Dean, Patrick G.

Pediatric kidney transplant recipients have a higher rate of coronary artery disease (CAD) as adults. The angiogenesis inhibitor, endostatin, has been implicated in the development of atherosclerosis. Endostatin levels will vary between adult patients who received a kidney transplant as a child. We conducted a study in young adult patients who had undergone pediatric kidney (n = 12) or liver transplantation (n = 8). Coronary arterial calcification was measured using electron beam CT. Values were compared with age-matched control subjects from an epidemiologic database. Serum endostatin levels were measured using enzyme-linked immunosorbent assay. Risk factors for atherosclerosis were assessed. Kidney transplant recipients had a higher rate of CAD compared with liver transplant recipients (33 vs 0%, P = 0.03). Mean (± standard error of mean) serum endostatin levels were higher in kidney transplant recipients compared with liver transplant recipients (26 ± 7 vs 14 ± 3 ng/mL, P = 0.04) and control subjects (26 ± 7 vs 11 ± 1 ng/ mL, P = 0.01). Pediatric kidney transplantation is associated with a higher rate of adult-onset CAD compared with liver transplantation. Endostatin levels were greater in kidney transplant recipients compared with liver transplant recipients and healthy control subjects. Endostatin may play a role in the development of atherosclerosis after kidney transplantation and may serve as a biomarker for atherosclerotic disease.

Abstract INTRODUCTION: Type 1 Diabetes (T1D) patients have an increased risk for major adverse cardiovascular events (MACE). Pancreas Transplantation Alone (PTA) in patients with T1D achieves near normal glucose control for a prolonged period but limited data are available to date regarding MACE during a 10 year follow up period after the procedure. OBJECTIVE: We studied incidence of MACE after PTA in T1D patients over a 10 year follow-up period. METHODS: Retrospectively, we studied 113 T1D recipients of PTA at Mayo Clinic, Rochester with the procedure performed between January 1998 and August 2018 and follow up of at least 1 year. Data were collected before transplantation and up to 10 year follow up after the first PTA. MACE data were gathered until primary non function, re-transplantation, or complete loss of c-peptide (<0.01ng/ml). We report vascular risk factors including hypertension, hyperlipidemia, smoking and BMI along with MACE (defined as cardiac events as unstable angina, Myocardial Infarction (MI), need for re-vascularization, cardiac death, cerebral events as Transient ischemic attack (TIA), stroke, need for re-vascularization and peripheral arterial disease as need for re-vascularization, gangrene and amputation). RESULTS: Eighteen subjects had pre-transplant MACE. A total of 14 subjects had graft failure within 24 to 36 hours due to thrombosis, with 3 in pre-transplant MACE cohort and 11 in no MACE cohort. Thus, we followed 99 subjects for the development of post-transplant MACE for a period of 6.3 ± 3.6 years. T1D subjects with MACE (n=15) had baseline characteristics: Age 48± 7.8 years, gender F/M 9/6,, duration of diabetes 33 ± 12 years, BMI 26± 3.1(Kg/m2), HbA1c 9.3 ± 1.5% and C-peptide 0.09 ng/ml. 84 T1D patients without MACE were age 42 ± 10.6 years, gender F/M 55/29, duration of diabetes 26.5 ± 10.7 years, BMI 26 ± 5.2(Kg/m2), HbA1c 6.7 ± 2.5 and C-peptide 0.09 ng/ml. There are a total of 584 person-years of follow up to first MACE event and 632 person-years of graft failure, death or last follow-up. Nine patients developed 11 MACE events post-PTA. Therefore, the event rate is 1.5 MACE events per 100 person-years for first MACE event and the total event rate is 1.7 MACE events per 100 person-years of follow-up. Age, smoking (yes), gender, duration of diabetes, HTN and Hyperlipidemia presence did not show any significant impact on post-transplant MACE outcome based on univariate Cox regression but the pre-transplant BMI (HR = 1.14; CI = (1.04, 1.26); p = 0.008) and pre-transplant HbA1c (HR = 1.26; CI = (1.06, 1.51); p = 0.01) showed statistically significant impact. CONCLUSIONS: At our center, MACE is low in PTA recipients. There is no impact of presence of pre-transplant MACE on development of post-transplant MACE but pre-transplant BMI and HbA1c account for risk of MACE.

Abstract Background Immunosuppressant therapeutic drug monitoring (TDM) usually requires outpatient travel to hospitals or phlebotomy sites for venous blood collection; however Mitra® Microsampling Device (MSD) sampling could allow self-collection and shipping of samples to a laboratory for analysis. This study examined the feasibility of using volumetric microsampling by MSD for TDM of tacrolimus (TaC) and cyclosporin A (CsA) in transplant patients, along with their feedback on the process. Methods MSD was used to collect TaC and CsA from venous (VB) or capillary (CB) blood. The MSDs were rehydrated, extracted, and analyzed using on-line solid phase extraction coupled to tandem mass spectrometry (SPE-MS/MS). We report an abbreviated method validation of the MSD including: accuracy, precision, linearity, carry-over, and stability using residual venous whole blood (VB) samples. Subsequent clinical validation compared serially collected MSD + CB against VB (200 µL) from transplant patients. Results Accuracy comparing VB vs. MSD+VB showed high clinical concordance (TaC = 89% and CsA = 98%). Inter- and intra-precision was ≤11.5 %CV for TaC and CsA. Samples were stable for up to 7 days at room temperature with an average difference of <10%. Clinical validation with MSD+CB correlated well with VB for CsA (slope = 0.95, r2 = 0.88, n = 47) and TaC (slope = 0.98, r2 = 0.82, n = 49). CB vs. VB gave concordance of 94% for CsA and 79% for TaC. A satisfaction survey showed 82% of patients preferred having the capillary collection option. Conclusion Transplant patients favored having the ability to collect capillary samples at home for TaC/CsA monitoring. Our results demonstrate good concordance between MSD+CB and VB for TaC and CsA TDM, but additional studies are warranted.

AbstractBackgroundCurrent therapy for Type 1 diabetes (T1D) is characterized by significant glucose variability (GV). Pancreas transplantation (PT) is performed in certain T1D patients with and without end‐stage renal disease. To date, GV has been examined to a limited extent after PT.MethodsWe investigated GV using continuous glucose monitoring (CGM) 3‐6 weeks after PT.ResultsEleven patients had simultaneous kidney pancreas transplantation (SPK), nine pancreas after kidney (PAK), and six pancreas transplantation alone (PTA). Mean CGM showed no difference between SPK, 126.5 ± 13.9, PAK 119.9 ± 12.8, and PTA 131.1 ± 29 mg/dL (P value .6). Percentage of time in range (TIR, 70‐180 mg/dL) was 92% for SPK, 93.4% in PAK, and 88.5% in PTA with only 0.3%, 1.5%, and 0.3% of time <70 mg/dL. Percentage >180 mg/dL was 7.9% for SPK, 4.9% PAK, and 11% in PTA. Other measures of GV were similar in the three cohorts. In six patients, CGM was performed before and after PT and improved significantly. GV was also better compared with a matched cohort of T1D patients.ConclusionsAll 3 types of PT resulted in excellent glucose control 3‐6 weeks post‐procedure. CGM outcomes represent an important objective outcome after PT.

Background. We examined the 10-year experience of Mayo Clinic's kidney paired donation (KPD).We aimed to determine the benefits for the recipients of enrolled ABO/HLA compatible pairs and determine the factors associated with prolonged KPD waiting time. Methods. We performed a retrospective study of 332 kidney transplants facilitated by the Mayo 3-site KPD program from September 2007 to June 2018. Results. The median (interquartile range) time from KPD entry to transplantation was 89 days (42-187 days). The factors independently associated with receiving a transplant >3 months after KPD entry included recipient blood type O and calculated panel reactive antibodies ≥98%. Fifty-four ABO/HLA compatible pairs participated in KPD for the following reasons: cytomegalovirus mismatch (18.5% [10/54]), Epstein-Barr virus (EBV) mismatch (EBV) (9.3% [5/54]), age/size mismatch (51.9% [28/54]), or altruistic reasons (20.3% [11/54]). Cytomegalovirus and EBV mismatch were avoided in 90% (9/10) and 100% (5/5) of cases. Recipients who entered KPD for age/size mismatch and altruistic reasons received kidneys from donors with lower Living Kidney Donor Profile Index scores than their actual donor (median [interquartile range] 31.5 [12.3-47]; P < 0.001 and 26 (-1 to 46); P = 0.01 points lower, respectively). Median time to transplant from KPD entry for compatible pair recipients was 70 days (41-163 days), and 44.4% (24/54) of these transplants were preemptive. All chains/swaps incorporating compatible pairs included ABO/HLA incompatible pairs. Conclusions. KPD should be considered for all living donor/recipient pairs because the recipients of these pairs can derive personal benefit from KPD while increasing the donor pool for difficult to match pairs.

Background. Active antibody-mediated rejection (AMR) that occurs during the amnestic response within the first month posttransplant is a rare but devastating cause of early allograft loss after kidney transplant. Prior reports of eculizumab treatment for AMR have been in heterogeneous patient groups needing salvage therapy or presenting at varied time points. We investigated the role of eculizumab as primary therapy for active AMR early posttransplant. Methods. We performed a retrospective observational study of a consecutive cohort of solitary kidney transplant recipients who were transplanted between January 1, 2014, and January 31, 2018, and had AMR within the first 30 days posttransplant and treated with eculizumab ± plasmapheresis. Results. Fifteen patients had early active AMR at a median (interquartile range [IQR]) of 10 (7–11) days posttransplant and were treated with eculizumab ± plasmapheresis. Thirteen cases were biopsy proven, and 2 cases were presumed on the basis of donor-specific antibody trends and allograft function. Within 1 week of treatment, the median estimated glomerular filtration rate increased from 21 to 34 mL/min (P = 0.001); and persistent active AMR was only found in 16.7% (2/12) of biopsied patients within 4–6 months. No graft losses occurred, and at last follow-up (median [IQR] of 13 [12–19] mo), the median IQR estimated glomerular filtration rate increased to 52 (46–60) mL/min. Conclusions. Prompt eculizumab treatment as primary therapy is safe and effective for early active AMR after kidney transplant or abrupt increases in donor-specific antibodies when biopsy cannot be performed for diagnosis confirmation.

Objective: With advancements in surgical equipment and procedures, human–system interactions in operating rooms affect surgeon workload and performance. Workload was measured across surgical specialties using surveys to identify potential predictors of high workload for future performance improvement. Summary Background Data: Surgical instrumentation and technique advancements have implications for surgeon workload and human–systems interactions. To understand and improve the interaction of components in the work system, NASA-Task Load Index can measure workload across various fields. Baseline workload measurements provide a broad overview of the field and identify areas most in need of improvement. Methods: Surgeons were administered a modified NASA-Task Load Index survey (0 = low, 20 = high) following each procedure. Patient and procedural factors were retrieved retrospectively. Results: Thirty-four surgeons (41% female) completed 662 surgery surveys (M = 14.85, SD = 7.94), of which 506 (76%) have associated patient and procedural data. Mental demand (M = 7.7, SD = 5.56), physical demand (M = 7.0, SD = 5.66), and effort (M = 7.8, SD = 5.77) were the highest rated workload subscales. Surgeons reported difficulty levels higher than expected for 22% of procedures, during which workload was significantly higher ( P < 0.05) and procedural durations were significantly longer ( P > 0.001). Surgeons reported poorer perceived performance during cases with unexpectedly high difficulty ( P < 0.001). Conclusions: When procedural difficulty is greater than expected, there are negative implications for mental and physical demand that result in poorer perceived performance. Investigations are underway to identify patient and surgical variables associated with unexpected difficulty and high workload. Future efforts will focus on re-engineering the surgical planning process and procedural environment to optimize workload and performance for improved surgical care.

Background Despite substantial evidence demonstrating clear benefit, rates of preemptive kidney transplantation (PreKTx) remain low in the United States. Our goal was to identify barriers to PreKTx. Methods Using a telephone-administered questionnaire including questions about barriers, timing of referral, timing of education, we retrospectively studied first living donor kidney transplant recipients (2006-2010) at Mayo Clinic, Rochester, MN. Of 235 patients, 145 (62%) responded to the questionnaire (74 PreKTx and 71 non-PreKTx). We compared categorical data with Fisher exact test and median times with Wilcoxon rank sum test. Results Polycystic kidney disease (PCKD), longer median time between diagnosis and transplant, and time between education about transplant and transplant correlated with PreKTx (P < 0.01). The presence of at least 1 patient-identified barrier (lack of referral, financial barriers, medical barriers, no identified living donor and donor evaluation delays) was associated with non-PreKTx (0.034) though no single barrier predominated. Age, education level, insurance status and source of referral (primary care, nephrology, and nonphysician referral) were not associated with the rate of PreKTx. Univariate logistic regression identified white race, PCKD, and increased time from diagnosis as factors favoring PreKTx; PCKD and increased time remained significant factors after multivariate analysis. Conclusions Even among a patient population that is primarily white, educated, and has a spouse or first-degree relative donor, PreKTx rates remain concerningly low. Increased time between diagnosis or education and transplant are predictors of PreKTx. Greater emphasis on transplant education earlier in the stages of chronic kidney disease and community outreach from transplant centers may help to increase the rate of PreKTx.

Abstract Aims Short-term studies have reported left ventricular (LV) dilatation following surgical creation of arteriovenous fistulas (AVF) or arteriovenous grafts (AVGs), but chronic cardiac structural and functional changes have not been examined or related to clinical outcomes following AVF/AVG. We sought to characterize the long-term changes in cardiac structure and function in patients undergoing shunt creation for haemodialysis. Methods and results A retrospective analysis was performed of patients undergoing echocardiography before and after surgical AVF/AVG creation for the initiation of haemodialysis. 137 patients underwent echocardiographic examinations prior to AVF and 2.6 years (median) after AVF creation. Following AVF and dialysis initiation, there were reductions in blood pressure, body weight and estimated plasma volume coupled with modest reverse LV remodelling. In contrast, AVF/AVG creation was associated with significant right ventricular (RV) dilatation and deterioration in RV function. Incident heart failure (HF) developed in 43% of patients in tandem with greater RV remodeling. The development of RV dilation following surgical AVF/AVG was independently associated with increased risk of death [HR 3.9, 95% CI (1.7–9.2), P = 0.001]. Conclusion In long-term follow-up, RV remodelling and dysfunction develop following AVF/AVG creation and dialysis initiation, despite improved control of LV pressure load through dialysis. Deleterious effects on right heart structure and function are coupled with development of incident HF and increased risk of death. Further study is required to identify patients at greatest risk for detrimental AVF/AVG changes who may benefit from alternate forms of dialysis or potentially ligation of existing AVF.