Evaluation of proteinuria
Summary
Average daily urinary protein excretion in adults is 80 mg/day, with normal excretion considered to be <150 mg/day.
Albumin represents approximately 15% of the daily urinary protein excretion in healthy people, with other plasma proteins (e.g., immunoglobulins, beta-2-microglobulin) and Tamm-Horsfall protein constituting the remaining 85%.
Proteinuria varies in amount and may be transient or persistent.[1][2]
Urinary excretion of abnormal quantities of protein for ≥3 months, with or without a decrease in glomerular filtration rate (GFR), is diagnostic of chronic kidney disease.[3][4]
Urine albumin measurement is an important component in screening for chronic kidney disease. The presence of proteinuria is an independent risk factor for cardiovascular disease, end-stage renal disease, stroke and death in the general population, and in patients with chronic kidney disease.[5][6][7][8][9][10][11] Presence of proteinuria is associated with a higher mortality in critically ill patients;[12][13] the degree of proteinuria post renal transplantation is predictive of graft and patient survival.[14]
Reduction of proteinuria by pharmacologic therapy is used as a surrogate marker in the management of chronic kidney disease and many acute glomerular diseases, and is associated with improved renal outcomes.[15][16][17][18][19][20][21]
Proteinuria definitions
Total urine protein or just the albumin fraction can be measured. Urine albumin measurements are better validated in regard to association with risk for chronic kidney disease progression and cardiovascular events.
Albuminuria
Albuminuria is graded as follows:[3]
A1 (normal to mildly increased albuminuria)
Albumin excretion rate: <30 mg/24 hours.
Albumin-to-creatinine ratio (ACR): <30 mg/g.
A2 (moderately increased albuminuria)
Albumin excretion rate: 30-300 mg/24 hours.
Albumin-to-creatinine ratio (ACR): 30-300 mg/g.
Associated with increased risk of progressive kidney disease and cardiovascular events.
A3 (severely increased albuminuria)
Albumin excretion rate: >300 mg/24 hours.
Albumin-to-creatinine ratio (ACR): >300 mg/g.
Larger amounts of proteinuria are associated with worse renal survival. These patients should be referred to a nephrologist.
Nephrotic-range proteinuria
Urine total protein: ≥3.5 g/day.
The presence of nephrotic-range proteinuria with edema, hypoalbuminemia (<3.0 g/dL), and hyperlipidemia is defined as nephrotic syndrome.
Glomerular proteinuria
Urine total protein: 1-20 g/day.
Passage of protein from glomerular capillary blood (mainly albumin) into the urine.
Tubular proteinuria
Urine total protein: <2 g/day.
Passage of low molecular weight proteins (e.g., retinol-binding protein, alpha-2-microglobulin, beta-2-microglobulin) into the urine.
Overflow proteinuria
Urine total protein: up to 20 g/day.
Overproduction of small proteins (e.g., myoglobin, light chains) leads to increased glomerular filtration and appearance in the urine.
Dipstick analysis of urine is a useful semiquantitative screening tool for proteinuria. 1+ corresponds to 30 mg/dL protein, 2+ to 100 mg/dL, and 3+ to 300 mg/dL. Very dilute urine can give a false-negative result. Very concentrated urine, alkaline urine, pus, vaginal secretions, or semen can give false-positive results.[22] Standardizing the protein measurement to the quantity of creatinine in the urine helps avoid errors introduced by dilute or concentrated urine samples.
Reagent strips should not be used to identify proteinuria in children and young people (because they are less useful to rule out proteinuria, the main goal, than to rule in proteinuria).[23]
Epidemiology
Proteinuria is common, and prevalence increases with kidney disease progression. There is evidence that both moderately and severely increased albuminuria is more common in black people than in white people.[24]
As the GFR declines from >90 mL/minute/1.73 m² to 15-59 mL/minute/1.73 m², the prevalence of moderately increased albuminuria (ACR <300 mg/g) increases from 6.0% to 23.2%, and the prevalence of severely increased albuminuria (ACR >300 mg/g) increases from 0.6% to 8.6%.[25]
Detection: semiquantitative testing
Semiquantitative urinary dipsticks can report albumin-to-creatinine ratios in the microalbumin range, as well as total protein-to-creatinine ratios.
Standardizing the protein measurement to the quantity of creatinine in the urine helps avoid errors introduced by dilute or concentrated urine samples. If unexplained proteinuria is an incidental finding on a reagent strip, eGFRcreatinine and ACR should be determined to check for CKD.[23]
Measuring total protein also allows detection of tubular and overflow proteinuria. The reported sensitivity of these semiquantitative dipsticks is 80% to 97% with a specificity of 33% to 80%.[26]
Detection: quantitative testing
Quantitative testing of albumin using urine albumin concentration or albumin-to-creatinine ratio is sensitive and specific for detecting albuminuria.[27][28]
Measuring urine albumin concentration without measuring urine creatinine concentration is less expensive, and has demonstrated similar sensitivity and specificity as albumin-to-creatinine ratio for screening purposes in diabetics.[28]
Twenty-four-hour urine collections have traditionally been used, although these collections are prone to over- and undercollection. Moreover, 24-hour urine collections are cumbersome for patients. Reporting the total 24-hour urine protein standardized to the 24-hour urine creatinine (g protein/g creatinine) helps adjust for variations in the duration of collection.
In women, an adequate collection typically has 15 to 20 mg of creatinine per kg of body weight, and in men, 20 to 25 mg/kg.
Alternatively, the expected grams of excreted creatinine can be estimated by 140 minus age multiplied by weight/5000 [(140 - age) × weight/5000], where weight is in kilograms. This result is multiplied by 0.85 in women.[29]
More commonly, a urine protein-to-creatinine ratio or albumin-to-creatinine ratio on a spot urine sample is used to approximate the 24-hour urine protein excretion and 24-hour urine albumin excretion, respectively.[30]
Albumin to creatinine ratio is more sensitive than protein to creatinine ratio in detecting low levels of proteinuria.[23]
A first morning sample most closely estimates 24-hour protein excretion, although a random sample is acceptable if a first morning void is unavailable.[3][29][31]
Because of diurnal variation, it is best to collect spot urine samples at the same time each day if being used to follow up patients long term. Additionally, the correlation of the spot sample with 24-hour protein excretion is less robust with nephrotic-range proteinuria. The spot ratio may also be less accurate in pregnant women with >300 mg of proteinuria.[32][33]
People with body surface areas of 1.73 m² excrete roughly 1 g of creatinine. As such, a protein-to-creatinine ratio of 1 g protein/g creatinine in an average-sized person approximates 1 g of proteinuria in 24 hours. It is important to recognize that a ratio of 2.5 g protein/g creatinine in a muscular person who excretes 2 g of creatinine in 24 hours may actually represent nephrotic-range proteinuria of 5 g/day. Similarly, an older, frail woman may excrete <1 g of creatinine per day, and in this setting, the spot ratio would overestimate her proteinuria.
Effect of albuminuria on prognosis of chronic kidney disease
Albuminuria is an independent risk factor for the progression of chronic kidney disease.[34] Severely increased levels of albuminuria in the setting of normal GFR may impart a greater risk for progressive chronic kidney disease than mildly reduced GFR with normoalbuminuria. [Figure caption and citation for the preceding image starts]: Prognosis of CKD by GFR and albuminuria category: CKD, chronic kidney disease; GFR, glomerular filtration rate; KDIGO, Kidney Disease Improving Global OutcomesReprinted by permission from Macmillan Publishers Ltd: Kidney International Supplements (vol 3, issue 1, January 2013), copyright 2013 [Citation ends].
In patients with advanced CKD, proteinuria is the strongest predictor of time to end-stage renal disease.[35][36] Moreover, changes in ACR correlate with the risk of developing end-stage renal disease.[37][38]
Differentials
Common
- Fever
- Heavy physical exertion
- Urinary tract infection
- Urologic hemorrhage
- Orthostatic proteinuria
- Minimal change disease
- Focal segmental glomerulosclerosis
- Membranous nephropathy
- Membranoproliferative glomerulonephritis
- IgA nephropathy
- Systemic lupus erythematosus
- Postinfectious glomerulonephritis
- Acute tubular injury
- Interstitial nephritis
- Urinary tract obstruction
- Metabolic syndrome
- Diabetic nephropathy
- Hypertension
- Medium- and small-vessel vasculitis
- Rhabdomyolysis (myoglobinuria)
Uncommon
- Pregnancy
- Amyloidosis
- Light and heavy chain deposition diseases
- Fibrillary and immunotactoid glomerulopathy
- Antiglomerular basement membrane (anti-GBM) disease (Goodpasture syndrome)
- Fanconi syndrome
- Cystic kidney disease
- Hypercalciuria
- Dent disease
- Aristolochic acid nephropathy
- Light chain cast nephropathy
- Fabry disease
- Hemolytic uremic syndrome (HUS)
- Thrombotic thrombocytopenic purpura (TTP)
- Scleroderma renal crisis
- Heavy metal poisoning
- Idiopathic nodular glomerulosclerosis
- Proliferative glomerulonephritis with monoclonal IgG deposits
- Polymyositis
- Renal vein thrombosis
Contributors
Authors
Sana Waheed, MD
Staff Nephrologist
Piedmont Nephrology and Internal Medicine
Atlanta
GA
Disclosures
SW declares that she has no competing interests.
Acknowledgements
Dr Sana Waheed would like to gratefully acknowledge Dr Derek M. Fine and Dr C. John Sperati, previous contributors to this topic.
Disclosures
DMF is an author of a reference cited in this topic. CJS declares that he has no competing interests.
Peer reviewers
Mark Perazella, MD
Associate Professor
Yale University School of Medicine
New Haven
CT
Disclosures
MP declares that he has no competing interests.
Arif Showkat, MD, FASN
Assistant Professor
Division of Nephrology
University of Tennessee
Memphis
TN
Disclosures
AS declares that he has no competing interests.
Guy Neild, MD, FRCP, FRCPath
Professor of Nephrology
Institute of Urology and Nephrology
University College London
London
UK
Disclosures
GN declares that he has no competing interests.
Frederick Tam, MBBS
Senior Lecturer in Renal Medicine
Division of Medicine
Imperial College London
UK
Disclosures
FT has received travelling grants from Amgen, MSD, Novartis, and Roche to attend International Nephrology conferences. He has also received research grants from Wellcome Trust, Medical Research Council UK, Baxter Biosciences, and Roche Palo Alto. He has also provided consultancy to research work with GE Healthcare and Baxter Biosciences.
Patient leaflets
Glomerulonephritis
Preeclampsia: what is it?
More Patient leafletsVideos
Venepuncture and phlebotomy: animated demonstration
More videos
Log in or subscribe to access all of BMJ Best Practice
Use of this content is subject to our disclaimer