hemolytic–uremic syndrome

After eating contaminated food, the first symptoms of infection can emerge anywhere from 1 to 10 days later, but usually after 3 to 4 days.{{cite web |title=E.coli (Escherichia coli): Symptoms |url=https://www.cdc.gov/ecoli/ecoli-symptoms.html |website=Centers for Disease Control and Prevention |publisher=U.S. Department of Health & Human Services |access-date=22 November 2018|date=2017-11-30 }} These early symptoms can include diarrhea (which is often bloody), stomach cramps, mild fever,{{cite web |title=Hemolytic uremic syndrome (HUS) |url=http://idph.iowa.gov/cade/disease-information/hus |website=Center for Acute Disease Epidemiology |publisher=Iowa Department of Public Health |access-date=21 November 2018 |archive-date=7 August 2020 |archive-url=https://web.archive.org/web/20200807190233/https://idph.iowa.gov/cade/disease-information/hus |url-status=dead }} or vomiting that results in dehydration and reduced urine. HUS typically develops about 5–10 days after the first symptoms, but can take up to 3 weeks to manifest, and occurs at a time when the diarrhea is improving. Related symptoms and signs include lethargy, decreased urine output, blood in the urine, kidney failure, low platelets, (which are needed for blood clotting), and destruction of red blood cells (microangiopathic hemolytic anemia). High blood pressure, jaundice (a yellow tinge in skin and the whites of the eyes), seizures, and bleeding into the skin can also occur. In some cases, there are prominent neurologic changes.{{cite journal|last1=Boyer |last2=Niaudet|first1=O |first2=P|title=Hemolytic Uremic Syndrome: New Developments in Pathogenesis and Treatments|journal=Int J Nephrol|date=August 2011|volume=2011|page=908407|doi=10.4061/2011/908407|pmid=21876803|pmc=3159990 |doi-access=free }}{{cite book|editor-last=Kumar|editor-last2=Cotran|editor-last3=Robbins|editor-first=V|editor-first2=RS|editor-first3=SL|title=Robbins Basic Pathology|year=2002|publisher=Saunders|location=Philadelphia, PA|isbn=978-0-7216-9274-6|url-access=registration|url=https://archive.org/details/robbinsbasicpath0000unse}}{{cite journal |last1=Nathanson |first1=S. |last2=Kwon |first2=T. |last3=Elmaleh |first3=M. |last4=Charbit |first4=M. |last5=Launay |first5=E. A. |last6=Harambat |first6=J. |last7=Brun |first7=M. |last8=Ranchin |first8=B. |last9=Bandin |first9=F. |last10=Cloarec |first10=S. |last11=Bourdat-Michel |first11=G. |last12=Piètrement |first12=C. |last13=Champion |first13=G. |last14=Ulinski |first14=T. |last15=Deschênes |first15=G. |display-authors=3 |title=Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome |journal=Clin J Am Soc Nephrol |year=2010 |volume=5 |issue=7 |pages=1218–1228 |doi=10.2215/CJN.08921209 |pmid=20498239 |pmc=2893076}}

People with HUS commonly exhibit the symptoms of thrombotic microangiopathy (TMA), which can include abdominal pain,{{cite journal|last1=Ohanian |last2=Cable |last3=Halka|first1=M |first2=C |first3=K|title=Eculizumab safely reverses neurologic impairment and eliminates the need for dialysis in severe atypical hemolytic uremic syndrome|journal=Clin Pharmacol|year=2011|volume=3|pages=5–12|pmid=22287852|doi=10.2147/CPAA.S17904|pmc=3262387 |doi-access=free }} low platelet count,{{cite journal|last1=Loirat |last2=Noris |last3=Fremaux-Bacchi|first1=C |first2=M |first3=V|title=Complement and the atypical hemolytic uremia syndrome in children|journal=Pediatr Nephrol|year=2008|volume=23|issue=11|pages=1957–1972|doi=10.1007/s00467-008-0872-4|pmid=18594873|pmc=6904381 |doi-access=free}} elevated lactate dehydrogenase LDH, (an enzyme released from damaged cells, and which is therefore a marker of cellular damage){{cite journal |last1=Caprioli |first1=J. |last2=Noris |first2=M. |last3=Brioschi |first3=S. |last4=Pianetti |first4=G. |last5=Castelletti |first5=F. |last6=Bettinaglio |first6=P. |last7=Mele |first7=C. |last8=Bresin |first8=E. |last9=Cassis |first9=L. |last10=Gamba |first10=S. |last11=Porrati |first11=F. |last12=Bucchioni |first12=S. |last13=Monteferrante |first13=G. |last14=Fang |first14=C. J. |last15=Liszewski |first15=M. K. |last16=Kavanagh |first16=D. |last17=Atkinson |first17=J. P. |last18=Remuzzi |first18=G. |display-authors=3 |title=Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome |journal=Blood |year=2006 |volume=108 |issue=4 |pages=1267–1279 |doi=10.1182/blood-2005-10-007252 |pmid=16621965 |pmc=1895874}} decreased haptoglobin (indicative of the breakdown of red blood cells) anemia (low red blood cell count), schistocytes (damaged red blood cells), elevated creatinine (a protein waste product generated by muscle metabolism and eliminated renally),{{cite journal |last1=Ariceta |first1=Gema |last2=Besbas |first2=Nesrin |last3=Johnson |first3=Sally |last4=Karpman |first4=Diana |last5=Landau |first5=Daniel |last6=Licht |first6=Christoph |last7=Loirat |first7=Chantal |last8=Pecoraro |first8=Carmine |last9=Taylor |first9=C. Mark |last10=Van de Kar |first10=Nicole |last11=VandeWalle |first11=Johan |last12=Zimmerhackl |first12=Lothar B. |display-authors=3 |title=Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome|journal=Pediatr Nephrol|year=2009|volume=24|issue=4|pages=687–696|doi=10.1007/s00467-008-0964-1|pmid=18800230|doi-access=free }} proteinuria (indicative of kidney injury),{{cite journal |last1=Sellier-Leclers |first1=A.-L. |last2=Fremeaux-Bacchi |first2=V. |last3=Dragon-Durey |first3=M.-A. |last4=Macher |first4=M.-A. |last5=Niaudet |first5=P. |last6=Guest |first6=G. |last7=Boudailliez |first7=B. |last8=Bouissou |first8=F. |last9=Deschenes |first9=G. |last10=Gie |first10=S. |last11=Tsimaratos |first11=M. |last12=Fischbach |first12=M. |last13=Morin |first13=D. |last14=Nivet |first14=H. |last15=Alberti |first15=C. |last16=Loirat |first16=C. |display-authors=3 |title=Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome |journal=J Am Soc Nephrol |year=2007 |volume=18 |issue=8 |pages=2392–2400 |doi=10.1681/ASN.2006080811 |pmid=17599974|doi-access=free }} confusion, fatigue,{{cite journal |last1=Noris |first1=M. |last2=Caprioli |first2=J. |last3= Bresin |first3=E. |last4=Mossali |first4=C. |last5=Pianetti |first5=G. |last6=Gamba |first6=S. |last7=Daina |first7=E. |last8=Fenili |first8=C. |last9=Castelletti |first9=F. |last10=Sorosina |first10=A. |last11=Piras |first11=R. |last12=Donadelli |first12=R. |last13=Maranta |first13=R. |last14=van der Meer |first14=I. |last15=Conway |first15=E. M. |last16=Zipfel |first16=P. F. |last17=Goodship |first17=T. H. |last18=Remuzzi |first18=G. |display-authors=3 |title=Relative role of genetic complement abnormalities in infrequent and familial aHUS and their impact on clinical phemotype |journal=Clin J Am Soc Nephrol |year=2010 |volume=5 |issue=10 |pages=1844–1859 |doi=10.2215/CJN.02210310 |pmid=20595690 |pmc=2974386}} swelling,{{cite journal |last1=Ståhl |first1=A.-L. |last2=Vazir-Sani |first2=F. |last3=Heinen |first3=S. |last4=Kristoffersson |first4=A.-C. |last5=Gydell |first5=K.-H. |last6=Raafat |first6=R. |last7=Gutierrez |first7=A. |last8=Beringer |first8=O. |last9=Zipfel |first9=P. F. |last10=Karpman |first10=D. |display-authors=3 |title=Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation |journal=Blood |year=2008 |volume=111 |issue=11 |pages=5307–5317 |doi=10.1182/blood-2007-08-106153 |pmid=18268093|doi-access=free }} nausea/vomiting,{{cite journal |last1=Dragon-Durey |first1=M.-A. |last2=Sethi |first2=S. K. |last3=Bagga |first3=A. |last4=Blanc |first4=C. |last5=Blouin |first5=J. |last6=Ranchin |first6=B. |last7=André |first7=J.-L. |last8=Takagi |first8=N. |last9=Cheong |first9=H. II |last10=Hari |first10=P. |last11=Le Quintrec |first11=M. |last12=Niaudet |first12=P. |last13=Loirat |first13=C. |last14=Fridman |first14=W. H. |last15=Frémeaux-Bacchi |first15=V. |display-authors=3 |title=Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome |journal=J Am Soc Nephrol |year=2010 |volume=21 |issue=12 |pages=2180–2187 |doi=10.1681/ASN.2010030315 |pmid=21051740 |pmc=3014031}} and diarrhea.{{cite journal|last1=Zuber |last2=Le Quintrec |last3=Sberro-Scussan |last4=Loirat |last5=Fremaux-Bacchi |last6=Legendre|first1=J |first2=M |first3=R |first4=C |first5=V |first6=C|s2cid=2054556 |title=New insights into postrenal transplant hemolytic uremic syndrome|journal=Nature Reviews Nephrology |year=2011|volume=7|issue=1|pages=23–35|doi=10.1038/nrneph.2010.155|pmid=21102542}} Additionally, patients with aHUS typically present with an abrupt onset of systemic signs and symptoms such as acute kidney failure, hypertension (high blood pressure), myocardial infarction (heart attack),{{cite journal|last1=Sallee |last2=Daniel |last3=Piercecchi|first1=M |first2=L |first3=M-D|title=Myocardial infarction is a complication of factor H-associated atypical HUS|journal=Nephrol Dial Transplant|year=2010|volume=25|issue=6|pages=2028–2032|doi=10.1093/ndt/gfq160|pmid=20305136|display-authors=1|doi-access=free}} stroke, lung complications, pancreatitis (inflammation of the pancreas), liver necrosis (death of liver cells or tissue), encephalopathy (brain dysfunction), seizure,{{cite journal|last1=Neuhaus |last2=Calonder |last3=Leumann|first1=TJ |first2=S |first3=EP|title=Heterogeneity of atypical haemolytic uraemis syndromes|journal=Arch Dis Child|year=1997|volume=76|pages=518–521|doi=10.1136/adc.76.6.518|pmid=9245850|pmc=1717216|issue=6}} and coma.{{cite journal|last1=Noris |last2=Remuzzi|first1=M |first2=G|title=Hemolytic uremic syndrome|journal=J Am Soc Nephrol|year=2005|volume=16|issue=4|pages=1035–1050|doi=10.1681/ASN.2004100861|pmid=15728781|doi-access=free}} Failure of neurologic, cardiac, renal, and gastrointestinal (GI) organs, as well as death, can occur unpredictably at any time, either very quickly or following prolonged symptomatic or asymptomatic disease progression.{{cite journal|last1=Mache |last2=Acham-Roschitz |last3=Fremeaux-Bacchi|first1=CJ |first2=B |first3=V|title=Complement inhibitor eculizumab in atypical hemolytic uremic syndrome|journal=Clin J Am Soc Nephrol|year=2009|volume=4|issue=8|pages=1312–1316|doi=10.2215/CJN.01090209|pmid=19556379 |display-authors=1|pmc=2723971}}

Shiga-toxin producing E. coli (STEC) HUS occurs after ingestion of a strain of bacteria expressing Shiga toxin such as enterohemorrhagic Escherichia coli (EHEC), of which E. coli O157:H7 is the most common serotype.{{cite journal|last1=Palermo |last2=Exeni |last3=Fernandez|first1=MS |first2=RA |first3=GC|s2cid=30420020 |title=Hemolytic Uremic Syndrome: pathogenesis and update of interventions|journal=Expert Rev Anti Infect Ther|year=2009|volume=7|issue=6|pages=697–707|doi=10.1586/eri.09.49|pmid=19681698|hdl=11336/55090 |hdl-access=free}}

{{Main|Atypical hemolytic uremic syndrome}}

Atypical HUS (aHUS) represents 5–10% of HUS cases and is largely due to one or several genetic mutations that cause chronic, uncontrolled, and excessive activation of the complement system, which is a group of immune signaling factors that promote inflammation, enhance the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the body, and directly attack the pathogen's cell membrane. This results in platelet activation, endothelial cell damage, and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count, hemolysis (breakdown of red blood cells), damage to multiple organs, and ultimately death.{{cite journal|last=Tsai|first=H-M|title=Pathophysiology of thrombotic thrombocytopenic purpura|journal=Int J Hematol|year=2010|volume=91|issue=1|pages=1–19|doi=10.1007/s12185-009-0476-1|pmid=20058209|pmc=3159000}} Early signs of systemic complement-mediated TMA include thrombocytopenia (platelet count below 150,000 or a decrease from baseline of at least 25%) and evidence of microangiopathic hemolysis, which is characterized by elevated LDH levels, decreased haptoglobin, decreased hemoglobin (the oxygen-containing component of blood), and/or the presence of schistocytes. Despite the use of supportive care, an estimated 33–40% of patients will die or have end-stage renal disease (ESRD) with the first clinical manifestation of aHUS, and 65% of patients will die, require dialysis, or have permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion (PE/PI) therapy. Patients who survive the presenting signs and symptoms of aHUS endure a chronic thrombotic and inflammatory state, which puts them at lifelong elevated risk of sudden blood clotting, kidney failure, other severe complications and premature death.

Historically, treatment options for aHUS were limited to plasma exchange or plasma infusion (PE/PI) therapy, which carries significant risks{{cite journal|last=George|first=JN|title=How I treat my patients with thrombotic thrombocytopenic purpura|journal=Blood|year=2010|volume=116|issue=20|pages=4060–4069|doi=10.1182/blood-2010-07-271445|pmid=20686117|s2cid=26844964 |doi-access=free}}{{cite journal|last1=Michon |last2=Moghrabi |last3=Winikoff|first1=B |first2=A |first3=R|title=Complications of apheresis in children|journal=Transfusion|year=2007|volume=47|issue=10|pages=1837–1842|doi=10.1111/j.1537-2995.2007.01405.x|pmid=17880609|s2cid=23613105 |display-authors=1}} and has not been proven effective in any controlled trials. People with aHUS and ESRD have also had to undergo lifelong dialysis, which has a 5-year survival rate of 34–38%.{{cite journal|last1=Collins |first1=Allan J.|title=Excerpts from the US Renal Data System 2009 Annual Data Report|journal=Am J Kidney Dis|year=2010|volume=55|issue=1 Suppl 1|pages=S1–S7|doi=10.1053/j.ajkd.2009.10.009|pmid=20082919|first2=Robert N.|last2=Foley |last3=Herzog|first3=Charles|last4=Chavers|first4=Blanche M.|last5=Gilbertson|first5=David|last6=Ishani|first6=Areef|last7=Kasiske|first7=Bertram L.|last8=Liu|first8=Jiannong|last9=Mau|first9=Lih-Wen|last10=McBean|first10=Marshall|display-authors=1|pmc=2829836}}{{cite book|last=European Renal Association- European Dialysis and Transplant Association Registry|title=ERA-EDTA Registry Annual Report 2009|year=2011|publisher=Academic Medical Center Department of Medical Informatics|location=Amsterdam, the Netherlands}}

{{Organize section|date=April 2025|reason=there are no subsections, making this section difficult to read}}

HUS is caused by ingestion of bacteria that produce Shiga toxins, with Shiga-toxin producing E. coli (STEC) being the most common type. E. coli can produce shigatoxin-1, shigatoxin-2, or both; with shigatoxin-2 producing organisms being more virulent and being much more likely to cause HUS.{{cite journal |last1=Freedman |first1=Stephen B. |last2=van de Kar |first2=Nicole C.A.J. |last3=Tarr |first3=Phillip I. |title=Shiga Toxin–Producing Escherichia coli and the Hemolytic–Uremic Syndrome |journal=The New England Journal of Medicine |date=12 October 2023 |volume=389 |issue=15 |pages=1402–1414 |doi=10.1056/NEJMra2108739|pmid=37819955 |s2cid=263907137 |url=https://repository.ubn.ru.nl//bitstream/handle/2066/297486/297486.pdf }} Once ingested, the bacteria move to the intestines where they produce the Shiga toxins. The bacteria and toxins damage the mucosal lining of the intestines, and thus are able to gain entry into the circulation. Shiga toxin enters the mesenteric microvasculature lining the intestines where it releases inflammatory cytokines including IL-6, IL-8, TNFα, and IL-1β. These inflammatory mediators lead to inflammation and vascular injury with microthrombi that are seen with HUS. It also further damages the intestinal barrier leading to diarrhea (usually bloody) and further entry of Shiga toxin from the intestines to the bloodstream as the intestinal barrier is compromised.

Once Shiga toxin enters the circulation it can travel throughout the body and cause the wide array of end organ damage and the multitude of symptoms seen with HUS. Shiga toxin gains entry to cells by binding to globotriaosylceramide (Gb3) which is a globoside found on cell membranes, it is found throughout the body including the surface of the glomerular endothelium of the kidney.{{cite journal|last1=Psotka |last2=Obata |last3=Kolling|first1=MA |first2=F |first3=GL|title=Shiga toxin 2 targets the murine renal collecting duct epithelium|journal=Infect Immun|year=2009|volume=77|issue=3|pages=959–969|doi=10.1128/IAI.00679-08|pmid=19124603|pmc=2643625|display-authors=1}} Shiga toxin gains entry to the cell via Gb3 and endocytosis, it then is transported to the Golgi apparatus where furin cleaves the A subunit of the Shiga toxin. It is then transported to the endoplasmic reticulum where it is further cleaved, leaving the A1 subunit of Shiga toxin free. The A1 subunit of Shiga toxin inhibits the 28s subunit of the ribosomal rRNA, this leads to inhibited protein production by the ribosomes. With the cell's protein synthesis inhibited by Shiga toxin, the cell is destroyed. This leads to vascular injury (including in the kidneys where Gb3 is concentrated). The vascular injury facilitates the formation of vascular microthrombi which are characteristic of TTP. The TTP leads to platelet trapping (and thrombocytopenia), red blood cell destruction (and anemia), and end organ damage that is characteristically seen with HUS and TTP.

HUS is one of the thrombotic microangiopathies, a category of disorders that includes STEC-HUS, aHUS, and thrombotic thrombocytopenic purpura (TTP). The release of cytokines and chemokines (IL-6, IL-8, TNF-α, IL-1β) that are commonly released by Shiga toxin are implicated in platelet activation and TTP.{{cite journal|last1=Guessous |first1=F |last2=Marcinkiewicz |first2=M| last3=Polanowska-Grabowska|first3=R|last4=Kongkhum|first4=S|last5=Heatherly|first5=D|last6=Obrig|first6=T|last7=Gear|first7=A|title=Shiga toxin 2 and lipopolysaccharide induce human microvascular endothelial cells to release chemokines and factor that stimulate platelet function|journal=Infect Immun|year=2005|volume=73|issue=12|pages=8306–8316|doi=10.1128/IAI.73.12.8306-8316.2005|pmid=16299328|pmc=1307066|display-authors=1}} The presence of schistocytes is a key finding that helps to diagnose HUS.

Shiga-toxin directly activates the alternative complement pathway and also interferes with complement regulation by binding to complement factor H, an inhibitor of the complement cascade. Shiga-toxin causes complement-mediated platelet, leukocyte, and endothelial cell activation, resulting in systemic hemolysis, inflammation and thrombosis.{{cite journal | vauthors = Orth D, Würzner R | title = Complement in typical hemolytic uremic syndrome | journal = Seminars in Thrombosis and Hemostasis | volume = 36 | issue = 6 | pages = 620–4 | date = September 2010 | pmid = 20865638 | doi = 10.1055/s-0030-1262883 | s2cid = 260321080 }}{{cite journal|last1=Stahl |last2=Startz |last3=Karpman|first1=AL |first2=L |first3=D|title=Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome|journal=Blood|year=2011|volume=117|issue=20|pages=5503–5513|doi=10.1182/blood-2010-09-309161|pmid=21447825|doi-access=free}}{{cite journal|last1=Thurman|first1=J.M. |last2=Marians |last3=Emlen|title=Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome|journal=Clin J Am Soc Nephrol|year=2009|volume=4|issue=12|pages=1920–1924|doi=10.2215/CJN.02730409|pmid=19820137|pmc=2798880|first2=R.|first3=W.|display-authors=1}} Severe clinical complications of TMA have been reported in patients from 2 weeks to more than 44 days after presentation with STEC-HUS, with improvements in clinical condition extending beyond this time frame, suggesting that complement activation persists beyond the acute clinical presentation and for at least 4 months.{{cite journal|last1=Mache |last2=Otto |last3=Gross|first1=C |first2=R |first3=B|title=Eculizumab in diarrhea-associated hemolytic uremic syndrome|journal=Presented at the 2nd International Conference on HUS-MPGN-PNH|date=June 2010|display-authors=1}}

The consumption of platelets as they adhere to the thrombi lodged in the small vessels typically leads to mild or moderate thrombocytopenia with a platelet count of less than 60,000 per microliter.{{cite journal|last=Tan|first=AJ|title=Hemolytic uremic syndrome in emergency medicine|url=http://emedicine.medscape.com/article/779218|journal=Medscape EMedicine|date=2017-12-27}} As in the related condition TTP, reduced blood flow through the narrowed blood vessels of the microvasculature leads to reduced blood flow to vital organs, and ischemia may develop. The kidneys and the central nervous system (brain and spinal cord) are the parts of the body most critically dependent on high blood flow, and are thus the most likely organs to be affected. However, in comparison to TTP, the kidneys tend to be more severely affected in HUS, and the central nervous system is less commonly affected.{{cite journal|last1=Kanso |last2=Abou Hassan |last3=Badr|first1=AA |first2=NM |first3=KF|title=Micro and macrovascular disease of the kidney|journal=In: Brenner BM, ed. The Kidney, 8th Edition|year=2008|pages=chapter 32}}

In contrast with typical disseminated intravascular coagulation seen with other causes of sepsis and occasionally with advanced cancer, coagulation factors are not consumed in HUS (or TTP) and the coagulation screen, fibrinogen level, and assays for fibrin degradation products such as "D-Dimers", are generally normal despite the low platelet count (thrombocytopenia).

HUS occurs after 3–7% of all sporadic E. coli O157:H7 infections and up to approximately 20% or more of epidemic infections.{{cite journal|last1=Mead |last2=Griffin|first1=PS |first2=PM|s2cid=38100845|title=Escherichia coli O157:H7|journal=Lancet|year=1998|volume=352|issue=9135|pages=1207–1212|doi=10.1016/S0140-6736(98)01267-7|pmid=9777854|url=https://zenodo.org/record/1259827}} Children and adolescents are commonly affected.{{cite journal|last1=Ruggenenti |last2=Noris |last3=Remuzzi|first1=P |first2=M |first3=G|title=Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura|journal=Kidney Int|year=2001|volume=60|issue=3|pages=831–846|doi=10.1046/j.1523-1755.2001.060003831.x|pmid=11532079|doi-access=free}} One reason could be that children have more Gb3 receptors than adults which may be why children are more susceptible to HUS. Cattle, swine, deer, and other mammals do not have GB3 receptors, but can be asymptomatic carriers of Shiga toxin-producing bacteria. Some humans can also be asymptomatic carriers. Once the bacteria colonizes, diarrhea followed by bloody diarrhea, hemorrhagic colitis, typically follows. Other serotypes of STEC also cause disease, inlduding HUS, as occurred with E. coli O104:H4, which triggered a 2011 epidemic of STEC-HUS in Germany.{{cite web|last=Robert Koch Institute|title=Technical Report: EHEC/HUS O104:H4 Outbreak, Germany, May/June 2011|url=http://www.rki.de/EN/Home/EHEC_Report.pdf?__blob=publicationFile.|publisher=Robert Koch Institute|location=Berlin, Germany|archive-url=https://web.archive.org/web/20160408140013/http://www.rki.de/EN/Home/EHEC_Report.pdf?__blob=publicationFile.|archive-date=2016-04-08}}

Grossly, the kidneys may show patchy or diffuse renal cortical necrosis. Histologically, the glomeruli show thickened and sometimes split capillary walls due largely to endothelial swelling. Large deposits of fibrin-related materials in the capillary lumens, subendothelially, and in the mesangium are also found along with mesangiolysis. Interlobular and afferent arterioles show fibrinoid necrosis and intimal hyperplasia and are often occluded by thrombi.

STEC-HUS most often affects infants and young children, but also occurs in adults. The most common form of transmission is ingestion of undercooked meat, unpasteurized fruits and juices, contaminated produce, contact with unchlorinated water, and person-to-person transmission in daycare or long-term care facilities.

Unlike typical HUS, aHUS does not follow STEC infection and is thought to result from one or several genetic mutations that cause chronic, uncontrolled, and excessive activation of complement. This leads to platelet activation, endothelial cell damage, and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count, hemolysis, damage to multiple organs, and ultimately, death. Early signs of systemic complement-mediated TMA include thrombocytopenia (platelet count below 150,000 or a decrease from baseline of at least 25%) and evidence of microangiopathic hemolysis, which is characterized by elevated LDH levels, decreased haptoglobin, decreased hemoglobin, and/or the presence of schistocytes.{{cite journal|last1=Zipfel |last2=Heinen |last3=Skerka|first1=PF |first2=S |first3=C|s2cid=28419 |title=Thrombotic microangiopathies: new insights and new challenges|journal=Current Opinion in Nephrology and Hypertension|year=2010|volume=19|issue=4|pages=372–378|doi=10.1097/MNH.0b013e32833aff4a|pmid=20539230}}

The similarities between HUS, aHUS, and TTP make differential diagnosis essential. All three of these systemic TMA-causing diseases are characterized by thrombocytopenia and microangiopathic hemolysis, plus one or more of the following: neurological symptoms (e.g., confusion, cerebral convulsions, seizures); renal impairment (e.g., elevated creatinine, decreased estimated glomerular filtration rate [eGFR], abnormal urinalysis{{cite journal|last1=Al-Akash |last2=Almond |last3=Savell |last4=Gharaybeth |last5=Hogue|first1=AI |first2=PS |first3=VH Jr |first4=SI |first5=C|s2cid=22334044 |title=Eculizumab includes long-term remission in recurrent post-transplant HUS associated with C3 gene mutation|journal=Pediatr Nephrol|year=2011|volume=26|issue=4|pages=613–619|doi=10.1007/s00467-010-1708-6|pmid=21125405}}); and gastrointestinal (GI) symptoms (e.g., diarrhea, nausea/vomiting, abdominal pain, gastroenteritis).The presence of diarrhea does not exclude aHUS as the cause of TMA, as 28% of patients with aHUS present with diarrhea and/or gastroenteritis. First diagnosis of aHUS is often made in the context of an initial, complement-triggering infection, and Shiga-toxin has also been implicated as a trigger that identifies patients with aHUS. Additionally, in one study, mutations of genes encoding several complement regulatory proteins were detected in 8 of 36 (22%) patients diagnosed with STEC-HUS.{{cite journal|last1=Gangnadoux |last2=Habib |last3=Gubler |last4=Bacri |last5=Broyer|first1=MF |first2=R |first3=MC |first4=JL |first5=M|title=Long-term (15-25 years) outcome of childhood hemolytic–uremic syndrome|journal=Clin Nephrol|year=1996|volume=46|issue=1|pages=39–41|pmid=8832149}} However, the absence of an identified complement regulatory gene mutation does not preclude aHUS as the cause of the TMA, as approximately 50% of patients with aHUS lack an identifiable mutation in complement regulatory genes.

Diagnostic work-up supports the differential diagnosis of TMA-causing diseases. A positive Shiga-toxin/EHEC test confirms a cause for STEC-HUS, and severe ADAMTS13 deficiency (i.e., ≤5% of normal ADAMTS13 levels) confirms a diagnosis of TTP.{{cite journal|last1=Zhen|last2= Wu |last3=Shang|first1=XL |first2=HM |first3=D|title=Multiple domains of ADAMTS13 are targeted by autoantibodies against ADAMTS13 in patients with acquired idiopathic thrombotic thrombocytopenic purpura|journal=Haematologica|year=2010|volume=95|issue=9|pages=1555–1562|doi=10.3324/haematol.2009.019299|pmid=20378566|pmc=2930958|display-authors=1}}

The effect of antibiotics in shiga toxin producing E. coli is unclear. While some early studies raised concerns more recent studies show either no effect or a benefit.

Treatment involves supportive care and may include dialysis, steroids, blood transfusions, and plasmapheresis. Early IV fluid hydration is associated with better outcomes including shorter hospital stays and reducing the risk of dialysis.

Empiric antibiotics are not indicated in those who are immunocompetent, and may worsen the HUS. Antidiarrheals and narcotic medications to slow the gut are not recommended as they are associated with worsening symptoms, increased risk of HUS in those with STEC infection, and adverse neurologic reactions. Platelet transfusions should not be used as the may drive the process of microangiopathy leading to worsening TTP.

While eculizumab is being used to treat atypical hemolytic uremic syndrome, no evidence as of 2018 supports its use in the main forms of HUS. Scientists are trying to understand how useful it would be to immunize humans or cattle.{{cite journal | last1 = O'Ryan | first1 = M | last2 = Vidal | first2 = R | last3= Del Canto | first3 = F | last4 = Salazar | first4 = J C | last5= Montero | first5 = D | title = Vaccines for viral and bacterial pathogens causing acute gastroenteritis: Part II: Vaccines for Shigella, Salmonella, enterotoxigenic E. coli (ETEC) enterohemorragic E. coli (EHEC) and Campylobacter jejuni | journal = Human Vaccines & Immunotherapeutics | volume = 11 | issue = 3 | pages= 601–619 | year = 2015 | doi=10.1080/21645515.2015.1011578 | pmc=4514228 | pmid=25715096}}

Acute renal failure occurs in 55–70% of people with STEC-HUS, although up to 70–85% recover renal function.{{cite journal|last=Parmar|first=MS|title=Hemolytic–uremic syndrome|url=http://emedicine.medscape.com/article/201181-overview#a0199|journal=Medscape EMedicine|year=2010}} With aggressive treatment, more than 90% of patients survive the acute phase of HUS, and only about 9% may develop ESRD. Roughly one-third of persons with HUS have abnormal kidney function many years later, and a few require long-term dialysis. Another 8% of persons with HUS have other lifelong complications, such as high blood pressure, seizures, blindness, paralysis, and the effects of having part of their colon removed. STEC-HUS is associated with a 3% mortality rate among young children and a 20% mortality rate in middle age or older adults. 15-20% of children infected with STEC develop HUS, with the highest risk being in children younger than 5 years old.

Patients with aHUS generally have poor outcomes, with up to 50% progressing to end-stage renal disease (ESRD) or irreversible brain damage; as many as 25% die during the acute phase.

The epidemiology of Hemolytic-Uremic Syndrome (HUS) shows marked geographic variation, with annual incidence rates ranging from 0.07 cases per 100,000 person-years in Australia to 2.7 cases per 100,000 in the United States, while European countries report intermediate rates around 0.62-2.1 cases per 100,000 person-years. Children under five years of age consistently show the highest incidence rates across all regions, with reported rates of 3.9 cases per 100,000 children per year in the United States and up to 7.9 cases per 100,000 children in Argentina, suggesting a particular vulnerability in this age group. The condition demonstrates a slight female predominance in adult cases, though gender distribution is equal in pediatric populations, and studies indicate that rural populations generally have higher incidence rates than urban areas, possibly due to increased exposure to Shiga toxin producing E. coli (STEC) infections. It is also likely that some regions (such as China) have high numbers of unreported cases of HUS, due to healthcare providers in those regions lacking understanding of the syndrome.{{Cite journal |last1=Aldharman |first1=Sarah S |last2=Almutairi |first2=Shahad M |last3=Alharbi |first3=Alaa A |last4=Alyousef |first4=Meshal A |last5=Alzankrany |first5=Khalid H |last6=Althagafi |first6=Mohammed K |last7=Alshalahi |first7=Emtenan E |last8=Al-jabr |first8=Khalid H |last9=Alghamdi |first9=Abdullrahman |last10=Jamil |first10=Syed F |date=2023-05-22 |title=The Prevalence and Incidence of Hemolytic Uremic Syndrome: A Systematic Review |journal=Cureus |volume=15 |issue=5 |pages=e39347 |language=en |doi=10.7759/cureus.39347 |doi-access=free |issn=2168-8184 |pmc=10284565 |pmid=37351232}}

HUS is now considered as a part of the broader group of Thrombotic microangiopathies (TMA). Thrombotic thrombocytopenic purpura (TTP), a TMA, was first described by the Hungarian born, American pathologist and physician Eli Moschcowitz (1879–1964).

In 1924,{{Cite journal |last1=Sukumar |first1=Senthil |last2=Lämmle |first2=Bernhard |last3=Cataland |first3=Spero R. |name-list-style=vanc |date=January 2021 |title=Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management |journal=Journal of Clinical Medicine |volume=10 |issue=3 |page=536 |doi=10.3390/jcm10030536 |issn=2077-0383 |pmc=7867179 |pmid=33540569 |doi-access=free}} Moschcowitz first described TTP as a distinct clinicopathologic condition that can mimic the clinical characteristics of Hemolytic–uremic syndrome (HUS). That was in a 16-year-old girl who died 2 weeks after the abrupt onset and progression of petechial bleeding, pallor, fever, paralysis, hematuria and coma; and called "Moschcowitz disease".{{Cite journal |last=Moschcowitz |first=Eli |author-link=Eli Moschcowitz |date=1925 |title=An Acute Febrile Pleiochromic Anemia with Hyaline Thrombosis of the Terminal Arterioles and Capillaries: An Undescribed Disease |url= |journal=Archives of Internal Medicine |volume=36 |issue=1 |pages=89–93 |doi=10.1001/archinte.1925.00120130092009 |issn=0730-188X |postscript=:}}

• {{Cite journal |last=Moschcowitz |first=Eli |author-mask=2 |date=1952 |title=An Acute Febrile Pleiochromic Anemia with Hyaline Thrombosis of the Terminal Arterioles and Capillaries: An Undescribed Disease |url=https://www.sciencedirect.com/science/article/abs/pii/0002934352900223 |journal=The American Journal of Medicine |volume=13 |issue=5 |pages=567–569 |doi=10.1016/0002-9343(52)90022-3 |issn=0002-9343 |pmid=12996533}}
• {{Cite journal |last=Moschcowitz |first=Eli |author-mask=2 |date=1978 |title=An Acute Febrile Pleiochromic Anemia with Hyaline Thrombosis of the Terminal Arterioles and Capillaries: An Undescribed Disease |url=http://www.thieme-connect.de/DOI/DOI?10.1055/s-0039-1681113 |journal=Thrombosis and Haemostasis |volume=40 |issue=4 |pages=004–008 |doi=10.1055/s-0039-1681113 |issn=0340-6245 |pmid=725850 |s2cid=29544299}}
• {{Cite journal |last=Moschcowitz |first=Eli |author-mask=2 |date=2003 |title=An Acute Febrile Pleiochromic Anemia with Hyaline Thrombosis of the Terminal Arterioles and Capillaries: An Undescribed Disease |url=https://archive.org/details/sim_mount-sinai-journal-of-medicine_2003-10_70_5/page/352/mode/2up |journal=The Mount Sinai Journal of Medicine |volume=70 |issue=5 |pages=352–355 |pmid=14631522}}{{cite book |url=https://www.sciencedirect.com/science/article/pii/B9780124485105501059 |title=Hematology |date=2000 |publisher=Academic Press |isbn=978-0-12-448510-5 |editor-last=Lichtman |editor-first=Marshall A. |pages=119–125 |chapter=Commentary on and reprint of Moschcowitz E, An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: An undescribed disease, in Archives of Internal Medicine (1925) 36:89–93 |doi=10.1016/B978-012448510-5.50105-9 |display-editors=etal |chapter-url=https://www.sciencedirect.com/science/article/abs/pii/B9780124485105501059}} Moreover, Moschcowitz was among the first to work in psychosomatic medicine, and he presented a paper in 1935 on the psychological origins of physical disease.

HUS was first described by Conrad Gasser in 1955, and the systemic character of HUS was subsequently defined.{{Citation |last=Gianantonio |first=Carlos A. |title=Hemolytic Uremic Syndrome |date=1984 |work=Acute Renal Failure |pages=327–339 |place=Boston, MA |publisher=Springer US |doi=10.1007/978-1-4613-2841-4_16 |isbn=978-1-4612-9794-9 |s2cid=46876846}} Bernard Kaplan identified several distinct entities that can manifest as HUS and emphasized that HUS was a syndrome with a common pathologic outcome. Kaplan is a Canadian professor and director of Pediatric Nephrology. He has an international reputation for his studies, over the past 34 years, on the hemolytic uremic syndromes.{{Cite journal |last1=Kaplan |first1=Bernard S. |last2=Drummond |first2=Keith N. |date=1978-04-27 |title=The Hemolytic-Uremic Syndrome Is a Syndrome |journal=The New England Journal of Medicine |volume=298 |issue=17 |pages=964–966 |doi=10.1056/nejm197804272981710 |issn=0028-4793 |pmid=642978}}

The discovery that endothelial cell injury underlies this broad spectrum of TMA disorders has come into focus during the last two decades. In the 1980s, Mohamed Karmali (1945–2016) was the first to make the association between Stx, diarrheal E. coli infection and the (then considered) idiopathic hemolytic uremic syndrome of infancy and childhood. Karmali's work showed that the hemolytic uremic syndrome the children in Canada was caused by this particular bacteria. Karmali also developed the system of classifying strains of E.coli and determining which cause disease in humans. He defined the presence of microvascular injury in diarrhea-associated HUS and the critical role of a verotoxin produced by specific strains of Escherichia coli.{{Cite web |author=OVC Communications |title=Dr. Mohamed Karmali – Solving the Mystery of the Haemolytic-Uremic Syndrome - June 10 |url=https://bulletin.ovc.uoguelph.ca/post/120469569400/dr-mohamed-karmali-solving-the-mystery-of-the |access-date=2023-08-21 |website=Tumblr}}{{Better source needed|reason=The current source is insufficiently reliable (WP:NOTRS).|date=April 2025}}

This verotoxin was subsequently found to be a member of a family of toxins first identified with Shigella and known as Shiga toxin (Stx).{{Cite journal |last1=Karmali |first1=M. A. |last2=Petric |first2=M. |last3=Lim |first3=C. |last4=Fleming |first4=P. C. |last5=Arbus |first5=G. S. |last6=Lior |first6=H. |date=1985-05-01 |title=The Association Between Idiopathic Hemolytic Uremic Syndrome and Infection by Verotoxin-Producing Escherichia coli |journal=Journal of Infectious Diseases |volume=151 |issue=5 |pages=775–782 |doi=10.1093/infdis/151.5.775 |issn=0022-1899 |pmid=3886804}} This relationship and the eventual link of TTP to abnormally high levels of ultra-large Von Willebrand factor (vWF) multimers caused by congenital or acquired reductions in ADAMTS13 activity was established at approximately the same time.

Paul Warwicker is an English nephrologist, whilst in Newcastle in the mid-1990s his research in molecular genetics with Professors Tim and Judith Goodship led to the genetic mapping of the familial form of atypical HUS and the descriptions of the first HUS-related mutations and polymorphisms in the factor H gene in both familial and sporadic HUS. He was awarded an MD in molecular genetics in 2000, and elected fellow of the Royal College of Physicians in the same year.{{Cite web |title=Dr Paul Warwicker: General (internal) medicine , Renal medicine |url=https://www.finder.bupa.co.uk/Consultant/view/26936/dr_paul_warwicker |access-date=2023-08-22 |website=finder.bupa.co.uk}} Paul Warwicker confirmed the association of atypical HUS (aHUS) to defects in a region on chromosome 1 that contains the genes for several complement regulatory proteins.{{Cite journal |last1=Warwicker |first1=Paul |last2=Goodship |first2=Timothy H.J. |last3=Donne |first3=Rosemary L. |last4=Pirson |first4=Yves |last5=Nicholls |first5=Anthony |last6=Ward |first6=Roy M. |last7=Turnpenny |first7=Peter |last8=Goodship |first8=Judith A. |date=April 1998 |title=Genetic studies into inherited and sporadic hemolytic uremic syndrome |journal=Kidney International |volume=53 |issue=4 |pages=836–844 |doi=10.1111/j.1523-1755.1998.00824.x |issn=0085-2538 |pmid=9551389 |doi-access=free}}

Later, mutations in complement factor H, complement factor I, membrane cofactor protein, factor B, C3, and thrombomodulin have now been found to cause many of the familial cases of aHUS.{{Citation needed|date=April 2025}} These discoveries have allowed a more comprehensive understanding of the pathogenesis, evaluation, and treatment of the entire spectrum of TMA disorders and provide a more rational and effective approach to the care of these children with complicated disease.{{Citation needed|date=April 2025}}

Prior to the use of monoclonal antibodies patients with aHUS had an extremely poor prognosis.{{Citation needed|date=April 2025}} Eculizumab is a humanized monoclonal complement inhibitor that is the first and only approved treatment for patients with aHUS by FDA in September 2011. Eculizumab binds with high affinity to C5, inhibiting C5 cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9, thus inhibiting complement-mediated TMA. Eculizumab was proven to be effective in patients with aHUS in which it resolved and prevented complement-mediated TMA, improving renal function and hematologic outcomes.{{Cite web |date=3 November 2018 |title=2011 Notifications |url=https://www.fda.gov/drugs/resources-information-approved-drugs/2011-notifications |website=FDA}}

The country with the highest incidence of HUS is Argentina{{cite journal|year=2011|last1=Rivero|first1=MA|last2=Passucci|first2=JA|last3=Rodriguez|first3=EM|last4=Signorini|first4=ML|last5=Tarabla|first5=HD|last6=Parma|first6=AE|title=Factors associated with sporadic verotoxigenic Escherichia coli infection in children with diarrhea from the Central Eastern Area of Argentina|journal=Foodborne Pathogens and Disease|volume=8|issue=8|pages=901–6|doi=10.1089/fpd.2010.0800|pmid=21492023|hdl=11336/100837|hdl-access=free}}{{cite journal|year=2003|last1=Rivas|first1=M|last2=Caletti|first2=MG|last3=Chinen|first3=I|last4=Refi|first4=SM|last5=Roldán|first5=CD|last6=Chillemi|first6=G|last7=Fiorilli|first7=G|last8=Bertolotti|first8=A|last9=Aguerre|first9=L|last10=Sosa Estani|first10=S|title=Home-prepared hamburger and sporadic hemolytic uremic syndrome, Argentina|journal=Emerging Infectious Diseases|volume=9|issue=9|pages=1184–6|doi=10.3201/eid0909.020563|pmid=14531383|pmc=3016759}}{{cite journal|year=2004|last1=Rivero|first1=MA|last2=Padola|first2=NL|last3=Etcheverría|first3=AI|last4=Parma|first4=AE|title=Enterohemorrhagic Escherichia coli and hemolytic–uremic syndrome in Argentina|journal=Medicina|volume=64|issue=4|pages=352–6|pmid=15338982}}{{cite web|url=http://www.lusuh.org.ar/tripticoingles.pdf|title=What is HUS?}} and it performs a key role in the research of this condition.

In the United States, the overall incidence of HUS is estimated at 2.1 cases per 100,000 persons/year, with a peak incidence between six months and four years of age.

HUS and the E. coli infections that cause it have been the source of much negative publicity for the FDA, meat industries, and fast-food restaurants since the 1990s, especially in the contaminations linked to Jack in the Box restaurants. In 2006, an epidemic of harmful E. coli emerged in the United States due to contaminated spinach. In June 2009, Nestlé Toll House cookie dough was linked to an outbreak of E. coli O157:H7 in the United States, which sickened 70 people in 30 states.{{cite journal |vauthors=Corrigan JJ, Boineau FG |title=Hemolytic–uremic syndrome |journal=Pediatr Rev |volume=22 |issue=11 |pages=365–9 |date=November 2001 |pmid=11691946 |doi=10.1542/pir.22-11-365}}

In May 2011 an epidemic of bloody diarrhea caused by E. coli O104:H4-contaminated fenugreek seeds hit Germany. Tracing the epidemic revealed more than 3,800 cases, with HUS developing in more than 800 of the cases, including 36 fatal cases. Nearly 90% of the HUS cases were in adults.{{cite journal|last1=Buchholz |last2=Bernard |last3=Werber|first1=U |first2=H |first3=D|title=German outbreak of Escherichia coli O104:H4 associated with sprouts|journal=N Engl J Med|year=2011|volume=365|issue=19|pages=1763–1770|pmid=22029753|doi=10.1056/NEJMoa1106482|display-authors=1|doi-access=free}}{{cite journal|last1=Frank |last2=Werber |last3=Cramer|first1=C |first2=D |first3=JP|s2cid=205093464 |title=Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany|journal=N Engl J Med|year=2011|volume=365|issue=19|pages=1711–1780|doi=10.1056/NEJMoa1106483|pmid=21696328|display-authors=1|doi-access=free}}

{{Reflist}}

{{Gram-negative proteobacterial bacterial diseases}}

{{Diseases of RBCs}}

{{Medical resources

| DiseasesDB = 13052

| ICD10 = {{ICD10|D|59|3|d|55}}

| ICD9 = {{ICD9|283.11}}

| OMIM = 235400

| MedlinePlus = 000510

| eMedicineSubj = ped

| eMedicineTopic = 960

| MeshID = D006463

}}

{{Authority control}}

{{DEFAULTSORT:Hemolytic-uremic syndrome}}

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