Approach
Proteinuria is often diagnosed incidentally on routine dipstick testing of urine samples. At other times, an appropriate index of suspicion is required to specifically request urinalysis for protein measurement. It is important to distinguish benign, self-limiting aetiologies from more significant illness. Although the list of differential diagnoses for proteinuria includes almost all aetiologies of kidney disease, it is useful to consider several principles when assessing proteinuria:
in general, diseases that affect pre-glomerular structures (e.g., medium-vessel vasculitis, heart failure), macroscopic structural abnormalities (e.g., cystic kidney disease, urinary tract obstruction), lower urinary tract infection, ischaemia, and medication toxicity result in minimal to low-grade proteinuria
aetiologies of significant proteinuria typically include glomerular diseases and plasma cell dyscrasias
the presence of haematuria with overt proteinuria suggests glomerulonephritis.
Although exceptions do exist, it is helpful to work within this framework.
Proteinuria itself typically has few signs or symptoms. Nephrotic-range proteinuria may, on occasion, result in foamy urine, although normal rates of protein excretion can also produce foam if the urine is highly concentrated. Nephrotic-range proteinuria may cause oedema, pleural effusions, and ascites, with resultant swelling, shortness of breath, and abdominal distention. Patients with persistent nephrotic-range proteinuria can lose weight and become more susceptible to infection.
History
A detailed history taking is key when investigating the cause of proteinuria.
Symptom history
Transient symptoms include fever, recent strenuous exercise, dysuria, urgency, frequency, foul-smelling/cloudy urine, and/or trauma. May develop alongside transient proteinuria (from fever, heavy physical exertion, urinary tract infection, urological haemorrhage, orthostatic proteinuria).
Symptoms of persistent proteinuria vary according to the cause:
Swelling: may be a symptom of minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, systemic lupus erythematosus (SLE), postinfectious glomerulonephritis, amyloidosis, light and heavy chain deposition diseases, fibrillary and immunotactoid glomerulopathy, light chain cast nephropathy, haemolytic uremic syndrome (HUS), or thrombotic thrombocytopenic purpura (TTP).
Gross haematuria: may present in patients with IgA nephropathy, anti-glomerular basement membrane (anti-GBM) disease (Goodpasture's syndrome), cystic kidney disease, or aristolochic acid nephropathy.
Pain: may be a symptom of cystic kidney disease, urinary tract obstruction, medium- and small-vessel vasculitis, heavy metal poisoning, renal vein thrombosis, and rhabdomyolysis. Patients with Fabry's disease may have a burning sensation of the hands with exercise and heat.
Altered bowel habit: may be a symptom of hypercalciuria (constipation) and HUS (diarrhoea).
Seizures: may be symptoms of TTP and SLE.
Polyuria: may be a symptom of hypercalciuria, Dent's disease, and urinary tract obstruction.
Ocular symptoms: may be present in patients with Fabry's disease, diabetic nephropathy, hypertension, and cystic kidney disease.
Respiratory symptoms: may be associated with medium- and small-vessel vasculitis, IgA nephropathy, and sclerodermal renal crisis.
Past medical history
It is important to enquire about previous medical history. Some examples include:
Diabetes and retinopathy
Upper respiratory infection
Gastrointestinal disorders: Crohn’s disease, coeliac disease, gastrointestinal dysmotility, diarrhoea
Hypertension
Malignancy: lymphoma (and stem cell transplant), multiple myeloma
Infective disorders: including streptococcal or staphylococcal infection, HIV, hepatitis B, hepatitis C, syphilis, endocarditis, recent Escherichia coli infection
Haematological disorders: cryoglobulinaemia, thrombotic microangiopathy, monoclonal gammopathy, anaemia, prior history of HUS/TTP, prior bone marrow transplant
Renal: rapidly progressive renal failure, recent nephrotoxic injury (such as hypotension, mechanical ventilation, and ischaemia), renal stones, acute renal failure, chronic renal failure, nephrocalcinosis, childhood nephronophthisis
Endocrine: insulin resistance/diabetes, dyslipidemia, obesity
Autoimmune/inflammatory: SLE, familial Mediterranean fever, sarcoidosis, Sjogren's disease, scleroderma
Ophthalmological: eye disorders, uveitis
Musculoskeletal: arthritis, rickets
Urogynaecological: benign prostatic hypertrophy, urinary retention, gynaecological malignancy
Neurological: cerebrovascular accident, neuropathy, headache
Cardiovascular: peripheral and coronary arterial disease, congestive heart failure
Trauma: recent crush injury, prolonged immobility
Other: hypohidrosis, pregnancy, postpartum state, multi-organ disorder
Family history
Atypical HUS/TTP
Fanconi syndrome
Dent's disease.
Occupational/social history
Industrial/environmental exposures to old paint is a common source for heavy metal (lead) poisoning.
Heavy metal exposure may be associated with Fanconi syndrome.
Patients with anti-GBM disease (Goodpasture's syndrome) and idiopathic nodular glomerulosclerosis often have positive smoking histories.
Medication history
Non-steroidal anti-inflammatory drugs (NSAIDs), interferon, and lithium may be associated with minimal change disease.
Bisphosphonates may be associated with focal segmental glomerulosclerosis.[47][48]
NSAIDs, gold, and penicillamine may be associated with membranous nephropathy.[49]
NSAIDs, aminoglycosides, amphotericin B, zoledronic acid, oral phosphate bowel preparations, and intravenous contrast may be associated with acute tubular injury.
NSAIDs, antibiotics, allopurinol, and proton pump inhibitors may be associated with interstitial nephritis.
Medications such as tenofovir may be associated with Fanconi syndrome.
Aristolochic acid and other weight loss medications may be associated with aristolochic acid nephropathy (previously called Chinese herb nephropathy).[50] Aristolochic acid weight loss medications may also be associated with tubulointerstitial disease.
Ciclosporin, clopidogrel, gemcitabine, and bevacizumab (vascular endothelial growth factor inhibitor) may be associated with HUS or TTP.
Prednisone may be associated with scleroderma renal crisis.[51]
Statins may be associated with rhabdomyolysis.
Bevacizumab is associated with hypertension and high-grade proteinuria.[52]
History of illicit drug use
Heroin use may be associated with focal segmental glomerulosclerosis.[53]
Illicit/adulterated alcohol may be a source for heavy metal (lead) poisoning.
Other factors to consider
Age
Proteinuria in children and adolescents is commonly due to orthostatic proteinuria and minimal change disease.[56]
Minimal change disease and membranous nephropathy are also common in older patients.[57][58][59]
Ethnicity
Physical examination
Signs of transient proteinuria (from fever, heavy physical exertion, urinary tract infection, urological haemorrhage, orthostatic proteinuria) are present.
They may include elevated temperature >38.0°C (100.4°F), flank pain (if pyelonephritis), bladder tenderness on palpation, and/or gross haematuria.
There are no specific findings for heavy physical exertion or orthostatic proteinuria.
Signs of persistent proteinuria vary according to the cause.
Fever may be a sign of interstitial nephritis, Fabry's disease, HUS, or TTP.
Volume overload (in the form of pleural effusion, ascites, or peripheral oedema) may be a sign of minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, SLE, post-infectious glomerulonephritis, amyloidosis, light and heavy chain deposition diseases, fibrillary and immunotactoid glomerulopathy, light chain cast nephropathy, HUS, or TTP.
Hypertension may cause proteinuria or may be a sign of other causes, including HUS, TTP, scleroderma renal crisis, glomerular disease, IgA nephropathy, SLE, post-infectious glomerulonephritis, amyloidosis, light and heavy chain deposition disease, fibrillary and immunotactoid glomerulopathy, light chain cast nephropathy, metabolic syndrome, and Fabry's disease.
Neurological weakness may be a sign of hypercalciuria, heavy metal poisoning, SLE, diabetic neuropathy, or medium- and small-vessel vasculitis.
Altered mental status may be a sign of hypercalciuria, TTP, medium- and small-vessel vasculitis, heavy metal poisoning, or SLE.
High BMI may be a sign of metabolic syndrome, Fabry's disease, or focal segmental glomerulosclerosis.
Rash may be a sign of membranoproliferative glomerulonephritis, cryoglobulinaemia, interstitial nephritis, HUS, TTP, medium- and small-vessel vasculitis, heavy metal poisoning, Fanconi syndrome, or SLE. Vasculitis typically causes a purpuric rash. Patients with SLE may have a butterfly-shaped facial rash or a discoid rash of erythematous raised patches.
Who to test
Patients who have persistent proteinuria on a urine dip test
Patients with chronic kidney disease
Patients with hypertension
Require screening for moderately increased albuminuria at diagnosis and then annually in high-risk groups (e.g., diabetes mellitus, reduced kidney function).[65]
Patients with type 1 diabetes mellitus
Require annual screening with a spot urinary albumin-to-creatinine ratio from 5 years after diagnosis.[66]
Patients with type 2 diabetes mellitus
Require annual screening with a spot urinary albumin-to-creatinine ratio.[66]
Screening should constitute part of the assessment of patients with metabolic syndrome, oedema, acute kidney injury, haematuria, or systemic disease (e.g., cirrhosis, HIV infection, vasculitis). and patients taking medicines that can affect kidney function.[23]
Routine testing of the general population is not recommended by professional societies.
The frequency of follow-up protein measurement varies on the basis of the clinical scenario. Formal guidelines recommend yearly measurement in patients with diabetes mellitus and high-risk patients with hypertension.[65][66] Although specific recommendations do not exist for patients with abnormal renal function, in general, patients are typically re-evaluated and protein excretion remeasured 3 to 4 times per year. A particular patient may require more- or less-frequent monitoring depending on their circumstances.
How to test
Initial tests
All patients should have a spot urine albumin-to-creatinine ratio (ACR), serum creatinine measurement and estimation of glomerular filtration rate.
A confirmed ACR of >30 mg/g (3 mg/mmol) is regarded as clinically important. A spot urine ACR between 30 mg/g (3 mg/mmol) and 700 mg/g (70 mg/mmol) should be repeated on a first void sample. If the ACR is >700 mg/g (70 mg/mmol) the test does not need to be repeated.[23] This test is more sensitive for detecting low levels of albuminuria than protein-to-creatinine ratio.[23]
Albuminuria is graded as follows:[3]
A1 (normal to mildly increased albuminuria)
Albumin excretion rate: <30 mg/24 hours
ACR: <30 mg/g
A2 (moderately increased albuminuria)
Albumin excretion rate: 30-300 mg/24 hours
ACR: 30-300 mg/g
A3 (severely increased albuminuria)
Albumin excretion rate: >300 mg/24 hours
ACR: >300 mg/g
The work-up of proteinuria is similar for glomerular, tubular, and overflow proteinuria. Further laboratory assessment is directed by the results of a comprehensive history and physical examination. Unless the clinical history overwhelmingly supports tubular proteinuria, glomerular proteinuria is typically assessed first.
Spot protein-to-creatinine ratio
When ACR is 70 mg/mmol or more, protein:creatinine ratio can be used as an alternative to ACR.[23]
Urine dipstick
Positive for protein
Can detect haematuria, pyuria, nitrites, and glucose
Not recommended for screening populations at risk of proteinuria (e.g., patients with diabetes or chronic kidney disease)[67]
If proteinuria is present in 2 urine samples 1 to 2 weeks apart, follow-up with quantitative testing.[3]
24 hour urine collection
An alternative to serum creatinine and estimated glomerular filtration rate (GFR), although more cumbersome for the patient
May show normal or decreased creatinine clearance
In patients with a GFR >60 mL/minute/1.73 m², Modification of Diet in Renal Disease (MDRD) may underestimate true kidney function. For these patients, 24-hour urine collection for measurement of creatinine clearance may be more accurate.
Tests for metabolic or cardiovascular disease
Fasting plasma glucose ≥7.0 mmol/L (≥126 mg/dL), HbA1c ≥48 mmol/mol, or 2-hour plasma glucose ≥11.1 mmol/L (200 mg/dL) during oral glucose tolerance test indicates diabetes mellitus[68]
Elevated triglycerides ≥1.7 mmol/L (≥150 mg/dL) or reduced HDL <1.03 mmol/L (<40 mg/dL) (men) or <1.3 mmol/L (<50 mg/dL) (women) indicates metabolic syndrome[69]
Blood pressure: systolic BP ≥130 mmHg or diastolic BP ≥85 mmHg indicate metabolic syndrome[69]
Echocardiogram: may show evidence of left ventricular dysfunction.
Tests for overt proteinuria
Complete blood count with differential: may show anaemia in chronic kidney disease
HIV, hepatitis B and hepatitis C serology: if there is suspicion of infection
Antinuclear antibodies and anti-double stranded DNA antibodies: if there is clinical suspicion of systemic lupus erythematosus (SLE)
CH50, C3, and C4: if there is clinical suspicion of SLE, post-infectious glomerulonephritis, cryoglobulinaemia/hepatitis C, or membranoproliferative glomerulonephritis. CH50, C3 and C4 are low in SLE
Antineutrophil cytoplasmic antibody (ANCA): if ANCA-associated vasculitis is suspected
Serum and urine protein electrophoresis with immunofixation/serum-free light chain measurement: may detect a paraprotein if there is a plasma cell dyscrasia
Rheumatoid factor: if there is clinical suspicion of cryoglobulinaemia or hepatitis C
Cryoglobulins: if there is clinical suspicion of hepatitis C or cryoglobulinaemic vasculitis
Anti-glomerular basement membrane (anti-GBM) antibody: if there is clinical suspicion of anti-GBM disease (Goodpasture syndrome)
Renal ultrasound: may identify structural abnormality or obstruction of the urinary tract
Renal biopsy: may be required for prognostic and therapeutic decision-making, and to secure a diagnosis if one is not readily apparent from history and serological testing.
Tests for suspected tubular proteinuria
Heavy metal screening: if heavy metal poisoning is suspected
Evaluation for glucosuria, phosphaturia, and renal tubular acidosis: if Fanconi syndrome is suspected. All 3 are present in the setting of tubular proteinuria
Urinary albumin/beta-2-microglobulin: ratio of approximately 1 to 13 is consistent with tubular proteinuria.
If orthostatic proteinuria is suspected, the protein-to-creatinine ratio in a first morning voided urine specimen should be compared with the ratio from a random sample later in the day. The absence of proteinuria in the morning sample and presence of proteinuria in the later (daytime) sample confirms orthostatic proteinuria.
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