Characterization of Mesoamerican Nephropathy in a Kidney Failure Hotspot in Nicaragua

Joseph Kupferman, MD; Juan José Amador, MD, MPH; Katherine E. Lynch, MD, SM; Rebecca L. Laws, PhD, MPH; Damaris López-Pilarte, MPH; Oriana Ramírez-Rubio, MD, MPH, PhD; James S. Kaufman, MD; Jorge Luis Lau, MD; Daniel E. Weiner, MD, MS; Ninoska Violeta Robles, BS; Karina P. Verma, BA; Madeleine K. Scammell, DSc; Michael D. McClean, ScD; Daniel R. Brooks, DSc; David J. Friedman, MD

Disclosures

Am J Kidney Dis. 2016;68(5):716-725. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

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.[1–4] 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.[3–7] 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.[8–10] Cases of CKD not explained by traditional risk factors have also been reported in Guatemala, Honduras, Costa Rica, Panama, and Southern Mexico.[4,7,11–13] 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,[11,14] the Nicaraguan departments of Chinandega and León,[3,15–17] and the Guanacaste province in Costa Rica.[7]

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[15,18,19] and agricultural work, particularly in sugarcane.[16–21] 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.[19,22] 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.[1–3,6,12,23–27]

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.[18,19,28–31] Some individuals have pyuria not explained by infection.[22,29] Discomfort with urination, locally known as "chistata," is commonly reported in the region; whether this symptom is related to MeN has not been established.[1,3,22,24] Small studies have reported hyponatremia, hypokalemia, and hyperuricemia among patients with MeN in El Salvador.[29,30] 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.[25,28,32] 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,[1,3,27,33–35] remain hotly debated topics.[36]

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%.[16] 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.

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