About Hemolytic Uremic Syndrome

Overview

How did these otherwise harmless E. coli become such killers? 

From Diarrhea to Dialysis

The chain of events leading to HUS begins with ingestion of Stx producing E. coli (e.g., E. coli 0157: H7) in contaminated food, beverages or through person to person transmission. These E. coli rapidly multiply in the intestines causing colitis (diarrhea), and tightly bind to cells that line the large intestine.  This snug attachment facilitates absorption of the toxin into the 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) Gb3 receptors 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 are hemolyized (destroyed) 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. 

Symptoms and Diagnosis

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 few 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 and inflamed bowel is found. 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).

Treatment

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 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 involvement is rare, but can be fatal. Brain involvement can cause stroke and/or cerebral edema (swelling of the brain).

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 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. Fortunately, children who survive display an amazing ability to recover, though neurological impairment can be permanent.

Outcomes

What is the Expected Short and Long-term Outcome?

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 multiorgan 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 impared renal function as well as ongoing hyperfiltration injury.  This combination occurs in less than 10% of patients until 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 is most likely heading toward ESRD because of ongoing hyperfiltration injury.  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 work 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 aging process, the number of nephrons slowly decreases.   This nephron obsolescence places additional strain on the already damaged kidneys.  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 life long 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.  For more research.

What if the Kidneys Don’t Recover?

Although kidney failure is usually temporary in D+HUS, some never regain sufficient kidney function to survive without immediate renal replacement therapy (dialysis, transplantation).  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 (signs of hyperfiltration injury).  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 during pregnancies and after 30 years of age when renal obsolescence, as part of the normal aging process, accelerates progressive hyperfiltration injury.  Sufficient long-term experience to accurately predict the life-time risk for end-stage renal disease (ESRD) is not available, but is at least 10%.

What is Normal Kidney Function and What can be done to Maximize Health during Progressive Renal Failure?

In order to understand the course of chronic kidney failure it is necessary to know the reasons that normal kidney function is pivotal to health and well being.  The following lists the most important functions of the kidneys and what can be done when they start to fail.

1. Excretion of waste products and fluid and electrolyte balance:   Kidneys play a critical role not only in excreting waste products, but also in maintaining electrolyte (e.g., sodium, potassium, bicarbonate) and water balance.  As kidney function declines, nitrogenous waste products (e. g., blood urea nitrogen [BUN], and creatinine) accumulate.  Reducing the intake of protein, which is the source of these waste products, is helpful. The typical American diet contains much more protein then needed, but care must be taken to be sure that intake is sufficient to meet the recommended daily allowance (RDA).  This is especially important in children and teens.
   
   Normal kidney function allows wide latitude in the amount of salt, potassium and fluid ingested because the kidneys make the proper adjustments, that is, they retain what the body needs and excrete what it does not need.  As kidney failure progresses and kidneys lose their ability to maintain homeostasis (balance), salt, potassium and fluid intake has to be decreased accordingly.  Working with a Renal Dietitian is essential.
2. Acid Base Balance:  Normal metabolism produces large quantities of acid, mainly sulfuric acid, resulting from protein metabolism.  Healthy kidneys excrete this acid.  Once renal excretion of acid is insufficient to offset its production, reducing its source by restricting dietary protein is helpful, but alone is insufficient to maintain acid base balance.  Thus, patients also need to take base (alkali) such as sodium bicarbonate to neutralize remaining body acid.  Failure to do so results in poor appetite, poor growth and weakened bones.
3. Production of red blood cells:  Bone marrow is dependent on a hormone, called erythropoietin, that is produced by kidneys and that directs the bone marrow to make red blood cells (RBC).  Prior to the availability of human recombinant erythropoietin, blood transfusions were the only choice.  Today, the injection of erythropoietin makes that unnecessary.
4. Bone health:  Healthy bones require modification of vitamin D before it is biologically active and able to control the intestinal absorption of calcium, the renal excretion of phosphorous, and bone deposition of calcium and phosphorous.  This chemical modification of vitamin D occurs in the kidneys.  The parathyroid gland is next to the thyroid gland and produces a hormone called parathyroid hormone (PTH), which in turn is under control of the blood calcium level.  In health, PTH keeps blood calcium and phosphorous levels normal and bones healthy.  It is activated by low levels of blood calcium, low biologically active vitamin D, and high levels of phosphorous.  But in kidney failure the hormone’s attempt to maintain a normal blood calcium level occurs at the expense of the bones.  That is, it draws calcium out of the bones.  Failure to adequately control hyperparathyroidism results in osteopenia, that is, reduced bone density and growth. This can be catastrophic for children and teens.  Treatment consists of the oral administration of vitamin D that has been modified in the laboratory to its biologically active form (1-25-vitamin D).  In addition, calcium supplementation, and phosphorous restriction (combined with binders that reduce absorption of phosphorous from the intestine), are necessary. The goal is to keep the PTH level no more than twice the upper limits of normal.  Achieving and maintaining this delicate balance requires close medical supervision and the assistance of a Renal Dietician.
5. Blood pressure control: BP is, to a large extent, controlled by the kidneys, via the production of the proper balance of vasoconstrictive and vasodilatory chemicals and by maintaining normal salt and water balance.  High blood pressure afflicts the majority of renal failure patients, but can often be controlled by maintaining normal sodium (salt) balance via dietary salt restriction and/ or the use of diuretics (water pills).  However, in most cases, this is insufficient, and the administration of antihypertensive drugs is also necessary.  Failure to maintain normal blood pressure increases the risk of heart failure, heart attack, and stroke.
6. Normal growth:   Healthy kidneys are required for normal linear growth.   Children with even moderate degrees of renal failure often fall behind in their linear growth.  As long as the bone growth centers have not yet closed, linear growth can be improved.  First, it is necessary to assure adequate caloric and protein intake, to correct acidosis, and to control hyperparathyroidism.  If this regimen does not adequately stimulate growth, human recombinant growth hormone can be started.  For maximum growth, a daily injection of growth hormone is necessary. In almost all cases linear growth improves, and many experience enough catch-up growth to achieve normal adult height.

End Stage Renal Disease - What are the Options Once Kidney Failure is Advanced

It is time to make plans for renal replacement therapy (dialysis, transplant) when kidney function falls to 20% of normal (since it will be needed for survival once kidney function drops to less than 10% or  of normal); sooner in children who are not thriving.  This is called end-stage renal disease (ESRD).  Assuming that patients have been followed, evaluated and treated as described above, they may be healthy enough to receive a pre-emptive transplant, that is, without first requiring dialysis.  This usually requires that a living related kidney donor  (e.g., parent or sibling) is  available.
 

Kidney Dialysis

Dialysis is a treatment designed to perform the functions of normal kidneys - that is, to remove uremic toxins, and normalize body fluid and electrolytes.  Even so, dialysis is not nearly as efficient as normal native kidneys. It is like “switching” normal kidney function on during treatment and off between treatments.  Of the two dialytic treatments (hemodialysis, peritoneal dialysis), hemodialysis is more efficient, per unit of time (e.g., per hour) than is peritoneal dialysis.

Both dialytic treatments depend on the phenomenon of osmosis.  That is, if two compartments are separated by a semi-permeable membrane and one compartment (in this case, the body) contains uremic toxins and excess electrolytes (e.g., sodium, potassium), and the compartment on the other side of the membrane (dialysate) is free of these substances, toxins and electrolytes will move across the membrane until they are in equal concentrations on both sides.  In peritoneal dialysis, excess body fluid (edema) is removed by dialysate made hypertonic by the addition of dextrose.  Fluid moves across the membranes until the osmotic concentration is equal on both sides of the membrane. If the fluid (dialysate) is continually being replaced, the process can be continued until satisfactory improvement of fluid, electrolytes and uremic toxins is achieved.  With HD, excess fluid (swelling) is removed by creating pressure gradients between the blood and dialysate compartments.

Peritoneal Dialysis (PD)

PD is usually best for infants and small children, but it can also be used in teens and adults. In children it can be done at home while the child sleeps.  There are now several automated machines that infuse a set volume of warmed dialysate that remains for a set period of time and is then drained.  In order to perform PD, a catheter is surgically placed in the peritoneal cavity where the semi-permeable membrane is the peritoneal membrane that lines the peritoneal cavity and the outer surface of the intestines.  This hourly cycle of infusion, dwell, and drainage, usually occurs 10-12 times a night.  Since there is no danger of blood loss (as there is with hemodialysis), there is no need for continual monitoring by the parents.  If the fluid stops flowing in and out of the peritoneal cavity, an alarm sounds, and the parents can call the dialysis staff for advice.  Although it is less efficient than hemodialysis, it is gentler on the system because it removes toxins and excess body fluid, and balances electrolytes more slowly.  The major draw back is the risk of peritonitis, which is a bacterial infection of the peritoneal cavity.  Parents are trained to recognize the signs of peritonitis, and to collect a sample of the dialysate fluid (which is usually cloudy), and to take it to the nearest laboratory for a gram stain which identifies bacteria, a culture, that documents the type of bacteria, and determines antimicrobial sensitivities (for selection of the appropriate antibiotic).  Antibiotics are added to the dialysate, allowing treatment at home, with daily phone contact with the dialysis staff, as long as the child is stable with no signs of sepsis (systemic infection).  Children whose condition is unstable, and infants, need to be hospitalized. 

Hemodialysis (HD)

HD is more suitable for older children, adolescents, and adults, but can be used in small children and even infants if PD is no longer effective (e.g. scarred peritoneal membrane from repeated bouts of peritonitis).  Blood access is achieved by surgically attaching a native artery (usually in the arm) to an adjacent vein.  Over time, the vein enlarges and develops thicker and stronger walls that will accept a dialysis catheter.  With this procedure the catheter is inserted at the initiation, and removed at the end of each treatment.  As an alternative, a section of artificial vessel material (e.g., Gortex) can be used to create a vein-to-vein graft that can be used almost immediately.  Blood is circulated from the patient through a cartridge that contains thousands of tiny tubules (semi-permeable membranes) that are bathed in dialysis fluid which is free of toxins, and whose concentration of electrolytes and minerals are designed to normalize those of the patient.  The advantage over peritoneal dialysis is that it is more efficient, and thereby requires only 3-4 hours of out-patient treatment three times a week.  Disadvantages include disequilibrium syndrome characterized by headache, weakness, and nausea, which is thought to be secondary to rapid removal of uremic toxins.  Also, most patients ingest much more fluid between dialysis treatments than can easily be removed, and thus require aggressive ultrafiltration (to remove edema fluid).  Rapid contraction of the extra cellular fluid compartment can cause low blood pressure, nausea and vomiting.  Also, on occasion, skin bacteria can enter the blood stream resulting in sepsis, a life threatening illness requiring rapid diagnosis and treatment.

Kidney Transplantation

The goal for patients with ESRD is a renal transplant. It results in a better lifestyle, longer survival, and better health, than does dialysis.  This certainly applies for those whose ESRD is due to D+HUS. In contrast to atypical (non-Shiga toxin) HUS, those with classic D+HUS rarely experience recurrent disease in their renal graft.
 
Transplant is not a “cure”, however, and should not be viewed as such.  A renal transplant (renal graft) rarely lasts for a lifetime and several transplants should be anticipated.  If the patient has been followed and monitored during the course of progressive renal failure, and if a related living donor (LRD) is available, the transplant can be timed to occur just as the patient is entering end-stage renal disease (ESRD) and is known as a pre-emptive transplant.  If not, the patient begins dialysis and is put on the waiting list.  

Children receive special consideration and do not have to wait as long adults. Many factors determine the anticipated waiting time for a cadaveric transplant, but the major one is the patients’ ABO blood type. Even though a few centers are now doing transplants across ABO blood groups, ABO blood group compatibility is still a requirement in almost all programs.  Recipients with the AB blood group have no pre-formed antibodies against a donor’s ABO system, irrespective of the donor’s blood group, while recipients with type O blood have antibodies against all donors’ ABO blood groups.  Therefore, those with type O blood have to wait the longest for a transplant, while those with type AB blood the shortest.  The wait for patients with either type A or B is between the AB and O groups.

Pre-transplant protocol

Before a living related donor can be considered, he/she must undergo a rigorous evaluation to ensure that donating a kidney will not be a threat to the donor’s health.  While it is preferable to transplant a kidney from a younger person (e.g., sibling who has reached the age of majority, a parent), kidneys have been taken from healthy older donors with only modest reduction in graft survival.   One advantage of being able to schedule the transplant is that it permits the initiation of immunosuppressive medications prior to the transplant.  Children need to achieve a weight of about 15 lbs before most centers will proceed.  To do otherwise increases the risk of surgical mishap in suturing the child’s vessels to those of the much larger donor kidney. There is also an increased risk of losing the graft to vessel thrombosis. 

Previously kidneys from cadaveric donors (CAD) were considerably inferior relative to those of living related donor kidneys.  With today’s potent anti-rejection medications, however, graft survival is approaching that of LRD kidneys with a one year graft survival 95% with LRD vs. 90% with CAD.  Although all efforts are made to be sure that the cadaveric kidney is healthy and ABO compatible, there have been rare reports of cancer transmission from donor kidney to recipient.  Also, about half of potential donors have inactive Cytomegalovirus (CMV) that can become active in immunocompromized recipients.  Since CMV infection can be treated, the question of whether or not to accept such a kidney depends on the urgency of transplanting a patient.