In a recent issue of CKJ, Gutierrez-Peña et al reported a high incidence and prevalence of advanced chronic kidney disease (CKD) in Aguascalientes, Mexico. This contradicts Global Burden of Disease estimates that should be updated. A key component of this high burden of CKD relates to young people aged 20 to 40 years in whom the cause of CKD was unknown (CKDu). The incidence of kidney replacement therapy in this age group in Aguascalientes is among the highest in the world, second only to Taiwan. However, high altitude Aguascalientes with a year-round average temperature of 19 °C does not fit the geography of other CKDu hotspots. Furthermore, kidney biopsies in young people showed a high prevalence of focal segmental glomerulosclerosis. Potential causes of CKDu in Aguascalientes include the genetic background (no evidence, although podocytopathy genes should be explored) and environmental factors. The highest prevalence of CKD was found in Calvillo, known for guava farming. Thus, guava itself, known to contain bioactive, potentially nephrotoxic molecules, and pesticides should be explored. Additionally, there are reports of water sources in Aguascalientes contaminated with heavy metals and/or pesticides. These include fluoride (increased levels found in Calvillo drinking water) as well as naturally occurring arsenic, among others. Fluoride may accumulate in bone and cause kidney disease years later, and maternal exposure to excess fluoride may cause kidney disease in offspring. We propose a research agenda to clarify the cause of CKDu in Aguascalientes. that should involve international funders. The need for urgent action to identify and stem the cause of the high incidence of CKD extends to other CKD hotspots in Mexico, including Tierra Blanca in Veracruz and Poncitlan, Jalisco.

Lack of awareness of a diagnosis of chronic kidney disease (CKD) by patients and physicians is a major contributor to fueling the CKD pandemic by also making it invisible to researchers and health authorities. This is an urgent matter to tackle if dire predictions on future CKD burden are to be addressed. CKD is set to become the fifth global cause of death by 2040, and the second cause of death before the end of the century in some countries with long life expectancy. Coronavirus disease 2019 (COVID-19) illustrated this invisibility: only after summer 2020 it became clear that CKD was a major driver of COVID-19 mortality, both in terms of prevalence as a risk factor and of the risk conferred for lethal COVID-19. However, by that time the damage was done: news outlets and scientific publications continued to list diabetes and hypertension, but not CKD, as major risk factors for severe COVID-19. In a shocking recent example from Sweden, CKD was found to be diagnosed in just 23% of 57880 persons which fulfilled diagnostic criteria for CKD. In the very same large cohort, diabetes or cancer were diagnosed in 29% of persons, hypertension in 82%, cardiovascular disease in 39% and heart failure in 28%. Thus, from the point of view of physicians, patients and health authorities, CKD was the least common comorbidity in persons with CKD, ranking sixth, after other better-known conditions. One consequences of this lack of awareness, was that nephrotoxic medications were more commonly prescribed in patients with CKD that did not have a diagnosis of CKD. Low awareness of CKD may also fuel concepts such as the high prevalence of hypertensive nephropathy when CKD is diagnosed after the better-known condition of hypertension.

Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It was carried out in two groups of patients with extreme phenotypes (toxicity versus control) newly treated with a fluoropyrimidine, during the first three cycles of treatment. A novel nonsense gene variant (c.2197insA) was most likely responsible for fluoropyrimidine-induced toxicity in one patient, while neither DPYD mRNA expression nor plasma uracil concentration was globally associated with early toxicity. Our present work may help improve pharmacogenetic testing to avoid severe and undesirable adverse reactions to fluoropyrimidine treatment and it also supports the idea of looking beyond DPYD.

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Aguascalientes, Mexico has a high incidence and prevalence of advanced chronic kidney disease (CKD). CKD is especially frequent in young people aged 20 to 40 years in whom the cause of CKD was unknown (CKDu), 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 to 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.