Efficacy and Safety of Everolimus Plus Low-Dose Tacrolimus Versus Mycophenolate Mofetil Plus Standard-Dose Tacrolimus in De Novo Renal Transplant Recipients: 12-Month Data.

In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti-thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% [-3.0, 11.4]). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow-up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 [22.0] vs. 63.1 [19.5] mL/min/1.73 m2 ) and safety was comparable. In conclusion, EVR+LTac missed noninferiority versus MMF+STac based on the 10% noninferiority margin. Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs.

The role of donor-specific HLA alloantibodies in liver transplantation.

The impact of donor-specific HLA alloantibodies (DSA) on short- and long-term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody-mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody-mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell-mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver-kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under-appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.

Long-term administration of enteric-coated mycophenolate sodium (EC-MPS; myfortic) is safe in kidney transplant patients.

BACKGROUND: To date, there are no data on long-term use of enteric-coated mycophenolate sodium (EC-MPS; myfortic) from time of renal transplantation. We report the first long-term safety and efficacy data on EC-MPS when administered for up to 3 years post transplant. METHODS: De novo renal transplant recipients completing 1 year of treatment in a multicenter, randomized, double-blind trial of EC-MPS versus mycophenolate mofetil (MMF) were invited to take part in an open-label extension during which all patients received EC-MPS 720 mg b.i.d. Results from the period 12 - 36 months post transplant were compared to comparable data from MMF-treated patients taking part in two studies of everolimus versus MMF (RAD 201 and RAD 251). RESULTS: Of 367 patients completing the blinded core study, 247(62%) entered the open-label extension phase. During the first 24 months of the extension, the incidence, type and severity of adverse events were comparable between the newly-exposed and long-term EC-MPS patients. There were 2 deaths in the newly-exposed group and 4 among long-term EC-MPS patients, with 1 and 2 graft losses, respectively. Six patients (5%) in the newly-exposed group and 4 (3%) in the long-term EC-MPS group experienced biopsy-proven acute rejection. Cross-study comparisons indicated that the tolerability profile of EC-MPS was similar to MMF, including the incidence of adverse events, infections and malignancies, as was the incidence of efficacy events. CONCLUSION: These results demonstrate that EC-MPS with cyclosporine and steroids provides good long-term efficacy and tolerability, and confirm the safety of converting renal transplant patients from MMF to EC-MPS.

Functional nature of glomerular injury in progressive diabetic glomerulopathy.

We describe in physiological terms the increasing glomerular capillary wall (GCW) dysfunction of 20 patients with diabetic glomerulopathy and heavy proteinuria. The clearances of uncharged polysaccharide markers of graded size were used to probe the glomerular filter on three occasions over a 24-mo period. The findings were analyzed with a theoretical model of solute transport that depicts most of the GCW as an isoporous membrane and the minor portion as a nondiscriminatory shunt pathway. Initially, the mean glomerular ultrafiltration coefficient Kf is computed to have been 3-5 times lower and mean pore radius of the major membrane component (r0) 2 A smaller than normal control values. In contrast, the model computes the fraction of filtrate volume permeating the nondiscriminatory shunt pathway (omega 2) to have been sixfold elevated above control values and to have correlated strongly in individual patients with the fractional clearances of albumin (r = .72) and of IgG (r = .73). Sequential studies after 12 and 24 mo revealed an invariable decline in glomerular filtration rate (GFR). Fractional clearances of albumin and IgG increased with time in most patients but declined in a few instances (20-25%). Change in omega 2 tended to occur in parallel with fractional protein clearance, regardless of its direction. We conclude that in progressive diabetic glomerulopathy GFR declines because of a loss by glomerular capillaries of ultrafiltration capacity, proteinuria is largely a consequence of increasingly impaired barrier-size selectivity, and the foregoing injuries reflect damage to different parts of the GCW and may become dissociated from one another with the passage of time.

The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine.

The pharmacokinetics of cyclosporine were studied in the blood of five normal healthy volunteers (two men and three women) after each received oral and intravenous cyclosporine alone and with concomitant oral ketoconazole. Administration of ketoconazole caused a significant decrease in intravenous cyclosporine clearance (0.18 +/- 0.05 L/kg/hr versus 0.32 +/- 0.09 L/hr/kg) and a significant increase in cyclosporine oral bioavailability (56.4% +/- 11.7% versus 22.4% +/- 4.8%) compared with values before ketoconazole administration. Steady-state volume of distribution for intravenously administered cyclosporine was unchanged (1.26 +/- 0.44 L/kg versus 1.10 +/- 0.27 L/kg). Hepatic bioavailability (1 - hepatic extraction ratio) calculated for intravenous cyclosporine increased by 11% in the presence of ketoconazole (86.3% +/- 3.7% versus 75.2% +/- 6.6% without ketoconazole), which accounts for only one third of the observed increase in cyclosporine oral bioavailability. Because it is unlikely that ketoconazole had a significant effect on either cyclosporine absorption or hepatic blood flow, the increase in cyclosporine bioavailability observed in this study is most likely explained by inhibition of gastrointestinal cytochrome P450 enzymes.

Recurrent focal glomerulosclerosis: natural history and response to therapy.

PURPOSE: Recurrent focal glomerulosclerosis (FGS) has been well documented since it was first reported in 1972. However, the course of the disease after transplantation and the optimal treatment regimen have not been well defined since the introduction of newer treatment modalities. PATIENTS AND METHODS: We reviewed all the charts of patients with biospy-proven FGS who received renal transplants at our institution from January 1980 through December 1990. Case histories consistent with diagnoses other than primary FGS (such as reflux nephropathy or intravenous drug use) were eliminated from the study. During this time period, 78 allografts were received by 71 patients with FGS. Independent variables that were analyzed included sex, race, time in months between the diagnosis of FGS and end-stage disease (dialysis or transplantation), age at time of transplantation, type of dialysis, source of allograft (cadaveric or living related), haplotype matching, donor-specific transfusions, age and sex of the donor, post-transplantation acute tubular necrosis, rejection episodes, immunosuppression regimen, use of plasmapheresis and angiotensin converting enzyme (ACE) inhibitors, and outcome. RESULTS: FGS recurred in 25 allografts (32%) of 21 patients. Biopsy-proven diagnosis of recurrence was made a mean of 7.5 months (range: 0.5 to 44 months) after transplantation. Patients who had rapid progression to end-stage disease tended to experience more frequent recurrences. Of seven patients who received a second transplant, five patients lost the first graft to recurrent FGS, and four of those patients (80%) had a recurrence in the second allograft. Recurrent disease developed in 34% of patients concurrently treated with cyclosporine and in 28% of those treated with prednisone and azathioprine alone (NS). Patients with recurrent FGS who were treated with ACE inhibitors benefited from a significant reduction of proteinuria. Six patients underwent plasmapheresis after diagnosis of the recurrence. Three of five patients in whom the diagnosis was made early in the course of the disease and in whom plasmapheresis was initiated immediately had reversal of epithelial foot process effacement and remission of proteinuria. End-stage disease eventually developed in 14 allografts (56%) an average of 23.7 months (range: 1 to 65 months) after diagnosis of recurrent disease. The cause of failure was chronic rejection in four allografts and recurrent disease in the remaining 10 allografts. CONCLUSIONS: FGS recurs in approximately 30% of allografts and causes graft loss in half of these. Patients who have lost a first allograft to recurrent FGS are at high risk for developing recurrent disease in a second allograft. Prolonged allograft survival is possible in patients with recurrent FGS and may best be obtained with a combination of treatment modalities including cyclosporine (perhaps in higher dosages than are routinely used in clinical renal transplantation), ACE inhibitors, and early use of plasmapheresis. The efficacy of these modalities supports the notion that recurrent FGS is caused by a circulating humoral mediator.

Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups.

BACKGROUND: The search for more effective and less toxic immunosuppressive agents to control transplant rejection has led to the extensive testing of mycophenolate mofetil (MMF) in clinical renal transplantation. METHODS: A pooled analysis of three phase III, randomized, double-blind, multicenter clinical trials conducted in the United States, Canada, Europe, and Australia was performed to further characterize the efficacy of MMF in renal allograft recipients. The three studies enrolled a total of 1493 patients. Triple- and quadruple-therapy regimens of cyclosporine, corticosteroids, and standardized MMF dosages with and without antilymphocyte induction were used: MMF in twice-daily doses of 1.0 g or 1.5 g (MMF 2 g or 3 g) was compared with placebo (PLA) or azathioprine (AZA). The primary efficacy endpoint in the individual trials was biopsy-proven rejection or treatment failure at 6 months. This pooled analysis focused on graft loss, patient death, incidence and treatment of rejection episodes, and graft function (serum creatinine) at 1 year. RESULTS: At 1 year, the graft survival rate was 90.4% and 89.2% in the MMF 2 g and 3 g groups, respectively, compared with 87.6% in the PLA/AZA group. This difference was not statistically significant. MMF significantly reduced the incidence of rejection episodes: 40.8% for PLA/AZA patients versus 19.8% and 16.5% for the MMF 2 g and MMF 3 g groups, respectively. Renal function was consistently better for both MMF treatment groups at 3, 6, and 12 months. CONCLUSIONS: MMF proved superior to AZA as a posttransplant immunosuppressant in conjunction with cyclosporine and corticosteroids. MMF-treated groups showed reduced incidence and severity of rejection episodes, similar graft survival, and better graft function over 12 months.

Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil--a prospective randomized study. Steroid Withdrawal Study Group.

BACKGROUND: Prospective randomized trials have shown a reduced rate of acute rejection (AR) in mycophenolate mofetil-treated kidney transplant recipients. We hypothesized that this increased protection from AR could allow successful prednisone (P) withdrawal in cyclosporine/mycophenolate mofetil/P-treated recipients. METHODS: A multicenter, prospective, randomized, double-blind trial of P withdrawal at 3 months post-transplant was initiated. Entry criteria were: primary transplant, adult, no AR by 90 days, mycophenolate mofetil dose > or =2 g/day, cyclosporine dose = 5-15 mg/kg/ day, P dose = 10-15 mg/day. Study participants were randomized to have P tapered over 8 weeks (beginning at 3 months posttransplant) to 0 vs. 10 mg/day. Prestudy power analysis determined 500 recipients should be randomized for 80% statistical power to test equivalence of the primary endpoint, AR, or treatment failure at 1 year posttransplant. By design, the study was to be stopped if interim data precluded reaching equivalence. An established data safety monitoring board monitored the study. RESULTS: After 266 patients were enrolled, the patient enrollment was stopped (after safety monitoring board review) because of excess rejection in the P withdrawal group. The Kaplan-Meier estimate of the cumulative incidence of rejection or treatment failure within 1 year posttransplant (+/-95% confidence interval) for the maintenance group was 9.8% (4.4%; treatment failure, 14.9%); for the withdrawal group, 30.8% (21.0%; 39.3%). Treatment differences in the distribution of time to event were highly significant (P = 0.0007). Of note, risk was higher in blacks (39.6%) versus nonblacks (16.0%) (P<0.001). At 1 year post-transplant, there was no difference between groups in patient or graft survival. For the patients with functioning grafts at 6 months posttransplant, withdrawal patients had lower cholesterol (P = 0.0005), had higher creatinine (P = 0.03), and were less likely to use antihypertensives (P = 0.001). These differences persist to 1 yr posttransplant. CONCLUSIONS: We conclude that for recipients on cyclosporine/mycophenolate mofetil/P with no AR at 90 days, the chance of developing subsequent AR is small; if P is tapered and withdrawn, the risk increases (but the majority remain free of acute and chronic rejection). After withdrawal, the risk of AR is different for blacks versus nonblacks. Withdrawal patients had a lower cholesterol level and less need for antihypertensives.

Determination of blood flow to the transplanted kidney. A novel application of phase-contrast, cine magnetic resonance imaging.

There is at present no noninvasive method that reliably measures blood flow in the poorly functioning renal allograft. The present study was designed to evaluate phase-contrast cine magnetic resonance imaging (PC-cine-MRI) for this purpose. We recruited for study 18 patients who had received kidney transplants 13-66 months earlier from closely related living donors. As judged by the glomerular filtration rate, which was elevated for a single kidney (76 +/- 4 ml/min 1.73 m2), allograft function was excellent, permitting the assumption of unimpaired renal extraction of paminohippuric acid (PAH). Allograft blood flow was determined consecutively on the same day, first by the standard PAH clearance technique and they by the product of the velocity of protons and renal vein cross-sectional area using PC-cine-MRI. MRI determinations could not be completed because of claustrophobia in two patients and failure to image the terminus of the allograft vein another two. Comparison of blood flow in the remaining 14 subjects revealed the two techniques to be strongly related (r = 0.91, P < 0.001). On the average, the renal blood flow rate was similar by each method; 732 +/- 62 by PAH clearance and 703 +/- 69 ml/min by PC-cine-MRI, but the agreement among individuals between the two methods was only modest, with a 95% confidence interval of agreement from -214 to +254 ml/min. We conclude that PC-cine-MRI provides a fairly accurate and noninvasive method for determining the rate of blood flow in the transplanted kidney. With further refinement it should permit the role of depressed blood flow in a variety of acute and chronic forms of human allograft dysfunction to be elucidated in humans for the first time.

Immunologic and patient selection strategies for successful utilization of less than 15 kg pediatric donor kidneys--long term experiences with 40 transplants.

Renal transplantation using infant donors is associated with significantly less graft survival (GS) and increased morbidity, especially from very young and small donors. We report our results using specific strategies to determine which age and size donor require en bloc renal transplant reconstruction and associated immunologic protocols for optimization of subsequent GS. Forty cadaveric pediatric en bloc renal transplants were performed. Mean donor age was 23.6+/-18.4 months with subgroups: 2-12 months, n=14; 13-24 months, n=19; and 25-60 months, n=7. Mean donor weight was 14.4+/-4.5 kg. All kidneys were placed in primary, nonsensitized (peak PRA = 7.9+/-5.6%) adult (41.6+/-16 years) recipients. Low weight was preferred (62.4+/-12.8 kg). Mean cold ischemia time was 26.9+/-8.6 hr. Immunosuppression consisted of quadruple immunosuppression (QI) with OKT3 induction. All patients had ureteral stents placed intraoperatively. Mean follow-up was 16.9 months. Actuarial GS at 12, 24, and 33 months were 100% (n=13), 85% (n=20), and 71% (n=7), respectively. Total GS was 35/40=88%. All grafts functioned immediately and there were no technical losses. Biopsy proven rejections occurred in 12 (30%) patients, developing at 16-167 days postoperatively (mean = 50.3 days). Mean serum creatinine at one week and 1, 6, 12, and 18 months were 2.1+/-2.0, 1.5+/-0.8, 1.3+/-0.5, 1.1+/-0.4, and 0.9+/-0.4 mg/dl, respectively. Functional isotopic renography, as well as sonographic monitoring reflected rapid initial and continued growth in these kidneys. Mean BP at 12 and 24 months postoperatively were 145/83+/-18/13 and 122/76+/-20/10 mmHg, respectively, with no significant proteinuria noted. Excellent results with minimal complications utilizing very small and young infant donors can be achieved with QI immunosuppression, and selection of low immune reactive and noncomplicated adult recipients. Additionally, maximal renal dosing by minimizing recipient weight may prevent future hyperfiltration damage.

The beneficial effect of pretransplant blood transfusions in cyclosporine-treated cadaver renal allograft recipients.

212 cyclosporine-treated recipients of mismatched first cadaveric renal allografts are evaluated with respect to the effect of pretransplant random blood transfusions. It is determined that transfusions do not effect patient survival or morbidity. Pretransplant random blood transfusions correlate with significantly improved allograft success. There is also a trend, although not statistically significant, for further improvement of allograft survival with increasing numbers of transfusions. The transfusion effect is not related to the time at which the transfusions are given up to 2 years prior to transplantation. Transfused patients have a higher percent reactive antibody (PRA) than untransfused patients, but this does not cause them to wait for a cadaveric allograft significantly longer than the untransfused patients. Rejections are less severe in transfused patients. It is concluded that cyclosporine-treated recipients of first cadaveric renal allografts benefit from pretransplant blood transfusions.

Histopathological concordance of paired renal allograft biopsy cores. Effect on the diagnosis and management of acute rejection.

To assess the effect of sampling error on renal allograft biopsies, we determined the concordance of diagnoses between 2 biopsy samples from the same renal allograft and the frequency with which 1 biopsy sample would underdiagnose or lead to the undertreatment of acute rejection. Two core samples from the same allograft biopsy procedure were labeled as core A and core B and presented to both unblinded and blinded pathologists, and each pathologist independently assigned an acute and a chronic rejection grade. A set of clinical data with pertinent prebiopsy information was combined with either the core A or core B histopathological diagnosis and presented to 3 transplant nephrologists who made treatment recommendations for each combination. Two cores were obtained in 79 allograft biopsies. Core pairs differed by > or = 1 grade of acute rejection in 30% and 50% of cases for unblinded and blinded pathologist readings, respectively. Moderate or severe acute rejection would have been missed with a 1 core in 9.5% of cases, increasing to 25.6% if only biopsy pairs containing at least 1 reading of moderate or severe acute rejection are included. Therapy would have failed to be increased with a single core in 7.5% of cases, increasing to 10.5% if only pairs containing at least one recommendation of an increase in therapy are included. The use of 2 cores of renal allograft tissue provides better diagnostic information and thereby leads to appropriate increases in antirejection therapy without increasing the complication rate of the procedure.

Alterations in skeletal muscle structure are minimized with steroid withdrawal after renal transplantation.

BACKGROUND: Limitations in exercise capacity in kidney transplant recipients are thought to result in part from changes in muscle structure and function associated with immunosuppression therapy. METHODS: We compared the percent distribution of skeletal muscle fiber types, cross-sectional areas, and ultrastructural morphologies in kidney transplant recipients treated with standard prednisone maintenance therapy (n=21) to those undergoing rapid withdrawal of prednisone using Simulect (interleukin 2 receptor inhibitor) (n=13). Skeletal muscle biopsy specimens from the vastus lateralis were analyzed at 3 and 12 months after transplantation and compared with sedentary controls (n=15). RESULTS: Compared with the control group, the group receiving prednisone maintenance therapy had a significantly lower percentage of type I fibers and a higher percentage of type IIB/x fibers, evident at 3 and 12 months. Fiber type distribution in patients withdrawn from prednisone did not differ from controls. In patients withdrawn from prednisone, the cross-sectional areas of type I and IIA fibers were lower and the area of type IIB/x fibers was higher compared with controls. Likewise, ultrastructural studies revealed reduced volume densities of myofibrils and higher densities of interfibrillar and subsarcolemmal mitochondria. At 12 months there were no ultrastructural differences between the patients withdrawn from prednisone and controls. CONCLUSIONS: We conclude that prednisone maintenance therapy contributes to the lower exercise capacity by altering the ratio of type I to type IIB/x fibers and by reducing myofilament density. The increase in mitochondria in patients receiving prednisone may reflect a switch from carbohydrate to lipid metabolism resulting from the glucocorticoid therapy.

Cytokine and T cell receptor gene expression at the site of allograft rejection.

Intragraft cytokine and T cell receptor gene expression was analyzed in rejecting renal allografts by polymerase chain reaction (PCR). Message for IL-1 beta, IL-6, and TNF-alpha was detected in nephrectomy tissue with pathological evidence of acute or chronic rejection. Similarly, mRNA for both IL-6 and TNF-alpha was present in renal biopsies from acute rejecting kidneys. IL-2R, IL-4, and IL-5 mRNA was present in both rejecting and rejected kidney allografts, indicating that these cytokines may play a role in ongoing renal allograft rejection. Conversely, IL-2, IL-7, and IFN-gamma message was detected infrequently. In order to address the diversity of T cells in rejecting kidneys, we have analyzed the clonality of the TcR present within the allograft tissue. Rearranged TcR genes were identified in all allografts examined (n = 16) indicating the presence of T cells bearing the alpha/beta TcR. We have determined that there is a heterogeneous infiltration of T cells in the rejected allograft with TcR representing x = 7.47 +/- 2.4 families rearranged in samples obtained from nephrectomies, whereas x = 5.33 +/- 0.58 families were detected in samples obtained from biopsy tissue. These data indicate that (1) cytokines are produced locally which may contribute to graft cell destruction, (2) the heterogeneity of intragraft T cells during kidney allograft rejection may exist because nonspecific lymphocytes have been recruited to the site by locally produced cytokines or because T cells are responding to multiple epitopes or multiple donor antigens. Detection of intragraft cytokines and TcR may prove useful in elucidating the mechanism of rejection and therefore lead to improved immunosuppression.

The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors.

Liver allografts from HBcAb(+), IgM(-), HBsAg(-) donors can transmit HBV to uninfected recipients. We currently no longer accept these livers for transplantation while continuing to accept the kidneys. The purpose of this study is to determine the risk of donor-transmitted HBV infections from HBcAb(+), HBIgM(-), HBsAg(-) organ donors and determine if the risk of donor-transmitted HBV infections and their severity is dependent on the organ being transplanted. This study consists of a retrospective review of the posttransplant course of recipients of HBcAb(+), HBIgM(-), HBsAg(-) donors accepted at UCSF from 6/85 to 12/93. Transmitted HBV infection was defined as one in which the recipient changed from HBsAg(-) prior to transplantation to HBsAg(+) posttransplant, with no other source. There were 25 of 1190 donors who were HBcAb(+), HBIgM(-), HBsAg(-); 1/42 kidney, 3/6 liver, and 0/7 heart HBsAg(-) transplant recipients of organs from these donors became HBsAg(+) after transplantation. This difference in infection rate (liver vs. kidney and heart) is statistically significant. The clinical course of the liver recipients was also more severe. All of the patients who became infected were HBsAb(-) and HBcAb(-) prior to transplant. We conclude that (1) HBV can be transmitted from HBcAb(+), HBIgM(-), HBsAg(-) organ donors, (2) the rate of transmission is highest and severity of infection is worst in the liver recipients; and (3) we will continue to transplant kidneys from these donors, preferably into immunized recipients.

Transplant glomerulopathy as a cause of late graft loss.

Several pathophysiological processes contribute to chronic kidney transplant rejection. Among the most distinctive is transplant glomerulopathy, characterized by widening of the subendothelial space with accumulation of flocculent material and duplication of the basement membrane. The current study assessed the course of graft loss in patients with and without this form of injury. Twenty-five patients with prominent transplant glomerulopathy were identified from biopsies performed at a single center during 4 years. These patients were compared with control patients with a similar degree of renal dysfunction in whom biopsies showed chronic rejection without transplant glomerulopathy. Patients with transplant glomerulopathy showed an increased rate of graft loss after biopsy. Biopsies were performed longer after transplantation in these patients, however, than in control patients with an equal degree of graft dysfunction. Graft survival from the time of transplantation was therefore not different between the two groups. Morphological studies showed that transplant glomerulopathy was not associated with increased severity of chronic vascular injury characterized by arterial and arteriolar intimal thickening or hyalinosis. These findings show that transplant glomerulopathy may develop late after transplantation and separately from chronic vascular rejection. The appearance of transplant glomerulopathy on a biopsy specimen is followed by accelerated graft loss.

Cyclosporine-induced hemolytic uremic syndrome in a heart transplant recipient.

We report a case of hemolytic uremic syndrome associated with the use of cyclosporine in a heart transplant recipient. The patient manifested many classic signs and symptoms of hemolytic uremic syndrome, and a diagnosis was confirmed by kidney biopsy. Treatment with plasma exchange was effective in halting the hemolysis, but renal function failed to improve. Rechallenge with cyclosporine caused recurrence of microangiopathic hemolysis. Because of concerns regarding allograft rejection, an experimental immunosuppressive agent, RS-61443, was used that was effective in controlling rejection and was not associated with recurrence of hemolytic uremic syndrome.

Pharmacokinetics of orally and intravenously administered cyclosporine in pre-kidney transplant patients.

The pharmacokinetics of cyclosporine (CSA) and four metabolites were evaluated in eight hemodialysis subjects awaiting renal transplantation to compare metabolic patterns with those observed in post-transplant patients and normal volunteers. Each subject received a single 4-mg/kg intravenous and a single 10-mg/kg oral dose separated by a 1-week washout period. Blood samples were collected before and at .5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, and 24 hours after CSA dosing. Cyclosporine blood, plasma, and metabolite (M17, M1, M18, M21) levels were determined by high-pressure liquid chromatography. Mean (+/- standard deviation) CSA blood clearance was .47 +/- .15 L/hour/kg, steady-state volume of distribution (Vss) was 1.9 +/- .5 L/kg, and mean residence time (MRT) was 4.4 +/- 1.8 hours after intravenous dosing. With plasma, mean clearance was .70 +/- .31 L/hour/kg, Vss was 2.4 +/- 1.2 L/kg, and MRT was 3.7 +/- 2.2 hours. Cyclosporine bioavailability (F) averaged 24 +/- 11 and 24 +/- 15%, using blood and plasma, respectively. Values for clearance and Vss were approximately 30 to 100% greater than comparable estimates in healthy volunteers, but F and MRT were not altered to this extent. These changes might be explained on the basis of decreased protein binding in uremic patients. The area under the curve ratio for M17 and M1 to CSA increased an average of 1.7- and 3.9-fold, respectively, after oral dosing compared with intravenous administration, indicating increased conversion during first-pass metabolism.

Effect of food on the pharmacokinetics of cyclosporine in healthy subjects following oral and intravenous administration.

The pharmacokinetics of cyclosporine were studied in healthy subjects following administration of cyclosporine both orally (10 mg kg-1) and intravenously (4 mg kg-1) without and with high fat meals. Both blood and plasma samples (separated at 37 degrees C) were analyzed for cyclosporine concentration. Blood and plasma clearances of cyclosporine were calculated to be 0.36 and 0.47 L hr-1 Kg-1, respectively, and volume of distribution at steady state was calculated to be 1.21 L Kg-1, when cyclosporine was administered without a high fat meal. Using plasma analysis, the oral bioavailability of cyclosporine was estimated to be 21 and 79%, when administered without and with a high fat meal, respectively. When cyclosporine was administered intravenously together with a high fat meal, both clearance and volume of distribution increased significantly. Blood and plasma clearances of cyclosporine were 0.44 and 0.70 L hr-1 Kg-1, respectively, when cyclosporine was administered along with a high fat meal. We conclude that food not only enhances the absorption of cyclosporine but also enhances its clearance and volume of distribution. The observed variability in clearance, bioavailability, and volume of distribution values for cyclosporine across various pharmacokinetic studies can be partially accounted by the type of food administered and the sampling matrix used for analysis.

Immunopharmacodynamic studies of cyclosporine in patients awaiting renal transplantation.

The immunopharmacodynamics of cyclosporine were investigated in eight hemodialysis patients awaiting renal transplantation. Cyclosporine was administered orally (10 mg/kg) and intravenously (4 mg/kg), with both administrations separated by at least one week. Plasma samples were processed at 37 degrees C and analyzed for specific cyclosporine and its four major metabolites (AM1, AM1c, AM9, and AM4N) using high-performance liquid chromatography. In addition, the in vitro immunosuppressive activity of these serial plasma samples was estimated as a relative percentage inhibition of third party mitogenic lymphocyte proliferation stimulated with phytohemagglutinin. The relationships between concentration and effect of cyclosporine versus time were noted. These results suggest that unchanged cyclosporine concentrations in plasma correlate with mitogen-induced lymphocyte suppression yielding significant immunosuppressant activity of cyclosporine. Control studies with plasma from healthy volunteers spiked with cyclosporine in the concentration range of 0-10,000 ng/mL were developed. A sigmoidal Emax model was fitted to the effect versus plasma concentration data. The ratio of effect versus predicted effect were calculated for intravenous cyclosporine dosing. There was a good correlation between the observed and predicted inhibitory effect.