Promoting transportation safety in adolescence: the drivingly randomized controlled trial.

BACKGROUND: The impact of young drivers' motor vehicle crashes (MVC) is substantial, with young drivers constituting only 14% of the US population, but contributing to 30% of all fatal and nonfatal injuries due to MVCs and 35% ($25 billion) of the all medical and lost productivity costs. The current best-practice policy approach, Graduated Driver Licensing (GDL) programs, are effective primarily by delaying licensure and restricting crash opportunity. There is a critical need for interventions that target families to complement GDL. Consequently, we will determine if a comprehensive parent-teen intervention, the Drivingly Program, reduces teens' risk for a police-reported MVC in the first 12 months of licensure. Drivingly is based on strong preliminary data and targets multiple risk and protective factors by delivering intervention content to teens, and their parents, at the learner and early independent licensing phases. METHODS: Eligible participants are aged 16-17.33 years of age, have a learner's permit in Pennsylvania, have practiced no more than 10 h, and have at least one parent/caregiver supervising. Participants are recruited from the general community and through the Children's Hospital of Philadelphia's Recruitment Enhancement Core. Teen-parent dyads are randomized 1:1 to Drivingly or usual practice control group. Drivingly participants receive access to an online curriculum which has 16 lessons for parents and 13 for teens and an online logbook; website usage is tracked. Parents receive two, brief, psychoeducational sessions with a trained health coach and teens receive an on-road driving intervention and feedback session after 4.5 months in the study and access to DriverZed, the AAA Foundation's online hazard training program. Teens complete surveys at baseline, 3 months post-baseline, at licensure, 3months post-licensure, 6 months post-licensure, and 12 months post-licensure. Parents complete surveys at baseline, 3 months post-baseline, and at teen licensure. The primary end-point is police-reported MVCs within the first 12 months of licensure; crash data are provided by the Pennsylvania Department of Transportation. DISCUSSION: Most evaluations of teen driver safety programs have significant methodological limitations including lack of random assignment, insufficient statistical power, and reliance on self-reported MVCs instead of police reports. Results will identify pragmatic and sustainable solutions for MVC prevention in adolescence. TRIAL REGISTRATION: ClinicalTrials.gov # NCT03639753.

The impact of delayed school start time on adolescent beverage consumption, findings from the START study.

OBJECTIVES: We sought to examine the effects of high school start time delay, a proven sleep-promoting intervention, on sugary beverage (SB) consumption among U.S. adolescents. METHODS: In the Spring of 2016 (baseline), the START study recruited 2134 ninth grade students who were enrolled high schools in the Twin Cities, MN metropolitan area. These participants were surveyed again in their 10th and 11th grade years, in Spring 2017 and 2018 (follow-ups 1 and 2). All five high schools started early (7:30 or 7:45 a.m.) at baseline. By follow-up 1, two "policy change" schools shifted their start times later (8:20 or 8:50 a.m.) and maintained these later start times through follow-up 2 while three "comparison schools" retained an early start time at all time points. Generalized estimating equations using a negative binomial distribution were used to obtain estimates of the number of sugary beverages consumed per day at each wave as well as the difference in difference (DiD) estimates between baseline and each follow-up period comparing policy change to comparison schools. RESULTS: Mean baseline sugary beverage consumption was 0.9 (1.5) beverages per day in policy change schools and 1.2 (1.7) beverages per day in the comparison schools. While there was no evidence of impact of start time change on total SB consumption, DiD estimates revealed a small decrease in the number of caffeinated sugary beverages consumed between baseline and the second follow-up period in students attending the policy change schools relative to comparison schools in both crude (0.11/day reduction, p-value = 0.048) and adjusted analyses (0.11/day reduction, p-value = 0.028). CONCLUSION: Although the differences in this study were quite modest, a population-wide reduction in sugary beverage consumption could have public health benefit.

Primary Hyperoxaluria Type 3 Can Also Result in Kidney Failure: A Case Report.

Primary hyperoxaluria (PH) is a group of genetic disorders that result in an increased hepatic production of oxalate. PH type 3 (PH3) is the most recently identified subtype and results from mutations in the mitochondrial 4-hydroxy-2-oxoglutarate aldolase gene (HOGA1). To date, there have been 2 cases of kidney failure reported in PH3 patients. We present a case of a young man with a history of recurrent urinary tract infections and voiding dysfunction who developed kidney failure at 33 years of age. He developed a bladder stone and bilateral staghorn calculi at 12 years of age. Initial metabolic evaluation revealed hyperoxaluria with very low urinary citrate excretion on multiple measurements for which he was placed on oral citrate supplements. Further investigation of the hyperoxaluria was not completed as the patient was lost to follow-up observation until he presented at 29 years of age with chronic kidney disease stage 4 (estimated glomerular filtration rate 24mL/min/1.73m2). Hemodialysis 3 times a week was started at 33 years of age, and subsequent genetic testing revealed a homozygous HOGA1 mutation (C.973G>A p.Gly325Ser) diagnostic of PH3. The patient is currently being evaluated for all treatment options including possible liver/kidney transplantation. All cases of a childhood history of recurrent urinary stone disease with marked hyperoxaluria should prompt genetic testing for the 3 known PH types. Hyperhydration and crystallization inhibitors (citrate) are standard of care, but the role of RNA interference agents for all 3 forms of PH is also under active study.

Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex.

Cadmium (Cd) is a nephrotoxic environmental pollutant that causes a generalized dysfunction of the proximal tubule characterized by polyuria and proteinuria. Even though the effects of Cd on the kidney have been well-characterized, the molecular mechanisms underlying these effects have not been fully elucidated. MicroRNAs (miRNAs) are small non-coding RNAs that regulate cellular and physiologic function by modulating gene expression at the post-transcriptional level. The goal of the present study was to determine if Cd affects renal cortex miRNA expression in a well-established animal model of Cd-induced kidney injury. Male Sprague-Dawley rats were treated with subcutaneous injections of either isotonic saline or CdCl2 (0.6 mg/kg) 5 days a week for 12 weeks. The 12-week Cd-treatment protocol resulted in kidney injury as determined by the development of polyuria and proteinuria, and a significant increase in the urinary biomarkers Kim-1, ß2 microglobulin and cystatin C. Total RNA was isolated from the renal cortex of the saline control and Cd treated animals, and differentially expressed miRNAs were identified using µParafloTM microRNA microarray analysis. The microarray results demonstrated that the expression of 44 miRNAs were significantly increased and 54 miRNAs were significantly decreased in the Cd treatment group versus the saline control (t-test, p ≤ 0.05, N = 6 per group). miR-21-5p, miR-34a-5p, miR-146b-5p, miR-149-3p, miR-224-5p, miR-451-5p, miR-1949, miR-3084a-3p, and miR-3084c-3p demonstrated more abundant expression and a significant two-fold or greater increased expression in the Cd-treatment group versus the saline control group. miR-193b-3p, miR-455-3p, and miR-342-3p demonstrated more abundant expression and a significant two-fold or greater decreased expression in the Cd-treatment group versus the saline control group. Real-time PCR validation demonstrated (1) a significant (t-test, p ≤ 0.05, N = 6 per group) increase in expression in the Cd-treated group for miR-21-5p (2.7-fold), miR-34a-5p (10.8-fold), miR-146b-5p (2-fold), miR-224-5p (10.2-fold), miR-3084a-3p (2.4-fold), and miR-3084c-3p (3.3-fold) and (2) a significant (t-test, p ≤ 0.05, N = 6 per group) 52% decrease in miR-455-3p expression in the Cd-treatment group. These findings demonstrate that Cd significantly alters the miRNA expression profile in the renal cortex and raises the possibility that dysregulated miRNA expression may play a role in the pathophysiology of Cd-induced kidney injury. In addition, these findings raise the possibility that Cd-dysregulated miRNAs might be used as urinary biomarkers of Cd exposure or Cd-induced kidney injury.

Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria.

The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli Δ tolC mutant strain.

Development of a cyclosporin A derivative with excellent anti-hepatitis C virus potency.

Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.

Massive hemorrhage and transfusion in the operating room.

PURPOSE: In this Continuing Professional Development module, we review the pathophysiology and clinical manifestations associated with massive hemorrhage as well as laboratory investigations and appropriate therapeutic measures. In addition to reviewing the available blood/plasma products and adjunct therapy, we also explore the role of the anesthesiologist in a massive transfusion protocol scenario. PRINCIPAL FINDINGS: Massive hemorrhage can be either anticipated or unexpected. The coinciding presence of acidosis, hypothermia, and hypotension contribute greatly to a poor outcome. Red blood cells not only increase oxygen carrying capacity, but they also play a role in providing hemostasis. While timely laboratory results, including point-of-care testing, are important, transfusion remains a clinical decision. Adjunct therapies other than blood components have contributed to improved outcomes. The pathophysiology of massive obstetric hemorrhage is unique when compared with the non-obstetric population. The approach to massive hemorrhage and its treatment vary considerably from institution to institution. CONCLUSIONS: Massive hemorrhage is a multidisciplinary challenge that requires immediate response and communication between clinicians, nurses, other healthcare providers, laboratory testing, and blood banks. Basic knowledge and utilization of available products and therapies are inconsistent. A massive transfusion protocol can be used effectively to reduce chaos and ensure that correct treatments and proper dosing occur in a timely manner.

Ureteral stent duration and the risk of BK polyomavirus viremia or bacteriuria after kidney transplantation.

OBJECTIVES: Ureteral stents are used in kidney transplantation (KTX) to decrease post-operative complications, but they are associated with BK polyomavirus viremia (BKV). Our primary outcome was to determine the association between ureteral stent duration and BKV. Secondary outcome measures were the association between bacteriuria and stent duration or use of ureteral stent strings. METHODS: Between January 2010 and January 2015, 403 patients underwent KTX at the Virginia Mason Medical Center and met inclusion criteria. Stent duration was classified as short (<3 weeks) or long (>3 weeks). Multivariate logistic regression models were created to assess for factors associated with BKV. The covariates in the BKV model were chosen a priori based on stent duration and risk factors previously described in the literature. RESULTS: Ureteral stents were placed in 304 (75.4%) transplants. Stent strings were left attached in 166 (54.6%) patients. On multivariate analyses, long stent duration was significantly associated with increased risk of BKV compared with no stent (odds ratio [OR] 1.92, P=.044, 95% confidence interval [CI] 1.04-3.74). Short stent duration was not associated with BKV. Sixty-two (15.4%) patients had bacteriuria. Bacteriuria was associated with female gender (OR 2.77, P<.001, 95% CI 1.58-4.95), and there was a dose-dependent effect with stent duration compared with no stent-short duration (OR 2.46, P=.049, 95% CI 1.05-6.49) and long duration (OR 3.58, P=.004, 95% CI 1.58-9.25). Stent strings were not associated with either complication. CONCLUSIONS: The association between ureteral stents and BKV may be dose dependent.

Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition.

Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.

Comparison of address-based sampling and random-digit dialing methods for recruiting young men as controls in a case-control study of testicular cancer susceptibility.

Random-digit dialing (RDD) using landline telephone numbers is the historical gold standard for control recruitment in population-based epidemiologic research. However, increasing cell-phone usage and diminishing response rates suggest that the effectiveness of RDD in recruiting a random sample of the general population, particularly for younger target populations, is decreasing. In this study, we compared landline RDD with alternative methods of control recruitment, including RDD using cell-phone numbers and address-based sampling (ABS), to recruit primarily white men aged 18-55 years into a study of testicular cancer susceptibility conducted in the Philadelphia, Pennsylvania, metropolitan area between 2009 and 2012. With few exceptions, eligible and enrolled controls recruited by means of RDD and ABS were similar with regard to characteristics for which data were collected on the screening survey. While we find ABS to be a comparably effective method of recruiting young males compared with landline RDD, we acknowledge the potential impact that selection bias may have had on our results because of poor overall response rates, which ranged from 11.4% for landline RDD to 1.7% for ABS.

Development of Zn-ProPhenol-catalyzed asymmetric alkyne addition: synthesis of chiral propargylic alcohols.

The development of a general and practical zinc-catalyzed enantioselective alkyne addition methodology is reported. The commercially available ProPhenol ligand (1) has facilitated the addition of a wide range of zinc alkynylides to aryl, aliphatic, and α,ß-unsaturated aldehydes in high yield and enantioselectivity. New insights into the mechanism of this reaction have resulted in a significant reduction in reagent stoichiometry, enabling the use of precious alkynes and avoiding the use of excess dimethylzinc. The enantioenriched propargylic alcohols from this reaction serve as versatile synthetic intermediates and have enabled efficient syntheses of several complex natural products.

Thionium ion initiated medium-sized ring formation: the total synthesis of asteriscunolide D.

The first synthesis of the biologically active humulene natural product asteriscunolide D has been accomplished in nine steps without the use of protecting groups. The challenging 11-membered ring was forged via a diastereoselective thionium ion initiated cyclization, which constitutes a formal aldol disconnection to form a strained macrocycle. A stereospecific thioether activation-elimination protocol was developed for selective E-olefin formation, thus providing access to the most biologically active asteriscunolide. The absolute stereochemical configuration was established by the Zn-ProPhenol catalyzed enantioselective addition of methyl propiolate to an aliphatic aldehyde to afford a γ-hydroxy propiolate as a handle for butenolide formation via Ru-catalyzed alkene-alkyne coupling.

Torsion of an undescended testis located in the inguinal canal.

BACKGROUND: Torsion of undescended testis located within the inguinal canal is a rare finding in the emergency department (ED). This diagnosis can present as undifferentiated abdominal or groin pain, and a full genitourinary examination is essential to making this diagnosis. OBJECTIVES: We present this case to increase awareness among emergency physicians regarding torsion of undescended testis. CASE REPORT: A 5-year-old boy presented to the ED with abdominal pain and a mass in his right groin. Physical examination and Doppler ultrasound were used to diagnose torsion of undescended testis. CONCLUSIONS: In a patient with undescended testis, torsion must be considered as a cause of abdominal or groin pain. Full genitourinary examination is essential to making this diagnosis.

Cryoprotectant agent toxicity in porcine articular chondrocytes.

Large articular cartilage defects have proven difficult to treat and often result in osteoarthritis of the affected joint. Cryopreservation of articular cartilage can provide an increased supply of tissues for osteochondral allograft but cryoprotective agents are required; however, few studies have been performed on the toxicity of these agents. This study was designed to determine the order of toxicity of five commonly used cryoprotectant agents as well as interactions that occur between them. Isolated porcine articular chondrocytes were exposed to individual cryoprotectant agents and combinations of these agents at 1M and 3M concentrations for 5 min and 120 min. Cell viability was determined using membrane integrity dyes and a metabolic activity assay. Subsequently, a regression analysis based study was undertaken to extract the maximum amount of information from this data. Results of this study demonstrated that all 1M solutions were minimally toxic. The 3M solutions demonstrated varying toxicity after 120 min. Ethylene glycol and glycerol were less toxic than propylene glycol, dimethyl sulfoxide, and formamide. Combinations of cryoprotectant agents were less toxic than single cryoprotectant agents at the same concentration. This is the most comprehensive study investigating cryoprotectant agent toxicity in articular chondrocytes and has resulted in important information regarding the order of toxicity and interactions that occur between these agents.

Statistical prediction of the vitrifiability and glass stability of multi-component cryoprotective agent solutions.

Long-term biologic storage of articular cartilage has proven elusive due to cellular degradation over time or acute damage during attempts at cryopreservation. Vitrification is one option that may result in successful cryopreservation but difficulty with cryoprotective agent (CPA) toxicity at high concentrations of a single cryoprotectant has hindered development of successful protocols. This study was designed to determine the vitrifiability and glass stability of solutions containing combinations of commonly used CPAs and to document CPA interactions that occur. One hundred and sixty-four multi-CPA combination solutions of 6-9 M were evaluated for vitrifiability and glass stability using direct visualization after immersion in liquid nitrogen for 30 min and upon warming. Binary and ordinal logistic regression analysis was used to statistically analyze each CPA for its ability to vitrify and its effect on glass stability in multi-component CPA solutions. Propylene glycol had the greatest incremental contribution to vitrification while formamide had the least contribution. A threshold was established whereby the ability of a solution to vitrify could be determined by calculation. Glass stability was not as clearly defined due to variability in the results; however, contributions of interactions between CPAs to the glass stability of solutions were determined. This study provided values that predict if a solution will vitrify. Furthermore, the glass stability of solutions containing multiple CPAs do not behave as linear additions of binary solutions and interactions between CPAs have a significant effect on the glass stability of these solutions. These variables should be considered when designing vitrification solutions.

Reduced dose rabbit anti-thymocyte globulin induction for prevention of acute rejection in high-risk kidney transplant recipients.

BACKGROUND: Despite the prevalent use of rabbit antithymocyte globulin (rATG) as an induction agent in kidney transplantation, the appropriate dose for preventing acute rejection in high-risk patients is not known. Few studies have examined total exposure of rATG less than 6 mg/kg, with fewer studies examining lower dose rATG in patients with increased risk factors for acute rejection. METHODS: We retrospectively analyzed outcomes of 83 kidney transplant recipients at increased risk for acute rejection (repeat transplant, African American race, and panel reactive antibody > or =20%) from July 2004 to July 2007 who were treated with rATG 1.5 mg/kg per day for 3 (n=39) or 4 (n=44) doses for induction to determine the impact of reduced-exposure rATG in the prevention of acute rejection. rATG was initiated intraoperatively and continued on consecutive days. All patients received triple maintenance immunosuppression including prednisone and calcineurin inhibitor. Patients requiring dialysis within 48 hr after transplant were excluded from analysis. RESULTS: One-year acute rejection rates were 10% and 11% in the 3- and 4-dose cohorts, respectively, with 100% patient and graft survival at 1 year in both groups. Patients in the 3-dose cohort were discharged from the hospital sooner than the 4-dose cohort (median length of hospital stay, 3 vs. 4 days; P=0.004). CONCLUSIONS: Our results suggest that a 3- or 4-dose course of rATG (1.5 mg/kg/dose) provides excellent protection against acute rejection even in patients at increased risk, with the potential for cost savings from a reduction in hospital stay and medication administration.

Standard criteria donor pancreas donation status is associated with improved kidney transplant outcomes.

BACKGROUND: Organ donor characteristics can be used to predict outcomes in kidney transplantation. We hypothesized that pancreas donation status could reflect organ quality and be predictive of kidney graft outcomes following Standard Criteria Donor (SCD) kidney transplantation. METHODS: We performed a retrospective analysis of deceased donor kidney alone (DD KA) transplants reported to SRTR from 1992 to 2005. Group 1 = kidney alone recipients from pancreas donors (KA, P+) and Group 2 = kidney alone recipients from non-pancreas donors (KA, P-). We compared patient and graft survival between groups at 10-yr post-transplant. RESULTS: Group 1 (KA, P+) comprised 19 633 (20%) recipients and Group 2 (KA, P-) comprised 78 737 (80%) recipients. Ten-yr graft survival for Group 1 vs. Group 2 was 42.6% and 36.9% (p < 0.0001), respectively. Pancreas donation status (non-pancreas donor) was associated with a hazard ratio for graft loss of 1.23 on univariate analysis (p < 0.0001), and KA, P-remained an independent risk factor for graft failure at 10 yr, HR 1.09 (p < 0.0001). CONCLUSION: Donor pancreas donation status is an independent predictor of improved outcomes of SCD kidney recipients. Further study of the pancreas organ donor pre-procurement is warranted to optimize not only pancreas utilization but also kidney graft outcomes.

Comparable effectiveness of caudal vs. trans-foraminal epidural steroid injections.

STUDY DESIGN: Retrospective case-control study. OBJECTIVE: To compare the effectiveness between caudal and trans-foraminal epidural steroid injections for the treatment of primary lumbar radiculopathy. SUMMARY OF BACKGROUND DATA: Spinal injections with steroids play an important role in non-operative care of lumbar radiculopathy. The trans-foraminal epidural steroid injection (TESI) theoretically has a higher success rate based on targeted delivery to the symptomatic nerve root. To our knowledge, these results have not been compared with other techniques of epidural steroid injection. METHODS: 93 patients diagnosed with primary lumbar radiculopathy of L4, L5, or SI were recruited for this study: 39 received caudal epidural steroid injections (ESI) and 54 received trans-foraminal epidural steroid injections (TESI). Outcomes scores included the SF-36, Oswestry disability index (ODI) and pain visual analogue scale (VAS), and were recorded at baseline, post-treatment (<6 months), long-term (>1 year). The average follow-up was 2 years, and 16 patients were lost to follow-up. The endpoint "surgical intervention" was a patient-driven decision, and considered failure of treatment. Intent-to-treat analysis, and comparisons included t-test, Chi-square, and Wilcoxon rank-sum test. RESULTS: Baseline demographics and outcomes scores were comparable for both treatment groups (ESI vs. TESI): (SF-36 PCS (32.3 +/- 7.5 vs. 29.5 +/- 8.9 respectively; p = 0.173), MCS (41.2 +/- 12.7 vs. 41.1 +/- 10.9, respectively; p = 0.971), and VAS (7.4 +/-2.1 vs. 7.9 +/- 1.2, respectively; p = 0.228)). Surgery was indicated for failure of treatment at a similar rate for both groups (41.0% vs. 44.4%, p=0.743). Symptom improvement was comparable between both treatment groups (ESI vs. TESI): SF-36 PCS improved to 42.0+/-11.8 and 37.7+/-12.3, respectively; p=0.49; ODI improved from 50.0+/-21.2 to 15.6+/-17.9and from 62.1+/-17.9 to 26.1+/-20.3, respectively (p=0.407). CONCLUSIONS: The effectiveness of TESI is comparable to that of ESI (approximately 60%) for the treatment of primary lumbar radiculopathy. The increased complexity of TESI is not justified for primary cases, and may have a more specific role in recurrent disease or for diagnostic purposes.

Simultaneous pancreas-kidney versus deceased donor kidney transplant: can a fair comparison be made?

BACKGROUND: Simultaneous pancreas-kidney transplantation (SPK) may provide superior patient and kidney graft survival compared with deceased donor kidney transplant alone (DD KA), not because of the addition of a pancreas transplant but because of differences in organ donor, recipient, and transplant characteristics. METHODS: We performed a retrospective analysis from the scientific registry of transplant recipients database comparing patient and kidney graft survival of SPK and DD KA recipients from 1997 to 2005, segregating the DD KA recipients into (a) recipients of KA from pancreas donors (KA, P+) and (b) recipients of KA from non-pancreas donors to control for donor differences. RESULTS: Of 8453 SPK waitlisted patients, 7952 received SPK, 101 received KA, P+, and 401 received KA from non-pancreas donors (KA, P-). Five-year kidney graft survival was not different in the SPK and KA, P+ groups (76.2% vs. 81.9%, P=0.15) and was significantly better than the KA, P- group (64.3%, SPK vs. KA, P-, P=0.002; KA, P+ vs. KA, P-, P=0.01). When controlling for recipient and transplant differences by multivariate analysis, KA, P+ transplant was associated with a 50% reduction in risk for kidney graft loss compared with SPK. CONCLUSIONS: Donor, recipient, and transplant differences exist when comparing SPK to DD KA that bias outcomes in favor of SPK and limit conclusions regarding superior graft and patient survival.

Twelve-month pancreas graft function significantly influences survival following simultaneous pancreas-kidney transplantation.

BACKGROUND AND OBJECTIVES: Simultaneous pancreas-kidney transplantation (SPK) is regarded as the treatment of choice for type 1 diabetes (T1DM) and kidney dysfunction, despite the morbidity associated with pancreas transplantation. These morbidities often influence selection of SPK versus living-donor kidney alone (LD KA) transplant. This study quantifies the impact of pancreas graft function on outcomes following SPK. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using the SRTR database, SPK wait-listed patients transplanted from 1997 to 2005 were evaluated and segregated as: (1) SPK recipients with functioning pancreas graft 12 mo posttransplant (SPK, P+); (2) SPK recipients with loss of pancreas graft function within 12 mo posttransplant (SPK, P-); (3) recipients of deceased donor (DD) KA; (4) recipients of LD KA. The study compared patient and kidney graft survival to 84 mo posttransplant. RESULTS: Patient survival for SPK, P+ was significantly better than the LD KA; SPK, P-; and DD KA cohorts (88.6% versus 80.0%, 73.9% and 64.8%, respectively [P < 0.001]), a finding confirmed by multivariate analysis and not influenced by pancreas-after-kidney transplantation (PAK) rates and outcomes. Unadjusted graft survival was also highest in the SPK, P+ cohort (72.0% versus 63.6%, 59.8%, 49.7%, P = 0.015 versus LD KA). CONCLUSIONS: SPK recipients with functioning pancreas grafts have superior survival compared with LD KA and DD KA, including in the setting of PAK. Early pancreas graft failure results in kidney and patient survival rates similar to KA. These data help further clarify the decision-making of SPK versus KA transplant options for patients and providers.