What Is Really in This Weight Loss Supplement?

A previously healthy 55-year-old woman with no history of kidney disease presented for a routine physical examination and was found to havenephrotic-range proteinuria of approximately 6 g/day. For the past year, the patient and her 50-year-old sister had been taking a weight loss supplement (MetaSwitchTM) they purchased online. The younger sister was found to have nephrotic syndrome, and subsequent kidney biopsies from both sisters were consistent with membranous nephropathy (MN). This disease can be idiopathic in nature or it can occur secondary to a wide range of etiologies, such as autoimmunity and toxin exposure (1); however, familial variants are exceedingly rare. The proteinuria gradually resolved in both sisters within 6 months of ceasing the intake of the supplements; this result raises strong suspicion of a nephrotoxic agent in the supplement. The claimed contents of the supplement were unremarkable in terms of ingredients with overt nephrotoxic potential: α lipoic acid, ginseng,citrulline, leucine, d-ribose-l-cysteine, potassium, and vitamins [vitamin D2, B1 (thiamine), B5 (pantetheine), B6, B12]. The laboratory was contacted to further investigate this case of suspected supplement contamination after common causes of MN were ruled out with extensive studies including serum and urine protein electrophoresis, antinuclear antibody and infectious disease screens, complement levels, and age-appropriate malignancy screens. Supplement capsules were provided to the laboratory, where the investigations centered on heavy metals and drugs as potential causes of MN and common contaminants of weight loss supplements (1, 2). Heavy metal analysis was initially performed on the powdered capsule contents (Fig. 1) with inductively coupled plasma mass spectrometry. Lead, mercury, and chromium were identified in the amount of 0.043, 0.026, and 0.054 μg per capsule, respectively. A review of the case history indicated the sisters were taking 6 pills every day for 8–12 months before diagnosis, which would have resulted in cumulative exposures for each metal of not more than 120 μg. Intriguingly, the case history also revealed that the sisters noted the formulation of the capsule had changed from a clear casing (not shown) to an opaque white casing (Fig. 1) about 6 months before the diagnosis of proteinuria. Considering this observation, the casing of the supplement was also analyzed for heavy metals, revealing lead, nickel, and chromium in the amount of 0.010, 0.097, and 0.051 μg per capsule, respectively. Concurrent with the heavy metal analysis, investigations into the presence of contaminating drugs or other compounds were carried out. GC-MS on the powder from 2 separate capsules initially identified 2 of the claimed components, α lipoic acid and leucine. To further probe the powder contents, ultrahigh-performance LC-MS/MS was employed. The supplement labeling stated it was stimulant-free, but this analysis revealed the presence of norepinephrine as a major constituent of the supplement powder. Norepinephrine is not commonly included in routine drug screening; in this case, it was first identified by its exact mass at <5 ppm mass accuracy and a partial mass spectrum and subsequently confirmed against a norepinephrine standard. Altogether, laboratory investigations revealed both heavy metal and stimulant contamination of the dietary supplement. The identified contaminants were assessed in the context of the case presentation and literature to determine their potential as etiological agents of MN in these 2 sisters. Both patients in this case consumed 6 weight loss supplement capsules per day. Each capsule consisted of a heterogenous off-white and yellow powder enclosed in an opaque white gelatin-based material. More than half of the US adult population takes dietary supplements (3), which commonly include vitamins, minerals, herbs or other botanicals, and/or amino acids. Dietary supplements in the US are regulated by the Food and Drug Administration (FDA) under the 1994 Dietary Supplement Health and Education Act. As part of this Act, supplements are categorized as foods, not drugs, and the FDA is not authorized to review the safety and efficacy of dietary supplements before they are sold to the public over the counter and/or online. Supplement manufacturers are responsible for following Current Good Manufacturing Practices and ensuring that their products meet the safety and labeling requirements of the FDA and Dietary Supplement Health and Education Act. However, cases have been reported of the sale and consumption of supplements that do not contain the claimed ingredients or, more dangerously, are adulterated with undeclared pharmaceuticals or contaminated with toxic compounds (2). In this case, 2 sisters presented with nephrotic-range proteinuria after taking a weight loss supplement they had purchased online. The kidney is particularly susceptible to toxic insults owing in part to its high blood flow, intricate capillary networks, metabolic activities, and filtration functions. Natural products commonly found in dietary supplements have been implicated in various mechanisms of nephrotoxicity (4). Here, kidney biopsies from both sisters were consistent with membranous nephropathy (MN), which is one of the most common causes of nephrotic syndrome in nondiabetic adults (1). The biopsies showed characteristic MN patterns, including glomerular basement membrane thickening by light microscopy, IgG and C3 deposits along the glomerular basement membrane by immunofluorescence, and subepithelial deposits by electron microscopy (1). MN is very rarely a familial disease, and studies of familial cases suggest that genetic susceptibility is X linked (5), making it even more unlikely that these 2 sisters, with unaffected brothers, had a familial glomerulopathy. Considering secondary MN causes, the Kidney Disease: Improving Global Outcomes 2012 Clinical Practice Guideline for Glomerulonephritis includes 71 reported causes of MN listed in 5 major categories: autoimmune, infections, malignancies (carcinomas and noncarcinomas), drugs and toxins, and miscellaneous (1). Based on the clinical history and negative workup for autoimmune, infectious, and malignant causes, the working diagnosis was exposure to a nephrotoxic drug or toxin. The weight loss supplement was the only common medication or shared potential toxic exposure identified between the 2 sisters, as they live in separate households, and the temporal association between cessation of supplement intake and resolution of nephrotic-range proteinuria strongly implicates the supplement as the precipitating or causative agent of MN. It is worth noting that only 3% of dietary supplement users report taking them for weight loss (3), yet a recent study indicated that weight loss supplements were responsible for over 25% of supplement-related emergency department visits (6). The supplements ingested in this case were investigated for any contaminants that alone or in combination might cause or contribute to MN. Membranous nephropathy may be primary or secondary, with a wide range of secondary causes, including exposure to heavy metals, drugs, or other toxic compounds. Cases of dietary supplement-induced toxicity may go unnoticed because of lack of awareness among healthcare providers and/or patients. Extended laboratory toxicology testing may reveal substances not reported by the manufacturer. When this testing is performed on an encapsulated material, it is worth investigating not only the capsule contents but also the casing. It is important to consider bioavailability when evaluating the extent of a toxic exposure from an orally administered substance. Clinicians should consider promoting awareness of supplement-associated adverse events, asking all patients if they are consuming dietary supplements, and reporting any suspected adverse events to the FDA at www.fda.gov/Food/DietarySupplements/ReportAdverseEvent/default.htm. Reporting can be done by patients, clinicians, or even laboratorians involved in cases of suspected supplement contamination. The heavy metals chromium, lead, nickel, and mercury were identified at trace levels in the casing and/or powder. Other heavy metals were detected but in insignificant amounts. While chromium has not been previously linked to MN, it has been found to contaminate capsule casings and pose a significant health risk, requiring confiscation and recall of millions of medicinal capsules and development of specialized methods for metal testing in casings (7). Neither lead nor nickel are known causes of MN, but mercury has been previously linked to MN development. Specifically, in a case study of 11 patients with chronic mercury exposure, 5 involved intake of mercury-contaminated pills before MN development and resolution of proteinuria following cessation of mercury exposure (8). Analysis of those pills revealed 6.7-μg mercury per pill (8), which is substantially greater than the trace levels observed in this case (0.026 μgper capsule). Guidelines for provisional tolerable weekly intake of mercury indicate that exposure of the 2 patients in this report was approximately 2% of the tolerable limit (9). However, mercury is particularly damaging to the kidney, and experts have noted that there has been no blood concentration of mercury identified below which symptoms of mercury toxicity will not occur (10). Unfortunately, serum or urine samples from the sisters during the phase of active disease or other specimens such as hair or nails were not available, limiting any further assessments of the actual heavy metal exposures or accumulation that might have occurred. Assessment of the capsule contents with mass spectrometry confirmed 2 of the claimed components and at the same time revealed the presence of norepinephrine as 1 unexpected major constituent. Norepinephrine may be used in the treatment of shock or low blood pressure; it is administered by intravenous injection and exhibits a short half-life in the circulation (11). Chronic exposure to a vasopressor, such as norepinephrine, could conceivably contribute to kidney disease by promoting vasoconstriction and increasing renal blood pressure. However, when orally ingested as in this case report, norepinephrine has limited bioavailability (11), and both patients were normotensive at presentation. While norepinephrine was a contaminant in the “stimulant-free” weight loss supplement taken by the 2 sisters in this case, its poor bioavailability limits its potential as the basis of MN development. Our laboratory investigations uncovered contaminants in both the supplement powder and the casing by using specialty toxicology testing. While the specific cause of MN in these 2 sisters remains undetermined, the weight loss supplements are overall still the most probable source of an etiological agent for MN. The possibility of lot-to-lot variation of additional contaminants with nephrotoxic potential cannot be ruled out, especially when considering the extended period of intake and possible accumulation of toxic substances. Identification of additional etiological agents for MN may have been limited by current clinical laboratory techniques and/or testing menus. Thus, given that there is an incomplete understanding of the causes and mechanisms that lead to MN, it is possible that the supplements in this case harbor a previously unreported cause of MN.

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