EDTAKI: a Nephrology and Public Policy Committee platform call for more European involvement in acute kidney injury

Abstract

INTRODUCTION

Until the beginning of this century, at least 30 definitions of acute kidney injury (AKI) were in use [1, 2]. The introduction of classification systems, although not perfect, resulted in a more systematic approach, acknowledging that minor changes in kidney function are related to worse outcomes [3]. Nevertheless, AKI is not one disease but an amalgam involving many specialties, with a broad spectrum of causes, including hypovolaemia, hypoperfusion, nephrotoxicity, haem pigments, intravascular coagulation, inflammation, post-renal obstruction [4] and conditions where several factors coincide, like sepsis [5, 6]. The two most involved specialties are nephrology and intensive care medicine [7]. The nephrologist’s role, although considered essential [8], may vary depending on the local situation.

Traditionally chronic kidney disease (CKD) and AKI were viewed as separate entities, but recent knowledge considers the two conditions as intertwined [9]. If the acute condition evolves into CKD and long-term kidney replacement therapy, this heavily weighs on prognosis, and even more so in countries with limited resources.

The risk of AKI is increased by the presence of comorbidities, including diabetes mellitus, congestive heart failure, arterial hypertension, cardiovascular disease, chronic obstructive pulmonary disease, secondary immune deficient states like HIV, chronic liver disease, cancer and CKD [10, 11]. Not coincidentally, the non-communicable (chronic) diseases in this list are also linked to CKD development [12]. The increasing survival with most of these comorbidities also widens the time window over which patients are susceptible to AKI [13]. Also, the progressively growing fraction of elderly people [14] is at increased risk of AKI and the need for KRT in case of AKI [15].

The epidemiology and phenotypes of AKI patients differ between high-income countries (HICs) and low- to middle-income countries (LMICs) [4, 10, 16], which also applies to Europe, as European countries belong to both categories [17]. Global warming may promote further shifts in epidemiology, especially in southern Europe, by increasing the risk of dehydration and infectious diseases such as malaria and dengue [18, 19].

Current status

The burden of AKI is immense due to its immediate consequences as well as the increased risk of long-term problems such as cardiovascular events in survivors [20]. Even mild AKI is associated with a reduction in survival, which remains present even if kidney function recovers [21]. These problems are associated with a health-economic and societal burden, owing to the severity of disease, the multiple comorbidities and complications, the need for highly technological interventions (dialysis, artificial ventilation, close monitoring, haemodynamic support, major surgery etc.) and lengthy recovery periods [22, 23]. They also raise ethical questions on who to treat and who not [24].

The recent global increase in awareness and action with regards to AKI can to a substantial extent be attributed to the International Society of Nephrology, which launched in 2015 the ambitious 0by25 initiative (0 preventable deaths due to AKI worldwide by 2025) [25]. Although this action mainly aimed at improving the situation in LMICs, it applies to HICs as well, and AKI was recently identified as an important target for the Western European nephrology community [26].

In the context of its key role in clinical nephrology and research, the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) convened several stakeholders in the Nephrology and Public Policy Committee (NPPC) to consider future avenues advancing European clinical kidney research. The NPPC defined eight topics to stimulate research collaboration and grant applications in Europe and decided to translate this plan into public policy action [27]. One of the selected topics was to ‘extend understanding of AKI progression and complications’. The question arising in this context is where Europe and European academia are positioned in the fight against AKI and its consequences. Some may perceive that Europe is lagging behind, but objective pan-European data on this assumption are lacking.

To answer this question, we reviewed the available literature to assess European involvement in AKI compared with other regions worldwide and especially compared with countries with a similar economic or scientific stature, such as the USA, Australia–New Zealand (ANZ) and Canada. Based on these data, we propose a model on how to promote clinical collaboration and nephrology networking on AKI across Europe.

Literature analysis—methods

We first undertook an Endnote search for the entire year 2018 with key terms ‘acute kidney injury’ or ‘acute renal failure’ in the title (referred to by the aggregated term ‘AKI’ in what follows). As this analysis was started in 2019, the year 2018 was selected, as it was the most recent year with complete literature data. Experimental and clinical studies and case reports were included. We excluded publications that were not directly on AKI (e.g. papers on acute graft rejection) and letters and comments. Papers were not excluded based on language or quality criteria. We recorded the nationality of the first author as representative for the origin of the publications.

We first performed an analysis of the absolute number of publications on AKI per region, either a continent, part of a continent (Latin America and ANZ), a group of countries (the non-European Mediterranean countries) or an individual country (USA and Canada). We then normalized these data per million population (pmp), which we used as a surrogate for the human resource capacity to perform scientific and/or clinical analyses. The non-European Mediterranean countries were considered as a separate geographic entity because their physicians and researchers are eligible for ERA-EDTA membership.

One of the major questions was the relative scientific output of Europe versus the USA, the other large Western entity with vested research interests. To exclude the possibility of a general trend for a different European kidney research endeavour versus the USA, we performed a similar scientific output analysis with search terms ‘chronic kidney disease’ and two more restricted nephrology topics where specific European networks are active: ‘uremic toxins’ (EUTox) and ‘hemolytic uremic syndrome’ (HUS; ERKNet). The ratio of the number of publications for Europe versus the USA for AKI was compared with that for the three other topics. We also calculated the mean impact factor of the journals in which the analysed publications appeared.

We then ranked all European countries (except those with <100 000 inhabitants) for the number of generated AKI publications pmp. We also performed subanalyses comparing Western and Central and Eastern Europe and the highest, middle and lowest tertiles of countries classified based on their gross domestic product (GDP) pmp. Central and Eastern Europe was defined as the geographic area that was formerly under communist political influence (former Soviet Union, Warsaw Pact countries and Yugoslavia and Albania) plus Turkey. GDP was expressed in US dollars as provided by Worldometer [28].

The above comprehensive 1-year analysis did not permit assessment of the evolution over time. To answer this question, in a second, more restricted investigation we assessed the number of publications with the acronym ‘AKI’ in the title (referred to as ‘AKI in title’ in what follows) for the years 2012–19 and compared the percent share of European contributions to the rest of the world. This examination was also used to assess the contribution of nephrologists vis-à-vis other specialties in Europe and per country. Here also, assessments were based on the nationality of the first author. To analyse specialty involvement, only countries with more than four contributions in the database were included.

RESULTS

The first large-scale analysis for the year 2018 comprised 1554 references. When analysing the publication rate in absolute numbers, Asia had the highest production (564 publications), followed by Europe (438) and the USA (362) (Table 1;Supplementary data, Figure S1). When the publication rate was normalized pmp, the list is headed by ANZ and the USA (both 1.1 publications pmp) and Canada (1.01). The rate for Europe was almost 50% lower (0.59 pmp) than that for the USA (Table 1; Supplementary data, Figure S1).

These differences could, however, be an illustration of a general trend for lower European activity in scientific and clinical nephrology reporting. We therefore also compared European activity to that of the USA for uraemic toxicity, HUS and CKD. The ratio of European versus US production was higher for these three topics than for AKI (Figure 1). The mean journal impact factors for the European and US AKI papers were the same (4.2 ± 7.3 and 4.3 ± 7.7).

FIGURE 1

Ratio of the number of publications in Europe versus the USA for AKI, CKD, HUS and uraemic toxins (Utox) 2018.

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Analysis of scientific output per European country normalized pmp showed substantial differences, from 2.5 pmp (Iceland) to 0.05 pmp (Ukraine and the Russian Federation) (Table 2), while 12 of the 43 countries (27.9%) produced no publications. Of note, the scientific output list is headed by two countries with a population ≤500 000, so that even a single publication gave high scores. When countries were stratified according to a scientific output of >1.00, 0.51–1.00, 0.01–0.50 and 0 pmp, a definite East–West gradient was observed, with a lower scientific output in Central and Eastern Europe (Figure 2; Table 3). This dichotomy, however, was paralleled by marked differences in country wealth. GDP pmp was almost 5 times higher in Western than in Central and Eastern Europe (Table 3). Stratification of European countries in tertiles depending on GDP pmp showed a gradient in proportion to GDP (Table 3). However, there are exceptions to this trend, essentially corresponding to smaller countries (Slovenia in the middle GDP tertile with a publication rate of 1.43 pmp and Croatia in the upper part of the lower GDP tertile with 0.98).

FIGURE 2

European publication rate on AKI in 2018 per country normalized pmp. Darkness of shade in proportion to publication rate (darkest for highest rate). Rates were calculated as the number of publications on AKI based on AKI in the title. Blue colours: publication rate >1.00 pmp, 0.51–1.00 pmp, 0.01–0.50 pmp. Grey: publication rate 0. There is a marked East–West gradient.

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The longitudinal analysis based on inclusion of the acronym AKI in the publication title (2012–19) included 213 publications. It showed an unmodified share of European contributions versus the rest of the world in the range of 20–30% over the entire period under consideration (Figure 3; Supplementary data, Table S1). With all data taken together, the share of nephrologists as first author was slightly ˂50%, whereas other specialists, mainly intensive care physicians, contributed to the remaining half (Figure 4). Considering individual countries with four or more publications, there were marked differences in contributions from nephrologists, ranging from the majority of contributions by nephrologists (Germany, Spain and Italy) to only a minority (the Netherlands and France) (Supplementary data, Table S2).

FIGURE 3

Year-by-year European contribution to publications on AKI (% of publications out of overall worldwide publications, based on AKI in title). There was no significant trend.

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FIGURE 4

Percentage contribution of different specialties in European publications with AKI in the title (2012–19).

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DISCUSSION

This study analysed the European contribution to both basic and clinical AKI research as compared with other regions and made an internal comparison within Europe. The principal findings are:

• Normalized to pmp inhabitants, the European contribution to AKI research is substantially smaller than that of regions with a similar socio-economic status, such as North America or ANZA.

• The discrepancy versus the USA was not observed for other nephrology research topics, such as HUS, uraemic toxicity or CKD. These differences are not paralleled by the mean of the impact factors of the journals in which the papers appeared.

• A manifest East–West gradient in scientific output exists and this trend parallels disparities in country wealth.

• The contribution of nephrology to European AKI publications is ˂50%, with intensive care medicine as an almost equivalent contributing specialty.

• There is no signal of change in European activity over the past decade.

The relatively low contribution of European nephrology to AKI research is worrisome in view of the clinical and health-economic burden of AKI [20]. In addition, contributing factors to the incidence of this condition will very likely gain in importance in the future due to the aging population [24] and improved outcomes of other associated conditions such as cardiovascular disease [29, 30] and cancer [31]. Also, related costs are projected to increase [22]. Hence research in this field is essential for the medical community, patients and society alike. It would be unfavourable for Europe not to be in the front line of unravelling the pathophysiology of and searching for new cures for AKI, as a backlog in progress would force European nephrology to largely depend on non-European data and therapeutic solutions.

Some may argue that the scanty European contribution in AKI is emblematic of a global lack of European interest in kidney research. However, this assumption is not mirrored for other nephrology topics, and especially not for areas where European networks like EUTox or ERKNET are active (Figure 1). Likewise, one may argue that if the analysis had been limited to Western Europe, scientific output would have been closer to that from the USA, Canada or ANZ. However, it would be unlikely for scientific output in those countries to be geographically more homogeneous than it is in Europe. In addition, for policy action and improvement initiatives, it is preferable to consider the European Union and Europe as one entity. Finally, even if the first author is not European, Europeans might be ranked as co-authors. However, we thought that the first author is in most cases the most important contributor to a publication, reflecting the place where the analysis, observations or study took place, and in addition they most often are junior staff members, who constitute the future of medical interest in a given topic, in this case AKI.

The essential role of the nephrologist in AKI has repeatedly been emphasized [9, 32, 33]. First, not all AKI cases are in need of critical care, and in those patients the nephrologist may be crucial for timely identification of the problem and its causes and for instituting therapy, as well as playing an educational role and raising awareness among non-nephrologists and non-AKI physicians. Also, in ICU patients, the causes may not be the more usual critical conditions, like sepsis or kidney hypoperfusion, but intrinsic kidney disorders for which nephrologists can be instrumental in diagnosis and management. In addition, nephrologists can advise on correction of electrolyte disorders [32] and interpretation of serum creatinine [34]. Second, nephrologists master a broad spectrum of kidney replacement therapies, including intermittent and extended haemodialysis and peritoneal dialysis [35], which may help in overwhelmed healthcare systems like during the ongoing coronavirus disease 2019 (COVID-19) pandemic [36]. Third, nephrologists may assist in avoiding futile therapy, e.g. in frail AKI patients [24, 32, 37]. Fourth, and above all, in view of the frequent link with CKD, the nephrologist can play a role in preventing evolution towards CKD and to steer the approach and follow-up if kidney function does not recover [9, 38, 39]. Thus we call not only for European research activity on AKI, but also for clinical involvement of nephrologists in AKI outside the nephrology unit. Unfortunately, if the publication activity as illustrated in this study is representative of the clinical involvement of nephrologists, our data suggest ample room for increasing this participation. In contrast, more commitment will increase the visibility of nephrology regarding AKI. As the relation with other specialties might differ between countries and hospitals, mapping of the current situation might be of interest.

The representation of intensive care unit (ICU) specialists in the AKI literature does not reflect the actual epidemiology of AKI in hospitals and is likely biasing understanding of AKI. In a recent European study from a single tertiary hospital, based on electronic screening of patient records using Kidney Disease: Improving Global Outcomes criteria, ICU cases accounted for only 3% of hospital-acquired AKI [40]. Of note, this analysis is based on a single centre and the situation might differ in settings with different healthcare systems or patient mixes. In addition, the study contained but was by definition not limited to ICU patients, but in this way exactly stresses that AKI is also frequent outside the ICU.

The recent COVID-19 pandemic illustrates several of the concerns raised above. The frequent presence of cytokine storm suggested a high propensity for AKI [41] and the many negative facets of AKI, such as the high complication rate, mortality and technical demands, emerging in a time-condensed way, while AKI appeared to be a major complication in many of the most severely affected COVID-19 patients [42–45]. However, especially in the early phase of the pandemic, European nephrology needed to rely on epidemiologic data from China [46] or the USA [47], although the first cases in Europe and the USA were reported almost simultaneously [48, 49]. The ERA-EDTA took the laudable decision to open a registry on COVID-19 and its links to kidney disease (ERACODA) [50, 51], but to the best of our knowledge, this database remained limited to dialysis patients and transplant recipients.

To improve this situation and boost the European contribution to AKI, we propose the development of a European nephrology network of clinicians and researchers with interest in AKI. For each country, one or more coordinators are invited to convene interested groups in their regional/national environment. Networks are among the tools to advance interest, knowledge and outcomes in AKI [52] and exist already in some European countries like the UK [53] and France [54], but they should be rolled out on a broad European level, e.g. by applying for a European Cooperation in Science and Technology action. Once installed, participants will be offered the opportunity to contribute to European registration and research projects and proposals for European Union support via Framework Programmes like Horizon Europe [55]. Some initiatives may be global and include a broad array of participants; others may be restricted to a few interested parties, applying a model similar to that of the EUTox Work Group [56, 57]. The network could also be instrumental in developing pan-European projects to improve clinical outcomes, such as developing a uniform laboratory AKI alert system, preferably inspired by existing systems [58]. However, networking may not be the only solution. An additional focus point could be the extension of involvement of nephrologists in AKI outside nephrology (intensive care, but also other specialties like oncology, cardiology, surgery etc.). A European network could also play a crucial coordinating role in promoting and organizing this evolution.

The group should define its immediate and long-term research priorities. A preliminary, non-exhaustive list of such topics can be found in Table 4.

The lower participation in Central and Eastern Europe should not be considered as a symptom of lack of interest or quality care, but the parallelism with GDP is striking. We can only speculate on the reasons, but a probable role can be attributed to fewer resources for research, lack of time for physicians possibly resulting in less attention to AKI cases or, since the number of nephrologists is lower in Central and Eastern than in Western Europe [59], lower specialist numbers. We plead for active involvement of Central and Eastern Europe, especially since differences in epidemiology may lead to interesting observations and broader pathophysiologic diversity.

Our analysis has a number of drawbacks. First, the analysis covered only 1 year. Countries might have achieved a different profile in another year. It is unlikely, however, that this would have affected the general comparisons between regions or countries. Second, a number of references may have been missed if the title did not contain the pre-defined keywords, but again, this was unlikely to affect general trends. Third, the use of the address of the first author may not always be representative to define the country where the study was executed. Fourth, the long-term analysis with comparisons between specialties was based on a second, smaller database, which might have been biased by the smaller number of retrieved papers, while the term AKI in the title might have been used to a different degree depending on the year, specialty or country of origin. Finally, the lower publication rate in Central and Eastern Europe might be attributable to a number of publications in a local language, which may have been missed in our search.

On the other hand, our analysis also has a number of strengths. To our knowledge, this is the first analysis of scientific output on AKI research in the European nephrology community with comparisons of aspects such as regional and country activity, evolution over time and involved specialties and the impact of country wealth. In addition, it was broad enough to provide useful information on how to inform future initiatives to modify the situation.

In conclusion, this analysis shows, compared with countries or regions with comparable socio-economic stature, a relative lack of European initiatives to study and report on clinical observations with regards to AKI. As for other focus areas defined by the NPPC, Central and Eastern European and low-income countries appear to demand special consideration [60]. The data also underscore that the involvement of nephrologists in this domain could be improved. The fact that only one author of this article is a woman suggests that there is also room for more involvement of women. More time could be devoted to AKI in European nephrology conferences (in the recent ERA-EDTA meetings markedly more slots were devoted to CKD than to AKI) and in continuing medical education courses, especially in LMICs. Furthermore, increased focus on AKI in European research programmes with more funding for AKI studies is another necessity. To cope with these problems, a European nephrology network of researchers and clinicians interested in AKI will be created under the auspices of ERA-EDTA, with the intent to inspire interest in AKI and to develop common research projects.

SUPPLEMENTARY DATA

Supplementary data are available at ndt online.

CONFLICT OF INTEREST STATEMENT

H.J.A. reports personal fees from Secarna; grants and personal fees from Previpharma and personal fees from Novartis, Bayer, GlaxoSmithKline, Boehringer and AstraZeneca, outside the submitted work. P.T.M. reports personal fees from AM-Pharma, FAST Biomedical and Renibus Therapeutics, outside the submitted work. A.O. reports grants from Servier, Sanofi and Mundipharma and personal fees from Sanofi, Amgen, AstraZeneca, Otsuka and Kyowa, outside the submitted work. E.R. reports grants, personal fees and non-financial support from Alexion Pharmaceuticals, outside the submitted work. None of the remaining authors declared any conflicts of interest.

DATA AVAILABILITY STATEMENT

The data underlying this article are available in the article and in its online supplementary material.

Twitter handles: @EKHA_EU and @ERAEDTA

REFERENCES