Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children

INTRODUCTION — The nephrotic syndrome is caused by increased permeability across the glomerular filtration barrier. It is classically characterized by nephrotic range proteinuria, hypoalbuminemia, and edema. The first two features are diagnostic.

The clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children are reviewed here. The complications and treatment of idiopathic childhood nephrotic syndrome and specific kidney diseases that present as nephrotic syndrome in children are discussed separately.

●(See "Complications of nephrotic syndrome in children".)

●(See "Treatment of idiopathic nephrotic syndrome in children".)

●(See "Minimal change disease: Etiology, clinical features, and diagnosis in adults".)

●(See "Congenital nephrotic syndrome".)

●(See "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)

PATHOGENESIS — Two issues are important in the pathogenesis of nephrotic syndrome: the mechanisms of glomerular injury and proteinuria.

●Mechanisms of glomerular injury — A variety of disease-specific mechanisms have been described in the nephrotic syndrome. These are discussed in detail elsewhere:

•Factors causing increased permeability in minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS). (See "Mechanisms of immune injury of the glomerulus", section on 'Glomerular permeability factors'.)

•Circulating immune factors in disorders such as membranoproliferative glomerulonephritis, poststreptococcal glomerulonephritis, and lupus nephritis. (See "Mechanisms of immune injury of the glomerulus".)

•Mutations in podocyte or slit diaphragm proteins (eg, CD2AP, podocin, and nephrin) in inherited forms of congenital, infantile, or glucocorticoid-resistant nephrotic syndrome. (See "Congenital nephrotic syndrome" and "Steroid-resistant nephrotic syndrome in children: Etiology", section on 'Genetic variants'.)

●Mechanisms of proteinuria — The proteinuria in glomerular disease is due to increased filtration of macromolecules (such as albumin) across the glomerular capillary wall. The mechanism varies by type of glomerular injury and is discussed in detail elsewhere:

•(See "Evaluation of proteinuria in children".)

•(See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Types of proteinuria'.)

•(See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Pathogenesis'.)

CLASSIFICATION AND ETIOLOGY — In this discussion, children with nephrotic syndrome are initially classified based upon whether signs of systemic disease are absent (primary nephrotic syndrome) or present (secondary nephrotic syndrome) (table 1). It is important to note that nephrotic syndrome can present together with findings suggestive of nephritic disease.

Primary nephrotic syndrome — Primary nephrotic syndrome is defined as nephrotic syndrome in the absence of systemic disease (table 1). This includes the following diseases, which are discussed in detail separately:

•Idiopathic nephrotic syndrome, which is the most common form of childhood nephrotic syndrome. It represents more than 90 percent of cases between 1 and 10 years of age and 50 percent after 10 years of age [1]. Idiopathic nephrotic syndrome is further classified by steroid responsiveness, which is associated with prognosis.

-Most patients with idiopathic nephrotic syndrome have histologic findings of minimal change disease (MCD) on kidney biopsy (although biopsy is no longer a routine part of the diagnosis for many children). (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Outcome based on response'.)

-Primary focal segmental glomerulosclerosis (FSGS) is another histologic lesion seen in idiopathic nephrotic syndrome in children. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)

•Primary membranous nephropathy. Membranous nephropathy is discussed in detail elsewhere. (See "Membranous nephropathy: Pathogenesis and etiology".)

•Membranoproliferative glomerulonephritis (MPGN), which is a pattern of kidney injury rather than a distinct disease. MPGN can be caused by multiple etiologies. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

•Immunoglobulin A (IgA) nephropathy. (See "IgA nephropathy: Clinical features and diagnosis".)

Secondary nephrotic syndrome — Secondary nephrotic syndrome is defined as nephrotic syndrome that is either associated with systemic disease or is secondary to another process that causes glomerular injury (ie, exposure to drugs, toxins). This includes the following diseases, which are discussed in detail separately:

•Membranous nephropathy, which may be due to systemic lupus erythematosus (SLE) or chronic hepatitis B infection. (See "Membranous nephropathy: Pathogenesis and etiology".)

•Secondary FSGS due to nephron loss resulting from kidney scarring or hypoplasia. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Differentiating between primary, secondary, and genetic FSGS'.)

•Postinfectious glomerulonephritis and infective endocarditis. (See "Poststreptococcal glomerulonephritis" and "Kidney disease in the setting of infective endocarditis or an infected ventriculoatrial shunt".)

•Lupus nephritis. (See "Lupus nephritis: Diagnosis and classification".)

•Vasculitides, such as IgA vasculitis (Henoch-Schönlein purpura), and, rarely, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. (See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

•Other causes include sickle cell disease (which is usually associated with secondary FSGS), Alport syndrome, amyloidosis, hemolytic uremic syndrome, malignancy, drugs or toxins. (See "Sickle cell disease effects on the kidney" and "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)" and "Renal amyloidosis".)

Congenital/infantile nephrotic syndrome — Congenital nephrotic syndrome occurs in children less than three months of age. These cases can be either primary, likely due to a genetic disorder, or secondary, likely due to congenital or acquired infection. Infantile nephrotic syndrome occurs between three months and one year of age. Two-thirds of nephrotic syndrome cases that occur during the first year of life and as many as 85 percent of cases that occur during the first three months of life have a genetic basis and a poor outcome [2]. (See "Congenital nephrotic syndrome".)

EPIDEMIOLOGY — The estimated incidence of idiopathic nephrotic syndrome is 2 to 3 per 100,000 children per year [3-5]. It is more common in younger children, particularly in those less than six years of age [1,4,5]. There is a male predominance, with reported ratios of boys to girls of 2 to 1 [3].

Minimal change disease (MCD) is the most commonly seen diagnosis of childhood nephrotic syndrome based on histopathology. This was illustrated in a classic study from the International Study of Kidney Disease in Children (ISKDC) of 521 children (age range 12 weeks to 16 years of age) who presented with primary nephrotic syndrome. The study was conducted in 24 centers in North America, Europe, and Asia between 1967 and 1974 [1]. Kidney biopsies were obtained in all children.

The following findings were noted on kidney biopsy:

●MCD – 77 percent

●Membranoproliferative glomerulonephritis (MPGN) – 8 percent

●Focal segmental glomerulosclerosis (FSGS) – 7 percent

●Proliferative glomerulonephritis – 2 percent

●Mesangial proliferation – 2 percent

●Focal and global glomerulosclerosis – 2 percent

●Membranous glomerulonephropathy – 2 percent

Eighty percent of patients with MCD and 50 percent of patients with FSGS presented before six years of age. In contrast, none of the 39 patients with MPGN presented before six years of age.

Subsequent studies have demonstrated an increasing prevalence of FSGS [6,7]. Whether this is due to a true increase in prevalence or is a result of improved detection of the histologic changes consistent with FSGS on kidney biopsy is unknown. Since the diagnosis of FSGS is made by the detection of one or more glomeruli with segmental glomerulosclerosis, one cannot be certain that a patient with an initial diagnosis of MCD does not actually have FSGS that was missed because of sampling error.

There is an increased incidence of nephrotic syndrome in family members when compared with the general population [8,9]. In affected siblings, nephrotic syndrome usually presents at the same age with the same histopathology and outcome [9]. These patients are often steroid-resistant and have genetic disorders of the glomerular filtration barrier [10]. (See "Steroid-resistant nephrotic syndrome in children: Etiology".)

CLINICAL MANIFESTATIONS — Although both nephrotic range proteinuria and hypoalbuminemia are required for diagnosis of nephrotic syndrome, edema is the most common presenting symptom in most cases. Hyperlipidemia is another common finding in nephrotic syndrome whose presence is not required for diagnosis.

Nephrotic range proteinuria — All children with nephrotic syndrome have nephrotic range proteinuria, which is discussed in detail below. (See 'Confirming the diagnosis' below.)

Hypoalbuminemia — Hypoalbuminemia is also required for diagnosis. It is discussed in detail below. (See 'Confirming the diagnosis' below.)

Edema — Although children with nephrotic syndrome most often present with edema, it does not occur in every patient. Periorbital edema is typically noted first and is often misdiagnosed as a manifestation of allergy. The edema is gravity dependent, so throughout the day, periorbital edema decreases while edema of the lower extremities increases. In the reclining position, edema localizes to the back and sacral area. Other dependent areas that can become edematous include the scrotum, penis, or labia. The affected areas are nonerythematous, soft, and pitting. Edema increases gradually and becomes detectable when fluid retention exceeds 3 to 5 percent of body weight.

Some patients develop anasarca (ie, generalized and massive edema), which may present as any of the following:

●Marked peripheral edema

●Abdominal distension resulting from ascites

●Pleural and/or pericardial effusions

●Marked scrotal or vulvar edema

●Severe periorbital edema resulting in swollen shut eyelids

Hyperlipidemia — Hyperlipidemia does not occur in every patient with the condition. Hyperlipidemia in nephrotic syndrome is usually characterized by increased total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride (TG) levels (table 2). HDL cholesterol remains unchanged or low, particularly HDL2, leading to an increased LDL/HDL cholesterol ratio. Patients with severe hypoalbuminemia also have increased TG and VLDL levels. Additionally, the levels of lipoprotein Lp(a) are elevated in nephrotic patients, and this further contributes to an increased risk of cardiovascular and thrombotic complications [11,12]. (See "Lipid abnormalities in nephrotic syndrome".)

Other presenting features — In addition to edema, children with nephrotic syndrome may also present with hypertension, hematuria, hypovolemia, or rare complications:

●Hypertension – Hypertension is infrequent in patients with minimal change disease. However, it is common in patients with glomerulonephritis, who may also have nephrotic syndrome and hypertension. For patients with glomerulonephritis, hypertensive encephalopathy is an uncommon but serious complication. (See "Glomerular disease: Evaluation in children", section on 'Clinical features' and "Approach to hypertensive emergencies and urgencies in children".)

●Hematuria – Gross hematuria is rare in idiopathic nephrotic syndrome, although microscopic hematuria is seen in 20 percent of cases [1]. In contrast, gross hematuria is most often seen in patients with glomerulonephritis (eg, postinfectious glomerulonephritis or membranoproliferative glomerulonephritis). (See "Glomerular disease: Evaluation in children", section on 'Urinalysis and urinary protein'.)

●Signs of hypovolemia – Despite the marked increase in extracellular fluid volume, some children with nephrotic syndrome present with or develop signs of a decrease in effective circulating volume [13]. These may include:

•Tachycardia

•Hypotension

•Peripheral vasoconstriction

•Oliguria

•Decreased glomerular filtration rate (GFR)

•Elevation of plasma renin, aldosterone, and norepinephrine [13]

This occurs primarily in those with minimal change disease (MCD). In these children, a further insult such as diuretic therapy, sepsis, or diarrhea can lead to hypotension and, rarely, shock [14]. (See "Symptomatic management of nephrotic syndrome in children", section on 'Edema'.)

DIAGNOSIS

When to suspect nephrotic syndrome — Nephrotic syndrome is generally suspected in children or adolescents who present with new onset edema. Nephrotic syndrome may also be identified in patients who are being worked up for proteinuria or hypoalbuminemia. Hyperlipidemia or hypertension may also prompt evaluation for nephrotic syndrome.

Confirming the diagnosis — The diagnosis of nephrotic syndrome is confirmed by the presence of both nephrotic range proteinuria and hypoalbuminemia:

●Nephrotic range proteinuria – Nephrotic range proteinuria is usually defined as >50 mg/kg/day or 40 mg/hr/m² in a 24-hour urine collection. In children, early morning 'spot' urine protein to creatinine ratio is often used to quantify proteinuria because it may be difficult to perform a 24-hour urine collection. Values exceeding 2 mg protein/mg creatinine (200 mg/mmol) are the most commonly reported cut off value for nephrotic range proteinuria and correspond to a dipstick value +3 and above.

●Hypoalbuminemia – The plasma albumin level is typically less than 3 g/dL (30 g/L) and may be less than 1 g/dL (10 g/L). Plasma protein levels are also markedly reduced due to hypoalbuminemia, often less than 5 g/dL (50 g/L). Electrophoresis, if performed, typically shows low albumin and increased alpha2- and beta-globulins The level of gamma-globulins depends on the cause of the nephrotic syndrome. For example, IgG levels are markedly reduced in minimal change disease and elevated in systemic lupus erythematosus.

ADDITIONAL EVALUATION — In patients with established nephrotic syndrome, additional clinical and laboratory evaluation is warranted to identify the specific underlying cause and assess for possible complications. Often in clinical practice, testing is initiated as soon as nephrotic syndrome is suspected. Although we have separated out the steps of testing for discussion in this topic, in practice these laboratory tests are performed at the same time as diagnostic testing to confirm nephrotic syndrome. Our approach is consistent with the following initial evaluation of nephrotic syndrome developed by the Children's Nephrotic Syndrome Consensus Conference [15].

History and physical examination — In patients with nephrotic syndrome, the history and physical examination should focus on potential complications and causes of nephrotic syndrome. In particular, a comprehensive history and examination should include evaluation for the following:

●Potential complications, which may include the following:

•Pleural or pericardial effusion, ascites, or anasarca, which are complications of edema

•Thromboembolic events (ie, pulmonary embolism, deep vein thrombosis, cerebral veinous thrombosis, renal vein thrombosis)

•Peritonitis, cellulitis, or another serious bacterial infection

•Tachycardia, suggesting hypovolemia

•Hypertension

•Pancreatitis

Complications of nephrotic syndrome in children are discussed in detail separately. (See "Complications of nephrotic syndrome in children".)

●Features suggestive of potential causes:

•Palpable purpura or nonblanching rashes, which could suggest vasculitis

•Malar rash, adenopathy, arthritis, fevers, weight loss, which could suggest systemic lupus erythematosus (SLE)

•History of recent group A streptococcus infection of the throat or skin, or erythematous rash/skin lesions consistent with group A streptococcus

•Dysmorphic features or ambiguous genitalia, which may indicate a syndromic cause of nephrotic syndrome

•Birth history to evaluate risk for congenital infections (ie, HIV, Hepatitis B, Hepatitis C, syphilis)

•Family history of kidney problems or congenital syndromes suggestive of genetic causes for nephrotic syndrome.

Additional laboratory evaluation — Although idiopathic nephrotic syndrome (and specifically minimal change disease [MCD]) is the most common cause in children, evaluation should include a basic assessment to rule out potential secondary causes.

●For all patients – For all patients with nephrotic syndrome, we evaluate the following tests:

•Urinalysis with microscopy – Patients with MCD have a relatively inactive urine sediment (ie, oval fat bodies and hyaline casts, but few red cells and no red cell or other cellular casts). The presence of active urine sediment indicates glomerular inflammation and a likely nephritic disorder. (See "Glomerular disease: Evaluation in children", section on 'Urinalysis and urinary protein'.)

•Blood urea nitrogen (BUN) and creatinine – Children with MCD usually have normal kidney function. The presence of impaired kidney function makes the diagnosis of MCD less likely. Nevertheless, impaired kidney function does not necessarily rule out the possibility of MCD.

Children with MCD can have moderately impaired kidney function due to intravascular volume depletion [16]. Additionally, acute kidney injury (AKI) is a common occurrence in children who are hospitalized with nephrotic syndrome [17]. Risk factors for AKI in this group of patients include concurrent infection, exposure to nephrotoxic agents, and steroid-resistant disease [16,17].

•Complement studies – Serum complement testing can be useful in the diagnosis of a specific kidney or systemic disorder that presents with nephrotic syndrome.

-Serum complement is normal in patients with idiopathic nephrotic syndrome [1].

-Low C3 levels are typically seen in patients with membranoproliferative glomerulonephritis (MPGN) and postinfectious glomerulonephritis (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis" and "Poststreptococcal glomerulonephritis".)

-Low C3 and C4 are seen in patients with lupus nephritis. (See "Lupus nephritis: Diagnosis and classification".)

•Complete blood count – Hemoglobin and hematocrit may be increased in children with nephrotic syndrome, particularly MCD, as a result of plasma volume contraction. Thrombocytosis is common and platelet counts may reach 500,000 to 1 million counts/microL. Hemoconcentration and thrombocytosis may contribute to hypercoagulability and thrombotic complications. An elevated white blood cell count is not characteristic of nephrotic syndrome and may indicate the presence of infection. (See "Complications of nephrotic syndrome in children", section on 'Thromboembolism' and "Complications of nephrotic syndrome in children", section on 'Infection'.)

•Serum lipids – Hyperlipidemia is a characteristic feature of nephrotic syndrome, as discussed above (see 'Hyperlipidemia' above). Although we prefer a fasting lipid panel for assessment of hyperlipidemia, we often screen children with a nonfasting lipid panel because fasting can be challenging for children. If the initial screen is abnormal, we obtain a follow-up fasting lipid panel. (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis", section on 'Choice of screening test'.)

•Serum electrolytes – Hyponatremia can be present, due to decreased free water excretion resulting from hypovolemic stimulation of the release of antidiuretic hormone (ADH). Hyponatremia has also been attributed to the generation of non-sodium (non-Na+) and non-potassium (non-K+) osmoles in response to plasma-volume contraction secondary to hypoalbuminemia [18]. Serum potassium may be high in oliguric patients. Serum calcium is low as a result of hypoproteinemia but ionized calcium is usually normal.

•For selected children – In children with signs or symptoms of a systemic disorder, we evaluate additional tests:

-In children with signs of systemic lupus erythematosus (ie, malar rash, adenopathy, arthritis, fevers, weight loss), we check an antinuclear antibody (ANA) level and anti-ds DNA antibody. These patients usually require kidney biopsy to confirm the etiology of nephrotic syndrome. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis".)

-Children with findings suggestive of vasculitis (ie, palpable purpura or nonblanching rashes) warrant a thorough investigation, which is discussed in detail elsewhere. These children require kidney biopsy if the diagnosis is uncertain or there is severe kidney involvement. (See "Vasculitis in children: Evaluation overview".)

-In children at high risk of having human immunodeficiency virus (HIV), hepatitis B, or hepatitis C, or syphilis (ie, born to a mother with HIV, hepatitis B, hepatitis C, or syphilis), we check HIV, hepatitis, and syphilis serologies. These patients usually require a kidney biopsy to confirm the etiology of nephrotic syndrome. (See "Pediatric HIV infection: Classification, clinical manifestations, and outcome" and "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents" and "Hepatitis C virus infection in children" and "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis".)

-In children with a recent history of group A streptococcal (GAS) infection (ie, throat or skin infection), we check an antistreptolysin antibody. Kidney biopsy is not usually required in these children, as resolution of post-streptococcal glomerulonephritis generally starts within one week of presentation. (See "Poststreptococcal glomerulonephritis".)

Genetic testing in selected children — Infants less than three months of age and children of any age with family history or extra-renal features suggesting a hereditary cause of nephrotic syndrome should undergo genetic testing [19]. Extra-renal findings that may be consistent with a congenital syndrome include dysmorphic features, ambiguous genitalia, eye abnormalities, or developmental delays. Consanguinity or other family members with proteinuria, nephrotic syndrome, or another kidney disease also suggest hereditary nephrotic syndrome. Congenital nephrotic syndrome is discussed in detail separately. (See "Congenital nephrotic syndrome".)

Genetic testing, if available, should also be performed in children with primary steroid resistant nephrotic syndrome, particularly those with a family history of proteinuria and those with extra-renal symptoms. It is not recommended for children who respond to steroid therapy with complete remission of proteinuria [19]. (See "Steroid-resistant nephrotic syndrome in children: Management", section on 'Genetic testing'.)

We use whole exome sequencing technology, which detects a monogenic disease in 10 to 30 percent of cases. The identification of the most frequent variants (ie, NPHS2, WT1, NPHS1) has important clinical implications [20]. For example, immunosuppressive treatment is ineffective for patients with these mutations, and they have a low risk of recurrence after renal transplantation. (See "Steroid-resistant nephrotic syndrome in children: Management", section on 'Genetic testing'.)

Decision to biopsy — We perform a kidney biopsy when it is unlikely that the patient has minimal change disease (MCD). The likelihood of MCD changes depending on the age of the child at presentation and/or the presence of findings consistent with a secondary cause of nephrotic syndrome.

Infants under three months of age — We usually perform genetic testing rather than a kidney biopsy for infants under three months of age, as nephrotic syndrome in these patients is most often due to a genetic cause. Exceptions to this include infants with extra-renal symptoms suggesting a secondary cause (ie, malar rash, purpura, adenopathy) and those with a birth history suggesting a congenital infection (ie, HIV, Hepatitis B or C, syphilis). These infants should be evaluated with additional tests, as discussed above. (See 'Additional laboratory evaluation' above.)

If we do not identify a genetic cause on initial testing, we perform a kidney biopsy to identify the cause of nephrotic syndrome or treat presumptively for MCD with a course of glucocorticoids. The decision of which modality to choose is based on the likelihood that the nephrotic syndrome is secondary to another disorder.

Our approach to performing genetic testing rather than kidney biopsy for patients under three months of age is largely supported by a study reporting that as many as 85 percent of nephrotic syndrome cases that occur during the first three months of life have a genetic basis and are unlikely to respond to steroids [2]. These disorders are discussed in detail separately. (See "Congenital nephrotic syndrome".)

Children 3 to 12 months of age — For children between 3 and 12 months of age without extrarenal manifestations, we rarely perform kidney biopsy as an initial step in evaluation. Rather, we proceed first to genetic testing or presumptively treat for MCD with steroids, depending on individual clinical factors [21]:

●For those who have historical findings suggesting an inherited syndrome (including consanguinity or other family members with proteinuria, nephrotic syndrome, or another kidney disease), we perform genetic testing first. Although children in this age group are not as likely to have a genetic etiology as younger infants, up to 50 percent have an inherited form [2,22].

If genetic testing is negative, we start empiric steroid therapy.

●For children without findings suggesting an inherited cause, the likelihood is high that they have primary nephrotic syndrome (ie, MCD), and so we treat presumptively with steroids rather than pursue kidney biopsy. We proceed with genetic testing for those who do not respond to steroid therapy (ie, who have steroid-resistant nephrotic syndrome). (See "Treatment of idiopathic nephrotic syndrome in children" and "Steroid-resistant nephrotic syndrome in children: Management".)

We generally reserve kidney biopsy for those children who have both negative genetic testing and are steroid resistant in order to look for other causes of nephrotic syndrome.

Children 1 to 12 years of age — For most children 1 to 12 years of age, we defer biopsy and empirically treat for MCD with glucocorticoids, since primary nephrotic syndrome (ie, MCD) is the most likely cause in these children. Exceptions that prompt kidney biopsy include features suggesting a secondary cause, such as extra-renal symptoms (ie, malar rash, purpura, adenopathy, recent group A streptococcal infection) or atypical features (macroscopic hematuria, low C3 levels, elevated serum creatinine, hypertension). We also favor kidney biopsy over presumptive glucocorticoids in children between 10 to 12 years who show signs of pubertal development, as steroids may cause unacceptable side effects during puberty. (See "Treatment of idiopathic nephrotic syndrome in children" and "Steroid-resistant nephrotic syndrome in children: Management".)

In a child between 1 and 12 years of age, with no syndromic features or family history, and without specific clinical features suggestive of a secondary cause, the diagnosis of MCD is very likely. As many as 90 percent of these patients are steroid responsive, so an initial trial of steroid therapy is most often administered without further evaluation. In this sense, an initial trial of steroid therapy in children likely to have MCD is both a diagnostic and a therapeutic measure.

For children who do not respond to empiric steroids, we perform kidney biopsy. Treatment of idiopathic nephrotic syndrome (and MCD) is discussed in detail separately. (See "Treatment of idiopathic nephrotic syndrome in children" and "Steroid-resistant nephrotic syndrome in children: Management".)

This approach is supported by evidence suggesting that age and certain clinical features can reasonably distinguish minimal change disease from other causes of nephrotic syndrome. Specifically, in the International Study of Kidney Disease in Children (ISKDC), age <10 years, normal kidney function and complement levels, and the absence of hypertension and gross hematuria, predicted minimal change disease on kidney biopsy compared with other glomerulopathies. Thus, it is reasonable to presumptively treat such patients for minimal change disease based on clinical features alone. This approach avoids invasive kidney biopsy in 80 percent of children between 1 and 10 years of age who present with nephrotic syndrome, since the majority of patients with MCD respond to steroid therapy. In one study, only 10 percent of children less than 10 years of age failed to respond to steroids for presumptive minimal change disease [1,23]. Although the age threshold for presumptive diagnosis of MCD in the ISKDC was 10 years, subsequent evidence also suggests that the likelihood of MCD is high in children up to 12 years old.

Age >12 years old — We proceed with kidney biopsy in children presenting with nephrotic syndrome at >12 years of age regardless of whether they have findings of secondary causes because they are less likely to have MCD. In addition, steroid therapy in these children may cause unacceptable side effects.

Histologic interpretation of biopsy findings — Histology of kidney biopsy generally reveals the underlying glomerulopathy. Idiopathic nephrotic syndrome is characterized by diffuse foot process effacement on electron microscopy and minimal changes (MCD), focal segmental glomerulosclerosis (FSGS), or mesangial proliferation on light microscopy. It is unclear whether these three light microscopic patterns represent separate disorders or are a spectrum of a single disease process [24]. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults" and "Focal segmental glomerulosclerosis: Clinical features and diagnosis" and "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Minimal change variants'.)

Histologic features of other glomerular processes that might cause nephrotic range proteinuria are discussed elsewhere.

●(See "Membranous nephropathy: Clinical manifestations and diagnosis", section on 'Characteristic histologic features'.)

●(See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Pathology and pathogenesis'.)

●(See "IgA nephropathy: Clinical features and diagnosis", section on 'Histologic features'.)

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

●Classification and etiology – Nephrotic syndrome (NS) is caused by kidney diseases that increase the permeability across the glomerular filtration barrier. It is characterized by nephrotic range proteinuria, hypoalbuminemia, and edema. It is classified based on the underlying cause: primary NS, secondary NS, and congenital and infantile NS (table 1). (See 'Pathogenesis' above and 'Classification and etiology' above.)

●Clinical manifestations

•Edema – Children with NS most often present with periorbital edema, which can localize to dependent areas (ie, sacrum, back, scrotum, labia). (See 'Edema' above.)

•Hyperlipidemia – Hyperlipidemia is frequent, but does not occur in every patient with the condition (table 2). (See 'Hyperlipidemia' above.)

•Other presenting features – Children with NS may also present with hypertension, hematuria, hypovolemia, or rare complications such as bacterial or viral infection, thromboembolism, or pancreatitis. (See 'Other presenting features' above.)

●Diagnosis – The diagnosis of NS is confirmed by the presence of both of the following (see 'Diagnosis' above):

•Nephrotic range proteinuria, defined as >50 mg/kg/day or 40 mg/hr/m² in a 24-hour urine collection. In children we use an early morning 'spot' urine protein to creatinine ratio >2 mg protein/mg creatinine (200 mg/mmol) as the threshold for proteinuria.

•Hypoalbuminemia, with the plasma albumin level less than 3 g/dL (30 g/L). Plasma protein levels are also markedly reduced.

●Additional evaluation – In patients with established NS, additional evaluation is done to identify the underlying cause and assess for possible complications (algorithm 1). This includes the following:

•History and physical evaluation, including family history suggestive of hereditary causes of NS (ie, consanguinity, proteinuria, nephrotic syndrome, another kidney disease) and extra-renal findings that may be consistent with a systemic disorder (ie, malar rash, purpura, adenopathy, recent group A streptococcal infection). (See 'History and physical examination' above.)

•Laboratory evaluation for all patients with NS, including labs to both confirm the diagnosis and to assess for possible causes and complications (algorithm 1). Additional laboratory evaluation for children with signs or symptoms of a systemic disorder (ie, vasculitis, systemic lupus erythematosus, group A streptococcal infection, congenital infection) includes additional tests for the suspected disease. (See 'Additional laboratory evaluation' above.)

•Genetic testing – Infants less than three months of age and children of any age with family history or extra-renal features suggesting a hereditary cause of nephrotic syndrome (ie, dysmorphic features, ambiguous genitalia, eye abnormalities, developmental delays) should undergo genetic testing. Children who fail to respond to a trial of corticosteroid therapy should also undergo genetic testing. (See 'Genetic testing in selected children' above.)

•Decision to biopsy – A kidney biopsy is performed when it is unlikely that the patient has minimal change disease (MCD). The likelihood of MCD changes depending on the age of the child at presentation and/or the presence of findings consistent with a secondary cause of nephrotic syndrome.

In general, kidney biopsy is not necessary in most children under 12 years of age unless they have features suggestive of a secondary cause (ie, vasculitis, systemic lupus erythematosus, group A streptococcal infection, risk for congenital infection). We proceed with kidney biopsy in children presenting with nephrotic syndrome at >12 years of age regardless of whether they have findings of secondary causes because they are less likely to have MCD. (See 'Decision to biopsy' above.)

●Histologic interpretation of biopsy findings – The histology of kidney biopsy generally reveals the underlying glomerulopathy. (See 'Histologic interpretation of biopsy findings' above.)