A case of Fanconi syndrome that developed following a year of consumption of a red yeast rice supplement (2025)

Abstract

Although some dietary supplements have been reported to cause renal dysfunction, there have been few reports of supplement-induced Fanconi syndrome. We present the case of a 56-year-old woman with Fanconi syndrome that developed after she consumed a red yeast rice supplement. She was referred to our hospital because of renal dysfunction, and was found to have electrolyte abnormalities, including hypophosphatemia and hypouricemia, renal diabetes, and hyperchloremic metabolic acidosis, and was, therefore, diagnosed with Fanconi syndrome. Renal biopsy revealed proximal tubular injury characterized by severely degenerated tubular epithelial cells as well as mild hypocellular fibrosis. We speculated that the red yeast rice supplement, which the patient had been consuming for approximately 1year, might be a cause of her syndrome, because reports of renal dysfunction associated with the consumption of red yeast rice supplements have emerged in Japan since 2024. After the supplement was discontinued and oral prednisolone treatment was initiated, the patient’s renal function improved and her electrolyte abnormalities were ameliorated. Furthermore, even after tapering off and discontinuing the prednisolone over approximately 12weeks, her renal function remained. Because Fanconi syndrome may be caused by various exogenous substances, the taking of a thorough medical history is crucial, including with respect to the use not only of prescription medications, but also other substances, including supplements.

Introduction

Fanconi syndrome is characterized by a global dysfunction in reabsorption in the proximal renal tubules [1]. Its principal clinical feature is an excessive loss of solutes, including phosphate, amino acids, glucose, uric acid, low-molecular-weight proteins, and bicarbonate [2]. Fanconi syndrome can be inherited or acquired. Acquired Fanconi syndrome can develop in the presence of systemic diseases, such as monoclonal gammopathy and autoimmune diseases, drug administration, and other causes [2]. Fanconi syndrome is well known to be caused by anticancer drugs, antibacterial drugs, anti-convulsant drugs, and antiviral agents, but it has also been reported to be caused by heavy metals such as cadmium [3, 4] and lead [5], chemicals such as paraquat [6] and toluene [7], aristolochic acid [8], and fumaric acid [9, 10].

Although dietary supplements have been reported to cause renal dysfunction, which can be caused through such as direct injury to the kidneys or rhabdomyolysis-induced acute kidney injury [11], there have been few reports of Fanconi syndrome in association with supplement use. Since 2024, renal dysfunction associated with the consumption of red yeast rice supplements has been reported in Japan [12]. Here, we present the first case of suspected Fanconi syndrome that developed following the consumption of a red yeast rice supplement for 1year.

Case report

A 56-year-old woman was admitted to the Nephrology department because of renal dysfunction. She had no relevant medical history, except for smoking, and no evidence of renal disease or urinary abnormalities was identified at annual medical check-ups. She had no family history of kidney disease and no history of drug or food allergy. She had been taking an over-the-counter (OTC) intestinal medication for 2–3years. During the preceding year, she had also been consuming a beauty supplement, as well as a red yeast rice supplement (Beni Koji Choleste Help, Kobayashi Pharmaceutical Co., Ltd., Osaka, Japan). The ingredients of the OTC medication and the two supplements are summarized in Table1. She started to experience shortness of breath, vomiting, and loss of appetite 1month before visiting our hospital, but no abnormalities were identified on upper gastrointestinal endoscopy at the time.

On admission (Day 0), the patient was 151cm tall and weighed 38.8kg, and her body weight had decreased by 2kg over the preceding 4weeks. Her blood pressure and body temperature were 127/75mmHg and 36.2°C, respectively, and she did not have any skin eruptions, joint pain, or lymphadenomegaly. Table 2 shows the results of urinalysis and blood testing. Urinalysis showed glucosuria (3 +), proteinuria (2.34g/gCr), urine β2-microglobulin (β2MG) elevation (82,520µg/L), and N-acetylglucosaminidase elevation (26.7U/L). Blood testing revealed serum creatinine (Cr) elevation (1.39mg/dL), hypokalemia (3.2mEq/L), hypophosphatemia (1.4mg/dL), hypouricemia (1.4mg/dL), and hyperchloremic metabolic acidosis (pH 7.28, pCO₂ 34.6mmHg, chloride 115mEq/L, bicarbonate 15.6mEq/L). These findings imply a global dysfunction of the proximal tubule, manifesting as renal tubular acidosis, renal diabetes, and hypophosphatemia, and therefore, Fanconi syndrome was diagnosed. Because there were no episodes of allergic symptoms such as fever, skin eruptions, or diarrhea, and laboratory tests showed no elevation of eosinophils or leukocyturia, we did not actively suspect allergy involvement in renal dysfunction. Consequently, a drug-induced lymphocyte stimulation test was not performed.

A renal biopsy was performed on the day of admission (Day 0). Light microscopic examination of the sections revealed severe tubular injury, characterized by degenerated tubular epithelial cells with luminal dilatation and indistinct brush borders (Fig.1). Mild interstitial fibrosis was also observed, accompanied by sparse lymphocytic infiltration. Immunohistochemical analysis demonstrated that the majority of the injured tubules exhibited CD10 positivity, indicating that the proximal tubules were predominantly affected (Fig.2). Immunohistochemical staining for myogenin revealed no positively stained casts within the renal tubules (data not shown). Global sclerosis was present in 1 of 48 glomeruli, but no significant histopathological changes were apparent in the others. Immunofluorescence and electron microscopic studies did not reveal immune complex deposition or ultrastructural abnormalities in the glomeruli (data not shown). In contrast, electron microscopy revealed flattened proximal tubular epithelial cells with decreased microvilli and hydropic changes (Fig.3). These tubular epithelial cells contained myelin body-like lamellar structures with virus-like electron dense particles in their cytoplasm, and desquamating tubular epithelia were also observed (Fig.3). Mitochondria showed no obvious abnormalities, and no electron dense substance was found in the tubular basement membrane. Based on these findings, we diagnosed the patient with severe tubular injury of undetermined etiology.

A range of potential causes of acquired Fanconi syndrome, including systemic diseases, such as multiple myeloma and Sjögren’s syndrome, and exposure to exogenous substances such as heavy metals, chemicals, or prescription drugs, were ruled out. However, she had been taking one OTC drug and two supplements, and we considered the possibility of proximal tubule toxicity owing to the drug or the supplements. Therefore, the patient discontinued all of these from the day before admission, the day of her first visit.

The patient’s clinical course is shown in Fig.4. The oral administration of sodium bicarbonate and potassium L-aspartate was started on the day following admission (Day 1). Although severe interstitial cellular infiltration was not apparent on renal biopsy, the patient was also administered oral prednisolone (PSL 30mg) from day 17, to suppress interstitial fibrosis. After 2 and 4weeks of PSL administration, the patient’s serum Cr concentration and proteinuria decreased to 0.93mg/dL and 0.23g/gCr, and 0.88mg/dL and 0.16g/gCr, respectively. The dose of PSL was tapered off by 5mg every 2weeks and the drug was discontinued on Day 101. One week after the discontinuation of PSL, there had been no increase in the serum Cr or urinary β2MG concentrations. The oral administration of sodium bicarbonate and potassium L-aspartate was discontinued on Days 29 and 51, respectively, because her metabolic acidosis and hypokalemia had been ameliorated.

Discussion

We have described a case of Fanconi syndrome in a middle-aged woman with no relevant medical history who was not taking any prescription medications. Renal biopsy revealed degenerative tubular epithelial cells along with luminal dilatation and loss of brush border. Immunohistochemical analysis indicated that the proximal tubules were predominantly affected. Mild fibrosis with edema was present, but inflammatory infiltration was minimal. No evidence of renal disease or urinary abnormalities was identified at annual health check-ups. Furthermore, the laboratory findings after the patient’s admission to our hospital were not indicative of any disease that could cause renal dysfunction or Fanconi syndrome. Therefore, we considered the possibility of Fanconi syndrome induced by the OTC medication or supplements that the patient was taking, and we instructed her to discontinue these from the day before her admission, the day of her first visit. After the renal biopsy, oral PSL was administered, and the patient’s renal function rapidly improved.

Acquired Fanconi syndrome has been reported to be caused by numerous exogenous substances [1]. In the present case, the patient was taking an OTC medication and two supplements. A search of PubMed identified one case report of Fanconi syndrome caused by an OTC medication [13]. Specifically, this was a case of heavy metal toxicity that was associated with the use of an unlabeled Ayurvedic medication containing heavy metals. In addition, the literature search identified reports of cases of Fanconi syndrome due to the consumption of dietary supplements comprising Chinese herbs [14, 15], such as those containing Glycyrrhiza species and aristolochic acid, and l-Lysine [16]. In the present case, the patient’s Fanconi syndrome was suspected to have been induced by the OTC drug or supplements. To the best of our knowledge, however, the patient consumed none of the ingredients previously been reported to be associated with Fanconi syndrome, as shown in Table1.

Although the causative agent for the Fanconi syndrome of the present patient was not definitively established, the nephrotoxicity appeared to be caused mainly by the degeneration of the proximal tubules, according to the results of renal biopsy. Many of the drugs that cause Fanconi syndrome are taken up by proximal tubular cells from the bloodstream through transporters expressed on the cell membranes [17], including organic cation transporters [18], organic anion transporters [19], and P-glycoprotein [20]. As a result of this, the intracellular concentrations of these substances in the proximal tubules may be high, and therefore have toxic effects. The mechanisms that cause proximal tubular dysfunction are still poorly understood and may vary according to the drug administered, although some of the mechanisms are only partially understood, such as the mitochondrial dysfunction induced by antiviral drugs [1, 17, 21].

The present patient had been taking a red yeast rice supplement for approximately 1year; however, the product was announced to be immediately discontinued in Japan in March 2024, because of the possibility that it was nephrotoxic, by the Ministry of Health, Labour and Welfare, the Ministry of Agriculture, Forestry and Fisheries, and the manufacturing company [22]. The interim report (47 cases) of a survey conducted by the Japanese Society of Nephrology regarding the renal impairment associated with the consumption of this red yeast rice supplement [23]related laboratory findings suggestive of Fanconi syndrome, and renal biopsies indicated that the main lesions were tubulointerstitial nephritis, tubular necrosis, and acute tubular injury, consistent with the findings in the present patient. Furthermore, the lot number of the red yeast rice supplement the patient was taking matched one of the lot numbers that were recalled by the manufacturer in March 2024 [24]. We cannot rule out the possibility that the patient’s Fanconi syndrome may have been induced by the OTC medication or the beauty supplement; to the best of our knowledge, however, none of the exogenous substances that the patient was taking, other than the red yeast rice supplement, have been previously reported to induce Fanconi syndrome.

Although our case presented no serological inflammation, renal biopsy showed only minimal cellular infiltration, and renal function had begun to improve, we decided to initiate steroid therapy for the following two reasons. First, when the steroid therapy was initiated, it was prior to the reporting of renal dysfunction associated with the consumption of the red yeast rice supplement, and the cause of renal dysfunction was not identified. Furthermore, renal dysfunction had not returned to the baseline level, and there was no assurance that renal function would continue to improve following discontinuation of the OTC medication or supplements. Second, although the causative agent had not been completely identified, microscopic examination suggested that the clinical findings, including Fanconi’s syndrome, could be attributed to proximal tubular injury and mild fibrosis. This led us to speculate that this case had some similarity to aristolochic acid nephropathy and Balkan endemic nephropathy [25, 26]. The effective treatment for aristolochic acid nephropathy and Balkan endemic nephropathy remains unknown, but steroid therapy has been reported to slow the progression of renal dysfunction in some patients [27–30]. In the present case, the patient’s renal function improved and the urinary β2MG concentration decreased after starting steroid therapy. However, whether the improvement in renal function was due to steroid therapy or the natural course after discontinuation of supplements cannot be determined from this case alone. Further accumulation of cases is necessary to conclude whether steroid therapy is effective in renal dysfunction associated with the consumption of red yeast rice supplements or to determine which cases would benefit from steroid use.

Although the possibility of mold contamination during the manufacturing process of the red yeast rice supplement has been reported [31], further careful investigations are merited. The handling of red yeast rice products varies by country, and owing to the cholesterol-lowering effect of monacolin K, which is structurally identical to lovastatin [32], red yeast rice is recommended as a dietary supplement for the management of hypercholesterolemia in the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) Guidelines [33]. However, red yeast rice products cannot be sold as dietary supplements in the United States, because the Food and Drug Administration approved lovastatin for use as a new drug before it was marketed as a food or dietary supplement [34]. Although red yeast rice has been theorized to induce rhabdomyolysis [11], a guaranteed safe dietary intake of monacolin from red yeast rice has not been identified [35, 36]. In the present case, the absence of an elevated serum creatine kinase and lack of muscle symptoms did not suggest the presence of rhabdomyolysis. This finding was further supported by the negative immunohistochemical staining results for myogenin.

Virus-like particles and lamellar myelin-like structures were observed by electron microscopy. The particles did not have membrane boundaries, and their electron density appeared rather uniform, suggesting that they differed from lysosomes [37]. These structures might be associated with red yeast rice supplements, but further studies are required to determine the molecules composing these structures and the mechanisms by which they damage tubular epithelial cells.

In conclusion, we have described a case of Fanconi syndrome that was associated with no medical history or the use of prescription medication, and we suspected that the red yeast rice supplement being consumed by the patient was the cause. Because Fanconi syndrome can be caused by various exogenous substances, the taking of a thorough medical history, which includes not only the use of prescription medication, but also other substances, including supplements, is crucial. The analysis of further accumulated cases is needed to determine whether there is a definite link between the consumption of a red yeast rice supplement and Fanconi syndrome, which is accompanied by the pathological findings of proximal tubular injury characterized by degenerated tubular epithelial cells with luminal dilatation and indistinct brush borders, as well as mild hypocellular fibrosis.

Acknowledgements

We are grateful to Junri Hayakawa (Laboratory for Electron Microscopy, Kyorin University School of Medicine) for providing excellent technical assistance for ultrastructural analysis. We also thank Mark Cleasby, PhD from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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