2026: Excessive fluoride induces renal cell apoptosis and subsequent renal dysfunction

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Zhang Y, Xu Z, Xie P, Xiao Y, Dong S, Chen C, Chen Q - "Excessive fluoride induces renal cell apoptosis and subsequent renal dysfunction" Toxicol Lett. 111862 (2026) doi: 10.1016/j.toxlet.2026.111862
https://linkinghub.elsevier.com/retriev ... 7426000457

Abstract

This study investigated the mechanisms of renal injury and dysfunction induced by chronic excessive fluoride exposure. Sixty female Sprague-Dawley rats were administered sodium fluoride (NaF) at 0, 50, 100, or 150 mg/L in drinking water for 2, 4, or 6 months. NaF exposure was confirmed by elevated urinary fluoride levels. Renal function was assessed by the increase in serum creatinine, and structural damage was evaluated by histopathology. The expression of key apoptosis-related markers (Bax, Bcl-2, Caspase-3) was analyzed using qRT-PCR, immunohistochemistry, and Western blotting. Fluoride exposure caused a dose- and time-dependent increase in serum creatinine, indicating impaired glomerular filtration. Histopathological analysis confirmed significant tubular degeneration. Notably, functional impairment occurred despite no pathological change in kidney yet, suggesting that functional deficits preceded overt morphological alterations. Mechanistically, fluoride exposure induced a clear pro-apoptotic molecular shift with increased Bax and decreased Bcl-2 expression, culminating in the activation of Caspase-3. The histopathological findings were consistent with a mixed pattern of cell death. However, the integrated molecular evidence demonstrated that the activation of the intrinsic (mitochondrial) apoptotic pathway was a key mechanism contributing to the excessive fluoride-induced nephrotoxicity. In summary, a central molecular pathway involved in fluoride-induced renal injury was demonstrated, providing a foundation for assessing excessive fluoride toxicological impact.

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Hinojosa S, Triozzi JL, Wang G, Wilson OD, Hung A, Million Veteran Program - "Mendelian Randomization of Hypothyroidism and Kidney Function in Veterans" Journal of the American Society of Nephrology 34(11S):689 (2023)
https://doi.org/10.1681/ASN.20233411S1689b
(Genetically predicted hypothyroidism was associated with lower estimated GFR, which implies higher serum creatinine on average, since eGFR and creatinine are inversely related.)

Background:
Hypothyroidism and chronic kidney disease (CKD) are highly prevalent conditions with a potential mechanistic link. A previous study in women from the WGHS (N 3336) demonstrated an association of hypothyroidism and CKD. We studied the association of genetically predicted hypothyroidism in MVP, a large cohort composed of 93% men (exposure), and kidney function (outcome). The outcomes were creatinine-based GFR and cystatin-based GFR (both log-transformed) from CKDGen. We replicated our findings using two additional genetic datasets for the exposure.

Methods:
Two-sample MR was conducted to study the associations between hypothyroidism and kidney function. The primary genetic instrument of the exposure for MR was derived from GWAS of hypothyroidism using data from MVP in 289,307 European American individuals (18,740 cases, 270,567 controls). We repeated the analysis in the FinnGen study (26,064 cases, 59,912 controls) and in UKBB (16,376 cases, 320,783 controls). In MVP and UKBB, the definition of hypothyroidism was based on diagnosis codes, and in FinnGen, on levothyroxine prescription purchases. The outcome was evaluated using summary statistics from GWAS for eGFR from CKDGen for eGFR creatinine (N 133,413) and eGFR-cystatin (N 32,834).

Results:
Genetically predicted hypothyroidism demonstrated a causal relation with the risk of lower kidney function. In our primary analysis Cohorts: MVP/CKDGen (beta (SE): -0.009 (0.002), p 0.001). Results were consistent in sensitivity and replication analyses, as shown in Table 1. There was no evidence of horizontal pleiotropy.

Conclusions:
Our study findings support that hypothyroidism is causally associated with lower kidney function. The mendelian randomization methodology supports a causal relationship and is less susceptible to confounding and reverse causation biases.