1. Summary of Recommendations:
Haemolytic uremic syndrome (HUS) is a condition that affects the blood and blood vessels resulting in destruction of blood platelets, anaemia and kidney failure. There are two types of HUS; Typical (cause by infection) atypical (usually genetic default). In this essay aHUS is referred to as Complement-mediated TMA, to emphasise the cause of the disease. There is a 5–10% mortality rate due to the disease however there is a in 55–70% chance of acute renal failure. Recently a drug named eculizumab have been approved by the NHS for the treatment of aHUS however there are issues relating to high cost of this lifelong treatment.
This essay will firstly explain the molecular significance of the disease, secondly discuss the clinical challenges faced by the NHS and lastly a potential solution in order to successfully face these challenges by introducing Ex vivo technique to monitor complement activation and eculizumab effectiveness in aHUS.
2. Background:
Haemolytic uremic syndrome, happens when an immune reaction destroys the red blood cells are destroyed. This results in low red blood cell levels, low platelet levels, and kidney injury due to blockage of kidneys’ filtering system. The most common underlying cause of HUS in children is infection with Escherichia Coli (E. coli) There are also many non-bacterial causes of HUS in adults that are less common (Table.1)1.
Haemolytic Uraemia Syndrome
ST-HUS (tHUS)
COMPLEMENT-MEDIATED TMA (aHUS)
. CAUSE by infection (certain strain of E. coli, which release toxic substances called shiga-like toxin)
. CAUSE by genetic mutation
Symptoms:
. Initially severe
. Severe diarrhoea
. Kidney failure not permanent in most cases
. Blood pressure regulation problem
. Most often affect children younger than 10
Symptoms:
. Initially are not severe.
. No Severe diarrhoea
. characterized by three major features related to abnormal clotting: haemolytic anaemia, thrombocytopenia, and kidney failure.
. Can occur at any age
. Less likely to involve recurrent attacks of kidney damage that lead to ESRD.
. Often kidney failure recurrent resulting in ESRD.
2.1. Atypical haemolytic-uremic syndrome (HUS)
In the majority of aHUS cases, the disease results from the complement-mediated damage to the microvascular endothelium due to inherited defects in complement genes or autoantibodies against complement regulatory proteins. CFH antibodies (responsible for defective CFH-dependent cell protection) account for about 10% of complement-mediated TMA. Along other functions the complement system is one of the major means by which the body recognizes foreign agents and pathogens2.
For the purpose of this essay it is important to understand the alternative pathway described below Components of the complement system that are exclusive to the alternative pathway are factor B, factor D and properdin. Factors B and D have been studied in vivo and demonstrated both proteins are required for efficient alternative pathway activation by zymosan3.
Hereditary complement-mediated TMA may result from either a loss-of-function mutation in a regulatory gene (CFH, CFI, or CD46) or a gain-of-function mutation in an effector gene (CFB or C3)4,5. These genetic abnormalities may contribute to the loss of alternative pathway regulation.
In contrast to the specific protein-protein or protein-carbohydrate interactions that characterize the pathway activation, the alternative pathway is capable of auto-activation because of a process termed “tickover” * of C36. The alternative pathway can also be initiated as an “amplification loop” when fixed C3b (product of C3 cleavage) activation binds factor B, again resulting in conformational changes in factor B that allow factor D to cleave it similarly to the tickover process. Due to the spontaneous activating capabilities, the alternative pathway requires continuous active control. this control can be overwhelmed by specific activators of this pathway, increased concentrations of alternative pathway components7, by release of these proteins by infiltrating neutrophils8 or insufficient function of the complement regulatory proteins. An “activating” surface is, in large part, one without adequate regulatory protein function to control alternative pathway activation9 or one that is not favorable to control of the alternative pathway by factor H10 Congenital or acquired deficiency of the complement regulatory proteins can result from Abs that block endogenous regulatory mechanisms11 or decreased expression of complement regulatory proteins12. Non-Shiga-toxin-associated HUS, or atypical HUS (aHUS), has been linked with mutations of the fluid phase alternative pathway inhibitor factor H13. the membrane-bound inhibitor membrane cofactor protein (CD46) Mutations14 in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial haemolytic uremic syndrome, factor I15, and autoantibodies to factor H16. Alternative pathway activation during the disease has been detected by decreased levels of C3 and factor B as well as increased levels of C3 activation fragments, whereas C4 levels are unaffected4,17.C3 but not C4 is also deposited in the glomeruli and arterioles of patients with aHUS18. Interestingly, the regulatory protein mutations associated with aHUS are generally heterozygous. The mutations of factor H associated with aHUS reduce the ability of the protein to bind polyanion-rich surfaces (such as the glomerular basement membrane)19 perhaps allowing uncontrolled alternative pathway activation after insults such as certain infections or drugs4.
2.2Theraputic area
Acute kidney injury and hypertension are prominent abnormalities in complement-mediated TMA (Table.1). The current diagnostic criteria are those that were used in clinical trials involving a total of 37 patients, which supported the approval of eculizumab21 (a humanized monoclonal antibody that blocks the generation of C5a and C5b) (figure 2) for atypical HUS treatment in 2011. These criteria include: a serum creatinine level at/above the upper limit of the normal range, microangiopathic hemolytic anemia, thrombocytopenia, ADAMTS13 activity of 5%/more, and negative stool tests for Shiga toxin–producing infection22. These criteria may also occur in all other primary TMA syndromes as well as in other patients with microangiopathic haemolytic anaemia and thrombocytopenia21. Complement genetic studies, now commercially available with a rapid return of results, providing a more specific diagnosis. Normal plasma levels of C3, C4, and complement factors H, B, do not exclude the diagnosis of complement-mediated TMA.
2.3Unmet clinical need23,24
Safe clinical trials need to be run in order to determine the most appropriate length of anti-complement therapy and to develop surveillance markers to confirm renal remission is critical. Further genetic investigation is required to explain the heterozygosity and low penetrance of currently identified complement mutations and also to determine the cause of disease in patients who may have complement-mediated TMA but in whom no mutation has been identified. Additionally, the high price of Eculizumab treatment is $0.5M per patient per year. therefore, better diagnostic criteria could be the key of lowering the costs as well as improving patient’s lives.
2.4. Clinical challenges
One of the clinical challenges is identification of the genetic and environmental factors that confer susceptibility for development of HUS in select patients following infection with STEC4,14. symptoms of STEC associated HUS overlap with symptoms noted in patients with aHUS. additional research is required to determine if a subset of patients with STEC HUS such as the patient described above may benefit from solely supportive care or disease specific therapy.
Anti-complement therapy can be used to supplement plasma therapy and potentially prevent liver transplantation25. Eculizumab is currently the only available anti-complement agent. Its effect may be limited among patients who have C5 mutations26. The nonspecific diagnostic criteria and the fact that patients with no identified complement mutation may have a response to anti-complement therapy makes the decision to use an anti-complement agent as initial therapy difficult4,27. This therapy is a reasonable initial treatment for patients with antibodies against complement factor H. However, the use of immunosuppression to reduce the antibody titer should be considered. The high cost of eculizumab and the implication that it should be continued indefinitely are critical issues. The risk of meningococcal infection in connection with eculizumab therapy must be considered.
Before the use of eculizumab, the risks of end-stage renal disease or death and of recurrence after kidney transplantation were primarily dependent on mutational analyses, with CFH mutations causing the greatest risk4. It is assumed that anti-complement treatment will improve outcomes.
3.Current Drug Discovery Approaches :
“Dynamics of complement activation in aHUS and how to monitor eculizumab therapy28”
As mentioned above aHUS is associated with genetic complement abnormalities/anti–complement factor H antibodies, which is how treatment is done with eculizumab. In a particular study 44 aHUS patients test new assays of complement activation followed by verification of whether such abnormality occurs also in unaffected mutation carriers, and search for a tool for eculizumab titration. An abnormal circulating complement profile (low C3, high C5a) was found in 47% to 64% of patients (irrespective of disease severity). Acute aHUS serum, but not serum from remission, caused wider C3 and C5b-9 deposits than control serum on unstimulated human microvascular endothelial cells (HMEC-1). In adenosine 5′-diphosphate–activated HMEC-1, also sera from 84% and 100% of patients in remission, and from all unaffected mutation carriers, induced excessive C3 and C5b-9 deposits. At variance, in most patients with C3 glomerulopathies/immune complex-associated membranoproliferative glomerulonephritis, serum-induced endothelial C5b-9 deposits were normal. In 8 eculizumab-treated aHUS patients, C3/SC5b-9 circulating levels did not change after treatment with eculizumab, whereas serum-induced endothelial C5b-9 deposits normalized after the treatment, paralleled or even led to remission, and guided drug dosing and timing. These results point to efficient complement inhibition on endothelium for aHUS treatment.
3.1. Impact and probability of success
That this might be the case is supported here by the 2 adult patients (cases 7 and 8) in whom treatment could be spaced every 3 and 4 weeks, respectively, with the support of prospective evaluation of ex vivo C5b-9 deposits on ADP-activated endothelium, without changes in clinical parameters. Prospective studies in a larger number of patients are needed to prove the sensitivity of the ex vivo test proposed here to guide eculizumab dosage and spacing in aHUS patients, particularly in the presence of inciting events like infections or pregnancies.
4.Conclusion and recommendation:
Although eculizumab has been approved by regulatory agencies in the United States and Europe to be used for the treatment of aHUS, the extremely high cost of eculizumab ($0.5M per patient per year) and the need of lifelong treatment may be an important limitation to its use.
“it is crucial to explore the most appropriate dose, dosage intervals and duration of treatment to reduce the enormous financial burden of eculizumab therapy.”29
On May 2013 Uk health minister rejected a recommendation from the experts for the drug to be routinely provided nationally and therefore a woman with aHUS was refused to be funded for the treatment. After that, the National Health System published a policy defining: patients to whom eculizumab treatment will be provided, pending evaluation and final decision by the National Institute for Health and Care Excellence.
In this regard the ex vivo test shows that C5b-9 endothelial deposits could be a helpful tool to monitor and eculizumab effectiveness, adjust the dose, and the interval between doses to the minimum requirement to block complement at the endothelial level, avoiding waste of money considering the extremely high cost of the drug28.