Hypertension in the Pediatric Kidney Transplant Recipient.

Hypertension after kidney transplant is a frequent occurrence in pediatric patients. It is a risk factor for graft loss and contributes to the significant burden of cardiovascular disease (CVD) in this population. The etiology of posttransplant hypertension is multifactorial including donor factors, recipient factors, medications, and lifestyle factors similar to those prevalent in the general population. Ambulatory blood pressure monitoring has emerged as the most reliable method for measuring hypertension in pediatric transplant recipients, and many consider it to be essential in the care of these patients. Recent technological advances including measurement of carotid intima-media thickness, pulse wave velocity, and myocardial strain using specked echocardiography and cardiac magnetic resonance imaging have improved our ability to assess CVD burden. Since hypertension remains underrecognized and inadequately treated, an early diagnosis and an appropriate control should be the focus of therapy to help improve patient and graft survival

The impact of arteriovenous fistulas on aortic stiffness in patients with chronic kidney disease

Contexte. La création d'une fistule artérioveineuses (FAV) chez les patients atteints d'insuffisance rénale chronique (IRC) a des effets néfastes sur le profil central de l'onde de pouls, suggérant l'augmentation de la rigidité artérielle. Le but de la présente étude est d'évaluer de manière prospective l'effet de la création d'une FAV sur la rigidité artérielle. Méthode. Trente et un patients atteints d'IRC stade 5 ont subi une évaluation hémodynamique avant et 3 mois après la création d'une FAV. La pression artérielle (PA), l'analyse centrale et carotidienne du profil de l'onde de pouls et la vitesse de l'onde de pouls (VOP) carotido-fémorale et carotido-radiale ont été étudiées. Le test-t de Student et le test de Wilcoxon ont été utilisés pour comparer les paramètres hémodynamiques pré-FAV et post-FAV , le cas échéant. Pour déterminer l'association entre les variables, des corrélations de Pearson ainsi que des régressions linéaires simples et multiples ont été utilisées. Résultats. Après la création de la FAV, la PA périphérique et la PA centrale ont diminué, sans changements significatifs de la fréquence cardiaque (FC) ou de la pression puisée. La VOP carotido-fémorale (VOPc-f) a diminué de 13,2 ± 4,1 à 11,7 ± 3,1 m/s (P < 0,001). L'indice d'augmentation centrale a monté de 20,8% ± 11,5 à 23,7% ±11,6, à la limite de la signifiance statistique (P = 0,08). Le ratio de viabilité sous-endocardique a diminué de façon significative (153 % ± 34 versus 143 % ± 32, P < 0,05), principalement comme conséquence de la diminution de l'indice de temps de la pression diastolique (ITPD), sans modification significative de la durée diastolique. La réduction de la VOPc-f s'explique par les changements de la PA moyenne et de la FC (R =0,29). La réduction de l'ITPD était liée à des changements de la PA diastolique centrale et de la PA fin systolique centrale (R = 0,87). L'amélioration significative de la rigidité aortique est principalement le résultat de la réduction relative de la VOPc-f dans le sous-groupe de patients ayant une valeur basale de la VOPc-f supérieure à la valeur médiane de 13 m/s. Conclusion. La création de la FAV est associée à une amélioration passive de la rigidité aortique, en particulier chez les patients avec artères plus rigides. Cette amélioration de la rigidité artérielle pourrait être bénéfique pour le système cardiovasculaire

Modifications des propriétés structurelles et fonctionnelles des gros troncs artériels dans l'insuffisance rénale (valeur pronostique et évolution après transplantation)

La maladie rénale chronique (MRC) est caractérisée par une fréquence élevée de complications cardiovasculaires (CV). La rigidité artérielle est un marqueur de la maladie CV, corrélé avec la morbi-mortalité des patients en dialyse chronique. Notre équipe a déjà observé que des modifications structurelles et fonctionnelles des gros troncs artériels apparaissent néanmoins dès les stades précoces de la MRC.Le suivi prospectif d une large cohorte de patients insuffisants rénaux non dialysés, nous a permis de démontrer que le remodelage artériel s accentue avec la progression de la MRC, avec notamment une augmentation de la rigidité carotidienne, une diminution de l épaisseur intima-média, une augmentation du diamètre interne de la carotide et du stress circomférentiel. Notre étude prospective a permis de montrer que le stress circonférentiel est prédictif de la vitesse de dégradation de la fonction rénale, même après ajustement sur les autres facteurs de risque CV et de progression de la MRC. Nous avons également étudié la morbi-mortalité globale et CV en fonction des paramètres artériels mesurés lors de l inclusion. Après analyse multivariée, il apparaît que la rigidité aortique est corrélée au risque de décès ou de survenue d un événement CV, alors que le diamètre interne de la carotide est associé à la mortalité globale, même après ajustement sur les facteurs CV classiques. La transplantation rénale permet une amélioration du pronostic CV des patients insuffisants rénaux. Nos études, réalisées sur 2 cohortes prospectives de patients transplantés rénaux ont permis d objectiver une nette amélioration de la rigidité aortique dans les mois qui suivent la greffe. Nous démontrons par ailleurs que le remodelage artériel est également réversible, avec diminution du diamètre interne, augmentation de l épaisseur intima-média et correction partielle du stress circonférentiel au niveau de la carotide interne. Cette réversibilité de la rigidité est particulièrement importante chez les receveurs bénéficiant d une transplantation avec un donneur jeune, et ceci indépendamment du degré d amélioration la fonction rénale observée dans la période post-greffe.Elle est aussi beaucoup plus marquée chez les patients recevant un greffon rénal provenant d un donneur vivant.La qualité du greffon, déterminée par l âge du donneur ou son origine (donneur vivant vs donneur décédé) est donc capitale pour prédire l amélioration des paramètres artériels chez le receveur et indirectement son pronostic CV à moyen terme.Chronic Kidney Disease (CKD) is associated with frequent cardiovascular complications. Arterialstiffness is a marker of cardiovascular (CV) disease and is associated with mortality in patients with end-stagerenal disease (ESRD). Our group has previously suggested that a maladaptative arterial remodeling occurs earlyduring CKD, even in patients with mild kidney dysfunction. Our first prospective study was based on a large CKD cohort. Our data confirm that the large arteries modifications, which include increase of carotid stiffness, decrease of intima-media thickness, carotid arterydilatation with enhancement of circumferential wall stress (CWS), worsen during CKD progression. We also showthat initial CWS is associated with the rate of kidney function deterioration, even after adjustment for other CV andCKD risk factors. In addition, we found that aortic stiffness was associated with both the overall survival and therisk of cardiovascular events. The internal carotid diameter is predictive of the overall mortality, after multivariateanalysis. Kidney transplantation reduces the CV risk of ESRD patients. Our 2 prospective studies demonstratethat aortic stiffness can improve during the first year after transplantation. The maladaptative arterial remodelingcan also reverse after transplantation, with a significant reduction of the carotide diameter, an increase of theintima-media thickness and a partial correction of the CWS. The improvement of the aortic stiffness and thereversal of this maladaptative arterial remodeling is particularily important in patients receiving a kidney allograftform a young allograft donor, independently of the post-transplant renal function. The kidney recipients with aliving donor experience a major improvement of their arterial parameters when compared with recipients withdeceased donors, and this difference remains significant after adjustment for other confounding factors. Inconclusion, the quality of the kidney allograft (age and source) may play an important role in the cardiovascularoutcome of the recipient. This advantage could be mediated a beneficial effect of transplantation on centralarteries structure and function.PARIS5-Bibliotheque electronique (751069902) / SudocPARIS-BIUM-Bib. électronique (751069903) / SudocSudocFranceF

Predictors of cardiovascular disease and mortality in patients with advanced chronic kidney disease

Cardiovascular disease is the leading cause of high mortality in advanced chronic kidney disease (CKD) patients. Treatment and prevention of cardiovascular disease should be in focus to improve prognosis in this high-risk population. The aim of the study was to assess cardiovascular determinants of mortality, to study the effect of diabetes on arterial endothelial function and structure, to evaluate exercise capacity and abdominal aortic calcification (AAC) in patients with advanced CKD, not on dialysis. 210 participants of the Chronic Arterial Disease, quality of life and mortality in chronic KIDney injury -study underwent maximal bicycle ergometry stress test, echocardiography, lateral lumbar radiograph to study AAC score, ultrasound measures of arterial structure and function, and laboratory measures. Determinants of mortality were stress ergometry performance, AAC score, E/e’ ratio of echocardiography, and cardiac biomarkers and albumin. Diabetes was a significant determinant of AAC but did not associate with endothelial dysfunction or increased carotid intima-media thickness. Maximal stress ergometry performance was associated with troponin T (TnT) and AAC. The progression of AAC was rapid and the increment rate was similar in patients transitioning to different modalities of renal replacement therapy. To conclude, stress ergometry performance, AAC, E/e’ of echocardiography, and cardiac biomarkers and albumin predict mortality, and diabetes is associated with AAC in advanced CKD. TnT and AAC are associated with maximal ergometry stress test and AAC progresses at a comparable rate across the CKD treatment groups.Sydän- ja verisuonitautien ja kuolleisuuden ennustekijät loppuvaiheen munuaisten vajaatoimintaa sairastavilla Loppuvaiheen munuaisten vajaatoimintapotilailla sydän- ja verisuonitaudit ovat johtava kuolleisuuden syy. Sydän- ja verisuonitautien hoito ja ennaltaehkäisy tulisi olla keskiössä tämän korkean riskin ryhmän ennusteen parantumiseksi. Tutkimuksessa arvioitiin kuolleisuuteen vaikuttavia sydän- ja verisuonitautitekijöitä, diabeteksen vaikutusta verisuonen sisäkalvon toimintaan ja suonirakenteeseen, suorituskykyä, sekä vatsa-aortan kalkkisuutta ei-dialyysihoitoisessa loppuvaiheen munuaisten vajaatoiminnassa. 210 potilasta osallistui Krooninen valtimotauti, elämänlaatu ja mortaliteetti vaikeaa munuaisten vajaatoimintaa sairastavilla -tutkimukseen. Tutkittaville tehtiin polkupyörärasituskoe, sydämen ultraäänitutkimus, lannerangan röntgenkuvaus aortan kalkkisuuden määrittämiseksi, verisuoniultraäänitutkimus verisuonen rakenteen ja toiminnan tutkimiseksi sekä otettiin laboratoriokokeet. Kuolleisuutta määrittivät suorituskyky, vatsa-aortan kalkkisuus, sydämen ultraäänitutkimuksen E/e’ suhde, sydänmerkkiaineet ja albumiini. Diabetes määritti vatsa-aortan kalkkisuutta merkittävästi, mutta ei ollut yhteydessä verisuonen laajenemiskykyyn eikä kaulavaltimon seinämäpaksuuteen. Maksimaalinen suorituskyky oli yhteydessä troponiini T:hen (TnT) ja vatsa-aortan kalkkisuuteen. Vatsaaortan kalkkisuus kehittyi nopeasti ja kehityksen suuruus oli sama eri keinomunuaishoitomuodoissa. Yhteenvetona todetaan, että suorituskyky, vatsa-aortan kalkkisuus, sydämen ultraäänitutkimuksen E/e’ suhde, sydänmerkkiaineet ja albumiini ennustavat kuolleisuutta, ja diabetes on yhteydessä vatsa-aortan kalkkisuuteen, mutta ei verisuonen laajenemiskykyyn tai sisäkalvopaksuuteen, loppuvaiheen munuaisten vajaatoiminnassa. TnT ja vatsa-aortan kalkkisuus ovat yhteydessä maksimaaliseen suorituskykyyn, ja vatsa-aortan kalkkisuus etenee samalla nopeudella eri munuaiskorvaushoitomuodoissa

Cardiovascular effects of metabolic syndrome after transplantation: convergence of obesity and transplant-related factors.

Children are at increased risk of developing metabolic syndrome (MS) after kidney transplantation, which contributes to long-term cardiovascular (CV) morbidities and decline in allograft function. While MS in the general population occurs due to excess caloric intake and physical inactivity, additional chronic kidney disease and transplant-related factors contribute to the development of MS in transplant recipients. Despite its significant health consequences, the interplay of the individual components in CV morbidity in pediatric transplant recipients is not well understood. Additionally, the optimal methods to detect early CV dysfunction are not well defined in this unique population. The quest to establish clear guidelines for diagnosis is further complicated by genetic differences among ethnic groups that necessitate the development of race-specific criteria, particularly with regard to individuals of African descent who carry the apolipoprotein L1 variant. In children, since major CV events are rare and traditional echocardiographic measures of systolic function, such as ejection fraction, are typically well preserved, the presence of CV disease often goes undetected in the early stages. Recently, new noninvasive imaging techniques have become available that offer the opportunity for early detection. Carotid intima-media thickness and impaired myocardial strain detected by speckle tracking echocardiography or cardiac magnetic resonance are emerging as early and sensitive markers of subclinical CV dysfunction. These highly sensitive tools may offer the opportunity to elucidate subtle CV effects of MS in children after transplantation. Current knowledge and future directions are explored in this review

Inflammatory cytokines, endothelial function and cardiac allograft vasculopathy in children: an investigation of the donor and recipient vasculature after heart transplantation

Cardiac allograft vasculopathy (CAV) limits the life span of paediatric heart transplant recipients. I investigated blood markers of inflammation, endothelial dysfunction and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from paediatric heart transplant recipients for markers of inflammation and endothelial activation. The presence of systemic inflammation was assessed using serum markers including interleukin (IL) 1beta, IL 6, IL 8, c reactive protein (CRP), serum amyloid A (SAA) and tumour necrosis factor (TNF) alpha, an increase signifying the presence of a general inflammatory state. In order to assess endothelial activation measurements of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, P selectin and E selectin were taken. Each of these molecules belongs to a family of cell adhesion molecules present on the surface of endothelial cells. They are responsible for the adhesion of white blood cells and platelets to the endothelial surface and are markers of increased endothelial activation. Investigation into thrombotic mechanisms was determined by measuring Tissue Factor (TF), an important component of the coagulation cascade, von Willebrand Factor(vWF), an important protein involved in binding platelets to the site of endothelial injury and Thrombomodulin (TM), a protein involved in controlling excessive coagulation through natural anticoagulant properties and preventing inflammation. IL 10 is a cytokine with many effects on regulating the immune system and inflammation, acting to down regulate inflammation and moderating the immune response. Monocyte chemoattractant protein (MCP-1) regulates the migration and adhesion of monocytes and macrophages to atherosclerotic plaques and is present as part of a proinflammatory response. Vascular endothelial growth factor (VEGF) is involved in regulating angiogenesis, vascular permeability and inflammation and is a candidate protein involved in the development of atherosclerosis amongst other vascualar disorders. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5mm was used to define significant CAV. 48 children (25 male) aged 8 to 18 years were enrolled in the study. Patients were a median (IQR) 4.1 (2.2 to 8.7) years after transplant. Patients had increased levels of circulating IL 6 (3.86 (2.84-4.95) vs 1.66 (1.22-2.63), p < 0.0001*), VCAM1 (539(451-621) vs 402(342-487), p<0.001*), ICAM1 305(247-346) vs 256(224- 294), p=0.002* and TM (7.1(5.5-8.1) vs 3.57(3.03-4.71,) p<0.0001*) and decreased levels of TNF alpha, E selectin and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum TM. Post-transplant TM levels are elevated after transplant but significantly lower in those with mIMT > 0.5mm. TM is a protein bound to the endothelium that moderates the deleterious effects of inflammation, coagulopathy and fibrosis. vWF supports platelet to platelet adhesion and is involved in the stabilisation of clots in response to injury. This suggests that subclinical inflammation is present and natural anticoagulant/TM activity is an important area for future transplant research into CAV. This is the first time that the protective role of TM has been identified in a clinical cohort of children after heart transplantation

Uraemic vascular damage and calcification in children with chronic kidney disease

Summary of thesis: Cardiovascular disease is the most common cause of death in patients with chronic kidney disease. Structural and functional vascular abnormalities and arterial calcification begins early in the course of renal decline and can be found even in children, contributing to their high mortality risk. Through clinical and laboratory studies, this thesis sought to investigate the causes of uraemic vascular damage and calcification in children with chronic kidney disease and on dialysis. Dysregulated mineral metabolism, manifested by hyperparathyroidism and high phosphate, in association with low vitamin D levels, is key to the pathophysiology of ectopic vascular and soft tissue calcification. In addition, a number of treatment- related factors can potentially lead to a high calcium load, contributing to an increased risk of calcification. Importantly, these are modifiable risk factors and have been associated with an increased mortality risk in adult dialysis patients. Using established surrogate measures of vascular damage, carotid artery intima media thickness, pulse wave velocity and multi-slice CT scan, I have studied a cohort of children on chronic dialysis, and shown that those with mean parathyroid hormone levels above twice the upper limit of normal had increased vascular thickness, stiffer vessels and a higher prevalence of coronary artery calcification, whereas those with lower levels had vascular measures that were similar to age-matched controls. Also, a higher vitamin D dosage was associated with thicker vessels and coronary calcification. To explore this association, in a further study I have measured the levels of 25-hydroxy and 1,25-dihydroxy vitamin D and shown that both low and high levels of 1,25-dihydroxy vitamin D are associated with thicker vessels and calcification. Also, 1,25-dihydroxy vitamin D showed a strong inverse association with high sensitivity CRP, and we speculate that vitamin D’s influence on calcium-phosphate homeostasis and inflammation may be lead to this bimodal effect. Levels of the circulating calcification inhibitors, fetuin-A, osteoprotegerin and Matrix Gla-protein, may influence an individual patients’ susceptibility to calcify, and but have not been described in children. I found that these levels influenced vascular stiffness and calcification, and that there may be a protective upregulation of fetuin-A in the early stages of exposure to a pro-calcific and pro-inflammatory uraemic environment. In a subsequent translational study I have sought to find direct evidence of vascular damage and calcification in the vessels. Using intact human arteries removed at the time of routine surgery, I have shown that calcium accumulation begins pre-dialysis, but dialysis induced vascular smooth muscle cell apoptosis coupled with osteo/chondrocytic transformation and a loss of the normal calcification inhibitors leads to overt calcification. Our currently available clinical measures are not sensitive enough to detect the earliest stages of calcification. On in vitro culture in calcifying media, dialysis but not control vessels showed accelerated time-dependent calcification, suggesting that these vessels had lost their smooth muscle cell defence mechanisms and were primed to undergo rapid calcification. Apoptotic cell death was a key event that triggerred calcification, and this was a vesicle mediated process, possibly involving oxidative DNA damage. This thesis investigates the role of modifiable risk factors in uraemic vascular damage and calcification in children with CKD and explores the earliest changes in the pathophysiology of uraemic medial calcification in intact human vessels

The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation

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Bone Mineral Density and Vascular Calcification in Children and Young Adults with Chronic Kidney Disease

Introduction: Older adults with chronic kidney disease (CKD) can have low bone mineral density (BMD) with concurrent vascular calcification. It is not known if mineral accrual by the growing skeleton protects young people with CKD from extraosseous calcification. My hypothesis was that children and young adults with increasing BMD do not develop vascular calcification. Methods: Multicentre longitudinal study in children and young people (5-30 years) with CKD stages 4-5 or on dialysis. Cortical (Cort) and trabecular (Trab) BMD were assessed by peripheral quantitative Computed Tomography and lumbar spine BMD by DXA (Dual Energy X-ray Absorptiometry). Vascular calcification was assessed by cardiac CT for coronary artery calcification (CAC) and ultrasound for carotid intima-media thickness (cIMT). Arterial stiffness was measured by pulse wave velocity (PWV) and carotid distensibility. Results: One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed-up after a median of 1.45 years. The cohort had a significant bone and cardiovascular disease burden. 10% suffered at least one previous atraumatic fracture, and 58% reported bone pain affecting activities of daily living. The majority had evidence of vascular calcification and arterial stiffness with increased cIMT and PWV z-scores. 10% had CAC at baseline. Baseline TrabBMD was independently associated with cIMT (R2=0.10, β=0.34, p=0.001). An annualised increase in TrabBMD was an independent predictor of cIMT increase (R2=0.48, β=0.40, p=0.03), with 6-fold greater odds of an increase in ΔcIMT in those with an increase in ΔTrabBMD [(95%CI 1.88 to 18.35), p=0.003]. Young people that demonstrated statural growth (n=33) had attenuated vascular changes compared to those with static growth. Conclusion: These hypothesis generating studies suggest that children and young adults with CKD or on dialysis may develop vascular calcification even as BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraskeletal calcification

Effects of pioglitazone on subclinical atherosclerosis and insulin resistance in nondiabetic renal allograft recipients.

BACKGROUND: The aim of this study was to evaluate the effect of pioglitazone treatment on the progression of subclinical atherosclerosis and insulin resistance in renal allograft recipients with no preoperative history of diabetes. METHODS: Eighty-three patients without diabetes were randomly assigned to either the pioglitazone group or the control group. Carotid intima-media thickness (IMT), serum adiponectin level and lipid profile were assessed before transplantation and at 12 months after transplantation. Insulin secretory function and insulin resistance were evaluated by the oral glucose tolerance test. RESULTS: The pioglitazone group showed a significant reduction in the mean and maximum carotid IMT compared with the control group after 12 months (mean carotid IMT, 0.05 +/- 0.04 vs -0.03 +/- 0.07 mm, P < 0.001; maximum carotid IMT, 0.08 +/- 0.05 vs -0.05 +/- 0.09 mm, P < 0.001). Pioglitazone increased the adiponectin level, and the change in adiponectin was negatively correlated with carotid IMT changes. Pioglitazone treatment increased the insulin sensitivity index compared with the control group (-0.8 +/- 3.1x10(-)(2) vs +1.1 +/- 3.7x10(-)(2), P = 0.036). CONCLUSIONS: These results suggest that pioglitazone treatment reduces the progression of carotid IMT and improves insulin resistance in renal allograft recipients without a history of diabetes. Trial Registration. Clinicaltrials.gov Identifier: NCT00598013ope