The proximal tubule contains an autonomous renin-angiotensin system that regulates transport independently of circulating angiotensin II. Androgens are known to increase expression of angiotensinogen, but the effect of androgens on proximal tubule transport is unknown. In this in vivo microperfusion study, we examined the effect of androgens on proximal tubule transport. The volume reabsorptive rate in Sprague-Dawley rats given dihydrotestosterone (DHT) injections was significantly higher than in control rats given vehicle injections (4.57 +/- 0.31 vs. 3.31 +/- 0.23 nl x min(-1) x mm(-1), P < 0.01). Luminally perfusing with either enalaprilat (10(-4) M) to inhibit production of angiotensin II or losartan (10(-8) M) to block the angiotensin receptor decreased the proximal tubule volume reabsorptive rate in DHT-treated rats to a significantly greater degree than in control vehicle-injected rats. The renal expression of angiotensinogen was shown to be higher in the DHT-treated animals, using Northern blot analysis. The expression of angiotensin receptors, determined by specific binding of angiotensin II, was not different in the two groups of animals. Brush-border membrane protein abundance of the Na/H exchanger, a membrane transport protein under angiotensin II regulation, was also higher in DHT-treated rats vs. control rats. Rats that received DHT had higher blood pressures than the control rats but had no change in their glomerular filtration rate. In addition, serum angiotensin II levels were lower in DHT-treated vs. control rats. These results suggest that androgens may directly upregulate the proximal tubule renin-angiotensin system, increase the volume reabsorptive rate, and thereby increase extracellular volume and blood pressure and secondarily decrease serum angiotensin II levels.

X-linked hypophosphatemia is the most prevalent inherited form of rickets. In this disorder, rickets results from hyperphosphaturia and inappropriately normal levels of 1,25(OH) 2-vitamin D. Current therapy with oral phosphate and vitamin D improves the rickets, but has significant morbidity and does not significantly affect the short stature and hypophosphatemia. In the present study, we demonstrate that Hyp mice, which have a mutation homologous to that in patients with X-linked hypophosphatemia, have a 2-fold greater urinary prostaglandin E 2 (PGE2) excretion than C57͞B6 mice. To determine whether PGs were involved in the pathogenesis of this disorder, Hyp and C57͞B6 mice received i.p. injections with vehicle or indomethacin (1 mg͞kg of body weight twice daily for 4 days) and were studied Ϸ12 h after the last dose of indomethacin. In the Hyp mice, indomethacin treatment decreased the fractional excretion of phosphate from 13.0 ؎ 3.2% to 2.2 ؎ 1.1% (P < 0.05), and increased serum phosphate from 2.9 ؎ 0.2 mg͞dl to 4.1 ؎ 0.2 mg͞dl (P < 0.05). There was no effect of indomethacin in C57͞B6 mice. Indomethacin did not affect serum creatinine or inulin clearance, demonstrating that the normalization of urinary phosphate excretion was not caused by changes in glomerular filtration rate. Indomethacin treatment increased renal brush border membrane vesicle NaPi-2 protein abundance in Hyp mice to levels comparable to that of C57͞B6 mice, but had no effect in C57͞B6 mice. In vitro isolated perfused proximal tubule studies demonstrate directly that 10 ؊6 M bath indomethacin normalized the phosphate transport defect in Hyp mice but had no effect on C57͞B6 mice. In conclusion, there is dysregulation of renal PG metabolism in Hyp mice, and indomethacin treatment normalizes the urinary excretion of phosphate by a direct tubular effect.X-linked hypophosphatemia ͉ rickets ͉ sodium͞phosphate cotransporter NaPi-2

The Center for Medicaid and Medicare Services (CMS) has recently revised their end-stage renal disease (ESRD) Medical Evidence Report, Medicare Entitlement, and Patient Registration CMS 2728 Form. The modified algorithm calls for the use of formulae to estimate glomerular filtration rate (GFR). The new criterion is defined as estimated GFR of less than 20 ml/min per 1.73 m(2). GFR is either estimated by Schwartz formula (C(SCH)) in children or Modification of Diet in Renal Disease formula (C(MDRD)) in adults. The purpose of this communication is to test the validity of the new CMS GFR algorithm in detecting children who need renal replacement therapy. We evaluated two cohorts of children. Group I included single-center data from 626 (125)I-iothalamate clearance studies (C(IO)) that were compared with the simultaneous estimation of GFR by C(SCH). Group II included data on 659 children from the patient incidence registry obtained from the ESRD Network of Texas between February 1996 and October 2003. In group I there were 76 children (76 C(IO)) with C(SCH) less than 20 ml/min per 1.73 m(2) of whom 50 (67%) had C(IO) less than 15 ml/min per 1.73 m(2). Of children with C(IO) less than 15 ml/min per 1.73 m(2), 62% had a C(SCH) less than 20 ml/min per 1.73 m(2). The ability of C(SCH) greater than 20 ml/min per 1.73 m(2 ) to predict C(IO) greater than 15 ml/min per 1.73 m(2 )(negative predictive value) is 0.95. The number of children who were started on dialysis in Texas within the study period was 659 (group II). The mean C(SCH)+/-SD was 10.8+/-7.7 ml/min per 1.73 m(2). Of the patients who were initiated on dialysis, 94% had C(SCH) less than 20 ml/min per 1.73 m(2). The results were sustained when race, gender, age range, and type of diagnosis were considered. The new CMS algorithm provides a good negative predictive estimate of GFR less than 15 ml/min per 1.73 m(2).