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  • Stumpf J
  • Budde K
  • Witzke O
  • Sommerer C
  • Vogel T
  • et al.
E Clinical Medicine. 2023 Dec 22;67:102381 doi: 10.1016/j.eclinm.2023.102381.
BACKGROUND:

Optimal initial tacrolimus dosing and early exposure of tacrolimus after renal transplantation is not well studied.

METHODS:

In this open-label, 6 months, multicenter, randomized controlled, non-inferiority study, we randomly assigned 432 renal allograft recipients to receive basiliximab induction, mycophenolate and steroids and either standard prolonged-release tacrolimus (trough levels: 7-9 ng/ml; Standard Care arm), or an initial 7-day fixed 5 mg/day dose of prolonged-release tacrolimus followed by lower tacrolimus predose levels (trough levels: 5-7 ng/ml; Slow & Low arm). The primary end point was the combined incidence rate of biopsy-proven acute rejections (BPAR; including borderline), graft failure, or death at 6 months with a non-inferiority margin of 12.5%. (EudraCT-Nr: 2013-001770-19.

FINDINGS:

The combined primary endpoint in the Slow & Low arm was non-inferior compared to the Standard Care arm (22.1% versus 20.7%; difference: 1.4%, 90% CI -5.5% to 8.3%). The overall rate of BPAR including borderlines was similar (Slow & Low 17.4% versus Standard Care 16.6%). Safety parameters such as delayed graft function, kidney function, donor specific HLA-antibodies, infections, or post-transplantation diabetes mellitus did not differ.

INTERPRETATION:

This is the first study to show that an initial fixed dose of 5 mg per day followed by lower tacrolimus exposure is non-inferior compared to standard tacrolimus therapy and equally efficient and safe within 6 months after renal transplantation. These data suggest that therapeutic drug monitoring for prolonged release tacrolimus can be abandoned until start of the second week after transplantation.

FUNDING:

Investigator-initiated trial, financial support by Astellas Pharma GmbH.

  • Bai J
  • Zhang T
  • Wang Y
  • Cao J
  • Duan Z
  • et al.
Ren Fail. 2023 Dec;45(1):2201341 doi: 10.1080/0886022X.2023.2201341.
CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This is a well-conducted systematic review that searched multiple databases and included data from 966 renal transplant patients with FSGS (38% recurrence after transplantation). A review protocol was recorded in advance and the literature search and data extraction was completed in duplicate. Significant heterogeneity was identified between studies and was not explored by the authors with sensitivity analysis. This identified one study as a key source of heterogeneity, that was then later removed from statistical analysis. Publication bias was also checked statistically and was only present for one risk factor analysis (age at transplantation); correcting for this had no effect on the pooled estimate. In summary, this study showed that the overall recurrence risk of FSGS after renal transplantation is high. Age at transplant, age at onset, time from diagnosis to kidney failure, proteinuria prior to transplant, related donor and native nephrectomy were all associated with a higher risk of FSGS recurrence. Multiple other risk factors were examined and not found to be associated with risk of recurrence of FSGS: HLA mismatch, duration of dialysis, sex, living donor, tacrolimus and previous transplant.
Expert Review
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating 3
Review: Whilst transplantation is the treatment of choice for renal failure due to focal segmental glomerular sclerosis (FSGS), it is one of the few indications for transplantation with a known risk of recurrent disease in the transplant kidney that can affect graft survival post-transplant. Treatments such as pre-emptive plasmapheresis with or without rituximab have been used to prevent or treat post-transplant recurrence, but the evidence for effectiveness is limited (1). A number of publications have attempted to correlate demographic and clinical features with risk of recurrence post-transplant. In a recent systematic review and meta-analysis, Bai and colleagues have attempted to summarise and synthesise this literature (2). They identified 22 studies with 966 patients, showing an overall rate of FSGS recurrence of 38%. Risk factors for recurrence were identified as younger age at transplant, older age of disease onset, shorter time from diagnosis to kidney failure, higher levels of proteinuria prior to transplant, a related living donor transplant and native nephrectomy. The review methodology was sound, with searches in multiple databases, multiple reviewers screening the literature and an evaluation of risk of bias. As might be expected when exploring retrospective cohort studies, there was heterogeneity seen in some outcomes, in particular age at transplant and pre-transplant proteinuria. Most underlying studies included in the meta-analysis explored risks in univariate analysis, without correction for confounding, and there is no way in meta-analysis to explore the interactions between risks. Limited data are available on the distinction between primary and secondary FSGS, and the impact of testing for genetic mutations and risk of recurrence (3). Despite the limitations, the review still provides a useful guide when assessing patients with FSGS for transplantation. The findings allow us to stratify risk of recurrence and set realistic expectations during the consent process. References 1. Boonpheng B, Hansrivijit P, Thongprayoon C et al. Rituximab or plasmapheresis for prevention of recurrent focal segmental glomerulosclerosis after kidney transplantation: A systematic review and meta-analysis. World Journal of Transplantation 2021; 11: 303. 2. Bai J, Zhang T, Wang Y et al. Incidence and risk factors for recurrent focal segmental glomerulosclerosis after kidney transplantation: a meta-analysis. Renal Failure 45: 2201341. 3. Uffing A, Hullekes F, Riella LV, Hogan JJ. Recurrent Glomerular Disease after Kidney Transplantation. Clinical Journal of the American Society of Nephrology : CJASN 2021; 16: 1730
Aims: This study aimed to investigate the incidence and risk factors associated with focal segmental glomerulosclerosis (FSGS) following kidney transplantation.
Interventions: A literature search was conducted on PubMed, Cochrane Library, Medline, Embase, Web of Science, CNKI, CBMdisc, Wanfang, and Weipu (VIP). Study selection and data extraction were performed by two independent authors. The methodological quality of the included studies were assessed using the Newcastle–Ottawa Scale (NOS).
Participants: 22 studies were included in the review.
Outcomes: FSGS recurrence rate posttransplantation and risk factors of FSGS.
Follow Up: N/A
AIMS:

To systematically review the incidence and risk factors for recurrent FSGS after kidney transplantation.

METHODS:

We searched PubMed, Embase, Medline, Web of Science, the Cochrane Library, CNKI, CBMdisc, Wanfang, and Weipu for case-control studies related to recurrent FSGS from the establishment until October 2022. The protocol was registered on PROSPERO (CRD42022315448). Data were analyzed using Stata 12.0, with odds ratios (counting data) and standardized mean difference (continuous data) being considered as effect sizes. If the I2 value was greater than 50%, the random-effects model was used; otherwise, a fixed-effects model was used. A meta-analysis on the incidence and risk factors for recurrent FSGS after kidney transplantation was performed.

RESULTS:

A total of 22 studies with 966 patients and 12 factors were included in the meta-analysis. There were 358 patients with recurrent FSGS and 608 patients without FSGS after kidney transplantation. The results showed that the recurrence rate of FSGS after kidney transplantation was 38% (95% CI: 31%-44%). Age at transplantation (SMD = -0.47, 95% CI -0.73 to -0.20, p = .001), age at onset (SMD = -0.31, 95% CI -0.54 to -0.08, p = .008), time from diagnosis to kidney failure (SMD = -0.24, 95% CI -0.43 to -0.04, p = .018), proteinuria before KT (SMD = 2.04, 95% CI 0.91 - 3.17, p < .001), related donor (OR 1.99, 95% CI 1.20 - 3.30, p = .007) and nephrectomy of native kidneys (OR 6.53, 95% CI 2.68 - 15.92, p < .001) were associated with recurrent FSGS, whereas HLA mismatches, duration of dialysis before KT, sex, living donor, tacrolimus use and previous transplantation were not associated with recurrent FSGS after kidney transplantation.

CONCLUSIONS:

The recurrence of FSGS after kidney transplantation remains high. Clinical decision-making should warrant further consideration of these factors, including age, original disease progression, proteinuria, related donor, and nephrectomy of native kidneys.

  • Annamalai C
  • Kute V
  • Sheridan C
  • Halawa A
Transplant Rev (Orlando). 2023 Dec;37(4):100792 doi: 10.1016/j.trre.2023.100792.
INTRODUCTION:

Despite its use to prevent acute rejection, lifelong immunosuppression can adversely impact long-term patient and graft outcomes. In theory, immunosuppression withdrawal is the ultimate goal of kidney transplantation, and is made possible by the induction of immunological tolerance. The purpose of this paper is to review the safety and efficacy of immune tolerance induction strategies in living-donor kidney transplantation, both chimerism-based and non-chimerism-based. The impact of these strategies on transplant outcomes, including acute rejection, allograft function and survival, cost, and immune monitoring, will also be discussed.

MATERIALS AND METHODS:

Databases such as PubMed, Scopus, and Web of Science, as well as additional online resources such as EBSCO, were exhaustively searched. Adult living-donor kidney transplant recipients who developed chimerism-based tolerance after concurrent bone marrow or hematopoietic stem cell transplantation or those who received non-chimerism-based, non-hematopoietic cell therapy using mesenchymal stromal cells, dendritic cells, or regulatory T cells were studied between 2000 and 2021. Individual sources of evidence were evaluated critically, and the strength of evidence and risk of bias for each outcome of the transplant tolerance study were assessed.

RESULTS:

From 28,173 citations, 245 studies were retrieved after suitable exclusion and duplicate removal. Of these, 22 studies (2 RCTs, 11 cohort studies, 6 case-control studies, and 3 case reports) explicitly related to both interventions (chimerism- and non-chimerism-based immune tolerance) were used in the final review process and were critically appraised. According to the findings, chimerism-based strategies fostered immunotolerance, allowing for the safe withdrawal of immunosuppressive medications. Cell-based therapy, on the other hand, frequently did not induce tolerance except for minimising immunosuppression. As a result, the rejection rates, renal allograft function, and survival rates could not be directly compared between these two groups. While chimerism-based tolerance protocols posed safety concerns due to myelosuppression, including infections and graft-versus-host disease, cell-based strategies lacked these adverse effects and were largely safe. There was a lack of direct comparisons between HLA-identical and HLA-disparate recipients, and the cost implications were not examined in several of the retrieved studies. Most studies reported successful immunosuppressive weaning lasting at least 3 years (ranging up to 11.4 years in some studies), particularly with chimerism-based therapy, while only a few investigators used immune surveillance techniques. The studies reviewed were often limited by selection, classification, ascertainment, performance, and attrition bias.

CONCLUSIONS:

This review demonstrates that chimerism-based hematopoietic strategies induce immune tolerance, and a substantial number of patients are successfully weaned off immunosuppression. Despite the risk of complications associated with myelosuppression. Non-chimerism-based, non-hematopoietic cell protocols, on the other hand, have been proven to facilitate immunosuppression minimization but seldom elicit immunological tolerance. However, the results of this review must be interpreted with caution because of the non-randomised study design, potential confounding, and small sample size of the included studies. Further validation and refinement of tolerogenic protocols in accordance with local practice preferences is also warranted, with an emphasis on patient selection, cost ramifications, and immunological surveillance based on reliable tolerance assays.

  • Pérez-Sáez MJ
  • Montero N
  • Oliveras L
  • Redondo-Pachón D
  • Martínez-Simón D
  • et al.
Transplant Rev (Orlando). 2023 Dec;37(4):100787 doi: 10.1016/j.trre.2023.100787.
BACKGROUND:

Kidney transplant (KT) recipients of HLA identical siblings (HLAid) have lower immunological risk, but there are no specific recommendations for immunosuppression. Our aim was to analyze evidence about results from HLAid living-donor recipients under different immunosuppression in the current era of immunological risk assessment.

METHODS:

Systematic review of studies describing associations between outcomes of HLAid living-donor KT recipients according to their immunological risk and applied immunosuppression.

RESULTS:

From 1351 studies, 16 (5636 KT recipients) were included in the analysis. All studies were retrospective, ten comparing immunosuppression strategies, and six immunological risk strata. Of those ten, six studies were published in 1990 or earlier and only three included tacrolimus. The evidence is poor, and the inclusion of calcineurin inhibitors does not demonstrate better results. Furthermore, only few studies describe different immunosuppression regimens according to the patient immunological risk and, in general, they do not include the assessment with new solid phase assays.

CONCLUSIONS:

There are no studies analyzing the association of outcomes of HLAid KT recipients with current immunological risk tools. In the absence of evidence, no decision or proposal of immunosuppression adapted to modern immunological risk assessment can be made currently by the Descartes Working Group.

  • Li Y
  • Tang Y
  • Lin T
  • Song T
Front Immunol. 2023 Nov 28;14:1277017 doi: 10.3389/fimmu.2023.1277017.
BACKGROUND:

IgA nephropathy may recur in patients receiving kidney transplantation due to IgA nephropathy induced renal failure. The risk factors for recurrence are still at issue. The aim of this study was to conduct a systematic review and meta-analysis to assess risk factors and outcomes for IgA nephropathy recurrence.

METHODS:

We used PubMed, EMBASE, Cochrane Library, Web of Science, Scopus, CNKI, WanFang, VIP and CBM to search for relevant studies published in English and Chinese. Cohort or case-control studies reporting risk factors or outcomes for IgA nephropathy recurrence were included.

RESULTS:

Fifty-eight studies were included. Compare to no recurrence group, those with IgAN recurrence had younger age (mean difference [MD]=-4.27 years; risk ratio [RR]=0.96), younger donor age (MD=-2.19 years), shorter time from IgA nephropathy diagnosis to end stage renal disease (MD=-1.84 years; RR=0.94), shorter time on dialysis (MD=-3.14 months), lower human leukocyte-antigen (HLA) mismatches (MD=-0.11) and HLA-DR mismatches (MD=-0.13). HLA-B46 antigen (RR=0.39), anti-IL-2-R antibodies induction (RR=0.68), mycophenolate mofetil (RR=0.69), and pretransplant tonsillectomy (RR=0.43) were associated with less IgAN recurrence. Of note, male recipient gender (RR=1.17), related donor (RR=1.53), retransplantation (RR=1.43), hemodialysis (RR=1.68), no induction therapy (RR=1.73), mTOR inhibitor (RR=1.51), angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (RR=1.63) were risk factors for IgAN recurrence. Recurrence increased the risk of graft loss (RR=2.19).

CONCLUSIONS:

This study summarized the risk factors for recurrence of IgA nephropathy after kidney transplantation. Well-designed prospective studies are warranted for validation.

SYSTEMATIC REVIEW REGISTRATION:

https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=377480, identifier CRD42022377480.

  • Battle R
  • Pritchard D
  • Peacock S
  • Hastie C
  • Worthington J
  • et al.
Int J Immunogenet. 2023 Nov;50 Suppl 2:3-63 doi: 10.1111/iji.12641.

Solid organ transplantation represents the best (and in many cases only) treatment option for patients with end-stage organ failure. The effectiveness and functioning life of these transplants has improved each decade due to surgical and clinical advances, and accurate histocompatibility assessment. Patient exposure to alloantigen from another individual is a common occurrence and takes place through pregnancies, blood transfusions or previous transplantation. Such exposure to alloantigen's can lead to the formation of circulating alloreactive antibodies which can be deleterious to solid organ transplant outcome. The purpose of these guidelines is to update to the previous BSHI/BTS guidelines 2016 on the relevance, assessment, and management of alloantibodies within solid organ transplantation.

  • Al-Awadhi S
  • Raynaud M
  • Louis K
  • Bouquegneau A
  • Taupin JL
  • et al.
Front Immunol. 2023 Oct 2;14:1265796 doi: 10.3389/fimmu.2023.1265796.
INTRODUCTION:

Several studies have investigated the impact of circulating complement-activating anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) on organ transplant outcomes. However, a critical appraisal of these studies and a demonstration of the prognostic value of complement-activating status over anti-HLA DSA mean fluorescence intensity (MFI) level are lacking.

METHODS:

We conducted a systematic review, meta-analysis and critical appraisal evaluating the role of complement-activating anti-HLA DSAs on allograft outcomes in different solid organ transplants. We included studies through Medline, Cochrane, Scopus, and Embase since inception of databases till May 05, 2023. We evaluated allograft loss as the primary outcome, and allograft rejection as the secondary outcome. We used the Newcastle-Ottawa Scale and funnel plots to assess risk of bias and used bias adjustment methods when appropriate. We performed multiple subgroup analyses to account for sources of heterogeneity and studied the added value of complement assays over anti-HLA DSA MFI level.

RESULTS:

In total, 52 studies were included in the final meta-analysis (11,035 patients). Complement-activating anti-HLA DSAs were associated with an increased risk of allograft loss (HR 2.77; 95% CI 2.33-3.29, p<0.001; I²=46.2%), and allograft rejection (HR 4.98; 95% CI 2.96-8.36, p<0.01; I²=70.9%). These results remained significant after adjustment for potential sources of bias and across multiple subgroup analyses. After adjusting on pan-IgG anti-HLA DSA defined by the MFI levels, complement-activating anti-HLA DSAs were significantly and independently associated with an increased risk of allograft loss.

DISCUSSION:

We demonstrated in this systematic review, meta-analysis and critical appraisal the significant deleterious impact and the independent prognostic value of circulating complement-activating anti-HLA DSAs on solid organ transplant risk of allograft loss and rejection.

  • Kok G
  • Ilcken EF
  • Houwen RHJ
  • Lindemans CA
  • Nieuwenhuis EES
  • et al.
Ann Surg Open. 2023 Sep 15;4(3):e334 doi: 10.1097/AS9.0000000000000334.
OBJECTIVE:

We aim to investigate the effects of genetically based HLA matching on patient and graft survival, and acute and chronic rejection after liver transplantation.

BACKGROUND:

Liver transplantation is a common treatment for patients with end-stage liver disease. In contrast to most other solid organ transplantations, there is no conclusive evidence supporting human leukocyte antigen (HLA) matching for liver transplantations. With emerging alternatives such as transplantation of bankable (stem) cells, HLA matching becomes feasible, which may decrease the need for immunosuppressive therapy and improve transplantation outcomes.

METHODS:

We systematically searched the PubMed, Embase, and Cochrane databases and performed a meta-analysis investigating the effect of genetic HLA matching on liver transplantation outcomes (acute/chronic rejection, graft failure, and mortality).

RESULTS:

We included 14 studies with 2682 patients. HLA-C mismatching significantly increased the risk of acute rejection (full mismatching: risk ratio = 1.90, 95% confidence interval = 1.08 to 3.33, P = 0.03; partial mismatching: risk ratio = 1.33, 95% confidence interval = 1.07 to 1.66, P = 0.01). We did not discern any significant effect of HLA mismatching per locus on acute rejection for HLA-A, -B, -DR, and -DQ, nor on chronic rejection, graft failure, or mortality for HLA-DR, and -DQ.

CONCLUSIONS:

We found evidence that genetic HLA-C matching reduces the risk of acute rejection after liver transplantation while matching for other loci does not reduce the risk of acute rejection, chronic rejection, graft failure, or mortality.

  • Hirt-Minkowski P
  • Handschin J
  • Stampf S
  • Hopfer H
  • Menter T
  • et al.
J Am Soc Nephrol. 2023 Aug 1;34(8):1456-1469 doi: 10.1681/ASN.0000000000000160.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: Whilst many studies have demonstrated associations between biomarkers and acute rejection in renal transplantation, few have prospectively assessed the value of routine monitoring. This study randomised de novo kidney recipients to monitoring with urine CXCL10, or to routine care. In the control arm, CXCL10 measurements were taken but concealed. In the study arm, response to CXCL10 measurements was protocolised, with a biopsy undertaken in patients with elevated levels to inform clinical management. The authors found no difference in one-year clinical outcomes in either intent-to-treat or per-protocol analysis with monitoring. This is an interesting study as it highlights the challenges of translating biomarker association into real-world clinical monitoring. It is possible that the timepoints selected for monitoring, or the frequency of monitoring, was not optimum. Successful monitoring also requires adequate response to an abnormal result – both by undertaking biopsy and treating abnormal findings. In this study, 23% indicated biopsies were not completed, and 24% detected rejection episodes were not treated. Successful monitoring also assumes that the biomarker detects an abnormality (e.g. rejection) at a stage where intervention can have an impact on clinical outcome.
Aims: This study aimed to examine whether renal allograft monitoring by urine CXCL10 led to an improvement in clinical outcomes posttransplantation.
Interventions: Participants were randomised into two groups: the intervention arm, where a renal allograft biopsy were performed if levels of urine CXCL10 were above a predefined cutoff without the presence of confounders; and the control arm, in which the urine CXCL10 analyses was also assessed but the results were concealed.
Participants: 241 adult kidney transplant recipients.
Outcomes: The primary outcome was a combined endpoint at 1 year following transplantation, including death-censored graft loss, clinical rejection, acute rejection, chronic active T-cell–mediated rejection, development of de novo donor-specific HLA antibodies, or an estimated glomerular filtration rate (eGFR) of 25 ml/min.
Follow Up: 1 year
SIGNIFICANCE STATEMENT:

This study is the first randomized controlled trial to investigate the clinical utility of a noninvasive monitoring biomarker in renal transplantation. Although urine CXCL10 monitoring could not demonstrate a beneficial effect on 1-year outcomes, the study is a rich source for future design of trials aiming to explore the clinical utility of noninvasive biomarkers. In addition, the study supports the use of urine CXCL10 to assess the inflammatory status of the renal allograft.

BACKGROUND:

Urine CXCL10 is a promising noninvasive biomarker for detection of renal allograft rejection. The aim of this study was to investigate the clinical utility of renal allograft monitoring by urine CXCL10 in a randomized trial.

METHODS:

We stratified 241 patients, 120 into an intervention and 121 into a control arm. In both arms, urine CXCL10 levels were monitored at three specific time points (1, 3, and 6 months post-transplant). In the intervention arm, elevated values triggered performance of an allograft biopsy with therapeutic adaptations according to the result. In the control arm, urine CXCL10 was measured, but the results concealed. The primary outcome was a combined end point at 1-year post-transplant (death-censored graft loss, clinical rejection between month 1 and 1-year, acute rejection in 1-year surveillance biopsy, chronic active T-cell-mediated rejection in 1-year surveillance biopsy, development of de novo donor-specific HLA antibodies, or eGFR <25 ml/min).

RESULTS:

The incidence of the primary outcome was not different between the intervention and the control arm (51% versus 49%; relative risk (RR), 1.04 [95% confidence interval, 0.81 to 1.34]; P = 0.80). When including 175 of 241 (73%) patients in a per-protocol analysis, the incidence of the primary outcome was also not different (55% versus 49%; RR, 1.11 [95% confidence interval, 0.84 to 1.47]; P = 0.54). The incidence of the individual end points was not different as well.

CONCLUSIONS:

This study could not demonstrate a beneficial effect of urine CXCL10 monitoring on 1-year outcomes (ClinicalTrials.gov_ NCT03140514 ).

  • van den Broek DAJ
  • Meziyerh S
  • Budde K
  • Lefaucheur C
  • Cozzi E
  • et al.
Transpl Int. 2023 Jul 25;36:11321 doi: 10.3389/ti.2023.11321.

Solid phase immunoassays improved the detection and determination of the antigen-specificity of donor-specific antibodies (DSA) to human leukocyte antigens (HLA). The widespread use of SPI in kidney transplantation also introduced new clinical dilemmas, such as whether patients should be monitored for DSA pre- or post-transplantation. Pretransplant screening through SPI has become standard practice and DSA are readily determined in case of suspected rejection. However, DSA monitoring in recipients with stable graft function has not been universally established as standard of care. This may be related to uncertainty regarding the clinical utility of DSA monitoring as a screening tool. This consensus report aims to appraise the clinical utility of DSA monitoring in recipients without overt signs of graft dysfunction, using the Wilson & Junger criteria for assessing the validity of a screening practice. To assess the evidence on DSA monitoring, the European Society for Organ Transplantation (ESOT) convened a dedicated workgroup, comprised of experts in transplantation nephrology and immunology, to review relevant literature. Guidelines and statements were developed during a consensus conference by Delphi methodology that took place in person in November 2022 in Prague. The findings and recommendations of the workgroup on subclinical DSA monitoring are presented in this article.