Successful Resolution of Suspected Red Yeast Rice-induced Nephropathy

Abstract

Recently, several Japanese patients have developed interstitial nephritis or acute tubular injury/necrosis, both accompanied by Fanconi syndrome, after consuming a specific red yeast rice supplement. In most cases, the renal function did not fully recover even after discontinuation of supplements and glucocorticoid treatment. A 52-year-old woman developed interstitial nephritis and Fanconi syndrome after receiving supplements. A renal biopsy revealed mild lymphocytic infiltration. Her renal function recovered after discontinuing the supplement without glucocorticoids. The supplement was contaminated with puberulic acid, a known cause of tubular necrosis; however, the cause of interstitial nephritis remains uncertain. Biopsy findings guided the decision to avoid glucocorticoids.

Introduction

Interstitial nephritis is commonly induced by drugs (1). The pathogenesis of drug-induced interstitial nephritis is an immunological reaction mediated by a type IV hypersensitivity response, with antimicrobials and non-steroidal anti-inflammatory drugs being the most common causative agents (2). Early glucocorticoid (GC) therapy and elimination of the offending antigen source are recommended treatments for drug-induced interstitial nephritis (3). Drug-induced interstitial nephritis rarely progresses to tubular damage, leading to Fanconi syndrome; however, several cases have been reported (1,4-11). Interstitial nephritis and Fanconi syndrome may be caused by aristolochic acid, which is present in Chinese herbs (12).

In 2024, a series of cases of kidney impairment caused by supplementation with red yeast rice (Monascus pilosus) were reported in Japan (13-21). Red yeast rice is used as a dietary supplement because of its monacolin K content, which has the same structure as lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor commonly prescribed to reduce low-density lipoprotein cholesterol levels (22). Few cases have shown complete restoration of the renal function, even after discontinuation of red yeast rice supplements and administration of GCs (15,16,20).

This is the first report to describe the complete recovery of the renal function following discontinuation of the supplement without GC treatment in a patient who developed Fanconi syndrome and interstitial nephritis after using a red yeast rice supplement.

Case Report

A 52-year-old woman with proteinuria and renal failure was referred to our hospital. A health examination 4 months prior had revealed no abnormalities (creatinine level, 0.76 mg/dL, estimated glomerular filtration rate of 62.6 mL/min/1.73 m²), no history of allergies, and no exposure to heavy metals in daily life. The patient was not using any medications; however, she had been consuming various supplements (Table 1), including a red yeast rice supplement at a dose of three capsules per day, for two years and two months, which she regularly purchased online every three months. She had started taking a new batch of a red yeast rice supplement with the manufacturing number “H306,” which was later recalled, 18 days before presenting to our hospital; however, she had discontinued its use because she experienced nausea 6 days before presentation.

Table 1.

Supplements Used by the Patient.

Red yeast rice supplement

Blueberry supplement

Proteoglycan supplement

Salacinol supplement

Vitamin D3

Vitamin C

During an outpatient visit, the patient's vital signs were as follows: clear consciousness, temperature 36.5°C, blood pressure 134/77 mmHg, and pulse 74 beats/min. A physical examination revealed bilateral lower leg edema. Laboratory tests revealed a serum creatinine level of 2.06 mg/dL, urine β2-microglobulin level of 50,250 μg/L, and N-acetyl-beta-D-glucosaminidase (NAG) level of 31.1 U/L, suggesting renal tubular injury and interstitial nephritis. Additional laboratory tests showed hypokalemia (3.3 mmol/L), hypophosphatemia (2.0 mg/dL), hypouricemia (1.7 mg/dL), hyperchloremia (112 mmol/L), and normal sodium (138 mmol/L) and low bicarbonate (18.9 mmol/L) levels, indicating metabolic acidosis. A urinalysis revealed glucosuria (4+), proteinuria (2+), and amino aciduria, indicating Fanconi syndrome (Table 2). Laboratory results were negative for rheumatoid factor, antinuclear antibodies, cryoglobulins, and M-proteins in both urine and serum. No eosinophils were detected in the patient's urine.

Table 2.

Clinical Characteristics of Patients before and after Red Yeast Rice Supplementation.

Blood counts			Serology
White blood cell	6,200	/μL	Anti-nuclear antibody	<40	-fold
Hemoglobin	12.0	g/dL	Rheumatoid factor	1.06	U/mL
Blood chemistry			Cryoglobulins	-
Total protein	6.9	g/dL	Serum M-proteins	-
Albumin	3.6	g/dL	PR3-ANCA	0.1	U/mL
Total bilirubin	0.5	mg/dL	MPO-ANCA	0.1	U/mL
AST	15	U/L	Anti-DNA antibody	<2.0	U/mL
ALT	24	U/L	Anti-GBM antibody	<2.0	U/mL
ALP	59	U/L	Urine test
γGTP	9.0	U/L	Urine protein	2+
LDH	534	U/L	Urine glucose	4+
Creatinine kinase	106	U/L	Urine blood	2+
Urea nitrogen	20.9	mg/dL	Urine pH	6.0
Creatinine	2.06	mg/dL	Urine sediment
eGFR	20.9	mL/min/1.73m2	Red blood cell	1-4	/HPF
Uric acid	1.7	mg/dL	White blood cell	5-9	/HPF
Sodium	138	mEq/L	Urine chemistry
Potassium	3.3	mEq/L	Protein to creatinine ratio	2.21	g/g/Cr
Chloride	112	mEq/L	Urobilinogen	0.1	mg/dL
HCO3-	18.9	mmol/L	β-2 microglobulin	50,250	μg/L
Calcium	9.4	mg/dL	N-acetyl-beta-D-glucosaminidase	31.1	U/L
Phosphorus	2.0	mg/dL	Urine M-proteins	-

AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, γGTP: gamma-glutamyl transpeptidase, LDH: lactate dehydrogenase, eGFR: estimated glomerular filtration rate, PR3-ANCA: proteinase 3-anti-neutrophil cytoplasmic antibodies, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibodies, DNA: deoxyribonucleic acid, GBM: glomerular basement membrane

Two weeks later, we hospitalized the patient for 5 days to perform a renal biopsy when the serum creatinine level was 1.12 mg/dL. Light microscopy revealed mild interstitial lymphocyte infiltration and mild tubular injury involving approximately 10-20% of the tubulointerstitial region, with 17 normal glomeruli and 1 glomerulus showing global sclerosis (Fig. 1a-c). An immunofluorescence analysis revealed the absence of immune complex deposition. Electron microscopy did not reveal any specific findings. A renal biopsy revealed mild inflammation; therefore, GC administration was considered unnecessary. Nine weeks after discontinuing the red yeast rice supplement, laboratory tests revealed a serum creatinine level of 0.85 mg/dL and estimated glomerular filtration rate of 55.1 mL/min/1.73 m², with no proteinuria and electrolyte levels within normal range. Tubular injury markers decreased somewhat but remained elevated, with a urinary β2-microglobulin level of 627.3 μg/L and an NAG level of 13.3 U/L. Complete recovery was confirmed at 45 weeks after discontinuing the supplement with a serum creatinine level of 0.73 mg/dL, estimated glomerular filtration rate of 64.7 mL/min/1.73 m², urinary β2-microglobulin level of 150.6 μg/L, and NAG level of 5.5 U/L (Fig. 2).

Figure 1.

Kidney biopsy findings observed using light microscopy. (a) A representative image of periodic acid-Schiff (PAS) staining of the renal specimen showing mild interstitial infiltration of inflammatory cells, mainly lymphocytes, in the interstitium of the kidney cortex (original magnification, ×200). (b) PAS staining of the renal specimen revealed normal glomeruli (original magnification, ×400). (c) A representative image of Masson’s trichrome staining of the renal specimen showing mild interstitial fibrosis (original magnification, ×100).

Figure 2.

Clinical course of the patient.

Discussion

Our patient presented with interstitial nephritis and Fanconi syndrome following consumption of a red yeast rice supplement. On day 12, after starting a new batch of supplements, the patient experienced nausea and stopped using all supplements. A renal biopsy performed three weeks after supplement discontinuation showed only mild interstitial nephritis. Based on the renal biopsy results, we decided not to initiate GC treatment, and her renal function fully recovered.

It is uncommon to diagnose drug-induced interstitial nephritis and Fanconi syndrome concurrently. Many drugs can cause interstitial nephritis; however, only a few, such as rifampin, adefovir, metamizole, pamidronate, zoledronate, ifosfamide, valproate, and ranitidine, reportedly cause Fanconi syndrome and interstitial nephritis (4-11). Initiating GCs within two weeks after discontinuation of the presumed causative drug is crucial for preventing interstitial fibrosis (3). In a series of case reports (published in Japan in 2024) on kidney impairment caused by red yeast rice (Monascus pilosus) supplements, renal pathological findings included interstitial nephritis in seven patients and acute tubular injury or necrosis in eight patients (13-21) (Table 3). Fanconi syndrome is present in nearly all reported patients, including the present patient. Of the eight patients with proximal tubular injury, the renal function completely recovered in two who received GCs, whereas a complete recovery was not achieved in the six who did not receive GCs (14,15,17-21). GC treatment should be considered if tubular injury has been confirmed. Only one of the seven patients with interstitial nephritis experienced complete recovery of the renal function after GC treatment (13,16,18,19,21). Thus, mild inflammatory cell infiltration, which did not require GC treatment, along with mild chronic lesions that were unlikely to cause irreversible damage, likely contributed to the improvement in the present case. In clinical practice, the renal function can sometimes be restored solely by discontinuing supplements without the use of GCs, particularly in cases of mild renal impairment. However, this case highlights the importance of a histological evaluation to determine the need for GC administration. It may be important to perform a renal biopsy to assess the pattern and extent of tubulointerstitial damage and to determine whether or not GC treatment is appropriate.

Table 3.

Summary of Previously Reported Cases Associated with Red Yeast Rice Supplements.

Cases	Age	Gender	Cr before onset (mg/dL)	Peak Cr (mg/dL)	Urine β2MG (µg/L)	NAG (U/L)	Pathology		Treatment with glucocorticoids	Prognosis
							Tubulointerstitial nephritis	Tubular injury
(13)	73	F	Normal range	1.27	52,201	27.0	+	-	+	Improved
	53	F	Normal range	1.41	8,373	30.4	+++	-	+	Improved
	55	F	N/A	2.38	19,833	19.4	+++	-	+	Improved
(16)	58	F	Normal range	2.75	126,473	71.7	+	-	+	Recovered
(15)	56	F	Normal range	1.39	82,520	26.7	+	+++	+	Recovered
(21)	49	F	Cr 0.84	20.00	N/A	N/A	++	++	+	Improved
(14)	47	F	Cr 1.09	4.26	109,677	16.6	-	++	+	Improved
(20)	42	M	Normal range	2.12	43,852	22.6	-	++	+	Recovered
(17)	62	M	Normal range	1.43	41,475	40.0 (U/gCr)	-	++	-	Improved
(18)	66	F	Cr 0.61	1.74	56,500	18.5	+	+++	-	Not improved
	54	M	Cr 0.84	1.31	59,712	4.5	++	++	-	Not improved
(19)	51	F	Cr 0.72	5.07	52,945	33.3	+	++	-	Improved
This case	52	F	Cr 0.76	2.28	50,250	31.1	+	-	-	Recovered

β2MG: β2-microglobulin, NAG: N-acetyl-beta-D-glucosaminidase

Red yeast rice may not be the underlying cause of renal impairment. Kidney impairment occurs in patients who consume a particular batch of red yeast rice supplements, suggesting that they are contaminated (13-21). Until 2023, red yeast rice supplement-related renal impairment was mainly caused by rhabdomyolysis (23). As creatine kinase levels were not elevated in our patient, rhabdomyolysis was not indicated as the cause of tubular damage. Citrinin, a mycotoxin produced by several fungal strains belonging to the genera Penicillium, Aspergillus, and Monascus, causes nephrotoxicity and acute tubular necrosis in animal models (24). Although contamination with red yeast rice supplements has been a social concern (25), citrinin was not detected in the series of supplements used by our patient (26). Puberulic acid (C₈H₆O₆), which is produced by Penicillium adametziodes, as well as C₂₈H₄₂O₈ and C₂₃H₃₄O₇, which are novel compounds that are modified forms of monacolin K resulting from the co-incubation of P. adametziodes and Monascus fungus, were found in a particular batch of red yeast rice supplements (27). Puberulic acid has been found to cause tubular necrosis in rats, and acute tubular necrosis has been reported in patients who consumed this supplement (27,28). However, the causative agents of interstitial nephritis in our patient and previous cases remain unknown.

In conclusion, we herein report a case of interstitial nephritis and Fanconi syndrome following the intake of red yeast rice supplements. Complete recovery of the kidney function was achieved without GC treatment. The results of the renal biopsy guided the decision to refrain from GC administration.

Informed consent was obtained from all individual participants included in the study.

The authors state that they have no Conflict of Interest (COI).