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The handle
http://hdl.handle.net/1887/138013
holds various files of this Leiden
University dissertation.
Author: Bank, J.R.
Title: Early monitoring strategies in kidney transplant recipients
Issue date: 2020-11-10
Chapter 1
General introduction 9
In July 2020 the new organ donation law will become effective in the Netherlands. In this law every Dutch citizen above the age of 18 is considered to be a potential organ donor unless consent is actively withdrawn (opting-out)1. Nowadays, many people
haven’t registered their choices about organ and tissue donation and this law was introduced to encourage an active discussion and decision-making about organ dona-tion. This system has been set-up in order to overcome the shortage of suitable organs for transplantation. The introduction of this law has, however, also resulted in major debate across the country about the ‘obligation’ to donate and the question remains whether the end-results will indeed improve the ongoing organ shortage.
Organ shortage is not a problem restricted to the Netherlands, but a major world-wide issue. To illustrate the magnitude of the problem, in 2018 the waiting list in the United States included 113.350 patients who needed a (sometimes directly lifesaving) organ transplant, while only 36.530 organs were transplanted2. The majority of these
transplantations were kidney transplantations (21.247)3. As a comparison, in the
Netherlands 1159 patients were listed on the waiting list at the end of 2018, while a total of 817 deceased organ transplantations were performed, of which 488 were deceased kidney transplants. In case of kidney transplantation, we are increasingly relying on living kidney donation, nowadays the most frequent kidney transplant procedure performed in the Netherlands (510 in 2018)4. However, even with this high
proportion of living kidney transplants the supply remains inadequate to meet the increasing demands, resulting in long waiting times while on maintenance dialysis.
Living donor kidney transplantation is the preferred transplant option, because these patients can be transplanted pre-emptive, i.e. before the initiation of dialysis. Pre-emptive transplantation is associated with better kidney graft as well as patient survival, improved quality of life and lower socio-economic costs5. Unfortunately, a
potential living donor may not be available for every patient with or approaching end-stage renal failure. In this case a kidney from a deceased donor is the remaining option, for which donors can be distinguished in donation after brain death (DBD) and donation after circulatory death (DCD). In case of circulatory death, blood circulation is stopped leading to an oxygen deficit in the nonperfused organs and ischemic dam-age of the kidney. This process also plays a role in the DBD kidney donation procedure but to a lesser extent. DCD kidneys generally have more extensive ischemic damage and are therefore more vulnerable to additional reperfusion injury as compared to kidneys obtained from DBD donors6,7.
In order to meet the increasing demands for kidney donors, accepting criteria are increasingly stretched. As such it is inclined to accept kidneys which are considered not optimal, for example from older patients or patients with a history of diabetes and/or hypertension8. These suboptimal kidney donors have long been called
10 Chapter 1
more or less been abandoned after the introduction of the so-called kidney donor risk index (KDRI). The KDRI was developed in order to estimate graft survival based on the most relevant available pre-implantation donor characteristics, including DCD dona-tion procedure but also age, height, weight, ethnicity, stroke, hypertension, diabetes mellitus, hepatitis C virus and estimated donor kidney function9.
Early complications after transplantation
DCD kidney transplant recipients have an increased risk of early complications post transplantation such as acute rejection and delayed graft function (DGF). The incidence of acute rejection within the first year after transplantation is higher for deceased donation, as compared to living donation10,11. Besides deceased donation,
there are several other risk factors for acute rejection that play a role in the early post-transplant period, including the presence of (preformed) donor specific anti-bodies (DSAs) against ‘human leucocyte antigens’ (HLA) and elevated panel reactive antibodies (PRA). In order to reduce the risk of acute rejection, HLA matching between the kidney donor and recipient should be optimal. Furthermore, depending on the anticipated immunological risk, induction therapy using interleukin-2 receptor block-ing antibodies (IL2-RB) or T-lymphocyte deletblock-ing antibodies are infused at the time of transplantation.
Standard induction therapy for kidney transplant recipients in most centers world-wide (including our center) is Basiliximab, a chimeric antibody directed against (part of) the IL2-receptor. Patients with a relatively high risk of acute rejection receive in-duction therapy with depleting antibodies, such as Alemtuzumab or Anti-Thymocyte Globulin (ATG). Large prospective studies have documented lower acute rejection rates with both strategies12-14. However, because of the significant differences in side
effects, induction therapy with depleting antibodies is reserved for the high(er) risk kidney transplant recipients.
With the more frequent use of DCD donors, DGF has also become increasingly prevalent11,15 . DGF results in longer hospitalization and higher transplantation costs16.
The impact of DGF on the long-term is still a debate. Some studies reported that DGF negatively affected long-term outcome parameters, whereas others found no such relationship16-20. The principal cause of the clinical syndrome called DGF is ischemic
injury to the kidney during organ procurement and preservation, which is further aggravated after reperfusion, the so-called ischemia and reperfusion injury (IRI). IRI results in extensive loss of both endothelial and tubular epithelial cells, of which the latter are primary responsible for the absorption and excretion of glucose, amino ac-ids and several other biochemical substances. In renal biopsies this finding is referred to as ‘acute tubular necrosis’, and is considered to be a histological hallmark of IRI21.
General introduction 11
Monitoring strategies
A sensitive and specific biomarker to monitor the occurrence of an acute rejection episode or (the resolution of) DGF is unfortunately not available to date. For a definite diagnosis, a kidney allograft biopsy remains the so-called ‘golden standard’. A per-cutaneous kidney biopsy is, however, an invasive procedure with a principal risk of complications and the potential of sampling errors. As an alternative, to monitor all functioning nephrons, nuclear imaging with a 99m
Technetium-mercaptoacetyltrigly-cine (99mTc-MAG3) renography has been used. This diagnostic method allows
simul-taneous assessment of kidney perfusion, overall tubular extraction and excretion of the isotope by the transplanted kidney22. Unfortunately, this is a time-consuming and,
in clinical practice, semi-quantitative method and patients are repeatedly exposed to radiation22.
Guidance in daily clinical practice by a simple but reliable marker is needed, and can help to monitor regular resolution of DGF and/or identify intercurrent problems such as acute rejection episodes. Such a marker may potentially reduce the medical need and risks of invasive diagnostic procedures including repeated nuclear imaging and renal allograft biopsies. In clinical practice, classical biomarkers such as serum creatinine and urinary output are not sensitive enough. Serum creatinine lacks specificity for tubular injury and serum values increase relatively late after the initial insult or its resolution, whereas urinary output is of limited value in patients with residual diuresis and kidney function23,24. Because of these limitations, other
biomark-ers have been proposed to be of interest, including kidney injury molecule -1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), Interleukin-18 (IL-18), Cystatin C, liver-type fatty-acid binding protein (L-FABP), Tissue inhibitor of metalloproteinases 2 (TIMP-2) and Insulin-like growth factor-binding protein 7 (IGFBP7)25,26. In addition,
an alternative approach in the search for novel biomarkers may be a proteomic, or metabolomic strategy, studying the urinary (small molecule) substrates and products of altered metabolism27.
Aims and outline of this thesis
Identification of risk factors are crucial in the prevention of DGF and acute rejection. Furthermore, being able to predict DGF and the duration of DGF would allow us to adjust patient management and may eventually contribute to the development of new treatment strategies. In the current thesis we investigated risk factors of acute rejection and DGF. In addition, the most promising biomarkers of kidney injury ac-cording to current literature (i.e. KIM-1, NGAL, TIMP-2, IGFBP7) were investigated in the prediction of DGF. These biomarkers were determined in urine, serum and renal biopsies.
12 Chapter 1
In chapter 2 we used the demographics, clinical characteristics, outcome param-eters as well as body fluids from a cohort of simultaneous pancreas and kidney trans-plant recipients to investigate the incidence and timing of acute rejections early post transplantation in patients receiving either ATG or Alemtuzumab induction therapy. Acute rejections occurring after Alemtuzumab induction were studied more exten-sively, including composition and alloreactivity of lymphocytes at time of rejection, doses of immunosuppressants and actual Alemtuzumab plasma levels.
In chapter 3, the presence, localization and distribution of the biomarkers KIM-1 and NGAL in 64 renal allograft biopsies derived from prospectively followed cohort of DCD kidney transplant recipients was studies. Subsequently, their association with DGF was assessed. Finally, in order to obtain more detailed insights into the kinetics, localization and distribution of KIM-1 and NGAL, immunohistochemical stainings were performed in a rat model of IRI.
In chapter 4, in a cohort of DCD kidney transplant recipients, the impact of DGF on 1- and 5-year renal allograft function was studied. In addition, risk factors for DGF and prolonged duration of DGF were evaluated. Subsequently, the predictive values of the tubular function slope (TFS) (a marker derived from a 99mTc-MAG3 renography) and
fractional excretion of NGAL in DGF and prolonged duration of DGF were compared. In chapter 5 we investigated the kinetics of the recently discovered biomarkers TIMP-2 and IGFBP7 in the first 10 days after transplantation and analyzed the diagnos-tic utility for predicting DGF and prolonged duration of DGF (>21 days).
In chapter 6 we used an alternative approach in the search for biomarkers by ana-lyzing smaller molecules with Nuclear Magnetic Resonance (NMR) spectroscopy. With this method we investigated the metabolic changes in urine from 10 days until 1 year after transplantation in the same cohort of DCD transplant recipients.
In chapter 7 a general discussion of the reported studies is described within a broader view of recent literature and future perspectives.
General introduction 13
1. Reinders MEJ, Reiger-van de Wijdeven J, de Jonge J, Haase-Kromwijk B. Dutch Law Ap-proves Opt-out System. Transplantation. 2018;102(8):1202-1204.
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3. Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2018 Annual Data Report: Kidney. American
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4. Stichting NT. Jaarverslag 2018. https://www.transplantatiestichting.nl/files/bestanden/ NTS%20Jaarverslagen%202000-nu/nts-jaarverslag-2018.pdf ?dc33543cbd. Published 2018. Accessed 29-01-2020.
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7. Schaapherder A, Wijermars LGM, de Vries DK, et al. Equivalent Long-term Transplanta-tion Outcomes for Kidneys Donated After Brain Death and Cardiac Death: Conclusions From a Nationwide Evaluation. EClinicalMedicine. 2018;4-5:25-31.
8. Peters-Sengers H, Berger SP, Heemskerk MB, et al. Stretching the Limits of Renal Trans-plantation in Elderly Recipients of Grafts from Elderly Deceased Donors. J Am Soc Nephrol. 2017;28(2):621-631.
9. Rao PS, Schaubel DE, Guidinger MK, et al. A comprehensive risk quantification score for deceased donor kidneys: the kidney donor risk index. Transplantation. 2009;88(2):231-236. 10. Singh RP, Farney AC, Rogers J, et al. Kidney transplantation from donation after cardiac
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Clini-cal transplantation. 2011;25(2):255-264.
11. Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2012 Annual Data Report: kidney.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2014;14 Suppl 1:11-44.
12. 3C Study Collaborative Group HR, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014;384(9955):1684-1690.
13. Hwang SD, Lee JH, Lee SW, et al. Efficacy and Safety of Induction Therapy in Kidney Transplantation: A Network Meta-Analysis. Transplantation proceedings. 2018;50(4):987-992. 14. van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmaco-kinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation.
Clin Pharmacokinet. 2018;57(2):191-207.
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14 Chapter 1
18. Marcen R, Orofino L, Pascual J, et al. Delayed graft function does not reduce the survival of renal transplant allografts. Transplantation. 1998;66(4):461-466.
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