Continuing Education Activity

Nephrotic syndrome (NS) is a clinical syndrome defined by massive proteinuria (greater than 40 mg/m2 per hour) responsible for hypoalbuminemia (less than 30 g/L), with resulting hyperlipidemia, edema, and various complications. It is caused by increased permeability through the damaged basement membrane in the renal glomerulus especially infectious or thrombo-embolic. It is the result of an abnormality of glomerular permeability that may be primary with a disease-specific to the kidneys or secondary to congenital infections, diabetes, systemic lupus erythematosus, neoplasia, or certain drug use. This activity reviews the causes, pathophysiology, and presentation of nephrotic syndrome and highlights the role of the interprofessional team in its management.

Objectives:

• Identify the etiology of nephrotic syndrome.
• Review the presentation of a patients with nephrotic syndrome.
• Summarize the treatment and management options available for nephrotic syndrome.
• Describe interprofessional team strategies for improving care and outcomes in patients with nephrotic syndrome.

Introduction

Nephrotic syndrome (NS) is a clinical syndrome defined by massive proteinuria (greater than 40 mg/m2 per hour) responsible for hypoalbuminemia (less than 30 g/L), with resulting hyperlipidemia, edema, and various complications. It is caused by increased permeability through the damaged basement membrane in the renal glomerulus especially infectious or thrombo-embolic. It is the result of an abnormality of glomerular permeability that may be primary with a disease-specific to the kidneys or secondary to congenital infections, diabetes, systemic lupus erythematosus, neoplasia, or certain drug use. [1][2][3]

The disorder can affect people of all ages. In most children, the first sign of nephrotic syndrome is facial swelling. Adults usually present with dependent edema.

Etiology

An episode of infectious diseases, particularly the upper respiratory tract, is found as a triggering factor in almost half of case, an allergic reaction in a third of cases and more rarely, an insect bite, vaccination, treatment psychological stress.[4]

Primary causes: Minimal­-change nephropathy, focal glomerulosclerosis, membranous nephropathy, hereditary nephropathies

Secondary causes:

• Diabetes mellitus
• Immune: lupus erythematosus, antibody vasculitis, antineutrophil cytoplasmic neutrophils [ANCA], Berger disease, Goodpasture syndrome, glomeruli acute post-infectious nephritis, extramembranous glomerulonephritis or membranoproliferative, alloantibodies from enzyme replacement therapy, thrombotic microangiopathy, or toxicity (nonsteroidal anti-inflammatory drugs [NSAIDs], gold salts)
• Infection: HIV, hepatitis B virus, human immunodeficiency virus, hepatitis C, cytomegalovirus, toxoplasmosis, parvovirus B1, amyloidosis and paraproteinemias, preeclampsia

The most common cause in children is minimal change glomerulonephritis. In white adults, nephrotic syndrome is most frequently due to membranous nephropathy whereas in populations of African ancestry the most common cause of nephrotic syndrome is focal segmental glomerulosclerosis.

Clinically, nephrotic syndrome may be steroid-resistant, steroid-sensitive, steroid-dependent or frequently relapsing.

The cause of nephrotic syndrome may be due to immune complex deposition, development of phospholipase antibodies or due to the formation of allo-antibodies.

Epidemiology

Nephrotic syndrome is an important chronic disease in children. The estimated annual incidence of nephrotic syndrome in healthy children is two to seven new cases per 100,000 children younger than 18 years of age. More common in boys than girls in younger age groups, but once adolescence is reached there is no significant difference between genders. Increased incidence and more severe disease seen in African American and Hispanic populations. [5]

Overall, nephrotic syndrome is more common in men.

Pathophysiology

The glomerular capillaries are lined by a fenestrated endothelium that sits on the glomerular basement membrane, which in turn is covered by glomerular epithelium, or podocytes, which envelops the capillaries with cellular extensions called foot processes, these processes interdigitate with special cell-cell junctions called the slit diaphragm which together forms the glomerular filter. Normally, larger proteins (greater than 69 kD) are excluded from filtration. Destruction of podocytes above a critical mass also leads to irreversible glomerular damage.[6][7][8]

Proteinuria that is more than 85% albumin is selective proteinuria. Albumin has a net negative charge, and it is proposed that loss of glomerular membrane negative charges could be important in causing albuminuria. Nonselective proteinuria, being a glomerular leakage of all plasma proteins, would not involve changes in glomerular net charge but rather a generalized defect in permeability.

Mutations in several podocyte proteins have been identified in families with inherited nephrotic syndrome; a plasma factor may alter glomerular permeability, especially in patients with the steroid-resistant nephrotic syndrome and lastly altered T-lymphocyte polarized immune responses, in that the T-cells could result in the production of a permeability factor. Increased plasma levels of IgE, IgG4, and association with atopy suggest type II cytokine bias in patients with MCNS.In vitro studies suggest that podocytes express receptors for IL-4 and IL-13, the activation of these receptors might disrupt glomerular permeability resulting in proteinuria. No particular cytokine triggers the nephrotic syndrome.

Many of the complications of nephrotic syndrome can be linked to dysregulated lipid metabolism and dyslipidemia. These abnormalities include elevated plasma levels of cholesterol, triglycerides, and the apolipoprotein B; decreased lipoprotein lipase activity in the endothelium, muscle and adipose tissues; decreased hepatic lipase activity, and increased levels of the enzyme PCSK9. Also, there is an increase in the plasma levels of immature HDL particles and reduced cholesterol efflux.

Histopathology

Minimal change disease: Most common pathology found in childhood (77% to 85%). Usually idiopathic. Light microscopy of renal biopsy samples shows no change, on electron microscopy, effacement of the foot processes can be seen. Immunofluorescent staining for immune complexes is negative.

Focal segmental glomerulosclerosis: 10% to 15% of cases. Light microscopy of renal biopsy sample shows scarring, or sclerosis, of portions of selected glomeruli which can progress into global glomerular sclerosis and tubular atrophy. In most cases, negative immunofluorescence.

Membranoproliferative glomerulonephritis: More commonly presents as nephrotic syndrome. Involves immune complex deposition. Immunofluorescence staining shows the granular pattern. On light microscopy, can see thickened basement membrane

Membranous glomerulonephritis: Just 2% to 4% of cases in children, but the most common type in adults. Thickened basement membrane and granular pattern on immunofluorescence. On electron microscopy, characteristic “spike and dome” appearance seen, with membrane deposition growing around subepithelial immune complex deposition.

History and Physical

The classic NS presentation is edema, in the early phase is located in the face in the morning on waking with puffiness of the eyelids and the impression of the folds of sheets on the skin and ankles at the end of the day. Without measure corrective, they become more pronounced, diffuse and lead to anasarca with ascites, hydrocele or pleural effusion, may also be revealed by a complication such as hypovolemia, infection (pneumonia and peritonitis due to Streptococcus pneumoniae), deep-vein or arterial thromboses, and pulmonary embolism.

Moderate arterial hypertension is present in 25% cases, and hypotension may reveal a state of effective hypovolemia.

Functional renal failure is possible. Microscopic hematuria is noted in about 20% of cases, macroscopic hematuria being exceptional and having to make look for thrombosis of the renal veins.

Evaluation

Urine tests: Nephrotic-range proteinuria will be apparent by 3+ or 4+ readings on the dipstick, or by semiquantitative testing by sulfosalicylic acid. A 3+ reading represents 300 mg/dL of urinary protein or more, which correlates with a daily loss of 3 g or more and thus is in the nephrotic range. Urine samples over 24 hours (for an accurate measure), proteinuria (3 g protein )is diagnostic.[9][10][11]

Urinalysis may demonstrate casts (hyaline, granular, fatty, waxy, or epithelial cell). Lipiduria, the presence of free lipid or lipid within tubular cells, within casts, or as free globules, suggests a glomerular disorder.

Blood tests:  The serum albumin level is classically low in nephrotic syndrome, serum albumin often is < 2.5 g/dL. Creatinine concentrations vary by degree of renal impairment. Total cholesterol and triglyceride levels are typically increased.

• Serologic studies: The role of testing for secondary causes of nephrotic syndrome (is controversial because yield may be low). Tests are best done as indicated by clinical context. Consider: Serum glucose or glycosylated Hb (HbA), Antinuclear antibodies, Hepatitis B and C serologic tests, Serum or urine protein electrophoresis, Cryoglobulins, Rheumatoid factor, Serologic test for syphilis (eg, rapid plasma reagin), HIV antibody test, Complement levels (CH50, C3, C4)

Test results may alter management and preclude the need for biopsy.

Ultrasonographic: Individuals with a single kidney may be prone to developing focal glomerulosclerosis, having only one kidney is also a relative contraindication to kidney biopsy. Ultrasonography also demonstrates renal echogenicity. Increased renal echogenicity is consistent with intrarenal fibrosis

Renal biopsy: indicated for the following: congenital nephrotic syndrome, children older than 8 years at the onset, steroid resistance, frequent relapses or steroid dependency, significant nephritic manifestations.

Treatment / Management

A detailed evaluation is necessary before starting treatment with corticosteroids. The height, weight and blood pressure should be recorded. Regular weight record helps monitor the decrease or increase of edema. Physical examination is done to detect infections and underlying systemic disorder.[12][13][14]

Steroid therapy is applied to all children whatever the histopathology. Initial prednisone therapy consists of 60 mg/m2 administered daily for four weeks(maximum dose, 60 mg/day), 40 mg/m2/on alternate days for four weeks,  reduce dose by 5 mg/m2 to 10 mg/m2 each week for another four weeks then stop.

Rituximab is also effective steroid-sparing treatment in children. However, achieving drug-free remissions with rituximab can be difficult. The drug is ideally used to managed steroid-resistant disease.

Relapse: Prednisolone should be restarted once a relapse has been diagnosed: 2 mg/kg daily (maximum 60 mg) until the urine is negative or trace for three days, then 40 mg/m 2 /on alternate days for 4 weeks then stop or taper the dose over 4 to 8 weeks.[15][16]

Frequent Relapses: Low-dose alternate-day prednisolone may prevent relapses or:

• Levamisole: less useful for children who are steroid dependent. The dose is 2.5 mg/kg on alternate days for 6 months to a year.
• Cyclophosphamide: the dose of 3 mg/kg/ day for 8 weeks.
• Cyclosporin: At a dose of 2.5 mg/kg bid usually for one year may be used as a steroid-sparing agent. Levels should be checked after 1 to 2 weeks. Monitor BP and renal function.
• Mycophenolate mofetil (MMF): Can be given to children showing signs of cyclosporin toxicity. Doses of 600 mg two times a day. Should be monitored for leukopenia.
• Diuretics are often required to prevent fluid retention
• Statins may be required to control the persistent hyperlipidemia
• Diabetics with nephrotic syndrome should be treated with ACE inhibitors or angiotensin receptor blockers

Differential Diagnosis

The differential diagnosis includes:

• Hepatic: insufficiency, hepatocellular cirrhosis, Budd-Chiari syndrome
• Digestive: exudative enteropathy, lymphangiectasia, malnutrition
• Cardiac: hereditary angioneurotic edema
• Immune: anaphylaxis

Staging

• Remission: Urine albumin nil or trace for three consecutive early morning specimens
• Relapse: Urine albumin 3+ or 4+ (or proteinuria greater than 40 mg/m2/h) for three consecutive early morning specimens, having been in remission previously.
• Frequent relapses: Two or more relapses in initial 6 months or more than four relapses in any 12 months.
• Steroid dependence: Two consecutive relapses when on alternate day steroids or within 14 days of its discontinuation.
• Steroid resistance: Absence of remission despite therapy with daily prednisolone at a dose of 2 mg/kg per day for 4 weeks.
• Congenital: presenting within the first 3 months of life, and in these children, there is usually a genetic mutation.

Prognosis

For patients with minimal change pathology, the prognosis is very good, with most patients going into remission following corticosteroid treatment. 85 to 90 % of patients are steroid-responsive and may relapse placing them at risk for steroid toxicity, systemic infections, and other complications.

For patients with focal-segmental glomerulosclerosis, the prognosis is grave. Generally will progress to an end-stage renal disease requiring dialysis and kidney transplant.

Complications

• Generalized edema
• Respiratory distress
• Sepsis
• Peritonitis
• Thromboembolism
• Failure to thrive

Consultations

• Nephrologist
• Pediatrician

Deterrence and Patient Education

Low-salt diet

Pearls and Other Issues

In some cases, there are many unanswered questions, including who develops NS and why, what explains the individual variability in response to different treatments, and what are the specific triggers that provoke relapse. NS has to be evaluated differently in every patient.

Enhancing Healthcare Team Outcomes

Because there are many causes of nephrotic syndrome, the condition is best managed by an interprofessional team. Once the diagnosis of nephrotic syndrome is made, patient education is vital in order to prevent high morbidity.

Since most are outpatients, the pharmacist should encourage compliance with the medications. In addition, the doses of the drugs (diuretics and ACE inhibitors) may need continual reassessment depending on the patient's response. if the patient has been started on a corticosteroid, then the pharmacist must assist the team by monitoring the patient for the adverse effects of these medications. The nurse should educate the patient on the importance of immunization and appropriate diet.

For those children who have a failure to thrive, a dietary consult should be sought. Many of these children may require vitamin D or calcium supplements to prevent bone loss. The nurse should also educate the family on how to measure urine output on a daily basis and record the amount-this will provide an indication of how the disease is progressing. Finally, a dietary consult should be obtained to educate the patient on a low-salt diet to prevent an aggravation of the edema. Only through such an approach can the morbidity of nephrotic syndrome be lowered.  [17][18][Level 5]

Due to the rarity and complexity of this disease, an interprofessional approach to evaluation, treatment, and education of the patient and family will lead to the best outcomes. [Level 5]

Outcomes

Prior to the era of antibiotics, survival was rare for patients with nephrotic syndrome. Today, the majority of patients with nephrotic survive, and the prognosis usually depends on the cause of kidney dysfunction. However, the prognosis in infants with nephrotic syndrome is still poor- only those who are able to undergo dialysis or kidney transplantation have good survival. Patients who develop focal glomerulosclerosis, remission from proteinuria is only seen in one-third of patients. Because of frequent relapses, many of these patients require long-term corticosteroids- and consequently also develop many adverse effects from these medications. About a third of these patients will require dialysis in 5 years. The best prognosis is for patients with minimal change nephropathy, who have few relapses and less than 5% require long-term corticosteroids. The long-term risk of renal failure in these patients is low. Patients who show a poor response to steroids usually have a poor outcome. For those who develop nephrotic syndrome due to a secondary cause, the morbidity is primarily related to the cause. Diabetic patients who respond to ACE inhibitors may develop slowing down of proteinuria and stabilize renal function. Those who develop amyloidosis usually have a guarded prognosis. [19][20][21](Level V)