Atypical Hemolytic Uremic Syndrome

Hemolytic uremic syndrome refers to the symptom triad of hemolytic anemia, thrombocytopenia and renal insufficiency, with most cases being triggered by bacterial pathogens. A minor share of cases is of unknown etiology and are classified as atypical hemolytic uremic syndrome.

Overview

Hemolytic uremic syndrome (HUS) is the chosen designation for the symptom triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure [1] and it has first been described by the Swiss pediatrician Conrad von Gasser and colleagues in 1955 [2]. Indeed, it is primarily diagnosed in pediatric patients, especially in young children aged less than five years. Nevertheless, it may affect patients of any age. The vast majority of cases is attributed to an infection with enterohemorrhagic, Shiga-like toxin-producing serotypes of Escherichia coli (i.e., serotype O157:H7 and, less prevalent, non-O157:H7 serotypes). Additionally, HUS may develop secondary to infection with Shigella dysenteriae, Citrobacter spp. and Streptococcus pneumoniae, among others [1]. HUS is associated with an acute mortality rate of 5% in children and frequent long-term sequelae with possible progression to end-stage renal disease [3] [4].

Cases that cannot be related to an infectious agent are deemed atypical hemolytic uremic syndrome (aHUS). aHUS accounts for less than 10% of all cases diagnosed in pediatric patients, whereas adults diagnosed with HUS are more likely to suffer from the atypical form of the disease [5]. Distinct hypotheses regarding the disease' etiology have been proposed so far, with the theory of aHUS resulting from inherited complement disorders being the one most widely accepted. aHUS is a life-threatening condition ,often with a poor outcome; depending on the precise cause of aHUS. Roughly 38 to 73% develop end-stage renal disease within five years [3]. Mortality exceeds numbers reported for HUS patients and according to older literature, acute and overall mortality approaches 15 and 25%, respectively [6]. Patients remain at high risk for disease recurrence even after kidney transplantation.

Etiology

Both congenital and acquired aHUS may be caused by several primary diseases.

With regards to the former, congenital aHUS may be provoked by gene defects disturbing the balance between pro- and anti-thrombotic processes. aHUS may be induced by hereditary disorders of complement regulation that alter alternative complement pathway activation. Mutations have been identified in those genes encoding for factor H, factor I, C3, membrane cofactor protein (MCP), thrombomodulin and factor B, and are listed here in order of decreasing prevalence [7]. Factors H and I, MCP and thrombomodulin are required for C3b inactivation and thus for the downregulation of C3 convertase production. Deficiencies of these components of the complement system result in excess complement activation and consumption. Gain-of-function mutations affecting factor B may have similar consequences [8]. C3 mutations have been shown to impair factor I and MCP-mediated cleavage of C3b [9]. Complement disorders predisposing for aHUS may be inherited with an autosomal dominant or recessive trait, but mutations may also occur sporadically. The penetrance of mutations is incomplete.

Similar to the previously mentioned genetic causes of aHUS, dysregulation of the complement system may be triggered by an autoimmune-mediated depletion of complement factors. In this context, anti-factor H autoantibodies have recently been detected in blood samples obtained from aHUS patients [10].

Acquired aHUS has also been related to pre-existing glomerulopathy caused by autoimmune diseases like systemic lupus erythematosus and anti-phospholipid syndrome, infection with human immunodeficiency virus, solid organ and hematopoietic stem cell transplantation, malignancies and cancer therapy, pregnancy and use of oral contraceptives, application of calcineurin inhibitors, cyclosporin, quinine and other drugs [1] [3]. The causal relation between those entities and aHUS remains largely unknown, but the induction of complement anomalies has been proposed to explain at least some triggers of aHUS [7].

Of note, hereditary metabolic diseases causing symptoms consistent with HUS have previously been considered subtypes of aHUS. This applies for diacylglycerol kinase ε deficiency and disturbances of cobalamin metabolism [3]. Nowadays, these diseases are treated as own entities.

Epidemiology

The annual incidence of HUS has been estimated to be 6 per 100,000 children aged less than five years, whereas less than 2 per 100,000 patients are affected by the disease each year [7]. The incidence of aHUS is not known exactly, but is presumably less than 1 per 100,000 inhabitants per year. While some sources state the overall incidence of aHUS to be as low as 0.2 per 100,000, others claim it to account for the majority of HUS in adults [5] [11]. Literature reviews yield contradictory results owing to the inconsistent use of the term "atypical": Initially, aHUS has been diagnosed when HUS patients did not experience a prodromal period characterized by diarrhea. Only later, the diagnosis of aHUS has been reserved for cases of non-infectious origin. Some experts also recommend to exclude hereditary metabolic diseases from aHUS, and the present article follows that specification [3].

Sex distribution
Age distribution

Pathophysiology

According to current knowledge, aHUS is mainly triggered by complement disorders: Excess activation of the complement system is induced by deficiencies of inhibitors and gain-of-function mutations of factors that maintain this process. Since many complement factors are expressed by endothelial cells, such anomalies are associated with vascular damage. The latter is most prominent in small vessels, e.g., in capillaries forming glomeruli in the kidneys. Thus, affected individuals suffer from renal impairment. Thrombi easily form within damaged vessels, and thrombus formation may give rise to thromboembolic events. Eventually, platelets are consumed and the patient shows thrombocytopenia. Furthermore, erythrocytes passing through such vessels are subjected to mechanical stress and may be destroyed. This is the pathophysiological equivalent of microangiopathic hemolytic anemia. Consequently, fragments of erythrocytes, so-called schistocytes, may be detected in blood samples.

Mutations described in the previous paragraphs merely predispose for aHUS, and additional triggers are assumed to be necessary for the induction of an aHUS crisis. Under physiological conditions, the body is able to compensate for certain complement disorders, and only when confronted with pathogens, determined drugs or other challenges do these disorders manifest. Thus, aHUS follows a course of remission and relapse.

Prognosis

Morbidity is mainly due to permanent kidney damage resulting in proteinuria, renal hypertension, chronic kidney insufficiency and end-stage renal disease. The overall risk of long-term sequelae is high, with the majority of aHUS patients developing end-stage renal disease within five years after diagnosis [3]. Since aHUS is associated with progressive organ damage, an early diagnosis allows for the initiation of treatment before irreversible lesions occur, and this is the single most important favorable prognostic factor [12].

aHUS has been reported to be associated with mortality rates of up to 25% [6]. Recent studies offer a more distinctive consideration and reveal that both morbidity and mortality differ largely depending on the underlying disorder. Poorest outcomes have been described for defects of the gene encoding for factor H, with 60% of affected individuals developing end-stage renal disease and dying within one year [13].

Presentation

Both HUS and aHUS are most frequently diagnosed in children aged less than five years, with about 70% of them presenting a first episode of the disease during their first two years of life [5]. Thus, observation of the symptoms detailed below is highly suggestive of either form of the disease if presented by a young child.

During the prodromal stage, patients may suffer from gastroenteritis with abdominal pain and diarrhea, possibly containing blood. Historically, diarrhea has been assumed to be typical of HUS but not of aHUS, but this distinction no longer holds true [5]. Nevertheless, the prodromal phase may also be characterized by an upper respiratory infection or influenza, or may not be observed at all [11].

Symptom onset is usually sudden, and the disease follows a course of apparent remission and recurrence:

  • Parents report feeding difficulties, and the patients themselves suffer from lethargy, fatigue and vomiting.
  • Due to anemia, patients often appear pale or cyanotic, and tachycardia may be noted.
  • Thrombocytopenia rarely manifests in form of petechiae, hematoma or spontaneous hemorrhages.
  • Development of peripheral edema is related to renal loss of proteins and subsequent hypoalbuminemia. However, clinical symptoms associated with renal insufficiency may also be limited to hematuria during early stages of the disease, while they tend to worsen with each episode of aHUS. Oliguria or anuria may occur. Disease progression varies largely and some patients may develop end-stage renal disease as early as during their first bout of aHUS.

Only minor shares of patients present with an incomplete aHUS triad and only show one or two symptoms of the classical symptom complex.

In advanced stages of the disease, long-term sequelae of renal impairment may manifest:

Workup

The aforedescribed symptoms are not specific and usually prompt laboratory analyses of blood samples. These may yield findings consistent with microangiopathic hemolytic anemia, thrombocytopenia and acute kidney impairment, i.e.,

  • Hemoglobin levels <10 g/dl, undetectable haptoglobin and enhanced concentrations of lactate dehydrogenase, reticulocytosis, and schistocytes in blood smears
  • Platelet counts <150*10^9/l, often <60*10^9/l
  • Levels of urea >50 mg/dl and creatinine >1.2 mg/dl

Furthermore, urine analyses are of major importance for HUS and aHUS diagnosis. Proteinuria and hematuria are the most common findings. While urine parameters may initially normalize between episodes of the disease, proteinuria and hematuria may eventually become chronic. Such findings indicate the progressive worsening of kidney function.

It may be a major challenge to distinguish HUS from aHUS, and it is strongly advised not to delay the initiation of therapy until the disease etiology can be clarified. However, long-term treatment regimens and the patient's prognosis depend on the specific form of the disease and immediate medical attention should thus be accompanied by further diagnostic measures.

  • Stool samples should be obtained and analyzed; in rare cases, causative pathogens may also originate from the urinary tract [14]. Detection of pathogens or toxins associated with HUS is highly suggestive but not diagnostic of this form of the disease [5] [11]. In turn, negative results don't rule out HUS.
  • Concentrations of complement factors like factors H and I and C3 should be evaluated in serum samples. Reduced levels are indicative of a complement disorder. However, the sensitivity of such measurements is restricted since anomalies may be temporarily restricted to the endothelium.
  • Genetic screens may reveal inherited complement disorders, but a single patient cannot possibly be tested for all possible mutations related to aHUS. A targeted approach is possible only if their familial history or disease course implies a particular defect.
  • Circulating autoantibodies against factor H may be detected by employing immunoassays like ELISA [12].

Treatment

To date, only supportive treatment is available for therapy of aHUS patients. The following measures may be taken to delay disease progression and to relieve affected individuals of symptoms:

  • Plasma therapy and apheresis are indicated as immediate measures, even before the disease underlying aHUS has been identified. This procedure aims at delivering functional complement factors and to remove abnormal molecules. During the first five days after diagnosis, up to 75 ml per kg body weight (approximately 1.5 × plasma volume) should be exchanged in daily sessions [7] [14]. Subsequently, the frequency of treatments is reduced to five per week for two weeks and eventually three per week for two weeks [14]. By this time, hemoglobin levels and platelet counts should have returned to reference ranges. Creatinine levels are not to be used as marker for the patient's response to plasmapheresis. The timely initiation of plasma therapy has a major impact on the patient's prognosis.
  • Non-responders to plasmapheresis may require treatment with eculizumab, which has been approved for use in aHUS in late 2011 [15]. This compound inhibits complement activation by blocking the cleavage of C5 to C5a and C5b, and thus, response to therapy may be assessed by evaluating terminal complement markers. Eculizumab is initially administered weekly with subsequent reduction to bimonthly infusion. Unfortunately, long-term therapy with eculizumab is very expensive.
  • Patients may also be considered for liver or kidney transplantation, particularly if long-term therapy with eculizumab is not an option or the patient does not respond to such treatment: Several complement factors are synthesized in the liver and thus, a healthy liver may provide functional proteins to those individuals diagnosed with determined deficiencies (e.g., factors H and I and C3). As well, there are few alternatives to renal transplantation if a patient develops end-stage renal disease. Recurrence and long-term graft survival rates depend on the precise underlying disorder.
  • Patients suffering from aHUS due to an autoimmune response directed against complement factor H may benefit from immunosuppressive therapy.

Prevention

No specific measures can be recommended to prevent aHUS. Because gene defects associated with aHUS merely predispose for the disease, which may or may not be triggered by as-of-yet unknown factors, the benefit of genetic screens of family members of affected individuals is questionable.

Patient Information

Hemolytic uremic syndrome (HUS) refers to the symptom triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury, i.e., HUS patients suffer from low levels of hemoglobin, lack of platelets and renal impairment. Their general condition is reduced, they suffer from fatigue, tachycardia and palpitations, are prone to spontaneous bleeding and renal failure. Their damaged kidneys lose protein and are unable to maintain normal blood pressure. Thus, HUS patients develop edema and hypertension.

In most cases, HUS manifests after an infection with determined serotypes of Escherichia coli, with Shigella dysenteriae, Citrobacter spp. or Streptococcus pneumoniae. Less than 10% of all cases cannot be associated with such an infection and are thus deemed atypical hemolytic uremic syndrome (aHUS). aHUS is often related to gene defects.

It is of utmost importance to diagnose aHUS during early stages of the disease in order to initiate therapy as soon as possible. This way, the risk of end-stage renal disease, renal failure and death may be reduced. Treatment options comprise plasma exchange, drug therapy and liver and kidney transplantation.

Search symptoms now!

References

  1. Scheiring J, Andreoli SP, Zimmerhackl LB. Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol. 2008; 23(10):1749-1760.
  2. Gasser C, Gautier E, Steck A, et al. [Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia]. Schweiz Med Wochenschr. 1955; 85(38-39):905-909.
  3. Kaplan BS, Ruebner RL, Spinale JM, et al. Current treatment of atypical hemolytic uremic syndrome. Intractable Rare Dis Res. 2014; 3(2):34-45.
  4. Spinale JM, Ruebner RL, Copelovitch L, et al. Long-term outcomes of Shiga toxin hemolytic uremic syndrome. Pediatr Nephrol. 2013; 28(11):2097-2105.
  5. Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011; 6:60.
  6. Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol. 1998; 9(6):1126-1133.
  7. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009; 361(17):1676-1687.
  8. Marinozzi MC, Vergoz L, Rybkine T, et al. Complement factor B mutations in atypical hemolytic uremic syndrome-disease-relevant or benign? J Am Soc Nephrol. 2014; 25(9):2053-2065.
  9. Martínez-Barricarte R, Heurich M, López-Perrote A, et al. The molecular and structural bases for the association of complement C3 mutations with atypical hemolytic uremic syndrome. Mol Immunol. 2015; 66(2):263-273.
  10. Dragon-Durey MA, Loirat C, Cloarec S, et al. Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005; 16(2):555-563.
  11. Constantinescu AR, Bitzan M, Weiss LS, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis. 2004; 43(6):976-982.
  12. Hofer J, Giner T, Jozsi M. Complement factor H-antibody-associated hemolytic uremic syndrome: pathogenesis, clinical presentation, and treatment. Semin Thromb Hemost. 2014; 40(4):431-443.
  13. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007; 18(8):2392-2400.
  14. Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009; 24(4):687-696.
  15. Schmidtko J, Peine S, El-Housseini Y, Pascual M, et al. Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab. Am J Kidney Dis. 2013; 61(2):289-299.

  • n.a.


Search symptoms now!