Top

Published in:

01-08-2016 | Original Article

Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection

Authors: Meghan H. Pearl, Anjali B. Nayak, Robert B. Ettenger, Dechu Puliyanda, Miguel Fernando Palma Diaz, Qiuheng Zhang, Elaine F. Reed, Eileen W. Tsai

Published in: Pediatric Nephrology | Issue 8/2016

Abstract

Background

Current therapeutic strategies to effectively treat antibody-mediated rejection (AMR) are insufficient. Thus, we aimed to determine the benefit of a therapeutic protocol using bortezomib for refractory C4d + AMR in pediatric kidney transplant patients.

Methods

We examined seven patients with treatment-refractory C4d + AMR. Immunosuppression included antithymocyte globulin or anti-CD25 monoclonal antibody for induction therapy with maintenance corticosteroids, calcineurin inhibitor, and anti-metabolite. Estimated glomerular filtration rate (eGFR) calculated by the Schwartz equation, biopsy findings assessed by 2013 Banff criteria, and human leukocyte antigen (HLA) donor-specific antibodies (DSA) performed using the Luminex single antigen bead assay were monitored pre- and post- bortezomib therapy.

Results

Seven patients (86 % male, 86 % with ≥6/8 HLA mismatch, and 14 % with pre-formed DSA) age 5 to 19 (median 15) years developed refractory C4d + AMR between 1 and 145 (median 65) months post-transplantation. All patients tolerated bortezomib. One patient had allograft loss. Of the six patients with surviving grafts (86 %), mean pre-bortezomib eGFR was 42 ml/min/1.73 m² and the mean 1 year post-bortezomib eGFR was 53 ml/min/1.73 m². Five of seven (71 %) had improvement of histological findings of AMR, C4d staining, and/or acute cellular rejection. Reduction in HLA DSAs was more effective for class I than class II.

Conclusions

Bortezomib appears safe and may correlate with stabilization of eGFR in pediatric kidney transplant patients with refractory C4d + AMR.

Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B (2004) Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 4:378–383CrossRefPubMed

Sellares J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, Hidalgo LG, Famulski K, Matas A, Halloran PF (2012) Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant 12:388–399CrossRefPubMed

(2010) North American Pediatric Renal Trials and Collaborative Studies. 2010 Annual Transplant Report. Available at http://web.emmes.com

Wiebe C, Gibson IW, Blydt-Hansen TD, Pochinco D, Birk PE, Ho J, Karpinski M, Goldberg A, Storsley L, Rush DN, Nickerson PW (2015) Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody. Am J Transplant 15:2921–2930CrossRefPubMed

Kim JJ, Balasubramanian R, Michaelides G, Wittenhagen P, Sebire NJ, Mamode N, Shaw O, Vaughan R, Marks SD (2014) The clinical spectrum of de novo donor-specific antibodies in pediatric renal transplant recipients. Am J Transplant 14:2350–2358CrossRefPubMed

Huber L, Lachmann N, Niemann M, Naik M, Liefeldt L, Glander P, Schmidt D, Halleck F, Waiser J, Brakemeier S, Neumayer HH, Schonemann C, Budde K (2015) Pretransplant virtual PRA and long-term outcomes of kidney transplant recipients. Transpl Int 28:710–719CrossRefPubMed

Sapir-Pichhadze R, Tinckam KJ, Laupacis A, Logan AG, Beyene J, Kim SJ (2015) Immune sensitization and mortality in wait-listed kidney transplant candidates. J Am Soc Nephrol. doi:10.1681/ASN.2014090894 PubMed

2012 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 2004-2012. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association, Ann Arbor, MI. http://www.srtr.org/

Mohan S, Palanisamy A, Tsapepas D, Tanriover B, Crew RJ, Dube G, Ratner LE, Cohen DJ, Radhakrishnan J (2012) Donor-specific antibodies adversely affect kidney allograft outcomes. J Am Soc Nephrol 23:2061–2071CrossRefPubMedPubMedCentral

10.

Terasaki PI, Ozawa M, Castro R (2007) Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival. Am J Transplant 7:408–415CrossRefPubMed

11.

Everly MJ, Everly JJ, Arend LJ, Brailey P, Susskind B, Govil A, Rike A, Roy-Chaudhury P, Mogilishetty G, Alloway RR, Tevar A, Woodle ES (2009) Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss. Am J Transplant 9:1063–1071CrossRefPubMed

12.

Bonomini V, Vangelista A, Frasca GM, Di Felice A, Liviano D’Arcangelo G (1985) Effects of plasmapheresis in renal transplant rejection. A controlled study. Trans Am Soc Artif Intern Organs 31:698–703PubMed

13.

Blake P, Sutton D, Cardella CJ (1990) Plasma exchange in acute renal transplant rejection. Prog Clin Biol Res 337:249–252PubMed

14.

Allen NH, Dyer P, Geoghegan T, Harris K, Lee HA, Slapak M (1983) Plasma exchange in acute renal allograft rejection. A controlled trial. Transplantation 35:425–428CrossRefPubMed

15.

Roberts DM, Jiang SH, Chadban SJ (2012) The treatment of acute antibody-mediated rejection in kidney transplant recipients-a systematic review. Transplantation 94:775–783CrossRefPubMed

16.

Zarkhin V, Li L, Kambham N, Sigdel T, Salvatierra O, Sarwal MM (2008) A randomized, prospective trial of rituximab for acute rejection in pediatric renal transplantation. Am J Transplant 8:2607–2617CrossRefPubMed

17.

Vo AA, Choi J, Cisneros K, Reinsmoen N, Haas M, Ge S, Toyoda M, Kahwaji J, Peng A, Villicana R, Jordan SC (2014) Benefits of rituximab combined with intravenous immunoglobulin for desensitization in kidney transplant recipients. Transplantation 98:312–319CrossRefPubMed

18.

Dorje C, Midtvedt K, Holdaas H, Naper C, Strom EH, Oyen O, Leivestad T, Aronsen T, Jenssen T, Flaa-Johnsen L, Lindahl JP, Hartmann A, Reisaeter AV (2013) Early versus late acute antibody-mediated rejection in renal transplant recipients. Transplantation 96:79–84CrossRefPubMed

19.

Pefaur J, Diaz P, Panace R, Salinas P, Fiabane A, Quinteros N, Chea R, Naranjo E, Wurgaft A, Beltran E, Elgueta S, Wegmann ME, Gajardo JG, Contreras L (2008) Early and late humoral rejection: a clinicopathologic entity in two times. Transplant Proc 40:3229–3236CrossRefPubMed

20.

Sun Q, Liu ZH, Ji S, Chen J, Tang Z, Zeng C, Zheng C, Li LS (2006) Late and early C4d-positive acute rejection: different clinico-histopathological subentities in renal transplantation. Kidney Int 70:377–383CrossRefPubMed

21.

Gupta G, Abu Jawdeh BG, Racusen LC, Bhasin B, Arend LJ, Trollinger B, Kraus E, Rabb H, Zachary AA, Montgomery RA, Alachkar N (2014) Late antibody-mediated rejection in renal allografts: outcome after conventional and novel therapies. Transplantation 97:1240–1246CrossRefPubMed

22.

Banasik M, Koscielska-Kasprzak K, Myszka M, Bartoszek D, Zabinska M, Boratynska M, Kaminska D, Mazanowska O, Zmonarski S, Krajewska M, Halon A, Dawiskiba T, Nowakowska B, Klinger M (2014) A significant role for anti-human leukocyte antigen antibodies and antibody-mediated rejection in the biopsy-for-cause population. Transplant Proc 46:2613–2617CrossRefPubMed

23.

Flechner SM, Fatica R, Askar M, Stephany BR, Poggio E, Koo A, Banning S, Chiesa-Vottero A, Srinivas T (2010) The role of proteasome inhibition with bortezomib in the treatment of antibody-mediated rejection after kidney-only or kidney-combined organ transplantation. Transplantation 90:1486–1492CrossRefPubMed

24.

Chaudhuri A, Ozawa M, Everly MJ, Ettenger R, Dharnidharka V, Benfield M, Mathias R, Portale A, McDonald R, Harmon W, Kershaw D, Vehaskari VM, Kamil E, Baluarte HJ, Warady B, Li L, Sigdel TK, Hsieh SC, Dai H, Naesens M, Waskerwitz J, Salvatierra O Jr, Terasaki PI, Sarwal MM (2013) The clinical impact of humoral immunity in pediatric renal transplantation. J Am Soc Nephrol 24:655–664CrossRefPubMedPubMedCentral

25.

Touzot M, Couvrat-Desvergnes G, Castagnet S, Cesbron A, Renaudin K, Cantarovich D, Giral M (2015) Differential modulation of donor-specific antibodies after B-cell depleting therapies to cure chronic antibody-mediated rejection. Transplantation 99:63–68CrossRefPubMed

26.

Waiser J, Budde K, Schutz M, Liefeldt L, Rudolph B, Schonemann C, Neumayer HH, Lachmann N (2012) Comparison between bortezomib and rituximab in the treatment of antibody-mediated renal allograft rejection. Nephrol Dial Transplant 27:1246–1251CrossRefPubMed

27.

Ryckewaert A, Allain-Launay E, Moreau A, Blancho G, Cesbron A, Blin N, Roussey G (2013) Failure of bortezomib to cure acute antibody-mediated rejection in a non-compliant renal transplant patient. Pediatr Transplant 17:E131–E136CrossRefPubMed

28.

Twombley K, Thach L, Ribeiro A, Joseph C, Seikaly M (2013) Acute antibody-mediated rejection in pediatric kidney transplants: a single center experience. Pediatr Transplant 17:E149–E155CrossRefPubMed

29.

Walsh RC, Brailey P, Girnita A, Alloway RR, Shields AR, Wall GE, Sadaka BH, Cardi M, Tevar A, Govil A, Mogilishetty G, Roy-Chaudhury P, Woodle ES (2011) Early and late acute antibody-mediated rejection differ immunologically and in response to proteasome inhibition. Transplantation 91:1218–1226CrossRefPubMed

30.

Nguyen S, Gallay B, Butani L (2014) Efficacy of bortezomib for reducing donor-specific antibodies in children and adolescents on a steroid minimization regimen. Pediatr Transplant 18:463–468CrossRefPubMed

31.

Marks SD (2014) Treatment strategies to treat antibody-mediated rejection and to reduce donor-specific antibodies. Pediatr Transplant 18:417–419CrossRefPubMed

32.

Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M (2014) Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant 14:255–271CrossRefPubMedPubMedCentral

33.

Claes DJ, Yin H, Goebel J (2014) Protective immunity and use of bortezomib for antibody-mediated rejection in a pediatric kidney transplant recipient. Pediatr Transplant 18:E100–E105CrossRefPubMed

34.

Roberti I, Vyas S (2015) Successful treatment of severe acute antibody-mediated rejection of renal allografts with bortezomib - a report of two pediatric cases. Pediatr Transplant. doi:10.1111/petr.12612 PubMed

35.

Kim JS, Lee JI, Shin JY, Kim SY, Shin JS, Lim JH, Cho HS, Yoon IH, Kim KH, Kim SJ, Park CG (2009) Bortezomib can suppress activation of rapamycin-resistant memory T cells without affecting regulatory T-cell viability in non-human primates. Transplantation 88:1349–1359CrossRefPubMed

36.

Li J, Li Y, Huang B, Zheng D, Chen M, Zhou Z (2015) Drug-induced modulation of T lymphocytes as a potential mechanism of susceptibility to infections in patients with multiple myeloma during bortezomib therapy. Cell Biochem Biophys 71:457–464CrossRefPubMed

37.

Philogene MC, Sikorski P, Montgomery RA, Leffell MS, Zachary AA (2014) Differential effect of bortezomib on HLA class I and class II antibody. Transplantation 98:660–665CrossRefPubMed

38.

Blumberg JM, Gritsch HA, Reed EF, Cecka JM, Lipshutz GS, Danovitch GM, McGuire S, Gjertson DW, Veale JL (2013) Kidney paired donation in the presence of donor-specific antibodies. Kidney Int 84:1009–1016CrossRefPubMedPubMedCentral

39.

Woodle ES, Light J, Rubin M, Thielke J, Morrow WR, Mahle W, Franklin C, Gabardi S, Gill J, Roberti I, Shapiro R, Wall GE, Walsh RC, Zand M, Alloway RR (2010) Proteasome inhibitor therapy for antibody-mediated rejection: initial report from a multicenter collaborative. Am J Transplant 10:83–84CrossRef

40.

Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB, Castro MC, David DS, David-Neto E, Bagnasco SM, Cendales LC, Cornell LD, Demetris AJ, Drachenberg CB, Farver CF, Farris AB 3rd, Gibson IW, Kraus E, Liapis H, Loupy A, Nickeleit V, Randhawa P, Rodriguez ER, Rush D, Smith RN, Tan CD, Wallace WD, Mengel M (2014) Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 14:272–283CrossRefPubMed

41.

Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637CrossRefPubMedPubMedCentral

42.

Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, Goldberg A, Birk PE, Rush DN, Nickerson PW (2012) Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant 12:1157–1167CrossRefPubMed

43.

Reed EF, Rao P, Zhang Z, Gebel H, Bray RA, Guleria I, Lunz J, Mohanakumar T, Nickerson P, Tambur AR, Zeevi A, Heeger PS, Gjertson D (2013) Comprehensive assessment and standardization of solid phase multiplex-bead arrays for the detection of antibodies to HLA. Am J Transplant 13:1859–1870CrossRefPubMedPubMedCentral

44.

Kannabhiran D, Everly MJ, Walker-McDermott JK, Tiongko S, Friedlander R, Putheti P, Sharma V, Dadhania D (2012) Changes in IgG subclasses of donor specific anti-HLA antibodies following bortezomib-based therapy for antibody-mediated rejection. Clin Transpl:229-235

45.

Khuu T, Cadeiras M, Wisniewski N, Reed EF, Deng MC (2015) Reduced HLA class II antibody response to proteasome inhibition in heart transplantation. J Heart Lung Transplant 34:863–865CrossRefPubMed

46.

Philogene MC, Sikorski P, Montgomery RA, Leffell MS, Zachary AA (2014) Differential effect of bortezomib on HLA class I and class II antibody. Transplantation 18:463–468

47.

Shi J, Tricot GJ, Garg TK, Malaviarachchi PA, Szmania SM, Kellum RE, Storrie B, Mulder A, Shaughnessy JD Jr, Barlogie B, van Rhee F (2008) Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma. Blood 111:1309–1317CrossRefPubMedPubMedCentral

48.

Willicombe M, Brookes P, Sergeant R, Santos-Nunez E, Steggar C, Galliford J, McLean A, Cook TH, Cairns T, Roufosse C, Taube D (2012) De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy. Transplantation 94:172–177CrossRefPubMed

49.

Everly MJ, Everly JJ, Susskind B, Brailey P, Arend LJ, Alloway RR, Roy-Chaudhury P, Govil A, Mogilishetty G, Rike AH, Cardi M, Wadih G, Tevar A, Woodle ES (2008) Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection. Transplantation 86:1754–1761CrossRefPubMed

Title: Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection
Authors: Meghan H. Pearl
Anjali B. Nayak
Robert B. Ettenger
Dechu Puliyanda
Miguel Fernando Palma Diaz
Qiuheng Zhang
Elaine F. Reed
Eileen W. Tsai
Publication date: 01-08-2016
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 8/2016
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-016-3319-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 8/2016

Dyslipidemia, carotid intima-media thickness and endothelial dysfunction in children with chronic kidney disease

Incidence of contrast-induced acute kidney injury in a pediatric setting: a cohort study

Utility of fractional excretion of urea in the differential diagnosis of acute kidney injury in children

Is serum CRP level a reliable inflammatory marker in pediatric nephrotic syndrome?

Genome-wide association studies in pediatric chronic kidney disease

The multifaceted role of the renal microvasculature during acute kidney injury