Renal sodium handling and nighttime blood pressure.

Blood pressure follows a circadian rhythm with a physiologic 10% to 20% decrease during the night. There is now increasing evidence that a blunted decrease or an increase in nighttime blood pressure is associated with a greater prevalence of target organ damage and a faster disease progression in patients with chronic kidney diseases. Several factors contribute to the changes in nighttime blood pressure including changes in hormonal profiles such as variations in the activity of the renin-angiotensin and the sympathetic nervous systems. Recently, it was hypothesized that the absence of a blood pressure decrease during the nighttime (nondipping) is in fact a pressure-natriuresis mechanism enabling subjects with an impaired capacity to excrete sodium to remain in sodium balance. In this article, we review the clinical and epidemiologic data that tend to support this hypothesis. Moreover, we show that most, if not all, clinical conditions associated with an impaired dipping profile are diseases associated either with a low glomerular filtration rate and/or an impaired ability to excrete sodium. These observations would suggest that renal function, and most importantly the ability to eliminate sodium during the day, is indeed a key determinant of the circadian rhythm of blood pressure.

Top Three Pharmacogenomics and Personalized Medicine Applications at the Nexus of Renal Pathophysiology and Cardiovascular Medicine.

Pharmacogenomics is a field with origins in the study of monogenic variations in drug metabolism in the 1950s. Perhaps because of these historical underpinnings, there has been an intensive investigation of 'hepatic pharmacogenes' such as CYP450s and liver drug metabolism using pharmacogenomics approaches over the past five decades. Surprisingly, kidney pathophysiology, attendant diseases and treatment outcomes have been vastly under-studied and under-theorized despite their central importance in maintenance of health, susceptibility to disease and rational personalized therapeutics. Indeed, chronic kidney disease (CKD) represents an increasing public health burden worldwide, both in developed and developing countries. Patients with CKD suffer from high cardiovascular morbidity and mortality, which is mainly attributable to cardiovascular events before reaching end-stage renal disease. In this paper, we focus our analyses on renal function before end-stage renal disease, as seen through the lens of pharmacogenomics and human genomic variation. We herein synthesize the recent evidence linking selected Very Important Pharmacogenes (VIP) to renal function, blood pressure and salt-sensitivity in humans, and ways in which these insights might inform rational personalized therapeutics. Notably, we highlight and present the rationale for three applications that we consider as important and actionable therapeutic and preventive focus areas in renal pharmacogenomics: 1) ACE inhibitors, as a confirmed application, 2) VDR agonists, as a promising application, and 3) moderate dietary salt intake, as a suggested novel application. Additionally, we emphasize the putative contributions of gene-environment interactions, discuss the implications of these findings to treat and prevent hypertension and CKD. Finally, we conclude with a strategic agenda and vision required to accelerate advances in this under-studied field of renal pharmacogenomics with vast significance for global public health.

Genetics of calcium homeostasis in humans: continuum between monogenic diseases and continuous phenotypes

Extracellular calcium participates in several key physiological functions, such as control of blood coagulation, bone calcification or muscle contraction. Calcium homeostasis in humans is regulated in part by genetic factors, as illustrated by rare monogenic diseases characterized by hypo or hypercalcaemia. Both serum calcium and urinary calcium excretion are heritable continuous traits in humans. Serum calcium levels are tightly regulated by two main hormonal systems, i.e. parathyroid hormone and vitamin D, which are themselves also influenced by genetic factors. Recent technological advances in molecular biology allow for the screening of the human genome at an unprecedented level of detail and using hypothesis-free approaches, such as genome-wide association studies (GWAS). GWAS identified novel loci for calcium-related phenotypes (i.e. serum calcium and 25-OH vitamin D) that shed new light on the biology of calcium in humans. The substantial overlap (i.e. CYP24A1, CASR, GATA3; CYP2R1) between genes involved in rare monogenic diseases and genes located within loci identified in GWAS suggests a genetic and phenotypic continuum between monogenic diseases of calcium homeostasis and slight disturbances of calcium homeostasis in the general population. Future studies using whole-exome and whole-genome sequencing will further advance our understanding of the genetic architecture of calcium homeostasis in humans. These findings will likely provide new insight into the complex mechanisms involved in calcium homeostasis and hopefully lead to novel preventive and therapeutic approaches. Keyword: calcium, monogenic, genome-wide association studies, genetics.

Effect on renal function of tenofovir co-administered with either efavirenz or boosted lopinavir or boosted atazanavir: the Swiss HIV Cohort Study

Reduced re'nal function has been reported with tenofovir disoproxil fumarate (TDF). It is not clear whether TDF co-administered with a boosted protease inhibitor (PI) leads to a greater decline in renal function than TDF co-administered with a non-nucleoside reverse transcriptase inhibitor (NNRTI).Methods: We selected ail antiretroviral therapy-naive patients in the Swiss HIV Cohort Study (SHCS) with calibrated or corrected serum creatinine measurements starting antiretroviral therapy with TDF and either efavirenz (EFV) or the ritonavir-boosted PIs, lopinavir (LPV/r) or atazanavir (ATV/r). As a measure of renal function, we used the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to estimate the glomerular filtration rate (eGFR). We calculated the difference in eGFR over time between two therapies using a marginal model for repeated measures. In weighted analyses, observations were weighted by the product of their point of treatment and censoring weights to adjust for differences both in the sort of patients starting each therapy and in the sort of patients remaining on each therapy over time.Results: By March 2011, 940 patients with at least one creatinine measurement on a first therapy with either TDF and EFV (n=484), TDF and LPVlr (n=269) or TDF and ATV/r (n=187) had been followed for a median of 1. 7, 1.2 and 1.3 years, respectively. Table 1 shows the difference in average estimated GFR (eGFR) over time since starting cART for two marginal models. The first model was not adjusted for potential confounders; the second mode! used weights to adjust for confounders. The results suggest a greater decline in renal function during the first 6 months if TDF is used with a PI rather than with an NNRTI, but no further difference between these therapies after the first 6 months. TDF and ATV/r may lead to a greater decline in the first 6 months than TDF and LPVlr.Conclusions: TDF co-administered with a boosted PI leads to a greater de cline in renal function over the first 6 months of therapy than TDF co-administered with an NNRTI; this decline may be worse with ATV/r than with LPV/r.

Maladies infectieuses [Infectious diseases]

In 2008, several publications have highlighted the role of climate change and globalization on the epidemiology of infectious diseases. Studies have shown the extension towards Europe of diseases such as Crimea-Congo fever (Kosovo, Turkey and Bulgaria), leismaniosis (Cyprus) and chikungunya virus infection (Italy). The article also contains comments on Plasmodium knowlesi, a newly identified cause of severe malaria in humans, as well as an update on human transmission of the H5NI avian influenza virus. It also mentions new data on Bell's palsy as well as two vaccines (varicella-zoster and pneumococcus), and provides a list of recent guidelines for the treatment of common infectious diseases.

Renal transplantation following aorto-iliac reconstruction is a safe a strategy

Introduction: Renal transplantation is considered the treatment of choice for end-stage renal disease. However, the association of occlusive aorto-iliac disease and chronic renal failure is frequent and aorto-iliac reconstruction may be necessary prior to renal transplantation. This retrospective study reviews the results of this operative strategy.Material and Methods: Between January 2001 and June 2010, 309 patients underwent renal transplantation at our institution and 8 patients had prior aorto-iliac reconstruction using prosthetic material. There were 6 men and 2 women with a median age of 62 years (range 51-70). Five aorto-bifemoral and 2 aorto-bi-iliac bypasses were performed for stage II (n=5), stage IV (n=1) and aortic aneurysm (n=1). In one patient, iliac kissing stents and an ilio-femoral bypass were implanted. 4 cadaveric and 4 living donor renal transplantations were performed with an interval of 2 months to 10 years after revascularization.The results were analysed with respect of graft and patients survival. Differences between groups were tested by the log rank method.Results: No complications and no death occurred in the post-operative period. All bypasses remained patent during follow-up. The median time of post transplantation follow-up was 46 months for all patients and 27 months for patients with prior revascularization. In the revascularized group and control group, the graft and patient survival at 1 year were respectively 100%/96%, 100%/99% and at 5 years 86%/86%, 86%/94%, without significant differences between both groups.Discussion: Our results suggest that renal transplantation following prior aorto-iliac revascularisation with prosthetic material is safe and effective. Patients with end-stage renal disease and concomitant aorto-iliac disease should therefore be considered for renal transplantation. However, caution in the interpretation of the results is indicated due to the small sample size of our study.

Heritability, determinants and reference values of renal length: a family-based population study.

OBJECTIVES: In this population-based study, reference values were generated for renal length, and the heritability and factors associated with kidney length were assessed. METHODS: Anthropometric parameters and renal ultrasound measurements were assessed in randomly selected nuclear families of European ancestry (Switzerland). The adjusted narrow sense heritability of kidney size parameters was estimated by maximum likelihood assuming multivariate normality after power transformation. Gender-specific reference centiles were generated for renal length according to body height in the subset of non-diabetic non-obese participants with normal renal function. RESULTS: We included 374 men and 419 women (mean ± SD, age 47 ± 18 and 48 ± 17 years, BMI 26.2 ± 4 and 24.5 ± 5 kg/m(2), respectively) from 205 families. Renal length was 11.4 ± 0.8 cm in men and 10.7 ± 0.8 cm in women; there was no difference between right and left renal length. Body height, weight and estimated glomerular filtration rate (eGFR) were positively associated with renal length, kidney function negatively, age quadratically, whereas gender and hypertension were not. The adjusted heritability estimates of renal length and volume were 47.3 ± 8.5 % and 45.5 ± 8.8 %, respectively (P < 0.001). CONCLUSION: The significant heritability of renal length and volume highlights the familial aggregation of this trait, independently of age and body size. Population-based references for renal length provide a useful guide for clinicians. KEY POINTS: • Renal length and volume are heritable traits, independent of age and size. • Based on a European population, gender-specific reference values/percentiles are provided for renal length. • Renal length correlates positively with body length and weight. • There was no difference between right and left renal lengths in this study. • This negates general teaching that the left kidney is larger and longer.

Atrial natriuretic peptides: reproducibility of renal effects and response of liver blood flow.

To assess the variability of the response to exogenous atrial natriuretic peptide (ANP), it was infused at the rate of 1 microgram/min for 2 h in 6 salt-loaded normal volunteers under controlled conditions on 2 occasions at an interval of 1 week. The effect on solute excretion and the haemodynamic and endocrine actions were highly reproducible. The constant ANP infusion caused a delayed and prolonged excretion of sodium, chloride and calcium, no change in potassium or phosphate excretion or in glomerular filtration rate but a marked decrease in renal plasma flow. Blood pressure, heart rate and the plasma levels of angiotensin II, aldosterone, arginine vasopressin and plasma renin activity were unaltered. The effect of a 2-h infusion of ANP 0.5 microgram/min or its vehicle on apparent hepatic blood flow (HBF) was also studied in 14 normal volunteers by measuring the indocyanine green clearance. A 21% decrease in HBF was observed in subjects who received the ANP infusion (p less than 0.01 vs vehicle). Thus, ANP infused at a dose that did not lower blood pressure decreased both renal and liver blood flow in normotensive volunteers. The renal and endocrine responses to ANP were reproducible over a 1-week interval.

Renal response to the angiotensin II receptor subtype 1 antagonist irbesartan versus enalapril in hypertensive patients.

OBJECTIVE: To compare the acute and sustained renal hemodynamic effects on hypertensive patients of 100 mg irbesartan and 20 mg enalapril each once daily. PATIENTS: Twenty patients (aged 35-70 years) with uncomplicated, mild-to-moderate essential hypertension and normal serum creatinine levels completed this study. STUDY DESIGN: After random allocation to treatment (n=10 per group), administration schedule (morning or evening) was determined by further random allocation, with crossover of schedules after 6 weeks' therapy. Treatment and administration assignments were double-blind. Twenty-four-hour ambulatory blood pressure was monitored before and after 6 and 12 weeks of therapy. Renal hemodynamics were determined on the first day of drug administration and 12 and 24 h after the last dose during chronic treatment. RESULTS: Administration of each antihypertensive agent induced a renal vasodilatation with no significant change in glomerular filtration rate. However, the time course appeared to differ: irbesartan had no significant acute effect 4 h after the first dose, but during chronic administration a renal vasodilatory response was found 12 and 24 h after the dose; enalapril was effective acutely and 12 h after administration, but no residual effect was found 24 h after the dose. Both antihypertensive agents lowered mean ambulatory blood pressure effectively, with no significant difference between treatments or between administration schedules (morning versus evening). CONCLUSIONS: Irbesartan and enalapril have comparable effects on blood pressure and renal hemodynamics in hypertensive patients with normal renal functioning. However, the time profiles of the renal effects appear to differ, which might be important for long-term renoprotective effects.

Microbiota abnormalities in inflammatory airway diseases - Potential for therapy.

Increasingly the development of novel therapeutic strategies is taking into consideration the contribution of the intestinal microbiota to health and disease. Dysbiosis of the microbial communities colonizing the human intestinal tract has been described for a variety of chronic diseases, such as inflammatory bowel disease, obesity and asthma. In particular, reduction of several so-called probiotic species including Lactobacilli and Bifidobacteria that are generally considered to be beneficial, as well as an outgrowth of potentially pathogenic bacteria is often reported. Thus a tempting therapeutic approach is to shape the constituents of the microbiota in an attempt to restore the microbial balance towards the growth of 'health-promoting' bacterial species. A twist to this scenario is the recent discovery that the respiratory tract also harbors a microbiota under steady-state conditions. Investigators have shown that the microbial composition of the airway flora is different between healthy lungs and those with chronic lung diseases, such as asthma, chronic obstructive pulmonary disease as well as cystic fibrosis. This is an emerging field, and thus far there is very limited data showing a direct contribution of the airway microbiota to the onset and progression of disease. However, should future studies provide such evidence, the airway microbiota might soon join the intestinal microbiota as a target for therapeutic intervention. In this review, we highlight the major advances that have been made describing the microbiota in chronic lung disease and discuss current and future approaches concerning manipulation of the microbiota for the treatment and prevention of disease.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases.

The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society's Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A-D for the 'Strength of a recommendation'. The 'level of evidence' received a score of I-III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.

Switch to Sirolimus-based immunosuppresion in stable renal transplant recipients

Purpose: Sirolimus (SRL) has been used to replace calcineurin inhibitors (CNI) for various indications including CNI-induced toxicity. The aim of this study was to evaluate the efficacy and safety of switching from CNI to SRL in stable renal transplant recipients (RTR) with low grade proteinuria (<1 g/24 h). Methods and materials: Between 2001 and 2007, 41 patients (20 females, 21 males; mean age 47 ± 13) were switched after a median time post-transplantation of 73.5 months (range 0.2-273.2 months). Indications for switch were CNI nephrotoxicity (39%), thrombotic micro-angiopathy (14.6%), post-transplantation cancer (24.4%), CNI neurotoxicity (7.4%), or others (14.6%). Mean follow-up after SRL switch was 23.8±16.3 months. Mean SRL dosage and through levels were 2.4 ± 1.1 mg/day and 8 ± 2.2 ug/l respectively. Immunosuppressive regiments were SRL + mycophenolate mofetil (MMF) (31.7%), SRL + MMF + prednisone (36.58%), SRL + prednisone (19.51%), SRL + Azathioprine (9.75%), or SRL alone (2.43%). Results: Mean creatinine decreased from 164 to 143 μmol/l (p <0.03), mean estimated glomerular filtration rate (eGFR) increased significantly from 50.13 to 55.01 ml/minute (p <0.00001), mean systolic and diastolic blood pressure decreased from 138 to 132 mm Hg (p <0.03) and from 83 to78 mm Hg (p <0.01), but mean proteinuria increased from 0.21 to 0.63 g/24 h (p <0.001). While mean total cholesterolemia didn't increased significantly from 5.09 to 5.56 mmol/l (p = 0.06). The main complications after SRL switch were dermatitis (19.5%), urinary tract infections (24.4%), ankle edema (13.3%), and transient oral ulcers (20%). Acute rejection after the switch occurred in 7.3% of patients (n = 3), and 2 acute rejections were successfully treated with corticosteroids and 1 did not respond to treatment (not related to switch). SRL had to be discontinued in 17% of patients (2 nephrotic syndromes, 2 severe edema, 1 acute rejection, 1 thrombotic micro-angiopathy, and 1 fever). Conclusion: In conclusion, we found that switching from CNI to SRL in stable RTR was safe and associated with a significant improvement of renal function and blood pressure. Known side-effects of SRL led to drug discontinuation in less than 20% of patients and the acute rejection rate was 7.3%. This experience underlines the importance of patient selection before switching to SRL, in particular regarding preswitch proteinuria.

IV thrombolysis and renal function.

OBJECTIVE: To investigate the association of renal impairment on functional outcome and complications in stroke patients treated with IV thrombolysis (IVT). METHODS: In this observational study, we compared the estimated glomerular filtration rate (GFR) with poor 3-month outcome (modified Rankin Scale scores 3-6), death, and symptomatic intracranial hemorrhage (sICH) based on the criteria of the European Cooperative Acute Stroke Study II trial. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Patients without IVT treatment served as a comparison group. RESULTS: Among 4,780 IVT-treated patients, 1,217 (25.5%) had a low GFR (<60 mL/min/1.73 m(2)). A GFR decrease by 10 mL/min/1.73 m(2) increased the risk of poor outcome (OR [95% CI]): (ORunadjusted 1.20 [1.17-1.24]; ORadjusted 1.05 [1.01-1.09]), death (ORunadjusted 1.33 [1.28-1.38]; ORadjusted 1.18 [1.11-1.249]), and sICH (ORunadjusted 1.15 [1.01-1.22]; ORadjusted 1.11 [1.04-1.20]). Low GFR was independently associated with poor 3-month outcome (ORadjusted 1.32 [1.10-1.58]), death (ORadjusted 1.73 [1.39-2.14]), and sICH (ORadjusted 1.64 [1.21-2.23]) compared with normal GFR (60-120 mL/min/1.73 m(2)). Low GFR (ORadjusted 1.64 [1.21-2.23]) and stroke severity (ORadjusted 1.05 [1.03-1.07]) independently determined sICH. Compared with patients who did not receive IVT, treatment with IVT in patients with low GFR was associated with poor outcome (ORadjusted 1.79 [1.41-2.25]), and with favorable outcome in those with normal GFR (ORadjusted 0.77 [0.63-0.94]). CONCLUSION: Renal function significantly modified outcome and complication rates in IVT-treated stroke patients. Lower GFR might be a better risk indicator for sICH than age. A decrease of GFR by 10 mL/min/1.73 m(2) seems to have a similar impact on the risk of death or sICH as a 1-point-higher NIH Stroke Scale score measuring stroke severity.

Molecular detection and identification of zygomycetes species from paraffin-embedded tissues in a murine model of disseminated zygomycosis: a collaborative European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) evaluation.

The present study was performed to assess the interlaboratory reproducibility of the molecular detection and identification of species of Zygomycetes from formalin-fixed paraffin-embedded kidney and brain tissues obtained from experimentally infected mice. Animals were infected with one of five species (Rhizopus oryzae, Rhizopus microsporus, Lichtheimia corymbifera, Rhizomucor pusillus, and Mucor circinelloides). Samples with 1, 10, or 30 slide cuts of the tissues were prepared from each paraffin block, the sample identities were blinded for analysis, and the samples were mailed to each of seven laboratories for the assessment of sensitivity. A protocol describing the extraction method and the PCR amplification procedure was provided. The internal transcribed spacer 1 (ITS1) region was amplified by PCR with the fungal universal primers ITS1 and ITS2 and sequenced. As negative results were obtained for 93% of the tissue specimens infected by M. circinelloides, the data for this species were excluded from the analysis. Positive PCR results were obtained for 93% (52/56), 89% (50/56), and 27% (15/56) of the samples with 30, 10, and 1 slide cuts, respectively. There were minor differences, depending on the organ tissue, fungal species, and laboratory. Correct species identification was possible for 100% (30 cuts), 98% (10 cuts), and 93% (1 cut) of the cases. With the protocol used in the present study, the interlaboratory reproducibility of ITS sequencing for the identification of major Zygomycetes species from formalin-fixed paraffin-embedded tissues can reach 100%, when enough material is available.