Nephrology Grand Rounds

Vasishta Tatapudi, MD
9th July, 2013
 History

• C/C: A 34 year old Chinese American male patient presented with

complaints of inability to move b/l lower extremities.

• HPI: Patient reported onset of nasal congestion and runny nose one
day prior to presentation. Awoke that day with generalized body
aches and tingling of feet. Patient became nauseous, had 3 episodes
of non bloody, non bilious vomiting, then noted severe b/l lower
extremity weakness that lasted 15min. Patient noted some recovery
of motor function by the time he presented to urgent care at NYU.
• Medical history: Hypertension - 3 years. Underwent w/u for
secondary causes.

• Surgical history: Arthroscopic surgery of left knee, right wrist and

ankle – all for soccer related injuries.

• Medications: HCTZ/Lisinopril 25mg/20mg tab daily, multivitamin

cap daily, CoQ10 10mg cap daily. Reportedly compliant.

• Allergies: None.
• Family History: Mother had hypertension, maternal grandfather had
liver cancer.

• Social History: No smoking, alcohol or illicit drug use. Works as a

pastry chef.
 Physical Exam

General: No acute distress. Lean body habitus.

Vital signs: T 98 , P 83, RR 16, BP 155/100, BMI 22.4 m2/kg.
HEENT: moist oral mucosa, no sinus tenderness.
Neck: No carotid bruit, no thyromegaly.
Chest: CTA.
CVS: S1, S2 normal, regular rhythm, no added sounds.
Abdomen: Non distended, no bruit, soft, non tender.
CNS: Motor strength 5/5 in all ext. Normal sensation, reflexes.
Extremities: No edema, well perfused.
 Laboratory Data

Hemoglobin 13.3 Sodium 142 Protein 7.6

Hematocrit 39.8 Potassium 2.4 Albumin 4.4
WBC 5.6 Chloride 93 ALT 25
Platelets 207 Bicarbonate 37 AST 30
Blood urea 9 ALP 66
INR 1.1 Creatinine 1.0 Total Bili. 1.7
PT 11.6 Glucose 128 Direct Bili. 0.0
Calcium 9.5 Magnesium 2.0
AG 12
Urinalysis

Color Yellow • EKG: 80 bpm,

Specific Gravity 1.007 normal sinus rhythm,
pH 7.5 TWI in infero-lateral leads.
Glucose Negative
Bilirubin Negative • Chest x-ray: clear lung fields.
Ketones Negative
Blood Negative
Protein Negative
Leuk. Est. Negative
Nitrite Negative
RBC 0-2
WBC 0-2
Casts Negative
Bacteria Negative
Clinical Approach
Laboratory Data - PAC/PRA Screen

Plasma Aldosterone Concentration 38.4

Plasma Renin Activity <0.1
Aldosterone/Renin Ratio 384
Jerome W. Conn
Rachel Booth, et al , Advan in Physiol Edu 26:8-20, 2002.
 Genomic Actions

Rachel Booth, et al , Advan in Physiol Edu 26:8-20, 2002.

 Time course of action

Rachel Booth, et al , Advan in Physiol Edu 26:8-20, 2002.

 Subtypes of Primary Aldosteronism

• Aldosterone-producing adenoma.
• Bilateral idiopathic hyperaldosteronism.
• Unilateral hyperplasia or primary adrenal hyperplasia .
• Familial hyperaldosteronism type I (GRA) and type II (the familial
occurrence of aldosterone-producing adenoma or bilateral idiopathic
hyperplasia or both).
• Pure aldosterone-producing adrenocortical carcinomas and ectopic
aldosterone-secreting tumors.
 Clinical Features

• Hypertension.
• Hypokalemia.
• Lack of edema – “Aldosterone Escape”.
• Metabolic alkalosis.
• Muscle weakness.
• Hypernatremia.
• Cardiovascular risk.
 Hypertension

• Nonsuppressible hypersecretion of aldosterone is an underdiagnosed

cause of hypertension.
• Conn suggested 20% of people with hypertension could have this
disorder.
• For decades aldosteronism was thought to be a rare disease,
diagnosed only in academic institutions.
• Studies of unreferred patients supported a prevalence 1%.
• Studies since 1999 suggest the prevalence is about 10% of patients
with hypertension.

Stella Douma, et al, Lancet 2008; 371: 1921–26

 Prevalence among patients with resistant hypertension

Stella Douma, et al, Lancet 2008; 371: 1921–26

 Prevalence among patients with resistant hypertension

Stella Douma, et al, Lancet 2008; 371: 1921–26

 Hypokalemia and Hypertension - Classic but inconsistent
Findings

• Normokalemia is more common than hypokalemia in patients

diagnosed with primary aldosteronism. (1)
• In another series, hypokalemia was found in 50 percent of patients
with aldosterone-producing adenomas, and 17 percent of patients
with bilateral hyperplasia. (2)
• Normokalemia is the rule in patients with GRA.
• A few patients have hypokalemia but a normal systemic blood
pressure.(3)

1. Mulatero P, et al, J Clin Endocrinol Metab. 2004;89(3):1045.

2. Rossi GP, et al, J Am Coll Cardiol. 2006;48(11):2293.
3. Kono T, et al,J Clin Endocrinol Metab. 1981;52(5):1009.
• 1688 nonhypertensive participants - Framingham Offspring Study.
• Mean age - 55 years, followed over 4 years.
• Blood-pressure category had increased in 33.6 percent of
participants.
• Hypertension developed in 14.8 percent.
• The highest serum aldosterone quartile, relative to the lowest, was
associated with :
 1.60-fold risk of an elevation in blood pressure.
 1.61-fold risk of hypertension.
 Lack of Edema – Aldosterone Escape

Granger JP, Smith MJ Jr, Premen AJ, Hypertension 1983; 6(2 Pt 2):I-183.
 Mechanism of Escape

• Thiazide-sensitive Na-Cl cotransporter as mediator of the

aldosterone-escape phenomenon. (1)
• Atrial Natriuretic Factor – Evidence for guanylate cyclase mediated
pathway. (2)
• Pressure Natriuresis. (3)

1. Wang XY et al, J Clin Invest. 2001;108(2):215.

2. Yokota N et al J Clin Invest. 1994;94(5):1938.
3. Zhang et al Am J Physiol Renal Physiol 270:F1004-F1014, 1996.
 Na-Cl cotransporter

Wang XY et al, J Clin Invest. 2001;108(2):215.

 Densitometric analysis

Wang XY et al, J Clin Invest. 2001;108(2):215.

 Immunohistochemistry - DCT

Wang XY et al, J Clin Invest. 2001;108(2):215.

 Cardiovascular risk

Paul Milliez, et al, Journal of the American College of Cardiology Vol. 45, No. 8, 2005
 Results

Pitt B, et al, N Engl J Med. 1999;341(10):709.

 Case Detection Testing

• 2008 Endocrine Society Guidelines:

• Hypertension and spontaneous or low dose diuretic-induced
hypokalemia.
• Severe hypertension (>160 mmHg systolic or >100 mmHg diastolic)
or drug-resistant hypertension.
• Hypertension with adrenal incidentaloma.
• Hypertension and a family history of early-onset hypertension or
cerebrovascular accident at a young age (<40 years).
• All hypertensive first-degree relatives of patients with primary
aldosteronism.
 Test Performance

• Morning, ambulatory, paired, random plasma aldosterone

concentration (PAC) and plasma renin activity (PRA) or plasma
renin concentration (PRC).
• PRA and PRC are undetectable in primary aldosteronism.
• PAC is >15 ng/dL (416 pmol/L).
• PAC/PRA ratio greater than 20 (laboratory dependent).
• The combination of a PAC above 20 ng/dL and a PAC/PRA ratio
above 30 had a sensitivity and specificity of 90 percent for the
diagnosis of aldosterone-producing adenoma.
• Higher cut offs, use of captopril and losartan.

Blumenfeld JD, et al, Ann Intern Med. 1994;121(11):877.

Weinberger MH, et al, Arch Intern Med. 1993;153(18):2125.
 Effect of β Blockers

Primary Aldosteronism Primary Hypertension

• Consider the risks of modifying antihypertensive medication.

• Hypertensive crisis, atrial fibrillation, heart failure.
 Effect of Mineralocorticoid Antagonists

Primary Aldosteronism Primary Hypertension

• Hold mineralocorticoid antagonists for 6 weeks.

• May continue ENaC blockers.
 RAAS Blockade

• Angiotensin-converting enzyme (ACE) inhibitors, angiotensin

receptor blockers (ARBs), and direct renin inhibitors could
potentially elevate PRC in patients with primary aldosteronism.
• Thus, in a patient treated with one of these drugs, a detectable PRA
level or a low PAC/PRA ratio does not exclude the diagnosis of
primary aldosteronism.
• On the other hand, a strong predictor for primary aldosteronism is an
undetectable PRA or PRC in a patient taking one of these drugs.
 Laboratory Data - 24 hour urine collection

Total Volume 3400ml

Creatinine, Urine – per 24h 1496ml/d
Expected Creatinine, Urine – per 24h 1360ml/d
Aldosterone, Urine – per 24h 129.5µg/d (0-6µg/d)
 Role of 24h urine collection

•• 24h K+ measurement:
24h urine collection for Aldosterone measurement:
 Confirmatory
24 hour urine collection
test. was typically obtained to document the
presence of inappropriate potassium wasting.
 NO LONGER ordered for screening unless the PRA is not
suppressed, the PAC is not elevated, or there is a suspicion of
surreptitious vomiting.
 Interpretation of the rate of potassium excretion requires attention to
the patient's volume status and rate of sodium excretion.
 Sodium-induced hypokalemia is strongly suggestive of
nonsuppressible hyperaldosteronism.
 Confirmation Testing

• Primary aldosteronism must be confirmed by demonstrating

inappropriate aldosterone secretion.
• Orally administered sodium chloride and measurement of urine
aldosterone excretion.
• Intravenous sodium chloride loading and measurement of PAC.

Young WF, Clin Endocrinol (Oxf). 2007;66(5):607.

 Subtype Classification

• Adenomas account for 35 percent of cases and should be considered

for surgical removal.
• Bilateral adrenal hyperplasia, accounts for 60 percent of cases,
should be treated with an aldosterone receptor antagonist.
CT abdomen pelvis with contrast
 CT abdomen pelvis with contrast - Report

• Both adrenal glands are well visualized. There is a 1.1 cm adenoma

in the left adrenal gland. The kidneys enhance symmetrically. No
calcification, hydronephrosis, or soft tissue attenuation renal mass.
 Role of CT Scan

• When imaging adrenal glands, CT has superior spatial resolution

when compared with MRI.
• 2008 Endocrine Society Guidelines - CT should be the initial study
to determine subtype.
• A solitary hypodense lesion >1 cm - unilateral macroadenoma.
• An abnormality in both glands suggests adrenal hyperplasia.
• The diagnosis of an adrenal carcinoma should be suspected when a
unilateral large (>4 cm) adrenal mass is found on CT.
 Limitations of CT Scan

• Aldosterone-producing adenomas can be very small and lesions less

than 1 cm in diameter may be missed on CT.
• Normal CT may represent missed APA or bilateral hyperplasia.
• Some adrenal nodules are non functional. More common > 40yr.
• Bilateral lesions are not diagnostic of hyperplasia (because some
patients with an aldosteronoma in one adrenal gland have a
nonfunctioning adrenal nodule in the other).
Young WF Jr, Hogan MJ. Renin-independent hypermineralocorticoidism. Trends Endocrinol Metab 1994; 5:97.
 Adrenal Vein Sampling - Results
Prior to ACTH
Aldosterone Cortisol
Left adrenal vein 3000 17.6
Right adrenal vein 18.9 1.7
Infra-renal IVC 40.4 2.6

Post ACTH
Aldosterone Cortisol
Left adrenal vein 18,480 583
Right adrenal vein 12.6 13.0
Infra-renal IVC 99.1 10.7
Laparoscopic left adrenal adenalectomy
Thank you.