Choosing fluids to reduce the risks of acute electrolyte disturbances in children after a kidney transplant.

Intravenous (i.v.) fluid therapy is critically important in pediatric kidney transplantation. Because of the high volumes given perioperatively, transplant recipients can develop significant electrolyte abnormalities depending on the types of fluids used. Current practices in pediatric transplantation aim to balance risks of hyponatremia from traditionally used hypotonic fluids, such as 0.45% sodium chloride, against hyperchloremia and acidosis associated with isotonic 0.9% sodium chloride. Using the balanced solution Plasma-Lyte 148 as an alternative might mitigate these risks.

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.

Baseline Characteristics and Representativeness of Participants in the BEST-Fluids Trial: A Randomized Trial of Balanced Crystalloid Solution Versus Saline in Deceased Donor Kidney Transplantation.

Delayed graft function (DGF) is a major complication of deceased donor kidney transplantation. Saline (0.9% sodium chloride) is a commonly used intravenous fluid in transplantation but may increase the risk of DGF because of its high chloride content. Better Evidence for Selecting Transplant Fluids (BEST-Fluids), a pragmatic, registry-based, double-blind, randomized trial, sought to determine whether using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce DGF. We sought to evaluate the generalizability of the trial cohort by reporting the baseline characteristics and representativeness of the trial participants in detail. Methods: We compared the characteristics of BEST-Fluids participants with those of a contemporary cohort of deceased donor kidney transplant recipients in Australia and New Zealand using data from the Australia and New Zealand Dialysis and Transplant Registry. To explore potential international differences, we compared trial participants with a cohort of transplant recipients in the United States using data from the Scientific Registry of Transplant Recipients. Results: During the trial recruitment period, 2373 deceased donor kidney transplants were performed in Australia and New Zealand; 2178 were eligible' and 808 were enrolled in BEST-Fluids. Overall, trial participants and nonparticipants were similar at baseline. Trial participants had more coronary artery disease (standardized difference [d] = 0.09; P = 0.03), longer dialysis duration (d = 0.18, P < 0.001), and fewer hypertensive (d = -0.11, P = 0.03) and circulatory death (d = -0.14, P < 0.01) donors than nonparticipants. Most key characteristics were similar between trial participants and US recipients, with moderate differences (|d| ≥ 0.2; all P < 0.001) in kidney failure cause, diabetes, dialysis duration, ischemic time, and several donor risk predictors, likely reflecting underlying population differences. Conclusions: BEST-Fluids participants had more comorbidities and received slightly fewer high-risk deceased donor kidneys but were otherwise representative of Australian and New Zealand transplant recipients and were generally similar to US recipients. The trial results should be broadly applicable to deceased donor kidney transplantation practice worldwide.

Effectiveness of growth hormone on growth and final height in paediatric chronic kidney disease.

BACKGROUND: The effectiveness of rhGH on growth and final height (FH) was determined in children with CKD and kidney failure using data linkage from two national databases. METHODS: Data on Australian children with CKD and kidney failure treated with rhGH were obtained by linking ANZDATA and OzGrow registries. The CKD cohort included children treated with rhGH prior to kidney replacement therapy (KRT). The KRT cohort consisted of children with kidney failure, some received rhGH, and some were untreated. Height standard deviation scores (Ht-SDS) were calculated with final height defined as last height recorded in girls > 16 years of age and boys > 17 years of age. RESULTS: In the CKD group, there were 214 children treated with rhGH prior to KRT. In the KRT group, there were 1,032 children, 202 (19%) treated with rhGH and 830 (81%) untreated. Growth significantly improved in the rhGH-treated CKD group (ΔHt-SDS = +0.80 [+0.68 to +0.92]; p < 0.001) and the rhGH-treated KRT group (ΔHt-SDS = +0.38 [+0.27 to +0.50]; p < 0.001). Within the KRT cohort, final height was available for 423 patients (41%), of which 137 (32%) had been treated with rhGH. The rhGH-treated group demonstrated marginally better catch-up growth (ΔHt-SDS = +0.05 [-0.18 to 0.29]) compared to the non-rhGH-treated group (ΔHt-SDS = -0.03 [-0.16 to 0.10]; p = 0.49). CONCLUSIONS: This large linkage study confirms rhGH is effective in improving height in children with CKD pre-KRT. However, rhGH appears to have a variable impact on growth once children have commenced KRT resulting in a marginal impact on final height.

The impact of donor/recipient age difference and HLA mismatch on graft outcome in pediatric kidney transplantation.

BACKGROUND: Understanding the relationship between the factors that influence long-term kidney transplant survival remains a key priority for pediatric nephrologists. We assessed the relative impact of donor/recipient age difference and HLA matching on long-term graft outcomes. METHODS: We conducted a retrospective cohort study of pediatric and adolescent recipients who received a primary kidney transplant in Australia and New Zealand between January 1, 1990, and December 31, 2015. The primary outcome was graft survival analyzed by Kaplan-Meier method. RESULTS: During the 26-year period, 1134 primary (395 DD and 739 LD) kidney transplants were performed in recipients less than 20 years of age. The median follow-up time was 10.2 years. Overall, 405 patients (35.7%) lost their transplant with graft survival 93.8% at 1 year, 82.5% at 5 years, 65.8% at 10 years, and 49.9% at 15 years post-transplant. There was consistently higher graft loss of DD kidneys as compared to LD kidneys at each time point. Both increasing donor/recipient age difference (aHR 1.11 per 10 years; 95% CI, 1.02-1.20; P = 0.009) and increasing HLA mismatch (aHR 1.20 per mismatch; 95% CI, 1.10-1.30; P < 0.001) were associated with decreased graft survival. CONCLUSIONS: Donor/recipient age difference and HLA matching are important factors influencing long-term graft outcomes in pediatric kidney transplantation. HLA mismatch remains a strong predictor of graft loss. For patients without the option of a LD, we suggest that the degree of HLA mismatch should not be discounted as part of the decision-making process of organ allocation.

Socio-economic status and quality of life in children with chronic disease: A systematic review.

Reduced quality of life (QoL) is a known consequence of chronic disease in children, and this association may be more evident in those who are socio-economically disadvantaged. The aims of this systematic review were to assess the association between socio-economic disadvantage and QoL among children with chronic disease, and to identify the specific socio-economic factors that are most influential. MEDLINE, Embase and PsycINFO were searched to March 2015. Observational studies that reported the association between at least one measure of social disadvantage in caregivers and at least one QoL measure in children and young people (age 2-21 years) with a debilitating non-communicable childhood disease (asthma, chronic kidney disease, type 1 diabetes mellitus and epilepsy) were eligible. A total of 30 studies involving 6957 patients were included (asthma (six studies, n = 576), chronic kidney disease (four studies, n = 796), epilepsy (14 studies, n = 2121), type 1 diabetes mellitus (six studies, n = 3464)). A total of 22 (73%) studies reported a statistically significant association between at least one socio-economic determinant and QoL. Parental education, occupation, marital status, income and health insurance coverage were associated with reduced QoL in children with chronic disease. The quality of the included studies varied widely and there was a high risk of reporting bias. Children with chronic disease from lower socio-economic backgrounds experience reduced QoL compared with their wealthier counterparts. Initiatives to improve access to and usage of medical and psychological services by children and their families who are socio-economically disadvantaged may help to mitigate the disparities and improve outcomes in children with chronic illnesses.

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.

A retrospective review of telehealth services for children referred to a paediatric nephrologist.

BACKGROUND: Telemedicine has emerged as an alternative mode of health care delivery over the last decade. To date, there is very limited published information in the field of telehealth and paediatric nephrology. The aim of this study was to review our experience with paediatric telenephrology in Queensland, Australia. METHODS: A retrospective audit of paediatric nephrology telehealth consultations to determine the nature of the telehealth activity, reasons for referral to telehealth, and to compare costs and potential savings of the telehealth service. RESULTS: During a ten-year period (2004 - 2013), 318 paediatric telenephrology consultations occurred for 168 patients (95 male) with the median age of 8 years (range 3 weeks to 24 years). Congenital anomalies of the kidney and urinary tract (30 %), followed by nephrotic syndrome (16 %), kidney transplant (12 %), and urinary tract infection (9 %) were the most common diagnoses. The estimated cost savings associated with telehealth were $31,837 in 2013 (average saving of $505 per consultation). CONCLUSIONS: Our study suggests that paediatric telenephrology is a viable and economic method for patient assessment and follow up. The benefits include improved access to paediatric nephrology services for patients and their families, educational opportunity for the regional medical teams, and a substantial cost saving for the health care system.

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.

Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: new developments and revised recommendations.

The publication of the Australasian Creatinine Consensus Working Group's position statements in 2005 and 2007 resulted in automatic reporting of estimated glomerular filtration rate (eGFR) with requests for serum creatinine concentration in adults, facilitated the unification of units of measurement for creatinine and eGFR, and promoted the standardisation of assays. New advancements and continuing debate led the Australasian Creatinine Consensus Working Group to reconvene in 2010. The working group recommends that the method of calculating eGFR should be changed to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, and that all laboratories should report eGFR values as a precise figure to at least 90 mL/min/1.73 m(2). Age-related decision points for eGFR in adults are not recommended, as although an eGFR < 60 mL/min/1.73 m(2) is very common in older people, it is nevertheless predictive of significantly increased risks of adverse clinical outcomes, and should not be considered a normal part of ageing.If using eGFR for drug dosing, body size should be considered, in addition to referring to the approved product information. For drugs with a narrow therapeutic index, therapeutic drug monitoring or a valid marker of drug effect should be used to individualise dosing. The CKD-EPI formula has been validated as a tool to estimate GFR in some populations of non-European ancestry living in Western countries. Pending publication of validation studies, the working group also recommends that Australasian laboratories continue to automatically report eGFR in Aboriginal and Torres Strait Islander peoples. The working group concluded that routine calculation of eGFR is not recommended in children and youth, or in pregnant women. Serum creatinine concentration (preferably using an enzymatic assay for paediatric patients) should remain as the standard test for kidney function in these populations.

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.

Review: Pharmacodynamic monitoring of immunosuppression in kidney transplantation.

Advances in immunosuppressive therapies have improved kidney transplant outcomes. However, immunosuppressant drug-induced toxicities continue to reduce tolerability and impact patient and graft survival. A major ongoing challenge in kidney transplantation is to establish ways of tailoring immunosuppressant therapy so as to maintain efficacy while minimizing toxicity. Pharmacodynamic monitoring by direct measurement of immune cell function has the potential to personalize immunosuppression. The purpose of this review is to provide the clinician with an overview of the methodology and use of immune function monitoring in the field of kidney transplantation.

Epidemiology and outcomes of peritonitis in children on peritoneal dialysis in Australasia.

Peritonitis is a common complication and major cause of morbidity in children on peritoneal dialysis. In this retrospective longitudinal study, we analysed data retrieved from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) on 167 patients aged less than 18 years of age who were treated with peritoneal dialysis during the period from October 2003 to December 2007. During this period there were 100 episodes of peritonitis in 57 patients (0.71 episodes/patient-year), with Gram-positive organisms most commonly isolated (44%). Peritonitis occurred frequently in the first 6 months after starting dialysis, with survival analysis showing peritonitis-free survival rates of 72%, 56% and 36% at 6 months, 1 year and 2 years respectively. Age was a weak predictor of peritonitis on univariate analysis, but previous peritonitis was the only significant predictor in a multivariate Cox proportional hazards model (adjusted hazard ratio 2.02; 95% CI: 1.20 to 3.40, p = 0.008). Peritonitis episodes infrequently resulted in relapse (5%), recurrence (7%) or the need for either temporary or permanent haemodialysis (5% and 7% respectively) and there were no patient deaths directly attributable to peritonitis. Compared with single organism peritonitis, polymicrobial peritonitis was not associated with any statistically significant differences in outcome. Further prospective studies are required to determine the most appropriate prophylactic measures and antibiotic regimens for use in pediatric patients.

Antibiotic prophylaxis and recurrent urinary tract infection in children.

BACKGROUND: Antibiotics are widely administered to children with the intention of preventing urinary tract infection, but adequately powered, placebo-controlled trials regarding efficacy are lacking. This study from four Australian centers examined whether low-dose, continuous oral antibiotic therapy prevents urinary tract infection in predisposed children. METHODS: We randomly assigned children under the age of 18 years who had had one or more microbiologically proven urinary tract infections to receive either daily trimethoprim-sulfamethoxazole suspension (as 2 mg of trimethoprim plus 10 mg of sulfamethoxazole per kilogram of body weight) or placebo for 12 months. The primary outcome was microbiologically confirmed symptomatic urinary tract infection. Intention-to-treat analyses were performed with the use of time-to-event data. RESULTS: From December 1998 to March 2007, a total of 576 children (of 780 planned) underwent randomization. The median age at entry was 14 months; 64% of the patients were girls, 42% had known vesicoureteral reflux (at least grade III in 53% of these patients), and 71% were enrolled after the first diagnosis of urinary tract infection. During the study, urinary tract infection developed in 36 of 288 patients (13%) in the group receiving trimethoprim-sulfamethoxazole (antibiotic group) and in 55 of 288 patients (19%) in the placebo group (hazard ratio in the antibiotic group, 0.61; 95% confidence interval, 0.40 to 0.93; P = 0.02 by the log-rank test). In the antibiotic group, the reduction in the absolute risk of urinary tract infection (6 percentage points) appeared to be consistent across all subgroups of patients (P > or = 0.20 for all interactions). CONCLUSIONS: Long-term, low-dose trimethoprim-sulfamethoxazole was associated with a decreased number of urinary tract infections in predisposed children. The treatment effect appeared to be consistent but modest across subgroups. (Australian New Zealand Clinical Trials Registry number, ACTRN12608000470392.)

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.