Introduction

Chronic kidney disease (CKD) prevalence has increased over the past two decades [1, 2]. Furthermore, CKD has emerged as one of the leading causes of death in the world, ranking as the 12th leading cause of death in 2017 [1]. Although country-wide estimates of CKD prevalence report that around 10% of the global population is affected [3], within-country heterogeneity in CKD prevalence, cause, and mortality likely exists. For example, in Central America and South Latin America, CKD ranks as the second and fifth in the list of causes of death, respectively [1]. In some countries within Latin America, a kidney disease not associated with diabetes, hypertension or glomerular disease, termed Mesoamerican Nephropathy (MeN), exists at high prevalence within coastal regions [4–7]. A similar profile of kidney disease exists in other regions including Uddanam Nephropathy in Central India [8] and Sri Lankan nephropathy in Sri Lanka [9]. These regions have been broadly classified as hotspots of chronic kidney disease of unknown etiology (CKDu). Risk factors CKDu include an occupation involving strenuous labor in high temperatures, applying agrochemical pesticides without protection, and drinking untreated water [4–6, 10, 11].

CKDu was recognized in the early twenty-first century due to astute observations from clinicians working in affected areas. Whether similar phenomena of subnational hotspots of CKD exist elsewhere is uncertain, partly due to limited capacities of CKD detection, and cause of death attribution [12–16]. Furthermore, CKD detection is not often included in large-scale epidemiological studies, even in countries implementing large-scale diabetes or cardiovascular risk assessment surveys [17]. With the hypothesis that CKDu exemplifies a potentially broader phenomenon of subnational variation in kidney disease prevalence and mortality, we evaluated data from the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) to describe hotspots for CKD across the world. This analysis, based on survey data from local kidney disease stakeholders, may provide the earliest signal to the global nephrology community on the locations and populations disproportionately affected by CKD. The ISN-GKHA captures insights from diverse regions, especially those where academic research, surveillance systems, and electronic health records are limited. Additionally, assessing the local stakeholders’ perspective on the underlying etiologies of these hotspots provides insight into possible preventative efforts and research collaborations.

Methods

Results

Country and ISN regional distribution

Out of 167 countries included in the ISN-GKHA, 162 (97%) responded to questions related to subnational hotspots of kidney disease. Forty-six (28%) participating countries reported a regional variation in rates of kidney disease within their countries (Table 1, Fig 1). There was complete internal consistency for this question among respondents from the same country regardless of role. Latin America had the highest percentage (12 of 21, 57%) of countries reporting a regional CKD hotspot followed by the regions of North and East Asia, and Western Europe. The countries reporting CKD hotspots were distributed across every country income level with the highest proportion (14 of 37, 38%) from upper-middle income countries (Table 1). CKD hotspots were most often reported in countries where the leading causes of kidney failure were diabetes or hypertension.

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Fig 1. Chronic kidney disease hotspots.

Abbreviation: CKD = chronic kidney disease. *Chorotega region is located within the Guanacaste province. This map was created using Microsoft Excel powered by Bing. (https://www.microsoft.com/en-us/maps/bing-maps/product#:~:text=(b)%20Attribution%20and%20proprietary%20notices,party%20attribution%20provided%20by%20Microsoft).

https://doi.org/10.1371/journal.pgph.0004014.g001

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Table 1. Presence of regional hotspots of CKD by ISN region and World Bank income groups (N, %).

https://doi.org/10.1371/journal.pgph.0004014.t001

Age distribution

Regional CKD hotspots were most commonly reported to affect 18–44-year-olds (Fig 2). In two regions—North and East Asia, and Western Europe—CKD hotspots were reported to occur mostly in the 65+ years age group (Fig 2).

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Fig 2.

Age categories affected by CKD categorized by (A) ISN regions and (B) by World Bank income groups. Abbreviations: CKD = chronic kidney disease; ISN = International Society of Nephrology; NIS = Newly Independent States.

https://doi.org/10.1371/journal.pgph.0004014.g002

Contributors to CKD

The most common reported contributors to CKD hotspots overall were hypertension (34 of 46 countries reporting hotspots, 74%) and diabetes (33 of 46 countries, 72%) (Fig 3A). Notably, after these clinical risk factors, cultural factors, such as diet, use of non-steroidal agents, and herbal medications, were reported to be the most common contributor (31 of 46 countries, 67%). Obesity (27 of 46, 59%), environmental (20 of 46, 43%), and genetics (17 of 46, 37%) were also commonly reported as contributors. Climate (13 of 46, 28%), biological contributors (HIV, tuberculosis, or kidney stones) (9 of 46, 20%), and other causes (4 of 46, 9%) were less commonly reported.

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Fig 3.

3A and 3B: (3A) Causes of CKD Hotspots and (3B) Industries in CKD Hotspot Areas. Abbreviation: CKD = chronic kidney disease; HTN = hypertension.

https://doi.org/10.1371/journal.pgph.0004014.g003

The reported causes of these CKD hotspots differed based on ISN region (S1 Fig), with Latin American region countries more often citing climate and environmental factors. Although diabetes and hypertension were the most commonly cited causes in other regions, 12 countries outside of Latin America reported environment as a contributing factor. The contribution of cultural risk factors was similar between Latin America and other regions.

Discussion

In this multinational survey of kidney disease in 162 countries, we found that regional hotspots of CKD were common and included countries in most regions and across all income levels. Latin America had the highest proportion of countries reporting regional CKD hotspots. The age group most affected by CKD hotspots was reported to be 18- to 44-year-olds, and clinical factors were the most common contributor to the disproportionate burden of CKD among subnational geographic areas or specific racial or ethnic populations, followed by cultural and environmental factors. Agricultural work was the most commonly associated occupation group. Investigating regional variation in CKD may identify geographic, environmental, and cultural factors that drive CKD incidence and progression, which provides new pathways to mitigate kidney disease-related morbidity and mortality.

The vast majority of data underpinning the current practices in managing kidney disease are derived from North America and Western Europe. Even the measures of kidney function, and the definition of kidney disease versus kidney health, are derived primarily from Caucasian populations. Based on data from these best-studied regions, providers most commonly ascribe kidney disease to either hypertension or diabetes. Existing cohorts of kidney disease generally lack kidney biopsy data, detailed exposure assessments for cultural practices, or occupational or environmental histories, which could potentially accelerate CKD in the background of hypertension or diabetes [22]. Our survey spotlights that these ‘non-traditional’ factors may contribute to disproportionate burdens of kidney disease. Given that some endemic nephropathies, such as Balkan endemic [13, 23] nephropathy and Itai-Itai disease [24], were linked to medication and environmental factors, and therefore amenable to preventive interventions, it is critical to focus on these under-investigated exposures to identify novel, low-cost preventive interventions.

In addition to non-traditional factors that contribute to CKD hotspots, these results highlight that there are disproportionate burdens of traditional CKD within countries. This finding could be due to relatively high prevalences of hypertension, diabetes, cardiovascular disease, and other traditional risk factors in certain areas due to socioeconomic determinants of health, genetic predisposition, or biological factors. The globally increasing prevalence of these CKD-antecedent noncommunicable diseases may be affecting certain vulnerable populations more than others [25, 26]. In addition, the traditional risk factors of diabetes or hypertension may have a higher proclivity for kidney disease manifestation in specific regions or populations within a country. Studying high-risk populations has yielded one of the most important advances in kidney disease—the identification of APOL1 high risk genotypes, for which promising therapies are now under development [27, 28]. Similarly, Hoy et al. focused on the high incidence of kidney failure among the Australian Aboriginal population and delineated the possible contribution of low nephron mass [29]. With access to novel diagnostic approaches, advances in biochemical tissue analysis have identified leukocyte chemotactic factor 2 (LECT2) as a novel subtype of amyloid causing kidney disease, primarily among Hispanic persons in the Southwest region of the United States [30–32]. The survey responses presented here suggest there is an increasing burden of CKD both from the rise of traditional CKD risk factors and from nontraditional factors such as culture and the environment. Both disease pathways should be investigated to implement disease prevention, and to define the etiological factors causing CKD in these populations. Increased CKD surveillance through increased screening (possibly with innovative devices or instruments), registries, and reporting systems is vital to identify and address emerging CKD hotspots.

Another notable finding in our study is the identification of rural areas and poorer populations as subnational CKD hotspots by our survey respondents. One framework for kidney disease casts the disease as a “downstream” or “end-organ” manifestation of cardiovascular disease or diabetes. Global public health surveillance efforts have in part coalesced to a greater degree on these antecedent diseases [33]. Indeed, rural populations appear to be at risk for the development of traditional CKD-antecedent diseases, such as diabetes and hypertension, as unhealthy lifestyle changes (such as increased access to unhealthy, processed food) occur where there is often limited access to medical care. Furthermore, a lack of public infrastructure, medical care, and health literacy may leave them more vulnerable to risk factors such as untreated drinking water, agrochemical exposure, and herbal medication use. Quantifying the association of these risk factors with kidney disease requires not only prioritization by policy makers, but potentially the development of new methods.

Our study is limited primarily by the lack of granular epidemiologic data to corroborate stakeholders’ responses. Due to the lack of directly acquired clinical data, there is no confirmation of findings or adjustment for confounders. For example, there was no age standardization based on country age distribution. Despite the presence of CKD databases in some nations, population-representative surveys to estimate kidney disease prevalence are rare, especially from resource-poor regions [18]. Therefore, our study can only serve as hypothesis generating on the basis of on-the-ground observations, and as a starting point for future studies and interventions.

The data in this study, although limited, was collected from national representatives or leaders in kidney care, and their answers were based on their perspectives on practice type and location, knowledge, and expertise in kidney disease. Responses were completely internally consistent, meaning that multiple stakeholders in the country recognized the identified hotspots as such. The internal consistency in their responses provides strong rationale for investment in regional, national, and subnational data on CKD prevalence and incidence. Furthermore, the heterogeneity in associated contributors (e.g., high prevalence of diabetes among native communities versus agricultural work in the MeN hotspots) highlights the importance of targeted solutions, informed by data. In some cases, where granular data were available the survey data generally yielded responses consistent with existing literature [34], such as the contributors to the CKD hotspots in Latin America. These are often attributed in scientific literature to climate, cultural, environmental factors, and associated with residence near the agricultural industry [10, 35, 36], as was also reported in our survey.

Conclusions

In-country stakeholders in kidney disease care identify a remarkable number of sub-national geographic regions where they perceive a disproportionately high prevalence of CKD, relative to other regions within their country. While CKD hotspots were certainly reported in known CKDu-endemic areas, this survey also identified new CKD hotspots. Regions or populations with a high prevalence of CKD should be prioritized for CKD screening, risk factor management, treatment, and research. Since unexpectedly young populations may be affected within these reported hotspots, population-representative screening would be most appropriate. Detection requires a pathway to care, so any comprehensive screening efforts will require a priori capacity for diagnostics and therapeutics, but also ascertainment of understudied risk factors such as occupational history and use of alternative medicines. Therefore, a collaborative effort by healthcare providers, health systems, and policy makers is imperative to protect vulnerable populations. Our preliminary findings should encourage researchers to engage in further conversations with local policymakers and conduct more structured studies on the CKD hotspots and disproportionately affected populations identified in our survey.

Supporting information

Acknowledgments

The International Society of Nephrology provided administrative support for the design and implementation of the survey and data collection activities. The authors appreciate the support from the ISN’s Executive Committee, especially ISN Executive Director Charu Malik, ISN regional leadership, and ISN Affiliated Society leaders at the regional and country levels for their help with the ISN-GKHA. The authors also thank the Alberta Kidney Disease Network staff, in particular Ghenette Houston and Sophanny Tiv.