Altered immune cell phenotypes within chronically ischemic human kidneys distal to occlusive renal artery disease.

Renal artery stenosis (RAS) is a major cause of ischemic kidney disease, which is largely mediated by inflammation. Mapping the immune cell composition in ischemic kidneys might provide useful insight into the disease pathogenesis and uncover therapeutic targets. We used mass cytometry (CyTOF) to explore the single-cell composition in a unique data set of human kidneys nephrectomized due to chronic occlusive vascular disease (RAS, n = 3), relatively healthy donor kidneys (n = 6), and unaffected sections of kidneys with renal cell carcinoma (RCC, n = 3). Renal fibrosis and certain macrophage populations were also evaluated in renal sections. Cytobank analysis showed in RAS kidneys decreased cell populations expressing epithelial markers (CD45-/CD13+) and increased CD45+ inflammatory cells, whereas scattered tubular-progenitor-like cells (CD45-/CD133+/CD24+) increased compared with kidney donors. Macrophages switched to proinflammatory phenotypes in RAS, and the numbers of IL-10-producing dendritic cells (DC) were also lower. Compared with kidney donors, RAS kidneys had decreased overall DC populations but increased plasmacytoid DC. Furthermore, senescent active T cells (CD45+/CD28+/CD57+), aged neutrophils (CD45+/CD15+/CD24+/CD11c+), and regulatory B cells (CD45+/CD14-/CD24+/CD44+) were increased in RAS. RCC kidneys showed a distribution of cell phenotypes comparable with RAS but less pronounced, accompanied by an increase in CD34+, CD370+, CD103+, and CD11c+/CD103+ cells. Histologically, RAS kidneys showed significantly increased fibrosis and decreased CD163+/CD141+ cells. The single-cell platform CyTOF enables the detection of significant changes in renal cells, especially in subsets of immune cells in ischemic human kidneys. Endogenous pro-repair cell types in RAS warrant future study for potential immune therapy.NEW & NOTEWORTHY The single-cell platform mass cytometry (CyTOF) enables detection of significant changes in one million of renal cells, especially in subsets of immune cells in ischemic human kidneys distal to renal artery stenosis (RAS). We found that pro-repair cell types such as scattered tubular-progenitor-like cells, aged neutrophils, and regulatory B cells show a compensatory increase in RAS. Immune cell phenotype changes may reflect ongoing inflammation and impaired immune defense capability in the kidneys.

Using Ultrahigh b -Value Diffusion-Weighted Imaging to Noninvasively Assess Renal Fibrosis in a Rabbit Model of Renal Artery Stenosis.

OBJECTIVE: This study aimed to investigate the feasibility of diffusion-weighted imaging with ultrahigh b values ( ub DWI) for the evaluation of renal fibrosis (RF) induced by renal artery stenosis (RAS) in a rabbit model. METHODS: Thirty-two rabbits underwent left RAS operation, whereas 8 rabbits received sham surgery. All rabbits underwent ub DWI ( b = 0-4500 s/mm 2 ). The standard apparent diffusion coefficient (ADC st ), molecular diffusion coefficient ( D ), perfusion fraction ( f ), perfusion-related diffusion coefficient ( D *) and ultrahigh apparent diffusion coefficient (ADC uh ) were longitudinally assessed before operation and at weeks 2, 4, and 6 after operation. The degree of interstitial fibrosis and the expression of aquaporin (AQP) 1 and AQP2 were determined through pathological examination. RESULTS: In the stenotic kidney, the ADC st , D , f , and ADC uh values of the renal parenchyma significantly decreased compared with those at baseline (all P < 0.05), whereas the D * values significantly increased after RAS induction ( P < 0.05). The ADC st , D , D *, and f were weakly to moderately correlated with interstitial fibrosis as well as with the expression of AQP1 and AQP2. Furthermore, the ADC uh negatively correlated with interstitial fibrosis ( ρ = -0.782, P < 0.001) and positively correlated with AQP1 and AQP2 expression ( ρ = 0.794, P < 0.001, and ρ = 0.789, P < 0.001, respectively). CONCLUSIONS: Diffusion-weighted imaging with ultrahigh b values shows the potential for noninvasive assessment of the progression of RF in rabbits with unilateral RAS. The ADC uh derived from ub DWI could reflect the expression of AQPs in RF.

Effect of Hypoxia Preconditioning on the Regenerative Capacity of Adipose Tissue Derived Mesenchymal Stem Cells in a Model of Renal Artery Stenosis.

Atherosclerotic renal artery stenosis (ARAS) is associated with irreversible parenchymal renal disease and regenerative stem cell therapies may improve renal outcomes. Hypoxia preconditioning (HPC) may improve the regenerative functions of adipose tissue-derived mesenchymal stem cells (AMSC) by affecting DNA 5-hydroxymethylcytosine (5hmC) marks in angiogenic genes. Here, we investigated using a porcine ARAS model, whether growth of ARAS AMSCs in hypoxia (Hx) versus normoxia (Nx) would enhance renal tissue repair, and comprehensively analyze how HPC modifies DNA hydroxymethylation compared to untreated ARAS and healthy/normal pigs (n=5 each). ARAS pigs exhibited elevated serum cholesterol, serum creatinine and renal artery stenosis, with a concomitant decrease in renal blood flow (RBF) and increased blood pressure (BP) compared to healthy pigs. Renal artery injection of either autologous Nx or Hx AMSCs improved diastolic BP, reduced kidney tissue fibrosis, and inflammation (CD3+ T-cells) in ARAS pigs. In addition, renal medullary hypoxia significantly lowered with Nx but not Hx AMSC treatment. Mechanistically, levels of epigenetic 5hmC marks (which reflect gene activation) estimated using DNA immunoprecipitation technique were elevated in profibrotic and inflammatory genes in ARAS compared with normal AMSCs. HPC significantly reduced 5hmC levels in cholesterol biosynthesis and oxidative stress response pathways in ARAS AMSCs. Thus, autologous AMSCs improve key renovascular parameters and inflammation in ARAS pigs, with HPC mitigating pathological molecular effects on inflammatory and profibrotic genes which may play a role in augmenting regenerative capacity of AMSCs.

Exogenous pericyte delivery protects the mouse kidney from chronic ischemic injury.

Pericytes are considered reparative mesenchymal stem cell-like cells, but their ability to ameliorate chronic ischemic kidney injury is unknown. We hypothesized that pericytes would exhibit renoprotective effects in murine renal artery stenosis (RAS). Porcine kidney-derived pericytes (5 × 105) or vehicle were injected into the carotid artery 2 wk after the induction of unilateral RAS in mice. The stenotic kidney glomerular filtration rate and tissue oxygenation were measured 2 wk later using magnetic resonance imaging. We subsequently compared kidney oxidative stress, inflammation, apoptosis, fibrosis, and systemic levels of oxidative and inflammatory cytokines. Treatment of xenogeneic pericytes ameliorated the RAS-induced loss of perfusion, glomerular filtration rate, and atrophy in stenotic kidneys and restored cortical and medullary oxygenation but did not blunt hypertension. Ex vivo, pericytes injection partially mitigated RAS-induced renal inflammation, fibrosis, oxidative stress, apoptosis, and senescence. Furthermore, coculture with pericytes in vitro protected pig kidney-1 tubular cells from injury. In conclusion, exogenous delivery of renal pericytes protects the poststenotic mouse kidney from ischemic injury, underscoring the therapeutic potential role of pericytes in subjects with ischemic kidney disease.NEW & NOTEWORTHY Our study demonstrates a novel pericyte-based therapy for the injured kidney. The beneficial effect of pericyte delivery appears to be mediated by ameliorating oxidative stress, inflammation, cellular apoptosis, and senescence in the stenotic kidney and improved tissue hypoxia, vascular loss, fibrosis, and tubular atrophy. Our data may form the basis for pericyte-based therapy, and additional research studies are needed to gain further insight into their role in improving renal function.

Effects of obesity on reparative function of human adipose tissue-derived mesenchymal stem cells on ischemic murine kidneys.

INTRODUCTION: Obesity is a health burden that impairs cellular processes. Mesenchymal stem/stromal cells (MSCs) are endowed with reparative properties and can ameliorate renal injury. Obesity impairs human MSC function in-vitro, but its effect on their in-vivo reparative potency remains unknown. SUBJECTS AND METHODS: Abdominal adipose tissue-derived MSC were harvested from patients without ('lean') or with obesity ('obese') (body mass index <30 or ≥30 kg/m2, respectively) during kidney donation or bariatric surgery, respectively. MSC (5 × 105/200 µL) or vehicle were then injected into 129S1 mice 2 weeks after renal artery stenosis (RAS) or sham surgery (n = 8/group). Two weeks later, mice underwent magnetic resonance imaging to assess renal perfusion and oxygenation in-vivo, and kidneys then harvested for ex-vivo studies. RESULTS: Similar numbers of lean and obese-MSCs engrafted in stenotic mouse kidneys. Vehicle-treated RAS mice had reduced stenotic-kidney cortical and medullary perfusion and oxygenation. Lean (but not obese) MSC normalized ischemic kidney cortical perfusion, whereas both effectively mitigated renal hypoxia. Serum creatinine and blood pressure were elevated in RAS mice and lowered only by lean-MSC. Both types of MSCs alleviated stenotic-kidney fibrosis, but lean-MSC more effectively than obese-MSC. MSC senescence-associated beta-gal activity, and gene expression of p16, p21, and vascular endothelial growth factor correlated with recipient kidney perfusion and tissue injury, linking MSC characteristics with their in-vivo reparative capacity. DISCUSSION: Human obesity impairs the reparative properties of adipose-tissue-derived MSCs, possibly by inducing cellular senescence. Dysfunction and senescence of the endogenous MSC repair system in patients with obesity may warrant targeting interventions to restore MSC vitality.

Reliable Assessment of Swine Renal Fibrosis Using Quantitative Magnetization Transfer Imaging.

OBJECTIVES: Quantitative magnetization transfer (qMT) is useful for measurement of murine renal fibrosis at high and ultrahigh field strengths. However, its utility at clinical field strengths and in human-like kidneys remains unknown. We tested the hypothesis that qMT would successfully detect fibrosis in swine kidneys with unilateral renal artery stenosis (RAS) at 3.0 T. METHODS: The qMT protocol is composed of MT scans with variable flip angles and offset frequencies, and of B0, B1, and T1 mapping. Pigs were scanned 10 weeks after RAS or control. A 2-pool model was used to fit the bound pool fraction f of the renal cortex (CO) and outer medulla (OM). Then qMT-derived f in 5 normal and 10 RAS pigs was compared with histological fibrosis determined using Masson's trichrome staining and to renal perfusion assessed with computed tomography. RESULTS: The qMT 2-pool model provided accurate fittings of data collected on swine kidneys. Stenotic kidneys showed significantly elevated f in both the CO (9.8% ± 2.7% vs 6.4% ± 0.9%, P = 0.002) and OM (7.6% ± 2.2% vs 4.7% ± 1.1%, P = 0.002), as compared with normal kidneys. Histology-measured renal fibrosis and qMT-derived f correlated directly in both the cortex (Pearson correlation coefficient r = 0.93, P < 0.001) and OM (r = 0.84, P = 0.002), and inversely with stenotic kidney perfusion (r = 0.85, P = 0.002). CONCLUSIONS: This study demonstrates the feasibility of qMT for measuring fibrosis in human-like swine kidneys, and the association between tissue macromolecule content and renal perfusion. Therefore, qMT may be useful as a tool for noninvasive assessment of renal fibrosis in subjects with RAS at clinical field strengths.

Moyamoya disease with refractory hypertension associated with peripheral arterial stenosis in the renal parenchyma.

Moyamoya disease (MMD) has long been known to be associated with hypertension. While renal artery stenosis (RAS) is considered one of the causes of hypertension with MMD, most hypertension causes remain unexplained. A boy with MMD was diagnosed with renovascular hypertension (RVH) due to left-sided RAS by angiography. Although nephrectomy on the affected side for unilateral RVH was performed, hypertension poorly improved. Histopathological examination of the resected specimens revealed that the vascular lumen not only of the renal artery but also of peripheral vessels in the renal parenchyma was narrowed. He developed end-stage renal disease caused by multiple wasp stings and received a kidney transplant from a living donor with his remaining right kidney resected. His hypertension improved dramatically just after the operation. In histopathological findings, the narrowed vascular lumen was also observed in the resected right renal parenchyma similar to that in the left kidney. In our case, these pathological findings were the same as those of major vessels previously reported in MMD patients. Immunohistochemical staining with anti-renin antibody on bilateral intrinsic kidneys was strongly revealed in the Juxtaglomerular apparatus. He has been normotensive with the minimum amount of amlodipine since transplantation and resection of his intrinsic right kidney. This is the first report to show the possibility that peripheral arterial stenosis in the renal parenchyma due to MMD would result in refractory hypertension. If MMD patients have hypertension of unknown origin without significant RAS, it should be considered that the etiology may be peripheral arterial stenosis in the renal parenchyma.

Mesenchymal stem cells protect renal tubular cells via TSG-6 regulating macrophage function and phenotype switching.

Tumor necrosis factor (TNF)-α-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of mesenchymal stem cells (MSCs), but its ability to protect the ischemic kidney is unknown. In a swine model of renal artery stenosis (RAS) and metabolic syndrome (MetS), we assessed the contribution of TSG-6 produced by MSCs to their immunomodulatory properties. Pigs were studied after 16 wk of diet-induced MetS and unilateral RAS and were either untreated or treated 4 wk earlier with intrarenal autologous adipose tissue-derived MSCs (n = 6 each). Lean, MetS, and RAS sham animals served as controls. We studied renal function in vivo (using computed tomography) and kidney histopathology and macrophage phenotype ex vivo. In vitro, TSG-6 levels were also measured in conditioned media of human MSCs incubated with TNF-α and levels of the tubular injury marker lactate dehydrogenase in conditioned media after coculturing macrophages with injured human kidney 2 (HK-2) cells with or without TSG-6. The effects of TSG-6 on macrophage phenotype (M1/M2), adhesion, and migration were also determined. MetS + RAS showed increased M1 macrophages and renal vein TNF-α levels. After MSC delivery, renal vein TSG-6 increased and TNF-α decreased, the M1-to-M2 ratio decreased, renal function improved, and fibrosis was alleviated. In vitro, TNF-α increased TSG-6 secretion by human MSCs. TSG-6 decreased lactate dehydrogenase release from injured HK-2 cells, increased expression of macrophage M2 markers, and reduced M1 macrophage adhesion and migration. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype. These observations suggest that TSG-6 is endowed with renoprotective properties.NEW & NOTEWORTHY Tumor necrosis factor-α-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of MSCs, but its ability to protect the ischemic kidney is unknown. In pigs with renal artery stenosis, we show that MSC delivery increased renal vein TSG-6, decreased kidney inflammatory macrophages, and improved renal function. In vitro, TSG-6 decreased inflammatory macrophages and tubular cell injury. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype.

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.

Renovascular Disease Induces Senescence in Renal Scattered Tubular-Like Cells and Impairs Their Reparative Potency.

Scattered tubular-like cells (STCs), dedifferentiated renal tubular epithelial cells, contribute to renal self-healing, but severe injury might blunt their effectiveness. We hypothesized that ischemic renovascular disease (RVD) induces senescence in STC and impairs their reparative potency. CD24+/CD133+ STCs were isolated from swine kidneys after 16 weeks of RVD or healthy controls. To test their reparative capabilities in injured kidneys, control or RVD-STC (5×105) were prelabeled and injected into the aorta of 2 kidneys, 1-clip (2k,1c) mice 2 weeks after surgery. Murine renal function and oxygenation were studied in vivo 2 weeks after injection using micro-magnetic resonance imaging, and fibrosis, tubulointerstitial injury, capillary density, and expression of profibrotic and inflammatory genes ex vivo. STC isolated from swine RVD kidneys showed increased gene expression of senescence and senescence-associated secretory phenotype markers and positive SA-ß-gal staining. Delivery of normal pig STCs in 2k,1c mice improved murine renal perfusion, blood flow, and glomerular filtration rate, and downregulated profibrotic and inflammatory gene expression. These renoprotective effects were blunted using STC harvested from RVD kidneys, which also failed to attenuate hypoxia, fibrosis, tubular injury, and capillary loss in injured mouse 2k,1c kidneys. Hence, RVD may induce senescence in endogenous STC and impair their reparative capacity. These observations implicate cellular senescence in the pathophysiology of ischemic kidney disease and support senolytic therapy to permit self-healing of senescent kidneys.

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 fibrosis detected by diffusion-weighted magnetic resonance imaging remains unchanged despite treatment in subjects with renovascular disease.

Tissue fibrosis is an important index of renal disease progression. Diffusion-weighted magnetic resonance imaging's (DWI-MRI) apparent diffusion coefficient (ADC) reveals water diffusion is unobstructed by microstructural alterations like fibrosis. We hypothesized that ADC may indicate renal injury and response to therapy in patients with renovascular disease (RVD). RVD patients were treated with medical therapy (MT) and percutaneous transluminal renal angioplasty (MT + PTRA) (n = 11, 3 bilaterally, n = 14 kidneys) or MT (n = 9). ADC and renal hypoxia (R2*) by blood-oxygen-level-dependent MRI were studied before (n = 27) and 3 months after (n = 20) treatment. Twelve patients underwent renal biopsies. Baseline ADC values were correlated with changes in eGFR, serum creatinine (SCr), systolic blood pressure (SBP), renal hypoxia, and renal vein levels of pro-inflammatory marker tumor necrosis-factor (TNF)-α. Renal oxygenation, eGFR, and SCr improved after MT + PTRA. ADC inversely correlated with the histological degree of renal fibrosis, but remained unchanged after MT or MT + PTRA. Basal ADC values correlated modestly with change in SBP, but not in renal hypoxia, TNF-α levels, or renal function. Lower ADC potentially reflects renal injury in RVD patients, but does not change in response to medical or interventional therapy over 3 months. Future studies need to pinpoint indices of kidney recovery potential.

The Value of Contrast-Enhanced Ultrasound versus Doppler Ultrasound in Grading Renal Artery Stenosis.

OBJECTIVE: This study is aimed at exploring the accuracy of contrast-enhanced ultrasound (CEUS) in grading renal artery stenosis. METHODS: 122 renal arteries with suspected renal artery stenosis were selected. DSA, DUS, and CEUS were performed for all patients with suspected renal artery stenosis in the research. DSA was selected as the gold standard. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of CEUS or Doppler ultrasound (DUS) in the diagnosis of renal artery stenosis were analyzed. The consistency between CEUS and digital subtraction angiography (DSA) was compared. The accuracy of DUS or CEUS in grading renal artery stenosis was assessed by the area under the receiver operating characteristic (ROC) curves and compared between groups. RESULTS: The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CEUS in the diagnosis of renal artery stenosis were 88.9%, 87.8%, 88.5%, 93.5%, and 80.0%, respectively. There was no significant difference in grading renal artery stenosis between CEUS and DSA (X 2 = 0.643, P = 0.424). 77 of the 122 renal arteries were diagnosed with the stenosis rate more than 30% by CEUS. Compared with the results of DSA, the kappa value of CEUS was 0.749 (P < 0.05). CONCLUSION: CEUS is accurate in grading renal artery stenosis, and it may represent the method of choice in diagnosing renal artery stenosis.

Adjunctive mesenchymal stem/stromal cells augment microvascular function in poststenotic kidneys treated with low-energy shockwave therapy.

Effective therapeutic strategies are needed to preserve renal function in patients with atherosclerotic renal artery stenosis (ARAS). Low-energy shockwave therapy (SW) and adipose tissue-derived mesenchymal stem/stromal cells (MSCs) both stimulate angiogenesis repair of stenotic kidney injury. This study tested the hypothesis that intrarenal delivery of adipose tissue-derived MSCs would enhance the capability of SW to preserve stenotic kidney function and structure. Twenty-two pigs were studied after 16 weeks of ARAS, ARAS treated with a SW regimen (bi-weekly for 3 weeks) with or without subsequent intrarenal delivery of adipose tissue-derived MSCs and controls. Four weeks after treatment, single-kidney renal blood flow (RBF) before and after infusion of acetylcholine, glomerular filtration rate (GFR), and oxygenation were assessed in vivo and the renal microcirculation, fibrosis, and oxidative stress ex vivo. Mean arterial pressure remained higher in ARAS, ARAS + SW, and ARAS + SW + MSC compared with normal. Both SW and SW + MSC similarly elevated the decreased stenotic kidney GFR and RBF observed in ARAS to normal levels. Yet, SW + MSC significantly improved RBF response to acetylcholine in ARAS, and attenuated capillary loss and oxidative stress more than SW alone. Density of larger microvessels was similarly increased by both interventions. Therefore, although significant changes in functional outcomes were not observed in a short period of time, adjunct MSCs enhanced pro-angiogenic effect of SW to improve renal microvascular outcomes, suggesting this as an effective stratege for long-term management of renovascular disease.

Advancements in medical and surgical treatments of Takayasu arteritis-induced renal arteritis: a systematic review.

BACKGROUND: Takayasu arteritis-induced renal arteritis (TARA), commonly seen in Takayasu arteritis (TA), has become one of the main causes of poor prognosis and early mortality in patients with TA. TARA progressing into Takayasu arteritis-induced renal artery stenosis (TARAS), could lead to severe complications including malignant hypertension, cardiac-cerebral vascular disease, and ischemic nephropathy. Since there existed no guidelines on treatments, this study aimed to review the comprehensive treatments for TARA. METHODS: We searched systematically in databases including PubMed, Ovid-Medline, EMBASE, Web of Science, China National Knowledge Infrastructure, Wanfang, and SinoMed, from inception to May 2018. Literature selection, data extraction, and statistical analysis were performed. RESULTS: Eighty-two literatures were recruited focusing on medical treatments (n = 34) and surgical treatments (n = 48). We found that combined medical treatments of glucocorticoids and conventional synthetic disease-modifying anti-rheumatic drugs could reach high rates of remission in patients with TARA, and biological disease-modifying anti-rheumatic drugs were preferred for refractory patients. After remission induction, surgical treatment could help reconstruct renal artery and recover renal function partly. Percutaneous transluminal angioplasty was the first choice for patients with TARAS, while open surgery showed a good long-term survival. CONCLUSIONS: Patients with TARA should benefit both from medical treatments and from surgical treatments comprehensively and sequentially. Multidisciplinary team coordination is recommended especially in patients with severe complications.

Experimental Renovascular Disease Induces Endothelial Cell Mitochondrial Damage and Impairs Endothelium-Dependent Relaxation of Renal Artery Segments.

BACKGROUND: Mitochondria modulate endothelial cell (EC) function, but may be damaged during renal disease. We hypothesized that the ischemic and metabolic constituents of swine renovascular disease (RVD) induce mitochondrial damage and impair the function of renal artery ECs. METHODS: Pigs were studied after 16 weeks of metabolic syndrome (MetS), renal artery stenosis (RAS), or MetS + RAS, and Lean pigs served as control (n = 6 each). Mitochondrial morphology, homeostasis, and function were measured in isolated primary stenotic-kidney artery ECs. EC functions were assessed in vitro, whereas vasoreactivity of renal artery segments was characterized in organ baths. RESULTS: Lean + RAS and MetS + RAS ECs showed increased mitochondrial area and decreased matrix density. Mitochondrial biogenesis was impaired in MetS and MetS + RAS compared with their respective controls. Mitochondrial membrane potential similarly decreased in MetS, Lean + RAS, and MetS + RAS groups, whereas production of reactive oxygen species increased in MetS vs. Lean, but further increased in both RAS groups. EC tube formation was impaired in MetS, RAS, and MetS + RAS vs. Lean, but EC proliferation and endothelial-dependent relaxation of renal artery segments were blunted in MetS vs. Lean, but further attenuated in Lean + RAS and MetS + RAS. CONCLUSIONS: MetS and RAS damage mitochondria in pig renal artery ECs, which may impair EC function. Coexisting MetS and RAS did not aggravate EC mitochondrial damage in the short time of our in vivo studies, suggesting that mitochondrial injury is associated with impaired renal artery EC function.

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.

Management of Renal Arteries in Conjunction with Thoracic Endovascular Aortic Repair for Complicated Stanford Type B Aortic Dissection: The Japanese Multicenter Study (J-Predictive Study).

Background Management of abdominal branches associated with Stanford type B aortic dissection is controversial without definite criteria for therapy after thoracic endovascular aortic repair (TEVAR). This is in part due to lack of data on natural history related to branch vessels and their relationship with the dissection flap, true lumen, and false lumen. Purpose To investigate the natural history of abdominal branches after TEVAR for type B aortic dissection and the relationship between renal artery anatomy and renal volume as a surrogate measure of perfusion. Materials and Methods This study included patients who underwent TEVAR for complicated type B dissection from January 2012 to March 2017 at 20 centers. Abdominal aortic branches were classified with following features: patency, branch vessel origin, and presence of extension of the aortic dissection into a branch (pattern 1, supplied by the true lumen without branch dissection; pattern 2, supplied by the true lumen with branch dissection, etc). The branch artery patterns before TEVAR were compared with those of the last follow-up CT (mean interval, 19.7 months) for spontaneous healing. Patients with one kidney supplied by pattern 1 and the other kidney by a different pattern were identified, and kidney volumes over the course were compared by using a simple linear regression model. Results Two hundred nine patients (mean age ± standard deviation, 66 years ± 13; 165 men and 44 women; median follow-up, 18 months) were included. Four hundred fifty-nine abdominal branches at the last follow-up were evaluable. Spontaneous healing of the dissected branch occurred in 63% (64 of 102) of pattern 2 branches. Regarding the other patterns, 6.5% (six of 93) of branches achieved spontaneous healing. In 79 patients, renal volumes decreased in kidneys with pattern 2 branches with more than 50% stenosis and branches supplied by the aortic false lumen (patterns 3 and 4) compared with contralateral kidneys supplied by pattern 1 (pattern 2 vs pattern 1: -16% ± 16 vs 0.10% ± 11, P = .002; patterns 3 and 4 vs pattern 1: -13% ± 14 vs 8.5% ± 14, P = .004). Conclusion Spontaneous healing occurs more frequently in dissected branches arising from the true lumen than in other branch patterns. Renal artery branches supplied by the aortic false lumen or a persistently dissected artery with greater than 50% stenosis are associated with significantly greater kidney volume loss. © RSNA, 2019 Online supplemental material is available for this article.