Elsevier

The Lancet

Volume 390, Issue 10095, 12–18 August 2017, Pages 681-696
The Lancet

Seminar
Haemolytic uraemic syndrome

https://doi.org/10.1016/S0140-6736(17)30062-4Get rights and content

Summary

Haemolytic uraemic syndrome is a form of thrombotic microangiopathy affecting predominantly the kidney and characterised by a triad of thrombocytopenia, mechanical haemolytic anaemia, and acute kidney injury. The term encompasses several disorders: shiga toxin-induced and pneumococcus-induced haemolytic uraemic syndrome, haemolytic uraemic syndrome associated with complement dysregulation or mutation of diacylglycerol kinase ɛ, haemolytic uraemic syndrome related to cobalamin C defect, and haemolytic uraemic syndrome secondary to a heterogeneous group of causes (infections, drugs, cancer, and systemic diseases). In the past two decades, experimental, genetic, and clinical studies have helped to decipher the pathophysiology of these various forms of haemolytic uraemic syndrome and undoubtedly improved diagnostic approaches. Moreover, a specific mechanism-based treatment has been made available for patients affected by atypical haemolytic uraemic syndrome due to complement dysregulation. Such treatment is, however, still absent for several other disease types, including shiga toxin-induced haemolytic uraemic syndrome.

Introduction

Haemolytic uraemic syndrome is a rare but severe disease that has in the past two decades generated many studies. Experimental and genetic studies have helped to decipher the pathophysiology of various forms of haemolytic uraemic syndrome, while clinical studies have better delineated the picture and improved diagnosis. These breakthroughs have paved the way for new targeted therapies. Haemolytic uraemic syndrome is a rapidly evolving field but is one of the best examples of precision medicine—ie, tailored mechanism-based treatment—and of how translational research can improve the management of a disease. In this Seminar, we discuss the definitions and classifications, pathophysiology, genetics, clinical presentation, diagnostics, and management of haemolytic uraemic syndrome subsets.

Section snippets

Definitions and classifications

Haemolytic uraemic syndrome belongs to a range of thrombotic microangiopathies and arises from an initial endothelial cell injury. The term thrombotic microangiopathy refers primarily to pathological features of vascular damage. In haemolytic uraemic syndrome, these features are documented mainly in the kidney as fibrin and platelet thrombi in capillaries and arterioles, endothelial cell swelling and detachment from the glomerular basement membrane, and the appearance of so-called double

Incidence and epidemiology

In children with haemolytic uraemic syndrome, the proportion with STEC–haemolytic uraemic syndrome is 85–90%, atypical haemolytic uraemic syndrome is 5–10%, and S pneumoniae–haemolytic uraemic syndrome is about 5%. By contrast, the respective frequency of haemolytic uraemic syndrome secondary to coexisting diseases or conditions, or infections; and atypical haemolytic uraemic syndrome is not precisely documented in adults.

Although the frequency of invasive pneumococcal disease substantially

Pathophysiology

The common feature to all forms of haemolytic uraemic syndrome is the presence of endothelial cell lesions in the microvasculature of the kidney and, less frequently, of other organs. The trigger of endothelial cell lesions might be extrinsic and transient, such as Streptococcus pneumoniae or STEC infections, drugs, or cancer. In these settings, the thrombotic microangiopathy process usually abates once the trigger has been removed or controlled, with no risk of relapse. Conversely, the driving

Genetics

Haemolytic uraemic syndrome can be a familial monogenic recessive disease caused by pathogenic variants in a single gene (cblC-defect–haemolytic uraemic syndrome4 and DGKE–haemolytic uraemic syndrome6). Complement–haemolytic uraemic syndrome is frequently sporadic (85% of families2) despite presence of pathogenic variants in complement genes in the patient and one of their healthy parents. These findings suggest that the genetic background predisposes the patient to the disease rather than

Clinical presentation

The clinical symptoms of haemolytic uraemic syndrome are non-specific and include fatigue, pallor, shortness of breath, reduced urine output, and oedema. STEC–haemolytic uraemic syndrome frequently follows prodromic bloody diarrhoea88, 89, 90 (appendix pp 4, 5) and by contrast has seldom been reported after STEC urinary tract infection.91 S pneumoniae–haemolytic uraemic syndrome occurs in individuals with severe S pneumoniae sepsis, associated usually with pleural or pulmonary infection, and in

Diagnostic investigations and differential diagnosis

A practical diagnostic approach of patients suspected of haemolytic uraemic syndrome is detailed in figure 3.105, 106, 107 Several working groups have proposed diagnostic algorithms.1, 19, 108, 109 This approach relies on stepwise procedures, which aim to confirm or rule out distinct causative forms of haemolytic uraemic syndrome on the basis of direct tests. However, diagnosis of atypical haemolytic uraemic syndrome can be made by default when other causes have been eliminated with a

Management and outcome

Supportive therapy (appendix p 10) is the cornerstone of haemolytic uraemic syndrome treatment and has largely contributed to the decrease in mortality following development of any form of haemolytic uraemic syndrome.

S pneumoniae–haemolytic uraemic syndrome

Early recognition and prompt initiation of antibiotics (mainly amoxicillin or third generation cephalosporin in case of meningitis) with supportive intensive care largely accounts for the improvement of S pneumoniae–haemolytic uraemic syndrome outcomes in the past two decades (appendix pp 4, 5). Because plasma contains anti-Thomsen–Friedenreich antibodies, which might enhance agglutination of Thomsen–Friedenreich-anti-Thomsen–Friedenreich and worsen haemolytic uraemic syndrome course, plasma

Outcome and predictive factors

Central to management of STEC–haemolytic uraemic syndrome is early assessment of haemolytic uraemic syndrome severity, which correlates with the risk of sequelae (appendix pp 4, 5). Overall, early death rates have been reduced to 1·4–2·9% in children since the early 2000s;89, 118 whereas people aged 60 years or older still have the highest risk of death.15 In the same period, the proportion of children who progressed to end-stage renal disease was 1·4%, or had renal (chronic kidney disease

Outcome and predictive factors

Before eculizumab was available for treatment of haemolytic uraemic syndrome, the death rate (reported in two European cohorts)2, 3 was higher in children than in adults (8–14% vs 2–4%) at 3–5 years' follow-up. Conversely, the rate of end-stage renal disease was higher in adults than in children (table 2 and appendix pp 4, 5).2, 3 In adults, outcomes were similarly poor irrespective of whether a patient had a complement variant or not. CFH–haemolytic uraemic syndrome had the most severe

Secondary haemolytic uraemic syndrome

Haemolytic uraemic syndrome associated with coexisting diseases or conditions comprise a heterogeneous group, of a variety of types of endothelial cell damage (table 1). The identification of complement alternative pathway dysregulation as a major driver of atypical haemolytic uraemic syndrome has prompted some investigators to reconsider the pathogenesis of secondary haemolytic uraemic syndrome, leading for instance to the reclassification of pregnancy–haemolytic uraemic syndrome. Similarly,

Haemolytic uraemic syndrome in pregnancy

Pregnancy can trigger different types of thrombotic microangiopathies, including ADAMTS13-deficiency–thrombotic thrombocytopenic purpura (mostly during the second and third trimesters), haemolytic uraemic syndrome (mostly in peripartum or post-partum), and HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome, a thrombotic microangiopathy affecting the liver and inconstantly the kidney (table 1). Features of thrombotic microangiopathy might also be encountered in severe

Renal transplantation and haemolytic uraemic syndrome

The different forms of haemolytic uraemic syndrome whose pathogenic mechanism primarily involves damage to the endothelial cells by environmental factors have a low rate of recurrence after kidney transplantation. By contrast, atypical haemolytic uraemic syndrome related to complement alternative pathway dysregulation, involving circulating factors, is associated with a high rate of recurrence after kidney transplantation (appendix p 16). Importantly, in the pre-eculizumab era, atypical

Conclusion

Much has been achieved in the field of haemolytic uraemic syndrome in the past 10 years (appendix p 17). A mechanistic approach of haemolytic uraemic syndrome has been developed, an innovative efficacious treatment— the anti-C5 antibody eculizumab—has been made available for atypical haemolytic uraemic syndrome, and new mechanisms of pathogenesis have been identified. Several aspects remain unclear. Reliable biomarkers for the diagnosis and monitoring of haemolytic uraemic syndrome are missing.

Search strategy and selection criteria

We searched PubMed between Jan 1, 1989, and March 1, 2016, with the terms “hemolytic uremic syndrome”, “thrombotic microangiopathy”, “shigatoxin”, “pneumococcus”, “cobalamin C defect”, “complement”, and “eculizumab” in combination with the terms “pathophysiology”, “diagnosis”, “causes”, and “treatment”. We restricted our search to English and French publications. We selected reports from the past 5 years but did not exclude important and highly cited older publications. We searched the

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