Impact of HLA Mismatching on Early Subclinical Inflammation in Low-Immunological-Risk Kidney Transplant Recipients

Domingo Hernández, Teresa Vázquez, Juana Alonso-Titos, Myriam León, Abelardo Caballero, María Angeles Cobo, Eugenia Sola, Verónica López, Pedro Ruiz-Esteban, Josep María Cruzado, Joana Sellarés, Francesc Moreso, Anna Manonelles, Alberto Torio, Mercedes Cabello, Juan Delgado-Burgos, Cristina Casas, Elena Gutiérrez, Cristina Jironda, Julia Kanter, Daniel Serón, Armando Torres, Domingo Hernández, Teresa Vázquez, Juana Alonso-Titos, Myriam León, Abelardo Caballero, María Angeles Cobo, Eugenia Sola, Verónica López, Pedro Ruiz-Esteban, Josep María Cruzado, Joana Sellarés, Francesc Moreso, Anna Manonelles, Alberto Torio, Mercedes Cabello, Juan Delgado-Burgos, Cristina Casas, Elena Gutiérrez, Cristina Jironda, Julia Kanter, Daniel Serón, Armando Torres

Abstract

The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches (p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06-1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04-2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions.

Keywords: Banff criteria; HLA compatibility; kidney transplantation; low-immunological risk; subclinical inflammation.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
ROC curve for total number of HLA mismatches as a predictor of subclinical inflammation in the entire study population (A) and excluding patients with isolated mild inflammation (B). The optimal predictor cut-off value (*) was that of the highest sensitivity together with the lowest number of false positives (specificity). This value corresponds to 6 HLA-mismatches. (C,D) ROC curves for class II mismatches as a predictor of SCI in the entire population and excluding patients with isolated inflammation, respectively. The optimal predictor cut-off value (*) was 3 HLA mismatches.
Figure 2
Figure 2
Proportion of biopsies performed on the third month post-kidney transplantation with and without subclinical inflammation in individuals with ≤6 vs. >6 HLA-mismatches. Abbreviations: NI, No inflammation; SCI, subclinical inflammation

References

    1. Ojo A.O., Morales J.M., González-Molina M., Steffick D.E., Luan F.L., Merion R.M., Ojo T., Moreso F., Arias M., Campistol J.M., et al. Comparison of the long-term outcomes of kidney transplantation: USA versus Spain. Nephrol. Dial. Transplant. 2013;28:213–220. doi: 10.1093/ndt/gfs287.
    1. Moreso F., Hernandez D. Has the survival of the graft improved after renal transplantation in the era of modern immunosuppression? Nefrologia. 2013;33:14–26. doi: 10.3265/Nefrologia.pre2012.Oct.11739.
    1. Sola E., Gonzalez-Molina M., Cabello M., Burgos D., Ramos J., Gutierrez C., Lopez V., Soler J., de la Vega E., Hernandez D. Long-term improvement of deceased donor renal allograft survival since 1996: A single transplant center study. Transplantation. 2010;89:714–720. doi: 10.1097/TP.0b013e3181c892dd.
    1. Loupy A., Haas M., Solez K., Racusen L., Glotz D., Seron D., Nankivell B.J., Colvin R.B., Afrouzian M., Akalin E., et al. The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology. Am. J. Transplant. 2017;17:28–41. doi: 10.1111/ajt.14107.
    1. Ortiz F., Gelpi R., Helanterä I., Melilli E., Honkanen E., Bestard O., Grinyo J.M., Cruzado J.M. Decreased Kidney Graft Survival in Low Immunological Risk Patients Showing Inflammation in Normal Protocol Biopsies. PLoS ONE. 2016;11:e0159717. doi: 10.1371/journal.pone.0159717.
    1. Mehta R., Sood P., Hariharan S. Subclinical Rejection in Renal Transplantation: Reappraised. Transplantation. 2016;100:1610–1618. doi: 10.1097/TP.0000000000001163.
    1. Mehta R., Bhusal S., Randhawa P., Sood P., Cherukuri A., Wu C., Puttarajappa C., Hoffman W., Shah N., Mangiola M., et al. Short-term adverse effects of early subclinical allograft inflammation in kidney transplant recipients with a rapid steroid withdrawal protocol. Am. J. Transplant. 2018;18:1710–1717. doi: 10.1111/ajt.14627.
    1. Rush D.N., Gibson I.W. Subclinical Inflammation in Renal Transplantation. Transplantation. 2019;103:e139–e145. doi: 10.1097/TP.0000000000002682.
    1. Nankivell B.J., Agrawal N., Sharma A., Taverniti A., P’Ng C.H., Shingde M., Wong G., Chapman J.R. The clinical and pathological significance of borderline T cell-mediated rejection. Am. J. Transplant. 2019;19:1452–1463. doi: 10.1111/ajt.15197.
    1. Shapiro R., Randhawa P., Jordan M.L., Scantlebury V.P., Vivas C., Jain A., Corry R.J., McCauley J., Johnston J., Donaldson J., et al. An analysis of early renal transplant protocol biopsies--the high incidence of subclinical tubulitis. Am. J. Transplant. 2001;1:47–50. doi: 10.1034/j.1600-6143.2001.010109.x.
    1. Choi B.S., Shin M.J., Shin S.J., Kim Y.S., Choi Y.J., Moon I.S., Kim S.Y., Koh Y.B., Bang B.K., Yang C.W. Clinical significance of an early protocol biopsy in living-donor renal transplantation: Ten-year experience at a single center. Am. J. Transplant. 2005;5:1354–1360. doi: 10.1111/j.1600-6143.2005.00830.x.
    1. Van Loon E., Lerut E., Senev A., Coemans M., Pirenne J., Monbaliu D., Jochmans I., Sainz Barriga M., De Vusser K., Van Craenenbroeck A.H., et al. The Histological Picture of Indication Biopsies in the First 2 Weeks after Kidney Transplantation. Clin. J. Am. Soc. Nephrol. 2020;15:1484–1493. doi: 10.2215/CJN.04230320.
    1. Opelz G., Döhler B. Effect of human leukocyte antigen compatibility on kidney graft survival: Comparative analysis of two decades. Transplantation. 2007;84:137–143. doi: 10.1097/01.tp.0000269725.74189.b9.
    1. Lim W.H., Chadban S.J., Clayton P., Budgeon C.A., Murray K., Campbell S.B., Cohney S., Russ G.R., McDonald S.P. Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients. Clin. Transplant. 2012;26:E428–E437. doi: 10.1111/j.1399-0012.2012.01654.x.
    1. Williams R.C., Opelz G., McGarvey C.J., Weil E.J., Chakkera H.A. The Risk of Transplant Failure with HLA Mismatch in First Adult Kidney Allografts from Deceased Donors. Transplantation. 2016;100:1094–1102. doi: 10.1097/TP.0000000000001115.
    1. Wiebe C., Kosmoliaptsis V., Pochinco D., Gibson I.W., Ho J., Birk P.E., Goldberg A., Karpinski M., Shaw J., Rush D.N., et al. HLA-DR/DQ molecular mismatch: A prognostic biomarker for primary alloimmunity. Am. J. Transplant. 2019;19:1708–1719. doi: 10.1111/ajt.15177.
    1. Wiebe C., Rush D.N., Gibson I.W., Pochinco D., Birk P.E., Goldberg A., Blydt-Hansen T., Karpinski M., Shaw J., Ho J., et al. Evidence for the alloimmune basis and prognostic significance of Borderline T cell-mediated rejection. Am. J. Transplant. 2020;20:2499–2508. doi: 10.1111/ajt.15860.
    1. Leeaphorn N., Pena J.R.A., Thamcharoen N., Khankin E.V., Pavlakis M., Cardarelli F. HLA-DQ Mismatching and Kidney Transplant Outcomes. Clin. J. Am. Soc. Nephrol. 2018;13:763–771. doi: 10.2215/CJN.10860917.
    1. Ruck J.M., Jackson A.M., Massie A.B., Segev D.L., Desai N., Garonzik-Wang J. Temporal Changes in the Impact of HLA Mismatching Among Pediatric Kidney Transplant Recipients. Transplantation. 2019;103:1267–1271. doi: 10.1097/TP.0000000000002426.
    1. Williams R.C., West L.J., Opelz G. The Risk of Failure with HLA Mismatch and Recipient Age in First Pediatric (<18 years) Kidney Transplants. Transplant. Direct. 2018;4:e365. doi: 10.1097/TXD.0000000000000801.
    1. Foroutan F., Friesen E.L., Clark K.E., Motaghi S., Zyla R., Lee Y., Kamran R., Ali E., De Snoo M., Orchanian-Cheff A., et al. Risk Factors for 1-Year Graft Loss After Kidney Transplantation: Systematic Review and Meta-Analysis. Clin. J. Am. Soc. Nephrol. 2019;14:1642–1650. doi: 10.2215/CJN.05560519.
    1. Su X., Zenios S.A., Chakkera H., Milford E.L., Chertow G.M. Diminishing significance of HLA matching in kidney transplantation. Am. J. Transplant. 2004;4:1501–1508. doi: 10.1111/j.1600-6143.2004.00535.x.
    1. Morales J.M., Marcén R., Andrés A., Molina M.G., Castillo D.D., Cabello M., Capdevila L., Campistol J.M., Oppenheimer F., Serón D., et al. Renal transplantation in the modern immunosuppressive era in Spain: Four-year results from a multicenter database focus on post-transplant cardiovascular disease. Kidney Int. Suppl. 2008:S94–S99. doi: 10.1038/ki.2008.547.
    1. Ashby V.B., Port F.K., Wolfe R.A., Wynn J.J., Williams W.W., Roberts J.P., Leichtman A.B. Transplanting kidneys without points for HLA-B matching: Consequences of the policy change. Am. J. Transplant. 2011;11:1712–1718. doi: 10.1111/j.1600-6143.2011.03606.x.
    1. Lim W.H., Chapman J.R., Coates P.T., Lewis J.R., Russ G.R., Watson N., Holdsworth R., Wong G. HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients. Clin. J. Am. Soc. Nephrol. 2016;11:875–883. doi: 10.2215/CJN.11641115.
    1. Rush D., Arlen D., Boucher A., Busque S., Cockfield S.M., Girardin C., Knoll G., Lachance J.G., Landsberg D., Shapiro J., et al. Lack of benefit of early protocol biopsies in renal transplant patients receiving TAC and MMF: A randomized study. Am. J. Transplant. 2007;7:2538–2545. doi: 10.1111/j.1600-6143.2007.01979.x.
    1. Filippone E.J., Farber J.L. Humoral Immune Response and Allograft Function in Kidney Transplantation. Am. J. Kidney Dis. 2015;66:337–347. doi: 10.1053/j.ajkd.2015.03.033.
    1. Noble J., Jouve T., Malvezzi P., Süsal C., Rostaing L. Transplantation of Marginal Organs: Immunological Aspects and Therapeutic Perspectives in Kidney Transplantation. Front. Immunol. 2019;10:3142. doi: 10.3389/fimmu.2019.03142.
    1. Gaynor J.J., Ciancio G., Guerra G., Sageshima J., Roth D., Goldstein M.J., Chen L., Kupin W., Mattiazzi A., Tueros L., et al. Lower tacrolimus trough levels are associated with subsequently higher acute rejection risk during the first 12 months after kidney transplantation. Transpl. Int. 2016;29:216–226. doi: 10.1111/tri.12699.
    1. Hill P., Cross N.B., Barnett A.N., Palmer S.C., Webster A.C. Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database Syst. Rev. 2017;1:Cd004759. doi: 10.1002/14651858.CD004759.pub2.
    1. de Sandes-Freitas T.V., Mazzali M., Manfro R.C., de Andrade L.G.M., Vicari A.R., Vinicius de Sousa M., Medina Pestana J.O., Garcia V.D., Rosa de Boni Monteiro de Carvalho D., de Matos Esmeraldo R., et al. Exploring the causes of the high incidence of delayed graft function after kidney transplantation in Brazil: A multicenter study. Transpl. Int. 2021 doi: 10.1111/tri.13865.
    1. Nankivell B.J., P’Ng C.H., Chapman J.R. Does tubulitis without interstitial inflammation represent borderline acute T cell mediated rejection? Am. J. Transplant. 2019;19:132–144. doi: 10.1111/ajt.14888.
    1. Tambur A.R. Human leukocyte antigen matching in organ transplantation: What we know and how can we make it better (Revisiting the past, improving the future) Curr. Opin. Organ Transplant. 2018;23:470–476. doi: 10.1097/MOT.0000000000000538.
    1. Wehmeier C., Amico P., Hirt-Minkowski P., Georgalis A., Hoenger G., Menter T., Mihatsch M., Burkhalter F., Steiger J., Dickenmann M., et al. Acute Rejection Phenotypes in the Current Era of Immunosuppression: A Single-Center Analysis. Transplant. Direct. 2017;3:e136. doi: 10.1097/TXD.0000000000000650.
    1. Moreso F., Ibernon M., Goma M., Carrera M., Fulladosa X., Hueso M., Gil-Vernet S., Cruzado J.M., Torras J., Grinyo J.M., et al. Subclinical rejection associated with chronic allograft nephropathy in protocol biopsies as a risk factor for late graft loss. Am. J. Transplant. 2006;6:747–752. doi: 10.1111/j.1600-6143.2005.01230.x.
    1. Mehta R.B., Tandukar S., Jorgensen D., Randhawa P., Sood P., Puttarajappa C., Zeevi A., Tevar A.D., Hariharan S. Early subclinical tubulitis and interstitial inflammation in kidney transplantation have adverse clinical implications. Kidney Int. 2020;98:436–447. doi: 10.1016/j.kint.2020.03.028.
    1. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group KDIGO clinical practice guideline for the care of kidney transplant recipients. Am. J. Transplant. 2009;9(Suppl. S3):S1–S155. doi: 10.1111/j.1600-6143.2009.02834.x.
    1. Senev A., Coemans M., Lerut E., Van Sandt V., Kerkhofs J., Daniëls L., Driessche M.V., Compernolle V., Sprangers B., Van Loon E., et al. Eplet Mismatch Load and De Novo Occurrence of Donor-Specific Anti-HLA Antibodies, Rejection, and Graft Failure after Kidney Transplantation: An Observational Cohort Study. J. Am. Soc. Nephrol. 2020;31:2193–2204. doi: 10.1681/ASN.2020010019.
    1. Wiebe C., Nickerson P. Strategic Use of Epitope Matching to Improve Outcomes. Transplantation. 2016;100:2048–2052. doi: 10.1097/TP.0000000000001284.

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