UNASSIGNED: Drug-induced tubulointerstitial injury is a common cause of renal impairment. Since the mechanisms of drug-induced tubular injury are diverse, various treatment approaches are needed according to the pathogenesis. Renal biopsy is indispensable to determine not only the pathological diagnosis, but also the underlying mechanism, and to guide appropriate treatment. Most recently, one of the red yeast supplements has been widely highlighted as a novel cause of tubular damage, mainly in Japan and Asia. However, neither detailed pathological findings nor the mechanism of renal impairment has been sufficiently reported.
UNASSIGNED: Two cases of renal impairment after taking red yeast supplement internally are presented. Both cases showed renal dysfunction with low uric acid, potassium, and phosphorus levels, characteristic features of Fanconi syndrome. The renal biopsy findings of both cases showed severe injury to the proximal tubules with mild inflammatory cell infiltration. The proximal tubules exhibited diffuse loss of the brush border, flattening, and tubular lumen dilation. Immunofluorescence showed no deposition of immunoglobulin and complement in the glomeruli and tubules. Electron microscopic findings indicated proximal tubular damage without crystal deposition. Moreover, immunohistochemistry using the proximal tubular marker CD10 and a marker for distal tubules including the loop of Henle, E-cadherin, collectively demonstrated that the focus of renal injury in both cases was mainly the proximal tubules.
UNASSIGNED: The red yeast rice supplement itself, its metabolized product, or other unknown contaminant components might directly induce proximal tubulopathy rather than an allergic reaction-related tubulointerstitial nephritis.

Fanconi syndrome (FS) is a complex disorder characterized by a reabsorption defect in the proximal renal tubule (PT), leading to urinary loss of molecules such as glucose, phosphate, calcium, amino acids, bicarbonate, potassium, and low-molecular-weight proteins. Its etiology can be genetic or acquired, with drug toxicity being a significant cause of the acquired forms. The heterogeneous manifestations of FS, whether in its partial or complete form, can pose challenges in the emergency department; nevertheless, it should be considered in certain patients, as understanding its cause is crucial for initiating effective treatment. We present the case of a 59-year-old female patient with FS who was treated with lenalidomide in the context of stage III IgG kappa multiple myeloma according to the Salmon Durie classification. We highlight the recurrent nature of this syndrome in this patient.

In infantile nephropathic cystinosis, variants of the CTNS gene cause accumulation of cystine in lysosomes, causing progressive damage to most organs. Patients usually present before 1 year of age with signs of renal Fanconi syndrome. Cysteamine therapy allows cystine clearance from lysosomes and delays kidney damage but does not prevent progression to end-stage kidney disease, suggesting that pathways unrelated to cystine accumulation are also involved. Among these, impaired autophagy, altered endolysosomal trafficking, and increased apoptosis have emerged in recent years as potential targets for new therapies. We previously showed that luteolin, a flavonoid compound, improves these abnormal pathways in cystinotic cells and in zebrafish models of the disease. Herein, we have investigated if prolonged luteolin treatment ameliorates kidney damage in a murine model of cystinosis. To this end, we have treated Ctns-/- mice from 2 to 8 months with 150 mg/kg/day of luteolin. No significant side effects were observed. Compared to untreated animals, analyses of kidney cortex samples obtained after sacrifice showed that luteolin decreased p62/SQSTM1 levels (p <0.001), improved the number, size, and distribution of LAMP1-positive structures (p <0.02), and decreased tissue expression of cleaved caspase 3 (p <0.001). However, we did not observe improvements in renal Fanconi syndrome and kidney inflammation. Kidney function remained normal during the time of the study. These results indicate that luteolin has positive effects on the apoptosis and endo-lysosomal defects of cystinotic proximal tubular cells. However, these beneficial effects did not translate into improvement of renal Fanconi syndrome.

Multiple myeloma commonly manifests with symptoms arising from the involvement of various organs, particularly the bone and kidneys. In this report, we detail the case of a 44-year-old man who was diagnosed with multiple myeloma associated with reduced bone density. He exhibited clinical findings of osteomalacia due to Fanconi syndrome (characterized clinically by bone pain and proximal weakness and biochemically by elevated serum alkaline phosphatase, hypophosphatemia, hypouricemia, and glucosuria). With phosphate replacement, there was a notable improvement in bone pain, osteomalacia, and bone mineral density. Nevertheless, the patient continued to experience renal wasting of phosphate, uric acid, and glucose despite achieving remission from multiple myeloma for nearly 2 years. Our case highlights several important clinical features of myeloma-associated Fanconi syndrome, including the need to recognize this complication to appropriately treat the underlying bone disease while avoiding osteoclast inhibitors and the long-term persistence of the proximal renal tubulopathy despite achieving remission from myeloma and correction of osteomalacia.

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 1 year, 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 12 weeks, 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.

Patients with ifosfamide-induced renal damage present with Fanconi syndrome. Karyomegalic nephropathy/interstitial nephritis (KNIN) is a rare form of chronic tubulo-interstitial nephritis that was initially considered a type of familial nephropathy. However, several reports of drug-induced KNIN, i.e., KNIN-like nephropathy, have been reported in recent years. We present the case of an 18-year-old man who presented with Fanconi syndrome and progressive renal dysfunction after receiving chemotherapy including ifosfamide and cisplatin for right femoral osteosarcoma. Renal biopsy revealed numerous atrophied tubular epithelial cells with large, polymorphic nuclei, and the definitive diagnosis was KNIN. Most patients with KNIN-like nephropathy who receive ifosfamide are concomitantly treated with cisplatin, indicating that ifosfamide and cisplatin might act synergistically to increase the risk for KNIN-like nephropathy. Further investigation in case series is warranted to reveal potential treatment approaches and to evaluate prognosis.

Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them.
OBJECTIVE: The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age.
METHODS: Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022.
RESULTS: Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides.
CONCLUSIONS: If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF.

Fanconi syndrome (FS) can present with hypophosphatemia, renal glycosuria, hypouricemia and aminoaciduria. Phosphate depletion is the most critical clinical aspect of FS as it leads to osteomalacia. Some patients present with symptoms and signs related to hypophosphatemic osteomalacia (HO). Thus, these patients present with these symptoms and are misdiagnosed. From an investigation of the published literature, HO symptoms are found to be non-specific and were thus misdiagnosed in various centers. The present study describes the case of a a 46-year-old male with FS who suffered from joint pain and was first misdiagnosed. After he was referred to the authors\' hospital, his case was evaluated and following a consideration of the results of this evaluation, he was diagnosed with idiopathic FS with multiple osteoporotic fractures. Furthermore, the present study performs a brief literature review other cases of patients that were misdiagnosed and whose symptoms were later found to be due to HO are also discussed. It is hoped that the present study may increase the awareness of HO among physicians and may help to draw attention to such cases of patients presenting with non-specific symptoms.

Twenty-eight individuals who experienced proximal renal tubulopathy (PRT, Fanconi syndrome) while receiving tenofovir disoproxil initiated tenofovir alafenamide (TAF) and were followed for 5 years. None developed recurrent PRT or experienced significant changes in estimated glomerular filtration rate (by creatinine or cystatin-C), albuminuria, proteinuria, retinol-binding proteinuria, fractional excretion of phosphate, alkaline phosphatase, or bone mineral density at the lumbar spine. These data suggest that TAF is a well tolerated treatment option for individuals vulnerable to developing PRT.

A 62-year-old man visited his primary care physician with the complaints of loss of appetite and fatigue. He was admitted to our hospital based on a diagnosis of acute kidney injury, Fanconi syndrome as indicated by hypokalemia, hypouricemia, hypophosphatemia, elevated glucose levels in urine, and aminoaciduria. He had been taking multiple supplements, including Red Yeast Rice Cholesterol Help®, for one and a half years. After admission, all the supplements were stopped. Blood samples were collected; however, the samples were negative for diseases that could cause Fanconi syndrome. Renal biopsy revealed renal proximal tubular damage, mainly characterized by simplification of the proximal tubular epithelium. The mycotoxin, citrinin, which is reported to be produced by the mold used for producing red yeast rice, but not the mold Monascus pilosus used for Red Yeast Rice Cholesterol Help®, reportedly causes proximal tubular damage. However, although the causative agent has not been identified, it was thought that a substance similar to citrinin, produced by the mold used for Red Yeast Rice Cholesterol Help®, caused proximal tubular damage, leading to acute kidney injury and Fanconi syndrome. Hence, all supplements were stopped, and the patient was treated with oral potassium and phosphorus preparations, leading to gradual recovery of his kidney function. We herein report the first case of acute kidney injury and Fanconi syndrome in a patient taking multiple health supplements, including Red Yeast Rice Cholesterol Help®. Early discontinuation of the oral supplements was probably useful in improving the patient\'s kidney function.