Disease Process Of The Haemolytic Uraemic Syndrome Biology Essay

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To understand the management of the Haemolytic Uraemic Syndrome, one must understand the disease process leading up to it, as such a short summary of the pathology must be undertaken.

HUS is a syndrome comprising of intravascular haemolysis, microangiopathic haemolysis, thrombocytosis, and acute renal failure. The syndrome is often subsequent to a febrile illness, most frequently gastroenteritis. As such there are two more commonly recognised differentiations of the syndrome. Diarrhoea associated HUS (D+HUS), and non-diarrhoea induced HUS (D-HUS). Of D+HUS, the more commonly associated organism is Escherichia Coli, frequently strain 0157, which produces verocytotoxin (shiga toxin). Neutrophils transport the toxin to endothelial cells; this has an effect on protein synthesis and damages the endothelial cells. The net result is the formation of thrombi in smaller arteries and arterioles, in the kidneys, this leads to acute renal failure. Most patients with D+HUS will recover renal function, however until then supportive care is required, this comprises of dialysis, maintenance of fluid and electrolyte balance, antihypertensive medication (due to loss of regulatory function by the kidneys) and nutritional support. D-HUS has a poorer prognosis, several familial forms of the disease exist, and is thought to be caused by gene mutations causing the loss of function of one of a various proteins. The result is deterioration of regulation of blood pressure. D-HUS has also been associated with pregnancy, SLE, metastatic cancer, scleroderma, HIV infection, malignant hypertension, and several drugs, including oral contraceptives, ciclosporin, tacrolimus, several chemotherapeutic agents, and heparin. Pneumoccus-associated HUS is a rare complication of Streptococcus pneumonia infection, the bacteria produce an enzyme, which upon contact with red blood cells, expose an antigen (known as the Thomson antigen), antibodies produced results in an antibody- antigen reaction, the reaction can lead to HUS and anaemia. Newer classifications of HUS are sometimes expanded to include neurological involvement and fever, although the pathological mechanism is still poorly understood. [1] , [2] , [3] 

Management of HUS


This is standard treatment for those with HUS, renal failure being a feature of the syndrome. There is a lack of studies conducted establishing its worth in the treatment, mainly because it would be unethical to refuse to treat the renal failure in those with the syndrome. The significance of dialysis in the treatment of renal failure has been known for years. An acute fall in renal perfusion pressure for any reason results in a rapid rise in plasma urea and creatinine, symptoms of fluid overload, hyperkalaemia, and metabolic acidosis. Prolonged ischaemia leads to the irreversible loss of nephrons, and consequently an irreversible affect on quality and length of life in those who survive. The possible consequences include pronounced effects on the circulatory system, as the kidneys are extensively involved in circulatory haemostasis; anaemia and hypertension are amongst the most damaging long term sequelae. Dialysis works by allowing the diffusion of solutes and the ultra filtration of fluid across a semi permeable membrane, thus concentrations of solutes in the blood (such as urea, creatinine and potassium) can be filtered out. [4] Since the aim of principal aim of dialysis in HUS is the treatment of renal failure, one can assume that other methods to treat renal failure can (theoretically) be used in the treatment of HUS. Studies analysing dialysis used in conjunction with other treatments, including loop diuretics, dopamine, natiuretic peptides, renal replacement therapies, insulin-like growth factor-1, and thyroxine, showed no significant change in renal recovery and survival. Thus suggesting that dialysis is the treatment of choice.4


The use of anticoagulants in the treatment was discussed early after the recognition of the syndrome, early theories rationalized that the primary initiation event of the pathology was the activation of the coagulation pathway. Early investigations found fibrin in the renal lesions, that coupled with early early experimental evidence suggesting that microangiopathic haemolytic anaemia could be induced by inhibiting fibrinolysis, and reduced by the use of anticoagulation. However studies carried out more recently have failed to demonstrate this relationship, and investigations evaluating the use of heparin in children have failed to show a decreased recovery time, indeed the risk to the patient may be slightly increased due to the possible side effects of heparin. One such study found that after analysing 9 children with reported HUS, (of which four received heparin, and four received nothing), found that at follow up, 6 to 18 months later, all the children had recovered. The rate at which the children had recovered, as measured by the return of the platelet count to normal, and the rate of dialysis required, was very similar had the patients been heparinised or not, all of the patients also required a similar amount of blood transfusions. The study concluded that there was no indication to heparinise patients with HUS. This study however, was very small, and doesn’t provide a relative risk or confidence intervals, only proving mean recovery times for the patients. [5] 

Plasma treatment

Advances in the understanding of the endothelial/platelet interactions in clotting, and the recognition of positive effect of the use of fresh plasma infusions in the treatment of some patients with HUS, led to the theories suggesting that deficiencies in a certain substance was the cause. It was recognized that the balance of PGI2 produced from endothelial cells and TxA2 produced by the platelet play a large role in regulation of platelet aggregation (PGI2 inhibiting, and TxA2 aggregating). A deficiency in the production of PGI2 by some patients endothelial cells was noted, and in certain patients this infusions of fresh plasma was shown to help. It was also found however that some patients that didn’t respond to plasma infusions, plasma exchange improved their condition. This suggested an inhibitor of PGI2 production was involved in some cases of HUS. Conversely a very recent systematic review of 7 RCTs in 476 children has found that the use of all “fresh frozen plasma transfusion, heparin with or without urokinase or dipyridamole, Shiga toxin-binding protein, and steroid” were not superior to supportive treatment alone. The review does admit that the data from the trials is subject to suboptimal reporting in the review trials, small numbers of participants with atypical HUS, and other confounding factors. Plasmapheresis is still used due to the lack of complete information, and a lack of treatments available 1, [6] 

Antibiotic treatment

The use of antibiotics in those with D+HUS is also debated, some studies have found that using antibiotics can actually worsen the HUS in those patients. Retrospective studies assessing the risk of complications of administering antibiotics, against the risk of not administering antibiotics in sepsis are often of poor quality and make the role of antibiotics unclear. However the general consensus is that the risk of non-administration of antibiotics in those with sepsis is generally associated with an unfavourable outcome and as such their use is rationalized. A systematic review of studies attempted determine the relative risk of developing HUS, in those treated with antibiotics and those not treated, 688 patients were looked at, a relative risk of 1.15 95% CI (0.79 to 1.68) was found. Thus showing neither clear benefit nor any clear harm associated with the admission of antibiotics. [7] 


The central aim of treatment in the haemolytic uraemic syndrome is the management of the associated renal failure. This is understandable considering the mortality levels in those with renal failure, this is managed with dialysis and plasmapheresis. Attempts and understanding the pathology have been largely unsuccessful, possibly due to several underlying multifactorial mechanisms, suggesting several forms of the disease. Even seemingly more commonly agreed upon elements of medical management are not as clear cut, i.e. the treatment infection with antibiotics, is debatable and not of proven benefit. There is room for a large degree of research in the area, and interesting conclusions about the mechanisms of coagulation can probably be reached.