AIM:This study aimed to characterise hand tremor and examine its relationship with tacrolimus administration time and systemic exposure in adult kidney transplant recipients early post-transplantation. METHODS:Quantitative and qualitative data on hand tremor were collected from patients receiving immediate-release tacrolimus, approximately 1 month post-transplantation. Smartphone accelerometry was used to objectively assess tremor pre- and 2 h post-tacrolimus administration and values were compared using a Wilcoxon signed-rank test. A Welch's analysis of variance (ANOVA) was used to determine if tacrolimus trough concentration (C0), 2 h post-dose concentration (C2) and the ratio of C2/C0 were significantly different between patients reporting no, mild or moderate/severe tremor. RESULTS:One hundred and seven patients enrolled in the study. Eighty percent of patients reported hand tremor, often during voluntary hand movement. Thirty-eight percent said it interfered with daily activities, impeding their ability to perform basic daily tasks required for eating, drinking, accessing medicines and working. Hand tremor was not more severe at 2 h post-tacrolimus intake. Tacrolimus exposure was not associated with patient-reported tremor severity. Significantly greater amplitude and power in hand movement were detectable by smartphone accelerometry in patients reporting hand tremor. CONCLUSION:Hand tremor is highly prevalent early post-transplantation and has a major impact on patient functionality and quality of life. Further research is needed to develop novel tacrolimus exposure estimates that better correlate with tremor, and to identify improved ways to clinically assess, manage and mitigate the impact of hand tremor following transplantation. Smartphone accelerometry may be a useful tool in assessing tremor in future studies.

Background:BK polyomavirus (BKPyV) is a common opportunistic infection in kidney transplant recipients, typically reactivating in the context of immunosuppression. Although asymptomatic in immunocompetent individuals, reactivation in transplant recipients can cause BKPyV-associated nephropathy (BKPyVAN), a leading cause of graft dysfunction and loss. BKPyV viremia affects approximately 10%-15% of transplant recipients, and once BKPyVAN is established, the risk of graft failure can exceed 50%. The current standard of care involves immunosuppression reduction to restore virus-specific immunity, but this approach increases the risk of acute and chronic rejection. Intravenous immunoglobulin (IVIg), which contains antiviral and immunomodulatory antibodies, has been proposed as an adjunctive therapy, although evidence supporting its efficacy remains limited to small observational studies. Methods:The BEAT-BK trial is a multicenter, adaptive, randomized controlled trial comparing standard immunosuppression reduction with or without IVIg in kidney and simultaneous pancreas-kidney transplant recipients with BKPyV viremia or biopsy-confirmed BKPyVAN. The trial will enroll participants aged 2 y and older, randomizing them 1:1 to receive standard care alone or in combination with a total IVIg dose of 2 g/kg for 8 wk. An adaptive Bayesian design will permit interim analyses with the potential for early trial success or futility. Results:The primary endpoint is a composite ordinal outcome at 12 wk, incorporating death, graft loss, estimated glomerular filtration rate decline, acute rejection, viral load, and degree of immunosuppression reduction. Secondary outcomes include viral clearance, development of BKPyVAN and donor-specific antibodies, infections, malignancy, quality of life, and cost-effectiveness. Conclusions:This trial will provide the first high-quality evidence on the role of IVIg in BKPyV management and inform clinical decision-making in posttransplant care.

BACKGROUND:After kidney transplantation, therapeutic drug monitoring (TDM) of tacrolimus (Tac) relies mainly on the predose concentration (C0). However, C0 has limited ability to accurately reflect systemic Tac exposure. The area under the concentration-time curve (AUC) provides a more comprehensive measure of total systemic exposure and can be estimated using a limited sampling strategy (LSS). This review aimed to identify effective LSSs for predicting Tac AUC from 0 to 12 hours (AUC0-12) using 1, 2, or 3 blood samples collected between predose and 6 hours following administration of immediate-release Tac. METHODS:A literature search was conducted to identify studies reporting LSSs as predictors of Tac AUC0-12 in adult kidney transplant recipients. In the articles selected for review, the predictive performance of the strategies was evaluated based on the correlation between the predicted and the full reference AUC, as well as the associated bias and precision. Findings were synthesized using a narrative approach. RESULTS:Nineteen studies evaluating LSSs for predicting Tac AUC0-12, involving a total of approximately 600 patients, were reviewed. Compared with C0, most single concentrations measured within 6 hours of administration demonstrated a stronger correlation with Tac AUC0-12. Most 2- or 3-concentration time-point strategies could predict Tac AUC0-12 with percentage prediction error and absolute percentage prediction error of less than 10%. Correlations of 0.99 were achieved with some strategies. CONCLUSIONS:LSSs using as few as 2 or 3 concentrations obtained between predose and 6 hours after administration may estimate Tac AUC with strong predictive performance. The evidence supports the incorporation of intermittent AUC-based monitoring into TDM protocols as a complement to routine C0 measurement.

BACKGROUND:Immunosuppressant usage in kidney transplant recipients is commonly associated with toxicity which can manifest in a variety of adverse effects. This study aimed to compare the nature and frequency of patient-reported symptoms before and after kidney transplantation. METHODS:A single-center study was conducted involving adult kidney transplant recipients at 3 to 11 weeks post-transplantation. Patients completed a questionnaire pertaining to the prevalence of symptoms experienced a few months before and since transplantation. A paired Student's t-test and Wilcoxon signed-rank tests were used to identify changes in the number and frequency of symptoms, respectively, with a p-value <.05 considered statistically significant. RESULTS:Eighty patients completed this non-interventional study. While a similar number of symptoms (mean ± standard deviation) were experienced before and after transplantation (9.9 ± 4.8 and 9.0 ± 4.7, respectively; p = .098) there was a shift in the frequency of symptoms. Since transplantation, there was an improvement (reduced frequency) in itch (p ≤ .001), tiredness/fatigue (p = .045), nausea (p ≤ .001), headache/migraine (p ≤ .001), fidgetiness/restlessness (p = .018) and mind going blank (p = .022). However, hand tremor (p ≤.001), tremor elsewhere (p ≤.001), waking at night (p ≤.001), and dysesthesia (thermodysregulation and paresthesia) (p = .008) worsened (increased frequency), as reported by 75%, 26%, 45%, and 38% of patients, respectively. CONCLUSION:Many patients experience tremor and dysesthesia as new symptoms or report them more frequently early after transplantation. Further research into understanding and managing these toxicities over this period is warranted.

BACKGROUND:Therapeutic monitoring is routinely performed to ensure tacrolimus whole-blood concentrations fall within a predefined target. Despite this, patients still experience inefficacy and toxicity that could be related to variability in free (unbound) tacrolimus exposure. Therefore, the aim of this study was to compare tacrolimus-free plasma (Cu), total plasma (Cp), and whole-blood (Cwb) concentrations in adult kidney transplant recipients and to characterize tacrolimus disposition across different matrices. METHODS:Twelve-hour concentration-time profiling was performed in 15 recipients, allowing simultaneous measurement of Cu, Cp, and Cwb. Pharmacokinetic parameters were estimated using noncompartmental analysis. The relationship between Cwb and Cp were examined using a capacity-limited binding model, incorporating the hematocrit fraction (fHCT) to estimate maximum binding concentration (Bmax) and dissociation constant (Kd). The relationship between Cp and Cu was evaluated using a linear binding model to estimate the nonspecific binding parameter (Nplasma). Nonlinear regression analysis was used to obtain estimates of Bmax, Kd, and Nplasma. RESULTS:A total of 195 paired Cwb, Cp, and Cu values were collected. The median ratios of Cwb:Cp, Cp:Cu, and Cwb:Cu were 9:1, 20:1, and 138:1, respectively. Variability in free plasma exposure was large; free trough values ranged from 8 to 51 ng/L and free area-under-the-concentration-time-curve values ranged from 424 to 7160 ng·h/L. Median (range) estimates of Bmax, Kd, and Nplasma were 90.4 µg/L (22.4-752.5 µg/L), 2.36 µg/L (0-69.2 µg/L), and 0.05 (0.035-0.085), respectively. The interindividual variability (CV%) in binding parameters was considerable (Bmax 117.2%; Nplasma 32.5%). CONCLUSIONS:Large variability was observed in tacrolimus-free plasma exposure and binding parameters. Future research to characterize the relationship between tacrolimus Cu and patient outcomes may be of benefit.

Background. Recurrent glomerulonephritis (GN) is an important cause of allograft loss after transplantation when GN is the primary cause of kidney failure. Retransplantation after allograft loss from recurrent disease requires careful consideration. We aimed to determine the probability of relisting and the risk of allograft loss after retransplantation in recipients with prior allograft loss from recurrent GN. Methods. Using data from the Australia and New Zealand Dialysis and Transplant Registry and multivariable Cox modeling, we compared the probability of waitlisting and allograft loss after second transplantation between those with and without prior allograft loss from recurrent disease. Results. Of 3276 patients who received a second kidney transplant, 179 (5%) lost their first allograft from recurrent GN. Between 2006 and 2021, 1524 patients with failed first allografts (6% with recurrent GN, 45% with primary GN but no disease recurrence) were relisted for transplantation. Compared with patients without primary GN, the adjusted hazard ratios (95% confidence intervals) for relisting in patients with primary GN, with and without disease recurrence, were 1.09 (0.88-1.34) and 1.16 (1.05-1.29), respectively. The respective adjusted hazard ratios for allograft loss after repeat transplantation were 0.77 (0.59-1) and 1.02 (0.9-1.16). Of the 81 patients who received a second allograft after losing their first allograft to GN recurrence, 18 patients (22%) also lost their second allograft because of recurrent GN. Conclusions. Patients with prior allograft loss from GN recurrence were not disadvantaged, with comparable waitlist potential and allograft outcome after repeat transplantation. However, >20% of those with prior allograft loss from disease recurrence also lost their second allografts from recurrent disease.

The pharmacokinetics of immunosuppressant drugs may change with advancing age, potentially affecting patient outcomes. To characterise the effects of age on the pharmacokinetic and exposure parameters of tacrolimus, mycophenolate, and prednisolone. Pharmacokinetic profiling, involving whole blood tacrolimus, total and free plasma mycophenolic acid (MPA), total plasma mycophenolic acid glucuronide (MPAG), and total and free plasma prednisolone, was performed in an older and younger adult cohort. Thirteen samples were drawn on a single occasion, pre-oral dose and then at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, and 12 h post-dose. Non-compartmental analysis was conducted using the PKNCA package, and pharmacokinetic and exposure parameters were compared between age groups using a Mann–Whitney test. A regression analysis was conducted for free MPA and MPAG using significant variables of interest. This exploratory study included 21 older and 18 younger adults. Dose-adjusted tacrolimus, total MPA and free prednisolone pharmacokinetic parameters were not different between age groups; however, for free MPA and MPAG, older recipients had significantly greater minimum and maximum concentrations, trough concentrations, and half-life. There was a two-fold increase in free MPA exposure in older adults (median dose-adjusted AUC0–12: 1284 vs. 684 μg h/L, p < 0.0001); MPAG exposure similarly increased. Age was significantly associated with free MPA and MPAG exposure, and free MPA exposure was associated with haematocrit (p < 0.05). Differences in MPA were found with advancing age and may be due to altered kidney function, haematocrit, plasma protein binding and/or drug absorption. Future research should explore specific covariate contributions to this further.

Keratinocyte carcinomas such as basal cell carcinomas and squamous cell carcinomas are a major burden affecting morbidity and mortality in solid organ transplant recipients (SOTRs). Best treatment includes frequent skin checks for early detection and surgery for high incidence of skin cancers. Sirolimus is an immunosuppressive drug which may reduce the burden of skin cancer but may be poorly tolerated when given orally. Topical sirolimus has been proven effective at reducing the burden of skin cancers in animal models, and its safety has long been established in children with tuberous sclerosis. A recent 12-week phase II trial of topical sirolimus suggested it was safe and effective at reducing the early signs of skin cancer in the absence of major side effects. The aim of the SiroSkin trial is to determine whether topical sirolimus can fill a major gap in current therapies by reducing the onset and number of new skin cancers thus reducing burden of disease and cost-effectiveness. Protocol for a multi-centred phase III, participant- and clinician assessor-blinded, placebo-controlled randomised trial in SOTRs. A minimum 146 participants randomised 1:1 will be treated with 1

BACKGROUND:The numbers of Māori and Pasifika peoples with kidney failure living in Australia are rising. However, data describing outcomes of those proceeding to transplantation are limited. This study describes clinical outcomes of Māori and Pasifika peoples who received a kidney transplant in Australia. AIMS:This study describes clinical outcomes of Maori and Pasifika peoples who received a kidney transplant in Australia. METHODS:A retrospective review was conducted of kidney transplant recipients aged ≥18 years receiving their first graft between 1 January 2002 and 31 December 2021, as recorded in the Australia and New Zealand Dialysis and Transplant Registry. The primary outcome was death-censored graft survival. Secondary outcomes included delayed graft function (DGF), rejection and patient survival. RESULTS:Of 12 543 transplant recipients, mean age was 50 years and the majority identified as male sex. A total of 89 patients identified as Māori and 313 as Pasifika. Māori and Pasifika patients were more likely to have diabetic kidney disease or obesity at time of transplantation (body mass index > 30 kg/m2) and be current or former smokers compared to other ethnicities. Times to graft loss were shorter for Māori (adjusted hazard ratio (HR) 2.06, 95% confidence interval (CI) 1.36-3.11) and Pasifika (adjusted HR 1.78, 95% CI 1.39-2.029, P < 0.001) people compared to other ethnicities. The incidences of DGF were significantly higher in the Māori (30%) and Pasifika groups (28%) compared with 22% for other ethnicities (P < 0.005). Overall patient survival was comparable (Māori HR 0.93, 95% CI 0.57-1.49, P = 0.75; Pasifika HR 1.18, Cl 0.88-1.60, P = 0.26). CONCLUSIONS:Times to graft loss for Māori and Pasifika kidney transplant patients were shorter than for other ethnicities.

Solid organ transplant recipients are at an increased risk of developing skin cancers due to chronic immunosuppression, particularly with calcineurin inhibitors. Tacrolimus is the most prescribed calcineurin inhibitor in this patient cohort, and understanding tacrolimus concentrations in the skin will facilitate the development of anti-cancer preventive and therapeutic strategies. Here, we show that in mice, tacrolimus blood levels peaked rapidly ∼1 h post last oral dose while skin levels rose more slowly and remained high for at least 6 h. Subsequently, tacrolimus skin and blood concentrations were assessed in 15 kidney transplant recipients. The mean age was 61 years, the average time post-transplant was 7 years (range 0–21 years) and 87% were male. The average skin sampling time post tacrolimus dosing was 6 h 32 min. Skin tacrolimus concentrations ranged from 7.1 ng/g to 71.2 ng/g and correlated with blood concentrations (r = 0.6). Mouse and human mean skin concentrations were in a similar range. Our data suggests that tacrolimus measurements in the blood may be used to approximate tacrolimus concentrations in the skin of kidney transplant recipients, and further exploited for the delivery of anti-cancer therapies designed to antagonize the immunosuppressive effects of tacrolimus in the skin.

Clinical TransplantationEarly View e15175 LETTER TO THE EDITOR Characteristics of the gastrointestinal microbiota following prebiotic supplementation in acute kidney transplant recipients: Results from a randomised controlled trial Samuel Chan, Corresponding Author Samuel Chan [email protected] orcid.org/0000-0002-8321-4447 Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Correspondence Samuel Chan, Australasian Kidney Trials Netowrk and the Medical School, The University of Queensland, Brisbane, Queensland, Australia. Email: [email protected]Search for more papers by this authorDavid LA Wood, David LA Wood Microbia Life Sciences, Brisbane, Queensland, AustraliaSearch for more papers by this authorCarmel M. Hawley, Carmel M. Hawley Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia Translational Research Institute, Brisbane, Queensland, AustraliaSearch for more papers by this authorKatrina L. Campbell, Katrina L. Campbell Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorScott B. Campbell, Scott B. Campbell Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorChristopher Cao, Christopher Cao Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorRoss S. Francis, Ross S. Francis Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorRachael Hale, Rachael Hale Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorNicole M. Isbel, Nicole M. Isbel Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia Translational Research Institute, Brisbane, Queensland, AustraliaSearch for more papers by this authorElaine M. Pascoe, Elaine M. Pascoe Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorDavid W. Johnson, David W. Johnson Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia Translational Research Institute, Brisbane, Queensland, AustraliaSearch for more papers by this authorMark Morrison, Mark Morrison Faculty of Medicine, University of Queensland Frazer Institute, Translational Research Institute, Woolloongabba, Queensland, AustraliaSearch for more papers by this author Samuel Chan, Corresponding Author Samuel Chan [email protected] orcid.org/0000-0002-8321-4447 Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Correspondence Samuel Chan, Australasian Kidney Trials Netowrk and the Medical School, The University of Queensland, Brisbane, Queensland, Australia. Email: [email protected]Search for more papers by this authorDavid LA Wood, David LA Wood Microbia Life Sciences, Brisbane, Queensland, AustraliaSearch for more papers by this authorCarmel M. Hawley, Carmel M. Hawley Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia Translational Research Institute, Brisbane, Queensland, AustraliaSearch for more papers by this authorKatrina L. Campbell, Katrina L. Campbell Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorScott B. Campbell, Scott B. Campbell Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorChristopher Cao, Christopher Cao Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorRoss S. Francis, Ross S. Francis Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorRachael Hale, Rachael Hale Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorNicole M. Isbel, Nicole M. Isbel Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia Translational Research Institute, Brisbane, Queensland, AustraliaSearch for more papers by this authorElaine M. Pascoe, Elaine M. Pascoe Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaSearch for more papers by this authorDavid W. Johnson, David W. Johnson Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia Translational Research Institute, Brisbane, Queensland, AustraliaSearch for more papers by this authorMark Morrison, Mark Morrison Faculty of Medicine, University of Queensland Frazer Institute, Translational Research Institute, Woolloongabba, Queensland, AustraliaSearch for more papers by this author First published: 30 October 2023 https://doi.org/10.1111/ctr.15175Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES 1Markowiak P, Śliżewska K. Effects of probiotics, prebiotics, and synbiotics on human health. Nutrients. 2017; 9(9): 1021. 10.3390/nu9091021 PubMedWeb of Science®Google Scholar 2Zhang Y, Chen J, Wu J, Chalson H, Merigan L, Mitchell A. Probiotic use in preventing postoperative infection in liver transplant patients. Hepatobiliary Surg Nutr. 2013; 2(3): 142-147. PubMedGoogle Scholar 3Chan S, Hawley CM, Pascoe EM, et al. PREBIOTIC: a study protocol of a randomised controlled trial to assess prebiotic supplementation in kidney transplant recipients for preventing infections and gastrointestinal upset—a feasibility study. Pilot Feasibility Stud. 2023; 9: 11. 10.1186/s40814-023-01236-y PubMedGoogle Scholar 4Chan S, Hawley CM, Pascoe EM, et al. Prebiotic supplementation in kidney transplant recipients for preventing infections and gastrointestinal upset: a randomized controlled feasibility study. 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Introduction: BK polyomavirus-associated nephropathy (BKPyVAN) is associated with graft dysfunction and loss; however, knowledge of immunosuppression reduction strategies and long-term graft, and pa-tient outcomes across the disease spectrum is lacking. Methods: This cohort study included 14,697 kidney transplant recipients in Australia and New Zealand (2005-2019), followed for 91,306 person years. Results: BKPyVAN occurred in 460 recipients (3%) at a median posttransplant time of 4.8 months (inter -quartile range, 3.1-10.8). Graft loss (35% vs. 21%, P < 0.001), rejection (42% vs. 25%, P < 0.001), and death (18% vs. 13%, P = 0.002) were more common in the BKPyVAN group. The most frequent changes in immunosuppression after BKPyVAN were reduction (#50%) in tacrolimus (172, 51%) and mycophenolate doses (134, 40%), followed by the conversion of mycophenolate to leflunomide (62, 19%) and tacrolimus to ciclosporin (20, 6%). Factors associated with the development of BKPyVAN included (adjusted hazard ratio [HR]; 95% confidence interval) male sex (1.66; 1.34-2.05), recipient age (>= 70 vs. <20 [2.46; 1.30-4.65]), recipient blood group (A vs. B [2.00; 1.19-3.34]), donor age (>= 70 vs. <20 [2.99; 1.71-5.22]), earlier era (1.74; 1.35-2.25), donor/recipient ethnic mismatch (1.52; 1.23-1.87), tacrolimus use (1.46; 1.11-1.91), and transplantation at a lower-volume transplant center (1.61; 1.24-2.09). The development of BKPyVAN was associated with an increased risk of all-cause (1.75; 1.46-2.09) and death-censored graft loss (2.49; 1.99-3.11), but not mortality (1.15; 0.91-1.45). Conclusions: BKPyVAN is associated with an increased risk of all-cause and death-censored graft loss, but not death. Interventional trials are urgently needed to evaluate the efficacy of immunosuppression reduction and novel strategies to minimize the adverse outcomes associated with BKPyVAN.

Purpose: Tremor, headache and insomnia have been linked to the immunosuppressant, tacrolimus. The aim of this systematic review was to determine if there is a correlation between tacrolimus exposure and new-onset tremor, headache and insomnia experienced by adult kidney transplant recipients.Methods: PubMed, Embase, Cochrane Library and CINAHL databases were searched up to 11 April 2023 for published studies which reported on tacrolimus exposure in adult kidney transplant recipients, alongside in-formation on treatment-emergent neurologic manifestations, including tremor, headache and insomnia. Review articles, case studies, conference abstracts and articles not published in English in peer-reviewed journals were excluded. The Physiotherapy Evidence Database and Newcastle-Ottawa Quality Assessment Scales were used to assess risk of bias. Extracted data was analysed via a narrative synthesis.Results: Eighteen studies involving 4030 patients in total were included in the final analysis. These comprised five randomised control trials and thirteen observational studies. Studies failed to find significant association between tacrolimus trough concentrations in whole blood and the incidence of neurologic side effects such as tremor, headache and insomnia; however, in one study the incidence of toxicity requiring a dose reduction increased with increasing, supratherapeutic targeted levels. Females, especially Black females, and older age were positively associated with the prevalence of neurologic adverse effects. Results were conflicting regarding whether extended-release formulations were associated with fewer neurologic complications than immediate-release formulations.Conclusion: The varied study designs and criteria for reporting tremor, headache and insomnia impacted on the quality of the data for exploring the relationship between tacrolimus exposure and the onset of neurologic manifestations experienced after kidney transplantation. Studies that examine defined neurologic complications as the primary outcome, and that consider novel markers of tacrolimus exposure while assessing the potential contribution of multiple covariate factors, are required.

Background Modulating the microbiota in the large intestine of kidney transplant recipients through prebiotic supplementation may prevent infectious complications from occurring. To date, there have been no interventional trials which have investigated this novel treatment in kidney transplantation. The aim of PREBIOTIC is to assess the feasibility of performing a randomised controlled trial of prebiotics in reducing infections and gastrointestinal symptoms in kidney transplant recipients. Methods Sixty kidney transplant patients will be recruited to a double-blind, placebo-controlled, randomised feasibility trial. Patients will be provided with prebiotic therapy or placebo for 4 to 6 weeks. Outcomes will include recruitment, adherence, tolerance, retention, laboratory parameters (including serum indoxyl sulphate, ρ-cresyl sulphate and stool collection), patients’ self-assessed quality of life, gastrointestinal symptoms and clinical outcomes. Discussion This trial will assess the feasibility of prebiotic supplementation in kidney transplant recipients. Prebiotics not only may alter the gut microbiota and their inherent metabolism and production of uraemic toxins but also may prevent infections from occurring in kidney transplant recipients. Trial registration Australian New Zealand Clinical Trials Registry number ACTRN12618001057279p. The date of registration was 25th June 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375370&isReview=true .

Background.Kidney transplants from small pediatric donors are considered marginal and often transplanted as dual grafts. This study aimed to compare long-term outcomes between recipients of single kidney transplants (SKTs) and dual en bloc kidney transplants (EBKTs) from small pediatric donors. Methods.Data were obtained from the Australia and New Zealand Dialysis and Transplant Registry. All adult recipients of kidney transplants from donors aged & LE;5 y were identified. The primary outcome of interest was death-censored graft survival by donor type. The secondary outcomes were early graft loss, delayed graft function, serum creatinine posttransplantation, acute rejection, and patient survival. Results.There were 183 adult recipients of kidney transplants from donors aged & LE;5 y old. Of these, 60 patients had EBKT grafts, 79 patients had SKT grafts, and 44 patients had grafts of unknown type. Compared with SKT donors, EBKT donors had lower mean age (P < 0.001) and body weight (P < 0.001). There was no significant difference in death-censored graft survival between the groups, with median survival of 23.8 y (interquartile range 21.2-25) in the EBKT cohort and 21.8 y (11.6-26.8) in the SKT cohort (hazard ratio 1.3; 95% confidence interval, 0.59-2.64; P = 0.56). EBKT grafts had lower acute rejection rates than SKT grafts (P = 0.014). There was no significant difference observed between groups with respect to early graft loss, delayed graft function, posttransplantation serum creatinine posttransplantation, or patient survival. Conclusions.EBKT and SKTs from small pediatric donors are associated with excellent long-term graft survival rates.

Importance The extent to which major high-risk features of squamous cell carcinomas (SCCs) in organ transplant recipients (OTRs) differ from SCCs in the general population is not known.Objective To quantify the relative frequency of perineural invasion, invasion below the dermis, lack of cellular differentiation, and tumor diameter greater than 20 mm in SCCs in OTRs and the general population, by anatomic site.Design, Setting, and Participants This dual-cohort study in Queensland, Australia, included a cohort of OTRs at high risk of skin cancer ascertained from 2012 to 2015 (Skin Tumours in Allograft Recipients [STAR] study) and a population-based cohort ascertained from 2011 (QSkin Sun and Health Study). The STAR study comprised population-based lung transplant recipients and kidney and liver transplant recipients at high risk of skin cancer recruited from tertiary centers and diagnosed with histopathologically confirmed SCC from 2012 to 2015. The QSkin participants were recruited from Queensland's general adult population, and primary SCCs diagnosed from 2012 to 2015 were ascertained through Medicare (national health insurance scheme) and linked with histopathology records. Data analysis was performed from July 2022 to April 2023.Main Outcomes and Measures Prevalence ratio (PR) of head/neck location, perineural invasion, tumor invasion to/beyond subcutaneous fat, poor cellular differentiation, and tumor diameter greater than 20 mm among SCCs in OTRs vs the general population.Results There were 741 SCCs excised from 191 OTRs (median [IQR] age, 62.7 [56.7-67.1] years; 149 [78.0%] male) and 2558 SCCs from 1507 persons in the general population (median [IQR] age, 63.7 [58.0-68.8] years; 955 [63.4%] male). The SCCs developed most frequently on the head/neck in OTRs (285, 38.6%), but on arms/hands in the general population (896, 35.2%) (P < .001). After adjusting for age and sex, perineural invasion was more than twice as common in OTRs as in population cases (PR, 2.37; 95% CI, 1.70-3.30), as was invasion to/beyond subcutaneous fat (PR, 2.37; 95% CI, 1.78-3.14). Poorly vs well-differentiated SCCs were more than 3-fold more common in OTRs (PR, 3.45; 95% CI, 2.53-4.71), and prevalence of tumors greater than 20 mm vs 20 mm or smaller was moderately higher in OTRs (PR, 1.52; 95% CI, 1.08-2.12).Conclusions and Relevance In this dual-cohort study, SCCs in OTRs had significantly worse prognostic features than SCCs in the general population, reinforcing the necessity of early diagnosis and definitive management of SCCs in OTRs.

Organ transplant recipients (OTRs) are at greater risk of basal cell carcinomas (BCCs) than non-OTRs, but histopathologic differences between BCCs in OTRs and the general population are largely unknown. We compared clinicopathologic features of BCCs in OTRs vs the general population in Queensland, Australia. Details of BCC tumors (site, size, level of invasion, subtype, biopsy procedure) were collected from histopathology reports in two prospective skin cancer studies, one in OTRs and one general-population-based. We used log-binomial regression models to estimate age- and sex-adjusted prevalence ratios (PR) with 95% confidence intervals (CIs) for BCC features. Overall, there were 702 BCCs in 200 OTRs and 1725 BCCs in 804 population cases. Of these, 327 tumors in 128 OTRs were higher risk BCCs (any head and neck BCC; ≥ 2 cm on trunk/extremities), more per person than 703 higher risk BCCs in 457 cases in the general population (chi-square p = 0.008). Among head/neck BCCs, OTRs were more likely than general population cases to have BCCs on scalp/ear than on face/lip/neck (PR = 1.5, 95%CI 1.2–1.8). Although aggressive subtypes were less common among higher risk BCCs in OTRs, BCCs invading beyond the dermis were almost twice as prevalent in OTRs (PR = 1.8, 95% CI 1.3–2.6) than the general population.

The inclusion of blood group- and human leukocyte antigen-compatible donor and recipient pairs (CPs) in kidney paired donation (KPD) programs is a novel strategy to increase living donor (LD) transplantation. Transplantation from a donor with a better Living Donor Kidney Profile Index (LKDPI) may encourage CP participation in KPD programs. We undertook parallel analyses using data from the Scientific Registry of Transplant Recipients and the Australia and New Zealand Dialysis and Transplant Registry to determine whether the LKDPI discriminates death-censored graft survival (DCGS) between LDs. Discrimination was assessed by the following: (1) the change in the Harrell C statistic with the sequential addition of variables in the LKDPI equation to reference models that included only recipient factors and (2) whether the LKDPI discriminated DCGS among pairs of prognosis-matched LD recipients. The addition of the LKDPI to reference models based on recipient variables increased the C statistic by only 0.02. Among prognosis-matched pairs, the C statistic in Cox models to determine the association of the LKDPI with DCGS was no better than chance alone (0.51 in the Scientific Registry of Transplant Recipient and 0.54 in the Australia and New Zealand Dialysis and Transplant Registry cohorts). We conclude that the LKDPI does not discriminate DCGS and should not be used to promote CP participation in KPD programs.

BACKGROUND:Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and associated mortality and morbidity in solid organ transplant recipients. Here, we aimed to identify a compound capable of re-establishing antitumor T-cell control in the skin despite the presence of tacrolimus.METHODS:In this study, we performed time-resolved fluorescence resonance energy transfer to identify molecules capable of antagonizing the interaction between tacrolimus and FKBP12. The capacity of these molecules to rescue mouse and human T-cell function in the presence of tacrolimus was determined in vitro, and the antitumor effect of the lead compound, Q-2361, was assessed in "regressor" models of skin cancer in immunosuppressed mice. Systemic CD8 T-cell depletion and analyses of intratumoral T-cell activation markers and effector molecule production were performed to determine the mechanism of tumor rejection. Pharmacokinetic studies of topically applied Q-2361 were performed to assess skin and systemic drug exposure.RESULTS:Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and reversed the inhibition of the nuclear factor of activated T cells activation by tacrolimus following T-cell receptor engagement in human Jurkat cells. Q-2361 rescued T-cell function in the presence of tacrolimus, rapamycin, and everolimus. Intratumoral injection of Q-2361-induced tumor regression in mice systemically immune suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted T-cell activation, proliferation, and effector function within tumors. When CD8 T cells were depleted, Q-2361 could not induce tumor regression. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in the skin with negligible drug in the blood.CONCLUSIONS:Our findings demonstrate that the local application of Q-2361 permits T-cells to become activated driving tumor rejection in the presence of tacrolimus. The data presented here suggests that topically applied Q-2361 has great potential for the reactivation of T-cells in the skin but not systemically, and therefore represents a promising strategy to prevent or treat skin malignancies in immunosuppressed organ transplant recipients.