Editing Proteinuria

{{Short description|Presence of an excess of serum proteins in the urine}}
{{Use dmy dates|date=April 2025}}
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{{Infobox medical condition (new)
 |name          = Proteinuria
 |synonym       =
 |image         = 2020-04-03 10.07.45 Wonju Sevrance Christian Hospital Healthcare Center.jpg
 |image_size    = 350px
 |alt           =
 |caption       = Various test tubes of urine
 |pronounce     = {{IPAc-en|ˌ|p|r|oʊ|t|iː|ˈ|nj|ʊər|i|ə}}
 |specialty     = [[Nephrology]]
 |symptoms      =
 |complications = [[Protein toxicity]]
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 |diagnosis     =
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'''Proteinuria''' is the presence of excess [[protein]]s in the [[urine]]. In healthy persons, urine contains [[clinical urine tests#Proteins and enzymes|very little protein]], less than 150&nbsp;mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy (although this symptom may also be caused by other conditions). Severe proteinuria can cause [[nephrotic syndrome]] in which there is worsening swelling of the body.

==Signs and symptoms==
Proteinuria often causes no symptoms and it may only be discovered incidentally.<ref>{{Cite web |title=Proteinuria Causes, Symptoms, Diagnosis and Treatment |url=https://cura4u.com/conditions/proteinuria |access-date=19 October 2023 |website=Cura4U |language=en-us}}</ref>

Foamy urine is considered a cardinal sign of proteinuria, but only a third of people with foamy urine have proteinuria as the underlying cause.<ref>{{cite journal |last1=Khitan |first1=Zeid J. |last2=Glassock |first2=Richard J. |title=Foamy Urine: Is This a Sign of Kidney Disease? |journal=Clinical Journal of the American Society of Nephrology |date=November 2019 |volume=14 |issue=11 |pages=1664–1666 |doi=10.2215/CJN.06840619 |pmid=31575619 |pmc=6832055 |doi-access=free }}</ref> It may also be caused by [[bilirubin]] in the urine ([[bilirubinuria]]),<ref name=friedlander >{{Cite web |title=Urinalysis |first=Ed|last=Friedlander |website=pathguy.com |date=1 January 2016|url= http://www.pathguy.com/lectures/urine.html|url-status=dead|archive-url=https://web.archive.org/web/20060816080010/http://www.pathguy.com/lectures/urine.htm|archive-date=16 August 2006}}{{self-published inline|date=April 2025}}</ref>{{Better source needed|date=April 2025}} [[retrograde ejaculation]], pneumaturia (air bubbles in the urine) due to a [[fistula]],<ref>{{Cite GPnotebook|1161101335|Pneumaturia}} Retrieved 20 January 2007</ref> or drugs such as [[pyridium]].<ref name=friedlander />{{Better source needed|date=April 2025}}

== Causes ==
There are three main mechanisms to cause proteinuria:<ref>{{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. |date=4 July 2012 |title=Understanding the Mechanisms of Proteinuria: Therapeutic Implications |journal=International Journal of Nephrology |volume=2012 |pages=546039 |doi=10.1155/2012/546039 |pmc=3398673 |pmid=22844592 |doi-access=free }}</ref>
* Due to disease in the [[Glomerulus (kidney)|glomerulus]]
* Because of increased quantity of proteins in [[blood serum|serum]]  (overflow proteinuria)
* Due to low reabsorption at [[proximal tubule]] ([[Fanconi syndrome]])

Proteinuria can also be caused by certain biological agents, such as [[bevacizumab]] (Avastin) used in cancer treatment.  Excessive fluid intake (drinking in excess of 4 litres of water per day) is another cause.<ref>{{cite journal |vauthors=Clark WF, Kortas C, Suri RS, Moist LM, Salvadori M, Weir MA, Garg AX | title = Excessive fluid intake as a novel cause of proteinuria | journal = Canadian Medical Association Journal | volume = 178 | issue = 2 | pages = 173–175 | year = 2008 | pmid = 18195291 | pmc = 2175005 | doi = 10.1503/cmaj.070792 }}</ref><ref>{{cite news |url=http://www.canada.com/montrealgazette/news/story.html?id=378f85de-27de-4046-815e-293b772666e5 |title=Drinking too much water called latest threat to health |date=January 2008 |newspaper=Montreal Gazette |url-status=dead |archive-url=https://web.archive.org/web/20120214005346/http://www.canada.com/montrealgazette/news/story.html?id=378f85de-27de-4046-815e-293b772666e5 |archive-date=14 February 2012 }}</ref>

===Conditions with proteinuria===

Proteinuria may be a feature of the following conditions:<ref name="pmid15791892"/>
* [[Nephrotic syndromes]] (i.e. intrinsic [[kidney failure]])
* [[Pre-eclampsia]]
* [[Eclampsia]]
* Toxic lesions of [[kidney]]s
* Amyloidosis
* Collagen vascular diseases (e.g. [[systemic lupus erythematosus]])
* Dehydration
* [[Glomerulus (kidney)|Glomerular]] diseases, such as [[membranous glomerulonephritis]], focal segmental [[glomerulonephritis]], minimal change disease ([[lipoid nephrosis]])
* Strenuous exercise
* Stress
* [[Benign orthostatic (postural) proteinuria]]
* [[Focal segmental glomerulosclerosis]] (FSGS)
* [[IgA nephropathy]] (i.e. Berger's disease)
* [[IgM nephropathy]]
* [[Membranoproliferative glomerulonephritis]]
* [[Membranous nephropathy]]
* [[Minimal change disease]]
* [[Sarcoidosis]]
* [[Alport syndrome]]
* [[Diabetes mellitus]] ([[diabetic nephropathy]])
* Drugs (e.g. [[NSAIDs]], [[nicotine]], [[penicillamine]], [[lithium carbonate]], gold and other [[Heavy metal (chemistry)|heavy metals]], [[ACE inhibitors]], [[antibiotics]], or [[opiates]] (especially [[heroin]])<ref name="pmid15709895">{{cite journal |vauthors=Dettmeyer RB, Preuss J, Wollersen H, Madea B | title = Heroin-associated nephropathy | journal = Expert Opinion on Drug Safety | volume = 4 | issue = 1 | pages = 19–28 | year = 2005 | pmid = 15709895 | doi = 10.1517/14740338.4.1.19 }}</ref>
* [[Fabry disease]]
* Infections (e.g. [[HIV]], [[syphilis]], [[hepatitis]], [[poststreptococcal infection]], urinary [[schistosomiasis]])
* [[Aminoaciduria]]
* [[Fanconi syndrome]] in association with [[Wilson disease]]
* [[Hypertensive nephrosclerosis]]
* [[Interstitial nephritis]]
* [[Sickle cell disease]]
* [[Hemoglobinuria]]
* [[Multiple myeloma]]
* [[Myoglobinuria]]
* [[Organ rejection]]:<ref>{{cite journal |last1=Naesens |first1=Maarten |last2=Lerut |first2=Evelyne |last3=Emonds |first3=Marie-Paule |last4=Herelixka |first4=Albert |last5=Evenepoel |first5=Pieter |last6=Claes |first6=Kathleen |last7=Bammens |first7=Bert |last8=Sprangers |first8=Ben |last9=Meijers |first9=Björn |last10=Jochmans |first10=Ina |last11=Monbaliu |first11=Diethard |last12=Pirenne |first12=Jacques |last13=Kuypers |first13=Dirk R.J. |title=Proteinuria as a Noninvasive Marker for Renal Allograft Histology and Failure: An Observational Cohort Study |journal=Journal of the American Society of Nephrology |date=January 2016 |volume=27 |issue=1 |pages=281–292 |doi=10.1681/ASN.2015010062 |pmid=26152270 |pmc=4696583 }}</ref>
* [[Ebola virus disease]]
* [[Nail–patella syndrome]]
* [[Familial Mediterranean fever]]
* [[HELLP syndrome]]
* [[Systemic lupus erythematosus]]
* [[Granulomatosis with polyangiitis]]
* [[Rheumatoid arthritis]]
* [[Glycogen storage disease]] type 1<ref name="pmid11949931">{{cite journal |vauthors=Chou JY, Matern D, Mansfield BC, Chen YT | title = Type 1 Glycogen Storage Diseases: Disorders of the Glucose-6-Phosphatase Complex | journal = Current Molecular Medicine | volume = 2 | issue = 2 | pages = 121–143 | year = 2002 | pmid = 11949931 | doi = 10.2174/1566524024605798 }}</ref>
* [[Goodpasture syndrome]]
* [[Henoch–Schönlein purpura]]
* A [[urinary tract infection]] which has spread to the kidney(s)
* [[Sjögren syndrome]]
* [[Post-infectious glomerulonephritis]]
* [[Kidney transplantation|Living kidney donor]]<ref>{{Cite journal|last=Fernando|first=B.S.|date=14 June 2008|title=A Doctor's Perspective|journal=BMJ|volume=336|issue=7657|pages=1374–6|doi=10.1136/bmj.a277|pmid=18556321|pmc=2427141}}</ref>
* [[Polycystic kidney disease]]<ref>{{cite journal |last1=Chapman |first1=A B |last2=Johnson |first2=A M |last3=Gabow |first3=P A |last4=Schrier |first4=R W |title=Overt proteinuria and microalbuminuria in autosomal dominant polycystic kidney disease |journal=Journal of the American Society of Nephrology |date=December 1994 |volume=5 |issue=6 |pages=1349–1354 |doi=10.1681/ASN.V561349 |pmid=7894001 |doi-access=free }}</ref>
{{Incomplete list|date=December 2008}}

===Bence–Jones proteinuria===
* [[Amyloidosis]]
* Pre-malignant [[plasma cell dyscrasia]]s:
** [[Monoclonal gammopathy of undetermined significance]]
** [[Smoldering multiple myeloma]]
* Malignant [[plasma cell dyscrasia]]s
** [[Multiple myeloma]]
** [[Waldenström's macroglobulinemia]]
* Other malignancies
** [[Chronic lymphocytic leukemia]]
** Rare cases of other [[Lymphoid leukemia]]s
** Rare cases of [[Lymphoma]]s

==Pathophysiology==

[[Protein]] is the building block of all living organisms.<ref name="Lab Tests Online">{{cite web | title=Urine Protein | website=Lab Tests Online | url=https://labtestsonline.org/tests/urine-protein-and-urine-protein-creatinine-ratio | access-date=21 May 2019}}</ref> When kidneys are functioning properly by filtering the blood, they distinguish the proteins from the wastes which were previously present together in the blood.<ref name="Lab Tests Online"/> Thereafter, kidneys retain or reabsorb the filtered proteins and return them to the circulating blood while removing wastes by excreting them in the urine.<ref name="Lab Tests Online"/> Whenever the kidney is compromised, their ability to filter the blood by differentiating protein from the waste, or retaining the filtered protein then returning which back to the body, is damaged.<ref name="Lab Tests Online"/> As a result, there is a significant amount of protein to be discharged along with waste in the urine that makes the concentration of proteins in urine high enough to be detected by medical machine.<ref name="Lab Tests Online"/>

Medical testing equipment has improved over time, and as a result tests are better able to detect smaller quantities of protein.<ref name="Lab Tests Online"/> Protein in urine is considered normal as long as the value remains within the normal reference range.<ref name="Lab Tests Online"/> Variation exists between healthy patients, and it is generally considered harmless for the kidney to fail to retain a few proteins in the blood, letting those protein discharge from the body through urine.<ref name="Lab Tests Online"/>

===Albumin and immunoglobins===

Albumin is a protein produced by the liver which makes up roughly 50%-60% of the total proteins in the blood while the other 40%-50% are proteins other than albumin, such as immunoglobins.<ref name="Lab Tests Online II">{{cite web | title=Globulin | website=Lab Tests Online | url=https://labtestsonline.org/glossary/globulin | access-date=22 May 2019}}</ref><ref name="Lab Tests Online"/> This is why [[albuminuria|the concentration of albumin in the urine]] is one of the single sensitive indicators of kidney disease, particularly for those with diabetes or hypertension, compared to routine proteinuria examination.<ref name="Lab Tests Online"/>

As the loss of proteins from the body progresses, the suffering will gradually become symptomatic.<ref name="Lab Tests Online"/>

The exception applies to the scenario when there's an overproduction of proteins in the body, in which the kidney is not to blame.<ref name="Lab Tests Online"/>

==Diagnosis==
{|class="wikitable" align="right"
!colspan=3| Protein dipstick grading
|-
!rowspan=2| Designation !! colspan=2| Approx. amount
|-
| Concentration<ref>{{EMedicine|article|984289|Pediatric Proteinuria}}</ref> || Daily<ref>{{cite journal |vauthors=Ivanyi B, Kemeny E, Szederkenyi E, Marofka F, Szenohradszky P | title = The value of electron microscopy in the diagnosis of chronic renal allograft rejection | journal = Mod. Pathol. | volume = 14 | issue = 12 | pages = 1200–8 | date = December 2001 | pmid = 11743041 | doi = 10.1038/modpathol.3880461 | doi-access = free }}</ref>
|-
| Trace || 5–20&nbsp;mg/dL ||
|-
| 1+ || 30&nbsp;mg/dL || Less than 0.5 g/day
|-
| 2+ || 100&nbsp;mg/dL || 0.5–1 g/day
|-
| 3+ || 300&nbsp;mg/dL || 1–2 g/day
|-
| 4+ || More than 1000&nbsp;mg/dL || More than 2 g/day
|}
Conventionally, proteinuria is diagnosed by a simple [[Urine test strip|dipstick test]], although it is possible for the test to give a false negative reading,<ref name="pmid15791892">{{cite journal |last1=Simerville |first1=Jeff A. |last2=Maxted |first2=William C. |last3=Pahira |first3=John J. |title=Urinalysis: a comprehensive review |journal=American Family Physician |date=15 March 2005 |volume=71 |issue=6 |pages=1153–1162 |id={{ProQuest|234160912}} |pmid=15791892 |url=https://www.aafp.org/link_out?pmid=15791892 }}</ref> even with nephrotic range proteinuria if the urine is dilute.<ref>{{cite book |doi=10.1016/B978-0-323-04107-2.50126-5 |chapter=Proteinuria |title=Decision Making in Medicine |date=2010 |pages=358–361 |isbn=978-0-323-04107-2 | vauthors = Worobey CC, Singh AK }}</ref> False negatives may also occur if the protein in the urine is composed mainly of [[globulin]]s or [[Bence Jones proteins]] because the reagent on the test strips, [[bromophenol blue]], is highly specific for albumin.<ref name="pmid15791892"/><ref>{{cite web |url=http://medlib.med.utah.edu/WebPath/TUTORIAL/URINE/URINE.html |title=Urinalysis |access-date=6 August 2006 |url-status=dead |archive-url=https://web.archive.org/web/20060810213920/http://medlib.med.utah.edu/WebPath/TUTORIAL/URINE/URINE.html |archive-date=10 August 2006 }} Retrieved 20 January 2007</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 name=friedlander />{{Better source needed|date=April 2025}}<ref>{{cite web |url=http://www.answers.com/topic/protein-electrophoresis |title=Answers - the Most Trusted Place for Answering Life's Questions |website=[[Answers.com]] |access-date=6 August 2006 |url-status=live |archive-url=https://web.archive.org/web/20070212061659/http://www.answers.com/topic/protein-electrophoresis |archive-date=12 February 2007 }} Retrieved 20 January 2007</ref>

More recently developed technology detects [[human serum albumin]] (HSA) through the use of [[liquid crystal]]s (LCs). The presence of HSA molecules disrupts the LCs supported on the AHSA-decorated slides thereby producing bright optical signals which are easily distinguishable. Using this assay, concentrations of HSA as low as 15&nbsp;μg/mL can be detected.<ref name="Aliño">{{cite journal |vauthors=Aliño VJ, Yang KL | title = Using liquid crystals as a readout system in urinary albumin assays. | journal = Analyst | volume = 136 | issue = 16 | pages = 3307–13 | year = 2011 | pmid = 21709868 | doi = 10.1039/c1an15143f | bibcode = 2011Ana...136.3307A }}</ref>

Alternatively, the concentration of protein in the urine may be compared to the [[creatinine]] level in a spot urine sample. This is termed the protein/creatinine ratio. The 2005 UK Chronic Kidney Disease guidelines state that protein/creatinine ratio is a better test than 24-hour urinary protein measurement. Proteinuria is defined as a protein/creatinine ratio greater than 45&nbsp;mg/mmol (which is equivalent to [[Microalbuminuria|albumin/creatinine ratio]] of greater than 30&nbsp;mg/mmol or approximately 300&nbsp;mg/g) with very high levels of proteinuria having a ratio greater than 100&nbsp;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 |date=27 September 2005 |publisher=UK Renal Association |url-status=dead |archive-url=https://web.archive.org/web/20130219152620/http://www.renal.org/CKDguide/full/Conciseguid141205.pdf |archive-date=19 February 2013 }} – see Guideline 4 Confirmation of proteinuria, on page 9</ref>

Protein dipstick measurements should not be confused with the amount of protein detected on a test for [[microalbuminuria]] which denotes values for protein for urine in mg/day versus urine protein dipstick values which denote values for protein in mg/dL. That is, there is a basal level of proteinuria that can occur below 30&nbsp;mg/day which is considered non-pathology. Values between 30 and 300&nbsp;mg/day are termed [[microalbuminuria]] which is considered pathologic.<ref>{{cite journal|title=Urinary dipstick protein: a poor predictor of absent or severe proteinuria.|journal=Am J Obstet Gynecol |pmid=8296815|volume=170|issue=1 Pt 1 |date=Jan 1994|pages=137–41|doi=10.1016/s0002-9378(94)70398-1|vauthors=Meyer NL, Mercer BM, Friedman SA, Sibai BM }}</ref> Urine protein lab values for microalbumin of >30&nbsp;mg/day correspond to a detection level within the "trace" to "1+" range of a urine dipstick protein assay.  Therefore, positive indication of any protein detected on a urine dipstick assay obviates any need to perform a urine microalbumin test as the upper limit for microalbuminuria has already been exceeded.<ref>{{cite web|title=The Urine Dipstick|url=http://www.georgiahealth.edu/alliedhealth/pa/documents/ClinicianReviewsCC.UrineDipstick.Gunder.pdf|publisher=Georgia Regents University|url-status=dead|archive-url=https://web.archive.org/web/20130616063747/http://www.georgiahealth.edu/alliedhealth/pa/documents/ClinicianReviewsCC.UrineDipstick.Gunder.pdf|archive-date=16 June 2013}}</ref>

===Analysis===
It is possible to analyze urine samples in determining [[albumin]], [[hemoglobin]] and [[myoglobin]] with an optimized [[Micellar electrokinetic chromatography|MEKC]] method.<ref>{{cite journal |vauthors=Kočevar Glavač N, Injac R, Kreft S | year = 2009 | title = Optimization and Validation of a Capillary MEKC Method for Determination of Proteins in Urine | journal = Chromatographia | volume = 70 | issue = 9–10| pages = 1473–1478 | doi = 10.1365/s10337-009-1317-3 }}</ref>

==Treatment==
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 |vauthors=Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD | 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 | doi = 10.1681/ASN.2009070737 }}</ref> or [[angiotensin receptor blocker]] (ARB)<ref name="Burgess">{{cite journal |vauthors=Burgess E, Muirhead N, Rene de Cotret P, Chiu A, Pichette V, Tobe S | 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 | doi = 10.1681/ASN.2008040416 }}</ref> may further reduce protein loss.

[[Atrasentan]] (Vanrafia) was approved for medical use in the United States in April 2025.<ref name="Novartis PR 20250403">{{cite press release | title=Novartis receives FDA accelerated approval for Vanrafia (atrasentan), the first and only selective endothelin A receptor antagonist for proteinuria reduction in primary IgA nephropathy (IgAN) | website=Novartis | date=3 April 2025 | url=https://www.novartis.com/news/media-releases/novartis-receives-fda-accelerated-approval-vanrafia-atrasentan-first-and-only-selective-endothelin-receptor-antagonist-proteinuria-reduction-primary-iga-nephropathy-igan | access-date=4 April 2025}}</ref>

==See also==
* [[List of terms associated with diabetes]]

==References==
{{reflist}}

==External links==
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