A novel allocation strategy for the difficult-to-allocate donor: audit of deceased donor kidneys utilised for preemptive recipients within Western Australia.

Kidney donor allocation can occasionally be difficult in Australia given a small population spread over vast distances. Therefore, between 2017 and 2019 our service allowed transplantation from deceased donors into local (same-state) preemptive recipients, only if no well-matched dialysis-dependent transplant waitlist recipient was available. Transplantation using this novel allocation pathway was associated with good clinical and immunological outcomes.

Haemodialysis vascular catheter-related blood stream infection: Organism types and clinical outcomes.

Catheter-related bloodstream infection (CRBI) is an important complication of catheter use for haemodialysis, but it remains unclear whether clinical outcomes following CRBI are influenced by organism type. This study aims to compare clinical outcomes following CRBI from Gram-positive and non-Gram-positive organisms. This was a retrospective cohort study of patients with kidney failure receiving haemodialysis (HD) via vascular catheters who had a documented episode of CRBI in Western Australia between 2005 and 2018. The associations between organism type, likelihood of hospitalization, catheter removal and death from CRBI were examined using adjusted logistic regression models. There were 111 episodes of CRBI in 99 patients (6.1 episodes per 1000-catheter-days at risk). Of the study cohort, 53 (48%) were male and 38 (34%) identified as Aboriginal or Torres Strait Islander. Gram-positive organisms were identified in 73 (66%) CRBI episodes, most commonly Staphylococcus aureus. Of those with non-Gram-positive CRBI, 9 (24%) were attributed to Pseudomonas aeruginosa. One-hundred and two (92%) episodes of CRBI required hospitalization and 15 (13%) patients died from CRBI. Compared with non-Gram-positive CRBI, Gram-positive CRBI was associated with an increased risk of hospitalization and catheter removal, with adjusted odds ratio of 9.34 (95% CI 1.28-68.03) and 3.47 (95% CI 1.25-9.67), respectively. There was no association between organism type and death from CRBI. Staphylococcus aureus remains the most common organism causing CRBI in HD patients. CRBI is associated with substantial morbidity, particularly CRBI attributed to Gram-positive organisms.

Sex-Based Differences in Risk Factors and Complications of Chronic Kidney Disease.

Globally, females are ∼30% more likely to have pre-dialysis chronic kidney disease (CKD) than males for reasons that are not fully understood. CKD is associated with numerous adverse health outcomes which makes understanding and working to eradicating sex based disparities in CKD prevalence essential. This review maps both what is known, and what is unknown, about the way sex and gender impacts (1) the epidemiology and risk factors for CKD including age, diabetes, hypertension, obesity, smoking, and cerebrovascular disease, and (2) the complications from CKD including kidney disease progression, cardiovascular disease, CKD mineral and bone disorders, anaemia, quality-of-life, cancer and mortality. This mapping can be used to guide future research.

Important lack of difference in tacrolimus and mycophenolic acid pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients.

AIM: To examine whether differences in tacrolimus and mycophenolic acid (MPA) pharmacokinetics contribute to the poorer kidney transplant outcomes experienced by Aboriginal Australians. METHODS: Concentration-time profiles for tacrolimus and MPA were prospectively collected from 43 kidney transplant recipients: 27 Aboriginal and 16 Caucasian. Apparent clearance (CL/F) and distribution volume (V/F) for each individual were derived from concentration-time profiles combined with population pharmacokinetic priors, with subsequent assessment for between-group difference in pharmacokinetics. In addition, population pharmacokinetic models were developed using the prospective dataset supplemented by previously developed structural models for tacrolimus and MPA. The change in NONMEM objective function was used to assess improvement in goodness of model fit. RESULTS: No differences were found between Aboriginal and Caucasian groups or empirical Bayes estimates, for CL/F or V/F of MPA or tacrolimus. However, a higher prevalence of CYP3A5 expressers (26% compared with 0%) and wider between-subject variability in tacrolimus CL/F (SD = 5.00 compared with 3.25 L/h/70 kg) were observed in the Aboriginal group, though these differences failed to reach statistical significance (p = .07 and p = .08). CONCLUSION: There were no differences in typical tacrolimus or MPA pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients. This means that Bayesian dosing tools developed to optimise tacrolimus and MPA dosing in Caucasian recipients may be applied to Aboriginal recipients. In turn, this may improve drug exposure and thereby transplant outcomes in this group. Aboriginal recipients appeared to have greater between-subject variability in tacrolimus CL/F and a higher prevalence of CYP3A5 expressers, attributes that have been linked with inferior outcomes.

Equity and diversity in the nephrology workforce in Australia and New Zealand.

BACKGROUND: Despite diversity initiatives, inequities persist in medicine with negative implications for the workforce and patients. Little is known about workplace inequity in nephrology. AIM: To describe perceptions and experiences of bias by health professionals in the Australian and New Zealand Society of Nephrology (ANZSN), focussing on gender and race. METHODS: A web-based survey of ANZSN members recorded degree of perceived inequity on a Likert scale, ranging from 1 (none) to 5 (complete). Groups were compared using Mann-Whitney U-test and logistic regression. Comments were synthesised using qualitative methods to explore themes of inequity and pathways to an inclusive future. RESULTS: Of the 620 members of the ANZSN, there were 134 (22%) respondents, of whom 57% were women and 67% were White. The majority (88%) perceived inequities in the workforce. Perceived drivers of inequity were gender (84/113; 75%), carer responsibilities (74/113; 65%) and race (64/113; 56%). Half (74/131) had personally experienced inequity, based on gender in 70% (52/74) and race in 39% (29/75) with perceived discrimination coming from doctors, patients, academics and health administrators. White males were least likely (odds ratio 0.39; 95% confidence interval 0.18-0.90) to experience inequity. Dominant themes from qualitative analysis indicated that the major impacts of inequity were limited opportunities for advancement and lack of formal assistance for those experiencing inequities. Proposed solutions to reduce inequity included normalising the discourse on inequity at an organisational level, with policy changes to ensure diverse representation on committees and in executive leadership positions. CONCLUSIONS: Inequity, particularly driven by gender and race, is common for nephrology health professionals in Australia and New Zealand and impacts career progression.

mTOR Inhibitors Induce Erythropoietin Resistance in Renal Transplant Recipients.

Aim: To elucidate the role of mTOR inhibitors on iron, hepcidin and erythropoietin-mediated regulation of hemopoiesis in stable renal transplant recipients (RTR). Background: Impaired hemopoiesis is common following renal transplantation managed using mTOR inhibitors. The mechanisms responsible are uncertain but include direct effects on iron, hepcidin or erythropoietin-mediated hemopoiesis. Methods: We conducted a single center prospective case-control study of 26 adult RTR with stable allograft function. RTR received stable mTOR dosing (cases, 11/26 [42%]) or stable tacrolimus dosing (controls, 15/26 [58%]). Baseline demographics, full blood count, renal function, iron studies, hepcidin-25, Interleukin-6 (IL-6) and erythropoietin (EPO) levels were determined. Results: There were no differences in age, gender or allograft function. Mean daily sirolimus dose for cases was 1.72 mg, with mean trough level of 8.46 ng/mL. Mean daily tacrolimus dose for controls was 4.3 mg, with mean trough level of 5.8 ng/mL. There were no differences in mean hemoglobin (143 vs. 147 g/L; p = 0.59), MCV (88 vs. 90 fL; p = 0.35), serum ferritin (150 vs. 85.7 µg/L; p = 0.06), transferrin saturation (26 vs. 23.3%; p = 0.46), IL-6 (11 vs. 7.02 pg/ml; p = 0.14) or hepcidin-25 (3.62 vs. 3.26 nM; p = 0.76) between the groups. EPO levels were significantly higher in the group receiving mTOR therapy (16.8 vs. 8.49 IU/L; p = 0.028). On logistic regression analysis EPO level was the only variable that had a significant impact providing an odds ratio of 0.84 (95%CI 0.66-0.98). The area under the receiver operator characteristic curve (ROC) for the analysis was 0.77 (95%CI 0.54-0.94) with p = 0.04.Conclusion: Higher levels of EPO in the absence of deranged iron biochemistry or hepcidin-25 levels suggest that EPO resistance rather than impaired iron metabolism may contribute to the impaired hemopoiesis previously demonstrated in RTR on mTOR therapy.

Allograft and Patient Outcomes Between Indigenous and Nonindigenous Kidney Transplant Recipients.

BACKGROUND: Kidney transplant outcomes of indigenous Australians are poorer compared with nonindigenous Australians, but it is unknown whether the type of acute rejection differs between these patient groups or whether rejection mediates the effect between ethnicity, death-censored graft failure (DCGF), and death with a functioning graft (DWFG). METHODS: Biopsy-proven acute rejection (BPAR) rates and types were compared between indigenous and nonindigenous recipients. The associations between ethnicity, BPAR, DCGF, and DWFG were examined using adjusted competing risk analyses, and mediation analysis was conducted to determine whether BPAR mediated the adverse effects between ethnicity and outcomes. RESULTS: Fifty-seven (9.3%) of 616 patients who have received kidney-only transplants between 2000 and 2010 in Western Australia were indigenous. Compared with nonindigenous recipients, BPAR rates were higher in indigenous recipients (42 versus 74 episodes/100 recipients, P < 0.01), with an excess of antibody-mediated rejections. During a median follow-up of 8 years, indigenous recipients were more likely to experience BPAR, DCGF, and DWFG compared with nonindigenous recipients, with adjusted subdistribution hazard ratio of 1.94 (1.39-2.70), 1.53 (0.85-2.76; P = 0.159), and 2.14 (1.13-4.06; P = 0.020), respectively. Although 70% of the effect between ethnicity and DCGF was mediated by BPAR, no similar association was found for DWFG. CONCLUSIONS: Indigenous recipients experienced poorer allograft and patient outcomes compared with nonindigenous recipients, with BPAR an important determinant for DCGF. Future research identifying other risk factors and mediators associated with patient survival in indigenous recipients should be considered a priority.

A retrospective study of tunnelled haemodialysis central line-associated bloodstream infections.

Infection is a serious complication of tunnelled haemodialysis catheters. We aimed to describe the epidemiology of tunnelled haemodialysis central line-associated bloodstream infections (CLABSI) in an Australian centre. We performed a retrospective audit of tunnelled haemodialysis CLABSI from June 2010 to June 2014. From 674 catheter insertions, 70 CLABSI occurred in 55 patients at a rate of 0.95 infections per 1000 catheter days. Aboriginal and Torres Strait Islanders (ATSI) compared to non-ATSI had a higher rate of CLABSI (1.70 vs 0.58 CLABSI per 1000 catheter days, p < 0.001). Staphylococcus aureus (n = 22, 31.4%), coagulase negative Staphylococci (n = 14, 17.5%), and Gram negative bacilli (n = 28, 35.0%) were the predominant causative organisms. Two patients who died both had Staphylococcus aureus infection. In conclusion, our infection rate and microbiology are similar to prior reports. Morbidity and mortality are associated with Staphylococcus aureus as the causative organism.

Cytomegalovirus viraemia and mortality in renal transplant recipients in the era of antiviral prophylaxis. Lessons from the western Australian experience.

BACKGROUND: Cytomegalovirus (CMV) establishes a lifelong infection that is efficiently controlled by the immune system; this infection can be reactivated in case of immunosuppression such as following solid organ transplantation. CMV viraemia has been associated with CMV disease, as well as increased mortality and allograft failure. Prophylactic antiviral medication is routinely given to renal transplant recipients, but reactivation during and following cessation of antiviral prophylaxis is known to occur. The aims of this study were to assess the incidence, timing and impact of CMV viraemia in renal transplant recipients and to determine the level of viraemia associated with adverse clinical outcomes. METHODS: Data from all adult (18 years and over) Western Australian renal transplant recipients transplanted between 1 January 2007 and 31 December 2012 were obtained from the Australia and New Zealand Dialysis and Transplant registry and were supplemented with data obtained from clinical records. Potential risk factors for detectable CMV viraemia (≥600 copies/ml) and all-cause mortality were assessed using univariable analysis and Cox Proportional Hazards Regression. RESULTS: There were 438 transplants performed on 435 recipients. The following factors increased the risk of CMV viraemia with viral loads ≥600 copies/ml: Donor positive/Recipient negative status; receiving a graft from a deceased donor; and receiving a graft from a donor aged 60 years and over. CMV viraemia with viral loads ≥656 copies/ml was a risk factor for death following renal transplantation, as was being aged 65 years and above at transplant, being Aboriginal and having vascular disease. Importantly 37% of the episodes of CMV viraemia with viral loads ≥656 copies/ml occurred while the patients were expected to be on CMV prophylaxis. CONCLUSIONS: CMV viraemia (≥656 copies/ml) was associated with all-cause mortality in multivariable analysis, and CMV viraemia at ≥656 copies/ml commonly occurred during the period when renal transplant recipients were expected to be on antiviral prophylaxis. A greater vigilance in monitoring CMV levels if antiviral prophylaxis is stopped prematurely or poor patient compliance is suspected could protect some renal transplant recipients from adverse outcomes such as premature mortality.

Infectious complications in indigenous renal transplant recipients in Western Australia.

BACKGROUND: Infectious complications remain a significant risk following renal transplantation. AIM: To examine the burden and pattern of infection following renal transplantation in Aboriginal and Torres Strait Islander (ATSI) compared to non-ATSI. METHODS: A retrospective cohort study of 141 consecutive adult renal transplant recipients in Western Australia between 2005 and 2011 was conducted. We determined baseline serological status for relevant organisms, the number of patients with specific infections, infectious admission in the first year post-transplantation and the rate of infectious death during follow up. RESULTS: There were 57 ATSI and 84 non-ATSI renal transplant recipients. ATSI compared to non-ATSI had a high rate of cytomegalovirus (CMV) seropositivity (98.2% vs 73.2%, P < 0.001), HBcAb positivity (100% vs 13.3%, P < 0.001) and strongyloides seropositivity (ATSI 3/12 tested). In the first year post-transplant, ATSI compared to non-ASTI had a higher rate of pneumonia (17.9% vs 3.6% of patients, P = 0.006), and non-significant trend to higher rates of gastrointestinal parasitic infection (7.0% vs 1.2% of patients, P = 0.158), invasive fungal infection (10.5% vs 4.8% of patients, P = 0.316), and hospitalisation because of infection (10.0 vs 5.5 days, P = 0.071). Overall 5-year cumulative survival was lower for ATSI versus non-ATSI (0.64 vs 0.86, P = 0.022) with two-thirds of ATSI deaths attributed to infection. CONCLUSIONS: ATSI are at high risk of infectious complications after renal transplantation associated with a burden of hospitalisation and death. Augmented screening and prophylaxis for infectious diseases should be considered. Further study needs to identify contributing environmental and immunity factors.

Optimal use of plasma and urine BK viral loads for screening and predicting BK nephropathy.

BACKGROUND: BK virus is a polyoma virus causing renal allograft nephropathy. Reduction of immunosuppression with the early recognition of significant BK viral loads in urine and plasma can effectively prevent BKV associated nephropathy (BKVN), however the optimal compartment and frequency of BK viral load measurement post renal transplantation are undetermined. Our purpose was to examine time to detection and viral loads in urine compared to plasma, and establish viral load cut-offs associated with histological BKVN. METHODS: We performed a retrospective analysis of the BKV screening frequency and compartment(s) of 277 adult renal transplant recipients (RTR). RESULTS: BKVN was histologically diagnosed in 17 (6.1 %) RTR. In cases where both urine and plasma were tested fortnightly for 6 months (n = 53), BKV was detected in the urine 29 days earlier than plasma. Fortnightly (n = 72) versus 3-monthly (n = 78) testing demonstrated that BKV was detected in the urine significantly earlier (median 63 versus 97 days, p = 0.001) and at a lower level (median 3.27 versus 6.71 log10 c/mL, p < 0.001) with more frequent testing, but this difference was not evident in plasma first detection (80 versus 95 days, p = 0.536) or first positive viral load (3.18 versus 3.30 log10 c/mL, p = 0.603). The optimum cut-off BK viral load for histological diagnosis of BKVN was 4.10 log10 c/mL for the first positive urine, 3.79 log10 c/mL for the first positive plasma, 9.24 log10 c/mL for the peak urine, and 4.53 log10 c/mL for the peak plasma. CONCLUSIONS: Frequent urinary BK viral load screening for the prevention of BKVN is suggested due to its high sensitivity and earlier detection.

The Relationship Between Presentation and the Time of Initial Administration of Antibiotics With Outcomes of Peritonitis in Peritoneal Dialysis Patients: The PROMPT Study.

INTRODUCTION: The impact of time to treatment on clinical outcome is an established precept in infectious disease but is not established in peritoneal dialysis-related peritonitis (PDRP). METHODS: In a prospective multicenter study of PDRP, symptom-to-contact time (SC), contact-to-treatment time (CT), defined as the time from health care presentation to initial antibiotic, and symptom-to-treatment time (ST) were determined. RESULTS: One hundred sixteen patients had 159 episodes of PDRP. Median SC for all episodes was 5.0 hours (first to third quartile [Q1-Q3]: 1.3-13.9); CT, 2.3 hours (Q1-Q3: 1.2-4.0); and ST, 9.0 hours (Q1-Q3: 4.7-25.3). Thirty-eight (23.9%) patient episodes (28 catheter removals and 10 deaths) met the primary composite outcome of PD failure at 30 days (PD-fail). The risk of PD-fail increased by 5.5% for each hour of delay of administration of antibiotics (odds ratio [OR] for CT: 1.055; 95% confidence interval [CI]: 1.005-1.109; P = 0.032). Neither SC (OR: 1.00; 95% CI: 0.99-1.01; P = 0.74) nor ST (OR: 1.00; 95% CI: 0.99-1.01; P = 0.48) was associated with PD-fail. In a multivariable analysis, only CT for presentation to a hospital-based facility compared with a community facility (OR: 1.068; 95% CI: 1.013-1.126; P = 0.015) and female sex (OR: 2.4; 95% CI: 1.1-5.4; P = 0.027) were independently associated with PD-fail. Each hour of delay in administering antibacterial therapy from the time of presentation to a hospital facility increased the risk of PD failure or death by 6.8%. DISCUSSION: Strategies targeted to expedited antibiotic treatment should be implemented to improve outcomes from PDRP.

Peri-operative third party red blood cell transfusion in renal transplantation and the risk of antibody-mediated rejection and graft loss.

Historic red blood cell transfusion (RBCT) may induce anti-HLA antibody which, if donor specific (DSA), is associated with increased antibody-mediated rejection (AMR). Whether post-operative RBCT influences this risk is unknown. We examined the RBCT history in 258 renal transplant recipients stratified according to prevalent recipient HLA antibody (DSA, Non-DSA or No Antibody). AMR occurred more frequently in patients who received RBCT both pre and post transplant compared with all other groups (Pre+Post-RBCT 21%, Pre-RBCT 4%, Post-RBCT 6%, No-RBCT 6%, HR 4.1 p=0.004). In the 63 patients who received Pre+Post-RBCT, 65% (13/20) with DSA developed AMR compared with 0/6 in the Non-DSA group and 2/37 (5%) in the No-Antibody group (HR 13.9 p<0.001). In patients who received No-RBCT, Pre-RBCT or Post-RBCT there was no difference in AMR between patients with DSA, Non-DSA or No-Antibody. Graft loss was independently associated with Pre+Post-RBCT (HR 6.5, p=0.001) AMR (HR 23.9 p<0.001) and Non-AMR (6.0 p=0.003) after adjusting for DSA and delayed graft function. Re-exposure to RBCT at the time of transplant is associated with increased AMR only in patients with preformed DSA, suggesting that RBCT provides additional allostimulation. Patients receiving Pre+Post-RBCT also had an increased risk of graft loss independently of AMR or DSA. Both pre and post procedural RBCT in renal transplantation is associated with modification of immunological risk and warrants additional study.

Our experience with rituximab therapy for adult-onset primary glomerulonephritis and review of literature.

BACKGROUND: B cell-targeted immunosuppression with rituximab as primary treatment or when conventional therapy is contraindicated or unsuccessful can induce remission in idiopathic membranous nephropathy (IMN). We explored the efficacy and safety of rituximab therapy in an adult population with IMN and other primary glomerulonephritides. METHOD: This study is a single-centre retrospective case review of 24 adult patients who received rituximab (RTX) for IMN (n = 11), minimal change disease (MCD, n = 7), focal segmental glomerulosclerosis (FSGS, n = 4), and membranoproliferative glomerulonephritis (MPGN, n = 2). Outcomes included the proportion of patients with complete and partial remission, frequency of relapse, the amount of post-RTX immunosuppression, and toxicity. RESULTS: The median follow-up for all patients was 31.5 months (IQR: 15.0-44.0). Rituximab therapy induced remission in 19/24 (79.2 %) patients (IMN: 63.6 %, MCD: 100 %, FSGS: 75 %, and MPGN: 100 %). Disease recurrence in patients with ≥ 3 relapses pre-RTX therapy (MCD, n = 6 and FSGS, n = 1) decreased from 37.0 to 19.6 events per 1,000 patient-months. All patients with steroid maintenance, discontinued or achieved at least a 50 % dose reduction at 3.0 months (IQR: 1.5-8.0) post-treatment. One patient ceased CSA in addition to a 50 % steroid dose reduction 13 months post-RTX. Rituximab was well tolerated with a single serious infection (4.2 %) responsive to treatment. CONCLUSIONS: Rituximab induced remission in IMN comparable with published reports but had an additional benefit in inducing remission in other common glomerulonephritides. Additional randomized studies are needed to confirm its potential therapeutic benefit and optimal dosing for adult-onset primary glomerulonephritis.

Acute irreversible oxalate nephropathy in a lung transplant recipient treated successfully with a renal transplant.

We report a 29 year old male cystic fibrosis patient with end stage lung disease and normal renal function who underwent a sequential double lung transplant. Medical history included: an ileal resection and pancreatic exocrine dysfunction. The postoperative period was complicated with haemorrhage and repeat surgery, requiring multiple blood transfusions and extensive antibiotic cover. Pancreatic supplements were interrupted. Acute renal failure attributed to haemodynamically-mediated acute tubular necrosis was managed expectantly. He remained dialysis dependent 8 weeks post surgery and was maintained on triple immunosuppression with tacrolimus, mycophenolate and prednisolone. A DTPA study was consistent with ATN. Renal biopsy revealed features consistent with tubular injury due to acute oxalate nephropathy (AON). Further biochemical characterization excluded primary hyperoxaluria but confirmed increased 24 hour urinary oxalate. He was maintained on enhanced frequency HDF and subsequently received an uncomplicated live related renal transplant 10 months post lung transplant with only additional basiliximab. Calcium carbonate was continued to manage post transplant hyperoxaluria and an early renal biopsy excluded recurrent oxalate injury. Enteric hyperoxaluria due to malabsorption in patients with CF especially with ileal resection, in addition to loss of gut Oxalobacter formigenes due to prolonged antimicrobials, increases the risk of AON. Increased awareness of this condition and screening prior to lung transplant is recommended.