Sex differences in renal hemodynamics and renin-angiotensin system activity post-CPAP therapy in humans with obstructive sleep apnea.

Men have faster loss of kidney function and greater renal renin-angiotensin system (RAS) activity compared with women. Obstructive sleep apnea (OSA) is common in chronic kidney disease; the vascular effects of OSA differ by sex, and OSA-associated glomerular hyperfiltration can be reversed by continuous positive airway pressure (CPAP) therapy. We evaluated sex differences in the effect of CPAP on renal hemodynamics and the renal RAS in OSA. Twenty-nine Na+-replete, otherwise healthy study participants with OSA (10 women and 19 men) with nocturnal hypoxemia were studied pre- and post-CPAP (>4 h/night for 4 wk). Renal hemodynamics [renal plasma flow (RPF), glomerular filtration rate (GFR), and filtration fraction(FF)] were measured at baseline and in response to ANG II challenge, as a marker of renal RAS activity, pre- and post-CPAP therapy for 1 mo. In women, CPAP was associated with increased RPF (626 ± 22 vs. 718 ± 43 mL/min, P = 0.007, pre- vs. post-CPAP), maintained GFR (108 ± 2 vs. 105 ± 3 mL/min, P = 0.8), and reduced FF (17.4 ± 0.8% vs. 15.0 ± 0.7%, P = 0.017). In men, CPAP was associated with maintained RPF (710 ± 37 vs. 756 ± 38 mL/min, P = 0.1), maintained GFR (124 ± 8 vs. 113 ± 6 mL/min, P = 0.055), and reduced FF (18.6 ± 1.7% vs. 15.5 ± 1.1%, P = 0.035). Pre-CPAP, there were no sex differences in renal hemodynamic responses to ANG II. CPAP use was associated with a greater renovasoconstrictive response to ANG II in women (RPF at Δ30 min: -100 ± 27 vs. -161 ± 25 mL/min, P = 0.007, and RPF at Δ60 min: -138 ± 27 vs. -206 ± 32 mL/min, P = 0.007) but not men. CPAP use was associated with improved renal hemodynamics in both sexes and downregulated renal RAS activity in women but not men.

Extracellular Fluid Volume Expansion Uncovers a Natriuretic Action of GLP-1: A Functional GLP-1-Renal Axis in Man.

PURPOSE: We have previously demonstrated that glucagon-like peptide-1 (GLP-1) does not affect renal hemodynamics or function under baseline conditions in healthy participants and in patients with type 2 diabetes mellitus. However, it is possible that GLP-1 promotes natriuresis under conditions with addition of salt and water to the extracellular fluid. The current study was designed to investigate a possible GLP-1-renal axis, inducing natriuresis in healthy, volume-loaded participants. METHODS: Under fixed sodium intake, eight healthy men were examined twice in random order during a 3-hour infusion of either GLP-1 (1.5 pmol/kg/min) or vehicle together with an intravenous infusion of 0.9% NaCl. Timed urine collections were conducted throughout the experiments. Renal plasma flow (RPF), glomerular filtration rate (GFR), and uptake and release of hormones and ions were measured via Fick's principle. RESULTS: During GLP-1 infusion, urinary sodium and osmolar excretions increased significantly compared with vehicle. Plasma renin levels decreased similarly on both days, whereas angiotensin II (ANG II) levels decreased significantly only during GLP-1 infusion. RPF and GFR remained unchanged on both days. CONCLUSIONS: In volume-loaded participants, GLP-1 induces natriuresis, probably brought about via a tubular mechanism secondary to suppression of ANG II, independent of renal hemodynamics, supporting the existence of a GLP-1-renal axis.

Enfermedad renal en pacientes gestantes / Kidney disease in pregnant patients

No disponible

Concerted regulation of renal plasma flow and glomerular filtration rate by renal dopamine and NOS I in rats on high salt intake.

Under high sodium intake renal dopamine (DA) increases while NOS I expression in macula densa cells (MD) decreases. To explore whether renal DA and NOS I, linked to natriuresis and to the stability of the tubuloglomerular feedback, respectively, act in concert to regulate renal plasma flow (RPF) and glomerular filtration rate (GFR). Male Wistar rats were studied under a normal sodium intake (NS, NaCl 0.24%) or a high sodium intake (HS, NaCl 1% in drinking water) during the 5 days of the study. For the last two days, the specific D1-like receptor antagonist SCH 23390 (1 mg kg bwt-1 day-1, sc) or a vehicle was administered. HS intake increased natriuresis, diuresis, and urinary DA while it decreased cortical NOS I expression (P < 0.05 vs. NS), Nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity in MD (P < 0.001 vs. NS) and cortical nitrates+nitrites (NOx) production (NS 2.04 ± 0.22 vs. HS 1.28 ± 0.10 nmol mg protein-1, P < 0.01). Treatment with SCH 23390 to rats on HS sharply decreased hydroelectrolyte excretion (P < 0.001 vs. HS) while NOS I expression, NADPH-d activity and NOx production increased (P < 0.05 vs. HS for NOS I and P < 0.001 vs. HS for NADPH-d and NOx). SCH 23390 increased RPF and GFR in HS rats (P < 0.01 HS+SCH vs. HS). It did not cause variations in NS rats. Results indicate that when NS intake is shifted to a prolonged high sodium intake, renal DA through the D1R, and NOS I in MD cells act in concert to regulate RPF and GFR to stabilize the delivery of NaCl to the distal nephron.

The enigma of continual plasma volume expansion in pregnancy: critical role of the renin-angiotensin-aldosterone system.

Pregnancy is characterized by avid renal sodium retention and plasma volume expansion in the presence of decreased blood pressure. Decreased maternal blood pressure is a consequence of reduced systemic vascular tone, which results from an increased production of vasodilators [nitric oxide (NO), prostaglandins, and relaxin] and decreased vascular responsiveness to the potent vasoconstrictor (angiotensin II). The kidneys participate in this vasodilatory response, resulting in marked increases in renal plasma flow and glomerular filtration rate (GFR) during pregnancy. In women, sodium retention drives plasma volume expansion (∼40%) and is necessary for perfusion of the growing uterus and fetus. For there to be avid sodium retention in the presence of the potent natriuretic influences of increased NO and elevated GFR, there must be modifications of the tubules to prevent salt wasting. The purpose of this review is to summarize these adaptations.

Evaluation of functional outcomes after laparoscopic partial nephrectomy using renal scintigraphy: clamped vs clampless technique.

OBJECTIVES: To examine differences in postoperative renal functional outcomes when comparing clampless with conventional laparoscopic partial nephrectomy (LPN) by using renal scintigraphy, and to identify the predictors of poorer postoperative renal functional outcomes after clampless LPN. PATIENTS AND METHODS: Between September 2010 and September 2012, 87 patients with renal masses suitable for LPN were prospectively enrolled in the study. From September 2010 to September 2011, LPN with renal artery clamping was performed and from September 2011 to September 2012 clampless LPN (no clamping of renal artery) was performed. Patients who underwent clampless LPN were unselected and consecutive, and the procedure was performed at the end of surgeon's learning curve. Patients were divided into two groups according to warm ischaemia time (WIT): group A, conventional LPN and group B, clampless-LPN (WIT = 0 min). Demographic and peri-operative data were collected and analysed and functional outcomes were evaluated using biochemical markers and renal scintigraphy at baseline and at 3 months after surgery. The percentage loss of renal function, evaluated according to renal scintigraphy, was calculated. Chi-squared and Student's t-tests were carried out and regression analysis was performed. RESULTS: Group A was found to be similar to group B in all variables measured except for WIT and blood loss (P < 0.001). The percentage reduction in renal scintigraphy values was not significantly different between the groups (reductions of 5% in group A and 6% in group B for split renal function [SRF] and 12% in group A and 17% in group B for estimated renal plasmatic flow [ERPF]; P = 0.587 and P = 0.083, respectively). Multivariate analysis in group B showed that the lower the baseline values of SRF and ERPF, the poorer the postoperative functional outcome of the treated kidney. CONCLUSIONS: In our experience, even clampless LPN was not found to be functionally harmless. The patients who benefitted most from a clampless approach were those with the poorest baseline renal function.

A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements.

BACKGROUND: Renal hemodynamic measurements are complicated to perform in patients with cirrhosis, yet they provide the best measure of risk to predict hepatorenal syndrome (HRS). Currently, there are no established biomarkers of altered renal hemodynamics in cirrhosis validated by measured renal hemodynamics. METHODS: In this pilot study, simultaneous measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), renal resistive indices and biomarkers were performed to evaluate renal hemodynamic alterations in 10 patients with cirrhosis (3 patients without ascites, 5 with diuretic-sensitive and 2 diuretic-refractory ascites). RESULTS: Patients with diuretic-refractory ascites had the lowest mean GFR (36.5 ml/min/1.73 m(2)) and RPF (133.6 ml/min/1.73 m(2)) when compared to those without ascites (GFR 82.9 ml/min/1.73 m(2), RPF 229.9 ml/min/1.73 m(2)) and with diuretic-sensitive ascites (GFR 82.3 ml/min/1.73 m(2), RPF 344.1 ml/min/1.73 m(2)). A higher mean filtration fraction (FF) (GFR/RPF 0.36) was noted among those without ascites compared to those with ascites. Higher FF in patients without ascites is most likely secondary to the vasoconstriction in the efferent glomerular arterioles (normal FF ~0.20). In general, renal resistive indices were inversely related to FF. While patients with ascites had lower FF and higher right kidney main and arcuate artery resistive indices, those without ascites had higher FF and lower right kidney main and arcuate artery resistive indices. While cystatin C and ß2-microglobulin performed better compared to Cr in estimating RPF, ß-trace protein, ß2-microglobulin, and SDMA, and (SDMA+ADMA) performed better in estimating right kidney arcuate artery resistive index. CONCLUSION: The results of this pilot study showed that identification of non-invasive biomarkers of reduced RPF and increased renal resistive indices can identify cirrhotics at risk for HRS at a stage more amenable to therapeutic intervention and reduce mortality from kidney failure in cirrhosis.

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

During the first trimester of human pregnancy, the maternal systemic circulation undergoes remarkable vasodilation. The kidneys participate in this vasodilatory response resulting in marked increases in renal plasma flow (RPF) and glomerular filtration rate (GFR). Comparable circulatory adaptations are observed in conscious gravid rats. Administration of the corpus luteal hormone relaxin (RLN) to nonpregnant rats and humans elicits vasodilatory changes like those of pregnancy. Systemic and renal vasodilation are compromised in midterm pregnant rats by neutralization or elimination of circulating RLN and in women conceiving with donor eggs who lack a corpus luteum and circulating RLN. Although RLN exerts both rapid (minutes) and sustained (hours to days) vasodilatory actions through different molecular mechanisms, a final common pathway is endothelial nitric oxide. In preeclampsia (PE), maternal systemic and renal vasoconstriction leads to hypertension and modest reduction in GFR exceeding that of RPF. Elevated level of circulating soluble vascular endothelial growth factor receptor-1 arising from the placenta is implicated in the hypertension and disruption of glomerular fenestrae and barrier function, the former causing reduced Kf and the latter proteinuria. Additional pathogenic factors are discussed. Last, potential clinical ramifications include RLN replacement in women conceiving with donor eggs and its therapeutic use in PE. Another goal has been to apply knowledge gained from investigating circulatory adaptations in pregnancy toward identifying and developing novel therapeutic strategies for renal and cardiovascular disease in the nonpregnant population. So far, one candidate to emerge is RLN and its potential therapeutic use in heart failure.

Aldosterone dysregulation with aging predicts renal vascular function and cardiovascular risk.

Aging and abnormal aldosterone regulation are both associated with vascular disease. We hypothesized that aldosterone dysregulation influences the age-related risk of renal vascular and cardiovascular disease. We conducted an analysis of 562 subjects who underwent detailed investigations under conditions of liberal and restricted dietary sodium intake (1124 visits) in the General Clinical Research Center. Aldosterone regulation was characterized by the ratio of maximal suppression to stimulation (supine serum aldosterone on a liberal sodium diet divided by the same measure on a restricted sodium diet). We previously demonstrated that higher levels of this Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI) indicate greater aldosterone dysregulation. Renal plasma flow (RPF) was determined via p-aminohippurate clearance to assess basal renal hemodynamics and the renal vascular responses to dietary sodium manipulation and angiotensin II infusion. Cardiovascular risk was calculated using the Framingham Risk Score. In univariate linear regression, older age (ß=-4.60; P<0.0001) and higher SASSI (ß=-58.63; P=0.001) predicted lower RPF and a blunted RPF response to sodium loading and angiotensin II infusion. We observed a continuous, independent, multivariate-adjusted interaction between age and SASSI, where the inverse relationship between SASSI and RPF was most apparent with older age (P<0.05). Higher SASSI and lower RPF independently predicted higher Framingham Risk Score (P<0.0001) and together displayed an additive effect. Aldosterone regulation and age may interact to mediate renal vascular disease. Our findings suggest that the combination of aldosterone dysregulation and renal vascular dysfunction could additively increase the risk of future cardiovascular outcomes; therefore, aldosterone dysregulation may represent a modifiable mechanism of age-related vascular disease.

Simultaneous determination of renal plasma flow and glomerular filtration rate in conscious mice using dual bolus injection.

INTRODUCTION: The present report describes and evaluates a simple protocol for serial measurements of glomerular filtration rate (GFR) and renal plasma flow (RPF) in conscious mice. METHODS: In conscious mice, a bolus of [(3)H]methoxy-inulin and [(14)C]para-amino-hippuric (PAH) was injected in the tail vein whereupon eight blood samples were taken during the following 75min. Plasma concentrations were determined by liquid scintillation and clearances of the injected markers were calculated by non-compartmental pharmacokinetic data analysis of the plasma disappearance curves. In anaesthetized mice, the renal extraction ratio of PAH was determined by infusion of PAH and subsequent analysis of blood taken from the carotid artery and the renal vein. The acquired value (0.70±0.02) was used for all subsequent calculations of RPF. To evaluate the protocol, a crossover study was performed where either the vehicle or the angiotensin II AT1 receptor antagonist candesartan was given prior to the clearance measurements. RESULTS: Baseline values of GFR and RPF were in line with those earlier reported in mice. Administration of candesartan increased RPF and reduced the filtration fraction, whereas GFR was unaltered. These changes are supported by earlier findings and demonstrate that GFR and RPF can be determined independently. Furthermore, modelling experiments demonstrated that acceptable results are obtained even if the number of blood samples is reduced to four which is a way to further simplify the procedure. DISCUSSION: The method provides an effective way for repeated measurements of GFR and RPF in mice without potentially confounding effects of anaesthesia.

Restoration of renal function by a novel prostaglandin EP4 receptor-derived peptide in models of acute renal failure.

Acute renal failure (ARF) is a serious medical complication characterized by an abrupt and sustained decline in renal function. Despite significant advances in supportive care, there is currently no effective treatment to restore renal function. PGE(2) is a lipid hormone mediator abundantly produced in the kidney, where it acts locally to regulate renal function; several studies suggest that modulating EP(4) receptor activity could improve renal function following kidney injury. An optimized peptidomimetic ligand of EP(4) receptor, THG213.29, was tested for its efficacy to improve renal function (glomerular filtration rate, renal plasma flow, and urine output) and histological changes in a model of ARF induced by either cisplatin or renal artery occlusion in Sprague-Dawley rats. THG213.29 modulated PGE(2)-binding dissociation kinetics, indicative of an allosteric binding mode. Consistently, THG213.29 antagonized EP(4)-mediated relaxation of piglet saphenous vein rings, partially inhibited EP(4)-mediated cAMP production, but did not affect Gα(i) activation or ß-arrestin recruitment. In vivo, THG213.29 significantly improved renal function and histological changes in cisplatin- and renal artery occlusion-induced ARF models. THG213.29 increased mRNA expression of heme-oxygenase 1, Bcl2, and FGF-2 in renal cortex; correspondingly, in EP(4)-transfected HEK293 cells, THG213.29 augmented FGF-2 and abrogated EP(4)-dependent overexpression of inflammatory IL-6 and of apoptotic death domain-associated protein and BCL2-associated agonist of cell death. Our results demonstrate that THG213.29 represents a novel class of diuretic agent with noncompetitive allosteric modulator effects on EP(4) receptor, resulting in improved renal function and integrity following acute renal failure.

Vitamin D3 therapy corrects the tissue sensitivity to angiotensin ii akin to the action of a converting enzyme inhibitor in obese hypertensives: an interventional study.

CONTEXT: Vitamin D deficiency and obesity are associated with increased tissue renin-angiotensin system (RAS) activity. OBJECTIVE: The objective of the study was to evaluate whether vitamin D(3) therapy in obesity reduces tissue-RAS activity, as indicated by an increase in tissue sensitivity to angiotensin II (AngII). PARTICIPANTS: Participants included obese subjects with hypertension and 25-hydroxyvitamin D less than 25 ng/ml. DESIGN: Subjects were studied before and after 1 month of vitamin D(3) 15,000 IU/d, while in dietary sodium balance, and off all interfering medications. Fourteen subjects successfully completed all study procedures. SETTING: The study was conducted at a clinical research center. OUTCOME MEASURES: At each study visit, tissue sensitivity to AngII was assessed by measuring renal plasma flow (RPF), mean arterial pressure (MAP), and adrenal secretion of aldosterone during an infusion of AngII. Subjects were then given captopril, and a second AngII infusion to evaluate the effect of captopril on tissue-RAS activity. RESULTS: Vitamin D(3) therapy increased 25-hydroxyvitamin D (18 to 52 ng/ml) and basal RPF (+5%) and lowered supine MAP (-3%) (all P < 0.01). There was a greater decline in RPF and higher stimulation of aldosterone with AngII infusion after vitamin D(3) therapy (both P < 0.05). As anticipated, captopril increased the renal-vascular, MAP, and adrenal sensitivity to AngII, but this effect was much smaller after vitamin D(3) therapy, indicating that vitamin D(3) therapy corrected the tissue sensitivity to AngII akin to captopril. CONCLUSIONS: Vitamin D(3) therapy in obese hypertensives modified RPF, MAP, and tissue sensitivity to AngII similar to converting enzyme inhibition. Whether chronic vitamin D(3) therapy abrogates the development of diseases associated with excess RAS activity warrants investigation.

Exaggerated natriuresis during clamping of systemic NO supply in healthy young men.

NO (nitric oxide) may be involved in fluid homoeostasis. We hypothesized that increases in NO synthesis contribute to acute, saline-induced natriuresis, which, therefore, should be blunted when NO availability is stabilized. Young men were studied during simultaneous infusions of L-NAME [NG-nitro-L-arginine methyl ester; bolus of 750 µg·kg⁻¹ of body weight and 8.3 µg·min⁻¹·kg⁻¹ of body weight] and SNP (sodium nitroprusside), the latter at a rate preventing L-NAME from increasing total peripheral resistance ('NO-clamping'). Slow volume expansion (saline, 20 µmol of NaCl·min⁻¹·kg⁻¹ of body weight for 3 h) was performed with and without concomitant NO-clamping. NO-clamping itself decreased RPF (renal plasma flow; P~0.02) and tended to decrease arterial blood pressure [MABP (mean arterial blood pressure)]. Volume expansion markedly decreased the plasma levels of renin, AngII (angiotensin II) and aldosterone (all P<0.001), while MABP (oscillometry), heart rate, cardiac output (impedance cardiography), RPF (by p-aminohippurate), GFR [glomerular filtration rate; by using 51Cr-labelled EDTA] and plasma [Na+] and [K+] remained constant. Volume expansion increased sodium excretion (P<0.02) at constant filtered load, but more so during NO-clamping than during control (+184% compared with 52%; P<0.0001). Urinary nitrate/nitrite excretion increased during volume expansion; plasma cGMP and plasma vasopressin were unchanged. The results demonstrate that NO-clamping augments sodium excretion in response to volume expansion at constant MABP and GFR, reduced RPF and decreased renin system activity, a response termed hypernatriuresis. The results indicate that mediator(s) other than MABP, RPF, GFR and renin system activity contribute significantly to the homoeostatic response to saline loading, but the specific mechanisms of hypernatriuresis remain obscure.

Renal resistive index--a valid tool to assess renal endothelial function in humans?

BACKGROUND: In humans, renal endothelial function is assessed by the vasoconstrictive response to L-NG-monomethyl arginine (L-NMMA). We hypothesized that Doppler sonographic measurements of the renal resistive index in response to inhibition of nitric oxide synthase offer a new methodological approach for testing renal endothelial function. METHODS: Forty-one patients without nephropathy were included. Para-aminohippurate and inulin clearance were performed under basal conditions and during L-NMMA infusion. In parallel, renal resistive index was assessed by Doppler sonography, and central blood pressure was determined. RESULTS: Following nitric oxide synthase inhibition, renal resistive index increased significantly, and 29% of our patients developed Doppler sonographic diastolic zero flow. Renal plasma flow decreased in response to L-NMMA, and conversely, renal vascular resistance increased. There was no correlation of renal vascular resistance and renal resistive index at baseline and during nitric oxide synthase inhibition. Changes in renal resistive index were not related to changes in renal perfusion or renal vascular resistance. Renal resistive index correlated with central pulse pressure at baseline and during L-NMMA infusion, whereas renal vascular resistance did not correlate with central pulse pressure. CONCLUSION: Our data do not support the hypothesis that renal resistive index is a tool to test renal endothelial function in humans and should not be used interchangeably with renal vascular resistance.

Effects of tetrahydrobiopterin on nitric oxide bioavailability and renal hemodynamics in healthy volunteers.

BACKGROUND: The endothelial nitric oxide (NO) system plays a central role in regulating vascular tone. Endothelial dysfunction has been closely linked to reduced activity in the NO system. Tetrahydrobiopterin (BH4) is an essential cofactor of all NO synthase isoforms. METHODS: We examined the effects of BH4 on the NO system assessed by measurement of serum cGMP levels and NO breakdown products (NOx) in 12 healthy volunteers. RESULTS: Application of a total of 19 mg/kg BH4 intravenously (i.v.) over 3 hours led to a dose-dependent increase in serum cGMP concentrations from a median 3.3 nM (interquartile range [IQR] 1.1-5.6) to 5.7 nM (IQR 2.4-13.3, p=0.008) and NOx from a median 49.3 microM (IQR 39.8-56.6) to 59.7 microM (39.6-85.5) (p=0.058). Systemic and renal hemodynamics measured by inulin and p-aminohippuric acid (PAH) clearance remained unchanged. Plasma renin activity was significantly increased (2.0 [IQR 1.0-2.8] to 2.3 ng AngI/mL per hour [IQR 1.7-4.0], p=0.045), whereas aldosterone, erythropoietin and B-type natriuretic peptide levels did not change. In a second study, oral BH4 given over 3 days (800 mg/day) similarly increased serum cGMP and ameliorated the depressive effects of the NO synthase inhibitor L-NAME (1.5 mg/kg i.v.) on the glomerular filtration rate. CONCLUSIONS: Application of BH4 in high doses is safe and enhances formation of cGMP, pointing to increased bioavailability of NO.

Treatment with pyrrolidine dithiocarbamate improves proteinuria, oxidative stress, and glomerular hypertension in overload proteinuria.

We evaluated whether the blockade of the proinflammatory transcription factor NF-kappaB would modify the oxidative stress, inflammation, and structural and hemodynamic alterations found in the kidney as a result of massive proteinuria. Twenty male Sprague-Dawley rats were injected with 2 g of BSA intraperitoneally daily for 2 wk. Ten of them received in addition the inhibitor of NF-kappaB activation pyrrolidine dithiocarbamate (PDTC; 200 mg.kg(-1).day(-1) sc) and the rest received vehicle. Seven rats that received intraperitoneal saline were used as controls. Glomerular hemodynamics were studied after 14 days. Markers of oxidative stress (NF-kappaB subunit p65+ cells, 3-nitrotyrosine, and 4-hydroxynonenal), inflammation (cortical CD68+ cells and NOS-II), and afferent arteriole damage were assessed by immunohistochemistry and morphometry. Activity of antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase was evaluated in renal cortex and medulla. Albumin overload induced massive proteinuria, oxidative stress with reduced activity of antioxidant enzymes, NF-kappaB activation, inflammatory cell infiltration, a significant presence of proteinaceous casts, systemic and glomerular hypertension, as well as arteriolar remodeling. Treatment with PDTC prevented or improved all of these findings. In this model of nephrotic syndrome, we demonstrate a key role for oxidative stress and inflammation in causing systemic and glomerular hypertension and proteinuria. Oxidative stress and inflammation may have a key role in accelerating renal injury associated with intense proteinuria.

Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans.

BACKGROUND: Pharmacological interruption of the renin-angiotensin system focuses on optimization of blockade. As a measure of intrarenal renin activity, we have examined renal plasma flow (RPF) responses in a standardized protocol. Compared with responses with angiotensin-converting enzyme inhibition (rise in RPF approximately 95 mL x min(-1) x 1.73 m(-2)), greater renal vasodilation with angiotensin receptor blockers (approximately 145 mL x min(-1) x 1.73 m(-2)) suggested more effective blockade. We predicted that blockade with the direct oral renin inhibitor aliskiren would produce renal vascular responses exceeding those induced by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. METHODS AND RESULTS: Twenty healthy normotensive subjects were studied on a low-sodium (10 mmol/d) diet, receiving separate escalating doses of aliskiren. Six additional subjects received captopril 25 mg as a low-sodium comparison and also received aliskiren on a high-sodium (200 mmol/d) diet. RPF was measured by clearance of para-aminohippurate. Aliskiren induced a remarkable dose-related renal vasodilation in low-sodium balance. The RPF response was maximal at the 600-mg dose (197+/-27 mL x min(-1) x 1.73 m(-2)) and exceeded responses to captopril (92+/-20 mL x min(-1) x 1.73 m(-2); P<0.01). Furthermore, significant residual vasodilation was observed 48 hours after each dose (P<0.01). The RPF response on a high-sodium diet was also higher than expected (47+/-17 mL x min(-1) x 1.73 m(-2)). Plasma renin activity and angiotensin levels were reduced in a dose-related manner. As another functional index of the effect of aliskiren, we found significant natriuresis on both diets. CONCLUSIONS: Renal vasodilation in healthy people with the potent renin inhibitor aliskiren exceeded responses seen previously with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The effects were longer lasting and were associated with significant natriuresis. These results indicate that aliskiren may provide more complete and thus more effective blockade of the renin-angiotensin system.

Independent assessment of a wide-focus, low-pressure electromagnetic lithotripter: absence of renal bioeffects in the pig.

OBJECTIVE: To assess the renal injury response in a pig model treated with a clinical dose of shock waves (SWs) delivered at a slow rate (27 SW/min) using a novel wide focal zone (18 mm), low acoustic pressure (<20 MPa) electromagnetic lithotripter (Xi Xin-Eisenmenger, XX-ES; Xi Xin Medical Instruments Co. Ltd., Suzhou, PRC). MATERIALS AND METHODS: The left kidneys of anaesthetized female pigs were treated with 1500 SWs from either an unmodified electrohydraulic lithotripter (HM3, Dornier MedTech America, Inc., Kennesaw, GA, USA; 18 kV, 30 SW/min) or the XX-ES (9.3 kV, 27 SW/min). Measures of renal function (glomerular filtration rate, GFR, and renal plasma flow) were collected before and after SW lithotripsy, and kidneys were harvested for histological quantification of vascular haemorrhage, expressed as a percentage of the functional renal volume (FRV). A fibre-optic probe hydrophone was used to characterize the acoustic field, and the breakage of gypsum model stones was used to compare the function of the two lithotripters. RESULTS: Kidneys treated with the XX-ES showed no significant change in renal haemodynamic function and no detectable tissue injury. Pigs treated with the HM3 had a modest decline from baseline ( approximately 20%) in both GFR (P > 0.05) and renal plasma flow (P = 0.064) in the treated kidney, but that was not significantly different from the control group. Although most HM3-treated pigs showed no evidence of renal tissue injury, two had focal injury measuring 0.1% FRV, localized to the renal papillae. The width of the focal zone for the XX-ES was approximately 18 mm and that of the HM3 approximately 8 mm. Peak positive pressures at settings used to treat pigs and break model stones were considerably lower for the XX-ES (17 MPa at 9.3 kV) than for the HM3 (37 MPa at 18 kV). The XX-ES required fewer SWs to break stones to completion than did the HM3, with a mean (sd) of 634 (42) and 831 (43) SWs, respectively (P < 0.01). However, conditions were different for these tests because of differences in physical configuration of the two machines. CONCLUSION: The absence of renal injury with the wide focal zone XX-ES lithotripter operated at low shock pressure and a slow SW rate suggests that this lithotripter would be safe when used at the settings recommended for patient treatment. That the injury was also minimal using the Dornier HM3 lithotripter at a slow SW rate implies that the reduced tissue injury seen with these two machines was because they were operated at a slow SW rate. As recent studies have shown stone breakage to be improved when the focal zone is wider than the stone, a wide focal zone lithotripter operated at low pressure and slow rate has the features necessary to provide better stone breakage with less tissue injury.

The effect of KW-3902, an adenosine A1 receptor antagonist, on renal function and renal plasma flow in ambulatory patients with heart failure and renal impairment.

BACKGROUND: The kidney is the only organ in which adenosine is a paracrine vasoconstrictor. This raises the possibility of using adenosine A1 receptor (AA1R) antagonists to selectively vasodilate the kidney in conditions, such as congestive heart failure, in which a selective decrease in renal vascular resistance would be salutary. The present study was undertaken to test the effectiveness of an AA1R antagonist as a renal vasodilator in patients with reduced kidney function superimposed on congestive heart failure. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled, two-way crossover study was conducted in 32 outpatients with congestive heart failure and renal impairment (median glomerular filtration rate [GFR] 50 mL/min). Baseline GFR and renal plasma flow were assessed by iothalamate and para-amino-hippurate clearances, respectively, 3 hours before treatment. Subjects then received furosemide administered intravenously along with the AA1R antagonist, KW-3902 (rolofylline), or placebo. Clearance measurements were repeated, at intervals, throughout 8 hours beginning with the administration of the study drug. After a washout period of 3 to 8 days, subjects returned to undergo the crossover portion of the study. After the patients received KW-3902, GFR increased by 32% (P < .05 vs. placebo) and renal plasma flow increased by 48% (P < .005 vs. placebo) averaged over the ensuing 8 hours. Furthermore, those subjects who initially received KW-3902 returned for the crossover phase (median 6 days) with a persistent 10 mL/min increase in GFR more than their previous baseline (P < .05). CONCLUSIONS: AA1R activity contributes substantially to renal vascular tone in ambulatory patients with chronic congestive heart failure and impaired kidney function. Blockade of these receptors vasodilates the kidney and increases GFR. The increase in GFR seems to persist several days longer than predicted by pharmacokinetics, suggesting a resetting of one or more controllers among the complex network of physical and biological processes that interact to determine the kidney function. There may be short- or long-term benefits of using AA1R antagonists to improve kidney function in patients with congestive heart failure.

Diet therapy in diabetic nephropathy.

Although protein restriction has been suggested as a mainstay of therapy for patients with diabetic nephropathy, controversy exists regarding the exact dietary prescription and stage of disease for implementation. This chapter reviews the pathophysiology and stages of diabetic nephropathy, clinical studies of dietary therapy in diabetic nephropathy, and provides a framework for using diet in the treatment of diabetic renal disease.