Proliferative retinopathy and retinal detachment in pediatric atypical hemolytic uremic syndrome.

We report the case of a 14-year-old boy with history of microangiopathic hemolytic crises secondary to atypical hemolytic uremic syndrome presenting with new-onset decreased vision, flashes, and floaters in his left eye. The patient had a history of chronic retinal detachment in the right eye and retinal neovascularization in the left eye treated with panretinal photocoagulation at age 5. He was now found to have a new combined tractional-rhegmatogenous retinal detachment in the left eye. Despite surgical reattachment of the retina, he had progressive retinal and optic nerve ischemia, with resultant left eye visual acuity of light perception. To our knowledge, this is the first reported case of proliferative retinopathy and tractional and rhegmatogenous retinal detachments in a pediatric patient with atypical hemolytic uremic syndrome.

Transplantation in pediatric aHUS within the era of eculizumab therapy.

aHUS is caused by the over-activation and dysregulation of the alternative complement pathway. Data regarding outcomes of pediatric aHUS patients after kidney transplantation are still very scarce. Accordingly, the aim of this study was to describe the clinical findings and outcomes of pediatric aHUS patients after renal transplantation. This is a retrospective, multicenter study including 12 patients from the national registry system. Among the 12 patients, eight had received prophylactic eculizumab and none of those patients (except one) had experienced aHUS recurrence during a median follow-up period of 58.5 (min-max, 4-94) months. Although eculizumab had been started on the day before transplantation in one of them, aHUS recurrence occurred during the transplantation procedure. Eculizumab had been stopped in only one patient who had no complement gene mutation after 35 months of therapy, and recurrence had not been observed during the 19 months of follow-up. In three patients, maintenance doses had been spaced out without any recurrence. One additional patient with anti-CFH antibody received only two doses of eculizumab for transplantation and had been followed for 46 months without aHUS recurrence. The remaining three patients had not received anti-C5 therapy and none of those patients experienced aHUS recurrence during a median follow-up period of 21 (min-max, 9-42) months. Prophylactic eculizumab is a safe and effective treatment for the prevention of aHUS recurrence. Eculizumab interval prolongation, discontinuation, and transplantation without eculizumab prophylaxis can be tried in selected patients with close follow-up.

Atypical Hemolytic Uremic Syndrome: New Challenges in the Complement Blockage Era.

Atypical hemolytic uremic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and multisystem end organ involvement, most commonly affecting the kidney. Diagnosis is clinical, after exclusion of other TMA causes. Primary aHUS arises from genetic abnormalities, resulting in uncontrolled complement activity, while a variety of clinical scenarios cause secondary aHUS, including infection, pregnancy, malignancy, autoimmune disease, and medications. They can also induce a temporary complement deregulation with an overlap between both scenarios, which can make differential diagnosis difficult. Primary aHUS can be sporadic or familial and is associated with a high rate of progression to ESRD. Many aHUS patients relapse in the native or transplanted kidneys, leading to kidney failure. The introduction of eculizumab has changed the prognosis of aHUS, by inducing hematologic remission, improving or stabilizing kidney functions, and preventing graft failure. The early institution of appropriate therapy can prevent multiorgan damage, so is essential to recognize and differentiate the TMA syndromes. Eculizumab is considered now the first-line treatment, and it is recommended lifelong therapy. However, the high cost of therapy has led to make efforts to develop precise complement functional and genetic studies that help physicians to determine the appropriate duration of eculizumab therapy. Nowadays, more studies are needed to select candidates to adjustment of therapy.

Peri- and Post-operative Evaluation and Management of Atypical Hemolytic Uremic Syndrome (aHUS) in Kidney Transplantation.

Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy characterized by over-activation of the alternative complement pathway. The etiology of the dysregulated complement system is commonly a genetic variant in one or more complement proteins as identified in ∼ 60%-70% patients. The risk of recurrence after a kidney transplantation is high and depends on the underlying complement abnormality. For a long time, kidney transplantation was contraindicated in these patients because of the high rate of recurrence and subsequent allograft loss. Over the past decade, advancements in the understanding of etiopathogenesis of aHUS and approval of the anti-complement drug, eculizumab, have allowed for successful kidney transplantation in these patients. All patients with ESRD due to aHUS should undergo screening for complement genetic variants. Patients in whom a genetic variant is not identified or in whom a genetic variant of uncertain significance is identified should undergo further testing to determine etiology of disease. This review aims to shed light on the diagnostic and therapeutic considerations in patients with aHUS preceding and following kidney transplantation.

Use of Highly Individualized Complement Blockade Has Revolutionized Clinical Outcomes after Kidney Transplantation and Renal Epidemiology of Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade-based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country. METHODS: To evaluate this strategy's effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (n=397) between 2007 and 2016. RESULTS: The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients. CONCLUSIONS: Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.

Renal Transplantation in Patients With Atypical Hemolytic Uremic Syndrome: A Single Center Experience.

PURPOSE: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic anemia, thrombocytopenia, and acute kidney injury. HUS is mostly associated with diarrhea (90%). However, 10% of cases are not associated with diarrhea and are thus called as atypical HUS (aHUS); these cases are usually caused by dysregulation of the complement system. Eculizumab, a monoclonal antibody against C5, is the drug of choice for treating aHUS. Herein we aimed to present 8 cases of renal transplantation performed on patients with aHUS. MATERIALS AND METHODS: A total of 8 patients who had been diagnosed with aHUS between the years 2012 to 2018 were enrolled and underwent transplantations. All patients received induction treatment, standard immunosuppresive treatment (tacrolimus, mycophenolic acid, prednisolone), and eculizumab. Eculizumab was administered at a dosage of 900 mg/wk for the first month and 1200 mg every 2 weeks thereafter. Patients were followed up and recorded in terms of demographic features, serum creatinine, lactate dehydrogenase, acute rejection episodes, and allograft outcomes. RESULTS: Mean age was 34 ± 8 years (Male/Female: 6/2). One of the patients had a second transplantation. Median hemodialysis vintage (25%-75% interquartile range) was 37 (9-63) months. Four patients had pretransplant plasmapheresis and 2 patients had posttransplant plasmapheresis. Induction treatment was ATG in 7 patients, and basiliximab was used only in 1 patient. The median follow-up period was 25 (13-59) months. Mean serum creatinine levels were 1.9 ± .6, 1.2 ± .7, and 1 ± .1 mg/dL for the first day, first month, and last values, respectively. Mean lactate dehydrogenase levels were 286 ± 203, 239 ± 27, and 218 ± 86 U/L for first day, first month, and last values, respectively. None of the patients had an acute rejection episode. Currently, all patients have functioning allografts. CONCLUSION: Patients with aHUS may be transplanted successfully with eculizumab with good allograft outcomes.

Trasplante renal exitoso con protocolo de eculizumab, timoglobulina y belatacept en paciente altamente sensibilizada con síndrome hemolítico urémico atípico por mutación del factor H / Successful kidney transplant with eculizumab, thymoglobulin and belatacept therapy in a highly-sensitised patient with atypical haemolytic uraemic syndrome due to factor H mutation

El síndrome hemolítico urémico atípico es una enfermedad relacionada con alteración en la regulación del complemento que generalmente evoluciona a enfermedad renal crónica terminal, con alta tasa de recaída en el trasplante renal y elevado riesgo de pérdida del injerto. La terapia anticomplemento ha mejorado el pronóstico de estos pacientes, logrando tener remisión de la enfermedad en la mayoría de los casos, aumentando la posibilidad de un trasplante renal exitoso e incrementando la supervivencia del paciente y del injerto; igualmente el uso de medicamentos con bajo riesgo de inducción de microangiopatías trombóticas como el belatacept y micofenolato se han utilizado con resultados satisfactorios. Presentamos el caso de una paciente joven de alto riesgo inmunológico, con síndrome hemolítico urémico atípico por mutación del factor H, a quien se realizó trasplante renal exitoso con eculizumab, timoglobulina, belatacept, micofenolato y esteroides conservando excelente función del injerto y sin recaídas de su enfermedad

Atypical haemolytic uremic syndrome is a disease caused by complement regulation abnormalities that generally progresses to chronic end-stage renal disease with a high rate of recurrence in kidney transplantation and a high risk of graft loss. Anti-complement therapy has improved the prognosis of these patients, achieving disease remission in most cases, increasing the likelihood of a successful kidney transplant and increasing patient and graft survival. Drugs with low risk of induction of thrombotic microangiopathies such as belatacept and mycophenolate have also been used with satisfactory results. We present the case of a young patient at high immunological risk, with atypical haemolytic uraemic syndrome due to factor H mutation, who underwent a successful kidney transplantation with eculizumab, thymoglobulin, belatacept, mycophenolate and steroids, to date preserving excellent graft function without disease recurrence

Successful kidney transplant with eculizumab, thymoglobulin and belatacept therapy in a highly-sensitised patient with atypical haemolytic uraemic syndrome due to factor H mutation. / Trasplante renal exitoso con protocolo de eculizumab, timoglobulina y belatacept en paciente altamente sensibilizada con síndrome hemolítico urémico atípico por mutación del factor H.

Atypical haemolytic uremic syndrome is a disease caused by complement regulation abnormalities that generally progresses to chronic end-stage renal disease with a high rate of recurrence in kidney transplantation and a high risk of graft loss. Anti-complement therapy has improved the prognosis of these patients, achieving disease remission in most cases, increasing the likelihood of a successful kidney transplant and increasing patient and graft survival. Drugs with low risk of induction of thrombotic microangiopathies such as belatacept and mycophenolate have also been used with satisfactory results. We present the case of a young patient at high immunological risk, with atypical haemolytic uraemic syndrome due to factor H mutation, who underwent a successful kidney transplantation with eculizumab, thymoglobulin, belatacept, mycophenolate and steroids, to date preserving excellent graft function without disease recurrence.

Successful 7-Year Eculizumab Treatment of Plasmapheresis-Resistant Recurrent Atypical Hemolytic-Uremic Syndrome due to Complement Factor H Hybrid Gene: A Case Report.

Atypical hemolytic-uremic syndrome (aHUS) is an extremely rare disease, and up to 70% of the patients have a genetic mutation in the encoding components of complement activation or anti-complement factor H autoantibodies. The risk of recurrence after kidney transplantation is 10% to 80%. Eculizumab, a monoclonal antibody that binds complement protein C5, has shown to be highly effective in patients with aHUS; however, there are only few reports on the efficacy and safety of long-term eculizumab treatment in children with recurrent aHUS. Only 3 case reports regard treatment in patients with complement factor H (CFH/CFHR1/CFHR3) hybrid gene. This report presents the efficacy and safety of long-term eculizumab treatment in a child with recurrent aHUS who has been successfully treated with eculizumab for more than 7 years. The patient presented as a 9-year-old with aHUS due to CFH/CFHR1/CFHR3 hybrid gene and received deceased donor kidney transplantation. After the transplantation, he experienced recurrence of aHUS 2 months later. Daily plasma exchanges were ineffective in the transplanted kidney; the patient became anuric and hemodialysis was needed. Eculizumab was started as therapy and led to complete remission of aHUS including restoration of diuresis. Eculizumab has been given as therapy for 7 years. The young patient is in a sustained remission without any adverse events. This patient is only the sixth patient reported with recurrent aHUS due to CFH/CFHR1/CFHR3 hybrid gene and is the patient with the longest remission of recurrent aHUS ever published.

Renal Transplant Immunosuppression in Patients With Hemolytic Uremic Syndrome: Four Case Reports.

A high rate of recurrence has been described in atypical hemolytic uremic syndrome renal transplant recipients, favored by certain immunosuppressant drugs that can induce complement activation. We present four case series in which three patients were diagnosed pretransplantation and a fourth who had onset in the very early post-transplantation period. The patients received different immunosuppression schedules, and all had improvement after more than 2-years. We suggest the need to stratify the risk of atypical hemolytic uremic syndrome recurrence using genetic studies and the available drugs as the main factors that allow graft survival improvement today.

Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis.

Atypical haemolytic uraemic syndrome (aHUS) often leads to end-stage renal disease (ESRD) and kidney transplantation; graft loss rates are high due to disease recurrence. A post hoc analysis of four prospective clinical trials in aHUS was performed to evaluate eculizumab, a terminal complement inhibitor, in patients with native or transplanted kidneys. The trials included 26-week treatment and extension periods. Dialysis, transplant and graft loss were evaluated. Study endpoints included complete thrombotic microangiopathy (TMA) response, TMA event-free status, haematologic and renal parameters and adverse events. Of 100 patients, 74 had native kidneys and 26 in the transplant subgroup had a collective history of 38 grafts. No patients lost grafts and only one with pre-existing ESRD received a transplant on treatment. Efficacy endpoints were achieved similarly in both subgroups. After 26 weeks, mean absolute estimated glomerular filtration rate increased from baseline to 61 and 37 ml/min/1.73 m2 in native (n = 71; P < 0.0001) and transplanted kidney (n = 25; P = 0.0092) subgroups. Two patients (one/subgroup) developed meningococcal infections; both recovered, one continued therapy. Eculizumab was well tolerated. Eculizumab improved haematologic and renal outcomes in both subgroups. In patients with histories of multiple graft losses, eculizumab protected kidney function.

Living Donor Kidney Transplantation in Atypical Hemolytic Uremic Syndrome: A Case Series.

BACKGROUND: The development of complement inhibitors has greatly improved the outcome of patients with atypical hemolytic uremic syndrome (aHUS), making kidney transplantation a more feasible option. Although prophylactic eculizumab therapy may prevent recurrent disease after transplantation, its necessity for all transplant recipients is debated. STUDY DESIGN: A case series. SETTING & PARTICIPANTS: Patients with aHUS who underwent living donor kidney transplantation after 2011 at 2 university centers, prospectively followed up with a protocol of eculizumab therapy limited to only recipients with documented posttransplantation recurrent thrombotic microangiopathy. In addition, the protocol emphasized lower target level tacrolimus and aggressive treatment of high blood pressure. OUTCOMES: Recurrence of aHUS, kidney function, acute kidney injury. RESULTS: We describe 12 female and 5 male patients with a mean age of 47 years. 5 patients had lost a previous transplant due to aHUS recurrence. 16 patients carried a pathogenic or likely pathogenic variant in genes encoding complement factor H, C3, or membrane cofactor protein, giving a high risk for aHUS recurrence. Median follow-up after transplantation was 25 (range, 7-68) months. One patient had aHUS recurrence 68 days after transplantation, which was successfully treated with eculizumab. 3 patients were treated for rejection and 2 patients developed BK nephropathy. At the end of follow-up, median serum creatinine concentration was 106 (range, 67-175) µmol/L and proteinuria was negligible. LIMITATIONS: Small series and short duration of follow-up. CONCLUSIONS: Living donor kidney transplantation in aHUS without prophylactic eculizumab treatment appears feasible.

Favorable long-term outcomes of isolated liver transplantation in a child with atypical hemolytic uremic syndrome caused by a novel complement factor H mutation
.

Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury that is usually caused by complement dysregulation. Complement factor H (CFH) is a regulator of the complement system produced in the liver, and CFH gene mutations are the most frequent causes of aHUS. To date, the therapeutic options for aHUS with CFH mutations have consisted of plasma infusions, plasma exchange, kidney transplantation, isolated liver transplantation, or combined liver and kidney transplantation. Recently, eculizumab, a humanized monoclonal antibody directed against complement C5, has been proven to be effective against aHUS. However, life-long eculizumab maintenance therapy is usually required for aHUS; therefore, other curative options should be considered. We describe a case of neonatal onset aHUS caused by a novel mutation of CFH and treated with an isolated liver transplantation at the age of 24 months. Nearly 5 years post-transplant, the patient's health has been generally good without evidence of aHUS. This case report suggests that isolated liver transplantation in aHUS patients with CFH mutations and preserved eGFR could be a curative therapeutic option in contrast to long-term eculizumab therapy.
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Cost-effectiveness of eculizumab treatment after kidney transplantation in patients with atypical haemolytic uraemic syndrome.

Background: Kidney transplantation in patients with atypical haemolytic uraemic syndrome (aHUS) is frequently complicated by recurrence of aHUS, often resulting in graft loss. Eculizumab prophylaxis prevents recurrence, improving graft survival. An alternative treatment strategy has been proposed where eculizumab is administered upon recurrence. We combined available evidence and performed a cost-effectiveness analysis of these competing strategies. Methods: A cost-effectiveness analysis using a decision analytical approach with Markov chain analyses was used to compare alternatives for aHUS patients with end-stage renal disease (ESRD): (i) dialysis treatment, (ii) kidney transplantation, (iii) kidney transplantation with eculizumab therapy upon recurrence of aHUS, (iv) kidney transplantation with eculizumab induction consisting of 12 months of prophylaxis and (v) kidney transplantation with lifelong eculizumab prophylaxis. We assumed that all patients received a graft from a living donor and that recurrence probability was 28.4% within the first year of transplantation. Results: At 8.34 quality-adjusted life years (QALYs) gained and a cost of €402 412, kidney transplantation without eculizumab was the least costly alternative. By comparison, dialysis was more costly and resulted in fewer QALYs gained. Eculizumab upon recurrence resulted in 9.55 QALYs gained at a cost of €425 097. The incremental cost-effectiveness ratio (ICER) was €18 748 per QALY. Both eculizumab induction and lifelong eculizumab were inferior to eculizumab upon recurrence, as both resulted in fewer QALYs gained and higher costs. Conclusions: Kidney transplantation is more cost effective than dialysis to treat ESRD due to aHUS. Adding eculizumab treatment results in a substantial gain in QALYs. When compared with eculizumab upon recurrence, neither eculizumab induction nor lifelong eculizumab prophylaxis resulted in more QALYs, but did yield far higher costs. Therefore, eculizumab upon recurrence of aHUS is more acceptable.

Long-term successful liver-kidney transplantation in a child with atypical hemolytic uremic syndrome caused by homozygous factor H deficiency.

BACKGROUND: Rational options for the treatment of end-stage renal disease (ESRD) due to atypical hemolytic uremic syndrome (aHUS) in children are still open to discussion. In the case of human complement factor H (CFH) deficiency, the choice is either kidney transplantation in combination with eculizumab, a humanized anti-C5 monoclonal antibody, or a combined liver-kidney transplantation. CASE-DIAGNOSIS/TREATMENT: A child with a homozygous CFH deficiency underwent a successful liver-kidney transplantation. CFH levels normalized within days. After 6 years of follow-up, the graft function (Cockroft clearance 100 ml min-1 1.73 m-2) and the liver functions were normal. RESULTS AND CONCLUSIONS: The results of this long-term follow-up confirm that combined liver-kidney transplantation remains a reasonable option in patients with ESRD due to aHUS when an identified genetic abnormality of the C3 convertase regulator synthesized in the liver has been identified.

[Genetics of aHUS and transplant recurrence]. / Genetica della Sindrome Emolitico Uremica atipica e recidiva nel trapianto.

Hemolytic uremic syndrome (HUS) is a rare disease with a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Several genetic and acquired abnormalities leading to abnormal activation of the alternative pathway of complement have been identified in patients with atypical HUS (aHUS). Studies over the past decade have shown that the risk of post-transplant recurrence of aHUS depends on the underlying genetic abnormality. The risk is high in patients with mutations in genes (CFH, CFI, C3, CFB) encoding circulating complement proteins and regulators, while patients with mutations in membrane cofactor protein (MCP) and diacylglycerol kinase ɛ (DGKE) generally show good transplant outcome. Recent data provided evidence about the efficacy of the anti-C5 monoclonal antibody Eculizumab in the prevention and treatment of post-transplant aHUS recurrences.

Successful living-related renal transplantation in a patient with factor H antibody-associated atypical hemolytic uremic syndrome.

CFH-Ab-associated aHUS requires different diagnostic and therapeutic approaches and then the genetically defined aHUS forms. The risk of post-transplant recurrence with graft dysfunction in CFH-Ab aHUS is not well documented. It is suggested that recurrence can be expected if a significant CFH-Ab load persists at the time of transplantation. A pretransplant procedure to reduce CFH-Ab titer seems reasonable, but accurate recommendations are lacking. Whether further prophylactic interventions after transplantation are necessary has to be decided on an individual basis. We report the case of a late diagnosed CFH-Ab HUS with initial ESRD and a successful living-related renal transplantation over a post-transplant period of four and a half years on the basis of a prophylactic pretransplant IVIG admission.

Favorable four-yr outcome after renal transplantation in a patient with complement factor H antibody and CFHR1/CFHR3 gene mutation-associated HUS.

UNLABELLED: aHUS is a clinical challenge for successful renal transplantation. CASE REPORT: A 14-yr-old girl lost her kidneys at the age of 7, due to CFH antibodies and CFH-related protein (CFHR1/CFHR3) homozygous deletion-associated aHUS. CFH, CFI, and MCP gene mutations were excluded. The patient was a candidate for renal transplantation despite persistent presence of CFH antibodies (up to 539 AU/mL). Treatment with MMF, IVIG, and repeated PF (n = 8) was introduced while being placed on urgent waiting list. Three years after aHUS onset, the patient underwent the deceased donor renal transplantation "under cover" of PF, as PF was performed directly prior to surgery and, then, PFs were repeated up to overall 14 sessions. Quadruple immunosuppression (basiliximab + tacrolimus + MMF + prednisolone) was used. Moderate symptoms of aHUS (hemolysis, low platelets, and low C3) were present within first seven days post-transplant and then normalized with PF therapy. The patient remained stable during four yr of further follow-up after transplantation. CONCLUSION: Specific pre- and post-transplant management allowed successful renal transplantation in a CFH antibody-positive patient.