Manual in Nephrology

Acid-Base and Electrolytes Michael Emmett, MD Ajay K. Singh, MB, MRCP(UK)

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

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1. Introduction

2. Acid-Base Disorders

Disorders of acid-base and electrolytes are common in both examination and clinical situations. Solving acid-base or electrolyte conundrums requires a basic knowledge of the underlying physiology, some knowledge of the homeostatic mechanisms available to the body, and the use of some simple formulas. The purpose of this chapter is to review the major acid base and electrolyte disorders, focusing particularly on board examination favorites.

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

A primary rise in PaCO2 (respiratory acidosis) or fall in plasma [HCO3-] (metabolic acidosis) reduces pH, whereas a primary fall in PaCO2 (respiratory alkalosis) or rise in plasma [HCO3-] (metabolic alkalosis) increases pH. Each primary disorder should trigger a compensatory response that returns the pH toward normal. The magnitude of each compensatory response is predictable as shown in Table 1.

Equation 1: pH = 6.1 + log [HCO3] (0.03)ÎąPCO2

Table 1 Acid-Base Disorders and Compensatory Responses

Disorder

H+

pH

HCO3

Metabolic acidosis

Metabolic alkalosis

PaCO2

Adaptive Response

Time For Adaptation

PCO2 = (1.5)HCO3 + 8 PCO2 = HCO3 + 15

12-24 hr

PCO2 = >40 - <55

24-36 hr

HCO3/ pCO2 = 1/10 or HCO3 = 0.1 pCO2

Minutes-Hours

Respiratory acidosis

Acute Chronic

HCO3 / pCO2 = 3/10 HCO3 = 0.3 pCO2

Respiratory alkalosis Acute

Chronic

Double arrows indicate the primary disturbance

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Days HCO3 / pCO2= 2/10 HCO3 = 0.2 pCO2

Minutes-Hours

HCO3 / pCO2 = 5/10 HCO3 = 0.5 pCO2

Days

Metabolic Acidosis

Metabolic acidosis is a pathologic process which, if unopposed, will cause a primary decrease in plasma [HCO3]. One or more of the following mechanisms is usually responsible: 1) Abnormally high loss of alkali into the stool or urine.

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

[Cl], should approximate the quantitative reduction in [HCO3]. (These relationships assume the sodium concentration [Na] is normal and remains unchanged – this is further discussed below.)

Some Important Formulas for Both Management of Metabolic Acidosis and for Coping with Examination Questions: Expected pCO2 in a metabolic acidosis pCO2 falls 1.2 mm Hg for every 1 mEq/L fall in HCO3.

Winter’s formula pCO2 = 1.5 X (observed HCO3) + 8±2

3) Decreased renal capacity to excrete acid.

It is also helpful to divide the metabolic acidoses into those with an increased anion gap (AG) and those with increased chloride concentration [Cl]1.

Figure 1 shows how the anion gap is calculated and Figure 2 illustrates why the [AG], the [Cl], or both must increase when metabolic acidosis develops.

Note that the quantitative increase in [AG], and/or

A quick rule of thumb The pCO2 should approximate the last two digits of pH. For example, pH 7.25, pCO2 should be close to 25 mm Hg. Expected pCO2 = 1.5 * HCO3- + 8 +/- 2

Figure 1 How the anion gap is calculated

K4

Pr 16

Ca 5 Mg 2

HCO3 25

Na 140

Cl 102

OA 4 PO42 SO42

{

AG 8 HCO3 25

Na 140

Cl 102

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

Figure 2 The anion gap, the chloride concentration, or both, must increase when metabolic acidosis develops

H20+CO2

H2CO3

{ {

Na-HCO3 + H-X Na-X

NORMAL

NORMAL AG METABOLIC ACIDOSIS (HYPERCHLOREMIC)

HIGH AG METABOLIC ACIDOSIS

Na

140

140

140

C1

105

115

105

HCO3

25

15

15

ANION GAP

LACTATE

10

1

10

1

20

11

When any relatively strong acid, such as HX, is added to the ECF the H+ dissociates and combines with HCO3- to form H2CO3, which then dehydrates to generate H2O and CO2. The X- remains and can be considered NaX. If HX is HCl, then the increase in [Cl] will match the fall in HCO3-; if X- is any non-HCl acid the fall in HCO3- will be matched by a similar increase in the anion gap. A loss of NaHCO3 will also produce a hyperchloremic acidosis.

Anion Gap Na - (Cl + HCO3-) Delta Gap Anion Gap - 12 (nl anion gap) Urinary Anion Gap UAG = [Na+]+ [K+] - [Cl-] 4

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Hyperchloremic Metabolic Acidosis

When metabolic acidosis reduces the [HCO3] and the [AG] remains normal, then relative hyperchloremia must exist. Relative hyperchloremia means the [Cl] is increased compared with the sodium concentration [Na]. When hypernatremia or hyponatremia develop the [Cl] should increase or decrease proportionately with [Na] – ie, in a 1:1.4 ratio. So, if the [Na] increases from 140 to 154 mEq/l then [Cl] should increase from 100 to 110 mEq/l. This is an “appropriate” degree of hyperchloremia and reflects dehydration but not an acidbase disorder. Relative hyperchloremia exists when the [Cl] is higher then expected for the coexisting [Na]. Relative hypochloremia exists when the [Cl] is higher then expected for the coexisting [Na]. Relative hypochloremia exists when the [Cl] is lower than expected for the coexisting [Na]. Relative hypochloremia or hyperchloremia are usually due to acid-base disorders.

Hyperchloremic acidosis generally develops in one of two ways: 1. Fluids containing high concentrations of NaHCO3 , or potential NaHCO3 (see below) are lost from the ECF. 2. Excess HCl, or potential HCl, is added to the ECF. Any organic sodium salt that can be metabolized to NaHCO3 represents potential NaHCO3. For example, NaLactate, NaCitrate, NaAcetate, and NaButyrate all generate eqimolar amounts of NaHCO3 when the organic anion is metabolized to substances such as glucose or CO2 and H2O. Similarly, organic chloride salts that can be metabolized to CO2 and H2O, proteins, or urea represent potential HCl. Examples include NH4Cl, lysine Cl and arginine Cl. The causes of hyperchloremic acidosis are listed in Table 2 and reviewed in detail elsewhere.2,3 Diarrhea is the most common cause of hyperchloremic metabolic acidosis and this disturbance develops

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 acid excretion (or excessive HCO3 loss) as a result of tubular defects in the absence of a major reduction in glomerular filtration.5 They are divided into three types: type I (or classic distal) RTA, type II (or proximal) RTA, and type IV (or hyperkalemic) RTA. Type III RTA was a condition once described in children but is no longer considered a distinct variant.

Type I, or classic distal RTA, results from an inability of the renal tubules to generate and/or maintain a normal pH gradient (the normal minimal U pH is <5.5 vs. 7.4 in blood).6 These patients always excrete inappropriately alkaline urine. It may be due to an inherited defect (either autosomal dominant or recessive) in one of several acid/base transporters or enzymes required to acidify the distal tubule fluid.7 They include the cytosolic carbonic anhydrase, the vacuolar H-ATPase, and the basolateral chloridebicarbonate exchanger (AE1). Associated clinical problems include hearing deficits, cerebral calcifications and osteopetrosis. The most common cause of acquired distal RTA in adults is probably Sjögren syndrome.8 Hypercalciuria is also very commonly associated with distal RTA. It is not always clear whether hypercalciuria occurs first and causes RTA, the RTA occurs first and generates the hypercalciuria, or if they are transmitted together. Distal RTA frequently causes medullary calcifications and leads to formation of calcium containing renal stone, due to the combination of hypercalciuria and deficient urine citrate excretion (the citrate deficit may be the more important abnormality). Treatment (see below) will raise urine citrate and often stop new kidney stone formation. Table 3 lists the major causes of distal RTA. Coexistent hyperchloremic acidosis and alkaline urine suggests distal RTA. However, two other possibilities must be considered and ruled out. Urinary tract infections can alkalinize the urine because some bacteria metabolize urinary urea to yield NH4+ & CO2. The NH4+ added to the urine sharply raises its pH. Therefore, always rule out UTI when the urine is more alkaline than expected. Some

Table 2 Hyperchloremic (Normal AG) Metabolic Acidosis

GI Loss of HCO3

a. Diarrhea b. Ureterosigmoidostomy Renal HCO3– Loss

a. Proximal RTA b. Carbonic Anhydrase Inhibitors c. Ileal loop bladder/Ureterosigmoidostomy/Intestinal interposition in GU stream Reduced renal H+ secretion

a. Distal RTA b.Type 4 RTA 1) Hyporeninemic-Hypoaldosteronism – Diabetes Mellitus, Tubulointerstitial disease, NSAIDs 2) Defective Mineralocorticoid (MC) synthesis or secretion – Addison Disease, Chronic Heparin Rx, Congenital Adrenal Defects 3) Inadequate renal response to MC-Sickle Cell Disease, SLE, K-sparing diuretics, “Chloride Shunts” c. Early Kidney Failure HCl/HCl Precursor Ingestion/Infusion

a. HCl b. NH4Cl c. Arginine HCl Other

a. Post chronic Hyperventilation b. Recovery from DKA c. Toluene Inhalation

patients with hyperchloremic acidosis and marked hypokalemia generated by diarrhea will excrete “abnormally” alkaline urine. This is not due to any ACID-BASE AND ELECTROLYTES

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form of renal acidification problem but rather results from the combination of persistent acidemia and hypokalemia. These two factors markedly stimulate renal NH4+ generation and result in very high urine NH4+ levels. This NH4+ raises the urine pH. Renal acid excretion is very high despite the relatively alkaline urinary pH. Measurement of urine NH + 4

excretion will readily differentiate these possibilities (as will a careful history!).9,10 Among patients with hyperchloremic metabolic acidosis, the urine anion gap (UAG) is frequently helpful in distinguishing gastrointestinal from renal causes (eg, a distal RTA).10 The UAG is estimated by measuring specific cations and anions excreted in the urine. The cations normally present in urine are

Na+, K+, NH4+, Ca++ and Mg++. The anions normally present are Cl-, HCO3 -, sulfate, phosphate and some organic anions. Only Na+, K+ and Cl- are commonly measured in urine so the other charged species are the unmeasured anions (UA) and cations (UC). Because electroneutrality is required, total anion charge always equals total cation charge. Cl+ UA = Na+ + K+ + UC. Thus, the UAG is defined by the following equation.

Urinary Anion Gap = (UA - UC) = [Na+]+ [K+] [Cl-] The UAG provides a rough index of urinary ammonium excretion. Ammonium is positively charged so a rise in its urinary concentration (ie, increased

Table 3 Distal Renal Tubular Acidosis

A. Primary 1. Familial 2. Idiopathic B. Secondary to genetically transmitted diseases 1. Ehler's Danlos 2. Hereditary elliptocytosis 3. Sickle cell disease 4. Carbonic anhydrase deficiency 5. Medullary cystic disease 6. Wilson disease 7. Fabry disease 8. Hereditary hypercalcuria 9. Hereditary fructose intolerance 10.Familial hypergammaglobulemia C. Secondary to autoimmune disorders 1. Hypergammaglobulinemia 2. Hyperglobulinemic purpura 3. Cryoglobulinemia 4. Sjรถgren syndrome 5. Thyroiditis 6. Pulmonary fibrosis 7. Chronic active hepatitis 8. Primary biliary cirrhosis 9. Systemic lupus erythematosus 10.Arteritis

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D. Hypercalcuria and nephrocalcinosis 1. Primary hyperparathyroidism 2. Vitamin D intoxication 3. Hyperthyroidism 4. Idiopathic hypercalcuria 5. Medullary sponge kidney E.

Drugs and toxins 1. Amphotericin B 2. Toluene 3. Analgesics 4. Cyclamate

F.

Tubulointerstitial Disease 1. Balkan nephropathy 2. Chronic pyelonephritis 3. Obstructive uropathy 4. Renal transplantation 5. Leprosy 6. Jejuno-ileal bypass with oxaluria

G. Miscellaneous 1. Hepatic cirrhosis 2. Empty sella syndrome 3. Osteopetrosis

unmeasured cations) results in a fall in UAG. If the acidosis is due to loss of bicarbonate via the bowel then the kidneys can response appropriately by increasing ammonium excretion to cause a net loss of H+ from the body. The UAG would tend to be decreased. If the acidosis is due to loss of bicarbonate via the kidney, then as the problem is with the kidney it is not able to increase ammonium excretion and the UAG will not be increased. In a patient with a hyperchloremic metabolic acidosis: A negative UAG suggests gastrointestinal loss of bicarbonate (eg, diarrhea). In patients with severe diarrhea the UAG may be quite negative (-10 to -27 range).

A positive UAG suggests impaired renal distal acidification (ie, distal renal tubular acidosis).

Type II, or proximal RTA, is caused by a reduction in this tubule segment’s renal NaHCO3 reabsorptive capacity.11 Normally the proximal tubule reabsorbs 90% of the filtered NaHCO3 when the plasma [HCO3] is in the normal range. A decrease in this tubule segment reabsorptive capacity results in major bicarbonaturia. This continues until the plasma [HCO3] has fallen to a level that can be effectively reabsorbed. If one attempts to raise the plasma [HCO3] level above the abnormally low renal tubule threshold (for example, when exogenous NaHCO3 is administered), a large amount of NaHCO3 is excreted into the urine. It is important to recognize that these patients can appropriately acidify their urine when the serum [HCO3] falls below the threshold concentration.

Isolated proximal RTA (pRTA) is very rare and may occur without other functional defects.12 It presents usually in infancy and early childhood with growth retardation. Isolated pRTA has 3 types or varieties based on the method of genetic transmission: autosomal dominant pRTA; autosomal recessive pRTA with ocular abnormalities; and sporadic isolated pRTA. Much more commonly, other proximal tubule defects coexist. When renal glucosuria, phosphate wasting, excessive uric acid excretion, and/or low molecular weight proteinuria are documented, the Fanconi syndrome exists.11,13 Inherited causes of Fanconi syndrome include a number of enzymatic defects that affect amino acid or carbohydrate metabolism. Fanconi syndrome is associated with the deposition of protein crystals in the proximal tubules, as a result of a monoclonal gammopathy,14

and is a very common treatment side effect of the alkylating agent ifosfamide.15,16 At this time, these are the most common causes of the acquired syndrome in adults. Table 4 lists the major causes of proximal, or type II, RTA. Hypoaldosteronism, or an inadequate renal tubule response to aldosterone, often generates hyperkalemia and hyperchloremic metabolic acidosis.13,17,18 This disorder is called Type 4 RTA. Mineralocorticoid deficiency directly impairs renal acidification (it slows the rate of distal proton secretion, but usually does not affect the maximal pH gradient which can be achieved). In addition, the development of hyperkalemia inhibits renal NH4+ synthesis and excretion and this effect is a major contribution to development of metabolic acidosis. The most common acquired cause of hypoaldosteronism in adults is a renin deficiency state–ie, hyporeninemic hypoaldosteronism.17,18,19 Often this is due to damage to the renin secreting J-G apparatus in patients with diabetes. Analgesic nephropathy and chronic urinary outlet obstruction, especially in elderly men, also generates hyporeninemic hypoaldosteronism.

Blocking the renin-angiotensin axis at any step also can cause similar pathophysiology. Thus angiotensin converting drugs and angiotensin receptor blockers reduce adrenal aldosterone synthesis and create these abnormalities. When aldosterone levels are high, renal tubule resistance to the hormone occurs in a number of diseases including systemic lupus, sickle cell disease, and interstitial nephritis. Diuretics which compete with aldosterone (spironolactone) or block distal tubule sodium channels (amiloride, triamterene) also generate hyperkalemic metabolic acidosis (type IV RTA).19 Gastrointestinal epithelium, especially colonic tissue, avidly absorbs chloride and secretes both HCO3– and K. Therefore, if this epithelium is exposed to urine, the urine chloride is removed, while HCO3– and K is secreted. Excretion of urine with this altered chemical profile generates hypokalemia and hyperchloremic metabolic acidosis. Ureterosigmoidostomy, ileal loop bladders or interposition of any ileal or colonic segment into the urinary stream can produce this acid base derangement.20

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Proximal RTA is difficult to correct with exogenous NaHCO3 because the kidney will rapidly excrete NaHCO3 as soon as its plasma level increases above the threshold.4 Furthermore, delivery of large quantities of NaHCO3 to the distal nephron exacerbates K losses and hypokalemia. Sometimes maneuvers to increase the threshold, such as moderate ECF

contraction induced with thiazide diuretics, may be helpful. When Fanconi syndrome exists, treatment of associated abnormalities such as hypophosphatemia and vitamin D deficiency is often more important than correction of the low NaHCO3 per 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. Sporatic a. Isolated bicarbonate wasting b. Fanconi syndrome 2. Familial a. Isolated bicarbonate wasting b. Fanconi syndrome Secondary

1. Genetic - Familial a. Disorders of amino acid metabolism 1) Cystinosis 2)Tyrosinemia b. Disorders of carbohydrate metabolism 1) Galactosemia 2) Hereditary fructose intolerance 3) Glycogen storage disease with Fanconi syndrome c. Wilson disease (copper accumulation) d. Lowe syndrome (oculocerebral-renal syndrome) e. Metachromatic leukodystrophy f. Osteopetrosis 2. Dysproteinemic states a. Multiple myeloma b. Light chain disease c. Monoclonal gammopathy d. Amyloidosis

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3. Excess parathyroid hormone a. Primary hyperparathyroidism b. Secondary hyperparathyroidism 1) Renal failure 2) Vitamin D deficiency 3) Abnormal vitamin D metabolism 4. Drugs – Chemicals a. Carbonic anhydrase inhibitors 1) Acetazolamide 2) Mefenide (Sulfamylon®) b. Ifosfamide c. Streptozotocin d. Methyl-3-chromone e. Maleic acid f. D-serine g. Toluene h. Cadmium i. Lead j. Mercury 5. Interstitial renal disease a. Sjögren syndrome b. Medullary cystic disease c. Renal transplant rejection d. Chronic renal vein thrombosis e. Balkan nephropathy 6. Miscellaneous a. Malignancy b. Nephrotic syndrome c. Paroxysmal nocturnal hemoglobinuria (iron deposition) d. Congenital heart disease

potential NaHCO3 (ie, Shohl’s solution).4 NaHCO3 therapy simultaneously corrects the acidosis, reverses volume contraction, ameliorates renal K wasting (in contradistinction to proximal RTA), and increases urine citrate levels. Normalizing citrate excretion helps solubilize urine calcium and opposes renal papillary calcification and kidney stone formation. The metabolic acidosis of type IV RTA generally improves with correction of hyperkalemia—accomplished with diuretics or K binding gels. Some of these patients may require exogenous mineralocorticoids; others respond well to diuretics and for some exogenous NaHCO3 is required. The metabolic acidosis and volume depletion secondary to diarrhea can also be corrected by the administration of NaHCO3.

Metabolic Acidosis with an Increased Anion Gap (AG)

AG metabolic acidosis develops when organic and/or non-Cl inorganic acids accumulate at rates that exceed the capacity to excrete or metabolize them.21-23 Calculation of the anion gap (AG) is essential in the differential diagnosis of metabolic acidosis. The AG is defined as the difference between the plasma concentrations of the measured plasma cation (ie, Na+) and the measured anions (ie, chloride [Cl-], HCO3 -).

AG calculation = (Na+) - ([Cl-] + [HCO3 -]) The normal AG is 8-16 mEq/L, (averages around 12 mEq/L). Metabolic acidosis with a high AG is associated with the addition of endogenously or exogenously-generated acids. Metabolic acidosis with a normal AG is associated with the loss of HCO3 or the failure to excrete H+ from the body. There are several mnemonics used to promptly recall the differential diagnosis of high anion gap acidosis. Two popular 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-salicylates.

MAPLES: D-DKA; R-renal; M-methanol; A-alcoholic ketoacidosis; P-paraldehyde, phenformin; Llactic (ie, CO, HCN); E-ethylene glycol; S-salicylates. Causes of a High AG metabolic acidosis are listed in Table 5.

Lactic Acidosis

Lactic acidosis occurs when lactate production exceeds consumption and body buffer systems become overburdened. This is reviewed in detail elsewhere.4,25 Lactic acidosis results in increased blood lactate levels that can be easily measured.

Lactic acid exists in two forms, L-lactate and D-lactate. L-lactate is the only form produced in human metabolism. Its excess represents increased anaerobic metabolism due to tissue hypoperfusion. In contrast, D-lactate is a byproduct of bacterial metabolism and may accumulate in patients with short-gut syndrome or in those with a history of gastric bypass or small bowel resection.26 Lactic acidosis is classified into 2 categories: Type A lactic acidosis is characterized by decreased tissue ATP in the setting of poor tissue perfusion or oxygenation.27,28 Type B lactic acidosis is characterized by the absence (at least overt absence) of poor tissue perfusion or oxygenation. Type B is divided into 3 subtypes: Type B1 is association with systemic disease such as renal and hepatic failure, diabetes, and malignancy. Type B2 results from drugs and toxins such as biguanides, alcohols, iron, isoniazid, and salicylates. Type B3 is due to inborn errors of metabolism.

Type A lactic acidosis usually results from local or systemic underperfusion or overt shock.2 It is usually treated by reversing the underlying cause of the poor perfusion state.27,29 Treatments directed at the low bicarbonate level itself are generally doomed to fail. A common type of transient reversible lactic acidosis is postictal or post-exertion lactic acidosis.

These lactic acidoses result from rapid muscle generation of lactate combined with reduced hepatic oxidation as a result of temporary hepatic underperfusion. They rapidly resolve as an individual recovers from the exertion or seizure. Less common causes of Type A lactic acidosis include a severe and acute arterial hypoxemia and very severe anemia –

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Table 5 High Anion Gap Metabolic Acidosis

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

Ketoacidosis

1. Lactic acidosis 2. Ketoacidosis 3. Uremia 4. Methanol ingestion 5. Ethylene glycol ingestion 6. Salicylate poisoning 7. D-Lactic acidosis

especially when due to iron deficiency.

Of the causes of type B lactic acidosis, drugs that interfere with lactate (and pyruvate) metabolism are important to consider. For example, a high concentration of metformin inhibits the enzyme pyruvate dehydrogenase. This results in cytosolic accumulation of pyruvic and lactic acid and sometimes generates severe lactic acidosis. Because metformin is excreted by the kidney, it can accumulate whenever renal insufficiency exists or develops. Pyruvate dehydrogenase also requires the cofactor thiamine pyrophosphate and its activity falls when thiamine is deficient. Consequently, thiamine deficiency can produce profound lactic acidosis. Another class of drugs which can lead to lactic acidosis is the reverse transcriptase inhibitors used to treat HIV. This is apparently a consequence of direct mitochondrial toxicity. For example, zidovudine and stavudine have been associated with chronic lactic acidosis, fatty liver and myopathy. A number of inherited mitochondrial enzyme defects produce chronic lactic acidosis.30 When associated with a myopathy— seizures and strokes—these disorders are grouped as the MELAS syndromes (Mitochondrial myopathy, Encephalopathy, Lactic acidosis, and Stroke).31 Many other inherited and acquired cytosolic and mitochondrial enzyme disorders also produce lactic acidosis. Table 6 shows another classification sys-

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The two most important causes of ketoacidosis are diabetes and alcoholism. Diabetic ketoacidosis (DKA) reflects a state of absolute or relative insulin deficiency resulting in hyperglycemia exacerbated by extracellular volume depletion and acidosis.32 DKA is characterized by blood sugars >300 mg/dL and acidemia (arterial pH <7.30, serum HCO3 <15 mEq/L). Ketonemia and ketonuria are also present. Common causes include underlying infection, disruption of insulin treatment, and new onset of diabetes. It is frequently precipitated by the metabolic stress of an intercurrent medical or a surgical complication.

Alcoholic ketoacidosis (AKA) is characterized by an acute metabolic acidosis occurring in alcoholics who have recently engaged in binge drinking, starved themselves of food, and been vomiting.33 Laboratory data in AKA demonstrates elevated serum ketone levels and a high anion gap. A concomitant metabolic alkalosis (secondary to vomiting and volume depletion) may also be present. In both DKA and AKA, the accumulating acid anions are both acetoacetate and betahyroxybutyrate. It is important to note that the commonly used “ketone” tests for both plasma and urine are based on the nitroprusside reaction and this reacts with acetoacetate but not betahydroxybutyrate. These two compounds are in equilibrium via an NAD/NADH driven enzyme.

Changes in the redox state of a patient can therefore markedly affect the “ketone” test, independent of changes in severity of the metabolic acidosis. Acetone also accumulates and causes the distinctive “ketotic” odor, but this is not an acid and does not contribute to the acidosis or elevated anion gap.

Drugs and Toxins

Methanol and ethylene but not isopropanol overdoses typically present with an anion gap metabolic acidosis.34,35 Methanol is metabolized to formaldehyde and then formic acid. These toxic metabolites are responsible for the frequent

development of blindness. The formic acid causes the anion gap acidosis. When ethylene glycol is ingested it is metabolized to glycine, glyoxalate and oxalic acid. The oxalate combines with calcium and precipitates in the brain, lungs, peripheral nerves, and kidneys. Abundant calcium oxalate crystals in the urine is a major clue suggesting ethylene glycol poisoning, and renal failure occurs very commonly.

Early diagnosis in both methanol and ethylene glycol poisoning are key. A useful screening test is determination of the osmolar gap. If the osmolar gap is greater than 10, it indicates the presence of appreciable quantities of low molecular weight substances such as methanol or ethylene glycol (see

section on body water/osmolality).36 Osmole Gap = Measured Serum Osmolality â&#x20AC;&#x201C; 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 elevated in methanol ingestion than with ethylene glycol ingestions because of the lower molecular weight of methanol. Blood methanol and ethylene

Table 6 Lactic Acidosis

Decreased ATP Production

Lactate overproduction (with relative ATP deficiency)

A. Circulatory failure 1. Volume depletion 2. Severe heart failure 3. Massive pulmonary emboli 4. Vascular collapse: septic shock, anaphylaxis, vasodilators (nitroprusside) B. Severe acute tissue hypoxia 1. Acute respiratory failure 2. Carbon monoxide poisoning 3. Severe anemia 4. 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)

A. Muscle hyperactivity 1. Severe exertion 2. Seizure 3. Hypothermia-?shivering (and decreased perfusion) 4. Exertional heat stroke B. Disseminated tumor, especially leukemia/lymphoma C. Tumor lysis syndrome D. Gluconeogenic enzyme defects 1. Glucose-6-phosphatase defect (von Gierke disease) 2. Fructose-1,6-diphosphatase defect E. Catecholamine excess - Pheochromocytoma F. Methanol G. Ethylene glycol Decreased lactate utilization

A. Advanced liver disease

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glycol levels can be measured but the test is not widely available (methanol and ethylene glycol levels >20mg/dl are associated with significant toxicity). The treatment of both methanol and ethylene glycol poisoning requires urgent inhibition of the enzyme alcohol dehydrogenase.37-39 This blocks conversion of the ingested alcohols to organic acids and other more toxic metabolites. Inhibition is accomplished by administration of ethanol or the specific inhibitor fomepizole.40 Hemodialysis is often required to remove the ingested poison and toxic metabolites and to simultaneously correct the metabolic acidosis and electrolyte abnormalities.41

sis.26 Usually, this disorder occurs when large carbohydrate loads are delivered to the colon where bacterial metabolism generates D-lactic acid. When systemically absorbed, this acid is slowly metabolized and this generates both the acidosis and a spectrum of neurological abnormalities including confusion, ataxia, slurred speech, and generalized weakness. D-lactic acid is not detected by routine enzymatic assays for lactic acid (which are stereoisomer specific for L-lactic acid). When it is suspected, D-lactic acid can be identified with specific enzymatic assays for D-lactate or gas-liquid chromatography.

Salicylate poisoning generates an anion gap acidosis because toxic concentrations uncouple oxidative phosphorylation and results in generation of multiple organic acids.42-44 In addition, most adults with salicylate poisoning also develop respiratory alkalosis (see below â&#x20AC;&#x201C; mixed acid base disorders). The relative severity of the two disturbances determines the arterial pH, and this is very age dependent â&#x20AC;&#x201D; babies generally have more severe metabolic acidosis, while adults have more profound respiratory alkalosis. Nonetheless, most patients have elements of each disturbance.

Metabolic Alkalosis

Uremia

Uremic metabolic acidosis is often a hyperchloremic acidosis early in the course (due to impaired NH4 excretion) and then evolves into an anion gap acidosis as multiple organic and inorganic anions (SO4, HPO4, etc.) accumulate as a result of the low GFR.45,46 In uremic patients, the metabolic acidosis may contribute to other clinical abnormalities, such as hyperventilation, anorexia, stupor, decreased cardiac response (congestive heart failure), and muscle weakness.

D-Lactate

Mammals primarily synthesize, and metabolize, the L optical isomer of lactic acid, while many bacteria generate and utilize both the L and D isomers.

Patients with short gut syndromes can develop Dlactic acidosis, an unusually high anion gap acido-

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Metabolic alkalosis is very common, both in practice and in examination setting as a question. There are several excellent reviews on this topic available in the literature.47-5 Metabolic alkalosis represents a primary increase in [HCO3 ]. A modest compensatory increase in PaCO2 should develop (Table 1).

The increase in [HCO3 ] results from either a loss of H+ from the body or a gain in HCO3 -. In its pure form, metabolic alkalosis presents as alkalemia (pH >7.40). However, because of homeostasis there is usually a secondary or compensatory response resulting in alveolar hypoventilation with a rise in arterial carbon dioxide tension ( PaCO2). This causes an attenuation in the change in pH that would otherwise occur.

Under normal circumstances, as a rule of thumb, the compensatory ventilatory response results in a 0.5-0.7 mm Hg increase in arterial PaCO2 for every 1 mEq/L increase in [HCO3 ] concentration. If the change in PaCO2 is not within this range, then a mixed acid-base disturbance exists.

Normally, kidneys filter between 4000 and 5000 mEq of NaHCO3 per day and therefore should be able to rapidly excrete large quantities of NaHCO3.

The administration, or generation, of HCO3 cannot markedly increase the [HCO3] unless renal NaHCO3 excretion is decreased. Therefore, the answers to the following two questions provide insight to the pathogenesis of metabolic alkalosis and suggests the best therapeutic approach:

1. Where did the HCO3 originate? Was it generated endogenously or enter the body from some exogenous source?

2. Why has the kidney not efficiently excreted the HCO3?

First, in regard to question number 1, exogenous HCO3 can be acquired as NaHCO3 (or less commonly KHCO3), or the Na salt of an organic ion that represents potential HCO3 such as lactate, acetate, etc. (see above). The stomach and the kidney are the only two organs that can generate relatively large amounts of HCO3. These organs generate net HCO3 loads when the acid they secrete is removed from the body (ie, HCl generated by the stomach must be removed via N-G suction or vomiting and the kidney must excrete acids —as NH4Cl or titratable acid—into the urine).

Second, consider the possible answers to question number 2 (why has the kidney not efficiently excreted the HCO3?). They include the following: 1. General kidney dysfunction or failure. Although kidney failure usually generates a metabolic acidosis—because normally generated acids are retained—large loads of HCO3 can generate a metabolic alkalosis. For example, metabolic alkalosis can occur in dialysis patients who ingest baking soda (NaHCO3) or vomit.

2. The patient is volume depleted (whether a true deficit or an “effective” arterial volume deficit).

The proximal tubule will then avidly reabsorb filtered Na in exchange for protons – ie, NaHCO3 is reabsorbed. These patients are also invariably chloride depleted.

3. Potassium deficits and hypokalemia occur very commonly with metabolic alkalosis and this enhances renal tubule proton secretion (HCO3 reabsorption and generation).

4. Persistent distal tubule acid secretion (HCO3 reabsorption), usually due to the delivery of large

Na loads to this tubule segment, combined with unrestrained mineralocorticoid activity.

Vomiting or N-G suction causes an external loss of HCl and NaCl containing gastric fluid and generates endogenous HCO3. Metabolic alkalosis persists because of volume contraction and potassium deficiency (generated by renal losses of K). The key pathophysiologic mechanisms responsible for development and maintenance of gastric alkalosis are shown in Figure 3.

The other very common cause of metabolic alkalosis is chronic use of a thiazide and/or loop diuretic.

These two classes of diuretics reduce renal reabsorption of filtered NaCl and increase its delivery to more distal nephron tubule segments and the urine.

The ECF contracts and stimulates the renin/angiotensin/aldosterone axis. Persistent distal NaCl delivery, systemic volume contraction and Cl depletion combine with aldosterone activity to accelerate Na reabsorption in the collecting tubule.

At this site, Na reabsorption generally stimulates the secretion of protons and K and generates metabolic alkalosis and hypokalemia. Hypokalemia, ECF contraction and ongoing distal tubule Na delivery and reabsorption also maintains the alkalosis. Thus, the kidney is the site of both HCO3 generation and maintenance of the alkalosis in patients with diuretic induced metabolic alkalosis. Gastric fluid loss and diuretics probably account for more than 90% of the cases of clinically significant metabolic alkalosis.

The metabolic alkaloses can be classified on the basis of a spot urine chloride concentration53,54 (Table 7). Intravascular volume contraction (both true contraction associated with a low ECF volume as well as “effective” intravascular contraction as occurs in edema forming conditions such as cirrhosis and CHF) stimulates the kidneys to avidly reabsorb filtered Cl and generally reduces the excreted urine [Cl] to < 20 mEq/L. Thus, the urine [Cl] can act as an analog equivalent of the intravascular volume status as sensed by the kidney. The metabolic alkaloses with a low spot urine [Cl] are also called “Cl sensitive” because, in general, administration of NaCl expands the ECF and usually corrects the alkalosis. The metabolic alkalosis of vomiting, N-G suction, and diuretics have been discussed. ConACID-BASE AND ELECTROLYTES

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Table 7 Differential DX of Metabolic Alkalosis

Low Urine [C1] < 20 mEq/1

High Urine [C1]>20 mEq/1

Chloride 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 â&#x20AC;&#x153;Apparentâ&#x20AC;? mineralocorticoid excess states including licorice Liddle syndrome Low blood pressure

Bartter syndrome Gitelman syndrome Diuretics (remote)

Diuretics (recent) Severe K depletion

genital chloridorrhea is a disorder due to a defective Cl- HCO3 exchanger in the colon and ileum, and results in loss of HCl, NH4Cl and other potential HCl salts into the stool. The metabolic alkalosis generated by thiazide and loop diuretics may have either a low or high urine [Cl], depending on whether the diuretic effect is present (high) or has worn off (low). The pathophysiology of diuretic induced hypokalemic metabolic alkalosis is shown in Figure 4.

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EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

The metabolic alkaloses with high urine [Cl] (>20 mEq/l) generally have generation and maintenance mechanisms related to the combination of persistent mineralocorticoid stimulation and generous distal tubule delivery of NaCl, and are usually also hypokalemic. ECF expansion and hypertension characterize many of these disorders. The prototypical example of this group is primary hyperaldosteronism. Other mineralocorticoid excess states produce a similar constellation of clinical and biochem-

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 NaHCO3 loss leads to additional ECF volume contraction further reducing the GFR. Renin, angiotensin II and aldosterone levels all increase. The filtered HCO3– load falls in concert with GFR reduction. The NaHCO3, which is filtered, is avidly reabsorbed by the proximal and distal tubules. The additional reabsorption of NaHCO3 in the distal tubule is associated with H and K secretion. Saline expansion of the ECF should reverse most of the factors which drive HCO3– reabsorption and rapidly correct the alkalosis. KCl is usually also required to correct the K deficit that invariably exists.

ical findings. This group also includes mineralocorticoid independent acceleration of distal tubule Na+ reabsorption such as that caused by Liddle’s syndrome, which is the result of a genetic defect that causes the distal tubule epithelial sodium channels to remain open. These disorders are further discussed in the section on hypokalemia.

Recent diuretic use will cause a high urine [Cl] as discussed. The Bartter and Gitelman syndromes have many similarities to diuretic-induced metabolic alkalosis and hypokalemia since they are

due to inherited defects of the transporters inhibited by diuretics. These disorders are also further discussed in the hypokalemia section.

Generally, NaCl infusion does not correct metabolic alkaloses in the high urine [Cl] group — indeed the volume expansion, hypertension and metabolic disturbances of the mineralocorticoid excess group will worsen. Consequently, these disorders are also called the chloride unresponsive, or resistant, metabolic alkaloses.

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Figure 4 The pathophysiology of diuretic induced hypokalemic metabolic alkalosis

NaCl

Na+

Na+

Na+

H+

K+

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

Respiratory Acidosis

Respiratory acidosis results from alveolar hypoventilation.55-57 Thus, the primary disorder is an increase in PaCO2 (ie, hypercapnia). The reference range for PaCO2 is 36-44 mmHg. The acidemia produced by the high PaCO2 is compensated by an increase in [HCO3 ]. Acute respiratory acidosis causes a small increase [HCO3 ] which is mainly due to cellular buffering. Chronic respiratory acidosis produces a larger increase in [HCO3] by stimulating renal generation of HCO3. The expected level of compensation is shown in Table 1. Completely compensated chronic respiratory acidosis results in an arterial pH that is slightly below normal. If the [HCO3] is higher than the level predicted by these compensation ratios, this will result in a normal (or high) pH, and metabolic alkalosis probably coexists.

In acute respiratory acidosis, the PaCO2 level is >45 mm 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 pH because of a secondary or compensatory response by the kidneys. Thus, there is an associated elevation in the serum bicarbonate (ie, HCO3 - >30 mm Hg).

Acute respiratory acidosis results from a failure of ventilation. Causes include depression of the central respiratory center by cerebral disease or drugs, inability to ventilate adequately due to neuromuscular disease (eg, myasthenia gravis, amyotrophic lateral sclerosis, Guillain-BarrĂŠ syndrome, muscular

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

Chronic respiratory acidosis commonly occurs as a consequence of COPD with decreased responsiveness to hypoxia and hypercapnia, increased ventilation-perfusion mismatch leading to increased dead space ventilation, and decreased diaphragm function secondary to fatigue and hyperinflation.58 Other causes include chronic obesity hypoventilation syndrome (OHS; ie, Pickwickian syndrome),59 neuromuscular disorders such as amyotrophic lateral sclerosis,60 and severe restrictive ventilatory defects as observed in interstitial fibrosis and thoracic deformities.

Rules of Thumb for Expected Change in [HCO3-] in Respiratory Acidosis are: Acute respiratory acidosis HCO3 - increases 1 mEq/L for each 10-mm Hg rise in PaCO2.

Chronic respiratory acidosis HCO3- rises 3.5 mEq/L for each 10-mm Hg rise in PaCO2.

Table 8 Causes of Respiratory Acidosis

CNS Depression

Sedatives/CNS lesions Neuromuscular Disorders

Myopathies/Neuropathies Thoracic Cage Restriction

Kyphoscoliosis/Scleroderma

The expected compensatory responses for acute and chronic respiratory alkalosis are shown in Table 1.

The acute response, a small increase in HCO3, is due mainly to cell buffering processes and the chronic response, a greater increase in HCO3, is largely generated by renal excretion of HCO3 (or renal retention of additional acid). Chronic respiratory alkalosis is the best buffered acid base disturbance and usually results in a normal arterial pH. In acute respiratory alkalosis, the PaCO2 level is low but the pH is in the alkalemic range. In chronic respiratory alkalosis, the PaCO2 level is low, but the pH level is normal or near normal because of secondary or compensatory response by the kidneys.

Impaired Lung Motion

Pleural Effusion/Pneumothorax Acute Obstructive Lung Disease

Aspiration/Tumor/Bronchospasm Chronic Obstructive Lung Disease Miscellaneous

Ventilator Malfunction/CPR

Rules of Thumb for Expected Change in pH with Respiratory Acidosis Can Be Estimated with the Following 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 hyperventilation.60,61 The clinical consequence is a decreased PaCO2 level (hypocapnia) and alkalemia.

The major causes of respiratory alkalosis are shown in Table 9. Respiratory alkalosis is the most common acid-base abnormality observed in patients who are critically ill. It is a common finding in patients undergoing mechanical ventilation.

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Table 9 Causes of Respiratory Alkalosis

Anxiety

Rules of Thumb Expected Change in pH with Respiratory Alkalosis: Acute respiratory alkalosis Change in pH = 0.008 X (40 – PaCO2) Chronic respiratory alkalosis Change in pH = 0.017 X (40 – PaCO2)

CNS Disorders

CVA/Tumor/Infection Hormones

Progesterone/Catecholamines Drugs

Salicylates/Analeptics Sepsis/Endotoxemia Hyperthyroidism Hypoxia Pregnancy Cirrhosis Pulmonary Edema Lung Diseases

Restriction/Pulmonary Emboli/Pneumonia Ventilator Induced

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 mm Hg in the PaCO2 (Limit of compensation: [HCO3 -] = 12-20 mEq/L)

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Mixed Disorders/Acid-Base Disorders

Mixed acid-base disorders may generate extreme pH abnormalities (ie, metabolic and respiratory acidosis; metabolic and respiratory alkalosis) or normalize the pH (ie, respiratory acidosis and metabolic alkalosis).63 Certain clinical disorders such as cardiac arrest, septic shock, drug intoxication, ingestion of various poisons, and renal, respiratory, or hepatic failure are often associated with mixed acid-base disorders.

One group of mixed disorders are those due to either inadequate or excessive “compensation” for a primary acid-base disturbance. For example, when metabolic acidosis reduces the [HCO3 ], but the PaCO2 is higher than predicted (Table 1), then respiratory acidosis may co-exist. This often produces a very low pH. Mixed metabolic and respiratory acidosis occurs frequently when patients suffer a cardiopulmonary arrest. Conversely, if a patient with metabolic acidosis has a PaCO2 that is too low, then respiratory alkalosis may co-exist. This mixed disorder will tend to normalize the pH. This mixed disorder often occurs with sepsis because circulating endotoxin directly stimulates the respiratory center and hypotension leads to lactic acidosis. Salicylate poisoning also produces metabolic acidosis/respiratory alkalosis because toxic ASA levels directly stimulate respiration and simultaneously uncouple cellular oxidative metabolism, generating an AG acidosis.

An excessive, or inadequate, HCO3 response to a primary respiratory acid-base disorder is recognized similarly and also defines mixed acid-base disorders. Another group of mixed disorders are those recognized by a comparison of the [AG] and [HCO3].

Figure 5 Laboratory studies of a man with a history of chronic alcohol abuse that is admitted with decompensated cirrhosis and probable hepato-renal syndrome

AG

AG

HCO3

HCO3

Na

Na

AG HCO 3

Na

Cl

Cl

Cl

A

B

C

140 104 4.0 24

140 104 4.0 12

140 92 4.0 24

AG = 12

AG = 24

AG = 24 pH pO2 pCO2 HCO

A simple AG acidosis should quantitatively increase the [AG] by approximately the same magnitude as the fall in [HCO3]. This is sometimes called the Δ [AG]/Δ [HCO3]. When metabolic alkalosis complicates an AG metabolic acidosis this will increase the [HCO3], but not significantly affect the large AG. Therefore, whenever the [AG] increase exceeds the reduction in [HCO3] mixed metabolic acidosis/metabolic alkalosis probably exists. For example, Figure 5 shows the laboratory studies of a man with a history of chronic alcohol abuse that is admitted with decompensated cirrhosis and probable hepato-renal syndrome. Six months ago (panel A) his electrolytes were normal. On admission he has an AG metabolic acidosis (panel B) – toxins, uremic and lactic acidosis are considered. There is no osmolar gap (see below). Following admission, an NG tube is placed because of abdominal distension and vomiting. The electrolyte pattern shown in

-

7.53 70 30 mmHg 24 mEq/l

panel 3 then develops. The AG remains large but the [HCO3] has increased and the [Cl] has fallen.

This is due to the still persistent AG metabolic acidosis and a superimposed “gastric” metabolic alkalosis. The ABG shows he actually has a triple disturbance because his PaCO2 is too low for the concurrent [HCO3]. Respiratory alkalosis occurs commonly in patients with severe liver disease, probably as a result of high progesterone levels, which stimulate the CNS respiratory center, and hypoxia related to pulmonary A-V shunts and diaphragms pushed up by ascites.

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3. Water Spaces, Osmolality, and Sodium The normal distribution of water and electrolyte solutes and their contribution to extracellular fluid space (ECF) (and plasma) osmolality and intracellular fluid space (ICF) osmolality are shown in Figure 6. Normally Na salts account for almost the entire ECF osmolality. Osmotic gradients are not maintained across most cell membranes. When the osmolality increases or decreases in either the ECF or ICF, water will shift until the osmolality is

Normal distribution of water and electrolyte solutes and their contribution to ECF and ICF

Total Body Water (TBW) = 60% Weight (kg) 20%

Weight (kg) 40%

Osmolality= 290 mOsm/kg

Osmolality= 290 mOsm/kg

Na = 145 mEq/kg

K = 145 mEq/kg

ICF

In a 70-kg man, Total Body Water (TBW) will = 42 L; Extracellular Fluid (ECF) = 14 L; Intracellular Fluid (ICF) = 28 L. The ECF includes plasma (about 3.5 L), interstitial and transcellular water. The major solutes of ECF are sodium salts that are largely restricted to this compartment. The ECF, plasma or serum osmolality can be calculated as: Posm=2X[Na]. The intracellular solutes are primarily potassium salts. Most cell membranes have very high water permeability so that water quickly moves across them rapidly to eliminate any osmotic gradient. Therefore, assume the ECF and ICF osmolality are equal. When the osmolality of the ECF or the ICF is altered, a water shift quickly reestablishes the osmolal equality in these fluid spaces.

20

Equation 2: Posm = 2X[Na] + [BUN] + [Glucose] 2.8 18 (The constants 2.8 and 18 convert the urea and glucose concentrations from mg/100 mL to mmol/L).

Figure 6

ECF

equalized. When non-sodium solutes accumulate in the ECF, they contribute to osmolality in proportion to their molar concentrations. For example, high glucose and/or urea concentrations have the following effect:

EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

However, glucose and urea have very different effects on water distribution and the plasma [Na].

When glucose levels increase, this solute is largely restricted to the ECF. The attendant increase in ECF osmolality causes a rapid water shift from the ICF to the ECF. This water translocation simultaneously reduces the ECF, and increases the ICF, solute concentrations and osmolality. Water continues to shift until the ECF and ICF osmolalities are again equal.

Each 100 mg/100 mL increase in glucose concentration 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] by about 1.6 mEq/L. (Recent studies suggest the ratio may be closer to 2.4 mEq Na/100 mg% glucose, but the true value remains uncertain and ratios between 1.6 and 2.4 are acceptable.) Mannitol, which is often used to treat cerebral edema and is an osmotic diuretic, has molecular weight and compartmental distribution characteristics similar to glucose and therefore has similar effects on water distribution and sodium concentration.

In contrast urea, a smaller molecule rapidly penetrates cell membranes. When the urea concentration increases, its ICF and ECF concentrations rapidly equilibrate because urea enters cells rather than any water shift. This is not the case when urea levels increase or decrease very rapidly â&#x20AC;&#x201D; ie, with efficient hemodialysis. In that circumstance the very abrupt reduction in ECF urea may cause water to shift into cells and produce neurologic symptoms.

Other small solutes such as ethanol, methanol and ethylene glycol also readily penetrate cell membranes, and like urea they do not cause much water shift when their concentrations increase. Glycine

has membrane permeability properties intermediate between glucose and urea. Glycine-based solutions are used during TURP, endometrial ablation, and arthroscopic procedures. Occasionally, large quantities of glycine irrigant are accidentally infused intravenously, or are absorbed, and produce hyponatremia. This occurs for two reasons. First, the most commonly used glycine irrigation solutions are hypo-osmolal (approximately 200 mOsm/kg) so “free water” is infused. Second, to the extent glycine is restricted to the ECF, it will cause a water shift from the ICF similar to mannitol or glucose.

Some molecules that can accumulate in the ECF and raise plasma osmolality are not sodium salts, glucose or urea. Therefore, they are not included in equation 2. In such cases, the measured osmolality will exceed the calculated osmolality—this difference is the “osmolal gap.” Mannitol, glycine, ethanol, methanol, isopropanol, and ethylene glycol represent some solutes that can produce an osmolal gap.

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

Figure 7 When osmolality increases above 290 mOsm/kg, ADH is released and thirst is triggered

ADH

270

280

290

300

Plasma Osmolality

ADH causes relatively solute free water reabsorption (equilibration with the medullary osmolality) in the distal nephron and can increase urine osmolality to the 800-1200 mOsm/kg range. When plasma osmolality falls below 280 mOsm/kg ADH, secretion is inhibited. In the absence of ADH, maximally dilute urine (50-80 mOsm/kg) is normally excreted.

ADH is also released independently of plasma osmolality in response to systemic hypotension, a 7%-10% decrease in plasma volume, vomiting, or a reduced effective arterial blood volume, which often complicates hepatic cirrhosis or congestive heart failure. Non-osmotic factors such as dry mucous membranes, certain psychotropic medications, and high angiotensin levels can also increase thirst.

Hyponatremia

Hyponatremia is a common problem especially among hospitalized patients. The differential diagnosis and management has been extensively reviewed elsewhere.63-69 Hyponatremia may be associated with a normal, low or even high osmolality.

One classification scheme based on the plasma and urine osmolalities is shown in Table 10. Pseudohyponatremia is an artifactual reduction in sodium concentration due to very high lipid and/or protein concentrations. This is a “displacement” artifact which may occur when plasma contains much less than the normal 93% water. Pseudohyponatremia was a major artifact when flame photometer devices were used to measure [Na] and [K]. These instruments measured mEq/L of plasma. The artifact does not exist when electrolytes are analyzed with direct ion selective electrode methods, which actually measure mEq/L plasma water. However, indirect ion selective electrodes, which many facilities use, are susceptible to this artifact because a specific quantity of plasma is mixed with a diluent. The measurement of osmolality is not affected by water displacement artifacts and therefore reflects the concentration of sodium (and other solutes) in plasma water.

Hyponatremia with normal or increased osmolality can be generated by hyperglycemia or high mannitol concentrations (see above). Water moves from the ICF into the ECF, reducing the sodium concentration as described above. This form of hyponaACID-BASE AND ELECTROLYTES

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Table 10 Classification of Hyponatremia

Plasma Osmolality

Urine Osmolality

Appropriately Reduced

Low

High

Normal

High

PseudoHyponatremia

Translocational Hyponatremia

Tea and toast syndrome Beer drinker's potomania (See Table 11) Hyperlipidemia Hyperproteinemia Psychogenic water ingestion Kidney failure

tremia is called translocational hyponatremia (not pseudo-hyponatremiaâ&#x20AC;&#x201C;the sodium concentration is really low but the osmolality is not).

Hypo-osmolar hyponatremia indicates an excess of total body water relative to total body solute. The low ECF osmolality means that ICF osmolality is equally reduced. The most feared and dangerous effect of hypo-osmolar hyponatremia is cerebral edema which may develop when water shifts into the brain cells.

Otherwise normal individuals can excrete up to 18 liters of dilute urine each day. Consequently, they should be able to rapidly correct hyponatremia.

Although most patients with hypo-osmolar hyponatremia have high ADH levels and excrete inappropriately concentrated urine, four unusual hyponatremic conditions associated with dilute are shown in Table 10. The pathophysiology of beer drinkerâ&#x20AC;&#x2122;s hyponatremia and the tea and toast syndrome are similar and are related to very low levels of solute excretion.70 These patients generally eat very little protein and not much salt but drink large amounts of fluid. Therefore they do not excrete much urea or Na. Large volumes of even dilute urine still require solute to be excreted. The patients with psychogenic polydipsia may ingest enormous quantities of water very rapidly and overwhelm normal urine dilution mechanisms. Furthermore, as the [Na] is sharply reduced, the development of nausea can convert this condition to one with high ADH levels and concentrated urine and thereby exacerbate the problem. A low GFR will reduce the quantity of dilute urine a

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Hyperglycemia Mannitol Glycine

patient can excrete.

Much more frequently, hypo-osmolar hyponatremia will be associated with high ADH levels and inappropriately concentrated urine. Table 11 subdivides hypo-osmolar hyponatremia on the basis of ECF volume and effective intravascular volume status.

The history, physical examination (with special attention to BP, pulse and the presence of orthostatic changes, edema, ascites, rales, etc.), urine [Na] and [osmolality], and the plasma BUN and uric acid concentrations indicate the appropriate category and direct further W/U and Rx. Although ADH levels can be measured, the measurement rarely narrows the differential diagnosis because it is almost always increased in such patients.

Expansion of the volume-depleted hyponatremic patient with normal saline increases the GFR and the delivery of Na and fluid to the distal tubule and simultaneously inhibits ADH release. This produces a water diuresis that will correct the hyponatremia.

Patients with an expanded ECF but low EABV (CHF, cirrhosis, etc.) require treatment directed at the underlying organ dysfunction. Salt intake must usually be restricted in this group of patients. Water restriction is required when the [Na] is <125 mEq/L. Loop diuretics can sometimes be used to promote natruresis and to simultaneously reduce maximal renal concentrating capacity. Other treatment options are discussed below.

Many euvolemic hyponatremic patients have the syndrome of inappropriate antidiuretic hormone

Table 11 Evaluation of Hypo-osmolar Hyponatremia with High Urine Osmolality Volume Depleted

Euvolemic

Volume Expandeda

Low

Normal to high

Low

GI fluid losses Third spacing Adrenal insufficiency Renal salt-wasting

SIADH Hypothyroidism Glucocorticoid deficiency

Congestive heart failure Cirrhosis Nephrotic syndrome

<10 mEq/L

>10 mEq/L

<10 mEq/L

High

High

High

Plasma ADH

Elevated

Elevated

Elevated

BUN

Elevated

<10 mg/dL

Elevated

Serum uric acid

Elevated

<4 mg/dL

Elevated

ECF Volume Status Effective arterial volume Clinical syndromes

b

Biochemical Results Urine sodium Urine osmolality

c

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

secretion (SIADH).71,72 The major causes of SIADH are pulmonary diseases, central nervous system dysfunction, drugs, and carcinomas â&#x20AC;&#x201C; especially small cell lung cancer. Important pulmonary causes include pneumonia, tuberculosis, empyema, abscess, asthma, and COPD. CNS causes include head trauma, stroke, hydrocephalus, meningitis, and subarachnoid hemorrhage. Cancers that should be considered include, lung, brain, pancreas, prostate, and ovary. While the drug list is long, some key drugs to consider are analgesics (eg, narcotics, nonsteroidal anti-inflammatory drugs [NSAIDs]), antidepressants (eg, monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors [SSRIs]), antineoplastics (eg, vincristine, vinblastine, cyclophosphamide), neuroleptics (eg, phenothiazines), and oral hypoglycemics (eg, chlorpropamide, tolbutamide). Hypothyroidism and cortisol deficiency can also produce euvolemic hyponatremia and must be ruled out to establish a diagnosis of SIADH.

The treatment of hyponatremia is determined on the basis of its etiology, chronicity and associated symptoms.65,73-76 If the causative pathology cannot be eliminated then the [Na] itself may require therapy.

Chronic, moderately symptomatic hyponatremia (usually an outpatient disorder) is treated conservatively with the goal of correcting the [Na] over many days. Water restriction is the cornerstone of therapy for these patients. Adjunctive therapy includes the administration of loop diuretics, which reduce maximal renal concentrating capacity, combined with liberal NaCl intake. This strategy may reduce the requirement for severe water restriction.

Demeclocycline (300-600 mg PO bid) has been used to produce reversible nephrogenic diabetes insipidus, thereby promoting renal free water excretion. Oral urea (0.5-1.0 g/kg qd) is another option that may prove helpful for some patients. Urea acts as an osmotic diuretic and increases the excretion of electrolyte free water into the urine. A number of oral, non-peptide, ADH antagonists (aquaretics), are currently being studied and will probably soon ACID-BASE AND ELECTROLYTES

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be used to treat a variety of chronic hyponatremic conditions.77-79 Aggressive and very rapid correction of chronic hyponatremia can result in a catastrophic neurologic complication called central pontine and extra pontine myelinolysis, or the osmotic demyelination syndrome.74,75 Although this is often a fatal disorder, many more subtle cases are now also recognized on the basis of characteristic MRI changes and clinical findings. This syndrome is much less likely to occur if the rate of [Na] correction is limited to <0.5 mEq/hr and the absolute level of acute [Na] correction is kept <120 mEq/L. The underlying cause of this complication remains unknown but the pathophysiology may be related to the issue of “idiogenic” brain osmoles. Although most of the intracellular solute is comprised of electrolyte salts a small but very important component are organic molecules such as myoinositol, choline, glutamine and taurine. The concentrations of these molecules are actively regulated. Therefore, when hypertonicity develops (hyperglycemia, etc.) and water moves out of brain cells, the concentrations of these solutes increase to minimize brain cell shrinkage. Conversely, when hypo-osmolar hyponatremia causes brain cell swelling, the concentration of intracellular organic solutes falls and reduces the degree of swelling. This “auto-correction” of cell volume may contribute to the adverse effects of too rapid correction of chronic hyponatremia (or chronic hypernatremia).

Acute symptomatic hyponatremia is more commonly recognized in hospitalized patients.76 When the [Na] falls rapidly to <120 mEq/L, nausea, vomiting, irritability, mental confusion, and seizures may occur, and below 110 mEq/L, coma and death.

Otherwise healthy young women undergoing elective surgery may be especially susceptible to a unique form of severe, and often fatal, acute postoperative hyponatremia. Symptomatic acute hyponatremia requires prompt and aggressive therapy.

Hypertonic (3% = 517 mEq/l) saline may be infused to increase the [Na]. The quantity of NaCl required to increase the plasma [Na] is calculated with the following equation:

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EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

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 because changes in [Na] generate water shifts which equalize osmolality in the ECF and ICF. However, this calculation does not consider ongoing urinary, GI or insensible free water or electrolyte loss. Thus, it is a theoretical first approximation, and plasma electrolytes must be frequently monitored during such treatment, especially if the urine or GI output is large. Loop diuretics may also be used together with the hypertonic saline to increase free water excretion and to prevent ECF volume overload. A reasonable therapeutic goal for the partial correction of acute, symptomatic hyponatremia is to increase the [Na] 1-2 mEq/hr for several hours but then slow down the correction rate to achieve a change of about 15-20 mEq during the first 24 hours of Rx. Recently, the development of acute hyponatremia which occurs during and following marathon races has become better recognized and understood.80 Affected individuals are those who gain weight during the race apparently because they drink excessive amounts of fluids. Symptomatic hyponatremia in these individuals should be urgently treated with hypertonic saline. Participants should be encouraged to weigh themselves before and after practice runs and races, and attempt to adjust fluid intake to maintain a stable weight.

Hypernatremia

A plasma [Na] >145 mEq/L defines hypernatremia (and hyperosmolality).81-85 The overall incidence of hyponatremia ranges from 0.12%-3.5% in hospitalized patients. The geriatric population appears to be particularly at risk. Usually hypernatremia develops when fluids containing relatively low electrolyte concentration (<140 mEq/l) are lost from the body.

The losses may be renal, GI or insensible. Less commonly, hypernatremia is generated by the infusion of hypertonic NaCl or NaHCO3. Hypothalamic sensors detect the hypernatremia and produce signals which increase thirst and the synthesis and

Table 12 Causes of Hypernatremia

I. Increased Water Loss

A. Insensible 1. Burns 2. Fever/Heat 3. Mechanical Ventilation/Hyperventilation B. G.I. Loss 1. Vomiting/N-G Suction 2. Diarrhea C. Renal 1. Central DI 2. Nephrogenic DI 3. Osmotic Diuresis II. Reduced Water Intake

A. Hypothalamic Dysfunction 1. Reduced Thirst 2. Essential Hypernatremia?

B. Inability to Drink Water 1. Coma 2. Infant III. Hypertonic Infusions

A. Saline/NaHOC3 IV. Water Shift Out of ECF

A. Seizure/Extreme Exercise B. GI Bleeding with Intraluminal Protein Catabolism

release of ADH. Patients who have an isolated abnormal ADH response and/or an impaired renal response to ADH do not usually become markedly hypernatremic if their thirst mechanisms are intact and they have access to water. Therefore, persistent hypernatremia usually indicates the existence of an abnormal thirst mechanism or an inability to ingest sufficient quantities of water as well as abnormal ADH and/or renal concentration mechanisms.

Hypernatremia produces lethargy, weakness, and irritability and when severe can cause seizures, coma and death. The symptoms reflect the severity

and the rapidity of development of the hypernatremia. The causes of hypernatremia are shown in Table 12.

Hypernatremia should stimulate ADH and increase the U-[osm]; therefore, a reduced U-[osm] in a hypernatremic patient indicates malfunction of ADH/renal concentrating mechanisms (diabetes insipidus, DI).86-89 Etiologies include defective pituitary synthesis and/or release of ADH (central DI), accelerated peripheral ADH destruction (rare, occurring in some pregnant patients), or a defective renal response to ADH (nephrogenic DI). Some forms of central DI and nephrogenic DI are inherited. More commonly, DI is an acquired disorder.

Acquired central DI may be due to infiltrative or granulomatous diseases (such as sarcoidosis), trauma, neoplasm, neurosurgery, or severe hypoxia.

Patients with central DI rapidly respond to administration of ADH (or the synthetic analog DDAVP) by concentrating their urine. This response represents both a positive diagnostic test as well as appropriate therapy.

Acquired nephrogenic DI can be produced by several drugs (lithium, demeclocycline), chronic hypokalemia, hypercalcemia, sickle cell trait and disease, and amyloidosis.87-89 The loop diuretics also produce a renal concentrating defect as a result of a reduction in the medullary concentration gradients.

In contrast to patients with central DI, those with nephrogenic DI will not respond to ADH or DDAVP. Another cause of increased renal free water loss with an inadequate renal ADH response is osmotic diuresis. Hospitalized patients may develop hypernatremia as a result of a urea osmotic diuresis produced by high protein intake, GI bleeding (absorption of digested blood proteins) and/or glucocorticoid Rx (accelerated catabolism). Again, it must be stressed that hypernatremia should not occur if the patient is awake, can sense thirst and has access to water.

Hypernatremia usually represents an absolute water

ACID-BASE AND ELECTROLYTES

25

4. Disorders of Potassium Balance, Hypokalemia and Hyperkalemia deficit. Therefore, therapy requires water replacement and, if possible, correction or treatment of the underlying pathology.81,90 The water deficit can be calculated with the following formula: (— -1) Equation 4: Water Deficit = (0.6)(Weightkg) [Na] 140 Note that, as in the hyponatremia equation number 3 above, total body water is also used in this calculation.

Whenever possible, attempt to replace water deficits via the oral or gastric route. If intravenous replacement is required, D5%W or one-quarter NaCl can be utilized. Plasma glucose concentration must be carefully monitored when dextrose-containing fluids are administered because rapid infusion can generate hyperglycemic. This can produce a glucose osmotic diuresis that results in “chasing one’s tail,” as urine output progressively increases and the infusion rate of D5%W is increased to match output. About 50% of the water deficit should be replaced in the first 24 hours of Rx. Overly rapid water replacement can produce cerebral edema.

Always evaluate and address the hypernatremic patient’s ECF volume status (and effective arterial volume). Patients who are volume depleted (those with hypotension, orthostatic fall in blood pressure, etc.) may require immediate ECF expansion. In these patients, isotonic NaCl may be the appropriate initial fluid. The water deficit should be addressed only after ECF volume has been restored. Conversely, some hypernatremic patients may be volume overloaded (for example, when hypertonic salts infusion is the etiology of the hypernatremic state) and may then require diuretic therapy as well as water infusion.

Disorders of potassium metabolism are common, both in hospitalized and ambulatory patients and as a primary manifestation of kidney disease as well as reflecting 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 compartment. The ratio of intracellular to extracellular potassium is tightly regulated because this ratio influences the cellular membrane potential. The concentration gradient of [K] is maintained by the sodium- and potassium-activated adenosine triphosphatase (Na+/K+–ATPase) pump. Small changes in the extracellular potassium level can have profound effects on the function of the cardiovascular and neuromuscular systems. The normal potassium level is 3.5-5.0 mEq/L, and total body potassium stores are approximately 50 mEq/kg (3500 mEq in a 70-kg person). Hyperkalemia is defined as a K> 5.0 -5.5 mEq/L (depending on the biochemistry laboratory’s reference range).

The intracellular fluid (ICF) potassium concentration [K] is between 120 and 150 mEq/L and K is the principal intracellular cation. The [K] in the extracellular fluid (ECF) and in plasma is much lower – in the 3.5-5.0 mEq/L range. This very large transcellular gradient is the result of Na/K ATPase pumps which actively transport K across cell membranes and the ionic permeability characteristics of these membranes. The 30-40 fold transmembrane [K] gradient is the principal determinant of the –90 mV transcellular resting potential gradient (cell interior negative) (Figure 8). Normal cell function requires maintenance of the ECF [K] within a relatively narrow range and this is particularly important for excitable cells such as myocytes and neurons. Most of the clinical manifestations of K disorders are due to pathophysiologic effects on these cells.

Potassium intakes vary widely – a typical Western diet provides between 50 and 100 mEq K per day.

Under normal, steady state conditions, an equal amount is excreted, mainly in urine (about 90%), and to a lesser extent in stool (5%-10%) and sweat (1%-10%). Rapid transcellular shifts regulate plasma [K] and prevent extreme hyperkalemia after

26

EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Figure 8 Transcellular ion movement

Na [K] 140 mEq/L

Na

+

3 Na H

Insulin ?

Ca

[K] 4 mEq/L + AT P

+

- 90 mV

+

K

2K

+

+

++

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

each meal. Normal postprandial insulin secretion stimulates cellular uptake of both K and glucose.

Insulin release with meals is primarily related to increased plasma glucose, but increasing [K] also directly stimulates release of insulin from β-cells in the pancreatic islets. Therefore, insulin deficiency and/or resistance increase plasma [K]. Epinephrine and norepinephrine also rapidly regulate transcellular K balance and play an important role during and following vigorous exercise. Hyperadrenergic states, such as alcohol withdrawal, hyperthyroidism, tocolytic therapy and theophylline poisoning often generate hypokalemia due to translocation of K from the ECF into cells.

Metabolic alkalosis stimulates cellular K uptake, while some forms of hyperchloremic and other inorganic (mineral) acidoses enhance movement of K out of cells. However, the common organic metabolic acidoses (lactic and ketoacidosis) do not directly generate a transcellular K shift. Respiratory acid-base abnormalities generally have minor effects. Although it had been assumed that the alkalemia produced by respiratory alkalosis would

move K into cells, the opposite has been found, ie, a small increase in plasma [K] due to associated Îą-adrenergic stimulation. Respiratory acidosis increases plasma [K] slightly. Hyperosmotic conditions that shift fluid out of cells are an important cause of K translocation to the ECF. Finally, hypokalemia per se moves K from the intra- to the extracellular space.

Pathogenesis

Potassium absorption in the small intestine is not specifically controlled. Although colonic epithelial cells can increase K secretion in response to chronic hyperkalemia (patients with chronic kidney disease), the net effect on K balance is minor. Although the [K] of stool water may increase, the water content of formed stool is small â&#x20AC;&#x201C; thus absent diarrhea, total stool K excretion remains low. Therefore ingested K is largely absorbed.

Potassium excretion is principally into the urine and the main regulator of body K balance is the kidney.

Potassium is freely filtered (600-800 mEq/d) and

ACID-BASE AND ELECTROLYTES

27

Figure 9 K handling by the cortical collecting duct

CD 2K

Na Na

PC

ATP

3Na

A

Aldo

K

Aldosterone has multiple effects on electrolyte transport in the cortical collecting duct (CCD). Sodium (Na) absorption increases through stimulation of basolateral Na/K ATPase activity and increased number and “open state” of the luminal Na channel (ENaC). The influx of Na causes a negative charge to develop within the lumen. This stimulates K (and H) secretion into the lumen down electrical and chemical gradients.

Volume contracted states result in little Na delivery to the CCD (due to avid, more proximal absorption) so that K (and H) secretion is slight despite high aldosterone levels. Volume expanded states enhance delivery of Na to the CCD and cause physiologically adequate levels of K (and H) secretion despite suppressed aldosterone levels.

then largely reabsorbed in the proximal tubule and thick ascending loop of Henle. Only about 10%15% of filtered K is delivered to the cortical collecting duct (CCD) and major regulation of K excretion occurs in this segment. Sodium (Na) reabsorption and K (and H) secretion in the CCD is determined by the amount of delivered Na, the “absorbability” of its accompanying anion, and the activity of the mineralocorticoid aldosterone. CCD Na absorption occurs across epithelial Na channels (ENaC) on the luminal surface of the predominant (principal) cells 28

EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

in this segment. Sodium is absorbed more readily than most anions (Cl, HCO3 , and others) and this generates a negative charge within the lumen that enhances the secretion of K and H (Figure 9).

Aldosterone regulates the rate of Na absorption through these channels at multiple levels. It increases energy (ATP) generation and the activity of Na-K ATPase pumps, and it also increases the number and “open state” of the ENaC channels themselves.

Normally, an inverse relationship exists between aldosterone activity and CCD Na delivery. High salt intakes expand ECF volume and increase distal delivery and excretion of Na but simultaneously depress renin and aldosterone levels. Increased distal Na delivery counterbalances low aldosterone activity with a net effect of normal CCD K and H secretion and excretion. Conversely, low salt intakes contract the ECF, stimulating renin and aldosterone levels and markedly reducing distal CCD Na delivery and excretion. Under these conditions, reduced CCD Na delivery is associated with increased aldosterone activity. Once again, normal CCD K and H secretion and excretion is maintained. This physiologic reciprocal interplay between aldosterone activity and distal Na delivery results in maintenance of both volume and electrolyte homeostasis.

Pathophysiologic conditions exist when high CCD Na delivery combines with high aldosterone activity, or reduced CCD Na delivery coexists with low aldosterone activity. In the first circumstance, absolute CCD Na absorption increases markedly and generates major and excessive K and H secretion.

Hypokalemia and metabolic alkalosis result. Conversely, reduced distal Na delivery and aldosterone levels results in very little CCD Na reabsorption and very low rates of K and H secretion. Hyperkalemia and metabolic acidosis result. The pathologic conditions which combine high CCD Na delivery and high aldosterone levels include primary hyperaldosteronism, administration of thiazide and/or loop diuretics, and excretion of Na with anions such as ketoacids (with DKA) or hippurate. Reduced Na delivery to the CCD combines with low aldosterone activity in some forms of hyporeninemic aldosteronism and with the administration of aldosterone antagonists to patients with reduced “effective”

Figure 10 Cell depolarization and hyperpolarization depends on extracellular potassium

mVolts

normal

depolarized

0 -30 Caâ&#x2020;&#x2018;

-60

TP Caâ&#x2020;&#x201C;

-90

TP RP

TP

RP RP

-120 Normal

Hyperkalemia

Hypokalemia

An action potential is generated when the cell depolarizes from its resting potential (RP) to the threshold potential (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 by hypokalemia or hyperkalemia is clinically similar. Calcium raises the TP, ameliorating the effects of hyperkalemia, while hypocalcemia has the opposite effect.

arterial volume such as hepatic cirrhosis or congestive heart failure.

Nerve and muscle cells are especially sensitive to changes in transcellular voltage and therefore most affected by hypo- or hyperkalemia. Figure 10 shows how either condition can cause muscle weakness.

unexcitable. Severe K depletion may cause rhabdomyolysis and paralytic ileus. The renal manifestations of hypokalemia include metabolic alkalosis, increased ammonia generation and excretion, and nephrogenic diabetes insipidus. Chronic hypokalemia also causes structural abnormalities of the kidney including cyst formation, and has also been implicated in the development of hypertension.

Hypokalemia increases the resting potential across the myocyte membrane (it becomes more negative) making the cell less sensitive to excitation. Severe hypokalemia causes a hyperpolarization block and flaccid paralysis. Following depolarization, the cell is unable to adequately repolarize and becomes

Hyperkalemia reduces the membrane resting potentialâ&#x20AC;&#x201D;it becomes less negative. Severe hyperkalemia causes a depolarization block and flaccid paralysis.

Clinical manifestations include fatigue, myalgia, and muscle weakness (especially lower extremity), hyporeflexia, paresthesias, muscle cramps, and

Clinical Manifestations

ACID-BASE AND ELECTROLYTES

29

Figure 11 Electrocardiographic tracings with hypokalemia and hyperkalemia

Hyperkalemia initially causes peaking (â&#x20AC;&#x153;tentingâ&#x20AC;?) of T waves and then progresses to widening of the QRS and PR intervals, sinus bradycardia and arrest, AV-block, fusion of QRS with T (sine-wave appearance), idioventricular rhythm, and finally ventricular tachycardia and fibrillation, and asystole.

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

ECG changes and cardiac arrhythmia (Figure 11).

Muscle weakness may progress to ascending paralysis, 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 contributions of K shift vs. change in total body K, and (d.) coexisting abnormalities which either potentiate or blunt the [K] effects, including underlying heart disease, drugs (digoxin, antiarrhythmic agents), hypo- or hypercalcemia, cardiac pacing devices, and others.

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EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

The resting membrane potential is determined by the ratio of intracellular and extracellular [K] (Ki/Ke). An acute K shift into or from the intracellular space alters intracellular [K] only minimally since it is quantitatively so large; about 3000 mEq or 98% of total body K is within cells. However, the effect on the extracellular concentration can be dramatic, because the quantity of extracellular K is only about 60 mEq. Therefore, acute K shifts markedly affect the Ki/Ke ratio and can produce profound cellular hyper- or depolarization with muscular, neurological, and cardiac symptoms (Figure 12). In contrast, states of chronic K depletion, or loading, affect both intra- and extracellular

Figure 12

Table 13

K distribution with intracellular K shift vs. K depletion

Causes of Hypokalemia

Normal

[K] = 120 mEq/L

Renal Losses

[K] = 4 .0 mEq/L K i/K e : 30

Total Body K depletion

[K] = 90 mEq/L

[K] = 2 .0 mEq/L K i/K e : 45

K shifts into cells

[K] = 122 mEq/L

[K] = 2 .0 mEq/L K i/K e : 61

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

Total body K depletion reduces both intracellular and extracellular [K]. The Ki/Ke ratio increases and the cell becomes hyperpolarized.

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

K levels and may have a smaller effect on Ki/Ke and thereby generate fewer and less severe clinical manifestations. Furthermore, K shifts produce very rapid changes in plasma [K]; thus shift effects are

Diuretics Vomiting, NG suction Osmotic diuresis (especially uncontrolled diabetes) Drugs Excretion of non-reabsorbable anions (Penicillin) Exogenous mineralocorticoids Inhibitors of 11 -hydroxysteroid dehydrogenase Toxic reactions (aminoglycosides, cis-platinum) Primary hyperaldosteronism Liddle syndrome Cushing disease Renal tubular acidosis type I and type II (when treated with NaHCO3) Bartter and Gitelman syndrome Magnesium deficiency Extrarenal Losses Diarrhea, laxatives Ileostomy Ureteral diversion into colon Transcellular Shift

Insulin β 2-adrenergic agonists Thyrotoxicosis Periodic paralysis Drugs â&#x20AC;&#x201C; barium, cesium, chloroquine Rapid expansion of cell mass Anabolic states, Rx of pernicious anemia

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

Comorbid illnesses such as coronary heart disease can amplify the clinical importance of potassium disorders by increasing the risk of serious arrhythmia. Hyperkalemic effects on cardiac conduction are well documented and are the principal reason it constitutes a medical emergency (Figure 11). While hypokalemia has well defined EKG effects, its car-

ACID-BASE AND ELECTROLYTES

31

A serum [K] below 3.5 mEq/L defines hypokalemia, and Table 13 lists some of the causes and clinical conditions associated with this disorder.95,96 The most common causes are thiazide or loop diuretic use, vomiting/nasogastric suction, and diarrhea (or laxatives). These etiologies are usually readily apparent unless the patient is covertly using drugs or vomiting. A more elaborate evaluation becomes necessary when the cause is not apparent. It is then important to determine if an intracellular shift has occurred and/or whether excessive renal or gastrointestinal K losses (sometimes combined with reduced intake) accounts for the hypokalemia.

Hypokalemic periodic paralysis may have a dramatic clinical presentation. At least two distinct subtypes of this syndrome have been characterized: a rare familial form, usually due to an autosomal dominant mutation affecting a calcium channel; and a relatively more common form associated with hyperthyroidism. Hyperthyroid periodic paralysis is especially prevalent among young men of Asian (or less often Hispanic) ancestry. They typically present with profound acute muscle paralysis affecting mainly proximal limb muscle groups with sparing of ocular and respiratory muscles. Deep tendon reflexes are generally absent. Paralysis often develops after a period of exercise (increased β-agonist activity) or following carbohydrate ingestion (increased insulin). Clinical signs and symptoms of thyrotoxicosis may be subtle. A prior history of recurrent episodes of weaknesses is common.

Plasma [K] is often below 2 mEq/L, and both hypophosphatemia and mild hypomagnesemia may occur. Acute treatment with exogenous K salts is appropriate, but rebound hyperkalemia often develops since total body K is normal. Treatment with β-blockers such as propranolol is helpful and correction of the hyperthyroid state is usually curative.

The pathophysiology of this disorder includes the effect of thyroid hormone on the Na/K ATPase, an exaggerated insulin response, the hyperadrenergic state of hyperthyroidism, genetic and racial predisposition, and probably inherited mutations of muscle ion transport which remain subclinical until magnified by the hyperthyroid state.

Hypokalemia due to transcellular K shifts may generate impressive clinical presentations. This occurs with several forms of hypokalemic periodic paralysis, administration of β2-agonists to treat obstructive lung disease or premature labor, theophylline poisoning and conditions that enhance beta-agonist activity such as hyperthyroidism and hypothermia.

Insulin drives K into cells and promotes hypokalemia. Barium poisoning, cesium, and chloroquine overdose block K exit from cells and cause K accumulation within the ICF and profound hypokalemia. Another cause of intracellular K accumulation is rapid expansion of cell mass with refeeding after prolonged starvation, into rapidly growing tumors, and when severe pernicious anemia is treated with vitamin B12.

Reduced total body K stores may be due to gastrointestinal loss, renal loss, or both. The 24-hour urine potassium excretion helps define the etiology. A patient with hypokalemia should excrete less than 20 to 30 mEq K per day. If this is found, renal losses are generally excluded and either gastrointestinal losses 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 conservation. For example, although diuretics cause excess renal K losses, the urine K excretion falls to the low range when the diuretic effect wears off. Similarly, vomiting or NG suction cause excess renal K loss during the active phase but in the “equilibrium phase” the K excretion becomes very low.

diac risk for otherwise healthy patients are less well established. However, patients with acute myocardial infarction and those treated with digoxin do have an increased risk of dangerous ectopy.

Calcium has important effects on myocyte depolarization. Hypocalcaemia reduces the depolarization threshold potential and renders the cardiac myocyte more excitable. Conversely, hypercalcemia reduces membrane excitability by increasing the depolarization threshold (Figure 10). These calcium related depolarization threshold shifts can reverse hyperkalemic cardiac toxicity. Coexisting hyperkalemia and hypocalcaemia is a particularly pernicious combination and is common in patients with severe kidney failure.

Hypokalemia

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EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

If a 24-hour urine collection cannot be accomplished, an alternative useful measurement is the trans-tubular [K] gradient, or TTKG. This calculation attempts to correct the urinary [K] for the increase generated by distal water reabsorption after the tubular fluid has exited the CCD. In theory, the TTKG approximates the [K] gradient in the cortical collecting 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 appropriate renal K conservation in a patient with hypokalemia.

However, the TTKG cannot be interpreted if urine osmolality is less than plasma osmolality, or when distal nephron sodium delivery is very low, ie, urine sodium below 20 mEq/L. Assessment of a patient’s volume status and blood pressure provides additional diagnostic clues.

Patients with hypokalemia, volume expansion and hypertension may have primary or exogenous hypermineralocorticoidism. A high plasma aldosterone level with a simultaneous low plasma renin activity indicates autonomous aldosterone secretion. An aldosterone/PRA ratio >30 (and an aldosterone level >20 ng/dL) also suggests primary hyperaldosteronism. Primary hyperaldosteronism may be due to a unilateral aldosterone secreting adenoma (Conn syndrome), bilateral adrenal hyperplasia (idiopathic hyperaldosteronism), or rarely, adrenal cancer. Radiological evaluation often permits determination of the specific syndrome, but adrenal vein sampling is necessary in some cases.

Another cause of primary hyperaldosteronism is glucocorticoid-remediable aldosteronism. This rare disorder is due to an autosomal dominant mutation which causes ACTH to stimulate the synthesis and secretion of aldosterone. Glucocorticoids suppress ACTH and reverse the clinical and biochemical abnormalities of this disorder. Pseudohyperaldosteronism is characterized by the biochemical and clinical features of an autonomous mineralocorticoid excess state but with suppressed aldosterone levels. It may be due to secretion of a non-aldosterone mineralocorticoid.

Examples include adrenal tumors secreting the mineralocorticoid deoxycorticosterone (DOC), some forms of congenital adrenal hyperplasia (17- and 11-hydroxylase deficiency), and certain conditions which cause glucocorticoids to develop potent mineralocorticoid properties. Both mineralocorticoids and glucocorticoids can activate the mineralocorticoid receptor. However, selectivity is achieved by virtue of the enzyme 11 -hydroxysteroid dehydrogenase type 2. This enzyme exists in high concentration in most mineralocorticoid receptor rich tissues where it inactivates the glucocorticoids (but not mineralocorticoids). In the absence of this enzyme, physiologic levels of glucocorticoids will produce a mineralocorticoid excess state. The enzyme is congenitally absent or defective in patients with the “apparent mineralocorticoid excess or (AME)” syndrome who exhibit a hyperaldosterone-like disorder of hypokalemia, metabolic alkalosis, volume expansion, and hypertension, but low aldosterone levels. The enzyme 11 -hydroxysteroid dehydrogenase type 2 is also antagonized by glycyrrhetinic acid, the active ingredient in true licorice, several decongestants available in Europe, and some brands of chewing tobacco. Excessive use results in the same clinical presentation. Also, this enzyme may be overwhelmed when cortisol levels are markedly elevated in some patients with Cushing syndrome, in particular the form due to ectopic ACTH secretion.

Liddle syndrome also has features of a mineralocorticoid excess state but all known mineralocorticoids are reduced. The disorder is due to an autosomal dominant mutation which causes the epithelial Na channels (ENaC) in the collecting duct to remain persistently “open” in the absence of mineralocorticoid stimulation. Clinical and biochemical findings mimic a non-aldosterone mineralocorticoid excess state—volume expansion, hypertension, hypokalemia, metabolic alkalosis, and suppressed levels of renin and aldosterone.

Elevated aldosterone levels secondary to stimulation by high renin levels is called secondary hyperaldosteronism. It occurs in patients with renal artery stenosis as well as in some patients with markedly elevated blood pressure whose major renal arteries are anatomically normal (but blood flow in smaller renal vessels is probably reduced). Rare renin ACID-BASE AND ELECTROLYTES

33

secreting tumors have been described. They result in severe secondary hyperaldosteronism, hypertension and hypokalemia. These pathologic forms of secondary hyperaldosteronism are all associated with volume expansion and hypertension.

More commonly, secondary hyperaldosteronism is associated with (and due to) reduced ECF volume and hypotension. This may be due to most diuretics and several renal tubular disorders. Combining high distal renal tubule Na delivery with high aldosterone activity leads to renal K wasting, hypokalemia, and variable degrees of metabolic alkalosis. This is a common effect of loop or thiazide diuretics (acetazolamide will also produce hypokalemia and metabolic acidosis, due to the excretion of sodium bicarbonate). Combining a loop and thiazide diuretic generates an especially powerful kaliuretic response and should be used judiciously.

Two classes of autosomal recessive genetic disorders mimic the effects of thiazide or loop diuretics.97-100 Gitelman syndrome is due to a defect of the thiazide sensitive NaCl transporter in the early distal renal tubule.101 Bartter syndrome is caused by one of several generic mutations that impair the function of the Na-K-2Cl transporter in the thick ascending limb of Henle that is also inhibited by loop diuretics.102 Both are characterized by similar clinical and biochemical abnormalities: volume contraction, hypotension, high levels of urinary prostaglandins, renal K and NaCl wasting, and high renin and aldosterone levels. A major distinguishing characteristic is the reduced urine calcium excretion and severe hypomagnesemia seen with Gitelman syndrome but hypercalciuria in those with Bartter syndrome. It is virtually impossible to discern these patients from those using these diuretics surreptitiously, unless urine is assayed for these substances and/or specific genetic mutations are identified.

While Bartter syndrome is usually diagnosed early in life, the phenotype of Gitelman syndrome is often subclinical and first recognized in adults.

In the intensive care unit, osmotic diuresis is a relatively common cause of hypokalemia and hypernatremia. The combination of a catabolic state, parenteral nutrition, or tube feeding, +/- exogenous

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EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

glucocorticoids, results in hyperglycemia and/or high urea levels. The glucose and/or urea diuresis also delivers sodium to an actively reabsorbing distal tubule where Na is effectively exchanged for K and H. Mannitol infusions can produce a similar syndrome. Aminoglycoside antibiotics, amphotericin B, cisplatin, and foscarnet are drugs that can increase distal tubule Na delivery and promote K secretion and excretion. Some also cause tubular damage that leads to magnesium wasting and hypomagnesemia which itself promotes kaliuresis.

Patients with acute myeloid or lymphoblastic leukemia may develop proximal or distal tubule dysfunction which generates hypokalemia, metabolic acidosis, hyponatremia, hypocalcemia, hypophosphatemia, and hypomagnesemia.

Sometimes Na is delivered to the distal nephron with a poorly reabsorbed non chloride anion. If the Na is reabsorbed, this accelerates K and H secretion.

The problem is magnified when ECF contraction increases renin and aldosterone levels (Figure 9).

This occurs with high doses of Na-penicillin, diabetic ketoacidosis (Na-β-hydroxybutyrate), with inhalation of toluene glue (Na-hippurate), and with metabolic alkalosis due to vomiting or nasogastric suction (NaHCO3). When patients with proximal renal tubular acidosis (RTA type 2) are treated with exogenous bicarbonate salts, they excrete NaHCO3 and develop hypokalemia. Although patients with classic distal tubular acidosis (RTA type 1) also manifest accelerated distal tubule Na-K exchange and hypokalemia, their response to NaHCO3 therapy is distinctly different. With that disorder, exogenous HCO3 reduces renal excretion and ameliorates hypokalemiaâ&#x20AC;&#x201D;in part as a result of ECF volume expansion.

The normal colon secretes K and absorbs Cl in exchange for HCO3. If urine enters the colonic lumen, Cl is removed while K and HCO3 are secreted. This results in hypokalemia and a hyperchloremic metabolic acidosis. Clinical situations in which this occurs include ureteral implants into the sigmoid colon and interposition of colon segments between the kidney and bladder.

Table 14 Oral Potassium Salts

KCL KCl Elixir KCl Extended Release Tablets

15 mEq/20 mL 8-10 mEq/tab

Micro-K®, K-Lor ®, Slow-K®, K-Dur ®, Kaon-Cl®, Klor-Con ®, Klotrix ®.

KCl Powder

20-25 mEq/pk

Kay Ciel ®, Klor-Con

KCl Solution

20 mEq/15 mL

Kchlor ®, Kay Ciel, Kaon-Cl

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 /Tablets

6.7mEq/5 mL 2- 5 mEq/tablet

Kaon® Elixir, Glu-K®

KHCO3/Organic Anion Mixtures

15 mEq/5 mL 50 mEq/tab

Tri-K®, K-Lyte DS

KHCO3 & K Organic Salts

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

Treatment of Hypokalemia

The treatment of hypokalemia depends on several factors. These include the underlying etiology and clinical setting (age of the patient, other abnormalities such as acid-base perturbations), the rapidity in the development of the hypokaelmia, and the presence or absence of cardiac disease.93-96,103,104 It is best to anticipate and whenever possible prevent the development of hypokalemia. Combined administration of loop and thiazide diuretics often causes major renal K excretion. Adding an aldosterone antagonist, such as spironolactone or eplerenone, or a distal tubule Na channel blocker such as amiloride or 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 part by reducing aldosterone levels. Exogenous potassium replacement is obviously indicated when K loss has depleted total K stores. However, exogenous K may also be required to treat acute clinical manifestations caused by major K shifts into cells.

Under those conditions, replacement must be very cautious since total body K stores are normal and rebound hyperkalemia may occur after the stimulus responsible for the shift has resolved. Specific treatments are available for some of these disorders (eg, β-blockers or treatment of hyperthyroidism for various forms of periodic paralysis).

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Whenever possible, K should be replenished via the oral 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 compared to caloric content. Further, food K is largely comprised of organic salts, which may be less effective, especially when metabolic alkalosis also exists (see below).

Major K deficits require oral or intravenous supplementation. In general, a plasma [K] between 3-3.5 mEq/L represents a K deficit of 200 to 400 mEq, while plasma [K] between 2.0-3.0 mEq/L requires 400-800 mEq. Potassium replacement salts are divided into two broad classes: potassium chloride (KCl) and potassium bicarbonate (KHCO3). Organic K salts are metabolized, mole for mole, to KHCO3 and are therefore included with the second group. Alkalizing K salts are more palatable and better tolerated than oral KCl. However, KHCO3 and the organic K salts should not be used to treat hypokalemia associated with metabolic alkalosis. Under these conditions, alkalinizing K salts are poorly retained and less effectively reverse the K deficit (and metabolic alkalosis). KCl is the most appropriate and effective replacement for K deficits associated with metabolic alkalosis. Conversely, alkalinizing K salts (KHCO3, K-citrate, K-acetate, K-gluconate) are indicated to treat hypokalemia associated with metabolic acidosis, such as RTA, or chronic diarrhea conditions. Table 14 lists the various forms of oral potassium salts.

When the oral route cannot be used, or total K deficits are severe, intravenous replacement becomes necessary.103,104 Parenteral fluid KCl concentrations of 20-40 mEq/liter are generally well tolerated. KCl concentrations of 60 mEq/L and greater produce local pain and may result in peripheral vein necrosis. When large volumes of intravenous fluid cannot be given, solutions with K concentrations of up to 200 mEq/L (20 mEq in 100 ml of isotonic saline) may be administered via a central vein. Under these circumstances, the K administration rate should not exceed 10-20 mEq per hour. In general, central venous administration of these concentrated K solutions should be accomplished with 36

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a rate-controlling pump. The composition of intravenous fluid must also be considered, because dextrose increases insulin and shifts K into cells, thereby potentially worsening hypokalemia!

Administration of NaHCO3 has the same potential effect.

Hyperkalemia

Hyperkalemia is a common problem and when severe can be life-threatening.91-94 The causes of hyperkalemia, defined as a serum [K] above 5.0 mEq/L, are listed in Table 15. Acute or chronic renal failure is by far the most common cause or major contributor to hyperkalemia. When the kidney and the renin-angiotensin-aldosterone axis function normally, the plasma [K] is maintained in the normal range despite wide extremes in intake. Therefore, persistent or chronic hyperkalemia almost always indicates impaired renal excretion, either due to intrinsic pathology or inadequate endocrine signaling. However, rapid K shifts from cells to the ECF can generate acute hyperkalemia, despite normal renal and endocrine function. Such â&#x20AC;&#x153;shiftâ&#x20AC;? hyperkalemia is exacerbated by coexistent renal dysfunction and/or hormonal derangements.

Pseudohyperkalemia is an artifact related to the collection and/or preparation of the specimen or an artifact of the K measurement procedure itself.105 It is generally a diagnosis of exclusion and should not delay prompt intervention. Potential causes include: repeated fist clenching during phlebotomy, hemolysis due to traumatic venipuncture, particularly with small gauge needles, delayed processing of the specimen (especially when placed on ice), K release from white blood cells in severe leukocytosis (usually >100 x 103/microliters) or from platelets with extreme thrombocytosis (usually >1,000 x 103/ÎźL),106 and prolonged tourniquet application in some individuals. Some patients inherit a propensity to leak K from red blood cells ex vivo due to a membrane defect. Measurement of plasma rather than serum [K] may eliminate some of these artifacts.

A transcellular shift of K from the intra- to the extracellular space is a common cause of acute hyperkalemia. It is often due to direct damage or destruction of cell membranes. Examples include tumor

Table 15 Causes of Hyperkalemia

Renal Retention

Acute renal failure Chronic renal failure (especially interstitial renal disease) 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)

lysis related to chemotherapy, acute intravascular hemolysis due to infection, transfusion reaction or severe hemolytic anemia, hemolysis developing within a large hematoma, extensive burns, rhabdomyolysis, and with intestinal ischemia/necrosis.

Excessive K efflux may also develop across intact cell membranes as a result of certain drugs, metabolic disorders and inherited diseases. Drugs that block beta-agonist activity favor K efflux from cells.107 The muscle relaxant succinylcholine consistently promotes cellular K efflux and many cases of profound hyperkalemia have been reported, especially in patients with an underlying neuromuscular

or renal disorder. A pharmacologic dose of digitalis inhibits Na/K ATPase in cardiac myocytes, but toxic levels inhibit these pumps in systemic muscle cells and may thereby generate extreme hyperkalemia.

Potassium translocation also occurs with insulin deficiency or resistance, certain hyperosmolar conditions such as hyperglycemia, and some forms of inorganic (usually hyperchloremic) metabolic acidoses. It was previously assumed that acidemia, especially with metabolic acidosis, caused protons to move into cells with reciprocal K efflux. However, organic metabolic acidoses, such as keto- and lactic acidosis, do not generate K shifts. Although hyperkalemia may develop in these patients, it is usually the result of a pathophysiological process and not the acidemia per se. Hyperkalemia does occur frequently with lactic acidosis, but is principally due to tissue ischemia/necrosis and concomitant renal insufficiency. Hyperkalemia, also a common finding with diabetic ketoacidosis, is due to the combination of insulin deficiency, hyperosmolarity (hyperglycemia), and decreased renal perfusion, rather than acidemia per se. In contrast, the infusion of some inorganic acids, such as HCl, will directly shift K out of cells. “Shift” hyperkalemia also develops when HCl precursors, such as the chloride salts of arginine or lysine, are infused. Genetic defects of cell membrane ion transporters, usually epithelial Na-channels, cause the syndrome of hyperkalemic periodic paralysis.

Most non-physiologic states of hypoaldosteronism (ie, not secondary to ECF/vascular expansion) generate chronic hyperkalemia because of reduced distal tubule (CCD) K secretion. This is exacerbated by concomitant renal insufficiency or markedly reduced distal tubule Na delivery. Pathologic hypoaldosteronism may be the consequence of a direct block of hormonal synthesis (a congenital or acquired enzyme defect or adrenal damage), or secondary to dysregulation of the signals mediating aldosterone synthesis and release. The most important physiologic regulator of systemic aldosterone is angiotensin II activity, and the most common form of pathologic hypoaldosteronism is that due to reduced renin activity and hence angiotensin II levels.108-110 This “hyporeninemic hypoaldosteronism” often develops in patients with long-standing diabetes mellitus as a result of progressive interstitial renal disease with atrophy and/or destruction of the ACID-BASE AND ELECTROLYTES

37

renin-secreting cells in the juxtaglomerular apparatus. Other interstitial renal diseases, such as those associated with sickle cell disease, analgesic nephropathy, and chronic urinary outlet obstruction (especially in elderly men), may produce a state of hyporeninemic hypoaldosteronism as well.

Hypoaldosteronism slows the rate of distal tubule proton secretion.111 In addition, hyperkalemia inhibits renal ammonia synthesis and reduces NH4Cl excretion. These defects combine to generate a syndrome of hyperkalemic, hyperchloremic metabolic acidosis called renal tubular acidosis type 4. Correction of the hyperkalemia often increases urine ammonia excretion and reverses the metabolic acidosis.

Inhibition, at any step, of the endocrine sequence from renin → angiotensin I → angiotensin II → aldosterone → activation of CCD Na reabsorption and 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 by angiotensin converting enzyme inhibitors (ACEIs).

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

5. Inhibition of the enzymatic sequence responsible for aldosterone synthesis by drugs such as heparin or ketoconazole.

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

7. Competitive antagonism of mineralocorticoid receptors by spironolactone or eplerenone.

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

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9. Blunted renal epithelial response to aldosterone as a result of a series of inherited disorders (the congenital pseudohypoaldosteronism syndromes).

Many other factors contribute to the hyperkalemia which commonly develops in patients with diabetes mellitus. Autonomic sympathetic neuropathy reduces renin levels and blunts beta-activity, thus promoting K efflux. The multiple medications often prescribed include ACEIs, ARBs, aldosterone antagonists, and NSAIDs (see below). These patients may also ingest excess K in the form of salt substitute and their global kidney function is typically impaired. With suboptimal diabetic control, the combined effects of insulin deficiency and hyperglycemia will increase plasma [K] acutely and dramatically.

The contribution of reduced renal K excretion to the development of hyperkalemia is usually readily apparent. When it is not, a quantitative urine collection to measure daily K excretion may be helpful.

Chronic hyperkalemia should stimulate renal K excretion and the 24-hour urine should contain >7080 mEq/d. If a quantitative urine collection cannot be obtained, the trans-tubular potassium gradient (TTKG), which is described in the hypokalemia section, should be >10 (the urine osmolality must be >300 and urinary Na excretion >20 mEq/L for the TTKG to be interpretable).

Treatment of Hyperkalemia

It is better to prevent hyperkalemia than to treat it. A careful review of patient medications, diet, and in particular over-the-counter drugs (NSAIDs) is mandatory. Hidden sources of K, such as herbal medicines, sports drinks, and salt substitutes, must be sought. The recent demonstration that aldosterone antagonists provide a survival benefit to patients with CHF (who are usually also taking ACE-I and/or ARB drugs plus β-blockers; this has generated a major increase in the prevalence of hyperkalemia among these patients).

When hyperkalemia is acute and severe, emergency intervention is necessary.112,113 Treatment options for acute and severe hyperkalemia are:

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 expansion and kaluretic diuretics b. Via the gastrointestinal tract by inducing diarrhea and K binding resins c. Via dialysis for patients with severe acute or chronic renal failure If [K] is greater than 6.4 and peaked T waves are an isolated ECG abnormality, calcium should probably be infused. It is clearly indicated when a hyperkalemic patient manifests more ominous ECG abnormalities (Figure 11). Calcium directly antagonizes the cardiac membrane depolarizing effects of hyperkalemia (Figure 10). The indication for calcium in the absence of electrocardiographic changes is unclear; however, such infusions are relatively safe in the absence of overt hypercalcemia, marked hyperphosphatemia, or digitalis toxicity. One ampule (10 mL) of 10% calcium gluconate contains 4.6 mEq of elemental calcium and is given as a slow IV push over 2-5 minutes. Alternatively, one ampule (10 mL) of calcium chloride 10%, containing about three times as much elemental calcium (13.6 mEq) is acceptable, but should be given more slowly and cautiously. Extravasation of either salt can produce tissue necrosis (calcium chloride is more irritating then calcium gluconate). The beneficial effect on the ECG is usually seen immediately.

The dose of calcium may be repeated if ECG abnormalities persist or recur. Although the available data is limited, wide experience indicates it to be almost universally effective in reversing hyperkalemiainduced cardiotoxicity. Lidocaine is contraindicated because it can precipitate ventricular fibrillation and asystole. Importantly, calcium infusions do not

directly affect the plasma [K] per se and their beneficial effects are short-lived (about 1-2 hours).

Therefore, this treatment must be promptly followed by other treatment regimens that ultimately reduce plasma [K] by translocation into cells or excretion.

The three agents that drive extracellular potassium into cells are listed above. Insulin stimulates Na-K ATPase (and the Na-H exchanger—Figure 8) and reliably reduces [K] by 0.5-1 mEq/L within 10-20 minutes in virtually all patients. For a maximum K lowering effect, supraphysiologic levels of insulin are required, typically 10 units of regular insulin IV push. Subcutaneous or intramuscular injections and “low-dose” IV infusions should not be utilized because they do not produce adequate plasma insulin levels. Intravenous glucose is also administered if the patient is not already hyperglycemic. A reasonable approach is to administer one ampule (50 mL) of 50% glucose, followed by an intravenous infusion of 10% glucose at about 75 mL/hr.

Hyperglycemia must be avoided because this will shift K out of cells. Infusion of glucose alone to stimulate endogenous insulin secretion in non diabetic patients is less effective because it generates lower peak insulin levels.

The β2-agonist albuterol also stimulates Na-K ATPase and moves K into cells.114,115 This effect is additive to that of insulin and occurs within 30-60 minutes. The parenteral form of albuterol is not available in the United States, and the drug is given via the respiratory tract by nebulizer at a dose of 10 to 20 mg in 4 mL of saline. This relatively high dose is well tolerated by most patients, but contraindicated for patients with acute cardiac ischemia or severe myocardial disease. However, it is less reliable than insulin because a significant number of patients are resistant to its K-lowering effect and therefore should never be used alone.

Hypertonic NaHCO3, 1-3 ampules (44 mEq/50 mL each) by intravenous infusion over 30-45 minutes, has been used in the treatment of hyperkalemia for many years. Overall, its potassium lowering effect is weak and of slow onset. Hypertonic NaHCO3 lowers [K] via multiple mechanisms including expansion of the ECF (causing dilution of the K)

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5. Selected Disorders of Divalent Metabolism and transcellular K uptake. Hypertonic NaHCO3 does expand the ECF and should be avoided in volume overloaded patients and those with congestive heart failure.

Hyperkalemia associated with increased total K stores requires K to be removed. If kidney function is adequate, loop and thiazide diuretics (and especially in combination) can markedly increase urinary K excretion. Thiazide diuretics are particularly helpful in the treatment of hyporeninemic hypoaldosteronism. Thiazides become less effective when kidney function declines, whereas high dose loop diuretics may remain useful until renal function reaches â&#x20AC;&#x153;end-stage.â&#x20AC;? Occasionally, patients with hypoaldosteronism are volume contracted and then the exogenous mineralocorticoid fludrocortisone may be useful.

Stool potassium excretion is enhanced by administering laxatives to generate electrolyte-rich diarrhea and by binding gastrointestinal luminal K to nonabsorbable resins, such as sodium polystyrene sulfonate. The resin powder is generally premixed with sorbitol (15 g suspended in per 60 mL of 70% sorbitol) which speeds its transit through the GI tract and also itself increases fecal K loss. The usual oral dose is 30 gm. The resin powder can also be ingested with other laxatives. The acute K lowering effect of this treatment is minor, and resin K binders may be more effective for chronic therapy. These resins can also be administered via enema, though this route may be less effective. A rare complication of the sodium polystyrene sulfonate in sorbitol suspension is bowel necrosis. This may be due to the hypertonic sorbitol rather than the resin itself and is more common with rectal administration.

Acute hemodialysis, generally reserved for patients with acute or chronic severe kidney failure, rapidly lowers plasma [K] and can reduce total body K stores by about 25-50 mEq per hour.

Hypercalcemia Hypercalcemia may be a common manifestation of a serious disease or reflect an incidental finding that leads to the diagnosis of some underlying disease.116-121 Approximately 90% of the patients with hypercalcemia have either primary hyperparathyroidism or an underlying malignancy. Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting,117,118 whereas a malignancy is the most frequent cause of hypercalcemia in a hospitalized patient.119 Other causes of elevated calcium are less common and usually not considered until malignancy and parathyroid disease are ruled out.

The reference range of serum calcium levels is 8.710.4 mg/dL. A calcium level of >14 mg/dL corresponds to severe hypercalcemia or hypercalemic crisis. Plasma calcium is maintained within the reference range by a complex interplay of 3 major hormones, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (ie, calcitriol), and calcitonin.

These 3 hormones act primarily on the bone, kidney, and small intestine sites to maintain appropriate calcium levels. Approximately 40% of the calcium is bound to protein, primarily albumin, while 50% is ionized and is in physiologic active form. The remaining 10% is complexed to anions.

Patients with hypercalcemia can be asymptomatic or severely symptomatic depending on the degree and rate of increase. The hallmark clinical findings in hypercalcemia are neuromuscular and neurological alterations, mental status change, depression, fatigue, and muscle weakness. Notably, Trousseau and Chvostek signs may or may not be positive depending on the severity. Accompanied gastrointestinal symptoms include constipation, nausea, and vomiting. A history of polyuria, polydipsia, nephrolithiasis and nephrocalcinosis is relatively common. Cardiac symptoms can be exhibited as heart block, arrhythmias, or minor ECG changes (shortened QT interval). Patients may have a positive family history or medication intake.

As a general rule, the kidney does not actively contribute to hypercalcemia; rather, the kidney defends against the development of hypercalcemia. There-

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fore, in most disorders involving hypercalcemia, the renal threshold of calcium excretion must be exceeded in order to produce significant hypercalcemia.

Primary Hyperparathyroidism Most commonly observed in women who have hyperplasia or adenoma of the parathyroid causing an excessive secretion of the parathyroid hormone (PTH).117,118 Primary hyperparathyroidism originally was the disease of “stones, bones, and abdominal groans.” In most primary hyperparathyroidism cases, the calcium elevation is caused by increased intestinal calcium absorption. This is mediated by the PTH-induced calcitriol synthesis that enhances calcium absorption. The increase in serum calcium results in an increase in calcium filtration at the kidney. Because of PTH-mediated absorption of calcium at the distal tubule, less calcium is excreted than might be expected. In PTH-mediated hypercalcemia, bones do not play an active role because most of the PTH-mediated osteoclast activity that breaks down bone is offset by hypercalcemicinduced bone deposition. Hypercalcemia of this disorder may remain mild for long periods because some parathyroid adenomas respond to the feedback generated by the elevated calcium levels.

Humoral Hypercalcemia of Malignancy (HHM) HHM makes up about 80% of all cases of malignancy related hypercalcemia.119 Ectopic secretion of parathyroid hormone-related-peptide (PTHrP) stimulates bone osteoclastic resorption.120 The most common cancers associated with HHM are squamous cell cancer of the lung, renal cell, breast, and ovarian carcinomas, whereas lymphomas make up a small percentage. The typical presentation is that of hypercalcemia and hypophosphatemia. Unfortunately, patients are often diagnosed at an advance stage of malignancy.121 Other malignant disease can also cause hypercalcemia. Cancers include lymphoma (increased production of 1,25(OH)2 vitamin D), advanced breast cancer (osteolytic bone metastases), multiple myeloma (bone destruction). Bisphosonate administration can be used effectively to treat the hypercalcemic skeletal complications of such diseases.

Medications These include lithium through interaction with the CaR to alter the set point for PTH secretion in relation to extracellular calcium; thiazides—usually mild hypercalcemia due to inhibition of urinary calcium excretion. vitamin A and D intoxication, theophylline, and estrogen therapy.

Milk-alkali Syndrome This syndrome is relatively common and characterized by hypercalcemia, alkalosis, and renal insufficiency after large amounts of calcium and antacid ingestion122. Milk-alkali syndrome frequently results from excessive calcium carbonate ingestion due to peptic ulcer disease.

Immobilization Chronically bedridden patients may develop hypercalcemia, although the mechanism is not well understood123. The syndrome is characterized by a low PTH and 1,25(OH)2 vitamin D levels after weeks of inactivity. Ostepenia can be reversed with resumption of activity and bisphosphonate therapy.

Granulomatous Disease Granulomatous disease (eg, sarcoidosis, leprosy, disseminated candidasis, and acquired immunodeficiency syndrome, leprosy) is often complicated by hypercalcemia.124 The likely mechanism is an alteration in vitamin D metabolism with an increased production of 1,25(OH)2 vitamin D from non-renal sites.

Treatment of Hypercalcemia

Management of hypercalcemia comprises general treatment and more specific etiology-driven treatment.125-128 The foremost component in treating hypercalcemia is repletion of the extracellular fluid compartment with 0.9% (normal) saline – a key management step since many patients are volume depleted. A loop diuretic (eg, furosemide) may be used with hydration to increase calcium excretion.

This may also prevent volume overload during therapy. In contrast to loop diuretics, avoid thiazide diuretics because they increase the reabsorption of calcium. Patients who are already on chronic dialysis and severely hypercalcemic should undergo hemodialysis or peritoneal dialysis with a low-calcium dialysate as first line therapy. BisphosphoACID-BASE AND ELECTROLYTES

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

Mg2+ excretion by the kidneys â&#x20AC;&#x201C; patients are taking magnesium-containing antacids, laxatives, enemas, or infusions in the context of acute or chronic kidney failure. Acute rhabdomyolysis is also associated with hypermagnesemia.

The treatment of primary hyperparathyroidism is reviewed in detail elsewhere.133 Mithramycin blocks osteoclastic function and can be given for severe malignancy-related hypercalcemia.134 However, mithramycin has significant hepatic, renal, and marrow toxicity. The detailed management of malignancy associated hypercalcemia is detailed elsewhere.135-7

Hypermagnesemia may present clinically with lethargy, drowsiness, hypotension, nausea, vomiting, facial flushing, urinary retention and ileus.

These symptoms are usually observed when the serum Mg2+ level exceeds 4 to 6mg/dL. If untreated, this condition may progress to flaccid skeletal muscular paralysis and hyporeflexia, bradycardia and bradyarrhythmias, complete heart block, and respiratory depression and death. Nonspecific ECG changes are often seen and may include prolonged PR intervals and increased QRS duration.

Hypotension and cutaneous flushing may be the result of vasodilator effect and inhibition of norepinephrine release from sympathetic postganglionic nerves. Voluntary muscle paralysis and general smooth muscle paralysis can cause the life threatening complication of respiratory muscle paralysis and apnea. Coma and cardiac arrest may eventually ensue in patients with severe Mg2+ toxicity.

Hypermagnesemia Magnesium (Mg2+) is the second most common intracellular cation after potassium. Magnesium is required for deoxyribonucleic acid (DNA) and protein synthesis.138 Mg2+ is also an essential cofactor for most enzymes in phosphorylation reactions.

Mg2+ also plays an important role in parathyroid hormone synthesis.

The total body content of Mg2+ is 2000 mEq, or 24 g. Mg is distributed in bone (67%), intracellularly (31%), and extracellularly (a mere 1%). The intracellular concentration is 40 mEq/L, while the normal serum concentration is 1.5-2.0 mEq/L. Of this 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 in stool and urine. The minimum daily requirement of Mg2+ is 300-350 mg, or 15 mmol; this amount is easily obtainable with a normal daily intake of fruits, seeds, and vegetables because magnesium is a component of chlorophyll and is present in high concentrations in all green plants.

Hypermagnesemia is a rare electrolyte abnormality because the kidney is very effective in excreting excess Mg2+ 1.139-141 The kidney is the main regulator of magnesium concentrations. Absorption occurs primarily in the proximal tubule and thick ascending limb of the loop of Henle â&#x20AC;&#x201C; an increase of Mg2+ to greater than 1.1 mmol/L (2.2 meq/L) (2.6 mg/dL). The most common cause of hypermagnesemia is excessive intake in the setting of impaired 42

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Treatment of Hypermagnesemia

The most important steps are to withdraw Mg2+ infusion and volume replete the patient.Volume repletion should be with 0.9% saline and intravenous furosemide. In patients that have severe complications that may require emergent treatment, administration of Ca2+ (1 g over 2 to 5 minutes of IV calcium chloride or calcium gluconate) may be useful. Patients with kidney failure may require dialysis against a low magnesium bath. Generally, the expected change in serum Mg2+ after 3 to 4 hours of dialysis with a high-efficiency membrane is approximately one-third to one-half the difference between the dialysate Mg2+ concentration and the predialysis serum ultrafilterable Mg2+ level (estimated at 80% of total serum Mg2+). Peritoneal dialysis can also be used to effectively remove Mg2+ in patients who cannot tolerate hemodialysis.

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

Mg2+ level <1.8 mEq/L. Hypomagnesemia is common – up to 60% of the patients in intensive care units are estimated to be hypomagnesemic according to surveys of serum Mg2+ levels.142,143 Hypomagnesemia is often the result of renal or gastrointestinal losses and may be related to loop diuretic use, other drugs, alcohol use, and chronic diarrhea.139 Cutaneous losses are thought to be due to excessive sweating on exercise excretion and also in patients with severe burn injury. Intravenous fluid therapy and volume-expanded states may also cause hypomagnesemia due to a dilutional effect.

Rarely, familial incidence has been reported primarily in isolated familial hypomagnesemia, familial hypokalemia, and familial hypomagnesemiahypercalciuria.

Patients with hypomagnesemia may be asymptomatic or have a number of clinical manifestations that could reflect other electrolyte abnormalities.138,139 Multiple body systems can be involved, including the heart, neuromuscular, central nervous system (CNS). Cardiac symptoms include tachyarrhythmias, torsades de pontes, tachycardia, and fibrillation resistant to standard treatment but responding to Mg2+ repletion. ECG changes reflect abnormal cardiac repolarization with bifid T waves, U waves, and prolongation of QT or QU interval.

Neuromuscular symptoms are similar to hypocalcemia, including tremor, twitching, frank tetany, and positive Trousseau and Chvostek signs. CNS symptoms may include generalized, tonic-clonic, or multifocal motor seizures that are triggered by loud noises and can lead to sudden death. Nystagmus and Wernicke encephalopathy may also be present.

The most important aspects of managing hypomagnesemia is to distinguish if the lack of Mg2+ is due to a decreased intake/absorption or increased losses.

A key test is to measure a 24-hour quantitative urinary Mg2+ excretion to distinguish increased versus decreased urinary excretion of Mg2+. An increased urinary excretion in a patient with hypomagnesemia is invariably due to renal Mg2+ wasting. A decreased urinary excretion may be primarily due to renal conservation of Mg2+ in an attempt to restore Mg2+ equilibrium in the face of inadequate Mg2+ intake. Renal Mg2+ wasting can be seen in patients with defective sodium resorption (diuretic use), use

of renal toxins (amphotericin B, cisplatin, aminoglycosides, pentamidine, cyclosporine A), and osmotic diuresis (DM). Extrarenal losses may be due to nutrition deficiency (eg, alcoholism, proteincalorie malnutrition, parenteral nutrition), decreased absorption (eg, chronic diarrhea, intestinal malabsorption syndromes), and cutaneous losses (eg, burn patients, marathon runners).

Rarely, bone redistribution may occur in patients who have “hungry bone syndrome” where chronically elevated PTH is corrected with parathyroidectomy.

The treatment of asymptomatic Mg2+ deficiency is controversial. Patients with Mg2+ deficiency and associated cardiac disease should receive Mg2+ supplementation to avoid the risk of developing digoxin cardiotoxicity. For unknown reasons, patients on parenteral nutrition have an increased demand for Mg2+. Therefore, Mg2+ supplementation should be increased to prevent further deficiencies. Symptomatic Mg2+ deficiency requires repletion to prevent complications such as seizure disorder and ongoing electrolyte imbalance. Intravenous replacement is the route of choice on patients with IV access. Depending on the severity of symptoms, the standard preparation of MgSO4·7H2O may be infused at different dosages. In a patient who is actively seizing or who has a cardiac arrhythmia, 8 to 16mEq (1 to 2 g) may be administered intravenously over 2 to 4 minutes; otherwise, a slower rate of repletion is safer. A slower rate of infusion can also decrease urinary losses because of the delayed Mg2+ equilibration with the intracellular compartment. Repletion should be continued for 1 to 2 days despite normalization of serum Mg2+ levels. The dosage of Mg2+ repletion should be reduced 25%-50% in patients who have a reduced glomerular filtration rate to prevent hypermagnesemia. Several Mg2+ salts may be administered orally to replenish mild cases of hypomagnesemia where ongoing losses may be present. Patients with ongoing renal losses and Mg2+ wasting should be treated with a potassium-sparing diuretic.

Amiloride and triamterene can effectively reduce renal Mg2+ clearance after furosemide diuresis.

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8. Pessler F, Emery H, Dai L, Wu YM, Monash B, Cron RQ, Pradhan M. The spectrum of renal tubular acidosis in paediatric SjĂśgren syndrome. Rheumatology (Oxford). 2006 Jan;45(1):85-91. Epub 2005 Sep 13.

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