We have demonstrated in previous studies that luminal administration of low doses of angiotensin II (ANG II) stimulate and high doses of ANG II inhibit fluid and HCO3- transport in proximal tubules of rat kidney. However, the role of ANG II on Na+ and HCO3- transport in the distal nephron has not yet been fully elucidated. The superficial early and late distal tubules (DT) of the nephron segments correspond to the distal convoluted tubule and initial collecting tubule. Accordingly, we investigated the effects of ANG II on Na+, HCO3-, and K+ transport in the early and late DT by separate perfusion of these tubule segments in vivo. [3H]inulin, Na+, K+, and total CO2 concentrations were measured in the perfusate and collected fluid, and transport of sodium (JNa), bicarbonate (JHCO3), potassium (JK), and fluid (JV) were analyzed as an index of the hormone effect. Intravenous infusion of the ANG II receptor antagonist [Sar1,Ile8]ANG II (1 microgram.kg-1.min-1) decreased JV, JNa, and JHCO3 in the early DT and decreased Jv and JNa in the late DT. Addition of ANG II (10(-11) M) to the tubular perfusate significantly increased the Jv, JNa, and JHCO3 in the early DT. Similar studies in late DT demonstrated an increase in Jv and JNa, decrease in JK, but no effect on JHCO3. The effects of ANG II on fluid and ion transport were abolished by the luminal application of amiloride (10(-3) M) and of the angiotensin-receptor blocker [Sar1,Ile8]ANG II (10(-6) M). These results suggest that ANG II stimulates Na+/H+ exchange in the early DT (distal convoluted tubule) and amiloride-sensitive Na+ transport (Na+ channels) in the late DT (initial collecting tubule) of cortical nephrons.

Bicarbonate transport was studied in vivo by separate microperfusion experiments of early and late distal tubules. Total CO2 was measured by microcalorimetry and fluid absorption by 3H-inulin. Significant bicarbonate absorption was observed in all experimental conditions. Bicarbonate transport was loaddependent upon increasing the luminal bicarbonate concentration from 15 to 50 mM in both early and late distal tubule segments and remained constant at higher concentrations at a maximum rate of 100-110 pmol/min per mm. At low lumen bicarbonate concentrations (15 mM), higher rates of bicarbonate absorption were observed in early (32.9±4.57 pmol/min per mm) as compared to late distal tubules (10.7±3.1 pmol/ min per mm). Amiloride and ethyl-isopropylamiloride both inhibited early but not late distal tubule bicarbonate absorption whereas acetazolamide blocked bicarbonate transport in both tubule segments. Fluid absorption was significantly reduced in both tubule segments by amiloride but only in early distal tubules by ethyl-isopropylamiloride. Substitution of lumen chloride by gluconate increased bicarbonate absorption in late but not in early distal tubules. Bafilomycin Al, an inhibitor of HATPase, inhibited late and also early distal tubule bicarbonate absorption, the latter at higher concentration. After 8 d on a low K diet, bicarbonate absorption increased significantly in both early and late distal tubules. Schering compound 28080, a potent H-K ATPase inhibitor, completely blocked this increment of bicarbonate absorption in late but not in early distal tubule. The data suggest bicarbonate absorption via Na+-H+ exchange and H-ATPase in early, but only by amiloride-insensitive H' secretion (H-ATPase) in late distal tubules. The study also provides evidence for activation of K+-H+ exchange in late distal tubules of K depleted rats. Indirect evidence implies a component of chloride-dependent bicarbonate secretion in late distal tubules and suggests that net bicarbonate transport at this site results from bidirectional bicarbonate movement. (J. Clin.

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BackgroundAntimicrobials for suspected urinary tract infection (UTI) in advanced cancer patients transitioning to comfort measures (CM) may benefit from stewardship intervention.MethodsWe identified adults ≥65 years with advanced cancer who had ≥1 urine culture obtained during admission to Yale New Haven Hospital from July 2014 to October 2016 that involved transition to CM. We evaluated whether patients met 2017 National Healthcare Safety Network criteria for symptomatic urinary tract infection (UTI). Antimicrobials for suspected UTI and total calendar days of therapy including postdischarge days were evaluated. Factors associated with antimicrobial use were assessed using χ2 or Fisher’s exact testing and fitted in a modified multivariable Poisson regression model.ResultsWe identified 327 adults with advanced cancer and ≥1 urine culture obtained during admission involving transition to CM. Median age was 74 years (range, 65–99), 48% (N = 157) were male, and 73% (N = 239) had solid tumors, 21% (N = 70) had liquid tumors, and 6% (N = 18) had unknown primary tumors. Overall, 306 (94%) patients with suspected UTI did not meet criteria for symptomatic UTI. Of these, 14% (N = 43/306) received antimicrobials for suspected UTI resulting in 273 total calendar-days of therapy. Antimicrobial use for suspected UTI was associated with asymptomatic or symptomatic bacteriuria or candiduria (Table 1). In a multivariable model adjusted for gender, length of stay, liquid tumor, and UTI signs or symptoms, antimicrobial use remained associated with bacteriuria or candiduria (RR = 29.0, 95% CI 11.6, 72.6).ConclusionIn advanced cancer patients transitioning to CM, inappropriate antimicrobial use for suspected UTI is independently associated with bacteriuria or candiduria but not with UTI signs or symptoms. These findings highlight a potential target for diagnostic (i.e., restricting urine culture orders) and antimicrobial stewardship in this population to promote comfort at the end of life.Table 1: Antimicrobial Use for Suspected UTI According to Urine Culture and Associated Signs or SymptomsAntimicrobial Use P valueUrine cultureYes (N = 43)No (N = 263) Growtha3830<.001 No growth5233UTI signs or symptoms Present6280.60 Absent37235 aBacterial or fungal growth.Disclosures M. Juthani-Mehta, Iterum Therapeutics: Scientific Advisor, Consulting fee