Review

Global kidney health 2017 and beyond: a roadmap for

closing gaps in care, research, and policy
Adeera Levin†, Marcello Tonelli†, Joseph Bonventre, Josef Coresh, Jo-Ann Donner, Agnes B Fogo, Caroline S Fox, Ron T Gansevoort,
Hiddo J L Heerspink, Meg Jardine, Bertram Kasiske, Anna Köttgen, Matthias Kretzler, Andrew S Levey, Valerie A Luyckx, Ravindra Mehta,
Orson Moe, Gregorio Obrador, Neesh Pannu, Chirag R Parikh, Vlado Perkovic, Carol Pollock, Peter Stenvinkel, Katherine R Tuttle, David C Wheeler,
Kai-Uwe Eckardt†, on behalf of the ISN Global Kidney Health Summit participants*

Lancet 2017; 390: 1888–917 The global nephrology community recognises the need for a cohesive plan to address the problem of chronic kidney
Published Online disease (CKD). In July, 2016, the International Society of Nephrology hosted a CKD summit of more than 85 people
April 20, 2017 with diverse expertise and professional backgrounds from around the globe. The purpose was to identify and prioritise
[Link]
key activities for the next 5–10 years in the domains of clinical care, research, and advocacy and to create an action
S0140-6736(17)30788-2
plan and performance framework based on ten themes: strengthen CKD surveillance; tackle major risk factors for
*Members of the Working
Groups listed in the appendix CKD; reduce acute kidney injury—a special risk factor for CKD; enhance understanding of the genetic causes of
†co-chairs of the ISN Global
CKD; establish better diagnostic methods in CKD; improve understanding of the natural course of CKD; assess and
Kidney Health Summit on behalf implement established treatment options in patients with CKD; improve management of symptoms and complications
of the International Society of of CKD; develop novel therapeutic interventions to slow CKD progression and reduce CKD complications; and
Nephrology increase the quantity and quality of clinical trials in CKD. Each group produced a prioritised list of goals, activities,
Department of Medicine, and a set of key deliverable objectives for each of the themes. The intended users of this action plan are clinicians,
University of British Columbia,
Vancouver, BC, Canada
patients, scientists, industry partners, governments, and advocacy organisations. Implementation of this integrated
(A Levin MD); Department of comprehensive plan will benefit people who are at risk for or affected by CKD worldwide.
Medicine, University of
Calgary, Calgary, AB, Canada Introduction
(M Tonelli MD); Brigham and
Women’s Hospital, Harvard
Defining the problem Background statements
Medical School, Boston, MA, Chronic kidney disease (CKD) is increasingly recognised
USA (J Bonventre MD); Johns as a global public health problem.1 Kidney failure is the • CKD affects as many as 10–15% of the population
Hopkins University Bloomberg most severe form of CKD, and is fatal if not treated by worldwide, and is due to multiple causes
School of Public Health, George • CKD is associated with impaired quality of life and
W Comstock Center for Public
renal replacement therapy (RRT), which can be dialysis or
Health Research and kidney transplantation. The prevalence and associated strongly reduced life expectancy
Prevention, and Johns Hopkins burden of CKD is rising worldwide;2–4 with the fastest • CKD is associated with increased risk of cardiovascular
University School of Medicine, growth occurring in low-income and middle-income disease, different disease manifestations, and more
Welch Center for Prevention, frequent and severe cardiovascular disease outcomes
Epidemiology and Clinical
countries. The incidence of acute kidney injury (AKI) has
Research, Baltimore, MD, USA also substantially increased over the past two decades, • CKD reflects a serious complication of many different
(J Coresh PhD); International and AKI is now recognised as an important cause of CKD diseases, including diabetes, hypertension, and systemic
Society of Nephrology,
and kidney failure. immune disorders
Brussels, Belgium • The cause of CKD remains uncertain in a large proportion
(J Donner MLT; Department of
Pathology, Microbiology and
of affected individuals, hindering specific therapeutic
Key messages
Immunology, Vanderbilt approaches
University Medical Center, • A global collaborative effort of all stakeholders is required • The mechanisms that cause progressive kidney failure and
Nashville, TN, USA
for a multifaceted action plan to combat the growing associated systemic complications, including
(A B Fogo MD); Merck Research
Laboratories, Boston, MA, USA burden of CKD and its complications cardiovascular disease, remain incompletely understood,
(C S Fox MD); Department of • More work is needed to understand the causes and resulting in few available targeted therapies
Internal Medicine pathophysiology of CKD at the individual patient level, • Nephrology lags behind other medical disciplines with
(R T Gansevoort PhD) and
and at the population level in regions where CKD is respect to the number, size, and quality of clinical trials
Department of Clinical
Pharmacy and Pharmacology endemic undertaken
(H J L Heerspink PhD); University • Existing data and biomaterial sources must be better used • CKD and acute kidney injury are related manifestations of
Medical Center Groningen, by promoting collaborative efforts and reducing renal impairment with mutual predisposition, functional
University of Groningen,
administrative hurdles and structural overlap, and potentiating adverse
Groningen, Netherlands; The
George Institute for Global • The clinical and research workforce needs to grow consequences
Health, Sydney, NSW, Australia substantially in order to address the global burden of CKD, • The costs of treating CKD-associated complications
(M Jardine PhD); Concord especially in low and middle income countries (including kidney failure) provide a challenge for health-care
Repatriation General Hospital,
• A concerted effort is required to increase the number, size, budgets that cannot be met in many parts of the world
Concord, NSW, Australia
(M Jardine); Hennepin County and quality of clinical trials investigating how to reduce • Successful prevention and treatment of CKD is strongly
Medical Center, Minneapolis, the burden of CKD and its complications linked to progress on the Sustainable Development Goals
MN, USA (B Kasiske MD);
University of Minnesota, CKD=chronic kidney disease. CKD=chronic kidney disease.

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CKD is associated with impaired quality of life and research about how to prevent, mitigate, and cure CKD. Minneapolis, MN, USA
substantially reduced life expectancy at all ages. It is also Knowledge about mechanisms that cause progressive loss (B Kasiske); Division of Genetic
Epidemiology, Faculty of
associated with excess risk for cardiovascular disease and of kidney function and its complications is also insufficient. Medicine and Medical Center,
other conditions such as diabetes, infection, and cancer.5 Inconsistency and variability of clinical information University of Freiburg,
Even patients in wealthy countries do not always have between studies hinder pooling of data that could enable Freiburg, Germany
optimal access to preventive treatment and methods for analyses with sufficient statistical power and adequate (A Köttgen MD); Department of
Internal Medicine and
the early detection of CKD. There are few strategies representation of less common diseases. Several high- Department of
currently available to slow CKD progression. Although profile interventional trials of promising therapies did not ComputationalMedicine and
RRT has been available for decades in high-income show a significant benefit, which discourages the search Bioinformatics, University of
countries, relatively little is known about the benefits of for innovative treatment approaches.24–29 Nephrology lags Michigan, Ann Arbor, MI, USA
(M Kretzler MD); Tufts Medical
RRT compared with conservative care in some patient behind other medical disciplines in terms of the number, Center, Tufts University School
groups, such as those with multi-morbidity, or advanced size, and quality of completed clinical trials. There are of Medicine, Boston, MA, USA
age. In low-income and middle-income countries, most many reasons for this, including few promising molecular (A S Levey MD); Institute of
people with kidney failure have insufficient access to life- targets, the slow rate of progression in many forms of CKD Biomedical Ethics and Klinik
für Nephrologie University
saving dialysis and kidney transplantation.6,7 Worldwide, that require long observation periods, uncertainty about Hospital, University of Zurich,
only half of those people requiring RRT can be treated; the potential of surrogate markers, a culture that does not Zurich, Switzerland
estimates of the number who are untreated range from foster the robust testing of focused hypotheses, and a (V A Luyckx MBBCh);
Department of Medicine,
2·5 million to 5 million.6 The costs of treating CKD and failure to recognise clinical equipoise that would justify
University of California,
its complications are unaffordable for governments and such trials. Since 2014, several international initiatives San Diego, CA, USA
individuals in many parts of the world. Annual costs of have emerged to foster collaboration in observational and (R Mehta MD); Department of
dialysis and kidney transplantation alone range interventional research, including KDIGO, ISN Advancing Internal Medicine and Charles
and Jane Pak Center of Mineral
between US$35 000 and $100 000 per patient. Although Clinical Trials (ISN-ACT) and International Network of
Metabolism and Clinical
better access to dialysis and transplantation in low- CKD cohort studies (ISN-iNET CKD), the CKD Prognosis Research, University of Texas
income and middle-income countries reflects progress Consortium (CKD-PC), and the Kidney Health Initiative Southwestern Medical Center,
on development goals, the associated costs have profound (KHI). Dallas, TX, USA (O Moe MD);
Faculty of Health Sciences,
consequences for families and health-care systems, and
Universidad Panamericana,
the provision of RRT depends on sustainable health-care The need for a plan Mexico City, Mexico
infrastructure, personnel, and supplies.8 Medications In view of the need for a cohesive plan to address the (G Obrador MPH); Department
that attenuate the course of CKD and its consequences problem of CKD, the ISN organised a summit in of Medicine, University of
Alberta, Edmonton, AB,
are substantially less expensive than RRT, but still out of
Canada (N Pannu MD); Program
reach of many patients with CKD.9 of Applied Translational
CKD is defined by the Kidney Disease: Improving Global Panel: Key areas and themes Research, Department of
Outcomes (KDIGO) CKD guideline as abnormalities of Medicine, Yale University, New
Improve the identification of CKD and reduce risk factors Haven, CT, USA
kidney structure or function, present for more than for CKD (C R Parikh PhD); Veterans
3 months, with implications for health.10 Although there Theme 1: Strengthen CKD surveillance Affairs Medical Center,
are issues in identifying population prevalence based on Theme 2: Tackle major risk factors for CKD West Haven, CT, USA
this definition,11 as much as 10–15% of the adult population (C R Parikh); The George
Theme 3: Reduce acute kidney injury—a special risk factor Institute for Global Health,
are affected worldwide.12–17 Nevertheless, CKD is not for CKD Sydney, NSW, Australia
included in most priority lists of non-communicable (V Perkovic PhD); University of
diseases, and few countries have explicit policies or public Improve the understanding of causes and consequences Sydney, Sydney, NSW,
programmes aimed at CKD prevention and control. This is of CKD Australia (V Perkovic); Kolling
Theme 4: Enhance understanding of the genetic causes of CKD Institute of Medical Research,
despite the fact that the presence of impaired kidney University of Sydney, Sydney,
function is a risk amplifier of all non-communicable Theme 5: Establish better diagnostic methods in CKD NSW, Australia (C Pollock PhD);
diseases, and is associated with the use of more Theme 6: Improve understanding of the natural course of CKD Division of Renal Medicine,
resources.3,8,18–23 Acute events such as infection, dehydration, Department of Clinical Science,
Improve outcomes with current knowledge Intervention and Technology,
and exposure to toxins or contrast media during imaging Theme 7: Assess and implement established treatment Karolinska Institutet,
can affect kidney function, especially in people with options in patients with CKD Stockholm, Sweden
underlying CKD. Recognising the need for action, an Theme 8: Improve management of symptoms and (P Stenvinkel MD); Providence
increasing number of global advocacy initiatives such as Medical Research Center,
complications of CKD Providence Health Care Kidney
World Kidney Day, International Society of Nephrology Research Institute, Nephrology
(ISN) 0by25, and the Lancet Kidney Campaign aim to raise Develop and test new therapeutic strategies Division and Institute for
public awareness of the consequences, costs, and Theme 9: Develop novel therapeutic interventions to slow Translational Health Sciences,
importance of both CKD and AKI. CKD progression and reduce CKD complications University of Washington,
Spokane, WA, USA
Despite the many recognised causes of CKD such Theme 10: Increase the quantity and quality of clinical trials
(K R Tuttle MD); Centre for
as diabetes, hypertension, vascular disease, or in CKD Nephrology, Royal Free
glomerulonephritis, the aetiology of CKD remains CKD=chronic kidney disease.
Hospital, University College
London, London, UK
uncertain in most affected individuals, which hinders

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(D C Wheeler MD); and Vancouver, BC, Canada, in July, 2016, co-chaired by countries compared with low-income countries. A meta-
Department of Nephrology authors AL, MT, and K-UE. Participants included more analysis of 100 studies of CKD prevalence resulted in an
and Hypertension, University
of Erlangen-Nürnberg,
than 85 individuals with diverse international expertise estimate of global CKD prevalence of 13% (appendix
Erlangen, Germany (clinicians, basic scientists, clinical researchers, p 5),32 which might overestimate the true prevalence
(K-U Eckardt MD) epidemiologists, methodologists, and industry scientists). given the limitations in the source literature. Other work
Correspondence to: The purpose of the meeting was to identify and prioritise has documented substantial variation in the apparent
Dr A Levin, University of British key activities for the next 5–10 years in clinical care, prevalence of CKD across studies done in different
Columbia, St Paul’s Hospital,
research, and advocacy; to identify potential partners European populations (eg, the prevalence of CKD in
Vancouver, BC V6Z1Y8, Canada
alevin@[Link] within and outside the nephrology community; and to northern Germany is five times higher than that in Italy
For more on World Kidney Day create an action plan and performance framework. This and Norway).33 It is unclear how much of this variation is
see [Link] was the first time that such an activity has been undertaken because of research methods and how much caused by
For more on 0by25 see by the global nephrology community. true population differences.34 Data published in 2016
[Link] from the USA13 suggest that initial increases in CKD
For the Lancet Kidney Brief methods prevalence12 have plateaued since the mid-2000s,13 largely
Campaign see [Link]. Participants met for 2·5 days to develop the plan, which due to a decrease in CKD in people older than 65 years.
com/campaigns/kidney
was based on ten themes predefined by the three co- However, CKD prevalence in high-risk groups (such as
For more on KDIGO see
[Link]
chairs with input from the ISN Executive Committee African-Americans and people with diabetes) has
(panel). All delegates participated in two of ten working continued to rise.
For the ISN see
[Link] groups, each of which addressed a single theme. We Dialysis and kidney transplantation registries are non-
For the CKD Prognosis
identified key issues and did supporting literature existent in many countries, and in many countries, there
Consortium see [Link] searches before the meeting to facilitate the working is no mandate to enter patient data into registries, nor to
[Link]/ckdpc groups. By use of an iterative process, each group ensure the accuracy of them. Furthermore, RRT is only
For the Kidney Health Initiative produced a prioritised list of key issues, goals, activities, one measure of the burden of kidney failure—many
see [Link] and deliverable objectives. Special emphasis was placed patients worldwide are unable to receive or choose not to
khi/[Link]
on aligning these objectives with the Sustainable have RRT. Population-based registries of less severe
See Online for appendix Development Goals (SDGs).30 forms of CKD are infrequent in most countries.
The next sections of this Review elaborate on the Identification of individuals with CKD relies primarily
specific themes discussed at the ISN summit, describing on serum creatinine measurements and equations to
the current knowledge gaps and activities required to estimate glomerular filtration rate (GFR). Measurement
move the field forward. The performance framework is of creatinine and albuminuria are central to the diagnosis
articulated to facilitate tracking of the activities, since and stage classification of CKD. Prevalence estimates
“what gets measured gets done”. Progress will be remain sensitive to calibration errors in creatinine
reported regularly at national and international meetings, measurement.35 The CKD Epidemiology Collaboration
in peer-reviewed publications, and as part of the Global equation for estimating GFR is becoming the global
Kidney Health Atlas (GKHA), to be updated every 2 years. standard, but much of the older literature used the
The GKHA describes updates on CKD-relevant access to Modification of Diet in Renal Disease Study equation,
care, health infrastructure, national and regional policies, which results in somewhat higher prevalence estimates.36,37
and research capacity. Urine measures of protein for CKD (protein-to-creatinine
ratio, albumin-to-creatinine ratio [ACR], and qualitative
Improve the identification of CKD and reduce dipstick for protein or albumin) are more difficult to
risk factors for CKD standardise and suffer from high physiological variation
Theme 1: Strengthen CKD surveillance of ACR,38 with dipsticks providing even lower accuracy.
Although the number, geographical distribution, size, Few studies have fully staged CKD by cross-classifying
and quality of the studies examining CKD prevalence GFR and ACR categories, as recommended by the most
and incidence have increased over the past decade, global recent KDIGO CKD guideline.10 Estimates of reduced
capacity for CKD surveillance remains far less developed GFR or increased albuminuria have not been confirmed
than that for disorders such as hypertension, diabetes, in most studies, which might have led to overestimation
and cardiovascular disease. Moreover, fewer data on in prevalence figures.11,39
prevalence are available in low-income and middle- The first step to making progress in improving CKD
income countries as compared with high-income monitoring activities (table 1) is to fully engage
countries. stakeholders by making sure the rationale for monitoring
A 2010 systematic review identified 33 studies that programmes is clear and tailored appropriately for
reported age-specific and sex-specific prevalence of CKD different settings (appendix p 6).
in representative populations worldwide.31 The global To achieve valid comparisons over time (when
prevalence of CKD was estimated at about 10%, meaningful trends in kidney function are often a small
corresponding to almost 500 million people, with similar relative change of 2–10% per year10) and across regions,
estimates in men and women, and in high-income standardisation of measurements and methods must be

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Partners Deliverables
Monitor the prevalence of CKD
Develop and disseminate a clear rationale Policy experts, third party payers Published position statement; clarify the different measures of CKD
for monitoring CKD prevalence burden (renal replacement therapy, CKD stages, use of health-care
facilities, death from kidney failure, costs) in the general population
and high-risk groups
Achieve a uniform measurement of CKD International Federation of Clinical Published position statement; develop and share quality control
markers in CKD prevalence studies Chemists (IFCC) procedures and materials
Promote inclusion of measuring CKD and Organisers of large studies, registries, Inventory of studies of patients with and without CKD and CKD
its awareness in all large chronic disease such as WHO STEPS (102 countries), for awareness; assembly of a task force to identify key contacts and
cohort or health surveys cardiovascular disease, diabetes, and include reporting of CKD and CKD awareness
oncology surveillance
Develop a plan to harness claims data for Health-care providers, aggregators of Established collaboration with regional and national societies and
CKD surveillance health data (eg, US Medicare, national registries; workshop to assess feasibility and define action plan details;
health data repositories) encourage validation of diagnostic codes in different regions; develop
a plan to monitor strengths and limitations of claims data over time
Incorporate new CKD classification in WHO WHO Incorporation into ICD-11
ICD coding
Establish CKD registries in special populations
Establish registries of chronic dialysis and Established registries Inventory of CKD registries as part of the GKHA project; task force to
transplantation in all countries explore the development of a generic software application; define
minimal dataset required for these registries, facilitate
implementation, suggest methods to assess comprehensiveness;
encourage the use and usefulness of the registries to improve policy,
observational research, and clinical trials
Establish registries for special CKD Established registries, special interest Inventory of CKD registries as part of the GKHA project; task force to
groups—eg, children, rare diseases, special groups explore the development of a generic software application to facilitate
causes, and regions where CKD appears to the establishment of CKD registries; define criteria for when a registry
be endemic is high priority; encourage effective use of the registries to improve
policy, observational research, and clinical trials
Identify individuals with CKD in high-risk groups
Implement the respective KDIGO CKD Professional societies, medical and Implementation survey; case finding strategies in high-risk groups to
guideline public health agencies be implemented in most countries
Support efforts to strengthen the evidence Researchers and funding agencies Research reports (focus on high-risk groups by condition, ethnicity,
base underlying additional strategies for and region)
case finding in high-risk groups
Ensure that wherever serum creatinine is Clinical chemists (IFCC) Focused extension of the GKHA project; IFCC committees; national
measured, estimated GFR is reported and international laboratory professional groups and health-care
institutions
Develop and share computer-assisted Electronic medical record experts, Workshop to assess feasibility; position statement
methods for identification and follow-up health-care systems
of CKD cases

CKD=chronic kidney disease. STEPS=STEPwise approach to Surveillance. ICD=International Classification of Diseases. GKHA=Global Kidney Health Atlas. KDIGO=Kidney
Disease: Improving Global Outcomes. GFR=glomerular filtration rate.

Table 1: Theme 1, goals and actions to strengthen CKD surveillance

of high quality. To address this, large studies could use of medical claims data for CKD surveillance would be
consider shipping samples to a reference laboratory; complementary and should also be seriously considered.
reference materials could be prepared with known values As electronic medical records are becoming standard
for use in multiple studies worldwide; and where worldwide, the potential for aggregating information is
appropriate, point-of-care testing with reliable accuracy large, although the validity of claims or International
could be implemented that would increase the Classification of Diseases (ICD)40 codes for various
accessibility of diagnostic testing globally. medical conditions is limited. Codes for identifying CKD
A systematic effort to ensure the inclusion of CKD are often very insensitive, missing most diseases, but are
measures in large ongoing or planned chronic disease quite specific.41,42 Even unvalidated codes can give
studies could greatly enhance global efforts for CKD important clues to the evolving CKD epidemic. For
surveillance. The cost of including and standardising example, a recent publication from China43 showed that
measurements of serum creatinine and albuminuria in 19 million people discharged from tertiary hospitals,
would be modest compared with the total cost of such the prevalence of CKD due to diabetes was higher than
surveys, especially if implemented in the context of other the prevalence of glomerulonephritis, in stark contrast to
non-communicable disease-related initiatives. Systematic the situation a decade ago.43 When electronic medical

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records include laboratory data, researchers will be able to compare individual risk across countries and enable
apply standardised definitions and staging of CKD to delivery of targeted therapies. Increasing efforts to use
large populations. For example, Carrero and colleagues44 albuminuria and eGFR in combination should be coupled
tracked the prevalence of CKD in over 1 million people in with reporting of eGFR whenever serum creatinine is
the Stockholm region, and showed that even in a high- measured. This is already the standard in much of the
income country with universal health care, not all patients world and can be implemented at minimal cost elsewhere
with advanced CKD consult a nephrologist for various if digital data on age and sex are available.47 Point-of-care
reasons, including restricted access to services, personal testing is now available for use in rural and remote areas,
choice, and physician’s choice. Given the high cost of which should improve ability to determine eGFR in low-
dedicated research studies and the increasing income and middle-income countries, although the
computerisation of health-care records, development of practicality and sustainability of long-term use in these
methods to increase the validity of imperfect health-care settings has not been assessed.
data appears to be a promising option for improving Once CKD is identified, health-care providers might
global CKD surveillance, especially in conjunction with need support with management. Computer-assisted
focused validation studies.45 methods such as electronic decision support tools and
ICD coding forms the foundation for the systematic protocols are being used in many settings to identify,
classification and enumeration of disease globally. follow, and care for patients with CKD.48,49 Sharing these
Therefore, it is vital that the most recent KDIGO CKD methods can be an efficient way to advance CKD
classification scheme, which is based on estimated GFR monitoring and care; combining implementation efforts
(eGFR) and albuminuria, is integrated into the upcoming with cluster randomised designs to show efficacy should
ICD-11 coding system. Additionally, a uniform system for lead to continued improvement and further investment.
specific coding of causes of CKD should be adopted Although there is much enthusiasm for population-
worldwide; a potential candidate is the scheme by the based CKD screening, the evidence base supporting this
European Renal Association-European Dialysis and approach is insufficient. Since expectations for potential
Transplant Association (ERA-EDTA), which was benefits of screening are often substantially different
developed in collaboration with the International Health from true benefits, screening strategies should be
Terminology Standards Development Organisation developed and tested in a randomised setting so that
(IHTSDO).46 efficacy can be appropriately measured. Although this
One special population of interest is people with has not yet been done for CKD, opportunities do exist to
kidney failure who receive RRT (ie, dialysis or assess new strategies with control groups, possibly using
transplantation); the prevalence of RRT reflects access to a stepped wedge design with cluster randomisation—for
For the CanSolveCKD study care and the burden of severe CKD—both of which are example, CanSolveCKD aims to screen Indigenous
Identifying diabetes and CKD relevant to society and decision makers as well as to communities for CKD comparing a standard and an
in indigenous communities see
[Link]
individuals. Therefore, emphasis should be placed on enhanced approach.
earlier-diagnosis/identifying- establishing registries of chronic dialysis and trans­
diabetes-and-ckd-in-indigenous- plantation in all countries. Identifying patients who Theme 2: Tackle major risk factors for CKD
communities-case-finding-in- need RRT but do not receive it is an important, albeit CKD has multiple causes, both inherited and acquired.
indigenous-communities/
challenging task. Given the specialised and expensive Some risk factors for CKD, particularly diabetes and
nature of RRT and the rapid conversion of medical care hypertension, are well known; others are emerging, and
into the digital age, there is an excellent opportunity to yet others are presumably unknown (table 2). Including
improve the quality and coverage of such registries. measures of kidney function (serum creatinine with
Shared minimal data standards and architecture could eGFR or albuminuria) in population-based health
greatly facilitate this work. surveys or assessments of non-communicable disease
Simple registries for special populations such as burden will not only facilitate CKD surveillance, but
children, patients with rare diseases, and residents of could also help to identify unknown risk factors and
regions where CKD appears to be endemic (ie, hotspots) assist efforts to control known risk factors.
should collect data to support targeted efforts for An example of unknown causes and risk factors for CKD
improved care and prevention and clinical trials. is the hotspots of CKD of unidentified origin (CKDu) in
Establishing and promoting a minimum dataset for specific regions close to the equator. These clusters of
registries (regardless of population or location) would CKDu are an important and growing health problem;
enhance comparability across countries and facilitate CKDu might be the leading cause of death affecting young
global estimates of CKD prevalence. field workers in parts of Sri Lanka, Central America, and
A third population of interest is high-risk groups South India.50 Despite the recognition of these hotspots,
(eg, patients with known hypertension, diabetes, or there has been little success in identifying the root cause,
cardiovascular disease) in which testing for CKD is already which could include recurrent AKI; heat stress;
recommended. Supporting efforts to increase testing for dehydration; infections; exposure to agrochemicals, over
both albuminuria and eGFR will help to understand and the counter medication, heavy metal contamination, poor

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Partners Deliverables
Identify unknown risk factors for CKD
Promote inclusion of measuring CKD in all large ·· Inventory of studies including and not
communicable and non-communicable disease including CKD (and CKD awareness); task force
surveys to identify key contacts and include CKD and
CKD awareness reporting
Establish and implement comprehensive research ISN, WHO, and governments Position statements and research reports
strategies to identify the causes of endemic CKDu including: case definitions, research agendas,
hotspots using a lifecycle approach standardisation of data collection tools;
consistent framework for surveillance and
investigation for epidemics of CKD around the
world with reduction in time from
identification to solving of problem, through
this consistent approach
Mitigate known risk factors for CKD—diabetes
Promote healthy lifestyles and food composition, Governments, payers, regulatory authorities, Appropriate references to the respective
implement prevention programmes, surveillance, health-care organisations, patients, community recommendations in publications, educational,
case finding, and treatment according to local or groups, professional groups, global, regional, and and advocacy activities of nephrology
regional needs and guidelines national societies, public health practitioners organisations; reduction in proportion of
patients with kidney failure and diabetes
Assess for the presence of CKD in individuals with ·· Implementation survey
diabetes
Mitigate known risk factors for CKD—hypertension
Promote healthy lifestyles and prevention Governments, payers, health-care organisations, Appropriate references to the respective
programmes, implement surveillance, case finding, regulatory authorities, patients, community groups, recommendations in publications, educational,
and treatment according to local or regional needs professional groups, global, regional, and national and advocacy activities of nephrology
and guidelines societies for hypertension and cardiovascular health, organisations; improved blood pressure control
public health practitioners in populations at risk
Assess the presence of CKD in individuals with Governments, payers, regulatory authorities, Implementation survey
hypertension health-care organisations, patients, community
groups, professional groups, global, regional, and
national societies, public health practitioners
Mitigate known risk factors for CKD—prescribed medications
Raise awareness of long-term medication use as a risk Funding agencies, industry partners, and research Research reports; reduction in proportion of
factor for CKD networks patients with kidney failure attributable to
medication overuse or misuse
Educate public and health practitioners about correct NGOs, governments, practitioners, pharmacists, Inclusion in CME programmes
prescribing methods of potentially nephrotoxic CME organisations, communities, health insurance
medications, and need for surveillance organisations
Mitigate known risk factors for CKD—traditional and alternative remedies
Identify which (if any) traditional, alternative, and ·· Research reports
herbal remedies are risk factors for CKD
Establish a health promotion and public education NGOs, governments, traditional healers, alternative Inclusion in CME programmes
programme on the risk of the use of traditional and practitioners, media, communities, and public
complementary medicine health practitioners
Require regulation of alternative medicine MOHs, industry partners, and alternative remedy Task force to establish a concrete strategy with
manufacture, labelling, and marketing manufacturers tailored approaches
Assess the presence of CKD in individuals with Governments, NGOs, practitioners, traditional ··
significant exposure to remedies that have been healers, communities, global, regional, and national
shown to be risk factors for CKD societies, and researchers
Mitigate known risk factors for CKD—kidney stones
Promote access to adequate clean water, healthy diets Communities, governments, professional ··
(eg, those with sodium and protein), and work associations (Centers for Disease Control and
conditions that avoid dehydration Prevention, American College of Physicians, Caring
for Australians with Renal Impairment, Urology
associations), health-care organisations, water
companies, public health practitioners
Assess the presence of CKD in individuals that have Urologists, primary care providers, and Survey existing guidelines on kidney stones for
previously had kidney stones nephrologists the inclusion of this recommendation and work
towards its inclusion in future updates
(Table 2 continues on next page)

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Partners Deliverables
(Continued from previous page)
Mitigate known risk factors for CKD—infections
Endorse population-level infection prevention and Public health providers and campaigners, Centres ··
control policies and participate in educational for Disease Control and Prevention, and primary
activities care providers
Increase access to vaccinations against infections that Public health providers and campaigners, Centres ··
are linked to AKI or CKD, or both for Disease Control and Prevention, and primary
care providers
Do studies to assess the effect of interventions that Centres for Disease Control and Prevention (regional Epidemiological studies showing a positive
increase access to treatment for infections on the and national) effect of interventions that increase access to
incidence and prevalence of infection-related AKI and treatment for infections on the incidence and
CKD prevalence of infection-related AKI and CKD
Mitigate known risk factors for CKD—poor maternal and fetal health
Increase the understanding of the link between Obstetricians, paediatricians, epidemiologists, Research reports; increase surveillance practices
variations in birthweight, gestational age, exposure public health practitioners, and researchers of high-risk births and mothers in specific
to gestational diabetes or pre-eclampsia and the regions
development of CKD in the fetus during childhood
and adulthood
Document each child’s birthweight, gestational age at MOH, WHO, traditional birth attendants, Survey existing documentation policy as part of
birth, exposure to gestational diabetes, pre- community health workers, health information an extension of the Global Kidney Health Atlas
eclampsia, and any neonatal AKI, and maintain this systems, paediatricians, neonatologists, project
information in their health record in high-income obstetricians, patients (build upon MDG advances in
countries, and establish methods for data capture in maternal and child health)
low-income and middle-income countries
Promote strategies to improve maternal and fetal Patients, communities, public health practitioners, Appropriate references to the respective
health by reduction of risk factors—eg, smoking, and WHO guidelines recommendations in publications, educational,
obesity, diabetes, alcohol, and infections; and and advocacy activities of nephrology
improve socioeconomic factors—eg, access to family organisations
planning, equity and education for women, reduction
of poverty, and adequate nutrition

CKD=chronic kidney disease. CKDu=CKD of unknown cause. ISN=International Society of Nephrology. NGO=non-governmental organisation. CME=Continuing Medical
Education. MOH=ministry of health. AKI=acute kidney injury. MDG=Millennium Development Goals.

Table 2: Theme 2, goals and actions to tackle major risk factors for CKD

quality drinking water; or some combination thereof.51–60 bodyweight) for CKD prevention and variance of such
Kidney biopsy samples in patients with CKDu show targets, eg, by age, gender, and ethnic origin.
chronic interstitial nephritis. Because proteinuria is mild Nephrotoxin exposure is a common and under-
or absent, simple urinalysis is not effective in screening for recognised risk factor for AKI and CKD.68–74 Nephrotoxic
these cases. Comparative studies of patients with CKDu agents include prescribed medications—eg, non-steroidal
from different areas are urgently needed to identify anti-inflammatory drugs (NSAIDs), iodinated contrast
similarities and differences that could help to identify the media, and some traditional and alternative remedies.
cause or causes of CKD in these populations. Because of Over 80% of people in low-income and middle-income
limitations in resources and infrastructure, diagnosing countries are estimated to use traditional remedies that
and characterising CKDu, determining its incidence and are often the only affordable or accessible means of health
prevalence, and assessing exposures remains challenging, care.75 Many of these remedies are untested and
despite recognition of CKDu for over 10 years in several unregulated, with potential for inter-product variability
regions. and high risk of toxicity.76 Electronic prompting and
Diabetes and hypertension are the dominant global risk prescription tracking might reduce medication errors,
factors for CKD. Obesity is closely linked to diabetes and overuse, and nephrotoxicity, especially in high-income
hypertension, and might also predispose people to CKD. countries. Such efforts should be combined with
Good management of diabetes, hypertension, and excess education of the public and health practitioners about
bodyweight reduces the risk of CKD and improves correct prescribing of potentially nephrotoxic medications
outcomes in patients with CKD.61–67 However, several and the need for surveillance. There is also increasing
important questions remain. For example, only about a interest in de-prescribing medications, especially in the
third of patients with diabetes develop CKD; identifying elderly due to high incidence of side-effects and
factors that protect against CKD in the presence of questionable effectiveness.77–80 Surveillance for CKD
diabetes could inform novel therapeutic approaches. among those exposed to potential nephrotoxins (including
Studies are also still required to optimise risk factor traditional remedies) should be a priority, especially in
targets (eg, Haemoglobin A1c, blood pressure [BP], low-income and middle-income countries.

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Kidney stones are another important CKD risk eGFR to baseline, are associated with long-term risk of
factor.81–83 Modifiable contributors to the risk of developing de-novo CKD, CKD progression, and kidney failure in
kidney stones include diet and environmental multiple clinical settings.113–115 In a meta-analysis
exposures.82,83 Individuals who have had a kidney stone from 2012,115 survivors of hospital-associated AKI were
are at higher risk for another one, and secondary 8 times more likely to develop CKD. Occurrence of AKI
prevention is key to reduce risks of recurrent stones and in people without CKD is a risk factor for CKD, and pre-
CKD.82,84 Activities to reduce the risk of kidney stones (eg, existing albuminuria and reduced eGFR are strong risk
ensuring adequate intake of clean water and work factors for AKI.116–120 Chronic kidney damage, impaired
conditions that avoid dehydration) together with renal reserve, and compromised vascular autoregulation
appropriate follow-up of people with a history of kidney might be contributors to AKI risk in the CKD population.
stones could prevent long-term complications of CKD. However, despite the epidemiological association of
Infections are a major cause of AKI and CKD, especially AKI and CKD, the effect of preventing AKI on long-term
in resource-limited regions.69,85–87 HIV, malaria, and CKD remains to be shown. Patients who develop AKI
tuberculosis—included in the Millennium Development often have other risk factors for CKD and CKD
Goals (MDGs)—and other infections such as impetigo, progression, so it is possible that the observed association
hepatitis B, hepatitis C, and various tropical diseases, between AKI and kidney function loss is confounded by
have been shown to be associated with increased risk of illness severity. Moreover, it can be difficult to distinguish
CKD.87–101 However, the regional CKD burden related to AKI from progression of CKD, and it is possible that the
infections is not well documented, so the effect on CKD observed associations are to some extent due to
prevalence of prophylaxis (vaccines), clean water, or misclassification—especially in low-income and middle-
treatment of these infections remains unknown. income countries, where laboratory testing is infrequent
Low birthweight, prematurity, and high birthweight or unavailable and baseline kidney function is often
(eg, in infants born to mothers with diabetes) are unknown.121 AKI is common in all populations
associated with increased risks of hypertension, diabetes, irrespective of geographical location: although causes
obesity, cardiovascular disease, and CKD.102–105 Childhood might vary, the effect of AKI events due to ischaemia,
obesity and pre-term birth are important risk amplifiers toxins, inflammation, or a combination of these factors is
for CKD.106–108 Mothers who experienced pre-eclampsia or profound.
eclampsia have an increased life-time risk of hypertension Progress in the management of people with CKD will
and CKD.109–112 Antenatal clinics and delivery sites could be require targeting of individuals who are at risk for AKI
central locations for identification of women and children with preventive activities such as avoiding toxic drugs,
at risk of AKI and CKD who will require long-term follow- identification of AKI events when they occur, and
up. Good pregnancy and delivery care reduce risks for improvement in the quality of follow-up care after an
AKI, but whether interventions during pregnancy or soon episode of AKI (table 3). Greater recognition of CKD as a
after birth could reduce subsequent CKD risk in mothers, risk factor for AKI and selective assessment of kidney
babies, or both remains unknown. Research is required to function before high-risk exposures (eg, cardiac
better understand the pathophysiology of renal risk related catheterisation) is achievable through education, quality
to developmental programming; how to rescue kidney improvement processes, and leveraging of existing
development; how premature babies should be optimally methods such as electronic medical records. The ability
treated and nourished to avoid AKI and long-term to identify and flag these patients allows an opportunity
metabolic consequences that might lead to CKD; how to for intervention (such as prophylactic hydration,
reduce risks from pre-eclampsia; and how long-term risk reduction in use of contrast during imaging, or non-
might be modified through lifestyle or early interventions. contrast followed by contrast procedure, as necessary)
Documentation of birthweight, gestation age at birth, and creates the opportunity for follow-up and specialist
exposure to gestational diabetes or pre-eclampsia, and any referral if required. Research collaborations using large
neonatal AKI should occur globally and this information population-based datasets (including participants from
maintained in health records. Strategies to improve low-income and middle-income countries) might permit
maternal and fetal health through reduction of risk factors increased understanding of the exact contribution of
(including smoking, obesity, diabetes, alcohol, and CKD to global AKI risk and the attributable risk of AKI to
infections) and improvement of socioeconomic factors CKD progression.
(including access to family planning, equity and education Educational tools for the lay public, patients with CKD,
for women, reduction of poverty, and adequate nutrition) and their families might help to avoid high-risk exposures
will also improve kidney health. that could result in AKI (as proposed for the ISN-0by25
initiative for AKI).122 Education for providers is also
Theme 3: Reduce AKI—a special risk factor for CKD and important. Most patients with CKD are managed by
CKD progression primary care providers and only a few are under specialist
By contrast with what had been long assumed, episodes nephrology care, particularly in low-income and middle-
of AKI, even if they appear fully reversible with return of income countries. Routine follow-up of patients with CKD

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Partners Deliverables
Mitigate known risk factors for CKD—AKI
Promote strategies to avoid and mitigate episodes of AKI Non-nephrology disciplines, and 0by25 Progress reports of 0by25 initiative
in people without CKD according to regional needs and
established guidelines
Identify CKD patients at risk for AKI
Develop and implement educational tools identifying Health systems, and governments Inventory of countries and regions and whether they
known risk factors, including prediction equations have access to specific education tools for general use;
improved ability to identify individuals at risk exists
within all communities
Identify regional risk factors for AKI in individuals with CKD Regional health systems, and industry Research report; complete catalogue with
partners participating countries within 2 years
Identify patient with CKD (tagging) to health-care Health systems, primary care, and industry ··
providers partners
Identify episodes of AKI in patients with CKD
Monitor kidney function in high-risk clinical scenarios or Relevant non-nephrology specialties Demonstration of capacity to monitor kidney
exposures (radiology, cardiology, and infectious function longitudinally in high-risk populations;
disease), and government improved ability to identify people at risk exists
within all communities
Identify and assess methods to better assess structural Industry partners, and research funders Advocate to funding agencies; improved access to
and functional aspects of the kidney in CKD and after AKI diagnostic facilities in all regions of the world
Promote electronic medical record alerting—include Health systems, and government Conference to discuss research and clinical possibilities
kidney function in checklists for health-care workers who
manage high-risk scenarios
Educate patients and providers regarding AKI Governments, health systems, and public Coordination of efforts such as educational initiatives
health campaigners and tool development as described in the 0by25
activities
Identify indications for biopsy sampling when patient Industry partners Consensus conference with published report; increase
diagnosis is not clear (AKI or progressive CKD) access to diagnostic methods in all regions
Improve care during and after AKI
Promote and monitor kidney function surveillance and Governments, health systems, and Identify capacity for AKI care as part of the Global
CKD care after AKI primary care Kidney Health Atlas project
Promote or complete trials of appropriate interventions ·· Adding representation to trials groups; improved
after AKI to minimise the risk of CKD progression evidence base for clinical decision making; better
outcomes of AKI
Promote or complete trials of AKI prevention in patients Industry partners, International Society of Adding experts in AKI outcome ascertainment to
with CKD Nephrology—Advancing Clinical Trials, clinical trials groups
other interest groups such as
international cardiology trials networks

CKD=chronic kidney disease. AKI=acute kidney injury.

Table 3: Theme 3, goals and actions to reduce AKI, a special risk factor for CKD and CKD progression

is often guided by the presence of comorbidities and contrast CT scans are common procedures in high-
(eg, diabetes, heart failure, hypertension), and testing for income countries, and are frequently done in patients
albuminuria and reduced eGFR might be infrequent. It is with or at risk for CKD. However, serum creatinine is not
therefore imperative that everyone with CKD be considered always tested for after a CT with contrast,125 possibly
at risk for AKI by all providers caring for these patients. because such testing is not reimbursed by insurance, or
Education should include risk mitigation strategies and the because there is an absence of awareness of the need for
need for ongoing monitoring of kidney function. Urinalysis follow-up, so AKI that could contribute to CKD
for proteinuria and urine microscopy with assessment for progression might go undetected. In low-income and
eosinophils and casts are inexpensive methods for middle-income countries or remote areas in high-income
diagnosing AKI even in resource-poor settings.123,124 countries, innovative methods such as telemedicine
Patients should be encouraged to report symptoms (eg, could be useful to facilitate access to medical advice and
diarrhoea, vomiting) that might facilitate earlier guide management of AKI and CKD.
recognition of AKI.69 Toolkits based on the 5R approach Even with optimal efforts at education and prevention,
(risk, recognition, response, renal support, and the prevalence of AKI is likely to increase further
rehabilitation) for AKI management described by the because of an ageing population and increased use of
ISN-0by25 initiative69,122 can be customised for this medicines, and parallel efforts are needed to improve
purpose. For instance, outpatient cardiac catheterisations the quality of follow-up care. The KDIGO guideline for

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AKI management126 recommends longitudinal patient research, particularly in kidney cell types, hinders the
follow-up after admission to hospital, targeted at identification of causal genes and variants, mechanistic
providing appropriate care for patients with, or at high insights, and ultimately translation to the clinic.133 Finally,
risk of, long-term sequelae of AKI. In settings where our current understanding of gene–environment
there is little access to medical care, the detection of interactions and their relevance for CKD is incomplete. A
AKI might represent the sole opportunity to identify better understanding of these interactions will provide
and treat CKD. Several centres in Canada and the USA insights into patient subgroups and help in targeted
have established AKI survivor clinics,127 but no therapy and prevention.
interventions to manage AKI or its sequelae after Accordingly, future activities should work toward five
discharge have been proven to improve outcomes so goals (table 4): to increase awareness about the
far. Since it is neither practical nor feasible for importance of genetics for understanding and treating
nephrologists to care for all patients with CKD who CKD; to increase the diversity of genotyped populations
develop AKI, a targeted approach based on risk and beyond those of European ancestry; to increase
opportunities for intervention is needed, based on accessibility of genetic data to a broader range of
evidence of effectiveness. scientists; to generate new methods for functional
genomics; and to promote better understanding of gene–
Improve the understanding of causes and environment interactions that are relevant to causes and
consequences of CKD consequences of CKD.
Theme 4: Improve understanding of the genetic causes Professional organisations including patient advocacy
of CKD organisations, scientific journals, the media, the
Understanding the genetic contributors to kidney pharmaceutical industry, medical schools, teaching
function in health and disease and the interaction hospitals, and the ISN should develop and disseminate
between genetic susceptibility factors and the relevant educational materials. Topics should include the
environment can provide insights into renal physiology discussion of challenges in genetic research (eg, privacy,
and pathophysiology, including the identification of how to report incidental findings)134,135 and opportunities
novel therapeutic or preventive targets. Genome-wide (eg, discovery of novel pathophysiological mechanisms;
association studies (GWAS), as well as whole-exome and development of new therapies). Educational activities in
whole-genome sequencing, have become standard countries of all income levels136 should include the
techniques to identify genetic loci in which variation is communication of realistic timelines for the translation
associated with complex forms of CKD and with impaired of genetic findings (appendix p 8).133
kidney function. These techniques can detect mutations Findings from large-scale sequencing projects of
that cause monogenic kidney diseases.128–130 Several patients with CKD and healthy individuals can provide
hundred genes are currently known in which mutations adjusted estimates of the prevalence and penetrance of
can cause single gene disorders with a kidney phenotype, suspected pathogenic variants and give insights into the
as well as dozens of genetic loci in which common phenotypic presentation spectrum for variants of a given
genetic variants are associated with kidney function and gene, which would help in counselling and risk
with complex diseases of the kidney130 (appendix p 7). prediction.134,137–140 Knowledge of mutation prevalence and
However, there are five main limitations in penetrance can also guide the choice of which variants to
understanding the genetic causes of CKD. First, awareness pursue experimentally, the timing and scope of genetic
of the importance of genetic research is limited—especially testing, and pharmacogenomic decisions.132
of the initiation and type of genetic testing, assessment of The APOL1 gene for apoliporotein 1 has been identified
the pathogenicity of detected genetic variants, and as a major susceptibility gene for kidney disease in
importance of patient counselling. Second, most existing individuals of African ancestry,131,141 which shows that
genetic research has been done for individuals of European ancestry-specific determinants exist. Genetic research in
ancestry, despite the fact that indigenous populations of indigenous populations with high rates of CKD could be
non-European ancestry often show high rates of kidney particularly informative about susceptibility genes or
disease and that there is evidence for region-specific gene–environment interactions, and might lead to a
genetic risk factors for CKD.131 The available knowledge, better understanding of allelic diversity, reducing the risk
therefore, might not be representative globally, which of false attribution of pathogenicity to ancestry-specific
could have substantial implications.132 Third, genetic variants.132 Genetic investigations in populations at high
research can reach its full potential only through risk for CKD can also help understanding of whether
widespread data sharing, which currently is not commonly kidney function variants identified in the general
practised, and data are often available only in non-standard population142–145 contribute to endemic or advanced CKD.
formats. Thus, comprehensive inventories of existing To increase the application of clinical genomics to
genetic datasets and their accessibility are important populations at high risk of developing CKD (such as
prerequisites to maximise the use of existing data. Fourth, indigenous populations, groups with rare diseases, and
the few methods available for functional genomics some ethnic groups), study protocols and policies must

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Partners Deliverables
Increase awareness about the value and importance of genetics for understanding and treating CKD
Educate clinicians and researchers about the value and Nephrology fellows, medical schools, geneticists, Inventory of existing training and educational programmes; double the
importance of clinical genomics and genetic research for professional organisations, patient advocacy number of programmes in 5 years; offer training programmes in
CKD, including challenges (eg, ethical aspects, limitations organisations groups, industry partners, and nephrogenetics at international nephrology meetings or as stand-alone
in variant interpretation), opportunities, and realistic technology and biotechnology companies meetings; increase in proportion of patients who participate in genetic
timelines for mechanistic understanding and translation research vs those who decline
Educate patients and the public about the value of clinical Geneticists, professional organisations, patient Increased media coverage in the next 2–5 years; increase in proportion of
genomics and genetic research advocacy organisations groups, journals, offprint patients who participate in genetic research vs those who decline
media, and industry partners
Educate clinicians and researchers about findings from Medical schools, teaching hospitals, university and Research reports and review articles in the next 2 years, including discussion
large-scale sequencing projects of nephrology patients hospital nephrology divisions, professional societies, of potential implications for counselling; increase in proportion of patients
and asymptomatic individuals that provide adjusted patient advocacy organisations and groups, industry who participate in genetic research vs those who decline
estimates of prevalence and penetrance of presumably partners, and nephrology journals
pathogenic variants necessary for counselling and risk
prediction
Educate clinicians about the diverse clinical presentations of Medical schools, teaching hospitals, professional Research reports and reviews on spectrum of clinical presentations for
genetic kidney disease and revise genetic testing accordingly societies, patient advocacy organisations, industry kidney disease genes; published recommendations about which genes to
partners, journals, and clinical sequencing laboratories sequence for which presentation; and development of standard gene
panels for different nephrological diseases (tubular, FSGS) with region-
specific content
Increase diversity of genotyped populations beyond European ancestry
Protect indigenous populations, rare disease groups, ethnic Communities, governments, regulatory authorities, Inventory of genotyped populations and their diversity in CKD hotspots;
minorities, small communities, family or heritage beliefs to and Institutional Review Boards review of existing protocol or policy recommendations and publication of
enable their inclusion in genetic analysis and increase recommendation about where to focus genotyping efforts in the next
diversity of genotyped populations 2 years; increase in proportion of patients who participate in genetic
research vs those who decline
Improve SNP diversity on commercially available chips; and Genotyping companies (Affymetrix, Illumina), and Development of affordable genotyping for worldwide populations;
improve imputation reference panels for ethnically diverse computational biologists (for improved and diverse provision of improved genotype imputation for non-European ancestry
populations imputation platforms) populations; promote comprehensive SNP array genotyping for CKDu in
CKD hotspots to identify a potential major gene effect; produce timely
research reports
Educate groups, patients, populations, and other Communities, governments, regulatory authorities, Increase media and journal coverage of the value of genetic research in
stakeholders about the value of genetic research in diverse Institutional Review Boards, genotyping companies diverse populations
populations (Affymetrix, Illumina), computational biologists (for
improved and diverse imputation platforms), and
media
Increase accessibility of genetic data
Increase accessibility and usability of existing and future International Society of Nephrology-iNET CKD, Development and publication of position statement on standardised format
datasets by promoting standardised format, broad data journal editors, technology companies, CKDGen, for data sharing; tracking of number of publications, number of requests for
sharing, and increased usage biobanks and biorespositories, dbgap, Big Data 2 data, review of catalogued resources, and reduction of redundancies
Knowledge initiative, Accelerating Medicines
Partnership portal, Cohorts for Heart and Aging
Research in Genomic Epidemiology consortium, and
National Human Genome Research Institute and
Genome-Wide Association Studies Catalog (now
European Bioinformatics Institute)
Develop data mining tools and search functions to Computational scientists, and industry partners Shared tools (eg, search functions) to investigate publicly available data;
catalogue existing datasets research publications based on existing datasets (secondary use)
Promote common data elements, phenotypes, or Clinical chemistry, epidemiologists, and lab assay Establishment of consensus on a set of core nephrological parameters to
standards in existing and future datasets (eg, age, sex, developers enable kidney disease genetics research and consensus on how to identify
serum creatinine, urine albumin-to-creatinine ratio, and patients with CKD from EMR; more focused research in genetics within the
ethnicity); improve renal phenotype harmonisation and field of renal medicine
lab assays used to measure renal function parameters; and
develop EMR search tools for renal patients
Create incentives for data sharing Journals and industry partners Develop journal guidelines that require data sharing for publication;
sponsor platforms, portals, and infrastructure to share data; more focused
research in genetics within the field of renal medicine
Catalogue and aggregate existing data repositories and Computational scientists, and industry partners Develop concept for centralised platforms, portals, and infrastructure to
biobanks or biospecimens to enable more rapid and share data and identify funding mechanisms; more focused research in
accessible research genetics within the field of renal medicine
Link biomarkers to genetic data to attribute causality Statisticians, and industry partners Development of software that facilitates Mendelian randomisation
(Mendelian randomisation) using publicly available analyses and make publicly available
summary statistics databases
(Table 4 continues on next page)

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Partners Deliverables
(Continued from previous page)
Generate tools for functional genomics
Develop methods for applying function of genetic findings Geneticists, bioinformaticians and computational Inventory of available tools, cell types, cell lines in the next 2–5 years; tracking
to identify the causal gene or variant, and the genetic biologists, technology companies, industry partners, of published papers with mechanism of action of genetic findings and
mechanism of action to facilitate translational research; and funding agencies collection in a centralised resource; faster time from discovery to phase 1
methods should be shared broadly clinical trials and phase 2 trials in nephrology with less failure of compounds
Promote the creation of disease-relevant cellular assays, Geneticists, bioinformaticians and computational Published research reports elucidating mechanism of action of newly
bioinformatics pipelines, and tools for use in the scientific biologists, technology companies, industry partners, uncovered genetic loci; development of assays that are available upon
community and funding agencies request; faster time from discovery to phase 1 and phase 2 trials in
nephrology with less failure of compounds
Generate tools to study genetic modifiers, including Geneticists, bioinformaticians and computational Creation of tools as documented in published research reports of epigenetic
epigenetic effects to understand mutations in their biologists, technology companies, industry partners, catalogues of different kidney cell types; faster time from discovery to
genomic context and identify potential therapeutic targets and funding agencies phase 1 and phase 2 trials in nephrology with less failure of compounds
Promote better understanding of genes by environment interactions
Promote existing large initiatives such as the Precision CKDGen, iNET CKD, biobanks and biorespositories, Research reports
Medicine Initiative or the UK Biobank data to elucidate CKDu investigators
genes by environmental interactions
Develop EMR search tools for the most common Computational scientists, specialists for Consensus on a small set of potentially most important interactors and
environmental CKD risk factors environmental risk factors, and epidemiologists standardisation of their definition and methods for data capture
Develop renal endophenotypes to increase the power of GXE ·· Use of biomarkers and genomics, proteomics, and metabolomics data for
interactions; use renal endophenotypes (including genetics) the identification of more homogeneous subgroups of CKD to identify
to identify more homogeneous subgroups of patients to novel genes and GXE interactions; produce timely research reports
facilitate GXE discoveries
Promote comprehensive SNP array genotyping for CKDu in Environmental scientists Research report
CKD hotspots to identify a major gene effect present in
populations exposed to a specific environment

CKD=chronic kidney disease. SNP=single-nucleotide polymorphism. GXE=genetics by environment. FSGS=focal segmental glomerulosclerosis. CKDu=CKD of unknown cause. CKDGen=CKD Genetics
consortium. EMR=electronic medical records.

Table 4: Theme 4, improve understanding of the genetic causes of CKD

ensure the protection of each of these unique groups research. The use of similar measurements and
from exploitation and misuse of data by including them definitions maximises the potential for the use of
in specific patient engagement activities, while being datasets in different centres as well as in combination,
mindful of family or heritage beliefs to allow for culturally to increase power of under-represented groups.
sensitive genetic research. The development and Important potential partners in this process are
implementation of culturally sensitive methods by which biomedical journals, which could insist on data access
to engage communities worldwide is imperative if new for all original publications as a condition for
knowledge is to be comprehensive and applicable to publication, international research collaborations
multiple populations. (eg, CKD Genetics Consortium, CKD-PC, ISN-iNet
To broaden the knowledge base of genetic variants in CKD) for the definition of common renal phenotypes,
high-risk populations, researchers need to work with and the data scientists who develop and maintain
genotyping companies and computational scientists to resources for the establishment of data sharing formats
provide affordable and comprehensive genotyping for (eg, the National Human Genome Research
worldwide populations, and to improve reference panels Initiative GWAS Catalogue).147 Governments and the
for non-European ancestry populations. As outlined in the pharmaceutical industry should support data sharing
FAIR (findability, accessibility, interoperability, reusability) infrastructure, as they have already done with platforms
guidelines,146 individual and aggregate datasets should be generated through the Big Data to Knowledge (BD2K)
available with few barriers to access in a useful, project148 or the Accelerating Medicines Partnership
standardised format. The accessibility and effectiveness of project for type 2 diabetes.149 Many of these resources
existing and future datasets could be increased by already exist in high-income countries, but in low-
promoting standardised formats, common data elements income and middle-income countries, primary data
and standardised phenotype definitions, and broad data generation can be challenging.
sharing. Data sharing could also be complemented by New methods for functional genomics will be needed
cataloguing and aggregating existing data repositories and to enable the translation of loci uncovered through
specimens for correlation of biomarkers to genetic data to genetic screens including GWAS and sequencing
identify causality (eg, Mendelian randomisation). studies133 (appendix p 8). Functional genomics methods
There are tremendous potential benefits from are used to identify causal genes and variants and to
developing common data elements relevant to kidney elucidate their mechanisms of action, to focus on

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translation of the most promising findings.150,151 One Theme 5: Establish better diagnostic methods in CKD
example is the original discovery of the APOL1 gene The KDIGO definition enables the diagnosis of CKD in
region, where the signal was initially attributed to a the absence of knowledge about the cause in individual
neighbouring gene, MYH9, illustrating that causal genes cases.10 This has been crucial in determining the incidence
are not always the ones that are initially suspected on the and prevalence of CKD, identifying CKD cases, and
basis of proximity.152 increasing disease awareness, but prognosis and treatment
Emerging technologies such as epigenetics,153 are highly dependent on the underlying aetiology and
metagenomics, metabolomics,154,155 and proteomics156 pathological mechanisms. Attempting to assess the cause
will help further with interpretation of genetic data. of CKD is an explicit KDIGO recommendation. However,
The Genotype-Tissue Expression (GTEx) project157 even in high-income countries, the cause of CKD remains
currently has only a few kidney samples available; unknown in about half of all patients, even in those under
development of libraries of kidney cell types with nephrology care.167 In low-income and middle-income
epigenetic maps and robust cellular assays in models countries, where access to sequential laboratory
for disease and cell-types will be necessary to realise the assessments of eGFR, albuminuria, kidney biopsy
full potential of kidney disease genetics. The short-term samples, and other laboratory tests are limited or non-
deliverables for this goal include the tracking of existent, the spectrum of diseases responsible for CKD in
published datasets and accessible methods; the ultimate the population is usually unknown. Thus, there is a strong
goal is to gain insights into biological pathways and global need for increased use of existing diagnostic tests,
novel biomarkers to enable prevention of disease and including kidney biopsies, as well as for expanding the
improve drug development. Drug targets with diagnostic armoury, including non-invasive imaging,
underlying human genetic support are twice as likely to biomarkers, functional and genetic testing (table 5).
be approved as those that are not supported by genetic Consistent attempts to ascertain the aetiology of CKD in
evidence.158 individuals should be made, to ensure the most appropriate
Additional efforts will be needed to better understand therapies are implemented, and that information can be
how environmental factors interact with genetic garnered from all patients.
variants to modify the risk of CKD. Examples of such Analysis of kidney biopsy samples can be used to
interactions include IgA nephropathy and the intestinal stratify CKD into distinct subgroups of diseases on the
immune response to helmintic infections that basis of specific histological patterns, when combined
correspond to higher prevalence of IgA nephropathy in with the clinical presentation. Additionally, kidney
east Asia159 (appendix p 9), and APOL1-associated biopsies can provide information on disease activity,
kidney disease and trypanosomiasis that correspond to molecular mechanisms, and prognosis. However, even
higher rates of kidney failure in individuals of African in high-income countries, renal biopsy is only done in a
ancestry.131,160 Other interactions of gene and small number of patients with CKD—usually in patients
environmental risk variants could include diabetes and with suspected glomerular disease in whom knowledge
hypertension,161,162 the main causes of CKD in many of biopsy findings—eg, confirmation of a specific cause,
regions of the world, and other yet unknown evidence for active inflammation and tubular damage, or
environmental factors that contribute to CKD sclerosis and fibrosis—might trigger a change in clinical
hotspots.163,164 Unravelling the effects of genes and management. For the more common causes of CKD
environment can be challenging when their interaction such as diabetes and hypertension, renal biopsies are
is required to cause disease or when the genetic effect only done in instances for which the presentation or
or interaction is small. clinical course is atypical. Kidney biopsies are invasive,
The existence of multiple hotspots (eg, in Central and require resources and expertise in ultrasound and
Latin America, Sri Lanka, India, and Malaysia) might pathology, need special facilities, and create a risk of
allow the identification of a genetic cause of CKDu in a bleeding and pain for the patient, but they offer the
given population. Prerequisites for success include the possibility that specific causes and potential opportunities
availability of inexpensive and ethnicity-specific high- for treatment might be uncovered.
throughput genotyping arrays, the ability to identify Even after categorisation by biopsy findings, there is
individuals exposed to specific environmental factors substantial heterogeneity in pathophysiology and
(perhaps using existing data from populations surveys prognosis within a specific category of CKD. Most
or electronic medical records), and pre-existing current histological diagnoses group diseases with
standardised data collection procedures.165 Improved multiple underlying mechanisms together into
phenotyping can increase the power of detecting gene– syndromic categories. Different, specific pathogenetic
environment interactions and allows for the completion events show indistinguishable structural alterations in
of genetic studies in more homogeneous subgroups the kidney (eg, mutations in different genes causing
(ie, those exposed to a particular environmental factor), familial nephrotic syndrome show the same pattern of
which should enhance the ability to identify CKD focal segmental glomerulosclerosis). Conversely, the
risk genes.166 same single mechanism can give rise to different

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Partners Deliverables
Promote diagnosis and staging of CKD as proposed by KDIGO
Work towards global implementation of the diagnosis (assess or Health-care providers, and clinical Increased ability to accurately diagnose CKD in
attempt to assess cause) and staging of CKD on the basis of chemists different regions
measuring or estimating glomerular filatration rate and measuring
albuminuria
Improve renal biopsy-based CKD diagnosis
Endorse the need to obtain renal biopsy samples in a broader range KDIGO; health-care system, and Consensus conference with published report;
of presentations, including CKD, AKI, and glomerulonephritis pathology departments increased ability to accurately diagnose CKD in
different regions
Sustain or establish regional centres of excellence for renal biopsy Ongoing efforts of the International Consensus report with definition of standards for
sample analyses and interpretation worldwide Society of Nephrology Renal tissue processing and histological analyses;
Pathology Committee increase biopsy capacity in all countries
Support implementation of standards in renal biopsy reporting RPS Consensus report—eg, RPS, Mayo Clinic
standardised reporting of glomerulonephritis
Sustain and expand efforts to increase capacity for performing renal International Society of Nephrology Offering of renal biopsy training courses, covering
biopsies worldwide Interventional Nephrology indication, risk, performance, and monitoring;
Committee increase biopsy capacity in all countries
Investigate and implement opportunities for molecular diagnosis of Funding agencies, research networks Produce timely research reports; increase biopsy
renal biopsies capacity in all countries
Link existing and novel renal biopsy registries with clinical data ·· Establishment of a global network and
exploration of opportunities for data sharing and
joint analyses
Improve non-invasive imaging analyses of the kidney in patients with CKD
Work towards global availability of diagnostic ultrasound imaging Public policy Monitoring of access to ultrasound diagnosis as
part of the Global Kidney Health Atlas project
Develop better non-invasive imaging tools of renal structure and Funding agencies, and the Research conference devoted to this topic;
function Radiology Society increase number and types of tools available for
assessment of CKD
Facilitate identification, validation, and implementation of diagnostic biomarkers of CKD
Sustain and increase efforts to identify and validate biomarkers that Research networks, industry Research reports; increase number and types of
indicate cause, dominant pathophysiological mechanisms, or partners tools available for assessment of CKD
therapeutic responsiveness
Advocate for local, national, and international biobanking efforts to ·· Task force to explore opportunities and develop
include renal samples a concrete strategy
Provide guidance on biosampling for markers of renal structure and CKD research networks Development of a consensus statement with
function minimum standards and outline of how sample
collection and storage procedures affect sample
utility; increase engagement of CKD networks in
collaborative research
Promote sharing of biobanking inventories, protocols, and biosamples Funding agencies and CKD research Development of a guidance document for
networks governance of research network: network
internal policy developments, biosamples usage,
sample sharing, and challenges of international
collaboration
Improve the clinical assessment of renal function and the underlying mechanisms of pathology in CKD
Endorse research efforts to assess renal functional domains and Funding agencies ··
mechanisms of pathology with their interaction and complexity
(function of different tubular segments, inflammation, fibrosis, and
renal endothelial function)
Assess the diagnostic and prognostic utility of renal functional Funding agencies ··
reserve assessment

CKD=chronic kidney disease. KDIGO=Kidney Disease: Improving Global Outcomes. AKI=acute kidney injury. RPS=Renal Pathology Society.

Table 5: Theme 5, establish better diagnostic methods in CKD

histological diagnoses in different patients (eg, biopsy insights into disease causes and mechanisms is an
samples from patients with mutations in podocin important goal.
causing nephrotic syndrome, type 2, can vary from Increasing the use of kidney biopsies will require
minimal change disease to focal segmental education, capacity building, and enhanced efforts.
glomerulosclerosis). Thus, increasing the use of kidney Ideally, we will be able to compare biopsy findings across
biopsy samples to gain better diagnostic and prognostic centres and settings, and support the implementation of

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standards for renal biopsy reporting. Regional centres for As the research into CKD moves towards more
renal biopsy procedures should be established worldwide, complete assessment on the basis of imaging and tissue
with appropriate access to expertise and supplies. Key and fluid-based biomarkers, it will be important to
elements will include technical expertise, with hands-on incorporate assessments of functional status into
training of histology technicians in sectioning and diagnostic processes. Methods for assessing renal
staining technologies, including special stains beyond functional domains and pathological mechanisms are
haematoxylin and eosin (eg, periodic acid–Schiff and already available, and could be refined to target more
silver stains). Sophisticated staining technology will be specific parameters (such as function of different tubular
key to the success of regional centres because multiple segments, presence of inflammation or fibrosis, renal
steps are needed to detect focal lesions.168 Renal pathology endothelial function, or renal functional reserve).
centres should also use electron microscopy for optimal
diagnostic sensitivity, as some conditions—such as Theme 6: Improve understanding of the natural course
IgA nephropathy and membranous nephropathy— of CKD
cannot be adequately diagnosed from light and There is a well described variability in kidney and
immunofluorescence or immunohistochemistry alone; cardiovascular outcomes in patients with CKD. Thus,
patients are misdiagnosed about 15–20% of the time there is a need to identify and validate prognostic
when electron microscopy is unavailable.169 biomarkers that will help to predict risk of specific events
The potential of traditional pathological assessment of and to better understand the underlying molecular
biopsy tissue would be magnified if analysis of kidney mechanisms of cardiovascular disease and CKD
biopsy samples was coupled with broader availability of progression (table 6).
techniques for molecular diagnosis, and the capacity to Guidelines already recommend measurement of
link renal biopsy registries with clinical data. To ensure albuminuria over time in people with CKD.176 This
the effect of such registries standard values—such as recommendation is inconsistently followed even in
minimum needed data and clinical follow-up variables— high-income countries, which compromises our
must be defined, as well as additional parameters for understanding of CKD progression in individuals and
specific subcategories of diseases. After diagnosis the populations. At the same time, more needs to be
remaining tissue should be stored for potential future understood about to what extent changes in albuminuria
studies, to explore the aetiology and pathogenesis of and eGFR over time are clinically meaningful and how
CKD. they should influence clinical management.
Current standards for biopsy reporting have been Current risk algorithms for cardiovascular disease in
published by the Renal Pathology Society (RPS) and by a CKD are based on traditional cardiovascular risk factors
joint working group of renal pathologists and and do not include albuminuria or eGFR. The ability to
nephrologists from the Mayo Clinic.170 The scarcity of better predict cardiovascular disease in patients with
well-trained renal pathologists, even in high-income CKD would permit assessment of targeted therapies in
countries, is a major obstacle to use of biopsy samples. clinical trials and risk stratification in clinical practice.
The ISN is working worldwide to enhance development Given the different cardiovascular disease phenotypes
of local renal pathology expertise. observed with increasing severity of CKD, risk prediction
Ultrasound-guided visualisation of the kidney and the instruments should be gauged for their ability to
lower urinary tract is safe, requires minimal training, discriminate between events mediated by traditional
and can be done with low-cost equipment—but is rarely atherosclerotic processes versus those mediated by CKD-
available in low-income and middle-income countries. specific processes. There is potential for developing a
Therefore, working towards global availability of risk prediction method that integrates CKD markers with
diagnostic ultrasound imaging through the provision of traditional cardiovascular disease risk factors, but the
equipment and training should be a priority, as well as benefit of this approach would need to be shown, ideally
developing better non-invasive imaging methods to through a well-designed prospective trial.177
monitor and assess renal structure and function. The renal community should take advantage of existing
On the basis of developments in other fields, it appears large observational cohort studies with stored
likely that blood-based and urine-based biomarkers will biomaterials and long-term follow-up to study and
play an important role in the future.171–175 This will require validate established and novel biomarkers. Testing of
sustained and enhanced efforts to identify and validate new web-based cardiovascular disease risk scores
biomarkers that indicate cause, dominant patho­ involving the renal risk markers albuminuria and eGFR
physiological mechanisms, therapeutic responsiveness, can be accomplished with existing databases and
or a combination of these factors. Networks of collaborations (eg, EUTox),178 industry partners, and CKD
translational scientists and clinical investigators are biomarkers consortia. It will be important to achieve
needed that support sustainable and integrated agreement on strategy by which to investigate and
biobanking and biomarker research—including the use validate the complex and diverse expression of
of common protocols and practices. cardiovascular disease in CKD. Given that cardiovascular

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Partners Deliverables
Improve monitoring of kidney disease progression among patients with CKD
Implement regular measurements of ACR and serum Policy makers, professional societies, Increase in number of countries able to measure ACR:estimated
creatinine-based estimated GFR for monitoring CKD guideline developers, and WHO GFR ratio relative to current state
Increase awareness and empower patients in self- Patient organisations, print and Formal interactions with partners to develop a collaboration to
management and their understanding of their health electronic media, and the accomplish the goal (eg, International Federation of Kidney
(eg, by implementing health technology applications) International Society of Nephrology Foundation)
Define changes in albuminuria and GFR that are Scientists, FDA, and EMA Report on optimal change in albuminuria and association with
meaningful for individual patients and how they outcome in 2018; international collaboration with ongoing
should relate to clinical action initiatives (eg, National Kidney Foundation, FDA, and EMA
workshop)
Improve cardiovascular disease risk prediction in patients with CKD
Develop a risk prediction tool, integrating CKD Endocrinologists, cardiologists, Web-based risk scores for cardiovascular disease involving renal
markers in cardiovascular disease risk assessment in general practitioners, and if possible, risk markers (albuminuria or estimated GFR); evidence of use of
patients with CKD renal pharmacists risk scores in clinical practice
Facilitate identification, validation, and implementation of prognostic biomarkers in CKD
Sustain and increase efforts to identify and validate Regulatory authorities (eg, FDA and Conference with the partners to develop guidance and principles
biomarkers that indicate the progression or EMA), industry partners, and payers
therapeutic responsiveness, or both, of CKD
Sustain and increase efforts to identify and validate European Uremic Toxin working Conference with partners; correlation of uraemic toxins to
biomarkers that indicate the development of group, CKD biomarkers consortium, phenotype; increased acceptance and uptake of diagnostic tests
cardiovascular disease events in patients with CKD and industry partners for specific conditions in many regions
Improve global access to strategies and agents that delay the progression of CKD
Development of an early-stage CKD toolkit Non-nephrology health-care CKD toolkits for different regional settings; generation of
providers, and health-care politicians toolkit that is multi-interventional, has specific goals, simple
interventions, and simple measures such as blood pressure and
urine tests; identification of workforce with capacity to deliver
package; and translations into different languages
Work towards global access to affordable blood WHO, and regional health-care Monitor availability of the four treatments; assess change in
pressure-lowering and glucose-lowering drugs, providers implementation and uptake and publicise results; extend the
renin–angiotensin system blockade for proteinuric GKHA project to include this monitoring; increase availability of
diabetic kidney disease, and statins for cardiovascular these agents or polypill (eg, a combination tablet of statin,
disease prevention ACE-inhibitor, and aspirin) for at-risk populations
Develop and implement decision support tools ·· Create inventory of existing decision support tools for early CKD
by country; extend the GKHA project

CKD=chronic kidney disease. ACR=albumin-creatinine ratio. GFR=glomerular filtration rate. US FDA=Food and Drug Administration. EMA=European Medicines Agency.
GKHA=Global Kidney Health Atlas.

Table 6: Theme 6, improve understanding of the natural course of CKD

disease risk profiles, CKD populations, and health of patients, and enhance relationships with regulatory
systems vary worldwide, special consideration should be authorities and industry partners.
given to whether recommendations should differ by Also important is the recognition of how biomarkers
setting (eg, in low-income countries vs high-income change with disease progression or with therapy, and
countries).179 whether such changes predict clinical outcomes, including
Although additional benefit can be derived from CKD progression. High-throughput screening techniques
consistent use of existing parameters such as eGFR and (ie, transcriptomics, proteomics, and metabolomics) in
albuminuria, new prognostic biomarkers in CKD are conjunction with well phenotyped clinical cohorts offer an
needed to individualise patient management and enhance opportunity to achieve this objective.181 Studies examining
recruitment of patients with similar prognosis into clinical biomarker profiles should include populations from low-
trials. Creating formal collaborations between existing income and middle-income countries and people from
research consortia will sustain efforts to identify and assess diverse ethnic backgrounds. Young researchers should
such biomarkers. Given the clinical heterogeneity of most also be trained in all aspects of biomarker research, from
unselected CKD populations, progress might be most discovery to clinical implementation.
likely to occur in well characterised cohorts of people with
specific kidney diseases. Real-world assessments of new Improve outcomes with current knowledge
biomarkers should be done to identify whether or not they Theme 7: Assess and implement established treatment
improve clinical care at reasonable cost before options in patients with CKD
recommending their uptake into practice.180 As for genetic Although there is a huge unmet need for CKD therapies,
epidemiology cohorts, efforts will be required to some treatment options have been shown to reduce the
standardise outcomes, share protocols, protect the privacy risk of cardiovascular events and progression to RRT.

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Such therapies include: lowering of blood pressure;182,183 advice. Physicians might not adopt best practices, or
reduction of proteinuria;182,184 treatment with angiotensin might not have access to methods and equipment for
converting enzyme inhibitors or angiotensin 2 receptor standardised treatment. For example, the uptake of well
blockers;185 and treatment with statins to reduce established therapies such as renin–angiotensin blockade
atherosclerotic events (table 7).186,187 Glycaemic control in in patients with CKD followed up by nephrologists is less
patients with type 1 or type 2 diabetes also improves than 70%, partly193 due to problems with tolerance of
cardiovascular and clinical outcomes188,189 and newer specific medications or adherence.194
drugs such as sodium-glucose co-transporter 2 inhibitors So-called treatment gaps, defined as the difference
and glucagon-like receptor agonists have the additional between the number of people who have an indication for
benefit of reducing albuminuria, cardiovascular a therapy and those who actually receive it, represent
outcomes, and progression of CKD in diabetes.190–192 CKD opportunities to reduce morbidity and mortality.195 The
caused by primary glomerular diseases is potentially advent of electronic medical records and other internet-
curable with relatively short periods of treatment based frameworks offer potential mechanisms for
compared with CKD from other causes. surveillance of treatment gaps; at present, little is known
However, the implementation of established therapies about the magnitude and determinants of treatment gaps,
is variable within and between regions. Physician, particularly in low-income and middle-income countries.
patient, and health-care system factors could all play a Most focus has appropriately been on which treatments
role in successful uptake of recommended treatment. are available or affordable; as access to care improves in
Access to care or therapies is often restricted by poor low-income and middle-income countries, focus should
availability, expense, or reduced access to specialist shift to identifying and closing other potential causes.

Partners Deliverables
Increase global capabilities to treat glomerular diseases
Establish best practices and indications for biopsy Pathologists and Inventory of current capacity and potential capacity; identification of
procedures and sample handling; increase capacity for laboratory supporters barriers and work plans to address; extend the Global Kidney Health
trained pathologists to interpret specimens; establish key Atlas project
accessible medications for treatment of common
glomerulonephritis
Sustain and increase development, dissemination, and awareness of clinical practice guidelines
Continue to develop, update, and improve clinical practice KDIGO and other Novel guidelines and guideline updates; conference sessions on
guidelines pertinent to CKD on a global scale guideline organisations guidelines; ensure global access to guidelines; international
ambassador programmes to incorporate guideline education
Promote guideline dissemination and education KDIGO and other Task force to survey non-nephrology guidelines, to establish contacts
guideline organisations with non-nephrology guideline organisations and to work towards
the inclusion of CKD-related recommendations in future updates;
inclusion of guidelines in Continuing Medical Education programmes
and dissemination of nephrology guidelines to other specialty
guideline groups; increase number of individuals being treated
according to recommendations
Develop implementation science expertise in nephrology
Develop and expand implementation science WHO Task force to explore opportunities and develop a concrete plan,
infrastructure within the nephrology community taking into account experience in other fields; possibly supported by
workshops or a consensus conference, or both; develop expertise
through expert group, educational meetings, and training
mechanisms; tool and curriculum or plan; funding for international
and country-specific fellowships or ambassadors; regional
presentations and collaboration on specific projects
Investigate implementation strategies pertinent to CKD in Government health Conduct a trial to assess pre-intervention use versus short-term and
clinical trials, tailor effective trial design to local ministries, industry long-term effects of intervention; tailor effective trial designs to the
circumstances and scale or spread successful partners, and funding local circumstances (eg, comparative effectiveness and step-wedge
dissemination strategies for maximum worldwide effects agencies trials); partner with government and health services to embed
research in clinical care—facilitation of comparative effectiveness
studies when previously unused therapies are introduced to ensure
focus of resources on high-yielding interventions
Inclusion of considerations related to implementation in KDIGO and other Future guidelines consider recommending an ideal and an absolutely
guidelines guideline organisations acceptable minimum recommendation for increased uptake in high-
income countries and low-income and middle-income countries alike
Identify indications for biopsy in individuals in whom Industry partners Consensus conference with published report; increase access to
diagnosis is unclear (AKI vs progressive CKD) diagnostic methods in all regions

CKD=chronic kidney disease. KDIGO=Kidney Disease: Improving Global Outcomes.

Table 7: Theme 7, investigate and implement established treatment options in patients with CKD

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There are a variety of approaches to closure of treatment advice regarding treatment and goals to slow common
gaps, including reminders, checklists, and pre-printed causes of CKD progression could reduce the global
orders, especially in high-income countries with burden of CKD. Decision support toolkits where
universal health care.196–198 Cost reduction or income guideline-based advice is automatically generated from
supplementation is logical in situations where economic the entry of routine clinical data, for example in laboratory
barriers are important. Affordable versions of drugs that systems or electronic medical records, are also of potential
control blood pressure and glucose metabolism and importance. To promote uptake and effectiveness, the
inhibit the renin–angiotensin system should be available approach should be generalisable to different workforces
in all health settings. The nephrology community should and health-care settings.
advocate for the widespread uptake of the Model List of
Essential Medications by WHO,199 which will help to Theme 8: Improve management of symptoms and
achieve this objective. Making low-cost immuno­ complications of CKD
suppressive medications more widely available is In addition to progressive loss of kidney function, CKD is
paramount to treat glomerulonephritis in low-income associated with multiple complications that cause
and middle-income countries, but their use also requires morbidity and mortality, and reduce health-related
appropriate infrastructure for establishing the diagnosis. quality of life (HRQOL). These complications manifest
Clinical practice guidelines and associated schemes are as a variety of symptoms (eg, fatigue, pruritus, and
additional important mechanisms to assess the evidence nausea), abnormalities of physiological and laboratory
for the benefits and risks of diagnostic and therapeutic parameters (eg, hypertension, anaemia, or hyper­
strategies, and promote the uptake of beneficial phosphataemia), and increased incidence of several
treatments in clinical practice. Guideline development adverse outcomes (eg, bone fractures, cardiovascular
for patients with kidney disease is pursued at a global events).200,201 Despite considerable research, the patho­
level by KDIGO and should continue, aiming to cover the physiological links between CKD and these complications
major CKD management issues. There is an increasing remain incompletely understood; the benefits of
need to ensure that guidelines and treatment strategies correcting physiological and laboratory variables remain
are also tailored to low-income and middle-income poorly defined, and strategies to reduce the cardiovascular
countries, and that decision makers and funders burden associated with CKD are insufficient. Moreover,
understand the clinical and socioeconomic benefits of increasing investigation appears to be warranted into the
improving access to care. causes and optimal treatment of CKD-associated
Guideline development must be complemented by symptoms (table 8).200,201
effective knowledge translation efforts aimed at end Pruritus, restless legs, nausea, poor appetite, and sexual
users, including care providers, patients, and families. dysfunction are common in patients with CKD, especially
The introduction of any therapy represents an those with kidney failure.201,202 These symptoms are likely
opportunity to assess implementation methods and to do to be multifactorial; their pathophysiology is incompletely
comparative effectiveness studies, which should include understood, and little is known about their treatment.201,202
a randomised and adequately controlled trial. A better How these symptoms influence HRQOL and other
understanding of the factors that drive effective outcomes important to patients, such as employability
implementation will lead to more effective dissemination and functional status, has not been completely studied.
of established therapies with an expansion of the number The relative importance of each symptom to the total
of people receiving current established therapies, symptom burden is not well understood; this information
reduction in the time to uptake of new therapies, and is necessary to prioritise future studies. Few, if any, drugs
potentially increased efficiencies for health service have been approved for the treatment of uraemic
providers. Nephrology-specific implementation activities symptoms and there is little evidence to support the off-
should be actively developed and increased. Achievable label treatments that are recommended. Appraising the
short-term targets for building nephrology-specific best candidates for well-designed clinical trials should be
capacity include formal curricula and the creation of a high priority, which could include treatments for similar
training positions, perhaps within nephrology residency symptoms associated with other conditions (eg,
programmes. In low-income and middle-income chemotherapy-associated nausea or phototherapy for
countries, implementation science will also maximise pruritus not associated with CKD). These approaches
the efficiency of health service investment as well as should be complemented by research efforts that
outcomes for patients. capitalise on new technologies, such as metabolomics
It is important to recognise that worldwide, most people and proteomics, to link uraemic toxins with symptoms
who have access to care for early CKD receive this care in and to identify the pathophysiology that causes or
primary and general health settings, so general providers exacerbates symptom burden.
have the greatest opportunity (and responsibility) to Data showing that management of hypertension,
intervene in the course of CKD progression. A toolkit for anaemia, and metabolic bone disease improves outcomes
these health-care workers that provides simple targeted have been sparse, and the results of randomised trials

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Partners Deliverables
Improve symptoms associated with CKD
Develop better understanding of symptoms associated with CKD and Patients and Task force to establish interaction and joint plan with patient
their effect on health-related quality of life, employability, and caregivers groups; symptom survey of patients with CKD; review
functional status summarising current evidence and gaps in knowledge;
reduction in suffering of patients with CKD
Promote basic and clinical research about understanding the Industrial partners Produce timely research reports
pathophysiology of the key symptoms, to better target therapeutic efforts and funding
agencies
Improve symptom management in patients with CKD ·· Multidisciplinary meetings; educational materials for different
target groups; consider educational and advocacy activities
about the symptom burden—eg, World Kidney Day
Optimise the management of haematological, hormonal, and metabolic abnormalities associated with CKD
Promote research to understand the links between laboratory Funding agencies Research reports; more research funding spent on this area
abnormalities and clinically relevant outcomes (symptoms, and industry
cardiovascular disease outcomes, and progression of CKD) partners
Promote consistent assessment and documentation of laboratory Patients Survey of guideline implementation
abnormalities in CKD populations according to KDIGO guideline
Promote research and education into region-specific causes of KDIGO Produce timely research reports; educational toolkits
abnormalities in patients with CKD (eg, nematode infection causing
anaemia)
Promote availability of affordable point-of-care measurement devices and Policy makers Survey availability as part of the Global Kidney Health Atlas
treatments for hormonal, haematological, and biochemical abnormalities project; access to point-of-care testing in many areas where it
does not exist now
Improve prevention and management of cardiovascular complications in people with CKD
Develop an integrated research programme to better understand Funding agencies Research reports; research conferences
vascular and cardiac diseases occurring in the context of CKD populations and industry
partners
Improve understanding of global variation in cardiovascular disease Cardiologists Analysis of cardiovascular disease morbidity in cohort studies
associated with CKD in different regions
Identify barriers to dissemination and implementation of existing KDIGO Produce timely research reports; more patients receive
guidelines on dyslipidaemia and hypertension management to reduce appropriate care (current reports <65%)
cardiovascular risk in CKD, and implement strategies to overcome those
barriers
Develop new therapeutic approaches to reduce cardiovascular disease Funding agencies, New therapeutic agents; clinical trials focusing on
risk in patients with CKD industry partners cardiovascular disease outcomes in patients with CKD
Promote further research into optimal therapeutic targets for Policy makers Produce timely research reports; complete well-designed large
cardiovascular disease risk factor management (eg, blood pressure clinical trials
control) and how best to achieve them

CKD=chronic kidney disease. KDIGO=Kidney Disease: Improving Global Outcomes.

Table 8: Theme 8, improve management of symptoms and complications of CKD

have typically been disappointing.203–205 Guidelines accounts for a substantial proportion of the costs of CKD
advising on management of these abnormalities suffer care, especially for patients with kidney failure. However,
from limited evidence and do not usually account for it seems clear that these abnormalities contribute to
practice conditions in low-income and middle-income symptom burden and possibly outcomes in patients with
countries.203,205,206 Moreover, underlying causes of these CKD.207 More research is needed to assess the mechanisms
abnormalities can vary by country. For example, parasitic by which these abnormalities affect outcomes, and
infections or nutritional deficiencies can cause or identify how they can best be treated. Establishing how to
exacerbate anaemia in patients with CKD in low-income reduce the clinical and economic burden of appropriate
and middle-income countries. Global guidelines also monitoring of laboratory abnormalities and clinical
assume the availability of sophisticated laboratory assays symptoms, especially in low-income and middle-income
and treatments, which are often not available or countries, is an important goal.
affordable in low-income or middle-income countries. Cardiovascular disease in patients with CKD is more
Developing adequate, affordable point-of-care devices frequent, more severe, and shows different manifestations
should be a high priority for future research and could compared with the non-CKD population. Atypical coronary
provide an incentive for public–private partnerships. disease, uraemic cardiomyopathy, and peripheral vascular
Additionally, haematological, hormonal, and metabolic disease are major causes of mortality in patients with
abnormalities are not necessarily important to patients CKD. Although the risk of conventional atherosclerotic
per se; yet monitoring and treating these abnormalities events does increase when kidney function is reduced,

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most of the excess risk associated with CKD is due to governments. Scientists from varied backgrounds will
so-called non-Framingham or non-atherosclerotic need to be engaged, and clinicians across the world will
pathologies, such as left ventricular hypertrophy with require education to involve both themselves and patients
diastolic and systolic dysfunction, dysrhythmia, sudden in the necessary clinical trials to develop the evidence base
cardiac death, valvular calcification, arterial calcification, for new treatments to be introduced into clinical practice.
and haemorrhagic stroke. The pathophysiology of these Consortia members will inevitably be required to design,
conditions appears due in part to a high burden of develop, and conduct trials differently, since current
traditional cardiovascular risk factors as well as uraemia- strategies have not led to the development of many new
specific factors.201 Although there is some evidence that therapeutics in CKD. Hence, a focused strategy with local
management of traditional cardiovascular risks improves and regional adaptation by high-income countries and low-
outcomes in earlier forms of CKD, it is unknown how best income and middle-income countries is required.
to reduce cardiovascular risk in advanced CKD or kidney Breaking down structural impediments, and opening up
failure.208 The well documented but poorly understood scientific, regulatory, financial, management, and legal
regional variations in cardiovascular disease in populations silos represents a formidable but not insurmountable
with CKD might offer new insights into how outcomes challenge.
can be improved—eg, Japanese haemodialysis patients To drive the availability of new treatments for CKD,
appear to have a much lower risk of sudden death than three linked sets of activities are required: identifying
those patients in other countries. Much remains to be therapeutic drug targets, enhancing capacity for pre-
understood about fundamental aspects of vascular risk clinical and early clinical development, and encouraging
reduction in CKD (eg, optimal target blood pressure, increased investment in the development of CKD
benefits of aspirin in patients on dialysis, implantable therapies (table 9).
defibrillators to prevent sudden cardiac death).209 The likelihood of identifying potential drug targets will
In addition to a high burden of traditional risk factors, be enhanced by coordinated efforts to analyse samples of
cardiovascular disease in CKD appears to be driven by human kidney tissue and other biomaterial (urine and
risk factors specific to CKD. For example, abnormalities blood) using state of the art genomic, proteomic, and
in phosphate, fibroblast growth factor 23, and Klotho all metabolomics approaches, in conjunction with detailed
appear to contribute to cardiovascular disease in patient phenotyping and use of existing biomarkers to
populations with renal abnormalities. Continued work is identify and qualify new therapeutic targets. Such efforts
needed to translate discoveries from biomedical science should link genetic data with existing phenotypic
into treatments that address these risk factors and information or generate personalised human tissue
mitigate the burden of cardiovascular disease. models, using induced pluripotent stem cells and
Although controlling traditional risk factors has not been targeted mutation followed by differentiation to human
as successful in reducing mortality in patients with kidney kidney tissue. To support these efforts, better models of
disease as it has in the general population, control of blood disease are needed to reflect the complexity of CKD
pressure,210 treatment with statins,211 and blockade of the (eg, AKI in the setting of CKD, CKD in the setting of
renin–angiotensin–aldosterone axis212,213 have reduced vascular disease, diabetes, and the metabolic syndrome).
cardiovascular events. However, the evidence base varies Building capacity for pre-clinical (ie, animal and in-
across CKD stages. For example, in dialysis patients, the vitro models) and early clinical development could be
target for control of blood pressure is unknown, but severe facilitated by better use of existing infrastructure
hypertension is clearly harmful—and organised (eg, leveraging research networks for CKD to facilitate
programmes should encourage better blood pressure data acquisition), as well as developing new infrastructure
control strategies that minimise harmful side-effects. to collect and analyse biological materials (eg, kidney
There is general consensus about the merits of controlling biopsy specimens). Human capacity will also be crucial—
blood pressure, blood sugar, and dyslipidaemia in most there is a need to facilitate interaction and exchange of
people with CKD—yet worldwide people consistently do ideas between academic researchers and drug, device,
not receive these treatments. and diagnostic manufacturers, to promote collaborations
and mutual understanding of each other’s environments
Develop and test new therapeutic strategies and objectives.
Theme 9: Develop novel therapeutic interventions to Partnerships with industry are crucial for drug
slow CKD progression and reduce CKD complications discovery, but existing frameworks for academic–
Better treatments to reduce the risk of progression from industrial collaboration do not encourage (and might
CKD to kidney failure are needed, and—as mentioned in even inhibit) such collaborations. Work is needed on how
Theme 8—there is only a small evidence base for therapies best to recognise and support academic nephrologists
that reduce cardiovascular mortality in CKD. Progress will and researchers who move in and out of an industry or
require research consortia to be developed among biotechnology research environment. An essential
academia, industry partners, biotechnology companies, element will be identifying how to give academic credit
philanthropic and funding bodies, policy makers, and to researchers who participate in such interactions,

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Partners Deliverables
Improve identification of potential therapeutic drug targets
Investigate human samples using state of the art genomics, proteomics, Research consortia, industry or Inventory of current capacity and activities,
and metabolomics approaches, merged with detailed patient phenotyping biotechnology companies, with annual updating of changes in capacity or
and existing biomarkers to identify and qualify new therapeutic targets systems biologists, and activities and outputs
geneticists
Increase participation in cross-disciplinary research on pathophysiological Global, regional, and national Development of series of meetings with non-
mechanisms relevant for CKD and other diseases (eg, fibrosis research) societies, networks, and ISN renal scientists around areas or mechanisms
(new meeting format or strategy); number of
new targets increased since 2016
Focus academic preclinical research on identification of druggable targets Funding agencies and research ··
networks
Improve models of disease (animal and human) to better reflect the Scientists, industry partners, Research reports
complexity of human CKD (eg, acute kidney injury in the setting of CKD, CKD and biotechnology companies
in the setting of vascular disease, diabetes, and metabolic syndrome)
Increase the capacity for preclinical and early clinical development
Promote research networks for CKD and segmented disease populations to ISN and industry partners Inventory of current capacity and changes over
facilitate data acquisition and trial recruitment time (1–3 years)
Develop infrastructure to do state of the art analyses of human tissue ·· Increase in number of new drugs available for
(CKD biopsy sample collections) to better understand the pathobiology specific causes of CKD since 2016
of CKD and its progression
Facilitate interaction and exchange of ideas between academic researchers ISN, industry partners, and Development of innovative meeting formats,
and drug, device, or diagnostic manufacturers, aiming to promote scientists such as Pitch for Partners as stand-alone
collaborations and mutual understanding of each other’s environment and meetings or in conjunction with major
objectives conferences
Recognise and support academic nephrologists and kidney PhD scientists to Industry partners and academic Establish special scholarships to increase
move in and out of an industry or biotechnology research environment institutions capacity
Give credit to ongoing involvement of academic, industry, and Academic institutions and Policy statement at academic institutions
biotechnology collaborations in therapeutic development and in academic health sector, biotechnology recognising activities and tabulating towards
career development companies, and industry career development
partners
Increase the availability of novel therapeutic approaches
Investigate opportunities for repurposing of existing drugs for diverse Industry partners and system Workshops or conferences for establishing
disease for treatment of CKD and its complications biologists programme of work and for reporting of
results
Improve access to effective but costly drugs or biologics and devices, Industry or biotechnology Inventory of current availability of any
especially in low-income and middle-income countries; support from companies, governments, therapeutics, regular update (via GKHA or
Organisation for Economic Co-operation and Development countries to international and national targeted ancillary survey) in specific
low-income and middle-income countries, aiming to target prevention agencies, ministries of health, low-income and middle-income countries
and treatment of CKD corporations, and foundations within the next 3–10 years
Encourage increased investment in the development of CKD therapies
Document differences in CKD practice patterns and therapeutic needs in ISN, global, regional, and Extension of the GKHA project
different countries national nephrology societies
Encourage industry, biotechnology, and government investment in the Industry, government, Tailored plans and strategies accepted by
development of new therapies for CKD researchers, biotechnology, funders, governments, WHO, World Bank, and
and venture capitalists foundations
Market economic opportunity and develop business case Academic institutions and ··
industry partners
Assess opportunities for repurposing of existing drugs for diverse diseases Industry partners and system Workshops or conferences for establishing
for treatment of CKD and its complications biologists programme of work and for reporting of
results

CKD=chronic kidney disease. ISN=International Society of Nephrology. GKHA=Global Kidney Health Atlas.

Table 9: Theme 9, develop novel therapeutic interventions to slow CKD progression and reduce CKD complications

which might not always yield traditional scholarly enhance efficacy. Although the focus of improving
deliverables such as publications. therapeutic strategies has usually been on scientific
Development of effective drug delivery systems is as development, development of novel therapeutics has also
important as identification of novel targets, and advances been hindered by identification of project funding
in therapeutics beyond small molecules to DNA and sources, availability of suitable manufacturing companies
RNA therapeutics should help in this regard, together that are compliant with Good Manufacturing Practice,
with targeted bioavailability to reduce side-effects and and protection by investigators and industry of

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intellectual property generated from scientific studies. of people with advanced CKD in whom progression is
Taxation and regulatory policies, including offering considered to be more predictable than in patients with
patent exclusivity and expedited review for breakthrough earlier stages of CKD—but interventions that slow
therapies for CKD, should provide incentives to develop progression during earlier stages might not be effective in
innovative therapeutics in CKD. Clinical trials later stages, and vice versa. A doubling of serum creatinine
repurposing generic therapeutics—such as allopurinol (equivalent to a 57% decline in eGFR) has been accepted as
and metformin, both of which have shown potential in a surrogate for the development of kidney failure for many
the attenuation of progression of CKD through years. A workshop convened by the US National Kidney
mechanisms related to oxidative stress and fibrosis215,216— Foundation and Food and Drug Administration (FDA)
should be prioritised where there is sufficient scientific recommended that the threshold might be reduced to a
evidence. Strategies that extend the patent life of drugs decline of GFR by 30–40% under specific circumstances,
without commitment to assess repurposing should be to improve trial feasibility.218 This reduction is clinically
discouraged. If the above goals are achieved, treatment to meaningful because it is established to be on the causal
stop, slow, or reverse CKD might become accessible to pathway to RRT or death. In addition, this 30–40%
populations worldwide. reduction metric is used in clinical practice, and trials are
being planned using it.
Theme 10: Increase the quantity and quality of clinical Few intermediate, validated endpoints or biomarkers
trials in CKD are accepted by the regulatory agencies for approval of
High-quality clinical trials are the cornerstone of new treatments. Change in albuminuria as an endpoint
evidence-based prevention and treatment of disease, but in kidney trials continues to be debated, with no clear
nephrology has a strikingly weak base of these trials. The consensus.219,220 Other markers of kidney damage, such as
number of trials in nephrology is less than any other biopsy findings, biomarkers of disease activity, or imaging
specialty, and shows little evidence of improvement.216 results, might be suitable in some kidney diseases. For
Trials in populations with kidney disease tend to be example, the US FDA has approved total kidney volume
smaller than those in other specialties, and are less likely as a prognostic marker for polycystic kidney disease (PKD)
to be randomised or masked.217 Building the evidence trials, but this required substantial scientific collaboration
base to improve outcomes for people with kidney disease by members of the PKD Outcomes Consortium.221 In
requires both greater quantity and better quality of trials other areas of medicine, conditional approval is granted
(table 10). by regulatory agencies on the basis of benefits shown on
Most phase 2–4 trials in populations with CKD have approved surrogate outcomes, while requiring
not shown benefit for their primary endpoint and several appropriate trials assessing effects on hard outcomes to
have been stopped due to safety concerns (appendix be undertaken post approval. A similar approach in CKD
pp 10–11). Different causes of CKD will probably require would increase investment in the specialty and should be
different targeted therapies to alter initiation and promoted. In any case, it is important that both efficacy
persistence of kidney injury. However, some mechanisms and safety endpoints are developed with input from
for progression of CKD might be similar (regardless of patients, which the Standardised Outcomes in
cause) and require an inclusive approach by those Nephrology (SONG) initiative is trying to address.222,223
involved in clinical trials and regulatory authorities. The likelihood of successful trials, and the appropriate
Industry investment in new therapies for CKD is driven generalisation of evidence from these trials to the clinic,
by large clinical need, but hampered by the high risk of will be enhanced if participants can be enrolled on the
failure, which has been reinforced by the history of basis of the likelihood of a positive response as well as of
disappointing large studies. risk of progression. More specific inclusion and exclusion
Among a number of factors that have contributed to this criteria are required in clinical trials to improve the
situation, the selection of valid and appropriate endpoints likelihood of answering the important research
in kidney disease trials has been especially problematic. questions. The recognised variability in progress and
The most clinically important outcome in patients with response to therapy in a complex condition such as CKD
CKD is kidney failure requiring renal replacement (dialysis requires studies designed to determine efficacy and
or transplantation), which can lead to death. However, this safety in responders. This could affect generalisability
endpoint typically develops over many years (or decades), but would answer clinically important questions and
so defining the effects of interventions on this endpoint is target populations that are likely to benefit. Active so-
often difficult, if not impossible. The long-term nature of called run-in periods are one way that this is being done,
trials required to generate regulatory approval and allow but enrichment or adaptive approaches are likely to also
revenue generation also presents a key barrier because add merit to the study. An adaptive approach assesses the
kidney-relevant outcomes thought to be of importance treatment by observing participant outcomes, and
often take 5–10 years to manifest—which is far beyond the possibly other measures, and modifying parameters of
duration of clinical trials in other fields, such as oncology. the trial protocol in accord with the observations.224,225 An
To make trials feasible, many studies enrol large numbers enrichment approach attempts to find a study population

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Partners Deliverables
Strongly encourage and promote the conduct of clinical trials in people with CKD
Develop value proposition for trials in kidney disease Health economists and payers Published position statement
Promote trials in areas of unmet need and orphan diseases, Advocacy organisations, Consensus conference with published report
including outcome development (eg, biopsy and hospitalisation) regulatory authorities, and KDIGO
Engage activated patient groups, payers, and other stakeholders, Advocacy organisations, major Trial stakeholder workshop within 2 years; increase in
aiming to substantially increase the number of clinical trials in payers, and WHO number of clinical trials in nephrology
CKD
Promote models for early conditional approval of new therapies Regulatory authorities and KHI Position statement
to encourage investment
Work to increase the number of people with CKD who are Regulatory authorities, FDA, EMA, Position statement; inventory of CKD-related
included in cardiovascular, diabetes, and oncology trials, aiming and non-nephrology disciplines inclusion and exclusion criteria in major non-kidney
to reflect the prevalence of CKD in these patient populations trials to monitor implementation; increase in number
of clinical trials with CKD included (vs excluded) as an
important subgroup
Develop a regular stand-alone meeting to review ongoing and KDIGO, KHI, global, regional, and First stand-alone meeting within 2 years
planned clinical trials with patients with CKD on a global scale national nephrology societies
Optimise the design of clinical trials in people with CKD
Develop and refine appropriate endpoints for CKD trials and NKF, FDA, EMA, KHI, Standardised Conference on albuminuria or estimated glomerular
promote their uptake and dissemination Outcomes in Nephrology filtration rate in 2018 (US NKF, FDA, and EMA);
position statement
Assess factors that lead to success or failure of clinical trials in Industry partners Conferences, conference reports, and formal inclusion
CKD trials of this topic in proposed annual nephrology meetings

Facilitate strategies to pre-select patients for clinical trials Industry partners, Published reanalysis of selected trials to differentiate
according to their risk for progression or likelihood to respond to bioinformaticians, clinicians, progressors or non-progressors and responders or
an intervention and scientists non-responders
Develop innovative trial designs to increase feasibility and ·· Integration into clinical trial meetings
success of CKD trials
Implement priority setting exercises for interventions to be ISN, KDIGO, global, regional, and Global exercise completed in 2 years; at least
tested in clinical trials worldwide and by region national nephrology societies 2 regional processes within 3 years
Establish recommendations for clinical trials in people with CKD Industry partners, ISN, global, Convene a panel to address this topic, including
for use by ethical and regulatory boards, including opportunities regional, and national nephrology stakeholders with appropriate expertise in relevant
for sample collection for future analyses societies disciplines
Grow capacity in conducting clinical trials in people with CKD
Develop networks of kidney clinical trialists, including Funding agencies Convene a meeting of established clinical trial groups
community physicians, and other specialties
Catalogue sites or centres capable of participating in kidney trials Academic research organisations Catalogue and mechanism available by end of 2017,
with mechanism for linking trials and centres;
develop mechanisms for internationalisation of trials,
particularly including low-income and
middle-income countries
Develop and implement professional training in trial design and Trial training providers, global, First course at World Congress of Neurology 2017, put
conduct, involving nephrology and related specialties regional, and national nephrology online by end 2017, rollout in at least two regions
societies during 2018; award fellowships for the planning and
completion of clinical trials; increase size and quality
of clinical trials in nephrology

CKD=chronic kidney disease. KDIGO=Kidney Disease: Improving Global Outcomes. KHI=Kidney Health Initiative. FDA=Food and Drug Administration. EMA=European
Medicines Agency. NKF=National Kidney Foundation. ISN=International Society of Nephrology.

Table 10: Theme 10, increase the quantity and quality of clinical trials in CKD

in which the effect of a treatment can be most readily meetings. Until recently, most clinical trial designs have
demonstrated.226,227 Enrichment or adaptive approaches been static; but some studies that are in progress are using
will add complexity and further work to understand the adaptive and enrichment protocols—eg, CREDENCE
trade-offs that will be required—eg, generalisability (NCT02065791) and SONAR (NCT1858532). Additionally,
versus specificity, and effectiveness versus safety. trials have mostly focused on the needs of high-income
Compared with other specialties, the nephrology countries, with little input from (and limited relevance to)
community has less experience, infrastructure, and patients and health-care workers in low-income and
capacity in doing clinical trials. The science of designing middle-income countries. Development of a regular stand-
these trials has received little attention, with no dedicated alone meeting to review ongoing and planned clinical trials
discussion forum and a low profile at existing major kidney in CKD on a global scale is a priority for the field.

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Discussions at such a meeting should also systematically change and big ideas, but could greatly improve
include the analysis of outcomes, including evidence for secondary prevention and treatment of CKD.
harm and insufficient efficacy of treatments from
terminated trials, to inform and improve future trial design. Summary and conclusions
Much of the infrastructure around existing trials in There are substantial gaps in research, care, and policy
nephrology has grown from industry-sponsored trials, that have severely compromised our ability to improve
without an overarching framework for engagement of the outcomes of patients with CKD around the world.
participating centres. Similarly, there is little support for The international community recognises these gaps, and
multicentre clinical trial groups from the National has developed a comprehensive plan to address them
Institutes of Health (NIH) or other government sponsors. systematically.
Collaboration between national, regional, and global trial We have involved many stakeholders: individuals with
networks has been scarce and often ad hoc, leading to broad and diverse expertise and different professional,
waste of existing resources. Much potential interaction scientific, and cultural backgrounds. The content of this
with other health-care providers (nurses, allied health document, including the recommendations, was
professionals, primary care, and other specialties) is also developed in a step-wise process, including several
under-developed. A scarcity of training and capacity rounds of internal review, plenary discussion at the
development opportunities has also meant that little summit meeting hosted by the ISN, and subsequent
infrastructure exists in many parts of the world, further working group deliberations. Despite this strength, the
limiting recruitment capacity and trial management. As selection of goals and activities and their priorities
a result, trials in CKD are not prioritised by funders, and remains subjective, and views on several issues are likely
are seen as a relatively high-risk endeavour compared to differ throughout the community. In the current time
with other therapeutic areas. of patient-centred care, many efforts to engage patients
It is also important to recognise that many trials— in these processes are ongoing. The broad scope of this
particularly trials in cardiovascular disease—exclude Review precluded in-depth analysis of each topic, but
participants with CKD, mainly because of concerns about inclusion of the full spectrum of themes relevant to the
the safety profile of novel therapies. However, given the prevention and treatment of CKD is an important
high prevalence of CKD as a comorbid condition, this strength of this document.
restriction limits the generalisability of the trial Our proposed activities include education, research,
outcomes, and results in lost opportunities to generate policy creation, and implementation of these recom­
evidence for optimal care of patients with CKD. The mendations. Partners in these endeavours include
incorporation of people with CKD into any trial should academic institutions, health-care institutions, govern­
be strongly requested by regulatory agencies if CKD is mental agencies, industry partners, research funding
prevalent in the target groups. agencies, clinicians, researchers, policymakers, and
Several new approaches to clinical trials might be patients.
particularly well suited to CKD. These include large Targeted, culturally appropriate educational activities
simple trial designs, randomised registry trials, cluster for patients, policy-makers, and clinicians in all areas of
randomised trials, and adaptive trials. Simple trials with the world are crucial for progress. Education about risk
minimal data collection would also increase the feasibility factors, the importance of genetics, and the need to be
of multicentre trials with increased ethnic diversity, and involved in clinical studies will enhance the community’s
thus improve the generalisability of studies. capacity to close many of the gaps identified.
The challenges to doing clinical trials in CKD could be Research activities that harness existing databases and
addressed by the use of a broad, strategic, sustained, biorepositories, both within and outside the nephrology
collaborative approach, encompassing better trial design community, will require the development of standardised
and increased capacity and willingness to deliver these definitions, improved methods of data collection and
trials. Motivated people with kidney disease, advocacy storage, and some minimal standard dataset that can be
organisations, and health-care funders are important shared between countries. The development or
stakeholders in this process, and need to be more enhancement of registries in countries around the world
engaged in all CKD research-related activities. Greater will be an important step forward in documenting current
investment in kidney disease trials might require robust disease burden and changes. The ability to collaborate
business cases, clearly articulating the size of the across borders and disciplines is predicated on a change
population affected, achievable benefits, and cost savings in policies and attitude about data sharing and academic–
for health-care systems and patients by changing or industry collaborations. Progress towards this goal should
delaying the progress of kidney diseases and reducing be quantifiable using bibliometric indices.
cardiovascular disease events and death. Activities should be targeted to all regions of the globe,
As a stretch goal for the community, we propose that although toolkits, strategies, and research methods will
30% of patients with CKD should be involved in relevant need to be adapted for geographical, socioeconomic,
clinical trials by 2030. This will require transformative cultural, and political considerations.

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