Molecular clock is involved in predictive circadian adjustment of renal function.

Renal excretion of water and major electrolytes exhibits a significant circadian rhythm. This functional periodicity is believed to result, at least in part, from circadian changes in secretion/reabsorption capacities of the distal nephron and collecting ducts. Here, we studied the molecular mechanisms underlying circadian rhythms in the distal nephron segments, i.e., distal convoluted tubule (DCT) and connecting tubule (CNT) and the cortical collecting duct (CCD). Temporal expression analysis performed on microdissected mouse DCT/CNT or CCD revealed a marked circadian rhythmicity in the expression of a large number of genes crucially involved in various homeostatic functions of the kidney. This analysis also revealed that both DCT/CNT and CCD possess an intrinsic circadian timing system characterized by robust oscillations in the expression of circadian core clock genes (clock, bma11, npas2, per, cry, nr1d1) and clock-controlled Par bZip transcriptional factors dbp, hlf, and tef. The clock knockout mice or mice devoid of dbp/hlf/tef (triple knockout) exhibit significant changes in renal expression of several key regulators of water or sodium balance (vasopressin V2 receptor, aquaporin-2, aquaporin-4, alphaENaC). Functionally, the loss of clock leads to a complex phenotype characterized by partial diabetes insipidus, dysregulation of sodium excretion rhythms, and a significant decrease in blood pressure. Collectively, this study uncovers a major role of molecular clock in renal function.

Place de ta vitamine D, du sevelamer et du cinacalcet dans la prise en charge des patients en insuffisance rénale [Treatment of secondary hyperparathyroidism in renal insufficiency: role of calcitriol, sevelamer and cinacalcet]

Along with the decrease in kidney function arises a secondary hyperparathyroidism, which constitutes one of the most important risk factor for mortality in patients suffering from renal insufficiency. Treating secondary hyperparathyroidism is challenging, as most of the parameters of mineral metabolism are interconnected. We review here the pathophysiology and treatment options of this entity.

Increased Expression of Renal Cyclooxygenase-2 and Neuronal Nitric Oxide Synthase in Hypertensive Cx40-Deficient Mice.

Cx40-deficient mice (Cx40-/-) are hypertensive due to increased renin secretion. We evaluated the renal expression of neuronal nitric oxide synthase (nNOS) and cyclooxygenases COX-1 and COX-2, three macula densa enzymes. The levels of nNOS were increased in kidneys of Cx40-/- mice, as well as in those of wild-type (WT) mice subjected to the two-kidney one-clip model of hypertension. In contrast, the levels of COX-2 expression were only increased in the hypoperfused kidney of Cx40-/- mice. Treatment with indomethacin lowered blood pressure and renin mRNA in Cx40-/- mice without affecting renin levels, indicating that changes in COX-2 do not cause the altered secretion of renin. Suppression of NOS activity by N(G)-nitro-L-arginine methyl ester (L-NAME) decreased renin levels in Cx40-/- animals, indicating that NO regulates renin expression in the absence of Cx40. Treatment with candesartan normalized blood pressure in Cx40-/- mice, and decreased the levels of both COX-2 and nNOS. After a treatment combining candesartan and L-NAME, the blood pressure of Cx40-/- mice was higher than that of WT mice, showing that NO may counterbalance the vasoconstrictor effects of angiotensin II in Cx40-/- mice. These data document that renal COX-2 and nNOS are differentially regulated due to the elevation of renin-dependent blood pressure in mice lacking Cx40.

Low-molecular-weight or unfractionated heparin in venous thromboembolism: the influence of renal function.

BACKGROUND: In patients with acute venous thromboembolism and renal insufficiency, initial therapy with unfractionated heparin may have some advantages over low-molecular-weight heparin. METHODS: We used the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) Registry data to evaluate the 15-day outcome in 38,531 recruited patients. We used propensity score matching to compare patients treated with unfractionated heparin with those treated with low-molecular-weight heparin in 3 groups stratified by creatinine clearance levels at baseline: >60 mL/min, 30 to 60 mL/min, or <30 mL/min. RESULTS: Patients initially receiving unfractionated heparin therapy (n = 2167) more likely had underlying diseases than those receiving low-molecular-weight heparin (n = 34,665). Propensity score-matched groups of patients with creatinine clearance levels >60 mL/min (n = 1598 matched pairs), 30 to 60 mL/min (n = 277 matched pairs), and <30 mL/min (n = 210 matched pairs) showed an increased 15-day mortality for unfractionated heparin compared with low-molecular-weight heparin (4.5% vs 2.4% [P = .001], 5.4% vs 5.8% [P = not significant], and 15% vs 8.1% [P = .02], respectively), an increased rate of fatal pulmonary embolism (2.8% vs 1.2% [P = .001], 3.2% vs 2.5% [P = not significant], and 5.7% vs 2.4% [P = .02], respectively), and a similar rate of fatal bleeding (0.3% vs 0.3%, 0.7% vs 0.7%, and 0.5% vs 0.0%, respectively). Multivariate analysis confirmed that patients treated with unfractionated heparin were at increased risk for all-cause death (odds ratio, 1.8; 95% confidence interval, 1.3-2.4) and fatal pulmonary embolism (odds ratio, 2.3; 95% confidence interval, 1.5-3.6). CONCLUSIONS: In comparison with low-molecular-weight heparin, initial therapy with unfractionated heparin was associated with a higher mortality and higher rate of fatal pulmonary embolism in patients with creatinine clearance levels >60 mL/min or <30 mL/min, but not in those with levels between 30 and 60 mL/min.

Free-breathing renal MR angiography with steady-state free-precession (SSFP) and slab-selective spin inversion: initial results.

BACKGROUND: The aim of our study was the investigation of a novel navigator-gated three-dimensional (3D) steady-state free-precession (SSFP) sequence for free-breathing renal magnetic resonance angiography (MRA) without contrast medium, and to examine the advantage of an additional inversion prepulse for improved contrast. METHODS: Eight healthy volunteers (mean age 29 years) and eight patients (mean age 53 years) were investigated on a 1.5 Tesla MR system (ACS-NT, Philips, Best, The Netherlands). Renal MRA was performed using three navigator-gated free-breathing cardiac-triggered 3D SSFP sequences [repetition time (TR) = 4.4 ms, echo time (TE) = 2.2 ms, flip angle 85 degrees, spatial resolution 1.25 x 1.25 x 4.0 mm(3), scanning time approximately 1 minute 30 seconds]. The same sequence was performed without magnetization preparation, with a non-slab selective and a slab-selective inversion prepulse. Signal-to-noise ratio (SNR), contrast-to-noise (CNR) vessel length, and subjective image quality were compared. RESULTS: Three-dimensional SSFP imaging combined with a slab-selective inversion prepulse enabled selective and high contrast visualization of the renal arteries, including the more distal branches. Standard SSFP imaging without magnetization preparation demonstrated overlay by veins and renal parenchyma. A non-slab-selective prepulse abolished vessel visualization. CNR in SSFP with slab-selective inversion was 43.6 versus 10.6 (SSFP without magnetization preparation) and 0.4 (SSFP with non-slab-selective inversion), P < 0.008. CONCLUSION: Navigator-gated free-breathing cardiac-triggered 3D SSFP imaging combined with a slab-selective inversion prepulse is a novel, fast renal MRA technique without the need for contrast media.

The "open" chimney graft technique for juxtarenal aortic aneurysms with discrepant renal arteries.

OBJECTIVES: A straightforward original Chimney Graft (CG) protocol has been developed at our institution in selected cases of juxtarenal aortic aneurysm (JRAA). The aim of this study was to present our clinical experience of consecutive series with use of uncovered self-expanding stent (SES) as "Open Chimney" (OCh) in the endovascular repair (EVAR) of JRAA. METHODS: A standard endograft with suprarenal fixation struts is delivered with its proximal covered edge just below the highest RA in JRAA presenting the ostium of the two renal arteries at a different aortic level and the distance between the highest renal artery and the beginning of the aneurysm (improved landing zone) ≥10 mm. The low-lying renal artery is maintained patent by the OCh graft (standard SES) delivered from left brachial access (6 Fr). All clinical, anatomical, and operative data were prospectively collected and retrieved for the study analysis. RESULTS: From July 2010 to November 2012, OCh EVAR was offered to 22 consecutive patients considered unfit for JRAA open repair. All procedures were technically successful with aneurysm exclusion and patent OCh graft. One small perioperative type Ia endoleak spontaneously disappeared at the 3-month CT control. One patient died because of acute decompensated heart failure. One patient presented a left hemispheric stroke. The median follow-up of 18 months (range 7-35) showed aneurysm exclusion in all patients without type I and III endoleaks, SES stenosis, and/or renal impairment. CONCLUSIONS: OCh-EVAR is a straightforward technique that can be employed in selected cases of JRAA, avoiding the more complex and expensive fenestrated EVAR.

Can dopamine prevent the renal side effects of indomethacin? A prospective randomized clinical study.

BACKGROUND: Indomethacin therapy for closure of a patent ductus arteriosus in preterm neonates is responsible for transient renal insufficiency. Dopamine theoretically reduces the renal side effects of indomethacin therapy. PATIENTS: 33 neonates with a mean gestational age of 28.5 weeks who received indomethacin for treatment of a symptomatic PDA were included in a prospective randomized controlled clinical study. METHOD: 15 patients were treated with indomethacin alone (control group), 18 patients with indomethacin and dopamine (study group). Indomethacin was given in a dose of 0.2 mg/kg/dose intravenously, all patients received three doses with intervall of 12 hours. The dose of dopamine was in all patients 4 micrograms/kg per minute commencing 2 hours prior to the first dose of indomethacin and continuing for 12 hours after the third dose. RESULTS: Indomethacin induced a significant increase in serum creatinin (76.3 mumol/l vs 99.7 mumol/l for the control group, and 70.7 mumol/l vs 93.0 mumol/l for the study group), and weight (1259 g vs 1316 g for the control group, and 1187 g vs 1221 g for the study group). The increase systolic blood pressure (61 mmHg vs 65.7 mmHg) in the study group was significant (p < 0.05) but remained unchanged in the control group. The changes between the study group and the control group were not significant either in serum creatinin, fractional excretion of sodium, or weight gain. The failure rate of ductal closure was not different between the two groups. CONCLUSION: The additional use of dopamine does not reduce the renal side effects of indomethacin.

Molecular evidence of interhuman transmission in an outbreak of Pneumocystis jirovecii pneumonia among renal transplant recipients.

S. Gianella, L. Haeberli, B. Joos, B. Ledergerber, R.P. Wüthrich, R. Weber, H. Kuster, P.M. Hauser, T. Fehr, N.J. Mueller. Molecular evidence of interhuman transmission in an outbreak of Pneumocystis jirovecii pneumonia among renal transplant recipients. Transpl Infect Dis 2009. All rights reserved Abstract: Pneumocystis jirovecii pneumonia (PCP) remains an important cause of morbidity and mortality in immunocompromised individuals. The epidemiology and pathogenesis of this infection are poorly understood, and the exact mode of transmission remains unclear. Recent studies reported clusters of PCP among immunocompromised patients, raising the suspicion of interhuman transmission. An unexpected increase of the incidence of PCP cases in our nephrology outpatient clinic prompted us to conduct a detailed analysis. Genotyping of 7 available specimens obtained from renal transplant recipients was performed using multi-locus DNA sequence typing (MLST). Fragments of 4 variable regions of the P. jirovecii genome (ITS1, 26S, mt26S, beta-tubulin) were sequenced and compared with those of 4 independent control patients. MLST analysis revealed identical sequences of the 4 regions among all 7 renal allograft recipients with available samples, indicating an infection with the same P. jirovecii genotype. We observed that all but 1 of the 19 PCP-infected transplant recipients had at least 1 concomitant visit with another PCP-infected patient within a common waiting area. This study provides evidence that nosocomial transmission among immunocompromised patients may have occurred in our nephrology outpatient clinic. Our findings have epidemiological implications and suggest that prolonged chemoprophylaxis for PCP may be warranted in an era of more intense immunosuppression.

Hypercalcaemia and acute renal failure after major burns: An under-diagnosed condition.

BACKGROUND: Hypercalcaemia has been shown to occur in about 20% of patients with major burns requiring prolonged intensive care unit (ICU) treatment, and it may be associated with renal failure. Having observed the early onset of hypercalcaemia, the study aimed to determine the frequency and timing of this condition in a European patient cohort. METHODS: A retrospective cohort study on a prospectively collected, computerised database of the 225 burn-injury ICU admissions between 2001 and 2007 was undertaken. The inclusion criteria included: burns &gt;20% of the body surface area (BSA) or in-hospital stay &gt;20 days. Hypercalcaemia was defined as an ionised plasma calcium (Ca(2+)) concentration &gt;1.32 mmol l(-1) (or total corrected calcium=[Ca]c&gt;2.55 mmol l(-1)). Four emblematic cases are reported in this article. RESULTS: A total of 73 patients met the inclusion criteria (age: 13-88 years, burns: 12-85% BSA): of these, 22 (30%) developed hypercalcaemia. The median time to the first hypercalcaemia value was 21 days. Only 11 patients had both high Ca(2+) and elevated [Ca]c (which remained normal in others). The risk factors of the disorder were burned surface (p=0.017) and immobilisation (fluidised bed use: p&lt;0.05, duration: p=0.02) followed by burned BSA. Acute renal failure tended to be more frequent in hypercalcaemic patients (five (23%) vs. three (6%): p=0.11), while mortality was not increased. The disorder resolved with hydration and mobilisation in most cases: pamidronate was successful in three cases that were most severe. CONCLUSION: Hypercalcaemia and associated acute renal failure occur more frequently and earlier than previously reported. Determining the ionised Ca rather than the total Ca with albumin correction enables earlier detection of hypercalcaemia. Bisphosphonates are an effective treatment option in controlling severe hypercalcaemia and preventing bone loss.

Trasplante hepato-renal. Caso clínico

La hiperoxaliuria primaria tipo I es una enfermedad genética autosómica recesiva, cuyo defecto primario es el déficit, parcial o completo, de la enzima glioxilato aminotransferasa en el hígado que produce la formación de oxalato. El depósito progresivo de oxalato en el riñón es el causante, primero de urolitiasis y nefrocalcinosis, y después de un daño renal progresivo, que lleva a una insuficiencia renal crónica y posteriormente al acúmulo sistémico de oxalato en el sistema músculo-esquelético, en las arterias y en el sistema nervioso. La existencia de oxalosis sistémica es el principal factor de morbi-mortalidad antes y después del trasplante, dada su asociación a malnutrición y daño óseo. En estos casos el trasplante hepatorenal es la mejor opción para resolver el defecto metabólico. La realización de este trasplante es técnicamente más fácil al no existir hipertensión portal y en general la hemodiálisis se mantiene durante el postrasplante para facilitar la eliminación de la sobrecarga de oxalato existente mientras la función renal no se normaliza completamente. A continuación presentamos un caso en el que se expone la evolución clínica de un paciente afecto de esta patología y que se sometió a un trasplante hepatorenal.

Dominant TNF-α(+) Mycobacterium tuberculosis-specific CD4(+) T cell responses discriminate between latent infection and active disease.

Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4(+) T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4(+) T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4(+) T cells is a new tool for the rapid diagnosis of active tuberculosis disease.