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-producing (Stx) E. coli (STEC).

The cascade 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. The bacteria rapidly multiply in the gut, causing inflammation and diarrhea (colitis) as they tightly bind to cells that line the large intestine. This snug attachment becomes a route for the toxin to travel from the gut into the bloodstream, where it attaches to weak receptors on white blood cells (WBCs). From there, WBCs carry the toxin to the kidneys and other organs. 

To induce toxicity in target cells, Shiga toxins must first bind to specific receptors on their surface (Gb3 receptors). Organ injury is primarily a function of Gb3 receptor location and density. They are found on epithelial, endothelial, mesangial, and glomerular cells of the kidney, as well as microvascular endothelial cells of the brain and intestine. Because this attachment causes these organs to be susceptible to the toxicity of Shiga toxins, this distribution explains the involvement of the gut, kidney, and brain in STEC-associated hemolytic uremic syndrome (HUS).[1]

Within the target organ, Shiga toxins disrupt the cellular machinery, resulting in cell injury and/or death. Within the intestine, infectious bacterial lesions cause derangements in the intestinal lining, disrupting the structure of the villi, affecting absorption in the gut, and eventually leading to watery diarrhea. Damage to the intestinal endothelium also causes mucosal/submucosal edema and, hemorrhage, introducing blood into the diarrhea.

Within the circulatory system, Shiga toxins are directly involved in platelet activation and aggregation (clot formation). The thrombotic microangiopathy that characterizes hemolytic uremic syndrome (HUS) occurs when platelet microthrombi (tiny clots) form in the walls of small blood vessels (arterioles and capillaries) causing platelet consumption. This pathologic reduction in platelets is called thrombocytopenia and is one of the hallmarks of HUS.[2]Within the microvasculature of the kidney these clots disturb blood flow to the organ, causing acute kidney injury and kidney failure.

How hemolytic uremic syndrome (HUS) causes permanent kidney damage.

The kidney is the main target organ in STEC-mediated HUS. The nephron is the functional unit of the kidney. Each kidney contains approximately 1.2 million nephrons. At the heart of each nephron is a microscopic bundle of blood vessels called the glomerulus. The glomerulus represents the initial location of the renal filtration of blood.[3] Blood enters the glomerulus through the afferent arteriole at the vascular pole, undergoes filtration in the glomerular capillaries, and exits the glomerulus through the efferent arteriole at the vascular pole.

Bowman’s capsule surrounds the glomerular capillary loops and participates in the filtration of blood from the glomerular capillaries. Bowman’s capsule also has a structural function and creates a urinary space through which filtrate can enter the nephron and pass to the proximal convoluted tubule. Liquid and solutes of the blood must pass through multiple layers to move from the glomerular capillaries into Bowman’s space to ultimately become filtrate within the nephron’s lumen. This ends the first stage in the production of urine.

In the rare event that the results of renal biopsies are known, microthrombi have been identified in the glomerular capillaries, resulting in extensive endothelial damage and, frequently, death of the nephron.[4] Severe cases develop acute cortical necrosis affecting most cells in the renal cortex. Damage to tubular cells results in electrolyte disturbances, acidosis and decreased urine production. 

As seen in other kidney diseases, in STEC-HUS patients the progression to CKD is the consequence of renal mass reduction due to the loss of nephrons during the acute stage. Hyperfiltration,[5] or abnormally elevated glomerular filtration rate (GFR), followed by significant and persistent albuminuria is the first marker of glomerular hypertension; however, it could appear several years later, especially in patients who have had a mild disease not requiring dialysis.[6]This is analogous to running a car 24 hours a day—it would be taxing on the vehicle, wearing it out faster. In the kidneys, it can lead to early nephron cell death.

Loss of the filtration units of the kidney—the nephrons—is permanent. 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. 

Studies have shown a correlation between an increased number of days of anuria (lack of urination) or oliguria (decreased urination) and worse prognosis.[7] Patients who have been anuric/oliguric and required dialysis are at the highest risk for late complications; however, even those who were not dialyzed are not spared. Research has consistently shown that these patients commonly progress to chronic kidney disease within 5 years.

Acute Kidney Injury (AKI) is the term that has recently replaced the term ARF. AKI is defined as an abrupt (within hours) decrease in kidney function, which encompasses both injury (structural damage) and impairment (loss of function).[8] There are usually no symptoms until kidney function is at least moderately to severely impaired. When present, signs and symptoms of serious kidney injury reflect reduced filter function leading to buildup of toxic wastes, and may include high blood pressure, protein in the urine, swelling of the lower extremities, loss of appetite, nausea/vomiting, sleepiness, confusion, and difficulty thinking. 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 using the creatinine value. The key is whether filter function changes over time. Since one of the primary functions of the kidneys is to 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 related to nephron loss.

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 history of HUS; they demonstrated that functional renal reserve was reduced in children with a 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 despite 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 checkups.

 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 the manuscript by Vaterrodt,, the investigators noted that in a retrospective single center study, clinical and laboratory data of the acute phase and 1-10 year follow up visits were  analyzed.   The authors conclude that although renal outcomes has improved over the investigated decades, patients with HUS still had a high risk of permanent renal damage and that these findings underline the importance of a consequent long-term follow-up in HUS patients.  

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%).

As previously mentioned some children who did not require dialysis had late complication of HUS.  One third of the children in the study by Alconcher, et. al. (Pediat Neph, 2023 evolved into CKD after a median of 5 years.  In addition CKD appeared in some patients 15 years after the acute episode.   In addition, these investigators reinforced that all non-dialyzed should be followed into adulthood.  

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 several 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 aged 0-17 years is approximately 275-300 days while the average waiting time for patient’s aged 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 aged 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 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 can 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. HUS has a mortality rate of 1-3%. And, even if the child survives, it may well be left with chronic health problems for the remainder of his/her life.

Additional Resources

[1]           Chan, Y.S., Ng, T.B. Shiga toxins: From structure and mechanism to applications. (2016). Appl Microbiol Biotechnol 100, 1597–1610.

[2]           HUS is thrombotic microangiopathy characterized by the presence of a triad of symptoms: thrombocytopenia, acute renal impairment, and microangiopathic hemolytic anemia. Bhandari, J., & Sedhai, Y. R. Hemolytic uremic syndrome (HUS). (2020). State University of New York.

[3]           Falkson SR, Bordoni B. Anatomy, Abdomen and Pelvis, Bowman Capsule. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2022. PMID: 32119361.

[4]           Renal biopsies are not routinely carried out as HUS diagnoses are usually clinically derived and patients are usually thrombocytopenic. Obrig, T. G., & Karpman, D. (2012). Shiga toxin pathogenesis: kidney complications and renal failure. Ricin and Shiga Toxins: Pathogenesis, Immunity, Vaccines and Therapeutics, 105-136.

[5]           Helal, I., Fick-Brosnahan, G. M., Reed-Gitomer, B., & Schrier, R. W. (2012). Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nature Reviews Nephrology8(5), 293-300.

[6]           Alconcher, L. F., Lucarelli, L. I., & Bronfen, S. (2023). Long-term kidney outcomes in non-dialyzed children with Shiga-toxin Escherichia coli associated hemolytic uremic syndrome. Pediatric Nephrology38(7), 2131-2136.

[7]           Pundzienė, B., Dobilienė, D., Čerkauskienė, R., Mitkienė, R., Medzevičienė, A., Darškuvienė, E., Jankauskienė, A. (2015). Long-term follow-up of children with typical hemolytic uremic syndrome. (2015). Medicina 51(3)146-151.

[8]           Makris, K., & Spanou, L. (2016). Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes. The Clinical biochemist. Reviews37(2), 85–98.