Dénervation rénale pour le traitement de l'hypertension artérielle résistante: proposition pour une attitude multidisciplinaire commune [Renal denervation in resistant hypertension: proposal for a common multidisciplinary attitude].

The prevalence of resistant hypertension ranges between 5-30%. Patients with resistant hypertension are at increased risk of cardiovascular events. Radiofrequency renal denervation is a recent and promising technique that can be used in the setting of resistant hypertension. However, long-term safety and efficacy data are lacking and evidence to use this procedure outside the strict setting of resistant hypertension is missing. The aim of the article is to propose a common work-up for nephrologists, hypertensiologists, cardiologists and interventional radiologists in order to avoid inappropriate selection of patients and a possible misuse of this procedure.

Circadian regulation of renal function and potential role in hypertension.

PURPOSE OF REVIEW: Previous studies have shown that a variety of specific renal functions exhibit circadian oscillations. This review aims to provide an update on the molecular mechanisms underlying circadian rhythms in the kidney, and to discuss how dysregulation of circadian rhythms can interfere with kidney function. RECENT FINDINGS: The molecular mechanism responsible for generating and maintaining circadian rhythms has been unraveled in great detail. This mechanism, known as the circadian clock, drives circadian oscillation in expression levels of a large number of renal mRNA transcripts. Several proteins critically involved in renal homeostatic functions have been shown to exhibit significant circadian oscillation in their expression levels or in their posttranslational modifications. In transgenic mouse models, disruption of circadian clock activity results in dramatic changes in the circadian pattern of urinary sodium and potassium excretion and causes significant changes in arterial blood pressure. A growing amount of evidence suggests that dysregulation of circadian rhythms is associated with the development of hypertension and accelerated progression of chronic kidney disease and cardiovascular disease in humans. Chronotherapy studies have shown that the efficacy of antihypertensive medication is greatly dependent on the circadian time of drug administration. SUMMARY: Recent research points to the major role of circadian rhythms in renal function and in control of blood pressure.

Percutaneous drainage and sclerotherapy as definitive treatment of renal lymphangiomatosis.

We report the technique and outcome of percutaneous drainage and sclerotherapy as primary treatment of renal lymphangiomatosis. Between January and May 2009, two patients presenting with symptomatic renal lymphangiomatosis were treated in our department by a minimally invasive modality combining percutaneous drainage with repeated sclerotherapy. We retrospectively analysed recurrence, complications and patient satisfaction. In this limited case series, percutaneous drainage and repeated sclerotherapy proved to be safe and effective for treating renal lymphangiomatosis. This procedure provides a minimally invasive option for selected patients, potentially avoiding a surgical procedure and any risk of complications.

Molecular bases of circadian rhythmicity in renal physiology and pathology.

The physiological processes that maintain body homeostasis oscillate during the day. Diurnal changes characterize kidney functions, comprising regulation of hydro-electrolytic and acid-base balance, reabsorption of small solutes and hormone production. Renal physiology is characterized by 24-h periodicity and contributes to circadian variability of blood pressure levels, related as well to nychthemeral changes of sodium sensitivity, physical activity, vascular tone, autonomic function and neurotransmitter release from sympathetic innervations. The circadian rhythmicity of body physiology is driven by central and peripheral biological clockworks and entrained by the geophysical light/dark cycle. Chronodisruption, defined as the mismatch between environmental-social cues and physiological-behavioral patterns, causes internal desynchronization of periodic functions, leading to pathophysiological mechanisms underlying degenerative, immune related, metabolic and neoplastic diseases. In this review we will address the genetic, molecular and anatomical elements that hardwire circadian rhythmicity in renal physiology and subtend disarray of time-dependent changes in renal pathology.

Uric acid and cardio-metabolic risk factors : an epidemiological approach

The role of serum uric acid (SUA) in cardio-metabolic conditions has long been contentious. It is still unclear if SUA is an independent risk factor or marker of cardio-metabolic conditions and most observed associations are not necessarily causal. This study aimed to further understand and explore the causal role of SUA in cardio-metabolic conditions using genetic and non-genetic epidemiological methods in population-based data. In the first part of this study, we found moderate to high heritability estimates for SUA and fractional excretion of urate (FEUA) suggesting the role of genetic factors in the etiology of hyperuricemia. With regards to the role of SUA on inflammatory markers (IMs), a strong positive association of SUA with C-reactive protein (CRP) and a weaker positive association with tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was observed, which was in part mediated by body mass index (BMI). These findings suggest that SUA may have a role in sterile inflammation. In view of the inconsistency surrounding the causal nature and direction of the relation between SUA and adiposity, we applied a bidirectional Mendelian randomization approach using genetic variants to decipher the association. The finding that elevated SUA is a consequence rather than a cause of adiposity was not totally unexpected and is compatible with the hypothesis that hyperinsulinemia, accompanying obesity, enhances renal proximal tubular reabsorption of uric acid. The fourth part of this study examined the relationship between SUA and blood pressure (BP) in young adults. The association between SUA and BP, significant only in females, was strongly attenuated upon adjustment for BMI. The possibility that BMI lies in the causal pathway may explain the attenuation observed in the associations of SUA with BP and IMs. Finally, a significant hockey-stick shaped association of SUA with social phobia in our data suggests a protective effect of SUA only up to a certain concentration. Although our study findings have shed some light on the uncertainty underlying the pathophysiology of SUA, more compelling evidence using longitudinal designs, randomized controlled trials and the use of robust genetic tools is warranted to increase our understanding of the clinical significance of SUA.

Blockade of the Renin-Angiotensin system in hypertensive patients with atherosclerotic renal artery stenosis.

Renin angiotensin system (RAS) blockers are generally considered as contraindicated when an atheromatous renal artery stenosis (ARAS) is diagnosed. The main reason is the fear of inducing renal ischemia and, hence, accelerating renal fibrosis and the progression towards end stage renal disease, albeit RAS blocker have been shown to be highly effective in controlling blood pressure. Part of the solution came by the development of the revascularization. There is now growing evidence showing no superiority of angioplasty over medical treatment on cardiovascular events and mortality, renal function and blood pressure control. Hence, RAS blockers resurfaced based on their proven beneficial effects on blood pressure control and cardiovascular prevention in high risk atherosclerotic patients. Thus, RAS blockers belong today to the standard treatment of hypertensive patients with ARAS. However they were not systematically prescribed in trials focusing on ARAS. The ongoing CORAL trial will give us further information on the place of this class of antihypertensive drugs in patients with ARAS.

Urotensin-II System in Genetic Control of Blood Pressure and Renal Function.

Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates.

Concentrações séricas de minerais e funções hepática e renal de frangos intoxicados com aflatoxina e tratados com montmorilonita sódica

O objetivo deste trabalho foi avaliar as concentrações séricas de minerais e as funções hepática e renal de frangos de corte intoxicados, experimentalmente, com 3 ppm de aflatoxina, e submetidos a diferentes concentrações de montmorilonita sódica na dieta. Foram utilizados 720 frangos, machos, da linhagem Cobb, divididos em seis tratamentos: T1, dieta normal; T2, dieta com aflatoxina (3 ppm); T3, dieta com montmorilonita sódica (0,25%); T4, dieta com aflatoxina (3 ppm) + montmorilonita sódica (0,25%); T5, dieta com montmorilonita sódica (0,5%); T6, dieta com aflatoxina (3 ppm) + montmorilonita sódica (0,5%), com seis repetições por tratamento. A dieta com 3 ppm de aflatoxina (T2) resultou em uma diminuição significativa na concentração sérica de proteínas totais, albumina, globulinas e aspartato amino transferase; a concentração sérica de ácido úrico diminuiu, significativamente, na dieta com aflatoxina (3 ppm) + momtmorilonita sódica a 0,25%; ocorreu diminuição significativa nas concentrações séricas de fósforo na dieta com aflatoxina + montmorilonita sódica a 0,5%. A aflatoxina na concentração de 3 ppm altera a função hepática de frangos de corte; o uso da montmorilonita sódica, na concentração de 0,5%, é eficaz na prevenção dos efeitos tóxicos da aflatoxina, mas diminui os níveis séricos de fósforo.

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.

BACKGROUND/AIMS: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. METHODS: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. RESULTS: All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. CONCLUSIONS: This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.

Agents anti-infectieux et fonction réna!e: vers des posologies sur mesure [Antimicrobial agents and renal elimination: towards individual dosage adjustment?].

The efficacy and safety of anti-infective treatments are associated with the drug blood concentration profile, which is directly correlated with a dosing adjustment to the individual patient's condition. Dosing adjustments to the renal function recommended in reference books are often imprecise and infrequently applied in clinical practice. The recent generalisation of the KDOQI (Kidney Disease Outcome Quality Initiative) staging of chronically impaired renal function represents an opportunity to review and refine the dosing recommendations in patients with renal insufficiency. The literature has been reviewed and compared to a predictive model of the fraction of drug cleared by the kidney based on the Dettli's principle. Revised drug dosing recommendations integrating these predictive parameters are proposed.

Reference values and factors associated with renal resistive index in a family-based population study.

Increased renal resistive index (RRI) has been recently associated with target organ damage and cardiovascular or renal outcomes in patients with hypertension and diabetes mellitus. However, reference values in the general population and information on familial aggregation are largely lacking. We determined the distribution of RRI, associated factors, and heritability in a population-based study. Families of European ancestry were randomly selected in 3 Swiss cities. Anthropometric parameters and cardiovascular risk factors were assessed. A renal Doppler ultrasound was performed, and RRI was measured in 3 segmental arteries of both kidneys. We used multilevel linear regression analysis to explore the factors associated with RRI, adjusting for center and family relationships. Sex-specific reference values for RRI were generated according to age. Heritability was estimated by variance components using the ASSOC program (SAGE software). Four hundred women (mean age±SD, 44.9±16.7 years) and 326 men (42.1±16.8 years) with normal renal ultrasound had mean RRI of 0.64±0.05 and 0.62±0.05, respectively (P<0.001). In multivariable analyses, RRI was positively associated with female sex, age, systolic blood pressure, and body mass index. We observed an inverse correlation with diastolic blood pressure and heart rate. Age had a nonlinear association with RRI. We found no independent association of RRI with diabetes mellitus, hypertension treatment, smoking, cholesterol levels, or estimated glomerular filtration rate. The adjusted heritability estimate was 42±8% (P<0.001). In a population-based sample with normal renal ultrasound, RRI normal values depend on sex, age, blood pressure, heart rate, and body mass index. The significant heritability of RRI suggests that genes influence this phenotype.

A new technique with high reproducibility to estimate renal oxygenation using BOLD-MRI in chronic kidney disease.

OBJECTIVES: To assess inter-observer variability of renal blood oxygenation level-dependent MRI (BOLD-MRI) using a new method of analysis, called the concentric objects (CO) technique, in comparison with the classical ROI (region of interest)-based technique. METHODS: MR imaging (3T) was performed before and after furosemide in 10 chronic kidney disease (CKD) patients (mean eGFR 43±24ml/min/1.73m(2)) and 10 healthy volunteers (eGFR 101±28ml/min1.73m(2)), and R2* maps were determined on four coronal slices. In the CO-technique, R2* values were based on a semi-automatic procedure that divided each kidney in six equal layers, whereas in the ROI-technique, all circles (ROIs) were placed manually in the cortex and medulla. The mean R2*values as assessed by two independent investigators were compared. RESULTS: With the CO-technique, inter-observer variability was 0.7%-1.9% across all layers in non-CKD, versus 1.6%-3.8% in CKD. With the ROI-technique, median variability for cortical and medullary R2* values was 3.6 and 6.8% in non-CKD, versus 4.7 and 12.5% in CKD; similar results were observed after furosemide. CONCLUSION: The CO-technique offers a new, investigator-independent, highly reproducible alternative to the ROI-based technique to estimate renal tissue oxygenation in CKD.

The ADVANCE trial: clarifying the role of perindopril/indapamide fixed-dose combination in the reduction of cardiovascular and renal events in patients with diabetes mellitus.

Patients with type 2 diabetes mellitus exhibit a marked increase in cardiovascular and renal risk. A number of interventional trials have shown that these patients benefit greatly from aggressive BP lowering, especially when the drug regimen comprises an inhibitor of the renin-angiotensin system. The results of the placebo-controlled ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) trial, conducted in patients with type 2 diabetes, are exemplary in this respect. The systematic use of a fixed-dose combination containing the ACE inhibitor perindopril and the diuretic indapamide afforded substantial protection against cardiovascular mortality and myocardial infarction, while providing important renoprotection, reducing the development of micro- and macroalbuminuria, and allowing regression of nephropathy. The beneficial effects were obtained regardless of baseline BP and whether or not the patients were receiving antihypertensive therapy.

Função hepática e renal de frangos de corte alimentados com dietas com aflatoxinas e clinoptilolita natural

O objetivo deste trabalho foi avaliar os minerais séricos e as funções hepática e renal de frangos de corte, alimentados com dietas com aflatoxinas e dietas com aflatoxinas e argila clinoptilolita natural. Foram utilizados 528 frangos de corte machos, da linhagem Ross, distribuídos em seis tratamentos com quatro repetições cada: T1 - testemunha: ração sem aflatoxina ou clinoptilolita; T2 - ração com 5 ppm de aflatoxinas; T3 - ração com 0,25% de clinoptilolita; T4 - ração com 5 ppm de aflatoxinas e 0,25% de clinoptilolita; T5 - ração com 0,5% de clinoptilolita; e T6 - ração com 5 ppm de aflatoxinas e 0,5% de clinoptilolita. As aves foram submetidas aos tratamentos do 1º ao 42º dia de idade. Foram abatidos 72 animais, e foram analisadas as concentrações séricas de cálcio, fósforo, uréia, creatinina, ácido úrico, colesterol, triglicerídeos e gamaglutamil-transferase (GGT). As aflatoxinas diminuem o nível sérico de colesterol. A clinoptilolita diminui o nível sérico do ácido úrico, quando na concentração de 0,25%. As aflatoxinas com 0,25% de clinoptilolita diminuem os níveis séricos da creatinina, do ácido úrico e do colesterol. As aflatoxinas acrescidas por 0,5% de clinoptilolita diminuem os níveis séricos da creatinina e do colesterol e elevam os de gamaglutamil-transferase.