Atypical hemolytic uremic syndrome

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Atypical hemolytic uremic syndrome (aHUS) is a very rare, life-threatening, progressive disease that frequently has a genetic component. In most cases it is caused by chronic, uncontrolled activation of the complement system,[1] a branch of the body’s immune system that destroys and removes foreign particles.[2] The disease affects both children and adults and is characterized by systemic thrombotic microangiopathy (TMA), the formation of blood clots in small blood vessels throughout the body, which can lead to stroke, heart attack, kidney failure, and death.[1][3][4] The complement system activation may be due to mutations in the complement regulatory proteins (factor H, factor I, or membrane cofactor protein),[4][5] or is occasionally due to acquired neutralizing autoantibody inhibitors of these complement system components, for example anti–factor H antibodies.[6]:1933 Despite the use of supportive care, historically an estimated 33-40% of patients died or developed end-stage renal disease (ESRD) with the first clinical bout of aHUS. Including subsequent relapses, a total approximately two-thirds (65%) of patients died, required dialysis, or had permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion (PE/PI).[5]

Usage[edit]

Atypical hemolytic uremic syndrome (aHUS) has also been referred to as diarrhea-negative hemolytic-uremic syndrome (D- HUS).[7]:2170

Signs and symptoms[edit]

Clinical signs and symptoms of complement-mediated TMA can include abdominal pain,[8] confusion,[8] fatigue,[4] edema (swelling),[9] nausea/vomiting[10] and diarrhea.[11] aHUS often presents with malaise and fatigue, as well as microangiopathic anemia.[6]:1931 However, severe abdominal pain and bloody diarrhea are unusual.[6]:1931 Laboratory tests may also reveal low levels of platelets (cells in the blood that aid in clotting),[1] elevated lactate dehydrogenase (LDH, a chemical released from damaged cells, and which is therefore a marker of cellular damage),[5] decreased haptoglobin (indicative of the breakdown of red blood cells),[5] anemia (low red blood cell count)/schistocytes (damaged red blood cells),[1][5] elevated creatinine (indicative of kidney dysfunction),[12] and proteinuria (indicative of kidney injury).[13] Patients with aHUS often present with an abrupt onset of systemic signs and symptoms such as acute kidney failure,[1] hypertension (high blood pressure),[4] myocardial infarction (heart attack),[14] stroke,[8] lung complications,[14] pancreatitis (inflammation of the pancreas),[10] liver necrosis (death of liver cells or tissue),[4] encephalopathy (brain dysfunction),[4] seizure,[15] or coma.[16] Failure of neurologic, cardiac, kidney, 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.[1][13][17][18][19] For example, approximately 1 in 6 patients with aHUS initially will present with proteinuria or hematuria without acute kidney failure.[13] Patients who survive the presenting signs and symptoms endure a chronic thrombotic and inflammatory state, which puts many of them at lifelong elevated risk of sudden blood clotting, kidney failure, other severe complications and premature death.[9][20]

Pathogenesis[edit]

In healthy individuals, complement is used to attack foreign substances, and the complement system is highly regulated to prevent it from damaging healthy tissues and organs.[1][17] However, in most patients with aHUS, it has been demonstrated that chronic, uncontrolled, and excessive activation of complement can result from production of anti-factor H autoantibodies or from genetic mutations in any of several complement regulatory proteins (e.g., factor H, factor HR1 or HR3, membrane cofactor protein, factor I, factor B, complement C3, and thrombomodulin).[17] This results in platelet activation, damage to endothelial cells (cells that line the blood vessels), 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 often, death.[13][18][21]

Diagnosis[edit]

aHUS is not the only condition that causes systemic TMA, a fact that makes differential diagnosis essential. Historically, the clinical diagnosis of TMA-causing diseases was grouped into a broad category that (in addition to aHUS) included thrombotic thrombocytopenic purpura (TTP) and Shiga-toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS).[18][20] However, it is now understood that although aHUS, STEC-HUS, and TTP have similar clinical presentations, they have distinct causes and specific tests can be conducted to differentiate these diseases. In addition, there are other conditions that can cause TMA as a secondary manifestation; these entities include systemic lupus erythematosus (SLE), malignant hypertension, progressive systemic sclerosis (PSS, also known as scleroderma), the pregnancy-associated HELLP (hemolysis, liver dysfunction, and low platelets) syndrome, and toxic drug reaction (e.g., to cocaine, cyclosporine, or tacrolimus). Nevertheless, aHUS should be suspected in patients presenting with systemic TMA, and appropriate diagnostic work-up should be undertaken.

The neurological and kidney-related signs and symptoms of aHUS overlap with those of TTP.[12][22] However, unlike aHUS, TTP is primarily an autoimmune disorder in which the presence of an inhibitory autoantibody results in severe deficiency of ADAMTS13, an enzyme that cleaves von Willebrand factor (vWf), a large protein involved in blood clotting, into smaller pieces.[21] (TTP also can be a genetic disorder characterized by mutations in the ADAMTS13 gene leading to severe ADAMTS13 deficiency. This congenital cause of ADAMTS13 deficiency is called Upshaw-Schülman syndrome.[23]) A lab test showing ADAMTS13 activity levels of ≤5% is indicative of TTP.[21]

Similarly, the gastrointestinal (GI) signs and symptoms of aHUS overlap with those of STEC-HUS.[11][24][25] Stool samples from patients with diarrhea or other GI symptoms should be tested for STEC and the presence of Shiga-toxin. However, a positive identification of Shiga-toxin, which is required to diagnose STEC-HUS, does not rule out aHUS. Nevertheless, in the appropriate clinical setting, a positive identification of Shiga-toxin makes aHUS very unlikely.[12][25]

Comorbidities[edit]

Although many patients experience aHUS as a single disease, comorbidities are common. In one study, 25% (47/191) of patients with no known family history of aHUS were found to have a coexisting disease or condition. Comorbidities in this study included malignant hypertension (30%), TMA with a history of transplant (23%), TMA associated with pregnancy (21%), glomerulopathy (17%), systemic disease such as SLE[disambiguation needed] or PSS[disambiguation needed] (6%), and malignancy (1%).[4] The presence of mutations in complement regulatory proteins, or of disease-associated variations in the genes encoding these proteins (i.e., in most patients with comorbid conditions as well as in patients with aHUS as a single disease), suggests that deviations from the normal genetic coding of these factors could result in a genetic predisposition to TMA. Individuals so predisposed could have aHUS episodes precipitated by one of the known disease triggers (e.g., infection, pregnancy, surgery, trauma) as well as by other systemic diseases (e.g., malignant hypertension, SLE, cancer).

Treatment[edit]

Before the introduction of eculizumab (INN and USAN, trade name Soliris), a monoclonal antibody that is a first-in-class terminal complement inhibitor, management options for patients with aHUS were extremely limited. Guidelines issued by the European Paediatric Study Group for HUS recommend rapid administration of plasma exchange or plasma infusion (PE/PI), intensively administered daily for 5 days and then with reducing frequency.[22] However, the American Society for Apheresis offers a “weak” recommendation for plasma exchange to treat aHUS, due to the “low” or “very low” quality of evidence supporting its use. Although some patients experienced improvements in red blood cell and platelet counts, plasma therapies generally did not result in full remission.[26]

Plasma exchange/infusion (PE/PI)[edit]

Although PE/PI is frequently used, there are no controlled trials of its safety or efficacy in aHUS. Even though PE/PI often partially controls some of the hematological manifestations of aHUS in some patients, its effectiveness has not been demonstrated in terms of inducing total disease remission. PE/PI is associated with significant safety risks, including risk of infection, allergic reactions, thrombosis, loss of vascular access, and poor quality of life.[22][27] Importantly, terminal complement activation has been shown to be chronically present on the surface of platelets in patients with aHUS who appear to be clinically well while receiving chronic PE/PI.[9][28]

Eculizumab[edit]

Eculizumab has been shown to inhibit terminal complement activity in children and adults with aHUS, and to eliminate the need for PE/PI and new dialysis.[29] Its efficacy and safety in aHUS have been studied in two prospective studies. One study (Study 1) involved 17 patients with progressing TMA (median age 28 years, range 17-68) who were resistant to or intolerant of PE/PI. The other study (Study 2) involved 20 patients with long duration of aHUS (median age 28 years, range 13–63; median duration from diagnosis of aHUS to screening 48 months) who were receiving – and had become dependent upon – chronic PE/PI. TMA-related endpoints in these trials included the following:[29][30][unreliable medical source?][31][unreliable medical source?]

  • platelet count change from baseline
  • hematologic normalization (maintenance of normal platelet counts and LDH levels for at least four weeks)
  • complete TMA response (hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of four weeks)
  • TMA-event free status (absence for at least 12 consecutive weeks of a decrease in platelet count of >25% from baseline, PE/PI, and new dialysis requirement)
  • Daily TMA intervention rate (defined as the number of PE/PI interventions and the number of new dialyses required per patient per day)
  • Time course of changes in renal function as measured by estimated glomerular filtration rate (eGFR)
  • Proportion of patients with improvement by ≥1 chronic kidney disease (CKD) stage, eGFR increase by ≥15 mL/min/1.73m2 or serum creatinine decrease by ≥25%

Patient outcome in these studies was also measured by the application of a health-related quality of life (QoL) questionnaire.[30][31]

In these two prospective clinical trials, the most commonly reported adverse events (AEs) were hypertension (35%), upper respiratory infection (35%), diarrhea (32%), headache (30%), anemia (24%), vomiting (22%), and nausea (19%). Twenty of 37 patients (54%) in the prospective trials experienced a serious adverse event (SAE); the most commonly reported SAEs were hypertension (16%) and infections (14%).[29]

In addition to the above studies, there are dozens of published case reports of the use of eculizumab in patients with aHUS, including several reporting complete or partial recovery of renal function with no need for subsequent kidney replacement therapy.[32] In one case, a pediatric patient who was initially diagnosed shortly after birth and experienced four separate clinical TMA complications within 18 months following discontinuation of PE/PI has been treated with eculizumab for 36 months as of December 2011, with no evidence of aHUS clinical manifestation, adverse events, or serious infections; this is the longest reported event-free period in the clinical literature.[33]

Eculizumab inhibits terminal complement activation and therefore makes patients vulnerable to infection with encapsulated organisms. Life-threatening and fatal meningococcal infections have occurred in patients who received eculizumab.[29] Clinicians are therefore advised to comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies. Due to the increased risk of meningococcal infections, meningococcal vaccination is recommended at least 2 weeks prior to receiving eculizumab, unless the risks of delaying eculizumab therapy outweigh the risk of developing a meningococcal infection. If urgent eculizumab therapy is indicated in an unvaccinated patient, the meningococcal vaccine should be administered as soon as possible.[12] However, current meningococcal vaccines do not protect against strains of meningococcus with a serogroup B antigen,[34] and thus may not be sufficient to protect patients. In clinical trials, 33 of 67 patients with aHUS were treated with eculizumab less than 2 weeks after meningococcal vaccination, and 31 of these 33 patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after vaccination. Some authorities recommend the indefinite continuation of antibiotic prophylaxis. Patients should be monitored for early sign of meningococcal infection, and should be evaluated immediately if infection is suspected.[29]

Eculizumab treatment is recommended to continue for the patient’s lifetime, unless discontinuation of therapy is clinically indicated.[35] After discontinuing eculizumab, patients with aHUS should be monitored for signs and symptoms of TMA complications for at least 12 weeks. In aHUS clinical studies, 18 patients (five in the prospective studies) discontinued eculizumab treatment; five patients experienced TMA complications following a missed dose (i.e., up to almost one year after the last dose), and eculizumab was reinstated in four of these five patients. If TMA complications occur after eculizumab discontinuation, the clinician should consider reinstitution of eculizumab treatment, PE/PI, or appropriate organ-specific supportive measures.[29]

Dialysis[edit]

Patients with aHUS who have ESRD are generally consigned to lifelong dialysis, which carries a 5-year survival rate of 34-38%,[36][37] with infections accounting for 14% of deaths.[38] These patients also remain at ongoing risk of non-kidney systemic complications of the disease.

Kidney transplantation[edit]

Despite its history of use in patients with aHUS, kidney transplantation does not address the continued and uncontrolled complement activation that leads to progressive, systemic TMA. As many as 90% of patients with aHUS experience TMA in the transplanted organ, leading to transplant failure.[11][39] Patients who have undergone kidney transplantation are still at continued risk of neurological, gastrointestinal, and cardiovascular complications and, importantly, premature mortality. Following kidney transplantation, the ongoing, uncontrolled, chronic complement activation associated with aHUS causes graft loss in 66% of children and 55% of adults, as well as continued inflammatory and TMA insult to other organs.[1][4] Combined liver-kidney transplantation is only available to very few patients, due to the limited supply of solid organs. In addition, there is a substantial near-term risk of mortality, which many physicians and patients consider excessive.[1] In recent years, some transplant centers have begun to administer eculizumab to patients with TMA who receive a kidney transplant. This strategy has been effective in preventing TMA recurrences in these patients.[40]

Prognosis[edit]

Patients with aHUS have an extremely poor prognosis. Among those with the most commonly identified aHUS genetic mutation, the proportion of patients experiencing negative outcomes (e.g., need for dialysis, permanent kidney damage, death) within the first year rises to 70%.[5] However, sudden morbidity and mortality can occur regardless of mutational status. aHUS can arise at any age, with more than 40% of cases first reported after 18 years of age.[4] The oldest presentation in one study was at age 83.[4] As noted above, kidney transplantation for aHUS patients with ESRD was rarely considered because of a high incidence of graft loss due to TMA recurrence in the transplanted organ in up to 90% of patients.[11][39] Consequently, most aHUS patients with ESRD undergo chronic dialysis, which is associated with significant morbidities and worsened prognosis.[11] Combined liver-kidney transplantation has been attempted in patients with aHUS, although this high-risk procedure has a mortality rate approaching 50%.[41]

Quality of life is very poor for patients with aHUS, who are burdened with fatigue, renal complications, hypertension, neurological impairment, gastrointestinal distress, clotting at the site of venous access, and ultimately, death.[5] PE/PI is also reported to be associated with significant safety risks and is highly disruptive to patients’ lives due to the requirements for extensive vascular access and frequent administration.[12][34]

Epidemiology[edit]

aHUS can be inherited or acquired, and does not appear to vary by race, gender, or geographic area.[17] As expected with an ultra-rare disease, data on the prevalence of aHUS are extremely limited. A pediatric prevalence of 3.3 cases per million population is documented in one publication of a European hemolytic uremic syndrome (HUS) registry involving 167 pediatric patients.[42]

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