Variation in Access to Kidney Transplantation Across Renal Programs in Ontario, Canada.

In the United States, kidney transplant rates vary significantly across end-stage renal disease (ESRD) networks. We conducted a population-based cohort study to determine whether there was variability in kidney transplant rates across renal programs in a health care system distinct from the United States. We included incident chronic dialysis patients in Ontario, Canada, from 2003 to 2013 and determined the 1-, 5-, and 10-year cumulative incidence of kidney transplantation in 27 regional renal programs (similar to U.S. ESRD networks). We also assessed the cumulative incidence of kidney transplant for "healthy" dialysis patients (aged 18-50 years without diabetes, coronary disease, or malignancy). We calculated standardized transplant ratios (STRs) using a Cox proportional hazards model, adjusting for patient characteristics (maximum possible follow-up of 11 years). Among 23 022 chronic dialysis patients, the 10-year cumulative incidence of kidney transplantation ranged from 7.4% (95% confidence interval [CI] 4.8-10.7%) to 31.4% (95% CI 16.5-47.5%) across renal programs. Similar variability was observed in our healthy cohort. STRs ranged from 0.3 (95% CI 0.2-0.5) to 1.5 (95% CI 1.4-1.7) across renal programs. There was significant variation in kidney transplant rates across Ontario renal programs despite patients having access to the same publicly funded health care system.

Economic consequences incurred by living kidney donors: a Canadian multi-center prospective study.

Some living kidney donors incur economic consequences as a result of donation; however, these costs are poorly quantified. We developed a framework to comprehensively assess economic consequences from the donor perspective including out-of-pocket cost, lost wages and home productivity loss. We prospectively enrolled 100 living kidney donors from seven Canadian centers between 2004 and 2008 and collected and valued economic consequences ($CAD 2008) at 3 months and 1 year after donation. Almost all (96%) donors experienced economic consequences, with 94% reporting travel costs and 47% reporting lost pay. The average and median costs of lost pay were $2144 (SD 4167) and $0 (25th-75th percentile 0, 2794), respectively. For other expenses (travel, accommodation, medication and medical), mean and median costs were $1780 (SD 2504) and $821 (25th-75th percentile 242, 2271), respectively. From the donor perspective, mean cost was $3268 (SD 4704); one-third of donors incurred cost >$3000, and 15% >$8000. The majority of donors (83%) reported inability to perform usual household activities for an average duration of 33 days; 8% reported out-of-pocket costs for assistance with these activities. The economic impact of living kidney donation for some individuals is large. We advocate for programs to reimburse living donors for their legitimate costs.

Kidney function endpoints in kidney transplant trials: a struggle for power.

Kidney function endpoints are commonly used in randomized controlled trials (RCTs) in kidney transplantation (KTx). We conducted this study to estimate the proportion of ongoing RCTs with kidney function endpoints in KTx where the proposed sample size is large enough to detect meaningful differences in glomerular filtration rate (GFR) with adequate statistical power. RCTs were retrieved using the key word "kidney transplantation" from the National Institute of Health online clinical trial registry. Included trials had at least one measure of kidney function tracked for at least 1 month after transplant. We determined the proportion of two-arm parallel trials that had sufficient sample sizes to detect a minimum 5, 7.5 and 10 mL/min difference in GFR between arms. Fifty RCTs met inclusion criteria. Only 7% of the trials were above a sample size of 562, the number needed to detect a minimum 5 mL/min difference between the groups should one exist (assumptions: α = 0.05; power = 80%, 10% loss to follow-up, common standard deviation of 20 mL/min). The result increased modestly to 36% of trials when a minimum 10 mL/min difference was considered. Only a minority of ongoing trials have adequate statistical power to detect between-group differences in kidney function using conventional sample size estimating parameters. For this reason, some potentially effective interventions which ultimately could benefit patients may be abandoned from future assessment.

Risk of kidney stones with surgical intervention in living kidney donors.

A kidney stone in a person with a solitary kidney requires urgent attention, which may result in surgical and/or hospital attention. We conducted a matched retrospective cohort study to determine if living kidney donors compared to healthy nondonors have a higher risk of: (i) kidney stones with surgical intervention, and (ii) hospital encounters for kidney stones. We reviewed all predonation charts for living kidney donations from 1992 to 2009 at five major transplant centers in Ontario, Canada, and linked this information to healthcare databases. We selected nondonors from the healthiest segment of the general population and matched 10 nondonors to every donor. Of the 2019 donors and 20 190 nondonors, none had evidence of kidney stones prior to cohort entry. Median follow-up time was 8.4 years (maximum 19.7 years; loss to follow-up <7%). There was no difference in the rate of kidney stones with surgical intervention in donors compared to nondonors (8.3 vs. 9.7 events/10 000 person-years; rate ratio 0.85; 95% confidence interval [CI] 0.47-1.53). Similarly there was no difference in the rate of hospital encounters for kidney stones (12.1 vs. 16.1 events/10 000 person-years; rate ratio 0.75; 95% CI 0.45-1.24). These interim results are reassuring for the safety of living kidney donation.

Dynamic challenges inhibiting optimal adoption of kidney paired donation: findings of a consensus conference.

While kidney paired donation (KPD) enables the utilization of living donor kidneys from healthy and willing donors incompatible with their intended recipients, the strategy poses complex challenges that have limited its adoption in United States and Canada. A consensus conference was convened March 29-30, 2012 to address the dynamic challenges and complexities of KPD that inhibit optimal implementation. Stakeholders considered donor evaluation and care, histocompatibility testing, allocation algorithms, financing, geographic challenges and implementation strategies with the goal to safely maximize KPD at every transplant center. Best practices, knowledge gaps and research goals were identified and summarized in this document.

Evaluation of a collaborative chronic care approach to improve outcomes in kidney transplant recipients.

Several studies found that renal transplant recipients with chronic kidney disease have untreated complications and do not attain recommended clinical targets. Using a before/after design with propensity score-matched controls, we evaluated whether an advanced practice nurse-led interprofessional collaborative chronic care approach could improve clinical outcomes for CKD transplant patients compared with a traditional physician-led model. The intervention included strategies for disease self-management, shared decision making, and healthcare system reorganization. The primary outcome was the proportion of patients attaining at least seven of nine targets as per published guidelines. A greater proportion of intervention patients achieved the outcome (68% vs. 10%; p = 0.0001) and had discussions about end-stage treatment options (88% vs. 13%; p = 0.0001) compared with controls. The intervention patients had significantly fewer emergency room visits (incidence rate ratio [IRR] 0.53; 95% CI 0.29-0.91; p = 0.02) and hospital admissions (IRR 0.34; 95% CI 0.16-0.68; p = 0.001) compared with the control patients. There were no significant differences found between the groups in systolic/diastolic blood pressure, carbon dioxide, hemoglobin, or phosphate parameters. An advanced practice nurse-led approach, based on the chronic care model, has the potential to improve clinical outcomes for renal transplant recipients and needs to be tested in a multicenter randomized controlled trial.

Poor seroprotection but allosensitization after adjuvanted pandemic influenza H1N1 vaccine in kidney transplant recipients.

BACKGROUND: Seasonal and pandemic influenza virus infections in renal transplant patients are associated with poor outcomes. During the pandemic of 2009-2010, the AS03-adjuvanted monovalent H1N1 influenza vaccine was recommended for transplant recipients, although its immunogenicity in this population was unknown. We sought to determine the safety and immunogenicity of an adjuvant-containing vaccine against pandemic influenza A H1N1 2009 (pH1N1) administered to kidney transplant recipients. METHODS: We prospectively enrolled 124 adult kidney transplant recipients in the fall of 2009 at two transplant centers. Cohort 1 (n = 42) was assessed before and after pH1N1 immunization, while Cohort 2 (n = 82) was only assessed post immunization. Humoral response was measured by the hemagglutination inhibition assay. Vaccine safety was assessed by adverse event reporting, graft function, and human leukocyte antigen (HLA) alloantibody measurements. RESULTS: Cohort 1 had a low rate of baseline seroprotection to pH1N1 (7%) and a low rate of seroprotection after immunization (31%). No patient <6 months post transplant (n = 5) achieved seroprotection. Seroprotection rate was greater in patients receiving double as compared with triple immunosuppression (80% vs. 24%, P = 0.01). In Cohort 2, post-immunization seroprotection was 35%. In both cohorts, no confirmed cases of pH1N1 infection occurred. No difference was seen in estimated glomerular filtration rate before (54.3 mL/min/1.73 m(2) ) and after (53.8 mL/min/1.73 m(2) ) immunization, and no acute rejections had occurred after immunization at last follow-up. In Cohort 1, 11.9% of patients developed new anti-HLA antibodies. CONCLUSION: An adjuvant-containing vaccine to pH1N1 provided poor seroprotection in renal transplant recipients. Receiving triple immunosuppression was associated with a poor seroresponse. Vaccination appeared safe, but some patients developed new anti-HLA antibodies post vaccination. Alternative strategies to improve vaccine responses are necessary.

Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes.

Individual studies indicate that kidney transplantation is associated with lower mortality and improved quality of life compared with chronic dialysis treatment. We did a systematic review to summarize the benefits of transplantation, aiming to identify characteristics associated with especially large or small relative benefit. Results were not pooled because of expected diversity inherent to observational studies. Risk of bias was assessed using the Downs and Black checklist and items related to time-to-event analysis techniques. MEDLINE and EMBASE were searched up to February 2010. Cohort studies comparing adult chronic dialysis patients with kidney transplantation recipients for clinical outcomes were selected. We identified 110 eligible studies with a total of 1 922 300 participants. Most studies found significantly lower mortality associated with transplantation, and the relative magnitude of the benefit seemed to increase over time (p < 0.001). Most studies also found that the risk of cardiovascular events was significantly reduced among transplant recipients. Quality of life was significantly and substantially better among transplant recipients. Despite increases in the age and comorbidity of contemporary transplant recipients, the relative benefits of transplantation seem to be increasing over time. These findings validate current attempts to increase the number of people worldwide that benefit from kidney transplantation.

Accepting kidneys from older living donors: impact on transplant recipient outcomes.

Older living kidney donors are regularly accepted. Better knowledge of recipient outcomes is needed to inform this practice. This retrospective cohort study observed kidney allograft recipients from Ontario, Canada between January 2000 and March 2008. Donors to these recipients were older living (≥ 60 years), younger living, or standard criteria deceased (SCD). Review of medical records and electronic healthcare data were used to perform survival analysis. Recipients received 73 older living, 1187 younger living and 1400 SCD kidneys. Recipients of older living kidneys were older than recipients of younger living kidneys. Baseline glomerular filtration rate (eGFR) of older kidneys was 13 mL/min per 1.73 m² lower than younger kidneys. Median follow-up time was 4 years. The primary outcome of total graft loss was not significantly different between older and younger living kidney recipients [adjusted hazard ratio, HR (95%CI): 1.56 (0.98-2.49)]. This hazard ratio was not proportional and increased with time. Associations were not modified by recipient age or donor eGFR. There was no significant difference in total graft loss comparing older living to SCD kidney recipients [HR: 1.29 (0.80-2.08)]. In light of an observed trend towards potential differences beyond 4 years, uncertainty remains, and extended follow-up of this and other cohorts is warranted.

The long-term quality of life of living kidney donors: a multicenter cohort study.

Previous studies that described the long-term quality of life of living kidney donors were conducted in single centers, and lacked data on a healthy nondonor comparison group. We conducted a retrospective cohort study to compare the quality of life of 203 kidney donors with 104 healthy nondonor controls using validated scales (including the SF36, 15D and feeling thermometer) and author-developed questions. Participants were recruited from nine transplant centers in Canada, Scotland and Australia. Outcomes were assessed a median of 5.5 years after the time of transplantation (lower and upper quartiles of 3.8 and 8.4 years, respectively). 15D scores (scale of 0 to 1) were high and similar between donors and nondonors (mean 0.93 (standard deviation (SD) 0.09) and 0.94 (SD 0.06), p = 0.55), and were not different when results were adjusted for several prognostic characteristics (p = 0.55). On other scales and author-developed questions, groups performed similarly. Donors to recipients who had an adverse outcome (death, graft failure) had similar quality of life scores as those donors where the recipient did well. Our findings are reassuring for the practice of living transplantation. Those who donate a kidney in centers that use routine pretransplant donor evaluation have good long-term quality of life.

Nucleic acid testing (NAT) of organ donors: is the 'best' test the right test? A consensus conference report.

Nucleic acid testing (NAT) for HIV, HBV and HCV shortens the time between infection and detection by available testing. A group of experts was selected to develop recommendations for the use of NAT in the HIV/HBV/HCV screening of potential organ donors. The rapid turnaround times needed for donor testing and the risk of death while awaiting transplantation make organ donor screening different from screening blood-or tissue donors. In donors with no identified risk factors, there is insufficient evidence to recommend routine NAT, as the benefits of NAT may not outweigh the disadvantages of NAT especially when false-positive results can lead to loss of donor organs. For donors with identified behavioral risk factors, NAT should be considered to reduce the risk of transmission and increase organ utilization. Informed consent balancing the risks of donor-derived infection against the risk of remaining on the waiting list should be obtained at the time of candidate listing and again at the time of organ offer. In conclusion, there is insufficient evidence to recommend universal prospective screening of organ donors for HIV, HCV and HBV using current NAT platforms. Further study of viral screening modalities may reduce disease transmission risk without excessive donor loss.

Impact of immunosuppressive medication on the risk of renal allograft failure due to recurrent glomerulonephritis.

Recurrent glomerulonephritis is a major problem in kidney transplantation but the role of immunosuppression in preventing this complication is not known. We used data from the United States Renal Data System to examine the effect of immunosuppressive medication on allograft failure due to recurrent glomerulonephritis for 41,272 patients undergoing kidney transplantation from 1990 to 2003. Ten-year incidence of graft loss due to recurrent glomerulonephritis was 2.6% (95% confidence interval [CI]: 2.3-2.8%). After adjusting for important covariates, the use of cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, sirolimus or prednisone was not associated with graft failure due to recurrent glomerulonephritis. There was no difference between cyclosporine and tacrolimus or between azathioprine and mycophenolate mofetil in the risk of graft failure due to recurrent glomerulonephritis. However, any change in immunosuppression during follow-up was independently associated with graft loss due to recurrence (adjusted hazard ratio 1.30, 95% CI: 1.06-1.58, p = 0.01). In patients with a pretransplant diagnosis of glomerulonephritis, the risk of graft loss due to recurrence was not associated with any specific immunosuppressive medication. The selection of immunosuppression for kidney transplant recipients should not be made with the goal of reducing graft failure due to recurrent glomerulonephritis.

Quenched flow analysis of exocytosis in Paramecium cells: time course, changes in membrane structure, and calcium requirements revealed after rapid mixing and rapid freezing of intact cells.

Synchronous exocytosis in Paramecium cells was analyzed on a subsecond time scale. For this purpose we developed a quenched flow device for rapid mixing and rapid freezing of cells without impairment (time resolution in the millisecond range, dead time approximately 30 ms). Cells frozen at defined times after stimulation with the noncytotoxic secretagogue aminoethyldextran were processed by freeze substitution for electron microscopic analysis. With ultrathin sections the time required for complete extrusion of secretory contents was determined to be less than 80 ms. Using freeze-fracture replicas the time required for resealing of the fused membranes was found to be less than 350 ms. During membrane fusion (visible 30 ms after stimulation) specific intramembranous particles in the cell membrane at the attachment sites of secretory organelles ("fusion rosette") disappear, possibly by dissociation of formerly oligomeric proteins. This hitherto unknown type of rapid change in membrane architecture may reflect molecular changes in protein-protein or protein-lipid interactions, presumably crucial for membrane fusion. By a modification of the quenched flow procedure extracellular [Ca++] during stimulation was adjusted to less than or equal to 3 x 10(-8) M, i.e., below intracellular [Ca++]. Only extrusion of the secretory contents, but not membrane fusion, was inhibited. Thus it was possible to separate both secretory events (membrane fusion from contents extrusion) and to discriminate their Ca++ requirements. We conclude that no Ca++ influx is necessary for induction of membrane fusion.

Fusion of liposomes with the plasma membrane of epithelial cells: fate of incorporated lipids as followed by freeze fracture and autoradiography of plastic sections.

The fusion of liposomes with the plasma membrane of influenza virus-infected monolayers of an epithelial cell line, Madin-Darby canine kidney cells (van Meer et al., 1985. Biochemistry. 24:3593-3602), has been analyzed by morphological techniques. The distribution of liposomal lipids over the apical and basolateral plasma membrane domains after fusion was assessed by autoradiography of liposomal [3H]dipalmitoylphosphatidylcholine after rapid freezing or chemical fixation and further processing by freeze substitution and low temperature embedding. Before fusion, radioactivity was solely detected on the apical cell surface, indicating the absence of redistribution artifacts and demonstrating the reliability of lipid autoradiography on both a light and electron microscopical level. After induction of fusion by a low pH treatment, the basolateral plasma membrane domain became progressively labeled, indicative of rapid lateral diffusion of [3H]dipalmitoylphosphatidylcholine in the plasma membrane. Analysis of individual fusion events by freeze fracture after rapid freezing confirmed the rapid diffusion of the liposomal lipids into the plasma membrane, as intramembrane particle-free lipid patches were never observed. After the induction of liposome-cell fusion, well-defined intramembrane particles were present on the otherwise smooth liposomal fracture faces and on the fracture faces of the plasma membrane. Morphological evidence thus was obtained in favor of a local point fusion mechanism with an intramembrane particle as a specific structural fusion intermediate.

Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy.

Cypher is a member of a recently emerging family of proteins containing a PDZ domain at their NH(2) terminus and one or three LIM domains at their COOH terminus. Cypher knockout mice display a severe form of congenital myopathy and die postnatally from functional failure in multiple striated muscles. Examination of striated muscle from the mutants revealed that Cypher is not required for sarcomerogenesis or Z-line assembly, but rather is required for maintenance of the Z-line during muscle function. In vitro studies demonstrated that individual domains within Cypher localize independently to the Z-line via interactions with alpha-actinin or other Z-line components. These results suggest that Cypher functions as a linker-strut to maintain cytoskeletal structure during contraction.

Is phosphorus recovery from waste water feasible?

Phosphorus (P) recovery from waste water must become a predominant goal of all countries to face the limited resources of this essential nutrient. The induced crystallisation of calcium phosphates straight from the waste water phase applying tobermorite-rich calcium silicate hydrate compounds (CSH) from the construction industry as the trigger material has proved to be a suitable method. Laboratory and semi-technical scale experiments were carried out in fixed bed, stirred reactor and expanded bed mode. P-loads of the crystallisation substrates of up to 13 wt-% total P (P-tot) (30 wt-% P2O5) were achieved. Recycling options of the generated products, both as substitute for phosphate rock in the phosphate industry and as a new fertiliser in agriculture, were demonstrated. Indicative operating and investment costs were estimated for conversion of conventional waste water treatment plants (WWTP) designed for nutrient removal and P-precipitation with iron and aluminium reagents to the proposed new crystallisation technology for simultaneous P-removal and P-recovery.

Use of the embedded peritoneal dialysis catheter: experience and results from a North American Center.

Since 2000, the Ottawa Hospital Home Dialysis Program has used a variation on the embedded peritoneal dialysis catheter technique described by Moncrief et al. In this paper, we describe our approach to placement of peritoneal access and report our experience with 304 embedded catheters placed between January 2000 and December 2003. We review the advantages and disadvantages of this technique and describe factors that have been important to the success of our program.

Long-term safety and efficacy after conversion of maintenance renal transplant recipients from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPA, myfortic).

AIM: A 12-month multicenter, double-blind trial in which maintenance renal transplant patients were randomized to remain on mycophenolate mofetil (MMF) or convert to enteric-coated mycophenolate sodium (EC-MPS, myfortic) has demonstrated that conversion from MMF to EC-MPS is safe. Patients completing the study were invited to enter an open-label extension. Upon entry to the extension, patients who had received MMF during the randomized phase were converted to EC-MPS ("newly-exposed EC-MPS" group) and were monitored separately from those who had been randomized to EC-MPS ("long-term EC-MPS" group). The aim of the extension study was to collect long-term safety and efficacy data on EC-MPS, and to confirm the safety of conversion from MMF to EC-MPS in a larger patient population. METHODS: All patients received EC-MPS 720 mg b.i.d. with cyclosporine microemulsion and corticosteroids per local practice. Data derived from the analysis of the first 24 months of the extension phase are presented. RESULTS: Of the 297 patients who completed the core study, 260 (88%) entered the extension; 195 (75%) completed the 24-month extension visit. For on-treatment patients > 95% of the planned daily dose of EC-MPS was administered, and < 13% of patients in both groups had discontinued EC-MPS due to adverse events by 24 months. The overall incidence of adverse events during the extension phase, including infections and hematological abnormalities, was comparable to that seen in the core study, with a similar safety profile in the newly-exposed and long-term EC-MPS groups. There were 3 deaths during the first 24 months of the extension, and 2 graft failures in both the "newly-exposed" and "long-term" EC-MPS groups. CONCLUSIONS: These data demonstrate that long-term use of EC-MPS is effective and has an acceptable tolerability profile in renal transplant patients, and confirm that conversion of maintenance renal transplant patients from MMF to EC-MPS is a safe therapeutic option.