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

INTRODUCTION — 

The nephrotic syndrome (NS) 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 NS in children are reviewed here. The complications and treatment of idiopathic childhood NS and specific kidney diseases that present as NS 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 NS: the mechanisms of glomerular injury and proteinuria.

●Mechanisms of glomerular injury – A variety of disease-specific mechanisms have been described in NS. 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 (MPGN), 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 NS. (See "Steroid-resistant nephrotic syndrome in children: Evaluation and management", section on 'Possible etiologies'.)

●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 "Evaluation of proteinuria in adults".)

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

CLASSIFICATION AND ETIOLOGY — 

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

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

•Idiopathic NS, which is the most common form of childhood NS. 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 NS is further classified by steroid responsiveness, which is associated with prognosis.

-Most patients with idiopathic NS 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 NS 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 NS is defined as NS 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 due to systemic lupus erythematosus (SLE), chronic hepatitis B infection, other infections, or drug exposure. (See "Membranous nephropathy: Pathogenesis and etiology".)

•Secondary FSGS due to hyperfiltration caused by reduced number of nephrons (eg, because of 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-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 NS 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 NS occurs between three months and one year of age. Two-thirds of NS 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 "Steroid-resistant nephrotic syndrome in children: Evaluation and management", section on 'Possible etiologies'.)

EPIDEMIOLOGY — 

The estimated incidence of idiopathic NS is 2 to 3 per 100,000 children per year [3-6]. It is more common in younger children, particularly in those less than six years of age [1,4,5]. Among younger children, there is a male predominance, with reported ratios of boys to girls of 2:1 [3].

Minimal change disease (MCD) is the most commonly seen diagnosis of childhood NS 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 NS. The study was conducted in 24 centers in North America, Europe, and Asia between 1967 and 1974 [1]. Kidney biopsies were obtained at presentation 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 [7,8]. 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 NS in family members when compared with the general population [9,10]. In affected siblings, NS usually presents at the same age with the same histopathology and outcome [10]. These patients are often steroid-resistant and have genetic disorders of the glomerular filtration barrier [11]. (See "Steroid-resistant nephrotic syndrome in children: Evaluation and management", section on 'Evaluation for etiology'.)

CLINICAL MANIFESTATIONS — 

Edema is the characteristic presenting symptom for NS, and subsequent evaluation typically reveals nephrotic range proteinuria, hypoalbuminemia, and hyperlipidemia.

Edema — Children with NS most often present with edema. 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

Nephrotic range proteinuria — All children with NS 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.)

Hyperlipidemia — Hyperlipidemia in NS is usually characterized by increased total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride (TG) levels (table 2). High-density lipoprotein (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 very-low-density lipoprotein 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 [12,13]. (See "Lipid abnormalities in nephrotic syndrome".)

Hyperlipidemia is most problematic in children with therapy-unresponsive NS, since it typically abates if NS is in remission.

Other presenting features — In addition to edema, children with NS may also present with hypertension, hematuria, or hypovolemia:

●Hypertension – Hypertension is infrequent in patients with minimal change disease (MCD). However, it is common in patients with glomerulonephritis, who may also have NS 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 NS, 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 [MPGN]). (See "Glomerular disease: Evaluation in children", section on 'Urinalysis and urinary protein'.)

●Signs of hypovolemia – Despite the marked increase in total body water, some children with NS present with or develop signs of decreased effective circulating volume [14]. These may include:

•Tachycardia

•Hypotension

•Peripheral vasoconstriction

•Oliguria

•Decreased glomerular filtration rate

•Elevation of plasma renin, aldosterone, and norepinephrine [14]

In these children, further loss of intravascular volume (eg, from diuretic therapy, sepsis, or diarrhea) can lead to hypotension and, rarely, shock [15]. (See "Symptomatic management of nephrotic syndrome in children", section on 'Edema'.)

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

DIAGNOSIS

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

Confirming the diagnosis — The diagnosis of NS is made when both nephrotic range proteinuria and hypoalbuminemia are present:

●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 in NS is less than 3 g/dL (30 g/L). Most patients have an albumin level less than 2.5 g/dL (25 g/L), and some have a level 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 NS. For example, IgG levels are markedly reduced in minimal change disease (MCD) and elevated in systemic lupus erythematosus (SLE).

ADDITIONAL EVALUATION — 

In patients with established NS, 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 NS 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 NS. Our approach is consistent with the following initial evaluation of NS developed by the Children's Nephrotic Syndrome Consensus Conference [16].

History and physical examination — In patients with NS, the history and physical examination should focus on potential complications and causes of NS. 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 NS 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 (GAS) infection of the throat or skin, or erythematous rash/skin lesions consistent with GAS

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

•Birth history to evaluate risk for congenital infections (ie, human immunodeficiency virus [HIV], Hepatitis B, Hepatitis C, syphilis)

•Family history of kidney problems or congenital syndromes suggestive of genetic causes for NS

Additional laboratory evaluation — Although idiopathic NS (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 NS, 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 [17]. Additionally, acute kidney injury (AKI) is a common occurrence in children who are hospitalized with NS [18]. Risk factors for AKI in this group of patients include concurrent infection, exposure to nephrotoxic agents, and steroid-resistant disease [17,18].

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

-Serum complement is normal in patients with idiopathic NS [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 NS 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 NS 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 NS, 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. Hyponatremia has also been attributed to the generation of nonsodium (non-Na+) and nonpotassium (non-K+) osmoles in response to plasma-volume contraction secondary to hypoalbuminemia [19]. 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 SLE (ie, malar rash, adenopathy, arthritis, fevers, weight loss), we check an antinuclear antibody level and anti-double-stranded deoxyribonucleic acid (dsDNA) antibody. These patients usually require kidney biopsy to confirm the etiology of NS. (See "Childhood-onset systemic lupus erythematosus (cSLE): 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 if there is severe kidney involvement. (See "Vasculitis in children: Evaluation overview".)

-In children at high risk of having 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 NS. (See "Pediatric HIV infection: Epidemiology, 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 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".)

Subsequent evaluation — Options for the next steps in the evaluation of NS include:

●Genetic testing to evaluate for an inherited form of NS.

●Presumptively treating for MCD with glucocorticoids as both a diagnostic and therapeutic measure.

●Kidney biopsy to establish a histologic diagnosis.

The choice among them depends on the clinical suspicion for a hereditary NS versus steroid-responsive MCD versus a secondary cause of NS; this in turn depends on the clinical features and the age of the patient, as outlined below (algorithm 1).

Children with features suggestive of a genetic cause — We proceed directly to genetic testing (rather than presumptive glucocorticoids or kidney biopsy) for the following children:

●Infants with disease onset before three months of age, and in some cases up to one year of age. The approach in these age groups is discussed in further detail elsewhere. (See 'Age <3 months' below and 'Age 3 to 12 months' below.)

●Children of any age with extrarenal features that suggest a hereditary cause of NS [20]. Such features include those consistent with a congenital syndrome, such as dysmorphic features, ambiguous genitalia, eye abnormalities, or developmental delays.

●Children of any age who have family members with proteinuria, NS, or another kidney disease. Such family history is associated with hereditary NS.

Laboratory panels that test for mutations in genes linked to NS or kidney disease are increasingly available. The identification of the most frequent variants (ie, NPHS2, WT1, NPHS1) has important clinical implications [21].

The specific genetic tests to perform in the evaluation of NS are outlined elsewhere. (See "Steroid-resistant nephrotic syndrome in children: Evaluation and management", section on 'Possible etiologies'.)

Children with atypical features suggestive of a secondary cause — For patients whose clinical presentation suggests a secondary cause of NS, we proceed to kidney biopsy to make a histologic diagnosis prior to treatment. (See 'Histologic interpretation of biopsy findings' below.)

Such features include:

●Hypertension

●Gross hematuria

●Elevated serum creatinine/impaired kidney function

●Low complement levels

●Extrarenal features suggestive of autoimmune disorder or infection, such as malar rash, purpuric lesions, and adenopathy

Although children with these features can still have MCD, the likelihood is low enough that we favor establishing the diagnosis rather than presumptively treating MCD with glucocorticoids. (See 'Histologic interpretation of biopsy findings' below.)

Children without congenital or atypical features

Age <3 months — For children with onset of NS before three months of age, we proceed directly to genetic testing. The vast majority of these children (up to 85 percent), even those without syndromic features or suggestive family history, have a genetic cause of NS [2]. (See "Congenital nephrotic syndrome".)

If genetic testing does not identify a causal mutation, we presumptively treat for MCD with glucocorticoids. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Initial steroid course'.)

We reserve kidney biopsy for those who have had both negative genetic testing and nonresponse to glucocorticoids. (See 'Histologic interpretation of biopsy findings' below.)

Age 3 to 12 months — For children who have onset of NS between 3 and 12 months of age and do not have familial, extrarenal, or atypical features that suggest a genetic or secondary cause, our approach is consistent with guidelines from the International Pediatric Nephrology Association [22]. These guidelines present the following as appropriate options:

●Initial genetic testing as long as results are rapidly available (with glucocorticoid treatment if negative) (see "Congenital nephrotic syndrome")

●Initial kidney biopsy with subsequent management based on results (see 'Histologic interpretation of biopsy findings' below)

●Initial presumptive glucocorticoid treatment (with genetic testing and biopsy in patients who do not respond) (see "Treatment of idiopathic nephrotic syndrome in children", section on 'Initial steroid course')

We use shared decision-making with parents to individualize the choice. However, some other experts proceed to genetic testing for all children in this age group, given that it is widely available and easy to perform.

Older infants are less likely to have a genetic cause of NS than infants younger than three months; however, up to 50 percent have an inherited form [2,23]. Among those without an inherited form or atypical features, the likelihood of MCD is high.

Age 1 to 12 years — For children aged 1 to 12 years who do not have familial, extrarenal, or atypical features that suggest a genetic or secondary cause, we suggest presumptive treatment for MCD with glucocorticoids rather than genetic testing or kidney biopsy. In these children, primary NS (ie, MCD) is the most likely cause, and the vast majority of patients with MCD respond to glucocorticoids. Thus, response to a presumptive glucocorticoid trial reasonably establishes the diagnosis of MCD. The initial dosing of glucocorticoids and evaluation of response are discussed elsewhere. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Initial steroid course'.)

For children who do not respond to presumptive glucocorticoids, additional diagnostic evaluation with genetic testing and/or kidney biopsy is warranted. (See "Steroid-resistant nephrotic syndrome in children: Evaluation and management", section on 'Genetic testing'.)

This approach is supported by evidence suggesting that age and certain clinical features can reasonably distinguish MCD from other causes of NS. The combination of age <12 years old, normal kidney function, normal complement levels, and no hypertension or gross hematuria predicted MCD on kidney biopsy (rather than other glomerulopathies) [1,24]. Presumptively treating MCD based on these clinical features alone avoids the need for invasive kidney biopsy in the vast majority of children in this age group who present with NS. In one study, only 10 percent of children less than 10 years of age failed to respond to glucocorticoids for presumptive MCD treatment [1,24].

Age >12 years — For children >12 years old who do not have familial, extrarenal, or atypical features that suggest a genetic or secondary cause, we generally offer kidney biopsy for histologic diagnosis (see 'Histologic interpretation of biopsy findings' below). However, presumptive treatment of MCD with glucocorticoids is a reasonable alternative, particularly if children and families prefer avoiding biopsy, and there are not major concerns about the potential adverse effects of glucocorticoids.

For those who opt for presumptive glucocorticoids, genetic testing and/or kidney biopsy are warranted for those who do not respond. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Initial steroid course'.)

Other causes of NS are as likely as MCD in this age group, and many of those causes are not responsive to glucocorticoids or have other management implications; thus, biopsy is often necessary to establish the diagnosis and determine the appropriate treatment regimen.

Histologic interpretation of biopsy findings — Histologic evaluation of kidney biopsy specimens generally reveals the underlying glomerulopathy. Idiopathic NS is characterized by diffuse foot process effacement on electron microscopy and 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 [25]. (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'.)

Some histologic features, such as diffuse mesangial sclerosis, warrant genetic testing, if not already performed. (See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis'.)

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'.)

Details on performing kidney biopsy are found elsewhere. (See "The kidney biopsy".)

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; edema can also localize to dependent areas (ie, sacrum, back, scrotum, labia). (See 'Edema' above.)

•Hyperlipidemia – Total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride (TG) levels are usually elevated (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 – This is defined as >50 mg/kg/day or 40 mg/hr/m² in a 24-hour urine collection. However, in children we generally check an early morning 'spot' urine protein to creatinine ratio; the threshold for NS is >2 mg protein/mg creatinine (200 mg/mmol).

•Hypoalbuminemia – The plasma albumin level is <3 g/dL (30 g/L). Plasma protein levels are also markedly reduced.

●Additional evaluation – In patients with established NS, potential secondary causes and possible complications should be evaluated (algorithm 1):

•History and physical examination – This includes family history of kidney disease and identification of extrarenal features that could be consistent with a congenital syndrome (eg, dysmorphic features, developmental delays) or a systemic disorder (eg, malar rash, purpura, adenopathy, recent group A streptococcal [GAS] infection). (See 'History and physical examination' above.)

•Laboratory evaluation – In addition to testing to confirm the diagnosis, we check complete blood count, basic metabolic panel, serum complement levels, serum lipids, and urinalysis with microscopy (algorithm 1). For selected children, we test vasculitis, systemic lupus erythematosus (SLE), GAS infection, congenital infections, or other causes of secondary NS. (See 'Additional laboratory evaluation' above.)

●Establishing the cause – Depending on the age, clinical features, and family history, subsequent evaluation to establish the cause can include genetic testing, presumptive treatment of minimal change disease (MCD) with glucocorticoids, or kidney biopsy (algorithm 1).

•Children with features suggesting a hereditary cause of nephrotic syndrome – These include family history of kidney disease and congenital abnormalities. For these children, we perform genetic testing prior to presumptive glucocorticoids or kidney biopsy. (See 'Children with features suggestive of a genetic cause' above.)

•Children with atypical features suggestive of a secondary cause of nephrotic syndrome – These include hypertension, gross hematuria, impaired kidney function, low complement levels, and extrarenal manifestations (eg, malar or vasculitic rash). For these children, kidney biopsy is generally warranted to establish the cause. (See 'Children with atypical features suggestive of a secondary cause' above and 'Histologic interpretation of biopsy findings' above.)

•Children with none of these features – In this setting, our approach varies by age:

-Age <3 months – We proceed first to genetic testing for infants with onset of NS before three months. The vast majority has an inherited cause.

-Age 3 to 12 months – Initial genetic testing, initial kidney biopsy, or presumptive glucocorticoid treatment are all reasonable options.

-Age 1 to 12 years – We presumptively treat MCD with glucocorticoids rather than first performing genetic testing or kidney biopsy. MCD is the most common cause in this age group, and glucocorticoids are both diagnostic and therapeutic. (See 'Age 1 to 12 years' above and "Treatment of idiopathic nephrotic syndrome in children", section on 'Empiric steroid therapy versus kidney biopsy'.)

-Age >12 years – We offer kidney biopsy to establish a histologic diagnosis in this age group, as they are less likely to have MCD. However, an initial attempt at presumptive treatment with glucocorticoids is a reasonable option, and some children and families may prefer it. (See 'Age >12 years' above and 'Histologic interpretation of biopsy findings' above.)