Nephrotic Syndrome Workup

Updated: Dec 24, 2016
  • Author: Eric P Cohen, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Workup

Approach Considerations

Diagnostic studies for nephrotic syndrome may include the following:

  • Urinalysis
  • Urine sediment examination
  • Urinary protein measurement
  • Serum albumin
  • Serologic studies for infection and immune abnormalities
  • Renal ultrasonography
  • Renal biopsy

In infants with nephrotic syndrome, genetic testing for the NPHS1 and NPHS2 mutations may be useful. These are mutations of nephrin and podocin, respectively. In children with steroid-resistant nephrotic syndrome, testing for the NPHS2 mutation may be indicated.

In the future, novel urinary biomarkers may become available that can identify the cause and severity of nephrotic syndrome. [34]  See Novel Biomarkers of Renal Function.

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Urine Studies

Urinalysis

Urinalysis is the first test used in the diagnosis of nephrotic syndrome. 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. The chemistry of the dipsticks is such that albumin is the major protein that is tested.

Glucosuria points to diabetes.

Urine sediment examination

The urine sediment exam may show cells and/or casts.

Waxy casts mark proteinuric renal disease. By use of a polarizing microscope, one can see oval fat bodies and also fatty casts. These point to the nephrotic syndrome. They occur because of glomerular filtration of lipoproteins; the tubular cells that endocytose these lipoproteins then fall off into the urine. Viewed by polarizer, the oval fat bodies and fatty casts cause a "Maltese cross" appearance.

The presence of more than 2 red blood cells (RBCs) per high power field is indicative of microhematuria. Microhematuria may occur in membranous nephropathy but not in minimal-change nephropathy.

Glomerular disease may allow RBCs to traverse the damaged glomerular basement membrane, and the RBCs in the sediment may then be deformed, or dysmorphic. This points to glomerular disease with inflammation and destruction of the normal structures (ie, a nephritis, and thus a nephritic picture, with hematuria, oliguria, azotemia, and hypertension). This could occur in, for example, nephrotic syndromes associated with IgA nephropathy or proliferative glomerulonephritis.

More than 2 granular casts in the entire sediment is a biomarker for renal parenchymal disease. Variable-caliber and broad granular casts point to reduced renal function.

Urinary protein measurement

Urinary protein is measured by a timed collection or a single spot collection. [35] A timed collection is typically done over a 24-hour period, starting at 7 am and finishing the next day at the same time. In healthy individuals, less than 150 mg of total protein is present in a 24-hour urine collection.

A single spot urine collection is much easier to obtain. When the ratio of urine protein to urine creatinine is greater than 2 g/g, this corresponds to 3 g of urinary protein per day or more.

The exact type of urine protein is of potential interest. This can be tested by urine protein electrophoresis. Proteinuria that does not include albumin may point to overflow proteinuria that occurs in paraproteinemias, such as multiple myeloma.

There has been intermittent interest in establishing whether proteinuria is "selective" for albumin (ie, >85% albumin), as opposed to nonselective. In the case of selective proteinuria, a charge-selective leak of albumin across the glomerular barrier may be occurring, perhaps due to reduced negative charges on that barrier, whereas nonselective proteinurias point to more substantial glomerular injury and perhaps also predict lesser response to prednisone treatment.

 

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Renal Biopsy

For childhood nephrotic syndrome, a renal biopsy is indicated for the following:

  • Congenital nephrotic syndrome
  • Children older than 8 years at onset
  • Steroid resistance
  • Frequent relapses or steroid dependency
  • Significant nephritic manifestations

Adult nephrotic syndrome of unknown origin may require a renal biopsy for diagnosis. Reaching a pathological diagnosis is important because minimal-change disease, focal glomerulosclerosis, and membranous nephropathy have different treatment options and prognoses. It is important to differentiate minimal-change disease presenting in adults from focal glomerulosclerosis, as the former has an excellent response to steroids. Another entity called immunoglobulin M (IgM) nephropathy falls in between the two and has an intermediate response to steroids.

A renal biopsy is not indicated in adults with nephrotic syndrome from an obvious cause. For example, in a patient with longstanding diabetes and diabetic retinopathy, the nephrotic syndrome is likely to be secondary to diabetic nephropathy, so kidney biopsy may be unnecessary. However, it is important to not assume diabetic nephropathy as the causative factor for nephrotic syndrome in all diabetic persons. A duration of diabetes of less than 5 years and the absence of retinopathy and neuropathy are clues to non-diabetic kidney disease.

It is worth noting that in clinical experience with kidney biopsies, the cause of nephrotic-range proteinuria is glomerular disease, not tubular disease. This contradicts the proposal that tubular function determines proteinuria. [3]

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Laboratory Studies

Kidney function

Serum tests for kidney function are essential. Serum creatinine will be in the normal range in uncomplicated nephrotic syndrome, such as that occurring in minimal-change nephropathy. In children, the serum creatinine level will be lower than it is in adults. The normal adult serum creatinine level is approximately 1 mg/dL, whereas that of a child aged 5 years will be about 0.5 mg/dL. Values higher than this in children indicate reduced kidney function.

Serum albumin

The serum albumin level is classically low in nephrotic syndrome, being below its normal range of 3.5-4.5 g/dL. In a single-center study of patients who underwent kidney biopsy for idiopathic proteinuria, Gupta et al found that the frequency of focal and segmental glomerulosclerosis increased to three-quarters of the cases when patients had near-normal serum albumin levels. [36]

Serologic studies

In adults with nephrotic syndrome, tests for hepatitis B and C, HIV, and even syphilis may be useful. Tests for lupus, including antinuclear antibody (ANA), anti–double stranded DNA (anti-dsDNA) antibodies, and complement, may be useful. Testing for antineutrophil cytoplasmic antibodies (ANCA) is not indicated in typical nephrotic syndrome, because that test is associated with rapidly progressive glomerulonephritis, which presents with a nephritic picture rather than one that is typically nephrotic.

Tests for previous streptococcal infection, such as antistreptolysin O, are not usually indicated for nephrotic syndrome, since postinfectious glomerulonephritis usually causes a nephritic rather than a nephrotic syndrome.

Phospholipase A2 receptor

Phospholipase A2 receptor (PLA2 R) is a cell surface transmembrane receptor expressed on the surface of podocytes. Seventy percent of patients with idiopathic membranous nephropathy have autoantibodies directed against PLA2 R. [37] Levels of this antibody have a strong correlation with clinical disease activity and thus help in monitoring disease activity and treatment efficacy. [38]  Absence of these antibodies may suggest secondary membranous nephropathy such as that associated with cancers.

During treatment, the levels of the antibodies generally decline before remission of proteinuria. After treatment, about half the patients who are PLA2R negative remain in remission for 5 years, but those who remain PLA2R positive relapse in just 2 years. Use of the PLA2R antibody test has changed the diagnosis and treatment of idiopathic membranous nephropathy.

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Histologic Findings

These are particular to the causes of nephrotic syndrome, such as minimal change nephropathy, membranous nephropathy, or diabetic nephropathy, and are discussed in the Medscape Reference articles on those conditions.

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Ultrasonography

Ultrasonographic scanning shows whether a patient has two kidneys. 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 (ie, chronic disease with reduced kidney function).

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