CYT003, a TLR9 agonist, in persistent allergic asthma - a randomized placebo-controlled Phase 2b study.

BACKGROUND: New treatment options are required for patients with asthma not sufficiently controlled with inhaled therapies. In a Phase 2a trial, CYT003, a Toll-like receptor-9 agonist immunomodulator, improved asthma control during inhaled glucocorticosteroid reduction in patients with allergic asthma. This double-blind Phase 2b study assessed the efficacy and safety of CYT003 in patients with persistent moderate-to-severe allergic asthma not sufficiently controlled on standard inhaled glucocorticosteroid therapy with/without long-acting beta-agonists (LABAs). METHODS: Overall, 365 patients received seven doses of subcutaneous CYT003 (0.3, 1, or 2 mg) or placebo as add-on therapy to conventional controller medication. Change from baseline in Asthma Control Questionnaire (ACQ) score was the primary outcome; secondary outcomes included change in forced expiratory volume, Mini Asthma Quality of Life Questionnaire, and safety. RESULTS: All groups, including placebo, showed a clinically important improvement in ACQ score; however, there was no significant difference between the CYT003 and placebo groups at week 12 (least-squares mean difference 0.3 mg: -0.027 [95% confidence interval -0.259 to 0.204]; 1 mg: 0.097 [-0.131 to 0.325]; 2 mg: 0.081 [-0.148 to 0.315]). No significant differences were seen in secondary outcomes. CYT003 was well tolerated; the most common treatment-emergent adverse events were injection site reactions. Due to lack of efficacy, the study was prematurely terminated at the end of the treatment phase with no further follow-up. CONCLUSIONS: Toll-like receptor-9 agonism with CYT003 showed no additional benefit in patients with insufficiently controlled moderate-to-severe allergic asthma receiving standard inhaled glucocorticosteroid therapy with or without LABAs.

[Prescribing diuretics: what a practitioner needs to know]. / Utilisation des diurétiques: ce que le praticien doit connaître.

Diuretics are among the most frequently prescribed drugs. Most of them act by inhibiting sodium reabsorption in various nephron segments. By understanding their pharmacological characteristics, it is possible to adapt the type of diuretic to different clinical situations. Practical aspects of their use, including in heart failure, cirrhosis, the nephrotic syndrome and renal failure, are discussed.

[Oxalate nephropathy: a new entity of acute kidney injury in diabetic patients?]. / La néphropathie aiguë à oxalates: une cause d'insuffisance rénale aiguë à rechercher.

Acute oxalate nephropathy is a severe cause of acute kidney injury characterized by tubule-interstitial oxalate deposits with an inflammatory infiltrate. Three cases of AKI occuring in diabetic patients, and whose renal biopsy gave a diagnosis of acute oxalate nephropathy are reported. This cristal deposit AKI is due to either primary hyperoxaluria or secondary to enteric hyperabsorption. Its prognosis is dismal and rapid recognition by renal biopsy and determination of the cause of hyperoxaluria is mandatory in order to avoid end-stage kidney disease. This diagnosis should be suspected in cases of non resolving AKI, especially in diabetic patients who may have undetected pancreatic exocrine insufficiency.

IgG-mediated down-regulation of IgE bound to mast cells: a potential novel mechanism of allergen-specific desensitization.

BACKGROUND: Allergen-specific IgGs are known to inhibit IgE-mediated mast cell degranulation by two mechanisms, allergen-neutralization and engagement of the inhibitory FcγRIIB recruiting the phosphatase SHIP-1. Here we unravel an additional mechanism of IgG-mediated mast cell desensitization in mice: down-regulation of allergen-specific IgE. METHODS: Mast cells were loaded in vitro and in vivo with monoclonal IgE antibodies specific for Fel d1 and exposed to immune complexes consisting of Fel d1-specific IgG antibodies recognizing different epitopes. Down regulation of IgE was followed by flow cytometry. RESULTS: Mast cells loaded with 2 different IgE antibodies efficiently internalized the IgE antibodies if exposed to recombinant Feld d1. In contrast, no down-regulation occurred if mast cells were loaded with IgE antibodies exhibiting a single specificity before stimulation with recombinant Fel d1 [corrected]. Interestingly, however, IgEs of a single specificity were rapidly down-regulated in vitro and in vivo in the presence of Fel d1-specific monoclonal IgGs recognizing another epitope on Fel d1. Despite FceRI-internalization, little calcium flux or mast cell degranulation occurred. FcγRIIB played a dual role in the process since it enhanced IgE internalization and prevented cellular activation as documented by the inhibited calcium flux and mast cell degranulation. Similar observations were made in the presence of low concentrations of IgEs recognizing several epitopes on Fel d1. CONCLUSION: We demonstrate here that Fel d1-specific IgG antibodies interact with FcγRIIB which (i) promotes IgE internalization; and (ii) inhibits mast cell activation. These results broaden our understanding of allergen-specific desensitization and may provide a mechanism for long-term desensitization of mast cells by selective removal of long-lived IgE antibodies on mast cells.

[The cardiorenal syndrome in 2013: definition, mechanisms and new possible treatments]. / Le syndrome cardio-rénal en 2013: définition, physiopathologie et options thérapeutiques.

The cardiorenal syndrome refers to a group of conditions resulting in cardiac and renal dysfunctions. The mechanisms contributing to this syndrome depend on which organ is primarily affected. Even if the correction of a potential underlying cause is the first therapeutic step, appropriate fluid management is nonetheless essential. Both diuretics and ultrafiltration strategies are discussed and new possible treatments are mentioned.

Targeted mupirocin-based decolonization for Staphylococcus aureus carriers and the subsequent risk of mupirocin resistance in haemodialysis patients - a longitudinal study over 20 years.

Mupirocin-based decolonization of Staphylococcus aureus carriers undergoing haemodialysis is not widely implemented due to concerns of mupirocin resistance. In our haemodialysis unit, a strategy combining universal S. aureus screening with targeted mupirocin-based decolonization was introduced two decades ago. In this study of haemodialysis patients, mupirocin resistance was assessed in blood and colonizing S. aureus isolates during two periods. Mupirocin resistance in S. aureus was infrequent in both blood and colonizing isolates. Furthermore, in the years 2003-2021, a decreasing trend in the annual rate of S. aureus bloodstream infections was observed. Targeted mupirocin-based decolonization of S. aureus carriers undergoing haemodialysis is a sustainable measure for preventing healthcare-associated infections.

[Is the use of vitamin K antagonists harmful in patients with CDK?]. / Anticoagulants de type antivitamines K: effets délétères potentiels chez les patients avec une IRC.

As chronic kidney disease (CKD) is a contraindication to the use of the new anticoagulants, the vitamin K antagonists (VKA) are still valid in patients with CKD, though their use may be harmful. During overanticoagulation, some patients can develop acute kidney injury (AKI), especially those with CKD, by obstruction of the renal tubules and Bowman's spaces by erythrocytes. In addition, VKA increase atherogenesis through vitamin K deficiency, which is essential for the carboxylation of proteins that inhibit calcification of vessels. Eventually, hemodialysed patients under VKA have an increased risk of stroke, especially those over 75 years of age. Therefore anticoagulation with VKA in patients with CKD should be carefully implemented and its monitoring more frequent than in non-CKD patients.

[Nephrology]. / Néphrologie.

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.

[Diuretics in acute kidney failure: useful or harmful?]. / Diurétiques dans le traitement de l'insuffisance rénale aiguë: utiles ou délétères?

Loop diuretics are commonly prescribed within different clinical settings to prevent and or to treat acute renal failure. In most cases they facilitate fluid management following an increased urine output. Experimental models in animals revealed protective effects of loop diuretics in acute renal failure. Several clinical trials have failed to outline better outcomes associated with the use of diuretics in acute renal failure as there was no recovery in renal function nor a reduction in the number of dialysis sessions required. Glomerular filtration rate did not improve with the administration of loop diuretics after continuous renal replacement therapy. The administration of loop diuretics in the management of acute renal failure should be mainly restricted to patients with hypervolemia.

[Treatment of gout in patients with chronic kidney disease]. / Traitement de la goutte chez l'insuffisant rénal.

Hyperuricemia and its clinical manifestations, such as gout, are frequently encountered in patients with chronic renal disease and renal transplants. Usual treatments are either contraindicated or are prone to side-effects in these patients. Presently, there is no clear concensus regarding therapeutic guidelines of hyperuricemia and gout in this subset of patients. Steroids remain the more effective and safer treatment in absence of superimposed infection. Though allopurinol is not recommended for prophylaxis of hyperuricemia, this drug is still the cornerstone in the treatment of patients suffering from gout and is rather well tolerated when posology is adapted.

[The importance of education in the management of chronic kidney disease patient]. / Prise en charge du patient insuffisant rénal: intérêt d'une approche educative complémentaire au suivi médical.

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.

[Nephrology]. / Néphrologie.

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.

Celecoxib versus ibuprofen in the prevention of heterotopic ossification following total hip replacement: a prospective randomised trial.

We examined whether a selective cyclooxygenase-2 (COX-2) inhibitor (celecoxib) was as effective as a non-selective inhibitor (ibuprofen) for the prevention of heterotopic ossification following total hip replacement. A total of 250 patients were randomised to receive celecoxib (200 mg b/d) or ibuprofen (400 mg t.d.s) for ten days after surgery. Anteroposterior radiographs of the pelvis were examined for heterotopic ossification three months after surgery. Of the 250 patients, 240 were available for assessment. Heterotopic ossification was more common in the ibuprofen group (none 40.7% (50), Brooker class I 46.3% (57), classes II and III 13.0% (16)) than in the celecoxib group (none 59.0% (69), Brooker class I 35.9% (42), classes II and III 5.1% (6), p=0.002). Celecoxib was more effective than ibuprofen in preventing heterotopic bone formation after total hip replacement.

[Renal metabolic acidosis: physiopathology, diagnosis and treatment]. / L'acidose métabolique rénale: physiopathologie, diagnostic et traitement.

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.

[Anticoagulation in patients with chronic renal failure]. / Anticoagulation chez l'insuffisant rénal.

Anticoagulation may be difficult to implement in patients suffering from chronic renal failure on account of platelet disorders and impaired clearance of some anticoagulant drugs. Although no adjustment of heparin and coumarin dosage is necessary, more frequent testing of coagulation pathways may be required when these drugs are used in patients with renal failure. Long-term use of LMWH should be implemented cautiously with regular testing of anti-factor Xa activity and a half-dose may be advocated in patients with a creatinine clearance < 30 ml/mn. Danaparoid and thrombin inhibitors should be used mainly in patients suffering from renal failure and heparin-induced thrombocytopenia with regular monitoring of coagulation tests.

[Nephrology]. / Néphrologie.

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.

Expression of human papillomavirus 16 E2 protein in Schizosaccharomyces pombe delays the initiation of mitosis.

Infection by some types of human papillomavirus (HPV) is associated with the development of cervical cancer. Analysis of viral DNA from cervical tumours shows that the E2 gene is frequently disrupted during integration into the host cell's DNA. It has therefore been suggested that loss of E2p is an important step in malignant transformation. Expression of E2p in the fission yeast Schizosaccharomyces pombe retards the G2-M transition, by delaying activation of Cdc2p kinase. In contrast, S phase progression, and commitment to cell division in late G1 are not affected. The delay is independent of the transcriptional trans-activation function of E2p, and does not result from E2p DNA binding mimicking DNA damage. Increased expression of E2p also delays mitotic initiation in mammalian cells. S. pombe may thus provide a simple model for the analysis of E2p function.

Risk factors for early failure of native arteriovenous fistulas.

INTRODUCTION: Current guidelines recommend native arteriovenous fistulas (AVF) as the vascular access of choice for hemodialysis on account of the lower incidence of complications. However, this kind of vascular access has a high rate of early failure (early thrombosis or non-maturation). Our aim was to examine whether clear risk factors for early AVF failure could be identified in our patients. SUBJECTS AND METHODS: Data of all patients who underwent creation of an AVF at the Geneva University Hospital from January 1998 to December 2002 were reviewed. Early failure was defined as a non-functioning fistula (thrombosis or absence of fistula maturation). RESULTS: 119 patients underwent the creation of 148 native AVF, 88 (59.5%) in the forearm and 60 (40.5%) in the upper arm. 48 (32.4%) fistulae were created in diabetic patients. In a multiple logistic regression analysis, significant predictive factors of early failure were a distal location (adjusted odds ratio (aOR) = 8.21, 95% CI = 2.63-25.63, p < 0.001), female gender (aOR = 4.04, 95% CI = 1.44-11.30, p = 0.008), level of surgical expertise (aOR = 3.97, 95% CI = 1.39-11.32, p = 0.010) and diabetes mellitus (aOR = 3.19, 95% CI = 1.17-8.71, p = 0.024). CONCLUSION: Early failure of AVF occurs mainly in forearm sites among women and diabetic patients. Surgical expertise has also a significant influence. These results suggest that selection of a distal site for a native AVF has to be rigorously made for women and diabetic patients and that surgeon's dedication is of primary importance to avoid early AVF failure occurrence.

[Prevention of contrast nephropathy: myth or reality?]. / Prevention de la néphropathie au produit de contraste: du mythe a la réalité.

Prevention of Contrast Media induced acute renal failure is of importance, especially in patients with chronic renal failure. Vasodilatators such as fenoldopam and prophylactic hemodialysis have been reported to procure disappointing results. Hydratation prior to and post- exposure to contrast media remains the cornerstone of prevention. Urine alcalinisation with sodium bicarbonate may bring additional renoprotection. Use of a small quantity of contrast media and Acetylcysteine concomitantly to hydratation are also recommended.

Urinary calcium/creatinine ratio as a predictor of preeclampsia.

Hypocalciuria has been associated with preeclampsia (gestational hypertension with proteinuria or other maternal organ dysfunction) but not usually with pure gestational hypertension or normal pregnancy. We hypothesized that hypocalciuria would be a marker of emerging preeclampsia in women presenting with gestational hypertension who later developed preeclampsia. Eighty-one women with de novo hypertension in the second half of pregnancy (n = 81) were enrolled prospectively. At first assessment, calcium/creatinine ratio was determined in a spot urine. Patients were followed until delivery and were classified subsequently according to the occurrence of preeclampsia. Gestational hypertensive patients who became preeclamptic (n = 31) had lower urinary calcium/creatinine ratios at presentation (ratio = 0.07, interquartile range [IQR] = 0.04-0.11) than women who remained as gestational hypertensives (n = 50; ratio = 0.17, IQR = 0.08-0.21; P = .002). Intact plasma parathyroid hormone (PTH) concentrations were similar between groups. Using a receiver operator curve, the best threshold value for the development of preeclampsia was a calcium/creatinine ratio of 0.10, which yielded a sensitivity of only 68% and a specificity of 70%. A low calcium/creatinine ratio preceded the emergence of preeclampsia by 12 (7-24) (median [IQR]) days among a group of women with gestational hypertension. Though this implies primary or secondary disturbances of renal calcium handling even before preeclampsia is clinically apparent, this measurement does not have sufficient sensitivity to recommend its use as a screening test for the emergence of preeclampsia.