Belatacept Rescue Therapy in Kidney Transplant Recipients With Vascular Lesions: A Case Control Study.

Immunosuppression in kidney transplant recipients with decreased graft function and severe histological vascular changes can be particularly challenging. Belatacept could be a valuable option, as a rescue therapy in this context. We report a retrospective case control study comparing a CNI to belatacept switch in 17 patients with vascular damage and low eGFR to a control group of 18 matched patients with CNI continuation. Belatacept switch was performed on average 51.5 months after kidney transplantation (6.2-198 months). There was no difference between the two groups regarding eGFR at inclusion, and 3 months before inclusion. In the "CNI to belatacept switch group," mean eGFR increased significantly from 23.5 ± 6.7 mL/min/1.73m2 on day 0, to 30.4 ± 9.1 mL/min/1.73 m2 on month 6 (p < 0.001) compared to the control group, in which no improvement was observed. These results were still significant on month 12. Two patients experienced biopsy-proven acute rejection. One was effectively treated without belatacept discontinuation. Two patients needed belatacept discontinuation for infection. In conclusion, the remplacement of CNI with belatacept in patients with decreased allograft function and vascular lesions is associated with an improvement in eGFR.

Compliance with good practice guidelines for the prevention of vascular access infections: the multi-centre PHYDEL survey in French haemodialysis units.

BACKGROUND: French guidelines for the prevention of vascular access infections in a haemodialysis setting were released in 2005. Compliance with these guidelines is currently unknown. The aim of this study was to assess compliance with the guidelines for vascular access infection prevention in French haemodialysis units, and to describe the difficulties reported. METHODS: A cross-sectional survey was conducted between March and December 2019 in 200 haemodialysis units in France, selected at random. Data were collected via questionnaire, completed by telephone interview with an infection control practitioner. A practice was deemed compliant when >85% of units declared that they always complied with the guidelines. RESULTS: In total, 103 units (51.5%) agreed to participate. Most practices complied with the guidelines; however, some practices did not reach the 85% compliance threshold for working in pairs when connecting central venous catheter (CVC) lines, performing hand hygiene before disconnecting lines, rinsing antiseptic soap before painting CVC exit site or arteriovenous fistula (AVF) puncture site, allowing antiseptic paint to dry, handling CVC branches with antiseptic impregnated gauze, performing hand hygiene after AVF compression with gloves, wearing protective eyewear when connecting/disconnecting CVC or when puncturing AVF, and wearing a gown when puncturing AVF. The most frequently reported difficulties were understaffing, difficulties with skin preparation because of exit site skin damage, and lack of buttonhole technical expertise. CONCLUSIONS: Despite good overall compliance, this survey highlights some shortcomings in compliance with infection prevention guidelines, which could be associated with either higher risk of vascular access infection or increased blood-borne virus transmission.

GW body disassembly triggered by siRNAs independently of their silencing activity.

GW bodies (or P-bodies) are cytoplasmic granules containing proteins involved in both mRNA degradation and storage, including the RNA interference machinery. Their mechanism of assembly and function are still poorly known although their number depends upon the flux of mRNA to be stored or degraded. We show here that silencing of the translational regulator CPEB1 leads to their disappearance, as reported for other GW body components. Surprisingly, the same results were obtained with several siRNAs targeting genes encoding proteins unrelated to mRNA metabolism. The disappearance of GW bodies did not correlate with the silencing activity of the siRNA and did not inhibit further silencing by siRNA. Importantly, in most cases, GW bodies were rapidly reinduced by arsenite, indicating that their assembly was not prevented by the inhibition of the targeted or off-target genes. We therefore propose that some siRNA sequences affect mRNA metabolism so as to diminish the amount of mRNA directed to the GW bodies. As an exception, GW bodies were not reinduced following Rck/p54 depletion by interference, indicating that this component is truly required for the GW body assembly. Noteworthy, Rck/p54 was dispensable for the assembly of stress granules, in spite of their close relationship with the GW bodies.

[Renal transplantation, anxiety and depressive disorders and quality of life]. / Transplantation rénale, troubles anxiodépressifs et qualité de vie.

Until now there are few data in the literature describing psychiatric comorbidity in patients waiting for renal transplantation. We have conducted a cross sectional study estimating the prevalence of anxiety and depressive disorders in three groups of renal transplant patients, before transplantation, six months and one year after. The MINI was used to estimate the prevalence of anxiety and depressive disorders. Anxiety and depressive symptoms were assessed using the HAD. Patients' quality of life was also assessed using the SF-36. This study did not find any major impact of renal transplantation on the prevalence of structured psychiatric disorders. Indeed, the prevalence of depressive and anxiety disorders did not differ significantly between the three groups. The mean scores of anxiety did not differ significantly between the three groups in contrast to the mean scores of depression, which differed significantly between the group "before transplantation" and the group "one year after transplantation". We did not find any significant difference concerning the scores of patient's quality of life between the three groups, except for the item "health perceived by the patients themselves". Health perceived by the patients was greater in the group "after transplantation". The quality of life of dialysed or transplant patients was strongly correlated with anxiety and depressive symptoms scores, emphasizing the major interest of a multidisciplinary approach for these patients.

Regulation of mitochondrial mRNA stability by RNase L is translation-dependent and controls IFNalpha-induced apoptosis.

Interferons (IFNs) inhibit the growth of many different cell types by altering the expression of specific genes. IFNs activities are partly mediated by the 2'-5' oligoadenylates-RNase L RNA decay pathway. RNase L is an endoribonuclease requiring activation by 2'-5' oligoadenylates to cleave single-stranded RNA. Here, we present evidence that degradation of mitochondrial mRNA by RNase L leads to cytochrome c release and caspase 3 activation during IFNalpha-induced apoptosis. We identify and characterize the mitochondrial translation initiation factor (IF2mt) as a new partner of RNase L. Moreover, we show that specific inhibition of mitochondrial translation with chloramphenicol inhibits the IFNalpha-induced degradation of mitochondrial mRNA by RNase L. Finally, we demonstrate that overexpression of IF2mt in human H9 cells stabilizes mitochondrial mRNA, inhibits apoptosis induced by IFNalpha and partially reverses IFNalpha-cell growth inhibition. On the basis of our results, we propose a model describing how RNase L regulates mitochondrial mRNA stability through its interaction with IF2mt.

The 2'-5' oligoadenylate/RNase L/RNase L inhibitor pathway regulates both MyoD mRNA stability and muscle cell differentiation.

The 2'-5' oligoadenylate (2-5A)/RNase L pathway is one of the enzymatic pathways induced by interferon. RNase L is a latent endoribonuclease which is activated by 2-5A and inhibited by a specific protein known as RLI (RNase L inhibitor). This system has an important role in regulating viral infection. Additionally, variations in RNase L activity have been observed during cell growth and differentiation but the significance of the 2-5A/RNase L/RLI pathway in these latter processes is not known. To determine the roles of RNase L and RLI in muscle differentiation, C2 mouse myoblasts were transfected with sense and antisense RLI cDNA constructs. Importantly, the overexpression of RLI in C2 cells was associated with diminished RNase L activity, an increased level of MyoD mRNA, and accelerated kinetics of muscle differentiation. Inversely, transfection of the RLI antisense construct was associated with increased RNase L activity, a diminished level of MyoD mRNA, and delayed differentiation. In agreement with these data, MyoD mRNA levels were also decreased in C2 cells transfected with an inducible RNase L construct. The effect of RNase L activity on MyoD mRNA levels was relatively specific because expression of several other mRNAs was not altered in C2 transfectants. Therefore, RNase L is directly involved in myoblast differentiation, probably through its role in regulating MyoD stability. This is the first identification of a potential mRNA target for RNase L.

Characterization of RNABP, an RNA binding protein that associates with RNase L.

The 2',5'-oligoadenylate (2-5A)/RNase L pathway is one of several enzymatic pathways induced by interferons (IFN). RNase L is a latent endoribonuclease that is activated on its binding by 2-5A and inhibited by the ribonuclease L inhibitor (RLI). We have shown previously by coimmunoprecipitation that RNase L may be associated with a 90-kDa RNA binding protein (RNABP), identified with a monoclonal antibody (mAb) raised against an RNase L complex purified under native conditions on 2-5A-sepharose. Here we confirm, by gel-filtration and pull-down analysis, the association of RNase L and RNABP, and we demonstrate that this association is significantly increased in the presence of 2-5A. Moreover, we found that RNABP protein levels decrease during terminal differentiation in various cell lines but do not vary during vesicular stomatitis virus (VSV) or encephalomyocarditis virus (EMCV) infection or following IFN-alpha/beta treatment. In this latter case, although total cellular RNABP levels do not vary, the amount of RNABP found in the cytoplasm increases in comparison to that found in the nucleus, indicating a cytoplasmic localization of RNABP after IFN-alpha/beta treatment. Finally, we demonstrate the interaction between RNase L and RNABP in intact cells. Microinjection of an mAb against RNABP into HeLa cells inhibits RNase L antiviral activity and partially inhibits the IFN-alpha/beta-induced antiviral activity.

[Interstitial nephropathies of toxic or drug origin. New causes, new prospects]. / Néphropathies interstitielles d'origine médicamenteuse ou toxique. De nouvelles causes, de nouvelles perspectives.

PHENOTYPING INTERSTITIAL INFILTRATIONS: Recent progress has led to the distinction between type I and type II fibroblasts in the renal interstitium. The cellular phenotype of pathological infiltrations can be identified with monoclonal antibodies. DRUG-INDUCED INTERSTITIAL NEPHROPATHIES: Extrarenal manifestations (skin eruptions, fever, joint pain) often suggests the diagnosis but may be absent, in which case renal histology is required. CAUSAL DRUGS: Among the different causal agents, nonsteroid anti-inflammatory drugs cause abnormal leakage from glomerular capillaries favoring the development of a nephrotic syndrome associated with renal failure and major cell infiltration into the interstitial tissue. CHRONIC DISEASE: Chronic interstitial nephropathy is nearly asymptomatic and may only be discovered at an advanced stage. Briefly, there are three categories which result from long-term administration of 5-aminosalicylate, use of Chinese herbal medicines to lose weight, and chronic intoxication with ochratoxin (a mycotoxin). COMPLEX PHYSIOPATHOLOGY: Immunological mechanisms are involved although it is not always easy to distinguish between manifestations of humoral and cellular reactions. Both could be implicated as indicated in recent experimental animal models which throw more light on the pathological process in humans. RENAL PROGNOSIS: Different strategies can be used to halt or limit the development of fibrosis and thus improve prognosis of toxic interstitial nephropathies: counteract cellular immunity reactions, inhibit fibroblast proliferation and activation, reduce synthesis and stimulate degradation of the extracellular matrix, and inhibit collagen formation.

[Nephrotic syndrome complicating treatment with interferon alpha]. / Syndrome néphrotique compliquant un traitement par interféron alpha.

UNLABELLED: We report two cases of nephrotic syndrome with minimal glomerular change complicating alpha-interferon therapy. CASE REPORTS: The first patient was a 60-year-old man with Waldenström's disease who was given 1 million units of alpha-interferon three times a week for 22 months. Acute renal failure developed when a second protocol was started. Renal biopsy revealed intraglomerular deposits and no cellular proliferation. Total remission could not be achieved with corticosteroids. The second case was a 46-year-old man given high dose alpha-interferon (15 million units 3 times a week) for lymph node metastasis of a malignant melanoma. A nephrotic syndrome without renal failure developed during the third month of treatment. Minimal glomerular involvement was seen. Symptomatic treatment led to resolution of the nephrotic syndrome. DISCUSSION: Nine other cases of nephrotic syndrome complicating alpha-interferon therapy have been reported in the literature.

[Functional acute kidney failure]. / Insuffisances rénales aiguës fonctionnelles.

Prerenal acute renal failure is defined as a reduction in the glomerular filtration rate due to a primary disturbance in renal hemodynamics in the absence of any structural kidney damage. In case of moderate hypotension or hypovolemia, a number of adaptative systemic and intrarenal responses preserve renal perfusion and filtration rates, particularly by inducing a marked reduction in preglomerular arteriolar resistance and an increase in postglomerular resistance. However, these mechanisms are inherently limited. In the presence of advanced circulatory failure or iatrogenic pharmacologic interventions compromising these renal defense mechanisms, prerenal failure becomes evident. Therefore, prerenal failure may occur during acute hemodynamic disturbances due to hypovolemia or systemic vasodilatation, in severe cardiac failure, in cirrhosis with ascites, and in certain clinical situations following administration of nonsteroidal antiinflammatory agents or angiotensin converting enzyme inhibitors. The treatment depends on the underlying cause.

[Inflammation markers in daily practice]. / Quels indicateurs de l'inflammation choisir en pratique quotidienne.

Cardiovascular diseases and infections remain the first mortality causes in ESRD patients. European recommendations for good clinical practice in the hemodialysis field advocate to use the inflammation markers in daily practice. These markers foretell both cardiovascular and global mortality. They also enable to detect the silent infections (parodontitis, Heliobacter pilory infection, shunt infection in PTFE), to make sure of the dialysis biocompatibility (microbiological quality of the dialysate, use of biocompatible membrane). The C-reactive protein is the most current and used marker. Its use, combined with the procalcitonin measurement, specific marker for bacterial infection, would enable the diagnostic and therapeutic strategy improvement.

The 2-5A/RNase L/RNase L inhibitor (RLI) [correction of (RNI)] pathway regulates mitochondrial mRNAs stability in interferon alpha-treated H9 cells.

Interferon alpha (IFNalpha) belongs to a cytokine family that exhibits antiviral properties, immuno-modulating effects, and antiproliferative activity on normal and neoplasic cells in vitro and in vivo. IFNalpha exerts antitumor action by inducing direct cytotoxicity against tumor cells. This toxicity is at least partly due to induction of apoptosis. Although the molecular basis of the inhibition of cell growth by IFNalpha is only partially understood, there is a direct correlation between the sensitivity of cells to the antiproliferative action of IFNalpha and the down-regulation of their mitochondrial mRNAs. Here, we studied the role of the 2-5A/RNase L system and its inhibitor RLI in this regulation of the mitochondrial mRNAs by IFNalpha. We found that a fraction of cellular RNase L and RLI is localized in the mitochondria. Thus, we down-regulated RNase L activity in human H9 cells by stably transfecting (i) RNase L antisense cDNA or (ii) RLI sense cDNA constructions. In contrast to control cells, no post-transcriptional down-regulation of mitochondrial mRNAs and no cell growth inhibition were observed after IFNalpha treatment in these transfectants. These results demonstrate that IFNalpha exerts its antiproliferative effect on H9 cells at least in part via the degradation of mitochondrial mRNAs by RNase L.

Altered flow-dependent vasodilatation of conduit arteries in maintenance haemodialysis.

BACKGROUND: An altered arterial nitric oxide (NO) pathway could partly explain the damage to arteries observed in haemodialyzed (HD) patients. The present study was designed to non-invasively evaluate the NO pathway of peripheral conduit arteries in HD patients. METHODS: Twelve normotensive, non-diabetic HD patients treated with erythropoietin and 12 matched healthy controls (C) were included in the study. The effect of endogenous release of NO was assessed by measuring the flow-dependent vasodilatation of the radial artery (post-ischaemic hyperaemia), and the response to exogenous NO assessed using sublingual glyceryl trinitrate administration (GTN). RESULTS: Radial artery diameter (echo-tracking), radial blood flow (RBF: Doppler) and mean arterial pressure (Finapres) were identical at baseline in HD patients and in healthy subjects. The flow-dependent vasodilatation of the radial artery was decreased in HD patients (C: 9 +/- 1% vs HD: 3 +/- 05%, P < 0.05). The decrease in radial vascular resistance (C: -44 +/- 4% vs HD: -24 +/- 2%, P < 0.05) and the increase in radial diameter (C: 31 +/- 2% vs HD: 25 +/- 2%, P < 0.05) after GTN administration were less in HD patients than in controls. The ratio between the increase in diameter after hyperaemia to the increase in diameter after GTN, was also diminished in HD patients (C: 30 +/- 3% vs HD: 13 +/- 2%, P < 0.001). CONCLUSIONS: The flow-dependent vasodilatation of peripheral conduit arteries is altered in HD patients and is associated with a slight but significant decrease in the vasodilating response to exogenous NO. These results suggest, in the absence of changes in basal radial vascular resistance and arterial diameter, more a decrease in endothelial NO bioavailability, than an increase in basal vascular tone.