Resolving the Enigma of the Mesoamerican Nephropathy: A Research Workshop Summary

The First International Research Workshop on Mesoamerican Nephropathy (MeN) met in Costa Rica in November 2012 to discuss how to establish the extent and degree of MeN, examine relevant causal hypotheses, and focus efforts to control or eliminate the disease burden. MeN describes a devastating epidemic of chronic kidney disease of unknown origin predominantly observed among young male sugarcane cutters. The cause of MeN remains uncertain; however, the strongest hypothesis pursued to date is repeated episodes of occupational heat stress and water and solute loss, probably in combination with other potential risk factor(s), such as nonsteroidal anti-inflammatory drug and other nephrotoxic medication use, inorganic arsenic, leptospirosis, or pesticides. At the research workshop, clinical and epidemiologic case definitions were proposed in order to facilitate both public health and research efforts. Recommendations emanating from the workshop included measuring workload, heat, and water and solute loss among workers; quantifying nephrotoxic agents in drinking water and food; using biomarkers of early kidney injury to explore potential causes of MeN; and characterizing social and working conditions together with methods for valid data collection of exposures and personal risk factors. Advantages and disadvantages of different population study designs were detailed. To elucidate the etiology of MeN, multicountry studies with prospective cohort design, preferably integrating an ecosystem health approach, were considered the most promising. In addition, genetic, experimental, and mechanistic methods and designs were addressed, specifically the need for kidney biopsy analysis, studies in animal models, advances in biomarkers, genetic and epigenetic studies, a common registry and repository of biological and demographic data and/or specimens, and other areas of potential chronic kidney disease experimental research. Finally, in order to improve international collaboration on MeN, workshop participants agreed to establish a research consortium to link these Mesoamerican efforts to other efforts worldwide. The First International Research Workshop on Mesoamerican Nephropathy (MeN) met in Costa Rica in November 2012 to discuss how to establish the extent and degree of MeN, examine relevant causal hypotheses, and focus efforts to control or eliminate the disease burden. MeN describes a devastating epidemic of chronic kidney disease of unknown origin predominantly observed among young male sugarcane cutters. The cause of MeN remains uncertain; however, the strongest hypothesis pursued to date is repeated episodes of occupational heat stress and water and solute loss, probably in combination with other potential risk factor(s), such as nonsteroidal anti-inflammatory drug and other nephrotoxic medication use, inorganic arsenic, leptospirosis, or pesticides. At the research workshop, clinical and epidemiologic case definitions were proposed in order to facilitate both public health and research efforts. Recommendations emanating from the workshop included measuring workload, heat, and water and solute loss among workers; quantifying nephrotoxic agents in drinking water and food; using biomarkers of early kidney injury to explore potential causes of MeN; and characterizing social and working conditions together with methods for valid data collection of exposures and personal risk factors. Advantages and disadvantages of different population study designs were detailed. To elucidate the etiology of MeN, multicountry studies with prospective cohort design, preferably integrating an ecosystem health approach, were considered the most promising. In addition, genetic, experimental, and mechanistic methods and designs were addressed, specifically the need for kidney biopsy analysis, studies in animal models, advances in biomarkers, genetic and epigenetic studies, a common registry and repository of biological and demographic data and/or specimens, and other areas of potential chronic kidney disease experimental research. Finally, in order to improve international collaboration on MeN, workshop participants agreed to establish a research consortium to link these Mesoamerican efforts to other efforts worldwide. During the last 20 years, several regions in Central America have seen a dramatic increase in rapidly progressive chronic kidney disease (CKD) unexplained by conventional risk factors such as diabetes and hypertension and concentrated in relatively young men, particularly sugarcane workers.1Wesseling C. Crowe J. Hogstedt C. Jakobsson K. Lucas R. Wegman D. Mesoamerican Nephropathy: Report From the First International Research Workshop on MeN. SALTRA/IRET-UNA; 2013, Heredia, Costa Rica2013http://www.saltra.una.ac.cr/images/SALTRA/Documentacion/SerieSaludTrabajo/seriesaludytrabajo10.pdfGoogle Scholar In November 2012, the Program on Work, Health and Environment in Central America (SALTRA) organized an international research workshop on this Mesoamerican nephropathy (MeN) designed to review the present knowledge of MeN and similar epidemics elsewhere, set research priorities, and establish international collaborations. Much work has been done in the 8 years since the first SALTRA workshop on MeN2Cuadra S.N. Jakobsson K. Hogstedt C. Wesseling C. Chronic kidney disease in Central America: an assessment of the available information.in: SALTRA. Chronic Kidney Disease: Assessment of Current Knowledge and Feasibility for Regional Research Collaboration in Central America. Section 1. Work & Health Series, No 2. SALTRA; 2006, Heredia, Costa Rica2006http://www.saltra.una.ac.cr/index.php/sst-vol-2Google Scholar: studies from Central America have been published and there also is evidence suggesting MeN-like kidney diseases in several countries in Asia. Much more remains to be done. The disease has yet to be characterized in Guatemala, Honduras, Panama, and Mexico, as well as in regions of Nicaragua, El Salvador, and Costa Rica, the 3 Mesoamerican countries in which MeN has been well documented.3Torres C. Aragón A. González M. et al.Evidence of widespread chronic kidney disease of unknown cause in Nicaragua, Central America.Am J Kidney Dis. 2010; 55: 485-496Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 4Peraza S. Wesseling C. Aragón A. et al.Decreased kidney function among agricultural workers in El Salvador.Am J Kidney Dis. 2012; 59: 531-540Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 5Orantes C.M. Herrera R. Almaguer M. et al.Chronic kidney disease and associated risk factors in the Bajo Lempa region of El Salvador: Nefrolempa Study, 2009.MEDICC Rev. 2011; 13: 14-22PubMed Google Scholar, 6Cerdas M. Chronic kidney disease in Costa Rica.Kidney Int Suppl. 2005; 97: S31-S33Crossref PubMed Scopus (62) Google Scholar We need to characterize the patterns and trends of the disease in all these settings and better understand prevalence in populations that are less well studied or not identified as high risk, such as women and adolescents. Future studies should forcefully target elucidating the cause of MeN and promote interventions, and simultaneously attract international funding for the problem. Our objective here is to reflect the workshop’s considerations and agreements on how best to establish the extent and degree of MeN, examine relevant causal hypotheses, and focus efforts to control or eliminate the disease burden. This information is intended to benefit future studies. Of particular interest for population studies is agreeing on a case definition for MeN, which priority exposures to focus on, methods to measure exposures and personal risk factors, and study design selection. There are different objectives to defining a case, for both clinical diagnosis and use in population studies of early or predisease. A basic clinical definition for patients with MeN was reasonably agreed on: persons living in Mesoamerica who have abnormal kidney function, per internationally accepted standards (KDIGO [Kidney Disease: Improving Global the Outcomes] 2012 guidelines7Kidney DiseaseImproving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.Kidney Int Suppl. 2013; 3: 1-150Crossref Scopus (1615) Google Scholar), with no other known causes—for example, diabetes, hypertension, or polycystic kidney disease—for their CKD. MeN patients have low kidney function, frequently have hypokalemia, and typically have no hypertension or edema on physical examination. Clinical diagnosis is reasonably standardized (see Box 1).Box 1Elements Needed for Clinical DiagnosisNecessary•History: Clinical history, family history, information about work, liquid intake, medication including NSAIDs intake•Physical examination: Blood pressure, edema•Blood tests: Electrolytes, hemoglobin, eGFR (SCr, cystatin C), uric acid, glucose•Urine samples: Proteinuria, hematuria, biomarkers for tubular damage such as NAG, α1-microglobulin, β2-microglobulinDesirable•Imaging studies: Ruling out polycystic kidney disease•Kidney biopsy: Light microscopy, immunofluorescence, electron microscopyAbbreviations: eGFR, estimated glomerular filtration rate; NAG, N-acetyl-β-D-glucosaminidase; NSAIDs, nonsteroidal anti-inflammatory drugs; SCr, serum creatinine. Necessary•History: Clinical history, family history, information about work, liquid intake, medication including NSAIDs intake•Physical examination: Blood pressure, edema•Blood tests: Electrolytes, hemoglobin, eGFR (SCr, cystatin C), uric acid, glucose•Urine samples: Proteinuria, hematuria, biomarkers for tubular damage such as NAG, α1-microglobulin, β2-microglobulinDesirable•Imaging studies: Ruling out polycystic kidney disease•Kidney biopsy: Light microscopy, immunofluorescence, electron microscopy Abbreviations: eGFR, estimated glomerular filtration rate; NAG, N-acetyl-β-D-glucosaminidase; NSAIDs, nonsteroidal anti-inflammatory drugs; SCr, serum creatinine. In epidemiologic studies, a case definition based on criteria emanating from a composite clinical case definition may be valuable for descriptive purposes: for example, it may be used to calculate the need for medical care in the community. However, if the aim of an epidemiologic study is to explore risk and susceptibility factors, the clinical definition falls short because it emphasizes the advanced disease stage. Instead, several different components should be investigated with focus on both early and more advanced signs of adverse effects. Although there is not yet definitive agreement on criteria, the following basic considerations can be stated:•A creatinine assay, which is traceable to a reference method based on isotope-dilution mass spectrometry8Peake M. Whiting M. Measurement of serum creatinine—current status and future goals.Clin Biochem Rev. 2006; 27: 173-184PubMed Google Scholar•The CKD-EPI (CKD Epidemiology Collaboration) formula for estimating glomerular filtration rate (GFR), which is evaluated in multiple ethnicities9Stevens L.A. Claybon M.A. Schmid C.H. et al.Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating the glomerular filtration rate in multiple ethnicities.Kidney Int. 2011; 79: 555-562Crossref PubMed Scopus (346) Google Scholar and in accordance with the recent KDIGO 2012 guidelines7Kidney DiseaseImproving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.Kidney Int Suppl. 2013; 3: 1-150Crossref Scopus (1615) Google Scholar•A semiquantitative dipstick for proteinuria; a morning spot sample is best but may be impractical. The nature and timing of samples should be reported for proper interpretation. If possible, albumin-creatinine ratio in urine should be determined because it corrects for the effect of body water loss on the level of proteinuria•The KDIGO 2012 guidelines7Kidney DiseaseImproving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.Kidney Int Suppl. 2013; 3: 1-150Crossref Scopus (1615) Google Scholar should be used for “quasi staging” only. Proteinuria, serum creatinine level, and estimated GFR should always be reported separately and as multiple (not binary) categories•Information on hypertension and diabetes, at a minimum self-report on health care provider diagnosis There is no single study that will allow us to investigate the many different exposures that are hypothesized to be associated with MeN due to the different agents of interest, the potential for both occupational and nonoccupational exposure, and the different objectives to be addressed by the research. Because all these factors will influence the design of a study, a conceptual model was developed to summarize the different ways in which exposure could be characterized and related to disease status (Fig The of the workshop was that repeated heat exposure, water and solute loss or and work in may be risk factors or C. Crowe J. Hogstedt C. Jakobsson K. Lucas R. Wegman D. Mesoamerican Nephropathy: Report From the First International Research Workshop on MeN. SALTRA/IRET-UNA; 2013, Heredia, Costa Rica2013http://www.saltra.una.ac.cr/images/SALTRA/Documentacion/SerieSaludTrabajo/seriesaludytrabajo10.pdfGoogle Scholar other exposures were considered as hypotheses, potential with body water loss, or disease factors, in use of nonsteroidal anti-inflammatory in inorganic arsenic, leptospirosis, and assessment will need to exposure and of exposure a of assessment with the exposures to be from of physical and in the work and to biomarkers and to characterize present and personal is to examine potential the occupational and with exposure assessment are workload, heat exposure, and nephrotoxic biomarkers of exposure, and of were and rate can be used as a measure of as well as and it is and for rate data can be by a assessment of work done for example, measuring of in a or using international standards or such as the International for or the and Health to heat exposure can be and body The can be but and heat stress for example, the of the on on the International Scholar conditions can be using data from and with to the body in settings and is valid for the single to heat of water or solute loss or from urine and to in body and in body was considered the and most of an However, this method in the with a for the to on and for R. on working on measuring exposure to work heat stress and Wesseling C. Crowe J. Hogstedt C. Jakobsson K. Lucas R. Wegman D. Mesoamerican Nephropathy: Report From the First International Research Workshop on MeN. Heredia, Costa Scholar and are to in and L.A. A. Blood and of status progressive PubMed Scopus Google Scholar it is that be used to status on a and as of status in in the PubMed Scopus Google Scholar are about the of the drinking in particular and water if these agents may not be risk factors for MeN, that these have to drinking water is a from a public health The workshop participants agreed among the of exposure to populations at risk, characterizing drinking water and should be the with inorganic and that are known to cause kidney as priority experimental evidence that information for of or also should be C. R. et and kidney Wesseling C. Crowe J. Hogstedt C. Jakobsson K. Lucas R. Wegman D. Mesoamerican Nephropathy: Report From the First International Research Workshop on MeN. 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