Optimizing tacrolimus therapy in the maintenance of renal allografts: 12-month results

BACKGROUND: The determination of optimal tacrolimus (TAC) trough levels is needed to prevent adverse effects of calcineurin inhibitors. METHODS: Stable transplant recipients currently receiving cyclosporine (CsA) were assigned randomly (1:1:1) to continue CsA (target trough level of 50-250 ng/mL); or convert to "reduced" TAC (target trough level 3.0-5.9 ng/mL) or "standard" TAC (target trough level 6.0-8.9 ng/mL). RESULTS: At 12 months, there was a significant improvement in renal function in the reduced TAC versus CsA group with lower serum creatinine (P=0.004) and cystatin C (P<0.001), and higher estimated creatinine clearance (P=0.017). However, there were no statistically significant differences in any renal parameter in the standard TAC versus CsA group. Total and low-density lipoprotein cholesterol were significantly reduced in both TAC groups versus the CsA group (P<0.001). Patient and graft survival and episodes of biopsy-confirmed acute rejection were similar for all treatment groups, and no statistically significant differences were observed between groups in the incidence of new-onset diabetes or cardiac conditions, or in the prevalence of hyperglycemia, hypertension, or hyperlipidemia among patients who did not have these conditions at baseline. Alopecia developed more commonly among TAC-treated patients than CsA-treated patients (P<0.001). CONCLUSIONS: Compared with CsA continuation, conversion to reduced TAC target trough concentrations resulted in significantly improved renal function without increasing the risk of rejection. Conversion to TAC, regardless of target concentration, resulted in improved serum lipid profiles in kidney transplant recipients at 12 months.     

No difference in degree of interstitial Sirius red-stained area in serial biopsies from area under concentration-over-time curves-guided cyclosporine versus tacrolimus-treated renal transplant recipients at one year

Interstitial fibrosis is the main characteristic of chronic allograft nephropathy and long-term graft failure. Cyclosporin (CsA) is thought to be more fibrogenic than tacrolimus. In a prospective, randomized, multicenter trial using a calcineurin-sparing regimen, renal interstitial volume was compared in CsA- and tacrolimus-treated renal transplant recipients by image analysis of Sirius red (SR)-stained cortical areas in protocol biopsies obtained at 6 mo (n = 94) and 12 mo (n = 97) after transplantation. Immunosuppression consisted of CsA or tacrolimus, CD25 mAb, mycophenolate mofetil, and prednisolone. CsA therapy increased the 6-mo risk for subclinical rejection. The prevalence of subclinical rejection was 38.8% in the CsA-treated and 15.2% in the tacrolimus-treated patient group (P = 0.012). Strikingly, no difference in the degree of interstitial SR-stained area was detectable between the two treatment groups. In particular, previous subclinical rejection episodes did not influence the degree of interstitial volume. Also, no difference in GFR occurred at 1 yr, when the mean GFR mounted 63 ml/min. No significant differences in the degree of interstitial SR-stained area could be observed at 6 and 12 mo between CsA- and tacrolimus-treated renal transplant recipients. Although CsA-treated patients developed significantly more subclinical rejections at 6 mo, this did not influence the degree of SR staining or the change in renal function at 1 yr.     

Outcome of cadaveric renal transplant patients treated for 10 years with cyclosporine: is chronic allograft nephropathy the major cause of late graft loss?

BACKGROUND: The introduction of cyclosporine (CsA) has improved the short-term outcome of renal transplantation, but its effect on the long-term survival is not well known. METHODS: We analyzed 128 cadaveric first renal transplant recipients with CsA and prednisone as basal immunosuppression followed for at least 10 years, and we have compared them with a group of 185 historical patients treated with azathioprine (Aza) and prednisone. RESULTS: The 1-year graft survival was 83% in the CsA-treated patients and 68% in the Aza-treated patients (P<0.025), and the differences were significant for 3 years. Acute rejection accounted for the 10.9% of losses in CsA-treated patients and for 23.8% of losses in Aza-treated patients (P=0.046). Chronic allograft nephropathy was the cause of graft losses in 40.6% and 16.8% of cases (P=0.008). Patient survival at 5 years was 88% in CsA-treated patients and 79% in the Aza-treated patients (P<0.025). When analyzing the data of the 64 CsA-treated patients and the 84 Aza-treated patients with one functioning graft at 10 years, mean serum creatinine values were significantly higher in the CsA-treated patients at all time points but the increases were not significantly different. At 10 years, mean blood pressure was higher (P=0.002), and hypercholesterolemia (P=0.011) and hyperuricemia (P=0.000) were more prevalent in the CsA-treated patients. CONCLUSIONS: CsA resulted in a better short-time patient and graft survival that was not maintained in the long-term outcome. Chronic allograft nephropathy was the leading cause of graft loss in CsA-treated patients. Graft function was poorer in the CsA-treated patients, but its decline was similar in the two groups.     

Individualization of immunosuppressive therapy: I. Sirolimus improves outcomes in African-American renal transplant recipients

INTRODUCTION: African-American renal transplant recipients are prone to acute rejection episodes and graft loss owing to genetic, pharmacokinetic, cultural, and socioeconomic factors. While more intense exposures to antirejection agents can mitigate this propensity, heightened immunosuppressive regimens are accompanied by an array of toxicities. Our study sought to examine the impact of a combination of sirolimus (SRL) and cyclosporine (CsA) on the outcomes of African-Americans vs Caucasians. MATERIALS AND METHODS: The outcomes of African-Americans treated with either CsA-prednisone (Pred, n = 90) or SRL-CsA-Pred (n = 86) were compared with 148 SRL-CsA-Pred-treated Caucasians. RESULTS: The addition of SRL to a CsA-Pred regimen reduced the rate of acute rejection episodes within 2 years in African-Americans from 43.3% to 17% (P = .004), a value similar to that observed in Caucasian patients (18%). At 2 years, the graft survival rate of 79% among African-American patients treated with SRL-CsA-Pred was similar to that in the Caucasian cohort (80%). The respective patient survival rates also were similar: 93% and 90%, respectively. Multivariate analysis of 5-year outcomes among patients treated with SRL-CsA-Pred revealed the hazard ratios of African-Americans vs Caucasians to actually be reduced for acute rejection (.22; P = .01) and for death (.15; P = .01), but similar for chronic rejection (.77; P = NS) and graft loss (1.03; P = NS). CONCLUSION: The use of SRL-based regimens mitigated the otherwise enhanced risk for acute rejection episodes or graft loss otherwise experienced by CsA-treated African-American renal transplant recipients.     

Tc-99m DTPA scans in renal allograft rejection and cyclosporine nephrotoxicity

Renal allograft dysfunction arising from rejection or cyclosporine (CsA) nephrotoxicity can currently only be distinguished reliably by allograft biopsy. We have assessed Technetium (Tc)-99m diethylamine pentacetic acid (DTPA) scanning in 30 CsA-treated patients with allograft dysfunction. Scintigrams were performed during 20 biopsy-proved episodes of rejection and during 14 episodes of CsA nephrotoxicity. These results were compared with the scintigrams of 15 allografts showing stable function. Quantitative indices expressing allograft perfusion (flow index) and function (uptake index) derived from the DTPA scintigrams showed no significant differences between the groups of patients with rejection, CsA nephrotoxicity, or stable or improving function. Similarly, the flow and uptake indices of individual allografts obtained during periods of stable or improving function and then during episodes of dysfunction due to rejection or CsA nephrotoxicity did not significantly change. We conclude that Tc-99m DTPA scintigrams are of limited value in the management of allograft dysfunction in patients immunosuppressed with CsA.     

Cyclosporine A toxicity in association with reduced renal mass

The long-term effect of cyclosporine A (CsA) in male Wistar rats with reduced renal mass was studied. The aim of the study was to highlight the relationship of CsA effect on rats, simulating patients with two functioning kidneys (eg, heart, liver transplant recipients) and one kidney (renal transplant recipients). The Wistar rats were subjected to unilateral nephrectomy (Unx, n = 14) and to 5/6 nephrectomy (STnx, n = 14). Half of these rats and half of the sham operated ones (control, n = 13) were administered CsA (10 mg/kg/d) for 28 days IP. The serum creatinine (S(CR)), total protein (S(P)), and urine protein (U(P)) values as well as the whole blood CsA levels were determined on the 28th day of the study. The remnant kidneys were evaluated by image analyses and semiquantitative methods after sacrifice on the 28th day.In the three non-CsA-treated groups (Unx, STnx, and control) S(CR) was significantly higher in STnx rats than in Unx rats (P =.011). Percent of renal scarring (PRS) was significantly higher in Unx (P =.02) and in STnx rats (P =.017), compared with the control group. Among CsA-treated three groups S(CR) was significantly higher in STnx rats compared with Unx (P =.017). In addition, segmental sclerosis rate (SSR) was higher in STnx rats, compared with the control group (P =.008), whereas S(P) was higher in the control group (P =.005). When CsA-treated groups were compared with non-CsA-treated ones, U(P) of the Unx rats not receiving CsA were significantly higher than the Unx rats receiving CsA (P =.026). Also, U(P) was higher in non-CsA-treated groups (P =.014), whereas S(CR) (P =.001), S(P) (P =.001), and PRS (P =.001) were higher in CsA-treated rats.In conclusion, we suggest that preserved renal mass is not enough to prevent CsA toxicity and that CsA should be administered to patients with both kidneys (eg, heart, pancreas recipients) as carefully as to patients with one functioning kidney (renal transplant recipients).     

The relationship between cyclosporine pharmacokinetic parameters and subsequent acute rejection in renal transplant recipients

The best approach to determining the optimal dose of cyclosporine in renal transplant recipients is unclear. In this prospective investigation, CsA pharmacokinetic studies were performed in 45 patients 1, 4, and 12 weeks after the initiation of CsA. Data from 104 studies were then combined to analyze the relationship between CsA kinetic parameters and posttransplant clinical events. Random trough levels, used in the day-to-day adjustment of CsA dose, were examined separately in 19 of the 45 study patients. All CsA levels were measured with high-performance liquid chromatography. Results showed: (1) trough CsA levels, obtained by random sampling, or from the kinetic studies, correlated poorly with dose; however, there was a good correlation between CsA dose and maximum concentration (Cmax, r = .39, P less than .001), area under the concentration-time curve (AUC, r = .45, P less than .001), and terminal elimination half-life (r = .43, P less than .001); (2) several pharmacokinetic parameters correlated with subsequent rejection episodes; patients with acute rejection within 2 or 4 weeks after study had 15-31% lower Cmax (P less than .05) and 13-19% lower AUC (P less than .05) compared to those who were rejection-free; and (3) levels of blood constituents known to bind CsA also correlated with rejection, and this correlation was independent of the impact of kinetic parameters on rejection. Altogether, these results suggested that a limited number of CsA pharmacokinetic studies may be more useful than multiple, random trough levels in monitoring CsA therapy.     

Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic progressive allograft dysfunction: the "creeping creatinine" study

BACKGROUND: This study determined whether cyclosporine A (CsA)-treated renal allograft recipients with deteriorating renal function ("creeping creatinine") secondary to chronic allograft nephropathy (CAN) benefit from the addition of mycophenolate mofetil (MMF) to their immunosuppressive regimen, followed by withdrawal of CsA. METHODS: In a controlled, open, multicenter study, CsA-treated renal allograft recipients with progressively deteriorating renal function were randomized to have their CsA discontinued with the concomitant addition of MMF to their regimen (group A) or to continue treatment with CsA (group B). The primary endpoint was the response rate over the 6-month period after withdrawal of CsA in group A or the equivalent time in group B. Response was defined as a stabilization or reduction of serum creatinine (SCr), as evidenced by a flattening or positive slope of the 1/SCr plot and no graft loss. Secondary endpoints included the incidence of acute rejection, graft and patient survival, and changes in selected metabolic parameters. RESULTS: The response rate in the primary intent-to-treat population (n=122) was 58% (36/62) in group A versus 32% (19/60) in group B (P=0.0060). The corresponding percentages of responders in the per-protocol population (n=107) were 60% (36/60) and 26% (12/47), respectively (P=0.0008). There were no acute rejections in group A during the study period. Patients in this group also experienced a significant decrease in total cholesterol. CONCLUSIONS: In patients with progressively deteriorating renal function secondary to CAN, addition of MMF followed by withdrawal of CsA results in a significant improvement in transplant function without the risk of acute rejection.     

C2 monitoring of cyclosporine in stable renal transplant patients results in lower costs and improved renal function

INTRODUCTION: C2 (2-hour post-absorption levels) monitoring of cyclosporine (CsA) seems to reduce the rate of acute rejection episodes (ARE) without increasing nephrotoxicity during the first months after transplant. There are a few reports on the impact of adopting this strategy in patients with stable renal transplants. We herein report a prospective trial in long-term renal transplant patients (>6 months) monitored by C0 or C3 who were switched to C2 monitoring. METHODS: Seventy-six (mean age = 43 +/- 11 years) kidney transplant patients (mean = 37 +/- 21 months after transplant) receiving CsA, steroids, and azathioprine were switched to C2 monitoring, seeking to achieve a target range of 800 +/- 100 ng/mL. The patients were followed for at least 6 months. RESULTS: At conversion the C2 values of 61% of the patients were above and 17% below the therapeutic range. Six months after conversion there was a significant reduction in BUN (29 +/- 11 vs 27 +/- 10, P < .01), Creatinine (Cr), cholesterol, and triglyceride levels were unchanged. Mean CsA dose was decreased 10% from 244 +/- 63 to 220 +/- 52 (P < .01), implying a net savings of 390 US dollars per patient per year. Among the group of patients who showed a high C2 level, there was also a reduction in BUN (30 +/- 12 vs 27 +/- 10, P < .01) and a nonsignificant decrease in Cr (1.53 +/- 0.6 vs 1.50 +/- 0.6). CONCLUSIONS: C2 monitoring in stable kidney transplant recipients is feasible and safe. The strategy results in reduced drug costs and improved renal function.     

Expression of multidrug resistance P-glycoprotein in kidney allografts from cyclosporine A-treated patients.

BACKGROUND: The multidrug resistance (MDR) gene product P-glycoprotein (P-gp) is a transmembrane efflux pump for hydrophobic, potentially toxic compounds, including the immunosuppressant cyclosporine A (CsA). We have previously shown that CsA increases P-gp expression in proximal tubule and endothelial cells in vitro. The aim of the present study was to investigate the in vivo relevance of these observations in renal allograft biopsies from CsA-treated patients. METHODS: P-gp expression was determined by immunohistochemistry of paraffin sections using two different monoclonal antibodies (UIC2 and MRK16). Biopsies were taken from CsA-treated renal transplant patients with different histopathological diagnoses (N = 79) and were compared with biopsies from normal human kidneys (N = 13) or with allograft biopsies from patients under a CsA-free immunosuppression (N = 15). Moreover, biopsies from 10 donor kidneys before implantation and during rejection episodes ("zero biopsies") were investigated. RESULTS: P-gp expression in biopsies with acute tubular necrosis (ATN; N = 10) after CsA treatment was significantly higher in arterial endothelia, proximal tubules, and epithelial cells of Bowman's capsule (BC), whereas P-gp was sparsely induced in CsA nephrotoxicity (N = 19) compared with controls. Acute cellular (N = 30) and vascular rejection (N = 10) or chronic allograft nephropathy (N = 10) after CsA was associated with strong P-gp expression in infiltrating leukocytes and increased P-gp expression in arterial endothelia, proximal tubules, and BC. In contrast, biopsies of patients treated with a CsA-free immunosuppression regimen did not show increases in P-gp expression compared with controls. Zero biopsies showed a weak, homogeneous, nonpolarized expression of P-gp in tubules and an increased expression of P-gp after CsA therapy in the brush border, arterial endothelia, and BC. CONCLUSIONS: CsA treatment was associated with increased P-gp expression in parenchymal cells of kidney transplants with ATN, acute or chronic transplant rejection, but P-gp was not increased in patients with CsA nephrotoxicity. This indicates that CsA induces its own detoxification by P-gp and that inadequate up-regulation of P-gp in renal parenchymal cells contributes to CsA nephrotoxicity. Increased expression of P-gp in infiltrating leukocytes correlated with the severity of allograft rejection, suggesting that P-gp may decrease the immunosuppressive efficacy of CsA. Thus, individual differences in the P-gp induction response of CsA-exposed renal parenchymal cells and/or infiltrating leukocytes may predispose to either CsA nephrotoxicity or rejection, respectively.     

Expression of HLA-DR antigens on peripheral blood T lymphocytes and renal graft tubular epithelial cells in association with rejection

Since the expression of HLA-DR antigens on peripheral blood T lymphocytes and renal graft tubular epithelial cells may be associated with immunological stimulation, we investigated the expression of these antigens on blood T lymphocytes and graft tubular epithelium in 84 renal transplant patients. Peripheral blood T lymphocytes were monitored by flow cytometry during the first 3 months after transplantation. Since the DR+ lymphocytes were selected by a double-labeling technique used for the Leu2a phenotype, the majority of the DR+ lymphocytes were also Leu2a+ with a small percentage of unidentified Leu2a- lymphocytes. Forty-one patients were treated with cyclosporine (CsA) and 43 with azathioprine (Aza), while both groups received low-dose steroids. Frozen sections of 57 renal biopsies from 43 patients (21 on CsA and 22 on Aza) were stained for HLA-DR antigens. In the Aza group, clinical rejection episodes correlated with an increased percentage of DR+ peripheral lymphocytes (P = 0.0005), and the expression of DR antigens on graft epithelial cells (P less than 0.001). In the CsA group, no relation between the expression of DR antigens on blood lymphocytes and clinical rejection episodes was evident, and the correlation between tubular DR staining and clinical rejection episodes was weaker than in the Aza group (P = 0.03). In both the Aza and CsA group, an increase in DR+ peripheral lymphocytes correlated with positive staining of the renal tubular cells for HLA-DR antigens (P less than 0.001).     

Randomized study comparing cyclosporine with azathioprine one year after renal transplantation-15-year outcome data

BACKGROUND: The introduction of cyclosporine (CsA) improved 1-year graft survival and reduced the incidence of acute rejection episodes after renal transplantation compared to azathioprine (Aza). However, CsA has many side effects and reducing exposure of this drug after the first year may benefit long-term patient and graft survival. METHODS: We report 15-year outcome data from a single center, randomized controlled study comparing CsA withdrawal and conversion to Aza with continuation of CsA 1-year posttransplant. RESULTS: Two hundred sixteen patients who showed a serum creatinine less than 300 mumol/L with no acute rejection episodes in the preceding 6 months were enrolled (CsA 114, Aza 102). There was no difference in patient survival at 15 years: 62.4% in the CsA group and 64.4% in the Aza group (P=0.6). Fifteen-year transplant survival was 41.9% for the CsA group and 48.8% for the Aza group (P=0.8). Fifteen-year graft survival censoring for death with a functioning graft was 58% in the CsA group and 72% in the Aza group (P=0.5). Predictors of patient survival were younger recipient age (P<0.001) and lower systolic blood pressure at randomization (P=0.01). Predictors of graft survival were older recipient age (P<0.001) and better renal function at randomization (P=0.01). Assigned drug showed no effect on graft or patient survival. Patients assigned to CsA showed significantly worse renal function up to 10 years posttransplantation and required more anti-hypertensive treatment throughout the study period. CONCLUSION: In a selected group of patients, either Aza or low-dose CsA is safe and effective. Despite lower estimated glomerular filtration rate (eGFR) up to 10 years posttransplantation and increased use of anti-hypertensive agents, low-dose CsA was not associated with a worse patient or graft survival.     

Risk factors for rising creatinine in renal allografts with 1 and 3 yr survival

BACKGROUND: Determining factors associated with negative slope of inverse creatinine vs. time (1/Cr vs. t) may help prevent a decline in renal allograft function. METHODS: A total of 1389 adult recipients of primary renal transplants were divided into quartiles based on the slope of 1/Cr vs. t calculated from 6 and 12 months post transplant. A multivariate analysis of risk factors for being in the worst vs. best quartile employed these variables: donor source, HLA mismatch, recipient age, donor age, panel-reactive antibody (PRA), acute rejection (AR), 3-month cyclosporin A (CsA) level, 1-yr CsA level and acute tubular necrosis. Two separate analyses compared risk factors in patients with 1 and 3 yr survival, respectively. RESULTS: In recipients with > or = 1 yr graft survival, high PRA and AR were associated with negative slopes of 1/Cr vs. t. For those with > or = 3 yr graft survival, both AR and 3-month CsA level > 150 ng/mL were significant risk factors, using both 6- and 12-month slopes. Stratification of AR showed 1 AR episode > or = 6 months and multiple AR episodes carried significant risk for negative slopes. CONCLUSION: Optimization of allograft function invokes a conundrum between the needs to avoid both AR and high early CsA levels. We support a policy of carefully balancing these two risks.     

中国成人肝移植受体服用微乳化环孢素A两小时后浓度监测

目的评估微乳化环孢素A(CsAME)服用2h后药物浓度(C2)监测的安全性和可靠性,初步确定适合中国成人肝移植受体的C2目标浓度。方法将53例肝移植术后1～2个月的中国成人肝移植受体随机分为C0组(n=17)、高浓度C2组(n=18)、低浓度C2组(n=18),每组均设定了相应的目标浓度,随访期间定期监测CsA浓度、心、肝、肾功能、机体免疫状态及排斥反应的发生情况。结果低浓度C2组口服CsA的剂量最低,仅为2.51±0.37mg·kg-1·d-1,与C0组和高浓度C2组相比差异具有显著性(P<0.01)。低浓度C2组心、肝、肾功能受损程度最小,高浓度C2组受损伤程度最重。低浓度C2组的CD+4/CD+8T细胞比值为1.04±0.68,与C0组无显著性差异(P>0.05)。各组的排斥反应发生率无显著性差异。低浓度C2组的临床获益率最高(72.22%),高浓度C2组最低(11.11%)。结论通过设定合理的目标浓度,C2监测可以提供更合理的CsA口服剂量,在明显降低毒副作用的同时不增加排斥反应的发生率。适合中国成人肝移植受体的术后CsAMEC2目标浓度初步确定为:术后1～6个月600～800ng/ml,术后7～12个月400～600ng/ml。     

肾移植后免疫抑制用药方案与移植肾长期存活的关系

目的 分析肾移植后不同的免疫抑制用药方案对移植肾长期存活的影响。方法 根据不同用药组合将患者分为环孢素Ａ（ＣｓＡ）、硫唑嘌呤（Ａｚａ）和泼尼松（Ｐｒｅｄ）三联治疗组、ＣｓＡ和Ｐｒｅｄ二联治疗组、Ａｚａ和Ｐｒｅｄ传统二联治疗组。统计分析免疫抑制用药、排斥反应发生及人、肾存活情况;对发生排斥反应的患者追踪其发生排斥前１２个月内的药物更动情况。结果 采用三联治疗的患者人／肾５年存活率（８８％／７８％）显     

Effect of lymph leakage on renal allograft outcome from living donors

Lymph leakage is a cause of prolonged fluid discharge in renal transplant patients. Lymph leakage during early post-transplantation is responsible for extracting immune substances; therefore, it may play a role in prognosis of the transplanted kidney. In this study, we aimed to investigate the effects of lymph leakage on different factors that play significant roles in renal allograft outcome. During the present case-control study, we evaluated 62 renal allograft recipients in which 31 subjects were complicated with lymph leakage and enrolled as the study group. The other 31 subjects were included in the control group who did not experience any lymph leakage during their post-transplantation period. All kidneys were transplanted from living donors. We investigated and compared the renal allograft rejection rate, hospitalization duration, serum urea, creatinine (Cr) and cyclosporine (CsA) levels, antithymoglobin (ATG) administration and treatment duration between the study and the control groups. There were no significant difference in the urea and Cr levels between the two groups (P >0.05). Early (one week) and late (one month) serum CsA levels of the study group were significantly higher than in the control group (P = 0.005 and P = 0.006). The number of days in which ATG receivers responded to therapy was significantly lower for the control group (P = 0.008). 21.93% of the study group subjects experienced allograft rejection, while this rejection probability was 28.38% for the control group (P = 0.799). Lymph leakage has no prominent role in renal function, which is estimated by Cr and urea levels in patients' serum during the days after transplantation. CsA level was higher in patients with lymph leakage, and all cases of allograft rejection were in the subjects with lymph leakage.     

Complete replacement of methylprednisolone by azathioprine in cyclosporine-treated primary cadaveric renal transplant recipients

In cyclosporine (CsA)-treated renal transplant recipients complete corticosteroid withdrawal followed by CsA monotherapy has been associated with severe rejection episodes in a significant proportion of patients. We report the results of replacement of steroids by azathioprine (AZA) in 25 primary cadaveric renal transplant recipients initially treated with CsA and methylprednisolone (MP). MP taper was started 8.8 +/- 5.6 months posttransplant when the MP dose was either 10 mg/day or 20 mg every other day. MP was tapered off over a 5-month period. At the initiation of MP taper, AZA was added at 1 mg/kg/day and increased to 1.5 mg/kg/day after two months. The CsA dose was adjusted to maintain trough serum levels as measured by radioimmunoassay (RIA) of 50-75 ng/ml, during and after MP withdrawal. Seventeen patients have remained continuously off MP for 14.6 +/- 5.0 months with stable renal function. Reinstitution of MP at 10 mg/day was required in 8 patients, 6 for rejection (1.8 +/- 0.7 months after MP withdrawal), 1 for AZA-induced leukopenia, and 1 for de novo glomerulopathy. Renal function returned to baseline in all 6 patients with rejection after reinstitution of MP. Two of these patients have again been successfully retapered off MP. In the patients withdrawn from MP, body weight and mean arterial blood pressure had decreased by 2.1 +/- 1.3 kg (P less than .05) and 11 +/- 7 mmHg (P less than .05), respectively, at the time of the most recent follow-up compared with values at the initiation of steroid withdrawal. The number of blood pressure medications per patient decreased by 38% (P less than .05) and 6 patients were able to discontinue all antihypertensive drugs after cessation of steroids. Discontinuation of MP also resulted in a decrease in serum cholesterol concentration from 248 +/- 50 to 217 +/- 55 mg/dl (P less than .05). We conclude that steroids can be replaced by AZA in the majority of CsA-treated primary cadaveric renal transplant recipients by the end of the first posttransplant year without an adverse effect on graft survival. This protocol resulted in significant reductions in serum cholesterol, mean arterial blood pressure, and body weight, and may avoid the long-term side effects of steroid therapy.     

Elective conversion from cyclosporine to azathioprine in sensitized patients following cadaveric renal transplantation

The safety of conversion from cyclosporine to azathioprine following renal transplantation in patients generally considered to be at immunologic risk for allograft loss has not been established. We examined a group of 59 patients who underwent cadaveric renal transplantation and elective conversion from cyclosporine to azathioprine 8.3 +/- 3.8 months following transplantation. Forty-three of these patients received a first transplant and had panel-reactive antibodies (PRA) less than 40% (unsensitized). Sixteen patients received at least their second allograft or had PRA of 40% or more (sensitized). Average follow-up was 17.9 +/- 8.2 months. Nine patients (15%) failed conversion as manifested by the need to restart cyclosporine 1 to 10 months following conversion. All were in the unsensitized group. Of those successfully converted, there were six allograft failures, two from patient death, one from acute rejection, one from recurrent diabetic nephropathy, and two from patient noncompliance. All were in the unsensitized group, although the difference from the sensitized group was not statistically significant (P = 0.051). There were three rejection episodes, all successfully reversed, in the sensitized group and six rejection episodes in the unsensitized group, five of which were reversed. Overall renal function improved in both groups as shown by a significant decrease in serum creatinine. Neither group required increased doses of steroid to compensate for lack of cyclosporine. From these data we can recommend conversion from cyclosporine to azathioprine in patients with cytotoxic antibodies or those undergoing retransplantation.     

A phase III prospective,randomized study to evaluate concentration-controlled sirolimus (rapamune) with cyclosporine dose minimization or elimination at six months in de novo renal allograft recipients

BACKGROUND: This study evaluated the safety and efficacy of sirolimus plus steroids as a maintenance regimen with or without small-dose cyclosporine (CsA) adjunctive therapy in renal transplant recipients. METHODS: A total of 133 recipients of kidney allograft transplantations recruited in the United Kingdom and Ireland were enrolled into the study and are presented in this interim analysis. In the first 3 months, all patients received CsA plus sirolimus and small-dose steroids after transplantation. At 3 months, patients were randomized 1:1 to CsA elimination (e)CsA or CsA dose minimization (m)CsA. Dosing of agents was concentration-controlled and open label. RESULTS: Patient and graft survival were 97.7% and 95.5%, respectively (n = 133), whereas the biopsy-proven acute rejection rate in the first 6 months was 19.5% (26 episodes in 133 patients); incidents of acute rejection rates comprised 22 episodes (16.5%) during the first 3 months of the study and four episodes (3%) after randomization. Eighty-seven patients were randomized to receive eCsA or mCsA. At 6 months, creatinine clearance was significantly higher in the eCsA group versus mCsA group, respectively (65 mL/min vs. 57 mL/min; P = 0.027). There was no significant difference in serum cholesterol, triglycerides, low-density lipoprotein, or high-density lipoprotein levels between the groups. CONCLUSION: These data demonstrate that withdrawal of CsA from a small-dose sirolimus maintenance regimen is safe and is associated with an improvement in renal function. The study also suggests that the addition of small-dose CsA to a sirolimus maintenance regimen does not increase immunosuppressive efficacy.     

Insensitivity to cyclosporine may explain the HLA-DRw6 recipient effect

Clinical as well as experimental studies have found an interindividual variability in the immunosuppressive effect of cyclosporine (CsA). In renal transplant patients treated with CsA and prednisolone alone, biopsy-verified rejections were significantly more frequent in DRw6-positive than in DRw6-negative graft recipients. The relative risk for developing a graft rejection independently of the CsA blood levels increased in HLA-DRw6-positive transplant patients. Although no statistical significance of the CsA levels within different DR phenotypes could be assessed, HLA-DR2-positive graft recipients with biopsy-verified rejection episodes had significantly lower CsA levels than DR2-negative patients (P = 0.01). Our results would indicate a very low CsA sensitivity of HLA-DRw6-positive graft recipients and might explain previous results describing an increased incidence of rejection and decreased graft survival rates in these patients.