IL-17 deficiency attenuates allograft injury and prolongs survival in a murine model of fully MHC-mismatched renal allograft transplantation.

IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of inflammatory and autoimmune diseases. However the role of IL-17 in renal allograft rejection has not been fully explored. Here, we investigate the impact of IL-17 in a fully MHC-mismatched, life-sustaining, murine model of kidney allograft rejection using IL-17 deficient donors and recipients (IL-17(-/-) allografts). IL-17(-/-) allografts exhibited prolonged survival which was associated with reduced expression of the Th1 cytokine IFN-γ and histological attenuation of acute and chronic allograft rejection, as compared to wild-type allograft recipients. Results were confirmed in WT allograft recipients treated with an IL-17 blocking antibody. Subsequent experiments using either donors or recipients deficient in IL-17 showed a trend towards prolongation of survival only when recipients were IL-17(-/-) . Administration of a depleting anti-CD25 antibody to IL-17(-/-) recipients abrogated the survival advantage conferred by IL-17 deficiency, suggesting the involvement of a CD4(+) CD25(+) T cell regulatory mechanism. Therefore, IL-17 deficiency or neutralization was protective against the development of kidney allograft rejection, which may be mediated by impairment of Th1 responses and/or enhanced protection by Tregs.

Cost to government and society of chronic kidney disease stage 1-5: a national cohort study.

BACKGROUND: Costs associated with chronic kidney disease (CKD) are not well documented. Understanding such costs is important to inform economic evaluations of prevention strategies and treatment options. AIM: To estimate the costs associated with CKD in Australia. METHODS: We used data from the 2004/2005 AusDiab study, a national longitudinal population-based study of non-institutionalised Australian adults aged ≥25 years. We included 6138 participants with CKD, diabetes and healthcare cost data. The annual age and sex-adjusted costs per person were estimated using a generalised linear model. Costs were inflated from 2005 to 2012 Australian dollars using best practice methods. RESULTS: Among 6138 study participants, there was a significant difference in the per-person annual direct healthcare costs by CKD status, increasing from $1829 (95% confidence interval (CI): $1740-1943) for those without CKD to $14 545 (95% CI: $5680-44 842) for those with stage 4 or 5 CKD (P < 0.01). Similarly, there was a significant difference in the per-person annual direct non-healthcare costs by CKD status from $524 (95% CI: $413-641) for those without CKD to $2349 (95% CI: $386-5156) for those with stage 4 or 5 CKD (P < 0.01). Diabetes is a common cause of CKD and is associated with increased health costs. Costs per person were higher for those with diabetes than those without diabetes in all CKD groups; however, this was significant only for those without CKD and those with early stage (stage 1 or 2) CKD. CONCLUSION: Individuals with CKD incur 85% higher healthcare costs and 50% higher government subsidies than individuals without CKD, and costs increase by CKD stage. Primary and secondary prevention strategies may reduce costs and warrant further consideration.

External validation of the estimated posttransplant survival score for allocation of deceased donor kidneys in the United States.

The US kidney allocation system adopted in 2013 will allocate the best 20% of deceased donor kidneys (based on the kidney donor risk index [KDRI]) to the 20% of waitlisted patients with the highest estimated posttransplant survival (EPTS). The EPTS has not been externally validated, raising concerns as to its suitability to discriminate between kidney transplant candidates. We examined EPTS using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. We included 4983 adult kidney-only deceased donor transplants over 2000-2011. We constructed three Cox models for patient survival: (i) EPTS alone; (ii) EPTS plus donor age, hypertension and HLA-DR mismatch; and (iii) EPTS plus log(KDRI). All models demonstrated moderately good discrimination, with Harrell's C statistics of 0.67, 0.68 and 0.69, respectively. These results are virtually identical to the internal validation that demonstrated a c-statistic of 0.69. These results provide external validation of the EPTS as a moderately good tool for discriminating posttransplant survival of adult kidney-only transplant recipients.

Pregnancy outcomes for kidney transplant recipients.

Pregnancy outcomes in a transplant population have not been well documented. Data from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) and the National Perinatal Epidemiology and Statistics Unit (NPESU) were analyzed. We described pregnancy outcomes within the transplant population and compared these to outcomes for the general population. Six hundred ninety-two pregnancies in 447 transplant recipients were reported between 1971 and 2010 (ANZDATA); a corresponding 5 269 645 pregnancies were reported nationally in Australia between 1991 and 2010 (NPESU). At pregnancy transplant mothers had a median age of 31 years (interquartile range [IQR]: 27, 34), a median creatinine of 106 µmol/L (IQR: 88, 1103 µmol/L) and a functioning transplant for a median of 5 years (IQR: 3, 9). The mean gestational age at birth was 35 ± 5 weeks in transplant recipients, significantly shorter than the national average of 39 weeks (p < 0.0001). Mean live birth weight for transplant recipients was 873 g lower than the national average (2485 ± 783 g vs. 3358 ± 2 g); a significant difference remained after controlling for gestational age. There was lower perinatal survival rate in babies born to transplant recipients, 94% compared with 99% nationally (p < 0.001). Although transplant pregnancies are generally successful, outcomes differ from the general population, indicating these remain high-risk pregnancies despite good allograft function.

Quantification of the early risk of death in elderly kidney transplant recipients.

To inform decision making regarding transplantation in patients ≥ 65 years, we quantified the early posttransplant risk of death by determining the time to equal risk and equal survival between transplant recipients and wait-listed dialysis patients in the United States between 1995 and 2007 (total n = 25 468). Survival was determined using separate multivariate nonproportional hazards analyses in low-, intermediate- and high-risk cardiovascular risk patients. Compared to wait-listed patients with similar cardiovascular risk, standard criteria (SCD) and expanded criteria (ECD) recipients had a higher risk of death in the perioperative and early-posttransplant period. In contrast, low and intermediate risk living donor (LD) recipients had an immediate survival advantage compared to similar risk wait-listed patients. In all risk groups, transplantation was associated with a long-term survival advantage compared to dialysis, but there were marked differences in time to equal risk of death, and time to equal survival by donor type. For example, survival in high-risk recipients of an LD, SCD and ECD transplant became equal to that in similar risk wait-listed patients 130, 368 and 521 days after transplantation. Early posttransplant mortality risk is eliminated in low- and intermediate-risk patients, and markedly reduced in high-risk patients with LD transplantation.

Inferior early posttransplant outcomes for recipients of right versus left deceased donor kidneys: an ANZDATA registry analysis.

Anatomical differences between right and left kidneys could influence transplant outcome. We compared graft function and survival for left and right kidney recipients transplanted from the same deceased organ donor. Adult recipients of 4900 single kidneys procured from 2450 heart beating deceased donors in Australia and New Zealand from 1995 to 2009 were included in a paired analysis. Right kidneys were associated with more delayed graft function (DGF) (25 vs. 21% for left kidneys, p < 0.001) and, if not affected by DGF, a slower fall in serum creatinine. One-year graft survival was lower for right kidneys (89.1 vs. 91.1% for left kidneys, p = 0.001), primarily attributed to surgical complications (66 versus 35 failures for left kidneys). Beyond the first posttransplant year, kidney side was not associated with eGFR, graft or patient survival. Receipt of a right kidney is a risk factor for inferior outcomes in the first year after transplantation. A higher incidence of surgical complications suggests the shorter right renal vein may be contributory. The higher susceptibility of right kidneys to injury should be considered in organ allocation.

Steroids and recurrent IgA nephropathy after kidney transplantation.

We studied the impact of steroid use on kidney graft loss due to recurrent IgA nephropathy (IgAN). We used data from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) to conduct a survival analysis of adult recipients of a first kidney transplant for IgAN who received a graft between 1988 and 2007. Predictors of graft loss due to recurrent IgAN were analyzed in a competing risk survival analysis with steroid use modeled as a time-varying covariate. Fifteen hundred twenty-one recipients with kidney failure due to biopsy-proven IgAN received a first kidney transplant during the study period. Four hundred and twenty-eight recipients experienced graft loss, of which 54 losses (12.6%) were attributed to recurrent IgAN. The overall 10-year cumulative incidence of graft loss from recurrent IgAN was 4.3% (95% CI 3.1-5.8). Prevalence of steroid use was 92% at baseline, 84% at 1 year and 64% at 5 years. After adjusting for age, sex, HLA mismatch, dialysis duration and transplant era, steroid use was strongly associated with a reduced risk of recurrence (subhazard ratio 0.50, 95% CI 0.30-0.84). These results suggest that the risk of graft loss from recurrent disease should be considered when tailoring immunosuppression for patients with IgAN.

Effect of type 2 diabetes on mortality risk associated with end-stage kidney disease.

AIMS/HYPOTHESIS: Patients with end-stage kidney disease (ESKD) and patients with diabetes mellitus experience higher mortality rates than the general population. Whether ESKD imparts the same excess in mortality risk for those with diabetes as it does for those without diabetes is unknown. METHODS: Included in the study were all white patients aged > or =25 years with incident ESKD and type 2 diabetes (n = 4,141) or with incident ESKD but without diabetes (n = 13,289) in Australia from 1991 to 2005, and all the individuals aged > or =25 years without ESKD and with type 2 diabetes (n = 909) or without ESKD without diabetes (n = 10,302) enrolled in the AusDiab Study--a nationwide Australian representative cohort--from 1999 to 2005. Excess mortality was analysed in patients with ESKD by diabetes status, using age-, sex- and diabetes-status-specific standardised mortality ratios (SMRs) in the first 8 years after first renal replacement therapy among ANZDATA patients relative to AusDiab participants. RESULTS: The SMRs in patients with ESKD were, in non-diabetic patients and in those with type 2 diabetes, respectively: 14.2 (95% CI 13.9-14.6) and 10.8 (95% CI 10.4-11.2) (p < 0.01); in people aged <60 years, 28.7 (95% CI 27.2-30.4) and 18.6 (95% CI 17.1-20.4) (p < 0.01); in people aged > or =60 years, 12.5 (95% CI 12.1-12.9) vs 9.7 (95% CI 9.3-10.1) (p < 0.01); in men, 11.0 (95% CI 10.7-11.4) vs 8.9 (95% CI 8.4-9.3) (p < 0.01); and in women, 23.4 (95% CI 22.5-24.3) vs 16.2 (95% CI 15.2-17.3) (p < 0.01). CONCLUSIONS/INTERPRETATION: ESKD was associated with a greater relative increase in mortality in the non-diabetic study populations than in the type 2 diabetes population. Excess mortality was greater among younger people and women.

High prevalence of chronic kidney disease in Thailand.

We describe the prevalence of stage III and IV chronic kidney disease in Thailand from a representative sample of individuals aged 35 years and above using a stratified, multistage, cluster-sampling method. Population estimates were calculated by applying sampling weights from the 2000 Thai census. Glomerular filtration rates were estimated from serum creatinine using the Cockroft-Gault and the simplified Modification of Diet in Renal Disease (MDRD) formulae. The prevalence of stage III disease among individuals aged 35 years and above was estimated to be about 20% using the Cockroft-Gault formula and about 13% from the MDRD formula. Stage IV disease was present in about 0.9 and 0.6% of this population using the respective formulae. The highest prevalence rates were observed in less well-developed rural areas and the lowest in developed urban areas. The prevalence of chronic kidney disease was significantly higher than that reported in individuals over 40 years old from the United States for both stage III and IV disease and higher than the reported incidence in Taiwan and Australia. This high prevalence of chronic kidney disease in Thailand has obvious implications for the health of its citizens and for the allocation of health-care resources.

Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcgammaRII.

Human autoimmune diseases thought to arise from the combined effects of multiple susceptibility genes include systemic lupus erythematosus (SLE) and autoimmune diabetes. Well-characterised polygenic mouse models closely resembling each of these diseases exist, and genetic evidence links receptors for the Fc portion of immunoglobulin G (FcR) with their pathogenesis in mice and humans [1] [2] [3]. FcRs may be activatory or inhibitory and regulate a variety of immune and inflammatory processes [4] [5]. FcgammaRII (CD32) negatively regulates activation of cells including B cells and macrophages [6]. FcgammaRII-deficient mice are prone to immune-mediated disease [7] [8] [9]. The gene encoding FcgammaRII, Fcgr2, is contained in genetic susceptibility intervals in mouse models of SLE such as the New Zealand Black (NZB) contribution to the (NZB x New Zealand White (NZW)) F1 strain [1] [10] [11] and the BXSB strain [12], and in human SLE [1] [2] [3]. We therefore sequenced Fcgr2 and identified a haplotype defined by deletions in the Fcgr2 promoter region that is present in major SLE-prone mouse strains (NZB, BXSB, SB/Le, MRL, 129 [13]) and non-obese diabetic (NOD) mice but absent in control strains (BALB/c, C57BL/6, DBA/2, C57BL/10) and NZW mice. The autoimmune haplotype was associated with reduced cell-surface expression of FcgammaRII on macrophages and activated B cells and with hyperactive macrophages resembling those of FcgammaRII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.

Glomerulonephritis.

The term glomerulonephritis encompasses a range of immune-mediated disorders that cause inflammation within the glomerulus and other compartments of the kidney. Studies with animal models have shown the crucial interaction between bone-marrow-derived inflammatory cells and cells intrinsic to the kidney that is both fundamental and unique to the pathogenesis of glomerulonephritis. The mechanisms of interaction between these cells and the mediators of their coordinated response to inflammation are being elucidated. Despite these pathophysiological advances, treatments for glomerulonephritis remain non-specific, hazardous, and only partly successful. Glomerulonephritis therefore remains a common cause of end-stage kidney failure worldwide. Molecule-specific approaches offer hope for more effective and safer treatments in the future.

Chronic kidney disease in the general population.

End-stage kidney disease (ESKD), defined as the need for dialysis, receipt of a transplant, or death from chronic kidney failure, generally affects fewer than 1% of the population. However ESKD is the end result of chronic kidney disease (CKD), a widely prevalent but often silent condition with elevated risks of cardiovascular morbidity and mortality and a range of metabolic complications. A recently devised classification of CKD has facilitated prevalence estimates that reveal an "iceberg" of CKD in the community, of which dialysis and transplant patients are the tip. Hypertension, smoking, hypercholesterolemia, and obesity, currently among the World Health Organization's (WHO's) top 10 global health risks, are strongly associated with CKD. The factors, together with increasing diabetes prevalence and an aging population, will result in significant global increases in CKD and ESKD patients. Treatments now available effectively reduce the rate of progression of CKD and the extent of comorbid conditions and complications. The challenges are (1) to intervene effectively to reduce the excess burden of cardiovascular morbidity and mortality associated with CKD, (2) to identify those at greatest risk for ESKD and intervene effectively to prevent progression of early CKD, and (3) to ultimately introduce cost-effective primary prevention to reduce the overall burden of CKD. The vast majority of the global CKD burden will be in developing countries, and policy responses must be both practical and sustainable in these settings.

Increased risk of hemorrhagic complications in renal allograft recipients receiving systemic heparin early posttransplantation.

UNLABELLED: The aim of this paper is to document the risk of hemorrhagic complications in renal allograft recipients requiring systemic heparinisation within the first 2 weeks posttransplantation. METHODS: A retrospective chart review of 326 RA recipients from January 1998 to July 2003 was subjected to statistics by SPIDA with P values <.05 considered significant. RESULTS: 16/326 (4.9%) recipients were initiated on intravenous (IV) heparin within the study period. Enoxaparin was subsequently used in 10/16 (62.5%) of these recipients. Intravenous heparin was instituted at a median 8 (1-14) days posttransplantation. Hemorrhagic complications occurred in 10/16 (62.5%) recipients on IV heparin versus 11/310 (3.5%) nonanticoagulated RA recipients (P = .0001). Hemorrhage occurred at a mean 9.75 (2-43) days into the course of IV heparin. The median peak APTT 24 hours prior to hemorrhage in RA recipients on heparin was 68.5 (58-180) versus a median peak APTT of 70 (50-140) among recipients on heparin who did not sustain a hemorrhagic complication (P = .30). A major intervention (predominantly surgery) was required in 6/16 (37%) recipients on IV heparin versus 7/310 (2.2%) nonheparinised RA recipients (P < .0001). Enoxaparin was instituted at a mean 22.5 (4-55) days posttransplantation. Delayed hemorrhage subsequently occurred in 4/10 (40%) recipients on enoxaparin. In conclusion, major and minor hemorrhagic complications occur more commonly among recipients requiring early post transplant IV heparin. Hemorrhage occurred despite APTT monitoring with APTT levels tending to be similar in RA recipients with versus without complications. Delayed hemorrhage was also seen with the subsequent use of enoxaparin.

Urine macrophage migration inhibitory factor concentrations as a diagnostic tool in human renal allograft rejection.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is a potent activator of macrophages and T cells. Previous studies have shown that local MIF production is increased in acute renal allograft rejection, suggesting that it may play an important role in the rejection process. AIMS: To determine if urine and serum MIF concentrations: (1) are increased in acute rejection, and (2) can be used as noninvasive tools to discriminate between acute rejection (AR) and cyclosporine nephrotoxicity (CyA toxicity). METHODS: In a prospective study of nine renal allograft patients (five acute rejection and four stable), serial urine MIF concentrations were measured by ELISA in the first 14 days after transplantation. In a retrospective study, MIF concentrations in urine and serum were measured in 24 patients who were biopsied for acute renal transplant dysfunction (11 AR, 13 CyA toxicity). Urine and serum MIF were also measured in 23 stable renal transplant patients and 10 normals. RESULTS: MIF was readily detected in the urine of normal healthy controls (106+/-61 pg/micromol creatinine). In the prospective study, the urinary MIF concentration was increased substantially on day 1 posttransplantation and subsequently fell in parallel with the serum creatinine. However, urine MIF increased before episodes of biopsy proven acute rejection. The retrospective study showed that urine MIF concentrations in patients with AR were increased 5-fold compared to normal controls (439+/-313 pg/micromol Cr; P<0.01). In contrast, urine MIF concentrations in CyA toxicity were not significantly different to normal controls (145+/-119 pg/micromol Cr; P=NS). A marked increase in MIF immunostaining was seen in biopsies of AR, but not in CyA toxicity. No significant differences were evident in serum MIF levels between normals and any transplant patient group. CONCLUSIONS: These results suggest that measurement of urine MIF concentration may be useful in monitoring renal transplant patients for acute rejection and as a discriminator from cyclosporine nephrotoxicity.

Treatment for lupus nephritis.

BACKGROUND: Lupus nephritis is the renal manifestation of systemic lupus erythematosus (SLE) - a disease mainly affecting young women with substantial morbidity and mortality. It is classified by the World Health Organization (WHO) criteria I - VI based on histology. WHO Class IV is a diffuse proliferative glomerulonephritis which has the worst prognosis without treatment, with a reported 17% five year survival in the era 1953-1969. This survival was 82% in the early 1990's and continues to improve. An important factor behind this has been the use of cytotoxics such as cyclophosphamide in addition to steroids. OBJECTIVES: To assess the benefits and harms of different treatments in biopsy-proven proliferative lupus nephritis (LN). SEARCH STRATEGY: We searched the Cochrane Renal Group's specialised register (January 2003), the Cochrane Central Register of Randomised Controlled Trials (CENTRAL - The Cochrane Library issue 1, 2003), MEDLINE (1966 - 31 January 2003), EMBASE (1980 - 31 January 2003) and handsearched reference lists of retrieved articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing treatments for PLN in both adult and paediatric patients with Class III, IV, Vc, Vd lupus nephritis were included. All treatments were considered. DATA COLLECTION AND ANALYSIS: Data was extracted and quality assessed independently by two reviewers, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) and measurements on continuous scales are reported as weighted mean differences (WMD) with 95% confidence intervals. Subgroup analysis by study quality, drug type and drug route have been performed where possible to explore reasons for heterogeneity. MAIN RESULTS: Of 920 articles identified, 25 were RCTs suitable for inclusion, which enrolled 915 patients. The majority compared cyclophosphamide or azathioprine plus steroids versus steroids alone. Cyclophosphamide plus steroids reduced the risk of doubling of serum creatinine (RR 0.59, 95% CI 0.40 to 0.88) compared to steroids alone but had no impact on mortality (RR 0.98, 95% CI 0.53 to 1.82). The risk of ovarian failure was significantly increased (RR 2.18, 95% CI 1.10 to 4.34). Azathioprine plus steroids reduced the risk of all cause mortality compared to steroids alone (RR 0.60, 95% CI 0.36 to 0.99), but did not alter renal outcomes. Neither therapy was associated with increased risk of major infection. No benefit was found with addition of plasma exchange to cyclophosphamide or azathioprine plus steroids for mortality ( RR 0.71, 95% CI 0.50 to 1.02), doubling of serum creatinine (RR 0.17, 95% CI 0.02 to 1.26) or end-stage renal failure (RR 1.24, 95% CI 0.60 to 2.57). There was also no increased risk of major infection (RR 0.69, 95% CI 0.35 to 1.37). REVIEWER'S CONCLUSIONS: Until future RCTs of newer agents are completed, the current use of cyclophosphamide combined with steroids remains the best option to preserve renal function in proliferative LN. The smallest effective dose and shortest duration of treatment should be used to minimise gonadal toxicity, without compromising efficacy.

Reduced and standard target concentration tacrolimus with sirolimus in renal allograft recipients.

We report 6-month results of renal allograft recipients enrolled in seven Australian centers as part of a worldwide, multicenter, randomized, open-label, concentration-controlled trial comparing standard tacrolimus (sTAC) with reduced tacrolimus (rTAC) both with sirolimus (SRL) and steroids. Patients were randomized 1:1 to either rTAC (n = 33) with a target maintenance concentration of SRL of 8 to 15 ng/mL and TAC of 3 to 7 ng/mL, or sTAC (n = 31) with SRL target of 5 to 10 ng/mL and TAC of 8 to 12 ng/mL. Antibody induction was prohibited. Adult recipients of a first or second cadaveric or non-HLA-identical living donor renal graft were eligible for enrollment. Recipients with a panel-reactive antibody level of >50% and recipients of regrafts who had lost their first graft from rejection within the first 6 months were ineligible. The groups were compared for graft function, incidence of rejection, and patient and graft survival at 6 months. There were no differences in demographics. There were 30% and 29% discontinuations in the rTAC and sTAC groups mainly due to adverse events in the first month. The 6-month patient and graft survival by intention-to-treat analysis was 94% and 91% for rTAC and 100% and 97% for sTAC (P = NS), respectively. Incidence and severity of biopsy-proven acute rejection was not different between the two groups, being 21% for rTAC and 19% for sTAC. The mean serum creatinine was 121 micromol/L and 148 micromol/L for rTAC and sTAC groups (P =.09), respectively. Glomerular filtration rate (GFR) was 68 mL/min and 62 mL/min (P =.23), respectively. Adverse events, infections, and antihypertensive and antilipidemic agent usage were similar. Of interest is that the overall incidence of thrombotic microangiopathy was 14%. These results support the safety and efficacy of SRL + TAC. Reduced TAC is associated with a trend toward improved renal function.