ABSTRACT

Objective.

To identify factors associated with chronic kidney disease of non-traditional causes among children in Guatemala.

Methods.

A cross-sectional survey was conducted. The study population was all pediatric patients with stage 5 chronic kidney disease active in FUNDANIER’s pediatric nephrology unit (N = 156). Simple random sampling led to a total of 100 participants. Data collection consisted of a questionnaire addressing individual and household characteristics, access and utilization of health care, and place of residence when the disease began. Chronic kidney disease etiology was obtained from medical records. Municipality-level secondary data were collected. Descriptive statistics were estimated. Logistic regression was used for bivariate and multivariate analysis.

Results.

The odds ratio (OR) for almost all variables approached 1. Notable exceptions in household characteristics were mother’s education level up to primary school (OR 2.2727) and living in an urban setting when symptoms began (OR 0.4035). Exceptions in municipal characteristics are zones with intensive small-scale agriculture (OR 3.8923) and those with intensive large-scale agriculture (OR 0.3338). P-values and confidence intervals show that the sample was not big enough to capture statistically significant associations between variables.

Conclusions.

Study findings suggest that factors associated with chronic kidney disease of non-traditional causes among children in Guatemala are intensive agricultural practices in their municipality of residence, and mother’s level of education. Future research in children could use case-control designs or population-based studies in agricultural communities. Public health interventions that involve kidney function screening among children are recommended.

Keywords
Renal insufficiency, chronic; kidney failure, chronic; risk factors; child health; epidemiology; Guatemala

RESUMEN

Objetivo.

Determinar los factores asociados a la enfermedad renal crónica por causas no tradicionales en niños en Guatemala.

Métodos.

Se realizó una encuesta transversal. La población de estudio fue la totalidad de pacientes pediátricos con enfermedad renal crónica en fase 5 ingresados en la unidad de nefrología pediátrica de Fundanier (N = 156). Mediante el muestreo aleatorio simple se dispuso de un total de 100 participantes. La recopilación de datos consistió en un cuestionario que abordaba las características individuales y del hogar, el acceso y el uso de la atención de salud y el lugar de residencia al inicio de la enfermedad. La etiología de la enfermedad renal crónica se obtuvo a partir de los expedientes médicos y los datos secundarios se recopilaron a nivel municipal. Se calcularon las estadísticas descriptivas y se empleó el método de regresión logística para el análisis bifactorial y multifactorial.

Resultados.

La razón de posibilidades (OR) se aproximó a 1 en casi todas las variables. Dos excepciones destacables en lo relativo a las características domésticas fueron el nivel de escolaridad de la madre hasta la educación primaria (OR 2,2727) y el lugar de residencia en un entorno urbano en la aparición de los síntomas (OR 0,4035). Las excepciones con respecto a las características municipales fueron las zonas de agricultura intensiva a pequeña escala (OR 3,8923) y las zonas de agricultura intensiva a gran escala (OR 0,3338). Los valores P y los intervalos de confianza indican que la muestra no fue lo suficientemente amplia para recoger las asociaciones estadísticamente significativas entre variables.

Conclusiones.

Los resultados del estudio sugieren que los factores asociados a la enfermedad renal crónica por causas no tradicionales en niños en Guatemala son las prácticas agrícolas intensivas en el municipio de residencia y el nivel de escolaridad de la madre. Las futuras investigaciones con niños podrían incluir el diseño de casos o los estudios poblacionales en comunidades agrícolas. Se recomiendan intervenciones de salud pública que incorporen el tamizaje de la función renal en niños.

Palabras clave
Insuficiencia renal crónica; fallo renal crónico; factores de riesgo; salud del niño; epidemiología; Guatemala

RESUMO

Objetivo.

Identificar os fatores associados a doença renal crônica de etiologia não tradicional em crianças na Guatemala.

Métodos.

Foi realizado um estudo transversal em uma população que consistiu de todos os pacientes pediátricos com doença renal crônica ativa em estágio 5 atendidos na unidade de nefrologia pediátrica da Fundación para el Niño Enfermo Renal (FUNDANIER) (N = 156). O processo de amostragem aleatória simples determinou a obtenção de uma amostra com 100 participantes. Um questionário foi usado para a coleta de dados sobre as características pessoais e familiares dos participantes, acesso à assistência de saúde e utilização de serviços e local de residência ao início da doença. Informação sobre a etiologia da doença renal crônica foi obtida dos prontuários médicos. Também foram coletados dados secundários ao nível da localidade. Estatísticas descritivas foram estimadas e um modelo de regressão logística foi usado nas análises bivariada e multivariada.

Resultados.

As razões de chance (odds ratio, OR) de quase todas as variáveis se aproximaram de 1. As exceções nas variáveis relativas às características familiares foram escolaridade da mãe de nível fundamental (OR 2,2727) e residir em área urbana ao início dos sintomas (OR 0,4035). As exceções nas variáveis ao nível municipal foram áreas de agricultura intensiva em pequena escala (OR 3,8923) e em grande escala (OR 0,3338). Os valores de p e os intervalos de confiança indicam que o tamanho da amostra não foi grande o suficiente para detectar associações estatisticamente significativas entre as variáveis.

Conclusões.

O estudo demonstrou que práticas agrícolas intensivas na localidade de residência e nível de escolaridade da mãe são fatores associados a doença renal crônica de etiologia não tradicional em crianças na Guatemala. Outros estudos em crianças devem ser realizados como estudos de caso-controle ou estudos populacionais em comunidades agrícolas. Recomendam-se também intervenções de saúde pública com a avaliação preventiva da função renal em crianças.

Palavras-chave
Insuficiência renal crônica; falência renal crônica; fatores de risco; saúde da criança; epidemiologia; Guatemala

In the past four decades, chronic kidney disease (CKD) has increased worldwide so extensively that some consider it a pandemic (¹1. Jayasumana C, Orantes C, Herrera R, Almaguer M, Lopez L, Silva LC, et al. Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants. Nephrol Dial Transplant. 2017;32:234–41. doi: 10.1093/ndt/gfw346. Accessed 28 August 2019.
https://doi.org/10.1093/ndt/gfw346... ). CKD can lead to renal failure that is treatable only by peritoneal dialysis, hemodialysis, or renal transplantation, all of which come with important financial burdens and social impacts. The worldwide rise in CKD cases is attributable to the increased number of people living with diabetes and high blood pressure. Other, less common causes such as infection, injury, and exposure to toxins from drugs, herbal supplements, or environmental pollution are on the rise and affect primarily male agricultural workers between their 20s and 50s (²2. Orantes-Navarro C, Herrera-Valdés R, Almaguer-López M, López-Marin L, Vela-Parada XF, Hernandez-Cuchillas M, et al. Toward a comprehensive hypothesis of chronic interstitial nephritis in agricultural communities. Adv Chronic Kidney Dis. 2019;24(2):101–6. doi: 10.1053/j.ackd.2017.01.001. Accessed 28 August 2019.
https://doi.org/10.1053/j.ackd.2017.01.0... , ³3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35... ). There is documentation that these less common causes may affect women, children, and men who do not directly work in agriculture (³3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35... , ⁴4. Johnson R, Wesseling C, Lee Newman L. Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med. 2019;380(19):1843–52. doi: 10.1056/NEJMra1813869. Accessed 28 August 2019.
https://doi.org/10.1056/NEJMra1813869... ), a trend documented mainly in Central America and Sri Lanka, with additional reports from Egypt, India, Mexico, and Sudan (¹1. Jayasumana C, Orantes C, Herrera R, Almaguer M, Lopez L, Silva LC, et al. Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants. Nephrol Dial Transplant. 2017;32:234–41. doi: 10.1093/ndt/gfw346. Accessed 28 August 2019.
https://doi.org/10.1093/ndt/gfw346... , ²2. Orantes-Navarro C, Herrera-Valdés R, Almaguer-López M, López-Marin L, Vela-Parada XF, Hernandez-Cuchillas M, et al. Toward a comprehensive hypothesis of chronic interstitial nephritis in agricultural communities. Adv Chronic Kidney Dis. 2019;24(2):101–6. doi: 10.1053/j.ackd.2017.01.001. Accessed 28 August 2019.
https://doi.org/10.1053/j.ackd.2017.01.0... , ⁴4. Johnson R, Wesseling C, Lee Newman L. Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med. 2019;380(19):1843–52. doi: 10.1056/NEJMra1813869. Accessed 28 August 2019.
https://doi.org/10.1056/NEJMra1813869... ). Although the disease has been given different names, such as CKD of unknown cause, Central American nephropathy, Sri Lankan nephropathy, Uddanam nephropathy (India), chronic interstitial nephritis in agricultural communities, and El Salvador nephropathy (¹1. Jayasumana C, Orantes C, Herrera R, Almaguer M, Lopez L, Silva LC, et al. Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants. Nephrol Dial Transplant. 2017;32:234–41. doi: 10.1093/ndt/gfw346. Accessed 28 August 2019.
https://doi.org/10.1093/ndt/gfw346...

2. Orantes-Navarro C, Herrera-Valdés R, Almaguer-López M, López-Marin L, Vela-Parada XF, Hernandez-Cuchillas M, et al. Toward a comprehensive hypothesis of chronic interstitial nephritis in agricultural communities. Adv Chronic Kidney Dis. 2019;24(2):101–6. doi: 10.1053/j.ackd.2017.01.001. Accessed 28 August 2019.
https://doi.org/10.1053/j.ackd.2017.01.0...

3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35...

4. Johnson R, Wesseling C, Lee Newman L. Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med. 2019;380(19):1843–52. doi: 10.1056/NEJMra1813869. Accessed 28 August 2019.
https://doi.org/10.1056/NEJMra1813869... -⁵5. Wesseling C, Glaser J, Rodríguez-Guzmán J, Weiss I, Lucas R, Peraza S, et al. Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress. Rev Panam Salud Publica. 2020;44:e15. doi: 10.26633/RPSP.2020.15. Accessed 13 February 2020.
https://doi.org/10.26633/RPSP.2020.15... ), the Pan American Health Organization (PAHO) has recommended to consider them all as possibly the same disease, and to call it CKD of non-traditional causes (CKDnT) (³3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35... ). In Central America, CKDnT is a public health priority because it has reached epidemic proportions (³3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35... ). The cause of CKDnT remains unknown, although available evidence shows that its main driver is occupational heat stress (⁵5. Wesseling C, Glaser J, Rodríguez-Guzmán J, Weiss I, Lucas R, Peraza S, et al. Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress. Rev Panam Salud Publica. 2020;44:e15. doi: 10.26633/RPSP.2020.15. Accessed 13 February 2020.
https://doi.org/10.26633/RPSP.2020.15... ). Possible causes under study include heat exposure, exposure to pesticides, consumption of water containing heavy metals, overconsumption of anti-inflammatory medications, tobacco use, inadequate hydration, infections (leptospirosis, hantavirus, malaria), low birthweight, and genetic predisposition (³3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35... , ⁴4. Johnson R, Wesseling C, Lee Newman L. Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med. 2019;380(19):1843–52. doi: 10.1056/NEJMra1813869. Accessed 28 August 2019.
https://doi.org/10.1056/NEJMra1813869... ). Most researchers attribute CKDnT to multifactorial causes, with an interplay of repeated heat exposure and poor hydration working in synergy with exposure to toxins and infectious agents to damage the kidneys (¹1. Jayasumana C, Orantes C, Herrera R, Almaguer M, Lopez L, Silva LC, et al. Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants. Nephrol Dial Transplant. 2017;32:234–41. doi: 10.1093/ndt/gfw346. Accessed 28 August 2019.
https://doi.org/10.1093/ndt/gfw346...

2. Orantes-Navarro C, Herrera-Valdés R, Almaguer-López M, López-Marin L, Vela-Parada XF, Hernandez-Cuchillas M, et al. Toward a comprehensive hypothesis of chronic interstitial nephritis in agricultural communities. Adv Chronic Kidney Dis. 2019;24(2):101–6. doi: 10.1053/j.ackd.2017.01.001. Accessed 28 August 2019.
https://doi.org/10.1053/j.ackd.2017.01.0... -³3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35... ). In adults, signs and symptoms may include fatigue, fainting, cramps, joint pain, polyuria, dysuria, foamy urine, hypotension, normal fundoscopy, vascular irregularities of lower limbs, altered neurological reflexes, and hearing loss. Characteristic laboratory findings are absence of severe proteinuria and markers of tubular damage. Renal histology shows evidence of chronic tubulointerstitial nephritis with glomerulosclerosis and mild chronic vascular changes (¹1. Jayasumana C, Orantes C, Herrera R, Almaguer M, Lopez L, Silva LC, et al. Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants. Nephrol Dial Transplant. 2017;32:234–41. doi: 10.1093/ndt/gfw346. Accessed 28 August 2019.
https://doi.org/10.1093/ndt/gfw346...

2. Orantes-Navarro C, Herrera-Valdés R, Almaguer-López M, López-Marin L, Vela-Parada XF, Hernandez-Cuchillas M, et al. Toward a comprehensive hypothesis of chronic interstitial nephritis in agricultural communities. Adv Chronic Kidney Dis. 2019;24(2):101–6. doi: 10.1053/j.ackd.2017.01.001. Accessed 28 August 2019.
https://doi.org/10.1053/j.ackd.2017.01.0...

3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35...

4. Johnson R, Wesseling C, Lee Newman L. Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med. 2019;380(19):1843–52. doi: 10.1056/NEJMra1813869. Accessed 28 August 2019.
https://doi.org/10.1056/NEJMra1813869... -⁵5. Wesseling C, Glaser J, Rodríguez-Guzmán J, Weiss I, Lucas R, Peraza S, et al. Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress. Rev Panam Salud Publica. 2020;44:e15. doi: 10.26633/RPSP.2020.15. Accessed 13 February 2020.
https://doi.org/10.26633/RPSP.2020.15... ).

Although the number of studies on CKDnT has been increasing in recent years, the information related to pediatric population is scarce. At the largest pediatric nephrology center in Guatemala, 43% of CKD cases were attributed to undetermined causes, the majority of which patients came from regions with documented cases of CKDnT in adults (⁶6. Cerón A, Fort MP, Morine CM, Lou-Meda R. Chronic kidney disease among children in Guatemala. Rev Panam Salud Publica. 2014;36(6):376–82.). In El Salvador, a descriptive epidemiologic study (⁷7. Orantes, CM, Herrera R, Almaguer M, Brizuela EG, Alvarado NP, Fuentes EJ, et al. Chronic kidney disease in children and adolescents in Salvadoran farming communities: NefroSalva pediatric study (2009–2011). MEDICC Rev. 2016;18(1–2):15–21.) among children under 18 years in three agricultural regions with known high prevalence of CKDnT identified a CKD prevalence of 3.9%. In Nicaragua, a cross-sectional study (⁸8. Ramirez O, Amador JJ, Kaufman JS, Weiner DE, Parikh CR, Khan U, et al. Urine biomarkers of kidney injury among adolescents in Nicaragua, a region affected by an epidemic of chronic kidney disease of unknown aetiology. Nephrol Dial Transplant. 2016;31(3):424–32. doi: 10.1093/ndt/gfv292. Accessed 12 November 2019.
https://doi.org/10.1093/ndt/gfv292... ) of teenagers from four schools compared regions hypothesized to have different levels of environmental exposures leading to kidney injury at a young age. The four schools were located in communities that differed in overall CKD mortality, types of predominant agricultural activity, and altitude. Levels of kidney injury were significantly higher among participants who came from the school located in a community where adults primarily work in sugar cane plantations. No additional studies focusing on risk factors of CKDnT have been identified in the literature (¹1. Jayasumana C, Orantes C, Herrera R, Almaguer M, Lopez L, Silva LC, et al. Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants. Nephrol Dial Transplant. 2017;32:234–41. doi: 10.1093/ndt/gfw346. Accessed 28 August 2019.
https://doi.org/10.1093/ndt/gfw346...

2. Orantes-Navarro C, Herrera-Valdés R, Almaguer-López M, López-Marin L, Vela-Parada XF, Hernandez-Cuchillas M, et al. Toward a comprehensive hypothesis of chronic interstitial nephritis in agricultural communities. Adv Chronic Kidney Dis. 2019;24(2):101–6. doi: 10.1053/j.ackd.2017.01.001. Accessed 28 August 2019.
https://doi.org/10.1053/j.ackd.2017.01.0...

3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35...

4. Johnson R, Wesseling C, Lee Newman L. Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med. 2019;380(19):1843–52. doi: 10.1056/NEJMra1813869. Accessed 28 August 2019.
https://doi.org/10.1056/NEJMra1813869... -⁵5. Wesseling C, Glaser J, Rodríguez-Guzmán J, Weiss I, Lucas R, Peraza S, et al. Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress. Rev Panam Salud Publica. 2020;44:e15. doi: 10.26633/RPSP.2020.15. Accessed 13 February 2020.
https://doi.org/10.26633/RPSP.2020.15... ).

In Guatemala, the estimated prevalence and incidence of CKD among children are 4.9 and 4.6 per million age-related population, respectively (⁶6. Cerón A, Fort MP, Morine CM, Lou-Meda R. Chronic kidney disease among children in Guatemala. Rev Panam Salud Publica. 2014;36(6):376–82.). The country’s capacity to comprehensively treat children with CKD through its public health care system was solidified in 2003, when parents of children with CKD created the Fundación para el Niño Enfermo Renal (Foundation for Children with Kidney Disease, FUNDANIER) (⁹9. Lou-Meda R. Prevention of CKD in Guatemala. Clin Nephrol. 2010;74(suppl 1):26–8., ¹⁰10. Lou-Meda R. ESRD in Guatemala and a model for preventive strategies: outlook of the Guatemalan Foundation for Children with Kidney Disease. Ren Fail. 2006;28:689–91. doi: 10.1080/08860220600938258. Accessed 13 May 2019.
https://doi.org/10.1080/0886022060093825... ). Since its inception, FUNDANIER has supported a pediatric nephrology unit at one of the country’s tertiary-level referral hospitals in Guatemala City, and it has helped found the country’s only pediatric kidney replacement therapy program. FUNDANIER’s pediatric nephrology unit receives patients from all over the country, accepts walk-ins and referrals by any health care provider, does not charge patients for any medical fees for services or donated products, and sometimes covers lodging costs for families in need. Given its location in Guatemala City, patients from rural areas may face geographic and associated financial barriers to access. While pediatricians and general practitioners see common renal problems, it can be assumed that the great majority of pediatric patients with advanced CKD are eventually seen in FUNDANIER’s pediatric nephrology unit.

The goal of this study was to identify factors associated with CKDnT among children in Guatemala at the individual, household, and community levels, with a special emphasis on elucidating the role of access to health care services and environmental factors suggested by previous research (⁶6. Cerón A, Fort MP, Morine CM, Lou-Meda R. Chronic kidney disease among children in Guatemala. Rev Panam Salud Publica. 2014;36(6):376–82.).

MATERIALS AND METHODS

Research design

A cross-sectional survey was designed to determine factors associated with CKDnT. Independent variables were defined using a conceptual model based on three complementary sources. First, causal models derived from reviews of literature on CKDnT, which emphasize certain environmental exposures related to temperature, altitude, and exposure to agrochemicals (¹1. Jayasumana C, Orantes C, Herrera R, Almaguer M, Lopez L, Silva LC, et al. Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants. Nephrol Dial Transplant. 2017;32:234–41. doi: 10.1093/ndt/gfw346. Accessed 28 August 2019.
https://doi.org/10.1093/ndt/gfw346...

2. Orantes-Navarro C, Herrera-Valdés R, Almaguer-López M, López-Marin L, Vela-Parada XF, Hernandez-Cuchillas M, et al. Toward a comprehensive hypothesis of chronic interstitial nephritis in agricultural communities. Adv Chronic Kidney Dis. 2019;24(2):101–6. doi: 10.1053/j.ackd.2017.01.001. Accessed 28 August 2019.
https://doi.org/10.1053/j.ackd.2017.01.0...

3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35... -⁴4. Johnson R, Wesseling C, Lee Newman L. Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med. 2019;380(19):1843–52. doi: 10.1056/NEJMra1813869. Accessed 28 August 2019.
https://doi.org/10.1056/NEJMra1813869... ). Second, the behavioral model of health services use, which categorizes predisposing, enabling, and need factors associated with access and utilization of health care services (¹¹11. Aday LA, Andersen RM. Equity of access to medical care: a conceptual and empirical overview. Med Care. 1981;19(12):4–27.,¹²12. Aday LA, Andersen RM. A framework for the study of access to medical care. Health Serv Res. 1974;9(3):208–20.). Third, published sources that describe factors which affect access to health care in Guatemala (¹³13. Becerril-Montekio V, López-Dávila L. Sistema de Salud de Guatemala. Salud Publica Mex. 2011;53(2):197–208.). Independent variables identified through these sources were organized in a conceptual framework with factors at the individual, household, and municipal levels.

Population and sample

The study population was the total of pediatric patients with stage 5 CKD who were active at the end of July 2015 in the clinical database of FUNDANIER’s pediatric nephrology unit (N = 156). The population included patients identified in the FUNDANIER database classified as stage 5 CKD, using the guidelines of the National Kidney Foundation’s Kidney Disease Outcome Quality Initiative (KDOQI), if they showed an estimated glomerular filtration rate (eGFR) of <15 mL/min/1.73m², or were on renal replacement therapy (¹⁴14. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002;39(suppl 1):S1–S266. Available from: https://www.kidney.org/sites/default/files/docs/ckd_evaluation_classification_stratification.pdf. Accessed 22 March 2019.
https://www.kidney.org/sites/default/fil... ), with a documented etiology for CKD, and who were accompanied by a parent or guardian. A sample size of 90 was estimated through simple random sampling, with an alpha of 0.05 and a proportion of CKDnT cases in the population of 84% based on FUNDANIER’s database. A decision was made to aim at recruiting 105 participants, with the goal to account for incomplete information in patient medical records.

Data collection

Participants were recruited after their appointments in FUNDANIER’s pediatric nephrology unit. Interviews were conducted between September 2015 and April 2016, in Spanish, in a private space, and consisted of a questionnaire that took between 20 and 30 minutes to administer by author LPMA. The questionnaire had been previously validated in five FUNDANIER patients with stage 4 CKD for comprehension, internal consistency, and duration. The questionnaire (available from authors upon request) consisted of 70 questions, addressing individual (e.g., age, sex, ethnicity, level of education) and household (e.g., income, parental level of education, primary language) characteristics, access and utilization of health care (e.g., time to diagnosis, access to the clinic, home care), treatment adherence (for a separate analysis reported elsewhere) (¹⁵15. Ramay BM, Cerón A, Méndez-Alburez LP, Lou-Meda R. Factors associated to acceptable treatment adherence among children with chronic kidney disease in Guatemala. PLoS ONE. 2017;12(10):e0186644. doi: 10.1371/journal.pone.0186644. Accessed 15 May 2019.
https://doi.org/10.1371/journal.pone.018... ), and place of residence when the disease began. Additionally, data collected from medical records included CKD etiology (used for classifying the dependent variable), and KDOQI classification (used to confirm inclusion criteria).

Information about place of residence when symptoms began was used as a proxy for investigating the environmental and health care access factors in the conceptual model. Municipality-level data were collected on average temperature, average humidity, average evapotranspiration (¹⁶16. Instituto Nacional de Sismología, Vulcanología, Meteorología e Hidrología [Internet]. Guatemala City: INSIVUMEH. c2004. Atlas Climatológico. Available from: http://www.insivumeh.gob.gt/hidrologia/ATLAS_HIDROMETEOROLOGICO/Atlas_Clima.htm. Accessed 15 June 2017.
http://www.insivumeh.gob.gt/hidrologia/A... ), total population, percentage of people dedicated to agriculture (¹⁷17. Guatemala, Instituto Nacional de Estadística. Encuesta Nacional de Condiciones de Vida 2014. Guatemala City: INE; 2016.), number of health care facilities (¹⁸18. Ministerio de Salud Pública y Asistencia Social; United States Agency for International Development. Proyecto Diálogo Database of Health Care Facilities. Guatemala City: MSPAS, USAID; 2008.), and predominant use of land (¹⁹19. Asociación para el Avance de las Ciencias Sociales en Guatemala. Regiones y zonas agrarias de Guatemala. Guatemala City: AVANCSO; 2001.). Predominant use of land classifies municipalities into six agrarian zones: zone 1 corresponds to intensive small-scale agriculture linked to distribution systems; zone 2 refers to small-scale agriculture within regions dedicated to large-scale exports; zone 3 describes marginal use of agriculture combined with seasonal work in other industries; zone 4 refers to small-scale industries combined with multiple informal activities; zone 5 corresponds to growing small-scale agriculture restricted by large-scale industries; and zone 0 refers to metropolitan urban areas. As a general pattern (¹⁹19. Asociación para el Avance de las Ciencias Sociales en Guatemala. Regiones y zonas agrarias de Guatemala. Guatemala City: AVANCSO; 2001.), municipalities in agrarian zone 1 use intensive agriculture to compete in local and regional markets, while municipalities in agrarian zone 3 use agriculture for self-consumption. Municipalities in agrarian zone 2 have large plantations dedicated to export crops and surrounding communities dedicated to agriculture for self-consumption. Small-scale agricultural workers from zones 1 and 3 are often seasonal workers in plantations located in zone 2.

Data analysis

The dependent variable was classified as CKDnT if the medical records showed that etiological investigation had classified the final diagnosis as “CKD of undetermined cause,” which FUNDANIER has been classifying for several years as those patients with renal ultrasound without hydronephrosis, cystography free of reflux, and no history suggesting nephritic or nephrotic syndrome. No data about biopsy diagnosis were collected. This definition is compatible with the PAHO definition for suspect case of CKDnT, defined as a person under 60 years of age with one abnormal result that meets the Kidney Disease Improving Global Outcomes (KDIGO) CKD criteria, and who has no history of type 1 diabetes, no history of hypertensive disease, and no history of other known causes of CKD (²⁰20. Hoy W, Ordunez P, editors. Epidemic of chronic kidney disease in agricultural communities in Central America. Case definitions, methodological basis and approaches for public health surveillance. Washington, DC: PAHO; 2017. Available from: http://iris.paho.org/xmlui/bitstream/handle/123456789/34132/9789275119594-eng.pdf Accessed 15 October 2019.
http://iris.paho.org/xmlui/bitstream/han... ). A database (available from authors upon request) was built with the questionnaire results and the additional municipality-level variables. Statistical analysis used STATA® 12.1 (StataCorp LP, College Station, Texas, United States of America). For each variable, descriptive statistics were estimated. Logistic regression was used for bivariate and multivariate analysis, using a 0.05 threshold to assess if associations were statistically significant.

Research ethics

Ethics approval was obtained from the Institutional Review Board at the University of Denver, and the ad-hoc research ethics committee at FUNDANIER. Written informed consent was obtained from parents or guardians accompanying minors who participated in this study, and written informed assent was obtained from minors between the ages of 7 and 17 years old. Consent, assent, and the interview were carried out in a private space. To guarantee participants’ anonymity, personal identifiers, including names and clinical record identification, were not collected.

RESULTS

We approached every patient who arrived for clinic appointments until we recruited 105 participants. Five patients were excluded because they did not have a completed etiological investigation in their medical records. The remaining 100 patients were included in the study, of which 76 (76%) were classified as CKD of undetermined cause, and 24 (24%) had an identified etiology as follows: 14 (14%) congenital anomalies of the kidney and urinary tract—CAKUT (6 neurogenic bladder, 7 vesicoureteral reflux, 1 prune belly syndrome); 7 (7%) glomerulopathies (6 idiopathic glomerulopathies, 1 lupus nephritis); 1 (1%) tubulopathy; 1 (1%) hereditary nephritis (branchio-oto-renal syndrome); and 1 (1%) nephrolithiasis. All patients were receiving renal replacement therapy, including 40 (40%) on peritoneal dialysis, 25 (25%) on hemodialysis, while 35 (35%) patients had a transplant.

Fifty-four participants were female. Median age was 14 years, with 12 (12%) participants aged 6–9 years, 42 (42%) aged 10–14, and 46 (46%) aged 15–18 (mean age 13.66, minimum 6, maximum 18, standard deviation 3.09). Thirty-nine (39%) self-identified as indigenous, all participants (100%) spoke Spanish as their first language, although five (5%) also spoke an indigenous language. Sixty-six (66%) patients had attended up to primary school, 19 (19%) had attended secondary school, and 5 (5%) had attended high school or vocational school. Fifty-nine (59%) were attending school regularly.

Table 1 presents the household- and municipality-level variables most relevant to the analysis and discussion. Mothers were the primary caregiver for 72 (72%) patients, 11 (11%) had rotating care between relatives, 7 (7%) were taken care of by another member of the nuclear family, and 10 (10%) by aunts, grandparents, or neighbors. Eighty-five (85%) mothers spoke Spanish to the child participant, 10 (10%) spoke combined Spanish and an indigenous language, 1 (1%) spoke an indigenous language, and 4 (4%) did not respond to this question. Twenty-two (22%) participants lived less than 2 hours from the clinic, 47 (47%) 2–4 hours, 21 (21%) 4–6 hours, and 3 (3%) patients lived more than 6 hours away. Sixty-six (66%) participants used the public bus system for transport to clinic appointments, 13 (13%) used their family vehicle, and the rest (21%) used a combination of bus, taxi, and private vehicle. Sixty-seven (67%) participants lived in urban areas at the time of questionnaire administration. Twenty-three (23%) participants reported having moved their hometown due to their illness, to be closer to health care facilities, or to improve household sanitary conditions.

Municipalities where participants lived when symptoms started represent 44 out of the country’s 340 municipalities, distributed in 15 departments (provinces) out of the country’s 22 departments (Figure 1). Average annual rainfall in these municipalities ranges from 15 to 27.5 inches. Fifty-six (56%) participants came from municipalities with 20 inches of average rainfall. While relative humidity in these municipalities was in the range 70%–85%, 94 (94%) participants originated from municipalities with relative humidity of 70%–75%.

From the time when symptoms started, participants reported waiting a median of 30 days to be referred to FUNDANIER (range 0–5 000 days, mean 421 days, standard deviation 92). Primary health care facilities in these municipalities ranged from 2 to 55 per 100 000 population.

The percentage of economically active population (EAP) dedicated to agriculture ranged between 2% and 88% in the municipalities where participants lived in when symptoms began. Participants lived in municipalities that fall under four out of the six agrarian zones described in the methods section (Table 2).

Bivariate analysis

Table 3 shows the results of the bivariate analysis. The odds ratios (OR) for all individual-level, most household-level, and most municipal-level characteristics approach 1. Exceptions to the category of household characteristics were mother’s education level up to primary school (OR 2.2727), the type of place of residence (rural or urban), when participants’ symptoms began (OR 0.4035), currently living in a city (OR 0.3241), and presence of several caregivers (OR 0.3304). Exceptions in municipal characteristics are agrarian zone 1 (OR 3.8923) and agrarian zone 2 (OR 0.3338). P-values and confidence intervals show that the sample was not big enough to capture statistically significant associations between variables.

Multivariate analysis

Table 4 presents results from the multivariate analysis where odds ratios are consistent with reported values from the bivariate analysis for patients with mothers who have education up to primary school, living in a city, and agrarian zones 1 and 2.

DISCUSSION

Results from this study are insufficient to conclude that any of the studied factors are associated with increased or decreased odds of having CKDnT at a statistically significant level. It is, however, important to offer an interpretation of non-significant results, in light of the research question, conceptual model, and current knowledge about CKDnT. While factors showing narrow confidence intervals point to more precise estimates, and factors showing wide confidence intervals point to more potential for random error, point estimates showing a tendency are worth examining further, keeping in mind that this study compared participants who already had stage 5 CKD and is not representative of the population as a whole.

Patients coming from agrarian zone 1 demonstrated an increased odds of CKDnT while zones 2 and 0 showed reduced odds of CKDnT. Evidence derived from research carried out in adults shows that working in plantations, similar to those defined in agrarian zone 2, is the main driver of CKDnT. Contrary to findings in adult patients, we show decreased odds of CKDnT in this zone. There is no clear insight into what may explain cases among children (⁴4. Johnson R, Wesseling C, Lee Newman L. Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med. 2019;380(19):1843–52. doi: 10.1056/NEJMra1813869. Accessed 28 August 2019.
https://doi.org/10.1056/NEJMra1813869... , ⁵5. Wesseling C, Glaser J, Rodríguez-Guzmán J, Weiss I, Lucas R, Peraza S, et al. Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress. Rev Panam Salud Publica. 2020;44:e15. doi: 10.26633/RPSP.2020.15. Accessed 13 February 2020.
https://doi.org/10.26633/RPSP.2020.15... ). In adults, although some analyses point to a potential role of agrochemicals (¹1. Jayasumana C, Orantes C, Herrera R, Almaguer M, Lopez L, Silva LC, et al. Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants. Nephrol Dial Transplant. 2017;32:234–41. doi: 10.1093/ndt/gfw346. Accessed 28 August 2019.
https://doi.org/10.1093/ndt/gfw346... , ²2. Orantes-Navarro C, Herrera-Valdés R, Almaguer-López M, López-Marin L, Vela-Parada XF, Hernandez-Cuchillas M, et al. Toward a comprehensive hypothesis of chronic interstitial nephritis in agricultural communities. Adv Chronic Kidney Dis. 2019;24(2):101–6. doi: 10.1053/j.ackd.2017.01.001. Accessed 28 August 2019.
https://doi.org/10.1053/j.ackd.2017.01.0... ) or heavy metals in water sources (³3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35... ), results have been inconclusive. The role of agricultural work-related heat stress has been more thoroughly investigated and shows a clearer association with CKDnT (⁴4. Johnson R, Wesseling C, Lee Newman L. Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med. 2019;380(19):1843–52. doi: 10.1056/NEJMra1813869. Accessed 28 August 2019.
https://doi.org/10.1056/NEJMra1813869... , ⁵5. Wesseling C, Glaser J, Rodríguez-Guzmán J, Weiss I, Lucas R, Peraza S, et al. Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress. Rev Panam Salud Publica. 2020;44:e15. doi: 10.26633/RPSP.2020.15. Accessed 13 February 2020.
https://doi.org/10.26633/RPSP.2020.15... ), opening up the question of whether its presence in children may signal that they also have been exposed to heat stress in working conditions (⁵5. Wesseling C, Glaser J, Rodríguez-Guzmán J, Weiss I, Lucas R, Peraza S, et al. Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress. Rev Panam Salud Publica. 2020;44:e15. doi: 10.26633/RPSP.2020.15. Accessed 13 February 2020.
https://doi.org/10.26633/RPSP.2020.15... ). Contrary to our assumptions based on previous research on the topic (⁶6. Cerón A, Fort MP, Morine CM, Lou-Meda R. Chronic kidney disease among children in Guatemala. Rev Panam Salud Publica. 2014;36(6):376–82.), none of the variables measuring availability and utilization of health care services showed an association with CKDnT. Similarly, at the municipal level, the majority of environmental factors, such as temperature, humidity, and altitude, which are part of conceptual models of CKDnT, did not show an association in this sample. A closer look at people, families, and communities and their dynamics in relation to agriculture, agricultural practices, and agricultural products may help get closer to an explanation. For instance, Krisher et al. found distinct levels of kidney damage among sugar cane workers depending on where they seasonally migrate from (²¹21. Krisher LK, Butler-Dawson J, Dally M, Jaramillo D, Newman LS. Enfermedad renal crónica de causa desconocida: investigaciones en Guatemala y oportunidades para su prevención. Ciencia, Tecnología y Salud. 2020;7(1) Available from: https://digi.usac.edu.gt/ojsrevistas/index.php/cytes/article/view/884 Accessed 20 June 2020.
https://digi.usac.edu.gt/ojsrevistas/ind... ), Ramirez et al. found that altitude and type of agricultural practices are associated with higher prevalence of tubular renal damage in adolescents (⁸8. Ramirez O, Amador JJ, Kaufman JS, Weiner DE, Parikh CR, Khan U, et al. Urine biomarkers of kidney injury among adolescents in Nicaragua, a region affected by an epidemic of chronic kidney disease of unknown aetiology. Nephrol Dial Transplant. 2016;31(3):424–32. doi: 10.1093/ndt/gfv292. Accessed 12 November 2019.
https://doi.org/10.1093/ndt/gfv292... ), while Herrera-Ruiz showed that labor flexibilization has shaped workers’ seasonal migration and agricultural practices (²²22. Herrera-Ruiz S. La determinación económica, social y laboral de la enfermedad renal crónica de causas no tradicionales (ERCnT) en la costa sur de Guatemala. Ciencia, Tecnología y Salud. 2020;7(1) Available from: https://digi.usac.edu.gt/ojsrevistas/index.php/cytes/article/view/892 Accessed 20 June 2020.
https://digi.usac.edu.gt/ojsrevistas/ind... ). Since available evidence on CKDnT in adults (¹1. Jayasumana C, Orantes C, Herrera R, Almaguer M, Lopez L, Silva LC, et al. Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants. Nephrol Dial Transplant. 2017;32:234–41. doi: 10.1093/ndt/gfw346. Accessed 28 August 2019.
https://doi.org/10.1093/ndt/gfw346...

2. Orantes-Navarro C, Herrera-Valdés R, Almaguer-López M, López-Marin L, Vela-Parada XF, Hernandez-Cuchillas M, et al. Toward a comprehensive hypothesis of chronic interstitial nephritis in agricultural communities. Adv Chronic Kidney Dis. 2019;24(2):101–6. doi: 10.1053/j.ackd.2017.01.001. Accessed 28 August 2019.
https://doi.org/10.1053/j.ackd.2017.01.0...

3. Chapman E, Haby MM, Illanes E, Sanchez-Viamonte J, Elias V, et al. Risk factors for chronic kidney disease of non-traditional causes: a systematic review. Rev Panam Salud Publica. 2019;43:e35. doi: 10.26633/RPSP.2019.35. Accessed 28 August 2019.
https://doi.org/10.26633/RPSP.2019.35...

4. Johnson R, Wesseling C, Lee Newman L. Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med. 2019;380(19):1843–52. doi: 10.1056/NEJMra1813869. Accessed 28 August 2019.
https://doi.org/10.1056/NEJMra1813869... -⁵5. Wesseling C, Glaser J, Rodríguez-Guzmán J, Weiss I, Lucas R, Peraza S, et al. Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress. Rev Panam Salud Publica. 2020;44:e15. doi: 10.26633/RPSP.2020.15. Accessed 13 February 2020.
https://doi.org/10.26633/RPSP.2020.15... ) shows that they are usually diagnosed between the third and fifth decades of life, when the disease has already progressed, and available data in children (⁷7. Orantes, CM, Herrera R, Almaguer M, Brizuela EG, Alvarado NP, Fuentes EJ, et al. Chronic kidney disease in children and adolescents in Salvadoran farming communities: NefroSalva pediatric study (2009–2011). MEDICC Rev. 2016;18(1–2):15–21., ⁸8. Ramirez O, Amador JJ, Kaufman JS, Weiner DE, Parikh CR, Khan U, et al. Urine biomarkers of kidney injury among adolescents in Nicaragua, a region affected by an epidemic of chronic kidney disease of unknown aetiology. Nephrol Dial Transplant. 2016;31(3):424–32. doi: 10.1093/ndt/gfv292. Accessed 12 November 2019.
https://doi.org/10.1093/ndt/gfv292... ) show that renal damage starts early in life in areas with high CKD mortality, it is reasonable to hypothesize that exposure during childhood may find clinical expression in early adulthood. This hypothesis should be tested in future studies, and kidney function screening in children living in high-risk areas may lead to early detection and treatment of CKD. An important finding is that factors commonly associated with health inequities in Guatemala, like ethnicity, sex, and income, did not show an association with CKDnT in this sample. Although CKD more generally disproportionally affects people with lower incomes, CKDnT does not seem to be more deeply affected. It should be noted that 89 participants’ household income was below the officially estimated average market basket of consumer goods and services (known as the canasta básica) (²³23. Guatemala, Instituto Nacional de Estadística. Costo mensual de la canasta básica y ampliada. Guatemala City: INE; 2020. Available from: https://www.ine.gob.gt/ine/canasta-basica-alimentaria/. Accessed 15 June 2020.
https://www.ine.gob.gt/ine/canasta-basic... ). Additionally, while CKDnT in adults disproportionally affects males, in this sample sex was not an associated factor. Participants who had mothers with a lower level of formal education showed increased odds of CKDnT. The mother’s level of education is commonly found to be a significant risk factor for many health problems, such as immunization rates, child survival, child nutrition, and health care utilization. It has most commonly been interpreted as a variable that summarizes a constellation of social and economic factors at play, like financial security, access to social support, cultural capital, and access to information (²⁴24. Desai S, Alva S. Maternal education and child health: is there a strong causal relationship?. Demography. 1998;35:71–81.

25. Hatt LE, Waters HR. Determinants of child morbidity in Latin America: a pooled analysis of interactions between parental education and economic status. Soc Sci Med. 2006;62(2):375–86.-²⁶26. LeVine RA, LeVine S, Schnell-Anzola B, Rowe ML, Dexter E. Literacy and mothering: how women’s schooling changes the lives of the world’s children. Oxford: Oxford University Press; 2012.).

Limitations

Limitations of this study are the known ones for cross-sectional surveys based on self-reporting. In addition, the municipality-level analysis by definition may insert the ecological fallacy into the analysis. The statistical significance was affected by the number of research participants and the study duration, in turn affected by the number of actual pediatric patients with CKDnT. Finally, the dependent variable, CKDnT, and the municipal-level variables come from secondary data. The main strength of this study is that it is the first one to focus on risk factors of CKDnT in children.

Conclusion

The results from this study suggest that factors associated with CKDnT among children in Guatemala are agricultural practices in their municipality of residence, and mother’s level of education. Other variables derived from the conceptual model at the individual, household, and community level did not show an association with CKDnT. This study’s emphasis was on elucidating the role of access to health care services and environmental factors suggested by previous research (⁶6. Cerón A, Fort MP, Morine CM, Lou-Meda R. Chronic kidney disease among children in Guatemala. Rev Panam Salud Publica. 2014;36(6):376–82.).

Future research in children could use case-control designs, but it may prove more fruitful to design population-based studies in agricultural communities, focused on early detection and a life-cycle approach. Conducting similar studies in other affected countries, or multi-country studies, is needed for testing hypotheses in different contexts. Public health interventions that involve kidney function screening among children, especially in high CKD mortality areas, are recommended.

Disclaimer.

Authors hold sole responsibility for the views expressed in the manuscript, which may not necessarily reflect the opinion or policy of the RPSP/PAJPH and/or PAHO.

REFERENCES

Publication Dates

History