Molecular genetic evaluation of pediatric renovascular hypertension due to renal artery stenosis and abdominal aortic coarctation in neurofibromatosis type 1.

The etiology of renal artery stenosis (RAS) and abdominal aortic coarctation (AAC) causing the midaortic syndrome (MAS), often resulting in renovascular hypertension (RVH), remains ill-defined. Neurofibromatosis type 1 (NF-1) is frequently observed in children with RVH. Consecutive pediatric patients (N = 102) presenting with RVH secondary to RAS with and without concurrent AAC were prospectively enrolled in a clinical data base, and blood, saliva and operative tissue, when available, were collected. Among the 102 children, 13 were having a concurrent clinical diagnosis of NF-1 (12.5%). Whole exome sequencing was performed for germline variant detection, and RNA-Seq analysis of NF1, MAPK pathway genes and MCP1 levels were undertaken in five NF-1 stenotic renal arteries, as well as control renal and mesenteric arteries from children with no known vasculopathy or NF-1. In 11 unrelated children with sequencing data, 11 NF1 genetic variants were identified, of which 10 had not been reported in gnomAD. Histologic analysis of NF-1 RAS specimens consistently revealed intimal thickening, disruption of the internal elastic lamina and medial thinning. Analysis of transcript expression in arterial lesions documented an approximately 5-fold reduction in NF1 expression, confirming heterozygosity, MAPK pathway activation and increased MCP1 expression. In summary, NF-1-related RVH in children is rare but often severe and progressive and, as such, important to recognize. It is associated with histologic and molecular features consistent with an aggressive adverse vascular remodeling process. Further research is necessary to define the mechanisms underlying these findings.

Association of De Novo RNF213 Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy.

OBJECTIVE: To test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents. METHODS: Exome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents. RESULTS: We identified 3 novel rare de novo RNF213 variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114-4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta. CONCLUSIONS: These results indicate a novel syndrome associated with RNF213 rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.

Expression of Cyr61 in ApoE-/- mice with chronic unilateral renal artery ligation.

Cyr61 is a member of the CCN family of proteins that is expressed in atherosclerotic lesions and regulated by angiotensin II. It is unknown whether renal artery stenosis (RAS) increases Cyr61 expression. Male ApoE-/- mice were randomized to surgically induced RAS, RAS + treatment with either irbesartan, aliskiren or amlodipine or sham-surgery. RAS resulted in increased plasma angiotensin II levels, a mild, sustained increase in systolic blood pressure and increased aortic lipid deposition compared to sham-surgery. Surgically induced RAS led to the formation of atheroma in the infrarenal aorta and there was consistent and intense staining for Cyr61 within the atheroma. Treatment with irbesartan, aliskiren and amlodipine were associated with decreased aortic lipid deposition and decreased staining for Cyr61 in aortic atheroma. Serum levels of Cyr61 were not increased in mice or humans with RAS. In summary, Cyr61 expression in aortic atheroma but not serum is increased by RAS in ApoE-/- mice and is reduced by agents that lower blood pressure.

The Transcription Factor Sox6 Controls Renin Expression during Renal Artery Stenosis.

Background: Renal artery stenosis (RAStenosis) or renal artery occlusion is an intractable problem affecting about 6% of people >65 and up to 40% of people with coronary or peripheral vascular disease in the Unites States. The renal renin-angiotensin-aldosterone system plays a key role in RAStenosis, with renin (which is mainly produced in the kidney) being recognized as the driver of the disease. In this study, we will determine a new function for the transcription factor Sox6 in the control of renal renin during RAStenosis. Methods: We hypothesize that knocking out Sox6 in Ren1d-positive cells will protect mice against renovascular hypertension and kidney injury. To test our hypothesis, we used a new transgenic mouse model, Ren1dcre/Sox6fl/fl (Sox6 KO), in which Sox6 is knocked out in renin-expressing cells. We used a modified two-kidney, one-clip (2K1C) Goldblatt mouse model to induce RAStenosis and renovascular hypertension. BP was measured using the tail-cuff method. Renin, prorenin, Sox6, and NGAL expressions levels were measured with Western blot, in situ hybridization, and immunohistochemistry. Creatinine levels were measured using the colorimetric assay. Results: Systolic BP was significantly lower in Sox6 KO 2 weeks after RAStenosis compared with Sox6 WT (Ren1dcre/Sox6wt/wt). Renin, prorenin, and NGAL expression levels in the stenosed kidney were lower in Sox6 KO compared with Sox6 WT mice. Furthermore, creatinine clearance was preserved in Sox6 KO compared with Sox6 WT mice. Conclusions: Our data indicate that Sox6 controls renal renin and prorenin expression and, as such, has a function in renovascular hypertension induced by RAStenosis. These results point to a novel transcriptional regulatory network controlled by Sox6.

Increased cellular senescence in the murine and human stenotic kidney: Effect of mesenchymal stem cells.

Cell stress may give rise to insuperable growth arrest, which is defined as cellular senescence. Stenotic kidney (STK) ischemia and injury induced by renal artery stenosis (RAS) may be associated with cellular senescence. Mesenchymal stem cells (MSCs) decrease some forms of STK injury, but their ability to reverse senescence in RAS remains unknown. We hypothesized that RAS evokes STK senescence, which would be ameliorated by MSCs. Mice were studied after 4 weeks of RAS, RAS treated with adipose tissue-derived MSCs 2 weeks earlier, or sham. STK senescence-associated ß-galactosidase (SA-ß-Gal) activity was measured. Protein and gene expression was used to assess senescence and the senescence-associated secretory phenotype (SASP), and staining for renal fibrosis, inflammation, and capillary density. In addition, senescence was assessed as p16+ and p21+ urinary exosomes in patients with renovascular hypertension (RVH) without or 3 months after autologous adipose tissue-derived MSC delivery, and in healthy volunteers (HV). In RAS mice, STK SA-ß-Gal activity increased, and senescence and SASP marker expression was markedly elevated. MSCs improved renal function, fibrosis, inflammation, and capillary density, and attenuated SA-ß-Gal activity, but most senescence and SASP levels remained unchanged. Congruently, in human RVH, p21+ urinary exosomes were elevated compared to HV, and only slightly improved by MSC, whereas p16+ exosomes remained unchanged. Therefore, RAS triggers renal senescence in both mice and human subjects. MSCs decrease renal injury, but only partly mitigate renal senescence. These observations support exploration of targeted senolytic therapy in RAS.

Renal ischemia alters expression of mitochondria-related genes and impairs mitochondrial structure and function in swine scattered tubular-like cells.

Scattered tubular-like cells (STCs) are dedifferentiated surviving tubular epithelial cells that repair neighboring injured cells. Experimental renal artery stenosis (RAS) impairs STC reparative potency by inducing mitochondrial injury, but the exact mechanisms of mitochondrial damage remain unknown. We hypothesized that RAS alters expression of mitochondria-related genes, contributing to mitochondrial structural damage and dysfunction in swine STCs. CD24+/CD133+ STCs were isolated from pig kidneys after 10 wk of RAS or sham (n = 3 each). mRNA sequencing was performed, and nuclear DNA (nDNA)-encoded mitochondrial genes and mitochondrial DNA (mtDNA)-encoded genes were identified. Mitochondrial structure, ATP generation, biogenesis, and expression of mitochondria-associated microRNAs were also assessed. There were 96 nDNA-encoded mitochondrial genes upregulated and 12 mtDNA-encoded genes downregulated in RAS-STCs versus normal STCs. Functional analysis revealed that nDNA-encoded and mtDNA-encoded differentially expressed genes were primarily implicated in mitochondrial respiration and ATP synthesis. Mitochondria from RAS STCs were swollen and showed cristae remodeling and loss and decreased ATP production. Immunoreactivity of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and expression of the mitochondria-associated microRNAs miR-15a, miR-181a, miR-196a, and miR-296-3p, which target several mtDNA genes, were higher in RAS-STCs compared with normal STCs, suggesting a potential modulation of mitochondria-related gene expression. These results demonstrate that RAS induces an imbalance in mtDNA- and nDNA-mitochondrial gene expression, impairing mitochondrial structure and function in swine STCs. These observations support development of gene gain- and loss-of-function strategies to ameliorate mitochondrial damage and preserve the reparative potency of STCs in patients with renal ischemia.

Renal Fibrosis Is Significantly Attenuated Following Targeted Disruption of Cd40 in Experimental Renal Ischemia.

Background Renal artery stenosis is a common cause of renal ischemia, contributing to the development of chronic kidney disease. To investigate the role of local CD40 expression in renal artery stenosis, Goldblatt 2-kidney 1-clip surgery was performed on hypertensive Dahl salt-sensitive rats (S rats) and genetically modified S rats in which CD40 function is abolished (Cd40mutant). Methods and Results Four weeks following the 2-kidney 1-clip procedure, Cd40mutant rats demonstrated significantly reduced blood pressure and renal fibrosis in the ischemic kidneys compared with S rat controls. Similarly, disruption of Cd40 resulted in reduced 24-hour urinary protein excretion in Cd40mutant rats versus S rat controls (46.2±1.9 versus 118.4±5.3 mg/24 h; P<0.01), as well as protection from oxidative stress, as indicated by increased paraoxonase activity in Cd40mutant rats versus S rat controls (P<0.01). Ischemic kidneys from Cd40mutant rats demonstrated a significant decrease in gene expression of the profibrotic mediator, plasminogen activator inhibitor-1 (P<0.05), and the proinflammatory mediators, C-C motif chemokine ligand 19 (P<0.01), C-X-C Motif Chemokine Ligand 9 (P<0.01), and interleukin-6 receptor (P<0.001), compared with S rat ischemic kidneys, as assessed by quantitative PCR assay. Reciprocal renal transplantation documented that CD40 exclusively expressed in the kidney contributes to ischemia-induced renal fibrosis. Furthermore, human CD40-knockout proximal tubule epithelial cells suggested that suppression of CD40 signaling significantly inhibited expression of proinflammatory and -fibrotic genes. Conclusions Taken together, our data suggest that activation of CD40 induces a significant proinflammatory and -fibrotic response and represents an attractive therapeutic target for treatment of ischemic renal disease.

Renal Artery Stenosis Alters Gene Expression in Swine Scattered Tubular-Like Cells.

BACKGROUND: Scattered tubular-like cells (STCs) proliferate and differentiate to support neighboring injured renal tubular cells during recovery from insults. Renal artery stenosis (RAS) induces renal ischemia and hypertension and leads to loss of kidney function, but whether RAS alters renal endogenous repair mechanisms, such as STCs, remains unknown. We hypothesize that RAS in swine modifies the messenger RNA (mRNA) profile of STCs, blunting their in vitro reparative capacity. METHODS: CD24+/CD133+ STCs were isolated from pig kidneys after 10-weeks of RAS or sham (n = 3 each) and their gene cargo analyzed using high-throughput mRNAseq. Expression profiles for upregulated and downregulated mRNAs in RAS-STCs were functionally interpreted by gene ontology analysis. STC activation was assessed by counting the total number of STCs in pig kidney sections using flow cytometry, whereas cell proliferation was assessed in vitro. RESULTS: Of all expressed genes, 1430 genes were upregulated and 315 downregulated in RAS- versus Normal-STCs. Expression of selected candidate genes followed the same fold change directions as the mRNAseq findings. Genes upregulated in RAS-STCs were involved in cell adhesion, extracellular matrix remodeling, and kidney development, whereas those downregulated in RAS-STCs are related to cell cycle and cytoskeleton. The percentage of STCs from dissociated kidney cells was higher in RAS versus Normal pigs, but their proliferation rate was blunted. CONCLUSIONS: Renal ischemia and hypertension in swine induce changes in the mRNA profile of STCs, associated with increased STC activation and impaired proliferation. These observations suggest that RAS may alter the reparative capacity of STCs.

Obstructive Kidney Disease.

Obstructive kidney disease is a common urologic diagnosis and includes kidney stones, polycystic kidney disease, and renal artery stenosis. Kidney stones are a common emergency department admission in the United States. Men are affected more than women. Polycystic kidney disease is a genetic renal disease that may not reveal symptoms until an individual reaches age 30 years. Renal artery stenosis contributes to decreased perfusion to the kidneys, which contributes to hypertension and end-stage renal disease.

Development of a Simple Risk Score Model to Predict Renal Artery Stenosis.

BACKGROUND/AIMS: Renal artery stenosis (RAS) is a known cause of secondary hypertension and renal failure. Although renal artery angiography is the gold standard for diagnosing RAS, a simple method to estimate if patients will develop RAS is required. The aim of this retrospective study was to develop a simple risk score to predict significant RAS. METHODS: Four thousand one hundred seventy-seven patients who underwent renal angiography between 2002 and 2016 at Tehran Heart Center were included. Significant RAS was defined as narrowing of the renal artery by at least 70%. Multiple predictors of the RAS were determined using multivariable logistic regression with a backward elimination method. The scoring system obtained from the final model was presented as nomogram. The possible nonlinear effect of continuous variables was evaluated using restricted cubic splines. Overfitting of the final model was assessed applying the tenfold cross-validation method. Model performance was checked using calibration plot as well as Hosmer-Lemeshow goodness of fit test, and area under the receiver operating characteristics (ROC) curve. RESULTS: The prevalence of RAS was 14.1%. Female sex (OR [95% CI]: 1.53 [1.26-1.85]), hypertension (OR [95% CI]: 1.38 [1.08-1.77]), estimated glomerular filtration rate (OR [95% CI]: 0.98 [0.97-0.98]), body mass index (OR [95% CI]: 0.97 [0.95-0.99]), and age (OR [95% CI]: 1.01 [1.00-1.02]) were determined as the multiple predictors of RAS. The area under the ROC curve of the final predictive model was 0.702 (95% CI: 0.679-0.725). CONCLUSION: This model assesses the risk of RAS using available information. This model can be used for both clinical and research purposes.

Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation.

Mesenchymal stem/stromal cells (MSCs) have distinct capability for renal repair, but may have safety concerns. MSC-derived extracellular vesicles emerged as a novel noncellular alternative. Using a porcine model of metabolic syndrome and renal artery stenosis we tested whether extracellular vesicles attenuate renal inflammation, and if this capacity is mediated by their cargo of the anti-inflammatory cytokine interleukin (IL) 10. Pigs with metabolic syndrome were studied after 16 weeks of renal artery stenosis untreated or treated four weeks earlier with a single intrarenal delivery of extracellular vesicles harvested from adipose tissue-derived autologous MSCs. Lean and sham metabolic syndrome animals served as controls (seven each). Five additional pigs with metabolic syndrome and renal artery stenosis received extracellular vesicles with pre-silenced IL10 (IL10 knock-down). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were studied in vivo and renal injury pathways ex vivo. Retention of extracellular vesicles in the stenotic kidney peaked two days after delivery and decreased thereafter. Four weeks after injection, extracellular vesicle fragments colocalized with stenotic-kidney tubular cells and macrophages, indicating internalization or fusion. Extracellular vesicle delivery attenuated renal inflammation, and improved medullary oxygenation and fibrosis. Renal blood flow and glomerular filtration rate fell in metabolic syndrome and renal artery stenosis compared to metabolic syndrome, but was restored in pigs treated with extracellular vesicles. These renoprotective effects were blunted in pigs treated with IL10-depleted extracellular vesicles. Thus, extracellular vesicle-based regenerative strategies might be useful for patients with metabolic syndrome and renal artery stenosis.

Association of MYH9 rs3752462 and rs5756168 Polymorphisms With Transplanted Kidney Artery Stenosis.

Allelic variants of the MYH9 gene, encoding myosin nonmuscle heavy chain type IIA, have been shown to correlate with diminished glomerular filtration rates and end-stage kidney disease in individuals of Caucasian ancestry. Myosin nonmuscle heavy chain type IIA is expressed during development as well as in injured vessels and kidney structures. We hypothesized that MYH9 risk variants may correlate with kidney artery injury and dysfunctional healing, such as transplant renal artery stenosis (TRAS). Our study aimed at evaluating the association of MYH9 risk allelic variants (rs4821480, rs4821481, rs3752462, rs11089788, rs136211, rs5756168, rs2032487, and rs2239784) with TRAS, defined as >50% renal artery lumen reduction. Genotyping was performed with the use of custom Taqman genotyping assays on DNA samples (n = 295) from white deceased-donor kidney transplant recipients and genomic DNA from the corresponding donors. Statistical analysis was performed with the use of Kaplan-Meier estimates, log-rank tests, and proportional hazard Cox models. Recipients carrying TT in rs5756168 experienced diminished risk of TRAS (hazard ratio [HR], 0.31; P < .009), whereas organs carrying CC in rs3752462 were exposed to excessive TRAS risk (HR, 2.54; P < .047). In multivariate stepwise analysis TRAS was 10.9-fold increased in kidneys originating from rs3752462 CC, whereas the risk was decreased 3.45-fold (adjusted HR, 0.29) in recipients carrying rs5756168 TT (P < .007 and P < .033, respectively). Intracranial bleeding or trauma compared with other mechanisms of donor death diminished TRAS risk by 87% and 91%, respectively (P < .030 and P < .017). Our study is the first to identify genetic predisposition to transplant renal artery stenosis.

CXCL16 regulates renal injury and fibrosis in experimental renal artery stenosis.

Recent studies have shown that inflammation plays a critical role in the initiation and progression of hypertensive kidney disease, including renal artery stenosis. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We found that CXCL16 was induced in the kidney in a murine model of renal artery stenosis. To determine whether CXCL16 is involved in renal injury and fibrosis, wild-type and CXCL16 knockout mice were subjected to renal artery stenosis induced by placing a cuff on the left renal artery. Wild-type and CXCL16 knockout mice had comparable blood pressure at baseline. Renal artery stenosis caused an increase in blood pressure that was similar between wild-type and CXCL16 knockout mice. CXCL16 knockout mice were protected from RAS-induced renal injury and fibrosis. CXCL16 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the stenotic kidneys, which was associated with less expression of extracellular matrix proteins. Furthermore, CXCL16 deficiency inhibited infiltration of F4/80(+) macrophages and CD3(+) T cells in the stenotic kidneys compared with those of wild-type mice. Taken together, our results indicate that CXCL16 plays a pivotal role in the pathogenesis of renal artery stenosis-induced renal injury and fibrosis through regulation of bone marrow-derived fibroblast accumulation and macrophage and T-cell infiltration.

Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension.

Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH.

Circulating and renal vein levels of microRNAs in patients with renal artery stenosis.

BACKGROUND: MicroRNAs (miRs) are small non-coding RNAs that are important regulators of gene expression and have been implicated in atherosclerosis. Kidney injury distal to atherosclerotic renal artery stenosis (ARAS) is aggravated by atherosclerosis. Therefore, this study tested the hypothesis that renal miR expression would be altered in patients with ARAS. METHODS: Patients with essential hypertension (EH; n = 13) or ARAS (n = 13) underwent a 3-day protocol study under controlled conditions. For miR levels, blood samples were collected from EH and ARAS renal vein (RV) and inferior vena cava or peripheral vein of matched normotensive healthy volunteers (HV; n = 13) and patients with coronary atherosclerosis (CA; n = 11). Single-renal blood flow was measured in EH and ARAS using computer tomography to calculate renal gradients and release of miRs. RESULTS: Glomerular filtration rate (GFR) was lower in ARAS compared with the other groups. Systemic levels of most miRs were elevated in CA. RV miR levels were lower than systemic levels in both ARAS and EH. GFR-adjusted RV levels of miR-21, 155 and 210 were reduced only in ARAS patients compared with systemic levels in HV, although cross-kidney gradients were not different from EH. RV levels of miR-21, 126, 155 and 210 correlated with GFR. CONCLUSIONS: Levels of atherosclerosis-related miR-21, 126, 155 and 210 are decreased in the stenotic-kidney vein of ARAS compared with EH patients, likely due to decreased GFR. Yet, these miRs might be implicated in modulating renal injury in ARAS, and their RV level may be a marker reflecting their renal expression.

Association of smoking with phenotype at diagnosis and vascular interventions in patients with renal artery fibromuscular dysplasia.

The pathogenesis of fibromuscular dysplasia (FMD) remains unclear, but tobacco use is thought to be involved. This retrospective cross-sectional study aimed to evaluate smoking first as a risk factor for renal artery FMD diagnosis and second as a modifier of the clinical and radiological phenotype of this disease. We retrieved 337 adult patients diagnosed with FMD in a referral center for hypertension management, who were first individually matched to controls with essential hypertension for sex, age, systolic blood pressure, number of antihypertensive drugs, and year of visit. Smoking status and other relevant data were collected at first visit. The proportion of current smokers was higher for patients with FMD than for the controls (30% and 18%, respectively, P<0.001; odds ratio, 2.5 [95% confidence interval, 1.6-3.9]). Second, characteristics of FMD were compared between current smokers and other patients. Among patients with multifocal FMD, current smokers experienced an earlier diagnosis of hypertension (36 versus 42 years, respectively; P<0.001) and FMD (43 versus 51 years; P<0.001) than other patients, and a greater likelihood of renal artery interventions (57% versus 31%; P<0.001) and of kidney asymmetry (21% versus 4%; P=0.001). In conclusion, current smoking is associated with a higher likelihood of renal artery FMD diagnosis. Rather than a higher incidence of FMD, this may reflect a more aggressive course in smokers, who have earlier hypertension leading to increased and earlier recognition of the disease. Smoking cessation should be strongly encouraged in patients with FMD.

SNP rs198389 (T-381 C) polymorphism in the B-type natriuretic peptide gene promoter in patients with atherosclerotic renovascular hypertension.

INTRODUCTION: Renovascular hypertension caused by renal artery stenosis (RAS) accounts for 3-5% of all cases of hypertension. OBJECTIVES: The aim of the study was to determine the association between SNP rs198389 (T-381 C) polymorphism in the B-type natriuretic peptide promoter (BNP) gene and the degree of RAS in patients with atherosclerotic renovascular hypertension. PATIENTS AND METHODS: Thirty-six patients scheduled for invasive diagnostic evaluation of atherosclerotic renovascular hypertension were enrolled in the study. Arteriography was performed through a femoral artery access. In order to identify SNP rs198389 (T-381 C) polymorphism in the BNP gene genotyping was performed using genomic DNA isolated from peripheral blood leukocytes. Amplified by polymerase chain reaction and purified product was used to minisequencing. Capillary electrophoresis was applied to separate and detect minisequencing products. The analysis enabled to discriminate TC heterozygotes, TT homozygotes, and CC homozygotes at position 381 of the BNP gene promoter. RESULTS: Patients homozygous for C allele occurred more frequently in patients with high-grade RAS in comparison with the moderate and mild stenosis groups. TT homozygotes were observed more frequently in mild stenosis patients compared to the moderate and high-grade stenosis groups. None of the patients who had mild RAS was homozygous for C allele and none of the patients who had severe RAS was homozygous for T allele. CONCLUSIONS: We demonstrated the association between SNP rs198389 (T-381 C) polymorphism in the BNP gene promoter and the degree of RAS in patients with atherosclerotic renovascular hypertension. It appears that subjects homozygous for C allele at position 381 of the BNP precursor gene promoter are more prone to develop atherosclerotic lesions in renal arteries.

[Renal artery stenosis : atheromatous disease and fibromuscular dysplasia]. / Sténoses de l'artère rénale athéromateuses et fibrodysplasiques.

Renal artery stenosis may be due to atheromatous disease or renal fibromuscular dysplasia (FMD). Management of both diseases requires treatment of hypertension usually observed in such patients; however, clinical presentation, mechanism and treatment of these 2 diseases are usually different. Renal FMD is now considered as a systemic disease, the cause of which may be genetic (although the exact cause is still elusive). Renal arteries are the most frequent localizations of FMD, but extra renal arteries may also be involved (usually carotid arteries). Risk factors of hypertension-induced renal FMD include estrogen treatment and smoking. Renal FMD are mostly found in young women and in children who present with recent severe and/or refractory symptomatic hypertension. Diagnosis is usually easy (Doppler, CT-scan), and treatment of renal FMD is angioplasty in most cases. Atheromatous renal artery stenosis is usually found in patients with other atheromatous disease (peripheral artery disease, carotid, coronary artery disease...). Clinical presentation include severe or refractory hypertension, recurrent flash pulmonary edema in a patient with hypertension, progressive renal dysfunction spontaneously or after medical treatment with converting-enzyme inhibition or angiotensin II blockade, hypertension in a patient (usually smoker or ex-smoker) with diffuse atheromatous vascular disease. Management of atheromatous renal artery disease is medical treatment in all patients (aggressive treatment of cardiovascular risk factors, control of arterial pressure); revascularization is required in some patients only since it rarely cures hypertension: the goal of revascularization is mostly renal function protection, which may be observed in selected patients. Revascularization must be decided by physicians or teams involved in the care of such patients. Patients with atheromatous renal artery disease are at very high renal and cardiovascular risk : aggressive management of cardiovascular risk factors is crucial.

Management of a child with renal artery stenosis and homozygous factor V Leiden mutation.

Presence of factor V Leiden mutation is a known risk factor for thrombosis. It contributes for premature occlusion of vascular anastomosis. This report describes the intraoperative and postoperative anticoagulation management of a girl with homozygous factor V Leiden mutation and renal artery stenosis after her renovascular reconstruction surgery. This report suggests that postoperative anticoagulation may be helpful for the successful maturation of vascular anastomoses in children with underlying acquired or hereditary risk factors for thrombosis including factor V Leiden mutation.

Inheritance of arterial lesions in renal fibromuscular dysplasia.

We have previously shown that patients with renal fibromuscular dysplasia (FMD) have asymptomatic carotid lesions and that familial forms may occur. The objective of this study was to test whether carotid lesions could be detected in relatives of familial cases. High-resolution echotracking of the carotid artery was performed in 47 relatives of 13 cases from six families. This non-invasive investigation led to a semiquantitative arterial score that was compared with that obtained for 47 controls matched for age and sex and that for 125 sporadic cases. Familial resemblance was tested by using a generalized estimating equation approach taking into account the clustering of scores in families. As expected, FMD cases had a significantly higher score than controls (4.02 vs 2.52, P<10(-5)). Familial cases were not significantly different from sporadic cases. Of interest, the 47 apparently healthy relatives of familial cases had also a high carotid score (4.17), very significantly higher than that of controls (2.52, P<10(-5)) even though lower than the corresponding index FMD cases (4.81, P=0.01). Segregation analysis showed that 52% of the descendants of subjects with a score >4 had a score >4, a proportion consistent with autosomal-dominant transmission of the trait. Altogether these results strengthen the hypothesis of renal FMD being a systemic arterial disease and argue for a familial resemblance that may be due to a major genetic effect. The carotid score obtained by high-resolution echotracking may provide a non-invasive surrogate marker for renal FMD of potential value for use in linkage strategies on large pedigrees.