Transplant Candidates of 70+ Years Have Superior Survival If Receiving Pre-Emptively a Living Donor Kidney.

Background: The number of kidney transplant recipients over 70 years of age is increasing but detailed data on patient and graft survival in the modern era of immune suppression are few. Methods: A single-center cohort of patients of 70 years and older (n = 349) at time of kidney transplantation from 2010-2020 were followed until January 2023. Results: The median age was 73 years with a median follow-up of 4.3 years. Fifty percent of recipients of a living donor kidney (LDK, n = 143) received their graft pre-emptively. Cumulative death-censored graft survival was excellent in the LDK group and reached 98% at 5 years vs. 85% in the deceased donor kidney (DDK) group. Primary non-function (38%) and rejection (43%) were the major causes of graft loss in the first year after DDK transplantation. Rejection-related graft loss was 4.6% during follow-up. Median recipient survival was superior in the subgroup of pre-emptively transplanted LDK patients compared to non-pre-emptively LDK transplanted patients (11.1 versus 6.2 years). Non-pre-emptively transplanted patients had a significantly increased incidence of infection (HR 3.81, 1.46-9.96) and cardiovascular-related causes of death (HR 3.35, 1.16-9.71). Pre-emptive transplantation was also associated with a significantly improved graft survival in the DDK recipients but this result was confounded by significantly better HLA matching and younger donor age in this group. Conclusions: Pre-emptive LDK transplantation in patients of 70 years or older confers superior graft and recipient survival.

Imlifidase Desensitization in HLA-incompatible Kidney Transplantation: Finding the Sweet Spot.

Imlifidase, derived from a Streptococcus pyogenes enzyme, cleaves the entire immunoglobulin G pool within hours after administration in fully cleaved antigen-binding and crystallizable fragments. These cleaved fragments can no longer exert their antibody-dependent cytotoxic functions, thereby creating a window to permit HLA-incompatible kidney transplantation. Imlifidase is labeled, in Europe only, for deceased donor kidney transplantation in highly sensitized patients, whose chances for an HLA-compatible transplant are negligible. This review discusses outcomes of preclinical and clinical studies on imlifidase and describes the phase III desensitization trials that are currently enrolling patients. A comparison is made with other desensitization methods. The review discusses the immunological work-up of imlifidase candidates and especially the "delisting strategy" of antigens that shift from unacceptable to acceptable with imlifidase desensitization. Other considerations for clinical implementation, such as adaptation of induction protocols, are also discussed. Imlifidase cleaves most of the currently used induction agents except for horse antithymocyte globulin, and rebound of donor-specific antibodies should be managed. Another consideration is the timing and interpretation of (virtual) crossmatches when bringing this novel desensitization agent into the clinic.

Lowering maintenance immune suppression in elderly kidney transplant recipients; connecting the immunological and clinical dots.

The management of long-term immune suppressive medication in kidney transplant recipients is a poorly explored field in the area of transplant medicine. In particular, older recipients are at an increased risk for side effects and have an exponentially increased risk of infection-related death. In contrast, an aged immune system decreases the risk of acute T-cell-mediated rejection in older recipients. Recent advances in alloimmunity research have shown a rapid and substantial decline in polyfunctional, high-risk CD4+ T cells post-transplantation. This lowers the direct alloreactivity responsible for T-cell-mediated rejection, also known as donor-specific hyporesponsiveness. Chronic antibody-mediated rejection (c-aABMR) is the most frequent cause of kidney graft loss in the long term. However, in older adults, c-aABMR as a cause of graft loss is outnumbered by death with a functioning graft. In addition, DSA development and a diagnosis of c-aABMR plateau ~10 years after transplantation, resulting in a very low risk for rejection thereafter. The intensity of immune suppression regimes could likely be reduced accordingly, but trials in this area are scarce. Tacrolimus monotherapy for 1 year after transplantation seems feasible in older kidney transplant recipients with standard immunological risk, showing the expected benefits of fewer infections and better vaccination responses.

The self-regulation skills instrument in transplantation (SSIt): Development and measurement properties of a self-report self-management instrument.

OBJECTIVE: To develop a self-management instrument for organ transplant recipients that incorporates self-regulations skills and to determine its measurement properties. METHODS: The instrument includes concepts from social cognitive models: problem awareness, attitude, self-efficacy, motivation, social support, goal setting, goal pursuit, skills and goal affect. The measurement properties were evaluated based on the COSMIN guidelines. Face and content validity were determined through patient assessment, Three-Step Test-Interview and expert assessment using the Content Validity Index. Structural validity and reliability were tested using exploratory factor analysis and Cronbach's alpha. Construct validity was tested by comparing subscales with the Health Education Impact Questionnaire (heiQ). RESULTS: After face and content validity assessment 47 items were entered into the exploratory factor analysis. The analysis showed two meaningful factors, with internal consistency of 0.90 and 0.89. Spearman correlations between the subscales and heiQ were moderate (0.55; 0.46). The final version consists of 21 items, divided into two scales: 'Setbacks' and 'Successes'. CONCLUSIONS: The Self-regulation skills instrument in transplantation (SSIt) is a valid and reliable instrument to asses necessary skills for self-management after transplantation and may be useful for other patients as well. PRACTICE IMPLICATIONS: Insight into self-regulation competencies can help healthcare professionals to tailor self-management support.

Increasing Kidney-Exchange Options Within the Existing Living Donor Pool With CIAT: A Pilot Implementation Study.

Computerized integration of alternative transplantation programs (CIAT) is a kidney-exchange program that allows AB0- and/or HLA-incompatible allocation to difficult-to-match patients, thereby increasing their chances. Altruistic donors make this available for waiting list patients as well. Strict criteria were defined for selected highly-immunized (sHI) and long waiting (LW) candidates. For LW patients AB0i allocation was allowed. sHI patients were given priority and AB0i and/or CDC cross-match negative HLAi allocations were allowed. A local pilot was established between 2017 and 2022. CIAT results were assessed against all other transplant programs available. In the period studied there were 131 incompatible couples; CIAT transplanted the highest number of couples (35%), compared to the other programs. There were 55 sHI patients; CIAT transplanted as many sHI patients as the Acceptable Mismatch program (18%); Other programs contributed less. There were 69 LW patients; 53% received deceased donor transplantations, 20% were transplanted via CIAT. In total, 72 CIAT transplants were performed: 66 compatible, 5 AB0i and 1 both AB0i and HLAi. CIAT increased opportunities for difficult-to-match patients, not by increasing pool size, but through prioritization and allowing AB0i and "low risk" HLAi allocation. CIAT is a powerful addition to the limited number of programs available for difficult-to-match patients.

The Incidence of Antibody-Mediated Rejection Is Age-Related, Plateaus Late After Kidney Transplantation, and Contributes Little to Graft Loss in the Older Recipients.

It is not known whether antibody-mediated rejection (ABMR) is age-related, whether it plateaus late after transplantation, and to what extent it contributes to graft loss in older recipients. Patients transplanted between 2010 and 2015 (n = 1,054) in a single center had regular follow-up until January 2023. Recipients were divided into age groups at transplantation: 18-39 years ("young"), 40-55 years ("middle age"), and >55 years ("elderly"). Ten years after transplantation the cumulative % of recipients with ABMR was 17% in young, 15% in middle age, and 12% in elderly recipients (p < 0.001). The cumulative incidence of ABMR increased over time and plateaued 8-10 years after transplantation. In the elderly, with a median follow-up of 7.5 years, on average 30% of the recipients with ABMR died with a functional graft and ABMR contributed only 4% to overall graft loss in this group. These results were cross-validated in a cohort of recipients with >15 years follow-up. Multivariate cox-regression analysis showed that increasing recipient age was independently associated with decreasing risk for ABMR. In conclusion, the cumulative risk for ABMR is age-dependent, plateaus late after transplantation, and contributes little to overall graft loss in older recipients.

Tacrolimus Monotherapy is Safe in Immunologically Low-Risk Kidney Transplant Recipients: A Randomized-Controlled Pilot Study.

In this randomized-controlled pilot study, the feasibility and safety of tacrolimus monotherapy in immunologically low-risk kidney transplant recipients was evaluated [NTR4824, www.trialregister.nl]. 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.

Investigational drugs for the treatment of kidney transplant rejection.

INTRODUCTION: Kidney transplant rejection remains an important clinical problem despite the development of effective immunosuppressive therapy. Two major types of rejection are recognized, T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), which have a different pathophysiology and are treated differently. Unfortunately, long-term outcomes of both TCMR and ABMR remain unsatisfactory despite current therapy. Hence, alternative therapeutic drugs are urgently needed. AREAS COVERED: This review covers novel and investigational drugs for the pharmacological treatment of kidney transplant rejection. Potential therapeutic strategies and future directions are discussed. EXPERT OPINION: The development of alternative pharmacologic treatment of rejection has focused mostly on ABMR, since this is the leading cause of kidney allograft loss and currently lacks an effective, evidence-based therapy. At present, there is insufficient high-quality evidence for any of the covered investigational drugs to support their use in ABMR. However, with the emergence of targeted therapies, the potential arises for individualized treatment strategies. In order to generate more high-quality evidence for such strategies and overcome the obstacles of classic randomized controlled trials, we advocate the implementation of adaptive trial designs and surrogate clinical endpoints. We believe such adaptive trial designs could help to understand the risks and benefits of promising drugs such as tocilizumab, clazakizumab, belimumab, and imlifidase.

The Burden of Gastrointestinal Complaints in Kidney Transplant Recipients Using Tacrolimus With and Without Mycophenolate Mofetil: A Randomized Controlled Study.

Background: Tacrolimus (TAC) combined with mycophenolate mofetil (MMF) is the immunosuppressive regimen in the majority of solid organ transplant recipients. Gastrointestinal complaints are frequent, which is considered predominantly a side effect of MMF. However, systematic research in this field is lacking. The aim of this study is to systematically investigate the burden of gastrointestinal complaints in TAC-treated kidney transplant recipients with and without MMF. Methods: In a single-center, open-label, randomized controlled trial, low immunological risk recipients were randomized to either TAC and MMF or to TAC monotherapy from 6 months after kidney transplantation onwards [NTR4672],. They filled in the Gastrointestinal Symptom Rating Scale questionnaire, which covers five dimensions (abdominal pain, reflux, indigestion, constipation, and diarrhea), 6, 12, and 15 months after transplantation. Results: Seventy-nine recipients were randomized and 72 completed all questionnaires (34 TACmono and 38 TAC/MMF). At baseline, the mean age was 59 years with 72% male, mean BMI 28 kg/m2, eGFR 55 ml/min/1.73m2, mean daily dose MMF 1200 mg and TAC 5.8 mg, with trough levels of 2.1 mg/L and 7.4 ug/L. Six months after transplantation, 75% of recipients reported troublesome symptoms (score ≥3). Diarrhea was the most troublesome (mean 3.3) and discontinuing MMF significantly reduced it (mean Δ score between month 6 and 15 TAC/MMF -0.9 vs. TACmono -1.8, p=0.03). In recipients with troublesome symptoms, abdominal pain (2.7 to 1.8, p=0.003), indigestion (2.8 to 2.3, p=0.012), and reflux (2.9 to 1.7, p=0.007) significantly decreased over time, independent of MMF use. Conclusion: The majority of kidney transplant recipients with TAC and MMF experienced troublesome gastrointestinal symptoms 6 months after transplantation. While constipation remained troublesome, indigestion, abdominal pain, and reflux improved over time by month 15. Diarrhea only improved after discontinuing MMF.

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].

Alemtuzumab as Second-Line Treatment for Late Antibody-Mediated Rejection of Transplanted Kidneys.

Whether the anti-CD52 monoclonal antibody alemtuzumab can be an effective treatment option for late antibody-mediated rejection (ABMR) is not known. In a single-center pilot study, 12 patients with late ABMR were given 30 mg subcutaneous alemtuzumab.Median time from transplantation to biopsy was 22 months with 10 of 12 recipients fulfilling criteria for the histologic diagnosis chronic-active ABMR. The estimated glomerular filtration rate (eGFR) loss before diagnosis was 1.2 mL/min/mo with graft loss (eGFR <15 mL/min) expected to occur within 2 years in 11 of 12 cases. All recipients showed no or an inadequate response to initial treatment with steroids and intravenous immunoglobulin. eGFR at time of alemtuzumab administration was 35 mL/min/1.73 m2 (IQR, 30-42) and stabilized or improved in 10 of 12 recipients within 12 months. Proteinuria was stable in the year after alemtuzumab. At 3-year follow-up, the death-censored graft survival was 68% (uncensored graft survival was 58%). Five cases of 10 cases that could be evaluated at 3-year follow-up had stable eGFR (on average 44 mL/min at 12 months and 42 mL/min at 36 months). Alemtuzumab was generally well tolerated and only 2 cases of opportunistic infections were noted. One case of symptomatic parvovirus B infection and 1 case of BK viral infection occurred, which both cleared at follow-up. In conclusion, alemtuzumab may be of value as a second-line treatment for late ABMR with rapid loss of eGFR.

Is simplification of immunosuppressive medication a way to promote medication adherence of kidney transplant recipients? Findings from a randomized controlled trial.

After kidney transplantation, a strict immunosuppressive medication regimen is necessary for graft survival. However, nonadherence to medication has been shown to occur early after transplantation and to increase over time. Weaning the recipient off dual therapy onto monotherapy in order to reduce immunosuppressive burden may also be a way to promote adherence, although little is known about the impact of such a regimen on fear of rejection. We performed a cohort study on medication adherence and fear of rejection in a randomized, investigator-driven, open-label, single-centre pilot study. Recipients were randomized at 6-months post-transplant to either continue Tacrolimus and Mycophenolate mofetil (TAC/MMF) or to taper MMF at 6 months and discontinue MMF at 9 months (TAC monotherapy). Recipients completed questionnaires about medication adherence and fear of rejection at 6 and 12-months post-transplantation. Medication adherence was significantly higher in the TAC monotherapy group compared to dual TAC/MMF therapy group (χ2 (1) = 4.582; P = 0.032). We found no difference in fear of rejection between the two groups of recipients (P = 0.887). Simplification of the medication regimen is a potential tool for increasing adherence in clinical practice (Netherlands Trial Register - NL4672).

ARHGDIB and AT1R autoantibodies are differentially related to the development and presence of chronic antibody-mediated rejection and fibrosis in kidney allografts.

The role of non-HLA autoantibodies in chronic-active antibody-mediated rejection (c-aABMR) of kidney transplants is largely unknown. In this study, the presence and clinical relevance of non-HLA autoantibodies using a recently developed multiplex Luminex-based assay were investigated. Patients with a kidney allograft biopsy at least 6 months after transplantation with a diagnosis of c-aABMR (n = 36) or no rejection (n = 21) were included. Pre-transplantation sera and sera at time of biopsy were tested for the presence of 14 relevant autoantibodies. A significantly higher signal for autoantibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) was detected in recipients with c-aABMR as compared to recipients with no rejection. However, ARHGDIB autoantibodies did not associate with graft survival. Levels of autoantibodies against angiotensin II type 1-receptor (AT1R) and peroxisomal trans-2-enoyl-CoA reductase (PECR) were increased in recipients with interstitial fibrosis in their kidney biopsy. Only the signal for AT1R autoantibody showed a linear relationship with the degree of interstitial fibrosis and was associated with graft survival. In conclusion, anti-ARHGDIB autoantibodies are increased when c-aABMR is diagnosed but are not associated with graft survival, while higher levels of AT1R autoantibody are specifically associated with the presence of interstitial fibrosis and graft survival.

Pretransplant Donor-Specific Anti-HLA Antibodies and the Risk for Rejection-Related Graft Failure of Kidney Allografts.

BACKGROUND: The presence of donor-specific antibodies (DSAs) against HLA before kidney transplantation has been variably associated with decreased long-term graft survival. Data on the relation of pretransplant DSA with rejection and cause of graft failure in recipients of donor kidneys are scarce. METHODS: Patients transplanted between 1995 and 2005 were included and followed until 2016. Donor-specific antibodies before transplantation were determined retrospectively. For cause, renal transplant biopsies were reviewed. RESULTS: Pretransplant DSAs were found in 160 cases on a total of 734 transplantations (21.8%). In 80.5% of graft failures, a diagnostic renal biopsy was performed. The presence of pretransplant DSA (DSApos) increased the risk of graft failure within the first 3 months after transplantation (5.2% vs. 9.4%) because of rejection with intragraft thrombosis (p < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos, p < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos, p < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos. CONCLUSIONS: Pretransplant DSAs are a risk factor for early graft loss and increase the incidence for humoral rejection and graft loss but do not affect the risk for T cell-mediated rejection.

ABO-Incompatible Kidney Transplant Outcomes: A Meta-Analysis.

BACKGROUND AND OBJECTIVES: ABO blood group-incompatible kidney transplantation is considered a safe procedure, with noninferior outcomes in large cohort studies. Its contribution to living kidney transplantation programs is substantial and growing. Outcomes compared with center-matched ABO blood group-compatible control patients have not been ascertained. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Comprehensive searches were conducted in Embase, Medline, Cochrane, Web-of-Science, and Google Scholar. Meta-analyses Of Observational Studies in Epidemiology study guidelines for observational studies and Newcastle Ottawa bias scale were implemented to assess studies. Meta-analysis was performed using Review Manager 5.3. A subgroup analysis on antibody removal technique was performed. RESULTS: After identifying 2728 studies addressing ABO-incompatible kidney transplantation, 26 studies were included, describing 1346 unique patients who were ABO-incompatible and 4943 ABO-compatible controls. Risk of bias was low (all studies ≥7 of 9 stars). Baseline patient characteristics revealed no significant differences in immunologic risk parameters. Statistical heterogeneity of studies was low (I2 0% for graft and patient survival). One-year uncensored graft survival of patients who were ABO-incompatible was 96% versus 98% in ABO-compatible controls (relative risk, 0.97; 95% confidence interval, 0.96 to 0.98; P<0.001). Forty-nine percent of reported causes of death in patients who were ABO-incompatible were of infectious origin, versus only 13% in patients who were ABO-compatible (P=0.02). Antibody-mediated rejection (3.86; 95% confidence interval, 2.05 to 7.29; P<0.001), severe nonviral infection (1.44; 95% confidence interval, 1.13 to 1.82; P=0.003), and bleeding (1.92; 95% confidence interval, 1.36 to 2.72; P<0.001) were also more common after ABO-incompatible transplantation. CONCLUSIONS: ABO-incompatible kidney transplant recipients have good outcomes, albeit inferior to center-matched ABO-compatible control patients.

T-Cell Composition of the Lymph Node Is Associated with the Risk for Early Rejection after Renal Transplantation.

BACKGROUND: The T-cell composition within the lymph node (LN) of end-stage renal disease (ESRD) patients differs from the composition within the circulation. Activation of the alloreactive T-cell response within secondary lymphoid organs is important after organ transplantation. However, to date no data are present on LN T-cell subsets and the risk for acute rejection after kidney transplantation. METHODS: T cells from LNs of ESRD patients were analyzed for frequency of recent thymic emigrants, relative telomere length, expression of differentiation markers, and were related to the development of early acute rejection (EAR), occurring within 3 months after renal transplantation (RT). Furthermore, the alloreactive potential of mononuclear cells isolated from the LN and peripheral blood of 10 patients was analyzed. Measures of alloreactive potential included proliferation, cytokine production, frequencies of interferon-gamma-producing cells, and the presence of cytotoxic molecules. RESULTS: Patients with EAR were younger (p = 0.019), cytomegalovirus-seropositive (p = 0.037) and usually received dialysis prior to RT (p = 0.030). Next to this, patients with EAR showed a lower CD4:CD8 ratio (p = 0.027) within the LN. T cells from the LN were similar with regard to alloreactive capacity compared with those within the circulation. Univariate regression analysis showed that the CD4:CD8 ratio (OR: 0.67, p = 0.039), patient age (OR: 0.93, p = 0.024), and preemptive RT (OR: 0.11, p = 0.046) were associated with EAR. After a multivariate analysis, only the CD4:CD8 ratio (OR: 0.58, p = 0.019) and preemptive RT (OR:0.05, p = 0.012) were associated with EAR. CONCLUSION: A lower CD4:CD8 ratio in the LN is associated with a higher risk for the development of rejection within 3 months after RT.

Primary Polyomavirus Infection, Not Reactivation, as the Cause of Trichodysplasia Spinulosa in Immunocompromised Patients.

Classic human polyomaviruses (JC and BK viruses) become pathogenic when reactivating from latency. For the rare skin disease trichodysplasia spinulosa, we show that manifestations of the causative polyomavirus (TSPyV) occur during primary infection of the immunosuppressed host. High TSPyV loads in blood and cerebrospinal fluid, sometimes coinciding with cerebral lesions and neuroendocrine symptoms, marked the acute phase of trichodysplasia spinulosa, whereas initiation and maturation of TSPyV seroresponses occurred in the convalescent phase. TSPyV genomes lacked the rearrangements typical for reactivating polyomaviruses. These findings demonstrate the clinical importance of primary infection with this rapidly expanding group of human viruses and explain the rarity of some novel polyomavirus-associated diseases.