Soisungwan Satarug , David A. Vesey , Glenda C. Gobe , Kenneth R. Phelps
{"title":"镉肾病白蛋白尿的发病机制","authors":"Soisungwan Satarug , David A. Vesey , Glenda C. Gobe , Kenneth R. Phelps","doi":"10.1016/j.crtox.2023.100140","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Urinary cadmium excretion (E<sub>Cd</sub>) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since β<sub>2</sub>-microglobulinuria (E<sub>β2M</sub>) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (E<sub>alb</sub>) to E<sub>β2M</sub> in Cd-exposed subjects would provide evidence of similar mishandling of both proteins.</p></div><div><h3>Methods</h3><p>To depict excretion rates per functional nephron, E<sub>Cd</sub>, E<sub>alb</sub>, and E<sub>β2M</sub> were normalized to creatinine clearance (C<sub>cr</sub>), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate E<sub>alb</sub>/C<sub>cr</sub>, E<sub>β2M</sub>/C<sub>cr</sub>, and eGFR to several independent variables. Simple linear regressions of eGFR, E<sub>alb</sub>/C<sub>cr</sub>, and E<sub>β2M</sub>/C<sub>cr</sub> on E<sub>Cd</sub>/C<sub>cr</sub> were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in E<sub>alb</sub>/C<sub>cr</sub> and E<sub>β2M</sub>/C<sub>cr</sub> and decrements in eGFR were quantified through four quartiles of E<sub>Cd</sub>/C<sub>cr</sub>.</p></div><div><h3>Results</h3><p>As age or E<sub>Cd</sub>/C<sub>cr</sub> rose, E<sub>alb</sub>/C<sub>cr</sub> and E<sub>β2M</sub>/C<sub>cr</sub> also rose, and eGFR fell. In linear regressions, slopes relating E<sub>alb</sub>/C<sub>cr</sub> and E<sub>β2M</sub>/C<sub>cr</sub> to E<sub>Cd</sub>/C<sub>cr</sub> were similar. After adjustment of dependent variables for age, coefficients of determination (R<sup>2</sup>) for all regressions rose by a multiple, and slopes approached unity. E<sub>alb</sub>/C<sub>cr</sub> and E<sub>β2M</sub>/C<sub>cr</sub> were similarly associated with each other. Mean E<sub>alb</sub>/C<sub>cr</sub> and E<sub>β2M</sub>/C<sub>cr</sub> rose and mean eGFR fell in stepwise fashion through quartiles of E<sub>Cd</sub>/C<sub>cr</sub>. Whereas E<sub>β2M</sub>/C<sub>cr</sub> did not vary with blood pressure, E<sub>alb</sub>/C<sub>cr</sub> rose in association with hypertension in two of the four quartiles.</p></div><div><h3>Conclusions</h3><p>Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and β<sub>2</sub>M similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100140"},"PeriodicalIF":2.9000,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X23000385/pdfft?md5=fb62735e49213e668766e81df7ba0200&pid=1-s2.0-S2666027X23000385-main.pdf","citationCount":"0","resultStr":"{\"title\":\"The pathogenesis of albuminuria in cadmium nephropathy\",\"authors\":\"Soisungwan Satarug , David A. Vesey , Glenda C. Gobe , Kenneth R. Phelps\",\"doi\":\"10.1016/j.crtox.2023.100140\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Urinary cadmium excretion (E<sub>Cd</sub>) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since β<sub>2</sub>-microglobulinuria (E<sub>β2M</sub>) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (E<sub>alb</sub>) to E<sub>β2M</sub> in Cd-exposed subjects would provide evidence of similar mishandling of both proteins.</p></div><div><h3>Methods</h3><p>To depict excretion rates per functional nephron, E<sub>Cd</sub>, E<sub>alb</sub>, and E<sub>β2M</sub> were normalized to creatinine clearance (C<sub>cr</sub>), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate E<sub>alb</sub>/C<sub>cr</sub>, E<sub>β2M</sub>/C<sub>cr</sub>, and eGFR to several independent variables. Simple linear regressions of eGFR, E<sub>alb</sub>/C<sub>cr</sub>, and E<sub>β2M</sub>/C<sub>cr</sub> on E<sub>Cd</sub>/C<sub>cr</sub> were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in E<sub>alb</sub>/C<sub>cr</sub> and E<sub>β2M</sub>/C<sub>cr</sub> and decrements in eGFR were quantified through four quartiles of E<sub>Cd</sub>/C<sub>cr</sub>.</p></div><div><h3>Results</h3><p>As age or E<sub>Cd</sub>/C<sub>cr</sub> rose, E<sub>alb</sub>/C<sub>cr</sub> and E<sub>β2M</sub>/C<sub>cr</sub> also rose, and eGFR fell. In linear regressions, slopes relating E<sub>alb</sub>/C<sub>cr</sub> and E<sub>β2M</sub>/C<sub>cr</sub> to E<sub>Cd</sub>/C<sub>cr</sub> were similar. After adjustment of dependent variables for age, coefficients of determination (R<sup>2</sup>) for all regressions rose by a multiple, and slopes approached unity. E<sub>alb</sub>/C<sub>cr</sub> and E<sub>β2M</sub>/C<sub>cr</sub> were similarly associated with each other. Mean E<sub>alb</sub>/C<sub>cr</sub> and E<sub>β2M</sub>/C<sub>cr</sub> rose and mean eGFR fell in stepwise fashion through quartiles of E<sub>Cd</sub>/C<sub>cr</sub>. Whereas E<sub>β2M</sub>/C<sub>cr</sub> did not vary with blood pressure, E<sub>alb</sub>/C<sub>cr</sub> rose in association with hypertension in two of the four quartiles.</p></div><div><h3>Conclusions</h3><p>Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and β<sub>2</sub>M similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.</p></div>\",\"PeriodicalId\":11236,\"journal\":{\"name\":\"Current Research in Toxicology\",\"volume\":\"6 \",\"pages\":\"Article 100140\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2023-12-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2666027X23000385/pdfft?md5=fb62735e49213e668766e81df7ba0200&pid=1-s2.0-S2666027X23000385-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current Research in Toxicology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2666027X23000385\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"TOXICOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Research in Toxicology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2666027X23000385","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"TOXICOLOGY","Score":null,"Total":0}
The pathogenesis of albuminuria in cadmium nephropathy
Background
Urinary cadmium excretion (ECd) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since β2-microglobulinuria (Eβ2M) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (Ealb) to Eβ2M in Cd-exposed subjects would provide evidence of similar mishandling of both proteins.
Methods
To depict excretion rates per functional nephron, ECd, Ealb, and Eβ2M were normalized to creatinine clearance (Ccr), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate Ealb/Ccr, Eβ2M/Ccr, and eGFR to several independent variables. Simple linear regressions of eGFR, Ealb/Ccr, and Eβ2M/Ccr on ECd/Ccr were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in Ealb/Ccr and Eβ2M/Ccr and decrements in eGFR were quantified through four quartiles of ECd/Ccr.
Results
As age or ECd/Ccr rose, Ealb/Ccr and Eβ2M/Ccr also rose, and eGFR fell. In linear regressions, slopes relating Ealb/Ccr and Eβ2M/Ccr to ECd/Ccr were similar. After adjustment of dependent variables for age, coefficients of determination (R2) for all regressions rose by a multiple, and slopes approached unity. Ealb/Ccr and Eβ2M/Ccr were similarly associated with each other. Mean Ealb/Ccr and Eβ2M/Ccr rose and mean eGFR fell in stepwise fashion through quartiles of ECd/Ccr. Whereas Eβ2M/Ccr did not vary with blood pressure, Ealb/Ccr rose in association with hypertension in two of the four quartiles.
Conclusions
Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and β2M similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.
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