Tuberculosis in renal transplant recipients

BACKGROUND: Tuberculosis is an important cause of morbidity and mortality in renal transplant recipients, but there are insufficient data regarding the efficacy and complications of therapy and of INH prophylaxis. METHODS: This study is a retrospective review of the records of 880 renal transplant recipients in two centers in Turkey. RESULTS: Tuberculosis developed in 36 patients (4.1%) at posttransplant 3-111 months, of which 28 were successfully treated. Eight patients (22.2%) died of tuberculosis or complications of anti-tuberculosis therapy. Use of rifampin necessitated a mean of 2-fold increase in the cyclosporine dose, but no allograft rejection occurred due to inadequate cyclosporine levels. Hepatotoxicity developed in eight patients during treatment, two of whom died due to hepatic failure. No risk factor, including age, gender, renal dysfunction, hepatitis C, or past hepatitis B infection, was found to be associated with development of hepatic toxicity. A subgroup of 36 patients with a past history of or radiographic findings suggesting inactive tuberculosis, was considered to be at high risk for developing active disease, of whom 23 were given isoniazid (INH) prophylaxis. None versus 1 of 13 (7.7%) of cases with and without INH prophylaxis, respectively, developed active disease (P>0.05). None of the patients receiving INH had hepatic toxicity or needed modification of cyclosporine dose. CONCLUSIONS: These data show that tuberculosis has a high prevalence in transplant recipients, that it can effectively be treated using rifampin-containing antituberculosis drugs with a close follow-up of serum cyclosporine levels, and that INH prophylaxis is safe but more experience is needed to define the target population.     

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.     

Effect of prophylaxis with low-dose anti-thymocyte globulin on prevention of acute kidney allograft rejection

INTRODUCTION: During kidney transplantation, the first contact between the recipient's immune system and the donor organ takes place immediately following the arterial anastomosis. The aim of this study was to evaluate the efficacy of a single, low-dose anti-thymocyte globulin (ATG) prophylaxis in the reduction of early acute rejection in renal allograft recipients. METHODS: In a randomized, controlled clinical trial, we studied the rate of acute rejection within the first month of kidney transplantation in patients who had received their transplant at a single center between the years 2004 and 2007. The patients were divided into 2 groups: group 1 (n = 37) received cyclosporine, mycophenolate mofetil or azathioprine, and prednisolone; group 2 (n = 31) received the above-mentioned agents plus a single ATG bolus (Thymoglobulin; SangStat, Lyon, France; 4-5 mg/kg) the night before the transplantation ( approximately 12 hours before the operation). Blood urea and serum creatinine levels were measured regularly in the posttransplantation period. Acute allograft rejection was justified clinically and/or pathologically. Statistical analysis was performed by SPSS 13.0 using Student t test and Fisher exact test. A P value < or = .05 was considered to indicate statistical significance. RESULTS: There were no significant differences regarding the age and gender ratio between the 2 groups. Acute allograft rejection was found in 32.4% (n = 12) of group 1 patients, and was reduced to 12.9% (n = 4) in group 2 (P = .05). Hence, the first-month acute rejection episodes decreased by approximately 60% with ATG prophylaxis in renal transplant recipients. CONCLUSION: Prophylactic administration of a single and low-dose ATG the night before kidney transplantation could reduce the risk of acute allograft rejection in renal transplant recipients. However, further studies with a greater number of patients should be conducted to confirm these results.     

Prospective randomised trial of isoniazid prophylaxis in renal transplant recipient

Renal transplantation (RT) recipients are at a high risk of developing tuberculosis (TB) following transplantation. Effectiveness of isoniazid (INH) in preventing TB is well documented in immunocompetent as well as immunocompromised persons. There is paucity of data on role of INH prophylaxis in RT recipients. Thus, a prospective randomised trial of INH in RT recipients was carried out to determine the efficacy of daily INH monotherapy in the prevention of TB in these patients. Patients of end stage renal disease (ESRD) taken for RT formed the subjects of study. Patients with active TB and active hepatitis at the time of RT were excluded from the study. Patients were randomised to receive INH 300 mg with pyridoxine 20 mg daily from the day of RT. The duration of the treatment was planned for 1 year or till the development of TB, which ever was earlier. Between October 1998 and September 2000, 114 RT were done at our hospital. Of these, 24 (21%) patients had active TB at the time of RT and thus were excluded. Patients included were randomised with 1:2 ratio of treatment and control group. Of the 90 patients thus enrolled, 30 were randomised in treatment group and 60 in control group. Of the included patients five patients had very early graft loss (three in treatment and two in control group) within days and thus excluded from the analysis. Three of the 27 (11.1%) patients in treatment group and 15 (25.8%) in control group developed TB (P = 0.10). The risk ratio of (RR) of INH versus control group of TB was 0.36 (95% CI, 0.10–1.32) but the difference was not statistically significant (P = 0.12). Only one patient developed INH induced hepatitis. In conclusion, with INH prophylaxis, there was a trend towards protection from TB, though it was not statistically significant. Further, all patients tolerated INH and hepatotoxicity was not a major problem in this group of patients.     

Tuberculosis in renal transplants in Rio de Janeiro

Retrospective analysis of 982 renal transplants over 21 years (1981 to 2002) sought to evaluate the prevalence of tuberculosis (TB). This analysis included 74 patients: 30 with a past TB history, who had INH prophylaxis since the beginning of immunosuppression, and 44 who only became TB infected after receiving transplants. The diagnosis of TB was made by a compatible medical situation with bacteriological/histological confirmation, which when not possible, underwent a therapeutic test occur. The average time for the illness to surge was 3 years. The mortality rate was 34.9% (15/44). Patients with hepatitis C were more affected. Among those who used INH prophylaxis only one contracted TB, showing that the drug displayed a protection rate of 96.6% (29/30).     

Mycobacterium tuberculosis infection in renal transplant recipients

Mycobacterium tuberculosis (TB) infection is more common among renal allograft recipients compared with the general population due to immunosuppression. The epidemiological risk in a country is an important determinant of transplant TB after transplantation. We retrospectively analyzed 283 renal transplant recipients who underwent renal transplantation between 1990 and 2004. We evaluated the incidence, patient and disease characteristics, prognosis, and outcome of TB infection. Tuberculosis developed in 10 (seven men and three women of mean age of 41+/-9 years) among 283 patients (3.1%). All patients were culture-positive for M tuberculosis. Although pulmonary TB was the most common presentation in the general population, 50% of patients in the study group developed extrapulmonary TB. The mean elapsed time from renal transplantation was 38 months. Three patients (1%) developed TB in the first year after transplantation. All patients were treated with a quartet of anti-TB therapy. One patient developed isoniazid-related reversible hepatotoxicity. No acute allograft rejection occurred during the anti-TB therapy. Two patients (20%) with pulmonary TB died due to dissemination of the disease. In conclusion, extrapulmonary presentations of TB are more common among renal transplant recipients with the increased risk of mortality.     

Impact of mycophenolate mofetil on recurrent rejection in kidney transplant patients

PURPOSE: Mycophenolate mofetil (MMF) has emerged as a valuable adjunctive agent in renal transplantation. However, due to intolerable adverse effects associated with MMF use in our transplant population, we have used MMF selectively in patients at high risk for recurrent graft rejection, since these patients are known to be at risk for poor long-term graft outcomes. The purpose of this study was to assess the efficacy of MMF in preventing the recurrence of acute rejection following an initial rejection episode in kidney transplant patients in the first year following transplantation. METHODS: Forty-four kidney transplant recipients were given MMF prospectively following treatment of their initial rejection episode to prevent recurrent rejection. MMF 1-2 g/d was given. Doses were adjusted based on tolerance; MMF therapy was to be continued for at least 6 months. The control group consisted of 124 consecutive kidney transplant recipients who had received standard anti-rejection therapy without the addition of MMF. Maintenance immunosuppression consisted predominantly of cyclosporine, prednisone+/-azathioprine. Anti-rejection therapy for both groups consisted of either corticosteroids (methylprednisolone 500 mg i.v. for 3 d or oral prednisone 2 mg/kg/d with rapid taper over 3 wk), OKT3 5 mg/d for 10 d or ATG 15 mg/kg/d for 10 d. All rejection episodes were confirmed by biopsy. RESULTS: The majority of rejection episodes were characterized histologically as mild or moderate. Most patients (76%) received corticosteroids for treatment of their first rejection episode. There was a 68% reduction in the incidence of recurrent rejection episodes within the first year of transplant in patients receiving MMF; only 14% of recipients receiving MMF developed recurrent rejection compared to 44% of patients in the control group (p<0.05). Approximately 50% of patients developed MMF-associated adverse effects (leukopenia, GI toxicity). Only 52% of patients remained on MMF at 6 months. One-yr graft survival was 86% in the MMF group and 89% in the control group (p>0.05). One-year patient survival was 93 and 100%, respectively (p>0.05). CONCLUSIONS: The addition of MMF to maintenance therapy for patients experiencing acute renal allograft rejection may prevent recurrent rejection episodes in the subsequent follow-up year.     

Mycobacterium tuberculosis infection in solid organ transplant recipients: experience from a single center in China

OBJECTIVE: We sought to explore the prevalence, clinical manifestations, diagnostic procedures, and treatment of tuberculosis (TB) after solid organ transplantation. PATIENTS AND METHODS: In this study, we retrospectively analyzed data of 1947 renal transplant recipients and 85 liver transplant recipients. RESULTS: TB developed in 28 organ transplant recipients with a prevalence of 1.38% (28/2032). The median interval between transplantation and development of TB was 32 months (range, 1-142 months). Mycobacterium tuberculosis isolation, histologic signs of caseating granulomas, and TB-DNA detection directly supported the diagnosis in 10 (35.71%), 7 (25.00%), and 5 (17.86%) patients, respectively. In addition, 6 patients (21.43%) highly suspected of TB infection received tentative antituberculosis treatment with favorable responses. Most renal transplant recipients (22/25; 78.57%) received isoniazid, rifampicin (or rifabutin), and ethambutal (or pyrazinamide) for a mean duration of 10 months (range, 6-14 months). Three liver transplant recipients received a different protocol: isoniazid, rifabutin, ethambutal, and ofloxacin for 3 months; then isoniazid and rifabutin for 6 months. Upon follow-up, 8 subjects (28.57%) died; 5 of the deaths were related to TB. During the antituberculosis therapy, toxic hepatitis was seen in 12 patients (42.86%); cyclosporine levels decreased in 15 patients (53.57%); and allograft rejection developed in 6 of them. CONCLUSIONS: The peak incidences of TB in liver and kidney transplantations are in the first year and after the first year posttransplantation, respectively. Response to antituberculosis treatment should be considered to make a diagnosis among patients highly suspected of TB infections. Except in special circumstances, antituberculosis treatment protocols including isoniazid and rifampicin for about 10 months seem significantly effective and tolerable for non-liver transplant patients. Fluoroquinolones should be emphasized in posttransplantation TB treatment.     

Tuberculosis in Renal Transplant Recipients: A Brazilian Center Registry

Renal transplant recipients receiving immunosuppression show an increased risk for developing opportunistic infections, such as tuberculosis (TB). TB represents the major cause of morbidity and mortality in the world, mainly in underdeveloped countries. The aim of this study was to analyze the incidence of TB and its presentation among renal transplant recipients over 20 years.

Patients and Methods

This retrospective analysis included medical records of renal transplant recipients from January 1984 to April 2007.

Results

Among 1342 renal transplant recipients, 31 received treatment for TB due to clinical disease (n = 23) or prophylaxis (n = 8). The overall incidence of TB was 1.71%, which was diagnosed at 53 ± 49 months posttransplantation. The indications for TB prophylaxis were a previous history of TB (n = 6) or direct contact with a TB carrier (n = 1). The most common clinical presentation was extrapulmonary (n = 13). The classical treatment was effective in 16 cases. However, 7 cases of resistant TB required ethambutol added to therapy. Adverse events of treatment included liver toxicity (n = 1) and peripheral neuropathy (n = 1). Three patients died due to TB-related complications. Graft loss was observed in 3 patients after cessation of TB treatment. None of the patients on prophylaxis developed clinical disease.

Conclusions

TB incidence was significantly greater among renal transplant recipients compared with the local population, with a higher incidence of extrapulmonary disease. TB prophylaxis in selected cases was effective, avoiding new infections.     

Use of simulect can reduce the incidence of acute rejection and demonstrates with superior 3-year patient and graft survival rates in renal transplantation

Background

Acute rejection is a major cause of graft loss in renal transplantation. Because the highest risk for acute rejection is in the first month posttransplantation, improved prophylaxis could be most beneficial in this period. Simulect administration provides 30 to 45 days of immunoprophylaxis against acute rejection during the critical period after transplantation.

Objectives

We sought to assess the incidence of acute rejection episodes and the safety and tolerability of Simulect plus Neoral immunosuppression. Patient and graft survival rates up to 3 years posttransplantation were evaluated.

Method

Forty-one transplant recipients received Simulect by intravenous infusion of an initial 20-mg dose on the day of renal transplantation and a second 20-mg dose on day 4 posttransplant. All renal recipients received immunosuppression with Neoral and steroid.

Results

There were eight cases (19.5%) of acute rejection within 1 year. The rejection episodes were easily reversed with steroid pulse therapy in seven patients except for graft loss. The 1-, 2-, and 3-year graft survival rates were 95%, 93%, and 88%, respectively. Overall, the 3-year patient survival rate was 100%.

Conclusions

Simulect in combination with Neoral and steroid-reduced the incidence of acute rejection without an increase in adverse events. The low incidence and severity of acute rejection may have led to the superior 3-year patient and graft survival rates in renal transplantation.     

Tuberculosis in Egyptian kidney transplant recipients: study of clinical course and outcome

BACKGROUND: Tuberculosis (TB) is an important infection encountered post-transplantation especially in developing countries, with high incidences of morbidity and mortality. In this report, we study the risk factors and impact of TB on the outcome of kidney transplantation. METHODS: Of 1200 live-donor Egyptian kidney transplantations, 45 (3.8%) patients developed post-transplant TB. Of these, five had had TB pre-transplantation and 40 were male. The mean age was 32.6 +/- 10.5 years. Primary immunosuppression treatment for 39 (86.7%) patients was cyclosporine (CsA). RESULTS: The mean time interval between transplantation and TB diagnosis was 49.8 +/- 41.5 (range 2-180) months. In 86.7% of patients, TB was diagnosed one year post-transplantation. Urinary TB was the most common form (53%), while pleuropulmonary TB accounted for 38%. All post-transplant TB patients received a triple anti-tuberculous therapy (rifampicin, ethambutol and INH) with a favorable response in all but two patients who needed another 24-month course. Hepatotoxicity was seen in 11 patients, eight were mild with normalization after temporary withdrawal of rifampicin, and three cases were severe, but mortality was not attributable to hepatocellular failure. Twelve patients died, 11 of them due to unrelated causes. Chronic rejection occurred in more than half of the patients (55.6%), of whom 24 (96%) were CsA-treated, which can be attributed to rifampicin/CsA interaction. More than 35% of TB patients lost their graft as a result. Pre-transplant tuberculosis patients had a comparable post-transplant course. CONCLUSIONS: TB is a common infection in renal transplant recipients with a peak incidence occurring one year post-transplant. Chronic rejection is a serious complication that had a negative impact on the graft survival, especially in CsA-treated recipients. INH prophylaxis is safe in pre-transplant TB. The post-transplantation outcome in the pre-transplant tuberculosis patients is no different from non-TB patients.     

Challenge of tuberculosis in renal transplantation

There is very high incidence of tuberculosis (TB) in dialysis and renal transplant (RT) recipients in developing countries. Clinical manifestation of TB may be atypical or obscure in initial stages. Common clinical abnormalities include pyrexia, pulmonary infiltrates, exudative pleural effusion, and exudative ascites. Aggressive investigations must be done in patients with pyrexia, pulmonary abnormalities, scanty sputum, and weight loss. BAL and computed tomography (CT) scan of the chest should be done in such cases. Tuberculin skin test is not helpful in the majority of patients. New blood tests to quantitate PPD reactivity in vivo and tests to distinguish between latent M tuberculosis infection from BCG-induced reactivity have been devised recently. Side effects of anti-TB drugs, especially hepatitis, need close observation because of the frequent occurrence of viral hepatitis in such cases. Tests to confirm latent TB are desirable before starting chemoprophylaxis in RT recipients. INH prophylaxis cannot be recommended universally in all RT recipients.     

OKT3 treatment of steroid-resistant renal allograft rejection

The monoclonal antibody, Orthoclone OKT3 (OKT3), has been used with great efficacy in a prospective multicenter trial as therapy for first rejection episodes in cadaveric donor (CD) renal allograft recipients treated with azathioprine (AZA) and prednisone (P). However, although almost all rejection episodes were reversed, recurrent rejection occurred in approximately two-thirds of OKT3-treated patients in this earlier trial; infections also occurred in about two-thirds of patients, often related to the additional immunosuppression necessary to reverse the rerejection episodes. In the current series of patients, OKT3 was used to treat rejection in CD renal graft recipients in a protocol differing from the multicenter trial in two respects: baseline immunosuppression was cyclosporine (CsA) and P or CsA, AZA, and P (probably more potent immunosuppressive combinations than the AZA and P in the multicenter trial); and OKT3 treatment was reserved for rejection episodes resistant to 3 bolus infusions of methylprednisolone (MP), 5-10 mg/kg, rather than as primary therapy for first rejection episodes. Using this protocol, 46 of 74 rejection episodes (62%) diagnosed between 3/85 and 3/86 in CD renal allograft recipients were treated successfully with MP. Of the remaining 28 steroid-resistant rejection episodes, 27 (96%) were reversed with a 7-14-day course of OKT3, 5 mg/day. Only 5 recurrent rejection episodes (19%) have been observed in the 2-14-month follow-up period after OKT3 treatment; infections have occurred in 10 patients (36%), and three grafts (11%) have been lost in OKT3 treated patients. These results suggest that recurrent rejection and subsequent infection after OKT3 is used to treat rejection may be reduced in a protocol where CD renal allograft recipients are treated with baseline immunosuppression regimens including CsA and where OKT3 is reserved for steroid-resistant rejection. This approach appears to be both more cost-effective than, and as effective therapeutically as, treating all first rejection episodes with the monoclonal antibody.     

Successful renal transplantation in high-risk small children with a completely thrombosed inferior vena cava

BACKGROUND: Inferior vena cava (IVC) thrombosis is generally a contraindication to renal transplantation in small children because of the technical difficulty and limitations in allograft venous outflow drainage that risk graft thrombosis. METHODS: The records of six consecutive children (9.9-27.4 kg) with end-stage renal disease and thrombosed IVCs were reviewed. Small deceased donor renal allografts were utilized in all cases where immediate posttransplant venous renal outflow would theoretically not exceed the drainage capacity of the iliac or adjacent pelvic collateral veins. RESULTS: There is 100% patient survival with two patients returning to dialysis at seven and three years posttransplantation. There were no surgical complications or delayed graft function. Postoperatively, progressive renal vein and simultaneous iliac venous enlargement was observed in five of six recipients concomitant with renal allograft enlargement. In these patients, maximum renal volume achieved was between 152 and 275 ml and last recorded Schwartz glomerular filtration rates ranged from 67 to 118 ml/min. The sixth allograft had an early, severe rejection episode that limited renal growth and attainment of good renal function. All patients demonstrated resumption of growth rates commensurate with age but without significant catch-up growth. CONCLUSION: A small deceased donor kidney can provide freedom from dialysis and better quality of life for small children with IVC thrombosis during an age when dialysis treatment is difficult and the complications of the thrombosed IVC may compromise life. Good renal function was attained in patients without rejection episodes. In those with rejection, our approach allowed for patient growth during allograft function, providing a bridge for a repeat transplant.     

Posttransplant tubulointerstitial nephritis: clinicopathological correlation

As a cause of graft dysfunction, tubulointerstitial nephritis (TIN) seems to be the third most common pathology after rejection and cyclosporine nephrotoxicity. Among 540 needle biopsies obtained from 280 renal transplant patients between 1996 and 1999, acute TIN was detected in 23 patients (8%). The cause of acute TIN was secondary to bacterial infection in 17 patients and secondary to cytomegalovirus (CMV) infection in three patients. The remaining three cases showed granulomatous pyelonephritis due to Mycobacterium tuberculosis (n = 2) and Candida albicans (n = 1). During follow-up, 13 of 23 patients (56.5%) showed at least one acute rejection episode. The average number of urinary tract infection (UTI) episodes in the 23 patients was 1.4 +/- 07. We observed that the number of UTI episodes showed a significant association with the development of chronic allograft nephropathy (P = .03) and graft loss (P < .01). Twelve patients (52.2%) lost their grafts during 5 years posttransplantation. Only 6 of 17 patients with bacterial TIN lost their graft at a mean time of 52.5 +/- 14 months. But all patients with CMV TIN or granulomatous TIN lost their grafts at a mean time of 31 +/- 3.1 months and 39 +/- 3 months, respectively (P < .05). In conclusion, these results support the pathological role of tubulointerstitial nephritis as a pathway of graft rejection or renal allograft deterioration among recipients after transplantation.     

Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination

BACKGROUND: Sirolimus (Rapamune; SRL) in combination with cyclosporine (CsA) reduces the incidence of acute rejection episodes in renal allograft recipients. This study evaluated whether renal function could be improved by elimination of CsA from an SRL-based regimen. METHODS: This phase 2, open-label, controlled, randomized study was conducted at 17 centers in the United States and Europe. Two hundred forty-six first cadaveric renal allograft recipients were enrolled, and 197 were randomized to full-dose CsA (microemulsion) plus fixed-dose SRL (2 mg/day; group A, n=97) or reduced-dose CsA plus concentration-controlled SRL (troughs 10-20 ng/mL; group B, n=100). Most patients with acute tubular necrosis-delayed graft function that resolved later than posttransplantation day 7 were not randomized but were assigned to a third group (nonrandomized, n=49) and received up to 5 mg per day of SRL as part of their individualized treatment regimen. All patients received standard doses of corticosteroids. At the end of posttransplantation month 2, eligible patients (those not treated for rejection within 3 weeks) in group B had CsA tapered and eliminated over the subsequent 4 to 6 weeks. RESULTS: At 12 months after transplantation, renal function was significantly better in the CsA-elimination arm. In patients who were on therapy and who had not experienced an acute rejection episode before month 6, serum creatinine level was significantly lower (1.38 mg/dL vs. 1.82 mg/dL, P < 0.001) and calculated glomerular filtration rate (Nankivell method) was significantly higher (73.5 mL/min vs. 57.1 mL/min, P < 0.001) in group B than in group A. In the intention-to-treat population, rates of biopsy-confirmed acute rejection at 12 months were similar between groups A and B (18.6% vs. 22.0%, respectively; P = 0.598). In addition, graft survival (92.8% and 95.0%) and patient survival (96.9% and 96.0%) rates at 12 months were not significantly different between groups A and B, respectively. Furthermore, there were no significant differences between black and nonblack recipients within treatment groups in terms of rejection rates and graft survival at 12 months. Black recipients in group B had better serum creatinine levels at 12 months compared with black recipients in group A (1.55 mg/dL vs. 2.69 mg/dL, respectively, P = 0.011), as did nonblack recipients in group B compared with nonblack recipients in group A (1.53 mg/dL vs. 1.75 mg/dL, respectively, P = 0.055). Black patients in group A had higher mean serum creatinine levels (2.69 mg/dL) than nonblack patients in group A (1.75 mg/dL, P = 0.028). Hypertension, edema, hypomagnesemia, and dyspnea were reported significantly less frequently in patients randomly assigned to undergo CsA elimination compared with patients in group A (P < 0.05); group B patients had a significantly greater (P < 0.05) incidence of abnormal liver function tests, diarrhea, hypokalemia, and thrombocytopenia. CONCLUSION: Concentration-controlled SRL with early elimination of CsA is safe and results in improved renal function. Reduced exposure to CsA does not result in a clinically significant increase in the incidence of acute rejection episodes. This is true for both black and nonblack recipients. SRL may be used to reduce the exposure of renal allograft recipients to the nephrotoxic effects of CsA.     

Characteristics of long-term renal transplant survivors

Despite the high rates of rejection, allograft failure, and patient death in the early years of renal transplantation, some patients have done remarkably well. Forty-three (17 living related donor and 26 cadaver donor recipients) such patients with an allograft that functioned for 19 years or more (range, 19 to 29 years) were followed up at this center. The patients included 24 men and 19 women, with a mean age at transplantation of 29 years, of whom 39 were white and four were black. At most recent follow-up, the mean daily dose of azathioprine was 104 mg (range, 50 to 175 mg) and that of prednisone was 10 mg (range, 5 to 20 mg). Mean serum creatinine level was 1.6 mg/dL (range, 0.7 to 5.4 mg/dL). Acute rejection occurred in 14 (33%) patients. Nine patients had one episode and five patients had two episodes of acute rejection. Long-term risks to the recipients appeared in the form of coronary artery disease in 10 (23%) patients; malignancy in 13 (30%) patients, which included nine patients with skin malignancy; and chronic hepatitis C virus (HCV) infection in four patients, two of whom died of complications of liver failure. Other complications included avascular bone necrosis in five patients, which required total hip replacement in two patients; hyperlipidemia requiring treatment in 16 (37%) patients; posttransplantation diabetes mellitus in 10 (23%) patients after a median of 17.5 years (range, 1 to 23 years); and hypertension in 23 (53%) patients. There were seven deaths (three of coronary artery disease, two of liver failure, one each of sepsis and malignancy) and eight graft losses (five to death with function, two to chronic rejection, and one to focal and segmental glomerulosclerosis). Although long-term allograft success results in patients receiving minimal amounts of immunosuppression and having good renal function, long-term renal transplant survivors are at risk for significant morbidity even in the third decade posttransplantation.     

在移植肾功能稳定的受者中主动撤除环孢素A的临床研究

目的 研究在移植肾功能稳定的受者中主动撤除环孢素A(CSA)对急性排斥反应发生率及肾功能的影响.方法 选择35例肾功能稳定的肾移植受者,其中尸体肾移植23例,亲属活体肾移植12例.除2例为再次肾移植外,其余均为初次肾移植.分别在肾移植术后6个月～6年时停用CsA,平均为术后(13.3±9.1)个月.撤除CsA后免疫抑制方案为:霉酚酸酯(MMF)+西罗莫司(SRL)+泼尼松(Pred).撤除CsA前有9例做了移植肾穿刺活检,8例测定了抗HLA抗体.结果 对35例受者随访6个月～4.5年,平均14.8个月.撤除CsA前、后血肌酐平均值分别为(88.1±15.5)μmol/L和(92.3±23.7)/μmol/L(P0.05).撤除CsA后,有2例经活检证实发生急性排斥反应,治疗后均逆转;CsA所致的毒副作用,如牙龈增生、糖耐量异常和多毛症等明显改善.9例移植肾活检中,有3例肾功能正常的受者已出现轻度慢性移植肾肾病表现.抗HLA抗体检测中,7例阴性者在撤除CsA前、后肾功能无明显变化.1例抗HLA抗体呈强阳性者在撤除CsA后进展为慢性移植肾肾病,恢复血液透析.结论 对移植肾功能稳定的受者在移植6个月后撤除CsA,转换为"霉酚酸酯+西罗莫司+泼尼松"的免疫抑制方案是安全的,不增加急性排斥反应风险;撤除CsA有利于消除一些与其相关的毒副作用;对抗HLA抗体呈强阳性者.撤除CsA后很难改变肾功能的进展.     

Current thinking on chronic renal allograft rejection: issues, concerns, and recommendations from a 1997 roundtable discussion

Chronic rejection accounts for most renal allograft losses after the first year posttransplantation. On March 24 and 25, 1997, a roundtable of five transplant surgeons, two nephrologists, and one pathologist assembled in Dallas, Texas, to review critical issues surrounding chronic renal allograft rejection. This article summarizes the presentations and relevant discussions of this meeting regarding the cause of chronic rejection, clinical diagnoses, risk factors, future prospects for intervention strategies, and general recommendations for the transplant community. Growing evidence indicates that chronic rejection is the aggregate sum of irreversible immunologic and nonimmunologic injuries to the renal graft over time. A history of acute rejection episodes and inadequate immunosuppression, likely attributable to inconsistent cyclosporine exposure or poor patient compliance, are among the most recognizable immunologic risk factors for chronic rejection. Donor organ quality, delayed graft function, and other donor and recipient variables leading to reduced nephron mass are nonimmunologic factors that contribute to the progressive deterioration of renal graft function. Clinical management of renal transplant recipients should incorporate both immunologic- and nonimmunologic-based intervention strategies aimed at minimizing risk factors to thwart the progression of chronic rejection and improve long-term allograft and patient survival.     

RAD in de novo renal transplantation: comparison of three doses on the incidence and severity of acute rejection

BACKGROUND: The effects of three doses of RAD (40-O-[2-hydroxyethyl]-rapamycin), a novel macrolide with potent immunosuppressive and antiproliferative properties, on the incidence and severity of acute rejection episodes as well as its tolerability were evaluated in a dose-ranging study in de novo renal transplant recipients. METHODS: In this double-blind, parallel group, multicenter study, recipients were randomized to receive 1 mg, 2 mg, or 4 mg/day of RAD in combination with Neoral (cyclosporine, USP MODIFIED) and corticosteroids. The incidence and severity of biopsy-proven acute rejection episodes, graft survival, patient survival, infection rates, laboratory measurements, and adverse events were compared across groups after 6 months of therapy. RESULTS: Among the 103 recipients, patients receiving 1, 2, or 4 mg/day experienced a 32.4%, 14.7%, or 25.7% incidence of biopsy-proven acute rejection episodes within the first 6 months posttransplantation, respectively. Even though the study was not powered to demonstrate efficacy, the incidence of moderate and severe acute rejection episodes was found to be significantly lower among patients in the 2 mg and 4 mg/day groups than in the 1 mg/day group (P=0.002 and P=0.006, respectively). Overall graft and patient survival rates were excellent. RAD was generally well tolerated. Although blood lipid levels increased in all groups, changes were manageable with lipid-lowering agents and did not warrant discontinuation of study medication. The incidence of viral and fungal infections was low; however, it was higher among recipients treated with 4 mg/day. CONCLUSIONS: In combination with Neoral and corticosteroids, RAD doses of 2 mg and 4 mg/day resulted in lower rates of acute rejection episodes and efficacy failure than the 1 mg/day dose and were significantly more effective in reducing the severity of rejection. Large-scale, controlled, follow-up studies are currently in progress to confirm these initial findings.