Acute hemolytic uremic syndrome (HUS)
Post-diarrheal hemolytic uremic syndrome (D+HUS) is a severe, life-threatening complication that occurs in about 10 percent of those infected with E. coli O157:H7 or other Shiga toxin- (Stx-) producing E. coli.
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 damage 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.
Each kidney has between 700,000 and 1,000,000 filtering units, called “nephrons.” The heart of each filter is a microscopic bundle of blood vessels called glomeruli. Blood goes into each glomerulus and waste products pass through a membrane into tubules, which connect together and ultimately collect the urine and pass it out of the kidney.
The glomerulus is the main filter of the nephron and is located within the Bowman's capsule. The glomerulus resembles a twisted mass of tiny tubes through which the blood passes. The glomerulus is semipermeable, allowing water and soluble wastes to pass through and be excreted out of the Bowman's capsule as urine. The filtered blood passes out of the glomerulus into the efferent arteriole to be returned through the medullary plexus to the intralobular vein. Meanwhile, the filtered water and aqueous wastes are passed out of the Bowman's capsule into the proximal convoluted tubule.
In HUS, a certain number of glomeruli are permanently damaged due to loss of blood flow as tiny thrombi occlude those blood vessels. The toxins from E. coli O157:H7 also have a direct effect on the cells lining the blood vessels and tubules and can cause cell death. Once a filter is gone, it is gone forever. When a lot of filters are gone, the remaining ones work harder because there are fewer of them. If enough filters are lost, the remaining filters experience “hyperfiltration,” which leads to enlargement, and over time, scarring, which in turn leads to the loss of more filters.
Serious kidney injury usually manifests through reduced filter function, hypertension, and/or proteinuria. It is easy to get a rough estimate of kidney filter function by looking at the level of waste products, especially creatinine in the blood over time. There are also formulas to estimate filter function once you have a creatinine value. The key is whether filter function changes over time. Since the kidneys primarily regulate blood pressure, the development of hypertension after HUS also signals serious kidney injury and is considered a bad prognostic sign. So too is proteinuria—the passage of protein molecules in the urine—which is a sign that the glomeruli have been damaged, and the remaining filters are hyperfiltrating—i.e. they are being overworked due to the loss of filtering capacity of other dead or damaged filters.
If enough filters are lost either due to injuries suffered during the acute HUS illness, or later in life due to the process of hyperfiltration, a patient will reach end stage renal disease (“ESRD”). ESRD, truly a worst-case scenario for someone who has survived the acute HUS illness, is a very painful process that can take decades to play out. The demands on the kidneys increase through puberty and, for women, especially during pregnancy, adding another variable to issues of future renal health for girls who have suffered severe HUS.
Long-term consequences of hemolytic uremic syndrome (HUS)
Multiple studies have demonstrated that children with HUS who have apparently recovered will develop hypertension, urinary abnormalities and/or renal insufficiency during long-term follow-up. One of the best predictors is the duration of anuria and/or oliguria.
Milford, et al, (J Pediatrics, 1991) studied the importance of proteinuria at one year following the acute episode of HUS in 40 children. They found that a poor prognosis defined as hypertension, decreased renal function or end stage renal disease was strongly associated with proteinuria at the one year follow up.
Perlstein et al, (Arch Dis Child, 1991) reported results of oral protein loading in 17 children with a past history of HUS; they 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 suggests that functional renal reserve in children with HUS is 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, (Clinical Nephrology, 1996) 29 children were evaluated 15-25 years after the acute phase of HUS. Only 10 of the 29 children were normal, 12 had hypertension, 3 had chronic renal failure and 4 had end stage renal disease (65.5%). Severe sequelae occurred in children with oligo/anuria for more than or equal to 7 days.
Other studies (Caletti, et al, Pediatric Nephrology, 1996) have demonstrated that histological finding of focal and segmental sclerosis and hyalinosis are observed several years following HUS. In that article, only 25% of the children had normal renal function during long-term follow-up.
Similarly, Moghal, et al. (Journal of Pediatrics, 1998) performed kidney biopsies in children with persistent proteinuria three to seven years following the acute episode of HUS. Global glomerulosclerosis was noted in six of the seven patients and two had segmental sclerosis as well. In addition, tubular atrophy and interstitial fibrosis was seen in all but one. Finally, the glomeruli in the children with HUS were significantly larger than those in normal children. These are finding that are typically found in individual with reduced nephron number and are consistent with changes of hyperperfusion and hyperfiltration is surviving nephrons. Hyperfiltration is a process that frequently leads to progressive renal damage and the development of end stage renal failure.
In 1997 Spizzirri, et al, (Pediatr Nephrol, 1997), reported that 69.2% of children with 11 or more days of anuria and 38.4% of children with 1-10 days of anuria had chronic sequelae. In addition, of patients with proteinuria at the 1-year follow-up, 86% had renal abnormalities at the end of the follow-up. The authors suggested that children with residual proteinuria with or without hypertension would probably develop progressive chronic renal failure.
In 2002, Blahova, et al, reported that long term follow up of 18 children who had HUS 10 or more years previously, only 6 children were normal while the other 12 children had either residual renal symptoms, chronic renal insufficiency or renal failure (66.6%). Many of the children with residual renal symptoms or chronic renal insufficiency/renal failure had appeared to have recovered normally at earlier check ups.
Recently, Lou-Meda, et al, reported that 14 patients with microabluminuria and no overt proteinuria at 6 to 18 months after the acute phase of HUS, on long term follow up three had a decreased glomerular filtration (GFR), one had overt proteinuria, and four had hypertension. Eight of the 14 patients had at least one sequelae for an incidence of 57.1%. Six children had overt proteinuria and at the most recent follow up, two had hypertension, four and a low renal function and two had continued proteinuria; four (66.6%) had at least one renal sequale.
Recently, Oakes, et al, determined the risk of later complications in children who had HUS several years earlier; they found that the incidence of late complications increased markedly in those with more than 5 days of anuria or 10 days of oliguria. Among children with greater than 10 days of oliguria 63.3% had a low glomerular filtration rate, 33.3% had hypertension and 88.7% had at least one long term complication.
In summary, many children who have recovered normal renal function following the acute episode of HUS have a high risk for the development of late complications from their acute episode of HUS. The risk is substantially lower in children who did not require dialysis and in children who were not oliguria or anuric while the risk is the highest in children who had oligo/anuria for more than 7 days. In one study, all children with oligo/anuria for 14 days had residual renal disease (100%).
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.
Long-term side effects of hemolytic uremic syndrome (HUS)
Adolescents and young adults with chronic kidney disease face a number of complications from their chronic kidney disease (Andreoli SP, Acute and Chronic Renal Failure in Children, 2009) including alterations in calcium and phosphate balance and renal osteodystrophy (softening of the bones, weak bones and bone pain), anemia (low blood count and lack of energy), hypertension (high blood pressure) as well as other complications.
Renal osteodystrophy (softening of the bones) is an important complication of chronic renal failure. Bone disease is nearly universal in patients with chronic renal failure; in some patients symptoms are minor to absent while others may develop bone pain, skeletal deformities and slipped epiphyses (abnormal shaped bones and abnormal hip bones) and have a propensity for fractures with minor trauma. Treatment of the bone disease associated with chronic renal failure includes control of serum phosphorus and calcium levels with restriction of phosphorus in the diet, supplementation of calcium, the need to take phosphorus binders and the need to take medications for bone disease.
Anemia (low blood cell count that leads to a lack of energy) is a very common complication of chronic renal failure. The kidneys make a hormone that tells the bone marrow to make red blood cells and this hormone is not produced in sufficient amounts in children with chronic renal failure. Thus, children with chronic renal failure gradually become anemic while their chronic renal failure is slowly progressing. The anemia of chronic renal failure is treated with human recombinant erythropoietin (a shot given under the skin one to three times a week or once every few weeks with a longer acting human recombinant erythropoietin).
Renal replacement therapy can be in the form of dialysis (peritoneal dialysis or hemodialysis) or renal transplantation. The average waiting time for a deceased donor kidney for children age 0-17 years is approximately 275-300 days while the average waiting time for patient’s age 18-44 years is approximately 700 days (United States Renal Data Systems, Table 7.8, 2005).
Following transplantation, a patient will need to take immunosuppressive medications for the remainder of his/her life to prevent rejection of the transplanted kidney. Medications used to prevent rejection have considerable side effects. Corticosteroids are commonly used following transplantation. The side effects of corticosteroids are Cushingnoid features (fat deposition around the cheeks and abdomen and back), weight gain, emotional liability, cataracts, decreased growth, osteomalacia and osteonecrosis (softening of the bones and bone pain), hypertension, acne and difficulty in controlling glucose levels.
Cyclosporine and/or tacrolimus are also commonly used as immunosuppressive medications following transplantation. Side effects of these drugs include hirsutism (increased hair growth), gum hypertrophy, interstitial fibrosis in the kidney (damage to the kidney), as well as other complications. Meclophenalate is also commonly used after transplantation (sometimes imuran is used); each of these drugs can cause a low white blood cell count and increased susceptibility to infection. Many other immunosuppressive medications and other medications (anti-hypertensive agents, anti-acids, etc.) are prescribed in the postoperative period.
Lifelong immunosuppression as used in patients with kidney transplants is associated with several complications including an increased susceptibility to infection, accelerated atherosclerosis (hardening of the arteries) and increased incidence of malignancy (cancer) and chronic rejection of the kidney.
A patient may need more than one kidney transplant during his/her life. United States Renal Data Systems (USRDS) report that the half-life (time at which 50% of the kidneys are still functioning and 50% have stopped functioning) is 10.5 years for a deceased transplant in children age 0-17 years and 15.5 years for a living related transplant in children 0-17 years. Similar data for a transplant at age 18 to 44 years is 10.1 years and 16.0 years for a deceased donor and a living related donor, respectively. Thus, depending upon age when the patient receives his/her first transplant he/she may need 1-2 transplants. The life expectancy of a person with a kidney transplant is significantly less than the general population and the life expectancy of person on dialysis a markedly less than the general population.
If and when a child needs a second kidney transplant after loss of his/her first transplant, he/she will need dialysis until a subsequent transplant can be performed. He/She can be on peritoneal dialysis or on hemodialysis. Peritoneal dialysis has been a major modality of therapy for chronic renal failure for several years. Continuous Ambulatory Peritoneal Dialysis (CAPD) and automated peritoneal dialysis also called Continuous Cycling Peritoneal Dialysis (CCPD) are the most common form of dialysis therapy used in children with chronic renal failure. In this form of dialysis, a catheter is placed in the peritoneal cavity (area around the stomach); dialysate (fluid to clean the blood) is placed into the abdomen and changed 4 to 6 times a day. Parents and adolescents are able to perform CAPD/CCPD at home. Peritonitis (infection of the fluid) is major complication of peritoneal dialysis.
E. coli O157:H7 and other shiga-toxin producing E. coli are very dangerous bacteria – especially to children. The acute phase – even for those who do not progress to hemolytic uremic syndrome (HUS) – can be a painful and frightening experience. For those who progress to HUS, the risk of death is real. And, even if the child survives, it may well be left with chronic health problems for the remainder of its life.