Reducing major risk factors for chronic kidney disease

Abstract

Chronic kidney disease (CKD) is a global public health concern and a key determinant of poor health outcomes. While the burden of CKD is reasonably well defined in developed countries, increasing evidence indicates that the CKD burden may be even greater in developing countries. Diabetes, hypertension, and obesity are major contributors to the global burden of the disease and are important traditional CKD risk factors; however, nontraditional CKD risk factors such as nephrotoxin exposure, kidney stones, fetal and maternal factors, infections, environmental factors, and acute kidney injury are also increasingly being recognized as major threats to global kidney health. A broad approach to CKD prevention begins with the identification of CKD risk factors in the population, followed by the development of appropriate mitigation strategies. Effective prevention policies rely on an accurate understanding of the incidence and prevalence of CKD in a given setting, as well as the distribution and burden of risk factors. Populations or individuals at CKD risk must be screened and treated early to prevent the onset of and delay the progression of the kidney disease. Systematically collected data should be analyzed at country, province, and district levels to identify regional disparities and CKD hotspots and develop targeted prevention strategies. Race-ethnicity, genetics, sex, socioeconomic status, and geography are likely modifiers of CKD risk. A comprehensive, informed approach to prevention that takes into account all of these factors is therefore required to successfully tackle the global CKD epidemic.

Chronic kidney disease (CKD) is increasingly recognized as a global public health concern and an important contributor to morbidity and mortality.¹ While the burden of CKD is reasonably well defined in developed countries, increasing evidence indicates that the CKD burden may be even greater in developing countries.1, 2 Of the major contributors to the global burden of disease, diabetes, hypertension, and obesity are traditional risk factors for CKD.¹ Nontraditional CKD risk factors such as nephrotoxins (e.g., prescription medicines and alternative remedies), kidney stones, fetal and maternal exposures, infections, environmental exposures, and acute kidney injury (AKI) are also being increasingly recognized as major threats to kidney health.³ The burden of CKD that is attributable to nontraditional risk factors is unknown and may even predominate in low- and middle-income countries (LMICs).

A broad approach to CKD prevention begins with the identification of the incidence, prevalence, and distribution of risk factors, followed by the development of mitigation strategies. At-risk populations or individuals must be screened and treated early to prevent onset and delay progression. Reducing CKD risk is also highly dependent on addressing the fact that it is both a consequence of and a contributor to socioeconomic disparities. This review expands on the recently published International Society of Nephrology (ISN) CKD roadmap,⁴ which discusses the globally relevant major traditional and nontraditional risk CKD factors (outlined in Table 1), highlights gaps in knowledge, and recommends strategies to close these gaps and enhance CKD prevention.

Table 1.

Global relevance of major risk factors for chronic kidney disease and suggested mitigation strategies

Risk factor	Global prevalence	Primary prevention	Projected CKD risk	Secondary prevention of CKD	Knowledge gaps	Relevance for HIC	Relevancy for LIC	Advocacy required	Refs
Diabetes type 2	All diabetes 387 million with largest concentrations in Western Pacific (138 million) and Southeast Asia (75 million) Type 2: About 95% of overall global prevalence	Education, lifestyle, diet, exercise, weight management	∼40% overall and >50% in most non-White populations	Glucose control, BP control, lifestyle factors (avoiding high dietary protein), ACEI, or ARB	Glucose targets, best medications, need for novel therapies for diabetic kidney disease	Obesity, DM, GDM	Increasing obesity and DM, GDM Poor facilities for diagnosis and treatment	Policy development around food content and prices of healthy food, urban planning to increase walking opportunities, tobacco UHC Access to diagnosis, reliable access to medication and lifestyle	37, 42, 43, 59
Diabetes type 1	Type 1: About 5% of overall global prevalence	Viral exposure?	∼30% not known to vary by race-ethnicity	Glucose control, BP control, lifestyle factors (avoiding high dietary protein), ACEI, or ARB	Glucose targets, novel therapies for diabetic kidney disease	Glycemic control	Glycemic control, poor facilities for diagnosis and treatment	UHC Access to diagnosis Reliable access to medication and lifestyle	37
Hypertension	2010: 31% of adults globally (28.5% in HIC, 31.5% LMIC) 1.39 billion people (349 million in HIC, 1.04 billion in LMIC)	Education, lifestyle, diet, exercise, weight management, smoking, stress reduction	∼10%	BP control, ACEI, or ARB if high-level albuminuria, other medication types?	Albuminuria-based targets?	Obesity, dietary sodium	Obesity, dietary sodium, strokes also high Awareness, treatment, and control very low in LMIC	Policy development around food sodium content, tobacco, and alcohol Need to increase awareness, treatment, and control globally UHC Consider polypill strategy Awareness, access to diagnosis Reliable access to medication and lifestyle	23
Obesity (Risks may vary for childhood and adult obesity)	Adult: Overweight 2013: 36.9% men, 38.0% women Obesity 2014: 10.8% men, 14.9% women Children: In 2014, 41 million children aged <5 yr were overweight or obese (48% in Asia, 25% in Africa)	Education, lifestyle, diet, exercise, weight management, stress reduction	Unknown proteinuria or macroalbuminuria present in 4%–10% obese patients In morbidly obese, risk of GFR decline of ≥30% over 4 yr was 48.2 per 1000 person-yr Adolescent obesity associated with HR of 6.9 for all ESKD and HR of 19.4 for diabetic ESKD	Diet, exercise, weight loss, bariatric surgery (HIC) ACEI or ARB for proteinuria	CKD risk optimal BMI and variance by race-ethnicity and age, safe and effective weight management strategies, namely bariatric surgery	Access to weight management programs	Access to weight management programs Social roots of obesity, namely poverty, culture, access to nutritious food	Policy development to regulate food content, food prices, urban planning to permit physical exercise Access to better diet, education, physical activity education	140, 159, 160, 161, 162, 163
Medications (Antibiotics, NSAIDs, PPI, counterfeit drugs, contrast media)	AKI: 24% globally related to nephrotoxins (29% HIC, 22% UMIC, 23% LLMIC) CKD: Unknown	Improve awareness, prescription flagging, stop unnecessary prescriptions	70% of children with nephrotoxin-induced AKI had CKD at 6 mo CKD risk variable, by medication	Early detection, urine screening for leukocytes, stop medications early	Burden of disease Which medication may increase CKD risk	Electronic alert systems, prescription data-sharing databases, package warnings	Reduce counterfeit drugs, regulate drug manufacturers to reduce adulterants	Awareness, prescription practices, marketing	64, 71, 72
Traditional/ alternative remedies	Frequent use globally, >80% in LMIC	Improve awareness, improve access to alternatives (UHC)	35% of AKI in Africa Unknown contribution to CKD, increased risk of ESKD with consumption of some remedies	Stop medication, hydration	Burden of disease, toxic compounds	Huge market of OTC and over-the-Internet Need regulation of the industry	Engage with communities to understand reasons for use, barriers to western medicine, etc.	Policies to regulate manufacture and sale of alternative remedies, limit unfounded or fraudulent advertising UHC Awareness, collaboration with traditional healers, improve access to medical care or affordability of medication, encourage publication of case reports to build database	76, 86, 164
Kidney stones	Geographic variability Adults: 5%–9% Europe, 12% Canada, 13%–15% USA, 1%–5% East, 20% Saudi Arabia	Increase awareness of local risks, emphasize on the importance of hydration, certain infections	GFR tends to be reduced in stone formers vs. non–stone formers	Hydration, diet, recurrent stone prevention, early reversal of obstruction	Regional risks	High costs	Likely unrecognized important cause of CKD and infections	Access to clean water, reduce environmental or occupational risks Increase awareness of need for follow-up for CKD, CVD in stone formers	88, 90, 106
Low birth weight/SGA/ prematurity	Globally: LBW 15%, Preterm 10% In LMIC, 2010: 13.7 million babies preterm; 2010: 43.3 million babies LBW/SGA	Avoid obesity, maintain healthy lifestyle	70% increased risk	Screen for BP and proteinuria Treat early	Would reduction impact future risk?	Increased maternal age, assisted reproduction, maternal chronic illness	Preeclampsia, maternal malnutrition, poverty, war, poor antenatal care, pregnancy spacing, child marriage	Awareness, public health care measures, optimize maternal and child health, avoid childhood obesity UHC Document birth weights, prematurity in health care record Need for long-term follow-up of children at risk	112, 114
Preeclampsia/ eclampsia	2%–5% globally Global prevalence 2013: 1.3 million	Optimize maternal health prepregnancy	RR HT–3.7 RR microalbuminuria 4–8 RR ESKD 4.7 RR kidney biopsy 3.3	Screen for BP and proteinuria and treat early	How to diagnose and prevent?	Prematurity, later CVD, ESKD	Prematurity, CVD, ESKD	Maternal health Access to antenatal care UHC Mothers require long-term follow-up for CKD and CVD	124, 145, 165, 166
HIV	2013: 35 million worldwide, 24.7 million in sub-Saharan Africa	Education, use of condoms	Africa: 6.0%–48.5%, Europe 3.5%–18%, Hong Kong 18%, Brazil 1.1%–5.6%, India 27%, Iran 20%	PEP, HAART	Impact of HAART on all forms of renal disease, other kidney diseases in HIV-infected individuals	Competing risks of mortality	Poverty, suboptimal access to ART, ongoing infection risk, ApoL1 genotype with African origin	Policies around needle sharing, prostitution UHC National policies for prevention education, access to ART, reduce gender and/or sexuality discrimination, empower women, surveillance of renal function on ART	134
Hepatitis B	Global prevalence 2013: 331.0 million	Education Reduce scarification Vaccination	Hepatitis B-associated GN: 3% France, 3% China	Treatment Hepatitis B	Impact of routine vaccination on CKD burden	Reduce HCC, liver failure transplant	High prevalence	Policies around needle sharing, vaccination Advocacy for sexual health, drug abuse Equity in access to vaccination. (Vaccination reduced membranous nephropathy among Taiwanese children) Equity in access to antiviral therapy	145, 146, 149
Hepatitis C	Global prevalence 2013: 147.8 million	Education	Global: 10%–16% glomerular lesions in 54.8% HCV-positive subjects at autopsy	Treatment of hepatitis C	Impact of treatment on disease burden	Reduce HCC, liver failure, kidney transplant. New medication is very costly	Lower prevalence, unlikely to gain access to expensive therapies	Policies around needle sharing Advocacy against drug abuse Lobby for access to therapy in HIC and LMIC	145, 146, 147
Bacterial skin diseases	Global prevalence 2013: 5.8 million	Sanitation, early treatment	Acute PSGN 9 per 100,000 in LMIC Higher frequency or CKD after post-streptococcal GN, worse in adults	Early detection of renal involvement, treatment and follow-up	Contribution to CKD burden in LIC unknown	Likely low	Likely high	Policies to improve child nutrition, school feeding schemes Poverty, overcrowding, scabies prevention and early treatment. Consider screening school children for hematuria, proteinuria	144, 145, 167
Schistosomiasis	Global prevalence 2013: 290.6 million	Safe water Education	Obstruction (urinary) 2%–62%, chronic glomerulonephritis (hepatosplenic) in 15%	Prompt treatment, screening for obstruction	Obstruction usually not severe, renal function preserved. Regional contribution to ESKD may be 3%–7% (Egypt)	Low	High regional	Public health care policies, neglected tropical diseases Clean water Consider screening school children for hematuria, proteinuria. Prompt access to diagnosis and treatment	132, 145, 148, 168, 169
Diarrheal illnesses	Global prevalence 2013: 4.24 million	Safe water, sanitation, nutrition, vaccination	Important cause of AKI worldwide	Appropriate hydration, antibiotics when needed	Burden of CKD related to diarrhea-associated AKI. Impact of vaccination on AKI/CKD	Relatively low, diarrhea-associated HUS	High, important cause of childhood AKI through volume depletion, sepsis, HUS	Public health care policies, sanitation, water education, infrastructure, vaccination Advocacy to chlorinate water, handwashing, improve water safety, equitable access to vaccination, education about oral rehydration therapy	145
Malaria	Worldwide prevalence 2013: 351 million	Use of ITNs, vector control, prompt treatment with correct drugs	AKI <1% to >50% in adults with severe falciparum malaria. CKD not often reported among survivors	Early screening, diagnosis, and management	Contribution to CKD burden regionally unknown, possible differences among those living in endemic areas or not? May be associated with CKDu	Low	High regional	Public health care policies, vector control, insecticide-treated nets, monitor medication resistance, combat counterfeit medication, introduce RDT Access to prevention, diagnosis, appropriate treatment	136, 137, 138, 139, 145
Tuberculosis	Worldwide prevalence 2013: 12.1 million	Healthy diet, reduce poverty, reduce HIV	Genitourinary 27% of extrapulmonary TB (obstruction, parenchymal infection, interstitial nephritis)	Prompt diagnosis and full treatment	Low	Low, higher in immigrant, prison, indigenous, immune-suppressed populations	High, regional. Often coinfection with HIV	Public health care policies on detection, supervision of therapy, GeneXpert, management of MDR, XDR, integration with HIV services Poverty, comorbid illness, nutrition, overcrowding, occupational exposure (mining), HIV infection	143, 145
Leptospirosis	Global incidence 1.03 million	Use of ITNs, vector control, prompt treatment	AKI (Weil’s disease) 10%–60%	Early diagnosis	Contribution to burden of CKD unknown	Little	High, regional	Public health care policies, neglected tropical diseases Poverty, water quality, overcrowding	137, 170
Environmental factors	Unknown risk factor prevalence for CKDu– likely association with environment (heat), occupation, poor fluid intake, coinfections, traditional remedies	Avoid occupational, climate, and environmental hazards	Prevalence 13%–26% in high-risk populations	Hydration Avoid nephrotoxins	Causes and pathophysiology unknown	Low	CKDu major problem in multiple LMIC	Policies around working conditions, environmental contamination	5, 139, 171
AKI	21% of hospital admissions (global data insufficient for accurate quantification)	Early risk identification, treat underlying cause early, avoid nephrotoxins	Adults: 25.8 per 100 person-yr (CKD), 8.6 per 100 person-yr (ESKD) Children: 3.1 per 100 person-yr (proteinuria), 0.9 per 100 person-yr (ESKD)	Early diagnosis and treatment of AKI	Actual risk of CKD after AKI in population, impact of interventions to reduce AKI on the prevalence CKD	Predominantly hospital acquired, older adults, multiple comorbidities	Predominantly community acquired, adults younger, few comorbidities	Increase awareness of risk of AKI and need for prompt treatment, require accessible methods to diagnose AKI, awareness of CCKD risk requiring long-term follow-up after severe AKI	150, 153, 154

ACEI, angiotensin converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; ART, antiretroviral therapy; BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; CKDu, chronic kidney disease of uncertain etiology; CVD, cardiovascular disease; DM, diabetes mellitus; ESKD, end-stage kidney disease; GDM, gestational diabetes mellitus; GFR, glomerular filtration rate; GN, glomerulonephritis; HAART, highly active antiretroviral therapy; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIC, high-income country; HT, hypertension; HUS, Hemolytic-uremic syndrome; HZ, hazard ratio; ITN, insecticide-treated nets; LBW, low birth weight; LIC, low-income country; LMIC, low- and middle-income countries; MDR, multi-drug resistance; NSAID, nonsteroidal antiinflammatory drug; OTC, over-the-counter; PEP, postexposure prophylaxis; PPI, proton pump inhibitor; PSGN, post-streptococcal glomerulonephritis; RDT, rapid diagnostic testing; RR, relative risk among those who experineced preeclampsia versus those who did not for the listed outcomes; Rx, treatment; SDG, sustainable development goal; SGA, small for gestational age; TB, tuberculosis; UHC, universal health care; UMIC, upper middle–income country; XDR, extensive drug resistance.

Prioritization of CKD and detection and investigation of CKD hotspots

To understand whether CKD is a priority within a country, incidence and prevalence, as well as the contribution of various risk factors for the burden of disease should be determined. Systematic and reliable data collection is required. It is important that such data are analyzed at region, country, province, and district levels to identify local disparities and CKD hotspots. For example, the global burden of disease study has identified several hotspots in Central America where the prevalence of CKD is high and requires attention.5, 6, 7 These include Mexico, where women have one of the highest disability-adjusted life-year rates for CKD (related to obesity, diabetes, and hypertension), as well as pockets in Nicaragua, Guatemala, and El Salvador, where CKD of unspecified cause is highly prevalent in men, primarily related to nontraditional risk factors.7, 8

To illustrate the importance of subregional local analysis, in Nicaragua, increased CKD rates in male farmers aged <60 years were associated with pesticide exposure, dehydration, alcohol consumption, and exposure to heavy metals.⁹ Costa Rica has reported a higher incidence of CKD among young sugarcane workers, with clinical and histological findings of chronic interstitial nephritis.¹⁰ In El Salvador, a high prevalence of CKD (17%) was observed among male farmers exposed to toxic pollutants.11, 12 Studies in Sri Lanka reported an association between pesticide poisoning and pollutants, with repeated episodes of AKI and CKD.¹³ In India and Pakistan, a large percentage of CKD cases are of undetermined etiology, potentially related to environmental factors.¹⁴ Many knowledge gaps remain regarding these regional epidemics of CKD of unspecified cause.⁵

Gaps

There are no reliable statistics about the prevalence of CKD in most of the developing world. Improving and expanding local data collection and processing and research infrastructure is recommended to ensure a better understanding of the burden and regional distribution of specific CKD risk factors.

Action strategies

Including screening for kidney disease in established noncommunicable disease (NCD) risk factor surveys will add significant value to existing efforts to monitor the prevalence of NCD risk factor, likely at a lower cost than duplicating efforts with parallel CKD surveillance programs. Combining such survey data with global positioning technology will permit the identification of regional and local variations in CKD occurrence. For example, the World Health Organization (WHO) STEPwise approach to surveillance is an NCD household survey that was launched in 2002.¹⁵ To date, 122 countries have participated.¹⁶ Depending on the local resources, the survey collects behavioral risk factors (step 1); physical measurements, including blood pressure (BP), height, and weight (step 2); and biochemical parameters (blood glucose and lipids; step 3).¹⁷ Advocacy efforts in Uruguay succeeded in including serum creatinine and urine protein measurements in the STEPwise approach to surveillance survey in 2006. This effort captured the attention of policy makers and resulted in a policy mandating kidney disease screening in individuals with hypertension or diabetes at regular health checkups in the employed population. This program is raising CKD awareness and will permit tracking of prevention efforts.¹⁸

Importantly, surveillance or outreach activities must include vulnerable groups and ensure equitable representation of the population. Monitoring activities should integrate national data at regional and local levels with data obtained in research and screening activities to optimize efficiency, facilitate surveillance, and permit the rapid identification of geographic hotspots for CKD that require focused attention.¹⁹ A task force supported by global experts should be setup to investigate hotspots rapidly. Investigations should include standardized data on social, structural, and clinical risk factors, clinical course, and potential interventions. A guideline-based approach should be disseminated and adapted in regions experiencing CKD hotspots. An example is the international study group on CKD of unspecified cause in Mesoamerica, organized by the Central American Program for Work, Environment, and Health.²⁰ Such efforts require a multi-sectoral approach with sustainable financing.²¹

Tackling CKD risk factors: diabetes, hypertension, and obesity

The WHO global action plan for the prevention and control of NCDs does not include CKD among the four priority NCDs. However, diabetes, hypertension, and cardiovascular disease (CVD) are acknowledged to be integrally linked with CKD. Notably, CKD is an important risk amplifier within these conditions.²² Across the world, 415 million adults have diabetes, 1.4 billion adults have hypertension, and 2.1 billion children and adults are overweight or obese.23, 24, 25 The prevalence of CKD in adults with type 2 diabetes is approximately 25% to 40%, depending on population factors.26, 27, 28 In the United States, the prevalence of CKD is approximately 30% among adults with hypertension and 17% among obese adults.²⁶ The size of the population at CKD risk is influenced by regional differences in demographics, different approaches to diagnosis and management, and effectiveness of local interventions to address lifestyle-related risks. Reduction of lifestyle-related risks is a cornerstone of mitigating the public health impact of diabetes, hypertension, and obesity. There is clear evidence that links upstream factors such as poor diet, poverty, food insecurity, tobacco consumption, and other lifestyle factors with the risk of developing CKD.29, 30, 31, 32, 33, 34, 35, 36 Conversely, interventions to manage hypertension and promote weight loss are associated with reduced risks of developing CKD and better outcomes among those living with CKD.2, 37, 38, 39, 40, 41, 42, 43

Gaps

Epidemiological assessment, followed by prioritization of CKD risk factors according to their contribution to the local burden of the disease, is important to determine where public health care efforts should be focused on reducing the population burden of CKD. In addition, existing barriers to the implementation of locally relevant strategies for the prevention and management of diabetes, hypertension, and obesity must be identified. Barriers may include resistance to change in the communities themselves or push back from industry and others that are potentially affected by lifestyle modification campaigns.

Action strategies

Population-based studies are needed to determine the impact of diabetes, hypertension, and obesity prevention programs on the prevalence and incidence of CKD. Longitudinal studies are necessary to understand the impact of prevention programs on the rates of CKD and end-stage kidney disease (ESKD) and related comorbidities, including cardiovascular complications and infections. Studies are required to better understand appropriate risk-benefit thresholds (target hemoglobin A1c, BP, and weight) for CKD prevention and management and to understand interactions between race-ethnicity, genetics, socioeconomic status, and geography as modifiers of CKD risk and progression. The impact of tobacco consumption on CKD needs to be studied further.

Strategies to reduce CKD risk attributable to diabetes, hypertension, and obesity will be most effectively implemented as part of a broad approach to NCD prevention. Interventions to reduce lifestyle-related NCD risk factors are most successful when implemented at both patient and community levels, supported by legislation and regulation.⁴⁴ Public health care approaches with the greatest evidence of effectiveness in reducing NCD risk include economic incentives to lower the price of healthy food, taxation on unhealthy food, education and physical activity programs in schools, food advertising restrictions and standards, providing more recreation spaces and facilities, sustained media campaigns for smoking cessation, cigarette packet warnings, restrictions on tobacco advertising, higher taxes on tobacco, and restrictions on smoking in public areas and workplaces.⁴⁵ Several countries have made efforts to reduce population consumption of sugary beverages, high-fat foods, and salt with the endorsement of the Panamerican Health Organization and WHO; however, more research is needed to understand which lifestyle interventions will have the greatest impact on CKD burden.22, 46, 47

An example of the importance of rigorous epidemiologic evidence required to inform policymaking and action is the ongoing debate on the utility of sodium reduction as a population measure to reduce BP and CVD.48, 49, 50, 51, 52, 53 Recent studies have demonstrated a J- or U-shaped relationship of sodium intake with BP and mortality.54, 55, 56 The benefit of salt reduction is greater among hypertensive people, but definitive effects on kidney disease outcomes remain uncertain. Interventional studies have demonstrated that estimated glomerular filtration rate (eGFR) and albuminuria (proteinuria) increased with higher salt intake, and a recent study showed that reduction of sodium intake reduced albuminuria.⁵⁷ In the United Kingdom, voluntary food-manufacturing targets achieved a lower sodium intake of 15% between 2001 and 2011, which was associated with a decrease in mean BP (3 mm Hg) and 40% reduction in deaths owing to stroke and ischemic heart disease.50, 58 However, the respective role of sodium reduction versus other treatments for hypertension, dyslipidemia, and CVD are not clearly delineated.50, 58

Implementing population-level approaches to reduce NCDs requires action across multiple sectors of the government and society, as well as a commitment of the governments. This is consistent with the Health in All policy strategies outlined by WHO, which emphasizes the importance of multi-sectoral engagement for the successful implementation of public health care policies.44, 46 At the level of health care departments, health care providers must have the necessary technology, tools, medicines, and services that are required for efficient assessment and control of risk factors. Community engagement and education are crucial to optimize success. Patients themselves are also a key to NCD prevention. In the chronic care model, patient self-care takes on great importance, while the roles and responsibilities of physicians, nurses, and community health care workers are being redefined through innovative strategies and technologies.²¹ Ongoing monitoring and evaluation of policy implementation will permit a better understanding of barriers to and facilitators of CKD prevention. This is especially true of LMICs, where the major barriers are quality, price, and availability of drug treatments for diabetes and hypertension. Understanding how such barriers and facilitators vary by jurisdiction, health care system, race-ethnicity, age, sex, and socioeconomic status helps to inform the development of effective local strategies.

Systematic surveillance is recommended for the screening of diabetes, hypertension, and obesity using, for example, the STEPwise approach to surveillance survey model. Once individuals with these conditions are identified, they should be recognized as being at high risk for CKD and should be evaluated for eGFR and albuminuria. Clinical guidelines on BP, blood glucose, and weight and physical activity targets should be clear and easy to implement to optimize CKD risk factor management. Screening and early intervention when CKD is detected were shown to reduce ESKD and be cost-effective.40, 59, 60, 61

Nephrotoxins as risk factors for AKI and CKD

Nephrotoxic agents can cause both AKI and CKD.⁶² Nephrotoxin exposure is common in hospitalized patients and may account for up to 25% of AKI cases.63, 64, 65 Common agents associated with AKI include nonsteroidal antiinflammatory drugs, antibiotics, iodinated contrast media, and chemotherapeutic drugs.66, 67 Clinician and patient education are important to reduce the risk of nephrotoxicity. Where electronic medical records exist, alerts to reduce the risk of nephrotoxic exposure and drug interactions can be activated.68, 69 Electronic medical records can simultaneously be used to monitor prescription practices, responsiveness to alerts and prompts, rates of AKI, and barriers to effective implementation.70, 71 In high-income countries, AKI typically develops during hospitalization and may impact long-term health. For example, CKD (urinary abnormalities, low eGFR, or hypertension) was found in 70% of children 6 months after nephrotoxin-induced AKI.⁷²

The list of medications that can induce CKD is steadily expanding. The mechanisms range from interstitial inflammation to glomerular and tubular injury.73, 74, 75 Strategies should be implemented to reduce nephrotoxin-induced AKI and CKD, as well as to emphasize the risks of medication overuse and dose adjustments for eGFR. Detection of medications that lead to CKD is challenging given the long lag time. As recently described for proton pump inhibitors, linkage between clinical and prescription databases can identify novel associations between CKD and medications, which enables ongoing surveillance.⁷³

The use of culturally traditional and alternative remedies is common worldwide, reaching over 80% of the population in many regions.⁷⁶ The rates of associated AKI and CKD are unknown, although up to 30% of AKI in sub-Saharan Africa may be related to traditional remedy use.⁷⁷ In Europe and North America, the market for alternative remedies generates billions of dollars per year.⁷⁸ Remedy production is often unregulated, leading to high interproduct variability and underappreciated risk of kidney injury.⁷⁹ In LMICs, traditional remedies are often the only affordable means of health care. Given the large number of people worldwide using these remedies, toxicity cannot be universal but instead may relate to individual susceptibility, which remains underinvestigated.⁷⁶

Gaps

The true risk of nephrotoxicity of commonly used medications or remedies is uncertain given the unknown denominators of use. Some medications are known to be nephrotoxic, especially in particular circumstances such as nonsteroidal antiinflammatory drugs with volume depletion. The magnitude of risk, which compounds are most toxic and under which circumstances, and how to best use these compounds safely if no alternatives exist remain unknown. In LMICs, traditional medicines are used for many reasons other than medical ones; therefore, a better understanding of the role that remedies play in people’s lives is required.⁸⁰ Further studies are required to identify potentially toxic remedies, risk factors that may exacerbate nephrotoxicity, herb-medication interactions, and potentially beneficial compounds.81, 82, 83, 84, 85, 86, 87

Action strategies

In settings with electronic medical records, the use of medicines and alternative remedies should be captured. These databases will permit the monitoring of prescription practices to establish a true denominator of subjects who are at risk and to permit surveillance for determining associations with nephrotoxicity and potential exacerbating factors. Screening protocols should be developed to identify nephrotoxic effects of medications to improve consistency in case/compound identification and comparability of outcomes. When nephrotoxicity is suspected, attempts should be made to analyze culprit remedies, and detailed case reports should be published. Education of health care practitioners is important to foster regular prescription reviews. Guidelines should emphasize the measurement of eGFR prior to the prescription of potentially nephrotoxic medications, with electronic warnings for medication interactions and risks. Shared pharmaceutical prescription databases will avoid repeat prescriptions or drug interaction potential. Research should continue to develop effective alternative agents with reduced nephrotoxicity.

To reduce the use of nephrotoxic remedies, it is important to ensure that individuals have access to essential medical care and medication. Where alternative remedy use is widespread, strategies should be identified to minimize exposure to nephrotoxins. Such approaches should be customized based on the region, economic realities, and community perspectives to improve safety without alienating groups or challenging fundamental beliefs. Engagement with traditional healers is crucial to foster collaboration, educate on kidney disease, and learn about potentially beneficial remedies. The public and health care workers (HCWs) must be educated about nephrotoxicity and drug interactions relevant to herbal remedies and over-the-counter preparations.⁸⁷ Clinicians should be encouraged to ask about alternative remedy use. A global free web–based adverse event reporting site (across income settings) should be developed to gather data and study associations of remedy use with rates of CKD.

Given easy access to alternative remedies, governments should develop policies about the accuracy of advertising and health claims touted on the Internet and require efficacy data similar to that required for pharmaceuticals. Policies should enforce minimum standards of safety, manufacturing, labeling, and adverse event reporting on the alternative remedy industry.

Kidney stones and CKD risk

Kidney stone disease is now recognized as a chronic health condition that is associated with CKD and ESKD risks.88, 89, 90, 91, 92 The association between kidney stones and CKD is partly explained by shared risk factors such as diabetes,93, 94, 95 obesity,96, 97 hypertension,94, 97, 98 metabolic syndrome,99, 100 and CVD.101, 102, 103 However, kidney stones may also directly contribute to the development and progression of CKD via urinary tract obstruction and/or infection, nephrocalcinosis, and oxalate nephropathy.88, 104, 105 The worldwide prevalence of kidney stones among adults is 5% to 9% and is apparently increasing, with variations between regions and countries.106, 107 The rising global rate of kidney stones may be contributing to the overall CKD burden related to dietary factors, obesity, global warming, and environmental and occupational exposures (e.g., high ambient temperatures, contact with zinc or cadmium).90, 97, 105, 107 Individuals who have experienced a single stone event are at an increased risk for a symptomatic stone recurrence (up to 50% within the first 5 years).¹⁰⁵ Therefore, prevention among these individuals is an important strategy to reduce further stone formation and CKD risks.⁹⁰ Higher fluid intake, avoidance of low dietary calcium and sweetened beverages and the reduction of dietary sodium and red meat intake reduce stone formation risk.108, 109, 110

Gaps

A better understanding of regional risk for kidney stones is important to prioritize stone prevention and reduce CKD risk. The regional impact of climate change on kidney stones is unknown. Long-term surveillance should permit a better understanding of the impact of stone prevention strategies (lifestyle habits and medication) and treatments (e.g., lithotripsy and surgery) on the risks of new-onset and progressive CKD. Health care costs for kidney stone disease require further studies. The effectiveness and cost-effectiveness of prevention strategies across populations are unknown.

Action strategies

Tracking mechanisms and research should be developed to determine the relationships between kidney stones and the incidence, prevalence, progression, and complications of CKD in regional contexts. Environmental or occupational hotspots should be detected through surveillance. Understanding stone types and risk factors (e.g., genetics, infections, and diet) are important to inform local prevention strategies. Together with public health care strategies to reduce diabetes, hypertension, and obesity, surveillance activities should include impact on the rates of kidney stones and those of stone-related CKD to identify high-risk groups for targeted prevention and cost-effectiveness.⁹⁰ In areas with a high risk for stone formation, public and HCW education campaigns should increase awareness and emphasize simple prevention strategies (e.g., fluid intake and dietary modification). Where occupational exposure is detected as important, engagement with policy makers and employers is important to modify work conditions.¹¹¹

Maternal, fetal, and childhood health as CKD risk factors

Low birth weight (LBW), small for gestational age, and preterm birth (PTB) impact the number of nephrons an individual starts life with and are increasingly being recognized as CKD risk factors.112, 113 In 2010, over 43 million babies in 139 LMICs were born too soon or too small, suggesting many children are born with a CKD risk.¹¹⁴ Developmental programming for CKD results from many structural, environmental, social, and physical factors that impact maternal and fetal health throughout pregnancy, as well as the child’s nutrition and growth.¹¹² Recent evidence also indicates high birth weight (especially an infant of a diabetic mother), in addition to LBW and PTB, to be a risk factor for obesity, hypertension, diabetes, and CKD.115, 116, 117, 118, 119 Early onset of diabetes in offspring exposed to diabetes in utero in part explains the higher CKD risk in these individuals.115, 120 Childhood obesity is also an important risk amplifier for CKD after LBW, small for gestational age, or PTB.¹²¹ Preterm babies are at an increased risk for AKI related to reduced nephron number, frequent nephrotoxin exposure, and comorbidities, which increase their subsequent CKD risk.122, 123 Not only the children of troubled pregnancies are at long-term risk of CKD, however. Women who develop pre-eclampsia/eclampsia have a higher life-time risk of hypertension, CKD, and CVD, and those who experience gestational diabetes mellitus have an increased risk for developing diabetes.124, 125, 126 Preeclampsia occurs in 1% to 5% of pregnancies worldwide, and gestational diabetes mellitus occurs in around 2% to 6% of pregnancies in Europe, but in up to 25% in some LMICs.125, 126, 127 Many individuals at a long-term CKD risk can be identified early in prenatal clinics and delivery rooms.

Gaps

The contribution of maternal and fetal risk factors to the CKD burden is unknown. In vivo counting of nephron number is not yet possible and poses an obstacle to further understanding the impact of developmental programming in the kidney. Variability of nephron number between racial and ethnic groups and geographic locations is largely unknown. Tracking fetal size by fundal height, ultrasound, and Doppler velocimetry can detect intrauterine growth restriction, but the impact of interventions during pregnancy or soon after birth on CKD risk is unknown. Similarly, the impact of PTB on CKD requires longitudinal studies. The impact of high birth weight on CKD risk has rarely been studied. Better methods to screen for and treat preeclampsia and its consequences require further studies.

Action strategies

The impact of fetal and early life development on the risk of adult NCDs is underappreciated. Monitoring the incidence of LBW, high birth weight, PTB, and fetal growth restriction is required to understand the burden with regard to the region and to raise awareness of potential long-term risks. Identification of regional and demographic disparities in birth weights or PTB within countries requires specific interventions or intensification of prevention efforts. Babies must be weighed at birth or soon thereafter, and the birth weight and gestational age should be documented in an enduring health record, which is often not done in LMICs.114, 128 Similarly, neonatal AKI should also be documented as a future CKD risk factor and should trigger follow-up. Education of the public, HCW, and traditional birth attendants is required to raise awareness of the long-term risks of LBW, growth restriction, PTB, gestational diabetes mellitus, and preeclampsia for mother and child. Both require early and ongoing education on healthy lifestyles and lifelong follow-up. Engagement with mothers, communities, traditional birth attendants, and HCW is important to encourage optimal feeding of LBW, high birth weight, small for gestational age, and preterm children to ensure healthy growth while avoiding obesity. Ensuring access to essential health care and medications is crucial to optimize child and maternal health.

Given the attention focused on improvements in maternal and child health initiated by the millennium development goals and sustainable development goals, most countries have some form of data reporting or monitoring.¹²⁹ Policies should not focus only on maternal health during pregnancy and at delivery but should also include access to family planning, equity, and education for women, reduction of poverty, and access to better nutrition. Monitoring women throughout pregnancy is important to detect and manage problems early. Innovative programs have improved prenatal clinic visits and deliveries attended by skilled birth attendants.¹³⁰ Such programs should be utilized to improve documentation of birth circumstances, maternal preeclampsia, or gestational diabetes mellitus, thereby identifying individuals who require long-term follow-up and to initiate lifestyle education peripartum. In LMICs, engagement with traditional birth attendants is important to build trust and educate them to detect and refer problem cases. Women with preeclampsia should undergo long-term follow-up to determine the impact of interventions to reduce long-term CVD and CKD risks.

Infections as CKD risk factors

CKD and AKI are considered as NCDs, but infections are an important cause of both conditions, especially in LMICs. Infections are also a common cause of AKI worldwide.64, 131, 132 The three diseases, namely HIV, malaria, and tuberculosis (TB), that received much attention under the millennium development goals can cause CKD. In 2015, 36.7 million people were living with HIV.¹³³ The risk of HIV nephropathy (HIVAN) varies from <10% to almost 50% in Africa.¹³⁴ HIVAN is a well-recognized form of CKD that can be prevented and treated with access to effective antiretroviral therapy.134, 135 However, the impact of antiretroviral therapy on kidney disease is not straightforward. Although antiretroviral therapy reduces the incidence and rate of HIVAN progression to ESKD, it also reduces the competing risk of death; therefore, the prevalence of HIVAN-ESKD tends to increase in treated populations.¹³⁴ Antiretroviral therapy does not reduce the incidence and/or rate of progression of non-HIVAN forms of CKD.¹³⁴ Kidney disease prevention in HIV infection is also affected by comorbidities such as diabetes and viral hepatitis and therefore requires additional management and health screening programs.134, 135 In 2015, 241 million cases of malaria were reported worldwide. AKI secondary to malaria occurs in up to 40% of adults with severe infection.¹³⁶ Although kidney function typically recovers in survivors, severe AKI may eventually lead to CKD.136, 137, 138 A Sri Lankan study also reported an association of malaria with CKD of unknown cause.¹³⁹ Malaria-associated AKI can be prevented by widespread vector control, use of insecticide-treated bed nets, and access to rapid diagnosis and treatment.¹³⁶ In 2014, 9.6 million people became infected with TB.140, 141 Genitourinary TB may be a cause of CKD through miliary involvement or urinary obstruction and may occur in 27% of cases with extrapulmonary TB.142, 143 HIV and TB infections frequently coexist; therefore, the combined kidney risk, exacerbated by medication toxicities and interactions, may be higher.

Many infections other than HIV, malaria, and TB increase CKD risk. Impetigo is frequent in adults and children living in disadvantaged conditions. CKD risk among adults with impetigo is high, strongly supporting proactive prevention and early treatment of skin infections as a possible means to reduce CKD risk.¹⁴⁴ The worldwide prevalence of hepatitis B (HBV) was 331 million people in 2013 and that of hepatitis C was 148 million.¹⁴⁵ The global risk of HBV-associated CKD is likely to be under 10%, whereas the risk of hepatitis C-associated CKD is likely to be higher.146, 147 HBV- and hepatitis C-associated CKD may be unrecognized contributors to chronic glomerulonephritis, which is a leading cause of ESKD in LMICs. Other infections such as leptospirosis and schistosomiasis are neglected tropical diseases associated with CKD.137, 148 Given the direct associations among infections, AKI, and CKD, it is likely that strategies to prevent infection will reduce the global CKD burden.

Gaps

The magnitude of regional CKD burden related to specific infections is unknown. How increasing the effectiveness and reach of public health care interventions could reduce the CKD burden needs to be further studied. The impact of the successful treatment of malaria on the incidence of malaria-associated AKI should be tracked, as fewer people may develop endemic immunity and may be more susceptible to severe disease.

Action strategies

Many guidelines mention CKD as a risk factor for infections, but few recognize CKD as a complication. A survey of existing guidelines is necessary to gauge the current level of awareness and intervention for infection as a CKD risk factor. HBV vaccination, for example, successfully reduced the incidence of childhood HBV-associated membranous nephropathy.¹⁴⁹ Efforts should be made to ensure access to vaccinations to reduce infection-associated risks of AKI and CKD. Short- and long-term surveillance for kidney disease in regions where these vaccines are implemented should be conducted to determine the impact. Where the CKD burden associated with a specific infection is high, research is required to develop locally effective and sustainable methods to prevent and treat these infections. Such strategies require partnerships with local policy makers, public health care practitioners, governmental organizations, and communities to raise awareness and develop implementation strategies. HCWs and communities should be educated about the risks of AKI and CKD associated with infections to support prompt diagnosis, institution of i.v. fluids and antibiotics, and avoidance of nonsteroidal antiinflammatory drugs and other nephrotoxins. Governments should suppress the use of counterfeit drugs, which contribute to increasing disease severity and risk of AKI in infections.

AKI as a CKD risk factor

Worldwide, approximately 20% of patients admitted to hospitals develop AKI.¹⁵⁰ This statistic is largely derived from high-income countries where the majority of AKI is hospital acquired. The true AKI incidence in LMICs is less well known but is likely at least as high.150, 151 Worldwide, it is estimated that 2 million people die of AKI annually.¹⁵² The number of AKI survivors is unknown, and a considerable proportion will develop CKD.153, 154, 155

Gaps

The actual CKD risk after AKI is not known. Risk modifiers and the long-term impact of AKI prevention on CKD burden are unknown.

Action strategies

Regionally adapted strategies should be promoted to avoid AKI. Given that most AKI cases in high-income countries are hospital acquired, efforts to reduce AKI incidence should focus on increasing awareness among clinicians and encouraging proactive patient management. Strategies may include electronic medical record alerts for AKI risk and medication prescriptions.68, 69, 156 In LMICs, the majority of AKI cases are community acquired, suggesting that prevention should start before hospital admission. Strategies include implementation of public health care measures to reduce the risk of infections and use of nephrotoxins; ensure access to clean water; reduce poverty, accidents, and trauma; improve maternal health; and provide access to essential health care and medication. Education campaigns should be conducted in communities and among HCWs to increase awareness of AKI risk, avoid nephrotoxins, and seek health care promptly.¹⁵⁷ Once patients present to a hospital, guidelines and facilities should be available to institute an appropriate therapy. Long-term follow-up of patients with AKI is required to determine the true burden of subsequent CKD and potential risk modifiers.

Conclusions

Morbidity and mortality owing to CKD are increasing worldwide, and CKD is progressively being recognized as an important contributor to the global burden of the disease.1, 8 Major contributors to the CKD burden are the growing frequencies of diabetes, hypertension, and obesity, which are well-established traditional risk factors for CKD. Public health care policies directed to address many lifestyle factors that contribute to these conditions are expected to positively impact CKD risk. Systematic screening for CKD in at-risk individuals is required for timely intervention when needed and to understand the impact of such policies on CKD incidence. The contribution of nontraditional CKD risk factors, including nephrotoxin exposure, kidney stones, fetal and maternal factors, infections, environmental factors, and AKI, to the global CKD burden is unknown. Moreover, many nontraditional risk factors may predominate in LMICs. The impact of reducing nontraditional CKD risk factors requires further studies. Mitigation of nontraditional CKD risk factors will require advocacy efforts to support policy development, implementation of strategies to reduce disparities, improve access to essential health care and maternal and child health, reduce environmental exposures, prevent AKI, better understand traditional remedy use, and prevent infections.2, 3, 158 Race-ethnicity, genetics, sex, socioeconomic status, and geography likely modify the impact of CKD risk factors. Effective coordination within health care systems, and importantly in the era of the sustainable development goals, a broad multi-sectoral approach are required to identify and tackle achievable goals to reduce CKD risk factors and thereby the global burden of CKD.

Disclosure

KRT declared consulting fees from Eli Lily and Company, Boehringer Ingelheim, and Gilead and grant support from National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Patient-Centered Outcomes Research Institute, and Health Sciences and Services Administration of Washington State. GGG declared consulting fees from Pisa Farmaceutica. MBG declared lecture fees from Amgen, B. Braun, Leo Pharma, Novartis, Novo-Nordisk, Promopharm, Roche, Sanofi, Servier, Sophadial, and Sothema. HJLH declared consulting fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Fresenius, Janssen, and Merck; lecture fees from AstraZeneca; and grant support from Boehringer Ingelheim. DWJ declared consulting fees from AstraZeneca; lecture fees from Baxter Healthcare, Fresenius, and Medical Care; and support from Baxter Extramural and Clinical Evidence Council grants. ZAM declared lecture fees from Amgen and Genzyme; grant support from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp and Dohme-Chibret, Genzyme (a Sanofi Company), Eli Lilly and Company, and Otsuka; as well as government research grant support for the CKD REIN PROJECT and additional support for clinical and experimental works from AMGEN, Bayer, Merck Sharp and Dohme, and Genzyme. OM declared consulting fees from Allena and Adelyx; grant support from National Institutes of Health, American Heart Association, and Department of Defense; and is named as a coinventor of effervescent calcium magnesium citrate and synthetic antiKlotho antibodies. DCW declared consulting fees from Amgen, Boehringer Ingelheim, Akebia, Union Chimique Belge Celltech, Bristol-Myers Squibb, Vifor Fresenius, Otsuka, Janssen, Alberta Innovates Health Solutions, AstraZeneca, and Bio Nano; lecture fees from Fresenius, Amgen, Janssen, ZS Pharma, and Vifor Fresenius; and grant support from British Heart Foundation, Healthcare Quality Improvement Partnership, Kidney Research UK, National Institute for Health Research, and Australian National Health & Medical Research Council. All the other authors declared no competing interests.

Publication of this article was supported by the International Society of Nephrology.