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Table of Contents
Year : 2021  |  Volume : 15  |  Issue : 4  |  Page : 346-350

Kidney transplantation in sensitized patients: Two case reports

Department of Nephrology and Organ Transplantation, New ERA Hospital and Research Institute; Department of Nephrology, Orange City Hospital and Research Institute, Nagpur, Maharashtra, India

Date of Submission31-Jan-2021
Date of Decision24-Aug-2021
Date of Acceptance01-Sep-2021
Date of Web Publication30-Dec-2021

Correspondence Address:
Dr. Shivnarayan J Acharya
203, Aum Ganga Apartment, 120, Farm Land, Ramdaspeth, Nagpur - 440 010, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijot.ijot_4_21

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Dreaded complication of kidney transplantation in a sensitized patient is hyper-acute rejection immediately after vascular anastomosis. Although pretransplant complement-dependent cytotoxic cross match (CDC) has been the gold standard for many years, this assay is not perfect. The Luminex-based anti-HLA antibody detection assay is more sensitive and specific. While performing live-related kidney transplantation, luminex cross match is routinely performed but in a situation like deceased donor transplantation, in view of time constraints, we do CDC cross match and go ahead with transplantation if the result is negative (Cell lysis <10%). Here, we present two cases of deceased donor transplantation where CDC cross match was negative, based on this report, we went ahead with kidney transplantation but report of Luminex cross match turned out to be positive after the transplantation was already over. Both the recipients had the features of hyper acute rejection. One patient could be salvaged but the other lost the graft.

Keywords: Cytotoxic cross match cross match, hyperacute rejection, luminex cross match

How to cite this article:
Acharya SJ. Kidney transplantation in sensitized patients: Two case reports. Indian J Transplant 2021;15:346-50

How to cite this URL:
Acharya SJ. Kidney transplantation in sensitized patients: Two case reports. Indian J Transplant [serial online] 2021 [cited 2022 Aug 10];15:346-50. Available from: https://www.ijtonline.in/text.asp?2021/15/4/346/334431

  Introduction Top

Sensitized patient can be identified by carrying pretransplant complement-dependent cytotoxic cross match (CDC), flow cytometry or Luminex anti-HLA antibody detection assay, later being more sensitive and specific. Sensitized patient must not be transplanted as it will result in hyper acute rejection of the graft unless desensitized. Flow cytometry is not available with us but both CDC cross match and Luminex based anti HLA detection assay are available at our facility.

  Case Reports Top

Case report 1

NKH 41 male underwent second kidney transplantation in December 2020 with deceased donor. The patient had first kidney transplant 9 years ago; donor being his paternal uncle. Graft functioned well for 7 years till he stopped all immunosuppressive medications on his own. The patient was back on dialysis after 4 months of stopping drugs. He got registered for deceased donor transplantation with local Zonal Transplant Co-ordination Center. The deceased donor was aged 54, male, with head injury due to vehicular accident resulting in brain-stem death. Cold ischemia time was 70 min. Complement-dependent cytotoxic cross match (CDC cross match) was negative (<10%). The patient was given injection basiliximab 20 mg and injection methylprednisolone 1 g before vascular anastomosis. Immediately, after vascular anastomosis, the graft became pink, but there was no urination. On table Doppler study showed blood flow till cortex but venous flow was not appreciable (suggestive of high resistance). Graft biopsy was done. A DJ Stent was put in view of anuria on table.

As the patient remained anuric, the patient was put on dialysis. Luminex cross match report came after few hours showed strongly positive cross match against both class I and Class II HLA [Table 1]. Biopsy showed 10 glomeruli, showing intra-capillary occlusive margination of neutrophils and mononuclear cells (g2), well-formed double contours or significant mesangial matrix was not seen (cg0, mm0). There was no crescent formation, segmental sclerosis, intracapillary thrombi, or tuft necrosis. Tubular atrophy and interstitial fibrosis involved about 10%–12% of sampled cortex (ci1 and ct1). Viable tubules showed prominent cytoplasmic vacuolar change and evidence of acute injury. Few hyaline casts were seen in tubular lumina. Significant interstitial inflammation or areas of tubulitis were not observed (i0, ti0, t0). Stain for SV40 (aimed at detecting BK Polyoma virus infection) was negative in the visualized tubular epithelial cell nuclei. Arterioles revealed variable hyalinosis lesions (ah1) and vacuolization in the smooth muscle cells of the media. Peritubular capillaries showed minimal (sub-threshold) cell margination (ptc 0) and revealed focal positivity for C4d (C4d 2: By IHC) [Figure 1]. Impression-Renal allograft, needle biopsy: Specimen adequacy-Marginal (Banff 97 criteria). Banff scores: I0, ti0, t0, v0, mm0, g2, cg0, ci1, ct1, cv0, ah1, ptc0 (Banff 2017 update). Stain for C4d (by IHC) showed focal positivity along peritubular capillaries (C4d 2). Patchy acute tubular injury is observed.
Figure 1: Graft biopsy – Case report 1. Intracapillary occlusive margination of neutrophils and mononuclear cells, viable tubules show prominent cytoplasmic vacuolar change and evidence of acute injury

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Table 1: Donor-specific antibodies cross match result (case 1)

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This biopsy showed evidence of acute/active tissue injury in the form of glomerulitis (microvascular inflammation). In the context of focal C4d positivity along the peri-tubular capillaries, the features were suggestive of acute antibody-mediated (humoral) rejection processes.

Clinical course

The patient was treated with Injection methylprednisolone 1 g daily for 3 days and second dose of Injection Basiliximab 20 mg after 4 days of transplant. In view of positive cross match and biopsy showing features of active antibody-mediated rejection (AMR), plasmapheresis was started. The patient received total six cycles of plasmapheresis.

Urine output started on the fourth day and gradually picked up after 7 days. He underwent alternate day hemodialysis till urine output significantly improved associated with decline in serum creatinine. He received five sittings of hemodialysis. Once urine output was adequate, DJ stent was removed cystoscopically but unfortunately developed urinary infection postprocedure.

On discharge, his urine output was 1700 ml per day and creatinine was 3 mg/dl. During the follow-up period, his latest creatinine was 1.5 mg/dl after 4 weeks of transplantation.

Postplasmapheresis, in view of risk of recurrent AMR injection Rituximab was planned, but deferred in view of urinary infection. Repeat luminex test was not done postpheresis.

Case report 2

DS 40-year-old female, case of polycystic kidney disease was on dialysis since 6 months, underwent deceased donor kidney transplantation on May 3, 2019. CDC cross match was negative. Induction with antithymocyte globulin (rabbit) and inj methylprednisolone 1 g was given before vascular anastomosis. Following anastomosis, the kidney was pink but turned bluish after few minutes. On table Doppler showed good blood flow to the graft but with high resistance. Graft biopsy was done before closure.

Graft biopsy showed severe ischemic alterations and widespread fibrin thrombi in capillary tufts, C4d by IHC showed focal positivity along peritubular capillaries. The features of acute tubular injury were noted. Necrotising and thrombotic arteriolar lesions were noted (thrombotic microangiopathy). These features were suggestive of acute AMR [Figure 2].
Figure 2: Graft biopsy – Case report 2. Graft biopsy within 1 h of transplantation showing severe ischemic alterations and widespread fibrin thrombi in capillary tufts

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Report of donor-specific antibodies (DSAs) received a day after, were detected against both class I (PRA single antigen bead cross match 11%) and Class II antigens (PRA single antigen bead cross match 42%). Details of single antigen bead against different alleles are given in [Table 2].
Table 2: Antibodies detected against human leukocyte antigen class I and II antigens (case 2)

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Clinical course

The patient was put on plasmapheresis and hemodialysis. The patient started having urination up to a liter daily from the 5th day onward.

On the 7th day, the patient deteriorated. She had fever, hypotension, oliguria, graft became tender, had thrombocytopenia (platelets 30,000/cmm), leukocytosis (TLC 18,000/cmm), high prothrombin time (PT INR 2.4), high LDH (14000 U/L), and metabolic acidosis. After stabilizing with dialysis, platelet transfusion, fresh-frozen plasma and antibiotics, exploratory laparotomy done. As the graft looked bluish and renal vein exploration showed large amount of thrombi filling its whole lumen, graft nephrectomy was done.

Cut section of the graft showed widespread clots all over the graft and necrotic tissue [Figure 3]. Microscopy examination revealed cortical necrosis [Figure 4].
Figure 3: Graft nephrectomy – Case report 2. Graft nephrectomy on the 11th postoperative day. Cut section of the graft showing widespread clots

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Figure 4: Graft nephrectomy-histopathology case report 2. Cortical necrosis of transplanted kidney on the 11th postoperative day

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  Discussion Top

Preformed DSAs to HLA antigens can cause acute AMR after kidney transplantation (KT).[1]

To detect preexisting antibodies against the transplanted organ, present available modalities are complement dependent cytotoxic cross match (CDC cross match), cell based flow cytometry cross match (FCXM), and fluorescent bead assay. In the fluorescent bead assay technique, mean fluorescent intensity is measured (MFI). Cutoff value for MFI varies from laboratory to laboratory. MFI value of more than 1000 is considered significant.

In the study by Baranwal et al.,[2] none of the patients having HLA Class I DSA with MFI values <1000 showed positivity for T-cell FCXM or CDC crossmatch, while in the group having MFI values between 1000 and 3000, 54% showed positivity for the FCXM but none by the CDC method. However, in the group having MFI values >3000, 95% of cases were positive for flow cytometry cross match. Those groups with MFI values between 3000 and 5000, only 36% were positive for CDC cross-match, while 90% showed positivity in the group with MFI >7000. Thus fluorescent bead assay technique is far more superior to FCXM or CDC cross match.

While time required for CDC cross match is few hours, time for fluorescent-based cross match is about 12 h. Hence, in a cadaver transplant situation, CDC cross match is accepted mode of going ahead with transplantation procedure.

The same procedure was followed in our two cases too. The CDC cross match was negative (meaning <10% of cell lysis), so we went ahead with the transplantation procedure.

Acute and chronic antibody-mediated rejections have been primarily seen in patients who have higher mean fluorescence intensity and flow-cytometric cross-match channel shift values or pretransplantation positive complement-dependent-cytotoxicity.[3] Currently, 35% of patients who are on the waiting list for a transplant are sensitized and have calculated panel-reactive antibody (cPRA) concentrations >0%, and 15% are highly sensitized with cPRA concentrations >80%.[4]

Antibody reduction and immune-modulatory treatment in the pre- and peri-transplantation period, a process known as desensitization, has been applied in sensitized patients using therapies such as plasmapheresis, intravenous (IV) immune-globulin (IVIg), and rituximab in various combinations. Kidney transplantation through desensitization protocols has been shown to improve survival for some patients compared to remaining on dialysis therapy.[5]

Bortezomib, a proteasome inhibitor, has had limited success with modest reductions in anti-HLA antibody titers but at the cost of adverse effects.[6]

A new treatment option, IdeS (immunoglobulin G [IgG]-degrading enzyme of Streptococcus pyogenes), for highly sensitized patients is now available. IdeS is an extracellular cysteine proteinase produced by S pyogenes.[4],[7],[8] The immediate effect of IgG endopeptidase on DSAs in the preliminary study was profound, with near or complete reduction of HLA antibodies at 6 h.[8]

For patients with HLA-incompatible donors, kidney paired exchange remains the preferred option to find a compatible donor. This approach leads to the administration of less potent immunosuppression, lower acute rejection rates, and better allograft survival.[9],[10] If kidney paired exchange does not produce a transplant for a sensitized patient within 12 months, desensitization options could be explored.[11]

Mathur et al.[12] reported their 3 years' experience in across transplant centers in South India. A total of 1129 renal transplants were done at various centers and total 42 cases of AMRs were reported. Out of 42 patients, 36 patients had pretransplant history of CDC negative and Luminex DSA cross match being positive.

Removal of ABO isoagglutinins or anti-HLA antibodies through a combination of therapeutic plasma exchange (TPE) and immunosuppression has enabled the successful transplantation of incompatible KT recipients.[13]

Conventional plasma exchange nonselectively removes plasma proteins including albumin and immunoglobulins and requires a high amount of replacement fluid in the form of plasma, albumin, and normal saline. Although FFP is frequently used as supplementary fluid in plasmapheresis therapy, it entails higher risks of infection because of unknown pathogens. Double filtration plasmapheresis (DFPP) has proved to be effective to prevent and treat AMR for DFPP was designed to selectively remove the immunoglobulin fraction from serum and, as a result, to minimize the volume of substitution fluid.[14],[15]

Immunoadsorbtion (IA) is a specific technique for removing isoagglutinins and is part of the ABO-I desensitization protocol in most European centers at present. IA can remove DSA faster than DFPP. Compared to plasmapheresis, IA allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of FFP or albumin.[16],[17]

It must be kept in mind that TPE can only remove antibodies, but drugs can suppress endogenous antibody rebound after depletion with TPE, and serves to restore antimicrobial immunoglobulins removed during plasmapheresis. Thus, TPE has various patterns and combination therapy is necessary. The treatment should be individualized and precise diagnosis and multimodal treatment will yield better outcomes.[18]

In our both patients, cytotoxic cross match was negative. Kidney transplantation was done based on that report and both developed acute AMR. Luminex DSA cross match report showing positive cross match report was available later in the day by that time transplantation was already over.

One patient improved following plasmapheresis and high dose steroids. After the fourth cycle of plasmapheresis, diuresis started and kidney functions started improving. Serum creatinine after 3 weeks was 1.5 mg/dl. The other patient did not improve and had severe rejection needing graft nephrectomy.

Hyperacute rejection is the result of specific recurrent anti-donor antibodies against HLAs, ABO, or other antigens resulting in irreversible rapid destruction of graft occurs. There is glomerular thrombosis, fibrinoid necrosis, and polymorphonuclear infiltration.[19] Only treatment is the surgical removal of the allograft.

The latest data from the North American Pediatric Renal Trials and Collaborative Studies show the incidence of hyperacute rejection to be <0.25% (17 cases) over the last 15 years.[20]

  Conclusion Top

Successful transplantation results in survival benefit, improved quality of life, and lower cost compared with chronic dialysis. However, progressive kidney function loss and graft dysfunction usually occur in the patients with HLA-sensitized transplantation, ABO-I transplantation, and AMR.

For patients with AMR, antibody depletion can be accomplished by intensive treatment with TPE or IA or/and additional immunosuppression. PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR.[3]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Marfo K, Lu A, Ling M, Akalin E. Desensitization protocols and their outcome. Clin J Am Soc Nephrol 2011;6:922-36.  Back to cited text no. 1
Baranwal AK, Bhatt DK, Goswami S, Agrawal SK, Kaur G, Kaur J, et al. Comparative analysis of Luminex-based donor-specific antibody mean fluorescence intensity values with complement-dependent cytotoxicity and flow crossmatch results in live donor renal transplantation. Indian J Med Res 2017;145:222-8.  Back to cited text no. 2
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Akalin E, Dinavahi R, Friedlander R, Ames S, de Boccardo G, Sehgal V, et al. Addition of plasmapheresis decreases the incidence of acute antibody-mediated rejection in sensitized patients with strong donor-specific antibodies. Clin J Am Soc Nephrol 2008;3:1160-7.  Back to cited text no. 3
Jordan SC, Lorant T, Choi J, Kjellman C, Winstedt L, Bengtsson M, et al. IgG endopeptidase in highly sensitized patients undergoing transplantation. N Engl J Med 2017;377:442-53.  Back to cited text no. 4
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Moreno Gonzales MA, Gandhi MJ, Schinstock CA, Moore NA, Smith BH, Braaten NY, et al. 32 doses of bortezomib for desensitization is not well tolerated and is associated with only modest reductions in anti-HLA antibody. Transplantation 2017;101:1222-7.  Back to cited text no. 6
Collin M, Björck L. Toward clinical use of the IgG specific enzymes IdeS and EndoS against antibody-mediated diseases. Methods Mol Biol 2017;1535:339-51.  Back to cited text no. 7
Huang E, Jordan SC. Immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS), desensitization, and the kidney allocation system: Complementary approaches to increase transplantation in highly HLA sensitized patients. CJASN 2018;13:799-801.  Back to cited text no. 8
Kute VB, Agrawal SK, Sahay M, Kumar A, Rathi M, Prasad N, et al. Kidney paired donation to increase living donor kidney transplantation in India: Guidelines in Indian Society of Organ Transplantation-2017. Indian J Transplant 2018;12:67-74.  Back to cited text no. 9
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]


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