Atypical Hemolytic Uremic Syndrome

The Foundation for Children with Atypical HUS, a 501c3 non-profit foundation, was founded by a parent, Bill Biermann whose son, Nathan, came down with this disease as an infant. His story, our stories can be found on the page entitled "Our Lives with Atypical HUS". Bill's contact information can be found on the page marked "Resources".

Where does hope lie? Hope lies within the hearts and minds of those with the power to commit funds to the search for a better treatment, an intervention that will shed light on the cause of this disease, a disease that condemns these children, these families, to a life of disease and disability. In the end what we, these children, their families and this country loses is the potential of all that could have been - a life of normalcy, a life blessed with health, a life that contributes to a better world.

Research holds the key to a healthy future for all those with atypical HUS. The results of the most recent research funded by the Foundation can be seen in the November 8, 2003 article in Lancet -

Background: Atypical Hemolytic-uremic syndrome (HUS) is a clinical syndrome characterized by progressive renal failure associated with microangiopathic hemolytic anemia and thrombocytopenia.

HUS, the type caused by e coli, is the most common cause of acute renal failure in children and increasingly is being recognized in adults. Thrombotic thrombocytopenic purpura (TTP), childhood HUS, and adult HUS differ in their clinical presentations but have many common features.

Increasing knowledge about the pathogenesis and clinical associations of thrombotic microangiopathies (TMAs) has led to the realization that despite diverse causes and clinical associations, these disorders share similar clinical manifestations and it is hoped that by investing in TMA research all it's causes will benefit, especially atypical HUS which is very rare but devastating.

Pathophysiology: Endothelial cell damage is the primary event in the pathogenesis of both forms of HUS. The cardinal lesion is composed of arteriolar and capillary microthrombi (the TMAs) and red cell fragmentation.

The primary feature is the ability to injure endothelial cells in general and, specifically in HUS, the ability to damage the endothelial cells of the renal vasculature.


Genetic factors: The literature describes 2 types of familial HUS in familial and relapsed HUS.

In typical HUS, diarrhea is common and symptoms occur within a few days to weeks among family members. Verotoxin-producing Escherichia coli (VTEC) infection or other infectious agents are the cause.

Atypical HUS occurs without prodromal diarrhea and has an unfavorable prognosis. The disease involves several members at intervals of 1 year or several years. In some families, the mode of transmission is autosomal recessive; in others, the mode of transmission may be autosomal dominant. Genetically determined deficiencies in factor H are involved in both autosomal-dominant and autosomal-recessive hemolytic-uremic syndrome and identify short consensus repeat 20 (SCR20) as a hot spot for mutations. Some family members may manifest features of TTP, while others manifest HUS. Atypical HUS often is relapsing.

Atypical or sporadic HUS is rare in children younger than 2 years. The disease occurs year round, and physicians do not observe a gastrointestinal prodrome. The initial phase may be progressive and misleading. Relapses can occur, and most cases evolve to terminal renal failure. Familial occurrence is possible. The typical lesion most often is arterial TMA.

Clinicians report secondary HUS in both children and adults following bone marrow transplant, radiation therapy, or complicating preexisting renal disorders. Secondary HUS is associated with pregnancy or puerperium, oral contraceptive use, cancers (chiefly mucin-producing adenocarcinomas), cyclosporine use, mitomycin-C use, malignant hypertension, and collagen vascular disease (eg, systemic lupus erythematosus [SLE]), primary glomerulopathies, tissue transplantation).

There is no standard treatment, as each case is different. Children with typical HUS are in a life threatening situation, but if they survive the initial stages of the disease, they usually respond good to the supportive treatment.

Children with Atypical HUS are much more likely to develop complications. These complications may be:
--Kidney failure
--Seizures/Neurological problems
--No response to supportive treatments
--Return of HUS even after s kidney transplant occurs
--Severe Hypertension (high blood pressure)

Therapy is supportive. The symptoms are analyzed and a treatment plan is developed. Nephrologists have tried drugs that interfere with clotting, drugs that interfere with platelet function, blood transfusions, Plasma infusions (plasma is the liquid part of the blood), plasmapheresis (a blood filtering process). The best therapy is to closely monitor the disease, provide supportive techniques to control blood pressure and minimized the damage to kidneys thru plasma and blood transfusions. Early dialysis may be life saving until the kidney function is able to return to normal. Recurring cases must be watched very closely, and immediate treatment should begin to prevent another full blown HUS episode.

The Symptoms

In most cases, Atypical HUS does not begin with a violent illness. Instead, the child starts off ill, fatigue, irritable, and lethargic to a point where hospitalization is needed. Supportive treatment is absolutely necessary in order to prevent further damage.

Typical HUS cases begin rather violently, with a severe bout of gastroenteritis that may be accompanied by bloody diarrhea.

Thereafter, symptoms of both typical and Atypical HUS may be similar. HUS causes clotting, and therefore results in vascular enlargement. Clotting tends to affect the kidneys, and may result in acute kidney failure, requiring dialysis or kidney transplants.

A wide variety of symptoms can occur. Life threatening intestinal problems may occur. Neurological problems such as seizures, blindness and coma could develop. Profound intestinal or neurological diseases are indicative of a more severe HUS, and have poor prognosis. Nearly 5% of children will die during the acute phase of the disease as a result of renal failure or multiple organ complications. However, one the acute phase of the disease passes, most patients will recover eventually in full.

However, a small percentage of HUS patients are diagnosed with Atypical HUS. This group is especially prone to recurrences of the disease and are much more likely to develop chronic renal failure and other complications such as chronic high blood pressure. Atypical patients can have HUS episodes set off by routine colds and infections.

Kidney failure is seen in 50% of patients with rejection seen in 20-50% of those transplanted. It has been reported that in cases where an unaffected sibling donates that the disease presents in the donor.

 My Ongoing Education and Understanding of Atypical HUS

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?

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.


The 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.

Recurrence of haemolytic-uraemic syndrome in renal transplants: a single-centre report RB Miller, BA Burke, WJ Schmidt, KJ Gillingham, AJ Matas, M Mauer and CE Kashtan University of Minnesota, Department of Pediatrics, Minneapolis 55455, USA.

The 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.