NDT Perspectives Chronic kidney disease in low- and middle-income countries

Most of the global burden of chronic kidney disease (CKD) is occurring in low- and middle-income countries (LMICs). As a result of rapid urbanization in LMICs, a growing number of populations are exposed to numerous environmental toxins, high infectious disease burdens and increasing rates of noncommunicable diseases. For CKD, this portends a high prevalence related to numerous etiologies, and it presents unique challenges. A better understanding of the epidemiology of CKD in LMICs is urgently needed, but this must be coupled with strong public advocacy and broad, collaborative public health efforts that address environmental, communicable, and non-communicable risk factors.


I N T R O D U C T I O N
Chronic kidney disease (CKD) contributes significantly to the global burden of disease, yet its priority is low within the public health response to the growing noncommunicable disease (NCD) burden in low-and middle-income countries (LMICs) [1,2]. Nearly 500 million people are estimated to have CKD, with the majority (80%) of those people living in LMICs, but these estimates belie the true burden of CKD [3]. The epidemiological data remain poorly characterized for CKD in most LMICs due to few community-based studies, inconsistent assessments of kidney function and nonstandardized or noncalibrated approaches; however, rapid urbanization coupled with changes in the environment, as well as numerous communicable and noncommunicable risk factors indicate an already high prevalence of CKD that may be growing quickly [4][5][6].

C K D I S A M A J O R B U T P O O R LY U N D E R S TO O D H E A LT H B U R D E N I N L M I C S
The majority of the world's population lives in LMICs, where most of the population growth is also occurring. As a result, the NCD burden falls most heavily on people living in these countries where mortality is disproportionately worse [7]. Accordingly, the burden of CKD continues to rise for nearly every country in the world, with the majority of it disproportionately afflicting people in LMICs [3]. As a cause of death worldwide, CKD now ranks 19th, which represents an 82% increase since 1990, and in many LMICs, including Turkey, El Salvador, Mexico, Venezuela and Tunisia, the annual rate of change in deaths attributed to CKD is growing at >5% (Figure 1 ) [1].
Nonetheless, despite these trends, knowledge of CKD epidemiology remains incomplete in many LMIC regions due to few studies, variable quality in reporting and inconsistent methods for assessing and defining kidney dysfunction, which can be misleading when making important comparisons (Table 1). For many LMIC populations, validated creatinine-based equations for estimating glomerular filtration rate or standardized, quality-controlled measurements of serum creatinine or urinary protein are not available [19]. Additionally, current studies from LMICs assessing urinary protein apply several different methods, including urinalysis dipsticks, semi-quantitative proteinuria dipsticks and spot or timed quantitative proteinuria measurements [26].
In Asia, which has 60% of the global population, the reported prevalence of CKD is among the highest in the world, yet robust knowledge of CKD epidemiology remains limited. In East Asia, population-based surveys have been conducted in Thailand, Malaysia and China [8][9][10]12,19,22,[27][28][29]. The Thai Screening and Early Evaluation of Kidney Disease (SEEK) study reported a prevalence of 18%, which was higher than previous estimates of 14% [8,10]. In Malaysia, the prevalence has been reported to be approximately 10%, and in China, estimates range from 10 up to 19% in the Tibetan regions [9,12,[27][28][29][30]. One of the largest population-based prevalence studies to date included 47 204 participants from several regions of China, and it reported a prevalence of 11%, which equates to nearly 120 million people living with CKD in China [11]. In Southeast Asia, studies from Bangladesh, India and Pakistan have reported CKD prevalence estimates near or >20% in some communities, and in Nepal and Sri Lanka the prevalence appears to be between 10 and 20% [13][14][15][16][31][32][33].
In sub-Saharan Africa, the prevalence of CKD in several countries may approximate or exceed that of many highincome countries [26]. Although data are sparse and of variable quality, several community-based surveys from Senegal, Ghana, Democratic Republic of Congo and Tanzania have now  Thailand 2008 CrCl and eGFR (MDRD) 13.2% a Hooi et al. [10] Malaysia 2011 Spot quantitative urine protein and eGFR (CKD-EPI) 9.1% Zhang et al. [11] China 2012 Spot quantitative urine protein and eGFR (MDRD) b 10.8% Chen et al. [12] Tibet 2010 Spot quantitative urine protein and eGFR (MDRD) b 19.1% Anand et al. [13] Bangladesh 2014 Spot quantitative urine protein and eGFR (CKD-EPI) 26.0% Jafar et al. [14] Pakistan Modified for Chinese population. c Estimated by the CKD-EPI (modified without the race factor).

N D T P E R S P E C T I V E S
C K D i n L M I C s demonstrated prevalence estimates ranging from 5 to 17% concurrent with very low awareness [6,[17][18][19]34]. However, these high prevalence estimates alone fail to highlight the extent of the CKD burden in this impoverished region. Not only are most of the countries unable to provide access to renal replacement therapies (RRTs), but they are also ill-prepared for managing the cardiovascular consequences of CKD [35,36]. As such, in the context of other highly prevalent diseases such as human immunodeficiency virus (HIV), which also have significant cardiovascular consequences, the burden is augmented.
In Latin America, both urban and rural populations are heavily burdened by CKD. In Mexico, alarming rates of diabetes and obesity have led, in part, to the highest urban rates of CKD and incident end-stage renal disease (ESRD) in the world [20,37]. On the other hand, rural agricultural communities in El Salvador, Guatemala, Costa Rica, Honduras and Nicaragua are facing unique challenges related to CKD [38]. Young male agricultural workers in these countries have disproportionately high rates of CKD of uncertain etiology (CKDu), and in El Salvador, where the prevalence of CKD in some agricultural communities is near 20%, ESRD attributed to CKDu is the leading cause of hospital deaths [21,22,[39][40][41].
In the Middle East, epidemiological data are very limited, though the burden is presumed to be great [42]. Many Middle Eastern countries have diabetes prevalence rates >25% and they are rapidly growing, and in several of those countries, including Saudi Arabia, Egypt and Lebanon, diabetic nephropathy is attributed as the major cause of ESRD [43]. In Iran, the prevalence may be as high as 23%, though reports vary, with a few studies estimating a CKD prevalence of 5-15% [23,24,44,45]. In Turkey, the Chronic Renal Disease in Turkey (CREDIT) Study reported a prevalence of 16% among adults [25].
In LMICs, the demographic transition occurring as a result of urbanization parallels the rise of NCDs [46]. For CKD, this transition creates unique public health challenges. In addition to lifestyle changes, including decreased physical activity, highcalorie and sodium-rich diets and increased consumption of processed foods, rapid urbanization has led to densely crowded cities with unplanned infrastructure, poor sanitation and waste disposal and heavy environmental pollution [47]. As a result, a growing number of people live in settings where numerous environmental toxins, high infectious disease burdens and increasing rates of NCDs, including hypertension and diabetes, are all juxtaposed [4,48]. In the context of CKD, these populations are especially vulnerable.
Epidemiological studies from LMICs in sub-Saharan Africa, Asia and Latin America demonstrate the heterogeneity of global CKD with its numerous potential etiologies ( Table 2). In sub-Saharan Africa, diabetes, hypertension and HIV appear to account for only a portion of the significant CKD burden, especially in urban settings, where many risk factors remain undetermined [6,17,18]. Likewise, in India, Bangladesh, Nepal and China, diabetes and hypertension are common etiologies, but they are not always associated with CKD in the affected populations [11,13,15,16]. In Latin America, even where the prevalence of diabetes is among the highest in the world, many of the causes still remain unknown [22,39].
Few longitudinal studies on CKD have been conducted in LMICs, which significantly limits conclusions about causal etiologies, e.g. hypertension as a cause or a result of CKD cannot be inferred from cross-sectional analyses. Studies on CKDu in Sri Lanka and El Salvador and the identification of Balkan  [22,33,39,49]. Additionally, genetic differences and intrauterine fetal exposures play important roles in CKD susceptibility, and careful longitudinal studies of the interaction between genetic risk factors and fetal, childhood and adult environmental exposures, including nutrition, will be critical in understanding the development of CKD in LMICs [50][51][52].

D I S PA R I T I E S I N AC C E S S TO T R E AT M E N T FO R E S R D I N L M I C S
Currently, >2 million people worldwide have ESRD [53]. Despite a doubling of the global prevalence of maintenance dialysis since 1990, the vast majority (80%) of the people who receive RRT are from only five countries (the USA, Japan, Germany, Brazil and Italy), which in total represent 10% of the world's population [47]. In Asia, apart from those who live in countries with funded renal programs, such as Korea, Singapore and Taiwan, 9 of 10 patients diagnosed with ESRD die within a few months due to lack of continued access [54]. In India, <10% of ESRD patients receive RRT, and of those, >70% die within the first 3 months due to inadequate resources to continue therapy [55,56]. Renal transplant may be a preferable option, and in some LMICs such as Costa Rica, India, South Africa and Sudan, transplant programs are growing [57]. However, due to issues related to access, ethics, religious and moral taboos, immunosuppressive medications, malnutrition, expertise and infrastructure, the rate of living or deceased donor transplant in most of the developing world is 0-10 persons per million, which precludes it from being a viable option for most [58]. Additionally, renal transplant tourism, which may account for many of the transplants performed in countries like Cambodia and the Philippines, highlights the challenges with implementation of ethical and regulatory policies as outlined in the Declaration of Istanbul on organ trafficking and transplant tourism [59,60].
Peritoneal dialysis (PD) has generally been regarded as a potentially cheaper, more accessible and more sustainable mode of delivering RRT. In LMICs, the use of PD in the treatment of renal failure continues to rise: the rate of PD increased by 25 patients per million from 1996 to 2008 [61]. Nonetheless, PD utilization is widely heterogeneous with highly variable uptake [62]. In a few sub-Saharan African LMICs, PD has recently become an accessible treatment option, as it can be managed in low-technology environments without reliable electricity [63]. However, supplies, timely diagnosis and professional expertise remain significant challenges, and most people in sub-Saharan Africa continue to have limited access to any RRT modality, as these resources are mostly concentrated in large, urban areas [64].
Likewise, in Asian LMICs, such as Sri Lanka, India and Nepal, only a handful of patients are receiving PD [54]. However, Thailand adopted a PD first policy in 2008 and now up to 20% patients with ESRD currently receive PD [65]. In Latin America, while hemodialysis is also the most common form of RRT, PD and renal transplant are becoming more widely available, with 20% of ESRD patients using PD and 20% having a functioning renal allograft. In fact, as of 2012, PD was a major form of RRT in the countries of Mexico, El Salvador and Guatemala [61,66].

P R E V E N T I O N A N D T R E AT M E N T O F C K D W I L L R E Q U I R E A B RO A D A P P RO AC H
The World Health Organization's Action Plan for NCDs stated that 'conditions such as kidney disease result from lack of early detection and management of hypertension and diabetes … and kidney disease should be addressed through a common response to other major NCDs' [67]. Similarly, the United Nations High Level Meeting on NCDs in 2011 neglected kidney disease, and instead mentioned it only in the context of addressing NCDs more broadly through a common response [68]. However, CKD is unique. Its status as an NCD does not fully emphasize its heterogeneous causes and pathologic expressions, and the public health agendas in LMICs need to prioritize CKD by reflecting these distinctions ( Figure 2).
Addressing NCDs, including treatment of hypertension, prevention of diabetes and obesity and cardiovascular risk reduction, will be a necessary and critical component of the public health response to CKD in LMICs, but it alone will not be sufficient. Considering the myriad causes of CKD, it is not surprising that hypertension and diabetes were responsible for fewer than half of the worldwide deaths attributed to CKD in 2010 [1]. As such, the prevention and treatment of CKD will require a broader and more nuanced approach than an NCD Action Plan targeting hypertension and diabetes, and recent efforts to understand the global epidemiology of CKD have highlighted this gap.
Nephrologists and renal epidemiologists must engage other professionals in eliminating infectious causes of CKD globally. Incorporating CKD into active research and public health efforts with global priorities, such as access to safe drinking water, urban planning with a focus on sanitation improvement, vaccination programs, mass treatment programs such as those targeting schistosomiasis and filariasis, vector control and HIV, tuberculosis and malaria eradication, will be a critical component of effective CKD prevention and treatment. At the same time, it will be an efficient means of funding much needed research on CKD in LMICs.
Experts in kidney disease must also lead efforts to study and reduce environmental and occupational exposures that are potentially nephrotoxic [48]. In LMICs, exposures to chemicals that are known to be nephrotoxic, such as phthalates, aromatic hydrocarbons, dioxins and perfluoroalkyl acids among many others, occur via numerous sources, including agricultural pesticides, fertilizers, processed foods and food packaging, dye additives in personal hygiene products, plastics, manufacturing waste products, cleaning supplies and air pollution [48]. Heavy metals, including arsenic, mercury, lead, gold and cadmium, are also commonly found in food chains, water supplies, commercial products and soil in LMICs, all of which are potentially nephrotoxic [69]. Iatrogenic factors such as inappropriate drug dosing and iodinated contrast administration, may also be N D T P E R S P E C T I V E S C K D i n L M I C s important causes of CKD in LMICs, and increasing CKD detection, awareness and appropriate prescribing practices will be an important factor in reducing unnecessary exposures.
Additionally, the sale of counterfeit drugs is a $30 billion global economy, and in some LMICs, anywhere from 10 to 60% of the drug market may include counterfeit drugs [70,71]. These uncontrolled substances may not only be a significant cause of CKD in LMICs, but individuals with CKD may be particularly vulnerable to adverse effects stemming from them [72]. Similarly, over-the-counter analgesics and traditional medicines, especially herbal-based medicines, are unregulated and ubiquitous in LMICs, where they form a major part of healthcare for many individuals [73][74][75][76].
Lastly, prevention of acute kidney injury (AKI) and increasing access to RRT should be priorities in the multifaceted approach to CKD in LMICs. In LMICs, AKI most commonly affects individuals who are young, economically productive community members, and it is a major independent risk factor for the development of CKD and ESRD [77][78][79]. Finding innovative and cost-effective ways of delivering dialysis to such vulnerable populations in these settings is urgently needed. Efforts such as the Kidney Disease XPRIZE Challenge and the Kidney Health Initiative may prove fundamental in changing the way that RRT is delivered around the globe, and educational programs through the International Society of Nephrology are training numerous physicians and nurses from LMICs in nephrology care [80,81]. Both could potentially increase access for millions in LMICs.

CO N C L U S I O N S
In LMICs, the demographic transition occurring as a result of urbanization exposes a growing number of people to numerous environmental toxins, infectious diseases and NCDs. As a result, CKD is a major but poorly understood growing health burden in LMICs, leading to significant morbidity and mortality due to undertreated cardiovascular disease and kidney failure.
There are numerous potential causes of CKD in LMICs; however, specific etiologies remain unknown in most settings. Because CKD is a heterogeneous condition, a better understanding of the epidemiology is urgently needed, and accordingly, the response needs to be broad and must address environmental, communicable and non-communicable risk factors with a particular focus on the process of urbanization. Finally, ongoing advocacy, such as the Kidney Health for Life Initiative and the World Kidney Fund, needs to be coupled with collaborative, cross-disciplinary public health and research efforts aimed at better understanding the epidemiology and addressing the multifaceted burden.

CO N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare that they have no conflicting interests. All authors had full final responsibility for the decision to publish. F I G U R E 2 : Conceptual diagram illustrating a multifaceted approach to CKD prevention and treatment in LMICs.