Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial.

BACKGROUND: Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. METHODS: BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). FINDINGS: Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48). INTERPRETATION: Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. FUNDING: Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.

Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis.

BACKGROUND AND OBJECTIVES: FSGS can recur after kidney transplantation and is associated with poor graft outcomes. We aimed to assess the incidence of FSGS recurrence post-transplant and determine the effect of graft source on recurrence and graft survival in patients with biopsy-proven FSGS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using the Australian and New Zealand Dialysis and Transplant Registry, we assessed incidence of FSGS, the influence of donor type on the risk of FSGS recurrence, and graft loss in recipients with ESRD caused by primary FSGS using Kaplan-Meier and logistic regression analyses. RESULTS: Between 1992 and 2011, 736 first kidney transplants were performed in 666 adults and 70 children (≤20 years old) with biopsy-proven primary FSGS. FSGS recurred in 76 (10.3%) patients. Younger age (P<0.001), nonwhite ethnicity (P=0.02), and having a live donor (P=0.02) were independent risk factors associated with recurrence. Median graft survival was significantly better for live donor compared with deceased donor grafts (14.8 versus 12.1 years; P<0.01). Disease recurrence predicted poor graft outcomes, with 52% (95% confidence interval, 40% to 63%) 5-year graft survival in the recurrence group compared with 83% (95% confidence interval, 79% to 86%) in the group without recurrent disease (P<0.001). CONCLUSIONS: FSGS recurrence after kidney transplantation was more common in live donor kidneys. Despite this, graft survival in live donor recipients was significantly better for both children and adults with FSGS. We propose that live donor transplantation should not be avoided in patients with FSGS.

Post-transplant lymphoproliferative disorder: no relationship to recombinant human growth hormone use in Australian and New Zealand pediatric kidney transplant recipients.

PTLD is a potentially life-limiting complication of pediatric transplantation. Previous registry-based studies in renal transplantation have suggested a link between rhGH use and PTLD. In this study, demographic and transplant data on those aged <18 yr and transplanted between 1991 and 2008 were collected from the ANZDATA Registry. Associations between gender, age at time of transplant, recipient CMV and EBV status, use of monoclonal antibody therapy, and use of rhGH were studied as potential predictors of PTLD. Among 650 transplants, there were 20 cases (3.1%) of PTLD, with half presenting within two yr post-transplant. Eight patients exposed to rhGH at any time developed PTLD, and this association was not statistically significant (RR = 1.5[0.6-3.4], p = 0.36). On multivariate analysis, there were no significant predictors for PTLD. In this study, previously identified potential risk factors were not identified as significant predictors for the development of PTLD. Although limited sample size may affect our ability to infer safety, this large retrospective cohort study does not suggest an increased risk of PTLD in pediatric kidney transplant recipients who received rhGH treatment.

Cytomegalovirus & Epstein Barr Virus serostatus as a predictor of the long-term outcome of kidney transplantation.

AIM: Cytomegalovirus (CMV) and Epstein Barr Virus (EBV) disease and asymptomatic infection have been associated with poor outcomes in kidney transplantation. Recipients who acquire primary infection through transplantation from a seropositive donor may be at particular risk of complications. The primary aim of this study was to evaluate the relationship between donor/recipient (D/R) CMV and EBV serostatus pretransplant and allograft and patient survival in a large cohort of kidney transplant recipients. METHODS: Data were obtained from the Australian and New Zealand Dialysis and Transplant Registry and the Australian and New Zealand Organ Donation Registry on 4516 first deceased donor kidney transplants performed between 1998 and 2010. Graft and patient survival were analysed using the Kaplan-Meier method. RESULTS: Pretransplant CMV D/R serostatus was available for the whole cohort, with EBV D/R serostatus available for 2566 transplants (56.8%). Serostatus for both viruses was significantly associated with donor and recipient age and recipient smoking status. For both viruses the majority of transplants were in a D+/R+ serostatus setting: 45.3% for CMV and 77.9% for EBV. D/R serostatus for either virus did not have a significant effect on graft or patient survival. CONCLUSION: We conclude that in the current era of viral prophylaxis and surveillance, long-term outcome for the kidney transplant population is unaffected by D/R CMV and EBV serostatus.

Original article anti-oxidant pathways are stimulated by mesenchymal stromal cells in renal repair after ischemic injury.

BACKGROUND AIMS: Ischemia-reperfusion (IR) injury is a common cause of acute renal failure. Bone marrow (BM)-derived mesenchymal stromal cells (MSC) delivered after renal IR are renoprotective, but knowledge of the protective mechanism is still in development. This investigation analyzed the protective molecular mechanisms of MSC, in particular relating to modulated oxidative stress. METHODS: In vivo and in vitro models of renal IR were analyzed with and without MSC. In vivo, adult male Sprague-Dawley rats were subjected to 40-min unilateral renal IR. Rat BM-derived MSC were administered at 24 h post-IR (IR + MSC). Other groups had IR but no MSC, or MSC but no ischemia (all groups n = 4). Apoptosis, inflammation, oxidative stress and reparative signal transduction molecules or growth factors were studied 4 days post-IR. In vitro, protection by MSC against oxidative stress (0.4 mm hydrogen peroxide) was investigated using rat renal tubular epithelial cells (NRK52E) with or without MSC in co-culture (tissue culture trans-well inserts), followed by similar analyses to the in vivo investigation. RESULTS: In vivo, kidneys of IR + MSC animals had significantly increased cell proliferation/regeneration (cells positive for proliferating cell nuclear antigen, expression of epidermal growth factor), increased heme-oxygenase-1 (improved cell survival, anti-oxidant) and decreased 8-OHdG (decreased oxidative stress). In vitro, MSC delivered with oxidative stress significantly decreased apoptosis and Bax (pro-apoptotic protein), and increased mitosis and phospho-ERK1/2, thereby minimizing the damaging outcome and maximizing the regenerative effect after oxidative stress. CONCLUSIONS: The benefits of MSC, in IR, were primarily pro-regenerative, sometimes anti-apoptotic, and novel anti-oxidant mechanisms were identified.

Immunosuppression by mesenchymal stromal cells: from culture to clinic.

Extensive in vitro studies have shown that multipotent mesenchymal stromal cells (MSC) can exert profound immunosuppressive effects via modulation of both cellular and innate immune pathways. Their ability to be readily isolated from a number of tissues and expanded ex vivo makes them attractive candidates for systemic immunosuppressive therapy. In this article, we will review recent experimental data on the mechanisms by which MSC inhibit the alloproliferative response and the clinical relevance for their potential use in hematopoietic stem cell transplantation, solid organ transplantation, and treatment of autoimmune diseases. While in vitro data consistently demonstrate the immunosuppressive capability of MSC, current studies in animals and humans suggest that MSC are less effective in producing systemic immunosuppression. Further mechanistic studies and randomized controlled trials using standardized cell populations are needed to define the optimal conditions for the use of MSC as immunotherapy.

Mesenchymal stem cells: immunobiology and therapeutic potential in kidney disease.

Mesenchymal stem cells (MSC) are non-haematopoietic cells that are prevalent in the adult bone marrow but can also be isolated from a variety of other postnatal tissues. MSC are non-immunogenic and are immunosuppressive, with the ability to inhibit maturation of dendritic cells and suppress the function of naïve and memory T cells, B cells and NK cells. In addition to their immunomodulatory properties, MSC are capable of differentiating into various tissues of mesenchymal and non-mesenchymal origin and migrating to sites of tissue injury and inflammation to participate in tissue repair. A number of studies in animal models of cardiac injury, stroke and ischaemic renal injury have demonstrated the clinical potential of MSC in tissue regeneration and repair. MSC are currently being evaluated in various preclinical and clinical studies in humans and offer significant potential as a novel cellular therapy for tissue regeneration and immunological conditions. The present review focuses on the unique immunomodulatory and regenerative properties of MSC and their potential role in the treatment of kidney disease.

Estimated donor glomerular filtration rate is the most important donor characteristic predicting graft function in recipients of kidneys from live donors.

We hypothesized that predictors of outcome in live donor transplants were likely to differ significantly from deceased donor transplants, in which cold ischaemia time, cause of donor death and other donor factors are the most important predictors. The primary aim was to explore the independent predictors of graft function in recipients of live donor kidneys (LDK). Our secondary aim was to determine which donor characteristics are the most useful predictors. A retrospective analysis was undertaken of all patients receiving live donor (n = 206) renal transplants at our institution between 31 May 1994 and 15 October 2002. Twelve patients were excluded from the analysis. Follow-up was completed on all patients until graft loss, death or 22 November 2003. We explored predictors of Nankivell glomerular filtration rate (GFR) at 6 months by multivariate linear regression. In the 194 patients studied, the mean recipient 6-month Nankivell GFR was 59 +/- 15 ml/min/1.73 m(2). Independent predictors of recipient GFR in at 6 months were donor Cockcroft-Gault GFR (CrCl; beta 0.16; CI 0.13 to 0.29; P < 0.0001), steroid resistant rejection (beta-6.07; CI -12.05 to -0.09; P = 0.006) and delayed graft function (DGF) (beta-10.0; CI -19.52 to -0.49; P = 0.039). Renal function in an LDK transplant recipients is predicted by donor GFR, episodes of steroid resistant rejection and DGF. Importantly, donor Cockcroft-Gault GFR is the most important characteristic for predicting the recipient renal function.

Grandparent donors in paediatric renal transplantation.

The outcome of transplantation from grandparent donors in comparison with parental donors in paediatric renal transplantation was evaluated in 53 living related donor (LRD) transplantations performed between January 1996 and August 2003. The donor in 13 cases (25%) was a grandparent (Gpar group), and the remaining donors formed the parent group (Par group). The median age of recipients in the Gpar group was 2.75 (1.7-10.6) years and in the Par group was 12.75 (2.4-22) years (P<0.0001). There was no evidence of a difference in patient and graft survival, glomerular filtration rate (GFR) after transplantation, or the number of biopsy proven episodes of rejection between the groups. Doses of prednisolone in the first year following transplantation were greater in recipients from Gpar donors, but the other immunosuppression doses were similar. The median age of donors in the Gpar group was 56 (50-67) years and in the Par group was 41 (27-58) years (P<0.0001). There was no evidence of a difference between the two donor groups in mean creatinine clearance at last follow-up. There were two major donor complications in the Gpar group and one in the Par group. There was no evidence that the length of stay differed between the two groups in either the donors or recipients. These results support the use of carefully selected healthy grandparents as LRDs in children. This option potentially allows for the use of parent donors for a subsequent transplantation.