During metabolic acidosis, P i serves as an important buffer to remove protons from the body. Pi is released from bone together with carbonate buffering protons in blood. In addition, in the kidney, the fractional excretion of phosphate is increased allowing for the excretion of more acid equivalents in urine. The role of intestinal P i absorption in providing Pi to buffer protons and compensating for loss from bone during metabolic acidosis has not been clarified yet. Inducing metabolic acidosis (NH 4Cl in drinking water) for 2 or 7 days in mice increased urinary fractional P i excretion twofold, whereas serum Pi levels were not altered. Na ϩ -dependent Pi transport in the small intestine, however, was stimulated from 1.89 Ϯ 3.22 to 40.72 Ϯ 11.98 pmol/mg protein (2 days of NH 4Cl) in brush-border membrane vesicles prepared from total small intestine. Similarly, the protein abundance of the Na ϩ -dependent phosphate cotransporter NaPi-IIb in the brush-border membrane was increased 5.3-fold, whereas mRNA levels remained stable. According to immunohistochemistry and real-time PCR NaPi-IIb expression was found to be mainly confined to the ileum in the small intestine, and this distribution was not altered during metabolic acidosis. These results suggest that the stimulation of intestinal P i absorption during metabolic acidosis may contribute to the buffering of acid equivalents by providing phosphate and may also help to prevent excessive liberation of phosphate from bone. phosphate SEVERAL MECHANISMS CONTRIBUTE to the buffering and elimination of excessive protons and acid equivalents during metabolic acidosis. Besides respiration, increased release of buffer substances from bone and stimulated reabsorption of bicarbonate and increased excretion of protons by the kidneys are the major mechanisms to restore acid-base balance (11, 16). Excretion of protons by the kidney requires so called titratable acids, i.e., ammonia, citrate, and phosphate, buffering protons in urine in the collecting duct and thus increasing the maximal acid excretion rate (16). The renal excretion of ammonia and phosphate is highly increased during metabolic acidosis, whereas excretion of citrate is decreased (3). Ammonia (NH 3 ) is synthetized from glutamine metabolism in the kidney proximal tubule in response to metabolic acidosis (27). In addition, it is thought that inhibition of renal reabsorption of phosphate contributes mainly to increased phosphate excretion (1). In a rat model for metabolic acidosis, a decrease in mRNA and protein of the major Na ϩ -P i cotransporter NaPi-IIa as well as in Na ϩ -dependent P i uptake into brush border membrane (BBM) vesicles (BBMV) has been found (1). Systemic P i levels are only slightly decreased during metabolic acidosis, an effect that has been attributed to the acid-stimulated release of P i from bone together with Ca 2ϩ and carbonate (23). Indeed, the release of phosphate from bone during short-and long-term metabolic acidosis in in vivo and in in vitro models has been extensively documented a...
Aims To determine the risk of subsequent adverse clinical outcomes in anticoagulated patients with atrial fibrillation (AF) who experienced a new bleeding event. Methods and results Anticoagulated AF patients were followed in two prospective cohort studies. Information on incident bleeding was systematically collected during yearly follow-up visits and events were adjudicated as major bleeding or clinically relevant non-major bleeding (CRNMB) according to the International Society on Thrombosis and Haemostasis guidelines. The primary outcome was a composite of stroke, myocardial infarction (MI), or all-cause death. Time-updated multivariable Cox proportional-hazards models were used to compare outcomes in patients with and without incident bleeding. Median follow-up was 4.08 years [interquartile range (IQR): 2.93–5.98]. Of the 3277 patients included (mean age 72 years, 28.5% women), 646 (19.7%) developed a new bleeding, 297 (9.1%) a major bleeding and 418 (12.8%) a CRNMB. The incidence of the primary outcome was 7.08 and 4.04 per 100 patient-years in patients with and without any bleeding [adjusted hazard ratio (aHR): 1.36, 95% confidence interval (CI): 1.16–1.61; P < 0.001; median time between a new bleeding and a primary outcome 306 days (IQR: 23–832)]. Recurrent bleeding occurred in 126 patients [incidence, 8.65 per 100 patient-years (95% CI: 7.26–10.30)]. In patients with and without a major bleeding, the incidence of the primary outcome was 11.00 and 4.06 per 100 patient-years [aHR: 2.04, 95% CI: 1.69–2.46; P < 0.001; median time to a primary outcome 142 days (IQR: 9–518)], and 59 had recurrent bleeding [11.61 per 100 patient-years (95% CI: 8.99–14.98)]. The incidence of the primary outcome was 5.29 and 4.55 in patients with and without CRNMB [aHR: 0.94, 95% CI: 0.76–1.15; P = 0.53; median time to a composite outcome 505 days (IQR: 153–1079)], and 87 had recurrent bleeding [8.43 per 100 patient-years (95% CI: 6.83–10.40)]. Patients who had their oral anticoagulation (OAC) discontinued after their first bleeding episode had a higher incidence of the primary composite than those who continued OAC (63/89 vs. 159/557 patients; aHR: 4.46, 95% CI: 3.16–6.31; P < 0.001). Conclusion In anticoagulated AF patients, major bleeding but not CRNMB was associated with a high risk of adverse outcomes, part of which may be explained by OAC discontinuation. Most events occurred late after the bleeding episode, emphasizing the importance of long-term follow-up in these patients.
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