The recent European E. coli O104:H4 Outbreak is now reporting over 2,000 ill (nearly 70% women) and 19 dead in what has now become the world’s most deadly E. coli Outbreak and its third largest.  However, what is most staggering are the numbers of people who have developed Hemolytic Uremic Syndrome – over 550 to date – an attack rate of over 27%.   In some respect it reminds me of the 2006 Dole Spinach E. coli O157:H7 Outbreak, which, according to the CDC:

Among the ill persons, 102 (51%) were hospitalized and 31 (16%) developed a type of kidney failure called hemolytic-uremic syndrome (HUS). One hundred forty-one (71%) were female and 22 (11%) were children under 5 years old. The proportion of persons who developed HUS was 29% in children (<18 years old), 8% in persons 18 to 59 years old, and 14% in persons 60 years old or older.

Whether it is E. coli O104:H4 or E. coli O157:H7 caused Hemolytic Uremic Syndrome, it is a very nasty outcome.  So, lets get some answers:

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.

Hemolytic Uremic Syndrome: A Dangerous Complication of E. coli

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From Diarrhea to Dialysis

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) 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 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%. 

What is Normal Kidney Function?

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 wellbeing.  The following lists the most important functions of the kidneys and what can be done when they start to fail.  

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.

Maintain 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 (not stomach) acid.  Failure to do so results in poor appetite, poor growth and weakened bones.

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.

Maintain 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.  Low levels of blood calcium, low biologically active vitamin D, and high levels of phosphorous activate it.  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), is 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.

Control blood pressure:

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.

Maintain normal growth:

Healthy kidneys are required for normal linear growth.   Children with even moderate degrees of chronic renal failure often fall behind in their 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 (HGH) 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.

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

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 % of normal); sooner in children who are not thriving.  This is called end-stage renal disease (ESRD) or Stage 5 chronic kidney disease.  Assuming that patients have been followed, evaluated and treated as described above, they may 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 function like 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, but peritoneal dialysis is safer and easier in infants and small children. Toxin removal in both dialytic treatments depends 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.  Excess body fluid (edema) is removed, in peritoneal dialysis (PD), by making dialysate 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 fluid balance is achieved.  With hemodialysis (HD), excess fluid 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 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 cycle (e.g., hourly) 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 (per unit of time) than hemodialysis, it is gentler on the circulatory system because it removes toxins and excess body fluid, and balances electrolytes more slowly.  The major drawback 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 needle 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 dialysate (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 is that it is more efficient, and thereby requires only 3-4 hours of outpatient 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.  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 life style, 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 could 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 to those from living related donors.  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 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 a 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. 

Transplant protocol

In the case of living related donors, the donor and recipient are placed in separate but adjacent operating rooms.  One team is assigned to harvest the kidney from the donor while another team is preparing the recipient.  In most centers the donor kidney is harvested through a traditional surgical flank incision, but other centers are now providing the option of kidney retrieval using laparoscopic technique.  This results in less pain and faster recovery for the donor.  Cadaveric kidneys are sometimes harvested at distant sites, flushed and shipped on ice.  This may result in a prolonged “cold ischemia time” and these kidneys often do not work for a number of days due to ischemic injury.  During this time, the patient may need to be supported with dialysis.

The original anatomic site (the flank) is not used for the transplanted kidney because of technical difficulty and poor post transplant accessibility.   In adults, teens and larger children, the renal graft is placed in the recipient’s pelvis and the donor renal artery and vein are connected to the recipient’s vessels. The donor ureter is inserted through the recipient’s bladder wall and sutured in place. Many centers use a non-refluxing insertion and others do not. Vesico- (bladder) ureteral reflux increases the risk of infection (pyelonephritis) in the renal graft.   In small children’s and infants, the kidney is too large for the pelvis and must be placed within the peritoneal cavity, which can extend from the pubic bone to the sternum.

Post transplant protocol

Since all kidneys except those from an identical twin are recognized as “foreign” by the recipient’s immune system, it is necessary to use immunosuppressive medications to reduce the risk of rejection.  It is now common to start with immediate intravenous “induction therapy” such as rabbit antithymocyte globulin (ATG) while starting oral anti-rejection medications (e.g., cyclosporine, mycophenolate mofetil).  Compared to previous decades, today’s powerful immunosuppressants are responsible for markedly improved short-term graft survival.

What are these medications?

Calcineurin inhibitors (cyclosporine [e.g., Neoral], tacrolimus [Prograf]) are powerful medications that need to be prescribed and monitored by physicians who are well schooled in the various drug interactions, proper dosing, and side effects. Blood levels need to be monitored.  It is imperative to know that the metabolism and clearance of cyclosporine and tacrolimus are reduced by more than two-dozen other medications, which can result in toxic blood levels.  Conversely, there are about half a dozen other medications that accelerate metabolism and reduce blood levels, thereby increasing the risk of acute rejection.

Since these medications can cause microvascular injury (a feature of HUS), there was at one time a reluctance to use them in patients whose ESRD was caused by HUS.  It is now recognized that Calcineurin inhibitors can be used in those who had D+HUS, and that recurrence of HUS in the renal graft is uncommon.

Side effects are numerous.  Both cyclosporine and tacrolimus can be toxic to the renal graft and cause graft dysfunction. If toxicity is progressive in spite of careful monitoring of blood levels, and is verified by renal graft biopsy, cautious withdrawal of cyclosporine/tacrolimus may be necessary.  Hyperkalemia (elevated blood potassium concentration), diarrhea, headache, hypertension, elevated blood lipid levels (cholesterol, triglyceride), and tremor are common side effects.  Tacrolimus is more likely to cause diabetes mellitus, but less likely to cause hypertrichosis (excessive hair growth) and gum hypertrophy, special concerns for adolescent girls.

Mycophenolate Mofetil (CellCept) is a popular agent that is often combined with Calcineurin inhibitors.  It has largely replaced azathioprine (Imuran) as an adjunctive immunosuppressive medication.  The side effect profile includes pancytopenia (reduced white, red, and platelet cells) and increased opportunistic infections and malignancies.

Sirolimus (Rapamune) a newer drug, Sirolimus, combined with Cyclosporine, has not been shown to improve graft survival, and may even decrease it.  The ability to inhibit cell growth, however, makes it an attractive agent in those with post-transplant cancer.  Its side effects include increased opportunistic infections and elevated blood lipid levels.

Glucocorticoids The long term use of cortisone related drugs (e.g., prednisone, methylprednisolone) is no longer required for most patients. In fact, at least with children, steroid side effects such as “moon” facies”, abdominal and intracapsular fat, emotional instability, stretch marks, diabetes, bone damage and poor linear growth are all largely a thing of the past. Many pediatric transplant programs taper LRD recipients off prednisone very rapidly, and some do not use them at all, except perhaps as induction therapy.

Newer experimental anti-rejection therapies For the most part, the newer therapies are designed to eliminate, or at least reduce the need for powerful anti-rejection medications and their associated, often severe, side effects.  The goal is to induce immune tolerance, that is, to induce the recipient’s immune system to coexist with the foreign tissue (renal graft) while still maintaining its ability to respond appropriately to infectious agents (various types of germs).

Studies, infusing cells from the prospective donor’s bone marrow are encouraging.  One group of doctors at a major medical center has successfully transitioned four of five kidney transplant patients off the usual regimen of anti-rejection drugs. They first weakened the patient’s immune system with drugs and medications, and then infused the donors’ bone marrow at the time of renal graft surgery.  They used anti-rejection medication initially, but were able to successfully wean four of the five patients off drugs by about one year.  Another team from a leading transplant center are harvesting stem cells from the prospective donor’s bone marrow and infusing them into prospective recipients.  Stem cells in the bone marrow can mature into cells (T-cells, plasma cells) that are important in the immune response. The hope is that the recipient’s immune system will gradually tolerate (get used to) the stem cells and the renal graft. Their preliminary results are encouraging.

Acute rejection treatment 

Acute rejection now occurs infrequently, and the likelihood of renal graft loss secondary to acute rejection within the first year is less than 10% for cadaveric grafts and less than 5% for living related donor kidneys.  The introduction of newer potent medications is responsible for fewer acute rejection episodes, and if they occur, for reducing their intensity.  Compared to previous decades, when patients developed fever, tender renal graft, hypertension, and reduced urinary output, the onset of acute rejection is now often quite subtle.  Presently, the only sign is usually a modest rise in the serum creatinine concentration.  Often, a percutaneous needle graft biopsy is required to determine if the serum creatinine elevation is due to acute rejection, or Calcineurin nephrotoxicity.

A short course of high dose IV methylprednisolone is usually effective for acute rejection. If unsuccessful, administration of monoclonal antibody (OKT3) directed against CD3 T cells is usually effectual since acute rejection is mediated primarily by activated T lymphocytes. The threat of life threatening side effects require premedication and very close observation, at least during the first few daily doses.

Infections

One of the consequences of effective immunosuppressive therapy is an impaired ability to ward off infections (viral, fungal and bacterial). Two of the more frequent infections are:

Polyoma virus (BKV) nephropathy:  This common virus causes overt disease in those with a suppressed immune system, and can lead to graft dysfunction. Present therapy consists of the cautious reduction in the dose of immunosuppressive medication.  A number of additional approaches are being studied.

Cytomegalovirus (CMV) infection:  CMV is another frequent infection that plays havoc in the transplant population.  It can occur from reactivation of host infection or from its acquisition in the renal graft.  Active CMV infections can involve multiple organs and can be life threatening.  It is so frequent that most programs give prophylactic ganciclovir during the first three months post transplant.

Post transplant cancer

Another consequence of immunosuppression is impaired cancer surveillance.  Although almost all cancers can occur, skin cancer and non-Hodgkin’s lymphomas are the most frequent.

Skin cancer of the non-melanomic variety, especially squamous cell cancer, is the most frequent of all cancers.  Its incidence increases as the duration of immunosuppression increases. Although metastasis and death from these cancers are uncommon in the general population, they can be fatal in the transplant population.

Lymphoproliferative Disease (PTLD). Is a serious malignancy that can occur during the first year post-transplant is Post Transplant Most cases result from activation of, or acquired infection with the Epstein-Barr virus (EBV).  Optimal therapy is evolving, but is presently limited to reducing immunosuppressive medications, administering anti-viral agents, and chemotherapy. Consideration should be given to switching from tacrolimus (that increases risk of PTLD) to Sirolimus, which has been shown to decrease metastasis and cell growth in non-human studies.  Even with optimal therapy, first year mortality approaches 50%

Premature coronary artery disease

Coronary artery disease (myocardial infarction) is the most common cause of death in the transplant population and is largely responsible for shortened lifespan.  Treatable predisposing factors include elevated blood lipid levels (LDL cholesterol, triglycerides), hypertension, smoking, obesity, and sedentary life style.

Osteopenia

An additional post-transplant risk is osteopenia (loss of bone calcium).  Also as graft function slowly declines over the years secondary to chronic rejection, the same health challenges enumerated in the” What can be Done to Maximize Health During Progressive Renal Failure” section apply.

Chronic Allograft Nephropathy (Chronic Rejection)

Although tremendous progress has been made in preventing/treating acute rejection and increasing short-term graft survival, much less progress has been made in preventing/treating chronic rejection, also now known as chronic allograft nephropathy (CAN). It is thought that both immune and nonimmune factors converge to cause CAN.  There is some evidence that the risk of CAN is reduced in those on MMF compared to those taking its predecessor, azathioprine (Imuran).  CAN is the most frequent cause of eventual graft loss.

Renal Graft Survival

Graft (transplanted kidney) Survival, is the length of time transplants function well enough to keep recipients from either needing initiation of (or return to) dialysis, or another transplant. This is influenced by a number of things:

1.  How well the donor kidney cells match those of the recipient.  This is determined by tissue typing, using human leukocyte antigens (HLA); these antigens are tiny protein structures on white blood cells (WBC), as well as other body cells (including kidney cells) that are important determinants of the immune response.  The more disparate the HLA between the donor kidney cells and those of the recipient are, the greater the immune response (rejection).  Even though HLA typing does not detect all antigenic differences, it is useful in predicting graft survival and in deciding which potential donors will provide the best chances for long-term graft survival. The types of HLA matches are:

Perfect match is of course ideal, but only occurs between identical twins.

Four antigen match, which occurs between some siblings, is next best. There is a one in four chance that any given sibling pair will match in all four of the major (HLA) antigens (there is also a one in four chance that they will fail to match with any of the HLA antigens).  Even when the HLAs match, there are still subtle antigenic differences that are not identified by HLA typing.

Two antigen match.  There is a one in two chance that any pair of siblings will match in two of the HLA antigens.   A biological parent (of either gender) is often chosen as the donor for pediatric transplants (usually the mother, for reason of smaller kidney size).  Two of the four patient’s HLA antigens come from the mother and two from the father.  This is what is called a haplotype (two antigen) match.

Mismatch, is anticipated if the donor kidney is from a living, unrelated person (spouse, non-first degree relatives) or from a deceased (cadaveric) donor.  Mismatched kidneys (grafts) survive much better today that they did a decade or so ago because the newer more powerful anti-rejection medications partly compensate for the HLA disparity

Whether the kidney is from a living related donor (LRD) or is a cadaveric donation (CD).  Given a similar degree of HLA mismatch, a living donor kidney is preferable to a cadaveric kidney.

The reasons for this are probably the following:

  1. Ischemia time is generally shorter for a LRD kidney; that is, the time the kidney is without blood perfusion (ischemia time).  Perfusing the kidney with special solutions and keeping the kidney cold until it is implanted in the recipient lessen ischemic damage.  This can vary from less than an hour to many hours (e.g., if the kidney is shipped from a distant site)
  2. LRD kidneys are less likely to be injured or damaged, from either ischemia or chronic disease.  Living donors undergo an extensive battery of tests to be sure the prospective donor kidney is free of disease/damage (and to be sure that the prospective donor can tolerate removal of one half of the functional units [nephrons]).  Conversely, kidneys from deceased donors might have damage from disorders such as hypertension, or nephritis that are unknown to the donor’s family.  Few centers routinely biopsy cadaveric kidneys prior to implantation

Acute rejection episodes:  The presence and (frequency) of acute rejection episodes (during the first    year post-transplant) is associated with decreased long-term graft survival.

Serum creatinine concentration (graft function) at one year:  impaired graft function at one-year post- transplant predicts reduced long-term graft survival.

Calcineurin inhibitors: These powerful anti-rejection medications have a down-side, namely, they can cause chronic progressive renal damage.  Their use (and blood levels) has to be carefully monitored.

Recurrence of the original disease in the renal graft:  Certain primary disorders (that originally caused the kidney failure) can recur in the renal graft; post-diarrheal HUS rarely does, however.

Other risk factors:  chronic hypertension, high cholesterol, obesity, diabetes, either type 1 or type 2; in other words, factors associated with poor health in general also reduce graft survival.

Graft survival statistics

Cadaveric kidney graft survival for adult patients (based on 2009, 2005 SRTR National Report and 2002 UNOS report) is:

One year:  91%

Three years: 79%

Five years:  53%

10 years:  51%

Graft survival for children is similar.

Living donor graft survival:

One year:  96%

Three years:  89%

Five years:  81%

10 years:  68%

Again, graft survival in children is similar.

These data are inclusive, and are not stratified according to tissue typing, (i.e., those with closer matching do somewhat better).  Median graft survival (the mid-point; time in years when 50% of grafts are still functioning and 50% are not):

Cadaveric graft: 10 yrs

Living related donor:  15 years

Research

D+HUS is caused by Shiga toxin producing E. coli (e.g., E. coli O157:H7) and is the most common cause of acute kidney failure during childhood.  The syndrome is defined by the presence of thrombocytopenia, hemolytic anemia, and acute kidney failure.  Most patients require blood transfusions and dialysis, and life threatening involvement of vital organs (especially the brain) results in a 3-5% mortality rate.  Although patients who experience prolonged oligoanuria are at highest risk for eventual ESRD, life-long evaluation is recommended for all patients.  Much can be done to maximize health and well being in HUS survivors who are left with persistent kidney damage, and renal replacement therapy (dialysis, transplantation) is available for those who develop ESRD.  Kidney transplantation is the goal for all patients, and even though it is fraught with complications, it offers improved survival, dialysis-free living, and greater well being.

Literature on acute Hemolytic Uremic Syndrome and the prognosis of individuals who develop HUS

For help with terms used in these abstracts, see below, our Glossary of HUS Terms.

Hemolytic Uremic Syndrome is less common in adolescents and much more common in younger children. In one study (Siegler, Arch Pediatrics and Adolescent Medicine, 1997), adolescents accounted for 5.8% of the cases of HUS. While HUS is less common in adolescents, significant complications of HUS occur in teenagers as occurs in younger children, and the incidence of complications is very similar to the incidence of complications that occurs in younger children. In an earlier study by Siegler, et al, (Journal of Pediatrics, 1991) 61 children were followed for a mean of 9.6 years following the acute episode of HUS. The risk of late complications was 39% of all children with a past history of Hemolytic Uremic Syndrome. The duration of oligo/anuria was found to be the best predictor of late complications. Among 34 children with oliguria, 15 (44%) had proteinuria at follow-up. In children who required dialysis, 52%, 41%, and 56% had proteinuria, decreased creatinine clearance or any renal sequelae, respectively. Abnormalities appeared after an interval of apparent recovery.

In the article by Perlstein, et al, oral protein loading in 17 children with a past history of Hemolytic Uremic Syndrome demonstrated that functional renal reserve was reduced in children with a past history of HUS who had normal renal function and normal blood pressure as compared to normal children. This study suggested that functional renal reserve in children with HUS might be reduced although renal function and blood pressure are normal. The authors point out that the long-term significance of this finding is unknown and needs to be determined, but the study suggests that functional renal reserve may be reduced in spite of normal recovery and that children with HUS need long-term follow-up.

In the article by Gagnadouz, et al, 29 children were evaluated 15-25 years after the acute phase of Hemolytic Uremic Syndrome. Only 10 of the 29 children were normal, 12 had hypertension, 3 had chronic renal failure and 4 had end stage renal disease. Severe sequelae occurred in children with oligo/anuria for more than or equal to 7 days. The renal histology was the best predictor of long-term complications. Other studies by Caletti, et al, have also demonstrated that histologic finding of focal and segmental sclerosis and hyalinosis are observed several years following HUS. In that article, only a quarter of the children had normal renal function during long-term follow-up.

In the article by Milford, et al (J Peds 1991), 40 children with Hemolytic Uremic Syndrome were studied to determine the risk of late complication. Of the 40 children, 17 required dialysis while 23 did not require dialysis. Of the 17 children who required dialysis, 6 had hypertension with or without chronic renal failure during follow up for an incidence of 35.5% of the 29 children who were considered to have recovered completely and demonstrated a normal urinalysis during follow up, 4 had proteinuria during later follow up for an incidence of 13%.

In the article by Fitzpatrick, et al (British Medical Journal, 1991), 88 children were followed up 5.1 to 21 years (mean, 8.5 years) following the acute episode of HUS. Eleven of 74 children who required dialysis for less than 16 days had a reduced glomerular filtration rate (less than 80 ml/min/1.732) during follow up (14.8%) while one of 12 children (8.3%) who required dialysis for 1 to 5 days had a glomerular filtration rate less than 80 ml/min/1.732 during follow up.

In the article by Tonshoff, et al, (Nephron) 26% of patients with oliguria of less than 7 days had long-term renal complications. In the article by de Jong, 96 children with HUS were followed for 10 years. Seven of 29 children with oliguria of 7-14 days duration or anuria for less than 7 days had reduced GFR, proteinuria, or hypertension for an incidence of 24.1%.

In the article by O’Regan, et al, (Clinical Nephrology, 1989) eleven of thirty-seven children with a previous episode of Hemolytic Uremic Syndrome had a reduced glomerular filtration rate as measured by clearance of radioactive DTPA. The authors concluded that HUS might result in an appreciable deterioration of GFR that is not detectable by routine laboratory tests.

Thus, 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 long 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.

All persons who have experienced HUS should be formally evaluated by nephrologists—a kidney specialist—at 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.

Physicians doing follow-up on HUS patients will carefully look for indications of kidney injury. These will include whether there is an abnormal amount of protein in the urine that may signal a significant injury to the kidneys or blood in the urine, which also can reflect kidney injury. As assessment of the HUS patient’s glomerular filtration rate—“GFR”—is essential to determining whether the kidneys are functioning in the range of normal for that person age, sex, and size. It is also important to establish a baseline GFR so that future assessment of kidney function can reflect any potential loss of filtering capacity over time.

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, an 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.

Medical follow-up is important because of the risk of deteriorating kidney function after one study of HUS patients noted that: “Of the 28 patients with a normal GFR at 1 year, 3 deteriorated into mild CRF [chronic renal failure] at 5 years.” The study’s authors went on to conclude – We conclude that renal function at 1 year following HUS cannot be predicted with any certainty from the initial illness and should be formally assessed. However, renal function was within normal limits and remained stable between 1 and 5 years following HUS in most children. The results suggest that longer-term follow-up can probably be restricted to those with proteinuria, hypertension, and abnormal ultrasound and/or impaired GFR at 1 year.  Small G, et. al., Hemolytic uremic syndrome: defining the need for long-term follow-up Clinical Nephrology 1999 Dec; 52(6) l352-6.

There is simply no way to precisely measure the extent of damage to the kidneys as a result of HUS. And there are still no studies that have followed HUS patients over their lifetimes. Thus, the best practice is to make sure that any child or young adult follows-up with a kidney specialist until that physician is convinced that further follow-up is no longer necessary.

Terms

Allograft – Graft derived from an individual of the same species that is sufficiently unlike genetically to interact antigenically.

Antagonist – In biochemistry, an antagonist acts against and blocks an action.

Anticoagulant – Any agent used to prevent the formation of blood clots.

Antigen – A protein or carbohydrate substance (as a toxin or enzyme) capable of stimulating an immune response.

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.

Anuria – Absence of urine excretion.

Case fatality rate – The proportion of deaths among a group of persons with a particular condition or disease.

Basal ganglia – A region consisting of 3 clusters of neurons located at the base of the brain that are responsible for involuntary movements.

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

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.

Cortical necrosis – Tissue death of the outer layer of the kidney.

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.

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).

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.

Dysphasia – Difficulty in swallowing.

Electroencephalograph (EEG) – An apparatus for detecting and recording brain waves.

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.

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.

Etiology – The cause of a disease.

Fibrinolytics – Clot-dissolving drugs.

Gastric – Relating to the stomach.

Genotype – The genetic constitution (the genome) of a cell, an individual or an organism.

Glomerular filtration rate (GFR) – The rate at which blood is filtered through tufts of capillaries in the kidney.

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.

Glomerular – Pertaining to the glomerulus, a tiny structure in the kidney that filters the blood to form urine.

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.

Hemiparesis – Muscular weakness or partial paralysis restricted to one side of the body.

Hemolytic anemia – Anemia caused by excessive destruction (as in chemical poisoning, infection, or sickle-cell anemia) of red blood cells.

Hemorrhagic colitis – Bloody infection/inflammation of the colon (bowel).

Histological – In reference to the minute structure of tissues discernible with the microscope.

Hyperfiltration – Abnormal increase in the filtration rate of the renal glomeruli.

Hypertension – High blood pressure.

Hyponatremia – Deficiency of sodium (salt) in the blood.

Infarct/infarction – An area of necrosis (death) in a tissue or organ resulting from obstruction of the local circulation by a thrombus or embolus.

Internal/external capsule – Fibrous express ways that contain nerves to transmit information within certain parts of the brain.

In vitro – Outside the living body and in an artificial environment.

Intravenous (IV) – Within a vein.

Ischemia – Localized tissue anemia due to obstruction of the inflow of arterial blood (as by the narrowing of arteries by spasm or disease).

Leukocyte – White blood cell.

Leukocytosis – Increase in the number of white blood cells.

Microangiopathy – A disease of very fine blood vessels.

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.

Monoclonal antibody – An antibody derived from a single cell in large quantities for use against a specific antigen.

Morphologic – Of, relating to, or concerned with form or structure.

Mortality – The number of deaths in a given time or place; the proportion of deaths in a given population.

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

Morbidity – The incidence of disease; the rate of sickness (as in a specified community or group).

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.

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.

Oliguria – Reduced excretion of urine.

Parenteral – Drug or substance, like supplementary nutrition, administration by intravenous, intramuscular, or subcutaneous injection; especially introduced other than by way of the intestines.

Paresis – Paralysis.

Pathogenesis – The origin of a disease and the chain of events leading to that disease.

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.

Plasmapheresis – Separating out the plasma from the whole blood, replacing the plasma, and returning plasma and original blood cells to the patient.

Platelet – An irregular, disc-shaped element in the blood that assists in blood clotting. During normal blood clotting, the platelets clump together.

Placebo – An inert or harmless substance used especially in controlled experiments testing the efficacy of another substance (as a drug).

Primary – First in order of time or development.

Proteinuria – Protein in the urine.

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.

Prodromal – A symptom or set of symptoms that occur before the onset of a disease or condition.

Prothrombotic – A substance which encourages the production of blood clots.

Receptor – A structure on the surface of a cell (or inside a cell) that selectively receives and binds a specific substance.

Rectal prolapse – The falling down or slipping of the rectum (the terminal part of the intestine) from its usual position.

Renal – Kidney.

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.

Sequelae – An after effect of disease, injury, procedure, or treatment.

Serotype / group – A group of intimately related microorganisms distinguished by a common set of antigens.

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.

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.

Tetraspastic – A state of hypertonicity or increase over the normal tone of a muscle, with heightened deep tendon reflexes, affecting all four extremities.

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).

Thrombocytopenia – Persistent decrease in the number of blood platelets that is often associated with hemorrhagic conditions — called also thrombopenia.

Stupor – Decreased mental status or consciousness; loss of alertness.

Thrombosis – The formation or presence of a blood clot within a blood vessel.

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.

Thrombogenic – Tending to produce a thrombus (a clot of blood formed within a blood vessel and remaining attached to its place of origin).

Vascular endothelial growth factor – Substance made by cells that stimulates new blood vessel formation.

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.