Aminoaciduria Caused by Fanconi Syndrome in a Heifer.

A case study of renal tubular dysfunction consistent with idiopathic Fanconi syndrome is reported in an 18-month-old Holstein heifer. The clinical, biochemical, and histopathological features are described. The heifer had clinical signs of growth retardation, wasting, and persistent diarrhea. Biochemical blood analysis identified hypokalemia, hyponatremia, and hypochloremia. Urinalysis identified glycosuria, proteinuria, and acidic pH. Histological examination of the kidney disclosed mild tubular necrosis with proteinaceous casts in the lumina of renal tubules. We performed LC-HRMS on urine to confirm Fanconi syndrome. Using this technique, we identified severe generalized aminoaciduria suggestive of idiopathic renal Fanconi syndrome in this heifer.

Interactions of vitamin D and the proximal tubule.

Severe vitamin D deficiency (reduction in serum 25(OH)D concentration) in infants and children can cause features of the Fanconi syndrome, including phosphaturia, glycosuria, aminoaciduria, and renal tubular acidosis. This indicates that vitamin D and its metabolites influence proximal tubule function. Filtered 25(OH)D bound to vitamin D binding protein (DBP) is endocytosed by megalin-cubilin in the apical membrane. Intracellular 25(OH)D is metabolized to 1,25(OH)2D or calcitroic acid by 1-α-hydroxylase or 24-hydroxylase in tubule cell mitochondria. Bone-produced fibroblast growth factor 23 (FGF23) bound to Klotho in tubule cells and intracellular phosphate concentrations are regulators of 1-α-hydroxylase activity and cause proximal tubule phosphaturia. Aminoaciduria occurs when amino acid transporter synthesis is deficient, and 1,25(OH)2D along with retinoic acid up-regulate transporter synthesis by a vitamin D response element in the promoter region of the transporter gene. This review discusses evidence gained from studies in animals or cell lines, as well as from human disorders, that provide insight into vitamin D-proximal tubule interactions.

Atypical presentation of distal renal tubular acidosis in two siblings.

Primary distal renal tubular acidosis (dRTA) is an inherited disease characterized by the inability of the distal tubule to lower urine pH <5.50 during systemic acidosis. We report two male siblings who presented with severe hyperchloremic metabolic acidosis, high urinary pH, nephrocalcinosis, growth retardation, sensorineural hearing loss, and hypokalemic paralysis. Laboratory investigations revealed proximal tubular dysfunction (low molecular weight proteinuria, generalized hyperaminoaciduria, hypophosphatemia with hyperphosphaturia, and hypouricemia with hyperuricosuria). There was significant hyperoxaluria and laboratory evidence for mild rhabdomyolysis. Under potassium and alkali therapy, proximal tubular abnormalities, muscular enzymes, and oxaluria normalized. A homozygous mutation in the ATP6V1B1 gene, which is responsible for dRTA with early hearing loss, was detected in both siblings. In conclusion, proximal tubular dysfunction and hyperoxaluria may be found in children with dRTA and are reversible under appropriate therapy.

Renal tubular dysfunction in alpha-thalassemia.

Shortened red cell life span and excess iron cause functional and physiological abnormalities in various organ systems in thalassemia patients. In an earlier study, we showed that beta-thalassemia patients have a high prevalence of renal tubular abnormalities. The severity correlated with the degree of anemia, being least severe in patients on hypertransfusion and iron chelation therapy, suggesting that the damage might be caused by the anemia and increased oxidation induced by excess iron deposits. This study was designed to define the renal abnormalities associated with alpha-thalassemia and to correlate the renal findings with clinical parameters. Thirty-four pediatric patients (mean age 8.2+/-2.8 years) with Hb H disease or Hb H/Hb CS were studied. Ten patients (group 1) were splenectomized, with a mean duration post splenectomy of 3.5+/-1.4 years; 24 patients (group 2) had intact spleens. The results were compared with 15 normal children. Significantly higher levels of urine N-acetyl-beta- d-glycosaminidase, malondialdehyde (MDA), and beta(2)-microglobulin were found in both groups compared with normal children. An elevated urine protein/creatinine ratio was recorded in 60% of group 1 and 29% of group 2. Two patients (5.9%), 1 in each group, had generalized aminoaciduria. We found proximal tubular abnormalities in alpha-thalassemia patients. Increased oxidative stress, possibly iron induced, may play an important role, since urine MDA levels were significantly increased in both groups of patients.

Heteromeric amino acid transporters: biochemistry, genetics, and physiology.

The heteromeric amino acid transporters (HATs) are composed of two polypeptides: a heavy subunit (HSHAT) and a light subunit (LSHAT) linked by a disulfide bridge. HSHATs are N-glycosylated type II membrane glycoproteins, whereas LSHATs are nonglycosylated polytopic membrane proteins. The HSHATs have been known since 1992, and the LSHATs have been described in the last three years. HATs represent several of the classic mammalian amino acid transport systems (e.g., L isoforms, y(+)L isoforms, asc, x(c)(-), and b(0,+)). Members of the HAT family are the molecular bases of inherited primary aminoacidurias cystinuria and lysinuric protein intolerance. In addition to the role in amino acid transport, one HSHAT [the heavy subunit of the cell-surface antigen 4F2 (also named CD98)] is involved in other cell functions that might be related to integrin activation. This review covers the biochemistry, human genetics, and cell physiology of HATs, including the multifunctional character of CD98.

Aminoaciduria in calcium-deficiency rickets in northern Nigeria.

Generalized aminoaciduria is associated with vitamin D-deficiency rickets in humans, but there is little information regarding aminoaciduria in rickets caused by primary calcium deficiency. In contrast to rickets in other parts of the world, this bone disease in Nigeria is caused primarily by inadequate intake of dietary calcium. We conducted a clinical trial in Jos, Nigeria in 10 children with radiographically and biochemically proven rickets; an equal number of non-rachitic healthy children from the same area served as controls. Serum and 24 h urine samples were obtained at baseline and at 24 h, 1 week, 4 weeks, and 12 weeks after initiation of calcium supplementation (1000 mg/day) and were analysed for their content of amino acids. Serum calcium, phosphorus, intact parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were also measured at each time point. In the rachitic subjects urinary amino acid concentrations were elevated from 2- to 16-fold at baseline, while serum amino acid levels increased 1.5- to 3.8-fold compared to controls. After 12 weeks of calcium supplementation, serum and urine amino acids decreased. There was no correlation between the degree of aminoaciduria and serum PTH or 1,25-dihydroxyvitamin D concentrations. We conclude that the aminoaciduria in these rachitic children was related to their calcium status and not to their vitamin D or PTH status.

Aminoaciduria and glycosuria following severe childhood lead poisoning.

To determine the incidence of renal functional abnormalities after lead poisoning, we evaluated the parameters of renal tubular function in 134 children and young adults, 8-13 years after chelation therapy for severe lead poisoning. There was no evidence of hypertension or reduced kidney function as assessed by serum creatinine (Cr) concentrations. Urinary alpha-amino nitrogen (Uaan) concentrations were significantly increased compared with 19 healthy age-matched controls. Ninety-four children (70%) had aminoaciduria (Uaan/Cr >0.23). Urinary glucose excretion was also significantly higher than that of 2 historical controls. Thirty-two children (24%) had glycosuria (>125 mg/24 h). Fractional excretion of phosphate was normal in all children. We conclude that a partial Fanconi syndrome can persist up to 13 years after childhood lead poisoning.

Amino-aciduria and enzymuria in patients with artificial heart valves.

Fifteen patients with artificial heart valves and evidence of chronic intravascular haemolysis were studied for proximal tubular dysfunction. Three patients had haemosiderinuria and haemoglobinuria; 2 had haemoglobinuria alone. Increased urinary amino acid nitrogen occurred in 8, raised fractional beta 2-microglobulin excretion in 2, hypophosphataemia in 4, renal glycosuria in 1 and enhanced fractional urate excretion in 1. Urinary N-acetyl-beta-glucosaminidase (NAG) excretion increased in 7; the mean urinary NAG/creatinine ratio was raised to twice the upper limit of the normal range. Renal haemosiderosis due to chronic intravascular haemolysis could cause tubular injury.

Organic acidurias: a review. Part 2.

Laboratory findings are an essential part of the diagnostic approach to organic acidemias. In most organic acidemias, metabolism of glucose, ketone bodies, and ammonia is deranged primarily or secondarily, in addition to derangement of the acid-base balance. Hypoglycemia, lactic and/or ketoacidosis, and hyperammonemia of varying severity accompany the overt or compensated acidosis. In most instances, a definite diagnosis will be achieved by gas chromatography/mass spectrometry (GC/MS) studies of the urine. We detail the pattern of excreted organic acids in the major disorders. When the diagnosis reached by clinical and laboratory assessments is not conclusive, it must be supported by loading tests. We list the available methods of demonstrating the putative enzyme deficiency in the patient's cells and tissues. The majority of organic acidemias may be treated by limiting the source of or removing the toxic intermediary metabolite. We provide lists of available diets, supplements, and medications. In some instances, residual defective enzyme activity may be stimulated. We describe symptomatic management of the disturbed acid-base and electrolyte balance.

[Metabolic disorders of branched-chain amino acids: most common forms of organic aciduria in the neonatal period]. / Abbaustörungen verzweigtkettiger Aminosäuren: Häufigste Organoazidurieformen in der Neonatalperiode.

Defects in the branched chain amino acid metabolism are the most common forms of organic aciduria. Two thirds of the cases manifest themselves during the neonatal period, most of them with an acute onset. Prompt diagnosis of organic acidurias is a task of the pediatrician and the neonatologist and depends on their early identification of children with suspect clinical symptoms. Between 1984 and 1987 9 patients presented with an organic aciduria at the Pediatric Department of the University of Innsbruck, 7 of them were neonates. 4 of these 7 children had a defect in the branched chain amino acid metabolism, 3 with propionic acidemia, one with maple syrup urine disease. The remaining 3 children presented with lactic aciduria. In all our patients diagnosis was performed by combined gas chromatography and mass spectrometry of spontaneous urine samples. Diagnostic procedures and therapeutic measures applied in the acute metabolic crisis are presented. Continuous arteriovenous hemofiltration has been found to be an efficient method for eliminating toxic metabolites in intractable metabolic acidosis.

Persistent nephrogenic diabetes insipidus, tubular proteinuria, aminoaciduria, and parathyroid hormone resistance following longterm lithium administration.

We report a patient who developed persistent nephrogenic diabetes insipidus associated with renal tubular acidosis, renal resistance to parathyroid hormone, aminoaciduria and proximal tubule pattern proteinuria in the presence of a reduced glomerular filtration rate (19-24 ml/min). A review of the previous reports of persistent nephrogenic diabetes insipidus revealed that in all patients the glomerular filtration rate had been less than 60 ml/min at presentation. Chronic renal failure may therefore predispose to the development of persistent nephrogenic diabetes insipidus in patients receiving lithium.

Aminoaciduria of severe trauma.

Plasma and urine levels of free amino acids were measured in 15 severely traumatized adult patients while they were receiving fluids free of calories and nitrogen. Endogenous plasma clearance and the relative rates of reabsorption of free amino acids from renal tubules were calculated. These data were compared with similar studies of eight control subjects. Multiple injury provoked distinct patterns of free amino acids in plasma and urine. Hypoaminoacidemia and hyperaminoaciduria were seen in severe trauma. There was a marked depletion of nonessential amino acids in plasma of trauma victims. In contrast, the urinary loss of all amino acids was increased 5-10 times. This enhanced loss in patients, however, represented only 2.1% of total N excreted compared with 0.7% in control subjects. Considerable variations were seen in the selectivity with which various amino acids were reabsorbed by renal tubules. This may partly be due to the abnormal pattern of amino acids presented to renal tubules.

Effect of vitamin D deficiency on amino acid excretion in the phosphate-depleted rat.

Vitamin D deficiency is associated with a generalized aminoaciduria which has been shown to be independent of parathyroid hormone (PTH) and urinary cyclic AMP excretion. To further characterize the mechanism underlying the tubulopathy, weanling rats were placed on one of the following diets for 5 weeks: (1) control [0.7% phosphorus (P), 5.5 micrograms % vitamin D]; (2) D-P- (0.1% P, 0 vitamin D); (3) D+P- (0.1% P, 5.5 micrograms % vitamin D); (4) D-P+ (0.3% P, 0 vitamin D); (5) D-P++ (0.7% P, 0 vitamin D). All diets contained 1.2% calcium (Ca). A group of rats raised on D-P++ for 4 weeks were fed D-P- for 7 days after which they received 500 pmol of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3; SUPP] or an equal volume of the vehicle (ETH). The above diets resulted in partial vitamin D depletion in that 1,25(OH)2D levels were 50.25-79 pg/ml in the presence of very low 25(OH)D concentrations. Augmentation in the urinary excretion of 6 out of 8 amino acids measured was observed in P depletion irrespective of vitamin D status. For the most part, acute supplementation with 1,25(OH)2D3 did not ameliorate the tubulopathy. Plasma PTH and Ca concentrations remained normal in all diets, except D+P-, where plasma Ca was 15.88 +/- 0.54 mg/dl. P depletion was associated with hypercalciuria, hypophosphatemia, avid reabsorption of P and growth retardation, irrespective of vitamin D status. Using taurine as a representative of the amino affected, there was a strong correlation between urinary taurine on the one hand and dietary P content (r = 0.613), plasma P (r = 0.399) and 1,25(OH)2D levels (r = -0.576) on the other. The present study suggests that the aminoaciduria of vitamin D deficiency is not related to elevated levels of PTH. A similar defect may be produced by P depletion, suggesting the possibility of a common pathway for the effect.

Asymptomatic low molecular weight proteinuria: a report on 5 cases.

In children with asymptomatic proteinuria, a high proportion of low molecular weight (LMW) proteins is an indicator of tubular malfunction. In a routine screening program covering the last 15 years and involving 280,000 children, aged between 3 and 19 years, we have identified 5 boys with LMW proteinuria. In 4 of these, renal biopsy was histologically normal on the first presentation. Follow-up for 4-16 years showed normal growth curves, but further evidence of tubular dysfunction appeared: glycosuria and hypophosphatemia in 2 patients; one of them had also aminoaciduria and rising serum creatinine (greater than 1.2 mg/100 ml). Another patient had only increased serum creatinine. The other two, still less than 13 years old, show so far no other abnormality than persistent LMW proteinuria. It is suggested that early identification of LMW proteinuria may presage gradual development of progressive tubular dysfunction with age and that such patients should be followed up indefinitely.

Abnormal amino acid concentrations in plasma and urine of experimentally diabetic dogs.

Free amino acid concentrations have been determined in plasma and urine of nonketotic, severely diabetic dogs and age-matched normal controls. Plasma from fasted (as well as fed) diabetics contained supranormal concentrations of several amino acids, including the branched-chain amino acids. In contrast to other species, however, the concentration of only one plasma amino acid (tryptophan) was subnormal in fasted diabetic dogs. Urine collected at the same time showed that the excretion of most amino acids was not abnormal in diabetes. Urinary concentrations of some amino acids were not abnormal despite supranormal levels in plasma. Nevertheless, eight of the 21 amino acids studied reached concentrations significantly greater than normal in the urine of diabetic dogs. Six of the eight amino acids (arginine, histidine, phenylalanine, tyrosine, tryptophan, glutamic acid) showed elevated concentrations in urine even though their plasma concentrations were not elevated. The observed disturbance in the urine/plasma ratio of certain amino acids suggests a possible defect in the renal handling of amino acids in diabetes.