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People in Transplantation

Holdaas, Hallvard MD, PhD

doi: 10.1097/TP.0000000000002658
In View: People in Transplantation
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You have worked for 30+ years at the National Center for Transplantation in Norway. What have been major milestones in your long career at one center?

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HH: A single national transplant center has allowed the rapid introduction of new immunosuppressants and the development of clinical trials. When I started out, there were a lot of trials assessing rejection rates and short-term graft outcomes in kidney transplant patients, comparing different immunosuppressive drugs and regimes. It surprised me that there were neither trials looking at cardiovascular outcomes nor large-scale patient outcome trials. This provided an opportunity to initiate randomized, controlled trials. We started out by looking at the effects of statins in 2 large double-blind randomized controlled trials, demonstrating that statins were safe and effective in the early posttransplant period (however, without affecting rejection rates). We observed that long-term statin therapy could reduce cardiovascular events, thus establishing the basis for statin treatment following renal transplantation.

In Norway, we were—through necessity—quick to adopt living donor transplantation, initially from related and later from unrelated donors and established registries and a thorough follow-up of living donors. We have recently shown that in the very long term, living donors have an increased risk (albeit a small absolute risk) for cardiovascular and all-cause mortality, and of developing end-stage renal failure. This has generated world-wide discussion and changed the information provided to potential donors while emphasizing on the importance of lifetime follow-up.

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The National Center in Oslo is the only Transplant center in the country. Norway has a distance from North to South of 1100 miles. What are challenges and opportunities?

HH: We have used a “hub and spoke” model with 24/7 ambulance service to retrieve organs over vast distances covering all of Norway. We have worked closely with 25 hospitals throughout Norway to perform pretransplant work-up for both recipients and potential living donors, thus increasing local “ownership” and an active participation in the transplant process. With collaborative efforts by local hospitals and the National Transplant Center, patients are either waitlisted for a deceased donor or scheduled for a living donor transplantation. When an organ is coming available for a waitlisted patient, the recipient is contacted via the local nephrologist and transported (mostly by air) to Oslo. Following transplantation, recipients stay in a specialized patient-hotel in Oslo for 8 weeks and are followed in our out-patient clinic. With “24/7” transplant surgeon availability, excellent laboratories for monitoring immunosuppression/opportunistic infections combined with state-of-the-art imaging and pathology services, this model is efficient and leads to a safe and superior early posttransplant surveillance that has provided excellent patient and graft outcomes. The close communication between the National Center and local hospital provides “readiness” for all patients, however remote, at the time of transplant. With all transplant recipients staying in Oslo for 8 weeks, we also have an opportunity to include patients into multiple randomized controlled trials and have thus laid a very solid groundwork for the future.

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Have you developed special techniques to follow patients living in remote areas after transplantation?

HH: After 8 weeks stay in Oslo, patients are followed by local hospitals that have developed solutions to monitor patients in remote areas. To date, most Norwegian doctors are “old-fashioned” and like to have regular face-to-face consultations. In the future, I foresee more consultations using electronic communications including Skype. We have also recently evaluated a novel Volumetric Absorptive Microsampling device for finger-prick capillary blood to measure Tac concentrations. This technique works perfectly, allowing a close correlation of Tac-trough levels measured at home with dosage adaptations. Currently, we are also looking into the possibility of monitoring mycophenolic acid, and other parameters using the Volumetric Absorptive Microsampling technology.

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The database of an entire country collected in one national hospital may offer unique opportunities. How have you utilized those data?

HH: The Registry was formally founded by the National Nephrology Association in 1985. All transplants since 1969 have been registered with complete and lifetime follow-up. We also have a separate living donor kidney registry going back to 1963, with a comparable follow-up. The primary intention of the registry is to ensure an optimal quality life-of-life and long-term health. Moreover, the complete data set provides excellent research opportunities. More than 30 PhD theses originate from Registry data with approximately 200 scientific publications.

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Early in your career you spend time as a Visiting Professor in Internal Medicine at the University of Iowa. What impact did this visit have on your career?

HH: I was granted a Fulbright Scholarship in 1982 to spend a year in Dr DiBona’s laboratory in Iowa City. I had a unique opportunity to expand on my earlier animal research in renal physiology. Moreover, the stay in Iowa allowed me to enjoy the American research culture and to meet international collaborators who have had a major impact on my career in subsequent years.

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You spent 10 years as a medical Consultant planning and building a new national Hospital in Oslo. One could envision this to be both, a dream or a nightmare. What were lessons that you have learnt from this time?

HH: Early on, it was certainly a “nightmare.” I was the medical coordinator and in collaboration with other clinicians responsible to structure the care in a new tertiary hospital in Norway—the Rikshospitalet. The first challenge was to reconcile space and manpower for each specialty. In any academic hospital, there are many strong “Kings on the hill” demanding space and manpower for their own “kingdom,” at times unrealistic or unachievable. The other challenge was a rather huge bureaucratic organization called “The Norwegian Directorate of Public Construction and Property” working on behalf of the Norwegian Government that had underestimated costs and requirement. We fought for a budget increase. Things got delayed by a few years, but at the end we had a beautiful and well-functioning hospital liked by patients and clinicians. An early large visiting group of Italian doctors told me: “Dr Holdaas this is not a hospital, it is an art gallery.”

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You have played a critical role in many multicenter trials. What have been the most exciting outcomes? What have been challenges?

HH: Compared with other Specialties, Renal Medicine, including Renal Transplantation, has the lowest number of randomized controlled trials. The predominant problem is recruitment of patients. Notably, the problem does not start with patients but rather with recruiting physicians, and the reluctance of Pharma to include subgroups of patients needed to reflect the clinical complexity. The trial must answer relevant scientific questions with a timely impact on clinical practice; the engagement of investigators needs to be encouraged—ideally by meeting “face to face.” More recently, Pharma support has been the “drying up” while administrative burdens imposed by Health Authorities have piled up. Particular exciting parts were the clinical statin trials (ALERT and SOLAR). Those trials initiated other larger trials in the dialysis population, such as AURORA and SHARP, and a multitude of trials with immunosuppressive drugs, most recently with mammalian target of rapamycin inhibitors. The ability to perform large trials in Nephrology and Transplantation that directly impacted patient care has been one of the most exciting parts of my career, regardless of trial outcomes.

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You have published on long-term outcomes of living donors. Where do you see the role of live donor kidney transplants in the future?

HH: Not only the health of a kidney donor but also the willingness to donate will be based on a long-term, ideally lifelong follow-up. I feel strongly that a limited follow-up, as practiced in some countries, is not compatible with living donor transplantation. Our studies were meant to encourage living donation while informing healthy, highly motivated, donors on risks and benefits.

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Genomic analysis in renal transplantation is another research interest. Where do you see translational potential?

HH: With whole exome sequencing available at reasonable costs provide opportunities for a more precise diagnosis. Risk of disease recurrence after transplantation may be elucidated (eg, hereditary vs idiopathic focal segmental glomerulosclerosis,), and one may rule out or reveal the genotype (and the risk of disease development) in a potential living kidney donor. Moving from Mendelian genetic causes of kidney disease to the study of genetic variation in the context of, for example, cardiovascular risk or risk of transplant failure, it is harder to envision the immediate application of genome-wide association study results in posttransplant care. Common variants investigated in genome-wide association study appear to have very modest effect sizes on clinical risk assessment. However, polygenic risk scores may prove to be useful biomarkers and may help to stratify patients within trials, allowing focused interventions.

Our group has recently reported on a cardiovascular risk score based on 27 single nucleotide polymorphisms in both a nontransplant as well as in a transplant cohort. Interestingly, the magnitude of effect ascribed to each individual single nucleotide polymorphism was quite different in transplant recipients compared with the original study population. Thus, polygenic risk scores require validation in the transplant population.

The field of epigenetics is also emerging as an intriguing novel research area. This area may fill knowledge gaps in understanding differences in transplant longevity and susceptibility to rejection. Recent studies have indicated that epigenetic modifications may have a role in mediating response to injury while determining fibrogenesis.

Whichever aspect of “transplantomics” we want to pursue, there is an obvious need for large international collaborations as large samples are necessary. Funding issues may become a limiting step, because there is limited immediate gain for pharmaceutical companies in sponsoring large-scale genetic initiatives in transplantation.

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Your professional life has certainly been very demanding. How do you like to spend your time outside of Medicine?

HH: Life outside medicine? Not an easy question with many opportunities for wonderful activities. The outdoors always had priority, time allowed. For the last 4–5 decades, wilderness hiking and hunting in remote mountain areas in the autumn with a well-trained dog as a companion has been compulsory. In summer, fishing in salmon rivers offers tranquility in a peaceful setting. During the winter time, downhill, but most of all cross-country skiing, hundreds of miles of tracks just a few minutes away from the city, or, as another alternative a few days mountain trekking. At home? Classical music and a good book, good food and fine wines.

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