Clinical significance of donor-specific anti-HLA-DR51/52/53 antibodies for antibody-mediated rejection in kidney transplant recipients

Borae Geum Park; Younhee Park; Dong Jin Joo; Kyu Ha Huh; Myoung Soo Kim; Soon Il Kim; Yu Seun Kim; Hyon-Suk Kim

doi:10.4285/jkstn.2019.33.3.47

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Park, Park, Joo, Huh, Kim, Kim, Kim, and Kim: Clinical significance of donor-specific anti-HLA-DR51/52/53 antibodies for antibody-mediated rejection in kidney transplant recipients

Original Article

Korean J Transplant 2019;33(3):47-54.

Published online: 30 September 2019

DOI: https://doi.org/10.4285/jkstn.2019.33.3.47

Clinical significance of donor-specific anti-HLA-DR51/52/53 antibodies for antibody-mediated rejection in kidney transplant recipients

Borae Geum Park^1,²

, Younhee Park¹

, Dong Jin Joo³

, Kyu Ha Huh³

, Myoung Soo Kim³

, Soon Il Kim³

, Yu Seun Kim³

, Hyon-Suk Kim¹

¹Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

²Department of Laboratory Medicine, Korea University Guro Hospital, Seoul, Korea

³Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

Correspondence to: Hyon-Suk Kim Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: +82-2-2228-2443, Fax: +82-2-364-1583 E-mail: kimhs54@yuhs.ac

Received 14 March 2019 Revised 12 August 2019 Accepted 13 August 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

The presence of donor-specific antibodies (DSAs) to human leukocyte antigen (HLA) increases the risk of antibody-mediated rejection (ABMR) after kidney transplantation (KT). However, the clinical relevance of anti-HLA-DR51/52/53 antibodies remains unclear because of their weak antigen expression. This study evaluated the association between anti-HLA-DR51/52/53 DSAs and ABMR.

Methods

We retrospectively reviewed the single-antigen-bead panel reactive antibody (single PRA) results of 130 patients tested between August 1, 2009 and March 6, 2015, based on clinical necessity after allograft KT. Single PRA analysis was performed using Luminex assay kits (Lifecodes LSA class I and II). We reviewed the clinical course and biopsy results of patients with anti-HLA-DR51/52/53 DSAs.

Results

Post-KT DSAs were identified in 89 of the 130 patients (68.5%), with 26 of 32 class I DSAs and 63 of 66 class II DSAs being immunodominant DSAs. Thirteen patients had anti-HLA-DR51/52/53 DSAs. Three patients with anti-HLA-DR51/52/53 immunodominant DSAs alone were diagnosed with biopsy-proven ABMR. One patient who developed anti-HLA-DR DSA 13 days after KT showed a rapid increase in anti-HLA-DR51 DSA and had biopsy-proven ABMR.

Conclusions

Although the expression of the HLA-DR51/52/53 antigen was weak, anti-HLA-DR51/52/53 DSAs might be correlated with biopsy-proven ABMR. Therefore, anti-HLA-DR51/52/53 DSAs must be evaluated as a cause of ABMR after transplantation.

Keywords: Donor specific antibody, Antibody mediated rejection, Human leukocyte antigen

REFERENCES

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Fig. 1.

Pathologic results according to immunodominant donor-specific antibody (DSA). A total of 70 biopsy results could be obtained at the time of DSA detection. HLA, human leukocyte antigen; g, glomerulitis; ptc, peritubular capillaritis.

Table 1.

Linked genes between HLA-DRB1 and -DRB3/4/5

Gene	Coding protein	Linked HLA DR antigen
DRB3	Beta chain of DR52	DR11, DR12, DR13, DR14, DR17(3), DR18(3)
DRB4	Beta chain of DR53	DR4, DR7, DR9
DRB5	Beta chain of DR51	DR15(2), DR16(2)
None	None	DR1, DR8, DR10

HLA, human leukocyte antigen.

Table 2.

Distribution of the DSA with highest MFI level (immunodominant DSA) detected in 130 patients with elevated serum creatinine levels after kidney transplantation

Immunodominant DSA			Number of patients (%)	MFI range	Median follow–up day (range)
Class I			26 (20.0)
	Anti-HLA-A		9 (6.9)	1,653–17,249	2,811 (1,682–7,579)
		Anti-HLA-A DSA alone	8 (6.2)
		Anti-HLA-A with class II DSA	1 (0.7)
	Anti-HLA-B		14 (10.8)	1,328–4,790	3,003 (68–8,542)
		Anti-HLA-B DSA alone	12 (9.2)
		Anti-HLA-B with class II DSA	2 (1.5)
	Anti-HLA-C		3 (2.3)	1,755–4,656	1,109 (970–6,256)
Class II			63 (48.5)
	Anti-HLA-DR		23 (17.7)	1,543–16,203	2,834 (13–7,943)
		Anti-HLA-DR DSA without class I DSA	19 (14.6)
		Anti-HLA-DR DSA with class I DSA	4 (3.1)
		Anti-HLA-DRB1 DSA with anti-HLA-DR51/52/53 DSA	10 (7.7)
		Anti-HLA-DRB1 DSA alone with or without class I DSA	10 (7.7)
		Anti-HLA-DR51/52/53 DSA alone with or without class I DSA	3 (2.3)
	Anti-HLA-DQ		40 (30.8)	1,105–20,611	1,739 (33–7,252)
		Anti-HLA-DQ DSA alone	30 (23.1)
		Anti-HLA-DQ DSA with anti-HLA-DR DSA	8 (6.2)
		Anti-HLA-DQ DSA with class I DSA	2 (1.5)
No DSA			41 (31.5)		2,346 (66–9,019)

DSA, donor-specific antibody; MFI, mean fluorescence intensity; HLA, human leukocyte antigen.

Table 3.

Clinical data and biopsy results of 10 patients who developed both anti-HLA-DR 51/52/53 DSA and anti-HLA-DRB1 DSA

HLA-DR typing		DSA to HLA-DRB1 or class I (MFI)	DSA to HLA-DRB3/4/5 (MFI)	Day after transplantation	Kidney biopsy
Recipient	Donor	DSA to HLA-DRB1 or class I (MFI)	DSA to HLA-DRB3/4/5 (MFI)	Day after transplantation	Kidney biopsy
DR11, DR13, DR52, DR52	DR4, DR11, DR53, DR52	DR4 (2,802)	DR53 (1,252)	325	Transplant glomerulopathy, C4d(–), g0, ptc0
DR10, DR15, DR51	DR13, DR15, DR52, DR51	DR13 (12,654), A24 (2,599)	DR52 (13,131)	1,361	ABMR, C4d(+, diffuse), g2, ptc1
DR4, -, DR53	DR4, DR13, DR53, DR52	DR13 (13,859)	DR52 (5,252)	990	ABMR, C4d(–), g3, ptc0
DR15, DR4, DR51, DR53	DR15, DR13, DR51, DR52	DR13 (15,190)	DR52 (14,878)	2,671	TCMR, type 1B, ABMR, C4d(–), g1, ptc0
DR4, DR14, DR53, DR52	DR4, DR15, DR53, DR51	DR15 (10,736),	DR51 (15,615)	257	TCMR, type 2B, ABMR, grade II, C4d(+, diffuse) g0, ptc2
DR4, DR13, DR53, DR52	DR15, DR13, DR51, DR52	A24 (2,344) DR15 (6,763)^a)	DR51 (12,850)	13	ABMR, C4d(+, diffuse), g0, ptc1
DR13, -DR52	DR7, DR13, DR53, DR52	DR7 (10,616)	DR53 (11,322)	3,622	ABMR, grade II, C4d(–), g0, ptc3
DR8,-	DR8, DR13, DR52	DR13 (11,372)	DR52 (14,261)	3,409	ABMR, grade II, C4d(+, diffuse), g1, ptc2
DR10, DR11, DR52	DR9, DR10, DR53	DR9 (15,822)	DR53 (2,692)	2,996	ABMR, grade II, C4d(+, diffuse), g1, ptc0
DR1, DR4, DR53	DR1, DR13, DR52	DR13 (16,203)	DR52 (2,711)	3,417	ABMR, grade II, C4d(+, diffuse), g0, ptc2

HLA, human leukocyte antigen; DSA, donor-specific antibody; MFI, mean fluorescence intensity; ABMR, antibody-mediated rejection; TCMR, T-cell-mediated rejection; g, glomerulitis; ptc, peritubular capillaritis.

^a) Anti-HLA-DR15 (1,461) preformed DSA was detected before transplantation.

Table 4.

Clinical review data and biopsy results of three patients with anti-HLA-DR 51/52/53 highest DSA without anti-HLA-DRB1 DSA

HLA typing (recipient/donor)	Age (yr)/sex	Type of transplant	Year after transplantation	DR51/52/53 (recipient/donor)	DSA (MFI)	Cr	Kidney biopsy
A2, A24, B52, -, Cw1, -, DR15, -/A2, -, B44, -, Cw1, -, DR15, DR7	58/Male	Living-related donor KT	20.5	DR51, -/DR51, DR53	DR53 (18,752) without other HLA antibodies	3.99	ABMR, grade II C4d(+, diffuse, g1, ptc2
A2, A11, B62, -, DR4, DR14/A2, A30, B64, B62, DR4, DR15	52/Male	Living-related donor KT	9.1	DR52, DR53/DR51, DR53	DR51 (17,848) without other HLA antibodies	1.70	TCR and ABMR C4d(+, diffuse, g1, ptc3
A2, A11, B46, B71, Cw1, Cw8, DR8, DR9/A24, A11, B35, B71, Cw3, Cw8, DR9, DR15	62/Male	Living-related donor KT	8.7	DR53, -/DR51, DR53	DR51 (12,172), A24 (1,498)	2.25	ABMR, grade II C4d(+, diffuse, g1, ptc3

HLA, human leukocyte antigen; DSA, donor-specific antibody; MFI, mean fluorescence intensity; Cr, creatinine; KT, kidney transplantation; ABMR, antibody-mediated rejection; TCR, T-cell-mediated rejection; g, glomerulitis; ptc, peritubular capillaritis.

Table 5.

Clinical data and biopsy results of 10 patients who developed both anti-DQ DSA and anti-HLA-DR or class I DSA

DSA to HLA-DQ (MFI)	DSA to HLA-DR or class I (MFI)	Cr	Day after transplantation	Kidney biopsy
DQ6 (7,583)	DR14 (4,843)	NA	3,670	ABMR, grade II, C4d(+, diffuse), g2, ptc1
DQ9 (9,432)	DR9 (8,633)	2.07	4,120	ABMR, grade II, C4d(+, diffuse), g0, ptc2
DQ2 (20,687)	DR7 (2,109)	2.56	4,681	Chronic ABMR, C4d(+, diffuse), g3, ptc1
DQ7 (12,702)	DR12 (453)	1.47	869	ABMR, grade II, C4d(+, diffuse), g1, ptc1
DQ8 (12,386)	DR4 (1,764)	3.18	3,095	Chronic ABMR, C4d(+, focal), g3, ptc1
DQ9 (17,644)	DR9 (15,822)	2.10	2,996	ABMR, grade II, C4d(+, diffuse), g1, ptc3
DQ7 (15,059)	DR11 (1,397)	2.34	1,785	Chronic ABMR, C4d(+, diffuse), g3, ptc2
DQ9 (15,609)	DR9 (658)	1.59	441	C4d(+/–, weak), g0, ptc3
DQ6 (9,456)	A2 (1,100)	2.02	265	ABMR, grade II, C4d(+, diffuse), g0, ptc2
DQ8 (8,035)	B44 (416)	NA	2,611	ABMR, grade II, C4d(+, diffuse), g2, ptc2

DSA, donor-specific antibody; HLA, human leukocyte antigen; MFI, mean fluorescence intensity; Cr, creatinine; NA, not applicable; ABMR, antibody-mediated rejection; g, glomerulitis; ptc, peritubular capillaritis.

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