Proteinuria: Difference between revisions

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<br><br>'''To view a comprehensive algorithm of common findings of urine composition and urine output, click [[Urine#Algorithm of Common Urinary Findings|here]]'''<br>
<br><br>'''To view a comprehensive algorithm of common findings of urine composition and urine output, click [[Urine#Algorithm of Common Urinary Findings|here]]'''<br>
==Overview ==
==Overview ==
Proteinuria (from ''protein'' and ''urine'') means the presence of an excess of serum [[protein]]s in the [[urine]].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]]),[[retrograde ejaculation]], [[pneumaturia]] (air bubbles in the urine) due to a [[fistula]],or drugs such as [[pyridium]].
[[Excretion]] of the [[proteins]] in the [[urine]] may suggest variety of medical conditions from benign to severe [[kidney injury]]. The amount of proteinuria can be used as a clue to estimate the site and the cause of proteinuria. Three factors which are involved in development of proteinuria are glomerular-capillary barrier, tubular reabsorption capability, and protein's characteristics.
 
==Classification  ==
==Classification  ==
Proteinuria is classified based upon the site and the amount of protein in the urine.
Proteinuria is classified based upon the '''site''' and the '''amount''' of protein in the urine.<ref name="Venkat2004">{{cite journal|last1=Venkat|first1=K K.|title=Proteinuria and Microalbuminuria in Adults: Significance, Evaluation, and Treatment|journal=Southern Medical Journal|volume=97|issue=10|year=2004|pages=969–979|issn=0038-4348|doi=10.1097/01.SMJ.0000140833.51533.46}}</ref>
<small>
{| class="wikitable"
{| class="wikitable"
 
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Types
!Types
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Definition
!Definition
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Level of proteinuria
!Level of proteinuria
|-
|-
!Glomerular proteinuria
! align="center" style="background:#DCDCDC;" + |Glomerular proteinuria
|Increased filtration rate of protein due to the damage to the glomerular-capillary barrier  
|Increased filtration rate of [[protein]] due to the damage to the [[Glomerulus|glomerular]]-capillary barrier.
|Variable,  
|Variable,  
usually > 2g/day
usually > 2g/day
Line 22: Line 23:
'''Dipstick:'''Positive
'''Dipstick:'''Positive
|-
|-
!Tubular proteinuria
! align="center" style="background:#DCDCDC;" + |Tubular proteinuria
|Decreased tubular reabsorption of proteins due to tubular cell damage
|Decreased tubular reabsorption of [[proteins]] due to tubular cell damage.


|< 2 g/day   
|< 2 g/day   
'''Dipstick:'''Negative
'''Dipstick:'''Negative
|-
|-
!Overflow proteinuria
! align="center" style="background:#DCDCDC;" + |Overflow proteinuria
|Increased urinary excretion of proteins due to exceeding reabsorption capacity of renal tubules
|Increased urinary [[excretion]] of [[proteins]] due to exceeding reabsorption capacity of renal tubules.
|Variable up to 20g/day
|Variable up to 20g/day


'''Dipstick:'''Negative
'''Dipstick:'''Negative
|-
|-
!Post-renal proteinuria
! align="center" style="background:#DCDCDC;" + |Post-renal proteinuria
|Increased urinary excretion of the small amount of protein especially IgA and IgG  
|Increased urinary [[excretion]] of the small amount of protein especially [[IgA]] and [[IgG]].


|Variable,
|Variable,
usually < 1g/day
usually < 1g/day
|-
|-
!Isolated proteinuria
! align="center" style="background:#DCDCDC;" + |Isolated proteinuria
|Proteinuria with normal urinary sediment with no history of renal disease  
|Proteinuria with 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
|< 2 g/day
|}
|}
{| class="wikitable"
{| class="wikitable"
|+
|+
!Proteinuria
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Proteinuria
!Amount
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Amount
|-
|-
!Normal range  
! align="center" style="background:#DCDCDC;" + |Normal range  
|'''Total protein excretion''' in urine (proteinuria): < 150 mg/day, average 80 mg/day   
|'''Total protein excretion''' in urine (proteinuria): < 150 mg/day, average 80 mg/day<br/>  
'''Albumin excretion:''' < 20 mg/day (15 mcg/min), 15% of urine total protein
'''Urine protein/creatinine ratio''' > 0.2 mg/mg<ref name="pmid6656849">{{cite journal| author=Ginsberg JM, Chang BS, Matarese RA, Garella S| title=Use of single voided urine samples to estimate quantitative proteinuria. | journal=N Engl J Med | year= 1983 | volume= 309 | issue= 25 | pages= 1543-6 | pmid=6656849
 
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=6656849 }}</ref><br/>
(remaining 85% constitutes Tamm-Horsfall proteins, IgA, urokinase) <ref name="ViswanathanUpadhyay2011">{{cite journal|last1=Viswanathan|first1=Gautham|last2=Upadhyay|first2=Ashish|title=Assessment of Proteinuria|journal=Advances in Chronic Kidney Disease|volume=18|issue=4|year=2011|pages=243–248|issn=15485595|doi=10.1053/j.ackd.2011.03.002}}</ref> <ref>{{cite journal|doi=10.3265/Nefrologia.pre2011.Jan.10807}}</ref>
'''Albumin excretion:''' < 20 mg/day (15 mcg/min), 15% of urine total protein<br/>
(remaining 85% constitutes [[Tamm-Horsfall protein|Tamm-Horsfall proteins]], [[IgA]], [[urokinase]]) <ref name="ViswanathanUpadhyay2011">{{cite journal|last1=Viswanathan|first1=Gautham|last2=Upadhyay|first2=Ashish|title=Assessment of Proteinuria|journal=Advances in Chronic Kidney Disease|volume=18|issue=4|year=2011|pages=243–248|issn=15485595|doi=10.1053/j.ackd.2011.03.002}}</ref><ref>{{cite journal|doi=10.3265/Nefrologia.pre2011.Jan.10807}}</ref>


<small>(The rate of proteinuria increases proportionally with age and body weight)</small>
<small>(The rate of proteinuria increases proportionally with age and body weight)</small>
|-
|-
!Albuminuria
! align="center" style="background:#DCDCDC;" + |Albuminuria
(microalbuminuria)
(microalbuminuria)
|30-300 mg/day (20 to 200 mcg/min)
|30-300 mg/day (20 to 200 mcg/min)
|-
|-
!Overt proteinuria
! align="center" style="background:#DCDCDC;" + |Overt proteinuria
(macroalbuminuria)
(macroalbuminuria)
|Albuminuria > 300 mg/day (200 mcg/min) up to 3500 mg/day, positive dipstick
|[[Albuminuria]] > 300 mg/day (200 mcg/min) up to 3500 mg/day, positive dipstick
|-
|-
!Nephrotic range
! align="center" style="background:#DCDCDC;" + |Nephrotic range
|Total protein excretion: ≥ 3.5 g/day  
|Total protein excretion: ≥ 3.5 g/day
Protein–to-creatinine ratio: > 3-3.5 mg protein/mg creatnine<ref name="pmid6656849">{{cite journal| author=Ginsberg JM, Chang BS, Matarese RA, Garella S| title=Use of single voided urine samples to estimate quantitative proteinuria. | journal=N Engl J Med | year= 1983 | volume= 309 | issue= 25 | pages= 1543-6 | pmid=6656849
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=6656849 }}</ref>
|}
|}
</small>


==Pathophysiology  ==
==Pathophysiology  ==
The amount of proteins present in the urine is < 150 mg/day with an intact glomerular-capillary barrier and functioning tubules, thus increased levels of proteinuria can demonstrate kidney damage (glomerular or tubular). Overproduction of proteins which exceeds the absorption capacity of the tubules causes proteinuria in spite of relatively normal renal function (overflow). Normally filtration of all plasma proteins like albumin, globulins and other high-molecular-weight proteins through the glomerular-capillary wall is prevented by '''charge''' and '''size''' of the proteins and glomerular-capillary barrier. The type and quantity of proteins in the urine identifies the cause and site of kidney damage. As injury to the glomerular-capillary barrier causes albuminuria, tubular damage and overflow proteinuria lead to increase loads of low-molecular-weight proteins in the urine. The severity of protein loss in the urine depends on the mechanism of renal injury.
* The amount of [[proteins]] present in the urine is < 150 mg/day with an intact glomerular-capillary barrier and functioning tubules, thus increased levels of proteinuria can demonstrate [[kidney damage]] ([[glomerular]] or [[tubular]]).
* Overproduction of proteins which exceeds the absorption capacity of the tubules causes proteinuria in spite of relatively normal [[renal function]] (overflow).
* Normally filtration of all [[plasma proteins]] like [[albumin]], [[globulins]] and other high-molecular-weight proteins through the glomerular-capillary wall is prevented by '''charge''' and '''size''' of the proteins and glomerular-capillary barrier .
* The type and quantity of proteins in the urine may identify the etiology and site of [[kidney damage]].
* As injury to the glomerular-capillary barrier causes [[albuminuria]], tubular damage and overflow proteinuria lead to increase loads of low-molecular-weight proteins in the urine.
* The severity of protein loss in the urine depends on the mechanism of renal injury.


'''Glomerular-capillary barrier:''' It consists of endothelial cells of capillary, Glomerular basement membrane and epithelial cells. The endothelial cells of vessels organize a barrier with pores of 100 nm which impede the passing of the proteins from blood to the urinary space. Glomerular basement membrane and epithelial cells (podocytes) prevent the protein passage and trap the proteins especially with the size of > 100 kDa. The slit diaphragm acts as the most selective barrier for protein passage. The endothelial cells, podocytes, and glomerular basement membrane impede traversal of the negative-charge proteins due to the presence of negative charges in their constitution.     
=== '''Glomerular-capillary barrier''' ===
* It consists of [[endothelial cells]] of [[capillary]], [[glomerular basement membrane]], and [[epithelial cells]].  
* The [[endothelial cells]] of vessels organize a barrier with pores of 100 nm which impede the passing of the [[proteins]] from [[blood]] to the [[urinary]] space.  
* [[Glomerular basement membrane]] and [[epithelial cells]] ([[Podocyte|podocytes]]) prevent the [[protein]] passage and traps the [[proteins]] especially with the size of > 100 [[kDa]].  
* The slit diaphragm acts as the most selective barrier for [[protein]] passage.  
* The [[endothelial cells]], [[podocytes]], and [[glomerular basement membrane]] impede traversal of the negative-charge [[proteins]] due to the presence of negative charges in their constitution <ref name="ToblliBevione20123">{{cite journal|last1=Toblli|first1=Jorge E.|last2=Bevione|first2=P.|last3=Di Gennaro|first3=F.|last4=Madalena|first4=L.|last5=Cao|first5=G.|last6=Angerosa|first6=M.|title=Understanding the Mechanisms of Proteinuria: Therapeutic Implications|journal=International Journal of Nephrology|volume=2012|year=2012|pages=1–13|issn=2090-214X|doi=10.1155/2012/546039}}</ref>.     


'''Tubular reabsorption:''' Almost all the proteins which are filtered through glomerulus are reabsorbed by proximal tubular cells by endocytosis. The tubulointerstitial diseases damage the cells cause tubular proteinuria. In circumstances which large amounts of protein is filtered, tubular proteinuria occurs due to exceeding the reabption capacity of the cells. Not all the proteins in the tubules are toxic to the cells but proximal tubule injury, light chain deposition and tubule obstruction (cast nephropathy) due to the large level of light chain may cause further proteinuria by the overwhelming capacity of tubular cells.  
=== '''Tubular reabsorption''' ===
* Almost all the proteins which are filtered through glomerulus are reabsorbed by proximal tubular cells by [[endocytosis]].  
* The tubulointerstitial diseases damage the cells cause tubular proteinuria.  
* In circumstances where large amounts of protein is filtered, tubular proteinuria occurs as the filtered [[protein]] exceeds the reabsorption capacity of the cells.  
* Not all the proteins in the tubules are toxic to the cells but proximal tubule injury, light chain deposition, and tubule obstruction (cast nephropathy) due to the large amount of light chain may cause further proteinuria by the overwhelming capacity of tubular cells.  


'''Proteins:''' The size of the protein is one of the determinants of traversal through the glomerular-capillary barrier. Immunoglobulins like IgG and other high-molecular-weight proteins have the higher molecular radius, therefore, there are not able to pass over the barrier. Low-molecular-weight proteins are the ones with < 40kDa and molecular radius < 30 Å are filtered almost completely and reabsorbed by tubular cells.
=== '''Proteins''' ===
* The size of the protein is one of the determinants of traversal through the glomerular-capillary barrier. [[Immunoglobulins]] like [[IgG]] and other high-molecular-weight proteins have the higher molecular radius, therefore, there are not able to pass over the barrier.
* Low-molecular-weight proteins are the ones with < 40kDa and molecular radius < 30 Å are filtered almost completely and reabsorbed by tubular cells.<ref name="D'AmicoBazzi2003">{{cite journal|last1=D'Amico|first1=Giuseppe|last2=Bazzi|first2=Claudio|title=Pathophysiology of proteinuria|journal=Kidney International|volume=63|issue=3|year=2003|pages=809–825|issn=00852538|doi=10.1046/j.1523-1755.2003.00840.x}}</ref>


<br>
* In normal physiological condition, HMW proteins do not cross the glomerular barrier. The small percentage of [[albumin]] passes the barrier which is reabsorbed completely in the proximal tubules. LMW proteins are filtered and reabsorbed completely. <ref name="ToblliBevione20122">{{cite journal|last1=Toblli|first1=Jorge E.|last2=Bevione|first2=P.|last3=Di Gennaro|first3=F.|last4=Madalena|first4=L.|last5=Cao|first5=G.|last6=Angerosa|first6=M.|title=Understanding the Mechanisms of Proteinuria: Therapeutic Implications|journal=International Journal of Nephrology|volume=2012|year=2012|pages=1–13|issn=2090-214X|doi=10.1155/2012/546039}}</ref>
* In normal physiological condition, HMW proteins do not cross the glomerular barrier. The small percentage of albumin passes the barrier which is reabsorbed completely in the proximal tubules. LMW proteins are filtered and reabsorbed completely.  


* Moderate alteration of permeability of glomerular barrier named as selective proteinuria, demonstrates with loss of negative-charged proteins like albumin, LMW proteins and small percetage of HMW proteins in the urine with exceeding the reabsorbtion capacity of tubular cells.   
* Moderate alteration of permeability of glomerular barrier named as selective proteinuria, demonstrates with loss of negative-charged proteins like [[albumin]], LMW proteins and small percentage of HMW [[proteins]] in the urine with exceeding the reabsorption capacity of tubular cells.   
* Severe damage to the barrier, causes loss of the greater percentage of HMW proteins in the urine which is called nonselective proteinuria.  
* Severe damage to the barrier causes loss of the greater percentage of HMW proteins in the urine which is called nonselective proteinuria.  
* Profound damage to glomerular barrier causes severe proteinuria of all classes especially LMW and HMW. Increasing loads of protein which exceed the reabsorption capability of tubular cells causes damage to tubular cells and worsens proteinuria.  
* Profound damage to [[glomerular]] barrier causes severe proteinuria of all classes especially LMW and HMW. Increasing loads of protein which exceed the reabsorption capability of tubular cells causes damage to tubular cells and worsens proteinuria.  
<small>(an average protein has 250 amino acids which equals molecular weight( MW) of approximately 34 kDa)</small>
<small>(an average protein has 250 amino acids which equals molecular weight( MW) of approximately 34 kDa)</small>
[[File:Glomerular-capillary wall.JPG|thumb|100px|center| Glomerular-capillary wall, (ɔ) Image courtesy of WikiDoc.org, by '''"[[User: Saeedeh Kowsarnia|Saeedeh Kowsarnia M.D.]]"''']]
[[File:Glomerular-capillary wall.JPG|frame|center| Glomerular-capillary wall, (ɔ) Image courtesy of WikiDoc.org, by '''"[[User: Saeedeh Kowsarnia|Saeedeh Kowsarnia M.D.]]"''']]


==Causes  ==
==Causes  ==
'''<small>For more details on the causes of glomerular proteinuria, click [[Glomerular disease|here]].</small>'''
'''<small>For more details on the causes of tubular proteinuria, click [[Tubulointerstitial diseases of the kidney|here]].</small>'''<br>
{| class="wikitable"
{| class="wikitable"
|+
|+
!Classification
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Classification
!Etiology
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Etiology
|-
|-
!Glomerular proteinuria
! align="center" style="background:#DCDCDC;" + |Glomerular proteinuria
|Diabetic nephropathy, orthostatic proteinuria,  glomerulonephropathies, hypertensive nephrosclerosis, preeclampsia, collagen vascular disease, infections, cancer, lymphoma, chronic renal transplant rejection, drugs, amyloidosis, post-transplant proteinuria  
|[[Diabetic nephropathy]], orthostatic proteinuria,  glomerulonephropathies, [[hypertensive nephrosclerosis]], [[Pre-eclampsia|preeclampsia]], [[Collagen vascular diseases|collagen vascular disease]], infections, cancer, [[lymphoma]], chronic [[renal transplant rejection]], drugs, [[amyloidosis]], post-transplant proteinuria  


'''Transient:''' Exercise-induced proteinuria, fever, Infection, heart failure, joint inflammation, hyperlipidemia (LDL > 120 mg/dL), hyperglycemia (HbA1c > 8%), hypertension (BP >160/100 mmHg)
'''Transient:''' Exercise-induced proteinuria, fever, Infection, [[Congestive heart failure|heart failure]], joint inflammation, hyperlipidemia (LDL > 120 mg/dL), hyperglycemia (HbA1c > 8%), hypertension (BP >160/100 mmHg)
|-
|-
!Tubular proteinuria
! align="center" style="background:#DCDCDC;" + |Tubular proteinuria
|Tubulointerstitial diseases, cryoglobulinemia, Sjögren's syndrome, immunosuppressive agents, analgesic use
|[[Tubulointerstitial diseases of the kidney|Tubulointerstitial diseases]], [[cryoglobulinemia]], [[Sjögren's syndrome]], [[immunosuppressive agents]], [[analgesic]] use
<small>'''Excluding criteria:''' Proteinuria (≥ 3.5 g/day), edema, hypoalbuminemia, lipiduria, active urine sediment</small>
 
<small>(red blood cells and/or cast), decreased GFR, hypertension</small>
|-
|-
!Overflow proteinuria
! align="center" style="background:#DCDCDC;" + |Overflow proteinuria
|Light chains of immunoglobulins (multiple myeloma), lysozyme (AML), myoglobin (rhabdomyolysis), free hemoglobin not bound to haptoglobin (intravascular hemolysis), lymphoma, amyloidosis
|Light chains of immunoglobulins ([[multiple myeloma]]), [[lysozyme]] ([[AML]]), [[myoglobin]] ([[rhabdomyolysis]]), free hemoglobin not bound to [[haptoglobin]] (intravascular hemolysis), [[lymphoma]], [[amyloidosis]]
|-
|-
!Post-renal proteinuria
! align="center" style="background:#DCDCDC;" + |Post-renal proteinuria
|Nephrolithiasis, urinary tract tumors or infections
|[[Nephrolithiasis]], urinary tract tumors or infections
|-
|-
!Isolated proteinuria
! align="center" style="background:#DCDCDC;" + |Isolated proteinuria
|damage to tubular cells or the lower urinary tract, There is a 20% risk for renal insufficiency in the next 10 years, observation with blood pressure measurement, urinalysis and a creatinine clearance every 6 months should be considered.
|Damage to tubular cells or the lower urinary tract
<small>There is a 20% risk for developing renal insufficiency in the next 10 years, close follow up with blood pressure measurement, urinalysis and creatinine clearance every 6 months</small> <ref name="pmid6824253">{{cite journal| author=Abuelo JG| title=Proteinuria: diagnostic principles and procedures. | journal=Ann Intern Med | year= 1983 | volume= 98 | issue= 2 | pages= 186-91 | pmid=6824253 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6824253  }}</ref>
|-
|-
!Microalbuminuria
! align="center" style="background:#DCDCDC;" + |Microalbuminuria
|
|
Essential hypertension, early diabetes, early stages of glomerulonephritis (especially with active sediments; RBCs, RBC casts)
[[Essential hypertension]], early diabetes, early stages of [[glomerulonephritis]] (especially with active sediments; RBCs, RBC casts)
|-
|-
!Macroalbuminuria
! align="center" style="background:#DCDCDC;" + |Macroalbuminuria
|
|
Fever, exercise, CHF, orthostatic proteinuria, intermittent proteinuria, the kidney disease associated with myeloma, all diseases which are mentioned as the causes of microalbuminuria
[[Fever]], exercise, [[Congestive heart failure|CHF]], orthostatic proteinuria, intermittent proteinuria, the kidney disease associated with myeloma, all diseases which are mentioned as the causes of microalbuminuria
|-
|-
!Nephrotic range proteinuria
! align="center" style="background:#DCDCDC;" + |Nephrotic range proteinuria
|Diabetes, minimal change disease, amyloidosis, FSGS, membranous glomerulopathy, IgA nephropathy
|[[Diabetes]], [[minimal change disease]], [[amyloidosis]], [[Focal segmental glomerulosclerosis|FSGS]], [[Membranous glomerulonephritis|membranous glomerulopathy]], [[IgA nephropathy]]  
 
|}
 
==Risk Factors ==
* Race and ethnicity
* Obesity
* Age
* Medications
==Epidemiology and Demographics==
* Prevalence of albuminuria is 6100 and 9700 per 100,000 in male and female population, respectively <ref name="JonesFrancis2002">{{cite journal|last1=Jones|first1=Camille A.|last2=Francis|first2=Mildred E.|last3=Eberhardt|first3=Mark S.|last4=Chavers|first4=Blanche|last5=Coresh|first5=Josef|last6=Engelgau|first6=Michael|last7=Kusek|first7=John W.|last8=Byrd-Holt|first8=Danita|last9=Narayan|first9=K.M.Venkat|last10=Herman|first10=William H.|last11=Jones|first11=Camara P.|last12=Salive|first12=Marcel|last13=Agodoa|first13=Lawrence Y.|title=Microalbuminuria in the US population: Third National Health and Nutrition Examination Survey|journal=American Journal of Kidney Diseases|volume=39|issue=3|year=2002|pages=445–459|issn=02726386|doi=10.1053/ajkd.2002.31388}}</ref>.
* The estimated prevalence rate of albuminuria among diabetes population is 28,800 per 100,1000.
* Approximately,16,000 per 100,000 hypertensive cases have albuminuria.
* Isolated albuminuria with normal renal function is estimated 3,300 per 100,000 adult population.
 
==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 associated with left ventricular abnormalities, increased atherosclerosis and cardiovascular morbidity and mortality.
* Proteinuria is an independent risk factor for developing cardiovascular disease and end stage renal disease <ref name="AstorMatsushita2011">{{cite journal|last1=Astor|first1=Brad C.|last2=Matsushita|first2=Kunihiro|last3=Gansevoort|first3=Ron T.|last4=van der Velde|first4=Marije|last5=Woodward|first5=Mark|last6=Levey|first6=Andrew S.|last7=Jong|first7=Paul E. de|last8=Coresh|first8=Josef|title=Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts|journal=Kidney International|volume=79|issue=12|year=2011|pages=1331–1340|issn=00852538|doi=10.1038/ki.2010.550}}</ref>.
* Higher amounts of albuminuria, even in normal range is associated with an increased risk of cardiovascular events.
* Microalbuminuria can be considered as a predictor of morbidity and mortality in patients with no significant renal diseases.
* The presence of proteinuria in renal transplant patients predicts graft and patients survival <ref name="BorregoMazuecos2013">{{cite journal|last1=Borrego|first1=J.|last2=Mazuecos|first2=A.|last3=Gentil|first3=M.A.|last4=Cabello|first4=M.|last5=Rodríguez|first5=A.|last6=Osuna|first6=A.|last7=Pérez|first7=M.A.|last8=Castro|first8=P.|last9=Alonso|first9=M.|title=Proteinuria as a Predictive Factor in the Evolution of Kidney Transplantation|journal=Transplantation Proceedings|volume=45|issue=10|year=2013|pages=3627–3629|issn=00411345|doi=10.1016/j.transproceed.2013.10.025}}</ref>.
* Treatment of proteinuria in patients with chronic renal disease improves outcomes.
* Increases Urinary albumin to creatinine ratio in patients with different medical conditions increases mortality.
* Albuminuria in any measurable levels is associated with increased risk of myocardial infarction in hypertensive patients.
 
==Diagnosis==
===Diagnostic Study of Choice ===
'''<big>Qualitative measures</big>'''
 
'''Urine dipstick:''' The standard urine dipstick is sensitive to urine albumin not to the non-albumin proteins, so the positive result indicates glomerular proteinuria. The dipstick grading is semiquantitative to the amount of protein in the urine and is dependent upon urine concentration. The '''sensitivity''' of the urinary dipstick for detection of albumin in the urine ranges from 83% to 98% with a '''specificity''' of 59% to 86% <ref>{{Cite journal
| author = [[Mark J. Siedner]], [[Allan C. Gelber]], [[Brad H. Rovin]], [[Alison M. McKinley]], [[Lisa Christopher-Stine]], [[Brad Astor]], [[Michelle Petri]] & [[Derek M. Fine]]
| title = Diagnostic accuracy study of urine dipstick in relation to 24-hour measurement as a screening tool for proteinuria in lupus nephritis
| journal = [[The Journal of rheumatology]]
| volume = 35
| issue = 1
| pages = 84–90
| year = 2008
| month = January
| pmid = 18085740
}}</ref>. At the lower level of albuminuria, especially microalbuminuria the urine dispstick is specific but not sensitive, therefore microalbuminuria cannot be detected easily by urine dipstick unless the urine is properly concentrated. Few data suggests using specific gravity to estimate the amount of proteinuria, especially with the dipstick result of trace or 1+. Highly concentrated urine overestimates the amount of proteinuria in the urine, similarly, highly diluted urine underestimates the degree of proteinuria detected by dipstick.
* '''False-positive result:''' Urine PH > 8, administration of radiocontrast agents (iodinated), gross hematuria 
* Newer dipsticks can detect albumin-to-creatinine and total protein-to-creatinine ratios which can help to avoid errors associated with diluted or concentrated urines and non-albumin proteinuria, respectively. 
 
'''Sulfosalicylic acid test (SSA):''' Use of SSA is indicated in patients with the possibility of myeloma in the presence of negative or trace dipstick with renal function impairment. Adding SSA to the urine precipitates all proteins, therefore positive dipstick with SSA demonstrates overflow or tubular proteinuria.
* '''Fals-positive result:''' Administration of radiocontrast agents (iodinated), gross hematuria, penicillins
<br>
 
{| style="background:gray; color:black" -
|-
! '''Reference range for proteinuria '''
!'''Standard dipstick +/- SSA'''
|-
|- style="background:silver; color:black"
!'''Trace'''
| Slight turbidity (1 to 10 mg/dL)
|-
|- style="background:silver; color:black"
!'''1+'''
| Turbidity through which print can be read (15 to 30 mg/dL)
|-
|- style="background:silver; color:black"
! '''2+'''
| White cloud without precipitate through which print can be seen (40 to 100 mg/dL)
|- style="background:silver; color:black"
! '''3+'''
| White cloud with fine precipitate through which print cannot be seen (150 to 350 mg/dL)
|- style="background:silver; color:black"
! '''4+'''
| Fluffy precipitate (>500 mg/dL)
|}
|}


'''<big>Quantitative measures</big>'''
'''24-hour urine collection:''' It is the gold standard test to determine the amount of proteinuria in patients who presents with persistent proteinuria (normal value < 150 mg/day).As collecting urine for 24 is cumbersome and erroneous, spot urine of first and second morning samples with protein-creatinine ratio can be used as an estimate of total protein excretion in 24 hour<ref>{{Cite journal
| author = [[Mark J. Siedner]], [[Allan C. Gelber]], [[Brad H. Rovin]], [[Alison M. McKinley]], [[Lisa Christopher-Stine]], [[Brad Astor]], [[Michelle Petri]] & [[Derek M. Fine]]
| title = Diagnostic accuracy study of urine dipstick in relation to 24-hour measurement as a screening tool for proteinuria in lupus nephritis
| journal = [[The Journal of rheumatology]]
| volume = 35
| issue = 1
| pages = 84–90
| year = 2008
| month = January
| pmid = 18085740
}}</ref>.
24-hour protein excretion= Urine protein concentration / Urine creatinine concentration
* Urine creatinine is higher in individuals with higher body muscle mass, therefore urine-protein ratio underestimates proteinuria, similarly in cachectic patients with lower muscle mass, urine-protein ratio overestimates the degree of proteinuria.
'''Renal biposy:'''


===History and Symptoms===
'''History:'''
* Fever
* Cardiac disease
* Renal disease
* Infections (HIV, hepatitis)
* Frothy, smoky, red urine
* Edema
* Hypertension
* Diabetes
* Family history of renal disease
* Hypercholesterolemia
* Chronic inflammatory disease
* Medications
'''Symptoms:'''
* Systemic symptoms (fever, night sweats, weight loss, bone pain)
* Heart diseases
* Edema (ankle, periorbital, labial, scrotal)
* High blood pressure
* Hematuria
*
*
===Physical Examination===
* Check blood pressure, orthostatic and supine, JVP
* Weight gain or weight changes
* Edema
* Signs of infectious diseases
* Signs of heart diseases
* Signs of systemic diseases
* Signs for complications (thrombosis, infections)
*
===Laboratory Findings===
Laboratory investigations to be considered in proteinuria:{{Columns-list|2|
* FBS, HbA1c
* Hb, Hct
* Serum urate
* Serum albumin, lipid levels
* Serum electrolytes
* ESR
* HIV, VDRL, hepatic serologic tests
* Serum, urine protein electrophoresis
* Complement C3, C4
* Antistreptolysin O titer
* ANA
* Renal sonography
* Chest radiography
}}
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. <ref>http://medlib.med.utah.edu/WebPath/TUTORIAL/URINE/URINE.html Retrieved 2007-01-20</ref><ref name="pmid15791892">{{cite journal |author=Simerville JA, Maxted WC, Pahira JJ |title=Urinalysis: a comprehensive review |journal=American family physician |volume=71 |issue=6 |pages=1153-62 |year=2005 |pmid=15791892 |doi= |url=http://www.aafp.org/afp/20050315/1153.html}}</ref> 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]].<ref>http://www.pathguy.com/lectures/urine.htm Retrieved 2007-01-20</ref><ref>http://www.answers.com/topic/protein-electrophoresis Retrieved 2007-01-20</ref>
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 [[Microalbuminuria|Albumin:creatinine ratio]] of >30 mg/mmol) with very high levels of [[nephrotic syndrome]] being for PCR > 100 mg/mmol.<ref>{{cite web |title=Identification, management and referral of adults with chronic kidney disease: concise guidelines |url=http://www.renal.org/CKDguide/full/Conciseguid141205.pdf |format=PDF |date=27/9/05 |publisher=UK Renal Association}} - see Guideline 4 Confirmation of proteinuria, on page 9</ref>
==Treatment==
Specific treatments of proteinuria demands proper diagnosis of the cause.
Non-specific treatments reduce the amount of proteinuaria and the rate of progression or address the complications of proteinuria.
'''Diuretics:''' The treatment of fluid overload in patients with moderate to severe proteinuria along with salt restriction is diuretics. For refractory cases two different diuretics with will be used if the increasing doses are not effective. Acute renal failure may happen due to aggressive therapy with diuretics.
'''ACE inhibitors and ARBs:''' These agents decrease the progression and the amount of proteinuria by decreasing the intraglomerular pressure. Inhibiting vasoconstriction of efferent arterioles, maintaining the glomerular-capillary wall and decreasing the sclerosis and fibrosis of glomeruls are the action of these drugs aside the anti-hypertensive effects. In normotensive individuals with proteinuria low dose of these drugs have the effect without evident hypotension. Adverse effects are cough, angioedema and hyperkalemia. Adding mineralocorticoid receptor antagonists like eplerenone, spironolactone, help reducing proteinuria further but increase the rate of hyperkalemia. Eplerenone is the new drug in this category which is not associated with hyperkalemia.     
'''Anticoagulants:''' Urinary loss of proteins in the urine especially anticoagulant proteins like antithrombin III and protein S and C put the patients at the risk of thrombosis and emboli. There is no eveidence supporting the use of anticoagulants as prophylaxis.       
'''Calcium-channel blockers:''' Diltiazem and verapamil decrease proteinuria by prevent vasoconstriction of both afferent and efferent arterioles. Other CCBs act on afferent arteriols only which worsen proteinuria. New drugs such as efonidipine and benedipine are used along with ARBs and ACE inhibitors in proteinuria.       
T reating proteinuria mainly needs the 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]])<ref name="Mehdi">{{cite journal|doi=10.1681/ASN.2009070737|author=Mehdi UF, Adams-Huet B, Raskin P, et al. |title=Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximum angiotensin-converting enzyme inhibition in diabetic nephropathy. |journal=J Am Soc Nephrol |volume=20|issue=12 |pages=2641–50 |year=2009 |pmid=19926893|pmc=2794224 }}</ref> or angiotensin receptor blocker (ARB)<ref name="Burgess">{{cite journal|doi=10.1681/ASN.2008040416|author=Burgess E, Muirhead N, Rene de Cotret P, et al. |title=Supramaximal dose of candesartan in proteinuric renal disease. |journal=J Am Soc Nephrol |volume=20|issue=4 |pages=893–900 |year=2009 |pmid=19211712|pmc=2663827 }}</ref> 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.   
==Related Chapters==
*[[Albuminuria]]
*[[Microalbuminuria]]
*[[List of terms associated with diabetes]]
===Causes by Organ System===
===Causes by Organ System===
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</small>
<small>
===Causes in Alphabetical Order===


===Causes in Alphabetical Order===
<small>
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</small>
==Risk Factors ==
The risk factors for proteinuria include:
* [[Race]] and [[ethnicity]] <ref name="BrysonRoss2006">{{cite journal|last1=Bryson|first1=Chris L.|last2=Ross|first2=Heather J.|last3=Boyko|first3=Edward J.|last4=Young|first4=Bessie A.|title=Racial and Ethnic Variations in Albuminuria in the US Third National Health and Nutrition Examination Survey (NHANES III) Population: Associations With Diabetes and Level of CKD|journal=American Journal of Kidney Diseases|volume=48|issue=5|year=2006|pages=720–726|issn=02726386|doi=10.1053/j.ajkd.2006.07.023}}</ref>
* [[Obesity]] <ref name="RosenstockPommier2018">{{cite journal|last1=Rosenstock|first1=Jordan L.|last2=Pommier|first2=Max|last3=Stoffels|first3=Guillaume|last4=Patel|first4=Satyam|last5=Michelis|first5=Michael F.|title=Prevalence of Proteinuria and Albuminuria in an Obese Population and Associated Risk Factors|journal=Frontiers in Medicine|volume=5|year=2018|issn=2296-858X|doi=10.3389/fmed.2018.00122}}</ref>
* Age (> 65)
* [[Medications]]
* [[Hypertension]] <ref name="OngPunithavathi2013">{{cite journal|last1=Ong|first1=Loke Meng|last2=Punithavathi|first2=Narayanan|last3=Thurairatnam|first3=Dharminy|last4=Zainal|first4=Hadzlinda|last5=Beh|first5=Mei Li|last6=Morad|first6=Zaki|last7=Lee|first7=Sharleen YS|last8=Bavanandan|first8=Sunita|last9=Kok|first9=Lai Sun|title=Prevalence and risk factors for proteinuria: The National Kidney Foundation of Malaysia Lifecheck Health Screening programme|journal=Nephrology|volume=18|issue=8|year=2013|pages=569–575|issn=13205358|doi=10.1111/nep.12112}}</ref>
* [[Diabetes]] <ref name="BhallaZhao2012">{{cite journal|last1=Bhalla|first1=V.|last2=Zhao|first2=B.|last3=Azar|first3=K. M. J.|last4=Wang|first4=E. J.|last5=Choi|first5=S.|last6=Wong|first6=E. C.|last7=Fortmann|first7=S. P.|last8=Palaniappan|first8=L. P.|title=Racial/Ethnic Differences in the Prevalence of Proteinuric and Nonproteinuric Diabetic Kidney Disease|journal=Diabetes Care|volume=36|issue=5|year=2012|pages=1215–1221|issn=0149-5992|doi=10.2337/dc12-0951}}</ref>
* [[Heart diseases]]
* Family history of [[kidney disease]]
==Screening==
* Urinalysis may be considered as a part of routine health evaluation.
* Monitor of renal function and proteinuria (micro- and microalbuminuria) is recommended in individuals with systemic diseases who are at risk of proteinuria.
* Isolated proteinuria (non-nephrotic), no edema or [[hypoalbuminemia]], no clinical or serologic evidences of systemic diseases may be screened by [[antinuclear antibody]] (ANA), [[antineutrophil cytoplasmic antibody]] (ANCA), complement component C3 and C4 levels, and [[Hepatitis|hepatitis serologies]].
==Epidemiology and Demographics==
* Prevalence of albuminuria is 6100 and 9700 per 100,000 in male and female population, respectively.<ref name="JonesFrancis2002">{{cite journal|last1=Jones|first1=Camille A.|last2=Francis|first2=Mildred E.|last3=Eberhardt|first3=Mark S.|last4=Chavers|first4=Blanche|last5=Coresh|first5=Josef|last6=Engelgau|first6=Michael|last7=Kusek|first7=John W.|last8=Byrd-Holt|first8=Danita|last9=Narayan|first9=K.M.Venkat|last10=Herman|first10=William H.|last11=Jones|first11=Camara P.|last12=Salive|first12=Marcel|last13=Agodoa|first13=Lawrence Y.|title=Microalbuminuria in the US population: Third National Health and Nutrition Examination Survey|journal=American Journal of Kidney Diseases|volume=39|issue=3|year=2002|pages=445–459|issn=02726386|doi=10.1053/ajkd.2002.31388}}</ref>
* The estimated prevalence rate of albuminuria among [[diabetes]] population is 28,800 per 100,000 individuals.
* The estimated prevalence rate of albuminuria among [[Hypertension|hypertensive]] population is 16,000 per 100,000 individuals.
* Isolated albuminuria with normal renal function is estimated 3,300 per 100,000 adult population.
==Natural History, Complications, and Prognosis==
==== '''Natural History''' ====
* Proteinuria which different mechanisms causes loss of [[albumin]], regulatory proteins, [[hormones]] and [[anticoagulant]] proteins in the urine.
* [[Hypoalbuminemia]] decreases [[oncotic pressure]] and causes fluid movement from capillaries to [[interstitium]] which leads to [[edema]].
* Shift of fluids from capillaries is perceived as decreased effective vascular volume.
* Activation of the [[renin-angiotensin system]] and [[sympathetic nervous system]] along with increase [[Antidiuretic hormone|ADH]] secretion will occur which enhance salt and water reabsorption and worsen edema.
* Loss of regulatory [[proteins]] change [[hepatic]] synthesis of proteins and may cause in [[hypercholesterolemia]].
* Loss of [[antithrombin III]], proteins S and C cause [[platelet aggregation]] and [[thrombosis]].
* Loss of [[immunoglobulins]] enhances the risk of infections.
==== '''Complications''' ====
* [[Pulmonary edema]]
* [[Renal insufficiency|Renal failure]]
* Increased risk of infections
* Increased risk of [[Thromboembolic disease|thromboembolic events]]
* Increased risk of [[cardiovascular disease]]
==== '''Prognosis''' ====
* Proteinuria is associated with left ventricular abnormalities, increased [[atherosclerosis]], cardiovascular morbidity and [[mortality]].
* Proteinuria is an independent risk factor for developing cardiovascular disease and [[end stage renal disease]].<ref name="AstorMatsushita2011">{{cite journal|last1=Astor|first1=Brad C.|last2=Matsushita|first2=Kunihiro|last3=Gansevoort|first3=Ron T.|last4=van der Velde|first4=Marije|last5=Woodward|first5=Mark|last6=Levey|first6=Andrew S.|last7=Jong|first7=Paul E. de|last8=Coresh|first8=Josef|title=Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts|journal=Kidney International|volume=79|issue=12|year=2011|pages=1331–1340|issn=00852538|doi=10.1038/ki.2010.550}}</ref>
* Higher amounts of [[albuminuria]], even in normal range is associated with an increased risk of cardiovascular events.
* [[Microalbuminuria]] can be considered as a predictor of morbidity and [[mortality]] in patients with no significant renal diseases.
* The presence of proteinuria in [[renal transplant]] patients predicts graft and patients survival.<ref name="BorregoMazuecos2013">{{cite journal|last1=Borrego|first1=J.|last2=Mazuecos|first2=A.|last3=Gentil|first3=M.A.|last4=Cabello|first4=M.|last5=Rodríguez|first5=A.|last6=Osuna|first6=A.|last7=Pérez|first7=M.A.|last8=Castro|first8=P.|last9=Alonso|first9=M.|title=Proteinuria as a Predictive Factor in the Evolution of Kidney Transplantation|journal=Transplantation Proceedings|volume=45|issue=10|year=2013|pages=3627–3629|issn=00411345|doi=10.1016/j.transproceed.2013.10.025}}</ref>
* Treatment of proteinuria in patients with [[chronic renal disease]] improves outcomes.
* Increases urinary [[albumin]] to [[creatinine]] ratio in patients with different medical conditions increases [[mortality]].
* [[Albuminuria]] in any measurable levels is associated with increased risk of [[myocardial infarction]] in [[hypertensive]] patients.
==Diagnosis==
===Diagnostic Study of Choice ===
==== '''<big>Qualitative measures</big>''' ====
* '''Urine dipstick:'''
** The standard urine dipstick is sensitive to urine [[albumin]] not to the non-albumin proteins, so the positive result indicates [[glomerular]] proteinuria.
** The dipstick grading is semiquantitative to the amount of [[protein]] in the [[urine]] and is dependent upon [[urine]] concentration.
** The '''sensitivity''' of the [[urinary]] dipstick for detection of [[albumin]] in the urine ranges from 83% to 98% with a '''specificity''' of 59% to 86%.<ref>{{Cite journal
| author = [[Mark J. Siedner]], [[Allan C. Gelber]], [[Brad H. Rovin]], [[Alison M. McKinley]], [[Lisa Christopher-Stine]], [[Brad Astor]], [[Michelle Petri]] & [[Derek M. Fine]]
| title = Diagnostic accuracy study of urine dipstick in relation to 24-hour measurement as a screening tool for proteinuria in lupus nephritis
| journal = [[The Journal of rheumatology]]
| volume = 35
| issue = 1
| pages = 84–90
| year = 2008
| month = January
| pmid = 18085740
}}</ref>
** At the lower level of albuminuria, especially [[microalbuminuria]] the urine dipstick is specific but not sensitive, therefore [[microalbuminuria]] cannot be detected easily by urine dipstick unless the [[urine]] is properly concentrated.
** Few data suggests using specific gravity to estimate the amount of proteinuria, especially with the [[Dipsticks|dipstick]] result of trace or 1+.
** Highly concentrated urine overestimates the amount of proteinuria in the urine, similarly, highly diluted urine underestimates the degree of proteinuria detected by dipstick.
** False-positive result: Urine PH > 8, administration of [[radiocontrast agents]] (iodinated), gross [[hematuria]]. 
** Newer dipsticks can detect albumin-to-creatinine and total protein-to-creatinine ratios which can help to avoid errors associated with diluted or concentrated urines and non-albumin proteinuria, respectively. 
* '''Sulfosalicylic acid test (SSA):''' Use of SSA is indicated in patients with the possibility of myeloma in the presence of negative or trace dipstick with renal function impairment. Adding SSA to the urine precipitates all proteins, therefore positive dipstick with SSA demonstrates overflow or tubular proteinuria.
** False-positive result: Administration of [[radiocontrast agents]] (iodinated), gross [[hematuria]], [[penicillin]].
<br>
<small>
{| style="background:gray; color:black" -
|-
! '''Reference range for proteinuria '''
!'''Standard dipstick +/- SSA'''
|-
|- style="background:silver; color:black"
!'''Trace'''
| Slight turbidity (1 to 10 mg/dL)
|-
|- style="background:silver; color:black"
!'''1+'''
| Turbidity through which print can be read (15 to 30 mg/dL)
|-
|- style="background:silver; color:black"
! '''2+'''
| White cloud without precipitate through which print can be seen (40 to 100 mg/dL)
|- style="background:silver; color:black"
! '''3+'''
| White cloud with fine precipitate through which print cannot be seen (150 to 350 mg/dL)
|- style="background:silver; color:black"
! '''4+'''
| Fluffy precipitate (>500 mg/dL)
|}
</small>
'''<big>Quantitative measures</big>'''
* '''Spot urine collection:'''
** Both the urinary protein to creatinine ratio and the urinary albumin creatinine ratio (ACR) can help diagnose proteinuria.<ref name="kdigo-diabetes-ckd">https://kdigo.org/guidelines/diabetes-ckd/</ref>
* The normal value for the urinary ACR is less than 30<ref name="kdigo-diabetes-ckd"/>
One study of patients with CKD found that the protein creatinine ratio was about three times higher than the albumin creatinine ratio<ref name="pmid24041612">{{cite journal| author=Fisher H, Hsu CY, Vittinghoff E, Lin F, Bansal N| title=Comparison of associations of urine protein-creatinine ratio versus albumin-creatinine ratio with complications of CKD: a cross-sectional analysis. | journal=Am J Kidney Dis | year= 2013 | volume= 62 | issue= 6 | pages= 1102-8 | pmid=24041612 | doi=10.1053/j.ajkd.2013.07.013 | pmc=3840083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24041612  }} </ref>.
* '''24-hour urine collection:'''
** It is the gold standard test to determine the amount of proteinuria in patients who presents with persistent proteinuria (normal value < 150 mg/day). As collecting urine for 24 is cumbersome and erroneous, spot urine of first and second morning samples with protein-creatinine ratio can be used as an estimate of total protein excretion in 24 hour.<ref>{{Cite journal
| author = [[Mark J. Siedner]], [[Allan C. Gelber]], [[Brad H. Rovin]], [[Alison M. McKinley]], [[Lisa Christopher-Stine]], [[Brad Astor]], [[Michelle Petri]] & [[Derek M. Fine]]
| title = Diagnostic accuracy study of urine dipstick in relation to 24-hour measurement as a screening tool for proteinuria in lupus nephritis
| journal = [[The Journal of rheumatology]]
| volume = 35
| issue = 1
| pages = 84–90
| year = 2008
| month = January
| pmid = 18085740
}}</ref>
<div style="text-align: center;">24-hour protein excretion= Urine protein concentration / Urine creatinine concentration</div>
* Urine [[creatinine]] is higher in individuals with higher body muscle mass, therefore urine-protein ratio underestimates proteinuria, similarly in cachectic patients with lower [[muscle mass]], urine-protein ratio overestimates the degree of proteinuria.
* '''Renal biopsy: R'''enal biopsy is indicated in:
** All nephrotic range proteinuria (> 3.5 gr/day)
** Non-nephrotic range proteinuria with:
*** Active urine sediment
*** Persistent proteinuria > 1 gr/day
*** Decreased [[Glomerular filtration rate|GFR]]
*** Progression of proteinuria or developing active sediment or [[hypertension]]
===History and Symptoms===
'''History:'''
* [[Fever]]
* [[Cardiac disease]]
* [[Renal disease]]
* [[Infections]] ([[HIV]], [[hepatitis]])
* Frothy, smoky, red urine
* [[Edema]]
* [[Hypertension]]
* [[Diabetes]]
* Family history of systemic or [[renal disease]]
* [[Hypercholesterolemia]]
* [[Chronic inflammatory disease|Chronic inflammatory diseases]]
* [[Medications]]
'''Symptoms:'''
* Systemic symptoms ([[fever]], night sweats, weight loss, [[bone pain]])
* [[Heart diseases]]
* [[Edema]] (ankle, periorbital, labial, scrotal)
* [[Hypertension]]
* [[Hematuria]]
===Physical Examination===
* Check for [[blood pressure]], orthostatic and supine
* Measure JVP
* [[Weight change|Weight changes]]
* [[Edema]]
* Signs of [[infectious diseases]]
* Signs of [[heart diseases]]
* Signs of [[systemic diseases]]
* Signs for [[complications]] ([[thrombosis]], [[Infection|infections]])
*
===Laboratory Findings===
Laboratory investigations to be considered in proteinuria:
* [[FBS|Fasting blood glucose]], [[HbA1c]]
* [[Hemoglobin]], [[Hematocrit]]
* Serum [[urate]]
* Serum [[albumin]], lipid [[levels]]
* [[Electrolyte|Serum electrolytes]]
* [[ESR]]
* [[HIV]], [[VDRL]], hepatitis serologic tests
* Serum and urine [[protein electrophoresis]]
* [[Complement]] C3, C4 levels
* [[Antistreptolysin O titer]]
* [[ANA]]
* Renal [[ultrasound]]
* Chest radiography
==Treatment ==
===Medical Therapy===
'''<big>Specific treatments</big>''' of proteinuria demands proper diagnosis of the causes.
'''<small>For the details on the treatments of glomerular diseases, click [[Glomerular disease|here]].</small>'''
'''<small>For the details on the treatments of tubular diseases, click [[Tubulointerstitial diseases of the kidney|here]].</small>'''
'''<big>Non-specific treatments</big>''' reduce the amount of proteinuaria and the rate of progression or address the complications of proteinuria.
* '''Diuretics:'''
** The treatment of fluid overload in patients with moderate to severe proteinuria along with salt restriction is [[diuretics]].
** For refractory cases two different class of [[diuretics]] are used if the increasing doses are not effective.<ref name="FukudaKimura20082">{{cite journal|last1=Fukuda|first1=Michio|last2=Kimura|first2=Genjiro|title=Diuretics should be used as the second-line agent in combination with RAS inhibitors in ptoteinuric patients with CKD|journal=Kidney International|volume=74|issue=10|year=2008|pages=1358|issn=00852538|doi=10.1038/ki.2008.466}}</ref>
** [[Acute renal failure]] is the consequence of aggressive therapy with [[diuretics]].
* '''ACE inhibitors and ARBs:'''
** These agents decrease the progression and the amount of proteinuria by decreasing the intraglomerular pressure.<ref name="HsuLin2017">{{cite journal|last1=Hsu|first1=Feng-Yi|last2=Lin|first2=Fang-Ju|last3=Ou|first3=Huang-Tz|last4=Huang|first4=Shih-Hui|last5=Wang|first5=Chi-Chuan|title=Renoprotective Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Diabetic Patients with Proteinuria|journal=Kidney and Blood Pressure Research|volume=42|issue=2|year=2017|pages=358–368|issn=1420-4096|doi=10.1159/000477946}}</ref>     
** Inhibiting [[vasoconstriction]] of [[efferent arterioles]], maintaining the glomerular-capillary wall and decreasing the [[sclerosis]] and fibrosis of glomerulus are the action of these drugs aside the anti-hypertensive effects.<ref name="ToblliBevione2012">{{cite journal|last1=Toblli|first1=Jorge E.|last2=Bevione|first2=P.|last3=Di Gennaro|first3=F.|last4=Madalena|first4=L.|last5=Cao|first5=G.|last6=Angerosa|first6=M.|title=Understanding the Mechanisms of Proteinuria: Therapeutic Implications|journal=International Journal of Nephrology|volume=2012|year=2012|pages=1–13|issn=2090-214X|doi=10.1155/2012/546039}}</ref>     
** In normotensive individuals with proteinuria low dose of these drugs have the effect without evident [[hypotension]].<ref name="pmid9010883">{{cite journal| author=Gansevoort RT, de Zeeuw D, de Jong PE| title=ACE inhibitors and proteinuria. | journal=Pharm World Sci | year= 1996 | volume= 18 | issue= 6 | pages= 204-10 | pmid=9010883 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9010883  }}</ref>     
** Adverse effects of ACE inhibitors are cough, angioedema and hyperkalemia.     
* '''Mineralocorticoind receptor antagonists'''     
** Adding mineralocorticoid receptor antagonists like [[eplerenone]] and [[spironolactone]], help reducing proteinuria further but increase the rate of [[hyperkalemia]].       
** [[Eplerenone]] is the new drug in this category which is not associated with hyperkalemia.     
* '''Anticoagulants:'''
** Urinary loss of proteins in the urine especially anticoagulant proteins like [[antithrombin III]], [[protein S]], and [[protein C]] put the patients at the risk of [[thrombosis]] and [[emboli]].       
** There is no evidence supporting the use of anticoagulants as prophylaxis in [[nephrotic syndrome]].       
** [[Warfarin]] is recommended in patients with severe [[albuminuria]] (serum albumin <  2.5 g/dL).       
* '''Calcium-channel blockers:'''
** [[Diltiazem]] and [[verapamil]] decrease proteinuria by prevent [[vasoconstriction]] of both [[afferent]] and [[efferent arterioles]].       
** Other CCBs act on afferent arterioles only which worsen proteinuria.       
** New drugs such as efonidipine and [[benidipine]] are used along with ARBs and ACE inhibitors in proteinuria.<ref name="TotoTian2008">{{cite journal|last1=Toto|first1=Robert D.|last2=Tian|first2=Min|last3=Fakouhi|first3=Kaffa|last4=Champion|first4=Annette|last5=Bacher|first5=Peter|title=Effects of Calcium Channel Blockers on Proteinuria in Patients With Diabetic Nephropathy|journal=The Journal of Clinical Hypertension|volume=10|issue=10|year=2008|pages=761–769|issn=15246175|doi=10.1111/j.1751-7176.2008.00016.x}}</ref> <ref>{{Cite journal
| author = [[Katsuyuki Ando]]
| title = L-/N-type calcium channel blockers and proteinuria
| journal = [[Current hypertension reviews]]
| volume = 9
| issue = 3
| pages = 210–218
| year = 2013
| month = August
| pmid = 24479751
}}</ref>       
* '''Vitamin D:'''
** Down-regulating gene expression and immunosuppressive characteristic of [[vitamin D]] and its analogues help decrease proteinuria by blocking the [[renin-angiotensin-aldosterone system]].<ref>{{cite journal|doi=10.3265/Nefrologia.pre2013.Apr.12025}}</ref>       
* '''Management of infections:'''
** [[Antibiotics]] and [[vaccines]] are indicated for the treatment and prophylaxis of infectious diseases in individuals with proteinuria due to loss of [[immunoglobulins]], [[complements]], and circulating blood T cells.
* '''Diet:'''
** Excessive salt consumption decreases the effect of [[antihypertensive medications]] and leads to [[end-stage renal failure]]. 
===Primary Prevention===
* Primary prevention of proteinuria includes early diagnosis and treatment of diseases which lead to proteinuria.
===Secondary Prevention===
* Effective measures for secondary prevention of proteinuria include:
** Monitor the level of proteinuria to assess the progression of the disease 
** Monitor and treat lipid abnormalities 
** Check for effectiveness of the therapy and medications' side effects
** Monitor the [[renal function]] regularly
** Monitor and treat the complications of proteinuria
** Monitor for new signs of other diseases to address the treatment properly
==Related Chapters==
*[[Albuminuria]]
*[[Microalbuminuria]]
*[[List of terms associated with diabetes]]


==References==  
==References==  
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Latest revision as of 03:21, 1 May 2024

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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

Excretion of the proteins in the urine may suggest variety of medical conditions from benign to severe kidney injury. The amount of proteinuria can be used as a clue to estimate the site and the cause of proteinuria. Three factors which are involved in development of proteinuria are glomerular-capillary barrier, tubular reabsorption capability, and protein's characteristics.

Classification

Proteinuria is classified based upon the site and the amount of protein in the urine.[1]

Types Definition Level of proteinuria
Glomerular proteinuria Increased filtration rate of protein due to the damage to the glomerular-capillary barrier. Variable,

usually > 2g/day

Dipstick:Positive

Tubular proteinuria Decreased tubular reabsorption of proteins due to tubular cell damage. < 2 g/day

Dipstick:Negative

Overflow proteinuria Increased urinary excretion of proteins due to exceeding reabsorption capacity of renal tubules. Variable up to 20g/day

Dipstick:Negative

Post-renal proteinuria Increased urinary excretion of the small amount of protein especially IgA and IgG. Variable,

usually < 1g/day

Isolated proteinuria Proteinuria with normal urinary sediment with no history of renal disease. < 2 g/day
Proteinuria Amount
Normal range Total protein excretion in urine (proteinuria): < 150 mg/day, average 80 mg/day

Urine protein/creatinine ratio > 0.2 mg/mg[2]
Albumin excretion: < 20 mg/day (15 mcg/min), 15% of urine total protein
(remaining 85% constitutes Tamm-Horsfall proteins, IgA, urokinase) [3][4]

(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

Protein–to-creatinine ratio: > 3-3.5 mg protein/mg creatnine[2]

Pathophysiology

  • The amount of proteins present in the urine is < 150 mg/day with an intact glomerular-capillary barrier and functioning tubules, thus increased levels of proteinuria can demonstrate kidney damage (glomerular or tubular).
  • Overproduction of proteins which exceeds the absorption capacity of the tubules causes proteinuria in spite of relatively normal renal function (overflow).
  • Normally filtration of all plasma proteins like albumin, globulins and other high-molecular-weight proteins through the glomerular-capillary wall is prevented by charge and size of the proteins and glomerular-capillary barrier .
  • The type and quantity of proteins in the urine may identify the etiology and site of kidney damage.
  • As injury to the glomerular-capillary barrier causes albuminuria, tubular damage and overflow proteinuria lead to increase loads of low-molecular-weight proteins in the urine.
  • The severity of protein loss in the urine depends on the mechanism of renal injury.

Glomerular-capillary barrier

Tubular reabsorption

  • Almost all the proteins which are filtered through glomerulus are reabsorbed by proximal tubular cells by endocytosis.
  • The tubulointerstitial diseases damage the cells cause tubular proteinuria.
  • In circumstances where large amounts of protein is filtered, tubular proteinuria occurs as the filtered protein exceeds the reabsorption capacity of the cells.
  • Not all the proteins in the tubules are toxic to the cells but proximal tubule injury, light chain deposition, and tubule obstruction (cast nephropathy) due to the large amount of light chain may cause further proteinuria by the overwhelming capacity of tubular cells.

Proteins

  • The size of the protein is one of the determinants of traversal through the glomerular-capillary barrier. Immunoglobulins like IgG and other high-molecular-weight proteins have the higher molecular radius, therefore, there are not able to pass over the barrier.
  • Low-molecular-weight proteins are the ones with < 40kDa and molecular radius < 30 Å are filtered almost completely and reabsorbed by tubular cells.[6]
  • In normal physiological condition, HMW proteins do not cross the glomerular barrier. The small percentage of albumin passes the barrier which is reabsorbed completely in the proximal tubules. LMW proteins are filtered and reabsorbed completely. [7]
  • Moderate alteration of permeability of glomerular barrier named as selective proteinuria, demonstrates with loss of negative-charged proteins like albumin, LMW proteins and small percentage of HMW proteins in the urine with exceeding the reabsorption capacity of tubular cells.
  • Severe damage to the barrier causes loss of the greater percentage of HMW proteins in the urine which is called nonselective proteinuria.
  • Profound damage to glomerular barrier causes severe proteinuria of all classes especially LMW and HMW. Increasing loads of protein which exceed the reabsorption capability of tubular cells causes damage to tubular cells and worsens proteinuria.

(an average protein has 250 amino acids which equals molecular weight( MW) of approximately 34 kDa)

Glomerular-capillary wall, (ɔ) Image courtesy of WikiDoc.org, by "Saeedeh Kowsarnia M.D."

Causes

For more details on the causes of glomerular proteinuria, click here.

For more details on the causes of tubular proteinuria, click here.

Classification Etiology
Glomerular proteinuria Diabetic nephropathy, orthostatic proteinuria, glomerulonephropathies, hypertensive nephrosclerosis, preeclampsia, collagen vascular disease, infections, cancer, lymphoma, chronic renal transplant rejection, drugs, amyloidosis, post-transplant proteinuria

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, immunosuppressive agents, analgesic use

Excluding criteria: Proteinuria (≥ 3.5 g/day), edema, hypoalbuminemia, lipiduria, active urine sediment

(red blood cells and/or cast), decreased GFR, hypertension

Overflow proteinuria Light chains of immunoglobulins (multiple myeloma), lysozyme (AML), myoglobin (rhabdomyolysis), free hemoglobin not bound to haptoglobin (intravascular hemolysis), lymphoma, amyloidosis
Post-renal proteinuria Nephrolithiasis, urinary tract tumors or infections
Isolated proteinuria Damage to tubular cells or the lower urinary tract

There is a 20% risk for developing renal insufficiency in the next 10 years, close follow up with blood pressure measurement, urinalysis and creatinine clearance every 6 months [8]

Microalbuminuria

Essential hypertension, early diabetes, early stages of glomerulonephritis (especially with active sediments; RBCs, RBC casts)

Macroalbuminuria

Fever, exercise, CHF, orthostatic proteinuria, intermittent proteinuria, the 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


Causes by Organ System

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

Causes in Alphabetical Order

Risk Factors

The risk factors for proteinuria include:

Screening

  • Urinalysis may be considered as a part of routine health evaluation.
  • Monitor of renal function and proteinuria (micro- and microalbuminuria) is recommended in individuals with systemic diseases who are at risk of proteinuria.

Epidemiology and Demographics

  • Prevalence of albuminuria is 6100 and 9700 per 100,000 in male and female population, respectively.[14]
  • The estimated prevalence rate of albuminuria among diabetes population is 28,800 per 100,000 individuals.
  • The estimated prevalence rate of albuminuria among hypertensive population is 16,000 per 100,000 individuals.
  • Isolated albuminuria with normal renal function is estimated 3,300 per 100,000 adult population.

Natural History, Complications, and Prognosis

Natural History

Complications

Prognosis

Diagnosis

Diagnostic Study of Choice

Qualitative measures

  • Urine dipstick:
    • The standard urine dipstick is sensitive to urine albumin not to the non-albumin proteins, so the positive result indicates glomerular proteinuria.
    • The dipstick grading is semiquantitative to the amount of protein in the urine and is dependent upon urine concentration.
    • The sensitivity of the urinary dipstick for detection of albumin in the urine ranges from 83% to 98% with a specificity of 59% to 86%.[17]
    • At the lower level of albuminuria, especially microalbuminuria the urine dipstick is specific but not sensitive, therefore microalbuminuria cannot be detected easily by urine dipstick unless the urine is properly concentrated.
    • Few data suggests using specific gravity to estimate the amount of proteinuria, especially with the dipstick result of trace or 1+.
    • Highly concentrated urine overestimates the amount of proteinuria in the urine, similarly, highly diluted urine underestimates the degree of proteinuria detected by dipstick.
    • False-positive result: Urine PH > 8, administration of radiocontrast agents (iodinated), gross hematuria.
    • Newer dipsticks can detect albumin-to-creatinine and total protein-to-creatinine ratios which can help to avoid errors associated with diluted or concentrated urines and non-albumin proteinuria, respectively.
  • Sulfosalicylic acid test (SSA): Use of SSA is indicated in patients with the possibility of myeloma in the presence of negative or trace dipstick with renal function impairment. Adding SSA to the urine precipitates all proteins, therefore positive dipstick with SSA demonstrates overflow or tubular proteinuria.


Reference range for proteinuria Standard dipstick +/- SSA
Trace Slight turbidity (1 to 10 mg/dL)
1+ Turbidity through which print can be read (15 to 30 mg/dL)
2+ White cloud without precipitate through which print can be seen (40 to 100 mg/dL)
3+ White cloud with fine precipitate through which print cannot be seen (150 to 350 mg/dL)
4+ Fluffy precipitate (>500 mg/dL)

Quantitative measures

  • Spot urine collection:
    • Both the urinary protein to creatinine ratio and the urinary albumin creatinine ratio (ACR) can help diagnose proteinuria.[18]
  • The normal value for the urinary ACR is less than 30[18]

One study of patients with CKD found that the protein creatinine ratio was about three times higher than the albumin creatinine ratio[19].

  • 24-hour urine collection:
    • It is the gold standard test to determine the amount of proteinuria in patients who presents with persistent proteinuria (normal value < 150 mg/day). As collecting urine for 24 is cumbersome and erroneous, spot urine of first and second morning samples with protein-creatinine ratio can be used as an estimate of total protein excretion in 24 hour.[20]
24-hour protein excretion= Urine protein concentration / Urine creatinine concentration
  • Urine creatinine is higher in individuals with higher body muscle mass, therefore urine-protein ratio underestimates proteinuria, similarly in cachectic patients with lower muscle mass, urine-protein ratio overestimates the degree of proteinuria.
  • Renal biopsy: Renal biopsy is indicated in:
    • All nephrotic range proteinuria (> 3.5 gr/day)
    • Non-nephrotic range proteinuria with:
      • Active urine sediment
      • Persistent proteinuria > 1 gr/day
      • Decreased GFR
      • Progression of proteinuria or developing active sediment or hypertension

History and Symptoms

History:

Symptoms:

Physical Examination

Laboratory Findings

Laboratory investigations to be considered in proteinuria:

Treatment

Medical Therapy

Specific treatments of proteinuria demands proper diagnosis of the causes.

For the details on the treatments of glomerular diseases, click here.

For the details on the treatments of tubular diseases, click here.

Non-specific treatments reduce the amount of proteinuaria and the rate of progression or address the complications of proteinuria.

  • Diuretics:
    • The treatment of fluid overload in patients with moderate to severe proteinuria along with salt restriction is diuretics.
    • For refractory cases two different class of diuretics are used if the increasing doses are not effective.[21]
    • Acute renal failure is the consequence of aggressive therapy with diuretics.
  • ACE inhibitors and ARBs:
    • These agents decrease the progression and the amount of proteinuria by decreasing the intraglomerular pressure.[22]
    • Inhibiting vasoconstriction of efferent arterioles, maintaining the glomerular-capillary wall and decreasing the sclerosis and fibrosis of glomerulus are the action of these drugs aside the anti-hypertensive effects.[23]
    • In normotensive individuals with proteinuria low dose of these drugs have the effect without evident hypotension.[24]
    • Adverse effects of ACE inhibitors are cough, angioedema and hyperkalemia.
  • Mineralocorticoind receptor antagonists
    • Adding mineralocorticoid receptor antagonists like eplerenone and spironolactone, help reducing proteinuria further but increase the rate of hyperkalemia.
    • Eplerenone is the new drug in this category which is not associated with hyperkalemia.

Primary Prevention

  • Primary prevention of proteinuria includes early diagnosis and treatment of diseases which lead to proteinuria.

Secondary Prevention

  • Effective measures for secondary prevention of proteinuria include:
    • Monitor the level of proteinuria to assess the progression of the disease
    • Monitor and treat lipid abnormalities
    • Check for effectiveness of the therapy and medications' side effects
    • Monitor the renal function regularly
    • Monitor and treat the complications of proteinuria
    • Monitor for new signs of other diseases to address the treatment properly

Related Chapters

References

  1. Venkat, K K. (2004). "Proteinuria and Microalbuminuria in Adults: Significance, Evaluation, and Treatment". Southern Medical Journal. 97 (10): 969–979. doi:10.1097/01.SMJ.0000140833.51533.46. ISSN 0038-4348.
  2. 2.0 2.1 Ginsberg JM, Chang BS, Matarese RA, Garella S (1983). "Use of single voided urine samples to estimate quantitative proteinuria". N Engl J Med. 309 (25): 1543–6. PMID 6656849.
  3. Viswanathan, Gautham; Upadhyay, Ashish (2011). "Assessment of Proteinuria". Advances in Chronic Kidney Disease. 18 (4): 243–248. doi:10.1053/j.ackd.2011.03.002. ISSN 1548-5595.
  4. . doi:10.3265/Nefrologia.pre2011.Jan.10807. Missing or empty |title= (help)
  5. Toblli, Jorge E.; Bevione, P.; Di Gennaro, F.; Madalena, L.; Cao, G.; Angerosa, M. (2012). "Understanding the Mechanisms of Proteinuria: Therapeutic Implications". International Journal of Nephrology. 2012: 1–13. doi:10.1155/2012/546039. ISSN 2090-214X.
  6. D'Amico, Giuseppe; Bazzi, Claudio (2003). "Pathophysiology of proteinuria". Kidney International. 63 (3): 809–825. doi:10.1046/j.1523-1755.2003.00840.x. ISSN 0085-2538.
  7. Toblli, Jorge E.; Bevione, P.; Di Gennaro, F.; Madalena, L.; Cao, G.; Angerosa, M. (2012). "Understanding the Mechanisms of Proteinuria: Therapeutic Implications". International Journal of Nephrology. 2012: 1–13. doi:10.1155/2012/546039. ISSN 2090-214X.
  8. Abuelo JG (1983). "Proteinuria: diagnostic principles and procedures". Ann Intern Med. 98 (2): 186–91. PMID 6824253.
  9. 9.0 9.1 Van Vleet TR, Schnellmann RG (2003). "Toxic nephropathy: environmental chemicals". Semin Nephrol. 23 (5): 500–8. PMID 13680539.
  10. Bryson, Chris L.; Ross, Heather J.; Boyko, Edward J.; Young, Bessie A. (2006). "Racial and Ethnic Variations in Albuminuria in the US Third National Health and Nutrition Examination Survey (NHANES III) Population: Associations With Diabetes and Level of CKD". American Journal of Kidney Diseases. 48 (5): 720–726. doi:10.1053/j.ajkd.2006.07.023. ISSN 0272-6386.
  11. Rosenstock, Jordan L.; Pommier, Max; Stoffels, Guillaume; Patel, Satyam; Michelis, Michael F. (2018). "Prevalence of Proteinuria and Albuminuria in an Obese Population and Associated Risk Factors". Frontiers in Medicine. 5. doi:10.3389/fmed.2018.00122. ISSN 2296-858X.
  12. Ong, Loke Meng; Punithavathi, Narayanan; Thurairatnam, Dharminy; Zainal, Hadzlinda; Beh, Mei Li; Morad, Zaki; Lee, Sharleen YS; Bavanandan, Sunita; Kok, Lai Sun (2013). "Prevalence and risk factors for proteinuria: The National Kidney Foundation of Malaysia Lifecheck Health Screening programme". Nephrology. 18 (8): 569–575. doi:10.1111/nep.12112. ISSN 1320-5358.
  13. Bhalla, V.; Zhao, B.; Azar, K. M. J.; Wang, E. J.; Choi, S.; Wong, E. C.; Fortmann, S. P.; Palaniappan, L. P. (2012). "Racial/Ethnic Differences in the Prevalence of Proteinuric and Nonproteinuric Diabetic Kidney Disease". Diabetes Care. 36 (5): 1215–1221. doi:10.2337/dc12-0951. ISSN 0149-5992.
  14. Jones, Camille A.; Francis, Mildred E.; Eberhardt, Mark S.; Chavers, Blanche; Coresh, Josef; Engelgau, Michael; Kusek, John W.; Byrd-Holt, Danita; Narayan, K.M.Venkat; Herman, William H.; Jones, Camara P.; Salive, Marcel; Agodoa, Lawrence Y. (2002). "Microalbuminuria in the US population: Third National Health and Nutrition Examination Survey". American Journal of Kidney Diseases. 39 (3): 445–459. doi:10.1053/ajkd.2002.31388. ISSN 0272-6386.
  15. Astor, Brad C.; Matsushita, Kunihiro; Gansevoort, Ron T.; van der Velde, Marije; Woodward, Mark; Levey, Andrew S.; Jong, Paul E. de; Coresh, Josef (2011). "Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts". Kidney International. 79 (12): 1331–1340. doi:10.1038/ki.2010.550. ISSN 0085-2538.
  16. Borrego, J.; Mazuecos, A.; Gentil, M.A.; Cabello, M.; Rodríguez, A.; Osuna, A.; Pérez, M.A.; Castro, P.; Alonso, M. (2013). "Proteinuria as a Predictive Factor in the Evolution of Kidney Transplantation". Transplantation Proceedings. 45 (10): 3627–3629. doi:10.1016/j.transproceed.2013.10.025. ISSN 0041-1345.
  17. Mark J. Siedner, Allan C. Gelber, Brad H. Rovin, Alison M. McKinley, Lisa Christopher-Stine, Brad Astor, Michelle Petri & Derek M. Fine (2008). "Diagnostic accuracy study of urine dipstick in relation to 24-hour measurement as a screening tool for proteinuria in lupus nephritis". The Journal of rheumatology. 35 (1): 84–90. PMID 18085740. Unknown parameter |month= ignored (help)
  18. 18.0 18.1 https://kdigo.org/guidelines/diabetes-ckd/
  19. Fisher H, Hsu CY, Vittinghoff E, Lin F, Bansal N (2013). "Comparison of associations of urine protein-creatinine ratio versus albumin-creatinine ratio with complications of CKD: a cross-sectional analysis". Am J Kidney Dis. 62 (6): 1102–8. doi:10.1053/j.ajkd.2013.07.013. PMC 3840083. PMID 24041612.
  20. Mark J. Siedner, Allan C. Gelber, Brad H. Rovin, Alison M. McKinley, Lisa Christopher-Stine, Brad Astor, Michelle Petri & Derek M. Fine (2008). "Diagnostic accuracy study of urine dipstick in relation to 24-hour measurement as a screening tool for proteinuria in lupus nephritis". The Journal of rheumatology. 35 (1): 84–90. PMID 18085740. Unknown parameter |month= ignored (help)
  21. Fukuda, Michio; Kimura, Genjiro (2008). "Diuretics should be used as the second-line agent in combination with RAS inhibitors in ptoteinuric patients with CKD". Kidney International. 74 (10): 1358. doi:10.1038/ki.2008.466. ISSN 0085-2538.
  22. Hsu, Feng-Yi; Lin, Fang-Ju; Ou, Huang-Tz; Huang, Shih-Hui; Wang, Chi-Chuan (2017). "Renoprotective Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Diabetic Patients with Proteinuria". Kidney and Blood Pressure Research. 42 (2): 358–368. doi:10.1159/000477946. ISSN 1420-4096.
  23. Toblli, Jorge E.; Bevione, P.; Di Gennaro, F.; Madalena, L.; Cao, G.; Angerosa, M. (2012). "Understanding the Mechanisms of Proteinuria: Therapeutic Implications". International Journal of Nephrology. 2012: 1–13. doi:10.1155/2012/546039. ISSN 2090-214X.
  24. Gansevoort RT, de Zeeuw D, de Jong PE (1996). "ACE inhibitors and proteinuria". Pharm World Sci. 18 (6): 204–10. PMID 9010883.
  25. Toto, Robert D.; Tian, Min; Fakouhi, Kaffa; Champion, Annette; Bacher, Peter (2008). "Effects of Calcium Channel Blockers on Proteinuria in Patients With Diabetic Nephropathy". The Journal of Clinical Hypertension. 10 (10): 761–769. doi:10.1111/j.1751-7176.2008.00016.x. ISSN 1524-6175.
  26. Katsuyuki Ando (2013). "L-/N-type calcium channel blockers and proteinuria". Current hypertension reviews. 9 (3): 210–218. PMID 24479751. Unknown parameter |month= ignored (help)
  27. . doi:10.3265/Nefrologia.pre2013.Apr.12025. Missing or empty |title= (help)

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