Nephrotic Syndrome

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Continuing Education Activity

Nephrotic syndrome (NS) is a clinical syndrome defined by massive proteinuria (greater than 40 mg/m^2 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. It results from 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.


  • Identify the etiology of nephrotic syndrome.
  • Review the presentation of 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.


Nephrotic syndrome (NS) is a clinical syndrome defined by massive proteinuria responsible for hypoalbuminemia, 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 results from an abnormality of glomerular permeability that may be primarily due to an intrinsic renal disease in the kidneys or secondary due to congenital infections, diabetes, systemic lupus erythematosus, neoplasia, or certain drug use.[1][2][3] Nephrotic-range proteinuria is defined as the urinary loss of 3 grams or more of proteins per 24 hours or, on a single spot urine sample, the presence of 2 g of protein per gram of urinary creatinine. This proteinuria can also result from other systemic diseases, such as amyloidosis.[4]

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.

The nephrotic syndrome could affect adults and children of both genders and any race. Also, it could occur in a typical form or with nephritic syndrome. The latter denotes glomerular inflammation leading to hematuria and impaired renal function.

The first indication of nephrotic syndrome in children is the swelling of the face which then progresses to the entire body. Adults may present with dependent edema. Other common features are fatigue and loss of appetite.


Common primary causes of nephrotic syndrome are intrinsic kidney diseases, such as membranous nephropathy, minimal-­change nephropathy, and focal glomerulosclerosis. Secondary causes may include systemic diseases, such as lupus erythematosus, diabetes mellitus, and amyloidosis. Congenital/hereditary focal glomerulosclerosis could occur because of genetic mutations in podocyte proteins, such as podocin, nephrin, or the cation channel 6 protein.[5] An episode of infectious diseases, particularly the upper respiratory tract, is a triggering factor in almost half of cases, an allergic reaction in a third of cases, and more rarely, an insect bite or vaccination.[6] Nephrotic syndrome can also result from drugs of abuse, including heroin.[7]

Secondary causes of nephrotic syndrome include the following:

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

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 the nephrotic syndrome is focal segmental glomerulosclerosis.

One more scenario where nephrotic-range proteinuria can occur is in the third trimester of pregnancy, a classical preeclampsia finding. However, it may start de novo or be superimposed on chronic kidney disease from before. There would have been preexisting proteinuria in the latter, which worsened during pregnancy.

Medication may also cause nephrotic syndrome. This includes the following:

  • The infrequent occurrence of minimal­-change disease with nonsteroidal anti-inflammatory drugs (NSAIDs)[8]
  • The occurrence of membranous glomerulonephritis with gold, bucillamine, and penicillamine use, which are used for rheumatic diseases[9]
  • Focal glomerulosclerosis may occur due to bisphosphonates[10]
  • Lithium and interferon therapy has been found to be associated with focal glomerulosclerosis[11]


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 less than 18 years of age. It is more common in boys than girls at younger ages, but once adolescence is reached, there is no significant difference between genders. Increased incidence and more severe diseases are seen in African American and Hispanic populations.[12]

We will look at the statistics from different regions of the world.

United States Statistics

Diabetic nephropathy associated with nephrotic syndrome is most common, with an estimated rate of around 50 cases per million population. In the pediatric population, nephrotic syndrome could occur at a rate of 20 cases per million.[13]

International Statistics

In India and Turkey, biopsy results in children with nephrotic syndrome have revealed similar histology types compared to what would be expected in Western countries.[14][15]In Pakistani adult patients with nephrotic syndrome, the histological patterns of kidney biopsies are similar to those seen in western countries.[16]

In parts of the Middle East and Africa, glomerular diseases have also been linked with urogenital schistosomal infection.[17] However, tropical nephrotic syndrome due to parasitic diseases such as malaria or schistosomiasis may be non-existent.

Doe et al. reported causes of nephrotic syndrome in the African pediatric population where kidney biopsy most often revealed typical histologic findings, such as minimal change disease and focal and segmental glomerulosclerosis.[18] Nephrotic syndrome due to quartan malaria is not a very well-established phenomenon. In the Congo, Pakasa and Sumaili call attention to the fall of parasite-associated nephrotic syndrome.[19][20]

Race-, sex-, and Age-related Demographics

Because diabetes mellitus is one of the major causes of nephrotic syndrome, American Indians, African Americans, and Hispanics have an increased incidence of nephrotic syndrome than White persons. HIV-associated nephropathy is a consequence of HIV infection that is uncommon in Whites; however, it is frequently seen in African Americans because of their greater prevalence of the ApoL1 alleles.[21] Focal glomerulosclerosis seems to be overrepresented as one of the causes of nephrotic syndrome in African-Americans as opposed to White children.[22] There is a male predominance in nephrotic syndrome, as seen in chronic kidney disease in general. This pattern is also observed in paraneoplastic membranous nephropathy.[23] However, lupus nephritis affects mostly women.


The glomerular capillaries are lined by fenestrated endothelium, which sits on the glomerular basement membrane, covered by glomerular epithelium, or podocytes, which envelop the capillaries with the capillaries' cellular extensions called foot processes. These processes interdigitate with special cell-cell junctions called the slit diaphragm, which together form the glomerular filter. Normally, larger proteins (greater than 69 kD) are excluded from filtration. The destruction of podocytes above a critical mass also leads to irreversible glomerular damage.[24][25][26]

In a healthy person, the loss of plasma albumin through the glomerular filtration barrier is less than 0.1%.[27] Filtration of plasma water and solutes occurs extracellularly and through the filtration slits and endothelial fenestrae. The glomerular changes that may lead to proteinuria are damage to the glomerular basement membrane, the endothelial surface, or the podocytes. Albumin is the main constituent in proteinuria, accounting for 85%. Albumin carries a net negative charge. The loss of glomerular membrane negative charge plays an important role in causing albuminuria. A generalized defect in glomerular permeability is associated with nonselective proteinuria causing a glomerular leakage of various plasma proteins. This phenomenon does not allow a clear-cut separation of causes of proteinuria.

Pathogenesis of Edema

The following are the two hypotheses for the occurrence of edema in nephrotic syndrome:

Underfill Hypothesis

Increased glomerular permeability causes albuminuria, eventually leading to hypoalbuminemia. Consequently, hypoalbuminemia results in a decline in plasma colloid osmotic pressure, in turn causing increased transcapillary filtration of water in the body. Subsequently, this process leads to the development of edema. Capillary hydrostatic pressure and oncotic pressure control the fluid movement from the vascular compartment into the interstitium. Protein content mainly determines the oncotic pressure. For edema to occur, the amount of fluid filtered should exceed the maximal lymphatic flow, which happens secondary to a low enough intravascular oncotic pressure and a high enough capillary hydrostatic pressure. In nephrotic syndrome, this results in reduced plasma volume, with a secondary rise in sodium and water retention via the kidneys.[28]

Overfill Hypothesis

An alternative hypothesis states that an intrinsic defect in the renal tubules leads to a decline in sodium excretion. This might occur if the intraluminal protein directly causes renal epithelial sodium reabsorption.[29] The following points support this hypothesis:

  • Sodium retention occurs even before the serum albumin level starts to fall
  • Intravascular volume is normal or even raised in many patients with nephrotic syndrome
  • There is an exaggerated peripheral capillary permeability to albumin, as reported in the radioisotopic technique in studies of 60 patients with nephrotic syndrome.[30] This would lead to increased interstitial oncotic pressure and fluid retention in the peripheral tissues.


There are different types of glomerulonephritis causing nephrotic syndrome, and they all behave differently when it comes to histopathological features of the kidney biopsy.

Minimal change disease is the 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.[31] Immunofluorescent staining for immune complexes is negative.

Focal segmental glomerulosclerosis accounts for 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. It involves immune complex deposition. Immunofluorescence staining shows a granular pattern. On light microscopy, one can see thickened basement membrane.[32]

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. A characteristic “spike and dome” appearance is visible on electron microscopy, with membrane deposition growing around subepithelial immune complex deposition.[33]

History and Physical

The first sign of nephrotic syndrome in the pediatric population is usually swelling on the face. This is followed by edema of the entire body. Adult patients can present with dependent edema. Frothy urine may be a presenting symptom.[34] Tiredness and lack of appetite are common features. A thrombotic consequence, such as deep venous thrombosis (DVT) of the calf veins or a pulmonary embolus, could be the first indication of nephrotic syndrome.

Additional features in a patient's history are related to the cause of the nephrotic syndrome. For instance, a recent commencement of NSAIDs suggests such drugs as the cause. Similarly, a more than 10-year history of diabetes mellitus with symptomatic neuropathy suggests diabetic nephropathy.

Physical Examination

Edema is the most prominent feature of nephrotic syndrome, and in the beginning, it develops around the eyes and legs. Over time, the edema becomes generalized and leads to increasing weight and the development of ascites or pleural effusions. Hematuria and hypertension may be present less frequently, although these are more prominently seen in nephritic syndrome.[35]

Additional features on examination vary according to the cause of the nephrotic syndrome. Also, it depends on whether or not renal function impairment is present. For instance, in the case of longstanding diabetes mellitus, the patient could have diabetic retinopathy, which is closely associated with diabetic nephropathy. If the kidney function is impaired, the patient may have anemia, hypertension, or both.


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) and proteinuria (3 g protein) is diagnostic.[36][37][38]

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 less than the normal range of 3.5 to 4.5 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 (e.g., rapid plasma reagin), HIV antibody test, complement levels (CH50, C3, C4)

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

Ultrasonography: 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: This is indicated for the following: congenital nephrotic syndrome, children older than eight years at the onset, steroid resistance, frequent relapses or steroid dependency, significant nephritic manifestations. It is worth noting that in clinical practice, kidney biopsies frequently reveal glomerular diseases to be the cause of nephrotic-range proteinuria and not tubular diseases. This contradicts the idea that tubular function determines proteinuria.[39]

Phospholipase A Receptor (PLA R): it is a transmembrane receptor expressed on the surface of podocytes. 70% of cases with idiopathic membranous nephropathy have autoantibodies against PLA R.[40] There is a strong correlation between levels of this antibody and clinical disease activity. Therefore it helps in monitoring disease activity and treatment efficiency.[41] The absence of these autoantibodies could indicate secondary membranous nephropathy, such as that linked to cancers.

Treatment / Management

A detailed assessment is necessary before starting corticosteroids. The patient's height, weight, and blood pressure should be monitored. Regular weight record helps in monitoring the decrease or increase of edema. Physical examination is carried out to detect infections and underlying systemic disorders.[42][43][44]

Specific treatment of nephrotic syndrome is dependent on its cause. Therefore, management varies between adult and pediatric populations. Kidney Disease Improving Global Outcomes (KDIGO) issued guidance in 2012 that included recommendations for treating nephrotic syndrome.

Specific Treatment in Children

Corticosteroids are mainly used for children with idiopathic nephrotic syndrome. Alternative immunosuppressive agents are often necessary for children with frequently relapsing or steroid-dependent nephrotic syndrome. Examples of these drugs include cyclophosphamide, mycophenolate mofetil (MMF), calcineurin inhibitors, and levamisole. In cases of steroid-resistant nephrotic syndrome, the first-line choice is calcineurin inhibitors, and if there is no response, then agents such as MMF or prolonged and/or intravenous pulse corticosteroids could be used.[45][46][47]

Rituximab, an anti-B cell antibody, has proved to be an effective steroid-sparing agent in the pediatric population. However, rituximab may fail to achieve drug-free remission in children dependent on both calcineurin inhibitors and steroids. Rituximab may also have a role in children with steroid-resistant disease.[45]

In children with complicated steroid-resistant nephrotic syndrome who respond to rituximab, Okutsu et al. observed that an additional rituximab treatment at B cell recovery may maintain prolonged remission.[48]

Specific Treatment in Adults

Treatment varies by etiology, as follows:

  • Minimal change nephropathy in adults usually responds to prednisone.
  • In lupus nephritis, prednisone combined with cyclophosphamide or mycophenolate mofetil induces remission.
  • Secondary amyloidosis with nephrotic syndrome will improve with the anti-inflammatory management of the primary disease.[49]

Acute Nephrotic Syndrome in Childhood

Hospitalization is not usually necessary with close outpatient follow-up care and good parental and patient education. Hospitalization becomes helpful if any of the following are present:

  • Generalized edema severe enough to result in respiratory distress
  • Tense scrotal or labial edema
  • Complications such as bacterial peritonitis, pneumonia, sepsis, or thromboembolism[50]
  • Failure to thrive
  • Uncertainty regarding the compliance of patient or family with treatment

Diuretics are usually needed. Furosemide (1 mg/kg/day) and spironolactone (2 mg/kg/day) help when fluid retention is severe enough, provided there are no signs of kidney failure or volume contraction. Achieving a satisfactory diuresis is hard when serum albumin level is less than 1.5 g/dL, so sometimes albumin has to be given.  

To prevent infections, penicillin can be started in children with overt edema. Abdominal paracentesis is recommended in patients showing signs of peritonitis, and bacterial infections should be treated sooner.[51] Non-immune patients with varicella should receive immunoglobulin therapy if exposure to chickenpox occurs, and acyclovir should be started if the patient develops chickenpox.

Acute Nephrotic Syndrome in Adults

The principles of treatment in adults with acute nephrotic syndrome are not different from those for children. Diuretics, such as furosemide, spironolactone, and even metolazone, may be needed. Diuretic use may lead to volume depletion, which should be assessed by monitoring symptoms, weight, pulse, and blood pressure.

Anticoagulation has been suggested to prevent thromboembolic complications, but its role in primary prevention is not proven. Hypolipidemic agents could be used.[52]

In patients with secondary nephrotic syndrome, such as that secondary to diabetic nephropathy, some medications are widely used to reduce proteinuria, such as angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin 2 receptor blockers.[53] By reducing proteinuria, these drugs will lead to reduced intraglomerular pressure causing a reduction in systemic blood pressure.

Diet and Activity

The diet in patients with nephrotic syndrome is aimed to provide sufficient caloric and protein (1 g/kg/d) intake. Supplemental dietary proteins are of no proven value. A low-salt diet helps limit fluid retention and edema.[54]

Long-Term Monitoring

The patient's edema and proteinuria define the adjustment of diuretics and angiotensin antagonists. Follow-up in the nephrotic syndrome also involves immunizations and monitoring for steroid toxicity.

Routine immunizations should be deferred until there are no relapses and the patient has been off immunosuppressants for at least three months.

Differential Diagnosis

The differential diagnoses for nephrotic syndrome include the following:

  • Hepatic: insufficiency, hepatocellular cirrhosis, Budd-Chiari syndrome[55]
  • Digestive: exudative enteropathy, lymphangiectasia, malnutrition
  • Cardiac: hereditary angioneurotic edema
  • Immune: anaphylaxis
  • Renal: chronic glomerulonephritis, diabetic nephropathy, focal segmental glomerulosclerosis, HIV-associated nephropathy, IgA nephropathy, membranous glomerulonephritis, minimal change disease.


  • Remission: Urine albumin nil or trace for three consecutive early morning specimens
  • Relapse: Urine albumin 3+ or 4+ (or proteinuria greater than 40 mg/m^2/h) for three consecutive early morning specimens, having been in remission previously
  • Frequent relapses: Two or more relapses in the initial six 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 four weeks
  • Congenital: presenting within the first three months of life, and in these children, there is usually a genetic mutation


The prognosis is excellent for patients with minimal change pathology, with most patients going into remission following corticosteroid treatment.[31] However, 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 (FSGS), the prognosis is grave.[56] Generally will progress to an end-stage renal disease requiring dialysis and kidney transplant. Only around 20% of patients with focal glomerulosclerosis go into remission of proteinuria; another 10% improve but stay proteinuric. Between 25 and 30% of patients with FSGS develop end-stage renal disease (ESRD) within five years. There have been some studies to suggest a better 5-year renal outcome in Chinese adults with primary FSGS in comparison to the west.[57]

Of patients with membranous nephropathy, around 30% undergo spontaneous remission. However, for patients with persistent nephrotic syndrome, 40% to 50% develop ESRD over a period of ten years.


Metabolic Consequences of Proteinuria

Following are the metabolic consequences of the nephrotic syndrome:

  • Infection
  • Hypocalcemia and bone abnormalities
  • Hyperlipidemia and atherosclerosis[58]
  • Hypercoagulability
  • Hypovolemia

Acute kidney injury may suggest underlying glomerulonephritis but is more commonly precipitated by hypovolemia or sepsis. Another proposition is that the edema of the kidneys causes a pressure-­mediated reduction in the GFR. Additional consequences include the following:

  • Hypertension due to reduced kidney function and fluid retention
  • Edema of the gut could cause defective absorption resulting in malnutrition[59]
  • Ascites and pleural effusions
  • Generalized edema
  • Respiratory distress
  • Sepsis
  • Peritonitis
  • Thromboembolism[60]
  • Failure to thrive

Deterrence and Patient Education

Patients should be educated on taking a low-salt diet as it helps manage their symptoms. There are no restrictions on physical activity for patients with nephrotic syndrome, and staying active is preferred over bed rest as it reduces the risk of blood clots. Adverse effects of steroids, such as slowing growth, can be detected by monitoring patients every three months in the outpatient clinic. Patients should be given information that bone health is essential, and due to steroids, their bone health can be affected; therefore, supplemental calcium and vitamin D may be protective.[61] Patients should get a yearly checkup to look for cataracts. In the community, patients with nephrotic syndrome should have monitoring in terms of their vaccination.

Enhancing Healthcare Team Outcomes

Because there are many causes of nephrotic syndrome, the condition is best managed by an interprofessional team. Once nephrotic syndrome is diagnosed, patient education is vital 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, 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 an 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 daily and record the amount, as 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.[62][63] [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]

Prior to the era of antibiotics, survival was rare for patients with nephrotic syndrome. Today, most patients with nephrotic syndrome survive, and the prognosis usually depends on the cause of kidney dysfunction. However, the prognosis in infants with nephrotic syndrome is still poor, and only those who can undergo dialysis or kidney transplantation have good survival. In 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 within five years.

The best prognosis is for patients with minimal change nephropathy, with 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 poor outcomes. 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 a slowing down of proteinuria and stabilize renal function. Those who develop amyloidosis will usually have a guarded prognosis.[64][65][66] [Level 5]



Khalid Bashir


5/29/2023 4:57:47 PM



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