COVID-19-associated acute kidney injury: Difference between revisions
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**[[Prerenal]] [[AKI]] | **[[Prerenal]] [[AKI]] | ||
**[[Rhabdomyolysis]]-induced [[AKI]] | **[[Rhabdomyolysis]]-induced [[AKI]] | ||
**[[Intrinsic]] [[AKI]] | **[[Intrinsic]] [[AKI]] is the most common subtype of [[AKI]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
* [[Angiotensin-converting enzyme 2]] ([[ACE2]]), which is a primary receptor for [[SARS-CoV-2]] entry into cells, mostly presents in renal tubular epithelial cells as well as lungs and heart.<ref name="MalhaMueller2020">{{cite journal|last1=Malha|first1=Line|last2=Mueller|first2=Franco B.|last3=Pecker|first3=Mark S.|last4=Mann|first4=Samuel J.|last5=August|first5=Phyllis|last6=Feig|first6=Peter U.|title=COVID-19 and the Renin-Angiotensin System|journal=Kidney International Reports|volume=5|issue=5|year=2020|pages=563–565|issn=24680249|doi=10.1016/j.ekir.2020.03.024}}</ref> | * [[Angiotensin-converting enzyme 2]] ([[ACE2]]), which is a primary [[receptor]] for [[SARS-CoV-2]] entry into cells, mostly presents in [[renal]] [[tubular]] [[epithelial]] cells as well as [[lungs]] and [[heart]].<ref name="MalhaMueller2020">{{cite journal|last1=Malha|first1=Line|last2=Mueller|first2=Franco B.|last3=Pecker|first3=Mark S.|last4=Mann|first4=Samuel J.|last5=August|first5=Phyllis|last6=Feig|first6=Peter U.|title=COVID-19 and the Renin-Angiotensin System|journal=Kidney International Reports|volume=5|issue=5|year=2020|pages=563–565|issn=24680249|doi=10.1016/j.ekir.2020.03.024}}</ref> | ||
* Despite kidney injury following [[COVID-19]] infection is less frequent than severe lung injury, [[ACE2]]: [[ACE]] ratio is higher in the kidneys compared to the [[respiratory system]]. (1:1 in the kidneys VS 1:20 in the respiratory system)<ref name="MalhaMueller2020">{{cite journal|last1=Malha|first1=Line|last2=Mueller|first2=Franco B.|last3=Pecker|first3=Mark S.|last4=Mann|first4=Samuel J.|last5=August|first5=Phyllis|last6=Feig|first6=Peter U.|title=COVID-19 and the Renin-Angiotensin System|journal=Kidney International Reports|volume=5|issue=5|year=2020|pages=563–565|issn=24680249|doi=10.1016/j.ekir.2020.03.024}}</ref> | * Despite kidney injury following [[COVID-19]] infection is less frequent than severe lung injury, [[ACE2]]: [[ACE]] ratio is higher in the kidneys compared to the [[respiratory system]]. (1:1 in the kidneys VS 1:20 in the respiratory system)<ref name="MalhaMueller2020">{{cite journal|last1=Malha|first1=Line|last2=Mueller|first2=Franco B.|last3=Pecker|first3=Mark S.|last4=Mann|first4=Samuel J.|last5=August|first5=Phyllis|last6=Feig|first6=Peter U.|title=COVID-19 and the Renin-Angiotensin System|journal=Kidney International Reports|volume=5|issue=5|year=2020|pages=563–565|issn=24680249|doi=10.1016/j.ekir.2020.03.024}}</ref> | ||
* After [[SARS-CoV-2]] enters through the nasal cavity, it may travel to the kidneys and enters the bloodstream leading to severe inflammatory response activation and [[cytokine]] storm. | * After [[SARS-CoV-2]] enters through the [[nasal cavity]], it may travel to the [[kidneys]] and enters the bloodstream leading to severe [[inflammatory]] response activation and [[cytokine]] storm. | ||
**[[Cytokine]] induced [[AKI]] may occur due to intrarenal [[inflammation]], hyperpermeability of vessels, [[hypovolemia]] and [[cardiomyopathy]], leading to [[cardiorenal syndrome]] type 1 that is characterized by '''third space''' '''volume overload''' such as [[pleural effusion]], [[edema]] and '''intravascular volume loss''' ([[hypovolemia]]) and [[hypotension]].<ref name="pmid32273593">{{cite journal| author=Ronco C, Reis T| title=Kidney involvement in COVID-19 and rationale for extracorporeal therapies. | journal=Nat Rev Nephrol | year= 2020 | volume= 16 | issue= 6 | pages= 308-310 | pmid=32273593 | doi=10.1038/s41581-020-0284-7 | pmc=7144544 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32273593 }} </ref> | **[[Cytokine]] induced [[AKI]] may occur due to [[intrarenal]] [[inflammation]], hyperpermeability of vessels, [[hypovolemia]] and [[cardiomyopathy]], leading to [[cardiorenal syndrome]] type 1 that is characterized by '''third space''' '''volume overload''' such as [[pleural effusion]], [[edema]] and '''intravascular volume loss''' ([[hypovolemia]]) and [[hypotension]].<ref name="pmid32273593">{{cite journal| author=Ronco C, Reis T| title=Kidney involvement in COVID-19 and rationale for extracorporeal therapies. | journal=Nat Rev Nephrol | year= 2020 | volume= 16 | issue= 6 | pages= 308-310 | pmid=32273593 | doi=10.1038/s41581-020-0284-7 | pmc=7144544 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32273593 }} </ref> | ||
**The major [[cytokine]] is [[IL-6]], which induces [[inflammation]] and lung [[endothelial cell]] injury, leading to [[ARDS]] and [[hypoxia]] that subsequently cause renal [[tubular cell]] injury and [[AKI]]. <ref name="pmid27337068">{{cite journal| author=Husain-Syed F, Slutsky AS, Ronco C| title=Lung-Kidney Cross-Talk in the Critically Ill Patient. | journal=Am J Respir Crit Care Med | year= 2016 | volume= 194 | issue= 4 | pages= 402-14 | pmid=27337068 | doi=10.1164/rccm.201602-0420CP | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27337068 }} </ref><ref name="pmid32273593">{{cite journal| author=Ronco C, Reis T| title=Kidney involvement in COVID-19 and rationale for extracorporeal therapies. | journal=Nat Rev Nephrol | year= 2020 | volume= 16 | issue= 6 | pages= 308-310 | pmid=32273593 | doi=10.1038/s41581-020-0284-7 | pmc=7144544 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32273593 }} </ref> | ***[[cardiomyopathy]] and [[COVID-19-associated myocarditis]] can lead to [[hypotension]] and reduction in [[renal]] [[perfusion]]. | ||
**The major [[cytokine]] is [[IL-6]], which induces [[inflammation]] and lung [[endothelial cell]] injury, leading to [[ARDS]] and [[hypoxia]] that subsequently cause [[renal]] [[tubular cell]] injury and [[AKI]]. <ref name="pmid27337068">{{cite journal| author=Husain-Syed F, Slutsky AS, Ronco C| title=Lung-Kidney Cross-Talk in the Critically Ill Patient. | journal=Am J Respir Crit Care Med | year= 2016 | volume= 194 | issue= 4 | pages= 402-14 | pmid=27337068 | doi=10.1164/rccm.201602-0420CP | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27337068 }} </ref><ref name="pmid32273593">{{cite journal| author=Ronco C, Reis T| title=Kidney involvement in COVID-19 and rationale for extracorporeal therapies. | journal=Nat Rev Nephrol | year= 2020 | volume= 16 | issue= 6 | pages= 308-310 | pmid=32273593 | doi=10.1038/s41581-020-0284-7 | pmc=7144544 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32273593 }} </ref> | |||
[[File:IL-6-AKI-COVID-19.PNG|600px|center]] | [[File:IL-6-AKI-COVID-19.PNG|600px|center]] | ||
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**[[Hypovolemia]] and [[Hypotension]] | **[[Hypovolemia]] and [[Hypotension]] | ||
**[[Hypoxemia]] | **[[Hypoxemia]] | ||
**Blood clots formation due to [[ | **Blood [[clots]] formation due to [[hypercoagulable]] state, leading to impaired blood flow in the [[renal]] [[arterioles]]. | ||
[[File:AKI physiopathology COVID.PNG|700px|center]] | [[File:AKI physiopathology COVID.PNG|700px|center]] | ||
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== Risk Factors == | == Risk Factors == | ||
* The most potent risk factors in the development of [[COVID-19]] associated [[AKI]] include<ref name="pmid32250968">{{cite journal| author=Rabb H| title=Kidney diseases in the time of COVID-19: major challenges to patient care. | journal=J Clin Invest | year= 2020 | volume= 130 | issue= 6 | pages= 2749-2751 | pmid=32250968 | doi=10.1172/JCI138871 | pmc=7259985 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32250968 }} </ref> <ref name="pmid32457068">{{cite journal| author=Selby NM, Forni LG, Laing CM, Horne KL, Evans RD, Lucas BJ | display-authors=etal| title=Covid-19 and acute kidney injury in hospital: summary of NICE guidelines. | journal=BMJ | year= 2020 | volume= 369 | issue= | pages= m1963 | pmid=32457068 | doi=10.1136/bmj.m1963 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32457068 }} </ref>: | * The most potent [[risk factors]] in the development of [[COVID-19]] associated [[AKI]] include<ref name="pmid32250968">{{cite journal| author=Rabb H| title=Kidney diseases in the time of COVID-19: major challenges to patient care. | journal=J Clin Invest | year= 2020 | volume= 130 | issue= 6 | pages= 2749-2751 | pmid=32250968 | doi=10.1172/JCI138871 | pmc=7259985 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32250968 }} </ref> <ref name="pmid32457068">{{cite journal| author=Selby NM, Forni LG, Laing CM, Horne KL, Evans RD, Lucas BJ | display-authors=etal| title=Covid-19 and acute kidney injury in hospital: summary of NICE guidelines. | journal=BMJ | year= 2020 | volume= 369 | issue= | pages= m1963 | pmid=32457068 | doi=10.1136/bmj.m1963 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32457068 }} </ref>: | ||
** [[Elderly]] | ** [[Elderly]] | ||
*** Age>60 years | *** Age>60 years | ||
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*Severe [[COVID-19]] pneumonia and severe [[acute respiratory distress syndrome]] are associated with developing [[AKI]].<ref name="PeiZhang2020">{{cite journal|last1=Pei|first1=Guangchang|last2=Zhang|first2=Zhiguo|last3=Peng|first3=Jing|last4=Liu|first4=Liu|last5=Zhang|first5=Chunxiu|last6=Yu|first6=Chong|last7=Ma|first7=Zufu|last8=Huang|first8=Yi|last9=Liu|first9=Wei|last10=Yao|first10=Ying|last11=Zeng|first11=Rui|last12=Xu|first12=Gang|title=Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia|journal=Journal of the American Society of Nephrology|volume=31|issue=6|year=2020|pages=1157–1165|issn=1046-6673|doi=10.1681/ASN.2020030276}}</ref> | *Severe [[COVID-19]] pneumonia and severe [[acute respiratory distress syndrome]] are associated with developing [[AKI]].<ref name="PeiZhang2020">{{cite journal|last1=Pei|first1=Guangchang|last2=Zhang|first2=Zhiguo|last3=Peng|first3=Jing|last4=Liu|first4=Liu|last5=Zhang|first5=Chunxiu|last6=Yu|first6=Chong|last7=Ma|first7=Zufu|last8=Huang|first8=Yi|last9=Liu|first9=Wei|last10=Yao|first10=Ying|last11=Zeng|first11=Rui|last12=Xu|first12=Gang|title=Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia|journal=Journal of the American Society of Nephrology|volume=31|issue=6|year=2020|pages=1157–1165|issn=1046-6673|doi=10.1681/ASN.2020030276}}</ref> | ||
* Approximately half of the new [[AKI]] cases following [[COVID-19]] is mild with good short-term prognosis. | * Approximately half of the new [[AKI]] cases following [[COVID-19]] is mild with good short-term [[prognosis]]. | ||
* If no improvement occurs during follow-up, it is contributed to higher mortality.<ref name="PeiZhang2020">{{cite journal|last1=Pei|first1=Guangchang|last2=Zhang|first2=Zhiguo|last3=Peng|first3=Jing|last4=Liu|first4=Liu|last5=Zhang|first5=Chunxiu|last6=Yu|first6=Chong|last7=Ma|first7=Zufu|last8=Huang|first8=Yi|last9=Liu|first9=Wei|last10=Yao|first10=Ying|last11=Zeng|first11=Rui|last12=Xu|first12=Gang|title=Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia|journal=Journal of the American Society of Nephrology|volume=31|issue=6|year=2020|pages=1157–1165|issn=1046-6673|doi=10.1681/ASN.2020030276}}</ref> | * If no improvement occurs during follow-up, it is contributed to higher [[mortality]].<ref name="PeiZhang2020">{{cite journal|last1=Pei|first1=Guangchang|last2=Zhang|first2=Zhiguo|last3=Peng|first3=Jing|last4=Liu|first4=Liu|last5=Zhang|first5=Chunxiu|last6=Yu|first6=Chong|last7=Ma|first7=Zufu|last8=Huang|first8=Yi|last9=Liu|first9=Wei|last10=Yao|first10=Ying|last11=Zeng|first11=Rui|last12=Xu|first12=Gang|title=Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia|journal=Journal of the American Society of Nephrology|volume=31|issue=6|year=2020|pages=1157–1165|issn=1046-6673|doi=10.1681/ASN.2020030276}}</ref> | ||
== Diagnosis == | == Diagnosis == | ||
=== Symptoms === | === Symptoms === | ||
* Patients in the early stages of [[kidney failure]] may be asymptomatic. If left untreated, patients may progress to develop [[Azotemia]] and [[Uremia]], which occur due to the buildup of waste materials in the blood. | * Patients in the early stages of [[kidney failure]] may be [[asymptomatic]]. If left untreated, patients may progress to develop [[Azotemia]] and [[Uremia]], which occur due to the buildup of waste materials in the blood. | ||
* Symptoms of kidney injury include | * Symptoms of kidney injury include <ref name="Skorecki">{{cite book |vauthors=Skorecki K, Green J, Brenner BM |veditors=Kasper DL, Braunwald E, Fauci AS |title=Harrison's Principles of Internal Medicine|url=https://archive.org/details/harrisonsprincip00kasp |url-access=limited |edition=16th |year=2005 |publisher=McGraw-Hill |location=New York, NY |isbn=978-0-07-139140-5 |pages=[https://archive.org/details/harrisonsprincip00kasp/page/n1681 1653]–63 |chapter=Chronic renal failure|display-editors=etal}}</ref>: | ||
**[[Nausea]] and [[Vomiting]] | **[[Nausea]] and [[Vomiting]] | ||
**[[Weakness]] | **[[Weakness]] | ||
**[[Fatigue]] | **[[Fatigue]] | ||
**[[ | **[[Weight loss]] | ||
**[[Loss of appetite]] | **[[Loss of appetite]] | ||
=== Physical Examination === | |||
*Physical examination of patients with [[AKI]] is usually remarkable for: | |||
**Signs of [[dehydration]], such as [[tachycardia]], [[tachypnea]], [[hypotension]], and dry [[mucosa]] | |||
**[[Fluid retention]], leading to [[edema]] and swelling of periorbital and [[extremities]] | |||
**[[Confusion]] due to severe [[dehydration]] and [[electrolyte]] imbalances | |||
**Decrease in [[urine output]]:[[Oliguria]] or [[Anuria]] | **Decrease in [[urine output]]:[[Oliguria]] or [[Anuria]] | ||
** | **[[cardiac arrhythmia]] due to [[electrolyte]] imbalances such as high level of [[Potassium]] | ||
=== Laboratory Findings === | === Laboratory Findings === | ||
* Laboratory findings of COVID-19-associated [[AKI]] include: | * Laboratory findings of COVID-19-associated [[AKI]] include: | ||
**Elevated [[BUN]] level | **Elevated [[BUN]] level | ||
***Plasma BUN-creatinine ratio> 20 in [[prerenal]] [[AKI]] | ***Plasma [[BUN]]-[[creatinine]] ratio> 20 in [[prerenal]] [[AKI]] | ||
***Plasma BUN-creatinine ratio< 15 in intrinsic [[AKI]] or [[acute tubular necrosis]] | ***Plasma [[BUN]]-[[creatinine]] ratio< 15 in intrinsic [[AKI]] or [[acute tubular necrosis]] | ||
**Based on KDIGO definition for the diagnosis of [[AKI]]<ref name="pmid22890468">{{cite journal| author=Khwaja A| title=KDIGO clinical practice guidelines for acute kidney injury. | journal=Nephron Clin Pract | year= 2012 | volume= 120 | issue= 4 | pages= c179-84 | pmid=22890468 | doi=10.1159/000339789 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22890468 }} </ref>: | **Based on KDIGO definition for the diagnosis of [[AKI]]<ref name="pmid22890468">{{cite journal| author=Khwaja A| title=KDIGO clinical practice guidelines for acute kidney injury. | journal=Nephron Clin Pract | year= 2012 | volume= 120 | issue= 4 | pages= c179-84 | pmid=22890468 | doi=10.1159/000339789 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22890468 }} </ref>: | ||
***Elevated serum Creatinine by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours; or | ***Elevated serum [[Creatinine]] by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours; or | ||
***Elevated serum Creatinine to ≥1.5 times baseline within the previous 7 days; or | ***Elevated serum [[Creatinine]] to ≥1.5 times baseline within the previous 7 days; or | ||
***Urine volume < 0.5 ml/kg/h for >6 hours | ***Urine volume < 0.5 ml/kg/h for >6 hours | ||
**Fractional excretion of sodium ([[FENa]]) | **Fractional excretion of [[sodium]] ([[FENa]]) | ||
***([[FENa]])< 1% in [[prerenal]] [[AKI]] | ***([[FENa]])< 1% in [[prerenal]] [[AKI]] | ||
***([[FENa]])> 2% in intrinsic [[AKI]] or [[acute tubular necrosis]] | ***([[FENa]])> 2% in intrinsic [[AKI]] or [[acute tubular necrosis]] | ||
**Urinary sediment | **Urinary sediment | ||
***[[Hyaline casts]] in [[prerenal]] [[AKI]] | ***[[Hyaline casts]] in [[prerenal]] [[AKI]] | ||
***Granular or Muddy brown casts in intrinsic [[AKI]] or [[acute tubular necrosis]] | ***[[Granular]] or Muddy brown [[casts]] in intrinsic [[AKI]] or [[acute tubular necrosis]] | ||
**Several [[biomarkers]] have been found to diagnose and predict [[AKI]] that include<ref name="pmid28076311">{{cite journal| author=Kashani K, Cheungpasitporn W, Ronco C| title=Biomarkers of acute kidney injury: the pathway from discovery to clinical adoption. | journal=Clin Chem Lab Med | year= 2017 | volume= 55 | issue= 8 | pages= 1074-1089 | pmid=28076311 | doi=10.1515/cclm-2016-0973 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28076311 }} </ref> <ref name="pmid27474473">{{cite journal| author=Schrezenmeier EV, Barasch J, Budde K, Westhoff T, Schmidt-Ott KM| title=Biomarkers in acute kidney injury - pathophysiological basis and clinical performance. | journal=Acta Physiol (Oxf) | year= 2017 | volume= 219 | issue= 3 | pages= 554-572 | pmid=27474473 | doi=10.1111/apha.12764 | pmc=5575831 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27474473 }} </ref> <ref name="pmid32050834">{{cite journal| author=Oh DJ| title=A long journey for acute kidney injury biomarkers. | journal=Ren Fail | year= 2020 | volume= 42 | issue= 1 | pages= 154-165 | pmid=32050834 | doi=10.1080/0886022X.2020.1721300 | pmc=7034110 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32050834 }} </ref>: | **Several [[biomarkers]] have been found to diagnose and predict [[AKI]] that include<ref name="pmid28076311">{{cite journal| author=Kashani K, Cheungpasitporn W, Ronco C| title=Biomarkers of acute kidney injury: the pathway from discovery to clinical adoption. | journal=Clin Chem Lab Med | year= 2017 | volume= 55 | issue= 8 | pages= 1074-1089 | pmid=28076311 | doi=10.1515/cclm-2016-0973 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28076311 }} </ref> <ref name="pmid27474473">{{cite journal| author=Schrezenmeier EV, Barasch J, Budde K, Westhoff T, Schmidt-Ott KM| title=Biomarkers in acute kidney injury - pathophysiological basis and clinical performance. | journal=Acta Physiol (Oxf) | year= 2017 | volume= 219 | issue= 3 | pages= 554-572 | pmid=27474473 | doi=10.1111/apha.12764 | pmc=5575831 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27474473 }} </ref> <ref name="pmid32050834">{{cite journal| author=Oh DJ| title=A long journey for acute kidney injury biomarkers. | journal=Ren Fail | year= 2020 | volume= 42 | issue= 1 | pages= 154-165 | pmid=32050834 | doi=10.1080/0886022X.2020.1721300 | pmc=7034110 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32050834 }} </ref>: | ||
***[[neutrophil gelatinase-associated lipocalin]] ([[NGAL]]) | ***[[neutrophil gelatinase-associated lipocalin]] ([[NGAL]]) | ||
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=== Medical Therapy === | === Medical Therapy === | ||
* Management of [[AKI]] following [[COVID-19]] includes | * Management of [[AKI]] following [[COVID-19]] includes [[antiviral]] therapies, identifying [[electrolyte]] disorders, and [[intravenous fluid]] resuscitation. | ||
** Early diagnosis and treatment of [[AKI]] in patients with [[COVID-19]] can avoid the progression of [[AKI]] into [[ESRD]] and reduce mortality.<ref name="pmid32416769">{{cite journal| author=Ronco C, Reis T, Husain-Syed F| title=Management of acute kidney injury in patients with COVID-19. | journal=Lancet Respir Med | year= 2020 | volume= | issue= | pages= | pmid=32416769 | doi=10.1016/S2213-2600(20)30229-0 | pmc=7255232 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32416769 }} </ref> | ** Early diagnosis and treatment of [[AKI]] in patients with [[COVID-19]] can avoid the progression of [[AKI]] into [[ESRD]] and reduce mortality.<ref name="pmid32416769">{{cite journal| author=Ronco C, Reis T, Husain-Syed F| title=Management of acute kidney injury in patients with COVID-19. | journal=Lancet Respir Med | year= 2020 | volume= | issue= | pages= | pmid=32416769 | doi=10.1016/S2213-2600(20)30229-0 | pmc=7255232 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32416769 }} </ref> | ||
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*** [[Isotonic crystalloid]] is recommended among all patients who develop [[AKI]]. <ref name="pmid22890468">{{cite journal| author=Khwaja A| title=KDIGO clinical practice guidelines for acute kidney injury. | journal=Nephron Clin Pract | year= 2012 | volume= 120 | issue= 4 | pages= c179-84 | pmid=22890468 | doi=10.1159/000339789 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22890468 }} </ref> | *** [[Isotonic crystalloid]] is recommended among all patients who develop [[AKI]]. <ref name="pmid22890468">{{cite journal| author=Khwaja A| title=KDIGO clinical practice guidelines for acute kidney injury. | journal=Nephron Clin Pract | year= 2012 | volume= 120 | issue= 4 | pages= c179-84 | pmid=22890468 | doi=10.1159/000339789 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22890468 }} </ref> | ||
** Correction of [[electrolyte]] disorders | ** Correction of [[electrolyte]] disorders | ||
**[[antiviral]] therapy: | |||
***Recently, [[Remdesivir]] has been found effective against [[COVID-19]]. <ref name="pmid32275812">{{cite journal| author=Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A | display-authors=etal| title=Compassionate Use of Remdesivir for Patients with Severe Covid-19. | journal=N Engl J Med | year= 2020 | volume= 382 | issue= 24 | pages= 2327-2336 | pmid=32275812 | doi=10.1056/NEJMoa2007016 | pmc=7169476 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32275812 }} </ref> | |||
** [[Anticoagulants]] in hypercoagulable conditions | ** [[Anticoagulants]] in hypercoagulable conditions | ||
**[[Loop diuretics]] | **[[Loop diuretics]] | ||
Line 160: | Line 166: | ||
** If [[AKI]] is unresponsive to conservative therapy | ** If [[AKI]] is unresponsive to conservative therapy | ||
** In [[volume overload]] conditions | ** In [[volume overload]] conditions | ||
** Modality of choice in unstable hemodynamic status and [[ESRD]], severe [[metabolic acidosis]], severe [[hyperkalemia]] | ** Modality of choice in [[unstable]] hemodynamic status and [[ESRD]], severe [[metabolic acidosis]], severe [[hyperkalemia]] | ||
**[[renal replacement therapy]] is associated with hypercoagulation.<ref name="pmid32457068">{{cite journal| author=Selby NM, Forni LG, Laing CM, Horne KL, Evans RD, Lucas BJ | display-authors=etal| title=Covid-19 and acute kidney injury in hospital: summary of NICE guidelines. | journal=BMJ | year= 2020 | volume= 369 | issue= | pages= m1963 | pmid=32457068 | doi=10.1136/bmj.m1963 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32457068 }} </ref> | **[[renal replacement therapy]] is associated with hypercoagulation.<ref name="pmid32457068">{{cite journal| author=Selby NM, Forni LG, Laing CM, Horne KL, Evans RD, Lucas BJ | display-authors=etal| title=Covid-19 and acute kidney injury in hospital: summary of NICE guidelines. | journal=BMJ | year= 2020 | volume= 369 | issue= | pages= m1963 | pmid=32457068 | doi=10.1136/bmj.m1963 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32457068 }} </ref> | ||
* Sequential [[extracorporeal therapy]] | * Sequential [[extracorporeal therapy]] | ||
**It removes [[cytokines]]. | **It removes [[cytokines]], which reduces systemic [[inflammation]] and subsequent [[organ failure]]. | ||
== Prevention == | == Prevention == | ||
* Patients with [[COVID-19]] should be evaluated for intravascular volume status based on [[physical examination]] and fluid balance.<ref name="pmid32457068">{{cite journal| author=Selby NM, Forni LG, Laing CM, Horne KL, Evans RD, Lucas BJ | display-authors=etal| title=Covid-19 and acute kidney injury in hospital: summary of NICE guidelines. | journal=BMJ | year= 2020 | volume= 369 | issue= | pages= m1963 | pmid=32457068 | doi=10.1136/bmj.m1963 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32457068 }} </ref> | * Patients with [[COVID-19]] should be evaluated for [[intravascular]] [[volume]] status based on [[physical examination]] and fluid balance.<ref name="pmid32457068">{{cite journal| author=Selby NM, Forni LG, Laing CM, Horne KL, Evans RD, Lucas BJ | display-authors=etal| title=Covid-19 and acute kidney injury in hospital: summary of NICE guidelines. | journal=BMJ | year= 2020 | volume= 369 | issue= | pages= m1963 | pmid=32457068 | doi=10.1136/bmj.m1963 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32457068 }} </ref> | ||
**[[BUN]], serum [[creatinine]], and [[electrolytes]] such as [[sodium]], [[potassium]] and [[bicarbonate]] should be monitored frequently every 48 hours or more in high risk patients.<ref name="pmid32457068">{{cite journal| author=Selby NM, Forni LG, Laing CM, Horne KL, Evans RD, Lucas BJ | display-authors=etal| title=Covid-19 and acute kidney injury in hospital: summary of NICE guidelines. | journal=BMJ | year= 2020 | volume= 369 | issue= | pages= m1963 | pmid=32457068 | doi=10.1136/bmj.m1963 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32457068 }} </ref> | **[[BUN]], serum [[creatinine]], and [[electrolytes]] such as [[sodium]], [[potassium]] and [[bicarbonate]] should be monitored frequently every 48 hours or more in high risk patients.<ref name="pmid32457068">{{cite journal| author=Selby NM, Forni LG, Laing CM, Horne KL, Evans RD, Lucas BJ | display-authors=etal| title=Covid-19 and acute kidney injury in hospital: summary of NICE guidelines. | journal=BMJ | year= 2020 | volume= 369 | issue= | pages= m1963 | pmid=32457068 | doi=10.1136/bmj.m1963 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32457068 }} </ref> | ||
** [[Isotonic saline]] is recommended as a prevention strategy for patients who are at increased risk for [[AKI]] by expanding intravascular volume. <ref name="pmid22890468">{{cite journal| author=Khwaja A| title=KDIGO clinical practice guidelines for acute kidney injury. | journal=Nephron Clin Pract | year= 2012 | volume= 120 | issue= 4 | pages= c179-84 | pmid=22890468 | doi=10.1159/000339789 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22890468 }} </ref> | ** [[Isotonic]] [[saline]] is recommended as a prevention strategy for patients who are at increased risk for [[AKI]] by expanding [[intravascular]] [[volume]]. <ref name="pmid22890468">{{cite journal| author=Khwaja A| title=KDIGO clinical practice guidelines for acute kidney injury. | journal=Nephron Clin Pract | year= 2012 | volume= 120 | issue= 4 | pages= c179-84 | pmid=22890468 | doi=10.1159/000339789 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22890468 }} </ref> | ||
==References== | ==References== |
Revision as of 05:03, 6 July 2020
For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2], Nasrin Nikravangolsefid, MD-MPH [3]
Synonyms and keywords: COVID-19-associated AKI
Overview
COVID-19 can involve many organs leading to organ failure, one of which is kidneys that manifest with mild proteinuria to advanced acute kidney injury (AKI).
Historical Perspective
- Early reports from China revealed that COVID-19 rarely involves the kidneys, as acute renal failure was not seen among COVID-19 hospitalized patients and mild BUN or creatinine rise [10.8%] and mild proteinuria [7.2%] occurred. [1]
- However, recent study found 75.4% of hospitalized patients with COVID-19 pneumonia developed hematuria, proteinuria, and AKI. But, these findings are not significantly different from other critical diseases.[2]
Classification
Pathophysiology
- Angiotensin-converting enzyme 2 (ACE2), which is a primary receptor for SARS-CoV-2 entry into cells, mostly presents in renal tubular epithelial cells as well as lungs and heart.[4]
- Despite kidney injury following COVID-19 infection is less frequent than severe lung injury, ACE2: ACE ratio is higher in the kidneys compared to the respiratory system. (1:1 in the kidneys VS 1:20 in the respiratory system)[4]
- After SARS-CoV-2 enters through the nasal cavity, it may travel to the kidneys and enters the bloodstream leading to severe inflammatory response activation and cytokine storm.
- Cytokine induced AKI may occur due to intrarenal inflammation, hyperpermeability of vessels, hypovolemia and cardiomyopathy, leading to cardiorenal syndrome type 1 that is characterized by third space volume overload such as pleural effusion, edema and intravascular volume loss (hypovolemia) and hypotension.[5]
- cardiomyopathy and COVID-19-associated myocarditis can lead to hypotension and reduction in renal perfusion.
- The major cytokine is IL-6, which induces inflammation and lung endothelial cell injury, leading to ARDS and hypoxia that subsequently cause renal tubular cell injury and AKI. [6][5]
- Cytokine induced AKI may occur due to intrarenal inflammation, hyperpermeability of vessels, hypovolemia and cardiomyopathy, leading to cardiorenal syndrome type 1 that is characterized by third space volume overload such as pleural effusion, edema and intravascular volume loss (hypovolemia) and hypotension.[5]
- To conclude, COVID-19-associated AKI can occur as a result of[4]:
- Sepsis and cytokine storm
- Hypovolemia and Hypotension
- Hypoxemia
- Blood clots formation due to hypercoagulable state, leading to impaired blood flow in the renal arterioles.
Causes
- SARS-CoV-2 may have a Kidney tropism. As a recent study found SARS-CoV-2 antigens in renal tubules which suggests the direct damage of SARS-CoV-2 on the kidneys. https://www.medrxiv.org/content/10.1101/2020.03.04.20031120v4. Missing or empty
|title=
(help)
Epidemiology and Demographics
- AKI is frequently seen among patients with COVID-19 hospitalized in ICU, with prevalence of 0.6-29% in China "Acute Kidney Injury in COVID-19 Patients | COVID-19". and 22.2% in the USA.[9]
- Approximately 43% of critically ill patients with COVID-19 developed AKI during the admission period. [3]
- The incidence of AKI in critcally ill patients with COVID-19 is estimated between 27-85%. "Acute Kidney Injury in COVID-19 Patients | COVID-19".
Age
Gender
- Men are more likely to be affected and have higher risk of COVID-19 complications. [10]
- 57.1% of AKI cases following COVID-19 were male.[3]
Race
Risk Factors
- The most potent risk factors in the development of COVID-19 associated AKI include[11] [12]:
- Elderly
- Age>60 years
- Comorbidities
- Elderly
Natural History, Complications, and Prognosis
Natural History
- AKI is more likely to develop in the late stages of COVID-19 in critically ill patients.[13]
- Severe COVID-19 pneumonia and severe acute respiratory distress syndrome are associated with developing AKI.[2]
Diagnosis
Symptoms
- Patients in the early stages of kidney failure may be asymptomatic. If left untreated, patients may progress to develop Azotemia and Uremia, which occur due to the buildup of waste materials in the blood.
- Symptoms of kidney injury include [14]:
Physical Examination
- Physical examination of patients with AKI is usually remarkable for:
- Signs of dehydration, such as tachycardia, tachypnea, hypotension, and dry mucosa
- Fluid retention, leading to edema and swelling of periorbital and extremities
- Confusion due to severe dehydration and electrolyte imbalances
- Decrease in urine output:Oliguria or Anuria
- cardiac arrhythmia due to electrolyte imbalances such as high level of Potassium
Laboratory Findings
- Laboratory findings of COVID-19-associated AKI include:
- Elevated BUN level
- Plasma BUN-creatinine ratio> 20 in prerenal AKI
- Plasma BUN-creatinine ratio< 15 in intrinsic AKI or acute tubular necrosis
- Based on KDIGO definition for the diagnosis of AKI[15]:
- Elevated serum Creatinine by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours; or
- Elevated serum Creatinine to ≥1.5 times baseline within the previous 7 days; or
- Urine volume < 0.5 ml/kg/h for >6 hours
- Fractional excretion of sodium (FENa)
- Urinary sediment
- Hyaline casts in prerenal AKI
- Granular or Muddy brown casts in intrinsic AKI or acute tubular necrosis
- Several biomarkers have been found to diagnose and predict AKI that include[16] [17] [18]:
- Elevated BUN level
Electrocardiogram
- There are no specific ECG findings associated with AKI. However, electrolyte disturbances such as hyperkalemia might lead to various ECG abnormalities.
Approach to Patients with Elevated Biomarkers
Treatment
Medical Therapy
- Management of AKI following COVID-19 includes antiviral therapies, identifying electrolyte disorders, and intravenous fluid resuscitation.
- Treatment of AKI following COVID-19 includes:[13] [12]
- Correction of hypovolemia and hypotension by the administration of adequate intravenous fluid
- Isotonic crystalloid is recommended among all patients who develop AKI. [15]
- Correction of electrolyte disorders
- antiviral therapy:
- Recently, Remdesivir has been found effective against COVID-19. [19]
- Anticoagulants in hypercoagulable conditions
- Loop diuretics
- In volume overload conditions
- Diuretics should not be used regularly as they predispose patients to volume depletion.
- Correction of hypovolemia and hypotension by the administration of adequate intravenous fluid
Interventions
- renal replacement therapy
- If AKI is unresponsive to conservative therapy
- In volume overload conditions
- Modality of choice in unstable hemodynamic status and ESRD, severe metabolic acidosis, severe hyperkalemia
- renal replacement therapy is associated with hypercoagulation.[12]
- Sequential extracorporeal therapy
- It removes cytokines, which reduces systemic inflammation and subsequent organ failure.
Prevention
- Patients with COVID-19 should be evaluated for intravascular volume status based on physical examination and fluid balance.[12]
- BUN, serum creatinine, and electrolytes such as sodium, potassium and bicarbonate should be monitored frequently every 48 hours or more in high risk patients.[12]
- Isotonic saline is recommended as a prevention strategy for patients who are at increased risk for AKI by expanding intravascular volume. [15]
References
- ↑ Wang, Luwen; Li, Xun; Chen, Hui; Yan, Shaonan; Li, Dong; Li, Yan; Gong, Zuojiong (2020). "Coronavirus Disease 19 Infection Does Not Result in Acute Kidney Injury: An Analysis of 116 Hospitalized Patients from Wuhan, China". American Journal of Nephrology. 51 (5): 343–348. doi:10.1159/000507471. ISSN 0250-8095.
- ↑ 2.0 2.1 2.2 Pei, Guangchang; Zhang, Zhiguo; Peng, Jing; Liu, Liu; Zhang, Chunxiu; Yu, Chong; Ma, Zufu; Huang, Yi; Liu, Wei; Yao, Ying; Zeng, Rui; Xu, Gang (2020). "Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia". Journal of the American Society of Nephrology. 31 (6): 1157–1165. doi:10.1681/ASN.2020030276. ISSN 1046-6673.
- ↑ 3.0 3.1 3.2 3.3 Pei G, Zhang Z, Peng J, Liu L, Zhang C, Yu C; et al. (2020). "Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia". J Am Soc Nephrol. 31 (6): 1157–1165. doi:10.1681/ASN.2020030276. PMC 7269350 Check
|pmc=
value (help). PMID 32345702 Check|pmid=
value (help). - ↑ 4.0 4.1 4.2 4.3 Malha, Line; Mueller, Franco B.; Pecker, Mark S.; Mann, Samuel J.; August, Phyllis; Feig, Peter U. (2020). "COVID-19 and the Renin-Angiotensin System". Kidney International Reports. 5 (5): 563–565. doi:10.1016/j.ekir.2020.03.024. ISSN 2468-0249.
- ↑ 5.0 5.1 5.2 Ronco C, Reis T (2020). "Kidney involvement in COVID-19 and rationale for extracorporeal therapies". Nat Rev Nephrol. 16 (6): 308–310. doi:10.1038/s41581-020-0284-7. PMC 7144544 Check
|pmc=
value (help). PMID 32273593 Check|pmid=
value (help). - ↑ Husain-Syed F, Slutsky AS, Ronco C (2016). "Lung-Kidney Cross-Talk in the Critically Ill Patient". Am J Respir Crit Care Med. 194 (4): 402–14. doi:10.1164/rccm.201602-0420CP. PMID 27337068.
- ↑ Ye M, Wysocki J, William J, Soler MJ, Cokic I, Batlle D (2006). "Glomerular localization and expression of Angiotensin-converting enzyme 2 and Angiotensin-converting enzyme: implications for albuminuria in diabetes". J Am Soc Nephrol. 17 (11): 3067–75. doi:10.1681/ASN.2006050423. PMID 17021266.
- ↑ Perico L, Benigni A, Remuzzi G (2020). "Should COVID-19 Concern Nephrologists? Why and to What Extent? The Emerging Impasse of Angiotensin Blockade". Nephron. 144 (5): 213–221. doi:10.1159/000507305. PMC 7179544 Check
|pmc=
value (help). PMID 32203970 Check|pmid=
value (help). - ↑ Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW; et al. (2020). "Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area". JAMA. doi:10.1001/jama.2020.6775. PMC 7177629 Check
|pmc=
value (help). PMID 32320003 Check|pmid=
value (help). - ↑ Sharma G, Volgman AS, Michos ED (2020). "Sex Differences in Mortality from COVID-19 Pandemic: Are Men Vulnerable and Women Protected?". JACC Case Rep. doi:10.1016/j.jaccas.2020.04.027. PMC 7198137 Check
|pmc=
value (help). PMID 32373791 Check|pmid=
value (help). - ↑ Rabb H (2020). "Kidney diseases in the time of COVID-19: major challenges to patient care". J Clin Invest. 130 (6): 2749–2751. doi:10.1172/JCI138871. PMC 7259985 Check
|pmc=
value (help). PMID 32250968 Check|pmid=
value (help). - ↑ 12.0 12.1 12.2 12.3 12.4 Selby NM, Forni LG, Laing CM, Horne KL, Evans RD, Lucas BJ; et al. (2020). "Covid-19 and acute kidney injury in hospital: summary of NICE guidelines". BMJ. 369: m1963. doi:10.1136/bmj.m1963. PMID 32457068 Check
|pmid=
value (help). - ↑ 13.0 13.1 13.2 Ronco C, Reis T, Husain-Syed F (2020). "Management of acute kidney injury in patients with COVID-19". Lancet Respir Med. doi:10.1016/S2213-2600(20)30229-0. PMC 7255232 Check
|pmc=
value (help). PMID 32416769 Check|pmid=
value (help). - ↑ Skorecki K, Green J, Brenner BM (2005). "Chronic renal failure". In Kasper DL, Braunwald E, Fauci AS, et al. Harrison's Principles of Internal Medicine (16th ed.). New York, NY: McGraw-Hill. pp. 1653–63. ISBN 978-0-07-139140-5.
- ↑ 15.0 15.1 15.2 Khwaja A (2012). "KDIGO clinical practice guidelines for acute kidney injury". Nephron Clin Pract. 120 (4): c179–84. doi:10.1159/000339789. PMID 22890468.
- ↑ Kashani K, Cheungpasitporn W, Ronco C (2017). "Biomarkers of acute kidney injury: the pathway from discovery to clinical adoption". Clin Chem Lab Med. 55 (8): 1074–1089. doi:10.1515/cclm-2016-0973. PMID 28076311.
- ↑ Schrezenmeier EV, Barasch J, Budde K, Westhoff T, Schmidt-Ott KM (2017). "Biomarkers in acute kidney injury - pathophysiological basis and clinical performance". Acta Physiol (Oxf). 219 (3): 554–572. doi:10.1111/apha.12764. PMC 5575831. PMID 27474473.
- ↑ Oh DJ (2020). "A long journey for acute kidney injury biomarkers". Ren Fail. 42 (1): 154–165. doi:10.1080/0886022X.2020.1721300. PMC 7034110 Check
|pmc=
value (help). PMID 32050834 Check|pmid=
value (help). - ↑ Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A; et al. (2020). "Compassionate Use of Remdesivir for Patients with Severe Covid-19". N Engl J Med. 382 (24): 2327–2336. doi:10.1056/NEJMoa2007016. PMC 7169476 Check
|pmc=
value (help). PMID 32275812 Check|pmid=
value (help).