Immunolocalization of the calcium-sensing receptor in developing human kidney.

BACKGROUND: The calcium-sensing receptor (CSR) is a G-protein receptor that plays a critical role in calcium regulation. In the kidney, the CSR regulates calcium reabsorption in the thick ascending limb, where stimulation of the CSR inhibits calcium reabsorption in response to increased calcium in the peritubular fluid. In the collecting duct, apical CSR activation may play a role in osmoregulation, increasing water excretion in response to increased luminal calcium. METHODS: We studied the ontogeny of the CSR in developing human kidney using immunohistochemical methods. RESULTS: The CSR is first expressed in the S-shaped body in the region destined to form the ascending limb and distal tubule. Other regions of the S-shaped body, as well as ureteric buds, do not express the CSR. The CSR is observed in thick ascending limb as early as 20 wk of development. The CSR is not observed in proximal tubule or collecting duct between 20 and 40 wk of human development. CONCLUSION: During early human renal development, CSR expression is limited to the thick ascending limb and distal tubule, where this receptor may play a role in calcium homeostasis between 20 and 40 wk of human development.

Immuno-localization of CD44 and osteopontin in developing human kidney.

CD44 is observed in ureteric bud structures and is implicated in branching morphogenesis during early mouse renal development. Healthy adult kidney demonstrates minimal CD44, but CD44 is up-regulated in renal diseases. CD44 may mediate binding of calcium oxalate crystals to tubular epithelia via the ligands osteopontin (OPN) and hyaluronan. Because 15% of premature infants develop nephrocalcinosis, developmental tubular CD44 expression might promote nephrocalcinosis. We studied CD44 and OPN immuno-localization in developing human kidney by immunohistochemical analysis. Human renal tissue between 18 and 40 wk of gestation showed CD44 immuno-localization in ureteric buds, with staining decreasing with increasing gestational age; CD44 was rarely observed in developing renal tubules. OPN was diffusely observed in proximal tubules, rarely observed in distal tubules, ureteric buds or metanephric structures. These data support the role of CD44 in early human nephron formation and branching morphogenesis. Rare CD44 staining in developing tubular epithelium suggests no role for CD44 in promoting calcium oxalate adherence to tubular epithelia in premature infants. Immuno-localization of OPN in tubules supports its role in tubular differentiation, but OPN does not seem to be necessary during early nephron formation.

Type 3 renal tubular acidosis associated with growth hormone deficiency.

BACKGROUND: We identified two boys with type 3 renal tubular acidosis (RTA) and growth hormone deficiency and we sought to differentiate them from children with classic type 1 distal RTA. METHODS: We reviewed all children <6 years of age with RTA referred over a 13-year period and compared the growth response to alkali therapy in these two boys and in 28 children with only type 1 distal RTA. RESULTS: All children with type 1 RTA reached the 5th percentile or higher on CDC growth charts within 2 years of alkali therapy. Their mean height standard deviation score (SDS) improved from -1.4 to -0.6 SDS and their mean mid-parental height (MPH) SDS improved from -0.6 to 0 SDS after 2 years. In contrast, the boys with growth hormone deficiency had a height SDS of -1.4 and -2.4 SDS after 2 years of alkali and the MPH SDS were both -2.6 SDS after 2 years of alkali therapy. Growth hormone therapy accelerated their growth to normal levels and led to long-term correction of RTA. CONCLUSIONS: A child with type 1 RTA whose height response after 2 years of alkali therapy is inadequate should undergo provocative growth hormone testing.

Preliminary observations of urinary calcium and osteopontin excretion in premature infants, term infants and adults.

Osteopontin is an acidic glycoprotein which may prevent nephrocalcinosis and nephrolithiasis by inhibiting the growth and retention of calcium oxalate crystals within the tubular lumen. The purpose of this study was to obtain preliminary data regarding urinary osteopontin in premature infants at risk for nephrocalcinosis. We examined urinary osteopontin concentration in premature infants, term infants and adults, and examined the relationship between urinary calcium and osteopontin concentration in these groups. The urinary osteopontin concentration of 17 premature infants of 3.7 +/- 1.2 microg/ml was not significantly different from the urinary osteopontin concentration of 12 term infants of 6 +/- 6 microg/ml, while the urinary osteopontin concentration in 23 urine specimens from adults of 27 +/- 15 microg/ml was significantly higher than premature infants and term infants (p < 0.05). Urinary osteopontin concentration did not correlate with urinary calcium concentration in premature infants, while there was a correlation between the osteopontin/creatinine ratio and calcium/creatinine ratios in premature infants. Diminished urinary concentration of osteopontin may enhance the risk for nephrocalcinosis in premature infants.