ACID BASE BALANCE & REGULATION OF pH

K HOMEOSTASIS

• EC [H+] ~ 40 nanomol/L• Essential for normal renal function, • When there is a change in [H+], proteins gain or

lose H+ ions, resulting in • Prot(-) + H(+)<---prot-H

– alterations in charge distribution,– molecular configuration, and – protein function.

• The process of H+ regulation involves 3 basic steps– Chemical buffering by the EC & IC buffers– Control of the partial pressure of CO2 in the blood by

alterations in the rate of alveolar ventilation– Control of plasma HCO3 by changes in renal H+

secretion

-6

• Under normal conditions, the steady state is preserved, as renal H+ secretion varies

directly with the rate of H+ production• Plasma [H+] and pH are maintained

within narrow limits.

pH [H+]neq/L Pco2,mmHg [HCO3-],meq/l

Arterial 7.37 – 7.43 37 - 43 36 – 44 22 - 26 Venous 7.32 – 7.38 42 – 48 42 – 50 23 - 27

• The kidneys must excrete the 50 to 100 meq of noncarbonic acid generated each day

• This is achieved by H+ secretion, although the mechanisms are different in the PT & TALH (Na H exchange) and in the CT (H-ATPase).

• The daily acid load cannot be excreted unless virtually all of the filtered HCO3 has been reabsorbed, because HCO3 loss in the urine is equivalent to adding H+ ions to the body

• Secreted H+ ions are excreted by binding to either filtered buffers, such as HPO4- & creatinine, or to NH3 to form NH4+. NH4+ is generated from the metabolism of glutamine in the PT; the rate of which this occurs can be varied according to physiologic needs.

• The extracellular pH is the primary physiologic regulator of net acid excretion. In pathophysiologic states, however, the effective circulating volume, aldosterone, & the plasma K+ concentration can all effect acid secretion, independent of the systemic pH.

• H2CO3 ----- H(+) + HCO3(-)• HCl ----- H(+) + Cl(-)• NH4(+) ----- H(+) + NH3• H2PO4(-)----- H(+) + HPO4(2-)• ACIDS: BASE carbonic acid noncarbonic acids

Law of mass action =the velocity of a reaction is proportional to the product of the

concentration of the reactants

• H2O ----- H(+) + OH(-)• v1 = k1 [H2O], v2 = k2 [H+] [OH-]• At equilibrium v1 = v2

• k1 [H2O] = k2 [H+] [OH-]• K’ = = • [H2O] ~ constant, Kw = [H+] [OH-] (at body temp) = 2.4 x 10

V1/k1

V2/k2

K1 [H+] [OH-] k2 [H2O]

-14

pH• pH = - log [H+], = 7.40• Tightly regulated in the range 7.38 – 7.42• Relationship between arterial pH and [H+] in the

physiologic range pH [H+] nmol/L 7.80 16 7.70 20 7.60 26 7.50 32 7.40 40 7.30 50 7.20 63 7.10 80 7.00 100 6.90 125 6.80 160

• Oxidative metabolism produces CO2 (volatile acid) & H2O

• CO2 + H2O H2CO3 H(+) + HCO3(-)

• Non – volatile acids results from the metabolism of dietary protein, resulting in the accumulation of ~ 70 mmol acid per day

• Buffer systems prevent changes in pH– HCO3 / CO2– HPO4(2-) / H2PO4(-)– Plasma & IC proteins, Hb– Bone

c.a.

Rate limiting step

Henderson – Hasselbalch equiation

[H+] = 24 X PCO2

[HCO3]

Role of the kidney

Accounts for reabsorption of some 85% of filtered bicarbonate, and operates at high capacity, but generates a low gradient of [H+] across the epithelium, with the luminal pH falling only slightly from 7.4 at the glomerulus to around 7.0 at the end of the PT. bicarbonate reabsorption also occurs at the CT, together with acid secretion

Net acid secretion

• The tubules must secrete further acid into the tubular lumen beyond that needed to reabsorb all filtered bicarbonate

• Provide a buffer in the tubular fluid to assist in the removal of this acid

• Buffer: H2PO4(2-), titratable acid NH3 / ammonia Net acid excretion = titratable acidity +

NH4(+) – HCO3(-)

Bicarbonate secretion• In metabolic alkalosis• HCO3- secretion by a second population of

intercalated cells in CCT• Polarity of the membrane transporters can be

reversed

ATP

Cl-

HCO3-CA

CO2 + OH-

H2O

H+

Stimulated by IC acidosis,and elevated Pco2

• Glutamine NH4(+) + glutamate(-) NH4(+) + α-ketoglutarate(2-)• Enzymes : glutaminase; & glutamate dehydrogenase • NH4+ excretion can be increased

– Increasing proximal NH4+ production from glutamine– Lowering urine pH,which will increase NH3 diffusion into the lumen in the

medullary CT

• Titratable acidity– HPO4(-)– Minor: other weak acids ,such as creatinine, uric acid

• Extracellular pH = major physiologic regulator of renal H+ secretion– Enhanced luminal Na-H exchange, by binding of H+ on the exchanger,

and by synthesis of new exchangers– Increased activity of Na-3HCO3 cotransporter in the basolateral

membrane– Increased NH4+ production from glutamine– Alteration IC pH

Disturbances in acid base balance

• Respiratory acidosis – Acute, – Chronic

• Metabolic acidosis, • Respiratory alkalosis

– Acute– chronic

• Metabolic alkalosis

Disorder pH [H+] primary compensatory disturbance response

Metabolic Acidosis [HCO3] PCO2

Metabolic Alkalosis

Respiratory Acidosis PCO2 [HCO3]

Respiratory Alkalosis

Renal & Respiratory compensation

• Disorder Primary change Compensatory response

Disorder Primary change Compensatory response

Metabolic acidosis [HCO3] 1.2 mmHg decrease Pco2 / 1 meq/L fall in [HCO3]

Metabolic alkalosis [HCO3] 0.7 mmHg elevation Pco2 / 1 meq/L rise [HCO3]

Respiratory acidosis Pco2 acute 1 meq/L increase in [HCO3] / 10 mmHg rise Pco2 chronic 3.5 / 10

Respiratory alkalosis Pco2 acute 2 meq/L reduction in [HCO3] /10 mmHg fall in Pco2 chronic 4 / 10

Respiratory acidosis• Accumulation of CO2 in the body as a result of

failure of pulmonary ventilation, hypercapnia– Lesion CNS (cerebral function, spinal cord)– Peripheral nervous pathways involved in ventilation

(peripheral nerve & muscle disorders)– Lung disease involving impaired gas diffusion

• This is initially buffered to a limited extend by IC buffers, such as Hb

• Over a few days, a new steady state is achieved;– renal excretion of net acid matches that being

retained by the lungs– Urine pH low, [HCO3] high

Acute respiratory acidosis

• There is virtually no EC buffering, because HCO3(-) cannot buffer H2CO3

• Renal response takes time to develop, the cell buffers, Hb and proteins, constitute the only protection against acute hypercapnia

• H2CO3 + Buf(-) HBuf + HCO3(-)• Plasma [HCO3] will increase 1 meq/L for

every 10 mmHg rise in PCO2.

Chronic respiratory acidosis

• The persistent elevation in PCO2 stimulates renal H(+) secretion, resulting in the addition of HCO3 to ECF

• The net effect is that, after 3-5 days, a new steady state is attained,

~ 3.5 meq/L increase in plasma [HCO3] for every 10 mmHg increment in the PCO2 • The rise in plasma [HCO3] is determined solely

by the increase in renal H(+) secretion

Alveolar – Arterial Oxygen Gradient• Calculation of the A-a oxygen gradient may be useful in

differentiating intrinsic pulmonary disease from extrapulmonary disorders as the cause of hypercapnia

• The sum of the partial pressures of the other gasses in the alveolus must be equal to 150 mmHg, i.e. to the partial pressure of oxygen in the inspired air, PIO2.

• (A-a) O2 gradient = PIO2 – 1.25PaCO2 – PaO2 • A normal gradient essentially excludes intrinsic

pulmonary disease; and suggest some form of central alveolar hypoventilation, or chest wall / ventilotory muscle abnormality

• The (A-a) O2 gradient is always increased in hypercapnic patients with intrinsic pulmonary disease

Metabolic Acidosis

• Accumulation of non-volatile acids• Inability of the kidneys to excrete the dietary H+

load or an increase in the generattion of H+, due to either the addition of H+ or to the loss of HCO3-

• Protective response– Physicochemical buffering of H(+) by available bases, HCO3, IC & EC

proteins, tissue PO4; complete within a few min; further buffering in bone & other tissues over the ensuing hrs – days

The intracellular entry of H(+) is associated in part with the movement of K(+) out of the cell to maintain electroneutrality, especially if the MA are due to an excess of non-organic acids, such as in renal failure and diarrhea

– Respiratory response, the low pH acts as a potent stimulus to increase alveolar ventilation (stimulates the central & peripheral chemoreceptors ); manifest by a deep, rapid breathing pattern (kussmaul respiration) in 1-2 hrs, max level at 12-24 hrs, this response drives the CO2 below normal; provides a medium term compensation for the acidosis

P(CO2) will fall 1.2 mmHg for every 1.0 meq/L reduction in plasma [HCO3] to a minimum P(CO2) of 10 – 15 mmHg

– Renal response, steady state correction requires the development over several days of an increased capacity by the kidney to excrete the metabolic acid load;

this involves reabsorption of all fitered HCO3, maximum titration of filtered buffers with secreted H(+), and increased intrarenal synthesis of ammonia, which combines with the secreted hydrogen ions in the lumen and appears in the urine as ammonium

Urine pH falls to a minimum (~4.5), and the plasma bicarbonate is elevated back up

• While the resulting pH is brought up towards normal, it never overshoots

• Principal factors causing an increase in H(+) secretion by the nephron– Increase in filtered load of bicarbonate– Decrease in ECF volume

– Decrease in plasma pH– Increase in blood p(CO2)– Hypokalemia– Aldosterone

result in increased Proximal bicarbonatereabsorption

Decrease IC pH of theTubular cells activatesH(+) secretion and enhances NH3 synthesis.Enhances net acid secretion

Patterns of metabolic acidosis• Acid is added as hydrochloric / mineral acid; there is no

addition to the plasma of a new acid anion• Primary loss of bicarbonate buffer from ECF; the

accumulating acid might be in the form of an organic acid where the acid anion accumulates in the plasma to replace the falling bicarbonate

• Anion Gap / AG = [Na] – ([Cl] + [HCO3]), normal 8 – 12• AG = unmeasured anions – unmeasured cations• Δ AG / Δ [HCO3] normally between 1 – 2 in an

uncomplicated high AG metabolic acidosis– < 1:1 suggest a combined high and normal AG acidosis– > 2:1 suggest that the fall in plasma [HCO3] < expected due to

concurrent metabolic alkalosis

c.a. inh.: acetazolamide

(RTA)

hyperalimentation

Alcoholic patients have a predisposition to a # forms of increase AG metab. acidosis;starvation ketosis, lactic acidosis, and intoxication by methanol or ethylene glycol.Where metab. Acidosis is associated with advanced renal failure, the cause is usually the accumulation of complex organic acids normally excreted by the kidneys, and the result is an increased AG

• Urine AG = ([Na] +[K]) – [Cl], pos/nearO = unmeasured anions – unmeasured cations

• Major unmeasured urinary cation = NH4(+), 20-40 meq/L• In normal AG metabolic acidosis, the excretion of NH4(+) [and of Cl(-)]

to maintain electroneutrality should increase markedly , -20 to >-50 meq/L

• The acidosis in renal failure and RTA 1&4 is due to impaired H(+) & NH4(+) excretion, and the urinary AG retains its normal positive value

• Two conditions in which the urinary AG cannot be used– High AG acidosis, e.g. ketoacidosis, the unmeasured ketoacid anions will

counteract the effect of NH4(+), U-AG may be positive– Volume depletion with avid Na retention U[Na]<25 meq/L; the decrease in

distal Na delivery impairs distal acidification, the concurrent increase in Cl absorption prevents the excretion of NH4Cl and the development of a negative U-AG

Urine osmolar gap• Calculated urine osmolality = 2x ([Na] +[K]) + [BUN]/2.8 + [glucose]/18• The gap between the measured and

calculated urine osmolality should largely represent ammonium salts

• E.g. urine Osm G = 100 mosm/kg; ammonium excretion should be approximately one-half this value – due to accompanying anions – or 50 meq/L

Renal Tubular Acidosis

• Metabolic acidosis results from diminished net tubular H+ secretion

• Not associated with accumulaton of any organic acid anion

• Normal Anion Gap• Congenital / acquired

Type1/distal Type 2/proximal type 4

Basic defect Decreased distal acidification Diminished prox. HCO3 reabsorption Aldosteron deficiency/ resistance

Urine pH > 5.5 Variable:>5.5 if above reabsorptive Usually <5.5during acidemia threshold; <5.5 if below

Plasma [HCO3] May be below 10 meq/L Usually 14 - 20 meq/L Usually above 15 meq/L untreated

Fractional excretion <3% in adults, may reach 5 – 19 % > 15 – 20% < 3%HCO3 at normal [HCO3] in young children

Diagnosis Response to NaHCO3 or NH4Cl Response to NaHCO3 Measure plasma [Aldosterone]

Plasma [K] Usually reduced / normal Normal / reduced Elevated elevated with voltage defect (urinary K wasting)

Dose of HCO3 1 – 2 in adults; 4 – 14 in children 10 – 15 1 – 3, may require no alkalimeq/kg/d to normalize if hyperK correctedplasma [HCO3]

Nonelectrolyte Nephrocalcinosis & renal stones Rickets / osteomalacia / None complications (hypercalciuria, hyperphosphaturia) osteopenia

Hereditairy, disorders of Calcium metabolism, associated with hyperK, marked volume depletion

ifosfamideHypocalcemia, vit D deficiency

RTA 1

• Defect H(+)ATPase pump in the cortex or in the medulla• A reduction in the cortical Na(+) reabsoption, diminishing

the degree of luminal negativity and producing a voltage – dependent defect. This will lead to a concurrent impairment in K(+) secretion, which is also driven in part by the favorable electrical gradient. Hyperkalemia will accompany the metabolic acidosis. E.g. with urinary tract obstruction, sickle cell ds.

• Increase in membrane permeability, which allows for back diffusion of H(+) ions. E.g. Amphotericine B

FEHCO3 (%) =Urine [HCO3] x plasma [Creatinine]

Plasma [HCO3] x urine [Creatinine]X 100

RTA 2• Proximal HCO3 reabsorption is reduced as is total HCO3

reabsorptive capacity• Self-limiting disorder in which the plasma [HCO3] is

usually between 14 & 20 meq/L• Intact reabsorptive capacity of distal nephron• 3 factors are of primary importance in proximal HCO3

reabsorpyion:– Na-H exchanger in the luminal membrane– Na-K ATPase pump in the basolateral membrane that provide

the energy for NHE by maintaining a low cell [Na] & therefore a favorable gradient for passive Na-entry into the cell

– The enzyme Carbonic Anhydrase which is located both in the cell and in the lumen

• Phosphate wasting & hypophosphatemia, renal glucosuria, & aminoaciduria, hypocalcemia, hypouricemia

RTA 1 VS RTA 2 • Response to raising the plasma HCO3 concentration

with NaHCO3 (infused at a rate of 0.5 - 1.0 meq/kg/h).• the urine pH remain constant in RTA1, • will rise markedly in RTA2, if the reabsorptive

threshold is exceeded• incomplete RTA1, plasma HCO3 is normal; diagnosis by

giving an acid load as NH4Cl, 0.1 g/kg, this should induce a 4-5 meq/L fall in plasma [HCO3] within 4-6H

• urine pH willl remain above 5.5 in RTA1 • But <5 in normal subjects

RTA 4

• Aldosterne deficiency / resistance• HyperK impairs NH4 production &

excetion• Most have underlying renal insufficiency

Signs & Symptoms

• Increase in minute ventilation, hyperpnea, dyspnea.• Fall in pH< 7.0-7.2 predisposes to ventricular

arrhythmias, and can reduce both cardiac contractility and the inotropic response to catecholamines.

• Neurologic: range lethargy to coma• related to pH in CSF, more prominent in respiratory

acidosis. CO2 crosses BBB more rapidly• Skeletal problems, due in part to release of Ca(2+)

HCO3 required to correct the acidemia

• HCO3 def = HCO3space X HCO3 def/L• Bicarbonat space is appoximately 60 % lean

BW for mild to moderate metabolic acidosis• Can reach 70% or more for [HCO3] below 10

meq/L• e.g. 70 kg male, raise [HCO3] from 6 to 10; • HCO3 def = 0.7 x body weight(kg) x (10-6) =

196 meq

Respiratory Alkalosis• Increase in alveolar ventilation will produce a decrease in

pCO2, with a resulting increase in plasma pH.• Acute Respiratory Alkalosis • within 10 min, H+ ions move from the cell nto the ECF,

where they combine with HCO3• H(+) + HCO3(-) ----> H2CO3• These H+ ions are primarily derived from protin,

phophate, & Hb buffers in the cell, and from an alkalemia induced increase in cellular lactic acid production.

• HBuf ----> H(+) + Buf(-)

Chronic Respiratory Alkalosis• In the presence of persistent hypocapnia, there is a

compensatory decrease in renal H+ secretion that begins within 2 hrs, but is not complete for 2 or 3 days

• Manifested by HCO3 loss in urine and decreased urinary NH4 excretion

• Etiology: hypoxemia, pumonary ds, direct stimulation of the medullary respiratory center, mechanical ventilation

• Symptoms: increased irritability, lightheadedness, paresthesias, cramps, carpopedal spasm, ventricular & supraventricular arrhytmias

Case

• A 5 year old child is brought to the emergency room in a stuporous condition. The only pertinent history is that he had been playing with a bottle of aspirin tablets earlier that day.

• Arterial pH = 7.48 , PCO2 = 20 mmHg, [HCO3-] = 16 meq/L (expected = 20)

• The most likely explanation is salicylate overdose & salicylate - induced metabolic acidosis

Metabolic Alkalosis• Increase in pH, [HCO3-], PCO2

• Primary elevation [HCO3] is usually induced by H+ loss from the GI tract or in the urine

• These H+ ions are derived from the intracellular dissociation of H2CO3H(+) + HCO3(-)

• There will be an equimolar generation of HCO3- for each meq of H+ loss

• Administration HCO3, by H+ movement into the cells (hypoK, K out H in), and by certain forms of volume contraction (contraction alkalosis)

• Perpetuation of metabolic alkalosis requiresw an impairment in renal HCO3- excretion (reduction GFR, & filtered HCO3 load, elevation in tubular reabsorption)

Causes of metabolic alkalosis

• Loss of hydrogen– GI loss: vomiting, nasogastric tube, chloride losing diarrhea– Renal loss: loop / thiazide diuretic, mineralocorticoid excess, post

chronic hypercapnia, low Cl intake, hypercalcemia– H+ movement into the cell: hypokalemia, refeeding

• Retention of bcarbonate– Massive blood transfusion– Administration of HCO3– Milk alkali syndrome

• Contraction alkalosis– Loop / thiazide diuretics– Gastric losses in patients with achlorhydria– Sweat losses in cystic fibrosis

Causes of impaired HCO3 excretion that allows metabolic alkalosis to persist

• Decreased glomerular filtration rate– Effective circulating volume depletion– Renal failure (usually associated with metabolic acidosis)

• Increased tubular reabsorption– Effective circulating volume depletion– Chloride depletion– Hypokalemia– hyperaldosteronism

• Symptoms– Asymptomatic– Related to volume depletion– Related to hypokalemia– Neurologic abnormality in posthypercapnic alkalosis

probably due to a sudden fall in PCO2

• Diagnosis– Urine Chloride; Metabolic alkalosis is the major clinical

setting in which Urine [Cl-] may be a more accurate estimate of volume status than the Urine [Na+]

– The urine [Cl-] may not be useful in patients who are unable to maximally conserve Cl because of a defect in tubular reabsorption, e.g. renal insufficiency, severe hypokalemia (plasma [K] < 2.0 meq/L)

Urine [Cl-] in patients with metabolic alkalosis

• Less than 25 meq/L– Vomiting /nasogastric

suction– Diuretics (late)– Posthypercapnia– Cystic fibrosis– Low Cl- intake– Refeeding

• Greater than 40 meq/L– Mineralocorticoid

excess– Diuretics (early)– Alkali load, HCO3 or

other organic anion– Severe hypokalemia

([K] < 2.0 meq/L)

• Saline responsive alkalosis & saline resisitant alkalosis

• Hypovolaemic & normovolaemic (or hypervolaemic) metabolic alkalosis

Saline responsive Saline resistant

Vomiting or nasogastric suction Edematous statesDiuretics Mineralocorticoid excessPosthypercapnia Severe hypokalemiaLow Cl intake Renal failure

• Saline responsive alkalosis– Can be reversed by administration of NaCl water– This will lower [HCO3] in three ways

• Reversal of the contraction component• Removing the stimulus to renal Na retention, permitting

NaHCO3 excretion in the urine• Reverses distal Cl delivery, which will promote HCO3

secretion in the cortical CT

– Effectiveness can be followed bedside by measuring the urine pH

– Urine [Cl-] will remain <25 meq/L until the Cl deficit is corrected

– Any K depletion should be corrected with KCl

Saline resistant alkalosis• Edematous states, heart failure, hepatic cirrhosis,

nephrotic syndrome– Most commonly due to diuretic therapy– reduction in effective circulating volume & renal insufficiency can

contribute to the inability to excrete the excess HCO3– Therapy: withholding diuretics if possible, acetazolamide, HCl, or

dialysis• HCO3 excess = HCO3 space X HCO3 excess per liter =

the amount of HCl required to normalize plasma [HCO3-]• In metabolic alkalosis the HCO3 space is ~ 50% lean

body weight• E.g. 60kg patient [HCO3] = 40 meq/L;

HCO3 excess = 0.5 x 60 x (40-24) = 480 meq• This formula underestimates the acid requirement of a

patient in a non steady state

• Mineralocorticoid excess– Characterized by mild volume expansion and a rate of urinary [Na]

excretion eual to intake (due to aldosterone escape)– The combination of hypokalemia & hyperaldosteronism that is

responsible for perpetuation of the alkalosis– Correction of hypokalemia allows for increased HcO3 excretion, &

causes H+ ions to move out of the cell into the extracellular fluid

• Severe hypokaleemia – Patients with metabolic alkalosis and hypovolaemia may be

resistant to NaCl therapy in the presence of severe K depletion– This defect in Cl conservation appears to be due to diminished

distal Cl reabsorption– If Cl reabsorption is impaired and the availability of K for exchange

with Na is limited, then Na reabsorption must be accompanied by increased H+ secretion and HCO3- reabsorption

K Homeostasis

Cellular mechanisms of renal potassium transport: proximal tubuleand thick ascending limb. A, Proximal tubule potassium reabsorptionis closely coupled to proximal sodium and water transport.Potassium is reabsorbed through both paracellular and cellularpathways. Proximal apical potassium channels are normallyalmost completely closed. The lumen of the proximal tubule is negativein the early proximal tubule and positive in late proximaltubule segments. Potassium transport is not specifically regulated inthis portion of the nephron, but net potassium reabsorption isclosely coupled to sodium and water reabsorption. B, In the thickascending limb of Henle’s loop, potassium reabsorption proceedsby electroneutral Na+-K+-2Cl- cotransport in the thick ascendinglimb, the low intracellular sodium and chloride concentrations providingthe driving force for transport. In addition, the positivelumen potential allows some portion of luminal potassium to bereabsorbed via paracellular pathways [11]. The apical potassiumchannel allows potassium recycling and provides substrate to theapical Na+-K+-2Cl- cotransporter [12]. Loop diuretics act by competingfor the Cl- site on this carrier.

Cellular mechanisms of renal potassium transport: cortical collectingtubule. A, Principal cells of the cortical collecting duct: apicalsodium channels play a key role in potassium secretion by increasingthe intracellular sodium available to Na+-K+-ATPase pumps andby creating a favorable electrical potential for potassium secretion.Basolateral Na+-K+-ATPase creates a favorable concentration gradientfor passive diffusion of potassium from cell to lumen throughpotassium-selective channels. B, Intercalated cells. Under conditionsof potassium depletion, the cortical collecting duct becomes a sitefor net potassium reabsorption. The H+-K+-ATPase pump is regulatedby potassium intake. Decreases in total body potassiumincrease pump activity, resulting in enhanced potassium reabsorption.This pump may be partly responsible for the maintenance ofmetabolic alkalosis in conditions of potassium depletion [11].

Hypokalemia and magnesium depletion. Hypokalemia and magnesium depletion can occur concurrently in a variety of clinical settings, including diuretic therapy, ketoacidosis, aminoglycosidetherapy, and prolonged osmotic diuresis (as with poorly controlled diabetes mellitus). Hypokalemia is also a common finding in patients with congenital magnesium-losing kidney disease. Thepatient depicted was treated with cisplatin 2 months before presentation. Attempts at oral and intravenous potassium replacement of up to 80 mEq/day were unsuccessful in correcting thehypokalemia. Once serum magnesium was corrected, however, serum potassium quickly normalized [14].

Physiologic basis of the transtubular potassium concentrationgradient (TTKG). Secretion of potassium in the cortical collectingduct and outer medullary collecting duct accounts for the vastmajority of potassium excreted in the urine. Potassium secretion in these segments is influenced mainly by aldosterone, plasma potassium concentrations, and the anion composition of the fluid in the lumen. Use of the TTKG assumes that negligible amounts of potassium are secreted or reabsorbed distal to these sites. The final urinary potassium concentration then depends on water reabsorption in the medullary collecting ducts, which results in a rise in the final urinary potassium concentration without addition of significant amounts of potassium to the urine. The TTKG is calculated as follows:

TTKG = ([K+]urine/(U/P)osm)/[K+]plasma

The ratio of (U/P)osm allows for “correction” of the final urinarypotassium concentration for the amount of water reabsorbed inthe medullary collecting duct. In effect, the TTKG is an index of the gradient of potassium achieved at potassium secretory sites, independent of urine flow rate. The urine must at least be iso-osmolal with respect to serum if the TTKG is to be meaningful

• Major physiologic functions– Cell metabolism, protein & glycogen synthesis– Ratio of [K+] in the cell and ECF is the major

determinant of the resting membrane potential across the cell membrane

• Distribution of K between cells and ECF

Hypokalemia • Decreased net intake, starvation, inadequate replacement after operation• Increased entry into cell

– Elevation in EC pH,alkalosis– Increased availability of insulin– Elevated β-adrenergic activity– Periodic paralyse, hypokalemia form– Pseudohypokalemia– Treatment of megaloblastic anemia with B12 / folic acid; or neutropenia with GM-CSF– Hypothermia

• Increased GI losses,vomiting diarrhea, villous adenoma• Increased urinary losses

– Diuretics, loop / thiazide, RTA– Mineralocorticoid excess– Increased flow to distal nephron– Na reabsorption with a nonreabsorbable anion: vomiting, metabolic acidosis, penicillin

derivatives– Amphotericin B– HypoMg– Polyuria– L-dopa

• Increased sweat losses• Dialysis• K depletion

Increased entry into cells• Elevation in extracellular pH; H+ ions are released from

the cellular buffers and move into the extracellular fluid to minimize the elevation in pH. To preserve electroneutrality K+ (& Na+) enter the cell. The pasma [K] falls less than 0.4 meq/L per 0.1 unit increase in extracellular pH.This also happens with HCO3 administration

• Increased availability of Insulin; insulin increases the activity of the Na-K-ATPase pump.Elevated B-adrenergic activity; catecholamines promote K entry into the cell, a response mediated by B2-adrenergic receptors, involves increased activity of Na-K-ATPase

• Periodic paralyse (hyperK, hypoK, normokalemic forms)– Hypokalemic Periodic Paralyse may be familial

(AD), or aquired (thyrotoxicosis). episodes can be precipitated by rest after excercise, carbohydrate meal, stress, administration of insulin, epinephrine.

– Attacks are associated with the sudden movement of K into the cell. Similar acute form of paralysis can be induced by barium poisoning; barium blocks the K-channels in the cells

• Treatment of anemia or neutropenia. – Associated with K uptake by the new cells.

• Multiple transfusion with frozen, washed red blood cells;– these cells lose up to 50% of their K+ during storage. in the

recipient, K moves rapidly into the cells.

• Pseudohypokalemia;– K uptake by metabolically active cells after the blood has been

drawn, e.g. acute myeloid leukemia, if the blood is allowed to stand for a prolonged period at room temperature.

• Hypothermia – can lower the plasma [K] as a result of K entry into the cells.

Increased GI losses• Normally 3-6 L of gastric, pancreatic, biliary, and

intestinal secretions are secreted into the gastrointestinal lumen each day.

• Almost all of this fluid are reabsorbed, as only 100-200 ml of water and 5-10 meq of K are lost in the stool.

• Each of these secretion contains K+.• Loss of any of them can lead to K depletion• vomiting, diarrhoea, intestinal fistulas / drainage,

chronic laxative abuse, colonic secretions from villous adenoma, cholera, VIPoma syndrome.

Increased urinary losses• Loop & thiazide diuretics

– Increased flow to distal nephron– Enhanced secretion of aldosterone

• Mineralocorticoid excess– Primary hyperaldosteronism: adenoma, carcinoma, hyperplasia

– Cushing Disease– Congenital adrenal hyperplasia

• 17-α-hydroxylase def• 17-β-hydroxylase def

– Chronic use of mineralocorticoid: fludrocortison– Hyperreninism

• renal artery stenosis, renin secreting tumor– hypersecretion of deoxycocorticosterone, other mineralocorticoid,

incl apparent mineralocorticoid excess (licorice)– Bartter's syndrome

Mineralocorticoid excess• Stimulates reabsorption of Na+,& secretion of

K+ & H+ (often with hypertension & hypernatremia [145])

• Can lead to hypokalemia & metabolic alkalosis• Initial Na retention is followed by spontaneous

natriuresis, edema does not usually occur• This phenomenon is referred to as Aldosterone

Escape ( increse in BP & ANP)• For hypokalemia to occur there must be

adequate delivery of Na & water to the distal nephron

Primary hyperaldosteronism• Adenoma 60 %,hyperplasia most of remaining• Plasma Renin Activity is typically reduced• Hyperplasia

– Central serotoninergic pathways (inhibition of aldosterone secretion by cyproheptadine)

– Increased sensitivity of the adrenal zona glomerulosa to Angiotensin II

– AD glucocorticoid suppressible hyperaldosteronism, chimeric gene containing the enzyme 11β-hydroxylase in the ACTH sensitive zona fasciculata

Cushing Syndrome / glucocorticoid excess

• Cortisol is produced in zona fasciculata under the influence of ACTH

• Hypercortisolism– Hypersecretion of ACTH ( pituitary adenoma,

nonendocrine ACTH producing tumor)– primary adrenal adenoma / carcinoma

• Hypertension– PRA usually normal, or increased, not reduced as

with aldosterone excess– Cortisol induced increased sensitivity to endogenous

pressors (AII)

Diagnosis• Autonomous hypersercretion of cortisol must be confirmed

– Increased urinary free cortisol excretion in a 24 h urine collection– Lack of adequate suppression of 24h urine hydroxycorticosteroid (to <4mg/d)

after administration of 0.5mg dexamethasone q6h for 8 doses = the low dose dexamethasone suppression test

• The specific cause: pituitary tumor vs adrenal adenoma vs ectopic ACTH production, can be identified my measuring plasma ACTH and cortisol levels

– At 8 a.m. on 2 successive days, the second after administering 8mg (high dose) dexamethasone at 11 p.m. the previous night

– Before & after administratration of 2mg dexamethasone q6h for 8 doses = the high dose dexamethasone suppression test

• Patients with adrenal diseaseadrenal disease have low to absent ACTH levels and cortisol secretion, that is not suppressed by dexamethasone. Next step should be CT / MRI

• Pituitary diseasePituitary disease is associated with normal or elevated ACTH secretion, and both ACTH & cortisol are suppressed by >50% by dexamethasone

• ACTH levels are increased with ectopic productionectopic production, is not suppressed by dexamethasone– If the results are equivocal, the response to an infusion of corticotrropin releasing factor

(CRF) can be assessed; ACTH will rise by >50% and cortisol >20% with pituitary disease; unchanged with ectopic production

• Patients with pituitary disease should undergo gadalinium-enhanced MRI to confirm the diagnosis and locate the tumor; bilateral inferior petrosal sinus sampling can be used to identify the affected side

• Congenital adrenal hyperplasia– Deoxycorticosterone (DOC) & corticosterone are synthesized in the adrenal

cortex, and have significant mineralocorticoid activity– Secretion is regulated by ACTH, not AII / [K]– When cortisol production is reduced because of enzyme def.,ACTH, DOC,&

corticosterone will be persistently elevated– Synthesis of aldosterone also impaired– Glucocorticoid and [K] balance can be restored by administration of cortisol

• Risk of inducing Na wasting & hyperkalemia• Mineralocorticoid replacement with fludrocortisone may be required

– Familial glucocorticoid resistance, • inherited abnormality in glucocorticoid receptor• Cannot bind to cortisol• Adrenal stimulation due to high ACTH levels

• Syndrome of apparent mineralocorticoid excess– Licorice in chewing tobacco, candies,– Steroid in licorice: glycyrrhetinic acid

• Has sligh meneralocorticoid activity• Impairs the action of enzyme 11β-hydroxysteroid dehydrogenase that converts cortisol

to cortisone in aldosterone target tissues– Hypertension, hypokalemia, and metabolic alkalosis

• Other mineralocorticoids: DOC producing adenomas, Liddle’s syndrome:– Low renin & low aldosterone

Bartter’s syndrome

• Hyperreninemia & hyperaldosteronism• Hyperplasia juxtaglomerular apparatus• Hypokalemic alkalosis• Increased secretion of vasodilator

prostaglandins (PG E & PC)– May partially explain the normal BP

• Defect in NaCl reabsorption in TALH or DT• Changes in Bartter’s syndrome ~ surreptious

use of loop / thiazide diuretics

• Classic Bartter’s syndrome

– Generally presents early in life, before age 6– Associated with retarded growth, mental retardation, polyuria, polidipsia,

decreased concentrating ability, hypercalciuria, & plasma [Mg] that is normal / mildly reduced

– Defect medullary portion of the thick ascending limb; central role in creating countercurrent gradient required for urine concentration

• Gitelman’s syndrome– More benign, and usually diagnosed incidentally in late childhood /

adulthood– Mg wasting & hypomagnesemia (sometimes tetany)– Calcium excretion tends to be reduced, hypocalciuria– Concentrating ability is maintained suggesting intact function in the

medullary thick limb– Primary defect is in the cortical aspect of the thick ascending limb or in

the distal tubule, the major site of active Mg & Ca reabsorption• Fall in NaCl reabsorption,Na & water loss volume depletion

Enhanced renin secretion AII & aldosterone, Combination of increased distal flow & hyperaldosteronism

promotes K+ secretion, and the development of hypokalemia, that may be exacerbated by concurrent hypomagnesemia.

Prostaglandins directly increases renin release,also contribute to this process

Diagnosis of primary hyperaldosteronism• Should be suspected in any patient with hypertension & unexplained hypokalemiahypertension & unexplained hypokalemia• Occasionally, patients are normokalemic, or hypokalemic but normotensive• 24h Urine collection for K+,

– Diuretics must be discontinued prior to collection– Important that the patient not be volume depleted– The degree of K wasting can be enhanced by high Na diet– Na-induced hypokalemia is strongly indicative of nonsuppressible hyperaldosteronism

• Plasma renin activity• Aldosterone secretion; plasma [aldosterone] or urinary excretion of aldosterone /

metabolites– Low renin low aldosterone ~ nonaldosterone mineralocorticoid

• Congenital adrenal hyperplasia, DOC producing tumor• Licorice• Liddle’s syndrome

– Low renin high aldosterone >30 μg/dl ~ hyperaldosteronism– Diagnostic accuracy can be increased by attempting to suppress aldosterone production by

giving 2 L NS IV over 4h• Normal, should fall to 6ug/dl or less• Values >10 ug/dl are diagnostic• Values between 6&10 are nondiagnostic; a more prolonged suppression test should be done; using high Na diet plus 0.6 -1.2 mg fludrocortisone for 3 days

– Potential confounding variables should be eliminated• Plasma [aldosterone] should be measured with the patient recumbent, off K supplements,• Relative normokalemia

• Adenoma vs hyperplasia– Usually hyperplasia is less severe– Rise in [aldosterone] following assumption of the

upright posture between 8 a.m. and noon• May reflect increased sensitivity of the zona glomerulosa to

AII ~ hyperplasia• Induces no change in [aldosterone] with an adrenal adenoma

– CT scanning / MRI– Measurement of adrenal vein aldosterone

• Unilateral adenoma ~ > 10 fold increase in [aldosterone] on the side of the tumor

• To be certain that the samples are from the adrenal vein, an ACTH-stimulated [cortisol] should also be measured; roughly the same on both sites, but much greater in a peripheral vein

– (131)I-iodocholesterol (precursor of aldosterone) scintillation scanning

Acid base disorders in hypokalemia

• Metabolic acidosis– Loss of lower intestinal secretions– Ketoacidosis– RTA– Salt wasting nephropathies

• Metabolic alkalosis– Diuretic therapy– Vomiting / nasogastric suction– Mineralocorticoid excess– Penicillin derivatives

Treatment• K deficit can only be approximated; there ‘s no definite

correlation between plasma [K+] and body K+ stores.• In general, a reduction in [K] from 4 to 3 meq/L requires

the loss of > 200 meq K+. An additional 200 – 400 meq def will lower the plasma [K+] to 2 meq/L

• Oral KCl• IV KCl;

– in most circumstances K+ 20-40meq (max 60 meq, if through a peripheral vein) is added to 1L of dextrose / saline solution

– The addition of that much K in a dextrose solution may lead to a transient reduction in the plasma [K+] of 0.2 – 1.4 meq/L

– Generally IV K+ is administered at a maximum rate of 10-20 meq/h

Hyperkalemia • Increased intake: oral, IV• Movement from cells to ECF

– Pseudohyperkalemia– Metabolic acidosis– Insulin deficiency & hyperosmolality in uncontrolled DM– Acute hyperosmolality due to hypernatremia or hypertonic mannitol

administration– Tissue catabolism– Β-adrenergic blockade– Severe exercise– Digitalis overdose– Hyperkalemic periodic paralysis– Cardiac surgery– Succinylcholine– Arginine

• Decreased urinary secretion– Renal failure– Effective circulating volume depletion– Hypoaldosteronism– RTA type I – hyperkalemic form– Selective K secretory defect

Defense against hyperkalemia• Initial uptake of most of the excess K by the

cells, mediated by insulin, β2-adrenergic receptors, and K+ itself

• Subsequent urinary K+ secretion of most of the excess K+ within 6-8h; the small elevation in plasma [K+] is responsible for this increase in K excretion, both directly and by increasing aldosterone release

• The ability to tolerate a K+ load is increased by the chronic ingestion of a high-K diet ~ K adaptation

• Pseudohyperkalemia; due to K+ movement out of the cells during or after the blood specimen has been drawn.– Mechanical trauma during venipuncture– Measurement of the serum after clotting has occurred, e.g.in

leukocytosis (>100,000/mm3), & thrombocytosis (serum [K+] rises 0.15meq/L for every100,000/mm3 elevation)

• Increase in plasma osmolality; – pulls water out of the cells, leads to the parallel movement of K+ into the

ECF• Loss of water raises [K] IC• Solvent drag

• Cardiac surgery; – Washout of ischemic areas that were underperfused– Rewarming, hypothermia causes K to move into the cells

• Succinylcholine;– Acts by depolarizing the cell membrane, cell interrior becomes less

electronegative– Favors movement of K+ ions out of the cell

• Arginine HCl;– Cationic arginine enters the cell, & K+ out

• Renal failure; multiple factors– Too few nephrons – Oliguria, decrease in flow to the distal

secretory site– Increased dietary K load– Low [K] IC & impaired cellular uptake– Decreased Na-K-ATPase

• Effective circulating volume depletion;– Often associated with K depletion– But impaired ability to handle K load

• Reduction in urinary K secretion (distal flow)• Reduced K entry into cells

Diagnosis of hypoaldosteronism• Discontinuation of any potensial offending drug,e.g.

nsaids heparin, ACE-I, ARB, k-sparing diuretics,• Measurement of morning plasma renin activity,

aldosterone, cortisol• To minimize confounding borderline values, give 20-

40mg furosemide at 6 pm & 6 am before blood drawing• An indirect way to estimate the effect of aldoterone is to

measure the tubular fluid [K+] at the end of the cortical collecting tubule; with the following assumptions– Uosm at this site ~ Posm – equilibration with the isoosmotic

interstitium will occur in the presence of ADH– Little / no K secretion or reabsorption takes place in the

medullary collecting tubule• Transtubular K+ gradient, TTKG =

as long as U(Na)>25 meq/LU(K+) / ( Uosm/Posm) P(K+)

• TTKG in normal subjects on a egular diet is 8 – 9, and rises to >11 with a K+ load indicating increased K secretion

• A value <7, particularly <5 in a hyperkalemic patient is highly suggestive for hypoaldosteronism

• E.g. U(K)=30meq/L, P(K)=6.5meq/L, Uosm=560 mosm/kg, Posm=280mosm/kg TTKG = =2.3 30/(560/280)

6.5

Type I RTA – hyperkalemic form

• Type I RTA, usually hypokalemia• Na reabsorption occurs in exchange for K• Hyperkalemia

– Inability to reabsorb Na– Impairs generation of lumen-negative

potential difference– Impairs H / K secretion

• E.g.: obstructive uropathy, sickle cell disease,

Treatment • Antagonism of membrane action

– Calcium– Hypertonic Na solution (if hyponatremic)

• Increased K entry into cells– Glucose & insulin– NaHCO3– Β2-adrenergic agonists– Hypertonic Na solutions (if hyponatremic)

• Removal of K excess– Diuretics– Cation exchange resins– Dialysis

• Hyponatremia increases the toxicity of hyperkalemia to the heart