Atypical Hemolytic Uremic Syndrome
The A B C’s of Atypical HUS
How I Came to Understand Atypical HUS
Pearl L. Lewis
Two similar expressions of the same phenomena:
Thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (HUS) are clinical syndromes defined by the presence of thrombocytopenia and microangiopathic hemolytic anemia. TTP has generally been recognized as “adult HUS.” There are many possible causes all of which act through the common mechanism of inducing endothelial cell damage. The damage triggers a cascade of biochemical events that ultimately leads to the characteristic feature of TTP - widespread dissemination of hyaline thrombi, composed predominantly of platelets and fibrin, which occlude the terminal arterioles and capillaries (microcirculation) of most of the major body organs, commonly, the heart, brain, kidneys, pancreas and adrenals. Other organs are involved to a lesser degree. In HUS the kidneys are predominantly affected. The patho-physiology of this disease results in multisystem abnormalities and the clinical manifestations of the syndrome.
How the hematological (blood) system and renal (kidney) system interact -
To understand atypical HUS you have to understand the role of blood and vascular system as well as the kidneys and how they work together. Many articles have been brought together in this document.
The average adult has about five liters of blood, the average child less, living inside of their body, coursing through their vessels, delivering essential elements, and removing harmful wastes.
Blood is the fluid of life and growth, transporting oxygen from the lungs to body tissue and carbon dioxide from body tissue to the lungs, transporting nourishment from digestion and hormones from glands throughout the body. Blood is the fluid of health, transporting disease fighting substances to the tissue and waste to the kidneys.
Because containing living cells, is alive. Red blood cells and white blood cells are responsible for nourishing and cleansing the body. Since the cells are alive, they too need nourishment. Vitamins and minerals keep the blood healthy. The blood cells have a definite life cycle, just as all living organisms do.
Approximately 55 percent of blood is plasma, a straw-colored clear liquid. The liquid plasma carries the solid cells and the platelets which help blood clot. Without blood platelets, you would bleed to death.
The kidneys play an important roll in making sure we have enough red blood cells and in removing toxins, waste products of metabolism, from the body. Red blood cells have a life cycle of 120 and in response to red cell death recognized by the kidney; the kidney secretes erythropoietin, an enzyme that encourages the bone marrow to produce more red blood cells.
What are the probable causes in both TTP and atypical HUS? -
In HUS it is thought that Factor H, a protein that protects the endothelium, tissue located at the interface between the blood and the vessel wall of the kidney, is deficient in some of those with atypical HUS resulting in damage triggering a cascade of events that result in clots blocking arterioles and capillaries of the kidney. The platelets clump together (aggregate) and cause blood clotting and low platelet counts also called consumptive thrombocytopenia.
In TTP there seems to be a mutation in the ADAMST13 gene responsible for von Willebrand factor which is required for normal platelet adhesion. The thrombi (clots) in TTP are rich in von Willebrand factor and platelets but poor in fibrin. The anemia is caused by hemolysis when RBCs are “sliced”, thus the term Schistocytes. The thrombocytopenia is caused by platelet deposition in thrombi leading to tissue damage. Testing for the ADAMST13 gene can be done at Albert Einstein Medical College. Contact Dr. Tsai in the Department of Hematology.
While years ago it was known that plasmapheresis was efficacious in both HUS and TTP the reason why was not understand. Now it seems clear that by replacing plasma deficient in Factor H in HUS and normal von Willebrand factor in TTP the body is returned to homeostasis.
Treatment with Plasmapheresis – from the MD Website
Plasmapheresis is a process in which the fluid part of the blood, called plasma, is removed from blood cells by a device known as a cell separator. The separator works either by spinning the blood at high speed to separate the cells from the fluid or by passing the blood through a membrane with pores so small that only the fluid part of the blood can pass through. The cells are returned to the person undergoing treatment, while the plasma, which contains the antibodies, is discarded and replaced with in this case, healthy plasma, and plasma not deficient in the proteins thought to be deficient in atypical HUS. Medication to keep the blood from clotting (an anticoagulant) is given through a vein during the procedure.
What combination of drugs and treatments show promise in atypical HUS?
Antiplatelet agents act by inhibition of platelet aggregation and thrombus formation. These agents shorten the duration of thrombocytopenia but are not beneficial alone; they are used in combination with plasma exchange.
Plasma infusion (fresh frozen plasma [FFP]) is effective in select patients. Plasma infusion supplements deficient plasma factors, with an overall response of 60%. Most patients require a large volume of plasma, which creates the possibility of circulatory overload. Dialysis may be required.
Plasma exchange is the treatment of choice in TTP, with an overall response of 80%. This procedure removes insulting agents and supplements deficient plasma factors. Malvinder S Parmar, MD, FRCPC, FACP, Medical Director, Medical Program, Timmins & District Hospital, Assistant Professor (VPT), Faculty of Medicine, University of Ottawa, Department of Internal Medicine,
What's involved in a plasmapheresis treatment?
A plasmapheresis treatment takes several hours and can be done on an outpatient basis. It can be uncomfortable but is normally not painful. The number of treatments needed varies greatly depending on the particular disease and the person's general condition. An average course of plasma exchanges is six to 10 treatments over two to 10 weeks. In some centers, treatments are performed once a week, while in others, more than one weekly treatment is done.
A person undergoing plasmapheresis can lie in bed or sit in a reclining chair. A small, thin tube (catheter) is placed in a large vein, usually the one in the crook of the arm, and another tube is placed in the opposite hand or foot (so that at least one arm can move freely during the procedure). Blood is taken to the separator from one tube, while the separated blood cells, combined with replacement fluids, are returned to the patient through the other tube.
The amount of blood outside the body at any one time is much less than the amount ordinarily donated in a blood bank.
Are there risks associated with plasmapheresis?
Yes, but most can be controlled. Any unusual symptoms should be immediately reported to the doctor or the person in charge of the procedure. Symptoms that may seem trivial sometimes herald the onset of a serious complication.
The most common problem is a drop in blood pressure, which can be experienced as faintness, dizziness, blurred vision, coldness, sweating or abdominal cramps. A drop in blood pressure is remedied by lowering the patient's head, raising the legs and giving intravenous fluid.
Bleeding can occasionally occur because of the medications used to keep the blood from clotting during the procedure. Some of these medications can cause other adverse reactions, which begin with tingling around the mouth or in the limbs, muscle cramps or a metallic taste in the mouth. If allowed to progress, these reactions can lead to an irregular heartbeat or seizures.
An allergic reaction to the solutions used to replace the plasma or to the sterilizing agents used for the tubing can be a true emergency. This type of reaction usually begins with itching, wheezing or a rash. The plasma exchange must be stopped and the person treated with intravenous medications.
Excessive suppression of the immune system can temporarily occur with plasmapheresis, since the procedure isn't selective about which antibodies it removes. In time, the body can replenish its supply of needed antibodies, but some physicians give these intravenously after each plasmapheresis treatment. Outpatients may have to take special precautions against infection.
Medication dosages need careful observation and adjustment in people being treated with plasmapheresis because some drugs can be removed from the blood or changed by the procedure.
Plasmapheresis has been of benefit in atypical HUS as well as Early dialysis may be life saving until the kidney function is able to return to normal.
Inheritance and HUS – Bernard Kaplan, MD CHOPS
Fewer than 5% of cases of HUS are inherited either by autosomal recessive or autosomal dominant modes. In autosomal recessive inheritance of HUS, the onset in siblings is separated by more than 1 year, and children are more often affected than neonates and adults. The prognosis is poor, with a mortality rate of approximately 65%. Patients may have recurrences before and/or after renal transplantation, regardless of the donor source of the kidney or the use of cyclosporin A.
Most affected people with autosomal dominant inheritance of HUS are adults, recurrences can occur, and the prognosis is poor, with a combined morbidity and mortality rate of more than 90%. A diagnosis of inherited HUS cannot be made in the first affected case in the kindred. Clues to the diagnosis include a family member who was affected at a remote time, a nondiarrheal prodrome or no prodrome, a progressive course, and recurrences. The histologic changes are predominantly renal arteriolar changes with intimal proliferation, thrombi, and collapsed ischemic glomeruli. These findings are similar to those of atypical D- HUS (idiopathic HUS). Treatment with Fresh Frozen Plasma and plasmapheresis is recommended but is of unproven value. Genetic counseling should be offered, but there are no markers to determine the heterozygote state or whether a fetus is affected. There is preliminary evidence of linkage to the factor H locus on chromosome 1 in autosomal dominant inheritance of HUS.
assumption that HUS is a syndrome and that there are many causes and
associations of the disease is widely accepted. There have been enormous
advances in defining the etiology, epidemiology, pathogenesis, and
histopathologic features of Shiga toxin-associated HUS. However, although the
acute mortality rate has declined, patients continue to die, in part because
there is no specific treatment of the endothelial injury and its consequences.
Attempts to prevent the disease by vaccines and pharmacologic agents show
promise, but public and personal health measures are of paramount importance in
preventing the contamination of foods and fluids and person-to-person transfer.
Similar advances have not been made in the idiopathic and inherited forms of
HUS. Although these forms constitute a small percentage of the total, they
continue to have very high mortality and morbidity rates.Journal of the American
Society of Nephrology
Volume 9 • Number 6 • June 1998
Copyright © 1998 American Society of Nephrology
Transplantation and Atypical HUS – Facts
The incidence of recurrence of haemolytic-uraemic syndrome (HUS) in renal allografts appears to vary by centre, with the highest rates reported from the University of Minnesota. It is possible that the high rate of HUS recurrence at this institution reflects a transplant population skewed towards patients with a form of HUS that is more likely to recur in the allograft. RESULTS: Eighteen of the 24 patients had atypical HUS, three had classical HUS, and in three patients the presence or absence of a diarrhoeal prodrome could not be determined. Recurrent HUS, defined as microangiopathic haemolytic anemia, thrombocytopenia, renal insufficiency, and allograft biopsy findings compatible with HUS, occurred 16 times in 14 grafts in 11 patients. Nine of these patients had atypical HUS, one had classical HUS, and in one the nature of the prodrome could not be determined. Eleven of the 14 initial recurrences took place within 2 months of transplant. Recurrence was not more frequent in patients who received cyclosporin or antilymphocyte preparations. Actuarial analysis using matched controls showed poorer graft survival in patients with a primary diagnosis of HUS (P = 0.007), due to the high frequency of graft loss in HUS patients with recurrence. CONCLUSION: Based upon these data and a review of the literature, it can be concluded that the risk of recurrence of HUS in the allograft is confined almost entirely to patients with atypical forms of HUS.
experience of this center, while its numbers are reflective of its patient
population – those with atypical HUS - it mirrors worldwide experience. If a
transplant is considered make sure you are aware of the risk of rejection and
recurrence of disease.