Textor, Stephen C.

Cyclosporine induces hypertension and wide-spread vasoconstriction after transplantation in addition to reducing kidney function. We studied hemodynamic, renal, and hormonal effects of monotherapy with nifedipine XL (n = 37) in liver transplant recipients within a year after transplant (median, 4.4 months). Systemic hemodynamics were determined with thoracic electrical bioimpedance. Blood pressure before therapy was 172 +/- 4/108 +/- 2 mm Hg. Sixty-four percent of recipients achieved blood pressures less than 140/90 mm Hg mediated by a fall in systemic vascular resistance index (2427 +/- 245 dyne.s.cm-5.m-2 in responders versus 2905 +/- 281 in nonresponders, P < .01). Despite the fall in systemic vascular resistance, glomerular filtration rates were not changed during nifedipine therapy, as measured by both creatinine and iothalamate clearances. Urinary prostacyclin (6-ketoprostaglandin F1 alpha) was suppressed below normal from 2468 +/- 323 ng/d before transplant to 1103 +/- 99 ng/d (P < .01) after transplant and did not change during nifedipine therapy. Urinary thromboxane B2 and plasma renin activity also fell after transplant and remained low during nifedipine. These data demonstrate that nifedipine can reverse systemic vasoconstriction associated with hypertension after transplantation. Systemic effects were not transmitted to the kidney sufficiently to improve glomerular filtration rate or reverse hormonal changes within the kidney. Hence, vascular and functional regulation of the kidney was dissociated from the systemic circulation during nifedipine administration after transplantation.

Hypertension develops in most patients after transplantation when immunosuppression is based on cyclosporine and prednisone. The pathogenesis appears to be multifactorial but involves rapidly rising vasoconstrictor tone in renal and systemic vascular beds. Much of this tone reflects abnormal vascular function, characterized by impaired prostacyclin and EDRF effects, in conjunction with increased vasoconstriction due to endothelin and possibly other factors. Effective management of the transplant recipient depends on preventing excessive vasoconstriction, usually with calcium channel blocking agents.

Studies of normotensive offspring of hypertensive parents offer the potential to identify inherited abnormalities that contribute to essential hypertension. We compared renal and systemic hemodynamic responses to saline infusion between normotensive sons of two hypertensive parents (SOHT) and sons of two normotensive parents (SONT) selected from the general population of Rochester, Minn. Hemodynamic measurements were performed after a week of low sodium intake (10 meq/day) and were repeated after a week of high sodium intake (200 meq/day). Despite being in the normotensive range, blood pressures in SOHT were higher than those in SONT during low sodium (124 +/- 3/85 +/- 3 versus 118 +/- 2/71 +/- 2 mm Hg, p less than 0.01) and high sodium (122 +/- 3/80 +/- 3 versus 112 +/- 2/70 +/- 2 mm Hg, p less than 0.05) conditions. Higher pressures in SOHT were associated with elevated systemic and renal vascular resistance. After a high sodium diet, renal vascular resistance in SOHT rose further during acute saline infusion, whereas systemic vascular resistance did not change. After a low sodium diet, this renal vasoconstrictor response to saline infusion in SOHT was not present, and renal vascular resistance fell to levels not different from SONT. Plasma renin activity, aldosterone, and atrial natriuretic peptide did not differ between SONT and SOHT. Circulating levels of norepinephrine were higher in SOHT. These data demonstrate a renal vasoconstrictor response to saline infusion in normotensive SOHT, which depends on prior sodium intake. This alteration in renal hemodynamics may represent an inherited abnormality related to the development of hypertension.

Renal artery stenosis (RAS) promotes microvascular rarefaction and fibrogenesis, which may eventuate in irreversible kidney injury. We have shown that percutaneous transluminal renal angioplasty (PTRA) or endothelial progenitor cells (EPC) improve renal cortical hemodynamics and function in the poststenotic kidney. The renal medulla is particularly sensitive to hypoxia, yet little is known about reversibility of medullary injury on restoration of renal blood flow. This study was designed to test the hypothesis that PTRA, with or without adjunct EPC delivery to the stenotic kidney, may improve medullary remodeling and tubular function. RAS was induced in 21 pigs using implantation of irritant coils, while another group served as normal controls ( n = 7 each). Two RAS groups were then treated 6 wk later with PTRA or both PTRA and EPC. Four weeks later, medullary hemodynamics, microvascular architecture, and oxygen-dependent tubular function of the stenotic kidneys were examined using multidetector computed tomography, microcomputed tomography, and blood oxygenation level-dependent MRI, respectively. Medullary protein expression of vascular endothelial growth factor, endothelial nitric oxide synthase, hypoxia-inducible factor-1α, and NAD(P)H oxidase p47 were determined. All RAS groups showed decreased medullary vascular density and blood flow. However, in RAS+PTRA+EPC animals, EPC were engrafted in tubular structures, oxygen-dependent tubular function was normalized, and fibrosis attenuated, despite elevated expression of hypoxia-inducible factor-1α and sustained downregulation of vascular endothelial growth factor. In conclusion, EPC delivery, in addition to PTRA, restores medullary oxygen-dependent tubular function, despite impaired medullary blood and oxygen supply. These results support further development of cell-based therapy as an adjunct to revascularization of RAS.

Although the two-kidney, one-clip (2K1C) model is widely used as a model of human renovascular hypertension, mechanisms leading to the development of fibrosis and atrophy in the cuffed kidney and compensatory hyperplasia in the contralateral kidney have not been defined. Based on the well-established role of the transforming growth factor (TGF)-β signaling pathway in renal fibrosis, we tested the hypothesis that abrogation of TGF-β/Smad3 signaling would prevent fibrosis in the cuffed kidney. Renal artery stenosis (RAS) was established in mice with a targeted disruption of exon 2 of the Smad3 gene (Smad3 KO) and wild-type (WT) controls by placement of a polytetrafluoroethylene cuff on the right renal artery. Serial pulse-wave Doppler ultrasound assessments verified that blood flow through the cuffed renal artery was decreased to a similar extent in Smad3 KO and WT mice. Two weeks after surgery, systolic blood pressure and plasma renin activity were significantly elevated in both the Smad3 KO and WT mice. The cuffed kidney of WT mice developed renal atrophy (50% reduction in weight after 6 wk, P < 0.0001), which was associated with the development of interstitial fibrosis, tubular atrophy, and interstitial inflammation. Remarkably, despite a similar reduction of renal blood flow, the cuffed kidney of the Smad3 KO mice showed minimal atrophy (9% reduction in weight, P = not significant), with no significant histopathological alterations (interstitial fibrosis, tubular atrophy, and interstitial inflammation). We conclude that abrogation of TGF-β/Smad3 signaling confers protection against the development of fibrosis and atrophy in RAS.

Atherosclerotic renal artery stenosis has a range of manifestations depending on the severity of vascular occlusion. The aim of this study was to examine whether exceeding the limits of adaptation to reduced blood flow ultimately leads to tissue hypoxia, as determined by blood oxygen level dependent MRI. We compared 3 groups of hypertensive patients, 24 with essential hypertension, 13 with “moderate” (Doppler velocities 200–384 cm/s), and 17 with “severe” atherosclerotic renal artery stenosis (ARAS; velocities >384 cm/s and loss of functional renal tissue). Cortical and medullary blood flows and volumes were determined by multidetector computed tomography. Poststenotic kidney size and blood flow were reduced with ARAS, and tissue perfusion fell in the most severe lesions. Tissue medullary deoxyhemoglobin, as reflected by R2* values, was higher as compared with the cortex for all of the groups and did not differ between subjects with renal artery lesions and essential hypertension. By contrast, cortical R2* levels were elevated for severe ARAS (21.6±9.4 per second) as compared with either essential hypertension (17.8±2.3 per second; P <0.01) or moderate ARAS (15.7±2.1 per second; P <0.01). Changes in medullary R2* after furosemide administration tended to be blunted in severe ARAS as compared with unaffected (contralateral) kidneys. These results demonstrate that severe vascular occlusion overwhelms the capacity of the kidney to adapt to reduced blood flow, manifest as overt cortical hypoxia as measured by blood oxygen level–dependent MRI. The level of cortical hypoxia is out of proportion to the medulla and may provide a marker to identify irreversible parenchymal injury.

Metabolic syndrome (MetS) is associated with glomerular hyperfiltration and is a risk factor for chronic kidney disease, but the underlying mechanisms are poorly defined. This study tested the hypothesis that increased glomerular filtration rate (GFR) in early MetS is associated with renal adiposity and microvascular proliferation. Twelve MetS-prone Ossabaw pigs were randomized to 10 wk of a standard (lean, n = 6) or atherogenic (MetS, n = 6) diet. Kidney hemodynamics and function, perirenal fat volume, and tubular dynamics were assessed in vivo by multidetector computed tomography (CT) and blood oxygen level-dependent (BOLD)-MRI. Microvascular architecture was assessed ex vivo with micro-CT. Candidate injury mechanisms were evaluated in kidney tissue by Western blotting and histology. Basal GFR, renal blood flow, and renal cortical perfusion and volume were elevated in the MetS group. Perirenal and kidney tissue fat, proximal-nephron intratubular fluid concentration, and endothelial nitric oxide synthase expression were increased in MetS. GFR levels correlated with tissue triglyceride levels. Elevated spatial density of 20- to 40-μm cortical microvessels was accompanied by mild oxidative stress, inflammation, and with proximal tubular vacuolization. Medullary size and perfusion were relatively preserved, and BOLD-MRI showed intact medullary tubular response to furosemide. Increased GFR in early MetS is associated with renal adiposity and microvascular proliferation, which involve mainly the renal cortex and precede significant activation of oxidative stress and inflammation. Renal adiposity and proliferative microvessels may represent novel therapeutic targets for preserving renal function in early MetS.

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.