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Background: Although measuring albuminuria is the preferred method for defining and staging chronic kidney disease (CKD), total urine protein or dipstick protein is often measured instead. Objective(s): To develop equations for converting urine protein-creatinine ratio (PCR) and dipstick protein to urine albumin-creatinine ratio (ACR) and to test their diagnostic accuracy in CKD screening and staging. Design(s): Individual participant-based meta-analysis. Setting(s): 12 research and 21 clinical cohorts. Participant(s): 919 383 adults with same-day measures of ACR and PCR or dipstick protein. Measurements: Equations to convert urine PCR and dipstick protein to ACR were developed and tested for purposes of CKD screening (ACR >=30 mg/g) and staging (stage A2: ACR of 30 to 299 mg/g; stage A3: ACR >=300 mg/g). Result(s): Median ACR was 14 mg/g (25th to 75th percentile of cohorts, 5 to 25 mg/g). The association between PCR and ACR was inconsistent for PCR values less than 50 mg/g. For higher PCR values, the PCR conversion equations demonstrated moderate sensitivity (91%, 75%, and 87%) and specificity (87%, 89%, and 98%) for screening (ACR >30 mg/g) and classification into stages A2 and A3, respectively. Urine dipstick categories of trace or greater, trace to +, and ++ for screening for ACR values greater than 30 mg/g and classification into stages A2 and A3, respectively, had moderate sensitivity (62%, 36%, and 78%) and high specificity (88%, 88%, and 98%). For individual risk prediction, the estimated 2-year 4-variable kidney failure risk equation using predicted ACR from PCR had discrimination similar to that of using observed ACR. Limitation(s): Diverse methods of ACR and PCR quantification were used; measurements were not always performed in the same urine sample. Conclusion(s): Urine ACR is the preferred measure of albuminuria; however, if ACR is not available, predicted ACR from PCR or urine dipstick protein may help in CKD screening, staging, and prognosis. Primary

Item does not contain fulltext, BACKGROUND: Although measuring albuminuria is the preferred method for defining and staging chronic kidney disease (CKD), total urine protein or dipstick protein is often measured instead. OBJECTIVE: To develop equations for converting urine protein-creatinine ratio (PCR) and dipstick protein to urine albumin-creatinine ratio (ACR) and to test their diagnostic accuracy in CKD screening and staging. DESIGN: Individual participant-based meta-analysis. SETTING: 12 research and 21 clinical cohorts. PARTICIPANTS: 919 383 adults with same-day measures of ACR and PCR or dipstick protein. MEASUREMENTS: Equations to convert urine PCR and dipstick protein to ACR were developed and tested for purposes of CKD screening (ACR ≥30 mg/g) and staging (stage A2: ACR of 30 to 299 mg/g; stage A3: ACR ≥300 mg/g). RESULTS: Median ACR was 14 mg/g (25th to 75th percentile of cohorts, 5 to 25 mg/g). The association between PCR and ACR was inconsistent for PCR values less than 50 mg/g. For higher PCR values, the PCR conversion equations demonstrated moderate sensitivity (91%, 75%, and 87%) and specificity (87%, 89%, and 98%) for screening (ACR >30 mg/g) and classification into stages A2 and A3, respectively. Urine dipstick categories of trace or greater, trace to +, and ++ for screening for ACR values greater than 30 mg/g and classification into stages A2 and A3, respectively, had moderate sensitivity (62%, 36%, and 78%) and high specificity (88%, 88%, and 98%). For individual risk prediction, the estimated 2-year 4-variable kidney failure risk equation using predicted ACR from PCR had discrimination similar to that of using observed ACR. LIMITATION: Diverse methods of ACR and PCR quantification were used; measurements were not always performed in the same urine sample. CONCLUSION: Urine ACR is the preferred measure of albuminuria; however, if ACR is not available, predicted ACR from PCR or urine dipstick protein may help in CKD screening, staging, and prognosis. PRIMARY FUNDING SOURCE: Nati

Rationale & Objective: The number of people with diabetes and end-stage kidney disease (ESKD) is increasing worldwide, but it is unknown whether this indicates an increasing risk for ESKD in people with diabetes. We examined temporal trends in the incidence of ESKD within the Australian population with diabetes from 2002 to 2013. Study Design: Follow-up study using a national health care services registry. Setting & Participants: Registrants with type 1 or type 2 diabetes in Australia's National Diabetes Services Scheme (NDSS). Predictors: Age, sex, indigenous status, diabetes type, and calendar year. Outcome(s): Incidence of ESKD (dialysis or kidney transplantation) or death ascertained using the Australian and New Zealand Dialysis and Transplant Registry and the Australian national death index. Analytical Approach: NDSS registrants were followed up from 2002 or date of registration until onset of ESKD, death, or December 31, 2013. The incidence of ESKD in type 1 diabetes was calculated only in those younger than 55 years. Result(s): Among 1,375,877 registrants between 2002 and 2013, a total of 9,977 experienced incident ESKD, representing an overall incidence of ESKD in people with diabetes of 10.0 (95% CI, 9.8-10.2) per 10,000 person-years. Among those with type 1 diabetes, the age-standardized annual incidence was stable during the study period. Among those with type 2 diabetes, the incidence increased in nonindigenous people (annual percentage change, 2.2%; 95% CI, 0.4%-4.1%) with the greatest increases in those younger than 50 and those older than 80 years. No significant change over time was observed in indigenous people, although the adjusted incident rate ratio for indigenous versus nonindigenous was 4.03 (95% CI, 3.68-4.41). Limitation(s): Lack of covariates such as comorbid conditions, medication use, measures of quality of care, and baseline kidney function. Conclusion(s): The age-standardized annual incidence of ESKD increased in Australia from 2002 to

Background: The role of chronic kidney disease (CKD) as a risk factor for cognitive impairment independent of their shared antecedents remains controversial. Objective(s): To determine whether kidney damage (indicated by albuminuria) or kidney dysfunction (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2) predict future (12-year) cognitive function independently of their shared risk factors. Method(s): We studied 4,128 individuals from the 1999/00 population-based Australian Diabetes, Obesity, and Lifestyle (AusDiab) Study who returned in 2011/12 for follow-up cognitive function testing. Albuminuria was defined by urinary albumin:creatinine>=3.5 (women) or>=2.5 mg/mmol (men). Kidney dysfunction was indicated by eGFR <60 ml/min/1.73 m2. Cognitive function domains assessed included memory (California Verbal Learning Test [CVLT]) and processing speed (Symbol Digit Modalities Test [SDMT]). Result(s): Baseline albuminuria and kidney dysfunction were identified in 142 (3.4%) and 39 (0.9%) individuals, respectively, with minimal overlap (n = 7). Those with albuminuria demonstrated concurrently reduced 12-year SDMT (p = 0.084) and CVLT scores (p = 0.005) following adjustment for age, sex, and education. However, only CVLT performance remained worse (p = 0.027) following additional adjustment for myocardial infarction, stroke, and related risk factors (hypertension, diabetes, dyslipidemia, smoking, BMI, physical activity, and alcohol intake). Indeed, these collective covariates were responsible for 47% of the effect of albuminuria on SDMT, but only 21% of its effect on CVLT. Kidney dysfunction was not associated with either SDMT or CVLT performance (p > 0.10). Conclusion(s): Albuminuria predicted worse memory function at 12 years follow-up, whereas its effect on processing speed was driven largely by differences in cardiovascular risk. Kidney dysfunction based on eGFR predicted neither cognitive domain.Copyright © 2019-IOS Press and the authors. All rights rese

Aim: We aimed to describe the impact and experience of being deemed ineligible as a living kidney donor. Method(s): Semi-structured interviews were conducted with 27 ineligible donor candidates. Transcripts were analysed thematically. Result(s): Seven themes were identified: deriving health and relationship benefits in the process (strengthening emotional connection, identifying problematic health conditions); devastating loss and disappointment (harbouring guilt over personal failings, shattering confidence and hope, undermining relationships with extended family and friends, disrupting home dynamics); constrained within a rigid system (denied autonomy, resorting to other avenues); acknowledging as matter of fact (accepting the clinical decision, reassured by preventing a poor outcome); reluctant to relinquish the donor identity (unable to fulfil family duty, having the donor role stolen, holding onto other opportunities to donate); uncertainty in unpredictability, inconsistency and ambiguities (frustrated by inefficiencies, questioning clinician motivation, suspended donor status, unfairness in changeable eligibility criteria, unresolved concerns and questions of own health); and abandoned in despair (lacking practical support to meet eligibility criteria, ill prepared for rejection, dismissed and discarded by the system). Conclusion(s): Being deemed unsuitable for donation took an emotional toll on ineligible donor candidates who felt immense guilt for 'failing' the potential recipient. Ineligible donor candidates were frustrated and angry with the perceived lack of support from clinicians and rigidity of the evaluation process. Informing potential donors of available services, including psychological support, communicating the decision sensitively and with sufficient time, and full disclosure of their health status, may contribute to improved adjustment following the ineligibility decision.Copyright © 2019 Asian Pacific Society of Nephrology

Background Ensuring donor wellbeing warrants ongoing monitoring after living kidney donation. However, there is considerable variability in donor follow-up processes, including information provided to donors regarding self-care. Loss to follow-up is common, suggesting that the aims and benefits of monitoring and follow-up may not be apparent. We aimed to describe the experiences and expectations of living kidney donors regarding follow-up and self-care after donation. Methods Participants from 3 transplant centers in Australia and Canada participated in 14 focus groups (n = 123). Transcripts were analyzed thematically. Results We identified 4 themes: Lacking identification as a patient (invincibility and confidence in health, immediate return to normality, avoid burdening specialty services, redundancy of specialist attention, unnecessary travel), empowerment for health (self-preservation for devastating consequences, self-advocacy and education, needing lifestyle advice, tracking own results), safety net and reassurance (availability of psychosocial support, confidence in kidney-focused care, continuity and rapport, and access to waitlist priority), and neglect and inattention (unrecognized ongoing debilitations, primary focus on recipient, hospital abandonment, overlooking individual priorities, disconnected from system, coping with dual roles, and lacking support for financial consequences). Conclusions Living kidney donors who felt well and confident about their health regarded specialist follow-up as largely unnecessary. However, some felt they did not receive adequate medical attention, were prematurely detached from the health system, or held unresolved anxieties about the consequences of their decision to donate. Ongoing access to healthcare, psychosocial support, and education may reassure donors that any risks to their health are minimized.Copyright © 2017 Wolters Kluwer Health, Inc.

Background To determine the incremental gains in graft and patient survival under a risk-based, deceased donor kidney allocation compared with the current Australian algorithm. Methods Risk-based matching algorithms were applied to first graft, kidney only recipients (n = 7513) transplanted in Australia between 1994 and 2013. Probabilistic models were used to compare the waiting time, life, and QALYs and graft years between the 8 risk-based allocation strategies against current practice. Results Compared with current practice, Kidney Donor Risk Index-Estimated Posttransplant Survival matching of the lowest 20% of scores reduced median waiting time by 0.64 years (95% confidence interval [CI], 0.52-0.73) for recipients aged 30 years or younger, but increased waiting time by 0.94 years (95% CI, 0.79-1.09) for recipients older than 60 years. Among all age groups, the greatest gains occurred if Kidney Donor Risk Index-Estimated Posttransplant Survival matching of the lowest 30% of scores was used, incurring a median overall gain of 0.63 (95% CI, 0.03-1.25) life years and 0.78 (95% CI, 0.30-1.26) graft years compared with the current practice. A median gain in survival of 1.91 years for younger recipients (aged 30-45 years) was offset by a median reduction in survival (by 0.95 life years) among the older recipients. Prioritization of lower-quality donor kidneys for older candidates reduced the waiting time for recipients older than 45 years, but no changes in graft and patient survivals were observed. Conclusions Risk-based matching engendered a moderate, overall increase in graft and patient survivals, accrued through benefits for recipients 45 years or younger but disadvantage to recipients older than 60 years.Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Background andobjectives Living kidneydonor candidates accept a range of risks and benefits when they decide to proceed with nephrectomy. Informed consent around this decision assumes they receive reliable data about outcomes they regard as critical to their decision making. We identified the outcomes most important to living kidney donors and described the reasons for their choices. Design, setting, participants, & measurements Previous donors were purposively sampled from three transplant units in Australia (Sydney and Melbourne) and Canada (Vancouver). In focus groups using the nominal group technique, participants identified outcomes of donation, ranked them in order of importance, and discussed the reasons for their preferences. An importance score was calculated for each outcome. Qualitative data were analyzed thematically. Results Across 14 groups, 123 donors aged 27-78 years identified 35 outcomes. Across all participants, the ten highest ranked outcomes were kidney function (importance=0.40, scale 0-1), time to recovery (0.27), surgical complications (0.24), effect on family (0.22), donor-recipient relationship (0.21), life satisfaction (0.18), lifestyle restrictions (0.18), kidney failure (0.14), mortality (0.13), and acute pain/discomfort (0.12). Kidney function and kidney failure were more important to Canadian participants, compared with Australian donors. The themes identified included worthwhile sacrifice, insignificance of risks and harms, confidence and empowerment, unfulfilled expectations, and heightened susceptibility. Conclusions Living kidney donors prioritized a range of outcomes, with the most important being kidney health and the surgical, lifestyle, functional, and psychosocial effects of donation. Donors also valued improvements to their family life and donor-recipient relationship. There were clear regional differences in the rankings.Copyright © 2018 by the American Society of Nephrology.

Background Many donors and recipients report an improved relationship after transplantation; however, tension, neglect, guilt, and proprietorial concern over the recipient can impede donor and recipient well-being and outcomes. We aimed to describe donor and recipient expectations and experiences of their relationship in the context of living kidney donation. Study Design Thematic synthesis of qualitative studies. Setting & Population Living kidney donors and recipients. Search Strategy & Sources Electronic databases were searched to October 2015. Analytical Approach Thematic synthesis. Results From 40 studies involving 1,440 participants (889 donors and 551 recipients) from 13 countries, we identified 6 themes. "Burden of obligation" described the recipient's perpetual sense of duty to demonstrate gratitude to the donor. "Earning acceptance" was the expectation that donation would restore relationships. "Developing a unique connection" reflected the inexplicable bond that donor-recipient dyads developed postdonation. "Desiring attention" was expressed by donors who wanted recognition for the act of donation and were envious and resentful of the attention the recipient received. "Retaining kidney ownership" reflected the donor's inclination to ensure that the recipient protected "their" kidney. "Enhancing social participation" encompassed relieving both the caregiver from the constraints of dialysis and the recipient from increased involvement and contribution in family life. Limitations Non-English articles were excluded. Conclusions Living kidney donation can strengthen donor-recipient relationships but may trigger or exacerbate unresolved angst, tension, jealousy, and resentment. Facilitating access to pre- and posttransplantation psychological support that addresses potential relationship changes may help donors and recipients better adjust to changes in the relationship dynamics, which in turn may contribute to improved psychosocial and transplantation outcomes

Kidney transplant recipients are at a high risk of developing cancers after transplantation. Switching from calcineurin inhibitors to sirolimus has been shown to prevent secondary nonmelanoma skin cancer but whether everolimus with reduced exposure to calcineurin inhibitors has similar anti-cancer effects remains unknown. Therefore, we compared the risk of incident cancer over seven years of follow-up among kidney transplant recipients randomized to everolimus plus reduced exposure cyclosporine versus mycophenolate sodium and standard exposure cyclosporine. Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the seven-year risk of incident cancer and other graft outcomes among a subgroup of recipients who had participated in the A2309 study using adjusted Cox proportional hazard models. Of 95 recipients, 66 were randomized to everolimus (1.5 mg or 3 mg) with reduced cyclosporine and 29 received mycophenolate sodium and standard exposure cyclosporine. Compared to mycophenolate sodium and standard exposure cyclosporine, everolimus treatment was associated with unadjusted hazard ratios of 0.28 (95% confidence interval 0.11-0.74), 0.39 (0.16-0.98) and 0.41 (0.23-0.71), respectively for nonmelanoma skin cancer, non-skin cancers and any cancers. Interestingly, the adjusted hazard ratios were 0.34 (0.13-0.91), 0.35 (0.09-1.25) and 0.32 (0.15-0.71), respectively. There was no association between treatment groups and rejection, graft loss or death. Compared to standard-exposure cyclosporine, everolimus with reduced exposure to cyclosporine may be associated with a reduced risk of cancer, particularly for non-melanoma skin cancer. Thus, if confirmed in larger patient cohorts, de novo use of everolimus with reduced exposure to calcineurin inhibitors may enable a reduction in cancer burden after transplantation.Copyright © 2017 International Society of Nephrology

Background Recent literature suggests that living kidney donation may be associated with an excess risk of end-stage kidney disease and death. Efforts to maximize access to transplantation may result in acceptance of donors who do not fit within current guidelines, potentially placing them at risk of adverse long-Term outcomes. Methods We studied the risk profile of Australian and New Zealand living kidney donors using data from the Australia and New Zealand Dialysis and Transplant Living Kidney Donor Registry over 2004 to 2012. We compared their predonation profile against national guidelines for donor acceptance. Results The analysis included 2,932 donors (mean age 48.8 +/- 11.2 years, range 18-81), 58% female and 87% Caucasian. Forty (1%) had measured glomerular filtration rate less than 80 mL/min; 32 (1%) had proteinuria >300 mg/day; 589 (20%) were hypertensive; 495 (18%) obese; 9 (0.3%) were diabetic while a further 55 (2%) had impaired glucose tolerance; and 218 (7%) were current smokers. Overall 767 donors (26%) had at least one relative contraindication to donation and 268 (9%) had at least one absolute contraindication according to national guidelines. Conclusions Divergence of current clinical practice from national guidelines has occurred. In the context of recent evidence demonstrating elevated long-Term donor risk, rigorous follow-up and reporting of outcomes are now mandated to ensure safety and document any change in risk associated with such a divergence.Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Background: Living kidney donors must accept risks associated with nephrectomy. While this is ethically justified with informed consent, screening and access to follow up, the outcomes that are most important to donors are yet to be established. We aimed to identify living kidney donor's priorities for outcomes and describe the reasons for their choices. Method(s): Living kidney donors were purposively sampled from two Australian transplant centres. Participants identified important outcomes of kidney donation, ranked the importance of the outcomes, and discussed reasons for their priorities. For each outcome, we calculated a mean rank score from zero (least important) to 10 (most important) and analysed the transcripts thematically. Result(s): Across eight nominal groups, 67 participants aged 27-78 years identified 32 outcomes. The highest ranked outcomes were: time to recovery (mean rank score 5.39, SD =3.77), family life (5.24, SD = 4.02), donor-recipient relationship (4.25, SD = 4.07), diet and lifestyle restrictions (3.90, SD = 3.55), and kidney function (3.76, SD = 3.50). Kidney failure and mortality ranked 10th and 13th respectively. Women ranked the donor-recipient relationship, life satisfaction, and family life higher than men; whilst men ranked kidney failure, physical function (fitness), mortality and kidney function higher. The themes underpinning participants' priorities included: overriding concern for recipient wellbeing, undeterred by low risks, heightened susceptibility and unfulfilled expectations. Conclusion(s): Living kidney donors prioritised outcomes that could potentially disrupt their lifestyle and relationships, were unexpected, or caused fear and anxiety about their health. Donor assessment and follow up should address expectations regarding recovery time, relationship challenges and possible constraints on vocational and recreational activities; and donors may be more empowered with advice about diet, exercise and other healthy lifestyle

Research aims to improve health outcomes for patients. However, the setting of research priorities is usually performed by clinicians, academics, and funders, with little involvement of patients or caregivers and using processes that lack transparency. A national workshop was convened in Australia to generate and prioritize research questions in chronic kidney disease (CKD) among diverse stakeholder groups. Patients with CKD (n = 23), nephrologists/surgeons (n = 16), nurses (n = 8), caregivers (n = 7), and allied health professionals and researchers (n = 4) generated and voted on intervention questions across 4 treatment categories: CKD stages 1 to 5 (non-dialysis dependent), peritoneal dialysis, hemodialysis, and kidney transplantation. The 5 highest ranking questions (in descending order) were as follows: How effective are lifestyle programs for preventing deteriorating kidney function in early CKD? What strategies will improve family consent for deceased donor kidney donation, taking different cultural groups into account? What interventions can improve long-term post-transplant outcomes? What are effective interventions for post hemodialysis fatigue? How can we improve and individualize drug therapy to control post-transplant side effects? Priority questions were focused on prevention, lifestyle, quality of life, and long-term impact. These prioritized research questions can inform funding agencies, patient/consumer organizations, policy makers, and researchers in developing a CKD research agenda that is relevant to key stakeholders.Copyright © 2015 National Kidney Foundation, Inc.

Item does not contain fulltext, IMPORTANCE: The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of -57% or greater) is a late event. OBJECTIVE: To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated. DATA SOURCES AND STUDY SELECTION: Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data. DATA EXTRACTION AND SYNTHESIS: Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012. MAIN OUTCOMES AND MEASURES: End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR. RESULTS: The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of -57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of -30%. However, changes of -30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of -57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or al

Aim: We studied the risk-factor profile of Australian and New Zealand kidney donors over 2004-10. Background(s): Existing literature suggests that living kidney donation within the bounds of current guidelines is relatively safe. However, efforts to maximise access to transplantation may result in acceptance of donors who do not fit within current guidelines. Method(s): We extracted data from the ANZDATA Living Kidney Donor Registry, including donors from 2004-2010 and excluding pathological donors, and compared their profile against the Caring for Australasians with Renal Impairment (CARI) guidelines for donor acceptance. Result(s): The analysis included 2,349 donors aged 48.5 +/- 11.1 years (range 18-81). 1,356 donors (57.7%) were female, and the majority were Caucasian (2,051 donors, 87.3%). Forty-six donors (2.0%) had a measured GFR < 80 mL/ min and 32 (1.4%) had proteinuria > 300 mg/day. Cardiovascular risk factors were common - 323 (13.8%) were hypertensive; 978 (41.6%) were overweight (BMI 25-29.9 kg/m2) and 402 (17.1%) were obese (BMI >= 30 kg/m2); 7 (0.3%) were diabetic and 46 (2.0%) had impaired glucose tolerance; and 187 (8.0%) were smokers at the time of donation. Only 980 donors (41.7%) had no reported cardiovascular risk factors. According to CARI guidelines 457 donors (19.5%) had at least one relative contraindication to donation and 283 (12.0%) had at least one absolute contraindication to donation. Conclusion(s): The majority of living kidney donors in Australia and New Zealand have one or more cardiovascular risk factors, and a substantial minority have a relative or absolute contraindication to donation according to CARI guidelines. In the context of the known increase in cardiovascular risk associated with chronic kidney disease among the general community, these findings mandate tight followup of this cohort. Heightened awareness of donor risk may be appropriate.

Kidney transplant recipients receiving calcineurin inhibitor-based immunosuppression incur increased long-term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36-month, prospective, multinational, open-label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI-WD); everolimus with mycophenolate and steroid withdrawal (steroid-WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI-WD versus control was 65.1 ml/min/1.73 m2 vs. 67.1 ml/min/1.73 m 2 by ITT, which met predefined noninferiority criteria (P = 0.026). The CNI-WD group experienced a higher rate of BPAR(31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow-up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients. © 2013 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.

Aim: To generate and rank research priorities in chronic kidney disease (CKD). Background(s): Research aims to improve treatment and health outcomes for patients. Yet, research priorities are usually determined by clinicians, academics and funders; and there is little transparency in the prioritisation process. Method(s): A national priority setting partnership workshop was convened on the 7th February 2014. The 58 participants included patients with CKD (n = 23), caregivers (n = 7), nephrologists/surgeon (n = 16), nurses (n = 8), and allied health professionals and researchers (n = 4). In facilitated groups of 8-10, participants generated and "voted" on research questions in four CKD stages: early stage (non-dialysis-dependent) CKD, peritoneal dialysis, haemodialysis, and kidney transplantation. Votes were summed to identify the top 20 questions across all CKD stages which were then individually ranked by the participants. Result(s): Eighty-three research questions were formulated. The top five research questions were: (1) How effective are lifestyle programs such as diet, exercise and smoking cessation for preventing deterioration in kidney function in patients with early CKD? (2) What interventions can improve long-term post-transplant outcomes (drugs, lifestyle)? (3) What strategies will improve donor family consent to deceased donation taking different cultural groups into account? (4) What strategies help patients maintain work while on HD? (5) How can we improve and individualise drug therapy in terms of better management of side effects? Conclusion(s): Priority questions were focussed on prevention, lifestyle, quality of life, and long-term impact. Priority setting partnerships provide an opportunity for wide stakeholder engagement to explore and identify research priorities. The prioritised research questions can inform patient/consumer organisations, researchers, policy makers, and funding agencies in developing a CKD research agenda that is relevant to pa

Background: Low serum 25-hydroxyvitamin D (25[OH]D) levels have been associated with chronic kidney disease in cross-sectional studies. However, this association has not been studied prospectively in a large general population-based cohort. Study Design: Prospective cohort study. Setting & Participants: 6,180 adults 25 years or older participating in the baseline and 5-year follow-up phases of the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study. Predictor: Serum 25(OH)D levels <15 ng/mL were considered deficient. Outcomes & Measurements: Incident chronic kidney disease was defined as being negative at baseline but positive after 5 years for (1) reduced estimated glomerular filtration rate (eGFR; <60 mL/min/1.72 m2) or (2) albuminuria (spot urine albumin-creatinine ratio >=2.5 mg/mmol [>=22.1 mg/g] for men and >=3.5 mg/mmol [>=30.9 mg/g] for women). Result(s): 623 (10.9%) participants were vitamin D deficient, 161 developed incident reduced eGFR, and 222 developed incident albuminuria. In participants with and without vitamin D deficiency, annual age-standardized incidences were 0.92% (95% CI, 0.56%-1.30%) and 0.59% (95% CI, 0.51%-0.68%), respectively, for eGFR <60 mL/min/1.72 m2 and 1.50% (95% CI, 1.06%-1.95%) and 0.66% (95% CI, 0.56%-0.76%), respectively, for albuminuria. In multivariate regression models, vitamin D deficiency was associated significantly with the 5-year incidence of albuminuria (OR, 1.71; 95% CI, 1.12-2.61; P = 0.01), but not reduced eGFR (OR, 0.93; 95% CI, 0.53-1.66; P = 0.8). Limitation(s): The observational nature of the study does not account for unmeasured confounders. Only baseline 25(OH)D level was measured and therefore may not accurately reflect lifetime levels. Differences in baseline characteristics of participants who were included compared with those excluded due to missing data or follow-up may limit the applicability of results to the original AusDiab cohort. Conclusion(s): Our prospective cohort study shows that vitamin

Optimal detection and subsequent risk stratification of people with chronic kidney disease (CKD) requires simultaneous consideration of both kidney function (glomerular filtration rate [GFR]) and kidney damage (as indicated by albuminuria or proteinuria). Measurement of urinary albuminuria and proteinuria is hindered by a lack of standardisation regarding requesting, sample collection, reporting and interpretation of tests. A multidisciplinary working group was convened with the goal of developing and promoting recommendations that achieve consensus on these issues. The working group recommended that the preferred method for assessment of albuminuria in both diabetic and non-diabetic patients is urinary albumin-tocreatinine ratio (UACR) measurement in a first-void spot urine specimen. Where a first-void specimen is not possible or practical, a random spot urine specimen for UACR is acceptable. The working group recommended that adults with one or more risk factors for CKD should be assessed using UACR and estimated GFR every 1-2 years, depending on their risk-factor profile. Recommended testing algorithms and sex-specific cut-points for microalbuminuria and macroalbuminuria are provided. The working group recommended that all pathology laboratories in Australia should implement the relevant recommendations as a vital component of an integrated national approach to detection of CKD.

Background: Urine dipsticks, an inexpensive accessible test for proteinuria, are widely advocated for mass screening; however, their diagnostic accuracy in the general community is largely unknown. Study Design: Evaluation of diagnostic test accuracy in a cross-sectional cohort. Setting & Participants: AusDiab, a representative survey of Australian adults 25 years and older (conducted in 1999/2000). Stratified cluster random sampling from 11,247 individuals participating in the biomedical examination; complete urinalysis data available for 10,944. Index Test: Urine dipsticks (Bayer Multistix), with a positive result defined as <1+ or trace or higher protein. Reference Test: Albumin-creatinine ratio (ACR), measured on a random spot urine sample. Reference test positivity was defined as ACR <30 mg/g or ACR <300 mg/g. Result(s): Numbers of participants with ACR <30, 30-300, and <300 mg/g were 10,219 (93.4%), 634 (5.8%), and 91 (0.8%), respectively. The area under the receiver operating characteristic curve (AUC) for dipstick detection of ACR <30 mg/g was 0.8451 +/- 0.0129 (SE) in men and 0.7775 +/- 0.0131 in women (P < 0.001). The AUROC for dipstick detection of ACR <300 mg/g was 0.9904 +/- 0.0030 in men and 0.9950 +/- 0.0016 in women (P = 0.02). Dipstick result <1+ identified ACR <30 mg/g with 57.8% sensitivity (95% CI, 54.1%-61.4%) and 95.4% specificity (95% CI, 95.0%-95.8%) and identified ACR <300 mg/g with 98.9% sensitivity (99% CI, 92.1%-100%) and 92.6% specificity (99% CI, 92.0%-93.3%). A dipstick result of trace or higher identified ACR <30 mg/g with 69.4% sensitivity (95% CI, 65.9%-72.7%) and 86.8% specificity (95% CI, 86.1%-87.4%) and identified ACR <300 mg/g with 100% sensitivity (99% CI, 94.3%-100%) and 83.7% specificity (99% CI, 82.8%-84.6%). A negative dipstick result (less than trace) had a negative predictive value of 97.6% (95% CI, 97.2%-97.9%) for ACR <30 mg/g and a negative predictive value of 100% (99% CI, 99.9%-100%) for ACR <300 mg/g. The probabili

Background. Macrophages constitute 38% to 60% of infiltrating cells during acute renal allograft rejection. Their contribution to tissue damage during acute rejection was examined by depleting macrophages in a rat model. Methods. Lewis rats underwent bilateral nephrectomy and then received a Dark Agouti renal allograft and liposomal-clodronate, control phosphate-buffered saline liposomes, or saline intravenously (n=7 per group) on days 1 and 3 postsurgery. Grafts were harvested on day 5. Results. Liposomal-clodronate treatment resulted in a 70% reduction in blood ED1+ monocytes and 60% reduction in intragraft ED1+ macrophages (both P < 0.01). Half of all remaining interstitial ED1+ cells were undergoing apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling +/ED1+), and thus functional depletion of more than 75% of macrophages was achieved. Histologic and functional parameters of acute rejection were attenuated: interstitial infiltrate, tubulitis, and glomerulitis (P < 0.01); tubular cell apoptosis (P < 0.001); tubular cell proliferation (P < 0.001); and serum creatinine (P < 0.01). Production of inducible nitric oxide synthase by infiltrating cells and urinary nitric oxide excretion was reduced by 90% (P < 0.001). In contrast, no reduction in the number of other leukocytes was seen (CD3+, CD4+, CD8 +, and natural killer cells). Activation of lymphocytes (CD25 +) and production of lymphocyte effector molecules (granzyme B) were unaltered. Conclusion. This study demonstrates that macrophages contribute to tissue damage during acute rejection.

Macrophage accumulation has long been recognized as a feature of allograft rejection, yet the role of macrophages in rejection remains underappreciated. Macrophages contribute to both the innate and acquired arms of the alloimmune response and thus may be involved in all aspects of acute and chronic allograft rejection. Recent advances in macrophage biology have allowed a better understanding of the mechanisms of macrophage accumulation, their state of activation and the pleuripotent roles they play in allograft rejection. Therapeutic attention to macrophages, in addition to T lymphocytes, may lead to improved outcomes in organ transplantation. Copyright © 2005 by Lippincott Williams & Wilkins.

Background. Advances in immunosuppression have made renal transplantation an effective therapy for end stage renal failure; with low rejection rates and long graft survival times. However, the major adverse consequences, infection and malignancy have not diminished. To predict this risk a score of immune competence has been developed from the simultaneous laboratory assessment of multiple parameters of immune function. Methods. The immune status of 152 transplant recipients (138 renal and 14 pancreas/renal) was assessed by measurement of lymphocyte subsets, mitogen-induced T-cell proliferative responses, neutrophil phagocytic capacity and reactive oxygen species (ROS) generation. A scoring system was devised based on the average number of these parameters below 10th percentile of normal. Results. The most common abnormality was B-cell lymphopenia (85%) followed by reduced neutrophil ROS production (63% of patients), NK cell lymphopenia (50%), lymphocyte mitogen response (49%) and CD4 number (23%). The abnormalities were unrelated to the duration of immunosuppression (up to 15 years), and variable combinations of cyclosporine A, azathioprine, prednisolone and mycophenolate mofetil (MMF) (except for a consistent reduction in lymphocyte mitogen response in MMF treated patients). Retrospective comparison of infective episodes showed a significantly greater index of infections in patients with the worst score compared with a normal score. Conclusions. The data suggests that this quantification of immune function may allow assessment of the level of host immune defence reflecting the level of drug-induced immunosuppression and thus risks of immunosuppressive complications.

Interleukin-10 (IL-10) has been recognized as a growth factor for rat mesangial cells in vitro; however, its role in mesangioproliferative glomerulonephritis is unknown. We studied the expression of IL-10 mRNA in the rat anti-Thy-1 model of mesangioproliferative glomerulonephritis (experiment 1) and, subsequently, the effects of blocking IL-10 during anti-Thy-1 nephritis using the IL-10 inhibitor, AS101 (experiment 2). In experiment 1, PCR analysis failed to detect IL-10 mRNA in normal rat kidney, however, a clear signal for IL-10 mRNA was evident on day 6 of anti-Thy-1 nephritis. In situ hybridization showed IL-10 mRNA expression in focal glomerular areas in anti-Thy-1 nephritis. Combined in situ hybridization and immunohistochemistry showed that glomerular IL-10 mRNA was expressed by both macrophages and mesangial cells. In experiment 2, treatment with AS101 significantly downregulated renal IL-10 gene expression, as demonstrated by semiquantitative PCR. However, the induction of glomerular hypercellularity, mesangial proliferation (PCNA+ cells), mesangial cell activation (alpha-SMA expression) and macrophage accumulation (ED1+cells) seen in saline-treated anti-Thy-1 nephritis was unaffected by AS101 treatment. In conclusion, renal IL-10 gene expression is upregulated during pathological mesangial cell proliferation in rats with anti-Thy-1 nephritis. However, the inability of IL-10 suppression with AS101 to prevent anti-Thy-1 disease suggests that IL-10 is not essential for pathological mesangial cell proliferation.

Background. Studies of infiltrating cells from acutely rejecting renal allografts show that a high proportion of these cells are macrophages, and early macrophage infiltration is a poor prognostic sign for transplant survival. Macrophage colony-stimulating factor (M-CSF), produced by tubular and mesangial cells, has been associated with macrophage infiltration and proliferation in experimental and human kidney diseases. We investigated the expression of M-CSF in a model of acute rejection. Methods. Lewis rats underwent bilateral nephrectomies and received an orthotopic Dark Agouti allograft or Lewis isograft. Animals received cyclosporine (10 mg/kg/day) from day 0 to day 3 and were killed at days 4, 8, or 14 after transplantation. Macrophages (ED1+) and T cells (W3-13+) were identified by immunohistochemistry, and M-CSF expression was identified by Northern blotting and in situ hybridization. Results. Isografts had normal renal function without histological evidence of rejection. Allografts exhibited a moderate infiltrate at day 4 but progressed to severe rejection at day 14, with elevated serum creatinine level and severe tubulointerstitial damage. Macrophages and T cells were present in equal proportion in the infiltrate at day 4. At day 14, the number of macrophages increased fivefold (2580/mm2), although T cells were unchanged (380/mm2). Proliferating macrophages (ED1+, BrdU+) increased from day 4 (4%) to day 14 (10%). M-CSF mRNA expression was strongly up-regulated in allografts compared with isografts and normal rat. In situ hybridization demonstrated M-CSF expression by resident and infiltrating cells. Renal tubular expression was minimally increased at day 4 but strongly up-regulated at day 14 (more than 50% of tubules positive), particularly in areas of tubular damage. Tubular M-CSF expression colocalized with areas of intense macrophage infiltration and proliferation. Serial sections with double labeling demonstrated that T cells were the dominant source o

Background: Few risk factors for quality-of-life outcomes of simultaneous pancreas and kidney transplant recipients are known because of a paucity of data from prospective studies. Study Design: Pretransplant assessment and prospective 3-year follow-up. Setting & Participants: Consecutive potential recipients at a university teaching hospital assessed by Liaison Psychiatry. Predictors: Demographic data; pretransplant Transplant Evaluation Rating Scale scores; current, past 12 months, and prior lifetime psychiatric disorder. Outcomes & Measurements: 36-Item Short Form Health Survey (SF-36) scores. Result(s): 37 simultaneous pancreas and kidney transplant recipients were assessed pretransplant and at 4 months posttransplant. Posttransplant at 1 year, 29 (81% of survivors); at 2 years, 26 (79% of survivors and those reaching 2 years); and at 3 years, 22 (92% of survivors and those reaching 3 years) patients were assessed. SF-36 Mental Component Summary (MCS) scores (mean pretransplant, 46.8 +/- 8.2 [SD]; 4 months, 51.7 +/- 8.5; 1 year, 50.1 +/- 9.7; 2 years, 51.8 +/- 8.9; and 3 years, 50.8 +/- 13.8) and Physical Component Summary (PCS) scores (pretransplant, 40.6 +/- 10.6; 4 months, 43.6 +/- 12.0; 1 year, 45.6 +/- 11.3; 2 years, 48.1 +/- 10.2; and 3 years, 46.8 +/- 9.1) showed sustained improvement posttransplant. MCS scores became similar to population norms. Functionally significant decreases in MCS and PCS scores were seen in 4%-21% and 8%-30% at times posttransplant. Male sex predicted higher scores at 4 months for the MCS (P = 0.003; regression coefficient, -8.28 [95% CI, -13.6 to -2.9]; effect size, 0.22) and PCS (P = 0.05; regression coefficient, -6.91 [95% CI, -13.9 to 0.9]; effect size, 0.08). Current psychiatric disorder at pretransplant evaluation predicted higher PCS scores at 4 months (P = 0.002; regression coefficient, -15.42 [95% CI, -24.6 to -6.2]; effect size, 0.22) and 1 year (P = 0.002; regression coefficient, -17.3 [95% CI, -27.9 to -6.7]; effect si

Background: Microalbuminuria is an independent risk factor for cardiovascular morbidity and mortality in the general population. Standard immunochemical urinary albumin assays detect immunoreactive albumin, whereas high-performance liquid chromatography (HPLC) detects both immunoreactive and immunounreactive albumin. Method(s): Using data from the Australian Diabetes, Obesity, and Lifestyle cohort study of randomly selected community-based Australian adults, spot urine samples were tested for albuminuria (spot urine albumin-creatinine ratio [ACR]: normal, <30 mg/g; microalbuminuria, 30 to 300 mg/g; and macroalbuminuria, >300 mg/g) by using both immunonephelometry (IN) and HPLC (n = 10,010). Result(s): Bland-Altman analysis showed significant bias, with a greater ACR by means of HPLC, particularly at lower levels of ACR. Mean ACR was 15.8 mg/g (95% confidence interval [CI], 12.3 to 19.2) by means of IN compared with 30.0 mg/g (95% CI, 27.0 to 35.0) by means of HPLC. The prevalence of microalbuminuria was 4 times greater by means of HPLC compared with IN (20% versus 5.5%). In all demographic and comorbid subgroups associated with microalbuminuria, the prevalence of microalbuminuria increased by 2 to 4 times. A total of 1,743 subjects (17.4%) classified as normoalbuminuric by means of IN were reclassified as microalbuminuric by means of HPLC. Using multivariate logistic regression, women, patients with untreated and treated hypertension, and those with impaired glucose tolerance or diabetes were associated significantly with a change in category from normoalbuminuric to microalbuminuria by means of HPLC. Conclusion(s): HPLC measures significantly more urinary albumin within the normoalbuminuria and microalbuminuria range, resulting in a significant increase in prevalence of microalbuminuria. Longitudinal studies are needed to determine whether the extra individuals identified by means of HPLC are at increased risk for developing hard clinical outcomes (renal and cardio

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory molecule involved in cell-mediated immunity and delayed-type hypersensitivity (DTH). We inhibited systemic and local MIF production to determine its contribution to acute rejection (AR). Skin DTH response and acute rejection of skin and kidney allografts were examined using MIF gene knockout (MIF -/-) and wild-type mice (MIF +/+) with anti-MIF or control antibody. MIF-Ab reduced skin DTH by 60% (p<0.01), but absence of the MIF gene (MIF -/-) had no effect. Local absence of MIF had no effect on the survival of skin grafted onto BALB/c recipients. Similarly MIF +/+ and MIF -/- kidneys transplanted into BALB/c recipients showed a similar degree of histological rejection, graft dysfunction and cellular infiltrate suggesting that AR is not dependent on local MIF production. To investigate the influence of systemic MIF, BALB/c donor skin was grafted onto MIF +/+ and MIF -/- mice. The tempo of AR was not altered by systemic absence of MIF (MIF-Ab or MIF -/-). BALB/c kidneys transplanted into MIF +/+ (with or without MIF-Ab) and MIF -/- mice showed similar parameters of rejection. MIF blockade reduces the DTH response; however, neither local nor systemic MIF are required for the rejection of fully mismatched skin and renal allografts.

Macrophage accumulation within an acutely rejecting allograft occurs by recruitment and local proliferation. To determine the importance of M-CSF in driving macrophage proliferation during acute rejection, we blocked the M-CSF receptor, c-fms, in a mouse model of acute renal allograft rejection. C57BL/6 mouse kidneys (allografts, n = 20) or BALB/c kidneys (isografts, n = 5) were transplanted into BALB/c mice. Anti-c-fms antibody (AFS98) or control Ig (50 mg/kg/day, i.p.) was given daily to allografts from days 0-5. All mice were killed day 6 postoperatively. Expression of the M-CSF receptor, c-fms, was restricted to infiltrating CD68+ macrophages. Blockade of c-fms reduced proliferating (CD68+/BrdU+) macrophages by 82% (1.1 v 6.2%, p < 0.001), interstitial CD68+ macrophage accumulation by 53% (595 v 1270/mm2, p < 0.001), and glomerular CD68+ macrophage accumulation by 71% (0.73 V 2.48 CD68+ cells per glomerulus, p < 0.001). Parameters of T-cell involvement (intragraft CD4+, CD8+ and CD25+ lymphocyte numbers) were not affected. The severity of tubulointerstitial rejection was reduced in the treatment group as shown by decreased tubulitis and tubular cell proliferation. Macrophage proliferation during acute allograft rejection is dependent on the interaction of M-CSF with its receptor c-fms. This pathway plays a significant and specific role in the accumulation of macrophages within a rejecting renal allograft.

Background. A number of studies have demonstrated a pathological role for interleukin-1 (IL-1) in experimental models of glomerulonephritis, but the cellular pattern of renal IL-1 production remains poorly characterized. The aim of this study, therefore, was to identify the cell types expressing IL-1 in normal and diseased rat kidney. Methods. Renal IL-1beta expression was examined in normal rats and during a 21-day time course of rat accelerated anti-GBM glomerulonephritis by northern blotting, in situ hybridization and double immunohistochemistry. Results. Interleukin-1beta mRNA expression was readily detectable in normal rat kidney by northern blot analysis and in situ hybridization. Immunohistochemistry staining demonstrated constitutive IL-1beta expression by glomerular endothelial cells and cortical tubular epithelial cells. There was a marked increase in whole kidney IL-1beta mRNA in rat anti-GBM glomerulonephritis. Glomerular IL-1beta immunostaining was upregulated, being expressed by podocytes, mesangial cells and infiltrating macrophages, and was particularly prominent within glomerular crescents. Double staining with the ED1 antibody showed IL-1beta expression in up to 13% of glomerular macrophages, whereas 48% of macrophages within crescents stained for IL-1beta. However, the most marked increase in IL-1beta expression was seen in cortical tubular epithelial cells, particularly in areas of tubular damage. In situ hybridization confirmed that tubular IL-1beta staining was due to local cytokine synthesis rather than protein absorption. Conclusions. This study has identified constitutive IL-1beta expression by glomerular endothelium and tubular epithelial cells in normal rat kidney. In addition, the marked upregulation of IL-1beta expression by intrinsic glomerular cells and tubules in rat anti-GBM disease suggests an important role for these cells in IL-1 dependent crescent formation and tubulointerstitial injury.

Simultaneous pancreas - kidney (SPK) transplant recipients are at high immunological risk of rejection. Antibody induction is beneficial but lymphocyte-depleting therapy is associated with a high incidence of side-effects. We performed a historical controlled trial to compare OKT3 versus anti-CD25 antibody (basiliximab) induction therapy with regard to patient, kidney and pancreas survival, as well as to examine for any differences in acute rejection, graft function, and infective complications. Twenty-eight consecutive SPK transplants were performed at the Monash Medical Centre between December 1997 and November 2001. Anti CD3 monoclonal antibody (OKT3) was used prior to March 2000 (n = 12) and basiliximab was used after (n = 16), both in combination with cyclosporin, mycophenolate, and prednisolone. A retrospective comparison of outcomes was performed. At 6 months, patient (100 vs 100%), kidney (91.7 vs 91.7%) and pancreas (75 vs 83.3%) survival were similar in the OKT3 and basiliximab groups, respectively. A minority of subjects in each group remained free from rejection (42% basiliximab vs 25% on OKT3, P = NS). Renal function was superior in the basiliximab group (mean calculated creatinine clearance 79.4 +/- 11.9 vs 54.5 +/- 15.9 mL/min for basiliximab vs OKT3, P < 0.001). The incidence of major opportunistic infection was lower in basiliximab-treated patients (9 vs 50% in the OKT3 group, P = 0.033). Basiliximab was associated with similar 6-month patient, kidney and pancreas survival, superior renal function and less opportunistic infection as compared with OKT3 induction therapy in SPK transplants. Basiliximab is at least as effective and is safer than OKT3 for induction therapy in SPK transplantation.

Background: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) is more accurate than the Modification of Diet in Renal Disease (MDRD) Study equation. We applied both equations in a cohort representative of the Australian adult population. Study Design: Population-based cohort study. Setting & Participants: 11,247 randomly selected noninstitutionalized Australians aged >= 25 years who attended a physical examination during the baseline AusDiab (Australian Diabetes, Obesity and Lifestyle) Study survey. Predictors & Outcomes: Glomerular filtration rate (GFR) was estimated using the MDRD Study and CKD-EPI equations. Kidney damage was defined as urine albumin-creatinine ratio >= 2.5 mg/mmol in men and >= 3.5 mg/mmol in women or urine protein-creatinine ratio >= 0.20 mg/mg. Chronic kidney disease (CKD) was defined as estimated GFR (eGFR) >= 60 mL/min/1.73 m2 or kidney damage. Participants were classified into 3 mutually exclusive subgroups: CKD according to both equations; CKD according to the MDRD Study equation, but no CKD according to the CKD-EPI equation; and no CKD according to both equations. All-cause mortality was examined in subgroups with and without CKD. Measurements: Serum creatinine and urinary albumin, protein, and creatinine measured on a random spot morning urine sample. Result(s): 266 participants identified as having CKD according to the MDRD Study equation were reclassified to no CKD according to the CKD-EPI equation (estimated prevalence, 1.9%; 95% CI, 1.4-2.6). All had an eGFR >= 45 mL/min/1.73 m2 using the MDRD Study equation. Reclassified individuals were predominantly women with a favorable cardiovascular risk profile. The proportion of reclassified individuals with a Framingham-predicted 10-year cardiovascular risk >= 30% was 7.2% compared with 7.9% of the group with no CKD according to both equations and 45.3% of individuals retained in stage 3a using both equations. There was no evidence of increased all-cause mortality in the recla

Current experimental models of glomerulonephritis focus on the acute phases of renal injury. Models replicating the features of human glomerulonephritis, including hypertension, proteinuria, hyperlipidaemia, renal fibrosis and renal failure, are lacking. The aim of this experiment was to define a rat model of glomerulonephritis that replicates the features of progressive glomerulonephritis in humans. Passive accelerated antiglomerular basement membrane disease was induced in inbred Sprague-Dawley rats. Age-matched control rats received pre-immunisation, but were given saline rather than nephrotoxic serum. Groups of diseased rats (n = 4-6) were killed at 4, 6 and 7 weeks, and tissues were extracted for histological assessment. Diseased rats developed renal failure over 7 weeks (91% reduction in creatinine clearance vs controls at week 7, P < 0.001). Proteinuria reached a plateau from week 2 to week 7 (269.1 +/- 107.9 mg/24 h vs 1.00 +/- 0.18 mg/mL for controls at week 7, P < 0.001). Diseased rats became hyperlipidaemic (108% increase in cholesterol vs control, P < 0.05) and hypertensive (38% increase in systolic blood pressure vs controls, P < 0.001). Histology revealed progressive renal fibrosis and scarring, with fibrocellular crescent formation (93% of glomeruli by week 7), glomerulosclerosis and tubulointerstitial damage. alpha-Smooth muscle actin expression and interstitial matrix (collagen III) deposition increased progressively. Urinary transforming growth factor-beta excretion was increased by over eightfold versus controls. This model of passive accelerated antiglomerular basement membrane disease simulates many clinical and pathological features of chronic glomerulonephritis in humans, and may provide a good model to test new therapies.

Background: Diabetic nephropathy is a major global health problem. Progression to renal failure is common; however, the mechanisms are unknown. Experimental models suggest a role for macrophages. Therefore, macrophage accumulation and its relationship to the subsequent clinical course were studied. Method(s): A retrospective study of baseline histology and the subsequent clinical course over at least 5 years involving 20 consecutive patients with a histological and clinical diagnosis of diabetic nephropathy was performed. The relationship between macrophage accumulation in renal biopsy tissue (KP-1/anti-CD68+ cells), baseline measures of known predictors of progression (proteinuria, tubulointerstitial damage, myofibroblast accumulation) and progression over 5 years (plot of reciprocal of serum creatinine) was quantified. Result(s): Accumulation of macrophages was apparent in the glomeruli (2.8 + 0.7/gcs vs 1.0 + 0.2 for normals, P = not significant) and interstitium (296.9 + 63.3/mm2vs 19.0 + 1.3/mm2 for normals, P = 0.002) of patients with diabetic nephropathy. Glomerular macrophage number correlated with baseline serum creatinine (r = 0.548, P = 0.012) but not with progression of renal failure as glomerular macrophages were prevalent in early, but not advanced diabetic nephropathy. Interstitial macrophage accumulation correlated strongly with serum creatinine (r = 0.649, P = 0.002), proteinuria (r = 0.779, P < 0.0001), interstitial fibrosis (r = 0.774, P < 0.0001) and inversely with the slope of 1/serum creatinine (r = -0.531, P = 0.023). Conclusion(s): Macrophages accumulate within glomeruli and the interstitium in diabetic nephropathy and the intensity of the interstitial infiltrate is proportional to the rate of subsequent decline in renal function. These human data support animal studies that suggest a pathogenic role for the macrophage in diabetic nephropathy. © 2006 Asian Pacific Society of Nephrology.

Inhibition of major histocompatibility complex (MHC) class II expression by macrophages is the primary mechanism by which interleukin-10 (IL-10) exerts immune suppression. Little, however, is known of the effects of IL-10 on other types of cells which can be induced to express MHC class II during an inflammatory response. We therefore studied the effects of IL-10 treatment on the expression of MHC class II molecules in a rat model of immunologically induced glomerulonephritis. MHC class II mRNA levels in whole kidney were increased in saline-treated (control) animals with glomerulonephritis (2-6- fold increase versus normal, P = 0.028) and this was partially inhibited by treatment with IL-10 (P=NS). Double immunostaining of tissue sections was used to compare MHC class II expression by infiltrating macrophages and resident glomerular cells. IL-10 treatment reduced the proportion of glomerular macrophages which expressed detectable MHC class II (70% reduction, P=0.03). In contrast, IL-10 treatment was associated with an increase in the number of resident glomerular cells expressing MHC class II, particularly within mesangial areas. Therefore, the effects of IL-10 on macrophages and mesangial cells were compared in vitro. IL-10 reduced constitutive MHC class II mRNA and cell surface expression by peritoneal macrophages. In contrast, IFN-7-stimulated mesangial cells (1097 cell line) cultured with IL-10 for 24 hr showed increased MHC class II mRNA (26% increase) and surface expression (72% increase in percentage MHC II+ by flow cytometry, P=0.04) as compared with cells stimulated with IFN-gamma alone. IL- 10 also directly up-regulated expression of ICAM-1 by 1097 cells. In conclusion, IL-10 was found to have contrasting effects on the production and cell surface expression of MHC class II molecules by mesangial cells and by macrophages, both in vitro and in vivo. The implications of these findings for IL-10 mediated immunosuppression are discussed.

Background. Excessive alcohol consumption is a risk factor for hypertension and stroke; however, evidence for an association with chronic kidney disease is conflicting.Methods. A total of 6259 adults >=25 years of age, without a history of alcohol dependence, participating in baseline (1999-2000) and follow-up (2004-2005) phases of an Australian population-representative study (AusDiab) were the subject of this analysis. Alcohol consumption status and volumefrequency were collected by standardized interviewer administered questionnaires and self-administered food frequency questionnaires. The outcomes were as follows: (i) 5-year decline in estimated glomerular filtration rate (eGFR) >=10, with baseline eGFR >= 60 and final eGFR <60 mLmin1.73 m 2, and (ii) 5-year doubling of albumin to creatinine ratio (ACR) with final ACR >= 2.5 (males)>= 3.5 (females) mgmmol, in the absence of albuminuria at baseline.Results. Self-identification as a moderate or heavy, versus light, drinker was associated with elevated risk of albuminuria in males and females <65 years of age (OR, 95 CI: males 1.87, 0.99-3.52; females 2.38, 1.37-4.14). Odds of de novo eGFR <60 mLmin1.73 m2 were 0.34 (95 CI 0.22-0.59) and 0.68 (95 CI 0.36-1.27) in males and females, respectively, who were moderate-heavy drinkers. Alcohol intake of >=30 gday was associated with an increased risk of albuminuria after adjustment for age, sex and baseline kidney function (OR = 1.59, 95 CI 1.07-2.36), but a reduced risk of eGFR <60 mLmin1.73 m2 (OR = 0.59, 95 CI 0.37-0.95), compared with consumption of <10 gday.Conclusions. Moderate-heavy alcohol consumption may be an important modifiable risk factor for albuminuria in the general population. The natural history of alcohol-induced kidney damage and how this relates to markers of kidney function in the general population warrant further research.

Background. Lack of prospective psychosocial outcome studies on living kidney donors impedes identification of risk factors for poor outcome. Methods. Psychiatric assessment of living kidney donors was performed preoperatively and at 4 and 12 months postoperatively using a semistructured interview, the Short Form (SF)-36 Health Survey, and Patient Health Questionnaire psychiatric assessment. A total of 48 of 51 consecutive donors (94%) over a 5-year period were available for follow-up and completed all assessments. Results. At preoperative assessment, only 1 of the 48 donors (2%) had a Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition Axis I psychiatric disorder, but 15 (31%) developed a disorder during the 12 months, a 29% incidence. Disorders were depressive (12%), anxiety (6%), and adjustment (13%). Seven donors (15%) demonstrated a disorder at 12 months (depressive 10%, anxiety 2%, adjustment 2%). There was a corresponding decline in psychosocial function as measured by the SF-36 Mental Component Summary score; it decreased at both 4 and 12 months (P<0.01, P<0.05); for 19% of donors, this was a larger decrease than would be expected for the cohort (>2 standard error of measurement units). Scores for SF-36 scales of General Health and Vitality decreased significantly (P<0.05), as did those of Bodily Pain, indicating greater impairment from pain. Psychiatric disorder at 12 months was associated with donor psychosocial function (Mental Component Summary) and psychiatric disorder at 4 months (P<0.01), physical function (SF-36 Physical Component Summary score) at 4 and 12 months (P<0.01), and recipient psychiatric disorder at 12 months (P<0.05). Conclusions. Donors should be alerted to possible psychosocial impairment, assessed for risk factors, and monitored for at least 12 months. Treatment should be available.

Albuminuria is a risk factor for all-cause mortality. Urinary albumin is traditionally measured with an immunochemical method such as immunonephelometry (IN). High-performance liquid chromatography (HPLC) detects additional albumin that is missed by IN, but it is unknown if HPLC-detected albuminuria also predicts mortality in the general population. We measured urinary albumin at baseline with both IN and HPLC in 10,175 participants in the longitudinal Australian Diabetes, Obesity, and Lifestyle (AusDiab) study. Over 5.2 yr of follow-up, 319 participants died. In a Cox proportional hazards regression model, participants with albuminuria measured by IN or HPLC were approximately twice as likely to die as participants who were normoalbuminuric on both assays. Receiver-operator characteristic curve analyses suggest that each test has a similar ability to predict mortality. However, the HPLC assay provided information on mortality risk that the IN assay did not capture. We conclude that albuminuria, detected by either IN or HPLC, independently predicts mortality in a community-based sample. HPLC identifies some people at increased risk of mortality that IN would not detect. Copyright © 2007 by the American Society of Nephrology.

The association between pretransplant dialysis modality and transplant outcomes remains inconsistent. The aim of this study is to address the association between alteration in dialysis modality and post-transplant outcomes. Using Australia and New Zealand Dialysis and Transplant Registry, primary live- and deceased-donor renal transplant recipients (RTR) between 1997 and 2009 were examined. Pre-emptive and multiple-organ transplants were excluded. The association between initial and pretransplant dialysis modality and transplant outcomes were examined. Of the 6701 RTR, 18.6% were initiated-maintained on peritoneal dialysis pretransplant (PD-PD), 9.2% were initiated on PD, but maintained on haemodialysis (HD) pretransplant (PD-HD), 63.3% were HD-HD and 8.9% were HD-PD. PD-HD [odds ratio(OR)1.44, 95% CI 1.21,1.72] and HD-HD (OR1.25, 95% CI 1.12,1.41) were associated with a significantly greater risk of slow graft function compared with the overall mean of the groups, whereas a change in initial dialysis modality from HD to pretransplant PD was associated with higher risk of overall graft failure [hazard ratio(HR)1.19, 95% CI 1.04,1.36) and recipient death (HR1.34, 95% CI 1.13,1.59). Our registry analysis suggest that dialysis modality pretransplant may affect transplant outcomes and future studies evaluating patient selection, choice of modality and/or potential interventions in the pre and post-transplant period may have a beneficial effect on post-transplant outcomes. © 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.

Background and Aims: Physical inactivity is associated with cardiovascular risk however its relationship to chronic kidney disease is largely unknown. We examined the association between leisure-time physical activity and risk of chronic kidney disease in a prospective, population-based cohort of Australians aged >=25 years (AusDiab). Methods and Results: The baseline sample included 10,966 adults (4951 males and 6015 females). From this sample, 6318 participants with complete baseline and 5-year follow-up urinalysis and serum creatinine measurements formed the study population for longitudinal analysis. Self-reported leisure-time physical activity was measured using a validated, interviewer-administered questionnaire. Compared with sufficiently active individuals (>=150. min physical activity per week), those who were inactive (0. min/week) were more likely to have albuminuria at baseline (multivariate-adjusted OR = 1.34, 95% CI 1.10-1.63). Inactivity (versus sufficient physical activity) was associated with increased age- and sex-adjusted odds of an estimated glomerular filtration rate <3rd percentile (OR = 1.30, 95% CI 1.02-1.65), although this was not significant after multivariate adjustment (OR = 1.17, 95% CI 0.91-1.50). Obese, inactive individuals were significantly more likely to have albuminuria at baseline (multivariate-adjusted OR = 1.74, 95% CI 1.35-2.25), compared with sufficiently active, non-obese individuals. Baseline physical activity status was not significantly associated with longitudinal outcomes. Conclusion(s): Physical inactivity is cross-sectionally associated with albuminuria prevalence, particularly when combined with obesity. Future studies are needed to determine whether this association is causal and the importance of physical activity in CKD prevention. © 2009 Elsevier B.V.

The incidence of ESRD is increasing dramatically. Progression to end-stage may be halted or slowed when kidney damage is detected at an early stage. Kidney damage is frequently asymptomatic but is indicated by the presence of proteinuria, hematuria, or reduced GFR. Population-based studies relating to the prevalence of kidney damage in the community are limited, particularly outside of the United States. Therefore, the prevalence of proteinuria, hematuria, and reduced GFR in the Australian adult population was determined using a cross-sectional study of 11,247 non-institutionalized Australians aged 25 yr or over, randomly selected using a stratified, cluster method. Subjects were interviewed and tested for proteinuria - spot urine protein to creatinine ratio (abnormal: >=0.20 mg/mg); hematuria - spot urine dipstick (abnormal: 1+ or greater) confirmed by urine microscopy (abnormal: > 10,000 red blood cells per milliliter) or dipstick (abnormal: 1+ or greater) on midstream urine sample; and reduced GFR - Cockcroft-Gault estimated GFR (abnormal: <60 ml/min per 1.73 m2). The associations between age, gender, diabetes mellitus, and hypertension, and indicators of kidney damage were examined. Proteinuria was detected in 2.4% of cases (95% CI: 1.6%, 3.1%), hematuria in 4.6% (95% CI: 3.8%, 5.4%), and reduced GFR in 11.2% (95% CI: 8.6%, 13.8%). Approximately 16% had at least one indicator of kidney damage. Age, diabetes mellitus, and hypertension were independently associated with proteinuria; age, gender, and hypertension with hematuria; and age, gender, and hypertension with reduced GFR. Approximately 16% of the Australian adult population has either proteinuria, hematuria, and/or reduced GFR, indicating the presence of kidney damage. Identifying and targeting this section of the population may provide a means to reduce the burden of ESRD.

Interleukin-10 (IL-10) is a cytokine which has been suggested as a possible immunosuppressive treatment for kidney disease. The ability of IL- 10 to suppress antigen presentation to T cells, inhibit the delayed-type hypersensitivity reaction and to inhibit macrophage production of pro- inflammatory cytokines provides a logical basis for its use in the treatment of kidney disease. With the exception of Th1-mediated crescentic glomerulonephritis, however, IL-10 treatment of experimental kidney disease has produced disappointing results largely due to its stimulatory effects upon the humoral immune response, macrophage Fc-receptor expression and macrophage proliferation. Paradoxically, there is now evidence to suggest that endogenous production of IL-10 within the kidney may actually contribute to kidney damage through stimulating mesangial proliferation, immune complex deposition and macrophage infiltration. We await the outcome of studies designed to block IL-10 function in experimental disease models.