International comparison of trends in kidney transplantation rates and transplant recipient characteristics in Europe between 2008 and 2017

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International comparison of trends in kidney transplantation rates and

transplant recipient characteristics in Europe between 2008 and 2017

Master thesis November 2019 - June 2020 Author Rosalie Tuinhout Student number: 10984437 Email: r.e.tuinhout@amsterdamumc.nl Mentors Dr. Vianda Stel

Senior epidemiologist ERA-EDTA Registry Email: v.s.stel@amsterdamumc.nl

Rianne Boenink MSc. PhD student ERA-EDTA Registry Email: r.boenink@amsterdamumc.nl

Tutor

Prof. dr. Kitty Jager

Director and senior epidemiologist ERA-EDTA Registry Email: k.j.jager@amsterdamumc.nl

Location of the Scientific Research Project

ERA-EDTA Registry

Department of Medical Informatics Amsterdam UMC, location AMC Meibergdreef 15

1105 AZ Amsterdam The Netherlands

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transplantation by primary renal disease ... 78 G.7 Preemptive kidney transplant recipient with transplant overall counts by primary renal disease ... 79 G.8 Preemptive kidney transplant recipient with transplant from deceased kidney donor counts by primary renal disease ... 79 G.9 Preemptive kidney transplant recipient with transplant from living kidney donor counts by primary renal disease ... 80

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List of abbreviations

Abbreviation Term

CKD Chronic kidney disease

eGFR Estimated Glomerular Filtration Rate

ERA-EDTA European Renal Association – European Dialysis and Transplant Association

ESKD End-stage kidney disease

GODT Global Observatory on Donation and Transplantation

IQR Interquartile range

MAPC Mean annual percentage change

PKT Preemptive kidney transplantation

PMP Per million population

PRD Primary renal disease

RRT Renal replacement therapy

SD Standard deviation

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Nederlandse samenvatting

Achtergrond. In Europa bestaan grote verschillen in het aantal uitgevoerde niertransplantaties met

nieren afkomstig van zowel alle nierdonoren als wel van levende en overleden nierdonoren. Het doel van deze studie is het in kaart brengen van trends in het aantal uitgevoerde niertransplantaties en karakteristieken van de ontvangers van niertransplantaties in verschillende Europese landen.

Methode. Twintig Europese landen met nationale of regionale nierregistraties die individuele

patiëntdata of geaggregeerde data aanleveren aan de European Renal Association-European Dialysis en Transplant Association (ERA-EDTA) registratie en 14 Europese landen die data aanleveren aan de Global Observatory on Donation and Transplantation database tussen 2008 en 2017 deden mee aan deze studie over trends in uitgevoerde niertransplantaties. Elf Europese landen die individuele patiëntdata aanleveren aan de ERA-EDTA Registratie deden mee aan de studie over trends in de karakteristieken van de ontvangers van de getransplanteerde nieren. Trends werden geanalyseerd met Joinpoint regressie en gerapporteerd als het verschil in het gemiddelde jaarlijkse percentage verandering (MAPC) met een 95% betrouwbaarheidsinterval (CI). Frequentieverdelingen werden gebruikt om de trends in leeftijd, geslacht en oorzaken van de nieraandoening onder ontvangers van niertransplantaties te analyseren.

Resultaten. Tussen 2008 en 2017 steeg in Europa het jaarlijks aantal uitgevoerde niertransplantaties

significant met 2.7% (95% CI: 0.7, 4.2). Tussen Europese landen was een groot verschil in de trend in het aantal uitgevoerde niertransplantaties zichtbaar. In Litouwen (MAPC 6.3%, 95% CI: 1.1, 11.7) en Finland (MAPC 5.6%, 95% CI: 3.7, 7.5) was de grootste stijging zichtbaar in het aantal uitgevoerde niertransplantaties terwijl Duitsland (MAPC -4.6%, 95% CI: -6.2, -3.0) een daling vertoonde. Dit verschil komt voornamelijk door het aantal uitgevoerde niertransplantaties van overleden donoren in oost Europese landen en door niertransplantaties van levende donoren in west Europese landen. Het aantal uitgevoerde preemptive niertransplantaties in Europa steeg jaarlijks significant met 6.5% (95% CI: 4.9, 7.7). Denemarken (MAPC 14.5%, 95% CI: 10.4, 18.7) en Spanje (MAPC 9.3%, 95% CI: 7.1, 11.6) vertoonden de hoogste stijging in preemptive niertransplantaties terwijl Noorwegen het enige land was met een significante daling (MAPC -2.4%, 95% CI: -4.8, -0.0). Tussen 2008 en 2017 was er een significante stijging in het percentage mannen (MAPC 0.3%, 95% CI: 0.1, 0.4) dat een niertransplantaat ontving en in de gemiddelde leeftijd van de ontvanger (MAPC 1.3%, 95% CI: 0.4, 2.2). Deze stijging was voornamelijk zichtbaar bij niertransplantaties van overleden donoren. Wanneer gekeken wordt naar verschillende nieraandoeningen als primaire nierziekte was een significante stijging zichtbaar in het percentage ontvangers met diabetes mellitus (MAPC 1.3%, 95% CI: 0.4, 2.1) en hoge bloeddruk (MAPC 1.5%, 95% CI: 0.6, 2.5) terwijl een significante daling zich voordeed in het percentage ontvangers met glomerulonefritis (MAPC -0.9%, 95% CI: -1.6, -0.3) en alle overige oorzaken (MAPC -0.5%, 95% CI: -0.7, -0.3). Voor zowel ontvangers van niertransplantaties met diabetes mellitus, hypertensie als glomerulonefritis was een stijging in het aantal niertransplantaties van overleden donoren zichtbaar terwijl een daling zichtbaar was onder ontvangers van niertransplantaties met alle overige oorzaken als primaire nierziekte.

Conclusie. Dit Europese overzicht laat een stijgende trend in uitgevoerde niertransplantaties zien

voor Europa als geheel, maar ook dat er grote verschillen bestaan tussen Europese landen. In de karakteristieken van de ontvangers van de niertransplantaties is een stijgende trend zichtbaar voor leeftijd, het percentage mannen en het percentage patiënten met diabetes mellitus en hypertensie als primaire nierziekte en een dalende trend voor glomerulonefritis en alle andere oorzaken van de nieraandoening. De resultaten van dit onderzoek kunnen mogelijk succesvolle initiatieven voor het verhogen van het aantal donoren in een land identificeren en de beleidsmakers een richting geven voor toekomstige initiatieven.

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English summary

Background. Within Europe, large differences exist in the overall rates of performed kidney

transplantations as well as in those from living kidney donors and deceased kidney donors. The main aim of the study is to examine time trends in kidney transplantation rates as well as in characteristics of kidney transplant recipients in different European countries.

Methods. Twenty European countries with national or regional renal registries providing individual

patient data or aggregated data to the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry and fourteen European countries providing data to the Global Observatory on Donation and Transplantation database between 2008 and 2017 were included in the study on time trends in kidney transplantation rates. Eleven European countries that deliver individual patient data to the ERA-EDTA Registry participated in the study on trends in characteristics of the kidney transplant recipients. Time trends were studied with Joinpoint regression and reported as mean annual percentage change (MAPC) with 95% confidence intervals (CI). Absolute counts and percentages were used to analyze the trends in age, sex, and primary renal disease (PRD) groups of the kidney transplant recipients between 2008 and 2017.

Results. Between 2008 and 2017, the trend in overall kidney transplantation rate significantly

increased by 2.7% (95% CI: 0.7, 4.2) annually. There were major differences between European countries. In Lithuania (MAPC 6.3%, 95% CI: 1.1, 11.7) and Finland (MAPC 5.6%, 95% CI: 3.7, 7.5), the trend in kidney transplantation rate increased the most whereas Germany (MAPC -4.6%, 95% CI: -6.2, -3.0) showed a decreasing trend in kidney transplantation rate. When looking at the donor types, this increase was mainly explained by deceased kidney donors in eastern European countries and by living kidney donors in western European countries. The preemptive kidney transplantation (PKT) rate significantly increased by 6.3% (95% CI: 4.9, 7.7) annually. In Denmark (MAPC 14.5%, 95% CI: 10.4, 18.7) and Spain (MAPC 9.3%, 95% CI: 7.1, 11.6) the highest significant increase in PKT occurred whereas Norway was the only country with a significant decrease in PKT rate (MAPC 2.4%, 95% CI: -4.8, -0.0). Between 2008 and 2017, a significant increase occurred in the percentage of males receiving a kidney transplant (MAPC 0.3%, 95% CI: 0.1, 0.4) and for the median age of the kidney transplant recipients (MAPC 1.3%, 95% CI: 0.4, 2.2). This increase was mainly explained in the group of deceased kidney donor transplantations. When looking at different PRD-groups, a significant increase occurred in the percentage of kidney transplant recipients with diabetes mellitus (MAPC 1.3%, 95% CI: 0.4, 2.1) and hypertension/renal vascular disease (MAPC 1.5%, 95% CI: 0.6, 2.5) as PRD whereas a significant decrease in the percentage of kidney transplant recipients with glomerulonephritis (MAPC 0.9%, 95% CI: 1.6, 0.3) and all other causes (MAPC 0.5%, 95% CI: 0.7, -0.3) occurred. Kidney transplant recipients with diabetes mellitus, hypertension/renal vascular disease, and glomerulonephritis as PRD and a transplant from a deceased kidney donor experienced an increase in kidney transplantation rate, whereas kidney transplant recipients with all other causes as PRD experienced a decrease in kidney transplantation rates from deceased kidney donors.

Conclusion. This European overview shows an increasing trend in kidney transplantation rates for

Europe as a whole with substantial differences between European countries between 2008 and 2017. The trend in characteristics of the kidney transplant recipients shows an increase in the age and the proportion of male kidney transplant recipients. Kidney transplantation rates among kidney transplant recipients with diabetes mellitus and hypertension/renal vascular disease significantly increased, though the kidney transplantation rate among kidney transplant recipients with glomerulonephritis and all other causes decreased. The results of this research might be useful for identifying successful attempt to increase the donor pool which hopefully guide the medical community and policymakers on how and where to focus new strategies on.

Keywords: kidney transplantations, kidney transplant recipients, Europe, trends, primary renal

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1. Introduction

1.1 Kidney transplantation as renal replacement therapy for end-stage kidney

disease

Research has confirmed that kidney transplantation has better patient survival and quality of life compared to dialysis [1-3]. Within Europe, large differences exist in the overall rates of performed kidney transplantations as well as in those from living kidney donors and deceased kidney donors [4]. For two-thirds of the European countries, the 2017 overall transplant rate was below 50 per million population (pmp) with the lowest transplant rate in Ukraine (3 pmp, N = 112) and the highest transplant rate in Spain (70 pmp, N = 3269). The highest 2017 transplant rates from living kidney donors were in the Netherlands (30.6 pmp) [4, 5] and the lowest in Serbia (3.2 pmp) and Romania (3.2 pmp) [4]. Also, the 2017 transplant rate from deceased kidney donors in all countries combined was 23 pmp, with Spain (63 pmp) leading followed by Croatia (50 pmp) and France (47 pmp). On the other hand, deceased donor transplant rates in Georgia, Ukraine, and Bosnia and Herzegovina were the lowest with 1 pmp [4].

Even though preemptive kidney transplantation (PKT) has a better outcome in long-term patient and graft survival, only five percent of the patients receive kidney transplantation as their first renal replacement therapy (RRT) [4, 6-9]. Although PKT rates can be obtained from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry for many years for countries that provide individual patient data, PKT rates for countries providing aggregated data to the ERA-EDTA Registry are only known since 2016 [4, 10].

National and international renal registries publish annual data on kidney transplant counts and rates. To date, no overview of international time trends in overall, living kidney donor, deceased kidney donor, and preemptive kidney transplantation rates as well as characteristics of the kidney transplant recipient is available [5].

1.2 International time trends in kidney transplantation rates

Within Europe, countries face different barriers that play a role in the access to kidney transplantation [11-27]. In the past decade, Europe is faced with a rapidly growing active waiting list for kidney transplantation while the number of available donor kidneys stayed basically the same [28]. Therefore, the transplant community searched actively for initiatives to increase the living kidney and deceased kidney donor pool [5, 27, 29-35]. Initiatives have focused on for example the extension of the allocation criteria to decrease the number of discarded donated kidneys, giving elderly kidney transplant recipients better chances to receive kidney transplantation, and making better matches between recipient and donor [36-42]. Also, countries have changed their laws and regulations concerning deceased donors from an opt-in to an opt-out policy (i.e. presumed consent) [43]. Early adopters of this initiative are Spain (1979) [44], Austria (1982) [45], and Belgium (1986) [46] followed by the United Kingdom (2020) [47] and the Netherlands (2020) [48].

Identification of time trends in the overall kidney transplant rates as well as those from living kidney donors, deceased kidney donors, and PKT in each country might reveal successful attempts that increased the number of kidney transplantations from both living kidney donors and deceased kidney donors. Also, it might guide the medical community and policymakers on how and where to focus on new strategies to increase the number of patients with end-stage kidney disease (ESKD) that can be treated with kidney transplantation.

1.3 International time trends in characteristics of kidney transplant recipients

Not only the donor pool is changing over time, but also the recipient characteristics may change over time. Research has shown that the change in age of the kidney transplant recipient is one of the

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9 more noticeable changes of the last few years [49-51]. Furthermore, insufficient research has been done on time trends in primary renal disease (PRD) and sex of the kidney transplant recipient. Changes in PRD might be expected as the disease spectrum in the general population is changing [49, 51-54].

Except for age, there is no overview of international time trends in the characteristics of the kidney transplant recipients. Insight in these time trends will show if, over time, healthcare professionals have changed the profile of kidney transplant recipients for offering kidney transplantation as RRT.

1.4 Rationale and research objectives

At this moment, there is no overview of international time trends in kidney transplantation rates and of characteristics of transplant recipients in Europe as a whole and no comparison among European countries. Therefore, we compared time trends in (i) the overall kidney, preemptive kidney, living kidney donor, and deceased kidney donor transplantation rates in Europe as a whole and in different European countries from 2008 to 2017 and (ii) characteristics of kidney transplant recipients in Europe from 2008 to 2017, for overall, preemptive, living, and deceased kidney transplantation.

1.5 Aim and research questions

The main aim of the study is to examine time trends in kidney transplantation rates as well as in characteristics of kidney transplant recipients in different European countries. To achieve the aim the following research questions were formulated:

 What are the time trends in the overall kidney, preemptive kidney, living kidney donor, and deceased kidney donor transplantation rates in Europe as a whole and in different European countries from 2008 to 2017?

 What are the time trends in characteristics of the kidney transplant recipients in Europe as a whole from 2008 to 2017, overall and in recipients of preemptive kidney transplants and in those receiving kidneys from living kidney donors or deceased kidney donors?

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2. Preliminaries

2.1 The kidney

One of the twelve human organ systems is the urinary system [55]. It consists of the kidneys, the ureters, the urinary bladder, and the urethra. The kidneys are located in the upper abdominal area protected by the 11th and 12th rib. The main function of the kidneys is cleansing blood and producing urine.

The kidney consists of multiple nephrons that are involved in urine formation [55, 56] (Figure 1). The renal artery delivers blood to the glomerular capsule also known as Bowman’s capsule in the nephron of the kidney. As Figure 2 shows, the glomerular capsule is the shell that protects the glomerular capillaries. The osmotic pressure in the glomerular capsule determines the net filtration pressure (NFP) which mostly determines the Glomerular Filtration Rate (GFR). The GFR represents the number of milliliters filtrate formed per minute (ml/min) when no other physiological process is changed. An increase in GFR results in more urine production and vice versa. All together, they are responsible for the excretion of fluids (pre-urine) from the glomerular capillaries also known as glomerular filtration. The pre-urine is moving through the renal tubule towards the nephron loop. During this movement tubular reabsorption and tubular secretion take place. Tubular reabsorption is responsible for reclaiming essential ions (sodium, calcium, magnesium, and potassium), nutrients (glucose, vitamins, and amino acids), and water in the Proximal Convoluted Tubule (PCT), and tubular secretion for collecting the last waste of the highly concentrated fluid and move it towards the urine in the Distal Convoluted Tubule (DCT).

Figure 1 Nephron with blood vessels. Arrows indicate the direction of blood flow. Marieb, Elaine N.;

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Figure 2 (a) The glomerular capsule inside a nephron demonstrating the three major renal processes.

(b) Determination of the net filtration pressure. Calculated by the outward pressure (HPg) minus the

Reprinted by permission of Pearson Education, Inc., New York, New York. (Marieb, 2013: P.963-964) [55].

The process behind tubular extraction and tubular secretion in the nephron loop is also influencing the osmotic pressure [55, 56]. The reabsorption of water and sodium increases the osmotic value of the pre-urine extremely. In the DCT the sodium-potassium pump is responsible for the reabsorption of sodium and secretion of excess potassium by the hormone aldosterone. In the last phase of the DCT, aquaporins determine the volume of water that is reabsorbed under influence of the antidiuretic hormone. Afterwards, everything that remains in the tubule becomes urine.

2.2 Chronic Kidney Disease

Chronic kidney disease (CKD) is defined by an imbalance of ions, nutrients and water absorption and secretion in the kidneys [55, 57]. As a result, damage to the nephron causes big proteins like albumin to end up in the urine. Although medication and lifestyle changes can delay symptoms, complications, and progression of CKD, a decrease in kidney function is not reversible. Risk factors for the cause of CKD are diabetes mellitus (type I and II), hypertension, multiple kidney infections and an increase in age [52, 55, 58].

According to the Kidney Disease Outcomes Quality Initiative (KDOQI), CKD is divided into five stages (Figure 3) [57, 59]. Division into one of the five stages is usually based on the estimated Glomerular Filtration Rate (eGFR) expressed in ml/min/1.73m2 and Albumin-to-Creatinine Ratio (ACR) [57, 60-62]. Determination of the eGFR is based upon the serum creatinine level assessed twice with an interval of three months. When both of the measurements lead to an eGFR of ≤60 ml/min/1.73m2, the patient is diagnosed with CKD [57, 60-63]. In the stages G1 (i.e. eGFR≥90 ml/min/1.73m2 but presence of kidney disease markers) and G2 (i.e. eGFR 60-89 ml/min/1.73m2) there is some kidney damage with a normal (i.e. stage 1) to mild loss (i.e. stage 2) of kidney function [57, 60-64]. Stage G3 is subdivided into stages G3a (i.e. eGFR 45-59 ml/min/1.73m2) and G3b (i.e. eGFR 30-44 ml/min/1.73m2) and shows a decrease in kidney function of 30% (i.e. mild to severe loss of kidney function) [57, 60-62, 65, 66]. The more advanced stage (i.e. stage G4) is characterized by severe loss of kidney function corresponding with an eGFR of 15 to 29 ml/min/1.73m2 [57, 60-62, 67]. Patients who are in stage G5 with an eGFR of <15 ml/min/1.73m2 receive the diagnosis ESKD. The kidneys are damaged in such a way that it is irreversible and RRT, i.e. dialysis or kidney transplantation, is usually necessary to stay alive [68]. Patients then have the choice for this treatment or conservative care [68, 69].

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Figure 3 Five stages of chronic kidney disease according to the KDIGO 2012. Green: low risk; Yellow:

moderately increased risk; Orange: high risk; Red: very high risk. Reprinted by permission of KDIGO (KDIGO, 2012) [57].

2.3 Renal Replacement Therapy

2.3.1 Kidney transplantation

To keep the best quality of life, kidney transplantation is preferred by most of the ESKD patients [1]. The two types of kidney donors are deceased kidney donors and related or unrelated living kidney donors [70]. Due to better medical knowledge and circumstances, a shift to more deaths from cerebrovascular accidents is making the transplant community using different deceased kidney donors [71]. Also, it is necessary to adapt the terms and definitions for organ donation [72]. Deceased kidney donors are subdivided into donation after circulatory death also known as non-heart-beating donors and donation after brain death [72, 73].

In 1954, the first kidney transplantation between a living kidney donor and kidney transplant recipient was performed by Joseph Murray [74, 75]. To prevent rejection of the kidney by the kidney transplant recipient the immune response is suppressed with immunosuppressive medication. Immunosuppressive medication made kidney transplantation between an unrelated living kidney donor or a deceased kidney donor and kidney transplant recipient possible. Due to shortage in donors most patients are placed on a transplant waiting list.

To decrease the waiting time for kidney transplantation, Kidney Paired Donation (KPD) might be a good solution to increase the number of kidney transplantations with related and unrelated living kidney donors. KPD is based upon exchange of each other’s incompatible living kidney donor between two or more donor-recipient pairs. KPD could also be used by a combination of deceased

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13 kidney donors and living kidney donors where one deceased kidney donor initiates a KPD chain of living kidney donors [76].

2.3.2 Quality of life and graft survival

Throughout the last years, the transplant community has been faced with questions about the differences in terms of graft survival and Quality of Life after receiving a living kidney or a deceased kidney transplant. Over the past 30 years, graft survival has increased for both living kidney and deceased kidney transplantations [77-80]. This can be explained by the better methods used for kidney allocation such as blood type compatibility, panel reactive antibodies, and human leukocyte antigen matches [81, 82]. Graft survival, one year after kidney transplantation, in the United States (US) and Canada increased to 95.0% for living kidney donors and to 91.0% for deceased kidney donors in 2004 [30]. This is almost similar for Australia and New Zealand were the 1-year graft survival from living kidney donors was 95.9% and from deceased kidney donors was 90.2% [80]. In the past years, long-term graft survival has not improved at the same pace as the 1-year graft survival. However, the younger age of the living kidney donor results in a better long-term graft survival in comparison to a kidney from a deceased kidney donor [30, 77, 80].

Quality of Life is closely related to graft survival and kidney transplant recipients experience different outcomes depending on the type of kidney donor (i.e. living versus deceased) [79, 83, 84]. Quality of Life involves physical and mental components [79, 83, 84] which can be measured with the Short Form-36 (SF-36) questionnaire [84]. Transplantation from a living kidney donor is superior in terms of physical and mental health compared to kidney transplantation from deceased kidney donors [79, 83, 84]. A possible reason for this is the previously mentioned long waiting time for a deceased kidney donor and the corresponding higher risk of pretransplantation complications [79]. Therefore, the transplant community is committed to increase the donor pool and make the entire general population more aware of the benefits of living kidney donation [27, 29, 85].

2.3.3 Dialysis

Dialysis can be seen as an alternative to transplantation when there is a shortage of kidney donors or for patients that do not qualify for kidney transplantation. The two main types of dialysis are hemodialysis and peritoneal dialysis [86]. Hemodialysis can be divided into in-center hemodialysis and at-home hemodialysis. In hemodialysis, the patient is hooked up to a dialysis machine with a dialyzer (i.e. external artificial filter) [87-89]. Blood is pumped through the dialyzer to eliminate waste products and excess water. The counter-current flow gradient is responsible for the separation of waste products from the blood and is induced by dialysate (i.e. dialysis solution) flowing into one direction and blood in the opposite direction. The frequency of hemodialysis mostly varies between three days a week to each day of the week depending on the condition of the patient [86, 88, 89]. The duration of each hemodialysis session depends on the frequency and is on average between three to five hours [88].

Where hemodialysis uses an external artificial filter peritoneal dialysis is using the peritoneum of the abdomen [86, 87, 90]. Peritoneal dialysis is divided into two steps. First, the dialysate flows into the abdomen to absorb waste and stays there for the time prescribed by the nephrologist. During this time, the capillaries of the peritoneum are responsible for diffusion, ultrafiltration, and absorption of waste and excess water. Secondly, the used dialysate needs to leave the abdomen and to be replaced by fresh dialysate. This exchange can be done by hand (i.e. continuous ambulatory peritoneal dialysis) or by a machine (i.e. automated peritoneal dialysis).

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2.3.4 Conservative care

The approach for conservative care is to avoid further decrease in kidney function without using dialysis treatment or kidney transplantation and is sometimes the choice of elderly patients [68, 69]. When avoiding further decrease in kidney function is not possible, the focus shifts to slowing down the rate of decrease in kidney function. This approach depends on the PRD, co-morbidities, and daily medication. This treatment is mostly provided by joint teams that consist of a nephrologist, nurse, and social worker. Most patients consider conservative care as less intrusive in their daily life and it is therefore related to a better quality of life compared to dialysis [68, 69].

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3. Materials and methods

3.1 Data sources

ERA-EDTA Registry

The ERA-EDTA Registry collects data on ESKD patients receiving RRT in Europe through 53 national and regional renal registries in 37 countries. Individual patient data or aggregated data is yearly collected by the participating national or regional renal registries and sent to the ERA-EDTA Registry. Individual patient data include country of the registry, patient identifier, date of birth, sex, PRD, date of first RRT, date of event, type of event/treatment (dialysis or kidney transplantation), date, and cause of death. On the other hand aggregated data consists of information on the frequency of RRT patients expressed in summary statistics for a particular country.

The following countries that provided individual patient data in the period from 2008 to 2017 on all pediatric (except for Belgium and the United Kingdom) and adult patients were included: Austria, Belgium, Denmark, Finland, Greece, Iceland, Norway, Russia (except for 2014), Serbia, Sweden, The Netherlands, and the United Kingdom. Countries that provided aggregated data were: Czech Republic, Latvia, Portugal, and Spain. The countries that provided a mix of individual patient data and aggregated data were: Bosnia and Herzegovina, Croatia, Estonia, and France.

Global Observatory on Donation and Transplantation

The Global Observatory on Donation and Transplantation (GODT) database collects quantitative data on organ donation (heart, kidney, liver, lung, pancreas, and small bowel) of 194 Member States in six World Health Organization regions (WHO) [91]. On an annual basis, questionnaires are distributed to all countries that contribute data to the GODT database. Since 2007, in close collaboration with the Spanish Transplant Organization and the WHO, a dataset on transplantation counts around the world is made.

The following countries from the GODT database were included: Bulgaria, Cyprus, Germany, Hungary, Ireland, Italy, Lithuania, Malta (from 2009), Poland, Romania, Russia (2014) Slovakia, Slovenia (from 2009), Switzerland, and Turkey.

Inclusion criteria

Time trends in kidney transplantation rates

For the decision on the data source (ERA-EDTA Registry or GODT data) for each country we used the following criteria: (I) one data source for each country (except for Russia because the ERA-EDTA Registry did not have data for the year 2014) and (II) the ERA-EDTA Registry as the first choice except when the ERA-EDTA Registry had no data available for the complete study period from 2008 till 2017 or the coverage was higher for the GODT data (e.g. ERA-EDTA Registry has data for a region and the GODT for a whole country). Moreover, when using data from the ERA-EDTA Registry, individual patient data was the first choice except when aggregated data was available for the whole country and individual patient data only for certain regions (i.e. Spain). Patients who were 20 years or older and received their first kidney transplant between 2008 and 2017 in a country that provided individual patient data to the ERA-EDTA Registry during the entire study period were included in the preemptive analysis.

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Time trends in characteristics of the kidney transplant recipient s

The study population consisted of countries that provided individual patient data to the ERA-EDTA Registry between 2008 and 2017. These countries were Austria, Belgium, Denmark, Finland, France, Greece, Norway, Spain (Andalusia, Aragon, Asturies, Basque country, Catalonia, Cantabria, Castile-La Mancha, Castile and León, Extremadura, Galicia, and Madrid), Sweden, the Netherlands, and the United Kingdom. Patients who were 20 years and older and received a kidney transplant between 2008 and 2017 were included in the analysis on time trends in the characteristics of kidney transplant recipients.

General population data

For the general population data, we used the midyear population counts downloaded on December 20th, 2019 from Eurostat [92] for countries providing individual patient data to the ERA-EDTA Registry and countries from the GODT database (except for Russia in 2014 we used the United Nations Population Fund). In addition, the following countries delivered their own population data: Austria, Bosnia and Herzegovina, and the United Kingdom and countries that provided aggregated data to the ERA-EDTA Registry.

3.2 Definition of variables

Kidney transplantation rates were expressed per million population (pmp) and were calculated by dividing the kidney transplantation count (N) in a year by the general population multiplied by one million. PKT patients were defined as patients starting with kidney transplantation as first RRT. To be considered a PKT, the dates for first transplantation, start of RRT, and event needed to be equal.

Patient characteristics were reported by year as absolute numbers and percentages for categorical variables and as median and interquartile range (IQR) for continuous variables. The PRD groups consisted of diabetes mellitus (type I & II), hypertension/renal vascular disease, glomerulonephritis, other cause or unknown/missing.

3.3 Statistical analysis

Time trends in kidney transplantation rates

The Mean Annual Percentages Change (MAPC) with 95% confidence intervals (95% CI) of the time trends in kidney transplantation rates by country were analyzed with Joinpoint regression using the Joinpoint regression program [93]. The year was the independent variable, country was the by-variable, and the overall kidney, living kidney donor, deceased kidney donor, and preemptive kidney transplantation rates were the crude-rates. Joinpoint identifies points in time (e.g. years) in which the trend of transplantation rates significantly changed by using a sequence of permutation tests [94, 95]. For example, a trend may be stable for a certain period but may increase from a certain year onwards. According to the National Cancer Institute, the minimum and the maximum number of joinpoints depend on the number of data points [94]. Therefore, we used a maximum of two joinpoints corresponding to the availability of ten data points (i.e. years in our study period). In addition, we performed the same analysis using zero joinpoints. No time trend could be determined when the kidney transplantation rate for overall, living kidney donor, deceased kidney donor, and/or PKT contained zeros meaning no kidney transplantations were performed in a particular year. Moreover, the kidney transplantation rates pmp of preemptive kidney transplant recipients were calculated for each year for each country.

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Time trends in characteristics of the kidney transplant recipient s

Statistical analysis of time trends in the characteristics of the kidney transplant recipients were performed for age, sex, and PRD. Beforehand, we checked the distribution for age and concluded that the distribution of age was non-normal. Analyses were divided into three groups. The first group consisted of all kidney transplant recipients and the second group consisted of only first-time kidney transplant recipients who had their first transplantation between 2008 and 2017. In the last group, preemptive kidney transplant recipients were analyzed. Absolute counts and percentages were calculated for the age, sex, and PRD-group of the kidney transplant recipients for each year for all countries combined. For all analyses, the MAPC with 95% CI of the trends in the characteristics of the kidney transplant recipient were analyzed with Joinpoint regression using the Joinpoint regression program [93]. The year was the independent variable, the transplantations were the by-variable, the sex and PRD-groups were the percentages, and the median age was the age-adjusted rate. These analyses were accomplished for overall kidney transplantations as well as those from living kidney donors, deceased kidney donors, and PKT.

All analyses were performed using SAS 9.4 (2016; SAS Institute Inc., Cary, NC, USA) [96] or Joinpoint 4.2.0.4 (2015; National Cancer Institute, Calverton, MD, USA) [93]. P-values below 0.05 were considered statistically significant.

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4. Results

In total, kidney transplant counts and kidney transplantation rates of 34 European countries between 2008 and 2017 were included in the study about time trends in transplantation rates and 11 European countries were included in the study about time trends in characteristics of the transplant recipient.

4.1 Time trends in kidney transplantation by European country, 2008-2017,

Figures 4 and 5a to 5d show a map of Europe with the MAPC over a 10-year time period in overall transplantation rate (5a), deceased kidney donor transplantation rate (5b), living kidney donor transplantation rate (5c), and preemptive kidney transplantation rate (5d). Figures 6a to 6d display the 2017 transplantation rate plotted against the MAPC. Appendix A Tables A.1 to A.4 present the MAPC over a 10-year time period in overall kidney transplant rate (A.1), living kidney donor transplant rate (A.2), deceased kidney donor transplant rate (A.3), and PKT rate (A.4).

As shown in Figures 5a and 6a, the country-specific analyses indicated that the MAPC of the overall transplantation rate varied widely across Europe. Between 2008 and 2017, the MAPC for overall transplantation rate significantly increased in all 34 participating countries together by 2.7%, 95% CI: 0.7, 4.2. In fourteen countries (Czech Republic, Denmark, Finland, France, Hungary, Italy, Latvia, Lithuania, Poland, Russia, Spain, the Netherlands, Turkey, and the United Kingdom), the kidney transplantation rate rose significantly with the biggest increase in Lithuania (MAPC 6.3%, 95% CI: 1.1, 11.7) and Finland (MAPC 5.6%, 95% CI: 3.7, 7.5). Moreover, when comparing western European countries with eastern European countries, they had an equal number of countries (N = 7) with an increasing trend in overall transplantation rate. Interestingly, when looking at the high overall kidney transplantation rate (Figure 6a) in France, Hungary, Spain and the Netherlands, we noted that these countries also showed an increasing trend in overall transplantation rates. Figure 5a shows that a decrease was found in western European countries (Germany, Norway, and Portugal) as well as in eastern European countries (Cyprus, Estonia, Greece, Serbia, Slovakia, and Slovenia). The decreasing trend was only significant for Cyprus (MAPC -10.3%, 95% CI: -13.9, -6.5), Germany (MAPC -4.6%, 95% CI: -6.2, -3.0), and Norway (MAPC -2.4%, 95% CI: -4.0, -0.7). Interestingly, Germany already had a very low overall transplantation rate in 2017 (Figure 6a). In other countries, the transplantation rate remained unchanged for overall kidney transplantations in the study period.

Among the two types of kidney donors, deceased kidney donors and living kidney donors had similar number of countries with a significant increasing trend, respectively ten and twelve. As illustrated in Figures 5b, 5c, 6b, and 6c, transplantation rates among those two types of kidney donors dominated the split between western and eastern European countries. Specifically, transplantation rates of deceased kidney donors increased significantly among eastern European countries (Croatia, Czech Republic, Lithuania, Poland, Russia, and Turkey) whereas a significant increase in transplantation rates of living kidney donors occurred in mostly western European countries (Belgium, Finland, France, Ireland, Italy, Portugal, Spain, and the Netherlands). Noteworthy, Czech Republic and Hungary already had a very high transplantation rate for kidney transplants from deceased kidney donors (Figure 6b) and as shown in Figure 6c, whereas the Netherlands already had a high transplantation rate for living kidney donors in 2017. Over time, kidney transplantations from a living kidney donor improved significantly in twelve countries with the largest increase in Finland (MAPC 16.1%, 95% CI:8.0, 24.8), Ireland (MAPC 15.5%, 95% CI:9.5, 21.8), and Latvia (MAPC 30.5%, 95% CI: 16.5, 46.1). With regard to living kidney donors, a significant decreasing trend took place in seven countries (Croatia, Cyprus, Norway, Romania, Serbia, Sweden, and the United Kingdom), with the largest decrease in Croatia (MAPC 12.0%, 95% CI:21.0, 2.0), Romania (MAPC 10.7%, 95% CI: -15.2, -6.1), Serbia (MAPC -9.9%, 95% CI: -15.4, -4.1), and Cyprus (MAPC -9.3%, 95% CI: -14.4, -3.8). Three countries had a significant decrease in the number of deceased kidney donors performed (Estonia, Germany, and Ireland), whereas this trend was stable in six countries.

As shown in Figures 5d and 6d, the 10-year PKT time trend reveals a notable increasing trend for all countries combined (MAPC 6.3%, 95% CI: 4.9, 7.7). As shown in Figure 6d, Denmark, the

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19 Netherlands, and the United Kingdom had a relatively high PKT rate in 2017. These three countries showed a significant increase in the PKT rate along with France, Spain, and Sweden. Interestingly, those countries with a significant increase in PKT rate (Denmark, France, Spain, Sweden, the Netherlands, and the United Kingdom) were very similar to the countries with a significant increase in overall transplantation rate. During the complete study period, Denmark had the highest significant increase in PKT rate (MAPC 14.5%, 95% CI: 10.4, 18.7) followed by Spain (MAPC 9.3%, 95% CI: 7.1, 11.6). Norway already had a high PKT rate in 2017 (Figure 6d), still it was the only country with a significant decrease in PKT rate (MAPC -2.4%, 95% CI: -4.8, -0.0) in the study period.

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AT Austria IE Ireland

BA Bosnia and Herzegovina IT Italy

BE Belgium LT Lithuania

BG Bulgaria LV Latvia

CH Switzerland MT Malta

CY Cyprus NL the Netherlands

CZ Czech Republic NO Norway

DE Germany PL Poland DK Denmark PT Portugal EE Estonia RO Romania ES Spain RS Serbia FI Finland RU Russia FR France SE Sweden GR Greece SI Slovenia HU Hungary SK Slovakia HR Croatia TR Turkey

IS Iceland UK United Kingdom

Figure 4 Legend of European countries and their corresponding abbreviation according to the two letter country code

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Figure 5 Europe with the MAPC over a 10-year time period in overall transplantation rate (a), deceased kidney donor transplantation rate (b),

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22

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23 The trend in kidney transplantation rates might not be the same during the entire study period. Therefore, to investigate whether trends in MAPC changed during our study period, we also performed the analyses with a maximum of 2 joinpoints. Tables 1 to 4 show the overall kidney transplantation rate (1), the deceased kidney donor transplantation rate (2), the living kidney donor transplantation rate (3), and the PKT rate (4) of all participating countries. Appendix B Tables B.1 to B.4 present the overall kidney transplant counts (B.1), the living kidney donor transplant counts (B.2), the deceased kidney donor transplant counts (B.3), and the PKT counts (B.4). Appendix C Figures C.1 to C.4 contain a visual overview of the time trends in transplantation rate for overall (C.1), living kidney donor (C.2), deceased kidney donor (C.3), and PKT (C.4).

As presented in Table 1, the transplantation rate in Poland, the Netherlands, and Turkey increased in the first years respectively with a MAPC of 10.7%, 3.8%, and 15.5% and remained stable for the remaining study period, whereas the rate in Italy and Switzerland showed the exact opposite. Table 1 indicates that Germany had a stable rate from 2008 to 2010 (MAPC 4.0%, 95% CI: -12.4, 23.4) and that this rate decreased thereafter from 2010 to 2017 (MAPC -6.1%, 95% CI: -8.2, -3.9).

As shown in Table 2, deceased kidney donor transplantation rates in Sweden did not change until 2010 and significantly increased from 2010 onwards by 5.7% (95% CI: 3.3, 8.1). Poland experienced an increase in transplantation rates from deceased kidney donors from 2008 to 2014. At the beginning of 2014, this trend began to flatten and remained unchanged until 2017. Until 2013, the trend in deceased kidney donors remained unchanged in Spain. Thereafter, the transplantation rate of deceased kidney donors significantly increased (MAPC 8.1%, 95% CI: 4.1, 12.3). Deceased kidney donor transplant rates in France did not significantly change from 2008 to 2014. Beginning in 2014, France experienced a significant increase from 41.0 pmp in 2014 to 47.4 pmp in 2017 (MAPC 5.1%, 96% CI: 3.5, 6.7).

Living kidney donor rates in Estonia and Ireland remained unchanged for respectively the first 6 years and 2 years and significantly improved for the remaining years till 2017 (Table 3). Spain had a significant increase in living kidney donor transplant rates until 2013 and did not change from 2013 to 2017. Living kidney donor transplant rates in Germany substantially increased from 6.9 pmp in 2008 to 8.1 pmp in 2010 (Table 3). Since 2011, Germany experienced a continuous decrease until 6.7 pmp in 2017 (MAPC -5.9%, 95% CI: -8.0, -3.7). Until 2010 the trend in kidney transplantation rate from living kidney donors did not change in Sweden and the United Kingdom. Thereafter, the transplantation rate for living kidney donors significantly decreased. Only Romania showed a decreasing trend in the first years followed by a stable trend in recent years.

All countries combined had an increase in the PKT rate of 4.1 pmp in 2008 to 5.8 pmp in 2013 (MAPC 8.8%, 95% CI: 5.8, 11.9) and a stable trend from 2013 to 2017 (MAPC 3.0%, 95% CI: -1.0, 7.1) (Table 4). Belgium, Spain, and the Netherlands had a significant increase in PKT rate during the first years and remained stable during the last few years.

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Table 1 Overall transplantation rate pmp between 2008 and 2017 presented with the MAPC and 95% CI.

Country Overall kidney transplantation rate by year, pmp Trend 1 Trend 2

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 Period 1 ↑ MAPC % (95% CI) Period 2 ↑ MAPC % (95% CI)

↓ ↓

− −

Alla 27.5 29.3 30.4 31.7 35.1 31.5 32.2 38.9 33.5 34.1 2008-2017 ↑ 2.7 (0.7, 4.2) Austria 39.5 47.5 44.7 44.6 47.3 45.9 46.8 43.8 46.7 45.4 2008-2017 − 0.7 (-0.7, 2.1) Belgium 35.5 37.0 37.1 41.8 42.2 40.0 37.2 40.5 39.5 40.3 2008-2017 − 1.0 (-0.3, 2.4) Bosnia and Herzegovina 7.4 5.7 6.6 6.3 7.1 6.8 8.0 9.9 6.8 6.8 2008-2017 − 2.0 (-1.7, 5.8) Bulgaria 2.5 4.3 6.5 2.3 1.8 3.9 7.8 6.7 5.2 5.7 2008-2017 − 8.2 (-3.9, 21.9) Croatia 35.4 37.6 54.5 53.7 54.3 60.1 48.4 46.7 48.5 51.2 2008-2010 − 27.7 (-4.4, 70.5) 2010-2017 − -1.4 (-5.2, 2.5) Cyprus 73.7 43.3 38.6 36.4 33.6 36.0 36.4 23.6 22.3 22.1 2008-2017 ↓ -10.3 (-13.9, -6.5) Czech Republic 31.9 33.0 32.9 31.9 41.5 44.7 49.6 44.0 44.6 47.3 2008-2017 ↑ 5.3 (2.9, 7.7) Denmark 36.0 40.3 41.0 41.4 38.4 37.7 43.9 47.0 45.3 43.8 2008-2017 ↑ 2.1 (0.5, 3.7) Estonia 42.5 39.7 29.1 32.8 44.6 35.7 24.3 28.9 31.9 29.6 2008-2017 − -3.5 (-7.6, 0.7) Finland 27.9 32.8 32.4 32.7 35.8 34.4 43.9 44.7 47.5 43.2 2008-2017 ↑ 5.6 (3.7, 7.5) France 45.1 44.7 45.3 46.3 46.7 46.8 48.8 52.4 54.1 56.6 2008-2013 ↑ 1.0 (0.1, 1.9) 2013-2017 ↑ 4.9 (3.6, 6.2) Germany 33.5 33.8 35.9 35.5 32.2 28.2 26.3 26.9 25.4 23.2 2008-2010 − 4.0 (-12.4, 23.4) 2010-2017 ↓ -6.1 (-8.2, -3.9) Greece 23.6 14.9 11.1 17.8 16.9 14.7 12.6 10.5 13.1 16.9 2008-2017 − -3.2 (-8.8, 2.8) Hungary 25.8 27.3 30.7 25.2 27.8 29.4 39.2 34.8 34.8 30.3 2008-2017 ↑ 3.2 (0.2, 6.2) Iceland 15.8 22.0 15.7 34.5 18.7 24.7 24.4 21.2 14.9 23.3 2008-2017 − 0.9 (-5.8, 8.2) Ireland 32.5 37.9 38.2 41.9 35.4 40.0 32.6 32.5 36.2 39.9 2008-2017 − 0.1 (-2.4, 2.6) Italy 28.2 30.2 28.6 29.5 30.0 28.5 30.3 31.0 34.2 37.1 2008-2014 − 0.3 (-1.5, 2.2) 2014-2017 ↑ 7.6 (1.9, 13.6) Latvia 21.7 25.8 23.3 36.1 32.0 36.2 30.8 40.7 34.0 31.0 2008-2017 ↑ 4.7 (0.6, 9.0) Lithuania 15.9 26.6 22.9 24.8 29.5 28.7 24.6 39.6 38.7 26.9 2008-2017 ↑ 6.3 (1.1, 11.7) Maltab 29.1 33.8 43.2 21.4 30.5 46.0 18.0 43.9 44.9 2008-2017 − 2.6 (-8.0, 14.4) Norway 58.3 60.5 53.8 61.0 59.6 53.0 53.3 49.0 45.8 52.1 2008-2017 ↓ -2.4 (-4.0, -0.7) Poland 21.2 20.6 26.3 28.2 30.1 30.5 30.2 27.6 29.2 28.7 2008-2012 ↑ 10.7 (3.5, 18.4) 2012-2017 − -1.5 (-6.1, 3.2) Portugal 49.4 55.8 53.9 50.2 40.6 42.7 43.0 46.7 49.5 47.8 2008-2017 − -1.4 (-3.8, 1.2) Romania 11.1 9.6 10.5 10.9 8.8 14.7 15.6 12.4 13.5 7.6 2008-2017 − 0.9 (-5.1, 7.2)

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25 Russia 5.8 5.8 7.3 6.8 6.6 6.5 7.2 6.5 7.5 8.2 2008-2017 ↑ 2.8 (0.8, 4.9) Serbiab 12.9 13.4 15.6 12.5 16.6 9.7 8.5 7.4 11.0 2009-2017 − -6.3 (-12.4, 0.2) Slovakia 30.9 31.9 31.3 23.9 24.6 22.0 23.1 33.9 26.3 28.1 2008-2017 − -1.2 (-5.1, 2.8) Sloveniab 21.6 29.8 22.4 30.1 29.1 26.7 31.0 22.3 23.2 2009-2017 − -0.1 (-4.8, 4.9) Spain (all) 48.3 49.8 47.3 52.9 54.0 54.2 57.3 62.3 64.4 70.2 2008-2017 ↑ 4.2 (3.2, 5.2) Sweden 45.6 42.0 39.3 45.2 41.0 43.2 45.3 42.7 42.6 46.1 2008-2017 − 0.4 (-0.9, 1.8) Switzerland 37.4 37.6 37.6 35.6 31.4 34.4 36.8 38.9 36.4 42.6 2008-2012 − -3.9 (-8.6, 1.0) 2012-2017 ↑ 4.4 (0.8, 8.2) The Netherlands 46.9 50.0 52.8 51.6 57.1 56.4 59.2 57.9 58.8 54.6 2008-2014 ↑ 3.8 (1.8, 5.8) 2014-2017 − -2.3 (-7.7, 3.5) Turkey 23.4 32.8 32.8 39.6 38.6 38.7 38.0 41.0 43.2 41.6 2008-2011 ↑ 15.5 (2.0, 30.7) 2011-2017 − 1.2 (-2.9, 5.6) UK (all) 40.5 41.9 43.6 43.7 44.5 48.2 46.4 43.6 45.3 47.3 2008-2017 ↑ 1.3 (0.4, 2.3) a

Does not include Malta, Serbia, and Slovenia due to different time period

b

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Table 2 Deceased kidney donor transplantation rate pmp between 2008 and 2017 presented with the MAPC and 95% CI.

Country Deceased kidney donor transplantation rate by year, pmp Trend 1 Trend 2 Trend 3

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 Period 1 ↑ MAPC % (95% CI) Period 2 ↑ MAPC % (95% CI) Period 3 ↑ MAPC % (95% CI)

↓ ↓ ↓

− − −

Alla 21.0 21.5 22.2 22.6 22.6 22.3 21.8 23.1 24.1 24.7 2008-2011 ↑ 2.6 (0.7, 4.6) 2011-2014 − -1.0 (-4.7, 2.9) 2014-2017 ↑ 4.1 (2.1, 6.1) Austria 32.9 40.3 38.1 39.2 39.9 38.2 39.6 36.9 39.5 38.4 2008-2017 − 0.7 (-0.8, 2.2)

Belgium 32.2 32.9 33.8 38.3 39.3 36.0 33.7 36.6 35.6 35.6 2008-2017 − 0.8 (-0.8, 2.5) Bosnia and Herzegovina 2.6 0.3 2.3 1.7 3.4 1.4 2.0 2.8 3.1 1.1 2008-2017 − 6.2 (-12.1, 28.2) Bulgaria 1.1 2.3 4.9 1.1 0.5 2.3 6.1 5.3 3.6 4.5 2008-2017 − 15.2 (-4.5, 38.9) Croatia 26.1 25.9 49.8 43.6 50.4 57.2 46.4 45.2 46.6 49.8 2008-2010 − 41.6 (-1.1, 102.7) 2010-2017 − 0.8 (-4.0, 5.7) Cyprus 30.5 18.6 9.6 14.1 5.8 10.4 10.6 1.2 4.7 11.6 2008-2017 − -16.2 (-30.7, 1.5) Czech Republic 29.1 30.5 31.3 28.1 34.7 36.6 43.4 38.9 40.1 42.1 2008-2017 ↑ 4.8 (2.7, 6.8) Denmark 22.6 24.6 22.8 23.1 24.8 19.0 24.6 26.8 26.8 28.3 2008-2017 − 2.1 (-0.5, 4.7) Estonia 40.3 36.7 26.1 30.6 43.8 34.9 23.6 26.6 28.9 20.5 2008-2017 ↓ -5.1 (-9.7, -0.3) Finland 26.3 32.0 30.4 30.3 33.6 32.2 41.2 41.8 43.5 37.4 2008-2017 ↑ 4.8 (2.5, 7.2) France 41.5 41.1 40.8 41.6 41.1 40.7 41.0 44.1 45.5 47.4 2008-2014 − -0.0 (-0.6, 0.5) 2014-2017 ↑ 5.1 (3.5, 6.7) Germany 26.6 26.5 27.8 25.6 22.6 19.2 18.6 19.0 18.2 16.5 2008-2010 − 3.3 (-19.7, 32.8) 2010-2013 − -11.1 (-30.8, 14.3) 2013-2017 − -3.6 (-11.0, 4.4) Greece 17.3 11.8 7.2 13.2 12.6 10.1 8.4 7.0 8.2 10.7 2008-2017 − -5.0 (-11.1, 1.4) Hungary 23.4 24.9 26.5 20.5 22.5 25.4 34.6 30.8 31.4 26.3 2008-2017 − 3.1 (-0.5, 6.9) Icelandb 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Ireland 30.3 34.0 33.1 36.0 28.5 31.8 24.0 25.5 25.7 29.3 2008-2017 ↓ -2.8 (-5.5, -0.0) Italy 26.1 27.9 25.5 25.9 26.8 24.9 26.1 26.0 29.6 31.9 2008-2015 − -0.4 (-202, 1.5) 2015-2017 − 11.9 (-2.3, 28.1) Latvia 21.2 23.1 22.4 34.4 29.1 33.1 27.1 33.7 28.2 23.3 2008-2017 − 2.2 (-2.3, 7.0) Lithuania 14.4 23.7 20.3 23.8 25.4 26.4 20.1 36.5 36.6 24.7 2008-2017 ↑ 6.5 (0.9, 12.4) Maltac 14.5 26.5 28.8 19.0 23.5 34.5 18.0 32.9 34.2 2009-2017 − 6.4 (-2.3, 15.9) Norway 37.8 38.9 36.8 46.2 43.4 39.8 40.1 36.8 36.9 37.3 2008-2017 − -0.6 (-2.6, 1.4) Poland 20.7 20.0 24.9 27.2 28.7 29.0 28.8 26.0 27.9 27.3 2008-2012 ↑ 10.1 (2.9, 17.8) 2012-2017 − -1.6 (-6.2, 3.2) Portugal 44.8 49.9 49.1 45.7 36.2 37.9 37.8 40.8 43.3 40.3 2008-2017 − -2.0 (-4.5, 0.4) Romania 5.6 4.1 6.1 7.1 6.2 12.0 13.7 10.0 11.4 5.0 2008-2017 − 7.1 (-2.8, 17.9)

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27 Russia 4.7 4.7 6.1 5.6 5.3 5.2 5.9 5.2 5.9 6.8 2008-2017 ↑ 2.6 (0.2, 5.1) Serbiac 4.2 9.0 9.5 7.1 11.9 5.7 3.7 4.4 7.6 2009-2017 − -3.0 (-15.0, 10.5) Slovakia 27.0 28.4 30.0 21.5 24.0 20.1 20.3 30.4 22.8 26.1 2008-2017 − -1.3 (-5.2, 2.8) Sloveniac 21.1 29.8 22.4 30.1 29.1 26.7 31.0 21.3 22.3 2009-2017 − -0.4 (-5.6, 5.0) Spain (all) 44.9 44.8 42.2 46.3 46.3 46.0 48.2 54.0 57.0 63.1 2008-2013 − 0.7 (-2.0, 3.4) 2013-2017 ↑ 8.1 (4.1, 12.3) Sweden 30.7 24.6 21.1 25.7 24.8 27.5 29.6 29.3 29.1 33.7 2008-2010 − -13.3 (-26.8, 2.7) 2010-2017 ↑ 5.7* (3.3, 8.1) Switzerland 22.2 24.4 23.0 22.9 19.4 20.9 22.1 26.8 22.1 27.4 2008-2017 − 1.2 (-1.5, 3.9) The Netherlands 21.5 24.1 24.6 24.9 28.1 25.5 27.5 27.4 25.4 24.0 2008-2012 − 5.8 (-0.1, 12.0) 2012-2017 − -2.0 (-5.8, 2.1) Turkey 5.8 6.0 5.4 7.0 7.0 7.7 8.2 8.6 9.9 8.6 2008-2017 ↑ 6.2 (4.1, 8.3) UK (all) 25.4 26.0 27.2 27.3 29.4 32.2 31.1 29.5 31.8 33.6 2008-2017 ↑ 3.0 (1.9, 4.0) a

b

Absence of data indicates that data contained zeros

c

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Table 3 Living kidney donor transplantation rate pmp between 2008 and 2017 presented with the MAPC and 95% CI.

Country Living kidney donor transplantation rate by year, pmp Trend 1 Trend 2 Trend 3

↓ ↓ ↓

− − −

Alla 6,5 7,7 8,4 9,1 9,0 9,2 9,2 9,3 9,4 9,4 2008-2011 ↑ 11.0 (7.5, 14.6) 2011-2017 − 0.4 (-0.7, 1.5) Austria 6,6 7,2 6,6 5,5 7,3 7,7 7,2 6,9 7,1 7,0 2008-2017 − 0.9 (-1.5, 3.4)

Belgium 2,0 2,6 3,0 3,3 2,9 3,3 3,6 3,9 4,0 4,4 2008-2017 ↑ 7.5 (5.0, 10.0) Bosnia and Herzegovina 4,6 4,8 4,0 4,6 3,4 5,4 6,0 7,1 3,7 5,7 2008-2017 − 2.6 (-3.2, 8.7)

Bulgaria 1,5 2,0 1,6 1,2 1,2 1,5 1,7 1,4 1,5 1,1 2008-2017 − -2.3 (-6.3, 1.9) Croatia 3,6 2,7 4,3 7,5 1,9 1,5 2,0 1,5 1,9 1,3 2008-2017 ↓ -12.0 (-21.0, -2.0) Cyprus 43,2 24,8 28,9 22,3 27,8 25,5 25,8 22,4 17,6 10,5 2008-2017 ↓ -9.3 (-14.4, -3.8) Czech Republic 2,8 2,6 1,6 3,8 6,8 8,1 6,2 5,1 4,5 5,1 2008-2010 − -15.7 (-58.9, 72.9) 2010-2013 − 60.1 (-21.9, 228.2) 2013-2017 − -15.5 (-32.7, 6.0) Denmark 13,5 15,8 18,0 15,8 13,6 18,7 19,3 20,2 18,5 15,5 2008-2017 − 2.4 (-1.0, 5.9) Estonia 2,2 3,0 3,0 2,2 0,8 0,8 0,8 2,3 3,0 9,1 2008-2014 − -22.0 (-39.2, 0.0) 2014-2017 ↑ 127.2 (8.7, 374.8) Finland 1,5 0,7 2,1 2,4 1,8 2,2 2,7 2,7 4,0 5,1 2008-2017 ↑ 16.1 (8.0, 24.8) France 3,6 3,6 4,5 4,7 5,5 6,1 7,8 8,2 8,6 9,1 2008-2017 ↑ 12.4 (10.6, 14.1) Germany 6,9 7,3 8,1 9,9 9,5 9,0 7,7 7,9 7,2 6,7 2008-2011 ↑ 13.8 (6.5, 21.7) 2011-2017 ↓ -5.9 (-8.0, -3.7) Greece 6,3 3,1 3,9 4,6 4,2 4,6 4,1 3,5 4,9 6,2 2008-2017 − 1.4 (-4.5, 7.7) Hungary 2,4 2,4 4,2 4,7 5,3 4,0 4,7 4,1 3,5 4,1 2008-2011 ↑ 31.3 (0.5, 71.6) 2011-2017 − -4.6 (-12.8, 4.4) Iceland 15,8 22,0 15,7 34,5 18,7 24,7 24,4 21,2 14,9 23,3 2008-2017 − 0.9 (-5.8, 8.2) Ireland 2,2 4,0 5,0 5,9 7,0 8,2 8,6 7,0 10,5 10,6 2008-2010 − 53.8 (-2.3, 142.1) 2010-2017 ↑ 9.8 (3.3, 16.6) Italy 2,1 2,3 3,1 3,6 3,2 3,6 4,1 5,0 4,6 5,2 2008-2017 ↑ 10.2 (7.6, 12.8) Latvia 0,4 2,7 0,9 1,7 2,9 3,1 3,8 7,0 5,8 7,8 2008-2017 ↑ 30.5 (16.5, 46.1) Lithuania 1,6 2,8 2,6 1,0 4,0 2,4 4,4 3,1 2,1 2,1 2008-2017 − 3.4 (-7.9, 16.0) Maltabc 14,5 7,2 14,4 2,4 7,0 11,5 0,0 11,0 10,7 Norway 20,6 21,5 17,0 14,7 16,1 13,2 13,2 12,1 9,0 14,8 2008-2017 ↓ -6.6 (-10.3, -2.8) Poland 0,5 0,6 1,3 1,1 1,3 1,5 1,4 1,6 1,3 1,5 2008-2010 ↑ 59.2 (3.1, 145.6) 2010-2017 − 3.8 (-2.0, 10.0) Portugal 4,6 5,9 4,8 4,4 4,4 4,9 5,2 6,0 6,3 7,5 2008-2017 ↑ 3.9 (0.4, 7.6) Romania 5,5 5,5 4,3 3,7 2,6 2,7 1,9 2,3 2,1 2,6 2008-2014 ↓ -16.8 (-22.2, -11.0) 2014-2017 − 7.0 (-12.3, 30.4)

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29 Russia 1,1 1,1 1,2 1,3 1,4 1,3 1,3 1,3 1,6 1,4 2008-2017 ↑ 3.5 (1.9, 5.1) Serbiab 8,7 4,4 6,1 5,4 4,8 3,9 4,7 2,7 3,2 2008-2017 ↓ -9.9 (-15.4, -4.1) Slovakia 3,9 3,5 1,3 2,4 0,6 1,8 2,8 3,5 3,5 2,0 2008-2017 − 0.4 (-14.7, 18.1) Sloveniabc 0,5 0,0 0,0 0,0 0,0 0,0 0,0 1,0 1,0 Spain (all) 3,4 5,0 5,1 6,6 7,6 8,1 9,0 8,3 7,4 7,1 2008-2013 ↑ 19.2 (12.5, 26.3) 2013-2017 − -5.4 (-12.8, 2.6) Sweden 14,9 17,4 18,2 19,5 16,2 15,7 15,7 13,4 13,5 12,4 2008-2010 − 12.8 (-6.0, 35.3) 2010-2017 ↓ -6.0 (-8.2, -3.7) Switzerland 15,2 13,2 14,6 12,8 12,0 13,5 14,7 12,1 14,3 15,1 2008-2017 − 0.1 (-2.3, 2.5) The Netherlands 24,9 24,7 28,2 26,7 28,9 30,6 31,2 30,4 33,5 30,6 2008-2017 ↑ 3.0 (1.8, 4.3) Turkey 17,6 26,8 28,8 32,6 31,7 31,0 29,8 32,4 33,3 33,0 2008-2010 ↑ 28.9 (11.2, 49.4) 2010-2017 − 0.8 (-1.2, 2.8) UK (all) 15,1 15,9 16,5 16,4 15,1 15,7 14,9 13,2 13,0 13,0 2008-2010 − 5.6 (-7.8, 21.0) 2010-2017 ↓ -3.8 (-5.5, -2.0) a

b

Data from Malta, Serbia, and Slovenia are for 2009-2017

c

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Table 4 Preemptive kidney transplantation rate pmp between 2008 and 2017 presented with the MAPC and 95% CI.

Country Preemptive kidney transplantation rate by year, pmp Trend 1 Trend 2 Trend

↓ ↓ ↓ − − − All 4.1 4.5 5.0 5.3 5.8 6.4 6.6 6.5 6.6 7.4 2008-2013 ↑ 8.8 (5.8, 11.9) 2013-2017 − 3.0 (-1.0, 7.1) Austria 3.0 3.2 2.6 2.3 2.6 3.0 2.0 3.0 3.0 2.6 2008-2017 − -0.8 (-4.6, 3.2) Belgium 2.2 2.4 3.2 4.6 4.8 4.0 3.7 2.8 4.4 4.7 2008-2012 ↑ 23.4 (0.3, 52.0) 2012-2015 − -15.2 (-56.1, 63.8) 2015-2017 − 27.7 (-33.9, 146.6) Denmark 2.9 4.8 4.6 6.4 6.6 7.1 9.3 10.8 10.4 10.5 2008-2017 ↑ 14.5 (10.4, 18.7) Finlanda 0.2 0.0 0.0 0.0 0.4 0.0 0.4 0.5 0.4 1.3 France 3.6 3.4 3.6 3.5 4.0 4.4 5.3 5.1 5.1 6.4 2008-2017 ↑ 6.8 (4.7, 9.1) Greece 0.4 0.8 0.7 0.4 1.0 0.3 0.5 0.3 0.3 0.7 2008-2017 − -4.2 (-15.5, 8.6) Norway 13.8 14.5 12.1 13.5 14.3 12.4 12.1 9.8 11.5 12.5 2008-2017 ↓ -2.4 (-4.8, -0.0) Spain (all) 2.4 2.9 3.3 3.9 4.0 4.5 4.9 5.2 5.3 5.4 2008-2010 ↑ 19.6 (8.4, 31.9) 2010-2014 ↑ 9.8 (4.6, 15.3) 2014-2017 − 3.0 (-1.9, 8.2) Sweden 3.1 5.2 6.3 7.5 5.8 6.7 7.6 6.2 6.2 8.5 2008-2017 ↑ 6.5 (1.0, 12.3) The Netherlands 8.7 9.8 11.6 11.5 13.0 14.5 13.2 13.8 15.0 13.0 2008-2013 ↑ 9.6 (4.2, 15.4) 2013-2017 − -1.1 (-8.0, 6.3) UK (all) 5.6 6.2 7.2 7.4 8.1 9.6 9.5 9.1 8.7 10.4 2008-2017 ↑ 6.2 (4.0, 8.5) a

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4.2 Time trends in characteristics of the kidney transplant recipients, 2008 –

2017

Baseline characteristics

In total, 101,571 patients from 11 countries received 104,324 kidney transplantations between 2008 and 2017 (Table 5). Eighty-six percent (N = 89,763) concerned a first kidney transplant recipient and 16.2% (N = 14,562) of those first kidney transplant recipients received a preemptive transplant. During the study period, most patients (N = 64,049; 63.1%) were male, and the most common PRD group was other (50.8%) followed by glomerulonephritis (23.6%).The median age at transplantation of all years combined was 53.2 years (IQR: 42.4 – 63.8), the median age for PKT for all years combined was 51.1 (IQR: 40.6 – 61.1). Of all 104,324 performed kidney transplantations, the initial RRT modality of most patients was hemodialysis (56.8%), most patients received a kidney from a deceased kidney donor (75.5%), and 75.3% of all kidney transplant recipients had a deceased donor kidney as first donor type.

Table 5 Baseline characteristics of patients who received a kidney transplantation between 2008 and

2017 and donor features.

All kidney transplant recipients First kidney transplant recipients

Characteristics 2008-2017 2008-2017

Number of transplantations 104,324 101,571

Male, N/% 65,701/63.0 64,049/63.1

Age at RRT onset, median (IQR) 49.4 (37.1, 59.6) 49.4 (37.2, 59.7) Age at transplantation, median (IQR) 53.2 (42.4, 62.8)

Age at first transplantation, median (IQR) 53.9 (43.0, 63.3)

Age PKT, median (IQR) 51.1 (40.6, 61.1)

Primary renal disease, N/%

Diabetes mellitus type I & II 14,384 (13.8) 14,129 (13.9) Hypertension/renal vascular disease 10,858 (10.4) 10,567 (10.4) Glomerulonephritis 24,693 (23.7) 23,926 (23.6) Other 52,962 (50.8) 51,549 (50.8) Missing 1,427 (1.4) 1,400 (1.4) Initial RRT modality, N/% Hemodialysis 59,277 (56.8) 57,729 (56.8) Peritoneal dialysis 22,342 (21.4) 21,677 (21.3) Kidney transplant 17,097 (16.4) 16,696 (16.4) Missing 5,608 (5.4) 5,469 (5.4) Donor type, N/%

Living kidney donor 24,261 (23.3) Deceased kidney donor 78,729 (75.5)

Unknown kidney donor 1,334 (1.3) First donor type, N/%

Living kidney donor 21,114 (23.5)

Deceased kidney donor 67,555 (75.3)

Unknown kidney donor 1,094 (1.2)

Abbreviations used: RRT: renal replacement therapy; PKT: preemptive kidney transplantation; IQR: interquartile range Categories may not add up because of rounding off; when cells are left empty, data is unavailable

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Trends in characteristics of the kidney transplant recipients by sex

Figure 7 shows the proportion of males receiving a kidney transplantation (7a), a first kidney transplantation (7b), and a PKT (7c). Appendix D Tables D.1 to D.9 present the number and proportion of males and females receiving a kidney transplantation. Table 6 shows the proportion of male kidney transplant recipients with the corresponding MAPC.

Between 2008 and 2017, the percentage of males receiving a kidney transplant significantly increased from 62.2% in 2008 to 63.4% in 2017 (MAPC 0.2%, 95% CI: 0.1, 0.3) (Figure 7a and Table 6). When looking at the donor types, this increase was mainly explained by the deceased kidney donor transplantations whereas the proportion in the living kidney donor transplantations was more stable. When analyzing only first-time kidney transplant recipients, we found a similar trend in the proportion of males receiving a first transplantation compared to all transplantations (Figure 7b). For all first transplantations, we observed a significant increase in the proportion of males receiving a kidney transplantation of 62.7% in 2008 to 64.0% in 2017 (MAPC 0.3%, 95% CI: 0.1, 0.4) (Table 6). As for all transplantations, this increase was also mainly explained by the deceased kidney donor transplantations while transplantations from living kidney donors continued to be constant between 2008 and 2017.

The proportion preemptive male kidney transplant recipients was different from the overall male kidney transplant recipients, with a non-significant increase of kidney transplants received from a living kidney donor as well as from a deceased kidney donor (Figure 7c and Table 6).

Figure 7 International time trends of patients that received a kidney transplantation by sex between 2008 and 2017,

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Table 6 The proportion of male kidney transplant recipients between 2008 and 2017 presented with the MAPC and 95% CI.

Type of transplantation The proportion of male kidney transplant recipients by year, percentages

Trend 1 Trend 2

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 Period 1 ↑ MAPC % (95% CI) Period 2 ↑ MAPC % (95% CI)

↓ ↓

− −

All transplantations

Overall 62.2 62.7 62.9 62.6 63.0 63.3 63.0 62.7 63.7 63.4 2008-2017 ↑ 0.2 (0.1, 0.3) Deceased kidney donor 62.0 62.9 63.1 62.5 63.0 64.0 63.4 63.0 64.3 63.3 2008-2017 ↑ 0.3 (0.1, 0.4)

Living kidney donor 62.6 62.2 62.3 62.6 62.6 61.3 61.7 61.5 61.4 64.1 2008-2017 − -0.0 (-0.4, 0.4)

First transplantation

Overall 62.7 62.7 63.0 62.7 63.2 64.1 63.4 63.2 64.4 64.0 2008-2017 ↑ 0.3 (0.1, 0.4) Deceased kidney donor 62.5 62.8 63.0 62.5 63.2 64.9 63.7 63.5 64.8 63.9 2008-2017 ↑ 0.3 (0.1, 0.6)

Living kidney donor 63.2 62.4 62.6 63.0 62.8 61.9 62.3 62.1 62.7 64.6 2008-2015 − -0.1 (-0.5, 0.1) 2015-2017 − 1.9 (-0.4, 4.2) Preemptive kidney

transplantation

Overall 59.9 59.5 60.3 61.8 59.4 60.2 60.0 58.7 62.2 62.3 2008-2017 − 0.3 (-0.2, 0.8) Deceased kidney donor 60.4 59.8 59.6 58.8 56.7 60.5 57.6 58.9 62.4 60.7 2008-2017 − 0.2 (-0.6, 0.9) Living kidney donor 59.4 59.2 60.7 63.6 61.4 60.1 62.0 58.3 62.1 63.9 2008-2017 − 0.4 (-0.3, 1.2)

International comparison of trends in kidney transplantation rates and transplant recipient characteristics in Europe between 2008 and 2017