Pediatric Nephrotic Syndrome Workup
- Author: Jerome C Lane, MD; Chief Editor: Craig B Langman, MD more...
The first step in evaluating the child with edema is to establish whether nephrotic syndrome is present, because hypoalbuminemia can occur in the absence of proteinuria (such as from protein-losing enteropathy), and edema can occur in the absence of hypoalbuminemia (for example, in angioedema, capillary leak, venous insufficiency, congestive heart failure).
In order to establish the presence of nephrotic syndrome, laboratory tests should confirm (1) nephrotic-range proteinuria, (2) hypoalbuminemia, and (3) hyperlipidemia. Therefore, initial laboratory testing should include the following:
Urine protein quantification (by first-morning urine protein/creatinine or 24-hour urine protein)
Once the presence of nephrotic syndrome has been established, the next task is to determine whether the nephrotic syndrome is primary (idiopathic) or secondary to a systemic disorder and, if idiopathic nephrotic syndrome (INS) has been determined, whether signs of chronic kidney disease, kidney insufficiency, or other signs exclude the possibility of MCNS. Therefore, in addition to the above tests, the following should be included in the workup:
Complete blood count (CBC)
Metabolic panel (Serum electrolytes, BUN and creatinine, calcium, phosphorus, and ionized calcium levels)
Testing for HIV, hepatitis B and C
Complement studies (C3, C4)
Antinuclear antibody (ANA), anti–double-stranded DNA antibody (in selected patients)
Patients with INS lose vitamin D–binding protein, which can result in low vitamin D levels, and thyroid binding globulin, which can result in low thyroid hormone levels. Consideration should be given, especially in the child with frequently relapsing or steroid-resistant nephrotic syndrome, to testing for 25-OH-vitamin D; 1,25-di(OH)-vitamin D; free T4; and thyroid-stimulating hormone (TSH).
Other tests and procedures in selected patients may include the following:
Age plays an important role in the diagnostic evaluation of nephrotic syndrome. Children presenting with nephrotic syndrome younger than 1 year of age should be evaluated for congenital/infantile nephrotic syndrome. In addition to the above tests, infants should have the following tests:
Congenital infection (syphilis, rubella, toxoplasmosis, cytomegalovirus, HIV)
Kidney biopsy (see Procedures)
Genetic tests for NPHS1, NPHS2, WT1, and PLCE1 as guided by biopsy findings and clinical presentation; presence of extrarenal syndromic findings might indicate other genetic testing, such as LAMB2 (Pierson syndrome), LMX1B (nail-patella syndrome), and SMARCAL1 ( Schimke immunoosseous dysplasia)
Occasionally, a patient with nephrotic syndrome either presents with or develops clinical signs of an acute abdomen, which is frequently due to peritonitis. The diagnosis can usually be made clinically and confirmed by bacteriologic examination of the peritoneal fluid aspirate. The organism most often responsible for the peritonitis is Streptococcus pneumoniae; however, enteric bacteria may also cause peritonitis. Treatment is medical rather than surgical.
Microscopic hematuria is present in 20% of cases of INS and cannot be used to distinguish between minimal change nephrotic syndrome (MCNS) and other forms of glomerular disease.
RBC casts, if present, are suggestive of acute glomerulonephritis, such as postinfectious nephritis, or a nephritic presentation of chronic glomerulonephritis, such as membranoproliferative glomerulonephritis (MPGN).
Granular casts may be present and are non-specific to etiology
The presence of macroscopic (gross) hematuria is unusual in MCNS and suggests another cause, such as MPGN, or a complication of idiopathic nephrotic syndrome (INS), such as renal vein thrombosis.
Urine protein quantification
First morning urine protein/creatinine is more easily obtained than 24-hour urine studies, is possibly more reliable, and excludes orthostatic proteinuria. A urine protein/creatinine ratio of more than 2-3 mg/mg is consistent with nephrotic-range proteinuria.
A 24-hour urine protein level of more than 40 mg/m2/h also defines nephrotic-range proteinuria.
Serum albumin levels in nephrotic syndrome are generally less than 2.5 g/dL. Values as low as 0.5 g/dL are not uncommon.
Lipid panel findings are typically as follows:
Elevated total cholesterol, low-density lipoprotein (LDL)-cholesterol
Elevated triglycerides with severe hypoalbuminemia
High-density lipoprotein (HDL)-cholesterol (normal or low)
The patient with INS, even MCNS, can present with acute kidney failure due to intravascular volume depletion and/or bilateral renal vein thrombosis. In the absence of the above, elevated BUN and creatinine levels and signs of chronic kidney failure (such as poor growth, anemia, acidosis, hyperkalemia, hyperphosphatemia, elevated parathyroid hormone) suggest a chronic glomerular disease other than MCNS, such as one of the following:
Focal segmental glomerulosclerosis (FSGS)
Membranous nephropathy (MN)
Immunoglobulin (Ig)A nephropathy
Serum sodium levels are low in patients with INS because of hyperlipidemia (pseudohyponatremia), as well as dilution due to water retention. Total calcium levels are low because of hypoalbuminemia, but ionized calcium levels are normal.
On the CBC, an increased hemoglobin and hematocrit indicate hemoconcentration and intravascular volume depletion. The platelet count is often increased.
HIV infection, hepatitis B, and hepatitis C are important secondary causes of nephrotic syndrome. Consequently, screening for these viruses should be performed in all patients presenting with nephrotic syndrome. Consider checking liver enzymes, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), when screening for liver disease.
Low complement levels (C3, C4) are found in postinfectious nephritis, MPGN, and lupus nephritis.
ANA and anti–double-stranded DNA antibody assays are used to screen for collagen-vascular disease in patients with systemic symptoms (fever, rash, weight loss, joint pain) or any patient with nephrotic syndrome presenting in later school-age or adolescent years when lupus has a higher incidence.
Patients with infantile or congenital nephrotic syndrome should have testing for mutations in NPHS1 and WT1. If test results are normal, then testing for mutations in NPHS2 and PLCE1 should be considered. Genetic testing for WT1 mutations also should be considered in patients presenting with nephrotic syndrome and other extrarenal syndromic features of Denys-Drash (nephrotic syndrome, pseudohermaphroditism or genitourinary tract anomalies, and Wilms tumor) or Frasier syndrome (nephrotic syndrome, pseudohermaphroditism or genitourinary tract anomalies, and gonadoblastoma).
Infants with nephrotic syndrome and neurological or visual disturbances should be considered candidates for LAMB2 testing (Pierson syndrome). Presence of other extrarenal syndromic findings might indicate other genetic testing, such as LMX1B (nail-patella syndrome) and SMARCAL1 ( Schimke immuno-osseous dysplasia).
In patients initially or subsequently unresponsive to steroid treatment, in addition to kidney biopsy, consideration should be given to testing for mutations in podocin (NPHS2), ACTN4 and TRPC6.
Kidney ultrasonography findings are usually nonspecific. The kidneys are usually enlarged due to tissue edema. Increased echogenicity is usually indicative of chronic kidney disease other than MCNS, in which echogenicity is usually normal. A finding of small kidneys indicates chronic kidney disease other than MCNS and often accompanied by elevated serum creatinine levels.
Chest radiography is indicated in the child with respiratory symptoms. Pleural effusions are common, although pulmonary edema is rare.
Chest radiography also should be considered prior to steroid therapy to rule out tuberculosis (TB) infection, especially in the child with positive or previously positive Mantoux test or prior treatment for TB.
Mantoux test (purified protein derivative [PPD]) should be performed prior to steroid treatment to rule out TB infection.
Mantoux testing can be performed concurrent to starting steroid treatment, as treatment with steroids for 48 hours prior to reading the PPD does not mask a positive result and the risk associated with 2 days of steroids is minimal (if tests results are positive, steroids should be immediately stopped).
In children with a positive PPD, previously positive PPD, or prior treatment for TB, chest radiography should be performed.
A kidney biopsy is not indicated for first presentation of INS in the child 1-8 years of age unless the history, physical findings, or laboratory results indicate the possibility of secondary nephrotic syndrome or primary nephrotic syndrome other than MCNS. Kidney biopsy is indicated in patients younger than 1 year, when genetic forms of congenital nephrotic syndrome are more common, and in patients older than 8 years, when chronic glomerular diseases such as FSGS have a higher incidence.
In select preadolescent patients older than 8 years, empirical steroid treatment can be considered prior to kidney biopsy, but this should occur only under the care of a pediatric nephrologist experienced with nephrotic syndrome. Some authors have recommended performing a kidney biopsy in patients older than 12 years.
Kidney biopsy should also be performed when history, examination, or laboratory findings indicate secondary nephrotic syndrome or kidney disease other than MCNS. Thus, a kidney biopsy is indicated if patients have any of the following:
Symptoms of systemic disease (e.g., fever, rash, joint pain)
Laboratory findings indicative of secondary nephrotic syndrome (e.g., positive ANA findings, positive anti–double-stranded DNA antibody findings, low complement levels)
Elevated creatinine levels unresponsive to correction of intravascular volume depletion
A relevant family history of kidney disease
Finally, in patients who are initially or subsequently unresponsive to steroid treatment, kidney biopsy should be performed, because steroid unresponsiveness has a high correlation with prognostically unfavorable histology findings such as FSGS or MGN.
If a kidney biopsy is performed, various histologic findings can be present, depending on the etiology of the nephrotic syndrome. A detailed discussion of the various types of INS and histological findings is beyond the scope of this article. Briefly, the most common histological types of INS are as follows.
Minimal change nephrotic syndrome
MCNS indicates glomerular morphology that on light microscopic examination is little different from normal. Minimal mesangial hypercellularity may be present. Immunofluorescent microscopy (IF) usually reveals no presence of immune deposits.
Occasionally, mesangial IgM deposition may be seen on IF. Some consider the presence of IgM to indicate a separate entity (IgM nephropathy), whereas others consider this to be a variant of MCNS. The presence of IgM may indicate a more difficult course of nephrotic syndrome, with frequent relapses, steroid dependence, or steroid resistance, although the overall prognosis is still usually favorable. The only significant change seen on electron microscopy (EM) is flattening and fusion of the podocyte foot processes (effacement).
Diffuse mesangial proliferation
Diffuse mesangial proliferation (DMP) refers to increased mesangial matrix and increased mesangial hypercellularity. IF findings are negative and EM reveals the typical foot process effacement of MCNS. Patients with DMP have an increased incidence of steroid resistance, although whether these patients are at increased risk for progression to kidney failure is unclear.
FSGS describes a lesion in which, as seen on LM, discrete segments of the glomerular tuft reveal sclerosis (segmental); some glomeruli are involved, and others are spared (focal).
Adhesion of the glomerular tuft to Bowman capsule (synechiae) is observed. Glomerular hypertrophy is common. Interstitial fibrosis and tubular atrophy are often present and correlate with the severity of disease.
IF reveals IgM and C3 trapped in the sclerotic areas. As in MCNS, EM reveals effacement of the podocyte foot processes. Additionally, EM reveals obliteration of capillary lumens by fine granular and lipid deposits.
A subtype of FSGS, in which the glomerular tufts demonstrate collapse of capillaries (collapsing glomerulopathy) on LM, has a poorer prognosis and high rate of progression to end-stage kidney failure (ESKD).
FSGS is not a specific disease but a histopathological finding that can be associated with INS but can also be found in a wide variety of other conditions, including HIV nephropathy, heroin nephropathy, reflux nephropathy, obstructive uropathy, renal hypoplasia, hypertension, obesity, and Alport syndrome.
As always, clinical and histopathological correlations must always be made when considering the findings evident on kidney biopsy.
MPGN is also known as mesangiocapillary glomerulonephritis. Glomeruli are typically lobulated in appearance on LM findings and demonstrate mesangial proliferation. Silver stain may reveal characteristic duplication of the glomerular basement membrane ("tram-track" appearance). IF findings reveal characteristic capillary deposition of C3.
Three types of MPGN are recognized and can be distinguished by electron microscopy findings according to the location of immune deposits. Type 1 is subendothelial; type 2 has ribbon-like, dense intramembranous deposits; and type 3 is subendothelial and subepithelial. Some controversy surrounds the existence of type 3 MPGN as a distinct entity or a variant of type 1.
MN is a rare finding in INS of childhood, comprising only approximately 1% of biopsies, whereas in adult INS, MN can be found in 25-40% of cases. Light microscopy typically reveals thickening of the glomerular basement membrane. Silver stain may reveal characteristic "spikes," resulting from protrusion of basement membrane around immune deposits. IF reveals fine granular IgG and complement staining along the periphery of the glomerular capillary wall. EM reveals subepithelial electron-dense deposits.
The reader is referred to other articles regarding histology of congenital nephrotic syndrome, and secondary forms of nephrotic syndrome due to lupus, vasculitis, and other etiologies.
Various staging schemes are recognized for the different histological lesions of INS. In general, when referring to kidney biopsy, the severity and chronicity of the disease is determined by the extent of tubulointerstitial fibrosis. The greater the extent of fibrosis, the greater the irreversibility of the disease and the poorer the prognosis, regardless of histological subtype.
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