Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia.

INTRODUCTION: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. MATERIALS AND METHODS: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. RESULTS: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. CONCLUSION: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.

The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI.

Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the SLC2A2 gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS, SLC2A2 expression was ablated in mouse kidney and HK-2 proximal tubule cells. GLUT2Pax8Cre+ mice developed time-dependent glycogen accumulation in proximal tubule cells and recapitulated the renal Fanconi phenotype seen in patients. In vitro suppression of GLUT2 impaired lysosomal autophagy as shown by transcriptomic and biochemical analysis. However, this effect was reversed by exposure to a low glucose concentration, suggesting that GLUT2 facilitates the homeostasis of key cellular pathways in proximal tubule cells by preventing glucose toxicity. To investigate whether targeting proximal tubule glucose influx can limit glycogen accumulation and correct symptoms in vivo, we treated mice with the selective SGLT2 inhibitor dapagliflozin. Dapagliflozin reduced glycogen accumulation and improved metabolic acidosis and phosphaturia in the animals by normalizing the expression of Napi2a and NHE3 transporters. In addition, in a patient with FBS, dapagliflozin was safe, improved serum potassium and phosphate concentrations, and reduced glycogen content in urinary shed cells. Overall, this study provides proof of concept for dapagliflozin as a potentially suitable therapy for FBS.

Renal proximal tubulopathy in an HIV-infected patient treated with tenofovir alafenamide and gentamicin: a case report.

BACKGROUND: The nucleotide reverse transcriptase inhibitor Tenofovir Alafenamide (TAF) is a novel pro-drug of tenofovir (TFV) and possesses a superior renal safety profile compared with tenofovir disoproxil fumerate (TDF). Due to unique pharmacokinetic characteristics, treatment with TAF is not associated with significant renal proximal tubular accumulation of TFV. TAF is associated with a lower risk of acute kidney injury, chronic kidney disease, proteinuria and renal proximal tubular dysfunction than treatment with TDF. No cases of Fanconi syndrome have been reported in clinical trials of TAF. It is unknown whether treatment with TAF can lead to accumulation of TFV in proximal tubular cells and cause nephrotoxicity under certain clinical circumstances. CASE PRESENTATION: Here we report the case of a patient on stable TAF-based antiretroviral therapy with for HIV-1 infection who developed proximal tubulopathy when treated with gentamicin for febrile neutropenia in the context of relapsed Hodgkin lymphoma. Eighteen days after commencing chemotherapy for relapsed Hodgkin lymphoma the patient presented to hospital with fevers, hypotension and neutropenia. The patient was commenced on piperacillin, tazobactam and gentamicin. Within 24 h the patient developed marked hypokalaemia and hypophosphataemia requiring intravenous replacement therapy. There was proteinuria, glycosuria and evidence of marked urinary electrolyte wasting, consistent with acute proximal tubular dysfunction. Eleven days after the gentamicin was stopped the serum biochemistry normalised. The urinary electrolyte wasting and proteinuria had improved, and the glycosuria had resolved. CONCLUSION: This is the first case report to describe acute renal proximal tubulopathy in an HIV-infected patient treated with TAF and gentamicin. As the number of patients prescribed TAF outside the clinical trial setting increases, so too does the potential for previously unreported drug interactions and adverse events. Clinicians need to be aware of potential unreported adverse drug reactions as the use of TAF becomes increasingly common in clinical practice.

Retrospective analysis of the clinical characteristics of adefovir dipivoxil-induced Fanconi's syndrome in the Chinese population.

WHAT IS KNOWN AND OBJECTIVE: To explore the clinical characteristics of adefovir dipivoxil-induced Fanconi's syndrome in the Chinese population and provide a reference for rational drug use in the clinic. METHODS: By searching the CNKI, Wanfang, Chinese VIP, PubMed/MEDLINE, Web of Knowledge, Ovid, Elsevier and SpringerLink databases during 1 January 2008 to 31 December 2019, 78 studies of ADV-induced Fanconi's syndrome involving a total of 110 patients were collected and analysed retrospectively. RESULTS AND DISCUSSION: Prolonged usage of adefovir dipivoxil at low doses to treat hepatitis B might cause Fanconi's syndrome as the first symptom, especially for use over 12 months.The main clinical manifestation was bone pain accompanied by hypophosphataemia, elevated alkaline phosphatase (ALP), urine glycosuria and urine protein. X-rays and bone mineral density (BMD) examinations were mainly used to characterized osteoporosis. The patients had pain relief within 1 week to 1 month, and the biochemical indicators returned to normal within from 2 to 4 months. WHAT IS NEW AND CONCLUSION: Sufficient attention is required before and during exposure to long-term ADV therapy. The clinical picture, laboratory and radiograph alterations are important clues for ADV-induced Fanconi's syndrome.

[Marked improvement in renal tubular markers after switching from adefovir to tenofovir alafenamide in a case of Fanconi syndrome diagnosed through high ALP levels].

A woman in her 60s visited our hospital due to elevation of ALP (1357U/L). The patient had been treated with lamivudine (LAM) in 2005, LAM+adefovir (ADV) in 2009, and ADV+entecavir in 2015 for chronic hepatitis B (CH-B). The ALP isozyme was predominantly bone type. Urinary ß-2 microglobulin (MG) and α-1MG increased to 49635µg/L and 64.1mg/L, respectively. Though no fractures were found during bone scintigraphy, the patient was diagnosed with Fanconi syndrome. However, 3 months after switching from ADV to tenofovir alafenamide (TAF), ALP decreased to 856U/L, and urinary ß-2MG and α-1MG decreased to 624µg/L and 6.0mg/L, respectively. Fanconi syndrome should be considered when an increase in ALP is observed in patients treated with ADV, and urinary ß-2MG and α-1MG assays are useful for establishing a diagnosis. Switching from ADV to TAF was an effective therapeutic option.

Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis.

Inflammation is involved in the pathogenesis of many disorders. However, the underlying mechanisms are often unknown. Here, we test whether cystinosin, the protein involved in cystinosis, is a critical regulator of galectin-3, a member of the ß-galactosidase binding protein family, during inflammation. Cystinosis is a lysosomal storage disorder and, despite ubiquitous expression of cystinosin, the kidney is the primary organ impacted by the disease. Cystinosin was found to enhance lysosomal localization and degradation of galectin-3. In Ctns-/- mice, a mouse model of cystinosis, galectin-3 is overexpressed in the kidney. The absence of galectin-3 in cystinotic mice ameliorates pathologic renal function and structure and decreases macrophage/monocyte infiltration in the kidney of the Ctns-/-Gal3-/- mice compared to Ctns-/- mice. These data strongly suggest that galectin-3 mediates inflammation involved in kidney disease progression in cystinosis. Furthermore, galectin-3 was found to interact with the pro-inflammatory cytokine Monocyte Chemoattractant Protein-1, which stimulates the recruitment of monocytes/macrophages, and proved to be significantly increased in the serum of Ctns-/- mice and also patients with cystinosis. Thus, our findings highlight a new role for cystinosin and galectin-3 interaction in inflammation and provide an additional mechanistic explanation for the kidney disease of cystinosis. This may lead to the identification of new drug targets to delay cystinosis progression.

Functional and structural analysis of rare SLC2A2 variants associated with Fanconi-Bickel syndrome and metabolic traits.

Deleterious variants in SLC2A2 cause Fanconi-Bickel Syndrome (FBS), a glycogen storage disorder, whereas less common variants in SLC2A2 associate with numerous metabolic diseases. Phenotypic heterogeneity in FBS has been observed, but its causes remain unknown. Our goal was to functionally characterize rare SLC2A2 variants found in FBS and metabolic disease-associated variants to understand the impact of these variants on GLUT2 activity and expression and establish genotype-phenotype correlations. Complementary RNA-injected Xenopus laevis oocytes were used to study mutant transporter activity and membrane expression. GLUT2 homology models were constructed for mutation analysis using GLUT1, GLUT3, and XylE as templates. Seventeen FBS variants were characterized. Only c.457_462delCTTATA (p.Leu153_Ile154del) exhibited residual glucose uptake. Functional characterization revealed that only half of the variants were expressed on the plasma membrane. Most less common variants (except c.593 C>A (p.Thr198Lys) and c.1087 G>T (p.Ala363Ser)) exhibited similar GLUT2 transport activity as the wild type. Structural analysis of GLUT2 revealed that variants affect substrate-binding, steric hindrance, or overall transporter structure. The mutant transporter that is associated with a milder FBS phenotype, p.Leu153_Ile154del, retained transport activity. These results improve our overall understanding of the underlying causes of FBS and impact of GLUT2 function on various clinical phenotypes ranging from rare to common disease.

Hnf4a deletion in the mouse kidney phenocopies Fanconi renotubular syndrome.

Different nephron tubule segments perform distinct physiological functions, collectively acting as a blood filtration unit. Dysfunction of the proximal tubule segment can lead to Fanconi renotubular syndrome (FRTS), with major symptoms such as excess excretion of water, glucose, and phosphate in the urine. It has been shown that a mutation in HNF4A is associated with FRTS in humans and that Hnf4a is expressed specifically in proximal tubules in adult rat nephrons. However, little is known about the role of Hnf4a in nephrogenesis. Here, we found that Hnf4a is expressed in both presumptive and differentiated proximal tubules in the developing mouse kidney. We show that Hnf4a is required for the formation of differentiated proximal tubules but is dispensable for the formation of presumptive proximal tubules. Furthermore, we show that loss of Hnf4a decreased the expression of proximal tubule-specific genes. Adult Hnf4a mutant mice presented with FRTS-like symptoms, including polyuria, polydipsia, glycosuria, and phosphaturia. Analysis of the adult Hnf4a mutant kidney also showed proximal tubule dysgenesis and nephrocalcinosis. Our results demonstrate the critical role of Hnf4a in proximal tubule development and provide mechanistic insight into the etiology of FRTS.

Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure.

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure.Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations.Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death.Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.

Bone disease in nephropathic cystinosis is related to cystinosin-induced osteoclastic dysfunction.

Background: Bone impairment is a poorly described complication of nephropathic cystinosis (NC). The objectives of this study were to evaluate in vitro effects of cystinosin (CTNS) mutations on bone resorption and of cysteamine treatment on bone cells [namely human osteoclasts (OCs) and murine osteoblasts]. Methods: Human OCs were differentiated from peripheral blood mononuclear cells (PBMCs) of patients and healthy donors (HDs). Cells were treated with increasing doses of cysteamine in PBMCs or on mature OCs to evaluate its impact on differentiation and resorption, respectively. Similarly, cysteamine-treated osteoblasts derived from murine mesenchymal stem cells were assessed for differentiation and activity with toxicity and proliferation assays. Results: CTNS was expressed in human OCs derived from HDs; its expression was regulated during monocyte colony-stimulating factor- and receptor activator of nuclear factor-κB-dependent osteoclastogenesis and required for efficient bone resorption. Cysteamine had no impact on osteoclastogenesis but inhibited in vitro HD osteoclastic resorption; however, NC OC-mediated bone resorption was impaired only at high doses. Only low concentrations of cysteamine (50 µM) stimulated osteoblastic differentiation and maturation, while this effect was no longer observed at higher concentrations (200 µM). Conclusion: CTNS is required for proper osteoclastic activity. In vitro low doses of cysteamine have beneficial antiresorptive effects on healthy human-derived OCs and may partly correct the CTNS-induced osteoclastic dysfunction in patients with NC. Moreover, in vitro low doses of cysteamine also stimulate osteoblastic differentiation and mineralization, with an inhibitory effect at higher doses, likely explaining, at least partly, the bone toxicity observed in patients receiving high doses of cysteamine.

Glycosuria and hyperglycemia in the neonatal period as the first clinical sign of Fanconi-Bickel syndrome.

Fanconi-Bickel syndrome is a rare inherited disease characterized by the combination of hepatorenal glycogen accumulation, proximal renal tubular dysfunction and impaired utilization of glucose and galactose. The first symptoms of the disorder are recognized in late infancy as clinical characteristics appear. Therapeutic approach is mainly conservative with supplements of calcium, phosphate and vitamin D and small frequent feedings to avoid hypoglycemia. We report 1 clinical case of very early diagnosis, a 19 days old baby girl, in which the first clinical sign of the disease was the detection of glycosuria and vomits. Serum alkaline phosphatase levels were very high without rickets. The patient presented postprandial hyperglycemia and fasting hypoglycemia. A complete 24-hour glucose profile was obtained using a continuous glucose monitoring system in real time, which was fundamental not only for the diagnosis but also for the prevention of hypoglycemia. She received frequent small meals, galactose-free milk diet, and oral intakes of calcium, phosphorum, bicarbonate and vitamin D supplements with good evolution and normal height and weight gain.

Mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney.

AIM: Drug-induced kidney proximal tubular injury and renal failure (Fanconi syndrome; FS) is a clinical complication. Valproic acid (VPA) is among the FS-inducing drugs. The current investigation was designed to evaluate the role of mitochondrial dysfunction and oxidative stress in VPA-induced renal injury. METHODS: Animals received VPA (250 and 500 mg/kg, i.p., 15 consecutive days). Serum biomarkers of kidney injury and markers of oxidative stress were assessed. Moreover, kidney mitochondria were isolated and mitochondrial indices, including succinate dehydrogenase activity (SDA), mitochondrial depolarization, mitochondrial permeability transition pore (MPP), reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial glutathione, and ATP were determined. RESULTS: Valproic acid-treated animals developed biochemical evidence of FS as judged by elevated serum gamma-glutamyl transferase (γ-GT), alkaline phosphatase (ALP), creatinine (Cr), and blood urea nitrogen (BUN) along with hypokalaemia, hypophosphataemia, and a decrease in serum uric acid. VPA caused an increase in kidney ROS and LPO. Renal GSH reservoirs were depleted and tissue antioxidant capacity decreased in VPA-treated animals. Renal tubular interstitial nephritis, tissue necrosis, and atrophy were also evident in VPA-treated rats. Mitochondrial parameters including SDA, MMP, GSH, ATP and MPP were decreased and mitochondrial ROS and LPO were increased with VPA treatment. It was found that carnitine (100 mg/kg, i.p.) mitigated VPA adverse effects towards the kidney. CONCLUSIONS: These data suggest that mitochondrial dysfunction and oxidative stress contributed to the VPA-induced FS. On the other hand, carnitine could be considered a potentially safe and effective therapeutic option in attenuating VPA-induced renal injury.

Endocytic receptor LRP2/megalin-of holoprosencephaly and renal Fanconi syndrome.

Megalin (or LRP2) is an endocytic receptor that plays a central role in embryonic development and adult tissue homeostasis. Loss of this receptor in congenital or acquired diseases results in multiple organ dysfunctions, including forebrain malformation (holoprosencephaly) and renal reabsorption defects (renal Fanconi syndrome). Here, we describe current concepts of the mode of receptor action that include co-receptors and a repertoire of different ligands, and we discuss how these interactions govern functional integrity of the kidney and the brain, and cause disease when defective.

Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy.

We recently reported an autosomal dominant form of renal Fanconi syndrome caused by a missense mutation in the third codon of the peroxisomal protein EHHADH. The mutation mistargets EHHADH to mitochondria, thereby impairing mitochondrial energy production and, consequently, reabsorption of electrolytes and low-molecular-weight nutrients in the proximal tubule. Here, we further elucidate the molecular mechanism underlying this pathology. We find that mutated EHHADH is incorporated into mitochondrial trifunctional protein (MTP), thereby disturbing ß-oxidation of long-chain fatty acids. The resulting MTP deficiency leads to a characteristic accumulation of hydroxyacyl- and acylcarnitines. Mutated EHHADH also limits respiratory complex I and corresponding supercomplex formation, leading to decreases in oxidative phosphorylation capacity, mitochondrial membrane potential maintenance, and ATP generation. Activity of the Na(+)/K(+)-ATPase is thereby diminished, ultimately decreasing the transport activity of the proximal tubule cells.

Altered mTOR signalling in nephropathic cystinosis.

Lysosomes play a central role in regulating autophagy via activation of mammalian target of rapamycin complex 1 (mTORC1). We examined mTORC1 signalling in the lysosomal storage disease nephropathic cystinosis (MIM 219800), in which accumulation of autophagy markers has been previously demonstrated. Cystinosis is caused by mutations in the lysosomal cystine transporter cystinosin and initially affects kidney proximal tubules causing renal Fanconi syndrome, followed by a gradual development of end-stage renal disease and extrarenal complications. Using proximal tubular kidney cells obtained from healthy donors and from cystinotic patients, we demonstrate that cystinosin deficiency is associated with a perturbed mTORC1 signalling, delayed reactivation of mTORC1 after starvation and abnormal lysosomal retention of mTOR during starvation. These effects could not be reversed by treatment with cystine-depleting drug cysteamine. Altered mTORC1 signalling can contribute to the development of proximal tubular dysfunction in cystinosis and points to new possibilities in therapeutic intervention through modulation of mTORC-dependent signalling cascades.

[Renal hypophosphatemia:pathophysiology and treatment].

Serum level of phosphate is regulated by the kidney, especially proximal tubule. The transcellular transport of phosphate in the proximal tubule is mediated via Na dependent transporters, i.e., NPT2a and NPT2b at the luminal membrane, and unknown channel at the basolateral side. The transport of phosphate via NPT2a and NPT2b is further regulated by factors, such as PTH, FGF23, and 1,25(OH)(2)D. Several hereditary diseases that cause hypophoshatemia specically are known. In addition, dysfunction of proximal tubule may develop Fanconi syndrome, which also causes hypherphosphaturia. In this section, I describe the renal mechanisms of phosphate handling and the causes of hypophosphatemia along with its treatment.

The reduced expression of proximal tubular transporters in acquired Fanconi syndrome with κ light chain deposition.

In a case of acquired Fanconi syndrome associated with smoldering myeloma, we confirmed the deposition of protease-resistant κ light chain proteins in a proximal tubular injury and found the decreased expression of apical tubular transporters including sodium glucose co-transporter, sodium phosphate co-transporter, uric acid transporter 1, and a decrease of Na(+)/K(+)-ATPase in the basolateral membrane. The protease-resistant kappa light chain has a pathological role in the expression of tubular transporters in the proximal tubule and causes Fanconi syndrome associated with smoldering myeloma.

Fanconi syndrome and chronic renal failure in a chronic hepatitis B monoinfected patient treated with tenofovir

Tenofovir disoproxil fumarate (TDF) is one of the first-line treatment options in chronic hepatitis B (CHB). Despite its efficacy in suppressing viral load and a high resistance barrier, long life maintenance therapy is required. Registration studies demonstrated TDF to be a safe drug. However, post-marketing experience reported cases of serious nephrotoxicity associated with hypophosphatemia, osteomalacia and, even more recently, Fanconi syndrome associated with TDF therapy in CHB monoinfected patients. Here the authors report a case of a 40 year-old male, with a CHB monoinfection, that, three years after TDF therapy, developed a progressive chronic kidney disease with a serious hypophosphatemia and a secondary osteomalacia that was manifested by bone pain and multiple bone fractures. Further investigational analyses unveiled a proximal renal tubular dysfunction, which fulfilled most of the diagnostic criteria for a Fanconi syndrome. After TDF withdrawal and oral supplementation with phosphate and calcitriol, his renal function stabilized (despite not returning to normal), proximal renal tubular dysfunction abnormalities resolved as well as osteomalacia. In conclusion, physicians should be aware that, in CHB monoinfected patients under TDF therapy, serious renal damage is possible and preventable by timely monitoring serum creatinine and phosphate (AU)

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Mitochondrial dysfunction and electron transport chain complex defect in a rat model of tenofovir disoproxil fumarate nephrotoxicity.

The long-term use of tenofovir, a commonly used anti-HIV drug, can result in renal damage. The mechanism of tenofovir disoproxil fumarate (TDF) nephrotoxicity is not clear, although it has been shown to target proximal tubular mitochondria. In the present study, the effects of chronic TDF treatment on the proximal tubular function, renal mitochondrial function, and the activities of the electron transport chain (ETC) complexes were studied in rats. Damage to proximal tubular mitochondria and proximal tubular dysfunction was observed. The impaired mitochondrial function such as the respiratory control ratio, 2-(4,5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H-tetrazolium bromide (MTT) reduction, and mitochondrial swelling was observed. The activities of the electron chain complexes I, II, IV, and V were decreased by 46%, 20%, 26%, and 21%, respectively, in the TDF-treated rat kidneys. It is suggested that TDF induced proximal tubular mitochondrial dysfunction and ETC defects may impair ATP production, resulting in proximal tubular damage and dysfunction.