manual in nephrology

50
Contents 1. Introduction 2. Acid-Base Disorders 3. Water Spaces, Osmolality, and Sodium 4. Disorders of Potassium Balance, Hypokalemia and Hyperkalemia 5. Selected Disorders of Divalent Metabolism 6. References Acid-Base and Electrolytes Michael Emmett, MD Ajay K. Singh, MB, MRCP(UK) ACID-BASE AND ELECTROLYTES 1

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Page 1: Manual in Nephrology

Contents

1. Introduction

2. Acid-Base Disorders

3. Water Spaces, Osmolality, and Sodium

4. Disorders of Potassium Balance,Hypokalemia and Hyperkalemia

5. Selected Disorders of Divalent Metabolism

6. References

Acid-Base and Electrolytes

Michael Emmett, MD Ajay K. Singh, MB, MRCP(UK)

ACID-BASE AND ELECTROLYTES 1

Page 2: Manual in Nephrology

2. Acid-Base Disorders

The Henderson-Hasselbalch equation shows therelationship between the pH, PaCO2, and HCO3.

A primary rise in PaCO2 (respiratory acidosis) orfall in plasma [HCO3

-] (metabolic acidosis)reduces pH, whereas a primary fall in PaCO2 (res-piratory alkalosis) or rise in plasma [HCO3

-](metabolic alkalosis) increases pH. Each primarydisorder should trigger a compensatory responsethat returns the pH toward normal. The magnitudeof each compensatory response is predictable asshown in Table 1.

Equation 1:pH = 6.1 + log [HCO3]

(0.03)αPCO2

1. Introduction

Disorders of acid-base and electrolytes are commonin both examination and clinical situations. Solvingacid-base or electrolyte conundrums requires abasic knowledge of the underlying physiology,some knowledge of the homeostatic mechanismsavailable to the body, and the use of some simpleformulas. The purpose of this chapter is to reviewthe major acid base and electrolyte disorders, focus-ing particularly on board examination favorites.

2 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Table 1

Acid-Base Disorders and Compensatory Responses

Disorder H+ pH HCO3 PaCO2 Adaptive Response Time For Adaptation

Metabolic acidosis � PCO2 = (1.5)HCO3 + 8

� PCO2 = HCO3 + 15 12-24 hr

Metabolicalkalosis PCO2 = >40 - <55 24-36 hr

Respiratory acidosis

� HCO3/ � pCO2 = 1/10Acute or � HCO3 = 0.1 � pCO2 Minutes-Hours

Chronic � HCO3 / � pCO2 = 3/10 � HCO3 = 0.3 � pCO2

Respiratory alkalosis Days

Acute � HCO3 / � pCO2= 2/10 � HCO3 = 0.2 � pCO2 Minutes-Hours

Chronic � HCO3 / � pCO2 = 5/10 � HCO3 = 0.5 � pCO2 Days

Double arrows indicate the primary disturbance

Page 3: Manual in Nephrology

Metabolic Acidosis

Metabolic acidosis is a pathologic process which, ifunopposed, will cause a primary decrease in plasma[HCO3]. One or more of the following mechanismsis usually responsible:

1) Abnormally high loss of alkali into the stool orurine.

2) Exogenous or endogenous acid loads that exceednormal acid excretory or metabolic capacity.

3) Decreased renal capacity to excrete acid.

It is also helpful to divide the metabolic acidosesinto those with an increased anion gap (AG) andthose with increased chloride concentration [Cl]1.Figure 1 shows how the anion gap is calculated andFigure 2 illustrates why the [AG], the [Cl], or bothmust increase when metabolic acidosis develops.Note that the quantitative increase in [AG], and/or

[Cl], should approximate the quantitative reductionin [HCO3]. (These relationships assume the sodiumconcentration [Na] is normal and remainsunchanged – this is further discussed below.)

Some Important Formulas for Both Managementof Metabolic Acidosis and for Coping with Examination Questions:

Expected pCO2 in a metabolic acidosispCO2 falls 1.2 mm Hg for every 1 mEq/L fall inHCO3.

Winter’s formulapCO2 = 1.5 X (observed HCO3) + 8±2

A quick rule of thumbThe pCO2 should approximate the last two digits ofpH. For example, pH 7.25, pCO2 should be close to25 mm Hg.

Expected pCO2 = 1.5 * HCO3- + 8 +/- 2

ACID-BASE AND ELECTROLYTES 3

Figure 1

How the anion gap is calculated

Na140

Cl102

HCO325

Pr 16

Na140

Cl102

HCO325

AG 8PO42SO42

OA 4

K 4

Ca 5Mg 2

AG=NA - (Cl+HCO3)

{

The sum of all the anions and all the cations must be equal (all measured as mEq/l ). If only [Na], [Cl], and [HCO3 ], then an anion gap of 8-12 will be found.

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4 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Bicarb Deficit 0.4 * Wt in kg * (24 - Pt’s bicarb level)

Hyperchloremic Metabolic Acidosis

When metabolic acidosis reduces the [HCO3] andthe [AG] remains normal, then relative hyper-chloremia must exist. Relative hyperchloremiameans the [Cl] is increased compared with thesodium concentration [Na]. When hypernatremia orhyponatremia develop the [Cl] should increase ordecrease proportionately with [Na] – ie, in a 1:1.4ratio. So, if the [Na] increases from 140 to 154mEq/l then [Cl] should increase from 100 to 110mEq/l. This is an “appropriate” degree of hyper-chloremia and reflects dehydration but not an acid-base disorder. Relative hyperchloremia exists whenthe [Cl] is higher then expected for the coexisting[Na]. Relative hypochloremia exists when the [Cl]is higher then expected for the coexisting [Na]. Rel-ative hypochloremia exists when the [Cl] is lowerthan expected for the coexisting [Na]. Relativehypochloremia or hyperchloremia are usually dueto acid-base disorders.

Hyperchloremic acidosis generally develops in oneof two ways:

1. Fluids containing high concentrations ofNaHCO3 , or potential NaHCO3 (see below) arelost from the ECF.

2. Excess HCl, or potential HCl, is added to theECF.

Any organic sodium salt that can be metabolized toNaHCO3 represents potential NaHCO3. For exam-ple, NaLactate, NaCitrate, NaAcetate, and NaBu-tyrate all generate eqimolar amounts of NaHCO3when the organic anion is metabolized to substancessuch as glucose or CO2 and H2O. Similarly, organicchloride salts that can be metabolized to CO2 andH2O, proteins, or urea represent potential HCl.Examples include NH4Cl, lysine Cl and arginine Cl.

The causes of hyperchloremic acidosis are listed inTable 2 and reviewed in detail elsewhere.2,3 Diar-rhea is the most common cause of hyperchloremicmetabolic acidosis and this disturbance develops

Figure 2

The anion gap, the chloride concentration, or both, must increase whenmetabolic acidosis develops

When any relatively strong acid, such as HX, is addedto the ECF the H+ dissociates and combines withHCO3- to form H2CO3, which then dehydrates to gen-erate H2O and CO2. The X- remains and can be con-sidered NaX. If HX is HCl, then the increase in [Cl] willmatch the fall in HCO3

-; if X- is any non-HCl acid thefall in HCO3- will be matched by a similar increase inthe anion gap. A loss of NaHCO3 will also produce ahyperchloremic acidosis.

H2CO3 H20+CO2{

Na-HCO3 + H-X{Na-X

NORMAL

NORMAL AGMETABOLIC

ACIDOSIS(HYPERCHLOREMIC)

HIGH AGMETABOLIC

ACIDOSIS

Na

C1

ANION GAP

LACTATE

HCO3

140 140 140

105 115 105

25 15

10 10 20

1 1 11

15

Anion GapNa - (Cl + HCO3-)

Delta GapAnion Gap - 12 (nl anion gap)

Urinary Anion Gap UAG = [Na+]+ [K+] - [Cl-]

Page 5: Manual in Nephrology

because both NaHCO3 and potential NaHCO3(such as NaAcetate, NaButyrate, NaLactate, etc.)are lost into the stool. The renal tubular acidoses(RTA) all produce hyperchloremic acidosis.4,5

These disorders are all due to reduced renal acidexcretion (or excessive HCO3 loss) as a result oftubular defects in the absence of a major reductionin glomerular filtration.5 They are divided into threetypes: type I (or classic distal) RTA, type II (or prox-imal) RTA, and type IV (or hyperkalemic) RTA.Type III RTA was a condition once described inchildren but is no longer considered a distinct vari-ant.

Type I, or classic distal RTA, results from an inabil-ity of the renal tubules to generate and/or maintain anormal pH gradient (the normal minimal U pH is<5.5 vs. 7.4 in blood).6 These patients alwaysexcrete inappropriately alkaline urine. It may be dueto an inherited defect (either autosomal dominant orrecessive) in one of several acid/base transporters orenzymes required to acidify the distal tubule fluid.7

They include the cytosolic carbonic anhydrase, thevacuolar H-ATPase, and the basolateral chloride-bicarbonate exchanger (AE1). Associated clinicalproblems include hearing deficits, cerebral calcifi-cations and osteopetrosis. The most common causeof acquired distal RTA in adults is probably Sjögrensyndrome.8 Hypercalciuria is also very commonlyassociated with distal RTA. It is not always clearwhether hypercalciuria occurs first and causes RTA,the RTA occurs first and generates the hypercalci-uria, or if they are transmitted together. Distal RTAfrequently causes medullary calcifications and leadsto formation of calcium containing renal stone, dueto the combination of hypercalciuria and deficienturine citrate excretion (the citrate deficit may be themore important abnormality). Treatment (seebelow) will raise urine citrate and often stop newkidney stone formation. Table 3 lists the majorcauses of distal RTA.

Coexistent hyperchloremic acidosis and alkalineurine suggests distal RTA. However, two other pos-sibilities must be considered and ruled out. Urinarytract infections can alkalinize the urine becausesome bacteria metabolize urinary urea to yieldNH4

+ & CO2. The NH4+ added to the urine sharply

raises its pH. Therefore, always rule out UTI whenthe urine is more alkaline than expected. Some

patients with hyperchloremic acidosis and markedhypokalemia generated by diarrhea will excrete“abnormally” alkaline urine. This is not due to any

ACID-BASE AND ELECTROLYTES 5

Table 2

Hyperchloremic (Normal AG) Metabolic Acidosis

GI Loss of HCO3

a. Diarrheab. Ureterosigmoidostomy

Renal HCO3– Loss

a. Proximal RTAb. Carbonic Anhydrase Inhibitorsc. Ileal loop bladder/Ureterosigmoidostomy/Intestinal

interposition in GU stream

Reduced renal H+ secretion

a. Distal RTAb.Type 4 RTA

1) Hyporeninemic-Hypoaldosteronism – Diabetes Mellitus, Tubulointerstitial disease, NSAIDs

2) Defective Mineralocorticoid (MC) synthesisor secretion – Addison Disease, ChronicHeparin Rx, Congenital Adrenal Defects

3) Inadequate renal response to MC-SickleCell Disease, SLE, K-sparing diuretics,“Chloride Shunts”

c. Early Kidney Failure

HCl/HCl Precursor Ingestion/Infusion

a. HClb. NH4Clc. Arginine HCl

Other

a. Post chronic Hyperventilation b. Recovery from DKAc. Toluene Inhalation

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6 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

form of renal acidification problem but rather resultsfrom the combination of persistent acidemia andhypokalemia. These two factors markedly stimulaterenal NH4

+ generation and result in very high urineNH4

+ levels. This NH4+ raises the urine pH. Renal

acid excretion is very high despite the relativelyalkaline urinary pH. Measurement of urine NH4

+

excretion will readily differentiate these possibili-ties (as will a careful history!).9,10

Among patients with hyperchloremic metabolic aci-dosis, the urine anion gap (UAG) is frequently help-ful in distinguishing gastrointestinal from renalcauses (eg, a distal RTA).10 The UAG is estimated bymeasuring specific cations and anions excreted inthe urine. The cations normally present in urine are

Na+, K+, NH4+, Ca++ and Mg++. The anions nor-

mally present are Cl-, HCO3 -, sulfate, phosphateand some organic anions. Only Na+, K+ and Cl- arecommonly measured in urine so the other chargedspecies are the unmeasured anions (UA) and cations(UC). Because electroneutrality is required, totalanion charge always equals total cation charge. Cl-+ UA = Na+ + K+ + UC. Thus, the UAG is definedby the following equation.

Urinary Anion Gap = (UA - UC) = [Na+]+ [K+] -[Cl-]

The UAG provides a rough index of urinary ammo-nium excretion. Ammonium is positively chargedso a rise in its urinary concentration (ie, increased

Table 3

Distal Renal Tubular Acidosis

A. Primary1. Familial2. Idiopathic

B. Secondary to genetically transmitted diseases1. Ehler's Danlos2. Hereditary elliptocytosis3. Sickle cell disease4. Carbonic anhydrase deficiency5. Medullary cystic disease6. Wilson disease7. Fabry disease8. Hereditary hypercalcuria9. Hereditary fructose intolerance10.Familial hypergammaglobulemia

C. Secondary to autoimmune disorders1. Hypergammaglobulinemia2. Hyperglobulinemic purpura3. Cryoglobulinemia4. Sjögren syndrome5. Thyroiditis6. Pulmonary fibrosis7. Chronic active hepatitis8. Primary biliary cirrhosis9. Systemic lupus erythematosus10.Arteritis

D. Hypercalcuria and nephrocalcinosis1. Primary hyperparathyroidism 2. Vitamin D intoxication3. Hyperthyroidism4. Idiopathic hypercalcuria5. Medullary sponge kidney

E. Drugs and toxins1. Amphotericin B2. Toluene3. Analgesics4. Cyclamate

F. Tubulointerstitial Disease1. Balkan nephropathy2. Chronic pyelonephritis3. Obstructive uropathy4. Renal transplantation5. Leprosy6. Jejuno-ileal bypass with oxaluria

G. Miscellaneous1. Hepatic cirrhosis2. Empty sella syndrome3. Osteopetrosis

Page 7: Manual in Nephrology

unmeasured cations) results in a fall in UAG. If theacidosis is due to loss of bicarbonate via the bowelthen the kidneys can response appropriately byincreasing ammonium excretion to cause a net lossof H+ from the body. The UAG would tend to bedecreased. If the acidosis is due to loss of bicarbon-ate via the kidney, then as the problem is with thekidney it is not able to increase ammonium excre-tion and the UAG will not be increased. In a patientwith a hyperchloremic metabolic acidosis: A nega-tive UAG suggests gastrointestinal loss of bicarbon-ate (eg, diarrhea). In patients with severe diarrheathe UAG may be quite negative (-10 to -27 range).A positive UAG suggests impaired renal distal acid-ification (ie, distal renal tubular acidosis).

Type II, or proximal RTA, is caused by a reductionin this tubule segment’s renal NaHCO3 reabsorp-tive capacity.11 Normally the proximal tubule reab-sorbs 90% of the filtered NaHCO3 when the plasma[HCO3] is in the normal range. A decrease in thistubule segment reabsorptive capacity results inmajor bicarbonaturia. This continues until theplasma [HCO3] has fallen to a level that can beeffectively reabsorbed. If one attempts to raise theplasma [HCO3] level above the abnormally lowrenal tubule threshold (for example, when exoge-nous NaHCO3 is administered), a large amount ofNaHCO3 is excreted into the urine. It is important torecognize that these patients can appropriately acid-ify their urine when the serum [HCO3] falls belowthe threshold concentration.

Isolated proximal RTA (pRTA) is very rare and mayoccur without other functional defects.12 It presentsusually in infancy and early childhood with growthretardation. Isolated pRTA has 3 types or varietiesbased on the method of genetic transmission: auto-somal dominant pRTA; autosomal recessive pRTAwith ocular abnormalities; and sporadic isolatedpRTA. Much more commonly, other proximaltubule defects coexist. When renal glucosuria, phos-phate wasting, excessive uric acid excretion, and/orlow molecular weight proteinuria are documented,the Fanconi syndrome exists.11,13 Inherited causes ofFanconi syndrome include a number of enzymaticdefects that affect amino acid or carbohydratemetabolism. Fanconi syndrome is associated withthe deposition of protein crystals in the proximaltubules, as a result of a monoclonal gammopathy,14

and is a very common treatment side effect of thealkylating agent ifosfamide.15,16 At this time, theseare the most common causes of the acquired syn-drome in adults. Table 4 lists the major causes ofproximal, or type II, RTA.

Hypoaldosteronism, or an inadequate renal tubuleresponse to aldosterone, often generates hyper-kalemia and hyperchloremic metabolic acido-sis.13,17,18 This disorder is called Type 4 RTA. Miner-alocorticoid deficiency directly impairs renal acidi-fication (it slows the rate of distal proton secretion,but usually does not affect the maximal pH gradientwhich can be achieved). In addition, the develop-ment of hyperkalemia inhibits renal NH4

+ synthesisand excretion and this effect is a major contributionto development of metabolic acidosis. The mostcommon acquired cause of hypoaldosteronism inadults is a renin deficiency state–ie, hyporeninemichypoaldosteronism.17,18,19 Often this is due to damageto the renin secreting J-G apparatus in patients withdiabetes. Analgesic nephropathy and chronic uri-nary outlet obstruction, especially in elderly men,also generates hyporeninemic hypoaldosteronism.Blocking the renin-angiotensin axis at any step alsocan cause similar pathophysiology. Thusangiotensin converting drugs and angiotensinreceptor blockers reduce adrenal aldosterone syn-thesis and create these abnormalities. When aldos-terone levels are high, renal tubule resistance to thehormone occurs in a number of diseases includingsystemic lupus, sickle cell disease, and interstitialnephritis. Diuretics which compete with aldosterone(spironolactone) or block distal tubule sodium chan-nels (amiloride, triamterene) also generate hyper-kalemic metabolic acidosis (type IV RTA).19

Gastrointestinal epithelium, especially colonic tis-sue, avidly absorbs chloride and secretes bothHCO3– and K. Therefore, if this epithelium isexposed to urine, the urine chloride is removed,while HCO3– and K is secreted. Excretion of urinewith this altered chemical profile generateshypokalemia and hyperchloremic metabolic acido-sis. Ureterosigmoidostomy, ileal loop bladders orinterposition of any ileal or colonic segment into theurinary stream can produce this acid base derange-ment.20

ACID-BASE AND ELECTROLYTES 7

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8 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Proximal RTA is difficult to correct with exogenousNaHCO3 because the kidney will rapidly excreteNaHCO3 as soon as its plasma level increases abovethe threshold.4 Furthermore, delivery of large quan-tities of NaHCO3 to the distal nephron exacerbatesK losses and hypokalemia. Sometimes maneuversto increase the threshold, such as moderate ECF

contraction induced with thiazide diuretics, may behelpful. When Fanconi syndrome exists, treatmentof associated abnormalities such as hypophos-phatemia and vitamin D deficiency is often moreimportant than correction of the low NaHCO3per se. In contrast, distal RTA can generally be readily treated with 60-100 mEq/day of NaHCO3 or

Table 4

Proximal Renal Tubular Acidosis

Primary

1. Sporatica. Isolated bicarbonate

wastingb. Fanconi syndrome

2. Familiala. Isolated bicarbonate wastingb. Fanconi syndrome

Secondary

1. Genetic - Familiala. Disorders of amino acid metabolism1) Cystinosis2)Tyrosinemiab. Disorders of carbohydrate metabolism

1) Galactosemia2) Hereditary fructose intolerance3) Glycogen storage disease with

Fanconi syndromec. Wilson disease (copper

accumulation)d. Lowe syndrome (oculo-

cerebral-renal syndrome)e. Metachromatic leukodystrophyf. Osteopetrosis

2. Dysproteinemic statesa. Multiple myelomab. Light chain diseasec. Monoclonal gammopathyd. Amyloidosis

3. Excess parathyroid hormonea. Primary hyperparathyroidismb. Secondary hyperparathy-

roidism1) Renal failure2) Vitamin D

deficiency3) Abnormal vitamin D

metabolism4. Drugs – Chemicals

a. Carbonic anhydraseinhibitors1) Acetazolamide2) Mefenide (Sulfamylon®)

b. Ifosfamidec. Streptozotocind. Methyl-3-chromonee. Maleic acidf. D-serineg. Tolueneh. Cadmiumi. Leadj. Mercury

5. Interstitial renal diseasea. Sjögren syndromeb. Medullary cystic diseasec. Renal transplant rejectiond. Chronic renal vein

thrombosise. Balkan nephropathy

6. Miscellaneousa. Malignancyb. Nephrotic syndromec. Paroxysmal nocturnal

hemoglobinuria (iron deposi-tion)

d. Congenital heart disease

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ACID-BASE AND ELECTROLYTES 9

potential NaHCO3 (ie, Shohl’s solution).4 NaHCO3therapy simultaneously corrects the acidosis,reverses volume contraction, ameliorates renal Kwasting (in contradistinction to proximal RTA), andincreases urine citrate levels. Normalizing citrateexcretion helps solubilize urine calcium andopposes renal papillary calcification and kidneystone formation. The metabolic acidosis of type IVRTA generally improves with correction of hyper-kalemia—accomplished with diuretics or K bindinggels. Some of these patients may require exogenousmineralocorticoids; others respond well to diureticsand for some exogenous NaHCO3 is required. Themetabolic acidosis and volume depletion secondaryto diarrhea can also be corrected by the administra-tion of NaHCO3.

Metabolic Acidosis with an Increased AnionGap (AG)

AG metabolic acidosis develops when organicand/or non-Cl inorganic acids accumulate at ratesthat exceed the capacity to excrete or metabolizethem.21-23 Calculation of the anion gap (AG) is essen-tial in the differential diagnosis of metabolic acido-sis. The AG is defined as the difference between theplasma concentrations of the measured plasmacation (ie, Na+) and the measured anions (ie, chlo-ride [Cl-], HCO3 -).

AG calculation = (Na+) - ([Cl-] + [HCO3 -])

The normal AG is 8-16 mEq/L, (averages around 12mEq/L). Metabolic acidosis with a high AG is asso-ciated with the addition of endogenously or exoge-nously-generated acids. Metabolic acidosis with anormal AG is associated with the loss of HCO3 orthe failure to excrete H+ from the body. There areseveral mnemonics used to promptly recall the dif-ferential diagnosis of high anion gap acidosis. Twopopular mnemonics are: MUDPILES: M-methanol; U-uremia; D-DKA,AKA; P-paraldehyde, phenformin; I-iron, isoniazid;L-lactic (ie, CO, cyanide); E-ethylene glycol; S-sali-cylates.

MAPLES: D-DKA; R-renal; M-methanol; A-alco-holic ketoacidosis; P-paraldehyde, phenformin; L-lactic (ie, CO, HCN); E-ethylene glycol; S-salicy-lates. Causes of a High AG metabolic acidosis arelisted in Table 5.

Lactic Acidosis

Lactic acidosis occurs when lactate productionexceeds consumption and body buffer systemsbecome overburdened. This is reviewed in detailelsewhere.4,25 Lactic acidosis results in increasedblood lactate levels that can be easily measured.Lactic acid exists in two forms, L-lactate and D-lac-tate. L-lactate is the only form produced in humanmetabolism. Its excess represents increased anaero-bic metabolism due to tissue hypoperfusion. In con-trast, D-lactate is a byproduct of bacterialmetabolism and may accumulate in patients withshort-gut syndrome or in those with a history of gas-tric bypass or small bowel resection.26

Lactic acidosis is classified into 2 categories: TypeA lactic acidosis is characterized by decreased tissueATP in the setting of poor tissue perfusion or oxy-genation.27,28 Type B lactic acidosis is characterizedby the absence (at least overt absence) of poor tissueperfusion or oxygenation. Type B is divided into 3subtypes: Type B1 is association with systemic dis-ease such as renal and hepatic failure, diabetes, andmalignancy. Type B2 results from drugs and toxinssuch as biguanides, alcohols, iron, isoniazid, andsalicylates. Type B3 is due to inborn errors ofmetabolism.

Type A lactic acidosis usually results from local orsystemic underperfusion or overt shock.2 It is usu-ally treated by reversing the underlying cause of thepoor perfusion state.27,29 Treatments directed at thelow bicarbonate level itself are generally doomed tofail. A common type of transient reversible lacticacidosis is postictal or post-exertion lactic acidosis.These lactic acidoses result from rapid muscle gen-eration of lactate combined with reduced hepaticoxidation as a result of temporary hepatic underper-fusion. They rapidly resolve as an individual recov-ers from the exertion or seizure. Less commoncauses of Type A lactic acidosis include a severe andacute arterial hypoxemia and very severe anemia –

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especially when due to iron deficiency.

Of the causes of type B lactic acidosis, drugs thatinterfere with lactate (and pyruvate) metabolism areimportant to consider. For example, a high concen-tration of metformin inhibits the enzyme pyruvatedehydrogenase. This results in cytosolic accumula-tion of pyruvic and lactic acid and sometimes gener-ates severe lactic acidosis. Because metformin isexcreted by the kidney, it can accumulate wheneverrenal insufficiency exists or develops. Pyruvatedehydrogenase also requires the cofactor thiaminepyrophosphate and its activity falls when thiamineis deficient. Consequently, thiamine deficiency canproduce profound lactic acidosis. Another class ofdrugs which can lead to lactic acidosis is the reversetranscriptase inhibitors used to treat HIV. This isapparently a consequence of direct mitochondrialtoxicity. For example, zidovudine and stavudinehave been associated with chronic lactic acidosis,fatty liver and myopathy. A number of inheritedmitochondrial enzyme defects produce chronic lac-tic acidosis.30 When associated with a myopathy—seizures and strokes—these disorders are groupedas the MELAS syndromes (Mitochondrial myopa-thy, Encephalopathy, Lactic acidosis, and Stroke).31

Many other inherited and acquired cytosolic andmitochondrial enzyme disorders also produce lacticacidosis. Table 6 shows another classification sys-

10 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Table 5

High Anion Gap Metabolic Acidosis

1. Lactic acidosis

2. Ketoacidosis

3. Uremia

4. Methanol ingestion

5. Ethylene glycol ingestion

6. Salicylate poisoning

7. D-Lactic acidosis

tem for lactic acidosis based on restriction of ATPproduction, lactic acid overproduction, and lacticacid under-utilization.

Ketoacidosis

The two most important causes of ketoacidosisare diabetes and alcoholism. Diabetic ketoacido-sis (DKA) reflects a state of absolute or relativeinsulin deficiency resulting in hyperglycemiaexacerbated by extracellular volume depletionand acidosis.32 DKA is characterized by bloodsugars >300 mg/dL and acidemia (arterial pH<7.30, serum HCO3 <15 mEq/L). Ketonemia andketonuria are also present. Common causesinclude underlying infection, disruption of insulintreatment, and new onset of diabetes. It is fre-quently precipitated by the metabolic stress of anintercurrent medical or a surgical complication.Alcoholic ketoacidosis (AKA) is characterized byan acute metabolic acidosis occurring in alco-holics who have recently engaged in binge drink-ing, starved themselves of food, and been vomit-ing.33 Laboratory data in AKA demonstrates ele-vated serum ketone levels and a high anion gap. Aconcomitant metabolic alkalosis (secondary tovomiting and volume depletion) may also be pre-sent. In both DKA and AKA, the accumulatingacid anions are both acetoacetate and beta-hyroxybutyrate. It is important to note that thecommonly used “ketone” tests for both plasmaand urine are based on the nitroprusside reactionand this reacts with acetoacetate but not beta-hydroxybutyrate. These two compounds are inequilibrium via an NAD/NADH driven enzyme.Changes in the redox state of a patient can there-fore markedly affect the “ketone” test, indepen-dent of changes in severity of the metabolic acido-sis. Acetone also accumulates and causes the dis-tinctive “ketotic” odor, but this is not an acid anddoes not contribute to the acidosis or elevatedanion gap.

Drugs and Toxins

Methanol and ethylene but not isopropanol over-doses typically present with an anion gapmetabolic acidosis.34,35 Methanol is metabolized toformaldehyde and then formic acid. These toxicmetabolites are responsible for the frequent

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ACID-BASE AND ELECTROLYTES 11

development of blindness. The formic acid causesthe anion gap acidosis. When ethylene glycol isingested it is metabolized to glycine, glyoxalate andoxalic acid. The oxalate combines with calcium andprecipitates in the brain, lungs, peripheral nerves,and kidneys. Abundant calcium oxalate crystals inthe urine is a major clue suggesting ethylene glycolpoisoning, and renal failure occurs very commonly.Early diagnosis in both methanol and ethylene gly-col poisoning are key. A useful screening test isdetermination of the osmolar gap. If the osmolargap is greater than 10, it indicates the presence ofappreciable quantities of low molecular weight sub-stances such as methanol or ethylene glycol (see

Table 6

Lactic Acidosis

Decreased ATP Production

A. Circulatory failure1. Volume depletion2. Severe heart failure3. Massive pulmonary emboli4. Vascular collapse: septic shock,

anaphylaxis, vasodilators (nitroprusside)B. Severe acute tissue hypoxia

1. Acute respiratory failure2. Carbon monoxide poisoning3. Severe anemia4. Methemoglobinemia

C. Defective mitochondrial oxygen utilization/energy production

1. Electron transport defect: carbon monoxide, cyanide, severe iron deficiency

2. Decreased oxidative phosphorylation: salicylate intoxication, 2,4-dinitrophenol

3. Mitochondrial enzyme defect: pyruvate carboxylase, pyruvate dehydrogenase, cytochrome oxidase defects (MELAS syndromes, metformin toxicity, reverse transcriptase inhibitors)

4. Decreased pyruvate utilization: phenformin, acute beriberi

5. Phosphate trapping: fructose, xylitol, sorbitol, glucose-6-phosphatase deficiency (von Gierke disease)

Lactate overproduction (with relativeATP deficiency)

A. Muscle hyperactivity1. Severe exertion2. Seizure3. Hypothermia-?shivering (and

decreased perfusion)4. Exertional heat stroke

B. Disseminated tumor, especiallyleukemia/lymphoma

C. Tumor lysis syndromeD. Gluconeogenic enzyme defects

1. Glucose-6-phosphatase defect(von Gierke disease)

2. Fructose-1,6-diphosphatasedefect

E. Catecholamine excess - Pheochro-mocytoma

F. MethanolG. Ethylene glycol

Decreased lactate utilization

A. Advanced liver disease

section on body water/osmolality).36

Osmole Gap = Measured Serum Osmolality– Estimated Serum Osmolality

Estimated Serum Osmolality = 2(Na+) + [Glucose/18] + [BUN /2.8]

Normal serum osmolality is 280-295 mOsm/L

Of note, the osmolar gap is more likely to be ele-vated in methanol ingestion than with ethylene gly-col ingestions because of the lower molecularweight of methanol. Blood methanol and ethylene

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glycol levels can be measured but the test is notwidely available (methanol and ethylene glycol lev-els >20mg/dl are associated with significant toxic-ity). The treatment of both methanol and ethyleneglycol poisoning requires urgent inhibition of theenzyme alcohol dehydrogenase.37-39 This blocks con-version of the ingested alcohols to organic acids andother more toxic metabolites. Inhibition is accom-plished by administration of ethanol or the specificinhibitor fomepizole.40 Hemodialysis is oftenrequired to remove the ingested poison and toxicmetabolites and to simultaneously correct themetabolic acidosis and electrolyte abnormalities.41

Salicylate poisoning generates an anion gap acido-sis because toxic concentrations uncouple oxidativephosphorylation and results in generation of multi-ple organic acids.42-44 In addition, most adults withsalicylate poisoning also develop respiratory alkalo-sis (see below – mixed acid base disorders). The rel-ative severity of the two disturbances determinesthe arterial pH, and this is very age dependent —babies generally have more severe metabolic acido-sis, while adults have more profound respiratoryalkalosis. Nonetheless, most patients have elementsof each disturbance.

Uremia

Uremic metabolic acidosis is often a hyper-chloremic acidosis early in the course (due toimpaired NH4 excretion) and then evolves into ananion gap acidosis as multiple organic and inorganicanions (SO4, HPO4, etc.) accumulate as a result ofthe low GFR.45,46 In uremic patients, the metabolicacidosis may contribute to other clinical abnormali-ties, such as hyperventilation, anorexia, stupor,decreased cardiac response (congestive heart fail-ure), and muscle weakness.

D-Lactate

Mammals primarily synthesize, and metabolize, theL optical isomer of lactic acid, while many bacteriagenerate and utilize both the L and D isomers.Patients with short gut syndromes can develop D-lactic acidosis, an unusually high anion gap acido-

sis.26 Usually, this disorder occurs when large carbo-hydrate loads are delivered to the colon where bac-terial metabolism generates D-lactic acid. Whensystemically absorbed, this acid is slowly metabo-lized and this generates both the acidosis and a spec-trum of neurological abnormalities including confu-sion, ataxia, slurred speech, and generalized weak-ness. D-lactic acid is not detected by routine enzy-matic assays for lactic acid (which are stereoisomerspecific for L-lactic acid). When it is suspected, D-lactic acid can be identified with specific enzy-matic assays for D-lactate or gas-liquid chromatog-raphy.

Metabolic Alkalosis

Metabolic alkalosis is very common, both in prac-tice and in examination setting as a question. Thereare several excellent reviews on this topic availablein the literature.47-5 Metabolic alkalosis represents aprimary increase in [HCO3 ]. A modest compen-satory increase in PaCO2 should develop (Table 1).The increase in [HCO3 ] results from either a loss ofH+ from the body or a gain in HCO3 -. In its pureform, metabolic alkalosis presents as alkalemia (pH>7.40). However, because of homeostasis there isusually a secondary or compensatory responseresulting in alveolar hypoventilation with a rise inarterial carbon dioxide tension ( PaCO2). Thiscauses an attenuation in the change in pH that wouldotherwise occur.

Under normal circumstances, as a rule of thumb,the compensatory ventilatory response results in a0.5-0.7 mm Hg increase in arterial PaCO2 for every1 mEq/L increase in [HCO3 ] concentration. If thechange in PaCO2 is not within this range, then amixed acid-base disturbance exists.

Normally, kidneys filter between 4000 and 5000mEq of NaHCO3 per day and therefore should beable to rapidly excrete large quantities of NaHCO3.The administration, or generation, of HCO3 cannotmarkedly increase the [HCO3] unless renalNaHCO3 excretion is decreased. Therefore, theanswers to the following two questions provideinsight to the pathogenesis of metabolic alkalosisand suggests the best therapeutic approach:

12 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

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1. Where did the HCO3 originate? Was it generatedendogenously or enter the body from someexogenous source?

2. Why has the kidney not efficiently excreted theHCO3?

First, in regard to question number 1, exogenousHCO3 can be acquired as NaHCO3 (or less com-monly KHCO3), or the Na salt of an organic ion thatrepresents potential HCO3 such as lactate, acetate,etc. (see above). The stomach and the kidney are theonly two organs that can generate relatively largeamounts of HCO3. These organs generate net HCO3loads when the acid they secrete is removed fromthe body (ie, HCl generated by the stomach must beremoved via N-G suction or vomiting and the kid-ney must excrete acids —as NH4Cl or titratableacid—into the urine).

Second, consider the possible answers to questionnumber 2 (why has the kidney not efficientlyexcreted the HCO3?). They include the following:

1. General kidney dysfunction or failure. Althoughkidney failure usually generates a metabolic aci-dosis—because normally generated acids areretained—large loads of HCO3 can generate ametabolic alkalosis. For example, metabolic alka-losis can occur in dialysis patients who ingestbaking soda (NaHCO3) or vomit.

2. The patient is volume depleted (whether a truedeficit or an “effective” arterial volume deficit).The proximal tubule will then avidly reabsorb fil-tered Na in exchange for protons – ie, NaHCO3 isreabsorbed. These patients are also invariablychloride depleted.

3. Potassium deficits and hypokalemia occur verycommonly with metabolic alkalosis and thisenhances renal tubule proton secretion (HCO3reabsorption and generation).

4. Persistent distal tubule acid secretion (HCO3reabsorption), usually due to the delivery of large

Na loads to this tubule segment, combined withunrestrained mineralocorticoid activity.

Vomiting or N-G suction causes an external loss ofHCl and NaCl containing gastric fluid and generatesendogenous HCO3. Metabolic alkalosis persistsbecause of volume contraction and potassium defi-ciency (generated by renal losses of K). The keypathophysiologic mechanisms responsible fordevelopment and maintenance of gastric alkalosisare shown in Figure 3.

The other very common cause of metabolic alkalo-sis is chronic use of a thiazide and/or loop diuretic.These two classes of diuretics reduce renal reab-sorption of filtered NaCl and increase its delivery tomore distal nephron tubule segments and the urine.The ECF contracts and stimulates therenin/angiotensin/aldosterone axis. Persistent distalNaCl delivery, systemic volume contraction and Cldepletion combine with aldosterone activity toaccelerate Na reabsorption in the collecting tubule.At this site, Na reabsorption generally stimulates thesecretion of protons and K and generates metabolicalkalosis and hypokalemia. Hypokalemia, ECFcontraction and ongoing distal tubule Na deliveryand reabsorption also maintains the alkalosis. Thus,the kidney is the site of both HCO3 generation andmaintenance of the alkalosis in patients withdiuretic induced metabolic alkalosis. Gastric fluidloss and diuretics probably account for more than90% of the cases of clinically significant metabolicalkalosis.

The metabolic alkaloses can be classified on thebasis of a spot urine chloride concentration53,54

(Table 7). Intravascular volume contraction (bothtrue contraction associated with a low ECF volumeas well as “effective” intravascular contraction asoccurs in edema forming conditions such as cirrho-sis and CHF) stimulates the kidneys to avidly reab-sorb filtered Cl and generally reduces the excretedurine [Cl] to < 20 mEq/L. Thus, the urine [Cl] canact as an analog equivalent of the intravascular vol-ume status as sensed by the kidney. The metabolicalkaloses with a low spot urine [Cl] are also called“Cl sensitive” because, in general, administration ofNaCl expands the ECF and usually corrects thealkalosis. The metabolic alkalosis of vomiting, N-Gsuction, and diuretics have been discussed. Con-

ACID-BASE AND ELECTROLYTES 13

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genital chloridorrhea is a disorder due to a defectiveCl- HCO3 exchanger in the colon and ileum, andresults in loss of HCl, NH4Cl and other potentialHCl salts into the stool. The metabolic alkalosisgenerated by thiazide and loop diuretics may haveeither a low or high urine [Cl], depending onwhether the diuretic effect is present (high) or hasworn off (low). The pathophysiology of diureticinduced hypokalemic metabolic alkalosis is shownin Figure 4.

The metabolic alkaloses with high urine [Cl] (>20mEq/l) generally have generation and maintenancemechanisms related to the combination of persistentmineralocorticoid stimulation and generous distaltubule delivery of NaCl, and are usually alsohypokalemic. ECF expansion and hypertensioncharacterize many of these disorders. The prototypi-cal example of this group is primary hyperaldos-teronism. Other mineralocorticoid excess states pro-duce a similar constellation of clinical and biochem-

14 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Table 7

Differential DX of Metabolic Alkalosis

Low Urine [C1] < 20 mEq/1 High Urine [C1]>20 mEq/1Chloride Responsive Chloride Unresponsive

Vomiting/N-G suction High blood pressure

S/P chronic hypercarbia Primary hyperaldosteronism

Chloridorrhea Cushing disease

Ectopic ACTH

Exogenous mineralocorticoids

Mineralocorticoid-like substances

“Apparent” mineralocorticoidexcess states includinglicorice

Liddle syndrome

Low blood pressure

Bartter syndrome

Gitelman syndrome

Diuretics (remote) Diuretics (recent)

Severe K depletion

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ical findings. This group also includes mineralocor-ticoid independent acceleration of distal tubule Na+

reabsorption such as that caused by Liddle’s syn-drome, which is the result of a genetic defect thatcauses the distal tubule epithelial sodium channelsto remain open. These disorders are further dis-cussed in the section on hypokalemia.

Recent diuretic use will cause a high urine [Cl] asdiscussed. The Bartter and Gitelman syndromeshave many similarities to diuretic-inducedmetabolic alkalosis and hypokalemia since they are

due to inherited defects of the transporters inhibitedby diuretics. These disorders are also further dis-cussed in the hypokalemia section.

Generally, NaCl infusion does not correct metabolicalkaloses in the high urine [Cl] group — indeed thevolume expansion, hypertension and metabolic dis-turbances of the mineralocorticoid excess groupwill worsen. Consequently, these disorders are alsocalled the chloride unresponsive, or resistant,metabolic alkaloses.

ACID-BASE AND ELECTROLYTES 15

Figure 3

Key pathophysiologic mechanisms responsible for development and maintenance of gastric alkalasis

The stomach secretes HCl and NaCl, which are lost in vomitus. Secretion of HCl causes HCO3- to enter the ECF and the

plasma [HCO3-] increases. ECF contraction and Cl depletion develop simultaneously. The renal filtered load of HCO3

increases and some NaHCO3 is excreted. This bicarbonaturia partially corrects the alkalosis. However, renal NaHCO3loss leads to additional ECF volume contraction further reducing the GFR. Renin, angiotensin II and aldosterone levels allincrease. The filtered HCO3

– load falls in concert with GFR reduction. The NaHCO3, which is filtered, is avidly reabsorbedby the proximal and distal tubules. The additional reabsorption of NaHCO3 in the distal tubule is associated with H and Ksecretion. Saline expansion of the ECF should reverse most of the factors which drive HCO3

– reabsorption and rapidlycorrect the alkalosis. KCl is usually also required to correct the K deficit that invariably exists.

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Respiratory Acidosis

Respiratory acidosis results from alveolar hypoven-tilation.55-57 Thus, the primary disorder is an increasein PaCO2 (ie, hypercapnia). The reference range forPaCO2 is 36-44 mmHg. The acidemia produced bythe high PaCO2 is compensated by an increase in[HCO3 ]. Acute respiratory acidosis causes a smallincrease [HCO3 ] which is mainly due to cellularbuffering. Chronic respiratory acidosis produces alarger increase in [HCO3] by stimulating renal gen-eration of HCO3. The expected level of compensa-tion is shown in Table 1. Completely compensatedchronic respiratory acidosis results in an arterial pHthat is slightly below normal. If the [HCO3] ishigher than the level predicted by these compensa-tion ratios, this will result in a normal (or high) pH,and metabolic alkalosis probably coexists.

In acute respiratory acidosis, the PaCO2 level is >45mm Hg with an accompanying acidemia (ie, pH<7.35). In chronic respiratory acidosis, the PaCO2 is>45 mm Hg but with a normal or near-normal pHbecause of a secondary or compensatory responseby the kidneys. Thus, there is an associated eleva-tion in the serum bicarbonate (ie, HCO3 - >30 mmHg).

Acute respiratory acidosis results from a failure ofventilation. Causes include depression of the centralrespiratory center by cerebral disease or drugs,inability to ventilate adequately due to neuromuscu-lar disease (eg, myasthenia gravis, amyotrophic lat-eral sclerosis, Guillain-Barré syndrome, muscular

dystrophy), or airway obstruction related to asthmaor chronic obstructive pulmonary disease (COPD)exacerbation (Table 8).

Chronic respiratory acidosis commonly occurs as aconsequence of COPD with decreased responsive-ness to hypoxia and hypercapnia, increased ventila-tion-perfusion mismatch leading to increased deadspace ventilation, and decreased diaphragm functionsecondary to fatigue and hyperinflation.58 Othercauses include chronic obesity hypoventilation syn-drome (OHS; ie, Pickwickian syndrome),59 neuro-muscular disorders such as amyotrophic lateral scle-rosis,60 and severe restrictive ventilatory defects asobserved in interstitial fibrosis and thoracic defor-mities.

Rules of Thumb for Expected Change in [HCO3-]in Respiratory Acidosis are:

Acute respiratory acidosisHCO3 - increases 1 mEq/L for each 10-mm Hg risein PaCO2.

Chronic respiratory acidosisHCO3- rises 3.5 mEq/L for each 10-mm Hg rise inPaCO2.

16 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Figure 4

The pathophysiology of diuretic induced hypokalemic metabolic alkalosis

Na+ Na+ Na+

H+ K+

NaCl

Loop diuretics will reduce Na and Cl reabsorption in the thick ascending limb of Henle, and thiazide diuretics reduce Naand Cl reabsorption at more distal sites (the diluting segment). Both diuretics cause increased delivery of Na and Cl to thecollecting tubules where Na reabsorption is indirectly linked to H and K secretion.

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Rules of Thumb for Expected Change in pH withRespiratory Acidosis Can Be Estimated with theFollowing Equations:Acute respiratory acidosis

Change in pH = 0.008 X (40 - PaCO2)

Chronic respiratory acidosis

Change in pH = 0.003 X (40 - PaCO2)

Respiratory Alkalosis

Respiratory alkalosis results from alveolar hyper-ventilation.60,61 The clinical consequence is adecreased PaCO2 level (hypocapnia) and alkalemia.The major causes of respiratory alkalosis are shownin Table 9. Respiratory alkalosis is the most com-mon acid-base abnormality observed in patientswho are critically ill. It is a common finding inpatients undergoing mechanical ventilation.

The expected compensatory responses for acute andchronic respiratory alkalosis are shown in Table 1.The acute response, a small increase in HCO3, isdue mainly to cell buffering processes and thechronic response, a greater increase in HCO3, islargely generated by renal excretion of HCO3 (orrenal retention of additional acid). Chronic respira-tory alkalosis is the best buffered acid base distur-bance and usually results in a normal arterial pH. Inacute respiratory alkalosis, the PaCO2 level is lowbut the pH is in the alkalemic range. In chronic res-piratory alkalosis, the PaCO2 level is low, but thepH level is normal or near normal because of sec-ondary or compensatory response by the kidneys.

ACID-BASE AND ELECTROLYTES 17

Table 8

Causes of Respiratory Acidosis

CNS DepressionSedatives/CNS lesions

Neuromuscular DisordersMyopathies/Neuropathies

Thoracic Cage Restriction Kyphoscoliosis/Scleroderma

Impaired Lung MotionPleural Effusion/Pneumothorax

Acute Obstructive Lung DiseaseAspiration/Tumor/Bronchospasm

Chronic Obstructive Lung Disease

MiscellaneousVentilator Malfunction/CPR

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Rules of Thumb for Expected Change in Serum([HCO3 -]):

Acute respiratory alkalosis [HCO3 -] falls 2 mEq/L for each decrease of 10 mm Hg in the PaCO2 (Limit of compensation:[HCO3 -] = 12-20 mEq/L)

Chronic respiratory alkalosis [HCO3 -] falls 5 mEq/L for each decrease of 10 mmHg in the PaCO2 (Limit of compensation: [HCO3 -]= 12-20 mEq/L)

Rules of Thumb Expected Change in pH with Res-piratory Alkalosis:Acute respiratory alkalosisChange in pH = 0.008 X (40 – PaCO2)

Chronic respiratory alkalosis Change in pH = 0.017 X (40 – PaCO2)

Mixed Disorders/Acid-Base Disorders

Mixed acid-base disorders may generate extremepH abnormalities (ie, metabolic and respiratory aci-dosis; metabolic and respiratory alkalosis) or nor-malize the pH (ie, respiratory acidosis andmetabolic alkalosis).63 Certain clinical disorderssuch as cardiac arrest, septic shock, drug intoxica-tion, ingestion of various poisons, and renal, respi-ratory, or hepatic failure are often associated withmixed acid-base disorders.

One group of mixed disorders are those due to eitherinadequate or excessive “compensation” for a pri-mary acid-base disturbance. For example, whenmetabolic acidosis reduces the [HCO3 ], but thePaCO2 is higher than predicted (Table 1), then res-piratory acidosis may co-exist. This often producesa very low pH. Mixed metabolic and respiratory aci-dosis occurs frequently when patients suffer a car-diopulmonary arrest. Conversely, if a patient withmetabolic acidosis has a PaCO2 that is too low, thenrespiratory alkalosis may co-exist. This mixed dis-order will tend to normalize the pH. This mixed dis-order often occurs with sepsis because circulatingendotoxin directly stimulates the respiratory centerand hypotension leads to lactic acidosis. Salicylatepoisoning also produces metabolic acidosis/respira-tory alkalosis because toxic ASA levels directlystimulate respiration and simultaneously uncouplecellular oxidative metabolism, generating an AGacidosis.

An excessive, or inadequate, HCO3 response to aprimary respiratory acid-base disorder is recognizedsimilarly and also defines mixed acid-base disor-ders. Another group of mixed disorders are thoserecognized by a comparison of the [AG] and[HCO3].

18 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Table 9

Causes of Respiratory Alkalosis

Anxiety

CNS DisordersCVA/Tumor/Infection

HormonesProgesterone/Catecholamines

DrugsSalicylates/Analeptics

Sepsis/Endotoxemia

Hyperthyroidism

Hypoxia

Pregnancy

Cirrhosis

Pulmonary Edema

Lung DiseasesRestriction/Pulmonary Emboli/Pneumonia

Ventilator Induced

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panel 3 then develops. The AG remains large butthe [HCO3] has increased and the [Cl] has fallen.This is due to the still persistent AG metabolic aci-dosis and a superimposed “gastric” metabolic alka-losis. The ABG shows he actually has a triple dis-turbance because his PaCO2 is too low for the con-current [HCO3]. Respiratory alkalosis occurs com-monly in patients with severe liver disease, proba-bly as a result of high progesterone levels, whichstimulate the CNS respiratory center, and hypoxiarelated to pulmonary A-V shunts and diaphragmspushed up by ascites.

ACID-BASE AND ELECTROLYTES 19

Figure 5

Laboratory studies of a man with a history of chronic alcohol abuse that is admitted withdecompensated cirrhosis and probable hepato-renal syndrome

Na Na Na

Cl Cl Cl

AG AG AG

HCO HCO HCO

3 3 3

pCO 2 - 30 mmHg

HCO - 24 mEq/l

A B C

140

4.0

104

24

140

4.0

104

12

AG = 12 AG = 24

140

4.0

92

24

AG = 24

pH

pO2

-

-

7.53

70

A simple AG acidosis should quantitatively increasethe [AG] by approximately the same magnitude asthe fall in [HCO3]. This is sometimes called theΔ [AG]/Δ [HCO3]. When metabolic alkalosis com-plicates an AG metabolic acidosis this will increasethe [HCO3], but not significantly affect the largeAG. Therefore, whenever the [AG] increaseexceeds the reduction in [HCO3] mixed metabolicacidosis/metabolic alkalosis probably exists. Forexample, Figure 5 shows the laboratory studies of aman with a history of chronic alcohol abuse that isadmitted with decompensated cirrhosis and proba-ble hepato-renal syndrome. Six months ago (panelA) his electrolytes were normal. On admission hehas an AG metabolic acidosis (panel B) – toxins,uremic and lactic acidosis are considered. There isno osmolar gap (see below). Following admission,an NG tube is placed because of abdominal disten-sion and vomiting. The electrolyte pattern shown in

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3. Water Spaces, Osmolality, and Sodium

The normal distribution of water and electrolytesolutes and their contribution to extracellular fluidspace (ECF) (and plasma) osmolality and intracellu-lar fluid space (ICF) osmolality are shown in Figure6. Normally Na salts account for almost the entireECF osmolality. Osmotic gradients are not main-tained across most cell membranes. When theosmolality increases or decreases in either the ECFor ICF, water will shift until the osmolality is

equalized. When non-sodium solutes accumulate inthe ECF, they contribute to osmolality in proportionto their molar concentrations. For example, highglucose and/or urea concentrations have the follow-ing effect:

Equation 2:Posm = 2X[Na] + [BUN] + [Glucose]

2.8 18

(The constants 2.8 and 18 convert the urea and glu-cose concentrations from mg/100 mL to mmol/L).

However, glucose and urea have very differenteffects on water distribution and the plasma [Na].When glucose levels increase, this solute is largelyrestricted to the ECF. The attendant increase in ECFosmolality causes a rapid water shift from the ICF tothe ECF. This water translocation simultaneouslyreduces the ECF, and increases the ICF, solute con-centrations and osmolality. Water continues to shiftuntil the ECF and ICF osmolalities are again equal.Each 100 mg/100 mL increase in glucose concentra-tion will reduce the [Na] by about 1.6 mEq/L. Conversely, when hyperglycemia is corrected,water shifts from the ECF into the ICF so that a 100 mg/100 mL fall in [glucose] increases [Na] byabout 1.6 mEq/L. (Recent studies suggest the ratiomay be closer to 2.4 mEq Na/100 mg% glucose, butthe true value remains uncertain and ratios between1.6 and 2.4 are acceptable.) Mannitol, which isoften used to treat cerebral edema and is an osmoticdiuretic, has molecular weight and compartmentaldistribution characteristics similar to glucose andtherefore has similar effects on water distributionand sodium concentration.

In contrast urea, a smaller molecule rapidly pene-trates cell membranes. When the urea concentrationincreases, its ICF and ECF concentrations rapidlyequilibrate because urea enters cells rather than anywater shift. This is not the case when urea levelsincrease or decrease very rapidly — ie, with effi-cient hemodialysis. In that circumstance the veryabrupt reduction in ECF urea may cause water toshift into cells and produce neurologic symptoms.Other small solutes such as ethanol, methanol andethylene glycol also readily penetrate cell mem-branes, and like urea they do not cause much watershift when their concentrations increase. Glycine

20 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Figure 6

Normal distribution of water and electrolytesolutes and their contributionto ECF and ICF

20% 40%

Total Body Water (TBW) = 60%

Weight (kg)

Osmolality=290

mOsm/kg

Osmolality=290

mOsm/kg

Na = 145 mEq/kg

K = 145 mEq/kg

ECF ICF

Weight (kg)

In a 70-kg man, Total Body Water (TBW) will = 42 L; Extra-cellular Fluid (ECF) = 14 L; Intracellular Fluid (ICF) = 28 L.The ECF includes plasma (about 3.5 L), interstitial andtranscellular water. The major solutes of ECF are sodiumsalts that are largely restricted to this compartment. TheECF, plasma or serum osmolality can be calculated as:Posm=2X[Na]. The intracellular solutes are primarilypotassium salts. Most cell membranes have very highwater permeability so that water quickly moves acrossthem rapidly to eliminate any osmotic gradient. Therefore,assume the ECF and ICF osmolality are equal. When theosmolality of the ECF or the ICF is altered, a water shiftquickly reestablishes the osmolal equality in these fluidspaces.

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has membrane permeability properties intermediatebetween glucose and urea. Glycine-based solutionsare used during TURP, endometrial ablation, andarthroscopic procedures. Occasionally, large quanti-ties of glycine irrigant are accidentally infusedintravenously, or are absorbed, and producehyponatremia. This occurs for two reasons. First,the most commonly used glycine irrigation solu-tions are hypo-osmolal (approximately 200mOsm/kg) so “free water” is infused. Second, to theextent glycine is restricted to the ECF, it will cause awater shift from the ICF similar to mannitol or glucose.

Some molecules that can accumulate in the ECF andraise plasma osmolality are not sodium salts, glu-cose or urea. Therefore, they are not included inequation 2. In such cases, the measured osmolalitywill exceed the calculated osmolality—this differ-ence is the “osmolal gap.” Mannitol, glycine,ethanol, methanol, isopropanol, and ethylene glycolrepresent some solutes that can produce an osmolal gap.

The coordinated action of antidiuretic hormone(ADH), thirst, and the renal concentrating-dilutingsystem maintain normal plasma osmolality and the[Na]. When osmolality increases above 290mOsm/kg, ADH is released and thirst is triggered(Figure 7).

ADH causes relatively solute free water reabsorp-tion (equilibration with the medullary osmolality) inthe distal nephron and can increase urine osmolalityto the 800-1200 mOsm/kg range. When plasmaosmolality falls below 280 mOsm/kg ADH, secre-tion is inhibited. In the absence of ADH, maximallydilute urine (50-80 mOsm/kg) is normally excreted.ADH is also released independently of plasmaosmolality in response to systemic hypotension, a7%-10% decrease in plasma volume, vomiting, or areduced effective arterial blood volume, whichoften complicates hepatic cirrhosis or congestiveheart failure. Non-osmotic factors such as drymucous membranes, certain psychotropic medica-tions, and high angiotensin levels can also increasethirst.

Hyponatremia

Hyponatremia is a common problem especiallyamong hospitalized patients. The differential diag-nosis and management has been extensivelyreviewed elsewhere.63-69 Hyponatremia may be asso-ciated with a normal, low or even high osmolality.One classification scheme based on the plasma andurine osmolalities is shown in Table 10. Pseudohy-ponatremia is an artifactual reduction in sodiumconcentration due to very high lipid and/or proteinconcentrations. This is a “displacement” artifactwhich may occur when plasma contains much lessthan the normal 93% water. Pseudohyponatremiawas a major artifact when flame photometer deviceswere used to measure [Na] and [K]. These instru-ments measured mEq/L of plasma. The artifact doesnot exist when electrolytes are analyzed with direction selective electrode methods, which actuallymeasure mEq/L plasma water. However, indirection selective electrodes, which many facilities use,are susceptible to this artifact because a specificquantity of plasma is mixed with a diluent. Themeasurement of osmolality is not affected by waterdisplacement artifacts and therefore reflects theconcentration of sodium (and other solutes) inplasma water.

Hyponatremia with normal or increased osmolalitycan be generated by hyperglycemia or high manni-tol concentrations (see above). Water moves fromthe ICF into the ECF, reducing the sodium concen-tration as described above. This form of hypona-

ACID-BASE AND ELECTROLYTES 21

Plasma Osmolality280270 290 300

ADH

Figure 7

When osmolality increases above 290mOsm/kg, ADH is released and thirst istriggered

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tremia is called translocational hyponatremia (notpseudo-hyponatremia–the sodium concentration isreally low but the osmolality is not).

Hypo-osmolar hyponatremia indicates an excess oftotal body water relative to total body solute. Thelow ECF osmolality means that ICF osmolality isequally reduced. The most feared and dangerouseffect of hypo-osmolar hyponatremia is cerebraledema which may develop when water shifts intothe brain cells.

Otherwise normal individuals can excrete up to 18liters of dilute urine each day. Consequently, theyshould be able to rapidly correct hyponatremia.Although most patients with hypo-osmolar hypona-tremia have high ADH levels and excrete inappro-priately concentrated urine, four unusual hypona-tremic conditions associated with dilute are shownin Table 10. The pathophysiology of beer drinker’shyponatremia and the tea and toast syndrome aresimilar and are related to very low levels of soluteexcretion.70 These patients generally eat very littleprotein and not much salt but drink large amounts offluid. Therefore they do not excrete much urea orNa. Large volumes of even dilute urine still requiresolute to be excreted. The patients with psychogenicpolydipsia may ingest enormous quantities of watervery rapidly and overwhelm normal urine dilutionmechanisms. Furthermore, as the [Na] is sharplyreduced, the development of nausea can convert thiscondition to one with high ADH levels and concen-trated urine and thereby exacerbate the problem. Alow GFR will reduce the quantity of dilute urine a

patient can excrete.

Much more frequently, hypo-osmolar hyponatremiawill be associated with high ADH levels and inap-propriately concentrated urine. Table 11 subdivideshypo-osmolar hyponatremia on the basis of ECFvolume and effective intravascular volume status.The history, physical examination (with specialattention to BP, pulse and the presence of orthostaticchanges, edema, ascites, rales, etc.), urine [Na] and[osmolality], and the plasma BUN and uric acidconcentrations indicate the appropriate categoryand direct further W/U and Rx. Although ADH lev-els can be measured, the measurement rarely nar-rows the differential diagnosis because it is almostalways increased in such patients.

Expansion of the volume-depleted hyponatremicpatient with normal saline increases the GFR andthe delivery of Na and fluid to the distal tubule andsimultaneously inhibits ADH release. This producesa water diuresis that will correct the hyponatremia.Patients with an expanded ECF but low EABV(CHF, cirrhosis, etc.) require treatment directed atthe underlying organ dysfunction. Salt intake mustusually be restricted in this group of patients. Waterrestriction is required when the [Na] is <125 mEq/L.Loop diuretics can sometimes be used to promotenatruresis and to simultaneously reduce maximalrenal concentrating capacity. Other treatmentoptions are discussed below.

Many euvolemic hyponatremic patients have thesyndrome of inappropriate antidiuretic hormone

22 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Table 10

Classification of Hyponatremia

Plasma Osmolality Appropriately Reduced Normal High

Urine Osmolality Low High

Tea and toast syndromeBeer drinker's potomania (See Table 11)Psychogenic water ingestionKidney failure

Pseudo-Hyponatremia

HyperlipidemiaHyperproteinemia

TranslocationalHyponatremia

HyperglycemiaMannitolGlycine

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secretion (SIADH).71,72 The major causes of SIADHare pulmonary diseases, central nervous systemdysfunction, drugs, and carcinomas – especiallysmall cell lung cancer. Important pulmonary causesinclude pneumonia, tuberculosis, empyema,abscess, asthma, and COPD. CNS causes includehead trauma, stroke, hydrocephalus, meningitis, andsubarachnoid hemorrhage. Cancers that should beconsidered include, lung, brain, pancreas, prostate,and ovary. While the drug list is long, some keydrugs to consider are analgesics (eg, narcotics, non-steroidal anti-inflammatory drugs [NSAIDs]),antidepressants (eg, monoamine oxidase inhibitors,tricyclic antidepressants, selective serotonin reup-take inhibitors [SSRIs]), antineoplastics (eg, vin-cristine, vinblastine, cyclophosphamide), neurolep-tics (eg, phenothiazines), and oral hypoglycemics(eg, chlorpropamide, tolbutamide). Hypothy-roidism and cortisol deficiency can also produceeuvolemic hyponatremia and must be ruled out toestablish a diagnosis of SIADH.

The treatment of hyponatremia is determined on thebasis of its etiology, chronicity and associatedsymptoms.65,73-76 If the causative pathology cannot beeliminated then the [Na] itself may require therapy.Chronic, moderately symptomatic hyponatremia(usually an outpatient disorder) is treated conserva-tively with the goal of correcting the [Na] overmany days. Water restriction is the cornerstone oftherapy for these patients. Adjunctive therapyincludes the administration of loop diuretics, whichreduce maximal renal concentrating capacity, com-bined with liberal NaCl intake. This strategy mayreduce the requirement for severe water restriction.Demeclocycline (300-600 mg PO bid) has beenused to produce reversible nephrogenic diabetesinsipidus, thereby promoting renal free water excre-tion. Oral urea (0.5-1.0 g/kg qd) is another optionthat may prove helpful for some patients. Urea actsas an osmotic diuretic and increases the excretion ofelectrolyte free water into the urine. A number oforal, non-peptide, ADH antagonists (aquaretics),are currently being studied and will probably soon

ACID-BASE AND ELECTROLYTES 23

Table 11

Evaluation of Hypo-osmolar Hyponatremia with High Urine Osmolality

ECF Volume Status

Effective arterial volume

Clinical syndromes

Biochemical Resultsb

Urine sodium

Urine osmolality

Plasma ADH

BUN

Serum uric acid

Volume Depleted

Low

GI fluid lossesThird spacing

Adrenal insufficiencyRenal salt-wasting

<10 mEq/Lc

High

Elevated

Elevated

Elevated

Euvolemic

Normal to high

SIADHHypothyroidism

Glucocorticoid deficiency

>10 mEq/L

High

Elevated

<10 mg/dL

<4 mg/dL

Volume Expandeda

Low

Congestive heart failureCirrhosis

Nephrotic syndrome

<10 mEq/L

High

Elevated

Elevated

Elevated

a. Volume expanded includes patients with edema, ascites, and or pulmonary congestion whose effective arterial bloodvolume (EABV) is reduced. b. Assumes that no diuretic effect exists. c. Except will be high with renal salt wasting states.

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be used to treat a variety of chronic hyponatremicconditions.77-79

Aggressive and very rapid correction of chronichyponatremia can result in a catastrophic neurologiccomplication called central pontine and extra pon-tine myelinolysis, or the osmotic demyelinationsyndrome.74,75 Although this is often a fatal disorder,many more subtle cases are now also recognized onthe basis of characteristic MRI changes and clinicalfindings. This syndrome is much less likely to occurif the rate of [Na] correction is limited to <0.5mEq/hr and the absolute level of acute [Na] correc-tion is kept <120 mEq/L. The underlying cause ofthis complication remains unknown but the patho-physiology may be related to the issue of “idio-genic” brain osmoles. Although most of the intra-cellular solute is comprised of electrolyte salts asmall but very important component are organicmolecules such as myoinositol, choline, glutamineand taurine. The concentrations of these moleculesare actively regulated. Therefore, when hypertonic-ity develops (hyperglycemia, etc.) and water movesout of brain cells, the concentrations of these solutesincrease to minimize brain cell shrinkage. Con-versely, when hypo-osmolar hyponatremia causesbrain cell swelling, the concentration of intracellu-lar organic solutes falls and reduces the degree ofswelling. This “auto-correction” of cell volume maycontribute to the adverse effects of too rapid correc-tion of chronic hyponatremia (or chronic hypernatremia).

Acute symptomatic hyponatremia is more com-monly recognized in hospitalized patients.76 Whenthe [Na] falls rapidly to <120 mEq/L, nausea, vom-iting, irritability, mental confusion, and seizuresmay occur, and below 110 mEq/L, coma and death.Otherwise healthy young women undergoing elec-tive surgery may be especially susceptible to aunique form of severe, and often fatal, acute postop-erative hyponatremia. Symptomatic acute hypona-tremia requires prompt and aggressive therapy.Hypertonic (3% = 517 mEq/l) saline may be infusedto increase the [Na]. The quantity of NaCl requiredto increase the plasma [Na] is calculated with thefollowing equation:

Equation 3:mEq Na required = TBW X�[Na]mEq Na required = 0.6 X Wt.kg X�[Na]

Although infused Na is largely restricted to the ECF,total body water is used in this calculation becausechanges in [Na] generate water shifts which equal-ize osmolality in the ECF and ICF. However, thiscalculation does not consider ongoing urinary, GI orinsensible free water or electrolyte loss. Thus, it is atheoretical first approximation, and plasma elec-trolytes must be frequently monitored during suchtreatment, especially if the urine or GI output islarge. Loop diuretics may also be used togetherwith the hypertonic saline to increase free waterexcretion and to prevent ECF volume overload. Areasonable therapeutic goal for the partial correctionof acute, symptomatic hyponatremia is to increasethe [Na] 1-2 mEq/hr for several hours but then slowdown the correction rate to achieve a change ofabout 15-20 mEq during the first 24 hours of Rx.

Recently, the development of acute hyponatremiawhich occurs during and following marathon raceshas become better recognized and understood.80

Affected individuals are those who gain weight dur-ing the race apparently because they drink excessiveamounts of fluids. Symptomatic hyponatremia inthese individuals should be urgently treated withhypertonic saline. Participants should be encour-aged to weigh themselves before and after practiceruns and races, and attempt to adjust fluid intake tomaintain a stable weight.

Hypernatremia

A plasma [Na] >145 mEq/L defines hypernatremia(and hyperosmolality).81-85 The overall incidence ofhyponatremia ranges from 0.12%-3.5% in hospital-ized patients. The geriatric population appears to beparticularly at risk. Usually hypernatremia developswhen fluids containing relatively low electrolyteconcentration (<140 mEq/l) are lost from the body.The losses may be renal, GI or insensible. Less com-monly, hypernatremia is generated by the infusionof hypertonic NaCl or NaHCO3. Hypothalamicsensors detect the hypernatremia and produce sig-nals which increase thirst and the synthesis and

24 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

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release of ADH. Patients who have an isolatedabnormal ADH response and/or an impaired renalresponse to ADH do not usually become markedlyhypernatremic if their thirst mechanisms are intactand they have access to water. Therefore, persistenthypernatremia usually indicates the existence of anabnormal thirst mechanism or an inability to ingestsufficient quantities of water as well as abnormalADH and/or renal concentration mechanisms.Hypernatremia produces lethargy, weakness, andirritability and when severe can cause seizures,coma and death. The symptoms reflect the severity

and the rapidity of development of the hyperna-tremia. The causes of hypernatremia are shown inTable 12.

Hypernatremia should stimulate ADH and increasethe U-[osm]; therefore, a reduced U-[osm] in ahypernatremic patient indicates malfunction ofADH/renal concentrating mechanisms (diabetesinsipidus, DI).86-89 Etiologies include defective pitu-itary synthesis and/or release of ADH (central DI),accelerated peripheral ADH destruction (rare,occurring in some pregnant patients), or a defectiverenal response to ADH (nephrogenic DI). Someforms of central DI and nephrogenic DI are inher-ited. More commonly, DI is an acquired disorder.Acquired central DI may be due to infiltrative orgranulomatous diseases (such as sarcoidosis),trauma, neoplasm, neurosurgery, or severe hypoxia.Patients with central DI rapidly respond to adminis-tration of ADH (or the synthetic analog DDAVP) byconcentrating their urine. This response representsboth a positive diagnostic test as well as appropriatetherapy.

Acquired nephrogenic DI can be produced by sev-eral drugs (lithium, demeclocycline), chronichypokalemia, hypercalcemia, sickle cell trait anddisease, and amyloidosis.87-89 The loop diuretics alsoproduce a renal concentrating defect as a result of areduction in the medullary concentration gradients.In contrast to patients with central DI, those withnephrogenic DI will not respond to ADH orDDAVP. Another cause of increased renal freewater loss with an inadequate renal ADH responseis osmotic diuresis. Hospitalized patients maydevelop hypernatremia as a result of a urea osmoticdiuresis produced by high protein intake, GI bleed-ing (absorption of digested blood proteins) and/orglucocorticoid Rx (accelerated catabolism). Again,it must be stressed that hypernatremia should notoccur if the patient is awake, can sense thirst and hasaccess to water.

Hypernatremia usually represents an absolute water

ACID-BASE AND ELECTROLYTES 25

Table 12

Causes of Hypernatremia

I. Increased Water LossA. Insensible

1. Burns2. Fever/Heat3. Mechanical Ventilation/Hyperventilation

B. G.I. Loss1. Vomiting/N-G Suction2. Diarrhea

C. Renal1. Central DI2. Nephrogenic DI3. Osmotic Diuresis

II. Reduced Water IntakeA. Hypothalamic Dysfunction

1. Reduced Thirst2. Essential Hypernatremia?

B. Inability to Drink Water1. Coma2. Infant

III. Hypertonic InfusionsA. Saline/NaHOC3

IV. Water Shift Out of ECFA. Seizure/Extreme ExerciseB. GI Bleeding with Intraluminal Protein

Catabolism

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deficit. Therefore, therapy requires water replace-ment and, if possible, correction or treatment of theunderlying pathology.81,90 The water deficit can becalculated with the following formula: (— -1)

Equation 4:Water Deficit = (0.6)(Weightkg) [Na]

140

Note that, as in the hyponatremia equation number 3above, total body water is also used in this calcula-tion.

Whenever possible, attempt to replace waterdeficits via the oral or gastric route. If intravenousreplacement is required, D5%W or one-quarterNaCl can be utilized. Plasma glucose concentrationmust be carefully monitored when dextrose-con-taining fluids are administered because rapid infu-sion can generate hyperglycemic. This can producea glucose osmotic diuresis that results in “chasingone’s tail,” as urine output progressively increasesand the infusion rate of D5%W is increased tomatch output. About 50% of the water deficitshould be replaced in the first 24 hours of Rx.Overly rapid water replacement can produce cere-bral edema.

Always evaluate and address the hypernatremicpatient’s ECF volume status (and effective arterialvolume). Patients who are volume depleted (thosewith hypotension, orthostatic fall in blood pressure,etc.) may require immediate ECF expansion. Inthese patients, isotonic NaCl may be the appropriateinitial fluid. The water deficit should be addressedonly after ECF volume has been restored. Con-versely, some hypernatremic patients may be vol-ume overloaded (for example, when hypertonicsalts infusion is the etiology of the hypernatremicstate) and may then require diuretic therapy as wellas water infusion.

4. Disorders of Potassium Balance, Hypokalemia andHyperkalemia

Disorders of potassium metabolism are common,both in hospitalized and ambulatory patients and asa primary manifestation of kidney disease as well asreflecting systemic factors, such as GI disorders,acid-base abnormalities, and drugs and toxins.91-94

General Considerations

The overwhelming majority of body potassium [K](≈98% ) is contained in the intracellular compart-ment. The ratio of intracellular to extracellularpotassium is tightly regulated because this ratioinfluences the cellular membrane potential. Theconcentration gradient of [K] is maintained by thesodium- and potassium-activated adenosinetriphosphatase (Na+/K+–ATPase) pump. Smallchanges in the extracellular potassium level canhave profound effects on the function of the cardio-vascular and neuromuscular systems. The normalpotassium level is 3.5-5.0 mEq/L, and total bodypotassium stores are approximately 50 mEq/kg(3500 mEq in a 70-kg person). Hyperkalemia isdefined as a K> 5.0 -5.5 mEq/L (depending on thebiochemistry laboratory’s reference range).

The intracellular fluid (ICF) potassium concentra-tion [K] is between 120 and 150 mEq/L and K is theprincipal intracellular cation. The [K] in the extra-cellular fluid (ECF) and in plasma is much lower –in the 3.5-5.0 mEq/L range. This very large transcel-lular gradient is the result of Na/K ATPase pumpswhich actively transport K across cell membranesand the ionic permeability characteristics of thesemembranes. The 30-40 fold transmembrane [K]gradient is the principal determinant of the –90 mVtranscellular resting potential gradient (cell interiornegative) (Figure 8). Normal cell function requiresmaintenance of the ECF [K] within a relatively nar-row range and this is particularly important forexcitable cells such as myocytes and neurons. Mostof the clinical manifestations of K disorders are dueto pathophysiologic effects on these cells.

Potassium intakes vary widely – a typical Westerndiet provides between 50 and 100 mEq K per day.Under normal, steady state conditions, an equalamount is excreted, mainly in urine (about 90%),and to a lesser extent in stool (5%-10%) and sweat(1%-10%). Rapid transcellular shifts regulateplasma [K] and prevent extreme hyperkalemia after

26 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

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each meal. Normal postprandial insulin secretionstimulates cellular uptake of both K and glucose.Insulin release with meals is primarily related toincreased plasma glucose, but increasing [K] alsodirectly stimulates release of insulin from β-cells inthe pancreatic islets. Therefore, insulin deficiencyand/or resistance increase plasma [K]. Epinephrineand norepinephrine also rapidly regulate transcellu-lar K balance and play an important role during andfollowing vigorous exercise. Hyperadrenergicstates, such as alcohol withdrawal, hyperthy-roidism, tocolytic therapy and theophylline poison-ing often generate hypokalemia due to translocationof K from the ECF into cells.

Metabolic alkalosis stimulates cellular K uptake,while some forms of hyperchloremic and other inor-ganic (mineral) acidoses enhance movement of Kout of cells. However, the common organicmetabolic acidoses (lactic and ketoacidosis) do notdirectly generate a transcellular K shift. Respiratoryacid-base abnormalities generally have minoreffects. Although it had been assumed that the alka-lemia produced by respiratory alkalosis would

move K into cells, the opposite has been found, ie, asmall increase in plasma [K] due to associated α-adrenergic stimulation. Respiratory acidosisincreases plasma [K] slightly. Hyperosmotic condi-tions that shift fluid out of cells are an importantcause of K translocation to the ECF. Finally,hypokalemia per se moves K from the intra- to theextracellular space.

Pathogenesis

Potassium absorption in the small intestine is notspecifically controlled. Although colonic epithelialcells can increase K secretion in response to chronichyperkalemia (patients with chronic kidney dis-ease), the net effect on K balance is minor. Althoughthe [K] of stool water may increase, the water con-tent of formed stool is small – thus absent diarrhea,total stool K excretion remains low. Thereforeingested K is largely absorbed.

Potassium excretion is principally into the urine andthe main regulator of body K balance is the kidney.Potassium is freely filtered (600-800 mEq/d) and

ACID-BASE AND ELECTROLYTES 27

Figure 8

Transcellular ion movement

[K] 4 mEq/L

Na+

AT

P

3 Na+

2 K+

K+

Ca++

Na+

H+

[K] 140 mEq/L

Insulin ?

- 90 mV

Virtually all cells contain these pumps, antiporters, and channels. The effects of insulin, catecholamines and thyroid hormones on K transport are shown.

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then largely reabsorbed in the proximal tubule andthick ascending loop of Henle. Only about 10%-15% of filtered K is delivered to the cortical collect-ing duct (CCD) and major regulation of K excretionoccurs in this segment. Sodium (Na) reabsorptionand K (and H) secretion in the CCD is determinedby the amount of delivered Na, the “absorbability”of its accompanying anion, and the activity of themineralocorticoid aldosterone. CCD Na absorptionoccurs across epithelial Na channels (ENaC) on theluminal surface of the predominant (principal) cells

in this segment. Sodium is absorbed more readilythan most anions (Cl, HCO3 , and others) and thisgenerates a negative charge within the lumen thatenhances the secretion of K and H (Figure 9).Aldosterone regulates the rate of Na absorptionthrough these channels at multiple levels. Itincreases energy (ATP) generation and the activityof Na-K ATPase pumps, and it also increases thenumber and “open state” of the ENaC channelsthemselves.

Normally, an inverse relationship exists betweenaldosterone activity and CCD Na delivery. High saltintakes expand ECF volume and increase distaldelivery and excretion of Na but simultaneouslydepress renin and aldosterone levels. Increased dis-tal Na delivery counterbalances low aldosteroneactivity with a net effect of normal CCD K and Hsecretion and excretion. Conversely, low saltintakes contract the ECF, stimulating renin andaldosterone levels and markedly reducing distalCCD Na delivery and excretion. Under these condi-tions, reduced CCD Na delivery is associated withincreased aldosterone activity. Once again, normalCCD K and H secretion and excretion is main-tained. This physiologic reciprocal interplaybetween aldosterone activity and distal Na deliveryresults in maintenance of both volume and elec-trolyte homeostasis.

Pathophysiologic conditions exist when high CCDNa delivery combines with high aldosterone activ-ity, or reduced CCD Na delivery coexists with lowaldosterone activity. In the first circumstance, abso-lute CCD Na absorption increases markedly andgenerates major and excessive K and H secretion.Hypokalemia and metabolic alkalosis result. Con-versely, reduced distal Na delivery and aldosteronelevels results in very little CCD Na reabsorption andvery low rates of K and H secretion. Hyperkalemiaand metabolic acidosis result. The pathologic condi-tions which combine high CCD Na delivery andhigh aldosterone levels include primary hyperaldos-teronism, administration of thiazide and/or loopdiuretics, and excretion of Na with anions such asketoacids (with DKA) or hippurate. Reduced Nadelivery to the CCD combines with low aldosteroneactivity in some forms of hyporeninemic aldostero-nism and with the administration of aldosteroneantagonists to patients with reduced “effective”

28 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Figure 9

K handling by the cortical collecting duct

Na

K

Na

CD

PC

A Aldo

2K

3Na

ATP

Aldosterone has multiple effects on electrolyte trans-port in the cortical collecting duct (CCD). Sodium(Na) absorption increases through stimulation ofbasolateral Na/K ATPase activity and increased num-ber and “open state” of the luminal Na channel(ENaC). The influx of Na causes a negative charge todevelop within the lumen. This stimulates K (and H)secretion into the lumen down electrical and chemicalgradients.

Volume contracted states result in little Na delivery tothe CCD (due to avid, more proximal absorption) sothat K (and H) secretion is slight despite high aldos-terone levels. Volume expanded states enhancedelivery of Na to the CCD and cause physiologicallyadequate levels of K (and H) secretion despite sup-pressed aldosterone levels.

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arterial volume such as hepatic cirrhosis or conges-tive heart failure.

Clinical Manifestations

Nerve and muscle cells are especially sensitive tochanges in transcellular voltage and therefore mostaffected by hypo- or hyperkalemia. Figure 10 showshow either condition can cause muscle weakness.

Hypokalemia increases the resting potential acrossthe myocyte membrane (it becomes more negative)making the cell less sensitive to excitation. Severehypokalemia causes a hyperpolarization block andflaccid paralysis. Following depolarization, the cellis unable to adequately repolarize and becomes

unexcitable. Severe K depletion may cause rhab-domyolysis and paralytic ileus. The renal manifes-tations of hypokalemia include metabolic alkalosis,increased ammonia generation and excretion, andnephrogenic diabetes insipidus. Chronichypokalemia also causes structural abnormalities ofthe kidney including cyst formation, and has alsobeen implicated in the development of hypertension.

Hyperkalemia reduces the membrane resting poten-tial—it becomes less negative. Severe hyperkalemiacauses a depolarization block and flaccid paralysis.Clinical manifestations include fatigue, myalgia,and muscle weakness (especially lower extremity),hyporeflexia, paresthesias, muscle cramps, and

ACID-BASE AND ELECTROLYTES 29

Figure 10

Cell depolarization and hyperpolarization depends on extracellular potassium

mVolts

Ca↑

Ca↓

RP

TP TP RP

RP

TP

normal

Normal Hyperkalemia Hypokalemia

-120

-90

-60

-30

0

depolarized

An action potential is generated when the cell depolarizes from its resting potential (RP) to the threshold poten-tial (TP). Hyperkalemia moves the RP much closer to the TP and results in depolarization muscle paralysis.Hypokalemia hyperpolarizes the cell and thereby impairs depolarization.The flaccid paralysis caused byhypokalemia or hyperkalemia is clinically similar. Calcium raises the TP, ameliorating the effects of hyper-kalemia, while hypocalcemia has the opposite effect.

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ECG changes and cardiac arrhythmia (Figure 11).Muscle weakness may progress to ascending paral-ysis, hypoventilation, and respiratory failure.

The clinical manifestations of an abnormal plasma[K] vary greatly and depend on, (a.) its magnitude,(b.) its acuity of onset, (c.) the relative contributionsof K shift vs. change in total body K, and (d.) coex-isting abnormalities which either potentiate or bluntthe [K] effects, including underlying heart disease,drugs (digoxin, antiarrhythmic agents), hypo- orhypercalcemia, cardiac pacing devices, and others.

The resting membrane potential is determined bythe ratio of intracellular and extracellular [K](Ki/Ke). An acute K shift into or from the intracellu-lar space alters intracellular [K] only minimallysince it is quantitatively so large; about 3000 mEq or98% of total body K is within cells. However, theeffect on the extracellular concentration can be dra-matic, because the quantity of extracellular K isonly about 60 mEq. Therefore, acute K shiftsmarkedly affect the Ki/Ke ratio and can produceprofound cellular hyper- or depolarization withmuscular, neurological, and cardiac symptoms (Figure 12). In contrast, states of chronic K deple-tion, or loading, affect both intra- and extracellular

30 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Figure 11

Electrocardiographic tracings with hypokalemia and hyperkalemia

Hyperkalemia initially causes peaking (“tenting”) of T waves and then progresses to widening of the QRS and PRintervals, sinus bradycardia and arrest, AV-block, fusion of QRS with T (sine-wave appearance), idioventricularrhythm, and finally ventricular tachycardia and fibrillation, and asystole.

Hypokalemia causes ST depression, flattening of the T waves, and prominent U waves. This progresses tofusion of the T and U waves into a single wave and the ST segment becomes negative and descending. The QTinterval lengthens, especially if hypocalcemia or hypomagnesemia is present. Atrial and ventricular arrhythmiasmay develop.

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K levels and may have a smaller effect on Ki/Ke andthereby generate fewer and less severe clinical man-ifestations. Furthermore, K shifts produce veryrapid changes in plasma [K]; thus shift effects are

often more dramatic than those associated with totalbody K depletion or excess.

Comorbid illnesses such as coronary heart diseasecan amplify the clinical importance of potassiumdisorders by increasing the risk of serious arrhyth-mia. Hyperkalemic effects on cardiac conductionare well documented and are the principal reason itconstitutes a medical emergency (Figure 11). Whilehypokalemia has well defined EKG effects, its car-

ACID-BASE AND ELECTROLYTES 31

Table 13

Causes of Hypokalemia

Renal LossesDiureticsVomiting, NG suctionOsmotic diuresis (especially uncontrolled diabetes)Drugs

Excretion of non-reabsorbable anions (Penicillin)Exogenous mineralocorticoidsInhibitors of 11�-hydroxysteroid dehydrogenaseToxic reactions (aminoglycosides, cis-platinum)

Primary hyperaldosteronismLiddle syndromeCushing diseaseRenal tubular acidosis type I and type II (whentreated with NaHCO3)Bartter and Gitelman syndromeMagnesium deficiency

Extrarenal LossesDiarrhea, laxativesIleostomyUreteral diversion into colon

Transcellular ShiftInsulinβ 2-adrenergic agonists ThyrotoxicosisPeriodic paralysisDrugs – barium, cesium, chloroquine

Rapid expansion of cell massAnabolic states, Rx of pernicious anemia

Figure 12

K distribution with intracellular K shift vs. Kdepletion

[K] = 122 mEq/L

[K] = 2 .0 mEq/L

Ki/Ke: 45

[K] = 2 .0 mEq/L

Ki/Ke: 61

Total Body K depletion

K shifts into cells

Normal

[K] = 90 mEq/L

[K] = 120 mEq/L [K] = 4 .0 mEq/L

Ki/Ke: 30

The resting membrane potential is determined by theratio of intracellular and extracellular potassium(Ki/Ke).

Total body K depletion reduces both intracellular andextracellular [K]. The Ki/Ke ratio increases and thecell becomes hyperpolarized.

A transcellular shift of K into cells slightly increasesintracellular [K] and markedly reduces extracellular[K]. Therefore, the Ki/Ke ratio increases markedly and cellular hyperpolarization is severe and often produces clinical symptoms.

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diac risk for otherwise healthy patients are less wellestablished. However, patients with acute myocar-dial infarction and those treated with digoxin dohave an increased risk of dangerous ectopy.

Calcium has important effects on myocyte depolar-ization. Hypocalcaemia reduces the depolarizationthreshold potential and renders the cardiac myocytemore excitable. Conversely, hypercalcemia reducesmembrane excitability by increasing the depolariza-tion threshold (Figure 10). These calcium relateddepolarization threshold shifts can reverse hyper-kalemic cardiac toxicity. Coexisting hyperkalemiaand hypocalcaemia is a particularly pernicious com-bination and is common in patients with severe kid-ney failure.

Hypokalemia

A serum [K] below 3.5 mEq/L defines hypokalemia,and Table 13 lists some of the causes and clinicalconditions associated with this disorder.95,96 Themost common causes are thiazide or loop diureticuse, vomiting/nasogastric suction, and diarrhea (orlaxatives). These etiologies are usually readilyapparent unless the patient is covertly using drugs orvomiting. A more elaborate evaluation becomesnecessary when the cause is not apparent. It is thenimportant to determine if an intracellular shift hasoccurred and/or whether excessive renal or gas-trointestinal K losses (sometimes combined withreduced intake) accounts for the hypokalemia.

Hypokalemia due to transcellular K shifts may gen-erate impressive clinical presentations. This occurswith several forms of hypokalemic periodic paraly-sis, administration of β2-agonists to treat obstruc-tive lung disease or premature labor, theophyllinepoisoning and conditions that enhance beta-agonistactivity such as hyperthyroidism and hypothermia.Insulin drives K into cells and promoteshypokalemia. Barium poisoning, cesium, andchloroquine overdose block K exit from cells andcause K accumulation within the ICF and profoundhypokalemia. Another cause of intracellular Kaccumulation is rapid expansion of cell mass withrefeeding after prolonged starvation, into rapidlygrowing tumors, and when severe pernicious ane-mia is treated with vitamin B12.

Hypokalemic periodic paralysis may have a dra-matic clinical presentation. At least two distinctsubtypes of this syndrome have been characterized:a rare familial form, usually due to an autosomaldominant mutation affecting a calcium channel; anda relatively more common form associated withhyperthyroidism. Hyperthyroid periodic paralysis isespecially prevalent among young men of Asian (orless often Hispanic) ancestry. They typically presentwith profound acute muscle paralysis affectingmainly proximal limb muscle groups with sparingof ocular and respiratory muscles. Deep tendonreflexes are generally absent. Paralysis often devel-ops after a period of exercise (increased β-agonistactivity) or following carbohydrate ingestion(increased insulin). Clinical signs and symptoms ofthyrotoxicosis may be subtle. A prior history ofrecurrent episodes of weaknesses is common.Plasma [K] is often below 2 mEq/L, and bothhypophosphatemia and mild hypomagnesemia mayoccur. Acute treatment with exogenous K salts isappropriate, but rebound hyperkalemia often devel-ops since total body K is normal. Treatment withβ-blockers such as propranolol is helpful and cor-rection of the hyperthyroid state is usually curative.The pathophysiology of this disorder includes theeffect of thyroid hormone on the Na/K ATPase, anexaggerated insulin response, the hyperadrenergicstate of hyperthyroidism, genetic and racial predis-position, and probably inherited mutations of mus-cle ion transport which remain subclinical untilmagnified by the hyperthyroid state.

Reduced total body K stores may be due to gastroin-testinal loss, renal loss, or both. The 24-hour urinepotassium excretion helps define the etiology. Apatient with hypokalemia should excrete less than20 to 30 mEq K per day. If this is found, renal lossesare generally excluded and either gastrointestinallosses or a transcellular shift should be considered.Higher excretion rates indicate renal K wasting.However, some renal K losses occur intermittently,with intervening periods of appropriate K conserva-tion. For example, although diuretics cause excessrenal K losses, the urine K excretion falls to the lowrange when the diuretic effect wears off. Similarly,vomiting or NG suction cause excess renal K lossduring the active phase but in the “equilibriumphase” the K excretion becomes very low.

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If a 24-hour urine collection cannot be accom-plished, an alternative useful measurement is thetrans-tubular [K] gradient, or TTKG. This calcula-tion attempts to correct the urinary [K] for theincrease generated by distal water reabsorption afterthe tubular fluid has exited the CCD. In theory, theTTKG approximates the [K] gradient in the corticalcollecting tubule, and is calculated as:

Equation Number 5:TTKG = U [K] x P [Osm]

P [K] x U [Osm]

A TTKG below 2-3 generally indicates appropriaterenal K conservation in a patient with hypokalemia.However, the TTKG cannot be interpreted if urineosmolality is less than plasma osmolality, or whendistal nephron sodium delivery is very low, ie, urinesodium below 20 mEq/L.

Assessment of a patient’s volume status and bloodpressure provides additional diagnostic clues.Patients with hypokalemia, volume expansion andhypertension may have primary or exogenoushypermineralocorticoidism. A high plasma aldos-terone level with a simultaneous low plasma reninactivity indicates autonomous aldosterone secre-tion. An aldosterone/PRA ratio >30 (and an aldos-terone level >20 ng/dL) also suggests primaryhyperaldosteronism. Primary hyperaldosteronismmay be due to a unilateral aldosterone secreting ade-noma (Conn syndrome), bilateral adrenal hyperpla-sia (idiopathic hyperaldosteronism), or rarely,adrenal cancer. Radiological evaluation often per-mits determination of the specific syndrome, butadrenal vein sampling is necessary in some cases.Another cause of primary hyperaldosteronism isglucocorticoid-remediable aldosteronism. This raredisorder is due to an autosomal dominant mutationwhich causes ACTH to stimulate the synthesis andsecretion of aldosterone. Glucocorticoids suppressACTH and reverse the clinical and biochemicalabnormalities of this disorder. Pseudohyperaldos-teronism is characterized by the biochemical andclinical features of an autonomous mineralocorti-coid excess state but with suppressed aldosteronelevels. It may be due to secretion of a non-aldos-terone mineralocorticoid.

Examples include adrenal tumors secreting themineralocorticoid deoxycorticosterone (DOC),some forms of congenital adrenal hyperplasia (17- and 11-hydroxylase deficiency), and certainconditions which cause glucocorticoids to developpotent mineralocorticoid properties. Both mineralo-corticoids and glucocorticoids can activate the min-eralocorticoid receptor. However, selectivity isachieved by virtue of the enzyme 11�-hydroxys-teroid dehydrogenase type 2. This enzyme exists inhigh concentration in most mineralocorticoid recep-tor rich tissues where it inactivates the glucocorti-coids (but not mineralocorticoids). In the absence ofthis enzyme, physiologic levels of glucocorticoidswill produce a mineralocorticoid excess state. Theenzyme is congenitally absent or defective inpatients with the “apparent mineralocorticoidexcess or (AME)” syndrome who exhibit a hyperal-dosterone-like disorder of hypokalemia, metabolicalkalosis, volume expansion, and hypertension, butlow aldosterone levels. The enzyme 11�-hydroxys-teroid dehydrogenase type 2 is also antagonized byglycyrrhetinic acid, the active ingredient in truelicorice, several decongestants available in Europe,and some brands of chewing tobacco. Excessive useresults in the same clinical presentation. Also, thisenzyme may be overwhelmed when cortisol levelsare markedly elevated in some patients with Cush-ing syndrome, in particular the form due to ectopicACTH secretion.

Liddle syndrome also has features of a mineralocor-ticoid excess state but all known mineralocorticoidsare reduced. The disorder is due to an autosomaldominant mutation which causes the epithelial Nachannels (ENaC) in the collecting duct to remainpersistently “open” in the absence of mineralocorti-coid stimulation. Clinical and biochemical findingsmimic a non-aldosterone mineralocorticoid excessstate—volume expansion, hypertension,hypokalemia, metabolic alkalosis, and suppressedlevels of renin and aldosterone.

Elevated aldosterone levels secondary to stimula-tion by high renin levels is called secondary hyper-aldosteronism. It occurs in patients with renal arterystenosis as well as in some patients with markedlyelevated blood pressure whose major renal arteriesare anatomically normal (but blood flow in smallerrenal vessels is probably reduced). Rare renin

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secreting tumors have been described. They resultin severe secondary hyperaldosteronism, hyperten-sion and hypokalemia. These pathologic forms ofsecondary hyperaldosteronism are all associatedwith volume expansion and hypertension.

More commonly, secondary hyperaldosteronism isassociated with (and due to) reduced ECF volumeand hypotension. This may be due to most diureticsand several renal tubular disorders. Combining highdistal renal tubule Na delivery with high aldos-terone activity leads to renal K wasting,hypokalemia, and variable degrees of metabolicalkalosis. This is a common effect of loop or thi-azide diuretics (acetazolamide will also producehypokalemia and metabolic acidosis, due to theexcretion of sodium bicarbonate). Combining aloop and thiazide diuretic generates an especiallypowerful kaliuretic response and should be usedjudiciously.

Two classes of autosomal recessive genetic disorders mimic the effects of thiazide or loop diuretics.97-100 Gitelman syndrome is due to a defectof the thiazide sensitive NaCl transporter in theearly distal renal tubule.101 Bartter syndrome iscaused by one of several generic mutations thatimpair the function of the Na-K-2Cl transporter inthe thick ascending limb of Henle that is also inhib-ited by loop diuretics.102 Both are characterized bysimilar clinical and biochemical abnormalities: vol-ume contraction, hypotension, high levels of urinaryprostaglandins, renal K and NaCl wasting, and highrenin and aldosterone levels. A major distinguishingcharacteristic is the reduced urine calcium excretionand severe hypomagnesemia seen with Gitelmansyndrome but hypercalciuria in those with Barttersyndrome. It is virtually impossible to discern thesepatients from those using these diuretics surrepti-tiously, unless urine is assayed for these substancesand/or specific genetic mutations are identified.While Bartter syndrome is usually diagnosed earlyin life, the phenotype of Gitelman syndrome is oftensubclinical and first recognized in adults.

In the intensive care unit, osmotic diuresis is a rela-tively common cause of hypokalemia and hyperna-tremia. The combination of a catabolic state, par-enteral nutrition, or tube feeding, +/- exogenous

glucocorticoids, results in hyperglycemia and/orhigh urea levels. The glucose and/or urea diuresisalso delivers sodium to an actively reabsorbing dis-tal tubule where Na is effectively exchanged for Kand H. Mannitol infusions can produce a similarsyndrome. Aminoglycoside antibiotics, ampho-tericin B, cisplatin, and foscarnet are drugs that canincrease distal tubule Na delivery and promote Ksecretion and excretion. Some also cause tubulardamage that leads to magnesium wasting and hypo-magnesemia which itself promotes kaliuresis.Patients with acute myeloid or lymphoblasticleukemia may develop proximal or distal tubuledysfunction which generates hypokalemia,metabolic acidosis, hyponatremia, hypocalcemia,hypophosphatemia, and hypomagnesemia.

Sometimes Na is delivered to the distal nephronwith a poorly reabsorbed non chloride anion. If theNa is reabsorbed, this accelerates K and H secretion.The problem is magnified when ECF contractionincreases renin and aldosterone levels (Figure 9).This occurs with high doses of Na-penicillin, dia-betic ketoacidosis (Na-β-hydroxybutyrate), withinhalation of toluene glue (Na-hippurate), and withmetabolic alkalosis due to vomiting or nasogastricsuction (NaHCO3). When patients with proximalrenal tubular acidosis (RTA type 2) are treated withexogenous bicarbonate salts, they excrete NaHCO3and develop hypokalemia. Although patients withclassic distal tubular acidosis (RTA type 1) alsomanifest accelerated distal tubule Na-K exchangeand hypokalemia, their response to NaHCO3 ther-apy is distinctly different. With that disorder, exoge-nous HCO3 reduces renal excretion and ameliorateshypokalemia—in part as a result of ECF volumeexpansion.

The normal colon secretes K and absorbs Cl inexchange for HCO3. If urine enters the coloniclumen, Cl is removed while K and HCO3 aresecreted. This results in hypokalemia and a hyper-chloremic metabolic acidosis. Clinical situations inwhich this occurs include ureteral implants into thesigmoid colon and interposition of colon segmentsbetween the kidney and bladder.

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Treatment of Hypokalemia

The treatment of hypokalemia depends on severalfactors. These include the underlying etiology andclinical setting (age of the patient, other abnormali-ties such as acid-base perturbations), the rapidity inthe development of the hypokaelmia, and the pres-ence or absence of cardiac disease.93-96,103,104 It is bestto anticipate and whenever possible prevent thedevelopment of hypokalemia. Combined adminis-tration of loop and thiazide diuretics often causesmajor renal K excretion. Adding an aldosteroneantagonist, such as spironolactone or eplerenone, ora distal tubule Na channel blocker such as amilorideor triamterene to the diuretic regimen can be very

helpful. Angiotensin converting enzyme inhibitors(ACE-I) and angiotensin receptor blockers (ARB)also reduce K losses generated by diuretics—in partby reducing aldosterone levels. Exogenous potas-sium replacement is obviously indicated when Kloss has depleted total K stores. However, exoge-nous K may also be required to treat acute clinicalmanifestations caused by major K shifts into cells.Under those conditions, replacement must be verycautious since total body K stores are normal andrebound hyperkalemia may occur after the stimulusresponsible for the shift has resolved. Specific treat-ments are available for some of these disorders (eg,β-blockers or treatment of hyperthyroidism for vari-ous forms of periodic paralysis).

ACID-BASE AND ELECTROLYTES 35

Table 14

Oral Potassium Salts

KCL

KCl Elixir 15 mEq/20 mL Micro-K®, K-Lor ®, Slow-K®, K-Dur ®,KCl Extended 8-10 mEq/tab Kaon-Cl®, Klor-Con ®, Klotrix ®.Release Tablets

KCl Powder 20-25 mEq/pk Kay Ciel ®, Klor-Con

KCl Solution 20 mEq/15 mL Kchlor ®, Kay Ciel, Kaon-Cl

KHCO3 & K Organic Salts

KHCO3 25 mEq/tablet K-Lyte ® effervescent tablets, Klor-Con /EF

K Citrate Liquid 2 mEq/mL Polycitra-K®

K Citrate Tablets 5,10 mEq/Tab Urocit-K®

K Gluconate Liquid 6.7mEq/5 mL Kaon® Elixir, Glu-K®

/Tablets 2- 5 mEq/tablet

KHCO3/Organic 15 mEq/5 mL Tri-K®, K-Lyte DSAnion Mixtures 50 mEq/tab

The brand names represent the more commonly used drugs and many other brands are also available.

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Whenever possible, K should be replenished via theoral route. Unfortunately, potassium-rich foods(dried fruit, nuts, bananas, oranges, tomatoes,spinach, potatoes, and meat) are often ineffective.This is due to their relatively low K content com-pared to caloric content. Further, food K is largelycomprised of organic salts, which may be less effec-tive, especially when metabolic alkalosis also exists(see below).

Major K deficits require oral or intravenous supple-mentation. In general, a plasma [K] between 3-3.5mEq/L represents a K deficit of 200 to 400 mEq,while plasma [K] between 2.0-3.0 mEq/L requires400-800 mEq.

Potassium replacement salts are divided into twobroad classes: potassium chloride (KCl) and potas-sium bicarbonate (KHCO3). Organic K salts aremetabolized, mole for mole, to KHCO3 and aretherefore included with the second group. Alkaliz-ing K salts are more palatable and better toleratedthan oral KCl. However, KHCO3 and the organic Ksalts should not be used to treat hypokalemia associ-ated with metabolic alkalosis. Under these condi-tions, alkalinizing K salts are poorly retained andless effectively reverse the K deficit (and metabolicalkalosis). KCl is the most appropriate and effectivereplacement for K deficits associated withmetabolic alkalosis. Conversely, alkalinizing Ksalts (KHCO3, K-citrate, K-acetate, K-gluconate)are indicated to treat hypokalemia associated withmetabolic acidosis, such as RTA, or chronic diar-rhea conditions. Table 14 lists the various forms oforal potassium salts.

When the oral route cannot be used, or total Kdeficits are severe, intravenous replacementbecomes necessary.103,104 Parenteral fluid KCl con-centrations of 20-40 mEq/liter are generally welltolerated. KCl concentrations of 60 mEq/L andgreater produce local pain and may result in periph-eral vein necrosis. When large volumes of intra-venous fluid cannot be given, solutions with K con-centrations of up to 200 mEq/L (20 mEq in 100 mlof isotonic saline) may be administered via a centralvein. Under these circumstances, the K administra-tion rate should not exceed 10-20 mEq per hour. Ingeneral, central venous administration of these con-centrated K solutions should be accomplished with

a rate-controlling pump. The composition of intra-venous fluid must also be considered, because dex-trose increases insulin and shifts K into cells,thereby potentially worsening hypokalemia!Administration of NaHCO3 has the same potentialeffect.

Hyperkalemia

Hyperkalemia is a common problem and whensevere can be life-threatening.91-94 The causes ofhyperkalemia, defined as a serum [K] above 5.0mEq/L, are listed in Table 15. Acute or chronic renalfailure is by far the most common cause or majorcontributor to hyperkalemia. When the kidney andthe renin-angiotensin-aldosterone axis function nor-mally, the plasma [K] is maintained in the normalrange despite wide extremes in intake. Therefore,persistent or chronic hyperkalemia almost alwaysindicates impaired renal excretion, either due tointrinsic pathology or inadequate endocrine signal-ing. However, rapid K shifts from cells to the ECFcan generate acute hyperkalemia, despite normalrenal and endocrine function. Such “shift” hyper-kalemia is exacerbated by coexistent renal dysfunc-tion and/or hormonal derangements.

Pseudohyperkalemia is an artifact related to the col-lection and/or preparation of the specimen or anartifact of the K measurement procedure itself.105

It is generally a diagnosis of exclusion and shouldnot delay prompt intervention. Potential causesinclude: repeated fist clenching during phlebotomy,hemolysis due to traumatic venipuncture, particu-larly with small gauge needles, delayed processingof the specimen (especially when placed on ice), Krelease from white blood cells in severe leukocyto-sis (usually >100 x 103/microliters) or fromplatelets with extreme thrombocytosis (usually>1,000 x 103/μL),106 and prolonged tourniquetapplication in some individuals. Some patientsinherit a propensity to leak K from red blood cellsex vivo due to a membrane defect. Measurement ofplasma rather than serum [K] may eliminate someof these artifacts.

A transcellular shift of K from the intra- to the extra-cellular space is a common cause of acute hyper-kalemia. It is often due to direct damage or destruc-tion of cell membranes. Examples include tumor

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lysis related to chemotherapy, acute intravascularhemolysis due to infection, transfusion reaction orsevere hemolytic anemia, hemolysis developingwithin a large hematoma, extensive burns, rhab-domyolysis, and with intestinal ischemia/necrosis.

Excessive K efflux may also develop across intactcell membranes as a result of certain drugs,metabolic disorders and inherited diseases. Drugsthat block beta-agonist activity favor K efflux fromcells.107 The muscle relaxant succinylcholine consis-tently promotes cellular K efflux and many cases ofprofound hyperkalemia have been reported, espe-cially in patients with an underlying neuromuscular

or renal disorder. A pharmacologic dose of digitalisinhibits Na/K ATPase in cardiac myocytes, but toxiclevels inhibit these pumps in systemic muscle cellsand may thereby generate extreme hyperkalemia.Potassium translocation also occurs with insulindeficiency or resistance, certain hyperosmolar con-ditions such as hyperglycemia, and some forms ofinorganic (usually hyperchloremic) metabolic aci-doses. It was previously assumed that acidemia,especially with metabolic acidosis, caused protonsto move into cells with reciprocal K efflux. How-ever, organic metabolic acidoses, such as keto- andlactic acidosis, do not generate K shifts. Althoughhyperkalemia may develop in these patients, it isusually the result of a pathophysiological processand not the acidemia per se. Hyperkalemia doesoccur frequently with lactic acidosis, but is princi-pally due to tissue ischemia/necrosis and concomi-tant renal insufficiency. Hyperkalemia, also a com-mon finding with diabetic ketoacidosis, is due to thecombination of insulin deficiency, hyperosmolarity(hyperglycemia), and decreased renal perfusion,rather than acidemia per se. In contrast, the infusionof some inorganic acids, such as HCl, will directlyshift K out of cells. “Shift” hyperkalemia alsodevelops when HCl precursors, such as the chloridesalts of arginine or lysine, are infused. Geneticdefects of cell membrane ion transporters, usuallyepithelial Na-channels, cause the syndrome ofhyperkalemic periodic paralysis.

Most non-physiologic states of hypoaldosteronism(ie, not secondary to ECF/vascular expansion) gen-erate chronic hyperkalemia because of reduced dis-tal tubule (CCD) K secretion. This is exacerbated byconcomitant renal insufficiency or markedlyreduced distal tubule Na delivery. Pathologichypoaldosteronism may be the consequence of adirect block of hormonal synthesis (a congenital oracquired enzyme defect or adrenal damage), or sec-ondary to dysregulation of the signals mediatingaldosterone synthesis and release. The most impor-tant physiologic regulator of systemic aldosterone isangiotensin II activity, and the most common formof pathologic hypoaldosteronism is that due toreduced renin activity and hence angiotensin II lev-els.108-110 This “hyporeninemic hypoaldosteronism”often develops in patients with long-standing dia-betes mellitus as a result of progressive interstitialrenal disease with atrophy and/or destruction of the

ACID-BASE AND ELECTROLYTES 37

Table 15

Causes of Hyperkalemia

Renal Retention

Acute renal failure

Chronic renal failure (especially interstitial renaldisease)

Drugs (see text)

Addison disease

Renal tubular acidosis Type IV

Pseudohypoaldosteronism

Tissue Release & Transcellular Shifts of K

Tissue breakdown (hemolysis, rhabdomyolysis,ischemia, tumor lysis)

Insulin deficiency

Hyperosmolarity

Hyperchloremic metabolic acidosis

Drugs (succinylcholine, toxic digoxin levels)

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renin-secreting cells in the juxtaglomerular appara-tus. Other interstitial renal diseases, such as thoseassociated with sickle cell disease, analgesicnephropathy, and chronic urinary outlet obstruction(especially in elderly men), may produce a state ofhyporeninemic hypoaldosteronism as well.

Hypoaldosteronism slows the rate of distal tubule pro-ton secretion.111 In addition, hyperkalemia inhibitsrenal ammonia synthesis and reduces NH4Cl excre-tion. These defects combine to generate a syndrome ofhyperkalemic, hyperchloremic metabolic acidosiscalled renal tubular acidosis type 4. Correction of thehyperkalemia often increases urine ammonia excre-tion and reverses the metabolic acidosis.

Inhibition, at any step, of the endocrine sequencefrom renin → angiotensin I → angiotensin II →aldosterone → activation of CCD Na reabsorptionand K (and H) secretion will promote hyperkalemia.Clinically important causes include:

1. Suppression of renin secretion by beta-blockers,nonsteroid anti-inflammatory drugs.

2. (NSAIDs), cyclosporine, and tacrolimus.

3. Impaired angiotensin II generation byangiotensin converting enzyme inhibitors(ACEIs).

4. Blockade of type I angiotensin II receptor byangiotensin receptor blockers (ARBs).

5. Inhibition of the enzymatic sequence responsiblefor aldosterone synthesis by drugs such as heparinor ketoconazole.

6. Destruction of the adrenal gland as a result ofautoimmune disease or infection.

7. Competitive antagonism of mineralocorticoidreceptors by spironolactone or eplerenone.

8. Blockade of the cortical collecting duct epithelialsodium channels by triamterene, amiloride,trimethoprim, or pentamidine.

9. Blunted renal epithelial response to aldosteroneas a result of a series of inherited disorders (thecongenital pseudohypoaldosteronism syn-dromes).

Many other factors contribute to the hyperkalemiawhich commonly develops in patients with diabetesmellitus. Autonomic sympathetic neuropathyreduces renin levels and blunts beta-activity, thuspromoting K efflux. The multiple medications oftenprescribed include ACEIs, ARBs, aldosteroneantagonists, and NSAIDs (see below). Thesepatients may also ingest excess K in the form of saltsubstitute and their global kidney function is typi-cally impaired. With suboptimal diabetic control,the combined effects of insulin deficiency andhyperglycemia will increase plasma [K] acutely anddramatically.

The contribution of reduced renal K excretion to thedevelopment of hyperkalemia is usually readilyapparent. When it is not, a quantitative urine collec-tion to measure daily K excretion may be helpful.Chronic hyperkalemia should stimulate renal Kexcretion and the 24-hour urine should contain >70-80 mEq/d. If a quantitative urine collection cannotbe obtained, the trans-tubular potassium gradient(TTKG), which is described in the hypokalemiasection, should be >10 (the urine osmolality must be>300 and urinary Na excretion >20 mEq/L for theTTKG to be interpretable).

Treatment of Hyperkalemia

It is better to prevent hyperkalemia than to treat it. Acareful review of patient medications, diet, and inparticular over-the-counter drugs (NSAIDs) ismandatory. Hidden sources of K, such as herbalmedicines, sports drinks, and salt substitutes, mustbe sought. The recent demonstration that aldos-terone antagonists provide a survival benefit topatients with CHF (who are usually also takingACE-I and/or ARB drugs plus β-blockers; this hasgenerated a major increase in the prevalence ofhyperkalemia among these patients).

When hyperkalemia is acute and severe, emergencyintervention is necessary.112,113 Treatment options foracute and severe hyperkalemia are:

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1. Direct reversal of cardiotoxic effects with intravenous calcium infusion.

2. Translocating K into cells.

3. Insulin infusion – with glucose if appropriate.

4. β2-adrenergic agonists such as albuterol.

5. NaHCO3 infusion.

6. Increasing K excretion:

a. Via the kidney by ECF volume expansionand kaluretic diuretics

b. Via the gastrointestinal tract by inducingdiarrhea and K binding resins

c. Via dialysis for patients with severe acute orchronic renal failure

If [K] is greater than 6.4 and peaked T waves are anisolated ECG abnormality, calcium should probablybe infused. It is clearly indicated when a hyper-kalemic patient manifests more ominous ECGabnormalities (Figure 11). Calcium directly antago-nizes the cardiac membrane depolarizing effects ofhyperkalemia (Figure 10). The indication for cal-cium in the absence of electrocardiographic changesis unclear; however, such infusions are relativelysafe in the absence of overt hypercalcemia, markedhyperphosphatemia, or digitalis toxicity. Oneampule (10 mL) of 10% calcium gluconate contains4.6 mEq of elemental calcium and is given as a slowIV push over 2-5 minutes. Alternatively, oneampule (10 mL) of calcium chloride 10%, contain-ing about three times as much elemental calcium(13.6 mEq) is acceptable, but should be given moreslowly and cautiously. Extravasation of either saltcan produce tissue necrosis (calcium chloride ismore irritating then calcium gluconate). The benefi-cial effect on the ECG is usually seen immediately.The dose of calcium may be repeated if ECG abnor-malities persist or recur. Although the available datais limited, wide experience indicates it to be almostuniversally effective in reversing hyperkalemia-induced cardiotoxicity. Lidocaine is contraindicatedbecause it can precipitate ventricular fibrillation andasystole. Importantly, calcium infusions do not

directly affect the plasma [K] per se and their bene-ficial effects are short-lived (about 1-2 hours).Therefore, this treatment must be promptly fol-lowed by other treatment regimens that ultimatelyreduce plasma [K] by translocation into cells orexcretion.

The three agents that drive extracellular potassiuminto cells are listed above. Insulin stimulates Na-KATPase (and the Na-H exchanger—Figure 8) andreliably reduces [K] by 0.5-1 mEq/L within 10-20minutes in virtually all patients. For a maximum Klowering effect, supraphysiologic levels of insulinare required, typically 10 units of regular insulin IVpush. Subcutaneous or intramuscular injections and“low-dose” IV infusions should not be utilizedbecause they do not produce adequate plasmainsulin levels. Intravenous glucose is also adminis-tered if the patient is not already hyperglycemic. Areasonable approach is to administer one ampule(50 mL) of 50% glucose, followed by an intra-venous infusion of 10% glucose at about 75 mL/hr.Hyperglycemia must be avoided because this willshift K out of cells. Infusion of glucose alone tostimulate endogenous insulin secretion in non dia-betic patients is less effective because it generateslower peak insulin levels.

The β2-agonist albuterol also stimulates Na-KATPase and moves K into cells.114,115 This effect isadditive to that of insulin and occurs within 30-60minutes. The parenteral form of albuterol is notavailable in the United States, and the drug is givenvia the respiratory tract by nebulizer at a dose of 10to 20 mg in 4 mL of saline. This relatively high doseis well tolerated by most patients, but contraindi-cated for patients with acute cardiac ischemia orsevere myocardial disease. However, it is less reli-able than insulin because a significant number ofpatients are resistant to its K-lowering effect andtherefore should never be used alone.

Hypertonic NaHCO3, 1-3 ampules (44 mEq/50 mLeach) by intravenous infusion over 30-45 minutes,has been used in the treatment of hyperkalemia formany years. Overall, its potassium lowering effectis weak and of slow onset. Hypertonic NaHCO3lowers [K] via multiple mechanisms includingexpansion of the ECF (causing dilution of the K)

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and transcellular K uptake. Hypertonic NaHCO3does expand the ECF and should be avoided in vol-ume overloaded patients and those with congestiveheart failure.

Hyperkalemia associated with increased total Kstores requires K to be removed. If kidney functionis adequate, loop and thiazide diuretics (and espe-cially in combination) can markedly increase uri-nary K excretion. Thiazide diuretics are particularlyhelpful in the treatment of hyporeninemic hypoal-dosteronism. Thiazides become less effective whenkidney function declines, whereas high dose loopdiuretics may remain useful until renal functionreaches “end-stage.” Occasionally, patients withhypoaldosteronism are volume contracted and thenthe exogenous mineralocorticoid fludrocortisonemay be useful.

Stool potassium excretion is enhanced by adminis-tering laxatives to generate electrolyte-rich diarrheaand by binding gastrointestinal luminal K to non-absorbable resins, such as sodium polystyrene sul-fonate. The resin powder is generally premixed withsorbitol (15 g suspended in per 60 mL of 70% sor-bitol) which speeds its transit through the GI tractand also itself increases fecal K loss. The usual oraldose is 30 gm. The resin powder can also beingested with other laxatives. The acute K loweringeffect of this treatment is minor, and resin K bindersmay be more effective for chronic therapy. Theseresins can also be administered via enema, thoughthis route may be less effective. A rare complicationof the sodium polystyrene sulfonate in sorbitol sus-pension is bowel necrosis. This may be due to thehypertonic sorbitol rather than the resin itself and ismore common with rectal administration.

Acute hemodialysis, generally reserved for patientswith acute or chronic severe kidney failure, rapidlylowers plasma [K] and can reduce total body Kstores by about 25-50 mEq per hour.

5. Selected Disorders of Divalent Metabolism

Hypercalcemia Hypercalcemia may be a common manifestation ofa serious disease or reflect an incidental finding thatleads to the diagnosis of some underlying disease.116-121

Approximately 90% of the patients with hypercal-cemia have either primary hyperparathyroidism oran underlying malignancy. Primary hyperparathy-roidism is the most common cause of hypercal-cemia in the outpatient setting,117,118 whereas a malig-nancy is the most frequent cause of hypercalcemiain a hospitalized patient.119 Other causes of elevatedcalcium are less common and usually not consid-ered until malignancy and parathyroid disease areruled out.

The reference range of serum calcium levels is 8.7-10.4 mg/dL. A calcium level of >14 mg/dL corre-sponds to severe hypercalcemia or hypercalemiccrisis. Plasma calcium is maintained within the ref-erence range by a complex interplay of 3 major hor-mones, parathyroid hormone (PTH), 1,25-dihy-droxyvitamin D (ie, calcitriol), and calcitonin.These 3 hormones act primarily on the bone, kidney,and small intestine sites to maintain appropriate cal-cium levels. Approximately 40% of the calcium isbound to protein, primarily albumin, while 50% isionized and is in physiologic active form. Theremaining 10% is complexed to anions.

Patients with hypercalcemia can be asymptomaticor severely symptomatic depending on the degreeand rate of increase. The hallmark clinical findingsin hypercalcemia are neuromuscular and neurologi-cal alterations, mental status change, depression,fatigue, and muscle weakness. Notably, Trousseauand Chvostek signs may or may not be positivedepending on the severity. Accompanied gastroin-testinal symptoms include constipation, nausea, andvomiting. A history of polyuria, polydipsia,nephrolithiasis and nephrocalcinosis is relativelycommon. Cardiac symptoms can be exhibited asheart block, arrhythmias, or minor ECG changes(shortened QT interval). Patients may have a posi-tive family history or medication intake.

As a general rule, the kidney does not actively con-tribute to hypercalcemia; rather, the kidney defendsagainst the development of hypercalcemia. There-

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fore, in most disorders involving hypercalcemia, therenal threshold of calcium excretion must beexceeded in order to produce significant hypercal-cemia.

Primary HyperparathyroidismMost commonly observed in women who havehyperplasia or adenoma of the parathyroid causingan excessive secretion of the parathyroid hormone(PTH).117,118 Primary hyperparathyroidism originallywas the disease of “stones, bones, and abdominalgroans.” In most primary hyperparathyroidismcases, the calcium elevation is caused by increasedintestinal calcium absorption. This is mediated bythe PTH-induced calcitriol synthesis that enhancescalcium absorption. The increase in serum calciumresults in an increase in calcium filtration at the kid-ney. Because of PTH-mediated absorption of cal-cium at the distal tubule, less calcium is excretedthan might be expected. In PTH-mediated hypercal-cemia, bones do not play an active role becausemost of the PTH-mediated osteoclast activity thatbreaks down bone is offset by hypercalcemic-induced bone deposition. Hypercalcemia of this dis-order may remain mild for long periods becausesome parathyroid adenomas respond to the feed-back generated by the elevated calcium levels.

Humoral Hypercalcemia of Malignancy (HHM)HHM makes up about 80% of all cases of malig-nancy related hypercalcemia.119 Ectopic secretion ofparathyroid hormone-related-peptide (PTHrP) stim-ulates bone osteoclastic resorption.120 The mostcommon cancers associated with HHM are squa-mous cell cancer of the lung, renal cell, breast, andovarian carcinomas, whereas lymphomas make up asmall percentage. The typical presentation is that ofhypercalcemia and hypophosphatemia. Unfortu-nately, patients are often diagnosed at an advancestage of malignancy.121

Other malignant disease can also cause hypercal-cemia. Cancers include lymphoma (increased pro-duction of 1,25(OH)2 vitamin D), advanced breastcancer (osteolytic bone metastases), multiplemyeloma (bone destruction). Bisphosonate admin-istration can be used effectively to treat the hyper-calcemic skeletal complications of such diseases.

MedicationsThese include lithium through interaction with theCaR to alter the set point for PTH secretion in rela-tion to extracellular calcium; thiazides—usuallymild hypercalcemia due to inhibition of urinary cal-cium excretion. vitamin A and D intoxication, theo-phylline, and estrogen therapy.

Milk-alkali SyndromeThis syndrome is relatively common and character-ized by hypercalcemia, alkalosis, and renal insuffi-ciency after large amounts of calcium and antacidingestion122. Milk-alkali syndrome frequentlyresults from excessive calcium carbonate ingestiondue to peptic ulcer disease.

ImmobilizationChronically bedridden patients may develop hyper-calcemia, although the mechanism is not wellunderstood123. The syndrome is characterized by alow PTH and 1,25(OH)2 vitamin D levels afterweeks of inactivity. Ostepenia can be reversed withresumption of activity and bisphosphonate therapy.

Granulomatous DiseaseGranulomatous disease (eg, sarcoidosis, leprosy,disseminated candidasis, and acquired immunodefi-ciency syndrome, leprosy) is often complicated byhypercalcemia.124 The likely mechanism is an alter-ation in vitamin D metabolism with an increasedproduction of 1,25(OH)2 vitamin D from non-renalsites.

Treatment of Hypercalcemia

Management of hypercalcemia comprises generaltreatment and more specific etiology-driven treat-ment.125-128 The foremost component in treatinghypercalcemia is repletion of the extracellular fluidcompartment with 0.9% (normal) saline – a keymanagement step since many patients are volumedepleted. A loop diuretic (eg, furosemide) may beused with hydration to increase calcium excretion.This may also prevent volume overload during ther-apy. In contrast to loop diuretics, avoid thiazidediuretics because they increase the reabsorption ofcalcium. Patients who are already on chronic dialy-sis and severely hypercalcemic should undergohemodialysis or peritoneal dialysis with a low-cal-cium dialysate as first line therapy. Bisphospho-

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nates and calcitonin may also be used to blockosteoclastic bone resorption,129-131 but caution needsto be used in treating patients with kidney disease(bisphosphonates are contraindicated in patientswith kidney failure).132

The treatment of primary hyperparathyroidism isreviewed in detail elsewhere.133 Mithramycin blocksosteoclastic function and can be given for severemalignancy-related hypercalcemia.134 However,mithramycin has significant hepatic, renal, and mar-row toxicity. The detailed management of malig-nancy associated hypercalcemia is detailed else-where.135-7

Hypermagnesemia Magnesium (Mg2+) is the second most commonintracellular cation after potassium. Magnesium isrequired for deoxyribonucleic acid (DNA) and pro-tein synthesis.138 Mg2+ is also an essential cofactorfor most enzymes in phosphorylation reactions.Mg2+ also plays an important role in parathyroidhormone synthesis.

The total body content of Mg2+ is 2000 mEq, or 24 g. Mg is distributed in bone (67%), intracellu-larly (31%), and extracellularly (a mere 1%). Theintracellular concentration is 40 mEq/L, while thenormal serum concentration is 1.5-2.0 mEq/L. Ofthis serum component, 25%-30% is protein bound,10%-15% is complexed, and the remaining 50%-60% is ionized.

Magnesium is absorbed in the ileum and excreted instool and urine. The minimum daily requirement ofMg2+ is 300-350 mg, or 15 mmol; this amount iseasily obtainable with a normal daily intake offruits, seeds, and vegetables because magnesium isa component of chlorophyll and is present in highconcentrations in all green plants.

Hypermagnesemia is a rare electrolyte abnormalitybecause the kidney is very effective in excretingexcess Mg2+ 1.139-141 The kidney is the main regula-tor of magnesium concentrations. Absorptionoccurs primarily in the proximal tubule and thickascending limb of the loop of Henle – an increase ofMg2+ to greater than 1.1 mmol/L (2.2 meq/L) (2.6mg/dL). The most common cause of hypermagne-semia is excessive intake in the setting of impaired

Mg2+ excretion by the kidneys – patients are takingmagnesium-containing antacids, laxatives, enemas,or infusions in the context of acute or chronic kid-ney failure. Acute rhabdomyolysis is also associ-ated with hypermagnesemia.

Hypermagnesemia may present clinically withlethargy, drowsiness, hypotension, nausea, vomit-ing, facial flushing, urinary retention and ileus.These symptoms are usually observed when theserum Mg2+ level exceeds 4 to 6mg/dL. Ifuntreated, this condition may progress to flaccidskeletal muscular paralysis and hyporeflexia, brady-cardia and bradyarrhythmias, complete heart block,and respiratory depression and death. NonspecificECG changes are often seen and may include pro-longed PR intervals and increased QRS duration.Hypotension and cutaneous flushing may be theresult of vasodilator effect and inhibition of nore-pinephrine release from sympathetic postganglionicnerves. Voluntary muscle paralysis and generalsmooth muscle paralysis can cause the life threaten-ing complication of respiratory muscle paralysisand apnea. Coma and cardiac arrest may eventuallyensue in patients with severe Mg2+ toxicity.

Treatment of Hypermagnesemia

The most important steps are to withdraw Mg2+

infusion and volume replete the patient.Volumerepletion should be with 0.9% saline and intra-venous furosemide. In patients that have severecomplications that may require emergent treatment,administration of Ca2+ (1 g over 2 to 5 minutes ofIV calcium chloride or calcium gluconate) may beuseful. Patients with kidney failure may requiredialysis against a low magnesium bath. Generally,the expected change in serum Mg2+ after 3 to 4hours of dialysis with a high-efficiency membraneis approximately one-third to one-half the differ-ence between the dialysate Mg2+ concentration andthe predialysis serum ultrafilterable Mg2+ level(estimated at 80% of total serum Mg2+). Peritonealdialysis can also be used to effectively removeMg2+ in patients who cannot tolerate hemodialysis.

Hypomagnesemia The reference range for serum Mg2+ level is 1.8-3mEq/L. Usually, patients become symptomatic at1.8 mEq/L. Thus, hypomagnesemia is defined as a

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Mg2+ level <1.8 mEq/L. Hypomagnesemia is com-mon – up to 60% of the patients in intensive careunits are estimated to be hypomagnesemic accord-ing to surveys of serum Mg2+ levels.142,143

Hypomagnesemia is often the result of renal or gas-trointestinal losses and may be related to loopdiuretic use, other drugs, alcohol use, and chronicdiarrhea.139 Cutaneous losses are thought to be dueto excessive sweating on exercise excretion and alsoin patients with severe burn injury. Intravenousfluid therapy and volume-expanded states may alsocause hypomagnesemia due to a dilutional effect.Rarely, familial incidence has been reported primar-ily in isolated familial hypomagnesemia, familialhypokalemia, and familial hypomagnesemia-hypercalciuria.

Patients with hypomagnesemia may be asymp-tomatic or have a number of clinical manifestationsthat could reflect other electrolyte abnormali-ties.138,139 Multiple body systems can be involved,including the heart, neuromuscular, central nervoussystem (CNS). Cardiac symptoms include tach-yarrhythmias, torsades de pontes, tachycardia, andfibrillation resistant to standard treatment butresponding to Mg2+ repletion. ECG changes reflectabnormal cardiac repolarization with bifid T waves,U waves, and prolongation of QT or QU interval.Neuromuscular symptoms are similar to hypocal-cemia, including tremor, twitching, frank tetany,and positive Trousseau and Chvostek signs. CNSsymptoms may include generalized, tonic-clonic, ormultifocal motor seizures that are triggered by loudnoises and can lead to sudden death. Nystagmusand Wernicke encephalopathy may also be present.

The most important aspects of managing hypomag-nesemia is to distinguish if the lack of Mg2+ is dueto a decreased intake/absorption or increased losses.A key test is to measure a 24-hour quantitative uri-nary Mg2+ excretion to distinguish increased versusdecreased urinary excretion of Mg2+. An increasedurinary excretion in a patient with hypomagnesemiais invariably due to renal Mg2+ wasting. Adecreased urinary excretion may be primarily due torenal conservation of Mg2+ in an attempt to restoreMg2+ equilibrium in the face of inadequate Mg2+intake. Renal Mg2+ wasting can be seen in patientswith defective sodium resorption (diuretic use), use

of renal toxins (amphotericin B, cisplatin, amino-glycosides, pentamidine, cyclosporine A), andosmotic diuresis (DM). Extrarenal losses may bedue to nutrition deficiency (eg, alcoholism, protein-calorie malnutrition, parenteral nutrition),decreased absorption (eg, chronic diarrhea, intesti-nal malabsorption syndromes), and cutaneouslosses (eg, burn patients, marathon runners).Rarely, bone redistribution may occur in patientswho have “hungry bone syndrome” where chroni-cally elevated PTH is corrected with parathyroidec-tomy.

The treatment of asymptomatic Mg2+ deficiency iscontroversial. Patients with Mg2+ deficiency andassociated cardiac disease should receive Mg2+supplementation to avoid the risk of developingdigoxin cardiotoxicity. For unknown reasons,patients on parenteral nutrition have an increaseddemand for Mg2+. Therefore, Mg2+ supplementa-tion should be increased to prevent further deficien-cies. Symptomatic Mg2+ deficiency requires reple-tion to prevent complications such as seizure disor-der and ongoing electrolyte imbalance. Intravenousreplacement is the route of choice on patients withIV access. Depending on the severity of symptoms,the standard preparation of MgSO4·7H2O may beinfused at different dosages. In a patient who isactively seizing or who has a cardiac arrhythmia, 8 to 16mEq (1 to 2 g) may be administered intra-venously over 2 to 4 minutes; otherwise, a slowerrate of repletion is safer. A slower rate of infusioncan also decrease urinary losses because of thedelayed Mg2+ equilibration with the intracellularcompartment. Repletion should be continued for 1to 2 days despite normalization of serum Mg2+ lev-els. The dosage of Mg2+ repletion should bereduced 25%-50% in patients who have a reducedglomerular filtration rate to prevent hypermagne-semia. Several Mg2+ salts may be administeredorally to replenish mild cases of hypomagnesemiawhere ongoing losses may be present. Patients withongoing renal losses and Mg2+ wasting should betreated with a potassium-sparing diuretic.Amiloride and triamterene can effectively reducerenal Mg2+ clearance after furosemide diuresis.

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