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					Fibromuscular Dysplasia (FMD)
                          Table of Contents

   • Fibromuscular Dysplasia Overview
               –   Histology
               –   Components of Vascular System
               –   Pathology
               –   Etiology
               –   Clinical Presentation
               –   Associated Diseases
   • FMD Discussion by Arterial Involvement
               – Renal Arterial Involvement
                    •   Mechanisms of Hypertension
                    •   Natural History
                    •   Diagnosis
                    •   Treatment

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                         Table of Contents (Continued)

   • FMD Discussion by Arterial Involvement (cont.)
               – Carotid Arterial Involvement
                   •   Natural History
                   •   Diagnosis
                   •   Treatment
                   •   Associated Conditions
               – Non-Renal Abdominal Viscera Presentation and Treatment
               – Peripheral Artery Disease
   • Case Studies




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                         Fibromuscular Dysplasia (FMD)

   • Nonatherosclerotic, noninflammatory disease
   • More common in women and younger individuals
               – The incidence of FMD in children is unknown.
   • Described in almost every vascular bed1
               –   Renal arteries (60-75%)
               –   Cervicocranial arteries (25-30%)
               –   Non-renal visceral arteries (9%)
               –   Arteries in the extremities (5%)
               –   Others including pulmonary and coronary arteries
   • Multiple vascular beds in 28% of patients2




                          1Gray   BH et al In Peripheral Vascular Diseases 1996, 2Lüscher TF et al Nephron 1986   3
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                  FMD - Histology of Arteries

   •       Lumen
   •       Endothelium (basal lamina)
   •       Intima
   •       Internal elastic lamina
   •       Media
   •       External elastic lamina
   •       Adventitia




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               Components of the Vascular System




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               Elastic Laminae in a Large Artery




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                       FMD - Pathologic Classification

   • Intimal fibroplasia (less than 10%)
   • Medial dysplasia
               – Medial fibroplasia (80%)
               – Perimedial fibroplasia (10-15%)
               – Medial hyperplasia (1-2%)
   • Adventitial (periarterial) fibroplasia




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0506-0653801                             Harrison EG Jr and McCormack LJ Mayo Clinic Proc 1971
               FMD Pathology - Intimal Fibroplasia

   • Children and young adults
   • Circumferential deposition of collagen in the intima, often
     projecting into lumina
   • Internal elastic lamina may be duplicated or disrupted
     but can be identified
   • Long, irregular (tubular) or focal, smooth (concentric
     band) stenoses1




                                             1Stanley   JC et al Arch Surg 19758
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               FMD Pathology - Intimal Fibroplasia




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                        FMD Pathology - Medial Fibroplasia

   • 25-50 year old women
   • Thickened media alternating with thinned media  aneurysmal
     dilatation
               – “String of beads”
   • Thickened media is replaced by collagen
   • Internal elastic lamina may be thinned or fragmented
               – May lead to macroaneurysm formation1
   • Frequently affects the renal arteries bilaterally




                                                         1Stanley                   10
                                                                    JC Arch Surg 1975
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                       FMD Pathology- Perimedial Fibroplasia

   • 15-30 year old women
   • Collagen deposition in the outer half of the media
     replacing the external elastic lamina; intact adventitial
     connective tissue
               – “String of beads”
               – Can result in severe stenosis
   • Often associated with collateral circulation
   • Preferentially affects the renal artery (mid portion)




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                        FMD Pathology - Adventitial (periarterial) Fibroplasia

   • Adventitial (periarterial) fibroplasia
               – Very rare
               – Collagen replaces the fibrous adventitia
               – May extend beyond artery




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                         FMD - Etiology

   • Genetic
               – Autosomal dominant with variable penetrance in 60% of cases
                 based on “clinical symptoms”1
               – 11% prevalence angiographically2
   • Hormonal
               – No difference in gravidity or parity rates, effect on disease
                 progression3
               – Oral contraceptive pill use?4,5,




                  1Rushton AR Arch Intern Med 1980, 2Pannier-Moreau I et al J of Hypertens 1997, 3Stanley JC et al
                                                                                                                 13
0506-0653801       Arch Surg 1975, 4Sang CH et al Hypertension 1989, 5Hardy-Godon S et al J of Neuroradiol 1979
                       FMD - Etiology

   • Mechanical
               – Ptosis of the right kidney1
               – Repetitive trauma such as hyperextension and rotation of the
                 neck1
   • Mural ischemia
               – Occlusion of the vasa vasorum2
               – Vasospasm (ergotamines, methysergide)3
               – Tobacco use4




                               1LüscherTF et al Mayo Clin Proc 1987, 2Sottiurai V et al J of Surg Res 1978,14
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                                     3Fievez ML Med Hypotheses 1984, 4Sang CN et al Hypertension1989
                        FMD - Clinical Presentation

   • Asymptomatic
   • Nonspecific symptoms
               – Headaches, altered mentation, tinnitus, vertigo, carotidynia
   • Neurologic symptoms
               – Transient ischemic attacks, cerebral infarctions, subarachnoid
                 hemorrhages, syncope, Horner’s syndrome, cranial nerve
                 palsies




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0506-0653801                     Mettinger KL and Ericson K Stroke 1982, Houser OW et al Radiology 1971
                     FMD - Associated Diseases

   •       Turner’s syndrome          • Cystic medial necrosis
   •       Alport’s syndrome          • Hypertrophic cardiomyopathy
   •       Neurofibromatosis          • Heterozygous α1- antitrypsin
   •       Coarctation of the aorta     deficiency
   •       Moyamoya disease           • Pheochromocytoma




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               Arterial Involvement




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                               Slovut DP et al N Engl J Med 2004;350:1862
                         Renal Arteries

   • Leadbetter and Burkland (1938) reported the first case of FMD1
   • 40% of all patients with renovascular disease have FMD2
   • Symptomatic patients present with hypertension
               – Onset of hypertension before age 30
               – Epigastric bruit (systolic/diastolic)3
   • Less frequently develop ischemic renal atrophy and chronic renal
     failure




                                   1Leadbetter  WF and Burkland CE J Urol 1938, 2 Olin JW and Novick AC 18
0506-0653801                    In Peripheral Vascular Diseases 1996, 3Eipper DF et al Am J of Cardiol 1976
                      Renal Arteries




               Panel A shows string of beads.   Panel B shows gadolinium-enhanced
                                                MRA revealing bilateral medial fibroplasia
                                                of the renal arteries.
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                    Renal Arteries - Mechanism of Hypertension
                                    Ischemia


                                     Renin


               Angiotensinogen  Angiotensin I  Angiotensin II



                Direct Vasoconstriction & Aldosterone Secretion


                           Salt & Water Retention


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               Upper Percentiles of
               Blood Pressure for
               Girls




                 The Fourth Report on the Diagnosis, Evaluation, and
                 Treatment of High Blood Pressure in Children and
                 Adolescents Pediatrics 114(2) Part 3 of 3 August 2004.

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               Upper Percentiles of
               Blood Pressure for
               Boys




                The Fourth Report on the Diagnosis, Evaluation, and
                Treatment of High Blood Pressure in Children and
                Adolescents Pediatrics 114(2) Part 3 of 3 August 2004.

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                     Renal Arteries - Natural History


        • Angiographically-proven progression
               – Goncharenko (1981) 42/42 patients
                  • Follow-up 1 – 136 months
                  • 75% bilateral, 29% medial FMD, 62% change in kidney size 
                    0.5 cm
               – Schreiber (1984) 66 patients with medial FMD
                  • Follow-up 45 months angio, 104 months clinical
                  • 33% progression – 9% increase in creatinine, 27% atrophy of
                    ipsilateral kidney ( 1.5 cm)




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0506-0653801            Goncharenko V et al Radiology 1981, Schreiber MJ et al Urol Clin of North Am 1984
                      Renal Arteries - Natural History


        • Clinically-proven progression
               – Cragg (1989) –71 potential kidney donors (f/up 49)
                   • 26.6% developed hypertension at 7.5 years (30 w/o nephrectomy)
                   • 26.3% developed hypertension at 4.4 years (19 with nephrectomy)
                   • 6.1% age and sex-matched controls developed hypertension at 7.1
                     years
        • Clinical progression may reflect the development of concomitant
          development of essential hypertension or atherosclerosis




                                                                 Cragg AH et al Radiology 1989
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                     Renal Arteries - Diagnosis


        • Captopril renography (functional)
        • Spiral CT angiography1
               – Transverse sections and maximum-intensity projections
        • MR angiography2
        • Duplex Ultrasonography
               – Color power angio
        • Angiography




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                                     1Beregi   J-P et al AJR 1999, 2Leung DA et al Hypertension 1999
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                       Renal Arteries Diagnosis - Duplex Ultrasonography


                      STENOSIS                      DUPLEX CRITERIA



                         < 60%                           RAR < 3.5



                         60-99%                          RAR  3.5
               (EDV suggests > 80% stenosis)          (EDV  150 cm/sec)


                       Occlusion                  No flow signal from artery OR
                                               Low amplitude parenchymal signal 
                                                          small kidney


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                            Renal Arteries - Treatment

   • Stop smoking
   • Antiplatelet therapy
   • Medical therapy following JNC-VI guidelines1 and The
     Fourth Task Force Report2
               – Unilateral diseaseangiotensin-converting enzyme inhibitor,
                 angiotensin II antagonist
               – Bilateral diseasediuretic/calcium channel blocker




                                                                                                                  27
0506-0653801    1JNC-VI                                     2The
                          Guidelines Arch Intern Med 1997          Fourth Report Pediatrics 114(2) Part 3 of 3 August 2004
               Renal Arteries - Indications for Intervention

   • Blood pressure cannot be controlled despite three
     antihypertensive medications at maximal doses
   • The individual is intolerant to the medications
   • Compliance is an issue
   • An alternative to lifelong dependency on a medication in
     a relatively young individual




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                  Renal Arteries - Endovascular Therapy:BP


STUDY           pts   PRIMARY              IMPROVE                  CURE           F/UP MOS
                      PATENCY
 Ramsey (1990)         90.7%                   42%                   50%               11-26
     193

Tegtmeyer (1991)       100%                    59%                   39%                15.7
      66

Bonelli (1995) 105     88.6%                   63%                   22%                42.7


 Kløw (1998) 49        98%                     43%                   25%                11.3


                        Ramsey LE and Waller PC BMJ 1990, Tegtmeyer CJ et al Circulation 1991,29
 0506-0653801             Bonelli FS et al Mayo Clin Proc 1995, Kløw N-E et al Acta Radiol 1998
                     Renal Arteries - Endovascular Therapy: CRI


                             PRE-PTA    POST-PTA         IMPROVE (%)
                              (mg/dl)    (mg/dl)

                  BUN          40.4       24.6                     39

               CREATININE      2.4         1.7                     29

               PTS IMPROVE                                    (12) 86*


                 PTS NOT                                       (2) 14†
                IMPROVE


                                                                                   30
0506-0653801                                 Tegtmeyer CJ et al Circulation 1991
                     Renal Arteries - Endovascular Therapy:
                     Branch Lesions

        • Segmental renal arteries are affected in 30-56% of
          patients with FMD
        • Cluzel (1994) – 20 patients with 25 arteries
               – Technical success rate 84%
               – 91% patency rate at 6 months
               – Hypertension cure
                  • Post-PTRA 70%, 6-month 76%, long-term 68%
               – Hypertension improved
                  • Post-PTRA 25%, 6-month 24%, long-term 16%




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0506-0653801                                             Cluzel P et al Radiology 1994
                        Renal Arteries – Intervention Complications

   • Puncture site
               – AVF, pseudoaneurysm, bleeding/hematoma, femoral nerve injury,
                 infection
   • Catheter-related
               – Dissection, perforation/rupture, AED, balloon rupture, thrombosis, renal
                 artery spasm
   • Contrast Media
               – ARF, anaphylaxis
   • Medical




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               Renal Arteries – Predictors of Cure of
               Hypertension in FMD

   • Younger patients with milder hypertension of a shorter duration were
     most likely to be cured.
   • Some patients with an extremely low chance of cure might be
     managed with a trial of medical therapy
   • FMD is unlikely to progress to renal failure




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                         Renal Arteries - Surgery

   • Indications
               – Lack of endovascular expertise, recurrent disease, inaccessible branch
                 lesions
   • Approaches
               – Aortorenal bypass, extracorporeal revascularization &
                 autotransplantation, spleno- or hepato-renal
   • Blood pressure
               – 36-63% cure, 30-50% improvement
   • Outcomes
               – Low morbidity and mortality




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           Hansen KJ et al J Vasc Surg 1992, Novick AC et al JAMA 1987, Reiher L et al Eur J Endovasc Surg 2000
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                              Renal Arteries - Surgery

  • 45 children with renovascular FMD, 17 with aortic involvement
  • Average age at diagnosis was 9 years
  • Three with renal failure
  • Twenty-three of the 45 had bilateral vessel involvement
  • A variety of surgical approaches were used depending on the
    pathology encountered
  • Thirty-eight patients underwent revascularization, seven underwent
    primary nephrectomy, five underwent primary partial nephrectomy,
    and 12 had aortoaortic bypass performed
  • Seventy percent were cured, 26% improved; and 4% did not
    respond to treatment with up to 16 years of follow-up
  • There was no mortality.



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0506-0653801O'Neill   JA Jr.Long-term outcome with surgical treatment of renovascular hypertension. Pediatr Surg 1998;33(1):106-11
                    Carotid Arteries

   • Palubinskas and Ripley (1964) described a case of FMD
     involving the extracranial internal carotid artery1
   • Carotid arteries (95%) frequently bilaterally2
   • Vertebral involvement is rare and usually associated with
     carotid involvement3
   • Predominately affects extracranial segments




               1Palubinskas AJ
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                              and Ripley HR Radiology 1964, 2Healton EB In Stroke:Pathophysiology,
                         Diagnosis, and Management 1986, 3Osborn AG and Anderson RE Stroke 1977
                         Carotid Arteries




    Panel C, a 16 row multidetector of the ICA   Panel D, duplex ultrasonography of the ICA.
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                           Carotid Arteries

See Examples of FMD:




Panel A –severe concentric stenosis   Panel B – ICA after percutaneous   Panel C –shows sever redundancy &
in the ICA.                           angioplasty.                       a kink in the distal ICA.
                                                                                                             38
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                        Carotid Arteries - Natural History

   • Look at clinical outcome, not angiographic progression
               – Corrin (1981) 79 patients, 3 strokes (3.8%)
                   • 13 TIA/CVA, 10 SAH, TX [4 OR, 11 med]
               – Wells (1982) 17 patients, 2 strokes* (13%)
                   • 9 TIA, TX [1 OR, 3 med]
               – Stewart (1986) 45 patients, 0 strokes (0%) in the 35 who did not
                 have an operation
                   • 10 OR <3mos, 23/35 TIA/CVA only 1 symptomatic




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                                               Corrin LS et al Arch Neurol 1981, Wells RP and Smith RR
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                                                 Neurosurgery 1982, Stewart MT et al J Vasc Surg 1986
                             Carotid Arteries - Diagnosis

   •               Angiography remains the gold standard
               –     “String of beads”, smooth tubular stenoses, diverticula, well-
                     defined webs or septations1
               –     FMD has been associated with carotid kinks2
   •               Carotid duplex ultrasonography3
   •               Magnetic resonance angiography4




               1Osborn AG   and Anderson RE Stroke 1977, 2Schneider PA and Rutherford RB In Vascular Surgery 2000,
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                                              3Boespflug OJM Neuroradiology 1985, 4Heiserman JE et al AJNR 1992
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                         Carotid Arteries - Treatment

   • Stop smoking
   • Antiplatelet therapy
   • Intervention
               – Surgery including a resection with end-to-side anastomosis (or
                 interposition graft), endarterectomy, carotid-middle cerebral artery
                 bypass
               – Graduated intraluminal dilatation
               – Percutaneous transluminal angioplasty




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                         Carotid Arteries - Treatment

               Study       #Pts          OpTIA          OpCVA         Late CVA        Late Occ         Periop
                           (#op)                                                      Stenosis         Death

               Effeney      86            6.2%           2.3%            4.6%            N/A             0%
               (1980)      (130)

               Moreau        58           1.4%           1.4%            3.8%           2.8%             0%
               (1993)       (72)

          Schneider         115           6.0%           1.7%            1.2%           2.9%             0%
           (1994)          (168)


               Chiche        70           7.7%           2.6%            2.9%            0%            1.3%
               (1997)       (78)



         Effeney DJ et al Arch Surg 1980, Moreau P et al J Cardiovasc Surg 1993, Schneider PA                  et 42
0506-0653801              al In Vascular Surgery:Principles and Practice 1994, Chiche L et al Ann Vasc Surg 1997
                             Carotid Arteries - Associated Conditions

   • Intracranial “berry” aneurysms
               – Incidence 21% to 51%1
               – Multiple, found predominately in the internal carotid and middle
                 cerebral arteries2
               – Obtain a MRA for screening
   • Dissections3
   • Arteriovenous fistulas4




                 1Healton   EB In Stroke:Pathophysiology, Diagnosis, and Management 1986, 2Mettinger KL Stroke
                                   1982, 3Müller BT et al J Vasc Surg 2000, 4Hieshima GB et al Neurosurgery 1986 43
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               Non-Renal Abdominal Viscera

   • Celiac, superior mesenteric, inferior mesenteric, hepatic,
     and splenic arteries
   • More typically appear as long tubular stenoses1
   • Component of a systemic process mimicking vasculitis
     (intimal FMD)




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0506-0653801                            1Lüscher   TF et al Mayo Clin Proc 1987
                         Non-Renal Abdominal Viscera
                         Presentation & Treatment

   •               Asymptomatic
   •               Mesenteric ischemia1
               –     postprandial pain, weight loss, epigastric bruit
   •               Abdominal pain due to ruptured aneurysm2
   •               Bowel infarction is rare3
   •               Treatment with percutaneous transluminal angioplasty
                   or surgical revascularization




                                 1Yamaguchi   R et al Am J Gastro 1996, 2Jones HJ et al J Rheumatol 1998,
                                                       3Hamed RMA and Ghandour K J Pediatr Surg 1997        45
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                        Peripheral Arterial Disease

   • Lower extremities
               – External iliac, femoral popliteal, tibial, peroneal
               – Digital ischemia, intermittent claudication, acute limb ischemia1
   • Upper extremities
               – Subclavian, axillary, brachial, radial, ulnar
               – Arm claudication, paresthesias, subclavian steal syndrome,
                 weakness, ischemic digits (hypothenar hammer syndrome)




                                                            1Sauer   L et al J Vasc Surg 1990 46
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               Summary

   • FMD can occur in almost any arterial bed
   • Angiography remains the diagnostic test of choice but
     other, less invasive techniques may be useful
   • All patients must stop smoking and be treated with an
     antiplatelet agent
   • Intervention should be reserved for symptomatic patients




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FMD Case Studies
               Case Study 1

 • MF a 14 year old male          • BP 170/105 mmHg on repeat
 • Routine physical examination     measurements
   found to have hypertension     • EKG/ECHO – LV+
 • No symptoms or signs by        • Metabolic panel normal
   history or on examination




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               Case Study 1




                              DMSA shows
                              no scarring with
                              equal uptake by
                              both kidneys




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               Case Study 1




                     Angiography   51
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               Case Study 1




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                        Case Study 1

   • Management
               – Antihypertensives
               – Right nephrectomy after failed repair to a large thin walled extra-
                 parenchymal aneurysm
   • Follow-up
               – No further hypertension, off all medications. No indication of any
                 further vessel involvement after 36 months follow up.




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                Case Study 2

   • GB 13 year male
   • Presented with severe hypertension
   • Found by routine school screening
   • Poorly functional right kidney, small size , severe right renal artery
     stenosis
   • Normal left kidney and normal vessels
   • Right nephrectomy – off blood pressure medications




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                    Case Study 2

   •       GB now 15 years old
   •       Severe hypertension recurred
   •       Left kidney now with stenosis
   •       Repeated balloon dilatation
   •       Ongoing need for blood pressure medication




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                               Gerard Burns

                       Case Study 2




Left kidney with
trident renal artery
sub-branch
involvement




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               Case Study 3

• Patient JB                            • LVH
• Found to have HTN on routine          • Non-functional right kidney with
  Pediatrician’s visit                    severe right renal artery
• Past history of trauma to the right     narrowing
  flank and back related to             • Unilateral Nephrectomy
  baseball                              • No HTN after 3 years of follow up
• BP elevated to 160/100 mmHg




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                       For more information




               A voluntary, not-for-profit health organization dedicated to
               improving the lives of those affected by Fibromuscular
               Dysplasia (FMD) by building awareness and raising funds to
               promote research towards new medical treatments and
               diagnostic tools.
                          P.O. Box 999, Hudson, OH 44236-0999
                                     (330) 653-8416
                           www.fmdsa.org     admin@fmdsa.org
                                                                              58
0506-0653801

				
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