BRCU 2014- Course Schedule · • Rarely the only or main cause of hypokalemia • Decreased K...
Transcript of BRCU 2014- Course Schedule · • Rarely the only or main cause of hypokalemia • Decreased K...
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