sodium-bicarbonate and Growth-Disorders

Topics: Acidosis, Renal Tubular; Child; Child, Preschool; Citrates; Citric Acid; Failure to Thrive; Female; Follow-Up Studies; Growth Disorders; Humans; Infant; Sodium Bicarbonate; Sodium Citrate

Renal tubular acidosis represents a heterogenous group of disorders with various etiologies and mechanisms. The physiopathologic basis of each type of renal tubular acidosis is reviewed, focusing on the laboratory investigations necessary to define the nature of the hyperchloremic renal tubular acidosis. Clinically, the four types of renal tubular acidosis can be associated with complications such as osteomalacia, urolithiasis and failure to thrive. Very often, the chronic administration of alkali results in normal growth and development, and greatly reduces the risk of stone formation or nephrocalcinosis.

Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Bicarbonates; Child; Female; Growth Disorders; Humans; Infant; Kidney Calculi; Osteomalacia; Sodium; Sodium Bicarbonate

We have identified a novel homozygous nonsense mutation (W516X) in the kidney-type electrogenic sodium bicarbonate cotransporter 1 (NBC1) in a patient with isolated proximal renal tubular acidosis (pRTA). To specifically address the pathogenesis of this mutation, we created NBC1 W516X knock-in mice to match the patient's abnormalities. The expression of NBC1 mRNA and protein in the kidneys of NBC1(W516X/W516X) mice were virtually absent, indicating that nonsense-mediated mRNA decay (NMD) is involved in the defective transcription and translation of this mutation. These mice not only recapitulated the phenotypes of this patient with growth retardation, pRTA, and ocular abnormalities, but also showed anemia, volume depletion, prerenal azotemia, and several organ abnormalities, culminating in dehydration and renal failure with early lethality before weaning. In isolated renal proximal tubules, both NBC1 activity and the rate of bicarbonate absorption were markedly reduced. Unexpectedly, there was no compensatory increase in mRNA of distal acid/base transporters. Sodium bicarbonate but not saline administration to these mutant mice markedly prolonged their survival, decreased their protein catabolism and attenuated organ abnormalities. The prolonged survival time uncovered the development of corneal opacities due to corneal edema. Thus, NBC1(W516X/W516X) mice with pRTA represent an animal model for metabolic acidosis and may be useful for testing therapeutic inhibition of NMD in vivo.

Topics: Acidosis; Acidosis, Renal Tubular; Age Factors; Aging; Analysis of Variance; Anemia; Animals; Aquaporin 2; Bicarbonates; Codon, Nonsense; Corneal Opacity; Disease Models, Animal; Female; Gene Knock-In Techniques; Genotype; Growth Disorders; Homozygote; Humans; Hydrogen-Ion Concentration; Kidney Tubules, Proximal; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Phenotype; RNA, Messenger; Severity of Illness Index; Sodium Bicarbonate; Sodium-Bicarbonate Symporters; Transcription, Genetic

Incomplete distal renal tubular acidosis (idRTA) has recently been associated with osteoporosis and growth retardation, attributed to the mild persistent metabolic acidosis. We hypothesized a therapeutic benefit from bicarbonate therapy on growth parameters in children with idRTA. In a study group of 40 surgically treated patients with posterior urethral valve (PUV) and normal estimated glomerular filtration rate, we evaluated the change in height standard deviation scores (SDSs) while they were on bicarbonate therapy in the presence of idRTA and complete distal renal tubular acidosis (dRTA). Age- and gender-matched healthy subjects constituted the control group (n = 55). Incomplete dRTA was evaluated by ammonium chloride acidification. The baseline height SDS of -1.94 +/- 0.41 and -5.31 +/- 1.95 in the groups with idRTA and complete dRTA, respectively, were significantly lower than that of the controls. After a follow-up period of 24.7 +/- 8.3 months on sodium bicarbonate therapy, the idRTA patients had a 66% increase in height SDS compared with 26% and 3% increases in the patients with PUV with complete dRTA and without dRTA, respectively. At the end of follow-up, mean height SDS in the group with idRTA no longer remained significantly lower than that of the controls (P = 0.42). We concluded that bicarbonate therapy improves height SDS in idRTA. This issue needs further validation in larger studies.

Topics: Acidosis, Renal Tubular; Child; Child, Preschool; Female; Growth Disorders; Humans; Male; Prospective Studies; Sodium Bicarbonate

We evaluated how ileal augmentation cystoplasty predisposes growing animals to hyperchloremic acidosis and abnormal skeletal development.. Weanling female Wistar rats weighing 35 to 50 gm. underwent ileal augmentation cystoplasty or sham operation consisting of a similar ileal resection and closure (ileoileostomy). Both groups were stressed with 1% ammonium chloride loading. Serial bone densitometry measurements, weight and blood gas studies were performed in an 8-week growth period. Femur bone ashing and mineral analysis, arterial blood gas studies and serum bone mineral determinations (calcium, magnesium and phosphorus) were obtained at study conclusion.. Augmented and control animals had similar serum calcium, phosphorus and magnesium concentrations. In augmented animals metabolic acidosis developed with respiratory compensation and decreased mean serum bicarbonate plus or minus standard deviation compared to controls (18.34 +/- 3.23 versus 21.76 +/- 2.46 mEq./l., p <0.003). Growth curves of both groups were similar, although augmented animals had shorter femur lengths than controls (p <0.04). Bone density results were mixed. Whole body bone density was decreased (p <0.05), while bone ash and mineral content (except phosphorus) were not. When rats with augmentation cystoplasty given 1% ammonium chloride were fed an equal molar diet of sodium bicarbonate, metabolic acidosis and bone mineral density normalized to control values.. Acid challenged weanling rats that underwent ileal augmentation cystoplasty demonstrated decreased bone mineral density and growth compared to controls. These changes were prevented by bicarbonate replacement.

Topics: Acidosis; Ammonium Chloride; Animals; Animals, Newborn; Bone Development; Female; Growth Disorders; Ileum; Postoperative Complications; Rats; Rats, Wistar; Sodium Bicarbonate; Urinary Bladder