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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.

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., (Copyright © 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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.

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.

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.

The purpose of this study is to identify factors in the sera of highly sensitized (HS) patients (pts) that inhibit T-cell alloresponses. An in vitro assay was used to measure HLA class I and class II-like antiidiotypic antibodies (anti-ids). The stimulation index (SI) was used to measure PBL and T-cell responses to alloantigens. All HS sera (32 pts) and the IgG fraction inhibited PBL and CD4(+) T-cell responses to alloantigens. The SI with HS IgG was 7.9 +/- 1.7 as compared to 31.5 +/- 5.9 with normal IgG (p = 0.0003). In a subset of pts who were transiently sensitized, the SI was 6.6 +/- 1.0 with a high panel reactive antibody (PRA), but when their PRA was zero, the SI was 17.8 +/- 1.3 (p = 0.0000001). Anti-ids were found in 100% of 17 pts with a high PRA. The T-cell inhibitory factors reduced CD4(+) T-cell responses of HS pts to alloantigens in the presence of autologous anti-ids, were MHC restricted and were inactivated by in vitro generated antibodies to HLA class II-like anti-ids. The HLA class II-like anti-id IgG molecules bind to the TCR of CD4(+) T cells and may impair their ability to help in the downregulating antibody response to anti-ids.

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.

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.

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.

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.

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.

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.

Objective: To develop a set of comprehensive, standardized, evidence-based guidelines for the use of antiviral therapy to prevent cytomegalovirus disease in adult patients having undergone renal transplantation., Options: The use of medication, at the time of induction therapy or at the earliest sign of viremia. Treatments were evaluated by patient and donor serologic groups and the induction regimen used., Outcomes: The control of symptoms and features of cytomegalovirus disease over the first 6 mo to 1 yr after transplantation., Evidence: Articles, compiled using a MEDLINE search from 1976 to July 1997, were reviewed by representatives of nephrology, microbiology, pharmacy, and epidemiology. Additional information was obtained from recent review articles and conference abstracts, and from experts in the field., Values: The evidence-based methods and values of the Canadian Task Force on the Periodic Health Examinations were used. High value was placed on studies with a randomized controlled design and blinded outcome observers. Study quality was classified as poor when cointervention was present (especially with regard to immunosuppressive regimens), when more than 20% of patients were lost to follow-up, and when intention to treat analysis was not performed. Recommendations were made with a graded system (grades A and B: Use of the intervention advised, based on high or fair quality evidence, respectively; grades D and E: Use of the intervention not advised, based on high or fair quality evidence, respectively: grade C: No recommendation made because of insufficient or conflicting evidence)., Recommendations: (1) Seropositive recipient; donor seropositive or seronegative; immunosuppression with antilymphocyte products. Prophylaxis with antiviral therapy recommended (grade A recommendation). (2) Seronegative recipient; seropositive donor; immunosuppression with antilymphocyte products. Prophylaxis with antiviral therapy recommended (grade A recommendation) (3) Seronegative recipient; seropositive donor; conventional immunosuppression. Prophylaxis with antiviral therapy recommended (grade B recommendation). (4) Seronegative recipient; seronegative donor; any immunosuppressive regimen. No prophylaxis with antiviral therapy required (grade D/E recommendation). (5) Seropositive recipient: donor seropositive or seronegative; conventional immunosuppression. Prophylaxis left to the discrimination of the physician in charge (grade C recommendation).

1. The 5-year actuarial graft, patient and functional graft survival rates were analyzed in 743 consecutive primary cadaveric kidney transplants from The Toronto Hospital between January 1985-December 1997. 2. Recipient age > or = 55 years, male recipient sex, recipient diabetes mellitus, CIT > 36 hours and delayed graft function were found to significantly decrease patient survival. 3. Recipient age > or = 55 years, sensitization to HLA antigens (peak PRA > 50%), donor/recipient HLA antigen mismatches, CIT > 36 hours, delayed graft, function and 6-month SCr > 200 mumol/L were found to significantly decrease graft survival. 4. Acute rejection episodes had no significant impact on overall 5-year patient or graft survival. 5. The observation that serum creatinine > 200 mumol/L had a major adverse influence on long-term outcome reflects the importance of functional renal mass on graft survival.

Some uremic patients with a history of blood transfusion, pregnancy, and previous transplantation maintain high levels of alloreactive cytotoxic antibodies in the absence of continuous exogenous allogenic stimuli and are thus considered sensitized to the major histocompatibility proteins. To differentiate into antibody-producing cells, B lymphocytes must interact with T-helper (CD4+) cells. Whether ongoing help from these cells is necessary for the B cells to continue producing cytotoxic alloreactive antibodies in these sensitized uremic patients is unknown. To gain insight into the cellular mechanisms that are associated with sustained alloantibody production, T cell activation markers were measured and specific and nonspecific T-helper cell function was studied in three uremic groups with different levels of panel reactive antibodies: 10 patients whose sera reacted to more than 80% of a panel of normal lymphocytes for at least 6 months before the study were highly sensitized, 20 patients whose sera reacted to less than 80% of the panel were moderately sensitized, and 10 nonsensitized patients whose sera did not react to any cell on the panel. The number of total and activated T-helper cells was similar in the highly sensitized and nonsensitized patients. Peripheral blood lymphocyte proliferation in response to plant lectins, soluble OKT3, or alloantigens was similar in the three uremic groups. The spontaneous proliferation of pure T-helper cells and proliferative responses to immobilized OKT3 or alloantigens were also similar in highly sensitized and nonsensitized patients. Alloreactive interleukin-2-producing cell frequencies with pure CD4+ cells as responding cells were 771 +/- 77.9/10(6) cells in highly sensitized, 945 +/- 252/10(6) cells in nonsensitized, and 973 +/- 114/10(6) cells in controls (P = not significant). Panel reactive antibody levels did not correlate with any of the measures of T helper responses. There was a significant decrease of peripheral blood lymphocyte responses to alloantigens and anti-CD3 antibody in all uremic patients as compared with normals, suggesting a dysfunction in accessory cells that was quantitatively similar in sensitized and nonsensitized patients. In spite of the continuous production of alloantibodies by B cells, there is no evidence of either specific or nonspecific enhancement of T-helper cell function in sensitized patients. The absence of T cell immunity to alloantigens suggests that sustained activation of T-helper cells with subsequent interleukin-2 production is not necessary to maintain alloreactive B cell function.

A total 166 first cadaveric renal allograft recipients were randomly assigned to receive either rabbit antithymocyte serum (RATS) (n = 83) or OKT3 (n = 83) for 10 to 14 days after transplant as prophylaxis against rejection. Both groups were similar with respect to age, sex, donor age, diabetes, time on dialysis, panel-reactive antibody, HLA matching, and transfusion before transplantation. All patients were followed for 1 year after transplantation. A comparison of the rejection rates between the 2 groups of patients showed that patients receiving OKT3 had a rate of first rejection 1.87 times higher than those receiving RATS (95% confidence interval 1.18-2.8, P = 0.007). Twenty-five steroid-resistant rejections occurred in OKT3-treated patients as compared with 12 in the RATS-treated group (P < 0.05). There was no significant difference in early or late renal function between the 2 groups of patients. Actuarial 1-year graft survival for the RATS group was 78% and for the OKT3 group, 80.7% (P = NS). Actuarial 1-year patient survival was similar: 89.5% in the RATS group and 94.6% in the OKT3 group (P = NS). Total hospitalization time was 29.8 +/- 19.9 days for RATS vs. 39.5 +/- 22.1 days for those treated with OKT3 (P < 0.006). A number of infections were observed but there were no significant differences between the groups. We conclude that RATS provides better prophylaxis than OKT3 in first cadaveric renal transplants because it is associated with fewer rejection episodes, less hospitalization, and no additional morbidity or mortality.

Objective: Cyclosporine increases transmembrane calcium flux in mesangial and vascular smooth muscle cells, which may explain cyclosporine-induced decreases in renal bloodflow and glomerular filtration rate. Calcium antagonists, thus, may play a role in the prevention/reversal of cyclosporine nephrotoxicity., Design: In a single-blind, randomized, cross-over study the authors evaluated the effects of a one-week treatment with nifedipine 20 mg bid, diltiazem 120 mg bid or placebo on cardiac and renal functions of six stable heart transplant recipients treated chronically with cyclosporine., Results: Both calcium antagonists lowered blood pressure compared with placebo, but only nifedipine increased cardiac output and, therefore, decreased total peripheral resistance significantly more than diltiazem. Nifedipine induced a significant increase in effective renal plasma flow and an insignificant increase in glomerular filtration rate, whereas diltiazem caused a reduction in these parameters. Cyclosporine pharmacokinetics were not affected by either calcium antagonist to a clinically significant extent., Conclusions: Nifedipine and diltiazem exert distinctly different cardiac and renal hemodynamic effects in cardiac transplants, which may have clinical consequences.

Transplantation has become the treatment of choice for many chronic and debilitating diseases. Generally, the primary endpoints in evaluating therapy are graft and patient survival time. However, an important secondary outcome is the number of "rejection episodes" experienced by study patients. This response has a distinctive statistical character. That is, it is a categorical variable since it assumes only a small number of integer values, but it is measured on a ratio-level scale since the ratio of any two values is scientifically meaningful. Historical methods for analyzing this endpoint, for example, t tests, logistic regression and Kaplan-Meier analysis, have failed to take these characteristics into account. In this study, we investigated statistical procedures for analyzing the number of rejection episodes arising during the first three months posttransplant. Data compiled by the Multiple Organ Retrieval and Exchange (MORE) of the Province of Ontario were used for this purpose. It was found that assumptions underlying normal distributional techniques were not satisfied by these data. An alternative model based on Poisson regression models was considered and was shown to provide an adequate fit.

To determine whether hypertension occurring after heart transplant causes the development of cardiac hypertrophy, changes in pressure load (N = 13) and left ventricular anatomy (N = 11) were evaluated up to 1 year after heart transplant in a prospective longitudinal study. Pressure load was evaluated by 24-hour ambulatory blood pressure monitoring, and left ventricular anatomy and function were assessed by M-mode echocardiography under two-dimensional guidance. Body weight increased by 11 to 12 kg. Blood pressure showed a gradual increase during the first few months after transplant: diastolic pressure by 15 to 18 mm Hg and systolic pressure by 12 to 15 mm Hg, with hypertension persisting during the night. Nearly all patients required treatment with one or two antihypertensive drugs. The increase in blood pressure was related to increased total peripheral resistance with minor decreases in cardiac output. Both septal and posterior wall thickness and left ventricular mass (by 25 to 30 gm/m2) decreased during the initial months after transplant and subsequently remained at "normal" levels (100 gm/m2). The persistence of normal left ventricular mass may indicate either that the increases in daily pressure load and body weight were not sufficient to induce myocardial growth or that the latter was prevented by, for example, absence of cardiac sympathetic nerve activity.

Forty heart transplantations were performed at the Toronto Western Hospital, University of Toronto, from October 1987 to December 1989. Each heart extracted from a recipient was examined with the view of using the aortic valve as a homograft for another patient requiring aortic valve replacement. Of the 40 explanted hearts, 26 had normal aortic valves that were potentially suitable for homografting, and 14 had aortic valves judged as unsuitable. Of the potentially suitable valves, four were preserved for ex vivo arrhythmia studies requiring aortic root perfusion and four were damaged during harvesting. The remaining 18 usable valves were sized at the time of explantation and stored in an antibiotic solution at 4 degrees C. Thirteen valves were transplanted within 10 days of harvesting, and five were discarded because no suitable recipients were available within this period. There were no operative deaths or valve-related complications in the 13 homograft valve recipients. Mean follow-up was 13 months (range, 3 to 27 months). One patient required replacement of the homograft with a mechanical prosthesis because of insufficiency and stenosis. All patients are alive, are New York Heart Association functional class status I, and have insignificant valve gradients based on Doppler echocardiography. Although hearts removed from transplant recipients are severely diseased, the aortic valves are frequently normal and should be considered for use as homografts for other patients requiring aortic valve replacement.

Until recently, most transplant units required that a negative crossmatch using all available sera was an essential criterion which would ensure the best use of a donor kidney. This policy was accepted without clinical trial until 1982 when it was suggested that a donor kidney will function successfully in the majority of recipients with a negative crossmatch using current sera and a positive crossmatch with one or more non-current sera, i.e., sera taken 3 or more months prior to the time of the transplant. In the 14 reported series addressing this question, the average 1-year graft survival ranges between 53% and 100% in these highly sensitized patients who receive a primary graft, and between 0% and 100% in those who receive a secondary graft. Controversy does exist as to whether a positive crossmatch in non-current sera is an additional risk factor, i.e., that it decreases graft survival significantly when compared with a similar group of highly sensitized patients who were transplanted with a negative crossmatch on all available pre-transplant sera. Of the published studies on this subject, the majority, but not all, find that there is no difference between controls and positive crossmatch patients who receive a primary graft, but those that receive a secondary graft may be at increased risk. The reasons for the different results from these studies may be related to differences in the many variables which influence graft outcome between various study groups.

To determine whether routine preoperative pulmonary function tests provide useful prognostic information in orthotopic heart transplant candidates, we evaluated the pulmonary status of 33 patients who subsequently underwent transplantation. There was one perioperative death and five other fatalities within 9 months after operation. Mean age of the six patients who died (mean +/- SD 51.8 +/- 5.0 years) was significantly different (p less than 0.05) from that of the survivors (44.6 +/- 11.1 years). Mean preoperative pulmonary vascular resistance was significantly different (p less than 0.05) between those patients who had a fatal outcome (mean, 4.4 +/- 2.0 mm Hg/L/min) and those who survived (2.7 +/- 1.0 mm Hg/L/min). By contrast, we found that measures of forced vital capacity, forced expired volume in 1 second, diffusion capacity for carbon monoxide, and arterial blood gases bore no apparent relationship to outcome. We conclude that standard noninvasive measures of pulmonary function may be useful in preoperative preparation of heart transplant candidates, but they do not appear to be helpful in predicting eventual outcome.

Prolonged cold ischemia has been associated with impaired early cadaver renal allograft function. The role of CsA in potentiating these effects is not well understood, but CsA has been implicated in promoting delayed graft function and potentiating renal ischemic injury. In order to establish whether CsA is safely tolerated by kidneys subjected to protracted cold ischemia, we examined patient and graft outcome in a series of 1081 patients receiving cadaver-kidney transplants over an 8-year period (1981-1988). All patients received a standard immunosuppressive regimen that included CsA. Overall actuarial 1-year patient and graft survival rates were 96% and 80%, respectively. Renal preservation was achieved either by pulsatile perfusion (n = 261, 24%) or simple cold storage (n = 820, 76%). Results were analyzed according to total cold ischemic time as follows: 0-23 hr (n = 512; range, 0-23.9 hr); 24-35 hr (n = 380; range, 24.0-35.9 hr); 36-47 hr (n = 161; range, 36.0-47.7 hr); greater than or equal to 48 hr (n = 28; range, 48.0-70.6 hr). These groups did not differ significantly in recipient age, sex, incidence of diabetes, number of pretransplant blood transfusions, level of presensitization, or HLA match. There were no differences in overall actuarial 1-year patient or graft survival rates, incidence of rejection, or renal function at 1 year. There was a higher incidence of impaired early graft function for kidneys preserved greater than or equal to 48 hr, but eventual graft outcome, including serum creatinine at 1 year, was unchanged. Delayed introduction of CsA resulted in improved 1-year graft survival (84.4% vs. 74.7%, P less than 0.05) compared to CsA treatment begun at the time of transplantation ("initial CsA"). This improvement was present regardless of total cold ischemia time. The incidence of permanent graft nonfunction, which has been previously reported to increase with CsA therapy, was influenced by the timing of CsA therapy (initial: 12%; delayed: 3%, P less than 0.05) but was not affected by duration of cold ischemia. Thus, safe preservation of cadaver kidneys for up to 70 h can be achieved by standard techniques even when CsA is incorporated into the immunosuppressive regimen. The most important determinants of graft survival in these patients are the timing of CsA therapy and the presence of early graft function, not the duration of renal preservation.

This study sought to determine if low doses of ciclosporin (CS) designed to give fasting serum levels of 50-100 ng/ml achieve effective immunosuppression when used from the early postoperative period after renal transplantation. Ninety-four primary renal transplant recipients were studied. Group 1 patients were treated with CS 100 ng/ml and prednisone (0.15 mg/kg/day). Group 2 patients received CS 50 ng/ml, prednisone (0.15 mg/kg/day) and azathioprine (1 mg/kg/day). These patients were compared to a control group of 26 patients (group 3) maintained on only prednisone and azathioprine. CS-treated patients suffered significantly fewer rejection episodes than control subjects (rejection episodes per patient in first year: group 1: 0.3 +/- SD 0.6; group 2: 0.7 +/- SD 0.7; group 3: 1.3 +/- SD 1.1, p less than 0.005). In addition, a greater number of CS-treated patients were completely free of rejection episodes during the first year posttransplant (group 1: 63%; group 2: 64%; group 3: 19%, p less than 0.005). Patient and graft survival were similar in all groups after 1 year (group 1: 92 and 92% respectively; group 2: 95 and 87% respectively; group 3: 96 and 85% respectively). These data suggest that the dose of CS required for effective immunosuppression in vivo is lower than has been previously thought.

There is an increased risk of developing cutaneous neoplasms in patients with renal transplants who are receiving immunosuppressive therapy. We studied 523 consecutive white patients who had received renal transplants at a Canadian medical center. Malignant neoplasms developed in 7.5% of these patients, and 72% of these neoplasms were cutaneous in origin. Compared with the general population, the rate of development of all skin cancers, squamous cell carcinoma, and basal cell carcinoma was 3.2, 18.4, and 1.4 times, respectively. In our study the squamous cell carcinoma to basal cell carcinoma ratio was 2.3:1, compared with 0.2:1 in the general population. There was no significant difference in the site of development of skin cancer in patients with renal transplants compared with the general population. There was, however, a propensity for the development of multiple skin cancers at an earlier age, especially on sun-exposed areas. The results of this study have been compared with those of other world medical centers.

A prospective randomized drug trial was carried out on 59 patients with confirmed membranoproliferative glomerulonephritis (MPGN). The treatment group (27 patients) received cyclophosphamide, coumadin, and dipyridamole for 18 months, and the control group (32 patients) received no specific therapy. Complications of the renal disease such as hypertension and fluid retention were treated similarly in both groups. Entrance criteria included confirmed renal pathology demonstrating either types I or II MPGN, a corrected creatinine clearance (CCr) of less than 80 ml/min/1.73 m2, and/or proteinuria greater than 2 g/day. Actuarial survival was not different between the treatment and the control groups in either MPGN type and was 85% in type I and 90% in type II at 2 years. The change in renal function, as measured by both the slope of CCr and the plasma creatinine reciprocal (1/Cr) at 6, 12, and 18 months was not significantly different between treatment and control groups in either types I or II when tested by both parametric and nonparametric analysis. The age, sex, and initial level of CCr did not influence the rate of decline. Control and treatment group proteinuria was not different at any time point in either types I or II MPGN. The small numbers of type II MPGN cases do not give sufficient power to allow conclusions regarding this therapy in type II. We can conclude that this treatment is ineffective in altering the natural history of type I MPGN.

The difference in immunoregulation between stable renal transplant recipients and patients undergoing chronic rejection is unknown. In stable transplant recipients humoral responses to the allograft are controlled, but in patients with chronic rejection this control appears to be lost. In this study we evaluate B cell function in 24 stable transplant recipients and 5 patients with chronic rejection, using pokeweed mitogen (PWM)-stimulated in vitro lymphocyte production of immunoglobulin (Ig). Stable patients and patients with chronic rejection were similar with respect to time posttransplant, age, degree of HLA-A and B matching and immunosuppressive therapy. Unstimulated immunoglobulin production and serum immunoglobulin levels were similar in both groups and within the normal range. PWM stimulated IgG, and IgM production was significantly depressed in stable patients compared with normal controls and patients with chronic rejection. Patients with chronic rejection had normal PWM-stimulated Ig production. Mononuclear cell subsets--as determined by the monoclonal antibodies T4, T8, T11, B1, and M02, as well as the ratio of T4 to T8--were similar in the two patient groups and within the normal range. There was no correlation between decreased Ig production and decreased T4/T8 ratio. We conclude that stable renal transplant recipients have impaired in vitro humoral responses that may be important in maintaining allograft tolerance. In patients with chronic rejection PWM-stimulated responses have escaped control, and this may be important in the pathogenesis of antibody-mediated graft damage. Impaired Ig production in stable patients may be due to a suppressor cell mechanism--however, quantitative measurements of suppressor cells and the T4/T8 ratio do not predict humoral unresponsiveness.

Intensive plasma exchange (IPE) was used to treat 13 rejection episodes in eight renal transplant recipients with biopsy evidence of humoral rejection. Prior to IPE, each patients had several rejection episodes treated with high dose steroids. The IPE-treated rejections had not responded to conventional anti-rejection therapy and all patients appeared likely to lose their grafts. IPE reversed 7 of the 13 rejections (5 of 8 patients responded). Two of the 8 grafts continue to have adequate function 6 and 8 months after IPE. IPE temporarily reverses rejection but not increase long term graft survival.

Peripheral blood mononuclear cells from stable long-term kidney transplant patients were activated in vitro by Staphylococcus Aureus Cowan I (SAC) (a B cell mitogen). The effect of exogenous interleukin 2 and/or B cell growth factor (BCGF) on these cells was measured by 3H-thymidine incorporation and immunoglobulin production. Both proliferation and Ig production were lower in SAC-activated cells from transplanted patients compared to controls (P less than 0.01). BCGF significantly enhanced blastogenesis (P less than 0.01) and Ig production (P less than 0.01) in SAC-treated cells from either patients or controls; however, the SAC- and BCGF-treated cells of transplant patients did not reach normal proliferation or immunoglobulin production values (P less than 0.001, P less than 0.01, respectively). The addition of IL-2 to SAC-activated cells also increased proliferation and Ig production both in controls (P less than 0.05) and patients (P less than 0.005). However, cells from transplant patients treated with SAC and IL-2 did not reach the normal levels of proliferation or immunoglobulin production (P less than 0.05 for both). IL-2 did not enhance the increase of immunoglobulin production brought about by BCGF. SAC-activated B cells from transplant patients do not proliferate normally and do not produce normal amounts of Ig. The addition of IL-2 and BCGF results in a partial but subnormal improvement in both proliferation and Ig production. We conclude that the B cell abnormality in transplant patients may be due to lack of T cell lymphokines and an intrinsic B cell defect. These results suggest that the administration of exogenous lymphokines to transplant patients with B cell dysfunction may be clinically useful.

Over 11 1/2 years, 420 percutaneous needle biopsies were obtained from the transplanted kidneys of 205 patients at one institution. The procedure was performed by one nephrologist and 55 nephrology trainees. No limit was placed on the number of biopsies performed on one kidney, and the highest number was seven. The complications were macroscopic hematuria in 28 biopsies, prolonged hematuria (greater than 24 hours) in eight, transient anuria in five, and prolonged anuria requiring surgical intervention in one. Perinephric hematoma occurred in three patients; retroperitoneal hematoma led to compression of the iliac vein in one. None of these complications led to loss of the transplant. It is suggested that the freedom from serious complication is related to the safety of the technique and the precautions applied to preparation of the patient. These are described in detail.

This is an analysis of the outcome of 35 patients with end-stage autosomal dominant polycystic kidney disease (ADPKD) at Toronto Western Hospital (TWH) during a 10-year period. The primary treatment in each case was hemodialysis. In the 15 patients managed exclusively with hemodialysis the one- and five-year actuarial survival was 93% and 77% respectively. Twenty patients ultimately received a total of 26 cadaveric renal allografts. Graft survival at one year was 76%. One- and five-year patient survival was 92% and 73% respectively. Beyond 5 years a trend towards increased survival in the transplant group was seen, compared with the exclusively hemodialyzed group. Bilateral nephrectomy prior to transplantation was associated with high morbidity and mortality, and did not change either graft or patient survival. In view of the similar survival and because it is accepted that transplantation offers the highest quality of life amongst the modalities of treatment for end-stage renal failure, transplantation should be considered the treatment of choice for end-stage ADPKD. There is no justification for routine bilateral nephrectomy before renal transplantation.