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Occlusive disease of the renal arteries poses a major problem. Most cases result from atherosclerotic disease, and the prevalence of incidental renal artery disease detected during imaging studies for symptomatic coronary, aortic, and peripheral vascular disease ranges from 14% to >35%, increasing with age.1 Although many (perhaps most) of these lesions produce only minor hemodynamic effects, it has long been recognized that when some “critical” level of occlusion is breached, poststenotic renal blood flow and glomerular filtration rate (GFR) fall, especially after lowering systemic arterial pressure. In some cases, kidney function can recover after restoring blood flow with either endovascular or surgical revascularization. Several prospective, randomized trials have examined whether the loss of renal function due to atherosclerotic renal artery stenosis can be managed best by medical therapy alone or would further benefit from renal revascularization.2,3 The study reported by Madder and colleagues4 in this issue of Circulation: Cardiovascular Interventions directly challenges whether conventional criteria for estimating GFR and directional trends in such trials are valid. This matter is important for physicians serious about considering renovascular disease. Article see p 219 Atherosclerotic renal artery stenosis (ARAS) is primarily a disease of older persons, with mean ages for most series >70 years.1 Patient series subjected to renal artery procedures routinely have reduced kidney function, usually expressed as reduced GFR. Despite remarkable improvements for many hypertensive and cardiovascular end points, such as stroke and myocardial infarction, attributable in part to effective medical intervention, the prevalence of end-stage renal disease has continued to increase over the past several decades. These observations raise the possibility that occlusive ARAS may be partly responsible for progressive renal injury. How best to evaluate and characterize kidney function in these trials has been controversial. Previous observational reports of renal revascularization used a …

Many patients with occlusive atherosclerotic renovascular disease (ARVD) may be managed effectively with medical therapy for several years without endovascular stenting, as demonstrated by randomized, prospective trials including the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial and the Stent Placement and Blood Pressure and Lipid-Lowering for the Prevention of Progression of Renal Dysfunction Caused by Atherosclerotic Ostial Stenosis of the Renal Artery (STAR) and ASTRAL. These trials share the limitation of excluding subsets of patients with high-risk clinical presentations, including episodic pulmonary edema and rapidly progressing renal failure and hypertension. Although hemodynamically significant, ARVD can reduce renal blood flow and glomerular filtration rate; adaptive mechanisms preserve both cortical and medullary oxygenation over a wide range of vascular occlusion. Progression of ARVD to severe vascular compromise eventually produces cortical hypoxia, however, associated with active inflammatory cytokine release and cellular infiltration of the renal parenchyma. In such cases ARVD produces a loss of glomerular filtration rate that no longer is reversible simply by restoring vessel patency with technically successful renal revascularization. Each of these trials reported adverse renal functional outcomes ranging between 16 and 22% over periods of 2-5 years of follow-up. Blood pressure control and medication adjustment may become more difficult with declining renal function and may prevent the use of angiotensin receptor blocker and angiotensin-converting enzyme inhibitors. The objective of this review is to evaluate the current management of ARVD for clinical nephrologists in the context of recent randomized clinical trials and experimental research.

Many histopathologic findings within post-stenotic kidneys are nonspecific and represent conditions associated with aging, atherosclerosis and pre-existing hypertension. Two major abnormalities reported in patients with renovascular disease (RVD) are arteriolar nephrosclerosis and atheroembolic renal lesions. Other chronic renal “ischemia” markers include tubular atrophy, interstitial fibrosis and arteriolar sclerosis, but are less specific.

While atherosclerotic Renal Artery Stenosis (ARAS) is a common cause of secondary hypertension and poses a threat to kidney viability, the degree to which reduced blood flow to cortical or medullary segments leads to a reduction in tissue oxygenation and/or increased overall oxygen consumption is not well understood. These studies have been limited due to the lack of an adequate method to assess tissue oxygenation in humans. BOLD (blood oxygen-level-dependent) magnetic resonance imaging detects local levels of tissue deoxyhemoglobin without requiring contrast. The normal kidney circulation consistently develops tissue oxygen gradients, leaving some areas within the deep sections of medulla relatively hypoxic, reflected by corresponding differences in cortical and medullary R2* values. Moderate reductions in renal blood flow that occur with ARAS do not invariably lead to renal hypoxia, likely due to both a surplus of oxygenated blood and a parallel decrease in GFR and tubular reabsorption of sodium that leads to decrease in Oxygen consumption. However, at some point, vascular occlusion threatens the viability of the kidney and can lead to loss of kidney function. In this chapter we will review the implementation of BOLD MRI in the diagnosis and management of renovascular disease.

Background Renovascular hypertension (RVHT) increases cardiovascular morbidity and mortality. Renal revascularization with percutaneous transluminal renal angioplasty and stenting (PTRS) may reverse RVHT but may not fully regress cardiac remodeling and damage, possibly due to persistent myocardial insults. Bendavia is a mitochondrial targeted peptide that reduces ischemic cardiomyopathy by improving mitochondrial function. However, its potential for attenuating residual myocardial damage after reversal of RVHT has not been explored. We hypothesized that treatment with Bendavia as an adjunct to PTRS would improve cardiac function and oxygenation, and decrease myocardial injury in swine RVHT. Methods and results After 6 weeks of RVHT (unilateral renal artery stenosis) or control, pigs underwent PTRS (or sham), with adjunct continuous infusion of Bendavia (0.05 mg/kg intravenously, 30 min before to 3.5 h after PTRS) or vehicle (n = 7 each). Four weeks later, systolic and diastolic function were assessed by multidetector computed tomography, myocardial oxygenation by blood oxygen level-dependent MRI, and myocardial morphology, apoptosis, mitochondrial biogenesis, and fibrosis evaluated ex vivo. PTRS restored blood pressure in both groups, yet E/A ratio remained decreased. Myocardial oxygenation and mitochondrial biogenesis improved, and myocardial inflammation, oxidative stress, and fibrosis normalized in association with improvement in diastolic function in RVHT + PTRS + Bendavia animals. Conclusion Adjunct Bendavia during PTRS in swine RVHT improved diastolic function and oxygenation and reversed myocardial tissue damage. This approach may allow a novel strategy for preservation of cardiac function and structure in RVHT.

Few references have been published on the renal vascular system and its effect on the cardiovascular system as a whole. Clearly the kidney exerts a huge influence on the circulation and hypertension in particular, but there is a growing concentration on its function across many diseases. This book details the diagnosis, treatment and management of all renal vascular disease.

Loss of renal function beyond a renal vascular lesion presents a complex challenge to clinicians. This article summarizes current understanding of critical vascular lesions to the kidney and putative mechanisms by which loss of perfusion activates fibrogenic mechanisms in the kidney. The authors emphasize alterations in vasoactive pathways, including disturbed oxidative stress, activation of endothelin, and reduced nitric oxide, which modulate cytokines and inflammatory mediators within the renal parenchyma. Improved understanding of these mechanisms is essential in preventing irreversible interstitial fibrosis and restoring renal perfusion.

Renal artery stenosis (RAS) can accelerate or generate progressive hypertension and renal dysfunction. The goals for treating patients with RAS are to reduce cardiovascu-lar morbidity and mortality attributable to elevated arterial pressure and to preserve renal function beyond critical stenosis. Recent, randomized trials with current anti-hypertensive agents indicate that many patients with RAS can be managed for years without renal artery revascularization. As it does elsewhere, atherosclerotic disease can progress to more severe occlusion in the renal arteries. Rapid advances in endo-vascular techniques, including stenting, make restoration of renal blood flow possible in more patients than before. Therapeutic goals are achieved by 1) avoidance of tobacco, 2) reducing arterial pressure with antihypertensive drug therapy, particularly those agents capable of blocking the renin-angiotensin system, and 3) renal revascu-larization, using balloon angioplasty and stent placement, surgical bypass, or endart-erectomy. The major clinical challenges are to identify progressive occlusive disease and to determine appropriate timing for vascular intervention.

Renal artery stenosis (RAS) can accelerate or generate progressive hypertension and renal dysfunction. The goals for treating patients with RAS are to reduce cardiovascu-lar morbidity and mortality attributable to elevated arterial pressure and to preserve renal function beyond critical stenosis. Recent, randomized trials with current anti-hypertensive agents indicate that many patients with RAS can be managed for years without renal artery revascularization. As it does elsewhere, atherosclerotic disease can progress to more severe occlusion in the renal arteries. Rapid advances in endo-vascular techniques, including stenting, make restoration of renal blood flow possible in more patients than before. Therapeutic goals are achieved by 1) avoidance of tobacco, 2) reducing arterial pressure with antihypertensive drug therapy, particularly those agents capable of blocking the renin-angiotensin system, and 3) renal revascu-larization, using balloon angioplasty and stent placement, surgical bypass, or endart-erectomy. The major clinical challenges are to identify progressive occlusive disease and to determine appropriate timing for vascular intervention.

▪ Abstract Chronic azotemic renovascular disease is common in patients with atherosclerosis. Its prevalence appears to be increasing in the aging population. How often it is the primary cause of end-stage renal disease (ESRD) is not yet certain. Some studies suggest that 10%–40% of elderly hypertensive patients with newly documented ESRD and no demonstrable primary renal disease have significant renal artery stenosis (RAS). Atherosclerotic vascular occlusive disease of the renal arteries does progress, but current rates of progression and occlusion are lower than those reported a decade ago. Methods of identifying patients whose renal function is at true risk from vascular occlusive disease and determining who will benefit from intervention remain elusive. The presence of RAS in an azotemic patient can be assessed with noninvasive and risk-free radiologic techniques, including Duplex doppler velicometry and magnetic resonance angiography. Functional tests that predict the change in renal function after revascularization are not yet available. However, a renal length of greater than 7.5 cm in the absence of renal cysts and a short history of renal functional deterioration indicate a good prognosis. Patients with recent deterioration in renal function, those with bilateral renal artery stenosis or stenosis to a single functioning kidney, those with flash pulmonary edema, advanced chronic renal failure, or ESRD (who have much to gain), those with reversible azotemia during angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ARB) therapy, and those whose conditions cannot be managed medically should be considered for revascularization. Results from recent controlled clinical trials of the response to percutaneous transluminal renal artery angioplasty (PTRA) and stenting indicate that improvement in blood pressure control or renal function is not a predictable outcome of renal revascularization. In azotemic groups, 25%–30% of patients achieve important recovery of renal function. Thus, significant progress has been made recently in determining whether RAS is a frequent, treatable cause of renal failure. The decision to recommend revascularization remains a difficult balance between the risks and expense of the procedure and the undoubted benefits that accrue if renal function is successfully stabilized.

Calcineurin inhibitors are a mainstay of transplant immunosuppression and commonly induce hypertension. They are highly lipid soluble and penetrate vascular smooth muscle cell membranes readily. Changes in vascular tone are universally observed during administration of these agents, particularly within the kidney, leading to diminished glomerular filtration and enhanced sodium retention. Disturbances of endothelial function are prevalent in many tissues, including stimulation of endothelin and impaired nitric oxide synthesis. Multiple additional pathways produce increased vasoconstriction, leading to an increase in arterial pressure. Clinical manifestations include disturbances in circadian blood pressure patterns, left ventricular hypertrophy, and acceleration of atherosclerotic and renal injury. Rapid increases in pressure occasionally produce accelerated hypertension and microangiopathic tissue damage. Principles of therapy require recognition of hazards of changing arterial pressures during calcineurin use and preferential use of vasodilating drugs, particularly dihydropyridine calcium channel blocking agents. Attention must be paid to interactions between antihypertensive agents and calcineurin inhibitor blood levels.

To determine how often patients with renal artery stenosis (RAS) managed without revascularization progress to accelerated hypertension and/or renal failure.We examined the outcomes of 68 patients (mean +/- SEM age, 71.8 +/- 0.9 years) with high-grade (70%) RAS identified between 1989 and 1993 who were treated without renal revascularization for at least 6 months after angiography. The time to last follow-up averaged 38.9 +/- 2.8 months. Other vascular beds were affected in 66 of the 68 patients. End points were revascularization, nephrectomy, dialysis, or death.The mean +/- SEM serum creatinine level rose from 1.4 +/- 0.1 to 2.0 +/- 0.2 mg/dL (P.001). Mean +/- SEM blood pressure did not change (157 +/- 3/83+/-2 vs 155 +/- 3/79 +/- 2 mm Hg), but the need (mean +/- SEM) for medication increased from 1.6+/-0.1 to 1.9+/-0.1 drugs (P=.02). Four patients (5.8%) eventually underwent renal revascularization for refractory hypertension (1 patient), for progressive stenosis (1 patient), and during aortic reconstruction (2 patients). One additional patient underwent nephrectomy to improve blood pressure control. Five others (7.4%) developed end-stage renal disease (ESRD) for reasons other than progressive vascular disease, namely, diabetes (3 patients), atheroemboli (1 patient), and contrast toxicity without RAS progression (1 patient). In 1 further case, the reason for ESRD was unknown, and it may have been caused by vascular occlusion. During follow-up, 19 patients died of unrelated causes, including myocardial infarction and stroke.These data indicate that antihypertensive medication requirements increased and renal function deteriorated modestly in a subset of patients with atherosclerotic RAS managed initially without vascular intervention. Many achieved stable blood pressure for many years. Deterioration of renal function and mortality risk were greatest in patients with bilateral stenosis or stenosis to a solitary functioning kidney. These results reinforce the need for meticulous follow-up for disease progression but underscore the role of competing risks and high mortality from other cardiovascular diseases, which primarily determine the outcomes in patients with RAS and widespread atherosclerotic disease.

Resistant hypertension affects a minority of treated hypertensive patients, yet the resulting target organ damage causes disproportionate morbidity and increased risk of cardiovascular events. The clinical features and efforts to adjust drug treatment in a resistant hypertensive patient are described. As demonstrated, serial hemodynamic measurements using thoracic bioimpedance may provide a rationale for selection of effective combination antihypertensive therapy. (c)2000 by CHF, Inc.

Renal parenchymal inflammation is a critical determinant of kidney injury in renal artery stenosis (RAS) but is difficult to assess in the single kidney without tissue samples. Whether renal vein (RV) levels of inflammatory markers reflect active parenchymal inflammation remains unknown. We evaluated the relationship between net RV cytokine release and tissue inflammation in the post-stenotic kidney.Pigs were studied after 10 weeks of RAS treated 4 weeks earlier with intra-renal vehicle or anti-inflammatory mesenchymal stem cells (MSCs) or normal control. Single-kidney renal blood flow was measured by fast computerized tomography. RV and inferior vena cava levels of tumor necrosis factor (TNF)-α, interferon (IF)-γ, monocyte chemoattractant protein (MCP-1) and interleukin (IL)-10 were measured by enzyme-linked immunosorbent assay, and their net release calculated. Renal expression of the same cytokines was correlated with their net release.Net release of TNF-α, IF-γ and MCP-1 was higher in RAS compared with normal and to the contralateral kidney (all P0.05), decreased in MSC-treated pigs as was their tissue expression. Contrarily, the release of the anti-inflammatory IL-10 was lower in RAS and normalized in RAS+MSC. The net release of TNF-α, MCP-1 and IL-10 directly correlated with their tissue expression. The ratio of inflammatory-to-reparative macrophages directly correlated with the release of MCP-1, but inversely with the release of IL-10. In vitro cultured MSCs also induced a shift in the macrophage phenotype from inflammatory (M1) to reparative (M2).Our findings demonstrate that the release of inflammatory markers from the affected kidney provides an index of renal tissue inflammation in experimental RAS.

Reports from recent trials indicate little additional benefit from stent supported revascularization in patients with atherosclerotic renal artery stenosis. These data have been questioned, particularly on the basis of including subjects with modest occlusive disease and reports of clinical benefits to patients with episodic congestive heart failure. Nonetheless, these data have moved the pendulum away from renal revascularization as a primary maneuver to one reserved for refractory hypertension and/or progressive loss of renal function and circulatory congestion. Recent data emphasize the limits of the kidney adaptation to reduced blood flow, the eventual development of widespread renal hypoxia with activation of inflammatory and fibrogenic pathways. Experimental data now support developing adjunctive measures to support angiogenesis and anti-inflammatory renal repair mechanisms, such as those observed with cell-based therapy with mesenchymal stem/stromal cells.

Background— Atherosclerotic renal artery stenosis (ARAS) is known to reduce renal blood flow, glomerular filtration rate (GFR) and amplify kidney hypoxia, but the relationships between these factors and tubulointerstitial injury in the poststenotic kidney are poorly understood. The purpose of this study was to examine the effect of renal revascularization in ARAS on renal tissue hypoxia and renal injury. Methods and Results— Inpatient studies were performed in patients with ARAS (n=17; >60% occlusion) before and 3 months after stent revascularization, or in patients with essential hypertension (n=32), during fixed Na + intake and angiotensin converting enzyme/angiotensin receptors blockers Rx. Single kidney cortical, medullary perfusion, and renal blood flow were measured using multidetector computed tomography, and GFR by iothalamate clearance. Tissue deoxyhemoglobin levels ( R 2 *) were measured by blood oxygen level–dependent MRI at 3T, as was fractional kidney hypoxia (percentage of axial area with R 2 *>30/s). In addition, we measured renal vein levels of neutrophil gelatinase–associated lipocalin, monocyte chemoattractant protein-1, and tumor necrosis factor-α. Pre-stent single kidney renal blood flow, perfusion, and GFR were reduced in the poststenotic kidney. Renal vein neutrophil gelatinase–associated lipocalin, tumor necrosis factor-α, monocyte chemoattractant protein-1, and fractional hypoxia were higher in untreated ARAS than in essential hypertension. After stent revascularization, fractional hypoxia fell ( P Conclusions— These data demonstrate that despite reversal of renal hypoxia and partial restoration of renal blood flow after revascularization, inflammatory cytokines and injury biomarkers remained elevated and GFR failed to recover in ARAS. Restoration of vessel patency alone failed to reverse tubulointerstitial damage and partly explains the limited clinical benefit of renal stenting. These results identify potential therapeutic targets for recovery of kidney function in renovascular disease.

Renal artery stenosis (RAS) is an important cause of chronic renal dysfunction. Recent studies have underscored a critical role for CCL2 (MCP-1)-mediated inflammation in the progression of chronic renal damage in RAS and other chronic renal diseases. In vitro studies have implicated p38 MAPK as a critical intermediate for the production of CCL2. However, a potential role of p38 signaling in the development and progression of chronic renal disease in RAS has not been previously defined. We sought to test the hypothesis that inhibition of p38 MAPK ameliorates chronic renal injury in mice with RAS. We established a murine RAS model by placing a cuff on the right renal artery and treated mice with the p38 inhibitor SB203580 or vehicle for 2 wk. In mice treated with vehicle, the cuffed kidney developed interstitial fibrosis, tubular atrophy, and interstitial inflammation. In mice treated with SB203580, the RAS-induced renal atrophy was reduced (70% vs. 39%, P < 0.05). SB203580 also reduced interstitial inflammation and extracellular matrix deposition but had no effect on the development of hypertension. SB203580 partially blocked the induction of CCL2, CCL7 (MCP-3), CC chemokine receptor 2 (CCR2), and collagen 4 mRNA expression in the cuffed kidneys. In vitro, blockade of p38 hindered both TNF-α and TGF-β-induced CCL2 upregulation. Based on these observations, we conclude that p38 MAPK plays a critical role in the induction of CCL2/CCL7/CCR2 system and the development of interstitial inflammation in RAS.

Transplant immunosuppression using either cyclosporine (CsA) or tacrolimus (FK506) leads to renal vasoconstriction and nephrotoxicity. Despite producing similar effects within the kidney and blood vessels, clinical hypertension occurs less frequently with tacrolimus during the first year after transplantation, compared with CsA. To examine the role of steroid dose in early posttransplant hypertension, we measured blood pressure and kidney function in liver transplant recipients treated with tacrolimus and either high-dose (TAC-HI-P, n = 19) or low-dose (TAC-LO-P,n = 20) prednisone, compared with CsA-treated recipients (n = 29) receiving prednisone doses similar to the TAC-HI-P group. At 1 month, hypertension occurred more often with CsA (72%) than with TAC-HI-P (42%, P < 0.05) or TAC-LO-P (30%, P < 0.05). By 4 months after transplantation, hypertension developed in nearly twice as many TAC-HI-P (63%) as TAC-LO-P patients (32%, P < 0.05), with no difference between TAC-HI-P and CsA (86%, NS). Daily prednisone dose at 1 month closely paralleled cumulative steroid dose in the first month in the TAC-HI-P and TAC-LO-P groups. Fourteen of 19 TAC-HI-P patients (74%) required bolus steroids for treatment of rejection within the first month, compared with 3/20 (15%) TAC-LO-P and 10/29 (34%) CsA recipients. Glomerular filtration rate fell from pretransplant levels at 1 month and 4 months to the same degree in CsA, TAC-HI-P, and TAC-LO-P patients. These results demonstrate a central role for steroid dose in the rate of onset of hypertension early after liver transplantation using tacrolimus immunosuppression. Both daily dose and cumulative dosage, including bolus treatment for rejection, may impact on the development of hypertension. Since prevalence rates rise to levels comparable to CsA by 24 months regardless of steroid dose, hypertension after liver transplant may be mediated by different mechanisms at different stages of the posttransplant course.

Renal artery stenosis is an important cause of hypertension and progressive renal insufficiency. Additionally, there is increasing concern that renovascular disease is a significant, but previously-unrecognized, cause of end-stage renal disease in certain subsets of patients. Advances in revascularization techniques offer a greater opportunity for blood pressure control and for the restoration or preservation of renal function. Accurate imaging of the renal vasculature, however, is essential for the proper selection of those individuals who might best benefit from such intervention. Although conventional or digital subtraction arteriography remains the gold standard diagnostic test, significant advances in non-invasive imaging techniques now offer the clinician several options for the accurate diagnosis of hemodynamically significant renovascular disease. These techniques include captopril renography, duplex ultrasonography, magnetic resonance angiography, and spiral/fast computed tomography. In this review, the advantages and limitations of these imaging techniques are compared and contrasted with an emphasis on their usefulness in screening for renovascular disease. Also reviewed are recent applications of these techniques for measurement of renal function, predicting outcome of revascularization, and the clinical monitoring of patients with renovascular disease managed either medically or by revascularization.

Computer tomography-derived intrarenal blood flow in renovascular and essential hypertension. The effect of renal artery stenosis on intrarenal perfusion and volume in renovascular hypertensive patients is unclear. Alterations in these attributes may ultimately be involved in deterioration of renal function. We measured whole kidney, cortical, and medullary perfusion and volume with electron beam computed tomography (EBCT) in 33 hypertensive patients, with well-preserved renal function, scheduled for renal angiography. EBCT-derived whole kidney perfusion was lower in patients with atherosclerotic renal artery stenosis (RAS; N = 20) than in fibromuscular dysplasia (FMD; N = 10) or essential hypertension (N = 28; P < 0.05), as was cortical perfusion (2.44 ± 0.16 vs. 3.26 ± 0.17 and 3.07 ± 0.09 ml/min/cc tissue, respectively, P < 0.05), but medullary perfusion was similar. Whole kidney, cortical, and medullary perfusion correlated inversely with degree of stenosis in FMD, but not in atherosclerotic RAS. Renal volumes were similar. These results demonstrate that, in contrast to patients with FMD, in patients with atherosclerotic RAS the decrease in cortical perfusion is not directly related to the degree of stenosis in the main renal artery. Factors other than the stenosis itself may play a role in the pathophysiology of atherosclerotic RAS and associated renal failure.

Purpose: The primary aims of this study were to delineate trends in medical comorbidity and surgical approach in patients with renal atherosclerosis and azotemia.Methods: We reviewed 1643 patients undergoing renovascular surgery between 1970 and 1993. We focused on those with the most advanced kidney disease (serum creatinine >2 mg/dl) (n=402). Attention was focused specifically on trends in sex, age, medical risk factors, surgical technique (bypass vs endarterectomy), and outcome including eventual need for long-term dialysis.Results: From 1970 to 1980, 652 patients underwent renovascular surgery, with 98 (15%) having a serum creatinine >2 mg/dl. From 1980 to 1993, the percentage of patients with renal insufficiency increased to 31% (304 of 991) (p

Background An increased number of podocyte-derived extracellular vesicles (pEVs) may reflect podocyte injury in renal disease. Elevated glomerular pressure and other insults may injure podocytes, yet it remains unclear whether the numbers of pEVs are altered in hypertensive patients. We tested the hypothesis that urinary pEV levels would be elevated in patients with renovascular hypertension (RVH) compared with essential hypertension (EH) or healthy volunteers (HVs). Methods We prospectively enrolled patients with EH ( n = 30) or RVH ( n = 31) to study renal blood flow (RBF) and cortical perfusion using multidetector computed tomography under controlled condition (regulated sodium intake and renin-angiotensin blockade). After isolation from urine samples, pEVs (nephrin and podocalyxin positive) were characterized by flow cytometry. Fourteen RVH patients were studied again 3 months after stenting or continued medical therapy. HVs ( n = 15) served as controls. Results The fraction of pEV among urinary EVs was elevated in RVH compared with HVs and EH (11.4 ± 6.4, 6.8 ± 3.4 and 6.3 ± 3.7%, respectively; P < 0.001) and remained unchanged after 3 additional months of therapy and after controlling for clinical parameters. However, eGFR- and age-adjusted pEV levels did not correlate with any clinical or renal parameters. Conclusions In hypertensive patients under controlled conditions, urinary pEV levels are elevated in patients with RVH and low eGFR compared with patients with EH and relatively preserved renal function. These pEVs may reflect podocyte injury secondary to kidney damage, and their levels might represent a novel therapeutic target.

Atherosclerotic renal artery stenosis (ARAS) raises blood pressure and can reduce kidney function. Revascularization of the stenotic renal artery alone does not restore renal medullary structure and function. This study tested the hypothesis that addition of mesenchymal stem cells (MSC) to percutaneous transluminal renal angioplasty (PTRA) can restore stenotic-kidney medullary tubular transport function and attenuate its remodeling. Twenty-seven swine were divided into three ARAS (high-cholesterol diet and renal artery stenosis) and a normal control group. Six weeks after ARAS induction, two groups were treated with PTRA alone or PTRA supplemented with adipose-tissue-derived MSC (10 × 10(6) cells intra-renal). Multi-detector computed tomography and blood-oxygenation-level-dependent (BOLD) MRI studies were performed 4 weeks later to assess kidney hemodynamics and function, and tissue collected a few days later for histology and micro-CT imaging. PTRA effectively decreased blood pressure, yet medullary vascular density remained low. Addition of MSC improved medullary vascularization in ARAS+PTRA+MSC and increased angiogenic signaling, including protein expression of vascular endothelial growth-factor, its receptor (FLK-1), and hypoxia-inducible factor-1α. ARAS+PTRA+MSC also showed attenuated inflammation, although oxidative-stress remained elevated. BOLD-MRI indicated that MSC normalized oxygen-dependent tubular response to furosemide (-4.3 ± 0.9, -0.1 ± 0.4, -1.6 ± 0.9 and -3.6 ± 1.0 s(-1) in Normal, ARAS, ARAS+PTRA and ARAS+PTRA+MSC, respectively, p

Revascularization improves blood pressure but not renal function in most patients with atherosclerotic renal artery stenosis (ARAS), possibly related to injury incurred during renal reperfusion. Bendavia, a novel tetrapeptide that inhibits mitochondrial permeability transition pore opening, reduces apoptosis, oxidative stress, and ischemia-reperfusion injury in experimental models. However, its potential for improving renal response to revascularization of chronic ARAS is unknown. We hypothesized that adjunct Bendavia would improve renal structure and function after percutaneous transluminal renal angioplasty (PTRA). Pigs were treated after 6 weeks of ARAS or control with PTRA+stenting (or sham), adjunct continuous 4-hour infusion of Bendavia (0.05 mg/kg IV) or vehicle (n=7 each) during PTRA. Single-kidney renal blood flow and glomerular filtration rate were studied 4 weeks later and renal mitochondrial biogenesis, microvascular architecture, and injurious pathways evaluated ex vivo. Monocyte chemoattractant protein-1 levels rose after PTRA, suggesting inflammatory injury. Bendavia did not immediately affect inflammatory cytokine levels, yet 4 weeks later, stenotic kidney renal blood flow and glomerular filtration rate both improved (44.00 ± 0.21% and 36.40 ± 10.21%, respectively) in ARAS+PTRA+Bendavia compared with ARAS+PTRA+vehicle. Renal mitochondrial biogenesis was restored after PTRA+Bendavia, and microvascular rarefaction, apoptosis, oxidative stress, tubular injury, and fibrosis decreased. Infusion of Bendavia during PTRA preserved mitochondrial biogenesis, renal hemodynamics, and function, and attenuated tissue injury in swine ARAS. Thus, functional mitochondrial injury during renal reperfusion may sustain renal inflammatory injury and limit kidney recovery after PTRA. Potent antiapoptotic and antioxidant effects provide Bendavia a novel therapeutic potential for improving kidney outcomes after PTRA in experimental ARAS.

Background— The selection of patients with renal artery stenosis (RAS) likely to improve glomerular filtration rate (GFR) after percutaneous transluminal renal angioplasty is difficult. We examined basal hemodynamic and inflammatory factors linked to improved stenotic kidney (STK) function after percutaneous transluminal renal angioplasty in swine RAS. Methods and Results— Fifteen pigs after 6 weeks of hemodynamically significant RAS were studied before and 4 weeks after technically successful percutaneous transluminal renal angioplasty+stenting. STK and contralateral kidney hemodynamics and function were evaluated by multidetector computed-tomography before and after acetylcholine challenge. Single-kidney deoxyhemoglobin (R2*, reciprocal to blood relaxation) and energy-dependent tubular function were assessed using blood-oxygen-level–dependent magnetic resonance imaging before and after furosemide. Baseline renal vein and inferior vena cava levels of inflammatory markers were measured and their gradient and net release calculated. Baseline parameters were compared with normal (n=7) and sham-RAS (n=7) pigs and correlated with the change in STK-GFR after revascularization (ΔGFR). Four weeks after percutaneous transluminal, renal angioplasty blood pressure was normalized in all animals, but STK-GFR improved in 10 of 15 (ΔGFR =+22.0±8.5 mL/min). ΔGFR correlated inversely with basal STK-GFR, renal release of inflammatory markers, and medullary R2* response to furosemide, but directly with GFR response to acetylcholine. Basal contralateral kidney GFR correlated directly with ΔGFR. Conclusions— Low basal STK-GFR with preserved response to acetylcholine may predict benefit from revascularization in RAS, whereas renal inflammation and robust STK-R2* responses to furosemide (possibly reflecting avid tubular oxygen consumption) are associated with less favorable outcomes. These tools may be useful for identification of patients likely to improve renal function after revascularization.

Determinants of Intra-renal oxygenation in human RVD are poorly understood. Blood oxygen level-dependent (BOLD) MRI measures deoxyhemoglobin (R2*) to determine cortical and medullary R2* which have focal variations and gradients. We hypothesized that tissue fractional hypoxia (% of axial kidney area with R2*>30s -1 ) would correlate better with tissue perfusion, renal blood flow (RBF), and O2 consumption than using regions of interest (ROI). METHODS: Inpatient studies were performed in EH (n=68 kidneys), and high-grade RVD (n=18 kidneys, 71±5.5% occlusion) before and 3 months after stents. All were treated with ACE/ARB Rx and thiazides during 150 mEq/d Na+ intake. BOLD MR images were obtained at 3T before and after furosemide (20mg IV), and axial images analyzed to estimate R2* levels above 30s -1 (fractional hypoxia) over the entire kidney section. Maximal R2* levels using regions of interest (ROIs) also were determined. Single-kidney cortical and medullary RBF (ml/min) perfusion (ml/min/cc) were determined by MDCT. Results: RBF was lower in kidneys with untreated RVD than EH (285.6±141 vs. 399±159 ml/min p Conclusions: These data demonstrate for the first time that fractional hypoxia in the kidney is directly related to chronically reduced blood flow and cortical perfusion in human RVD, whereas selective ROI-based measures identified only minor changes in peak R2* gradients between cortex and medulla. The reversibility of fractional hypoxia after stenting supports the use of this new method to identify critical renovascular lesions.

Introduction: Morbidity and mortality attributable to hypertension are higher in African American (AAEH) compared to Caucasian essential hypertensive (EH) patients, possibly related to a differential effect on vascular injury and repair. While circulating endothelial progenitor cells (EPC) preserve endothelial integrity IEC detach from sites of injury and represent markers of vascular damage. We hypothesized that plasma levels of IEC and inflammatory markers would be higher in AAEH compared to EH patients. METHODS: Inferior vena cava levels of CD34+/KDR+ (EPC) and VAP-1+ (IEC) cells were measured by FACS in EH and AAEH under fixed sodium intake (150 mEq/d) and blockade of the renin-angiotensin-system, and compared to systemic levels in normotensive control subjects (n=19 each). Systemic levels of inflammatory cytokines and EPC homing factors were measured by Luminex. Results: Blood pressure, serum creatinine, lipids, antihypertensive medications, and EPC levels did not differ between EH and AAEH patients. Circulating IEC were higher in AAEH, and inversely correlated with EPC levels (Figure). Systemic levels of inflammatory cytokines and EPC homing factors were higher in AAEH compared to EH patients (Table), and correlated directly with IEC. Conclusion: Despite preserved kidney function and controlled BP, circulating inflammatory markers were elevated in AAEH and correlated with increased IEC and decreased EPC levels. Increased release of cytokines and IEC in AAEH may impair EPC reparative capacity and predispose to hypertensive vascular injury. This process may aggravate vascular damage and accelerate hypertension-related morbidity/mortality rates in AAEH.

The kidney plays a central role in the regulation of arterial blood pressure. A large body of experimental and physiological evidence indicates that renal control of extracellular volume and renal perfusion pressure are closely involved in maintaining the arterial circulation and blood pressure. Renal artery perfusion pressure directly regulates sodium excretion-a process known as pressure natriuresis-and influences the activity of various vasoactive systems such as the renin-angiotensin-aldosterone system. As a result, many researchers argue that identifying any marked rise in blood pressure requires resetting of the relationship between arterial blood pressure and urinary sodium excretion, which can occur by an array of systemic or local mechanisms. Almost all of the monogenic forms of hypertension affect sites in the kidney associated with sodium handling and transport. Experimental models of spontaneous hypertension, such as the Dahl salt-sensitive rat, have been used to study the effects of kidney transplantation on blood pressure. Results from studies of kidney transplantation indicate that pressure sensitivity to sodium intake 'follows' the kidney, meaning that the recipient of a 'salt-resistant kidney' acquires sodium resistance, and that the recipient of a 'salt-sensitive kidney' acquires pressure sensitivity. The examples above and discussed in this Review demonstrate that it should come as no surprise that most disorders that affect the kidney or the renal vasculature commonly lead to secondary forms of hypertension.

Aims The mechanisms mediating kidney injury and repair in humans with atherosclerotic renal artery stenosis (ARAS) remain poorly understood. We hypothesized that the stenotic kidney releases inflammatory mediators and recruits progenitor cells to promote regeneration. Methods and results Essential hypertensive (EH) and ARAS patients ( n = 24 each) were studied during controlled sodium intake and antihypertensive treatment. Inferior vena cava (IVC) and renal vein (RV) levels of CD34+/KDR+ progenitor cells, cell adhesion molecules, inflammatory biomarkers, progenitor cell homing signals, and pro-angiogenic factors were measured in EH and ARAS, and their gradient and net release compared with systemic levels in matched normotensive controls ( n = 24). Blood pressure in ARAS was similar to EH, but the glomerular filtration rate was lower. Renal vein levels of soluble E-Selectin, vascular cell adhesion molecule-1, and several inflammatory markers were higher in the stenotic kidney RV vs. normal and EH RV ( P < 0.05), and their net release increased. Similarly, stem-cell homing factor levels increased in the stenotic kidney RV. Systemic CD34+/KDR+ progenitor cell levels were lower in both EH and ARAS and correlated with cytokine levels. Moreover, CD34+/KDR+ progenitor cells developed a negative gradient across the ARAS kidney, suggesting progenitor cell retention. The non-stenotic kidney also showed signs of inflammatory processes, which were more subtle than in the stenotic kidney. Conclusion Renal vein blood from post-stenotic human kidneys has multiple markers reflecting active inflammation that portends kidney injury and reduced function. CD34+/KDR+ progenitor cells sequestered within these kidneys may participate in reparative processes. These inflammation-related pathways and limited circulating progenitor cells may serve as novel therapeutic targets to repair the stenotic kidney.

Renovascular disease, especially atherosclerotic renal artery stenosis (ARAS) in older subjects, is commonly encountered in clinical practice. This is at least in part due to the major advances in non-invasive imaging techniques that allow greater diagnostic sensitivity and accuracy than ever before. Despite increased awareness of ARAS, renal revascularization is less commonly performed, likely as a result of several prospective, randomized, clinical trials which fail to demonstrate major benefits of renal revascularization beyond medical therapy alone. Primary care physicians are less likely to investigate renovascular disease and nephrologists likely see more patients after a period of unsuccessful medical therapy with more advanced ARAS. The goal of this review is to revisit current diagnostic and therapeutic paradigms in order to characterize more clearly which patients will likely benefit from further evaluation and intensive treatment of renal artery stenosis.

Endothelial progenitor cells (EPC) and mesenchymal stem cells (MSC) augment tissue repair but possess slightly different properties. How the cellular phenotype affects the efficacy of this approach in renovascular disease is incompletely understood. This study tested the hypothesis that EPC and MSC protect the poststenotic kidney by blunting different disease pathways. Peripheral blood EPC and adipose-derived MSC were expanded and characterized by cell surface markers (e.g., CD34/kinase insert domain receptor, or CD44/CD90). Single-kidney hemodynamics and function were assessed in pigs after 10 weeks of renal artery stenosis (RAS) treated 4 weeks earlier with an intrarenal infusion of vehicle (n = 7), EPC (RAS+EPC) or MSC (RAS+MSC) (both 10 × 106, n = 6), and normal controls (n = 7). Kidney disease mechanisms were evaluated ex vivo. The ability of EPC and MSC to attenuate endoplasmic reticulum (ER) stress was also studied in isolated ER and in tubular cells cocultured with EPC and MSC. Glomerular filtration rate in RAS was lower than controls, increased in RAS+EPC, and further improved in RAS+MSC, although both improved renal blood flow similarly. EPC prominently enhanced renal growth factor expression and decreased oxidative stress, while MSC more significantly attenuated renal inflammation, ER stress, and apoptosis. Furthermore, MSC induced a greater decrease in caspase-3 and CHOP expression in cultured tubular cells through mechanisms involving cell contact. EPC and MSC achieve a comparable decrease of kidney injury in RAS by different mechanisms, although MSC elicited slightly superior improvement of renal function. These results support development of cell-based approaches for management of renovascular disease and suggest cell selection based on the underlying pathophysiology of kidney injury.

Reno-protective strategies are needed to improve renal outcomes in patients with atherosclerotic renal artery stenosis (ARAS). Adipose tissue-derived mesenchymal stem cells (MSCs) can promote renal regeneration, but their potential for attenuating cellular injury and restoring kidney repair in ARAS has not been explored. We hypothesized that replenishment of MSC as an adjunct to percutaneous transluminal renal angioplasty (PTRA) would restore renal cellular integrity and improve renal function in ARAS pigs. Four groups of pigs (n = 7 each) were studied after 16 weeks of ARAS, ARAS 4 weeks after PTRA and stenting with or without adjunct intrarenal delivery of MSC (10 × 10(6) cells), and controls. Stenotic kidney blood flow (renal blood flow [RBF]) and glomerular filtration rate (GFR) were measured using multidetector computer tomography (CT). Renal microvascular architecture (micro-CT), fibrosis, inflammation, and oxidative stress were evaluated ex vivo. Four weeks after successful PTRA, mean arterial pressure fell to a similar level in all revascularized groups. Stenotic kidney GFR and RBF remained decreased in ARAS (p = .01 and p = .02) and ARAS + PTRA (p = .02 and p = .03) compared with normal but rose to normal levels in ARAS + PTRA + MSC (p = .34 and p = .46 vs. normal). Interstitial fibrosis, inflammation, microvascular rarefaction, and oxidative stress were attenuated only in PTRA + MSC-treated pigs. A single intrarenal delivery of MSC in conjunction with renal revascularization restored renal hemodynamics and function and decreased inflammation, apoptosis, oxidative stress, microvascular loss, and fibrosis. This study suggests a unique and novel therapeutic potential for MSC in restoring renal function when combined with PTRA in chronic experimental renovascular disease.

To the Editor: Hypertension continues to be an important public health problem, with a substantial proportion of patients failing to achieve optimal blood pressure (BP) control. Recent data suggest that hypertension is characterized by a relative deficiency of the natriuretic peptide system, which has cardiorenal and vascular protective properties.1,2 Furthermore, we previously demonstrated that B-type natriuretic peptide (BNP) supplementation has BP-lowering actions in models of acute and chronic experimental hypertension.3,4 With all of this in mind, we designed a pilot study to investigate the effects of low-dose subcutaneous (SQ) BNP (nesiritide; Scios, Inc, Mountain View, CA) in patients with uncontrolled hypertension despite the use of conventional antihypertensive therapy. Herein we report the results from the first patient enrolled for the safety and dose-finding study (Trial Registration clinicaltrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00953472","term_id":"NCT00953472"}}NCT00953472; “B-Type Natriuretic Peptide [BNP] in Human Hypertension”), for which funding is currently being pursued. A 59-year-old white man (weight, 79 kg; body mass index, 27 kg/m2) with office BP of 150/90 mm Hg despite treatment with an angiotensin receptor blocker (losartan, 50 mg once a day orally) and a diuretic (hydrochlorothiazide, 25 mg once a day orally) consented to participate in this study. Ambulatory BP monitoring indicated hypertension (while awake: 148/87 mm Hg; heart rate, 67 beats/min; during sleep: 132/76 mm Hg; heart rate, 51 beats/min). Results of physical examination and laboratory analyses were normal, with no signs of secondary hypertension or renal insufficiency (serum creatinine, 0.8 mg/dL; to convert to μmol/L, multiply by 88.4). The patient was on a no-added-salt diet (120 mEq of sodium per day) for 7 days before admission to the Clinical Research Unit at Mayo Clinic. The Figure illustrates BP levels before and after repeated administration of 10 μg/kg of SQ BNP. (The dose was based on experience in patients with heart failure.5) On the morning of the study the patient withheld his standard medications to receive the first SQ BNP dose. Systolic and diastolic BP decreased (from 148/86 to 105/72 mm Hg) and remained reduced for the following 12 hours. Twelve hours after the first SQ BNP injection, the second dose was administered, and a reduction of both systolic and diastolic BP (from 123/75 to 101/56 mm Hg) followed, with no other antihypertensive therapy being given. On the following morning, 12 hours after the second dose, BP was 135/81 mm Hg. Again, the patient's standard medications were withheld. and the last dose of SQ BNP was given, which induced a BP reduction (from 135/81 to 113/74 mm Hg). The patient was discharged with a BP of 121/78 mm Hg and instructed to restart his standard therapy the following day. Plasma BNP1-32 increased from 53 pg/mL before treatment to 72 pg/mL 4 hours after the last injection; in contrast, corresponding plasma levels of endogenous N-terminal proBNP1-76 decreased from 48 pg/mL to 22 pg/mL. (to convert to pmol/L, multiply BNP1-32 by 0.289 and NT-proBNP1-76 by 0.118, respectively.) FIGURE Hyoptensive effects of 10 μg/kg of SQ BNP in a patient with uncontrolled hypertension. DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure; SQ BNP = subcutaneous B-type natriuretic peptide. Thus, this patient demonstrated effective BP reduction after BNP administration. This study was designed to assess the safety of low-dose (10 μg/kg) BNP, which normalized BP for the duration of the study without additional therapy. These encouraging results support further studies with SQ BNP as a potential antihypertensive drug, perhaps in combination with standard therapy, in patients who have resistant hypertension or poorly controlled BP.

Objectives To present the epidemiologic and clinical features of renovascular disease and discuss various diagnostic approaches. Design We describe the findings in patients with fibromuscular dysplasia or atherosclerotic disease of the renal arteries and review pertinent studies from the literature. Results Renovascular disease is an important cause of resistant hypertension and progressive renal insufficiency, particularly in the elderly population. Improved blood pressure control and renal function after revascularization have generated intense interest in identifying those patients likely to benefit from this intervention. Fibromuscular dysplasia and atherosclerotic renal artery stenosis account for most cases of renovascular disease. Both entities produce resistant hypertension; the latter is the more common cause of progressive renal insufficiency—occasionally leading to end-stage renal disease. Angiotensin-Converting enzyme inhibitor-related renal dysfunction, otherwise unexplained renal insufficiency, and recurrent pulmonary edema are increasingly recognized clinical manifestations of renovascular disease. Traditional screening tests such as intravenous pyelography, intravenous digital subtraction angiography, radionuclide scintirenography, and measurement of the peripheral venous plasma renin activity have limited accuracy for diagnosing renal artery stenosis and do not accurately predict the blood pressure response to revascularization. In comparison, recently developed noninvasive tests such as Captopril renography, renal artery duplex sonography, and magnetic resonance angiography seem to be more accurate and, in the case of Captopril renography, may be more predictive of the blood pressure response to revascularization. Conclusion Future directions in the area of renovascular disease should include a direct comparison among these new noninvasive diagnostic techniques, with a particular focus on the identification of those patients most likely to benefit from revascularization in terms of both blood pressure control and improved renal function.

Objective To describe the features and mechanisms of posttransplantation hypertension and suggest appropriate management of the disorder. Design We review our own experience and reports from the literature on hypertension in cyclosporine A (CSA)-treated transplant recipients. Results Soon after immunosuppression with CSA and corticosteroids, hypertension develops in most patients who undergo transplantation. The blood pressure increases, which are usually moderate, occur universally because of increased peripheral vascular resistance. Disturbances in circadian patterns of blood pressure lead to loss of the normal nocturnal decline, a feature that magnifies hypertensive target effects. Changes in blood pressure sometimes are severe and associated with rapidly developing target injury, including intracranial hemorrhage, left ventricular hypertrophy, and microangiopathic hemolysis. The complex mechanisms that underlie this disorder include alterations in vascular reactivity that cause widespread vasoconstriction. Vascular effects in the kidney lead to reduced glomerular filtration and impaired sodium excretion. Many of these changes affect local regulation of vascular tone, including stimulation of endothelin and suppression of vasodilating prostaglandins. Effective therapy includes use of vasodilating agents, often calcium channel blocking drugs. Caution must be exercised to avoid interfering with the disposition of CSA or aggravating adverse effects relative to kidney and electrolyte homeostasis. Conclusion Recognition and treatment of CSA-induced hypertension and vascular injury are important elements in managing the transplant recipient.

Recent attention has focused on renovascular compromise as a cause of chronic renal failure. The sequence by which kidneys functioning near the limits of "critical perfusion pressures" develop parenchymal injury is not well understood. We studied poststenotic renal pressures, glomerular volume, and renal function in conscious rats using an aortic coarct model during antihypertensive therapy with sodium restriction and angiotensin-converting enzyme inhibition over 4 weeks. These were compared with acute reduction of renal pressures using aortic ligation. Both models reduced poststenotic pressures to 50 to 60 mm Hg. Total aortic ligation produced tubular necrosis and glomerular collapse with 40-fold elevated urinary N-acetyl-glucosaminidase excretion. In contrast, angiotensin-converting enzyme inhibition reduced renal blood flow by 30% without evident disruption in tubular function, reflected by low fractional excretion of sodium levels and normal excretion of N-acetyl-glucosaminidase. The glomerular filtration rate and filtration fraction were reduced. These results indicate that gradual reduction of renal perfusion pressure produces functional and morphologic consequences different from those observed with acute ischemic injury. Mechanisms by which chronic renal perfusion deficits produce tissue injury are reviewed and may include disruption of vascular regulation, energy storage molecules, cellular ion gradients, free radical generation, and disruption of cytoskeletal configuration and repair mechanisms. Further study of the pathways of chronic renal parenchymal injury beyond arterial stenosis is essential to achieve rational intervention and revascularization in humans.

We conducted a treatment trial to determine the relative toxicity of FK-506 and cyclosporine A (CSA) in liver transplant recipients.Between October 1990 and October 1991, 37 patients were enrolled in an open-labeled, randomized study of two immunosuppressive regimens after liver transplantation.Of the 23 men and 14 women, 20 received FK-506 plus prednisone, and 17 received CSA plus prednisone and azathioprine. Renal function was assessed before and after transplantation (day 1, month 1, month 4, and month 12) by measurements of serum creatinine (SCr) and glomerular filtration rate (GFR) as determined by urinary iothalamate or creatinine clearance (or both). FK-506 trough plasma levels (enzyme immunoassay) were to be maintained between 0.2 and 5.0 ng/mL, and CSA trough blood levels (whole blood high-performance liquid chromatography) were to be maintained between 250 and 400 ng/mL. Severe nephrotoxicity was defined as sudden decreases in urine output to less than 10 mL/h or rapid increases in SCr (more than 0.5 mg/dL daily) that necessitated withdrawal of study medication for more than 48 hours. Mean patient age and values for SCr and GFR were comparable between the two groups at entry.Both study groups demonstrated a similar deterioration in renal function during a 12-month follow-up, although patients who received FK-506 had a significantly (P0.05) lower GFR when measured at 12 months than did patients treated with CSA (45 +/- 4 versus 64 +/- 6 mL/min per body surface area). Mild nephrotoxicity that responded to decreased drug doses was noted in 9 CSA-treated patients (53%) and 10 FK-506-treated patients (50%). Severe nephrotoxicity that necessitated drug withdrawal occurred in only four patients, all of whom were in the FK-506 group. These severe nephrotoxic reactions to FK-506 occurred early after transplantation, often during intravenous administration of the drug, and were not associated with poor liver allograft function or drug levels outside the therapeutic range.Both FK-506 and CSA are significantly nephrotoxic in liver transplant recipients. In this trial, however, we observed an early development of severe nephrotoxic reactions only in some patients who received FK-506.

African Americans develop hypertension earlier with more target manifestations than whites despite having a higher glomerular filtration rate (GFR) for any level of serum creatinine. STUDY DESIGNPARTICIPANTS: This study tested the hypothesis that increased GFR and sodium reabsorption in African Americans is associated with increased metabolic work and medullary hypoxia in 49 nondiabetic patients with essential hypertension (29 whites and 20 African Americans) following a constant-sodium diet (150 mEq/d) and renin-angiotensin system blockade.Ethnicity, age, measured GFR, sodium excretion, and body mass index.We examined cortical and medullary volumes and blood flows using multidetector computed tomography and intrarenal deoxyhemoglobin (R2*) using blood oxygen level-dependent magnetic resonance.Blood pressure and sodium excretion were similar, whereas African Americans were more obese and had higher iothalamate GFRs. Renal cortical volumes did not differ, but medullary volumes adjusted for body size and age were higher in African Americans (32.3 ± 11.2 vs 25.1 ± 7.4 cm(3)/m(2) body surface area; P0.001). Sodium reabsorption and blood flows were higher in African Americans. Basal cortical deoxyhemoglobin values were similar between ethnic groups, whereas medullary R2* was higher in African Americans (39.7 ± 5.1 vs 36.3 ± 6.5/s; P = 0.02), but decreased to levels similar to whites after furosemide treatment. Levels of the circulating isoprostane prostaglandin F(2α) were higher in African Americans and daily urinary prostaglandin F(2α) excretion in African Americans correlated directly with renal blood flow (R = 0.71; P0.01).Studies were limited to treated volunteers with normal kidney function without knowledge of prior nutrient intake.These data show for the first time that increased sodium reabsorption in obese African American patients with hypertension was associated with enlarged medullary volumes, functional hypoxia related to solute reabsorption, and a direct relationship between blood flows and urinary isoprostane levels. Our results support a model of increased oxygen consumption and oxidative stress in African Americans that may accelerate hypertension and target-organ injury compared with white patients with essential hypertension.