Circadian regulation of renal function and potential role in hypertension.

PURPOSE OF REVIEW: Previous studies have shown that a variety of specific renal functions exhibit circadian oscillations. This review aims to provide an update on the molecular mechanisms underlying circadian rhythms in the kidney, and to discuss how dysregulation of circadian rhythms can interfere with kidney function. RECENT FINDINGS: The molecular mechanism responsible for generating and maintaining circadian rhythms has been unraveled in great detail. This mechanism, known as the circadian clock, drives circadian oscillation in expression levels of a large number of renal mRNA transcripts. Several proteins critically involved in renal homeostatic functions have been shown to exhibit significant circadian oscillation in their expression levels or in their posttranslational modifications. In transgenic mouse models, disruption of circadian clock activity results in dramatic changes in the circadian pattern of urinary sodium and potassium excretion and causes significant changes in arterial blood pressure. A growing amount of evidence suggests that dysregulation of circadian rhythms is associated with the development of hypertension and accelerated progression of chronic kidney disease and cardiovascular disease in humans. Chronotherapy studies have shown that the efficacy of antihypertensive medication is greatly dependent on the circadian time of drug administration. SUMMARY: Recent research points to the major role of circadian rhythms in renal function and in control of blood pressure.

Anemia and chronic kidney disease are potential risk factors for mortality in stroke patients: a historic cohort study.

BACKGROUND: Chronic kidney disease (CKD) is associated to a higher stroke risk. Anemia is a common consequence of CKD, and is also a possible risk factor for cerebrovascular diseases. The purpose of this study was to examine if anemia and CKD are independent risk factors for mortality after stroke. METHODS: This historic cohort study was based on a stroke registry and included patients treated for a first clinical stroke in the stroke unit of one academic hospital over a three-year period. Mortality predictors comprised demographic characteristics, CKD, glomerular filtration rate (GFR), anemia and other stroke risk factors. GFR was estimated by means of the simplified Modification of Diet in Renal Disease formula. Renal function was assessed according to the Kidney Disease Outcomes Quality Initiative (K/DOQI)-CKD classification in five groups. A value of hemoglobin < 120 g/L in women and < 130 g/L in men on admission defined anemia. Kaplan-Meier survival curves and Cox models were used to describe and analyze one-year survival. RESULTS: Among 890 adult stroke patients, the mean (Standard Deviation) calculated GFR was 64.3 (17.8) ml/min/1.73 m2 and 17% had anemia. Eighty-two (10%) patients died during the first year after discharge. Among those, 50 (61%) had K/DOQI CKD stages 3 to 5 and 32 (39%) stages 1 or 2 (p < 0.001). Anemia was associated with an increased risk of death one year after discharge (p < 0.001). After adjustment for other factors, a higher hemoglobin level was independently associated with decreased mortality one year after discharge [hazard ratio (95% CI) 0.98 (0.97-1.00)]. CONCLUSIONS: Both CKD and anemia are frequent among stroke patients and are potential risk factors for decreased one-year survival. The inclusion of patients with a first-ever clinical stroke only and the determination of anemia based on one single measure, on admission, constitute limitations to the external validity. We should investigate if an early detection and management of both CKD and anemia could improve survival in stroke patients.

Azole resistance by loss of function of the sterol Δ⁵,⁶-desaturase gene (ERG3) in Candida albicans does not necessarily decrease virulence.

The inactivation of ERG3, a gene encoding sterol Δ⁵,⁶-desaturase (essential for ergosterol biosynthesis), is a known mechanism of in vitro resistance to azole antifungal drugs in the human pathogen Candida albicans. ERG3 inactivation typically results in loss of filamentation and attenuated virulence in animal models of disseminated candidiasis. In this work, we identified a C. albicans clinical isolate (VSY2) with high-level resistance to azole drugs in vitro and an absence of ergosterol but normal filamentation. Sequencing of ERG3 in VSY2 revealed a double base deletion leading to a premature stop codon and thus a nonfunctional enzyme. The reversion of the double base deletion in the mutant allele (erg3-1) restored ergosterol biosynthesis and full fluconazole susceptibility in VSY2, confirming that ERG3 inactivation was the mechanism of azole resistance. Additionally, the replacement of both ERG3 alleles by erg3-1 in the wild-type strain SC5314 led to the absence of ergosterol and to fluconazole resistance without affecting filamentation. In a mouse model of disseminated candidiasis, the clinical ERG3 mutant VSY2 produced kidney fungal burdens and mouse survival comparable to those obtained with the wild-type control. Interestingly, while VSY2 was resistant to fluconazole both in vitro and in vivo, the ERG3-derived mutant of SC5314 was resistant only in vitro and was less virulent than the wild type. This suggests that VSY2 compensated for the in vivo fitness defect of ERG3 inactivation by a still unknown mechanism(s). Taken together, our results provide evidence that contrary to previous reports inactivation of ERG3 does not necessarily affect filamentation and virulence.

Expression and function of macrophage migration inhibitory factor (MIF) in melioidosis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) has emerged as a pivotal mediator of innate immunity and has been shown to be an important effector molecule in severe sepsis. Melioidosis, caused by Burkholderia pseudomallei, is an important cause of community-acquired sepsis in Southeast-Asia. We aimed to characterize the expression and function of MIF in melioidosis. METHODOLOGY AND PRINCIPAL FINDINGS: MIF expression was determined in leukocytes and plasma from 34 melioidosis patients and 32 controls, and in mice infected with B. pseudomallei. MIF function was investigated in experimental murine melioidosis using anti-MIF antibodies and recombinant MIF. Patients demonstrated markedly increased MIF mRNA leukocyte and MIF plasma concentrations. Elevated MIF concentrations were associated with mortality. Mice inoculated intranasally with B. pseudomallei displayed a robust increase in pulmonary and systemic MIF expression. Anti-MIF treated mice showed lower bacterial loads in their lungs upon infection with a low inoculum. Conversely, mice treated with recombinant MIF displayed a modestly impaired clearance of B. pseudomallei. MIF exerted no direct effects on bacterial outgrowth or phagocytosis of B. pseudomallei. CONCLUSIONS: MIF concentrations are markedly elevated during clinical melioidosis and correlate with patients' outcomes. In experimental melioidosis MIF impaired antibacterial defense.

Agents anti-infectieux et fonction réna!e: vers des posologies sur mesure [Antimicrobial agents and renal elimination: towards individual dosage adjustment?].

The efficacy and safety of anti-infective treatments are associated with the drug blood concentration profile, which is directly correlated with a dosing adjustment to the individual patient's condition. Dosing adjustments to the renal function recommended in reference books are often imprecise and infrequently applied in clinical practice. The recent generalisation of the KDOQI (Kidney Disease Outcome Quality Initiative) staging of chronically impaired renal function represents an opportunity to review and refine the dosing recommendations in patients with renal insufficiency. The literature has been reviewed and compared to a predictive model of the fraction of drug cleared by the kidney based on the Dettli's principle. Revised drug dosing recommendations integrating these predictive parameters are proposed.

Pharmacokinetic and pharmacodynamic assessment of valganciclovir in solid organ transplant recipients

RESUME : Valganciclovir (Valcyte®) is an orally administered ester prodrug of the standard anticytomegalovirus (CMV) drug ganciclovir. This drug enabled an important reduction of the burden of CMV morbidity and mortality in solid organ transplant recipients. Prevention of CMV infection and treatment of CMV disease requires drug administration during many weeks. Oral drug administration is therefore convenient. Valganciclovir has been developed to overcome the poor oral availability of ganciclovir, which limits its concentration exposure after oral administration and thus its efficacy. This prodrug crosses efficiently the intestinal barrier, is then hydrolyzed into ganciclovir, providing exposure similar to intravenous ganciclovir. Valganciclovir is now preferred for the prophylaxis and treatment of CMV infection in solid organ transplant recipients. Nevertheless, adequate dosage adjustment is necessary to optimize its use, avoiding either insufficient or exaggerate exposure related to differences in its pharmacokinetic profile between patients. The main goal of this thesis was to better describe the pharmacokinetic and pharmacodynamic profile of valganciclovir in solid organ transplant recipients, to assess their reproducibility and their predictability, and thus to evaluate the current recommendations for valganciclovir dosage adjustment and the potential contribution of routine therapeutic drug monitoring (TDM) to patients' management. A total of 437 ganciclovir plasma concentration data from 65 transplant patients (41 kidney, 12 lung, 10 heart and 2 liver recipients, 58 under oral valganciclovir prophylaxis, 8 under oral valganciclovir treatment and 2 under intravenous ganciclovir) were measured using a validated chromatographic method (HPLC) developed for this study. The results were analyzed by non-linear mixed effect modeling (NONMEM). A two-compartment model with first-order absorption appropriately described the data. Systemic clearance was markedly influenced by GFR, with further differences between graft types and sex (CL/GFR = 1.7 in kidney, 0.9 in heart and 1.2 in lung and liver recipients) with interpatient variability (CV%) of 26% and interoccasion variability of 12%. Body weight and sex influenced central volume of distribution (V1 = 0.34 l/kg in males and 0.27 l/kg in females) with an interpatient variability of 20%. Residual intrapatient variability was 21 %. No significant drug interaction influenced GCV disposition. VGC prophylactic efficacy and tolerability were good, without detectable dependence on GCV profile. In conclusion, this analysis highlights the importance of thorough adjustment of VGC dosage to renal function and body weight. Considering the good predictability and reproducibility of GCV profile after oral VGC in solid organ transplant recipients, routine TDM does not appear to be clinically indicated. However, GCV plasma measurement may still be helpful in specific clinical situations such as documentation of appropriate exposure in patients with potentially compromised absorption, or lack of response to CMV disease treatment, or under renal replacement therapy. RESUME : Le valganciclovir (Valcyte®) est un promédicament oral du ganciclovir qui est un anti-infectieux de référence contre les infections à cytomegalovirus (CMV). Cet antiviral a permis de réduire les effets délétères de cette infection jusqu'ici responsable d'une importante morbidité et mortalité chez les transplantés d'organe. La prévention et le traitement de l'infection à CMV sont donc nécessaires mais requièrent l'administration d'un agent antiviral sur une longue période. Un médicament administré par voie orale représente donc un avantage évident. Le valganciclovir a été développé dans le but d'améliorer la faible absorption orale du ganciclovir, et donc son efficacité. Cet ester valylique du ganciclovir traverse plus facilement la barrière gastro-intestinale, puis est hydrolysé en ganciclovir dans la circulation sanguine, produisant une exposition comparable à celle d'une perfusion intraveineuse de ganciclovir. De ce fait, le valganciclovir est devenu largement utilisé pour la prophylaxie mais aussi le traitement de l'infection à CMV. Néanmoins une utilisation optimale de ce nouveau médicament nécessite de bonnes connaissances sur son profil pharmacocinétique afin d'établir un schéma de dose adapté pour éviter tant une surexposition qu'une sous-exposition résultant des différences d'élimination entre les patients. Le but de cette thèse a été d'étudier le profil pharmacocinétique et pharmacodynamique du valganciclovir chez les transplantés d'organe ainsi que sa reproductibilité et sa prédictibilité. Il s'agissait d'apprécier de manière critique le schéma actuellement recommandé pour l'adaptation des doses de valganciclovir, mais aussi la contribution éventuelle d'un suivi des concentrations sanguines en routine. Un total de 437 taux sanguins de ganciclovir ont été mesurés, provenant de 65 patients transplantés d'organe (41 rénaux, 12 pulmonaires, 10 cardiaques et 2 hépatiques, 58 sous une prophylaxie orale de valganciclovir, 8 sous un traitement de valganciclovir et 2 sous un traitement intraveineux). Une méthode de chromatographie liquide à haute performance a été développée et validée pour cette étude. Les résultats ont été ensuite analysés par modélisation non linéaire à effets mixtes (NONMEM). Un modèle à deux compartiments avec absorption de premier ordre a permis de décrire les données. La clairance systémique était principalement influencée par le débit de filtration glomérulaire (GFR), avec une différence entre les types de greffe et les sexes (CL/GFR = 1.7 chez les greffés rénaux, 0.9 pour les greffés cardiaques et 1.2 pour le groupe des greffés pulmonaires et hépatiques) avec un variabilité inter-individuelle de 26% (CV%) et une variabilité inter-occasion de 12%. Le poids corporel ainsi que le sexe avaient une influence sur le volume central de distribution (V1 = 0.34 l/kg chez les hommes et 0.27 l/kg chez les femmes) avec une variabilité inter-individuelle de 20%. La variabilité intra-individuelle résiduelle était de 21 %. Aucune interaction médicamenteuse n'a montré d'influence sur le profil du ganciclovir. La prophylaxie avec le valganciclovir s'est révélée efficace et bien tolérée. En conclusion, cette analyse souligne l'importance d'une adaptation de la dose du valganciclovir à la fonction rénale et au poids du patient. Au vu de la bonne reproductibilité et prédictibilité du profil pharmacocinétique du ganciclovir chez les patients transplantés recevant du valganciclovir, un suivi des concentrations sanguines en routine ne semble pas cliniquement indiqué. Néanmoins, la mesure des taux plasmatiques de ganciclovir peut être utile dans certaines situations particulières, comme la vérification d'une exposition appropriée chez des patients susceptibles d'absorption insuffisante, ou ne répondant pas au traitement d'une infection à CMV ou encore sous épuration extra-rénale. RESUME LARGE PUBLIC : Le valganciclovir est un précurseur capable de libérer du ganciclovir, récemment développé pour améliorer la faible absorption orale de ce dernier. Une fois le valganciclovir absorbé, le ganciclovir libéré dans la circulation sanguine devient efficace contre les infections à cytomégalovirus. Ce virus largement répandu est responsable de maladies insidieuses et parfois graves chez les personnes présentant une baisse des défenses immunitaires, comme les greffés d'organe recevant un traitement anti-rejet. Le ganciclovir est administré pendant plusieurs mois consécutifs soit pour prévenir une infection après la transplantation, soit pour traiter une infection déclarée. La facilité d'administration du valganciclovir par voie orale représente un avantage sur une administration du ganciclovir par perfusion, qui nécessite une hospitalisation. Toutefois, la voie orale peut être une source supplémentaire de variabilité chez les patients, avec un impact potentiel sur l'efficacité ou la toxicité du médicament. Le but de cette étude a été - de décrire le devenir de ce médicament dans le corps humain (dont l'étude relève de la discipline de la pharmacocinétique) - de définir les facteurs cliniques pouvant expliquer les différences de concentration sanguine observées entre les patients sous une posologie donnée - d'explorer les relations entre les concentrations du médicament dans le sang et son efficacité ou la survenue d'effets indésirables (dont l'étude relève de la discipline de la pharmacodynamie). Cette étude a nécessité le développement et la validation, d'une méthode d'analyse pour mesurer la concentration sanguine du ganciclovir, puis son application à 437 échantillons provenant de 65 patients transplantés d'organe solide (41 rénaux, 12 pulmonaires, 10 cardiaques et 2 hépatiques) recevant du valganciclovir. Les résultats des mesures effectuées ont été analysés à l'aide d'un outil mathématique afin d'élaborer un modèle du devenir du médicament dans le sang chez chaque patient et à chaque occasion. Cette étude a permis d'évaluer chez des patients recevant le valganciclovir, la vitesse à laquelle l'organisme absorbe, distribue, puis élimine le médicament. La vitesse d'élimination dépendait étroitement de la fonction rénale, du type de greffe et du sexe alors que la distribution dépendait du poids et du sexe du patient. La variabilité non expliquée par ces facteurs cliniques était modérée et vraisemblablement sans conséquence clinique évidente soit sur l'efficacité ou la tolérance, qui se révèlent très satisfaisantes chez les patients de l'étude. Les observations n'ont pas révélé de relation entre les concentrations de médicament et l'efficacité thérapeutique ou la survenue d'effets indésirables, confirmant que les doses relativement faibles utilisées dans notre collectif de patients suffisaient à produire une exposition reproductible à des concentrations adéquates. En conclusion, le profil (et par conséquent l'absorption) du valganciclovir chez les patients transplantés semble bien prédictible après une adaptation de la dose à la fonction rénale et au poids du patient. Un contrôle systématique des concentrations sanguines n'est probablement pas indiqué en routine, mais cette mesure peut présenter un intérêt dans certaines conditions particulières.

The epidthelial sodium channel ENaC and its regulators in the epidermal permeability barrier function

The highly amiloride-sensitive epithelial sodium channel ENaC is well known to be involved in controlling whole body sodium homeostasis and lung liquid clearance. ENaC expression has also been detected in the skin of amphibians and mammals. Mice lacking ENaC expression lose rapidly weight associated with an epidermal barrier defect that develops following birth. This dehydration is accompanied with a highly abnormal lipid matrix composition and an impaired skin surface acidification. This strongly suggests a role of ENaC in the maturation of barrier function rather than in the prenatal generation of the barrier, and may be as such an important modulator for skin hydration. In parallel, gene targeting experiments of regulators of ENaC activity, membrane serine proteases, also termed channel activating proteases, like CAP1/Prss8 and matriptase/MT-SP1 by themselves have been shown to be crucial for the epidermal barrier function. In our review, we mainly focus on the role of ENaC and its regulators in the skin and discuss their importance in the epidermal permeability barrier function.

Renal function in patients with HIV starting therapy with tenofovir and either efavirenz, lopinavir or atazanavir.

BACKGROUND: Tenofovir is associated with reduced renal function, but it is not clear whether there is a greater decline in renal function when tenofovir is co-administered with a boosted protease inhibitor rather than with a nonnucleoside reverse transcriptase inhibitor (NNRTI). METHODS: We calculated the estimated glomerular filtration rate (eGFR) for patients in the Swiss HIV Cohort Study. We estimated the difference in eGFR over time between first therapies containing tenofovir and either the NNRTI efavirenz or the protease inhibitors lopinavir (LPV/r) or atazanavir (ATV/r), both boosted with ritonavir. RESULTS: Patients on a first therapy of tenofovir co-administered with efavirenz (n  = 484), LPV/r (n = 269) and ATV/r (n =  187) were followed for a median of 1.7, 1.2 and 1.3 years, respectively. Relative to tenofovir and efavirenz, the estimated difference in eGFR for tenofovir and LPV/r was -2.6 ml/min per 1.73 m [95% confidence interval (CI) -7.3 to 2.2) during the first 6 months of therapy, then followed by a difference of 0.0 ml/min per 1.73 m (95% CI -1.1 to 1.1) for each additional 6 months of therapy. Relative to tenofovir and efavirenz, the estimated difference in eGFR for tenofovir and ATV/r was -7.6 ml/min per 1.73 m (95% CI -11.8 to -3.4) during the first 6 months of therapy, then followed by a difference of -0.5 ml/min per 1.73 m (95% CI -1.6 to 0.7) for each additional 6 months of therapy. CONCLUSION: Tenofovir with either boosted protease inhibitor leads to a greater initial decline in eGFR than tenofovir with efavirenz; this decline may be worse with ATV/r than with LPV/r.

Circadian glomerular function: from physiology to molecular and therapeutical aspects.

Life on earth is rhythmic by essence due to day/night alternation, and many biological processes are also cyclic. The kidney has a special role in the organism, controlling electrolytes and water balance, blood pressure, elimination of metabolic waste and xenobiotics and the production of several hormones. The kidney is submitted to changes throughout 24 h with periods of intense activity followed by calmer periods. Filtration, reabsorption and secretion are the three components determining renal function. Here, we review circadian changes related to glomerular function and proteinuria and emphasize the role of the clock in these processes.

Overlap Between Common Genetic Polymorphisms Underpinning Kidney Traits and Cardiovascular Disease Phenotypes: The CKDGen Consortium.

BACKGROUND: Chronic kidney disease is associated with cardiovascular disease. We tested for evidence of a shared genetic basis to these traits. STUDY DESIGN: We conducted 2 targeted analyses. First, we examined whether known single-nucleotide polymorphisms (SNPs) underpinning kidney traits were associated with a series of vascular phenotypes. Additionally, we tested whether vascular SNPs were associated with markers of kidney damage. Significance was set to 1.5×10(-4) (0.05/325 tests). SETTING & PARTICIPANTS: Vascular outcomes were analyzed in participants from the AortaGen (20,634), CARDIoGRAM (86,995), CHARGE Eye (15,358), CHARGE IMT (31,181), ICBP (69,395), and NeuroCHARGE (12,385) consortia. Tests for kidney outcomes were conducted in up to 67,093 participants from the CKDGen consortium. PREDICTOR: We used 19 kidney SNPs and 64 vascular SNPs. OUTCOMES & MEASUREMENTS: Vascular outcomes tested were blood pressure, coronary artery disease, carotid intima-media thickness, pulse wave velocity, retinal venular caliber, and brain white matter lesions. Kidney outcomes were estimated glomerular filtration rate and albuminuria. RESULTS: In general, we found that kidney disease variants were not associated with vascular phenotypes (127 of 133 tests were nonsignificant). The one exception was rs653178 near SH2B3 (SH2B adaptor protein 3), which showed direction-consistent association with systolic (P = 9.3 ×10(-10)) and diastolic (P = 1.6 ×10(-14)) blood pressure and coronary artery disease (P = 2.2 ×10(-6)), all previously reported. Similarly, the 64 SNPs associated with vascular phenotypes were not associated with kidney phenotypes (187 of 192 tests were nonsignificant), with the exception of 2 high-correlated SNPs at the SH2B3 locus (P = 1.06 ×10(-07) and P = 7.05 ×10(-08)). LIMITATIONS: The combined effect size of the SNPs for kidney and vascular outcomes may be too low to detect shared genetic associations. CONCLUSIONS: Overall, although we confirmed one locus (SH2B3) as associated with both kidney and cardiovascular disease, our primary findings suggest that there is little overlap between kidney and cardiovascular disease risk variants in the overall population. The reciprocal risks of kidney and cardiovascular disease may not be genetically mediated, but rather a function of the disease milieu itself.

Impact of restrictive intravenous fluid replacement and combined epidural analgesia on perioperative volume balance and renal function within a Fast Track program.

BACKGROUND AND OBJECTIVE: Key factors of Fast Track (FT) programs are fluid restriction and epidural analgesia (EDA). We aimed to challenge the preconception that the combination of fluid restriction and EDA might induce hypotension and renal dysfunction. METHODS: A recent randomized trial (NCT00556790) showed reduced complications after colectomy in FT patients compared with standard care (SC). Patients with an effective EDA were compared with regard to hemodynamics and renal function. RESULTS: 61/76 FT patients and 59/75 patients in the SC group had an effective EDA. Both groups were comparable regarding demographics and surgery-related characteristics. FT patients received significantly less i.v. fluids intraoperatively (1900 mL [range 1100-4100] versus 2900 mL [1600-5900], P < 0.0001) and postoperatively (700 mL [400-1500] versus 2300 mL [1800-3800], P < 0.0001). Intraoperatively, 30 FT compared with 19 SC patients needed colloids or vasopressors, but this was statistically not significant (P = 0.066). Postoperative requirements were low in both groups (3 versus 5 patients; P = 0.487). Pre- and postoperative values for creatinine, hematocrit, sodium, and potassium were similar, and no patient developed renal dysfunction in either group. Only one of 82 patients having an EDA without a bladder catheter had urinary retention. Overall, FT patients had fewer postoperative complications (6 versus 20 patients; P = 0.002) and a shorter median hospital stay (5 [2-30] versus 9 d [6-30]; P< 0.0001) compared with the SC group. CONCLUSIONS: Fluid restriction and EDA in FT programs are not associated with clinically relevant hemodynamic instability or renal dysfunction.

Incidence of Infectious Complications in Kidney Transplant Recipients Receiving Induction with Basiliximab, Thymoglobulin or Both

Background: The possible additional risk of infection in patients receiving induction with both basiliximab (Ba) and thymoglobulin (Th) is unclear. We assessed the 1-year incidence of infectious complications in 3 groups of kidney transplant recipients according to the type of induction therapy received.Methods: We compared the incidence of infection at 1 year in 3 groups of patients at our institution: fi rst transplant recipients received Ba 20mg at days 0 and 4 (Group Ba); in case of retransplantation or if PRA was >20% patients received Th 1 mg/kg for 3-5 days (Group Th); in case of delayed graft function (DGF), Ba was discontinued and Th was initiated (Group Ba+Th) or prolonged in Group Th. Kaplan-Meier curves were used to calculate the incidence of infection. A Cox analysis was used to identify risk factors for the development of infection.Results: Over 5 years, 170 consecutive kidney transplant recipients were performed:n=113 in Group Ba, n=39 in Group Th and n=18 in Group Ba+Th. As expected, more patients in Group Th received a second transplant (p<0.001). No differences in CMV serostatus were observed between groups (p=0.9). Incidences of CMV infection, CMV disease, BK viremia, BK nephropathy and urinary tract infection (UTI) is shown in Table 1. Table 1 Group Ba (n=113) Group Th (n=38) Group Ba+Th (n=18) CMV infection 31 (27%) 20 (51%) 8 (44%) CMV disease 7 (6%) 4 (10%) 0 BK viremia 11 (8%) 5 (13%) 4 (22%) BK nephropathy 5 (4%) 1 (2%) 2 (11%) UTI 43 (38%) 23 (59%) 6 (33%) Incidences of infection according to type of induction In a multivariate model taking into account CMV serostatus, age, pretransplant dialysis, type of organ transplanted, number of transplants and type of induction, Group Ba carried a lower risk of CMV infection (OR 0.45, p=0.006), and UTI (OR=0.6, p=0.05), but there were no differences in CMV disease (p=0.38). There was a trend towards higher incidence of BK viremia, but not nephropathy in Group Ba+Th (OR 2.2, p=0.23). There were no signifi cant differences in kidney function or graft loss at 1 year between groups.Conclusion: By multivariate analysis, we observed a lower risk of CMV infection andUTI in patients receiving Ba. The group Ba+Th had a similar risk for infection than the group receiving Th alone. Larger studies are needed to clarify whether combining Ba+Th in the setting of DGF may increase the risk of infectious complications, in particular BK infection.

Connexins: key mediators of endocrine function.

The appearance of multicellular organisms imposed the development of several mechanisms for cell-to-cell communication, whereby different types of cells coordinate their function. Some of these mechanisms depend on the intercellular diffusion of signal molecules in the extracellular spaces, whereas others require cell-to-cell contact. Among the latter mechanisms, those provided by the proteins of the connexin family are widespread in most tissues. Connexin signaling is achieved via direct exchanges of cytosolic molecules between adjacent cells at gap junctions, for cell-to-cell coupling, and possibly also involves the formation of membrane "hemi-channels," for the extracellular release of cytosolic signals, direct interactions between connexins and other cell proteins, and coordinated influence on the expression of multiple genes. Connexin signaling appears to be an obligatory attribute of all multicellular exocrine and endocrine glands. Specifically, the experimental evidence we review here points to a direct participation of the Cx36 isoform in the function of the insulin-producing β-cells of the endocrine pancreas, and of the Cx40 isoform in the function of the renin-producing juxtaglomerular epithelioid cells of the kidney cortex.

The effects of losartan on renal function in the newborn rabbit.

The low GFR of newborns is maintained by various factors including the renin-angiotensin system. We previously established the importance of angiotensin II in the newborn kidney, using the angiotensin-converting enzyme inhibitor perindoprilat. The present study was designed to complement these observations by evaluating the role of angiotensin-type 1 (AT(1)) receptors, using losartan, a specific AT(1)-receptor blocker. Increasing doses of losartan were infused into anesthetized, ventilated, newborn rabbits. Renal function and hemodynamic variables were assessed using inulin and para-aminohippuric acid clearances as markers of GFR and renal plasma flow, respectively. Losartan 0.1 mg/kg slightly decreased mean blood pressure (-11%) and increased diuresis (+22%). These changes can be explained by inhibition of the AT(1)-mediated vasoconstrictive and antidiuretic effects of angiotensin, and activation of vasodilating and diuretic AT(2) receptors widely expressed in the neonatal period. GFR and renal blood flow were not modified. Losartan 0.3 mg/kg decreased mean blood pressure significantly (-15%), probably by inhibiting systemic AT(1) receptors. GFR significantly decreased (-25%), whereas renal blood flow remained stable. The decrease in filtration fraction (-21%) indicates predominant efferent vasodilation. At 3 mg/kg, the systemic hypotensive effect of losartan was marked (mean blood pressure, -28%), with decreased GFR and renal blood flow (-57% and -51%, respectively), a stable filtration fraction, and an increase in renal vascular resistance by 124%. The renal response to this dose can be considered as reflex vasoconstriction of afferent and efferent arterioles, rather than specific receptor antagonism. We conclude that under physiologic conditions, the renin-angiotensin is critically involved in the maintenance of GFR in the immature kidney.

The presence of a CD4(+) CD25(high) CD45RO(+) CD127(high) T cell population correlates with the clinical status of kidney transplant recipients

Introduction: Recent data have suggested that a population of CD4+ CD25high T cells, phenotypically characterized by the expression of CD45RO and CD127, is significantly expanded in stable liver and kidney transplant recipients and represents alloreactive T cells. We analyzed this putative new alloreactive cellular marker in various groups of kidney transplant recipients. Patients & methods: Flow cytometry was used to analyze the expression of CD25, CD45RO and CD127 on peripheral CD4+ T cells. Of 73 kidney transplant recipients, 59 had a stable graft function under standard immunosuppressive therapy (IS), 5 had biopsy-proven chronic humoral rejection (CHR), 8 were stable under minimal IS and one was an operationally "tolerant" patient who had discontinued IS for more than 3 years. Sixty-six healthy subjects (HS) were studied as controls. Results: Overall, the alloreactive T cell population was found to be significantly increased in the 73 kidney recipients (mean ± SE: 15.03 ± 1.04% of CD4+ CD25high T cells) compared to HS (5.93 ± 0.39%) (p<0.001). In the 5 patients with CHR, this population was highly expanded (31.33 ± 4.16%), whereas it was comparable to HS in the 8 stable recipients receiving minimal IS (6.12 ± 0.86%), in 4 patients who had been switched to sirolimus (4.21 ± 0.53%) as well as in the unique "tolerant" recipient (4.69%). Intermediate levels (15.84 ± 0.93%) were found in the 55 recipients with stable graft function on standard CNI-based IS. Regulatory T cells, defined as CD4+CD25high FoxP3+ CD127low, were found to be significantly reduced in all recipients except in those with minimal or no IS, and this reduction was particularly striking in recipients with CHR. Conclusion: After kidney transplantation, an alloreactive T cell population was found to be significantly expanded and it correlates with the clinical status of the recipients. Interestingly, in stable patients with minimal (or no) IS as well as in patients on sirolimus, alloreactive T cells were comparable the healthy controls. Measuring circulating CD4+CD25high CD45RO+ CD127high T cells may become a useful monitoring tool after transplantation.