Fanconi Syndrome Research Articles

Palbociclib-associated nephrotoxicity in a patient with breast cancer

A patient with advanced breast cancer developed acute kidney injury and generalized renal tubular dysfunction manifested as Fanconi syndrome and distal renal tubular acidosis after treatment with palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor. A kidney biopsy showed acute tubular injury characterized by dilated tubular lumens, flattened epithelium, and loss of brush borders, with no significant interstitial fibrosis. This case illustrates the importance of close and long-term follow-up of kidney function and electrolyte levels after the initiation of a CDK4/6 inhibitor.

A review of renal tubular acidosis.

To review the current scientific literature on renal tubular acidosis (RTA) in people and small animals, focusing on diseases in veterinary medicine that result in secondary RTA. Scientific reviews and original research publications on people and small animals focusing on RTA. RTA is characterized by defective renal acid-base regulation that results in normal anion gap hyperchloremic metabolic acidosis. Renal acid-base regulation includes the reabsorption and regeneration of bicarbonate in the renal proximal tubule and collecting ducts and the process of ammoniagenesis. RTA occurs as a primary genetic disorder or secondary to disease conditions. Based on pathophysiology, RTA is classified as distal or type 1 RTA, proximal or type 2 RTA, type 3 RTA or carbonic anhydrase II mutation, and type 4 or hyperkalemic RTA. Fanconi syndrome comprises proximal RTA with additional defects in proximal tubular function. Extensive research elucidating the genetic basis of RTA in people exists. RTA is a genetic disorder in the Basenji breed of dogs, where the mutation is known. Secondary RTA in human and veterinary medicine is the sequela of diseases that include immune-mediated, toxic, and infectious causes. Diagnosis and characterization of RTA include the measurement of urine pH and the evaluation of renal handling of substances that should affect acid or bicarbonate excretion. Commonality exists between human and veterinary medicine among the types of RTA. Many genetic defects causing primary RTA are identified in people, but those in companion animals other than in the Basenji are unknown. Critically ill veterinary patients are often admitted to the ICU for diseases associated with secondary RTA, or they may develop RTA while hospitalized. Recognition and treatment of RTA may reverse tubular dysfunction and promote recovery by correcting metabolic acidosis.

Novel insights advancing the understanding of renal Fanconi syndrome in cystinosis

Novel insights advancing the understanding of renal Fanconi syndrome in cystinosis

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.

Use of dimethyl fumarate for MS not linked to Fanconi syndrome

Use of dimethyl fumarate for MS not linked to Fanconi syndrome

Mitochondrial Dysfunction in Kidney Tubulopathies.

Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption.

OPHTALMOLOGICAL CHANGES IN THE ALGORITHM OF DIAGNOSIS OF RARE (ORPHAN) DISEASE IN CHILDREN

About 5% of newborns are diagnosed with congenital anomalies or hereditary developmental disorders. Rare, or orphan, diseases include any disease that occurs with a frequency of less than one case per two thousand people worldwide. The vast majority (about 80%) of rare diseases have monogenic hereditary nature and are characterized by a chronic relapsing course, insensitivity to therapy, the occurrence of irreversible complications, a decrease in the quality of life and a reduction in life expectancy. The lack of attention to syndromic disorders on the part of other organs and systems is the main reason for untimely referral to a geneticist and late diagnosis, which significantly reduces the patient's chances of recovery even if adequate molecular therapy is prescribed. Depending on the leading symptoms of the hereditary syndrome, the patient is under the supervision of a paediatrician, neurologist, ophthalmologist, cardiologist, other specialists, but first of all, a family doctor providing primary care. The problem lies in the predominant concentration of doctors on those manifestations of the disease that are directly related to their specialization, and the diagnosis is then established in the following plane. The conducted research focuses the attention of healthcare professionals to monogenic hereditary diseases, which have a syndromal picture of the impairment of the visual analyzer. Based on the analysis of the International Statistical Classification of Diseases and Related Health Care Problems of the ICD-10 revision, rare diseases with ophthalmological manifestations have been identified that can contribute to the improvement of the diagnostic algorithm. The material, represented in the tables, should speed up the patient's referral to a geneticist. This approach can be helpful for paediatric and adult ophthalmologists, family doctors, paediatricians, geneticists and other specialties. The aim of this study is to determine the presence of ophthalmic pathology as an indicator of directing the diagnostic algorithm towards rare (orphan) diseases. Material and methods. The study included the methods of statistical, informational, and system-functional analysis of basic computer data. Results: Our analysis of six sections of the ICD-10 revealed that the most frequently observed visual system impairments were associated with rare monogenic diseases featuring metabolic disorders. These diseases included phenylketonuria, Gaucher disease, homocystinuria, Niemann-Pick disease, Fabry disease, Fanconi syndrome, galactosemia, as well as mucopolysaccharidoses of types I to VII (such as Gurler, Gaunter, Sanfilippo, Morquio, Scheille, Maroto-Lamy, Slay syndromes), and other hereditary syndromes. Conclusion. Based on our comprehensive analysis of six sections within the 10th revision of the international statistical classification, we have systematically identified and summarized ophthalmological manifestations associated with a range of rare, primarily monogenic hereditary diseases. These findings can serve as valuable diagnostic tools in the practice of syndromal diagnosis across various medical specialties, facilitating expedited referrals for genetic counseling.

Sirolimus Toxicity Manifested with Fanconi Syndrome in a Kidney Transplant Patient

Sirolimus Toxicity Manifested with Fanconi Syndrome in a Kidney Transplant Patient

Drug-Induced Fanconi Syndrome Presenting as Chronic Constipation: A Well-Known but Forgotten Entity

Drug-Induced Fanconi Syndrome Presenting as Chronic Constipation: A Well-Known but Forgotten Entity

A Varied Presentation of Fanconi Syndrome Following AKI in COVID-19 Infection

A Varied Presentation of Fanconi Syndrome Following AKI in COVID-19 Infection

Ifosfamide-Induced Fanconi Syndrome: A Complication that Cannot Be Overlooked

Ifosfamide-Induced Fanconi Syndrome: A Complication that Cannot Be Overlooked

Drug-Induced Fanconi Syndrome with Hyperphosphatemia

Drug-Induced Fanconi Syndrome with Hyperphosphatemia

Effects of N-Acetylcysteine on Evolution of Kidney Function in Patients with Acadian Variant Fanconi Syndrome

Effects of N-Acetylcysteine on Evolution of Kidney Function in Patients with Acadian Variant Fanconi Syndrome

THU464 An Uncommon Case Of Adult-Onset Hypophosphatemic Osteomalacia

Abstract Disclosure: P.M. Lockhart Pastor: None. N.M. Maalouf: None. Introduction: Hypophosphatemic conditions that interfere with bone mineralization and cause osteomalacia comprise many hereditary and acquired diseases. We describe a case of acquired hypophosphatemic osteomalacia associated with Multiple Myeloma (MM). Case Report: A 45-year-old man with MM and systemic AL amyloidosis was referred to our clinic for evaluation of low bone mass on DXA scan. He presented with progressive back pain, proximal muscle weakness, weight loss, and worsening proteinuria, eventually leading to the diagnosis of AL amyloidosis on fat pad biopsy and MM on bone marrow biopsy. Biochemical work up was remarkable for elevated serum alkaline phosphatase at 463 U/L (reference range 46-116) determined to be of skeletal origin. Additional studies included serum phosphorus 1.9 mg/dl (2.4-4.5), creatinine 1.0 mg/dl (0.7-1.2), calcium 9.0 mg/dl (8.4-10.2), albumin 4.1 g/dl (3.5-5.2), PTH 17.1 pg/ml (15-77), and 25-OH-D 52 ng/ml (30-80). Skeletal survey and PET/CT identified diffuse osteopenia but no fracture or lytic lesion. DXA scan showed Z-score of -5.0 at the L-spine and -4.2 at the femoral neck. Further work-up of hypophosphatemia was notable for fractional excretion (FE) phosphate of 37% (<20), serum 1,25-OH2-D 74 pg/ml (18-64), FGF-23 <14 pg/ml (<59), hypouricemia with high FE uric acid, and normoglycemia with glucosuria. Given his marked bone pain, hypophosphatemia, hypouricemia, glucosuria, and elevated alkaline phosphatase, he was diagnosed with hypophosphatemic osteomalacia presumably secondary to light chain accumulation in kidneys leading to proximal tubule dysfunction (acquired Fanconi syndrome). In addition to MM treatment (5 cycles of Dara-CyBorD then stem cell transplantation), he was started on phosphate supplementation, with marked improvement in bone pain, muscle strength, and serum alkaline phosphatase over 6 months. No anti-resorptive agents were used in treating his MM. Conclusion: This case highlights an unusual presentation of hypophosphatemic osteomalacia. It is important to recognize that bone pain in patients with MM is not only caused by osteolytic lesion but can also result from osteomalacia due to Fanconi syndrome due to light chain kappa deposition. In this patient, treatment with phosphate supplementation resulted in clinical improvement of bone pain and biochemical markers. To date, there are only few reported cases of hypophosphatemic osteomalacia due to Fanconi syndrome in the setting of MM. Presentation: Thursday, June 15, 2023

SAT145 Familial Renal Glycosuria - A Differential Diagnosis For Hypoglycemia

Abstract Disclosure: S. Syed: None. S. Naqvi: None. L. Menon: None. J. Holthoff: None. A.R. Kasireddy: None. S. Alshami: None. Background: Familial renal glycosuria can be an uncommon cause of hypoglycemia. We present the case of a woman who was referred to the endocrinology clinic for further evaluation of hypoglycemia and was found to have familial renal glycosuria due to a novel mutation in the solute carrier family 5 member 2 (SCL5A2) gene. Case presentation: A 24 year-old woman with past medical history of rheumatoid arthritis, hyperlipidemia and renal glycosuria presented for persistent hypoglycemia. She first started noticing these episodes four years ago and they have increased over the last year. These events occur in the early hours of the morning or overnight despite a high carbohydrate meal at bedtime. She had the following labs: fasting C-peptide 1.04 (0.9-4.3 ng/ml), insulin 4.1 (2.4-21.8 microU/ml), fasting glucose 84 (70-110 mg/dl) and HbA1c 4.8%. DEXCOM download showed hypoglycemic episodes 2-3 hours after meals. On urinalysis, glucose was >1000 mg/dl and a 24 hour urine collection for glucose was 16.8 g/24 hours. She was first diagnosed with asymptomatic glycosuria during her first pregnancy 7 years ago but the cause was never investigated. After seeing endocrinology, she was referred to nephrology who ordered further workup. Initial markers of a complete Fanconi syndrome were normal: urine pH 5.5, magnesium and phosphorus were normal. Genetic testing was done and the patient was found to have a missense mutation in the SCL5A2 gene which results in a single amino acid substitution of Arg to Cys at codon 60 in exon 2 and encodes the SGLT2 protein. On review of literature, this particular mutation has never been reported and the inheritance pattern is likely to be autosomal dominant since she had a heterozygous mutation. The hypoglycemia was noted to be reactive and occurred after meals. She was advised to avoid simple sugars which can precipitate reactive hypoglycemia within a couple of hours of eating foods with a high glycemic index. She also has a bicornuate uterus and history of recurrent urinary tract infections. Out of her 4 children, two have omphalocele and genetic analysis showed that they are recessive carriers for Smith-Lemi-Optiz syndrome. One of those children suffered from hypoglycemia following birth with prolonged NICU stay. No urinalysis or genetic analysis is available for that child. Her third child was born premature and had hydronephrosis. Conclusion: In literature, a total of 86 mutations of the SLC5A2 gene have been reported to be associated with familial renal glycosuria. There are case reports on some of these mutations also causing hypoglycemia. Our case highlights that renal glycosuria should be considered as a differential when evaluating patients with hypoglycemia since these may be correlated. The patient had a novel mutation causing glycosuria, hypoglycemia and could be associated with congenital malformations. More studies on this association are needed. Presentation: Saturday, June 17, 2023

Severe skeletal damage suggesting neoplastic disease as a manifestation of tenofovir-induced Fanconi syndrome in chronic hepatitis B.

Severe skeletal damage suggesting neoplastic disease as a manifestation of tenofovir-induced Fanconi syndrome in chronic hepatitis B.

The hidden diagnosis: hypogonadotropic hypogonadism unveiled in a rare Fanconi syndrome case—a case report and literature review

Introduction and importance: Fanconi syndrome affects kidney function, whereas hypogonadotropic hypogonadism (HH) is gonadal failure due to deficient hormones. Diagnosis involves assays and imaging, whereas treatment targets cause and fluid balance. Here, there is a reported co-occurrence in Pakistan. Case presentation: A 14-year-old girl presented with joint pain and developmental delay. Physical examination revealed wrist widening, genu-varum, and underdeveloped secondary sexual characteristics. Laboratory findings confirmed Fanconi syndrome and coincidental ultrasound findings revealed HH. The patient received treatment in the form of oral medications and supplements to manage the condition. Clinical discussion: Fanconi syndrome is a complex disorder affecting the proximal tubule of the kidneys, leading to impaired reabsorption of various substances. In this case, potential genetic and acquired causes were ruled out, including inborn errors of metabolism and heavy metal intoxication. Prolonged valproic acid use was also considered but not confirmed as the cause. The patient also presented with HH, which is unrelated but coexisting. Treatment for Fanconi syndrome focuses on correcting electrolyte imbalances, whereas hormone replacement therapy is considered for HH. The patient’s progress and response to treatment are under careful monitoring. Conclusion: This case highlights the need for further research and comprehensive diagnostic evaluation to better understand the association between Fanconi syndrome and HH, emphasizing the importance of early diagnosis and management to prevent long-term complications.

Role of the SLC22A17/lipocalin-2 receptor in renal endocytosis of proteins/metalloproteins: a focus on iron- and cadmium-binding proteins.

The transmembrane protein SLC22A17 [or the neutrophil gelatinase-associated lipocalin/lipocalin-2 (LCN2)/24p3 receptor] is an atypical member of the SLC22 family of organic anion and cation transporters: it does not carry typical substrates of SLC22 transporters but mediates receptor-mediated endocytosis (RME) of LCN2. One important task of the kidney is the prevention of urinary loss of proteins filtered by the glomerulus by bulk reabsorption of multiple ligands via megalin:cubilin:amnionless-mediated endocytosis in the proximal tubule (PT). Accordingly, overflow, glomerular, or PT damage, as in Fanconi syndrome, results in proteinuria. Strikingly, up to 20% of filtered proteins escape the PT under physiological conditions and are reabsorbed by the distal nephron. The renal distal tubule and collecting duct express SLC22A17, which mediates RME of filtered proteins that evade the PT but with limited capacity to prevent proteinuria under pathological conditions. The kidney also prevents excretion of filtered essential and nonessential transition metals, such as iron or cadmium, respectively, that are largely bound to proteins with high affinity, e.g., LCN2, transferrin, or metallothionein, or low affinity, e.g., microglobulins or albumin. Hence, increased uptake of transition metals may cause nephrotoxicity. Here, we assess the literature on SLC22A17 structure, topology, tissue distribution, regulation, and assumed functions, emphasizing renal SLC22A17, which has relevance for physiology, pathology, and nephrotoxicity due to the accumulation of proteins complexed with transition metals, e.g., cadmium or iron. Other putative renal functions of SLC22A17, such as its contribution to osmotic stress adaptation, protection against urinary tract infection, or renal carcinogenesis, are discussed.

Renal Fanconi syndrome and hypoglycemia: lessons for clinical nephrologists.

Renal Fanconi syndrome and hypoglycemia: lessons for clinical nephrologists.

Diagnostic accuracy of 99mTc-HYNIC-TOC SPECT/CT for detecting osteomalacia-associated tumors.

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disorder characterized by hypophosphatemia resulting from tumor-secreted fibroblast growth factor-23 (FGF23). Surgical resection of the culprit TIO is the first choice of treatment. However, TIO is difficult to detect with conventional diagnostic tools due to its small size and variable location in the body. Somatostatin receptor scintigraphy (SSR) has recently emerged as a functional molecular imaging choice for TIO detection and localization. This research was undertaken to evaluate the efficacy of 99mTc-labeled hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) SPECT/CT in detecting TIO. 99mTc-HYNIC-TOC SPECT/CT and the available clinical data of 25 patients with suspected TIO were analyzed retrospectively. The 99mTc-HYNIC-TOC SPECT/CT findings were compared with the post-surgical pathology diagnosis and clinical follow-up results. Using 99mTc-HYNIC-TOC SPECT/CT, suspicious tumors were found in 18 of the 25 patients, and 15 of them underwent surgical resection. The post-operative pathology confirmed a TIO in those 13 patients whose symptoms and biochemical anomalies gradually resolved after the surgery. The remaining five patients were finally considered false positives. Moreover, the 99mTc-HYNIC-TOC SPECT/CT results were negative in seven patients, with six patients being true negative (4 patients were diagnosed with acquired Fanconi syndrome and 2 patients responded well to conservative therapy) and one being false negative. Therefore, the sensitivity and specificity values of 99mTc-HYNIC-TOC SPECT/CT in the evaluation of TIO were 92.9% (13/14) and 54.5% (6/11), respectively. The overall accuracy of 99mTc-HYNIC-TOC SPECT/CT for detecting TIO was 76.0% (19/25). The 99mTc-HYNIC-TOC SPECT/CT is an accurate imaging modality for locating culprit tumors in TIO.