Saturday, January 28, 2012
Quantifying the benefit of early living-donor renal transplantation with a simulation model of the Dutch renal replacement therapy population
Background. Early living-donor transplantation improves patient- and graft-survival compared with possible cadaveric renal transplantation (RTx), but the magnitude of the survival gain is unknown. For patients starting renal replacement therapy (RRT), we aimed to quantify the survival benefit of early living-donor transplantation compared with dialysis and possible cadaveric transplantation and to estimate the population benefit from increasing the early transplantation rate. Methods. We used a decision-analytic computer-simulation model, with a lifetime time horizon, simulating patients starting RRT, using data from the Dutch End-Stage Renal Disease Registry and published data. We compared the (quality adjusted) life expectancy (LE) of ‘early living-donor RTx’ and ‘dialysis’ (with possible cadaveric RTx if available). Results. LE and quality-adjusted LE benefits of the early living-donor RTx compared with the dialysis strategy for 40-year-old patients ranged from 7.5 to 9.9 life years (LYs) [6.7–8.8 quality-adjusted life years (QALYs)] depending on the primary renal disease. For 70-year-old patients, the benefit was 4.3–6.0 LYs (4.3–6.0 QALYs). Increasing the early transplantation rate from currently 5.8 to 22.2% (the highest in Europe) would increase average LE by 1.2 LYs and total LE for annual incident cases in the Netherlands by 1800 LYs. Conclusions. Efforts to increase early living-donor RTx could potentially substantially increase LE for patients starting RRT, especially in younger patients (read more).
Renal transplant recipients have elevated frequencies of circulating myeloid-derived suppressor cells
Cancer, particularly cutaneous squamous cell carcinoma (SCC), is a major cause of mortality in renal transplant recipients (RTRs). Myeloid-derived suppressor cells (MDSC) play a central role in suppressing cancer immunosurveillance but their potential mobilisation in RTRs and levels relative to those of other immunoregulatory dendritic cell (DC) populations have not been analysed. Methods. The circulating frequencies of MDSC and DC were analysed by multicolour flow cytometry in immunocompetent patients without (n = 13) or with (ICI-SCCPos, n = 14) current SCC, normal donors (NDs, n = 34), chronic kidney disease patients (CKD patients, n = 22) and RTRs (n = 31). Results. Compared to NDs, RTRs had significantly elevated levels of both CD14Neg and CD14Pos MDSC subsets (P < 0.001), while CKD patients and ICI-SCCPos had significantly elevated levels of only the CD14Neg-MDSC subset. DC frequencies were significantly decreased in RTRs and CKD patients but were at normal levels in ICI-SCCPos. The MDSC/DC ratio was significantly elevated (P < 0.05) in RTRs (median = 5.7), CKD patients (median = 3.2) and ICI-SCCPos (median = 3.5) relative to NDs (median = 0.7). The use of immunosuppressive drugs in CKD patients and past/current occurrence of SCC in RTRs was associated with significantly increased CD14Neg-MDSC frequencies. MDSC enriched from RTRs, when co-cultured with activated NDs T cells significantly suppressed extracellular IL-10 levels and can, when activated with formyl-methionyl-leucyl-phenylalanine, inhibit T-cell proliferation. Conclusions. RTRs, CKD patients and ICI-SCCPos have increased MDSC frequencies and MDSC/DC ratios. These changes may impact on cancer immunosurveillance. Therefore, MDSC represent both a potential therapeutic target and prognostic marker in these patients, with respect to the development of SCC and other malignancies (read more).
Uremia induces functional incompetence of bone marrow-derived stromal cells
[A study with implications for autologous MSC therapy in kidney transplantation]
Chronic kidney disease (CKD) is associated with increased risk for cardiovascular diseases (CVD). We hypothesized that inadequate angiogenic response in uremic patients could result from dysfunction of bone marrow-derived stromal cells [mesenchymal stem cells (MSCs)]. Methods. We investigated whether MSCs are functionally competent in uremia induced by partial kidney ablation in C57Bl/6J mice. Results. Uremic MSCs showed decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)1 and stromal cell-derived factor (SDF)-1α, increased cellular senescence, decreased proliferation, defects in migration in response to VEGF and SDF-1α and in vitro tube formation. Interestingly, the expression of fibroblast-specific protein-1 was higher in uremic MSCs. Uremia decreased hypoxia-inducible factor-1α, VEGF and VEGFR1 expression under hypoxia and Akt phosphorylation in both basal and VEGF-stimulated states. A diminished mitogenic effect on endothelial proliferation was observed in conditioned media from uremic MSCs. In addition, intravital microscopic analysis showed decreased angiogenesis in uremic MSCs. Conclusion. These results clearly demonstrate the functional incompetence in MSCs under uremic conditions and may significantly contribute to the disproportionately high risk for CVD in patients with CKD (read more).
Outcome of the living kidney donor
Renal transplantation from living kidney donors is still relatively marginal in most of the European countries. However, this source of kidney grafts may help to overcome in part the organ donor shortage of cadaveric donors. The living donor strategy implies correct and objective information about donation risks and completely free acceptance of the living candidate of the donation. In this paper, we reviewed the consequences of kidney donation on the living donor health, considering very short term (linked to the surgery), short term (effect of nephrectomy on glomerular filtration rate) and long term (risk of mortality, chronic kidney disease, proteinuria and hypertension) consequences of kidney donation (read more).
Thursday, January 26, 2012
A Simplified Donor Risk Index for Predicting Outcome After Deceased Donor Kidney Transplantation
Background. We sought to determine the deceased donor factors associated with outcome after kidney transplantation and to develop a clinically applicable Kidney Donor Risk Index.
Methods. Data from the UK Transplant Registry on 7620 adult recipients of adult deceased donor kidney transplants between 2000 and 2007 inclusive were analyzed. Donor factors potentially influencing transplant outcome were investigated using Cox regression, adjusting for significant recipient and transplant factors. A United Kingdom Kidney Donor Risk Index was derived from the model and validated.
Results. Donor age was the most significant factor predicting poor transplant outcome (hazard ratio for 18–39 and 60+ years relative to 40–59 years was 0.78 and 1.49, respectively, P<0.001). A history of donor hypertension was also associated with increased risk (hazard ratio 1.30, P=0.001), and increased donor body weight, longer hospital stay before death, and use of adrenaline were also significantly associated with poorer outcomes up to 3 years posttransplant. Other donor factors including donation after circulatory death, history of cardiothoracic disease, diabetes history, and terminal creatinine were not significant. A donor risk index based on the five significant donor factors was derived and confirmed to be prognostic of outcome in a validation cohort (concordance statistic 0.62). An index developed in the United States by Rao et al., Transplantation 2009; 88: 231–236, included 15 factors and gave a concordance statistic of 0.63 in the UK context, suggesting that our much simpler model has equivalent predictive ability.
Conclusions. A Kidney Donor Risk Index based on five donor variables provides a clinically useful tool that may help with organ allocation and informed consent (read more).
Methods. Data from the UK Transplant Registry on 7620 adult recipients of adult deceased donor kidney transplants between 2000 and 2007 inclusive were analyzed. Donor factors potentially influencing transplant outcome were investigated using Cox regression, adjusting for significant recipient and transplant factors. A United Kingdom Kidney Donor Risk Index was derived from the model and validated.
Results. Donor age was the most significant factor predicting poor transplant outcome (hazard ratio for 18–39 and 60+ years relative to 40–59 years was 0.78 and 1.49, respectively, P<0.001). A history of donor hypertension was also associated with increased risk (hazard ratio 1.30, P=0.001), and increased donor body weight, longer hospital stay before death, and use of adrenaline were also significantly associated with poorer outcomes up to 3 years posttransplant. Other donor factors including donation after circulatory death, history of cardiothoracic disease, diabetes history, and terminal creatinine were not significant. A donor risk index based on the five significant donor factors was derived and confirmed to be prognostic of outcome in a validation cohort (concordance statistic 0.62). An index developed in the United States by Rao et al., Transplantation 2009; 88: 231–236, included 15 factors and gave a concordance statistic of 0.63 in the UK context, suggesting that our much simpler model has equivalent predictive ability.
Conclusions. A Kidney Donor Risk Index based on five donor variables provides a clinically useful tool that may help with organ allocation and informed consent (read more).
Pretransplant Immune Regulation Predicts Allograft Outcome: Bidirectional Regulation Correlates With Excellent Renal Transplant Function in Living-Related Donor-Recipient Pairs
Background. Tolerance to noninherited maternal antigens has provided clinical advantage when kidney transplants are exchanged between siblings but not when mother herself is the donor. This paradox prompted us to revisit the “two-way” hypothesis of transplant tolerance—that the immune status of both the organ recipient and the organ donor critically influences allograft outcome.
Methods. We obtained peripheral blood monocyte cells from 29 living donor-recipient pairs before transplant and used the trans-vivo-delayed type hypersensitivity assay to measure immune regulation in both the recipient antidonor and donor antirecipient directions.
Results. We found preexisting bidirectional regulation in all human leukocyte antigen (HLA)-identical sibling pairs tested (7/7), and one half (9/18) of the HLA haploidentical pairs. No significant regulation was found in four control living unrelated and two HLA haploidentical living-related donor recipient pairs, whereas unidirectional regulation was found in the remaining seven haploidentical pairs. Of the nine HLA haploidentical transplants with unidirectional or no pretransplant regulation, seven had an acute rejection episode and four of these experienced graft loss. In contrast, of the nine HLA haploidentical transplants with bidirectional regulation, only one had rejection. Renal function for the latter group was similar to HLA-identical kidney recipients at 3 years posttransplant. Significantly (P<0.05) lower mean serum creatinine values in bidirectional regulators were noted as early as 4 months and this difference became more pronounced at 12 (P<0.005) and 36 months (P<0.0001).
Conclusions. Contrary to the belief that only the recipient's immune status matters, the data indicate that pretransplant immune status of both donor and recipient influence posttransplant outcome (read more).
Methods. We obtained peripheral blood monocyte cells from 29 living donor-recipient pairs before transplant and used the trans-vivo-delayed type hypersensitivity assay to measure immune regulation in both the recipient antidonor and donor antirecipient directions.
Results. We found preexisting bidirectional regulation in all human leukocyte antigen (HLA)-identical sibling pairs tested (7/7), and one half (9/18) of the HLA haploidentical pairs. No significant regulation was found in four control living unrelated and two HLA haploidentical living-related donor recipient pairs, whereas unidirectional regulation was found in the remaining seven haploidentical pairs. Of the nine HLA haploidentical transplants with unidirectional or no pretransplant regulation, seven had an acute rejection episode and four of these experienced graft loss. In contrast, of the nine HLA haploidentical transplants with bidirectional regulation, only one had rejection. Renal function for the latter group was similar to HLA-identical kidney recipients at 3 years posttransplant. Significantly (P<0.05) lower mean serum creatinine values in bidirectional regulators were noted as early as 4 months and this difference became more pronounced at 12 (P<0.005) and 36 months (P<0.0001).
Conclusions. Contrary to the belief that only the recipient's immune status matters, the data indicate that pretransplant immune status of both donor and recipient influence posttransplant outcome (read more).
Accommodation: Does it Apply to Human Leukocyte Antigens?
The term “accommodation” was invoked to describe endothelial cell resistance to antibody-mediated rejection after ABO-incompatible kidney or experimental xenograft transplantation. Currently, there is much interest in how to achieve successful human leukocyte antigen (HLA)-incompatible allograft transplantation in HLA-sensitized patients and how to treat antibody-mediated rejection after ABO-compatible HLA-incompatible allotransplantation. The term “accommodation” is often used interchangeably to describe patients who have donor-specific ABO or HLA alloantibodies in the absence of damage to their allograft. Here, we suggest that there are important differences between the immune responses to protein versus carbohydrate antigens and that graft HLA molecules may respond differently to antibodies (and antibody isotypes) than ABO antigens. Neither the mechanisms nor a phenotype of accommodation have been defined fully. Further research is needed to define mechanisms of both resistance and susceptibility to antibody-mediated injury and to predict under which circumstances allograft accommodation may occur (read more).
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