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Offi cial reprint from UpToDatewww.uptodate.com ©2015 UpToDate

Author Patrick Niaudet, MD

Section Editor Tej K Mattoo, MD, DCH, FRCP

Deputy Editor Melanie S Kim, MD

Symptomatic management of nephrotic syndrome in children

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2015. | This topic last updated: Feb 28, 2014.

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 fe atures, but the first two are

used diagnostically because the last two may not be seen in all patients:

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. 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 nephrotic syndrome in children will be reviewed here. Specific treatment of

nephrotic syndrome in children is discussed separately. (See "Treatment of idiopathic nephrotic syndrome in

children".)

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 nephrotic syndrome (NS). 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 patients 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 failur e and increasing the risk of thrombosis

in this already susceptible group of patients [1,2]. Rarely, diuretics can contribute to severe volume depletion that

results in hypovolemic shock [3]. (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, the use of fractional excretion of sodium (FeNa)

distinguished patients with volume expansion (FeNa >2 percent) from those with volume contraction (FeNa <2

percent) [4]. Diuretic therapy alone was used successfully in 10 of 11 patients with FeNa greater than 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. The volume contracted group (ie, FeNa <2 percent) also had higher serum

renin, aldosterone, and antidiuretic hormone. (See "Fractional excretion of sodium, urea, and other molecules in

acute kidney injury (acute renal failure)".)

Furosemide may be given intravenously or orally without albumin. Although it is somewhat less effective, it can be

®

®

Nephrotic range proteinuria − Urine protein excretion greater than 50 mg/kg per day

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

Edema

Hyperlipidemia

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useful when given alone. Ongoing oral use of furosemide can still cause hypovolemia and hypokalemia, and close

monitoring of the patient is required.

Other diuretics used in childhood NS include:

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).

(See "Complications of nephrotic syndrome in children", section on 'Anasarca' .)

Albumin raises the intravascular oncotic pressure and thereby protects the intravascular compartment againstvolume 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

patients 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 [8]. 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 sufficient to threaten

perforation, peritonitis, or severe tissue breakdown [1,9]. 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. (See "Maintenance fluid therapy in children", section on 'Sensible and

insensible water loss'.)

HYPERCOAGULABILITY — Nephrotic patients with severe hypoalbuminemia are at risk for thromboembolic

complications. Preventative measures include regular ambulation, avoidance of hemoconcentration resulting from

hypovolemia, avoidance of central venous catheter if possible, and early treatment of sepsis or volume depletion[10]. (See "Complications of nephrotic syndrome in children", section on 'Thromboembolism' and "Renal vein

thrombosis and hypercoagulable state 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 [11]. In some centers, prophylactic warfarin therapy

is given to high-risk patients including adolescents (>12 years of age), or those with 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 [ 10]. 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 nephrotic syndrome (NS).

Thiazide diuretic − Thiazide diuretics, such as metolazone (2 mg/kg per dose), in combination with

furosemide, appear to enhance the natriuretic and diuretic effects of furosemide alone [5]. 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 [6,7]. It can be used in

combination with furosemide to decrease the risk of hypokalemia.

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Treatment of venous thromboembolism — Anticoagulation is most often initiated with low molecular weight

heparin, such as enoxaparin, at a starting dose of 1 mg/kg given every 12 hours. 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. Thrombolysis is

reserved only for severe cases. 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

"Renal vein thrombosis and hypercoagulable state in nephrotic syndrome", section on 'Anticoagulation for athromboembolic event'.)

INFECTION

Bacterial — Nephrotic children are at increased risk of developing infection (eg, peritonitis, pneumonia, and

sepsis) due to encapsulated bacteria, in part due to reduced serum concentrations of immunoglobulin, decreased

cellular immunity, and the administration of immunosuppressive therapy. The most common agent is

streptococcus pneumoniae followed by Escherichia coli. (See "Complications of nephrotic syndrome in children",

section on 'Bacterial infection'.)

Prophylactic antimicrobials are not recommended, but infections that do occur should be promptly treated.

Although antibody response can be blunted, all children with nephrotic syndrome (NS) should receive 23-valentpolysaccharide 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 [12]. As a result, in children with idiopathic NS and who are steroid dependent resulting

in a high risk for pneumococcal disease, administration of PPSV23 should be considered. (See "Pneumococcal

(Streptococcus pneumoniae) polysaccharide vaccines in children", section on 'Indications'.)

Varicella — Children with NS who require immunosuppressive therapy are at increased risk for developing

varicella. Varicella vaccination has been shown to be effective in children with NS, and should be given to all

patients with negative varicella titers [13]. It is ideally administered as a two-dose regimen when the child is in

remission and on low-dose alternative days or off of corticosteroid therapy.

In cases of exposure of patients who are receiving immunosuppressive therapy and do not have immunity to

varicella, VariZIG, a varicella zoster immune globulin product, can be administered. VariZIG 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 VariZIG may prolong the incubation period. Any patient who receives VariZIG should

receive varicella vaccine. Vaccine should be given five months after administration of VariZIG.

Acyclovir , a synthetic nucleoside analog that inhibits replication of human herpes viruses, is effective therapy for

primary varicella infection. It should be instituted promptly in any patient who is receiving immunosuppressive

therapy and exhibits any sign of varicella infection. Acyclovir has also been used prophylactically in children

exposed to varicella while receiving immunosuppressive therapy [14]. (See "Vaccination for the prevention of

varicella-zoster virus infection: Chickenpox".)

OTHER DIETARY MEASURES

Caloric intake — 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.

Calcium and vitamin D — Abnormalities in bone histology can be seen in patients with nephrotic syndrome (NS),

primarily due to two processes:

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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 currentlyno data that have shown this intervention to be effective.

HYPERLIPIDEMIA — Persistent hyperlipidemia is a risk factor for atherosclerosis and may play a role in the

progression of chronic renal failure. The lipid abnormalities induced by the nephrotic syndrome (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 is effective and safe in reducing total and LDL cholesterol,

and triglyceride levels [19]. Nevertheless, statins should be used with caution until controlled studies are

performed [19].

Data from adults with persistent proteinuria demonstrate the following:

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 "Inherited disorders of LDL-cholesterol metabolism", section on 'Familial hypercholesterolemia' and

"Dyslipidemia in children: Management" and "Dyslipidemia in children: Management", section on 'Rationale andcriteria for pharmacologic therapy'.)

LDL apheresis with steroid therapy has been proposed in patients with hyperlipidemia and refractory nephrotic

syndrome. In one study involving 11 children, this treatment resulted in complete remission in five and partial

remission in two patients [22].

A more complete discussion on the treatment of hyperlipidemia in adults with NS is found separately. (See "Lipid

abnormalities in nephrotic syndrome", section on 'Treatment' .)

HYPERTENSION AND ACE INHIBITORS — Children with nephrotic syndrome (NS) and persistent

hypertension are more likely to have chronic kidney disease with poor outcome. As a result, in patients with

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 [23]; the

antiproteinuric effect can be increased by low salt diet and/or diuretics [ 24]. 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 "Treatment of hypertension in children and adolescents", section on 'Pharmacologic therapy'.)

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 [15].

Prolonged corticosteroid therapy may lead to abnormalities in bone histology [16] and, subsequently,

osteoporosis [17]. 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 [18]. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Dietary modification has been shown to have little benefit.

The most successful hypolipidemic agents with persistent NS are the statins [ 20,21]. These agents generally

produce few side effects and can lower the plasma total and low-density lipoprotein (LDL) cholesterol

concentrations by 20 to 45 percent. There is a smaller reduction in triglyceride levels. (See "Lipid

abnormalities in nephrotic syndrome", section on 'Statins'.)

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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:

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REFERENCES

1. Hogg RJ, Portman RJ, Milliner D, et al. Evaluation and management of proteinuria and nephrotic syndromein children: recommendations from a pediatric nephrology panel established at the National KidneyFoundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE).Pediatrics 2000; 105:1242.

2. Sullivan MJ 3rd, Hough DR, Agodoa LC. Peripheral arterial thrombosis due to the nephrotic syndrome: theclinical spectrum. South Med J 1983; 76:1011.

3. Yamauchi H, Hopper J Jr. Hypovolemic shock and hypotension as a complication in the nephroticsyndrome. Report of ten cases. Ann Intern Med 1964; 60:242.

4. Kapur G, Valentini RP, Imam AA, Mattoo TK. Treatment of severe edema in children with nephroticsyndrome with diuretics alone--a prospective study. Clin J Am Soc Nephrol 2009; 4:907.

5. Garin EH. A comparison of combinations of diuretics in nephrotic edema. Am J Dis Child 1987; 141:769.

6. Deschênes G, Wittner M, Stefano A, et al. Collecting duct is a site of sodium retention in PAN nephrosis: arationale for amiloride therapy. J Am Soc Nephrol 2001; 12:598.

7. Doucet A, Favre G, Deschênes G. Molecular mechanism of edema formation in nephrotic syndrome:therapeutic implications. Pediatr Nephrol 2007; 22:1983.

8. Haws RM, Baum M. Efficacy of albumin and diuretic therapy in children with nephrotic syndrome. Pediatrics1993; 91:1142.

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 "Renal vein thrombosis and hypercoagulable state in nephrotic syndrome",

section on 'Prophylactic anticoagulation'.)

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, and varicella vaccines (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 remainpersistently nephrotic and have hyperlipidemia (Grade 2B). (See 'Hyperlipidemia' above and "Lipid

abnormalities in nephrotic syndrome", section on 'Treatment'.)

Children with NS and persistent hypertension are more likely to have chronic kidney disease 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".)

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Disclosures: Patrick Niaudet, MD Nothing to disclose. Tej K Mattoo, MD, DCH, FRCP Nothing to disclose. Melanie S Kim, MD

Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a

multi-level review process, and through requirements for references to be provided to support the content. Appropriately referencedcontent is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

9. Welch TR, Gianis J, Sheldon CA. Perforation of the scrotum complicating nephrotic syndrome. J Pediatr 1988; 113:336.

10. Kerlin BA, Haworth K, Smoyer WE. Venous thromboembolism in pediatric nephrotic syndrome. Pediatr Nephrol 2014; 29:989.

11. Kerlin BA, Ayoob R, Smoyer WE. Epidemiology and pathophysiology of nephrotic syndrome-associatedthromboembolic disease. Clin J Am Soc Nephrol 2012; 7:513.

12. Ulinski T, Leroy S, Dubrel M, et al. High serological response to pneumococcal vaccine in nephrotic childrenat disease onset on high-dose prednisone. Pediatr Nephrol 2008; 23:1107.

13. Furth SL, Arbus GS, Hogg R, et al. Varicella vaccination in children with nephrotic syndrome: a report of theSouthwest Pediatric Nephrology Study Group. J Pediatr 2003; 142:145.

14. Goldstein SL, Somers MJ, Lande MB, et al. Acyclovir prophylaxis of varicella in children with renal diseasereceiving steroids. Pediatr Nephrol 2000; 14:305.

15. Weng FL, Shults J, Herskovitz RM, et al. Vitamin D insufficiency in steroid-sensitive nephrotic syndrome inremission. Pediatr Nephrol 2005; 20:56.

16. Freundlich M, Jofe M, Goodman WG, Salusky IB. Bone histology in steroid-treated children with non-azotemic nephrotic syndrome. Pediatr Nephrol 2004; 19:400.

17. Gulati S, Godbole M, Singh U, et al. Are children with idiopathic nephrotic syndrome at risk for metabolicbone disease? Am J Kidney Dis 2003; 41:1163.

18. Leonard MB, Feldman HI, Shults J, et al. Long-term, high-dose glucocorticoids and bone mineral content in

childhood glucocorticoid-sensitive nephrotic syndrome. N Engl J Med 2004; 351:868.

19. Prescott WA Jr, Streetman DA, Streetman DS. The potential role of HMG-CoA reductase inhibitors inpediatric nephrotic syndrome. Ann Pharmacother 2004; 38:2105.

20. Coleman JE, Watson AR. Hyperlipidaemia, diet and simvastatin therapy in steroid-resistant nephroticsyndrome of childhood. Pediatr Nephrol 1996; 10:171.

21. Sanjad SA, al-Abbad A, al-Shorafa S. Management of hyperlipidemia in children with refractory nephroticsyndrome: the effect of statin therapy. J Pediatr 1997; 130:470.

22. Hattori M, Chikamoto H, Akioka Y, et al. A combined low-density lipoprotein apheresis and prednisonetherapy for steroid-resistant primary focal segmental glomerulosclerosis in children. Am J Kidney Dis 2003;42:1121.

23. Gansevoort RT, de Zeeuw D, de Jong PE. Dissociation between the course of the hemodynamic andantiproteinuric effects of angiotensin I converting enzyme inhibition. Kidney Int 1993; 44:579.

24. Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int 1989; 36:272.

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