Eculizumab therapy in a child with hemolytic uremic syndrome and CFI mutation

Background

Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in childhood. It usually occurs after a prodromal episode of diarrhea and it leads to significant morbidity and mortality during the acute phase. However, cases that start as diarrhea-positive HUS whose renal function fail to recover should be screened for genetic disorders of the complement system, which is called atypical HUS (aHUS).

Case-Diagnosis/Treatment

We herein report a 10-year-old girl, who initially came with bloody diarrhea and had features of HUS with delayed renal and hematological recovery despite plasma therapy. Eculizumab (600 mg/week) was initiated on day 15 for atypical presentation and later a complement factor I (CFI) mutation was detected. The girl recovered diuresis within 24 h and after the third eculizumab infusion, hemoglobin, platelet, and C3 levels normalized; renal function improved; and proteinuria completely disappeared in 2 weeks.

Conclusion

It is our belief that eculizumab can be the treatment of choice in children who have plasma exchange-refractory HUS with defective regulation of the alternative complement pathway.     

Neonatal onset atypical hemolytic uremic syndrome successfully treated with eculizumab

Background

Atypical hemolytic uremic syndrome (aHUS) is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Neonatal cases are extremely uncommon. Plasma therapy is the first choice therapy in patients with aHUS based on the belief of an underlying complement dysregulation. Alternatively, eculizumab, which targets complement 5, is used to block complement activation.

Case-diagnosis/treatment

Sudden onset macroscopic hematuria, hypertension, and bruises over the entire body were noted in a 5 day-old newborn. Investigations revealed hemolytic anemia, thrombocytopenia, renal impairment, and a low serum C3, leading to the diagnosis of aHUS. Fresh frozen plasma (FFP) infusions and peritoneal dialysis for acute kidney injury were initiated. This approach yielded full renal and hematological remission. The patient was discharged with FFP infusions, but subsequently developed three life-threatening disease recurrences at 1, 3, and 6 months of age. The last relapse presented with uncontrolled hypertension and impaired renal function while the patient was receiving FFP infusions. After the first dose of eculizumab, his renal and hematological parameters returned to normal and his blood pressure normalized. Genetic screening of the CFH gene revealed a novel homozygous p. Tyr1177Cys mutation.

Conclusion

Eculizumab can be considered as an alternative to plasma therapy in the treatment of specific patients with aHUS, even in infants.     

Long-term remission of atypical HUS with anti-factor H antibodies after cyclophosphamide pulses

Background

Anti-complement factor H (CFH) autoantibody (Ab)-associated atypical hemolytic uremic syndrome (aHUS) has a poor prognosis, but no consensus exists on its treatment.

Methods

We report the follow-up of four children with anti-CFH Ab (8,000 to >32,000 arbitrary units)-associated aHUS after plasma exchanges (PEs), prednisone, and cyclophosphamide pulse therapy with the evolution of anti-CFH Ab titers and kidney function.

Results

Patient 1 received PEs + prednisone + cyclophosphamide pulses after two relapses following PEs and then PEs + rituximab. The other three patients were treated with PEs + prednisone + cyclophosphamide pulses as a first-line therapy. In our four patients, the induction protocol combining PEs + prednisone + cyclophosphamide pulses led to a rapid and sustained remission up to 6 years, 4 years and 4 months without any maintenance therapy. Kidney function was normal and anti-CFH Ab titer decreased, but remained detectable during remission without any clinical or biological signs of relapse.

Conclusions

We demonstrate the long-term efficiency and safety of cyclophosphamide pulses combined with PEs and prednisone in anti-CFH Ab-associated aHUS leading to a prolonged decrease in anti-CFH Ab titers and prevention of relapses without the need for maintenance therapy.     

Efficacy and safety of eculizumab in childhood atypical hemolytic uremic syndrome in Japan

Background

Atypical hemolytic uremic syndrome (aHUS) is a severe life-threatening disease with frequent progression to end-stage renal disease (ESRD). Eculizumab, a humanized anti-C5 monoclonal antibody targeting the activated complement pathway, has recently been introduced as a novel therapy against aHUS. We, therefore, investigated the efficacy and safety of eculizumab in Japanese pediatric patients.

Methods

We retrospectively analyzed clinical course and laboratory data of the first ten children with aHUS treated with eculizumab nationwide.

Results

Seven patients were resistant to plasma therapy and three were dependent on it. Causative gene mutations were found in five patients. Two patients had anti-complement factor H autoantibody. Three patients had a family history of thrombotic microangiopathy (TMA). After initiation of eculizumab, all patients immediately achieved hematological remission and could successfully discontinue plasma therapy. The median periods to normalization of platelet count, lactate dehydrogenase levels and disappearance of schistocytes were 5.5, 17 and 12 days, respectively. Nine patients recovered their renal function and the median period to terminate renal replacement therapy (RRT) was 3 days. However, two patients progressed to ESRD and required chronic RRT at the last observation. No patients had a relapse of TMA under regular eculizumab therapy. No serious adverse events occurred during the follow-up period.

Conclusions

Eculizumab is efficacious and well-tolerated therapy for children with aHUS. Although pathogenic mutations could not be detected in five patients, all patients showed immediate normalization of hematological abnormalities, strongly suggesting complement-related aHUS. This prompt hematological amelioration can become an indicator for therapeutic efficacy of eculizumab. However, appropriate indications and optimal duration of the treatment remain unclear.

     

Macrovascular involvement in a child with atypical hemolytic uremic syndrome

Background

Atypical hemolytic uremic syndrome (aHUS) is a disorder of the complement system which leads to thrombotic microangiopathy. It is caused by either acquired or hereditary defects in the activation or regulation of the alternative complement pathway and is therefore considered to be a disease of local complement dysregulation in microvasculature with predominantly renal involvement. However, extrarenal manifestations are observed in approximately one-fifth of aHUS patients, with the myocardium and central nervous system (CNS) being involved most often. Additionally, there have been a few reports of aHUS with cerebral artery stenoses or periphereal gangrene, suggesting the possibility of ‘macrovascular’ involvement in aHUS.

Case-diagnosis/treatment

We present a child with early onset aHUS and a C3 gain-of-function mutation who developed cerebral artery stenoses, leading ultimately to death due to a massive stroke 9 days after successful renal transplantation under prophylactic eculizumab treatment. Similar cases described in the literature are also briefly summarized.

Conclusions

The disease course in our patient with aHUS confirms that dysregulated complement activation can induce arterial steno-occlusive lesions in the absence of acute episodes of HUS. Further studies are required to document the frequency of such macrovascular complications and the role of eculizumab treatment in preventing their development and progression.     

Atypical hemolytic uremic syndrome in the Tunisian population

Background

Hemolytic uremic syndrome consists of a triad of acquired hemolytic anemia, thrombocytopenia and renal failure.

Aim

Our objectives were to determine epidemiology, clinical and laboratory characteristics of patients with atypical hemolytic uremic syndrome (aHUS) to determine the relationship between the complement protein deficit and aHUS in the Tunisian population.

Methods

We studied retrospectively four cases of atypical HUS in adults admitted in the Nephrology Department of Fattouma Bourguiba Universitary Hospital in Monastir between 2000 and 2008.

Results

Three patients had renal failure that required dialysis. One of them received kidney transplantation with no further recurrence of aHUS. Three patients had normal C3, C4, CFH, and FB levels, and in all patients anti-FH autoantibodies were absent. The kidney biopsy of one patient showed in addition to lupus glomerulonephritis histological findings consistent with TMA. A decrease in C3, C4 and CFH levels in this patient was found both before and after the cure.

Conclusion

Nephrologists should be aware of autoimmune conditions and genetic abnormalities of the complement regulatory genes as possible pathogenic mechanisms in atypical HUS patients.     

Neurologic involvement in atypical hemolytic uremic syndrome and successful treatment with eculizumab

Background

Atypical hemolytic uremic syndrome (aHUS) is associated with defective regulation of the complement pathway. Neurological involvement is the most common extrarenal complication and represents a major cause of mortality and morbidity.

Case-diagnosis/treatment

Two girls aged 11 and 6 years, respectively, developed aHUS and were treated immediately with plasma exchange (PE) and fresh frozen plasma infusion (PI). Although initial improvement in renal function was seen in both cases, the first patient showed progressing thrombotic microangiopathy (TMA) despite daily PE, and neurological manifestations (seizures, vision loss, loss of balance, and confusion) developed after 1 month. The second patient developed cerebral TMA (seizures, vision loss, and nystagmus) 6 days after initial presentation and remained unresponsive to PE/PI. Neurological symptoms were similar in both patients, even though they had different complement protein mutations. Treatment with eculizumab achieved complete control of neurological symptoms within 24 h and gradually normalized hematological and renal parameters in both children.

Conclusions

Based on our two cases, we conclude that eculizumab is a rapid-acting, effective, and life-saving treatment for pediatric patients with aHUS and severe neurological involvement, which works by inhibiting complement-mediated TMA in the kidney and other organs, such as the brain.     

Successful long-term outcome after renal transplantation in a patient with atypical haemolytic uremic syndrome with combined membrane cofactor protein CD46 and complement factor I mutations

Background

Atypical haemolytic uremic syndrome (aHUS) is often associated with a high risk of disease recurrence and subsequent graft loss after isolated renal transplantation. Evidence-based recommendations for a mutation-based management after renal transplantation in aHUS caused by a combined mutation with complement factor I (CFI) and membrane cofactor protein CD46 (MCP) are limited.

Case-diagnosis/Treatment

We describe a 9-year-old boy with a first manifestation of aHUS at the age of 9 months carrying combined heterozygous mutations in the CFI and MCP genes. At the age of 5 years, he underwent isolated cadaveric renal transplantation. Fresh frozen plasma was administered during and after transplantation, tapered and finally stopped after 3 years.

Conclusions

During the 5-year follow-up after transplantation there have been no signs of aHUS recurrence and graft function has remained good. The combination of heterozygous MCP and CFI mutations with aHUS might have a positive impact on the post-transplant course, possibly predicting a lower risk of aHUS recurrence after an isolated cadaveric renal transplantation     

Novel C3 mutation p.Lys65Gln in aHUS affects complement factor H binding

Background

Atypical hemolytic uremic syndrome (aHUS) is associated with mutations affecting complement proteins and regulators and with autoantibodies against complement factor H (CFH). Approximately half of the aHUS patients progress to end-stage renal disease. DNA analysis of the risk factor genes is important for prognosis of aHUS recurrence after renal transplantation.

Methods

Mutational screening of C3 encoding the central complement component was performed by Sanger sequencing in 70 aHUS patients. Mutated and wild type recombinant C3b proteins were produced and their affinity to CFH was analyzed by ELISA.

Results

A single novel missense change p.Lys65Gln in C3 was found in 3 aHUS patients. The alteration leads to decreased binding of C3b to CFH in vitro. All three patients acquired the illness as adults and had a first aHUS episode after renal transplantation or suffered recurrence of the disease after transplantation.

Conclusions

The novel C3 change was found in 3 aHUS patients. It results in decreased C3b binding to CFH and thus might lead to impaired C3b inactivation in vivo. The p.Lys65Gln is likely to be associated with aHUS after kidney transplantation and, therefore, might be an important prognostic factor.     

Long-term eculizumab improves clinical outcomes in atypical hemolytic uremic syndrome

Background

Atypical hemolytic uremic syndrome (aHUS) is a rare genetic disorder caused by chronic uncontrolled complement activation.

Case-diagnosis/treatment

We present a 4-year-old girl with aHUS who had multiple severe clinical manifestations of thrombotic microangiopathy (TMA) including acute kidney injury, dilated cardiomyopathy, and cardiorespiratory arrest. She was managed with intensive plasma exchange and hemodialysis, which could not halt the progression of TMA. The initial single dose of eculizumab only temporarily improved the clinical symptoms of TMA. Sustained improvement of renal, hematological, and cardiac values were only achieved upon institution of chronic treatment with eculizumab. During long-term treatment with eculizumab (>2.5 years), she has had no further clinical manifestations of TMA, and required neither plasma exchange nor hemodialysis.

Conclusion

Chronic eculizumab treatment was associated with control of complement-mediated TMA and sustained long-term improvement in renal and cardiac function.     

Successful treatment of DEAP-HUS with eculizumab

Background

Deficiency of complement factor H-related (CFHR) proteins and CFH autoantibody-positive hemolytic uremic syndrome (DEAP-HUS) represents a unique subgroup of complement-mediated atypical HUS (aHUS). Autoantibodies to the C-terminus of CFH block CFH surface recognition and mimic mutations found in the genetic form of (CFH-mediated) aHUS. CFH autoantibodies are found in 10–15 % of aHUS patients and occur—so far unexplained—almost exclusively in the background of CFHR1 or CFHR3/CFHR1 deletions.

Methods

As a well-defined role for eculizumab in the treatment of complement-mediated aHUS is becoming established, its role in DEAP-HUS is less conspicuous, where a B-cell-depleting and immunosuppressive treatment strategy is being proposed in the literature.

Results

We here show eculizumab to be safe and effective in maintaining a disease-free state, without recurrence, in a previously plasma-therapy-dependent DEAP-HUS patient, and in another patient in whom, although showing a good clinical response to plasma therapy, the therapy was hampered by allergic reactions to fresh frozen plasma and contend there is a rationale for the use of eculizumab in concert with an immunosuppressive strategy in the treatment of DEAP-HUS. Considering the high rate of early relapse, the possible coexistence and contribution of both known and unknown complement-gene mutations, the probable pathogenic role of CFHR1 as a complement alternative pathway (CAP) regulator, the experimental nature of measuring and using anti-CFH autoantibodies to guide management, and until the positive reports of immunosuppression in addition to plasma therapy are confirmed in prospective studies, we feel that a complement-directed therapy should not be neglected in DEAP-HUS. Serial CFH autoantibody titer testing may become a valuable tool to monitor treatment response, and weaning patients off eculizumab may become an option once CFH autoantibody levels are depleted.

Conclusions

A prospective study of eculizumab treatment in a larger cohort of DEAP-HUS patients is required to validate the applicability of our positive experience.     

Additive antiproteinuric effect of enalapril and losartan in children with hemolytic uremic syndrome

Background

Angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers decrease postdiarrheal hemolytic uremic syndrome (D + HUS) sequelar proteinuria. However, proteinuria may persist in some patients. In nephropathies other than D + HUS, an additive antiproteinuric effect with coadministration of both drugs has been observed.

Methods

To assess such an effect in D + HUS, 17 proteinuric children were retrospectively studied. After a median period of 1 year post-acute stage (range 0.5–1.9) patients received enalapril alone for a median of 2.6 years (range 0.33–12.0) at a median dose of 0.4 mg/kg/day (range 0.2–0.56). As proteinuria persisted, losartan was added at a median dose of 1.0 mg/kg/day (range 0.5–1.5) during 2.1 years (range 0.5–5.0).

Results

The decrease in proteinuria with enalapril was 58.0 %, which was further reduced to 83.8 % from the initial value after losartan introduction. The percentage of reduction was significantly greater with the association of both drugs (p?=?0.0006) compared with the effect of enalapril exclusively (p?=?0.023). Serum potassium, glomerular filtration rate, and blood pressure remained unchanged.

Conclusions

Our results suggest that adding losartan to persisting proteinuric D + HUS children already on enalapril is safe and reduces proteinuria more effectively. Whereas this effect is associated with long-term kidney protection, it should be determined by prospective controlled studies.     

Does rituximab induce hypogammaglobulinemia in patients with pediatric idiopathic nephrotic syndrome?

Background

Rituximab (RTX) is a promising strategy for treating steroid-dependent idiopathic nephrotic syndrome (SDNS). RTX induces profound B-cell depletion, suggesting hypogammaglobulinemia as a potential side effect after long-term treatment.

Patients and methods

We analyzed immunoglobulin G (IgG) levels in 12 pediatric patients on RTX with a B-cell depletion of a minimum of 3 months and compared the results to 16 patients on orally administered immunosuppressive drugs, such as mycophenolate mofetil (MMF) and/or cyclosporine A (CyA). All patients were in stable remission of SDNS at the time of IgG analysis.

Results

IgG levels in the RTX group before RTX introduction were 6.2?±?1.0 g/L and were not significantly different from the MMF/CyA group (8.2?±?2.5 g/L). In the MMF/CyA group, five patients had at least one episode of hypogammaglobulinemia. In two of them, this episode was prolonged (>3 months), and only one required IgG supplementation. In the RTX group, eight patients had decreased IgG levels before RTX infusion. After RTX, hypogammaglobulinemia persisted in seven among those eight patients. No decreased IgG plasma levels were noted in patients with normal baseline IgG levels before RTX treatment.

Conclusion

RTX does not seem to directly induce decreased IgG levels in patients with SDNS, but it seems to prolong a preexisting low IgG levels.     

Atypical hemolytic uremic syndrome: a clinical conundrum

Background

Patients negative for Shiga toxin-producing E. coli (STEC) are categorized as having atypical hemolytic uremic syndrome (HUS) and are associated with an increased risk for complement mutations and poorer prognosis compared with typical HUS. However, STEC identification is limited by the natural history of HUS.

Methods

The current study is aimed at identifying HUS patients with poor outcomes based on the presence or absence of diarrhea (D) or Shiga toxin (S). A single-center retrospective review (2003–2012) of 42 HUS patients (follow-up 31.3?±?38.7 months) was carried out. HUS was managed clinically with supportive treatments such as dialysis, plasma therapy, and eculizumab.

Results

There was no significant difference in the D+S+ (31 %), D+S? (50 %) and D?S? (19 %) groups in the outcome variables of chronic kidney disease stages I–II (100 % vs 81 % vs 67 %) and proteinuria at follow-up (20 % vs 12.5 % vs 33.3 %), hospitalization duration (16.0?±?8.7 vs 18.1?±?9.5 vs 23.7?±?12.9 days); dialysis requirement (50 % vs 81 % vs 66.7 %), and dialysis duration (10.2?±?1.9 vs 33.3?±?72.8 vs 10.3?±?8.1 days). There was no significant difference in study outcomes in STEC+ (59 %) versus STEC– (41 %) groups. Genetic testing was performed in 12 % of HUS patients based on age, recurrent HUS, familial HUS, persistently low C3, or prolonged dialysis, and 80 % of the patients tested were positive for genetic mutations.

Conclusions

Our study does not show poorer outcomes in STEC? HUS. Indications and the cost-effectiveness of genetic testing, eculizumab, and plasmapheresis in STEC? HUS need to be evaluated further.

     

Adherence to a femoral neck fracture treatment guideline

Purpose

In 2007 the Dutch Surgical Society published a clinical practice guideline for the treatment of hip fracture patients, based on the best available international evidence at that time. We investigated to what extent treatment of femoral neck fracture patients in the Netherlands corresponded with these guidelines, and determined differences in patient characteristics between the treatment groups.

Methods

All femoral neck fracture patients treated in 14 hospitals between February 2008 and August 2009 were included. Patient characteristics, X-rays, and treatment data were collected retrospectively.

Results

From a total of 1,250 patients 59 % had been treated with arthroplasty, 39 % with internal fixation, and 2 % with a non-operative treatment. While 74 % of the treatment choices complied with the guideline, 12 % did not. In 14 % adherence could not be determined from the available data. Arthroplasty was preferred over internal fixation in elderly patients with severe comorbidity, pre-fracture osteoporosis and a displaced fracture, who were ambulatory with aids pre-fracture (odds ratio, OR 2.2–58.1). Sliding hip screws were preferred over cancellous screws in displaced fractures (OR 1.9).

Conclusions

Overall guideline adherence was good. Most deviations concerned treatment of elderly patients with a displaced fracture and implant use in internal fixation. Additional data on these issues, preferably at a higher scientific level of evidence, is needed in order to improve the guideline and to reinforce a more uniform treatment of these patients.     

Eculizumab in atypical haemolytic uraemic syndrome with severe cardiac and neurological involvement

Background

Atypical haemolytic uraemic syndrome (aHUS) is a rare disorder usually caused by dysregulation of the alternative complement pathway. Uncontrolled complement activation results in systemic complement-mediated thrombotic microangiopathy (TMA) and subsequent multi-organ damage. The two most common extrarenal complications comprise neurological and cardiovascular involvement. Eculizumab, a humanised anti-C5 monoclonal antibody, has recently been introduced as a therapy for this condition.

Case-diagnosis/treatment

A 19-month-old child suffering from aHUS with severe neurological involvement, dilated cardiomyopathy and renal impairment requiring dialysis received eculizumab as first-line treatment, initiated within 12 h of admission, resulting in significant improvements in her neurological state and normalisation of cardiac and renal function. These positive outcomes have been sustained with fortnightly eculizumab therapy (at the time of writing, on-going for 1 year). No further complications of TMA have occurred.

Conclusion

Severe cardiac involvement in a child with aHUS is an important indication for prompt, first-line treatment with eculizumab, resulting in rapid normalisation of cardiac function.     

Prospective 5-year follow-up of cyclosporine treatment in children with steroid-resistant nephrosis

Background

Cyclosporine has improved remission rates in children with steroid-resistant nephrotic syndrome (SRNS). However, little prospective long-term follow-up data is available.

Methods

We prospectively followed and analyzed 5-year outcomes of all 35 patients enrolled in our previous prospective multicenter trial with cyclosporine and steroids in children with SRNS. At enrollment, 23 cases were classified as minimal change (MC), five as diffuse mesangial proliferation (DMP), and seven as focal segmental glomerulosclerosis (FSGS).

Results

Renal survival at 5 years (median 7.7 years) was 94.3 %. Patient status was complete remission (CR) in 31 (88.6 %) (MC/DMP, 25; FSGS, 6); partial remission in one (FSGS); and non-remission in three (MC/DMP), including chronic kidney disease and end-stage kidney disease in one each. Among 31 patients with CR, 22 (71.0 %) were receiving treatment with immunosuppressants at 5 years, including cyclosporine in 19, and seven of these 22 continued to show frequent relapse. Response to cyclosporine at 4 months predicted 5-year outcome in 31 of 35 patients.

Conclusions

Although SRNS treatment with cyclosporine provides high renal survival and remission rates, many children require ongoing immunosuppression. Management has advanced from the prevention of end-stage kidney disease to the long-term maintenance of remission and management of relapse after induction therapy.     

A prospective audit of the use of diagnostic laparoscopy to establish the diagnosis of abdominal tuberculosis

Background

The incidence of abdominal tuberculosis is much higher in an HIV-positive cohort. The use of laparoscopy in the diagnostic work-up of suspected abdominal tuberculosis is underutilized and its use and efficacy in the context of HIV co-infection has never been examined.

Methods

A prospective clinical audit of the use of diagnostic laparoscopy was conducted in patients with clinically suspected abdominal tuberculosis but histologically or microbiologically unconfirmed tuberculosis at any site.

Results

From January 2008 to June 2010, 81 patients underwent diagnostic laparoscopy; 34 were male and 47 were female, with a mean age of 33 years, and 77 % were HIV-positive. Fifty-five patients (68 %) had positive histology or culture for tuberculosis. In 15 patients (19 %), histology revealed non-specific inflammation, no pathology was found in one patient, and no specimen was taken from one patient. Eighty percent of peritoneal deposits and 77 % of lymph nodes were positive for tuberculosis, whereas 35 % of ascitic fluid cultures were positive. In nine patients (11 %) an alternative diagnosis was found; nine patients (11 %) had conversion to laparotomy. There was no procedure-related death. Nine patients (11 %) died during the 2-month follow-up period.

Conclusions

Diagnostic laparoscopy avoids the morbidity and mortality of laparotomy in chronically ill patients, and reduces the rate of misdiagnosis of other abdominal conditions and unnecessary long-term therapy. Diagnostic laparoscopy and tissue sampling is a viable and reliable strategy in patients with suspected abdominal tuberculosis.     

Dorsal percutaneous screw fixation of delayed or nonunion of scaphoid fractures

Purpose

The purpose of the present study is to evaluate scaphoid delayed fractures or nonunions treated by percutaneous fixation with MRI correlations.

Methods

We evaluated 33 consecutive scaphoid delayed unions or nonunions treated by dorsal percutaneous fixation at a mean 16 months (range, seven to 48 months) after the operation. There were 31 male and two female patients with an average age of 29 years (range, 25–33 years).

Results

Pre-operative MRI revealed no signs of avascular necrosis. At the latest follow-up, all patients had good or excellent results.

Conclusion

We suggest dorsal percutaneous screw fixation for scaphoid delayed fractures or nonunions after eliminating the presence of AVN by pre-operative MRI examination.     

Liver transplantation for aHUS: still needed in the eculizumab era?

Background

The risk of disease recurrence after a kidney transplant is high in patients with atypical hemolytic uremic syndrome (aHUS) and mutations in the complement factor H (FH) gene (CFH). Since FH is mostly produced by the liver, a kidney transplant does not correct the genetic defect. The anti-C5 antibody eculizumab prevents post-transplant aHUS recurrence, but it does not cure the disease. Combined liver–kidney transplantation has been performed in few patients with CFH mutations based on the rationale that liver replacement provides a source of normal FH.

Methods

We report the 9-year follow-up of a child with aHUS and a CFH mutation, including clinical data, extensive genetic characterization, and complement profile in the circulation and at endothelial level. The outcome of kidney and liver transplants performed separately 3 years apart are reported.

Results

The patient showed incomplete response to plasma, with relapsing episodes, progression to end-stage renal disease, and endothelial-restricted complement dysregulation. Eculizumab prophylaxis post-kidney transplant did not achieve sustained remission, leaving the child at risk of disease recurrence. A liver graft given 3 years after the kidney transplant completely abrogated endothelial complement activation and allowed eculizumab withdrawal.

Conclusions

Liver transplant may definitely cure aHUS and represents an option for patients with suboptimal response to eculizumab.