Summary
Proteinuria is common, and prevalence increases with kidney disease progression. It is often diagnosed incidentally on routine dipstick testing of urine samples; an appropriate index of suspicion is required to specifically request urinalysis for protein measurement.
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] It is important to distinguish benign, self-limiting etiologies from more significant illness. New-onset proteinuria with features of systemic disease (e.g., progressive renal dysfunction, other organ system abnormalities) should be evaluated as soon as possible.
Kidney Disease Improving Global Outcomes (KDIGO) defines chronic kidney disease (CKD) as abnormalities of kidney structure or function, present for ≥3 months.[3] Albuminuria (albumin-to-creatinine ratio ≥30 mg/g) is one of the markers of kidney damage. CKD is classified based on cause, glomerular filtration rate (GFR) category and albuminuria category.[3]
Urine albumin measurement is an important component in screening for CKD. 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 CKD.[4][5][6][7][8][9][10] Presence of proteinuria is associated with a higher mortality in critically ill patients; the degree of proteinuria post renal transplantation is predictive of graft and patient survival.[11][12][13]
Reduction of proteinuria by pharmacologic therapy is used as a surrogate marker in the management of CKD and many acute glomerular diseases, and is associated with improved renal outcomes.[14][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 CKD 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.
ACR: 30-300 mg/g.
A3 (severely increased albuminuria)
Albumin excretion rate: >300 mg/24 hours.
ACR: >300 mg/g.
Nephrotic-range proteinuria
Urine total protein: ≥3.5 g/day.[21]
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.
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.[22]
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%.[23]
Effect of albuminuria on prognosis of chronic kidney disease
Albuminuria is an independent risk factor for the progression of CKD.[24] Severely increased levels of albuminuria in the setting of normal GFR may impart a greater risk for progressive CKD 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.[25][26] Moreover, changes in ACR correlate with the risk of developing end-stage renal disease.[27][28]
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 diseases
- 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
Associate Professor of Medicine
Emory University Division of Nephrology
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
Naveen Punchayil Narayanankutty, MD
Program Director of Nephrology
University of South Florida
Tampa
FL
Disclosures
NPN declares that he has no competing interests.
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.
References
Key articles
Kidney Disease: Improving Global Outcomes. KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease. Apr 2024 [internet publication].Full text
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021 Oct;100(4s):S1-276.Full text
National Institute for Health and Care Excellence. Chronic kidney disease: assessment and management. Nov 2021 [internet publication].Full text
Reference articles
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