Persistent kidney dysfunction in swine renal artery stenosis correlates with outer cortical microvascular remodeling

Alfonso Eirin; Xiang-Yang Zhu; Victor H Urbieta-Caceres; Joseph P Grande; Amir Lerman; Stephen C Textor; Lilach O Lerman

doi:10.1152/ajprenal.00697.2010

. 2011 Mar 2;300(6):F1394–F1401. doi: 10.1152/ajprenal.00697.2010

Persistent kidney dysfunction in swine renal artery stenosis correlates with outer cortical microvascular remodeling

Alfonso Eirin ¹, Xiang-Yang Zhu ¹, Victor H Urbieta-Caceres ¹, Joseph P Grande ^1,², Amir Lerman ^3,^✉, Stephen C Textor ¹, Lilach O Lerman ^1,³

PMCID: PMC3119141 PMID: 21367913

Abstract

Percutaneous transluminal renal stenting (PTRS) does not consistently improve renal function in patients with atherosclerotic renovascular disease, but the mechanisms underlying irreversible kidney injury have not been fully elucidated. We hypothesized that renal dysfunction after PTRS is linked to ongoing renal microvascular (MV) remodeling. Pigs were studied after 10 wk of atherosclerosis and renal artery stenosis (ARAS), ARAS treated with PTRS 4 wk earlier, and normal controls (n = 10 each). Renal blood flow (RBF) and glomerular filtration rate (GFR) were studied using multidetector computer tomography. Renal microvascular architecture (micro-CT), angiogenic activity, oxidative stress, and fibrosis were evaluated ex vivo. Four weeks after PTRS, blood pressure was normalized. However, GFR and RBF remained similarly decreased in untreated ARAS and ARAS+PTRS (P < 0.05 vs. normal). MV rarefaction was unaltered after revascularization, and the spatial density of outer cortical microvessels correlated with residual GFR. Interstitial fibrosis and altered expression of proangiogenic and profibrotic factors persisted after PTRS. Tubulointerstitial injury in ARAS persisted 4 wk after mechanically successful PTRS, and vessel loss correlated with residual renal dysfunction. MV loss and fibrosis in swine ARAS might account for persistent renal dysfunction after PTRS and underscore the need to assess renal parenchymal disease before revascularization.

Keywords: renal hypertension, atherosclerosis, renovascular disease

renal artery stenosis (RAS), most commonly caused by atherosclerosis, has an incidence of almost 7% in adults older than 65 years of age (21). Patients with atherosclerotic renovascular disease (ARVD) often develop renovascular hypertension, which significantly increases the risk for cardiovascular and end-stage renal disease (24). Furthermore, the presence of chronic kidney disease is associated with increased cardiovascular morbidity and mortality (14, 34).

Percutaneous transluminal renal stenting (PTRS) is a common clinical intervention in RAS, yet its efficacy in restoring renal function and improving blood pressure control is still controversial. In patients with fibromuscular dysplasia, which is a nonatherosclerotic, noninflammatory, localized disease and the second most common cause of RAS, revascularization often results in improvement of both renovascular hypertension and renal function (38). However, clinical trials show that restoration of vessel patency improves blood pressure, serum creatinine, and estimated glomerular filtration rate (GFR) only in a selected group of patients with ARVD (36, 41, 44, 45). However, virtually all randomized control trials of revascularization for ARVD failed to evaluate baseline renal ischemia as well as the presence of parenquymal renal disease. Indeed, the mechanisms underlying persistent renal dysfunction in ARVD after PTRS have not been clarified, partly because of the difficulty in assessing tissue injury in humans.

We previously showed that swine RAS is characterized by loss of cortical microvessels in the stenotic kidney (19). Previous studies in rats subjected to acute renal ischemic injury suggest that the loss of renal microvessels due to ischemia exacerbates renal hypoxia and impairs urinary concentrating ability (2). In addition, microvascular loss in rodents correlates directly with development of glomerular and tubulointerstitial scarring (25, 32). Therefore, microvascular rarefaction may account for progression of renal disease.

We also previously demonstrated that in a swine model of nonatherosclerotic RAS, revascularization successfully decreases blood pressure, improves GFR, promotes angiogenic activity, and improves microvascular endothelial function (19). However, the capability of PTRS to attenuate microvascular remodeling and improve renal function in the face of superimposed atherosclerosis remains unknown. Therefore, this study aimed to test the hypothesis that persistent renal dysfunction after PTRA involves ongoing renal microvascular remodeling.

METHODS

All protocols that used animals were approved by the Institutional Animal Care and Use Committee.

Thirty domestic female pigs (50–60 kg) were studied after 16 wk of observation and randomized into three groups: sham-treated pigs with early atherosclerosis + RAS (ARAS; n = 10), PTRS-treated ARAS (ARAS+PTRS; n = 10), and age- and body weight-matched normal controls (n = 10). At baseline, all ARAS pigs started on a high-cholesterol diet consisting of 2% cholesterol and 15% lard (TD-93296, Harlan-Teklad) (49) to simulate the clinical situation in which diffuse early atherosclerosis precedes the stenosis. Six weeks later, animals were anesthetized with 0.5 g of intramuscular ketamine and xylazine anesthesia and then maintained with intravenous ketamine (0.2 mg·kg⁻¹·min⁻¹) and xylazine (0.03 mg·kg⁻¹·min⁻¹). RAS was induced by placing in the main renal artery a local-irritant coil, which leads to a gradual development of unilateral RAS over a 7- to 10-day period, as previously described (13). After induction of RAS, a telemetry system was implanted in the left femoral artery to continuously measure mean arterial pressure (MAP) (47, 48) for the 10 following wk. The average MAP in the last 2 wk of the study was subsequently calculated.

Six weeks after induction of RAS, the degree of stenosis was determined by angiography, and PTRS or sham was performed. Briefly, a 7-mm balloon catheter wrapped with a standard tantalum stent was engaged in the proximal-middle section of the renal artery under fluoroscopic guidance, and the balloon was inflated to 8 atm, resulting in expansion of a stent to full-balloon diameter and restoration of luminal patency. Then, the balloon was deflated and removed, leaving the stent embedded in the vascular wall.

Four weeks after PTRS, the pigs were again similarly anesthetized, and angiography was repeated. Renal hemodynamics and function in each stenotic kidney were assessed using multidetector computer tomography (MDCT). Venous blood samples were collected for plasma renin activity (PRA) and creatinine measurements (GammaCoat PRA kit; DiaSorin, Stillwater, MN). The animals were then allowed a 3-day recovery period from the procedure and then were euthanized with a lethal intravenous dose of 100 mg/kg pentobarbital sodium (Sleepaway, Fort Dodge Laboratories, Fort Dodge, IA) (26).

The kidneys were removed using a retroperitoneal incision and immediately dissected, and sections were frozen in liquid nitrogen (and maintained at −80°C) or preserved in formalin (9). Renal fibrosis was evaluated by trichrome staining and by the expression of transforming growth factor (TGF)-β, plasminogen activator inhibitor (PAI-1), matrix metalloproteinases (MMP)-2 and MMP-9, membrane-type MMP (MT-MMP), and tissue transglutaminase (tTG). Renal hypoxia was evaluated by the expression of hypoxia-inducible factor-α (HIF-1α) and microvascular remodeling using micro-CT and by the expression of vascular endothelial growth factor (VEGF). Oxidative stress was assessed by the quantification of the systemic levels of oxidized low-density lipoproteins (OX-LDL) and in situ production of superoxide anion.

In Vivo Studies

MDCT is an ultra-fast scanner that provides accurate and noninvasive quantifications of single kidney volume, regional perfusion, renal blood flow (RBF), GFR, and tubular function (5, 8, 9, 13, 15). Briefly, 160 consecutive scans were performed following a central venous injection of iopamidol (0.5 ml·kg⁻¹·2 s⁻¹). Then, MDCT images were reconstructed and displayed with the Analyze software package (Biomedical Imaging Resource, Mayo Clinic, Rochester, MN). The same procedure was repeated after a 15-min interval and toward the end of a 10-min intra-aortic infusion of acetylcholine (Ach; 5 mg·kg⁻¹·min⁻¹) into a tracker catheter placed above the renal arteries to test endothelium-dependent microvascular reactivity. Hemodynamics and function were therefore measured over a stable 3-min observation period at baseline and during Ach infusion (8, 9).

For data analysis, regions of interest were selected from cross-sectional images from the aorta, renal cortex, and medulla to generate tissue attenuation curves in each region to obtain measures of renal function (15). Cortical and medullary volumes were calculated and RBF was computed as the sum of the products of cortical and medullary perfusions and corresponding volumes. GFR was assessed from the cortical curve using the slope of the proximal tubular curve.

In Vitro Studies

Renal histology.

Midhilar 5-μm cross sections of each kidney (one per animal) were examined using a computer-aided image analysis program (MetaMorph, Meta Imaging, Molecular Devices, Sunnyvale, CA). In each slide, trichrome staining was semiautomatically quantified in 15–20 fields, expressed as fraction of kidney surface area, and the results from all fields were averaged. Glomerular score (% of sclerotic out of 100 glomeruli) was also assessed (8–11).

Western blotting.

Western blotting protocols were followed using specific polyclonal antibodies against active and pro-MMP-2 and MMP-9, MT-MMP, PAI-1, TGF-β, tTG, HIF-1α, and VEGF (8, 9, 11). Protein expression was determined in each kidney, and the intensities of the protein bands (one per animal) were quantified and normalized for a GADPH loading control. MMP-2 and MMP-9 were normalized for their respective pro-MMP forms.

Microcomputed tomography analysis.

After the kidney was flushed, microfil MV122 (an intravascular contrast agent) was perfused into the stenotic kidney under physiological pressure through a cannula ligated in a branch of the renal artery. Samples were prepared and scanned at 0.5° angular increments at 18-μm resolution, and images were analyzed as previously described (19, 47). The spatial density, average diameter, and tortuousity of microvessels (diameters 20–500 μm) in the inner, middle, and outer thirds of the renal cortex were calculated using ANALYZE and classified according to diameter as small (<40 μm), medium (40–100 mm), or large (>100 μm) microvessels (11, 47).

Oxidative stress.

Circulating levels of OX-LDL (Mercodia, Uppsala, Sweden) were quantified from systemic venous blood samples, as we have shown before (13). In addition, in-situ renal production of superoxide anion was evaluated by fluorescence microscopy after dihydroethidium (DHE) staining (7).

Statistical analysis.

Results are expressed as means ± SD. Statistical analysis was performed using JMP software package version 8.0 (SAS Institute, Cary, NC). Comparisons within groups were performed using paired Student's t-test and among groups using ANOVA and unpaired t-test with Bonferroni correction. Regressions were calculated by the least-squares fit. Statistical significance for all tests was accepted for P ≤ 0.05.

RESULTS

All pigs had a similar body wt. Six weeks after induction of RAS, both sham- and PTRS-treated ARAS pigs achieved hemodynamically significant degrees of stenosis (37) (81.3 ± 15.7 and 76.0 ± 8.1%, respectively, P = 0.36). MAP was significantly and similarly elevated in ARAS and ARAS+PTRS (131.3 ± 32.7 and 126.1 ± 7.6 mmHg, respectively, P = 0.61) compared with normal (106.1 ± 18.1 mmHg, P = 0.02 and P = 0.05, respectively). The pigs were then randomized to PTRS or sham.

Four weeks after successful PTRS (0% stenosis in all ARAS+PTRS pigs), MAP decreased in this group (Fig. 1), but remained elevated in untreated ARAS (Table 1; P < 0.05 vs. ARAS, P = 0.43 vs. normal). Total cholesterol and LDL levels were significantly elevated in ARAS and ARAS+PTRS compared with normal (Table 1; P < 0.05 vs. normal; P > 0.05 vs. ARAS). Serum creatinine levels were significantly higher in ARAS compared with normal pigs and remained elevated after PTRS (Table 1; P < 0.05 vs. normal; P = 0.33 vs. ARAS). No significant differences in PRA were found among the groups, as typical to the chronic phase of untreated RAS (35).

Table 1.

Systemic characteristics and single-kidney hemodynamics in normal, untreated ARAS, and ARAS pigs 4 wk after PTRS

	Normal	ARAS	ARAS+PTRS
Number of pigs	10	10	10
Body weight, kg	48.5 ± 2.8	51.0 ± 8.8	51.1 ± 7.8
Diastolic blood pressure, mmHg	97.2 ± 13.0	114.6 ± 25.1^*^†	95.1 ± 16.0
Systolic blood pressure, mmHg	124.6 ± 17.0	148.7 ± 31.5^*^†	125.4 ± 17.9
Mean arterial pressure, mmHg	106.3 ± 14.0	126.0 ± 26.9^*^†	105.2 ± 16.5
Degree of stenosis, %	0	92.0 ± 17.3^*^†	0
Serum creatinine, mg/dl	1.29 ± 0.16	1.79 ± 0.37^*	1.85 ± 0.23^*
PRA, ng·ml⁻¹·h⁻¹	0.18 ± 0.14	0.20 ± 0.21	0.27 ± 0.18
Total cholesterol, mg/dl	92.5 ± 16.0	511.0 ± 128.1^*	385.7 ± 166.2^*
LDL cholesterol, mg/dl	47.3 ± 8.6	332.6 ± 127.4^*	235.9 ± 122.3^*
Oxidized-LDL, μg/ml	1.03 ± 0.51	2.76 ± 2.40^*	1.55 ± 0.85
Renal volume, ml	137.1 ± 22.1	93.6 ± 27.6^*	106.2 ± 21.8^*
Cortical perfusion, ml·min⁻¹·ml tissue⁻¹	4.7 ± 1.1	3.7 ± 0.9^*	4.2 ± 1.4
RBF, ml/min	609.9 ± 130.7	391.0 ± 172.2^*	468.0 ± 222.0^*
GFR, ml/min	77.4 ± 27.7	52.5 ± 14.0^*	57.0 ± 16.2^*

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Values are means ± SD. ARAS, atherosclerosis + renal artery stenosis; PTRS, percutaneous transluminal renal stenting; PRA, plasma renin activity; RBF, renal blood flow; GFR, glomerular filtration rate; LDL, low-density lipoprotein.

P ≤ 0.05 vs. normal.

^†

P ≤ 0.05 vs. ARAS+PTRS.

Renal Hemodynamics and Function

Basal renal volume and GFR were significantly decreased in the stenotic ARAS compared with normal kidneys (Table 1). Cortical perfusion improved after PTRS, while RBF slightly increased, but remained reduced compared with normal (P = 0.05), and not significantly higher than ARAS (P = 0.26). Furthermore, GFR and RBF responses to Ach were similarly attenuated in ARAS and ARAS+PTRS, suggesting persistent endothelial dysfunction (Fig. 1). Infusion of Ach was not associated with a persistent change in blood pressure, as we showed previously (8).

Microvascular Architecture

Transmural spatial density of cortical microvessels was significantly diminished in both ARAS and ARAS+PTRS compared with normal pigs (Fig. 2), while average vessel diameter increased (Table 2). Moreover, ARAS and ARAS+PTRS pigs showed a similar increase in microvascular tortuousity compared with normal animals, suggesting angiogenic activity to restore microvessels (Table 2). The decrease in spatial density was maintained throughout the outer, middle, and inner cortex in both ARAS and ARAS+PTRS pigs and was particularly determined by the number of small vessels (<40 μm) that were significantly reduced in ARAS and ARAS+PTRS compared with normal (Fig. 2), suggesting a selective loss of microvessels that PTRS failed to restore. Notably, the spatial density of outer cortical microvessels in ARAS and ARAS+PTRS (but no other cortical region) correlated linearly and significantly with GFR (Fig. 2), indicating that microvascular remodeling in the outer cortex might have contributed to the residual renal dysfunction observed 4 wk after PTRS.

Table 2.

Renal cortical microvascular architecture assessed by micro-CT in normal, ARAS, and ARAS+PTRS

	Normal	ARAS	ARAS+PTRS
Spatial density, vessels/cm²
Transmural	269.7 ± 103.9	161.0 ± 47.1^*	184.0 ± 58.1^*
Outer cortex	309.4 ± 86.8	165.1 ± 34.0^*	176.7 ± 54.4^*
Middle cortex	286.7 ± 110.4	163.0 ± 51.2^*	190.0 ± 58.2^*
Inner cortex	212.9 ± 114.5	155.0 ± 56.0^*	185.4 ± 63.6^*
Average vessel diameter, μm	92.02 ± 20.59	105.77 ± 16.96^*	101.98 ± 15.38^*
Tortuousity, ratio	1.32 ± 0.23	1.54 ± 0.39^*	1.51 ± 0.38^*

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Values are means ± SD.

P < 0.05 vs. normal. No significant differences were found between ARAS and ARAS+PTRS pigs.

Oxidative Stress

Systemic OX-LDL levels were significantly higher in ARAS compared with normal and slightly decreased after PTRS to levels that were not different from normal or sham ARAS (Table 1; P = 0.15 vs. ARAS+PTRS), indicating that systemic oxidative stress was improved but not abolished after revascularization. Moreover, in situ production of superoxide anion was similarly increased in ARAS and ARAS+PTRS compared with normal (P = 0.01 vs. normal, P = 0.99 vs. ARAS; Fig. 3).

Renal Hypoxia

HIF-1 expression was significantly increased in ARAS compared with normal (P = 0.02) and decreased after revascularization (Fig. 3), but it was not significantly different from ARAS+PTRS (P = 0.28).

Renal Scarring, Fibrogenic and Angiogenic Factors

Expression of VEGF protein was reduced in ARAS (P < 0.05 vs. normal; Fig. 3) and further decreased after revascularization (P < 0.05 vs. ARAS). PTRS also failed to restore the expression of the fibrogenic factors PAI-1 (P = 0.003 vs. normal) and TGF-β (P = 0.02 vs. normal), both of which were similarly upregulated in ARAS and ARAS+PTRS. On the other hand, no significant differences were found in the levels of MMP-2, MMP-9, MT-MMP, and tTG among the groups (Fig. 3).

Trichrome staining showed that tubulointerstitial fibrosis was elevated in ARAS and did not change after revascularization (P = 0.43 vs. ARAS; Fig. 4). Glomerular score (index of glomerulosclerosis) was higher in ARAS compared with normal (Fig. 4) and did not improve after revascularization (P < 0.001 vs. normal, P = 0.67 vs. ARAS). There was no significant difference in glomerular score between the outer and inner cortex in ARAS or ARAS+PTRS (P = 0.11 and P = 0.13, respectively; Fig. 4).

Fig. 4. — *Top*: representative images of renal trichrome staining in normal, ARAS, and ARAS+PTRS pigs (*top*) and its quantification (means ± SD; *middle*). *Bottom*: overall (*left*) and outer vs. inner (*right*) cortical glomerular score (% of sclerotic glomeruli). *P < 0.05 vs. normal.

DISCUSSION

The present study demonstrates that tubulointerstitial injury and renal dysfunction in experimental ARVD persist 4 wk after PTRS, despite resolution of hypertension. Four weeks after mechanically successful revascularization, serum creatinine levels remained higher and stenotic-kidney GFR significantly reduced compared with normal pigs, and their response to Ach was blunted, suggesting that endothelial function remained impaired after revascularization. Persistent dysfunction was spatially related to outer cortical microvascular loss and accompanied by relentless oxidative stress and renal fibrosis. This study therefore supports the need for evaluation of the extent of renal parenchymal disease before revascularization in patients with ARVD.

RAS remains the major cause of renovascular hypertension and may induce renal tissue injury leading to progressive renal failure (27, 39). Atherosclerosis is responsible for as many as 90% of all cases of renovascular disease (39). Previous studies demonstrated that renal functional outcomes are dependent on intrarenal parenchymal damage in patients with ARVD (46). Moreover, revascularization improves renal function in a minority of patients with ARVD, possibly because of direct effects of diffuse atherosclerosis on the kidney (28). Indeed, we previously showed that atherosclerosis-induced oxidative stress and inflammation amplified renal dysfunction in ARAS by augmenting tubulointerstitial and glomerular fibrosis (8). We also showed that in a model of nonatherosclerotic RAS, PTRS decreased blood pressure and improved the renal microvascular network, and while tubulointerstitial injury was not fully resolved, GFR recovered 4 wk after the procedure (19). The current study extends our previous observations and demonstrates that superimposition of atherosclerosis accentuates irreversible renal injury, as it is associated with persistent renal dysfunction after successful revascularization, as observed in many patients with ARVD (20), and supports the notion that parenchymal disease diminishes response to revascularization in ARVD.

Human ARAS is often superimposed on essential hypertension or severe preexisting renal injury, which sustains systemic hypertension after PTRS. Interestingly, this study underscores the ability of PTRS to decrease blood pressure in early stages of ARAS, likely by restoration of vessel patency, increase in renal perfusion pressure, and thereby downregulation of renal-angiotensin-aldosterone system activity (which does not necessarily reflect in systemic PRA). Contrary to systemic hypertension, renal damage in our model persisted 4 wk after revascularization. Evidently, the mild residual kidney damage observed in the stenotic swine kidney is not severe enough to maintain elevated blood pressure after PTRS.

Renal damage in patients with RAS is instigated by generation of angiotensin II, which after prolonged activation stimulates deleterious pathways that lead to progressive renal injury, including inflammation, fibrogenesis, and oxidative stress. This detrimental process is commonly initiated by endothelial injury (28), which might lead to endothelial dysfunction (4), reflected in our study by blunted responses to Ach. In addition, increased production of reactive oxygen species (ROS) in the stenotic ARAS kidney, suggested by increased renal production of superoxide anion and circulating levels of OX-LDL, might stimulate fibrogenic factors and amplify renal dysfunction and injury (8, 9). Indeed, in 2-kidney, 1-clip rats a superoxide dismutase mimetic (Tempol) improves renal oxygenation and function (33), and chronic administration of antioxidant vitamins E and C improves renal function and structure in swine RAS (11). Systemic oxidative stress was improved after revascularization, probably because of the decrease in blood pressure, but it was not abolished because the pigs remained hypercholesterolemic. However, the potential for paradoxical prooxidant effects of antioxidants (16) and disappointing results of cardiovascular clinical trials do not support routine use of antioxidants in patients with ARVD.

Persistent renal fibrosis was likely secondary to upregulation of the fibrogenic factors TGF-β and PAI-1 in the atherosclerotic milieu. These may be induced by angiotensin II, ROS, cytokines, and growth factors (17) and might have accounted for the continued glomerulosclerosis and tubulointerstitial fibrosis after PTRS. While chronic reduction of renal perfusion in ARAS may modulate microvascular structure (remodeling or regression) (1, 22, 42), in our model these were likely not mediated by the vascular remodeling factors tTG or MMP, because their levels were not different than normal.

Although PTRS restored the increased levels of HIF-1α, expression of the downstream angiogenic factor VEGF was decreased in ARAS and ARAS+PTRS, possibly mediated by oxidative stress, which may impair the ability of the kidney to generate new vessels. We observed decreased spatial density and selective loss of small microvessels in the renal cortex, and thereby an increase in average diameter of the remaining vessels. Considering the relatively mild glomerulosclerosis, the lost microvessels were likely primarily nutrient. Interlobular arteries may branch into a plexus of nutrient capillaries or perforating capsular arteries, which do not necessarily pass through the glomerulus (31). Furthermore, in the pig kidney afferent arterioles often give off small (<40 μm) secondary and tertiary branches (43). The increased microvascular tortuousity in ARAS suggests some formation of new vessels, yet this compensatory mechanism was not fully effective, possibly because of downregulation of VEGF due to high levels of ROS (23).

Previous studies documented the effect of loss (rarefaction) or damage of renal microvessels on progression of renal injury (25), deterioration of renal function, and glomerular and tubulointerstitial scarring (9, 12). Interestingly, the spatial density of microvessels located specifically in the outer cortex correlated linearly with GFR, underscoring the contribution of microvascular remodeling in this region to renal dysfunction in ARAS. This spatial selectivity might be partly related to anatomical and functional differences between the outer and deep renal cortex. Approximately 70% of RBF is distributed to the outer half of the cortex (40), which is selectively affected by a decrease in renal perfusion pressure (29, 30). Speculatively, microvascular loss in this region may be vital for renal function, as supported by the relative abundance of glomeruli in the outer third of the swine renal cortex (43). Furthermore, efferent arterioles located in the outer and middle cortex tend to perfuse nephron segments located in various cortical regions (3, 18), and might thus be more critical determinants of GFR than inner cortical efferent arterioles.

Limitations

Our study is limited by the use of relatively young animals and short duration of the disease. Alas, renal structure and function in our swine model are similar to human kidneys, and superimposition of atherosclerosis in RAS also accelerates renal functional compromise. We also observed that PTRS decreased blood pressure, which is not a consistent observation in ARVD. Indeed, human ARVD is multifactorial and prolonged, and often associated with other concurrent or preexisting pathophysiological conditions like essential hypertension, which account for unaltered blood pressure levels after revascularization. Our study therefore highlights the dissociation of potential benefits of revascularization for blood pressure reduction from its efficacy for renal function improvement in ARAS. Furthermore, a longer observation period may be needed to detect measurable improvement in renal function and structure.

In summary, the current study shows that tubulointerstitial injury, microvascular rarefaction, and renal dysfunction persisted after revascularization in swine ARAS. Moreover, we found that microvascular loss in the outer cortex might be an important determinant of persistent renal dysfunction after PTRS. Therefore, our study suggests a central role for outer cortical microvessels in maintaining GFR in ARVD and supports exploration of vasculo-protective strategies, such as administration of VEGF (6) or progenitor cells (12), for preserving microvascular integrity and function in the stenotic ARAS kidney. Finally, this study underscores the need for assessment of parenchymal disease in the selection of patients for revascularization.

GRANTS

This study was partly supported by National Institutes of Health Grants DK73608, DK77013, HL77131, HL085307, and RR018898.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

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38. Safian RD, Madder RD. Refining the approach to renal artery revascularization. JACC Cardiovasc Interv 3: 161–174, 2009 [DOI] [PubMed] [Google Scholar]
39. Safian RD, Textor SC. Renal artery stenosis. N Engl J Med 344: 431–442, 2001 [DOI] [PubMed] [Google Scholar]
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44. Webster J, Marshall F, Abdalla M, Dominiczak A, Edwards R, Isles CG, Loose H, Main J, Padfield P, Russell IT, Walker B, Watson M, Wilkinson R. Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis. Scottish and Newcastle renal artery stenosis collaborative group. J Hum Hypertens 12: 329–335, 1998 [DOI] [PubMed] [Google Scholar]
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49. Zhu XY, Rodriguez-Porcel M, Bentley MD, Chade AR, Sica V, Napoli C, Caplice N, Ritman EL, Lerman A, Lerman LO. Antioxidant intervention attenuates myocardial neovascularization in hypercholesterolemia. Circulation 109: 2109–2115, 2004 [DOI] [PubMed] [Google Scholar]

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[B35] 35. Pipinos II, Nypaver TJ, Moshin SK, Careterro OA, Beierwaltes WH. Response to angiotensin inhibition in rats with sustained renovascular hypertension correlates with response to removing renal artery stenosis. J Vasc Surg 28: 167–177, 1998 [DOI] [PubMed] [Google Scholar]

[B36] 36. Plouin PF, Chatellier G, Darne B, Raynaud A. Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Essai multicentrique medicaments vs angioplastie (EMMA) study group. Hypertension 31: 823–829, 1998 [DOI] [PubMed] [Google Scholar]

[B37] 37. Rognant N, Rouviere O, Janier M, Le QH, Barthez P, Laville M, Juillard L. Hemodynamic responses to acute and gradual renal artery stenosis in pigs. Am J Hypertens 11: 1216–1219, 2010 [DOI] [PubMed] [Google Scholar]

[B38] 38. Safian RD, Madder RD. Refining the approach to renal artery revascularization. JACC Cardiovasc Interv 3: 161–174, 2009 [DOI] [PubMed] [Google Scholar]

[B39] 39. Safian RD, Textor SC. Renal artery stenosis. N Engl J Med 344: 431–442, 2001 [DOI] [PubMed] [Google Scholar]

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[B41] 41. van Jaarsveld BC, Krijnen P, Pieterman H, Derkx FH, Deinum J, Postma CT, Dees A, Woittiez AJ, Bartelink AK, Man in't Veld AJ, Schalekamp MA. The effect of balloon angioplasty on hypertension in atherosclerotic renal artery stenosis. Dutch renal artery stenosis intervention cooperative study group. N Engl J Med 342: 1007–1014, 2000 [DOI] [PubMed] [Google Scholar]

[B42] 42. Verhoeff BJ, Siebes M, Meuwissen M, Atasever B, Voskuil M, de Winter RJ, Koch KT, Tijssen JG, Spaan JA, Piek JJ. Influence of percutaneous coronary intervention on coronary microvascular resistance index. Circulation 111: 76–82, 2005 [DOI] [PubMed] [Google Scholar]

[B43] 43. Vodenicharov A, Simoens P. Morphologic peculiarities of the renal cortical vasculature connected with blood redistribution in the kidney of the domestic pig. Anat Histol Embryol 27: 257–262, 1998 [DOI] [PubMed] [Google Scholar]

[B44] 44. Webster J, Marshall F, Abdalla M, Dominiczak A, Edwards R, Isles CG, Loose H, Main J, Padfield P, Russell IT, Walker B, Watson M, Wilkinson R. Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis. Scottish and Newcastle renal artery stenosis collaborative group. J Hum Hypertens 12: 329–335, 1998 [DOI] [PubMed] [Google Scholar]

[B45] 45. Wheatley K, Ives N, Gray R, Kalra PA, Moss JG, Baigent C, Carr S, Chalmers N, Eadington D, Hamilton G, Lipkin G, Nicholson A, Scoble J. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med 361: 1953–1962, 2009 [DOI] [PubMed] [Google Scholar]

[B46] 46. Wright JR, Duggal A, Thomas R, Reeve R, Roberts IS, Kalra PA. Clinicopathological correlation in biopsy-proven atherosclerotic nephropathy: implications for renal functional outcome in atherosclerotic renovascular disease. Nephrol Dial Transplant 16: 765–770, 2001 [DOI] [PubMed] [Google Scholar]

[B47] 47. Zhu XY, Chade AR, Rodriguez-Porcel M, Bentley MD, Ritman EL, Lerman A, Lerman LO. Cortical microvascular remodeling in the stenotic kidney: role of increased oxidative stress. Arterioscler Thromb Vasc Biol 24: 1854–1859, 2004 [DOI] [PubMed] [Google Scholar]

[B48] 48. Zhu XY, Daghini E, Chade AR, Napoli C, Ritman EL, Lerman A, Lerman LO. Simvastatin prevents coronary microvascular remodeling in renovascular hypertensive pigs. J Am Soc Nephrol 18: 1209–1217, 2007 [DOI] [PubMed] [Google Scholar]

[B49] 49. Zhu XY, Rodriguez-Porcel M, Bentley MD, Chade AR, Sica V, Napoli C, Caplice N, Ritman EL, Lerman A, Lerman LO. Antioxidant intervention attenuates myocardial neovascularization in hypercholesterolemia. Circulation 109: 2109–2115, 2004 [DOI] [PubMed] [Google Scholar]

PERMALINK

Persistent kidney dysfunction in swine renal artery stenosis correlates with outer cortical microvascular remodeling

Alfonso Eirin

Xiang-Yang Zhu

Victor H Urbieta-Caceres

Joseph P Grande

Amir Lerman

Stephen C Textor

Lilach O Lerman

Abstract