Changing strategies for organ transplantation in atypical haemolytic uraemic syndrome: a tertiary case series.

We present three cases of organ transplantation for atypical haemolytic uraemic syndrome secondary to complement factor H mutation: one isolated renal transplant; one previously reported isolated liver transplant; and one combined liver and kidney transplant. All three patients were treated prior to the licensing of eculizumab for this condition, and all have had favourable outcomes with maintenance of graft function for years following transplantation. We discuss the evolution of transplantation therapy for aHUS over the last two decades. Transplantation decision-making in aHUS has evolved over this time with expanding knowledge of pathophysiology and genetics, alongside refined plasma exchange and anticoagulation protocols and improved centre experience. Our cases demonstrate how individual patient factors within this heterogeneous condition also underlie transplantation decisions and outcomes. Whilst our cases demonstrate that transplantation in aHUS can be a successful long-term treatment providing good quality of life, worldwide experience has proven that most curative treatment for aHUS strategies represents significant risks. Whether new pharmacotherapies such as eculizumab will alter this risk is yet to be determined.

Plasma therapy for atypical haemolytic uraemic syndrome associated with heterozygous factor H mutations.

Atypical haemolytic uraemic syndrome (aHUS) is frequently associated with mutations in the gene encoding complement factor H (CFH). The clinical response to plasma therapy in aHUS is variable. We present here our experience of plasma therapy in three aHUS patients with CFH mutations. Three children presented aged 4, 22 and 6 months (patients 1-3 respectively) in acute kidney injury requiring dialysis. Plasma therapy consisting of plasma filtration (patient 1) or plasma exchange (PEX; patients 2 and 3) was commenced early following presentation. This resulted in aHUS remission and cessation of dialysis after 2 weeks, 9 days and 2 weeks respectively. Relapses were common and associated with increasing the interval between PEX, but all responded to intensification of PEX therapy. Patient 1 recovered 50% of renal function after first presentation. She had four relapses and started peritoneal dialysis 41 months after presentation. Mutation screening of CFH showed a missense mutation (c.3546 G > T, p.Arg1182Ser) in exon 23. PEX in patient 2 was slowly tapered over 4 months to fortnightly sessions, but she relapsed when PEX was extended to every 4 weeks. Renal function remained normal 12 months post-presentation. Mutation screening of CFH showed a mutation in exon 23 (c.3590 T > C, p.Val1197Ala) and two additional sequence variants in exons 3 and 4. Patient 3 had two relapses associated with intercurrent illnesses concurrent with reducing PEX to weekly doses. Renal function was normal 5 months post-presentation. All three patients showed a good response to PEX with improved renal function both initially and following a relapse. Further research is necessary to determine the best maintenance strategy to delay or prevent end-stage kidney disease.

Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom.

Atypical haemolytic uraemic syndrome (aHUS) is associated with a poor prognosis with regard to survival at presentation, recovery of renal function and transplantation. It is now established that aHUS is a disease of complement dysregulation with mutations in the genes encoding both complement regulators and activators, and autoantibodies against the complement regulator factor H. Identification of the underlying molecular abnormality in an individual patient can now help to guide their future management. In these guidelines we make recommendations for the investigation and management of aHUS patients both at presentation and in the long-term. We particularly address the role of renal transplantation alone and combined liver-kidney transplantation.

Plasma resistant atypical hemolytic uremic syndrome associated with a CFH mutation treated with eculizumab: a case report.

INTRODUCTION: Thrombotic microangiopathies are a group of diseases presenting as microangiopathic hemolytic anemia, thrombocytopenia and end-organ dysfunction. As the role of the complement system was elucidated in atypical hemolytic uremic syndrome pathogenesis, eculizumab was successfully introduced into clinical practice. We present a large pedigree with multiple individuals carrying a functionally significant novel factor H mutation. We describe the proband's presentation following a presumed infectious trigger requiring plasma exchange and hemodialysis. CASE PRESENTATION: A 32-year-old Caucasian woman presented with pyrexia and headache lasting one week to our Emergency Department. She gave no history of diarrhea or other symptoms to account for her high temperature. She was not taking any medication. She was pyrexial (38°C), tachycardic (110 bpm) and hypertensive (160/110 mmHg). Her fundoscopy revealed grade IV hypertensive retinopathy. She had mild pretibial and periorbital edema, with oliguria (450 mL/day). She had a pregnancy one year previously, during which she had hypertension, proteinuria and edema, with successful delivery at term. Her mother had died in her early 30s with a clinical picture consistent with thrombotic microangiopathy. Her laboratory evaluation showed microangiopathic hemolytic anemia. After 22 sessions of plasma exchange, her lactate dehydrogenase levels started to climb. As a result, she was classified as plasma resistant and eculizumab therapy was instituted. Her lactate dehydrogenase level and platelet count normalized, and her renal function recovered after three months of dialysis. CONCLUSIONS: We demonstrate that, even in patients with atypical hemolytic uremic syndrome and prolonged dialysis dependence, recovery of renal function can be seen with eculizumab treatment. We suggest a treatment regime of at least three months prior to evaluation of efficacy.

Atypical aHUS: State of the art.

Tremendous advances in our understanding of the thrombotic microangiopathies (TMAs) have revealed distinct disease mechanisms within this heterogeneous group of diseases. As a direct result of this knowledge, both children and adults with complement-mediated TMA now enjoy higher expectations for long-term health. In this update on atypical hemolytic uremic syndrome, we review the clinical characteristics; the genetic and acquired drivers of disease; the broad spectrum of environmental triggers; and current diagnosis and treatment options. Many questions remain to be addressed if additional improvements in patient care and outcome are to be achieved in the coming decade.

Complement therapy in atypical haemolytic uraemic syndrome (aHUS).

Central to the pathogenesis of atypical haemolytic uraemic syndrome (aHUS) is over-activation of the alternative pathway of complement. Inherited defects in complement genes and autoantibodies against complement regulatory proteins have been described. The use of plasma exchange to replace non-functioning complement regulators and hyper-functional complement components in addition to the removal of CFH-autoantibodies made this the 'gold-standard' for management of aHUS. In the last 4 years the introduction of the complement inhibitor Eculizumab has revolutionised the management of aHUS. In this review we shall discuss the available literature on treatment strategies to date.

Plasma therapy in atypical haemolytic uremic syndrome: lessons from a family with a factor H mutation.

Whilst randomised control trials are undoubtedly the best way to demonstrate whether plasma exchange or infusion alone is the best first-line treatment for patients with atypical haemolytic uremic syndrome (aHUS), individual case reports can provide valuable information. To that effect, we have had the unique opportunity to follow over a 10-year period three sisters with aHUS associated with a factor H mutation (CFH). Two of the sisters are monozygotic twins. A similar natural evolution and response to treatment would be expected for the three patients, as they all presented with the same at-risk polymorphisms for CFH and CD46 and no identifiable mutation in either CD46 or CFI. Our report of different modalities of treatment of the initial episode and of three transplantations and relapses in the transplant in two of them, strongly suggest that intensive plasma exchange, both acutely and prophylactically, can maintain the long-term function of both native kidneys and allografts. In our experience, the success of plasma therapy is dependent on the use of plasma exchange as opposed to plasma infusion alone, the prolongation of daily plasma exchange after normalisation of haematological parameters followed by prophylactic plasma exchange, the use of prophylactic plasma exchange prior to transplantation and the use of prophylactic plasma exchange at least once a week posttransplant with immediate intensification of treatment if there are any signs of recurrence.