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Approximately 6% of deceased kidney donors (DKDs) are diabetic; their kidneys may be associated with worse allograft survival, but published studies suggest that recipient diabetes status has a greater impact on mortality and survival. Since biopsy findings are the most common reason for organ discard, we sought to understand histologic and clinical factors that influence graft survival in patients who receive a kidney from a diabetic DKD. We retrospectively reviewed our institutional experience from 2005 to 2019, and re-evaluated pre-implantation and earliest post-transplant biopsies. Histologic findings were compared against a control cohort of non-diabetic DKD. Of 829 adult DKD transplants, 37 (4.5%) came from diabetic donors. There was no significant difference in diabetic vs. non-diabetic DKD graft survival for all-comers; however, when stratified by duration of donor diabetes, donor diabetes ≥6 years was associated with graft failure. In 25 patients with post-transplant biopsies available, diabetic DKD allografts had significantly greater non-glomerular chronic injury than non-diabetic DKD allografts. Moderate arteriolar hyalinosis (in 24%), moderate tubular atrophy and interstitial fibrosis (IFTA, in 36%), and diabetic glomerulopathy (in 24%) on early post-transplant biopsy were associated with allograft failure. Pre-implantation frozen section discrepancies were more common in long-standing donor diabetes, and arteriolar hyalinosis and IFTA scores on frozen accurately prognosticated graft loss. There was no morphologic improvement in lesions of diabetic nephropathy on short-term follow-up. In conclusion, donor diabetes ≥6 years, and histologic findings on frozen section and early post-transplant biopsy are associated with diabetic DKD allograft loss.

Graft function is crucial for successful kidney transplantation. Many factors may affect graft function or cause delayed graft function (DGF), which decreases the prognosis for graft survival. This study was designed to evaluate whether the perioperative use of dexmedetomidine (Dex) could improve the incidence of function of graft kidney and complications after kidney transplantation. A total of 780 patients underwent kidney transplantations, 315 received intravenous Dex infusion during surgery, and 465 did not. Data were adjusted with propensity scores and multivariate logistic regression was used. The primary outcomes are major adverse complications, including DGF and acute rejection in the early post-transplantation phase. The secondary outcomes included length of hospital stay (LOS), infection, overall complication, graft functional status, post-transplantation serum creatinine values, and estimated glomerular filtration rate (eGFR). Dex use significantly decreased DGF (19.37% vs. 23.66%; adjusted odds ratio, 0.744; 95% confidence interval, 0.564-0.981; P=0.036), risk of infection, risk of acute rejection in the early post-transplantation phase, the risk of overall complications, and LOS. However, there were no statistical differences in 90-day graft functional status or 7-day, 30-day, and 90-day eGFR. Perioperative Dex use reduced incidence of DGF, risk of infection, risk of acute rejection, overall complications, and LOS in patients who underwent kidney transplantation.

BACKGROUND: Kidney transplantation from hepatitis C seropositive (HCV+) donors may benefit hepatitis C RNA-positive (RNA+) candidates, but it is unclear how the willingness to be listed for and accept such kidneys affects waitlist and transplant outcomes. METHODS: In a single-center retrospective analysis, HCV+ transplant candidates (N = 169) listed from March 2004 to February 2015 were evaluated. All RNA+ candidates were offered the option to be listed for HCV+ donors. RNA− candidates were listed only for HCV− donors. RESULTS: Fifty-seven patients (51% of all RNA+ transplant candidates) willing to accept HCV+ donors were listed for both HCV+ and HCV− donor kidneys. During 6-year follow up, 43 (75%) of 57 patients accepting HCV+ versus 19 (35%) of 55 patients not accepting HCV+ received a deceased donor kidney transplant (P < 0.0001). Multivariable analysis demonstrated that willingness to be listed for and accept HCV+ kidneys was associated with receiving deceased donor kidney transplant (P = 0.0016). Fewer patients accepting HCV+ donors (7 [12%] vs 16 [29%]) were removed from the list due to death or deteriorated medical condition (P = 0.0117). Posttransplant patient and graft survival rates were not significantly different. Overall patient survival since the listing (combined waitlist and posttransplant survival) was similar among the groups. CONCLUSIONS: HCV RNA+ candidates had better access to transplantation and similar overall survival before the era of widespread use of direct-acting anti-HCV agents.

Background Limited data are available on whether donor kidneys with diffuse glomerular fibrin thrombi (GFT) are safe to use. In this study, the clinicopathologic characteristics of allografts with diffuse donor-derived GFT were examined. Methods All deceased donor kidney transplant implantation biopsies from our institution between July 2011 and February 2018 with diffuse GFT were included. A control group for comparison consisted of all cases with implantation biopsies obtained during the study period without diffuse GFT. Clinical data were extracted from electronic medical records for all study patients, including donor information. Results Twenty-four recipients received kidneys with diffuse GFT from 16 deceased donors. All donors died from severe head trauma. On average, 79% of glomeruli contained fibrin thrombi. Nineteen cases had subsequent biopsy; all revealed resolution of GFT. Compared with the control group, kidneys with diffuse GFT had longer cold ischemia time (34 versus 27 h), were more frequently pumped using machine perfusion (100% versus 81%), and recipients experienced a higher frequency of delayed graft function (58% versus 27%). Only 2 grafts with diffuse GFT failed within the first year. Overall graft survival was similar between the diffuse GFT group and control group. Conclusions Deceased donor kidneys with diffuse GFT appear to be safe to use given that nearly 92% of recipients in this cohort who received such allografts experienced good clinical outcomes. Histologically, GFT demonstrated rapid resolution following transplantation. Interestingly, diffuse GFT only occurred in donors who suffered severe head trauma in this cohort, which may be a predisposing factor.

To evaluate the correlation between the presence of bladder debris on ultrasound and urinalysis results in the emergency department setting. Adult patients presenting to the emergency department with an ultrasound of the bladder and a urinalysis performed within 24 h of the ultrasound were included in this retrospective study. Two radiologists in consensus evaluated for the presence or absence of debris within the bladder. Urinalysis results were recorded including continuous variables (specific gravity and pH) and categorical variables (presence of occult blood, bilirubin, ketones, glucose, protein, urobilinogen, nitrite, leukocyte esterase, white blood cells, and red blood cells). The presence and absence of white and red blood cells were defined as > 5 cells/high-powered field. To control the experimentwise type I error rate at 0.05, a Bonferroni-corrected significance level of 0.0042 was used to determine significant associations. The presence of bladder debris was associated with the presence of urobilinogen, nitrite, and white blood cells (p =

Background Fatty acids and their eicosanoid metabolites have been shown to be important mediators of the immune response in transplantation. We hypothesize that elevated pretransplant free fatty acids (FFA) levels may be associated with prolonged survival of kidney transplants. Methods Archived pretransplant sera of 130 patients who received a kidney transplant from 1991 to 1997 were analyzed by gas liquid chromatography for a comprehensive FFA profile. FFA levels were categorized by quartiles, and the association between quartiles of the levels for each free-fatty acid and graft survival was initially screened by serial univariate analyses (Kaplan-Meier). All significant variables (FFAs and transplant-specific risk factors) were entered into a multivariable (Cox regression) model. Results With >10 y of follow-up, 68 kidney allografts were lost. Factors associated with decreased graft survival by univariate analysis included delayed graft function (DGF), acute rejection (AR), and cold ischemic time (CIT) >24 h. High levels of arachidonic and γ-linolenic FFA were associated with higher graft survival rates. By multivariate analysis, only DGF, AR, CIT, and arachidonic acid levels were significant. The odds ratios for graft failure for the highest, third, and second quartiles of the pretransplant level of arachidonic acid, compared with the lowest quartile, were 0.18, 0.32, and 0.64, respectively(P = 0.050, log-rank test). For arachidonic acid the survival benefit appeared to be graded with the highest quartile associated with a greater than 80% reduction of risk of kidney graft failure. Conclusion Pretransplant level of arachidonic acid was independently associated with higher kidney graft survival rates. Further studies are necessary to identify the underlying mechanisms and to determine whether interventions aimed at increasing pretransplant arachidonic acid levels might prove beneficial for renal transplant outcomes.

Background Coronary artery disease (CAD) is the predominant cause of sudden cardiac death in the general population, and sudden cardiac death is the leading cause of mortality in end-stage renal disease (ESRD). Hypothesis QT-interval prolongation is an independent prognosticator in ESRD. Methods We reviewed clinical, electrocardiographic, stress test, and coronary angiography data on ESRD patients evaluated for transplantation at our institution between 2000 and 2004 who underwent coronary angiography. The QT interval was corrected for heart rate and QRS duration (QTc). All-cause mortality data were prospectively collected and verified against the Social Security Death Index database. Results During 40 ± 28 months of follow-up, 132 of the 280 (47%) patients died prior to renal transplantation. Patients with a prolonged QTc (39%) had 1-, 3-, and 5-year death-rates of 12%, 36%, and 47%, respectively, vs 8%, 24%, and 36% for those with normal QTc (log-rank P = 0.03). In a multivariate Cox regression model that adjusted for age, gender, diabetes mellitus, myocardial infarction, presence and severity of CAD on angiography, left ventricular (LV) hypertrophy, LV ejection fraction (EF), and multiple other variables, QTc remained to be an independent predictor of survival (hazard ratio [HR]: 1.008, 95% confidence interval [CI]: 1.001–1.014, P = 0.016). Female gender, decreasing LVEF, and decreasing severity of CAD on angiography were independent predictors of prolonged QTc. Conclusions QTc prolongation is an independent predictor of mortality in ESRD patients being evaluated for renal transplantation. The prognostic information gained from the QTc is additive to that provided by the LVEF and the severity of CAD. Copyright © 2010 Wiley Periodicals, Inc.

Cardiovascular events (CVE) are the leading cause of mortality in kidney transplant recipients. The adverse effects of long-term therapy with steroids on cardiovascular risk have motivated increasing interest in steroid withdrawal (SW). The objective of this study was to compare the incidences of CVE and all-cause mortality between patients who had undergone SW at 1 year posttransplant and control patients who continued on steroids.A cohort of 400 consecutive adult recipients of a kidney transplant between 1993 and 1998 who qualified for late SW was studied. At 1 year posttransplant 188 patients underwent SW, whereas 212 patients continued on steroids. Cox proportional-hazards analysis was used to estimate CVE (cardiac and cerebrovascular events) and all-cause mortality hazard ratios (HR) for patients who had undergone SW versus controls who continued on steroids beyond 1 year.The average follow-up was 61 months. There were 44 (11%) cardiac events, 18 (4.5%) cerebrovascular events, and 41 deaths (10.3%). The composite outcome of CVE and all-cause mortality was reached in 26 (13.8%) subjects who had undergone SW and 50 (23.6%) controls (P=0.013). In adjusted analyses, SW was associated with decreased risk for the composite outcome (HR 0.46, 95% confidence interval [CI] 0.28-0.76), cardiac events (HR 0.48, 95% CI 0.28-0.84), and all-cause mortality (HR 0.27, 95% CI 0.12-0.59). There was no association of SW with the risk for cerebrovascular events (HR 1.76, 95% CI 0.45-7.01).In this retrospective analysis, SW at 1 year posttransplant was associated with decreased risk for future CVE and all-cause mortality.

Cardiovascular disease is the major cause of mortality in patients with end-stage renal disease (ESRD). This study examined the all-cause mortality in 3,698 patients with ESRD evaluated for kidney transplantation at our institution from 2001 to 2004. Mean age for the cohort was 48 ± 12 years, and 42% were women. Stress myocardial perfusion imaging was done in 2,207 patients (60%) and coronary angiography in 260 patients (7%). There were 622 deaths (17%) during a mean follow-up period of 30 ± 15 months. The presence and severity of coronary disease on angiography was not predictive of survival. Coronary revascularization did not impact survival (p = 0.6) except in patients with 3-vessel disease (p = 0.05). The best predictor of death was left ventricular ejection fraction, measured by gated myocardial perfusion imaging, with 2.7% mortality increase for each 1% ejection fraction decrease. In conclusion, left ventricular ejection fraction is a strong predictor of survival in patients with ESRD awaiting renal transplantation. Strategies to improve cardiac function or earlier renal transplantation deserve further studies.

The use of cyclosporine and tacrolimus therapy in nonrenal (heart, heart/lung, lung, and liver) transplantation has resulted in improved patient and graft survival. Nephrotoxicity is one of the major side effects of tacrolimus and cyclosporine therapy and may lead to ESRD. The trend of referral of nonrenal solid-organ transplant recipients for kidney transplant evaluation at a large multiorgan transplant center was examined. Records of all patients who were referred for renal transplantation at the University of Alabama between January 1, 1993, and June 30, 2004, were reviewed. Eighty (0.96%) of 8318 individuals had previously undergone a nonrenal solid-organ transplant and were included in the study. The majority (72%) of patients had their nonrenal transplants performed at the University of Alabama. Twenty-two patients had their nonrenal transplant performed elsewhere and had fewer data available for analysis. From the period 1993-1996 to 2001-2004, an 11-fold increase in the absolute number of referrals of patients with nonrenal transplants was noted. Of patients who were referred for transplant evaluation, 25 became recipients of kidney transplants with a predominance of living-donor transplants. Referral for kidney transplant evaluation among nonrenal solid-organ transplant recipients is increasing and will exacerbate the existing shortage of deceased-donor kidneys that are available for transplantation. There was a trend for liver transplant recipients compared with other solid-organ recipients to develop ESRD at a greater rate.

Background: Chronic renal allograft failure (CRAF) is the leading cause of graft loss post-renal transplantation. This study evaluated the efficacy and safety of tacrolimus as secondary intervention in cyclosporine-treated kidney transplantation patients with impaired allograft function as indicated by elevated serum creatinine (SCr) levels. Methods: Patients receiving cyclosporine-based immunosuppression who had an elevated SCr at least 3 months post-renal transplantation were enrolled. Treatment allocation was 2:1 to switch to tacrolimus or continue cyclosporine. This analysis was performed after 2 yr; patients will be followed for an additional 3 yr. Results: There were 186 enrolled and evaluable patients. On baseline biopsy, 90% of patients had chronic allograft nephropathy. Baseline median SCr was 2.5 mg/dL in both treatment groups. For patients with graft function at month 24, SCr had decreased to 2.3 mg/dL in the tacrolimus-treated patients and increased to 2.6 mg/dL in the cyclosporine-treated patients (p = 0.01). Acute rejection occurred in 4.8% of tacrolimus-treated patients and 5.0% of cyclosporine-treated patients during follow-up. Two-year allograft survival was comparable between groups (tacrolimus 69%, cyclosporine 67%; p = 0.70). Tacrolimus-treated patients had significantly lower cholesterol and low-density lipoprotein levels and also had fewer new-onset infections. Cardiac conditions developed in significantly fewer tacrolimus-treated patients (5.6%) than cyclosporine-treated patients (24.3%; p = 0.004). Glucose levels and the incidences of new-onset diabetes and new-onset hyperglycemia did not differ between treatment groups. Conclusions: Conversion from cyclosporine to tacrolimus results in improved renal function and lipid profiles, and significantly fewer cardiovascular events with no differences in the incidence of acute rejection or new-onset hyperglycemia.

Autosomal-dominant polycystic kidney disease as a risk factor for diabetes mellitus following renal transplantation.BackgroundPosttransplant diabetes mellitus is an important complication of renal transplantation that is associated with a significant impact on quality of life and an increase in long-term morbidity and mortality. Autosomal-dominant polycystic kidney disease (ADPKD) is a hereditary disease that commonly leads to end-stage renal disease (ESRD) in adulthood. The association between ADPKD and posttransplant diabetes mellitus has not been previously studied in a large cohort of patients.MethodsTo address this question, we studied a cohort of 135 patients with ADPKD who received a first renal-only transplant between January 1985 and December 1999. An age, race, and date of transplant-matched cohort of 135 non-ADPKD subjects were used as the control population.ResultsThe cohorts were similar at baseline for gender distribution, body mass index (BMI), proportion of obese subjects (BMI greater than 30kg/m2), family history of diabetes mellitus, and type of donor (deceased or living). At 12 months, the incidence of posttransplant diabetes mellitus was significantly higher in patients with ADPKD when compared to the controls (17% vs. 7.4%) (P = 0.016), despite no significant differences in the BMI, percent increase in BMI, number of acute rejections, prednisone dose at 3 and 6 months, use of diuretics or beta blockers, delayed graft function, or serum creatinine levels. The proportion of subjects requiring insulin was significantly higher in the ADPKD group (11.1% vs. 3%) (P = 0.009).AbstractVariables significantly associated with posttransplant diabetes mellitus at 1 year by bivariate analyses were the diagnosis of ADPKD (P = 0.02), BMI at transplant (P = 0.04), obesity at 12 months (P = 0.01), and delayed graft function (P = 0.02). Gender of recipient (P = 0.9), family history of diabetes (P = 0.3), prednisone dose at 3 months (P = 0.9) and 6 months (P = 0.7), acute rejection (P = 0.9), use of beta blockers or tacrolimus (P = 0.8), deceased donor transplant (P = 0.2), and serum creatinine at 1 year (P = 0.5) were not associated with posttransplant diabetes mellitus. A trend toward increased incidence of posttransplant diabetes mellitus was found with the use of diuretics post transplant (P = 0.054). By multivariable analyses, in patients with ADPKD, the adjusted (by all the variables listed above) relative risk for development of posttransplant diabetes mellitus was 2.87 (95% CI = 1.24–6.65) (P = 0.014). Only the diagnosis of ADPKD (RR = 2.9) (P = 0.01), obesity at 1 year (RR 2.5) (P = 0.017), and delayed graft function (RR 2.4) (P = 0.03) contributed significantly to the fit of a stepwise logistic regression model. Patient survival was significantly worse in the cohort of patients who developed posttransplant diabetes mellitus (median survival 109.3 vs. 121 months) (P = 0.008).ConclusionIn our study patients with ADPKD were at a threefold increased risk for development of posttransplant diabetes mellitus within the first year following renal transplantation. Development of posttransplant diabetes mellitus was associated with a significant detrimental impact on patient survival. Further studies are needed to provide insight into the mechanisms of the association between ADPKD and posttransplant diabetes mellitus.

The introduction of mycophenolate mofetil (MMF) represented a major advance in transplant medicine, although optimal use may be limited by gastrointestinal (GI) side-effects. An enteric-coated formulation of mycophenolate sodium (EC-MPS; myfortic) has been developed with the aim of improving the upper GI tolerability of mycophenolic acid. Therapeutic equivalence of EC-MPS (720 mg b.i.d.) and MMF (1000 mg MMF b.i.d.), with concomitant cyclosporine microemulsion (Neoral) and corticosteroids, was assessed in 423 de novo kidney transplant patients recruited to a 12-month, double-blind study. Efficacy failure (biopsy-proven acute rejection [BPAR], graft loss, death or loss to follow up) at 6 months (EC-MPS 25.8% vs. MMF 26.2%; 95% CI: [-8.7, +8.0]) demonstrated therapeutic equivalence. At 12 months, the incidence of BPAR, graft loss or death was 26.3% and 28.1%, and of BPAR alone was 22.5% and 24.3% for EC-MPS and MMF, respectively. Among those with BPAR, the incidence of severe acute rejection was 2.1% with EC-MPS and 9.8% with MMF (p=ns). The safety profile and incidence of GI adverse events were similar for both groups. Within 12 months, 15.0% of EC-MPS patients and 19.5% of MMF patients required dose changes for GI adverse events (p=ns). Enteric-coated-MPS 720 mg b.i.d. is therapeutically equivalent to MMF 1000 mg b.i.d. with a comparable safety profile.

OBJECTIVE To compare outcomes between percutaneous transluminal angioplasty and stent placement in the treatment of transplant renal artery stenosis (TRAS). METHODS We retrospectively studied patients who underwent angiography for TRAS between 1/1/2008 and 9/20/2016 at 1 center. We compared the rates of restenosis in patients who were treated with angioplasty alone vs those who were treated with stenting. Secondary outcomes included serum creatinine and blood pressure after intervention and graft and patient survival. RESULTS A total of 82 patients were identified as having TRAS after angiography. Restenosis occurred in 28% (16 of 58) of the angioplasty patients compared with 8% (2 of 24) of the stented patients (P = .04). Repeat angiography occurred in 14% (8 of 58) of angioplasty patients vs 13% (3 of 24) of stented patients (P = .9). The stented group had significantly higher pre-intervention stenosis (71% vs 64%, P = .01) and lower postintervention stenosis (4% vs 30%, P

BACKGROUND HuM291 is a humanized anti-CD3 monoclonal antibody engineered to reduce binding to Fcgamma receptors and complement fixation. HuM291 has a long serum half-life and mediated profound depletion of circulating T cells in chimpanzees; HuM291 also has significantly less mitogenic and cytokine-releasing activity than OKT3 in vitro. METHODS A phase I dose-escalation study was conducted in 15 end-stage renal disease patients scheduled for renal allografts from living donors. Patients received one i.v. HuM291 injection before transplantation. Five doses were tested: 0.015 microg/kg, 0.15 microg/kg, 0.0015 mg/kg, 0.0045 mg/kg, and 0.015 mg/kg. Patients were followed for adverse events, laboratory abnormalities, serum cytokine levels, pharmacokinetics, and CD2+, CD3+, CD4+, and CD8+ T cell counts. RESULTS HuM291 was well tolerated; most adverse events were mild to moderate in severity and included headache, nausea, chills, and fever. These occurred within the first few hours after HuM291 administration, resolved within 24 to 48 hr, and were likely related to cytokine release. In general, peak tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 levels were detected 1 to 6 hr postdosing only at the three highest doses and were generally undetectable by 24-hr postdosing. Serious adverse events possibly related to HuM291 included clotting of a fistula (two patients), chemical cellulitis (one patient), and increased serum creatinine/decreased hematocrit (one patient). At doses > or = 0.0015 mg/kg (0.1 mg/70 kg), HuM291 induced rapid, marked depletion of peripheral T cells within 2 hr; duration of T cell depletion was dose dependent. At the two highest dose levels, T cells remained depleted for approximately 1 week. CONCLUSIONS A single HuM291 dose rapidly depleted circulating T cells in a dose-dependent manner and was associated with only mild to moderate symptoms of cytokine release.

Background The waiting list for cadaveric kidney transplantation has continued to grow, and with the relative scarcity of cadaver donors, the median waiting time for patients in the United States increased to 824 days in 1994. The median waiting times for patients with blood groups B or O were 1329 and 1007 days, respectively. Allocation of blood group A2 kidneys (20% of group A) to blood group O and B patients expands their potential donor pool and shortens their waiting time for a kidney transplantation. Methods Between May 1991 and June 1998, we transplanted 15 A2 kidneys into 6 blood group O and 9 blood group B patients. Anti-A isoagglutinins were measured before transplantation, and patients with anti-A1 titers > or = 1:8 underwent plasmapheresis (PP). Results One patient with high titer anti-A antibodies, who did not receive PP, lost her allograft because of hyperacute rejection. Allograft function was excellent in the remaining 14 patients, with a mean serum creatinine level of 1.7 (+/-0.89) mg/dl at 1 month and 1.3 (+/-0.34) mg/dl at 1 year. The actuarial 1-year graft survival rate was 93.3+/-6.4% and the patient survival rate was 100%. Conclusion We conclude that the allocation of blood group A2 kidneys for blood group O and B recipients is a practical way to expand the donor pool for these transplant candidates. PP may be important for reducing the levels of anti-A1 and anti-A2 antibodies and for reducing the risk of hyperacute rejection. Splenectomy seems to be unnecessary.

Human lymphocyte antigen (HLA)-identical sibling organs offer the best long-term outcomes for recipients of a renal transplant apart from an identical twin. Unlike cadaveric transplants, however, factors that affect long-term survival of these immunologically privileged grafts are not well described. We reviewed 108 HLA-identical transplants performed at our institution between January 1977 and February 1993. Variables chosen for graft survival analysis were: gender, age and ABO blood type of donors and recipients, panel reactivity antibodies (PRA), blood transfusions prior to transplant, pregnancies, and the underlying renal disease. Additionally, incidence of acute rejection (AR), timing of AR, serum creatinine levels at 1 wk and at 1 yr, and presence of hypertension were included in the analysis. Mean follow-up was 130.9 +/- 58.2 months (range 38-250 months). Actual 5-yr patient and graft survivals were 92 and 88%, respectively. Thirty-eight grafts were lost, and 22 recipients died during the observation period. Death was the main cause of graft failure. Cardiac events accounted for the majority of deaths. AR occurred in 46% and repeated rejections in 11% of recipients. Actuarial graft survival at 10 yr was poorer for patients with any AR (69%), and significantly worse with repeated AR (33%), compared to patients without AR (86%), p = 0.001). Sixty percent of all rejections and 88% of the first rejections occurred in the first 60 d post-transplantation. The first AR that occurred after 60 d was associated with poor graft survival (49 vs. 70%, p = 0.04). Recipients with renal diseases with potential to recur (membranous glomerulonephritis (MGN), membrano-proliferative glomerulonephritis (MPGN), focal and segmental glomerulonephritis (FSGN), polyarteritis nodosa (PAN), rapid progressive glomerulonephritis (RPGN), Henoch-Schoenlein purpura (HSP), diabetes mellitus (DM), interstitial nephritis, systemic lupus erythematosus (SLE) and chronic glomerulonephritis (CGN)) faired worse as a group than recipients with hypertensive nephrosclerosis (HTN), autosomal dominant polycystic kidney disease (ADPKD), Alport's, reflux or congenital dysplasia (68 vs. 96% at 10 yr, p = 0.0009). Poor patient survival was seen in diabetics (71 vs. 88% at 10 yr, p = 0.01). There was a trend to poorer graft survival in diabetic recipients when compared to non-diabetics (65 vs. 81% at 10 yr, p = 0.054). Elevated creatinine at 1 yr was associated with worse graft survival. Likewise, the magnitude of creatinine increase during the first year directly correlated with the risk of graft loss. Hypertensive patients were more likely to lose their grafts than normotensive recipients (72 vs. 86%, p = 0.04). Pre-transplant blood transfusion, pregnancy, and PRA level were not associated with increased graft failure or AR. Graft survival was not affected by gender, age, or ABO blood type of donors or recipients. In conclusion, better prevention and treatment of AR, hypertension, and cardiac disease should improve graft and patient survival. Close attention to recurrence of disease and subtle changes in the creatinine level during the first year might dictate early diagnostic and, hopefully, therapeutic interventions.

Interleukin-12 (IL-12) is a heterodimeric cytokine implicated in the early differentiation of naive T-lymphocytes into the Th1 subset. IL-12 is important for induction of the cellular immune response against viruses, intracellular parasites and neoplasms. Its role in alloresponsiveness has not been fully elucidated. Preliminary data in the literature point toward the prevalence of Th1 lymphocytes in processes of allograft rejection. In attempt to further investigate the expression of this cytokine during episodes of cellular rejection of renal allografts, we searched for IL-12 message in human kidney allograft biopsies using the reverse transcriptase-polymerase chain reaction technique. Twenty-three allograft core biopsies from 19 patients were obtained percutaneously for clinical indications in 18 cases, and as part of an investigational protocol in five cases. A portion of the tissue was used for RNA extraction using the guanidium-thiocyanide phenol-chloroform method. Histology was performed on the remaining core material. Ten mg of total RNA were used for reverse transcription. PCR of the c-DNAs was done for 40 cycles using primers for the p40 subunit of IL-12 and GAPDH which was used as a control. PCR products were photographed after electrophoresis, transferred to a nylon membrane and hybridized with a radiolabelled cloned human IL-12 p40 1 kb c-DNA fragment. Autoradiographies were developed after 20-min exposure. All samples were run in triplicate. IL-12 p40 m-RNA was expressed in all 17 biopsies showing acute cellular rejection as well as in all three biopsies showing focal interstitial fibrosis. No message was found in the presence of normal allograft histology. This is the first in vivo report of IL-12 p40 subunit m-RNA expression during renal allograft rejection in humans. The role of this Th1 cytokine in the alloresponse deserves further investigation.

Purpose: Living, genetically unrelated donor renal transplantation (LURT) is being performed with increasing frequency. We evaluated our single center experience with LURT and compared this to a cohort of living related donor renal transplants (LRT) to evaluate the short-term success of LURT at our center. Materials and Methods: We identified 99 consecutive patients who underwent LURT at our center and had at least 1 year of followup data. A control cohort of 99 patients who underwent LRT at our center matched for age, number of transplants and date of transplant was also identified. One-year graft and patient survival, and serum creatinine levels at 1, 3, 6 and 12 months were compared between the groups. Our data were compared with national and international data. Results: At our center 1-year graft survival was 95% in the LURT and LRT cohorts. One-year LURT patient survival was 99% compared with 97% in the LRT group and the serum creatinine levels were not significantly different. Conclusions: Patients undergoing LURT at our center have excellent 1-year graft and patient survival compared with LRT performed at our center, and national and international LURT. Genetically unrelated kidney donors should continue to be used to expand the kidney donor pool.

BACKGROUND In December 2010, a case of West Nile virus (WNV) encephalitis occurring in a kidney recipient shortly after organ transplantation was identified. METHODS A public health investigation was initiated to determine the likely route of transmission, detect potential WNV infections among recipients from the same organ donor, and remove any potentially infected blood products or tissues. Available serum, cerebrospinal fluid, and urine samples from the organ donor and recipients were tested for WNV infection by nucleic acid testing and serology. RESULTS Two additional recipients from the same organ donor were identified, their clinical and exposure histories were reviewed, and samples were obtained. WNV RNA was retrospectively detected in the organ donor's serum. After transplantation, the left kidney recipient had serologic and molecular evidence of WNV infection and the right kidney recipient had prolonged but clinically inapparent WNV viremia. The liver recipient showed no clinical signs of infection but had flavivirus IgG antibodies; however, insufficient samples were available to determine the timing of infection. No remaining infectious products or tissues were identified. CONCLUSIONS Clinicians should suspect WNV as a cause of encephalitis in organ transplant recipients and report cases to public health departments for prompt investigation of the source of infection. Increased use of molecular testing and retaining pretransplantation sera may improve the ability to detect and diagnose transplant-associated WNV infection in organ transplant recipients.

Objectives/hypothesis Laryngeal transplantation offers the potential for patients without a larynx to recover their voice, which is critical in our communication age. We report clinical and functional outcomes from a laryngotracheal transplant. Widespread adoption of this technique has been slowed due to the ethical concerns of life-long immunosuppression after a nonvital organ transplant. Our patient was already on immunosuppressive medication from prior kidney-pancreas transplantation, and therefore was not exposed to added long-term risk. We describe the unique technical advances, clinical course, and rehabilitation of this patient and the implications for future laryngeal transplantation. Study design Case report. Methods A laryngotracheal transplantation was performed in a 51-year-old prior kidney-pancreas transplant recipient presenting with complete laryngotracheal stenosis. Surgical modifications were made in the previously described technique related to retrieval, vascular supply, and reinnervation. This resulted in a robustly vascularized organ with well-perfused long-segment tracheal transplant and early return of motor reinnervation. Results A multidisciplinary approach resulted in a successful transplant without evidence of rejection to date. Postoperatively, the patient continues to rely on a tracheotomy but has had the return of an oral and nasal airway, vocalization, smell, and taste, all experienced for the first time in 11 years. Conclusions We have demonstrated that our methods may result in a successful laryngotracheal transplant. We describe the preparation, surgical technique, rehabilitation, and interventions employed in achieving optimal outcomes. This report contributes valuable information on this rarely performed composite transplant.

To determine if cardiac allograft outcome is improved among patients with fewer HLA-DR mismatches with their donors, we studied 132 recipients of a primary cardiac allograft who were transplanted between December 1985 and December 1991. These recipients and their donors all had high-confidence-level herological HLA-DR typing, previously shown to correlate highly with DNA DR typing. Patients were divided in two groups based on the HLA-DR mismatch with their donors. Group I consisted of 78 patients with 1 or zero DR mismatch and group II of 54 patients with 2 DR mismatches

This study examined the relation between heart rate (HR) response to adenosine and outcome in patients with end-stage renal disease (ESRD). The usual HR increase during adenosine infusion was caused by direct sympathetic stimulation. It was hypothesized that a blunted HR response, which was probably caused by sympathetic denervation, would be associated with a worse outcome in patients with ESRD. One hundred thirty-nine patients with ESRD being evaluated for renal transplantation who underwent coronary angiography and adenosine gated single-photon emission computed tomographic myocardial perfusion imaging were followed up for all-cause mortality. Percentage of change in HR (%DeltaHR) was calculated as [(peak HR during adenosine infusion - HR at rest)/HR at rest] * 100. A control group of 54 patients (normal renal function and no diabetes) was included for comparison of HR responses. Mean age of patients was 54 +/- 9 years, 30% were women, and 68% had type-2 diabetes mellitus. %DeltaHR was 19.2 +/- 18% in patients with ESRD versus 33 +/- 25% in the control group (p0.0001). At a mean follow-up of 3.4 +/- 1.5 years, 50 patients (36%) with ESRD died. %DeltaHR was lower in nonsurvivors than survivors (12.6 +/- 14% vs 23 +/- 19%; p = 0.0017). Patients with %DeltaHR less than the median value were more likely to have lower left ventricular ejection fraction and larger end-diastolic volume (p0.05 for each). In a multivariate logistic regression model, %DeltaHR alone was an independent predictor of all-cause mortality (adjusted odds ratio 5.5, 95% confidence interval 2.3 to 12.9, p = 0.0001). In conclusion, patients with ESRD had a blunted HR response to adenosine, and degree of blunting was strongly associated with all-cause mortality.

Patients with end-stage renal disease (ESRD) are at high risk of cardiovascular events. This study examined the prognostic power of stress myocardial perfusion imaging (MPI) in 150 patients with ESRD (mean age 53 +/- 9 years; 30% women; 66% with diabetes mellitus) being evaluated for renal transplantation with known coronary anatomy using angiography. Baseline data in addition to perfusion and angiographic parameters were compared between survivors and nonsurvivors. All-cause mortality was defined as the outcome measure. An abnormal MPI result was present in 85% of patients, 30% had left ventricular (LV) ejection fraction (EF)or =40%, and 40% had multivessel coronary artery disease using angiography. At a mean follow-up of 3.4 +/- 1.5 years, 53 patients died (35%). LVEFor =40%, LV dilatation (LV end-diastolic volume90 ml), and diabetes mellitus were associated with higher mortality (all p0.05). Both total perfusion defect size and mean number of narrowed coronary arteries using angiography were significantly higher in those who died (p0.05). In a multivariate model, abnormal MPI results (low LVEF or abnormal perfusion) and diabetes alone were independent predictors of death, whereas number of narrowed arteries using coronary angiography was not. Thus, MPI was a strong predictor of all-cause mortality in patients with ESRD. In conclusion, abnormal MPI results independently predicted worse survival and provided more powerful prognostic data than coronary angiography.

Individuals waiting for a renal transplant experience excessive cardiovascular mortality, which is not fully explained by the prevalence of ischemic heart disease in this population. Overt heart failure is known to increase the mortality of patients with ESRD, but the impact of lesser degrees of ventricular systolic dysfunction is unknown. For examination of the association between left ventricular ejection fraction(LVEF) and mortality of renal transplant candidates, the records of 2718 patients evaluated for transplantation at one institution were reviewed. During 6355 patient-years (median 27 mo) of follow-up, 681 deaths occurred. Patients with systolic dysfunction (LVEFor= 0.40) had significantly lower survival than those with higher systolic function (median 49 +/- 3.1 versus 72 +/- 4.0 mo; P 0.001) but had similar survival to patients with ischemia (48 +/- 2.5 mo). Multivariate modeling showed that those with systolic dysfunction were nearly twice as likely to die as those with normal systolic function, adjusted for risk factors including diabetes, left ventricular hypertrophy, and ischemia (adjusted hazard ratio 1.7; 95%confidence interval 1.43 to 2.07). In addition, a graded, reverse association between LVEF and mortality was identified. In conclusion, systolic dysfunction is strongly associated with mortality, in a graded manner, in renal transplant candidates.

Background. Gated single photon emission computed tomography (SPECT) provides information on myocardial perfusion and left ventricular ejection fraction (LVEF), which correlates with risk of cardiac events in patients with known or suspected coronary artery disease (CAD). We hypothesize that decreased LVEF at time of renal transplant evaluation is an independent risk factor for cardiac death and nonfatal events after transplant. Methods and Results. A total of 653 recipients of renal allografts between 1998 and 2005 had stress SPECT imaging before transplantation. One hundred and nineteen (18%) patients had left ventricular (LV) systolic dysfunction (LVEF ≤45%). The patients with LV dysfunction differed from the patients with normal LVEF having a higher proportion of males, smokers, left ventricular hypertrophy, previous left heart catheterization, and higher exposure to dialysis. During a mean follow-up of 3.01±1.86 years postrenal transplant, 66 patients died and 67 additional patients experienced at least one nonfatal cardiac-related complication. Patients with LV systolic dysfunction were at considerably higher risk for cardiac complications (hazard ratio [HR] 1.8, P=0.01) and all-cause mortality (HR 2.0, P=0.01) after transplantation. By multivariate analysis, LV systolic dysfunction was associated with a 5-fold increase in the cardiac mortality risk, a 2-fold increase in all-cause mortality risk, and a 70% increase in posttransplant cardiac complications. Conclusions. Systolic dysfunction is associated with increased risk for overall and cardiac-related death and nonfatal events after renal transplantation, an association independent of ischemic disease.

The calcineurin inhibitors cyclosporin A (CsA) and tacrolimus (FK506) are associated with dose- and efficacy-limiting adverse events, including nephrotoxicity, which may diminish their overall benefits for long-term graft survival. Nephrotoxicity is difficult to distinguish from chronic allograft rejection and is a particular problem in the setting of renal transplantation. Minimizing immunosuppressant-induced nephrotoxicity could improve long-term renal allograft survival. However, to obtain significant long-term improvement in renal allograft outcomes, it may be necessary to adopt new immunosuppressive regimens that rely less on calcineurin inhibitors. Recipients of other transplanted organs, as well as patients with autoimmune diseases who require immunosuppressant therapy, could also benefit from this change in immunosuppressive drug strategy because their healthy, native kidneys are particularly susceptible to the nephrotoxic effects of CsA and FK506. CsA- and FK506-sparing regimens, which use reduced doses of CsA and FK506 in combination with other nonnephrotoxic immunosuppressants, may be the best current option for reducing nephrotoxicity. The chemical immunosuppressant mycophenolate mofetil (MMF) has been used as part of CsA- and FK506-sparing regimens that provide improved renal function while maintaining adequate immunosuppression. Such regimens should reduce patient morbidity and mortality. Also, because immunosuppressant-induced nephrotoxicity has been associated with significant financial costs, CsA- and FK506-sparing regimens should result in substantial savings in health care costs.

As understanding of the molecular basis for the immune response has expanded rapidly, so have the possibilities for designing therapeutic interventions that are more effective, more specific, and safer than current treatment options. The promise of therapeutic advances in the future is based on the rapidly expanding insights into the pathogenesis of abnormal immunologic reactions. Nowhere is the understanding of molecular mechanisms, pathophysiology, and targeted therapy more relevant than in the field of renal transplantation, which makes up much of the clinical database for the use of immunosuppressive therapy for renal disease. Despite the recent advances in basic immunology, clinical validation of new agents and approaches is lacking for most drugs at present. This review will focus in the pharmacology of agents used in the therapy of immunologic renal disease and in renal transplantation. It should be recognized that clinical pharmacology and experience with newer agents is limited, and potential utility is based largely on experimental data.

To determine the prevalence of antibodies to hepatitis C virus (anti-HCV) and HCV RNA among cadaver organ donors and to correlate these results with donor liver histologic abnormalities and evidence for transmission of disease through organ transplantation.Retrospective testing of stored serum samples from cadaver organ donors for anti-HCV and HCV RNA.Transplantation service of the University of Miami/Jackson Memorial Medical Center and other cooperative medical centers furnishing follow-up data.Of 1096 cadaver organ donors harvested between 1 January 1979 and 28 February 1991, 484 had stored serum samples available for analysis. Recipients of organs from recombinant immunoblot assay (RIBA)-positive donors for whom adequate follow-up was available were also included in the analysis.Samples were tested for anti-HCV by enzyme-linked immunosorbent assay (ELISA). Confirmatory testing was done using a second-generation RIBA. Hepatitis C viral RNA was detected in serum using the polymerase chain reaction. Liver biopsies were obtained from the organ donor and interpreted blindly by a pathologist unaware of the clinical data. Liver chemistry profiles and serum sample analysis for HCV RNA were done for transplant recipients.From the 484 cadaver organ donors, 89 samples (18%; 95% Cl, 15% to 21%) were reactive by ELISA. Of these, 33 (6.8%; Cl, 4.6% to 9%) were RIBA seropositive. Hepatitis C viral RNA sequences were detected in 50% of the RIBA-positive serum samples tested. Liver tissue was available from 24 of the 33 RIBA-positive donors and showed chronic active hepatitis in 16, chronic persistent hepatitis in 2, and no abnormality in 6. Among the 46 recipients of a kidney from a RIBA-positive donor, 13 (28%; Cl, 15% to 41%) developed post-transplant liver disease, of which only 4 cases were highly suggestive of viral transmission from the donor. Little morbidity and no mortality could be attributed to liver disease in this cohort of recipients.These data suggest that HCV transmission by organ transplantation is low and that the consequences of infection are small. If the medical condition of the potential recipient is so serious that other options no longer exist, the use of an organ from an anti-HCV-seropositive donor should be considered.