Antithymocyte globulin is associated with a lower incidence of de novo donor-specific antibodies in moderately sensitized renal transplant recipients.

BACKGROUND: Recent evidence suggests that de novo donor-specific antibodies (dnDSA) are associated with antibody-mediated rejection (ABMR) and graft failure after kidney transplantation. The effects of induction immunosuppression on dnDSA are unknown. METHODS: The study population comprised 114 consecutive moderately sensitized (positive DSA and negative flow crossmatch) recipients who received deceased donor renal transplants between December 2009 and November 2011. Patients were divided into two groups based on induction immunosuppression: antithymocyte globulin (ATG) (n=85) or basiliximab (n=29) and were followed up for 36 months. RESULTS: Patients in the ATG group received a mean dose of 4.98 mg/kg ± 7.9 mg/kg, had a significantly higher PRA, and received more plasmapheresis and IVIG at the time of transplant. The incidence of dnDSA (P=0.02, HR=0.33, 95% CI 0.09-1.24) and ABMR (P=0.002, HR=0.2, 95% CI 0.04-0.87) was significantly lower in the ATG group. In multivariate regression analyses, ATG induction was the single most important variable associated with both ABMR and dnDSA. CONCLUSIONS: In moderately sensitized deceased donor renal transplant recipients, induction with ATG is associated with a reduction in the occurrence of dnDSA and ABMR when compared with basiliximab.

Outcomes of Clostridium difficile infection in recipients of solid abdominal organ transplants.

Knowledge of outcomes of Clostridium difficile infection (CDI) in solid organ transplant (SOT) recipients is limited. To evaluate this population, we undertook a retrospective cohort study of all recipients of kidney and liver transplants diagnosed with CDI at a single center over 14 yr. Data pertaining to all episodes of CDI were collected. Multivariate analysis using logistic regression was performed to determine independent predictors of clinical cure. Overall, 170 patients developed 215 episodes of CDI. Among these patients, 162 episodes (75%) were cured, and in 103 episodes (48%), patients were cured within 14 d. In a multivariate analysis, lack of clinical cure at 14 d was predicted by recurrent episode (0.21, 95% CI 0.06-0.72, p = 0.0128), treatment with vancomycin (OR 0.27, 95% CI 0.1-0.74, p = 0.011), vasopressor support (OR 0.23, 95% CI 0.07-0.76, p = 0.0161), and CDI before the year 2004 (OR 0.44, 95% CI 0.2-0.98, p = 0.0446). The latter three factors are likely markers for severity of illness. In this cohort, 13 patients (8%) died during hospitalization, and 49 patients (29%) died within one yr. No deaths were attributed to CDI. Recurrent episode was a major predictor of treatment failure, suggesting that research into development of therapeutic options for recurrent disease is needed.

Serum ß2-microglobulin at discharge predicts mortality and graft loss following kidney transplantation.

Serum ß(2)-microglobulin (ß(2)M), a novel marker of kidney function, predicts mortality and kidney failure in the general population, and its elevation following transplantation is a marker of acute rejection. The association between post-transplant serum ß(2)M and outcomes following kidney transplantation, however, is unknown. To help determine this, we conducted a retrospective cohort study of 2190 individuals receiving a primary kidney transplant with serum ß(2)M measured at discharge. A total of 452 deaths and 347 graft failures before death (669 total graft losses) occurred over a median of 4.1 years of follow-up. After adjustment, the highest quintile of ß(2)M (5.0 mg/l and above), compared with the lowest quintile (<2.3 mg/l), was associated with a hazard ratio of 4.6 (95% confidence interval 2.8, 7.5) for death, 4.1 (2.4, 7.0) for death-censored graft loss, and 3.8 (2.5, 5.6) for total graft loss. Serum ß(2)M was more strongly associated with each outcome than was serum creatinine. Higher serum ß(2)M at discharge was independently associated with each outcome in models stratified by the presence of delayed graft function, donor type, or estimated glomerular filtration rate at discharge. Thus, serum ß(2)M at discharge is a potent predictor of long-term mortality and graft loss in kidney transplant recipients, providing information on allograft function beyond that of serum creatinine.

Increased C4d in post-reperfusion biopsies and increased donor specific antibodies at one-week post transplant are risk factors for acute rejection in mild to moderately sensitized kidney transplant recipients.

In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor-specific antibody levels measured as mean fluorescence intensity (MFImax). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean-calculated panel-reactive antibody and MFImax ranged from 10.3-57.2% and 262-1691, respectively, between low- and high-risk protocols. Mean MFImax increased significantly from transplant to 1 week and 1 year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32%, including 14% cellular, 12% antibody-mediated, and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71-6.45) and increased specific antibodies at 1-week post transplant were significant predictors of rejection. A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in post-reperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients.

Native kidney function following liver transplantation using calcineurin inhibitors: single-center analysis with 20 years of follow-up.

INTRODUCTION: The incidence of chronic kidney disease (CKD) in liver transplant recipients has been estimated to be from 18% to 28% at 10 yr after transplantation. As outcomes from liver transplantation continue to improve, long-term native kidney function in these recipients becomes more critical to patient survival. METHODS: We analyzed 1151 adult, deceased-donor, single-organ primary liver transplantations performed at our center between 7/17/84 and 12/31/07. Analysis of renal function was performed on 972 patients with liver allograft survival >1 yr. RESULTS: Kaplan-Meier analysis revealed that 3%, 7%, and 18% of liver transplant recipients with allograft survival >1 yr developed end-stage renal disease (ESRD) at five, 10, and 20 yr, respectively. Significant independent risk factors for ESRD included dialysis during the transplant hospitalization, the stage of CKD at one yr, hypercholesterolemia, non-Caucasian race, and hepatitis C as the primary indication for liver transplantation. The initial immunosuppression of essentially all recipients was a calcineurin inhibitor-based regimen. CONCLUSION: Close, long-term follow-up of liver transplant recipients permits optimal management of liver allograft and native renal function and can lead to excellent long-term outcomes despite a calcineurin inhibitor-based immunosuppressive regimen.

Complications associated with liver transplantation in the obese recipient.

The prevalence of the metabolic syndrome with attendant morbid obesity continues to increase nationwide. A concomitant increase in non-alcoholic steatohepatitis (NASH) and associated end-stage liver disease requiring transplantation is expected to parallel this trend. Between January 1, 1997 and December 31, 2008, our center performed 813 solitary adult deceased-donor liver transplants. Patients were divided into groups based on the World Health Organization International Classification of obesity. Patients within each obesity class were compared to normal weight recipients. Preoperative demographics among all groups were similar. NASH was more common in higher BMI groups. Operative time, blood product usage, ICU length of stay, infectious complications, and biliary complications requiring intervention were all higher in obese recipients. Deep venous thrombosis occurred more commonly in patients with Class III obesity. Patients with Class II obesity had lower patient (HR 1.82, CI 1.09-3.01, p=0.02) and allograft survival (HR 1.62, CI 1.02-2.65, p=0.04). Obesity class did not reach statistical significance on multivariate analysis. Despite increased technical operative challenges and medical complexities associated with increasing recipient BMI, morbid obesity in and of itself should not be an absolute contraindication to liver transplantation as these patients have reasonable long-term outcomes.

Differential outcomes of expanded-criteria donor renal allografts according to recipient age.

BACKGROUND AND OBJECTIVES: Expanded-criteria donor (ECD) kidneys are used to expand the number of deceased-donor kidney transplants, often for elderly recipients. This study sought to determine whether older recipients had significantly worse outcomes from receiving ECD kidneys and whether outcomes of ECD versus standard-criteria donor (SCD) kidneys differed in younger recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a single-center, retrospective review of all primary deceased-donor kidney transplantations performed between 2000 and 2005. Group 1 consisted of patients ≥60 years of age (n=189) who received an ECD (n=96) or an SCD (n=93) kidney. Group 2 consisted of patients 40-59 years of age (n=370) who received an ECD (n=105) or an SCD (n=265) kidney. RESULTS: Older recipients (group 1) who received ECD kidneys demonstrated significantly shortened 5-year actuarial patient and graft survival rates compared with older recipients of SCD allografts. Group 1 ECD recipients also had significantly worse outcomes than younger (group 2) ECD recipients. In multivariate analysis, ECD kidneys remained an independent predictor of poorer outcome in group 1. CONCLUSIONS: Morbidity and mortality were increased in elderly recipients of ECD kidneys. These findings may have implications in kidney allocation policy developments that encourage placement of ECD kidneys for older recipients.

Alemtuzumab as compared to alternative contemporary induction regimens.

Between 1 January 2002 and 31 December 2007, our center performed 1687 adult renal transplants. A retrospective analysis was performed to compare outcomes between patients receiving alemtuzumab (n = 632) and those receiving either basiliximab (n = 690) or thymoglobulin (n = 125). Patients receiving alemtuzumab were younger (49 vs. 51 years, P = 0.02), had fewer HLA matches (1.7 vs. 2.0, P < 0.0001), were more likely to have a cytomegalovirus (CMV) donor(+)/recipient(-) transplant (22% vs. 17%, P = 0.03) and were less likely to receive a living donor allograft (32% vs. 37%, P = 0.04). Alemtuzumab recipients were less likely to receive tacrolimus (35% vs. 47%, P < 0.0001). The 1-, 3-, and 5-year cumulative incidence of antibody-mediated rejection (AMR) in alemtuzumab-treated patients was 19%, 24%, and 27%, vs. 11%, 15%, and 18% for the other group (P < 0.0001). The 1-, 3-, and 5-year allograft survival in the alemtuzumab group was 88%, 75%, and 67%, vs. 91%, 82%, and 74% for the other group (P < 0.0001). Patient survival was equivalent. Alemtuzumab was an independent risk factor for living donor allograft loss (HR 2.0, P = 0.004), opportunistic infections (HR 1.3, P = 0.01), CMV infections (HR 1.6, P = 0.001), and AMR (HR 1.5, P = 0.002). The significantly worse graft survival in the alemtuzumab cohort may be due to the increased rates of AMR and infectious complications.

The impact of hepatitis C virus donor and recipient status on long-term kidney transplant outcomes: University of Wisconsin experience.

The survival benefit of transplanting hepatitis C (HCV)-positive donor kidneys into HCV-positive recipients remains uncertain. The purpose of this study was to assess the effect of HCV-status of the donor (D) kidney on the long-term outcomes in kidney transplant recipients (R). We evaluated 2169 consecutive recipients of deceased-donor kidney transplants performed between 1991 and 2007. The following HCV cohorts were identified: D-/R- (n = 1897), D-/R+ (n = 59), D+/R- (n = 118), and D+/R+ (n = 95). Patients were followed for a mean of 6.02 (standard deviation = 4.26) yr. In a mulitvariable Cox-proportional hazards model, D+/R+ cohort had significantly lower patient survival (adjusted-hazard ratio [HR] 2.1, 95% CI [1.4-2.9]) with respect to the reference D-/R- group, whereas mortality was not increased in D-/R+ group. The rate of graft loss was increased in both D+/R+ and D-/R+ but was comparable with each other (adjusted-HR 1.8, 95% CI [1.4-2.5]) vs. adjusted-HR 2.0, 95% CI [1.4-2.8], respectively). D-/R+ cohort experienced significantly higher rate of rejection (adjusted-HR 1.7, 95% CI [1.2-2.5]) and chronic allograft nephropathy (adjusted-HR 2.1, 95% CI [1.2-3.7]). Neither donor nor recipient HCV-status impacted the risk of recurrent or de novo GN. Transplanting HCV-positive kidneys as opposed to HCV-negative kidneys into HCV-positive recipients provided similar graft survival but compromised patient survival in the long term.

Pretransplant immune regulation predicts allograft outcome: bidirectional regulation correlates with excellent renal transplant function in living-related donor-recipient pairs.

BACKGROUND: Tolerance to noninherited maternal antigens has provided clinical advantage when kidney transplants are exchanged between siblings but not when mother herself is the donor. This paradox prompted us to revisit the "two-way" hypothesis of transplant tolerance--that the immune status of both the organ recipient and the organ donor critically influences allograft outcome. METHODS: We obtained peripheral blood monocyte cells from 29 living donor-recipient pairs before transplant and used the trans-vivo-delayed type hypersensitivity assay to measure immune regulation in both the recipient antidonor and donor antirecipient directions. RESULTS: We found preexisting bidirectional regulation in all human leukocyte antigen (HLA)-identical sibling pairs tested (7/7), and one half (9/18) of the HLA haploidentical pairs. No significant regulation was found in four control living unrelated and two HLA haploidentical living-related donor recipient pairs, whereas unidirectional regulation was found in the remaining seven haploidentical pairs. Of the nine HLA haploidentical transplants with unidirectional or no pretransplant regulation, seven had an acute rejection episode and four of these experienced graft loss. In contrast, of the nine HLA haploidentical transplants with bidirectional regulation, only one had rejection. Renal function for the latter group was similar to HLA-identical kidney recipients at 3 years posttransplant. Significantly (P<0.05) lower mean serum creatinine values in bidirectional regulators were noted as early as 4 months and this difference became more pronounced at 12 (P<0.005) and 36 months (P<0.0001). CONCLUSIONS: Contrary to the belief that only the recipient's immune status matters, the data indicate that pretransplant immune status of both donor and recipient influence posttransplant outcome.

Simultaneous pancreas and kidney (SPK) retransplantation in prior SPK recipients.

INTRODUCTION: We have performed 113 renal and 28 isolated pancreas retransplants in our cohort of more than 1200 prior simultaneous pancreas and kidney (SPK) recipients. On the basis of these experiences, we began performing repeat SPK in prior SPK recipients (n = 9). METHODS: This retrospective review summarizes our experience with repeat SPK transplantation in prior SPK recipients. Mean age at retransplant was 39 yr; mean interval to retransplant was 7.8 yr. Thirty-three percent were pre-dialysis. Eighty-nine percent of patients underwent transplant nephrectomy (five during the repeat SPK and three prior to it), and 78% underwent transplant pancreatectomy (four during the repeat SPK and three prior to it). Enteric drainage was performed in all repeat SPKs. RESULTS: Median length of stay was 11 d. Perioperative complications included the following: renal artery thrombosis (1), pancreatic portal venous thrombosis (1), enteric leak (1), and hematoma (2). Overall pancreatic allograft survival was 78% at one yr and 67% at two yr. Overall renal allograft survival was 89% at one yr and 78% at two yr. Patient survival at one and three yr was 100%. CONCLUSIONS: Survival of repeat SPK allografts is acceptable despite the increased technical and immunologic demands of retransplantation. Graftectomy prior to or at the time of retransplantation is often necessary.

Chronic kidney disease stage progression in liver transplant recipients.

BACKGROUND AND OBJECTIVES: There is little information on chronic kidney disease (CKD) stage progression rates and outcomes in liver transplant recipients. Identifying modifiable risk factors may help prevent CKD progression in liver transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a retrospective review of 1151 adult, deceased-donor, single-organ primary liver transplants between July 1984 and December 2007 and analyzed kidney outcomes and risk factors for CKD stage progression. Seven hundred twenty-nine patients had an available estimated GFR at 1 year posttransplant to establish a baseline stage. The primary end point was the CKD progression from one stage to a higher stage (lower GFR). RESULTS: Kaplan-Meier estimates of patient survival were 91%, 74%, and 64% at 5, 10, and 15 years, respectively. Estimates of liver allograft survival were 89%, 71%, and 60% at the same time points. At 1 year, 7%, 34%, 56%, 3%, and 1% of patients were in CKD stages 1, 2, 3, 4, and 5. The incidence of stage progression was 28%, 40%, and 53% at 3, 5, and 10 years. The incidence of ESRD was 2.6%, 7.5%, and 18% at 5, 10, and 20 years. Multivariable Cox regression analyses demonstrated that CKD stage at 1 year, pretransplant diabetes and urinary tract infections/hypercholesterolemia in the first year proved to be independent risk factors for stage progression (hazard ratio 1.9, 0.28, 1.39, and 1.46, respectively, P < 0.05). CONCLUSIONS: Future studies will determine whether treatment of risk factors in the first posttransplant year prevent CKD progression in liver transplant recipients.

Luminex-based desensitization protocols: the University of Wisconsin initial experience.

BACKGROUND: We have demonstrated that immunodominant donor-specific antibody (DSA) more than 100 mean fluorescence intensity (MFI) at the time of transplant is associated with a significantly higher risk of rejection. We now present short-term outcomes of DSA-based desensitization (DSZ) strategies in patients with a negative complement-dependent cytotoxicity crossmatch. METHODS: Between January 1, 2009, and January 1, 2010, live-donor kidney transplant recipients were divided into three protocols based on their immunodominant DSA MFI pretransplant (D1: 100-500, D2: 501-1000, and D3: 1001-3000). Deceased donor kidney transplant recipients were stratified into two protocols (D4: 501-1000 and D5: 1001-3000). The intensity of the conditioning treatment increased with DSA levels and included thymoglobulin induction, plasmapheresis, and intravenous immunoglobulin in the highest risk groups. We compared outcomes between desensitized patients (DSZ) and those undergoing no DSZ (or D0) during the same interval. RESULTS: Forty-eight of 249 (23%) kidney transplants underwent DSZ (n=20, 4, 3, 4, and 17 in D1-D5 protocols, respectively). There was more retransplantation (50% vs. 18%, P<0.001) and live donor transplantation (56% vs. 30%, P<0.001) in the DSZ group. In this group, mean peak panel reactive antibody and MFI at transplant were 51% ± 7% and 960 ± 136, respectively. The incidence of antibody-mediated rejection (25% vs. 12.5%, P=0.008) and acute cellular rejection (23% vs. 14%, P=0.02) was greater in the DSZ group. However, mixed rejection (8%), graft loss (0 vs. 6), patient death (0 vs. 3), cytomegalovirus infection (15% vs. 12%), and 1-year serum creatinine (1.4 ± 0.5 and 1.4 ± 0.4 mg/dL) were similar between DSZ and no-DSZ groups. CONCLUSION.: Long-term follow-up is needed to determine the role of Luminex-based strategies in current preconditioning regimens.

Outcomes of simultaneous liver/kidney transplants are equivalent to kidney transplant alone: a preliminary report.

BACKGROUND: With adoption of Model for End-Stage Liver Disease, the number of simultaneous liver-kidney transplants (SLK) has greatly increased. A recent registry study questioned the equity of allocating kidney transplants (KTx) simultaneously with liver transplantation due to poor outcomes (Locke et al., Transplantation 2008; 85: 935). METHODS: To investigate outcome of KTx in SLK, all SLK (n=36) performed at our center from January 2000 to December 2007 were reviewed and KTx outcomes compared with those of kidney transplant alone (KTA) performed during that period (n=1283). We also reviewed whether pretransplant panel reactive antibody and donor-specific antibody affected KTx outcome in SLK. RESULTS: One- and 3-year KTx and patient survival were not different between KTA and SLK regardless of sensitization level. There were 348 (27%) KTx failures in KTA vs. 6 (17%) in SLK (NS). Overall freedom from acute cellular rejection (ACR) and antibody-mediated rejection (AMR) in SLK was 93 and 96% at 3 years, compared with 72 and 78% in KTA (P=0.0105 and P=0.0744, respectively). Sensitized KTx recipients had more ACR and AMR (32 and 38%) at 3 years compared with nonsensitized recipients (28 and 20%) (P=0.23 and 0.0001, respectively). No differences in ACR and AMR were observed when SLK was divided and level of sensitization compared (P=0.17 and 0.65, respectively). CONCLUSION: SLK is a life-saving procedure with excellent patient and graft survival. AMR incidence in the KTx appears reduced in SLK compared with KTA regardless of level of preoperative panel reactive antibody. A high level of donor-specific antibody should not preclude simultaneous transplantation when clinically indicated.

HLA-A, -B, and -DR zero-mismatched kidneys shipped to the University of Wisconsin, Madison, 1993-2006: superior graft survival despite longer preservation time.

BACKGROUND: To determine the impact at a single center of the United Network for Organ Sharing-mandated sharing program for human leukocyte antigen (HLA)-A/-B/-DR 0-mismatched (0MM) kidneys, we analyzed the results of 264 kidney transplants from 0MM distant donors between 1993 and 2006, with a follow-up through January 31, 2007. We compared these results with that of concurrent kidneys transplanted from HLA more than 0MM local donors and with shipped more than 0MM kidneys from "payback" donors. RESULTS: Despite a significantly longer preservation time, we found an 11% increase in 8-year graft survival (63% vs. 52%; P<0.003) of 0MM shipped versus locally procured, >0MM donor kidneys. Graft survival of 0MM shipped kidneys at 8 years was significantly better in nonsensitized (<20% panel reactive antibodies; 68% vs. 55%; P<0.0005) but not in sensitized (>or=20% panel reactive antibodies) recipients, who showed an early (2 years) but short-lived benefit. The benefit of receiving a HLA-A, -B, and -DR 0MM shipped kidney remained strong and statistically significant (0.71 relative risk of graft loss vs. local; P<0.02) when adjusted for 22 potentially confounding variables in a Cox proportional hazards analysis. CONCLUSIONS: The recent change in United Network for Organ Sharing policy restricting mandated sharing of 0MM kidneys to sensitized and pediatric recipients will give greater flexibility to the local organ procurement organization in allocating organs. However, the survival benefit to nonsensitized patients is real and long lasting and will be lost.

Mycophenolate mofetil versus enteric-coated mycophenolate sodium: a large, single-center comparison of dose adjustments and outcomes in kidney transplant recipients.

BACKGROUND: Although enteric-coated mycophenolate sodium (EC-MPS) was developed to reduce gastrointestinal (GI) side effects in kidney transplantation, a multicenter clinical trial of patients undergoing de novo renal transplantation found that efficacy failure and adverse GI event rates for EC-MPS were comparable with mycophenolate mofetil (MMF). A common strategy to mitigate mycophenolic acid-related GI adverse events includes dose manipulations such as split dosing, dose reduction, and discontinuation. Several studies have demonstrated that dose alterations with MMF are associated with poorer graft outcomes. METHODS: To determine whether there was a clinically significant difference in dose alterations and outcomes with EC-MPS compared with MMF, we conducted a retrospective study comparing MMF and EC-MPS in all consecutive kidney transplants (n=1709) between 2000 and 2006. RESULTS: Graft survival between MMF and EC-MPS patients was not different during the study period (P=0.9928). The incidence of biopsy-proven acute rejection at 2 years was higher in the MMF group (30.2% MMF vs. 21.9% EC-MPS, P=0.0004). The adjusted risk of dose reductions was significantly higher in MMF-treated patients (hazard ratio=1.703, P<0.0001). Similarly, the adjusted risk of drug discontinuation was higher in the MMF group (hazard ratio=1.507, P=0.0002). EC-MPS patients also demonstrated a trend toward a lower incidence of infections and a significantly lower incidence of fungal infections. CONCLUSION: EC-MPS was associated with fewer dose reductions or discontinuations, which may have translated into the observed significantly lower incidence of biopsy-proven rejection. EC-MPS has become the mycophenolic acid agent of choice at this large center.

Pretransplant donor-specific antibodies detected by single-antigen bead flow cytometry are associated with inferior kidney transplant outcomes.

BACKGROUND: The clinical significance of pretransplant donor-specific antibodies (pre-Tx DSAs) detected by single-antigen bead flow cytometry (SAB-FC) remains unclear. METHODS: To investigate the impact that pre-Tx DSAs detected by SAB-FC have on early clinical outcomes, we tested pre-Tx sera from all consecutive deceased-donor kidney transplants performed between January 2005 and July 2006 (n=237). RESULTS: In the study population of which 66% had a high-immunologic risk, mean fluorescence intensity (MFI) more than or equal to 100 for class I and more than or equal to 200 for class II were the lowest DSA thresholds associated with inferior antibody-mediated rejection-free graft survival (75% vs. 90%, P=0.004 and 76% vs. 87%, P=0.017, respectively). The hazard ratio for antibody-mediated rejection increased linearly with higher class II DSA from MFI 100 to 800 (1.7[0.8-3.2], P=0.1 for MFI ≥100 vs. 4.7[2.4-8.8], P<0.001 for MFI ≥ 800). Differences in graft function were only evident in patients with class II MFI more than or equal to 500 (estimated glomerular filtration rate: 47.6 vs. 54.3, P=0.02 and proteinuria: 0.6 ± 0.6 vs. 0.4 ± 0.3, P=0.03). A difference in death-censored graft survival was detected in patients with class II MFI more than or equal to 1000 (75% vs. 91.9%, P=0.055). CONCLUSION: High-pre-Tx DSAs detected by SAB-FC are associated with incrementally poor graft outcomes in deceased-donor kidney transplant with high-immunologic risk.

One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up.

OBJECTIVE: Simultaneous pancreas-kidney transplantation (SPK) is a procedure which frees the diabetic patient with end-stage nephropathy from dialysis and daily insulin injections. The purpose of this study is to report long-term outcomes of this procedure, and describe surgical and medical complications. METHODS: The analysis includes 1000 consecutive SPKs performed between 1985 and 2007. Bladder drainage was used in 390 patients and enteric drainage in 610 patients. In 362 patients, SPK transplantation was performed before initiation of dialysis. RESULTS: Patient survival at 1, 10, and 20 years is 97%, 80%, and 58%; kidney survival is 91%, 63%, and 38%; and pancreas survival is 88%, 63%, and 36%, respectively. There was no difference (P > 0.19) for patient, kidney, and pancreas survival between bladder and enteric drainage. Major surgical complications for bladder-drained patients were anastomotic leaks, urological complications, and infections. For enteric-drained patients, major surgical complications were infection, bleeding, and enzyme leak. Principal causes of death were myocardial infarction (n = 23), cerebrovascular accident (n = 18), and renal failure (n = 15). Graft failure for the kidney was due to acute rejection (n = 48), chronic rejection (n = 146), and death with a functioning graft (n = 99). Graft failure for the pancreas was caused by chronic graft loss (n = 44), thrombosis (n = 31), rejection (n = 80), and death with a functioning graft (n = 125). A total of 113 patients were retransplanted with either living related or unrelated donor kidneys (n = 64) or deceased donor kidneys (n = 42). Survival for retransplanted kidneys is 84% at 1 year and 68% at 5 years. Surviving bladder-drained patients underwent enteric conversion (>50%) for severe recalcitrant metabolic or urologic complications, most commonly enzyme leaks, hematuria, and recurrent urinary tract infection. CONCLUSIONS: Diabetic patients with end-stage renal failure have a poor prognosis without transplantation. Transplantation with SPK provides a marked extension of the patient's life and freedom from insulin injections. Enteric drainage is currently the surgical technique of choice. SPK transplantation should be considered the treatment of choice in this patient population.

Successful reduction of immunosuppression in older renal transplant recipients who exhibit donor-specific regulation.

BACKGROUND: We hypothesized that T-regulatory cells specific for donor alloantigens would protect a renal transplant during partial withdrawal of immunosuppression. METHODS: To test this hypothesis, 32 renal transplant recipients aged 55 years and older with excellent renal function were tested for donor-specific regulation (DSR) by trans-vivo delayed type hypersensitivity assay at the time of enrollment (T=0) and 6 months later (T=6). Twenty-two patients had prednisone withdrawn during a 3-month period, whereas 10 controls were maintained on triple therapy (prednisone, cyclosporine, and mycophenolate). RESULTS: Of 22 patients in the steroid withdrawal group, 10 were DSR+ and 12 were DSR- at the time of enrollment (T=0). None of the DSR+ patients experienced acute rejection, nor did any have donor-specific human leukocyte antigen (HLA) antibody during or after withdrawal. Of 12 DSR- patients, three developed acute rejection, which were reversed with bolus steroid treatment, and four were donor-specific antibody+ at T=0 or T=6. Two years later, 80% (8 of 10) of DSR+ patients in the withdrawal group remain steroid free while maintaining excellent renal function, as compared with only 58% (7 of 12) DSR- patients. Patient survival at 4 years was similar for DSR+ (9 of 10) and DSR- (11 of 12) patients in the withdrawal group. Patients maintained on triple therapy remained rejection free during the 4-year follow-up regardless of initial DSR status, with patient survival rate of 70% (7 of 10). CONCLUSIONS: DSR before steroid withdrawal may identify a subset of transplant patients who could benefit from reduction of immunosuppression without elevated risk of rejection or deteriorating renal function.

Alemtuzumab induction and antibody-mediated kidney rejection after simultaneous pancreas-kidney transplantation.

BACKGROUND: The best induction agent for simultaneous pancreas-kidney transplantation (SPKT) remains the subject of debate. Alemtuzumab is effective in preventing acute cellular rejection (ACR) in SPK recipients and has been used to prevent antibody-mediated rejection (AMR) in sensitized kidney transplant candidates. METHODS: A retrospective cohort study was performed including 136 SPK recipients receiving maintenance immunosuppression with tacrolimus, mycophenolic acid prodrugs, and prednisone. Two groups were compared: those who received induction with alemtuzumab (n=97) and those induced with basiliximab (n=39). RESULTS: Kidney ACR was more frequent in SPKT induced with basiliximab (2-year 12.8% vs. 3.1%, P=0.04), but the incidence of AMR was similar (2-year 18% with basiliximab vs. 13.8% with alemtuzumab, P=NS). Kidney rejection was associated with clinical pancreas rejection in 70% of cases, without differences between the groups. Postrejection kidney graft survival was similar in both groups (2-year basiliximab/alemtuzumab 94.7%/91.2%), but death-censored kidney graft survival was lower with alemtuzumab (100%/91.2%, P=0.056). In the basiliximab group, the predominant cause of kidney loss was death-with-function, whereas in the alemtuzumab group AMR accounted for all losses. Pancreas graft survival was similar in both groups, yet more pancreas losses due to acute rejection occurred in alemtuzumab-treated patients (4 vs. 1). CONCLUSIONS: Kidney AMR is more common than ACR in SPKT recipients treated with alemtuzumab, tacrolimus, mycophenolic acid, and steroids. ACR is better prevented by alemtuzumab than basiliximab, but no relevant difference is found in prevention of AMR. Despite the high incidence of AMR, survival rates are excellent in both groups.