Introduction: Mercury has long been prohibited for use in skin-lightening agents, but such products are still widely available in many parts of the world.Objective: To evaluate the characteristics of subjects with nephrotic syndrome caused by exposures to skin-lightening products containing mercury and the impact of treatments with chelation agents and/or steroids on the time to achieve remission of proteinuria and normal urine mercury concentrations.Methods: We searched Medline and Embase (1971-31 March 2019), Google Scholar (2001-March 2019) and WanFang Data (1999-March 2019), using mercury, mercury poisoning, cosmetics, skin-lightening and nephrotic syndrome as search terms. Affected subjects must have had nephrotic range proteinuria and a renal biopsy performed. The searches revealed 46 citations, but 32 were excluded because of a doubtful history, incomplete data collection, more than one source of mercury exposures, non-nephrotic proteinuria, treatments by herbal medicines and duplicate articles. The 14 remaining reports describing 30 cases formed the basis of this review.Incidence and geographical origins: There was an obvious increase in the number of reports with more complete information from Asia (n = 13) and Europe (n = 1) during 2002-2006 (n = 3) and 2010-2017 (n = 11), involving 3 subjects in 2002-2006 and 27 subjects in 2010-2017.Characteristics of subjects: All 30 subjects were Asian females, mostly aged 18-52 years (median 34 years). Nephrotic syndrome occurred 1-60 months (median 5 months) after exposures to mercury. The proteinuria was heavy (urinary protein excretion 3.2-20.7 g/day, median 5.7 g/day). Other features of mercury toxicity were generally absent. Blood mercury concentrations were normal in 6 subjects and 1.1-10.9 times (median 3.5 times) the upper limit of normal in 14 subjects. Urine mercury concentrations were much higher in 24 subjects, at 1.2-94.6 times (median 9.8 times) the upper limit of normal. Renal biopsy typically revealed minimal change disease (67%) or membranous nephropathy (23%).Etiological importance of mercury: Several clinical observations strongly support the etiological importance of mercury, including a positive relationship between body mercury burden (24-h urine mercury excretion) and severity of proteinuria, the parallel (often proportional) reductions in body mercury burden and proteinuria after cessation of exposures and initiation of chelation therapy and the risk of persistent proteinuria in subjects not treated with chelating agents.Natural history and impact of specific treatments: Spontaneous recovery (within 1.5 months) of mercury-induced nephrotic syndrome was rare.Twenty-three subjects were treated with chelating agents (n = 7) or chelating agents plus steroids (n = 16). There was relatively clear information on the time to remission of proteinuria (urine protein <150 mg/day) in nine subjects following chelation therapy (n = 5) or chelation therapy plus steroids (n = 4) (median 2 months, range 1-9 months). In comparison, the time to remission was longer in three subjects not treated with chelation therapy (≥12 months). There were fewer reports with relatively clear information on the time to achieve normal urine mercury concentrations (<35 nmol/day, <50 nmol/L or <5.0 nmol/mmol creatinine). In four subjects with treatment by chelating agents (n = 1) or chelating agents plus steroids (n = 3), this took 9-16 months (mean ∼11 months). The adjunctive role of steroids in mercury-induced nephrotic syndrome was unclear.Conclusions: Repeated exposures to inorganic mercury in skin-lightening cosmetic products typically cause minimal change disease or membranous nephropathy, resulting in nephrotic syndrome. Apart from cessation of product use, chelation therapy is clearly indicated, in view of the etiological importance of mercury and the presence of increased body burden with target organ damage. The optimal dosages and treatment strategies for unithiol (2,3-dimercapto-1-propanesulfonic acid) and succimer (dimercaptosuccinic acid) have yet to be determined.
Keywords: Mercury; cosmetics; mercury poisoning; nephrotic syndrome; skin-lightening.