| disease | Hematuria-toxic Syndrome |
| alias | HUS, Heomlytic Uremic Syndrome |
Hemolytic uremic syndrome (HUS) is a syndrome characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. It primarily affects infants and young children, with only a few dozen cases reported domestically, mostly in school-aged children. This condition is one of the common causes of acute renal failure in children and has caused minor outbreaks in Argentina, North America, and South America. There is no specific treatment for this disease, and the mortality rate was once as high as 77%. In recent years, due to comprehensive therapies, particularly the early application of peritoneal dialysis, the mortality rate has decreased to 4.5%.
bubble_chart Etiology
This disease is divided into three major categories: primary, secondary, and recurrent.
1. Primary cases: No clear disease cause.
2. Secondary cases: Can be further classified into the following types:
(1) Infection: Currently, the most clearly identified pathogens include large intestine bacilli O157:H7, O26, O111, O113, O145, which produce verocytotoxin. Shigella dysenteriae type I can also produce this toxin, and the neuraminidase produced by pneumococci can cause glomerular and vascular endothelial injury. Other infections include cold-damage disease, Campylobacter jejuni, Yersinia, Pseudomonas pseudomallei, Pseudomonas, Bacteroides, as well as viral infections such as myxovirus, Coxsackievirus, echovirus, influenza virus, EB virus, and rickettsial infections.
(2) Secondary to certain immunodeficiency diseases, such as agammaglobulinemia and congenital thymic dysplasia.
(3) Familial inheritance: This disease follows autosomal recessive or dominant inheritance patterns and occurs within the same family or among siblings. There have been domestic reports of three siblings in the same family being affected.
(4) Drugs: Such as cyclosporine, mitomycin, and contraceptives.(5) Others: Such as cases associated with pregnancy, organ transplantation, glomerular diseases, and tumors.
3. Recurrent cases: Mainly seen in individuals with genetic predisposition or post-transplant children, but sporadic cases may also occur.
Recent studies indicate that the pathogenesis of this disease is primarily due to endothelial cell {|###|}injury{|###|} caused by various factors, with the endothelial damage induced by the spiral cell toxins produced by {|###|}large intestine{|###|} bacilli and Shigella dysenteriae type I being particularly typical. Other factors such as viral and bacterial neuraminidases, circulating antibodies, and drugs can also lead to endothelial {|###|}injury{|###|}. Human vascular endothelial cells possess glycolipid receptors (GB3) that bind to spiral cell toxins with high affinity. Mycotoxins can inhibit protein synthesis in eukaryotic cells, leading to cell death. {|###|}Injury{|###|} and death of glomerular endothelial cells can cause detachment from the glomerular basement {|###|}membrane{|###|}, forming subendothelial gaps and triggering local intravascular coagulation and fibrin deposition. This reduces the filtration area and alters the permeability of the filtration {|###|}membrane{|###|}, resulting in decreased glomerular filtration rate and acute renal failure.
Endothelial cell {|###|}injury{|###|} and exposed collagen can activate platelet adhesion and aggregation. Red blood cells passing through deposited fibrin may undergo mechanical deformation and subsequent lysis. On the other hand, von Willebrand factor (VWF), a glycoprotein present in platelets and endothelial cells, is released after cell {|###|}injury{|###|} and can accelerate platelet adhesion and aggregation. Vascular endothelial {|###|}injury{|###|} also reduces the synthesis of prostacyclin (PGI2
Neutrophil infiltration releases elastase and other proteolytic enzymes, which exacerbate endothelial cell and glomerular basement {|###|}membrane{|###|} {|###|}injury{|###|}, promote VWF cleavage, inhibit PGI2 production, and accelerate thrombosis. Additionally, in this disease, the presence of microbial lipopolysaccharides and cytokines such as interleukin I and tumor necrosis factor produced by monocytes can amplify the effects of cytotoxins, increase endothelial cell damage, and enhance blood coagulation.
bubble_chart Pathological Changes
The primary lesions are in the kidneys; in recent years, reports have indicated the presence of thrombosis and fibrinoid necrosis in the brain, adrenal glands, liver, spleen, myocardium, and intestines.
Under light microscopy, thickening of the glomerular capillary walls, luminal stenosis, thrombosis, and congestion can be observed. Staining with periodic acid-Schiff (PAS) and periodic acid-silver methenamine (PASM) reveals proliferation of fibrinoid matrix-like substances or varying degrees of splitting of the glomerular basement membrane (GBM), mesangial hyperplasia, and occasional crescent formation. In the acute phase, injury to small vessels may manifest as thrombosis and fibrinoid necrosis. During the healing process, intimal fibrous proliferation and occlusion, as well as medial fibrosis, can be seen, resembling hypertensive vascular lesions. Mild to grade III tubulointerstitial lesions may also be present.
Electron microscopy typically reveals endothelial cell proliferation, swelling, and the formation of subendothelial spaces between endothelial cells and the GBM, containing fibrinoid material and lipids, along with fusion of epithelial cell foot processes. The capillary walls are thickened, the lumens are narrowed, and fragmented or shrunken red blood cells may be seen within the lumens. Splitting of the GBM occurs due to the formation of basement membrane by endothelial cells or occasional mesangial interposition.
The aforementioned changes may be focal, but in more severe cases, widespread glomerular and vascular thrombosis with bilateral cortical necrosis can be observed. These lesions are also seen in adult cases of hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Therefore, many scholars believe that HUS and TTP represent different manifestations of the same disease. The latter typically occurs in older individuals and has a poorer prognosis.
bubble_chart Clinical Manifestations
This disease is primarily seen in infants and young children, with an average age of <18 months in South America and South Africa, and <3 years in North America. In India, about 60% of cases occur in children under 2 years old. A domestic report of 38 cases showed that 19 were aged 7–13 years. Males are predominantly affected, with no significant difference from other countries.
The prodromal symptoms are often gastroenteritis, presenting as abdominal pain, vomiting, and diarrhea, which may be bloody and closely resemble ulcerative colitis. Some cases have been reported to mimic acute abdomen. A minority of cases (about 10–15%) present with respiratory infection symptoms. The prodromal phase typically lasts 3–16 days (average 7 days). Patients without gastroenteritis prodromes have a significantly higher mortality rate.
After the prodromal phase, there is an interval of several days to weeks before acute onset, with severe manifestations such as hemolytic anemia, acute renal failure, and bleeding tendencies developing within hours. The most common complaints include melena, hematemesis, anuria, oliguria, or hematuria. The child appears pale and weak. Hypertension occurs in 30%
–60% of cases, and nearly 25% of patients develop congestive heart failure and edema. Hepatosplenomegaly is observed in 30–50% of patients, while about one-third exhibit skin petechiae and subcutaneous hematomas. Jaundice is present in 15–30% of children.
Some symptoms vary by region. For example, in India, the disease often follows dysentery, with 60% of cases presenting with fever. In Argentina and Australia, central nervous system symptoms are more common (28–52%), including drowsiness, personality changes, spasms, unconsciousness, hemiplegia, and ataxia.
The primary determinant of prognosis is the extent of kidney damage. Oliguria occurs in 86–100% of cases, and 30% of patients experience anuria (lasting 4 days to several weeks). Some infant cases exhibit only transient oliguria and urinary abnormalities. Most patients recover full renal function, though some develop chronic renal insufficiency and hypertension. Recurrence is possible in affected children, and those with recurrence have a poorer prognosis.
bubble_chart Auxiliary Examination
1. Hematological Changes Due to acute hemolysis, hemoglobin levels drop significantly, possibly to 30–50 g/L, with a marked increase in reticulocytes and elevated serum bilirubin. A characteristic feature in peripheral blood smears is abnormal red blood cell morphology, including anisocytosis, polychromasia, triangular cells, burr cells, and red cell fragments. Leukocytosis is observed in 85% of patients. Thrombocytopenia is present in 90% of cases at the onset, with an average platelet count of 75 × 109/L, which typically normalizes within 2 weeks.
2. Coagulation Factor Tests The results are closely related to the disease stage. In the early phase, prolonged prothrombin time, decreased fibrinogen, elevated fibrin degradation products, and reduced levels of coagulation factors II, VIII, IX, and X may occur, but these usually return to normal within a few days.
3. Urinalysis Varying degrees of hematuria and red cell fragments are observed, with 10% of cases showing gross hematuria. Severe hemolysis may lead to hemoglobinuria. Additionally, proteinuria, leukocytes, and casts may be present to varying degrees. Renal function tests may reveal metabolic acidosis, hyperkalemia, and azotemia of varying severity.
The diagnosis can be easily made based on the prodromal symptoms and the sudden onset of three major features: hemolytic anemia, thrombocytopenia, and acute renal failure. However, it should be differentiated from acute renal failure, glomerulonephritis, thrombocytopenia, and hemolytic anemia caused by other etiologies.
bubble_chart Treatment Measures
There is no specific treatment for this disease. The main approach is early diagnosis, timely management of water and electrolyte imbalances, prompt control of hypertension, and early initiation of peritoneal dialysis or hemodialysis.
1. Treatment of Acute Renal Failure Similar to general acute renal failure treatment (see the section on acute renal failure for details). Emphasis should be placed on strict fluid intake control, aggressive hypertension management, and appropriate intravenous hyperalimentation.
2. Indications for Dialysis: ① No urine output for 24 hours; ② Rapid rise in BUN; ③ Severe fluid overload, such as congestive heart failure or volume-dependent hypertension unresponsive to furosemide; ④ Electrolyte and acid-base imbalances unresponsive to non-dialysis therapies, e.g., serum potassium >6 mmol/L.
3. Correction of Anemia Blood transfusions should be minimized, and small amounts should be given when necessary. If hemoglobin is below 50 g/L, transfuse washed fresh red blood cells three times, 2.5–5 ml/(kg·dose), infused slowly over 2–4 hours. For bleeding caused by thrombocytopenia, platelet transfusion may be administered.
4. Anticoagulation Therapy There is currently no standardized effective treatment.
(1) Heparin Therapy: Clinically controversial. Since the fundamental pathological change in this disease is localized intravascular coagulation, it is theoretically effective. However, it should be administered early, with attention to the disease's bleeding tendency, and conducted under close monitoring (see the section on renal vein thrombosis for details).
(2) Antiplatelet Aggregation Drugs: Aspirin and dipyridamole may shorten the duration of thrombocytopenia. However, since aspirin is a cyclooxygenase inhibitor, it suppresses both prostacyclin (PGI2) and thromboxane A2 (TXA2) production. To minimize PGI2 inhibition, the dosage should be small, 1–3 mg/(kg·d). Dipyridamole dosage should be higher, 5–10 mg/(kg·d).
(3) Increasing PGI2 Levels in Blood: Some reports suggest continuous intravenous infusion of PGI2 at 30–50 ng/(kg·min), fresh frozen plasma transfusion (to restore PGI2 activity), or plasmapheresis (to replenish plasma factors stimulating PGI2 production or remove PGI2-inhibiting substances). Preliminary observations indicate a rise in platelet count, diuretic effects, and improved renal function, but further research is needed.
(4) Other Therapies: Corticosteroids are no longer used due to their procoagulant effects. Additionally, in cases of HUC caused by pneumococcus, plasma transfusion is contraindicated. Intravenous gamma-globulin therapy is also ineffective.
The outcome primarily depends on the severity of kidney involvement. In some cases, death results from nervous system damage. Patients without prodromal illness, those with relapses, and those with a family history tend to have a poor prognosis. In the 1950s, the mortality rate was as high as 40–50%. Due to improved treatment for acute renal failure, the mortality rate has decreased to around 15% in recent years, with some reports as low as 4.5%.
During the acute phase, various complications of acute renal failure may occur, such as congestive heart failure, pulmonary edema, hypertensive encephalopathy, hyperkalemia, and metabolic acidosis. In the chronic phase, chronic renal insufficiency and sequelae of nervous system damage may develop, including intellectual disability, limb paralysis, abnormal mental behavior, and epileptic seizures.
Differentiation of the disease from similar diseases
