Case Studies
Case Studies
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Below are some older articles on Atypical HUS
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HEMOLYTIC UREMIC SYNDROME - CLINICAL ASPECTS AND OUTCOME OF AN OUTBREAK: REPORT OF 28 CASES
AbdelAziz Y. Elzouki, Khalid Mirza, Ayman Mahmood, Abdul Mohsen Al-Sowailem 113
Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two main subgroups: the typical form of HUS follows a diarrheal prodrome (D+HUS) and the atypical form is without the diarrheal prodrome (D-HUS). We have studied 28 children with HUS over a period of 15 months between 1992 and 1993. The median age was 2.2 years (range from six months to six years). All children had prodromal diarrhea. Hypertension was present in 71% and neurological complications in 39%. All the patients had oliguria or anuria (16 oliguric and 12 anuric). The mean duration of anuria was 16 days (range seven to 42 days). Serum creatinine on admission ranged between 112 and 1064 µmol/L (mean 453 µmol/L). The lowest hemoglobin level and platelet count during hospitalization ranged between 38 and 87 g/L and 7 to 147x109/L respectively. Leukocytosis on admission was present in 22 patients, low C3 was documented in 11 patients (34%), and four patients had low C4. All patients received fresh frozen plasma transfusion, a total of 25 patients received dialysis therapy, 19 patients were treated with peritoneal dialysis (PD), one patient had hemodialysis (HD), and five patients had both HD and PD. The mean duration of dialysis was 18 days (range three to 56 days). Only one patient died (mortality rate 3%). The median duration of hospital stay was 28 days (range eight to 90 days). We conclude that HUS is emerging as an important clinical and public health problem and that early comprehensive management including dialysis therapy, aggressive management of hypertension, fresh frozen plasma transfusion, and nutritional support all improve the outcome and decrease the mortality and morbidity in patients with HUS.
GENERAL CASE STUDY
Hemolytic Uremic Syndrome
Hemolytic uremic syndrome (HUS) is a predominantly pediatric condition that consists of the simultaneous triad of hemolytic anemia, thrombocytopenia and acute renal failure. Although uncommon, occurring in approximately 100 children in Canada per year, it is the most common cause of acute renal failure in children and is fatal in a small percentage o children (less than 5%).1 The recent E. coli epidemic in Walkerton, Ontario and ongoing concern about coliform contamination of water supplies has resulted in discussion of HUS in the media and has raised awareness of HUS in the general public. Timely diagnosis and optimal management require physicians to be knowledgeable about this syndrome and when to suspect HUS.
HUS - Causative Factors
HUS is commonly divided into two groups; those occurring after a diarrheal illness and non-diarrheal HUS. Diarrhea associated HUS is the most common, comprising 75% of all the cases. The most common causative agent is Escherichia coli 0157:H7. Most E.coli 0157 infections result in mild diarrhea but hemorrhagic colitis can occur. HUS occurs in about 10% of children with E.coli 0157:H7 hemorrhagic colitis.1 Diarrhea associated HUS usually occurs in young children (7 months to 6 years), predominantly in summer and early fall. Sources of contamination include undercooked meat, unpasteurized milk or juice or contaminated water. It can be passed from person to person. Other bacterial diarrheal agents that can cause HUS include Shigella and Salmonellas.
Non-diarrheal HUS is more uncommon and tends to occur in older or very young children and has no seasonal predilection. It can occur after Streptococcus pneumoniae infection, malignancy or certain drugs. Some are inherited in either an autosomal dominant or recessive pattern and these patients often experience relapse, hypertension and chronic renal disease.
Pathogenesis and Pathology
HUS pathology and pathogenesis is very similar to thrombocytopenic purpura (TTP) which occurs mainly in adults. The initiating factor seems to be injury of the glomerular endothelium or, in some cases, an imbalance of platelet aggregation factors. This results in fibrin deposits and platelet clumping within the capillaries. As this process continues, the capillaries occlude resulting in decreased glomerular filtration rate and renal failure. Red blood cells traveling through the plugged capillaries are damaged causing hemolytic anemia. Platelets are used up in the clumping process and are damaged in the blood vessels resulting in decreased platelets. This is a simplistic version of the possible events that occur in the development of HUS.2
On histologic examination in the kidney of patients with HUS, changes in glomeruli vary from minimal to severe with abnormalities such as endothelial edema, degeneration of endothelium, thickening of capillary walls, thrombi and fragmented RBCs. histologic abnormalities may occur in only some glomeruli. In patients with persistent renal abnormalities years after HUS, biopsy may show glomerulosclerosis.3
Clinical Clues to Diagnosis
Most patients present with diarrhea 3-12 days before the onset of HUS. It is important to know that the diarrhea may be resolving when HUS develops. The diarrheal illness may be like viral gastroenteritis and can be watery or bloody. The child may or may not have associated cramping, vomiting or fever. The early signs of HUS may be subtle. Often the child becomes more ill, restless, and irritable. Pallor develops due to the anemia. Petechiae, purpura and oozing may occur. Oliguria is an important indicator but it is often difficult to determine on history if the child is having significant diarrhea. If renal failure is not noted and excess fluids are given, signs of fluid overload such as edema, hypertension and chest congestion can occur. The central nervous system manifestations vary considerable and can include irritability, ataxia, coma or seizures. Gastrointestinal involvement may result in infarction, intussusseption, perforation or hepatomegaly. The clinical clues are important to elicit on history and physical exam as they prompt the appropriate investigations leading to a diagnosis.
Laboratory Investigations
Initial labs should include stool culture, CBC and differential, blood smear, electrolytes, urea, creatinine and urinalysis. In a child who is unwell with gastroenteritis, a CBC, electrolytes, urea and creatinine are often obtained and these alone should provide evidence for HUS. The stool culture is important for identification of the causative organism. E.coli 0157:H7 is the most common organism found and is a reportable infection. This allows public health officials to search for the source and identify possible outbreaks. The CBC initially shows thrombocytopenia and this may be the only abnormality early in the course. Later the platelets are often <40,000, anemia is present and the WBC may be normal or elevated. Reticulocytes are high. A blood smear shows schistocytes, burr cells and helmet cells due to hemolysis. Electrolyte abnormalities include hyponatremia, hyperkalemia and acidosis. The urea and creatinine may be elevated to varying degrees depending upon the severity at presentation. Urinalysis reveals protenuria, RBCs and casts.
Other lab values which may be done include the Coomb's test which is negative, high LDH due to hemolysis, high triglycerides, low complement (C3 and C4), normal PT and PTT and increased fibrinogen degradation products. Liver enzymes may also be slightly elevated and serum protein and albumin may be decreased. These tests are not necessary for diagnosis but some may be ordered to exclude other diagnoses and others, such as TGs may be helpful in caring for patients with HUS.
Clinical Course
The duration of HUS is variable depending on the severity. In mild HUS the urine output may be normal and the renal failure mild, resolving with close observations only. More severe HUS however, can involve days to weeks of anuria and dialysis, transfusion and the possibility of complications. The usual course lasts 1-2 weeks with an initial worsening and then stabilization followed by gradual recovery. Recovery is heralded by a rise in platelets, followed by improving urine output and then resolution of the anemia.
Management
The initial management involves the management of any child with a diarrheal illness where the causative agent is unknown or is found to be E.coli 0157:H7. They should not be treated with antimotility agents as this may result in longer diarrheal course and perhaps an increased risk of HUS although this controversial.4 There is certainly no benefit to antimotility agents. Antibiotics should not be given as it has been recently shown to be associated with an increased risk of HUS.5 If you are awaiting laboratory investigations but suspect HUS it is important to avoid overhydration. In a patient with diarrhea and poor urine output, one often desires to give extra fluids but it is advisable to be cautious with fluids until laboratory values and observation allow diagnosis.
In the near future, a child with diarrheal illness due to R.coli 0157:H7 or suspicious for this bacteria may be treated with an agent that binds the toxin within the bowel to prevent HUS. One such agent, SYSNSORB Pk, has been undergoing testing but is not yet generally available. Immunization strategies are also under investigation.6
Once HUS is diagnosed, the volume status of the child is paramount. If urine output is difficult to measure given the diarrhea, a catheter may be necessary. Consultation with a pediatrician and transfer to a tertiary care center should be done when HUS is diagnosed, since renal failure and other complications may progress rapidly. The patient's weight should be accurately measured and followed closely. Other investigations such as chest X-ray or abdominal films may be necessary to look for complications. When giving fluids in a child whose urine output is decreased, the input should be equal to the urine and stool output plus insensible losses. Electrolytes must be carefully monitored and potassium should not be added to the fluids unless hypolkalemia is noted. Vital signs should be monitored frequently including blood pressure as hypertension may occur. Blood transfusions are required only with significant anemia (Hgb<70) or symptomatic anemia. The volume of blood given must be considered when elevating fluid status.
In approximately 50-75% of patients with HUS the renal failure requires treatment with peritoneal dialysis. The decision to use dialysis is made by a pediatric nephrologist and is based on the child's urine output, electrolyte abnormalities and fluid status. Peritoneal dialysis has potential complications such as infection and fluid leakage but is generally well tolerated in most patients. It allows the fluid and electrolyte balance to be maintained until the child begins to recover and renal function is restored.
Other treatments have been tried in HUS including fresh frozen plasma, plasmapharesis and intravenous immunoglobulin. None of them have been found to be helpful in diarrhea associated HUS. SOme of these treatments may be used in patients with other causes of HUS. Because of the association of HUS with outbreaks of E. Coli 0157:H7 infection, the medical officer of health should be notified.
Outcome
The majority (65-85%) of children with HUS have full recovery from the illness. It is fatal in less than 5% of children with current management. Poor prognostic factors include elevated WBCs (>20,000), anuria for greater than 8 days, age over 3 years, atypical forms of HUS, hypertension and prominent central nervous system involvement. Chronic renal insufficiency is present in a proportion of patients after HUS. For example, GFR is decreased in 15-30% of children one year after HUS.7,8 When renal blood flow is measured, an even greater percentage of children show deficits. One study looked at children 5 years after HUS and found 23% had some sequelae such as protenuria or decreased GFR.8 Long term renal function 15 to 25 years after HUS may be less favorable than previously expected for those patients with persistent renal abnormalities.9 A small number of children eventually require renal transplantation. Unfortunately, HUS may reoccur in the new kidney.
Summary
HUS is an uncommon but significant childhood illness causing hemolytic anemia, thrombocytopenia and renal failure. HUS occurs most frequently in the context of a diarrheal illness which is a common compliant in pediatrics. As a result, it is important for all physicians who treat children to be aware of the syndrome, its key features and early management. Knowledge will enable early diagnosis and optimal treatment for those affected by HUS. The more recent increase in the discovery of coliform contamination and outbreaks of E.coli 0157:H7 in areas of Canada with usually infrequent cases of HUS serves as a additional impetus to review the current understanding of HUS and its management.
- Michelle Bailey
Thanks to Dr. Robert Bortolussi, Consultant in Infectious Diseases at the IWK Grace Hospital in Halifax NS for reviewing the draft copy of this article.
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Older Studies (Cont)
ABSTRACT: Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are syndromes of microangiopathic hemolytic anemia, and thrombocytopenia in which endothelial dysfunction appears to be an important factor in the sequence of events leading to microvascular thrombosis. They are termed thrombotic microangiopathies (TMA). Differentiation of the several primary forms of TMA is crucial to predict disease outcome and to establish the most appropriate therapeutic approach. Typical verotoxin-associated HUS, mostly due to E.coli 0157:H7 infection, is associated with prodromal diarrhea followed by acute renal failure, and considered a disease with a good outcome. Antibiotics are not necessary and antimotility agents are contraindicated. No specific therapies aimed at preventing or limiting the microangiopathic process have been proved to affect the course of the disease in children. Atypic HUS covers two clinical conditions: one characterized by severe gastrointestinal prodromes, acute onset anuria, and neurological involvement, and associated to high mortality rate; the second form without diarrhea prodromes but with progressive renal function deterioration and neurological involvement that resembles TTP. Supportive therapy is required in the diarrhea-associated form, while more specific therapies are needed in the latter form. Neurological symptoms usually dominate the clinical picture of acute TTP. Infusion or exchange of fresh frozen plasma have dramatically changed the outcome of a disease that in the sixties was almost invariably fatal. Relapsing episodes of TTP are being reported increasingly often because more patients recover from the initial acute episode thanks to improved treatments. Plasma infusion has been extensively used for this form of TTP, and remission of relapsing episodes documented in most cases. Plasma-resistant HUS or TTP have invariably a poor outcome if alternative treatments are not effective. Bilateral nephrectomy may be an effective rescue therapy for patients who failed to respond to plasma. Familial HUS/TTP is a form of TMA with recessive or dominant inheritance of unknown pathogenesis. The outcome is usually poor. In summary, a general consensus has been achieved that therapies (i.e. plasma exchange or infusion) aimed at stopping the microangiopathic process should always be tried in TTP and in adult and/or atypical forms of HUS to minimize the risk of death or long-term sequela. This approach is seldom effective in secondary forms whose outcome mainly depends on the prognosis of the underlying condition, and is not risk-effective in typical childhood HUS, that usually recovers spontaneously.
KEY WORDS:Hemolytic uremic syndrome, Thrombotic thrombocytopenic purpura, Thrombotic microangiopathies, Treatment guidelines
Introduction
The term thrombotic microangiopathy (TMA) defines syndromes of microangiopathic hemolytic anemia and thrombocytopenia associated with platelet aggregation in the microcirculation (1). They encompass hemolytic uremic syndrome (HUS) (2) and thrombotic thrombocytopenic purpura (TTP) (3) that share the same histolo-gical lesions characterized by widening of the subendothelial space and intraluminal platelet thrombi (1). A similar pathophysiologic process leading to hemolytic anemia and thrombocytopenia through erythrocyte disruption and platelet consumption has also been described (1). Thus the different clinical manifestations of the disease are essentially related to the different distribution of the microangiopathic lesions, being renal dysfunction and neurological symptoms the predominant features of HUS and TTP, respectively. In both cases, fever is an aspecific sign, not always present.
Here we will describe the etiopathogenesis, the clinical course, and the management of TMA, with particular focus on the different primary forms of these syndromes.
Pathophysiology of TMA: insights from experimental studies
Endothelial dysfunction is an important step in the sequence of events leading to intravascular platelet aggregation. Consistent with this is the evidence that all proposed causative agents for TMA including bacterial endo- and exotoxins, antibodies, immunocomplexes, and certain drugs are toxic to endothelium in vitro (1). During recent years it has emerged that up to 90% of children with diarrhea-associated (D+) HUS have some evidence of VTEC infection. The O157:H7 serotype was recognised in about 70% of these patients (2). VTEC can produce two types of lysogenic-phage encoded verotoxins: verotoxin-1 and verotoxin-2, which are also known as Shiga-like toxins due to their similarity to the toxin of Shigella dysenteriae type 1 (4). Verotoxins consist of two main subunits: subunit A accounts for the cytotoxic effects while subunit B binds to specific glycolipid (Gb3) receptors on the cell surface. After binding and internalization of the toxin, the A subunit is dissociated and transferred from the Golgi apparatus to the endoplasmatic reticulum, where it is cleaved into the A1 and A2 subunits. The toxic effect is mediated through the A1 subunit that inhibits protein biosynthesis by binding to the 60s ribosomal subunit (2). After the ingestion of contaminated food or water, E.coli binds to specific receptors on the colonic mucosa, multiplies and causes cell death. This process usually leads to diarrhea, and strains capable to produce verotoxins, such as E.coli O157:H7, can produce damage of the mucosal vasculature causing hemorrhagic colitis. Once the toxin has gained access to the systemic circulation, microvascular damage may also develop at target organs, thus leading to the clinical pictures of HUS or less frequently TTP (2,5,6). Since organ localization of the disease in rabbits, given verotoxin-1, follows the organ distribution of verotoxin receptors (7), it has been suggested that the organ involvement may reflect a different, possibly age-related, distribution of these receptors in children and adults. Bacterial derived lipopolysaccharides may act synergistically with verotoxins to initiate the inflammatory reaction in target organs by inducing the local production of inflammatory mediators like TNF-* or interleukins. In particular, enhanced TNF-* production might be pivotal in the pathogenesis of vascular injury by favouring neutrophil adhesion with subsequent release of cytotoxic mediators, to the vascular wall (8,9). Of interest, verotoxin and bacterial endotoxins may synergistically induce the production of TNF-* in the kidney (10). This phenomenon may at least in part account for the almost constant kidney involvement in VTEC associated HUS. In addition increased shear stress, the tractive force generated by the blood flow on endothelial mechanosensors, increases the release of nitric oxide (NO) from endothelial cells. NO in turn stimulates the secretion of TNF-* and interleukin-1 from inflammatory cells with further activation of leukocytes. NO may also interact with O2- radicals, derived from activated neutrophils, to form other highly cytotoxic radicals, thus favouring the inflammatory reaction with further morphological damage (2,11).
Injured vascular endothelium also releases unusually large von Willebrand factor (vWF) multimers, which are stored in the Weibel-Palade bodies of endothelial cells, into the circulation. In patients with chronic relapsing TTP, these multimers are chronically released into the circulation and disappear only during acute phases of the disease. By binding to platelet receptors they contribute to the formation of microvascular thrombi (12). Increased fluid shear stress may also contribute to the release of large vWF multimers from endothelial cells and may account for an enhanced proteolysis of vWF in the damaged microvasculature (13). It has been recently documented that perfusion of long capillary tubes with normal plasma can cause a shear stress dependent vWF fragmentation with loss of the largest multimers and increase of 140 and 176 kD fragments (14), which resembles abnormal vWF fragmentation observed during acute phase of HUS and TTP (13,15). It is therefore being speculated that abnormal vWF fragmentation during acute HUS/TTP can be the consequence of increased shear stress in the damaged microcirculation and that this phenomenon may sustain platelet activation and propagation of microvascular thrombosis (13). Additionally, a reduced bioavailability of prostaglandin I2 (PGI2) (16), and of plasma tissue factor pathway inhibitor, an endogenous anticoagulant protein that belongs to the serine protease inhibitors (17), and alternatively enhanced concentrations of plasminogen activator inhibitor may all contribute to sustain the microangiopathic process by decreasing endothelial thromboresistance and stabilising microvascular thrombi (1).
Injured endothelial cells may favour platelet aggregation by releasing platelet activating factor (PAF). Other specific platelet activators like a 37 kD protein (p37) that promotes platelet aggregation independent from ADP release, energy metabolism, or the cyclooxygenase pathway, have been detected in the circulation of some patients with TTP. P37 can be inhibited by IgG from serum of normal human adults or of patients with TTP in remission. The p37 binds to a 97 kD protein, identified by GPIV-antibodies, on platelets and endothelial cells (18).
Epidemiology
The overall incidence rate of HUS, the most common cause of acute renal failure in children, is estimated to be 2.1 cases per 100000 persons/year with a peak incidence in children younger than five years of age (6.1/100.000/ year) and the lowest rate in adults 50 to 59 years old (0.5/100.000/year) (6). Of interest the incidence of the disease parallels the increasing incidence and the seasonal fluctuation of E.coli O157:H7 infections with a peak between June and September (5,19), in particular in young children and elderly persons (6). This can be taken as additional epidemiologic evidence of the cause-effect relationship between VTEC infection and HUS. E.coli O157:H7 contaminated food appears to be the most important route for the transmission of the disease. Undercooked ground beef, meat patties, roast beef, ham, turkey, cheese sandwiches, potatoes, and unpasteurized milk have all been implicated in the transmission of E.coli. In a recent outbreak in Japan about 10,000 school children had
an acute enterocolitis due to E.coli O157:H7, complicated by HUS in almost 100 cases. Identical coli genotypes were isolated from affected patients and white radish sprouts. Of note, seeds used to grow the sprouts in Yokohama and Sakei City, the center of the outbreak, were imported from the same source in Oregon. Water-born as well as person to person transmission in either sporadic cases or outbreaks have also been reported. The repeated isolation of E.coli O157:H7 from milk and feces of cattle (19) suggests that cattle are an important reservoir for this pathogen. It is estimated that following exposition to E.coli O157:H7, 38% to 61% of persons develop hemorrhagic colitis, and 2% to 7% of these patients progress to overt HUS. Of interest free verotoxin can be demonstrated in 48% of Argentinian children, while E.coli O157:H7 infection has been documented only in 2% of cases. This provides convincing evidence that verotoxin producing pathogens other than E.coli O157:H7 are an important cause of HUS in Argentina (20). E.coli O157:H7 infection has also been demonstrated in four cases of TTP preceded by hemorrhagic colitis (6).
TTP is quite a rare disease reported in about 0.4 cases per 100,000 per year, with a peak incidence in the 3rd decade and a higher prevalence in the female sex.
Clinical manifestation and course of thrombotic microangiopathies
Thrombocytopenia and hemolytic anemia are the laboratory hallmarks of thrombotic microangiopathy (Fig. 1). Thrombocytopenia is usually more severe in TTP than in HUS. At the onset of TTP platelet count may fall below 20,000 per cubic millimeter, whereas values in between 30,000 and 100,000 per cubic millimeter are most commonly reported in HUS, with even normal or near-normal values in occasional cases. Anemia is usually severe with hemoglobin concentration below 10g/100ml. The increase in lactate dehydrogenase (LDH) is the most sensitive index of the ongoing hemolysis, and is usually associated with hyperbilirubinemia (mainly indirect), reticulocytosis, circulating free hemoglobin, and low or undetectable haptoglobin levels. Increased LDH level is, however, an aspecific marker of intravascular hemolysis and may also reflect tissue infarction, for instance of the kidney or the lung (21). Thus, detection of fragmented red blood cells (schistocytes) with the typical aspect of burr or helmet cells in the peripheral smear together with a negative Coombs test is needed to confirm the microangiopathic nature of the hemolysis. Classic HUS is often associated with leukocytosis with a left shift (22), whereas white cell count is usually normal in atypical HUS and TTP. Prothrombin time, partial thromboplastin time (PTT), factor V, Factor VIII, and fibrinogen are normal in most cases. Occasionally patients may have high levels of fibrin degradation products and prolonged thrombin time. Intravascular platelet aggregation results in reduced platelet survival and determines the thrombotic occlusion of small arterioles and capillaries.
Fig. 1 - A proposed algorithm for differential diagnosis of thrombotic microangiopathies. Patients with suggestive symptoms should be investigated for the presence of specific signs of microangiopathic hemolysis. In all adult cases a predisposing condition should be investigated to rule out secondary forms of the disease. A prompt and correct differential diagnosis may help predict disease outcome and establish the most appropriate therapy. Specific therapies should be considered only in adults or in atypical forms. In secondary forms, any effort should be aimed to treat the underlying condition.
The characteristic histologic lesion of HUS and TTP consists of vessel wall thickening (capillaries and arterioles), with swelling and detachment of the endothelial cells from the basement membrane and accumulation of fluffy material in the subendothelium (23). These changes are virtually identical and often undistinguishable from the microvascular lesions of scleroderma and malignant hypertension. In HUS, the microthrombi are confined primarily to the kidneys, and thus renal failure is the dominant feature. TTP mainly involves the brain and intravascular thrombi apparently form and disperse repeatedly, producing intermittent neurological signs. In pediatric patients, particularly in children younger than 2 years of age and in most cases of typical HUS, a pattern of glomerular injury prevails (24). In older children as in adults, the renal changes are located predominantly in arteries and arterioles with glomerular ischemia, retraction of the glomerular tuft, and thickening of the capillary wall (25,26). Prognosis is good in patients with predominantly glomerular changes, but is much more severe in those with primarily vascular damage.
Differentiation of the different primary forms of TMA is crucial to predict disease outcome and to establish the most appropriate therapeutic approach. To this purpose, TMA is classified as typical (verotoxin-associated) and atypical HUS, acute and chronic/relapsing TTP, plasma-resistant HUS/TTP, and familial HUS/TTP (Tab. 1).
Hemolytic Uremic Syndrome - Typical, verotoxin - associated
- Atypical
- Plasma resistant
Thrombotic Thrombocytopenic Purpura - Acute
- Chronic relapsing
- Plasma resistant
Familial Forms
Secondary Forms - Pregnancy- associated - TTP
- Severe pre-eclampsia/HELLP Syndrome
- Post-partum HUS
- HIV infection - associated
- Systemic disease - associated - Systemic lupus erythematosus, scleroderma
- Antiphospholipid syndrome
- Malignant hypertension
- Cancer- and chemiotherapy - associated
- Transplant- and cyclosporine - associated
Table I - Classification of HUS/TTP
Typical verotoxin-associated HUS
Typical (epidemic) HUS - mostly due to E.coli 0157:H7 infection (2) - is associated with prodromal diarrhea followed by acute renal failure, and is also referred to as D+HUS (27,28). D+HUS is usually considered a disease with a good outcome, with complete recovery in about 90% of cases. However, 3% to 5% of patients die during the acute phase (29), up to 5% are left with severe renal and extra-renal sequelae, and about 40% will still have low GFR at ten-year follow-up. Age under two years, severe gastrointestinal prodromes, elevated white cell count, and anuria early in the course of the disease are predictors of the severity of HUS. Anuria for more than ten days or need for dialysis in the acute phase, as well as proteinuria at 12 months follow-up have been associated with an increased risk of chronic renal failure in the long term (30). Patched cortical necrosis or involvement of more than 50% of glomeruli are further predictors of poor outcome.
Diagnosis rests on detection of E. coli 0157:H7 in stool cultures. Serologic tests for antibodies to verotoxin and O157 lipopolysaccharide can be done in research laboratories and tests are being developed for rapid detection of E. coli O157:H7 and shiga-like toxin in stools.
Undercooked ground beef is the commonest source of infection, but ham, turkey, cheese, unpasteurized milk, and water have also been implicated. Secondary person-to-person contact is an important way of spread in institutional centers, particularly day-care centers and nursing homes. Infected patients should be excluded from day-care centers until two consecutive stool cultures are negative for E. coli O157:H7 in order to prevent further transmission. However, the most important preventive measure in child-care centers is supervised hand-washing.
Atypical HUS
Atypical HUS is a general term currently used to define forms with a clinical course different from that of D+HUS (2, 31, 32). Atypical forms can be covered under two clinical pathways, one including forms with severe gastrointestinal prodromes, acute onset anuria, and malignant hypertension. These forms have a high mortality rate due to severe gastrointestinal or neurological involvement (33). Renal function fails to recover in about 50% of these cases (34). The second includes forms without diarrheal prodromes (non-diarrhea-associated HUS) but with progressive renal function deterioration, and neurological involvement that may resemble TTP (6). These forms may be familial and mostly follow a relapsing or progressive course to end-stage renal failure or death.
Acute TTP
About 90% of patients with TTP present with an abrupt onset of neurological signs, purpura and fever (3). Neurological symptoms usually dominate the clinical picture and may be fleeting and fluctuating, probably because of continuous thrombi formation and dispersion in the brain microcirculation. However, they usually subside within 48 hours of effective therapy. In the early sixties, acute TTP was almost invariably fatal, but nowadays, thanks to earlier diagnosis, improved intensive care facilities and new techniques such as plasma therapy, survival may reach 90%
(35, 36).
Chronic/relapsing TTP
Relapsing episodes of TTP are separated by a period of four weeks or more of apparent recovery and must be distinguished from recurrences of acute TTP, that are actually flare-ups of the same initial episode, usually because of stopping treatment too soon (37,38). This once rare form of TTP is being reported increasingly often - in up to 30% of cases in some institutions -, as more patients recover from the initial acute episode thanks to improved supportive and specific treatments. Relapses may occur even after symptom-free periods of months or years and sometimes spontaneous remissions have been reported (37,38). Although individual attacks usually respond to treatment, long-term prognosis is normally poor. Relapsing forms of thrombotic microangiopathy have also been reported in children, but with the clinical features of HUS (39).
An extremely rare variant of relapsing TTP is characterized by frequent episodes, recurring after regular symptom-free intervals. This form, also known as "chronic relapsing" or "frequently relapsing" TTP, is associated with persistency of abnormally large vWF multimers in the circulation
(12, 39). The long-term outcome is invariably poor if therapy fails to achieve long-lasting remission (2, 3).
Plasma-resistant HUS/TTP
Occasional patients with HUS or TTP fail to respond to plasma therapy and invariably have a poor outcome if alternative treatments are not effective.
Familial HUS/TTP
This is a form of TMA with a heterogeneous pattern of inheritance (recessive or dominant), that within each family resembles HUS or TTP or, less commonly, one or the other forms of TMA (2). The pathogenesis is unknown. However, finding that either HUS and TTP may occur in the same family or even in the same subject with different relapses, strongly corroborates the hypothesis that both syndromes are sustained by a similar pathogenetic mechanism. Decreased factor H bioavailability and low C3 complement fraction have been occasionally reported in familial HUS or TTP (40-43). Genetic counseling is important if further pregnancies are planned. Unfortunately, no markers are available to identify the heterozygous state or for antenatal
diagnosis by amniocentesis or chorionic villus biopsy. The outcome is usually poor with death or chronic renal failure being reported in 50% to 100% of cases.
Treatment guidelines for the different forms of TMA
Specific therapies aim to prevent or limit the cascade of events which ultimately causes intravascular thrombosis and tissue injury. However, the mechanisms accounting for the potentially beneficial effect of certain therapies are poorly understood. Plasma infusion and exchange are usually employed with the rationale of restoring a component which is missing in patient's plasma, possibly an enzyme that by modulating protease(s) activity in vWF handling may prevent abnormal fragmentation of the molecule during the acute phase of the disease (44). Steroids and immunosuppressants may limit or prevent the formation of autoantibodies or immunocomplexes which could in theory trigger endothelial injury in idiopathic forms of TMA, prostacyclin and antiplatelet agents may reduce the platelet interaction with the vascular wall, thus limiting microvascular thrombi.
Guidelines to therapy according to disease manifestation are the following (suggested indications are given in Tab. II and III).
Treatment Administration Indication-Comment
Treatment of acute renal failure - Peritoneal dialysis Continuous, 24 hour per day HUS
Well tolerated, may remove plasminogen activator inhibitor I
Verotoxin adsorption - Chromosorb Oral - 0.5 g per kg body weight, x 7 days HUS
HUS. May limit verotoxin absorption and microangiopathic lesions
Under clinical investigation
Antiplatelet agents TTP
- Aspirin Oral - 325-1,300 mg /day Unproven efficacy
- Dipyridamole Oral - 400-600 mg/day Unproven efficacy
- Dextran 70 Intravenous - 500 mg twice/day Unproven efficacy
- Prostacyclin Intravenous - 4-20 mg/kg/min Beneficial in occasional cases
May cause hypotension and worsen diarrhea
Antithrombotic agents HUS HUS
- Heparin Intravenous - 5000 U Some benefit suggested in post-partum HUS, increased risk of bleeding
Intravenous- 750-1,000 U/hour
- Streptokinase Intravenous - 250,000 U Unproven effectiveness. Should be avoided because of the high risk of hemorrhagic complications
Intravenous - 100,000 U/hour
Steroids/vincristine TTP
- Prednisone Oral - 60-200 mg/day, tapered by 5 mg/week Possibly effective in mild forms
- Vincristine Intravenous - 1 mg/4-7days x 5 Possibly effective in relapsing forms. Unproven effectiveness in acute and plasma resistant forms
Neurologic toxicity
Atypical / adult HUS, TTP
- Infusion 30-40 ml/kg on day 1, then 10-20 ml/kg/day Probably effective in atypical and adult forms, and in cases associated with neurological signs
- Exchange 1-2plasma volumes/day The same indications of plasma infusion
No risk of fluid overload
- Cryosupernatant see plasma infusion/exchange Occasionally effective in cases resistant to whole plasma
- Solvent detergent treated see plasma infusion/exchange May limit the risk of viral contamination
Other treatments - Vitamin E Oral - 1000 mg/sqm/day HUS. Safe. Probably effective in typical HUS
To be tested in controlled trials
- Gamma globulins Intravenous - 400 mg/kg/day HUS or TTP. Unproven efficacy
Rescue therapies - Splenectomy Occasionally effective in relapsing TTP Unproven effficacy in plasma resistant TTP
- Bilateral nephrectomy Effective in plasma resistant HUS
Table II - Treatments most commonly used in HUS/TTP, doses and modalities of administration
Disease Comment
Typical childhood HUS NO (usually complete spontaneous recovery)
Atypical childhood HUS Probably YES (to minimize the risk of sequelae)
Adult HUS YES (to minimize sequelae)
TTP (Acute and relapsing forms) YES (life-saving)
Familiar HUS / TTP Probably YES (but often ineffective)
Secondary TMA - pregnancy associated TTP YES (life saving )
HELLP syndrome Probably YES (in selected cases and after delivery)
post partum HUS Probably YES (but often ineffective)
- HIV associated HIV infection Probably YES (may be life saving)
AIDS Probably NO (usually ineffective)
- cancer associated mitomycin Probably YES (with drug withdrawal)
metastatic disease Probably NO (usually ineffective)
- transplant associated cyclosporin Probably YES (with drug reduction or withdrawal)
disease recurrency Probably YES (but often ineffective)
Table III - Indication to plasma infusion/exchange in the different forms of HUS/TTP
Typical verotoxin-associated HUS
Bowel rest is important for the enterohemorrhagic colitis associated with D+HUS, together with careful control of fluid balance, to avoid overhydration particularly in cases with oligo-anuria (2,44). Blood transfusions may be required for symptomatic anemia secondary to microangiopathic hemolysis. Dialysis, together with appropriate correction of fluid and electrolyte abnormalities and anemia, has played a major role in the overall reduction in mortality rate over the last 40 years. Antibiotics are not necessary and sulphametoxazole-trimethoprim may even increase toxin production (2). Antimotility agents are contraindicated as well, since they enhance the risk of HUS in patients with bloody diarrhea and E. coli O157:H7 infection, and increase the severity of neurological manifestations in patients with overt HUS. Specific therapies aimed at preventing target organ exposition to verotoxin including orally administered toxin-binding resins and active or passive immunization, are currently under investigation (45). A variety of specific oligosaccharides have been attached to inert carrier agents in an effort to bind pathogenic toxins within the lumen of the gastrointestinal tract. Chromosorb is an inert platform molecule - diatomaceous silicon dioxide - that is chemically linked to an oligosaccharide chain specifically tailored to maximize binding of individual enteric toxins. Thus, chromosorb neutralizes the biological activity of toxin A in stool samples and prevents injury to cultured cells. Its effectiveness in vivo is under investigation in two ongoing clinical trials aimed to test whether chromosorb prevents the occurrence of HUS in children with E. coli associated hemorrhagic colitis or, respectively, may limit the severity of acute renal failure and of extra-renal complications in patients with newly diagnosed HUS.
No specific therapy aimed at preventing or limiting the microangiopathic process has been proved to affect the course of D+HUS in children. Two prospective controlled trials found that plasma therapy may limit short-term renal lesions, but does not affect long-term renal outcome and patients' survival (46,47). Steroids should be avoided because may increase the risk of colonic perforation in patients with active colitis. Heparin and antithrombotic agents may increase the risk of bleeding and should be avoided. Whether tissue-type plasminogen activator (t-PA), discriminating between fibrin and fibrin-bound plasminogen, gives a better risk/benefit profile in the treatment of HUS is worth investigating.
Atypical HUS
The outcome of severe forms of typical HUS (often described after verotoxin producing E. coli (VTEC) infection) depends mainly on the quality of supportive therapy and on the possibility (under investigation) of limiting the consequences of infection, as reported for therapy of typical HUS.
Non-diarrhea associated HUS very likely constitutes a form of the disease that is closer to TTP and may require more specific therapies to stop the progression of the microangiopathic process (see therapy of Acute TTP). These atypical cases recur more often after kidney transplantation (48). Plasma infusion and exchange have been retrospectively found to limit residual renal insufficiency or the risk of end-stage renal failure in children with atypical HUS (49). Uncontrolled studies suggest that plasma infusion or exchange may remarkably lower the mortality rate and risk of end-stage renal failure in adults (1-3). However, plasma, either infused or exchanged, is contraindicated in patients with Streptococcus pneumonia HUS, since adult plasma contains antibodies against the Thomsen-Friedenreich antigen, that may accelerate polyagglutination and hemolysis (2). These patients should be treated with antibiotics and washed red blood cells. Whole blood or plasma should be avoided. Prostacyclin infusion has been attempted with the aim of correcting the reported deficit and controlling hypertension, but its utility has yet to be proved. Intravenous immunoglobulins have been suggested, to limit neurological involvement in atypical HUS, but their effectiveness too is still unproven.
Acute TTP
A general consensus credits the use of plasma infusion or plasma exchange in the therapy of acute TTP. A randomized trial (36) found an apparent superiority of plasma exchange over plasma infusion in the treatment of TTP. However, patients undergoing the exchange procedure were given three times the amount of plasma given to patients who received infusion alone. When equivalent volumes of plasma were given during plasma infusion or exchange, no difference in response rate or survival could be documented (3). Thus, plasma infusion and exchange may be equally effective in the treatment of acute TTP. However, in situations such as renal insufficiency or heart failure, that limit the amount of plasma that can be provided with infusion alone, plasma exchange should be considered as first choice therapy. Initial plasma infusion should be considered whenever plasma exchange is not readily available. Plasma infusion may also be considered as maintenance therapy after recovery has been achieved with plasma exchange. Occasional patients appear to require large amounts of plasma and several months of infusion or exchange before achieving remission. Thus, even in cases who fail to respond promptly to initial therapy, intensive plasma therapy may eventually succeed in inducing remission of the disease.
Treatments given in addition to plasma did not provide any benefit in terms of shorter illness duration, lower mortality, or fewer long-term sequelae (1,3). Antiplatelet drugs were almost invariably used in combination with steroids, plasma manipulation and/or splenectomy.
In the few studies in which antiplatelets were given alone, the response was less than 15% (1). The finding that patients treated with steroids and plasma, combined (36) or not (35) with antiplatelet drugs, had the same high survival rate, suggests that these agents are of little help in TTP. The effectiveness of prostacyclin is also unproven. In view of the risk of severe bleeding, antiplatelet agents, are best avoided in the acute phase of TTP. One of these agents, ticlopidine, has even been accused as a possible trigger of TTP. Antiplatelet agents have sometimes been recommended during the recovery phase since thrombocytosis may enhance platelet aggregation and the risk of potentially fatal relapses (50).
Patients with TTP have also been given corticosteroids on the assumption that it is an auto-immune disorder, but their effectiveness is difficult to prove since the steroids were always given in combination with other therapies. Thirty out of 108 patients with either TTP or HUS were recently reported to have recovered after treatment with corticosteroids alone. All of them, however, had mild forms (35). Anecdotal cases have been reported to respond to vincristine, sometimes when other treatment modalities failed (3,51). How-ever, these cases are too few to conclude that vincristine should be used as first-line therapy in acute TTP. Evidence that immunoglobulins inhibit in vitro platelet-aggregating activity of plasma from patients with acute TTP has led to some recommendations to use them to treat this disease. However, their effectiveness too is unproven.
Splenectomy was commonly used to treat acute TTP before plasma therapy was available, but it is no longer considered as first line therapy for acute TTP (3).
Moreover, the severe thrombocytopenia in TTP has led many physicians to administer platelet transfusions with the aim of preventing severe bleeding complications (3). However, reports of sudden death, decreased survival and delayed recovery after platelet transfusion dramatically document the danger of giving platelets to patients with TTP. Thus, platelet transfusions are contraindicated in acute TTP, sole except in cases of life-threatening bleeding.
Chronic/relapsing TTP
Plasma infusion has been extensively used for relapsing and chronic TTP and has been reported to induce remission of relapsing episodes in most cases. One patient of ours with chronic relapsing TTP provided evidence that at least in these relapsing cases effective treatment depended on infusing a certain amount of normal plasma (39). This patient, who had more than 100 relapses over seven years, was given different forms of treatment on different occasions: exchange, plasma infusion alone, or plasma removed and replaced with albumin and saline. Clinical remission and normalization of platelet count within a few days was invariably obtained by plasma exchange or infusion, but plasma removal never raised the platelet count. Thus, plasma infusion is now an established first-line treatment for relapsing episodes of TTP.
Vincristine has been reported to stop cyclic relapses of TTP in isolated cases, but its effectiveness in chronic relapsing TTP is unproven (3,51). Two cases of chronic relapsing TTP were reported to respond to cyclophosphamide and one to azathioprine. Interestingly, the response to azathioprine was associated with the disappearance of the unusually large vWF multimers from the circulation (3).
Also splenectomy might work by removing a major site of synthesis of an autoantibody or a vWF cofactor. Preliminary evidence is available that elective splenectomy during hematologic remission reduces the relapse rate and the need for plasma therapy in patients who have had one or more relapses of TTP (52). Thus, splenectomy could be considered in those patients with disabling disease requiring frequent and prolonged courses of plasma therapy.
Plasma-resistant HUS/TTP
Substitution of cryosupernatant fraction (i.e. plasma from which a cryoprecipitate containing the largest plasma vWF multimers, fibrinogen, and fibronectin, has been removed) for fresh frozen plasma has been successful in a small number of patients who did not respond to repeated exchanges or infusions with fresh frozen plasma (53). The rationale for this approach is that plasma cryosupernatant may provide the same beneficial factor(s) found in whole plasma, but does not contain the potentially harmful factors (including large vWF multimers) that might participate in the formation of intravascular thrombi.
Splenectomy is no longer considered for treating TTP refractory to plasma therapy. Indeed a deterioration of clinical status with a decrease in hematocrit and platelet count and high serum lactate dehydrogenase was reported in six patients undergoing splenectomy because of refractoriness to cortico-steroids and plasma exchange: four patients became comatose and one died abruptly (36). The five surviving patients progressively recovered after the reinstitution of plasma exchange. A recent study showed a higher mortality rate and longer disease duration in 13 patients undergoing splenectomy compared to 39 patients continuing on plasma therapy (38). Although this study was far from conclusive an account of its retrospective design, the role of splenectomy in plasma resistant TTP has to be carefully reconsidered unless new data become available to support its use (3).
When remission cannot be achieved by plasma therapy, atypical HUS invariably progresses to end-stage renal failure and disease activity normally subsides once renal function is irreversibly lost (2). In rare instances, however, persistent thrombocytopenia associated with severe refractory hypertension and signs of hypertensive encephalopathy may put the patient in imminent danger of death. In such dramatic cases bilateral nephrectomy was followed within two weeks by complete hematologic and clinical remission (13). The rationale of the procedure rests on evidence that removing the kidneys eliminates a major site of vWF fragmentation, which would limit platelet activation and protect patients from the further spreading of microvascular lesions (13). However, bilateral nephrectomy is irreversible and should be considered only for patients in whom all other approaches have failed. Potential candidates are patients who are plasma-resistant (defined as >20 procedures with no improvement of clinical and laboratory findings) or plasma-dependent (patients who have to be continuously infused with plasma to remain in remission, and in whom the platelet count invariably drops, with signs of hemolysis, within a few days after plasma is discontinued). Nephrectomy should not be considered unless a renal biopsy - taken as soon as the platelet count rises, even transiently with plasma to a level where the procedure is safe - shows chronic diffuse lesions associated with signs of the disease, meaning arteriolar thrombosis and myointimal proliferation. Finally, nephrectomy should be considered only in the presence of life-threatening signs such as major neurological dysfunction or coma, or uncontrolled bleeding as a consequence of refractory thrombocytopenia.
Familial HUS/TTP
No specific therapy is available. Plasma therapy is usually recommended, but its effectiveness is limited.
Clinical course, outcome, and management of secondary forms of TMA
Secondary forms of TMA represent distinct entities whose outcome and treatment is strongly dependent on the underlying condition. When this can be removed or treated, the microangiopathic process subsides too. Underlying diseases that do not respond to treatment are almost invariably associated with a poor outcome and TMA may be the final complication.
Pregnancy-associated TMA
TMA in pregnancy may manifest with the clinical features of acute TTP, of the hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome, or of HUS (54). Differential diagnosis between these conditions may serve to establish the most appropriate therapeutic approach.
TTP develops during the antepartum period in 89% of cases, usually within 24 weeks. Later in the course of pregnancy, clinical features of TTP and preeclampsia may overlap. Despite limited experience, available series show that the maternal mortality rate has fallen from 68% to almost zero with the institution of plasma therapy (54). Delivery is recommended only for those patients who do not respond to plasma therapy. However, delivery is the treatment of choice for preeclampsia/ HELLP syndrome. Measurement of plasma antithrombin (AT) III activity has been suggested as a useful tool to differentiate TTP and preeclampsia. Before gestational week 28 and when AT III plasma activity is normal, TTP is most likely. Plasma therapy could be tried and, if effective, it should be continued until term and/or complete remission of the disease. Delivery can be considered as "rescue" after failure of plasma therapy. The role of other treatments often employed in idiopathic TTP remains elusive. After week 34 of gestation, preeclampsia is most likely and is usually associated with decreased plasma AT III activity. Delivery is the treatment of choice and is usually followed by complete recovery within 24-48 hours. Persistent disease may be an indication to attempt a course of plasma therapy. Between 28 and 34 weeks, the optimal treatment is controversial. It is sometimes held that delivery should always be considered as first-line therapy whereas others believe that, if there is no evidence of fetal distress and plasma AT III activity is normal, a course of plasma therapy can be reasonably attempted before inducing delivery (1,3).
The HELLP (an acronym for hemolysis, elevated liver enzymes and low platelet count) syndrome is simply a form of severe preeclampsia in which besides hypertension and renal dysfunction, there is evidence of microangiopathic hemolysis and liver involvement (54). The syndrome is most common in white multiparous women with a history of poor pregnancy outcome. It arises in the antepartum period in 70% of cases. Postpartum, symptoms usually arise within 24-48 hours from delivery, occasionally after an uncomplicated pregnancy (54). Diagnosis is based on: 1) hemolysis (defined as fragmented erythrocytes in the circulation and lactic dehydrogenase >= 600 U/L), 2) elevated liver enzymes (serum glutamic oxaloacetic transaminase >70 U/L), and 3) low platelets (platelet count <100x103/mm3) (54). Overt disseminated intravascular coagulation (DIC) is reported in 25% of cases (55). Intrahepatic hemorrhage, subcapsular liver hematoma, and liver rupture are rare, life-threatening complications. The maternal and perinatal mortality rates range from 0% to 24% and from 7.7% to 60%, respectively. Most of the perinatal deaths are related to abruptio placentae, intrauterine asphyxia, and extreme prematurity. As many as 44% of the infants are growth-retarded. Termination of pregnancy is the only definitive therapy. Hydralazine or dihydralazine are the first-choice drugs to control pregnancy-induced hypertension, magnesium sulfate to prevent and treat convulsions. Both peritoneal dialysis and hemodialysis have been used to treat acute renal failure. Platelet transfusions are needed for clinical bleeding or severe thrombocytopenia (platelet count <20,000/µl). In approximately 5% of patients with HELLP syndrome, symptoms and laboratory abnormalities do not improve after delivery. These are cases with central nervous system abnormalities, associated with renal and cardiopulmonary dysfunction and activation of coagulation. Uncontrolled studies suggest that plasma exchange may help recovery in patients with persistent evidence of disease 72 hours or more after delivery. However, plasma therapy is ineffective during pregnancy and may increase fetal and maternal risk when used to delay delivery. Preliminary evidence suggests that, postpartum, corticosteroids may speed up disease recovery and, antepartum, may postpone delivery of previable fetuses and reduce the mother's need for blood products (3).
Postpartum HUS, by definition, follows a normal delivery by no more than six months (2). The clinical course is usually fulminant. Supportive care including dialysis, transfusions, and careful fluid management remains the most important form of treatment. Whether plasma therapy improves survival or limits renal sequelae has not been established so far. Antiplatelet agents, heparin and antithrombotic therapy may enhance the risk of bleeding and have no proven efficacy.
HIV-associated TMA
HUS and TTP are both among the complications of AIDS, which may account for as much as 30% of hospitalized HUS/TTP cases in some clinical settings. Plasma manipulation appears the only feasible approach (3). Uncontrolled series provide evidence that the survival rate in HIV patients without AIDS is comparable to that of idiopathic TTP. By contrast, patients with AIDS-associated TTP almost invariably have a poor outcome and do not appear to benefit from plasma therapy (3).
Cancer- and chemotherapy-associated TMA
TMA complicates almost 6% of cases of metastatic carcinoma. The prognosis is extremely poor and most patients die within a few weeks. A form of TMA resembling HUS has been described in 2 to 10% of cancer patients treated with mitomycin, particularly among those receiving cumulative doses of 60 mg or higher, or more than one course of therapy (56). Platinum- and bleomycin-containing combinations have also been reported to induce HUS (57). The median time to death is about four weeks. Patients surviving the acute phase often remain on chronic dialysis, or die later of recurrence of the tumor or metastases. Therapy is minimally effective. Administration of blood products to correct symptomatic anemia often results in exacerbation of the syndrome, with rapid worsening of hemolysis, deterioration of renal function, and pulmonary edema. The possibility to prevent the syndrome by giving steroids during mitomycin treatment has been suggested and needs to be confirmed in prospective controlled trials. Plasma exchange or perfusion over filters containing staphylococcal protein A have been attempted with the rationale of removing circulating immunocomplexes, but their effectiveness is unproven (44).
Transplant-associated TMA
Kidney transplantation is the treatment of choice for patients with HUS who develop end stage renal failure. From an overview of the published literature, it can be estimated that the overall risk of recurrence of HUS after a cadaveric kidney transplant is about 13%, with no differences attributable to cyclosporine (3). A 30% recurrence rate can instead be reasonably estimated in patients given a living transplant, at least on the basis of the scant available data. The reasons for this difference are not known. It has been pointed out that the risk of recurrence is higher in patients with recurrent and familial forms of HUS, and negligible in children with the typical form. A recurrence rate of 67% was reported among 18 children with atypical HUS and 17% in six children with typical D+HUS has been reported (48).
The outcome of post-transplant HUS is poor, with a five year graft failure rate of 63% in one series (58). In 25 children with end stage renal failure secondary to HUS, one- and five- year graft survival was 66% and 37% compared to 80% and 69% in all other pediatric recipients. In this series no recurrence of HUS was reported and the high graft loss was apparently due to an excess of chronic vascular rejection. The consistency of this evidence is however hard to establish because of the difficulties in differentiating vascular rejection and recurrent HUS (3,48). Early diagnosis and discontinuation of cyclosporine has occasionally led to reversal of the syndrome. However, using the newer immunosuppressive agents derived from fungal peptides, such as FK 506, instead of cyclosporine is not effective. Uncontrolled studies suggest that intravenous immunoglobulin infusion may permit successful management of HUS/TTP without graft loss. These findings however, need confirmation in controlled studies.
HUS may also ensue the novo in patients receiving a kidney transplant because of terminal renal failure due to diseases different from HUS. An immunological trigger has been hypothesized in some cases complicating acute vascular rejection. Whether cyclosporine or FK506 may have an independent pathogenetic role is controversial (44). TMA that complicates bone marrow transplantation is probably sustained by vascular injury caused by pre-transplant irradiation, chemotherapy, graft versus host disease and, possibly, concomitant Cytomegalovirus infection or high dose cyclosporine/FK506 therapy.
In conclusion, a general consensus has been achieved that therapies (i.e. plasma exchange or infusion) aimed at stopping the microangiopathic process should always be tried in TTP and in adult and/or atypical forms of HUS to minimize the risk of death or long-term sequelae. By contrast, this approach is seldom effective in secondary forms whose outcome mainly depend on the prognosis of the underlying condition and is not risk-effective in typical childhood HUS, that usually recovers spontaneously. Whenever indicated, specific therapy should be started as soon as diagnosis is established in order to speed up disease recovery and minimize the risk of sequelae. Treatment should be continued until complete disease remission is achieved.
Reprint requests to: Giuseppe Remuzzi, M.D. Mario Negri Institute for Pharmacological Research Via Gavazzeni 11 24125 Bergamo - Italy
References
1. Remuzzi G, Ruggenenti P., Bertani T. Thrombotic microangiopathies. In: Tisher CC, Brenner BM,eds. Renal Pathology, 2nd Ed. Philadelphia: J.B. Lippincott, 1994: 1154-84.
2. Remuzzi G, Ruggenenti P. The hemolytic uremic syndrome. Kidney Int 1995; 47: 2-19.
3. Ruggenenti P, Remuzzi G. The pathophysiology and management of thrombotic thrombocytopenic purpura. Eur J Haematol 1996; 56: 191-207.
4. O'Brien AD, Lively TA, Chen ME, Rothman S, Formal FB. Escherichia Coli O157:H7 strains associated with haemorrhagic colitis in the United States produce a shigella dyssenteriae I(Shiga) like cytotoxin. Lancet 1983; 1: 702.
5. Boyce TG, Swerdlow DL, Griffin PM. Escherichia coli O157:H7 and the hemolytic uremic syndrome. N Engl J Med 1995; 333: 364-8.
6. Su C, Brandt LJ. Escherichia coli O157:H7 infection in humans. Ann Intern Med 1995; 123: 698-714.
7. Zoja C, Corna D, Farina C, Sacchi G, Lingwood C, Doyle MP, Padhye VV,Abbate M, Remuzzi G. Verotoxin glycolipid receptors determine the localization of microagiopathic process in rabbits given verotoxin-1. J Lab Clin Med 1992; 120: 229-38.
8. Louise CB, Obrig TG. Shiga toxin-associated hemolytic uremic syndrome: Combined cytotoxic effects of Shiga toxin, interleukin-1ß, and tumor necrosis factor alpha on human vascular endothelial cells in vitro. Infect Immun 1991; 59: 4173-9.
9. Zoja C, Morigi M, Foppolo M, Figliuzzi M, Gallego MJ, Karmali MA, Remuzzi. Verotoxin-1 (VT-1) increases leukocyte adhesion to endothelial cells under dynamic flow conditions.VTEC 94, 2nd International Symposium and Workshop on 'Verocytotoxin (Shiga-like toxin)- producing Escherichia coli infections' June 27-30, 1994 Seminario Vescovile "Giovanni XXIII" Bergamo, Italy, 33,1994 (abstract)
10. Harel Y, Silva M, Giroir B, Weinberg A, Clearly TB, Beutler B. A reporter transgene indicates renal-specific induction of tumor necrosis factor (TNF) by Shiga-like toxin. J Clin Invest 1993; 92: 2110-6.
