Aisling E. Courtney

Recurrent Dense Deposit Disease After Renal Transplantation: An Emerging Role for Complementary Therapies

Dense deposit disease is a rare glomerulonephritis caused by uncontrolled stimulation of the alternative complement pathway. Allograft survival after kidney transplantation is significantly reduced by the high rate of disease recurrence. No therapeutic interventions have consistently improved outcomes for patients with primary or recurrent disease. This is the first reported case of recurrent dense deposit disease being managed with eculizumab. Within 4 weeks of renal transplantation, deteriorating graft function and increasing proteinuria were evident. A transplant biopsy confirmed the diagnosis of recurrent dense deposit disease. Eculizumab was considered after the failure of corticosteroid, rituximab and plasmapheresis to attenuate the rate of decline in allograft function. There was a marked clinical and biochemical response following the administration of eculizumab. This case provides the first evidence that eculizumab may have a place in the management of crescentic dense deposit disease. More information is necessary to clarify the effectiveness and role of eculizumab in dense deposit disease but the response in this patient was encouraging. The results of clinical trials of eculizumab in this condition are eagerly awaited.

The changing pattern of adult primary glomerular disease

BACKGROUND Published biopsy series have shown geographical and temporal variations in the patterns of primary glomerulonephritis (GN). IgA nephropathy is the most common type of GN in most European studies, but there is evidence suggesting that focal segmental glomerulosclerosis (FSGS) is increasingly common in the USA in all ethnic groups. We report the analysis of 30 years of native renal biopsies and the temporal pattern of primary glomerular disease in a single United Kingdom (UK) region. METHODS All 1844 adult native kidney biopsies for 30 years (1976-2005 inclusive) were analysed. The data were divided into three 10-year time frames, and trends in the biopsy rate and diagnosis of primary glomerular disease were considered. RESULTS Biopsy rates increased significantly from 2.02 to 7.08 per hundred thousand population per year (php/year) (chi(2) = 55.9, P < 0.001), and the mean patient age at biopsy rose from 33 to 49 years over the study period (F = 58, P < 0.001). Primary GN was documented in 49% of biopsies; the most common diagnoses within this group were IgA nephropathy (38.8%), membranous nephropathy (29.4%), minimal change disease (9.8%), membranoproliferative GN type 1 (9.6%) and FSGS (5.7%). There was a significant increase in the proportion of IgA nephropathy (chi(2) = 9.6, P = 0.008) and a decrease in membranous nephropathy (chi(2) = 7.2, P = 0.03) over time. The population incidence of FSGS was low and unchanged at 0.18 php/ year from 1986 to 2005. CONCLUSIONS Consistent with several other European studies, IgA nephropathy was the most common primary glomerular disease in this UK region. The diagnosis of FSGS was uncommon with no evidence of a rise in incidence.

Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

The impact of variation within genes responsible for the disposition and metabolism of calcineurin inhibitors (CNIs) on clinical outcomes in kidney transplantation is not well understood. Furthermore, the potential influence of donor, rather than recipient, genotypes on clinical endpoints is unknown. Here, we investigated the associations between donor and recipient gene variants with outcome among 4471 white, CNI-treated kidney transplant recipients. We tested for 52 single-nucleotide polymorphisms (SNPs) across five genes: CYP3A4, CYP3A5, ABCB1 (MDR1; encoding P-glycoprotein), NR1I2 (encoding the pregnane X receptor), and PPIA (encoding cyclophilin). In a discovery cohort of 811 patients from Birmingham, United Kingdom, kidney donor CC genotype at C3435T (rs1045642) within ABCB1, a variant known to alter protein expression, was associated with an increased risk for long-term graft failure compared with non-CC genotype (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.20-2.40; P=0.003). No other donor or recipient SNPs were associated with graft survival or mortality. We validated this association in 675 donors from Belfast, United Kingdom (HR, 1.68; 95% CI, 1.21-2.32; P=0.002), and in 2985 donors from the Collaborative Transplant Study (HR, 1.84; 95% CI, 1.08-3.13; P=0.006). In conclusion, these data suggest that an ABCB1 variant known to alter protein expression represents an attractive candidate for future study and risk stratification in kidney transplantation.

Association of Caveolin-1 Gene Polymorphism With Kidney Transplant Fibrosis and Allograft Failure

CONTEXT Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis. OBJECTIVE To study the association of CAV1 gene variation with kidney transplant outcome, using kidney transplantation as a model of accelerated fibrosis. DESIGN, SETTING, AND PATIENTS Candidate gene association and validation study. Genomic DNA from 785 white kidney transplant donors and their respective recipients (transplantations in Birmingham, England, between 1996 and 2006; median follow-up, 81 months) were analyzed for common variation in CAV1 using a single-nucleotide polymorphism (SNP) tagging approach. Validation of positive findings was sought in an independent kidney transplant donor-recipient cohort (transplantations in Belfast, Northern Ireland, between 1986 and 2005; n = 697; median follow-up, 69 months). Association between genotype and allograft failure was initially assessed by Kaplan-Meier analysis, then in an adjusted Cox model. MAIN OUTCOME MEASURE Death-censored allograft failure, defined as a return to dialysis or retransplantation. RESULTS The presence of donor AA genotype for the CAV1 rs4730751 SNP was associated with increased risk of allograft failure in the Birmingham group (donor AA vs non-AA genotype in adjusted Cox model, hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.29-3.16; P = .002). No other tag SNPs showed a significant association. This finding was validated in the Belfast cohort (in adjusted Cox model, HR, 1.56; 95% CI, 1.07-2.27; P = .02). Overall graft failure rates were as follows: for the Birmingham cohort, donor genotype AA, 22 of 57 (38.6%); genotype CC, 96 of 431 (22.3%); and genotype AC, 66 of 297 (22.2%); and for the Belfast cohort, donor genotype AA, 32 of 48 (67%); genotype CC, 150 of 358 (42%); and genotype AC, 119 of 273 (44%). CONCLUSION Among kidney transplant donors, the CAV1 rs4730751 SNP was significantly associated with allograft failure in 2 independent cohorts.

The Challenge of Doing What Is Right in Renal Transplantation: Balancing Equity and Utility

Arguably the greatest challenge faced by the transplant community is the disparity between the number of persons waiting for a solid organ transplant and the finite supply of donor organs. For renal transplantation the gap between supply and demand has risen annually reflecting the increasing prevalence of end-stage renal disease versus the relatively static deceased donor organ pool. Maximising the benefit from this scarce resource raises difficult ethical issues. For most patients on dialysis therapy a successful transplant offers improved quality and quantity of life, but the absolute gain in survival provided by a donated organ varies greatly depending on recipient factors such as age and co-morbid illnesses. The philosophies of equity (a fair opportunity for everyone in need to receive a transplant) and utility (optimal profit from each organ) are often competing. National allocation schemes and local policies regarding assessment of potential recipients and acceptance of organs are designed to balance these ethical principles in a standardized and socially acceptable manner. The ongoing debate surrounding these issues and modifications to such policies reflect the evolving clinical picture of renal transplantation and the challenge in maintaining equipoise between renal transplant utility and equity.

Renal transplantation in systemic vasculitis: when is it safe?

BACKGROUND There are no clear guidelines on renal transplantation in patients with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. METHODS We undertook a survey of transplant centres across Europe to assess whether there was consensus about how to manage transplantation in patients with vasculitis. We then identified 107 renal allograft recipients whose primary disease was systemic vasculitis and assessed their outcome post-transplant. RESULTS All questionnaire respondents felt that vasculitis should be in remission at transplantation, 16% believed that ANCA should be negative pre-transplant and 40% felt that one should wait >12 months after remission before transplanting. Remission was defined by all as an absence of clinical symptoms of vasculitis, but three respondents (13%) also required a negative ANCA test. Overall graft survival was 70% after 10 years (95% C.I. 58-82). A total of 30 (41% of those with known ANCA status) were ANCA-positive peri-transplantation, while 15 (14%) were transplanted <1 year post-remission. Severe vasculopathy occurred more frequently in ANCA-positive recipients (odds ratio 4.4, 95% C.I. 1.1-16.8, P < 0.05), although causation cannot be determined from this study. Vasculopathy significantly reduced 10-year graft survival to 47% (P < 0.05). However, ANCA status per se was not significantly associated with graft failure. The strongest predictor of death was transplantation <1 year post-vasculitis remission on both univariate and multivariate analysis (hazard ratio 2.3, P < 0.05). CONCLUSIONS In conclusion, circulating ANCA at transplant was associated with the development of vascular lesions in the graft but was not significantly correlated with graft survival. Most grafts were lost due to patient death, which was more likely if transplantation occurred <12 months following induction of remission of ANCA-positive vasculitis.

Association of Functional Heme Oxygenase‐1 Gene Promoter Polymorphism with Renal Transplantation Outcomes

Heme oxygenase‐1 (HO‐1) is a cytoprotective molecule and increased expression in experimental transplant models correlates with reduced graft injury. A functional dinucleotide repeat (GT)n polymorphism, within the HO‐1 promoter, regulates gene expression; a short number of repeats (S‐allele <25) increases transcription. The role of this HO‐1 gene promoter polymorphism on renal transplant outcomes was assessed. DNA from 707 donor/recipient pairs (n = 1414) of first deceased donor renal transplants (99% Caucasian) was genotyped. Graft survival was not significantly impacted by carriage of an S‐allele by the donor (hazard ratio 0.89, 95% CI 0.71–1.11; p = 0.28) or recipient (hazard ratio 1.19, 95% CI 0.95–1.48; p = 0.13). Similarly neither donor nor recipient genotype influenced recipient survival (hazard ratio 0.89, 95% CI 0.67–1.18; p = 0.41, and hazard ratio 1.22, 95% CI 0.93–1.62; p = 0.16). The hazard ratios changed only minimally in multivariate analysis including significant survival factors. Genotype did not alter the incidence of acute rejection or chronic allograft nephropathy. There is no evidence of a protective effect for the S‐allele of the HO‐1 gene promoter polymorphism on graft or recipient survival in clinical renal transplantation.

Recipient obesity and outcomes after kidney transplantation: a systematic review and meta-analysis

BACKGROUND The prevalence of obesity is increasing globally and is associated with chronic kidney disease and premature mortality. However, the impact of recipient obesity on kidney transplant outcomes remains unclear. This study aimed to investigate the association between recipient obesity and mortality, death-censored graft loss and delayed graft function (DGF) following kidney transplantation. METHODS A systematic review and meta-analysis was conducted using Medline, Embase and the Cochrane Library. Observational studies or randomized controlled trials investigating the association between recipient obesity at transplantation and mortality, death-censored graft loss and DGF were included. Obesity was defined as a body mass index (BMI) of ≥30 kg/m(2). Obese recipients were compared with those with a normal BMI (18.5-24.9 kg/m(2)). Pooled estimates of hazard ratios (HRs) for patient mortality or death-censored graft loss and odds ratios (ORs) for DGF were calculated. RESULTS Seventeen studies including 138 081 patients were analysed. After adjustment, there was no significant difference in mortality risk in obese recipients [HR = 1.24, 95% confidence interval (CI) = 0.90-1.70, studies = 5, n = 83 416]. However, obesity was associated with an increased risk of death-censored graft loss (HR = 1.06, 95% CI = 1.01-1.12, studies = 5, n = 83 416) and an increased likelihood of DGF (OR = 1.68, 95% CI = 1.39-2.03, studies = 4, n = 28 847). CONCLUSIONS Despite having a much higher likelihood of DGF, obese transplant recipients have only a slightly increased risk of graft loss and experience similar survival to recipients with normal BMI.

Prevalence and management of anaemia in renal transplant recipients: data from ten European centres.

Background: Although it is a known predictor of mortality, there is a relative lack of recent information about anaemia in kidney transplant recipients. Thus, we now report data about the prevalence and management of post-transplant anaemia (PTA) in Europe 5 years after the TRansplant European Survey on Anemia Management (TRESAM) study. Methods: In a cross-sectional study enrolling the largest number of patients to date, data were obtained from 5,834 patients followed at 10 outpatient transplant clinics in four European countries using the American Society of Transplantation anaemia guideline. Results: More than one third (42%) of the patients were anaemic. The haemoglobin (Hb) concentration was significantly correlated with the estimated glomerular filtration rate (eGFR) (r = 0.4, p < 0.001). In multivariate analysis, eGFR, serum ferritin, age, gender, time since transplantation and centres were independently and significantly associated with Hb. Only 24% of the patients who had a Hb concentration <110 g/l were treated with an erythropoiesis-stimulating agent. The prevalence of anaemia and also the use of erythropoiesis-stimulating agents were significantly different across the different centres, suggesting substantial practice variations. Conclusions: PTA is still common and under-treated. The prevalence and management of PTA have not changed substantially since the TRESAM survey.

Heme oxygenase 1: does it have a role in renal cytoprotection?

Heme oxygenase (HO) was first identified as the rate-limiting enzyme in the degradative pathway of heme, but is now recognized to be involved in diverse biological processes. Different isoforms of HO exist; HO-1 (HMOX1) is ubiquitously present in mammalian tissue with low constitutive expression under physiological conditions, but is upregulated in response to a variety of potentially noxious stimuli. HO-1, an integral component of an important cytoprotective mechanism, mediates its action through removal of heme, the generation of heme breakdown reaction products (biliverdin, free iron, and carbon monoxide), and modulation of key cellular molecules. Data from experimental models in which HO-1 was induced or inhibited, together with observations in genetically modified animals, showed a beneficial effect of HO-1 in several pathways leading to kidney injury. The discovery of a functional guanosine thymine tandem repeat polymorphism in the promoter region of the human HO-1 gene has stimulated clinical investigations in a variety of diseases. However, despite theoretical and experimental support for an important pathophysiological role for HO-1, the relevance of this polymorphism in native kidney or renal transplant function is equivocal. This article reviews the molecular genetics of HO-1, its myriad cytoprotective effects allied to how these are mediated, and relates these findings to experimental and clinical evidence of HO-1 involvement in renal disease.