M. R. Laftavi

Basiliximab plus low-dose cyclosporin vs. OKT3 for induction immunosuppression following renal transplantation.

Abstract: Background:  Current immunosuppressive therapies are very effective in preventing acute rejection (AR) and graft loss following renal transplantation. Newer agents now make it possible to develop equally efficacious but better tolerated and less toxic strategies. This is especially relevant for our ageing recipients. We now compare the efficacy of basiliximab combined with early low‐dose cyclosporin therapy to standard OKT3 induction therapy.

Prognostic Utility of Hypothermic Machine Perfusion in Deceased Donor Renal Transplantation

UNLABELLED Pulsatile pump perfusion of kidney transplants is known to decrease delayed graft function (DGF) and improve 1 year graft survival when compared to static cold preservation. Kidneys with better flow and resistance parameters on perfusion are likely to have a better post transplant function. These parameters are commonly used to evaluate kidneys being considered for transplantation. This study assesses the time frame for a kidney within which it reaches optimal perfusion parameters. All kidneys pumped between 5/2006 and 9/2009 on a Lifeport© kidney transporter at our local organ procurement agency were studied. 190 kidneys were evaluated and then divided into two groups based on whether terminal flows increased or declined after prolonged perfusion. All kidneys were assessed for changes in flow (F), resistance (R) and temperature at 15 minute intervals. Discards, DGF and one year graft survival were noted. The Student paired t test and Chi-square analysis were used to compare data. A multiple logistic regression analysis was performed to study independent predictors of DGF on pump perfusion. RESULTS For all kidneys, the mean initial flow was 59 ± 35 mL/min which improved to an average flow of 128 ± 38 mL/min with continued perfusion. The maximal flow and terminal flows were 148 ± 51 and 135 ± 38 mL/min respectively. The flows at 2, 4, and 6 hours was 125 ± 41, 128 ± 42 and 130 ± 39 mL/min respectively. Kidneys that improved on continued perfusion had a significantly lower discard rate (20 vs 34% p < 0.05), but a higher incidence of DGF (64 vs 39%, P < .05). One year graft loss (death censored) was comparable in the two groups. (4/42 vs. 3/33, P = .94). Resistance at 2, 4, and 6 hours was predictive of DGF, as was donor anoxia and cerebrovascular accident (CVA) as the cause of death. CONCLUSIONS Kidneys on pulsatile pump perfusion tend to show improved flows and decreased resistance over time. The average flow for a kidney is reached by 2 hours. Those kidneys that start with lower flow rates that improve after 2 hours with continued perfusion are less likely to be discarded but are still associated with a greater incidence of delayed graft function. Resistance at 2 hours predicts DGF while initial resistance predicts one year graft survival.

Low-Dose Rabbit Antithymocyte Globulin Versus Basiliximab Induction Therapy in Low-Risk Renal Transplant Recipients: 8-Year Follow-Up

Antibody induction is effective in preventing acute rejection, but its effects on long-term renal allograft function and survival remain controversial. Moreover, given the risks of antibody induction, full-dose lymphocyte-depleting therapy for low-risk patients is usually avoided. However, the benefit and risks associated with low-dose (Lo) rabbit antithymocyte globulin (rATG; 3-5 mg/kg total) induction in a low-risk population have not been explored. We now report the long-term outcomes in this patient population. We defined low risk as white, panel-reactive antibody<30%, and non-Donor with Cardiac Death (DCD) recipients. We compared the risk of acute rejection and graft survival for both living donor (LD) and deceased donor (DD) recipients. The average dose of rATG was 3.1±1.2 mg/kg. Forty DD recipients received basiliximab (BSX) and 145 patients were induced with Lo rATG. Twenty LD recipients received BSX and 64 received Lo rATG. The groups did not differ in demographics, donor characteristics, and maintenance immunosuppression. At 8 years, patient survival was higher for LD patients compared to DD recipients (91% vs 45%, P=.004). In recipients of LD kidneys, 8-year patient survivals were not different comparing Lo rATG and BSX groups (92% vs 91%, respectively, P=.55). In LD, 8-year graft survival was excellent irrespective of induction (Lo rATG 100% vs BSX 98%); however, Lo rATG was associated with a lower rate of acute rejection (7.8% vs 35% BSX, P<.01) and better mean serum creatinine at 3 and 5 years (1.2 vs 1.5, P=.02 and 1.18 vs 1.54, P=.04, respectively). For DD, Lo rATG was associated with a better long-term graft survival (86% vs 76% BSX, P=.02). Viral infections and cancer rates were similar for Lo rATG and BSX. Thus, we conclude that Lo rATG induction may add long-term benefit in low-risk patients compared to anti-interleukin-2 receptor therapy without incurring additional risks of infectious or malignant diseases.

Dual Kidney Transplants From Very Old or Very Young Donors: Long-Term Outcomes and Complications

The disparity between donors and the demand for organ transplants grows steadily. Annually, 4700 patients die on the kidney transplant waiting list in the United States. To increase utilization of deceased donor organs, we expanded our acceptable criteria to include very old (VO) or very young (VY) donors. We transplanted both such kidneys (dual transplant) into a single recipient and evaluated the long-term outcomes and complications. From July 2001 to December 2005, 16 patients (mean age 68, range 60-78) received dual kidneys from VO (mean age 72, range 60-79) donors and 6 patients (mean age 47, range 27-72) were transplanted from VY (mean age 17 months, range 2-36) donors. Seventy-four percent of these kidneys were imported after rejection by their local center due to low glomerular filtration rate (GFR) and extreme age. One- and 5-year patient survival rates were 100% and 88%, respectively. Death-censored 1- and 5-year graft survival rates for recipient of VO kidneys were 95% and 93%, and 66% and 50% for recipients of VY kidneys, respectively. Five-year graft survival rate for recipients of VO donor kidneys was 93% and was equal to the survival of standard deceased donor (SCD) kidney transplants (87%). The 5-year survival of dual transplants from VO donors was higher than expanded criteria deceased donor (ECD; P=.05). Over a mean follow-up of 66±28 months, rejection rates were 10%, not statistically different than other groups. Of 22 dual transplants, four patients experienced urinary tract infections; three developed incisional subcutaneous seromas, and there were more urinary leaks compared to SCD (13.6% vs 2%, P=.002). The average 1- and 5-year estimated GFR (Cockcroft-Gault) was 57.4 and 54.6 mL/min, respectively. When properly placed in a single patient, such marginal organs are a valuable resource that offer comparable outcomes to SCD transplants and superior outcomes to ECD organs.

African American renal transplant recipients (RTR) require higher tacrolimus doses to achieve target levels compared to white RTR: does clotrimazole help?

The number of African Americans (AAs) on the kidney waiting list is increasing in the United States. Several studies showed that AAs are at higher risk for rejection and graft loss. Because of genetic polymorphisms, AAs may metabolize calcineurin inhibitors faster than Caucasian (C) individuals. The goal of this study is to evaluate the tacrolimus (TAC) dose required to reach therapeutic levels and to assess the impact of clotrimazole on TAC metabolism in AAs compared to C patients. One hundred forty-two AA renal transplant recipients (RTRs) were compared to 309 C RTRs. Demographics were similar in both groups. Induction therapy and maintenance immunosuppression were similar in both groups and included TAC, mycophenolate acid (MPA), and steroids. The goal in all RTRs was to maintain a 12-hour trough level of 10 to 15 ng/mL in the first 3 months, 8 to 10 ng/mL for the first year, and 5 to 8 ng/mL thereafter. To achieve these levels, AA RTRs require a significantly higher dosage of TAC compared to C patients (5.9 ± 2.9 vs 3.6 ± 2 mg/d, respectively, P < .0001). By multivariate analysis, TAC dose requirements were not affected by age, gender, MPA or prednisone dose, diabetes, and renal function. Adding clotrimazole (CTM) to the RTR regimen significantly reduced the TAC dose requirements in all RTRs. When CTM was used, the TAC dose requirement was not statistically significantly different between AA and C patients (2.6 ± 1.2 mg/d vs 1.8 ± 1.5 mg/d, P = .07). We conclude that AAs required a higher TAC dose to reach the desired trough level in RTRs compared to C RTRs. The use of CTM eliminates the need for higher doses of TAC in AA RTRs. Thus, CTM may aid AA RTRs in achieving therapeutic TAC levels while reducing drug costs.

Induction Therapy in Renal Transplant Recipients: A Review

Transplant science has improved significantly over the last decade. Influenced by novel advancements, rejection rates and short-term graft losses diminished substantially. Induction therapy was shown to reduce rejection rates and improve short-term graft survival. In this article, we discuss the most commonly used induction agents and the choice of induction therapy in different renal transplant recipient subgroups. The medical literature as well as our own experience was used to prepare this review. At this time, induction therapy is commonly used in upwards of 80%, of renal transplant recipients. Depleting agents are the most frequently used agents and they account for more than 75% of all induction therapies in the United States. Currently, there is no consensus regarding the choice of induction therapy. The type of induction therapy is generally selected based on a comprehensive evaluation of the recipient and the donor’s immunological risks, the risk of developing opportunistic infection and malignancy, recipient comorbidities, financial burden and the choice of maintenance immunosuppressive regimen.

The increasing clinical importance of alloantibodies in kidney transplantation

Historically, cellular rather than humoral immunity has gathered the most attention in kidney transplantation. As the specter of cellular acute rejection and early graft loss has faded due to the availability of highly effective immunosuppressive therapy, scientific and clinical studies now focus on improving long-term graft survival. It is increasingly appreciated that alloantibodies directed against HLA and non-HLA antigens are key factors in determining graft longevity. Significant efforts are now being made to better understand the critical impact that B cells and alloantibodies make on organ allocation and graft survival. Future therapies directed specific for the humoral alloresponse will undoubtedly lead to improved outcomes after kidney transplantation. This review will cover some of the advances in the understanding and management of the continuum of humoral immunity in renal transplantation in the pre, peri and post-transplant periods.

Universal perioperative antimicrobial prophylaxis is not necessary in kidney transplantation.

Laftavi MR, Rostami R, Patel S, Kohli R, Laftavi H, Feng L, Said M, Dayton M, Pankewycz O. Universal perioperative antimicrobial prophylaxis is not necessary in kidney transplantation. 
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01531.x. 
© 2011 John Wiley & Sons A/S.

The Role of Antibiotic Prophylaxis in the New Era of Immunosuppression

Despite significant improvements in renal transplantation (RTX), certain basic issues remain unresolved such as the routine use of perioperative antibiotic prophylaxis (PAP). To address the need for PAP, we retrospectively evaluated the clinical course of 349 consecutive RTX patients who did not receive any PAP except for Bactrim. Of the 349 transplant recipients, 77% received induction therapy with low-dose rabbit antithymocyte globulin (rATG) and the others were treated with basiliximab. All patients received triple immunosuppression with tacrolimus, mycophenolic acid, and prednisone. Seven patients (2%) developed wound infections. Wound infections were more common in obese and older patients. All wound infections were superficial and responded well to wound drainage and outpatient antibiotic therapy. Six patients (1.7%) experienced a urinary tract infection (UTI) within the first postoperative month. UTIs were more common in the patient with ureteral stent compared to nonstented patients (11.4% vs 0.3%, P<.001). No patient or graft was lost due to perioperative bacterial infections (PBI). Our study shows that despite many predisposing factors, PBI are rare following RTX even in the absence of PAP. Therefore, in order to avoid emergence of multiantibiotic-resistant pathogens, excessive costs, and antibiotic-related adverse events, we suggest that PAP should be used only in selected circumstances such as in recipients older than 60 or when the body mass index is greater than 35.

Regulation of human interleukin 14 transcription in vitro and in vivo after renal transplantation.

Background. Alloantibodies and B lymphocytes are felt to contribute in increasingly important ways to the pathogenesis of both acute and chronic allograft injury. The mechanisms that lead to the formation of posttransplant alloantibodies despite immunosuppressive therapy have not been fully elucidated. Interleukin 14 (IL-14) or high molecular weight B cell growth factor secreted by activated T and B cells and follicular dendritic cells promotes B cell growth, survival and memory, and antibody production. The potential role of IL-14 in human transplantation has not been examined. Methods. Using quantitative polymerase chain reaction techniques, we examined IL-14 mRNA transcript levels in human cells and compared them to IL-2. Interleukin-14 mRNA levels were measured in isolated human T cells stimulated in vitro with mitogen and alloantigen in the presence or absence of immunosuppressive drugs. In vivo, IL-14 transcript levels were measured in peripheral blood leukocytes isolated from patients after renal transplantation. Results. In vitro, both IL-14 and IL-2 transcript levels increase after alloantigen and mitogen stimulation and are suppressed by currently used immunosuppressive agents. In vivo, IL-14 and IL-2 behave differently as IL-14 transcript levels are not reduced by immunosuppressive therapy. Interleukin-14 transcripts also increase after both immune and nonimmune injury to renal allografts. Conclusions. This is the first demonstration of human IL-14 mRNA regulation in vitro and in vivo. Given the important effects of IL-14 on B cell proliferation and antibody production, increases in IL-14 transcript levels may play a role in alloantibody formation after renal transplantation.