Idiopathic Adult Onset Fanconi’s Syndrome in a Patient Treated with Oxaliplatin

Proximal tubular injury is known complication of chemotherapy such as carboplatin. However, there are far more other causes of injury and in many situations, the etiology is difficult to elucidate. Here we describe a case of a patient who presented with a urine analysis consistent of Fanconi’s syndrome with signs and symptoms of the disorder prior to chemotherapy but requiring admission for aggressive electrolyte replacement soon after the chemotherapy was completed. We further discuss causes of Fanconi’s syndrome and the importance of evaluation of the proximal convoluted tubule prior to administration of chemotherapy.

Fanconi’s Syndrome and Dementia in a Patient With Chronic Hepatitis B Taking Nucleoside/ Nucleotide Analogue

A 58-year-old Chinese man was referred to the Endocrine Clinic for osteomalacia in Aug 2014. He started to have generalized bone pain since Apr 2013. Bone scan in Aug 2013 showed multiple active bone lesions especially at right femur. Magnetic resonance imaging (MRI) found avascular necrosis of both femoral heads with fractured right femoral neck and he underwent screw fixation of right hip in Feb 2014. In Aug 2014, his lab were as follows: serum (S) PO4 1.35(2.5–4.49)mg/dL; ALP 270 IU/ml (40–129); S creatinine (Cr) 1.36 (0.7–1.2) mg/dL; spot urine (U) PO4 23.2mg/dL.; U Cr 44.5mg/dL; parathyroid hormone 20.7 (15.1–65.1) pg/mL; 25-hydroxyvitamin D3 16.4ng/mL; TSH 3.4 uU/mL; S urate 1.7 mg/dL (3.4–7.0) mg/dL. U amino acid was increased to 5x upper limit of normal signifying U PO4 loss. He had hepatitis B (HBV) liver cirrhosis and took lamivudine 100mg qd (LAM) since 2005. Because of LAM resistance, adefovir dipivoxil 10mg qd (ADV) was added in Jul 2007. He was diagnosed Fanconi’s syndrome and osteomalacia after taking ADV for 6 years. ADV was changed to tenofovir disoproxil fumarate 300mg qd (TDF) in Dec 2014. He was given alfacalcidol 1mcg bd and PO4 mixture 1250mg/d. His S PO4 rose to 2.82mg/dL but later dropped to 2.14mg/dL because of poor drug compliance. ALP dropped to 126IU/L. His bone pain improved and could walk with stick. TDF was then switched to tenofovir alafenamide (TAF) 25mg qd in Mar 2019. His S PO4 further normalized to 3.13mg/dL in Jul 2019. His HBV remained suppressed. Alfacalcidol and PO4 solution were stopped. The patient developed depression since Sep 2017. He had poor short term memory since 2018 and was confirmed mild cognitive impairment in Apr 2019. MRI brain in May 2019 found moderate global cerebral atrophy with bilateral parietal lobes and cerebellar predilection. His cognitive assessment further declined to < 2%ile in Jan 2020. He was admitted for recurrent fall in Sep 2020 and showed Parkinsonism feature. He was given Sinemet 25/100 and rivastigmine by neurologist with some improvement. He now walked with frame. Nucleotide and nucleoside analogues (NA) can impose long term side effect on kidney. ADV and TDF are excreted from proximal renal tubule and can accumulate in the cytoplasm causing mitochondrial dysfunction. In this patient, hypoPO4 persisted after switching from ADV to TDF. TAF did not enter proximal renal tubular cells and the plasma concentration is lower than TDF and hence less nephrotoxic. The PO4 level in this patient normalized one month after changing to TAF. Low serum phosphorus level was found to have correlation with cerebral amyloid deposition on Pittburgh compound B positron tomography in a Korean study. The chronic hypoPO4 may be a contributing factor for the development of dementia in this patient which did not show reversibility. In summary, this case illustrates the nephrotoxicity of NA and importance of multi-disciplinary care as the side effect can be multi-systemic.

Persistently Elevated Urine β2-MG and Decreased BMD in a Patient with ADV-induced Hypophosphatemic Osteomalacia and Fanconi’s Syndrome After Drug Withdrawal

This is the first case of adefovir dipivoxil (ADV)-induced hypophosphatemic osteomalacia (HO) and Fanconi’s syndrome in which bone mineral density (BMD) is continuously reduced after drug discontinuation. Sustained elevation of urine β2-MG also supports the recent view that ADV-induced renal injury is not completely reversible.

Disorders of tubular electrolyte handling

Glycosuria—glucose reabsorption in the proximal tubule is carried out by two different pairs of apical Na+-dependent (SGLT1 and -2) and basolateral Na+-independent (GLUT1 and -2) glucose transporters. Abnormalities in renal glucose transport can be seen in association with other defects of proximal tubular transport. Familial renal glycosuria is a rare autosomal recessive condition caused by mutations in the SGLT2-encoding gene, SLC5A2. Phosphate-handling disorders—the plasma concentration of inorganic phosphate depends on the balance between intestinal absorption, renal excretion, and the internal contribution from bone. Changes of serum phosphate levels can be caused by numerous inherited and acquired conditions. Disorders associated with increased urinary phosphate excretion and low serum phosphate levels produce symptoms that mainly affect the bones: rickets in children and osteomalacia in adults. Magnesium-handling disorders—normal plasma magnesium concentration is achieved by variation of urinary magnesium excretion in response to altered uptake by the intestine. The main site of magnesium absorption is the small bowel, via paracellular simple diffusion at high intraluminal concentrations, and via active transcellular uptake through the magnesium channel TRPM6 at low concentrations. Regulation and fine-tuning of serum magnesium concentration occurs primarily in the kidney. Genetic disorders of magnesium handling include Gitelman’s syndrome. Aminoaciduria and renal Fanconi’s syndrome—most amino acids (except for tryptophan, which is protein bound) are freely filtered by the glomerulus, after which 95 to 99.9% are reabsorbed in the proximal tubules by apical Na+-dependent cotransporters and Na+-independent cotransporters. Aminoaciduria is defined as urinary excretion of more than 5% of the filtered load of an amino acid. Renal Fanconi’s syndrome is characterized by a generalized defect of both Na+-coupled and receptor-mediated proximal tubular transport.