Development Of Fanconi Syndrome Research Articles

Тубулоинтерстициальный нефрит с увеитом: серия клинических наблюдений

Tubulointerstitial nephritis and uveitis syndrome (TINU) is a rare autoimmune disease that develops predominantly in young people and is characterized by variable clinical manifestations and an uncertain prognosis. A single-center retrospective observational study included 3 pediatric patients (a girl and two boys) with clinically and morphologically confirmed TINU. Age of onset, clinical symptoms, gender-age-height-standardized blood pressure (BP), proteinuria (g/l), excretion level of β2-microglobulin, glucose, phosphorus in urine, blood pH and bicarbonate levels, Bedside Schwartz equation estimated glomerular filtration rate (eGFR, ml/min/1.73 m2, norm≥90 ml/min/1.73 m2), ophthalmoscopy data and the therapy were analyzed at the time of disease manifestation and during the follow-up. The duration of follow-up ranged from 3 to 7 years. The disease debuted at the age of 10 to 14 y/o with severe symptoms of intoxication, inflammatory activity, acute kidney damage (eGFR=22 to 35 ml/min/1.73 m2) and the development of Fanconi syndrome. Anterior uveitis had manifested in 1 to 5 months after the kidney disease. The TINU diagnosis was established after 6 to 9 months from the onset of the disease. All children received systemic steroid therapy coupled with the local treatment for uveitis. A significant decrease in blood creatinine levels and urine β2-microglobulin excretion with partial restoration of renal filtration function was noted by the sixth month of the therapy. All children developed chronic kidney disease (CKD) stages 2 to 3 over time. Stable remission of uveitis was achieved in 2 children after 3 to 10 months of treatment without complications; and in one patient a subacute uveitis led to the secondary changes in the cornea and decreased visual acuity. Conclusion: children with TINU have a high risk of developing CKD as a result of acute kidney disease; uveitis is characterized by a chronic course and, in the absence of remission, can lead to the development of ophthalmological complications.

Association of Familial Fanconi Syndrome with a Novel GATM Variant.

Fanconi syndrome is a disorder of the proximal renal tubule. Recently, advanced genetic analysis technology has revealed that several genes cause familial Fanconi syndrome. We identified a family with autosomal dominant Fanconi syndrome and chronic kidney disease with a novel glycine amidinotransferase (GATM) variant. Case 1 was a 57-year-old Japanese woman. Her father and two siblings had Fanconi syndrome or chronic kidney disease. She presented to our hospital at the age of 34 years with recurrent glucosuria. Her height and weight were 151 cm and 46.6 kg, respectively. Laboratory tests showed glucosuria, hypophosphatemia, hypouricemia, and normal renal function. Her serum creatinine level gradually increased over the following next two decades, and she developed end-stage renal disease. Case 2, the daughter of Case 1, was a 26-year-old woman. Her height and weight were 151 cm and 37.5 kg, respectively. Glucosuria was detected at the age of 13 years, which led to a referral to our hospital. Urinalysis showed low-molecular-weight proteinuria. She was diagnosed with Fanconi syndrome. At the age of 26 years, she had glucosuria, low-molecular-weight proteinuria, hypouricemia, and normal renal function. Genetic testing of both cases revealed a novel missense variant in GATM. The heterozygous missense variants in GATM have been reported to cause familial Fanconi syndrome, which manifests early in life and progresses to renal glomerular failure by mid-adulthood. The novel GATM variant detected in our cases was suspected to be associated with the development of Fanconi syndrome. GATM variants should be tested in patients with idiopathic Fanconi syndrome.

Hepatocyte nuclear factors play an important role in the pathogenesis of nephropathy

Hepatocyte nuclear factors play an important role in the pathogenesis of nephropathy

Clinical and genetic heterogeneity of HNF4A/HNF1A mutations in a multicentre paediatric cohort with hyperinsulinaemic hypoglycaemia.

The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY). We characterised an international multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations presenting with HH over a 25-year period (1995-2020). Clinical and genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis. A total of 34 patients (70.6% female, n = 24) with a mean age of 7.1 years (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 kg (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2-6.8). Nine patients (n = 9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR: 9.0-13.9). Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%). We build on the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.

WES Reveals Novel Heterozygous NBAS Gene Mutations Associated with Fanconi Syndrome in a Patient with SOPH Syndrome: Case Report

Variations in the NBAS gene is known to cause a spectrum of phenotypes ranging from isolated recurrent acute liver failure (RALF) to a multisystemic presentation known as SOPH syndrome. Patients with SOPH present with optic atrophy, acute liver failure, short stature, and Pelger-Huet anomaly. We report the presence of a novel pair of biallelic heterozygous mutations c.5139-5T>G and c.2203-2A>G in the NBAS gene of a patient with SOPH syndrome. A 9-year-old patient was clinically diagnosed with SOPH following clinical laboratory analyses. Current interventions for managing the disease encompass IVIG, methylprednisolone, calcium, and vitamin D administration. Whole-exome sequencing (WES) results showed two mutations: c.2203-2A>G and c.5139-5T>G, in the NBAS gene, which had not been previously reported. Notably, we hypothesize that NBAS mutations could potentially contribute to the development of Fanconi syndrome, a clinical diagnosis reported in our patient. Our study also supports the renaming of SOPH to SOPHIA to allow early detection and effective treatment.

THE NUCLEAR FACTOR OF HEPATOCYTES 1β (HNF1β)–ASSOCIATED DISEASE. CLINIC, DIAGNOSTIC, TREATMENT (LITERATURE REVIEW AND CLINICAL OBSERVATION)

Hepatocyte nuclear factor 1β (HNF1β)-associated disease is a rare autosomal dominant disease caused by various mutations in the HNF1β gene coding the hepatocyte nuclear factor 1β. HNF1β is a transcription factor that is critical for the development of kidney urogenital tract, pancreas, liver, brain, and parathyroid gland. Renal phenotype or HNF1β- nephropathy appeared to be extremely heterogenic: multicystic renal dysplasia, renal hypoplasia, unilateral renal agenesis, horseshoe kidney, atypical familial juvenile hyperuricemic nephropathy, urinary tract malformations and tubular dysfunction. Extrarenal phenotype of HNF1β-associated disease could be maturity-onset diabetes of the young (MODY), pancreatic atrophy and exocrine pancreatic dysfunction, elevated liver enzymes, neonatal cholestasis, congenital abnormalities of the genital tract, hyperparathyroidism, neurological symptoms. The multisystem phenotype makes clinical verification of the diagnosis extremely difficult. In this article, we present a clinical observation of a child with HNF1β – associated disease. The first clinical presentation of HNF1β-associated disease was ultrasound changes in the kidneys (hyperechogenic kidneys?), which were detected by prenatal ultrasonography in pregnancy. Renal ultrasound revealed polycystic kidney disease in the first days of life and bilateral medullary nephrocalcinosis by the age of three. The clinical examination showed a reduced renal function and developed Fanconi syndrome (glycosuria, low molecular proteinuria, hypophosphatemia, aminoaciduria, hyperuricosuria) in the first year of life. Also the child had a non-constant asymptomatic elevation of liver enzymes, hyperparathyroidism, osteoporosis. The diagnosis was confirmed by the results of next generation sequencing which revealed novel heterozygous mutation in exon 4 of the HNF1b gene (chr17: 36091813C>T), p.Cys273Tyr (c.818G>A). The identified mutation was validated by Sanger sequencing. Validation by Sanger sequencing did not reveal a chr17: 36091813C>T mutation in parents, which suggested the appearance of a mutation in the child de novo.

Chaperone-Mediated Autophagy Upregulation Rescues Megalin Expression and Localization in Cystinotic Proximal Tubule Cells.

Cystinosis is a lysosomal storage disorder caused by defects in CTNS, the gene that encodes the lysosomal cystine transporter cystinosin. Patients with nephropathic cystinosis are characterized by endocrine defects, defective proximal tubule cell (PTC) function, the development of Fanconi syndrome and, eventually, end-stage renal disease. Kidney disease is developed despite the use of cysteamine, a drug that decreases lysosomal cystine overload but fails to correct overload-independent defects. Chaperone-mediated autophagy (CMA), a selective form of autophagy, is defective in cystinotic mouse fibroblasts, and treatment with cysteamine is unable to correct CMA defects in vivo, but whether the vesicular trafficking mechanisms that lead to defective CMA in cystinosis are manifested in human PTCs is not currently known and whether PTC-specific mechanisms are corrected upon CMA upregulation remains to be elucidated. Here, using CRISPR-Cas9 technology, we develop a new human PTC line with defective cystinosin expression (CTNS-KO PTCs). We show that the expression and localization of the CMA receptor, LAMP2A, is defective in CTNS-KO PTCs. The expression of the lipidated form of LC3B, a marker for another form of autophagy (macroautophagy), is decreased in CTNS-KO PTCs indicating decreased autophagosome numbers under basal conditions. However, the autophagic flux is functional, as measured by induction by starvation or by blockage using the v-ATPase inhibitor bafilomycin A, and by degradation of the macroautophagy substrate SQSTM1 under starvation and proteasome-inhibited conditions. Previous studies showed that LAMP2A accumulates in Rab11-positive vesicles in cystinotic cells. Here, we show defective Rab11 expression, localization and trafficking in CTNS-KO PTCs as determined by confocal microscopy, immunoblotting and TIRFM. We also show that both Rab11 expression and trafficking in cystinotic PTCs are rescued by the upregulation of CMA using small-molecule CMA activators. Cystinotic PTCs are characterized by PTC de-differentiation accompanied by loss of the endocytic receptor megalin, and megalin recycling is regulated by Rab11. Here we show that megalin plasma membrane localization is defective in CTNS-KO PTCs and its expression is rescued by treatment with CMA activators. Altogether, our data support that CMA upregulation has the potential to improve PTC function in cystinosis.

Transient Fanconi syndrome in two preterm infants with hydronephrosis and urinary tract infection.

Type IV renal tubular acidosis is known to occur in obstructive uropathy with urinary tract infection. Fanconi syndrome, however, has not been described in these settings. We report two preterm infants who developed Fanconi syndrome associated with hydronephrosis and urinary tract infection. Patient 1 is a boy with 21 trisomy, bilateral renal hypoplasia and bilateral vesicoureteral reflux delivered at 35weeks' gestation. At postnatal day 42, he developed Fanconi syndrome after urinary tract infection, which persisted until the surgical correction of vesicoureteral reflux. Patient 2 was delivered at 35weeks' gestation. At postnatal day 9, he was admitted for severe dehydration. He had phimosis and ultrasonography showed left pelviectasis. Laboratory data were compatible with Fanconi syndrome, which resolved spontaneously after fluid therapy. Subsequently urine culture grew bacteria and treatment for infection and topical corticosteroid for phimosis were performed. DMSA scintigraphy performed later showed left renal scar. Tubular cell stretch, due to vesicoureteral reflux in Patient 1 and phimosis in Patient 2, and urinary tract infection in association with immaturity of tubules are thought to have caused Fanconi syndrome.

PO-0790 Fanconi Syndrome, Vitamin D Deficiency And Aki In Beta-thalassemia Paediatric Patient Receiving Deferasirox: A Case Report And Literature Review

Background and aims Deferasirox is a novel oral iron chelator for the treatment of iron-overload due to chronic hypertransfusion. Renal toxicity due to deferasirox was more recognised and deferasirox-induced tubulopathy has been increasing reports in the literature. We report a β-Thalassemia paediatric patient who developed Fanconi Syndrome (FS), AKI and vitamin D deficiency after deferasirox therapy. Methods Patient’s information was summarised and compared with literature. Results A 4.8-year-old girl with β-Thalassemia major commenced hypertransfusion at 1.3-year-olds and received deferasirox 21 mg/kg/day at 1.9-year-olds, which baseline serum ferritin was 2,216 ng/ml. After increasing deferasirox to 35 mg/kg/day for 11 months, serum ferritin was lowering to 781 mg/ml. She was admitted with gastroenteritis, which revealed severe normal anion gap hyperchloremic hypokalaemic metabolic acidosis, severe hypophosphatemia, hypocalcemia, glucosuria, albuminuria, phosphaturia and vitamin D deficiency. Serum creatinine increased from 0.45 mg/dl to 0.75 mg/dl before turning to normal two months following cessation of deferasirox, as others except acidosis that persistently need alkali treatment. There were only five paediatric cases reported for deferasirox-induced FS in β-Thalassemia patients and 2 out of 5 that presented AKI. A prospective study in children reported 2 out of 10 cases presented deferasirox-induced FS, which 90% were Thalassemia patients. Recovery of FS and AKI also literally presented within 3 months after deferasirox’s cessation. Conclusions – Deferasirox is potentially associated with renal toxicity in children, particularly FS and AKI. – Diligent and regularly monitoring of renal function should be mandated in deferasirox receiving patients. – Long-term consequences of kidney in deferasirox-treated children desire for further study.

G.P.317: Renal dysfunction in patients with Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD), characterized by intellectual deficits and epilepsy with cortical migration defects, is the most common congenital muscular dystrophy in Japan. Most patients die of congestive heart failure or respiratory dysfunction, as in Duchenne muscular dystrophy (DMD), in the second decade of life. Recent studies have found that renal dysfunction is a common complication of advanced DMD and is the third leading cause of death in these patients. Circulatory instability caused by cardiac dysfunction is thought to result in renal dysfunction, especially prerenal failure. We retrospectively evaluated renal function in 37 genetically diagnosed FCMD patients (1.3–32.9 years, mean age 13.7 ± 6.9 years) using Cystatin C. We examined possible relationships of Cystatin with the levels of blood natriuretic peptide and creatinine, as well as the cardiac echo results. Twenty-four patients were treated for cardiac dysfunction, but elevated Cystatin C was detected in only two. These two patients also showed proteinuria, glycosuria, hematuria and extremely high levels of β2-microglobulin on urine tests and were thus diagnosed as having kidney tubule cell damage. Since both patients were treated for intractable epilepsy with many types of antiepileptic drugs, including valproic acid (VPA), and had low serum carnitine levels, kidney tubule cell damage was thought to be an adverse effect of VPA. One patient improved in response to a reduced VPA dose, but the other developed Fanconi syndrome. Unlike DMD patients, none of our FCMD patients progressed to prerenal failure. Though FCMD patients also have cardiac dysfunction, careful fluid management is instituted early because dysphagia emerges in the early stage. In DMD patients, inadequate fluid management may also cause circulatory instability, which can progress to prerenal failure. On the other hand, kidney tubule cell damage should be noted in FCMD patients especially with VPA treatment for epilepsy.

Clinical features of adefovir dipivoxil-induced Fanconi syndrome and hypophosphatemic osteomalacia

Adefovir dipivoxil (ADV) is commonly used as an anti-viral agent in the treatment of chronic hepatitis B,with a dose-and time-dependent nephrotoxicity.Clinical analysis was made in 4 patients with chronic hepatitis B who developed Fanconi syndrome and hypophosphatemic osteomalacia after long-term use of ADV (10 mg/d). Key words: Adefovir dipivoxil ; Fanconi syndrome ; Hypophosphatemia; Osteomalacia

Hypophosphatemic Osteomalacia Associated with Tenofovir Use in HIVInfected Patients: A Case Series and Review of the Literature

We present three cases of HIV-infected patients who developed Fanconi syndrome, hypophosphatemic osteomalacia and bone fractures while on tenofovir, a nucleotide reverse transcriptase inhibitor, commonly used as part of HIV treatment. All patients presented with bone pain, electrolyte and radiographic abnormalities which improved with discontinuation of tenofovir. Although, there have been several studies demonstrating causality between tenofovir and Fanconi syndrome, there are only six previously reported cases of patients developing osteomalacia and fractures since the introduction of tenofovir in 2001. In addition to asymptomatic osteopenia, hypophosphatemic osteomalacia is an important, reversible adverse effect of tenofovir.

Pathophysiological consequences of hemolysis. Role of cell-free hemoglobin

Abundant hemolysis is associated with a number of inherent and acquired diseases including sickle-cell disease (SCD), polycythemia, paroxysmal nocturnal hemoglobinuria (PNH) and drug-induced hemolytic anemia. Despite different etiopathology of hemolytic diseases, many concomitant symptoms are comparable and include e.g. hypertension, hemoglobinuria and hypercoagulation state. Studies in the last years have shown a growing list of mechanisms lying at the basis of those symptoms, in particular irreversible reaction between cell-free hemoglobin (Hb) and nitric oxide (NO) - endogenous vasorelaxant and anti-thrombotic agent. Saturation of protective physiological cell-free Hb-scavenging mechanisms results in accumulation of Hb in plasma and hemoglobinemia. Extensive hemoglobinemia subsequently leads to hemoglobinuria, which may cause kidney damage and development of Fanconi syndrome. A severe problem in patients with SCD and PNH is pulmonary and systemic hypertension. It may lead to circulation failure, including stroke, and it is related to abolition of NO bioavailability for vascular smooth muscle cells. Thrombotic events are the major cause of death in SCD and PNH. It ensues from lack of platelet inhibition evoked by Hb-mediated NO scavenging. A serious complication that affects patients with excessive hemolysis is erectile dysfunction. Also direct cytotoxic, prooxidant and proinflammatory effects of cell-free hemoglobin and heme compose the clinical picture of hemolytic diseases. The pathophysiological role of plasma Hb, mechanisms of its elimination, and direct and indirect (via NO scavenging) deleterious effects of cell-free Hb are presented in detail in this review. Understanding the critical role of hemolysis and cell-free Hb is important in the perspective of treating patients with hemolytic diseases and to design new effective therapies in future.

Bilateral Pathologic Hip Fractures Associated with Antiretroviral Therapy

The use of antiretroviral medications in patients with human immunodeficiency virus (HIV) is highly effective in reducing HIV-related morbidity and mortality1,2. While HIV-positive patients continue to live longer with antiretroviral medications, adverse effects of long-term treatment include dyslipidemia, diabetes mellitus, and abnormalities of bone metabolism3,4. Metabolic bone disorders are common in patients with HIV infection, and many patients have premature osteoporosis and an increased risk of fracture5,6. While the mechanism of skeletal fragility in these patients remains inconclusive, antiretroviral medications have been described as a factor contributing to bone loss3,7. Tenofovir (Viread), a commonly prescribed antiretroviral drug, has recently been noted to cause Fanconi syndrome, a disorder characterized by renal tubular dysfunction, which leads to hypophosphatemia, hypokalemia, and metabolic acidosis as well as symptoms of polyuria and dehydration8. Patients with Fanconi syndrome can experience electrolyte disturbances due to impaired renal tubular reabsorption, which can ultimately lead to defects in bone mineralization8,9. In the following case report, we describe an HIV-infected patient who developed Fanconi syndrome as a result of tenofovir treatment and subsequently sustained bilateral hip fractures. Tenofovir-associated Fanconi syndrome places the patient at greater risk for developing abnormalities of bone metabolism, which, once detected, can be corrected by tenofovir cessation and electrolyte repletion. The objective of this case report is to raise orthopaedic surgeons’ awareness of the adverse drug complications that can occur in patients treated for HIV infection, which can lead to derangement of bone strength and thus result in fracture. The patient consented to the submission of the case data for publication. A fifty-four-year-old transgender woman with HIV infection presented with right hip pain after falling at her home. She had experienced increasing difficulty walking …

A Case of Acquired Fanconi Syndrome Induced by Zoledronic Acid

A 61-year-old woman with metastatic breast cancer was diagnosed as having acquired Fanconi syndrome. In this case, the cause of this syndrome was most likely zoledronic acid (Zometa), which had been infused intravenously at a dose of 4 mg over 15 minutes weekly because of malignancy-associated hypercalcemia. Zoledronic acid is nephrotoxic and may induce severe tubular dysfunction, which can cause development of Fanconi syndrome. Therefore, close monitoring of proximal tubular function is recommended during therapy with zoledronic acid, especially when frequent administration of zoledronic acid is needed.

Fanconi Syndrome Caused by Valproic Acid

Two severely disabled children with epilepsy, a 6-year-old boy and a 15-year-old girl, had been treated with valproic acid from the ages of 5 and 6 months, respectively, and developed Fanconi syndrome. Both patients were bedridden and fed by means of a nasogastric or gastrostomy tube. Because their Fanconi syndrome appeared to be caused by valproic acid, that treatment was stopped; for both patients, the Fanconi syndrome then resolved, in 6 months and 3 months, respectively. Severely handicapped children may be at risk for valproic acid-induced renal involvement. Although renal involvement is an uncommon adverse effect of valproic acid, Fanconi syndrome due to valproic acid therapy has rarely been reported. In the few previous cases, the patients, who were bedridden and fed through a nasogastric or a gastrostomy tube, had taken valproic acid for an average of approximately 7 years. Nonetheless, their valproic acid blood levels were normal. Urinary abnormalities disappeared in an average of 4 months, as also in the present two cases. The potential for Fanconi syndrome must be considered in children with epilepsy who are treated with valproic acid, especially in severely disabled children.

Development of Fanconi syndrome during infancy in a patient with cystinosis

Development of Fanconi syndrome during infancy in a patient with cystinosis

Development of Fanconi syndrome during infancy in a patient with cystinosis

Development of Fanconi syndrome during infancy in a patient with cystinosis

Acute renal failure and Fanconi syndrome in an AIDS patient on tenofovir treatment—case report and review of literature

Tenofovir disoproxil fumarate, a prodrug of tenofovir, is a potent nucleotide analogue reverse-transcriptase inhibitor with activity against human immunodeficiency virus (HIV). Although initially thought to be relatively safe with regards to nephrotoxic effects compared to its class drugs—adefovir and cidofovir, several cases of acute renal failure and proximal tubule dysfunction have been described in the last few months. We report another patient who developed Fanconi syndrome while on tenofovir. Her condition improved on discontinuation of the drug. We also review the literature of all patients who have developed Fanconi syndrome on tenofovir.

Fanconi syndrome caused by sodium valproate: report of three severely disabled children

We report three severely disabled children with epilepsy, a 4-year-old boy, 8-year-old girl and 14-year-old girl, who were treated with sodium valproate from the age of 2 months, 3 months and 7 years, respectively, and who developed Fanconi syndrome. All three patients were bed-ridden and fed by means of a nasogastric or gastrostomy tube. Since Fanconi syndrome was considered to be caused by sodium valproate, it was stopped. After the discontinuation of sodium valproate, renal involvement improved in all patients in 2–12 months. Severely handicapped children may be at risk for sodium valproate-induced renal involvement. Although among the adverse effects of sodium valproate, renal involvement is uncommon, Fanconi syndrome due to valproate therapy has rarely been reported. We have to pay attention to Fanconi syndrome in epileptic children treated with sodium valproate, especially in severely disabled children.