HMG CoA reductase inhibitors (statins) for preventing acute kidney injury after surgical procedures requiring cardiac bypass.

BACKGROUND: Acute kidney injury (AKI) is common in patients undergoing cardiac surgery among whom it is associated with poor outcomes, prolonged hospital stays and increased mortality. Statin drugs can produce more than one effect independent of their lipid lowering effect, and may improve kidney injury through inhibition of postoperative inflammatory responses. OBJECTIVES: This review aimed to look at the evidence supporting the benefits of perioperative statins for AKI prevention in hospitalised adults after surgery who require cardiac bypass. The main objectives were to 1) determine whether use of statins was associated with preventing AKI development; 2) determine whether use of statins was associated with reductions in in-hospital mortality; 3) determine whether use of statins was associated with reduced need for RRT; and 4) determine any adverse effects associated with the use of statins. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 13 January 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared administration of statin therapy with placebo or standard clinical care in adult patients undergoing surgery requiring cardiopulmonary bypass and reporting AKI, serum creatinine (SCr) or need for renal replacement therapy (RRT) as an outcome were eligible for inclusion. All forms and dosages of statins in conjunction with any duration of pre-operative therapy were considered for inclusion in this review. DATA COLLECTION AND ANALYSIS: All authors extracted data independently and assessments were cross-checked by a second author. Likewise, assessment of study risk of bias was initially conducted by one author and then by a second author to ensure accuracy. Disagreements were arbitrated among authors until consensus was reached. Authors from two of the included studies provided additional data surrounding post-operative SCr as well as need for RRT. Meta-analyses were used to assess the outcomes of AKI, SCr and mortality rate. Data for the outcomes of RRT and adverse effects were not pooled. Adverse effects taken into account were those reported by the authors of included studies. MAIN RESULTS: We included seven studies (662 participants) in this review. All except one study was assessed as being at high risk of bias. Three studies assessed atorvastatin, three assessed simvastatin and one investigated rosuvastatin. All studies collected data during the immediate perioperative period only; data collection to hospital discharge and postoperative biochemical data collection ranged from 24 hours to 7 days. Overall, pre-operative statin treatment was not associated with a reduction in postoperative AKI, need for RRT, or mortality. Only two studies (195 participants) reported postoperative SCr level. In those studies, patients allocated to receive statins had lower postoperative SCr concentrations compared with those allocated to no drug treatment/placebo (MD 21.2 µmol/L, 95% CI -31.1 to -11.1). Adverse effects were adequately reported in only one study; no difference was found between the statin group compared to placebo. AUTHORS' CONCLUSIONS: Analysis of currently available data did not suggest that preoperative statin use is associated with decreased incidence of AKI in adults after surgery who required cardiac bypass. Although a significant reduction in SCr was seen postoperatively in people treated with statins, this result was driven by results from a single study, where SCr was considered as a secondary outcome. The results of the meta-analysis should be interpreted with caution; few studies were included in subgroup analyses, and significant differences in methodology exist among the included studies. Large high quality RCTs are required to establish the safety and efficacy of statins to prevent AKI after cardiac surgery.

Cost-effectiveness of a new combined immunosuppressive and anti-infectious regimen in kidney transplantation.

OBJECTIVES: The aims of this study were to assess the 1-year cost-effectiveness of a new combined immunosuppressive and anti-infectious regimen in kidney transplantation to prevent both rejection and infectious complications. METHODS: Patients (pts) transplanted from January 2000 to March 2003 (Group A) and treated with a conventional protocol were compared with pts submitted to a combined regimen including universal cytomegalovirus (CMV) prophylaxis between April 2003 and July 2005 (Group B). Costs were computed from the hospital accounting system for hospital stays, and official tariffs for outpatient visits. Patients with incomplete costs data were excluded from analysis. RESULTS: Fifty-three patients were analyzed in Group A, and 60 in Group B. Baseline characteristics including CMV serostatus were not significantly different between the two groups. Over 12 months after transplantation, acute rejections decreased from 41.5 percent in Group A to 6.7 percent in Group B (p < .001), and CMV infections from 47 percent to 15 percent (p < .001). Overall, readmissions decreased from 68 percent to 55 percent (p = .160), and average hospital days from 28 +/- 19 to 20 +/- 11 days (p < .007). The average number of outpatient visits decreased from 49 +/- 10 to 39 +/- 8 (p < .001). Average 1-year immunosuppressive and CMV prophylaxis costs (per patient) increased from CHF20,402 +/- 7,273 to 27,375 +/- 6,063 (p < .001), graft rejection costs decreased from CHF4,595 +/- 10,182 to 650 +/- 3,167 (p = .005), CMV treatment costs from CHF2,270 +/- 6,161 to 101 +/- 326 (p = .008), and outpatient visits costs from CHF8,466 +/- 1'721 to 6,749 +/- 1,159 (p < .001). Altogether, 1-year treatment costs decreased from CHF39'957 +/- 16,573 to 36,204 +/- 6,901 (p = .115). CONCLUSIONS: The new combined regimen administered in Group B was significantly more effective, and its additional costs were more than offset by savings associated with complications avoidance.

Modulation of the epithelial sodium channel by serine proteases

Abstract The epithelial sodium channel (ENaC) is composed of three homologous subunits α, ß, and γ. This channel is involved in the regulation of sodium balance, which influences the periciliary liquid level in the lung, and blood pressure via the kidney. ENaC expressed in Xenopus laevis oocytes is preferentially and rapidly assembled into heteromeric αßγ complexes. Expression of homomeric α or heteromeric αß and αγ complexes lead to channel expression at the cell surface wíth low activities. Recent studies have demonstrated that α and γ (but not ß) ENaC subunits undergo proteolytic cleavage by endogenous proteases (i.e. furin) correlating with increased channel activity. We therefore assayed the full-length subunits and their cleavage products at the cell surface, as well as in the intracellular pool for all homo- and heteromeric combínations (α, ß, γ, ßγ, αß, αγ, ßγ and αßγ) and measured the corresponding channel activities as amiloride-sensitive sodíum transport (INa). We showed that upon assembly, cleavage of the y ENaC subunit ís responsible for increasing INa. We further demonstrated that in disease states such as cystic fibrosis (CF) where there is disequilibrium in the proteaseprotease inhibitor balance, ENaC is over-activated by the serine protease elastase (NE). We demonstrated that elevated NE concentrations can cleave cell surface expressed γ ENaC (but not α, or ß ENaC), suggesting a causal relationship between γ ENaC cleavage and ENaC activation, taking place at the plasma membrane. In addition, we demonstrated that the serine protease inhibitor (serpin) serpinH1, which is co-expressed with ENaC in the distal nephron is capable of inhibiting the channel by preventing cleavage of the γ ENaC subunit. Aldosterone mediated increases in INa aze known to be inhibted by TGFß. TGFß is also known to increase serpinHl expression. The demonstrated inhibition of γ ENaC cleavage and channel activation by serpinH1 may be responsible for the effect of TGFß on aldosterone stimulation in the distal nephron. In summary, we show that cleavage of the γ subunit, but not the α or ß subunit is linked to channel activation in three seperate contexts. Résumé Le canal épithélial à sodium (ENaC) est constitué de trois sous-unités homologues α, ß, and γ. Ce canal est impliqué dans le maintien de la balance sodique qui influence le niveau du liquide périciliaire du poumon et la pression sanguine via le rein. Dans les ovocytes de Xenopus laevis ENaC est préférentiellement et rapidement exprimé en formant un complexe hétéromérique αßγ. En revanche, l'expression homomérique de α ou hétéromérique des complexes αß et αγ conduit à une expression à la surface cellulaire d'un canal ENaC ne possédant qu'une faible activité. Des études récentes ont mis en évidence que les sous-unités α et γ d'ENaC (mais pas ß) sont coupées par des protéases endogènes (les farines) et que ces clivages augmentent l'activité du canal. Nous avons donc analysé, aussi bien à la surface cellulaire que dans le cytoplasme, les produits des clivages de combinaison homo- et hétéromérique des sous-unités d'ENaC (α, ß, γ, ßγ, αß, αγ, ßγ et αßγ). En parallèle, nous avons étudié l'activité correspondante à ces canaux par la mesure du transport de sodium sensible à l'amiloride (INa). Nous avons montré que lors de l'assemblage des sous-unités d'ENaC, le clivage de γ correspond à l'augmentation de INa. Nous avons également mis en évidence que dans une maladie telle que la fibrose cystique (CF) caractérisée par un déséquilibre de la balance protéase-inhibiteur de protéase, ENaC est suractivé par une sérine protéase nommée élastase (NE). L'augmentation de la concentration de NE clive γ ENaC exprimé à la surface cellulaire (mais pas α, ni ß ENaC) suggérant une causalité entre le clivage d'ENaC et son activation à la membrane plasmique. De plus, nous avons démontré que l'inhibiteur de sérine protéase (serpin) serpinH1, qui est co-exprimé avec ENaC dans le néphron distal, inhibe l'activité du canal en empêchant le clivage de la sous-unité γ ENaC. Il est connu que le INa induit par l'aldostérone peut être inhibé par TGFß. Or TGFß augmente l'expression de serpinH1. L'inhibition du clivage de γ ENaC et de l'activation du canal par la serpinH1 que nous avons mis en évidence pourrait ainsi être responsable de l'effet de TGFß sur la stimulation du courant par l'aldostérone dans le néphron distal. En résumé, nous avons montré que le clivage de la sous-unité γ, mais pas des sous-unités α et ß, est lié à l'activation du canal dans trois contextes distincts. Résumé tout public Le corps humain est composé d'environ 10 000 milliards de cellules et d'approximativement 60% d'eau. Les cellules du corps sont les unités fondamentales de la vie et elles sont dépendantes de certains nutriments et molécules. Ces nutriments et molécules sont dissous dans l'eau qui est présente dans et hors des cellules. Le maintien d'une concentration adéquate - de ces nutriments et de ces molécules dans l'eau à l'intérieur et à l'extérieur des cellules est -..essentiel pour leur survie. L'eau hors des cellules est nommée le fluide extracellulaire et peut être subdivisée en fluide interstitiel, qui se trouve autour des cellules, et en plasma, qui est le fluide des vaisseaux sanguins. Les fluides, les nutriments et les molécules sont constamment échangés entre les cellules, le fluide interstitiel, et le plasma. Le plasma circule dans le système circulatoire afin de distribuer les nutriments et molécules dans tout le corps et afin d'enlever les déchets cellulaires. Le rein joue un rôle essentiel dans la régulation du volume et de la concentration du plasma en éliminant sélectivement les nutriments et les molécules via la formation de l'urine. L'être humain possède deux reins, constitués chacun d'environ 1 million de néphrons. Ces derniers sont responsables de réabsorber et de sécréter sélectivement les nutriments et les molécules. Le canal épithélial à sodium (ENaC) est localisé à la surface cellulaire des néphrons et est responsable de la réabsorption du sodium (Na+). Le Na+ est présent dans quasiment toute la nourriture que nous mangeons et représente, en terme de molécule, 50% du sel de cuisine. Si trop de sodium est consommé, ENaC est inactif, si bien que le Na+ n'est pas réabsorbé et quitte le corps par l'urine. Ce mécanisme permet d'éviter que la concentration plasmatique de Na+ ne devienne trop grande, ce qui résulterait en une augmentation de la pression sanguine. Si trop peu de Na+ est consommé, ENaC réabsorbe le Na+ de l'urine primaire ce qui permet de conserver la concentration de Na+ et de prévenir une diminution de la pression sanguine par une perte de Na+. ENaC est aussi présent dans les cellules des poumons qui sont les organes permettant la respiration. La respiration est aussi essentielle pour la survie des cellules. Les poumons ne doivent pas contenir trop de liquide afin de permettre la respiration, mais en même temps ils ne doivent pas non plus être trop secs. En effet, ceci tuerait les cellules et empêcherait aussi la respiration. ENaC permet de maintenir un niveau d'humidité approprié dans les poumons en absorbant du Na+ ce qui entraîne un mouvement osmotique d'eau. L'absorption de sodium par ENaC ~ est augmentée par les protéases (in vitro et ex vivo). Les protéases sont des molécules qui peuvent couper d'autres molécules à des endroits précis. Nous avons démonté que certaines protéases augmentent l'absorption de Na+ en coupant ENaC à des endroits spécifiques. L'inhibition de ces protéases diminue le transport de Na+ et empêche le clivage d'ENaC. Dans certaines maladies telle que la mucoviscidose, des protéases sont suractivées et augmentent l'activité d'ENaC de manière inappropriée conduisant à une trop forte absorption de Na+ et à un déséquilibre de la muqueuse des poumons. Cette étude est donc particulièrement importante dans le cadre de la recherche thérapeutique de ce genre de maladie.

Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.

Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP-1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted. CONCLUSION: The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.

Is magnetic resonance imaging of hepatic hemangioma any different in liver fibrosis and cirrhosis compared to normal liver?

PURPOSE: To compare qualitative and quantitative magnetic resonance (MR) imaging characteristics of hepatic hemangiomas in patients with normal, fibrotic and cirrhotic livers. MATERIALS AND METHODS: Retrospective, institutional review board approved study (waiver of informed consent). Eighty-nine consecutive patients with 231 hepatic hemangiomas who underwent liver MR imaging for lesion characterization were included. Lesions were classified into three groups according to the patients' liver condition: no underlying liver disease (group 1), fibrosis (group 2) and cirrhosis (group 3). Qualitative and quantitative characteristics (number, size, signal intensities on T1-, T2-, and DW MR images, T2 shine-through effect, enhancement patterns (classical, rapidly filling, delayed filling), and ADC values) were compared. RESULTS: There were 160 (69%), 45 (20%), and 26 (11%) hemangiomas in groups 1, 2 and 3, respectively. Lesions were larger in patients with normal liver (group 1 vs. groups 2 and 3; P=.009). No difference was found between the groups on T2-weighted images (fat-suppressed fast spin-echo (P=.82) and single-shot (P=.25)) and in enhancement patterns (P=.56). Mean ADC values of hemangiomas were similar between groups 1, 2 and 3 (2.11±.52×10(-3)mm(2)/s, 2.1±.53×10(-3)mm(2)/s and 2.14±.44×10(-3)mm(2)/s, P=87, respectively). T2 shine-through effect was less frequently observed in cirrhosis (P=.02). CONCLUSION: MR imaging characteristics of hepatic hemangioma were similar in patients with normal compared to fibrotic and cirrhotic livers. Smaller lesion size was observed with liver disease and less T2 shine-through effect was seen in hemangiomas developed on cirrhosis, the latter being an important finding to highlight in these patients at risk of developing hepatocellular carcinoma.

No development of hypertension in the hyperuricemic liver-Glut9 knockout mouse.

Urate is the metabolic end point of purines in humans. Although supra-physiological plasma urate levels are associated with obesity, insulin resistance, dyslipidemia, and hypertension, a causative role is debated. We previously established a mouse model of hyperuricemia by liver-specific deletion of Glut9, a urate transporter that provides urate to the hepatocyte enzyme uricase. These LG9 knockout mice show mild hyperuricemia (120 μmol/l), which can be further increased by the urate precursor inosine. Here, we explored the role of progressive hyperuricemia on the cardiovascular function. Arterial blood pressure and heart rate were periodically measured by telemetry over 6 months in LG9 knockout mice supplemented with incremental amounts of inosine in a normal chow diet. This long-term inosine treatment elicited a progressive increase in uricemia up to 300 μmol/l; however, it did not modify heart rate or mean arterial blood pressure in LG9 knockout compared with control mice. Inosine treatment did not alter cardiac morphology or function measured by ultrasound echocardiography. However, it did induce mild renal dysfunction as revealed by higher plasma creatinine levels, lower glomerular filtration rate, and histological signs of chronic inflammation and fibrosis. Thus, in LG9 knockout mice, inosine-induced hyperuricemia was not associated with hypertension despite partial renal deficiency. This does not support a direct role of urate in the control of blood pressure.

Genome-wide association study of kidney function decline in individuals of European descent.

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.Kidney International advance online publication, 10 December 2014; doi:10.1038/ki.2014.361.

Copeptin is associated with kidney length, renal function, and prevalence of simple cysts in a population-based study.

Arginine vasopressin (AVP) has a key role in osmoregulation by facilitating water transport in the collecting duct. Recent evidence suggests that AVP may have additional effects on renal function and favor cyst growth in polycystic kidney disease. Whether AVP also affects kidney structure in the general population is unknown. We analyzed the association of copeptin, an established surrogate for AVP, with parameters of renal function and morphology in a multicentric population-based cohort. Participants from families of European ancestry were randomly selected in three Swiss cities. We used linear multilevel regression analysis to explore the association of copeptin with renal function parameters as well as kidney length and the presence of simple renal cysts assessed by ultrasound examination. Copeptin levels were log-transformed. The 529 women and 481 men had median copeptin levels of 3.0 and 5.2 pmol/L, respectively (P<0.001). In multivariable analyses, the copeptin level was associated inversely with eGFR (β=-2.1; 95% confidence interval [95% CI], -3.3 to -0.8; P=0.002) and kidney length (β=-1.2; 95% CI, -1.9 to -0.4; P=0.003) but positively with 24-hour urinary albumin excretion (β=0.11; 95% CI, 0.01 to 0.20; P=0.03) and urine osmolality (β=0.08; 95% CI, 0.05 to 0.10; P<0.001). A positive association was found between the copeptin level and the presence of renal cysts (odds ratio, 1.6; 95% CI, 1.1 to 2.4; P=0.02). These results suggest that AVP has a pleiotropic role in renal function and may favor the development of simple renal cysts.

Scrfl restriction fragment length polymorphism at the D7S23 locus (probe pKM.19), closely linked to cystic fibrosis

Source/Description: pKM.19 is a 1.0 kb EcoRI genomic fragment in pUC13 (ref. 1,2). pPl was isolated independently but contains the same fragment as pKM.19 (ref. 3)...