Introduction

Fanconi syndrome is a group of disorders in which generalized dysfunction of solute transport in the proximal tubule causes excessive urinary loss of substances that would normally be reabsorbed in the proximal tubule. Reabsorption of solutes, such as amino acids, glucose, and inorganic phosphorus bicarbonate, is impaired, resulting in metabolic acidosis and electrolyte abnormalities.

The causes of acquired Fanconi syndrome that develops in adulthood include monoclonal gammopathy of renal significance (MGRS), light-chain proximal tubulopathy (LCPT) [1], Sjogren syndrome [2], tubulointerstitial nephritis and uveitis (TINU) syndrome [3], tubulointerstitial nephritis including IgG4-related kidney disease (IgG4RKD), IgM-positive plasma cell-tubulointerstitial nephritis (IgMPC-TIN) [4], and chemical and metal-induced causes [5]. About a decade ago, nephropathy due to a Chinese herb containing aristolochic acid (AA) was reported as a cause of acquired Fanconi syndrome [6]. As a result, Chinese herbs containing AA were prohibited from sale in Japan.

Red Yeast Rice Cholesterol Help® is a supplement used to improve hypercholesterolemia, with proven efficacy [7]. However, since citrinin, which is a mycotoxin produced by the mold used for producing red yeast rice, is reported to damage the proximal tubule [8], a warning about red yeast rice has been issued in European countries [9]. However, Kobayashi Pharmaceutical Co., Ltd. has produced a new red yeast rice that is made using Monascus pilosus, which does not produce citrinin [10], and has created the product Red Yeast Rice Cholesterol Help® as a supplement for managing hypercholesterolemia.

We, herein, report the first case of acute kidney injury and Fanconi syndrome in a patient taking many supplements, including Red Yeast Rice Cholesterol Help®. Although the causative agent of the acute kidney injury in this case was unknown, it is predicted as being similar to citrinin, because the mechanism of proximal renal tubular damage was the same as that for citrinin.

Case report

A 62-year-old man visited his primary care physician with the complaints of loss of appetite and fatigue. He had lost 5 kg in weight within 1 month. Suspecting reflux esophagitis, vonoprazan fumarate and potassium-competitive acid blockers (P-CABs) were prescribed. Blood samples taken on the day of his visit revealed kidney injury and hypokalemia. He had previously undergone annual health checkups, the last of which had been 4 months earlier, which had indicated no kidney dysfunction or urine test abnormalities. He was referred to our hospital and admitted for acute kidney injury. On admission, his body temperature was 36.6 °C, heart rate was 90 bpm, and blood pressure was 138/88 mmHg. No vomiting or diarrhea was observed. He had a history of taking multiple health supplements, including Taisho Chinese herbal gastrointestinal medicine®, Red Yeast Rice Cholesterol Help®, DHA & EPA® and a Chinese herbal laxative®, in addition to P-CAB. After admission, all the supplements were discontinued and P-CAB was changed to rebamipide. Blood samples and urine tests on admission revealed acute kidney injury and hypokalemia, as well as hypouricemia, hypophosphatemia, and elevated levels of markers of renal tubular injury (Table 1). The urine β2-microglobulin (β2MG) value was 41,475 µg/L and the urine sugar level was 2168 mg/dL. Mild metabolic acidosis was also observed. Based on normal blood sugar and HbA1c levels and the presence of sugar in urine, it was determined that he had glucosuria from renal diabetes. Fractional excretion levels were as follows: sodium (FENa), 0.91%; BUN (FEUN), 23.75%; uric (FEUA) acid, 51.09% (normal range; 5–10%); and phosphorus (FEP), 55.28%. Aminoaciduria was also detected (Table 2). The patient was diagnosed with acute kidney injury and Fanconi syndrome. Anti-nuclear antibodies, anti-SSA antibodies, IgG4, anti-mitochondrial M2 antibodies, and trace metals (cadmium, lead, and chromium) were evaluated as potential causes of acquired Fanconi syndrome, but all were negative. Serum protein electrophoresis and urine protein electrophoresis were negative, and the free light-chain ratio was normal, ruling out acquired Fanconi syndrome due to the monoclonal gammopathy. Evaluation of the eyes by an ophthalmologist indicated no uveitis. Renal biopsy revealed global sclerosis in 2 of 14 glomeruli. Minor glomerular abnormalities and extensive renal proximal tubular damage were observed, characterized mainly by flattening of the tubular epithelium on Periodic Acid Schiff (PAS) staining (Fig. 1). Tubulointerstitial nephritis was not observed. He was treated with oral potassium and phosphorus preparations, which resulted in his electrolyte abnormalities improving to the point where he did not need medication, and his kidney function gradually recovered (Fig. 2). Urinary β2MG decreased to 504 µg/L at 2 weeks. His appetite also improved. However, 5 months later, the kidney dysfunction persisted, with a serum Cr level of 1.21 mg/dL and eGFR of 48.2 mL/min/1.73 m2. Subsequently, his serum cholesterol levels gradually increased until all supplements were discontinued, and a statin drug had to be started.

Table 1 Laboratory tests on admission
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Table 2 Urinary amino acid analysis
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Fig. 1
figure 1

Histopathological findings of proximal tubular injury with simplification of the tubular epithelial cells by Periodic Acid Schiff (PAS) staining (objective magnification ×100). Minor glomerular abnormalities were observed

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Fig. 2
figure 2

Patient’s clinical course. After discontinuation of Red Yeast Rice Cholesterol Help®, electrolyte abnormalities requiring oral medication improved, and the patient’s kidney function gradually improved

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Discussion

This is the first case report of acute kidney injury and Fanconi syndrome in a patient taking many health supplements, including Red Yeast Rice Cholesterol Help®.

As previously mentioned, acquired Fanconi syndrome can be caused by various diseases. Therefore, we evaluated the patient’s blood biochemistry, but were unable to identify any related diseases. The results were negative for serum and urine protein electrophoresis and normal for the ratio of free light-chain κ/λ ratio for MGRS, including LCPT. The results were negative for antinuclear antibodies and anti-SSA antibodies for Sjogren syndrome. There was no tubulointerstitial nephritis on light microscopy and no uveitis. Serum IgG4 levels were not elevated. The results were also negative for anti-mitochondrial M2 antibodies for TINU syndrome, IgG4RKD, and IgMPC-TIN. There was no history of chemical exposure and no elevation of cadmium, lead, or chromium levels.

Since the patient experienced persistent loss of appetite and weight, there might have been some pre-renal components to his condition. The values of FENa and FEUN also suggested the presence of a mild pre-renal component, although the patient’s blood pressure was not low. However, Fanconi syndrome is not associated with pre-renal damage.

Since the patient was receiving several drugs other than Red Yeast Rice Cholesterol Help®, their influence on the renal injury could not be ruled out. Regarding drug-related effects, there have been reports of kidney injury with P-CAB. However, kidney dysfunction was recognized before he started taking P-CAB, and there have been no reports of Fanconi syndrome due to P-CAB therapy. In particular, since nephropathy induced by AA in Fanconi syndrome has been reported [6], we strongly suspected its influence. However, no Chinese herbal medicine containing AA is currently available in Japan.

Recently, in Japan, many patients taking with Red Yeast Rice Cholesterol Help® oral medication in a certain period, presented with fatigue, anorexia and diagnosed with acute kidney injury and Fanconi syndrome. Japanese Society of Nephrology shows the data of questionnaires of 47 patients [11], but the mechanism due to the drug is unknown. Citrinin is a substance produced by the mold used for production of red yeast rice, which causes proximal tubular damage [8]. As mentioned previously, citrinin is not produced by the mold M. pilosus, which is used in the production of the new red yeast rice, Red Yeast Rice Cholesterol Help®. In this case, it was clear from the patient’s laboratory data and histological images that proximal tubular damage had occurred, although we could not identify other possible causes. Although the causative agent is not yet clear, we predicted that a substance might have caused the renal tubular damage. In fact, it was recently reported that Red Yeast Rice Cholesterol Help® created during a certain period contained puberulic acid. Puberulic acid is produced by the genus Blue Mold, although details about its nephrotoxic effects are not known. While it is possible that puberulic acid causes proximal tubular damage, further investigation of this is required in the future.

In this case, the patient was able to stop taking Red Yeast Rice Cholesterol Help® at an early stage, resulting in gradual recovery of his kidney function. This might suggest that early discontinuation of its administration is important in acute kidney injury and Fanconi syndrome potentially caused by Red Yeast Rice Cholesterol Help®.

Conclusion

This is the first case report of acute kidney injury and Fanconi syndrome in a patient taking many health supplements, including Red Yeast Rice Cholesterol Help®. Several reports of kidney damage caused by Red Yeast Rice Cholesterol Help® are emerging one after another in Japan, suggesting that a detailed investigation is necessary. Early discontinuation of its oral administration might be useful in improving kidney function in cases that suffer such injury.