Symptomatic management of nephrotic syndrome in children

INTRODUCTION — The nephrotic syndrome (NS) is caused by renal diseases that increase the permeability across the glomerular filtration barrier. It is classically characterized by nephrotic-range proteinuria, hypoalbuminemia, and edema. The first two features are diagnostic.

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 [1,2]. 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 [3].

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 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 delayed capillary refill), oliguria, and abdominal pain. A very low fractional excretion of sodium (FENa) less than 0.2 percent is suggestive of volume depletion [4,5]. 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 to 3 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 — We decide whether and how to give diuretics based on the severity of edema and the intravascular volume status of the child.

Patients with severe edema and normal or increased intravascular volume — For patients with severe edema and normal or increased intravascular volume (ie, FENa >0.2 percent), we treat with diuretics alone [4,5]. Furosemide is our diuretic of choice for these patients.

●Furosemide – We give furosemide orally or intravenously (IV), in the following doses:

•Orally – We start with 2 mg/kg once or twice daily

•IV – We start with 1 to 2 mg/kg/dose and give a second dose after six hours, if needed, to a maximum dose of 6 mg/kg

Close monitoring of the patient’s vital signs (ie, tachycardia, hypotension) and serum electrolyte levels is required because ongoing oral use of furosemide may cause hypovolemia and hypokalemia.

●Amiloride – Amiloride is a potassium-sparing diuretic that decreases sodium channel activity of the cortical collecting tubule. It can be used in combination with furosemide to counter the risk of hypokalemia. 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 inhibited by amiloride [6,7].

●Thiazide diuretics – Thiazide diuretics such as metolazone, in combination with furosemide, appear to enhance the natriuretic and diuretic effects of furosemide alone [8]. However, this combination of diuretics is associated with hypokalemia.

Patients with edema and intravascular hypovolemia — For patients with any degree of edema (including anasarca, or generalized and massive edema) and evidence of intravascular hypovolemia (ie, tachycardia, peripheral vasoconstriction, oliguria, FENa <0.2 percent), we give IV albumin and furosemide, as follows [4]:

●We start with an IV infusion of salt-poor albumin, 0.5 to 1 g/kg given over four hours

●We give IV furosemide at 1 mg/kg per dose in the middle and/or at the end of the albumin perfusion [9,10]

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 [11,12]. Rarely, diuretics can contribute to severe volume depletion that results in hypovolemic shock [13]. Because of the potential for serious complications, diuretic management should be supervised by a nephrologist who has expertise in treating children with NS. (See "Complications of nephrotic syndrome in children", section on 'Hypovolemia'.)

For patients with anasarca, treatment with furosemide (1 to 2 mg/kg per dose) and salt-poor albumin (0.5 to 1 g/kg infused over four hours) should be considered with caution due to the risk of severe complications, such as pulmonary edema, hypertension, or congestive heart failure [14,15]. A careful assessment of the patient's intravascular status is necessary before prescribing an albumin infusion [16]. (See "Complications of nephrotic syndrome in children", section on 'Anasarca'.)

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 [5]. 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".)

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'.)

Data evaluating the benefit of albumin and furosemide are limited and of low quality [10]. 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 [14]. 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 [11,17]. Other measures, such as salt and fluid restriction, are needed to prevent reaccumulation of fluid. (See "Clinical manifestations, diagnosis, and evaluation 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 [18]. Preventive measures include avoidance of immobilization, 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 [19,20]. (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 or antiplatelet treatment initially. This is due in large part to the lack of randomized trials to determine the efficacy and safety of such an approach [21]. However, it is important to assess the risk profile for thromboembolic complications including a known familial thrombophilic predisposition or a previous thrombotic event. In some centers, prophylactic low molecular weight heparin 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 [19,22].

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 [23]. 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

●Pathogens of concern – Nephrotic children are at increased risk of developing infection (eg, peritonitis, pneumonia, and sepsis) due to encapsulated bacteria [24-26]. The most common pathogen is Streptococcus pneumoniae followed by Escherichia coli and Hemophilus. NS increases the susceptivity to infection because of reduced serum concentrations of immunoglobulin G, decreased complement opsonins, decreased cellular immunity, and the administration of immunosuppressive therapy. (See "Complications of nephrotic syndrome in children", section on 'Bacterial infection'.)

●Management – Initial therapy of suspected infection includes cultures and the administration of empiric broad-spectrum antibiotics based on the site of infection [1,20].

As an example, children with nephrotic syndrome who have abdominal pain and fever should undergo diagnostic paracentesis to evaluate for peritonitis [2]. Empiric treatment of bacterial peritonitis includes intravenous antibiotics that are active against S. pneumoniae (eg, third-generation cephalosporins). Antibiotic therapy is modified based on culture results, including antimicrobial sensitives.

●Prevention – Vaccination is the mainstay of prevention. Prophylactic antimicrobials are not recommended [1].

Children with nephrotic syndrome should receive standard childhood immunizations at the appropriate age to reduce the risk of bacterial infections (figure 1 and figure 2). (See "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)

Additionally, nephrotic syndrome is a high-risk condition that warrants PPSV23 in addition to PCV for pneumococcal vaccination. We recommend PPSV23 in children with nephrotic syndrome even though antibody response may be blunted and even among those who are steroid dependent. Specific recommendations on pneumococcal vaccination in high-risk children, including those with nephrotic syndrome, are discussed in detail elsewhere. (See "Pneumococcal vaccination in children", section on 'Immunization of high-risk children and adolescents'.)

Although vaccines are ideally administered when the child is in remission and off of daily corticosteroid therapy in order to maximize the vaccine response, children who received immunization at the onset of their NS while on high-dose daily prednisone had good response, with a 10-fold increase in antibody levels to PPSV23 [27]. Nevertheless, pneumococcal infection despite vaccination has been reported in patents with nephrotic syndrome [28,29]. This may be because anti-pneumococcal antibody levels decrease more rapidly in children with NS as compared with healthy children [30,31].

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 [32]. 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 in patients who are receiving immunosuppressive therapy and do not have immunity to varicella, postexposure prophylaxis consists of varicella-zoster immune globulin. Timing and dosing of varicella-zoster immune globulin, subsequent monitoring, and consideration of subsequent vaccination are discussed in detail elsewhere. Antiviral postexposure prophylaxis is an alternative when varicella-zoster immune globulin cannot be used.

●Treatment of varicella – We suggest antiviral therapy for children with nephrotic syndrome who develop primary varicella infection; for patients receiving immunosuppressive therapy, we suggest intravenous acyclovir [20]. Details on administration are discussed elsewhere. (See "Treatment of varicella (chickenpox) infection", section on 'Antiviral therapy'.)

Influenza and COVID-19 vaccination — Annual influenza vaccination and vaccination against coronavirus disease 2019 (COVID-19) are recommended for all children six months and older, including children with NS (figure 1 and figure 2). Children with nephrotic syndrome who are immunocompromised or are taking immunosuppressive therapy should receive the inactivated influenza vaccine. (See "Seasonal influenza in children: Prevention with vaccines", section on 'Immunocompromised children' and "COVID-19: Vaccines", section on 'Dose and interval (for immunocompetent individuals)'.)

In a small case series of children with NS, an adequate antibody response to influenza A vaccine was observed and maintained for six months [33].

These vaccinations are generally effective even during frank NS; they help to attenuate or prevent the viral infections, as well as NS relapses that can be triggered by the infection. These benefits greatly outweigh the very minimal risk of vaccine-related relapses [34,35].

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 [36].

●Prolonged corticosteroid therapy may lead to abnormalities in bone histology [37] and, subsequently, osteoporosis [38]. 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 [39]. (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 — Dyslipidemia is common in children with persistent 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 3) [40]. The lipid abnormalities induced by the NS reverse with remission. For children who remain persistently nephrotic and have hyperlipidemia, the approach to pharmacotherapy depends on the low-density lipoprotein (LDL) cholesterol level and presence of other risk factors for cardiovascular disease. This is discussed in detail elsewhere. (See "Dyslipidemia in children and adolescents: Management", section on 'Hypercholesterolemia'.)

The optimal treatment of hyperlipidemia in children with persistent NS is unknown [41]. In children with NS, statin therapy based on limited short-term observational data are effective and safe in reducing total and LDL cholesterol, and triglyceride levels [42]. Nevertheless, statins should be used with caution until controlled studies are performed [42].

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 [43,44]. 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.

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 [45].

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 [46,47]. Levothyroxine is given to patients with hypothyroidism defined by a high serum thyroid-stimulating hormone levels (>10mU/L) and low thyroxine (T4) and triiodothyronine (T3) [48]. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

HYPERTENSION AND ANGIOTENSIN-CONVERTING ENZYME INHIBITORS — Children with NS and persistent hypertension are more likely to have chronic kidney disease with poor outcome. In addition, hypertension is a major risk factor for cardiovascular disease. As a result, antihypertensive therapy is given to children with chronic kidney disease, 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 [49]; the antiproteinuric effect can be increased by low salt diet and/or diuretics [50]. 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. (See "Nonemergent treatment of hypertension in children and adolescents", section on 'Management approach'.)

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

●Importance of symptomatic management – 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".)

●Hypovolemia – In patients with significant signs or symptoms of decreased intravascular volume, an albumin infusion may be used to restore intravascular volume (Grade 2C). (See 'Hypovolemia' above.)

●Edema – In patients with persistent proteinuria, salt and fluid restriction as well as diuretics (alone or in combination with salt-poor albumin) are used to control edema. (See 'Edema' above.)

●Reducing thromboembolic risk – 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'.)

●Reducing infectious risk – Children with NS are at increased risk for both bacterial and viral infections. They should receive standard childhood immunizations at the appropriate age to reduce the risk of such infections (figure 1 and figure 2). Additionally, for pneumococcal vaccination, nephrotic syndrome is a high-risk condition that warrants PPSV23 in addition to pneumococcal conjugate vaccine (PCV). (See 'Infection' above and "Pneumococcal vaccination in children", section on 'Immunization of high-risk children and adolescents'.)

●Dyslipidemia – The optimal treatment of hyperlipidemia in children with persistent NS is unknown. For children who remain persistently nephrotic and have hyperlipidemia, the approach to pharmacotherapy depends on the low-density lipoprotein (LDL) cholesterol level and presence of other risk factors for cardiovascular disease. This is discussed in detail elsewhere. (See 'Dyslipidemia' above and "Dyslipidemia in children and adolescents: Management", section on 'Hypercholesterolemia'.)

●Hypothyroidism – This is a complication of persistent pediatric NS. We recommend administration of synthetic thyroxine (levothyroxine) for patients with high serum thyroid-stimulating hormone levels and low thyroxine (T4) and triiodothyronine (T3) (Grade 1B). (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

●Hypertension – Children with NS and persistent hypertension are more likely to have chronic kidney disease with poor outcome. In these patients, we suggest that 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 angiotensin-converting enzyme inhibitors' above and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)