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A man in his early 70s was transferred to our hospital due to rapid decline in renal function and inflammation throughout the colon, indicating severe ischaemic enteritis. On the day following the start of intensive care, a stool specimen tested positive for verotoxin, and haemolytic uraemic syndrome (HUS) was diagnosed. On the same day, his vital signs deteriorated suddenly, and emergency surgery was performed due to the possibility of intestinal necrosis and perforation. Severe inflammation extending to the serosal surface of the whole colon was observed, but there was no obvious intestinal necrosis or perforation. Advanced mucosal necrosis of the entire colon suggested sepsis due to bacterial translocation, and subtotal colectomy was performed to remove the infection source. Postoperative management was successful. This case demonstrates the importance of considering HUS in patients with severe renal dysfunction and bloody stools, as well as the significance of colectomy in such patients., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hemolytic uremic syndrome (HUS) can occur as a primary process due to mutations in complement genes or secondary to another underlying disease. HUS sometimes occurs in the setting of glomerular diseases, and it has been described in association with Denys-Drash syndrome (DDS), which is characterized by the triad of abnormal genitourinary development; a pathognomonic glomerulopathy, diffuse mesangial sclerosis; and the development of Wilms tumor., Case Presentation: We report the case of a 46, XX female infant who presented with HUS and biopsy-proven thrombotic microangiopathy. Next generation sequencing of genes with known mutations causative of atypical HUS found that she was homozygous for the Complement Factor H H3 haplotype and heterozygous for a variant of unknown significance in the DGKE gene. Whole exome sequencing identified a de novo heterozygous WT1 c.1384C > T; p.R394W mutation, which is classically associated with Denys-Drash syndrome (DDS). At the time of bilateral nephrectomy five months after her initial biopsy, she had diffuse mesangial sclerosis, typical of Denys-Drash syndrome, without evidence of thrombotic microangiopathy., Conclusion: This unique case highlights HUS as a rare but important manifestation of WT1 mutation and provides new insight into the genetics underlying this association.

Background: Hemolytic uremic syndrome (HUS) can be triggered by Shiga toxin producing Escherichia coli (STEC) infection or it can be defined as atypical HUS (aHUS) if it is related to uncontrolled complement activation. aHUS is characterized by a high incidence of recurrence after kidney transplantation, and it can also occur de novo in transplant recipients. Eculizumab is used both to prevent and to treat aHUS following kidney transplantation. In this paper, we report our centre experience and we present 4 cases of HUS in patients who underwent kidney transplantation., Methods: This is a single-center experience about HUS development in transplanted patients., Results: Patient 1 with end-stage renal disease (ESRD) due to STEC-HUS undergoing kidney transplantation without prophylactic therapy with eculizumab. Patient 2 with HUS secondary to an episode of diarrhea at 8 years old. After a slow progression to ESRD, she underwent kidney transplantation and she received prophylactic therapy with eculizumab due to the presence of anti-complement factor H antibodies. Patient 3 underwent pre-emptive living donor ABO-incompatible kidney transplantation and developed HUS secondary to antibody-mediated rejection. Patient 4 developed de novo HUS 16 years after kidney transplantation without a known cause., Conclusion: The correct diagnosis of HUS and the identification of the complement component alterations in case of aHUS are important parameters required to predict the risk of post-transplant recurrence of the disease. In the cases we reported, eculizumab has been found to be effective both to prevent and to treat aHUS following kidney transplantation., (© 2017 S. Karger AG, Basel.)

Purpose: Haemolytic uraemic syndrome (HUS) is the commonest childhood cause of acute renal failure. Peritoneal dialysis peritonitis (PDP) is a well-recognised complication, with some children requiring surgical intervention (SI). The aim of this study is to determine whether the presence of enteric organisms in cases of PDP might predict the need for SI., Methods: Retrospective, 5-year (2009-2014) case note review of all HUS cases requiring PD presenting to a single centre. Mann-Whitney U test was used for continuous non-parametric data and χ (2) for categorical data., Results: 48 children required PD for HUS, 18/48 (38 %) developed PDP and of these 5/18 (28 %) required SI (subtotal colectomy n = 4, small bowel resection n = 1). Peritoneal fluid was cultured as part of the work-up for PDP. The presence of enteric organisms was associated with a 10.4 fold relative risk of requiring surgery (p = 0.02, 95 % CI 1.5-71.9), with 4/5 of these patients requiring surgery (median 17 days post-culture result). Only 1/13 patients not requiring surgery grew gram-negative bacteria., Conclusion: The presence of enteric bacteria in patients with PDP significantly decreases the chances of successful conservative management. In these patients early involvement of the surgical team is essential with a low threshold for SI.

Background: There is currently no large study of the U.S. transplant registry comparing the outcome of kidney transplantation for adults with and without hemolytic uremic syndrome (HUS). To date, information on the outcome of transplants for HUS in the U.S. is derived from single or combined-centers studies, but none has been of a nationwide scope., Material and Methods: We retrospectively studied a US registry for the outcome of 323 kidney transplants in adults with HUS and of 121,311 transplants in adults with other renal diseases during the period 1999-2009. We analyzed patient, over-all, and death-censored graft survival in the 5 years following transplantation using Kaplan-Meir curves and Cox hazard models., Results: In the 5 years following kidney transplantation, patient mortality was not significantly different [Hazard Ratio (HR) 1.27, 95% Confidence Interval (CI) 0.78-2.08], but death-censored graft loss was twice as common (HR 2.05, 95% CI 1.53-2.73) for allograft recipients whose native kidney disease was HUS compared to other transplant recipients. The subgroup (n=40 cases) with post-transplant HUS recurrence had a 5-year graft loss rate 5 times that of the subgroup (n=283 cases) without HUS-recurrence (graft survival 14.7% vs.77.4%, log rank 116.5; p<0.001)., Conclusions: In the largest US series to date of kidney transplants for adults with HUS, 5-year patient survival was not different, but graft outcome was inferior in recipients whose native renal disease were HUS compared to recipients with other kidney diseases. Native kidney HUS is associated with a 2-fold increased risk of death-censored graft loss after kidney transplantation.

Background: Atypical hemolytic uremic syndrome (aHUS) evolves into end-stage renal failure in nearly half of affected patients and is associated with defective regulation of the alternative complement pathway. Patients with a complement factor H (CFH) mutation have a 30-100% risk of graft loss due to aHUS recurrence or graft thrombosis. Since CFH is produced predominantly by the liver, combined liver-kidney transplant is a curative treatment option. One major unexpected risk includes liver failure secondary to uncontrolled complement activation. We report a successful combined liver-kidney transplantation with perioperative plasma exchange and use of the humanized anti-C5 monoclonal antibody eculizumab., Case Diagnosis/treatment: An 11-month-old female presented with oliguric renal failure after 3 weeks of flu-like symptoms in the absence of diarrhea. Following the identification of Escherichia coli 0157:H7 in her stool, she was discharged home on peritoneal dialysis with a diagnosis of Shiga toxin-associated HUS. Three months later, she developed severe anemia, thrombocytopenia, and neurological involvement. aHUS was diagnosed and confirmed, and genetic testing revealed a mutation in CFH SCR20. Once donor organs became available, she received preoperative plasma exchange followed by eculizumab infusion with intra-operative fresh frozen plasma prior to combined liver-kidney transplant. At 19 months post-transplant, she continues to have excellent allograft and liver function without signs of disease recurrence., Conclusion: Perioperative use of eculizumab in conjunction with plasma exchange during simultaneous liver-kidney transplant can be used to inhibit terminal complement activity, thereby optimizing successful transplantation by reducing the risk of graft thrombosis.

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.

Purpose of Review: This review considers the use of eculizumab in the treatment of atypical haemolytic uraemic syndrome (aHUS) as well as the other complement-mediated renal diseases, including dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). In addition, a brief discussion of the effectiveness of eculizumab for the prevention of antibody-mediated rejection (AMR) in the setting of renal transplant and the treatment of shiga toxin associated haemolytic uraemic syndrome (STEC HUS) is also provided., Recent Findings: No randomized controlled trials exist to support the use of eculizumab in renal disease. The results of two unpublished, prospective adult and adolescent trials support its utility in aHUS, whereas retrospective data support the effectiveness in paediatric aHUS. These two data sets form the basis of the sole renal indication for eculizumab. One small, single-centre trial and a growing number of case reports support the use of eculizumab in C3 glomerulopathy (C3G). There are limited trial data in AMR and renal transplant. Finally, there are conflicting data for the use of eculizumab in STEC HUS., Summary: The cumulative published data establish the effectiveness of eculizumab in a select group of renal diseases that have at the centre of their disease either abnormal complement control or maladaptive complement activation.

Objectives: To describe two cases of profound hearing loss secondary to enterohaemorrhagic Escherichia coli infection, and to report the efficacy of subsequent cochlear implantation., Results: The first case was a four-year-old girl admitted to hospital with Escherichia coli O157 infection and haemolytic uraemic syndrome. Mild hearing loss was confirmed five months after discharge, progressing to profound loss three months later. At the age of seven years, she underwent cochlear implantation, with remarkable improvement in speech perception and production. The second case was a three-year-old boy admitted with haemolytic uraemic syndrome caused by Escherichia coli O111 infection. One year after disease onset, profound hearing loss was confirmed. Cochlear implantation at the age of five years produced significant recovery of auditory function., Conclusion: This study represents the first published report of secondary hearing loss after recovery from haemolytic uraemic syndrome caused by enterohaemorrhagic Escherichia coli. It indicates that cochlear implantation can restore hearing function in such patients.

In the past decade, a large body of evidence has accumulated in support of the critical role of dysregulation of the alternative complement pathway in atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathies. These findings have paved the way for innovative therapeutic strategies based on complement blockade, and eculizumab, a monoclonal antibody targeting the human complement component 5, is now widely used to treat aHUS. In this article, we review 28 case reports and preliminary data from 37 patients enrolled in prospective trials of eculizumab treatment for episodes of aHUS involving either native or transplanted kidneys. Eculizumab may be considered as an optimal first-line therapy when the diagnosis of aHUS is unequivocal and this treatment has the potential to rescue renal function when administered early after onset of the disease. However, a number of important issues require further study, including the appropriate duration of treatment according to an individual's genetic background and medical history, the optimal strategy to prevent post-transplantation recurrence of aHUS and a cost-efficacy analysis. Data regarding the efficacy of eculizumab in the control of C3 glomerulopathies are more limited and less clear, but several observations suggest that eculizumab may act on the most inflammatory forms of this disorder.

We report the first observation of successful kidney transplantation under pre-emptive eculizumab treatment in a 7-year-old boy with atypical hemolytic uremic syndrome (aHUS) and a known hybrid CFH/CFHR1 gene, who was dependent on plasma therapy during the 3-year dialysis period. The hybrid CFH/CFHR1 protein has an altered C3b/C3d binding, is incapable to protect cells from complement attack and is directly implicated in aHUS pathogenesis. There was no evidence of recurrence during the first 16-month follow-up period. We conclude that eculizumab alone, without plasma therapy (plasma infusion and/or plasma exchange), is sufficient to prevent recurrence of aHUS and to maintain long-term graft function., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy often caused by mutations in complement factor H (CFH), the main regulator of alternative complement pathway. Because CFH is produced mainly by the liver, combined liver-kidney transplantation is a reasonable option in treatment of patients with severe aHUS. We studied complement activation by monitoring activation markers during liver transplantation in two aHUS patients treated extensively with plasma exchange and nine other liver transplantation patients. After the reperfusion, a clear increase in all the activation markers except C4d was observed indicating that the activation occurs mainly through the alternative pathway. Concentration of SC5b-9 was higher in the hepatic than the portal vein indicating complement activation in the graft. Preoperatively and early during the operation, the aHUS patients showed highest C3d concentrations but otherwise their activation markers were similar to the other patients. In the other patients, correlation was found between perioperative SC5b-9 concentration and postoperative alanine aminotransferase and histological changes. This study explains why supply of normal CFH by extensive plasma exchange is beneficial before combined liver-kidney transplantation of aHUS patients. Also the results suggest that perioperative inhibition of the terminal complement cascade might be beneficial if enhanced complement activation is expected., (© 2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Atypical hemolytic uremic syndrome (aHUS) in childhood is a rare disease associated with high morbidity and mortality. Most cases progress to end-stage renal failure. In approximately 50% of affected patients, mutations in genes encoding complement proteins are causative of the impairment in the regulation of the complement alternative pathway. This leads to deficient host cell protection and inappropriate complement activation on platelets and endothelial cells, particularly in the kidneys. Complement factor H (FH) heterozygosity induces unregulated activation of the membrane attack complex (MAC) C5b-9. Present therapeutic strategies for aHUS include lifelong plasmapheresis and renal dialysis. Unfortunately, kidney transplantation is frequently an unsatisfactory intervention due to the high rate of post-transplantation HUS recurrence, particularly in patients with FH mutation. Combined liver-kidney transplantation is also associated with poor outcome, mostly as a result of premature liver failure secondary to uncontrolled complement activation. Eculizumab is a complement C5 antibody that inhibits complement factor 5a (C5a) and the formation of the MAC. Thus, this antibody may be a promising new agent for patients with an aHUS undergoing kidney transplantation. We present the first case of a young patient with aHUS who received eculizumab as prophylactic treatment prior to a successful kidney transplantation.

Atypical hemolytic uremic syndrome was diagnosed in a 62-year-old man. Sequencing of the CFH gene, which encodes complement factor H, revealed a heterozygous adenine to guanine mutation at nucleotide 3550 of the complementary DNA, leading to a predicted substitution of alanine for threonine at amino acid position 1184 in the protein (c.3550A>G, p.Thr1184Ala). Three years later, he received a simultaneous liver-kidney transplant with plasmapheresis and intratransplant plasma infusion. The postoperative course was complicated by an anastomotic biliary stricture that was treated successfully using endoscopic stenting. One year later, he has excellent function of both transplants, emphasizing that simultaneous liver-kidney transplant is a valuable treatment option in the management of adult patients with atypical hemolytic uremic syndrome., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

A 33-year-old woman with a history of chronic transplant dysfunction because of repeated bouts of haemolytic uraemic syndrome (HUS) was considered for a second transplant. Extensive genetic investigation of the complement system was executed to rule out known mutations prone to development of HUS. This case illustrates the importance of genetic screening in patients with recurrent HUS.

A 15-year-old male patient developed atypical hemolytic uremic syndrome (aHUS) at 16 months of age leading to end-stage renal disease. The family history was suggestive of autosomal dominant aHUS, and he was more recently found to have a C3 heterozygous gene mutation (1835C>T mutation in exon 14, which determines the amino-acidic substitution R570W) with no other complement abnormalities. He had two renal transplants, the first at 2.5 years, and the second at 8 years of age, but allograft dysfunction developed in both transplants leading to graft failure due to recurrent HUS at 5 years and 18 months post-transplantation respectively. At 15 years of age he received a third transplant from a deceased donor with pre-emptive plasmapheresis. He had immediate graft function and nadir serum creatinine was 1.3-1.4 mg/dl. Severe allograft dysfunction and hypertension developed 2 months after transplantation following influenza infection. Renal allograft biopsy showed thrombotic microangiopathy. He received plasmapheresis followed by eculizumab therapy. Allograft function returned to baseline 3 weeks after starting therapy, and post-treatment allograft biopsies showed improvement in thrombotic microangiopathy. He continues to receive eculizumab every 2 weeks with stable graft function 13 months after transplantation.

In a recent study, eculizumab, a humanized monoclonal antibody which targets complement factor C5, appeared to resolve hemolysis and thrombocytopenia leading to recovery of renal function in a transplant patient during an episode of an atypical hemolytic uremic syndrome. We report the efficacy of eculizumab in a patient who presented with a recurrence of atypical hemolytic syndrome at 3 years after renal transplantation. After 17 months of eculizumab treatment, and without concomitant plasma therapy, renal function was maintained, the need for blood transfusions reduced, and acute thrombotic microangiopathy and hemolysis controlled. These data suggested that eculizumab should be considered to be a permanent treatment for this patient., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Patients with some hereditary nephropathies-including autosomal dominant polycystic kidney disease (ADPKD), Fabry disease and Alport syndrome-can progress to end-stage renal disease (ESRD) and are candidates for kidney transplantation. When considering whether a potential living donor is appropriate for a particular patient, clinicians should be aware of the increased risk of adverse outcomes for the donor and the recipient. Renal transplantation from a living related donor is not contraindicated in most nephropathies that have an autosomal recessive mode of inheritance (for example, autosomal recessive polycystic kidney disease and cystinosis). Renal transplant recipients with ADPKD, however, should only receive a kidney from a related donor if the disease has been excluded in the donor by imaging and/or genetic testing. Potential living related donors for patients with Alport syndrome should be evaluated carefully for the presence of microhematuria and microalbuminuria before a decision is made to perform transplantation, and mothers or heterozygous sisters of affected male recipients with X-linked Alport syndrome should be informed about the possible long-term increased risk of renal dysfunction associated with donation. Most patients with atypical hemolytic uremic syndrome should not receive a kidney transplant from a living donor because there is a high risk of disease recurrence and graft loss.

A male infant was diagnosed with atypical hemolytic uremic syndrome (aHUS) at the age of 5.5 months. Sequencing of the gene (CFH) encoding complement factor H revealed a heterozygous mutation (c.3644G>A, p.Arg1215Gln). Despite maintenance plasmapheresis he developed recurrent episodes of aHUS and vascular access complications while maintaining stable renal function. At the age of 5 years he received an isolated split liver graft following a previously established protocol using pretransplant plasma exchange (PE) and intratransplant plasma infusion. Graft function, renal function and disease remission are preserved 2 years after transplantation. Preemptive liver transplantation prior to the development of end stage renal disease is a valuable option in the management of aHUS associated with CFH mutations.

Complement factor H (CFH)-associated hemolytic uremic syndrome (HUS) is a genetic form of atypical HUS characterized by deficient CFH levels or activity, which cause a disorder of the regulation of the alternative pathway, leading to uncontrolled complement activation. This genetic disorder, which frequently leads to end-stage renal failure, often recurs in kidney transplants, resulting in the poorest graft outcomes among all atypical HUS forms, due to a mutation in genes encoding complement components and regulatory proteins. Herein we have report our experience with a 40-year-old woman, suffering from a clearly defined sporadic form of genetic atypical HUS, consisting of a heterozygous missense mutation in factor H gene. She underwent cadaveric kidney transplantation. At the moment of surgery she displayed positive hemolysis indices and C3 consumption. A calcineurin inhibitor (CNI)-free immunosuppressive regimen was based on sirolimus, mycophenolic acid and steroids after basiliximab induction. An early and intense prophylactic course of plasma exchange (PE), and fresh frozen plasma (40 mL/kg) was prescribed, starting before surgery and continuing daily for the first week. The frequency of PE slowly reduced over the following 2 weeks. After that, just plasma infusion at the same dose was performed once a week until 12 weeks after transplantation. There was prompt graft function and in third week there were no signs of hemolysis or of C3 consumption. More than 3 years after transplantation, the graft is still functioning well and there was no recurrence. In our opinion, this case indicates that, although evidence is lacking, avoidance of CNI and intensive prophylactic plasma therapy are essential to achieve good results in this peculiar type of kidney transplantation. Nevertheless, controlled, prospective studies are necessary to establish the actual role of these two therapeutic procedures in renal transplantation of patients with CFH-associated HUS., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Kidney transplant in patients with atypical hemolytic uremic syndrome (aHUS) is associated with a poor outcome because of recurrent disease, especially in patients known to have a factor H mutation. Long-term prophylactic plasma exchange and combined liver-kidney transplant have prevented graft loss caused by recurrence. However, the mortality associated with liver transplant is not negligible, and prophylactic plasma exchange requires permanent vascular access and regular hospitalization and exposes the patient to potential allergic reactions to plasma. Eculizumab is a high-affinity humanized monoclonal antibody that binds to C5 and thus prevents generation of C5a and the membrane attack complex. We report the case of a 17-year-old girl with aHUS associated with a mutation in the gene for complement factor H (CFH; c.3572C>T, Ser1191Leu) who was highly dependent on plasma exchange. Because of severe allergic reactions to plasma after the third renal graft, eculizumab was introduced in place of plasma exchange without problems. This and other reports suggest that the promise of complement inhibitors in the management of aHUS is going to be fulfilled., (Copyright 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Factor H (CFH) autoantibodies are associated with atypical hemolytic uremic syndrome (aHUS). Peritransplantation plasma exchange therapy and intensification of immunosuppression, with adjuvant use of anti-CD20 monoclonal antibodies has recently been advocated for cases of CFH-autoantibody associated aHUS. In this report, we describe successful deceased donor renal transplantation in a case of CFH-autoantibody associated aHUS with combined CFHR1 and 3 deficiency in addition to the CFH sequence variant, (cG2850T, pGln950His). CFH-autoantibodies were detected 2 weeks prior to transplantation. Disease recurrence was not observed using basiliximab, an IL2-receptor antagonist and high-dose corticosteroids with mycophenolate mofetil. Adjuvant therapies such as Rituximab nor intensification of plasma therapy were employed. Consequently, careful consideration needs to be given to the use of additional immunosuppression in certain cases of CFH-autoantibody associated aHUS. Serial measurement of CFH-autoantibodies is required in the immediate pre- and posttransplantation period to further clarify their role as a factor in the recurrence of aHUS posttransplantation. Furthermore, delineation of the functional significance of CFH-autoantibodies is warranted in individual cases.

Renal transplantation (Tx) is the treatment of choice for end-stage renal disease. The incidence of acute rejection after renal Tx has decreased because of improving early immunosuppression, but the risk of disease recurrence (DR) is becoming relatively high, with a greater prevalence in children than in adults, thereby increasing patient morbidity, graft loss (GL) and, sometimes, mortality rate. The current overall graft loss to DR is 7-8%, mainly due to primary glomerulonephritis (70-80%) and inherited metabolic diseases. The more typical presentation is a recurrence of the full disease, either with a high risk of GL (focal and segmental glomerulosclerosis 14-50% DR, 40-60% GL; atypical haemolytic uraemic syndrome 20-80% DR, 10-83% GL; membranoproliferative glomerulonephritis 30-100% DR, 17-61% GL; membranous nephropathy approximately 30% DR, approximately 50% GL; lipoprotein glomerulopathy approximately 100% DR and GL; primary hyperoxaluria type 1 80-100% DR and GL) or with a low risk of GL [immunoglobulin (Ig)A nephropathy 36-60% DR, 7-10% GL; systemic lupus erythematosus 0-30% DR, 0-5% GL; anti-neutrophilic cytoplasmic antibody (ANCA)-associated glomerulonephritis]. Recurrence may also occur with a delayed risk of GL, such as insulin-dependent diabetes mellitus, sickle cell disease, endemic nephropathy, and sarcoidosis. In other primary diseases, the post-Tx course may be complicated by specific events that are different from overt recurrence: proteinuria or cancer in some genetic forms of nephrotic syndrome, anti-glomerular basement membrane antibodies-associated glomerulonephritis (Alport syndrome, Goodpasture syndrome), and graft involvement as a consequence of lower urinary tract abnormality or human immunodeficiency virus (HIV) nephropathy. Some other post-Tx conditions may mimic recurrence, such as de novo membranous glomerulonephritis, IgA nephropathy, microangiopathy, or isolated specific deposits (cystinosis, Fabry disease). Adequate strategies should therefore be added to kidney Tx, such as donor selection, associated liver Tx, plasmatherapy, specific immunosuppression protocols. In such conditions, very few patients may be excluded from kidney Tx only because of a major risk of DR and repeated GL. In the near future the issue of DR after kidney Tx may benefit from alternatives to organ Tx, such as recombinant proteins, specific monoclonal antibodies, cell/gene therapy, and chaperone molecules.

Background: A case of calcineurin inhibitor (CNI)--induced haemolytic uremic syndrome (HUS) after liver transplantation leading to irreversible renal failure is described., Case Report: We present case history of 25-years old male after liver transplantation due to cryptogenic cirrhosis with prolonged worsening graft function, who developed HUS. Unsatisfactory graft function was the reason of performing numerous graft biopsies. Features of acute and chronic rejection (CR) of liver were histopathologically confirmed. Vanishing bile duct syndrome as manifestation of CR was stated and immunosuppressive regimen was intensified (tacrolimus placed cyclosporin). High blood levels of tacrolimus were maintained (approximately 20-22 ng/ml) on dose 3 mg twice a day. No clinical effect was observed. Renal failure was improving (serum creatinine was 3.3 mg/dl and eGFR was 24 ml/min/1.73 m(2)). After four months of maintaining high dose of tacrolimus patient was referred to our center in order to estimate indications for liver retransplantation. On admission severe haemolytic anaemia, thrombocytopenia and acute renal failure were detected. Atypical HUS probably related to CNI was diagnosed. Tacrolimus administration was discontinued. Blood and plasma transfusion as well as plasmapheresis were implemented. Haemolysis was limited, but renal function was not improved. Renal biopsy revealed features of irreversible nephropathy in course of thrombotic microangiopathy. Despite previously maintaining high dose of CNI, there were no signs of CNI nephrotoxicity. Patient required haemodialysis. Due to necessity of haemodialysis and worsening function of liver, patient was accepted to liver and kidney transplantation., Conclusions: High CNI blood concentration in patient after liver transplantation can be atypical cause of HUS and leads to irreversible renal failure.

Patients with atypical haemolytic uremic syndrome (aHUS) with a mutation in the gene encoding membrane cofactor protein (CD46) are known to have a better prognosis than those with mutations in factor H (CFH) or factor I (CFI), but a small number of the former still proceed to end-stage renal failure. Plasma therapy (PE) is the recommended approach to treat both acute episodes and prevent recurrences in aHUS, but studies have yet to show PE efficacy in aHUS associated with a CD46 mutation. The factors determining failure to treatment are not clear and may be related to the mutation involved or to insufficient treatment. Our experience of PE in a family of three sisters with CFH-associated aHUS suggests that intensive and prophylactic PE allows renal function to be maintained in both native kidneys and allografts. The success of this strategy has led us to use it in all cases of aHUS. Here, we describe the effect of this strategy in a child with aHUS and a CD46 mutation. The initial episode was treated with daily PE, resulting in the recovery of renal function. However, over the next 4 years, there was a progressive decline in renal function to end-stage renal failure, with evidence of an on-going thrombotic microangiopathy despite continuous prophylactic PE. Prophylactic PE does not influence the natural course of aHUS and CD46 mutation.

Kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) carrying mutations in the soluble complement regulators factor H (CFH) or factor I (CFI) is associated with elevated risk of disease recurrence and almost certain graft loss. In contrast, recurrence is unusual in patients with mutations in the membrane-associated complement regulator membrane cofactor protein (MCP) (CD46). Therefore, a panel of experts recently recommended the combined liver-kidney transplantation to minimize aHUS recurrence in patients with mutations in CFH or CFI. There was, however, very limited information regarding transplantation in patients carrying mutations in both soluble and membrane-associated complement regulators to support a recommendation. Here, we report the case of an aHUS patient with a heterozygous mutation in both CFI and MCP who received an isolated kidney transplant expressing normal MCP levels. Critically, the patient suffered from a severe antibody-mediated rejection that was successfully treated with plasmapheresis and IvIgG. Most important, despite the complement activation in the allograft, there was no evidence of thrombotic microangiopathy, suggesting that the normal MCP levels in the grafted kidney were sufficient to prevent the aHUS recurrence. Our results suggest that isolated kidney transplantation may be a good first option for care in aHUS patients carrying CFI/MCP combined heterozygous mutations.

Atypical hemolytic uremic syndrome is often associated with mutations in genes encoding complement regulatory proteins and secondary disorders of complement regulation. Progression to kidney failure and recurrence with graft loss after kidney transplantation are frequent. The most common mutation is in the gene encoding complement factor H. Combined liver-kidney transplantation may correct this complement abnormality and prevent recurrence when the defect involves genes encoding circulating proteins that are synthesized in the liver, such as factor H or I. Good outcomes have been reported when surgery is associated with intensified plasma therapy. A consensus conference to establish treatment guidelines for atypical hemolytic uremic syndrome was held in Bergamo in December 2007. The recommendations in this article are the result of combined clinical experience, shared research expertise, and a review of the literature and registry information. This statement defines groups in which isolated kidney transplantation is extremely unlikely to be successful and a combined liver-kidney transplant is recommended and also defines those for whom kidney transplant remains a viable option. Although combined liver-kidney or isolated liver transplantation is the preferred therapeutic option in many cases, the gravity of risk associated with the procedure has not been eliminated completely, and assessment of risk and benefit requires careful and individual attention.

Hemolytic uremic syndrome (HUS) associated with anti-Factor H (anti-FH) autoantibodies is a recently described pathophysiological entity. Monitoring of anti-FH IgG titer may be a sensitive marker of disease activity and guide treatment to eliminate circulating anti-FH antibodies. We report here a case of atypical HUS (aHUS) in which anti-FH autoantibodies were detected during the course of a fifth kidney transplant, 30 years after the first flare of aHUS. This exceptional case suggests that early, specific management based on immunosuppressive therapy and plasma exchanges monitored by anti-FH IgG titer may result in long-term graft survival.

Atypical hemolytic uremic syndrome, or the nondiarrheal form of hemolytic uremic syndrome, is a rare disorder typically classified as familial or sporadic. Recent literature has suggested that approximately 50% of patients have mutations in factor H (CFH), factor I (CFI), or membrane cofactor protein (encoded by CD46). Importantly, results of renal transplantation in patients with mutations in either CFH or CFI are dismal, with recurrent disease leading to graft loss in the majority of cases. We describe an adult renal transplant recipient who developed recurrent hemolytic uremic syndrome 1 month after transplantation. Bidirectional sequencing of CFH, CFI, and CD46 confirmed that the patient was heterozygous for a novel missense mutation, a substitution of a serine reside for a tyrosine residue at amino acid 369, in CFI. This report reemphasizes the importance of screening patients with atypical hemolytic uremic syndrome for mutations in these genes before renal transplantation and shows the challenges in the management of these patients.

Background and Objectives: A male infant with a family history of thrombotic microangiopathy developed atypical hemolytic uremic syndrome (aHUS)., Design, Setting, Participants, & Measurements: Case report., Results: Genetic analysis demonstrated a heterozygous mutation (S1191L) of CFH, the gene coding complement factor H (CFH). The child suffered many episodes of HUS, each treated with plasma exchange. In time, despite initiation of a prophylactic regimen of plasma exchange, his renal function declined significantly. At the age of 4 yr he received a (split liver) combined liver-kidney transplant (LKT) with preoperative plasma exchange and enoxaparin anticoagulation. Initial function of both grafts was excellent and is maintained for nearly 2 yr., Conclusions: This report adds to the small but growing number of individuals in whom LKT has provided a favorable outcome for aHUS associated with CFH mutation, expands the technique of using a split liver graft, and describes the unique histologic features of subclinical liver disease in HUS.

Over the past decade, atypical hemolytic uremic syndrome (aHUS) has been demonstrated to be a disorder of the regulation of the complement alternative pathway. Among approximately 200 children with the disease, reported in the literature, 50% had mutations of the complement regulatory proteins factor H, membrane cofactor protein (MCP) or factor I. Mutations in factor B and C3 have also been reported recently. In addition, 10% of children have factor H dysfunction due to anti-factor H antibodies. Early age at onset appears as characteristic of factor H and factor I mutated patients, while MCP-associated HUS is not observed before age 1 year. Low C3 level may occur in patients with factor H and factor I mutation, while C3 level is generally normal in MCP-mutated patients. Normal plasma factor H and factor I levels do not preclude the presence of a mutation in these genes. The worst prognosis is for factor H-mutated patients, as 60% die or reach end-stage renal disease (ESRD) within the first year after onset of the disease. Patients with mutations in MCP have a relapsing course, but no patient has ever reached ESRD in the first year of the disease. Half of the patients with factor I mutations have a rapid evolution to ESRD, but half recover. Early intensive plasmatherapy appears to have a beneficial effect, except in MCP-mutated patients. There is a high risk of graft loss for HUS recurrence or thrombosis in all groups except the MCP-mutated group. Recent success of liver-kidney transplantation combined with plasmatherapy opens this option for patients with mutations of factors synthesized in the liver. New therapies such as factor H concentrate or complement inhibitors offer hope for the future.

A 12-month-old boy and his 16-year-old aunt became acutely ill 6 months apart and were diagnosed to have atypical hemolytic uremic syndrome (aHUS). Genetic analysis revealed heterozygous R1215Q mutation in complement factor H (CFH) in both patients. The same mutation was found in five healthy adult relatives indicating incomplete penetrance of the disease. The patients developed terminal renal failure and experienced reversible neurological symptoms in spite of plasma exchange (PE) therapy. In both cases, liver-kidney transplantation was successfully performed 6 months after the onset of the disease. To minimize complement activation and prevent thrombotic microangiopathy or overt thrombotic events due to the malfunctioning CFH, extensive PE with fresh frozen plasma was performed pre- and perioperatively and anticoagulation was started a few hours after the operation. No circulatory complications appeared and all four grafts started to function immediately. Also, no recurrence or other major clinical setbacks have appeared during the postoperative follow-up (15 and 9 months) and the grafts show excellent function. While more experience is needed, it seems that liver-kidney transplantation combined with pre- and perioperative PE is a rational option in the management of patients with aHUS caused by CFH mutation.

Non-Shiga toxin-associated hemolytic uremic syndrome (non-Stx-HUS) is a rare disease. The clinical outcome is often unfavorable: 50% of patients progress to end-stage renal failure. Several mutations in complement regulatory genes predispose to non-Stx-HUS. Transplantation outcomes are poor among patients with either mutation in the genes encoding complement H or I factors, with 80% graft loss due to HUS recurrence. In contrast, patients with mutation in the gene encoding MCP have no disease relapse after transplantation. There are no treatment guidelines for non-Stx-HUS recurrence. Herein we have presented 8 patients with non-Stx-HUS recurrence after transplantation during the last 10 years in the South of France. HUS recurrence, which occurred early after transplantation in all but 1 patient, was treated by plasma exchange (PE) with substitution by fresh frozen plasma (FFP). Three patients still treated with long-term plasma therapy have no recurrence at 15, 19, or 24 months. An international registry would help to define new guidelines.

Mutations in factor H (CFH), factor I (IF), and membrane cofactor protein (MCP) genes have been described as risk factors for atypical hemolytic uremic syndrome (aHUS). This study analyzed the impact of complement mutations on the outcome of 46 children with aHUS. A total of 52% of patients had mutations in one or two of known susceptibility factors (22, 13, and 15% of patients with CFH, IF, or MCP mutations, respectively; 2% with CFH+IF mutations). Age <3 mo at onset seems to be characteristic of CFH and IF mutation-associated aHUS. The most severe prognosis was in the CFH mutation group, 60% of whom reached ESRD or died within <1 yr. Only 30% of CFH mutations were localized in SCR20. MCP mutation-associated HUS has a relapsing course, but none of the children reached ESRD at 1 yr. Half of patients with IF mutation had a rapid evolution to ESRD, and half recovered. Plasmatherapy seemed to have a beneficial effect in one third of patients from all groups except for the MCP mutation group. Only eight (33%) of 24 kidney transplantations that were performed in 15 patients were successful. Graft failures were due to early graft thrombosis (50%) or HUS recurrence. In conclusion, outcome of HUS in patients with CFH mutation is catastrophic, and posttransplantation outcome is poor in all groups except for the MCP mutation group. New therapies are urgently needed, and further research should elucidate the unexplained HUS group.

Thrombotic microangiopathy and acute renal failure are cardinal features of postdiarrheal hemolytic uremic syndrome (HUS). These conditions are related to endothelial and epithelial cell damage induced by Shiga toxin (Stx) through the interaction with its globotriaosyl ceramide receptor. However, inflammatory processes contribute to the pathogenesis of HUS by sensitizing cells to Stx fractalkine (FKN), a CX(3)C transmembrane chemokine expressed on epithelial and endothelial cells upon activation, is involved in the selective migration and adhesion of specific leukocyte subsets to tissues. Here, we demonstrated a selective depletion of circulating mononuclear leukocytes expressing the receptor for FKN (CX(3)CR1) in patients with HUS. We found a unique phenotype in children with HUS distinct from that seen in healthy, uremic, or infected controls, in which monocytes lost CX(3)CR1, down-modulated CD62L, and increased CD16. In addition, the CD56(dim) natural killer (NK) subpopulation was decreased, leading to an altered peripheral CD56(dim)/CD56(bright) ratio from 10.0 to 4.5. It is noteworthy that a negative correlation existed between the percentage of circulating CX(3)CR1(+) leukocytes and the severity of renal failure. Finally, CX(3)CR1(+) leukocytes were observed in renal biopsies from patients with HUS. We suggest that the interaction of CX(3)CR1(+) cells with FKN present on activated endothelial cells may contribute to renal injury in HUS.

A genetic predisposition involving complement regulatory genes has become evident in some patients with atypical HUS. In this paper, a patient with a heterozygous missense mutation in factor I (IF) is described. Although the serum level of IF was normal, a mild functional defect in the alternative pathway of complement could be demonstrated in the affected members of the family. After an episode of atypical HUS, chronic renal insufficiency started at the age of 15 months. Recurrence of HUS, with loss of the renal transplant, occurred twice in this patient. The recurrence of HUS in the graft was not reflected by haematological abnormalities (haemolysis, thrombocytopenia). One additional transplant was lost due to arterial thrombosis of the renal artery. This report confirms the gloomy outcome of renal transplants in patients with an IF deficiency. New therapies should be evaluated in these patients.

Haemolytic uraemic syndrome (HUS) is the primary diagnosis of 4.5% of children on chronic renal replacement therapy. Approximately 5% of all HUS cases have an "atypical" or recurrent course. Atypical HUS is an inadequate term that applies to a heterogeneous group of conditions. We describe this group as non-diarrhoeal (D-) ), non-EHEC (EHEC - ) HUS. Patients in the non-diarrhoeal, non-EHEC, relapsing group are much more likely to exhibit severe hypertension, histological findings of arterial as well as arteriolar disease, chronic and end-stage renal failure. In general, these patients have an alarmingly high risk of graft loss from disease recurrence or thrombosis ranging from 60-100%. Family history is crucial, and where family members have relapsing disease, transplantation is a very high risk procedure (recurrence 100%). Patients with (D-)HUS need very careful consideration before transplantation, including molecular investigation of complement regulators (and von Willebrandt protease (ADAMTS13) activity, although this goes beyond the scope of this review). Guidelines are accessible under http://www.espn.ucwm.ac.uk . On no account should live related donation take place unless the risks of graft loss are understood. International collaboration to identify safer ways of transplanting these challenging patients is urgently needed.

The hemolytic uremic syndrome (HUS) is a severe disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. We herein report our experience with a 43-year-old female patient who underwent a second cadaveric kidney transplantation in February 2005, for adult-onset HUS. The first renal transplantation, which was performed in 1996, required removal after 3 weeks for probable recurrence of HUS. The immunosuppressive regimen for the second transplant included basiliximab, tacrolimus, mycophenolate mofetil, and steroids. On postoperative day (POD) 7, she received steroid treatment for an acute rejection episode with improved renal function. On POD 19 due to worsening renal function, a graft biopsy showed HUS recurrence, thus we instituted hemodialysis and then plasmapheresis treatments. At two months after transplantation, the patient continued under plasmapheresis treatment due to clinical evidence of HUS. On POD 80, cytomegalovirus infection was diagnosed and intravenous gancyclovir treatment started for 3 weeks. After 110 days from transplant, a deterioration in renal function was evident: the graft was swollen and painful with Doppler ultrasound showing patency of both the renal artery and vein but, low blood flow. After 2 weeks of hemodialysis, the patient underwent transplantectomy. In adult-onset HUS the recurrence rate reduces graft survival, particularly among patients undergoing second transplantation.

Hemolytic uremic syndrome (HUS) includes a heterogeneous group of hemolytic disorders. Among the identified causes of HUS are infections, particularly infections with Shiga toxin-producing ESCHERICHIA COLI (STEC), complement disorders, and disorders interfering with the degradation of von Willebrand factor (VWF). Other causes for atypical HUS include the cobalamin metabolism; pregnancy/hemolysis, elevated liver enzymes, and low platelets syndrome (HELLP); drugs; and other disorders (e.g., systemic diseases appearing as HUS, such as systemic lupus erythematosus and rejection after transplantation). The group not related to STEC is often also called atypical HUS. Most of the occurrences of infectious HUS have only one episode. Recurrent episodes (recurrent HUS) have strong relationships to diseases of the complement system. In these two subgroups the prognosis is poor, with severe renal insufficiency, together with the need for renal replacement therapy. Severe arterial hypertension is common. Treatment options are limited. To better define this group of patients, the European Society for Pediatric Nephrology supported an initiative to develop a European HUS registry. In this registry, 167 patients were acquired; 73 were female (43.8%). The year of onset of the disease ranged from 1974 to 2005. The prevalence of atypical HUS/recurrent HUS can be calculated as 3.3 per million child population (< 18 years). Underlying disorders included factor H, factor I, MCP-1, pneumococci, and von Willebrand factor disturbances. In 33 patients at least one renal transplantation was performed (total, 55 kidneys); 18% were successful and 73% demonstrated recurrence or thrombosis. Treatment options were plasma substitution or plasmapheresis. Despite continued efforts, transplantation is not recommended at present for these patients. Living-related transplantation should be abandoned. New therapeutic strategies are urgently needed.

Mutations in the genes for three complement regulators-complement factor H (CFH), membrane cofactor protein (MCP), and factor I (IF)-have now been described in patients with atypical HUS. The functional effects of these mutations have been studied in detail and have been shown to affect secretion, expression, and regulatory function. Genotype-phenotype correlations have shown that the majority of patients with CFH, MCP, and FI mutations develop end-stage renal failure. The outcome of transplantation is poor in patients known to have either a CFH or FI mutation, with approximately 80% of patients losing the graft to recurrent disease within 2 years. In contrast, patients known to have only an MCP mutation have a satisfactory transplantation outcome. This is expected because MCP is a transmembrane regulator and allografts will therefore be protected by wild-type MCP. Combined liver/kidney transplantation for patients known to have a CFH mutation has not been successful to date. There is optimism that in the future, targeted complement inhibitors will be of major therapeutic benefit in this condition.

Thrombotic microangiopathy (TMA) and hemolytic uremic syndrome (HUS) represent serious threats to kidney allograft recipients. During a 4-year period, among 850 kidney transplantations, seven recipients with primary HUS and seven recipients (eight transplants) with previous or de novo TMA/HUS were identified and given calcineurin inhibitor (CNI)-free immunosuppression by sirolimus (SRL), mycophenolate mofetil and steroids. Thirteen out of 15 transplantations were successful in the long term; resulting in a mean creatinine of 101 mumol/L (16.4 months follow-up). In patients maintained on CNI-free regimen, no TMA/HUS recurrences were observed. A high rate of acute rejections (53%) may indicate insufficient immunosuppressive power and/or a causative relationship between TMA/HUS and rejection. Wound-related complications were abundant (60%), and call for surgical/immunosuppressive countermeasures. Our experience supports the idea that CNI's are major offenders in TMA/HUS induction. Total CNI elimination seems essential, as the nephrotoxic combination CNI + SRL may promote TMA. Features of TMA/HUS should be carefully explored in recurrent 'high responders'.

More than 50% of patients with non-Shiga toxin-associated hemolytic uremic syndrome (non-Stx-HUS) progress to ESRD. Kidney transplant failure for disease recurrence is common; hence, whether renal transplantation is appropriate in this clinical setting remains a debated issue. The aim of this study was to identify possible prognostic factors for renal transplant outcome by focusing on specific genetic abnormalities associated with the disease. All articles in literature that describe renal transplant outcome in patients with ESRD secondary to non-Stx-HUS, genotyped for CFH, MCP, and IF mutations, were reviewed, and data of patients who were referred to the International Registry of Recurrent and Familial HUS/TTP and data from the Newcastle cohort were examined. This study confirmed that the overall outcome of kidney transplantation in patients with non-Stx-HUS is poor, with disease recurring in 60% of patients, 91.6% of whom developed graft failure. No clinical prognostic factor that could identify patients who were at high risk for graft failure was found. The presence of a factor H (CFH) mutation was associated with a high incidence of graft failure (77.8 versus 54.9% in patients without CFH mutation). Similar results were seen in patients with a factor I (IF) mutation. In contrast, graft outcome was favorable in all patients who carried a membrane co-factor protein (MCP) mutation. Patients with non-Stx-HUS should undergo genotyping before renal transplantation to help predict the risk for graft failure. It is debatable whether a kidney transplant should be recommended for patients with CFH or IF mutation. Reasonably, patients with an MCP mutation can undergo a kidney transplant without risk for recurrence.