Successful Simultaneous Liver-Kidney Transplant in an Adult With Atypical Hemolytic Uremic Syndrome Associated With a Mutation in Complement Factor H
2011; Elsevier BV; Volume: 58; Issue: 1 Linguagem: Inglês
10.1053/j.ajkd.2011.04.008
ISSN1523-6838
AutoresColin Wilson, Nick Torpey, Bryon Jaques, Lisa Strain, David Talbot, Derek Manas, Tim Goodship,
Tópico(s)Neonatal Health and Biochemistry
ResumoAtypical 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. 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. Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury in the absence of a preceding diarrheal illness.1Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (909) Google Scholar Approximately 60% of patients with aHUS have mutations in the genes encoding both regulators and activators of the alternative complement pathway (CFH [complement factor H], CFI [complement factor I], CD46, CFB [complement factor B], and C3 [complement component 3]). Approximately 8% of patients with aHUS die during their presenting illness, and of those who survive, most require long-term renal replacement therapy.2Noris M. Caprioli J. Bresin E. et al.Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.Clin J Am Soc Nephrol. 2010; 5: 1844-1859Crossref PubMed Scopus (671) Google Scholar, 3Sellier-Leclerc A.L. Fremeaux-Bacchi V. Dragon-Durey M.A. et al.Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome.J Am Soc Nephrol. 2007; 18: 2392-2400Crossref PubMed Scopus (305) Google Scholar Kidney transplant in those with either a CFH or CFI mutation has an ∼80% risk of transplant loss to recurrent disease within 2 years of transplant.4Bresin E. Daina E. Noris M. et al.Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background.Clin J Am Soc Nephrol. 2006; 1: 88-99Crossref PubMed Scopus (182) Google Scholar Because factor H is produced predominantly by the liver, combined liver-kidney transplant represents a logical therapy. This was first undertaken in 2002.5Remuzzi G. Ruggenenti P. Codazzi D. et al.Combined kidney and liver transplantation for familial haemolytic uraemic syndrome.Lancet. 2002; 359: 1671-1672Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Since then, there have been at least 14 combined liver-kidney and 2 liver-alone transplants in patients with aHUS (Table 1). The success of the combined procedure has varied, with overall 1-year patient survival of ∼75%. All recipients except one have been children. We report a successful simultaneous liver-kidney transplant in an adult.Table 1Liver-Alone and Simultaneous Liver-Kidney Transplants Reported for Atypical HUSReferenceAge at TransplantSurvival at 1-y PosttransplantRemuzzi et al,5Remuzzi G. Ruggenenti P. Codazzi D. et al.Combined kidney and liver transplantation for familial haemolytic uraemic syndrome.Lancet. 2002; 359: 1671-1672Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Lancet 20022 yAliveCheong et al,6Cheong H.I. Lee B.S. Kang H.G. et al.Attempted treatment of factor H deficiency by liver transplantation.Pediatr Nephrol. 2004; 19: 454-458Crossref PubMed Scopus (64) Google Scholar Pediatr Nephrol 20043 moaLiver-alone transplant.DiedRemuzzi et al,7Remuzzi G. Ruggenenti P. Colledan M. et al.Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor H gene mutation.Am J Transplant. 2005; 5: 1146-1150Crossref PubMed Scopus (114) Google Scholar Am J Transplant 20052 yDiedSaland et al,8Saland J.M. Emre S.H. Shneider B.L. et al.Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation.Am J Transplant. 2006; 6: 1948-1952Crossref PubMed Scopus (106) Google Scholar Am J Transplant 20065 yAliveJalanko et al,9Jalanko H. Peltonen S. Koskinen A. et al.Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H.Am J Transplant. 2008; 8: 216-221PubMed Google Scholar Am J Transplant 20071 yAliveJalanko et al,9Jalanko H. Peltonen S. Koskinen A. et al.Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H.Am J Transplant. 2008; 8: 216-221PubMed Google Scholar Am J Transplant 200716 yAliveSaland et al,10Saland J.M. Shneider B.L. Bromberg J.S. et al.Successful split liver-kidney transplant for factor H associated hemolytic uremic syndrome.Clin J Am Soc Nephrol. 2009; 4: 201-206Crossref PubMed Scopus (55) Google Scholar Clin J Am Soc Nephrol 20094 yaLiver-alone transplant.AliveHaller et al,11Haller W. Milford D.V. Goodship T.H. Sharif K. Mirza D.F. McKiernan P.J. Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H.Am J Transplant. 2010; 10: 2142-2147Crossref PubMed Scopus (26) Google Scholar Am J Transplant 20104 yAliveAbbreviation: HUS, hemolytic-uremic syndrome.a Liver-alone transplant. Open table in a new tab Case ReportA 62-year-old man presented with general malaise, no significant medical history, and no preceding diarrheal illness. Investigations showed the following values: plasma creatinine, 18.5 mg/dL (1,635 μmol/L); blood urea, 62.3 mmol/L (22.2 mg/dL); platelet count, 124 × 103/μL (124 × 109/L); hemoglobin, 7.4 g/dL (74 g/L); and serum lactate dehydrogenase, 1,608 U/L. Renal ultrasound showed normal-sized kidneys, and a kidney biopsy was performed. Light microscopy showed thrombotic microangiopathy with severe chronic tubulointerstitial damage. A diagnosis of aHUS was made, and hemodialysis therapy was initiated. Further investigation showed the following values: C3, 1.29 (reference range, 0.68-1.80) g/L; C4, 0.29 (reference range, 0.18-0.60) g/L; CFI, 83 (reference range, 38-58) mg/L; and CFH, 0.89 (reference range, 0.35-0.59) g/L. CFH mutation screening showed a heterozygous adenine to guanine mutation in exon 23 (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). This was not present in 220 control individuals within the Wellcome Trust Case Control Consortium.12The Wellcome Trust Case Control ConsortiumGenome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature. 2007; 447: 661-678Crossref PubMed Scopus (7704) Google Scholar, 13Burton P.R. Clayton D.G. Cardon L.R. et al.Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.Nat Genet. 2007; 39: 1329-1337Crossref PubMed Scopus (1140) Google Scholar No mutations were detected in CFI, CD46, C3, CFB, and the thrombomodulin gene THBD. Copy numbers of genes for CFH-related 1 and 3 (CFHR1 and CFHR3) measured using multiplex ligation-dependent probe amplification showed one copy of each. CFH autoantibodies were undetectable.Because of the CFH mutation, the patient was counseled that the risk of recurrent disease with a kidney transplant alone was very high. He was eager to explore the option of simultaneous liver-kidney transplant and underwent assessment. Ultrasound scans and magnetic resonance images suggested the presence of multiple intrahepatic cysts up to 11 mm in diameter. Cardiovascular reserve, assessed using cardiopulmonary exercise testing and echocardiography, was satisfactory. After discussion at both institutional liver and kidney transplant assessment meetings, he was listed for simultaneous liver-kidney transplant. The possibility of “domino” transplant of his liver into another recipient also was considered, but the consensus was not to proceed with this for 2 reasons. First, the risk of the mutant CFH to induce HUS in a potential recipient was unknown, and second, the nature and implications of the multiple liver cysts could not be evaluated fully until after explantation.After 7 months, the patient was offered organs from a 26-year-old male brainstem-dead donor. He was admitted, and after hemodialysis, he underwent a 3.5-L plasma exchange with fresh frozen plasma replacement. After this, 20 mg of basiliximab was administered intravenously. Because of a delay in the retrieval process, an additional 2.5-L plasma exchange was performed before implantation, in keeping with the recommendation that plasma exchange be undertaken within 4-6 hours before surgery,14Saland J.M. Ruggenenti P. Remuzzi G. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome.J Am Soc Nephrol. 2009; 20: 940-949Crossref PubMed Scopus (139) Google Scholar necessitating an additional 20-mg dose of basiliximab.Whole-liver orthotopic transplant was undertaken after hepatectomy. Kidney transplant into the right iliac fossa then was performed. Fresh frozen plasma, 1.8 L, was administered before kidney transplant, after liver reperfusion. The explant was examined histologically and the multiple lesions seen on magnetic resonance imaging were found to be a combination of biliary hamartomas and simple biliary cysts.Postoperatively, both organs functioned immediately with only mild liver reperfusion injury (Fig 1). Initial immunosuppression was with tacrolimus (target trough level, 5-10 ng/mL), mycophenolate mofetil (1 g/d), and steroids (prednisone, 20 mg/d). Thromboprophylaxis was instituted according to the unit protocol rather than the currently published guideline,14Saland J.M. Ruggenenti P. Remuzzi G. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome.J Am Soc Nephrol. 2009; 20: 940-949Crossref PubMed Scopus (139) Google Scholar with intravenous unfractionated heparin at 500 IU/h for the first 5 days and a single dose of aspirin (75 mg) orally after this.The patient's initial recovery was uneventful, and he was discharged from the hospital on postoperative day 12. However, on day 14, he developed cholestatic jaundice. Ultrasound scanning suggested a biliary stricture with intra- and extrahepatic biliary dilatation. Endoscopic retrograde cholangiopancreatography confirmed the presence of an anastomotic stricture, for which a stent was placed successfully. Unfortunately, this procedure was complicated by acute pancreatitis, which required analgesia and fluid administration before spontaneous recovery. He was discharged with excellent transplant function 7 days later (Fig 1). At 1 year posttransplant, estimated glomerular filtration rate is 85 mL/min/1.73 m2 (calculated using the isotope-dilution mass spectrometry–traceable 4-variable Modification of Diet in Renal Disease [MDRD] Study equation), and liver function is normal.DiscussionAlthough most patients with aHUS present in childhood,15Loirat C. Noris M. Fremeaux-Bacchi V. Complement and the atypical hemolytic uremic syndrome in children.Pediatr Nephrol. 2008; 23: 1957-1972Crossref PubMed Scopus (168) Google Scholar this case is a reminder that the condition can present at any age. Recently published guidelines for the investigation and management of patients with aHUS recommend that mutation screening of CFH, CD46, CFI, CFB, and C3 be undertaken in all patients with aHUS and that autoantibodies against CFH also should be sought.16Taylor C.M. Machin S. Wigmore S.J. Goodship T.H. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom.Br J Haematol. 2010; 148: 37-47Crossref PubMed Scopus (152) Google Scholar, 17Ariceta G. Besbas N. Johnson S. et al.Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome.Pediatr Nephrol. 2009; 24: 687-696Crossref PubMed Scopus (263) Google Scholar In this patient, there was a heterozygous mutation (c.3550A>G, p.Thr1184Ala) in exon 23 of CFH. Although this particular mutation has not been reported previously in patients with aHUS, we previously have described a mutation affecting the same amino acid (c.3551C>G, p.Thr1184Arg).18Richards A. Buddles M.R. Donne R.L. et al.Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition.Am J Hum Genet. 2001; 68: 485-490Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar This amino acid is in short consensus repeat 20 (SCR20) of CFH, where many aHUS-associated mutations have been shown to cluster. Although the functional significance of changes in this amino acid have not been studied previously, it has been clearly shown that mutations affecting SCR20 impair the ability of CFH to protect host cells against complement activation.19Manuelian T. Hellwage J. Meri S. et al.Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome.J Clin Invest. 2003; 111: 1181-1190Crossref PubMed Scopus (300) Google ScholarThe poor outcome of kidney transplant in patients with a CFH mutation has been well documented,2Noris M. Caprioli J. Bresin E. et al.Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.Clin J Am Soc Nephrol. 2010; 5: 1844-1859Crossref PubMed Scopus (671) Google Scholar, 4Bresin E. Daina E. Noris M. et al.Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background.Clin J Am Soc Nephrol. 2006; 1: 88-99Crossref PubMed Scopus (182) Google Scholar, 20Zuber J. Le Quintrec M. Sberro-Soussan R. Loirat C. Fremeaux-Bacchi V. Legendre C. New insights into postrenal transplant hemolytic uremic syndrome.Nat Rev Nephrol. 2011; 7: 23-35Crossref PubMed Scopus (132) Google Scholar with an 80% risk of losing a transplant to recurrent disease within 2 years of transplant. How can such patients undergo transplant? There are 3 options. The first is to undertake a kidney transplant alone with prophylactic plasma exchange preoperatively,21Davin J.C. Strain L. Goodship T.H. Plasma therapy in atypical haemolytic uremic syndrome: lessons from a family with a factor H mutation.Pediatr Nephrol. 2008; 23: 1517-1521Crossref PubMed Scopus (42) Google Scholar postoperatively, and long term. Although this approach has been used successfully,21Davin J.C. Strain L. Goodship T.H. Plasma therapy in atypical haemolytic uremic syndrome: lessons from a family with a factor H mutation.Pediatr Nephrol. 2008; 23: 1517-1521Crossref PubMed Scopus (42) Google Scholar, 22Hirt-Minkowski P. Schaub S. Mayr M. et al.Haemolytic uraemic syndrome caused by factor H mutation: is single kidney transplantation under intensive plasmatherapy an option?.Nephrol Dial Transplant. 2009; 24: 3548-3551Crossref PubMed Scopus (28) Google Scholar disease can recur and patients may become intolerant of plasma exchange. The second option is to undertake kidney transplant alone, but instead of plasma exchange, use a complement inhibitor as prophylaxis against recurrent disease. This has been undertaken using the anti-C5 monoclonal antibody eculizumab both in the immediate postoperative period23Zimmerhackl L.B. Hofer J. Cortina G. et al.Prophylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndrome.N Engl J Med. 2010; 362: 1746-1748Crossref PubMed Scopus (121) Google Scholar and after a patient has become intolerant of plasma exchange.24Davin J.C. Gracchi V. Bouts A. Groothoff J. Strain L. Goodship T. Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH mutation.Am J Kidney Dis. 2010; 55: 708-711Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar The third option, used in this patient, is to undertake a simultaneous liver-kidney transplant. This is curative in patients known to have only a CFH mutation. Initial reports of this procedure were not favorable,5Remuzzi G. Ruggenenti P. Codazzi D. et al.Combined kidney and liver transplantation for familial haemolytic uraemic syndrome.Lancet. 2002; 359: 1671-1672Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 7Remuzzi G. Ruggenenti P. Colledan M. et al.Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor H gene mutation.Am J Transplant. 2005; 5: 1146-1150Crossref PubMed Scopus (114) Google Scholar but the introduction of intensive plasma exchange to cover the operative and immediate postoperative periods was associated with improved outcome.8Saland J.M. Emre S.H. Shneider B.L. et al.Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation.Am J Transplant. 2006; 6: 1948-1952Crossref PubMed Scopus (106) Google Scholar, 9Jalanko H. Peltonen S. Koskinen A. et al.Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H.Am J Transplant. 2008; 8: 216-221PubMed Google Scholar This forms part of the recommendations for the management of patients with aHUS undergoing liver-kidney transplant published after a consensus conference in 2007.14Saland J.M. Ruggenenti P. Remuzzi G. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome.J Am Soc Nephrol. 2009; 20: 940-949Crossref PubMed Scopus (139) Google ScholarTo our knowledge, there have been 2 liver and 15 simultaneous liver-kidney transplants, including the case we describe here, performed in patients with aHUS. All except one of these were known to have a CFH mutation; the other had a CFB mutation. The outcome of 8 of these procedures has been reported previously5Remuzzi G. Ruggenenti P. Codazzi D. et al.Combined kidney and liver transplantation for familial haemolytic uraemic syndrome.Lancet. 2002; 359: 1671-1672Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 6Cheong H.I. Lee B.S. Kang H.G. et al.Attempted treatment of factor H deficiency by liver transplantation.Pediatr Nephrol. 2004; 19: 454-458Crossref PubMed Scopus (64) Google Scholar, 7Remuzzi G. Ruggenenti P. Colledan M. et al.Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor H gene mutation.Am J Transplant. 2005; 5: 1146-1150Crossref PubMed Scopus (114) Google Scholar, 8Saland J.M. Emre S.H. Shneider B.L. et al.Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation.Am J Transplant. 2006; 6: 1948-1952Crossref PubMed Scopus (106) Google Scholar, 9Jalanko H. Peltonen S. Koskinen A. et al.Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H.Am J Transplant. 2008; 8: 216-221PubMed Google Scholar, 10Saland J.M. Shneider B.L. Bromberg J.S. et al.Successful split liver-kidney transplant for factor H associated hemolytic uremic syndrome.Clin J Am Soc Nephrol. 2009; 4: 201-206Crossref PubMed Scopus (55) Google Scholar, 11Haller W. Milford D.V. Goodship T.H. Sharif K. Mirza D.F. McKiernan P.J. Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H.Am J Transplant. 2010; 10: 2142-2147Crossref PubMed Scopus (26) Google Scholar (Table 1). Based on these published reports and follow-up with the investigators, we estimate 1-year patient survival for simultaneous liver-kidney transplants of ∼75% in 12 of these patients compared with 86% for liver-kidney transplant undertaken over a 20-year period in 117 patients with primary hyperoxaluria.25Jamieson N.V. A 20-year experience of combined liver/kidney transplantation for primary hyperoxaluria (PH1): the European PH1 transplant registry experience 1984-2004.Am J Nephrol. 2005; 25: 282-289Crossref PubMed Scopus (130) Google Scholar The 2 liver-only transplants were undertaken in patients with recurrent aHUS, but maintained kidney function. One died 11 months posttransplant,6Cheong H.I. Lee B.S. Kang H.G. et al.Attempted treatment of factor H deficiency by liver transplantation.Pediatr Nephrol. 2004; 19: 454-458Crossref PubMed Scopus (64) Google Scholar and the other is well 2 years posttransplant.11Haller W. Milford D.V. Goodship T.H. Sharif K. Mirza D.F. McKiernan P.J. Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H.Am J Transplant. 2010; 10: 2142-2147Crossref PubMed Scopus (26) Google ScholarWhat will the optimal treatment be in the future for patients with aHUS with a CFH or CFI mutation who currently are on dialysis therapy? Results of trials with eculizumab undoubtedly will influence the recommendations of current guidelines. However, the case that we present provides evidence that liver-kidney transplant can be successful in adult patients with aHUS. Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury in the absence of a preceding diarrheal illness.1Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (909) Google Scholar Approximately 60% of patients with aHUS have mutations in the genes encoding both regulators and activators of the alternative complement pathway (CFH [complement factor H], CFI [complement factor I], CD46, CFB [complement factor B], and C3 [complement component 3]). Approximately 8% of patients with aHUS die during their presenting illness, and of those who survive, most require long-term renal replacement therapy.2Noris M. Caprioli J. Bresin E. et al.Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.Clin J Am Soc Nephrol. 2010; 5: 1844-1859Crossref PubMed Scopus (671) Google Scholar, 3Sellier-Leclerc A.L. Fremeaux-Bacchi V. Dragon-Durey M.A. et al.Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome.J Am Soc Nephrol. 2007; 18: 2392-2400Crossref PubMed Scopus (305) Google Scholar Kidney transplant in those with either a CFH or CFI mutation has an ∼80% risk of transplant loss to recurrent disease within 2 years of transplant.4Bresin E. Daina E. Noris M. et al.Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background.Clin J Am Soc Nephrol. 2006; 1: 88-99Crossref PubMed Scopus (182) Google Scholar Because factor H is produced predominantly by the liver, combined liver-kidney transplant represents a logical therapy. This was first undertaken in 2002.5Remuzzi G. Ruggenenti P. Codazzi D. et al.Combined kidney and liver transplantation for familial haemolytic uraemic syndrome.Lancet. 2002; 359: 1671-1672Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Since then, there have been at least 14 combined liver-kidney and 2 liver-alone transplants in patients with aHUS (Table 1). The success of the combined procedure has varied, with overall 1-year patient survival of ∼75%. All recipients except one have been children. We report a successful simultaneous liver-kidney transplant in an adult. Abbreviation: HUS, hemolytic-uremic syndrome. Case ReportA 62-year-old man presented with general malaise, no significant medical history, and no preceding diarrheal illness. Investigations showed the following values: plasma creatinine, 18.5 mg/dL (1,635 μmol/L); blood urea, 62.3 mmol/L (22.2 mg/dL); platelet count, 124 × 103/μL (124 × 109/L); hemoglobin, 7.4 g/dL (74 g/L); and serum lactate dehydrogenase, 1,608 U/L. Renal ultrasound showed normal-sized kidneys, and a kidney biopsy was performed. Light microscopy showed thrombotic microangiopathy with severe chronic tubulointerstitial damage. A diagnosis of aHUS was made, and hemodialysis therapy was initiated. Further investigation showed the following values: C3, 1.29 (reference range, 0.68-1.80) g/L; C4, 0.29 (reference range, 0.18-0.60) g/L; CFI, 83 (reference range, 38-58) mg/L; and CFH, 0.89 (reference range, 0.35-0.59) g/L. CFH mutation screening showed a heterozygous adenine to guanine mutation in exon 23 (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). This was not present in 220 control individuals within the Wellcome Trust Case Control Consortium.12The Wellcome Trust Case Control ConsortiumGenome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature. 2007; 447: 661-678Crossref PubMed Scopus (7704) Google Scholar, 13Burton P.R. Clayton D.G. Cardon L.R. et al.Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.Nat Genet. 2007; 39: 1329-1337Crossref PubMed Scopus (1140) Google Scholar No mutations were detected in CFI, CD46, C3, CFB, and the thrombomodulin gene THBD. Copy numbers of genes for CFH-related 1 and 3 (CFHR1 and CFHR3) measured using multiplex ligation-dependent probe amplification showed one copy of each. CFH autoantibodies were undetectable.Because of the CFH mutation, the patient was counseled that the risk of recurrent disease with a kidney transplant alone was very high. He was eager to explore the option of simultaneous liver-kidney transplant and underwent assessment. Ultrasound scans and magnetic resonance images suggested the presence of multiple intrahepatic cysts up to 11 mm in diameter. Cardiovascular reserve, assessed using cardiopulmonary exercise testing and echocardiography, was satisfactory. After discussion at both institutional liver and kidney transplant assessment meetings, he was listed for simultaneous liver-kidney transplant. The possibility of “domino” transplant of his liver into another recipient also was considered, but the consensus was not to proceed with this for 2 reasons. First, the risk of the mutant CFH to induce HUS in a potential recipient was unknown, and second, the nature and implications of the multiple liver cysts could not be evaluated fully until after explantation.After 7 months, the patient was offered organs from a 26-year-old male brainstem-dead donor. He was admitted, and after hemodialysis, he underwent a 3.5-L plasma exchange with fresh frozen plasma replacement. After this, 20 mg of basiliximab was administered intravenously. Because of a delay in the retrieval process, an additional 2.5-L plasma exchange was performed before implantation, in keeping with the recommendation that plasma exchange be undertaken within 4-6 hours before surgery,14Saland J.M. Ruggenenti P. Remuzzi G. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome.J Am Soc Nephrol. 2009; 20: 940-949Crossref PubMed Scopus (139) Google Scholar necessitating an additional 20-mg dose of basiliximab.Whole-liver orthotopic transplant was undertaken after hepatectomy. Kidney transplant into the right iliac fossa then was performed. Fresh frozen plasma, 1.8 L, was administered before kidney transplant, after liver reperfusion. The explant was examined histologically and the multiple lesions seen on magnetic resonance imaging were found to be a combination of biliary hamartomas and simple biliary cysts.Postoperatively, both organs functioned immediately with only mild liver reperfusion injury (Fig 1). Initial immunosuppression was with tacrolimus (target trough level, 5-10 ng/mL), mycophenolate mofetil (1 g/d), and steroids (prednisone, 20 mg/d). Thromboprophylaxis was instituted according to the unit protocol rather than the currently published guideline,14Saland J.M. Ruggenenti P. Remuzzi G. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome.J Am Soc Nephrol. 2009; 20: 940-949Crossref PubMed Scopus (139) Google Scholar with intravenous unfractionated heparin at 500 IU/h for the first 5 days and a single dose of aspirin (75 mg) orally after this.The patient's initial recovery was uneventful, and he was discharged from the hospital on postoperative day 12. However, on day 14, he developed cholestatic jaundice. Ultrasound scanning suggested a biliary stricture with intra- and extrahepatic biliary dilatation. Endoscopic retrograde cholangiopancreatography confirmed the presence of an anastomotic stricture, for which a stent was placed successfully. Unfortunately, this procedure was complicated by acute pancre
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