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American Journal of Kidney Diseases

Characterization of Mesoamerican Nephropathy in a Kidney Failure Hotspot in Nicaragua

Published:August 27, 2016DOI:https://doi.org/10.1053/j.ajkd.2016.06.012

      Background

      Mesoamerican nephropathy (MeN) is a kidney disease of unknown cause that mainly affects working-age men in Central America. Despite being a major cause of morbidity and mortality in this region, its clinical characteristics have not been well defined.

      Study Design

      Cross-sectional family-based study.

      Setting & Participants

      266 members of 24 families with high chronic kidney disease (CKD) burdens in a MeN hotspot in Northwestern Nicaragua. We compared clinical and biochemical characteristics of affected individuals first with their unaffected relatives and then with NHANES (National Health and Nutrition Examination Survey) participants with CKD in order to reveal identifying features of MeN.

      Predictor

      CKD defined as serum creatinine level ≥ 1.5 mg/dL in men and ≥1.4 mg/dL in women.

      Outcomes

      Clinical and biochemical parameters, including serum sodium, potassium, bicarbonate, calcium, magnesium, phosphorus, and uric acid.

      Results

      Hyperuricemia, in many cases severe, was common among patients with MeN. Uric acid levels in patients with MeN were higher than those in NHANES participants (mean, 9.6 vs 7.4 mg/dL for men in each group) despite more frequent use of uric acid–lowering medications in Nicaraguan individuals (71.7% vs 11.2%). In multivariable linear mixed-effects regression analysis, uric acid levels were 2.0 mg/dL (95% CI, 1.0-3.0; P < 0.001) higher in patients with MeN compared with their NHANES counterparts after adjusting for age, estimated glomerular filtration rate, and uric acid–lowering therapies. In contrast to prior reports, hyponatremia and hypokalemia were not common.

      Limitations

      CKD defined by single serum creatinine measurement; population likely not representative of full MeN phenotype spectrum across Central America; major differences between MeN and NHANES groups in important characteristics such as age, ancestry, and recruitment method.

      Conclusions

      Hyperuricemia out of proportion to the degree of decreased kidney function was common among Nicaraguan patients with MeN. Our results suggest that rather than being solely a consequence of CKD, hyperuricemia may play a role in MeN pathogenesis, a hypothesis that deserves further study.

      Index Words

      Mesoamerican nephropathy (MeN) is a newly described endemic form of chronic kidney disease (CKD) that mainly affects young male agricultural workers in the Pacific lowlands of Central America. It is not associated with diabetes, hypertension, or other known causes of CKD.
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      The Central American epidemic of CKD.
      • Wesseling C.
      • Crowe J.
      • Hogstedt C.
      • et al.
      Resolving the enigma of the Mesoamerican nephropathy: a research workshop summary.
      Though precise historical data are lacking, MeN has likely been present in the region for decades, causing thousands of deaths, mostly in El Salvador and Nicaragua.
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      • et al.
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      Age-standardized mortality rates for CKD in these 2 countries are among the 10 highest in the world. These rates are 17 times higher than those of Cuba, 11 times higher than in the United States and Brazil, and 6-fold greater compared with nearby Colombia and Venezuela.
      Cases of CKD not explained by traditional risk factors have also been reported in Guatemala, Honduras, Costa Rica, Panama, and Southern Mexico.
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      • et al.
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      • et al.
      Mesoamerican nephropathy: geographical distribution and time trends of chronic kidney disease mortality between 1970 and 2012 in Costa Rica.
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      Mesoamerica's mystery killer.
      • Ordunez P.
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      Chronic kidney disease epidemic in Central America: urgent public health action is needed amid causal uncertainty.
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      Within Mesoamerica, disease risk appears not to be evenly distributed, but rather concentrated in geographic hotspots, such as the Lempa river banks in El Salvador,
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      Mesoamerica's mystery killer.
      • Orantes C.M.
      • Herrera R.
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      • et al.
      Chronic kidney disease and associated risk factors in the Bajo Lempa region of El Salvador: Nefrolempa study, 2009.
      the Nicaraguan departments of Chinandega and León,
      • O'Donnell J.K.
      • Tobey M.
      • Weiner D.E.
      • et al.
      Prevalence of and risk factors for chronic kidney disease in rural Nicaragua.
      • Raines N.
      • Gonzalez M.
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      • et al.
      Risk factors for reduced glomerular filtration rate in a Nicaraguan community affected by Mesoamerican nephropathy.
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      • et al.
      A population-based study of prevalence and risk factors of chronic kidney disease in Leon, Nicaragua.
      and the Guanacaste province in Costa Rica.
      • 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.
      Although there is general agreement that the etiology of MeN is likely multifactorial, the specific causes remain to be elucidated. Risk factors identified by cross-sectional community-based studies include residence at low altitude
      • O'Donnell J.K.
      • Tobey M.
      • Weiner D.E.
      • et al.
      Prevalence of and risk factors for chronic kidney disease in rural Nicaragua.
      • Peraza S.
      • Wesseling C.
      • Aragon A.
      • et al.
      Decreased kidney function among agricultural workers in El Salvador.
      • Torres C.
      • Aragon A.
      • Gonzalez M.
      • et al.
      Decreased kidney function of unknown cause in Nicaragua: a community-based survey.
      and agricultural work, particularly in sugarcane.
      • Raines N.
      • Gonzalez M.
      • Wyatt C.
      • et al.
      Risk factors for reduced glomerular filtration rate in a Nicaraguan community affected by Mesoamerican nephropathy.
      • Lebov J.F.
      • Valladares E.
      • Pena R.
      • et al.
      A population-based study of prevalence and risk factors of chronic kidney disease in Leon, Nicaragua.
      • Peraza S.
      • Wesseling C.
      • Aragon A.
      • et al.
      Decreased kidney function among agricultural workers in El Salvador.
      • Torres C.
      • Aragon A.
      • Gonzalez M.
      • et al.
      Decreased kidney function of unknown cause in Nicaragua: a community-based survey.
      • Sanoff S.L.
      • Callejas L.
      • Alonso C.D.
      • et al.
      Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua.
      • Orantes C.M.
      • Herrera R.
      • Almaguer M.
      • et al.
      Epidemiology of chronic kidney disease in adults of Salvadoran agricultural communities.
      There also appears to be an excess of CKD in other occupations involving strenuous physical activity at hot temperatures, such as mining, construction, and port work.
      • Torres C.
      • Aragon A.
      • Gonzalez M.
      • et al.
      Decreased kidney function of unknown cause in Nicaragua: a community-based survey.

      McClean M, Amador JJ, Laws R, et al. Biological Sampling Report: Investigating Biomarkers of Kidney Injury and Chronic Kidney Disease Among Workers in Western Nicaragua. 2012. http://www.cao-ombudsman.org/cases/document-links/documents/Biological_Sampling_Report_April_2012.pdf. Accessed August 3, 2016.

      Several potential causes for the development of CKD have been proposed, including heat stress leading to repeated episodes of subclinical acute kidney injury (AKI), agrichemicals, environmental toxins, nephrotoxic medications, and infections such as leptospirosis.
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.
      • Weiner D.E.
      • McClean M.D.
      • Kaufman J.S.
      • Brooks D.R.
      The Central American epidemic of CKD.
      • Ordunez P.
      • Saenz C.
      • Martinez R.
      • Chapman E.
      • Reveiz L.
      • Becerra F.
      The epidemic of chronic kidney disease in Central America.
      • Ordunez P.
      • Martinez R.
      • Reveiz L.
      • et al.
      Chronic kidney disease epidemic in Central America: urgent public health action is needed amid causal uncertainty.
      • Johnson R.J.
      • Sanchez-Lozada L.G.
      Chronic kidney disease: Mesoamerican nephropathy–new clues to the cause.
      • Ramirez-Rubio O.
      • Brooks D.R.
      • Amador J.J.
      • Kaufman J.S.
      • Weiner D.E.
      • Scammell M.K.
      Chronic kidney disease in Nicaragua: a qualitative analysis of semi-structured interviews with physicians and pharmacists.
      • Garcia-Trabanino R.
      • Jarquin E.
      • Wesseling C.
      • et al.
      Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador–a cross-shift study of workers at risk of Mesoamerican nephropathy.
      • Paula Santos U.
      • Zanetta D.M.
      • Terra-Filho M.
      • Burdmann E.A.
      Burnt sugarcane harvesting is associated with acute renal dysfunction.
      • Yaqub F.
      Kidney disease in farming communities remains a mystery.
      Though not well defined, clinical characteristics of MeN include nonproteinuric progressive disease with bland urine sediment and a primarily tubulointerstitial pattern of injury on biopsy.
      • Peraza S.
      • Wesseling C.
      • Aragon A.
      • et al.
      Decreased kidney function among agricultural workers in El Salvador.
      • Torres C.
      • Aragon A.
      • Gonzalez M.
      • et al.
      Decreased kidney function of unknown cause in Nicaragua: a community-based survey.
      • Laws R.L.
      • Brooks D.R.
      • Amador J.J.
      • et al.
      Changes in kidney function among Nicaraguan sugarcane workers.
      • Herrera R.
      • Orantes C.M.
      • Almaguer M.
      • et al.
      Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.
      • Wijkström J.
      • Leiva R.
      • Elinder C.G.
      • et al.
      Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America.
      • Lopez-Marin L.
      • Chavez Y.
      • Garcia X.A.
      • et al.
      Histopathology of chronic kidney disease of unknown etiology in Salvadoran agricultural communities.
      Some individuals have pyuria not explained by infection.

      McClean M, Amador JJ, Laws R, et al. Biological Sampling Report: Investigating Biomarkers of Kidney Injury and Chronic Kidney Disease Among Workers in Western Nicaragua. 2012. http://www.cao-ombudsman.org/cases/document-links/documents/Biological_Sampling_Report_April_2012.pdf. Accessed August 3, 2016.

      • Herrera R.
      • Orantes C.M.
      • Almaguer M.
      • et al.
      Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.
      Discomfort with urination, locally known as “chistata,” is commonly reported in the region; whether this symptom is related to MeN has not been established.
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.

      McClean M, Amador JJ, Laws R, et al. Biological Sampling Report: Investigating Biomarkers of Kidney Injury and Chronic Kidney Disease Among Workers in Western Nicaragua. 2012. http://www.cao-ombudsman.org/cases/document-links/documents/Biological_Sampling_Report_April_2012.pdf. Accessed August 3, 2016.

      • Ramirez-Rubio O.
      • Brooks D.R.
      • Amador J.J.
      • Kaufman J.S.
      • Weiner D.E.
      • Scammell M.K.
      Chronic kidney disease in Nicaragua: a qualitative analysis of semi-structured interviews with physicians and pharmacists.
      Small studies have reported hyponatremia, hypokalemia, and hyperuricemia among patients with MeN in El Salvador.
      • Herrera R.
      • Orantes C.M.
      • Almaguer M.
      • et al.
      Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.
      • Wijkström J.
      • Leiva R.
      • Elinder C.G.
      • et al.
      Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America.
      Other studies in the region have documented decreases in estimated glomerular filtration rates (eGFRs) and increases in kidney injury biomarkers in sugarcane workers during the harvest season.
      • Garcia-Trabanino R.
      • Jarquin E.
      • Wesseling C.
      • et al.
      Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador–a cross-shift study of workers at risk of Mesoamerican nephropathy.
      • Laws R.L.
      • Brooks D.R.
      • Amador J.J.
      • et al.
      Changes in kidney function among Nicaraguan sugarcane workers.
      • Laws R.L.
      • Brooks D.R.
      • Amador J.J.
      • et al.
      Biomarkers of kidney injury among Nicaraguan sugarcane workers.
      The unique clinical features of MeN and its relationship to endemic nephropathies in other parts of the world, such as North Central Sri Lanka and Southeastern India,
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.
      • Yaqub F.
      Kidney disease in farming communities remains a mystery.
      • Athuraliya N.T.
      • Abeysekera T.D.
      • Amerasinghe P.H.
      • et al.
      Uncertain etiologies of proteinuric-chronic kidney disease in rural Sri Lanka.
      • Nanayakkara S.
      • Komiya T.
      • Ratnatunga N.
      • et al.
      Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka.
      • Wernerson A.
      • Wijkström J.
      • Elinder C.G.
      Update on endemic nephropathies.
      remain hotly debated topics.
      • Chatterjee R.
      Occupational hazard.
      We examined a community in Northwestern Nicaragua where the prevalence of decreased kidney function in men has been reported to be as high as ∼40%.
      • Raines N.
      • Gonzalez M.
      • Wyatt C.
      • et al.
      Risk factors for reduced glomerular filtration rate in a Nicaraguan community affected by Mesoamerican nephropathy.
      Anecdotal reports have suggested the presence of families decimated by CKD. We identified 24 families with a range of 3 to 24 affected members. We characterized individuals with and without CKD from these severely affected families to gain insight into the distinguishing features of MeN. We then compared patients with MeN with NHANES (National Health and Nutrition Examination Survey) participants with CKD to identify differences between MeN and more common kidney diseases.

      Methods

      Recruitment

      The study protocol was approved by the institutional review boards at the Nicaraguan Ministry of Health and Boston University Medical Center (institutional review board approval numbers provided in Item S1, available as online supplementary material). All participants provided written informed consent. Nicaraguan patients with CKD were identified through community-based recruitment. Specifically, we recruited potential participants through a local organization of former sugarcane workers with kidney disease. Recruitment tools included informational posters, announcements made by the association leadership, and recruitment visits to the association headquarters. Volunteers with CKD who reported at least 1 relative with CKD were investigated as potential probands. If the volunteer met inclusion criteria, permission was requested to contact their relatives. Initial contact was made by telephone or home visits. For individuals who agreed to participate, sample collection and interviews were done at their homes. Participants were enrolled from February 2014 through May 2015. For enrollment of a family, the proband and one first-degree relative were required to be 18 to 60 years old with a serum creatinine level ≥ 1.5 mg/dL for men or ≥1.4 mg/dL for women, based on medical records or point-of-care testing at enrollment. Exclusion criteria for the proband and first affected relative were history of diabetes or fingerstick glucose level > 200 mg/dL and history of hepatitis B or C, HIV (human immunodeficiency virus), or polycystic kidney disease. After inclusion of a family based on these criteria, the only requirement for enrollment of other family members was age 18 years or older.
      Details of sample collection, clinical testing, ascertainment of clinical and demographic characteristics, and the NHANES comparison group are described in Item S1.

      Data Analysis

      Participant characteristics were compared using linear regression for normally distributed continuous variables, Somers D test for non-normal continuous variables, and logistic regression for categorical variables. These analyses all accounted for clustering by family and used a significance level of α = 0.05. For comparison of Nicaraguan patients to NHANES participants, sample weights were used to generate estimates for the NHANES group. Six-year sample weights were created by taking one-third of the 2-year mobile examination center weight (“wtmec2yr”) for each cycle. Multivariable linear mixed-effects regression models were used to assess differences in uric acid levels between patients with MeN and NHANES participants with CKD, adjusting for eGFR and age. These mixed-effects models used family as a random effect, and NHANES participants were each given a unique family identifier. In the second model, the regression analysis was repeated after adjustment for use of uric acid−lowering medications. Sensitivity analyses were performed with subgroups restricted by age, diabetes status, and ethnicity. Analyses were performed using Stata, version 12.1 (StataCorp LP; see Item S1 for further details). Figure 1 was made in R (version 3.3.1) using the ggplot2 package.
      Figure thumbnail gr1
      Figure 1Scatterplot of uric acid levels by estimated glomerular filtration rate for men with chronic kidney disease (defined as serum creatinine ≥ 1.5 mg/dL) in Nicaragua and NHANES (National Health and Nutrition Examination Survey). Individual participants are denoted by triangles (Nicaragua) and circles (NHANES). Lines shown for each group were generated by unadjusted linear regression.

      Results

      Study Population

      We analyzed 266 individuals (178 men and 88 women) from 24 families in a community in the Nicaraguan department of Chinandega. Men and women were considered to have CKD if serum creatinine level was ≥1.5 and ≥1.4 mg/dL, respectively. We used creatinine rather than eGFR cutoffs because the local sugarcane company, which employs a large fraction of the community’s workforce, uses creatinine level to screen workers for kidney disease, and values above these thresholds preclude hiring. These relatively high creatinine level thresholds also increase the specificity of our case definition by minimizing the inclusion of individuals with transient mild creatinine level elevations as CKD cases. After excluding 3 individuals on dialysis therapy, 99 men and 8 women met the case definition. Assigning CKD status based on eGFR < 60 mL/min/1.73 m2 rather than creatinine level gave very similar results, reclassifying 4 men and 5 women as affected and 2 men as not affected (Table S1). Median eGFR in the group of 99 men with CKD was 30 mL/min/1.73 m2, whereas the corresponding value for the 8 affected women was 28 mL/min/1.73 m2 (Table 1).
      Table 1Clinical Characteristics and Kidney Disease Risk Factors for the Nicaraguan Group Stratified by Sex and CKD Status
      Men (n = 178)Women (n = 88)
      Non-CKD (n = 79)CKD (n = 99)P
      P values are for differences in a given parameter between patients with and without CKD for each sex. P values were calculated using linear regression accounting for clustering by family for normally distributed continuous variables, Somers D test accounting for clustering by family for non-normal continuous variables, and logistic regression accounting for clustering by family for categorical variables.
      Non-CKD (n = 80)CKD (n = 8)P
      P values are for differences in a given parameter between patients with and without CKD for each sex. P values were calculated using linear regression accounting for clustering by family for normally distributed continuous variables, Somers D test accounting for clustering by family for non-normal continuous variables, and logistic regression accounting for clustering by family for categorical variables.
      Serum creatinine, mg/dL1.0 [0.9-1.2]2.6 [1.9-4.0]<0.0010.7 [0.6-0.8]2.1 [1.6-3.0]<0.001
      eGFR, mL/min/1.73m291 [73-110]30 [18-45]<0.001104 [90-119]28 [16-34]<0.001
      Age, y33 [24-47]36 [29-48]0.243 [29-55]57 [44-71]0.07
      Past or present work in sugarcane industry75 (95)97 (98)0.240 (50)5 (63)0.8
      Diabetes3 (4)7 (7)
      Prevalence of diabetes in the group of 99 men with CKD. Because history of diabetes or fingerstick glucose level > 200mg/dL were exclusion criteria for some, but not all, participants (see “Recruitment” section of Methods), we also calculated the prevalence of diabetes in men with CKD after excluding participants who could not have diabetes by study design: this prevalence was 6 of 67 (9.0%; P=0.2 for comparison with men without CKD).
      0.36 (8)0 (0)NA
      Unable to calculate P value due to zero value in one category.
      BMI, kg/m223.7 ± 4.6; n = 5124.1 ± 3.9; n = 610.627.0 ± 5.9; n = 25n = 0NA
      Unable to calculate P value due to n = 0.
      Hypertension18 (23)45 (45)<0.00118 (23)5 (63)0.04
      Urine protein ≥ 2+3 (4); n = 7428 (29); n = 97<0.0010; n = 761 (14.3); n = 7NA
      Unable to calculate P value due to zero value in one category.
      Report of prior CKD diagnosis22 (28)94 (95)<0.0017 (9)3 (38)0.03
      NSAID use25 (32)41 (41)0.349 (61)4 (50)0.5
      Dysuria38 (48)34 (35); n = 980.247 (59)3 (38)0.3
      Note: Values for categorical variables are given as count (percentage); values for continuous variables are given as mean ± standard deviation if normally distributed or median [interquartile range] if non-normally distributed. Conversion factor for serum creatinine in mg/dL to μmol/L, ×88.4.
      Abbreviations: BMI, body mass index; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; NA, not applicable; NSAID, nonsteroidal anti-inflammatory drug.
      a P values are for differences in a given parameter between patients with and without CKD for each sex. P values were calculated using linear regression accounting for clustering by family for normally distributed continuous variables, Somers D test accounting for clustering by family for non-normal continuous variables, and logistic regression accounting for clustering by family for categorical variables.
      b Prevalence of diabetes in the group of 99 men with CKD. Because history of diabetes or fingerstick glucose level > 200 mg/dL were exclusion criteria for some, but not all, participants (see “Recruitment” section of Methods), we also calculated the prevalence of diabetes in men with CKD after excluding participants who could not have diabetes by study design: this prevalence was 6 of 67 (9.0%; P = 0.2 for comparison with men without CKD).
      c Unable to calculate P value due to zero value in one category.
      d Unable to calculate P value due to n = 0.

      Clinical Characteristics and CKD Risk Factors

      Male study participants had a median age in the mid-30s, whereas women were generally older. As expected for this region, work in sugarcane agriculture was very common, with almost all men and about half the women reporting past or present work in this industry, nearly all as field workers. Reported prevalences of diabetes and obesity were low (Table 1). Random glucose levels were >180 mg/dL in 4 (2.2%) men and 6 (7%) women. Of these 10 individuals, 3 had CKD and 6 did not report a diabetes diagnosis. Hypertension was more common in individuals with CKD. There were 29% of male patients with CKD who had proteinuria ≥ 2+ compared to 4% of those without CKD (P < 0.001).
      Almost all men who met study CKD criteria reported having had CKD previously diagnosed, but surprisingly, 28% of men not meeting our CKD criteria also reported receiving a prior CKD diagnosis (Table 1). All 22 individuals in this group had been sugarcane workers. They had a median creatinine level of 1.3 mg/dL and eGFR of 71 mL/min/1.73 m2; by contrast, the 57 men who did not meet study criteria for CKD and reported no history of CKD had a median creatinine level of 0.9 mg/dL and eGFR of 105 mL/min/1.73 m2 (P < 0.001). Table S2 presents a detailed comparison between these subgroups.

      Electrolytes

      In both the male and female CKD groups, mean serum sodium and potassium levels were 139 and 4.5 mmol/L, respectively (Table 2). Hyponatremia (sodium < 135 mmol/L) was present in 11 (11%) men with CKD, whereas hypokalemia (potassium < 3.5 mmol/L) was found in 8 (8%) men and 1 (13%) woman with CKD. There were no significant differences in mean magnesium levels by CKD status. There were 23 (25%) men with CKD who had hypomagnesemia (magnesium < 1.7 mg/dL).
      Table 2Selected Laboratory Values for the Nicaraguan Group Stratified by Sex and CKD Status
      Men (n = 178)Women (n = 88)
      Non-CKD (n = 79)CKD (n = 99)P
      P values are for differences in a given parameter between patients with and without CKD for each sex. P values were calculated using linear regression accounting for clustering by family for normally distributed continuous variables, Somers D test accounting for clustering by family for non-normal continuous variables, and logistic regression accounting for clustering by family for categorical variables.
      Non-CKD (n = 80)CKD (n = 8)P
      P values are for differences in a given parameter between patients with and without CKD for each sex. P values were calculated using linear regression accounting for clustering by family for normally distributed continuous variables, Somers D test accounting for clustering by family for non-normal continuous variables, and logistic regression accounting for clustering by family for categorical variables.
      Sodium, mmol/L139 ± 3; n = 78139 ± 4; n = 980.3140 ± 3139 ± 30.4
      Potassium, mmol/L4.2 ± 0.6; n = 784.5 ± 0.9; n = 980.0054.4 ± 0.64.5 ± 0.80.8
      Bicarbonate or total CO2, mmol/L24 ± 3; n = 6421 ± 3; n = 83<0.00123 ± 2; n = 7021 ± 4; n = 50.2
      SUN, mg/dL12 [10-15]24 [18-34]<0.0019 [7-11]19 [17-27]<0.001
      Glucose, mg/dL96 [84-108]95 [85-106]
      Median serum glucose in the group of 99 men with CKD. Because history of diabetes or fingerstick glucose level > 200mg/dL were exclusion criteria for some, but not all, individuals (see “Recruitment” section of Methods), we also calculated median serum glucose level in men with CKD after excluding participants who could not have diabetes by study design: this was 97 [IQR, 88-110] mg/dL (n=67; P=0.4 for comparison with men without CKD).
      0.997 [87-114]94 [86-101]
      Median serum glucose level in the group of 8 women with CKD. After excluding participants who could not have diabetes by study design, this value was 94 [IQR, 83, 101] mg/dL (n=7; P=0.4 for comparison with women without CKD).
      0.4
      Calcium, mg/dL9.3 ± 0.4; n = 769.0 ± 0.7; n = 920.0039.3 ± 0.4; n = 728.9 ± 0.6; (n = 7)0.2
      Magnesium, mg/dL2.0 ± 0.2; n = 761.9 ± 0.3; n = 920.32.1 ± 0.1; n = 722.1 ± 0.2; n = 60.9
      Phosphorus, mg/dL3.7 ± 0.7; n = 713.7 ± 0.8; n = 850.63.8 ± 0.6; n = 724.2 ± 1.3; n = 50.5
      Albumin, g/dL4.1 ± 0.3; n = 763.9 ± 0.4; n = 920.023.9 ± 0.3; n = 723.8 ± 0.7; n = 70.8
      Uric acid, mg/dL6.5 ± 1.6; n = 769.6 ± 2.2; n = 92<0.0014.7 ± 1.2; n = 728.0 ± 0.9; n = 7<0.001
      Allopurinol use14 (18)71 (72)<0.0013 (4)1 (13)0.3
      Hemoglobin, g/dL13.8 ± 1.4; n = 6411.5 ± 1.5; n = 84<0.00112.6 ± 1.1; n = 7010.3 ± 2.6; n = 50.06
      Note: Values for categorical variables are given as count (percentage); values for continuous variables are given as mean ± standard deviation if normally distributed or median [IQR] if non-normally distributed. Conversion factors for units: calcium in mg/dL to mmol/L, ×0.2495; creatinine in mg/dL to μmol/L, ×88.4; glucose in mg/dL to mmol/L, ×0.05551; phosphorus in mg/dL to mmol/L, ×0.3229; SUN in mg/dL to mmol/L, ×0.357; uric acid in mg/dL to μmol/L, ×59.48.
      Abbreviations: CKD, chronic kidney disease; CO2, carbon dioxide; IQR, interquartile range; SUN, serum urea nitrogen.
      a P values are for differences in a given parameter between patients with and without CKD for each sex. P values were calculated using linear regression accounting for clustering by family for normally distributed continuous variables, Somers D test accounting for clustering by family for non-normal continuous variables, and logistic regression accounting for clustering by family for categorical variables.
      b Median serum glucose in the group of 99 men with CKD. Because history of diabetes or fingerstick glucose level > 200 mg/dL were exclusion criteria for some, but not all, individuals (see “Recruitment” section of Methods), we also calculated median serum glucose level in men with CKD after excluding participants who could not have diabetes by study design: this was 97 [IQR, 88-110] mg/dL (n = 67; P = 0.4 for comparison with men without CKD).
      c Median serum glucose level in the group of 8 women with CKD. After excluding participants who could not have diabetes by study design, this value was 94 [IQR, 83, 101] mg/dL (n = 7; P = 0.4 for comparison with women without CKD).

      Uric Acid

      Uric acid levels were markedly higher in patients with CKD compared with individuals without CKD, in both men (mean, 9.6 vs 6.5 mg/dL; P < 0.001) and women (mean, 8.0 vs 4.7 mg/dL; P < 0.001; Table 2). It is particularly notable that men with CKD had this degree of hyperuricemia despite the fact that 72% of them were prescribed allopurinol. There were 40 (44%) men with CKD who had uric acid levels > 10 mg/dL, and 14 (15%) of them had levels > 12 mg/dL. Among individuals who did not meet the CKD case definition, uric acid levels were higher in those who had previously received a CKD diagnosis compared with those who had not (7.2 vs 6.2 mg/dL; P = 0.02; Table S2). In both the CKD and non-CKD groups, individuals receiving allopurinol had lower eGFRs than those who were not prescribed allopurinol (Table S3).

      Biochemical Sequelae of CKD and Other Laboratory Values

      Total serum calcium levels were lower in patients with CKD, who also had slightly lower albumin concentrations, a difference that was significant in men. Mean phosphorus levels did not differ by CKD status. Serum phosphorus level > 4.5 mg/dL was present in 12 (13%) individuals with CKD (11 men and 1 woman). There were no systematic abnormalities in liver biochemical test or thyroid function results. These and other laboratory parameters are shown in Tables 2 and S4.

      Comparison of Nicaraguan and NHANES CKD Patients

      Because MeN is a novel disease entity that has not been extensively characterized in large groups of patients, we compared clinical and biochemical characteristics of our patients with CKD with those of a representative group of individuals in the United States with kidney disease, using data from NHANES. Because most Nicaraguan participants with CKD were men, we restricted these analyses to men. Of 8,091 adult male participants from the 2007 to 2012 NHANES cycles, 279 had a serum creatinine level ≥ 1.5 mg/dL. We excluded 26 individuals who had received dialysis in the previous year and compared the remaining 253 participants with our 99 Nicaraguan male patients with CKD (Table 3). NHANES participants were older (median age, 74 vs 36 years) and had higher prevalences of diabetes (36.9% vs 7%), hypertension (68.8% vs 45%), and obesity (average body mass index, 29.2 vs 24.1 kg/m2). Nicaraguan patients had lower eGFRs (median, 30 vs 41 mL/min/1.73 m2).
      Table 3Clinical Characteristics and Kidney Disease Risk Factors of Men With CKD, Comparing Nicaraguan and NHANES Groups
      Nicaraguan Men With CKD (n = 99)NHANES Men With CKD (n = 253)
      Age, y36 [29-48]74 [61-80]
      Diabetes7%36.9% (29.3%-44.6%)
      Hypertension45%68.8% (61.2%-76.5%)
      Prior diagnosis of CKD95%32.5% (25.1%-39.9%)
      BMI, kg/m224.1 ± 3.9; n = 6129.2 (28.5-30.0) ± 7.4
      Serum creatinine, mg/dL2.6 [1.9-4.0]1.7 [1.6-2.0]
      eGFR, mL/min/1.73 m230 [18-45]41 [32-47]
      NSAID use41%5.3% (1.7%-8.9%)
      Note: For the Nicaraguan group, values for categorical variables are given as percentage; values for continuous variables are given as mean ± standard deviation if normally distributed or median [IQR] if non-normally distributed. For the NHANES group, values for categorical values are given as percentage (95% CI of percentage); values for continuous variables are given as mean (95% CI of mean) ± standard deviation if normally distributed and as median [IQR] if non-normally distributed. Conversion factor for serum creatinine in mg/dL to μmol/L, ×88.4.
      Abbreviations: BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; IQR, interquartile range; NHANES, National Health and Nutrition Examination Survey; NSAID, nonsteroidal anti-inflammatory drug.
      Table 4 compares selected laboratory parameters between the Nicaraguan and NHANES CKD groups. Serum sodium and potassium concentrations were similar. Uric acid levels were higher in Nicaraguan individuals (mean, 9.6 vs 7.4 mg/dL), despite the fact that more Nicaraguan patients were on uric acid–lowering therapy (72% vs 11.2%). Furthermore, 41.0% of NHANES participants used diuretics, which tend to elevate serum uric acid levels. Data for diuretic use in Nicaragua were not available.
      Table 4Select Laboratory Values in Men With CKD, Comparing Nicaraguan and NHANES Groups
      Nicaraguan Men With CKD (n = 99)NHANES Men With CKD (n = 253)
      Sodium, mmol/L139 ± 4; n = 98140 (139-140) ± 3
      Potassium, mmol/L4.5 ± 0.9; n = 984.3 (4.2-4.4) ± 0.7
      Bicarbonate or total CO2, mmol/L21 ± 3; n = 8324.2 (23.7-24.8) ± 3.9
      SUN, mg/dL24 [18-34]27 [20-34]
      Glucose, mg/dL95 [85-106]96 [89-127]
      Calcium, mg/dL9.0 ± 0.7; n = 929.3 (9.3-9.4) ± 0.6
      Phosphorus, mg/dL3.7 ± 0.8; n = 853.8 (3.7-3.9) ± 0.9
      Albumin, g/dL3.9 ± 0.44.1 (4.0-4.2) ± 0.5
      Uric acid, mg/dL9.6 ± 2.2; n = 927.4 (7.1-7.7) ± 2.4
      Use of uric acid–lowering medication
      Allopurinol in Nicaraguan participants, allopurinol or febuxostat in NHANES participants.
      72%11.2% (7.4%-14.9%)
      Diuretic useNot available41.0% (31.1%-50.9%)
      Hemoglobin, g/dL11.5 ± 1.5; n = 8413.4 (13.1-13.7) ± 2.3
      Note: For the Nicaraguan group, values for categorical variables are given as percentage; values for continuous variables are given as mean ± standard deviation if normally distributed or median [IQR] if non-normally distributed. For the NHANES group, values for categorical values are given as percentage (95% CI of percentage); values for continuous variables are given as mean (95% CI of mean) ± standard deviation if normally distributed and as median [IQR] if non-normally distributed. Conversion factors for units: calcium in mg/dL to mmol/L, ×0.2495; creatinine in mg/dL to μmol/L, ×88.4; glucose in mg/dL to mmol/L, ×0.05551; phosphorus in mg/dL to mmol/L, ×0.3229; SUN in mg/dL to mmol/L, ×0.357; uric acid in mg/dL to μmol/L, ×59.48.
      Abbreviations: CI, confidence interval; CKD, chronic kidney disease; CO2, carbon dioxide; IQR, interquartile range; NHANES, National Health and Nutrition Examination Survey; SUN, serum urea nitrogen.
      a Allopurinol in Nicaraguan participants, allopurinol or febuxostat in NHANES participants.

      Relationship Between Hyperuricemia and Decreased Kidney Function

      Given our striking findings of severe hyperuricemia in Nicaraguan patients with MeN, we sought to determine whether the degree of uric acid elevation is disproportionate to the severity of their decrease in kidney function. We compared the relationship of serum uric acid level and eGFR between men with CKD in NHANES and patients with MeN from our study (Fig 1). Multivariable linear mixed-effects regression analysis (accounting for family clustering in Nicaraguans) showed that after adjustment for eGFR and age, uric acid levels were higher on average by 1.2 (95% confidence interval [CI], 0.3-2.0) mg/dL in Nicaraguan men with CKD compared with men with CKD in NHANES (P = 0.006). There was no significant effect modification of eGFR on uric acid levels by group status (Nicaragua vs NHANES; P for interaction = 0.1). When use of uric acid–lowering therapy was added to the model, uric acid levels in Nicaraguan patients were higher on average by 2.0 (95% CI, 1.0-3.0) mg/dL (P < 0.001).
      The presence of diabetes has been associated with decreases in uric acid levels.
      • Herman J.B.
      • Mount F.W.
      • Medalie J.H.
      • et al.
      Diabetes prevalence and serum uric acid.
      • Shichiri M.
      • Iwamoto H.
      • Shiigai T.
      Diabetic renal hypouricemia.
      Because diabetes was common among NHANES participants in our comparison group, we performed a sensitivity analysis restricted to nondiabetic individuals and obtained similar results. In the model adjusted for eGFR and age, uric acid levels were higher by an average of 0.9 (95% CI, 0.0-1.9) mg/dL (P = 0.05) in Nicaraguan men; this estimate increased to 2.0 (95% CI, 0.8-3.2) mg/dL (P = 0.001) when hypouricemic therapies were also considered. These results and those of sensitivity analyses with other subgroups of NHANES participants (including younger individuals and Hispanics) are presented in Table 5. Tables S5 and S6 describe these subgroups in detail.
      Table 5Uric Acid Levels in Men With CKD, Comparing Nicaraguan and NHANES Groups
      All With CKDWith CKD and Without DMAge ≤ 65 y With CKDAge ≤ 65 y With CKD and Without DMHispanic With CKD
      No. of participants
       MeN9287898592
       NHANES253143623930
      Model 1, difference vs NHANES
      Model parameters for each outcome include group, age, and eGFR.
       MeN1.2 (0.3 to 2.0); P = 0.0060.9 (0.0 to 1.9); P = 0.050.7 (−0.2 to 1.6); P = 0.10.7 (−0.2 to 1.7); P = 0.10.8 (−0.5 to 2.0); P = 0.2
      Model 2
      Model parameters for each outcome include group, age, eGFR, and use of medications that lower uric acid levels.
      , difference vs NHANES
       MeN2.0 (1.0 to 3.0); P < 0.0012.0 (0.8 to 3.2); P = 0.0011.1 (−0.04 to 2.3); P = 0.061.2 (−0.1 to 2.6); P = 0.071.3 (−0.2 to 2.9); P = 0.1
      Note: Average difference in serum uric acid levels (95% CI) in mg/dL between patients with MeN and NHANES participants, restricted as indicated at the top of each column. Estimates were generated using multivariable linear mixed-effects regression analysis, accounting for family clustering in the Nicaraguan group.
      Abbreviations: CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; MeN, Mesoamerican nephropathy; NHANES, National Health and Nutrition Examination Survey.
      a Model parameters for each outcome include group, age, and eGFR.
      b Model parameters for each outcome include group, age, eGFR, and use of medications that lower uric acid levels.

      Discussion

      Despite the devastating impact of MeN, surprisingly little is known about the clinical features of this disease. Our study presents an extensive characterization of MeN in one of the most severely affected regions of Central America.
      Consistent with prior descriptions of MeN, our patients were young and had low prevalences of diabetes, obesity, and proteinuria.
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.
      • O'Donnell J.K.
      • Tobey M.
      • Weiner D.E.
      • et al.
      Prevalence of and risk factors for chronic kidney disease in rural Nicaragua.
      • Raines N.
      • Gonzalez M.
      • Wyatt C.
      • et al.
      Risk factors for reduced glomerular filtration rate in a Nicaraguan community affected by Mesoamerican nephropathy.
      • Peraza S.
      • Wesseling C.
      • Aragon A.
      • et al.
      Decreased kidney function among agricultural workers in El Salvador.
      • Torres C.
      • Aragon A.
      • Gonzalez M.
      • et al.
      Decreased kidney function of unknown cause in Nicaragua: a community-based survey.
      • Orantes C.M.
      • Herrera R.
      • Almaguer M.
      • et al.
      Epidemiology of chronic kidney disease in adults of Salvadoran agricultural communities.
      • Herrera R.
      • Orantes C.M.
      • Almaguer M.
      • et al.
      Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.
      Sugarcane agriculture is the main source of economic activity in this area of Nicaragua, and a history of work in this industry was common among the CKD and non-CKD groups in our study. An epidemiologic association between kidney disease and sugarcane work has been well established,
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.
      • Raines N.
      • Gonzalez M.
      • Wyatt C.
      • et al.
      Risk factors for reduced glomerular filtration rate in a Nicaraguan community affected by Mesoamerican nephropathy.
      • Peraza S.
      • Wesseling C.
      • Aragon A.
      • et al.
      Decreased kidney function among agricultural workers in El Salvador.
      • Torres C.
      • Aragon A.
      • Gonzalez M.
      • et al.
      Decreased kidney function of unknown cause in Nicaragua: a community-based survey.
      • Sanoff S.L.
      • Callejas L.
      • Alonso C.D.
      • et al.
      Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua.
      and occupational factors are strongly suspected to contribute to disease pathophysiology.
      • 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.
      • Garcia-Trabanino R.
      • Jarquin E.
      • Wesseling C.
      • et al.
      Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador–a cross-shift study of workers at risk of Mesoamerican nephropathy.
      • Paula Santos U.
      • Zanetta D.M.
      • Terra-Filho M.
      • Burdmann E.A.
      Burnt sugarcane harvesting is associated with acute renal dysfunction.
      • Laws R.L.
      • Brooks D.R.
      • Amador J.J.
      • et al.
      Changes in kidney function among Nicaraguan sugarcane workers.
      • Laws R.L.
      • Brooks D.R.
      • Amador J.J.
      • et al.
      Biomarkers of kidney injury among Nicaraguan sugarcane workers.
      Use of nonsteroidal anti-inflammatory drugs, which has also been proposed as a contributing factor,
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.
      • Weiner D.E.
      • McClean M.D.
      • Kaufman J.S.
      • Brooks D.R.
      The Central American epidemic of CKD.
      • Johnson R.J.
      • Sanchez-Lozada L.G.
      Chronic kidney disease: Mesoamerican nephropathy–new clues to the cause.
      • Ramirez-Rubio O.
      • Brooks D.R.
      • Amador J.J.
      • Kaufman J.S.
      • Weiner D.E.
      • Scammell M.K.
      Chronic kidney disease in Nicaragua: a qualitative analysis of semi-structured interviews with physicians and pharmacists.
      • Wernerson A.
      • Wijkström J.
      • Elinder C.G.
      Update on endemic nephropathies.
      was frequent in men and women with and without CKD. Consistent with prior reports,
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.

      McClean M, Amador JJ, Laws R, et al. Biological Sampling Report: Investigating Biomarkers of Kidney Injury and Chronic Kidney Disease Among Workers in Western Nicaragua. 2012. http://www.cao-ombudsman.org/cases/document-links/documents/Biological_Sampling_Report_April_2012.pdf. Accessed August 3, 2016.

      • Ramirez-Rubio O.
      • Brooks D.R.
      • Amador J.J.
      • Kaufman J.S.
      • Weiner D.E.
      • Scammell M.K.
      Chronic kidney disease in Nicaragua: a qualitative analysis of semi-structured interviews with physicians and pharmacists.
      pain with urination was commonly reported, with no differences by CKD status. Although there is evidence that chistata is not explained by urinary tract infections,

      McClean M, Amador JJ, Laws R, et al. Biological Sampling Report: Investigating Biomarkers of Kidney Injury and Chronic Kidney Disease Among Workers in Western Nicaragua. 2012. http://www.cao-ombudsman.org/cases/document-links/documents/Biological_Sampling_Report_April_2012.pdf. Accessed August 3, 2016.

      some investigators hypothesize that it may be related to dehydration and heat stress and possibly reflects the presence of urine microcrystals and/or nephrolithiasis.
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.
      • Ramirez-Rubio O.
      • Brooks D.R.
      • Amador J.J.
      • Kaufman J.S.
      • Weiner D.E.
      • Scammell M.K.
      Chronic kidney disease in Nicaragua: a qualitative analysis of semi-structured interviews with physicians and pharmacists.
      • Roncal-Jimenez C.
      • Garcia-Trabanino R.
      • Barregard L.
      • et al.
      Heat stress nephropathy from exercise-induced uric acid crystalluria: a perspective on Mesoamerican nephropathy.
      Despite the increasing recognition of MeN as an urgent public health problem,
      • Ordunez P.
      • Martinez R.
      • Reveiz L.
      • et al.
      Chronic kidney disease epidemic in Central America: urgent public health action is needed amid causal uncertainty.
      our current knowledge of its characteristics is based on small numbers of patients. Wijkström et al
      • Wijkström J.
      • Leiva R.
      • Elinder C.G.
      • et al.
      Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America.
      studied 8 Salvadoran agricultural workers with CKD. In another study from El Salvador, Herrera et al
      • Herrera R.
      • Orantes C.M.
      • Almaguer M.
      • et al.
      Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.
      described 46 patients with CKD of unknown cause. These reports suggested hyponatremia, hypokalemia, and hyperuricemia to be common features of MeN. In our patients, hyponatremia and hypokalemia were less common and less severe. In the Wijkström et al study,
      • Wijkström J.
      • Leiva R.
      • Elinder C.G.
      • et al.
      Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America.
      serum sodium levels were <130 mEq/L in 2 individuals, and 3 had potassium levels < 3.0 mEq/L, raising suspicion that marked hypokalemia may contribute to tubulointerstitial fibrosis in MeN.
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.
      • Johnson R.J.
      • Sanchez-Lozada L.G.
      Chronic kidney disease: Mesoamerican nephropathy–new clues to the cause.
      In our study, only 10 (10%) participants with CKD had hyponatremia and 9 (9%) had hypokalemia. Sodium levels were <130 mEq/L in only 3 patients, and potassium level was <3.0 mEq/L in only one. However, our finding of hypomagnesemia in 25% of men with CKD is similar to data from Herrera et al.
      • Herrera R.
      • Orantes C.M.
      • Almaguer M.
      • et al.
      Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.
      Although the significance of this is unclear, the possibility of electrolyte wasting in the context of a tubular disorder remains intriguing and deserves further study.
      Markedly elevated uric acid levels represent our most striking finding and may support a role for uric acid in MeN pathogenesis.
      • Garcia-Trabanino R.
      • Jarquin E.
      • Wesseling C.
      • et al.
      Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador–a cross-shift study of workers at risk of Mesoamerican nephropathy.
      • Herrera R.
      • Orantes C.M.
      • Almaguer M.
      • et al.
      Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.
      • Wijkström J.
      • Leiva R.
      • Elinder C.G.
      • et al.
      Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America.
      • Roncal-Jimenez C.
      • Garcia-Trabanino R.
      • Barregard L.
      • et al.
      Heat stress nephropathy from exercise-induced uric acid crystalluria: a perspective on Mesoamerican nephropathy.
      As evidence of hyperuricemia in MeN has emerged, a question that has not been formally posed is whether uric acid levels are elevated beyond what would be expected due to impairment of uric acid excretion from a reduction in GFR. Comparing uric acid levels of patients with MeN with NHANES participants with CKD begins to explore this question. We show that, adjusting for age and eGFR, Nicaraguan patients have higher uric acid levels than American patients with CKD of “traditional” causes, by an average of 1.2 mg/dL. When use of uric acid–lowering medications is considered, this estimate increases to 2.0 mg/dL. Our results suggest that rather than being simply a consequence of a decrease in kidney function, hyperuricemia may play a causal role in this disease, or at least that uric acid handling is dysregulated by the same processes that damage tubules in MeN.
      In particular, significant overlap may exist between mechanisms of hyperuricemia and pathophysiologic processes associated with severe volume depletion, which has been proposed to cause CKD due to repeated AKI episodes.
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.
      • Wesseling C.
      • Crowe J.
      • Hogstedt C.
      • et al.
      Resolving the enigma of the Mesoamerican nephropathy: a research workshop summary.
      • Johnson R.J.
      • Sanchez-Lozada L.G.
      Chronic kidney disease: Mesoamerican nephropathy–new clues to the cause.
      • Wernerson A.
      • Wijkström J.
      • Elinder C.G.
      Update on endemic nephropathies.
      • Roncal Jimenez C.A.
      • Ishimoto T.
      • Lanaspa M.A.
      • et al.
      Fructokinase activity mediates dehydration-induced renal injury.
      Consistent with that hypothesis, a significant increase in mean serum creatinine level was found in Salvadoran
      • Garcia-Trabanino R.
      • Jarquin E.
      • Wesseling C.
      • et al.
      Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador–a cross-shift study of workers at risk of Mesoamerican nephropathy.
      and Brazilian
      • Paula Santos U.
      • Zanetta D.M.
      • Terra-Filho M.
      • Burdmann E.A.
      Burnt sugarcane harvesting is associated with acute renal dysfunction.
      sugarcane cutters after a day of work. A parallel increase in creatine kinase levels found in the latter study
      • Paula Santos U.
      • Zanetta D.M.
      • Terra-Filho M.
      • Burdmann E.A.
      Burnt sugarcane harvesting is associated with acute renal dysfunction.
      suggests that pigment-induced injury may compound damage caused by hypovolemia. Uric acid overproduction due to muscle cell injury may accompany AKI, potentially contributing to the observed increase in uric acid levels in the Salvadoran workers after a cane-cutting shift.
      • Garcia-Trabanino R.
      • Jarquin E.
      • Wesseling C.
      • et al.
      Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador–a cross-shift study of workers at risk of Mesoamerican nephropathy.
      Urate crystals were found in some workers’ urine, and it has been proposed that such crystals may cause tubular injury.
      • Garcia-Trabanino R.
      • Jarquin E.
      • Wesseling C.
      • et al.
      Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador–a cross-shift study of workers at risk of Mesoamerican nephropathy.
      • Roncal-Jimenez C.
      • Garcia-Trabanino R.
      • Barregard L.
      • et al.
      Heat stress nephropathy from exercise-induced uric acid crystalluria: a perspective on Mesoamerican nephropathy.
      The specific mechanisms involved and whether there is any relationship to chistata remain to be clarified.
      Another potential explanation linking volume depletion, hyperuricemia, and progressive CKD is dehydration-induced activation of the renal polyol pathway with subsequent fructose generation. Metabolism of fructose by fructokinase may lead to uric acid production, inflammation, and oxidative stress.
      • Johnson R.J.
      • Rodriguez-Iturbe B.
      • Roncal-Jimenez C.
      • et al.
      Hyperosmolarity drives hypertension and CKD–water and salt revisited.
      Although support for this hypothesis exists in animal models of repetitive dehydration and other kidney diseases,
      • Roncal Jimenez C.A.
      • Ishimoto T.
      • Lanaspa M.A.
      • et al.
      Fructokinase activity mediates dehydration-induced renal injury.
      • Johnson R.J.
      • Rodriguez-Iturbe B.
      • Roncal-Jimenez C.
      • et al.
      Hyperosmolarity drives hypertension and CKD–water and salt revisited.
      • Johnson R.J.
      • Nakagawa T.
      • Jalal D.
      • Sanchez-Lozada L.G.
      • Kang D.H.
      • Ritz E.
      Uric acid and chronic kidney disease: which is chasing which?.
      data for humans are not yet available.
      A better understanding of the relationship between hyperuricemia and kidney disease has relevance beyond the Central American CKD epidemic. A vigorous debate is ongoing about the role of uric acid in the pathophysiology of CKD in general and its effect on kidney disease and cardiovascular outcomes.
      • Johnson R.J.
      • Nakagawa T.
      • Jalal D.
      • Sanchez-Lozada L.G.
      • Kang D.H.
      • Ritz E.
      Uric acid and chronic kidney disease: which is chasing which?.
      • Jalal D.I.
      • Chonchol M.
      • Chen W.
      • Targher G.
      Uric acid as a target of therapy in CKD.
      • Levy G.
      • Cheetham T.C.
      Is it time to start treating asymptomatic hyperuricemia?.
      Some studies have suggested that uric acid–lowering therapy may slow CKD progression.
      • Siu Y.P.
      • Leung K.T.
      • Tong M.K.
      • Kwan T.H.
      Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.
      • Goicoechea M.
      • de Vinuesa S.G.
      • Verdalles U.
      • et al.
      Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.
      • Goicoechea M.
      • Garcia de Vinuesa S.
      • Verdalles U.
      • et al.
      Allopurinol and progression of CKD and cardiovascular events: long-term follow-up of a randomized clinical trial.
      Most recently, a double-blind placebo-controlled trial of febuxostat in patients with CKD stages 3 to 4 and asymptomatic hyperuricemia found that during a 6-month follow-up, more patients in the placebo group had a >10% eGFR decline compared to the febuxostat group.
      • Sircar D.
      • Chatterjee S.
      • Waikhom R.
      • et al.
      Efficacy of febuxostat for slowing the GFR decline in patients with CKD and asymptomatic hyperuricemia: a 6-month, double-blind, randomized, placebo-controlled trial.
      Furthermore, some Mendelian randomization studies have suggested a causal role for uric acid in kidney disease
      • Testa A.
      • Mallamaci F.
      • Spoto B.
      • et al.
      Association of a polymorphism in a gene encoding a urate transporter with CKD progression.
      and cardiovascular
      • Kleber M.E.
      • Delgado G.
      • Grammer T.B.
      • et al.
      Uric acid and cardiovascular events: a mendelian randomization study.
      outcomes.
      It has been suggested that repetitive episodes of dehydration cause low-grade or subclinical kidney injury, which eventually leads to a progressive chronic decline in kidney function.
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.
      • Wesseling C.
      • Crowe J.
      • Hogstedt C.
      • et al.
      Resolving the enigma of the Mesoamerican nephropathy: a research workshop summary.
      • Laws R.L.
      • Brooks D.R.
      • Amador J.J.
      • et al.
      Biomarkers of kidney injury among Nicaraguan sugarcane workers.
      • Roncal Jimenez C.A.
      • Ishimoto T.
      • Lanaspa M.A.
      • et al.
      Fructokinase activity mediates dehydration-induced renal injury.
      Our finding that some individuals previously deemed ineligible to work due to CKD had apparent improvements in kidney function raises the possibility that decreased GFRs in workers diagnosed with CKD may have an acute component in some cases. Furthermore, some episodes of work-related AKI may be more severe and longer lasting than previously thought, suggesting that the distinction between CKD and prolonged AKI may not be well defined in this setting. Our findings also underscore the fact that little is known about the natural history of MeN and the risk factors for progression from subclinical injury to overt kidney disease. Individual susceptibility to kidney injury and capacity for recovery may be important factors influencing disease initiation and progression.
      An accumulating body of evidence shows that AKI is an important risk factor for CKD in several contexts,
      • Venkatachalam M.A.
      • Griffin K.A.
      • Lan R.
      • Geng H.
      • Saikumar P.
      • Bidani A.K.
      Acute kidney injury: a springboard for progression in chronic kidney disease.
      • Venkatachalam M.A.
      • Weinberg J.M.
      • Kriz W.
      • Bidani A.K.
      Failed tubule recovery, AKI-CKD transition, and kidney disease progression.
      • Chawla L.S.
      • Eggers P.W.
      • Star R.A.
      • Kimmel P.L.
      Acute kidney injury and chronic kidney disease as interconnected syndromes.
      • Hsu C.Y.
      Yes, AKI truly leads to CKD.
      including patients with normal baseline kidney function
      • Coca S.G.
      • Singanamala S.
      • Parikh C.R.
      Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis.
      • Bucaloiu I.D.
      • Kirchner H.L.
      • Norfolk E.R.
      • Hartle 2nd, J.E.
      • Perkins R.M.
      Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury.
      and children without cardiovascular disease or diabetes.
      • Chawla L.S.
      • Eggers P.W.
      • Star R.A.
      • Kimmel P.L.
      Acute kidney injury and chronic kidney disease as interconnected syndromes.
      • Askenazi D.J.
      • Feig D.I.
      • Graham N.M.
      • Hui-Stickle S.
      • Goldstein S.L.
      3-5 Year longitudinal follow-up of pediatric patients after acute renal failure.
      • Goldstein S.L.
      Acute kidney injury in children and its potential consequences in adulthood.
      Research on the AKI-CKD connection has focused on acute tubular necrosis and dialysis-requiring AKI.
      • Hsu C.Y.
      Yes, AKI truly leads to CKD.
      Whether permanent kidney damage can be caused by repetitive volume depletion has not generally been explored. Although our current data are not sufficient for a complete and rigorous study of these issues and random variation in creatinine levels may explain some of our observations, the possibility that episodes of overt, clinically significant AKI may be frequent in a group of sugarcane workers with very high CKD burden is provocative and deserves consideration in future studies to understand the natural history of MeN, and the connection between acute and chronic kidney disease in this setting.
      Our study provides the most extensive clinical and laboratory characterization of MeN in Nicaragua to date. Its larger size compared with prior reports
      • Herrera R.
      • Orantes C.M.
      • Almaguer M.
      • et al.
      Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.
      • Wijkström J.
      • Leiva R.
      • Elinder C.G.
      • et al.
      Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America.
      allows better understanding of the nature and frequency of electrolyte and other laboratory abnormalities, and our comparison to traditional CKD in NHANES participants begins to consider these findings in a broader context. Major differences in important characteristics between the Nicaraguan and NHANES groups (age distribution, ancestry, comorbid conditions, and case selection method) represent the most important limitation of our study. Although the contrasts between MeN and well-described kidney diseases of known causes are useful in highlighting the unique clinical features of MeN, we recognize the potential limitations associated with comparing specific aspects of diseases with fundamentally different pathophysiologies. For example, it is conceivable that dysregulation of uric acid handling in MeN may be related to tubulointerstitial injury through mechanisms that are common to primary tubular disorders rather than unique to MeN and are not shared with diseases of glomerular and/or vascular origin.
      Another limitation is the cross-sectional nature of our study. Specifically, the lack of longitudinal data precludes fulfillment of the strict definition of CKD (though many patients had well documented histories of elevated creatinine values in medical records) and assessment of disease progression. Confirmation of our findings suggesting that AKI may be common among sugarcane workers will also require studies with longitudinal follow-up.
      The manner in which our participants were identified constitutes both a strength and a limitation. Because the study was designed around finding familial clustering of disease, participants do not constitute a random sample of Nicaraguan patients with MeN, and it is likely that this single population does not represent the full spectrum of MeN. Conversely, the exceptionally high rates of disease in our population suggest an extreme phenotype on the MeN spectrum in which the principal characteristics of the disease may be most easily observed. This study represents an important step in efforts aimed at understanding the pathophysiology of this devastating disease and ultimately working to prevent it.

      Acknowledgements

      We thank all the members of the families who participated in this study.
      We greatly appreciate the support of the Centro Nacional de Diagnóstico y Referencia (CNDR) and the Nicaraguan Ministry of Health (MINSA) with storage, testing, and shipment of study samples. In particular, we thank Lic Martha Delgado (CNDR Director General), Dr Alberto Montoya, Lic Yara Saborio, Lic Leonel Pérez, Lic Carlos Morales, and Lic Juan López.
      At MINSA-SILAIS (Sistemas Locales de Atención Integral en Salud) Chinandega, we thank Drs Cruz Cano Díaz (Director General), Alejandro Paguagua, Sandra María Paz, and Eveling Mercado for support of our research.
      We thank Lic Alda Gabriela Amador and Dr Martha Pastora for work conducting interviews, as well as Ing Magaly Amador for work with data entry and analysis.
      Support: This work was supported by the Doris Duke Charitable Foundation (Dr Friedman is a recipient of the Clinical Scientist Development Award 2011035 ), a Satellite Healthcare Foundation Coplon Award, the Comité Nacional de Productores de Azúcar (CNPA), and funds from Beth Israel Deaconess Medical Center. Dr Kupferman was supported by the “Inherited Kidney Disease Training” grant from Genzyme Corporation ( 11784 ). This work was conducted with support from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102 ) and financial contributions from Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. The funders had no role in study design; collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.
      Financial Disclosure: The authors declare that they have no other relevant financial interests.
      Contributions: Research idea and study design: JK, JJA, MKS, MDM, DRB, DJF; data acquisition: JK, JJA, DLP, JLL, NVR; data analysis/interpretation: JK, JJA, KEL, RLL, DLP, ORR, JSK, JLL, DEW, KPV, MDM, DRB, DJF; statistical analysis: JK, KEL, RLL; supervision and mentorship: DRB, DJF. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. DRB and DJF take responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
      Peer Review: Evaluated by 3 external peer reviewers, a statistician, and the Acting Editor-in-Chief.

      Supplementary Material

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