Faculty Bibliography

Clinical and laboratory tests in clinical medicine include a range of measurements that may be categorized as "normal range" tests, positive or negative tests, or contextual tests. Normal range test results are quantitative and are compared to a reference interval or range provided by the laboratory. Positive or negative tests are also quantitative tests and characteristically have a cutoff value that specifies the result. Contextual tests require a context, a physiological condition, to correctly interpret the result. A closer examination of reference intervals suggests that these also are contextual. The fact that there is a range of apparently normal values indicates the presence of cultural, biological, physiological and behavioral diversity in the population sampled to determine normality. As such, the reference interval describes the population from which it was determined and may have utility in this regard.

AIMS: To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction 5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. CONCLUSIONS: Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.

This 8-week, multi-center, open-label study assessed the safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Patients (n=32) with mean sitting systolic blood pressure (msSBP) 140 mm Hg (after a 2-5-week washout of previous antihypertensive medications) and estimated glomerular filtration rate (eGFR) 15 and <60 ml min(-1) 1.73 m(-2) received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control (msSBP 130 mm Hg and mean sitting diastolic blood pressure (msDBP) 80 mm Hg) and without safety concerns. Safety was assessed by monitoring and recording all adverse events (AEs) and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP. The mean baseline BP was 151.6/86.9 mm Hg, urinary albumin/creatinine ratio (UACR) geometric mean was 7.3 mg mmol(-1) and eGFR was 30 and <60 in 25 (78.1%) patients and was 15 and <30 in 7 (21.9%) patients. Fourteen (43.8%) patients reported at least one AE, which were mild in severity. No severe AEs or deaths were reported. There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5+/-11.3 and 8.3+/-6.3 mm Hg, respectively, from baseline to Week 8 end point. LCZ696 was generally safe and well tolerated and showed effective BP reduction in Japanese patients with hypertension and renal dysfunction without a decline in renal function.

Dietary sodium reduction and, as necessary, pharmacologic treatment are recommended for hypertension management. This prospective, randomized, open-label, blinded-end point, multicenter, crossover study investigated the effect of dietary sodium intake on mean ambulatory systolic blood pressure (maSBP) in patients with hypertension receiving aliskiren 300 mg once daily. Following a 2- to 4-week washout period, patients were randomized to a high- (>/= 200 mmol/d) or low- (/= 20-mm Hg reduction from baseline) was greater with the low- (76.5%) versus the high-sodium diet (42.6%; P < .0001). Overall, 40.9% patients had >/= 1 adverse event and the rates were similar between groups. In this study, aliskiren was well tolerated and a low-sodium diet accentuated its antihypertensive effect.

Acute hypercapnia may develop during periodic breathing from an imbalance between abnormal ventilatory patterns during apnea and/or hypopnea and compensatory ventilatory response in the interevent periods. However, transition of this acute hypercapnia into chronic sustained hypercapnia during wakefulness remains unexplained. We hypothesized that respiratory-renal interactions would play a critical role in this transition. Because this transition cannot be readily addressed clinically, we modified a previously published model of whole-body CO2 kinetics by adding respiratory control and renal bicarbonate kinetics. We enforced a pattern of 8 h of periodic breathing (sleep) and 16 h of regular ventilation (wakefulness) repeated for 20 days. Interventions included varying the initial awake respiratory CO2 response and varying the rate of renal bicarbonate excretion within the physiological range. The results showed that acute hypercapnia during periodic breathing could transition into chronic sustained hypercapnia during wakefulness. Although acute hypercapnia could be attributed to periodic breathing alone, transition from acute to chronic hypercapnia required either slowing of renal bicarbonate kinetics, reduction of ventilatory CO2 responsiveness, or both. Thus the model showed that the interaction between the time constant for bicarbonate excretion and respiratory control results in both failure of bicarbonate concentration to fully normalize before the next period of sleep and persistence of hypercapnia through blunting of ventilatory drive. These respiratory-renal interactions create a cumulative effect over subsequent periods of sleep that eventually results in a self-perpetuating state of chronic hypercapnia.

In rat ileum and colon, apical membrane Cl(-)/HCO(3)(-) exchange and net Cl(-) absorption are stimulated by increases in Pco(2) or [HCO(3)(-)]. Because changes in Pco(2) stimulate colonic Na(+) absorption, in part, by modulating vesicular trafficking of the Na(+)/H(+) exchanger type 3 isoform to and from the apical membrane, we examined whether changes in Pco(2) affect net Cl(-) absorption by modulating vesicular trafficking of the Cl(-)/HCO(3)(-) exchanger anion exchanger (AE)1. Cl(-) transport across rat distal ileum and colon was measured in the Ussing chamber, and apical membrane protein biotinylation of these segments and Western blots of recovered proteins were performed. In colonic epithelial apical membranes, AE1 protein content was greater at Pco(2) 70 mmHg than at Pco(2) 21 mmHg but was not affected by pH changes in the absence of CO(2). AE1 was internalized when Pco(2) was reduced and exocytosed when Pco(2) was increased, and both mucosal wortmannin and methazolamide inhibited exocytosis. Wortmannin also inhibited the increase in colonic Cl(-) absorption caused by an increase in Pco(2). Increases in Pco(2) stimulated ileal Cl(-) absorption, but wortmannin was without effect. Ileal epithelial apical membrane AE1 content was not affected by Pco(2). We conclude that CO(2) modulation of colonic, but not ileal, Cl(-) absorption involves effects on vesicular trafficking of AE1

The small and large intestine secrete guanylin, a peptide homologous to heat stable enterotoxin (STa) elaborated by enterotoxigenic Escherichia coli. Guanylin's role in intestinal electrolyte transport was investigated in guanylin-deficient knockout mice and heterozygous littermate controls. Segments of mid-jejunum, distal ileum, and proximal and distal colon were studied in Ussing chambers in HCO3- Ringer under short circuit conditions. We found that (1) under basal conditions, all segments in control and knockout mice absorb Na+, and the knockout mouse proximal colon secretes Cl-; (2) all segments except the jejunum of knockout mice respond by increasing absorption in response to reductions in pH from 7.6 to 7.1; (3) all segments exhibit decreased absorption in response to 1 mM cAMP; (4) the jejunum and ileum of knockout and control mice, and the proximal colon of control mice (but not knockout mice) respond to the mucosal addition of 50 nM STa with decreases in absorption; and (5) mucosal guanylin caused similar decreases in proximal colon absorption in control and guanylin-deficient mice. These findings suggest that guanylin deficiency causes basal Cl- secretion and reduced responsiveness to STa in mouse proximal colon. The effectiveness of guanylin in this segment suggests a difference in the intestinal secretory actions of STa and guanylin

Carbonic anhydrase (CA) inhibition reduces NaCl absorption in rat distal ileum, a pH-sensitive, low CA activity tissue, and in distal colon, a CO(2)-sensitive, high CA activity tissue. We hypothesized that CA plays a non-catalytic role in NaCl absorption in these segments. Unidirectional fluxes of Na(+) and Cl(-), and total HCO(3)(-) generation (estimated as the sum of radiolabeled HCO(3)(-) and CO(2) produced from glucose) were measured in Ussing chambers in nominally CO(2), HCO(3)(-)-free HEPES Ringer. Measurements were made in the presence and absence of 0.1 mM methazolamide, a membrane-permeant CA inhibitor. Ringer pH reduction from 7.6 to 7.1 stimulated ileal but not colonic Na(+) and Cl(-) absorption. In the ileum, methazolamide reduced J(ms)(Na) and J(ms)(Cl) and caused net Cl(-) secretion at pH 7.6, and prevented the stimulatory effect of lowering pH. In the colon, methazolamide reduced Na(+) and Cl(-) absorption at pH 7.6. Total HCO(3)(-) generation was minimal in HEPES at pH 7.6 and 7.1 in both segments, was minimally affected by methazolamide, and did not account for the changes in Cl(-) absorption caused by pH or methazolamide. We conclude that CA plays a role in ileal and colonic NaCl absorption independent of its catalytic function