INTRODUCTION — The nephrotic syndrome (NS) is caused by renal diseases that increase the permeability across the glomerular filtration barrier. It is classically characterized by four clinical features, but the first two are used diagnostically because the last two may not be seen in all patients:
●Nephrotic range proteinuria – Urine protein excretion >50 mg/kg per day
●Hypoalbuminemia – Serum albumin <3 g/dL (30 g/L)
●Edema
●Hyperlipidemia
Idiopathic NS is the most common form of NS in children, representing more than 90 percent of cases before 10 years of age and 50 percent after 10 years of age. The majority of children with NS will respond to steroid therapy. However, symptomatic treatment is important in the early course of therapy, as response to steroid therapy may take several weeks [1]. Symptomatic treatment also becomes the mainstay of therapy in children who fail to respond to steroids, especially in those with genetic mutations that cause their NS.
The symptomatic management of NS in children will be reviewed here. Specific treatment of NS in children is discussed separately. (See "Treatment of idiopathic nephrotic syndrome in children".)
HYPOVOLEMIA — Despite a total increase in body water, children with NS may typically have a decreased intravascular volume. Serious intravascular volume depletion may be observed at onset of the NS with severe hypoalbuminemia and may be aggravated by diarrhea or diuretics. Clinical signs and symptoms may be present in patients with significant intravascular volume depletion including tachycardia, findings of peripheral vasoconstriction (eg, cool extremities and delay in capillary refill), oliguria, and abdominal pain. A very low fractional excretion of sodium (FENa) less than 0.2 percent is suggestive of volume depletion [2]. In this situation, an albumin infusion can be safely administered if clinically required.
EDEMA
Salt restriction — Edema is treated by salt restriction because renal retention of sodium is one of two principal mechanisms that lead to edema in the NS. Dietary salt intake should be restricted to less than 2 mEq/kg per day. In an already edematous patient, salt restriction alone will not significantly improve edema, but can reduce further accumulation of fluid. (See "Pathophysiology and treatment of edema in adults with the nephrotic syndrome", section on 'Evidence supporting primary renal sodium retention'.)
Diuretics — Although diuretics are commonly used in adults with NS, their role in often severely hypoalbuminemic children is less clear. Affected children may be intravascularly volume depleted and aggressive diuresis may lead to further volume depletion, thereby possibly precipitating acute renal failure and increasing the risk of thrombosis in this already susceptible group of patients [3,4]. Rarely, diuretics can contribute to severe volume depletion that results in hypovolemic shock [5]. (See "Complications of nephrotic syndrome in children", section on 'Hypovolemia'.)
Diuretics should only be given in cases of severe edema and only if there is not significant intravascular volume depletion. In a study of 30 children with NS and severe edema, a fractional excretion of sodium (FENa) value <0.2 percent identified patients with severe edema and volume contraction who also had higher serum renin, aldosterone, and antidiuretic hormone [6]. Diuretic therapy alone was used successfully in 10 of 11 patients with FENa >0.2 percent. In one patient with an elevated FENa, albumin was added to diuretic therapy because of a rise in serum creatinine and the development of hyponatremia. (See "Fractional excretion of sodium, urea, and other molecules in acute kidney injury".)
Furosemide may be given intravenously or orally without albumin. If used, it should be given twice because of its short duration of action. Although it is somewhat less effective, it can be useful when given alone. Ongoing oral use of furosemide may cause hypovolemia and hypokalemia, and close monitoring of the patient is required.
Other diuretics used in childhood NS include:
●Thiazide diuretic – Thiazide diuretics, such as metolazone, in combination with furosemide, appear to enhance the natriuretic and diuretic effects of furosemide alone [7]. However, this combination of diuretics is associated with hypokalemia.
●Amiloride – Amiloride is a potassium-sparing diuretic that decreases sodium channel activity of the cortical collecting tubule. The rationale for its use is that renal sodium retention is at least in part related to an activation of the epithelial sodium channel, which is abolished by amiloride [8,9]. It can be used in combination with furosemide to decrease the risk of hypokalemia.
Because of the potential for serious complications, diuretic management should be supervised by a nephrologist who has expertise in treating children with NS.
Furosemide and albumin — Patients with anasarca (generalized and massive edema) may be treated with furosemide (1 to 2 mg/kg per dose) in combination with salt-poor albumin (0.5 to 1 g/kg infused over four hours) [10]. However, this treatment modality should be considered with caution due to the risk of severe complications, such as pulmonary edema, hypertension, or congestive heart failure [11,12]. A careful assessment of the patient's intravascular status is necessary before prescribing an albumin infusion. Albumin and furosemide can be given to patients with evidence of intravascular hypovolemia (ie, FENa <0.2 percent), whereas patients who have normal or increased intravascular volume should be treated with diuretics alone (FENa >0.2 percent) [2]. (See "Complications of nephrotic syndrome in children", section on 'Anasarca'.)
Albumin raises the intravascular oncotic pressure and thereby protects the intravascular compartment against volume contraction. Albumin infusion also increases protein-binding of furosemide, which improves the rate of delivery to the kidney resulting in increased renal salt excretion. (See "Pathophysiology and treatment of edema in adults with the nephrotic syndrome", section on 'Treatment'.)
In a retrospective study, albumin and furosemide therapy in children with NS effectively removed fluid with a mean loss of 0.4 kg (1.2 percent of body weight) per infusion [11]. However, the effect is transient and can be associated with complications resulting from increased vascular volume, including hypertension and respiratory distress. As a result, aggressive diuresis with albumin and furosemide therapy should be reserved for patients with anasarca who have respiratory compromise due to ascites and/or pleural effusions, severe scrotal edema, peritonitis, or severe tissue breakdown [3,13]. Other measures, such as salt and fluid restriction, are needed to prevent reaccumulation of fluid. (See "Etiology, clinical manifestations, and diagnosis of nephrotic syndrome in children", section on 'Clinical manifestations'.)
Fluid restriction — Although there is debate on the role of fluid restriction, initial restriction of fluid intake to an equivalent volume of the patient's insensible losses plus his/her urine output will result in stabilizing the patient's weight without further accumulation of edema. In patients with hyponatremia with a serum sodium of less than 135 mEq/L, fluid restriction is required as fluid accumulation is a result of inappropriate antidiuretic hormone secretion, secondary to intravascular volume depletion.
HYPERCOAGULABILITY — Nephrotic patients with severe hypoalbuminemia are at risk for thromboembolic complications. Patients with infections have a higher risk of venous thromboembolism [14]. Preventive measures include avoidance of prolonged bed rest, regular ambulation, compression stockings, avoidance of hemoconcentration resulting from hypovolemia, avoidance of central venous catheter if possible, and early treatment of sepsis or volume depletion [15,16]. (See "Complications of nephrotic syndrome in children", section on 'Thromboembolism' and "Hypercoagulability in nephrotic syndrome", section on 'Pathogenesis'.)
Most clinicians do not give prophylactic anticoagulation initially. This is due in large part to the lack of randomized trials to determine the efficacy and safety of such an approach [17]. In some centers, prophylactic warfarin therapy is given to high-risk patients including adolescents (>12 years of age) who have additional risk factors including a serum albumin concentration of less than 2 g/dL (20 g/L), a fibrinogen level of more than 6 g/L, or an antithrombin III level less than 70 percent of normal, although there is no evidence that it is beneficial [15,18]. Alternatively, high-risk patients can be treated with low-dose aspirin or dipyridamole, although there are no controlled trials that demonstrate their efficacy in thrombus prevention in children with NS.
Treatment of venous thromboembolism — Anticoagulation is most often initiated with low molecular weight heparin, such as enoxaparin. Neonates and infants may require doses as high as 3 mg/kg given every 12 hours, while older children generally need only 1 mg/kg given every 12 hours [19]. It can be given subcutaneously (avoiding the need for central venous catheterization), and its pharmacokinetic profile is more predictable than unfractionated heparin. Antifactor Xa assay is used for therapeutic drug monitoring. In situations where short half-life and reversible anticoagulation is necessary, unfractionated heparin is utilized. The heparin dose necessary to obtain a therapeutic effect is often greater than normal due to decreased antithrombin III level. Warfarin treatment is given for long-term treatment, as anticoagulation should be continued for a minimum three- to six-month course [1]. Thrombolysis is reserved only for severe cases with life- or limb-threatening thromboembolism. In patients with previous thromboembolic complications, we will start treatment anticoagulation therapy if the patient remains nephrotic, which places them at continued risk for thrombosis. (See "Hypercoagulability in nephrotic syndrome".)
INFECTION
Bacterial — Nephrotic children are at increased risk of developing infection (eg, peritonitis, pneumonia, and sepsis) due to encapsulated bacteria [20-22]. Initial therapy of suspected infection includes cultures and the administration of empiric broad-spectrum antibiotics based on the site of infection [1,16]. Antibiotic therapy is modified on culture results, including antimicrobial sensitives.
NS increases the susceptivity to infection because of reduced serum concentrations of immunoglobulin G, decreased cellular immunity, and the administration of immunosuppressive therapy. The most common agent is Streptococcus pneumoniae followed by Escherichia coli and Hemophilus. (See "Complications of nephrotic syndrome in children", section on 'Bacterial infection'.)
Prophylactic antimicrobials are not recommended [1]. However, vaccination is recommended even though antibody response may be blunted. All children with NS should receive 23-valent polysaccharide vaccine (PPSV23) pneumococcal vaccine (if not already immunized). Although immunization is ideally administered when the child is in remission and off of daily corticosteroid therapy, children who received immunization at the onset of their NS while on high-dose daily prednisone responded with a 10-fold increase in antibody levels to PPSV23 [23]. As a result, in children with NS who are steroid dependent, administration of PPSV23 is recommended. (See "Pneumococcal vaccination in children", section on 'Immunization of high-risk children and adolescents'.)
However, anti-pneumococcal antibody levels decrease more rapidly in children with NS as compared with healthy children [24,25]. This explains the occurrence of pneumococcal infection despite the vaccination in some patients [26,27].
Varicella — Children with NS who require immunosuppressive therapy are at increased risk for developing varicella.
●Varicella vaccination – Varicella vaccination has been shown to be effective in children with NS, and should be given to all patients with negative varicella titers [28]. It is ideally administered as a two-dose regimen when the child is in remission and on low-dose alternate days (eg, less than 2 mg/kg of body weight on alternate days) or off of corticosteroid therapy. (See "Vaccination for the prevention of chickenpox (primary varicella infection)", section on 'Schedules in the United States'.)
●Varicella exposure, immunosuppression, and no immunity – In cases of exposure of patients who are receiving immunosuppressive therapy and do not have immunity to varicella, varicella-zoster immune globulin (human) product should be administered within 96 hours of the exposure at a recommended dose of 125 units/10 kg body weight, up to a maximum of 625 units (five vials); the minimum dose is 125 units. Patients should be monitored for varicella for 28 days after exposure, since varicella-zoster immune globulin may prolong the incubation period. Any patient who receives varicella-zoster immune globulin should receive varicella vaccine. The vaccine should be given five months after administration of varicella-zoster immune globulin. (See "Post-exposure prophylaxis against varicella-zoster virus infection".)
●Treatment of varicella – Acyclovir, a synthetic nucleoside analog that inhibits replication of human herpes viruses, is effective therapy for primary varicella infection. Intravenous acyclovir should be instituted promptly in any patient who is receiving immunosuppressive therapy and exhibits any sign of varicella infection [16]. Acyclovir has also been used prophylactically in children exposed to varicella while receiving immunosuppressive therapy [29]. (See "Treatment of varicella (chickenpox) infection", section on 'Antiviral therapy'.)
Influenza vaccination — Inactivated influenza vaccine is recommended for patients with immunodeficiency or receiving immunosuppressive therapy (see "Seasonal influenza in children: Prevention with vaccines", section on 'Immunocompromised children'). In a small case series of children with NS, an adequate antibody response to influenza A vaccine was observed and maintained for six months [30].
A major concern of vaccination in children with NS is that it may cause a relapse. However, vaccine-related relapses are not common, and the protection offered from vaccines greatly outweigh this minimal risk [31,32].
ENHANCED APPETITE AND EXCESSIVE WEIGHT GAIN — Increased caloric consumption as a result of appetite stimulation of corticosteroid therapy can lead to excessive weight gain. Dietary measures that limit excessive caloric consumption, including a low-fat diet, will help children avoid large weight gains.
PREVENTION OF METABOLIC BONE DISEASE — Abnormalities in bone histology can be seen in patients with NS, primarily due to two processes:
●Loss of vitamin D binding protein – In children with NS, urinary loss of vitamin D binding protein may result in low ionized calcium and 25-OH vitamin D3 (25-hydroxycholecalciferol) concentrations [33].
●Prolonged corticosteroid therapy may lead to abnormalities in bone histology [34] and, subsequently, osteoporosis [35]. However, one study using dual-energy x-ray absorptiometry did not find any difference in spinal or whole body mineral content of glucocorticoid-treated children with NS compared with control patients [36]. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Based on the above, calcium (500 mg/day) and vitamin D (2000 to 4000 units) supplements often are prescribed, especially when there are documented low calcium and/or vitamin D concentrations; however, there are currently no data that have shown this intervention to be effective.
DYSLIPIDEMIA — Persistent dyslipidemia is common in children with NS and is a risk factor for accelerated atherosclerosis, myocardial infarction, and stroke and may play a role in the progression of chronic renal failure (figure 1) [37]. The lipid abnormalities induced by the NS reverse with remission.
The optimal treatment of hyperlipidemia in children with persistent NS is unknown. In children with NS, statin therapy based on limited short-term observational data are effective and safe in reducing total and low-density lipoprotein (LDL) cholesterol, and triglyceride levels [38]. Nevertheless, statins should be used with caution until controlled studies are performed [38].
Data from adults with persistent proteinuria demonstrate the following:
●Dietary modification has been shown to have little benefit.
●The most successful hypolipidemic agents with persistent NS are the statins [39,40]. These agents generally produce few side effects and can lower the plasma total and LDL cholesterol concentrations by 20 to 45 percent. There is a smaller reduction in triglyceride levels.
Based on the above evidence, as well as data on the benefit of statin therapy in children with familial hypercholesterolemia, we treat children who remain persistently nephrotic and have hyperlipidemia with statin therapy. (See "Dyslipidemia in children and adolescents: Management" and "Dyslipidemia in children and adolescents: Management", section on 'Statin therapy' and "Society guideline links: Lipid disorders and atherosclerosis in children" and "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Familial combined hyperlipidemia'.)
LDL apheresis with steroid therapy has been proposed in patients with hyperlipidemia and refractory NS. In one study involving 11 children, this treatment resulted in complete remission in five and partial remission in two patients [41].
A more complete discussion on the treatment of hyperlipidemia in adults with NS is found separately. (See "Lipid abnormalities in nephrotic syndrome", section on 'Management'.)
HYPOTHYROIDISM — Patients with persistent NS may develop hypothyroidism due to the urinary loss of free and protein-bound thyroid hormones [42,43]. Levothyroxine is given to patients with hypothyroidism defined by a high serum thyroid-stimulating hormone (TSH) levels and low T4 (thyroxine) and T3 (triiodothyronine). (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)
HYPERTENSION AND ACE INHIBITORS — Children with NS and persistent hypertension are more likely to have chronic kidney disease (CKD) with poor outcome. In addition, hypertension is a major risk factor for cardiovascular disease. As a result, antihypertensive therapy is given to children with CKD, including those with NS, to reduce blood pressure (table 1 and table 2). (See "Nonemergent treatment of hypertension in children and adolescents", section on 'Target blood pressure goals' and "Chronic kidney disease in children: Complications", section on 'Hypertension'.)
For children with NS and hypertension, angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are the preferred anti-hypertensive agents because of their potential additive antiproteinuric benefit and ability to slow progression of renal impairment. The maximal antiproteinuric effect is observed after four weeks [44]; the antiproteinuric effect can be increased by low salt diet and/or diuretics [45]. ACE inhibitors and ARBs should be terminated if hyperkalemia cannot be controlled or the plasma creatinine concentration increases more than 30 percent above the baseline value. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
Other antihypertensive agents that have been used in children with NS include beta-blockers and calcium channel blockers (CCBs). (See "Nonemergent treatment of hypertension in children and adolescents".)
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 — The majority of children with nephrotic syndrome (NS) will respond to steroid therapy. However, symptomatic management is important in the early course of therapy, as response to steroid therapy may take several weeks, and it is the mainstay of therapy in children who fail to respond to steroids. (See "Treatment of idiopathic nephrotic syndrome in children".)
Symptomatic management includes the following:
●In patients with significant signs or symptoms of decreased intravascular volume, we suggest albumin infusion may be used to restore intravascular volume (Grade 2C).
●In patients with persistent proteinuria, salt and fluid restriction, and diuretics (alone or in combination with salt-pore albumin) are used to control edema. (See 'Edema' above.)
●Preventive measures to avoid thromboembolic complication include mobilization, avoidance of hemoconcentration resulting from hypovolemia, and early treatment of sepsis or volume depletion. We suggest not using routine prophylactic anticoagulation therapy in children with NS (Grade 2C). (See 'Hypercoagulability' above and "Hypercoagulability in nephrotic syndrome", section on 'Prevention of thromboembolism'.)
●Children with NS are at increased risk for both bacterial and viral infections. We recommend that these children receive 23-valent polysaccharide vaccine (PPSV23) pneumococcal (Grade 1B). We recommend that children with NS receive varicella vaccination (Grade 1B). (See 'Infection' above.)
●The optimal treatment of hyperlipidemia in children with persistent NS is unknown. Based upon data from adults with NS and hyperlipidemia, we suggest administering statin therapy to children who remain persistently nephrotic and have hyperlipidemia (Grade 2C). (See 'Dyslipidemia' above and "Lipid abnormalities in nephrotic syndrome", section on 'Management'.)
●Hypothyroidism is a complication of persistent pediatric NS. We recommend administration of synthetic thyroxine (levothyroxine) for patients with high serum thyroid-stimulating hormone (TSH) levels and low T4 (thyroxine) and T3 (triiodothyronine) (Grade 1B). (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)
●Children with NS and persistent hypertension are more likely to have chronic kidney disease (CKD) with poor outcome. In these patients, we suggest angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) be used to treat their hypertension because of their potential additive antiproteinuric benefit and ability to slow progression of renal impairment (Grade 2B). (See 'Hypertension and ACE inhibitors' above and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
