Treatment of idiopathic nephrotic syndrome in children

INTRODUCTION — The nephrotic syndrome (NS) is observed in children with kidney diseases associated with increased permeability of the glomerular filtration barrier. Idiopathic NS is the most common form of NS in children. It is characterized by diffuse foot process effacement on electron microscopy and any of a variety of findings on light microscopy that include minimal changes, focal segmental glomerulosclerosis (FSGS), and mesangial proliferation. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Primary nephrotic syndrome'.)

An overview of the treatment of idiopathic NS in children is presented here. The etiology, clinical manifestations, and diagnosis of NS in children are discussed separately. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children".)

The management of adults with NS is also discussed in greater detail separately. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults" and "Focal segmental glomerulosclerosis: Clinical features and diagnosis" and "Minimal change disease: Treatment in adults" and "Focal segmental glomerulosclerosis: Treatment and prognosis" and "Membranous nephropathy: Treatment and prognosis".)

DEFINITION

●Nephrotic syndrome (NS) is defined as a condition classically characterized by all three of the following features (see "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children"):

•Nephrotic range proteinuria – Urine protein excretion >50 mg/kg per day or a spot urine sample with a ratio (U_P/U_Cr) >3 mg of protein per mg of creatinine (see "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Confirming the diagnosis')

•Hypoalbuminemia – Serum albumin <3 g/dL (30 g/L)

•Edema

●Steroid-resistant NS (SRNS) is defined as NS resistant to steroid therapy, defined by the absence of complete remission after an initial course of daily prednisone therapy at a dose of 60 mg/m² per day [1,2].

●Complete remission is resolution of proteinuria defined as a urine protein-to-creatinine ratio (UPCR) based on a first morning void or 24-hour collection of ≤20 mg/mmol (0.2 mg protein/mg creatinine) or urine dipstick readings of negative or trace protein on three consecutive days.

●Partial remission is a decrease in proteinuria with a UPCR based on first morning void or 24-hour urine sample of >20 but <200 mg/mmol and, if available, serum albumin ≥30 g/L.

●Relapse is the recurrence of nephrotic-range proteinuria following either complete or partial remission.

MANAGEMENT OVERVIEW

Steroid therapy — Most children with idiopathic NS have minimal change disease (MCD), which is generally responsive to steroid therapy [3]. MCD is the underlying cause of NS in approximately 75 to 80 percent of pediatric cases and clinical findings are highly predictable in differentiating MCD from other forms of NS [4,5]. As a result, empiric steroid therapy is typically initiated in patients who are likely to have MCD based on clinical criteria without histological confirmation by kidney biopsy. In addition, some patients with focal segmental glomerular sclerosis (FSGS), which accounts for another 15 to 20 percent of idiopathic NS cases in children, may respond to steroid therapy. (See 'Empiric steroid therapy versus kidney biopsy' below and "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Primary nephrotic syndrome'.)

Clinical experience has demonstrated that the response to initial steroid therapy rather than the histologic features seen on kidney biopsy is a better predictor of long-term prognosis. As a result, patients with idiopathic NS can be defined by their response to steroid therapy as follows:

●Steroid-sensitive NS (SSNS) – More than 90 percent of patients who respond to steroid therapy have MCD [1]; FSGS is most commonly seen in the remaining patients [1]. Almost all patients with SSNS have an excellent outcome, with few patients developing late steroid resistance or end-stage kidney disease (ESKD) or chronic kidney disease. (See 'Steroid-sensitive nephrotic syndrome' below.)

●Steroid-resistant NS (SRNS) – Ten to 20 percent of children with idiopathic NS fail to respond to initial empirical steroid therapy. Kidney biopsy shows minimal changes in one-fourth of them and FSGS or mesangial proliferation in most of the remaining patients who are biopsied. These children are at increased risk for developing ESKD [1]. (See "Steroid-resistant nephrotic syndrome in children: Etiology".)

Nonimmune general measures — General measures are focused on preventing or minimizing complications due to the underlying NS and are discussed in greater detail separately (see "Symptomatic management of nephrotic syndrome in children" and "Complications of nephrotic syndrome in children").

These include:

●Infection control (see "Symptomatic management of nephrotic syndrome in children", section on 'Infection' and "Complications of nephrotic syndrome in children", section on 'Infection'):

•Prevention of infection with vaccination with 23-valent polysaccharide (PPSV23) pneumococcal and varicella vaccines if not previously immunized, as patients with NS are at increased risk of infection. However, live vaccinations should be avoided during relapse and while on daily immunosuppressive medications.

•Identification and treatment of suspected infections (pneumonia, cellulitis, sepsis, peritonitis) as these patients are immunosuppressed.

●Management of edema and anasarca with avoidance of excessive fluid intake, moderate restriction of dietary salt, elevation of extremities, and judicious use of diuretics. (See "Symptomatic management of nephrotic syndrome in children", section on 'Edema'.)

In patients with severe anasarca or edema, active mobilization of fluid can be undertaken with intravenous administration of a loop diuretic in conjunction with salt-poor 25 percent albumin. (See "Symptomatic management of nephrotic syndrome in children", section on 'Patients with edema and intravascular hypovolemia'.)

●Prevention of venous thromboembolism by avoiding restriction of patient mobilization and intravascular hypovolemia. (See "Symptomatic management of nephrotic syndrome in children", section on 'Hypercoagulability' and "Complications of nephrotic syndrome in children", section on 'Thromboembolism'.)

●Maintenance of adequate protein intake (130 to 140 percent of the recommended daily allowance).

INITIAL THERAPY

Empiric steroid therapy versus kidney biopsy — As noted above, the most common cause of pediatric NS is idiopathic NS, primarily minimal change disease (MCD), which is generally responsive to steroid therapy [3]. As a result, we initiate empiric steroid therapy in all patients with a high probability of having MCD on clinical criteria without confirmation of the diagnosis by kidney biopsy. This approach is consistent with guidelines from a number of organizations globally [6-8]. Thus, empiric therapy can be started in patients who fulfill all of the following clinical criteria that is predictive of MCD [1,9,10]:

●Age older than 1 year and younger than 10 years of age

●None of the following findings: hypertension, gross hematuria, marked elevation in serum creatinine

●Normal complement levels

●No extrarenal symptoms, such as malar rash or purpura

Although steroid therapy is often started immediately following the diagnosis of NS, it should be stressed that spontaneous remission occurs in 5 percent of cases within one or two weeks. Therefore, the initiation of steroid therapy may be delayed for a few days or a week [11].

In children who do not meet these criteria, a kidney biopsy is recommended because of the increased prevalence of other causes of NS. In these patients, therapeutic decisions are based on the histologic diagnosis. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children" and "Focal segmental glomerulosclerosis: Treatment and prognosis" and "Membranoproliferative glomerulonephritis: Treatment and prognosis" and "Membranous nephropathy: Treatment and prognosis" and "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Minimal change variants'.)

Initial steroid course

●Initial course – For children with NS who are likely to have MCD, initial treatment is with oral prednisone at a dose of 60 mg/m² per day (maximum of 60 mg/day) [2]. This dose can be given once daily or divided into two doses administered twice a day. After initiation of steroid therapy, patients and their parents/caregivers are taught to monitor urine protein levels by urine dipstick [12]. (See 'Monitoring' below.)

Complete remission is defined by the disappearance of proteinuria. Of the children who go into remission, approximately 90 percent of children will do so within the first four weeks of oral prednisone therapy and the remaining 10 percent respond after an additional two more weeks of steroid therapy (figure 1) [1].

●Slow responders – For patients who remain proteinuric after four weeks, our practice is to administer three intravenous pulses of methylprednisolone (1000 mg/1.73 m²) every other day rather than an additional course of oral prednisone used at other centers [2,13,14].

The five-year outcome of our protocol, using daily oral prednisone therapy and methylprednisolone pulses for refractory patients, was assessed in 188 children with NS [14]. Of the 174 patients who were steroid responsive, 164 children (93 percent) were responsive within the four weeks of initiating therapy, and 10 patients received intravenous methylprednisolone, which resulted in remission. At last follow-up, 36 of the 174 patients (21 percent) remained relapse-free. This regimen, compared with prolongation of daily administration of steroids, may produce remission more quickly in the few patients who require additional steroid therapy in the second month after diagnosis.

Other centers do not administer intravenous methylprednisolone as standard practice in initially refractory patients and may use one of the following alternate approaches in patients who are not in remission after an initial four-week course of daily steroid therapy:

•Biopsy patients without administering the three pulses of methylprednisolone, as there is an increased likelihood that they have another glomerular disease that may not be responsive to additional steroid therapy. Histologic findings guide further therapeutic decisions. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children" and "Steroid-resistant nephrotic syndrome in children: Etiology".)

•Continue daily steroid therapy for another two to four weeks because an additional 10 percent of steroid-responsive patients will respond after four weeks of therapy [1]. Patients who fail to respond to a maximum eight weeks of daily steroid therapy are considered steroid resistant [1]. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children" and 'No remission: Steroid-resistant nephrotic syndrome' below.)

Remission: Steroid-sensitive nephrotic syndrome — With the onset of remission, we continue prednisone at the same daily dose for 30 days and then switch to alternate-day therapy (at the same daily dose). Alternate-day therapy is tapered over a one- to two-month period.

●Duration of therapy – Although there is general agreement on the initial dosing of prednisone of 60 mg/m² or 2 mg/kg per day, there is no consensus on the total duration of initial steroid therapy following the onset of remission, as the optimal duration of therapy for reducing subsequent relapses remains uncertain [15]. As discussed above, in our practice, prednisone therapy is continued at the same daily dose for 30 days at the onset of remission and then switched to alternate-day therapy at a dose of 40 mg/m² (maximum dose 60 mg every other day) for the next four weeks and then discontinued.

Other published steroid regimens include the following:

•Children's Nephrotic Syndrome Consensus, a group of pediatric nephrologists from the southeast and midwest sections of the United States, published guidelines in 2009 that recommended initial steroid therapy of oral prednisone of 2 mg/kg per day for six weeks, followed by alternate-day prednisone of 1.5 mg/kg for an additional six weeks [6].

•The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommended initial prednisone therapy of 60 mg/m² or 2 mg/kg per day for four to six weeks (maximum dose of 60 mg/day), followed by alternate-day prednisone of 40 mg/m² or 1.5 mg/kg (maximum dose of 40 mg/day) and tapered over two to five months [7].

•The 2014 Canadian Society of Nephrology (CSN) guidelines recommended initial prednisone therapy of 2 mg/kg per day beyond 12 weeks and up to six months [8].

•The 2021 Indian Society of Pediatric Nephrology guidelines 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 administered in one to two divided doses) for six weeks, followed by 40 mg/m² (1.5 mg/kg, maximum 40 mg as a single morning dose) on alternate days for the next six weeks, and then discontinued [16].

The KDIGO and CSN guidelines adopted a long initial course of steroids based on earlier systematic reviews that showed that initial therapy of at least three to seven months, including periods of daily and alternate-day therapy, reduced the risk of subsequent relapses [7,17]. However, a subsequent systematic review concluded that older, high-risk-of-bias studies overestimated the effect of longer course therapy as compared with subsequent studies of higher quality. Two randomized controlled trials at low risk of bias from Japan and India showed that extending initial therapy beyond 8 to 12 weeks does not influence the time to first relapse or the risk of frequent relapses at one to two years' follow-up [18,19]. In addition, a more recent clinical trial of 237 children (age range from 1 to 14 years) with a first episode of steroid-sensitive NS (SSNS) reported similar outcome between an extended 16-week course and a standard 8-week course of prednisone regarding time to first relapse and the incidence of frequently relapsing NS (53 versus 50 percent), steroid-dependent NS (42 versus 44 percent), or requirement for alternative immunosuppressive treatment (54 versus 56 percent) [20].

As a result of the available evidence, treatment durations of two or three months are recommended for the management of the first episode of SSNS rather than longer durations [21,22]. Slow tapering to avoid adrenal suppression may be important to maintain long-term remission as demonstrated in a small study that reported moderate to severe post-prednisone adrenal suppression was associated with an increased risk of relapse [23].

No remission: Steroid-resistant nephrotic syndrome — Ten to 15 percent of children will fail to respond to steroid therapy and will continue to have persistent proteinuria after completion of the initial steroid therapy [13,14]. Evaluation for these children who have steroid-resistant NS (SRNS) is focused on identifying the etiology, as therapeutic decisions are based on the underlying cause. Evaluation may include screening for genetic disorders and/or kidney biopsy. Steroid therapy is weaned and additional therapeutic management is decided on the evaluations for SRNS.

The causes and management of SRNS in children are discussed separately. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children" and "Steroid-resistant nephrotic syndrome in children: Etiology" and "Steroid-resistant nephrotic syndrome in children: Management".)

No additional advantage with cyclosporine as initial therapy — Increasing initial immunosuppression by adding cyclosporine to steroid therapy has been proposed as a way to reduce the relapse rate. However, the addition of cyclosporine does not alter the two-year relapse rate, and the initial combination of cyclosporine and prednisone compared with prednisone alone results in a greater number of side effects [24,25]. As a result, steroids alone are used as the initial therapy for childhood idiopathic NS.

Outcome based on response — Outcome of response is based on published observational case series [9,26]. The majority of children who respond to steroid therapy with complete remission do well as noted by the following case series, whereas children who fail to respond to steroid therapy (SRNS) have a greater risk of developing end-stage kidney disease (ESKD).

●In a multicenter study of 389 children with biopsy-proven MCD diagnosed between 1967 and 1976, over 90 percent responded with complete remission to initial steroid therapy [9]. Approximately one-third of these patients had frequently relapsing disease, defined as four or more relapses per year or two or more relapses in the initial six months after diagnosis. At eight-year follow-up, 80 percent of patients remained in remission. Five of the 29 patients who were steroid resistant progressed to ESKD. Deaths occurring in less than 2 percent of patients were from complications related to nephrosis (eg, peritonitis).

●In a second case series of 631 children diagnosed with idiopathic NS treated between 1993 and 2016, approximately 93 percent of patients were responsive to an initial course of steroids of which approximately one-quarter remained in complete remission [26]. Approximately 60 percent of the cohort maintained long-term remission throughout childhood, but approximately one-third of the patients had frequently relapsing disease. Only 2 percent of the original cohort progressed to ESKD, including seven patients who were initially steroid sensitive and three who were steroid resistant. There were no deaths reported during the duration of the study period.

STEROID-SENSITIVE NEPHROTIC SYNDROME — The majority of children with idiopathic NS have minimal change disease (MCD) and will attain complete remission with an initial course of steroid therapy. However, 80 percent of steroid-responsive patients will experience one or more subsequent relapses, which typically remain responsive (sensitive) to steroid therapy [3,9,14,27]. The risk of relapse is greater in children aged less than five years at onset. Management for patients with steroid-sensitive NS (SSNS) is focused on early detection and treatment of any relapse to reduce the risk of complications associated with NS. (See 'Frequently relapsing/steroid-dependent nephrotic syndrome' below.)

Monitoring — Once a patient responds to steroid therapy, ongoing monitoring for proteinuria is required to detect relapses early and initiate therapy to prevent significant fluid accumulation (edema) and minimize the complications associated with NS. (See "Complications of nephrotic syndrome in children".)

Patients and their parents/caregivers are taught to routinely measure body weight as well as continue to monitor urine protein levels by urine dipstick on a daily basis [12]. Increased urine protein concentration typically provides the first indication of a relapse. When this occurs, the family/caregiver should call their health care provider for instructions regarding management.

Initial or infrequent relapse — With the first initial relapse or for infrequent relapses, steroid therapy is typically administered at a dose of 60 mg/m² or 2 mg/kg per day (maximum dose of 60 mg/day). The length of steroid therapy varies among pediatric nephrologists. In our practice, daily prednisone is given until proteinuria has disappeared for at least three consecutive days. Alternate-day therapy is then begun, and the dose tapered to 15 to 20 mg/m² every other day for another four weeks and then discontinued.

Our approach is similar to the one used by the Children's Nephrotic Syndrome Consensus group, which suggests treating the first relapse or infrequent relapse with prednisone therapy of 2 mg/kg per day (maximum dose of 60 mg/day) until the proteinuria has resolved for three consecutive days [6]. At that point, alternate-day prednisone is administered at a dose of 1.5 mg/kg per day (maximum dose of 45 mg/day) for four weeks.

However, the optimal management of relapses for children who are infrequent relapsers is uncertain. Since there are known adverse effects of prolonged steroid therapy, research including the following studies are focused on finding effective but shorter course of steroid therapy.

●A single-center open-label trial of 117 children with NS reported patients treated with a short course of prednisolone (40 mg/m² on alternate days for two weeks) compared with those managed by a standard regimen (40 mg/m² on alternate days for four weeks) had a similar rate of frequent relapse/steroid dependence at 12 months of follow-up (24 versus 23 percent) [28].

●A second open-label clinical trial of 78 children (ages 3 to 17 years) with SSNS who achieved remission after five days of consecutive steroids following a relapse provided additional support for a shorter course of alternative day steroids after remission is induced [29]. In this cohort, patients assigned to a short course of alternate day steroids (18 doses of 40 mg/m² of prednisone over 36 days) and those assigned to a more prolonged alternate day course (40 mg/m² tapered over 72 days by steps of 6 doses) had similar rates of relapse at six months (42 versus 58 percent).

Additional large clinical trials are needed to determine the optimal management of children with SSNS who have infrequent relapses to minimize steroid exposure without increasing the risk of relapse.

Frequently relapsing/steroid-dependent nephrotic syndrome — Approximately 25 to 30 percent of steroid-responsive patients will develop frequently relapsing NS, defined as four or more relapses per year or two or more relapses in the initial six months after diagnosis [9,14]. In addition, there is a group of patients who are steroid dependent (defined as relapsing during taper or within two weeks of discontinuation of steroid therapy). In our practice, for patients who relapse within one month after discontinuing therapy or while prednisone is decreased (steroid-dependent), daily prednisone therapy is reinitiated until remission, 40 to 60 mg/m² (maximum dose 60 mg), until proteinuria has disappeared for four to five days, followed by alternate-day therapy with tapering by 15 to 20 mg/m² every other day to the patient's steroid threshold (ie, the dose at which the relapse has occurred) [30]. This regimen is continued for 12 to 18 months. Although the management approach is similar, a distinction between frequent relapsers and steroid-dependent patients should be made, if possible, because frequently relapsing NS seems to have a slightly better prognosis regarding response to steroid-sparing agents and long-term remission [31].

Although children with frequently relapsing or steroid-dependent NS are at risk for steroid toxicity, prednisone remains the preferred therapy in the absence of significant steroid toxicity. Different steroid regimens have been used to treat patients with frequent relapses and/or who are steroid dependent. As noted above, in our center, we administer daily prednisone until proteinuria has resolved, which is then followed by alternate-day therapy to the patient's steroid threshold (ie, the dose at which the relapse has occurred) for 12 to 18 months.

Other regimens start with an initial prednisone dose of 60 mg/m² per day or 2 mg/kg per day at the time of relapse but differ on the duration of treatment, including alternate-day schedule. These other regimens include:

●The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines continue prednisone dosing of 60 mg/m² per day or 2 mg/kg per day until the urine protein tests are negative or trace for three consecutive days, followed by alternate-day prednisone for at least three months [7]. The dose of alternate-day prednisone should be the lowest dose needed to maintain remission without adverse side effects. In patients in whom alternate-day therapy is not effective in maintaining remission, the lowest possible dose of daily prednisone is given to maintain remission to minimize adverse side effects.

●The Children's Nephrotic Syndrome Consensus recommends prednisone therapy of 2 mg/kg per day (maximum of 60 mg/day) until the urine protein tests are negative or trace for three consecutive days, followed by alternate-day prednisone of 1.5 mg/kg for four weeks, which is then tapered over two months on an alternate-day schedule [6].

●An open-label randomized controlled trial reported that daily administration of low-dose prednisolone (0.2 to 0.3 mg/kg per day) is more effective than standard-dose alternate-day therapy (0.75 mg/kg every other day) in lowering relapse rates, sustaining remission, and enabling steroid-sparing [32].

Adrenocorticotropic hormone (ACTH) has been suggested as an alternative to corticosteroid therapy. However, in a study of patients with either frequently relapsing or steroid-dependent NS, ACTH administered twice a week at a dose of 80 international units/1.73 m² was ineffective at preventing relapses [33].

It is important to appreciate, especially when considering other therapeutic agents, that almost all frequent relapsers have a progressive decrease in the number of relapses over time and many ultimately go into permanent remission [34]. Steroid-sparing agents should be considered in children who have significant steroid toxicity. (See 'Alternative treatments for patients with steroid toxicity' below.)

Infections as relapse triggers — Viral infections are a documented trigger for a relapse in children with NS [35]. In our practice, a short-term increase to daily maintenance dosing (using the same dose that was given on alternate days) is administered to patients with frequent relapsing SSNS for five to seven days during an episode of intercurrent infections. This intervention appears to reduce the risk of relapse [36-39].

Late steroid resistance — In a small number of cases, patients who were initially steroid sensitive become steroid resistant [40-42]. Although data are limited, case reports suggest that complete or partial remission can be achieved in the majority of patients using alternative immunosuppressive therapeutic agents [40,41]. However, these patients are at risk for kidney function impairment and developing end-stage kidney disease (ESKD) [40].

Based on the available evidence, we suggest that nonsteroidal therapy be offered in patients who develop late steroid resistance. In our center, we use calcineurin inhibitors (CNIs) and/or rituximab. (See 'Calcineurin inhibitors' below.)

Alternative treatments for patients with steroid toxicity — Complications secondary to prolonged steroid therapy are well known and are seen in children with NS, especially those with frequent relapses or steroid dependency.

Indications — Steroid-sparing immunosuppressive agents are indicated for any child with NS who displays any of the major side effects of steroids [6-8,43]. (See "Major adverse effects of systemic glucocorticoids".)

In children with NS, the most frequent signs of steroid toxicity include:

●Statural growth impairment [44]. Low-dose alternate-day therapy can preserve growth [45], and catchup growth often occurs when steroid therapy is discontinued [46]. One small observational study found that growth was not negatively impacted with doses of prednisolone below 0.75 mg/kg per day [47]. We prefer alternate-day therapy whenever possible to preserve normal growth as much as possible.

●Cataracts [48,49]. (See "Major adverse effects of systemic glucocorticoids", section on 'Ophthalmologic effects'.)

●Excessive weight gain and cushingoid features, which can persist into adulthood [50]. (See "Major adverse effects of systemic glucocorticoids", section on 'Dermatologic effects and appearance'.)

●Suppression of the hypothalamic-pituitary-adrenal axis [51].

●Behavior disturbances (hyperactivity, depression). (See "Major adverse effects of systemic glucocorticoids", section on 'Neuropsychiatric effects'.)

●Hypertension.

●Osteopenia. (See "Major adverse effects of systemic glucocorticoids", section on 'Bone and muscle effects'.)

Choice of agent — In children with SSNS and evidence of steroid toxicity, the optimal steroid-sparing immunosuppressive agent should maintain long-term remission in the majority of patients, allowing for a reduction in steroid dosing and toxicity, and have no significant side effects. However, there is no clear evidence that any of the currently used immunosuppressive agents provide long-term efficacy without significant side effects [43]. These agents include levamisole, mycophenolate mofetil (MMF), CNIs, (cyclosporine and tacrolimus), alkylating agents, and rituximab.

Our approach:

●We suggest the use of levamisole, if it is available, as it has the least side effects and has shown to have a steroid-sparing effect.

●MMF is our next choice as it appears to have similar efficacy to other nonsteroidal immunosuppressive agents, but with less toxicity.

●In patients who fail to maintain remission after treatment with levamisole and/or MMF, we switch to a CNI.

Steroid-sparing immunosuppressive agents — The following discussion reviews data on specific steroid-sparing immunosuppressive agents.

Levamisole — Levamisole, which stimulates the immune system, has been shown to have a steroid-sparing effect in children with SSNS [43,52-59]. It is the least toxic and least expensive drug for preventing relapses, and if available, the initial preferred steroid-sparing medication. However, availability is limited worldwide [60] and it is not available in the United States or Canada.

In our practice, the dose of levamisole is usually 2 to 2.5 mg/kg given on alternate days (maximum dose of 150 mg), which is consistent with the recommendations from the 2012 KDIGO guidelines [7]. Regular monitoring of complete blood count should be performed because the most serious adverse effect of levamisole is reversible neutropenia. Monitoring of antineutrophil cytoplasmic autoantibody (ANCA) titers is recommended as ANCA vasculitis has been reported with cutaneous vasculitis or arthritis [61].

The following studies demonstrate the effectiveness of levamisole:

●In a multinational clinical trial of children managed with standard steroid therapy, the addition of levamisole for one year compared with placebo increased the time following termination of steroid therapy and increased the remission rate at 12 months (26 versus 6 percent) [59]. However, most patients relapsed after cessation of treatment. Reversible neutropenia was the most common adverse effect, occurring in approximately two percent of treated patients. Other reported rare severe adverse effects of levamisole (eg, hepatitis, seizures, and ANCA vasculitis) were not observed.

●In an open-label trial of children with frequently relapsing or steroid-dependent NS, levamisole (2.5 mg/kg on alternate days) and MMF (750 to 1000 mg/m²) had similar rates of sustained remission, reduction of steroid use, and frequency of relapses [62]. The rates of adverse effects were low and also similar in both groups treated with levamisole and MMF.

●A prospective study has shown that levamisole at 2.5 mg/kg daily was effective and safe. The mean number of relapses per patients was 2.8±0.8 in patients on an alternate-day schedule of levamisole and 1.3±0.9 on a daily schedule of levamisole [63].

Mycophenolate mofetil — Mycophenolate mofetil (MMF) inhibits T- and B-cell proliferation. Several studies suggest that MMF is effective in increasing the duration of remission in children with idiopathic NS, which may allow withdrawal of steroids or CNIs [62,64-70]. In one open-label trial, MMF was equally as effective as levamisole [62]. Data comparing MMF with CNIs (specifically cyclosporine) are limited, but suggest that MMF is not as effective as cyclosporine in achieving remission [43,71,72]. However, MMF is not nephrotoxic and as a result, we prefer to administer MMF as the initial steroid-sparing agent when levamisole is not available, and prescribe CNIs only if the patient fails to respond to MMF.

Relapses often occur after the treatment is discontinued. It also appears that higher mycophenolic acid (MPA, the active metabolite of MMF) exposure in children with NS compared with kidney transplant recipients are needed to sustain remission [73]. As a result, therapeutic drug monitoring is recommended so that target MPA-AUC (area under the curve) exposure is maintained above 45 microg·h/mL [74-77]. This higher level does not appear to be associated with increased side effects compared with lower exposure.

Side effects of MMF include gastrointestinal disturbances (abdominal pain and diarrhea) and hematological abnormalities. Because MMF is teratogenic, use of contraception is recommended in adolescent females [78].

Calcineurin inhibitors — CNIs, such as cyclosporine and tacrolimus, block T-cell activation and have been used to treat patients with frequently relapsing or steroid-dependent NS. However, long-term therapy is generally required to maintain remission, which increases the risk for drug-induced nephrotoxicity [79]. In our center, we use cyclosporine for patients who do not respond to MMF.

Because of the concern for nephrotoxicity, the plasma creatinine concentration should be monitored regularly in patients who are maintained on a long-term course of CNIs. Despite ongoing monitoring of kidney function, serial kidney biopsies may demonstrate histologic lesions of nephrotoxicity without clinical evidence of kidney function impairment. Thus, we routinely perform a kidney biopsy in asymptomatic patients after 18 to 24 months of CNI therapy [79-82]. (See "Cyclosporine and tacrolimus nephrotoxicity".)

Published data regarding the efficacy of CNIs are more robust for cyclosporine, which was the first available CNI:

●Cyclosporine – Data demonstrate that cyclosporine is effective in inducing or maintaining remission in patients with frequently relapsing or steroid-dependent NS [80,83-88]. However, most patients relapse when the drug is withdrawn, thus necessitating prolonged treatment and increasing the risk of nephrotoxicity [81,83,89,90].

The recommended starting cyclosporine dose is 150 mg/m² per day divided into two oral doses. The dose should be adjusted to maintain trough whole blood levels between 100 and 200 ng/mL, and the level should not exceed 200 ng/mL. To limit the risk of nephrotoxicity, once remission is achieved, we recommend decreasing the dose to <5 mg/kg, if possible.

It has been our experience that patients who relapse on cyclosporine or after cyclosporine withdrawal often respond poorly to a second or third course of treatment. Low-dose alternate-day prednisone in combination with cyclosporine may be a better approach in these patients.

●Tacrolimus – Limited data suggest that tacrolimus offers no advantage over cyclosporine on maintaining remission in children with SSNS, and it has the same risk of nephrotoxicity [91-93]. However, one advantage of tacrolimus over cyclosporine is the reduced cosmetic side effects (hypertrichosis, gum hypertrophy).

Alkylating agents — Alkylating agents, such as cyclophosphamide and chlorambucil, can induce longer lasting remissions than prednisone alone in patients who are frequent relapsers or steroid dependent. However, these medications, which result in depletion of immune-competent cells, have serious adverse effects. As a result, the use of alkylating agents as a steroid-sparing therapy has decreased in favor of other immunosuppressive agents with similar efficacy but less significant side effects. As a result, we do not use alkylating agents in our center to treat children with NS and steroid toxicity.

Several observational studies have shown that the use of alkylating agents compared with prednisone alone resulted in longer sustained remission in children with frequently relapsing and/or steroid-dependent NS [43,94-99]. Cyclophosphamide is less effective in sustaining remission in children with steroid-dependent NS compared with patients with frequent relapses [100,101]. In a systematic review of 38 studies with 1,504 children, the reported remission rates were 72 and 36 percent after two and five years in patients with frequent relapses compared with 40 and 24 percent in steroid-dependent patients [102].

Nevertheless, the following serious complications are associated with alkylating agents, which have led to their decreased use [102,103].

●Neutropenia and infection – Neutropenia is a serious adverse effect of bone marrow suppression by alkylating agents. Patients receiving these medications require monitoring of their complete blood cell counts. If the white cell count falls below 3000/mm³, the drug should be withdrawn until the count rises. Treatment also should be discontinued if infection develops. There are reported cases of significant morbidity and mortality associated with varicella and the administration of cyclophosphamide. If varicella infection occurs, acyclovir should be administered immediately and the alkylating agent discontinued. (See "Complications of nephrotic syndrome in children", section on 'Viral infections'.)

●Gonadal toxicity – The development of gonadal toxicity resulting in infertility generally requires a total dose greater than 200 to 300 mg/kg for cyclophosphamide, which exceeds the recommended cumulative dose used to treat children with NS (168 mg/kg for cyclophosphamide) [104,105]. The gonadal toxicity threshold for chlorambucil is 8 to 10 mg/kg.

●Malignancy – In a 2001 systematic review of the literature that included 1504 patients, 14 cases of malignancies were reported after high doses (greater than the above recommended standard dosing) of either cyclophosphamide or chlorambucil [102]. There was also a single reported case of malignancy (acute lymphoblastic leukemia) associated with cyclophosphamide administered in a child with NS using the above recommended regimen [106].

●Alopecia and hemorrhagic cystitis – These are uncommon complications that occur at the recommended doses used to treat children with NS.

●Seizures – Chlorambucil has been associated with an increased risk of seizures in children with NS [107].

If an alkylating agent is used, oral cyclophosphamide is given at a dose of 2 mg/kg per day for 12 weeks (cumulative dose 168 mg/kg). The maximum daily dose should not exceed 2.5 mg/kg. This cumulative dose appears to minimize the most serious long-term adverse effects.

Rituximab — Rituximab, a chimeric anti-CD20 monoclonal antibody that depletes B-cell lymphocytes, appears to be effective in prolonging remission in steroid-dependent or CNI-dependent patients and reducing the use of one or more immunosuppressive agents [43]. In our practice, rituximab is considered only for children with serious adverse effects from their immunosuppressive medications based on the judgement of clinicians who have expertise in the care of children with NS requiring multiple immunosuppressive agents because of concern for severe adverse effects and uncertainty regarding the optimum dosing of rituximab and long-term efficacy [43,108].

Several small trials, many of them open-label studies, have reported that administration of rituximab alone or with corticosteroids was associated with a longer duration of remission and allowed for discontinuation or decrease in the dose of one or more immunosuppressive agents [43,109-114]. However, there is significant heterogeneity amongst these studies with variation in the patient population including differences in previous immunosuppressive treatment, dosing and frequency of rituximab therapy, and outcome measurements. As a result, the optimum dosing schedule for rituximab in children with steroid-dependent NS or frequently relapsing NS has not been established. Low versus high dose and the use of single versus multiple administrations remain areas of controversy [115-117].

A significant proportion of patients relapse after rituximab administration with the recovery of B-cell lymphocytes [118,119]. In a randomized trial, treatment with a single dose of rituximab was superior to tacrolimus at one year follow-up (90 versus 63 percent relapse-free survival) [112], but all participants had relapsed by two years follow-up [119]. Maintenance therapy with either MMF or cyclosporine has been reported to reduce relapses after treatment with rituximab [119-121].

However, rituximab is associated with severe and potentially life-threatening complications [108].

●Infusion-related reactions occur within the initial 30 to 120 minutes of the first exposure and include headache, fever, chills, sweats, skin rash, dyspnea, mild hypotension, nausea, rhinitis, pruritus, asthenia, back pain, and less commonly, bronchospasm and hypotension. Certain signs and symptoms are highly suggestive of anaphylaxis, such as urticaria, repetitive cough, wheeze, and throat tightness/change in voice. In these patients, treatment with rituximab should be discontinued. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Infusion reactions' and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Management of infusion reactions'.)

●Leukopenia and/or hypogammaglobulinemia resulting in serious infections, including Pneumocystis carinii pneumonia [122,123]. In one case report, a child with NS developed viral myocarditis due to enterovirus requiring cardiac transplantation [124]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Effects on B cells, antibodies, and risk of infection'.)

●Other less common adverse effects include serious mucocutaneous reactions (Stevens-Johnson syndrome, vesiculobullous dermatitis, toxic epidermal necrolysis, and ulcerative gastrointestinal disease). There is also a published case report of death due to lung fibrosis [125].

●The development of anti-rituximab antibodies has also been reported, which may be associated with decreased efficacy and an increase in infusion reactions for subsequent repeated administration of rituximab [126-128]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Human antichimeric antibodies'.)

Long-term outcome of steroid-sensitive nephrotic syndrome — Limited data on adult long-term outcome of children with SSNS suggest that patients who had frequent relapses or steroid-dependent NS during childhood are at risk for relapses during adulthood and for drug adverse effects [50,129-131]. Kidney function remains normal in adulthood as long as the patients remain responsive to treatment [129,130] and long-term sequelae are generally related to side effects of medications.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nephrotic syndrome in children".)

SUMMARY AND RECOMMENDATIONS

●Initial management: Empiric steroids – In children with nephrotic syndrome (NS) who have a high probability of having minimal change disease (MCD) based on clinical and laboratory findings, we recommend empiric therapy with oral prednisone, thus avoiding kidney biopsy (Grade 1B). MCD is the most common cause of NS in children, accounting for 75 to 80 percent of pediatric cases. (See 'Empiric steroid therapy versus kidney biopsy' above.)

In our center, we start with oral prednisone at a dose of 60 mg/m² per day (maximum of 60 mg/day). When proteinuria disappears, prednisone is continued at the same daily dose for a total of 30 days, followed by alternate-day therapy at 40 mg/m² (maximum dose 60 mg) every other day for one month. Other experts in the field also use the same initial dose of steroid, but the duration of initial therapy following onset of remission varies among pediatric nephrologists. (See 'Initial steroid course' above.)

●Remission: Steroid-sensitive NS (SSNS) – Most children with idiopathic NS will respond to initial steroid therapy. After six months of initial steroid therapy, approximately 30 percent of children with SSNS will not relapse, 10 to 20 percent will have less than four relapses, and the remaining will have frequent relapses and/or relapse while on steroid therapy (steroid dependent). (See 'Outcome based on response' above.)

For children with SSNS, the preferred intervention generally is steroid therapy for subsequent relapses.

•With the initial relapse or for infrequent relapses, we administer oral prednisone at a daily dose of 60 mg/m² or 2 mg/kg (maximum of 60 mg/day) until proteinuria resolves for three days, at which point, alternative-day therapy is initiated and tapered over four weeks. Other centers use a similar approach with variation on the dosing and length of therapy. (See 'Initial or infrequent relapse' above.)

•For children with frequently relapsing and/or steroid-dependent NS, we administer oral prednisone at a daily dose of 40 to 60 mg/m² or 2 mg/kg (maximum of 60 mg/day) until proteinuria resolves, at which point, alternative-day therapy is initiated and tapered until the patient's threshold level and continued for 12 to 18 months.

●Steroid toxicity for patients with SSNS: Treatment options – For children who require steroids to maintain remission and have evidence of steroid toxicity, alternative nonsteroidal immunosuppressive agents can be added to maintain remission while reducing steroid dosing and toxicity. (See 'Initial or infrequent relapse' above and 'Frequently relapsing/steroid-dependent nephrotic syndrome' above and 'Alternative treatments for patients with steroid toxicity' above.)

•We suggest levamisole as the initial steroid-sparing immunosuppressive agent compared with other immunosuppressive agents (Grade 2C). It is the least expensive and least toxic of the effective therapeutic choices. However, levamisole has limited global availability. (See 'Levamisole' above.)

•If levamisole is not available, we suggest mycophenolate mofetil (MMF) as the initial therapy drug for patients with significant steroid toxicity compared with other agents (Grade 2C). Although perhaps not as effective as calcineurin inhibitors (CNIs), MMF is less nephrotoxic. (See 'Choice of agent' above and 'Levamisole' above and 'Mycophenolate mofetil' above.)

•In other centers, CNIs are used as the initial steroid-sparing agent. However, sustained remission with these agents requires prolonged treatment and increases the risk of potentially irreversible nephrotoxicity. As a result, in our practice, cyclosporine is only used in patients who fail to maintain remission after a course of MMF without a significant reduction in steroid dose. If CNIs are used, plasma creatinine concentration should be monitored regularly and a kidney biopsy should be performed even in asymptomatic patients after 18 to 24 months of therapy to screen for potential interstitial fibrosis. (See 'Calcineurin inhibitors' above.)

●Steroid-resistant NS (SRNS) – Ten to 15 percent of children will fail to respond to steroid therapy. These children with SRNS are at greatly increased risk for developing end-stage kidney disease (ESKD). Evaluation to determine the underlying etiology, including a kidney biopsy and screening for genetic disorders, should be performed as therapeutic decisions are based on the underlying cause. (See 'Outcome based on response' above and "Steroid-resistant nephrotic syndrome in children: Etiology".)