How do you diagnose Nephrotic Syndrome (a collection of symptoms indicating severe damage to the kidneys' glomeruli, including massive proteinuria, hyperlipidemia, and edema)?

From the Guidelines

Nephrotic syndrome is diagnosed through a combination of clinical evaluation, laboratory tests, and sometimes kidney biopsy, with a focus on identifying heavy proteinuria, hypoalbuminemia, edema, and hyperlipidemia. The diagnosis of nephrotic syndrome requires a comprehensive approach, including:

• Clinical evaluation to identify signs and symptoms such as edema, weight gain, and fatigue
• Laboratory tests, including:

• Urinalysis to detect protein
• 24-hour urine collection to quantify protein excretion (or a spot urine protein-to-creatinine ratio) 1
• Serum albumin levels
• Lipid panel
• Basic metabolic panel

• Additional blood tests to consider, including:

• Complement levels
• Antinuclear antibodies
• Hepatitis serologies
• HIV testing to help identify underlying causes

• Kidney function assessment with serum creatinine and estimated glomerular filtration rate
• Kidney biopsy to determine the specific cause of nephrotic syndrome, such as minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or other glomerular diseases 1

The diagnosis of nephrotic syndrome is typically made when there is evidence of heavy proteinuria (>3.5g/24 hours), hypoalbuminemia (<3.5g/dL), edema, and hyperlipidemia. The 2012 KDIGO clinical practice guideline for glomerulonephritis recommends that initial therapy be started only in patients with nephrotic syndrome and when at least one of the following conditions is met:

• Urinary protein excretion persistently exceeds 4 g/day and remains at over 50% of the baseline value, and does not show progressive decline during antihypertensive and antiproteinuric therapy during an observation period of at least 6 months 1
• The presence of severe, disabling, or life-threatening symptoms related to the nephrotic syndrome
• SCr level has risen by 30% or more within 6 to 12 months from the time of diagnosis but the estimated glomerular filtration rate (eGFR) is not less than 25–30 ml/min per 1.73 m2 and this change is not explained by superimposed complications.

In children, minimal change disease is the most common cause, and empiric steroid therapy may be initiated without biopsy, whereas adults typically require biopsy for definitive diagnosis. The Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis also recommends that initial therapy be started only in patients with nephrotic syndrome and when at least one of the following conditions is met 1.

From the FDA Drug Label

To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus The diagnosis of nephrotic syndrome is not directly addressed in the provided drug label, but it mentions the use of prednisone to induce a diuresis or remission of proteinuria in the nephrotic syndrome.

• The drug label does not provide information on how to diagnose nephrotic syndrome, only its treatment.
• Nephrotic syndrome diagnosis is not discussed in the label. 2

From the Research

Diagnosis of Nephrotic Syndrome

To diagnose nephrotic syndrome, the following criteria are used:

• Oedema, substantial proteinuria (> 3.5 g/24 hours), and hypoalbuminaemia (< 30 g/L) 3
• Proteinuria should be documented by a quantitative measurement, such as urine protein: creatinine ratio (PCR) or albumin: creatinine ratio (ACR) 3
• A PCR > 300-350 mg/mmol indicates nephrotic range proteinuria 3

Clinical Features

The clinical features of nephrotic syndrome include:

• Periorbital oedema (most noticeable in the morning) or dependent pitting oedema (more common later in the day) 3
• Fatigue, without evidence of heart failure or severe liver disease 4
• Hyperlipidaemia, thromboembolism, and an increased risk of infection 3

Diagnostic Tests

The following diagnostic tests are used to diagnose nephrotic syndrome:

• Urine protein analysis using the sulphosalicylic acid method and creatinine estimation by a modified Jaffe's method 5
• Spot urine examination to detect proteinuria, which is a simpler and less time-consuming method than 24-hour urinary protein excretion 5, 6
• Renal biopsy to establish the form of glomerular disease responsible for the nephrotic syndrome 3, 4

Quantitation of Proteinuria

The quantitation of proteinuria in nephrotic syndrome can be done by:

• 24-hour urine collection, which is the accepted method of evaluation 7, 6
• Spot urinary protein/creatinine ratio (P/C ratio) estimation, which correlates well with the 24-hour urine protein excretion 5, 6
• Urinary dipstick, which can be used to detect proteinuria, but is less accurate than the P/C ratio 6

Threshold Levels

The threshold levels for nephrotic-range proteinuria and albuminuria are:

• Urine total protein level of 3.5 g/d, which is equivalent to urine albumin level of 2.2 g/d 7
• Protein-creatinine ratio greater than 3.5 g/g, which indicates nephrotic-range proteinuria 7