Of flies, mice and men: a systematic approach to understanding the early life origins of chronic lung disease.

Despite intensive research efforts, the aetiology of the majority of chronic lung diseases (CLD) in both, children and adults, remains elusive. Current therapeutic options are limited, providing only symptomatic relief, rather than treating the underlying condition, or preventing its development in the first place. Thus, there is a strong and unmet clinical need for the development of both, novel effective therapies and preventative strategies for CLD. Many studies suggest that modifications of prenatal and/or early postnatal lung development will have important implications for future lung function and risk of CLD throughout life. This view represents a fundamental change of current pathophysiological concepts and treatment paradigms, and holds the potential to develop novel preventative and/or therapeutic strategies. However, for the successful development of such approaches, key questions, such as a clear understanding of underlying mechanisms of impaired lung development, the identification and validation of relevant preclinical models to facilitate translational research, and the development of concepts for correction of aberrant development, all need to be solved. Accordingly, a European Science Foundation Exploratory Workshop was held where clinical, translational and basic research scientists from different disciplines met to discuss potential mechanisms of developmental origins of CLD, and to identify major knowledge gaps in order to delineate a roadmap for future integrative research.

Effects of erythropoietin on muscle O2 transport during exercise in patients with chronic renal failure.

Erythropoietin (rHuEPO) has proven to be effective in the treatment of anemia of chronic renal failure (CRF). Despite improving the quality of life, peak oxygen uptake after rHuEPO therapy is not improved as much as the increase in hemoglobin concentration ([Hb)] would predict. We hypothesized that this discrepancy is due to failure of O2 transport rates to rise in a manner proportional to [Hb]. To test this, eight patients with CRF undergoing regular hemodialysis were studied pre- and post-rHuEPO ([Hb] = 7.5 +/- 1.0 vs. 12.5 +/- 1.0 g x dl-1) using a standard incremental cycle exercise protocol. A group of 12 healthy sedentary subjects of similar age and anthropometric characteristics served as controls. Arterial and femoral venous blood gas data were obtained and coupled with simultaneous measurements of femoral venous blood flow (Qleg) by thermodilution to obtain O2 delivery and oxygen uptake (VO2). Despite a 68% increase in [Hb], peak VO2 increased by only 33%. This could be explained largely by reduced peak leg blood flow, limiting the gain in O2 delivery to 37%. At peak VO2, after rHuEPO, O2 supply limitation of maximal VO2 was found to occur, permitting the calculation of a value for muscle O2 conductance from capillary to mitochondria (DO2). While DO2 was slightly improved after rHuEPO, it was only 67% of that of sedentary control subjects. This kept maximal oxygen extraction at only 70%. Two important conclusions can be reached from this study. First, the increase in [Hb] produced by rHuEPO is accompanied by a significant reduction in peak blood flow to exercising muscle, which limits the gain in oxygen transport. Second, even after restoration of [Hb], O2 conductance from the muscle capillary to the mitochondria remains considerably below normal.

Prévention de la maladie veineuse chronique: quels conseils donner à nos patients [Prevention of chronic venous disease: which advice for our patients?].

Chronic venous disease (CVD) is a major public health problem due to its high prevalence and socioeconomic costs. In absence of adequate care, it can lead to chronic venous insufficiency (CVI). Disturbed venous-flow patterns lead to venous hypertension. Therefore, prevention of CVD involves venous hypertension reduction. In primary prevention, it is essential to inform the patient about necessary lifestyle changes. In case of CVD, it is essential to propose treatment (compression, venoactive drugs, and interventional treatments) to avoid CVI appearance and eventually offer the best therapy solutions for CVI complications.

Innappropriate renin secretion unmasked by captopril (SQ 14 225) in hypertension of chronic renal failure

Captopril (SQ 14 225), an orally active inhibitor of angiotensin-converting enzyme, was given to 7 hypertensive patients with chronic renal failure whose plasma-creatinine ranged from 1.5--7.4 mg/dl; whose plasma-renin activity was normal; whose hypertension was not controlled by previous therapy consisting in 5 patients of three or more antihypertensive drugs; and whose blood-pressures averaged 176/111 +/- 11/3 mm Hg. Inhibition of converting enzyme by oral captopril, 200 mg twice daily, reduced blood-pressure to 156/100 +/- 9/5 mm Hg. 5 patients needed additional treatment by frusemide 40--250 mg/day orally. With this combined regimen the blood-pressure of all patients averaged 126/85 +/- 4/3 mm Hg after 8 +/- 2 weeks of captopril. The drug was well tolerated. These results suggest that inhibition of angiotensin-converting enzyme with or without sodium depletion is an efficient treatment for hypertension associated with chronic renal failure. It appears that although renin levels in patients with this condition may be "normal", they are inappropriate in relation to the subtle degree of sodium retention that occurs with this disorder.

Effects of Sucroferric Oxyhydroxide Compared to Lanthanum Carbonate and Sevelamer Carbonate on Phosphate Homeostasis and Vascular Calcifications in a Rat Model of Chronic Kidney Failure.

Elevated serum phosphorus, calcium, and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease in chronic renal disease. This study evaluated the effects of sucroferric oxyhydroxide (PA21), a new iron-based phosphate binder, versus lanthanum carbonate (La) and sevelamer carbonate (Se), on serum FGF23, phosphorus, calcium, and intact parathyroid hormone (iPTH) concentrations, and the development of vascular calcification in adenine-induced chronic renal failure (CRF) rats. After induction of CRF, renal function was significantly impaired in all groups: uremic rats developed severe hyperphosphatemia, and serum iPTH increased significantly. All uremic rats (except controls) then received phosphate binders for 4 weeks. Hyperphosphatemia and increased serum iPTH were controlled to a similar extent in all phosphate binder-treatment groups. Only sucroferric oxyhydroxide was associated with significantly decreased FGF23. Vascular calcifications of the thoracic aorta were decreased by all three phosphate binders. Calcifications were better prevented at the superior part of the thoracic and abdominal aorta in the PA21 treated rats. In adenine-induced CRF rats, sucroferric oxyhydroxide was as effective as La and Se in controlling hyperphosphatemia, secondary hyperparathyroidism, and vascular calcifications. The role of FGF23 in calcification remains to be confirmed.

On the rationale of population screening for chronic kidney disease : a public health perspective

Chronic kidney disease (CKD) and its complications represent an enormous and increasing public health burden worldwide [1]. More than one in ten adults suffers from CKD in the general population [2], with a majority of people being in its early stages (i.e. 1 to 3) [2]. In the general population, the prevalence of CKD sharply increases with age [3]. CKD can be considered as a condition associated with premature ageing with accelerated vascular disease [4]. The large number of people with CKD, or at high risk of CKD (i.e. patients with hypertension, diabetes and/or CVD), implies that primary care providers and specialists other than nephrologists frequently encounter patients with CKD [5], a situation in which most CKD cases are diagnosed via opportunistic kidney function screening or automated eGFR reporting. The aim of this review is to discuss the rationale and currently available evidence for, or against, population-based screening for CKD. The focus will be on the situation of screening asymptomatic individuals at early stages of CKD regardless of the presence or absence of CKD risk factors.

Chronic kidney disease in type 2 diabetic patients followed-up by primary care physicians in Switzerland: prevalence and prescription of antidiabetic drugs.

QUESTION UNDER STUDY: The aim of this study was to assess the prevalence of chronic kidney disease (CKD) among type 2 diabetic patients in primary care settings in Switzerland, and to analyse the prescription of antidiabetic drugs in CKD according to the prevailing recommendations. METHODS: In this cross-sectional study, each participating physician was asked to introduce anonymously in a web database the data from up to 15 consecutive diabetic patients attending her/his office between December 2013 and June 2014. Demographic, clinical and biochemical data were analysed. CKD was classified with the KDIGO nomenclature based on estimated glomerular filtration rate (eGFR) and urinary albumin/creatinine ratio. RESULTS: A total of 1 359 patients (mean age 66.5 ± 12.4 years) were included by 109 primary care physicians. CKD stages 3a, 3b and 4 were present in 13.9%, 6.1%, and 2.4% of patients, respectively. Only 30.6% of patients had an entry for urinary albumin/creatinine ratio. Among them, 35.6% were in CKD stage A2, and 4.1% in stage A3. Despite prevailing limitations, metformin and sulfonylureas were prescribed in 53.9% and 16.5%, respectively, of patients with advanced CKD (eGFR <30 ml/min). More than a third of patients were on a dipeptidyl-peptidase-4 inhibitor across all CKD stages. Insulin use increased progressively from 26.8% in CKD stage 1-2 to 50% in stage 4. CONCLUSIONS: CKD is frequent in patients with type 2 diabetes attending Swiss primary care practices, with CKD stage 3 and 4 affecting 22.4% of cases. This emphasizes the importance of routine screening of diabetic nephropathy based on both eGFR and urinary albumin/creatinine ratio, the latter being largely underused by primary care physicians. A careful individual drug risk/benefit balance assessment is mandatory to avoid the frequently observed inappropriate prescription of antidiabetic drugs in CKD patients.

Labyrinthine fenestration for stapes fixation in chronic ear disease others than otosclerosis.

The objective of this study is to assess the results of labyrinthine fenestration for fixed stapes in chronic ear disease. Using a prospective database, pre- and postoperative audiometric data from patients undergoing labyrinthine fenestration for fixation of the stapes in chronic ear disease others than otosclerosis between 2002 and 2012 were evaluated. Twenty-three labyrinthine fenestrations in chronic ear disease were performed (17 malleo-stapedotomies, 4 incus-stapedotomies, 1 neo-malleus-stapedotomy, 1 TORP-stapedotomy). Overall, the mean short-term (2 months) and long-term (42 months) postoperative air-bone gap (0.5-3 kHz) were 17.5 and 16.5 dB, respectively; long-term air-bone gap of <20 dB was obtained in 73 % of patients. There was no significant difference in air-bone gap closure between tympanosclerotic and post inflammatory osteogenic fixation of the stapes (p = 0.267). Hearing benefit success using the 'Belfast rule of the thumb' was achieved in 48 %. Normal bilateral hearing was achieved in 17 % and bilateral symmetric hearing impairment in 26 %. Only in 4 %, bone conduction worsened by more than 5 dB. Labyrinthine fenestration is an option in selected cases of stapes fixation in chronic ear disease and provides hearing gain without significant risk for sensorineural hearing loss. In those already selected cases, hearing benefit success 'Belfast rule of the thumb' is achieved only in half of the cases. This and the possible alternatives, should therefore be discussed preoperatively.

Sleep Characteristics in Early Stages of Chronic Kidney Disease in the HypnoLaus Cohort.

STUDY OBJECTIVES: To evaluate the association between early stages of chronic kidney disease (CKD) and sleep disordered breathing (SDB), restless legs syndrome (RLS), and subjective and objective sleep quality (SQ). METHODS: Cross-sectional analysis of a general population-based cohort (HypnoLaus). 1,760 adults (862 men, 898 women; age 59.3 (± 11.4) y) underwent complete polysomnography at home. RESULTS: 8.2% of participants had mild CKD (stage 1-2, estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m(2) with albuminuria) and 7.8% moderate CKD (stage 3, eGFR 30-60 mL/min/1.73 m(2)). 37.3% of our sample had moderate-to-severe SDB (apnea-hypopnea index [AHI] ≥ 15/h) and 15.3% had severe SDB (AHI ≥ 30/h). SDB prevalence was positively associated with CKD stages and negatively with eGFR. In multivariate analysis, age, male sex, and body mass index were independently associated with SDB (all P < 0.001), but kidney function was not. The prevalence of RLS was 17.5%, without difference between CKD stages. Periodic leg movements index (PLMI) was independently associated with CKD stages. Subjective and objective SQ decreased and the use of sleep medication was more frequent with declining kidney function. Older age, female sex, and the severity of SDB were the strongest predictors of poor SQ in multivariate regression analysis but CKD stage was also independently associated with reduced objective SQ. CONCLUSIONS: Patients with early stages of CKD have impaired SQ, use more hypnotic drugs, and have an increased prevalence of SDB and PLM. After controlling for confounders, objective SQ and PLMI were still independently associated with declining kidney function.

Characterization of nontypable haemophilus influenzae isolates recovered from adult patients with underlying chronic lung disease reveals genotypic and phenotypic traits associated with persistent infection

Nontypable Haemophilus influenzae (NTHi) has emerged as an important opportunistic pathogen causing infection in adults suffering obstructive lung diseases. Existing evidence associates chronic infection by NTHi to the progression of the chronic respiratory disease, but specific features of NTHi associated with persistence have not been comprehensively addressed. To provide clues about adaptive strategies adopted by NTHi during persistent infection, we compared sequential persistent isolates with newly acquired isolates in sputa from six patients with chronic obstructive lung disease. Pulse field gel electrophoresis (PFGE) identified three patients with consecutive persistent strains and three with new strains. Phenotypic characterisation included infection of respiratory epithelial cells, bacterial self-aggregation, biofilm formation and resistance to antimicrobial peptides (AMP). Persistent isolates differed from new strains in showing low epithelial adhesion and inability to form biofilms when grown under continuous-flow culture conditions in microfermenters. Self-aggregation clustered the strains by patient, not by persistence. Increasing resistance to AMPs was observed for each series of persistent isolates; this was not associated with lipooligosaccharide decoration with phosphorylcholine or with lipid A acylation. Variation was further analyzed for the series of three persistent isolates recovered from patient 1. These isolates displayed comparable growth rate, natural transformation frequency and murine pulmonary infection. Genome sequencing of these three isolates revealed sequential acquisition of single-nucleotide variants in the AMP permease sapC, the heme acquisition systems hgpB, hgpC, hup and hxuC, the 3-deoxy-D-manno-octulosonic acid kinase kdkA, the long-chain fatty acid transporter ompP1, and the phosphoribosylamine glycine ligase purD. Collectively, we frame a range of pathogenic traits and a repertoire of genetic variants in the context of persistent infection by NTHi.

Regulation of intercellular coupling in acute and chronic heart disease

Effective pump function of the heart depends on the precise control of spatial and temporal patterns of electrical activation. Accordingly, the distribution and function of gap junction channels are important determinants of the conduction properties of myocardium and undoubtedly play other roles in intercellular communication crucial to normal cardiac function. Recent advances have begun to elucidate mechanisms by which the heart regulates intercellular electrical coupling at gap junctions in response to stress or injury. Although responses to increased load or injury are generally adaptive in nature, remodeling of intercellular junctions under conditions of severe stress creates anatomic substrates conducive to the development of lethal ventricular arrhythmias. Potential mechanisms controlling the level of intercellular communication in the heart include regulation of connexin turnover dynamics and phosphorylation.

Acute AT1 receptor blockade does not improve the depressed baroreflex in rats with chronic renal hypertension

To assess the role of angiotensin II in the sensitivity of the baroreflex control of heart rate (HR) in normotensive rats (N = 6) and chronically hypertensive rats (1K1C, 2 months, N = 7), reflex changes of HR were evaluated before and after (15 min) the administration of a selective angiotensin II receptor antagonist (losartan, 10 mg/kg, iv). Baseline values of mean arterial pressure (MAP) were higher in hypertensive rats (195 ± 6 mmHg) than in normotensive rats (110 ± 2 mmHg). Losartan administration promoted a decrease in MAP only in hypertensive rats (16%), with no changes in HR. During the control period, the sensitivity of the bradycardic and tachycardic responses to acute MAP changes were depressed in hypertensive rats (~70% and ~65%, respectively) and remained unchanged after losartan administration. Plasma renin activity was similar in the two groups. The present study demonstrates that acute blockade of AT1 receptors with losartan lowers the MAP in chronic renal hypertensive rats without reversal of baroreflex hyposensitivity, suggesting that the impairment of baroreflex control of HR is not dependent on an increased angiotensin II level.

alpha-Smooth muscle actin and proliferating cell nuclear antigen expression in focal segmental glomerulosclerosis: functional and structural parameters of renal disease progression

The aim of the present study was to investigate the expression of alpha-smooth muscle actin (alpha-SM-actin) and proliferating cell nuclear antigen (PCNA) in renal cortex from patients with focal segmental glomerulosclerosis (FSGS) and their correlations with parameters of renal disease progression. We analyzed renal biopsies from 41 patients with idiopathic FSGS and from 14 control individuals. The alpha-SM-actin immunoreaction was evaluated using a score that reflected the changes in the extent and intensity of staining in the glomerular or cortical area. The PCNA reaction was quantified by counting the labeled cells of the glomeruli or renal cortex. The results, reported as median ± percentile (25th; 75th), showed that the alpha-SM-actin scores in the glomeruli and tubulointerstitium from the renal cortex were 2.0 (2.0; 4.0) and 3.0 (3.0; 4.0), respectively, in patients with FSGS, and 0.5 (0.0; 1.0) and 0.0 (0.0; 0.5) in the controls. The number of PCNA-positive cells per glomerulus and graded field of tubulointerstitium from the renal cortex was 0.2 (0.0; 0.4) and 1.1 (0.3; 2.2), respectively, for patients with FSGS, and 0.0 (0.0; 0.5) and 0.0 (0.0; 0.0) for controls. The present data showed an increase of alpha-SM-actin and PCNA expression in glomeruli and renal cortex from FSGS patients. The extent of immunoreaction for alpha-SM-actin in the tubulointerstitial area was correlated with the intensity of proteinuria. However, there was no correlation between the kidney expression of these proteins and the reciprocal of plasma creatinine level or renal fibrosis. These findings suggest that the immunohistochemical alterations may be reversible.

Circulating forms of parathyroid hormone detected with an immunofluorometric assay in patients with primary hyperparathyroidism and in hyperparathyroidism secondary to chronic renal failure

In patients with uremia, intact parathyroid hormone (PTH) measurement appears to overestimate the biologically active hormone in circulation. The recent description of the accumulation in these patients of a non-intact PTH form measured by the standard immunometric assays, re-opened the question. In this study we submitted serum samples from 7 patients with primary hyperparathyroidism (PHP) and from 10 patients with hyperparathyroidism secondary to chronic renal failure (SHP) to preparative HPLC in order to discriminate the molecular forms measured by our currently used immunofluorometric assay for intact PTH. The elution profile obtained with the HPLC system showed two clearly defined peaks, the first one corresponding to a lower molecular weight form, and the second to the intact PTH (1-84) form. In patients with SHP the area under the curve for the first peak (mean 29.5%, range 20.6 to 40.4%) was significantly greater than that observed for patients with PHP (mean 15.6%, range 5.6 to 21.9%). This confirms previous studies showing accumulation of molecular forms of slightly lower molecular weight, presumably PTH (7-84), in patients with SHP and, to a lesser extent, in patients with PHP. The real necessity of assays that discriminate between these two molecular forms is debatable.

Effect of dietary linoleic acid on the progression of chronic renal failure in rats

The role of linoleic acid in chronic renal failure (CRF) is controversial. In the present study 21 male Wistar rats submitted to 5/6 renal mass reduction (R) and 16 normal controls (C) were fed a supplement (S) or normal (N) linoleic acid diet for 60 days starting 10 days after CRF. As expected, serum creatinine, cholesterol and triglycerides (mean ± SEM) were higher in the CRF groups compared to the C groups (P<0.05). The RS group presented lower cholesterol (84 ± 4 vs 126 ± 13 mg%) and triglyceride (88 ± 9 vs 132 ± 19 mg%) levels compared to the RN group. Proteinuria and kidney weight did not differ between CRF groups. Glomerular area increased 78% in RS and 100% in RN compared to control rats. Glomerular sclerosis index tended to be lower in RS (27%) compared to RN (38%), tubulointerstitial damage was similar between CRF groups (RS = 1.91 ± 0.2 and RN = 2.14 ± 0.3), and mesangial fractional volume increased to the same extent in both CRF groups. The data suggest that a linoleic acid-enriched diet did not protect against the progression of CRF after 60 days.