Protocol For Kidney Transplantation Research Articles

Enhanced recovery after surgery recommendations for renal transplantation: guidelines.

Enhanced Recovery After Surgery (ERAS) protocols are now widely practiced in major surgery, improving postsurgical outcomes. Uptake of these programmes have been slow in kidney transplantation due to challenges in evaluating their safety and efficacy in this high-risk cohort. To date, there are no unified guidance and protocols specific to ERAS in kidney transplantation surgery. This paper aims to summarise current evidence in the literature and develop ERAS protocol recommendations for kidney transplantation recipients. PubMed, Cochrane, Embase and Medline databases were screened for studies relevant to ERAS protocols in kidney transplantation, up to August 2021. A secondary search was repeated for each ERAS recommendation to explore the specific evidence base available for each section of the protocol. Randomised controlled trials, case-control and cohort studies were included. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework was used to evaluate the quality of evidence available and recommendations. We identified six eligible studies with a total of 1225 participants. All studies found a reduction in length of hospital stay without affecting readmission rates. The evidence behind specific pre-operative, intra-operative and post-operative interventions included in current ERAS protocols are reviewed and discussed. Compared to other surgical specialties, the evidence base for ERAS in kidney transplantation remains lacking, with further room for research and development. However, significant improvements to patient outcomes are already possible with application of the currently available evidence. This has shown that ERAS in kidney transplantation surgery is safe and feasible, with improved postoperative outcomes.

Patient and Graft Survival Outcomes During 2 Eras of Immunosuppression Protocols in Kidney Transplantation: Indiana University Retrospective Cohort Experience

Since 1964 when Indiana University performed its first kidney transplant, immunosuppression protocol was steroid-based until 2004 when steroid-free immunosuppression protocol was adopted. We describe clinical outcomes on our patients administered early steroid withdrawal (ESW) protocol (5 days) compared with our historical cohort (HC), who were on chronic steroid-based immunosuppression. We performed a retrospective study evaluating kidney transplant recipients between 1993 and 2003 (HC, n=1689) and between 2005 and 2016 (ESW cohort, n=2097) at the Indiana University program, with a median follow-up of 10.5 years and 6.1 years, respectively. Primary outcomes were patient and death-censored graft survival at 1, 3, and 5 years in both study cohorts. Secondary outcomes were 1-year rates of biopsy-proven acute rejection; graft function at 1, 3, and 5 years; and risk of post-transplant infection (BK virus and cytomegalovirus) in the ESW cohort. Cox proportional model and Kaplan-Meier estimates were used to estimate survival probabilities. Fisher exact tests were used to compare episodes of acute rejection in the ESW cohort. No difference was observed in patient survival between the ESW and HC cohorts (P=.13). Compared with the ESW cohort, death-censored graft survival was significantly worse in the HC (5 year: 86.4% vs 90.6%, log-rank P < .001). One-year acute rejection reported in the ESW cohort alone was 15.7% and significantly worse in Black patients and younger patients (P < .05). In this sizeable single-center cohort study with significant ethnic diversity, ESW is a viable alternative to steroid-based immunosuppression protocol in kidney transplant recipients.

UNOS/OPTN Data-guided Assessment of Focal Segmental Glomerulosclerosis After Kidney Transplantation and Evaluation of Immunosuppressive Protocols in a Steroid-free Center.

Background.Focal segmental glomerulosclerosis (FSGS) is a common recurrent glomerulopathy associated with graft loss and patient survival after kidney transplantation (KT). However, its natural history, clinical predictors, and treatment response are still poorly understood. Steroid withdrawal regimens in KT have been associated with improvements in cardiovascular risk and patient outcomes. The Scripps Center for Organ Transplantation (SCOT) uses a rapid low-dose steroid withdrawal immunosuppression (IS) protocol for KT maintenance.Methods.We assessed the impact of our protocol on FSGS disease recurrence over a 10-y period to reassess our steroid and IS protocols and to evaluate if our patient outcomes diverge from published data. We compared 4 groups: steroids always, steroid free, steroid switch on, and steroid weaned off. We used IS and induction-matched retrospective data from United Network for Organ Sharing (UNOS) to investigate patient and graft survival for FSGS at SCOT.Results.Our analysis results differ from earlier studies showing that FSGS was associated with a higher risk of graft loss, perhaps because of selection of a UNOS data set filtered to match the SCOT IS protocol for making direct comparisons. Overall outcomes of graft failure and recipient death did not differ between SCOT patients and steroid-free transplant patient data from the UNOS data for FSGS. SCOT recurrence rate for FSGS was 7.5%, which was lower than in most published single-center studies.Conclusions.Based on our results, we believe that it is safe to continue the steroid avoidance protocols at SCOT and the steroid-free protocol may not be detrimental when the adverse effects and toxicities associated with steroid use are considered.

Critical Appraisal of International Clinical Practice Guidelines in Kidney Transplantation Using the Appraisal of Guidelines for Research and Education II Tool: A Systematic Review.

Although clinical practice guidelines (CPGs) are used for the development of local protocols in kidney transplantation (Ktx), the quality of their methodology is variable. This systematic review aimed to critically appraise international CPGs in all aspects of Ktx using the Appraisal of Guidelines for Research and Evaluation II tool. Clinical Practice Guidelines in Ktx and donation published between 2010 and 2017 were identified from MEDLINE, Embase, National Guideline Clearinghouse, National Health Service and National Institute for Health and Care Excellence Evidence Searches, and the websites of transplant societies. Using Appraisal of Guidelines for Research and Evaluation II, 3 appraisers assessed the quality of CPGs. Interrater reliability was measured using the intraclass correlation coefficient (ICC). Searches identified 3168 records, and 115 CPGs were included. The highest scoring Appraisal of Guidelines for Research and Evaluation II domain was "scope and purpose" (80%; range, 30%-100%), followed by "clarity of presentation" (77%; range, 43%-98%), "editorial independence" (52%; range, 0%-94%), "rigor of development" (47%; range 6%-97%) and "stakeholder involvement" (41%; range, 11%-85%). The poorest scoring domain was "applicability" (31%; range, 3%-74%). Most CPGs were recommended for future use either with (63%) or without (18%) modifications. A small number (14%) were not recommended for future use or reviewers (5%) did not agree on recommending the CPG. The overall mean CPG quality score was 4 of 7 (range, 2-7). The mean ICC of 0.74 indicated substantial agreement between reviewers. The quality of international CPGs in Ktx was variable, and most CPGs lacked key aspects of methodological robustness and transparency. Improvements in methodology, patient involvement, and strategies for implementation are required.

A Retrospective Study on Effectiveness and Safety of the Novel Once-Daily Melt-Dose Tacrolimus in a Spanish Cohort of Stable Kidney Transplant Recipients Converted from Once or Twice-Daily Formulations

The ReconocE study group. Background Tacrolimus (TAC) is currently included in most immunosuppressive protocols in kidney transplantation. Envarsus®, a new extended-release once-daily TAC formulation with an improved pharmacokinetic profile based on Melt-Dose technology, has become available recently. However, data on conversion between different TAC formulations obtained in routine clinical practice are lacking. The objective of this retrospective, non-interventional, multicenter study was to evaluate renal function, TAC trough levels (Cmin) and dosing, as well as safety parameters, following conversion from Prograf® or Advagraf® to Envarsus® in stable kidney transplant recipients. Patients and Methods The study was approved by the corresponding ethics committees. Stable adult kidney transplant recipients (>6 month after transplantation) with at least 3 months of post-conversion follow-up were included. Patients had been converted between December 2015 and October 2016. Demographic data, TAC Cmin, total daily dose (TDD), renal function (CKD-EPI) and biochemical parameters in the 3 months before conversion and 3 months after conversion were collected. The reference conversion ratio was 1:0.7, as recommended by Envarsus® SmPC. Results A total of 389 patients were included (62% males, mean age 56.6±13.6 years, 93.7% Caucasians). The mean time from transplant to conversion was 70.4 ± 63.1 months; the mean post-conversion follow-up was 8.4 months. 84.6% of the grafts were from deceased donors. Data from 365 patients were evaluated for effectiveness, and from 384 for safety analysis. There were no significant differences in TAC Cmin before and after conversion (7.4±2.5 ng/mL and 7.6±2.6 ng/mL respectively; p = 0.95). Mean TDD before and after the conversion was 4.3±3.3 mg and 3.1±2.3 mg respectively, a reduction of 28% (p<0.0001), reduction was larger in patients converted from Advagraf® (37%; n=197, p<0.0001). Melt-Dose technology enhanced TAC bioavailability by 34%. Mean eGFR (CPD-EPI) remained stable before and after conversion (52.3±21.3 and 51.5±21.6 ml/min/1,73m2, respectively; p=0.14). There were no significant differences in pre- and post-conversion laboratory parameters. None of the patients experienced treatment failure during the 3 month of follow-up. The mean number of post-conversion dose adjustments to maintain Cmin within target levels was 0.9±1.4. A total of 57 adverse reactions (AR), of them 4 serious were registered in 49 patients before conversion, and 11 AR (1 serious) in 10 patients after conversion. Neurotoxic side effects improved after conversion in 51.2% of patients. Conversion to Envarsus® was associated with a significant reduction in cost of TAC treatment. Conclusion In our real-life population, conversion to Envarsus® allowed for reducing TAC TDD by 28% while maintaining similar Cmin and renal function over 3 months after conversion. There were no episodes of graft rejection or new safety signals. In addition, the conversion was cost-effective.

Effect of tolerance versus chronic immunosuppression protocols on the quality of life of kidney transplant recipients.

Kidney transplant patients on tolerance protocols avoid the morbidity associated with the use of conventional chronic immunosuppressive regimens. However, the impact of tolerance versus conventional regimens on the quality of life (QOL) of kidney transplant patients is unknown. Five patients who achieved long-term immunosuppression-free renal allograft survival after combined kidney and bone marrow transplantation (tolerant group) were compared with thirty-two comparable kidney transplant recipients on conventional immunosuppression (conventional group). QOL was compared with 16 conventional recipients using the Kidney Disease Quality of Life Short Form 36 (KDQOL SF-36) and the Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD-59R). Patients in the tolerant group required significantly less treatment after transplant for hypertension and no medications for diabetes (P < 0.01). There was no incidence of diabetes, dyslipidemia, or malignancies in the tolerant group, while these were observed in 12.5%, 40.6%, and 11.8% of the conventional group, respectively. Tolerant patients experienced better overall health (P < 0.01) and scored higher on kidney transplant-targeted scales and healthy survey scales than patients in the conventional group according to the KDQOL SF-36 (P < 0.05). Tolerant patients were less likely to experience depression, dyspnea, excessive appetite/thirst, flatulence, hearing loss, itching, joint pain, lack of energy, muscle cramps, and lack of libido than conventional patients according to the MTSOSD-59R (P < 0.05). Kidney transplant recipients who achieved tolerance experience significantly fewer incidences of complications, improved QOL, and fewer comorbid symptoms compared with patients on conventional immunosuppression. These results support the expanded use of tolerance protocols in kidney transplantation.

Steroid and Calcineurin Inhibitor—Sparing Protocols in Kidney Transplantation

Recent improvements in kidney transplantation have been driven largely by lower acute rejection rates attributed to better immunosuppressive agents. In an effort to reduce the long-term toxicities of immunosuppressant drugs, corticosteroid- and calcineurin inhibitor (CNI)–sparing immunosuppression protocols have become increasingly popular in managing kidney transplant recipients. Nevertheless, these strategies may increase the risk of acute and chronic allograft injury (CAI) that may worsen the fate of transplant recipients. This article focuses on steroid and CNI sparing protocols to elucidate their safety and efficacy in patients receiving a kidney transplant. Steroid avoidance protocols are rapidly and increasingly being used. Studies have shown that corticosteroids are not essential to achieve excellent short- and intermediate-term results. However, the role of steroid withdrawal is only marginally beneficial and very often benefit overstated. CNI-sparing strategies have been used to help maintain the balance between allograft survival and nephrotoxicity. Trials evaluating CNI minimization have shown reduced incidence of CAI and preservation of allograft function. CNI withdrawal within 3 to 12 months after kidney transplantation improved graft function despite increased risk of acute rejection. This approach may be feasible with adequate exposure and proper usage of mammalian target of rapamacin inhibitors. Late withdrawal or conversion did not show a clear benefit. Timing and degree of renal dysfunction are key determining factors. With regards to CNI avoidance, earlier trials, such as the Symphony study, did not support the use of a CNI-free regimen of low-dose sirolimus as initial immunosuppression. However, recent studies using costimulatory blockade-based immusouppression showed that CNI avoidance is possible. The best maintenance immunosuppressive with CNI- or steroid-sparing is a work in progress and awaits longer term follow-up. The availability of newer biologics for costimulatory blockade and new immunosuppressive agents with novel mechanisms of action have the potential of using CNI- and steroid-sparing protocols to minimize the incidence of CAI and improve long-term outcomes in kidney transplant recipients.

Anaesthesiologic protocol for kidney transplantation in two patients with Fabry Disease: a case series

Fabry's Disease is a rare genetic syndrome, with a classic X-linked alpha -galactosidase A deficiency phenotype, responsible for glico-sphyngolypids metabolism impairment with clinical effects in several organs and functions. We describe the anaesthesiologic implications of two patients with Fabry disease who underwent a kidney transplantation from a deceased donor. We recommend careful preoperative evaluation, including cardiac sonography study and spirometry for Fabry disease patients, and according to our experience, we recommend advanced haemodynamic monitoring during surgery. Careful airway examination should be further performed, with particular attention to patient ventilability prediction and available alternative strategies for airway management in case of difficulties. A nephroprotective strategy and a particular care to the associated end-stage organ disease may significantly improve the long-term outcome of patients with Fabry Disease.

Stable Kidney Function in the Second Decade After Kidney Transplantation While on Cyclosporine-Based Immunosuppression

Calcineurin inhibitors (CNIs) have been the mainstay of immunosuppressive protocols in kidney transplantation over the past 20 years. However, in some recipients, the adverse effects of CNIs contribute to chronic allograft nephropathy and death with function--the two leading causes of late graft loss. Other recipients maintain stable graft function. We studied the impact of continuing CNI-based immunosuppression in the second decade after kidney transplantation. From 1984 through 1996, a total of 1,263 patients underwent a primary kidney transplant at the University of Minnesota and received cyclosporine-based immunosuppression. Antibody induction was used only in deceased donor recipients. The actuarial 20-year patient survival rate was 38%; graft survival, 30%; and death-censored graft survival, 60%. The annual mean serum creatinine level for recipients whose grafts survived > or =1 year remained stable, although recipients with a history of > or =1 acute rejection episode had a higher serum creatinine level vs. recipients who were rejection-free. The annual mean calculated creatinine clearance was also stable over time. In addition, for recipients who were acute rejection-free, chronic allograft nephropathy/chronic rejection was only responsible for 9% of graft losses. Our study suggests that some kidney transplant recipients tolerate long-term CNI-based immunosuppression with stable creatinine levels. Identifying certain recipients' predisposition to CNI toxicity and individualizing immunosuppressive therapy may be important in order to improve long-term kidney function, while simultaneously preserving low short-term acute rejection rates.

Immunosuppressive Therapy Protocols in Kidney Transplantation in Adults

In practical terms, regardless of HLA compatibility level, whenever tissues are transplanted from one person to another it is essential to suppress the immune response of the recipient. A variety of methods are available however, the most frequently used ones have the disadvantage of being immunologicaly non specific. The consequence is a difficult balance between immunosuppression sufficient to prevent the tissue rejection and maintenance of immune system at the level of ability to adequately deal with an infection. The goal, not yet achieved, is to find a way of generating donor specific immunosuppression that leaves the immune machinery otherwise completely intact. The major approaches to immunosuppression are described below.

CHRONIC REJECTION OF HUMAN KIDNEY TRANSPLANTS IS CHARACTERIZED BY SPECIFIC PHENOTYPIC AND GENE EXPRESSION ALTERATIONS IN THE CD8+ LYMPHOCYTE SUBSET.

O316* Aim: Whereas interruption of immunosuppression usually leads to graft rejection in renal transplantation, we identified a cohort of kidney transplant recipients with stable graft function despite no ongoing therapy. Peripheral blood lymphocytes from these drug-free “operationally tolerant” patients (DF-Tol) exhibited high Vbeta/HPRT ratio and skewed CDR3-LD compared to patients with chronic rejection (CR) and healthy controls (HC), essentially in the CD8+ subset. In the present study we analyzed in more detail the phenotype and gene expression profile of CD8 lymphocytes to identify differences between chronic rejection and operational tolerance. Methods: Peripheral blood lymphocytes were obtained by Ficoll gradient from DF-Tol, CR and HC. CD8+ lymphocyte populations were analysed by flow cytometry examining CD45RA, CCR7, CD28, CD27, GITR, CD69, perforin and granzyme A. Total RNA was extracted from T cells of Vbeta families with biased TCR expansions and analyzed by microarrays representing 30,000 cDNAs. Pair-wise two tailed T-test and SAM statistical analyses were performed and selected gene expression differences confirmed using real-time PCR. Results: Phenotyping of CD8 populations by FACS revealed a slight trend towards increase of the central memory CD45RA-CCR7+CD8+ cells in DF-Tol (19.6±7.6%) vs CR (14.7±4.5) with a concomitant increase of effector CD45RA+CCR7-CD8+ cells in CR (30.0±12.5%) vs. DF-Tol (21.3±9.6). We found a pronounced decrease of the expression of CD28 (20.8±15.5% vs. 57.5±11.1%) and CD27 (30.0±18.3% vs. 66.3±10.5%) on CD8+ lymphocytes in CR vs. DF-Tol (p<0.001, p=0.019 respectively) while the expression of CD28 and CD27 correlate tightly (r=0.94 p<0.001). The expression of both perforin (85.6±16.8% vs. 30.1±5.3) and granzyme A (32.7±15.7% vs. 6.8±8.4) is significantly higher in CR relative to DF-Tol (p<0.001, p=0.010 respectively). Whereas expression of perforin and granzyme A was correlated (r=0.74 p=0.003), there was an inverse correlation between CD28 and perforin (r=-0.89 p<0.001) suggesting a predominance of cytotoxic CD8+CD28- lymphocytes in CR. Of interest, HC showed a similar phentopic profile as DF-Tol. Micorarray analysis of altered Vβ families identified a set of 101 cDNA clones representing 76 unique genes that differentiate DF-Tol, CR, and HC. Focusing on the differences between DF-Tol and CR, T test and SAM analysis shared 26 genes that were significantly upregulated in DF-Tol, including CCR7. This profile was in agreement with Taqman analysis of selected genes and included immune response/inflammatory genes, transcription factors, cell-cycle regulated and apoptotic genes. Although DF-Tol could be differentiated from HC by other genes, only 6 out of the 26 genes identified in the comparison between DF-Tol and CR were also different between DF-Tol and HC. Conclusion: Phenotypic analysis indicated a strong cytotoxic CD8 signature in CR, with decreased CD28 and CD27 and increased perforine and granzyme A. This signature differentiated CR from both DF-Tol and HC, suggesting that operational tolerance is characterized by a suppression of pathogenic mechanisms. This was further confirmed by the complex gene signature of altered Vβ families which enabled to identify a specific profile in CR. These phenotypic and gene expression signatures in the CD8 lymphocyte subset will be explored in the monitoring of immunosuppressive protocols in kidney transplantation.

New therapeutic protocols in kidney transplantation.

New therapeutic protocols in kidney transplantation.