Long-term toxicity of antithymocyte globulin induction may vary with choice of agent: a single-center retrospective study.

BACKGROUND: Antithymocyte globulin (ATG) preparations are frequently used as induction treatment in renal transplantation, but little is known about the clinical equivalence of these different agents. We performed a retrospective, single-center study to compare the long-term clinical effects of ATG Fresenius (ATGF) and Thymoglobulin (SangStat, Fremont, CA) in renal transplant recipients. PATIENTS AND METHODS: A total of 194 consecutive renal transplant recipients were included who had undergone transplantation in our center between June 1993 and April 2001 and had received ATGF or Thymoglobulin as induction treatment. RESULTS: A total of 129 patients received ATGF and 65 patients received Thymoglobulin. Thirty patients (23%) in the ATGF group demonstrated cytomegalovirus (CMV) disease, whereas 24 patients (37%) in the Thymoglobulin group demonstrated CMV (P =0.02). Five patients (3.9%) in the ATGF group and eight patients (12.3%) in the Thymoglobulin group developed posttransplant malignancy (P =0.01). Five patients (3.9%) in the ATGF group and nine patients (13.8%) in the Thymoglobulin group died during follow-up (P =0.005). Cox regression analysis revealed that Thymoglobulin was an independent predictor of CMV disease (relative risk [RR] 2.16, confidence interval [CI] 95% [1.04-4.48]), malignancy (RR 2.16, CI 95% [1.04-4.48]), and death (RR 4.14, CI 95% [1.36-12.6]). CONCLUSION: In renal transplant recipients, induction therapy with Thymoglobulin seems to be associated with a significantly greater incidence of CMV disease, malignancy, and death compared with ATGF.

Antiphospholipid antibodies as a risk factor for atherosclerotic events in renal transplant recipients.

BACKGROUND: Epidemiologic studies reported that antiphospholipid antibodies (APAs) were independent predictors of atherosclerotic events. We recently reported a high prevalence of APAs in renal transplant recipients. Nevertheless, the role of APAs on atherosclerotic events has not been prospectively studied in this high-risk population. METHODS: Participants in the study were 324 consecutive renal transplant recipients. Patients were enrolled between January 1996 and May 1998 and followed up until June 2002. RESULTS: The patients were followed for a mean duration of 62 +/- 26 months. Eighty seven (26.8%) patients exhibited APAs. We found a slight, but significant, correlation between total plasma homocysteine (tHcy) concentration and anticardiolipin (ACA) titers (r = 0.26; P = 0.036). Fifty six athersclerotic events (17.2%) occurred in 54 patients. Atherosclerotic events occurred more frequently in patients with APAs (33% vs. 9%; P = 0.0003) and ACAs levels were higher in patients who experienced atherosclerotic events (23.7 +/- 13.1 IU vs. 13.9 +/- 9.4 IU; P = 0.003). APAs were associated with an increased risk of atherosclerotic events (RR, 2.82; 95% CI, 1.17 to 5.31). Cox regression analysis also revealed that age above the median (RR, 5.21; 95% CI, 1.67 to 17.13), a previous history of cardiovascular disease (RR, 3.54; 95% CI, 1.57 to 10.43), hyperhomocysteinemia (RR, 4.01; 95% CI, 1.22 to 14.61), and current smoking (RR, 2.17; 95% CI, 1.01 to 6.72) were risk factors for atherosclerotic events. CONCLUSION: The presence of APAs is an independent cardiovascular risk factor in renal transplant recipients. Prevention trials are necessary to assess the efficacy and safety of anticoagulation therapy in transplant patients with APAs.

Cyclosporin withdrawal with concomitant conversion from azathioprine to mycophenolate mofetil in renal transplant recipients with chronic allograft nephropathy: a 2-year follow-up.

Because recent large studies have demonstrated that mycophenolate mofetil (MMF) is superior to azathioprine (AZA) as a post-transplant immunosuppressant, it has been speculated that MMF could have a cyclosporin (CsA)-sparing effect in renal transplant recipients with chronic allograft dysfunction. Between April 1996 and October 1998, 31 patients with chronic allograft dysfunction were assigned to have conversion from AZA to MMF with concomitant CsA withdrawal. Patient and graft outcomes were analysed. Mean follow-up time after MMF conversion was 27+/-11 months. Serum creatinine concentration (sCt) significantly decreased after conversion and remained stable at the end of follow-up (227+/-31 micro mol/l vs. 185+/-50 micro mol/l; P<0.0005). Mean variation in sCt was -24% after conversion, whereas it was +20% in the year before conversion ( P<0.001). There was a significant inverse relationship between proteinuria at baseline and improvement in renal function (r=-0.35; P=0.01). Proteinuria increased during follow-up (0.79+/-0.6 vs. 1.79+/-1.08 g/day; P=0.04). Isolated CsA nephropathy was associated with the best outcome. Renal function significantly improved in patients with grade 1 chronic rejection and remained stable in patients with grade 2 chronic rejection. Two patients (6.5%) experienced late acute rejection, respectively 13 and 24 months after CsA withdrawal. Eight patients (29%) experienced systemic infections requiring hospitalization. Blood pressure control and lipid profile improved after conversion. CsA withdrawal with a concomitant switch from AZA to MMF allows a substantial and durable improvement in renal function. Both allograft histology and proteinuria at baseline are predictive of the evolution of renal function after conversion. Physicians should consider the risk of over-immunosuppression possibly associated with this therapeutic strategy.

Lymphocyte subsets and assessment of cancer risk in renal transplant recipients.

Renal transplant recipients have a well-recognized increased risk of de novo neoplasia. In this study, we investigated whether lymphocyte subset count could predict the risk of developing noncutaneous neoplasia (NCSC) in renal transplant recipients (RTR). Between January 1995 and December 1995, lymphocyte subsets (CD4, CD8, CD19) were measured in 281 RTR. This population was studied until November 1999 for the development of NCSC. The mean follow-up was 42+/-9 months. Neoplasm was diagnosed in 22 patients (7.9%). Patients who developed a cancer were significantly older (53.8+/-6 years vs 38+/-16 years, P<0.0001), had lower CD4 (234+/-126/mm(3) vs 543+/-214/mm(3), P<0.005) and CD19 (19+/-9/mm(3) vs 51+/-22/mm(3), P<0.0001) levels, and more frequently had past histories of skin cancer (24% vs 4%, P<0.01). Cox regression revealed that high CD4 levels (RR 0.73, 95% CI 0.62-0.89 for each 100/mm(3) increase in CD4 cell count) were associated with decreased risk of NCSC, whereas age (RR 2.49, 95% CI 1.12-5.92 for each 10-year increase in age) was predictive of the subsequent development of NCSC. To conclude, CD4 cell depletion is associated with the development of solid cancers and lymphoma in RTR.

Homocysteine, nutritional status and insulin in renal transplant recipients.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for the development of cardiovascular conditions in chronic stable renal-transplant recipients (RTR). Major determinants of plasma total homocysteine (tHcy) in RTR are renal function and folate levels. The data dealing with the possible regulation of the tHcy metabolism by insulin and nutritional status is conflicting in non-transplant populations. METHODS: We examined the relationship between tHcy, insulin and nutritional status in 103 chronic, stable RTR. Demographic, clinical, and biochemical parameters were assessed for each patient. RESULTS: Mean tHcy was 19.7+/-9.2 micro mol/l (range 8.6-53). The tHcy was strongly related to creatinine clearance (r=0.55, P<0.0001). Fasting tHcy levels were negatively related to folate concentrations (r=-0.32, P=0.01). There was a positive relationship between tHcy and LDL-cholesterol (r=0.34, P=0.03) and a significant negative correlation between tHcy and insulin (r=-0.38, P=0.01). Fasting tHcy concentrations were significantly higher in the lower quartile of insulin concentration than in the upper quartile (27.7+/-12.7 vs 15.9+/-9.5, P=0.01). In multivariate analysis, tHcy was associated with serum creatinine (P=0.001), insulin (P=0.02) and folate concentration (P=0.03). Patients with the highest IGF-1 concentration had lower tHcy than patients with the lowest IGF-1 concentration (16.8+/-5.7 vs 23.3+/-11 micro mol/l, P=0.01). CONCLUSION: We observed an inverse relationship between insulin and tHcy in chronic, stable RTR.

Hyperhomocysteinaemia therapy in haemodialysis patients: folinic versus folic acid in combination with vitamin B6 and B12.

BACKGROUND: In a recent uncontrolled retrospective report we suggested that the long-term supplementation of high-dose, i.v. folinic acid combined with high-dose i.v. pyridoxine was highly effective in correcting plasma total homocysteine (tHcy) concentrations in haemodialysis patients. To confirm these findings, we conducted a randomized, controlled trial aimed at evaluating whether i.v. or oral folinic acid provided improved tHcy-lowering efficacy in haemodialysis patients compared with oral folic acid. METHODS: In a 6-month prospective, randomized, controlled trial, 60 chronic haemodialysis patients, matched for age, gender, dialysis duration, and average screening pre-treatment-fasting tHcy levels, were given either 50 mg/week of i.v. calcium folinate (group 1), 50 mg/week of oral calcium folinate (group 2), or 45 mg/week oral folic acid (group 3). All 60 patients also received 750 mg/week of i.v. vitamin B6 and 3 mg/week of oral vitamin B12. RESULTS: Fasting tHcy decreased significantly and to a similar extent in the three groups after 2 months of treatment and remained stable at 4 and 6 months (16.6+/-3.5, 18.3+/-4, and 19.1+/-3.1, in groups 1, 2, and 3, respectively, P=NS). Mean percentage reduction at 6 months was also similar in the three treatment groups (46, 43, and 42% in groups 1, 2, and 3, respectively, P=NS). CONCLUSIONS: These findings show that the tHcy-lowering effects of high-dose i.v. folinic acid, oral folinic acid, or oral folic acid were comparable, suggesting that the hyperhomocysteinaemia observed in haemodialysis patients is not due to abnormal folate metabolism. Furthermore, they are compatible with the view that other abnormalities are also involved in the impaired clearance of homocysteine in uraemic patients.

Treatment of hyperhomocysteinemia with folic acid reduces oxidative stress in renal transplant recipients.

BACKGROUND: We conducted a prospective, uncontrolled, open study to assess the relationship between homocysteine (tHcy) and oxidative stress in chronic, stable, renal transplant recipients (RTR). METHODS: Included in the study were 17 chronic, stable RTR. All the patients received folic acid (5 mg/day). tHcy and total antioxidant capacity (TAOC) were measured before and at the end of the study period. RESULTS: Mean tHcy concentration was 26+/-10 micromol/L. tHcy significantly decreased during the study period (26+/-10 vs. 18+/-7 micromol/L; P<0.001). There was a significant inverse relationship between TAOC and tHcy (r= -0.33; P=0.01). TAOC significantly increased during the study period (1.49+/-0.23-1.78+/-0.6; P<0.001). There was an inverse relationship between the variation in tHcy and the variation in TAOC (r= -0.44; P=0.01). CONCLUSION: Our results demonstrate that hyperhomocysteinemia contributed to increased oxidative stress in RTR. tHcy-lowering treatment with folic acid may lower oxidative stress.

Serum total homocysteine and cardiovascular disease occurrence in chronic, stable renal transplant recipients: a prospective study.

Renal transplant recipients have disproportionately high rates of arteriosclerotic outcomes, and recent studies provided controlled evidence that clinically stable renal transplant recipients have an excess prevalence of hyperhomocysteinemia. Few studies suggest that hyperhomocysteinemia may be a cardiovascular risk factor in renal transplant recipients. In the study presented here, the association between atherosclerotic events and homocysteine concentrations was examined in 207 stable renal transplant recipients. The role of hyperhomocysteinemia was analyzed with respect to other known cardiovascular risk factors. The mean follow-up was 21.2 +/- 1.9 mo (range, 14 to 26). Mean total homocysteine (tHcy) was 21.1 +/-9.5 micromol/L and median concentration was 19 micromol/L. Seventy percent of patients (n = 153) were hyperhomocysteinemic (values >15 micromol/L). tHcy correlated negatively with folate concentration (r = -0.3; P < 0.01). tHcy was closely related to creatinine concentration (r = 0.54; P < 0.001). Cardiovascular disease events (CVE) including death were observed in 30 patients (14.5 %; 7.34 events per 1000 person-months of follow-up). Fasting tHcy values were higher in patients who experienced CVE (31.5 +/- 10.3 versus 17.8 +/- 7.5; P < 0.001). Cox regression analysis showed that tHcy was a risk factor for cardiovascular complications (relative risk [RR] 1.06; 95% confidence interval (95% CI), 1.04 to 1.09; P < 0.0001). This corresponds to an increase in RR for CVE of 6% per micromol/L increase in tHcy concentration. Age (RR 1.55; 95% CI, 1.09 to 2.19; P < 0.01) and creatinine concentration (RR 1.34; 95% CI, 1.08 to 1.66; P < 0.01) were also independent predictors for CVE. This study demonstrates that elevated fasting tHcy is an independent risk factor for the development of CVE in chronic stable renal transplant recipients. Randomized, placebo-controlled homocysteine studies of the effect of tHcy lowering on CVE rates are urgently required in this patient population.