Guidelines on 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 I highlights key changes in present guidelines compared to 2008 [7] and those recently proposed by the Kidney Disease Improving Global Outcomes [9].

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 prior to the meeting in New Delhi on 5 April 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 assessment of relative benefit versus harm, and relevance in context of availability and cost, and the feasibility of monitoring (Supp. Table I) [11]. Draft guidelines were again discussed in Pune on 21 December 2019. The final manuscript was circulated to all participants for approval.

Criteria for defining the course of nephrotic syndrome are shown in Box I [12-14]. 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-weeks’ prednisolone therapy (Box I) is discussed separately [10].

Patients with frequent 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 one year, be managed by pediatric nephrologists.

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 assessment for edema.

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 II).

Clinicopathological studies show that kidney biopsy is not routinely required in children with idiopathic nephrotic syndrome prior to therapy with corticosteroids [20-22]. 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-weeks 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 minutes); or extrarenal features of a systemic disease [20-23,25].

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 [20-22,26,27]. This might obviate the need for a kidney biopsy in adolescents presenting with typical nephrotic syndrome that is steroid sensitive.　Since infants (<12-months-old), 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 [20-22,28]. More than 90% 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 like levamisole, cyclo-phosphamide, mycophenolate mofetil (MMF) or rituximab [29]. The exception is prior to the use of CNI.

While there is limited guidance to support kidney biopsy in patients with SSNS prior to the therapy with CNI [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% biopsies following therapy (for 2.5-3.5 years) with cyclosporin or tacrolimus [33-35]. 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 CNI, particularly in patients with prolonged disease and unclear course, and to inform the clinician regarding baseline histological changes and allow 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 to 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].

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 Padiatrische 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 (Supp. Table II). These studies, representing outcomes in over 800 patients across 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 or longer versus 2-months therapy (RR 0.68; 95% CI 0.47-1.0), but not for 5-months 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 (Supp. Fig. 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.

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 (Supp. Table III). Well-powered studies are required to evaluate the optimal dose and duration of prednisolone for relapses.

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-yr, with minor modifications. Additionally, we propose that patients with three or more relapses in any 6-months be also classified as frequent relapsers (Box I). Steroid dependence, as previously defined, includes patients with two consecutive relapses, while receiving or within 2-weeks of discontinuing prednisolone [3,6].

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 (Fig. 1). (X)

Fig. 1. Management of frequently relapsing or steroid dependent nephrotic syndrome.

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 (Fig. 1). There is 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 II). Potent medications are preferred in patients with high threshold (>1 mg/kg on alternate day) relapses, relapses associated with life-threatening complications, or with significant steroid toxicity (Box I and Table II). The presence 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.

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 2 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 Fig. 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 post-pubertal 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.

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% patients (Supp. Table IV). 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 II).

More than one-half of relapses in SSNS occur following upper respiratory tract infections. Evidence from three studies (Supp. Table V) 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).

Data from an open-label RCT [60] and a case series [61] suggests 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].

Patients with nephrotic syndrome are at risk of complications of the disease, and side effects of its medications. Principles of management of hyper- tension, 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 one-year, should receive additional corticosteroids during conditions associated with physiological stress like 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.

A combination of clinical and biochemical features helps estimate intravascular volume (Box III, Fig. 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 [105-107], FENa <0.5% and potassium index >0.6 indicate high aldosterone activity, 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 [97,99-101,109,110].

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 minutes) and/or 5% albumin (10–15 ml/kg over 30-60 minutes) (Fig. 2). Subsequently, patients are managed with IV and oral hydration, and IV albumin (20%; 0.5–1 g/kg over 3-4 hr) [97,99,101].

Fig. 2. Management of edema in nephrotic syndrome.

Patients with mild edema do not require diuretic therapy. Corticosteroid therapy for relapse results in diuresis within one-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, pickles) and preserved foods (canned vegetables, soups and meat) are avoided in 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 hr), 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 absence of diuresis within 2-4 hr of its administration, switching to IV therapy may elicit a response. IV furosemide, given either as 1-2 mg/kg q 8-12 hr, 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 hr) 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 [97-99,101,112].

Patients with severe edema who are refractory to the above therapies are likely to have fluid overload, usually in 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 Fig. 2.

We suggest that serious bacterial infections associated with nephrotic syndrome be managed as indicated in Table III. (X)

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

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 [128-130].

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

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 [133-136]. Principles of immunization with live vaccines in immunocompromised children and their household contacts are listed in Table IV [124,134,137]. The schedule for administration of specific vaccines that are relevant to patients with nephrotic syndrome is summarized in Table V [133,134,138]. The risk of relapse following vaccination is negligible [135,139].

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 2-doses of PPSV23 are not recommended [134,135].

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 V) [134,138]. Two doses result in seroconversion in ~95% vaccinees; breakthrough varicella might occur in 2.2-7.3% 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 post-exposure prophylaxis are used to prevent viral transmission (Table VI) [124,133,134,138,146-149]. Unimmunized patients with nephrotic syndrome who are not immunosuppressed should receive the vaccine within 5-days of exposure [124]. The risk of post-exposure 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 Center for Disease Control recommends administration of varicella zoster immune globulin (VARIZIG) within 10-d 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], intravenous immunoglobulin (IVIG) is not recommended [124,134]. If VARIZIG is not available, similar to 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 VI).

Influenza accounts for 13% of all pneumonia, and 7% of severe pneumonia in children <5-yr-old [150,151]. Approximately 1 in 5 unvaccinated children are 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 V), and their household contacts [124,130,138].

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

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 yr, indicates that the frequency of relapses declines with age [3,4,157-159]. However, 5-42% patients may continue to have active disease in adulthood. Risk factors for illness persisting beyond 18-yr 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 cause 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 drop-out, 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’ nephro-logists by 18 year of age. National and international guidelines advocate for smooth transition, with emphasis on shared clinics and consideration of patient and parent perspectives [162].

The present guidelines, based on 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 VII). We hope that the present guidelines will standardize therapies and improve the quality of care for patients with the disease.

Note: Supplementary material related to these recommedations is available with the online version at www.indianpediatrics.net

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.

Funding: 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].

Competing interests: None stated.

Annexure I

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