Combination Drug Products for HIV-A Word of Caution for the Transplant Clinician.

Modern-day treatment regimens for human immunodeficiency virus (HIV) are not only highly effective, but are now more often available as convenient fixed-dose combination products. Furthermore, as medication adherence is of utmost importance in this setting, national guidelines endorse the use of such products. Transplant providers of HIV-infected patients will undoubtedly encounter these products, some of which contain medications known to drastically alter the metabolism of certain immunosuppressants. Herein, we describe an instance of drug interaction-induced calcineurin inhibitor (CNI) nephrotoxicity in a renal transplant recipient being started on a cobicistat-containing combination product for HIV. CNI toxicity, in turn, was resolved with the aid of phenytoin as an inducer of drug metabolism. This case underscores the importance of familiarity with newer combination products on the market and constant communication with HIV-positive transplant recipients and their providers.

Observations on the use of cidofovir for BK virus infection in renal transplantation.

BACKGROUND: In renal transplantation, BK virus infection can result in significant graft nephropathy and loss. While reduction in immunosuppression (IS) is considered standard therapy, adjunct agents may be warranted. Data are suggestive of a possible role of cidofovir for the management of BK. This study aims to describe the course of BK viremia (BKV) in a large cohort of renal transplant patients receiving adjunct cidofovir. METHODS: We evaluated kidney and kidney-pancreas recipients who received cidofovir combined with reduced IS for management of high-level BKV or BK virus nephropathy (BKVN). We examined the rate and timing of BKV clearance, and performed a multivariate analysis to identify risk factors associated with long-term (>6 months) viremia. RESULTS: In total, 75 patients received a median of 13 doses of cidofovir in conjunction with reduced IS; 32 patients (43%) had short-term BKV (≤6 months), and 43 (57%) had long-term BKV. Overall, 53 of 75 patients (71%) eventually cleared BKV at a median of 4.2 months (interquartile range 2.1-9.3 months). Independent factors associated with long-term BKV included older age (odds ratio [OR] 1.1, P = 0.02), delayed graft function (OR 31.4, P = 0.01), and higher peak BKV (OR 12.8, P = 0.02), while BKV reduction by at least 1 log(10) copies/mL at 1 month of treatment was associated with clearance within 6 months (OR 49.3, P < 0.01). Patients with earlier clearance maintained stable graft function and no graft losses, while long-term BKV was associated with a 15% decline in estimated glomerular filtration rate. CONCLUSIONS: Adjunct cidofovir resulted in preservation of renal function when viral clearance occurred within 6 months of initiation. This retrospective review defines factors predicting response to cidofovir in conjunction with reduced IS for BKVN or high-level BKV. Still, considering cost, frequency of administration, and treatment duration, a randomized trial is necessary to define the exact utility of cidofovir in the setting of BK virus infection.

Time differences in the formation of meteorites as determined from the ratio of lead-207 to lead-206.

Measurements of the lead isotopic composition and the uranium, thorium, and lead concentrations in meteorites were made in order to obtain more precise radiometric ages of these members of the solar system. The newly determined value of the lead isotopic composition of Canyon Diablo troilite is as follows: (206)Pb/(204)Pb = 9.307, (207)Pb/(2O4)Pb = 10.294, and (208)Pb/(204)Pb = 29.476. The leads of Angra dos Reis, Sioux County, and Nuevo Laredo achondrites are very radiogenic, the (206)Pb/(204)Pb values are about 200, and the uranium-thorium-lead systems are nearly concordant. The ages of the meteorites as calculated from a single-stage (207)Pb/(206)Pb isochron based on the newly determined primordial lead value and the newly reported (235)U and (838)U decay constants, are 4.528 x 10(9) years for Sioux County and Nuevo Laredo and 4.555 x 10(9) years for Angra dos Reis. When calculated with the uranium decay constants used by Patterson, these ages are 4.593 x 10(9) years and 4.620 x 10(9) years, respectively, and are therefore 40 to 70 x 10(6) years older than the 4.55 x 10(9) years age Patterson reported. The age difference of 27 x 10(6) years between Angra dos Reis and the other two meteorites is compatible with the difference between the initial (87)Sr/(86)Sr ratio of Angra dos Reis and that of seven basaltic achondrites observed by Papanastassiou and Wasserburg. The time difference is also comparable to that determined by (129)1-(129)Xe chronology. The ages of ordinary chondrites (H5 and L6) range from 4.52 to 4.57 x 10(9) years, and, here too, time differences in the formation of the parent bodies or later metamorphic events are indicated. Carbonaceous chondrites(C2 and C3) appear to contain younger lead components.

Selective corticosteroid and calcineurin-inhibitor withdrawal after pancreas-kidney transplantation utilizing thymoglobulin induction and sirolimus maintenance therapy.

Of 25 simultaneous pancreas-kidney transplant (SPK) recipients treated with thymoglobulin induction, sirolimus and reduced-dose cyclosporine (CsA), 18 low-immune responders (non-African-Americans, PRA < 30%) were withdrawn from prednisone on post-transplant day 5, whereas seven high-immune responders continued on prednisone. Most high- and low-immune responder recipients were converted from CsA to mycophenolic acid (MPA) at six months post-transplantation. At a mean follow-up of 28 +/- 10 months, two pancreas grafts were lost to pancreatitis. There were no patient or kidney graft losses, but one acute rejection episode. At 28 +/- 11 months, all 18 low-responder recipients remain steroid-free. Twenty recipients (14 low and six high-immune responders) were converted from CsA to MPA. During conversion, immune response was monitored by Flow-PRA and T-cell stimulation (Cylex) assays. Nineteen of 20 recipients displayed a post-conversion PRA of 0%, whereas one highly sensitized patient expressed a post-conversion PRA of 67%. Fifty-eight percent of individual T-cell stimulation scores were in the hypo-responsive range. Twelve of 18 low-immune responders are both steroid and CsA-free at a mean follow-up of 17 +/- 13 months, whereas five of seven high-immune responders remain CsA-free at a mean follow-up of 11 +/- 10 months. These data suggest that thymoglobulin induction with combined sirolimus and CsA maintenance therapy permits immunosuppression minimization in selected SPK recipients.

First and second line treatment--a retrospective view.

The case history of a single casualty is recorded. A critique of aspects of his treatment is presented. Some suggestions for modifying aspects of his treatment are considered. A factual account of the wounds received by a soldier during one of the land battles in the Falklands Campaign is presented together with an account of his initial (first and second line) and subsequent (third and fourth line) treatment. Comments and suggestions are offered on aspects of treatment given in the first and second line medical facilities as they existed during the Falklands Campaign.

Regulation of pyruvate dehydrogenase activity and glucose metabolism in post-ischaemic myocardium.

Pyruvate dehydrogenase (PDH) is regulated both by covalent modification and through modulation of the active enzyme by metabolites. In the isolated heart, post-ischaemic inhibition of PDH, leading to uncoupling of glycolysis and glucose oxidation and a decrease in cardiac efficiency, has been described. In vivo, post-ischaemic reperfusion leads to metabolic abnormalities consistent with PDH inhibition, but the effects of ischaemia/reperfusion on PDH are not well characterized. We therefore investigated PDH regulation following transient ischaemia in vivo. In 33 open-chest dogs, the left anterior descending (LAD) was occluded for 20 min followed by 4 h reperfusion. In 17 dogs, dichloroacetate (DCA) was injected prior to reperfusion, while 16 dogs served as controls. In dogs without DCA, glucose oxidation and lactate uptake were lower in reperfused than in remote tissue, suggesting reduced flux through PDH. However, percent active and total PDH measured in myocardial biopsies were similar in both territories, excluding covalent enzyme modification or loss of functional enzyme. DCA activated PDH activity similarly in both regions and abolished differences in glucose oxidation and lactate uptake. Thus, decreased PDH flux in reperfused myocardium does not result from covalent modification or loss of total enzyme activity, but more likely from metabolite inhibition of the active enzyme. DCA leads to essentially complete activation of PDH, increases overall glucose utilization and abolishes post-ischaemic inhibition of glucose oxidation.

A pilot study of immunosuppression minimization after pancreas-kidney transplantation utilizing thymoglobulin induction and sirolimus maintenance therapy.

AIMS: To determine outcomes utilizing thymoglobulin and sirolimus immunosuppression, with early steroid withdrawal in low-immune responder pancreas-kidney (SPK) recipients, and conversion from cyclosporine (CsA) to mycophenolic acid (MPA) in all recipients at 6 months posttransplantation. METHODS: SPK recipients received thymoglobulin, sirolimus, and reduced-dose CsA immunosuppression. Low immune responders (non-African-Americans with a pretransplant PRA < 30%) were withdrawn from prednisone on posttransplant day 5 and high immune responders were continued on prednisone. All recipients were converted from CsA to MPA at 6 months posttransplantation. During conversion, recipient immune response was monitored by flow PRA and a T-cell stimulation assay (Cylex). RESULTS: With a mean follow-up of 9 +/- 4 months, one pancreas was lost to pancreatitis, with no patient or kidney losses and no acute rejection episodes. All eight low immune responder patients were steroid-free at 9 +/- 5 months posttransplantation. Seven patients (five low and two high immune responders) with at least 6-month follow-up were converted from CsA to MPA. One high immune responder with a pretransplant PRA of 43% remained with a PRA of 53% +/- 2% postconversion. The second high immune responder had a pretransplant PRA of 34% and a postconversion PRA of 0%. The five low immune responders had a mean pretransplant PRA of 16% +/- 15% and a postconversion PRA of 0% (P < .01). The Cylex assay resulted in 67% low responsiveness for both high and low immune responders. CONCLUSION: Thymoglobulin induction with sirolimus maintenance therapy permitted immunosuppression minimization in selected pancreas transplant recipients. Posttransplant evaluation revealed a diminished (regulated) immune response in six of seven patients.

Graft survival and immune regulation of pancreas allograft recipients induced with thymoglobulin, sirolimus, and cyclosporine.

BACKGROUND: Our objective was to determine the impact of thymoglobulin-sirolimus-cyclosporine immunosuppression on the alloimmune response of pancreas-kidney transplant recipients. METHODS: Thirty-six pancreas transplant recipients received an induction protocol of thymoglobulin, sirolimus, reduced-dose cyclosporine, and corticosteroids. A subset of 10 recipients were also enrolled in a study to measure immune responsiveness. Flow PRA-determined HLA antibody, donor-specific flow cytometry crossmatching (FCXM), T-cell subset, and suppressor cell assays were performed at various timepoints during the first posttransplant year. RESULTS: One-year patient, kidney, and pancreas survivals were 97%, 94%, and 92%, respectively. There was 1 death due to sepsis, and 1 kidney and 2 pancreas graft losses. There were no acute rejection episodes. Recipients in the immune-monitoring study displayed depression of CD3, CD4, and CD8 counts (<80%) until 3 months posttransplant. At transplantation, 9 of 10 patients displayed <10% class I HLA antibody. By 3 months, 7 of 10 showed a transient elevation in class I HLA antibodies, with 2 patients expressing >80% flow PRA. At transplant 1 patient was FCXM-positive, whereas, by 3 months posttransplant, 2 of 10 patients demonstrated a positive FCXM. There were no clinical consequences to either the presence of HLA antibody or the positive FCXMs. By 6 months, 7 of 9 patients expressed immunoregulatory suppressor cell activity. CONCLUSIONS: The absence of acute rejection events was likely due to inhibition of donor-specific immunity. Seventy percent of patients demonstrated an early non-donor-directed HLA antibody response that had no adverse effect on graft function and 78% of the patients displayed immunoregulatory suppressor cell function, probably contributing to the successful clinical outcome.

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.

An unusual cause of lower back pain: uterus didelphys and unilateral cervical atresia.

Backache among adolescents and young women is an unusual presenting feature to the Accident and Emergency Department as well as orthopaedic clinics. Here, we present a challenging case of a mullerian duct abnormality, which collectively has an incidence of 0.0001% of the population, and how its consideration and investigation will ensure optimum management in both acute and long-term.

Glucose metabolism in reperfused myocardium measured by [2-18F] 2-fluorodeoxyglucose and PET.

OBJECTIVE: [2-18F] 2-fluorodeoxyglucose (FDG) is widely used to trace glucose metabolism for cardiac imaging with positron emission tomography. Because the transport and phosphorylation rates differ for glucose and FDG, a lumped constant (LC) is used to correct for these differences. The effects of ischemia and reperfusion on the LC in vivo are unknown. To determine the validity of FDG as a tracer of glucose metabolism in post-ischemic myocardium in vivo, the relationship between glucose uptake (GU) and FDG metabolic rate (FDG-MR) was assessed early post-reperfusion following a transient ischemic event. METHODS: FDG metabolic rate, measured with FDG and PET, was compared to invasive measurements of substrate metabolism in reperfused and global myocardium of dogs subjected to 25 min ischemia and 2 h reperfusion. RESULTS: The FDG metabolic rate was decreased 20 +/- 4% in reperfused relative to remote myocardium. Glucose oxidation and lactate uptake were also decreased in reperfused relative to global myocardium, by 26 +/- 6% and 60 +/- 8% respectively. Glucose uptake did not differ significantly between reperfused and global myocardium. A linear correlation between FDG metabolic rate and glucose uptake was found in both reperfused and remote myocardium. Estimates of the LC from the slopes of the regression lines were similar in reperfused and remote myocardium, 1.25 and 1.44 respectively, and did not differ significantly from the LC determined in control dogs, 1.1. CONCLUSIONS: We conclude that the FDG metabolic rate continues to correlate well with glucose metabolism in reperfused myocardium. While FDG metabolic rate was modestly decreased in the absence of a significant change in glucose uptake, large alterations in the LC are not found 2 h post-reperfusion in vivo.

Inhibition of glyceraldehyde-3-phosphate dehydrogenase in post-ischaemic myocardium.

OBJECTIVE: Myocardial reperfusion following brief period of ischaemic is associated with prolonged, reversible periods of metabolic dysfunction. As the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is inhibited in vitro by reactive oxygen species, we hypothesized that production of reactive oxygen species during reperfusion would lead to inhibition of GAPDH in post-ischaemic myocardium. METHODS: Anaesthetized closed-chest-dogs were subjected to 20 min balloon occlusion of the left anterior descending coronary artery. Biopsy samples were taken after 3 and 24 h of reperfusion, to determine the activity of GAPDH and the concentrations of glycolytic intermediates in post-ischaemic and remote, non-ischaemic territories. RESULTS: A significant reduction in GAPDH activity was observed in post-ischaemic relative to remote tissue after 3 h reperfusion (4.8 +/- 0.5 vs. 2.9 +/- 0.2 mumol/min/mg protein; P < 0.01). Western blotting revealed no reduction in the levels of GAPDH protein. Analysis of enzyme kinetics showed the loss of activity to be associated with decreased Vmax (5.9 +/- 0.5 vs. 3.2 +/- 0.2 mumol/min/mg protein; P < 0.01) with no significant change in the Km for glyceraldehyde-3-phosphate (GAP). Incubation of the inhibited enzyme under both mild and strong reducing conditions failed to reactivate the enzyme. The acute reduction in enzyme activity in post-ischaemic tissue was accompanied by regional differences in glycolytic intermediates, notably a twofold accumulation of GAP (P < 0.05), and a reduction in the glucose metabolic rate (GMR) determined by positron emission tomography and [18F]2-fluorodeoxyglucose. By 24 h reperfusion, no regional differences in GAPDH activity, reaction Vmax or Km, GAP concentrations or GMR were detectable. CONCLUSIONS: These results suggest that inhibition of GAPDH activity may represent an important point at which glycolysis is limited during reperfusion, and further, that the mechanisms of enzyme inhibition do not involve simple oxidation or S-thiolation of critical active site thiol groups.

The influence of acute rejection on long-term renal allograft survival: a comparison of living and cadaveric donor transplantation.

BACKGROUND: We investigated whether recipients of living donor grafts who suffer an acute rejection progress to graft loss because of chronic rejection at a slower rate than recipients of cadaveric grafts. METHODS: A retrospective review was made of 296 renal transplantations performed at Mount Sinai Hospital. Only grafts functioning for at least 3 months were included in this analysis. Demographic variables of donor and recipient age, race, sex, and serum creatinine at 3 months after transplantation were compared between groups. RESULTS: Among the acute rejection-free cohort, the estimated 5-year graft survival was 90% for those receiving transplants from living relatives and 88% for those receiving cadaveric transplants (P=0.76). However, in grafts with early acute rejection, the 5-year survival was 40% for cadaveric recipients compared with 73% for living related graft recipients (P<0.014). Using the proportional hazards model, cadaveric donor source, older donor age, African American recipient race, and elevated 3-month serum creatinine were independent predictors of long-term graft loss caused by chronic rejection. The severity of acute rejection and recipient age had no impact on the risk of graft loss because of chronic rejection. CONCLUSION: These data indicate that the benefit of living related transplantation results from the fact that a living related graft progresses from acute to chronic rejection at a slower rate than a cadaveric graft. Furthermore, a cadaveric graft that is free of acute rejection 3 months after transplantation has an equal likelihood of functioning at 5 years as that of a graft from a living related donor.

Rapamycin, cyclosporine, and perioperative donor-specific transfusions induce prolongation of cardiac allograft survival in the rat.

The effects of a subtherapeutic regimen of rapamycin (RAPA) combined with CsA and donor-specific blood transfusions (DST) were investigated in the ACI to LEW cardiac allograft model. Three protocols were studied. In protocol 1, recipients received a DST (day -1), RAPA intravenously at 0.08 mg/kg/day (day -1 to +5), and CsA intramuscularly at 5 mg/kg/day (day -1 to +1). In protocol 2, the course of CsA was extended to day +5, and in protocol 3 the treatment was further modified to include a second DST on day +3. Control groups received drug treatments alone or combined with DST or third-party blood transfusions. In all protocols, RAPA, CsA, or DSTs alone had little or no effect on graft survival. RAPA-DST or CsA-DST also had no effects beyond the ones induced by the drugs alone. In the RAPA-CsA groups, graft survivals were similar to the ones obtained with CsA alone. In contrast, in each of the protocols, the RAPA-CsA-DST treatment resulted in significant prolongation of graft survival as compared with all controls (P < 0.05). The administration of a second DST (CsA-RAPA-DSTx2) provided no additional benefits over a single DST. Lymph node cells from CsA-RAPA-DST subjects were hyporesponsive in MLR against donor cells and suppressed the proliferation of normal LEW cells in an MLR coculture assay, suggesting the presence of suppressor cells. Furthermore, in the CsA-RAPA-DST group, the anti-donor antibody response was suppressed. These data demonstrate that RAPA, CsA, and DST interact positively by inducing a clear-cut and significant prolongation of allograft survival in the rat model under conditions in which the individual components of the treatment are essentially ineffectual.

Cold ischemic injury accelerates the progression to chronic rejection in a rat cardiac allograft model.

BACKGROUND: The pathogenesis of chronic rejection likely involves an interplay between immunogenic and nonimmunogenic factors. The objective of this study was to determine the influence of cold ischemic preservation injury on the rate of progression to chronic rejection in the Lewis to F344 cardiac allograft model. METHODS: To induce an ischemic injury, donor hearts were stored for 3 hr at 4 degrees C in University of Wisconsin solution before transplantation. Allografts were excised at 1, 7, and 90 days after transplantation or at rejection. Vasculopathy was graded for degree of intimal thickening based on the involvement of vascular perimeter and luminal compromise. RESULTS: The degree of vessel injury in ischemic injured allografts at 90 days was significantly greater than in nonischemic injured allografts (2.8+/-0.4 vs. 1.6+/-0.5, P<0.05). Ischemic injury in syngeneic grafts did not induce a vasculopathy. Immunoperoxidase staining with R73 (anti-T cell) and ED1 (anti-macrophage) monoclonal antibodies revealed that, in ischemic injured allografts at 90 days after transplantation, the infiltrate was composed predominantly of T cells and macrophages. Additionally, ischemic injured allografts excised at 7 days after transplantation showed cellular infiltrates composed of R73-positive T cells and rare interleukin-2 receptor-positive cells, which was not observed in nonischemic allografts or ischemic syngeneic grafts. CONCLUSIONS: The progression to chronic vasculopathy in this model is principally an immunologic process, which is accelerated by an ischemic insult to the allograft. The vascular injury is mediated in part by T cells and macrophages.

Synergistic immunosuppressive actions of cyclosporine with a mouse anti-rat alpha/beta-T cell receptor monoclonal antibody.

A mouse IgG1 mAb (R73) directed against the rat alpha/beta-TCR was documented not only to prolong the survival of allografts across major RT1 plus non-RT1 antigenic disparities, but also to display a synergistic immunosuppressive interaction with CsA. Heterotopic cardiac transplants from Buffalo (RT1b) rats survived significantly longer in Wistar-Furth (RT1u) hosts treated immediately after the operation with 0.25 mg/kg R73 i.v., with a mean survival time of 11.0 +/- 5.5 versus 6.8 +/- 1.2 days in the untreated group (P < 0.01). Administration of 0.5 or 5.0 mg/kg R73 displayed dose-dependent prolongation of survival to 17.0 +/- 8.3 days (P < 0.05) or 28.6 +/- 14.0 days (P < 0.01), respectively. One 0.5 mg/kg i.v. dose of R73 delivered to normal Wistar-Furth hosts produced peripheral T cell depletion that reversed after 16 days. Three injections of 0.5 mg/kg R73 on days 0, 2, and 4 prolonged allograft survival to 52.5 +/- 38.6 days compared with 17.0 +/- 8.3 days with a single dose (P < 0.01). Addition of 3 daily doses of 5 or 10 mg/kg CsA administered per oral gavage to a single dose of 0.05, 0.25, or 0.5 mg/kg R73 injected on day 0 produced a synergistic effect to prolong allograft survival, as determined by the rigorous median-effect analysis. The synergistic interaction, which may be explained by the inhibitory effect of CsA on Ca(2+)-dependent pathways triggered after activation of TCR, the target of R73, warrants clinical investigation in order to assess the potential impact of anti-alpha/beta-TCR mAb on CsA-based immunosuppressive regimens.

Clinical evaluation of induction immunosuppression with a murine IgG2b monoclonal antibody (BMA 031) directed toward the human alpha/beta-T cell receptor.

Mouse mAbs directed against the alpha/beta-TCR were tested in clinical phase II and in triple-blind, randomized phase III studies. A clinical phase II trial administered 50 mg of murine anti-human alpha/beta-TCR mAb (BMA 031) intravenously on the day of, as well as 2 and 4 days after, cadaveric donor renal transplantation in combination with a CsA/prednisone regimen. None of 12 patients showed even moderately adverse side effects. A phase III, triple-blind randomized trial enrolled 24 patients in the BMA 031 group and 22 patients in a placebo control group. BMA 031 treatment significantly reduced the incidence of rejection events within the first 10 posttransplant days to 1 patient versus 9 episodes in the placebo group (P < 0.01). By the end of 30 days, 6 rejection episodes had occurred in the BMA 031 group and 11 in the control cohort (P = NS). After a minimum of 30 months follow-up, the actual allograft survival rate was 87% in the BMA-treated group compared with 68% in the control cohort.

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.

The diuretic action of 8-cyclopentyl-1,3-dipropylxanthine, a selective A1 adenosine receptor antagonist.

1. The diuretic effect of the selective A1 adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), was investigated in anaesthetized rats. 2. CPX (0.1 mg kg-1, i.v.) produced significant increases in urine flow, and the excretion rate and fractional excretion of both sodium and chloride. By contrast, CPX administration did not result in any significant change in the excretion of potassium. 3. The diuretic effect of CPX was accompanied by a transient increase in inulin clearance although p-amino-hippurate clearance was unaffected, indicating the CPX induced a temporary elevation of glomerular filtration rate but no change in renal blood flow. 4. The fractional excretion of lithium (a marker of delivery of fluid out of the proximal tubule) was also significantly increased by CPX. However, other measures of tubular function derived from lithium clearance indicated that there were no changes in the handling of sodium or water in the distal regions of the nephron. 5. CPX did not significantly alter the relationship between either free water reabsorption or free water clearance and the distal delivery of sodium, which suggests that CPX does not affect the renal concentration/dilution mechanism. 6. The results of this study show that the diuresis and increased excretion of sodium and chloride induced by CPX (0.1 mg kg-1) in the rat, occurs with only transient elevation in glomerular filtration rate and no change in renal blood flow. The primary reason for the diuresis appears to be inhibition of sodium reabsorption in the proximal tubule. Furthermore, the results provide evidence that production and release of endogenous adenosine modifies renal excretory function via stimulation of the A1 receptor subtype.

Amelioration of cisplatin-induced acute renal failure with 8-cyclopentyl-1,3-dipropylxanthine.

1. The effect of the selective adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), on the development of cisplatin-induced acute renal failure was investigated in the rat. 2. CPX at doses of 0.03, 0.1 and 0.3 mg kg-1, i.v. caused increasing degrees of antagonism of adenosine-induced bradycardia in anaesthetized rats. The magnitude of antagonism was not directly proportional to the increment in dose, but for each dose, it was similar in rats injected with either saline or cisplatin. CPX at a dose of 0.03 mg kg-1 significantly antagonized adenosine-induced bradycardia for up to 2.5 h, while doses of 0.1 and 0.3 mg kg-1 produced significant blockade for periods longer than 5 h. 3. Administration of cisplatin (6 mg kg-1, i.v.) caused acute renal failure characterized by decreased inulin and p-aminohippurate clearances, increased urine volume but decreased excretion of Na+, K+ and Cl- ions and by increased plasma levels of urea and creatinine. Kidney weight was increased in cisplatin-treated rats and renal tubule necrosis occurred. 4. Administration of CPX (0.03 mg kg-1, i.v.; twice daily for two days) to rats given cisplatin did not reduce the severity of the resultant renal failure. However, treatment with 0.1 mg kg-1 CPX attenuated the increases in plasma creatinine/urea levels observed in rats on days 3 and 7 after induction of renal failure. In addition, this dose significantly reduced renal tubule damage and increased inulin and p-aminohippurate clearances. A similar pattern of protection was noted with CPX at a dose of 0.3 mg kg-1 although the increase in inulin clearance was not statistically significant. However, this higher dose of CPX significantly increased Na+ and K+ excretion compared to vehicle-treated rats. 5 CPX at doses of 0.03, 0.1 and 0.3 mgkg- produced blockade of an A1-receptor mediated response i.e. adenosine-induced bradycardia, but only treatment with the higher doses of CPX (0.1 and 0.3mgkg-1) ameliorated nephrotoxicity produced by cisplatin. The lack of any protective effect afforded by the lowest dose of CPX could be a result of its shorter duration of action.6. This study indicates that adenosine plays a significant role in the pathophysiology of cisplatin-induced acute renal failure.