Solving the riddle of Aguascalientes nephropathy: nephron number, environmental toxins and family clustering

Abstract

Aguascalientes, Mexico, has a high incidence and prevalence of advanced chronic kidney disease (CKD). CKD is especially frequent in young people ages 20-40 years in whom the cause of CKD was unknown, although kidney biopsies frequently showed focal segmental glomerulosclerosis (FSGS) and glomerulomegaly. Macias-Diaz et al. have now pursued this lead by screening teenagers in Calvillo, one of the hardest hit municipalities. They uncovered clinical, laboratory, kidney biopsy and exposure findings that define a new entity, Aguascalientes nephropathy, and are consistent with familial exposure to common environmental toxins, potentially consisting of pesticides. They hypothesize that prenatal exposure to these toxins may decrease nephron number. The young age of persons with FSGS would be consistent with a novel environmental toxin introduced more than 50 years ago but not present in the environment before. Key takeaways from this research are the need to screen teenagers for albuminuria, to provide kidney-protective strategies to patients identified as having CKD and for the research community to support Aguascalientes nephrologists and health authorities to unravel the cause and potential solutions for this CKD hotspot. In this regard, the screening approach and the cohort generated by Macias-Diaz et al. represent a giant step forward. The next steps should be to screen younger children for albuminuria and kidney size and to identify the putative toxins.

Keywords: CKD hotspot; CKD of uncertain etiology; Mexico; burden of disease; familial; focal segmental glomerulosclerosis; pesticides.

FIGURE 1:

Conceptual framework for CKDu: the Aguascalientes hotspot as an example. Based on available evidence regarding the concentration of CKD cases within certain geographic locations and families, as well as on the association with certain environments and occupations, a conceptual framework implying a genetic susceptibility background in association/interacting with environmental exposures is a reasonable starting point to unravel the pathogenesis of CKDu. However, the familial incidence may also be due to familial exposure to the same environmental actor and/or to a shared microbiota pattern. The genetic background may be expected to have been present for centuries unless significant immigration occurred in recent decades. The age pattern evidenced by KRT and kidney biopsy epidemiology points to the initiation of the CKD hotspot in Aguascalientes ∼50 years ago, which may be hypothesized to be the date of the introduction of an environmental factor, and the more recent data on albuminuria and decreased kidney size in teenagers suggest that the CKD hotspot was still active 10–15 years ago and potentially today.

FIGURE 2:

The natural history of Aguascalientes nephropathy. Aguascalientes nephropathy is characterized by the presence of pathological albuminuria, decreased kidney size as observed by sonography and preserved kidney function in the second decade of life, associated with histological evidence of decreased nephron number and hyperfiltration-induced podocytopathy in the absence of significant fibrosis, which argues against recent nephron loss induced by acquired kidney injury. This evolves toward proteinuric FSGS in the third decade of life, associated with decreasing GFR that will need KRT peaking at age 30–40 years. It is yet unknown whether the decreased kidney size can be observed in foetuses, neonatally or during the first decade of life, whether this can be used for screening for the condition and when albuminuria first develops. It is also unknown whether conventional antiproteinuric therapy with renin–angiotensin system blockers slows CKD progression, although it does decrease albuminuria. Further unknowns relate to the triggers for the condition, as low birthweight or prematurity do not appear to be responsible, but family clustering and evidence suggesting exposure to agrochemical toxins were uncovered. Another unknown is whether low nephron number was determined in the past and accounts for the condition as a non-modifiable factor or whether continued exposure to a putative environmental toxin is still accelerating the loss of kidney function.

FIGURE 3:

Pesticide sales in Mexico and in Aguascalientes. (A) Total kilograms. Please note that data for Mexico are expressed as thousands of kilograms and data for Aguascalientes as kilograms. (B) Percentage of total kilograms represented by each pesticide. Source: Supplementary data, Table S4 from Macias-Diaz et al. [20], which used data from the Agrochemicals Marketing Survey 2020, Department of Sanitary Regulation, Aguascalientes, Mexico.