Conversion from cyclosporine to tacrolimus results in improved creatinine but does not alter lipid profile.

INTRODUCTION: While cyclosporine and tacrolimus use results in similar renal graft survival, the side effect profiles of the drugs are substantially different. We examined the electrolyte and lipid alterations that occurred in our patient population following conversion from cyclosporine to tacrolimus. METHODS: Data for electrolytes, lipid profile, and immunosuppression were analyzed from 98 patients with kidney or kidney-pancreas transplants who were converted from cyclosporine to tacrolimus between October 1994 and June 2001. Results, expressed as mean +/- SEM, were compared to baseline values using the Wilcoxon signed-rank test (P < .05 considered significant). RESULTS: Among these patients, there were 56 men, 42 women, 75 primary transplants, 15 repeat transplants, and 26 multiorgan transplants. The mean time to tacrolimus conversion was 769 +/- 122 days. Creatinine, BUN, and glucose improved after conversion to tacrolimus. Surprisingly, cholesterol, low-density lipoproteins, and high-density lipoproteins levels were not significantly altered, although triglyceride levels demonstrated a significant difference at 1 year. CONCLUSION: Significant improvements in creatinine and BUN were observed following conversion from cyclosporine to tacrolimus. While hypomagnesemia was also seen, there was surprisingly little alteration in lipid profile.

T-lymphocyte apoptosis is increased by non-interleukin-2-dependent induction in human mixed lymphocyte cultures.

INTRODUCTION: Transplant tolerance is dependent on the apoptotic deletion of allospecific T lymphocytes following interleukin-2 (IL-2)-dependent T-lymphocyte activation. Current immunosuppressive strategies block IL-2 and may prevent T-cell activation. We examined apoptotic alterations in mixed lymphocyte culture (MLC), a model of allospecific lymphocyte activation, by polyclonal rabbit antithymocyte antibody thymoglobulin (rATG) and monoclonal anti-IL-2 receptor antibody basiliximab. METHODS: Human lymphocytes were isolated using Ficoll-Paque gradient. Cesium-irradiated (2500 rad) stimulator cells (10(6) cells/mL) were cocultured with equal numbers of responder cells. Apoptosis was measured using annexin-V staining and propidium iodide exclusion using flow cytometry. Isolated protein was analyzed using Western blotting with densitometry. RESULTS: Apoptosis increased at days 3 and 7 in rATG MLC compared with control and basiliximab MLC. Fas was up-regulated in rATG MLC in a dose-dependent manner, whereas basiliximab did not alter fas. FasL was increased initially and at late time points in rATG MLC. CONCLUSIONS: Polyclonal rATG increased apoptosis and production of the proapoptotic proteins fas and fasL. In contrast, monoclonal basiliximab did not change lymphocyte apoptosis or apoptotic protein production. These results suggest that a specific IL-2 pathway blockade may prevent allospecific tolerance and that a non-IL-2 pathway blockade may encourage apoptosis of allospecifically activated T cells.

Role of anti-beta 2 glycoprotein 1 antibodies in ESRD patients with antiphospholipid antibody syndrome.

INTRODUCTION: End stage renal disorder (ESRD) patients with antiphospholipid antibody syndrome (APAS) are at high risk for the development of post-transplant renal thrombosis. Positive titre of anticardiolipin antibodies (ACA) is considered a major characteristic of APAS. However, several studies have suggested that ACA in patients with APAS do not bind to phospholipids alone. Beta 2 glycoprotein 1 (beta 2gp1), a 40-kD plasma protein is required. In this study, we have tested a hypothesis that significant portions of our ESRD patients with APAS have antibodies only to beta 2gp1. METHODS: Serum samples from each of 169 ESRD patients waiting for cadaver renal transplant in August 2000 were tested for ACA and anti-beta 2gp1 antibodies by enzyme-linked immunoabsorbent assay (ELISA) method. Twenty-four of these patients had clotting disorders that met the criteria established by the Eighth International Symposium on Antiphospholipid Antibodies. They included frequent arterio-venous (a-v) shunt thrombosis, cerebrovascular thrombosis, lupus, frequent abortions and microrenal angiopathy. RESULTS: Thirty-three of the patients (20%) had positive titre of either ACA or beta 2gp1 or both. Twenty-eight patients had ACA antibodies, of which eight had no evidence of clotting disorder while remaining 20 patients had various clotting disorders. Fourteen of these 20 patients with APAS had the positive titre of ACA only; the remaining six patients had both the antibodies, i.e. anti-beta 2gp1 as well as ACA. There were four patients with APAS that had positive titres of only beta 2gp1 antibodies. In total there were 11 patients with beta 2gp1 antibodies, 10 of which had APAS, the remaining one did not. The sensitivity and the specificity of ACA test were 83 and 94%, respectively, and the sensitivity and specificity of beta 2gp1 antibody test were 71 and 99%, respectively. The chi-square analysis demonstrated that there was statistically significant correlation between positive titres of both the antibodies and the presence of APAS. CONCLUSION: The APAS in the ESRD patients should be characterized by not only the positive titre of ACA but also the positive titres of anti-beta 2gp1 antibodies in association with history of clotting disorder.

Disseminated Pseudallescheria boydii (Scedosporium apiospermum) infection in a renal transplant patient.

Transplant recipients receive a number of immunosuppressive medications that result in an increased risk of infection, including infections with microbes that are normally not pathogenic. We describe a patient with end-stage renal disease who underwent kidney transplantation. Six months postoperatively, he presented with a lesion on his ankle, multiple thigh nodules, and right testicular pain. Biopsy of the ankle lesion demonstrated Pseudallescheria boydii (Scedosporium apiospermum), a common environmental fungus. Following orchiectomy, multiple fungal elements were found that were initially described as Aspergillus species, but later identified as P. boydii. In addition, multiple brain abscesses were found on magnetic resonance imaging. Despite treatment with multiple antifungal medications, the patient died of cardiac dysrhythmia. Current diagnostic and therapeutic alternatives for P. boydii are reviewed.

Improved flow cytometric detection of HLA alloantibodies using pronase: potential implications in renal transplantation.

BACKGROUND: Flow cytomeric crossmatch (FCXM) has grown in popularity and has become the "standard of practice" in many programs. Although FCXM is the most sensitive method for detecting alloantibody, the B cell FCXM has been problematic. Difficulties with the B cell FCXMs have been centered around high nonspecific fluorescence background owing to Fc-receptors present on the B cells and autoantibodies. To improve the specificity and sensitivity of the B cell FCXM, we utilized the proteolytic enzyme pronase to remove Fc receptors from lymphocytes before their use in FCXM. METHODS: Lymphocytes isolated from peripheral blood, spleen, or lymph nodes were treated with pronase and then used in a three-color FCXM. A total of 167 T- and B cell FCXMs using pronase-treated and untreated cells were performed. Testing used serial dilutions of HLA allosera (22 class I and 6 class II), with the titer of each antibody at one dilution past the titer at which the complement-mediated cytotoxicity anti-human globulin crossmatch became negative. RESULTS: After pronase treatment, the actual channel values of the negative control in both T cell and B cell FCXMs declined from 78+/-10 to 57+/-4 (P<0.05) and 107+/-11 to 49+/-3 (P<0.00001), respectively. Pronase treatment resulted in improved sensitivity of the T and B cell FCXM in detecting class I antibody by 20% and 80%, respectively. In no instance was a false-positive reaction observed. In this study, pronase treatment improved the specificity of B cell FCXM for detecting class II antibodies from 75% to 100% (P=0.03). In no instance was a false-negative reaction recorded. Lastly, on the basis of these observations we re-evaluated three primary transplant recipients who lost their allografts because of accelerated rejection. One of the patients was transplanted across negative T and B cell FCXM, whereas the other two patients were transplanted across a positive T cell, but negative B cell, FCXM. After pronase treatment, T and B cell FCXMs of each patient became strongly positive, and donor-specific anti-HLA class I antibody was identi. fied in each case. CONCLUSION: Utilization of pronase-treated lymphocytes improves both the sensitivity and specificity of the FCXM.

Progression of hepatic damage during cold storage after procurement in a liver and kidney donor with HELLP syndrome.

BACKGROUND: HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome and acute fatty liver of pregnancy are associated with preeclampsia and fetal defects in fatty acid metabolism. This defect causes the accumulation of metabolites that are harmful to the maternal liver. CASE REPORT: We report a liver and kidney donor with HELLP syndrome and describe the progression of disease in the liver during cold storage. Before procurement, liver biopsy demonstrated minimal necrosis. However, after cold storage, repeat biopsy demonstrated more than 30% necrosis. The liver was not engrafted; the kidneys were transplanted without complication. CONCLUSION: Livers procured from patients with HELLP syndrome should be carefully evaluated for progression of hepatic damage during cold storage and transport.

Frequency, potential risk and therapeutic intervention in end-stage renal disease patients with antiphospholipid antibody syndrome: a multicenter study.

BACKGROUND: Antiphospholipid antibody syndrome (APAS) is characterized by the presence of anticardiolipin antibodies (ACA) in association with thrombotic disorders of arterial and/or venus systems, spontaneous abortion(s) or thrombocytopenia. METHODS: In this multicenter study, 502 end-stage renal disease (ESRD) patients awaiting renal transplants were screened to determine the frequency of APAS, the potential risk associated with APAS, and strategies for therapeutic intervention. Ninety-three patients (19%) had high titers of ACA. Twenty-three patients had documented evidence of one or more of the thrombotic disorders such as lupus, frequent abortions, frequent thrombosis of arteriovenous shunts, biopsy-proven microrenal angiopathy, or thrombocytopenia and thus were diagnosed with APAS. Of these 23 patients, 11 received kidney transplants either with (4 patients) or without (7 patients), concomitant anticoagulation therapy. RESULTS: All seven of the patients with APAS not treated with anticoagulation therapy lost their allografts within 1 week as a result of renal thrombosis. In contrast, three out of four transplant patients with APAS treated with anticoagulation therapy maintained their allografts for over 2 years. The fourth patient lost his graft within a week because of thrombosis. Of the remaining 70 patients with high titers of ACA but no evidence of thrombotic disorders, 37 received kidney transplants. None lost their allografts as a result of thrombosis. Our data suggest that, although 19% of our ESRD patients exhibit high titer of ACA, only 5% of the patients have APAS. CONCLUSION: In conclusion, our data suggest that the patients with APAS are at high risk of posttransplant renal thrombosis. Anticoagulation therapy could prevent patients from posttransplant thrombosis in patients with APAS.

Effect of race on outcome after kidney and kidney-pancreas transplantation in type 1 diabetic patients.

OBJECTIVE: The racial impact on graft outcome is not well defined in diabetic recipients. The purpose of this study is to analyze our experience with kidney-alone (A) and kidney-pancreas (KP) transplantation in type 1 diabetic recipients and evaluate the impact of racial disparity on outcome. RESEARCH DESIGN AND METHODS: The records of 217 kidney transplants (118 KA, 99 KP) performed on type 1 diabetic patients between 1985 and 1995 at the Medical University of South Carolina and the University of Texas Medical Branch were reviewed. RESULTS: A total of 53 (31%) white patients and 15 (33%) black patients experienced at least one episode of biopsy-proven acute rejection of the renal graft (NS). Patient survival at 1, 2, and 5 years was similar in white (92, 87, 69%) and black (91, 91, 69%) patients (NS). Kidney graft survival at 1, 2, and 5 years in the KA group was 72, 62, and 42% in blacks, compared with 79, 76, and 53% in whites (NS). Kidney graft survival at 1, 2, and 5 years in the KP group was 92, 92, and 74% in blacks, compared with 83, 77, and 58% in whites (NS). Pancreas graft survival at 1, 2, and 5 years was 81, 81, and 81% in blacks, compared with 81, 75, and 62% in whites (NS). Cox regression analysis revealed that donor age > or = 40 years increased the risk of renal graft failure 6.2-fold (P = 0.0001), whereas the addition of a pancreas transplant to a kidney and a living-related transplant decreased the risk of failure of the kidney graft 0.2 (P = 0.005) and 0.1 times (P = 0.005). CONCLUSIONS: Our results suggest that when compared with whites, there may be a trend toward an improved kidney and pancreas graft outcome in blacks undergoing KP transplants. These findings suggest that diabetes may override the risk factors that account for the pronounced disparity in outcome observed between nondiabetic white and black recipients.

Renal allograft failure after simultaneous pancreas-kidney transplantation: univariate and multivariate analyses of donor and recipient risk factors.

Although donor and recipient risk factors for renal allograft failure are well known after kidney transplantation, they are less well defined after simultaneous pancreas-kidney transplantation. The purpose of this study is to evaluate the impact of donor and recipient risk factors on the outcome of the renal allograft in simultaneous pancreas-kidney recipients. Simultaneous pancreas-kidney transplant performed between 4/88 and 6/94 were reviewed (n = 61) and univariate (Kaplan-Meier) and multivariate (Cox regression) analyses of factors which affect kidney graft survival were performed. Twelve donor and eleven pre- and post-transplant recipient risk factors were evaluated. Overall kidney allograft survival rates at 1, 2 and 5 yr were 81%, 76% and 66%. Donor age > and = 40 yr (RR = 2.3), donor female gender (RR = 3.5), donor admission to pronouncement of brain death > and = 48 h (RR = 3), the occurrence of surgical complications (RR = 2.1), and serum > and = 2 mg/dl on post-transplant day (RR = 1.9) were independently associated with an increased hazard of graft failure. With the exception of length of donor admission, all of these factors were also shown to predict the risk of renal graft failure by univariate analysis. In conclusion, we have identified donor and recipient risk factors which independently predict the risk of renal graft failure after simultaneous pancreas-kidney transplantation. Whether the differences between our center-specific risk factors and those obtained from renal transplant registry data are true differences or simply reflect sampling error is unclear.

Treatment of renal allograft acute rejection with methylprednisolone: effect of fixed dose versus dose per body mass index.

Considerable interpatient variability in steroid pharmacokinetics has been observed in renal transplant recipients. The purpose of this retrospective study is to evaluate the relationship between the dose of methylprednisolone (MP) used to treat acute rejection (AR) after renal transplantation and the response to treatment. 117 first AR episodes from 408 renal transplants were reviewed. The dose of MP used to treat AR was < 45 mg/kg/m2 in 60 patients and > and = 45 mg/kg/m2 in 57 patients. The correlation between fixed dose ( < 1.25 vs. > and = 1.25 g) and dose based on BMI was evaluated by simple linear regression analysis (r2 = 0.78, p < 0.0005). Response to treatment was as follows: MP successful (Group 1, n = 80); MP failed, OKT3 successful (Group 2, n = 17); MP and OKT3 failed (Group 3, n = 3) and MP failed, no further treatment (n = 17). No relationship was observed between the dose of MP, whether fixed or based on BMI, and (1) response to treatment of the first AR, (2) incidence of a second AR and (3) response to subsequent treatment with OKT3. Actuarial graft survival was higher in Group 1 compared to Group 2 (p < 0.0005), lower in Black recipients (p = 0.02) and higher when > and = 45 mg/kg/m2 of MP was used to treat AR (p = 0.06). In conclusion, no relationship between the dose of MP, whether fixed or based on BMI, and the response to treatment of AR was observed. MP dosage based on BMI may be a reasonable alternative to a fixed-dose regimen with the advantage of limiting steroid exposure and the consequent side-effects.

Renal retransplants: effect of primary allograft nephrectomy on early function, acute rejection and outcome.

Although risk factors for failure of renal retransplants have been well studied, the impact of allograft nephrectomy on subsequent renal transplantation in the cyclosporin era is not well defined. The purpose of this study is to define the effect of nephrectomy of the primary allograft on subsequent allograft survival, early allograft function, incidence of acute rejection and patient sensitization. The records of 127 renal retransplant recipients were reviewed. Of these 127 patients who underwent retransplantation, 40 (31%) underwent nephrectomy of the primary allograft prior to retransplantation whereas 40 (31%) did not. Nephrectomy of cadaveric primary allografts was performed more commonly (48% vs 30%, p = 0.003) and earlier (78% vs 54% < 1 month post-transplant, p = 0.0006) in the pre-CSA period compared to the CSA period. Biopsy-proven acute rejection episodes occurred more frequently in the nephrectomy group (73% vs 42%, p = 0.03). Although primary allograft nephrectomy was associated with higher preformed antibody levels, it had no effect on early graft function, frequency of acute rejection or allograft outcome after retransplantation, in the CSA group. In conclusion, in the cyclosporin era, nephrectomy of the primary allograft has no significant influence on retransplantation.

Renal allograft and patient outcome after transplantation: pancreas-kidney versus kidney-alone transplants in type 1 diabetic patients versus kidney-alone transplants in nondiabetic patients.

Despite recent advances and improved outcome, pancreas transplantation remains controversial. The purpose of this review was to study renal allograft outcome after simultaneous pancreas-kidney transplants (SPK, n = 61), kidney-alone transplants in type I diabetic patients (KA-D, n = 63), and kidney-alone transplants in nondiabetic patients (KA-ND, n = 80). Patients were matched for donor age, donor gender, donor race, interval from donor admission to procurement, DR mismatch, and recipient gender. The mean renal allograft cold ischemic time and recipient age were lower in the SPK group. Patient survival was highest in the KA-ND group (99% and 86% at 1 and 5 years, respectively), intermediate in the SPK group (90% and 78% at 1 and 5 years, respectively), and lowest in the KA-D group (89% and 66% at 1 and 5 years, respectively) (P = 0.004). similarly, renal allograft survival was higher in the KA-ND (89% and 63% at 1 and 5 years, respectively) and SPK (82% and 69% at 1 and 5 years, respectively) groups compared with the KA-D group (76% and 49% at 1 and 5 years, respectively) (P = 0.07). This difference disappeared when renal graft survival was censored for death, which probably reflects the selection bias. Actuarial pancreas graft survival was 76% and 62% at 1 and 5 years, respectively. Acute rejection (AR) was more frequent in the SPK group than in the KA-D and KA-ND groups (41% v 16% v 29%; P = 0.007). Delayed graft function (DGF), on the other hand, occurred more frequently in the KA-D group than in the KA-ND and SPK groups (66% v 55% v 38%; P = 0.08). Death as a result of a cardiovascular event occurred more frequently in the KA-D group. Cardiovascular death and renal graft failure occurred earlier in the SPK group. Cox regression analysis revealed a 1.6 and 1.8 times higher risk of renal graft failure in the SPK group when the donor was > or = 40 years old or female and a five times higher risk of graft failure in the KA-ND group in the presence of AR. Graft survival in patients with AR/DGF was lower than that in patients with no AR/no DGF in both the KA-D (71% and 63% v 100% and 100% at 1 and 5 years, respectively; P = 0.03) and KA-ND (90% and 56% v 100% and 100% at 1 and 5 years, respectively; P = 0.001) groups. Acute rejection did not affect graft survival in the SPK group. In the absence of AR, DGF had no effect on graft survival in any of the groups. Although the selection bias in favor of pancreas transplantation does not allow for definitive conclusions, our results show that outcome after SPK transplantation is acceptable and factors that influence the outcome after this procedure may be different from the ones affecting KA-D recipients.

The impact of midline versus transverse incisions on wound complications and outcome in simultaneous pancreas-kidney transplants: a retrospective analysis.

Intraperitoneal placement of the pancreas allograft, usually through a midline incision, has so far achieved the best results in pancreas transplantation. The usefulness and safety of a transverse incision has not been previously reported. The purpose of this study was to compare midline and transverse incisions, with respect to wound complications and outcome, in simultaneous pancreas-kidney transplant recipients with intraperitoneal placement of the pancreatic graft. The incidence of deep abscess formation, superficial abscess formation, wound leak, and fascial dehiscence, as well as graft survival, were retrospectively compared in 41 bladder-drained simultaneous pancreas-kidney recipients with a midline incision and in 15 with a transverse incision. The overall incidence of wound complications was similar (34% vs 20%, P = NS) in the two groups. Deep abscess formation occurred more frequently in the midline group (27% vs 0%, P = 0.02). Staphylococcus epidermidis and Candida albicans were the most common microbial isolates from deep abscesses. Multivariate logistic regression analysis revealed donor age 40 years or older (P = 0.04), the occurrence of a bladder leak (P = 0.05), and a peak serum amylase in the 1st week of 1000 IU/l or greater (P = 0.02) to be independent risk factors for the development of wound complications. The type of incision, however, was not found to be an independent risk factor. Patient (90% vs 83%, P = NS), pancreas allograft (78% vs 82%, P = NS), and kidney allograft (83% vs 70%, P = NS) survival rates were similar for the midline and transverse groups. We conclude that the transverse incision is a reasonable alternative to the midline incision in simultaneous pancreas-kidney transplantation and it is presently the incision of choice at our institution. It offers excellent exposure and is associated with a similar wound complication rate and outcome when compared to the midline incision.