Baylor University Medical CenterDallas, Texas

PotassiumPhysiologic Principles, Hypokalemia & HyperkalemiaASN BRCU 2014 Michael Emmett MD

Renal excretion90 mEq/d

GI excretion10 mEq/d

K+ Homeostasis

- 90 mv

- 90 mv

Net Absorption100 mEq/d

Total Body K+ = 50-55 mEq/Kg Wt

2 % 98 %

Internal Homeostasis of Potassium

Unwin, RJ. Luft, FC, Shirley. DG. Pathophysiology & Mgmt. of Hypokalemia: a clinical perspective. Nat. Rev. Nephrol. 7, 75–84 (2011)

Potassium Cell Shifts: Major Transporters

Drives K+ Into Cells

Drives K+ Out Of Cells

Causes of Hypokalemia

• First Consider & R/O Pseudo-hypokalemia

• [K+] falls in the test tube

• True Hypokalemia

• Shifts into cells

• Gastrointestinal losses

• Renal losses

• Inadequate intake

Pseudohypokalemia

• Uptake is usually due to very high number of metabolically active cells - it usually occurs with acute myeloid leukemia

• Ambient temperature increases Na-K ATPase activity & shifts K into cells

• Generally prevented by rapidly separating plasma and cells or store blood at 4°C

• Often also associated with pseudohypoglycemia

Cell K+ Uptake in Test Tube

Spurious Hypokalemia in Myeloproliferative Disorders

Naparstek & Gutman A J Med Sci 288; 175 1984

R Polak et al Ann Clin Biochem 2010; 47: 179–181

Sodi R, et al The phenomenon of seasonal pseudohypokalemia: effects of ambient temperature, plasma glucose and role for sodium-potassium-exchanging-ATPase. Clin Biochem. 2009 Jun;42(9):813-8

Seasonal Pseudohypokalemia

True HypokalemiaIn Vivo Cell Shifts

HypokalemiaIn Vivo Cell Shifts (Continued)

• Anabolism

– Treatment of pernicious anemia

– Rapidly expanding cell mass:

leukemias and lymphomas• Barium, Cesium Poisoning/Chloroquine

intoxication

• Hypokalemic periodic paralysis

• Hypothermia

Hypokalemic Periodic Paralysis

Intermittent Acute Attacks of Muscle Weakness/HypokalemiaAcquired/sporadic form is associated with Hyperthyroidism(usually Graves Disease)

Inherited form is an autosomal dominant trait with incomplete penetrance. It is more severe in men. Prevalence 1:100,000

Attacks in both forms often occur during night/early morning Also is precipitated by strenuous exercise (usually occurs after the exercise); ingestion of carbohydrate-rich meals; cold exposure; or the administration of glucose, insulin, or glucocorticoids.

• Primarily a male disorder

• Hyperthyroidism usually due to Graves disease

Hyperthyroid symptoms extremely variable

• Asian, Hispanic, & American Indian predominance ~10 % of Asian men with hyperthyroidism

0.1-0.2 % of Asian women with hyperthyroidism

0.2% Caucasian men with hyperthyroidism

• Weakness proximal>distal muscles and lower>upper extremities Respiratory muscles rarely affected

• Paralysis tends to occur at night or after strenuous exercise and/or high carbohydrate meals.

Thyrotoxic Hypokalemic Paralysis

Lin & Huang J Am Soc Nephrol 23: 985–988, 2012

Thyrotoxic Periodic Paralysis

X

Biochemical findings• Severe hypokalemia (often <2.0 mmol/L)

• Hypophosphatemia & mild hypomagnesemia are also common

• Elevated Alkaline Phosphatase

Treatment• K supplementation – be very careful regarding

rebound hyperkalemia• Propranolol may reverse and prevent attacks

while awaiting hyperthyroid Rx• Avoid strenuous exercise & high-carbohydrate

diet

Inherited Hypokalemic Periodic Paralysis

AcetazolamideHigh‐K, low‐Na, low‐carbohydrate dietBedtime prophylactic doses of oral KCl

Rx of Inherited Hypokalemic Periodic Paralysis

Sigue G et al From profound hypokalemia to life-threatening hyperkalemia: a case of barium sulfide poisoning. Arch Intern Med. 2000

25 yo man ingested Magic Shave

Res

pira

tory

dis

tres

s/In

tuba

tion

K+

Hypokalemia – K+ Deficits

• Muscle Weakness• Rhabdomyolysis• EKG/Cardiac effects

• U waves• Arrhythmias

• Kidney Effects• Nephrogenic DI• Hypokalemic Nephropathy

Clinical Manifestations

• Rarely the only or main cause of hypokalemia

• Decreased K intake does often exacerbate hypokalemia due to other processes

• Urine K+ excretion should fall to the5-15 mEq/d range

Inadequate IntakeHypokalemia – K+ Deficits

(4.3 mEq/l)X(160 l/day)= 700 mEq/day

Normal or High K intakeExcrete 15-80% of

Filtered Load

Hypokalemia Excrete <1% ofFiltered LoadUnwin, R. J. et al.

Nat. Rev. Nephrol. 7, 75–84, 2011

TTKG

70 mEq/day

• Urinary K+ >25-30 mEq/day

• Spot K/Cr ratio > 13-15 mEq/gm

• Usually associated with high distal Na+ delivery combined with high mineralocorticoid activity

Due to Renal LossesHypokalemia – K+ Deficits

Diarrhea: Stool [K+] 10-40 mEq/L Urinary K+ < 20 mEq/L

Vomiting: Gastric Fluid [K+] 5-10 mEq/L

Hypokalemia is primarily due to renal K+ loss

Urine [K+] varies but intermittently is very high

Due to Gastrointestinal Losses

Hypokalemia – K+ Deficits

Cortical Collecting DuctPC

PC

PCIC

IC

apical

basolateral

ECFBlood

Na+Principal Cell

K+K+

Na+

Na+

Cl-

MR

Na+

ATP 2 K+

3 Na+

ATP 2 K+

3 Na+

ATP2 K+

3 Na+

ATP2 K+

3 Na+

K+

K+

paracellular

Intercalated Cell (A)

ATP 2 K+

3 Na+

ATPH+

ATP

H+

K+ HCO-3

Cl-

Na

NaNa

Na

Na

Factors Affecting Distal TubuleNa+ Reabsorption & The Secretion of K+ & H+

1. NaCl & Na-Aniondelivery

2. Volume3. Aldosterone Level4. Permeability of the

luminal anions5. K Status6. Acid/Base Status

Aldosterone

DistalTubule

Renin

CCT

AnionsAnions

The Normal Renin-Aldosterone Feedback Loop EAB Volume → Renin → Angiotensin → Aldosterone

JGCells

Renin

Angiotensin I

Angiotensin II

SodiumRetention

IncreasedEABV

2

3

4

5

6a

7

8

JGCells

Renin

Angiotensin I

Angiotensin II

JGCells

Renin

Angiotensin I

Angiotensin II

JGCells

Renin

Angiotensin I

Angiotensin II

SodiumRetention

IncreasedEABV

2

3

4

5

6a

7

8

Angiotensin IAngiotensin IAngiotensin IAngiotensinogen

ACE

Decreased RenalArtery Pressure1

6b

Pressor Effects

AldosteroneSecretion

PlasmaRenin

Activityng/ml/hr

Urine Aldosterone μg/day

Sodium ExcretionmEq/Day

ECF Volume

Secondary (Physiologic) Hyperaldosteronism

NaNa

ALDO

Distal NaDelivery

ReninAldo

ECF Volume Low Appropriate Secondary Hyperaldosteronism

DistalTubule

RENIN

CCT

PlasmaRenin

Activityng/ml/hr

Urine Aldosterone μg/day

Sodium ExcretionmEq/Day

ECF Volume

Secondary (Physiologic) Hypoaldosteronism

Na

NaNa

Na

Na

aldo

Na

NaNa

NaReninAldo

ECF Volume HighAppropriate Secondary Hypoaldosteronism

Distal NaDelivery

DistalTubule

renin

CCT

PrimaryHyperaldosteronism

Distal tubule Delivery & urine Na Excretion are High

RENIN

ALDO

Initial Na Rentention

K++H+ Loss

VOLUME

Generous DistalNa Delivery

12

3

4

PlasmaRenin

Activityng/ml/hr

Urine Aldosterone μg/day

Sodium ExcretionmEq/Day

ECF Volume

Secondary (Physiologic) Hypoaldosteronism

Na

NaNa

Na

Na

Na

NaNa

Na

ALDO

AldoDistal NaDelivery

1o “AUTONOMOUS” HPERALDOSTERONISM

DistalTubule

Renin

CCT

Hoorn, EJ; Lubbe, NVD and Zietse, R.The renal WNK kinase pathway: a new link to hypertension.Nephrol Dial Transplant 24: 1074–1077. 2009

Five Renal WNK kinases (Current): WNK 1, 2, 3, 4 & KS WNK1

Proline and alanine-rich kinase (SPAK)Oxidative stress-responsive kinase-1 (OSR1)Serum/glucocorticoid regulated kinase 1

(SGK10)Phosphatidyl inositol 3-kinase (PI3K)

Aldosterone producing adenoma (APA) 65%

Idiopathic Hyperaldosteronism

(IHA or BAH)34%

Glucocorticoid Remediable Hyperaldosteronism

<1%

Aldosterone producing carcinoma<1%

PRIMARY HYPERALDOSTERONISMHIGH ALDOSTERONE & LOW RENIN

LEVELS

Chromosome #8

Glucocorticoid Remediable Hyperaldosteronism (GRA)

Autosomal Dominant

Na

NaNa

Na

Na

Na

NaNa

Na

ALDO

AldoDistal NaDelivery

DIURETICS

DistalTubule

Renin

CCT

High Renin & High Aldosterone & High Distal Tubule Sodium Delivery

Hypokalemia and Metabolic Alkalosis Ensue

• Diuretics (thiazides/loop/proximal)• Genetic “diuretic-like” syndromes

• Bartter• Gitelman

• Poorly Absorbed Anions (Penicillins)• Gastric Metabolic Alkalosis (NaHCO3)

Increased “Autonomous”Non-Aldosterone Mineralocorticoid

(Or Mineralocorticoid-Like Substance)

Other Genetic Causes of Hypokalemic Metabolic Alkalosis and Hypertension

• Liddle syndrome

• Syndrome of apparent mineralocorticoid excess (Genetic or Acquired)

• Activating mutation of the mineralocorticoid receptor

↓ Renin ↓Aldosterone

Genetic Causes of Hypokalemic Metabolic Alkalosis and Hypertension

• Liddle syndrome

• Syndrome of apparent mineralocorticoid excess (Genetic or Acquired)

• Activating mutation of the mineralocorticoid receptor

↓ Renin ↓Aldosterone

• Low aldosterone &

• Low renin

• No response to exogenous aldosterone

• No response to

• competitive inhibitors of aldosterone (spironolactone)

• Good response to Triamterene/Amiloride normalizes BP and K+

• Renal transplant normalizes BP and K+

(NEJM 330:178, 1994)

Liddle Syndrome

• Liddle syndrome

• Syndrome of apparent mineralocorticoid excess (can also be acquired)

• Activating mutation of the mineralocorticoid receptor

Genetic Causes of Hypokalemic Metabolic Alkalosis and Hypertension

↓ Renin ↓Aldosterone

O

HO OHC O

CH2OH

CortisolO

O OHC O

CH2OH

Cortisone

PrednisoloneO

HO OHC O

CH2OH

O

O OHC O

CH2OH

Prednisone

11 -HydroxysteroidDehydrogenaseActive

InactiveActive

Inactive

2

1

11Carbon

Cortisol

Cortisone

11 -HydroxysteroidDehydrogenase

Active

Inactive

GlucocorticoidReceptor

GlucocorticoidReceptor

X

MineralocorticoidReceptor

11 -HydroxysteroidDehydrogenase-2

11 -HydroxysteroidDehydrogenase-2

Glycyrrhizic Acid

X

Active

Inactive

Apparent Mineralocorticoid

Excess (AME) SyndromeConcentration

3000X Aldo

Syndrome of Apparent Mineralocorticoid Excess

• Liddle syndrome

• Syndrome of apparent mineralocorticoid excess (can also be acquired)

• Activating mutation of the mineralocorticoid receptor

Genetic Causes of Hypokalemic Metabolic Alkalosis and Hypertension

↓ Renin ↓Aldosterone

Activating Mutation of Mineralocorticoid Receptor

apical

ATP 2 K+

3 Na+

barttin

basolateral

paracellular

K+

Na+2 Cl-

K+

Na+NKClCl

ROMKK+

Cl-ClC-Kb

NKCC2: Bartter syndrome I

ROMK: Bartter syndrome II

ClC-Kb: Bartter syndrome III

Barttin: Bartter syndrome IV

Tubule FluidThick Ascending

Limb of HenleTALH ECF

Blood

Bartter Syndromes

apical

ATP 2 K+

3 Na+

Cl-ClC-Kb

barttin

2 Cl-

K+

Na+NKCC2

ROMKK+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Tubule FluidThick Ascending

Limb of HenleTALH

ECFBlood

Ca2+

Ca Sensing Receptor

Ca2+

Ca Sensing Receptor

Bartter Syndromes

CaSR

Activating Mutation ofCalcium Sensing ReceptorBartter Syndrome V

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Ca++ and Mg++ Reabsorption TALH

3Na+

2K+2Cl-

K +

3Na+

2K+

Na+Na+

2Cl-

K +

Lumen Interstitium

Ca++

Mg++

LumenPositivePotential

3Na+

2K+2Cl-

K +

3Na+

2K+

Na+Na+

2Cl-

K +

Lumen Interstitium

Ca++

Mg++

LumenPotential

Falls TowardZero

Ca++ and Mg++ Wasting in Bartter Syndrome

(Loop Diuretics)

Distal Convoluted Tubule

3Na+

2K+

3Na+Na+Na+

Cl- 2K+Cl-

Lumen Interstitium

Na-Cl Co Transporter(NCCT) or

Thiazide Sensitive Co Transporter (TSC)

Thiazide diureticsGitelman syndrome

ClC-Kb (Cl Channel Kb) mutations are less common cause of Gitelman and Bartter syndrome

barttin

ClC-KbTRPM6Mg +

SLC12A3 gene (NaCl Cotransport)(Solute Carrier family 12, member 3)Mutations usually affect the trafficking of the protein to the plasma membrane, primarily due to protein misfolding, and retention in the endoplasmic reticulum, followed by rapid proteoasomal degradation. (These are type 2 mutations)

Bartter Syndrome

(Loop Diuretics)

Gitelman Syndrome(Thiazides)

Plasma K+ Low Low

Plasma HCO3 High High

Urinary Ca++ High Low

ConcentratingAbility

Impaired Normal

Volume Depletion

Marked Mild

Bartter vs Gitelman

apical

ATP 2 K+

3 Na+

barttin

basolateral

K+

Na+Cl-

ClC-Kb

ECFBlood

Urin

e F

low

Mg2+

Ca2+paracellular

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Tubule FluidThick Ascending

Limb of HenleTALH

K+

ROMK

2 Cl-

K+

Na+Na-K-Cl-Cl

Mg2+

Claudin 16Claudin 19

Magnesium & ROMK

ROMK = Renal Outer Medullary

K Channel“Inwardly Rectifying”

• A number of cases of Ogilvie Syndrome associated with severe hypokalemia have been reported.

• Very interestingly, the colonic fluid has been found to have very high K concentrations. This has not been reported in any other form of diarrhea or GI fluid lossing condition.

• It has been found that the colonic apical BK channels are markedly increased in both number & open state activity

Ogilvie Syndrome(Intestinal Pseudoobstruction)

& Hypokalemia

van Dinter TG Jr, Fuerst FC, Richardson CT, Ana CA, Polter DE, Fordtran JS, Binder HJ: Stimulated active potassium secretion in a patient with colonic pseudo-obstruction: A new mechanism of secretorydiarrhea. Gastroenterology 129: 1268–1273, 2005

Sandle GI, Hunter M: Apical potassium (BK) channels and enhanced potassium secretion in human colon. QJM 103: 85–89, 2010

Hypokalemia – Evaluation Scheme Treatment of Hypokalemia• Address underlying cause• Chronic treatment

– KCl: liquid or Slow K (Especially when associated with metabolic alkalosis)

– K-Bicarbonate Precursors when associated with metabolic acidosis

• Acute treatment– IV KCl (40-80 mEq/L at rate <20 mEq/h)

• In Saline NOT Dextrose

• If hypokalemia is accompanied by acidemia, start to correct hypokalemia before correcting the acidemia

POTASSIUM SALTS

POTASSIUM CHLORIDE SALTS

KCL Solution 20 or 40 mEq /15 mL

MicroK® Capsule 8 or 10 mEq

Klor-Con® 10, 15 0r 20 mEq

K-Tab® 10 mEq

POTASSIUM ALKALI SALTS

Polycitra 2 mEq/ml base

NaCitrate 1mEq/ml

K Citrate 1mEq/ml

Citric Acid

K Gluconate (Kaon) 1.33 mEq/ml or 5 mEq/tablet

KHCO3 & K Citrate (Klyte)

25 or 50 mEq/tablet

Electrolytes & AG for Selected FruitsBANANAS TOMATOES ORANGES

ELECTROLYTE mEq/inch mEq/100g mEq/100 g mEq/100 g

Potassium 2.23 12.0 10.0 5.5

Sodium 0.016 2.0 2.0 1.7

Chloride 0.02 2.0 4.0 2.5

Anion gap 12.0 8.0 4.7

Kopyt N, Dalal F, Narins RG. NEJM 313; 582, 1985

Orange, Tomato, Coconut, Noni ~50 mEq/l

HYPERKALEMIA

Differential Dx of Hyperkalemia• R/O Pseudohyperkalemia

– In Test Tube• Warm Temperature

• Fragility

• Clotting (Serum vs Plasma)

• Heparin (Reverse Pseudohyperkalemia)

– In the Arm – Fist Clenching/Tourniquet

• K shifts out of Cells

• Impaired renal excretion– Always contributes to sustained hyperkalemia

• Excess K+ intake may contribute

Sinclair, D et al Seasonal Pseudohyperkalaemia

J Clin Pathol 2003;56:385–388

Seasonal Pseudohyperkalemia

Autosomal dominant trait

Enhanced temperature dependent K+ leakage out of RBC’s

Maps to same gene locus as hereditary xerocytosis

(dessicocytosis, some forms of stomatocytosis)

Familial Pseudohyperkalemia

Kintzel PE1, Scott WL Pseudohyperkalemia in a patient with CLL & tumor lysis syndrome J Oncol Pharm Pract. 2012 Dec;18(4):432-5

Pseudohyperkalemia in CLL49-yo woman; stage IV CLL . Admitted for chemoRx.

WBC = 364,000 (96% lymphocytes); platelets 100.000. Rx: rituximab, cyclophosphamide, and fludarabine. Also given bicarbonate and allopurinol.

After Rx [K] = 10.7. Repeat = 11.2 mmol/L.

No acidosis, renal failure, or tumor lysis syndrome. Phosphate, calcium, and uric acid WNL. Given calcium chloride, albuterol, dextrose-insulin, furosemide, and sodium polystyrene

sulfonate. Emergent dialysis was being prepared. However, she denied any symptoms attributable to hyperkalemia (fatigue, muscle weakness, or palpitations).

EKG unremarkable.

Abraham et al. Clin Chem 54; 2008

“Reverse” Pseudohyperkalemia

Don BR, Sebastian A, Cheitlin M, Christiansen M, Schambelan M. Pseudohyperkalemia caused by fist clenching during phlebotomy. N Engl J Med. 322:1290-2. 1990

Pseudohyperkalemia

K+Na+

ATP2 K+

3 Na+ ATP 2 K+

3 Na+

K+

Na+

K+K+

= ~130mEq/l

K+ = ~4.0 mEq/l

PD = -90

Ki

Ko

1304.0

32.5= =

Ko

Ki

PD = 58 x log = -90Nernst Equation

K+

Normal

K+Na+

ATP2 K+

3 Na+ ATP 2 K+

3 Na+

K+Na+

K+K+

= ~130mEq/l

K+ = ~7.0 mEq/l

PD = -78

Ki

Ko

1307.0

18.6= =

Ko

Ki

PD = 58 x log = -78Nernst Equation

K+

HyperkalemiaDepolarization

Peaked T waveFlattened P waveProlonged PRProlonged QRS

EKG MANIFESTATIONS OF HYPERKALEMKIA

K=6.8

THERAPY OF HYPERKALEMIA #1 Direct Electrical Antagonism

• 10% Calcium Gluconate 10 mL IV

(4.5 mEq of calcium) or

• 10% Calcium Chloride 10 ml IV

( 13.6 mEq of Calcium)

mVolts

RP

RP

TP

normal

Normal Hyperkalemia-120

-90

-60

-30

0

depolarized

TP

HYPERKALEMIA & THE RESTING POTENTIALEFFECT OF CALCIUM INFUSION ON MUSCLE

THRESHOLD POTENTIAL

Ca TP

THERAPY OF HYPERKALEMIA #2

Shift K+ into Cells

• Regular insulin 10 U IV +

50 mL of 50 % glucose then D 10% at about 75 ml/hr Glucose

No glucose if baseline hyperglycemia exists

• Albuterol 10-20 mg in 4 mL of saline via IPPB (Usual “asthma” dose is 2.5 mg)

• NaHCO3 50-100 mEq IV

K+Na+

ATP2 K+

3 Na+ ATP 2 K+

3 Na+

K+Na+

H+

Na+

K+K+

= ~130mEq/l

Insulinβ2 Agonists

Insulin

Rx of HyperkalemiaShifting K+ into Cells

HCO3

Allon et al KI 1990

CHANGE IN PLASMA [K] WITH RxHemodialysis Patients

minutes

Insulin & Glucose

Albuterol, Insulin &Glucose

Albuterol

KmEq/l

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

015 30 45 60

NaHCO3

& Blumberg et al KI 1992hours

KmEq/l

-1.2

-0.8

-0.4

0

1 2 3 4 5 6

EFFECT OF IV NaHCO3 ON PLASMA [K]Hemodialysis Patients

Blumberg et al KI 1992

• Improve Kidney Function – Volume Expansion When Indicated

• Loop &/or Thiazide Diuretics

• Induce Diarrhea

• Na-polystyrene sulfonate (Kayexalate®) 15-30 gm PO ? Sorbitol

• ?Kayexalate® Enema ?? Sorbitol

• Fludrocortisone and Glycyrrhetinic Acid

• Experimental : RLY5016 & Zirconium silicate

THERAPY OF HYPERKALEMIA #3

Remove from Body

THERAPY OF HYPERKALEMIA #4Stop K Salts and K+ retaining

Medications

Chronic Management of Hyperkalemia - Continued

• Assess volume and blood pressure

• ↓ volume, Normal BP: consider fludrocortisone

• ↑ volume, ↑ BP: consider

• Diuretics

• NaHCO3

• +/- Kayexalate or other K Binders

Hyperkalemia

• Recent ingestion of large amounts of orange/tomato/coconut /noni juice

(Morinda citrifolia)

• Some pica syndromes

• Salt substitute

Excess intake (usually in setting of impaired renal excretion)

Hyperkalemia

• Cell injury: rhabdomyolysis, tumor lysis, massive hemolysis, ischemia

• Toxins/drugs: digoxin (Chan su), tetrodotoxin (Puffer Fish), succinylcholine

• Diabetic ketoacidosis, nonketotic hyperosmolar state

• Hyperkalemic periodic paralysis

Cell Shift

Hyperkalemic Periodic Paralysis

Metabolic Acidosis & K+ Shifts

• Inorganic (mineral acids) cause K+ shift BUT NOT organic acids

• Diabetic ketoacidosis & ↑ K– Insulin deficiency– Hyperosmolality

• Lactic acidosis & ↑ K– Cell ischemia– Reduced GFR

• Epsilon-aminocaproic acid, a synthetic amino acid structurally similar to lysine and arginine does cause K shift out of cells

H+

K+

OA-

Cl-

H+

Impaired Renal K+ Excretion

• Primary decrease in mineralocorticoid activity

• Primary decrease in distal Na+ delivery

• Abnormal cortical collecting duct

Renin

IMPAIRED RELEASEOF RENIN

NSAID’sBeta Blockers

Cyclosporine, TacrolimusDiabetesElderly

Angiotensin I Angiotensin II

ANGIOTENSIN-CONVERTING ENZYME

INHIBITORS

ANGIOTENSINRECEPTOR BLOCKERS

Aldosterone

IMPAIREDALDOSTERONEMETABOLISM

Adrenal DiseaseHeparin

Ketoconazole

SODIUM CHANNELBLOCKERS

AmilorideTriamterene

TrimethoprimPentamidine

Na+

Na+

K+

K+

SpironolactoneEplerenone

Yaz

LUMEN(-)

Afferent Arteriole

Juxtaglomerularcells

AdrenalGland

Collecting Duct(principal cell)

Modified from Palmer BF. N Engl J Med 351:585-92,2004

ALDOSTERONERECEPTORBLOCKERS

DrospirenoneA Progestin with Mineralocorticoid Antagonist Activity

• The progestin component of some relatively new oral contraceptives –

Yaz, Yasmin, Yasminelle

• The dose in OCPs has an effect like 25 mg spironolactone

• It may reduce BP

• It may generate hyperkalemia when other problems exist – ie CRD, use of other drugs which reduce K excretion, etc.

Pseudohypoaldosteronism Type IHyperkalemic acidosis with salt wasting

• Autosomal recessive– Inactivating mutations in α, β, or γ subunits of

ENaC

– Severe and unrelenting

– Associated with pulmonary infections

• Autosomal dominant– Inactivating mutations in the mineralocorticoid

receptor

– Mild and remits with age

Familial Hyperkalemic Hypertension (FHHt)Pseudohypoaldosteronism Type II

Gordon’s Syndrome“Chloride Shunt Hypothesis”

• Autosomal dominant

• Hypertension, hyperkalemia, normal gap metabolic acidosis, short stature

• Historically called a “Chloride Shunt”

• Responsive to thiazide diuretics

apical

basolateral

ECFBlood

Na+Principal Cell

K+K+

Na+

Na+

Cl-

MR

Na+

ATP 2 K+

3 Na+

ATP 2 K+

3 Na+

K+

K+

paracellular

Intercalated Cell (A)

ATP 2 K+

3 Na+

ATPH+

ATP

H+

K+ HCO-3

Cl-

Cl-

“Chloride Shunt”

Hoorn, EJ; Lubbe, NVD and Zietse, R.The renal WNK kinase pathway: a new link to hypertension.Nephrol Dial Transplant 24: 1074–1077. 2009

Five WNK kinases: WNK 1, 2, 3, 4 & KS WNK1

Proline and alanine-rich kinase (SPAK)Oxidative stress-responsive kinase-1 (OSR1)Serum/glucocorticoid regulated kinase 1

(SGK10)Phosphatidyl inositol 3-kinase (PI3K)

Gordon’s SyndromeHyperactive Thiazide Transporter (NCC) Hypothesis

• Opposite of Gitelman Syndrome– Hypertension– Hyperkalemia– Metabolic Acidosis– Low Renin and Aldosterone Levels– Hypercalciuria– Nephrolithiasis

• Rx – Thiazides• Several different genes cause this phenotype

– The “WNK” disorders– Inactivating mutations in WNK4 – Activating mutations in WNK1

Familial Hyperkalemic Hypertension (FHHt)Gordon’s Syndrome

“Hyperactive Thiazide Transporter (NCC) Hypothesis”

Hyperkalemia Secondary to Decreased Distal Na+ Delivery

• Oliguric acute renal failure

• Acute glomerulonephritis

• Pseudohypoaldosteronism type II