Mathilde Bories

Astrid Bacle

Hélène Gilardi

Pascal Le Corre
email: plecorre@univ-rennes1.fr

Pr Pascal Le Corre

Risk of acute kidney injury by initiation of non-steroidal anti-inflammatory drugs in hospitalized patients treated with diuretics and renin angiotensin aldosterone system inhibitors

Keywords: inflammatory drugs and risk of acute kidney injury Acute kidney injury, hospitalized patients, diuretics, non-steroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system inhibitors, clinical pharmacy, adverse drug reactions

Objectives

Concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) with diuretics and reninangiotensin-aldosterone system inhibitors (RAASI) has been associated to an increased risk of developing acute kidney injury (AKI) in ambulatory setting. There is currently no information on AKI prevalence in hospitalized patients where initiation of NSAID prescription is quite frequent. The aim of our study was to assess the prevalence of AKI in patients treated with diuretics and/or RAASI in the hospital setting when NSAIDs are initiated.

Methods

Retrospective single center study on inpatients receiving triple or dual association. AKI was established according to evidence-based clinical practice guidelines in kidney disease (Kidney Disease Improving Global Outcome, KDIGO criteria) using the following criteria : increase in SCr by ≥ 0.3mg/dL (or ≥26.5 µmol/L) within 48 hours or increase in SCr to ≥ 1.5 times baseline occurring within the last 7 days.

Results

AKI was identified in 5 of 151 patients (3.3%) treated with both diuretics and RAASI in whom NSAIDs were initiated with a 49 µM average increase in SCr within 48h compared to baseline. AKI was identified in 2 of 117 (1.7%) patients treated with diuretics and NSAIDs, and in 1 of 427 (0.23%) patients treated with RAASI and NSAIDs. The average increase in SCr within 2 days was 29µM. No Aki was identified in a control group of 1,886 patients treated by diuretics and RAASI with no NSAIDs initiation during their hospitalization.

Conclusion

Initiation of NSAID therapy in hospitalized patients already treated with diuretics and RAASI is a risk factor for AKI. The risk of AKI with the triple association appeared higher than with the dual association.

Introduction

Non-Steroidal anti-inflammatory drugs (NSAIDs) are widely used either as prescription or as over-thecounter drugs. Over the last decade (from 2006 to 2016) NSAID use in France has been relatively stable: 30 Define Daily Dose (DDDs) /1000 inhabitants/day for NSAIDs. Ibuprofen, the second-most used nonopioid analgesic, contributed to one-third of the NSAID consumption [START_REF] Hider-Mlynarz | Trends in analgesic consumption in France over the last 10 years and comparison of patterns across Europe[END_REF].

While gastro-intestinal and cardio-vascular side effects are well-known, renal effects, although considered as rare, should be taken in account. Indeed the hemodynamic interaction of NSAIDs with other therapies is important, particularly with diuretics and inhibitors of the renin-angiotensinaldosterone system (RAASI). Each drug can affect kidney function: NSAIDs cause renal afferent vasoconstriction mediated by prostacyclin inhibition, diuretics induce hypovolemia and RAASI reduce glomerular filtration (Supplementary material 1). This triple combination can therefore induce an episode of acute renal injury (AKI) especially in elderly or dehydrated subjects [START_REF] Griffin | Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons[END_REF].

Epidemiological studies performed in ambulatory settings have shown a robust link between NSAIDs use and AKI in patients with a two-fold increase risk of acute renal injury [START_REF] Schneider | Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: A population-based, nested case-control analysis[END_REF]. In general population, a modest higher risk in older people has been evidenced with an adjusted odds-ratio of 1.73 (95% CI 1.44-2.07) [START_REF] Zhang | Non-steroidal anti-inflammatory drug induced acute kidney injury in the community dwelling general population and people with chronic kidney disease: systematic review and meta-analysis[END_REF]. In a subgroup of older people (> 50 years), a somewhat higher odds of AKI with NSAID exposure was reported (OR 2.01, 95%CI 1.52-2.68) [START_REF] Chou | Adverse Effects of Oral Nonselective and cyclooxygenase-2-Selective NSAIDs on Hospitalization for Acute Kidney Injury: A Nested Case-Control Cohort Study[END_REF].

The interaction between NSAIDs, diuretics and RAASI has been investigated in ambulatory studies

showing that the combination of a NSAID with a diuretic or a RAASi was not associated with a higher risk of AKI compared to the use of diuretics or RAASi alone (RR =1.02) [START_REF] Lapi | Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study[END_REF]. On the other hand, the combination of NSAID with both diuretic and RAASi would result in a 31% higher risk of AKI [START_REF] Lapi | Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study[END_REF].

In view of these elements and the fact that there is currently no evaluation in the hospital setting, it appeared relevant to assess the prevalence of AKI induced by hospital prescribing of NSAID in adults treated with diuretics and/or RAASI and to compare them.

Methods

The study was performed as a retrospective (48 month-period from January 2017 to December 2018), observational, single-center study on 37,873 adult inpatients of Rennes University Hospital.

Inclusion criteria were: complete hospitalization, age over 18 years, absence of pre-existing renal disease or disease associated with impaired renal function, and co-prescription of other nephrotoxic treatments (list based on the recommendations of the national "Guide de Prescription et Rein", GPR available at http://sitegpr.com/fr/). Exclusion criteria were : Use of NSAID at hospital admission, complete hospitalization in the following departments : nephrology, dialysis and intensive care because patients in these departments have several medications correcting renal function impairment, and hematology and emergency department because they used a different CPOE system. Drug prescription data was extracted from the computerized physician order entry database (CPOE, DxCare® Software). This database also indicates the real-time administration of drugs to patients by the nurses that was recorded for the drugs of concern in this study.

3 groups of patients were identified and defined as follows:

-Triple association: Patients treated with diuretics and RAASI who were initiated with NSAIDs (IV or VO) (minimum overlap of 24 hrs).

-Dual association: Patients treated with diuretics or RAASI and who were initiated with NSAIDs (IV or VO) (minimum overlap of 24 hrs). The decrease in renal function was based on serum creatinine (SCr) measurement extracted from hospital biological database. According to evidence-based clinical practice guidelines in kidney disease [START_REF] Kdigo Aki | KDIGO clinical practice guideline for acute kidney injury[END_REF], AKI is defined by the increase in SCr (absolute or relative increase) or by the decrease in urine output. AKI is staged in 3 levels, stage 1 corresponding to the first level of acute renal impairment.

AKI not graded is defined as any of the following (7) :

-Increase in SCr by ≥ 0.3mg/dL (or ≥26.5 µmol/L) within 48 hours or -Increase in SCr to ≥ 1.5 times baseline occurring within the last 7 days, or -Diuresis less than <0.5ml/kg/h for at least 6 hours.

In our study, we only used SCr as criteria for detecting AKI because the urine output is not usually measured in hospitalized patients excepted patients in intensive care units, nephrology and dialysis departments.

The prevalence of AKI in patients with the dual association and in the control group was checked in patients from the departments where AKI was identified under the triple association (i.e., department of Orthopedic surgery, Pneumology, Neurology and Thoracic surgery). This was done to decrease the heterogeneity between groups. Indeed, including patients other medical or surgical departments in the control groups or in the dual association group may likely increase the heterogeneity, and hence the variability between groups.

The three groups were evaluated for differences in the prevalence of AKI by Fisher's exact test followed by Bonferroni pairwise comparisons. A p-value < 0.05 was considered significant. No AKI episode was detected among the 1,886 patients treated by diuretics and RAASI with no NSAIDs initiation during their hospitalization in the above-mentioned departments.

Results

In our study, the prevalence of AKI for the triple association was 3.3% with a 49 µM average increase in SCr within 48h compared to baseline. The prevalence of AKI for the dual association was 1.7% for patients treated with NSID and diuretics and was 0.23% for patients treated with NSAID and RAASI.

The average increase in SCr within 2 days was 29µM.

The risk of AKI was significantly different between the 3 groups (triple association, dual association and control patients, p<0.001) with significant differences between triple and dual association (p = 0.043), triple association and control (p < 0.001) and double association and control (p = 0.034).

Discussion

AKI occurs in nearly 20% (8) of hospitalizations and can reach a 60% rate in critically ill patients [START_REF] Hoste | Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study[END_REF]. This occurrence may therefore increase mortality, hospital length of stay and also health care cost, making it a major public health concern [START_REF] Hoste | Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study[END_REF]. Indeed, it has recently been shown that patients in whom AKI occurred had a higher risk of developing chronic kidney disease (CKD): 70% of elderly patients developed CKD within 2 years after their episode of AKI [START_REF] Chawla | Acute kidney injury and chronic kidney disease: an integrated clinical syndrome[END_REF].

The known risks associated with the triple association between NSAIDs, diuretics and RAASI are currently based on studies achieved in ambulatory patients. Lapi et al. [START_REF] Lapi | Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study[END_REF] showed a 31% increased risk of developing AKI in patients treated by NSAIDs, diuretics and RAASI compared to patients treated by diuretics or RAASI alone. However, they found that the dual associations (diuretics + NSAIDs or RAASI + NSAIDs) did not increase the risk of AKI. Dreischulte et al. [START_REF] Dreischulte | Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury[END_REF] showed that NSAIDs use was associated with a 66% increased risk of AKI when used either in triple association or in dual association. Hence, the impact of the dual association should be further studied to confirm or not its negative effect.

Our study showed that NSAIDs initiation in hospitalized patients treated with diuretics and/or RAASI is deleterious for the renal function. Comparison with the literature is not possible since to our knowledge this has not been previously studied in hospital setting. However, these results are in agreement with studies performed in ambulatory patients that showed that the triple association increased the risk of AKI [START_REF] Lapi | Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study[END_REF][START_REF] Dreischulte | Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury[END_REF]. Furthermore, it should be noticed that the dual association led to a smaller increase in the prevalence of AKI in patients in comparison with the triple association. It should be noticed that half of the patients had an increase in furosemide dosing regimen throughout their stay, and this may question a role of furosemide in AKI development. However, the impact of furosemide on AKI can be reasonably ruled out since furosemide is sometimes used in AKI. Indeed, a recent systematic review and meta-analysis comparing the role of furosemide in prevention and treatment at any stage of AKI concluded that furosemide had neither and impact on mortality nor requirement of renal replacement therapy [START_REF] Krzych | Impact of furosemide on mortality and the requirement for renal replacement therapy in acute kidney injury: a systematic review and meta-analysis of randomised trials[END_REF]. Moreover, a recent systematic review and metaanalysis in adult surgical patients has shown the use of furosemide in AKI was associated to very low to no firm evidence for benefit or harm [START_REF] Winther-Olesen | Effects of post-operative furosemide in adult surgical patients: A systematic review and meta-analysis of randomised clinical trials[END_REF].

The limitations of our study arise from the fact that it is a retrospective study, which results in some limitations of data collection. Indeed, SCr values were not available every 48h in all patients so that the number of patients, and therefore the prevalence and intensity of AKI may have been underestimated. Furthermore, the urine output is not measured in all the patients in our hospital and was not retained as a marker of AKI. This is a limitation because some patients could meet this criteria without increased SCr and might have underestimated the prevalence of AKI. It is well known that creatinine is secreted at the tubular kidney level so that a significant decrease in GFR is required to translate in an increase of SCr (i.e., when creatinine secretion is saturated). In addition, the study was conducted on a rather limited number of patients and future studies should take into account and control comorbidity (i.e., hypertension, diabetes, CKD, aging, dehydration) that are factors involved in AKI.

Conclusion

Our study indicates that the initiation of NSAID therapy in hospitalized patients already treated with diuretics and RAASI is a risk factor for AKI. The risk of AKI with this triple association appeared higher than with a dual association. Hospital pharmacists should inform clinicians of the potential risk of AKI with NSAID initiation in patients treated with diuretics and RAASI, as well as patients to prevent NSAID self-medication, especially those who experimented an AKI episode during hospitalization.

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 6 of 18 https://mc.manuscriptcentral.com/ejhpharm European Journal of Hospital Pharmacy ACCEPTED MANUSCRIPT 6 The hospital data base recorded 37,874 patients in 2 years with at least one of the drugs of interest (NSAIDs and/or diuretics and/or RAASI). Among these patients, 6,281 (mean age 74 ± 12.7 years) were treated by the association (395 NSAIDs + diuretics, 1,015 NSAIDs + RAASI, 4,871 diuretics + RAASI) and 151 (mean age 73 ± 11 years) by triple association (NSAIDs + diuretics + RAASI). Five (3.3 %) of the patients from the triple association group had an episode of AKI and were hospitalized in 4 different departments (Neurology, Cardio-Thoracic Surgery, Pneumology and Orthopedics). The evaluation of SCr as a function of time for these 5 patients is depicted in Figure 1A. Dual association group in the four departments included 544 patients: 117 patients received NSAIDs and diuretics and 427 received NSAIDs and RAASI. An AKI episode was detected in 3 patients during their hospital stay (2 patients had diuretics + NSAIDs and 1 patient had RAASI + NSAIDs). The evaluation of SCr as a function of time for these 3 patients is depicted in Figure 2B. Their mean SCr values at the admission, 48h after initiation of NSAID therapy and at discharge are presented in supplementary material (cf Supplementary material 2 data file). The characteristics of the patients with AKI and the drug treatment chronology are summarized in supplementary material (cf supplementary material 3 data file). Page 7 of 18 https://mc.manuscriptcentral.com/ejhpharm European Journal of Hospital Pharmacy

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 9 of 18 https://mc.manuscriptcentral.com/ejhpharm European Journal of Hospital Pharmacy ACCEPTED MANUSCRIPT 9

  /mc.manuscriptcentral.com/ejhpharm European Journal of Hospital Pharmacy

OSupplementary material 1 : 1 Supplementary material 2 :

 112 3-."&/.'%&,1%4'8$3'.1'('+1/.='5&>1%&:D'' " Page 14 of 18 https://mc.manuscriptcentral.com/ejhpharm European Journal of Hospital Pharmacy C o n f i d e n t i a l : F o r R e v i e w Hemodynamic interactions of non-steroidal anti-inflammatory drugs (NSAIDs) with diuretics and renin angiotensin aldosterone system inhibitors (RAASI). Page 15 of 18 https://mc.manuscriptcentral.com/ejhpharm European Journal of Hospital Pharmacy Average serum creatinine values (± SD) in patients with an AKI episode and treated by triple (A) and dual (B) association. AKI episode was defined according to KDIGO criteria: increase in SCr by > 26.5 µmol/L (or 0.3mg/dL) within 48 hours or increase in SCr to > 1.5 times reference value occurring within the last 7 days.

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	Page 17 of 18
		Time (days)	Diuretics	RAASI	NSAIDs	SCr (µM)
	Patient 1	0	Furosemide 40mg	Candesartan 4mg		86
		1 (NSAIDs initiation)	Cont'd	Cont'd	Ketoprofen 100mg IV
		2	Cont'd	Cont'd	Cont'd	94
		3		Cont'd	Cont'd
		4		Cont'd
		5		Cont'd
		6		Cont'd
		7		Cont'd
		8		Cont'd
		9		Cont'd
		10		Cont'd
		11
		12				140
		13				145
		14
		15				74
	Patient 2	0	Furosemide 20mg	Candesartan 8mg		105
		1 (NSAIDs initiation)	Furosemide 40mg	Cont'd	Ketoprofen 100mg PO	201
		2				236
		3				180
		4				171
		5				187
		6
		7
		8				113
	Patient 3	0	Spironolactone 25mg	Perindopril 8mg		89
		1 (NSAIDs initiation)	Cont'd	Cont'd	Ibuprofen 400mg PO
		2	Cont'd	Cont'd	Ibuprofen 800mg PO
		3	Cont'd	Cont'd	Cont'd
		4	Cont'd	Cont'd	Cont'd
		5	Cont'd	Cont'd	Cont'd
		6	Cont'd	Cont'd	Cont'd	101
		7	Cont'd	Cont'd	Ibuprofen 400mg PO
		8	Cont'd	Cont'd	Cont'd
		J9	Cont'd	Cont'd		117
		9	Cont'd			114
		10	Cont'd
		11	Cont'd
		12	Cont'd			96
		13	Cont'd	Perindopril 8mg
		14	Cont'd	Cont'd
		16	Cont'd	Cont'd
		17	Cont'd	Cont'd		86

https://mc.manuscriptcentral.com/ejhpharm European Journal of Hospital Pharmacy

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary material

Source of Funding

None.

Ethical approval retrospective studies

This study was approved by the hospital's Ethics Committee (number 19.107)

Conflict of interest

The authors declare that they have no conflict of interest.


Mehmet Şükrü Sever
email: mehmetsukrusever@gmail.com

Kitty J Jager

Raymond Vanholder

Benedicte Stengel

Jerome Harambat

Patrik Finne

Vladimir Tesař

Myftar Barbullushi

Inga A Bumblytė

Elena Zakharova

Mehmet S ¸u ¨kru ¨sever

Vladimir Tesa

Inga A Bumblyt

Goce Spasovski

Halima Resic

Andrzej Wiecek

Peter J Blankestijn

Annette Bruchfeld

Mario Cozzolino

Dimitris Goumenos

Maria Jose Soler

Ivan Rychlı ´k

Kate I Stevens

Christoph Wanner

Carmine Zoccali

Ziad A Massy

A roadmap for optimizing chronic kidney disease patient care and patient-oriented research in the Eastern European nephrology community

Keywords: chronic renal failure, CKD, dialysis, ESRD, kidney transplantation

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

CHRONIC KIDNEY DISEASE-A WORLDWIDE PROBLEM

Chronic kidney disease (CKD) is associated with several comorbidities, carrying a huge social and economic burden [START_REF] Vanholder | Reducing the costs of chronic kidney disease while delivering quality health care: a call to action[END_REF]. CKD affects 10% of the world population [START_REF] Bello | Global Kidney Health Atlas[END_REF] and 850 million people worldwide suffered from CKD in 2018 [START_REF] Jager | A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases[END_REF]. Alarmingly, the global all-age prevalence increased by 29.3% between 1990 and 2017 [START_REF]Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017[END_REF], making CKD an ever-growing health burden. Both direct and indirect health effects of CKD are of serious concern, especially as they continue to increase. In 2017, CKD and related cardiovascular disease mortality ranked as the 12th greatest cause of death [START_REF]Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017[END_REF], and it is predicted to become the 5th cause of death worldwide by 2040 [START_REF] Foreman | Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories[END_REF].

CKD is associated with psychosocial problems, including poorer educational attainment, lower income and reduced wellbeing and quality of life compared with the healthy population. Consequently these drawbacks perpetuate worse outcomes in CKD because social disadvantage often results in inadequate access to healthcare [START_REF] Morton | The impact of social disadvantage in moderate-to-severe chronic kidney disease: an equity-focused systematic review[END_REF]. Kidney failure, the final stage of CKD, is expensive to treat. The average annual cost of maintenance haemodialysis (HD) globally was Int$22 617 per person in 2016 [START_REF]Global Kidney Health Atlas[END_REF]. The total US Medicare spending on CKD and kidney failure was >$120 billion in 2017, accounting for 7.2% of overall claims paid by Medicare [START_REF] Saran | US Renal Data System 2019 annual data report: epidemiology of kidney disease in the United States[END_REF]. The mean annual total healthcare costs for different CKD stages or end-stage kidney disease differed significantly among countries in 2019: approximately $40 000 in the USA, $3600 in Italy and $16 000 in the UK [START_REF] Elshahat | The impact of chronic kidney disease on developed countries from a health economics perspective: a systematic scoping review[END_REF]. The substantial variation may be linked to differences in healthcare accountancy, clinical practices and/or the cost of care among countries [START_REF] Elshahat | The impact of chronic kidney disease on developed countries from a health economics perspective: a systematic scoping review[END_REF].

Several recent landmark publications elegantly describe the overall burden and management of CKD worldwide [START_REF] Vanholder | Reducing the costs of chronic kidney disease while delivering quality health care: a call to action[END_REF][START_REF]Global Kidney Health Atlas[END_REF][START_REF] Levin | Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy[END_REF][START_REF] Zoccali | The systemic nature of CKD[END_REF], pointing to significant disparities between countries [START_REF] Stanifer | Chronic kidney disease in low-and middle-income countries[END_REF][START_REF] Luyckx | Preventing CKD in developed countries[END_REF]. Various aspects of CKD differ significantly and are worse in the Eastern European nephrology community than Western Europe because of different geographic, socio-economic, infrastructure, cultural and educational features (Table 1) [START_REF] Bello | Global Kidney Health Atlas[END_REF][START_REF] Stanifer | Chronic kidney disease in low-and middle-income countries[END_REF][START_REF] Spasovski | Nephrology in the Eastern and Central European region: challenges and opportunities[END_REF][START_REF] Massy | Nephrology and Public Policy Committee propositions to stimulate research collaboration in adults and children in Europe[END_REF][START_REF]Non-communicable Disease (NCD) Risk Factor Collaboration. Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants[END_REF][START_REF]Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration. Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment[END_REF][START_REF]ERA-EDTA Registry Annual Report[END_REF][START_REF] Galsworthy | Europe's 'Horizon 2020' science funding programme: how is it shaping up?[END_REF][START_REF] Xie | Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016[END_REF][START_REF]Noncommunicable Diseases Country Profiles[END_REF][START_REF] Li | Kidney health for everyone everywhere-from prevention to detection and equitable access to care[END_REF].

The European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) recently commissioned the Nephrology and Public Policy Committee (NPPC) to evaluate the overall burden of CKD across Europe. The NPPC identified eight key topics to stimulate research collaboration and grant applications for screening, diagnosis, prevention and treatment of CKD and advises translating this plan into public policy action [START_REF] Massy | Nephrology and Public Policy Committee propositions to stimulate research collaboration in adults and children in Europe[END_REF].

In this document, the NPPC evaluated the extent of current problems and the state of epidemiological and clinical nephrology research related to CKD in the Eastern European nephrology community. It also summarized a potential role that various institutions can have in coping with these problems and how these institutions can contribute [START_REF] Massy | Nephrology and Public Policy Committee propositions to stimulate research collaboration in adults and children in Europe[END_REF][START_REF] Zoccali | The ERA-EDTA today and tomorrow: a progress document by the ERA-EDTA Council[END_REF]. These institutions include the ERA-EDTA, the European Kidney Health Alliance, European Kidney Patients' Federation and the various national nephrology societies and patient organizations.

UNIQUE FEATURES OF CKD IN EASTERN EUROPE

No consistent definition of Eastern Europe has been agreed upon. The Ural Mountains and River and the Caucasus Mountains form the Eastern geographical border of Europe, but the Western boundaries are controversial [24]. However, the most important difference affecting kidney health between Eastern and Western Europe is not geographical, but economic. According to the World Bank, gross national income (GNI) per capita is significantly lower in Eastern Europe than Western Europe, although Eastern Europe is highly heterogeneous itself (Tables 2 and3) [START_REF]GNI Per Capita, Atlas Method (Current US$) -Country Ranking[END_REF]. For the purpose of this review, we distinguished 12 Eastern European countries with GNI per capita US$12 000 from 11 others with higher GNI based on an arbitrary cut-off of US$1000 of personal income per month. We assumed that several features of lower-GNI Eastern European countries differ not only from Western European countries, but also from higher-income Eastern European countries, including CKD risk factors and CKD care.

As the economy is the driving force for social, infrastructure, cultural and educational development, it is also likely one of the main factors defining significant differences in the prevalence, aetiology, predisposing factors and treatment modalities of kidney failure in Eastern Europe (Tables 1 and2) [2, 12, 14, 16-18, 20-22, 25-27]. All CKD risk factors [i.e. DM (DM), hypertension, obesity, tobacco use, salt intake and physical inactivity] are more prominent in the general population (GP) of Eastern Europe. Accordingly, the prevalence of CKD Stages 3-5 is also significantly higher, especially in lower-income countries (Tables 2 and3) [START_REF]ERA-EDTA Registry Annual Report[END_REF][START_REF] Xie | Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016[END_REF][START_REF]Noncommunicable Diseases Country Profiles[END_REF][START_REF]GNI Per Capita, Atlas Method (Current US$) -Country Ranking[END_REF][START_REF] Erdem | Dietary sources of high sodium intake in Turkey: SALTURK II[END_REF][START_REF] Sengul | Changes in hypertension prevalence, awareness, treatment, and control rates in Turkey from 2003 to 2012[END_REF][START_REF] Suleymanlar | A population-based survey of chronic renal disease in Turkey-the CREDIT study[END_REF].

CKD and its complex array of potential causes and consequences may be neglected as health priorities in these countries. Therefore it is not easy to define simple 'one-size-fits-all' solutions. Nevertheless, several strategies for country-specific, patient-oriented research can be proposed while taking into account differences in prevalence, aetiology and economics.

Incidence and prevalence

In general, 80-90% of all CKD cases are in the early [glomerualr filtration rate (GFR) >60 mL/min] stages of the disease [START_REF] Jha | Chronic kidney disease: global dimension and perspectives[END_REF]. Few studies have analysed the country-specific prevalence of CKD in the Eastern European region. The Chronic REnal Disease in Turkey (CREDIT) study, a Turkish population-based study that included >10 000 subjects, reported prevalence rates for CKD Stages 1-5 of 5.4, 5.2, 4.7, 0.3 and 0.2%, respectively [START_REF] Suleymanlar | A population-based survey of chronic renal disease in Turkey-the CREDIT study[END_REF]. With age, the percentage of patients in Stages 2 and 3 increased, whereas the percentage of patients with Stage 1 CKD decreased.

The overall prevalence of CKD was 15.7% and was higher in females than in males (18.4% versus 12.8%; P < 0.001). In the PolNef study, CKD was reported to affect 18.4% of the GP [START_REF] Rutkowski | Epidemiology of chronic kidney disease in central and eastern Europe[END_REF]. In another Polish study (PolSenior), CKD was diagnosed in 29.4% of 4979 randomly selected elderly subjects, but only 3.2% were aware of the disease [START_REF] Chudek | The prevalence of chronic kidney disease and its relation to socioeconomic conditions in an elderly Polish population: results from the national population-based study PolSenior[END_REF]. In a population-based study on the prevention and awareness of CKD in Albania, among 1.1 million individuals (ages 35-70 years), the prevalence of elevated serum creatinine was 10.3%. Combining estimated GFR (eGFR) and albuminuria, the overall prevalence of CKD in adults (age 18 years) was 7.9% (M. Barbullushi, personal communication).

According to data from the World Health Organization, the prevalence of CKD Stages 3-5 is significantly higher in Eastern Europe than in Western Europe (Tables 2 and3, Figure 1) [START_REF]ERA-EDTA Registry Annual Report[END_REF][START_REF] Xie | Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016[END_REF][START_REF]Noncommunicable Diseases Country Profiles[END_REF][START_REF] Erdem | Dietary sources of high sodium intake in Turkey: SALTURK II[END_REF][START_REF] Sengul | Changes in hypertension prevalence, awareness, treatment, and control rates in Turkey from 2003 to 2012[END_REF][START_REF] Suleymanlar | A population-based survey of chronic renal disease in Turkey-the CREDIT study[END_REF]. This likely relates to the higher prevalence of risk factors for CKD in Eastern Europe. Furthermore, the increase in CKD prevalence over time in this region far exceeds that of the USA and Western European countries (Figure 2) [START_REF] Xie | Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016[END_REF].

The frequency of patients requiring kidney replacement therapy (KRT) is well documented in the ERA-EDTA Registry [START_REF]ERA-EDTA Registry Annual Report[END_REF] and the International Society of Nephrology (ISN) Global Kidney Health Atlas [START_REF]Global Kidney Health Atlas[END_REF]. A recent report including several countries from Eastern Europe underlines the wide variation in the incidence and prevalence of patients requiring per million population (pmp) and 934 (range 358-1052) pmp, respectively] [START_REF] Spasovski | Nephrology in the Eastern and Central European region: challenges and opportunities[END_REF].

The only European population-based study on the early stages of CKD in children was conducted in Turkey; the prevalence in children ages 5-18 years with an eGFR <75 mL/min/ 1.73 m 2 was 0.94% [START_REF] Soylemezoglu | Chronic renal disease in children aged 5-18 years: a population-based survey in Turkey, the CREDIT-C study[END_REF]. Several paediatric publications highlight inequalities within Europe with respect to access to KRT [START_REF] Chesnaye | Disparities in treatment rates of paediatric end-stage renal disease across Europe: insights from the ESPN/ERA-EDTA registry[END_REF][START_REF] Bonthuis | Results in the ESPN/ERA-EDTA registry suggest disparities in access to kidney transplantation but little variation in graft survival of children across Europe[END_REF]. Importantly, and perhaps consequently, in Eastern Europe, excess mortality is seen in children with kidney failure [START_REF] Chesnaye | Mortality risk disparities in children receiving chronic renal replacement therapy for the treatment of end-stage renal disease across Europe: an ESPN-ERA/EDTA registry analysis[END_REF].

Aetiology

The main aetiologies of CKD in Eastern Europe are similar to the rest of the world: DM, hypertension/vascular disease and glomerulonephritis [START_REF] Stanifer | Chronic kidney disease in low-and middle-income countries[END_REF][START_REF] Spasovski | Nephrology in the Eastern and Central European region: challenges and opportunities[END_REF][START_REF]ERA-EDTA Registry Annual Report[END_REF]. Overall, the prevalence of DM, the most frequent cause of CKD, is higher in Eastern Europe than in Western Europe. Weighted averages of 10.2 and 9.5% are noted in low-and medium-income Eastern European countries, respectively, compared with 8% in Western Europe. Specifically, the rates of DM are 10, 10.3 and 13.2% in Hungary, Bulgaria and Turkey, respectively (Tables 2 and3, Figure 1). Hypertension occurs with a similar pattern; weighted averages are 32 and 33% in low-and medium-income Eastern European countries, respectively, compared with 6% in Western Europe. The prevalence of hypertension has been reported to be 37% in Bosnia The number of transplants from all donors may be greater than the sum of living and deceased donors because of inclusion of transplants with an unknown donor source. GNI per capita was obtained from IndexMundi [START_REF]GNI Per Capita, Atlas Method (Current US$) -Country Ranking[END_REF]. Percentages for DM,elevated BP, obesity, physical inactivity, tobacco use and salt/sodium intake were derived from multiple references [START_REF]Noncommunicable Diseases Country Profiles[END_REF][START_REF] Erdem | Dietary sources of high sodium intake in Turkey: SALTURK II[END_REF][START_REF] Sengul | Changes in hypertension prevalence, awareness, treatment, and control rates in Turkey from 2003 to 2012[END_REF][START_REF] Suleymanlar | A population-based survey of chronic renal disease in Turkey-the CREDIT study[END_REF], whereas CKD prevalence was derived from Xie et al.

[20] and Suleymanlar et al. [START_REF] Suleymanlar | A population-based survey of chronic renal disease in Turkey-the CREDIT study[END_REF]. Prevalence of dialysis and Tx were derived from the ERA-EDTA Registry [START_REF]ERA-EDTA Registry Annual Report[END_REF].

The phrase 'elevated blood pressure' was used interchangeably with the term 'hypertension' for the purpose of presenting data in this table. NA, not available. The number of transplants from all donors may be greater than the sum of living and deceased donors because of inclusion of transplants with an unknown donor source. GNI per capita was obtained from IndexMundi [START_REF]GNI Per Capita, Atlas Method (Current US$) -Country Ranking[END_REF]. Percentages for DM, obesity, physical inactivity, tobacco use and salt/sodium intake was derived from the World Health Organization [START_REF]Noncommunicable Diseases Country Profiles[END_REF], whereas CKD prevalence was derived from Xie et al. [START_REF] Xie | Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016[END_REF]. Prevalence of dialysis and Tx were derived from the ERA-EDTA Registry [START_REF]ERA-EDTA Registry Annual Report[END_REF].

and Herzegovina and 41% in Croatia, significantly higher than in Western Europe (Tables 2 and3, Figure 1). Other factors that predispose to CKD are also more frequent in this region; e.g. tobacco is used by 38, 41 and 46% of the inhabitants of Bosnia and Herzegovina, Greece and Montenegro, respectively, and salt consumption is 10 g/day in several countries (Table 2 and Figure 1). Toxic nephropathies due to unconventional or herbal remedies and environmental toxins causing acute kidney injury (AKI) and CKD are increasing worldwide, especially in low-and middle-income countries (LMICs) [START_REF] Jha | Herbal medicines and chronic kidney disease[END_REF][START_REF] Mehta | International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology[END_REF]. Balkan endemic nephropathy, which is caused by the environmental phytotoxin aristolochic acid, is an important factor in the aetiology of CKD in this region of Europe [START_REF] Jelakovic | Balkan endemic nephropathy and the causative role of aristolochic acid[END_REF]. However, the overall contribution of this problem to CKD aetiology in Eastern Europe remains unclear.

Healthcare facilities and medical personnel

Treatment of CKD and resultant kidney failure necessitates a high-quality healthcare infrastructure, well-equipped facilities and well-trained medical personnel. All of these requirements closely correlate with national income, thus it is conceivable that there are more shortcomings in this regard in Eastern Europe. Notably, although the prevalence of DM, hypertension and CKD Stages 3-5 is significantly higher in Eastern Europe, the prevalence of dialysis patients and transplant recipients is lower (Tables 2 and3). These findings suggest that patients in CKD Stages 3-5 die prematurely before experiencing kidney failure or that dialysis and transplantation (Tx) cannot be provided to those who are in need . Possible reasons for this include an inadequate healthcare infrastructure and a shortage of nephrologists in specific regions [START_REF]Global Kidney Health Atlas[END_REF][START_REF] Spasovski | Nephrology in the Eastern and Central European region: challenges and opportunities[END_REF].

Economic concerns/funding

The treatment of kidney failure is costly, therefore financial support from governments is essential to ensure that all patients receive appropriate treatment. This imposes a major burden on the economy. According to the World Bank, only 74% of governments in Eastern and Central Europe provide full support for KRT [START_REF]Global Kidney Health Atlas[END_REF]. Funding of treatment in earlier stages of CKD is even more problematic because of the high number of patients and because the diagnosis may not be made in a timely manner. Although no objective data are available, it is very likely that

THE ROADMAP FOR POTENTIAL SOLUTIONS

To improve the situation for kidney patients and the nephrology community in Eastern Europe, interventions should be considered at different stages during the course of CKD (Figure 3) [START_REF] Levin | Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy[END_REF].

Raise awareness about the burden of CKD and primary diseases/factors leading to CKD

The most cost-effective method of decreasing the burden of CKD is primary prevention (i.e. intervening before CKD occurs or preventing the onset of illness) [START_REF] Vanholder | Reducing the costs of chronic kidney disease while delivering quality health care: a call to action[END_REF]. This can be accomplished only by raising awareness among the public, medical personnel and authorities of CKD as a major public health problem [START_REF] Li | Kidney health for everyone everywhere-from prevention to detection and equitable access to care[END_REF][START_REF] Hsiao | Raising awareness, screening and prevention of chronic kidney disease: it takes more than a village[END_REF].

The public. Public awareness of CKD is poor, even in developed countries [START_REF] Verhave | Prevalence, awareness, and management of CKD and cardiovascular risk factors in publicly funded health care[END_REF]. In a cross-sectional study of >75 000 individuals from 12 LMICs (including Bosnia and Herzegovina and Moldova in Eastern Europe), awareness of CKD was only 6 and 10% in the general and high-risk populations, respectively [START_REF] Ene-Iordache | Chronic kidney disease and cardiovascular risk in six regions of the world (ISN-KDDC): a cross-sectional study[END_REF]. In the elderly Polish population (age >65 years), the awareness of CKD was even lower at 3.2% [START_REF] Chudek | The prevalence of chronic kidney disease and its relation to socioeconomic conditions in an elderly Polish population: results from the national population-based study PolSenior[END_REF].

Approximately 25-40% of adults with type 2 diabetes and 30% with hypertension develop CKD. These diseases are the primary cause of CKD, yet the majority of patients with these diseases are not aware of this association [START_REF] Luyckx | Preventing CKD in developed countries[END_REF]. Importantly, both type 2 diabetes and hypertension are treatable, and even preventable if predisposing factors (e.g. obesity, salt consumption, tobacco use, sedentary lifestyle and unhealthy nutrition) are addressed promptly. Other aetiologies of CKD are completely avoidable (e.g. toxic nephropathies due to unconventional therapies) [START_REF] Jha | Herbal medicines and chronic kidney disease[END_REF]. Therefore the target must be to eliminate, or at least reduce, these causative factors by raising public awareness via visual and print media, as well as web-based education and social media [START_REF] Hsiao | Raising awareness, screening and prevention of chronic kidney disease: it takes more than a village[END_REF][START_REF] Gheewala | Public knowledge of chronic kidney disease evaluated using a validated questionnaire: a cross-sectional study[END_REF][START_REF] Chin | The effect of the World Kidney Day campaign on the awareness of chronic kidney disease and the status of risk factors for cardiovascular disease and renal progression[END_REF][START_REF] Schatell | Web-based kidney education: supporting patient self-management[END_REF]. Organizing and supporting national campaigns by collaborating with national societies, patient groups, charitable and philanthropic organizations and kidney foundations should also be considered [START_REF] Li | Kidney health for everyone everywhere-from prevention to detection and equitable access to care[END_REF].

Healthcare personnel. CKD and its complications should be very familiar to other specialists, not only nephrologists. General practitioners and specialists with a high probability of seeing CKD patients (e.g. internists, cardiologists, diabetologists, endocrinologists, oncologists, urologists and neurologists) should be comfortable identifying and diagnosing CKD [45]. However, this awareness is lacking even in well-developed countries. In a nationwide analysis of >450 000 adults followed by general practitioners in Italy, only 15% had been correctly diagnosed as suffering from CKD because serum creatinine levels in high-risk patients were measured infrequently [START_REF] Minutolo | Detection and awareness of moderate to advanced CKD by primary care practitioners: a cross-sectional study from Italy[END_REF]. Similar observations have been made in other studies [START_REF] Ravera | CKD awareness and blood pressure control in the primary care hypertensive population[END_REF][START_REF] Stevens | Low rates of testing and diagnostic codes usage in a commercial clinical laboratory: evidence for lack of physician awareness of chronic kidney disease[END_REF]. Importantly, late or inaccurate diagnosis may result in delayed referral to the nephrologist, which may then jeopardize the possibility of slowing disease progression and protecting against the complications of CKD. In addition, the risk of delayed or inadvertent initiation of KRT is increased.

Healthcare authorities. The creation of CKD-specific policies by healthcare authorities is essential to cope with and reduce the problem. However, only 58% of the countries located in Eastern and Central Europe have CKD-specific healthcare policies, and the application of these programs in practice is even more problematic, as only 29% of LMICs effectively apply such strategies [START_REF]Global Kidney Health Atlas[END_REF].

Detecting CKD

Although early detection of CKD is a very effective and cost-effective tool for secondary prevention, it is still not as good as primary prevention. CKD is mostly asymptomatic, thus early detection, prevention or halting progression is possible only via screening [START_REF] Li | Kidney health for everyone everywhere-from prevention to detection and equitable access to care[END_REF].

Screening of the general population is not cost effective [START_REF] Vanholder | Reducing the costs of chronic kidney disease while delivering quality health care: a call to action[END_REF][START_REF] Qaseem | Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: a clinical practice guideline from the American College of Physicians[END_REF]. Elective screening of high-risk groups (e.g. >65 years old, DM or hypertension, a family history of CKD, receiving potentially nephrotoxic drugs and suffering from AKI) has been suggested as a more efficient approach [START_REF] Li | Kidney health for everyone everywhere-from prevention to detection and equitable access to care[END_REF]. Thus far, screening strategies vary between countries, but patients with DM (93%) and hypertension (89%) are screened most frequently [START_REF]Global Kidney Health Atlas[END_REF]. Screening practices are influenced by country income and overall is suboptimal in Eastern and Central Europe [START_REF]Global Kidney Health Atlas[END_REF][START_REF] Rutkowski | Epidemiology of chronic kidney disease in central and eastern Europe[END_REF].

Screening consists of two parameters: serum creatinine determination, applying the Chronic Kidney Disease Epidemiology Collaboration formula to estimate the GFR; and measurement of the urine albumin:creatinine ratio (UACR). The Kidney Disease: Improving Global Outcomes guideline defines CKD as 3 months of persistent abnormalities in kidney function (e.g. eGFR <60 mL/min/1.73 m 2 or UACR 30 mg/g) [START_REF] Disease | Improving Global Outcomes CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease[END_REF]. The most practical approach for screening is a single determination of eGFR and UACR to classify CKD, if abnormal [START_REF]Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017[END_REF]. According to the ISN, the number of patients at high risk of CKD and screened is far from the desired range in the majority of LMICs, including several Eastern European countries [START_REF]Global Kidney Health Atlas[END_REF].

Preventing progression and minimizing complications of CKD

Intervening early in the course of CKD prevents progression to kidney failure and associated complications. It may also provide economic benefits [START_REF]Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017[END_REF]. All stakeholders linked with the disease (patients, physicians and authorities) should have a distinct role in the management protocol.

Patients. Educating patients to modify lifestyle factors is simple and cost-effective. For individuals with CKD, this encompasses smoking cessation [START_REF] Orth | Smoking: a risk factor for progression of chronic kidney disease and for cardiovascular morbidity and mortality in renal patients-absence of evidence or evidence of absence?[END_REF], decreasing salt intake [START_REF] Hosohata | Biomarkers for chronic kidney disease associated with high salt intake[END_REF], restricting dietary protein [START_REF] Disease | Improving Global Outcomes CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease[END_REF], limiting caloric intake in obese subjects [START_REF] Kovesdy | Obesity and kidney disease: hidden consequences of the epidemic[END_REF], following an optimal diet for glycaemic control in diabetic patients [START_REF] Hahr | Management of diabetes mellitus in patients with chronic kidney disease[END_REF], adherence to medication [START_REF] Nielsen | Adherence to medication in patients with chronic kidney disease: a systematic review of qualitative research[END_REF] and avoiding nephrotoxic herbs and traditional/alternative remedies [START_REF] Luyckx | Nephrotoxicity of alternative medicine practice[END_REF]. Obesity, DM, hypertension, tobacco use and excessive salt intake are more prominent in Eastern Europe. Therefore instruction of and collaboration with people is essential while avoiding a patronizing approach.

Healthcare professionals. Many studies have demonstrated that optimal management of primary kidney diseases and other diseases/factors that may result in slow CKD progression and improve outcomes. Therefore, treating obesity or metabolic syndrome [START_REF] Kovesdy | Obesity and kidney disease: hidden consequences of the epidemic[END_REF][START_REF] Hsu | Body mass index and risk for end-stage renal disease[END_REF], managing DM [START_REF] Wanner | Empagliflozin and progression of kidney disease in type 2 diabetes[END_REF][START_REF] Thomas | Diabetic kidney disease[END_REF], effectively controlling high blood pressure (BP) [START_REF]Non-communicable Disease (NCD) Risk Factor Collaboration. Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants[END_REF][START_REF] Xie | Renin-angiotensin system inhibitors and kidney and cardiovascular outcomes in patients with CKD: a Bayesian network meta-analysis of randomized clinical trials[END_REF][START_REF] Ruggenenti | Role of remission clinics in the longitudinal treatment of CKD[END_REF] and avoiding nephrotoxic drugs [START_REF] Pannu | An overview of drug-induced acute kidney injury[END_REF][START_REF] Lazarus | Adverse effects of proton pump inhibitors in chronic kidney disease-reply[END_REF] should be deemed key therapeutic options by healthcare professionals. Identifying and treating reversible causes of kidney injury early (e.g. hypovolemia, hypotension or urinary tract infection and obstruction) is vital.

CKD is highly prevalent and not all cases can be treated by nephrologists. Other specialists (cardiologists, diabetologists, geriatricians and neurologists) and general practitioners also play a pivotal role in the management of these patients. Therefore these professionals should keep abreast of updates Potential contributions to raise awareness about the burden of CKD and primary diseases/factors leading to CKD:

1. collaborate with national nephrology societies and the National Kidney Patients' Federation to increase awareness of the public, healthcare personnel and authorities toward CKD as a public health priority; 2. notify European and national societies of other specialties (family practitioners, internists, cardiologists and neurologists) to allow them to educate their members regarding CKD as a public health problem and 3. stimulate and play an advisory role in country-specific, patient-oriented research.

Proposed research topics:

• epidemiological studies on the incidence and prevalence of early stages of CKD and causes of CKD, • longitudinal studies on the course of diseases predisposing to CKD and • surveys on the awareness of public, healthcare personnel and authorities about CKD.

Potential contributions to detect CKD:

1. play an advisory role in conducting country-specific population-based surveys and research about the incidence and prevalence of CKD, 2. collaborate with European and national societies of other specialties to help inform and train their members about early detection of CKD, 3. organize local epidemiology and registry courses and/ or offer fellowships to young nephrologists for training in organizing/optimizing registry systems in their native countries and 4. support the development of high-quality renal registries (instead of aggregated data) to assess and optimize kidney care.

Proposed research topics:

• differences among various regions of a particular country on CKD incidence and prevalence, optimally by use of big data [START_REF] Saez-Rodriguez | Big science and big data in nephrology[END_REF]; • effects of early versus late referral of CKD patients and • economic burden of CKD as assessed by medical professionals in collaboration with health economists to collaborate with authorities on considering CKD a major public health problem in need of much larger healthcare and research budgets. on CKD management [START_REF] Jafar | Health education and general practitioner training in hypertension management: longterm effects on kidney function[END_REF]. Continuing medical education courses to train all healthcare workers are not practical; therefore, online educational programmes should be considered [START_REF] Li | Kidney health for everyone everywhere-from prevention to detection and equitable access to care[END_REF]. This is especially true in LMICs [START_REF] Levin | Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy[END_REF], where management of CKD patients is mostly performed by primary care providers. Secondary care referral to a nephrologist should be considered, at the latest, when eGFR falls to 30 mL/min/1.73 m 2 . The small number of nephrologists and nephrology trainees in Eastern and Central Europe (3.3 pmp; Western Europe 5.8 pmp) cannot be corrected in the near future and is clearly a major drawback to implementing any policy [START_REF]Global Kidney Health Atlas[END_REF].

Healthcare authorities. Authorities should be convinced by the kidney care stakeholders to prioritize CKD as a public health problem, finance educational courses, increase awareness of CKD and organize collaboration among various specialties related to CKD and with scientific societies to achieve these goals. Moreover, consumption of healthy food should be encouraged. Unhealthy nutrition must be limited by economic measures and national campaigns. Introducing measures to reduce the cost of healthy food, tax unhealthy products, restrict unhealthy food advertising and regulate specific food composition (salt, fats, trans-fats and sugar) is mandatory. Notifying the consumer of the health risks of the contents through food labelling has been suggested to be an optimal approach [START_REF] Luyckx | Preventing CKD in developed countries[END_REF].

Healthy environment and healthy kidneys. Reduced environmental pollution is also vital for kidney health because environmental and occupational pollutants frequently cause kidney injury. Long-term exposure to particulate matter, which primarily comprises solid particulates derived from the combustion of coal, gasoline and diesel fuels, may increase the risk of membranous nephropathy, and exposure to heavy metals and industrial and agricultural chemicals predisposes to kidney disease [START_REF] Xu | Environmental pollution and kidney diseases[END_REF]. Central and Eastern Europe have higher levels of pollution, mainly because of continued large-scale use of coal to generate electricity and rapid industrialization at the cost of environmental degradation [START_REF] Little | Public health in central and eastern Europe and the role of environmental pollution[END_REF][START_REF] Fitzgerald | Environmental pollution and child health in central and Eastern Europe[END_REF]. According to Greenpeace, the capital of Bulgaria, Sofia, boasted the highest levels of particulate matter 2.5 lm in Europe in 2018 [START_REF]Air Pollution Hotspots in Europe[END_REF].

Stimulating/prioritizing Tx and home dialysis as KRT modalities

When kidney failure develops, Tx is preferred because of its medical, social and economic advantages over dialysis [START_REF] Vanholder | Reducing the costs of chronic kidney disease while delivering quality health care: a call to action[END_REF]. However, the prevalence of Tx is low for several reasons. The most important factor is an imbalance between supply and demand of donor organs [START_REF]ERA-EDTA Registry Annual Report[END_REF]. According to the 2017 ERA-EDTA Registry, the prevalence of Tx was only 8.3 pmp in Kosovo versus 29.7 pmp in Ukraine [START_REF]ERA-EDTA Registry Annual Report[END_REF], but 509 pmp in Croatia (Table 2). The latter is the result of extensive policy measures targeting transplant coordination, donor hospital reimbursement, public awareness, donor legislation and donor quality [START_REF] Zivcic-Cosic | Development of the Croatian model of organ donation and transplantation[END_REF]. Therefore, although challenging, increasing Tx rates is possible in many regions of Europe if appropriate measures are taken. Optimizing the follow-up of transplant recipients may contribute to favourable graft and patient outcomes, although the scarcity of transplant nephrologists in many countries may be a drawback.

If Tx is impossible, and if palliative treatment is not considered, then dialysis remains the only alternative. There is wide variation in the prevalence of dialysis in Europe overall; it is 1077 pmp in Greece versus 180 pmp in Ukraine [START_REF]ERA-EDTA Registry Annual Report[END_REF]. Home dialysis, including home HD and peritoneal dialysis (PD), should be preferred over conventional in-centre HD because of better outcomes, quality of life and, in most countries, lower costs [START_REF] Vanholder | Reducing the costs of chronic kidney disease while delivering quality health care: a call to action[END_REF][START_REF] Kerr | Home hemodialysis: what is old is new again[END_REF][START_REF] Klarenbach | Economic evaluation of dialysis therapies[END_REF][START_REF] Van Der Tol | A call for harmonization of European kidney care: dialysis reimbursement and distribution of kidney replacement therapies[END_REF]. These modalities are not frequently utilized in Europe, and even less so in Eastern Europe.

In a recent survey of the distribution of KRT modalities in 10 Eastern and Central European countries, a majority of kidney failure patients (73%) were receiving HD, whereas PD and Tx were used less frequently [START_REF] Spasovski | Nephrology in the Eastern and Central European region: challenges and opportunities[END_REF]. If Tx or dialysis is not an option, conservative (palliative) care is an alternative. The number of subjects with kidney failure who do not want or cannot receive dialysis is increasing steadily [START_REF] Russon | Palliative and end-of-life care in advanced renal failure[END_REF]. Usually these patients are elderly or have multiple or severe comorbidities, although exceptions may occur.

Using the option of end-of-life care, it is essential to respect patient priorities to offer dignity and the best quality of life possible and acceptable to the patient. A number of ethical issues warrant consideration [START_REF] Russon | Palliative and end-of-life care in advanced renal failure[END_REF][START_REF] Rak | Palliative care for patients with end-stage renal disease: approach to treatment that aims to improve quality of life and relieve suffering for patients (and families) with chronic illnesses[END_REF]. Reportedly, conservative care is less frequent in Eastern Europe, an issue deserving further investigation. Furthermore, the legal frameworks supporting conservative or palliative care are apparently inadequate [START_REF] Van Biesen | Nephrologists' perceptions regarding dialysis withdrawal and palliative care in Europe: lessons from a European Renal Best Practice survey[END_REF].

For all treatment modalities, education on diet and adherence to medications may improve prognosis and patient rehabilitation.

Potential contributions to prevent progression and to minimize the complications of CKD: Proposed research topics:

• effects of diet and various treatment protocols directly or indirectly related to the progression of CKD. If the initial results of these pilot studies are encouraging, countrywide or transnational long-term projects may be planned considering early experience and lessons learned from the pilot initiatives.

Potential contributions to stimulate/prioritize Tx and home dialysis as a modality of KRT:

1. stimulate multitiered country policies and an approach to promote organ donation, as well as kidney Tx [START_REF]Joint Statement. Thematic Network on Improving Organ Donation and Transplantation in the EU[END_REF]; 2. provide solutions to increase Tx and home dialysis rates and 3. train local nephrologists on transplant and dialysis patient care.

Proposed research topics:

• surveys on the attitudes of the public towards deceased and live donor kidney donation;

Disseminating/implementing guidelines and guided therapy

One of the most effective ways to prevent treatment mistakes is to follow clinical best practice guidelines based on current evidence; thus guided therapy has recently become the standard of care [START_REF] Kredo | Guide to clinical practice guidelines: the current state of play[END_REF]. Simple measures and guided therapy are effective in improving the outcomes of kidney patients; however, guidelines are underused in nephrology [START_REF] Kamath | Implementation strategies for interventions to improve the management of chronic kidney disease (CKD) by primary care clinicians: protocol for a systematic review[END_REF]. Many barriers to implementing guidelines in LMICs have been suggested, including, but not limited to, language barriers, guideline complexity and lack of familiarity, awareness, agreement, knowledge, motivation, practicalities and skills, all of which can be identified and overcome effectively [80-82].

Encouraging/supporting country-specific, patient-oriented research

The general and medical infrastructure as well as the priorities of each country may differ significantly between countries. Therefore implementing and supporting country-specific surveillance strategies and conducting patient-oriented clinical studies are vitally important to the detection of major problems and planning health policy [45]. However, a national strategy for non-communicable diseases exists in only half of the countries in Central and Eastern Europe [START_REF]Global Kidney Health Atlas[END_REF] and the quality and quantity of research on this issue is far from adequate.

CONCLUSIONS

Globally, CKD is an important public health burden with significant medical, social and economic consequences. The extent of this problem is more prominent in LMICs, which includes many Eastern European countries, largely due to a lack of public awareness, suboptimal health infrastructure, higher prevalence of conditions leading to CKD and failure in addressing significant lifestyle factors. Fewer nephrologists, country-specific health problems and restricted funds for healthcare services may further enhance the burden of CKD, and limited countryspecific clinical research leads to a lack of specific data on the extent and characteristics of the problem for the Eastern European nephrology community. Education and organization are suboptimal in Eastern European countries. It is advisable to develop a roadmap for supporting clinical and epidemiological research based on factual data in these countries. The financial support for such activities may be shared between several European institutions to help national societies. The ultimate goal is to coordinate efforts that should lead to improved screening, diagnosis, prevention and treatment of CKD in this part of Europe.

• surveys on the factors defining the number of transplant recipients and of PD and home self-care and in-centre HD patients who are not transplanted, and also the factors impacting Tx;

• short-and long-term outcomes of patients on various KRT modalities;

• prevalence of treatment-specific complications (e.g. vascular access complications in HD patients, peritonitis in PD patients; rejections and infections in transplant recipients); • economic and social burden of various KRT modalities and • prevalence and reasons for applying or not applying conservative comprehensive care.

Potential contributions to disseminating/implementing guidelines and guided therapy:

1. encourage and support the development of simplified, adapted and patient-involved guidelines in local languages; 2. identify and help overcome barriers to the implementation of guidelines; 3. prepare pragmatic educational materials (e.g. slide decks, flow charts, algorithms and patient booklets); 4. encourage, support and carry out updates to adapted guidelines in parallel with the original publications and 5. organize educational meetings and interactive workshops on the implementation of guidelines.

Proposed research topics:

• surveys about guideline implementation,

• studies on the efficacy of guided therapy versus standard treatment protocols and • studies on the economic benefit of guided therapy.

Potential contributions to encourage/support country-specific, patient-oriented research:

1. train local nephrologists on research methodology and 2. assign experts as advisors for patient-oriented research.

  and below the thick line indicate low-medium income and high-medium income countries, respectively. a Ratio of each specific parameter in the index population compared with the whole population of that particular country. b

  each specific parameter in the index population compared with the whole population of that particular country. b

FIGURE 1 :

 1 FIGURE 1: Data reported for various countries in Eastern and Western Europe. (A) Variations in salt consumption. Prevalence of: (B) hypertension (raised blood pressure), (C) DM (raised blood glucose), (D) CKD Stages 3-5, (E) dialysis and (F) Tx. Data were obtained from several references[START_REF]ERA-EDTA Registry Annual Report[END_REF][START_REF] Xie | Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016[END_REF][START_REF]Noncommunicable Diseases Country Profiles[END_REF][START_REF] Erdem | Dietary sources of high sodium intake in Turkey: SALTURK II[END_REF][START_REF] Sengul | Changes in hypertension prevalence, awareness, treatment, and control rates in Turkey from 2003 to 2012[END_REF][START_REF] Suleymanlar | A population-based survey of chronic renal disease in Turkey-the CREDIT study[END_REF]. The colour scale from green to brown shows increasing prevalence; white denotes missing data in the ERA-EDTA Registry for those particular countries.

FIGURE 2 :

 2 FIGURE 2: Trends in crude CKD prevalence in various regions of the world from 1990 to 2016. Note that the highest relative increases were noted in Central and Eastern Europe. Adapted from Xie et al. [20].

FIGURE 3 :

 3 FIGURE 3: The algorithm outlines the major steps and pragmatic approach for decreasing the incidence and prevalence of CKD and for optimizing management during various stages of the disease. Interventions aim to raise awareness of underlying aetiologies at the beginning and encourage Tx or home dialysis when the stages of kidney failure and KRT dependency are reached.

Table 1 .

 1 Reasons for differences in various characteristics of CKD in Eastern European countries compared with Western Europe Unhealthy lifestyle due to rapid urbanization and unplanned infrastructure, which may give rise to increasing rates of non-communicable diseases (especially hypertension and DM). Less public awareness about CKD. Deficient recognition and recording of CKD and insufficient statistics on CKD-related morbidity and mortality.

	Inadequate management of predisposing diseases (e.g. DM, hypertension, obesity) or causative factors (e.g. herbal remedies) associated
	with CKD.
	Region-or country-specific problems (e.g. Balkan nephropathy).
	o Low Tx rates.
	Few nephrologists per million population.
	o Limited funds for healthcare services.
	o Inadequate research on CKD.
	List adapted from several references [2, 12, 14-22].

Table 2 .

 2 Frequency of various aetiologies and risk factors for CKD and prevalence of Stages 3-5 CKD, dialysis and Tx in the Eastern European countries

		Prevalence of	kidney Tx	(pmp) a , all	donors b
	Prevalence of	kidney Tx	(pmp),	deceased	donor a
			Prevalence of	dialysis	(pmp) a
			CKD Stages	3-5 prevalence	(crude) (%) a
				Salt intake	(g/day) a
				Tobacco	use (%) a
				Physical	inactivity (%) a
				Obesity	(%) a
				Elevated	BP (%) a
				DM	(%) a
				GNI per	capita (US$)
				GP	(millions)	42.4
					Country
						Ukraine

Table 3 .

 3 Frequency of various aetiologies and risk factors for CKD and prevalence of Stages 3-5 CKD, dialysis and Tx in Western European countries

		Prevalence	of kidney	Tx (pmp) a ,	all donors b
	Prevalence of	kidney Tx	(pmp),	deceased	donor a
			Prevalence of	dialysis	(pmp) a
			CKD 3-5	prevalence	(crude) (%) a
			Salt in-	take	(g/day) a
				Tobacco	use (%) a
			Physical	inactivity	(%) a
				Obesity	(%) a
				Elevated	BP (%) a
				DM	(%) a	9.2
			GNI per	capita	(US$)	21 990
				GP	(millions)	10.3
					Country	Portugal

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