The circadian clock modulates renal sodium handling.

The circadian clock contributes to the control of BP, but the underlying mechanisms remain unclear. We analyzed circadian rhythms in kidneys of wild-type mice and mice lacking the circadian transcriptional activator clock gene. Mice deficient in clock exhibited dramatic changes in the circadian rhythm of renal sodium excretion. In parallel, these mice lost the normal circadian rhythm of plasma aldosterone levels. Analysis of renal circadian transcriptomes demonstrated changes in multiple mechanisms involved in maintaining sodium balance. Pathway analysis revealed the strongest effect on the enzymatic system involved in the formation of 20-HETE, a powerful regulator of renal sodium excretion, renal vascular tone, and BP. This correlated with a significant decrease in the renal and urinary content of 20-HETE in clock-deficient mice. In summary, this study demonstrates that the circadian clock modulates renal function and identifies the 20-HETE synthesis pathway as one of its principal renal targets. It also suggests that the circadian clock affects BP, at least in part, by exerting dynamic control over renal sodium handling.

Impact of Anti-T-Cell Therapy in the Immunogenicity of Seasonal Influenza Vaccine in Kidney Transplant Recipients.

BACKGROUND: The influence of anti-T-cell therapy in the immunogenicity of the influenza vaccine in kidney transplant recipients remains unclear. METHODS: During the 2010 to 2011 influenza season, we evaluated the immune response to the inactivated trivalent influenza vaccine in kidney transplant recipients having received Thymoglobulin or basiliximab as induction therapy. A hemagglutination inhibition assay was used to assess the immunogenicity of the vaccine. The primary outcome was geometric mean titers of hemagglutination inhibition after influenza vaccination. RESULTS: Sixty patients (Thymoglobulin n=22 and basiliximab n=38) were included. Patients in the Thymoglobulin group were older (P=0.16), showed higher creatinine levels (P=0.16) and had more frequently received a previous transplant (P=0.02). There were no significant differences in geometric mean titers for any of the three viral strains between groups (P=0.69 for H1N1, P=0.56 for H3N2, and P=0.7 for B strain). Seroconversion to at least one viral strain was seen in 15 (68%) of 22 patients in the Thymoglobulin group and 28 (73%) of 38 in the basiliximab group (P=0.77). In patients vaccinated during the first year after receiving anti-T-cell therapy (n=25), there was a trend toward lower vaccine responses in the Thymoglobulin group. Patients who received Thymoglobulin showed lower CD4 cell counts and lower levels of IgM, at an average of 16.2 months after transplantation. A multivariate analysis showed that only the absence of mycophenolate was associated with a better vaccine response (odds ratio=9.47; 95% confidence interval, 1.03-86.9; P=0.047). CONCLUSION: No significant differences were seen in immunogenicity of the influenza vaccine in kidney transplant recipients having received either Thymoglobulin or basiliximab.

Comparisons of serum vitamin d levels, status, and determinants in populations with and without chronic kidney disease not requiring renal dialysis: a 24-hour urine collection population-based study.

OBJECTIVE: Vitamin D deficiency is frequent in the general population and might be even more prevalent among populations with kidney failure. We compared serum vitamin D levels, vitamin D insufficiency/deficiency status, and vitamin D level determinants in populations without chronic kidney disease (CKD) and with CKD not requiring renal dialysis. DESIGN AND METHODS: This was a cross-sectional, multicenter, population-based study conducted from 2010 to 2011. Participants were from 10 centers that represent the geographical and cultural diversity of the Swiss adult population (≥15 years old). INTERVENTION: CKD was defined using estimated glomerular filtration rate and 24-hour albuminuria. Serum vitamin D was measured by liquid chromatography-tandem mass spectrometry. Statistical procedures adapted for survey data were used. MAIN OUTCOME MEASURE: We compared 25-hydroxy-vitamin D (25(OH)D) levels and the prevalence of vitamin D insufficiency/deficiency (serum 25(OH)D < 30 ng/mL) in participants with and without CKD. We tested the interaction of CKD status with 6 a priori defined attributes (age, sex, body mass index, walking activity, serum albumin-corrected calcium, and altitude) on serum vitamin D level or insufficiency/deficiency status taking into account potential confounders. RESULTS: Overall, 11.8% (135 of 1,145) participants had CKD. The 25(OH)D adjusted means (95% confidence interval [CI]) were 23.1 (22.6-23.7) and 23.5 (21.7-25.3) ng/mL in participants without and with CKD, respectively (P = .70). Vitamin D insufficiency or deficiency was frequent among participants without and with CKD (75.3% [95% CI 69.3-81.5] and 69.1 [95% CI 53.9-86.1], P = .054). CKD status did not interact with major determinants of vitamin D, including age, sex, BMI, walking minutes, serum albumin-corrected calcium, or altitude for its effect on vitamin D status or levels. CONCLUSION: Vitamin D concentration and insufficiency/deficiency status are similar in people with or without CKD not requiring renal dialysis.

The Effect Of Induced Intraocular Straylight (cataract Simulation) On Sensitivity Measures Of Standard Automated Perimetry, Pulsar Perimetry And Moorfields Motion Displacement Test

Purpose: To investigate the effect of incremental increases in intraocular straylight on threshold measurements made by three modern forms of perimetry: Standard Automated Perimetry (SAP) using Octopus (Dynamic, G-Pattern), Pulsar Perimetry (PP) (TOP, 66 points) and the Moorfields Motion Displacement Test (MDT) (WEBS, 32 points).Methods: Four healthy young observers were recruited (mean age 26yrs [25yrs, 28yrs]), refractive correction [+2 D, -4.25D]). Five white opacity filters (WOF), each scattering light by different amounts were used to create incremental increases in intraocular straylight (IS). Resultant IS values were measured with each WOF and at baseline (no WOF) for each subject using a C-Quant Straylight Meter (Oculus, Wetzlar, Germany). A 25 yr old has an IS value of ~0.85 log(s). An increase of 40% in IS to 1.2log(s) corresponds to the physiological value of a 70yr old. Each WOFs created an increase in IS between 10-150% from baseline, ranging from effects similar to normal aging to those found with considerable cataract. Each subject underwent 6 test sessions over a 2-week period; each session consisted of the 3 perimetric tests using one of the five WOFs and baseline (both instrument and filter were randomised).Results: The reduction in sensitivity from baseline was calculated. A two-way ANOVA on mean change in threshold (where subjects were treated as rows in the block and each increment in fog filters was treated as column) was used to examine the effect of incremental increases in straylight. Both SAP (p<0.001) and Pulsar (p<0.001) were significantly affected by increases in straylight. The MDT (p=0.35) remained comparatively robust to increases in straylight.Conclusions: The Moorfields MDT measurement of threshold is robust to effects of additional straylight as compared to SAP and PP.

Genetic loci influencing kidney function and chronic kidney disease.

Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.

A Pneumocystis jirovecii pneumonia outbreak in a single kidney-transplant center: role of cytomegalovirus co-infection.

Pneumocystis jirovecii pneumonia (PCP) and cytomegalovirus (CMV) infection represent possible complications of medical immunosuppression. Between 2005 and 2010, non-human immunodeficiency virus (HIV) PCP patients admitted to a nephrology unit were analyzed for outcome, CMV comorbidity, and patient-to-patient contacts prior to PCP. In contrast to 2002-2004 (no cases) and 2008-2010 (10 cases), a PCP outbreak of 29 kidney-transplant recipients and one patient with anti-glomerular basement membrane disease occurred between 2005 and 2007. None of the patients were on PCP chemoprophylaxis. In four PCP patients, the genotyping data of bronchoalveolar lavage specimen showed an identical Pneumocystis strain. PCP cases had a higher incidence of CMV infection (12 of 30 PCP patients) and CMV disease (four patients) when compared to matched PCP-free controls (p < 0.05). Cotrimoxazole and, if applicable, ganciclovir were started 2.0 ± 4.0 days following admission, and immunosuppressive medication was reduced. In-hospital mortality was 10% and the three-year mortality was 20%. CMV co-infection did not affect mortality. CMV co-infection more frequently occurred during a cluster outbreak of non-HIV PCP in comparison to PCP-free controls. Here, CMV awareness and specific therapy of both CMV infection and PCP led to a comparatively favorable patient outcome. The role of patient isolation should be further investigated in incident non-HIV PCP.

Cost effectiveness of a new combined immunosuppressive and antiviral regimen on the one-year follow-up of kidney transplant patients.

Background: Medical prescription after organ transplant must prevent both rejection and infectious complications. We assessed the 1-year effectiveness and cost of introducing a new combined regimen in kidney transplantation. Methods: Patients transplanted from January 2000 to March 2003 (Period 1) were compared to patients transplanted from April 2003 to July 2005 (Period 2). In period 1, patients were treated with Basiliximab, Cyclosporin, steroids and Mycophenolate (MMF) or Azathioprine. Prophylaxis with Valacyclovir was prescribed only in CMV D+/R- patients. In period 2, immunosuppressive drugs were Basiliximab, Tacrolimus, steroids and MMF. A 3-month universal CMV prophylaxis with Valganciclovir was used. Medical charts of outpatient visits allowed identifying drug, laboratory and radiological tests use, and hospital information system causes of hospitalisation and length of stay (LOS) over the first year after transplant. Patients with incomplete costs data were excluded. Results: 53 patients were analysed in period 1, and 60 in period 2. CMV serostatus patterns were not significantly different between the 2 periods. Over 12 months, acute rejection decreased from 22 patients (42%) in period 1 to 4 patients (7%) in period 2 (p<0.001), and CMV infection from 25 patients (47%) to 9 patients (15%, p<0.001). Average total rehospitalisation LOS decreased from 28±19 to 20±11 days (p<0.007). Average outpatient visits decreased from 49±10 to 39±8 (p<0.001). Average immunosuppression and CMV prophylaxis costs increased from US$ 18,362±6,546 to 24,637±5,457 (p<0.001), while average graft rejection costs decreased form US$ 4,135±9,164 to 585±2,850 (p=0.005), and average CMV treatment costs from US$ 2,043±5,545 to 91±293 (p=0.008). Average outpatient visits costs decreased from US$ 7,619±1,549 to 6,074±1,043 (p<0.001), and other hospital costs from US$ 3,801±6,519 to 1,196±3,146 (p=0.007). Altogether, average 1-year treatment costs decreased from US$ 35,961±14,916 to 32,584±6,211 (p=0.115). Cost-effectiveness ratios to avoid graft rejection and CMV infection decreased from US$ 61,482±9,292 to 34,911± 1,639 (p=0.006) and US$ 68,070±11,122 to 39,899±2,650 (p=0.015), respectively. Conclusion: The new combined regimen administered in period 2 was significantly more effective. Its additional cost was more than offset by savings linked with complications avoidance.

Quality of life transformations before and after kidney transplantation: A prospective qualitative study.

The aim of this IRB-approved study was to analyze prospectively quality of life (QOL) and psychological changes in 30 ESRD patients before and after kidney transplantation (KT). Semi-structured interviews were conducted after inclusion on the waiting list (A). Follow-up interviews were performed 6 months later with patients still awaiting KT (B6, n= 15), and with transplant recipients 6, 12 and 24 months after KT (C6, n=15; C12, n=15; C24, n=14). Qualitative thematic analysis was performed. A: All patients reported loss of freedom, 87% tried to maintain normality; 57% modified medical directives. All mentioned emotional fragility, negative thoughts (43%), and suicidal thoughts (20%) related to loss of QOL from dialysis (D), and professional tension (26%). B6: 40% reported no change compared to baseline, while 60% mentioned increase of illness intrusiveness, 46% D side effects, 40% communication problems, and 33% concerns about the waiting list handling. Fear of emotional breakdown (40%), couple problems (47%), and worsened professional difficulties (20%) were reported. C6: All patients reported recovery of QOL and concerns about acute rejection. 73% were anxious about laboratory results. 93% felt dependent on immunosuppressants (IS), 47% reported difficulties coping with their regimen, and 47% were concerned about side effects; 67% had resumed work, but medical constraints led 40% to professional stigmatization. C12: All enjoyed good QOL. Adherence to IS was mandatory (100%). All were aware of the limited long-term graft survival and 47% anxious about a possible return to D. 60% underlined positive life value; 47% resumed a full time job; 40% were on social security. C24: Good QOL was underlined (86%). Patients stated they would prefer re-TX to resuming D (71%). Post-TX health problems were mentioned (64%); increase of creatinine levels induced fear (36%). 79% complained about side effects. 64% reported changes in life values. This study reveals positive QOL and psychological transformations after KT, which are associated with positive changes related to graft survival and freedom from D. Psychological follow-up should be offered to patients who face relapsing ESRD or post-TX co-morbidities.

Frequency and impact of autosomal dominant polycystic kidney disease in the Seychelles (Indian Ocean).

BACKGROUND: As little such data is available in African populations, we investigated the prevalence of ADPKD and the impact of the disease in the Seychelles islands, where approximately 65% of the population is of African descent and 30% of Caucasian or mixed descent. METHODS: Prevalent cases were identified over a 3-year period by requesting all the doctors in the country (most of them are employed within a national health system) to refer all presumed or confirmed cases and by systematically examining the family members of all confirmed cases. The diagnosis was based on standard criteria including ultrasonographic findings and family history. RESULTS: Forty-two cases were identified in this population of 74,331 inhabitants, a total prevalence (per 100,000 total population) of 57 (95% CI, 41-76). All but one of the cases were of Caucasian descent so that the prevalence rates of the disease in the populations of Black and Caucasian descents were respectively 2 (0-11) and 184 (132-249). The prevalence rates of the gene(s) carriers were estimated to be 75 (45-117) in the total population respectively 6 (0-33) and 236 (140-372) in the Black and Caucasian populations. Haplotype analysis in 58 cases from three families showed a common DNA fragment in all affected individuals. Cases had significantly higher blood pressure compared to the general population and 21% had serum creatinine higher than 120 mumol/l. Among the established pedigrees, mean age of death between 1960 and 1995 (haemodialysis was introduced in 1992) was younger in subjects with than those without ADPKD (50.5 vs 67.7 years; P < 0.001). CONCLUSIONS: In the Seychelles, ADPKD clusters in the Caucasian population (possibly a founder effect), is rare in individuals of black descent, and is associated with substantial clinical and survival impact.

Bicarbonate de sodium pour ralentir la progression de la maladie rénale chronique [Sodium bicarbonate to slow the progression of chronic kidney disease].

Metabolic acidosis is a prevalent complication in moderate and late stages of chronic kidney disease (CKD). It is established that the correction of metabolic acidosis may improve metabolic bone disorders and protein degradation in the skeletal muscle, two characteristic complications of patients with advanced CKD. In the last 18 months, three randomized controlled trials have drawn the attention on a novel indication to correct metabolic acidosis in these patients, i.e., halting CKD progression. These data show that sodium bicarbonate, a cheap and easily manageable treatment, may delay the progression of CKD and the need of a renal replacement therapy such as dialysis or kidney transplantation.

Evalution of Hot Mix Asphalt Moisture Sensitivity Using the Nottingham Asphalt Test Equipment, July 2005

Moisture sensitivity of Hot Mix Asphalt (HMA) mixtures, generally called stripping, is a major form of distress in asphalt concrete pavement. It is characterized by the loss of adhesive bond between the asphalt binder and the aggregate (a failure of the bonding of the binder to the aggregate) or by a softening of the cohesive bonds within the asphalt binder (a failure within the binder itself), both of which are due to the action of loading under traffic in the presence of moisture. The evaluation of HMA moisture sensitivity has been divided into two categories: visual inspection test and mechanical test. However, most of them have been developed in pre-Superpave mix design. This research was undertaken to develop a protocol for evaluating the moisture sensitivity potential of HMA mixtures using the Nottingham Asphalt Tester (NAT). The mechanisms of HMA moisture sensitivity were reviewed and the test protocols using the NAT were developed. Different types of blends as moisture-sensitive groups and non-moisture-sensitive groups were used to evaluate the potential of the proposed test. The test results were analyzed with three parameters based on performance character: the retained flow number depending on critical permanent deformation failure (RFNP), the retained flow number depending on cohesion failure (RFNC), and energy ratio (ER). Analysis based on energy ratio of elastic strain (EREE ) at flow number of cohesion failure (FNC) has higher potential to evaluate the HMA moisture sensitivity than other parameters. If the measurement error in data-acquisition process is removed, analyses based on RFNP and RFNC would also have high potential to evaluate the HMA moisture sensitivity. The vacuum pressure saturation used in AASHTO T 283 and proposed test has a risk to damage specimen before the load applying.

MRSA screening by the Xpert MRSA PCR assay: pooling samples of the nose, throat, and groin increases the sensitivity of detection without increasing the laboratory costs.

The performance of the Xpert MRSA polymerase chain reaction (PCR) assay on pooled nose, groin, and throat swabs (three nylon flocked eSwabs into one tube) was compared to culture by analyzing 5,546 samples. The sensitivity [0.78, 95 % confidence interval (CI) 0.73-0.82] and specificity (0.99, 95 % CI 0.98-0.99) were similar to the results from published studies on separated nose or other specimens. Thus, the performance of the Xpert MRSA assay was not affected by pooling the three specimens into one assay, allowing a higher detection rate without increasing laboratory costs, as compared to nose samples alone.

Fluconazole plus cyclosporine: a fungicidal combination effective against experimental endocarditis due to Candida albicans.

Recent observations demonstrated that fluconazole plus cyclosporine (Cy) synergistically killed Candida albicans in vitro. This combination was tested in rats with C. albicans experimental endocarditis. The MICs of fluconazole and Cy for the test organism were 0.25 and &gt;10 mg/liter, respectively. Rats were treated for 5 days with either Cy, amphotericin B, fluconazole, or fluconazole-Cy. Although used at high doses, the peak concentrations of fluconazole in the serum of rats (up to 4.5 mg/liter) were compatible with high-dose fluconazole therapy in humans. On the other hand, Cy concentrations in serum (up to 4.5 mg/liter) were greater than recommended therapeutic levels. Untreated rats demonstrated massive pseudohyphal growth in both the vegetations and the kidneys. However, only the kidneys displayed concomitant polymorphonuclear infiltration. The therapeutic results reflected this dissociation. In the vegetations, only the fungicidal fluconazole-Cy combination significantly decreased fungal densities compared to all groups, including amphotericin B (P &lt; 0.0001). In the kidneys, all regimens except the Cy regimen were effective, but fluconazole-Cy remained superior to amphotericin B and fluconazole alone in sterilizing the organs (P &lt; 0.0001). While the mechanism responsible for the fluconazole-Cy interaction is hypothetical, this observation opens new perspectives for fungicidal combinations between azoles and other drugs.