Approach to Hypokalemia

Ranjita Pallavi

Internal Medicine

PGY-2

Renal Vs Extra renal loss

Urinary K+: > 20 mEq/L – Renal loss

Urinary K + : < 20 mEq/L – Extrarenal loss

TTKG : Transtubular Potassium Gradient ( Urine K+ / Plasma K+ ) ( Urine Osm / Plasma Osm )

TTKG : Renal loss : > 4 Extra renal loss : < 4

RENIN HIGH ALD HIGH

RENIN LOW ALD HIGH

LOW RENIN LOW ALD

RAS Primary Hyperaldosteronism NORMAL CORTISOL :

Malignant HTN Glucorticoid remediable HTN Apparent mineralocorticoidexcess

Renin Secreting Tumor

Liddles syndrome

LicoriceDOC

LOW CORTISOL :

Adrenogenital syndrome 11 beta hydroxylase deficiency17 alpha hydroxylase deficiency

HIGH CORTISOL :

Familial Glucocorticoid ResistanceEctopic ACTHSevere Cushings Syndrome

PRIMARY ALDOSTERONISM

Primary Aldosteronism with an Adrenal Tumor

Primary Aldosteronism without an Adrenal Tumor

WHEN TO SCREEN?

Recommended in Hypertensive Patients with one of the following:

Hypokalemia Severe, resistant or relatively

acute hypertension Adrenal incidentaloma

PRIMARY ALDOSTERONISM WITH AN ADRENAL TUMOUR

Aldosterone producing adrenal adenoma( rarely adrenal carcinoma)

Also known as Conn’s Syndrome Usually unilateral M:F: 1:2 Commonly seen between 30-50

years ~1% patients present with

hypertension

PRIMARY ALDOSTERONISM WITHOUT AN ADRENAL TUMOUR

Idiopathic hyperaldosteronism and/or nodular hyperplasia

The adrenal are either normal in appearance or more commonly reveal Bilateral(10%) or rarely, unilateral(<1%) micro- or macronodular adrenal hyperplasia

THE CRITERIA FOR DIAGNOSIS OF PRIMARY ALDOSTERONISM

Diastolic hypertension without edema

Renin hyposecretion that fails to increase appropriately during volume depletion

Aldosterone hypersecretion that does not suppress appropriately to volume expansion

METHOD OF SCREENING

Aldosterone conc/Renin activity ratio Considered positive if ratio > 20,

usually > 30 In addition, the aldosterone conc.

Should be > 15 ng/dL

DIAGNOSIS

Aldosterone > 15ng/dL Aldosterone/renin ratio > 30 Confirmation with Na+ suppression

test Imaging of the adrenal glands Adrenal Vein sampling 18-OH Corticosterone levels may

help differentiate hyperplasia from adenoma

Aldosterone Suppression Tests

IV Saline suppression 500 ml 0.9% NaCl/hr for 4 hours OR 500 ml 0.9% over 30

mimutes, then 500ml/hr for 2 hours Draw PAC at time 0, 120 and 150 minutes Suppression if PAC< 8.5 ng/dL(<6 normal> 10 PA)

Oral sodium chloride suppression test 10 gms NaCl dily for 4 days On Day 4, collect 24 hour urine aldosterone, sodium

Suppression if aldosterone< 14 mcg and sodium > 200 eEq/24 hours

Fludrocortisone suppression test High salt diet and large doses of fludrocortisone over a 4 day

hospitalization

ADRENAL VEIN SAMPLING

Considered gold standard to distinguish adenoma and hyperplasia

Usually done under ACTH infusion Looking for localization of

aldosterone increase Very useful when no abnormalities

seen on imaging or bilateral nodules

LIDDLE’S SYNDROME

Clinical features include: Hypertension Hypokalemia with renal K+ wasting Metbolic alkalosis and Suppressed plasma renin activity Autosomal Dominant

Primary abnormality in renal tubule that enhances Na+ reabsorption: a defect in the cyutoplasmic domain of the epithelial Na+ channel that results in gain of fuction activating mutation of the channel

Amiloride and Triamterene are specific inhibitors of this channel, treatment with these agents corrects the electrolyte abnormalities and ameliorates the hypertension.

Mechanism of action

Cortisol Aldosterone

Cortisone (inactive)

11B-Hydroxysteroid dehydrogenase (11β-HSD)

Mineralocorticoid Receptor (MR)

Glycyrrhetinic Acid

11β-HSD

Cortisol

Cortisol nmol/L

Aldosterone pmol/L

Bartter and Gitelman Syndromes

Bartter syndrome genotype-phenotype correlations

Genetic Type Defective Gene Clinical Type

Bartter type I NKCC2 Neonatal

Bartter type II ROMK Neonatal

Bartter type III CLCNKB Classic

Bartter type IV BSND Neonatal with deafness

Bartter type V CLCNKB and CLCNKA Neonatal with deafness

Gitelman syndrome NCCT Gitelman syndrome

Indirect loss of NaHCO3 in glue sniffing.

Groeneveld J et al. QJM 2005;98:305-316

The Author 2005. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Functional evaluation of proximal bicarbonate absorption

Fractional excretion of bicarbonate Urine ph monitoring during IV administration

of sodium bicarbonate. FEHCO3 is increased in proximal RTA >15%

and is low in other forms of RTA.

Functional Evaluation of Distal Urinary Acidification and Potassium Secretion

Urine ph Urine anion gap Urine osmolal gap Urine Pco2 TTKG Urinary citrate

Urine ph

In humans, the minimum urine pH that can be achieved is 4.5 to 5.0.

Ideally urine ph should be measured in a fresh morning urine sample.

A low urine ph does not ensure normal distal acidification and vice versa.

The urine pH must always be evaluated in conjunction with the urinary NH4+ content to assess the distal acidification process adequately .

Urine sodium should be known and urine should not be infected.

Urine anion gap (UAG)

Urine anion gap = [Na+] + [K+] – [Cl-]

Normal: zero or positive Metabolic acidosis: NH4+ excretion increases (which is

excreted with Cl-) if renal acidification is intact

GI causes: “neGUTive” UAG Impaired renal acid excretion (RTA): positive or zero

Often not necessary b/c clinically obvious (diarrhea)

Urine anion gap

There are, however, two settings in which the urine AG cannot be used.

When the patient is volume depleted with a urine sodium concentration below 25 meq/L.

When there is increased excretion of unmeasured anions

Urine osmolal gap

When the urine AG is positive and it is unclear whether increased excretion of unmeasured anions is responsible, the urine ammonium concentration can be estimated from calculation of the urine osmolal gap.

UOG=Uosm - 2 x ([Na + K]) + [urea nitrogen]/2.8 + [glucose]/18.

UOG of >100 represents intact NH4 secretion.

Urine Pco2

Measure of distal acid secretion. In pRTA, unabsorbed HCO3 reacts with

secreted H+ ions to form H2CO3 that dissociate slowly to form CO2 in MCT.

Urine-to-blood pCO2 is <20 in pRTA. Urine-to-blood pCO2 is >20 in distal RTA

reflecting impaired ammonium secretion.

TTKG TTKG is a concentration gradient between

the tubular fluid at the end of the cortical collecting tubule and the plasma.

TTKG   =   [Urine K  ÷  (Urine osmolality / Plasma osmolality)]  ÷  Plasma K.

Normal value is 8 and above. Value <7 in a hyperkalemic patient

indicates hypoaldosteronism. This formula is relatively accurate as long

as the urine osmolality exceeds that of the plasma urine sodium concentration is above 25 meq/L

Urine citrate

The proximal tubule reabsorbs most (70-90%) of the filtered citrate.

Acid-base status plays the most significant role in citrate excretion.

Alkalosis enhances citrate excretion, while acidosis decreases it.

Citrate excretion is impaired by acidosis, hypokalemia,high–animal protein diet and UTI.

Renal Tubular Acidosis

First described clinically in 1935

Confirmed as a renal tubular disorder in 1946

Designated as RTA in 1951

Refers to disorders affecting the overall ability of the renal tubules either to secrete hydrogen

ions or to retain bicarbonate ions

All types produce hyperchloremic metabolic acidosis

with a normal anion gap.

Proximal RTA

Proximal RTA (Type 2) Caused by an

impairment of HCO3- reabsorption in the proximal tubules

Most cases occur in the context of Fanconi’s syndrome

Isolated proximal RTA is rare.

DISTAL RTA

Impairment of distal acidification

Inability to lower urine pH maximally below 6.0 under acid load

Pathomechanism is inability to secrete H+ adequately (secretory defect or classic distal RTA)

Gradient defect Voltage dependent

defect In children mainly a

genetic defect of the H+ pump

Adolsterone

Water

K+

Na

Na+

H+

Cl-RTA IV:

Hypoaldosteronism or pseudohypoaldosteronism

H20

Proximal RTA

Distal RTA RTA IV

Type of Acidosis

Hyperchloremic metabolic acidosis

Hyperchloremic metabolic acidosis

Hyperchloremic metabolic acidosis

Serum Potassium

low low high

Urine pH

< 5.5 >5.5 < 5.5

Urine bicarbonate loss