Indian Pediatrics 2002; 39:162-167
Atypical Hemolytic Uremic Syndrome
Hemolytic Uremic Syndrome (HUS) is one of the important causes of acute renal failure in children. It consists of a triad of acute renal failure, microangiopathic hemo-lytic anemia and thrombocytopenia. Two principal subgroups have been identified in children(1), namely typical cases with a diarrheal prodrome (sudden onset in young children and good prognosis) and atypical cases with an insidious onset (no antecedent diarrhea and worse prognosis). The atypical HUS subgroup is itself heterogenous with incomplete recovery in most patients(2). In this article, we present four cases of atypical HUS, discuss extrarenal complications and prognostic features of atypical HUS.
The clinical spectrum of these four patients who satisfied the criteria (acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia) for the diagnosis of HUS is depicted in Table I. Peripheral smear showed fragmented red blood cells, burr cells and helmet cells along with an elevated retic count (upto 11%). Antinuclear antibody, LE cell, double stranded DNA, antineutrophilic cytoplasmic antibody and antistreptolysin O titer were negative in all these children. Complement C3 was also normal. Patient A was a 6 year old male child who presented with history of vomiting and abdominal pain for 4 days and hematuria for one day prior to admission. There was no prior history sugges-tive of gastroenteritis or any other infection. He was non-oliguric and hypertensive. Urine examination revealed mild proteinuria. He received dialytic treatment in view of azotemia and other supportive care. Within two weeks, his renal functions and blood pressure returned to normal.
Table I__Key Features of the Clinical Spectrum and Outcome.
MAHA - Micro angiopathic hemolytic anemia, FFP - Fresh frozen Plasma, PRBC - Packed red blood cells, PD - Peritoneal dialysis, HD - Hemodialysis, CRF - Chronic renal failure, BP - Blood pressure, ESRD - End stage renal disease.
Patient B was a 7-year-old male child who presented with vomiting and hematuria for 4 days and progressive pallor. He was non-oliguric and normotensive. Urine examination showed hematuria. Renal functions improved and he came off dialysis but renal functions did not normalize with two weeks of dialysis treatment and supportive care. Two weeks later, he was re-admitted with worsening renal functions. He succumbed as he could not be dialysed due to financial constraints.
Patient C was a 5 year 6 month old male child who presented with vomiting, abdomi-nal pain, pallor, smoky urine and oliguria for 3 days prior to admission. He was hypertensive. Urine examination revealed mild proteinuria, hematuria and granular casts. In addition to dialysis and supportive care, he received five sitting of plasmapheresis. During his stay in the hospital, he developed left focal seizures with secondary generalization. CT scan of head revealed presence of multiple infarcts. His kidney biopsy was consistent with HUS (predominantly glomerular changes). After four weeks of stormy course, he had made a complete neurological recovery, partial renal recovery (serum creatinine 1.5 mg/dl) with hypertension. However, he had developed features of cardiomyopathy with a diminished ejection fraction, requiring fluid restriction, diuretics and Enalapril.
Patient D was a 7-year-old female who had received five sitting of intermittent peritoneal dialysis before being shifted to our hospital. She had evidence of disease activity on admission (active hemolysis, thrombocyto-penia). Urine examination showed non neph-rotic range proteinuria and granular casts. She was put on CAPD (continuous ambula-tory peritoneal dialysis) and given five sitting of plasmapheresis. Her kidney biopsy was consitent with changes of HUS (predomi-nantly arteriolar changes). She had severe hypertension not controlled with optimum doses of calcium channel blockers, angio-tensin converting enzyme inhibitors, alpha blockers (Prazosin), beta blockers and required use of Minoxidil. Though initially, there was some renal recovery (improvement in urine output, decrease in serum creatinine), it was transient. Four weeks later, she was dialysis dependent. However, she had no evi-dence of extra-renal involvement. Although, she had evidence of seizures during the hospital stay, CT scan of head was normal and the seizure was attributed to uncontrolled hypertension.
Hemolytic uremic syndrome is a hetero-genous group of disorders characterized by hemolytic anemia, thrombocytopenia and renal failure. The subgroup associated with a diarrheal prodrome has a better prognosis. Most cases in this subgroup recover completely although some may have residual nephropathy. Fitzpatrick et al.(3), in a follow up of diarrhea associated HUS, found a lower acute mortality (3%), fewer children progress-ing to end-stage renal failure (3%) but a higher proportion of children with renal sequelae (39%), whereas Srivastava et al.(4) reported an acute mortality of 60% with severe renal damage. In contrast to this, "atypical HUS" (non-diarrhea associated) has a poor prognosis. Renaud et al.(5) reported that 17 out of 21 children (81%) with atypical HUS had ESRD (end stage renal disease) in comparison to 18/21 (86%) patients with typical HUS having a good outcome. Of the 17 children, 7 died between day 30 and day 70 before dialysis was available (1955-1960) and the rest progressed to ESRD within 6 months. Uncontrollable hypertension was seen in 14 of these children necessitating bilateral nephrec-tomy in seven. Although some workers(6,7) reported no difference in outcomes between typical and atypical HUS, others(1,8) found poorer outcomes with atypical HUS. Bhuyan et al.(9) described 13 children with ARF and hypertension of which 4 had clinical and laboratory features of HUS and reported a higher mortality in them. In our series, only one out of four children with atypical HUS made complete recovery.
Extra renal involvement is common in atypical HUS and may even be the cause of death or sequelae in these patients(10,11). Colitis may last for about a week. Pancreatitis has been described in 18.2% of cases and diabetes mellitus may follow this insult (12,13). However, exocrine pancreatic insufficiency is not common. Elevation of transaminases with hepatomegaly may suggest involvement of the liver. Heart could be involved in the form of myocarditis or cardiomyopathy presenting as congestive cardiac failure. Lungs may be affected pre-senting as pulmonary infarct or hemorrhage. CNS dysfunction may be seen in upto 50% of the cases(14). This could present as drowsiness, agitation, irritability, lethargy, seizures or coma. CT scan may show infarcts or hypodensities more commonly in the basal ganglia. One of our patients had CNS involvement and one had cardiac involvement in the form of cardiomyopathy.
There are many prognostic factors implicated in HUS. Among them, indicators pointing towards bad prognosis are age at presentation(5,15) degree and duration of leucocytosis(16), severity of gastrointestinal symptoms including rectal prolapse(17), prolonged anuria for more than 8 days or oliguria exceeding 15 days(18), persistent or recurrent thrombocytopenia(17), presence of CNS symptoms(11), prolonged duration of prodromal illness and longer time between admission and starting PD(16). Kidney biopsy showing predominantly arteriolar changes is also a poor indicator(5). Because of the small number of patients, no definite conclusions can be drawn.
Good supportive care is the mainstay of therapy. Fluid and electrolyte balance should be maintained meticulously. Renal failure should be picked up early and treated promptly and aggressively. Dialysis therapy should be instituted early, especially in those with hyperkalemia, acidosis and severe azotemia. All our patients received plasma transfusions. Rizzoni et al.(19) found that plasma infusions did not significantly influence the outcome when patients with glomerular involvement were treated early and was not effective in severe HUS when given later in the course of the disease. Two of our patients received plasmapheresis with unfavourable results. Gianviti et al.(20) found that the evolution of renal function in treated (plasma exchange) and untreated patients is not significantly different, but chronic renal failure and endstage renal disease were present only in untreated patients. Plasma exchange and infusions have been tried because of the hypothesis of decreased synthesis of prostacyclin by leukocytes in acute HUS(1,5).
A comparison between key features of our patients and earlier series(1,2,7) is depicted in Table II.
Table II__Comparison with Other Series
Hemolytic uremic syndrome is a triad of microangiopathic hemolytic anemia, acute renal failure and thrombocytopenia. The typical cases with a diarrheal syndrome have a better prognosis. The atypical HUS group is heterogenous with incomplete recovery in most cases. Non diarrheal prodrome, proloned oligo-anuria, leukocytosis, persistent or recurrent thrombocytopenia, CNS symptoms and extrarenal involvement generally indicate a poor prognosis and indicate the need for aggressive management.
Contributors: IED was responsible for data collection and analysis, drafting the paper and case manage-ment; he will act as the guarantor for the manuscript. KDP and SDS assisted in drafting the paper.
Competing interests: None stated.