Fanconi’s syndrome

Renal Effects. The characteristics of early or acute lead-induced nephropathy in humans include nuclear inclusion bodies, mitochondrial changes, and cytomegaly of the proximal tubular epithelial cells dysfunction of the proximal tubules (Fanconi s syndrome) manifested as aminoaciduria, glucosuria, and phosphaturia with hypophosphatemia and increased sodium and decreased uric acid excretion. These effects appear to be reversible. Characteristics of chronic lead nephropathy include progressive interstitial fibrosis, dilation of tubules and atrophy or hyperplasia of the tubular epithelial cells, and few or no nuclear inclusion bodies, reduction in glomerular filtration rate, and azotemia. These effects are irreversible. The acute form is reported in lead-intoxicated children, whose primary exposure is via the oral route, and sometimes in lead workers. The chronic form is reported mainly in lead workers, whose primary exposure is via inhalation. Animal studies provide evidence of nephropathy similar to that which occurs in humans, particularly the acute form (see Section 2.2.3.2). 

In the course of studies on aminoaciduria in Fanconi s syndrome, Dent (Dl) isolated from the urine of the subject investigated a simple peptide identified as serylglycylglycine. Carsten (Cl) found in normal urine several peptides containing in every case one of the dicarboxylic amino acids. He discovered also two tetrapeptides, one of them consisting of equimolar amounts of aspartic acid and glycine, and the second composed of glycine, alanine, and glutamic acid in the ratio 2 1 1. The first of these tetrapeptides was also found in the urine of a patient with rheumatoid arthritis. 

Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence) are the most common adverse effects but rarely require discontinuation of therapy. Other potential adverse effects include headache and asthenia. Tenofbvir-associated proximal renal tubulopathy causes excessive renal phosphate and calcium losses and 1-hydroxylation defects of vitamin D, and preclinical studies in several animal species have demonstrated bone toxicity (eg, osteomalacia). Monitoring of bone mineral density should be considered with long-term use in those with risk factors for or with known osteoporosis, as well as in children. Reduction of renal function over time, as well as cases of acute renal failure and Fanconi s syndrome, have been reported in patients receiving tenofovir alone or in combination with emtricitabine. For this reason, tenofovir should be used with caution in patients at risk for renal dysfunction. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. 

A review of Japanese patients found that of the 15 patients who had developed hematological malignancies since 1975, 6 had other risk factors for leukemia, such as Fanconi s syndrome or prior chemotherapy or radiotherapy. The incidence of leukemia in this study was 3 per 100 000, similar to that in the general population of the same age (68). The National Cooperative Growth Study (NCGS—a postmarketing database that includes 19 846 patient-years since the time of growth hormone exposure) similarly reported no increase in the incidence of new leukemia when patients with other risk factors were excluded from the analysis (96). 

Whilst cells are normally equipped with extensive DNA repair systems these can sometimes become overwhelmed, or they may be defective for genetic reasons. Patients with genetic defects in their DNA repair systems (e.g. Xeroderma pigmentosum, Fanconi s syndrome, Bloom s syndrome) are predisposed to the development of cancer [132]. 

Fanconi s syndrome has also been reported (39), as have severe tubulo-interstitial nephritis (40), and acute toxic tubular necrosis (41). 

Moss AH, Gabow PA, Kaehny WD, Goodman SI, Haut LL. Fanconi s syndrome and distal renal tubular acidosis after glue sniffing. Ann Intern Med 1980 92(l) 69-70. 

Hereditary fructose intolerance is caused by an autosomal recessive hereditary defect of the enzyme fructose-l-phosphate aldolase. Whenever fructose is supplied, severe hypoglycaemia and functional disorders occur in the liver, kidneys and CNS. The prevalence is estimated at 1 20,000 births. As with galactose intolerance, the gene which codes aldolase B is also localized on chromosome 9. This enzyme defect causes fructose-l-phosphate to accumulate in the liver and tissue. The cleavage of fructose-1,6-biphosphate is only slightly compromised since the enzymes aldolase A and C are available for this process. The consumption of phosphate and ATP in the tissue results in various functional disorders (i.) inhibition of gluconeogenesis in the liver and kidneys, (2.) increase in lactate in the serum with metabolic acidosis, (3.) decrease in protein synthesis in the liver, and (4.) functional disorders of the proximal tubular cells with development of Fanconi s syndrome, (s. pp 593, 594) (193, 194, 196, 198)... 

Aminoglycoside-induced proximal tubular dysfunction, which causes some manifestations of Fanconi s syndrome, including electrolyte abnormalities, is rare. 

A 22-year-old woman took 5.4g of colloidal bismnth subcitrate in a suicide attempt and developed Fanconi s syndrome and acute renal insufficiency (35). She received hemodialysis and intravenons sodinm 2,3-mercapto-l-propanesulfonate 60 hours after intoxication. Her semm bismuth concentrations fell from 640 to 15 pg/l within 6 days, her renal function improved, and her tonsillar nlceration healed. Hemodialysis was discontinned on day 14. She had normal renal fnnction 6 weeks later. 

Hruz P, Mayr M, Low R, Drewe J, Huber G. Fanconi s syndrome, acute renal failure, and tonsil ulcerations after colloidal bismuth subcitrate intoxication. Am J Kidney Dis 2002 39(3) E18. 

Pratt CB, Meyer WEI, Jenkins JJ, Avery L, McKay CP, Wyatt RJ, Elancock ML. Ifosfamide, FanconI s syndrome and reickets. J Clin Oncol 9 1495-1499,1991... 

Yang SS, Chu P, Lin YF, Chen A, Lin SH. Aristoiochic acid-induced Fanconi s syndrome and nephropathy presenting as hypokalemic paralysis. Am J Kidney Dis 2002 39 El 4... 

Fee S, Fee T, Fee B, Choi El, Yang M, Ihm CG, Kim M. Fanconi s syndrome and subsequent progressive renal failure caused by a Chinese herb containing aristolochic acid. Nephrology (Carlton) 2004 9 126-129... 

Nausea and vomiting confusion nephrotoxicity metabolic acidosis and renal Fanconi s syndrome cardiac toxicity with high doses... 

Cadmium, a waste product from several industrial processes, is the cause of itai-itai ( ouch-ouch ) disease, which is characterized by osteomalacia with painful fractures of affected, bones and by nephropathy with an excretory pattern similar to that seen in Fanconi s syndrome. In... 

Malignant neoplasms Fanconi s syndrome Acute volume expansion Metabolic acidosis Renal transplantation Vitamin D deficiency and/or resistance Diuretics Acetazolamide Osmotic agents Glucocorticoids Sodium bicarbonate Internal redistribution Refeeding syndrome Parenteral nutrition... 

Other chronic disorders cause osteomalacia. " " Phosphate depletion from low dietary intake, phosphate-binding antacids, and oncogenic osteomalacia (potentially phosphaturic effect) can cause osteomalacia. Hypophosphatasia is an inborn error of metabolism in which deficient activity of alkaline phosphatase causes impaired mineralization of bone matrix. Acidosis from renal dysfunction, distal renal tubular acidosis, hypergammaglobulinemic states (e.g., multiple myeloma), and drugs (e.g., chemotherapy) compromises bone mineralization. Renal tubular disorders secondary to Fanconi s syndrome, hereditary diseases (e.g., Wilson s disease, a defect in copper metabolism), acquired disease (e.g., myeloma), and toxins (e.g., lead) cause osteomalacia to varying degrees. Chronic wastage of phosphorus and/or calcium limits mineralization, which may be further compromised by acidosis and secondary hyperparathyroidism. 

For osteomalacia with renal tubular acidosis, acidosis is corrected with oral bicarbonate. For osteomalacia from Fanconi s syndrome, treatment depends on the underlying disorder, but often includes phosphate supplements and vitamin D analogues. 

S. Deret, L. Denoroy, M. Lamarine, R. Vidal, B. Mougenot, B. Frangione, F. J. Stevens, P. M. Ronco, P. Aucouturier. Kappa light chain-associated Fanconi s syndrome molecular analysis of monoclonal immunoglobulin light chains from patients with and without intracellular crystals. Protein Eng. 1999, 12, 363-369. 

Nephrotoxicity is the principal dose-limiting side effect of intravenous cidofovir. Proximal tubular dysfunction includes proteinuria, azotemia, glycosuria, metabolic acidosis and, uncommonly, Fanconi s syndrome. Concomitant oral probenecid and saline prehydration reduce the risk of renal toxicity. 

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