eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Nephrotic Syndrome: Follow-up

Author: Jerome C Lane, MD, Assistant Professor of Pediatrics, Northwestern University Medical School; Attending Physician, Department of Pediatrics, Division of Kidney Diseases, Children's Memorial Hospital, Chicago
Contributor Information and Disclosures

Updated: Jun 12, 2009

Follow-up

Further Inpatient Care

• Admitting all new-onset patients with nephrotic syndrome (NS) to the hospital is not necessary. Individually address the decision on whether to admit the child or to investigate and initiate treatment on an outpatient basis.
• Possible medical indications for admission include the following:
  • Anasarca, especially when resistant to outpatient therapy and/or accompanied by respiratory compromise, massive ascites or scrotal/perineal or penile edema.
  • Significant hypertension
  • Anuria or severe oliguria
  • Peritonitis, sepsis, or other severe infection
  • Significant respiratory infection
  • Significant azotemia
• Hospital admission may be necessary because of social reasons and often is useful on initial presentation of idiopathic nephrotic syndrome (INS) in order to provide intensive education of the family regarding INS and long-term management at home.

Further Outpatient Care

• Ambulatory monitoring of the child's condition and response to treatment is a very important aspect of the overall management of nephrotic syndrome.
• Home monitoring of urine protein and fluid status is an important aspect of management. Parents and/or caregivers should be trained to monitor first morning urine proteins at home with urine dipstick. Weight should be checked every morning as well and a home logbook should be kept recording the patient’s daily weight, urine protein and steroid dose if being treated.
• Families and patients are instructed to call for any edema, weight gain, or urine testing 2+ or more for protein for more than 2 days. Rapid detection of relapse of proteinuria by home testing of urine can allow early initiation of steroid treatment before edema and other complications develop. Urine testing at home is also useful in monitoring response (or nonresponse) to steroid treatment.

Inpatient & Outpatient Medications

• See Medical Care.

Transfer

• Because of the complexity of care of INS in all but the simplest of cases, the lack of strong clinical evidence in treatment, and the great deal of experience required in successfully managing these patients, care of the patient with INS should always be performed in consultation with a pediatric nephrologist.
• In cases that have initially been managed by the primary care specialist, referral to a pediatric nephrologist is mandatory in cases of frequently relapsing nephrotic syndrome, steroid-dependent nephrotic syndrome (SDNS), steroid-resistant nephrotic syndrome (SRNS), secondary nephrotic syndrome, and situations in which a kidney biopsy is necessary (see Workup).

Deterrence/Prevention

• Yearly influenza vaccination is recommended to prevent serious illness in the immunocompromised patient, as well as to prevent this possible trigger of relapse.
• Pneumococcal vaccination should be administered to all patients with INS to reduce the risk of pneumococcal infection. Vaccination should be repeated every 5 years while the patient continues to have relapses.
• Routine childhood vaccines with live virus strains are contraindicated in patients taking steroids and until off steroid treatment for a minimum of 1 month.³² Care must be taken in administering live viral vaccines to children in remission with frequently relapsing nephrotic syndrome who might need to restart steroid therapy shortly after vaccination.
• Because of the high risk of varicella infection in the immunocompromised patient, in the nonimmune patient, postexposure prophylaxis with varicella-zoster immune globulin is recommended. Patient with varicella-zoster infection should be treated with acyclovir and carefully monitored.¹² Varicella immunization is safe and effective in patients with INS who are in remission and off steroid treatment (with the usual precautions for administering live viral vaccines to patients who have received steroids).³³
• Routine, nonlive viral vaccines should be administered according to their recommended schedules. Despite the former belief that routine immunization can trigger relapse of nephrotic syndrome, no solid evidence suggests this, and the risk of these preventable childhood illnesses exceeds the theoretical, unproven risk for triggering relapses.

Complications

• Infection
  • Before the advent of corticosteroids, a high mortality rate due to infection in patients with INS was observed.
  • Even after the availability of steroids, the ISKDC reported a mortality rate of 1.5% in children with INS.³⁴
  • Peritonitis and sepsis are the most common and serious infections. Peritonitis occurs at a rate of approximately 2-6% and may be accompanied by sepsis or bacteremia.
  • The predominant bacterial causes are Streptococcus pneumonia and Gram-negative enteric organisms such as Escherichia coli.³⁵
  • Various infections can also occur, including meningitis, cellulitis, viral infections, and others. Varicella is a particular concern in immunosuppressed patients and can be lethal. Prompt recognition and treatment with acyclovir (or postexposure prophylaxis with varicella-zoster immune globulin [VZIG]) is essential. Routine childhood varicella immunization has alleviated some of the concern regarding this complication.
  • Infection, viral or bacterial, can trigger relapse of INS and further complicate the course of the condition.
  • Pneumococcal vaccine should be administered to all patients with INS to reduce the risk of pneumococcal disease. Patients should be revaccinated every 5 years for the duration of their course of INS.
• Thrombosis
  • The incidence rate of thromboembolic complications (TEC) is about 1.8-5% but may be underestimated. One study found the subclinical rate of pulmonary embolism to be 28% using scintigraphic pulmonary ventilation and perfusion studies.³⁶
  • Incidence is higher in adults and children with secondary nephrotic syndrome. The incidence is especially high in membranous nephrotic syndrome.³⁷
  • Renal vein thrombosis, deep vein thrombosis, and pulmonary embolism (PE) are the most frequently encountered TEC in children.
  • Other venous sites of thrombosis include the superior sagittal sinus, other cerebral venous sites, and the inferior vena cava.
  • Arterial thrombosis, although less common than venous TEC, can occur and has been reported at the axillary, subclavian, femoral, coronary, and mesenteric arteries.³⁷
  • Initial treatment of TEC includes thrombolysis with anticoagulants (such as heparin) and/or fibrinolytic agents (tissue plasminogen activator, streptokinase, urokinase).³⁶
  • Following TEC, warfarin is often prescribed for a period of as long as 6 months.¹²
  • Empirical prophylactic anticoagulation is not routinely indicated in INS. Some practitioners advocate the use of chronic, low-dose aspirin in patients with chronic nephrotic syndrome (eg, frequently relapsing nephrotic syndrome, SDNS, SRNS). However, adequate controlled trials examining the use of aspirin have not been performed.³⁶
• Hyperlipidemia
  • Nephrotic syndrome results in hypercholesterolemia, hypertriglyceridemia, high low-density lipoprotein (LDL) cholesterol, and low high-density lipoprotein (HDL) cholesterol (see Pathophysiology).
  • Lipid abnormalities generally resolve when nephrotic syndrome is in remission.
  • Dietary modification does not appear to be effective in limiting hyperlipidemia during active nephrotic syndrome.³⁸
  • Chronic hyperlipidemia has been linked to increased risk of atherosclerosis and coronary artery disease.¹²
  • Chronic hyperlipidemia has also been associated with progression of renal disease. However, the small studies to date of lipid-lowering agents in pediatric INS have not shown an improvement with these agents in proteinuria or progression of renal disease.¹⁰
  • Dyslipidemias in adults with nephrotic syndrome have been successfully treated with statins (simvastatin, lovastatin), fibrates (gemfibrizil), bile-acid binding resins (cholestyramine), and probucol.
  • Children with INS have been effectively treated with probucol, but this agent has been associated with prolonged QT interval and is not available in the United States. Gemfibrozil has also been shown to be effective in childhood nephrotic syndrome in small studies.³⁸
  • Small studies have shown that simvastatin and lovastatin are well-tolerated and effective in childhood INS. Total cholesterol, triglycerides, and LDL cholesterol were reduced by 42%, 44%, and 46%, respectively. No changes in proteinuria, hypoalbuminemia, or progression of renal disease were noted.^5,39,38
  • In order to monitor for treatment associated rhabdomyolysis, children treated with statins should have creatine kinase prior to initiating therapy and every 6-12 weeks after starting treatment. Patients and families should be instructed to report muscle soreness, tenderness, or pain. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels should be measured before initiating treatment and about every 3 months thereafter to monitor for liver toxicity.³⁸
  • Long-term safety studies regarding statins in pediatrics are lacking, and routine use of statins were not recommended at this time by an expert panel. The only drugs recommended at this time by the panel are bile acid sequestrants.³⁸
• Acute kidney failure (AKF)
  • AKF is a rare complication of INS, occurring in about 0.8% of cases.⁴⁰
  • Causes include rapid progression of underlying disease (nephrotic syndrome other than minimal change nephrotic syndrome [MCNS], secondary nephrotic syndrome), bilateral renal vein thrombosis, acute interstitial nephritis (AIN) due to drug therapy (eg, antibiotics, nonsteroidal anti-inflammatory agents [NSAIDs], diuretics), and acute tubular necrosis (ATN) due to hypovolemia or sepsis.⁴⁰ Use of ACE inhibitors or angiotensin II receptor blockers (ARBs) in conjunction with volume depletion can also precipitate AKF.
  • In most cases, AKF is reversible with remission of nephrotic syndrome, correction of intravascular volume contraction, and/or removal of inciting agent in AIN.⁴⁰
  • Fever, rash, arthralgia and eosinophilia with a "bland" urinalysis (minimal cellular elements) in the presence of AKF are typical for AIN. However, obvious clinical symptoms may be absent except for the AKF and unremarkable urinalysis. Gross hematuria, flank pain, and thrombocytopenia may be signs of renal vein thrombosis. Hemoconcentration in the patient with anasarca might indicate intravascular volume depletion.
• Side effects of drug therapy
  • Corticosteroids
    • Behavioral changes, increased appetite, and Cushingoid signs (rounded, or "moon" facies) are common during the first 6 weeks of daily therapy but usually begin to subside during the alternate-day maintenance therapy period and, if steroids are successfully discontinued, usually disappear completely within 3-6 months
    • If longer periods of steroid therapy are required, the risk of complications increases. Complications of chronic steroid therapy may include infection, obesity, growth delay, osteopenia, avascular hip necrosis, cataracts, hypertension, hyperglycemia, nephrolithiasis, and hyperlipidemia.
    • Nutritional counseling and an exercise regimen may help to limit weight gain during steroid therapy.
    • Consideration should be given to monitoring of bone density by dual energy X-ray absorptiometry (DEXA) in patients on long-term steroids.
  • Diuretics: Loop diuretics (furosemide, bumetanide) commonly cause hypokalemia and contraction alkalosis. Serum electrolytes should be monitored and electrolyte abnormalities treated as indicated. Metolazone may augment these side effects. The use of potassium-sparing diuretics (spironolactone, amiloride) may help to limit hypokalemia.
  • Albumin: Infusion of 25% albumin can result in pulmonary edema and congestive heart failure. It should be used cautiously and sparingly only in those patients with hemoconcentration and/or diuretic-resistant edema. In the authors' experience, slow infusion of 1 g/kg as a continuous infusion over 24 hours helps to limit complications.
  • Calcineurin inhibitors: Cyclosporine (CSA) and tacrolimus (TAC) can cause increased susceptibility to infection, direct nephrotoxicity, hyperkalemia, and hypertension. CSA can also cause hirsutism and gingival hyperplasia, whereas TAC can cause impaired glucose tolerance and overt diabetes.
  • Alkylating agents: Cyclophosphamide (CYP), chlorambucil, and nitrogen mustard can cause dose-related infertility, azoospermia, oligospermia, amenorrhea, nausea, and hair loss. Hair loss, when it occurs, is usually mild and not cosmetically significant in the doses used for most types of INS. Alkylating agents can also cause myelosuppression and increased susceptibility to infection. CYP can cause hemorrhagic cystitis and increased incidence of bladder malignancy. The risk of infertility rises above a cumulative CYP dose of 200 mg/kg .
  • Mycophenolate mofetil (MMF): Side effects of MMF include cramps, diarrhea, GI distress, myelosuppression, and increased susceptibility to infection.
  • Antihypertensive agents: Side effects of blood pressure medications can include hyperkalemia and AKF (ACE inhibitors, ARBs), hypotension, bradycardia (beta-blocker), fatigue, sedation (clonidine), and electrolyte disturbances (diuretics), among many other side effects.

Prognosis

• Steroid-responsive INS
  • Patients who remain responsive to steroids with remission of proteinuria, even with frequent relapses, generally have a good prognosis. The ISKDC found that 93% of children with INS who responded to steroids had MCNS revealed on kidney biopsy findings.³ In contrast, patients who did not initially respond to steroids had histology other than MCNS in 75% of cases.
  • About 90% of children with MCNS (but only 20% of children with focal segmental glomerulosclerosis [FSGS]) achieve remission after the initial course of steroid treatment. Despite the generally favorable prognosis in patients who respond to steroids, the ISKDC reported a 60% rate of subsequent relapses, which can lead to complications, increased morbidity, and decreased quality of life.³ A longer course of initial steroid treatment (12 wk rather than the original ISKDC protocol of 8 wk) may reduce the rate of subsequent relapse to 36%,²⁰  which still represents a large number of patients who undergo repeated courses of immunosuppression, with possible hospitalizations, edema, infections, medication side effects, and other comorbidities. 
  • A long-term study of 398 children with INS found that the percentage of children who became free of relapses during the course of their disease rose from 44% one year after diagnosis to 69% at 5 years and 84% 10 years after diagnosis.^41,12  Although most children with INS who respond to steroids achieve long-term remission, relapses may continue into adulthood. Older studies suggested that more than 90% of children achieve long-term remission without further relapses by puberty. However, this has recently been challenged by surveys indicating a rate of relapse during adulthood as high as 27-42%.
  • A study of 42 adult patients with a history of childhood INS found that 33% of patients continued to relapse into adulthood. Fortunately, overall morbidity (eg, bone disease, infections, malignancies, cardiovascular complications) remained low, and patients had normal adult height, body mass index (BMI), and kidney function. Predictors of adult relapse included the number of relapses during childhood and the use of immunosuppressant medications other than steroids (CSA, chlorambucil, CSY).⁴²
• SRNS
  • Approximately 10% of patients overall with INS do not respond to an initial trial of steroids (2% of patients with MCNS do not respond to steroids). Additionally, about 1-3% of patients who initially do respond to steroids later become resistant to treatment ("late non-responders").⁶
  • Most patients who do not achieve remission of proteinuria with steroids have kidney biopsy findings other than MCNS. The most common diagnosis in these patients is FSGS.
  • More than 60% of patients with nephrotic syndrome and FSGS who fail to achieve remission with any treatment progress to end-stage kidney disease (ESKD). In contrast, only 15% progression to ESKD is observed in patients with FSGS who achieve remission by any treatment.⁴³ Gipson et al reported a 90% reduction in the risk of progression to ESKD in patients with INS who achieved remission.⁴⁴  
  • Thus, steroid-resistant INS has a good prognosis if remission of proteinuria can be achieved by other medications. Failure to respond to treatment (ie, failure to achieve remission) and kidney insufficiency at presentation are predictors of poor outcome and progression to ESKD.⁴⁵

Patient Education

• Soon after nephrotic syndrome is diagnosed, the patient and family should be educated about the disease, its management, and its expected course. The family should participate in therapeutic decisions and should be encouraged to adhere to the medical regimen. As with all chronic illnesses, many psychosocial issues may need to be addressed, including behavior, adherence to medication, adequate parental/caretaker supervision, medical insurance, missed work and school due to hospitalizations and outpatient visits, and many other important issues. Consultation with social workers and mental health care workers may be useful.
• Links to resources for parents can be found at the Web sites for the American Society of Pediatric Nephrology (ASPN) and the National Kidney Foundation.

Miscellaneous

Medicolegal Pitfalls

Potential medical/legal problems include the nephrotic syndrome:

• Failure to recognize secondary causes of nephrotic syndrome
• Failure to monitor for and recognize complications of nephrotic syndrome, such as infection and thrombosis
• Failure to thoroughly educate the patient and family regarding home monitoring and care of idiopathic nephrotic syndrome (INS) and how to recognize signs of relapse and complications such as peritonitis and other infections
• Continuation of corticosteroids for too long with resultant steroid toxicity in the patient with frequently-relapsing, steroid-dependent, or steroid-resistant nephrotic syndrome and failure to initiate alternative treatments, such as cyclophosphamide or cyclosporine
• Failure to refer to a pediatric nephrologist for complicated nephrotic syndrome (frequently relapsing, steroid-dependent, or steroid-resistant): Even in simple cases of INS, successful management requires a considerable amount of expertise. Complications, need for biopsy, or necessity of alternative treatments might not be readily apparent to the practitioner with limited experience with nephrotic syndrome.

Special Concerns

As with all chronic illnesses, many psychosocial issues may need to be addressed, including behavior, adherence to medication, adequate parental/caretaker supervision, medical insurance, missed work and school due to hospitalizations and outpatient visits, and many other important issues. Consultation with social workers and mental health care workers may be useful.

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