Leendert C. Paul, M.D. (1946–2004)

Leendert (Leen) C. Paul, an internationally recognized physician and scientific investigator, passed away on July 16, 2004 at an age of 58 years. Leen dedicated a major part of his life to elucidating the mechanisms underlying chronic allograft nephropathy. He had a major impact on the classification of renal biopsy parameters to distinguish different types of renal transplant rejection. Leen’s work in the early days focused on the translation of findings in patients to experimental models to study the mechanisms, mainly focused on the evaluation of chronic transplant rejection. Although it is impossible to detail his many contributions, each is a reflection of the person that he was and the way he preferred to live his life. He enjoyed being with his colleagues and had a leading role in conversations with much humor. Leen Paul received his M.D. degree in 1972 and continued his training in internal medicine and nephrology at Leiden University, The Netherlands. In 1979, he defended his Ph.D thesis, which dealt with the presence and significance of antibodies reactive with various cell types in renal allografts (1). From 1979 to 1981, he completed postdoctoral training at the Peter Bent Brigham Hospital in Boston under the leadership of Dr. C.B. Carpenter, focusing on the development of an immunogenetic model in the rat for the nonmajor histocompatibility complex (MHC) endothelial/monocyte antigen system. Transplantation of MHC-identical, but endothelial antigen incompatible, kidneys into naïve recipients did not result with acute rejection. However, prior (repeated) immunization with monocyte-containing lymphoid tissue produced an antibody response in some combinations; this response was associated in accelerated acute rejection together with deposition of IgG antibodies on the peritubular capillary endothelium (2). This model was identical in a number of aspects with that seen in human cases, as observed in the early days of clinical immunosuppression in HLA-identical living donor kidney transplants exhibiting clear signs of vasculitis in their biopsy specimen. His experience with models of experimental renal transplantation lead Dr. Paul to focus his later work on the model of chronic renal rejection in the Fisher (F344) to Lewis (LEW) model. Transplantation of kidneys from F344 to LEW rats clearly leads to the generation of an immune response against the transplanted kidney. Interestingly, the reverse transplantation of Lewis kidneys to Fisher rats does not lead to a significant response against kidney antigens. Extensive proteomic analysis of the antigens involved in the Fisher kidneys revealed that a major component of the response is directed towards antigens in the glomerular basement membrane, including perlecan and the α1-chain of collagen type IV in association with the α5-chain of collagen type IV (3). In the same model, telomere shortening and the induction of replicative senescence seem to be involved (4). In 1981, Dr. Paul returned to Leiden to take up his career in medicine as supervisor of the renal transplantation unit. However, because he had enjoyed his stay in Boston so much, in 1987 he decided to move to Canada, where he was appointed Professor of Medicine at the University of Calgary and Head of Nephrology at the Foothills Hospital. At the same time, he was a part-time teaching professor at the Free University in Brussels for six years. In 1993, he was working as Division Chief of Nephrology at St. Michael’s Hospital and was named the first Keenan Professor at the University of Toronto. Using the tubular micropuncture technique, he conducted hemodynamic studies in animal models of (chronic) allograft vasculopathy and reported on the beneficial effect of administering antihypertensive drugs (5) as an additional method of treatment of allograft nephropathy. In yet another report, he described the beneficial effects of mycophenolate mofetil in protection of rats from ischemia/reperfusion injury (6). Dr. Paul’s clinical experience in renal transplantation and his many studies on experimental models of (chronic) renal transplantation shaped and sharpened his views on the pathobiology of chronic renal transplant rejection. He summarized his intriguing thoughts and views in a number of excellent reviews (7–9) that have a clear impact on the field of transplantation today. In 1998, Dr. Paul returned to Leiden as Chairman of the Department of Nephrology and continued to conduct both human and experimental research. An analysis of renal grafts from deceased donors for delayed function showed that older age of the donor and low blood pressure in the recipient were most commonly associated with the occurrence of delayed graft function (DGF); although DGF was associated with inferior glomerular filtration rate (GFR), there was no independent effect on graft survival (10). Two main issues have been identified with the increased incidence of acute interstitial rejection as compared with kidneys from younger donors; secondly, once an interstitial rejection episode occurs, the ability to mount a tissue repair process seems to be impaired (11). The experimental studies using the Fisher to Lewis model in rats for the first time implicate a number of defined molecules that may play a role in chronic transplant rejection. Lenn’s insight into the generation of antibodies reactive with specific antigens upon transplantation allows more detailed studies to elucidate the mechanisms underlying chronic transplant rejection and to explain the occurrence of DGF. If antibody testing turns out to be a reliable predictor for graft loss, early monitoring might allow early interventions and thereby prolongation of allograft survival. While currently most therapies of DGF are directed towards T cells, inhibition of B cell activity and prevention of generation of antibodies against specific graft antigens may be an option. At the time of his death, Dr. Paul had just retired from his chairmanship of the Department of Nephrology at the Leiden University Hospital, The Netherlands. He stayed active, even though he was hindered in his physical mobility, by supervising young colleagues, and writing and finalizing a number of reviews on topics that intrigued him until the last days of his life. As he expected his death to come sooner or later, he arranged his farewell in a fashion that completely fitted his own wishes and thoughts. During his career, Dr. Paul occupied several professional and honorary positions. A partial list includes: President of the Canadian Society of Nephrology, Chairman of the Biomedical Research Council (Kidney Foundation of Canada), and Chair of the Training and Manpower Committee (American Society of Transplant Physicians). He served on several editorial boards and was Editor-in-Chief of Transplantation Reviews. His contributions to the field of transplantation are numerous, including three textbooks. In recognition of his scientific achievements, Dr. Paul was honorary member of the Transplantation Society of Southern Africa, as well as of the Transplantation Society of the Netherlands. In 2003, Dr. Paul retired prematurely from his position as Director of Department of Nephrology at the Leiden University Medical Center. At his farewell symposium, many of his friends from around the world were present, and they participated actively in the symposium held in his name. He was honored by the Kidney Foundation of Canada with the “Dr. Leen Paul Fellowship.” During his farewell symposium, surrounded by his friends and colleagues, he received a high Dutch royal decoration. Dr. Paul has made many novel scientific contributions to nephrology and to the field of transplantation in particular. His mentorship, personal warmth, and characteristic humor will be remembered by all of us. Leen was a true friend and a loyal colleague, and it was our pleasure and privilege to know him and work closely with him. Unfortunately, there was too little time to bring all ideas that Leen Paul had in mind to conclusion.FigureMohamed R. Daha Johan W. de Fijter Department of Nephrology Leiden University Medical Center Leiden, The Netherlands

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