Glycogen Accumulation in the Pars Recta of the Proximal Tubule in Fanconi Syndrome

We reviewed the renal pathology in 10 cases of renal Fanconi syndrome. Five cases showed the Armanni-Ebstein lesion, i.e., clear glycogen-filled cells limited to the pars recta of the proximal tubules. The 5 cases included 2 siblings with a unique syndrome characterized by death in infancy, severe Fanconi syndrome, severe rickets, carnitine deficiency, and atrophy of the exocrine pancreas. Two other siblings had glycogen storage disease type XI. One of 4 cases of putative tyrosinemia had the lesion. The ultrastructure was studied in 2 cases. The Armanni-Ebstein lesion in these cases was morphologically indistinguishable from that seen in diabetic patients dying after prolonged hyperglycemia. Glycosuria is the only common factor in both diabetic hyperglycemia and the varied proximal tubular diseases studied. The mechanism of the glycogen accumulation in this short parts recta segment of the proximal renal tubule was further investigated by reviewing the renal histology in cases of glycogen storage disease types I, II, III, and VIII None showed the Armanni-Ebstein lesion, but type I showed glycogen deposition throughout the proximal tubule. Thus, the Armanni-Ebstein lesion is not the result of an enzymatic deficiency for glycogen synthesis in the convoluted tubules.     

Developmental changes in proximal tubule tight junction proteins

We demonstrated previously that neonatal proximal tubules have a lower passive paracellular permeability to chloride ions and higher resistance than that of adult proximal tubules. In addition, administration of thyroid hormone to neonates, before the normal maturational increase in serum thyroid hormone levels, prematurely accelerates the developmental increase in chloride permeability to adult levels. To test the hypothesis that there is a maturational change in tight junction proteins and that thyroid hormone mediates these changes, we examined the two known tight junction proteins present in proximal tubules, occludin and claudin 2. Using immunoblot and immunohistochemistry, we demonstrated that claudin 2 has a 4-fold greater abundance in neonatal proximal tubules than in adult tubules. Occludin, however, has a 4-fold greater expression in adult tubules than in neonatal tubules. Administration of thyroid hormone to neonates did not affect claudin 2 expression, occludin expression, or the transepithelial resistance in rat proximal tubule cells in vitro. In conclusion, there are postnatal maturational changes in tight junction proteins. The factors that cause these maturational changes are unknown but unlikely to be due solely to the maturational increase in thyroid hormone.     

Developmental changes in rabbit juxtamedullary proximal convoluted tubule bicarbonate permeability

The bicarbonate transport rate in neonatal rabbit juxtamedullary proximal convoluted tubules (JMPCT) is lower than that in adults. The reduced rate of transport could be due to a decrease in active bicarbonate transport or an increase in the passive permeability of the tubule to bicarbonate. The present in vitro microperfusion study directly measured the bicarbonate permeability of neonatal and adult JMPCT. Bicarbonate permeability was measured at both slow and fast perfusion rates to simulate the neonatal and adult proximal tubule flow rates, respectively. At 38 degrees C in tubules perfused at 3 nL/min, bicarbonate permeability was 0.29 +/- 0.11 x 10(-5) cm/s in neonates and 1.70 +/- 0.49 x 10(-5) cm/s in adult PCT (p less than 0.05). At a perfusion rate of 10 nL/min, bicarbonate permeability was 0.11 +/- 0.27 x 10(-5) cm/s in neonatal PCT and 2.31 +/- 0.15 x 10(-5) cm/s in adult PCT (p less than 0.05). These results demonstrate that bicarbonate permeability in neonatal JMPCT is significantly lower than that in adult JMPCT. Thus, the lower rate of bicarbonate transport in neonatal PCT is entirely due to a lower rate of active bicarbonate transport.     

The Fanconi syndrome of cystinosis: insights into the pathophysiology

Cystinosis is a lysosomal storage disease, and is one of the most common causes of the Fanconi syndrome. In vitro studies of the cystine-loaded tubule provided insights into the pathophysiology of the proximal tubular defect. Proximal tubules loaded with cystine have a generalized proximal tubule transport defect characteristic of the Fanconi syndrome. The decrease in proximal tubular transport with cystine loading is due to a decrease in active transport. In cystine-loaded tubules the ATP production is severely compromised. The cystine-loaded tubule has a lower intracellular phosphate concentration than that of control tubules. This low intracellular phosphate concentration in cystine-loaded tubules likely plays an important role in maintaining intracellular ATP level. Preservation of intracellular phosphate at control levels prevents the decrease in intracellula, ATP and the proximal tubule respiratory dysfunction with cystine loading.     

Reversible Fanconi syndrome in a pediatric patient on deferasirox

Deferasirox (Exjade®, Novartis) is a widely used oral iron chelator for the treatment of patients with iron overload due to chronic transfusion therapy for diseases such as β‐thalassemia and sickle cell disease. Renal side effects of deferasirox are common and include non‐progressive increases in serum creatinine, however, the effect of deferasirox on proximal tubule function is unclear. We report one pediatric patient with reversible Fanconi syndrome associated with long‐term deferasirox therapy and one patient with mild proximal tubular dysfunction. Kidney and proximal tubular function should be periodically monitored in patients receiving deferasirox throughout their course of therapy. Pediatr Blood Cancer 2011;56:674–676. © 2010 Wiley‐Liss, Inc.     

新生儿Fanconi Ⅱ综合征一例

患儿女，26天。因发现尿蛋白阳性10余天入院。患儿系第一胎第一产，胎龄41周，自然分娩，生后无窒息。生后15d因“高胆红素血症”在当地住院治疗，其间多次查尿蛋白均为阳性至今未转阴。出生体重3．55kg，其母孕期无合并症及用药史，未接受放射线。入院查体：体重3．5kg，发育营养差，神志清，精神反应差。双眼睑无水肿，口唇略樱桃红色，呼吸平稳，心肺(-)，腹软，肝脾不大，双下肢无水肿。实验室检查：尿蛋白 尿糖 。入院诊断：先天性肾病?入院后反复查尿常规共10余次，结果为：尿蛋白 ～ ，尿糖 ～ 。     

Fanconi syndrome in a patient with a variant of isovaleric acidemia

Fanconi syndrome with proximal renal tubular acidosis is caused by a variety of anatomic, functional and metabolic disorders. We report a patient with a variant of isovaleric acidosis who developed proximal tubular acidosis. This patient was able to acidify the urine during metabolic acidosis, developed a hyperchloremic metabolic acidosis, and needed 24 mEq/kg/day of bicarbonate to maintain normal serum bicarbonate. She had a FE Bicarbonate of 12 +/- 4% during bicarbonate infusion. Isovaleric acidosis may be another toxic cause of proximal RTA.     

Ontogeny of the regulation of Na+,K(+)-ATPase activity in the renal proximal tubule cell.

This study examines the ontogeny of the regulation of Na+,K(+)-ATPase activity in the proximal tubule (PT) by a first messenger, dopamine (DA), and by direct stimulation of a third messenger, protein kinase C (PKC). PT segments dissected from 10- (PT10), 15-(PT15), 20- (PT20), and 40- (PT40) d-old rats were preincubated with DA 10(-5) M, diacylglycerol (DAG) 10(-5) M (an endogenous activator of PKC), or phorbol 12,13-dibutyrate (PDBu) 10(-6) M (an exogenous activator of PKC). DA inhibited Na+,K(+)-ATPase activity in PT40. In PT20, DA also inhibited Na+,K(+)-ATPase activity, but the inhibitory effect in PT20 was less pronounced than in PT40. In PT15, DA had no effect on Na+,K(+)-ATPase activity. DAG significantly inhibited Na+,K(+)-ATPase activity in PT40. DAG also inhibited Na+,K(+)-ATPase activity in PT20, but the inhibition was slightly less pronounced than in PT40. DAG had no effect on Na+,K(+)-ATPase activity in PT15. Na+,K(+)-ATPase activity in PT40 and PT20 preincubated with PDBu was significantly lower than with vehicle. The inhibitory effect in PT20 was less pronounced than in PT40. When PT40 and PT20 were preincubated with both PDBu and 5 x 10(-5) M sphingosine, an inhibitor of PKC activation, the inhibitory effect of PDBu was abolished. In both PT40 and PT20 incubated with 4-alpha-12,13 phorbol didecanoate 10(-7) M, a phorbol ester that will not activate PKC, Na+,K(+)-ATPase activity was not different from the control. In PT10, Na+,K(+)-ATPase activity was the same after PDBu incubation and after vehicle incubation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intracellular cystine loading causes proximal tubule respiratory dysfunction: effect of glycine.

The present study examined proximal tubular respiration in control proximal tubules and proximal tubules loaded with cystine using 2 mmol/L cystine dimethyl ester. Basal oxygen consumption was significantly less in cystine-loaded tubules (20.6 +/- 0.5 versus 12.1 +/- 0.6 nmol O2.min-1.mg protein-1, p < 0.001). In the presence of 10(-4) mol/L ouabain, an inhibitor of the NaK ATPase, oxygen consumption was 10.2 +/- 0.7 nmol O2.min-1.mg protein-1 in control tubules and 11.4 +/- 1.0 nmol O2.min-1.mg protein-1 in cystine-loaded tubules. Thus, proximal tubular intracellular cystine loading specifically inhibits oxygen metabolism directed toward transport. Compared with control proximal tubules, cystine-loaded proximal tubules also had a lower rate of O2 consumption when the cells were permeabilized to sodium with nystatin and when mitochondrial respiration was uncoupled. Glycine, an amino acid that is cytoprotective to hypoxic proximal tubule injury, ameliorated the respiratory dysfunction observed in cystine-loaded tubules.     

Extracutaneous Sweet syndrome involving the gastrointestinal tract in a patient with Fanconi anemia

Acute febrile neutrophilic dermatosis, or Sweet syndrome, is a cutaneous eruption characterized clinically by the appearance of painful red plaques and nodules and histologically by an intense dermal neutrophilic infiltrate. Extracutaneous manifestations are rare. We report a patient in whom otherwise typical cutaneous Sweet syndrome was accompanied by an extracutaneous manifestation in the ileum.