Cytomegalovirus prophylaxis with intravenous polyvalent immunoglobulin in high-risk renal transplant recipients

Cytomegalovirus (CMV) seronegative renal allograft recipients (R-), particularly those with a graft from a CMV-seropositive donor (D+), are at high risk for primary CMV infection. CMV resistance to antiviral oral therapy is an emerging problem in renal transplantation, prompting development of new prophylactic strategies. We retrospectively studied the 1-year posttransplantation incidence of CMV infection in high-risk renal transplant recipients, in whom polyvalent intravenous immunoglobulins (IVIg) were used as prophylaxis. Forty R- patients received immunoprophylaxis by polyvalent IVIg (0.25 g/kg weekly for 8 weeks, starting on the operative day). CMV serological tests remained negative in eight patients (20%). Eight patients (20%) had asymptomatic CMV infection while 24 (60%) developed CMV syndrome and were treated with gancyclovir (10 mg/kg/day intravenously for 3 weeks). None had CMV disease or opportunistic infection. Six patients (15%) had biopsy-proven acute rejection, which followed CMV syndrome in three cases. One-year renal allograft and patient survivals were 95% and 97.5%, respectively. Mean serum creatinine level was 124 +/- 33 micromol/L at 1 year. Clinical tolerance of IVIg was excellent, without any episode of acute renal failure. Polyvalent IVIg provides effective prophylaxis in renal transplant recipients at high risk for CMV infection and is associated with excellent 1-year allograft survival. Because of their immunomodulatory functions, IVIg may have a beneficial effect on the incidence of acute and chronic rejection and allograft survival. A randomized prospective study is required to evaluate long-term effects of CMV prophylaxis with polyvalent IVIg compared to antiviral agents in renal transplant recipients.     

Cytomegalovirus seromismatching increases the risk of acute renal allograft rejection

BACKGROUND: There is an association between cytomegalovirus (CMV) infection or disease and acute allograft rejection in the setting of renal transplantation. There is, however, debate regarding the nature of this association, with evidence supporting both a "forward" relationship (CMV infection or disease precedes acute rejection) and a "backward" relationship (CMV infection or disease follows acute rejection). The objective of this study was to determine whether CMV matching had an independent effect on the risk of acute renal allograft rejection, which would support the view that CMV infection or disease is a risk factor for acute rejection. METHODS: Retrospective single center study (using a prospectively maintained database) of 333 first cadaveric transplant recipients from January 1st 1991 to December 31st 1997. Primary end-point was incidence of acute rejection, diagnosed clinically or by renal biopsy, for different groups formed on the basis of CMV seromatching. RESULTS: One hundred and ninety-four patients (58.3%) had at least one acute rejection episode. CMV seromismatched patients (donor +/recipient-) had a significantly higher rate of acute rejection than non-seromismatched patients (72.6% vs. 54.2%, P=0.005). Using multiple logistic regression, CMV seromismatch, delayed graft function, and biological induction were identified as independent predictors of acute rejection. The adjusted odds ratios for these were 2.28, 1.65, and 0.52, respectively. CONCLUSIONS: Patients who are CMV seromismatched are at higher risk of acute renal allograft rejection. This finding suggests that CMV infection or disease is a risk factor for acute rejection.     

Cytomegalovirus infection and graft rejection in renal transplantation

BACKGROUND: Cytomegalovirus (CMV) infection and CMV disease have been associated with acute and chronic graft rejection. The introduction of the sensitive CMV antigenemia pp65 assay for detection of CMV infection allowed us to study the time course of CMV infection and acute rejection and the long-term outcome in renal transplant recipients with and without a CMV risk constellation. METHODS: Prospective single center study including 48 renal transplant recipients at risk for CMV infection (donor and/or recipient CMV seropositive) and a control group of 36 CMV seronegative recipients of CMV seronegative kidney donors. Evidence of CMV infection was monitored by the CMV antigenemia pp65 assay every 1 to 2 weeks and compared with the occurrence of acute rejection in the posttransplant period and graft function at 5 years. RESULTS: CMV infection developed in 83% (40/48) of patients of the CMV risk group within 4 months posttransplant. A total of 18 of patients experienced an acute rejection episode (control group 16/36; P=0.65). In 12/18 CMV infection followed rejection and in three patients antigenemia preceded the diagnosis of rejection. In three patients CMV antigenemia remained negative. Five-year follow up: Patient survival (44/48 vs. 31/36; P=0.48), graft survival (38/48 vs. 27/36; P=0.79), number of patients with at least one acute rejection episode: CMV risk group: 42.1%, control group 51% (P=0.46), serum creatinine: CMV risk group:130 +/- 66 micromol/iter, control group: 126 +/- 37 micromol/ liter (P=0.56), proteinuria: CMV risk group: 0.02 +/- 0.02 g/mmol creatinine, control group: 0.02 +/- 0.02 g/mmol creatinine (P=1.0). CONCLUSION: CMV infection within 4 months posttransplant, as defined by a positive antigenemia assay was not found to be a risk factor for acute graft rejection or chronic graft dysfunction at 5 years.     

Efficacy and Safety of Valganciclovir vs. Oral Ganciclovir for Prevention of Cytomegalovirus Disease in Solid Organ Transplant Recipients

We compared the efficacy and safety of valganciclovir with those of oral ganciclovir in preventing cytomegalovirus (CMV) disease in high-risk seronegative solid organ transplant (SOT) recipients of organs from seropositive donors (D+/R-). In this randomised, prospective, double-blind, double-dummy study, 364 CMV D+/R- patients received valganciclovir 900 mg once daily or oral ganciclovir 1000 mg three times a day (tid) within 10 days of transplant and continued through 100 days. CMV disease, plasma viremia, acute graft rejection, graft loss and safety were analyzed up to 6 and 12 months post-transplant. Endpoint committee-defined CMV disease developed in 12.1% and 15.2% of valganciclovir and ganciclovir patients, respectively, by 6 months, though with a difference in the relative efficacy of valganciclovir and ganciclovir between organs (i.e. an organ type-treatment interaction). By 12 months, respective incidences were 17.2% and 18.4%, and the incidence of investigator-treated CMV disease events was comparable in the valganciclovir (30.5%) and ganciclovir (28.0%) arms. CMV viremia during prophylaxis was significantly lower with valganciclovir (2.9% vs. 10.4%; p=0.001), but was comparable by 12 months (48.5% valganciclovir vs 48.8% ganciclovir). Time-to-onset of CMV disease and to viremia were delayed with valganciclovir; rates of acute allograft rejection were generally lower with valganciclovir. Except for a higher incidence of neutropenia with valganciclovir (8.2%, vs 3.2% ganciclovir) the safety profile was similar for both drugs. Overall, once-daily oral valganciclovir was as clinically effective and well-tolerated as oral ganciclovir tid for CMV prevention in high-risk SOT recipients.     

肾移植术后血脂的变化对移植肾功能的影响

目的:探讨肾移植患者血脂代谢情况及其对移植肾功能的影响。方法:检测89例肾移植患者肾移植前、后的血脂水平,并与移植后1年内发生急性排斥反应及移植后1年时发生慢性移植肾功能不全的患者进行血清肌酐水平相关性分析。结果:与正常对照组比较,肾移植前、后的血清总胆固醇、低密度脂蛋白胆固醇的水平显著升高(P<0.01),甘油三酯、高密度脂蛋白胆固醇、极低密度脂蛋白胆固醇水平无显著差异。血载脂蛋白A1水平显著低于正常对照组(P<0.01)。移植前、后上述血脂水平无显著差异。移植前高胆固醇血症与急性排斥反应的发生存在相关性,高胆固醇血症对慢性移植肾功能不全患者血清肌酐水平升高存在影响。结论:肾移植患者血脂代谢紊乱明显不同于正常人群,高脂血症对急性排斥反应及慢性移植肾功能不全的发生具有不良影响。     

Short-term outcomes of Thymoglobulin induction in pediatric renal transplant recipients

No data are currently available that describe the clinical outcomes associated with Thymoglobulin (rabbit polyclonal anti-thymocyte globulin) induction in pediatric renal transplant recipients. We report the outcomes of 17 pediatric renal transplant recipients (mean age 10.1+/-5.2 years) transplanted between 1 August 1999 and 31 July 2001. Eleven patients (65%) were Caucasian and 6 (35%) were African-American. Eleven (65%) recipients received cadaveric allografts. Two patients (12%) were second allograft recipients. One patient had primary allograft non-function secondary to vascular thrombosis. Two patients (12%) had delayed allograft function. Immunosuppression consisted of Thymoglobulin induction (mean number of doses 6+/-1.7) with tacrolimus (62%) or cyclosporine A (38%), mycophenolate mofetil, and prednisone. One year post transplant, patient and graft survival was 100% and 93%, respectively. No acute rejection episodes occurred during the first 6 months after transplantation in any of the recipients. Additionally, no rejection episode occurred among the 14 patients followed for 1 year after transplant. The incidences of asymptomatic cytomegalovirus (CMV) and Epstein-Barr virus (EBV) seroconversion at 1 year in seronegative recipients with a seropositive donor were 100% of 4 patients and 0% of 4 patients, respectively. No symptomatic CMV or EBV infections and no post-transplant lymphoproliferative disease have occurred in any patient. These short-term data suggest that Thymogobulin induction is safe and effective in combination with triple immunosuppressive therapy for preventing early rejection in pediatric renal transplant recipients.     

Flow cytometry crossmatching as a predictor of acute rejection in sensitized recipients of cadaveric renal transplants

Flow cytometry crossmatching (FCXM) was developed as a more sensitive assay than the standard complement-dependent cytotoxicity crossmatch (CDCXM) for the detection of anti-donor antibodies, that mediate hyperacute rejection and graft loss in the early post-transplant period in renal transplant recipients. The role of FCXM in predicting long-term clinical outcome in renal allograft recipients is unclear. This study examines the role of FCXM in predicting long-term clinical outcome in highly sensitized recipients of cadaveric renal transplants. All patients (n = 100) with peak panel reactive antibody (PRA) levels > 30%, who received cadaveric renal transplants between 1/1/'90 and 12/31/'95 at our institution, were divided into FCXM + and FCXM - groups. The incidence of acute rejection was determined for each group during the first yr after transplant. Graft survival rates at 1, 2, and 3 yr, and creatinine levels were also compared between groups. FCXM + patients experienced a higher incidence of acute rejection during the first yr after transplant (69 vs. 45%), and a higher percentage of FCXM + patients had more than one episode of acute rejection during the first yr after transplant (34 vs. 8%) when compared to FCXM - patients. There was no statistically significant difference in 1-, 2-, or 3-yr graft survival between FCXM + and FCXM - patients (76 vs. 83, 62 vs. 80, 62 vs. 72%, respectively). These results suggest that sensitized FCXM + cadaveric renal transplant recipients have a higher incidence of acute rejection episodes in the first yr after transplant. Given the association of multiple rejection episodes with poor long-term allograft survival, FCXM may be a useful predictor of long-term clinical outcome in this sub-group of renal transplant recipients.     

The association of viral infection and chronic allograft nephropathy with graft dysfunction after renal transplantation

BACKGROUND: The long-term effect of viral infections on graft dysfunction and rejection after renal transplantation is uncertain. METHODS: A cohort of 37 renal transplant recipients was followed prospectively for 3 years. Creatinine clearance rate at 6 months and 3 years and chronic allograft nephropathy were correlated with the detection of cytomegalovirus (CMV), human herpesvirus 6 and human herpesvirus 7 and BK virus DNA, CMV disease, and acute rejection. RESULTS: CMV disease was significantly associated with poor graft function at 6 months, whereas chronic allograft nephropathy was associated with graft dysfunction at 3 years. Both CMV disease and detection of human herpesvirus 6 DNA were associated with chronic allograft nephropathy. CONCLUSIONS: CMV disease was a significant cause of early graft dysfunction, whereas the presence of chronic allograft nephropathy was the main determinant of poor long-term graft function. The role of viral infections in chronic allograft nephropathy deserves further investigation.     

Post-transplant renal function in the first year predicts long-term kidney transplant survival

BACKGROUND: Improvements in long-term kidney graft survival have been recently noted. However, the reasons for this were unclear. This study examined post-transplant renal function within the first year as an independent variable influencing long-term survival. METHODS: The influence of demographic characteristics (age, sex, race); transplant variables (cadaver versus living donor, cold ischemia time, HLA mismatching, delayed graft function and transplant year), and post-transplant variables (immunosuppressive agents for the prevention of acute rejection, clinical acute rejection and post-transplant renal function in the first year) on graft survival were analyzed for 105,742 adult renal transplants between 1988 and 1998. Renal function in the first year was expressed as serum creatinine at six months and one year and delta creatinine (change in serum creatinine between 6 months and 1 year). Graft half-life was used to measure long-term survival. RESULTS: During this 11-year period, the one-year serum creatinine values for cadaver recipients steadily improved, from 1.82 +/- 0.82 mg/dL in 1988 to 1.67 +/- 0.82 mg/dL in 1998 (P < 0.001), as did the graft half-life. There was a progressive decline in graft half-life for each incremental increase of six month, one year and Delta creatinine for living and cadaver donor transplants as well for cadaver transplants with donor age > and < or =50 years. The Relative Hazard (RH) for graft failure was 1.63 (1.61, 1.65; P < 0.0001) with each increment of 1.0 mg/dL of serum creatinine at one year post-transplant and it increased to 2.26 (2.2, 2.31; P < 0.0001) when the Delta creatinine was 0.5 mg/dL. The RH reduction for graft failure was substantially lower for the years 1993, 1996, 1997 and 1998 when post-transplant renal function was not included in the model (P < 0.05). However, the RH reduction per year was not different when post-transplant creatinine was included in the model, 1.01 (0.94 to 1.05; P = 0.89). CONCLUSION: In conclusion, one-year creatinine and Delta creatinine values predict long-term renal graft survival. Recent improvements in graft half-life are related to conservation of renal function within the first year post-transplantation.     

Failure of ganciclovir prophylaxis to completely eradicate CMV disease in renal transplant recipients treated with intense anti-rejection immunotherapy

Ganciclovir prophylactic regimens have been shown to be effective in renal transplant recipients at risk for primary (donor seropositive/recipient seronegative) and secondary (recipient seropositive) cytomegalovirus (CMV) disease. However, in addition to serologic factors, the type and intensity of the administered immunosuppression is a strong risk factor for CMV disease. Since January 1995, we have utilized a potent immunosuppressive protocol selectively in recipients at high risk for immunologic graft loss, defined as retransplant recipients, recipients with delayed graft function, non-Caucasian recipients, and recipients suffering from acute rejection. Between January 1995 and December 1996, 110 consecutive renal transplants were performed in recipients who were either CMV seropositive or received an allograft from a CMV-seropositive donor. All recipients received ganciclovir prophylactic therapy for 3 months post-transplant. Group I (N = 43) consisted of recipients at high-immunologic risk for graft loss as defined above. These recipients were treated with an intense anti-rejection immunotherapeutic regimen consisting of Cellcept, Neoral, and prednisone, with the frequent addition of antilymphocyte antibody therapies and intravenous methylprednisolone. The remaining 67 recipients (group II) were treated with a less intense immunotherapeutic regimen consisting of azathioprine, Neoral, and prednisone. The incidence and severity of CMV disease and the patient and allograft survival were compared. The incidence of CMV syndrome was greater in group I (28%) compared with group II (7%), and was statistically significant (p < 0.05). The 1-yr patient and graft survival were similar, 95 and 91%, respectively, for group I compared with 97 and 97%, respectively, for group II. These data suggest that 3 months of ganciclovir prophylactic therapy is significantly less effective for the prevention of CMV disease in renal transplant recipients at high risk for acute rejection treated with an intense immunotherapeutic regimen. These data suggest that more effective prevention of CMV disease in these high-risk recipients will require the addition of other anti-viral agents, such as immunoglobulin preparation to the prophylactic regimen.     

Effect of donor/recipient body weight mismatch on patient and graft outcome in living-donor kidney transplantation

BACKGROUND/AIMS: There have been conflicting reports showing that kidneys from small donors may be at risk for graft loss if they are transplanted into large recipients. The aim of this work was to examine the donor/recipient body weight ratio (D/RBWR) on patient and graft outcome. METHODS: During the period from January 1990 to January 2002, 856 kidney transplants were performed. Of these, 776 kidney transplant recipients were selected after exclusion of pediatric, second transplant patients and those with a body mass index of 35. All patients achieved a minimum follow-up of 1-year. According to D/RBWR, patients were divided into 3 groups: low (0.9), medium (0.91-1.2) and high (1.2). Data were collected on graft function, acute and chronic rejection, post-transplant complications, and 1- and 5-year graft and patient survival. RESULTS: There was a statistically significant increase in the incidence of chronic rejection, post-transplant hypertension and diabetes mellitus in the low group. The incidence and frequency of acute rejection episodes were nearly the same in the 3 groups. Graft function, estimated by serum creatinine at 1 year, was significantly lower in the low group. The 5-year graft and patient survival was 71, 80, 88 and 81, 85 and 92%, in the low, medium and high groups, respectively. CONCLUSIONS: We conclude that a low D/RBWR may contribute to inferior long-term renal allograft survival. The hyperfiltration hypothesis due to low nephron mass in the low D/RBWR group may explain these findings.     

Effect of acute rejection episode on occurrence of chronic rejection after kidney transplantation

Chronic rejection is the most prevalent cause of renal transplant failure in the late post-transplant period. The clinical significance of acute rejection episodes on occurrence of chronic rejection is controversial. We analyzed 503 cases of the first renal transplantation maintained by calcinurine inhibitor for the correlation of acute rejection and clinical chronic rejection. The later the first episode of acute rejection occurred, the shorter was the half-life of graft. The acute rejection occurring within 3 post-transplant months worsens long-term graft survival if the peak creatinine level exceeds 2 mg/dl. Multivariate analysis by the Cox proportional hazard model for factors affecting cadaver graft loss by chronic rejection, revealed that the risk factor of acute early rejection was lower than those of donor age and post-transplant hypertension.     

Stable kidney function in the second decade after kidney transplantation while on cyclosporine-based immunosuppression

BACKGROUND: Calcineurin inhibitors (CNIs) have been the mainstay of immunosuppressive protocols in kidney transplantation over the past 20 years. However, in some recipients, the adverse effects of CNIs contribute to chronic allograft nephropathy and death with function--the two leading causes of late graft loss. Other recipients maintain stable graft function. METHODS: We studied the impact of continuing CNI-based immunosuppression in the second decade after kidney transplantation. From 1984 through 1996, a total of 1,263 patients underwent a primary kidney transplant at the University of Minnesota and received cyclosporine-based immunosuppression. Antibody induction was used only in deceased donor recipients. RESULTS: The actuarial 20-year patient survival rate was 38%; graft survival, 30%; and death-censored graft survival, 60%. The annual mean serum creatinine level for recipients whose grafts survived > or =1 year remained stable, although recipients with a history of > or =1 acute rejection episode had a higher serum creatinine level vs. recipients who were rejection-free. The annual mean calculated creatinine clearance was also stable over time. In addition, for recipients who were acute rejection-free, chronic allograft nephropathy/chronic rejection was only responsible for 9% of graft losses. CONCLUSIONS: Our study suggests that some kidney transplant recipients tolerate long-term CNI-based immunosuppression with stable creatinine levels. Identifying certain recipients' predisposition to CNI toxicity and individualizing immunosuppressive therapy may be important in order to improve long-term kidney function, while simultaneously preserving low short-term acute rejection rates.     

Peritubular capillary C4d staining in late acute renal allograft rejection – is it relevant?

Abstract: Background: In the early post-transplant period, renal allograft rejection with diffuse peritubular capillary (PTC) C4d deposition predicts poor graft survival. In the late post-transplant setting, that is, one or more yr after transplantation, the implication of diffuse PTC C4d deposition is still a topic of debate. The purpose of our study was to see if diffuse PTC C4d deposition, in late acute rejection (LAR), occurring more than one yr post-transplant, has any impact on graft survival and function. Methods: We selected cases, both cadaveric as well as living donor renal transplant recipients, in whom acute rejection with PTC C4d deposition was first detected after the first year post-transplant. Recipients with multiple acute rejection episodes during the first year post-transplant were excluded from the study. The first biopsy diagnosed with LAR was considered the index biopsy (n = 40). We formed two groups: group 1, C4d-positive LAR (n = 20), and group 2, C4d-negative LAR (n = 20). Groups were matched for maintenance and post-rejection immunosuppressive therapy, baseline serum creatinine levels before the time of the index biopsy, time from transplant to index biopsy, as well as chronic allograft damage index (CADI) score in the index biopsies. We compared the rate of graft loss, and the graft function of the surviving grafts at the end of the study period, as well as histologic parameters in the index biopsy specimens between the two groups. The mean follow-up period was 20 months. Results: No significant differences in the rate of graft loss or graft function were found between groups 1 and 2 at the end of the follow-up period. Histologically, PTC margination and transplant glomerulopathy were more common in the C4d-positive group, and this difference was statistically significant. There was no statistically significant difference in the degree of plasma cell infiltrates. Conclusions: Unlike in the acute setting, the presence or absence of PTC C4d staining in renal allografts with LAR may not have a predictive value regarding graft outcome.     

Concentration-controlled use of sirolimus associated with reduced exposure of cyclosporine in black recipients of primarily living renal allograft donors: 12-month results

AIM: This study was designed to identify optimal therapeutic sirolimus (SRL) concentrations in black kidney transplant recipients on reduced cyclosporine (CsA) exposure and prednisone. METHODS: Seventy patients (64 living/six deceased) received CsA (8-10 mg/kg/d), prednisone, and 15 mg loading dose followed by 5-mg fixed doses of SRL till day 7 when they were randomized to maintain SRL trough concentrations (high-performance liquid chromatography) of 8-12 (GI = 34) or 15-20 (GII = 36) ng/mL. RESULTS: Mean CsA concentrations were 109 +/- 53 vs. 89 +/- 41 ng/mL and 75 +/- 54 vs. 60 +/- 35 ng/mL (ns) at 2 and 6 months. Accordingly, mean SRL trough concentrations were 12.4 +/- 6.1 vs. 20.0 +/- 9.5 ng/mL (p < 0.001) and 10.8 +/- 5.8 vs. 18.0 +/- 6.1 ng/mL (p < 0.001). The incidence of biopsy-proven acute rejection [13% (GI: 18% vs. GII: 8%, ns)], graft loss or death was 16% (GI: 21% vs. GII: 11%, ns]. There were no deaths and three graft losses (GI = 1; GII = 2). Creatinine clearance was higher in GI (64.5 +/- 17 vs. 54.4 +/- 14.7 mL/min, p = 0.011). The incidence of post-transplant diabetes mellitus was 13% and no CMV disease was observed. CONCLUSION: In black recipients of primarily living renal allograft donors reduced CsA exposure and SRL concentration-controlled regimens produced low incidences of acute rejection, post-transplant diabetes mellitus and CMV disease, with no significant impairment in graft function.     

Serum levels of macrophage-colony stimulating factor (M-CSF): a marker of kidney allograft rejection.

BACKGROUND: Macrophage-colony stimulating factor (M-CSF) is the principal factor for survival of monocytes and macrophages that play an important role in allograft rejection. We studied M-CSF serum levels during successful renal transplantation and acute graft rejection. METHODS: A total of 114 kidney allograft recipients were assessed for M-CSF levels by enzyme-linked immunosorbent assay (ELISA). RESULTS: M-CSF serum levels were elevated in pre-transplant haemodialysis patients (611+/-355 IU/ml vs 168+/-61 in normal controls, P<0.01). Following successful renal transplantation, M-CSF decreased in the first month, stabilizing at 257+/-222 IU/ml (not significantly different from normal controls) in 52 post-transplant stable patients. There was no correlation between M-CSF level and creatinine clearance. M-CSF levels increased significantly (2-5 times) during biopsy-proven acute rejection episodes in 20 of 25 patients. All rejection episodes were successfully treated and serum M-CSF decreased rapidly to pre-rejection levels in 17/20 patients. In contrast, in five patients with cyclosporin toxicity and four patients with other causes of allograft dysfunction, M-CSF serum levels did not change. CONCLUSIONS: M-CSF serum level might be a specific marker of acute rejection. The source of increased production during rejection warrants further investigation, with infiltrating T cells and resident kidney cells being likely candidates.     

Safety and efficacy of steroid withdrawal two days after kidney transplantation: analysis of results at three years

BACKGROUND: Chronic steroid therapy in spite of myriad side effects is widely used in kidney transplantation. This prospective controlled study evaluated safety and efficacy of steroid withdrawal at 2 days in kidney recipients monitored by surveillance biopsy. METHODS: In all, 300 kidney recipients were studied; 150 in second-day steroid withdrawal group and 150 in steroid treated group (control group). Immunosuppression was basiliximab induction and maintenance was a calcineurin inhibitor and mycophenolate mofetil or sirolimus. Biopsy-proven acute rejection (BPAR) was treated by methylpredisolone. Surveillance biopsies were completed to evaluate subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Primary end point was acute rejection. Three-year patient and graft survival, new onset diabetes mellitus (NODM), serum creatinine and creatinine clearance were evaluated. RESULTS: Acute rejection was diagnosed in 14% in control group and 16% in steroid withdrawal group. Three-year patient and graft survival was 89% and 79% in control and 91% and 78% in steroid withdrawal group. Serum creatinine and creatinine clearance was 1.9+/-0.8 and 59+/-11 in control group and 1.8+/-0.9 mg/dl and 61+/-10 mls/minute in steroid withdrawal group. Incidence of SCAR and progression of CAN were comparable in the 2 groups. At 3-years NODM was diagnosed in 21% in control group and 4% in steroid withdrawal group (P<0.01). CONCLUSIONS: Two-day steroid withdrawal in kidney transplant recipients did not affect BPAR, SCAR, CAN, graft function and patient and graft survival compared to control group up to 3 years. NODM was significantly less in steroid withdrawal group. Two-day steroid withdrawal is safe and beneficial in kidney transplant recipients.     

The Relationship Between Donor Age and Cadaveric Renal Allograft Survival Is Modified by the Recipient''s Blood Pressure

Increasing donor age correlates with reduced renal allograft survival. In this study we analyzed variables that may modify this relationship. The study included 1285 cadaveric kidney allograft recipients followed for 7.2 + 4.5 years. By Cox, increasing donor age beyond 30 years was associated with significant increases in the hazard ratio for graft loss [age 31-46, hazard ratio (HR) = 1.4, p = 0.02; 46-60, HR = 1.55, p = 0.008; > 60, HR = 1.68, p = 0.03]. Increasing donor age was significantly associated with: older and heavier recipients; higher creatinine and blood pressure (BP) 6 months post-transplant; and lower total cyclosporine dose during the first year. Of interest, the 6-month serum creatinine and the BP level modified significantly the relationship between age and survival. Thus, increasing donor age was significantly related to reduced graft survival only in patients with a 6-month creatinine < 2 mg/dL. Furthermore, donor age related significantly to graft survival only among patients with higher BP levels 6 month post transplant. It is concluded that increasing donor age is associated with reduced cadaveric graft survival, but that relationship is significantly modified by graft function and BP. These data suggest that poorly functioning kidneys have reduced survival irrespective of age. Furthermore, elevated BP levels may have a particularly negative effect on the survival of older grafts.     

Reduced-exposure cyclosporine is safe and efficacious in de novo renal transplant recipients treated with enteric-coated mycophenolic acid and basiliximab

BACKGROUND: The lower limit of exposure to calcineurin inhibitors has not yet been established in de novo renal transplant patients receiving mycophenolic acid therapy with basiliximab. METHODS: A 12-month, multicenter, randomized, open-label trial was carried out in which de novo renal transplant patients received enteric-coated mycophenolate sodium, cyclosporine microemulsion, steroids and basiliximab. Patients were randomized to receive standard-exposure (n = 45) or reduced-exposure (n = 44) cyclosporine, based on differing C2 target ranges, after the first month post-transplant. RESULTS: Cyclosporine exposure gradually increased over the first month and was lower than previously recommended. Mean calculated creatinine clearance (primary end-point) was similar in the standard-exposure and reduced-exposure groups at month 6 (55.3+/-3.2 ml/min and 61.5+/-3.7 ml/min respectively, n.s.). There were 4 deaths but no death-censored graft losses, resulting in 95.5% patient and graft survival at one year in both groups. At 6 and 12 months, the incidence of biopsy-proven acute rejection was 17.8% and 17.8% in the standard-exposure group, and 13.6% and 15.9% in the reduced-exposure group. Adverse events were similar between treatment groups. Exploratory analyses could not identify a lower limit for the optimal CsA exposure range, but results suggested that high exposure at one year was associated with deteriorating renal function. CONCLUSIONS: These results indicate that enteric-coated mycophenolate sodium with reduced-exposure cyclosporine, steroids and basiliximab induction has an excellent therapeutic effect and is safe in de novo kidney transplant recipients. Lower C2 targets than previously recommended, particularly early post-transplant, do not appear to be associated with compromised efficacy.     

Acute rejection and cardiac allograft vascular disease is reduced by suppression of subclinical cytomegalovirus infection

BACKGROUND: Anticytomegalovirus (CMV) prophylaxis prevents the acute disease but its impact on subclinical infection and allograft outcome is unknown. We sought to determine whether CMV prophylaxis administered for three months after heart transplant would improve patient outcomes. METHODS: This prospective cohort study of 66 heart transplant recipients compared aggressive CMV prophylaxis (n = 21, CMV hyperimmune globulin [CMVIG] plus four weeks of intravenous ganciclovir followed by two months of valganciclovir); with standard prophylaxis (n = 45, intravenous ganciclovir for four weeks). Prophylaxis was based on pretransplant donor (D) and recipient (R) CMV serology: R-/D+ received aggressive prophylaxis; R+ received standard prophylaxis. Outcome measures were: CMV infection assessed by DNA-polymerase chain reaction on peripheral blood polymorphonuclear leukocytes, acute rejection, and cardiac allograft vascular disease (CAV) assessed by intravascular ultrasound. All patients completed one year of follow-up. RESULTS.: CMV infection was subclinical in all but four patients (two in each group). Aggressively treated patients had a lower incidence of CMV infection (73 +/- 10% vs. 94 +/- 4%; P = 0.038), and an independent reduced relative risk for acute rejection graded > or =3A (relative risk [95% CI] = 0.55 [0.26-0.96]; P = 0.03), as compared with the standard prophylaxis group. Aggressively prophylaxed patients also showed a slower progression of CAV, in terms of coronary artery lumen loss (lumen volume change=-21 +/- 13% vs. -10+/-14%; P = 0.05); and vessel shrinkage (vessel volume change = -15 +/- 11% vs. -3 +/- 18%; P = 0.03). CONCLUSIONS: Prolonged (val)ganciclovir plus CMVIG reduces viral levels, acute rejection, and allograft vascular disease, suggesting a role for chronic subclinical infection in the pathophysiology of the most common diseases affecting heart transplant recipients.