Mesoamerican Nephropathy (MeN), a form of chronic kidney disease of uncertain etiology, is a leading cause of death in Central America. The disease often presents in young adult male agricultural workers and progresses rapidly. Given the young age at presentation, we hypothesized that children in Central America experience subclinical kidney injury prior to working life.
We assessed specimens from a cross-sectional study of youth, aged 7–17 years, predominantly residing in a high-risk region of Nicaragua (n = 210). We evaluated urinary concentrations and risk factors for kidney injury biomarkers neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), monocyte chemoattractant protein 1 (MCP-1), and chitinase-3-like protein 1 (YKL-40). We evaluated the association between biomarkers and contemporaneous eGFR and compared biomarker concentrations with reference values from healthy children in other countries.
Median uNGAL, uIL-18, and uKIM-1 concentrations exceeded healthy reference values. A one-year increase in age was associated with 40% increase in odds of being in the highest quartile of uNGAL (OR 1.4; (95%CI 1.2, 1.5); p < 0.0001). Youth who reported ever experiencing dysuria had 2.5 times the odds of having uNGAL concentrations in the top quartile (OR 2.5; (95%CI 1.4, 4.6); p = 0.003). Girls had significantly higher concentrations of all biomarkers than boys. Nine percent of children demonstrated low eGFR (≤ 100 ml/min/1.73 m2), while 29% showed evidence of hyperfiltration (eGFR ≥ 160 ml/min/1.73 m2), both potentially indicative of renal dysfunction.
Children residing in regions of Nicaragua at high risk for MeN may experience subclinical kidney injury prior to occupational exposures.
This is a preview of subscription content,to check access.
Access this article
Data analyzed in this study are included in this published article as supplementary information.
Brooks DR, Ramirez-Rubio O, Amador JJ (2012) CKD in Central America: a hot issue. Am J Kidney Dis Off J Natl Kidney Found 59:481–484. https://doi.org/10.1053/j.ajkd.2012.01.005
Correa-Rotter R, Wesseling C, Johnson RJ (2014) CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy. Am J Kidney Dis 63:506–520
Lozier M, Turcios-Ruiz RM, Noonan G, Ordunez P (2016) Chronic kidney disease of nontraditional etiology in Central America: a provisional epidemiologic case definition for surveillance and epidemiologic studies. Rev Panam Salud Publica Pan Am J Public Health 40:294–300
Johnson RJ, Wesseling C, Newman LS (2019) Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med 380:1843–1852. https://doi.org/10.1056/NEJMra1813869
Wijkstrom J, Gonzalez-Quiroz M, Hernandez M et al (2017) Renal morphology, clinical findings, and progression rate in Mesoamerican nephropathy. Am J Kidney Dis Off J Natl Kidney Found 69:626–636. https://doi.org/10.1053/j.ajkd.2016.10.036
Gonzalez-Quiroz M, Camacho A, Faber D et al (2017) Rationale, description and baseline findings of a community-based prospective cohort study of kidney function amongst the young rural population of Northwest Nicaragua. BMC Nephrol 18:16. https://doi.org/10.1186/s12882-016-0422-4
Gonzalez-Quiroz M, Pearce N, Caplin B, Nitsch D (2018) What do epidemiological studies tell us about chronic kidney disease of undetermined cause in Meso-America? A systematic review and meta-analysis. Clin Kidney J 11:496–506. https://doi.org/10.1093/ckj/sfx136
Orantes-Navarro CM, Herrera-Valdes R, Almaguer-Lopez M et al (2017) Toward a comprehensive hypothesis of chronic interstitial nephritis in agricultural communities. Adv Chronic Kidney Dis 24:101–106. https://doi.org/10.1053/j.ackd.2017.01.001
Peraza S, Wesseling C, Aragon A et al (2012) Decreased kidney function among agricultural workers in El Salvador. Am J Kidney Dis Off J Natl Kidney Found 59:531–540. https://doi.org/10.1053/j.ajkd.2011.11.039
Ramirez-Rubio O, McClean MD, Amador JJ, Brooks DR (2013) An epidemic of chronic kidney disease in Central America: an overview. J Epidemiol Community Health 67:1–3. https://doi.org/10.1136/jech-2012-201141
Fischer RSB, Mandayam S, Chavarria D et al (2017) Clinical evidence of acute Mesoamerican nephropathy. Am J Trop Med Hyg 97:1247–1256. https://doi.org/10.4269/ajtmh.17-0260
Garcia-Trabanino R, Jarquin E, Wesseling C et al (2015) Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador--a cross-shift study of workers at risk of Mesoamerican nephropathy. Environ Res 142:746–755. https://doi.org/10.1016/j.envres.2015.07.007
Roncal-Jimenez C, Garcia-Trabanino R, Barregard L et al (2016) Heat stress nephropathy from exercise-induced uric acid Crystalluria: a perspective on Mesoamerican nephropathy. Am J Kidney Dis Off J Natl Kidney Found 67:20–30. https://doi.org/10.1053/j.ajkd.2015.08.021
Rodriguez MI (2014) Chronic kidney disease in our farming communities: implications of an epidemic. MEDICC Rev 16:77–78
Silva LC, Ordunez P (2014) Chronic kidney disease in central American agricultural communities: challenges for epidemiology and public health. MEDICC Rev 16:66–71
Kupferman J, Amador JJ, Lynch KE et al (2016) Characterization of Mesoamerican nephropathy in a kidney failure hotspot in Nicaragua. Am J Kidney Dis Off J Natl Kidney Found 68:716–725. https://doi.org/10.1053/j.ajkd.2016.06.012
Wesseling C, van Wendel de Joode B, Crowe J et al (2015) Mesoamerican nephropathy: geographical distribution and time trends of chronic kidney disease mortality between 1970 and 2012 in Costa Rica. Occup Environ Med 72:714–721. https://doi.org/10.1136/oemed-2014-102799
Dennen P, Parikh CR (2007) Biomarkers of acute kidney injury: can we replace serum creatinine? Clin Nephrol 68:269–278
Pontillo C, Mischak H (2016) Urinary biomarkers to predict CKD: is the future in multi-marker panels? Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc 31:1373–1375. https://doi.org/10.1093/ndt/gfv467
Shlipak MG, Day EC (2013) Biomarkers for incident CKD: a new framework for interpreting the literature. Nat Rev Nephrol 9:478–483. https://doi.org/10.1038/nrneph.2013.108
Wasung ME, Chawla LS, Madero M (2015) Biomarkers of renal function, which and when? Clin Chim Acta Int J Clin Chem 438:350–357. https://doi.org/10.1016/j.cca.2014.08.039
Coca SG, Parikh CR (2008) Urinary biomarkers for acute kidney injury: perspectives on translation. Clin J Am Soc Nephrol CJASN 3:481–490. https://doi.org/10.2215/CJN.03520807
Wesseling C, Garcia-Trabanino R, Wegman DH (2016) Mesoamerican nephropathy: do novel biomarkers of kidney damage have a role to play? Am J Kidney Dis Off J Natl Kidney Found 67:173–175. https://doi.org/10.1053/j.ajkd.2015.10.010
McClean M, Amador JJ, Laws RL, et al. (2012) Biological sampling report: investigating biomarkers of kidney injury and chronic kidney disease among workers in Western Nicaragua. Boston University School of public health, Boston
Laws RL, Brooks DR, Amador JJ et al (2016) Biomarkers of kidney injury among Nicaraguan sugarcane workers. Am J Kidney Dis Off J Natl Kidney Found 67:209–217. https://doi.org/10.1053/j.ajkd.2015.08.022
De Silva PMCS, Mohammed Abdul KS, Eakanayake EMDV et al (2016) Urinary biomarkers KIM-1 and NGAL for detection of chronic kidney disease of uncertain etiology (CKDu) among agricultural communities in Sri Lanka. PLoS Negl Trop Dis 10:e0004979. https://doi.org/10.1371/journal.pntd.0004979
Ramirez-Rubio O, Amador JJ, Kaufman JS et al (2016) 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 Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc 31:424–432. https://doi.org/10.1093/ndt/gfv292
Ramirez-Rubio O, Brooks DR, Amador JJ et al (2013) Chronic kidney disease in Nicaragua: a qualitative analysis of semi-structured interviews with physicians and pharmacists. BMC Public Health 13:350. https://doi.org/10.1186/1471-2458-13-350
Kavouras SA, Johnson EC, Bougatsas D et al (2016) Validation of a urine color scale for assessment of urine osmolality in healthy children. Eur J Nutr 55:907–915. https://doi.org/10.1007/s00394-015-0905-2
Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N (1993) Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 268:10425–10432
Cowland JB, Borregaard N (1997) Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Genomics 45:17–23. https://doi.org/10.1006/geno.1997.4896
Mishra J, Dent C, Tarabishi R et al (2005) Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet Lond Engl 365:1231–1238. https://doi.org/10.1016/S0140-6736(05)74811-X
Mori K, Lee HT, Rapoport D et al (2005) Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest 115:610–621. https://doi.org/10.1172/JCI23056
Moresco RN, Bochi GV, Stein CS et al (2018) Urinary kidney injury molecule-1 in renal disease. Clin Chim Acta Int J Clin Chem 487:15–21. https://doi.org/10.1016/j.cca.2018.09.011
Lobato GR, Lobato MR, Thome FS, Veronese FV (2017) Performance of urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and N-acetyl-beta-D-glucosaminidase to predict chronic kidney disease progression and adverse outcomes. Braz J Med Biol Res Rev Bras Pesqui Medicas E Biol 50:e6106. https://doi.org/10.1590/1414-431X20176106
Malhotra R, Siew ED (2017) Biomarkers for the early detection and prognosis of acute kidney injury. Clin J Am Soc Nephrol CJASN 12:149–173. https://doi.org/10.2215/CJN.01300216
Parikh CR, Jani A, Melnikov VY et al (2004) Urinary interleukin-18 is a marker of human acute tubular necrosis. Am J Kidney Dis Off J Natl Kidney Found 43:405–414
Kim MJ, Tam FWK (2011) Urinary monocyte chemoattractant protein-1 in renal disease. Clin Chim Acta Int J Clin Chem 412:2022–2030. https://doi.org/10.1016/j.cca.2011.07.023
Hall IE, Stern EP, Cantley LG et al (2014) Urine YKL-40 is associated with progressive acute kidney injury or death in hospitalized patients. BMC Nephrol 15:133. https://doi.org/10.1186/1471-2369-15-133
Mansour SG, Verma G, Pata RW et al (2017) Kidney injury and repair biomarkers in Marathon runners. Am J Kidney Dis Off J Natl Kidney Found 70:252–261. https://doi.org/10.1053/j.ajkd.2017.01.045
Mian AN, Schwartz GJ (2017) Measurement and estimation of glomerular filtration rate in children. Adv Chronic Kidney Dis 24:348–356. https://doi.org/10.1053/j.ackd.2017.09.011
Moledina DG, Hall IE, Thiessen-Philbrook H et al (2017) Performance of serum creatinine and kidney injury biomarkers for diagnosing histologic acute tubular injury. Am J Kidney Dis Off J Natl Kidney Found 70:807–816. https://doi.org/10.1053/j.ajkd.2017.06.031
Hornung RW, Reed LD (1990) Estimation of average concentration in the presence of nondetectable values. Appl Occup Environ Hyg 5:46–51. https://doi.org/10.1080/1047322X.1990.10389587
Fadrowski JJ, Furth SL (2011) GFR estimation in children: questions and answers (and questions). Clin J Am Soc Nephrol 6:1810. https://doi.org/10.2215/CJN.05900611
Wanigasuriya K, Jayawardene I, Amarasiriwardena C, Wickremasinghe R (2017) Novel urinary biomarkers and their association with urinary heavy metals in chronic kidney disease of unknown aetiology in Sri Lanka: a pilot study. Ceylon Med J 62:210–217. https://doi.org/10.4038/cmj.v62i4.8568
Butler-Dawson J, Krisher L, Yoder H et al (2019) Evaluation of heat stress and cumulative incidence of acute kidney injury in sugarcane workers in Guatemala. Int Arch Occup Environ Health. https://doi.org/10.1007/s00420-019-01426-3
Bennett MR, Nehus E, Haffner C et al (2015) Pediatric reference ranges for acute kidney injury biomarkers. Pediatr Nephrol Berl Ger 30:677–685. https://doi.org/10.1007/s00467-014-2989-y
Rybi-Szuminska A, Wasilewska A, Litwin M et al (2013) Paediatric normative data for urine NGAL/creatinine ratio. Acta Paediatr Oslo Nor 102:e269–e272. https://doi.org/10.1111/apa.12200
Warady BA, Chadha V (2007) Chronic kidney disease in children: the global perspective. Pediatr Nephrol Berl Ger 22:1999–2009. https://doi.org/10.1007/s00467-006-0410-1
Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW (2012) Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol 8:293–300. https://doi.org/10.1038/nrneph.2012.19
The authors gratefully acknowledge study participants, their families, and the BU Nicaragua study team for their time and efforts. We thank Sinead Keogh and Iris Delgado at Boston University for research assistance. The authors also express gratitude to Dr. Michael McClean at Boston University for his guidance and expertise.
The parent study was funded by the Comité Nacional de Productores de Azúcar (CNPA) in Nicaragua. The nested study was funded by the Fundación Renal Iñigo Alvarez de Toledo (FRIAT) in Spain. The funders had no role in study design, collection, analysis, and interpretation of data, or in the preparation or writing of this manuscript.
Conflict of interest
JHL, JJA, DLP, and DRB have received funding from Azucareros del Istmo Centroamericano (AICA) to support a study of agricultural workers in Nicaragua. AICA had no role in the current study.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Leibler, J.H., Ramirez-Rubio, O., Velázquez, J.J.A. et al. Biomarkers of kidney injury among children in a high-risk region for chronic kidney disease of uncertain etiology. Pediatr Nephrol 36, 387–396 (2021). https://doi.org/10.1007/s00467-020-04595-3