Calcifications vasculaires et déficit en vitamine K: un facteur de risque modifiable dans l'insuffisance rénale chronique [Vascular calcifications and vitamin K deficiency: a modifiable risk factor in chronic kidney disease].

The mechanisms of vascular calcifications in chronic renal failure are complex. Apart for clotting factors, vitamin K-dependent proteins include matrix Gla protein. Glutamic acid residues in matrix Gla protein are carboxylated by vitamin K-dependent gamma-carboxylase, which enables it to inhibit calcification. The purpose of this review is to discuss available evidence implicating vitamin K as a modifiable risk factor in the pathogenesis of vascular calcification in renal diseases.

Rein et tabac : revue de la littérature et mise au point [Kidney and smoking: literature review and focus].

Smoking remains a major public health problem. It is associated with a considerable number of deaths in the world's population. Smoking is just like high blood pressure, an independent predictor of progression to any primary renal disease and renal transplant patients. It seems that smoking cessation slows the progression of kidney disease in smokers. The literature data are sometimes contradictory about it because of some methodological weaknesses. However, experimental models highlight the harmful effects of tobacco by hemodynamic and non-hemodynamic factors. The conclusion is that a major effort should be further produced by the nephrology community to motivate our patients to stop smoking.

Renal tissue oxygenation in essential hypertension and chronic kidney disease.

Animal studies suggest that renal tissue hypoxia plays an important role in the development of renal damage in hypertension and renal diseases, yet human data were scarce due to the lack of noninvasive methods. Over the last decade, blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI), detecting deoxyhemoglobin in hypoxic renal tissue, has become a powerful tool to assess kidney oxygenation noninvasively in humans. This paper provides an overview of BOLD-MRI studies performed in patients suffering from essential hypertension or chronic kidney disease (CKD). In line with animal studies, acute changes in cortical and medullary oxygenation have been observed after the administration of medication (furosemide, blockers of the renin-angiotensin system) or alterations in sodium intake in these patient groups, underlining the important role of renal sodium handling in kidney oxygenation. In contrast, no BOLD-MRI studies have convincingly demonstrated that renal oxygenation is chronically reduced in essential hypertension or in CKD or chronically altered after long-term medication intake. More studies are required to clarify this discrepancy and to further unravel the role of renal oxygenation in the development and progression of essential hypertension and CKD in humans.

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

Rapport de synthèseApproche et objectifL'objectif de la recherche était de préciser les relations existant entre l'insuffisance rénale chronique, l'anémie et l'accident vasculaire cérébral parmi des patients hospitalisés au Centre Hospitalier Universitaire Vaudois (CHUV) pour un accident vasculaire cérébral (AVC). Les auteurs ont déterminé la prévalence de l'anémie et de l'insuffisance rénale chronique parmi ces patients et examiné s'ils sont des facteurs de risque indépendants de la mortalité suite à un AVC.L'insuffisance rénale chronique est associée à un risque élevé de développer un AVC. L'anémie est une complication et une conséquence fréquente qui découle de l'insuffisance rénale chronique et est également un facteur de risque pour les maladies cérébro- et cardiovasculaires.MéthodeLa présente étude de cohorte rétrospective se base sur le registre des AVC du CHUV et inclut tous les patients traités suite à un premier AVC au service de neurologie du CHUV entre les années 2000 et 2003.Les variables utilisées pour l'analyse sont les caractéristiques démographiques, l'insuffisance rénale chronique, le débit de filtration glomérulaire.(GFR), l'anémie et d'autres facteurs de risque d'AVC. Ils ont été récoltés au moyen du système informatique du laboratoire du CHUV, d'entretiens téléphoniques (patients ou proches) et du registre des AVC du CHUV.L'insuffisance rénale chronique a été calculée sur base de la ,,Kidney Disease Outcomes Quality Initiative (K/DOQI)-CKD Classification", laquelle est divisée en cinq stades. L'anémie a été définie par une hémoglobine de < 120g/L pour les femmes et < 130g/L pour les hommes.Les analyses statistiques réalisées sont des tests Chi-carré, des tests de Τ ainsi que des courbes de Kaplan-Meier et le modèle de régression de Cox.RésultatsParmi 890 patients adultes avec un AVC, le GFR moyen était de 64.3 ml/min/1.73 m2, 17% souffraient d'anémie et 10% sont décédés pendant la première année après la sortie de l'hôpital, suite à l'"AVC index". Parmi ceux-ci, 61% avaient une insuffisance rénale chronique de stade 3-5 et 39% de stade 1 ou 2 selon les critères de K/DOQI.D'autre part un taux d'hémoglobine élevé a pu être associé à un risque moins élevé de mortalité un an après la sortie de l'hôpital.Conclusion et perspectiveNous avons constaté que l'anémie ainsi que l'insuffisance rénale chronique sont fréquents parmi les patients souffrant d'un AVC et qu'ils sont des facteurs de risque d'un taux de mortalité élevé après un an. En conséquence, il pourrait être utile de traiter les patients souffrant d'anémie et d'insuffisance rénale dès que possible afin de diminuer les complications et comorbidités résultants de ces maladies.La perspective est de rendre les cliniciens attentif à l'importance de l'insuffisance rénale et de l'anémie parmi les patients ayants développé un AVC, ainsi que d'initier le traitement approprié afin de diminuer les complications, les comorbidités ainsi que les récidives d'un AVC. L'efficacité et l'économicité des interventions visant à améliorer le pronostic chez les patients présentant un AVC et souffrant d'une insuffisance rénale chronique et / ou d'une anémie doivent être évaluées par des études appropriées.

Expression of killer cell immunoglobulin-like receptors (KIRs) by natural killer cells during acute CMV infection after kidney transplantation.

Human cytomegalovirus (CMV) infection may be a serious complication related to immunosuppression after solid organ transplantation. Due to their cytotoxicity, T-cells and natural killer (NK) cells target and clear the virus from CMV-infected cells. Although immunosuppressive drugs suppress T-cell proliferation and activation, they do not affect NK cells that are crucial for controlling the infection. The regulation of NK cells depends on a wide range of activating and inhibitory receptors such as the family of killer-cell immunoglobulin-like receptors (KIRs). Several human genetic studies have demonstrated the association of KIR genes with the clearance of infections. Since the respective activities of the different KIR proteins expressed by NK cells during CMV infection have not been extensively studied, we analyzed the expression of KIRs in a cohort of 22 CMV-IgG(+) renal transplant patients at the time of CMV reactivation, after antiviral therapy and 6 months later. Our data revealed a marked expression of KIR3DL1 during the acute phase of the reactivation. We set up an in vitro model in which NK cells, derived either from healthy donors or from transplanted patients, target allogeneic fibroblasts, CMV-infected or uninfected. Our results demonstrate a significant correlation between the lysis of CMV-infected fibroblasts and the expression of KIR3DL1. Blocking experiments with antibodies to MHC-I, to NKG2D and to NKG2C confirmed the importance of KIR3DL1. Consequently, our results suggest that KIR proteins and especially KIR3DL1 could play an important role during CMV-infection or CMV reactivation in immunosuppressed patients.

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Anemia and chronic kidney disease are associated with poor outcomes in heart failure patients.

BACKGROUND: Chronic kidney disease (CKD) has been linked to higher heart failure (HF) risk. Anemia is a common consequence of CKD, and recent evidence suggests that anemia is a risk factor for HF. The purpose of this study was to examine among patients with HF, the association between CKD, anemia and inhospital mortality and early readmission. METHODS: We performed a retrospective cohort study in two Swiss university hospitals. Subjects were selected based the presence of ICD-10 HF codes in 1999. We recorded demographic characteristics and risk factors for HF. CKD was defined as a serum creatinine > or = 124 956;mol/L for women and > or = 133 micromol/L for men. The main outcome measures were inhospital mortality and thirty-day readmissions. RESULTS: Among 955 eligible patients hospitalized with heart failure, 23.0% had CKD. Twenty percent and 6.1% of individuals with and without CKD, respectively, died at the hospital (p < 0.0001). Overall, after adjustment for other patient factors, creatinine and hemoglobin were associated with an increased risk of death at the hospital, and hemoglobin was related to early readmission. CONCLUSION: Both CKD and anemia are frequent among older patients with heart failure and are predictors of adverse outcomes, independent of other known risk factors for heart failure.

Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection.

Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.

Not all inflammatory markers are linked to kidney function: results from a population-based study.

BACKGROUND: Several studies have reported increased levels of inflammatory biomarkers in chronic kidney disease (CKD), but data from the general population are sparse. In this study, we assessed levels of the inflammatory markers C-reactive protein (hsCRP), tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 across all ranges of renal function. METHODS: We conducted a cross-sectional study in a random sample of 6,184 Caucasian subjects aged 35-75 years in Lausanne, Switzerland. Serum levels of hsCRP, TNF-α, IL-6, and IL-1β were measured in 6,067 participants (98.1%); serum creatinine-based estimated glomerular filtration rate (eGFR(creat), CKD-EPI formula) was used to assess renal function, and albumin/creatinine ratio on spot morning urine to assess microalbuminuria (MAU). RESULTS: Higher serum levels of IL-6, TNF-α and hsCRP and lower levels of IL-1β were associated with a lower renal function, CKD (eGFR(creat) <60 ml/min/1.73 m(2); n = 283), and MAU (n = 583). In multivariate linear regression analysis adjusted for age, sex, hypertension, smoking, diabetes, body mass index, lipids, antihypertensive and hypolipemic therapy, only log-transformed TNF-α remained independently associated with lower renal function (β -0.54 ±0.19). In multivariate logistic regression analysis, higher TNF-α levels were associated with CKD (OR 1.17; 95% CI 1.01-1.35), whereas higher levels of IL-6 (OR 1.09; 95% CI 1.02-1.16) and hsCRP (OR 1.21; 95% CI 1.10-1.32) were associated with MAU. CONCLUSION: We did not confirm a significant association between renal function and IL-6, IL-1β and hsCRP in the general population. However, our results demonstrate a significant association between TNF-α and renal function, suggesting a potential link between inflammation and the development of CKD. These data also confirm the association between MAU and inflammation.

Interpretation of needle biopsies of the kidney for investigation of renal masses.

The development of new therapeutic options for renal tumors has lead to the need of a pretherapeutic diagnosis for an increasing proportion of patients presenting with a renal mass. This need is particularly important for a small, incidentally discovered renal mass (less than 4 cm) as it can be a benign lesion in a significant percentage of cases. Recent studies have shown that needle biopsy is an accurate and safe method allowing for a precise histopathological diagnosis of the mass in most cases. The aims of the biopsy are (1) to assess the benign or malignant nature of the lesion, (2) to assess the primary or secondary nature of the lesion, and (3), in case of a primary malignancy, to determine histological prognostic factors, such as the tumor type. This review, based on the most recent literature and our own experience, is intended to provide a practical approach to the diagnosis, relying on appropriate morphologic assessment and the use of immunohistochemistry.

Drug adherence in chronic kidney diseases and dialysis.

Poor long-term adherence and persistence to drug therapy is universally recognized as one of the major clinical issues in the management of chronic diseases, and patients with renal diseases are also concerned by this important phenomenon. Chronic kidney disease (CKD) patients belong to the group of subjects with one of the highest burdens of daily pill intake with up to >20 pills per day depending on the severity of their disease. The purpose of the present review is to discuss the difficulties encountered by nephrologists in diagnosing and managing poor adherence and persistence in CKD patients including in patients receiving maintenance dialysis. Our review will also attempt to provide some clues and new perspectives on how drug adherence could actually be addressed and possibly improved. Working on drug adherence may look like a long and tedious path, but physicians and healthcare providers should always be aware that drug adherence is in general much lower than what they may think and that there are many ways to improve and support drug adherence and persistence so that renal patients obtain the full benefits of their treatments.