Metabolic Acidosis

PaCO

Arterial blood pH

120 100 90 80 70 60 50

PaCO

120 100 90 80 70 60 50

T

FIGURE 6-15

Ninety-five percent confidence intervals for metabolic acidosis. Metabolic acidosis is the acid-base disturbance initiated by a decrease in plasma bicarbonate concentration ([HCO3]). The resultant acidemia stimulates alveolar ventilation and leads to the secondary hypocapnia characteristic of the disorder. Extensive observations in humans encompassing a wide range of stable metabolic acidosis indicate a roughly linear relationship between the steady-state decrease in plasma bicarbonate concentration and the associated decrement in arterial carbon dioxide tension (PaCO2). The slope of the steady state APaCO2 versus A[HCO3] relationship has been estimated as approximately 1.2 mm Hg per mEq/L decrease in plasma bicarbonate concentration. Such empiric observations have been used for construction of 95% confidence intervals for graded degrees of metabolic acidosis, represented by the area in color in the acid-base template. The black ellipse near the center of the figure indicates the normal range for the acid-base parameters [3]. Assuming a steady state is present, values falling within the area in color are consistent with but not diagnostic of simple metabolic acidosis. Acid-base values falling outside the area in color denote the presence of a mixed acid-base disturbance [4]. [H+] — hydrogen ion concentration.

SIGNS AND SYMPTOMS OF METABOLIC ACIDOSIS

Respiratory System

Cardiovascular System

Nervous System

Skeleton

Hyperventilation

Impairment of cardiac

Increased

Impaired metabolism

Osteomalacia

Respiratory distress

contractility, arteriolar

metabolic demands

Inhibition of cell

Fractures

and dyspnea

dilation, venoconstriction,

Insulin resistance

volume regulation

Decreased strength

and centralization of

Inhibition of

Progressive obtundation

of respiratory

blood volume

anaerobic glycolysis

Coma

muscles and

Reductions in cardiac

Reduction in adenosine

promotion of

output, arterial blood

triphosphate synthesis

muscle fatigue

pressure, and hepatic and renal blood flow

Hyperkalemia

Sensitization to reentrant

Increased

arrhythmias and reduction

protein degradation

in threshold for ventricular

fibrillation

Increased sympathetic

discharge but attenuation of

cardiovascular responsiveness

to catecholamines

Signs and symptoms of metabolic acidosis. Among the various clinical manifestations, particularly pernicious are the effects of severe acidemia (blood pH < 7.20) on the cardiovascular system. Reductions in cardiac output, arterial blood pressure, and hepatic and renal blood flow can occur and life-threatening arrhythmias can develop. Chronic acidemia, as it occurs in untreated renal tubular acidosis and uremic acidosis, can cause calcium dissolution from the bone mineral and consequent skeletal abnormalities.

Normal

A-10

HCO3-

24

Na+

Cl-

140

Normal anion gap High anion gap

(hyperchloremic) (normochloremic)

Na+ 140

A-10

Cl-126

Na+ 140

Cl-106

Causes Renal acidification defects Proximal renal tubular acidosis Classic distal tubular acidosis Hyperkalemic distal tubular acidosis Early renal failure Gastrointestinal loss of bicarbonate Diarrhea

Small bowel losses Ureteral diversions Anion exchange resins Ingestion of CaCl2 Acid infusion HCl

Arginine HCl Lysine HCl

Causes Endogenous acid load Ketoacidosis Diabetes mellitus Alcoholism Starvation Uremia

Lactic acidosis Exogenous toxins Osmolar gap present Methanol Ethylene glycol Osmolar gap absent Salicylates Paraldehyde

HCO3- 4

Lactic acidosis

FIGURE 6-18

Lactate-producing and lactate-consuming tissues under basal conditions and pathogenesis of lactic acidosis. Although all tissues pro

Causes of metabolic acidosis tabulated according to the prevailing pattern of plasma electrolyte composition. Assessment of the plasma unmeasured anion concentration (anion gap) is a very useful first step in approaching the differential diagnosis of unexplained metabolic acidosis. The plasma anion gap is calculated as the difference between the sodium concentration and the sum of chloride and bicarbonate concentrations. Under normal circumstances, the plasma anion gap is primarily composed of the net negative charges of plasma proteins, predominantly albumin, with a smaller contribution from many other organic and inorganic anions. The normal value of the plasma anion gap is 12 ± 4 (mean ± 2 SD) mEq/L, where SD is the standard deviation. However, recent introduction of ion-specific electrodes has shifted the normal anion gap to the range of about 6 ± 3 mEq/L. In one pattern of metabolic aci-dosis, the decrease in bicarbonate concentration is offset by an increase in the concentration of chloride, with the plasma anion gap remaining normal. In the other pattern, the decrease in bicarbonate is balanced by an increase in the concentration of unmeasured anions (ie, anions not measured routinely), with the plasma chloride concentration remaining normal.

duce lactate during the course of glycolysis, those listed contribute substantial quantities of lactate to the extracellular fluid under normal aerobic conditions. In turn, lactate is extracted by the liver and to a lesser degree by the renal cortex and primarily is reconverted to glucose by way of gluconeogenesis (a smaller portion of lactate is oxidized to carbon dioxide and water). This cyclical relationship between glucose and lactate is known as the Cori cycle. The basal turnover rate of lactate in humans is enormous, on the order of 15 to 25 mEq/kg/d. Precise equivalence between lactate production and its use ensures the stability of plasma lactate concentration, normally ranging from 1 to 2 mEq/L. Hydrogen ions (H+) released during lac-tate generation are quantitatively consumed during the use of lactate such that acid-base balance remains undisturbed. Accumulation of lactate in the circulation, and consequent lactic acidosis, is generated whenever the rate of production of lactate is higher than the rate of utilization. The pathogenesis of this imbalance reflects overproduction of lactate, underutilization, or both. Most cases of persistent lactic acidosis actually involve both overproduction and underutiliza-tion of lactate. During hypoxia, almost all tissues can release lactate into the circulation; indeed, even the liver can be converted from the premier consumer of lactate to a net producer [1,14].

Muscle Brain Skin n n

Anaerobic glycolysis

Liver Kidney cortex

Muscle Brain Skin n n

Anaerobic glycolysis

Liver Kidney cortex

Overproduction ^^ Lactic acidosis ^nj Underutilization

Glucose

Gluconeogenesis

Glucose

high+NADH

high+NADH

Lactate NAD+ Cytosol

Mitochondrial membrane

Oxaloacetate

Mitochondria

NADH NAD+ Acetyl-CoA

Oxaloacetate

FIGURE 6-19

Hypoxia-induced lactic acidosis. Accumulation of lactate during hypoxia, by far the most common clinical setting of the disorder, originates from impaired mitochondrial oxidative function that reduces the availability of adenosine triphosphate (ATP) and NAD+ (oxidized nicotinamide adenine dinucleotide) within the cytosol. In turn, these changes cause cytosolic accumulation of pyruvate as a consequence of both increased production and decreased utilization. Increased production of pyruvate occurs because the reduced cytosolic supply of ATP stimulates the activity of 6-phosphofruc-tokinase (PFK), thereby accelerating glycolysis. Decreased utilization of pyruvate reflects the fact that both pathways of its consumption depend on mitochondrial oxidative reactions: oxidative decarboxylation to acetyl coenzyme A (acetyl-CoA), a reaction catalyzed by pyruvate dehydrogenase (PDH), requires a continuous supply of NAD+; and carboxylation of pyruvate to oxaloacetate, a reaction catalyzed by pyruvate carboxylase (PC), requires ATP. The increased [NADH]/[NAD+] ratio (NADH refers to the reduced form of the dinucleotide) shifts the equilibrium of the lactate dehy-drogenase (LDH) reaction (that catalyzes the interconversion of pyruvate and lactate) to the right. In turn, this change coupled with the accumulation of pyruvate in the cytosol results in increased accumulation of lactate. Despite the prevailing mitochondrial dysfunction, continuation of glycolysis is assured by the cytosolic regeneration of NAD+ during the conversion of pyruvate to lactate. Provision of NAD+ is required for the oxidation of glyceraldehyde 3-phosphate, a key step in glycolysis. Thus, lactate accumulation can be viewed as the toll paid by the organism to maintain energy production during anaerobiosis (hypoxia) [14]. ADP—adenosine diphosphate; TCA cycle—tricarboxylic acid cycle.

CAUSES OF LACTIC ACIDOSIS

Type A:

Impaired Tissue Oxygenation

Type B: Preserved Tissue Oxygenation

Shock

Diseases and conditions

Drugs and toxins

Severe hypoxemia

Diabetes mellitus

Epinephrine,

Generalized convulsions

Hypoglycemia

norepinephrine,

Vigorous exercise

Renal failure

vasoconstrictor agents

Exertional heat stroke

Hepatic failure

Salicylates

Hypothermic shivering

Severe infections

Ethanol

Massive pulmonary emboli

Alkaloses

Methanol

Severe heart failure

Malignancies (lymphoma,

Ethylene glycol

Profound anemia

leukemia, sarcoma)

Biguanides

Mesenteric ischemia

Thiamine deficiency

Acetaminophen

Carbon monoxide poisoning

Acquired

Zidovudine

Cyanide poisoning

immunodeficiency syndrome

Fructose, sorbitol,

Pheochromocytoma

and xylitol

Iron deficiency

Streptozotocin

D-Lactic acidosis

Isoniazid

Congenital enzymatic defects

Nitroprusside Papaverine Nalidixic acid

FIGURE 6-20

Conventionally, two broad types of lactic acidosis are recognized. In type A, clinical evidence exists of impaired tissue oxygenation. In type B, no such evidence is apparent. Occasionally, the distinction between the two types may be less than obvious. Thus, inadequate tissue oxygenation can at times defy clinical detection, and tissue hypoxia can be a part of the pathogenesis of certain causes of type B lactic acidosis. Most cases of lactic acidosis are caused by tissue hypox-ia arising from circulatory failure [14,15].

> Cause-specific measures

/

No

Circulatory failure?

\

• Preload and afterload reducing agents

• Myocardial stimulants (dobutamine, dopamine)

• Avoid vasoconstrictors

• Volume repletion

• Preload and afterload reducing agents

• Myocardial stimulants (dobutamine, dopamine)

• Avoid vasoconstrictors

• Antibiotics (sepsis)

• Discontinuation of incriminated drugs

• Glucose (hypoglycemia, alcoholism)

• Operative intervention (trauma, tissue ischemia)

• Thiamine (thiamine deficiency)

• Low carbohydrate diet and antibiotics (D-lactic acidosis)

Severe/Worsening I metabolic acidemia? I

Alkali administration to maintain blood pH > 7.20

• Continue therapy

• Manage predisposing conditions

Lactic acidosis management. Management of lactic acidosis should focus primarily on securing adequate tissue oxygenation and on aggressively identifying and treating the underlying cause or predisposing condition. Monitoring of the patient's hemodynamics, oxygenation, and acid-base status should be used to guide therapy. In the presence of severe or worsening metabolic acidemia, these measures should be supplemented by judicious administration of sodium bicarbonate, given as an infusion rather than a bolus. Alkali administration should be regarded as a temporizing maneuver adjunctive to cause-specific measures. Given the ominous prognosis of lactic acidosis, clinicians should strive to prevent its development by maintaining adequate fluid balance, optimizing cardiorespiratory function, managing infection, and using drugs that predispose to the disorder cautiously. Preventing the development of lactic acidosis is all the more important in patients at special risk for developing it, such as those with diabetes mellitus or advanced cardiac, respiratory, renal, or hepatic disease [1,14-16].

Diabetic ketoacidosis and nonketotic hyperglycemia

Cortisol Epinephrine

Increased ketogenesis

Increased ketogenesis

Increased gluconeogenesis Increased glycogenolysis Decreased glucose uptake

Increased gluconeogenesis Increased glycogenolysis Decreased glucose uptake ft

Increased protein breakdown

Cortisol Epinephrine

Counterregulation

r-^si Ketonemia V,

(metabolic acidosis)

Hyperglycemia (hyperosmolality)

Increased protein breakdown

Decreased amino acid uptake

Decreased glucose excretion

Decreased ketone uptake

Decreased glucose excretion

Decreased glucose uptake

FIGURE 6-22

Role of insulin deficiency and the counter-regulatory hormones, and their respective sites of action, in the pathogenesis of hyper-glycemia and ketosis in diabetic ketoacido-sis (DKA).A, Metabolic processes affected by insulin deficiency, on the one hand, and excess of glucagon, cortisol, epinephrine, norepinephrine, and growth hormone, on the other. B, The roles of the adipose tissue, liver, skeletal muscle, and kidney in the pathogenesis of hyperglycemia and ketone-mia. Impairment of glucose oxidation in most tissues and excessive hepatic production of glucose are the main determinants of hyperglycemia. Excessive counterregula-tion and the prevailing hypertonicity, metabolic acidosis, and electrolyte imbalance superimpose a state of insulin resistance. Prerenal azotemia caused by volume depletion can contribute significantly to severe hyperglycemia. Increased hepatic production of ketones and their reduced utilization by peripheral tissues account for the ketonemia typically observed in DKA.

Feature

Pure DKA Mixed forms

Pure NKH

Incidence

5-10 times higher <=>

5-10 times lower

Mortality

5-10% <=>

10-60%

Onset

Rapid (<2 days) <=>

Slow (> 5 days)

Age of patient

Usually < 40 years <=>

Usually > 40 years

Type I diabetes

Common

Rare

Type II diabetes

Rare <==>

Common

First indication of diabetes

Often <==>

Often

Volume depletion

Mild/moderate <=>

Severe

Renal failure (most com-

Mild, inconstant <=>

Always present

monly of prerenal nature)

Severe neurologic

Rare <=>

Frequent

abnormalities

(coma in 25-50%)

Subsequent therapy with

Always < >

Not always

insulin

Glucose

< 800 mg/dL <==>

> 800 mg/dL

Ketone bodies

> 2 + in 1:1 dilution <==>

<2+ in 1:1 dilution

Effective osmolality

< 340 mOsm/kg <==>

> 340 mCsm/kg

pH

Decreased < >

Normal

[HCO-3]

Decreased < >

Normal

[Na+]

Normal or low < >

Normal or high

[K+]

Variable <=>

Clinical features of diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH). DKA and NKH are the most important acute metabolic complications of patients with uncontrolled diabetes mellitus. These disorders share the same overall pathogene-sis that includes insulin deficiency and resistance and excessive counterregulation; however, the importance of each of these endocrine abnormalities differs significantly in DKA and NKH. As depicted here, pure NKH is characterized by profound hyper-glycemia, the result of mild insulin deficiency and severe coun-terregulation (eg, high glucagon levels). In contrast, pure DKA is characterized by profound ketosis that largely is due to severe insulin deficiency, with counterregulation being generally of lesser importance. These pure forms define a continuum that includes mixed forms incorporating clinical and biochemical features of both DKA and NKH. Dyspnea and Kussmaul's respiration result from the metabolic acidosis of DKA, which is generally absent in NKH. Sodium and water deficits and secondary renal dysfunction are more severe in NKH than in DKA. These deficits also play a pathogenetic role in the profound hypertonic-ity characteristic of NKH. The severe hyperglycemia of NKH, often coupled with hypernatremia, increases serum osmolality, thereby causing the characteristic functional abnormalities of the central nervous system. Depression of the sensorium, somnolence, obtundation, and coma, are prominent manifestations of NKH. The degree of obtundation correlates with the severity of serum hypertonicity [17].

MANAGEMENT OF DIABETIC KETOACIDOSIS AND NONKETOTIC HYPERGLYCEMIA

Insulin

Fluid Administration

Potassium repletion

Alkali

1. Give initial IV bolus of 0.2 U/kg actual body weight.

2. Add 100 U of regular insulin to 1 L of normal saline (0.1 U/mL), and follow with continuous IV drip of 0.1 U/kg actual body weight per h until correction of ketosis.

3. Give double rate of infusion if the blood glucose level does not decrease in a 2-h interval (expected decrease is 40-80 mg/dL/h or 10% of the initial value.)

4. Give SQ dose (10-30 U) of regular insulin when ketosis is corrected and the blood glucose level decreases to 300 mg/dL, and continue with SQ insulin injection every 4 h on a sliding scale (ie, 5 U if below 150, 10 U if 150-200, 15 U if 200-250, and 20 U if 250-300 mg/dL).

Shock absent: Normal saline (0.9% NaCl) at 7 mL/kg/h for 4 h, and half this rate thereafter Shock present: Normal saline and plasma expanders (ie,albumin, low molecular weight dextran) at maximal possible rate Start a glucose-containing solution (eg, 5% dextrose in water) when blood glucose level decreases to 250 mg/dL.

Potassium chloride should be added to the third liter of IV infusion and subsequently if urinary output is at least 30-60 mL/h and plasma [K+]

Add K+ to the initial 2 L of IV fluids if initial plasma [K+]

< 4 mEq/L and adequate diuresis is secured.

Half-normal saline (0.45% NaCl) plus 1-2 ampules (44-88 mEq) NaHCC^ per liter when blood pH < 7.0 or total CO2 < 5 mmol/L; in hyper-chloremic acidosis, add NaHCC3 when pH < 7.20; discontinue NaHCC3 in IV infusion when total C02>8-10 mmol/L.

CO2—carbon dioxide; IV—intravenous; K+—potassium ion; NaCl—sodium chloride; NaHCO3—sodium bicarbonate; SQ—subcutaneous.

FIGURE 6-24

Diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) management. Administration of insulin is the cornerstone of management for both DKA and NKH. Replacement of the prevailing water, sodium, and potassium deficits is also required. Alkali are administered only under certain circumstances in DKA and virtually never in

NKH, in which ketoacidosis is generally absent. Because the fluid deficit is generally severe in patients with NKH, many of whom have preexisting heart disease and are relatively old, safe fluid replacement may require monitoring of central venous pressure, pulmonary capillary wedge pressure, or both [1,17,18].

Renal tubular acidosis

Feature

Proximal RTA

Classic Distal RTA

Hyperkalemic Distal RTA

Plasma bicarbonate

14-18 mEq/L

Variable, may be

15-20 mEq/L

ion concentration

< 10 mEq/L

Plasma chloride

Increased

Increased

Increased

ion concentration

Plasma potassium

Mildly decreased

Mildly to

Mildly to severely increased

ion concentration

severely decreased

Plasma anion gap

Normal

Normal

Normal

Glomerular filtration rate

Normal or

Normal or

Normal to

slightly decreased

slightly decreased

moderately decreased

Urine pH during acidosis

<5.5

>6.0

<5.5

Urine pH after acid loading

<5.5

>6.0

<5.5

U-B PCO2 in alkaline urine

Normal

Decreased

Decreased

Fractional excretion of

>15%

<5%

<5%

HCO3 at normal [HCO^

Tm HCO3

Decreased

Normal

Normal

Nephrolithiasis

Absent

Present

Absent

Nephrocalcinosis

Absent

Present

Absent

Osteomalacia

Present

Present

Absent

Fanconi's syndrome*

Usually present

Absent

Absent

Alkali therapy

High dose

Low dose

Low dose

FEATURES OF THE RENAL TUBULAR ACIDOSIS (RTA) SYNDROMES

FIGURE 6-25

Renal tubular acidosis (RTA) defines a group of disorders in which tubular hydrogen ion secretion is impaired out of proportion to any reduction in the glomerular filtration rate. These disorders are characterized by normal anion gap (hyperchloremic) metabolic acidosis. The defects responsible for impaired acidification give rise to three distinct syndromes known as proximal RTA (type 2), classic distal RTA (type 1), and hyperkalemic distal RTA (type 4).

Tm HCO3—maximum reabsorption of bicarbonate; U-B PCO2—difference between partial pressure of carbon dioxide values in urine and arterial blood.

*This syndrome signifies generalized proximal tubule dysfunction and is characterized by impaired reabsorption of glucose, amino acids, phosphate, and urate.

FIGURE 6-26

B. CAUSES OF PROXIMAL RENAL TUBULAR ACIDOSIS

FIGURE 6-26

A and B, Potential defects and causes of proximal renal tubular acidosis (RTA) (type 2). Excluding the case of carbonic anhydrase inhibitors, the nature of the acidification defect responsible for bicarbonate (HCO3) wastage remains unknown. It might represent defects in the luminal sodium ion- hydrogen ion (Na+-H+) exchanger, basolateral Na+-3HCO^ cotransporter, or carbonic anhydrase activity. Most patients with proximal RTA have additional defects in proximal tubule function (Fanconi's syndrome); this generalized proximal tubule dysfunction might reflect a defect in the basolateral Na+-K+ adenosine triphosphatase. K+—potassium ion; CA—carbonic anhydrase. Causes of proximal renal tubular acidosis (RTA) (type 2). An idiopathic form and cystinosis are the most common causes of proximal RTA in children. In adults, multiple myeloma and carbonic anhydrase inhibitors (eg, acetazo-lamide) are the major causes. Ifosfamide is an increasingly common cause of the disorder in both age groups.

Selective defect (isolated bicarbonate wasting)

Dysproteinemic states

Primary (no obvious associated disease)

Multiple myeloma

Genetically transmitted

Monoclonal gammopathy

Transient (infants)

Drug- or toxin-induced

Due to altered carbonic anhydrase activity

Outdated tetracycline

Acetazolamide

3-Methylchromone

Sulfanilamide

Streptozotocin

Mafenide acetate

Lead

Genetically transmitted

Mercury

Idiopathic

Arginine

Osteopetrosis with carbonic

Valproic acid

anhydrase II deficiency

Gentamicin Ifosfamide

York-Yendt syndrome

Generalized defect (associated with multiple dysfunctions of the proximal tubule)

Tubulointerstitial diseases

Primary (no obvious associated disease)

Renal transplantation

Sporadic

Sjögrens syndrome

Genetically transmitted

Medullary cystic disease

Genetically transmitted systemic disease

Other renal diseases

Tyrosinemia

Nephrotic syndrome

Wilson's disease

Amyloidosis

Lowe syndrome

Miscellaneous

Hereditary fructose intolerance (during

Paroxysmal

administration of fructose)

nocturnal hemoglobinuria

Cystinosis

Hyperparathyroidism

Pyruvate carboxylate deficiency

Metachromatic leukodystrophy

Methylmalonic acidemia

Conditions associated with chronic hypocalcemia

and secondary hyperparathyroidism

Vitamin D deficiency or resistance

Vitamin D dependence

FIGURE 6-27

A and B, Potential defects and causes of classic distal renal tubular acidosis (RTA) (type 1). Potential cellular defects underlying classic distal RTA include a faulty luminal hydrogen ion-adenosine triphosphatase (H+ pump failure or secretory defect), an abnormality in the basolateral bicarbonate ion-chloride ion exchanger, inadequacy of carbonic anhydrase activity, or an increase in the luminal membrane permeability for hydrogen ions (backleak of protons or permeability defect). Most of the causes of classic distal RTA likely reflect a secretory defect, whereas amphotericin B is the only established cause of a permeability defect. The hereditary form is the most common cause of this disorder in children. Major causes in adults include autoimmune disorders (eg, Sjogren's syndrome) and hypercalciuria [19]. CA—carbonic anhydrase.

Primary (no obvious associated disease) Sporadic

Genetically transmitted

Autoimmune disorders Hypergammaglobulinemia Hyperglobulinemic purpura Cryoglobulinemia Familial

Sjögrens syndrome Thyroiditis Pulmonary fibrosis Chronic active hepatitis Primary biliary cirrhosis Systemic lupus erythematosus Vasculitis

Genetically transmitted systemic disease Ehlers-Danlos syndrome Hereditary elliptocytosis Sickle cell anemia Marfan syndrome Carbonic anhydrase I deficiency or alteration Osteopetrosis with carbonic anhydrase II deficiency Medullary cystic disease Neuroaxonal dystrophy

Disorders associated with nephrocalcinosis Primary or familial hyperparathyroidism Vitamin D intoxication Milk-alkali syndrome Hyperthyroidism Idiopathic hypercalciuria Genetically transmitted Sporadic Hereditary fructose intolerance

(after chronic fructose ingestion) Medullary sponge kidney Fabry's disease Wilson's disease

Drug- or toxin-induced Amphotericin B Toluene Analgesics Lithium Cyclamate Balkan nephropathy Tubulointerstitial diseases Chronic pyelonephritis Obstructive uropathy Renal transplantation Leprosy Hyperoxaluria

B. CAUSES OF CLASSIC DISTAL RENAL TUBULAR ACIDOSIS

FIGURE 6-28

B. CAUSES OF HYPERKALEMIC DISTAL RENAL TUBULAR ACIDOSIS

Deficiency of aldosterone Associated with glucocorticoid deficiency Addison's disease Bilateral adrenalectomy Enzymatic defects 21-Hydroxylase deficiency 3-ß-ol-Dehydrogenase deficiency Desmolase deficiency Acquired immunodeficiency syndrome Isolated aldosterone deficiency Genetically transmitted Corticosterone methyl oxidase deficiency Transient (infants) Sporadic Heparin

Deficient renin secretion Diabetic nephropathy Tubulointerstitial renal disease Nonsteroidal antiinflammatory drugs ß-adrenergic blockers Acquired immunodeficiency syndrome Renal transplantation Angiotensin I-converting enzyme inhibition Endogenous

Captopril and related drugs Angiotensin AT, receptor blockers

Resistance to aldosterone action Pseudohypoaldosteronism type I (with salt wasting) Childhood forms with obstructive uropathy Adult forms with renal insufficiency Spironolactone

Pseudohypoaldosteronism type II

(without salt wasting) Combined aldosterone deficiency and resistance Deficient renin secretion Cyclosporine nephrotoxicity Uncertain renin status Voltage-mediated defects Obstructive uropathy Sickle cell anemia Lithium Triamterene Amiloride

Trimethoprim, pentamidine Renal transplantation

FIGURE 6-28

A and B, Potential defects and causes of hyperkalemic distal renal tubular acidosis (RTA) (type 4). This syndrome represents the most common type of RTA encountered in adults. The characteristic hyperchloremic metabolic acidosis in the company of hyperkalemia emerges as a consequence of generalized dysfunction of the collecting tubule, including diminished sodium reabsorption and impaired hydrogen ion and potassium secretion. The resultant hyperkalemia causes impaired ammonium excretion that is an important contribution to the generation of the metabolic acidosis. The causes of this syndrome are broadly classified into disorders resulting in aldosterone deficiency and those that impose resistance to the action of aldosterone. Aldosterone deficiency can arise from hyporeninemia, impaired conversion of angiotensin I to angiotensin II, or abnormal aldosterone synthesis. Aldosterone resistance can reflect the following: blockade of the mineralocorticoid receptor; destruction of the target cells in the collecting tubule (tubulointerstitial nephropathies); interference with the sodium channel of the principal cell, thereby decreasing the lumen-negative potential difference and thus the secretion of potassium and hydrogen ions (voltage-mediated defect); inhibition of the basolateral sodium ion, potassium ion-adenosine triphosphatase; and enhanced chloride ion permeability in the collecting tubule, with consequent shunting of the transepithelial potential difference. Some disorders cause combined aldosterone deficiency and resistance [20].

Benefits

• Prevents or reverses acidemia-related hemodynamic compromise.

• Reinstates cardiovascular responsiveness to catecholamines.

• "Buys time," thus allowing cause-specific measures and endogenous reparatory processes to take effect.

• Provides a measure of safety against additional acidifying stresses.

Benefits

• Prevents or reverses acidemia-related hemodynamic compromise.

• Reinstates cardiovascular responsiveness to catecholamines.

• "Buys time," thus allowing cause-specific measures and endogenous reparatory processes to take effect.

• Provides a measure of safety against additional acidifying stresses.

Risks

• Hypernatremia/ hyperosmolality

• Volume overload

• "Overshoot" alkalosis

• Hypokalemia

• Decreased plasma ionized calcium concentration

• Stimulation of organic acid production

• Hypercapnia

Treatment of acute metabolic acidosis. Whenever possible, cause-specific measures should be at the center of treatment of metabolic acidosis. In the presence of severe acidemia, such measures should be supplemented by judicious administration of sodium bicarbonate. The goal of alkali therapy is to return the blood pH to a safer level of about 7.20. Anticipated benefits and potential risks of alkali therapy are depicted here [1].

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