The following is a comprehensive description of the hemolytic uremic syndrome (HUS), its symptoms, and the complications and long-term risks associated with HUS.  (A glossary of terms can be found at the bottom of this entry).

Hemolytic uremic syndrome is a severe, life-threatening complication of an E. coli bacterial infection that was first described in 1955, and is now recognized as the most common cause of acute kidney failure in childhood. E. coli O157:H7 is responsible for over 90% of the cases of HUS that develop in North America. In fact, some researchers now believe that E. coli O157:H7 is the only cause of HUS in children. HUS develops when the toxin from E. coli bacteria, known as Shiga-like toxin (SLT) [1,2], enters cells lining the large intestine. The Shiga-toxin triggers a complex cascade of changes in the blood. Cellular debris accumulates within the body’s tiny blood vessels and there is a disruption of the inherent clot-breaking mechanisms. The formation of micro-clots in the blood vessel-rich kidneys leads to impaired kidney function and can cause damage to other major organs.

What are the Symptoms associated with Hemolytic Uremic Syndrome?

About ten percent of individuals with E. coli O157:H7 infections (mostly young children) goes on to develop Hemolytic Uremic Syndrome, a severe, potentially life-threatening complication. HUS is an extremely complex process that researchers are still trying to fully explain.

Its three central features describe the essence of Hemolytic Uremic Syndrome: destruction of red blood cells (hemolytic anemia), destruction of platelets (those blood cells responsible for clotting, resulting in low platelet counts, or thrombocytopenia), and acute renal failure. In HUS, renal failure is caused when the nephrons, or filtering units, become occluded (blocked) by micro-thrombi, which are tiny blood clots. In almost all cases, the filtering ability of the kidneys recovers as the body of the patient slowly dissolves the micro-thrombi within the microvessels.

A typical person is born with about one million filtering units, called nephrons, in each kidney. The core of the nephron is a bundle of tiny blood vessels, called a glomerulus, where osmotic exchange allows for the filtration of wastes that eventually collect in the urine and are excreted. During Hemolytic Uremic Syndrome, the lack of blood flow to the nephrons can cause them to die or be damaged, just as heart muscle can die as the result of coronary vessel occlusion during a heart attack. Dead nephrons do not regenerate.

In general, the longer a patient suffers kidney failure, the greater the loss of filtering units as a result. At some point, the damage to the kidneys’ filtering units can be so severe that the patient will, over a period of years, lose kidney function and suffer end-stage renal disease (ESRD), which requires chronic dialysis or transplantation.

HUS can also cause transient or permanent damage to other organs, which include the pancreas, liver, brain, and heart. The essential pathogenic process is the same regardless of the organ affected: microthrombi inhibit necessary blood flow and cause tissue death or damage. During the acute stage of Hemolytic Uremic Syndrome, patients must be carefully monitored for these extra-renal complications. It is very difficult to predict the severity and course of HUS once it initiates.

The active stage of Hemolytic Uremic Syndrome may be defined as that period of time during which there is evidence of hemolysis and the platelet count is less than 100,000. In HUS, the active stage usually lasts an average of six days (range, 2-16 days). It is during the active stage that the complications of HUS per se usually occur.

What are the complications and long-term risks associated with Hemolytic Uremic Syndrome?

Several studies have demonstrated that children with HUS who have apparently recovered will develop hypertension, urinary abnormalities and/or renal insufficiency during long-term follow-up.

End Stage Renal Disease, Dialysis and Kidney Transplantation

End Stage Renal Disease

Children and adolescents with chronic renal failure face a number of complications from the condition, including alterations in calcium and phosphate balance and renal osteodystrophy (softening of the bones, weak bones and bone pain), anemia (low blood cell count that leads to a lack of energy), growth failure (final height as an adult substantially below normal), hypertension (high blood pressure), and other complications.

Renal osteodystrophy (softening of the bones) is an important complication of chronic renal failure. Bone disease is nearly universal in patients with chronic renal failure; in some children, symptoms are minor to absent while others may develop bone pain, skeletal deformities and slipped epiphyses (abnormal shaped bones and abnormal hip bones) and have a propensity for fractures with minor trauma. Treatment of the bone disease associated with chronic renal failure includes control of serum phosphorus and calcium levels with restriction of phosphorus in the diet, supplementation of calcium, the need to take phosphorus binders, and the need to take medications for bone disease.

Anemia is a very common complication of chronic renal failure. The kidneys make a hormone that tells the bone marrow to make red blood cells and this hormone is not produced in sufficient amounts in children with chronic renal failure. Thus, children with chronic renal failure gradually become anemic while their chronic renal failure is slowly progressing. The anemia of chronic renal failure is treated with human recombinant erythropoietin (a shot given under the skin one to three times a week or once every few weeks with a longer acting human recombinant erythropoietin).

Growth failure ultimately leading to short height as an adult is a very common complication of chronic renal failure in children. The mechanisms of growth failure are complex and due to multiple causes. Poorly controlled renal osteodystrophy (bone disease), inadequate nutrition (insufficient intake of adequate calories), chronic acidosis (blood system too acid) and abnormalities of the growth hormone axis (growth hormone deficiency) are each major contributors to poor growth in the child with chronic renal failure. Growth hormone therapy with human recombinant growth hormone has been approved for use in children with chronic renal failure and such therapy has been shown to accelerate growth, induce persistent catch up growth and lead to normal adult height in children with chronic renal failure. Growth hormone therapy requires giving a shot under the skin once a day. Complications of growth hormone therapy are rare but may include glucose intolerance and exacerbation of poorly controlled renal osteodystrophy.

Dialysis and Kidney Transplantation

Renal replacement therapy can be in the form of dialysis (peritoneal dialysis or hemodialysis) or renal transplantation.

If the patient does not have a living related donor for their first kidney transplant and when they need a second kidney transplant after loss of the first transplant, they will need dialysis until a subsequent transplant can be performed. The patient can be on peritoneal dialysis or on hemodialysis.

Peritoneal dialysis has been a major modality of therapy for chronic renal failure for several years. Continuous Ambulatory Peritoneal Dialysis (CAPD) and automated peritoneal dialysis also called Continuous Cycling Peritoneal Dialysis (CCPD) are the most common forms of dialysis therapy used in children with chronic renal failure. In this form of dialysis, a catheter is placed in the peritoneal cavity (area around the stomach); dialysate (fluid to clean the blood) is placed into the abdomen and changed 4 to 6 times a day. Parents and adolescents are able to perform CAPD/CCPD at home. Peritonitis (infection of the fluid) is a major complication of peritoneal dialysis.

Hemodialysis has also been used for several years for the treatment of chronic renal failure during childhood. During hemodialysis, blood is taken out of the body by a catheter or fistula and circulated in an artificial kidney to clean the blood. Hemodialysis is usually performed three times a week for 3-4 hours each time in a dialysis unit.

Renal transplantation can be from a deceased or a living related donor (parent or sibling who is over the age of 18 who is compatible). Should the patient have a living related donor available to donate a kidney, they can undergo transplantation without the need for dialysis (preemptive transplantation). Should they not have a living related donor, they will likely need to undergo dialysis while on the waiting list for a deceased donor transplant. Fortunately, children have the shortest waiting time on the deceased donor transplant list. The average waiting time for children age 0-17 years is approximately 275-300 days while the average waiting time for patient’s age 18-44 years is approximately 700 days.

Following transplantation, the patient will need to take immunosuppressive medications for the remainder of their life to prevent rejection of the transplanted kidney. Medications used to prevent rejection have considerable side effects. Corticosteroids are commonly used following transplantation. The side effects of corticosteroids are Cushingnoid features (fat deposition around the cheeks and abdomen and back), weight gain, emotional liability, cataracts, decreased growth, osteomalacia and osteonecrosis (softening of the bones and bone pain), hypertension, acne and difficulty in controlling glucose levels. The steroid side effects, particularly the effects on appearance, are difficult for children, especially teenagers, and non compliance do to the side effects of medications is a risk in children; again, particularly teenagers.

Cyclosporine and/or tacrolimus are also commonly used as i
mmunosuppressive medications following transplantation. Side effects of these drugs include hirsutism (increased hair growth), gum hypertrophy, interstitial fibrosis in the kidney (damage to the kidney), as well as other complications. Meclophenalate is also commonly used after transplantation (sometimes imuran is used); each of these drugs can cause a low white blood cell count and increased susceptibility to infection. Many other immunosuppressive medications and other medications (anti-hypertensive agents, anti-acids, etc) are prescribed in the postoperative period.

Life long immunosuppression, as used in patients with kidney transplants, is associated with several complications including an increased susceptibility to infection, accelerated atherosclerosis (hardening of the arteries), increased incidence of malignancy (cancer) and chronic rejection of the kidney.

United States Renal Data Systems (USRDS) report that the half-life (time at which 50% of the kidneys are still functioning and 50% have stopped functioning) is 10.5 years for a deceased transplant in children age 0-17 years and 15.5 years for a living related transplant in children 0-17 years. Similar data for a transplant at age 18 to 44 years is 10.1 years and 16.0 years for a deceased donor and a living related donor, respectively. Thus, depending upon the age when the patient receives their first transplant they may need 2-3 transplants over the course of their life.

Thus, the life expectancy of a person with a kidney transplant is significantly less than the general population and the life expectancy of a person on dialysis is markedly less than the general population.

Hemolytic uremic syndrome patient follow-up

Children who appear to have recovered from HUS may develop late complications. A precise determination of the risk of late complications is not likely. It is important to note that the risks of longer term (more than 20 years) complications are unknown and are likely to be higher than risks at 10 years, as many of the above studies describe.

A nephrologist—a kidney specialist—should formally evaluate all persons who have experienced HUSat a year following their acute illness. Kidneys injured by HUS may slowly recover function over at least a six-month period following the acute episode and perhaps longer. Even persons with “mild” HUS who did not require dialysis should be formally evaluated. Such an evaluation should include a routine physical, blood pressure measurement, and blood and urine analyses from which kidney filtration rate can be calculated.

Studies done to date on HUS outcomes have largely confirmed a positive correlation between more severe kidney involvement acutely, particularly the need for extended dialysis, and increased incidence of future renal complications. However, it has been shown in multiple studies that even moderate kidney compromise in the acute phase of HUS can result in long-term complications due to damage to the filtering units in the kidneys.

Among survivors of HUS, estimates are that about five percent will eventually develop end stage kidney disease, with the resultant need for dialysis or transplantation, and another five to ten percent experience neurological or pancreatic problems which significantly impair quality of life. Since the longest available follow-up studies of HUS are about twenty (20) years, an accurate lifetime prognosis is not available, and as such, medical follow-up is indicated for even the mildest affected cases.

[1] Recent research suggests that E. coli O157:H7 acquired its pathological character when a bacteriophage (virus that infects bacteria) transmitted genetic material for the creation of the toxin from a closely related Shigella bacterial species (hence the epithet, Shiga-like toxin) to a formerly benign species of E. coli.

[2] Verotoxin-globotriaosyl ceramide binding receptors.

Glossary of terms

1. allograft: a graft derived from an individual of the same species that is sufficiently unlike genetically to interact antigenically

2. antagonist: in biochemistry, an antagonist acts against and blocks an action.

3. anticoagulant: any agent used to prevent the formation of blood clots.

4. antigen: a protein or carbohydrate substance (as a toxin or enzyme) capable of stimulating an immune response

5. antibody titers: a measure of proteins of high molecular weight that are produced normally after stimulation by an antigen and act specifically against the antigen in an immune response

6. anuria: absence of urine excretion

7. case fatality rate: the proportion of deaths among a group of persons with a particular condition or disease

8. basal ganglia: a region consisting of 3 clusters of neurons located at the base of the brain that are responsible for involuntary movements

9. C-reactive protein: a special type of protein produced by the liver that is only present during episodes of acute inflammation

10. CT scan: A computerized axial tomography scan is more commonly known by its abbreviated name, CAT scan or CT scan; an x-ray procedure which combines many x-ray images with the aid of a computer to generate cross-sectional views and, if needed, three-dimensional images of the internal organs and structures of the body

11. cortical necrosis: tissue death of the outer layer of the kidney

12. creatinine: a chemical waste molecule that is generated from muscle metabolism and transported through the bloodstream to the kidneys. The kidneys filter out most of the creatinine and dispose of it in the urine. As the kidneys become impaired, the creatinine will rise.

13. dialysis/hemodialysis: process of removing blood from an artery to purify it (remove wastes or toxins from the blood) and adjust fluid and electrolyte imbalances, adding vital substances, and returning it to a vein (see also peritoneal dialysis)

14. double-blinded study: A study in which neither the study groups nor the evaluator are aware of who receives the experimental treatment or procedure versus the placebo or comparison treatment

15. dysphasia: difficulty in swallowing

16. effective renal plasma flow (ERPF): the amount of plasma flowing through the kidney tubules per unit time; differentiated from renal plasma flow which is approximately 10% greater than ERPF

17. electroencephalograph (EEG): an apparatus for detecting and recording brain waves

18. end-stage renal disease (ESRD): the final stages of a terminal kidney disease or condition when there is complete or near complete failure of the kidneys to function

19. etiology: the cause of a disease

20. fibrinolytics: clot-dissolving drugs

21. gastric: relating to the stomach

22. genotype: the genetic constitution (the genome) of a cell, an individual or an organism.

23. glomerular: pertaining to the glomerulus, a tiny structure in the kidney that filters the blood to form urine.

24. glomerular filtration rate (GFR): the rate at which blood is filtered through tufts of capillaries in the kidney

25. glomerulonephritis: a disorder that causes inflammation of the internal kidney structures (specifically, the glomeruli); it may be a temporary and reversible condition, or it may be progressive.

26. graft: placing tissue or organs from one area on the body or from another person or an animal into the patient’s body; in this case transferring a kidney from one person to another

27. hemiparesis: muscular weakness or partial paralysis restricted to one side of the body

28. hemolytic anemia: anemia caused by excessive destruction (as in chemical poisoning, infection, or sickle-cell anemia) of red blood cells

29. hemorrhagic colitis: bloody infection/inflammation of the colon (bowel)

30. histological: in reference to the minute structure of tissues discernible with the microscope

31. hyperfiltration: abnormal increase in the filtration rate of the renal glomeruli

32. hypertension: high blood pressure

33. hyponatremia: deficiency of sodium (salt) in the blood

34. infarct/infarction: an area of necrosis (death) in a tissue or organ resulting from obstruction of the local circulation by a thrombus or embolus

35. internal/external capsule: fibrous express ways that contain nerves to transmit information within certain parts of the brain

36. in vitro: outside the living body and in an artificial environment

37. intravenous (IV): within a vein

38. ischemia: localized tissue anemia due to obstruction of the inflow of arterial blood (as by the narrowing of arteries by spasm or disease)

39. leukocyte: white blood cell

40. leukocytosis: increase in the number of white blood cells

41. microangiopathy: a disease of very fine blood vessels

42. microvascular: of, relating to, or constituting the part of the circulatory system made up of minute vessels (as venules or capillaries) that average less than 0.3 millimeters in diameter

43. monoclonal antibody: an antibody derived from a single cell in large quantities for use against a specific antigen

44. morbidity: the incidence of disease; the rate of sickness (as in a specified community or group)

45. morphologic: of, relating to, or concerned with form or structure

46. mortality: the number of deaths in a given time or place; the proportion of deaths in a given population

47. MRI/magnetic resonance imaging: a radiology technique using magnetism, radio waves, and a computer to produce images of body structures

48. nephrotic syndrome: a constellation of signs and symptoms including protein in the urine, low blood protein levels, high cholesterol levels, and swelling; results in damage to the kidneys, particularly the basement membrane of the glomerulus

49. neutrophil: type of white blood cell, filled with neutrally-staining granules, tiny sacs of enzymes that help the cell to kill and digest microorganisms it has engulfed

50. oliguria: reduced excretion of urine

51. parenteral: drug or substance, like supplementary nutrition, administration by intravenous, intramuscular, or subcutaneous injection; especially introduced other than by way of the intestines

52. paresis: paralysis

53. pathogenesis: the origin of a disease and the chain of events leading to that disease.

54. peritoneal dialysis: technique that uses the patient’s own body tissues inside of the belly (abdominal cavity) to act as a filter to remove waste products and excess water from the body

55. placebo: an inert or harmless substance used especially in controlled experiments testing the efficacy of another substance (as a drug)

56. plasmapheresis: separating out the plasma from the whole blood, replacing the plasma, and returning plasma and original blood cells to the patient

57. platelet: An irregular, disc-shaped element in the blood that assists in blood clotting. During normal blood clotting, the platelets clump together.

58. primary: first in order of time or development

59. prodromal: a symptom or set of symptoms that occur before the onset of a disease or condition

60. proteinuria: protein in the urine

61. prothrombotic: a substance which encourages the production of blood clots

62. randomized: things or persons put in a random order so that every thing or person is equally likely to be selected; study subjects are randomly distributed into groups which are either subjected to the experimental procedure (or use of a drug) or which serve as controls.

63. receptor: a structure on the surface of a cell (or inside a cell) that selectively receives and binds a specific substance.

64. rectal prolapse: the falling down or slipping of a the rectum (the terminal part of the intestine) from its usual position

65. renal: kidney

66. retina: the sensory membrane that lines most of the large posterior chamber of the eye; functions as the immediate instrument of vision by receiving the image formed by the lens and converting it into chemical and nervous signals which reach the brain by way of the optic nerve

67. sequelae: an after effect of disease, injury, procedure, or treatment

68. serotype/group: a group of intimately related microorganisms distinguished by a common set of antigens

69. Shiga toxin/Stx: a poisonous product of the E. coli organism; toxins are usually very unstable and can cause damage to cells. Toxins typically induce antibody formation.

70. sodium: the major positive ion (cation) in fluid outside of cells. When combined with chloride, the resulting substance is table salt. Excess sodium is excreted in the urine. Too much or too little sodium can cause cells to malfunction.

71. stupor: decreased mental status or consciousness; loss of alertness

72. tetraspastic: a state of hypertonicity or increase over the normal tone of a muscle, with heightened deep tendon reflexes, affecting all four extremities

73. thalamus/thalami: the part of the brain that serves to relay impulses and especially sensory impulses to and from the cerebral cortex (the gray matter of the cerebrum that functions chiefly in coordination of sensory and motor information)

74. thrombocytopenia: persistent decrease in the number of blood platelets that is often associated with hemorrhagic conditions — called also thrombopenia

75. thrombogenic: tending to produce a thrombus (a clot of blood formed within a blood vessel and remaining attached to its place of origin)

76. thrombosis: the formation or presence of a blood clot within a blood vessel

77. thrombotic thrombocytopenic purpura (TTP): a blood disorder characterized by low platelets, low red blood cell count (caused by premature breakdown of the cells), abnormalities in kidney function, and neurological abnormalities; caused by a deficiency in the von Willebrand Factor cleaving protease, known as ADAMTS13. The loss of this enzyme results in large complexes of von Willbrand factor circulating in the blood, which in turn causes platelet clumping and red blood cell destruction.

78. vascular endothelial growth factor: substance made by cells that stimulates new blood vessel formation

79. white matter: neural tissue that consists largely of myelinated (sheathed) nerve fibers, has a whitish color, and underlies the gray matter of the brain and spinal cord or is gathered into nerves