Hemolytic Uremic Syndrome: What is it? Signs, Symptoms, Diagnosis, Treatment and Prognosis

A variety of viruses have also been implicated as a causative agent. It is now the most common cause of acute kidney failure acquired in childhood.

Hemolytic uremic syndrome (HUS) is a disease characterized by a triad of hemolytic anemia (anemia caused by the destruction of red blood cells), acute kidney failure ( uremia ), and a low platelet count ( thrombocytopenia ).

Most cases are preceded by an episode of infectious diarrhea , sometimes bloody, acquired as a foodborne illness or by a contaminated water supply caused by E. coli O157: H7, other non-O157 E. coli serotypes: H7, Shigella, and Campylobacter.

It is a medical emergency and carries a mortality rate of 5-10%; of the rest, the majority recover without major consequences, approximately 30% suffer residual kidney damage.

The main target appears to be the vascular endothelial cell. This may explain the pathogenesis of hemolytic uremic syndrome, in which a characteristic kidney injury is capillary microangiopathy.

Hemolytic uremic syndrome was first defined as a syndrome in 1955.

The most common form of the disease, Shiga toxin-producing E. coli hemolytic-uremic syndrome (STEC-HUS), is triggered by the infectious agent E. coli O157: H7 and several other non-O157 E. coli serotypes: H7.

Certain Shigella dysenteriae strains that secrete Shiga toxin can also cause hemolytic uremic syndrome.

Approximately 5% of cases are classified as pneumococcal hemolytic uremic syndrome, which results from infection with Streptococcus pneumoniae, the agent that causes traditional lobar pneumonia.

There is also a rare, chronic and severe form known as atypical hemolytic uremic syndrome (aHUS), which is caused by genetic defects that produce chronic and uncontrolled complement activation.

Both Shiga toxin-producing E. coli hemolytic-uremic syndrome and atypical hemolytic uremic syndrome cause:

  • Endothelial damage
  • Activation of leukocytes.
  • Platelet activation and generalized inflammation and multiple thromboses in small blood vessels, a condition known as systemic thrombotic microangiopathy (TMA), which leads to thrombotic events and organ damage and death.

Signs and symptoms

Hemolytic-uremic syndrome of Shiga toxin-producing E. coli occurs after ingestion of a strain of bacteria that express Shiga toxins, usually types of E. coli, that express verotoxin (also called Shiga-like toxin).

E. coli can produce Shiga toxins stx1 and / or stx2, the latter being more dangerous.

A combination of both toxins in certain proportions is generally associated with hemolytic uremic syndrome.

These Shiga toxins bind to GB3 receptors, globotriaosylceramide, which are present in kidney tissue more than any other tissue and are also found in neurons in the central nervous system and other tissues.

Children have more GB3 receptors than adults, making children more susceptible to hemolytic uremic syndrome.

Cattle, pigs, deer, and other mammals do not have GB3 receptors, but they can be asymptomatic carriers of Shiga toxin-producing bacteria.

Some humans can also be asymptomatic carriers. Once the bacteria colonize, diarrhea usually follows followed by bloody diarrhea, hemorrhagic colitis.

Hemolytic uremic syndrome develops around 5-10 days after the onset of diarrhea, with:

  • Decreased urine output (oliguria).
  • Blood in the urine (hematuria).
  • Renal insufficiency.
  • Thrombocytopenia (low platelet levels).
  • Destruction of red blood cells (microangiopathic hemolytic anemia).

Hypertension is common. In some cases, there are prominent neurological changes.

Patients with hemolytic uremic syndrome commonly exhibit the signs and symptoms of thrombotic microangiopathy (TMA), which may include:

Abdominal pain, low platelet count, elevated lactate dehydrogenase (LDH), a chemical released from damaged cells and therefore a marker of cell damage).

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).

Proteinuria (indicative of kidney damage), confusion, fatigue, edema (swelling), nausea, vomiting, and diarrhea.

In addition, patients with atypical hemolytic uremic syndrome often have an abrupt onset of systemic signs and symptoms such as:

  • Acute kidney failure, hypertension (high blood pressure).
  • Myocardial infarction (heart attack).
  • Apoplexy.
  • Pulmonary complications.
  • Pancreatitis (inflammation of the pancreas).
  • Hepatic necrosis (death of the liver, cells, or tissue).
  • Encephalopathy (brain dysfunction).
  • Seizures and coma.

Neurological, cardiac, renal, and gastrointestinal (GI) organ failure, as well as death, can occur unpredictably at any time, either very rapidly or after prolonged symptomatic or asymptomatic disease progression.

Atypical hemolytic-uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) accounts for 5% to 10% of cases of hemolytic uremic syndrome and is largely due to one or more genetic mutations that cause chronic, uncontrolled, and excessive complement activation.

This results in endothelial cell damage from platelet activation and white blood cell activation, leading to systemic thrombotic microangiopathy, manifested by decreased platelet count, hemolysis (destruction of red blood cells), damage to multiple organs, and ultimately death. .

The first signs of systemic complement-mediated thrombotic microangiopathy include:

Thrombocytopenia –  Platelet count below 150,000 or a decrease since the start of the study of at least 25% and evidence of microangiopathic hemolysis, characterized by:

  • Elevated lactate dehydrogenase levels, decreased haptoglobin.
  • Decreased hemoglobin (oxygen -blood container), and / or the presence of schistocytes.

Despite the use of supportive care, it is estimated that between 33% and 40% of patients will die or have end-stage renal disease (ESRD) with the first clinical manifestation of atypical hemolytic uremic syndrome. .

And 65% will die, require dialysis, or have permanent kidney damage within the first year after diagnosis despite treatment with plasma or plasma infusion (PT / IP).

Patients who survive the presenting signs and symptoms of atypical hemolytic uremic syndrome experience a chronic inflammatory and thrombotic state, placing them at increased lifetime risk for sudden blood clots, kidney failure, other serious complications, and premature death.

Historically, treatment options for atypical hemolytic uremic syndrome were limited to plasma exchange therapy or plasma infusion (PT / IP), which carries significant safety risks and its efficacy has not been demonstrated in any controlled clinical trial.

Patients with atypical hemolytic-uremic syndrome and end-stage renal disease have also had to undergo lifelong dialysis, which has a 5-year survival rate of 34-38%.

In recent years, the monoclonal antibody eculizumab, a terminal complement inhibitor in its class, has been shown in clinical studies.

It blocks terminal complement activity in children and adults with atypical hemolytic uremic syndrome, and to eliminate the need for plasma exchange or plasma infusion and re-dialysis.

In these studies eculizumab was associated with a reduction in thrombotic microangiopathy activity, as shown by improvement in platelet count and renal function.

As well as hematologic normalization, complete thrombotic microangiopathy response, and thrombotic microangiopathy event-free status in a majority of patients.

Pathogenesis

Hemolytic uremic syndrome is one of the thrombotic microangiopathies, a category of disorders that includes:

  • Hemolytic-uremic syndrome of Shiga toxin-producing E. coli.
  • Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura (TTP).
  • Shiga-like toxin-producing E. coli.

Hemolytic uremic syndrome is generally preceded by a prodrome of diarrhea, which is often bloody.

And it is caused by Shiga-like toxin-producing bacteria, such as enterohemorrhagic Escherichia coli (EHEC), of which E.coli O157: H7 is the most common serotype.

Other serotypes also cause disease and may emerge as new causes of the hemolytic-uremic syndrome of Shiga toxin-producing E. coli, as occurred with E. coli O104: H4, which triggered an epidemic of Shiga-like toxin-producing E. coli in 2011. Hemolytic uremic syndrome in Germany.

The typical pathophysiology of hemolytic uremic syndrome involves Shiga-toxin binding to the globotriaosylceramide receptor (Gb3, also called ceramide trihexoside that accumulates in Fabry disease) on the surface of the glomerular endothelium.

This action includes a cascade of signaling events that lead to apoptosis and the attachment of leukocytes to endothelial cells.

Endothelial cells activated by Shiga toxin become thrombogenic (clot-producing) by mechanisms that are not fully understood, although they have been shown to induce the release of cytokines and chemokines that are involved in platelet activation.

Furthermore, the binding action of Shiga-toxin inactivates a metalloproteinase called ADAMTS13, the deficiency of which causes the closely related thrombotic thrombocytopenic purpura.

Once ADAMTS13 is inactivated, von Willebrand factor (VWF) multimers form and initiate platelet activation, causing microthrombi formation.

Platelet activation resulting from ADAMTS13 inhibition is due to hyperactivity of large uncleaved von Willebrand factor multimers.

The arterioles and capillaries of the body become clogged by the resulting complexes of activated platelets, which have adhered to the endothelium through the large multimeric von Willebrand factor.

Through a mechanism known as microangiopathic hemolysis, growing thrombi housed in smaller vessels destroy red blood cells (RBCs) as they are squeezed through narrowed blood vessels, forming schistocytes or crushed red blood cell fragments.

The presence of schistocytes is a key finding that helps diagnose hemolytic uremic syndrome. Typically, this hemolysis results in a hemoglobin level of less than 80 g / L.

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 activation of platelets, leukocytes, and endothelial cells, leading to systemic hemolysis, inflammation, and thrombosis.

Serious clinical complications of thrombotic microangiopathy have been reported in patients from 2 weeks to more than 44 days after presentation with hemolytic-uremic syndrome of Shiga toxin-producing E. coli.

With improvements in clinical status that extend beyond this time period, suggesting that complement activation persists beyond the acute clinical presentation and for at least 4 months.

Consumption of platelets as they adhere to thrombi lodged in small vessels generally leads to mild or moderate thrombocytopenia with a platelet count of less than 60,000 per microliter.

As in the related thrombocytopenic thrombotic condition, reduced blood flow through the narrow blood vessels of the microvasculature leads to reduced blood flow to vital organs, and ischemia can develop.

The kidneys and central nervous system (brain and spinal cord) are the parts of the body that depend most critically on high blood flow and are therefore the organs most likely to be affected.

However, compared to thrombotic thrombocytopenic purpura, the kidneys tend to be more severely affected in hemolytic uremic syndrome and the central nervous system is less frequently affected.

In contrast to the typical disseminated intravascular coagulation seen with other causes of sepsis and occasionally with advanced cancer.

Clotting factors are not consumed in hemolytic uremic syndrome (or thrombotic thrombocytopenic purpura, and the coagulation screen, fibrinogen level, and assays for fibrin degradation products such as “D-Dimers” are generally normal despite low blood counts. platelets (thrombocytopenia).

Hemolytic uremic syndrome occurs after 3-7% of all sporadic E. coli O157: H7 infections and up to approximately 20% or more of epidemic infections. Children and adolescents are commonly affected.

In general, the kidneys may show irregular or diffuse renal cortical necrosis. Histologically, the glomeruli show thickened and sometimes divided capillary walls due in large part to endothelial swelling.

Large deposits of fibrin-related materials in the capillary lumens, subendothelially, and in the mesangium are also found in conjunction with mesangiolysis.

The interlobular and afferent arterioles show fibrinoid necrosis and intimal hyperplasia and are often occluded by thrombi.

Hemolytic uremic syndrome produced by E. coli, which produces Shiga toxins, most often affects infants and young children, but also occurs in adults.

The most common form of transmission is through ingestion of undercooked meat, unpasteurized fruits and juices, contaminated produce, contact with non-chlorinated water, and person-to-person transmission in daycare or long-term care facilities.

Unlike typical hemolytic uremic syndrome, atypical hemolytic uremic syndrome does not follow infection with Shiga toxin-producing E. coli and is believed to result from one or more genetic mutations that cause chronic, uncontrolled, and excessive complement activation.

This leads to platelet activation, endothelial cell damage, and white blood cell activation, leading to systemic thrombotic microangiopathy, manifesting as decreased platelet count, hemolysis, damage to multiple organs, and ultimately death.

Diagnosis

The similarities between hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura make differential diagnosis essential.

All three of these systemic thrombotic diseases that cause microangiopathy are characterized by thrombocytopenia and microangiopathic hemolysis, plus one or more of the following:

Neurological symptoms (eg, confusion, brain seizures, seizures); kidney failure (eg, elevated creatinine, decreased estimated glomerular filtration rate, abnormal urinalysis); and gastrointestinal symptoms, eg, diarrhea, nausea / vomiting, abdominal pain, gastroenteritis).

The presence of diarrhea does not exclude atypical hemolytic uremic syndrome as the cause of thrombotic microangiopathy, since 28% of patients with atypical hemolytic uremic syndrome present with diarrhea and / or gastroenteritis.

The first diagnosis of atypical hemolytic uremic syndrome is often made in the setting of an initial complement-triggering infection, and Shiga toxin has also been implicated as a trigger that identifies patients with atypical hemolytic uremic syndrome.

Additionally, in one study, gene mutations encoding various complement regulatory proteins were detected in 8 of 36 (22%) patients diagnosed with hemolytic-uremic syndrome of Shiga toxin-producing E. coli.

However, the absence of an identified complement regulator gene mutation does not exclude atypical hemolytic uremic syndrome as the cause of thrombotic microangiopathy.

Since approximately 50% of patients with atypical hemolytic uremic syndrome lack an identifiable mutation in complement regulatory genes.

The diagnostic evaluation supports the differential diagnosis of diseases causing thrombotic microangiopathy.

A positive Shiga-toxin / Escherichia coli test confirms a cause of Shiga toxin-producing hemolytic-uremic E. coli syndrome.

And severe ADAMTS13 deficiency (ie, ≤5% of normal ADAMTS13 levels) confirms the diagnosis of thrombotic thrombocytopenic purpura.

Treatment

The effect of antibiotics in E. coli O157: H7 colitis is controversial. Certain antibiotics can stimulate verotoxin production and therefore increase the risk of hemolytic uremic syndrome.

However, there is also tentative evidence that some antibiotics such as quinolones can lower the risk of hemolytic uremic syndrome.

In the 1990s, a group of pediatricians at the University of Washington used a network of 47 collaborating laboratories in Washington, Oregon, Idaho, and Wyoming to identify 73 children under the age of 10 who had diarrhea caused by E. coli O157: H7 .

Hemolytic uremic syndrome developed in 5 of the 9 children who received antibiotics (56 percent) and in 5 of the 62 children who did not receive antibiotics (8 percent, P <0.001).

Treatment of hemolytic uremic syndrome is generally supportive, with dialysis as needed. Platelet transfusion can actually make the outcome worse.

In most children with postdiarrheal hemolytic uremic syndrome, there is a good chance of spontaneous resolution, so observation in a hospital is often all that is needed, with supportive care, such as hemodialysis, when indicated.

If the diagnosis of Shiga toxin-producing E. coli hemolytic-uremic syndrome is confirmed, plasmapheresis (plasma exchange) is contraindicated.

However, plasmapheresis may be indicated when there is a diagnostic uncertainty between hemolytic uremic syndrome and thrombotic thrombocytopenic purpura.

There are case reports of experimental treatments with eculizumab, a monoclonal antibody against CD5 that blocks part of the complement system, which is used to treat congenital atypical hemolytic uremic syndrome, as well as severe shiga-toxin-associated hemolytic uremic syndrome.

These have shown promising results.

Eculizeumab was approved by the US Food and Drug Administration (FDA) on March 13, 2007 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

A rare, progressive, and sometimes life-threatening disease characterized by excessive hemolysis; and on September 23, 2011 for the treatment of atypical hemolytic uremic syndrome (aHUS).

It was approved by the European Medicines Agency for the treatment of paroxysmal nocturnal hemoglobinuria on June 20, 2007 and on November 29, 2011 for the treatment of atypical hemolytic uremic syndrome.

However, the excessively high cost of treatment is noteworthy, with a year of the drug costing more than $ 500,000.

Scientists are trying to understand how useful it would be to immunize humans or cattle with vaccines.

Forecast

Acute renal failure occurs in 55-70% of patients with hemolytic-uremic syndrome of Shiga toxin-producing E. coli, although up to 70-85% recover renal function.

Patients with atypical hemolytic uremic syndrome generally have poor outcomes, with up to 50% progressing to end-stage renal disease or irreversible brain damage; up to 25% die during the acute phase.

However, with aggressive treatment, more than 90% of patients survive the acute phase of hemolytic uremic syndrome, and only about 9% may develop end-stage renal disease.

About a third of people with hemolytic uremic syndrome have abnormal kidney function many years later, and some require long-term dialysis.

Another 8% of people with hemolytic uremic syndrome have other life-long complications, such as high blood pressure, seizures, blindness, paralysis, and the effects of removing part of the colon.

The overall mortality rate for hemolytic uremic syndrome is 5-15%. Children and the elderly have a worse prognosis.

epidemiology

The country with the highest incidence of hemolytic uremic syndrome is Argentina and it plays a key role in the investigation of this condition.

In the United States, the global incidence of hemolytic uremic syndrome is estimated at 2.1 cases per 100,000 person / year, with a peak incidence between 6 months and 4 years of age.

Hemolytic uremic syndrome and the E. coli infections that cause it have been the source of much negative publicity for the Food and Drug Administration, meat industries, and fast food restaurants since the 1990s, especially in Jack-in-the-box-related contaminations. the Box restaurants.

The disease also appeared in Robin Cook’s novel Toxin. In 2006, an epidemic of harmful E. coli emerged in the United States due to contaminated spinach.

In June 2009, Nestle 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.

In May 2011, an epidemic of bloody diarrhea caused by fenugreek seeds contaminated with E. coli O104: H4 struck Germany.

Monitoring the epidemic revealed more than 3,800 cases, and hemolytic uremic syndrome developed in more than 800 of the cases, including 36 fatal cases.

Almost 90% of the cases of hemolytic uremic syndrome were in adults.

In response to the crisis, Alexion Pharmaceuticals, Inc., the makers of Soliris (eculizumab), initiated an open-label clinical trial to investigate eculizumab as a treatment for patients with Shiga toxin-producing E. coli hemolytic uremic syndrome.

Alexion also started an eculizumab access program whereby the company provided eculizumab for free throughout the crisis.

The study was designed to include all patients treated with eculizumab during the 2011 outbreak of Shiga-toxin-producing E. coli hemolytic uremic syndrome.