Islet transplantation stabilizes glycemic controlin patients with complicated diabetes mellitus. Rapid functional decline could be due to islet allograft rejection. However, there is no reliable... Show moreIslet transplantation stabilizes glycemic controlin patients with complicated diabetes mellitus. Rapid functional decline could be due to islet allograft rejection. However, there is no reliable method to assess rejection, and treatment protocols are absent. We aimed to characterize diagnostic features of islet allograft rejection and assess effectiveness of high-dose methylprednisolone treatment. Over a median follow-up of 61.8 months, 22% (9 of 41) of islet transplant recipients experienced 10 suspected rejection episodes (SREs). All first SREs occurred within 18 months after transplantation. Important features were unexplained hyperglycemia (all cases), unexplained C-peptide decrease (ΔC-peptide, 77.1% [−59.1% to −91.6%]; ΔC-peptide:glucose, −76.3% [−49.2% to −90.4%]), predisposing event (5 of 10 cases), and increased immunologic risk (5 of 10 cases). At 6 months post-SRE, patients who received protocolized methylprednisolone (n = 4) had significantly better islet function than untreated patients (n = 4), according to C-peptide (1.39 ± 0.59 vs 0.14 ± 0.19 nmol/L; P = .007), Igls score (good [4 of 4 cases] vs failure [3 of 4 cases] or marginal [1 of 4 cases]; P = .018) and β score (6.0 [6.0-6.0] vs 1.0 [0.0-3.5]; P = .013). SREs are prevalent among islet transplant recipients and are associated with loss of islet graft function. Timely treatment with high-dose methylprednisolone mitigates this loss. Unexplained hyperglycemia, unexpected C-peptide decrease, a predisposing event, and elevated immunologic risk are diagnostic indicators for SRE. Show less
Weerd, A.E. de; Fatly, Z. al; Boer-Verschragen, M.; Gestel, J.K.V.A.; Roelen, D.L.; Dieterich, M.; Betjes, M.G.H. 2022
In this randomized-controlled pilot study, the feasibility and safety of tacrolimus monotherapy in immunologically low-risk kidney transplant recipients was evaluated [NTR4824, ]. Low immunological... Show moreIn this randomized-controlled pilot study, the feasibility and safety of tacrolimus monotherapy in immunologically low-risk kidney transplant recipients was evaluated [NTR4824, ]. Low immunological risk was defined as maximal 3 HLA mismatches and the absence of panel reactive antibodies. Six months after transplantation, recipients were randomized if eGFR > 30 ml/min, proteinuria < 50 mg protein/mmol creatinine, no biopsy-proven rejection after 3 months, and no lymphocyte depleting therapy given. Recipients were randomized to tacrolimus/mycophenolate mofetil (TAC/MMF) or to taper and discontinue MMF at month 9 (TACmono). 79 of the 121 recipients were randomized to either TACmono (n = 38) or TAC/MMF (n = 41). Mean recipient age was 59 years and 59% received a living donor transplant. The median follow-up was 62 months. After randomization, 3 TACmono and 4 TAC/MMF recipients experienced a biopsy-proven rejection. At 5 years follow-up, patient survival was 84% in TACmono versus 76% in TAC/MMF with death-censored graft survival of 97% for both groups and no differences in eGFR and proteinuria. Eleven TACmono recipients had an infectious episode versus 22 TAC/MMF recipients (p < 0.03). Donor-specific anti-HLA antibodies were not detected during follow-up in both groups. Tacrolimus monotherapy in selected immunologically low-risk kidney transplant recipients appears safe and reduces the number of infections. Show less
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... Show moreKidney 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, ]. Show less
Roufosse, C.; Drachenberg, C.; Renaudin, K.; Willicombe, M.; Toulza, F.; Dominy, K.; ... ; Adam, B. 2020
Pancreas transplant longevity is limited by immune rejection, which is diagnosed by graft biopsy using the Banff Classification. The histological criteria for antibody-mediated rejection (AMR) are... Show morePancreas transplant longevity is limited by immune rejection, which is diagnosed by graft biopsy using the Banff Classification. The histological criteria for antibody-mediated rejection (AMR) are poorly reproducible and inconsistently associated with outcome. We hypothesized that a 34-gene set associated with antibody-mediated rejection in other solid organ transplants could improve diagnosis in pancreas grafts. The AMR 34-gene set, comprising endothelial, natural killer cell and inflammatory genes, was quantified using the NanoString platform in 52 formalin-fixed, paraffin-embedded pancreas transplant biopsies from 41 patients: 15 with pure AMR or mixed rejection, 22 with T cell-mediated rejection/borderline and 15 without rejection. The AMR 34-gene set was significantly increased in pure AMR and mixed rejection (P = .001) vs no rejection. The gene set predicted histological AMR with an area under the receiver operating characteristic curve (ROC AUC) of 0.714 (P = .004). The AMR 34-gene set was the only biopsy feature significantly predictive of allograft failure in univariate analysis (P = .048). Adding gene expression to DSA and histology increased ROC AUC for the prediction of failure from 0.736 to 0.770, but this difference did not meet statistical significance. In conclusion, assessment of transcripts has the potential to improve diagnosis and outcome prediction in pancreas graft biopsies. Show less
Groeneweg, K.E.; Duijs, J.M.G.J.; Florijn, B.W.; Kooten, C. van; Fijter, J.W. de; Zonneveld, A.J. van; ... ; Bijkerk, R. 2020
Acute rejection (AR) of a kidney graft in renal transplant recipients is associated with microvascular injury in graft dysfunction and, ultimately, graft failure. Circulating long noncoding RNAs ... Show moreAcute rejection (AR) of a kidney graft in renal transplant recipients is associated with microvascular injury in graft dysfunction and, ultimately, graft failure. Circulating long noncoding RNAs (lncRNAs) may be suitable markers for vascular injury in the context of AR. Here, we first investigated the effect of AR after kidney transplantation on local vascular integrity and demonstrated that the capillary density markedly decreased in AR kidney biopsies compared to pre-transplant biopsies. Subsequently, we assessed the circulating levels of four lncRNAs (LNC-RPS24, LNC-EPHA6, MALAT1, and LIPCAR), that were previously demonstrated to associate with vascular injury in a cohort of kidney recipients with a stable kidney transplant function (n= 32) and recipients with AR (n= 15). The latter were followed longitudinally six and 12 months after rejection. We found higher levels of circulating LNC-EPHA6 during rejection, compared with renal recipients with a stable kidney function (p= 0.017), that normalized one year after AR. In addition, LNC-RPS24, LNC-EPHA6, and LIPCAR levels correlated significantly with the vascular injury marker soluble thrombomodulin. We conclude that AR and microvascular injury are associated with higher levels of circulating LNC-EPHA6, which emphasizes the potential role of lncRNAs as biomarker in the context of AR. Show less
The Banff Digital Pathology Working Group (DPWG) was formed in the time leading up to and during the joint American Society for Histocompatibility and Immunogenetics/Banff Meeting, September 23-27,... Show moreThe Banff Digital Pathology Working Group (DPWG) was formed in the time leading up to and during the joint American Society for Histocompatibility and Immunogenetics/Banff Meeting, September 23-27, 2019, held in Pittsburgh, Pennsylvania. At the meeting, the 14th Banff Conference, presentations directly and peripherally related to the topic of "digital pathology" were presented; and discussions before, during, and after the meeting have resulted in a list of issues to address for the DPWG. Included are practice standardization, integrative approaches for study classification, scoring of histologic parameters (eg, interstitial fibrosis and tubular atrophy and inflammation), algorithm classification, and precision diagnosis (eg, molecular pathways and therapeutics). Since the meeting, a survey with international participation of mostly pathologists (81%) was conducted, showing that whole slide imaging is available at the majority of centers (71%) but that artificial intelligence (AI)/machine learning was only used in approximate to 12% of centers, with a wide variety of programs/algorithms employed. Digitalization is not just an end in itself. It also is a necessary precondition for AI and other approaches. Discussions at the meeting and the survey highlight the unmet need for a Banff DPWG and point the way toward future contributions that can be made. Show less
Interleukin (IL)-21 supports induction and expansion of CD8(+) T cells, and can also regulate the differentiation of B cells into antibody-producing plasma cells. We questioned whether the number... Show moreInterleukin (IL)-21 supports induction and expansion of CD8(+) T cells, and can also regulate the differentiation of B cells into antibody-producing plasma cells. We questioned whether the number of circulating donor-specific IL-21 producing cells (pc) can predict kidney transplant rejection, and evaluated this in two different patient cohorts. The first analysis was done on pre-transplantation samples of 35 kidney transplant recipients of whom 15 patients developed an early acute rejection. The second study concerned peripheral blood mononuclear cell (PBMC) samples from 46 patients obtained at 6 months after kidney transplantation of whom 13 developed late rejection. Significantly higher frequencies of donor-specific IL-21 pc were found by Elispot assay in both patients who developed early and late rejection compared to those without rejection. In addition, low frequencies of donor-specific IL-21 pc were associated with higher rejection-free survival. Moreover, low pre-transplant donor-specific IL-21 pc numbers were associated with the absence of anti-HLA antibodies. Donor-reactive IL-21 was mainly produced by CD4(+) T cells, including CD4(+) follicular T helper cells. In conclusion, the number of donor-specific IL-21 pc is associated with an increased risk of both early and late rejection, giving it the potential to be a new biomarker in kidney transplantation. Show less
