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The therapeutic effect of plasma infusion was evaluated in 10 children and seven adults with haemolytic uraemic syndrome. All but one patient responded to this treatment with rapid disappearance of haematological abnormalities. The patient who apparently failed to respond to plasma infusion obtained complete remission of the disease after plasmapheresis. Although 15 of the 17 patients were anuric or oliguric on admission, renal function recovered completely in eight children and two adults. Seven patients showed residual chronic renal failure and two required long-term maintenance haemodialysis. Treatment with plasma was also successful in patients with relapses or recurrent episodes. Plasma infusion is a promising therapeutic approach for the haemolytic uraemic syndrome and deserves further study in clinical trials.

In adults, the haemolytic-uraemic syndrome (HUS) is associated with probable causative factors in the minority of all cases. Cytotoxic drugs are one of these potential causative agents. Although metastatic cancer by itself is a recognized risk-factor for the development of HUS, therapy with mitomycin-C, with cis-platinum, and with bleomycin carries a significant, albeit extremely small, risk for the development of HUS, compared with all other cytotoxic drugs. Gemcitabine is a novel cytotoxic drug with promising activity against pancreatic adenocarcinoma. We are reporting on one patient with metastatic duodenal papillary carcinoma developing HUS while on weekly gemcitabine therapy. The presenting features in this patient were non-cardiac pulmonary oedema, renal failure, thrombocytopenia and haemolytic anaemia. The diagnosis of HUS was made on the day of admission of the patient to this institution. Upon aggressive therapy, including one single haemodialysis and five plasmaphereses, the patient recovered uneventfully, with modestly elevated creatinine-values as a remnant of the acute illness. Re-exposure to gemcitabine 6 months after the episode of HUS instituted for progressive carcinoma, thus far has not caused another episode of HUS. © 1999 Cancer Research Campaign

Prostacyclin (PGI2) production was diminished when rat aortic rings were incubated with plasma from 5 of 6 patients with the sporadic form of haemolytic uraemic syndrome but was normal in the presence of plasma from 7 patients with the epidemic form of haemolytic uraemic syndrome or from patients with other renal diseases. The reduced PGI2 production was caused by an unstable inhibitor, extractable into polar lipid solvents, in sporadic haemolytic uraemic plasma. These results suggest that there may be at least 2 different pathogenetic mechanisms in epidemic and sporadic haemolytic uraemic syndrome and that the reduced PGI2 production observed in the sporadic type is due to an inhibitor of PGI2 production rather than a deficiency of stimulating factors.

Certain strains of Escherichia coli producing verotoxin have been isolated in the stools of patients with the haemolytic uraemic syndrome. A platelet aggregating activity has been found in normal plasma after incubation with verotoxin at 37 degrees C for 24 h. This activity, unlike neuraminidase, has an effect that is independent of changing factor VIII related antigen, but requires the IIA and IIIB platelet surface glycoprotein (deficient in thrombasthenia) to mediate its effect. Prostacyclin totally inhibited this effect, but other antiplatelet drugs and heparin were without inhibitory effects.

Among 48 patients with a typhoid infection 6 (12·5%) developed the haemolytic-uraemic syndrome. Neither glucose-6-phosphate dehydrogenase deficiency nor therapy with chloramphenicol could be incriminated as the causal factor. Evidence presented here suggests that the mechanism is localized intravascular coagulation.

The presence of leucocytosis in typhoid fever suggests a complication and should alert one to the possibility of the haemolytic-uraemic syndrome. Furthermore, in our area typhoid should be suspected as a cause in any patient presenting with acute renal failure.

Factor VIII related activities and factor VIII related antigen multimeric analysis have been assessed in two sporadic and eleven epidemic cases of haemolytic uraemic syndrome. In all patients factor VIII related antigen was raised and had an abnormal multimer pattern at presentation. The return to normal of factor VIII related antigen values and multimeric analysis patterns paralleled clinical improvement and, therefore, may be useful in monitoring patients with haemolytic uraemic syndrome. We postulate that endothelial cell damage releases the abnormal high molecular weight factor VIII related antigen multimers and that this may cause platelet agglutination in vivo.

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Background

Haemolytic uraemic syndrome (HUS) is the most common cause of acute renal failure in children and is usually linked with Escherichia coli O157 infection. With a fatality rate of around 5%, some reports have associated antibiotic treatment with a worsening prognosis.

Case Presentation

We describe a female infant patient, initially treated for suspected meningococcal septicaemia, who went on to develop renal complications and thrombocytopenia characteristic of HUS. A subsequent positive stool sample for E. coli O157 confirmed HUS as an appropriate diagnosis, although there was no evidence of diarrhoea or vomiting throughout the course of her management.

Conclusion

The urgency of early recognition and treatment for suspected meningococcal disease in very young children while entirely appropriate can initially divert attention from other serious conditions. Evidence of infection with E. coli O157 infection in this case also highlights what can be a blurred distinction between atypical (non-diarrhoeal) HUS from classical HUS of infective origin.

The haemolytic-uraemic syndrome is the term used to describe the symptom complex of acute oliguric renal failure, haemolysis, and thrombocytopaenia. The pathogenesis of the syndrome is unknown though several factors have been postulated as important. Gastrointestinal disease is now recognised as a regular feature of the syndrome but hepatic involvement is uncommon and limited to occasional jaundice, hepatosplenomegaly and rises in serum transaminase values. A patient is described in whom cholestatic jaundice occurred during the prodromal illness. Its presence is unexplained but might indicate infection with an unrecognised hepatotropic agent or else lack of enteral nutrition during the prodromal phase.

Nine children had 10 attacks of the haemolytic-uraemic syndrome in an 11-month period. One child had 2 slight episodes. The remaining 8 children each had a severe attack which required peritoneal dialysis and, of these, the first 4 were also treated with heparin. All the patients survived without sequelae and the rate of recovery of dialysed patients was unaffected by the use of heparin. Peritoneal dialysis alone is therefore recommended as a simple and effective form of treatment for the haemolytic-uraemic syndrome. No infective aetiological agent could be identified and the distribution of HLA antigens among the children were unremarkable.

Shigella dysentery caused 65% of all cases of acute renal failure (ARF) seen in children treated at the Christian Medical College Hospital, Vellore, during the 33 months ending September 1977. In the 40 children with ARF secondary to shigella dysentery, haematological findings suggested that they were suffering from the haemolytic-uraemic syndrome, and glomerular hypercellularity and fibrin deposition were present in all 12 patients whose renal histology could be studied. Peritoneal dialysis was the main element of treatment: 43% of children who underwent dialysis improved, compared with only 25% of those who did not undergo dialysis. The haemolytic-uraemic syndrome precipitated by bacillary dystentery is therefore the most important cause of ARF in children aged under 5 years in Tamil Nadu and the adjoining area of Andhra Pradesh.

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Because low plasma vitamin E concentrations have been reported in patients with haemolytic uraemic syndrome and there is accumulating evidence of lipid peroxidation in this disease, treatment with the antioxidant vitamin E was undertaken in 16 consecutive children with the syndrome. Twelve children had features at presentation suggesting a poor prognosis for recovery but despite this all 16 patients survived and are well three months later. Fifteen children now have normal values for serum creatinine, blood pressure, and urinalysis for protein but one has slight renal impairment. Although this is not a report of a controlled trial, it seems that patients treated with vitamin E have fared considerably better than our previously treated patients with haemolytic uraemic syndrome, even in the presence of early, adverse prognostic features. We suggest that vitamin E alters the natural history of the disease, and in view of the absence of any observed side effects further experience with this treatment is being sought.

In four of five patients with thrombotic thrombocytopenic purpura (TTP) in whom serial tests of hemostatic function were performed, severe thrombocytopenia, normal plasma fibrinogen concentrations and mildly increased concentrations of fibrinogen/fibrin degradation products were observed. Widespread platelet thrombi were found in arterioles and capillaries. Fibrin could be seen around some of the platelet clumps and was the main component in a small number of the thrombi in two patients. The observations show that TTP is a disorder in which intravascular platelet consumption results in disseminated platelet thrombosis. The coagulation system is apparently activated secondarily to platelet aggregation and variable quantities of fibrin are incorporated into the thrombi. Clinical improvement resulted from combined therapy with corticosteroids, heparin and drugs that suppress platelet function.

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Three children with the haemolytic-uraemic syndrome were treated with intravenous heparin. Peritoneal dialysis was required for two of them, one of whom died after 26 days of therapy. Renal biopsy specimens from the two survivors showed widespread glomerular disease, which appeared permanent in one case, but only occasional thrombi. It is suggested that heparin therapy, by preventing further intrarenal thrombosis, allowed the normal fibrinolytic mechanisms to remove previously formed thrombi.

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Creatinine clearance and microalbuminuria were measured before and after an oral protein load in 17 children with a history of haemolytic uraemic syndrome, 11 with a single kidney, and 15 controls, all of them normotensive and without evidence of renal damage, to look for indirect evidence of glomerular hyperfiltration. While creatinine clearance increased significantly after the protein load in controls, it did not change in patients with either haemolytic uraemic syndrome or a single kidney. Basal microalbuminuria was significantly higher in those with haemolytic uraemic syndrome when compared with those with a single kidney and controls. It increased significantly in all groups after a water load; this increase was significantly higher in haemolytic uraemic syndrome. After the protein load microalbuminuria returned to baseline. In conclusion, children with a history of haemolytic uraemic syndrome have an abnormal renal functional reserve like children with a single kidney. Only patients with haemolytic uraemic syndrome exhibited an increased microalbuminuria, however, suggesting that it may be the expression of a pathophysiological mechanism involved in haemolytic uraemic syndrome and not in single kidney, that could account for their different prognosis.

Three cases of acute renal toxicity in patients receiving long-term therapy with mitomycin C and 5-fluorouracil are reported. Two of the patients (1 and 3) are from a multicentre trial of adjuvant chemotherapy for gastric carcinoma. All three cases showed extensive fibrin deposition in the kidneys and lungs, the appearances of the renal lesions being similar to those seen in the haemolytic-uraemic syndrome. Two of the three cases had received blood transfusions, and attention is drawn to the possibility that mitomycin C may sensitise the kidneys to minor mismatches. With the increasing use of these antimitotic agents, great vigilance should be exercised with regard to renal function and haemolytic status.

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Objective: To analyse the clinical and laboratory features of patients with thrombotic microangiopathic haemolytic anaemia (TMHA) associated with antiphospholipid antibodies (aPL).

Methods: A computer assisted (PubMed) search of the literature was performed to identify all cases of TMHA associated with aPL from 1983 to December 2002.

Results: 46 patients (36 female) with a mean (SD) age at presentation of TMHA of 34 (15) years were reviewed. Twenty eight (61%) patients had primary antiphospholipid syndrome (APS). TMHA was the first clinical manifestation of APS in 26 (57%) patients. The clinical presentations were haemolytic-uraemic syndrome (26%), catastrophic APS (23%), acute renal failure (15%), malignant hypertension (13%), thrombotic thrombocytopenic purpura (13%), and HELLP (haemolysis, elevated liver enzymes, and low platelet count in association with eclampsia) syndrome (4%). Lupus anticoagulant was detected in 86% of the episodes of TMHA, and positive anticardiolipin antibodies titres in 89%. Steroids were the most common treatment (69% of episodes), followed by plasma exchange (PE) (62%), anticoagulant or antithrombotic agents (48%), immunosuppressive agents (29%), and immunoglobulins (12%). Recovery occurred in only 10/29 (34%) episodes treated with steroids, and in 19/27 (70%) episodes treated with PE. Death occurred in 10/46 (22%) patients.

Conclusions: The results emphasise the need for systematic screening for aPL in all patients with clinical and laboratory features of TMHA. The existence of TMHA in association with an APS forces one to rule out the presence of the catastrophic variant of this syndrome. PE is indicated as a first line of treatment for all patients with TMHA associated with aPL.

Pulmonary haemorrhage is a potentially life-threatening event that may occur in patients with pulmonary-renal syndromes. These syndromes have typically been thought to occur in small-vessel vasculitides, such as ANCA-mediated disease, Goodpasture's disease and other autoimmune conditions including systemic lupus erythematosus or anti-phospholipid antibody syndrome. Here, we present a rare cause for pulmonary haemorrhage with associated renal failure—atypical haemolytic-uraemic syndrome. In this case, renal biopsy was integral to providing a diagnosis and guiding therapy.

Between January 1965 and December 1970, 212 patients with the haemolytic-uraemic syndrome in the Netherlands were analysed in an epidemiological and clinical study of the disease. The disorder typically occurs in early infancy, in children without antecedent illness. The majority of the patients were younger than 4 years. The incidence of the disease in the Netherlands is increasing. The disease occurs throughout the year but peak incidences were noted during the late spring and early summer. Apart from this seasonal influence there was a geographical clustering. The possible relation of the epidemiological features of the syndrome to a viral aetiology is discussed.

Accepted 6 May 1997


The proinflammatory cytokines tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-8 were measured in plasma and urine samples from 19 children with verocytotoxin-producing Escherichia coli (VTEC) induced haemolytic uraemic syndrome (HUS) and 30 controls. TNF-α was detected in the plasma of two cases and one control; IL-6 in the plasma of one, and the urine of two cases, and in the plasma of one control. IL-1β and IL-8 were each identified in eight of the 19 cases and in one and two controls respectively. Urinary IL-8 was found in seven cases, four of whom had plasma concentrations below the limit of detection suggesting renal secretion of this cytokine. Cytokine concentrations did not correlate with peripheral blood neutrophil count at onset of disease. These data confirm the systemic release of cytokines responsible for the coordination of acute inflammatory processes in some children with VTEC induced HUS.



Introduction

Abnormal control of the complement alternative pathway (CAP) (factor H, factor I and membrane cofactor protein (MCP) deficiencies) is a well established risk factor for the occurrence of haemolytic uraemic syndrome (HUS). In some instances, HUS may be associated with an unusual glomerulonephritis with isolated C3 deposits (glomerulonephritis C3). We determined whether HUS and glomerulonephritis C3 share common genetic susceptibility factors.

Methods

We identified 19 patients with glomerulonephritis C3. We measured levels of circulating complement components, performed assays for the detection of C3 nephritic factor (C3NeF) and screened factor H, factor I and MCP coding genes for the presence of mutations.

Results

Patients were divided in two groups based on renal pathology findings: group I (n = 13) had typical features of type I membranoproliferative glomerulonephritis (glomerulonephritis C3 with membranoproliferative glomerulonephritis (MPGN)) and group II (n = 6) was characterised by mesangial and epimembranous C3 deposits in the absence of mesangial proliferation (glomerulonephritis C3 without MPGN). Mutations in complement regulatory genes were detected in 4/6 patients with glomerulonephritis C3 without MPGN (heterozygous mutations in factor H gene (two patients) with low factor H antigenic level in one case, heterozygous mutations in factor I gene (two patients)) and in only 2/13 patients with glomerulonephritis C3 with MPGN (heterozygous mutations in factor H gene (one patient) and double heterozygous mutation in CD 46 gene (one patient)). In contrast, C3NeF was present in 5/13 patients with glomerulonephritis C3 with MPGN and in 2/6 patients with glomerulonephritis C3 without MPGN, one of whom had a factor H mutation.

Conclusion

HUS and glomerulonephritis C3 without MPGN share common genetic risk factors. Constitutional or acquired dysregulation of the CAP is probably associated with a wide spectrum of diseases, ranging from HUS to glomerulonephritis C3 with MPGN.

Background

The aim of this study was to investigate the characteristics and outcomes of patients receiving renal replacement therapy for end-stage kidney disease (ESKD) secondary to haemolytic uraemic syndrome (HUS).

Methods

The study included all patients with ESKD who commenced renal replacement therapy in Australia and New Zealand between 15/5/1963 and 31/12/2010, using data from the ANZDATA Registry. HUS ESKD patients were compared with matched controls with an alternative primary renal disease using propensity scores based on age, gender and treatment era.

Results

Of the 58422 patients included in the study, 241 (0.4%) had ESKD secondary to HUS. HUS ESKD was independently associated with younger age, female gender and European race. Compared with matched controls, HUS ESKD was not associated with mortality on renal replacement therapy (adjusted hazard ratio [HR] 1.14, 95% CI 0.87-1.50, p = 0.34) or dialysis (HR 1.34, 95% CI 0.93-1.93, p = 0.12), but did independently predict recovery of renal function (HR 54.01, 95% CI 1.45-11.1, p = 0.008). 130 (54%) HUS patients received 166 renal allografts. Overall renal allograft survival rates were significantly lower for patients with HUS ESKD at 1 year (73% vs 91%), 5 years (62% vs 85%) and 10 years (49% vs 73%). HUS ESKD was an independent predictor of renal allograft failure (HR 2.59, 95% CI 1.70-3.95, p < 0.001). Sixteen (12%) HUS patients experienced failure of 22 renal allografts due to recurrent HUS. HUS ESKD was not independently associated with the risk of death following renal transplantation (HR 0.92, 95% CI 0.35-2.44, p = 0.87).

Conclusions

HUS is an uncommon cause of ESKD, which is associated with comparable patient survival on dialysis, an increased probability of renal function recovery, comparable patient survival post-renal transplant and a heightened risk of renal transplant graft failure compared with matched ESKD controls.

Background: The aetiology of atypical haemolytic uraemic syndrome (aHUS) is, in contrast to classical, Shiga-like toxin induced HUS in children, largely unknown. Deficiency of human complement factor H and familial occurrence led to identification of the factor H gene (FH1) as the susceptibility gene, but the frequency and relevance of FH1 mutations are unknown.

Methods: We established a German registry for aHUS and analysed in all patients and 100 controls the complete FH1 gene by single strand confirmational polymorphism and DNA sequencing. In addition, complement C3 and factor H serum levels were assayed. Demographic data at onset of aHUS and follow up were compared for the mutation positive and negative groups.

Results: Of 111 patients with aHUS (68 female, 43 male, mean age 33 years) 14% had FH1 germline mutations, including two of eight patients with familial aHUS.For each of these eight patients, both parents were tested, and we were able to trace the mutation for five cases. In the other three cases (one with the mutation 3749 C/T, one with 3200 T/C, and one with 3566+1 G/A), we could not detect the mutation in either parent, although paternity was proven by genetic fingerprinting, suggesting that these subjects have new mutations. C3 was decreased in five mutation carriers but also in two non-carriers, and factor H was decreased in none of the carriers, but elevated in six carriers and 15 non-carriers. Clinical parameters including associated medications and diseases, and outcome of aHUS and of post-aHUS kidney transplantation were similar in the mutation positive and negative groups.

Conclusion: FH1 germline mutations occur with considerable frequency in patients with aHUS. Hypocomplementaemia is not regularly associated with a germline mutation, and factor H serum levels can even be elevated. Screening for FH1 mutations contributes to the classification of aHUS.

Background: In both familial and sporadic atypical haemolytic-uraemic syndrome (aHUS), mutations have been reported in regulators of the alternative complement pathway including factor H (CFH), membrane cofactor protein (MCP), and the serine protease factor I (IF). A characteristic feature of both MCP and CFH associated HUS is reduced penetrance and variable inheritance; one possible explanation for this is that functional changes in complement proteins act as modifiers.

Objective: To examine single nucleotide polymorphisms in both CFH and MCP genes in two large cohorts of HUS patients (Newcastle and Paris).

Results: In both cohorts there was an association with HUS for both CFH and MCP alleles. CFH and MCP haplotypes were also significantly different in HUS patients compared with controls.

Conclusions: This study suggests that there are naturally occurring susceptibility factors in CFH and MCP for the development of atypical HUS.

The treatment of five children with the haemolytic-uraemic syndrome using streptokinase is described to illustrate the difficulties and limitations of thrombolytic therapy in this disease. This experience is germane to the design of multicentre clinical trials.

A multivariate analysis relating clinical outcome to the data obtained at the time of admission was also carried out for 31 children with the disease treated in four centres. The results suggest that this technique may help to identify those patients likely to have a fatal outcome. An expanded form of this type of analysis should be incorporated in future clinical trials.

In 1982-3, 35 children from the West Midlands developed the haemolytic-uraemic syndrome. This was a higher incidence than expected and included an epidemic localised to the Wolverhampton area in July 1983 which comprised 11 cases in two weeks. Twenty three children were treated with dialysis, of whom three died. Six patients developed chronic renal failure, four of them from Wolverhampton. Extrarenal manifestations included neurological sequelae in four, two of whom also developed insulin dependent diabetes mellitus and chronic renal failure. Cardiomyopathy occurred in one child, who also had chronic renal failure. The outcome of these 35 patients was not predictable from prognostic criteria derived from previous experience in Britain. This, together with the high prevalence of extrarenal disease and the geographical localisation of the 1983 outbreak, suggested an aetiological agent new to the region. Faeces from 10 patients were examined for verotoxin producing Escherichia coli, and positive strains of serotype O157.H7 were found in three patients during the Wolverhampton outbreak.