Transcranial Doppler Pulsatility Index: What it is and What it Isn't.

BACKGROUND: Transcranial Doppler (TCD) pulsatility index (PI) has traditionally been interpreted as a descriptor of distal cerebrovascular resistance (CVR). We sought to evaluate the relationship between PI and CVR in situations, where CVR increases (mild hypocapnia) and decreases (plateau waves of intracranial pressure-ICP). METHODS: Recordings from patients with head-injury undergoing monitoring of arterial blood pressure (ABP), ICP, cerebral perfusion pressure (CPP), and TCD assessed cerebral blood flow velocities (FV) were analyzed. The Gosling pulsatility index (PI) was compared between baseline and ICP plateau waves (n = 20 patients) or short term (30-60 min) hypocapnia (n = 31). In addition, a modeling study was conducted with the "spectral" PI (calculated using fundamental harmonic of FV) resulting in a theoretical formula expressing the dependence of PI on balance of cerebrovascular impedances. RESULTS: PI increased significantly (p < 0.001) while CVR decreased (p < 0.001) during plateau waves. During hypocapnia PI and CVR increased (p < 0.001). The modeling formula explained more than 65% of the variability of Gosling PI and 90% of the variability of the "spectral" PI (R = 0.81 and R = 0.95, respectively). CONCLUSION: TCD pulsatility index can be easily and quickly assessed but is usually misinterpreted as a descriptor of CVR. The mathematical model presents a complex relationship between PI and multiple haemodynamic variables.

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.

Haemodialysis acutely reduces the plasma levels of ADMA without reversing impaired NO-dependent vasodilation.

End-stage renal disease patients have endothelial dysfunction and high plasma levels of ADMA (asymmetric omega-NG,NG-dimethylarginine), an endogenous inhibitor of NOS (NO synthase). The actual link between these abnormalities is controversial. Therefore, in the present study, we investigated whether HD (haemodialysis) has an acute impact on NO-dependent vasodilation and plasma ADMA in these patients. A total of 24 patients undergoing maintenance HD (HD group) and 24 age- and gender-matched healthy controls (Control group) were enrolled. The increase in forearm SkBF (skin blood flow) caused by local heating to 41 degrees C (SkBF41), known to depend on endothelial NO production, was determined with laser Doppler imaging. SkBF41 was expressed as a percentage of the vasodilatory reserve obtained from the maximal SkBF induced by local heating to 43 degrees C (independent of NO). In HD patients, SkBF41 was assessed on two successive HD sessions, once immediately before and once immediately after HD. Plasma ADMA was assayed simultaneously with MS/MS (tandem MS). In the Control group, SkBF41 was determined twice, on two different days, and plasma ADMA was assayed once. In HD patients, SkBF41 was identical before (82.2+/-13.1%) and after (82.7+/-12.4%) HD, but was lower than in controls (day 1, 89.6+/-6.1; day 2, 89.2+/-6.9%; P<0.01 compared with the HD group). In contrast, plasma ADMA was higher before (0.98+/-0.17 micromol/l) than after (0.58+/-0.10 micromol/l; P<0.01) HD. ADMA levels after HD did not differ from those obtained in controls (0.56+/-0.11 micromol/l). These findings show that HD patients have impaired NO-dependent vasodilation in forearm skin, an abnormality not acutely reversed by HD and not explained by ADMA accumulation.

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.

Transcranial Doppler ultrasound in the acute phase of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Angiographic studies suggest that acute vasospasm within 48 h of aneurysmal subarachnoid hemorrhage (SAH) predicts symptomatic vasospasm. However, the value of transcranial Doppler within 48 h of SAH is unknown. METHODS: We analyzed 199 patients who had at least 1 middle cerebral artery (MCA) transcranial Doppler examination within 48 h of SAH onset. Abnormal MCA mean blood flow velocity (mBFV) was defined as >90 cm/s. Delayed cerebral ischemia (DCI) was defined as clinical deterioration or radiological evidence of infarction due to vasospasm. RESULTS: Seventy-six patients (38%) had an elevation of MCA mBFV >90 cm/s within 48 h of SAH onset. The predictors of elevated mBFV included younger age (OR = 0.97 per year of age, p = 0.002), admission angiographic vasospasm (OR = 5.4, p = 0.009) and elevated white blood cell count (OR = 1.1 per 1,000 white blood cells, p = 0.003). Patients with elevated mBFV were more likely to experience a 10 cm/s fall in velocity at the first follow-up than those with normal baseline velocities (24 vs. 10%, p < 0.01), suggestive of resolving spasm. DCI developed in 19% of the patients. An elevated admission mBFV >90 cm/s during the first 48 h (adjusted OR = 2.7, p = 0.007) and a poor clinical grade (Hunt-Hess score 4 or 5, OR = 3.2, p = 0.002) were associated with a significant increase in the risk of DCI. CONCLUSION: Early elevations of mBFV correlate with acute angiographic vasospasm and are associated with a significantly increased risk of DCI. Transcranial Doppler ultrasound may be an early useful tool to identify patients at higher risk to develop DCI after SAH.

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.

Relationships among endogenous ouabain, alpha-adducin polymorphisms and renal sodium handling in primary hypertension.

OBJECTIVE: The basolateral Na pump drives renotubular reabsorption. In cultured renal cells, mutant adducins, as well as sub-nanomolar ouabain concentrations, stimulate the Na-K pump. METHODS: To determine whether these factors interact and affect Na handling and blood pressure (BP) in vivo, we studied 155 untreated hypertensive patients subdivided on the basis of their plasma endogenous ouabain or alpha-adducin genotype (ADD1 Gly460Trp-rs4961). RESULTS: Under basal conditions, proximal tubular reabsorption and plasma Na were higher in patients with mutated Trp ADD1 or increased endogenous ouabain (P = 0.002 and 0.05, respectively). BPs were higher in the high plasma endogenous ouabain group (P = 0.001). Following volume loading, the increment in BP (7.73 vs. 4.81 mmHg) and the slopes of the relationship between BP and Na excretion were greater [0.017 +/- 0.002 vs. 0.009 +/- 0.003 mmHg/(muEq min)] in ADD1 Trp vs. ADD1 Gly carriers (P &lt; 0.05). BP changes were similar, whereas the slopes of the relationship between BP and Na excretion were lower [0.016 +/- 0.003 vs. 0.008 +/- 0.002 mmHg/(muEq min)] in patients with low vs. high endogenous ouabain (P &lt; 0.05). In patients with high endogenous ouabain, volume loading increased the BP in the ADD1 Trp group but not in the Gly group (P &lt; 0.05). Thus, patients with ADD1 Trp alleles are sensitive to salt and tubular Na reabsorption remains elevated after volume expansion. CONCLUSION: With saline loading, BP changes are similar in high and low endogenous ouabain patients, whereas tubular Na reabsorption increases in the high endogenous ouabain group. Saline loading unmasks differences in renal Na handling in patients with mutant adducin or high endogenous ouabain and exposes an interaction of endogenous ouabain and Trp alleles on BP.

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.

The renal hemodynamic effects of Aspirin in newborn and young adult rabbits.

A group of neonatal (n=10) and 12-week-old (n=12) anesthetized, ventilated New Zealand white rabbits received an acute i.v. dose (40 mg/kg body weight) of acetylsalicylic acid (ASA, Aspirin). In the neonatal animals, i.v. ASA caused within 20 min a significant (P<0.01) fall in renal blood flow and glomerular filtration rate (GFR), with an equally significant (P<0.01) increase in filtration fraction and renal vascular resistance. The latter indicates greatly augmented renal vasconstriction or more precisely reduction in intrarenal vasodilatation by inhibition of vasodilatory prostaglandin (PG) synthesis. Urine volume decreased. The 12-week-old young adult animals responded in a similar, but significantly attenuated fashion. These experiments demonstrate that inhibition of PG synthesis in neonatal animals causes very rapid, reversible vasoconstriction, with a reduction in GFR. In addition, this study confirms previous observations that the renal hemodynamic response to the inhibition of PG synthesis is far more pronounced in neonatal animals than in (young) adult rabbits.