Low 1-year cyclosporine microemulsion doses are associated with better 5-year renal graft function: an insight from MOST, a multinational observational study

BACKGROUND: In earlier registry analyses, cyclosporine at doses of < 3 mg/kg/d at 1 year post-renal transplantation has been associated with significant graft loss or reduction in renal function. Improvements in cyclosporine formulation with increased bioavailability, plus the use of more efficient comedications, may now confer better outcomes. To determine the effect of the 1-year cyclosporine microemulsion (CsA-ME) dose on renal allograft function at 5 years, we analyzed data collected from 2889 patients with documented graft survival to year 5 in a prospective, multinational, observational study-Neoral MOST. RESULTS: Glomerular filtration rate (GFR) at year 1 was 63 +/- 20 mL/min and 59 +/- 22 mL/min at year 5. The multivariate analysis including year 1 CsA-ME dose as factor and GFR at 1 year as covariate revealed the most significant factors affecting GFR at year 5 were 1-year GFR, donor age > 60 years, and CsA-ME dose at 1 year. Risk factors associated with reduction in 5-year GFR (<65 mL/min) included donor or recipient age >60 years, delayed graft function, cadaveric donor, previous graft, and acute rejection. CsA-ME dose <3 mg/kg/d was found to protect GFR. Analysis of GFR at each year posttransplantation (Wilcoxon model) found 1-year CsA-ME (cutoff 3 mg/kg/d) had a significant effect at each time point. CONCLUSIONS: Compared to higher doses, CsA-ME <3 mg/kg/d at year 1 posttransplantation is associated with increased preservation of renal allograft function at year 5.     

Comparison of induction based on continuous vs discontinuous administration of antithymocyte globulins in renal transplant patients: efficacy and long-term safety

This retrospective study sought to compare two modes of administration of antithymocyte globulin (RATG) after renal transplantation. METHODS: Before 1993, group I patients (n = 93) received fixed doses of RATG (1 mg/kg per day) for 8 consecutive days. Thereafter, RATG was either continued at the same dose for 15 days, in cases of delayed graft function, or was infused every other day at the same dose until serum creatinine level became <150 micromol/L. After 1993, group II patients (n = 66) received RATG at full dose (1 mg/kg per day) during the first 3 days and thereafter the doses were adjusted to target a CD2 T-cell count <50/mm3. Both groups received steroids, azathioprine, and cyclosporine. The mean follow-up after transplantation was 117 +/- 31 months in group I and 93 +/- 19 months in group II. RESULTS: The RATG cumulative dose and consequently cost were significantly higher among group I than group II patients. Long-term patient and graft survival were similar in both groups. The rate of acute graft-rejection episodes was significantly higher among group I than group II patients. At 7 years posttransplantation, the serum creatinine level and creatinine clearance were similar in the two groups. The rate of cytomegalovirus infection, as well as the cumulative incidence of severe infections and cancers were also similar in both groups. Among the cancers, skin neoplasms represented 30% in group I and 26% in group II (P = ns). CONCLUSION: Adjusting RATG doses according to the CD2 lymphocyte count is safe, and a less expensive than using full doses.     

Thymoglobulin,sirolimus, and reduced-dose cyclosporine provides excellent rejection prophylaxis for pancreas transplantation

BACKGROUND: We investigated a novel immunosuppressive protocol including thymoglobulin induction in combination with sirolimus and corticosteroids, followed by introduction of markedly reduced exposures to cyclosporine to prevent pancreas-transplant rejection. METHODS: A 7-day course of thymoglobulin (1.5 mg/kg per day) was begun on postoperative day (POD) 0, together with 15 mg of sirolimus on POD 1, and followed by 5 mg per day, targeting these doses to achieve a trough of 10 to 20 ng/mL. When the serum creatinine was below 2.5 mg/dL, cyclosporine was introduced at 50 mg twice daily with dose adjustment to maintain a trough concentration of 100 to 125 ng/mL. RESULTS: The 18 patients included 14 simultaneous pancreas-kidney and 4 pancreas-after-kidney transplant recipients. Two patients were African-American, three patients had a pretransplant panel reactive antibody greater than 20%, and the human leukocyte antigen (HLA) mismatch was 4.5+/-1 (mean+/-standard deviation). With a mean follow-up of 13.6+/-4.7 months, patient, kidney, and pancreas graft survivals are 100%, 100%, and 94%, respectively. A single pancreas graft was lost to thrombosis. There were no acute rejection episodes and no opportunistic infections. Mean hospital stay was 9+/-3 days. At 3 months posttransplantation, the mean value of serum creatinine was 1.2+/-0.3 mg/dL, fasting glucose was 88+/-15 mg/dL, and sirolimus dose at month 3 was 6.3+/-3 mg per day and at month 12 2.7+/-1 mg per day. The average total daily cyclosporine A dose at month 3 was 208+/-62 mg per day and 133+/-13 mg per day at 1 year. CONCLUSIONS: This immunosuppressive regimen provided excellent prophylaxis against acute rejection with no opportunistic infections. We believe that careful monitoring of sirolimus and cyclosporine levels was critical to success of this protocol.     

Oral efficacy of the macrolide immunosuppressant SDZ RAD and of cyclosporine microemulsion in cynomolgus monkey kidney allotransplantation

BACKGROUND: 40-O-(2-Hydroxyethyl)-rapamycin (SDZ RAD) is a novel, potent, macrolide immunosuppressant. Its efficacy in rodent transplantation models provided the rationale for us to evaluate the compound in a more relevant, large animal transplantation model. METHODS: Life-supporting kidney allotransplantation was performed in cynomolgus monkeys: rejection was inferred from a rise in serum creatinine or urea and was subsequently confirmed by histopathology. This model was validated with the microemulsion formulation of cyclosporine (i.e., Neoral). Two studies with a microemulsion formulation of SDZ RAD were performed. First, in a dose-finding study, the SDZ RAD dose was reduced in a stepwise fashion until rejection occurred, either with SDZ RAD as monotherapy, or in combination with a fixed, suboptimal dose of cyclosporine. Second, an efficacy study was performed in which two fixed SDZ RAD doses (0.75 and 1.50 mg/kg/ day) were evaluated in monotherapy and compared with the same doses of rapamycin (sirolimus). All immunosuppressants were administered once daily by gastric gavage. RESULTS: Untreated control animals rejected their grafts between 4 and 8 days after transplantation. Cyclosporine (initially at 150 mg/kg/day, reduced to 100 mg/kg/day 2 weeks after transplantation) yielded long-term (>100 days) rejection-free allograft survival in four of five animals. A 10 mg/kg/day dose of cyclosporine led to rejection between 10 and 27 days after transplantation and was considered suboptimal. In the dose-finding study with SDZ RAD monotherapy, rejection occurred in most of the cases (four of six animals) when a dose level of 0.63 mg/kg/day had been reached. Combined with suboptimal cyclosporine, this threshold SDZ RAD dose was about 2-fold lower. In the efficacy study, median graft survival with histologically proven rejection was 32 days (range 8-91 days, n=6) for 0.75 mg(kg/day SDZ RAD and 59 days (range 28-85 days, n=6) for 1.50 mg/kg/day SDZ RAD. For sirolimus, median graft survival was 43 days (range 5-103 days, n=7) for the 0.75 mg/kg/day dose and 56 days (range 8-103 days, n=8) for the 1.50 mg/kg/day dose. There was no statistically significant difference in efficacy between SDZ RAD and sirolimus. CONCLUSION: SDZ RAD, in the absence of any other immunosuppressant and at doses that do not show any overt toxicity, considerably prolongs rejection-free survival of cynomolgus monkeys after life-supporting kidney allotransplantation.     

Cyclosporine and mycophenolate mofetil 48 hours before renal transplantation enables the use of low cyclosporine doses and achieves better graft function

Reducing calcineurin-inhibitor induced nephrotoxicity and simultaneously avoiding long-term side effects are desirable goals in renal transplantation. We examined the hypothesis that administration of cyclosporine and mycophenolate mofetil (MMF) 48 hours before renal transplantation allows reduction in the target cyclosporine C2 concentration, thus decreasing toxicity and improving graft function. We enrolled 80 kidney recipients in a single-center study comparing 2 cyclosporine-based protocols. Group I patients (n = 40) received a standard dose of cyclosporine (blood cyclosporine C2, 800-1500 ng/mL) with MMF and standard doses of corticosteroids. Group II patients (n = 40) were treated with a low dose of cyclosporine (blood cyclosporine C2, 450-800 ng/mL) and MMF plus low doses of corticosteroids after induction 48 hours before surgery with cyclosporine and MMF. Patient (97.5% vs 100%) and graft survivals (92.5% vs 95%) at 1 year were not different between the groups, although patients in group II experienced significantly fewer acute rejection episodes (10% vs 30%; P < .01). Delayed graft function occurred less often among group I than group II (17.5 vs 20%), but the difference was not significant. Graft function at 1 year was significantly better among group II (serum creatinine 1.31 vs 1.64 mg/dL and creatinine clearance 63 mL/min versus 47 mL/min; P < .05). We concluded that administration of cyclosporine and MMF 48 hours before renal transplantation allowed the safe effective use of low target C2 cyclosporine concentrations, enabling an early decrease in cyclosporine dose. These preliminary results indicated better 1-year graft function compared with the normal cyclosporine dose regimen.     

Conversion from cyclosporine to tacrolimus in patients at risk for chronic renal allograft failure: 60-month results of the CRAF Study

BACKGROUND: This study compared the long-term effects of switching from cyclosporine to tacrolimus on the incidence, progression, and severity of chronic renal allograft failure in patients with elevated serum creatinine levels. METHODS: Patients were assigned randomly (2:1) to switch to tacrolimus or remain on cyclosporine. Tacrolimus was initiated at 1/50th of the cyclosporine dose or 0.15 mg/kg/day, whichever dose was lower, to maintain trough concentrations between 5 and 15 ng/mL. Cyclosporine doses were adjusted to achieve trough concentrations between 100 and 300 ng/mL. RESULTS: At 60 months, the median change from baseline in serum creatinine was -0.2 mg/dL in the tacrolimus group and 0.3 mg/dL in the cyclosporine group (P=0.003). Median change in estimated creatinine clearance was 1.2 mL/min in the tacrolimus group and -4.1 mL/min in the cyclosporine group (P=0.019). The incidence of new-onset diabetes, hyperglycemia, hypertension, lymphoma, and malignancies was generally low and comparable between groups. Fewer patients in the tacrolimus group than in the cyclosporine group developed new cardiac conditions (11% vs. 28%, P=0.004), had low-density lipoprotein (LDL) cholesterol values more than 130 mg/dL (29% vs. 57%, P=0.002), or developed hyperlipidemia (24% vs. 67%, P=0.046) during the 60-month follow-up period. Despite these changes, patient and graft survival were similar for both groups. CONCLUSION: Switching from cyclosporine to tacrolimus resulted in improved renal function and a reduction in the occurrence of new-onset cardiac conditions and hyperlipidemia, with no increase in the incidence of new-onset diabetes or new-onset hyperglycemia. However, after 5 years there was no impact on patient or graft survival.     

Effect of thymoglobulin in graft survival and function 1 year after kidney transplantation using deceased donors

This study evaluated 1-year graft function and survival among kidney transplantations from deceased donors using thymoglobulin (Thymo) as an induction strategy. PATIENTS AND METHODS: Fifty-seven percent of patients were men and overall mean age was 42 +/- 15 years. Cold ischemia time was 20.1 +/- 4.8 hours. The primary outcome was defined as survival not censored for death after 1 year. The secondary outcome was defined as a comparison of function and survival among patients who received more or less then six doses of Thymo. RESULTS: Four patients experienced acute rejection episodes and the other three died during follow-up. One-year graft survival was 91% with a mean serum creatinine of 1.28 +/- 0.43 mg/dL. Cytomegalovirus infection occurred in 56%. Forty-two (64%) patients displayed acute tubular necrosis of mean duration of 6.89 +/- 7.48 days. Patients who received lower doses showed better serum creatinine values 3 months (1.45 vs 1.86 mg/dL, P = .013) and 12 months (1.05 vs 1.50 mg/dL, P = .04). The difference was probably due to acute tubular necrosis that produced a RR of 1.7 (P = .02; CI 1.04-2.97) when compared with patients with Scr values above 1.30 mg/dL. When censored for death, graft survival was not different between the two groups (< or =6 doses 93% vs >6 doses 97%, P = .43). CONCLUSION: Immunologic induction with Thymo produced excellent graft survival after 1 year with preservation of graft function. Delayed graft function was the most important determinant of graft function after 1 year.     

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.     

Sirolimus (rapamycin) reduces the incidence of acute rejection episodes in renal transplantation: an initial experience in Taiwan

BACKGROUND: Acute rejection is the major cause of graft loss in renal transplantation. Sirolimus (rapamycin) inhibits the effects of cytokines on T and B cells; therefore, it provides prophylaxis against acute renal rejection. This open-label trial assessed the incidence of biopsy-confirmed acute rejection episodes, variation in renal function, as well as graft and patient survival rates up to 12 months posttransplantation when using sirolimus in combination with cyclosporine and prednisolone as immunosuppressants. METHODS: Ten kidney transplant recipients received sirolimus 2 mg daily after a 6-mg loading dose. Doses were then adjusted to keep the whole-blood trough level between 5 and 20 mg/mL. All patients received sirolimus in combination with cyclosporine and prednisolone. RESULTS: At 12 months after renal transplantation, the graft and patient survival rates were 90% and 90%, respectively. One patient died at 2 months due to sepsis with a functioning graft. The mean serum creatinine levels at 1, 3, and 6 months were 1.59 mg/dL, 1.71 mg/dL, and 1.65 ml/dL, respectively. There was no biopsy-confirmed acute rejection episode within 12 months. CONCLUSIONS: Sirolimus in combination with cyclosporine and prednisolone significantly protected kidney transplant recipients from acute rejection for up to 1 year of follow-up.     

Oral efficacy of the new immunomodulator FTY720 in cynomolgus monkey kidney allotransplantation,given alone or in combination with cyclosporine or RAD

BACKGROUND: FTY720 is a novel immunomodulator with a unique mechanism of action, i.e. chemokine-dependent lymphocyte homing into secondary lymphoid organs associated with profound lymphocyte depletion in blood. We investigated its efficacy, either FTY720 alone or together with cyclosporine or the rapamycin derivative rapamycin derivative (RAD), in cynomolgus monkey kidney allotransplantation. METHODS: Life-supporting allotransplantation was performed in bilaterally nephrectomized hosts. Compounds were given once daily by oral gavage. Monitoring was done by serum creatinine and urea, and rejection was concluded when values exceeded 500 micromol/L and 50 mmol/L, respectively (5-6 times the upper limit of reference values). Rejection was confirmed by graft histology. The termination point was set to 100 days after transplantation. In addition, animals were monitored for 24 hr drug concentrations and thorough inspection of potential adverse side effects. RESULTS: FTY720 given alone at 3.0 mg/kg per day prolonged rejection-free survival (33-85 days, mean 24 hr concentration between 54 and 66 ng/mL [n=3]), but it was not efficacious at a 0.3 mg/kg per day dose. For cyclosporine alone, 30 mg/kg per day during maintenance was efficacious (average concentration above 100 ng/mL, historical data from our group), and for RAD alone 0.75 mg/kg per day (concentration above 10 ng/mL). Efficacious FTY720-cyclosporine-A (CsA) or FTY720-RAD combinations were established using 0.1-0.3 mg/kg per day FTY720, 10-30 mg/kg per day cyclosporine, and/or 0.25-0.50 mg/kg per day RAD. Compared with single-compound treatment, FTY720 effective doses and 24 hr trough concentrations were at least tenfold lower in combination treatment and those of cyclosporine and RAD about twofold lower, indicative of effective synergy between the compounds. Already at the lowest FTY720 dose tested (0.03 mg/kg per day), there was a profound lymphocyte depletion down to about 30% of pretransplant values, which further increased at the highest dose (3.0 mg/kg per day, to about 14% of pretransplant values). Lymphocyte depletion was reflected by a decrease in T and B subpopulations. CONCLUSION: FTY720 is an effective immunosuppressant in prevention of acute kidney allograft rejection in cynomolgus monkeys and synergizes with cyclosporine and/or RAD in yielding rejection-free allograft survival.     

Kidney Transplantation Achievements in Mongolia

Between August 2006 and August 2009, 33 patients with end-stage renal disease were the recipients of kidney transplantations. The donors were living related 29 operations with 4 recipients of 2 deceased donors following accidents with cardiac arrest controlled after permission by the next of kin. We used standard techniques for the donor and recipient operations.All recipients were prescribed 1 dose of alemtuzumab (Campath 1 H 20-30 mg), peroperatively preceded by 500 mg methylprednisolone. In 2 recipients, a second infusion of Campath 1 was administered on postoperative day 2.On postoperative day 3, we prescribed monotherapy with either cyclosporine (n = 29) at a starting dose of 7 mg/kg body weight or tacrolimus (n = 6) at a starting dose of 0.7 mg/kg body weight. With the exception of patients treated for an acute rejection episode, no patient received steroid therapy.There were 7 acute rejection episodes, which were treated with 3 consecutive daily doses of methylprednisolone (250 mg).The 1-year patient survival was 94% and 2-year graft survival, 84.8%. We concluded that the use of Campath 1 together with a non-steroid maintenance immunosuppressive regimen provided acceptable graft and patient survival in our developing country.     

Immunosuppressive Treatment of Primary Cadaveric Renal Transplant Patients Receiving Kidneys from Non-Heart Beating Donors

Abstract: Since November 1982, 276 primary cadaveric kidney transplants have been performed using kidneys from non-heart beating donors. Between November 1982 and December 1986, 49 transplant patients were treated with cyclosporine and steroid immunosuppressive therapy (CSA regimen). Twenty-seven patients were treated with low dose cyclosporine (initial dosage, 4 mg/kg/day), steroid therapy, and a 21-day course of 500 mg/day anti-lymphocyte globulin (ALG 1 regimen) between January 1987 and December 1987. Seventy-nine patients were treated with low dose cyclosporine (initial dosage, 6 mg/ kg/day), steroid therapy, and a 14-day course of 1,000 mg/day antilymphocyte globulin (ALG 2 regimen) between January 1988 and June 1990, and 85 patients were treated with low dose cyclosporine (initial dosage, 6 mg/ kg/day), steroid therapy, and a 14-day course of 1,000 mg/day antilymphocyte globulin followed by 2 mg/kg/day mizoribine (ALG 3 regimen) between July 1990 and May 1995. Ten patients, who showed hypersensitivity to antilymphocyte globulin therapy, were treated with low dose cyclosporine, steroid therapy, and mizoribine. Finally, 26 patients were treated with FK506 and steroid therapy (FK.506 regimen) between June 1990 and February 1992. Graft survival was 78% at 1 year, 69% at 3 years, 63% at 5 years, and 51% at 10 years in the CSA regimen group and 67% at 1 year, 52% at 3 years, and 48% at 5 years in the ALG 1 regimen group. It was 85% at 1 year, 70% at 3 years, and 62% at 5 years in the ALG 2 regimen group and 87% at 1 year and 67% at 3 years in the ALG 3 regimen group. In the FK506 regimen group, graft survival was 92% at 1 year and 80% at 3–5 years. Never-functioning grafts were observed in 3 CSA patients (6%), I ALG 1 patient (4%), 3 ALG 2 patients (4%), 3 ALG 3 patients (4%), and I FK506 patient (4%). These results indicate that low dose cyclosporine (initial dosage, 6 mg/kg/day), steroid therapy, and a 14 day course of antilymphocyte globulin therapy is beneficial for cadaveric renal transplant patients receiving kidneys from non-heart beating donors; FK506 and steroid therapy might be more effective than cyclosporine based immunosuppressive therapies even in such patients.     

HLA-identical renal transplants: impact of cyclosporine on intermediate-term survival and renal function

Seventy-two and 34 consecutive HLA-identical sibling renal transplant recipients were treated with azathioprine/prednisone (AZA; follow-up, 5.0 years) and cyclosporine/prednisone (CSA; mean follow-up, 2.9 years), respectively. Both groups were similar in age, sex, race, and number of transplants, but there were more diabetics in the CSA group (34% v 8%). Actual patient survival at 1 year and actuarial patient survival at 5 years were 100% and 96%, respectively in the CSA group compared with an actual patient survival of 91% and 82% at 1 and 5 years, respectively, in the AZA group. Actual graft survival at 1 year improved from 85% in the AZA group to 97% in the CSA-treated recipients (P less than 0.05). Mean serum creatinine at 5 years remained stable in the AZA group at a mean of 123 mumol/L (1.4 mg/dL) compared with a progressive increase in this parameter to a mean of 212 mumol/L (2.4 mg/dL) after the same time interval in the CSA patients. Furthermore, the slopes of the serum creatinine against time were significantly different between the two groups (P less than 0.01). Mean daily CSA dose averaged 4 mg/kg 12 months following transplantation, with a decrease to 2.4 mg/kg by the fifth year. Causes of death in the AZA group were cardiovascular (eight), sepsis (three), cancer (one); and in the CSA group, Kaposi's sarcoma (one). Causes of graft failure in the AZA group were immunological (six), sepsis (three), technical (two), recurrence of disease (one), and patient death with a functioning graft (five). Technical (one), noncompliance (two), recurrence of disease (one), and patient death with a functioning kidney (one) caused graft failure in the CSA group. No difference in posttransplantation serum cholesterol or incidence of new onset diabetes was observed between the two groups, but hypertension was significantly more frequent (51% v 21%, P less than 0.01) when CSA was used. In conclusion, intermediate-term results of CSA-treated HLA-identical transplant recipients showed improved patient and graft survival with less complications apart from hypertension. However, the slow, but relentless, increase in serum creatinine in the CSA-treated patients compared with those treated with AZA is of concern.     

One-year posttransplant renal function is a strong predictor of long-term kidney function: results from the Neoral-MOST Observational Study

BACKGROUND: Peritransplant risk factors influence short-term and long-term graft survival, and 1-year serum creatinine is known to predict long-term graft survival. To examine interrelationships between risk factors, renal function at 1 year, and long-term graft function in patients maintained on cyclosporine, we analyzed data collected from 10,692 de novo or maintenance renal transplant recipients in an ongoing international, prospective, observational study--Neoral-MOST (Multinational Observational Study in renal Transplantation). The effect of donor age, delayed graft function, acute rejection, donor type, panel-reactive antibodies, and previous graft on 1- and 5-year renal function and their relationship to 1-year serum creatinine was assessed. RESULTS: Donor age, delayed graft function, acute rejection, and donor type significantly increased the risk for serum creatinine > 130 micromol/L at 1 year posttransplant, and 1-year serum creatinine was the strongest predictor of 5-year renal function. After adjustment for 1-year serum creatinine, an ongoing influence was observed for donor age, donor type, and previous graft. Delayed graft function and acute rejection had a significant effect on serum creatinine at year 1 but no additional impact on long-term graft function. CONCLUSIONS: Serum creatinine at 1 year is influenced by risk factors known to affect overall graft survival and is predictive of 5-year renal graft function. The effects of delayed graft function and acute rejection appear to be limited to their influence on serum creatinine at 1 year, whereas donor type and previous graft predominantly affect later stages of graft life.     

Critical threshold of azathioprine dosage for maintenance immunosuppression in kidney graft recipients. Collaborative Transplant Study

BACKGROUND: There are conflicting reports in the literature concerning the efficacy of maintenance immunosuppression in renal transplantation with a regimen of azathioprine and steroids. METHODS: The daily dosage (mg/kg) of azathioprine administered 1 year after transplantation was analyzed in relation to subsequent long-term graft outcome. Transplants performed from 1985 to 1996 and reported to the Collaborative Transplant Study were analyzed. RESULTS: In patients on maintenance immunosuppression without cyclosporine, the daily dosage of azathioprine had a highly significant influence on long-term graft outcome. Patients who received > 1.5 mg/kg/ day of azathioprine had a 69% graft survival rate at 7 years, compared with a 55% rate in patients receiving 1.01-1.5 mg/kg/day (P<0.0001) and a 45% rate in patients receiving < or = 1.00 mg/kg/day (P<0.0001). This observation was valid for patients who were taken off cyclosporine during the first year as well as for patients who were treated with azathioprine and steroids (without cyclosporine) from the beginning. CONCLUSION: Maintenance immunosuppression with azathioprine and steroids results in good long-term kidney graft survival, provided azathioprine is administered at a daily dose of >1.5 mg/kg.     

Long-term evolution of lymphocytes subsets after induction therapy based on continuous versus discontinuous administration of anti-thymocyte globulins in renal-transplant patients

The aim of our retrospective study was to assess the long-term evolution of lymphocyte subsets after two modes of administration of anti-thymocyte globulin (ATG) after renal transplantation. METHODS: Before 1993, patients (group I, n = 93) received fixed doses of RATG (1 mg/kg per day) for 8 consecutive days. Thereafter, RATG was either continued at the same dose for 15 days, in cases of delayed graft function, or was infused every other day at the same dose until the serum creatinine level became <150 micromol/L. After 1993, patients (group II, n = 66) received RATG at full dose (1 mg/kg per day) during the first 3 days and, thereafter, doses were adapted to target a CD2 T-cell count <50/mm3. RATG cumulative dose was significantly higher among group I than group II (9.7 +/- 4.5 versus 7.4 +/- 3.2 mg/kg, P = .0002). RESULTS: In both groups, total lymphocyte and T lymphocyte subset (CD4, CD8, CD2, CD3) counts decreased significantly during the first month after transplantation, increasing slowly between the first month and the third year posttransplantation. Thereafter it rose rapidly, which was greater in group II. At last follow up, total lymphocyte, T lymphocyte subsets and NK cell counts were similar to those observed before transplantation. At all monitoring times, T lymphocyte, B lymphocyte, and NK cell counts were similar in both group, except for the total lymphocyte count at 6 months and CD4 T lymphocyte count at 1 year, which were significantly higher in group II compared to group I. CONCLUSION: Induction therapy based on continuous or discontinuous administration of ATG is associated with profound depletion of T, B, and NK cells during the first 3 years, followed by a progressive reconstitution of the lymphocyte pool after 5 years.     

Low-dose versus high-dose cyclosporine induction protocols in renal transplantation

BACKGROUND: Current immunosuppressive therapies are effective to prevent acute rejection episodes (ARE) and graft loss following renal transplantation. Newer agents now make it possible to develop equally efficacious but better tolerated, less toxic strategies. We compared the efficacy of early low- versus high-dose cyclosporine (CsA) induction therapy in living donor renal transplantation. METHODS: In this single-center study, 90 consecutive recipients of living donor kidney transplants between November 2002 to October 2003 including 51 females and mean average age of 48.23 years were treated with either CsA (5 mg/kg/d) plus mycophenolae mofetil (MMF; 30 mg/kg/d) and prednisolone (1 mg/kg/d; group 1; n=42); or CsA (8 mg/kg/d) plus MMF (30 mg/kg/d) and prednisolone (1 mg/kg/d; group 2; n=48). The 2 groups were matched with respect to age, sex, underlying renal diseases, pretransplantation dialysis period, number of transplantations, and panel-reactive antibody tests. CsA dose tapering was initiated in the 2 group 3 months after transplantation. At the end of the first year, the CsA dose was 3.5 +/- 0.65 mg/kg in group 1 and 3.4 +/- 0.34 mg/kg in group 2. Prednisolone was tapered within the first 2 months, reaching 10 mg/d in all patients. The MMF dose remained unchanged. The 2 groups were compared with respect to ARE, patient and graft survivals, and clinical outcomes within 2 years after transplantation. RESULTS: There were no significant differences between the 2 groups with respect to clinical outcomes, including 2-year patient survival (97.62% vs 97.92%; P=.76), 2-year graft survival (80.32% vs 80.41%; P=.82), ARE (47.61% vs 52.08%; P=.09), or length of immediate postsurgical hospital stay, number of readmissions, total hospitalization days, posttransplantation diabetes mellitus, and infectious, cardiovascular, gastrointestinal, and hematologic complications. There was more hypertension (67.5% vs 50.23%; P=.007), hypertriglyceridemia (45.5% vs 32.64%; P=.005), and elevated liver enzymes in group 2 (12.5% vs 7.14%; P=.018). CONCLUSIONS: Compared with 8 mg/kg CsA induction therapy, the lower doses of CsA were effective, well tolerated, and safe with relatively fewer side effects.     

Kidney transplantation without calcineurin inhibitor drugs: a prospective,randomized trial of sirolimus versus cyclosporine

BACKGROUND: Progressive nephrotoxicity caused by calcineurin inhibitor drugs contributes to the long-term decline in renal function in kidney transplant patients. METHODS: We conducted a randomized, prospective trial of calcineurin inhibitor drug avoidance in 61 adult primary kidney transplant recipients. Each patient received induction therapy with 20 mg basiliximab on days 0 and 4, and maintenance therapy with mycophenolate mofetil 1 g two times per day and steroids. Thirty-one patients received sirolimus, 5 mg daily after a 15-mg loading dose. Doses were then concentration-controlled to keep 24-hr trough levels at 10 to 12 ng/mL for 6 months and 5 to 10 ng/mL thereafter. Thirty patients began cyclosporine therapy at 6 to 8 mg/kg per day in divided doses and were then concentration-controlled to keep 12-hr troughs of 200 to 250 ng/mL. RESULTS: Mean follow-up is 18.1 months (range, 12-26 months). The percentages of 1-year patient survival, graft survival, and biopsy-confirmed acute rejection rates were not significantly different between the sirolimus-treated patients (96.7%, 96.7%, and 6.4%, respectively) and the cyclosporine-treated patients (100%, 95.4%, and 16.6%, respectively). At 6 and 12 months, respectively, the sirolimus-treated patients enjoyed significantly better (P=0.008 and P=0.004) mean serum creatinine levels (1.29 and 1.32 mg/dL) and calculated creatinine clearances (77.8 and 81.1 mL/min) than cyclosporine-treated patients (1.74 and 1.78 mg/dL, and 64.1 and 61.1 mL/min, respectively). Sirolimus-treated recipients have significantly (P=0.001) higher 1-year trough levels of mycophenolic acid (4.16 ng/mL) than cyclosporine-treated patients (1.93 ng/mL). Sirolimus also delays the repopulation of basiliximab-depleted CD25 T cells compared with cyclosporine. CONCLUSIONS: Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.     

Living related kidney transplantation without calcineurin inhibitors: initial experience in a Mexican center

We performed a prospective randomized trial comparing sirolimus/mycophenolate mofetil (MMF)/prednisone to cyclosporine/MMF/prednisone and selected induction therapy with basiliximab. Twenty patients received sirolimus (10 mg loading dose followed by 3 mg/m body surface area/day, keeping 24-hr trough levels at 10-15 ng/mL for six months and 5-10 ng/mL thereafter. Twenty-one patients began cyclosporine (4 to 8 mg/kg/day, keeping 12-hour trough levels at 150-300 ng/mL for 6 months and 100-200 ng/mL afterwards). Mean follow up was 15.8 months. One-year patient and graft survival was similar in both groups (>90%). Acute rejection rate was 16.6% in the sirolimus group and 5.2% in the cyclosporine group (P=NS). There were no differences in mean serum creatinine between groups. No patients who received basiliximab and had sirolimus target levels suffered acute rejection at one year. The sirolimus group had significantly higher cholesterol and triglycerides. A calcineurin inhibitor-free regimen using sirolimus produces comparable one-year transplant outcomes in living related kidney transplants compared to a calcineurin inhibitor regimen.     

The ability of pretransplant test-dose pharmacokinetic profiles to reduce early adverse events after renal transplantation.

Pretransplant test-dose pharmacokinetic profiles were used to determine individual cyclosporine drug bioavailability and clearance rates in renal transplant patients. Assuming a linear relation between dose and area under the concentration curve (AUC), starting i.v. and p.o. CsA doses were computed from the test-dose results. Target values were 400 ng/ml steady-state concentration (Css) during continuous intravenous infusion, and 500 ng/ml average drug concentration (Cavss = AUC/dosing interval) after oral administration, based upon measurements with the specific monoclonal antibody 3H-tracer radioimmunoassay. The outcomes after dose individualization with a 1-(n = 32), 2-(n = 38), or 3-(n = 41) hr i.v. infusion test dose and a p.o. test dose (n = 111) were compared with 228 historical control patients who received a uniform protocol of CsA i.v. at 2.5 mg/kg/day and p.o. at 14 mg/kg/day. The observed Css after i.v. CsA was within 10% of the target concentration in 73% of recipients tested with the 3-hr protocol, a significantly greater fraction than achieved with either the uniform dose (14%), or the 1-(34%) and 2-(25%) hr protocols. Patients in the 3-hr protocol group showed reduced incidences of delayed graft function, early graft loss, and rejection episodes, and a lower mean serum creatinine value, particularly at 7 but also at 30 days posttransplantation. Administration of the predicted oral dose produced a peak concentration of greater than or equal to 700 ng/ml drug absorption in 60% of recipients at 3 days, 90% at 5 days, and 98% at 7 days. The test-dose method less effectively predicted the appropriate oral CsA dose to produce target Cssav and failed to reduce the 90-day rejection incidence. Despite its limitations with the more-complicated p.o. route, the test-dose method successfully predicts i.v. CsA doses, thereby reducing the incidence of early adverse events.