Addition of induction therapy offsets the hazard of marked calcineurin minimization among renal transplant recipients treated with sirolimus.

AIMS: We sought to examine the improvement in renal function with preserved immunosuppression consequent to reducing de novo cyclosporine (CsA) doses combined with sirolimus and induction antibody treatment. MATERIALS AND METHODS: 408 renal recipients treated de novo with CsA-sirolimus included 91 patients who received high (> 5); 125, medium (2.5-5.0); or 192, low CsA doses (< 2.5 mg/kg/day) together with induction antibody among 5, 48 and 68% of subjects, respectively. At 2 years we excluded 21 (23), 30 (24) and 49 (25%) subjects who experienced the composite end-point, yielding 70 (71), 95 (76) and 143 (74%) cases, whose mean de novo CsA C2 values were 725, 400 and 306 ng/ml; for all cohorts, sirolimus C0 = 10-15 de novo and 8-12 ng/ml during maintenance treatment. The primary end-point--mean 4-year GFR by aMDRD--ascribed "0" to patients who experienced death or graft loss after 2 years. RESULTS: Although low-dose subjects were older (p = 0.008) and heavier (p < 0.001) with grafts exposed to longer cold ischemia times (p < 0.001), they displayed greater GFR: 64.8 versus 48.4 among the high and 54.1 ml/min/1.73 m(2) in the medium dose arms (p = 0.002). Polychotomous logistic regression revealed significant GFR predictors to be CsA dose (p = 0.015) and younger donor age (p < 0.001). Between 2 and 4 years, the incidences of the composite end-point were 17, 14 and 16%; including 13, 10 and 11% rejections. CONCLUSION: 80% reduction in de novo CsA exposure with antibody induction improved renal function at 4 years compared with 50 or 66% reductions.

Statins benefit outcomes of renal transplant recipients on a sirolimus-cyclosporine regimen.

BACKGROUND: Statins offer a strategy to address dyslipidemia commonly experienced by immunosuppressed transplant recipients. METHODS: This single-center, retrospective study of 325 recipients (mean posttransplant follow-up of over 6 years; 75.0+/-26.0 months) correlated four adverse outcomes-biopsy-confirmed acute rejection episodes, biopsy-confirmed chronic rejection/allograft nephropathy, graft loss, or death-with demographic and posttreatment variables. Patients were treated with a combination of sirolimus (SRL), cyclosporine (CsA), and various durations of steroids. Statins were prescribed for 259/325 (79%) recipients whose serum cholesterol exceeded 240 mg/dL and discontinued when the creatine phosphokinase increased fivefold (3.4%) or the liver function, threefold (3.0%) above normal. RESULTS: Upon univariate (hazard ratio [HR] 0.16; P<.001) and multivariate analysis (HR 0.38; P=.02), statins were markedly protective against acute rejection episodes. They reduced occurrence of chronic nephropathy/chronic rejection (HR 0.60; P=.03 and HR 0.52; P=.01, respectively). Incidences of graft loss were diminished (HR 0.26; P<.001 and HR 0.49; P=.01, respectively). Finally, the mortality rate was decreased (HR 0.21, P=.001 and HR 0.26, P=.01, respectively). Upon multivariate analysis, a reduced incidence of acute rejection was correlated with greater exposure to SRL (HR 0.78, P=.016) and CsA (HR 0.39; P=.006). CONCLUSIONS: This study demonstrated compelling effects of statins against all adverse outcomes among patients treated with SRL-based, CsA-containing regimens. The profoundly dyslipidemic properties of SRL may explain these unique findings compared with previous studies on patients treated with CsA-based regimens.

Use of sirolimus to facilitate steroid withdrawal from a cyclosporine regimen.

OBJECTIVE: Chronic steroid therapy has been associated with many comorbidities of transplant immunosuppression. Because sirolimus blocks one of the sites affected by steroids, we sought to examine whether substituting this drug mitigated these toxicities. METHODS: We used intent-to-treat methodology to compare the clinical outcomes and laboratory results between 30 renal transplant recipients converted from steroids to sirolimus with a cohort of demographically matched subjects who were transplanted concurrently with the study group and maintained on steroids. All patients received ongoing cyclosporine-based immunosuppression. To compensate for pharmacokinetic interactions with sirolimus, the cyclosporine exposure was markedly reduced in the study group. Statistical comparisons utilized analysis of variance, chi-square tests, and log rank evaluation of Kaplan-Meier curves. RESULTS: Conversion from prednisone to sirolimus was accomplished without difficulty in 27 of 30 patients. Treatment failures among the converted patients were due to chronic allograft nephropathy (n = 1), recurrence of original disease (n = 1), or chronic rejection (n = 2). By intent-to-treat analysis, the outcomes were similar in the study versus concurrent control groups. Laboratory values showed triglyceridemia as an adverse reaction to sirolimus, and reduced leukocytes, to steroid withdrawal. The observed clinical benefits solely reflected the markedly reduced cyclosporine exposure. Based on responses to a questionnaire administered prior to versus 12 and 24 months after steroid withdrawal, several domains revealed improvements in subjective complaints. CONCLUSION: Conversion from prednisone to sirolimus in combination with cyclosporine was easily accomplished in most renal transplant recipients. Although a 2-year follow-up failed to reveal objective benefits of the maneuver (other than those consequent to reduced cyclosporine exposure), most patients reported a subjectively improved health status.

Transplantation of single pediatric kidneys into adult recipients.

AIM: To evaluate the outcome of single pediatric kidneys transplanted into adult recipients. METHODS: A retrospective single-center review was performed of transplants from donors less than 5 years of age. Outcomes were compared with recipients of grafts from donors 18 to 45 years transplanted during the same time period. RESULTS: Thirty single renal transplants from pediatric donors and 117 transplants from adult donors between 18 and 45 years of age were performed during the study period. The mean age of the pediatric donors was 2.9 +/- 0.8 years versus 31.5 +/- 8.9 years for adult donors (P < .001). The mean age of the recipients of pediatric donors was 41.9 +/- 13 years versus 48 +/- 12.6 years for recipients of adult grafts (P = .020). The mean recipient weight of pediatric donors was 55.9 +/- 7.8 kg versus 78.0 +/- 17.7 kg for recipients of adult donors (P < .001). Sixty-six percent of pediatric donor recipients were of female gender compared to only 36% of adult donor recipients (P = .005). Death-censored actuarial graft survivals at 1 and 4 years for recipients of pediatric donor grafts were 90% and 85% compared to 93% and 85% for recipients of adult donor grafts (P = NS). The mean calculated creatinine clearances of adult donor graft recipients at 1 and 4 years posttransplantation were 70.8 +/- 26.5 and 73.7 +/- 27.2 mL/min, respectively, compared to 50.3 +/- 20.1 and 56.3 +/- 21.4 mL/min for pediatric donor grafts (P < .01 at 1 and 4 years). CONCLUSION: The use of single pediatric donor kidneys provides an excellent opportunity to safely expand the donor pool.

The effect of pancreas transplantation on peripheral vascular disease complications.

BACKGROUND: We sought to determine whether pancreas transplantation reduced the incidence of peripheral vascular complications in diabetics with renal insufficiency. METHODS: A retrospective single-center review was done of 36 kidney-pancreas (KP) and 88 kidney-alone (KA) recipients with a diagnosis of diabetes and end-stage renal disease (ESRD) transplanted between May 1997 and July 2002. Risk factors studied included type of transplant, age, gender, history of smoking, coronary artery disease, hypertension, and peripheral vascular disease (PVD). The endpoint was first peripheral vascular event occurring after transplantation, defined as either an amputation or revascularization procedure. RESULTS: The mean age of the cohort was 51 +/- 9 years, 64% of patients were of male gender, 20% with a history of smoking, 98% with hypertension, 15% with coronary artery disease (CAD), and 12% with a history of PVD. With a median follow-up of 45 months (12 to 79 months), 3/36 (8%) of KP recipients suffered a PVD complication, compared to 10/88 (11%) of KA recipients (P = NS). Similarly, age, gender, a past history of smoking, CAD, and hypertension were not predictive of PVD complications. Five of 15 patients (33%) with a pretransplant history of PVD suffered a postoperative PVD event compared to only 8 of 109 patients (7%) with no prior history of PVD (P =.008). CONCLUSIONS: Restoration of normoglycemia by pancreas transplantation did not reduce the risk of PVD complications in diabetics with renal failure. A pretransplant history of PVD was the only risk factor associated with posttransplant PVD events.

Use of sirolimus in kidney transplantation.

Sirolimus, which has a distinctive mechanism of action that inhibits cytokine-driven cell proliferation and maturation, provides an exciting addition to the immunosuppressive regimen for organ transplantation. A significant decrease in the number and severity of rejection episodes has been noted when sirolimus is used; it also offers the potential for patients to be withdrawn from steroids, making kidney transplantation an option for many more potential recipients. Toxic conditions such as hyperlipidemia, thrombocytopenia, and leukopenia become transient and manageable with reduction of the sirolimus dose and/or countermeasure therapy.

A pharmacokinetic comparison of the corn oil versus microemulsion gelcap formulation of cyclosporin used de novo after renal transplantation.

The initial poor absorption of the corn oil-based, gel capsule oral formulation of cyclosporin (CyA) greatly limits its use for inception of immunosuppressive therapy. Insufficient drug concentrations during the early post-transplant period predispose to renal allograft rejection. The present study served to compare the time required to achieve the therapeutic CyA concentrations after de novo administration of the corn oil-based gel capsule (CyA-GC; n = 11) versus the microemulsion (CyA-ME; n = 11) formulation of CyA. During the 1st month after renal transplantation, patients underwent serial pharmacokinetic profiling from which we obtained observed and dose-corrected values of several parameters. Although patients in neither the CyA-GC nor the CyA-ME group adequately absorbed the drug during days 0-2, from day 3 to 4 patients in the CyA-ME group showed significantly greater absorption than those in the CyA-GC group (P = 0.041). Patients in the CyA-ME group reached the 1st month target average concentration (Cav) values (> or = 550 ng/ml) earlier than those in the CyA-GC group and required significantly lower daily CyA doses (P = 0.018). We conclude that therapeutic CyA levels can be achieved more rapidly and with lower doses of the drug after de novo administration of CyA-ME than with CyA-GC.

Variable oral absorption of cyclosporine. A biopharmaceutical risk factor for chronic renal allograft rejection.

The inter- and intrapatient variability in cyclosporine (CsA) pharmacokinetics obfuscates the relationship between therapeutic outcome and administered dose, thereby impeding the development of secure algorithms for CsA therapy. In an attempt to understand these variabilities, we previously performed serial pharmacokinetic profiles on 160 renal transplant recipients during the first 3 posttransplant months. Drug exposure was estimated by the average CsA concentration (Cav), which was defined as a time-corrected (tau, hours) expression of the area under the concentration-time curve (AUC), i.e., Cav = (AUC/tau). Low Cav values correlated with an increased occurrence of acute rejection episodes and 1-year rate of renal transplant loss. The present study examines the results of serial pharmacokinetic profiling of a cohort of 204 patients treated for up to 5 years with CsA doses selected to achieve target Cav values. Multivariate analyses correlated demographic factors, laboratory values, clinical parameters, and CsA pharmacokinetic parameters with the occurrence of chronic rejection. The factors that predisposed to chronic rejection included a previous acute rejection episode, initial acute tubular necrosis, diastolic blood pressure above 85 mmHg, and African-American race. Once regression models were adjusted to account for the impact of these factors, we examined the association between the incidence of chronic rejection and individual pharmacokinetic parameters, including the mean values of the absolute and dose-corrected trough, peak, and Cav concentrations, as well as the percent coefficient of variation of each of these values. Receiver operating characteristic curves documented that 27% of the total risk for the occurrence of chronic rejection was attributable to a greater than 20% coefficient of variation of the dose-corrected Cav, namely, AUC/(tau.mg). This study suggests that variable oral bioavailability of CsA represents a biopharmaceutical risk factor for the occurrence of chronic rejection.

Oral cyclosporine preparations immediately following renal transplantation.

A cohort of 11 patients receiving de novo CyA-GC was compared to 11 patients receiving CyA-ME immediately following renal transplantation at five-dose intervals in the first 30 postoperative days. Neither group achieved target CyA concentrations during days 0 to 2, suggesting that additional immunosuppression exposure coverage may be needed at that interval. Thereafter, however, recipients of the CyA microemulsion (Neoral) formulation reached target levels earlier as well as required lower doses to reach target levels.

Chronic rejection in primary renal allograft recipients under cyclosporine-prednisone immunosuppressive therapy.

Although the introduction of cyclosporine-prednisone immunosuppression has improved early renal graft survival, chronic rejection remains a major cause of longterm graft dysfunction. This study retrospectively examined 69 cases of chronic rejection among 643 primary renal allograft recipients treated with cyclosporine-prednisone immunosuppression from July 1981 to October 1989. Chronic rejection was defined as a rejection episode diagnosed greater than 90 days posttransplantation with characteristics of progressive nonacute renal function deterioration, confirmed, in most cases, by renal biopsy. This group was compared with an equal-sized matched cohort. Among cadaveric recipients, 61 of 456 patients (13.4%) displayed chronic rejection, whereas among living-related recipients, 8 of 187 patients (4.3%) developed chronic rejection. The average time from the date of transplantation to diagnosis of chronic rejection was 15 +/- 14 months. One- and three-year graft survivals following diagnosis of chronic rejection were 51% (30/59) and 25% (13/51), respectively, compared with the cohort one- and three-year graft survivals of 98% (58/59) and 86% (32/37) at similar periods posttransplantation. HLA mismatch, PRA status, blood transfusion history, lipid levels, cyclosporine trough levels, incidence of prior acute rejection, and initial graft dysfunction were not significantly different between the chronic rejection group and the matched cohort. Hypertension and proteinuria were significantly associated with chronic rejection (P less than 0.001). Of 58 biopsies performed, findings solely consistent with chronic rejection were observed in 9 cases (15%) and "acute upon chronic" rejection in 49 cases (83%). Treatment of acute concomitants improved the renal function in 43% (27/63) by the time of hospital discharge. Nonetheless, at 12 months the incidence of improved renal function eroded to 22% (13/59), suggesting that the benefit was relatively short-lived. Although the overall incidence of chronic rejection in this group of cyclosporine-prednisone-treated patients was lower than previous azathioprine-prednisone cohorts, the clinical presentation and progression of chronic rejection was similar. Additionally, the incidence of chronic rejection within this series was lower among living-related recipients versus cadaveric recipients of donor organs.

Proteinuria in cyclosporine-treated renal transplant recipients.

Of 704 renal transplant recipients receiving long-term cyclosporine immunosuppression, 71 patients experienced proteinuria greater than 1 g/24 hr beyond the first month posttransplant. Eight patients displayed transient proteinuria, defined as lasting less than 3 months. In most cases this condition was attributed to biopsy-proved acute rejection. The transient proteinuria cohort experienced good graft outcome--namely, 87.5% one-year and 52.5% five-year actuarial graft survivals, which was similar to that observed in patients without proteinuria. In contrast, 52.4% of the 63 patients with nontransient proteinuria experienced graft loss within a median time of 6.1 months. The one- and five-year actuarial graft survivals in patients with nontransient proteinuria were 75.3% and 37.5%, respectively. Among the 63 patients with nontransient proteinuria, histopathologic diagnosis included chronic rejection in 19, transplant glomerulopathy in 14, acute rejection in 9, glomerulonephritis (GN) in 7 including 2 cases of membranous GN, and nonspecific interstitial fibrosis in 10 cases. Despite the overall poor prognosis for graft survival among the entire cohort of patients with nontransient proteinuria, the seven with allograft GN maintained prolonged graft function. They showed an 83.3% five-year actuarial graft survival versus 31.2% in patients with other causes of proteinuria (P = 0.043). These results suggest that posttransplant proteinuria in CsA-treated renal transplant recipients arises primarily as a consequence of allograft rejection and portends a poor graft outcome.

Lipid abnormalities in cyclosporine-prednisone-treated renal transplant recipients.

Hyperlipidemia and hypertension, two major risk factors for accelerated atherosclerosis, undoubtedly contribute to the excessive cardiovascular morbidity and mortality experienced by renal transplant recipients. The present survey of posttransplant hyperlipidemia in 500 cyclosporine-treated patients documented a 37.6% incidence of hypercholesterolemia, which occurred within 6 months posttransplant in 82% of patients. An etiologic relation to corticosteroid therapy was suggested by the strong correlation between prednisone doses and cholesterol levels, by the reduced cholesterol levels in patients undergoing steroid withdrawal, and by the reduction in hypercholesterolemia to 13% by 3 years posttransplant when steroid doses were less than 10 mg daily. Hypertriglyceridemia, which was present in 14.7% of the patients, was more severe under CsA-prednisone compared with azathioprine-prednisone therapy. Hypertriglyceridemia, which occurred later in the posttransplant course than hypercholesterolemia, strongly correlated with an excessive percent relative weight and elevated serum creatinine but not with steroid or CsA doses. Increasing age, diabetes mellitus, beta-blockers and nephrotic syndrome contribute to posttransplant hyperlipidemia in the CsA-Pred era as they did in the azathioprine era of immunosuppression.

On the mechanism of Clq binding to antibody-I. aggregation and/or distortion of IgG vs combining site-transmitted effects.

It was shown previously that in sheep calcium-dependent anti-GAT there is a subpopulation which reacts with and can be precipitated with poly G [Liberti (1975) Immunochemistry 12, 303-310]. This entire subpopulation was also found to react with the cross-reacting polypeptides GA and GT. Furthermore, from hydrogen exchange experiments, it was found that only the immunizing antigen GAT completely filled the combining sites of these antibodies whereas poly G was shown to occupy an average of 47% of all sites, and GA and GT, 75 and 85% respectively. Since precipitins formed with this subpopulation and each of these antigens should have reasonably similar densities and orientations of 'aggregated' IgG but differing combining sites occupancies, we have used this system to explore the relative role of Fc aggregation and/or IgG distortion vs combining site-transmitted effects on the binding of Clq to antibody. For two preparations of this subpopulation (one of high avidity, the other obtained via poly G-Sepharose and of lower avidity) there is only a 5% difference in the delta G (10.2-10.8 kcal/mole) of Clq-IgG interaction for a change in combining site occupancy of 47-100%. For the high-avidity preparation there is a correlation between delta G and degree of ligand occupancy of combining site. This could reflect combining site-transmitted effects or may be related to small differences in the molecular architecture of these precipitins. Clq saturation curves support the latter notion. In view of the very moderate effect of combining site filling (from 47 to 100%) on Clq-IgG interaction for the high-avidity preparation and the absence of any correlation for the lower-avidity preparation. It appears that an allosteric model for antibody initiation of complement is untenable. Unless combining site-originating contributions are completed when less than 50% of an antibody-binding site is occupied by ligand, it would seem that Clq binding to immune complexes must be governed either by enhanced interactions resulting from Fc clustering which occurs via antibody interactions with antigen or by distortion of the antibody molecular upon ligand binding or some combination thereof.