Etiology

The various etiologies of HUS allow classification into infection-induced, genetic, medication- induced, and HUS associated with systemic diseases characterized by microvascular injury (Tables 512-2 and 512-3). The most common form of HUS is caused by toxin-producing Escherichia coli that cause prodromal acute enteritis and is commonly termed diarrhea-associated HUS. In the subcontinent of Asia and southern Africa, the shiga toxin of Shigella dysenteriae type 1 is causative, whereas in Western countries verotoxin-producing E. coli (VTEC) are the usual causes.

Several serotypes of E. coli can produce verotoxin, and the O157:H7 type is most common in Europe and the Americas. The reservoir of VTEC is the intestinal tract of domestic animals, usually cows. Disease is usually transmitted by undercooked meat or unpasteurized milk or apple cider. Epidemics have followed ingestion of undercooked, contaminated hamburger at fast food restaurants. HUS outbreaks have also been associated with municipal water supply; petting farms; swimming in contaminated ponds, lakes, or pools; and consuming cheese, lettuce, or raw spinach contaminated with toxin (often by contact with meat on an unwashed cutting board). Less often, HUS has been spread by person-to-person contact within families or child care centers. A rare but distinct entity of infection-triggered HUS is related to neuraminidase-producing Streptococcus pneumoniae. HUS develops during acute infection with this organism, typically manifesting as pneumonia with empyema. A thrombotic microangiopathy, similar to HUS or TTP, also occurs in patients with untreated HIV infection.

Genetic forms of HUS compose the second major category of the disease that has become clearly defined (see Tables 512-2, 512-3). Inherited deficiencies of either von Willebrand factor–cleaving protease (ADAMTS 13) or complement factor H, I, or B and defects in vitamin B₁₂ metabolism can cause HUS. There remain familial cases transmitted in autosomal dominant or recessive patterns in which a specific genetic defect has not yet been identified. Most of the genetic forms do not have a preceding diarrhea prodrome. Genetic forms of HUS can be indolent and unremitting once they become manifest, or they can have a relapsing pattern precipitated by an infectious illness. The latter feature likely explains the association of many infectious agents with HUS, particularly in reports published before the recognition of the unique pathophysiology of VTEC and neuraminidase- producing pneumococci in causing HUS.

HUS can be superimposed on any disease associated with microvascular injury, including malignant hypertension, systemic lupus erythematosus, and antiphospholipid syndrome. It can also occur following bone marrow or solid organ transplantation and may be triggered by the use of the calcineurin inhibitors cyclosporine and tacrolimus in that setting. Several other medications can also induce HUS (see Table 512-2).

Pathology

Kidney biopsies are only rarely performed in HUS because the diagnosis is made by clinical criteria. The risks of biopsy are significant during the active phase of the disease. Early glomerular changes include thickening of the capillary walls caused by swelling of endothelial cells and accumulation of fibrillar material between endothelial cells and underlying basement membrane, causing narrowing of the capillary lumens. Platelet-fibrin thrombi are often seen in glomerular capillaries. Thrombi are also seen in afferent arterioles and small arteries with fibrinoid necrosis of the arterial wall, leading to renal cortical necrosis from vascular occlusion. Late findings include glomerular sclerosis and obsolescence secondary to either severe direct glomerular involvement or glomerular ischemia from arteriolar involvement.

Pathogenesis

Microvascular injury with endothelial cell damage is characteristic of all forms of HUS. In the common, diarrhea-associated form of HUS, enteropathic organisms produce either Shiga toxin or the highly homologous Shiga-like verotoxin that directly cause endothelial cell damage. Shiga toxin can directly activate platelets to promote their aggregation. In pneumococcal-associated HUS, neuraminidase cleaves sialic acid on membranes of endothelial cells, red cells, and platelets to reveal the underlying cryptic Thomsen-Friedenreich (T) antigen. Endogenous immunoglobulin M (IgM) recognizes the T antigen and triggers the microvascular angiopathy.

The familial recessive and dominant forms of HUS and the inherited deficiencies of ADAMTS 13 (usually TTP) and complement factor H probably predispose patients to developing HUS but do not cause the disease per se, because these patients might not develop HUS until later childhood or even adulthood. In such cases, HUS is often triggered by an inciting event such as an infectious disease. The absence of ADAMTS 13 impairs cleavage of von Willebrand factor multimers, which enhances platelet aggregation. Factor H plays a central role in complement regulation, primarily arresting amplification and propagation of complement activation. It may be that mild endothelial injury that would normally resolve instead evolves to an aggressive microangiopathy because of the inherited deficiencies of these factors.

In each form of HUS, capillary and arteriolar endothelial injury in the kidney leads to localized thrombosis, particularly in glomeruli, causing a direct decrease in glomerular filtration rate. Progressive platelet aggregation in the areas of microvascular injury results in consumptive thrombocytopenia. Microangiopathic hemolytic anemia results from mechanical damage to red blood cells as they pass through the damaged and thrombotic microvasculature.

Clinical Manifestations

HUS is most common in preschool and school-aged children, but it can occur in adolescents. In HUS caused by exotoxin-producing E. coli, onset of HUS occurs a few days (as few as 3) after onset of gastroenteritis with fever, vomiting, abdominal pain, and diarrhea. The prodromal intestinal symptoms may be severe and require hospitalization, but they can be relatively mild and considered trivial. The diarrhea is often bloody, but not necessarily so, especially early in the illness. Following the prodromal illness, the sudden onset of pallor, irritability, weakness, and lethargy herald the onset of HUS. Oliguria can be present in early stages but may be masked by ongoing diarrhea because the prodromal enteritis often overlaps the onset of HUS. Thus, patients can present with HUS either with significant dehydration or volume overload, depending on whether the enteritis or renal insufficiency from HUS predominates and the amount of fluid that was administered.

Patients with pneumococcus-associated HUS usually are ill with pneumonia and empyema when they develop HUS. Onset can be insidious in patients with the genetic forms of HUS, with HUS triggered by a variety of illnesses, including mild, nonspecific gastroenteritis or respiratory tract infections.

HUS can be relatively mild or can progress to a severe, and even fatal, multisystem disease. Leukocytosis and severe prodromal enteritis portend a severe course, but no presenting features reliably predict the severity of HUS in any given patient. Patients with HUS who appear mildly affected at presentation can rapidly develop severe, multisystem, life-threatening complications. Renal insufficiency can be mild but also can rapidly evolve into severe oliguric or anuric renal failure. The combination of rapidly developing renal failure and severe hemolysis can result in life-threatening hyperkalemia. Volume overload, hypertension, and severe anemia can all develop soon after onset and together can precipitate heart failure. Direct cardiac involvement is rare, but pericarditis, myocardial dysfunction, or arrhythmias can occur without predisposing features of hypertension, volume overload, or electrolyte abnormalities.

The majority of patients with HUS have some central nervous system (CNS) involvement. Most have mild manifestations, with significant irritability, lethargy, and nonspecific encephalopathic features. Severe CNS involvement occurs in ≤20% of cases. Seizures and significant encephalopathy are the most common manifestations in those with severe CNS involvement and result from focal ischemia secondary to microvascular CNS thrombosis. Small infarctions in the basal ganglion and cerebral cortex have also been reported, but large strokes and intracranial hemorrhage are rare. Intestinal complications can be protean and include severe inflammatory colitis, ischemic enteritis, bowel perforation, intussusception, and pancreatitis. Patients can develop petechiae, but significant or severe bleeding is rare despite very low platelet counts.

Diagnosis and Differential Diagnosis

The diagnosis is made by the combination of microangiopathic hemolytic anemia with schistocytes, thrombocytopenia, and some degree of kidney involvement (see Table 512-1). The anemia, mild at presentation, rapidly progresses. Thrombocytopenia is an invariable finding in the acute phase, with platelet counts usually 20,000-100,000/mm³. Partial thromboplastin and prothrombin times are usually normal. The Coombs test is negative, with the exception of pneumococci-induced HUS, where the Coombs test is usually positive. Leukocytosis is present and significant. Urinalysis typically shows microscopic hematuria and low-grade proteinuria. The renal insufficiency can vary from mild elevations in serum BUN and creatinine to acute, anuric kidney failure.

The etiology of HUS is often clear with the presence of a diarrheal prodrome or pneumococcal infection. The presence or absence of toxigenic, enteropathic organisms on stool culture has little role in making the diagnosis of diarrhea-associated, enteropathic HUS. Only a minority of patients infected with those organisms develops HUS, and the organisms that cause HUS may be rapidly cleared. Therefore the stool culture is often negative in patients who have diarrhea-associated HUS. If no history of diarrheal prodrome or pneumococcal infection is obtained, then evaluation for the genetic forms of HUS should be considered, because those patients are at risk for recurrence, have a severe prognosis, and can require different therapies.

Other causes of acute kidney failure associated with a microangiopathic hemolytic anemia and thrombocytopenia, such as systemic lupus erythematosus, malignant hypertension, and bilateral renal vein thrombosis, should be considered and excluded. A kidney biopsy is rarely indicated.

Prognosis and Treatment

The acute prognosis, with careful supportive care, for diarrhea-associated HUS has <5% mortality in most major medical centers. Half of the patients require dialysis support during the acute phase of the disease. Most recover renal function completely, but of surviving patients, 5% remain dependent on dialysis, and up to 20-30% are left with some level of chronic renal insufficiency. The prognosis for HUS not associated with diarrhea is more severe. Pneumococci-associated HUS causes increased patient morbidity, with mortality reported as 20%. The familial, genetic forms of HUS can be insidiously progressive or relapsing diseases and have a poor prognosis (see Table 512-3). Identification of specific factor deficiencies in some of these genetic forms provides opportunity for specific replacement therapy to improve outcomes.

The primary approach that has substantially improved acute outcome in HUS is early recognition of the disease, monitoring for potential complications, and meticulous supportive care. Supportive care includes careful management of fluid and electrolytes including correction of volume deficit, control of hypertension, and early institution of dialysis if the patient becomes anuric or significantly oliguric. Red cell transfusions are usually required because hemolysis can be brisk and recurrent until the active phase of the disease has resolved. In pneumococci-associated HUS, it is recommended that any administered red cells be washed before transfusion to remove residual plasma, because endogenous IgM directed against the revealed T antigen can play a pathogenic role. Platelets should generally not be administered, regardless of platelet count, to patients with HUS because they are almost immediately consumed by the active coagulation and can theoretically worsen the clinical course. Despite low platelet counts, serious bleeding is very rare in patients with HUS.

There is no evidence that any therapy directed at arresting the disease process of the most common, diarrhea-associated form of HUS provide benefit, and some can cause harm. Attempts have been made using anticoagulants, antiplatelets agents, fibrinolytic therapy, plasma therapy, immune globulin, and antibiotics. Anticoagulation, antiplatelet, and fibrinolytic therapy is specifically contraindicated because they increase the risk of serious hemorrhage. Antibiotic therapy to clear the toxigenic organisms can result in increased toxin release, potentially exacerbating the disease, and therefore is not recommended. Prompt treatment of any underlying pneumococcal infection is important. Attempts to bind Vero or Shiga toxin in the gut to prevent systemic absorption, and thereby prevent or ameliorate the course of HUS, have been unsuccessful in extensive controlled clinical trials.

Plasma infusion or plasmapheresis has been proposed for patients suffering severe manifestations of HUS, primarily serious CNS involvement. There are no controlled data demonstrating the effectiveness of this approach. Plasma therapy can be of substantial benefit to patients with identified deficits of ADAMTS 13 or factor H. It may also be considered in patients with other genetic forms of HUS, such as undefined familial (recessive or dominant) or sporadic but recurrent HUS.

Most patients with diarrhea-associated acquired forms of HUS recover completely with little risk of long-term sequelae. However, patients with hypertension, any level of renal insufficiency, or residual urinary abnormalities persisting a year after an episode of diarrhea-positive HUS require careful follow-up. Patients who have recovered completely, with no residual urinary abnormalities after a year, are unlikely to manifest long-term sequelae. Because of occasional reports of late sequelae in such patients, annual examinations with a primary physician are still warranted.