DESCRIPTION OF THE NEPHROLOGY TRAINING PROGRAMUNIVERSITY OF FLORIDA COLLEGE OF MEDICINE

The Division of Nephrology. Hypertension and Transplantation at the University of Florida has a distinguished faculty of 1 1individuals who are involved in patient care. research. and teaching activities. Clinical fellows are exposed to an activediagnostic and treatment service drawing from 548 beds in Shands Hospital. 433 beds in the adjacent Gainesville VeteransAffairs Medical Center. and the ambulatory care facilities from both hospitals. The clinical rotations are designed to emphasizethe diagnosis and management of renal disease and fluid and electrolyte disorders. Over 100 diagnostic renal biopsies areperformed each year. providing extensive experience in biopsy interpretation. The dialysis program provides fellows with theopportunity to manage acute renal failure by using a variety of techniques, including hemodialysis. hemofiltration, CAVH, andCAVHD. An outpatient chronic hemodialysis population of 70 patients and an ambulatory peritoneal dialysis population of 45patients provide practical experience in the management of ESRD requiring dialysis. The division supports an active transplantprogram that performs 125 kidney transplants each year. A clinical hypertension service provides in-depth clinical and researchopportunities for fellows in the field of hypertension.

Clinical and research training is a major focus of division activities. and three to four fellows are enrolled each year in theacademic program of the division. Fellows are offered the opportunity to obtain research experience in one of several researchlaboratories in the division. The faculty can offer extensive research experience in renal physiology. renal pathology. cellbiology and biochemistry. molecular biology. pharmacology. transplant immunobiology. hypertension. and related disciplines.Currently. there is also active collaboration in areas of mutual interest with faculty members in the departments ofpharmacology. biochemistry and molecular biology, pathology, and physiology, and fellows have the opportunity toparticipate in these activities. A particularly strong aspect of our training program is the extensive one-on-one interactionfellows enjoy with the faculty in both the clinical and the laboratory seffing.

The division also offers a special 1-yr transplant fellowship that provides the trainee with an in-depth experience in all phasesof solid organ transplantation. In addilion. the extensive inpatient and outpatient exposure to the management of transplantrecipients and their donors allows the trainee to become familiar with tissue typing and organ procurement. Opportunities are alsoprovided by the faculty for the fellows to pursue either clinical or laboratory investigation.

EDITORIAL COMMITIEE

Journal of the American Society of Nephrology 1347

Tomas Berl, EditorDenver, CO

William HenrichToledo, OH

Mark PaIIerMinneapolis, MN

Fred SilvaOklahoma City, OK

Extreme Blood Pressure Fluctuations in a Patient With IntactAutonom ic Reflexes a nd Intact Sod iu m ConservationYousri M. Barn,2 Marian C. Limacher, and Christopher S. Wilcox

1

Y.M. Barn, 0.5. Wilcox, Division of Nephrology, Hyper-tension and Transplantation, University of Florida,Gainesville, FL

MC. Limacher, Division of Cardiology, Universily ofFlorida, Gainesville, FL

(J. Am. Soc. Nephrol. 1995; 6:1347-1353)

ABSTRACTA patient who had episodes of profound hypotensionalternating with severe hypertension without an obvi-ous precipitating cause is reported. The hypotensive

episodes were accompanied by tiredness, syncope,

bradycardia, and a low norepinephrine concentra-

1 Received October 3, 1994. Accepted March 13, 1995.

2 Correspondence to Dr. Y.M. Barn, Department of Medicine, Presbyterian Hos-

pifal of Dallas, 8200 Walnut Hill Lane, Dallas, TX 75231.

1046.6673/0605-1347103.00/0

Journal of the American Society of NephrologyCopyright © 1995 by the American Society of Nephrology

tion while supine or standing. In contrast, the hyper-

tensive episodes were associated with marked tachy-cardia, sweating, anxiety, abdominal pain, and veryhigh levels of plasma norepinephrine concentration.Extensive investigations failed to support a diagnosis

of pheochromocyfoma. The testing of baroreceptorfunction and autonomic reflexes was normal. Bloodpressure was not salt sensitive. It was concluded thatthis patient has a unique clinical syndrome of ex-treme fluctuation of blood pressure and sympatheticnervous activity yet intact cardiovascular reflexes andnormal sodium conservation. The abnormal bloodpressure regulation most likely has a central origin.

Key Words: Hypotension. hypertension. autonomic. function.

baroreflex. norepinephrine

B lood pressure (BP) changes little with posture in

normal human subjects because of barorefiex

mechanisms that adjust the sympathetic and para-

sympathetic nervous discharge. The changes in heart

rate that occur on standing up or lying down are due

for the most part to this barorefiex mechanism. Severe

fluctuations in BP in the absence of changes in blood

volume usually imply interruption in this baroreflex

mechanism. For example. patients with autonomic

failure experience severe orthostatic hypotension,

sometimes accompanied by supine hypertension. The

plasma catecholamine levels are normal or sup-

pressed. Excessive release of catecholamines can oc-

cur with baroreflex failure or with pheochromocytoma

and is associated with episodic or sustained hyperten-

sion. On other occasions, pheochromocytoma can

cause hypertension alternating with hypotension and

tachycardia. In this study, we describe a patient with

episodes of hypotension alternating with hypertension

without evidence of pheochromocytoma who has ex-

treme fluctuation in plasma catecholamine levels, in-

tact autonomic reflexes, and normal salt conserva-

tion.

CASE REPORT

Clinical History

Our patient is a 67-yr-old female retired book-

keeper. For 1 yr. she has had intermittent episodes

that last several days at a time of orthostatic dizziness

with syncope and falls, accompanied by weakness and

lethargy. At these times, her systolic BP is typically 55

to 90 mm Hg with a heart rate of 60 to 70 beats/mm.

These symptoms alternate with episodes of head-

aches, sweating. palpitations. anxiety, nausea, vomit-Ing, and abdominal pain. At these times, her systolic

BP is typically 1 60 to 220 mm Hg with a heart rate of

100 to 160 beats/mm. During the hypotensive or

hypertensive episodes, there is little orthostatic fall in

BP and standing is accompanied by an appropriate

increase in heart rate. She has required frequent

hospital admissions, averaging once a month, pre-

dominantly for hypotenslon. On one occasion, she had

a syncopal episode, fell, and fractured her left lateral

malleolus. She denies flushing. diarrhea, visual symp-

toms, fever, chest pain. or shortness of breath. She

was referred to our Institution for a further work-up.

In 1983, she was diagnosed to have sick sinus syn-

drome and a demand pacemaker was inserted. Car-

diac catheterization at that time was normal. In 1986,

she developed diabetes mellitus that was well con-

trolled with insulin therapy. One year before presen-

tation, she developed Staphylococcus aureus endocar-

ditis, which was successfully treated with antibiotics.

She is a nonsmoker, and she denies alcohol or illicit

drug abuse. Her only regular medication at presenta-

tion was insulin (25 U of NPH in the morning and 1 2 U

in the evening, and 12 U of regular in the morning).

Physical Examination

Physical examination during the first clinic visit

when she was quite asymptomatic revealed a normal

affect, a lying BP of 156/66, a lying heart rate of 78

beats/mm. a standing BP of 126/78. and a standing

heart rate of 96 beats/mm. Examination of the optic

fundi was negative for evidence of diabetic or hyper-

tensive retinopathy. Otherwise, the examination was

unremarkable including a normal neurologic exami-

nation.

Laboratory InvestigationsInitial laboratory data revealed normal values for

serum creatinine, BUN, electrolytes, urinalysis, creat-mine clearance, and liver function tests. There was no

evidence of hypoglycemia during repeated tests, and

most blood sugar levels ranged between 80 and 200

mg/dL.

Cardiac Evaluation

She had a normal electrocardiogram, a normally

functioning pacemaker, and an echocardiogram that

revealed normal cardiac valves, and normal cardiac

output while lying and after head-up tilt of6O degrees.

Neither head-up tilt nor isoproterenol infusion in-

duced syncope.

Evaluation for Pheochromocyfoma

Plasma catecholamines were measured on several

occasions, particularly during the spontaneous epi-

sodes of hypertension and hypotension. On none of

these occasions was she taking any medication. The

plasma norepinephrine levels were remarkably van-

able and, as shown in Figure 1 , correlated closely with

the level of systolic BP. The normal range of plasma

norepinephrine is 1 10 to 700 pg/mL. When her sys-

tolic BP was low, the plasma norepinephrine concen-

tration was frequently below the limit of normal,

whereas when it was very high, it was frequenily wellabove the upper limit of normal. A clonidine suppres-

sion test was performed on two occasions to further

investigate the diagnosis of pheochromocytoma (Fig-

ure 2). On one occasion (during a hypotensive epi-

sode), plasma norepinephrine was below normal and

200

.

180

.

160

� -a.--- .

� 120

.� ___Q. 100 #{149}�00 � .Cl) �o #{149} r= +0.69

. n=16p<0.01

60.

40

20

0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600

Plasma Norepinephrlne (pg #{149}mr1)

Figure 1 . Relationship between systolic blood pressure (SBP)and plasma norepinephrine concentration determined on

several occasions.

Extreme Blood Pressure Fluctuations

1348 Volume 6 . Number 5 ‘ 1995

a � 2 3

0- �-O� �O 0

1 2 3

140

120

�100.:� 80

z

20’

n.

-.- Standing

-.- Lying

C0

aU‘Ca

0a

.xaC

E

Cl)

Posftlv. Na Balance

U f4#{149}�ve Na

0 1 2 3 4 5 6 7 8 9 10 11

Time (days)

Barn et al

Journal of the American Society of Nephrology 1349

140#{149}

130

C) 120I

E 110

,�- 1000.

�9080

I

1400’a)

.� 1200-C

�. __..1000.� 800wE� �) 600CO.� .�- 400

.� 200a.

0-�0

Time after clonidine (h)

Figure 2. Results of two clonidine suppression tests demon-strating changes in the systolic blood pressure (SBP) and

plasma norepinephrine concentration after 0.3 mg ofclonidine.

remained suppressed throughout, whereas on the

other occasion (during a hypertensive episode). the

initial norepinephrine level was high, but was sup-

pressed to normal after clonidine. A glucagon stimu-

lation test was also negative. This result does not

support the diagnosis ofpheochromocytoma. Further-

more, whole-body computed tomographic scans

(neck, chest, abdomen, and pelvis) revealed no lesion

to suggest the presence of an adrenal or extra-adrenal

mass. Serial venous sampling from the superior and

inferior vena cava, femoral and Internal jugular veins,

and the right atrium did not show a significant differ-

ence in the catecholamine levels.

Sodium Balance With Changes In Dietary Salt

The patient was admitted to the Clinical Research

Center (CRC) for 14 days to study the effects of

changes in dietary salt on sodium balance and BP.

During the first 7 days, the patient received a daily

intake of 1 89 mEq of sodium, and during the following

7 days, it was reduced to 20 mEq. The BP was

measured while lying and after head-up tilt of 60

degrees on the last day of each study period. Urinary

sodium excretion was determined every 1 2 h. She

developed a sudden episode ofhypotension on the last

day of high sodium intake that required an infusion of

0. 154 M saline. As shown in Figure 3, sodium reple-

tion or restriction failed to alter either the lying or the

tilted BP. There was a rapid and appropriate reduction

in sodium excretion during the salt restriction period

(Figure 3). On the last study day, the effect of normal

saline loading on BP and heart rate was tested. Initial

lying and posthead-up tilt BP and heart rate were

determined, and baseline hematocrit and catechol-

amine were measured. Two liters ofnormal saline was

infused over a 2-h period. and BP and heart rate were

measured again. Furosemide (40 mg) was given intra-

venously, and the BP and heart rate were determined

after 2 h. A urine output of 500 mL was observed over

a 2-h period after furosemide. Two liters of normal

saline was infused again over the next 2-h period. No

significant differences in BP or heart rate were ob-

served after normal saline infusion or furosemide

administration.

Figure 3. Heart rate (HR), systolic blood pressure (SBP), andsodium balance during changes In salt Intake.

-.0

0 ‘Qnitroprussid. �.

0’

+20

+16

+12

+8

+6

+4 A SBP (mmHg)

+10 +20 +30 +40

Assessment of the Baroreflex Mechanism

Studies of the barorefiex mechanism were under-

taken at the CRC. During these tests, the pacemaker

was deactivated to properly assess the changes in

heart rate. Valsalva’s maneuver was performed with

an intra-arterlal recording by blowing into a tube

connected to a pressure transducer to raise the in-

traoral pressure to 40 mm Hg for 20 s. There was a

normal response of hypotension and tachycardia dur-I I I I ‘..I I I I

ing forced expiration. followed Immediately after the .�o .�o .20 -10

procedure by a transient overshoot ofthe BP (Figure 4) � :�. �o�,associated with bradycardla (54 compared with 1 10 ______ .�

beats/mm). The baroreceptor reflex mechanism was I y=.0.2.0.32x II r.-0.98 I .12 -.In=9 Ifurther evaluated by graded Infusions of phenyleph- I P<#{176}.#{176}#{176}’j

rine and sodium nitroprusside. while monitoring the .16

heart rate, to Increase or decrease the systolic BP byA HR(mIn�1)

25 mm Hg. respectively. Phenylephrine was infused ata graded rate of 0. 125 to 0.75 p�g/kg/per minute and Figure 5. Changes In heart rate (HR) with changes In the

nitroprusside was Infused at a graded rate of 0.05 to systolic blood pressure (SBP) after phenylephrine or nitro-

1 .2 pg/kg/per minute to increase or decrease the prusside infusion as a test for the baroreflex mechanism.

systolic BP by 25 mm Hg, respectively. These tests

revealed appropriate Increases in heart rate during a quency and the severity of the hypotensive episodes

reduction in BP and decreases in heart rate during with the use of fludrocortisone, the hypertensive epi-

increases in BP (Figure 5). sodes became more frequent than before. However,

clonidine was effective In controlling these episodes.

Other InvestigationsA drug screen was negative on three occasions. The DISCUSSION

Watson-Schwartz test and the measurement of �-ami- This patient presented with clinical features char-

nolevulenic acid and porphobilinogen excretion for acterized by intermittent episodes of severe hypoten-porphyria were negative. Computed tomography ofthe sion associated with a slow heart rate, alternating

brain and an electroencephalogram were both normal. with episodes of hypertension associated with tachy-

A captopril test was negative with a postcaptopril cardia and symptoms of catecholarn.tne excess. Some

plasma renin activity of 2. 1 ng/mL per hour and of the diagnoses that were considered to explain theplasma aldosterone of 5.5 ng/dL. Her plasma cortisol symptoms of labile hypertension with excess plasma

in the morning was normal at 9.8 �g/dL. catecholarnines are summarized in Table 1 . Although

patients with pheochromocytoma usually present

Management with intermittent or sustained hypertension, presen-

The patient was treated with fludrocortisone, 0. 1 mg tatlon with hypotension or alternating hypertension

twice a day, to combat hypotension and clonidine as and hypotenslon has been previously documented

required to manage hypertension. Increased heart ( 13). The mechanisms of orthostatic hypotension in

rate, and symptoms of catecholamine excess. Al- pheochromocytoma include reduced plasma volume,

though there was a significant reduction in the fre- impaired cardiovascular reflexes, and eplnephrlne-induced vasodilatlon in blood vessels to skeletal mus-cle. In a recent review, the clonidine suppression testwas found to be 92% accurate in diagnosing pheo-

- chromocytoma (4). From the results of these extensive

E investigations and the favorable response to clonidine.�

! treatment, pheochromocytoma appears quite un-� likely. Several rare causes for this patient’s clinical

� condition were ruled out by appropriate evaluation1 and include: carotid sinus syndrome, vasovagal at-a

tacks, hypoglycemia, intracranial lesions or epileptic

seizure, illicit or self-administered drug use, acute

intermittent porphyria, mitral valve prolapse or other

valvular lesions, renovascular hypertension. and un-derlying psychiatric disorder.

Time (sec)Lesions resulting in autonomic dysfunction may

Figure 4. lntra-arterial record of the blood pressure during involve the afferent pathway, the central connections,

Valsava’s maneuver. the efferent pathway, the target organs, or a combina-

0 10 20 30 40 50

Extreme Blood Pressure Fluctuations

1350 Volume 6 ‘ Number 5 #{149}1995

TABLE 1 . Intermittent hypertension accompanied bystriking increases of plasma catecholamines

Basic Work-up for Patients Suspectedof Autonomic Insufficiency

Labile HypertensionOld ageAnxiety

PheochromocytomaBaroreflex Failure

Damage to carotid sinusesIdiopathic

Insulin-Induced Hypoglycemia

Intermittent AnoxiaSleep apnea

Drugs

Amphetamines and cocaineMonoamine oxidase inhibition and tyramine

Intracranial Space-Occupying Lesions

Cushing’s responsePosterior fossa tumors

Basilar artery aneurysmPorphyria

Intermittent acuteHereditary coproporphyriaPorphyria variegata

DiagnosisReconsider I

I Orthostatic 1 1 Orthostatic

I Hypotension � Hypotension I+ II t Heart Rate � - Heart Rate+

� _I Drug 1I Intake

Ition of these, depending on the disorder. The evalua-

tion of a patient with suspected autonomic insuffi-

ciency includes multiple tests involving all organsystems. Therefore, the selection of the investigations

should be designed to define the site of the lesion,

depending on the clinical presentation. Figure 6 de-

scribes a simple algorithm for the initial evaluation of

a patient suspected to have autonomic Insufficiency.

Further work-up will depend on the clinical presenta-

tion and the findings from the initial evaluation. Be-

cause our patient had evidence of abnormal BP regu-

lation, an evaluation of the autonomic control of BP

and cardiovascular reflexes was undertaken.

The autonomic nervous system is required for the

normal regulation of body fluid. Defective renal so-

dium conservation during salt restriction was de-

scribed in normal human subjects with the sympatho-

lytic drug guanethidmne (5). Sodium wasting was

further shown In patients with autonomic failure.

Although the defective sodium conservation was ac-

companied by subnormal aldosterone excretion, this

is only partly responsible for this defect (6). In this

patient, neither lying nor standing BP fell during

sodium restriction. We studied sodium balance and

BP in this patient during an alteration in salt intake.

with 1 wk of normal sodium intake followed by a week

of sodium restriction. As shown in Figure 3, appropri-

ate sodium excretion occurred during a high saltintake and sodium conservation occurred during pe-

nods of sodium restriction. In addition, sodium re-

striction was not associated with postural hypoten-

sion or lower BP In comparison to normal sodium

intake. Indeed, the patient actually developed a hypo-

tensive episode during the high sodium Intake.

Clearly. there was no correlation between sodium

No � Plasma CatecholaminesRelevent

DrugIntake F

Normal Normal

I Low or Low or High

1� 1k �kPeripheral Central Old age.autonomic autonomic Carotid arlery

failure, failure disease(Diabetes mellitus, (MSA.IOH, CerebrovascuiarPolyneuropathy) disease.

Parkinson’sdisease)

Figure 6. Basic work-up for patients suspected of autonomicinsufficiency. IOH, idiopathic orthostatic hypotension; MSA,multiple system atrophy.

intake and BP. Furthermore, no significant changes in

BP or heart rate were observed after normal saline

infusion or intravenous furosemide administration.

Therefore, this patient does not have salt-sensitive BP,

nor is the response to salt restriction suggestive ofautonomic neuropathy (5-7). The hypotensive epi-

sodes cannot be ascribed to defective sodium conser-

vation.

Both hypoadrenergic orthostatic hypotenslon and

hyperadrenergic orthostatic hypotension have been

described in different categories of patients with dia-

betes mellitus (8.9). Diabetic patients with hypoadren-

ergic postural hypotension usually have combined

autonomic and peripheral neuropathy. with a lower

than normal mean norepinephrine concentration in

both the supine and the standing positions ( 10). Sev-

eral studies have shown an association between pe-

ripheral and autonomic nerve dysfunction in long-

term insulin-dependent diabetics ( 1 1 . 1 2). The

absence of peripheral neuropathy and other featuressuggestive of autonomic neuropathy. such as gastro-

intestinal symptoms or defective sweating, argues

against the diagnosis of diabetic autonomic neuropa-

thy ( 12). Furthermore, the normal response to Valsal-

Barn et al

Journal of the American Society of Nephrology 1351

SuspectedAutonomicInsufficiency

a.b�ckers. Volume depletion,Vasodilators Pheochromocytoma,

cervical cordtransection,Prolonged bed

rest

Extreme Blood Pressure Fluctuations

1352 Volume 6 ‘ Number 5 ‘ 1995

va’s maneuver and appropriate heart rate changes

with phenylephrmne and sodium nitroprusside infu-

sions effectively exclude a diagnosis of autonomic

neuropathy due to diabetes mellitus. Patients with

diabetes mellitus may also have hyperadrenergic or-

thostatic hypotension. The increased sympathetic ac-

tivity in these patients has been attributed to a dimin-

ished Intravascular volume or a vascular resistance to

noreplnephrine (9). All patients studied had subnor-

mal blood volume, which may contribute to the ortho-

static hypotension and enhanced catecholamine 1ev-

els (9). In contrast, our patient had episodes of

hypotension associated with low norepinephrine con-

centrations, whereas high noreplnephrine concentra-

tions were associated with episodes oflabile hyperten-

sion. As shown in Figure 1 . the BP was directly

correlated with the plasma norepinephrine concentra-

tion. This suggests that the high norepinephrine con-

centration may be a marker of enhanced sympathetic

nervous system activity and may be causally related to

the tachycardia and high BP, and not a response to a

reduced blood volume. Furthermore, our patient had

hypertensive episodes, which are not a feature of

hypoadrenergic or hyperadrenergic orthostatic hypo-

tension. Therefore, the clinical picture of this patient

is not consistent with hypoadrenergic or hyperadren-

ergic orthostatic hypotension.

Baroreceptors in the carotid sinus, the aortic arch,

and great vessels in the thorax transmit neural signals

via the glossopharyngeal and vagus nerves to the

brain stem. Abnormalities in the vascular barorecep-

tors, their neural connections, or the brain stem can

lead to baroreflex failure. True barorefiex failure en-

tails the loss of buffering of BP and is characterized by

the volatility of BP and heart rate ( 13, 14). In a recentstudy, Robertson et al. described 1 1 patients with

barorefiex failure presenting with labile BP and hyper-

tensive episodes accompanied by high levels of plasma

catecholamines ( 1 5). However, our patient differs from

those described previously ( 1 5-1 7), because she had

prominent symptomatic hypotensive episodes. More-

over, she lacks a clinical cause, such as neck surgery,

for baroreceptor damage. Additionally, she had an

appropriate heart rate response to Valsalva’s maneu-

ver (Figure 4) and to induced changes in BP (5).

Therefore, this patient appears to have an intact

baroreflex arc.

The central autonomic network is an internal regu-

lation system through which the brain controls viscer-

omotor, neuroendocrine, pain. and behavioral re-

sponses ( 18). Bilateral lesions of the nucleus tractus

solitarli In experimental animals abolish the barore-

flex mechanism and result in fulminant neurogenic

hypertension or chronic lability ofBP ( 19). In humans,

intraoperative stimulation of the Insular, orbitofron-

tal, or anterior temporal cortex produces substantial

changes in arterial pressure and heart rate (20,21).

Structural lesions of the frontal or prefrontal cortex

and amygdala may be associated with autonomic

disturbances (22). The sudden onset ofthe episodes of

hypotension and hypertension and the association

with changing norepinephrine concentration in our

patient with intact baroreflex mechanism suggest that

the lesion is in the central integration of the sympa-

thetic outflow. The presence of a normal baroreflex

mechanism in our patient suggests that the lesion is

above the level of the nucleus tractus solitarli. Envi-

ronmental stress may be translated into increased

sympathetic nervous activity via the limbic-hypotha-

lamic-bulbar autonomic centers. In addition, acute

environmental stress in spontaneously hypertensiverats elicits a prompt and sustained increase In arterial

BP and heart rate (23). Our patient had no features to

suggest mental stress or major psychiatric illness to

explain her clinical condition. Although it is not pos-

sible to determine the exact site of lesion, the abnor-

mal BP regulation in this patient appears to be of

central origin.

Studies performed in this patient helped us to un-

derstand the underlying pathophysiology of her dis-

ease. The hypotensive episodes were more frequent

and required more hospital admissions than the hy-

pertensive episodes. The usual approach to the treat-

ment of orthostatic hypotension is to expand plasma

volume by administering fludrocortisone. Many pa-

tients with autonomic neuropathy have a normal

plasma volume (24) but may become volume ex-

panded during treatment with fludrocortisone. 5ev-

eral other pharmacologic agents such as prostag-

landin inhibitors (25). somastostatin analogues (26).

ergot alkaloids (27), and a1-adrenergic receptor ago-

nists (28) have been used with variable success and

side effects. Recently. erythropoletin has been re-

ported to be useful in the treatment of orthostatic

hypotension due to autonomic failure, although su-

pine hypertension was a side effect in some patients

(29,30). In our patient, fiudrocortisone, 0. 1 mg twice

daily, helped to reduce the frequency of hypotensive

episodes. The second aspect of the treatment of this

patient was the hypertensive episodes associated with

tachycardia and elevated norepinephrine levels,

which are most likely centrally mediated. Animal

studies have demonstrated that clonidine inhibits

central sympathetic outflow, reduces the release of

norepinephrine. and may have a vagomimetic action(3 1 .32). In humans, clonidine reduced muscle sympa-

thetic nerve activity and the sympathetic response to

the cold pressor test without modifying the ability of

the baroreceptors to respond to BP fluctuations (33).

In our patient, clonidine suppressed norepinephrlne

concentration to normal during the clonidine sup-

pression test (Figure 2). Furthermore, clonidine was

effective In reducing the BP and heart rate in our

patient during the hypertensive episodes when she

was hospitalized. Therefore, we have used initial treat-

ment with fludrocortisone on a regular basis to reduce

the frequency of hypotensive episodes and clonidine

intermittently to combat hypertension and tachycar-

dia mediated by increased sympathetic outflow.

In conclusion, this patient presents with extremes

Barn et al

Journal of the American Society of Nephrology 1353

of BP without an obvious precipitating factor. The

hypotensive episodes were associated with relative

bradycardia, tiredness, and a low norepinephrine level

that did not increase on standing. In contrast, the

hypertensive episodes were associated with tachycar-

dia, syncope, anxiety. sweating. and very high plasma

norepinephrine levels that increase further on stand-

Ing. She has intact autonomic reflexes and a BP that

appeared quite insensitive to change in salt intake.

This constellation of clinical findings appears not to

have been described before.

ACKNOWLEDGEMENTThis work was supported by the Clinical Research Center at the

University of Florida by Grant RR00082 from the NIH. We thank MelFregly. PhD. who kindly undertook the catecholamine measure-ments, and G.F. DiBona, MD, for helpful advice on the interpretation

of these studies.

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