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

Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy characterized by over-activation of the alternative complement pathway. The etiology of the dysregulated complement system is commonly a genetic variant in one or more complement proteins as identified in ∼ 60%-70% patients. The risk of recurrence after a kidney transplantation is high and depends on the underlying complement abnormality. For a long time, kidney transplantation was contraindicated in these patients because of the high rate of recurrence and subsequent allograft loss. Over the past decade, advancements in the understanding of etiopathogenesis of aHUS and approval of the anti-complement drug, eculizumab, have allowed for successful kidney transplantation in these patients. All patients with ESRD due to aHUS should undergo screening for complement genetic variants. Patients in whom a genetic variant is not identified or in whom a genetic variant of uncertain significance is identified should undergo further testing to determine etiology of disease. This review aims to shed light on the diagnostic and therapeutic considerations in patients with aHUS preceding and following kidney transplantation. Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy characterized by over-activation of the alternative complement pathway. The etiology of the dysregulated complement system is commonly a genetic variant in one or more complement proteins as identified in ∼ 60%-70% patients. The risk of recurrence after a kidney transplantation is high and depends on the underlying complement abnormality. For a long time, kidney transplantation was contraindicated in these patients because of the high rate of recurrence and subsequent allograft loss. Over the past decade, advancements in the understanding of etiopathogenesis of aHUS and approval of the anti-complement drug, eculizumab, have allowed for successful kidney transplantation in these patients. All patients with ESRD due to aHUS should undergo screening for complement genetic variants. Patients in whom a genetic variant is not identified or in whom a genetic variant of uncertain significance is identified should undergo further testing to determine etiology of disease. This review aims to shed light on the diagnostic and therapeutic considerations in patients with aHUS preceding and following kidney transplantation. Clinical Summary•Mutations in one or more genes encoding complement-regulatory proteins predispose to aHUS and its recurrence after kidney transplantation.•All patients with ESRD due to aHUS should be screened for complement abnormalities prior to transplantation.•Eculizumab is effective for the treatment of aHUS recurrence after a kidney transplant and as prophylaxis before transplantation.•Living-unrelated donor kidney or a deceased-donor kidney is preferred over a living-related kidney transplant. •Mutations in one or more genes encoding complement-regulatory proteins predispose to aHUS and its recurrence after kidney transplantation.•All patients with ESRD due to aHUS should be screened for complement abnormalities prior to transplantation.•Eculizumab is effective for the treatment of aHUS recurrence after a kidney transplant and as prophylaxis before transplantation.•Living-unrelated donor kidney or a deceased-donor kidney is preferred over a living-related kidney transplant. Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy (TMA).1Goodship T.H. Cook H.T. Fakhouri F. et al.Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "kidney disease: improving Global outcomes" (KDIGO) Controversies conference.Kidney Int. 2017; 91: 539-551Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar,2Grenda R. Jarmuzek W. Rubik J. et al.Favorable four-yr outcome after renal transplantation in a patient with complement factor H antibody and CFHR1/CFHR3 gene mutation-associated HUS.Pediatr Transpl. 2015; 19: E130-E134Crossref PubMed Scopus (8) Google Scholar The disease usually has a rapid onset and is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The major defect underlying aHUS is a dysregulated complement system (Fig 1) which often leads to overactivation with resultant organ damage.3Java A. Atkinson J. Salmon J. Defective complement inhibitory function predisposes to renal disease.Annu Rev Med. 2013; 64: 307-324Crossref PubMed Scopus (25) Google Scholar,4Liszewski M.K. Java A. Schramm E.C. Atkinson J.P. Complement dysregulation and disease: insights from contemporary genetics.Annu Rev Pathol. 2017; 12: 25-52Crossref PubMed Scopus (46) Google Scholar The most common etiology of an inadequately controlled complement system in aHUS is a rare, heterozygous, loss-of-function mutation in Factor H (FH), Factor I (FI), or membrane cofactor protein (MCP; CD46)—all regulators of the alternative pathway (AP). Loss-of-function mutation in a regulator leads to haploinsufficiency. In these cases, the protein is generally (a) not synthesized and/or not secreted or (b) secreted into the blood in normal amounts but is dysfunctional. Less frequently, a gain-of-function mutation in one of 2 activators (C3, Factor B) is identified. Approximately 60% of patients with aHUS carry a rare variant in one of these 5 complement proteins. Of note, ∼10% of affected patients carry more than 1 variant, suggesting that the disease in these cases may result from an additive effect of several genetic factors. Disease penetrance is approximately 50%, further suggesting that an environmental trigger is necessary in many cases.5Rodriguez de Cordoba S. Hidalgo M.S. Pinto S. Tortajada A. Genetics of atypical hemolytic uremic syndrome (aHUS).Semin Thromb Hemost. 2014; 40: 422-430Crossref PubMed Scopus (101) Google Scholar In 50-70% of children, this appears to be an infection, whereas in adults, pregnancy is a known predisposing factor. However, in many cases, the precipitating event is not apparent. Acquired deficiencies in the form of autoantibodies against FH also occur in ∼5-10% of patients with aHUS.6Dragon-Durey M.A. Sethi S.K. Bagga A. et al.Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome.J Am Soc Nephrol. 2010; 21: 2180-2187Crossref PubMed Scopus (203) Google Scholar A genetic defect, namely a deletion of CFHR1 and CFHR3 (complement FH-related 1 and 3) may predispose to the development of FH autoantibodies. Patients with FH mutations have the worst prognosis, with 60%-70% reaching ESRD within a year of disease onset7Le Quintrec M. Zuber J. Moulin B. et al.Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome.Am J Transplant. 2013; 13: 663-675Crossref PubMed Scopus (190) Google Scholar, 8Noris 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 (705) Google Scholar, 9Bresin 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 (185) Google Scholar, 10Salvadori M. Bertoni E. Update on hemolytic uremic syndrome: diagnostic and therapeutic recommendations.World J Nephrol. 2013; 2: 56-76Crossref PubMed Google Scholar (Table 1). The prognosis in patients with FI and C3 mutations is similarly poor. Patients with MCP mutations have a better prognosis with ∼80% remaining dialysis independent. Homozygous loss-of-function mutations in diacylglycerol kinase-epsilon (DGKE) have also been described as a cause of aHUS in the first year of life.11Lemaire M. Fremeaux-Bacchi V. Schaefer F. et al.Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.Nat Genet. 2013; 45: 531-536Crossref PubMed Scopus (342) Google Scholar The protein does not belong to the complement system but is expressed on platelets and endothelial cells. It has been postulated that loss of DGKE function results in a prothrombotic state. There is also a paucity of data on the role of thrombomodulin (THBD) gene mutations in aHUS.12Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (933) Google Scholar The overall outcome and prognosis of patients with aHUS has improved since the introduction and use of eculizumab, a humanized monoclonal antibody that neutralizes complement protein C5 and is the only FDA-approved treatment for aHUS.13Legendre C.M. Licht C. Muus P. et al.Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.N Engl J Med. 2013; 368: 2169-2181Crossref PubMed Scopus (1011) Google ScholarTable 1Complement Regulatory Proteins and Atypical Hemolytic Syndrome3Java A. Atkinson J. Salmon J. Defective complement inhibitory function predisposes to renal disease.Annu Rev Med. 2013; 64: 307-324Crossref PubMed Scopus (25) Google Scholar,4Liszewski M.K. Java A. Schramm E.C. Atkinson J.P. Complement dysregulation and disease: insights from contemporary genetics.Annu Rev Pathol. 2017; 12: 25-52Crossref PubMed Scopus (46) Google ScholarComplement ProteinSynthesis Site (Distribution)Frequency in aHUS (%)Risk of ESRD (%) (Pre-Eculizumab)Risk of Recurrence After Kidney Transplantation (%) (Pre-Eculizumab)Factor HLiver (serum)20-3050-7075-90MCPCells (wide distribution)10-200-6<20Factor ILiver (serum)5-155045-80C3Liver (serum)5-156050-60Factor BLiver (serum)<55040-70Abbreviations: aHUS, atypical hemolytic uremic syndrome; MCP, membrane cofactor protein. Open table in a new tab Abbreviations: aHUS, atypical hemolytic uremic syndrome; MCP, membrane cofactor protein. Patients with aHUS who progress to ESRD are candidates for kidney transplantation. Kidney transplantation had been contraindicated because of high risk of disease recurrence leading to early allograft loss. However, over the past decade, advances in our understanding of the pathophysiology of aHUS and availability of the anti-complement drug eculizumab have permitted successful kidney transplantation in these patients.14Noris M. Remuzzi G. Managing and preventing atypical hemolytic uremic syndrome recurrence after kidney transplantation.Curr Opin Nephrol Hypertens. 2013; 22: 704-712Crossref PubMed Scopus (51) Google Scholar Therefore, all patients with aHUS should undergo a comprehensive evaluation to screen for complement system abnormalities before transplantation. Patients who reached ESRD due to pregnancy-associated TMA or another secondary TMA whose evolution was unusually aggressive should also be evaluated. It has been reported that in ∼80% of patients with pregnancy-associated TMA, the disease is complement mediated.15Fakhouri F. Roumenina L. Provot F. et al.Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations.J Am Soc Nephrol. 2010; 21: 859-867Crossref PubMed Scopus (314) Google Scholar Therefore, misrecognition of complement dysregulation in these settings could lead to early postrenal transplant aHUS recurrence. Such evaluations, described in the following, will aid in diagnosis and inform disease etiology as well as facilitate ascertaining the risk of recurrence after kidney transplantation. These evaluations will also help determine whether a patient needs prophylactic eculizumab and/or requires lifelong treatment with the drug and thereby will help to define tailored therapy based on individual risk assessment. Serum C3, C4, CH50, and ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 13) levels should form part of a basic screen (Table 2). In almost all cases of aHUS, C4 levels are normal (with the exception of patients who harbor FH autoantibodies that may form antigen-antibody complexes leading to activation of classical complement pathway and low C4 levels). Low C3 levels are seen in ∼30-50% patients with mutations in CFH, CFI, or MCP. However, normal C3 levels do not exclude the presence of mutations in complement regulatory proteins.Table 2Recommended Testing for Pretransplantation Evaluation for aHUSSerum Antigenic Levels-ADAMTS13, C3, C4, Factor B, Factor H, Factor ICell surface expression of MCP by flow cytometryScreening for FH autoantibodiesGenetic testing-ADAMTS13, C3, CD46, CFB, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, DGKE, THBD, MMACHC, and PLG-Genomic rearrangements across the FH-FHR locus (eg, by multiplex ligation-dependent probe amplification [MLPA])Antiphospholipid antibody evaluationSerum free light chainsSee text for abbreviations. Open table in a new tab See text for abbreviations. Evaluation of aHUS should also include measurement of serum (or EDTA plasma) concentration of FH, FI, and anti-FH antibodies as well as MCP expression on leukocytes by flow cytometry. Because most cases of FH-associated aHUS have a heterozygous mutation in CFH, patients in whom the mutant protein is not expressed would be expected to have a 50% level. Factor H serum levels vary considerably, and the range changes with age.16Kavanagh D. Richards A. Fremeaux-Bacchi V. et al.Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome.Clin J Am Soc Nephrol. 2007; 2: 591-596Crossref PubMed Scopus (61) Google Scholar Most children reach adult levels (37-68 mg/dL) by 1 yr of age. No significant difference in FH levels has been shown between genders. Similar to FH, there are differences in FI concentration depending on the age. Again, most children reach adult levels (2.4-4.9 mg/dL) by 1 yr of age. Measurement of serum antigenic levels will detect ∼25% of patients with mutations in CFH and ∼40% of mutations in CFI. Flow cytometry to measure MCP expression will detect ∼75% of the mutations. All patients should also undergo screening for genetic mutations. A multigene panel that includes ADAMTS13, C3, CD46, CFB, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, DGKE, THBD, MMACHC, and PLG is recommended. Testing specifically designed to detect CFH/CFHR1 hybrid deletions and deletions of CFHR1/CFHR4 and CFHR3/CFHR1 should also be considered. The gene panel offered may vary slightly among the different laboratories conducting these tests. All variants are usually reported according to Human Genome Variation Society (HGVS) nomenclature and classified based on the guidelines established by the joint consensus of the American College of Medical Genetics (ACMG) and the Association of Molecular Pathology.17Richards S. Aziz N. Bale S. et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-424Abstract Full Text Full Text PDF PubMed Scopus (14880) Google Scholar Based on these standards, variants are classified as level 1: pathogenic; level 2: likely pathogenic; level 3: variants of uncertain clinical significance (VUS); level 4: likely benign; and level 5: benign. The implications of mutations reported as "pathogenic" or "likely pathogenic" in aHUS are clear in their ability to cause dysregulation of complement activation. However, less than 50% of the clinically identified variants have a known functional consequence or one that is readily predicted from the DNA sequence alteration (such as nonsense, splice-site, or frame-shift mutations).18Kavanagh D. Anderson H.E. Interpretation of genetic variants of uncertain significance in atypical hemolytic uremic syndrome.Kidney Int. 2012; 81: 11-13Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Several questions about the pathogenesis of this disease remain unanswered because a majority of the variants have not been functionally characterized. Computational prediction algorithms are used to predict the potential impact of these variants on the mature protein and take into consideration: (1) evolutionary conservation of an amino acid or nucleotide, (2) location and context within the protein sequence, (3) biochemical consequence of the amino acid substitution, and, in some cases, (4) topology of a previously solved structural domain or subdomain.19Java A. Pozzi N. Love-Gregory L.D. et al.A multimodality approach to assessing factor I genetic variants in atypical hemolytic uremic syndrome.Kidney Int Rep. 2019; 4: 1007-1017Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Based on these criteria, most variants are reported as "variants of uncertain clinical significance." The presence of such rare variants is particularly vexing for clinical management. Therefore, laboratories that specialize in functional analysis of genetic variants will need to be contacted so that they can assist in defining the significance of the variant. We recently reported five patients with aHUS in whom a genetic variant in FI was identified.19Java A. Pozzi N. Love-Gregory L.D. et al.A multimodality approach to assessing factor I genetic variants in atypical hemolytic uremic syndrome.Kidney Int Rep. 2019; 4: 1007-1017Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar These patients were referred to us for assistance in clinical decision-making relative to therapeutic options for kidney transplant and/or targeted therapy using eculizumab. To obtain a more comprehensive assessment of each patient's risk, we produced recombinant proteins, assessed regulatory function, and performed structural modeling of each variant protein. These analyses allowed us to functionally evaluate the FI variants and in 2 cases more definitively categorized them as pathogenic or benign. Based on these evaluations, we developed an individualized treatment plan for each patient. These studies highlight the utility of an integrated approach in defining the pathologic and clinical implications of rare genetic variants in aHUS (Fig 2). Nevertheless, the clinical relevance of common polymorphisms identified in complement genes as well as the definitive role of CFH-related proteins (CFHR1-5) remains unclear and is an area of further research. Also, patients in whom genetic variants in known complement proteins have been excluded or are reported as "benign" may need further investigation including whole exome sequencing to ascertain cause of disease because unidentified genetic abnormalities may exist. Living-related donor kidney transplant is relatively contraindicated for patients with aHUS. This is primarily for donor safety because nephrectomy may trigger TMA in the genetically susceptible donor. Although genetic analysis may be performed in donors, some patients may have more than 1 mutation, and in approximately one-third of patients with aHUS, genetic testing does not reveal a variant in the complement gene. In addition, given our current lack of understanding of the clinical relevance of several polymorphisms, a negative mutational analysis of a potential living-related donor does not guarantee freedom from mutations associated with aHUS. Therefore, living-donor transplants could be considered with caution on a case-by-case basis. We may consider living-related donor transplants in patients who carry a known pathogenic mutation in a complement protein which is determined to be the cause of disease in the patient and if the donor tests negative for that mutation. The recipient and the potential living donor should participate in decision making after they understand the risks and benefits of this option. Living unrelated donors however can be considered for a kidney transplant if genetic testing is negative. There are some data to suggest that aHUS relapse risk may be higher in deceased-donor kidneys compared to living donors. In a retrospective review by Bresin and colleagues,9Bresin 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 (185) Google Scholar the authors reported an overall 1-yr graft survival of 32% for cadaveric transplants compared to 50% for living-donor transplants. These results were compared to the UNOS Renal Transplant Registry data from 1990s20Cecka J.M. The UNOS scientific renal transplant Registry.Clin Transpl. 1999; : 1-21PubMed Google Scholar which showed that the 1-yr graft survival rate for deceased-donor kidney transplants was 87%, whereas for living-donor transplants, it was 93%. The difference may be partly explained by studies that demonstrate that prolonged cold ischemia time in deceased-donor transplants is associated with complement activation.21Casiraghi F. Azzollini N. Todeschini M. et al.Complement alternative pathway deficiency in recipients protects kidney allograft from ischemia/reperfusion injury and alloreactive T cell response.Am J Transpl. 2017; 17: 2312-2325Crossref PubMed Scopus (22) Google Scholar,22Yu Z.X. Qi S. Lasaro M.A. et al.Targeting complement pathways during cold ischemia and reperfusion prevents delayed graft function.Am J Transpl. 2016; 16: 2589-2597Crossref PubMed Scopus (31) Google Scholar Eculizumab is a humanized monoclonal antibody directed against the terminal pathway protein C5 [part of the membrane attack complex (MAC)]. It binds to and blocks the N-terminal cleavage of C5 into two effector molecules, C5b and C5a, thereby preventing formation of the MAC, C5b-9, and the liberation of C5a. Because it acts downstream of C3, eculizumab preserves the autoimmune protective and immune-enhancing proinflammatory functions of the opsonin C3b and the anaphylatoxin C3a. Treatment with eculizumab before transplantation should be considered in all patients with aHUS due to a known pathogenic mutation in a complement protein (except those with a pathogenic MCP mutation as cause of disease because MCP is a membrane-bound protein and the allograft brings in the nonmutated MCP). Prophylactic treatment should also be considered in patients who have a biopsy-proven diagnosis of TMA in the native kidney in whom a genetic variant has not been identified but other etiologies of TMA have been excluded. Although the optimal prophylactic regimen is not known, we recommend the following approach:•In patients who are receiving a living-unrelated donor kidney, we administer eculizumab at 900 mg intravenously 24 hours before transplantation and on days 7, 14, and 21 after transplantation, followed by 1200 mg on week 5 and then every 2 weeks thereafter.•In patients who are receiving a deceased-donor kidney, we administer eculizumab at 900 mg intravenously at the time of transplantation and continue 900 mg weekly for 3 additional doses, followed by 1200 mg on week 5 and then every 2 weeks thereafter. Among patients treated with eculizumab, hemoglobin, platelet count, and lactate dehydrogenase should be monitored daily while patients are hospitalized and then at each subsequent clinic visit (Table 3). To assess the effectiveness of complement blockade, we measure total hemolytic complement (THC; CH50) before each dose of eculizumab for the first four doses; patients with complete suppression should have a CH50 of <10%. Measurement of CH50 can also confirm whether dose adjustment is indicated in patients not responding to the initial dose of eculizumab. In addition, trough serum eculizumab levels (if available) can be measured with a target level of >100 μg/mL.23Wong E. Challis R. Sheerin N. et al.Patient stratification and therapy in atypical haemolytic uraemic syndrome (aHUS).Immunobiology. 2016; 221: 715-718Crossref PubMed Scopus (7) Google ScholarTable 3Posttransplant Monitoring for aHUS (Complete Blood Count, Renal Panel, Urinalysis, Lactate Dehydrogenase, Haptoglobin)Immediate Posttransplant (During Hospitalization)Daily, CH50/AH50 Before Eculizumab Administration for the 1st Four DosesUp to 6 monthsWeekly6-12 monthsBiweeklyAfter 12 monthsMonthlyAbbreviation: aHUS, atypical hemolytic uremic syndrome.A peripheral smear should be obtained in addition to the above if there is any concern for recurrence. Open table in a new tab Abbreviation: aHUS, atypical hemolytic uremic syndrome. A peripheral smear should be obtained in addition to the above if there is any concern for recurrence. The predominant concern is a life-threatening infection with Neisseria meningitidis (owing to blockage of the terminal complement pathway).24McNamara L.A. Topaz N. Wang X. et al.High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine.MMWR Morb Mortal Wkly Rep. 2017; 66: 734-737Crossref PubMed Scopus (158) Google Scholar Both MenACWY and MenB vaccines should be administered before transplantation, in addition to Prevnar and Pneumovax. A booster dose of MenACWY vaccine should be administered every 5 years, for the duration of complement inhibitor therapy. The Centers for Disease Control (CDC) does not currently have recommendations about if or when to administer booster doses of MenB vaccine. The vaccines should be given at least 2 weeks before administering the first dose of the complement inhibitor. In addition, appropriate antibiotics (penicillin or fluoroquinolone) should be used for at least 14 days if there is not enough time to wait for the immune response. Providers could also consider antimicrobial prophylaxis for the duration of eculizumab treatment to potentially reduce the risk for meningococcal disease although the effectiveness of this strategy has not been established. However, neither vaccination nor antimicrobial prophylaxis can be expected to prevent all cases of meningococcal disease. Therefore, suggestive symptoms of a bacteremia or septicemia should necessitate urgent investigation and antibiotic therapy. Owing to the high cost of eculizumab, some centers have tried to develop alternative transplant strategies that do not use prophylactic eculizumab. As an example, 1 case series from the Netherlands reported outcomes of 17 patients with aHUS, who underwent living-donor kidney transplantation without eculizumab prophylaxis.25Duineveld C. Verhave J.C. Berger S.P. van de Kar N. Wetzels J.F.M. Living donor kidney transplantation in atypical hemolytic uremic syndrome: a case series.Am J Kidney Dis. 2017; 70: 770-777Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Sixteen of 17 patients carried a pathogenic or likely pathogenic variant in CFH, CFI, or C3, and 5 had lost a previous allograft due to recurrent HUS. The transplant protocol was modified and consisted of induction therapy with basiliximab, followed by maintenance immunosuppression with low-dose tacrolimus (targeting ∼20-30% lower-than-usual trough levels), mycophenolate mofetil, and prednisone. Patients were instructed to perform home blood pressure measurements and were instructed to contact their physician in case of symptoms or signs concerning for aHUS recurrence (such as malaise, edema, hematuria on urine dipsticks, oliguria, and dyspnea) or in case of potential triggers of aHUS, such as infections. At a median of 25 months, all patients had stable graft function (median serum creatinine 1.2 mg/dL) without significant proteinuria; only one patient developed recurrent TMA. Eculizumab treatment in this patient induced hematologic remission and improvement in allograft function, although this was followed 3 months later by another relapse within a few days of eculizumab treatment discontinuation. Reinitiation of eculizumab therapy was again associated with hematologic remission, but with only partial improvement of kidney function. There are other reports of successful deceased-donor kidney transplantations in patients with aHUS, who received basiliximab induction in conjunction with a calcineurin inhibitor dosed to target lower trough concentration and who have not had a relapse with a median follow-up of 28 months.2Grenda R. Jarmuzek W. Rubik J. et al.Favorable four-yr outcome after renal transplantation in a patient with complement factor H antibody and CFHR1/CFHR3 gene mutation-associated HUS.Pediatr Transpl. 2015; 19: E130-E134Crossref PubMed Scopus (8) Google Scholar,26Waters A.M. Pappworth I. Marchbank K. et al.Successful renal transplantation in factor H autoantibody associated HUS with CFHR1 and 3 deficiency and CFH variant G2850T.Am J Transpl. 2010; 10: 168-172Crossref PubMed Scopus (27) Google Scholar Although these findings suggest that kidney transplant without prophylaxis may be feasible in aHUS, longer-term studies are required to confirm the efficacy and safety of this approach. A review of literature for studies reporting use of eculizumab prophylaxis and outcomes in patients with deceased- and living-donor transplants is shown in Table 4.Table 4Review of Studies Reporting Prophylactic Use of Eculizumab and Outcomes in Patients With Deceased- and Living-Donor TransplantsAuthorCasesGenetic VariantsEculizumab ProphylaxisType of TransplantMedian Follow-Up (months)aHUS RecurrenceAcute Rejection/Other ComplicationsZuber et al, 201227Zuber J. Fakhouri F. Roumenina L.T. Loirat C. Fremeaux-Bacchi V. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies.Nat Rev Nephrol. 2012; 8: 643-657Crossref PubMed Scopus (391) Google Scholar9CFH, 5; CFH/CFHR1, 3C3, 1YesLD, 1DD, 814.50Mixed rejection, 1Matar et al, 201428Matar D. Naqvi F. Racusen L.C. et al.Atypical hemolytic uremic syndrome recurrence after kidney transplantation.Transplantation. 2014; 98: 1205-1212Crossref PubMed Scopus (41) Google Scholar12CFH, 4; MCP, 1THB