Low income, community poverty and risk of end stage renal disease

BACKGROUND: The risk of end stage renal disease (ESRD) is increased among individuals with low income and in low income communities. However, few studies have examined the relation of both individual and community socioeconomic status (SES) with incident ESRD. METHODS: Among 23,314 U.S. adults in the population-based Reasons for Geographic and Racial Differences in Stroke study, we assessed participant differences across geospatially-linked categories of county poverty [outlier poverty, extremely high poverty, very high poverty, high poverty, neither (reference), high affluence and outlier affluence]. Multivariable Cox proportional hazards models were used to examine associations of annual household income and geospatially-linked county poverty measures with incident ESRD, while accounting for death as a competing event using the Fine and Gray method. RESULTS: There were 158 ESRD cases during follow-up. Incident ESRD rates were 178.8 per 100,000 person-years (105 py) in high poverty outlier counties and were 76.3 /105 py in affluent outlier counties, p trend = 0.06. In unadjusted competing risk models, persons residing in high poverty outlier counties had higher incidence of ESRD (which was not statistically significant) when compared to those persons residing in counties with neither high poverty nor affluence [hazard ratio (HR) 1.54, 95% Confidence Interval (CI) 0.75-3.20]. This association was markedly attenuated following adjustment for socio-demographic factors (age, sex, race, education, and income); HR 0.96, 95% CI 0.46-2.00. However, in the same adjusted model, income was independently associated with risk of ESRD [HR 3.75, 95% CI 1.62-8.64, comparing the < $20,000 income group to the > $75,000 group]. There were no statistically significant associations of county measures of poverty with incident ESRD, and no evidence of effect modification. CONCLUSIONS: In contrast to annual family income, geospatially-linked measures of county poverty have little relation with risk of ESRD. Efforts to mitigate socioeconomic disparities in kidney disease may be best appropriated at the individual level.

Transapical aortic valve replacement in extreme-risk patients: outcome, risk factors and mid-term results.

OBJECTIVES: Transcatheter aortic valve replacement (TAVR) provides good results in selected high-risk patients. However, it is unclear whether this procedure carries advantages in extreme-risk profile patients with logistic EuroSCORE above 35%. METHODS: From January 2009 to July 2011, of a total number of 92 transcatheter aortic valve procedures performed, 40 'extreme-risk' patients underwent transapical TAVR (TA-TAVR) (EuroSCORE above 35%). Variables were analysed as risk factors for hospital and mid-term mortality, and a 2-year follow-up (FU) was obtained. RESULTS: The mean age was: 81 ± 10 years. Twelve patients (30%) had chronic pulmonary disease, 32 (80%) severe peripheral vascular disease, 14 (35%) previous cardiac surgery, 19 (48%) chronic renal failure (2 in dialysis), 7 (17%) previous stroke (1 with disabilities), 3 (7%) a porcelain aorta and 12 (30%) were urgent cases. Mean left ventricle ejection fraction (LVEF) was 49 ± 13%, and mean logistic EuroSCORE was 48 ± 11%. Forty stent-valves were successfully implanted with six Grade-1 and one Grade-2 paravalvular leakages (success rate: 100%). Hospital mortality was 20% (8 patients). Causes of death following the valve academic research consortium (VARC) definitions were: life-threatening haemorrhage (1), myocardial infarction (1), sudden death (1), multiorgan failure (2), stroke (1) and severe respiratory dysfunction (2). Major complications (VARC definitions) were: myocardial infarction for left coronary ostium occlusion (1), life-threatening bleeding (2), stroke (2) and acute kidney injury with dialysis (2). Predictors for hospital mortality were: conversion to sternotomy, life-threatening haemorrhage, postoperative dialysis and long intensive care unit (ICU) stay. Variables associated with hospital mortality were: conversion to sternotomy (P = 0.03), life-threatening bleeding (P = 0.02), acute kidney injury with dialysis (P = 0.03) and prolonged ICU stay (P = 0.02). Mean FU time was 24 months: actuarial survival estimates for all-cause mortality at 6 months, 1 year, 18 months and 2 years were 68, 57, 54 and 54%, respectively. Patients still alive at FU were in good clinical condition, New York Heart Association (NYHA) class 1-2 and were never rehospitalized for cardiac decompensation. CONCLUSIONS: TA-TAVR in extreme-risk patients carries a moderate risk of hospital mortality. Severe comorbidities and presence of residual paravalvular leakages affect the mid-term survival, whereas surviving patients have an acceptable quality of life without rehospitalizations for cardiac decompensation.

Exaggerated exercise-induced pulmonary hypertension causes lung water accumulation and right ventricular dysfunction in patients with chronic mountain sickness

Background: Chronic mountain sickness (CMS) is characterized by exaggerated exercise-induced pulmonary hypertension. Evidences suggests that exercise may cause lung fluid accumulation at high altitude. We hypothesized that, in patients with CMS, exercise causes lung fluid accumulation.Methods: In 21 male CMS patients and 20 matched healthy controls born and permanently living in La Paz (Bolivia, 3600m) we assessed with echocardiogram, pulmonary artery pressure (PASP), right and left ventricular function and ultrasoundlung comets (ULCs, a marker of lung fluid accumulation) at rest and during mild bicycle exercise (10 min at 50W).Results: CMS patients presented a more than 2-fold greater exercise-induced increase in pulmonary artery pressure than controls (17.1±8.3 vs 7.2±7.9 mmHg, P=0.003). This exaggerated PASP response to exercise was associated with a roughly 3-fold greater increase in UCLs in patients with CMS than in controls (6.3±5.1 vs. 2.1±5.3, p<0.05), and there existed a significant relationship between PASP and UCLs (r=0.44, p<0.001). Finally, TDI on lateral tricuspid annulus decreased during exercise in patients with CMS (from 13.2±3.2 to 11.5±2.1 cm s-1, p=0.03), but increased in controls (from 13.1±2.9 to 14.9±2.6 cm s-1 , p=0.04). Left ventricular function remained unaltered in the 2 groups.Conclusions: we provide the first direct evidence in CMS patients that exaggerated exercise-induced pulmonary hypertension causes rapid lung fluid accumulation and right ventricular dysfunction. We speculate that in patients with CMS these two phenomena contribute to reduced exercise performances and Figure 1 increased cardiovascular morbidity and mortality that characterise these subjects.

Pretherapeutic gamma-glutamyltransferase is an independent prognostic factor for patients with renal cell carcinoma.

BACKGROUND: Gamma-glutamyltransferase (GGT) regulates apoptotic balance and promotes cancer progression and invasion. Higher pretherapeutic GGT serum levels have been associated with worse outcomes in various malignancies, but there are no data for renal cell carcinoma (RCC). METHODS: Pretherapeutic GGT serum levels and clinicopathological parameters were retrospectively evaluated in 921 consecutive RCC patients treated with nephrectomy at a single institution between 1998 and 2013. Gamma-glutamyltransferase was analysed as continuous and categorical variable. Associations with RCC-specific survival were assessed with Cox proportional hazards models. Discrimination was measured with the C-index. Decision-curve analysis was used to evaluate the clinical net benefit. The median postoperative follow-up was 45 months. RESULTS: Median pretherapeutic serum GGT level was 25 U l(-1). Gamma-glutamyltransferase levels increased with advancing T (P<0.001), N (P=0.006) and M stages (P<0.001), higher grades (P<0.001), and presence of tumour necrosis (P<0.001). An increase of GGT by 10 U l(-1) was associated with an increase in the risk of death from RCC by 4% (HR 1.04, P<0.001). Based on recursive partitioning-based survival tree analysis, we defined four prognostic categories of GGT: normal low (<17.5 U l(-1)), normal high (17.5 to <34.5 U l(-1)), elevated (34.5 to <181.5 U l(-1)), and highly elevated (⩾181.5 U l(-1)). In multivariable analyses that adjusted for the effect of standard features, both continuously and categorically coded GGT were independent prognostic factors. Adding GGT to a model that included standard features increased the discrimination by 0.9% to 1.8% and improved the clinical net benefit. CONCLUSIONS: Pretherapeutic serum GGT is a novel and independent prognostic factor for patients with RCC. Stratifying patients into prognostic subgroups according to GGT may be used for patient counselling, tailoring surveillance, individualised treatment planning, and clinical trial design.

Alterations in microRNA expression contribute to fatty acid-induced pancreatic beta-cell dysfunction.

OBJECTIVE: Visceral obesity and elevated plasma free fatty acids are predisposing factors for type 2 diabetes. Chronic exposure to these lipids is detrimental for pancreatic beta-cells, resulting in reduced insulin content, defective insulin secretion, and apoptosis. We investigated the involvement in this phenomenon of microRNAs (miRNAs), a class of noncoding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation. RESEARCH DESIGN AND METHODS: We analyzed miRNA expression in insulin-secreting cell lines or pancreatic islets exposed to palmitate for 3 days and in islets from diabetic db/db mice. We studied the signaling pathways triggering the changes in miRNA expression and determined the impact of the miRNAs affected by palmitate on insulin secretion and apoptosis. RESULTS: Prolonged exposure of the beta-cell line MIN6B1 and pancreatic islets to palmitate causes a time- and dose-dependent increase of miR34a and miR146. Elevated levels of these miRNAs are also observed in islets of diabetic db/db mice. miR34a rise is linked to activation of p53 and results in sensitization to apoptosis and impaired nutrient-induced secretion. The latter effect is associated with inhibition of the expression of vesicle-associated membrane protein 2, a key player in beta-cell exocytosis. Higher miR146 levels do not affect the capacity to release insulin but contribute to increased apoptosis. Treatment with oligonucleotides that block miR34a or miR146 activity partially protects palmitate-treated cells from apoptosis but is insufficient to restore normal secretion. CONCLUSIONS: Our findings suggest that at least part of the detrimental effects of palmitate on beta-cells is caused by alterations in the level of specific miRNAs.

Disposition of oral valganciclovir during continuous renal replacement therapy in two lung transplant recipients

Background: Oral valganciclovir (VGC) is hydrolysed into active ganciclovir (GCV) which is eliminated in the kidney by filtration and secretion. VGC dosage has to be adapted in renal failure with continuous renal replacement therapy (CRRT), a condition sometimes encountered early after solid organ transplantation. This investigation aimed to determine whether VGC 450 mg every 48 hours provides appropriate GCV exposure for cytomegalovirus (CMV) prophylaxis during CRRT. Methods: GCV pharmacokinetics were extensively studied during CRRT in two lung transplant recipients with acute renal failure receiving VGC 450 mg every 48 hours trough a nasogastric tube. In vitro experiments using blank whole blood spiked with GCV further investigated exchanges between plasma and erythrocytes. Results: GCV disposition was characterised by an area under the curve (AUC) of 98.0 and 55.4 mg h/L, resulting in trough concentrations of 0.7 and 0.2 mg/L, an apparent total body clearance of 3.3 and 5.8 L/h, a terminal half-life of 16.9 and 14.1 h, and an apparent volume of distribution of 60.3 and 104.9 L. The observed sieving coefficient (filtrate/plasma) was 1.05 and 0.96, and the hemofiltration clearance 3.3 and 3.1 L/h, respectively. High sieving values could be explained by an efflux of GCV from erythrocytes. In vitro experiments confirmed that erythrocytes are loaded with significant GCV amount and release it quickly into plasma, thus contributing to the apparent efficacy of hemofiltration. Conclusion: These results indicate that a VGC dosage of 450 mg every 48 hours was adequate for CMV prophylaxis during CRRT, providing GCV levels similar to those reported using 900 mg qd in transplant recipients with normal renal function.

Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

Background Brain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington's disease (HD), but its conditional administration is one of its most challenging problems. Results Here we used transgenic mice that over-express BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter (pGFAP-BDNF mice) to test whether up-regulation and release of BDNF, dependent on astrogliosis, could be protective in HD. Thus, we cross-mated pGFAP-BDNF mice with R6/2 mice to generate a double-mutant mouse with mutant huntingtin protein and with a conditional over-expression of BDNF, only under pathological conditions. In these R6/2:pGFAP-BDNF animals, the decrease in striatal BDNF levels induced by mutant huntingtin was prevented in comparison to R6/2 animals at 12 weeks of age. The recovery of the neurotrophin levels in R6/2:pGFAP-BDNF mice correlated with an improvement in several motor coordination tasks and with a significant delay in anxiety and clasping alterations. Therefore, we next examined a possible improvement in cortico-striatal connectivity in R62:pGFAP-BDNF mice. Interestingly, we found that the over-expression of BDNF prevented the decrease of cortico-striatal presynaptic (VGLUT1) and postsynaptic (PSD-95) markers in the R6/2:pGFAP-BDNF striatum. Electrophysiological studies also showed that basal synaptic transmission and synaptic fatigue both improved in R6/2:pGAP-BDNF mice. Conclusions These results indicate that the conditional administration of BDNF under the GFAP promoter could become a therapeutic strategy for HD due to its positive effects on synaptic plasticity.

Nedd4-2 modulates renal Na+-Cl- cotransporter via the aldosterone-SGK1-Nedd4-2 pathway.

Regulation of renal Na(+) transport is essential for controlling blood pressure, as well as Na(+) and K(+) homeostasis. Aldosterone stimulates Na(+) reabsorption by the Na(+)-Cl(-) cotransporter (NCC) in the distal convoluted tubule (DCT) and by the epithelial Na(+) channel (ENaC) in the late DCT, connecting tubule, and collecting duct. Aldosterone increases ENaC expression by inhibiting the channel's ubiquitylation and degradation; aldosterone promotes serum-glucocorticoid-regulated kinase SGK1-mediated phosphorylation of the ubiquitin-protein ligase Nedd4-2 on serine 328, which prevents the Nedd4-2/ENaC interaction. It is important to note that aldosterone increases NCC protein expression by an unknown post-translational mechanism. Here, we present evidence that Nedd4-2 coimmunoprecipitated with NCC and stimulated NCC ubiquitylation at the surface of transfected HEK293 cells. In Xenopus laevis oocytes, coexpression of NCC with wild-type Nedd4-2, but not its catalytically inactive mutant, strongly decreased NCC activity and surface expression. SGK1 prevented this inhibition in a kinase-dependent manner. Furthermore, deficiency of Nedd4-2 in the renal tubules of mice and in cultured mDCT(15) cells upregulated NCC. In contrast to ENaC, Nedd4-2-mediated inhibition of NCC did not require the PY-like motif of NCC. Moreover, the mutation of Nedd4-2 at either serine 328 or 222 did not affect SGK1 action, and mutation at both sites enhanced Nedd4-2 activity and abolished SGK1-dependent inhibition. Taken together, these results suggest that aldosterone modulates NCC protein expression via a pathway involving SGK1 and Nedd4-2 and provides an explanation for the well-known aldosterone-induced increase in NCC protein expression.

Effectiveness of a drug dosing service provided by community pharmacists in polymedicated elderly patients with renal impairment a comparative study

Background: Drug dosing errors are common in renal-impaired patients. Appropriate dosing adjustment and drug selection is important to ensure patients" safety and to avoid adverse drug effects and poor outcomes. There are few studies on this issue in community pharmacies. The aims of this study were, firstly, to determine the prevalence of dosing inadequacy as a consequence of renal impairment in patients over 65 taking 3 or more drug products who were being attended in community pharmacies and, secondly, to evaluate the effectiveness of the community pharmacist"s intervention in improving dosing inadequacy in these patients when compared with usual care. Methods: The study was carried out in 40 Spanish community pharmacies. The study had two phases: the first, with an observational, multicentre, cross sectional design, served to determine the dosing inadequacy, the drug-related problems per patient and to obtain the control group. The second phase, with a controlled study with historical control group, was the intervention phase. When dosing adjustments were needed, the pharmacists made recommendations to the physicians. A comparison was made between the control and the intervention group regarding the prevalence of drug dosing inadequacy and the mean number of drug-related problems per patient. Results: The mean of the prevalence of drug dosing inadequacy was 17.5% [95% CI 14.6-21.5] in phase 1 and 15.5% [95% CI 14.5-16.6] in phase 2. The mean number of drug-related problems per patient was 0.7 [95% CI 0.5-0.8] in phase 1 and 0.50 [95% CI 0.4-0.6] in phase 2. The difference in the prevalence of dosing inadequacy between the control and intervention group before the pharmacists" intervention was 0.73% [95% CI (−6.0) - 7.5] and after the pharmacists" intervention it was 13.5% [95% CI 8.0 - 19.5] (p < 0.001) while the difference in the mean of drug-related problems per patient before the pharmacists" intervention was 0.05 [95% CI( -0.2) - 0.3] and following the intervention it was 0.5 [95% CI 0.3 - 0.7] (p < 0.001). Conclusion: A drug dosing adjustment service for elderly patients with renal impairment in community pharmacies can increase the proportion of adequate drug dosing, and improve the drug-related problems per patient. Collaborative practice with physicians can improve these results.

Studies of the renal effects of angiotensin II receptor blockade: the confounding factor of acute water loading on the action of vasoactive systems.

The acute renal tubular effects of two pharmacologically distinct angiotensin II receptor antagonists have been evaluated in normotensive volunteers on various salt diets. In the first study, the renal response to a single oral dose of losartan (100 mg) was assessed in subjects on a low (50 mmol Na/d) and on a high (200 mmol Na/d) salt intake. In a second protocol, the renal effects of 50 mg irbesartan were investigated in subjects receiving a 100 mmol Na/d diet. Both angiotensin II antagonists induced a significant increase in urinary sodium excretion. With losartan, a modest, transient increase in urinary potassium and a significant increase in uric acid excretion were found. In contrast, no change in potassium and uric acid excretions were observed with irbesartan, suggesting that the effects of losartan on potassium and uric acid are due to the intrinsic pharmacologic properties of losartan rather than to the specific blockade of renal angiotensin II receptors. Assessment of segmental sodium reabsorption using lithium as a marker of proximal tubular reabsorption demonstrated a decreased distal reabsorption of sodium with both antagonists. A direct proximal tubular natriuretic effect of the angiotensin II antagonist could be demonstrated only with irbesartan. This apparent discrepancy allowed us to reveal the importance of acute water loading as a possible confounding factor in renal studies. The results of the present analysis show that acute water loading per se may enhance renal sodium excretion and hence modify the level of activity of the renin-angiotensin system expected from a given sodium diet. Since acute water loading is a common practice in clinical renal studies, this confounding factor should be taken into account when investigating the renal effects of vasoactive systems.

Short-term and sustained renal effects of angiotensin II receptor blockade in healthy subjects.

We investigated the short-term and sustained hormonal and renal effects of angiotensin II (Ang II) receptor blockade in normotensive healthy volunteers. Twenty-four subjects maintained on a fixed sodium diet were randomized to receive for 8 days a placebo or 10 or 50 mg doses of the Ang II antagonist irbesartan (SR 47436, BMS 186295) according to a double-blind, parallel group design. Plasma renin activity, plasma immunoreactive Ang II and aldosterone levels, blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 8 hours after the first and eighth administration of each dose of irbesartan or placebo. Ang II receptor blockade with irbesartan induced a dose-dependent compensatory increase in plasma renin activity and plasma angiotensin levels and a significant decrease in plasma aldosterone levels. The compensatory rise in plasma renin activity and Ang II levels was more pronounced on day 8, reflecting a long duration of the blocking effect of irbesartan. Irbesartan induced small changes in blood pressure and did not significantly modify renal blood flow and glomerular filtration rate. However, a significant decrease in filtration fraction was observed during receptor blockade on days 1 and 8. The tubular effects of irbesartan were characterized by a dose-dependent increase in sodium and chloride excretions. Interestingly, the cumulative natriuretic response to Ang II receptor blockade was similar on days 1 and 8, suggesting that in these subjects, renal Ang II receptors are not blocked over 24 hours during repeated administration even though this antagonist has a long duration of action (t1/2 of 15 to 17 hours).(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory chain dysfunction associated with multiple mitochondrial DNA deletions in antiretroviral therapy-related lipodystrophy.

Highly-active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome characterized by peripheral fat wasting and central adiposity, usually associated with hyperlipidaemia and insulin resistance [1,2]. Indirect data have led some authors to propose that mitochondrial dysfunction could play a role in this syndrome [3,4].To date, as recently outlined by Kakuda et al. [5] in this journal, HIV-infected patients developing lipodystrophy have not been studied for mitochondrial changes or respiratory chain capacity...

Interpretation of needle biopsies of the kidney for investigation of renal masses.

The development of new therapeutic options for renal tumors has lead to the need of a pretherapeutic diagnosis for an increasing proportion of patients presenting with a renal mass. This need is particularly important for a small, incidentally discovered renal mass (less than 4 cm) as it can be a benign lesion in a significant percentage of cases. Recent studies have shown that needle biopsy is an accurate and safe method allowing for a precise histopathological diagnosis of the mass in most cases. The aims of the biopsy are (1) to assess the benign or malignant nature of the lesion, (2) to assess the primary or secondary nature of the lesion, and (3), in case of a primary malignancy, to determine histological prognostic factors, such as the tumor type. This review, based on the most recent literature and our own experience, is intended to provide a practical approach to the diagnosis, relying on appropriate morphologic assessment and the use of immunohistochemistry.