Fanconi Syndrome Research Articles

Element analysis applied to investigate acute kidney injury induced by red yeast rice supplement.

Silica nanoparticles are used in functional foods and tablets to increase drug stability and delivery. We investigated a patient with acute kidney injury with Fanconi syndrome after taking functional food tablets made from red yeast rice using low-vacuum scanning electron microscopy (LVSEM) with an element analysis system. Kidney biopsy revealed proximal tubular necrosis and vacuolization with 10-20nm black granules, which were similar to the silica nanoparticles found in the functional food tablets and urinary samples, as determined via LVSEM with element analysis. Reabsorbed silica nanoparticles induce oxidative stress in the kidney. Element analysis by LVSEM is useful to investigate a possible cause of acute tubular necrosis in patients with Fanconi syndrome.

Presence of mitochondrial dysfunction in a case of Fanconi syndrome with normoglycemic MODY1.

Maturity-onset diabetes of the young 1 (MODY1) is characterized by macrosomia and transient hypoglycemia in neonates, in addition to diabetes mellitus (DM). Only patients with MODY1 harboring a pathogenic variant (c.187C > T; p.R63W) in HNF4A are sure to develop Fanconi syndrome (FS). Here we report the successful diagnosis of MODY1 in a patient harboring p.R63W before confirmation of DM-related hyperglycemia after being alerted to the presence of abnormal mitochondria in a kidney-biopsy specimen revealed by electron microscopy. The patient was born at 39weeks of gestation with macrosomia, elevated levels of liver enzymes, and transient hypoglycemia. At three years of age, proteinuria was found by chance, and further laboratory investigations revealed metabolic acidosis, mild renal dysfunction, hypouricemia, proteinuria, aminoaciduria, and glycosuria. On this basis, we diagnosed the patient as having FS and performed percutaneous renal biopsy. Light microscopy revealed no evidence of proximal tubule disorder, but electron microscopy demonstrated mitochondria with disordered cristae in glomerular podocytes and giant mitochondria in proximal tubules. Mitochondrial nephropathy was suspected, and skin fibroblasts from the patient grown on galactose medium showed decreased oxygen consumption suggestive of mitochondrial dysfunction. Therefore, genetic testing was performed and a pathogenic variant (c.187C > T; p.R63W) in HNF4A was detected. Mitochondrial dysfunction in a Drosophila and murine model of patients with both MODY1 and FS has already been reported, and we detected it in this human MODY1/FS patient on the basis of functional tests and imaging. We believe mitochondrial dysfunction may be involved in the pathogenesis of MODY1/FS.

Acute kidney injury with Fanconi syndrome following intake of a Red Yeast Rice Supplement

Acute kidney injury with Fanconi syndrome following intake of a Red Yeast Rice Supplement

Tenofovir alafenamide compared to tenofovir disoproxil fumarate, induces dysglycemia, and dyslipidemia in Wistar rats.

To determine the metabolic effects of tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF) in vivo . Male Wistar rats ( Rattus novergicus , 250-300 g body weight) were divided into three groups ( n = 8) and orally treated daily with 1.0 ml distilled water (group 1), TAF (0.42 mg/kg) (group 2), or TDF (5.0 mg/kg) (group 3), respectively, for 56 days. Glucose tolerance tests were done before the animals were sacrificed by halothane overdose, and blood was collected by cardiac puncture for the analysis of plasma lipids, electrolytes, and insulin. The kidney and pancreatic tissues were excised and homogenized to measure oxidative stress. Compartmentation of TAF and TDF was determined in NRK-52 and peripheral blood mononuclear cells (PBMCs). There were no significant differences in weight gain among controls, TAF- or TDF-treated rats. TAF-treated rats had significantly increased fasting blood glucose (FBG), fasting plasma insulin (FPI), insulin resistance, impaired glucose tolerance, and dyslipidemia compared to control or TDF-treated rats, respectively. There was increased lipid peroxidation in the pancreas of TAF-treated compared to TDF-treated or control animals, respectively. TDF- treated rats presented with symptoms of Fanconi syndrome compared to TAF-treated or control animals, respectively. Kidney homogenates from TDF-treated animals had significantly reduced antioxidant enzyme activity compared to TAF-treated animals or controls, respectively. Intracellular concentrations of TAF were significantly higher than TDF in both NRK-52E cells and PBMC, respectively. TAF treatment is weight-neutral and causes dysglycemia, and dyslipidemia but not Fanconi syndrome compared to TDF.

Tubulointerstitial nephritis with IgM-positive plasma cells complicated by liver failure.

Tubulointerstitial nephritis (TIN) is characterized by inflammation of the renal interstitium with the infiltration of immune cells, mainly consisting of T cells. Recently, patients with TIN with the predominant infiltration of immunoglobulin M (IgM)-positive plasma cells were reported, coined IgMPC-TIN. Here we report the case of a 70-year-old woman diagnosed with Fanconi syndrome and renal tubular acidosis. Renal biopsy revealed IgMPC-TIN. Her renal dysfunction and clinical findings improved after corticosteroid therapy. However, the patient died of progressive liver failure and spontaneous bacterial peritonitis. In laboratory tests, viral hepatitis was excluded, and autoantibodies associated with liver diseases were negative. Generally, IgMPC-TIN is often complicated by primary biliary cholangitis (PBC), whereas her autopsy revealed the local infiltration of IgM-positive plasma cells, obliterative portal venopathy, and nodular regenerative hyperplasia in liver. This case is the first demonstration that IgMPC-TIN is also seen in liver disease with nodular regenerative hyperplasia, although IgMPC-TIN is more common in anti-M2 antibody-positive disease.

Recurrent Plasma Cell Myeloma with Intracytoplasmic Auer Rod-like Inclusions after Autologous Hematopoietic Stem Cells Transplantation

Abstract Introduction/Objective Plasma cell myeloma (PCM) is a bone marrow based neoplastic disorder of plasma cells (PCs). The detection of intracytoplasmic Auer rod-like inclusions (ARLI) is rare in PCM. The correlation between the ARLI and the diagnosis, recurrence, prognosis of PCM remains unknown. Methods/Case Report Retrospective comparison of pathological findings between two separate bone marrow biopsies of a recurrent kappa-restricted, IgA-positive PCM with intracytoplasmic ARLI before and after autologous hematopoietic stem cell transplantation (HSCT) with a 7-year observation. A detailed review of all the published cases of PCM with intracytoplasmic ARLI. Results (if a Case Study enter NA) The neoplastic PCs exhibited anaplastic features in the original diagnosis but became relatively mature in the recurrence after the autologous HSCT. The intracytoplasmic ARLI were found in both cases and tended to increase in the recurrence. The patient’s renal function was within normal range at the first diagnosis and during the recurrence. To the best of our knowledge, about 41 cases have been published since the first description of ARLI in 1940 including 16 females (age of onset: 38 to 72 years, mean: 57.7 y), and 25 males (age of onset: 34 to 79 years, mean: 58.2 y). The lysosomal origin of ARLI with the predominance in kappa-restricted, IgG- producing PCM and possible correlation with adult Fanconi syndrome were described. Only 7 kappa-restricted, IgA- producing PCM with ARLI were among them. Conclusion Our case is the first recurrent kappa-restricted IgA PCM with ARLI after autologous HSCT. The morphologies of the neoplastic PCs have changed from anaplastic to relatively mature and more have ARLI in the recurrence. However, the correlation with the adult Fanconi syndrome is not observed in our case. The average age at diagnosis is similar between male and female and might be younger than the average age (69 years) at diagnosis for all PCM.

A Case of Fanconi Syndrome with Biopsy-Proven Acute Proximal Tubular Injury Induced by a Dietary Supplement, Benikoji

A Case of Fanconi Syndrome with Biopsy-Proven Acute Proximal Tubular Injury Induced by a Dietary Supplement, Benikoji

Unraveling the Mystery: McCune-Albright Syndrome as a Rare Cause of Fanconi Syndrome and Kidney Failure

Unraveling the Mystery: McCune-Albright Syndrome as a Rare Cause of Fanconi Syndrome and Kidney Failure

Novel Models to Study Fanconi Syndrome and CKD Due to Heterozygous GATMP341L Mutations

Novel Models to Study Fanconi Syndrome and CKD Due to Heterozygous GATMP341L Mutations

Partial Fanconi Syndrome following Ifosfamide

Partial Fanconi Syndrome following Ifosfamide

Ifosfamide-Induced Fanconi Syndrome: A Rare but Recognized Complication

Ifosfamide is an alkylating chemotherapeutic agent that was approved for medical use in the United States in 1987. It is frequently prescribed either alone or in combination with other agents to treat a variety of cancers, such as sarcomas, lymphomas, and lung cancers. It has increasingly been associated with the development of acquired Fanconi Syndrome. Fanconi Syndrome is characterized by the dysfunction of the proximal renal tubule, leading to the inability to reabsorb essential nutrients and electrolytes from the urine. This causes a wide range of abnormalities in electrolyte levels which can lead to a host of metabolic complications if not recognized and efficiently treated. We describe a case of a patient who developed acquired Fanconi Syndrome after starting a chemotherapy regimen with Ifosfamide for a known malignancy. Upon discontinuation of the Ifosfamide and repletion of electrolytes, the patient improved clinically with resolution of renal injury and stabilization of electrolyte levels. This report aims to increase awareness for Fanconi Syndrome and demonstrate the necessity for having high clinical suspicion of this condition, especially when managing patients who are on chemotherapeutic agents, such as Ifosfamide. Bangladesh J Medicine 2024; 35: 200-203

Tenofovir-Induced Fanconi Syndrome Associated with a Fragility Fracture of the Right Femoral Neck

Tenofovir-Induced Fanconi Syndrome Associated with a Fragility Fracture of the Right Femoral Neck

Leptin signalling altered in infantile nephropathic cystinosis-related bone disorder.

The CTNS gene mutation causes infantile nephropathic cystinosis (INC). Patients with INC develop Fanconi syndrome and chronic kidney disease (CKD) with significant bone deformations. C57BL/6 Ctns-/- mice are an animal model for studying INC. Hyperleptinaemia results from the kidney's inability to eliminate the hormone leptin in CKD. Ctns-/- mice have elevated serum leptin concentrations. Leptin regulates bone metabolism through its receptor that signals further via the hypothalamic melanocortin 4 receptor (MC4R). Leptin signalling may affect bone health in Ctns-/- mice. We first defined the time course of bone abnormalities in Ctns-/- mice between 1 and 12months of age. We used both genetic and pharmacological approaches to investigate leptin signalling in Ctns-/- mice. We generated Ctns-/-Mc4r-/- double knockout mice. Bone phenotype of Ctns-/-Mc4r-/- mice, Ctns-/- mice and wild type (WT) mice at 1, 4, and 9months of age were compared. We then treated 12-month-old Ctns-/- mice and WT mice with a pegylated leptin receptor antagonist (PLA) (7mg/kg/day, IP), a MC4R antagonist agouti-related peptide (AgRP) (2nmol, intracranial infusion on days 0, 3, 6, 9, 12, 15, 18, 21, 24, and 27), or vehicle (normal saline), respectively, for 28days. Whole-body (BMC/BMD, bone area) and femoral bone phenotype (BMC/BMD, bone area, length and failure load) of mice were measured by DXA and femoral shaft biochemical test. We also measured lean mass content by EchoMRI and muscle function (grip strength and rotarod activity) in mice. Femur protein content of JAK2 and STAT3 was measured by ELISA kits, respectively. Bone defects are present in Ctns-/- mice throughout its first year of life. The deletion of the Mc4r gene attenuated bone disorder in Ctns-/- mice. Femoral BMD, bone area, length, and strength (failure load) were significantly increased in 9-month-old Ctns-/-Mc4r-/- mice than in age-matched Ctns-/- mice. PLA and AgRP treatment significantly increased femoral bone density (BMC/BMD) and mechanical strength in 12-month-old Ctns-/- mice. We adopted the pair-feeding approach for this study to show that the protective effects of PLA or AgRP on bone phenotype are independent of their potent orexigenic effect. Furthermore, an increase in lean mass and in vivo muscle function (grip strength and rotarod activity) are associated with improvements in bone phenotype (femoral BMC/BMD and mechanical strength) in Ctns-/- mice, suggesting a muscle-bone interplay. Decreased femur protein content of JAK2 and STAT3 was evident in Ctns-/- mice. PLA or AgRP treatment attenuated femur STAT3 content in Ctns-/- mice. Our findings suggest a significant role for dysregulated leptin signalling in INC-related bone disorder, either directly or potentially involving a muscle-bone interplay. Leptin signalling blockade may represent a novel approach to treating bone disease as well as muscle wasting in INC.

Intermediate cystinosis: a case report of 10-year treatment with cysteamine

BackgroundCystinosis is a lysosomal storage disorder characterized by an autosomal recessive phenotype. Intermediate cystinosis, which progresses slowly and causes renal failure, accounts for approximately 5% of all cystinosis cases. Patients with intermediate cystinosis may not exhibit the typical symptoms of cystinosis, such as Fanconi syndrome and ocular symptoms. Because of its diverse clinical presentation and rarity, intermediate cystinosis can be difficult to diagnose. Additionally, few patients can tolerate cystine-depleting drugs, such as cysteamine, because of their complicated administration schedules and side effects. We report a case of intermediate cystinosis that was treated with cysteamine for 10 years.Case presentationUrinary abnormalities were first diagnosed when the patient was 3 years of age during a health examination specifically for 3-year-old children, which is unique to Japan. Cystinosis was diagnosed when the patient was 12 years of age. Cysteamine therapy was initiated and regular cystine concentration measurements were performed. Although proteinuria persisted, the patient’s renal function progressed slowly. Two renal biopsies were performed, and multinucleated podocytes and cystine crystals without focal segmental glomerulosclerosis lesions were observed in the biopsy specimens. The patient’s renal function remained stable.ConclusionsThis case of intermediate cystinosis was treated with cysteamine over the course of 10 years. Intermediate cystinosis requires an appropriate diagnosis and long-term treatment.

Hypokalemic paralysis and proximal renal tubular acidosis secondary to tenofovir-induced Fanconi syndrome: A contributing cause of death

Nucleotide reverse transcriptase inhibitors (NRTIs, primarily cidofovir and adefovir, less likely tenofovir) pose a well-known risk of nephrotoxicity. Acute renal failure, nephrogenic diabetes insipidus (NDI), and Fanconi syndrome (FS) are the primarily reported renal adverse effects associated with NRTIs. In this report, we describe a case of a 52-year-old female who presented to the outpatient department of a tertiary-care facility with polyuria, polydipsia, convulsions, myalgias, and hypokalemic paralysis (quadriparesis) after 10 months exposure to tenofovir disoproxil fumarate (TDF), which she was taking for HIV and Hepatitis-B virus coinfection. The patient developed hypokalemic paralysis and proximal renal tubular acidosis (pRTA) with normal anion gap hyperchloremic metabolic acidosis. On evaluation, renal tubulopathy was evident, which was resolved post-TDF discontinuation and therapeutic corrections. A diagnosis of TDF-induced FS, pRTA, and NDI were considered, as there were no clear alternative explanations. This report also highlights the characteristics of TDF-induced FS from the published case reports in the Indian context.

Recurrent acute kidney injury with Fanconi syndrome related to red yeast rice supplement.

A 51-year-old woman was admitted to our hospital for acute kidney injury (AKI) with an elevated serum creatinine level of 5.07mg/dL and Fanconi syndrome. The patient was discharged after partial recovery of kidney dysfunction with conservative treatment but was readmitted approximately three months later due to a recurrence of AKI with Fanconi syndrome. A kidney biopsy revealed findings consistent with acute tubular necrosis and localized tubulointerstitial nephritis, with no specific vascular or glomerular lesions. The patient's medical history revealed that prior to both AKI episodes, the patient had been taking "Red Yeast Cholestehelp", a lipid-lowering supplement for a period of time. Her kidney dysfunction and Fanconi syndrome improved with the discontinuation of the supplement and correction with oral medications. In Japan, a series of similar health hazards related to the red yeast rice supplement has been reported, but the causative toxin and its causal relationship with AKI have not been established. The present case provides firm evidence that clinically supports this relationship.

Reduced guanidinoacetate in plasma of patients with autosomal dominant Fanconi syndrome due to heterozygous P341L GATM variant and study of organoids towards treatment.

Autosomal dominant Fanconi syndrome due to a GATM variant (GATM-FS), causes accumulation of misfolded arginine-glycine amidinotransferase (AGAT) in proximal renal tubules leading to cellular injury. GATM-FS presents during childhood and progresses to end-stage kidney disease (ESKD) in adults. We study creatine metabolism in two individuals of unrelated families with a known GATM variant and the effect of creatine supplementation in kidney organoids. Plasma and urine metabolites were measured by mass spectrometry. Brain creatine was assessed by magnetic resonance spectroscopy (MRS). Guanidinoacetate (GAA) synthesis by the AGAT mutant was measured in patient-derived immortalized lymphocytes using stable isotopes of arginine and glycine. The effect of creatine on GATM expression was assessed in human kidney cells and organoids. Several family members from two unrelated families were diagnosed with Fanconi syndrome and had the c.1022C>T (p. P341L) variant in GATM. Two affected individuals in both families had moderately reduced plasma GAA levels. In comparison to wild-type cells, GAA synthesis by patient-derived GATM P341L+/- lymphoblastoid cell lines (LCL) was reduced, but not absent as in GATM cells from a patient with creatine deficiency syndrome. In vitro studies on human kidney organoids revealed reduced AGAT expression after treatment with creatine. Finally, we showed in one patient that creatine supplementation (5 g daily) substantially increased plasma creatine levels. We report low plasma and urine GAA in patients with autosomal dominant GATM-FS and show that creatine downregulates AGAT in human kidney cells.

Clinicopathological features and outcomes of PLA2R-related membranous nephropathy with renal glycosuria.

Membranous nephropathy (MN) is an immune complex-mediated disease. Massive proteinuria can lead to Fanconi syndrome, clinically manifesting as renal glycosuria. The prevalence and prognosis of M-type phospholipase A2 receptor (PLA2R)-related MN with renal glycosuria remain unknown. Patients diagnosed with PLA2R-related MN with renal glycosuria were reviewed, and the control group comprised patients with MN without renal glycosuria who were randomly selected at a ratio of 1:3. 50 patients diagnosed with PLA2R-related MN with renal glycosuria from January 2015 to January 2020 were included, with a prevalence of 2.3%. Compared with patients without renal glycosuria, those with renal glycosuria exhibited greater proteinuria, lower estimated glomerular filtration rate (eGFR), and higher use of diuretics, anticoagulants, antibiotics, traditional Chinese medicine, and tacrolimus within 3 months prior to renal biopsy (all p<0.05). Histologically, patients with renal glycosuria exhibited more severe pathological stages, acute/chronic tubulointerstitial lesions, and tubulointerstitial inflammation (all p<0.05). Of the 10 patients treated with rituximab (RTX), proteinuria remission was maintained in 6 (60%) patients, and urine glucose remission was achieved in 5 of these 6 patients (83.3%). Multivariate Cox regression analysis showed that renal glycosuria and age >50 years were independent risk factors for end-stage renal disease (ESRD) or a 30% reduction in the eGFR in patients with PLA2R-related MN. PLA2R-related MN patients with renal glycosuria presented with more severe clinicopathological manifestations and worse prognoses. Nephrotoxic drugs should be administered rationally, and RTX should be considered as a promising treatment option.

Long-term effects of luteolin in a mouse model of nephropathic cystinosis

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.

Safety of tenofovir alafenamide in people with HIV who experienced proximal renal tubulopathy on tenofovir disoproxil.

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.