Juan Carlos Q. Velez

The importance of the intrarenal renin–angiotensin system

Evidence suggests that virtually every organ system in the human body possesses a local renin–angiotensin system (RAS). These local systems seem to be independently regulated and compartmentalized from the plasma circulation, perhaps with the exception of the vascular endothelial system, which is responsible for maintaining physiological plasma levels of RAS components. Among these local RASs, the kidney RAS—the focus of this Review—seems to be of critical importance for the regulation of blood pressure and salt balance. Indeed, overactivation of the intrarenal RAS in certain disease states constitutes a pathogenic mechanism that leads to tissue injury, proliferation, fibrosis and ultimately, end-organ damage. Intrarenal levels of angiotensin peptides are considerably higher than those in plasma or any other organ tissue. Moreover, the kidney has a unique capacity to degrade angiotensin peptides, perhaps to maintain its intrinsic homeostasis. Interestingly, each local RAS has a distinct enzymatic profile resulting in different patterns of angiotensin fragment generation in different tissues. A better understanding of the autocrine and paracrine mechanisms involved in the renal RAS and other local RASs might direct future organ-specific therapy.

Intravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experience

BACKGROUND Intravenous conivaptan is a novel therapeutic agent indicated for the treatment of euvolaemic and hypervolaemic hyponatraemia. However, there is paucity of reported clinical experience using conivaptan for the treatment of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Moreover, while there is reasonable concern for overcorrection, no pre-treatment variables are known to be helpful to identify patients at risk for rapid correction. METHODS We searched our records for hospitalized patients treated with intravenous conivaptan for moderate to severe hyponatraemia due to SIADH, with a starting serum sodium <130 mmol/L, between 2006 and 2009 (n = 18), to examine its efficacy as aquaretic, and to search for pre-treatment variables that could predict degree of response. RESULTS Twenty-four hours after initiation of therapy, all patients had at least a 3-mmol/L increase in serum sodium, with 66.7% (12/18) of the patients having an absolute increase >or=4 mmol/L, and a median increase in serum sodium of 7 mmol/L (range: 3-16 mmol/L). Concomitantly, urine osmolality decreased in all patients with a mean reduction of 45.9 +/- 28.8% from baseline. Lower serum sodium, lower blood urea nitrogen and higher estimated glomerular filtration rate at baseline had a significant correlation with the magnitude of the absolute increase in serum sodium 24 hours after initiation of therapy. CONCLUSIONS We conclude that intravenous conivaptan is an effective aquaretic to treat hyponatraemia caused by SIADH, as evidenced by a simultaneous increase in serum sodium and decrease in urine osmolality. Baseline values of serum sodium, blood urea nitrogen and estimated glomerular filtration rate may help predicting the magnitude of response to therapy.

Page kidney as a rare cause of hypertension: case report and review of the literature.

Page kidney occurs by extrinsic compression of the renal parenchyma from a hematoma or a mass, leading to activation of the renin-angiotensin-aldosterone system and resulting in systemic hypertension. There have been about 100 cases of Page phenomenon reported in the literature. A review of cases published prior to 1991 revealed that football and nonsports-related trauma were the most common causes of Page kidney. Thereafter, 28 cases have been reported in the literature, including our case report presented here. These recent cases show that the etiology of Page kidney has shifted, perhaps because of the procedure-oriented current practice of medicine and the increased frequency of kidney transplant biopsies. In addition, management options have evolved, given the more frequent use of medications that block the renin-angiotensin-aldosterone system and the availability of less invasive procedures. Page kidney should be considered in the differential diagnosis of secondary hypertension.

Angiotensin I Is Largely Converted to Angiotensin (1-7) and Angiotensin (2-10) by Isolated Rat Glomeruli

Intraglomerular renin-angiotensin system enzyme activities have been examined previously using glomerular lysates and immune-based assays. However, preparation of glomerular extracts compromises the integrity of their anatomic architecture. In addition, antibody-based assays focus on angiotensin (Ang) II detection, ignoring the generation of other Ang I–derived metabolites, some of which may cross-react with Ang II. Therefore, our aim was to examine the metabolism of Ang I in freshly isolated intact glomeruli using matrix-assisted laser desorption ionization time of flight mass spectrometry as an analytic method. Glomeruli from male Sprague-Dawley rats were isolated by sieving and incubated in Krebs buffer in the presence of 1 μmol/L of Ang I for 15 to 90 minutes, with or without various peptidase inhibitors. Peptide sequences were confirmed by matrix-assisted laser desorption ionization time of flight tandem mass spectrometry or linear-trap-quadrupole mass spectrometry. Peaks were quantified using customized valine-13C·15N-labeled peptides as standards. The most prominent peaks resulting from Ang I cleavage were 899 and 1181 m/z, corresponding with Ang (1-7) and Ang (2-10), respectively. Smaller peaks for Ang II, Ang (1-9), and Ang (3-10) also were detected. The disappearance of Ang I was significantly reduced during inhibition of aminopeptidase A or neprilysin. In contrast, captopril did not alter Ang I degradation. Furthermore, during simultaneous inhibition of aminopeptidase A and neprilysin, the disappearance of Ang I was markedly attenuated compared with all of the other conditions. These results suggest that there is prominent intraglomerular conversion of Ang I to Ang (2-10) and Ang (1-7), mediated by aminopeptidase A and neprilysin, respectively. Formation of these alternative Ang peptides may be critical to counterbalance the local actions of Ang II. Enhancement of these enzymatic activities may constitute potential therapeutic targets for Ang II–mediated glomerular diseases.

Enzymatic processing of angiotensin peptides by human glomerular endothelial cells

The intraglomerular renin-angiotensin system (RAS) is linked to the pathogenesis of progressive glomerular diseases. Glomerular podocytes and mesangial cells play distinct roles in the metabolism of angiotensin (ANG) peptides. However, our understanding of the RAS enzymatic capacity of glomerular endothelial cells (GEnCs) remains incomplete. We explored the mechanisms of endogenous cleavage of ANG substrates in cultured human GEnCs (hGEnCs) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and isotope-labeled peptide quantification. Overall, hGEnCs metabolized ANG II at a significantly slower rate compared with podocytes, whereas the ANG I processing rate was comparable between glomerular cell types. ANG II was the most abundant fragment of ANG I, with lesser amount of ANG-(1-7) detected. Formation of ANG II from ANG I was largely abolished by an ANG-converting enzyme (ACE) inhibitor, whereas ANG-(1-7) formation was decreased by a prolylendopeptidase (PEP) inhibitor, but not by a neprilysin inhibitor. Cleavage of ANG II resulted in partial conversion to ANG-(1-7), a process that was attenuated by an ACE2 inhibitor, as well as by an inhibitor of PEP and prolylcarboxypeptidase. Further fragmentation of ANG-(1-7) to ANG-(1-5) was mediated by ACE. In addition, evidence of aminopeptidase N activity (APN) was demonstrated by detecting amelioration of conversion of ANG III to ANG IV by an APN inhibitor. While we failed to find expression or activity of aminopeptidase A, a modest activity attributable to aspartyl aminopeptidase was detected. Messenger RNA and gene expression of the implicated enzymes were confirmed. These results indicate that hGEnCs possess prominent ACE activity, but modest ANG II-metabolizing activity compared with that of podocytes. PEP, ACE2, prolylcarboxypeptidase, APN, and aspartyl aminopeptidase are also enzymes contained in hGEnCs that participate in membrane-bound ANG peptide cleavage. Injury to specific cell types within the glomeruli may alter the intrarenal RAS balance.

The Epidemiology of Sleep Quality and Consumption of Stimulant Beverages among Patagonian Chilean College Students

Objectives. (1) To assess sleep patterns and parameters of sleep quality among Chilean college students and (2) to evaluate the extent to which stimulant beverage use and other lifestyle characteristics are associated with poor sleep quality. Methods. A cross-sectional study was conducted among college students in Patagonia, Chile. Students were asked to complete a self-administered questionnaire to provide information about lifestyle and demographic characteristics. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality. In addition, students underwent a physical examination to collect anthropometric measurements. Results. More than half of students (51.8%) exhibited poor sleep quality. Approximately 45% of study participants reported sleeping six hours or less per night and 9.8% used medications for sleep. In multivariate analysis, current smokers had significantly greater daytime dysfunction due to sleepiness and were more likely to use sleep medicines. Students who reported consumption of any stimulant beverage were 1.81 times as likely to have poor sleep quality compared with those who did not consume stimulant beverages (OR:1.81, 95% CI:1.21–2.00). Conclusions. Poor sleep quality is prevalent among Chilean college students, and stimulant beverage consumption was associated with the increased odds of poor sleep quality in this sample.

A case of lactic acidosis induced by linezolid

Background. A 36-year-old African American man with end-stage renal disease on chronic maintenance hemodialysis was transferred first from a hospital to a long-term acute care facility for advanced care then to the intensive care unit of our university hospital with unexplained abdominal pain, nausea, hypotension, altered mental status and anion gap metabolic acidosis. Subsequent review of the patients medication list revealed that the he had been on linezolid for 6 weeks for the treatment of vancomycin-resistant Enterococcus fecalis bacteremia.Investigations. Medical history, physical examination, laboratory tests, CT imaging of the thorax, abdomen and pelvis and PCR-based tests to determine the presence of polymorphisms in the 16S ribosomal RNA gene.Diagnosis. Lactic acidosis associated with prolonged exposure to linezolid.Management. Discontinuation of linezolid.

Construct Validity and Factor Structure of the Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale in a Multi-National Study of African, South East Asian and South American College Students

Background The Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) are questionnaires used to assess sleep quality and excessive daytime sleepiness in clinical and population-based studies. The present study aimed to evaluate the construct validity and factor structure of the PSQI and ESS questionnaires among young adults in four countries (Chile, Ethiopia, Peru and Thailand). Methods A cross-sectional study was conducted among 8,481 undergraduate students. Students were invited to complete a self-administered questionnaire that collected information about lifestyle, demographic, and sleep characteristics. In each country, the construct validity and factorial structures of PSQI and ESS questionnaires were tested through exploratory and confirmatory factor analyses (EFA and CFA). Results The largest component-total correlation coefficient for sleep quality as assessed using PSQI was noted in Chile (r = 0.71) while the smallest component-total correlation coefficient was noted for sleep medication use in Peru (r = 0.28). The largest component-total correlation coefficient for excessive daytime sleepiness as assessed using ESS was found for item 1 (sitting/reading) in Chile (r = 0.65) while the lowest item-total correlation was observed for item 6 (sitting and talking to someone) in Thailand (r = 0.35). Using both EFA and CFA a two-factor model was found for PSQI questionnaire in Chile, Ethiopia and Thailand while a three-factor model was found for Peru. For the ESS questionnaire, we noted two factors for all four countries Conclusion Overall, we documented cross-cultural comparability of sleep quality and excessive daytime sleepiness measures using the PSQI and ESS questionnaires among Asian, South American and African young adults. Although both the PSQI and ESS were originally developed as single-factor questionnaires, the results of our EFA and CFA revealed the multi- dimensionality of the scales suggesting limited usefulness of the global PSQI and ESS scores to assess sleep quality and excessive daytime sleepiness.

Network Modeling Reveals Steps in Angiotensin Peptide Processing

New insights into the intrarenal renin–angiotensin (Ang) system have modified our traditional view of the system. However, many finer details of this network of peptides and associated peptidases remain unclear. We hypothesized that a computational systems biology approach, applied to peptidomic data, could help to unravel the network of enzymatic conversions. We built and refined a Bayesian network model and a dynamic systems model starting from a skeleton created with established elements of the renin–Ang system and further developed it with archived matrix-assisted laser desorption ionization-time of flight mass spectra from experiments conducted in mouse podocytes exposed to exogenous Ang substrates. The model-building process suggested previously unrecognized steps, 3 of which were confirmed in vitro, including the conversion of Ang(2–10) to Ang(2–7) by neprilysin, Ang(1–9) to Ang(2–9), and Ang(1–7) to Ang(2–7) by aminopeptidase A. These data suggest a wider role of neprilysin and aminopeptidase A in glomerular formation of bioactive Ang peptides and shunting their formation. Other steps were also suggested by the model, and supporting evidence for those steps was evaluated using model-comparison methods. Our results demonstrate that systems biology methods applied to peptidomic data are effective in identifying novel steps in the Ang peptide processing network, and these findings improve our understanding of the glomerular renin–Ang system.

Smoking and perceived stress in relation to short salivary telomere length among caregivers of children with disabilities

Abstract Telomere length (TL), the length of repeated DNA sequence that forms protective caps at the end of chromosomes, has emerged as a novel biomarker of cell aging and oxidative stress. There is increasing research exploring the associations of smoking and perceived stress with TL, and the results are inconsistent. This study aimed to examine whether smoking and perceived stress were associated with shortened salivary TL among primary caregivers of children with disabilities. Using a quantitative polymerase chain reaction method, salivary TL was assessed among 89 caregivers aged 19–69 years (87% were women) who took care of disabled children in the Patagonia Region, Chile. Interviewer-administered questionnaires were used to collect information on sociodemographic and lifestyle factors. The 14-item Perceived Stress Scale was used to assess perceived stress. Mean relative TL was 0.92 (standard error = 0.03). Smokers had age-adjusted mean TL that was 0.07 units lower (β = −0.07, standard error = 0.03; p = 0.012) than non-smokers. Smokers were 2.17 times more likely to have shorter TL ( < 0.73, the lowest quartile of TL) than non-smokers (odds ratio = 3.17; 95% confidence interval = 1.05–9.52) with adjustment for age and perceived stress. Caregivers with higher perceived stress were 2.13 times more likely to have shorter TL (odds ratio = 3.13; 95% confidence interval = 1.03–9.55) than caregivers with lower perceived stress after adjustment for age and smoking. This study provides the first evidence of strong associations between smoking and perceived stress and shortened salivary TL among caregivers of children with disabilities. Larger studies with detailed information on smoking status are warranted to confirm our findings.