ACE- Inhibitor-Enhanced MR Evaluation of Renovascular Hypertension

Overview

Status: Recruiting
Keywords: Renal Artery Stenosis , Hypertension , ACE Inhibitors , Magnetic Resonance Imaging , Renal Insufficiency, Chronic , Kidney Failure, Chronic
IRB Number: 00050500
Specialty: Radiology
Sub Specialties: Magnetic Resonance Imaging – MRI

Brief Summary

Renal artery stenosis is thought to be responsible for up to 5% of all cases of hypertension. Conventional x-ray angiography is considered the gold standard for the diagnosis of renal artery stenosis, but is an invasive procedure requiring use of iodinated, nephrotoxic contrast and ionizing radiation. Therefore, for screening patients with suspected renovascular hypertension, nuclear medicine scans performed with ACE-inhibitors such as captopril or enalaprilat are currently the procedure of choice. Renal scans do not visualize the renal arteries, but determine indirectly, through functional information about the perfusion and excretion of agents such as technetium-DTPA, whether there is physiologically significant renal artery stenosis. ACE-inhibitors enhance the sensitivity and specificity of renal scintigraphy by unmasking physiologically significant renal artery stenosis that is compensated for by efferent arteriolar constriction [1,2].
 
Because of its non-nephrotoxic contrast agent (gadolinium-DTPA), magnetic resonance (MR) imaging of the renal arteries is rapidly becoming a preferred alternative method for imaging the renal arteries in patients, especially those with renal insufficiency. The similarity between gadolinium-DTPA and the nuclear medicine agent used, technetium-99-DTPA, both established glomerular agents, has lead recent investigators to evaluate whether MR imaging could be used to acquire the same functional information as nuclear medicine renal scans [3,4]. In an earlier study performed at NYU, we evaluated 36 patients with suspected renovascular disease with a two-dimensional MR imaging technique before and after an ACE-inhibitor (enalaprilat). We demonstrated the clinical feasibility and safety of this ACE-inhibitor enhanced MR renography [5]. Limitations of the previous study include inadequate Gd-DTPA doses for evaluation of patients with renal insufficiency [6] and limited coverage of the kidneys and aorta with the two-dimensional imaging methods. With recent advances in MR hardware and software, fast three-dimensional imaging techniques are now available that can be used for MR renography. We have validated these methods [7] and now propose to implement and test ACE-inhibitor-enhanced 3D MR renography for the evaluation of patients with suspected renovascular disease.
 
Additionally, recently Textor et al [8] have demonstrated the potential utility of furosemide-enhanced BOLD imaging in the kidneys for the evaluation of renovascular disease. BOLD (Blood oxygen level dependent) MRI is well-established tool for functional brain imaging and measures tissue deoxygenated hemoglobin through its effects on the spin-spin relaxation time (T2*) in tissues. Textor and colleagues have shown that kidneys with significant RAS have a higher level of deoxyhemoglobin than contralateral nonstenotic kidneys and that the deoxyhemoglobin decreases substantially with administration of furosemide, presumably because of inhibition of the oxygen-consuming sodium/chloride transporters in the thick ascending loop of Henle. Prasad [9] and others have established that BOLD MRI is accurate and reproducible measurement of intrarenal oxygenation in healthy and diseased patients. We propose to supplement our ACE-inhibitor MR renography protocol with furosemide-enhanced BOLD imaging as a means of further increasing its accuracy for the diagnosis of renovascular disease.

In addition, the study will seek to evaluate whether MRI can measure the level of oxygen in the kidneys in diabetics and whether this information helps to evaluate the severity of kidney disease. The BOLD imaging technique, as discussed above, will be the method used to evaluate kidney tissue oxygenation. The difference is we are seeking to evaluate subjects using this technique not only in patients with RAS, but also subjects who have compromised kidney function and are also diabetic.

There are various distinct causes of kidney disease, include diabetes, hypertension, and glomerulonephritis, which all converge to the common pathway of chronic kidney disease.  Hypoxia is thought to be an important correlated and causative factor in the progression of CKD to ESRD (10-12).  As chronic kidney disease worsens, the number of capillaries in the peritubular capillary bed within the renal medulla decreases (13), resulting in decreased medullary oxygen tension.  This in turn contributes to the activation of a complex array of cytokines and other factors leading to tubulointersitial fibrosis and impaired renal function (14), which are the hallmarks of CKD and diabetic nephropathy.

Newly developed therapies are on the horizon which may change the treatment of diabetic nephropathy and other forms of CKD.  There are several mechanisms tied to hypoxia which likely contribute to the progression of CKD that can be targeted with therapeutic interventions.  For instance, the administration of vascular endothelial growth factor (VEGF) in a few studies with animal models of progressive kidney disease and thrombotic microangiopathy has been shown to stimulate aniogenesis, maintain peritubular capillary density, reduce renal interstitial fibrosis, increase the number of glomeruli with intact epithelium, stabilize renal function, and increase the expression of factors which promote renal perfusion (15,16).  Another approach to prevention or amelioration of CKD is the use of pharmacologic agents to prolong the half-life of hypoxia inducible factors (HIFs) in the kidney.  HIFs are transcription factors that are increased in renal hypoxia.  They have an array of effects which are generally protective against cellular damage from hypoxia.  Among these effects is the stimulation of erythropoietin production (17).  A drug inhibiting the breakdown of HIF is currently in phase three clinical trials (Fibrogen FG-4592) for the treatment of anemia in CKD patients not requiring dialysis.  This trial may demonstrate whether HIF promotion improves the clinical course of CKD by correction of anemia, or by other hypoxia protective effects of HIF.  Stem cell therapy with renal progenitor cells may reconstitute glomerular and peritubular capillary beds (reference).  A stage two clinical trial is currently under way (Allocure AC607) to investigate the use of stem cells in acute kidney injury.

Renal BOLD imaging is a non-invasive method to measure hypoxia in the kidneys.  Hypoxia plays a central role in the progression of CKD, and hypoxia and its secondary effects are the targets for promising new therapies.  Thus non-invasively imaging renal hypoxia with renal BOLD may become a centrally important method in evaluating therapy.

 


 

Principal Investigator: Vivian Lee
Department: University of Utah
Co Investigator:

Contact Information

Name:Kristi Carlston
Phone: (801) 585-6142
Email: kristi.carlston@hsc.utah.edu

Inclusion Criteria

All adult patients who are referred for evaluation of possible renovascular hypertension will be asked to participate in this study. Referring physicians will be contacted before patients are asked to participate to ensure that there are no contraindications to ACE-inhibitor administration. Referring physicians will also be asked if it would be clinically acceptable to have patients withhold chronic ACE-inhibitor therapy (if applicable) for 48 hours prior to the MRI study. As with captopril renography, the sensitivity of renographic results have been shown to be greater when chronic ACE-inhibitor therapy is withheld 48 hours prior to imaging and administration of the ACE-inhibitor for the imaging study. Pregnant patients will be excluded.

In addition to subjects with renal artery stenosis, our study includes subjects from the spectrum of diabetic nephropathy, from pre-diabetes or diabetes with no chronic kidney disease to diabetic subjects with end stage renal disease (ESRD) on dialysis.  Our study protocol has been modified to accomodate the inclusion of ESRD subjects, who will undergo a truncated protocol that omits the adminstration of intravenous contrast.  We have also modified the protocol to limit injection of enalaprilat to those subjects with clinically suspected renal artery stenosis.
 
In addition to the subjects described above, we would like to recruit 40-50 healthy volunteers in order to validate the reproducibility of GFR from injection in the absence of an ACE-inhibitor. Therefore, these healthy subjects will not receive the ACE-inhibitor injection. The total duration of the MR examination, including set-up time, will be approximately 1 hour. Subjects will be asked if it is ok to call them for follow up visits if needed.

 
Inclusion:
 
1.Both Genders
 
2. Age > 18

 3.Any ethnic background
 
4.Clinical evidence of RVD

5. Patients with renal insufficiency secondary to diabetic nephropathy
 

6. End stage renal disease with diabetes mellitus.

7. Pre-diabetics and diabetics without evidence of chronic kidney disease

 

Exclusion Criteria

1.Medically  unstable
 
2.Contraindications for MR imaging, including
 
a.Intracranial clips
 
b.Metal implants
 
c.Suspected or confirmed metal in eyes
 
d.Cardiac pacemaker, implanted defibrillator, other implanted electronic devices
 
3.Pregnancy: Pregnancy tests will be offered to women of childbearing age at no cost.
 
4.Patients with  sepsis or major infection, arterial or venous thromobosis.
 
5.History of pro inflammatory conditions and eGFR < 60ml/min/1.72m2
 
6.Allergies or previous adverse reactions to Gd-DTPA (gadopentetate Dimeglumine) or gadoteridol.
 
7.Severe Clautrophobia
 
8. Suspected renal artery stenosis and allergies or previous adverse reactions to ACE-I (such as enalprilat) or subjects thought to be at increased risk for ACE-I- induced renal insufficiency, including those with clinical evidence of renal insufficiency in the setting of a single functioning kidney.
 
9.Allergies or previous adverse reactions to furosemide.
 
10.Any history of Nephrogenc systemic fibrosis (NSF):