Homeostasis of β₂-microglobulin in diabetics and non-diabetics with modest cadmium intoxication

Abstract

Beta-2-microglobulin (β₂M) is released into plasma from nucleated cells, filtered by glomeruli, and degraded by proximal tubular cells (PTCs). Normally, < 1% of filtered β₂M is excreted in urine. Intoxication of PTCs by cadmium (Cd) reduces degradation and increases excretion of β₂M (TD_β2M and E_β2M). Diabetes may exacerbate these effects or produce them independently. Herein, we normalized fluxes to creatinine clearance (C_cr) to quantify amounts of β₂M excreted and degraded per volume of filtrate (E_β2M/C_cr and TD_β2M/C_cr). We then performed a case-control study of diabetics (DM, n = 65) and non-diabetics (CTRL, n = 72) with modest Cd exposure. β₂M influx (I_β2M, equated with β₂M filtration rate), serum β₂M ([β₂M]_s), and TD_β2M/C_cr were higher in DM. Fractional tubular degradation of filtered β₂M (FrTD_β2M) emerged as the least confounded descriptor of PT β₂M processing, and low values of FrTD_β2M were seen in a subset of diabetics with minimal Cd intoxication. FrTD_β2M varied inversely with E_Cd/C_cr in DM and directly with estimated GFR (eGFR) in DM and CTRL. In both groups, E_β2M/C_cr was inversely related to eGFR and FrTD_β2M, but at any value of FrTD_β2M, E_β2M/C_cr varied by a large multiple. We conclude that in subjects with modest Cd intoxication, I_β2M was variable in DM and CTRL and higher in DM; FrTD_β2M was related inversely to E_Cd/C_cr in DM and directly to eGFR in DM and CTRL; and E_β2M/C_cr varied inversely with eGFR and FrTD_β2M in both groups. E_β2M/C_cr did not depict FrTD_β2M precisely. We recommend FrTD_β2M as an indicator of proximal tubular dysfunction.

Keywords

Cadmium / cadmium nephropathy / beta-2-microglobulin / beta-2-microglobulin influx / beta-2-microglobulin degradation / beta-2-microglobulin excretion / diabetes

References

[1] Watanabe T,Hayashi K,Uneyama C.Dietary exposure of the Japanese general population to elements: total diet study 2013-2018.Food Saf2022;10:83-101 PMCID:PMC9509537

[2] Pokharel A.Dietary exposure to cadmium from six common foods in the United States.Food Chem Toxicol2023;178:113873

[3] Egger AE,Gollmann-Tepeköylü C.Chemical imaging and assessment of cadmium distribution in the human body.Metallomics2019;11:2010-9

[4] Almerud P,Lindroos AK.Cadmium, total mercury, and lead in blood and associations with diet, sociodemographic factors, and smoking in Swedish adolescents.Environ Res2021;197:110991

[5] Hill DT,Petroni M.Airborne levels of cadmium are correlated with urinary cadmium concentrations among young children living in the New York state city of Syracuse, USA.Environ Res2023;223:115450 PMCID:PMC9992329

[6] Johri N,Unwin R.Heavy metal poisoning: the effects of cadmium on the kidney.Biometals2010;23:783-92

[7] Satarug S,Ruangyuttikarn W,Gobe GC.The source and pathophysiologic significance of excreted cadmium.Toxics2019;7:55 PMCID:PMC6958378

[8] Phelps KR.A generic method for analysis of plasma concentrations.Clin Nephrol2020;94:43-9

[9] Heymsfield SB,McManus C,Moffitt S.Measurement of muscle mass in humans: validity of the 24-hour urinary creatinine method.Am J Clin Nutr1983;37:478-94

[10] Argyropoulos CP,Ng YH.Rediscovering beta-2 microglobulin as a biomarker across the spectrum of kidney diseases.Front Med2017;4:73 PMCID:PMC5471312

[11] Gauthier C,Vincent C,Pellet MV.Renal tubular absorption of beta 2 microglobulin.Kidney Int1984;26:170-5

[12] Norden AG,Lee PJ.Glomerular protein sieving and implications for renal failure in Fanconi syndrome.Kidney Int2001;60:1885-92

[13] Polesel M,Haenni D.Spatiotemporal organisation of protein processing in the kidney.Nat Commun2022;13:5732 PMCID:PMC9522658

[14] Satarug S,Gobe GC.The pathogenesis of albuminuria in cadmium nephropathy.Curr Res Toxicol2024;6:100140 PMCID:PMC10726218

[15] Zavala-Guevara IP,Narváez-Morales J.Increased endocytosis of cadmium-metallothionein through the 24p3 receptor in an in vivo model with reduced proximal tubular activity.Int J Mol Sci2021;22:7262 PMCID:PMC8303618

[16] Thévenod F,Schlabs C.Role of the SLC22A17/lipocalin-2 receptor in renal endocytosis of proteins/metalloproteins: a focus on iron- and cadmium-binding proteins.Am J Physiol Renal Physiol2023;325:F564-77

[17] Bernier GM.Catabolsm of human beta-2-microglobulin by the rat kidney.Am J Physiol1969;217:1359-62

[18] Karlsson FA,Sege K,Peterson PA.Turnover in humans of beta 2-microglobulin: the constant chain of HLA-antigens.Eur J Clin Invest1980;10:293-300

[19] Sumpio BE.Kinetics, competition, and selectivity of tubular absorption of proteins.Am J Physiol1982;243:F379-92

[20] Peterson PA,Berggård I.Differentiation of glomerular, tubular, and normal proteinuria: determinations of urinary excretion of beta-2-macroglobulin, albumin, and total protein.J Clin Invest1969;48:1189-98 PMCID:PMC322340

[21] Viberti GC,Jarrett RJ.Effect of control of blood glucose on urinary excretion of albumin and beta2 microglobulin in insulin-dependent diabetes.N Engl J Med1979;300:638-41

[22] Watts GF,Rowe DJ.Low-molecular-weight proteinuria in insulin-dependent diabetes mellitus: a study of the urinary excretion of beta 2-microglobulin and retinol-binding protein in alkalinized patients with and without microalbuminuria.Diabetes Res1989;12:31-6

[23] Groop L,Stenman S,Teppo AM.Urinary excretion of kappa light chains in patients with diabetes mellitus.Kidney Int1990;37:1120-5

[24] Satarug S,Pouyfung P,Vesey DA.Cadmium-induced tubular dysfunction in type 2 diabetes: a population-based cross-sectional study.Toxics2023;11:390 PMCID:PMC10144654

[25] Yimthiang S,Pouyfung P,Gobe GC.Chronic kidney disease induced by cadmium and diabetes: a quantitative case-control study.Int J Mol Sci2023;24:9050 PMCID:PMC10219459

[26] Han E,Lee YH,Lee BW.Association between nonalbumin proteinuria and renal tubular damage of N-acetyl-β-d-glucosaminidase and its clinical relevance in patients with type 2 diabetes without albuminuria.J Diabetes Complications2019;33:255-60

[27] Thethi TK.Challenging the conventional wisdom on diabetic nephropathy: is microalbuminuria the earliest event?.J Diabetes Complications2019;33:191-2

[28] Adokwe JB,Suwan K.Plant-based diet and glycemic control in type 2 diabetes: evidence from a Thai Health-Promoting Hospital.Nutrients2024;16:619 PMCID:PMC10934705

[29] Xu R,Li T,Li Y.Norepinephrine-induced AuPd aerogels with peroxidase- and glucose oxidase-like activity for colorimetric determination of glucose.Mikrochim Acta2021;188:362

[30] Apple F,Prosch A,Holmstrom V,Googins M.Creatinine clearance: enzymatic vs Jaffé determinations of creatinine in plasma and urine.Clin Chem32:388-90

[31] Trzcinka-Ochocka M,Janasik B.Useful and fast method for blood lead and cadmium determination using ICP-MS and GF-AAS; validation parameters.J Clin Lab Anal2016;30:130-9 PMCID:PMC6807167

[32] Hornung RW.Estimation of average concentration in the presence of nondetectable values.Appl Occup Environ Hyg1990;5:46-51

[33] Levey AS,Schmid CH.CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)A new equation to estimate glomerular filtration rate.Ann Intern Med2009;150:604-12 PMCID:PMC2763564

[34] Hayashi T,Watanabe Y.Benchmark dose of urinary cadmium for assessing renal tubular and glomerular function in a cadmium-polluted area of Japan.Toxics2024;12:836 PMCID:PMC11679213

[35] Satarug S,Nishijo M,Gobe GC.The effect of cadmium on GFR is clarified by normalization of excretion rates to creatinine clearance.Int J Mol Sci2021;22:1762 PMCID:PMC7916559

[36] Portale AA,Morris RC Jr.Dietary intake of phosphorus modulates the circadian rhythm in serum concentration of phosphorus. Implications for the renal production of 1,25-dihydroxyvitamin D.J Clin Invest1987;80:1147-54 PMCID:PMC442358

[37] Cappuccio FP,Ji C,Miller MA.Systematic review and meta-analysis of randomised controlled trials on the effects of potassium supplements on serum potassium and creatinine.BMJ Open2016;6:e011716 PMCID:PMC5013341

[38] Satarug S.Cadmium exposure and toxicity.Metal Toxicology HandbookCRC Press, 2020; pp 219-72

[39] Cheung CL,Cheung BM.Serum β-2 microglobulin predicts mortality in people with diabetes.Eur J Endocrinol2013;169:1-7

[40] Kim MK,Chun HJ.Clinical utility of serum beta-2-microglobulin as a predictor of diabetic complications in patients with type 2 diabetes without renal impairment.Diabetes Metab2014;40:459-65

[41] Poortmans J,Toussaint D.Urinary excretion of total proteins, albumin, and beta 2-microglobulin during rest and exercise in diabetic adolescents with and without retinopathy.Diabetes Care1982;5:617-23

[42] Russo LM,McKee M.The normal kidney filters nephrotic levels of albumin retrieved by proximal tubule cells: retrieval is disrupted in nephrotic states.Kidney Int2007;71:504-13

[43] Dickson LE,Sandoval RM.The proximal tubule and albuminuria: really!.J Am Soc Nephrol2014;25:443-53 PMCID:PMC3935594

[44] Comper WD,McCarthy KJ.New insights into proteinuria/albuminuria.Front Physiol2022;13:991756 PMCID:PMC9548894

[45] Molitoris BA,Yadav SPS.Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications.Physiol Rev2022;102:1625-67 PMCID:PMC9255719