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Introduction and Aims: Hyperkalaemia is a risk factor for mortality in patients with cardiovascular disease and chronic kidney disease (CKD) (Goyal, 2012; Torlen, 2012) and limits use of renin-angiotensin-aldosterone system inhibitors (RAASi) in these patients. Sodium (or calcium) polystyrene sulfonate (SPS/CPS) has uncertain efficacy and has been associated with substantial adverse events, as well as poor gastrointestinal tolerability, and hence is suboptimal for acute use and unsuitable for chronic use (Harel, 2013; Sterns, 2010). Therefore, there is a need for a hyperkalaemia treatment that rapidly reduces serum potassium (K+) and is safe and well tolerated in these patients. ZS-9, a nonabsorbed cation exchanger designed to specifically entrap excess K +, significantly reduced K+ vs placebo over 48 hr with excellent tolerability in patients with CKD (Ash, 2013). We report acute-phase efficacy in a Phase 3 trial of ZS-9 in patients with hyperkalemia. Methods: Patients (N=753) with serum K+ 5.0-6.5 mmol/L were randomised (1:1:1:1:1) to ZS-9 (1.25g, 2.5g, 5g or 10g) or placebo given three times daily (TID) with meals for 48 hr (acute phase), after which those with K+ ≤4.9 mmol/L (n=542) were re-randomised to ZS-9 or placebo once daily for Day 3-15. Serum K+ was measured at baseline and at predefined intervals, including 1, 4, 24, and 48 hr after the first dose. The acute-phase primary efficacy endpoint was the rate of K+ change over the first 48 hr, using longitudinal modeling to account for all post-baseline data. Results:Mean K+ at baseline was 5.3 mmol/L. Substantial percentages of patients had CKD (60%), a history of heart failure (40%), or diabetes (60%) or were on RAASi therapy (67%). ZS-9 demonstrated significant dose-dependent reductions in K+; the acute-phase primary efficacy endpoint was met for ZS-9 2.5g (p=0.0009), 5g (p

The aim of this study was to refine the description of the renal function based on MR images and through transit-time curve analysis on a normal population and on a population with renal failure, using the quantitative model of the up-slope. Thirty patients referred for a kidney MR exam were divided in a first population with well-functioning kidneys and in a second population with renal failure from ischaemic kidney disease. The perfusion sequence consisted of an intravenous injection of Gd-DTPA and of a fast GRE sequence T1-TFE with 90 degrees magnetisation preparation (Intera 1.5 T MR System, Philips Medical System). To convert the signal intensity into 1/T1, which is proportional to the contrast media concentration, a flow-corrected calibration procedure was used. Following segmentation of regions of interest in the cortex and medulla of the kidney and in the abdominal aorta, outflow curves were obtained and filtered to remove the high frequency fluctuations. The model of the up-slope method was then applied. Significant reduction of the cortical perfusion (Qc = 0.057+/-0.030 ml/(s 100 g) to Qc = 0.030 +/- 0.017 ml/(s 100 g), P0.013) of the medullary perfusion (Qm = 0.023 +/- 0.018 ml/(s 100 g) to Qm = 0.011 +/- 0.006 ml/(s 100 g), P0.046) and of the accumulation of contrast media in the medulla (Qa = 0.005 +/- 0.003 ml/(s 100 g) to Qa = 0.0009 +/- 0.0008 ml/(s 100 g), P0.001) were found in presence of renal failure. High correlations were found between the creatinine level and the accumulation Qa in the medulla (r2 = 0.72, P0.05), and between the perfusion ratio Qc/Qm and the accumulation Qa in the medulla (r2 = 0.81, P0.05). No significant difference was found in times to peak between both populations despite a trend showing Ta the time to the end of the increasing contrast accumulation period in the medulla, arriving later for renal failure. Advances in MR signal calibration with the building of quantitative model such as the up-slope allow to assess kinetic and haemodynamic and functional parameters of the diseased kidney.

C-peptide, the cleavage product of proinsulin processing exerts physiological effects including stimulation of Na(+),K(+)-ATPase in erythrocytes and renal proximal tubules. This study was undertaken to assess the physiological effects of connecting peptide on Na(+),K(+)-ATPase activity in the medullary thick ascending limb of Henle's loop.Na(+),K(+)-ATPase activity was measured as the ouabain-sensitive generation of (32)Pi from gamma[(32)P]-ATP and (86)Rb uptake on isolated rat medullary thick ascending limbs. The cell-surface expression of Na(+),K(+)-ATPase was evaluated by Western blotting of biotinylated proteins, and its phosphorylation amount was measured by autoradiography. The membrane-associated fraction of protein kinase C isoforms was evaluated by Western blotting.Rat connecting peptide concentration-dependently stimulated Na(+),K(+)-ATPase activity with a threshold at 10(-9) mol/l and a maximal effect at 10(-7) mol/l. C-peptide (10(-7) mol/l) already stimulates Na(+),K(+)-ATPase activity after 5 min with a plateau from 15 to 60 min. C-peptide (10(-7) mol/l) stimulated Na(+),K(+)-ATPase activity and (86)Rb uptake to the same extent, but did not alter Na(+),K(+)-ATPase cell surface expression. The stimulation of Na(+),K(+)-ATPase activity was associated with an increase in Na(+),K(+)-ATPase alpha-subunit phosphorylation and both effects were abolished by a specific protein kinase C inhibitor. Furthermore, connecting peptide induced selective membrane translocation of PKC-alpha.This study provides evidence that in rat medullary thick ascending limb, C-peptide stimulates Na(+),K(+)-ATPase activity within a physiological concentration range. This effect is due to an increase in Na(+),K(+)-ATPase turnover rate that is most likely mediated by protein kinase C-alpha phosphorylation of the Na(+),K(+)-ATPase alpha-subunit, suggesting that C-peptide could control Na(+) reabsorption during non-fasting periods.

Les AINS representent environ 5% de la prescription medicale, a laquelle s’ajoute une large utilisation sans ordonnance. Leur usage clinique est limite par leur toxicite digestive, cardio-vasculaire, renale et plaquettaire. La mise en evidence de 2 isoenzymes de la cyclooxygenase suggere que le lien entre les effets indesirables des AINS seraient lies a l’inhibition de la COX 1, alors que la COX 2 inductible serait leur lieu d’action desire. Si cette hypothese s’est averee correcte pour les effets gastrointestinaux qui est la complication la plus redoutee des AINS, on ne peut extrapoler sur leur effets secondaires renaux. Les donnees a disposition nous demontrent qu’il faut s’attendre aux memes effets indesirables renaux qu’avec les AINS classiques, a savoir l’insuffisance renale aigue (IRA) fonctionnelle, la retention hydro-sodee et l’hyperkaliemie, Nous avons d’ailleurs observes tous ces effets secondaires dans notre pratique hospitaliere depuis l’introduction des inhibiteurs selectifs COX 2. Avec les inhibiteurs selectifs COX 2, la meme prudence qu’avec les AINS classiques devrait etre appliquee. Nous pensons meme que le praticien devra etre plus vigilant car la meilleure tolerance digestive va entrainer une prescription plus large et de plus longue duree de cette classe d’AINS, augmentant le risque d’effets secondaires renaux. Les AINS dit selectifs sur la COX 2 representent une reelle innovation therapeutique avec une securite digestive accrue pour une efficacite comparable, toutefois leur securite renale et cardiovasculaire reste a confirmer en particulier lors de co-morbidites ou de co-medications affectant la perfusion renale.

Aquaporin-2 (AQP-2), a water channel located on the apical membrane of collecting duct cells, regulates water reabsorption under the control of vasopressin (AVP). Using an antibody directed to human AQP-2, a quantitative Western blot analysis was performed to determine the collecting duct responsiveness to an oral, nonpeptide, V2 receptor antagonist (VPA-985) in patients with chronic NYHA II and III heart failure. Standards were derived by conjugating the immunizing peptide to maleimide-activated bovine serum albumin and a standard curve was generated for each blot. Quantification of baseline steady-state AQP-2 excretion was done by collecting urine on the day before study drug administration. The next day patients received either placebo or VPA-985 at one of four different doses and urine was collected every 2 h. Thereafter, urinary AQP-2 excretion was calculated as a ratio of the urine flow and was expressed in pmol/h. During baseline, steady-state excretion did not change significantly (T0-T2, 458 +/- 44; T2-T4, 443 +/- 35; T4-T6, 422 +/- 35; T6-T8, 401 +/- 30). Compared to placebo, urinary AQP-2 excretion decreased significantly and in all groups in a dose-dependent manner during VPA-985 administration. The most impressive decrease was observed in the 250-mg group (T0-T2, 89 +/- 5; T2-T4, 50 +/- 18; T4-T6, 43 +/- 22; T6-T8, 42 +/- 23; P < 0.001 during each period compared with baseline and placebo results). VPA-985 significantly increased solute-free water clearance and urine output and significantly decreased urinary osmolality. Urinary AQP-2 excretion correlated best with solute-free water clearance during T0-T2 and T2-T4 collection, but a correlation with urinary osmolality and urinary output was also found during these periods. In conclusion, AQP-2 urinary excretion, as measured by quantitative Western analysis, is a sensitive biologic marker to assess the short-term responsiveness of the collecting duct to a V2 receptor AVP antagonist in chronic heart failure.

A disturbance in body water homeostasis is a common feature of advanced cirrhosis.1-4 This disturbance is always associated with the existence of ascites and is characterized by an inability to adjust the amount of water excreted in the urine to the amount of water ingested. This leads to water retention with subsequent increase in total body water and development of dilutional hyponatremia. The prevalence of hyponatremia (serum sodium ,130 mEq/L) in patients with cirrhosis and ascites is approximately 30%.5 Besides the clinical manifestations associated with low serum sodium concentration, hyponatremia has a negative impact on the quality of life of cirrhotic patients, because they should be subjected to fluid restriction to avoid further reduction in serum sodium concentration. In recent years, great advances have been made in the knowledge of mechanisms regulating water excretion, especially on the role of vasopressin (VP). These advances include a better understanding of the regulation of VP synthesis and secretion, identification and cloning of VP receptors, characterization of VP signaling in the collecting duct cells, identification and cloning of water channels responsible for water reabsorption, and development of drugs capable of selectively increasing water excretion either by inhibiting VP release or antagonizing the effects of VP in the renal tubules. These advances may prove to be very useful in the management of conditions, such as cirrhosis, associated with water retention and hyponatremia. The current article summarizes the contributions to a symposium on pathophysiology and treatment of water retention in cirrhosis organized by the International Ascites Club and held at the Palexpo Center in Geneva, Switzerland, on August 25, 1996. The symposium was chaired by Mauro Bernardi and was divided into two parts. In the first part, Tomas Berl, Daniel G. Bichet, and Robert W. Schrier discussed the renal regulation of water excretion, the synthesis and biological effects of VP, and the pathogenesis of water retention in cirrhosis, respectively. In the second part, Guilles Hamon, Jean Francois Liard, and Wladimiro Jimenez discussed the recently developed drugs that selectively increase water excretion, known as aquaretics, and their effects in experimental cirrhosis.

A decade ago, it was proposed that peripheral arterial vasodilation was an important event in the pathophysiology of ascites formation in patients with cirrhosis.1 At the same time, nitric oxide was demonstrated to be a potent vasodilator with a major role in the regulation of vascular tone,2 and it was hypothesized that nitric oxide could be the cause of the hyperdynamic circulation of patients with cirrhosis.3 Since then, studies in animals and humans with portal hypertension have provided evidence suggesting that nitric oxide has an important role in the hemodynamic abnormalities that characterize cirrhosis and the associated sodium and water . . .

Water retention is characteristic of pregnancy but the mechanism(s) of the altered water metabolism has yet to be elucidated. The collecting duct water channel, aquaporin 2 (AQP2), plays a pivotal role in the renal water regulation, and we hypothesized that AQP2 expression could be modified during pregnancy. Sprague-Dawley female rats were studied on days 7 (P7), 14 (P14), and 20 (P20) of pregnancy, and expression of AQP2 in papillae was examined. Nonpregnant (NP) littermates were used as controls. Plasma osmolalities were significantly lower in pregnant rats by day 7 of gestation (P7 283.8+/-1.82, P14 284.3+/-1.64, P < 0.001, P20 282. 4+/-1.32, P < 0.0001, vs. NP 291.8+/-1.06 mosmol/kgH2O). However, plasma vasopressin concentrations in pregnant rats were not significantly different than in nonpregnant rats (NP 1.03+/-0.14, P7 1.11+/-0.21, P14 1.15+/-0.21, P20 1.36+/-0.24 pg/ml, NS). The mRNA of AQP2 was increased early during pregnancy: AQP2/beta actin: P7 196+/-17.9, P14 200+/-6.8, and P20 208+/-15.5%, P < 0.005 vs. NP (100+/-11.1%). AQP2 protein was also increased during pregnancy: AQP2 protein: P7 269+/-10.0, P14 251+/-12.0, P < 0.0001, and P20 250+/-13.6%, P < 0.001 vs. NP (100+/-12.5%). The effect of V2 vasopressin receptor antagonist, OPC-31260, was then investigated. AQP2 mRNA was suppressed significantly by OPC-31260 administration to P14 rats (AQP2/beta actin: P14 with OPC-31260 39.6+/-1.7%, P < 0.001 vs. P14 with vehicle) and was decreased to the same level of expression as NP rats receiving OPC-31260. Similar findings were found with the analysis of AQP2 protein. The decreased plasma osmolality of P14 rats was not modified by OPC-31260. The results of the study indicate that upregulation of AQP2 contributes to the water retention in pregnancy through a V2 receptor-mediated effect. In addition to vasopressin, other factors may be involved in this upregulation.

Indirect evidence suggests that the renal and vascular production of prostaglandins is increased in cirrhosis with ascites. However, the activity of the enzymes regulating the prostaglandin pathway has not been investigated in cirrhosis. The aim of the current study was to determine the activity of phospholipase A2 (PLA2), the key enzyme in the regulation of prostaglandin synthesis, in kidney and vascular tissue obtained from rats with carbon tetrachloride-induced cirrhosis and ascites (n = 9) and control rats (n = 6). PLA2 activity was assayed in vitro using [14C]arachidonyl-phosphatidylcholine (PC) and [14C]arachidonyl-phosphatidylethanolamine (PE) as substrates in the presence of Ca2+. Kidneys from cirrhotic rats had significantly higher PLA2 activity compared with control rats, with both PC and PE (35 +/- 5 and 40 +/- 6 vs. 21 +/- 2 and 26 +/- 3 pmol/mg/min, respectively; P < .05 for both). PLA2 activity was increased in the renal cortex as well as in the renal medulla. Fractionation of the kidney extracts by Mono-Q anion-exchange chromatography showed that the elution position of PLA2 activity corresponded to the cytosolic PLA2 isoform (cPLA2). Increased amounts of cPLA2 protein were found in kidney extracts immunoblotted with an anti-cPLA2 antibody However, reverse-transcriptase polymerase chain reaction (RT-PCR) analysis did not detect any difference in cPLA2 mRNA. PLA2 activity was also higher in aortic tissue from cirrhotic rats than in controls (PC 38 +/- 5 vs. 26 +/- 1 and PE 66 +/- 8 vs. 41 +/- 3 pmol/mg/min; P < .05 for both). Incubation of renal and aortic extracts from cirrhotic rats with anti-cPLA2 antibody reduced PLA2 activity by 64% and 88%, respectively. In conclusion, PLA2 activity is increased in kidneys and vascular tissue from cirrhotic rats with ascites. This can be accounted for by an induction of cPLA2, which would mediate, at least in part, the increased renal and vascular production of prostaglandins in cirrhosis.

Pregnancy is characterized by hemodynamic and body fluid alterations. Increased nitric oxide (NO) production has been suggested to play a role in the hemodynamic alterations of pregnancy and has also been reported to increase arginine vasopressin (AVP) release. We therefore hypothesized that gestation could increase both NO synthase (NOS) constitutive isoforms, neuronal NOS and endothelial NOS, and thereby contribute to the hyposmolality and peripheral arterial vasodilation of pregnancy, respectively. The present study was therefore undertaken to examine the constitutive NOS isoforms in aortas, mesenteric arteries, and hypothalami of pregnant rats on day 20 of gestation compared with age-matched nonpregnant rats. Plasma AVP was determined by radioimmunoassay and hypothalamic mRNA AVP by solution hybridization assay. Hypothalamic neuronal NOS was assessed by Northern blot and Western blot; endothelial NOS was assessed by Western blot in arteries and hypothalamus. The results demonstrated that 1) plasma AVP and hypothalamic AVP mRNA are increased in pregnant rats (n = 8), 2) neuronal NOS protein and mRNA are increased in hypothalamus of pregnant rats (n = 4), and 3) endothelial NOS expression, as assessed by Western blot analysis, is increased in both conductance (aorta) as well as resistance (mesenteric) arteries of pregnant rats (n = 4). We conclude that both of the constitutive NOS isoforms are increased in pregnant rats, suggesting that the peripheral arterial vasodilation and hyposmolality of pregnancy could be mediated by these isoforms.

Nitric oxide (NO) is postulated to play a role in the pathogenesis of arterial vasodilation in chronic portal hypertension. This present study investigates the relationship between systemic hemodynamics and the vascular production of NO, as estimated by measuring cyclic guanosine monophosphate (cGMP) in aortic tissue in two models of chronic portal hypertension in the rat: the partial portal vein ligation (PVL) model and CCl4-induced cirrhosis. NOS was also examined by Western blotting in aortic and mesenteric vessels. Sham-operated rats and rats given phenobarbital were used as controls. PVL rats and rats with cirrhosis and ascites showed a typical pattern of a hyperdynamic circulatory state, when compared with their respective controls: mean arterial pressure; PVL: 113 +/- 2 versus 124 +/- 2, P.01 and cirrhotics: 103 +/- 5 versus 130 +/- 4 mm Hg, P.01. Cardiac index; PVL: 32 +/- 2 versus 26 +/- 1, P.01 and cirrhotics: 51 +/- 3 versus 30 +/- 1 mL . min-1 . 100 gm-1, P.0001. Systemic vascular resistance; PVL: 3.7 +/- 0.1 versus 4.9 +/- 0.2, P.01 and cirrhotics: 2.1 +/- 0.2 versus 4.4 +/- 0.2 mm Hg . min-1 100 g-1, P.0001. Aortic cGMP was markedly increased in cirrhotic rats with ascites (728 +/- 83 fmol/ mg protein) as compared with phenobarbital-treated controls (244 +/- 31 fmol/mg, P.001). This increase was abolished by chronic administration of N(omega)-nitro-L-arginine methyl ester. By contrast, PVL rats had an aortic cGMP concentration similar to sham-operated controls (282 +/- 16 fmol/mg vs. 274 +/- 33 fmol/mg, P = not significant) and significantly lower than that found in cirrhotic rats with ascites. Expression of cirrhotic aortic endothelial nitric oxide synthase (eNOS) was increased but PVL aortic eNOS did not differ from that of controls, whereas the mesenteric eNOS was increased in both PVL and cirrhotic rats as compared with the controls. These results suggest that vascular NO production is higher in cirrhotic rats than in PVL rats. This increased production may contribute to the more marked abnormalities in systemic hemodynamics seen in experimental cirrhosis as compared with PVL.

The present experiments were designed to test if induction of nitric oxide synthase (NOS) plays a role in the systemic vasodilation observed in hepatic cirrhosis. Because endotoxin levels are elevated in cirrhosis, and endotoxin stimulates inducible nitric oxide synthase (iNOS) expression in several cell lines, aortas of carbon tetrachloride-induced cirrhotic rats with ascites were evaluated for iNOS expression. Endotoxin-treated rats were studied as positive controls. Phenylephrine contraction was decreased in aortic rings with endothelium from both endotoxin-treated and cirrhotic rats as compared with controls. However, after endothelium denudation, the reduced contractility persisted in endotoxin-treated rats but disappeared in cirrhotic rats. L-Nitro-arginine-methylester (L-NAME), a nonselective inhibitor of NOS, potentiated the phenylephrine contraction of aortic rings with and without endothelium from endotoxin-treated rats but only rings with endothelium from cirrhotic rats. Moreover, aminoguanidine (AG), a preferential inhibitor of iNOS, did not affect phenylephrine contraction of rings with or without endothelium from cirrhotic rats but reversed the blunted response in endotoxin-treated rats. Northern analysis detected iNOS RNA (mRNA) expression in aortas of endotoxin-treated rats but did not detect it from cirrhotic rats. In summary, although several previous studies provide evidence for in vivo overproduction of nitric oxide in cirrhosis, the present results do not support iNOS induction as the source of nitric oxide in aortas of cirrhotic rats. Rather, because the aortic vascular hyporesponsiveness in cirrhosis is endothelium-dependent, overexpression or overstimulation of the endothelial constitutive isoform of NOS appears to be involved.

Body sodium and water homeostasis is regulated by multifactorial renal and extrarenal systems. Following a description of these systems, four common edema states are reviewed, with special emphasis on the pathophysiologic mechanisms leading to sodium and water retention.

Arterial vasodilation is considered to be the key factor in the development of sodium and water retention leading to ascites formation in cirrhosis. To determine if nitric oxide (NO) is involved in the pathogenesis of arterial vasodilation in cirrhosis, we measured the concentration of cyclic guanosine monophosphate (cGMP), the second messenger of NO, in arterial tissue from rats with carbon tetrachloride-induced cirrhosis. Aortic cGMP concentration was markedly increased in cirrhotic rats, particularly in those with ascites (ascites, 826 +/- 70; no ascites, 597 +/- 48; controls, 331 +/- 25 fmol/mg, ANOVA F = 23.1, P < .0001), and correlated inversely with arterial pressure (r = -.56, P < .0001) and systemic vascular resistance (r = -.69, P = .014) and directly with cardiac index (r = .74, P < .01). The chronic administration of the NO synthesis inhibitor NG-nitro-L-arginine-methyl-ester (L-NAME) (10 mg/kg/day for 7 days) induced a marked reduction in aortic cGMP concentration in cirrhotic rats with ascites to similar values obtained in L-NAME-treated control rats (86 +/- 14 vs. 89 +/- 8 fmol/mg, respectively, NS), indicating that the high-aortic cGMP content in cirrhotic rats was caused by an increased NO synthesis. Mean arterial pressure after L-NAME treatment increased to similar values in both groups of animals. These results suggest that in cirrhosis there is an increased vascular production of NO that may play a role in the pathogenesis of arterial vasodilation.

A need exists to noninvasively assess renal interstitial fibrosis, a common process to all kidney diseases and predictive of renal prognosis. In this translational study, Magnetic Resonance Imaging (MRI) T1 mapping and a new segmented Diffusion-Weighted Imaging (DWI) technique, for Apparent Diffusion Coefficient (ADC), were first compared to renal fibrosis in two well-controlled animal models to assess detection limits. Validation against biopsy was then performed in 33 kidney allograft recipients (KARs). Predictive MRI indices, ΔT1 and ΔADC (defined as the cortico-medullary differences), were compared to histology. In rats, both T1 and ADC correlated well with fibrosis and inflammation showing a difference between normal and diseased kidneys. In KARs, MRI indices were not sensitive to interstitial inflammation. By contrast, ΔADC outperformed ΔT1 with a stronger negative correlation to fibrosis (R(2) = 0.64 against R(2) = 0.29 p

Pathological proteinuria is a sign of renal disease, either tubular or glomerular. Proteinuria is considered as a major renal and cardiovascular risk factor Screening, and quantification of proteinuria is part of the care of chronic kidney disease (CKD) patients, but also of high renal risk patients and high cardiovascular risk patients. CKD is now classified according to estimated GFR and proteinuria to improve prediction of adverse events. in this article, we summarize the pathophysiology of proteinuria, its clinical qualification and implications.

Diabetes has a constantly growing prevalence and leads to a number of complications such as diabetic nephropathy. A systematic screening and an adapted management are needed to limit the renal and also the cardiovascular complications linked to diabetic nephropathy. An adequate glycemic and tensional control and control of proteinuria are the priority in the care of diabetic nephropathy. Other aspects such as phospho-calcium balance, lipid panel or lifestyle changes are also important and therefore a multidisciplinary approach is essential. A better understanding of the physiopathology may lead to even more effective treatments in the future. We resume in this article the actual management of a patient suffering from diabetic nephropathy and the future treatment perspectives.

The prevalence of chronic kidney disease (CKD) is high and diabetic nephropathy is a leading cause of CKD. One of the most common complications of CKD is anemia, the frequency and severity of which increase as kidney failure progresses. Renal anemia is primarily caused by reduced renal erythropoietin production. It can also be associated with iron deficiency caused by reduced iron absorption, occult blood loss and impaired iron mobilization. This work provides an overview of the management of renal anemia with focus on intravenous iron therapy, which is more effective than oral iron administration in CKD due to reduced iron absorption.

Several landmark studies have recently been published in nephrology. In summary, mycophenolate mofetil is superior to azathioprine in maintaining remission and preventing relapse in lupus nephritis. For patients with type I diabetes, long-term renal function is better preserved when optimal glycaemic control is obtained with intensive diabetes therapy from the onset of disease, and in patients with type 2 diabetes treatment with bardexolone may increase renal function. With respect to chronic kidney disease, the association of simvastatine and ezetimibe is effective in improving cardiovascular outcomes. There is no need to initiate dialysis in asymptomatic patients, and daily haemodialysis seems better than three times weekly hemodialysis. Finally, N-acetylcysteine does not prevent contrast nephropathy.

Acute kidney injury is associated with higher risk of chronic kidney disease or death. Diagnosis is based on increased serum creatinin, most often several days after the initial renal injury. Several novel biomarkers are being studied and validated in clinical settings. Cystatin C, NGAL, KIM-1, IL-18 or L-FABP are the most promising. Their elevation in serum or urine is specifically associated with kidney injury. They seem also to predict mortality and the need of dialysis. In the near future, these biomarkers could affect the way we treat patients with acute kidney injury, as well as their evolution. However, the real challenge will be in using the best combination of biomarkers and in the correct interpretation of their results.

Chronic kidney disease (CKD) is complex to manage, especially when a substitutive treatment has to be implemented. Strict medical follow-up is mandatory but not sufficient to provide optimal care to the CKD patients. Educational intervention gives more skills to the patients to cope with this chronic disease. In this approach, physicians and nurses help patients to have a greater acceptance of their illness and make their treatment their own. Therapeutic education is part of this patient-centred approach. Peer counselling is also used in our program as well as an educative journal.

Nephrogenic systemic fibrosis, another problem for patients with chronic renal failure Nephrogenic systemic fibrosis is a rare but severe disease described in patients with kidney failure. High morbidity ant mortality are associated with this new condition. Epidemiological studies strongly suggest a link between nephrogenic systemic fibrosis and gadolinium administration for magnetic resonance imaging enhancement. The disease is primarily cutaneous, with oedema affecting the limbs, later evolving to fibrosis that leads to joints contractures. The lesions can spread to the trunk and involve systemic organs like the heart, lungs and muscles. Given the lack of proved efficient therapy, careful evaluation of the risks and benefits of gadolinium administration should be done in patients with kidney disease. If really needed, a highly stable contrast media should be used.

According to recent results from observational studies, maintenance hemodialysis sessions will probably tend in the future towards more dialysis time, slower ultrafiltration rate and use of hemodiafiltration. Modes of renal replacement therapy in acute renal failure are still to be determined. Plasma exchange, rituximab, mycophenolate mofetil and ciclosporine are now widely used in the treatment of glomerulonephritides and represent an interesting alternative with less side-effects than cyclophosphamide.

Chronic kidney disease is associated with a decreased production of the active metabolite of vitamin D, 1 alpha,25-Dihydroxy-Vitamin D. This decrease has several consequences which are not only restricted to the bones. Indeed, vitamin D has multiple actions which are discussed in this review. Vitamin D substitution is considered early in the treatment of chronic kidney disease but uncertainties about the type of substitution remain. The role of vitamin D analogs are reviewed with emphasis on the comparison between calcitriol and paricalcitol.

Metabolic acidosis is not uncommon in clinical medicine. The kidney plays a pivotal role to maintain acid-base homeostasis. Understanding renal acid-base metabolism is essential to make an effective approach to the diagnosis and management of metabolic acidosis. Clinical approach includes the serum anion gap which allows to classify metabolic acidosis as increased anion gap or non-anion gap acidosis. Renal tubular acidosis refers to a group of functional disorders which differ depending on the localisation of the tubular defect. The management of metabolic acidosis is discussed according to the causes. The indications to use sodium bicarbonate are discussed as well as its potential adverse effects in some conditions.

ABO incompatibility and positive cross match between the donor and the recipient are no longer considered absolute counter indications to renal transplantation. One-year and 5-years graft survival are similar to ABO compatible transplantation, although a higher incidence of acute humoral rejection is observed. Calcineurin inhibitors nephrotoxicity can be reduced since the introduction of new immunosuppressive drugs. Two forms of peritoneal dialysis are available: continuous ambulatory peritoneal dialysis and automated peritoneal dialysis. In each situation the treatment must be tailored to the patient. Various clinical and biological parameters allow to judge the adequacy of the peritoneal dialysis. The last guidelines fixed the minimal target value of one of them, the Kt/V, at 1.7.

Measurement of glomerular filtartion rate (GFR) is crucial for the detection and follow-up of an early renal impairment. Inulin clearance or radio-isotopes are the gold standard but they cannot be used routinely. Serum creatinine and creatinine clearance are the most widely used, but they lack sensibility to detect an early renal impairment and in cases of obesity, malnutrition or advanced age. Looking for a more reliable marker is necessary and cystatin C seems to be interesting. This molecule is constantly produced by nucleated cells, then freely filtrated and catabolized in the proximal tube. Clinical studies showed that cystatin C might be a more reliable marker of GFR in determined groups of patients. Moreover this molecule may have an other interest as a predictive risk factor or mortality, especially for cardiovascular events.

Publications of relevance in nephrology during 2005 highlight the use of more specific molecules to treat glomerulonephritides and cast a doubt on the dogma: "the lower blood pressure, the better renal outcome". They report the effect of high dose Angiotensin 11 receptor blockers being used to lower proteinuria without any significant effect on blood pressure. In critically ill patients with acute renal failure, loop diuretics did not increase mortality. Should we treat end-stage renal failure patients with statins? probably not; with cinacalcet? definitely yes.

Alternative to nephrotoxic calcineurin inhibitors regimens are feasible in renal transplantation. Sirolimus is an effective immunosuppressive drug with less drug-induced nephrotoxicity. Enteric-coated mycophenolate sodium provides a safety and efficacy alternative to mycophenolate mofetil. In peritoneal effluent, cancer antigen 125 (Ca 125) is a mesothelial cell marker and of in vivo biocompatibility of the new dialysis solutions. Longterm PD and peritoneal sclerosis are associated with a low number of mesothelial cells and a low concentration of dialysate Ca 125. Exposure to glucose and degradation products (GDPs) is important in the genesis of mesothelial damage. Short results of the more biocompatible solutions are promising (increasing of Ca 125). In the future, exposure to glucose can be reduced by using combinations of various osmotic agents, each in a low concentration (glycerol and amino acid solution).

To study aquaporin-2 (AQP2) that mediates vasopressin-regulated collecting duct water permeability.Male Sprague-Dawley rats (200-250 g) underwent either a left coronary artery ligation, a model of CHF, or a shamoperation (Sham-Op). Five weeks after surgery, mean blood pressure (MBP) and cardiac output (CO) were measured by catheterization in the conscious animal. The rats were sacrificed 24 hours later. Left ventricular myocardial infarction size (LVMI) was estimated and the rats were divided into two groups according to the size of infarction. Total RNA and protein were extracted from whole kidney. AQP2 and GAPDH mRNA were measured by Northern blot and AQP2 protein expression by Western blot.AQP2/GAPDH mRNA densities of Sham-Op, LVMI20% rats and LVMIor = 20% rats were 1.385 +/- 0.023, 1.523 +/- 0.036, and 1.779 +/- 0.072 (P0.01). AQP2 protein Western blot densities were 100% +/- 10%, 157% +/- 13% and 202% +/- 25% (P0.01).Both mRNA and protein of AQP2 gene expression are increased in CHF rat and this upregulation is present in the compensated (LVMI20% rats) and decompensated (LVMIor = 20% rats) stage of CHF. This contributes to water retention associated with CHF.

The kidney medulla is exposed to very high interstitial osmolarity leading to the activation of mitogen-activated protein kinases (MAPK). However, the respective roles of increased intracellular osmolality and of cell shrinkage in MAPK activation are not known. Similarly, the participation of MAPK in the regulatory volume increase (RVI) following cell shrinkage remains to be investigated. In the rat medullary thick ascending limb of Henle (MTAL), extracellular hypertonicity produced by addition of NaCl or sucrose increased the phosphorylation level of extracellular signal-regulated kinase (ERK) and p38 kinase and to a lesser extent c-Jun NH(2)-terminal kinase with sucrose only. Both hypertonic solutions decreased the MTAL cellular volume in a dose- and time-dependent manner. In contrast, hypertonic urea had no effect. The extent of MAPK activation was correlated with the extent of MTAL cellular volume decrease. Increasing intracellular osmolality without modifying cellular volume did not activate MAPK, whereas cell shrinkage without variation in osmolality activated both ERK and p38. In the presence of 600 mosmol/liter NaCl, the maximal cell shrinkage was observed after 10 min at 37 degrees C and the MTAL cellular volume was reduced to 70% of its initial value. Then, RVI occurred and the cellular volume progressively recovered to reach about 90% of its initial value after 30 min. SB203580, a specific inhibitor of p38, almost completely inhibited the cellular volume recovery, whereas inhibition of ERK did not alter RVI. In conclusion, in rat MTAL: 1) cell shrinkage, but not intracellular hyperosmolality, triggers the activation of both ERK and p38 kinase in response to extracellular hypertonicity; and 2) RVI is dependent on p38 kinase activation.

Hyponatremia is common in advanced heart failure and relates to the severity of the disease. Non-osmotic arginine vasopressin (AVP) release and biosynthesis have been shown to be increased during chronic cardiac failure (CHF) and baroreceptors pathways have been demonstrated to play a major role in this non-osmotic stimulation of AVP. Decreased cardiac output unloads the baroreceptors and activates the sympathetic nervous system, thus stimulating AVP through a separate pathway which overrides the osmotic pathway. Besides sympathetic nervous system activation, neurohumoral peptides, such as angiotensin II, endothelins, natriuretic peptides and prostaglandins, could also participate in the non-osmotic AVP activation. The vasoconstrictor effect of AVP has been supported by the decrease systemic vascular resistance during the administration of V1 receptor AVP antagonist in CHF patients. Administration of V2 receptor AVP antagonists corrects the hyponatremia and has been demonstrated to improve survival in animal models of heart failure. Preliminary data in humans with CHF also demonstrate urinary dilution and correction of hyponatremia with orally active non-peptide V2 receptor antagonists. Finally, upregulation of the AVP-regulated water channels, aquaporin-2 (AQP2), located in the collecting duct cells has been shown in experimental heart failure. This AQP2 upregulation can be entirely suppressed by V2 receptor AVP antagonists paralleling the correction of the hyponatremia. Thus, non-osmotic release of AVP in CHF upregulates AQP2 water channels, enhances water reabsorption and causes hyponatremia. The V1, and perhaps the V2, receptor activation may also diminish cardiac function.

Vasopressin (AVP) is released in response to both osmotic and nonosmotic stimuli. Nonosmotic-stimulated AVP release occurs in cardiac failure, cirrhosis, and pregnancy in response to alterations in arterial circulatory integrity. Cardiac failure in rats is associated with increased plasma AVP and hypothalamic AVP mRNA, and in humans, it is associated with cardiac failure. Plasma AVP concentrations are elevated when measured with a sensitive radioimmunoassay. Urinary concentrations of AVP-responsive aquaporin-2 water channels are also elevated in cardiac failure. V2 receptor antagonists correct the impaired solute-free water excretion seen in rats with low-output cardiac failure and reverse the upregulation of renal aquaporin-2 water channels. Orally active non-peptide-selective V2 receptor antagonists administered to patients with congestive cardiac failure decrease urinary concentrations of aquaporin-2, increase solute-free water clearance, and correct the hyponatremia. Cirrhosis of the liver results in splanchnic arterial vasodilation and increased vascular capacity, most likely secondary to increased nitric oxide production. This relative underfilling of the arterial circulation stimulates nonosmotic AVP release with resultant water retention. Aquaporin-2 gene expression is upregulated in the kidneys of rats with cirrhosis of the liver. AVP-2 receptor antagonists administered to animals with cirrhosis reverse the water retention. Human studies using orally active, non-peptide-selective V2 receptor antagonists in patients with cirrhosis are currently underway. Pregnancy is another state of nitric oxide-mediated arterial vasodilation that is associated with plasma AVP concentrations that are relatively high for the degree of hypoosmolality. Upregulation of the water channel aquaporin-2 in the renal papillae of pregnant rats has also been demonstrated, and this effect is reversed by administration of a V2 receptor antagonist.

Effect of hypoxia on proximal tubules isolated from nitric oxide synthase knockout mice. Nitric oxide (NO) has been shown to be a mediator of hypoxic injury in rat renal proximal tubules (PT). However, the role of NO in hypoxic injury to mouse PT has not been examined. The aim of the present study was to determine the effect of knockout of nitric oxide synthase (NOS) isoforms on hypoxic injury in mouse PT. Mouse PTs were isolated by collagenase digestion and Percoll centrifugation. The nonselective NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 10 mM), but not its inactive stereoisomer D-NAME, protected against hypoxic injury as assessed by LDH release. Carboxy-imidazolineoxyl N-oxide (carboxy-PTIO, 100 μM), a stable NO scavenger, also afforded cytoprotection against hypoxic injury. To determine the role of the different NOS isoforms in the hypoxic injury, we examined the effect of hypoxia on PT isolated from knockout mice in which either the inducible NOS (iNOS), endothelial NOS (eNOS) or neuronal NOS (nNOS) gene was lacking. PT isolated from iNOS knockout mice were resistant to hypoxic injury compared to wild-type controls. In contrast, PT isolated from both nNOS and eNOS knockout mice were not protected against hypoxic injury. In conclusion, the present study demonstrates that NO is a mediator of hypoxic PT injury in the mouse and that knockout of the iNOS gene is cytoprotective against this hypoxic PT injury.

Indirect evidence suggests that the renal and vascular production of prostaglandins is increased in cirrhosis with ascites. However, the activity of the enzymes regulating the prostaglandin pathway has not been investigated in cirrhosis. The aim of the current study was to determine the activity of phospholipase A2 (PLA2), the key enzyme in the regulation of prostaglandin synthesis, in kidney and vascular tissue obtained from rats with carbon tetrachloride-induced cirrhosis and ascites (n = 9) and control rats (n = 6). PLA2 activity was assayed in vitro using [14C]arachidonyl-phosphatidylcholine (PC) and [14C]arachidonyl-phosphatidylethanolamine (PE) as substrates in the presence of Ca2+. Kidneys from cirrhotic rats had significantly higher PLA2 activity compared with control rats, with both PC and PE (35 +/- 5 and 40 +/- 6 vs. 21 +/- 2 and 26 +/- 3 pmol/mg/min, respectively; P.05 for both). PLA2 activity was increased in the renal cortex as well as in the renal medulla. Fractionation of the kidney extracts by Mono-Q anion-exchange chromatography showed that the elution position of PLA2 activity corresponded to the cytosolic PLA2 isoform (cPLA2). Increased amounts of cPLA2 protein were found in kidney extracts immunoblotted with an anti-cPLA2 antibody However, reverse-transcriptase polymerase chain reaction (RT-PCR) analysis did not detect any difference in cPLA2 mRNA. PLA2 activity was also higher in aortic tissue from cirrhotic rats than in controls (PC 38 +/- 5 vs. 26 +/- 1 and PE 66 +/- 8 vs. 41 +/- 3 pmol/mg/min; P.05 for both). Incubation of renal and aortic extracts from cirrhotic rats with anti-cPLA2 antibody reduced PLA2 activity by 64% and 88%, respectively. In conclusion, PLA2 activity is increased in kidneys and vascular tissue from cirrhotic rats with ascites. This can be accounted for by an induction of cPLA2, which would mediate, at least in part, the increased renal and vascular production of prostaglandins in cirrhosis.

Hyponatremia is common in advanced heart failure and relates to the severity of the disease. Non-osmotic arginine vasopressin (AVP) release and biosynthesis have been shown to be increased during chronic cardiac failure (CHF) and baroreceptors pathways have been demonstrated to play a major role in this non-osmotic stimulation of AVP. Decreased cardiac output unloads the baroreceptors and activates the sympathetic nervous system, thus stimulating AVP through a separate pathway which overrides the osmotic pathway. Besides sympathetic nervous system activation, neurohumoral peptides, such as angiotensin II, endothelins, natriuretic peptides and prostaglandins, could also participate in the non-osmotic AVP activation. The vasoconstrictor effect of AVP has been supported by the decrease systemic vascular resistance during the administration of V1 receptor AVP antagonist in CHF patients. Administration of V2 receptor AVP antagonists corrects the hyponatremia and has been demonstrated to improve survival in animal models of heart failure. Preliminary data in humans with CHF also demonstrate urinary dilution and correction of hyponatremia with orally active non-peptide V2 receptor antagonists. Finally, upregulation of the AVP-regulated water channels, aquaporin-2 (AQP2), located in the collecting duct cells has been shown in experimental heart failure. This AQP2 upregulation can be entirely suppressed by V2 receptor AVP antagonists paralleling the correction of the hyponatremia. Thus, non-osmotic release of AVP in CHF upregulates AQP2 water channels, enhances water reabsorption and causes hyponatremia. The V1, and perhaps the V2, receptor activation may also diminish cardiac function.

Normalization of the increased vascular nitric oxide (NO) generation with low doses of NG-nitro-L-arginine methyl ester (L-NAME) corrects the hemodynamic abnormalities of cirrhotic rats with ascites. We have undertaken this study to investigate the effect of the normalization of vascular NO production, as estimated by aortic cyclic guanosine monophosphate (cGMP) concentration and endothelial nitric oxide synthase (eNOS) protein expression in the aorta and mesenteric artery, on sodium and water excretion. Rats with carbon tetrachloride-induced cirrhosis and ascites were investigated using balance studies. The cirrhotic rats were separated into two groups, one receiving 0.5 mg/kg per day of L-NAME (CIR-NAME) during 7 d, whereas the other group (CIR) was administrated the same volume of vehicle. Two other groups of rats were used as controls, one group treated with L-NAME and another group receiving the same volume of vehicle. Sodium and water excretion was measured on days 0 and 7. On day 8, blood samples were collected for electrolyte and hormone measurements, and aorta and mesenteric arteries were harvested for cGMP determination and nitric oxide synthase (NOS) immunoblotting. Aortic cGMP and eNOS protein expression in the aorta and mesenteric artery were increased in CIR as compared with CIR-NAME. Both cirrhotic groups had a similar decrease in sodium excretion on day 0 (0.7 versus 0.6 mmol per day, NS) and a positive sodium balance (+0.9 versus +1.2 mmol per day, NS). On day 7, CIR-NAME rats had an increase in sodium excretion as compared with the CIR rats (sodium excretion: 2.4 versus 0.7 mmol per day, P < 0.001) and a negative sodium balance (-0.5 versus +0.8 mmol per day, P < 0.001). The excretion of a water load was also increased after L-NAME administration (from 28+/-5% to 65+/-7, P < 0.05). Plasma renin activity, aldosterone and arginine vasopressin were also significantly decreased in the CIR-NAME, as compared with the CIR rats. The results thus indicate that normalization of aortic cGMP and eNOS protein expression in vascular tissue is associated with increased sodium and water excretion in cirrhotic rats with ascites.

Sodium retention is the most common renal abnormality of cirrhosis and eventually leads to the formation of ascites. There is now a strong body of evidence that the arterial vasodilatation, mainly splanchnic, that occurs during liver cirrhosis is a major factor in the pathogenesis of renal sodium and water retention. The arterial vasodilatation and the subsequent hypotension stimulate a baroreceptor-mediated neurohormonal vasoconstrictor and antinatriuretic response in a attempt to compensate the relative underfilling of the circulation. The cause of the arterial vasodilatation is thought to be a circulating factor and several recent studies have implicated an excessive vascular production of nitric oxide (NO). In animal models of cirrhosis administration of NO antagonists corrects the hyperdynamic circulation and improves renal sodium excretion. The treatment of sodium retention is often difficult in liver cirrhosis and it is possible that the identification of a vasodilator substance which can be inhibited could provide a new tool in the therapeutic approach of sodium and water retention in cirrhosis.