Impact of Polypharmacy on Health-Related Quality of Life in Dialysis Patients.

INTRODUCTION: Dialysis patients are often prescribed a large number of medications to improve metabolic control and manage coexisting comorbidities. However, some studies suggest that a large number of medications could also detrimentally affect patients' health-related quality of life (HRQoL). Therefore, this study aims to provide insight in the association between the number of types of medications and HRQoL in dialysis patients. METHODS: A multicentre cohort study was conducted among dialysis patients from Dutch dialysis centres 3 months after initiation of dialysis as part of the ongoing prospective DOMESTICO study. The number of types of medications, defined as the number of concomitantly prescribed types of drugs, was obtained from electronic patient records. Primary outcome was HRQoL measured with the Physical Component Summary (PCS) score and Mental Component Summary (MCS) score (range 0-100) of the Short Form 12. Secondary outcomes were number of symptoms (range 0-30) measured with the Dialysis Symptoms Index and self-rated health (range 0-100) measured with the EuroQol-5D-5L. Data were analysed using linear regression and adjusted for possible confounders, including comorbidity. Analyses for MCS and number of symptoms were performed after categorizing patients in tertiles according to their number of medications because assumptions of linearity were violated for these outcomes. RESULTS: A total of 162 patients were included. Mean age of patients was 58 ± 17 years, 35% were female, and 80% underwent haemodialysis. The mean number of medications was 12.2 ± 4.5. Mean PCS and MCS were 36.6 ± 10.2 and 46.8 ± 10.0, respectively. The mean number of symptoms was 12.3 ± 6.9 and the mean self-rated health 60.1 ± 20.6. In adjusted analyses, PCS was 0.6 point lower for each additional medication (95% confidence interval [95% CI]: -0.9 to -0.2; p = 0.002). MCS was 4.9 point lower (95% CI: -8.8 to -1.0; p = 0.01) and 1.0 point lower (95% CI: -5.1-3.1; p = 0.63) for the highest and middle tertiles of medications, respectively, than for the lowest tertile. Patients in the highest tertile of medications reported 4.1 more symptoms than in the lowest tertile (95% CI: 1.5-6.6; p = 0.002), but no significant difference in the number of symptoms was observed between the middle and lowest tertiles. Self-rated health was 1.5 point lower for each medication (95% CI: -2.2 to -0.7; p < 0.001). DISCUSSION/CONCLUSION: After adjustment for comorbidity and other confounders, a higher number of medications were associated with a lower PCS, MCS, and self-rated health in dialysis patients and with more symptoms.

Funduscopy: Yes or no? Hypertensive emergencies and retinopathy in the emergency care setting; a retrospective cohort study.

According to international guidelines, patients with a suspected hypertensive emergency (HE) admitted to the emergency department (ED) should undergo comprehensive evaluation including funduscopic examination. However, funduscopy is not always readily available and little is known about the prevalence of retinopathy among these patients in the ED setting. In order to characterize patients who should undergo funduscopy, we studied the prevalence, characteristics and clinical outcome in patients with a suspected HE and retinopathy grade III/IV. We conducted a retrospective cohort study of consecutive patients with severe elevation of blood pressure (BP) admitted to the ED between 2012 and 2015. Patients with a systolic blood pressure (SBP) ≥180 mm Hg or diastolic blood pressure (DBP) ≥120 mm Hg at time of presentation were included. A total of 271 patients were included, of whom 18 (6.6%; 95%CI 3.9-10.5) had a HE. In 121 patients (44.6%; 95%CI 37.1-53.3), funduscopy was performed, of whom 17 (14.0%; 95%CI 8.2-22.5) had retinopathy grade III/IV. Mean SBP and DBP were significantly higher in patients with retinopathy (P < .001). However, retinopathy was also seen in patients with lower BP (SBP < 200 mm Hg and DBP < 120 mm Hg). No differences in other clinical characteristics, including visual disturbances, were found. One patient with retinopathy suffered an ischemic stroke after taking oral medication. The prevalence of retinopathy is high among examined patients. Except for higher BP, no clinical signs or symptoms are associated with the presence of retinopathy grade III/IV. We therefore conclude that funduscopic examination should be performed in every patient with a suspected HE.

Renal response to angiotensin II is blunted in sodium-sensitive normotensive men.

BACKGROUND: In hypertension, sodium sensitivity (SS) of blood pressure is associated with renal hemodynamic abnormalities related to increased activity of the renal renin-angiotensin aldosterone system (RAAS). The renal mechanisms of SS in normotensives are unknown. Therefore, we studied whether SS is related to renal hemodynamics and renal responsiveness to angiotensin II (AngII) in young healthy adults. METHODS: Blood pressure (mean arterial pressure (MAP)) and renal function were measured in 34 healthy men after 1-week low-sodium diet (LS; 50 mmol Na(+)/24 h), 1-week high-sodium diet (HS; 200 mmol Na(+)/24h), and 1-week HS-ACEi (enalapril 20 mg/day). The responses of effective renal plasma flow (ERPF; (131)I-Hippuran clearance) to graded infusion of AngII were assessed during each condition. RESULTS: The sodium-induced change in MAP ranged from -7 to +14 mm Hg. SS (a sodium-induced increase in MAP >3 mm Hg) was present in 13 subjects. ERPF was lower in SS subjects during LS and during HS-ACEi. The AngII-induced decrease in ERPF was blunted in SS on LS (-25 +/- 6 vs. -29 +/- 7% in sodium-resistant (SR) subjects, P < 0.05) and on HS (-30 +/- 5 vs. -35 +/- 6%, P < 0.05). The blunting was corrected by angiotensin-converting enzyme inhibitors (ACEi) (-36 +/- 6 vs. -37 +/- 7%). CONCLUSION: SS normotensive subjects have a blunted renal response to exogenous AngII. This is ameliorated by ACEi, supporting a role for inappropriately high intrarenal RAAS activity. As these findings cannot be attributed to subclinical renal hypertensive damage, high intrarenal RAAS activity and altered renal hemodynamics may be primary phenomena underlying SS.

Reduced cyclooxygenase involvement in vascular endothelial function in rat renal transplantation.

BACKGROUND: Cardiovascular disease is a major cause of death following renal transplantation. Mechanisms leading to vascular dysfunction outside the transplanted organ involve common risk factors such as hypertension, hypercholesterolemia, proteinuria, but immune-mediated factors may also be involved. We hypothesized that transplantation-associated risk factors are involved in the development of vascular dysfunction following renal transplantation. METHODS: Vascular function was studied in Fisher to Lewis allografts. Lewis to Lewis syngrafted rats served as controls. All rats received cyclosporin A for 10 days. Allografts were treated with ACE inhibition or AT1 receptor blockade or left untreated. After 34 weeks, aorta rings were studied for contractile and dilator responses in the presence or absence of L-NMMA and/or indomethacin. Tissue sections were immunostained for COX-1 and COX-2. RESULTS: In contrast to syngrafts and treated allografts, untreated allografts developed proteinuria and hypercholesterolemia. In aortic rings, NOS inhibition similarly increased contractile responses and decreased dilator responses in syngrafts and allografts, indicating comparable NO pathways. In contrast, indomethacin affected contractile and dilator responses in syngrafts, but not in treated and untreated allografts, indicating absence of COX-derived prostanoids in control over vascular tone in allografts. This was in line with immunohistologic analysis demonstrating reduced aortic COX-2 expression in allografts. COX-1 expression was unaltered. Interestingly, RAS blockade quantitatively increased endothelium-dependent dilation without qualitatively altering COX function and expression. CONCLUSION: Involvement of COX-derived prostaglandins in vascular endothelial function outside the transplanted organ is strongly diminished after allogeneic renal transplantation. RAS blockade improves common cardiovascular risk factors and endothelium-dependent dilation, but fails to restore prostaglandin function.

Salt loading affects cortisol metabolism in normotensive subjects: relationships with salt sensitivity.

We studied cortisol metabolism together with insulin sensitivity [homeostatic model assessment (HOMA)] and renal hemodynamics in 19 salt-resistant (sr) and nine salt-sensitive (ss) normotensive subjects after a low- and high-salt diet. Results are described as high- vs. low-salt diet. Sum of urinary cortisol metabolite excretion (sum(metabolites)) increased in sr subjects (3.8 +/- 1.6 vs. 3.1 +/- 1.1 microg/min per square meter, P < 0.05) and decreased in ss subjects (2.3 +/- 1.0 vs. 2.9 +/- 1.1 microg/min per square meter, P < 0.05). Plasma 0830 h cortisol decreased in sr subjects but did not change significantly in ss subjects. In all subjects, the absolute blood pressure change correlated negatively with the percentage change in sum(metabolites) (P < 0.05) and positively with the percentage change in renal vascular resistance (P < 0.05). Sum(metabolites) during high-salt diet correlated negatively with the percentage changes in plasma 0830 h cortisol (P < 0.05) and renal vascular resistance (P = 0.05). HOMA did not change in either group, but the percentage change in HOMA correlated positively with the percentage change in plasma cortisol (P = 0.001) and negatively with the percentage change in sum(metabolites) (P < 0.01). Parameters of 11 beta-hydroxysteroid dehydrogenase activity were not different between groups and did not change. In conclusion, these data suggest that cortisol elimination is affected differently after salt loading in sr and ss subjects. Changes in circulating cortisol might contribute to individual sodium-induced alterations in insulin sensitivity.

Angiotensin administration stimulates renal 11 beta-hydroxysteroid dehydrogenase activity in healthy men.

BACKGROUND: We examined whether acute administration of angiotensin modulates the activity of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD), the intracellular enzyme catalyzing the interconversion between the hormonally active cortisol and inactive cortisone. METHODS: Twenty-one male healthy subjects were examined after 1 week of a low- and high-salt diet (50 and 200 mmol/day, respectively). Separate infusions of angiotensin I (Ang I) and II (Ang II) were administered, both at rates of 4 and 8 ng/kg/min. The ratios of tetrahydrocortisol + allotetrahydrocortisol/tetrahydrocortisone (THF + allo-THF/THE) and of free cortisol/free cortisone (UFF/UFE) in urine were measured as indices of overall 11 beta HSD set point and activity of renal 11 beta HSD type 2, respectively. Glomerular filtration rate (GFR) was measured by constant infusion of (125)I-iothalamate. RESULTS: Ang I and Ang II infusion dose-dependently increased mean arterial blood pressure (MAP) and plasma aldosterone, and decreased plasma renin activity (PRA) and GFR at both diets. Ang I and Ang II infusion resulted in a dose-dependent decrease in the excretion of UFF, UFE, and of the UFF/UFE ratio at both diets, without changing the urinary (THF + allo-THF)/THE ratio. Salt restriction did not affect these 11 beta HSD variables, but was accompanied by a decrease in UFF and UFE excretion. CONCLUSION: This study suggests that acute angiotensin administration stimulates the activity of 11 beta HSD type 2 in human kidney. Angiotensin might therefore exert a dual effect on the mineralocorticoid receptor (i.e., an indirect agonistic effect by increasing aldosterone availability and a direct or indirect antagonistic effect by stimulation of renal 11 beta HSD type 2 activity).