What is the Hemolytic Uremic Syndrome and What Do I Need to Know about It?
Post-diarrheal Hemolytic Uremic Syndrome (D+HUS) is a severe, life-threatening complication that occurs in about 10% of those infected with E. coli O157:H7 or other Shiga toxin (Stx) producing E. coli. D+HUS was first described in 1955, but was not known to be secondary to E. coli infections until 1982. It is now recognized as the most common cause of acute kidney failure in infants and young children. Adolescents and adults are also susceptible, as are the elderly, who often succumb to the disease.
How did these otherwise harmless E. coli become such killers? It seems likely that DNA from a Shiga toxin producing bacterium known as Shigella dysenteria type 1 was transferred by a bacteriophage (a virus that infects bacteria) to harmless E. coli bacteria, thereby providing them with the genes to produce one of the most potent toxins known to man. So potent, that the Department of Homeland Security lists it as a potential bioterrorist agent. Although E. coli O157:H7 are responsible for the majority of cases in America, there are many additional Stx producing E. coli strains that can cause D+ HUS.
The chain of events leading to HUS begins with ingestion of Stx producing E. coli (e.g., E. coli O157: H7) in contaminated food, beverages, animal to person, or person-to-person transmission.
These E. coli rapidly multiply in the intestine causing colitis (diarrhea), and tightly bind to cells that line the large intestine. This snug attachment facilitates absorption of the toxin into the intestinal capillaries and into the systemic circulation where it becomes attached to weak receptors on white blood cells (WBC) thus allowing the toxin to “ride piggyback” to the kidneys where it is transferred to numerous avid (strong) Gb3receptors that grasp and hold on to the toxin.
Organ injury is primarily a function of Gb3 receptor location and density. Receptors are probably heterogeneously distributed in the major body organs, and this may explain why some patients develop injury in other organs (e.g., brain, pancreas).
Once Stx attaches to receptors, it moves into the cell’s cytoplasm where it shuts down the cells’ protein machinery resulting in cellular injury and/or death. This cellular injury activates blood platelets and the coagulation cascade, which results in the formation of clots in the very small vessels of the kidney resulting in acute kidney injury and failure.
The red blood cells undergo hemolytic destruction by Stx and/or damaged as they attempt to pass through partially obstructed microvessels. Blood platelets (required for normal blood clotting), are trapped in the tiny blood clots or are damaged and destroyed by the spleen.
What are the Signs and Symptoms of Post Diarrheal Hemolytic Syndrome (D+HUS) and how is the Diagnosis Made?
The bowel inflammation that occurs prior to the onset of HUS is generally referred to as the prodrome. Within a week (range 1-10 days) after ingesting Stx producing E. coli, the colon becomes severely inflamed causing diarrhea that soon becomes bloody. A stool specimen obtained at this point is usually positive for E. coli O157:H7 or Shiga toxin. However, in many patients the window for capturing E. coli O157:H7 is narrow.
During the prodromal phase of HUS, the initial diagnosis is often acute surgical abdomen, acute appendicitis, or ulcerative colitis. The large bowel inflammation (colitis) can be mistaken for acute appendicitis because the site of intense inflammation is in the right lower part of the abdomen. If this leads to an appendectomy, the appendix is almost always found to be normal, but the surrounding bowel is swollen and hemorrhagic. If a colonoscopy is conducted, severe inflammation, ulceration and pseudomembranes (comprised of sloughed mucosal cells, white blood cells and fibrin) are found.
If computerized tomography (CT) of the abdomen or a barium enema is performed, a thickened (inflamed) bowel is identified. Following several days of diarrhea, thrombocytopenia (low platelet count), hemolytic anemia and acute renal failure converge to form the trilogy that defines D+ HUS.
What are the Physical Signs and Laboratory Values on Admission to the Hospital?
Physical findings on admission to the hospital may include lethargy, abdominal tenderness, purpura (bruising) swelling or dehydration, depending on the net fluid balance. Occasionally, patients may be comatose. Features on admission that portend a severe or fatal outcome include coma, rectal prolapse, decreased or absent urine output (oligoanuria), or white blood cell count (WBC) greater than 20 x 109/l (i.e., greater than 20,000)
What to Expect During Hospitalization
The hospital course can range from mild to very severe. Children are generally in the hospital for about two weeks (range 3 days to 3 months), and adults longer, as their course tends to be more severe. Since there is no way to abort D+HUS, supportive therapy, including meticulous attention to fluid and electrolyte balance, is the cornerstone of survival.
The inflamed colon is usually non-functional for a week or two; so total parenteral nutrition (TPN) needs to be administered through a peripherally inserted central catheter (PICC). This provides access to a large vein in the upper chest that allows infusion of highly concentrated glucose. Even after intestinal function recovers most patients continue to have a poor appetite for a week or so longer. During this interim, nutrients may need to be given through a nasogastric (NG) tube.
Reduced or absent urine output (oligoanuria) occurs in most cases and usually lasts about a week, but can be as brief as two to three days, or as long as a month or greater. Dialysis is required during this time to cleanse the body of uremic toxins and to maintain fluid and electrolyte balance. Peritoneal dialysis (PD) is usually used for young children unless the colitis is severe. Fortunately, the colitis is often resolving by the time PD becomes necessary. Treatment requires placement of a catheter (tube) through the abdominal wall into the peritoneal cavity. Older children and adults are treated with hemodialysis that circulates blood through a hemodialysis machine to filter out (remove) uremic toxins, normalize blood chemistries and correct any edema (swelling). This requires that venous access be established by inserting a temporary catheter into a major vein that returns blood from the upper body to the heart.
The majority of HUS victims require one or more blood transfusions to treat severe anemia; platelet transfusions are sometimes needed to diminish the risk of bleeding in those with severe thrombocytopenia (i.e., platelet counts less than 10,000), to control bleeding, or in preparation for an invasive vascular procedure that can cause hemorrhage (e.g., insertion of a hemodialysis catheter).
More than half of patients experience high blood pressure (BP) that is usually mild and labile, but may be severe enough to require treatment with anti-hypertensive drugs. This condition usually resolves prior to, or soon after discharge from the hospital.
One has to remain vigilant for signs of extra renal involvement. Intestinal necrosis and perforation can occur at any time during the acute phase of the disease and can be fatal if not promptly diagnosed and surgically treated. Pancreatic damage can cause sugar diabetes that is almost always temporary, but may require insulin. Heart and lung injury is rare, but can be fatal. Brain damage can cause stroke and/or cerebral edema (swelling of the brain), and is the most frequent cause of death.
More frequently, however, the encephalopathy (brain dysfunction) is the result of acute metabolic imbalance (metabolic encephalopathy) and is due to abnormalities in the blood concentrations of sodium, glucose, calcium, or to very high levels of metabolic waste products. Since these metabolic abnormalities are the result of the acute kidney failure, they can be corrected by dialysis, and the outcome is favorable. The prevalence of metabolic encephalopathy 25 or more years ago was about 50%. With earlier diagnosis and more timely treatment, the prevalence is now down to about 25%. Convulsions are the most dramatic manifestation, and are more likely to occur in toddlers (30%) than older children (15%). Unfortunately, structural damage to the brain (i.e., stroke, swelling) has not decreased over time. When swelling is severe, the pressure strangulates the brain stem that is responsible for maintaining blood pressure, heart rate, and breathing. This usually results in rapid death.
What are the Expected Short and Long-term Outcomes?
The natural history (clinical course) of D+HUS improved remarkably with the advent of kidney dialysis and intensive care facilities for children. What was originally (in the 1950’s) a 40 % death rate is now only 3 to 5 % in developed countries. Patients today rarely die directly from the acute renal failure, and when death occurs, it is almost always due to our inability to prevent, recognize and effectively treat life threatening extra renal organ injury. Although brain damage is the single most common cause of death, severe multi-organ damage (e.g., renal cortical necrosis, bowel necrosis and stroke) is common in fatal cases.
Survivors usually escape immediate serious sequelae, but about 3-5% percent are left with long-term extra-renal damage, especially of the pancreas or brain. An equal number are left with severe kidney damage, and require chronic dialysis and kidney transplant from the start or after only a few years. A much larger number will develop future sequelae (hypertension, proteinuria, low glomerular filtration rate [GFR]) that correlate best with the presence and duration of oliguria and anuria. For example, one or more sequelae (e.g., proteinuria, low GFR, hypertension), albeit, usually mild, are seen in about a third of those with no recorded oliguria or anuria Thereafter the prevalence of one or more sequelae increases to 80 % in those with more than 10 days of oliguria and 90% if oliguria exceeds 15 days. Two thirds of those with anuria greater than five days duration have one or more sequelae, and essentially, all of those with anuria exceeding 10 days have sequelae.
High blood pressure is later found in approximately 10% of those with no oligoanuria, but rises to about 33% in those whose oliguria exceeds 15 days, and 66% in those whose anuria persists for more than 15 days.
Most concerning is the combination of both low glomerular filtration rate (GFR) and proteinuria, that is, the presence of both below normal kidney function and proteinuria, signs of impaired renal function as well as ongoing hyperfiltration injury. This combination occurs in less than 10 % of patients unless oliguria or anuria persists for more than 10 or five days, respectively. Thereafter, it increases to about 15% in those with greater than 10 days of oliguria, and 40 % if oliguria lasts for more than 15 days. Those with anuria of greater than five days duration exhibit both low GFR and proteinuria almost 20% of the time. It rises to 33 % in those with more than 10 days of anuria, and to 66 % in those whose anuria persists for more than 15 days.
This subset (who has both proteinuria and low GFR) is most likely heading toward end-stage renal disease; (class 5 chronic kidney disease) because of ongoing hyperfiltration injury.
Initially, hyperfiltration may manifest only as microalbuminuria, or if more severe, overt proteinuria This occurs when more than 50% of the nephrons have been destroyed, for example, as might happen during the acute phase of HUS. The remaining nephrons become hypertrophic (enlarged) in an attempt to compensate for the reduced renal population. They usually compensate well for a number of years, but eventually become “overworked”. Their “cry for help” is in the form of microalbuminuria. This convenient urinary marker can be used to estimate “hyperfiltration injury”; the higher the value the greater the injury. Microalbuminuria may precede the emergence of overt proteinuria (a sign of more severe hyperfiltration injury) by a number of years. Moreover, starting at about age 30, as part of the normal aging process, the number of nephrons slowly decreases. Medications (angiotensin enzyme inhibitors and angiotensin receptor blockers) can reduce hyperfiltration injury and thus slow the progressive loss of nephrons, but eventually, when more than 90% of the nephrons have been destroyed; end-stage renal disease (ESRD) ensues.
We do not know the life-time risk of ESRD; this will require lifelong tracking of a large group (cohort) of survivors. It is therefore recommended that all patients be evaluated several times during the first year to include blood pressure and serum creatinine measurements, and a first morning urine specimen for a complete urinalysis and microalbuminuria determination. Evaluations should be conducted yearly for the first decade, and every two years for the second decade; more frequently if abnormalities are found. Careful monitoring during any pregnancies is important since there may be an increased risk of toxemia (pre-eclampsia and eclampsia) of pregnancy. Thereafter, until we have life-long prognostic information, it seems prudent to recommend evaluations every five years for life.
What if the Kidneys Don’t Recover?
Although kidney failure is usually temporary in D+HUS, some never regain sufficient kidney function. Others initially regain enough function to not only survive but also to thrive, but experience progressive renal failure within a few years. A third group of survivors regain normal kidney function and appear to have recovered completely except that they have microalbuminuria or overt proteinuria (if the hyperfiltration injury is more severe/advanced). Renal hyperfiltration injury slowly grinds away at the remaining nephrons until more than 90% have been destroyed (converted to scar tissue) at which point dialysis or transplant is required. There is particular concern after 30 years of age when renal obsolescence, (as part of the normal ageing process), accelerates progressive hyperfiltration injury. Sufficient long-term experience to accurately predict the lifetime risk for end-stage renal disease (ESRD) is not available, but is at least 10%.