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Chronic opioid usage (COU) is common among patients with end-stage renal disease (ESRD) qualified for kidney transplantation and associated with inferior post-transplant outcomes. The magnitude of COU after kidney transplantation and its impact on transplant outcomes remain unknown. We performed a single-center retrospective study aimed to describe the prevalence of COU during the first year, to identify the predictors of COU and to determine the impact of COU on post-transplant outcomes including the rates of hospitalization and acute rejection during the first year, as well as long-term patient and graft survival. Among 1045 kidney transplant patients, 119 (11.4%) had required continued outpatient prescription of opioid analgesics during the first year after kidney transplantation, mostly for non-surgery-related pain (85%). A positive history of COU prior to transplantation was the strongest predictor of COU in the first year post-transplantation (adjusted odds ratio [AOR] 4.31, p

Unplanned hospital readmissions are common early post-kidney transplantation. We investigated the relationship between early hospital readmissions and clinical outcomes in a single-center retrospective study that included all adult kidney transplant patients between 2004 and 2008 with follow-up to December 2012. The early hospital readmissions within the first 30 d were numbered and the diagnosis ascertained. Patients were grouped as none, once, and twice or more readmissions. Predictors of early readmissions were assessed, and clinical outcomes and patient and death-censored kidney survival were compared. Among 1064 patients, 203 (19.1%) patients had once and 83 (7.8%) patients had twice or more readmissions within 30 d. Surgical complications, infections, and acute kidney injuries/acute rejection were three most common diagnoses. The length of initial hospital stay and African American race were among the variables associated significantly with readmissions. Patients with early readmissions had lower baseline renal function (p

Chronic opioid usage (COU) for analgesia is common among patients with end-stage renal disease. In order to test whether a prior history of COU negatively affects post-kidney transplant outcomes, we retrospectively examined clinical outcomes in adult kidney transplant patients. Among 1064 adult kidney transplant patients, 452 (42.5%) reported the presence of various body pains and 108 (10.2%) reported a prior history of COU. While the overall death or kidney graft loss was not statistically different between patients with and without a history of COU, the cumulative mortality rate at 1, 3, and 5 years after transplantation, and during the entire study period, appeared significantly higher for patients with than without a history of COU (6.5, 18.5, and 20.4 vs. 3.2, 7.5, and 12.7%, respectively). Multivariate Cox regression analysis adjusted for potential confounding factors in entire cohorts and Cox regression analysis in 1:3 propensity-score matched cohorts suggest that a positive history of COU was significantly associated with nearly a 1.6- to 2-fold increase in the risk of death (hazard ratio 1.65, 95% confidence interval 1.04-2.60, and hazard ratio 1.92, 95% confidence interval 1.08-3.42, respectively). Thus, a history of chronic opioid usage prior to transplantation appears to be associated with increased mortality risk. Additional studies are warranted to confirm the observed association and to understand the mechanisms.

Delayed graft function (DGF) is a common complication of deceased donor kidney transplantation with negative impact on clinical outcomes. In a single-center retrospective analysis, we compared patient and kidney survival, early renal function, and the incidence of acute rejection during the first year among all adult deceased donor kidney transplant patients without DGF, with DGF requiring one-time and/or more than one-time dialysis treatment between January 1, 2000, and December 31, 2008. Of 831 adult kidney transplant patients, 74 (8.9%) required one-time and 134 (16.1%) more than one-time dialysis treatment post-transplantation, respectively. While DGF patients with one-time dialysis treatment had comparable clinical outcomes to that of patients without DGF, patients with DGF requiring more than one-time dialysis treatment had a 45% increased risk for death (HR 1.45, 95% CI 1.02, 2.05, p = 0.04) after adjustment for the differences in demographic and baseline characteristics. Furthermore, DGF patients with more than one-time dialysis requirement displayed significantly lower renal function after recovery (OR 0.32, 95% CI 0.21, 0.49, p < 0.001, for eGFR ≥ 60 mL/min) and higher incidence of acute rejection during the first year (OR 1.66, 95% CI 1.11, 2.49, p = 0.015). Additional studies of therapeutic approaches to manage patients with prolonged DGF are needed.

Pancreas after kidney (PAK) transplantation is one of the accepted pancreas transplant modalities. We studied the impact of time interval between kidney and pancreas transplantation on the outcomes of PAK transplantation. Using OPTN/SRTR data, we included 1853 PAK transplants performed between 1996 and 2005 with follow-up until November 1, 2008. Kaplan-Meier survival and multivariate Cox regression analyses were performed using the time interval between kidney and pan- creas transplantation either as a categorical (less than one yr, between one and less than three yr, and greater than or equal to three yr) or as a continuous variable (months) to assess kidney graft and patient survival. Patients who received a pancreas transplant three yr or later after kidney transplantation had higher risk of death-censored kidney graft loss (HR 1.56, 95% CI 1.04, 2.32, p = 0.03). Each month beyond three yr between kidney and pancreas transplantation incurred 1% higher risk of subsequent death-censored kidney graft loss (HR 1.01, 95% CI 1.001, 1.02, p = 0.03). In conclusion, time interval between pancreas and kidney transplantation is an independent risk factor of kidney graft loss following pancreas trans- plantation. Shortening the time interval between pancreas and kidney transplantation to less than three yr may reduce the risk of kidney graft loss in qualified PAK transplant candidates.

Several studies have demonstrated that angiotensin-converting enzyme inhibitors (ACEIs) blunt progression of renal disease in nondiabetic patients with chronic kidney disease (CKD).1–4 However, ACEIs can cause hyperkalemia by impairing renal potassium excretion through interference with production and/or secretion of aldosterone.5 Hyperkalemia from ACEI use has been frequently described,6–8 and ACEIs are often underprescribed in patients with CKD because of concerns of hyperkalemia.9 β-Blocker (BB) use has also been associated with hyperkalemia, most likely through redistribution of potassium from intracellular to extracellular compartments as a result of blockade of β2-adrenoreceptor–mediated cellular potassium uptake.10,11 The African American Study of Kidney Disease and Hypertension (AASK) was a randomized clinical trial in nondiabetic African Americans with hypertensive CKD. One primary goal was to determine the effects of 3 different classes of antihypertensive agents on progression of renal disease: a dihydropyridine calcium channel blocker (CCB), a BB, and an ACEI. The most beneficial drug therapy was with ACEIs.12 The other primary goal was to determine the effects of 2 different BP goals on progression of renal disease; the trial demonstrated that a target mean arterial BP (MAP) of 102 to 107 mm Hg was as effective as stricter BP goal of a MAP lower than 92 mm Hg.12 Participants had a glomerular filtration rate (GFR) between 20 and 65 mL/min/1.73 m2 and no identified causes of renal insufficiency other than hypertension. After the close of the trial phase of the AASK, the investigators were directed by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) appointed Data Safety Monitoring Board to use the AASK database to explore factors associated with development of hyperkalemia. In this report, we describe the incidence of hyperkalemia by class of antihypertensive drug in the AASK and report the independent associations of other clinically measured factors

New-onset diabetes after transplant (NODAT) is a serious complication after kidney transplantation. We studied the relationship between steroid-free maintenance regimens and NODAT in a national cohort of adult kidney transplant patients.A total of 25,837 previously nondiabetic kidney transplant patients, engrafted between January 1, 2004, and December 31, 2006, were included in the study. Logistic regression analysis was used to compare the risk of developing NODAT within 3 years after transplant for patients discharged with and without steroid-containing maintenance immunosuppression regimens. The effect of transplant program-level practice regarding steroid-free regimens on the risk of NODAT was studied as well.The cumulative incidence of NODAT within 3 years of transplant was 16.2% overall; 17.7% with maintenance steroids and 12.3% without (P0.001). Patients discharged with steroids had 42% greater odds of developing NODAT compared with those without steroids (adjusted odds ratio [AOR]=1.42, 95% confidence interval [CI]=1.27-1.58, P0.001). The maintenance regimen of tacrolimus and mycophenolate mofetil or mycophenolate sodium was associated with 25% greater odds of developing NODAT (AOR=1.25, 95% CI=1.08-1.45, P=0.003) than the regimen of cyclosporine and mycophenolate mofetil or mycophenolate sodium. Several induction therapies also were associated with lower odds of NODAT compared with no induction. Patients from programs that used steroid-free regimens for a majority of their patients had reduced odds of NODAT compared with patients from programs discharging almost all of their patients on steroid-containing regimens.The adoption of steroid-free maintenance immunosuppression at discharge from kidney transplantation in selected patients was associated with reduced odds of developing NODAT within 3 years.

Luan FL, Langewisch E, Ojo A. Metabolic syndrome and new onset diabetes after transplantation in kidney transplant recipients. Clin Transplant 2010: 24: 778–783. © 2009 John Wiley & Sons A/S. Abstract: Background: Metabolic syndrome (MS) and new onset diabetes after transplant (NODAT) are common in kidney transplant patients. We studied the relationship between the two conditions and their impact on metabolic and cardiovascular risk profiles. Methods: All non-diabetic patients transplanted between 1999 and 2005 who were followed up to 2006 were included. MS and NODAT were determined. Kaplan–Meier survival and various regression analyses were performed to determine the clinical correlates for both conditions and their association with various cardiovascular risk factors. Results: Among 591 patients, 314 (53.1%) had MS and 90 (15.2%) developed NODAT. The two conditions were highly associated with each other as 84 patients with NODAT also had MS (14.2%). Elevated body mass index and fasting glucose levels at transplant were risk factors for both conditions, whereas weight gain after transplant was associated only with MS. African American, old age, and hypertension-related ESRD were risk factors for NODAT. Finally, the presence of MS was associated with reduced kidney function and elevated uric acid levels, whereas the presence of NODAT with elevated pulse pressure. Conclusions: MS and NODAT are highly prevalent and significantly associated with impaired metabolic and cardiovascular risk profiles. Early identification of such conditions may facilitate targeted therapeutic intervention.

Racial differences on the outcome of simultaneous pancreas and kidney (SPK) transplantation have not been well studied. We compared mortality and graft survival of African Americans (AA) recipients to other racial/ethnic groups (non-AA) using the national data. We studied a total of 6585 adult SPK transplants performed in the United States between January 1, 2000 and December 31, 2007. We performed multivariate logistic regression analyses to determine risk factors associated with early graft failure and immune-mediated late graft loss. We used conditional Kaplan-Meier survival and multivariate Cox regression analyses to estimate late death-censored kidney and pancreas graft failure and death between the groups. Although there was no racial disparity in the first 90 days, AA patients had 38% and 47% higher risk for late death-censored kidney and pancreas graft failure, respectively (p = 0.006 and 0.001). AA patients were twice more likely to lose the kidney and pancreas graft due to rejection (OR 2.31 and 1.86, p = 0.002 and 0.008, respectively). Bladder pancreas drainage was associated with inferior patient survival (HR 1.42, 95% CI 1.15, 1.75, p = 0.001). In the era of modern immunosuppression, AA SPK transplant patients continue to have inferior graft outcome. Additional studies to explore the mechanisms of such racial disparity are warranted.

Background. Malignancy is a dreaded complication of organ transplantation. Immunosuppressive drug therapy-induced impairment of the organ graft recipient's immune surveillance is considered to be the mechanism for the heightened incidence and metastatic progression. We identified a cell-autonomous and host-immunity independent mechanism for cyclosporine-associated tumor progression. In this study, we investigated the effect of rapamycin on tumor progression, in the presence and absence of cyclosporine. Methods. A spontaneously arising renal adenocarcinoma (renal cancer) of BALB/c origin was used as the model tumor. The effect of rapamycin on renal cancer cell phenotype, molecules (E-cadherin, p27 kipl, cyclin Dl) implicated in tumor progression, and the effect of rapamycin on in vivo tumor progression were explored in BALB/c mice and in T-cell, B-cell, and natural killer (NK) cell-deficient severe combined immune deficiency (SCID)-beige mice. In the SCID-beige mice, T24 human bladder transitional cell carcinoma also was used as the tumor inoculum. Results. Rapamycin conditioning of renal cancer cells upregulated E-cadherin expression and induced phenotypic transition from invasive spindle, or dome-shaped cells, with exploratory pseudopodia to noninvasive cuboidal cells that formed cell-to-cell adhesions. Rapamycin increased p27 kipl, reduced cyclinDl, and arrested the growth of renal cancer cells in G1/S phase. In vivo, rapamycin prevented tumor growth and metastatic progression in syngeneic BALB/c or SCID-beige mice, and in BALB/c or SCID-beige mice treated with cyclosporine. Rapamycin treatment alone, or with cyclosporine, prolonged the survival of mice inoculated with renal cancer cells or T24 human bladder cancer cells. Conclusions. Our findings, in addition to unlinking mechanisms of immunosuppression from that of tumor progression, suggest that rapamycin may be of value for the management of posttransplant malignancy.

Our center started routine monitoring of preformed and de novo human leukocyte antigen donor-specific antibodies (DSA) in September 2010 using single antigen beads on the Luminex platform. Recipients with preformed DSA or other high immunological risk factors had serial DSA monitoring at 3, 6, and 12-months posttransplant, and low-risk recipients were screened only at 12-months. Surveillance biopsies were performed at 3, 6, and 12-months post-transplant for all recipients. In addition, for-cause biopsies and DSA testing were performed when clinically indicated for allograft dysfunction. Among 150 adult kidney and kidney/pancreas transplant recipients included in the analysis, 14% had preformed DSA and 7.8% of recipients without preformed DSA developed de novo DSA by 12-months. De novo DSA developed in 25% of recipients on cyclosporine compared to 5% of those on tacrolimus (p = 0.02). The incidences of acute rejection were 34%, 48%, and 70% in recipients with no DSA, with preformed DSA, and with de novo DSA, respectively (p = 0.05). In all recipients with de novo DSA and rejection, the first rejection episode preceded or was concurrent with the emergence of de novo DSA. Despite the difference in rejection incidences, the estimated glomerular filtration rate at 1-year was not significantly different between recipients with or without DSA.

Background and Aims: Metabolic syndrome (MetS) is common among kidney transplant patients. We studied the relationship between MetS, vitamin D deficiency/insufficiency and hypoadiponectinemia early posttransplantation and their impact on clinical outcomes. Methods: Seventy-four previously nondiabetic kidney transplant patients were enrolled in a prospective cohort study between February and November 2008. Participants underwent a 2-hour oral glucose tolerance test and had their plasma levels of 25-hydroxyvitamin D (25[OH]D), adiponectin, insulin, intact parathyroid hormone and lipids measured at 11 weeks posttransplantation. Clinical events including cardiovascular events, new-onset diabetes after transplantation, acute rejection, graft loss and death were recorded during the follow-up to December 2012. Results: Thirty-four study patients (45.9%) had MetS. Patients with MetS had lower plasma concentrations of 25[OH]D (20.5 ± 7.2 vs. 24.8 ± 11.1 ng/ml, p = 0.049) and adiponectin (8.2 ± 4.5 vs. 14.6 ± 8.0 μg/ml, p < 0.0001) early on, and higher composite clinical event rate (61.8 vs. 27.5%, p = 0.003) during the follow-up. Multivariate analysis showed that the presence of MetS early after transplantation was independently associated with 25[OH]D deficiency/insufficiency (OR: 14.0, 95% CI: 1.8, 107.5; p = 0.011), depressed plasma adiponectin levels (β -6.39, r2 0.195, p < 0.0001) and increased risk for clinical events (OR: 5.6, 95% CI: 1.9, 16.5; p = 0.002). Conclusion: Kidney transplant patients with MetS early after transplantation had lower levels of 25[OH]D and adiponectin, and unfavorable clinical outcomes.

The long-term outcomes of kidney transplantation are suboptimal because many patients lose their allografts or experience premature death. Cross-country comparisons of long-term outcomes of kidney transplantation may provide insight into factors contributing to premature graft failure and death. We evaluated the rates of late graft failure and death among US and Spanish kidney recipients.This is a cohort study of US (n = 9609) and Spanish (n = 3808) patients who received a deceased donor kidney transplant in 1990, 1994, 1998 or 2002 and had a functioning allograft 1 year after transplantation with follow-up through September 2006. Ten-year overall and death-censored graft survival and 10-year overall recipient survival and death with graft function (DWGF) were estimated with multivariate Cox models.Among recipients alive with graft function 1 year after transplant, the 10-year graft survival was 71.3% for Spanish and 53.4% for US recipients (P0.001). The 10-year, death-censored graft survival was 75.6 and 76.0% for Spanish and US recipients, respectively (P = 0.73). The 10-year recipient survival was 86.2% for Spanish and 67.4% for US recipients (P0.001). In recipients with diabetes as the cause of ESRD, the adjusted DWGF rates at 10 years were 23.9 and 53.8 per 1000 person-years for Spanish and US recipients, respectively (P0.001). Among recipients whose cause of ESRD was not diabetes mellitus, the adjusted 10-year DWGF rates were 11.0 and 25.4 per 1000 person-years for Spanish and US recipients, respectively.US kidney transplant recipients had more than twice the long-term hazard of DWGF compared with Spanish kidney transplant recipients and similar levels of death-censored graft function. Pre-transplant medical care, comorbidities, such as cardiovascular disease, and their management in each country's health system are possible explanations for the differences between the two countries.

Purpose Serum creatinine functions as a poor surrogate marker of renal allograft dysfunction and long-term graft survival. By measuring multiple proteins simultaneously in the serum of transplant patients, we can identify unique protein signatures of graft dysfunction. Experimental design We utilized training and validation cohorts composed of healthy and volunteer subjects, stable renal transplant patients, and renal transplant patients experiencing acute allograft rejection. Utilizing our antibody microarray, we measured 108 proteins simultaneously in these groups. Results Using Mann–Whitney tests with Bonferroni correction, we identified ten serum proteins from 19 renal transplant patients with stable renal function, which are differentially expressed, compared to healthy control subjects. In addition, we identified 17 proteins that differentiate rejecting renal transplant recipients from stable renal transplant. Validation cohorts substantiated these findings. Conclusion and clinical relevance Our preliminary results support that a specific pattern of protein expression or “protein signature” may be able to differentiate between stable transplant patients from those with rejection. Future studies will focus on other etiologies of renal allograft dysfunction and the effect of treatment on protein expression and long-term outcome.

Pancreas after kidney (PAK) transplantation is one of the accepted pancreas transplant modalities. We studied the impact of time interval between kidney and pancreas transplantation on the outcomes of PAK transplantation. Using OPTN/SRTR data, we included 1853 PAK transplants performed between 1996 and 2005 with follow-up until November 1, 2008. Kaplan–Meier survival and multivariate Cox regression analyses were performed using the time interval between kidney and pancreas transplantation either as a categorical (less than one yr, between one and less than three yr, and greater than or equal to three yr) or as a continuous variable (months) to assess kidney graft and patient survival. Patients who received a pancreas transplant three yr or later after kidney transplantation had higher risk of death-censored kidney graft loss (HR 1.56, 95% CI 1.04, 2.32, p = 0.03). Each month beyond three yr between kidney and pancreas transplantation incurred 1% higher risk of subsequent death-censored kidney graft loss (HR 1.01, 95% CI 1.001, 1.02, p = 0.03). In conclusion, time interval between pancreas and kidney transplantation is an independent risk factor of kidney graft loss following pancreas transplantation. Shortening the time interval between pancreas and kidney transplantation to less than three yr may reduce the risk of kidney graft loss in qualified PAK transplant candidates.

Background. The economic merit of universal prophylaxis and preemptive therapy in the management of cytomegalovirus (CMV) infection for serology positive (R+) kidney transplant patients remains undefined. We performed cost effectiveness and cost utility modeling comparing these two approaches. Methods. The incidence of CMV infection under universal prophylaxis and preemptive therapy was determined among 653 R+ patients from our institution and 416 R+ patients from various clinic trials, respectively. Standardized decision tree analysis and Markov transitional models were used to calculate cost and quality-adjusted life years (QALYs) from the prototypical clinical data and published literature. Incremental cost effectiveness and cost utility were calculated as dollars for one case of infection avoided and one QALY gained over 10 years, respectively. One- and two-way sensitivity analyses were performed. Results. The incidence of CMV infection was 4.1% and 55.5% within the first year after transplant for universal prophylaxis and preemptive therapy, respectively. Compared with preemptive therapy, universal prophylaxis incurred $1464 more in direct cost while saving $7309 in indirect cost, and resulted in a net gain of 0.209 in QALYs per patient over a 10-year period. Thus, universal prophylaxis dominates over preemptive therapy with a cost saving of $27,967 for 1 QALY gained. This cost saving was sensitive to the variation in the rate of CMV infection and disease with each approach. Conclusion. Universal prophylaxis in CMV R+ kidney transplant patients is clinically effective and cost saving. It should be considered as the preferred approach.

Diabetes mellitus (DM) is a common and devastating disease, affecting up to 19.3 million Americans. It is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the United States. Diabetic patients with ESRD have a high incidence of cardiovascular disease and death. For those kidney transplant patients with no history of DM prior to transplantation, the development of new onset diabetes after transplantation (NODAT) also poses a serious threat to both graft and patient survival. Kidney transplantation is the best renal replacement option for diabetic ESRD and has the potential to halt the progression of cardiovascular diseases. Early referral for transplant evaluation is essential for pre-emptive or early kidney transplantation in this cohort of patients. In type 1 DM patients with ESRD, simultaneous pancreas and kidney transplantation (SPK) should be encouraged; and in patients facing prolonged waiting time for SPK transplantation but with an available living donor, living donor kidney transplantation followed by pancreas after kidney transplantation (PAK) is a suitable alternative. Islet transplantation in type 1 diabetics is deemed experimental by Medicare, and easy access to this modality remains restricted to qualified patients enrolled in clinical trials or with private insurance. The optimal management of kidney transplant patients with pre-existent DM or NODAT involves a multi-pronged approach consisting of pharmacological and nonpharmacological intervention to address all potential cardiovascular risk factors such as glycemic and lipid control, blood pressure control, weight loss, and smoking cessation. Finally, re-transplantation should be recommended in suitable kidney transplant patients when the kidney allograft demonstrates continuous and progressive decline in function.

Abnormal glucose metabolism (AGM) is common early after kidney transplantation and is a risk factor for new-onset diabetes after transplant (NODAT) (1, 2). The majority of NODAT occurs early after kidney transplantation, and it is associated with increased cardiovascular events and mortality (3–5). Metabolic syndrome (MS) is a constellation of metabolic and nonmetabolic disorders that occurs frequently in kidney transplant recipients as well, and it is associated with impaired long-term renal allograft function and poor patient survival (6, 7). In addition, various components of MS are shown to be risk factors for the development of AGM and NODAT (1, 8). It is unclear what relationship exists between AGM and MS early after kidney transplantation. Current guidelines recommend using fasting plasma glucose or oral glucose tolerance to diagnose AGM (9–11). However, in the kidney transplant population, it has been shown that the oral glucose tolerance test (OGTT) has a superior sensitivity in diagnosing AGM when compared with fasting glucose levels alone (12). Furthermore, the OGTT can clearly define a subgroup of patients who demonstrate an impaired glucose tolerance (IGT) that can be a precursor of type 2 diabetes mellitus and a predictor of mortality in the general population (13, 14). Thus, the early detection of AGM and MS after transplantation could be of great importance because it will allow for a more timely intervention to prevent or reduce the long-lasting deleterious effects of both conditions on patient and allograft survival. We performed a prospective observational study investigating the relationship between AGM and MS in de novo kidney transplant recipients. Here, we report the findings at 10 weeks after kidney transplantation.

Metabolic syndrome (MS) and new onset diabetes after transplant (NODAT) are common in kidney transplant patients. We studied the relationship between the two conditions and their impact on metabolic and cardiovascular risk profiles.All non-diabetic patients transplanted between 1999 and 2005 who were followed up to 2006 were included. MS and NODAT were determined. Kaplan-Meier survival and various regression analyses were performed to determine the clinical correlates for both conditions and their association with various cardiovascular risk factors.Among 591 patients, 314 (53.1%) had MS and 90 (15.2%) developed NODAT. The two conditions were highly associated with each other as 84 patients with NODAT also had MS (14.2%). Elevated body mass index and fasting glucose levels at transplant were risk factors for both conditions, whereas weight gain after transplant was associated only with MS. African American, old age, and hypertension-related ESRD were risk factors for NODAT. Finally, the presence of MS was associated with reduced kidney function and elevated uric acid levels, whereas the presence of NODAT with elevated pulse pressure.MS and NODAT are highly prevalent and significantly associated with impaired metabolic and cardiovascular risk profiles. Early identification of such conditions may facilitate targeted therapeutic intervention.

The risk of late-onset cytomegalovirus (CMV) infection remains a concern in seronegative kidney and/or pancreas transplant recipients of seropositive organs despite the use of antiviral prophylaxis. The optimal duration of prophylaxis is unknown. We studied the cost effectiveness of 6- versus 3-mo prophylaxis with valganciclovir. A total of 222 seronegative recipients of seropositive kidney and/or pancreas transplants received valganciclovir prophylaxis for either 3 or 6 mo during two consecutive time periods. We assessed the incidence of CMV infection and disease 12 mo after completion of prophylaxis and performed cost-effectiveness analyses. The overall incidence of CMV infection and disease was 26.7% and 24.4% in the 3-mo group and 20.9% and 12.1% in the 6-mo group, respectively. Six-month prophylaxis was associated with a statistically significant reduction in risk for CMV disease (HR, 0.35; 95% CI, 0.17 to 0.72), but not infection (HR, 0.65; 95% CI, 0.37 to 1.14). Cost-effectiveness analyses showed that 6-mo prophylaxis combined with a one-time viremia determination at the end of the prophylaxis period incurred an incremental cost of $34,362 and $16,215 per case of infection and disease avoided, respectively, and $8,304 per one quality adjusted life-year gained. Sensitivity analyses supported the cost effectiveness of 6-mo prophylaxis over a wide range of valganciclovir and hospital costs, as well as variation in the incidence of CMV disease. In summary, 6-mo prophylaxis with valganciclovir combined with a one-time determination of viremia is cost effective in reducing CMV infection and disease in seronegative recipients of seropositive kidney and/or pancreas transplants.

To evaluate the efficacy, safety, and costs of rabbit antithymocyte globulin (TMG) induction in patients who received kidney transplants from living unrelated donors.Retrospective cohort study.Large academic medical center.Eighty-seven patients who received kidney transplants from living unrelated donors: 40 of the recipients underwent transplantation between January 1, 2003, and December 31, 2004, and did not receive TMG induction (no induction group); 47 underwent transplantation between January 1, 2005, and June 30, 2006, and received TMG induction (induction group). All patients received cyclosporine-based immunosuppression.Biopsy-proven acute rejection, posttransplantation complications, and inpatient hospital costs for the first 12 months after transplantation were compared between groups using standard univariate statistical analyses. Induction significantly decreased the occurrence of biopsy-proven acute rejection versus no induction (2% vs 48%, p0.001). Fifty percent of rejection episodes in the no induction group required hospitalization, and 46% of rejection episodes required TMG treatment. Slightly elevated initial costs associated with TMG induction were offset by lower costs related to rejection treatment. Total inpatient costs for the 12 months after transplantation were comparable between the groups (no induction $66,038 vs induction $74,183, p0.05). For the no induction versus induction groups, no significant differences in cytomegalovirus disease (5% vs 6%), malignancy (3% vs 2%), graft failures (5% vs 6%), mortality (5% vs 4%), and serum creatinine concentrations (mean +/- SD 1.4 +/- 0.3 vs 1.5 +/- 0.3 mg/dl) were observed at 12 months (p0.05 for all comparisons).Five-day TMG induction effectively reduced the 1-year acute rejection rate without significantly increasing total inpatient costs or posttransplantation complications among recipients of kidney transplants from living unrelated donors.

Malignancy is a dreaded complication following organ transplantation. Immunosuppressive therapy-induced impairment of the host immune system is the prevailing hypothesis for the high incidence and aggressive progression of post-transplant neoplasm. We summarize our observations supporting an autonomous cellular mechanism for cyclosporine and tacrolimus associated metastases. Cyclosporine conferred tumor invasiveness by a direct effect on the tumor cells and promoted metastases in T-, B-, and NK cell deficient SCID- beige mice, and anti-TGF-beta antibodies reduced metastases. Tacrolimus, another calcineurin inhibitor widely used in transplantation, induced TGF-beta secretion by tumor cells and promoted metastases in the SCID- beige mice. The immunosuppressive macrolide rapamycin reversed an invasive phenotype to a non-invasive one, reduced circulating levels of TGF-beta1 and prevented tumor growth and metastases in the immocompetant BALB/c mice and in the SCID-beige mice. Our studies, in addition to demonstrating a cell autonomous mechanism for tumor progression, advance TGF-beta blockade as an anti-tumor strategy.

Steroid-free immunosuppression in kidney transplantation has been gaining popularity over the past decade, as documented by a continuous and steady rise in the number of kidney transplant patients discharged on steroid-free regimens. This increased interest in steroid-free immunosuppression is fueled by the recognition that half of transplant loss is related to patient death due to cardiovascular disease and/or infectious complications and that the long-term use of steroids contributes to such elevated cardiovascular morbidity and mortality. The availability of newer and more potent immunosuppressive agents has furthered such interest. Many clinical trials over the past two decades have demonstrated the feasibility of steroid-free regimens, at the expense of a slight increase in the rate of acute rejection, which is an important end point in any clinical trial of relatively short duration. The largest epidemiological study to date has reassured the transplant community that the selective use of steroid-free immunosuppression in kidney transplant patients provides no inferior outcome in patient and graft survival at intermediate term. Steroid-free regimens have the potential to improve cardiovascular risk profile. The challenges that remain are to identify the subset of kidney transplant patients who may not benefit from steroid-free immunosuppression and to demonstrate the survival advantage of steroid-free immunosuppresion in suitable kidney transplant candidates.

Steroid-free regimen is increasingly employed in kidney transplant recipients across transplant centers. However, concern remains because of the unknown impact of such an approach on long-term graft and patient survival. We studied the outcomes of steroid-free immunosuppression in a population-based U.S. cohort of kidney transplant recipients. All adult solitary kidney transplant recipients engrafted between January 1, 2000 and December 31, 2006 were stratified according to whether they were selected for a steroid-free or steroid-containing regimen at discharge. Multivariate Cox regression models were used to estimate graft and patient survival. The impact of the practice pattern on steroid use at individual transplant centers was analyzed. Among 95 755 kidney transplant recipients, 17.2% were steroid-free at discharge (n = 16 491). Selection for a steroid-free regimen was associated with reduced risks for graft failure and death at 1 year (HR 0.78, 95% CI 0.72-0.85, and HR 0.73, 95% CI 0.65-0.82, respectively, p < 0.0001) and 4 years (HR 0.83, 95% CI 0.78-0.87, and HR 0.76, 95% CI 0.71-0.83, respectively, p < 0.0001). This association was mostly observed at individual centers where less than 65% of recipients were discharged on the steroid-containing regimen. De novo steroid-free immunosuppression as currently practiced in the United States appears to carry no increased risk of adverse clinical outcomes in the intermediate term.

Posttransplant hypertension is a major risk factor for cardiovascular disease and chronic renal allograft dysfunction. A significant number of transplant recipients suffer from posttransplant hypertension in part because of corticosteroid and calcineurin inhibitor use. Although the optimal blood pressure range and the antihypertensive agents of choice in the transplant population have not been determined, the guidelines for blood pressure control in the general population can be extrapolated to the transplant population. The choice of an antihypertensive regimen should be tailored on the basis of the individual patient's risk factors and comorbidities.

Rapamycin is an effective inhibitor of human renal cancer metastasis. Background Human renal cell cancer (RCC) is common and is 10 to 100 times more frequent in patients with end-stage renal disease (ESRD) and candidates for renal transplantation. Treatment of metastatic RCC is largely ineffective and is further undermined by immunosuppressive therapy in transplant recipients. A treatment regimen that prevents transplant rejection while constraining RCC progression would be of high value. Methods We developed a human RCC pulmonary metastasis model using human RCC 786-O as the tumor challenge and the severe combined immunodeficient (SCID) beige mouse as the host. We explored the effect of rapamycin, cyclosporine, or rapamycin plus cyclosporine on the development of pulmonary metastases and survival. The effects of the drugs on tumor cell growth, apoptosis, and expression of vascular endothelial growth factor (VEGF-A) and transforming growth factor β1 (TGF-β1) were also investigated. Results Rapamycin reduced, whereas cyclosporine increased, the number of pulmonary metastases. Rapamycin was effective in cyclosporine-treated mice, and rapamycin or rapamycin plus cyclosporine prolonged survival. Rapamycin growth arrested RCC 786-O at the G 1 phase and reduced VEGF-A expression. Immunostaining of lung tissues for von Willebrand factor was minimal and circulating levels of VEGF-A and TGF-β1 were lower in the rapamycin-treated mice compared to untreated or cyclosporine-treated mice. Conclusion Our findings support the idea that rapamycin may be of value for patients with RCC and that its antitumor efficacy is realized by cell cycle arrest and targeted reduction of VEGF-A and TGF-β1. A regimen of rapamycin and cyclosporine, demonstrated to be effective in reducing acute rejection of renal allografts, may prevent RCC progression as wel, and has the potential to prevent mortality due to RCC in patients with ESRD who have received renal allografts.