Expression of killer cell immunoglobulin-like receptors (KIRs) by natural killer cells during acute CMV infection after kidney transplantation.

Human cytomegalovirus (CMV) infection may be a serious complication related to immunosuppression after solid organ transplantation. Due to their cytotoxicity, T-cells and natural killer (NK) cells target and clear the virus from CMV-infected cells. Although immunosuppressive drugs suppress T-cell proliferation and activation, they do not affect NK cells that are crucial for controlling the infection. The regulation of NK cells depends on a wide range of activating and inhibitory receptors such as the family of killer-cell immunoglobulin-like receptors (KIRs). Several human genetic studies have demonstrated the association of KIR genes with the clearance of infections. Since the respective activities of the different KIR proteins expressed by NK cells during CMV infection have not been extensively studied, we analyzed the expression of KIRs in a cohort of 22 CMV-IgG(+) renal transplant patients at the time of CMV reactivation, after antiviral therapy and 6 months later. Our data revealed a marked expression of KIR3DL1 during the acute phase of the reactivation. We set up an in vitro model in which NK cells, derived either from healthy donors or from transplanted patients, target allogeneic fibroblasts, CMV-infected or uninfected. Our results demonstrate a significant correlation between the lysis of CMV-infected fibroblasts and the expression of KIR3DL1. Blocking experiments with antibodies to MHC-I, to NKG2D and to NKG2C confirmed the importance of KIR3DL1. Consequently, our results suggest that KIR proteins and especially KIR3DL1 could play an important role during CMV-infection or CMV reactivation in immunosuppressed patients.

Increased renal responsiveness to vasopressin and enhanced V2 receptor signaling in RGS2-/- mice.

The antidiuretic effect of vasopressin is mediated by V2 receptors (V2R) that are located in kidney connecting tubules and collecting ducts. This study provides evidence that V2R signaling is negatively regulated by regulator of G protein signaling 2 (RGS2), a member of the family of RGS proteins. This study demonstrates that (1) RGS2 expression in the kidney is restricted to the vasopressin-sensitive part of the nephron (thick ascending limb, connecting tubule, and collecting duct); (2) expression of RGS2 is rapidly upregulated by vasopressin; (3) the vasopressin-dependent accumulation of cAMP, the principal messenger of V2R signaling, is significantly higher in collecting ducts that are microdissected from the RGS2(-/-) mice compared with their wild-type littermates; and (4) analysis of urine output of mice that were exposed to water restriction followed by acute water loading revealed that RGS2(-/-) mice exhibit an increased renal responsiveness to vasopressin. It is proposed that RGS2 is involved in negative feedback regulation of V2R signaling.

Validity of Charlson Comorbidity Index in patients hospitalised with acute coronary syndrome. Insights from the nationwide AMIS Plus registry 2002-2012.

OBJECTIVE: This study aimed to assess the impact of individual comorbid conditions as well as the weight assignment, predictive properties and discriminating power of the Charlson Comorbidity Index (CCI) on outcome in patients with acute coronary syndrome (ACS). METHODS: A prospective multicentre observational study (AMIS Plus Registry) from 69 Swiss hospitals with 29 620 ACS patients enrolled from 2002 to 2012. The main outcome measures were in-hospital and 1-year follow-up mortality. RESULTS: Of the patients, 27% were female (age 72.1 ± 12.6 years) and 73% were male (64.2 ± 12.9 years). 46.8% had comorbidities and they were less likely to receive guideline-recommended drug therapy and reperfusion. Heart failure (adjusted OR 1.88; 95% CI 1.57 to 2.25), metastatic tumours (OR 2.25; 95% CI 1.60 to 3.19), renal diseases (OR 1.84; 95% CI 1.60 to 2.11) and diabetes (OR 1.35; 95% CI 1.19 to 1.54) were strong predictors of in-hospital mortality. In this population, CCI weighted the history of prior myocardial infarction higher (1 instead of -0.4, 95% CI -1.2 to 0.3 points) but heart failure (1 instead of 3.7, 95% CI 2.6 to 4.7) and renal disease (2 instead of 3.5, 95% CI 2.7 to 4.4) lower than the benchmark, where all comorbidities, age and gender were used as predictors. However, the model with CCI and age has an identical discrimination to this benchmark (areas under the receiver operating characteristic curves were both 0.76). CONCLUSIONS: Comorbidities greatly influenced clinical presentation, therapies received and the outcome of patients admitted with ACS. Heart failure, diabetes, renal disease or metastatic tumours had a major impact on mortality. CCI seems to be an appropriate prognostic indicator for in-hospital and 1-year outcomes in ACS patients. ClinicalTrials.gov Identifier: NCT01305785.

Effect of captopril on renal vascular tone in patients with essential hypertension.

1. The effect of acute inhibition of angiotensin-converting enzyme by captopril (50 mg) on renal haemodynamics and function was assessed in nine patients with essential hypertension on unrestricted sodium intake (n = 8) or low sodium diet (n = 1). 2. Captopril induced a rapid and significant decrease in arterial pressure, which was maximal within 60 min. 3. Effective renal plasma flow (ERPF) increased, glomerular filtration rate (GFR) did not change and filtration fraction (FF) decreased after captopril. No change in sodium excretion and a decrease in urinary potassium occurred. 4. In the patient on low sodium diet, captopril induced striking increases in GFR and ERPF (64 and 106% respectively). 5. The logarithm of baseline plasma renin activity was positvely correlated with the change in ERPF and negatively correlated with changes in FF and renal resistance. 6. The results indicate that in patients with essential hypertension angiotensin participates actively in the maintenance of renal vascular tone at the efferent arteriolar level. A possible influence of kinins remains to be defined.

Effect of indomethacin on the renal response to angiotensin II receptor blockade in healthy subjects.

BACKGROUND: Non-steroidal anti-inflammatory drugs are known to promote sodium retention and to blunt the blood pressure lowering effects of several classes of antihypertensive agents including beta-blockers, diuretics and angiotensin converting enzyme (ACE) inhibitors. The purpose of the present study was to investigate the acute and sustained effects of indomethacin on the renal response to the angiotensin II receptor antagonist valsartan and to the ACE inhibitor enalapril. METHODS: Twenty normotensive subjects maintained on fixed sodium intake (100 mmol sodium/day) were randomized to receive for one week: valsartan 80 mg o.d., enalapril 20 mg o.d., valsartan 80 mg o.d. + indomethacin 50 mg bid and enalapril 20 mg o.d. + indomethacin 50 mg bid. This single-blind study was designed as a parallel (valsartan vs. enalapril) and cross-over trial (valsartan or enalapril vs. valsartan + indomethacin or enalapril + indomethacin). Renal hemodynamics and urinary electrolyte excretion were measured for six hours after the first and seventh administration of each treatment regimen. RESULTS: The results show that valsartan and enalapril have comparable renal effects characterized by no change in glomerular filtration rate and significant increases in renal plasma flow and sodium excretion. The valsartan- and enalapril-induced renal vasodilation is not significantly blunted by indomethacin. However, indomethacin similarly abolishes the natriuresis induced by the angiotensin II antagonist and the ACE inhibitor. CONCLUSIONS: This observation suggests that although angiotensin receptor antagonists do not affect prostaglandin metabolism, the administration of a non-steroidal anti-inflammatory drug blunts the natriuretic response to angiotensin receptor blockade.

Role of intra-operative duplex ultrasound in living renal donor transplantation

Objective: The treatment of choice in end-stage renal disease is¦transplantation.¦Hemodynamic disturbances can evoke graft loss, while early ultrasound¦identification of vascular problems improves outcome. The primary endpoint¦of this study was to identify differences in post-op complications with and¦without systematic, intraoperative Doppler ultrasound use. A secondary aim¦was to find a predictive resistance index limit which would show where surgical¦reintervention was necessary.¦Methods: Between Jan 2000 and Dec 2010, 108 renal transplants were¦performed from living donors at our institution. In group 1 (n = 67),¦intra-operative duplex ultrasound and intra-parenchymatous resistance index¦measurements assessed patients, while in group 2 (n = 41), no ultrasound was¦performed.¦Results. There were no inter-group differences in the overall post-op¦complication rate or in benefit to graft or patient survival with Doppler use,¦however, significantly more vascular complications (10% vs. 0%, p = 0·02) and¦more acute rejections (37% vs. 10%) occurred in group 2 than in group 1,¦respectively. When the resistance index was <0·5 intra-operatively, immediate¦surgical revision was undertaken to raise the index >0·6.¦Results: There were no inter-group differences in the overall post-op¦complication rate or in benefit to graft or patient survival with Doppler use,¦however, significantly more vascular complications (10% vs. 0%, p = 0·02) and¦more acute rejections (37% vs. 10%) occurred in group 2 than in group 1,¦respectively. When the resistance index was <0·5 intra-operatively, immediate¦surgical revision was undertaken to raise the index >0·6.¦Conclusion: This is the first report demonstrating benefits of systematic¦intraoperative Doppler ultrasound on post-operative complications in renal¦transplantation from living donors. Our results support surgical revision with a¦resistance index <0·5.

Bolus injections of synthetic atrial natriuretic peptide in patients with chronic renal failure or nephrotic syndrome.

The diuretic and natriuretic responses to exogenous synthetic atrial natriuretic peptide (ANP) were evaluated in patients with chronic renal failure (CRF) or nephrotic syndrome (NS). Patients were studied after an oral water load (8 ml/kg in CRF and 20 ml/kg in NS patients). A short intravenous bolus of either a placebo or ANP was administered when urine output was stable. In each group of patients, three doses of ANP were injected at 24 h intervals, i.e., 1.0, 1.5, and 2.0 micrograms/kg in the CRF and 1.0, 1.5, and 3.0 micrograms/kg in the NS group. Blood pressure and heart rate were monitored throughout the study and urinary volume and electrolyte excretion were measured every 20 min up to 3 h after the bolus. An acute and transient fall in blood pressure was observed immediately after the ANP injection. It was more pronounced in CRF than in NS patients. In CRF patients, ANP caused only a slight increase in urinary volume (13.5-44% over baseline) but a significant increase in urinary sodium excretion (45-114% over baseline). In NS patients, significant increases in both urine volume (60-105%) and sodium excretion (149-248%) were also found. In these latter patients, the renal response to ANP appeared to be better preserved. The hemodynamic and renal changes induced by ANP occurred mainly during the first 20 min following the ANP administration, when the peak plasma ANP levels were obtained. However, no clear dose-response effect could be evidenced in either group with the three doses of ANP chosen in this study.

The "open" chimney graft technique for juxtarenal aortic aneurysms with discrepant renal arteries.

OBJECTIVES: A straightforward original Chimney Graft (CG) protocol has been developed at our institution in selected cases of juxtarenal aortic aneurysm (JRAA). The aim of this study was to present our clinical experience of consecutive series with use of uncovered self-expanding stent (SES) as "Open Chimney" (OCh) in the endovascular repair (EVAR) of JRAA. METHODS: A standard endograft with suprarenal fixation struts is delivered with its proximal covered edge just below the highest RA in JRAA presenting the ostium of the two renal arteries at a different aortic level and the distance between the highest renal artery and the beginning of the aneurysm (improved landing zone) ≥10 mm. The low-lying renal artery is maintained patent by the OCh graft (standard SES) delivered from left brachial access (6 Fr). All clinical, anatomical, and operative data were prospectively collected and retrieved for the study analysis. RESULTS: From July 2010 to November 2012, OCh EVAR was offered to 22 consecutive patients considered unfit for JRAA open repair. All procedures were technically successful with aneurysm exclusion and patent OCh graft. One small perioperative type Ia endoleak spontaneously disappeared at the 3-month CT control. One patient died because of acute decompensated heart failure. One patient presented a left hemispheric stroke. The median follow-up of 18 months (range 7-35) showed aneurysm exclusion in all patients without type I and III endoleaks, SES stenosis, and/or renal impairment. CONCLUSIONS: OCh-EVAR is a straightforward technique that can be employed in selected cases of JRAA, avoiding the more complex and expensive fenestrated EVAR.

Relapsing acute respiratory failure induced by minocycline.

The antibiotic minocycline, which is used in the treatment of acne, has been associated with various pulmonary complications such as pulmonary lupus and hypersensitivity pneumonitis. We now report a particularly severe case of minocycline-related pulmonary toxicity that was characterized by a relapsing form of hypersensitivity eosinophilic pneumonia complicated by acute respiratory failure.

Défaillances respiratoires aiguës d'origine neuromusculaire [Acute respiratory failure due to neuromuscular disorders].

Numerous acute and chronic neuromuscular disorders may induce an acute ventilatory failure. The latter is sometimes triggered by a complication like a bronchial aspiration, a pneumonia, or an atelectasis. The acute ventilatory failure often develops insidiously and may be missed until the terminal event. Four different clinical presentations are depicted in this review: slowly progressive (Duchenne muscular dystrophy), rapidly progressive (Guillain-Barré syndrome), chronic with exacerbations (myasthenia gravis), and a form consecutive to critical care (critical care polyneuropathy and myopathy). For each type of ventilatory failure, the review discusses the preventive surveillance, the treatment of acute respiratory failure, and the long-term management.

Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4.

In AKI, dying renal cells release intracellular molecules that stimulate immune cells to secrete proinflammatory cytokines, which trigger leukocyte recruitment and renal inflammation. Whether the release of histones, specifically, from dying cells contributes to the inflammation of AKI is unknown. In this study, we found that dying tubular epithelial cells released histones into the extracellular space, which directly interacted with Toll-like receptor (TLR)-2 (TLR2) and TLR4 to induce MyD88, NF-κB, and mitogen activated protein kinase signaling. Extracellular histones also had directly toxic effects on renal endothelial cells and tubular epithelial cells in vitro. In addition, direct injection of histones into the renal arteries of mice demonstrated that histones induce leukocyte recruitment, microvascular vascular leakage, renal inflammation, and structural features of AKI in a TLR2/TLR4-dependent manner. Antihistone IgG, which neutralizes the immunostimulatory effects of histones, suppressed intrarenal inflammation, neutrophil infiltration, and tubular cell necrosis and improved excretory renal function. In summary, the release of histones from dying cells aggravates AKI via both its direct toxicity to renal cells and its proinflammatory effects. Because the induction of proinflammatory cytokines in dendritic cells requires TLR2 and TLR4, these results support the concept that renal damage triggers an innate immune response, which contributes to the pathogenesis of AKI.

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

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

Abnormalities of sodium excretion and other disorders of renal function in fulminant hepatic failure

Renal function was evaluated in 40 patients with fulminant hepatic failure, They were divided into two groups on the basis of glomerular filtration rates greater than 40 ml/min or less than 25 ml/min. A number of patients in group 1 had markedly abnormal renal retention of sodium together with a reduced free water clearance and low potassium excretion which could be explained by increased proximal tubular reabsorption of sodium. The patients in group 2 had evidence that renal tubular integrity was maintained when the glomerular filtration rate was greater than or equal ml/min (functional renal failure), but evidence of tubular damage was present when this was less than 3 ml/min (acute tubular necrosis).