Robert Harland

Interests

Teaching

Multi-disciplinary management of end organ disease,Immunosuppressive therapy,Vascular anastomoses and surgical transplantationDevelopment of autonomy and advanced skills in surgical trainees

Research

Organ and islet cell preservation methods,Utilization of sub-optimal donor organs,Transplantation of highly sensitized patientsApplication of novel methods of beta cell replacement in diabetic patients.

Courses

Scholarly Contributions

Chapters

• Harland, R. (2003). Pancreas Transplantation. In Essential Practice of Surgery(pp 617-622). New York: Springer-Verlag.

Journals/Publications

• Anteby, R., Fair, J. H., Forbes, R. C., Harland, R. C., Niederhaus, S., Olaitan, O. K., Ricordi, C., & Witkowski, P. (2021).

  Pancreatic Islets Quality and Potency Cannot be Verified as Required for Drugs: Reflection on the FDA Review of a Biological License Application for Human Islets.

  . Transplantation.
• Witkowski, P., Anteby, R., Olaitan, O. K., Forbes, R. C., Niederhaus, S., Ricordi, C., Fair, J. H., & Harland, R. C. (2021). Pancreatic Islets Quality and Potency Cannot be Verified as Required for Drugs: Reflection on the FDA Review of a Biological License Application for Human Islets. Transplantation.
• Witkowski, P., Odorico, J., Pyda, J., Anteby, R., Stratta, R. J., Schrope, B. A., Hardy, M. A., Buse, J., Leventhal, J. R., Cui, W., Hussein, S., Niederhaus, S., Gaglia, J., Desai, C. S., Wijkstrom, M., Kandeel, F., Bachul, P. J., Becker, Y. T., Wang, L. J., , Robertson, R. P., et al. (2021). Arguments against the Requirement of a Biological License Application for Human Pancreatic Islets: The Position Statement of the Islets for US Collaborative Presented during the FDA Advisory Committee Meeting. Journal of clinical medicine, 10(13).
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  The Food and Drug Administration (FDA) has been regulating human islets for allotransplantation as a biologic drug in the US. Consequently, the requirement of a biological license application (BLA) approval before clinical use of islet transplantation as a standard of care procedure has stalled the development of the field for the last 20 years. Herein, we provide our commentary to the multiple FDA's position papers and guidance for industry arguing that BLA requirement has been inappropriately applied to allogeneic islets, which was delivered to the FDA Cellular, Tissue and Gene Therapies Advisory Committee on 15 April 2021. We provided evidence that BLA requirement and drug related regulations are inadequate in reassuring islet product quality and potency as well as patient safety and clinical outcomes. As leaders in the field of transplantation and endocrinology under the "Islets for US Collaborative" designation, we examined the current regulatory status of islet transplantation in the US and identified several anticipated negative consequences of the BLA approval. In our commentary we also offer an alternative pathway for islet transplantation under the regulatory framework for organ transplantation, which would address deficiencies of in current system.
• Harland, R. C., Klintmalm, G., Jensik, S., Yang, H., Bromberg, J., Holman, J., Kumar, M. S., Santos, V., Larson, T. J., & Wang, X. (2020). Efficacy and safety of bleselumab in kidney transplant recipients: A phase 2, randomized, open-label, noninferiority study. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 159-171. doi:10.1111/ajt.15591
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  This study assessed the efficacy and safety of the anti-CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients over 36 months posttransplant. Transplant recipients were randomized (1:1:1) to standard of care (SoC: 0.1 mg/kg per day immediate-release tacrolimus [IR-TAC]; target minimum blood concentration [C ] 4-11 ng/mL plus 1 g mycophenolate mofetil [MMF] twice daily) or bleselumab (200 mg on days 0/7/14/28/42/56/70/90, and monthly thereafter) plus either MMF or IR-TAC (0.1 mg/kg per day; target C 4-11 ng/mL days 0-30, then 2-5 ng/mL). All received basiliximab induction (20 mg pretransplant and on days 3-5 posttransplant) and corticosteroids. One hundred thirty-eight transplant recipients received ≥1 dose of study drug (SoC [n = 48]; bleselumab + MMF [n = 46]; bleselumab + IR-TAC [n = 44]). For the primary endpoint (incidence of biopsy-proven acute rejection [BPAR] at 6 months), bleselumab + IR-TAC was noninferior to SoC (difference 2.8%; 95% confidence interval [CI] -8.1% to 13.8%), and bleselumab + MMF did not demonstrate noninferiority to SoC (difference 30.7%; 95% CI 15.2%-46.2%). BPAR incidence slightly increased through month 36 in all groups, with bleselumab + IR-TAC continuing to demonstrate noninferiority to SoC. Bleselumab had a favorable benefit-risk ratio. Most treatment-emergent adverse events were as expected for kidney transplant recipients (ClinicalTrials.gov NCT01780844).
• Witkowski, P., Philipson, L., Kaufman, D. B., Ratner, L., Abouljoud, M. S., Bellin, M., Buse, J., Kandeel, F., Stock, P., Mulligan, D., Markmann, J. F., Kozlowski, T., Andreoni, K., Alejandro, R., Baidal, D., Hardy, M. A., Wickrema, A., Mirmira, R. G., Fung, J., , Becker, Y., et al. (2020). The Demise of Islet Allotransplantation in the US: A Call for an Urgent Regulatory Update The "ISLETS FOR US" Collaborative. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.
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  Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). Across the world, human islets are appropriately defined as "minimally manipulated tissue" which has led to islet transplantation becoming a standard-of-care procedure for patients with type 1 diabetes mellitus and problematic hypoglycemia. As a result of the outdated US regulations, only eleven patients underwent allo-ITx in the US between 2011-2016 and all in the setting of a clinical trial. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both, better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.
• Harland, R. C., Klintmalm, G., Jensik, S., Yang, H., Bromberg, J., Holman, J., Kumar, M. S., Santos, V., Larson, T. J., & Wang, X. (2019). Efficacy and safety of bleselumab in kidney transplant recipients: A phase 2, randomized, open-label, noninferiority study. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 159-171. doi:10.1111/ajt.15591
  More info

  This study assessed the efficacy and safety of the anti-CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients over 36 months posttransplant. Transplant recipients were randomized (1:1:1) to standard of care (SoC: 0.1 mg/kg per day immediate-release tacrolimus [IR-TAC]; target minimum blood concentration [C ] 4-11 ng/mL plus 1 g mycophenolate mofetil [MMF] twice daily) or bleselumab (200 mg on days 0/7/14/28/42/56/70/90, and monthly thereafter) plus either MMF or IR-TAC (0.1 mg/kg per day; target C 4-11 ng/mL days 0-30, then 2-5 ng/mL). All received basiliximab induction (20 mg pretransplant and on days 3-5 posttransplant) and corticosteroids. One hundred thirty-eight transplant recipients received ≥1 dose of study drug (SoC [n = 48]; bleselumab + MMF [n = 46]; bleselumab + IR-TAC [n = 44]). For the primary endpoint (incidence of biopsy-proven acute rejection [BPAR] at 6 months), bleselumab + IR-TAC was noninferior to SoC (difference 2.8%; 95% confidence interval [CI] -8.1% to 13.8%), and bleselumab + MMF did not demonstrate noninferiority to SoC (difference 30.7%; 95% CI 15.2%-46.2%). BPAR incidence slightly increased through month 36 in all groups, with bleselumab + IR-TAC continuing to demonstrate noninferiority to SoC. Bleselumab had a favorable benefit-risk ratio. Most treatment-emergent adverse events were as expected for kidney transplant recipients (ClinicalTrials.gov NCT01780844).
• Kelly, A. C., Smith, K. E., Purvis, W. G., Min, C. G., Weber, C. S., Cooksey, A. M., Hasilo, C., Paraskevas, S., Suszynski, T. M., Weegman, B. P., Anderson, M. J., Camacho, L. E., Harland, R. C., Loudovaris, T., Jandova, J., Molano, D. S., Price, N. D., Georgiev, I. G., Scott, W. E., , Manas, D., et al. (2019). Oxygen Perfusion (Persufflation) of Human Pancreata Enhances Insulin Secretion and Attenuates Islet Proinflammatory Signaling. Transplantation, 103, 160-167. doi:10.1097/TP.0000000000002400
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  All human islets used in research and for the clinical treatment of diabetes are subject to ischemic damage during pancreas procurement, preservation, and islet isolation. A major factor influencing islet function is exposure of pancreata to cold ischemia during unavoidable windows of preservation by static cold storage (SCS). Improved preservation methods may prevent this functional deterioration. In the present study, we investigated whether pancreas preservation by gaseous oxygen perfusion (persufflation) better preserved islet function versus SCS.
• Kodali, L., Harland, R. C., Thajudeen, B., Roy-chaudhury, P., Martin, D. R., Kodali, L., Howlader, A., & Harland, R. C. (2019). Page Kidney Following Nephroureteral Stent Placement in a Renal Transplant Allograft.. Progress in transplantation (Aliso Viejo, Calif.), 29(1), 95-96. doi:10.1177/1526924818817014
• Howlader, A., Thajudeen, B., Kodali, L., Martin, D., Harland, R., & Roy-Chaudhury, P. (2018). Page Kidney Following Nephroureteral Stent Placement in a Renal Transplant Allograft. Progress in transplantation (Aliso Viejo, Calif.), 1526924818817014.
• Agrawal, N., Echenique, I. A., Meehan, S. M., Limaye, A. P., Cook, L., Chang, A., Harland, R. C., Javaid, B., Kadambi, P. V., Matushek, S., Williams, J., & Josephson, M. A. (2017). Variability in assessing for BK viremia: whole blood is not reliable and plasma is not above reproach - a retrospective analysis. Transplant international : official journal of the European Society for Organ Transplantation, 30(7), 670-678.
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  Polyomavirus nephropathy (PVN) is a major complication of kidney transplantation. Most reports describe polyomavirus viremia either precedes or is detectable at the time of diagnosis of PVN. This association is the basis of current screening recommendations. We retrospectively reviewed the PCR results of blood and urine samples from 29 kidney transplant recipients with biopsy-proven PVN. Biopsies were performed for a rise in serum creatinine or persistent high-level BK viruria. All biopsies showed polyoma virus large T-antigen expression in tubular epithelium using immunohistochemistry. All had viruria preceding or at the time of biopsy (range, 5.2 × 104 to >25 × 106 BKV DNA copies/ml). Twenty (69%) had viremia ranging from 2.5 × 103 to 4.3 × 106 copies/ml at the time of the biopsy. Via blood BK PCR assay, nine (31%) had no BK viremia detected either preceding or at the time of the biopsy. In five recipients where sufficient specimen permitted, additional plasma BK assessment revealed positive detection of viremia. A comparative analysis of assays from two centres was performed with spiked samples. BK DNA may not be detected in the blood of some kidney transplant recipients with histologically confirmed PVN. This may reflect limitation of whole blood as opposed to plasma-based BK DNA assessment.
• Ferng, A. S., Harland, R. C., Khalpey, Z. I., & Marsh, K. M. (2017).

  Dehumanizing Wartime Refugees: Global Impact of Organ Trafficking

  . Journal of The American College of Surgeons, 225(4), S100-S101. doi:10.1016/j.jamcollsurg.2017.07.220
• Galons, J. P., Harland, R. C., Min, C. G., Pandey, A., Papas, K. K., Steyn, L. V., & Taylor, M. J. (2017).

  Quality Assessments of Persufflation and Cold Storage Preservation in Subnormothermic Isolated Porcine Kidneys

  . Transplantation, 101, S85. doi:10.1097/01.tp.0000525113.95879.8e
• Dimou, F. M., Mehta, H. B., Adhikari, D., Harland, R. C., Riall, T. S., & Kuo, Y. (2016). The role of extended criteria donors in liver transplantation for nonalcoholic steatohepatitis. Surgery, 160(6).
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  Nonalcoholic steatohepatitis is expected to become the leading indication for liver transplantation. Use of extended criteria donors (ECD) may help with donor allocation in these patients. The objective of this study was to determine the use of ECDs in patients with nonalcoholic steatohepatitis undergoing liver transplantation to stimulate a liver-specific predictive model for ECD use.
• Dieplinger, G., Everly, M. J., Rebellato, L. M., Haisch, C. E., Briley, K. P., Bolin, P., Kendrick, W. T., Kendrick, S. A., Morgan, C., Harland, R. C., & Terasaki, P. I. (2014). Changes in successive measures of de novo donor-specific anti-human leukocyte antigen antibodies intensity and the development of allograft dysfunction. Transplantation, 98(10), 1097-104.
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  Many patients develop de novo donor-specific anti-human leukocyte antigen antibodies (dnDSA) after transplantation. Despite development of dnDSA, not all patients will immediately fail. This study analyzes dnDSA intensity and longitudinal trends as prospective clinical parameters to assess subsequent allograft function.
• Everly, M. J., Rebellato, L. M., Haisch, C. E., Briley, K. P., Bolin, P., Kendrick, W. T., Kendrick, S. A., Morgan, C., Maldonado, A. Q., Harland, R. C., & Terasaki, P. I. (2014). Impact of IgM and IgG3 anti-HLA alloantibodies in primary renal allograft recipients. Transplantation, 97(5), 494-501.
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  With standard IgG donor-specific anti-HLA antibody (DSA) testing, it is unclear which immunoglobulin-G (IgG) DSA positive patients will fail. We looked further into the immune response by studying immunoglobulin-M (IgM) and IgG subclass 3 (IgG3) DSA to determine if these identify the IgG DSA patients at highest risk for allograft loss.
• Terasaki, P. I., Rebellato, L. M., Morgan, C., Maldonado, A. Q., Kendrick, W., Kendrick, S. A., Harland, R. C., Haisch, C. E., Everly, M. J., Dieplinger, G., Briley, K. P., & Bolin, P. (2014). Actual 5-Year Post-De Novo DSA Outcomes in Low Risk Primary Kidney Transplant Recipients.: Abstract# B856. Transplantation, 98, 508. doi:10.1097/00007890-201407151-01700
• Zink, J. N., Torrent, D. J., Stoner, M. C., Morgan, C., Maness, M. R., Katz, E. C., Kachare, S. D., Harland, R. C., Haisch, C. E., Guyton, R. L., Colomb, A. G., & Barham, D. W. (2014). A Critical Examination of the HeRO Catheter Performance in Challenging Hemodialysis Access Cases. Journal of Surgical Research, 186(2), 667. doi:10.1016/j.jss.2013.11.729
• Zink, J. N., Torrent, D. J., Stoner, M. C., Morgan, C., Maness, M. R., Katz, E. C., Kachare, S. D., Harland, R. C., Haisch, C. E., Guyton, R. L., Colomb, A. G., & Barham, D. W. (2014). Examining Hemodialysis Reliable Outflow catheter performance and cost in hemodialysis access.. The Journal of surgical research, 192(1), 1-5. doi:10.1016/j.jss.2014.03.016
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  The Hemodialysis Reliable Outflow (HeRO) vascular access device is a hybrid polytetrafluoroethylene graft-stent construct designed to address central venous occlusive disease. Although initial experience has demonstrated excellent mid-term patency rates, subsequent studies have led to external validity questions. The purpose of this study was to examine a single center experience with this vascular access device in challenging access cases with associated costs..A retrospective study representing the authors' cumulative HeRO vascular access device experience was undertaken. The primary endpoint was graft failure or death, with secondary endpoints including secondary intervention rates and cost..Forty-one patients with 15,579 HeRO days and a mean of 12.7 ± 1.5 mo with the vascular access device were available for analysis. Secondary patency was 81.6% at 6 mo and 53.7% at 12 mo. The reintervention rate was 2.84 procedures per HeRO vascular access device year. Associated HeRO costs related to subsequent procedures were estimated at $34,713.63 per patient/y..These data on the patency and primary outcome data diverge significantly from initial multicenter studies and represent a real-world application of this technology. It is costly to maintain patency. Use of HeRO vascular access devices should be judicious with outcome expectations reduced.
• Cail, J., Huang, W., Terasaki, P. I., Everly, M. J., Briley, K. P., Haisch, C. E., Bolin, P., Kendrick, W. T., Kendrick, S. A., Morgan, C., Harland, R. C., & Rebellato, L. M. (2013). Novel biomarker combination predicts long-term allograft outcome. Clinical Transplantation, 319-24.
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  Donor specific human leukocyte antigen (HLA) antibodies (DSA) are a significant cause of allograft failure. However, it has been reported that some DSA negative patients still experience allograft failure. In addition, some DSA positive patients maintain good graft function for >20 years. These findings suggest that while DSA is a cause of failure, it is not the sole risk factor for graft dysfunction and that the presence of DSA alone may not predict the time course of graft failure. Here, we report the predictive value of a proprietary panel of four biomarkers in long-term renal allograft outcome. A total of 310 consecutive patients, who received kidney transplants between 1999 and 2012, were included in this study. Recipient sera was tested for HLA antibodies and biomarkers at 3, 6, 12, 24, and 36 months post-transplant. HLA antibodies were identified using Labscreen single antigen beads. The biomarker combination (BMC) test consisted of a proprietary panel of 4 biomarkers and was performed using Luminex. Sera were defined as positive when any one of the 4 biomarkers became detectable. Sera of normal healthy people were used as negative controls. Graft survival analyses were performed and compared between different patient groups based on the positivity of DSA and BMC. Our results indicate that 57% of DSA negative patients and 54% of DSA positive patients had detectable biomarkers. There was no significant difference in BMC positive patients between the DSA positive and negative groups, which suggests that presence of BMC is not associated with HLA DSA. DSA positive patients had a 10% lower 10-year graft survival rate than patients without DSA, while BMC positive patients had a 25% lower 10-year graft survival rate than patients without detectable BMC. When DSA negative patients were divided into two groups based on the positivity of BMC, BMC positive patients had a 20% lower 10-year graft survival rate compared to BMC negative patients (p
• Everly, M. J., Rebellato, L. M., Haisch, C. E., Ozawa, M., Parker, K., Briley, K. P., Catrou, P. G., Bolin, P., Kendrick, W. T., Kendrick, S. A., Harland, R. C., & Terasaki, P. I. (2013). Incidence and impact of de novo donor-specific alloantibody in primary renal allografts. Transplantation, 95(3), 410-7.
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  To date, limited information is available describing the incidence and impact of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSA) in the primary renal transplant patient. This report details the dnDSA incidence and actual 3-year post-dnDSA graft outcomes.
• Freitas, M. C., Rebellato, L. M., Ozawa, M., Nguyen, A., Sasaki, N., Everly, M., Briley, K. P., Haisch, C. E., Bolin, P., Parker, K., Kendrick, W. T., Kendrick, S. A., Harland, R. C., & Terasaki, P. I. (2013). The role of immunoglobulin-G subclasses and C1q in de novo HLA-DQ donor-specific antibody kidney transplantation outcomes. Transplantation, 95(9), 1113-9.
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  Anti-HLA-DQ antibodies are the predominant HLA class II donor-specific antibodies (DSAs) after transplantation. Recently, de novo DQ DSA has been associated with worse allograft outcomes. The aim of this study was to determine the further complement-binding characteristics of the most harmful DQ DSA.
• Wu, P., Everly, M. J., Rebellato, L. M., Haisch, C. E., Briley, K. P., Bolin, P., Kendrick, W. T., Kendrick, S. A., Morgan, C., Harland, R. C., & Terasaki, P. I. (2013). Trends and characteristics in early glomerular filtration rate decline after posttransplantation alloantibody appearance. Transplantation, 96(10), 919-25.
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  Approximately 7% to 9% of patients with donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) fail within 1 year post-DSA onset. However, little is known as to how this DSA-associated failure temporally progresses. This longitudinal study investigates DSA's temporal relationship to allograft dysfunction and identifies predictors of allograft function's progressive deterioration post-DSA.
• Kadambi, P. V., Chon, W. J., Josephson, M. A., Desai, A., Thistlethwaite, J. R., Harland, R. C., Meehan, S. M., & Garfinkel, M. R. (2012). Reuse of a previously transplanted kidney: does success come with a price?. Clinical kidney journal, 5(5), 434-437.
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  Longer wait times for deceased donor kidney transplant have prompted newer initiatives to expedite the process. Reuse of a previously transplanted kidney might be appropriate in certain circumstances. However, one must also consider the unique issues that may arise after such transplants. We describe our experience in one such case where the donor kidney had lesions of focal and segmental glomerulosclerosis and signs of alloreactivity (positive C4d staining) prior to transplantation and the recipient developed ganciclovir-resistant cytomegalovirus (CMV) infection, which was perhaps transmitted from the donor. Despite the challenges, the allograft function remained stable 5 years after reuse.
• Terasaki, P. I., Rebellato-devente, L. M., Parker, K., Ozawa, M., Kendrick, W. T., Kendrick, S. A., Harland, R. C., Haisch, C. E., Everly, M. J., Catrou, P. G., Briley, K. P., & Bolin, P. (2012). When Is the Best Time to Screen for De Novo Donor Specific Anti-HLA Antibodies (DSA) in Low-Risk Renal Transplant Recipients?: 2231. Transplantation, 94(10S), 1190. doi:10.1097/00007890-201211271-02362
• Winborne, C., Terasaki, P. I., Rebellato, L. M., Parker, K., Kendrick, W., Kendrick, S. A., Harland, R. C., Haisch, C. E., Everly, M. J., Bringolf, K., & Bolin, P. (2012). Mycophenolate Acid Reduce Donor Specific HLA Antibody Strength in Kidney Transplant Recipients: 2314. Transplantation, 94(10S), 1081. doi:10.1097/00007890-201211271-02142
• Wu, P. P., Terasaki, P. I., Rebellato-devente, L. M., Parker, K., Ozawa, M., Kendrick, W. T., Kendrick, S. A., Harland, R. C., Haisch, C. E., Everly, M. J., Catrou, P. G., Briley, K. P., & Bolin, P. (2012). Natural History and Temporal Relationship Between de Novo DSA and Allograft Dysfunction Based on Consecutive Kidney Transplant Patients Followed for Over 5 Years: 1181. Transplantation, 94(10S), 60-61. doi:10.1097/00007890-201211271-00111
• Rebellato, L. M., Everly, M. J., Haisch, C. E., Ozawa, M., Briley, K. P., Parker, K., Catrou, P. G., Bolin, P., Kendrick, W. T., Kendrick, S. A., Harland, R. C., Rebellato, L. M., Everly, M. J., Haisch, C. E., Ozawa, M., Briley, K. P., Parker, K., Catrou, P. G., Bolin, P., , Kendrick, W. T., et al. (2011). A report of the epidemiology of de novo donor-specific anti-HLA antibodies (DSA) in "low-risk" renal transplant recipients. Clinical transplants, 337-40.
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  The donor specific anti-HLA antibody (DSA) has been increasingly recognized as the major cause of allograft loss. Despite this, no published reports exist describing the true epidemiology of de novo DSA.Here we describe the epidemiology of DSA based on the results of one of the longest running antibody study in consecutive renal transplant recipients. The study includes 224 non-sensitized, non-HLA-identical patients who received a primary kidney transplant between 3/1999-3/2006. Protocol testing for DSA was done pre-transplant, at 1, 3, 6, 9, and 12 months, and then annually. DSA was tested using single antigen beads. Data from the East Carolina University transplant cohort indicate that the prevalence of DSA in the first year post-transplant is 12.1 cases per 100. The average annual incidence of DSA is 4.7 per 100 cases, per year. The highest incidence of DSA was in the first year post transplant. Although deceased donors and African-Americans have a higher incidence rate of DSA than the comparator living donors and non-African American groups, respectively, these factors were not associated with DSA onset. The one factor found to be predictive of DSA was DQ mismatch (p = 0.036). Based on these epidemiologic findings in combination with previous reports showing DSA is a cause of allograft failure, it seems reasonable that at least annual testing should be done even in "low-risk" transplant patients, because every year a new 5% of patients will develop DSA.
• Chon, W. J., Chon, W. J., Kadambi, P. V., Kadambi, P. V., Harland, R. C., Harland, R. C., Thistlethwaite, J. R., Thistlethwaite, J. R., West, B. L., West, B. L., Udani, S., Udani, S., Poduval, R., Poduval, R., Josephson, M. A., & Josephson, M. A. (2010). Changing attitudes toward influenza vaccination in U.S. Kidney transplant programs over the past decade. Clinical journal of the American Society of Nephrology : CJASN, 5(9), 1637-41.
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  Influenza infection in transplant recipients is often associated with significant morbidity. Surveys were conducted in 1999 and 2009 to find out if the influenza vaccination practices in the U.S. transplant programs had changed over the past 10 years.
• Harland, R., Agarwal, S., Dorafshar, A., Millis, J., & Gottlieb, L. (2010). Liver and vascularized posterior rectus sheath fascia composite tissue allotransplantation. Am J Transplant, 10(12):2712-6.
• Agarwal, S., Oak, N., Siddique, J., Harland, R. C., & Abbo, E. D. (2009). Changes in pediatric renal transplantation after implementation of the revised deceased donor kidney allocation policy. American Journal of Transplantation, 9(5), 1237-42.
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  In October 2005, the United Network for Organ Sharing (UNOS) implemented a revised allocation policy requiring that renal allografts from young deceased donors (DDs) (
• Eng, M. K., Zorn, K. C., Harland, R. C., Bernstein, A. J., Katz, M., Shikanov, S., & Shalhav, A. L. (2008). Fifteen-year follow-up of transplantation of a cadaveric polycystic kidney: a case report. Transplantation Proceedings, 40(5), 1747-50.
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  Kidneys from donors affected by autosomal-dominant polycystic kidney disease (ADPKD) are in general considered unsuitable for transplantation. To the best of our knowledge, only 12 cases of ADPKD transplanted renal units have been reported in the English literature; most have only short-term follow-up.
• Kadambi, P. V., Kadambi, P. V., Josephson, M. A., & Harland, R. C. (2008). CLINICAL UTILITY OF THE NOVEL METHOD OF IMMUNOSUPPRESSION MONITORING (IMMUKNOW ASSAY) IN CYTOMEGALOVIRUS INFECTIONS IN KIDNEY AND PANCREAS TRANSPLANT RECIPIENTS: 1178. Transplantation, 86(2S), 400. doi:10.1097/01.tp.0000331654.87647.2d
• Cook, R. I., Wreathall, J., Smith, A., Cronin, D. C., Rivero, O., Harland, R. C., Raman, J., Battles, J., & Reason, J. (2007). Probabilistic risk assessment of accidental ABO-incompatible thoracic organ transplantation before and after 2003. Transplantation, 84(12), 1602-9.
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  A widely reported ABO-mismatch accident in March of 2003 raised concerns about the reliability of the transplantation system. Because this type of failure is rare and significant, we performed a probabilistic risk assessment (PRA) of the donor-recipient matching processes for thoracic organ transplantation.
• Losanoff, J. E., Millis, J. M., Harland, R. C., & Testa, G. (2007). Hepato-spleno-mesenteric trunk. Journal of the American College of Surgeons, 204(3), 511.
• Josephson, M. A., Gillen, D., Javaid, B., Kadambi, P., Meehan, S., Foster, P., Harland, R., Thistlethwaite, R. J., Garfinkel, M., Atwood, W., Jordan, J., Sadhu, M., Millis, M. J., & Williams, J. (2006). Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation, 81(5), 704-10.
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  Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals.
• Losanoff, J. E., Harland, R. C., Thistlethwaite, J. R., Garfinkel, M. R., Williams, J. W., Milner, J., & Millis, J. M. (2006). Omega jejunoduodenal anastomosis for pancreas transplant. Journal of the American College of Surgeons, 202(6), 1021-4.
• Losanoff, J. E., Harland, R. C., Williams, J. E., Rivero, O. E., Reichman, T. W., & Millis, J. M. (2006). Combined kidney-pancreas transplant: early abdominal catastrophe in the donor may not be a contraindication. Transplantation, 81(8), 1223.
• Orvieto, M. A., Chien, G. W., Shalhav, A. L., Tolhurst, S. R., Rapp, D. E., Galocy, R. M., & Harland, R. C. (2006). Case report: robot-assisted laparoscopic pyeloureterostomy in a transplanted kidney with ureteral stricture. Journal of Endourology / Endourological Society, 20(1), 31-2.
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  Ureteral obstruction secondary to ischemia is the most common urologic complication of kidney transplantation. Although endoscopic management has shown satisfactory short-term success rates, surgical repair is considered the definitive therapy. To our knowledge, this procedure has been performed only through open surgery. We present a minimally invasive approach for reconstruction of a ureteral stricture in a renal transplant patient using the Da Vinci robotic system.
• Poduval, R. D., Kadambi, P. V., Josephson, M. A., Cohn, R. A., Harland, R. C., Javaid, B., Huo, D., Manaligod, J. R., Thistlethwaite, J. R., & Meehan, S. M. (2005). Implications of immunohistochemical detection of C4d along peritubular capillaries in late acute renal allograft rejection. Transplantation, 79(2), 228-35.
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  Immunohistochemical detection of the C4d complement product along peritubular capillaries (PC) may indicate humoral rejection of renal allografts. We examined the frequency of PC C4d expression in renal-allograft biopsies with acute rejection (AR) arising more than 6 months after transplantation and the impact of this finding.
• Williams, J. W., Javaid, B., Kadambi, P. V., Gillen, D., Harland, R., Thistlewaite, J. R., Garfinkel, M., Foster, P., Atwood, W., Millis, J. M., Meehan, S. M., & Josephson, M. A. (2005). Leflunomide for polyomavirus type BK nephropathy. The New England Journal of Medicine, 352(11), 1157-8.
• Laven, B. A., Orvieto, M. A., Chuang, M. S., Ritch, C. R., Murray, P., Harland, R. C., Inman, S. R., Brendler, C. B., & Shalhav, A. L. (2004). Renal tolerance to prolonged warm ischemia time in a laparoscopic versus open surgery porcine model. The Journal of Urology, 172(6 Pt 1), 2471-4.
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  To our knowledge the effects of renal warm ischemia (WI) during laparoscopic vs open surgery have not been investigated. Decreased renal blood flow during pneumoperitoneum may precondition the kidney to tolerate longer WI time. Traditionally 30 minutes has defined the limit of renal WI time in open surgery. However, recent reports show renal function recovery at WI times of 45 to 120 minutes. We assessed renal function recovery after prolonged WI during laparoscopic vs open surgery in a solitary kidney porcine model.
• Shalhav, A. L., Orvieto, M. A., Harland, R. C., Garfinkel, M. R., Galocy, M., & Chien, G. W. (2004). Bipolar electrocoagulation for clipless division of left renal vein branches during laparoscopic living donor nephrectomy.. Transplantation proceedings, 36(9), 2625-7. doi:10.1016/j.transproceed.2004.09.027
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  We present our experience of using the bipolar electrocautery for division of the left renal vein branches in laparoscopic right living donor nephrectomy. This has been performed in 160 cases with no complications related to the technique. The absence of laparoscopic clips allows easier and safer placement of the endostaple.
• Thistlewaite, J. R., Sokoloff, M. H., Shalhav, A. L., Harland, R. C., & Chien, G. W. (2004). Ex vivo partial nephrectomy and autotransplantation for renal cell cancer after laparoscopic renal harvest.. Urology, 63(6), 1182-3. doi:10.1016/j.urology.2004.02.017
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  Laparoscopic partial nephrectomy is an alternative to the open approach. For centrally located tumors, open extracorporeal partial nephrectomy has been used. We report 2 cases of laparoscopic nephrectomy for the purpose of extracorporeal partial nephrectomy and autotransplantation for renal cell cancer.
• Thistlethwaite, J. R., Schaffer, R., Murphy, P., Harland, R. C., Garfinkel, M. R., & Cronin, D. C. (2003). PANCREAS RETRANSPLANTATION: A SINGLE CENTER'S EXPERIENCE AND REVIEW OF THE LITERATURE: 01. Transplantation, 76(Supplement), S19. doi:10.1097/00007890-200308271-00001
• Thistlethwaite, J. R., Schaffer, R., Murphy, P., Harland, R. C., Garfinkel, M. R., & Cronin, D. C. (2003). PANCREAS RETRANSPLANTATION: A SINGLE CENTER'S EXPERIENCE AND REVIEW OF THE LITERATURE: 01. Transplantation, 76(Supplement), S19. doi:10.1097/00007890-200308271-00001
• Ching, C. D., Harland, R. C., Collins, B. H., Kendall, W., Hobbs, H., & Opara, E. C. (2001). A reliable method for isolation of viable porcine islet cells. Archives of Surgery (Chicago, Ill. : 1960), 136(3), 276-9.
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  Mechanical injury and oxidative stress caused by reoxygenation of isolated porcine islet cells result in their unresponsiveness to glucose stimulation.
• Schaffer, B. K., Meyers, W. C., Mcenaney, P. M., Kim, R. D., Hedeshian, M. H., Harland, R. C., & Chari, R. S. (2001). Hypoxia and hypothermia activate NF-kB through distinct cytoplasmic mechanisms with differential impact on cell viability in an in vitro primary rat hepatocyte model of cold hypoxia. Gastroenterology, 120(5), A346-A347. doi:10.1016/s0016-5085(08)81724-6
• Charles, K., Harland, R., Ching, D., & Opara, E. (2000). Storage and microencapsulation of islets for transplantation. Cell Transplantation, 9(1), 33-8.
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  Microencapsulation is an effective means of immunoisolation for pancreatic islet transplants. However, the process of isolating, purifying, encapsulating, and transplanting islets in a single day is labor intensive and difficult for routine use. There is an apparent need for reliable methods of islet storage, and cryopreservation has emerged as an attractive system of islet banking. While studies have shown that cryopreserved islets are viable when tested unencapsulated after thawing, it is not clear if the combination of freezing and encapsulation would affect islet function. The purpose of the present study was to determine the in vitro function of cryopreserved islets following thawing and microencapsulation. Islets were isolated from the pancreata of Sprague-Dawley rats and cryopreserved under liquid nitrogen for either 1 week or 1 month, following an overnight culture at 37 degrees C. Upon thawing, the islets were tested either unencapsulated or after encapsulation in polylysine-alginate membrane. In all experiments islets were preperifused for 1 h at 37 degrees C with a modified Krebs-Ringer bicarbonate buffer containing 3.3 mM (60 mg/dl) glucose and maintained at pH 7.4 by continuous gassing with 95% air/5% CO2. Following basal effluent sample collection on ice, the glucose concentration was raised to 16.7 mM (300 mg/dl). It was found that, within 10 min of high glucose stimulation, an average of twofold increase in insulin secretion (p < 0.01) was obtained in islets within or without microcapsules. We conclude that islets cryopreserved for 1 month prior to thawing and microencapsulation retained functional viability as determined in in vitro experiments.
• Foley, D. P., Collins, B. R., Magee, J. C., Platt, J. L., Katz, E., Harland, R. C., Meyers, W. C., & Chari, R. S. (2000). Bile acids in xenogeneic ex-vivo liver perfusion: function of xenoperfused livers and compatibility with human bile salts and porcine livers. Transplantation, 69(2), 242-8.
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  In recent years, hepatic support systems using xenogeneic cells have been developed to support patients in fulminant hepatic failure. The extent to which xenogeneic hepatocytes metabolize and excrete human organic anions is unclear. In these studies we examined the ability of the ex vivo porcine liver to clear human bile acids during extracorporeal liver perfusion (ELP).
• Ahsan, N., Bennett, W. M., Bertolatus, J. A., Brinler, K., C-yang, H., Chan, L., Cohen, D. M., Copley, J. B., Dunn, J., Ewell, M., Gonwa, T. A., Gores, P. F., Harland, R. C., Hayes, D. H., Helderman, J. H., Hodge, E. E., Hricik, D. E., Matas, A. J., Mcintosh, M., , Mendez, R., et al. (1999).

  Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil--a prospective randomized study. Steroid Withdrawal Study Group.

  . Transplantation, 68(12), 1865-74. doi:10.1097/00007890-199912270-00009
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  Prospective randomized trials have shown a reduced rate of acute rejection (AR) in mycophenolate mofetil-treated kidney transplant recipients. We hypothesized that this increased protection from AR could allow successful prednisone (P) withdrawal in cyclosporine/mycophenolate mofetil/P-treated recipients..A multicenter, prospective, randomized, double-blind trial of P withdrawal at 3 months post-transplant was initiated. Entry criteria were: primary transplant, adult, no AR by 90 days, mycophenolate mofetil dose > or =2 g/day, cyclosporine dose = 5-15 mg/kg/ day, P dose = 10-15 mg/day. Study participants were randomized to have P tapered over 8 weeks (beginning at 3 months posttransplant) to 0 vs. 10 mg/day. Prestudy power analysis determined 500 recipients should be randomized for 80% statistical power to test equivalence of the primary endpoint, AR, or treatment failure at 1 year posttransplant. By design, the study was to be stopped if interim data precluded reaching equivalence. An established data safety monitoring board monitored the study..After 266 patients were enrolled, the patient enrollment was stopped (after safety monitoring board review) because of excess rejection in the P withdrawal group. The Kaplan-Meier estimate of the cumulative incidence of rejection or treatment failure within 1 year posttransplant (+/-95% confidence interval) for the maintenance group was 9.8% (4.4%; treatment failure, 14.9%); for the withdrawal group, 30.8% (21.0%; 39.3%). Treatment differences in the distribution of time to event were highly significant (P = 0.0007). Of note, risk was higher in blacks (39.6%) versus nonblacks (16.0%) (P
• Opara, E. C., Harland, R. C., Ching, D., & Charles, K. (1999). Microencapsulation of cryopreserved islets for transplantation1. Current Surgery, 56(7), 383. doi:10.1016/s0149-7944(99)00135-x
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  Abstract Purpose: The development of islet banks and of techniques to immunoisolate islets by encapsulation has the potential to overcome the major barriers to the routine use of islet transplants as an alternative to insulin therapy in diabetic patients. Aim: The purpose of this study was to determine the in vitro function of islets stored by cryopreservation prior to microencapsulation. Method: Islets were isolated from the pancreata of Sprague-Dawley rats and stored frozen at −80°C in the presence of cryoprotectants for 1 month. After thawing and overnight culture, they were tested either unencapsulated or after microencapsulation with poly- l -lysine-alginate membrane using an air-jet syringe pump. Islets were tested for response to glucose stimulation using a perifusion procedure. Results: In the unencapsulated islets, the mean ± SEM rate of insulin secretion increased from a basal value of 832 ± 34 to a peak of 1448 ± 138 pg/6 islets/min, p Conclusion: Islets cryopreserved for 1 month retained viability after thawing and microencapsulation.
• Clavien, P. A., Selzner, M., Tuttle-Newhall, J. E., Harland, R. C., & Suhocki, P. (1998). Liver transplantation complicated by misplaced TIPS in the portal vein. Annals of Surgery, 227(3), 440-5.
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  The purpose of this study was to determine the incidence and complications related to transjugular intrahepatic portosystemic shunt (TIPS) stents found in the portal vein at the time of an orthotopic liver transplantation.
• Garfinkel, M. R., Harland, R. C., & Opara, E. C. (1998). Optimization of the microencapsulated islet for transplantation. The Journal of Surgical Research, 76(1), 7-10.
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  Microencapsulation of isolated islets is a good method for providing protection against immunologic reactions to the cells in both allogeneic and xenogenic grafts. Current methods of microencapsulation require chelation of the alginate-calcium core, which solubilizes the structural support of the capsules and may adversely affect durability. The purpose of the present study was to determine the in vitro response to glucose stimulation, of microencapsulated islets that have not been subjected to chelation.
• Lin, S. S., Weidner, B. C., Byrne, G. W., Diamond, L. E., Lawson, J. H., Hoopes, C. W., Daniels, L. J., Daggett, C. W., Parker, W., Harland, R. C., Davis, R. D., Bollinger, R. R., Logan, J. S., & Platt, J. L. (1998). The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants. The Journal of Clinical Investigation, 101(8), 1745-56.
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  Long-term success in xenotransplantation is currently hampered by acute vascular rejection. The inciting cause of acute vascular rejection is not yet known; however, a variety of observations suggest that the humoral immune response of the recipient against the donor may be involved in the pathogenesis of this process. Using a pig-to-baboon heterotopic cardiac transplant model, we examined the role of antibodies in the development of acute vascular rejection. After transplantation into baboons, hearts from transgenic pigs expressing human decay-accelerating factor and CD59 underwent acute vascular rejection leading to graft failure within 5 d; the histology was characterized by endothelial injury and fibrin thrombi. Hearts from the transgenic pigs transplanted into baboons whose circulating antibodies were depleted using antiimmunoglobulin columns (Therasorb, Unterschleisshein, Germany) did not undergo acute vascular rejection in five of six cases. Biopsies from the xenotransplants in Ig-depleted baboons revealed little or no IgM or IgG, and no histologic evidence of acute vascular rejection in the five cases. Complement activity in the baboons was within the normal range during the period of xenograft survival. In one case, acute vascular rejection of a xenotransplant occurred in a baboon in which the level of antidonor antibody rose after Ig depletion was discontinued. This study provides evidence that antibodies play a significant role in the pathogenesis of acute vascular rejection, and suggests that acute vascular rejection might be prevented or treated by therapies aimed at the humoral immune response to porcine antigens.
• Weidner, B. C., Platt, J. L., Parker, W., Mccurry, K. R., Logan, J. S., Lin, S. S., Lawson, J. H., Hoopes, C. W., Harland, R. C., Diamond, L. E., Davis, R. D., Daniels, L. J., Byrne, G. W., & Bollinger, R. R. (1998). The Contribution of Humoral Immune Response to the Pathogenesis of Acute Vascular Rejection. Transplantation, 66(8), S48. doi:10.1097/00007890-199810270-00221
• Yadav, S. S., Gao, W., Harland, R. C., & Clavien, P. A. (1998). A new and simple technique of total hepatic ischemia in the mouse. Transplantation, 65(11), 1433-6.
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  A model of total hepatic ischemia is currently not available in mice. Models described in rats using portosystemic shunts to achieve total ischemia have been notoriously difficult. In mice, the problem is compounded further when using this type of technique because of the small size of the animal. A new technique is described combining partial hepatectomy with clamping of the remnant liver.
• Yadav, S. S., Howell, D. N., Gao, W., Steeber, D. A., Harland, R. C., & Clavien, P. A. (1998). L-selectin and ICAM-1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver. The American Journal of Physiology, 275(6 Pt 1), G1341-52.
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  Leukocytes recruited during ischemia-reperfusion to the liver are important mediators of injury. However, the mechanisms of leukocyte adhesion and the role of adhesion receptors in hepatic vasculature remain elusive. L-selectin may critically contribute to injury, priming adhesion for later action of intercellular adhesion molecule-1 (ICAM-1). Paired experiments were performed using mutant mice (L-selectin -/-, ICAM-1 -/-, and L-selectin/ICAM-1 -/-) and wild-type mice (C57BL/6) to investigate leukocyte adhesion in the ischemic liver. Leukocyte adhesion and infiltration were assessed histologically. Aspartate aminotransferase levels were significantly reduced (2- to 3-fold) in mutant vs. wild-type mice in most groups but most significantly after 90 min of partial hepatic ischemia. Leukocyte adhesion was significantly reduced in all mutant mice. Areas of microcirculatory failure, visualized by intravital microscopy, were prevalent in wild-type but virtually absent in L-selectin-deficient mice. After total hepatic ischemia for 75 or 90 min, survival was better in mutant L-selectin and L-selectin/ICAM-1 mice vs. wild-type mice and ICAM-1 mutants. In conclusion, L-selectin is critical in the pathogenesis of hepatic ischemia-reperfusion injury. Poor sinusoidal perfusion due to leukocyte adhesion and clot formation is a factor of injury and appears to involve L-selectin and ICAM-1 receptors.
• Yadav, S. S., Tedder, T. F., Steeber, D. A., Lemasters, J. J., Harland, R. C., Currin, R. T., & Clavien, P. (1998). P-SELECTIN MEDIATES REPERFUSION INJURY IN THE WARM ISCHEMIC MOUSE LIVER. Transplantation, 66(8), S9. doi:10.1097/00007890-199810270-00065
• Clavien, P. A., Sharara, A. I., Camargo, C. A., Harland, R. C., & Fitz, J. G. (1996). Evidence that ursodeoxycholic acid prevents steroid-resistant rejection in adult liver transplantation. Clinical Transplantation, 10(6 Pt 2), 658-62.
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  Steroid-resistant rejection continues to be a serious problem in liver transplantation. Since ursodeoxycholic acid (UDCA) is beneficial in several cholestatic disorders and possesses in vitro immunomodulatory and immunosuppressive effects, we have tested in a pilot study the effects of adjuvant UDCA in the prevention of steroid-resistant rejection. Fifty consecutive liver transplant patients were treated with a standard cyclosporine immunosuppressive regimen. Treatment with UDCA (10 mg/kg/d) was initiated in each patient who developed biopsy-proven rejection or biochemical evidence of cholestasis. Clinical and laboratory features were monitored for evidence of rejection. Data were analyzed after at least a 10-month follow-up period was available in each patient. Seven patients died during the study period, all within 4 wk of surgery. No evidence of rejection was documented in these patients. Twenty three of the 43 survivors 53% (23/43) developed an episode of rejection, and UDCA was initiated in each of them. Only one patient had a second episode of rejection, which responded to intravenous methylprednisolone therapy; no patient required antilymphocyte therapy. There was no evidence of toxicity for UDCA. These data suggest that UDCA can be given safely following OLT and may contribute to prevention of steroid-resistant rejection in liver transplant recipients.
• Harland, R. C., & Platt, J. L. (1996). Prospects for xenotransplantation of the liver. Journal of Hepatology, 25(2), 248-58.
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  Because of the tremendous success of clinical transplantation of the liver and other organs in the last three decades, the demand for organs for transplantation has risen sharply and there is now a substantial shortage. The utilization of organs from other species, xenotransplantation, is increasingly viewed as a potential solution to this problem. The major limitation to xenotransplantation is the formidable immunological barriers that prevent the successful transplantation of non-human organs into human recipients. Here we review current knowledge about the immunology of xenotransplantation and the limited clinical and experimental experience in xenotransplantation of the liver.
• Suhocki, P. V., Conlon, P. J., Knelson, M. H., Harland, R., & Schwab, S. J. (1996). Silastic cuffed catheters for hemodialysis vascular access: thrombolytic and mechanical correction of malfunction. American Journal of Kidney Diseases : The Official Journal of the National Kidney Foundation, 28(3), 379-86.
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  Silastic cuffed catheters are assuming a greater role in providing long-term vascular access for hemodialysis patients. However, catheter thrombosis, fibrin sheath formation, and catheter malposition are recurrent problems that reduce extracorporeal flow rates and shorten catheter life. We reviewed 163 consecutive episodes of catheter malfunction that occurred in 121 catheters in 88 patients over a 3.5-year period. Intraluminal instillation of urokinase was successful in reestablishing an extracorporeal flow rate of > or = 300 mL/min in 74% of episodes. The 42 remaining episodes (26%) were radiologically evaluated. Two catheters required replacement for catheter kinking or insufficient catheter length. Two additional catheters were malpositioned; both were successfully repositioned with percutaneous techniques. A fibrin sheath was detected encasing the catheter in 38 instances. The fibrin sheath was successfully stripped from the distal portion of the catheter in 36 of the 38 instances. Using endoluminal thrombolytic therapy and percutaneous mechanical techniques, we have extended the mean survival for catheters intended for permanent vascular access to 12.7 months and have allowed 95% of the catheters inserted for temporary use to reach their use goal. Tunnel tract infection and catheter-mediated bacteremia were the primary reasons for catheter removal.
• Suhocki, P. V., Lawson, J. H., Harland, R. C., & Smith, T. P. (1996). Curing a consumption coagulopathy with transcatheter embolization of a visceral artery aneurysm. American Journal of Roentgenology, 166(4), 982-4.
• Collins, B. H., Chari, R. S., Magee, J. C., Harland, R. C., Lindman, B. J., Logan, J. S., Bollinger, R. R., Meyers, W. C., & Platt, J. L. (1995). Immunopathology of porcine livers perfused with blood of humans with fulminant hepatic failure. Transplantation Proceedings, 27(1), 280-1.
• Harland, R. C., Logan, J. S., Kooyman, D., Byrne, G. W., & Platt, J. L. (1994). Ex vivo perfusion of mouse hearts expressing the human complement regulatory protein CD59. Transplantation Proceedings, 26(3), 1245.
• Magee, J. C., Collins, B. H., Harland, R. C., Bollinger, R. R., Frank, M. M., & Platt, J. L. (1995). Prevention of hyperacute xenograft rejection by intravenous immunoglobulin. Transplantation Proceedings, 27(1), 271.
• Magee, J. C., Collins, B. H., Harland, R. C., Lindman, B. J., Bollinger, R. R., Frank, M. M., & Platt, J. L. (1995). Immunoglobulin prevents complement-mediated hyperacute rejection in swine-to-primate xenotransplantation. The Journal of Clinical Investigation, 96(5), 2404-12.
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  Immunoglobulins regulate the complement system by activating complement on foreign surfaces and diverting reactive complement proteins away from autologous cell surfaces. Based on this model, we explored the ability of Ig to balance complement activation versus control in a pig-to-primate cardiac xenotransplantation model in which the binding of xenoreactive antibodies of the recipient to graft blood vessels and the activation of complement cause hyperacute rejection. Human IgG added to human serum caused a dose-dependent decrease in deposition of iC3b, cytotoxicity, and heparan sulfate release when the serum was incubated with porcine endothelial cells. This decrease was not caused by alteration in antibody binding or consumption of complement but presumably reflected decreased formation of C3 convertase on the endothelial cells. Infusion of purified human IgG into nonhuman primates prevented hyperacute rejection of porcine hearts transplanted into the primates. As expected, the transplants contained deposits of recipient Ig and C1q but not other complement components. The inhibition of complement on endothelial cell surfaces and in the xenotransplantation model supports the idea that IgG regulates the classical complement pathway and supports therapeutic use of that agent in humoral-mediated disease.
• Pappas, T. N., Meyers, W. C., Harland, R. C., Collins, B. H., & Broome, A. H. (1995). Quality of life after pancreatic debridement. Gastroenterology, 108(4), A1214. doi:10.1016/0016-5085(95)29152-0
• Chari, R. S., Collins, B. H., Magee, J. C., DiMaio, J. M., Kirk, A. D., Harland, R. C., McCann, R. L., Platt, J. L., & Meyers, W. C. (1994). Brief report: treatment of hepatic failure with ex vivo pig-liver perfusion followed by liver transplantation. The New England Journal of Medicine, 331(4), 234-7.
• Collins, B. H., Chari, R. S., Magee, J. C., Harland, R. C., Lindman, B. J., Logan, J. S., Bollinger, R. R., Meyers, W. C., & Platt, J. L. (1994). Mechanisms of injury in porcine livers perfused with blood of patients with fulminant hepatic failure. Transplantation, 58(11), 1162-71.
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  Hyperacute rejection of renal and cardiac xenografts is initiated by the reaction of recipient natural antibodies and complement with endothelial cell antigens of the donor organ. The liver is thought to be less susceptible to this form of rejection; however, the mechanisms underlying its decreased susceptibility are not known. We investigated the organ injury occurring in porcine livers perfused with blood from 4 human subjects with fulminant hepatic failure. Nine porcine livers were perfused via an extracorporeal circuit in order to provide temporary metabolic support. Each porcine liver exhibited metabolic function, and the duration of xenoperfusion ranged from 2 to 5 hr. Histologic examination of the xenoperfused livers revealed focal hepatocellular necrosis, prominent infiltration of neutrophils, and, in 7 of 9 cases, periportal and centrilobular hemorrhage and thrombosis. Immunopathology demonstrated minimal or no human IgM and IgG along the small vessels and sinusoidal surfaces. Trace deposits of human IgM were observed along the luminal surfaces of large blood vessels in most cases. Trace deposits of C3 were noted in 2 of 9 livers; however, C4, iC3b, C5b, properdin, and the membrane attack complex were not detected. Human anti-porcine natural antibody titers decreased less than expected during the perfusions. Serum CH50, C3, and C4 levels were low before each procedure and decreased slightly with perfusion. One patient perfused 2 porcine livers and a human liver. The human liver had focal hepatocellular necrosis, trace deposits of IgM, no deposits of complement, and an infiltrate consisting of neutrophils; however, the neutrophil influx was less than that observed in the xenoperfused livers. To further evaluate the effects of alloperfusion, venovenous bypass was established in 2 pigs and the extracorporeal circuit was utilized to perfuse 2 porcine livers. The alloperfused porcine livers had focal hepatocellular necrosis and a minimal infiltrate of neutrophils. There were no deposits of porcine IgM, IgG, or complement components. In conclusion, although the porcine livers perfused by human blood sustained structural damage, the time course, the absence of immune deposits, and the findings of similar, albeit less severe, lesions in the alloperfused livers suggest that the pathogenesis of tissue injury in the xenoperfused livers differs from that of hyperacute rejection and may be related to the action of recipient neutrophils.
• Harland, R. C. (1994). Placement of permanent vascular access devices: surgical considerations. Advances in Renal Replacement Therapy, 1(2), 99-106.
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  The maintenance of adequate vascular access for hemodialysis is a challenge for all involved in the care of the patient on hemodialysis. Careful planning, early placement, a stepwise approach to vascular access, and careful observation for complications are necessary to assure the availability of long-term access. Above all, a coordinated approach involving the nephrologist, dialysis unit personnel, surgeon and radiologist is the best way to provide optimal, efficient care to the hemodialysis patient.
• Harland, R. C., Vernon, W. B., Bunzendahl, H., Thompson, J. K., Lawrence, C., & Bollinger, R. R. (1994). Ganciclovir/acyclovir prophylaxis reduces the incidence of cytomegalovirus infections in pancreas transplant recipients. Transplantation Proceedings, 26(2), 432-3.
• Bollinger, R. R., Fabian, M. A., Abernethy, K. A., Harland, R. C., DeBuysscher, E. V., & Baldwin, W. M. (1992). IgG is a prominent component of cynomolgus antiporcine natural xenoantibody. Transplantation Proceedings, 24(2), 435.
• Bollinger, R. R., Fabian, M. A., Harland, R. C., Murray, W. J., Baldwin, W. M., Abernethy, K., Britt, L., Sontag, M., & Halperin, E. C. (1991). Total lymphoid irradiation for cardiac xenotransplantation in nonhuman primates. Transplantation Proceedings, 23(1 Pt 1), 587-8.
• Halperin, E. C., Knechtle, S. J., Harland, R. C., Yamaguchi, Y., Sontag, M., & Bollinger, R. R. (1990). Irradiation for xenogeneic transplantation. Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology, 18(1), 29-37.
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  Xenogeneic transplantation (XT) is the transplantation of organs or tissues from a member of one species to a member of another. Mammalian species frequently have circulating antibody which is directed against the foreign organ irrespective of known prior antigen exposure. This antibody may lead to hyperacute rejection. There is no reliable means to avert hyperacute rejection once it ensues so efforts must be directed towards eliminating the pre-existing antibody. In those species in which hyperacute rejection of xenografts does not occur, cell-mediated rejection, similar to allograft rejection, may occur. It is in the prevention of this latter form of rejection that radiation is most likely to be beneficial in XT. Both total lymphoid irradiation (TLI) and selective lymphoid irradiation (SLI) have been investigated for use in conjunction with XT. TLI has contributed to the prolongation of pancreatic islet-cell xenografts from hamsters to rats. TLI has also markedly prolonged the survival of cardiac transplants from hamsters to rats. A more modest prolongation of graft survival has been seen with the use of TLI in rabbit-to-rat exchanges. Therapy with TLI, cyclosporine, and splenectomy has markedly prolonged the survival of liver transplants from hamsters to rats, and preliminary data suggest that TLI may contribute to the prolongation of graft survival in the transplantation of hearts from monkeys to baboons. SLI appears to have prolonged graft survival, when used in conjunction with anti-lymphocyte globulin, in hamster-to-rat cardiac graft exchanges. The current state of knowledge of the use of irradiation in experimental XT is reviewed.
• Yamaguchi, Y., Halperin, E. C., Harland, R. C., Wyble, C., & Bollinger, R. R. (1990). Significant prolongation of hamster liver transplant survival in Lewis rats by total-lymphoid irradiation, cyclosporine, and splenectomy. Transplantation, 49(1), 13-7.
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  The effects of total lymphoid irradiation, cyclosporine and splenectomy alone and in combination have been studied in liver transplants from the LVG hamster to the LEW rat. Neither CsA alone, splenectomy alone, nor TLI alone prolonged graft survival. CsA/splenectomy and TLI/CsA produced significant prolongation of graft survival. TLI/CsA/splenectomy prolonged graft survival by over sixfold compared with controls. While CsA alone was ineffective in reducing lymphocytotoxic antidonor antibody, splenectomy alone or CsA/splenectomy did significantly suppress production of antibody. Only very low levels of antibody could be detected in animals treated with TLI/CsA/splenectomy. TLI/CsA/splenectomy has an immunosuppressive effect sufficient to significantly prolong liver graft survival in the LVG hamster to LEW rat combination and may represent a promising treatment protocol in experimental cross-species transplantation.
• Bollinger, R. B., Yamaguchi, Y., Harland, R. C., Wyble, C., & Mori, K. (1989). Effects of donor splenocytes treated with mitomycin C on rat hepatic, cardiac, and intestinal allografts. Transplantation Proceedings, 21(1 Pt 1), 213-4.
• Harland, R. C., Halperin, E. C., Yamaguchi, Y., Ruiz, P., Scroggs, M. W., Sanfilippo, F., & Bollinger, R. R. (1989). Total lymphoid irradiation and cyclosporine prolongs cardiac allograft survival in the sensitized rat model. Transplantation Proceedings, 21(1 Pt 1), 1118-9.
• Knechtle, S. J., Yamaguchi, Y., Harland, R. C., Coundouriotis, A., & Bollinger, R. R. (1989). The role of class I antigens in hyperacute rejection of hepatic allografts in rats. Transplantation Proceedings, 21(3), 3557.
• Ruiz, P., Harland, R., Fuller, J., Yamaguchi, Y., Bollinger, R. R., & Sanfilippo, F. (1989). Characteristics of alloreactive rat T cell lines established from low and high rejecting orthotopic liver transplants. Transplantation Proceedings, 21(2), 3286-8.
• Yamaguchi, Y., Harland, R. C., Wyble, C., & Bollinger, R. R. (1989). The role of RT1.a major histocompatibility antigens in prolonging the survival of hepatic allografts in the rat. Transplantation Proceedings, 21(1 Pt 1), 792-3.
• Yamaguchi, Y., Harland, R. C., Wyble, C., & Bollinger, R. R. (1989). The role of class I major histocompatibility complex antigens in prolonging the survival of hepatic allografts in the rat. Transplantation, 47(1), 171-7.
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  In an attempt to study the role of class I major histocompatibility complex antigens in inducing immunological unresponsiveness, the survival rates of hepatic allografts were compared in rats pretreated with blood taken from various rat strains. A single intravenous injection of 1 ml fresh heparinized whole blood seven days before transplantation significantly prolonged the survival of subsequent donor-specific hepatic allografts in the fully allogeneic ACI(RT1a)-to-LEW(RT1l) rat combination. However, pretreatment with blood taken from the third-party strain BN(RT1n) did not produce suppression of rejection, attesting to the specificity of the pretransplant transfusion effect. Interestingly, pretransplant transfusion of PVG.r1 blood, sharing only the RT1.A MHC region with ACI, significantly prolonged the survival of ACI-to-LEW hepatic allografts. In addition, no lymphocytotoxic antibodies could be detected at 30 or 100 days after transplantation in animals with long-surviving hepatic allografts pretreated with either PVG.r1 or ACI whole blood. On the other hand, pretreatment with PVG(RT1c) blood increased the survival of ACI-to-LEW hepatic allografts only moderately compared with controls. This finding may be consistent with a partial effect of some third-party blood transfusion. The experimental data suggest that the class I MHC antigens can be immunosuppressive in rat hepatic allografts. Adoptive transfer of 5 x 10(7) splenocytes taken from long-term-surviving hepatic allografts pretreated with donor ACI whole blood or PVG.r1 blood into irradiated (750 rads) LEW rats prolonged the survival of donor-type skin grafts, whereas third-party strain (BN) grafts were rejected. This finding suggests the presence of donor-specific suppressor cells.
• Yamaguchi, Y., Harland, R., Wyble, C., Mori, K., & Bollinger, R. R. (1989). Variable allograft responses to pretreatment with donor splenocytes treated with mitomycin C in the rat. Transplantation, 47(2), 360-3.
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  In an attempt to investigate the nonspecificity of the effect of administration of donor splenocytes treated with mitomycin C (MMC) 7 days before transplantation in inducing immunological unresponsiveness, the survival rates of liver, heart, small bowel, and skin allografts were compared in the RT1-incompatible ACI(RT1a) to LEW(RT1l) rat combination. ACI donor splenocytes (3 x 10(6)) treated with MMC were administered i.p. or i.v. via the penile vein 7 days before transplantation. Both routes of administration prolonged the survival of hepatic allografts (greater than 87.2 +/- 22.2 days and greater than 78.9 +/- 28.2 days, respectively), compared with controls (10.6 +/- 0.5 days). Cardiac allograft survival in untreated controls was 6.0 +/- 0.4 days. A single i.v. injection of 3 x 10(6) donor splenocytes resulted in significantly prolonged survival (10.0 +/- 4.3 days), whereas i.p. injection showed rejection at a mean of 6.0 +/- 1.2 days. A single i.p. injection of 3 x 10(6) splenocytes did not increase survival of small bowel allografts (10.3 +/- 4.8 days), compared with controls (8.8 +/- 1.8 days). On the other hand, a single i.v. injection of donor splenocytes prior to transplantation significantly prolonged survival of small bowel allografts (13.4 +/- 3.5 days). No signs of graft-versus-host reaction (GVHR) were observed during these experiments. Neither a single i.p. nor a single i.v. injection of donor splenocytes resulted in prolonged survival of ACI-to-LEW skin allografts (6.3 +/- 0.8 days and 6.6 +/- 0.9 days, respectively), compared with controls (5.7 +/- 0.5 days). Interestingly, we confirmed the relative ease with which survival of hepatic allografts can be prolonged in the rat by donor antigen treatment alone, even in a strongly rejecting RT1-incompatible rat strain combination, in contrast to other organ allografts such as heart, small intestine, and skin. The discrepancy in survival of different organ allografts following pretreatment with donor splenocytes treated with MMC may be explained by a difference in the immunogenicity of the organs transplanted or other factors.
• Yamaguchi, Y., Harland, R., & Bollinger, R. R. (1988). Prolonged survival of hepatic xenografts in the hamster to rat combination: efficacy of cyclosporine in combination with splenectomy. Transplantation Proceedings, 20(1 Suppl 1), 731-3.
• Dickinson, R. G., Harland, R. C., Kaufman, S. N., Lynn, R. K., & Gerber, N. (1982). An osmotic explanation for valproic acid induced choleresis in the rat, dog and monkey. Arzneimittel-Forschung, 32(3), 241-7.
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  I.v. administration of sodium valproate (NaVPA), the sodium salt of 2-n-propylpentanoic acid, VPA, Depakene), to rats and dogs caused an immediate stimulation of bile flow, the magnitude and duration of which was dependent on the dose. In rats given 14C-erythritol, a linear relationship between biliary clearance of erythritol and bile flow indicated that the choleresis was canalicular, rather than ductular, in origin. Increased bile flow was not mediated through an enhanced output of bile acids. Bile produced during choleresis was lower in chloride and bicarbonate concentrations than equivalent bile from control rats given only saline i.v. This anion gap was more than compensated by the amount of VPA-glucuronide (anionic at physiological pH values) in the bile. A close linear relationship existed between the volume of additional bile produced and the amount of conjugated VPA excreted in the bile. The results support the hypothesis that VPA induces choleresis by the osmotic effects of transport of its metabolites across the canalicular membrane.
• Dickinson, R. G., Harland, R. C., Ilias, A. M., Rodgers, R. M., Kaufman, S. N., Lynn, R. K., & Gerber, N. (1979). Disposition of valproic acid in the rat: dose-dependent metabolism, distribution, enterohepatic recirculation and choleretic effect. The Journal of Pharmacology and Experimental Therapeutics, 211(3), 583-95.
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  A specific gas chromatographic assay has been developed for measurement of valproic acid (VPA) and its major conjugated metabolites. In rats given single intravenous doses, the decline in blood concentration of VPA was dose-dependent and followed first-order kinetics only at the lowest dose. The time required for the maximum concentration of VPA, after completion of the brief distribution phase, to decline by 50% was 11.7, 41 and 125 min at doses of 15, 150 and 600 mg of NaVPA per kg, respectively. A secondary increase in drug concentration, abolished by exteriorization of the bile, was observed in all intact rats with all doses. Some 45 to 55% of the dose appeared in the bile in 5 hr as VPA glucuronide. Urinary excretion of VPA glucuronide in intact animals accounted for 23 and 51% of the 15 and 150 mg/kg doses, respectively. Tissue distribution studies in rats sacrificed 20 and 90 min after dosage with [14C] NaVPA (150 mg/kg) showed that the drug concentration was highest in blood, moderate in liver, kidney, heart and lung and low in brain, fat, testis and skeletal muscle. During this interval the drug concentration declined in all tissues, whereas the total conjugated metabolites in the small intestine increased from 7 to 28% of the administered dose. The large intestine contained 30 times as much free drug as conjugate. Reabsorption of free VPA, released by hydrolysis of conjugate in the large bowel, accounted for the secondary rise in concentration of VPA observed in blood after single doses. The major urinary metabolites, VPA-glucuronide and 2-n-propylgutaric acid, were identified by gas chromatography/chemical ionization mass spectrometry. Sodium VPA caused a dose-dependent stimulation of bile flow, the magnitude and duration of which closely followed the blood concentration of VPA.
• Dickinson, R. G., Harland, R. C., Lynn, R. K., Smith, W. B., & Gerber, N. (1979). Transmission of valproic acid (Depakene) across the placenta: half-life of the drug in mother and baby. The Journal of Pediatrics, 94(5), 832-5.
• Gerber, N., Dickinson, R. G., Harland, R. C., Lynn, R. K., Houghton, L. D., Antonias, J. I., & Schimschock, J. C. (1979). Reye-like syndrome associated with valproic acid therapy. The Journal of Pediatrics, 95(1), 142-4.
• Dickinson, R. G., Harland, R. C., Rodgers, R. M., Gordon, W. P., Lynn, R. K., & Gerber, N. (1978). Dose dependent metabolism and enterohepatic recirculation of valproic acid in the rat. Proceedings of the Western Pharmacology Society, 21, 217-20a.
• Swanson, B. N., Harland, R. C., Dickinson, R. G., & Gerber, N. (1978). Excretion of valproic acid into semen of rabbits and man. Epilepsia, 19(6), 541-6.
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  Dipropylacetic acid (VPA, valproic acid) has been quantified in plasma and semen from rabbits and man using a new gas-liquid chromatographic assay. The drug assay is rapid, sensitive and free from interference by VPA metabolites. The beta phase half-life of VPA in rabbits after an i.v. dose (50 mg/kg) was 56 +/- 6 min. The concentration of VPA in rabbit plasma was 17 to 30 times the concentration in rabbit semen. In man, 500 mg doses of the free acid, p.o., resulted in VPA concentrations in plasma that were 11 to 17 times the concurrent levels in semen. VPA, in concentrations up to 10(-3) M, did not influence the motility of rabbit spermatozoa in vitro.

Presentations

• Harland, R. (2013, June 12). Access for Home Dialysis. Home Dialysis Regional Conference- SE Region. Greenville, NC: Davita.
• Harland, R. (2013, June 20-21). Gore Hybrid Stent Grafts. Gore Surgeon Training Course. Durham, NC: Gore.
• Harland, R. (2013, Nov 6). Kidney Disease and Diabetes: Understanding the Connection. 12th Annual Winning with Diabetes Symposium. Greenville, NC.
• Harland, R. (2011, June 2). Meeting the Challenges of Dialysis Access. Vascular Access Summit- SE Region. Wilmington, NC: Davita.
• Harland, R. (2009, April 30). Dual Kidney Transplantation. UNOS Region 7 Spring Collaborative Learning Session. Chicago, ILL: UNOS.
• Harland, R. (2009, May 5). Type 1.5 diabetes: The changing spectrum of diabetes. National Transplant Network Annual Clinical Update. San Diego, CA: Kaiser Permanente.
• Harland, R. (2008, Feb 11). Renal Dysfunction after Solid Organ Transplantation. American Society for Parenteral and Enteral Nutrition (ASPEN) Annual meeting. Chicago, IL: ASPEN.
• Harland, R. (2007, Oct 20). Pancreas Transplantation in 2007. American Academy of Pediatrics National Conference & Exhibition. San Francisco, CA.
• Harland, R. (2006, Aug 25). Recovery Techniques and Anatomy. NATCO Annual Meeting. Chicago, IL: NATCO.
• Harland, R. (2006, Feb 7). Teamwork: A Formula for Success. Leadership Development Institute. Chicago, IL: University of Chicago Academy.
• Harland, R. (2004, May 1). Transplantation for HIV+ Patients. Cigna National Transplant ConferenceCigna.
• Harland, R. (2005, April 9). State of Transplantation: 2005. National Kidney Foundation-Illinois Chapter/Living with TransplantNational Kidney Foundation.
• Harland, R. (2005, Nov 2). Sharing of Vessels for Extrarenal Organ Transplantation. Gift of Hope Procurement Forum.
• Harland, R. (2004, April 1). IVIG in Solid Organ Transplantation. Accredo Therapeutics National Sales MeetingAccredo Therapeutics.
• Harland, R. (2004, April 21). The Challenge of Transplanting the Sensitized Recipient. UNOS Region 7 Tri-annual Transplant ForumUNOS.
• Harland, R. (2004, Nov 11). What’s New in Pancreas Transplantation?. Kaiser Transplant NetworkKaiser.
• Harland, R. (2003, Aug 28). BK Polyomavirus in Transplantation. Southeast Organ Procurement Foundation Tri-Annual MeetingSoutheast Organ Procurement Foundation.
• Harland, R. (2003, July 23). BK Polyomavirus in Transplantation. Roche National Transplant Group Quarterly MeetingRoche.
• Harland, R. (2002, April 13). Living Happily Ever After With Your Transplant. National Kidney Foundation-Illinois Chapter/ Living with Transplant.
• Harland, R. (2002, March 11). What’s New in Kidney Transplantation?. Organ Transplant Support-Illinois.
• Harland, R. (2002, May 2). Expanding Donor Options for Kidney Transplantation. UNOS Region 7 Tri-annual Transplant ForumUNOS.
• Harland, R. (2002, Sept 22). Increasing the Kidney Donor Pool. United Resource Network Annual ConferenceUnited Resource Network.
• Harland, R. (2001, Feb 18). Steroid sparing regimens in transplantation. National Kidney Foundation-Illinois Chapter.
• Harland, R. (2001, May 18). Hand-assisted Laparoscopic Donor Nephrectomy. Transplant 2001-Annual Meeting of AST/ASTS.
• Harland, R. (1999, Nov 1). The Future: Xenotransplantation. Southeast Dialysis and Transplant Association Annual Meeting. New Orleans: Southeast Dialysis and Transplant Association.
• Harland, R. (1998, Feb 13). Barriers to Successful Xenotransplantation. Southeast Organ Procurement Foundation Tri-annual Meeting.
• Harland, R. (1998, May 21). Xenotransplantation. Southeast Organ Procurement Foundation Tri-Annual Meeting.

Others

• Harland, R., Klintmalm, G., Jensik, S., Yang, H., Bromberg, J., Holman, J., Anil Kumar, M., Santos, V., Larson, T., & Wang, X. (2018, June). Efficacy and Safety of Bleselumab in Kidney Transplant Recipients: A Phase 2, Randomized, Open-Label Study. American Transplant Congress.