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American Journal of Kidney Diseases

Mesoamerican Nephropathy: Do Novel Biomarkers of Kidney Damage Have a Role to Play?

      Related Article, p. 209
      Chronic kidney disease (CKD) prevalence has rapidly increased in recent years across the globe. It is common to attribute this increase to the global epidemic of metabolic syndrome,
      No authors listed
      The global issue of kidney disease.
      • Jha V.
      • Garcia-Garcia G.
      • Iseki K.
      • et al.
      Chronic kidney disease: global dimension and perspectives.
      but equally notable is the appearance of “hot spots” of CKD of unknown cause throughout the world.
      • Martín-Cleary C.
      • Ortiz A.
      CKD hotspots around the world: where, why and what the lessons are. A CKJ review series.
      A striking example is Mesoamerican nephropathy in Central America and Mexico, which has reached a crisis level.
      • Wesseling C.
      • Crowe J.
      • Hogstedt C.
      • Jakobsson K.
      • Lucas R.
      • Wegman D.
      The epidemic of chronic kidney disease of unknown etiology in Mesoamerica: a call for interdisciplinary research and action.
      No authors listed. Extended summary.
      Mesoamerican nephropathy first appeared in the published literature only 13 years ago,
      • Trabanino R.G.
      • Aguilar R.
      • Silva C.R.
      • Mercado M.O.
      • Merino R.L.
      [End-stage renal disease among patients in a referral hospital in El Salvador].
      although as is often the case with the discovery of new conditions, there is evidence that it has been in existence for at least 40 years.
      • Wesseling C.
      • van Wendel de Joode B.
      • Crowe J.
      • et al.
      Mesoamerican nephropathy: geographical distribution and time trends of chronic kidney disease mortality between 1970 and 2012 in Costa Rica.
      Now Mesoamerican nephropathy is acknowledged as a devastating epidemic of CKD not explained by traditional causes. It is estimated that more than 20,000 workers have died of Mesoamerican nephropathy,
      • Ramirez-Rubio O.
      • McClean M.D.
      • Amador J.J.
      • Brooks D.R.
      An epidemic of chronic kidney disease in Central America: an overview.
      and mortality continues to increase,
      • Wesseling C.
      • van Wendel de Joode B.
      • Crowe J.
      • et al.
      Mesoamerican nephropathy: geographical distribution and time trends of chronic kidney disease mortality between 1970 and 2012 in Costa Rica.
      • Ordunez P.
      • Saenz C.
      • Martinez R.
      • Chapman E.
      • Reveiz L.
      • Becerra F.
      The epidemic of chronic kidney disease in Central America.
      with a troubling expansion into the younger working populations.
      • Wesseling C.
      • van Wendel de Joode B.
      • Crowe J.
      • et al.
      Mesoamerican nephropathy: geographical distribution and time trends of chronic kidney disease mortality between 1970 and 2012 in Costa Rica.
      During the last 5 years, new knowledge on the geographical distribution, trends over time, pathophysiology, and clinical characteristics of Mesoamerican nephropathy has emerged. We now know with relative certainty that Mesoamerican nephropathy disproportionally affects sugarcane workers and, to a lesser degree, other workers in the Pacific coastal lowlands of Mexico and Central America.
      • Wesseling C.
      • Crowe J.
      • Hogstedt C.
      • Jakobsson K.
      • Lucas R.
      • Wegman D.
      The epidemic of chronic kidney disease of unknown etiology in Mesoamerica: a call for interdisciplinary research and action.
      The extent of the epidemic is likely much larger than current estimates, with cases appearing in new places;
      • Laux T.S.
      • Barnoya J.
      • Guerrero D.R.
      • Rothstein M.
      Dialysis enrollment patterns in Guatemala: evidence of the chronic kidney disease of non-traditional causes epidemic in Mesoamerica.
      and it is related to both environmental and occupational factors, in particular hot climates and strenuous work. However, we still lack sufficient understanding of the cause, disease mechanisms, and associated pathophysiology, which is needed in order to address this human tragedy through early disease detection and prevention of new and worsening disease.
      One particular knowledge gap is the potential of early biomarkers of kidney damage to study and track Mesoamerican nephropathy.
      • Correa-Rother R.
      • Kaufman J.
      2013 Biomarkers for early detection of CKD, and how/if biomarkers can be used for elucidations of pathophysiology.
      For the most part, Mesoamerican nephropathy has been identified through testing serum creatinine values and assessing end-stage renal disease mortality statistics in high-risk regions and worker populations, but this method captures cases at a relatively late stage unrelated to CKD cause. Appropriately sensitive biomarkers are needed to identify individuals at risk for Mesoamerican nephropathy before the condition is irreversible and, equally important, to understand the cause and track risk in large populations in order to prevent the onset of CKD.
      • Nickolas T.L.
      • Barasch J.
      • Devarajan P.
      Biomarkers in acute and chronic kidney disease.
      • Lopez-Giacoman S.
      • Madero M.
      Biomarkers in chronic kidney disease, from kidney function to kidney damage.
      • Devarajan P.
      The use of targeted biomarkers for chronic kidney disease.
      • Fassett R.G.
      • Venuthurupalli S.K.
      • Gobe G.C.
      • Coombes J.S.
      • Cooper M.A.
      • Hoy W.E.
      Biomarkers in chronic kidney disease: a review.
      In this issue of AJKD, Laws et al
      • Laws R.L.
      • Brooks D.R.
      • Amador J.J.
      • et al.
      Biomarkers of kidney injury among Nicaraguan sugarcane workers.
      present results of the first Mesoamerican nephropathy study using markers of kidney damage to elucidate the cause of the disease. The study specifically examined the markers neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-d-glucosaminidase (NAG), and interleukin 18 (IL-18) as markers of tubular damage and albuminuria as a marker of glomerular damage.
      • Laws R.L.
      • Brooks D.R.
      • Amador J.J.
      • et al.
      Biomarkers of kidney injury among Nicaraguan sugarcane workers.
      Nicaraguan sugarcane workers (selected for employment to have normal creatinine levels at baseline; baseline estimated glomerular filtration rates were >60 mL/min/1.73 m2 in all but 1 worker) were examined for job-specific differences in these biomarker levels, measured preharvest and near the end of one harvest season. The probability of exposure to heat, pesticides, leptospirosis, and metals was assigned to 7 job categories by the authors; only hydration practices were directly assessed (by worker self-report). Based on significant increases in NGAL, IL-18, and NAG levels among sugarcane workers in job categories designated as having “high” heat exposure along with findings of protective effects of higher intake of electrolyte solution, the authors conclude that their results are consistent with the hypothesis that occupational heat stress and volume depletion may be an important causal factor for the development of kidney disease in this population. This study is a commendable effort exploring early biomarkers to gain further insight into the cause of kidney disease in a population at high risk for Mesoamerican nephropathy.
      Whether these biomarkers are useful for understanding the cause of Mesoamerican nephropathy remains an open question. Scrutinizing the data in the Laws et al study, the patterns appear more complex than at first sight. Cane cutters, who perform exceptionally heavy physical labor in a hot environment,
      • Lucas R.A.
      • Bodin T.
      • García-Trabanino R.
      • et al.
      Heat stress and workload associated with sugarcane cutting - an excessively strenuous occupation [abstract]!.
      had significant or marginally significant cross-harvest increases in the 3 tubular biomarkers NGAL, NAG, and IL-18, as did seeders, another job category classified as having high heat exposure, albeit nonsignificantly. However, other categories classified as having high or medium heat exposure showed no cross-harvest changes (agrochemical applicators), decreases for all 3 markers (seed cutters), or only increased NGAL levels (irrigators). Particularly puzzling are the significant decreases in NAG levels over the harvest among factory workers and drivers, as well as the very high baseline NGAL values among women as compared with men.
      What should we conclude about the value of the biomarkers studied based on this evidence? Were the biomarkers in the study not optimal for detecting the specific kidney damage corresponding to Mesoamerican nephropathy? Or is the problem one of exposure assessment, in which the exposures assigned to job categories (imputed but not directly measured) do not correspond to the true exposure? Or were there important exposures experienced prior to the harvest that were not considered? Another problem of undetermined importance in interpreting these findings was the study’s large loss to follow-up, a problem that reflects the difficult conditions for research in current-day Nicaragua. In that light, how disappointing is the finding that the biomarker patterns were not consistent across different work groups? The authors briefly described the origin of each of the biomarkers studied. All 3 are thought to measure clinically relevant acute kidney injury and to help localize the site of the kidney damage. But does the pathophysiology underlying Mesoamerican nephropathy begin with acute kidney injury? Can additional meaning be found in the biomarker patterns that could further inform the mechanism of Mesoamerican nephropathy? Surely the long-term prognostic value of most of these markers is not yet well characterized,
      • Wasung M.E.
      • Chawla L.S.
      • Madero M.
      Biomarkers of renal function, which and when?.
      • Jakobsson K.
      • Brooks D.
      • Correa-Rotter R.
      Recommendations for methods of defining outcomes in epidemiological studies on renal function and kidney disease.
      and the difficulties interpreting the findings of the study by Laws et al should surprise no one. However, there is no doubt that Mesoamerican nephropathy researchers must continue and intensify their search for suitable early biomarkers to address at least 3 priorities: disease surveillance, including early detection as well as evaluation of disease progression; increasing understanding of the mechanisms and pathophysiology of the disease; and for use in etiologic epidemiology.
      It is important to acknowledge the resource-poor setting in which Mesoamerican nephropathy has been observed. The vast majority of patients with Mesoamerican nephropathy are workers who do hard manual labor with very limited opportunities for alternative employment. In the context of current practice and knowledge, most Mesoamerican nephropathy cases are diagnosed too late for any corrective action that would prevent progression or reverse the trajectory of disease and allow workers to stay active in the labor market. Thus, family poverty increases for affected workers. Hemodialysis as renal replacement therapy is rarely available, not to mention kidney transplantation. In our experience, workers who are offered peritoneal dialysis often refuse because they are worried it will accelerate the inevitable fatal outcome. Tools for early diagnosis are urgently needed to give individuals with Mesoamerican nephropathy a better chance to adapt their lives and improve their prognosis. At the same time, researchers should recognize the implications of using imperfect biomarkers as screening tools for hiring workers. A biomarker with poor specificity may result in employment denial to workers without actual kidney disease. Moreover, excluding workers with evidence of early disease, abnormal biomarker levels, or specific genotypes is unethical.
      • Palmer K.T.
      • Poole J.
      • Rawbone R.G.
      • Coggon D.
      Quantifying the advantages and disadvantages of pre-placement genetic screening.
      In any case, early detection and treatment will not prevent Mesoamerican nephropathy if causal factors persist. Although most researchers agree that exposure to a hot environment in the presence of exceptional physical labor is a major contributor, the pathophysiology underlying the kidney damage is not yet well understood. More experimental research is needed in animals and humans exposed to conditions that mimic field conditions. In addition, data like those presented by Laws et al can provide the opportunity to scrutinize the origin of abnormal marker levels and provide clues for mechanisms and cause.
      In summary, our ultimate goal is to prevent the development of Mesoamerican nephropathy, and the inclusion of biomarkers of kidney damage in a field study as reported by Laws et al is an important first step in the search for suitable markers. At the time of writing, epidemiologists, exposure assessment experts, nephrologists, physiologists, and social scientists are preparing to convene for the 2nd International Workshop on the Epidemic of Mesoamerican Nephropathy taking place November 18 to 20, 2015, in San José, Costa Rica, organized by the Central American Program on Work, Environment and Health (SALTRA) and the Consortium for the Epidemic of Nephropathy in Central America and Mexico (CENCAM). Among the topics for discussion are both biomarkers of kidney damage (for early detection and measuring disease progression) and biomarkers for measuring heat stress and other relevant exposures. We hope, together with the authors of this new study, that we will make significant progress in this essential field. We must not forget that until we understand the cause of Mesoamerican nephropathy and develop successful interventions, today’s study participants may become tomorrow’s casualties.

      Acknowledgements

      Support: None.
      Financial Disclosure: The authors declare that they have no relevant financial interests.

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