directions for evaluation and management of SSNS in children. Recommendations, proposed by the Indian Society of Pediatric Nephrology, in 2001 and 2008, have been revised based on systematic reviews, published studies, and expert opinion. The management of frequent relapses continues to be challenging, with morbidities associated with the disease as well as therapies. Well-designed prospective studies are required to address issues related to therapy of the initial episode and relapsing nephrotic syndrome [Table 7]. We hope that the present guidelines will standardize therapies and improve the quality of care for patients with the disease.
Table 7: Areas for clinical studies in steroid sensitive nephrotic syndrome

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Contributors

All authors were involved in review of literature, preparation of background document, drafting, and critically revising the manuscript. All authors approved the final version of the manuscript.

Acknowledgement

This article is reprinted with permission from Sinha A, Bagga A, Banerjee S, Mishra K, Mehta A, Agarwal I, Uthup S, Saha A, Mishra OP; Expert Group of Indian Society of Pediatric Nephrology. Steroid Sensitive Nephrotic Syndrome: Revised Guidelines. Indian Pediatr 2021;58:461-481.

Financial support and sponsorship

Indian Council of Medical Research; Advanced Centre for Research in Pediatric Kidney Diseases (5/7/1090/2013-RHN); Department of Biotechnology, Government of India (BT/PR11030/MED/30/1644/2016).

Conflicts of interest

There are no conflicts of interest.


  Annexure I Top






























Legend for risk of bias assessment




  Supplementary References Top


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  3. Sinha A, Saha A, Kumar M, Sharma S, Afzal K, Mehta A, et al. Extending initial prednisolone treatment in a randomized control trial from 3 to 6 months did not significantly influence the course of illness in children with steroid-sensitive nephrotic syndrome. Kidney Int 2015;87:217-24.
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  6. Sinha A, Gipson D, Wong C, Massengil S, Ahmed A, Hari P, et al. 6-months versus3-months prednisolone for initial therapy of steroid sensitive nephrotic syndrome: Open label RCT (abstract). Pediatr Nephrol 2019;34:2076.
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 
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Abstract
Objective
Process
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Daily prednisolo...
Daily prednisolo...
Mycophenolate mo...
Cyclophosphamide
Supportive Care
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Annexure I
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