High-risk Kidney Transplant Recipients Research Articles

Effects of induction therapy with alemtuzumab versus antithymocyte globulin among highly sensitized kidney transplant candidates.

We retrospectively compared induction therapy utilizing alemtuzumab and antithymoglobulin (ATG) in high-risk kidney transplant recipients in our center. Two hundred and fifty-one patients underwent kidney transplantation between 2009 and 2012. The high-risk patients were defined as those who had two or more times kidney transplantation and/or more than 30% panel reactive antibody. We studied 130 high-risk kidney transplant candidate; 58 (44.6%) patients received induction immunosuppressive therapy with alemtuzumab, and 72 (55.4%) with ATG. Delayed graft function developed in 11 patients receiving alemtuzumab, against the 27 patients who receiving ATG (P = 0.021). Acute cellular rejection episodes were observed in five patients in the alemtuzumab group and 19 patients in the ATG group (P = 0.009). There were three graft failures in the alemtuzumab group and eight graft failures in the ATG group due to rejection episodes. We found immunosuppressive induction therapy with alemtuzumab a significantly less incidence of acute rejection and delayed graft function than induction therapy with ATG in the high-risk kidney transplant recipients.

Alemtuzumab (Campath-1H) experience in kidney transplantation what we have learned; current practices; and scope for the future?

Alemtuzumab (Campath) usage as a preconditioning agent in kidney transplantation has gained considerable interest in the recent future. Alemtuzumab is currently available only by special request from Sanofi through its Campath distribution program. It is restricted to transplant programs with prior and continued experience with the agent. There may be a resurgence of interest for the utilization of this agent because of its ease of administration, and less cost and comparable or improved outcome in comparison to other induction agents. Alemtuzumab when combined with standard calcineurin inhibitor and mycophenolate mofetil is well tolerated and efficacious as an induction therapy and allows for long-term steroid avoidance in high-risk renal transplant recipients. The transplant community has advanced through a learning curve with the use of alemtuzumab over time; starting from an agent that was tried out to induce proper tolerance, minimization of nephrotoxic calcineurin inhibitors, and currently as a comparable depletional therapy that can reduce acute rejection in high-risk kidney transplant recipients.

Safe Conversion From Tacrolimus to Belatacept in High Immunologic Risk Kidney Transplant Recipients With Allograft Dysfunction

There is no literature on the use of belatacept for sensitized patients or regrafts in kidney transplantation. We present our initial experience in high immunologic risk kidney transplant recipients who were converted from tacrolimus to belatacept for presumed acute calcineurin inhibitor (CNI) toxicity and/or interstitial fibrosis/tubular atrophy. Six (mean age = 40 years) patients were switched from tacrolimus to belatacept at a median of 4 months posttransplant. Renal function improved significantly from a peak mean estimated glomerular filtration rate (eGFR) of 23.8 ± 12.9 mL/min/1.73 m(2) prior to the switch to an eGFR of 42 ± 12.5 mL/min/1.73 m(2) (p = 0.03) at a mean follow-up of 16.5 months postconversion. No new rejection episodes were diagnosed despite a prior history of rejection in 2/6 (33%) patients. Surveillance biopsies performed in 5/6 patients did not show subclinical rejection. No development of donor-specific antibodies (DSA) was noted. In this preliminary investigation, we report improved kidney function without a concurrent increase in risk of rejection and DSA in six sensitized patients converted from tacrolimus to belatacept. Improvement in renal function was noted even in patients with chronic allograft fibrosis without evidence of acute CNI toxicity. Further studies with protocol biopsies are needed to ensure safety and wider applicability of this approach.

Geographic Variation in Cold Ischemia Time: Kidney vs. Liver Transplantation in the United States, 2003-2011.

BackgroundRegional variations in kidney and liver transplant outcomes have been reported, but their causes remain largely unknown. This study investigated variations in kidney and liver cold ischemia times (CITs) across organ procurement organizations (OPO) as potential causes of variations in transplant outcomes.MethodsThis retrospective study analyzed the Standard Transplant Analysis and Research data of deceased donor kidney (n = 61,335) and liver (n = 39,285) transplants performed between 2003 and 2011. The CIT variations between the 2 types of organs were examined and compared. Factors associated with CIT were explored using multivariable regressions. Spearman rank tests were used to associate CIT with graft failure at the OPO level.ResultsSignificant CIT variations were found across OPOs for both organs (P < 0.05). The variation was particularly large for kidney CIT. Those OPOs with longer average kidney CIT were likely to have a lower graft survival rate (P = 0.01). For liver, this association was insignificant (P = 0.23). The regression analysis revealed sharp contrasts between the factors associated with kidney and liver CITs. High-risk kidney transplant recipients and marginal kidneys were associated with longer average CIT. The reverse was true for liver transplants.ConclusionsLarge variations in kidney CIT compared to liver CIT may indicate that there is a room to reduce kidney CIT. Reducing kidney CIT through managerial improvements could be a cost-effective way to improve the current transplant system.

83 Serum BAFF levels and B cell subsets in secondary lymphoid organs after rituximab administration: Its association with clinical outcomes

INTRODUCTION AND OBJECTIVES: Rituximab (RIT), antiCD20 antibody, has been applied to kidney transplantation because of its potent B-cell depleting effect. Although CD20+ cells in peripheral blood (PB) and spleen are consistently depleted in patients receiving RIT, the clinical effects are heterogeneous, probably related to differences in the depleting effects of secondary lymphoid organs (SLOs), such as peripheral lymph nodes (LNs). Meanwhile, B cell activation factor of the TNF family (BAFF) promotes B cell development and antibody secretion, and also serum BAFF levels increase after RIT administration. The aim of this study was to investigate the relationship between serum BAFF levels and B cell subsets in different lymphoid organs after RIT administration and its association with clinical outcomes. METHODS: Since April 2005, 50 patients with immunological high risks [ABO-incompatible (ABOI) or donor specific anti-HLA antibody (DSA) positive or both] received a single dose of RIT with 200 mg/ body at 3 weeks before kidney transplantation. They received 3 to 4 sessions of apheresis prior to transplantation. The induction immunosuppressive therapy was consisted of tacrolimus, MMF, steroid, and basiliximab. In all patients, the several pelvic LNs were dissected at the time of transplantation. Of those, 2 ABOI (induction period of RIT) and 6 DSA positive patients received splenectomy concurrently with transplantation. Immunohistochemical intensity of B cell subsets (CD20, CD27, CD79a, and CD138) in both LN and spleen was scored. Serum BAFF levels at day -7, 7, and 28 post-transplant were measured by ELISA. RESULTS: Acute antibody-mediated rejection (AAMR) developed in 9 patients (19%) in this series. The intensity score of CD138 in LNs was significantly higher in AMR patients (p<0.01) than those in non-AMR patients. No significant difference was found in the intensity scores of all B cell subsets in spleen among the patients with or without AMR. The serum BAFF levels at day -7 (p<0.01), 7 (p<0.05), and 28 (p<0.01) post-transplantation were significantly lower in AMR patients than in non-AMR patients. The existence of DSA before transplant, the intensity score of CD138 in LNs, and low serum BAFF level at 7 days before transplant were significantly associated with the occurrence of AAMR. CONCLUSIONS: In immunological high risk kidney transplant recipients receiving RIT before transplant, the plasma cell intensity in LNs and low serum BAFF level were risk factors of AAMR.

Efficacy and Safety of Combination Therapy With Tacrolimus and Sirolimus in Immunological High Risk Kidney Transplant Recipients.

Objective: The aim of this study was to evaluate the efficacy and safety of combination therapy with tacrolimus and sirolimus in immunological high risk recipients. Methods: From January 2010 to December 2011, 28 immunological high risk patients were enrolled according to the following criteria: 1) retransplantation, 2) Class I or II PRA >50%, 3) 5 or 6 HLA mismatches The efficacy endpoints were incidence of biopsy-proven acute rejection reaction, graft loss, patient death and renal function. The safety was evaluated by analyzing the adverse effects. Results: Among 28 total patients, 8 (28.6%) were dropped due to acute rejection, infection, pneumonitis, or postoperative hemorrhage. One patient death occurred due to fungal infection. Acute rejection developed in 6 (21.4%) patients. The mean eGFR (MDRD) for the 1st year after transplantation was 52.0 ± 4.0 mL/min/1.73m2. Fifteen (53.6%) patients had infections and 3 (10.7%) patients experienced pneumonitis. Lymphocele developed in 4 (14.3%) patients. Conclusion: The combination therapy with tacrolimus and sirolimus must be considered with caution for immunological high risk recipients due to high incidence of adverse events. Special attention should be given to the target blood concentration levels of the two drugs in order to minimize adverse events.

Improvement in Renal Function in High Immunologic Risk Kidney Transplant Recipients Switched From Tacrolimus to Belatacept.

Improvement in Renal Function in High Immunologic Risk Kidney Transplant Recipients Switched From Tacrolimus to Belatacept.

Prevention strategies for cytomegalovirus disease and long-term outcomes in the high-risk transplant patient (D+/R-): experience from the RESITRA-REIPI cohort.

Cytomegalovirus (CMV)-negative recipients of a graft from a CMV-positive donor (D+/R-) are at high risk of CMV disease. Current preventive strategies include universal prophylaxis (UP) and preemptive therapy (PT). However, the best strategy to prevent CMV disease and achieve better long-term outcomes remains a matter of debate. We analyzed the incidence of CMV disease and long-term outcomes including graft dysfunction and patient mortality at 5 years after transplantation with both preventive strategies. High-risk (D+/R-) kidney and liver transplant recipients from the RESITRA cohort were included. Of 2410 kidney or liver transplant patients, 195 (8.3%) were D+/R-. The final cohort included 58 liver and 102 kidney recipients. UP was given in 92 patients and 68 received PT; 10.9% and 36.8% developed CMV disease, respectively (P < 0.01). The independent risk factors for CMV disease were PT strategy (hazard ratio [HR], 3.30; 95% confidence interval [CI], 1.6-6.9), kidney transplantation (HR, 3.8; 95% CI, 1.4-9.9), and cyclosporine immunosuppression (HR, 2.4; 95% CI, 1.2-4.7). PT strategy was also a risk factor for CMV disease in both liver transplantation (HR, 11.0; 95% CI, 1.2-98.7) and kidney transplantation (HR, 2.7; 95% CI, 1.3-6.0), independently. The development of CMV replication during the first 2 years after transplantation was a risk factor for graft dysfunction at 5 years after transplantation (odds ratio, 3.4; 95% CI, 1.3-9.0). Nevertheless, no significant differences were seen in either graft dysfunction or mortality between the 2 strategies. The study supports the benefit of the UP strategy to prevent CMV disease in D+/R- liver or kidney transplant patients. The development of CMV replication during the first 2 years after transplantation was associated with graft dysfunction at 5 years after transplantation.

MP72-03 SERUM BAFF LEVELS AND B CELL SUBSETS IN DIFFERENT LYMPHOID ORGANS AFTER RITUXIMAB ADMINISTRATION: ITS ASSOCIATION WITH CLINICAL OUTCOMES

You have accessJournal of UrologyTransplantation & Vascular Surgery II1 Apr 2014MP72-03 SERUM BAFF LEVELS AND B CELL SUBSETS IN DIFFERENT LYMPHOID ORGANS AFTER RITUXIMAB ADMINISTRATION: ITS ASSOCIATION WITH CLINICAL OUTCOMES Mitsuru Saito, Shigeru Satoh, Kazuyuki Numakura, Mingguo Huang, Hiroshi Tsuruta, Susumu Akihama, Takamitsu Inoue, Shintaro Narita, Norihiko Tsuchiya, and Tomonori Habuchi Mitsuru SaitoMitsuru Saito More articles by this author , Shigeru SatohShigeru Satoh More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Mingguo HuangMingguo Huang More articles by this author , Hiroshi TsurutaHiroshi Tsuruta More articles by this author , Susumu AkihamaSusumu Akihama More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2242AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Rituximab (RIT), anti-CD20 antibody, has been applied to kidney transplantation because of its potent B-cell depleting effect. Although CD20+ cells in peripheral blood (PB) and spleen are consistently depleted in patients receiving RIT, the clinical effects are heterogeneous, probably related to differences in the depleting effects of secondary lymphoid organs (SLOs), such as peripheral lymph nodes (LNs). Meanwhile, B cell activation factor of the TNF family (BAFF) promotes B cell development and antibody secretion, and also serum BAFF levels increase after RIT administration. The aim of this study was to investigate the relationship between serum BAFF levels and B cell subsets in different lymphoid organs after RIT administration and its association with clinical outcomes. METHODS Since April 2005, 50 patients with immunological high risks [ABO-incompatible (ABOI) or donor specific anti-HLA antibody (DSA) positive or both] received a single dose of RIT with 200 mg/body at 3 weeks before kidney transplantation. They received 3 to 4 sessions of apheresis prior to transplantation. The induction immunosuppressive therapy was consisted of tacrolimus, MMF, steroid, and basiliximab. In all patients, the several pelvic LNs were dissected at the time of transplantation. Of those, 2 ABOI (induction period of RIT) and 6 DSA positive patients received splenectomy concurrently with transplantation. Immunohistochemical intensity of B cell subsets (CD20, CD27, CD79a, and CD138) in both LN and spleen was scored. Serum BAFF levels at day -7, 7, and 28 post-transplant were measured by ELISA. RESULTS Acute antibody-mediated rejection (AAMR) developed in 9 patients (19%) in this series. The intensity score of CD138 in LNs was significantly higher in AMR patients (p<0.01) than those in non-AMR patients. No significant difference was found in the intensity scores of all B cell subsets in spleen among the patients with or without AMR. The serum BAFF levels at day -7 (p<0.01), 7 (p<0.05), and 28 (p<0.01) post-transplantation were significantly lower in AMR patients than in non-AMR patients. The existence of DSA before transplant, the intensity score of CD138 in LNs, and low serum BAFF level at 7 days before transplant were significantly associated with the occurrence of AAMR. CONCLUSIONS In immunological high risk kidney transplant recipients receiving RIT before transplant, the plasma cell intensity in LNs and low serum BAFF level were risk factors of AAMR. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e824 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Mitsuru Saito More articles by this author Shigeru Satoh More articles by this author Kazuyuki Numakura More articles by this author Mingguo Huang More articles by this author Hiroshi Tsuruta More articles by this author Susumu Akihama More articles by this author Takamitsu Inoue More articles by this author Shintaro Narita More articles by this author Norihiko Tsuchiya More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Solid phase detection of C4d-fixing HLA antibodies to predict rejection in high immunological risk kidney transplant recipients

Protocols for recipient desensitization may allow for successful kidney transplantation across major immunological barriers. Desensitized recipients, however, still face a considerable risk of antibody-mediated rejection (AMR), which underscores the need for risk stratification tools to individually tailor treatment. Here, we investigated whether solid phase detection of complement-fixing donor-specific antibodies (DSA) has the potential to improve AMR prediction in high-risk transplants. The study included 68 sensitized recipients of deceased donor kidney allografts who underwent peritransplant immunoadsorption for alloantibody depletion (median cytotoxic panel reactivity: 73%; crossmatch conversion: n=21). Pre and post-transplant sera were subjected to detection of DSA-triggered C4d deposition ([C4d]DSA) applying single-antigen bead (SAB) technology. While standard crossmatch and [IgG]SAB testing failed to predict outcomes in our desensitized patients, detection of preformed [C4d]DSA (n=44) was tightly associated with C4d-positive AMR [36% vs. 8%, P=0.01; binary logistic regression: odds ratio: 10.1 (95% confidence interval: 1.6-64.2), P=0.01]. Moreover, long-term death-censored graft survival tended to be worse among [C4d]DSA-positive recipients (P=0.07). There were no associations with C4d-negative AMR or cellular rejection. [C4d]DSA detected 6months post-transplantation were not related to clinical outcomes. Our data suggest that pretransplant SAB-based detection of complement-fixing DSA may be a valuable tool for risk stratification.

Results of Immunosuppressive Switch in Polyoma Virus Nephropathy in Immunologically High Risk Kidney Transplant Recipients

Introduction: Polyoma virus nephropathy is one of the most dreadful complications after kidney transplantation and usually results in graft lost and jeopardizes the future possibility of re-transplantation. Here we present the results of five kidney transplant recipients (KTRs) who developed polyoma virus nephropathy (BKVN) within the first six months after living-related kidney transplantation (LRKT) and were switched to a new immunosuppressive regimen consisting of: low dose cyclosporin, low dose everolimus and reduced dose of antimetabolites. Methods: Four KTRs were men and one was a woman with an average age of 46 years. All were immunologically high risk KTRs with an average HLA mismatch of 4 and were transplanted their first grafts from living-related donors. All of them had received ATG (Fresenius S) and methylprednisolone (500 mg/day) as an induction therapy. The maintenance immunosuppressive treatment consisted of tacrolimus, mycophenolate mofetil (2 gm/day) and prednisolone (tapered from 40 mg/day to 5 mg/day within 6 weeks). Tacrolimus trough levels were monitored in all patients. All patients also received valganciclovir (900 mg/day) and TMP-SMX (400 mg/day) for prophylaxis. None of the recipients were diabetic but two of them developed NODAT and were receiving insulin treatment (HbA1C's %7.1 and 6.7). Results: Average time for BKVN after transplantation was 164 days. The initial presentation of the BKVN was an increase in serum creatinine levels (average increment from the baseline = 0.7 mg/dL) and CRP levels (average increment rate % 18). Mild proteinuria (< 500 mg/L) was detected in two patients. Average trough tacrolimus level was 9.8 mg/mL). The patients underwent graft biopsy and the biopsy samples were analyzed by a nephropathologist with light microscopy and immunofluorescent stainings. After receiving the initial pathology results, urine and plasma BKV PCRs were measured. Biopsies revealed BKVN with varying degrees of tubulointerstitial inflammation and all stained for SV40. Average plasma BKV copies were 800.000 copies/mL and urinary BKV copies were 160 million/mL. The average serum creatinine level was 1.8 mg/dL at the time of diagnosis. Tacrolimus was discontinued, MMF dose reduced to 1 gm/day and prednisolone dose was reduced to 5 mg/day immediately after diagnosis. Treatment with ciclosporin-A neoral 75 mg b.id. and everolimus 0.5 mg bid was initiated. Conclusion: Average follow-up period after this immunosupressive switch was 4 months. There was an initial increase in CRP and serum creatinine levels (average increase 0.3 mg/dL) after new regimen. The serum creatinine levels didn't return to baseline value but remained stable for four months for all of the patients. The average serum creatinine levels were 1.96 mg/dL at the end of four months. There was no graft loss and evidence of systemic polyoma virus infection. Although the follow-up period is brief and the number of patients in the study are insufficient, these preliminary findings suggest that low dose ciclosporin A and everolimus combination may prevent graft loss and rejection in immunologically high risk KTRs who develop BKVN in the early course after transplantation.

Studium 3 przypadków kwasicy nieoddechowej u pacjentów po przeszczepieniu nerki otrzymujących leczenie p/CMV

To preserve kidney graft function it is necessary to use ganciclovir or valganciclovir as a therapy for fresh CMV infection or prophylaxis in high-risk kidney transplant recipients. Ganciclovir-induced lactic acidosis has thus far not been reported. Three cases of nonrespiratory acidosis in kidney transplant recipients receiving ganciclovir or valganciclovir as anti-CMV therapy or prophylaxis are presented. Lactic acidosis developed in 2 patients, and the other patient had nonrespiratory acidosis of unknown origin. The possible mechanism of the development of lactic acidosis in presented cases is explored. The analysis of the described cases cannot eliminate the potential negative influence of anti-CMV therapy on acid-base equilibrium, especially with coexisting active viral infection.

PIN83 Cost-Effectiveness and Cost-Utility analysis of 200 Days Prophylaxis of Cytomegalovirus (CMV) infections in High Risk (D+/R-) Kidney Transplant Recipients in Poland

PIN83 Cost-Effectiveness and Cost-Utility analysis of 200 Days Prophylaxis of Cytomegalovirus (CMV) infections in High Risk (D+/R-) Kidney Transplant Recipients in Poland

Regarding: Humar et al. The Efficacy and Safety of 200 Days Valganciclovir Cytomegalovirus Prophylaxis in High-Risk Kidney Transplant Recipients. Am J Transplant 2010;10:1228–1237

Regarding: Humar et al. The Efficacy and Safety of 200 Days Valganciclovir Cytomegalovirus Prophylaxis in High-Risk Kidney Transplant Recipients. Am J Transplant 2010;10:1228–1237

Rabbit Anti-Thymocyte Globulin: Evidence for Clinical Benefit in High Immunological Risk Kidney Transplantation

Rabbit anti-thymocyte globulin is used worldwide to treat and prevent rejection in kidney transplantation. Multiple mechanisms of action of this polyclonal preparation are responsible for its success. Studies have supported clinical benefits of rabbit anti-thymocyte globulin in high immunological risk kidney transplant recipients when used as an induction agent at the time of transplant and for treatment of rejection when compared to other antibody therapy. The evidence of this clinical benefit will be reviewed in addition to examining the dosing and safety profile of rabbit anti-thymocyte globulin.

Prolonged Prophylaxis With Valganciclovir Is Cost Effective in Reducing Posttransplant Cytomegalovirus Disease Within the United States

Cytomegalovirus (CMV) disease in transplant patients is known to have a substantial clinical and economic burden, and its prevention is expected to have long-term benefits. Evidence from the Improved Protection Against CMV in Transplant trial proved that prolonged prophylaxis of 200 days with valganciclovir compared with 100 days significantly reduces the incidence of CMV in high-risk kidney transplant seropositive donors/seronegative recipients. The aim of this study was to develop a cost-effectiveness model to evaluate prolonged prophylaxis of 200 days with valganciclovir and its long-term economic impact. An economic model was designed to simulate long-term costs and outcomes of prolonged prophylaxis with valganciclovir (200 vs. 100 days) in a cohort of 10,000 high-risk renal transplant patients over 5 and 10 years. The first year of the model was based on the results of the Improved Protection Against CMV in Transplant trial and the extension to the long-term periods (5 and 10 years); and quality of life data were based on evidence retrieved through a systematic literature search. This analysis was conducted from the US healthcare payer perspective. For the 5-year time horizon, the incremental cost-effectiveness ratio of US $14,859/quality-adjusted life year (QALY) suggests that 200-day valganciclovir prophylaxis is cost effective over the 100-day regimen considering a threshold of US $50,000/QALY. The 10-year analysis revealed the 200-day prophylaxis as cost saving with a 2380 QALY gain and simultaneously lower cost. Prolonged prophylaxis with valganciclovir reduces the incidence of events associated with CMV infection in high-risk kidney transplant recipients and is a cost-effective strategy in CMV disease management.

Prophylactic Therapy With Valganciclovir in High-Risk (Cytomegalovirus D +/R −) Kidney Transplant Recipients: A Single-Center Experience

Background A prospective study was performed in kidney transplant patients at risk of developing cytomegalovirus (CMV) infection (CMV D +/R −). They were treated with valganciclovir (VGC) for 3 months as prophylactic therapy. The aim was to determine the safety and efficacy of prophylactic therapy with VGC. Methods Antigenemia and/or polymerase chain reaction CMV was routinely performed every 2 weeks up to month 3, monthly to month 6, and every other month until the end of the first year posttranplantation, as well as when clinically indicated. Results From July 2007 to April 2010, 366 renal transplantations were performed at our center, including 34 (9%) high-risk patients for CMV infection. The median age was 47 years; 19 were males and 15 females. Twelve (35%) patients developed CMV infections: 10 (34%) gastrointestinal disease and 3 viral syndromes. The timing of the clinical manifestations was 16% (3/12) between months 1 and 3, 75% (8/12) between months 4 and 6, and 8% (1/12) in month 9 posttransplantation. Conclusion Treatment with intravenous ganciclovir followed by oral VGC was successful in all patients. No opportunistic infections or allograft rejection were observed; only 1 patient developed thrombocytopenia as an adverse event to VGC.

Reduced Dose Rabbit Anti-Thymocyte Globulin Induction for Prevention of Acute Rejection in High-Risk Kidney Transplant Recipients

Despite the prevalent use of rabbit antithymocyte globulin (rATG) as an induction agent in kidney transplantation, the appropriate dose for preventing acute rejection in high-risk patients is not known. Few studies have examined total exposure of rATG less than 6 mg/kg, with fewer studies examining lower dose rATG in patients with increased risk factors for acute rejection. We retrospectively analyzed outcomes of 83 kidney transplant recipients at increased risk for acute rejection (repeat transplant, African American race, and panel reactive antibody > or =20%) from July 2004 to July 2007 who were treated with rATG 1.5 mg/kg per day for 3 (n=39) or 4 (n=44) doses for induction to determine the impact of reduced-exposure rATG in the prevention of acute rejection. rATG was initiated intraoperatively and continued on consecutive days. All patients received triple maintenance immunosuppression including prednisone and calcineurin inhibitor. Patients requiring dialysis within 48 hr after transplant were excluded from analysis. One-year acute rejection rates were 10% and 11% in the 3- and 4-dose cohorts, respectively, with 100% patient and graft survival at 1 year in both groups. Patients in the 3-dose cohort were discharged from the hospital sooner than the 4-dose cohort (median length of hospital stay, 3 vs. 4 days; P=0.004). Our results suggest that a 3- or 4-dose course of rATG (1.5 mg/kg/dose) provides excellent protection against acute rejection even in patients at increased risk, with the potential for cost savings from a reduction in hospital stay and medication administration.

Thymoglobulin Dose Optimization for Induction Therapy in High Risk Kidney Transplant Recipients

Thymoglobulin (rATG) has become the agent of choice for induction therapy in high immunological risk kidney transplant recipients. However, its optimal dosing in this subgroup has not been studied. To evaluate the effect of total rATG dosing on graft outcomes in such patients, we conducted a retrospective cohort study of 96 adult patients who received repeat transplants (85%) or had panel reactive antibody more than 40% (19%) and were maintained on tacrolimus, mycophenolate mofetil, and steroid. Group 1 (n=33) received less than or equal to 7.5 and group 2 (n=63) received more than 7.5 mg/kg rATG. Graft and patient survival, incidence of acute rejection (AR), and 12-month serum creatinine (SCr) were examined. The groups were comparable regarding demographics, donor source, retransplantation, panel reactive antibody, and human leukocyte antigen mismatch. Group 2 had more African Americans (44.4% vs. 21.2%, P=0.03). During the 25.4+/-18.0 months follow-up graft survival was 82.5% and 79.4%, respectively (P=0.54). Three in group 1 and four in group 2 died (P=0.65). The incidence of biopsy proven AR during the first 12-months did not differ between the groups (9.5% vs. 8.8%, respectively, P=0.9). SCr at 12 months was 1.6+/-0.7 in group 1 and 1.8+/-1.0 in group 2 (P=0.3). There was no independent association between rATG dose and graft survival (hazard ratio: 0.85, P=0.79, 95% CI: 0.26-2.7 for group 2 vs. 1) or 1-year SCr (regression coefficient=0.02 for ln(SCr), P=0.3; 95%CI: -0.01 to 0.6). Our results suggest that in high risk kidney transplant recipients total rATG doses less than or equal to 7.5 mg/kg are safe and effective in achieving a low rate of AR and graft outcomes comparable to higher doses.

Delayed-Onset Primary Cytomegalovirus Disease and the Risk of Allograft Failure and Mortality after Kidney Transplantation

During the contemporary era of antiviral prophylaxis, the impact of delayed-onset primary cytomegalovirus (CMV) disease on the outcome of kidney transplantation is not known. We evaluated the incidence, clinical features, risk factors, and outcomes of CMV disease among high-risk kidney transplant recipients. The medical records of CMV-seronegative recipients of kidney transplants from CMV-seropositive donors were reviewed. Cox proportional hazards regression was used to identify factors associated with CMV disease and to assess its impact on allograft loss and mortality. None of the 176 CMV-seronegative recipients of kidney transplants from CMV-seropositive donors developed breakthrough CMV disease during a median of 92 days (interquartile range, 90-92 days) of oral ganciclovir or valganciclovir prophylaxis. Thereafter, 51 patients (29%) developed CMV disease at a median of 61 days (interquartile range, 40-143 days) after stopping antiviral prophylaxis. Early-onset bacterial and fungal infection (hazard ratio, 3.61; 95% confidence interval, 1.78-7.33; p < .001) and a Charlson comorbidity index > or =3 (hazard ratio, 2.21; 95% confidence interval, 1.15-4.22; p = .011) were associated with a higher risk of delayed-onset primary CMV disease, and postrejection antiviral prophylaxis (hazard ratio, 0.29; 95% confidence interval, 0.09-0.94; P = .039) was associated with a lower risk of such CMV disease. A time-dependent Cox regression analysis revealed a statistically significant association between tissue-invasive CMV disease and allograft loss or mortality (hazard ratio, 2.85; 95% confidence interval, 1.22-6.67; P = .016). This study of a large cohort of CMV-seronegative recipients of kidney transplants from CMV-seropositive donors illustrates the ongoing challenge of delayed-onset primary CMV disease and its impact on transplantation outcomes despite antiviral prophylaxis. Better strategies for CMV disease prevention after kidney transplantation are warranted.