Successful living donor renal transplantation despite ABO incompatibility and a positive crossmatch

Potential live kidney donors have been rejected when the prospective recipients are blood type or crossmatch incompatible. By utilizing plasmapheresis combined with intravenous immune globulin (PP/IVIg) prior to surgery, donor-specific antibodies against blood group or human leukocyte antigens (HLA) have been removed, thereby allowing successful renal transplantation. A 26-yr-old male with a panel reactive antibody level of 100% and repeated positive crossmatches against deceased donor kidney offers, including zero HLA mismatched donors, successfully underwent ABO-incompatible kidney transplantation from his HLA-identical but nevertheless crossmatch-incompatible sister. The initial anti-A blood group isoagglutinin titers were 128, 256, and 1024 at room temperature, 37 degrees C, and 37 degrees C anti-IgG enhanced, respectively. With an individualized PP/IVIg regimen based on donor-specific antibody titer, however, the relevant antibodies were adequately reduced and hyperacute rejection avoided. Subsequent antibody-mediated rejection, likely directed against a minor histocompatibility antigen, was diagnosed on postoperative day 7 and successfully treated. Neither ABO, or crossmatch incompatibility, or both in combination prohibit kidney transplantation.     

A case of early graft loss due to hyperacute rejection after ABO-incompatible renal transplantation

Abstract:  Graft survival rates of ABO-incompatible (ABO-I) living-related kidney transplantations have greatly improved with the progress of immunosuppressive protocols. However, there are several case reports in which hyperacute rejections (HAR) or delayed hyperacute rejections (DHAR) occurred with immunosuppression, and acute humoral rejection is a risk factor for early graft loss in ABO-I kidney transplantations. We report a case of early graft loss after ABO-I kidney transplantation. A 51-yr-old male received an ABO-I kidney transplant from his wife. Graft function deteriorated immediately after surgery and HAR developed. Although plasma exchange and steroid pulse were performed, graft function did not recover. A renal biopsy on postoperative day (POD) 4 indicated compatible findings with HAR. Renal function was deemed irreversible and the renal graft was removed on POD 7. A biopsy performed one h after transplantation revealed a clot in the glomerulus. As this was a case of ABO-I transplantation without human leukocyte antigen class I and II antibodies in the pre- and postoperative flow panel reactive antibody, HAR was most likely caused by the presence of anti-blood group antibodies. The preoperative anti-A antibody value of ×64 was rather high in the present case. There is no clear standard for preoperative antibody values and it is difficult to predict prognosis preoperatively with the recent use of strong immunosuppressives. Although the mechanism of onset is unclear in this case, it is believed that the antibody titer should be reduced as much as possible prior to transplantation.     

ABO-incompatible living kidney transplantation

ABO-incompatible living kidney transplantation is nowadays a routine procedure to expand living donor pool. The past decades have seen the evolution of desensitization protocol and immunosuppression regimen. Despite increased bleeding events, infectious complications, and rejection episodes reported in some studies, favorable graft and patient survival rate are now achieved, regardless of various protocols among transplant centers. Several issues such as the usage of rituximab and standardization of blood group antibody titration remain to be settled. The deposition of C4d is no longer the histopathologic hallmark of antibody-mediated rejection, which have inspired innovative strategies of peripheral molecular screening and the improvement of histological diagnosis of AMR (antibody-mediated rejection). The better understanding of the underlying mechanism might facilitate the distinction and therapeutic schemes of AMR.     

Early subclinical inflammation correlates with outcomes in positive crossmatch kidney allografts

The aim of this study was to investigate correlations between early subclinical findings (10‐ and 90‐day histology and gene expression data) and late outcomes (transplant glomerulopathy and graft loss) in positive crossmatch kidney transplants (+XMKTx). We compared 34 +XMKTx (19 receiving eculizumab and 15 receiving standard of care without eculizumab) to 13 ?XMKTx (between August 2001 and August 2011). At 10 days, light microscopy identified subclinical inflammation in only 18% of +XMKTx, while intragraft gene expression identified inflammation in 79% (gene sets for activated macrophages, dendritic cells, NK cells or T cells). Inflammation persisted at 90 days and was associated with the development of transplant glomerulopathy by 2 years and graft loss. In contrast, endothelial cell (EC) changes present at 90 days by either electron microscopy or gene expression were not associated with transplant glomerulopathy or graft loss in this cohort. Eculizumab treatment did not appear to alter inflammation or EC changes. Therefore, intragraft inflammation might be an appropriate surrogate marker of progression and also a target of therapy to prevent chronic antibody‐mediated rejection.     

Biliary complications among live donors following live donor liver transplantation

Introduction

In live donor liver transplantation (LDLT), bile duct division is a critical step in donor hepatectomy. Biliary complications hence are a feared sequelae even among donors. Long term data on biliary complications in donors from India are sparse.

Aluminium mobilization following renal allograft transplantation may have an immunomodulatory role by reducing the incidence of graft rejection

Urinary aluminium excretion was prospectively monitored duringthe first year following first cadaver renal allograft transplantationin 79 consecutive patients. Plasma and urinary aluminium concentrationssteadily declined with time. Thirty-five patients had 0–1episodes of acute graft rejection compared to 44 with two ormore rejections; more of the former group had been prescribedaluminium-containing phosphate binders (74% versus 56%, P<0.02),and following transplantation this group had a persistentlygreater urinary aluminium excretion, suggesting a greater aluminiumbody burden. There were no significant differences in termsof gender distribution, blood transfusion, or HLA matching betweenthe groups, thus suggesting that either the subsequent mobilizationof aluminium body stores following transplantation and/or theaccumulation of aluminium in the reticuloendothelial systemprior to transplantation may have had an immunomodulatory effectin reducing the incidence of renal allograft rejection.     

Successful living donor intestinal transplantation in crossmatch positive recipients: Initial experience

Sensitized patients tend to have longer waiting times on the deceased donor list and are at increased risk of graft loss from acute or chronic rejection compared to non-sensitized candidates. Desensitization protocols are utilized to decrease the levels of alloantibodies and to convert an initial positive cross-match to prospective donors into a negative crossmatch. These procedures are mostly available in the setting of living donation. Due to the elective nature of the procedure, desensitization protocols can be extended until the desire result is obtained prior to transplantation. We present two cases of successful desensitization protocol applied to living donor intestinal transplant candidates that converted to negative cross-match to their donors. We present two cases of intestinal transplant candidates with a potential living donor to whom they are sensitized. Both cases underwent successful transplantation after desensitization protocol. No evidence of humoral rejection has occurred in either recipient. Living donor intestinal transplantation in sensitized recipients against the prospective donors provides the ability to implement a desensitization protocol to convert to negative crossmatch.     

Aggressive treatment of the first acute rejection episode using first-line anti-lymphocytic preparation reduces further acute rejection episodes after human kidney transplantation

Abstract The detrimental effect of acute rejection episodes on long-term outcome of renal allografts in cyclosporin-treated patients is well established, although has not been seen by all investigators. To analyse the possibility that aggressive treatment of the first episode may ameliorate this detrimental effect, we performed an open label, randomised prospective trial in cyclosporin-based, immunosuppressed recipients of postmortem renal allografts in order to compare two different treatment protocols during primary acute rejection episodes: (1) group 1 of 25 patients received 3 × 250 mg methylprednisolone (MP) i.v.; (2) group 2 of 25 patients received 7 × anti-thymocyte globulin (ATG)-Fresenius i.v. (4 mg/kg body weight). During a period of 4 years, the following clinical observations were made: (1) The incidence of an acute re-rejection episode was significantly reduced in the ATG-treated study group (16%) compared to the MP-treated study group (72 %); (2) The severity of the first acute rejection episode (intensity of renal dysfunction measured in terms of 10-day creatinine area under curve) showed no significant difference between the groups (37 mg × 10-d/dl to 58 mg × 10-d/dl); and (3) The half-lives of allografts in both groups have not shown any significant differences so far. In conclusion, aggressive treatment of the first rejection episode of renal allografts with the use of ATG reduced the incidence of re-rejection episodes which, however, are not reflected so far by improvement of the 4-year survival rate of these allografts. Since it could be observed that re-rejection is an even worse predictor for chronic transplant failure, a better long-term outcome of renal allografts in ATG-treated patients may be expected during a longer observation period. The incidence of a third episode was also reduced in the ATG-treated group (0 %) compared to the MP-treated group (12%).     

Dialysis prior to living donor kidney transplantation and rates of acute rejection.

BACKGROUND: The relationship between transplantation prior to chronic dialysis initiation and the pattern of acute rejection of kidneys from living donors (LDKT) has not been fully explored. METHODS: Using data provided by the United States Renal Data System, we performed a retrospective cohort study fitting multivariate proportional hazards models to characterize the association of chronic use of dialysis prior to transplantation [non-pre-emptive LDKT (non-PLDKT)] and acute rejection, and to examine if this association varies throughout the first year. RESULTS: Non-PLDKT was associated with a 2.5-fold higher rate of biopsy-confirmed rejection during the first month [adjusted HR 2.5, 95% confidence interval (1.85-3.33)], compared with no dialysis prior to transplantation. Increasing duration of pre-transplant dialysis was associated with increasing rate of biopsy-confirmed acute rejection during the first month (P = 0.001 for trend). Over the first year, there was a diminishing relationship between non-PLDKT and acute rejection: 2.5-, 2.22-, 2.13- and 1.78-fold elevation in the episodes of biopsy-confirmed acute rejection during the first, second, third through to the sixth and seventh through to the twelfth month post-transplant, respectively (P = 0.05 for trend). CONCLUSIONS: The waning of the association of non-PLDKT with acute rejection over time supports the hypothesis that dialysis exposure prior to transplantation may modulate the immune system to increase the rates of acute rejection.     

The impact of late acute rejection after cadaveric kidney transplantation

BACKGROUND: Acute graft rejection (AR) following renal transplantation results in reduced graft survival. However, there is uncertainty regarding the definition, aetiology and long-term graft and patient outcome of AR occurring late in the post-transplant period. AIM: To determine if rejection episodes can be classified by time from transplantation by their impact on graft survival into early acute rejection (EAR) and late acute rejection (LAR). MATERIALS AND METHODS: 687 consecutive adult renal transplant recipients who received their first cadaveric renal transplant at a single centre. All received cyclosporine (CyA)-based immunosuppression, from 1984 to 1996, with a median follow-up of 6.9 yr. Details were abstracted from clinical records, with emphasis on age, sex, co-morbid conditions, HLA matching, rejection episodes, patient and graft survival. ANALYSIS: Patients were classified by the presence and time to AR from the date of transplantation. Using those patients who had no AR (NAR) as a baseline, we determined the relative risk of graft failure by time to rejection. The characteristics of patients who had no rejection, EAR and LAR were compared. RESULTS: Compared with NAR, the risk of graft failure was higher for those patients who suffered a rejection episode. A much higher risk of graft failure was seen when the first rejection episode occurred after 90 d. Thus, a period of 90 d was taken to separate EAR and LAR (relative risk of 3.06 and 5.27 compared with NAR as baseline, p<0.001). Seventy-eight patients (11.4%) had LAR, 271 (39.4%) had EAR and 338 (49.2%) had NAR. The mean age for each of these groups differed (LAR 39.6 yr, EAR 40.8 yr compared with NAR 44 yr, p<0.003). The 5-yr graft survival for those who had LAR was 45% and 10-yr survival was 28%. HLA mismatches were more frequent in those with EAR vs. NAR (zero mismatches in HLA-A: 36 vs. 24%, HLA-B: 35 vs. 23% and HLA-DR: 63 vs. 41%, p<0.003). There was no difference in mismatching frequency between NAR and LAR. CONCLUSIONS: AR had a deleterious impact on graft survival, particularly if occurring after 90 d. AR episodes should therefore be divided into early and late phases. In view of the very poor graft survival associated with LAR, it is important to gain further insight into the main aetiological factors. Those such as suboptimal CyA blood levels and non-compliance with medication should be further investigated with the aim of developing more effective immunosuppressive regimens in order to reduce the incidence of LAR.     

ABO-incompatible kidney transplantation in perspective of deceased donor transplantation and induction strategies: a propensity-matched analysis

Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO-incompatible (ABOi) kidney transplantation with matched ABO-compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. We performed a retrospective study with propensity matching and compared patient and death-censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. 296 ABOi were compared with 1184 center and propensity-matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group, and PRA). Patient survival was better compared with deceased donor [hazard ratio (HR) for death of HR 0.69 (0.49–0.96)] and non-significantly different from ABOc living donor recipients [HR 1.28 (0.90–1.81)]. Rate of graft failure was higher compared with ABOc living donor transplantation [HR 2.63 (1.72–4.01)]. Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab-treated recipients (P < 0.001). ABOi kidney transplantation is superior to deceased donor transplantation. Rejection rate and graft failure are higher compared with matched ABOc living donor transplantation, underscoring the need for further studies into risk stratification and induction therapy [NTR7587, www.trialregister.nl ].     

Multiple arteries in live donor renal transplantation: surgical aspects and outcomes

PURPOSE: This retrospective study describes the surgical techniques and outcomes of live donor renal allografts with multiple arteries. MATERIALS AND METHODS: Between 1976 and 2000, 1,200 consecutive live donor renal transplants were done, including 1,087 with single (group 1) and 113 with multiple (group 2) arteries. Intracorporeal in situ anastomotic techniques were used for 94 grafts with multiple arteries, while ex vivo techniques were used for 19. During in situ surgery each one of the multiple arteries was anastomosed separately to an individual artery. In ex vivo surgery 2 or more arteries were joined together on the bench to form a common stem, which was then anastomosed to an iliac artery or the aorta. RESULTS: Patient and graft survival were comparable in groups 1 and 2. The 2 groups were comparable regarding complications, including arterial bleeding, hematoma, renal artery stenosis, acute rejection, new onset hypertension, acute tubular necrosis and urological complications. Mean serum creatinine +/- SD at 1 year was 1.4 +/- 0.5 and 1.5 +/- 0.6 mg./dl., and at 5 years it was 1.8 +/- 1 and 2.1 +/- 1.4 mg./dl. for the 2 groups, respectively. The difference was only significant at 1 year (p = 0.02). Graft and patient survival, and the incidence of the described complications were comparable for the ex vivo bench anastomotic techniques and intracorporeal in situ techniques in the group with multiple renal arteries. CONCLUSIONS: The use of multiple arteries in renal allografts does not adversely affect patient or graft survival. It is not associated with an increased rate of complications except for significantly higher mean serum creatinine at 1 year. Extracorporeal bench surgery was as effective as intracorporeal surgery for the anastomosis of multiple renal arteries with no increase in the incidence of relevant complications.     

Tacrolimus trough levels after month 3 as a predictor of acute rejection following kidney transplantation: a lesson learned from DeKAF Genomics

Most calcineurin inhibitor (CNI)‐based protocols reduce blood trough goals approximately 2–3 months post‐transplant in clinically stable kidney transplant recipients. The CNI target trough level to prevent rejection, after reduction, is unknown. Using a multivariate Cox proportional hazards model, we determined the association of time‐varying tacrolimus (TAC) trough levels with acute rejection (AR) occurring in the first 6 months post‐transplant, but specifically we assessed this association after 3 months. A total of 1930 patients received TAC‐based immunosuppression prior to AR in a prospective study. Of the 151 (7.8%) who developed AR, 47 developed AR after 3 months post‐transplant. In an adjusted time‐varying multivariate model, each 1 ng/ml decrease in TAC trough levels was associated with a 7.2% increased risk of AR [hazards ratio (HR) = 1.07, 95% confidence interval (CI) (1.01, 1.14) P = 0.03] in the first 6 months. There was an additional 23% increased risk of AR with each 1 ng/ml decrease in the TAC trough levels in months 3–6 [HR = 1.23, 95% CI (1.06, 1.43) P = 0.008]. In conclusion, lower TAC trough levels were significantly associated with increased risk of AR in the first 6 months post‐transplant with additional risk of AR between months 3 and 6 post‐transplant. The timing and practice of TAC dose reduction should be personalized based on the individual's risk factors.     

The use of NGAL and IP‐10 in the prediction of early acute rejection in highly sensitized patients following HLA‐incompatible renal transplantation

Acute rejection is a significant problem for patients undergoing HLA‐incompatible renal transplantation, affecting between 12 and 53% of patients. Any mechanism of detecting rejection in advance of current methods would offer significant benefit. This study aimed to evaluate whether serum biomarkers could predict rejection in HLAi transplants recipients. Sera from 94 HLAi transplant recipients from a single centre were analysed for a panel of biomarkers including: NGAL, KIM‐1, IP‐10, cystatin C, cathepsin L and VEGF. Biomarker levels pre‐operatively, day 1 and at day 30 post‐transplant were correlated with the development of early rejection. Significantly higher levels of IP‐10 and NGAL were seen on day 1 following transplant in those patients who developed acute rejection (P < 0.001 and 0.005) and generated AUC of 0.73 and 0.67, respectively. No differences were seen for the other biomarkers or at the other time points. In this study cohort, IP‐10 and NGAL have demonstrated good predictive ability for the development of acute rejection at a very early time point. They may have a role in identifying patients at higher risk for rejection and stratifying immunosuppression or surveillance.     

Conversion to belatacept within 1-year of renal transplantation in a diverse cohort including patients with donor-specific antibodies

Early conversion from a calcineurin inhibitor to belatacept has the potential to improve long-term renal allograft function; however, there remains limited experience with this strategy among African Americans and patients with preformed donor-specific antibodies (DSA). To examine these subgroups, we performed a single-center review of kidney transplant recipients converted to belatacept within 1-year of transplant between 01/2011 and 10/2017. All patients received lymphocyte-depleting induction with maintenance tacrolimus and mycophenolate +/− corticosteroids. Patients were switched to belatacept for clinical indication and followed from date of conversion until allograft failure or study conclusion. The primary endpoint at 1-year was a composite of allograft loss, biopsy proven rejection, de novo DSA formation, proteinuria, and declining renal function. Thirty-two patients were included in the review. The majority were African American, and 28.1% had DSA at transplant. Patient and allograft survival at 1-year was 96.9% and 93.8%, respectively, and estimated glomerular filtration rate improved from 41.9 to 58.4 mL/min. No African Americans or patients with pretreatment DSA developed rejection or allograft failure within 1-year. The only clinical variable correlated with suboptimal allograft function was baseline weight ≥80 kg (OR = 6.2; 95% CI, 1.2-32.3). Early conversion to belatacept appears safe for select patients with DSA and African Americans receiving lymphocyte-depleting induction.