Delayed graft function and the risk for death with a functioning graft.

Delayed graft function (DGF) associates with an increased risk for graft failure, but its link with death with graft function (DWGF) is unknown. We used the US Renal Data System to assemble a cohort of all first, adult, deceased-donor kidney transplant recipients from January 1, 1998, through December 31, 2004. In total, 11,542 (23%) of 50,246 recipients required at least one dialysis session in the first week after transplantation. Compared with patients without DGF, patients with DGF were significantly more likely to die with a functioning graft (relative hazard 1.83 [95% confidence interval 1.73 to 1.93] and 1.53 [95% CI 1.45 to 1.63] for unadjusted and fully adjusted models, respectively). The risk for DWGF was slightly higher among women with DGF than among men. There was no significant heterogeneity among other subgroups, and the results were robust to sensitivity analyses. Acute rejection within the first year attenuated the DGF-DWGF association. Cardiovascular and infectious deaths were slightly more prevalent in the DGF group, but the relative hazards of cause-specific death were similar between DWGF and deaths during total follow-up. In summary, DGF associates with an increased risk for DWGF; the mechanisms underlying the negative impact of DGF require further study.

Delayed graft function and the risk of death with graft function in living donor kidney transplant recipients.

BACKGROUND: The link between delayed graft function (DGF) and death with graft function (DWGF) in living donor kidney transplant recipients presently is unknown. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 44,630 adult living donor kidney recipients (first transplants only) in the US Renal Data System from January 1, 1994, to December 31, 2004. PREDICTOR: DGF, defined as the need for dialysis therapy in the first week after transplant. OUTCOME: Time to DWGF. MEASUREMENTS: Kaplan-Meier curves were constructed to assess the impact of DGF on DWGF. Recipients with DGF were 1:1 propensity score matched to those without DGF, and time-dependent Cox proportional hazards models were used to examine factors associated with DWGF. Subgroup and sensitivity analyses also were conducted. RESULTS: DWGF occurred in 3,878 patients during 3.9 years' (median) follow-up. In patients with DGF, survival with graft function at 1, 3, 5, and 10 years was 91.9%, 86.8%, 81.6%, and 61.7%, respectively (in patients without DGF, these values were 98.0%, 95.2%, 91.6%, and 80.1%, respectively; P < 0.001 compared with the DGF group). In a fully adjusted time-dependent Cox model, HRs for DWGF in patients with DGF (vs without DGF) were 6.55 (95% CI, 4.78-8.97), 3.55 (95% CI, 2.46-5.11), 2.07 (95% CI, 1.53-2.81), and 1.48 (95% CI, 1.26-1.73) at 0-1, 1-3, 3-12, and longer than 12 months posttransplant, respectively. Propensity score analysis showed similar results. Inferences were unchanged after adjustment for kidney function and acute rejection at 6 months and 1 year posttransplant. Cardiovascular and infectious causes of DWGF were more prevalent in patients with DGF. The association was more marked in female recipients and robust to various sensitivity analyses. LIMITATIONS: The impact of lesser decreases in early graft function could not be evaluated. CONCLUSIONS: DGF is associated with an increased risk of DWGF in living donor kidney recipients. The mechanisms underlying this relation require further study.

The role of anti-non-Gal antibodies in the development of acute humoral xenograft rejection of hDAF transgenic porcine kidneys in baboons receiving anti-Gal antibody neutralization therapy.

BACKGROUND: The present study was undertaken to determine the role of preformed and induced anti-non-Gal antibodies in the rejection of hDAF pig-to-baboon kidney xenotransplants after anti-Gal antibody neutralization therapy. METHODS: Seven baboons received life-supporting kidney transplants from hDAF transgenic pigs. Anti-Gal antibodies were neutralized by GAS914 or TPC (a Gal PEG glycoconjugate polymer). Group 1 (n=5) underwent a conventional immunosuppressive therapy with FK506, rabbit anti-thymocyte serum/immunoglobulin, mycophenolate mofetil, and steroids. Group 2 (n=2) received an anti-humoral immunity regimen with LF15-0195, Rituxan and cobra venom factor in addition to ATG, FK506 and steroids. Levels of anti-non-Gal antibodies and their mediated complement-dependent cytotoxic activities (CDC) were detected by flow cytometry using Gal knockout (k/o) pig lymphocytes (LC) or endothelial cells (EC) as targets. RESULTS: Continuous infusion of GAS914/TPC significantly reduced anti-Gal antibodies. In Group 1, four of five baboons developed severe acute humoral xenograft rejection (AHXR) and the rejection was associated with either a high level of preformed anti-non-Gal IgG or a marked elevation in induced anti-non-Gal IgG and IgM. Sera collected at the time of AHXR had a high level of CDC to porcine LC/EC from Gal k/o animals. The intensive anti-humoral therapy in Group 2 completely inhibited both anti-Gal and non-Gal antibody production and prevented AHXR. However, this therapy was not well tolerated by the baboons. CONCLUSION: In a pig-to-baboon kidney transplant model, both preformed and induced anti-non-Gal antibodies are strongly associated with the pathogenesis of AHXR when anti-Gal antibodies are neutralized.

A comparison of the effects of C2-cyclosporine and C0-tacrolimus on renal function and cardiovascular risk factors in kidney transplant recipients.

BACKGROUND: There are few data directly comparing the effects of two-hour postingestion monitored cyclosporine (C2-CsA) vs. trough-monitored tacrolimus (C0-Tac) on renal function and cardiovascular risk factors. METHODS: We studied 378 (202 C2-CsA vs. 176 C0-Tac) incident kidney transplant recipients in Toronto, Canada, from August 1, 2000 and December 31, 2003. Outcomes included changes in estimated glomerular filtration rate (eGFR at 1 and 6 months by modification of diet in renal disease four-variable equation), mean arterial pressure (MAP), total cholesterol (TC), and new-onset diabetes mellitus (NODM) at six months posttransplant. The independent effect of treatment/monitoring strategies on continuous outcomes and time-to-NODM was modeled using linear and Cox regression, respectively. RESULTS: Mean eGFR was 59.5 vs. 62.9 ml/min at one month and 50.6 vs. 61.2 ml/min at six months for C2-CsA vs. C0-Tac, respectively. Multiple linear regression revealed the slope of eGFR to be 0.93 ml/min/month lower in C2-CsA patients. This was equivalent to an adjusted average eGFR difference of 4.64 ml/min between months one and six posttransplant. There was no significant difference in average MAP and TC. In a stepwise multivariable Cox model and a propensity score analysis, there was no significant association between the type of treatment/monitoring strategy and time-to-NODM. CONCLUSIONS: There was a greater decline in eGFR for patients on C2-CsA (vs. C0-Tac) between one and six months posttransplant. However, MAP, TC, and the risk of NODM were comparable in both treatment/monitoring groups. The long-term impact of short-term reductions in eGFR as a function of the type of treatment/monitoring strategy requires further study.

Abnormal B-cell regulation in highly sensitized patients with sustained serum levels of antibody to HLA class I antigens.

BACKGROUND: There are anti-idiotypes in the sera of highly sensitized (HS) patients that stimulate B cells to produce antibody to HLA class I antigens. The purpose of this study is to determine if there is an abnormality in B cell responses to these anti-idiotypes. METHODS: Supernatants from normal and HS B cells exposed to either HLA-like anti-idiotypes or HS sera were tested for IgG and antibody to HLA class I antigens by ELISA and flow beads. RESULTS: When stimulated with HS sera, HS B cells produced antibody to HLA class I antigens (in vitro) (12/12) but normal B cells did not (0/10) (P<0.0001). When HS B cells were stimulated with isolated HLA-like anti-idiotypes, they produced more total IgG in the supernatant (603+/-105 ng/ml vs. 293+/-30 ng/ml; P<0.01) and more IgG1 (67+/-5.3 ng/ml vs. 32.3+/-5.4 ng/ml; P<0.001) and more IgG3 (33.3+/-9.2 vs. 2.03+/-0.2 ng/ml; P<0.0001) than normal B cells. The proliferative response to HLA-like anti-idiotypes was 1285+/-115 cpm from normal B cells and 1020+/-445 from HS B cells (p=NS). CONCLUSIONS: When exposed to HS sera, HS B cells produced antibody to HLA class I antigens and normal B cells did not. When exposed to isolated HLA-like anti-idiotypes, HS B cells produced more total IgG, primarily IgG1 and IgG3 with normal proliferation. This intrinsic abnormality in HS B cells permits antibody to HLA class I antigens to be produced and allows increased amounts of IgG1 and IgG3 to be secreted in the absence of an increase in proliferation.

Anti-idiotypic antibodies from highly sensitized patients stimulate B cells to produce anti-HLA antibodies.

BACKGROUND: Sustained allosensitization increases waiting time for transplantation and increases the risk of rejection. The purpose of this study is to examine the effect of anti-idiotypic antibodies on B-cell responses and to define their role in alloantibody production. METHODS: The Immunoglobulin G (IgG) fraction, or the sera of 19 highly sensitized (HS) patients was absorbed to remove anticlass I antibody and was incubated with B cells. The culture supernatant was assayed for antihistocompatibility leukocyte antigen (HLA) antibody and tested for reactivity against a panel of normal lymphocytes. Similar studies were performed in 5 of the 19 patients who had a fall in alloantibody levels. RESULTS: The IgG (HS) fraction induced anti-HLA antibody from normal and autologous B cells in all 19 HS patients studied. The reactivity to HLA antigens in the culture supernatant was similar to the sera for each patient studied. The in vitro generated anti-HLA antibody bound to the IgG fraction used to stimulate the B cells. The in vitro production of anti-HLA antibodies was absent in the serum of all five patients who became nonsensitized. CONCLUSIONS: All patients who have high levels of alloantibody have anti-idiotypic antibodies in their sera that stimulate B cells to produce anti-HLA class I antibody similar in reactivity to that of their own sera. In the patients who have nondetectable alloantibodies in their sera, the stimulating anti-idiotypes are not measurable. Anti-idiotypic antibodies may act as a vaccine and cause sustained levels of alloantibody production.

Improvement in rejection of human decay accelerating factor transgenic pig-to-primate renal xenografts with administration of rabbit antithymocyte serum.

BACKGROUND: Survival in pig-to-baboon kidney xenotransplantation is currently limited by acute humoral xenograft rejection (AHXR). We hypothesized that the administration of rabbit antithymocyte serum (RATS) would delay or prevent AHXR as compared with a cyclophosphamide (CyP)-based immunosuppressive regimen. METHODS: Nine baboons received life-supporting heterotopic single-kidney transplants from human decay accelerating factor transgenic pigs. Immunosuppression consisted of GAS (a galactosyl alpha-1,3-galactose analog), cyclosporine, and steroids. Group 1 (n=2) was also treated with CyP and a rapamycin derivative (RAD), group 2 (n=4) received RATS and RAD, and group 3 (n=3) received only RATS. Animals were maintained until death or sacrifice because of uncontrollable rejection or other complications. Graft histopathology was assessed at the study endpoint. RESULTS: Mean survival was 28+/-11.3 days, 23+/-2.5 days, and 20+/-2.5 days for groups 1, 2, and 3 (not significant). Graft rejection was the cause of death in both CyP-treated animals. One RATS-treated animal died of rejection; the others died of infections or bleeding. Two RATS-treated animals developed posttransplant lymphoproliferative disorder, and one died of cytomegalovirus pneumonitis. Histopathology revealed severe AHXR in group 1 kidneys, involving 100+/-0% of the tissue examined. In contrast, AHXR was reduced in groups 2 and 3, involving 21+/-14% and 18+/-28%, respectively, of the tissue examined (P<0.01). CONCLUSIONS: Substitution of RATS for CyP was well tolerated and resulted in reduced severity of AHXR in this model. Complications seen in RATS-treated animals may be preventable through the use of standard prophylaxis for infections. Our data suggest that further studies are warranted to explore the use of antilymphocyte agents in xenotransplantation.

A pilot study of reduced dose cyclosporine and corticosteroids to reduce new onset diabetes mellitus and acute rejection in kidney transplant recipients.

BACKGROUND: New onset diabetes mellitus (NODM) and acute rejection (AR) are important causes of morbidity and risk factors for allograft failure after kidney transplantation. METHODS: In this multi-center, open label, single-arm pilot study, 49 adult (≥18 years of age), low immunologic risk, non-diabetic recipients of a first deceased or living donor kidney transplant received early steroid reduction to 5 mg/day combined with Thymoglobulin® (Genzyme Transplant, Cambridge, MA, USA) induction, low dose cyclosporine (2-hour post-dose (C2) target of 600 to 800 ng/ml) and mycophenolic acid (MPA) therapy. RESULTS: Six months after transplantation, two patients (4%) developed NODM and one patient (2%) developed AR. Four patients had impaired fasting glucose tolerance based on 75-g oral glucose tolerance testing (OGTT). There was one patient death. There were no episodes of cytomegalovirus (CMV) infection or BK virus nephritis. In contrast, in a historical cohort of n = 27 patients treated with Thymoglobulin induction, and conventional doses of cyclosporine and corticosteroids, the incidence of NODM and AR was 18% and 15%. CONCLUSIONS: The pilot study results suggest that Thymoglobulin induction combined with early steroid reduction, reduced cyclosporine exposure and MPA, may reduce the incidence of both NODM and AR in low immunological risk patients. A future controlled study enriched for patients at high risk for NODM is under consideration. TRIAL REGISTRATION: ClinicalTrials.gov: http://NCT00706680.

The CLEAR study: a 5-day, 3-g loading dose of mycophenolate mofetil versus standard 2-g dosing in renal transplantation.

BACKGROUND AND OBJECTIVES: Adequate early mycophenolic acid (MPA) exposure is associated with lower rates of acute rejection in renal transplantation. The aim of this randomized controlled trial was to determine if higher initial mycophenolate mofetil (MMF) doses increased the proportion of patients reaching therapeutic MPA levels (30 to 60 mg.h/L) by day 5. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: De novo renal transplant patients were randomized to receive intensified dosing of MMF (1.5 g twice daily on days 1 to 5, then 1.0 g twice daily) or standard dosing (1.0 g twice daily). All recipients received tacrolimus and prednisone. Full MPA areas under the curve (AUCs) were completed on days 3 and 5, whereas a limited sampling strategy was utilized at four subsequent time points. RESULTS: At day 5, 47.5% of the MMF 3-g arm achieved the MPA therapeutic window versus 54.4% of the MMF 2-g arm. However, MPA AUC levels were significantly higher in the 3-g arm at day 3 and 5. This resulted in a trend for fewer treated acute rejections at 6 months. Significantly more acute rejections (treated, biopsy-proven including and excluding borderline) occurred in patients with MPA AUC levels<30 mg.h/L compared with those >or=30 mg.h/L at day 5. No significant differences were seen in common adverse events. CONCLUSIONS: A limited intensified dose of MMF increased early MPA exposure and was well tolerated. Further studies are required to determine whether limited intensified MMF dosing can reduce acute rejection.

Impact of deceased donor diabetes mellitus on kidney transplant outcomes: a propensity score-matched study.

BACKGROUND: There is a paucity of population-level data on the long-term outcomes of kidney transplants from deceased donors with a history of diabetes mellitus (DM). METHODS: We examined the association of donor DM with graft and patient survival in 66,654 deceased donor kidney transplant recipients (KTR) from January 1, 1994, to December 31, 2003, in the United States. KTR receiving kidneys from DM versus non-DM donors were compared in the total study population and in a 1:1 propensity score-matched cohort. RESULTS: A total of 2302 KTR received kidneys from DM donors over the study period. Older and female recipients, increased donor age, longer cold ischemia time, and transplants after 2000 were associated with a greater odds of receiving a DM donor. After propensity score matching, Cox proportional hazards models revealed hazard ratios of 1.11 (95% CI: 1.02-1.22), 1.17 (95% CI: 1.04-1.33), and 1.06 (95% CI: 0.94-1.18) for graft failure, death-censored graft failure, and patient mortality, respectively. No significant effect measure modification was seen across various patient subgroups. Longer duration of donor DM was generally associated with an increased risk of adverse outcomes. The results were robust to several sensitivity analyses. CONCLUSIONS: The long-term graft survival of KTR with DM donors is significantly inferior to non-DM donors, but the absolute difference is small. DM donors do not adversely impact patient survival. This suggests that DM donors may be effectively used to expand the donor pool, but evidence-based guidelines on the appropriate selection of these donors are needed.

Reduced incidence of new-onset diabetes mellitus after renal transplantation with 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors (statins).

Statins have anti-inflammatory effects, modify endothelial function and improve peripheral insulin resistance. We hypothesized that statins influence the development of new-onset diabetes mellitus in renal transplant recipients. The records of all previously non-diabetic adults who received an allograft in Toronto between January 1, 1999 and December 31, 2001 were reviewed with follow-up through December 31, 2002. All patients receiving cyclosporine or tacrolimus, mycophenolate mofetil and prednisone were included. New-onset diabetes was diagnosed by the Canadian Diabetic Association criteria: fasting plasma glucose > or =7.0 mmol/L or 2-h postprandial glucose > or =11.1 mmol/L on more than two occasions. Statin use prior to diabetes development was recorded along with other variables. Cox proportional hazards models analyzing statin use as a time-dependent covariate were performed. Three hundred fourteen recipients met study criteria, of whom 129 received statins. New-onset diabetes incidence was 16% (n = 49). Statins (p = 0.0004, HR 0.238[0.109-0.524]) and ACE inhibitors/ARB (p = 0.01, HR 0.309[0.127-0.750]) were associated with decreased risk. Prednisone dose (p = 0.0001, HR 1.007[1.003-1.010] per 1 mg/d at 3 months), weight at transplant (p = 0.02, HR 1.022[1.003-1.042] per 1 kg), black ethnicity (p = 0.02, HR 1.230[1.023-1.480]) and age > or =45 years (p = 0.01, HR 2.226[1.162-4.261]) were associated with increased diabetes. Statin use is associated with reduced new-onset diabetes development after renal transplantation.