Investigation into the Epidemic of Unexplained Kidney Disease in Nicaragua: Understanding the Acute Clinical Scenario and Natural History of Disease in Mesoamerican Nephropathy.

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Project Summary: An epidemic of severe, unexplained kidney disease in mostly young agriculture workers emerged at least two decades ago in Central America. The epidemic now spans, geographically, from Mexico to Panama, causing premature mortality, predominantly affecting rural, impoverished communities. Mesoamerican nephropathy (MeN) has caused an excess of 20,000 deaths, yet its etiology remains a mystery, and traditional risk factors for kidney disease are not risk factors for MeN. The curious disease has been previously described as an asymptomatic, insidious chronic kidney disease (CKD) of unknown etiology that progresses rapidly to end stage renal disease and death. However, recent studies by Dr. Fischer and team in a Nicaraguan agriculture worker population reveal evidence of an acute clinical syndrome preceding CKD and described for the first time AKI and acute tubulointerstitial nephritis in MeN. They also observed aggressive progression to CKD in a subset (9%) of patients. The new, paradigm-shifting evidence about acute MeN suggests an early, yet brief, window for clinical recognition and intervention. It also implies that early clinical markers for severe disease could lead to targeted interventions. In this proposal, Dr. Fischer will build on this research by leading a clinical investigation into MeN in a broader and more diverse populations. Based on a growing understanding that MeN affects a broader community, including women children, than previously thought, she will conduct community-based disease surveillance and establish the first community cohort of acute MeN patients. The aims of the research are to validate a clinical case definition of acute MeN and describe the natural history of disease with the overall goal of increasing our clinical understanding of MeN to enable disease surveillance and to facilitate early identification, diagnostic work-up, clinical intervention, and targeted future research. The proposed research is novel and addresses and urgent public health crisis, it and will serve as an important avenue for her career development. Dr. Fischer's strategic and thoughtful plan will address four career objectives through mentored research, formal courses, structured tutorials, and practical experiences: (1) enhanced clinical understanding of tropical disease; (2) maintaining multidisciplinary, long- distance collaborations; (3) advanced biostatistical techniques for complex data analysis and interpretation; and (4) communicating research through writing and presentations. Together, the outlined research, mentorship, and career enhancement will fortify the knowledge, skills, and confidence to advance and become competitive for R01 funding. The Fogarty award will afford protected time and resources for a rigorous mentored training period and transition to independence, as she forges long-term, international and multidisciplinary collaborations, advances her skill-set and leadership abilities, and becomes professionally poised to develop a research program that focus on reducing morbidity and mortality in Central America and other low-resource regions of the world.