Approach
The clinical distinction between nephrotic syndrome and nephritic syndrome can be ambiguous; therefore, on rare occasions, diseases with a typically nephritic presentation may present with a nephrotic picture.
In most cases, however, family history, drug history, symptom history, examination, and investigations (including renal biopsy) lead to the diagnosis of an underlying cause for nephrotic syndrome.
Initial evaluation includes:
Careful history and physical examination (see below).
Quantification of proteinuria by spot urine protein-to-creatinine ratio ((urine [PCR]) on a random urine specimen. A 24-hour urine collection is no longer part of routine practice and is not necessary.
Urinalysis (fresh urine) with microscopy to check for the presence of cellular casts. Urine should also be sent for urine protein electrophoresis.
Serological studies, including:
Auto-immune screen (ANA, dsDNA, ANCA, anti-phospholipase A2-receptor antibody, complement screen (C3, C4), cryoglobulins)
Protein electrophoresis, serum free light chains
Syphilis serology
Hepatitis B and C serology, HIV.
In children or young adults with steroid-resistant nephrotic syndrome (SRNS), a genetic panel investigating possible mutations should be considered.
Renal biopsy to determine the type of nephrotic syndrome. This test should always be performed in consultation with a nephrologist. Renal biopsy is not usually performed in children with minimal change disease (MCD) who are steroid-sensitive (steroid-sensitive nephrotic syndrome [SSNS]).[20]
History
The principal symptoms of nephrotic syndrome are oedema and foamy urine. The oedema, which starts in the legs, may be severe, involving the entire body.
Patients may also have symptoms suggestive of occult malignancy (e.g., cough, weight loss, night sweats, a change in bowel habit, gastrointestinal blood loss), systemic lupus erythematosus (SLE) (e.g., rash, mouth ulcers, or arthralgias), or Fabry's disease (e.g., painful neuropathy). Family history of Fabry's disease, amyloidosis, or any other renal disease should be noted.
Past medical history may include long-standing diabetes, end-organ damage (e.g., retinopathy), malignancy, SLE, viral infections, chronic bacterial infections, multiple myeloma, connective tissue diseases, or amyloidosis.
A full drug history should be taken. Some drugs (e.g., pamidronate, gold, penicillamine, or non-steroidal anti-inflammatory drugs [NSAIDs], and very rarely interferon alfa, lithium, or heroin) may be associated with nephrotic syndrome.[62] Illicit use of Chinese herbs or mercurial skin-lightening creams must be considered.
Common causes of nephrotic syndrome, such as MCD or focal segmental glomerulosclerosis (FSGS), are relapsing diseases.[31][63][64] Relapse rate is high.
Physical examination
Patients generally have mild oedema of the legs or severe oedema involving the entire body (anasarca). Swelling is more likely to involve the face, particularly peri-orbital oedema, than in patients with other causes of oedema (such as congestive heart failure or severe hepatic disease). Monitoring weight is helpful to assess fluid overload and response to treatment. Patients may have white banding of the nails from hypoalbuminaemia (known as Muehrcke's lines). Protein malnutrition leads to a loss in lean body mass in heavy proteinuria, but this is often concealed by weight gain due to simultaneous oedema. Additionally, patients may have xanthelasmata from severe hypercholesterolaemia.
These physical findings are useful for aiding diagnosis of nephrotic syndrome, but they are not useful for determining the cause.
Physical findings that may help to determine the cause of nephrotic syndrome include:
rash with possible arthralgia (consistent with SLE)
easy bruising and neuropathy (consistent with amyloidosis)
haem-positive stool (consistent with gastrointestinal malignancy), or
evidence of diabetic retinopathy (revealed during fundoscopic examination).
Laboratory evaluation
Proteinuria should be quantified by spot urine PCR ratio (mg/micromol). A urine PCR >300 mg/micromol is diagnostic for nephrotic-range proteinuria.
A fresh urine sediment preparation should be evaluated under a microscope. The presence of lipid droplets, oval fat bodies, birefringent Maltese cross, lipid laden casts, or cholesterol crystals suggests nephrotic syndrome.[65][66] Patients with nephrotic syndrome will typically have few cellular casts present in the urine.
All patients should have an assessment of basic blood biochemistries including renal function, FBC, lipid profile (typically total and LDL cholesterol levels are elevated in nephrotic syndrome), and serum albumin. Thyroid hormone testing may be abnormal due to urinary loss of thyroid hormones and thyroxine binding globulin.
Other laboratory tests
Tests to differentiate the cause of nephrotic syndrome, and that may prevent the need for renal biopsy, include:
Serum free light chains and urine protein electrophoresis
HIV test
Hepatitis serologies
Serum complement levels
Syphilis test (RPR)
Cryoglobulins, or antinuclear antibodies (ANA): measurement of cryoglobulins is particularly relevant in cases of suspected myeloma where a renal biopsy may delay the initiation of urgent chemotherapy. In this scenario, a renal biopsy may not add to the diagnosis of myeloma; however, serum free light chains are diagnostic.
Anti-phospholipase A2 receptor (PLA2R) antibody: renal biopsy is recommended in patients with a high anti-PLA2R antibody titre and abnormal renal function; renal biopsy may not be required in patients with a high anti-PLA2R antibody titre and preserved renal function.
Imaging studies
May be needed if malignancy is suspected (e.g., as a cause of membranous nephropathy). Underlying adenocarcinomas of the gastrointestinal tract/abdomen are associated with glomerular disease.[67] The choice of imaging and other studies will depend on the clinical presentation.
Renal ultrasound can assist in some diagnoses (e.g., small asymmetric kidneys can be seen in a secondary FSGS process, due to hyperfiltration of the remaining nephrons in renal dysplasia).
It is mandatory to use ultrasound (or other renal imaging) to assess kidney size to ensure it is safe to proceed with a renal biopsy. Small kidneys increase the risk of post-biopsy bleeding requiring renal arterial embolisation, or much more rarely, requiring an emergency nephrectomy if embolisation fails to stop the bleeding. The risk of a bleeding complication is higher when there is evidence of chronicity and small kidneys with a potentially lower diagnostic yield due to scarring and chronic renal damage. These risks must be weighed against the importance of discovering, and potentially treating, the underlying cause.
Renal biopsy
In children, almost all cases of nephrotic syndrome are due to MCD. Therefore, many paediatric nephrologists treat the patient for MCD with empirical corticosteroids. The International Pediatric Nephrology Association recommends starting corticosteroids without a renal biopsy in patients aged 1-12 years, unless there is a family history of SRNS, or atypical or extra-renal features.[20]
Renal biopsy is not usually performed if children with MCD are steroid-sensitive (SSNS).[20] Children with SRNS undergo renal biopsy, with the pathology most likely to be FSGS.
In adults, MCD is relatively uncommon and patients require a renal biopsy for definitive diagnosis, as history, physical examination, and laboratory evaluation are often not useful for differentiating the underlying cause.[68]
Early consultation with a kidney specialist is recommended. It may be wise to discontinue any anticoagulation therapy early to avoid delaying a renal biopsy. This must be considered carefully and a full risk-benefit analysis should be undertaken.
Contraindications to percutaneous renal biopsy include:[69]
Bleeding diathesis resistant to correction
Multiple, bilateral renal cysts
Renal tumour
Hydronephrosis
Active renal infection
Small kidneys secondary to chronic irreversible disease
Severe and resistant hypertension.
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