Textor, Stephen C.

AbstractRenovascular disease (RVD) remains a major cause of secondary and treatment-resistant hypertension. Most cases are related either to fibromuscular or atherosclerotic lesions, but a variety of other causes including arterial dissection, stent occlusion, and embolic disease can produce the same syndrome. Recent studies emphasize the kidney’s tolerance to moderate flow reduction during antihypertensive drug therapy and the relative safety of medical therapy to control blood pressure. Several prospective trials in moderate RVD fail to identify major benefits from endovascular revascularization for moderate atherosclerotic disease. However, high-risk and progressive renovascular syndromes are recognized to be relatively refractory to medical therapy only and respond better to combining renal revascularization with ongoing medical therapy. Clinicians caring for complex hypertension should be familiar with pathogenic pathways, imaging techniques, and a rational approach to managing renovascular hypertension in the current era.

Hypertension develops soon after organ transplantation using cyclosporine- or FK506-based immunosuppression. Sustained rises in blood pressure require intervention to reduce the risk of intracranial bleeding and other cardiovascular complications. Antihypertensive treatment is complicated by reduced renal function and potential interference with absorption and/or metabolism of cyclosporine or FK506. To manage early and long-term hypertension related to immunosuppression with cyclosporine or FK506 and prednisone following orthotopic liver transplantation, a comprehensive nurse-managed hypertension clinic was developed. Blood pressure, heart rate, and antihypertensive and immunosuppressive regimens were evaluated according to a standard protocol at 1, 4, 12, 24, and 36 months after orthotopic liver transplantation. Data indicate that posttransplantation hypertension develops within the first months after orthotopic liver transplantation and persists indefinitely. If comprehensively managed by the hypertension nurse-clinician, the percentage of controlled hypertension patients can increase over time.

Objectives Recent studies have indicated that excessive fat may confound assessment of diffusion in organs with high fat content, such as the liver and breast. However, the extent of this effect in the kidney, which is not considered a major fat deposition site, remains unclear. This study tested the hypothesis that renal fat may impact diffusion-weighted imaging (DWI) parameters, and proposes a 3-compartment model (TCM) to circumvent this effect. Methods Using computer simulations, we investigated the effect of fat on assessment of apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM), and TCM-derived pure-diffusivity. We also investigated the influence of magnetic resonance repetition (TR) and echo time (TE) on DWI parameters as a result of variation in the relative contribution of the fat signal. Apparent diffusion coefficient, IVIM and TCM DWI parameters were calculated in domestic pigs fed a high-cholesterol (obese group) or normal diet (lean group), and correlated to renal histology. Intravoxel incoherent motion–derived pure-diffusivity was also compared among 15 essential hypertension patients classified by body mass index (BMI) (high vs normal). Finally, pure-diffusivity was calculated and compared in 8 patients with atherosclerotic renal artery stenosis (ARAS) and 5 healthy subjects using IVIM and TCM. Results Simulations showed that unaccounted fat results in the underestimation of IVIM-derived pure diffusivity. The underestimation increases as the fat fraction increases, with higher pace at lower fat contents. The underestimation was larger for shorter TR and longer TE values due to the enhancement of the relative contribution of the fat signal. Moreover, TCM, which incorporates highly diffusion-weighted images (b > 2500 s/mm2), could correct for fat-dependent underestimation. Animal studies in the lean and obese groups confirmed lower ADC and IVIM pure-diffusivity in obese versus lean pigs with otherwise healthy kidneys, whereas pure-diffusivity calculated using TCM were not different between the 2 groups. Similarly, essential hypertension patients with high BMI had lower ADC (1.9 vs 2.1 × 10−3 mm2/s) and pure-diffusivity (1.7 vs 1.9 × 10−3 mm2/s) than those with normal BMI. Pure-diffusivity calculated using IVIM was not different between the ARAS and healthy subjects, but TCM revealed significantly lower diffusivity in ARAS. Conclusions Excessive renal fat may cause underestimation of renal ADC and IVIM-derived pure-diffusivity, which may hinder detection of renal pathology. Models accounting for fat contribution may help reduce the variability of diffusivity calculated using DWI.

Atherosclerotic renovascular disease (RVD) reduces renal blood flow (RBF) and GFR and accelerates poststenotic kidney (STK) tissue injury. Preclinical studies indicate that mesenchymal stem cells (MSCs) can stimulate angiogenesis and modify immune function in experimental RVD. We assessed the safety and efficacy of adding intra-arterial autologous adipose-derived MSCs into STK to standardized medical treatment in human subjects without revascularization. The intervention group ( n =14) received a single infusion of MSC (1.0 × 10 5 or 2.5 × 10 5 cells/kg; n =7 each) plus standardized medical treatment; the medical treatment only group ( n =14) included subjects matched for age, kidney function, and stenosis severity. We measured cortical and medullary volumes, perfusion, and RBF using multidetector computed tomography. We assessed tissue oxygenation by blood oxygen level–dependent MRI and GFR by iothalamate clearance. MSC infusions were well tolerated. Three months after infusion, cortical perfusion and RBF rose in the STK (151.8–185.5 ml/min, P =0.01); contralateral kidney RBF increased (212.7–271.8 ml/min, P =0.01); and STK renal hypoxia (percentage of the whole kidney with R2*>30/s) decreased (12.1% [interquartile range, 3.3%–17.8%] to 6.8% [interquartile range, 1.8%–12.9%], P =0.04). No changes in RBF occurred in medical treatment only subjects. Single-kidney GFR remained stable after MSC but fell in the medical treatment only group (−3% versus −24%, P =0.04). This first-in-man dose-escalation study provides evidence of safety of intra-arterial infusion of autologous MSCs in patients with RVD. MSC infusion without main renal artery revascularization associated with increased renal tissue oxygenation and cortical blood flow.

Mitochondrial injury contributes to renal dysfunction in several models of renal disease, but its involvement in human hypertension remains unknown. Fragments of the mitochondrial genome released from dying cells are considered surrogate markers of mitochondrial injury. We hypothesized that hypertension would be associated with increased urine mitochondrial DNA (mtDNA) copy numbers. We prospectively measured systemic and urinary copy number of the mtDNA genes cytochrome-c oxidase-3 and NADH dehydrogenase subunit-1 by quantitative polymerase chain reaction in essential (n=25) and renovascular (RVH, n=34) hypertensive patients and compared them with healthy volunteers (n=22). Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin served as indices of renal injury. Renal blood flow and oxygenation were assessed by multidetector computed tomography and blood oxygen level–dependent magnetic resonance imaging. Blood pressure, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 were similarly elevated in essential hypertension and RVH, and estimated glomerular filtration rate was lower in RVH versus healthy volunteers and essential hypertension. Renal blood flow was lower in RVH compared with essential hypertension. Urinary mtDNA copy number was higher in hypertension compared with healthy volunteers, directly correlated with urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 and inversely with estimated glomerular filtration rate. In RVH, urinary mtDNA copy number correlated directly with intrarenal hypoxia. Furthermore, in an additional validation cohort, urinary mtDNA copy number was higher in RVH compared with healthy volunteers (n=10 each). The change in serum creatinine levels and estimated glomerular filtration rate 3 months after medical therapy without or with revascularization correlated with the change in urinary mtDNA. Therefore, elevated urinary mtDNA copy numbers in hypertensive patients correlated with markers of renal injury and dysfunction, implicating mitochondrial injury in kidney damage in human hypertension.

Microvascular rarefaction distal to renal artery stenosis is linked to renal dysfunction and poor outcomes. Low–energy shockwave therapy stimulates angiogenesis, but the effect on the kidney microvasculature is unknown. We hypothesized that low–energy shockwave therapy would restore the microcirculation and alleviate renal dysfunction in renovascular disease. Normal pigs and pigs subjected to 3 weeks of renal artery stenosis were treated with six sessions of low–energy shockwave (biweekly for 3 consecutive weeks) or left untreated. We assessed BP, urinary protein, stenotic renal blood flow, GFR, microvascular structure, and oxygenation in vivo 4 weeks after completion of treatment, and then, we assessed expression of angiogenic factors and mechanotransducers (focal adhesion kinase and β 1-integrin) ex vivo . A 3-week low–energy shockwave regimen attenuated renovascular hypertension, normalized stenotic kidney microvascular density and oxygenation, stabilized function, and alleviated fibrosis in pigs subjected to renal artery stenosis. These effects associated with elevated renal expression of angiogenic factors and mechanotransducers, particularly in proximal tubular cells. In additional pigs with prolonged (6 weeks) renal artery stenosis, shockwave therapy also decreased BP and improved GFR, microvascular density, and oxygenation in the stenotic kidney. This shockwave regimen did not cause detectable kidney injury in normal pigs. In conclusion, low–energy shockwave therapy improves stenotic kidney function, likely in part by mechanotransduction-mediated expression of angiogenic factors in proximal tubular cells, and it may ameliorate renovascular hypertension. Low–energy shockwave therapy may serve as a novel noninvasive intervention in the management of renovascular disease.

Background Renovascular hypertension ( RVH ) impairs cardiac structure and left ventricular ( LV ) function, but whether mitochondrial injury is implicated in RVH ‐induced myocardial damage and dysfunction has not been defined. We hypothesized that cardiac remodeling in swine RVH is partly attributable to cardiac mitochondrial injury. Methods and Results After 12 weeks of hypercholesterolemic ( HC )‐ RVH or control (n=14 each), pigs were treated for another 4 weeks with vehicle or with the mitochondrial‐targeted peptide ( MTP ), Bendavia (0.1 mg/kg subcutaneously, 5 days/week), which stabilizes mitochondrial inner‐membrane cardiolipin (n=7 each). Cardiac function was subsequently assessed by multidetector‐computed tomography and oxygenation by blood‐oxygen‐level–dependent magnetic resonance imaging. Cardiolipin content, mitochondrial biogenesis, as well as sarcoplasmic‐reticulum calcium cycling, myocardial tissue injury, and coronary endothelial function were assessed ex vivo. Additionally, mitochondrial cardiolipin content, oxidative stress, and bioenergetics were assessed in rat cardiomyocytes incubated with tert‐butyl hydroperoxide ( tBHP ) untreated or treated with MTP . Chronic mitoprotection in vivo restored cardiolipin content and mitochondrial biogenesis. Thapsigargin‐sensitive sarcoplasmic reticulum Ca 2+ ‐ ATP ase activity that declined in HC ‐ RVH normalized in MTP ‐treated pigs. Mitoprotection also improved LV relaxation (E/A ratio) and ameliorated cardiac hypertrophy, without affecting blood pressure or systolic function. Myocardial remodeling and coronary endothelial function improved only in MTP ‐treated pigs. In tBHP ‐treated cardiomyocytes, mitochondrial targeting attenuated a fall in cardiolipin content and bioenergetics. Conclusions Chronic mitoprotection blunted myocardial hypertrophy, improved LV relaxation, and attenuated myocardial cellular and microvascular remodeling, despite sustained HC ‐ RVH , suggesting that mitochondrial injury partly contributes to hypertensive cardiomyopathy.