Safe Water and Healthy Hydration

Ann Nutr Metab 2019;74(suppl 3):45–50 Published online: June 14, 2019
DOI: 10.1159/000500345

International Society of Nephrology 0 by

25 Project: Lessons Learned
Etienne Macedo a Guillermo Garcia-Garcia b Ravindra L. Mehta a
     

Michael V. Rocco c  

a Department of Medicine, University of California San Diego, San Diego, CA, USA; b Nephrology Service, Hospital
   

Civil de Guadalajara Fray Antonio Alcalde, University of Guadalajara Health Sciences Center, Guadalajara, Mexico;
c Wake Forest School of Medicine, Medicine, Winston-Salem, NC, USA
 

Keywords J Am Soc Nephrol 2017]. In this review, we will comment on

Acute kidney injury · Dehydration · Mortality · Epidemiology the main findings and lessons learned from the 0 by 25 ini-
tiative. © 2019 The Author(s)
Published by S. Karger AG, Basel

Abstract
Acute kidney injury (AKI) is a common disorder with a high
risk of mortality and development of chronic kidney disease.
With the validation of the recent classification systems, RI- Introduction of 0 by 25 Projects
FLE in 2004 and KDIGO, in use today, our understanding of
AKI has evolved. We now know that community-acquired The worldwide application of the RIFLE/AKIN (Risk,
AKI is also associated with an increased risk of worse out- Injury, Failure, Loss of kidney function, and End-stage
comes. In addition, several epidemiological studies, includ- kidney disease/Acute Kidney Injury Network) and KDI-
ing cohorts from low-income and low-middle income coun- GO (Kidney Disease: Improving Global Outcomes) clas-
tries, have confirmed common risk factors for community- sification systems has confirmed the increasing incidence
acquired AKI. In 2013, the International Society of of AKI in different settings [5–9]. The efforts of nephrology
Nephrology launched the 0 by 25 campaign with the goal and critical care societies to create a unified classification
that no patient should die from preventable or untreated system have enabled comparisons of AKI incidence and
AKI in low-resource areas by 2025 [Mehta et al.: Lancet 2015; outcomes across diverse populations. The resultant epide-
385:2616–43]. The initial effort of the initiative was a meta- miological studies have shown increasing severity of AKI
analysis of AKI epidemiology around the world. The second cases and a higher risk of death associated with AKI, in both
project of the 0 by 25 initiative, the Global AKI Snapshot hospital and community settings [10–12]. In addition, AKI
(GSN) study, provided insights into the recognition, treat- is now a recognized important risk factor for new-onset
ment, and outcomes of AKI worldwide [Mehta et al.: Lancet chronic kidney disease (CKD), determining acceleration in
2016; 387: 2017–25]. Following the GSN, a Pilot Project was the progression to end-stage renal disease [13–15].
designed to test whether education and a simple protocol- The International Society of Nephrology (ISN) 0 by 25
based approach can improve outcomes in patients at risk of initiative aims to eliminate or at least reduce avoidable
community-acquired AKI in low-resource settings [Macedo: AKI-related deaths around the world by 2025 [1]. Two key

© 2019 The Author(s) Etienne Macedo

Published by S. Karger AG, Basel Department of Medicine
University of California San Diego
E-Mail karger@karger.com This article is licensed under the Creative Commons Attribution-
NonCommercial-NoDerivatives 4.0 International License (CC BY- 9500 Gilman Dr, La Jolla, CA 92093 (USA)
www.karger.com/anm E-Mail emmacedo @ ucsd.edu
NC-ND) (http://www.karger.com/Services/OpenAccessLicense).
Usage and distribution for commercial purposes as well as any dis-
tribution of modified material requires written permission.
points were essential for the initiative: defining preventable initions, plus 266 papers based on KDIGO or equivalent
death from AKI and promoting local recommendations AKI definitions, were analyzed [1]. The pooled incidence
for AKI care considering the health-care infrastructure rate by KDIGO stage in 266 studies (4,502,158 subjects)
and socioeconomic conditions [1, 16–19]. Based on previ- showed an overall rate of 20.9% of hospital admissions and
ous studies, preventable deaths from AKI are known to affected 3,000–5,000 patients per 1 million population per
occur as a result of 3 different situations [1]: (1) secondary year. Recent studies have described an incidence as high as
to public health problems such as unclean water, diarrhea, 15,000 per 1 million population per year. The data from
and endemic infections; (2) delayed or lack of recognition, these studies showed that the mortality rates continue to
lack of access to laboratory studies, inadequate response, be high in all regions and that there was a continued asso-
or iatrogenic factors resulting in additional insults to a fail- ciation of nonrenal recovery following AKI.
ing kidney; and (3) lack of dialysis support to treat life- Nevertheless, AKI incidence in low-middle income
threatening hyperkalemia, fluid overload, and acidosis [1]. countries (LMICs) is still uncertain as some studies have
Although knowledge of the epidemiology of AKI has im- shown lower levels than in high-income countries (HICs).
proved immensely since the use of a standardized AKI clas- It is likely that underreporting is the most common rea-
sification system, few studies have focused on community- son for the discrepancy when comparing HICs and com-
acquired AKI in low-resource settings. In the meta-analysis bined low-incomes plus LMIC. In addition, epidemiolog-
by the 0 by 25 initiative, the main issues regarding the epi- ical data from LMICs are difficult to interpret as there are
demiology of AKI were raised [1]. Information was pre- nonuniform cohorts and involve heterogeneous methods
sented regarding the increasing associated mortality of even of reporting as well as wide variations in ability to diag-
mild AKI, the effects of an AKI episode on long-term out- nose and treat AKI [1].
comes, and early detection and treatment of AKI in outpa- Another factor to consider is the high incidence of AKI
tient and low-resource settings. However, to reduce AKI- in the hospital settings of areas with more resources, in
related mortality and morbidity, knowledge of the factors contrast to community hospitals and rural areas, where
that affect AKI outcomes is a key step in implementing ini- AKI is often not detected [8, 19, 22–26]. Nonetheless, AKI
tiatives. The strategies to reduce the burden of AKI need to in this population is often preventable and reversible, af-
be based on the identification of patients at risk, implemen- fecting young, previously healthy individuals and might be
tation of preventive actions, application of diagnostic meth- secondary to tropical infectious diseases, animal venoms,
ods, and timely referral for specialist care [20, 21]. Develop- the use of herbal medicine, complications of pregnancy in-
ment of educational and training tools for raising awareness cluding septic abortion, and infectious diarrhea (Table 1).
and standardizing care of AKI cases is also essential.
As most studies on AKI are derived from developed
countries and mainly focus on ICU populations, the 0 by 25 GBD Study
initiative developed 2 projects to assess how AKI contrib-
utes to the global burden of health loss: the Global AKI Snap- The Global Burden of Disease (GBD) Study is an effort
shot (GSN) study, and the Pilot Study. The GSN study was of the World Health Organization to quantify leading
a prospective multinational cross-sectional project that in- causes of health loss secondary to illness or injury through-
cluded all patients with AKI who presented to the participat- out the world [27]. The GBD Study categorizes causes of
ing physicians on a given index day in 2014 [2]. The study health loss by age, sex, and geography for a specific time
included 4,018 patients with AKI across 6 continents and 72 point. This time-based measure combines years of life lost
countries. The Pilot Study is a prospective cohort of patients due to premature mortality (YLL) and years of life lost
with high risk for community-acquired AKI in 3 different due to time lived in states of less than full health (DALY).
countries [3, 4]. The following paragraphs will comment on The DALY metric was developed in the original GBD
the main findings from the 0 by 25 initiative so far. 1990 study to assess the burden of disease consistently
across diseases, risk factors, and regions.
As a part of the 0 by 25 initiative, the ISN has collabo-
AKI Meta-Analysis rated with the Institute of Health Metrics and Evaluation
that coordinates the GBD study to include AKI in future
A systematic search of the literature was performed, in- GBD reports. Incorporating AKI into the GBD will in-
cluding papers from January 2012 to August 2014. Four volve determining the relationship between AKI as an in-
hundred and ninety-nine papers that included all AKI def- termediate event associated with disability or death. It

46 Ann Nutr Metab 2019;74(suppl 3):45–50 Macedo/Garcia-Garcia/Mehta/Rocco

DOI: 10.1159/000500345
Table 1. Main risk factors for developing AKI

Patient Exposures
nonmodifiable modifiable environmental infrastructure

Comorbid medical conditions Dehydration Diarrhea Inadequate sanitation

Chronic kidney disease Intravascular volume Obstetric complications (including Limited clean water availability
Diabetes mellitus depletion septic absorption) Inadequate control of parasites
Cancer Hypotension Infectious diseases (malaria, Inadequate control of
Chronic heart disease Anemia leptospirosis, dengue, cholera, infection-carrying vectors
Chronic lung disease Hypoxia yellow fever, tetanus, Hantavirus) Poor transportation
Chronic gastrointestinal Use of nephrotoxic Animal venoms (snakes, bees and Inadequate health budget
disease agents (antibiotics, wasps, Loxosceles spiders, Lonomia Insufficient health care human
Demographic factors iodinated contrast, caterpillars) resources
Gender nonsteroidal Natural medicines Insufficient health services and
Older age anti-inflammatory drugs, Natural dyes hospitals
anticancer drugs, Prolonged physically overwhelming  
antiretroviral, work in an unhealthy environment  
calcineurin blockers)

Modified from [1].

AKI, acute kidney injury.

will be possible to follow the leading causes of AKI and munity. Most patients (46%) were at the ward or step-
the segments of the population most susceptible to AKI- down unit when AKI diagnosis occurred, with similar
related health loss. The main goal is to add strength to the rates across all country categories. Eighty percent of the
concept that a high proportion of cases of AKI in the com- cases were considered de novo AKI.
munity setting of low resource areas are preventable; it Hypotension/shock and dehydration were the more
also attempts to demonstrate that investment toward ear- frequent risk factors associated with AKI development.
ly recognition can be translated into reduce mortality and In HIC and UMIC, hypotension/shock was the most
improve outcomes. prevalent cause, whereas dehydration was the most fre-
In order to enable the inclusion of AKI in GBD, the ISN quent contributory factor for the development of AKI in
0 by 25 initiative helped to generate AKI epidemiological LMIC. Most dehydration episodes were associated with
data at the population level. The 0 by 25 initiative enabled inadequate oral intake (60%), followed by vomiting
the AKI Global Snapshot, a prospective observational co- (44%).
hort study, to compare risk factors, etiologies, diagnoses, Patients with stage 3 AKI were higher in LMICs than
management, and outcomes of AKI. The study was con- in HICs and UMICs (58 vs. 47 and 41%, respectively).
ducted from September 29, 2014, to December 7, 2014, However, more patients in LMICs experienced recovery
with over 600 participating centers in over 93 countries [2]. from AKI than did patients from HICs and UMICs. The
Patients were classified as having community-acquired large proportion of patients presenting with stage 3 AKI
AKI if they presented with AKI and hospital-acquired AKI has important implications.
if they developed it in the hospital setting. Patients were In a separate analysis of children, the main factors as-
considered as de novo AKI, AKI on CKD, or AKI with un- sociated with AKI in HIC were hypotension (30%), post-
known prior kidney history if a baseline creatinine was not surgical complications (27%), and dehydration (26%). In
known. Countries were classified into HICs, upper-mid- contrast, dehydration was the most common etiologic
dle-income countries (UMICs), and LMICs according to factor in LMIC (43.5%) and UMIC (30.6%) [9].
their 2014 gross national income per person, using thresh- Mortality rate varied from 11.45% in patients from
olds defined by the World Bank Atlas method [28]. LMIC to 13.6% in patients from UMIC. In pediatric pa-
Overall, community-acquired AKI was more frequent tients, the mortality rate was significantly different
than hospital-acquired AKI, and the difference was great- (19.6%) in LMIC compared to 1.2% in HIC [9]. Mortality
er in LMIC, where 79% of AKI cases occurred in the com- in community-acquired AKI was higher in LMIC (11%)

ISN 0 by 25 Project: Lessons Learned Ann Nutr Metab 2019;74(suppl 3):45–50 47

DOI: 10.1159/000500345
 Risk
Identifying high-risk individuals for primary
prevention of AKI
• Use of risk scores to predict risk of AKI
• Identification of modifiable risk factors

Rehabilitation
Post-discharge care of AKI
patients Recognition
• Follow-up of kidney Prompt diagnosis
function • Early and sequential sCr and UO
• Educational campaigns on assessment
the importance of • Availability of point of care tests
long-term follow-up and diagnostic tools

Response
Interventions for incipient and established
Renal support AKI
Renal replacement therapy in AKI • Use of protocol-based management of
• Timely intervention with RRT hemodynamic and fluid status
• Education and training of personnel • Avoidance of nephrotoxic drugs
for peritoneal dialysis • Appropriate drug dose adjustment for
kidney function

Fig. 1. ISN AKI 0 by 25 key elements for a sustainable infrastructure to support AKI care. sCr, serum creatinine;
RRT, renal replacement therapy; UO, urine output; AKI, acute kidney injury. Modified from [1].

vs. 9% in HIC. In the pediatric population, this difference bility of implementing an education and training pro-
was even more pronounced, 3% in HIC and 20% in LMIC. gram to optimize care of AKI, based on a protocol-driv-
In LMIC, mortality was higher among ICU patients (21%) en approach in rural areas. The Pilot feasibility study
in comparison to HIC (13%). AKI recovery was more of- was conducted at 3 sites located in Asia (Dharan, Ne-
ten complete in LMIC (39%) than in HIC (33%) or UMIC pal), Africa (Blantyre, Malawi), and Latin America (Co-
(28%). Recovery rates from community vs. acquired AKI chabamba, Bolivia). Each site comprised a health-care
were very similar in HIC and UMIC. In LMIC, the recov- cluster (including 3–4 community health centers, 1 dis-
ery occurred in 79% of patients with community-ac- trict hospital, 1 regional referral hospital) that provided
quired AKI and in only 20% of patients with hospital- services to the population around the site area. The
acquired AKI. study was approved by the Institutional Review Board
The results of the GSN underline the need to raise and the Ethics Committee of University of California
awareness of AKI to increase the detection of patients San Diego and by the 3 local sites. Patients were screened
who present with earlier stages of AKI. It also indicates for signs or symptoms a priori associated with high/
that the main causes of AKI in LMICs are dehydration, moderate risk of developing AKI. AKI was confirmed
infection, and sepsis. within 7 days by a serum creatinine concentration in-
crease or decrease of 0.3 mg/dL, or 1.5 times from the
reference value.
Pilot Study The results of the pilot study, soon to be published, will
provide an assessment of the current approach to diagno-
In the GSN study [2], we were able to demonstrate sis and management of AKI in community health centers
that there are significant similarities in the risk factors and will identify barriers to optimize care of these pa-
and causes of AKI worldwide; however, there was an tients. It will demonstrate the effect of simple interven-
underrepresentation of community-acquired AKI, par- tions, including education and provision of point-of-care
ticularly in rural settings. The primary aim of the 0 by tests, on the course and outcomes of patients with a high
25 AKI Pilot Feasibility Project was to assess the feasi- risk of developing AKI. As a part of the project, we devel-

48 Ann Nutr Metab 2019;74(suppl 3):45–50 Macedo/Garcia-Garcia/Mehta/Rocco

DOI: 10.1159/000500345
oped partnerships with the governments of the partici- training of health-care personnel is fundamental to
pating countries to establish the best approaches to de- achieve increased awareness and better care delivery in
crease preventable deaths from AKI. AKI. Additional key elements include improvement in
health care and diagnostic tool availability and provision
of acute renal replacement therapy for those in need. The
Next Steps worldwide heterogeneity in the cause, setting, and course
of AKI demands an integrative approach. The 0 by 25 ini-
AKI has been associated with high mortality rates; tiative proposed the utilization of the 5R framework: Risk
however, it is likely that a significant number of deaths assessment, Recognition, Response, Renal support, and
associated with AKI could be avoided. In addition, AKI is Rehabilitation (Fig. 1) [1, 30].
now a recognized important risk factor for new-onset Furthermore, this initiative is enabling the develop-
CKD, determining acceleration in progression to end- ment of sustainable infrastructure to improve education,
stage renal disease, leading to poor quality of life, disabil- training, care delivery, and implementation of diagnostic
ity, and long-term costs [29]. The Global Snapshot was and intervention studies. It provided evidence suggesting
the first large, epidemiologic study to map and scale the that the majority of AKI cases would be treatable and of-
outcomes associated with AKI around the world, includ- ten reversible, with early identification in high-risk pa-
ing data from ICU and non-ICU patients. It provided a tients and implementation of basic treatment.
solid basis to direct efforts for the ambitious goal of zero
deaths from AKI by 2025.
The ISN 0 by 25 initiative offers a critical opportunity Disclosure Statement
to help improve education, training, care delivery, and E.M., G.G.-G., and M.R. received travel expenses and registration
the implementation of diagnostic and intervention stud- fee from Danone Research to participate in the 2018 Hydration for
ies in AKI. A comprehensive approach for education and Health Scientific Conference. R.L.M. has nothing to disclose.

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50 Ann Nutr Metab 2019;74(suppl 3):45–50 Macedo/Garcia-Garcia/Mehta/Rocco

DOI: 10.1159/000500345