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Revision as of 17:05, 25 July 2018

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

Synonyms and keywords: Elevated urinary protein levels; Elevated urine protein

To view a comprehensive algorithm of common findings of urine composition and urine output, click here

Overview

Proteinuria (from protein and urine) means the presence of an excess of serum proteins in the urine.^[1] The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine (bilirubinuria),^[2] retrograde ejaculation,^[3] pneumaturia (air bubbles in the urine) due to a fistula,^[4] or drugs such as pyridium.^[5]

Classification

Types	Definition	Level of proteinuria
Glomerular proteinuria	Increased filtration rate of protein through capillary-glomerular barrier	Variable, usually > 2g/day Dipstick:Positive
Tubular proteinuria	Decreased tubular reabsorption of low molecular weight proteins like β 2-microglobulin, polypeptides, immunoglobulin (light chains), binding proteins	< 2 g/day Dipstick:Negative
Overflow proteinuria	Increased excretion of proteins filtered through glomerular filtration due to exceeding the reabsorption capacity of renal tubules	Variable up to 20g/day Dipstick:Negative
Post-renal proteinuria	Increased urinary excretion of small amount of proteins especially IgA and IgG	Variable, usually < 1g/day
Isolated proteinuria	Normal urinary sediment with no history of renal disease Excluding criteria: Proteinuria (≥ 3.5 g/day), edema, hypoalbuminemia, lipiduria, active urine sediment (red blood cells and/or cast), decreased GFR, hypertension	< 2 g/day


Proteinuria	Amount
Normal range	Total protein excretion in urine (proteinuria): < 150 mg/day, average 80 mg/day Albumin excretion: < 20 mg/day (15 mcg/min), 15% of urine total protein (remaining 85% constitutes Tamm-Horsfall proteins) ^[6] ^[7] (The rate of proteinuria increases proportionally with age and body weight)
Albuminuria (microalbuminuria)	30-300 mg/day (20 to 200 mcg/min)
Overt proteinuria (macroalbuminuria)	Albuminuria > 300 mg/day (200 mcg/min) up to 3500 mg/day, positive dipstick
Nephrotic range	Total protein excretion: ≥ 3.5 g/day

Pathophysiology

The mechanism of proteinuria is dependent of two factors: glomerular wall and tubular reabsorption.

Causes


Classification	Etiology
Glomerular proteinuria	Diabetic nephropathy, orthostatic proteinuria, glomerulonephropathies, hypertensive nephrosclerosis Transient: Exercise-induced proteinuria, fever, Infection, heart failure, joint inflammation, hyperlipidemia( LDL > 120 mg/dL), hyperglycemia (HbA1c > 8%), hypertension (BP >160/100 mmHg)
Tubular proteinuria	Tubulointerstitial diseases, cryoglobulinemia, Sjögren's syndrome, immunosuppresive agents, analgesic use
Overflow proteinuria	Light chains of immunoglobulins in multiple myeloma, lysozyme (AML), myoglobin (rhabdomyolysis), and free hemoglobin not bound to haptoglobin (intravascular hemolysis)
Post-renal proteinuria	Nephrolithiasis, urinary tract tumors or infections
Isolated proteinuria
Microalbuminuria	Essential hypertension, early diabetes, early stages of glomerulonephritis (especially with active sediments;RBCs, RBC casts)
Macroalbuminuria	Fever,exercise, CHF, orthostatic proteinuria, intermittent proteinuria, kidney disease associated with myeloma, all diseases which are mentioned as the causes of microalbuminuria
Nephrotic range proteinuria	Diabetes, minimal change disease, amyloidosis, FSGS, membranous glomerulopathy, IgA nephropathy

Common Causes

Renal disease

Genetics

Risk Factors

Race and ethnicity
Obesity
Age
Medications

Associated Conditions

Proteinuria may be a sign of renal (kidney) damage. Since serum proteins are readily reabsorbed from urine, the presence of excess protein indicates either an insufficiency of absorption or impaired filtration. Diabetics may suffer from damaged nephrons and develop proteinuria.

With severe proteinuria, general hypoproteinemia can develop which results in diminished oncotic pressure. Symptoms of diminished oncotic pressure may include ascites, edema, and hydrothorax.

Natural History, Complications, and Prognosis

Complications

Pulmonary edema
Renal failure
Increased risk of infections
Increased risk of thromboembolic events
Increased risk of cardiovascular disease

Prognosis

Proteinuria is an independent risk factor for developing cardiovascular disease and end stage renal disease ^[8].
Higher amounts of albuminuria, even in normal range is associated with an increased risk of cardiovascular events.
The presence of proteinuria in transplant patients predicts graft and patients survival.
Treatment of proteinuria in patients with chronic renal disease improves outcomes.

Diagnosis

Diagnostic Study of Choice

Urine dipstick:

Sulfosalicylic acid test:

Laboratory Findings

Proteinuria is often diagnosed by a simple dipstick test although it is possible for the test to give a false negative even with nephrotic range proteinuria if the urine is dilute. False negatives may also occur if the protein in the urine is composed mainly globulins or Bence-Jones Proteins because the reagent on the test strips, Bromphenol blue, is highly specific for albumin. ^[9]^[10] Traditionally dipstick protein tests would be quantified by measuring the total quantity of protein in a 24-hour urine collection test, and abnormal globulins by specific requests for Protein electrophoresis.^[11]^[12]

Alternatively the concentration of protein in the urine may be compared to the creatinine level in a spot urine sample. This is termed Protein/Creatinine Ratio (PCR). The 2005 UK Chronic Kidney Disease guidelines states that PCR is a better test than 24 hour urinary protein measurement. Proteinuria is defined as a Protein:creatinine ratio >45 mg/mmol (which is equivalent to Albumin:creatinine ratio of >30 mg/mmol) with very high levels of nephrotic syndrome being for PCR > 100 mg/mmol.^[13]

Reference Range
Physiologic protien elimination	<150mg protien/24 hours
Proteinuria	>150mg protein/24 hours
Microalbuminuria	<30mg albumin/24 hours

Treatment

Treating proteinuria mainly needs proper diagnosis of the cause. The most common cause is diabetic nephropathy; in this case, proper glycemic control may slow the progression. Medical management consists of angiotensin converting enzyme (ACE) inhibitors, which are typically first-line therapy for proteinuria. In patients whose proteinuria is not controlled with ACE inhibitors, the addition of an aldosterone antagonist (i.e., spironolactone)^[14] or angiotensin receptor blocker (ARB)^[15] may further reduce protein loss. Caution must be used if these agents are added to ACE inhibitor therapy due to the risk of hyperkalemia. Proteinuria secondary to autoimmune disease should be treated with steroids or steroid-sparing agent plus the use of ACE inhibitors.

@@ Line 75: / Line 75: @@
 ==Pathophysiology  ==
+The mechanism of proteinuria is dependent of two factors: glomerular wall and tubular reabsorption.
 ==Causes   ==
 {| class="wikitable"

Cardiovascular	Amyloidosis, benign orthostatic proteinuria, constrictive pericarditis, dehydration, eclampsia, hypertension, Nutcracker syndrome, preeclampsia, renal artery stenosis, renal vein thrombosis, shock , subacute bacterial endocarditis, tricuspid insufficiency
Chemical/Poisoning	Nitrosourea compounds, mercury, cadmium, trichloroethlene, bromobenzene , chloroform, aristolochic acids , paraquat, diquat, ethylene glycol
Dental	No underlying causes
Dermatologic	Scleroderma
Drug Side Effect	Acetaminophen and Oxycodone, Aflibercept, anticonvulsants, Artemether and lumefantrin, bevacizumab, captopril, carmustine, caspofungin, cisplatin, deferasirox, diflunisal, febuxostat, gemcitabine, gold, heavy metal ingestion, heroin, Interferon gamma, Lenvatinib, Lincomycin Hydrochloride, lomustine, micafungin, mithramycin, NSAIDS, Olsalazine, Oxaprozin, pazopanib, penicillamine, pramipexole, rifaximin, Sodium aurothiomalate, Sorafenib, Streptozocin, sulfasalazine, sulindac, Telavancin hydrochloride, [Thalidomide]], Tolmetin , Ziv-aflibercept
Ear Nose Throat	No underlying causes
Endocrine	Diabetes mellitus, hypothyroidism
Environmental	Allergens, irradiation
Gastroenterologic	Cirrhosis of liver, Wilson's disease, hemochromatosis
Genetic	Alport syndrome, Alström syndrome, aminoaciduria, amyloidosis, Balkan nephropathy, connatal tubulopathies, cystinosis, Dent disease, diabetes mellitus, Fabry's disease, familial mediterranean fever, galactosemia, glycogen storage disease type I, hepatorenal tyrosinemia, hereditary fructose intolerance, idiopathic multicentric osteolysis, Imerslund-Grasbeck syndrome, Lecithin cholesterol acyltransferase deficiency, Nail-patella syndrome, polycystic kidney disease , recurrent hereditary polyserositis, Wilson's disease, X-linked hypophosphatemia
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	Epstein-barr virus, helminthic, hepatitis B, HIV, infectious mononucleosis, Legionella pneumophila, leprosy, malaria, poststreptococcal glomerulonephritis, Prostitis, acute Pyelonephritis, Subacute bacterial endocarditis, toxoplasmosis, urinary tract infection, viral illness, yellow fever, genitourinary tuberculosis
Musculoskeletal/Orthopedic	rhabdomyolysis
Neurologic	No underlying causes
Nutritional/Metabolic	extreme obesity
Obstetric/Gynecologic	Eclampsia, preeclampsia
Oncologic	Renal cell carcinoma, multiple myeloma
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	stress
Pulmonary	No underlying causes
Renal/Electrolyte	Amyloidosis, Bence-jones proteinuria, crescentic glomerulonephritis, dehydration, Fanconi syndrome, fibrillary glomerulopathies, focal segmental glomerulosclerosis , hyperoxaluria, hypertension-related kidney failure, hyperuricemia, hypokalemic nephropathy, interstitial nephritis, medullary cystic kidney disease, myoglobinuria, nephritic syndrome, nephritis of pregnancy, nephrotic syndrome), Papillary necrosis, autosomal dominant polycystic kidney disease ), Poststreptococcal glomerulonephritis, Proliferative glomerulonephritis, Proximal renal tubular acidosis, acute Pyelonephritis, renal artery stenosis, renal metastases, renal neoplasm, renal tubular acidosis, renal vein thrombosis, rhabdomyolysis, toxic nephropathy, unilateral kidney, Urinary tract infection, X-linked hypophosphataemia
Rheumatology/Immunology/Allergy	Allergens, arteriolar nephrosclerosis, autoimmune conditions, Bence-jones proteinuria, Collagen vascular diseases, crescentic glomerulonephritis, Fanconi syndrome, fibrillary glomerulopathies, focal segmental glomerulosclerosis ), Henoch-schonlein syndrome, hepatitis b, IgA nephropathy (i.e., Berger's disease), IgM nephropathy, increased formation of polyclonal free light chains, interstitial nephritis, mixed cryoglobulinemia, multiple myeloma, Organ rejection- kidney transplant patients], Polyarteritis nodosa, recurrent hereditary polyserositis, rheumatoid disease, sarcoidosis, systemic lupus erythematosis, systemic sclerosis, Wegener's granulomatosis
Sexual	No underlying causes
Trauma	musculoskeletal trauma
Urologic	Retrograde ejaculation
Miscellaneous	No underlying causes