Kidney Transplantation in Patients With Atypical Hemolytic Uremic Syndrome: A Therapeutic Dilemma (or Not)?
2017; Elsevier BV; Volume: 70; Issue: 6 Linguagem: Inglês
10.1053/j.ajkd.2017.08.005
ISSN1523-6838
AutoresMarina Noris, Piero Ruggenenti, Giuseppe Remuzzi,
Tópico(s)Renal Diseases and Glomerulopathies
ResumoRelated Article, p. 770 Related Article, p. 770 Atypical hemolytic uremic syndrome (aHUS) due to genetic and acquired abnormalities of the complement alternative pathway has been associated with high risk for recurrence after kidney transplantation.1Noris 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 Before the introduction of the anti-C5 monoclonal antibody eculizumab, recurrence was reported in 60% to 80% of aHUS transplant recipients1Noris 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 and was strongly associated with transplant failure because of the poor response to treatment with plasma exchange.2Le 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 (189) Google Scholar Insults resulting from ischemia-reperfusion injury and alloimmune responses, as well as certain immunosuppressive drugs, cause endothelial injury in the transplant and activate complement, thus triggering disease relapse. Available data suggest that the risk for posttransplantation recurrence is dictated by the underlying genetic defects. Patients with abnormalities in genes encoding complement circulating proteins, complement factor H (CFH), factor I (CFI), factor B (CFB), and C3, carry a high risk for recurrence because the altered proteins persist in the blood after transplantation.1Noris 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 In contrast, the risk for recurrence is low in patients with isolated genetic abnormalities in the transmembrane and intracellular proteins membrane cofactor protein and diacyl-glycerol kinase ɛ, respectively,1Noris 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 because kidney transplants (typically from donors without aHUS) express normal proteins. Based on clinical studies demonstrating the efficacy of eculizumab in inducing remission of acute episodes of aHUS and maintaining long-term remission in both native and transplanted kidneys,3Legendre 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 (999) Google Scholar, 4Greenbaum L.A. Fila M. Ardissino G. et al.Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome.Kidney Int. 2016; 89: 701-711Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar the drug has been widely used as prophylaxis to prevent aHUS recurrence in transplants of genetically at-risk recipients.1Noris 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, 5Zimmerhackl 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 (124) Google Scholar What is unclear is whether eculizumab should be given as a lifelong treatment. Apart from the low risk for meningococcal infection in immunized patients, eculizumab is exceedingly expensive, with an annual cost of ∼$700,000 for an adult patient.6America's Health Insurance PlansHigh-Priced Drugs: Estimates of Annual Per-Patient Expenditures for 150 Specialty Medications. Center for Policy and Research, Washington, DC2016Google Scholar The cost of indefinite eculizumab therapy is consequently a barrier to its use in many countries with national health systems, as well as in resource-rich nations with private insurance companies. Most importantly, patients living in low-income regions and several developing countries do not have access to the drug. Very recently, evidence has started emerging that eculizumab therapy may be discontinued in patients with aHUS after remission has been achieved in the native kidney, with cases of relapse effectively responding to prompt resumption of anti-C5 therapy.7Macia M. de Alvaro Moreno F. Dutt T. et al.Current evidence on the discontinuation of eculizumab in patients with atypical haemolytic uraemic syndrome.Clin Kidney J. 2017; 10: 310-319PubMed Google Scholar, 8Merrill S.A. Brittingham Z.D. Yuan X. Moliterno A.R. Sperati C.J. Brodsky R.A. Eculizumab cessation in atypical hemolytic uremic syndrome.Blood. 2017; 130: 368-372Crossref PubMed Scopus (59) Google Scholar, 9Fakhouri F. Fila M. Provot F. et al.Pathogenic variants in complement genes and risk of atypical hemolytic uremic syndrome relapse after eculizumab discontinuation.Clin J Am Soc Nephrol. 2017; 12: 50-59Crossref PubMed Scopus (121) Google Scholar Until now, lifelong prophylaxis with eculizumab has been advised after kidney transplantation, particularly in patients who either carry pathogenetic variants associated with high risk for recurrence or who have had recurrence in a previous transplant.10Goodship 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 (353) Google Scholar In this issue of AJKD, Duineveld et al11Duineveld C. Verhave J.C. Berger S.P. Van de Kar N.C.A.J. 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 (30) Google Scholar describe their experience with kidney transplantation in patients with aHUS who were managed at 2 centers in the Netherlands according to a protocol without eculizumab prophylaxis. To reduce the risk for triggering aHUS relapse in transplants, the authors used a protocol with living kidney donors to limit ischemia-reperfusion injury, together with an immunosuppressive regimen comprising basiliximab, prednisone, high-dose mycophenolate mofetil, and tacrolimus dosed to target lower-than-usual blood concentrations in the first 30 posttransplantation days (20%-30% of the standard protocol at their transplantation centers) to minimize potential kidney endothelial cell injury. The protocol additionally included strict early blood pressure control, as well as statin therapy and angiotensin-converting enzyme inhibition, to further mitigate endothelial injury and protect the kidney transplant. Patients were closely monitored until 4 months posttransplantation, with gradual extension of the follow-up interval thereafter. Eculizumab was administered when evidence of aHUS relapse was detected. The cohort comprised 17 patients with aHUS who underwent transplantation with this protocol, extending the initial experience in their first 4 patients previously reported by these investigators.12Verhave J.C. Westra D. van Hamersvelt H.W. van Helden M. van de Kar N.C. Wetzels J.F. Living kidney transplantation in adult patients with atypical haemolytic uraemic syndrome.Neth J Med. 2013; 71: 342-347PubMed Google Scholar Sixteen of the 17 patients were at high risk for posttransplantation recurrence because they carried pathogenetic, or likely pathogenetic, variants in CFH (7 patients), C3 (8 patients), or combined CFI and membrane cofactor protein likely-pathogenetic variants (1 patient). In addition, some specific variants identified in their recipients are known to be associated with transplant relapse, namely the p.Arg161Trp and the p.Lys65Gln in C3,13Roumenina L.T. Frimat M. Miller E.C. et al.A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function.Blood. 2012; 119: 4182-4191Crossref PubMed Scopus (109) Google Scholar, 14Volokhina E. Westra D. Xue X. Gros P. van de Kar N. van den Heuvel L. Novel C3 mutation p.Lys65Gln in aHUS affects complement factor H binding.Pediatr Nephrol. 2012; 27: 1519-1524Crossref PubMed Scopus (35) Google Scholar as well as p.R1210C in CFH.15Martinez-Barricarte R. Pianetti G. Gautard R. et al.The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome.J Am Soc Nephrol. 2008; 19: 639-646Crossref PubMed Scopus (70) Google Scholar The p.Gln950His CFH variant, found in 2 of their patients and present in 0.6% of the European population, has been shown to have only a mild effect on factor H function16Mohlin F.C. Nilsson S.C. Levart T.K. et al.Functional characterization of two novel non-synonymous alterations in CD46 and a Q950H change in factor H found in atypical hemolytic uremic syndrome patients.Mol Immunol. 2015; 65: 367-376Crossref PubMed Scopus (21) Google Scholar and thus is less likely to significantly affect disease recurrence risk. Further underscoring their cohort's risk profile, 5 of 6 patients who previously underwent transplantation had experienced HUS transplant relapse. The investigators reported that during follow-up ranging from 7 to 68 months after transplantation, only 1 patient treated with their protocol had clinical signs of recurrence, confirmed by histologic evidence of arteriolar hyalinosis and intraluminal thrombosis in the absence of rejection in the transplant biopsy. Eculizumab treatment in this patient, a CFH likely-pathogenetic variant carrier, induced hematologic remission and improvement in transplant function, although this was followed 3 months later by another relapse within a few days of eculizumab treatment discontinuation. Re-initation of eculizumab therapy was again associated with hematologic remission, but with only partial improvement of transplant function; hence, complement inhibition was discontinued after 6 months of re-treatment. With about 2 months of follow-up after eculizumab therapy discontinuation, Tables 3 and Table S1 in Duineveld et al imply that no further HUS relapse was recorded, although transplant function continued to decline. The course of this single patient suggests that in cases of posttransplantation relapses, eculizumab treatment should not be discontinued. Living related donation has been considered a contraindication in aHUS because of both the high risk for recurrence and the potential risk to donors in whom aHUS can be triggered by uninephrectomy in biological relatives who may carry complement gene abnormalities. Duineveld et al report good short-term posttransplantation outcomes in the 3 recipients of kidneys from a living related donor. Known genetic abnormalities were excluded before donation in 2 of the living related donors,12Verhave J.C. Westra D. van Hamersvelt H.W. van Helden M. van de Kar N.C. Wetzels J.F. Living kidney transplantation in adult patients with atypical haemolytic uraemic syndrome.Neth J Med. 2013; 71: 342-347PubMed Google Scholar whereas no information was provided for the third. However, data for these living related donors should be interpreted cautiously because aHUS is a complex genetic disorder, with multiple genetic factors including pathogenic variants and risk polymorphisms and haplotypes17Bresin E. Rurali E. Caprioli J. et al.Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype.J Am Soc Nephrol. 2013; 24: 475-486Crossref PubMed Scopus (261) Google Scholar likely combining to determine the risk for relapse in the recipient and of aHUS onset in biological relatives. How does one reconcile this report with previous large cohort studies showing an unfavorable outcome of transplantation in patients with aHUS?1Noris 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, 2Le 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 (189) Google Scholar, 18Bresin E. Daina E. Noris M. et al.Outcome of renal transplantation in patients with non-Shiga toxin-associated haemolytic uremic syndrome: prognostic significance of genetic background.Clin J Am Soc Nephrol. 2006; 1: 88-99Crossref PubMed Scopus (185) Google Scholar The first possible explanation is that the majority of patients in prior reports received deceased donor kidneys. This notion is underscored by the finding in one large aHUS recipient cohort that 1-year kidney transplant survival was 32% and 50% for recipients of deceased and living donor transplants, respectively.18Bresin E. Daina E. Noris M. et al.Outcome of renal transplantation in patients with non-Shiga toxin-associated haemolytic uremic syndrome: prognostic significance of genetic background.Clin J Am Soc Nephrol. 2006; 1: 88-99Crossref PubMed Scopus (185) Google Scholar However, because most donors were not genotyped, the presence of complement pathogenetic variants could not be excluded. Second, a large body of literature has indicated that the complement cascade is activated in the kidney transplant during conditions of ischemia and/or reperfusion and plays a role in the development of ischemia-reperfusion injury.19Yu Z.X. Qi S. Lasaro M.A. et al.Targeting complement pathways during cold ischemia and reperfusion prevents delayed graft function.Am J Transplant. 2016; 16: 2589-2597Crossref PubMed Scopus (31) Google Scholar, 20Casiraghi 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 Transplant. 2017; 17: 2312-2325Crossref PubMed Scopus (22) Google Scholar For this reason, using a living rather than deceased donor kidney to minimize ischemic injury to the transplant could plausibly limit triggering an aHUS exacerbation in patients who have genetically defective control of complement activation. However, living donation alone is not enough to explain the very low incidence of relapse reported by Duineveld et al because 2 patients in their cohort had experienced a disease relapse in previous living donor kidney transplants.12Verhave J.C. Westra D. van Hamersvelt H.W. van Helden M. van de Kar N.C. Wetzels J.F. Living kidney transplantation in adult patients with atypical haemolytic uraemic syndrome.Neth J Med. 2013; 71: 342-347PubMed Google Scholar Third, the choice of an immunosuppressive regimen targeting reduced tacrolimus concentrations may be an important factor because calcineurin inhibitors (CNIs) cause vascular renal injury and can trigger de novo HUS posttransplantation.1Noris 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 Endothelial cells exposed to CNIs in vitro and in vivo release microparticles that activate the alternative complement pathway, causing injury to bystander endothelial cells.21Renner B. Klawitter J. Goldberg R. et al.Cyclosporine induces endothelial cell release of complement-activating microparticles.J Am Soc Nephrol. 2013; 24: 1849-1862Crossref PubMed Scopus (58) Google Scholar However, previous studies have found that completely avoiding CNIs in patients with aHUS with use of mTOR inhibitors, also known to cause endothelial toxicity, does not prevent recurrence while exposing patients to risk for rejection.1Noris 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 Thus, the protocol of Duineveld et al that combines tacrolimus targeted to reduced levels, in conjunction with basiliximab induction, steroids, and high-dose mycophenolate mofetil, appears to be a more appropriate strategy to limit endothelial injury while simultaneously maintaining sufficient control of the immune response. Basiliximab, a humanized antibody that binds selectively to the CD25 subunit of the interleukin 2 receptor, blocks T-cell activation without inducing complement-mediated cell lysis.22van den Hoogen M.W. Hilbrands L.B. Use of monoclonal antibodies in renal transplantation.Immunotherapy. 2011; 3: 871-880Crossref PubMed Scopus (35) Google Scholar Whether basiliximab may have a role in preventing aHUS relapse posttransplantation remains to be established. Of interest, there are reports of successful deceased donor kidney transplantations in 3 patients with aHUS, with a CFI variant,23Ranghino A. Tognarelli G. Basso E. et al.A newly identified mutation in the complement factor I gene not associated with early post-transplant recurrence of atypical hemolytic-uremic syndrome: a case report.Transplant Proc. 2013; 45: 2785-2787Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar a CFH variant,24Waters 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 Transplant. 2010; 10: 168-172Crossref PubMed Scopus (27) Google Scholar and anti–factor H antibodies,25Grenda 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 Transplant. 2015; 19: E130-E134Crossref PubMed Scopus (8) Google Scholar respectively, who received basiliximab induction as part of their posttransplantation immunosuppression regimen. Further, at our own clinical center, 7 patients with aHUS who received deceased donor kidneys using a regimen of basiliximab induction together with a CNI dosed to target a reduced concentration have had no relapse with a median follow-up of 28 months (range, 4-41 months; Fig 1). A couple of limitations in the Duineveld et al report should be highlighted: the small cohort size and relatively short-term follow-up (<1 year in 5 patients). Although ∼80% of recurrences occur in the first posttransplantation year and the risk for relapse decreases thereafter over time,18Bresin E. Daina E. Noris M. et al.Outcome of renal transplantation in patients with non-Shiga toxin-associated haemolytic uremic syndrome: prognostic significance of genetic background.Clin J Am Soc Nephrol. 2006; 1: 88-99Crossref PubMed Scopus (185) Google Scholar late events are not infrequent. Taking into account these limitations, the article by Duineveld et al opens an avenue for future controlled studies in larger cohorts and with longer follow-up to establish whether the paradigm for posttransplantation eculizumab therapy should change from a prophylaxis strategy to a rescue approach. Whether such a strategy could be extended to recipients of deceased donor kidneys, possibly with the support of machine perfusion26Kaths J.M. Paul A. Robinson L.A. Selzner M. Ex vivo machine perfusion for renal graft preservation.Transplant Rev (Orlando). 2017; (http://dx.doi.org/10.1016/j.trre.2017.04.002)PubMed Google Scholar to improve organ preservation, is worth investigating. Specific tests of complement activation on cell surface, such as ex vivo serum-induced C5b-9 deposition on endothelial cells,27Noris M. Galbusera M. Gastoldi S. et al.Dynamics of complement activation in aHUS and how to monitor eculizumab therapy.Blood. 2014; 124: 1715-1726Crossref PubMed Scopus (223) Google Scholar may help identify patients at imminent risk for relapse and guide complement-inhibitory therapy in order to prevent transplant injury in those with relapsing disease. Support: This report is supported by a grant from the European Union Seventh Framework Programme FP7-EURenOmics project number 305608. Financial Disclosure: Dr Noris has received honoraria from Alexion Pharmaceuticals for giving lectures and participating in advisory boards and research grants from Omeros and Chemocentryx. None of these activities has had an influence on the results or interpretation in this article. Dr Remuzzi has consultancy agreements with AbbVie, Alexion Pharmaceuticals, Bayer Healthcare, Reata Pharmaceuticals, Novartis Pharma, AstraZeneca, Otsuka Pharmaceutical Europe, and Concert Pharmaceuticals; no personal remuneration is accepted, compensation is paid to his institution for research and educational activities. The other authors declare no conflict of interest. Peer Review: Editorial input from an Associate Editor and Deputy Editor Berns. Living Donor Kidney Transplantation in Atypical Hemolytic Uremic Syndrome: A Case SeriesAmerican Journal of Kidney DiseasesVol. 70Issue 6PreviewThe development of complement inhibitors has greatly improved the outcome of patients with atypical hemolytic uremic syndrome (aHUS), making kidney transplantation a more feasible option. Although prophylactic eculizumab therapy may prevent recurrent disease after transplantation, its necessity for all transplant recipients is debated. Full-Text PDF
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