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Unraveling the Mysteries of CKD of Uncertain Etiology

2022; Lippincott Williams & Wilkins; Volume: 17; Issue: 9 Linguagem: Inglês

10.2215/cjn.08430722

1555-905X

Pablo García, Shuchi Anand,

Hemoglobinopathies and Related Disorders

An unusual kidney disease afflicting otherwise healthy agricultural workers was identified more than two decades ago (1). Since then, CKD of uncertain etiology (CKDu), also named Mesoamerican nephropathy and chronic interstitial nephritis in agricultural communities, continues to claim lives and confound scientists. What we know about the disease can be encapsulated briefly: it is a primarily tubulointerstitial process with nonproteinuric loss of kidney function, disproportionately affects young and middle-aged men, and concentrates among specific occupations in certain hotspots of the world, including Central America, India, and Sri Lanka (2). What we do not know about CKDu is sufficient to keep the "u" firmly in place. At what stage of life does the kidney injury begin? Is the same disease process occurring across disparate geographic regions, or are disparate insults resulting in the same pathologic finding? How do we diagnose CKDu early, without waiting for the substantial loss of kidney function that occurs by the time affected populations reach the official CKD threshold of eGFR <60 ml/min per 1.73 m2? What is the threshold for kidney biopsy? How do we evaluate antecedent exposures, when exposures may vary substantially over time? The leading hypotheses for potential causes of CKDu include genetic factors, infections, heat, or environmental exposures such as silica, heavy metals, or agrochemicals. Of these, agrochemicals are among the hardest to investigate. Agrochemical exposures may be multitude and transient. Their application varies from season to season; their half-life in the environment and in the body varies from hours to years. Current laboratory methodology fails to capture the cumulative (lifetime) exposure of most commonly used pesticides, meaning that researchers must rely on self-report and creative methods, such as life history calendars (3), to probe recalls of study participants. In this issue of CJASN, Holliday et al. (4) attempt to investigate a specific agrochemical, paraquat, as a potential etiologic agent for CKDu using a clinic-to-benchside approach. Their approach is reminiscent of the approach that ultimately identified Balkan endemic nephropathy, the closest historical corollary of CKDu, as resulting from aristolochic acid exposure. The initial identification of aristolochic acid as a potential nephrotoxic carcinogen was via molecular methods, and thereafter, Hranjec et al. conducted a classic case-control study indicating higher recognition of Aristolochia clematitis in the wheat fields of patients who were affected (5). Similarly, although in reverse order, Holliday et al. (4) first identified 52 patients matching the case definition of Mesoamerican nephropathy receiving dialysis care at the Harris Health System in Houston, and two sets of Latin American immigrant participants serving as controls. The first control set of 63 patients was also receiving dialysis and had a specific cause of kidney disease identified; a second set of 16 participants were matched for age and country of origin but did not have kidney disease. Compared with the first set of control patients on dialysis, in patients judged to have end-stage kidney disease due to Mesoamerican nephropathy there was a higher prevalence of agrochemical exposure and specifically paraquat exposure; models adjusting for age and sex continued to show a significantly higher odds of agrochemical exposure among patients, although the confidence intervals widened to cross one as additional confounders were added (e.g., type of crop, exposure to well water). Although the small sample size did not permit modeled estimates, patients judged to have Mesoamerican nephropathy were also more likely than healthy controls to report exposure to agrochemicals without personal protective equipment use. Given the signal for higher self-reported paraquat exposure (even compared with other self-reported agrochemicals), Holliday et al. (4) tested the effects of chronic low-dose paraquat exposure in the kidneys of mice and determined the expression of organic cation transporter-2 and multidrug and toxin extrusion 1 in paraquat-treated mice and Nicaraguan patients with acute Mesoamerican nephropathy (n=8 for biopsies available for staining for both transporters). After 15 weeks of intraperitoneal paraquat injections, male mice demonstrated increases in serum creatinine, with kidney tissue showing fibrosis, and T cell and macrophage infiltration; the findings were less pronounced among female mice. At the dose (20 mg/kg) and intraperitoneal (versus inhalational, dermal, or oral) route of exposure used in the experiments, the authors did not observe injury in lung tissue, the predominant site of injury in patients who have self-poisoned (6). In kidney biopsies, Nicaraguan patients with acute Mesoamerican nephropathy compared with controls with other forms of tubulointerstitial kidney disease, the authors reported higher semiquantitative organic cation transporter-2 and lower multidrug and toxin extrusion 1 expression, leading the authors to speculate for potential higher uptake and lower paraquat elimination from the kidneys of affected patients. The hypothesis-generating findings by Holliday et al. (4) will need future validation. In vivo models that evaluate the effects of intraperitoneal exposure to other commonly applied agrochemicals, which if they do not result in similar increases in serum creatinine or kidney fibrosis, could serve as important negative controls and isolate paraquat as the agrochemical of interest in CKDu/Mesoamerican nephropathy investigations. At the same time, positive controls using agents known to cause tubular injury would contextualize the extent of injury observed. Additionally, larger case-control studies that include an evaluation of bioburden of paraquat, or better yet, a prospective study that tests an association between baseline and repeated assessment of paraquat exposure and incident CKDu are critical. A larger sample size helps address the concern for misclassification of patients versus controls (7), and a prospective design addresses recall and survivor bias. We note that an attempt to evaluate bioburden in a prospective study from the endemic area in Nicaragua was missing evaluation of paraquat, but it failed to demonstrate a higher bioburden of commonly used agrochemicals among persons rapidly losing kidney function compared with other healthy participants living and working in the region (8). Nonetheless, this study provides an intriguing signal for paraquat as a possible nephrotoxic agent in common use in CKD and Mesoamerican nephropathy areas. More importantly, the study provides a roadmap for future investigations into putative etiologies of CKDu. Classic, rigorous epidemiology will need to be matched with laboratory experiments that elucidate a potential mechanistic pathway of injury. Biopsies from affected patients, beyond their diagnostic and prognostic value, will provide the lynchpin, if specialized immunohistochemical stains or transcriptomic sequencing can support the hypothesized mechanism of injury in blinded comparisons with other tubulointerstitial kidney diseases. Following this rubric, multidisciplinary, multinational groups, including the newly formed National Institutes of Health (National Institute for Diabetes and Digestive and Kidney Diseases; National Institute of Environmental Health Sciences; Fogarty)–sponsored CKDu in Agricultural Communities Research Consortium, the large community-based prospective study from Nicaragua (8), the ongoing MesoAmerican Nephropathy Occupational Exposures study (9), our cohort of patients with CKDu in Sri Lanka (10), and several prospective efforts in Sri Lanka and India (11), among others, are positioning themselves to conduct epidemiology and molecular investigations in parallel. These studies are tackling fundamental questions about the distinction between kidney health and early kidney disease in diverse populations, characterizing a new range of environmental risk factors for kidney disease, evaluating their interaction with genetics, focusing pathologists on the neglected tubulointerstitial compartment of the kidney, and building capacity for kidney-related research, including for safe kidney biopsies and high-quality processing of kidney tissue in under-resourced areas. Even as investigations into the causes of CKDu continue, it is evident that studying CKDu is advancing knowledge about kidney disease and kidney health worldwide. Disclosures S. Anand reports having consultancy agreements with GLG group and Vera Therapeutics; reports receiving honoraria from St. Rose Hospital (Continuing Medical Education activity); reports serving on the Executive Committee of American Nephrologists of Indian Origin and chairing the International Society of Nephrology's International Consortium of Collaborators on CKDu (i3C), unpaid; and reports that the Ascend Clinical Laboratory funded sample assays for their coronavirus disease 2019 seroepidemiology work. The remaining author has nothing to disclose. Funding This work is supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK127138.