Developmental aspects of renal beta-amino acid transport. III. Ontogeny of transport in isolated renal tubule segments.

Isolated renal tubules were prepared from newborn and adult Sprague-Dawley rats. They were used to study the uptake and accumulation of the beta-amino acid, taurine, by renal epithelium. Initial rate as well as steady-state kinetics were studied. Initial rate studies revealed heterogeneity of uptake in newborn and adult tubules. Slower uptake was present in the newborn in the low-affinity system. Slowed efflux was found in neonatal tissue. Newborn tubules in contrast to adult tubules demonstrated uptake under anaerobic conditions. Adult and newborn tissues showed decreased uptake of taurine when incubated with beta-alanine. Physiologic taurinuria, be it in the rat or man, may be due to less rapid initial uptake and/or efflux from ren in neonatal tissue. Newborn tubules in contrast to adult tubules demonstrated uptake under anaerobic conditions. Adult and newborn tissues showed decreased uptake of taurine when incubated with beta-alanine. Physiologic taurinuria, be it in the rat or man, may be due to less rapid initial uptake and/or efflux from ren in neonatal tissue. Newborn tubules in contrast to adult tubules demonstrated uptake under anaerobic conditions. Adult and newborn tissues showed decreased uptake of taurine when incubated with beta-alanine. Physiologic taurinuria, be it in the rat or man, may be due to less rapid initial uptake and/or efflux from renal epithelium.

Development aspects of renal beta-amino acid transport II. Ontogeny of uptake and efflux processes and effect of anoxia.

Renal cortex slices from newborn, 2-week, and 4-week-old Sprague-Dawley rats had reduced initial rates of taurine uptake compared to adult slices after short (less than 30 min) incubation periods. From birth onward, steady-state accumulation occurred by at least two sodium-dependent uptake systems. The first system had an "apparent Km1" = 0.1 mM and a Vmax varying from 1.8 to 5.1 mumoles/ml ICF/120 min at four ages. The second uptake mode had an apparent Km2 = 12-16 mM and a Vmax of 45 mumoles/ml ICF/120 min. Efflux of taurine was reduced in slices from younger animals possibly accounting for taurinuria. Only other beta-amino acids inhibited accumulation. Anoxia inhibited uptake at high concentration ( greater than 1.0 mM) at each age, but taurine accumulation at low concentrations ( less than 0.4 mM) was relatively protected from anoxia in neonatal ( less than 36 hr of age) tissue. Preincubation in taurine-free medium for 120 min enhanced low concentration, but not high concentration uptake in neonatal and 2-week slices. After preincubation in dibutyryl cyclic AMP (dbcAMP) enhanced uptake of taurine was found in adult cortex, but not in neonatal cortex. The ontogeny of renal taurine transport in cortex slices appeared to involve faster initial uptake rates and faster efflux as well as greater dependence on aerobic metabolism with maturation. Age-related differences in the response to preincubation and cyclic nucleotides were also indicative of maturation events in renal tubular amino acid transport.

Developmental aspects of renal beta-amino acid transport I. Ontogeny of taurine reabsorption and accumulation in rat renal cortex.

Newborn Sprague-Dawley rat pups were found to have reduced net tubular reclamation of the beta-amino acid taurine in vivo. The reabsorption of this compound increased between the 2nd and 4th week of life and the excreted taurine fell despite a rise in glomerular filtration rate indicative of increased transport with maturation. Kidney cortex in vivo accumulated taurine from plasma against a large chemical gradient. Newborn cortex slices in vitro accumulated taurine to higher levels at steady state at less than 0.4 mM, but uptake was less efficient at higher taurine concentrations. Further metabolism of taurine by cortex slices was not found at any age. Accumulation in adult and newborn cortex was greatest at 10-15 mEa/liter K in the external medium. Slices from younger animals had slightly higher pH optima for uptake and temperature elevation increases uptake more in neonatal than in adult kidney.

Effect of prednisone on growth and bone mineral content in childhood glomerular disease.

Children with acquired glomerular disease were divided into two groups: Group 1 patients received short-term daily or long-term alternate-day prednisone (up to 2.7 mg/kg/48 hr); group 2 patients received no corticosteroids. Height, bone mineral content (BMC), and bone density were evaluated in the two groups and compared to those of 800 sex- and age-matched controls; BMC and bone density were assessed by the photon absorption technique. Significant demineralization was present in 18 of 25 prednisone-treated and none of the 17 nonprednisone-treated patients (P less than .001). Group 1 patients were 5.3 +/- 0.7% shorter than controls, while group 2 patients were only 1.9 +/- .8% shorter (P less than .02). Height velocity was 2.6 +/- 0.8 cm/yr in group 1 and 5.1 +/- 0.8 cm/yr in group 2 patients (P less than .05). When prednisone therapy was discontinued, six patients had an increase in height and BMC toward normal values. This study suggests that BMC and height velocity are correlated. Both appear to be influenced by alternate-day prednisone therapy rather than by glomerular disease per se.

Increased growth after long-term oral 1alpha,25-vitamin D3 in childhood renal osteodystrophy.

We evaluated oral 1,25-vitamin D3 for as long as 26 months in six prepubescent children with renal osteodystrophy previously treated with vitamin D2. Therapy was given at 14 to 41 ng per kilogram per day to correct hypocalcemia and reverse bone disease. Serum levels of 1,25-vitamin D3 were initially reduced at 15 +/- 5 pg per milliliter (mean +/- S.E.M.) and after treatment rose to 54 +/- 13. Serum calcium rose from 7.5 +/- 1.6 mg per deciliter (mean +/- S.D.) to 9.8 +/- 0.6 after one month (P less than 0.02). Alkaline phosphatase activity fell from 536 +/- 298 to 208 +/- 91 IU per liter after 12 months (P less than 0.05). Serum immunoreactive parathyroid levels fell from 900 +/- 562 microliter eq per milliliter 411 +/- 377. Healing of rickets and subperiosteal erosions was found. Remineralization of bone was demonstrated by the photon absorption technic. In four patients growth velocity, evaluated for 12 months before and after therapy, increased from 2.6 +/- 0.8 to 8.0 +/- 3.2 cm per year. Growth velocity per year increased from less than third percentile in each to the 10th to 97th percentile after therapy. Height increment ranged from 27 to 113 per cent of that expected for change in chronologic age and 40 to 114 per cent expected for change in bone age after therapy. This trial demonstrates that oral 1,25-vitamin D3 can reverse renal bone disease and increase growth in uremic children.

Bone mineral status measured by direct photon absorptiometry in childhood renal disease.

Bone width (BW), bone mineral content (BMC), and their ration (BMC/BW ratio) were measured in renal patients using direct photon absorptiometry. Serial measurements were made on the radius and ulna in 74 children with renal diseases. Values were compared to age-, sex-, height-, and weight-matched controls. The SD from the mean in normal subjects is +/- 10%. Significant demineralization (greater than -2 SD) was found in 42% of all patients and in 75% with tubulointerstitial disease. Twelve patients with nephrotic syndrome and two with systemic lupus erythematosus, all of whom were receiving prednisone therapy and had a serum creatinine level less than 1.0 mg/dl, and three treated with anticonvulsants had significant demineralization. Severe demineralization (greater than -3 SD) was found in four rachitic patients with tubulointerstitial disease. Normal mineralization was present in 32 patients with various primary glomerular diseases, seven of whom had a serum creatinine level greater than 1.5 mg/dl. BMC declined with daily prednisone therapy but increased with alternate-day dosage in seven patients. This study suggests that demineralization is more common in patients with tubulointerstitial disease and in patients with primary glomerular disease who are receiving prednisone (16 patients) or anticonvulsants. Photon absorptiometry appeared more useful than conventional radiographic evaluation in assessing skeletal involvement in childhood renal disease.

Heterogeneity of the beta-amino-preferring transport system in rat kidney cortex. Differential influence of glutathione oxidation.

Taurine, a naturally found beta-amino acid, is inert in rat renal cortex slices. Its active accumulation by slices is abolished by anaerobiosis, a strongly acidic media or the removal of Na+. Concentration-dependent uptake studies reveal more than one taurine carrier: the apparent Km value for uptake below 1.1 mM is 0.4 mM and the apparent Km value above 1.1 mM is 14.5 mM. Of all amino acids tested only beta-alanine, another beta-compound, inhibited uptake. The oxidizing agent diamide was used to lower the concentration of GSH in rat cortex slices. The ability to accumulate taurine by the low Km system was decreased in diamide-treated slices, but not by the high Km system. Diamide was found to greatly augment efflux of taurine taken up from lower concentrations but not from higher concentrations. GSH in the media prevented this diamide-induced inhibition of uptake and enhanced efflux at lower taurine concentrations. A possible mechanism of diamide inhibition of uptake is that intracellular GSH depletion leads to greatly enhanced efflux of taurine, thus preventing uptake.