Distal Renal Tubular Acidosis

In distal (classic or type 1) RTA, the urine cannot be maximally acidified because of impaired hydrogen ion secretion in the collecting ducts, and urine pH typically is above 6.0, despite moderately to markedly decreased plasma HCO₃⁻ concentration. Increased urine pH (>6.0) in the presence of acidosis is the hallmark of distal RTA. Urinary tract infection by a urease-positive organism (e.g., Proteus sp., Staphylococcus aureus) must be ruled out before considering distal RTA. Urinary net acid excretion is decreased, but bicarbonaturia usually is mild because urinary HCO₃⁻ concentration is only 1 to 3 mEq/L in the pH range of 6.0 to 6.5. Nephrolithiasis (usually calcium phosphate stones), nephrocalcinosis (resulting from alkaline urine pH and decreased urinary citrate concentration), bone demineralization (resulting from loss of bone buffer stores during chronic acidosis), and urinary potassium wasting with hypokalemia are features of distal RTA in human patients. Mutations in cytosolic carbonic anhydrase, the basolateral Cl⁻/HCO₃⁻ anion exchanger, and luminal H⁺-ATPase that affect function of the α-intercalated cells have been associated with inherited forms of distal renal tubular acidosis in humans.¹⁷³ Urinary fractional excretion of HCO₃⁻ is normal (<5%) in distal RTA when plasma HCO₃⁻ concentration is increased to normal by alkali administration.

A diagnosis of distal RTA may be confirmed by an ammonium chloride tolerance test during which urine pH is monitored (using a pH meter) before and at hourly intervals for 5 hours after oral administration of 0.2 g/kg NH₄Cl. Under such conditions, the urine pH of normal dogs decreased to a minimum value of 5.16 at 4 hours after administration of ammonium chloride.²¹⁴ Dogs in this study also developed systemic acidosis (pH approximately 7.22 and HCO₃⁻ approximately 14 mEq/L at 2 hours after ammonium chloride administration). The amount of alkali required to correct the acidosis in human patients with distal RTA is variable but typically less than that required in proximal RTA. The required dosage of alkali in distal RTA may be as little as 1 mEq/kg/day (i.e., that required to offset daily endogenous acid production) or more than 2 to 4 mEq/kg/day. A combination of potassium and sodium citrate (depending on potassium balance) may be the preferred source of alkali.¹⁹⁶

Proximal Renal Tubular Acidosis

In proximal (type 2) RTA, renal reabsorption of HCO₃⁻ is markedly reduced and urinary fractional excretion of HCO₃⁻ is increased (>15%) when plasma HCO₃⁻ concentration is increased to normal. Bicarbonaturia is absent and urine pH is appropriately low when metabolic acidosis is present and plasma HCO₃⁻ concentration is decreased because distal acidifying ability is intact. When plasma HCO₃⁻ concentration is decreased, the filtered load of HCO₃⁻ is reduced, and almost all of the filtered HCO₃⁻ is reabsorbed in the distal tubules, despite the presence of the proximal tubular defect. Thus, proximal RTA can be viewed as a “self-limited” disorder in which plasma HCO₃⁻ stabilizes at a lower than normal concentration after the filtered load falls sufficiently enough that distal HCO₃⁻ reabsorption can maintain plasma HCO₃⁻ at a new but lower steady-state concentration. Mutations in renal tubular transport proteins, such as the electrogenic basolateral Na⁺/ 3HCO₃⁻ cotransporter⁷³ and one of the five forms of the luminal Na⁺/H⁺ antiporter, have been implicated in the pathogenesis of inherited forms of proximal renal tubular acidosis in humans.¹¹⁸

Other abnormalities of proximal tubular function typically accompany impaired HCO₃⁻ reabsorption in proximal RTA, and these include defects in glucose, phosphate, sodium, potassium, uric acid, and amino acid reabsorption. This combination of proximal tubular defects is known as Fanconi syndrome. Serum potassium concentration usually is normal in affected human patients at the time of diagnosis, but alkali therapy may precipitate hypokalemia and aggravate urinary potassium wasting, presumably by increasing distal delivery of sodium and HCO₃⁻.

The diagnosis of proximal RTA is made by finding an acid urine pH (<5.5 to 6.0) in the presence of hyperchloremic metabolic acidosis and a normal GFR but an increased urine pH (>6.0) and increased urinary fractional excretion of HCO₃⁻ (>15%) after plasma HCO₃⁻ concentration has been increased to normal by alkali administration. If present, the detection of other defects in proximal tubular function (e.g., glucosuria with normal blood glucose concentration) establishes the diagnosis. Correction of metabolic acidosis by alkali therapy is more difficult in proximal RTA than in distal RTA because of the marked bicarbonaturia that occurs when plasma HCO₃⁻ concentration is increased to normal. Alkali dosages in excess of 10 mEq/kg/day may be required to correct the plasma HCO₃⁻ concentration, and such therapy may result in frank hypokalemia. Thus, potassium citrate may be the preferred source of alkali.

Multiple renal tubular reabsorptive defects resembling Fanconi syndrome have been reported in young basenji dogs.26–28,⁸⁰ Clinical findings included polyuria, polydipsia, weight loss, dehydration, and weakness. Affected dogs had abnormal fractional reabsorption of glucose, bicarbonate, phosphate, sodium, potassium, and urate, and they had isolated cystinuria or generalized aminoaciduria. The renal tubular disorder in affected basenji dogs is thought to be the result of a metabolic or membrane defect affecting sodium movement or increased back leak or cell-to-lumen flux of amino acids. In one study, brush border membranes isolated from basenji dogs with Fanconi syndrome had decreased sodium-dependent glucose transport but no abnormality of cystine uptake despite the observed reabsorptive defect for cystine.¹⁵⁷ Defective urinary concentrating ability leads to isosthenuria or hyposthenuria, and the GFR may be normal initially but decreased later in the course of the disease. Hypokalemia has also been observed late in the course of the disease.⁸⁰ Death usually results from acute renal failure and papillary necrosis or acute pyelonephritis. A distinctive renal lesion is hyperchromatic karyomegaly of renal tubular cells.

Fanconi syndrome has been observed sporadically in other breeds^{81,143,156,182,213} and has been reported in association with administration of some drugs.^16,28,160 In one case, Fanconi syndrome developed in association with primary hypoparathyroidism and resolved after treatment with calcium and calcitriol.⁸⁸ Rickets in growing children and osteomalacia in adults are features of Fanconi syndrome in human patients that usually are not observed in affected dogs. However, congenital Fanconi syndrome and renal dysplasia were associated with histologic features of rickets in two Border terriers.⁶⁴ The skeletal abnormalities in one of the affected dogs resolved after treatment with calcitriol and potassium phosphate. Transient Fanconi syndrome and proximal renal tubular acidosis also have been reported in a dog with high liver enzyme activities, and toxin exposure was considered as a possible explanation.¹¹⁵ Idiopathic transient renal tubular dysfunction also has been reported in a Labrador retriever¹²⁶ and greyhound.¹ Fanconi-like syndrome occurred in Australian dogs that had been fed dried chicken treats from China in 2007 and another product (not containing chicken and not from China) in 2009.⁸⁷ Affected dogs had polyuria, polydipsia, glucosuria, acidosis, hypokalemia, hypophosphatemia, and azotemia. Most of them survived with conservative medical management. Finally, Fanconi syndrome has been reported in several dogs with copper storage hepatopathy, and tubular dysfunction resolved after copper chelation therapy.^10,111

In one report, an 8-year-old female German shepherd had hyperchloremic metabolic acidosis, polyuria, polydipsia, isosthenuria, glucosuria with normal blood glucose concentration, and alkaline urine pH (7.46) after oral administration of NH₄Cl.⁷⁰ The metabolic acidosis was unresponsive to NaHCO₃ administration at dosages up to 4 mEq/kg/day. This dog appeared to have distal (type 1) RTA and renal glucosuria. In another case of apparent distal RTA, a 5-year-old mixed breed dog was presented for evaluation of anorexia and was determined to have alkaline urine pH with hyperchloremic metabolic acidosis.¹⁹¹ In another report, an 8-year-old female German shepherd was presented for polyuria, polydipsia, weight loss, and lethargy.²⁴ It had a normal GFR, metabolic acidosis, hyposthenuria, and intermittent glucosuria. Fractional reabsorption of sodium, glucose, and HCO₃⁻ was decreased, but reabsorption of chloride, phosphate, potassium, urate, and amino acids was normal. The dog gained weight, and its clinical signs were reversed after treatment with NaHCO₃ at approximately 10 mEq/kg/ day. This dog appeared to have proximal (type 2) RTA.

Distal RTA has been reported in two cats with pyelonephritis caused by Escherichia coli.^77,236 Clinical signs included polyuria, polydipsia, anorexia, lethargy, enlarged kidneys, and isosthenuria. In one cat, urine pH was 5.0 at the time pyelonephritis was first diagnosed, but distal RTA was documented at a later time by the presence of hyperchloremic metabolic acidosis, alkaline urine pH, and failure to lower urine pH after oral administration of NH₄Cl.⁷⁷ Findings were similar for the other cat, but hyperphosphaturia and persistent hypokalemia also were detected.²³⁶ Distal RTA and hepatic lipidosis were reported in another cat without urinary tract infection²⁹ and in a cat with concurrent hyperaldosteronism and severe hypokalemia.²²⁸ Distal renal tubular acidosis also has been reported in association with immune-mediated hemolytic anemia in three dogs.²¹⁵ Distal renal tubular acidosis is associated with some immune-mediated diseases in human patients, but not specifically immune-mediated hemolytic anemia. The clinical features of proximal (type 2) and distal (type 1) RTA are summarized in Table 10-2.

Table 10-2 Clinical Features of Proximal and Distal Renal Tubular Acidosis

* Decreased fractional reabsorption of sodium, potassium, phosphate, urate, glucose, and amino acids.

Hyporeninemic hypoaldosteronism, characterized by hyperkalemia with decreased plasma renin and aldosterone concentrations, occurs in some human patients, notably those with diabetes mellitus who also have mild to moderate renal insufficiency.⁶⁵ The hyperchloremic metabolic acidosis observed in these patients has been called Type 4 RTA. This syndrome has not been characterized in veterinary medicine but should be considered in dogs and cats with hyperkalemia and mild to moderate hyperchloremic metabolic acidosis after hypoadrenocorticism has been ruled out by an adrenocorticotropic hormone (ACTH) response test. The diagnosis may be established by finding an inappropriately decreased plasma aldosterone concentration in the presence of hyperkalemia.

Pathophysiology

EG is first metabolized in the liver to glycoaldehyde by alcohol dehydrogenase. Glycoaldehyde uncouples oxidative phosphorylation and may contribute to neurologic signs observed early in the course of intoxication. Subsequent steps in metabolism produce glycolic and glyoxylic acids. Glycolic acid is primarily responsible for the severe metabolic acidosis that occurs in animals poisoned by EG.⁵⁰ Renal tubular injury results from glycoaldehyde, glycolic acid, and glyoxylic acids, and calcium oxalate crystals are deposited within renal tubules. The observation of these birefringent crystals in the presence of acute tubular nephrosis confirms the diagnosis of EG intoxication.

Vomiting, polydipsia, and polyuria may occur soon after ingestion of EG, but the owners of poisoned animals often do not detect these signs. Within 12 hours of ingestion, neurologic signs (e.g., lethargy, ataxia, stupor, seizures, coma) may develop. Cardiac and pulmonary manifestations (e.g., tachypnea, tachycardia) occur 12 to 24 hours after ingestion but rarely are detected in clinical cases. Oxalate crystals may be detected in the urine as early as 3 to 6 hours after ingestion of EG.^68,69 Renal failure occurs in dogs as early as 24 to 48 hours after ingestion and is manifested by anorexia, lethargy, vomiting, and oliguria or anuria.⁹⁷ In cats, azotemia may develop within 12 to 24 hours after ingestion of EG.⁶⁸ Unfortunately, most dogs and cats with EG poisoning are presented for veterinary attention after renal failure has already developed.

A severe normochloremic (i.e., high anion gap) metabolic acidosis occurs within 3 hours of EG ingestion and persists for at least 24 hours.^68,69,97,227 Serum hyperosmolality and osmolal gap peak 1 to 6 hours after ingestion and persist for 12 to 24 hours,^68,69,97 but the osmolal gap may be normal in animals presented later in the course of the disease.²²⁷ Activated charcoal preparations containing propylene glycol and glycerol can increase osmolality and osmolal gap, and potentially complicate the diagnosis of EG ingestion. Measured serum osmolality peaked at 4 hours (353 mOsm/kg), osmolal gap at 6 hours (52 mOsm/kg), and serum lactate concentration at 4 hours (4.5 mmol/L) after administration of 4 g/kg of an activated charcoal preparation containing propylene glycol and glycerol.³³ Results returned to baseline 24 hours after administration of the activated charcoal preparation.

Calcium oxalate dihydrate crystals (“Maltese cross” or “envelope” forms) may be observed in the urine, but calcium oxalate monohydrate crystals (“picket fence” or “dumbbell” forms) are observed more commonly. Calcium oxalate dihydrate crystals occasionally are found in the urine of normal dogs and cats, whereas calcium oxalate monohydrate crystals rarely are seen except in animals that have ingested EG (Fig. 10-5).^68,227 Crystals previously referred to as hippurates actually are calcium oxalate monohydrate crystals.^134,226 Other laboratory findings include azotemia, isosthenuria, hypocalcemia, hyperphosphatemia, and hyperglycemia.²²⁷ Hyperphosphatemia observed very early in the course of EG intoxication (3 to 12 hours after ingestion) probably is the result of the high phosphorus content of rust-retardant antifreeze preparations.^57,69 Hyperechogenicity of the renal cortex is observed on renal ultrasonography as early as 5 hours after ingestion of EG.²

Figure 10-5 Photomicrographs of (A) calcium oxalate monohydrate and (B) dihydrate crystals in urine sediment.

(From Chew DJ, DiBartola SP. Diagnosis and pathophysiology of renal disease. In: Ettinger SJ, editor. Textbook of veterinary internal medicine. Philadelphia: WB Saunders, 1989: 1907.)

Treatment

The response to treatment depends on the amount of EG ingested and the amount of time that elapses before treatment. In early studies, dogs that ingested less than 10 mL/kg EG were saved if treated within 2 to 4 hours of ingestion,^17,175,205 and cats survived up to 6 mL/kg EG if treated within 4 hours.¹⁸⁷ Treatment consists of inducing vomiting with apomorphine or performing gastric lavage with activated charcoal if ingestion has been recent (<8 hours before presentation). Severe hypocalcemia is corrected with calcium gluconate, and NaHCO₃ is administered to combat metabolic acidosis. A NaHCO₃ dosage of 1 to 2 mEq/kg may be used empirically. Calcium gluconate and NaHCO₃ must not be given simultaneously because calcium carbonate crystals form, and the solution becomes turbid. Attempts to stimulate urine production with furosemide (2 to 4 mg/kg) or mannitol (1 g/kg) usually are futile.

Alcohol dehydrogenase has greater affinity for ethanol than EG. For this reason, 20% ethanol has been administered intravenously to affected dogs at a dosage of 5.5 mL/kg every 4 hours for five treatments and then every 6 hours for four additional treatments.⁹⁶ Cats are treated with 20% ethanol at a dosage of 5 mL/kg every 6 hours for five treatments and then every 8 hours for four additional treatments. This treatment is unlikely to be of benefit if more than 12 to 24 hours have elapsed since ingestion of EG. Fomepizole (4-methylpyrazole) is a pharmacologic inhibitor of alcohol dehydrogenase that can be used to treat dogs with EG toxicosis.^67,69 In dogs, it is superior to ethanol because it does not cause central nervous system (CNS) depression, but it must be administered within 8 hours of EG ingestion. The dosage of fomepizole used in dogs with EG intoxication is 20 mg/kg intravenously, followed by 15 mg/kg intravenously at 12 and 24 hours and 5 mg/kg intravenously at 36 hours.^57,67,69 Unfortunately, fomepizole was not efficacious in EG-intoxicated cats unless administered at the same time as the EG was consumed.⁶⁸ A study to investigate the difference in efficacy of fomepizole between dogs and cats found that the percentage inhibition of canine and feline alcohol dehydrogenase was similar when the concentration of fomepizole applied to feline liver homogenates was 6 times higher than that applied to canine liver homogenates.⁵⁸ When cats that received lethal doses of EG were treated within 3 hours of ingestion using 125 mg/kg fomepizole followed by 31 mg/kg at 12, 24, and 36 hours, 5 of 6 survived.⁵⁹ One cat developed acute renal failure but recovered. Cats treated with this high dosage of fomepizole developed mild sedation, but no biochemical evidence of toxicity was identified.

Thiamine promotes conversion of glyoxylate to glycine, and pyridoxine promotes conversion of glyoxylate to α-hydroxy-β-ketoadipate (see Fig. 10-4). These vitamins may be administered to promote alternative pathways of glyoxylate metabolism, but efficacy has not been demonstrated for such treatment. In one study, all nonazotemic dogs treated with fomepizole within 2 to 8.5 hours after EG ingestion survived, whereas only 1 of 21 azotemic dogs treated 8.5 to 38 hours after ingestion survived.⁵⁷

Peritoneal dialysis or hemodialysis is necessary if the animal has anuric or oliguric renal failure at the time of presentation. Early dialysis may also be helpful to remove toxic intermediate metabolites. Despite dialysis, affected dogs may progress to end-stage renal disease and become dependent on dialysis. The prognosis for survival in adult dogs and cats with anuric or oliguric acute renal failure caused by EG intoxication is unfortunately very poor.^57,227

Pathophysiology

Overproduction of acetoacetic acid (pK’_a = 3.58) and β-hydroxybutyrate (pK’_a = 4.70) by the liver occurs in diabetes mellitus because of a deficiency of insulin and relative excess of glucagon. An increase in glucagon and a decrease in insulin shift the liver from its normal role in esterification of fatty acids into triglycerides to β-oxidation of fatty acids into ketoacids. At the normal pH of ECF (7.40), these organic acids are completely dissociated, and the hydrogen ions that are released titrate HCO₃⁻ and other body buffers. Acetone is formed by the nonenzymatic decarboxylation of acetoacetate and does not contribute additional fixed acid. The pathophysiology and treatment of diabetic ketoacidosis are discussed in detail in Chapter 20.

Metabolic acidosis is common in dogs and cats with diabetic ketoacidosis. In one series, mean plasma HCO₃⁻ concentration in 72 dogs with diabetic ketoacidosis was approximately 11 mEq/L at the time of diagnosis with a range of 4 to 20 mEq/L, whereas the mean HCO₃⁻ concentration in 20 affected cats was 13 mEq/L with a range of 8 to 22 mEq/L.⁸³ In an early study of dogs with diabetes mellitus, mean plasma HCO₃⁻ concentration was 13.7 mEq/L in eight survivors (range, 9.3 to 21.0 mEq/L) and 18.1 mEq/L in five nonsurvivors (range, 13.4 to 30.2 mEq/L).¹³⁸ In another study of dogs with diabetic ketoacidosis, mean arterial pH and HCO₃⁻ concentration were 7.201 (range, 6.986 to 7.395) and 11.1 mEq/L (range, 4.1 to 19.7 mEq/L) before treatment and 7.407 ± 0.053 and 18.2 ± 0.7 mEq/L 24 hours after treatment.¹⁴² Only three dogs (those with pH <7.1) received sodium bicarbonate treatment. Metabolic acidosis with median pH of 7.14 (range, 7.04 to 7.24) and HCO₃⁻ concentration of 10 mEq/L (range, 6 to 15 mEq/L) was found in 25 of 33 cats evaluated by venous blood gas analysis in a survey of cats with diabetic ketoacidosis.³¹ Cats with HCO₃⁻ concentrations below 14 mEq/L received bicarbonate supplementation of their fluids. In another series of diabetic cats, median total CO₂ was 13 mEq/L in ketoacidotic cats and 15 mEq/L in nonketoacidotic cats.⁶³ In a study of 116 dogs with diabetes mellitus, 43 (37%) had diabetic ketoacidosis with median venous blood pH of 7.228 (range, 6.979 to 7.374) and median bicarbonate concentration of 10.1 mEq/L (range, 4.0 to 19.3 mEq/L).⁷⁸ In a study of 127 dogs with ketoacidosis, acid-base status at presentation had substantial impact on outcome.¹¹⁷ Nonsurvivors had lower venous pH and larger base deficits, and for each unit improvement in base deficit there was a 9% increase in likelihood of discharge from the hospital.

The nitroprusside reagent (e.g., Acetest, Bayer, Tarrytown, N.Y.) detects only ketone (−C=O) groups (e.g., acetoacetate, acetone). The concentration of β-hydroxybutyrate typically exceeds that of acetoacetate in uncontrolled diabetic ketoacidosis, and the dipstick reaction underestimates the degree of ketonuria. This problem can be overcome by adding a few drops of hydrogen peroxide to urine, which nonenzymatically converts β-hydroxybutyrate to acetoacetate.¹⁷¹ When insulin is administered and metabolism of ketones proceeds, there is a shift toward acetoacetate, and the dipstick reaction transiently becomes more strongly positive. This possibility should be recognized by the clinician and should not cause concern. In a study of 116 diabetic dogs (of which 88 had not previously received insulin), all ketotic and ketoacidotic dogs and 21 of 32 (66%) “nonketotic” dogs (i.e., negative urine dipstick test for ketones) had abnormally high serum β-hydroxybutyrate concentrations (>0.15 mmol/L) at presentation.⁷⁸ Although not as readily available, measurement of plasma ß-hydroxybutyrate concentrations is more valuable than use of dipstick tests in the characterization of ketonemia in diabetic dogs and cats.^74,242,243 The increase in unmeasured anions (as reflected in the anion gap) gives a rough estimate of the concentration of ketoanions in serum. However, this estimate is inaccurate if lactic acidosis develops because lactate also is an unmeasured anion. In one study of diabetic dogs, however, acidosis was correlated primarily with serum ketone concentration, and not with serum lactate concentration.⁷⁹

To some extent, the anions of these ketoacids are excreted in urine along with sodium and potassium for electroneutrality. These organic anions are lost from the body and cannot be metabolized to HCO₃⁻ after correction of diabetic ketoacidosis with insulin therapy. Their loss thus contributes to depletion of body buffer and cation stores. Osmotic diuresis is induced by hyperglycemia and also contributes to the whole-body cation deficit. The extent of impairment in renal function may determine whether patients with diabetic ketoacidosis have an increased anion gap metabolic acidosis or hyperchloremic metabolic acidosis at the time of presentation. Patients with severe volume depletion have an increased anion gap because of retention of ketoanions, whereas those without volume depletion have hyperchloremia as a result of increased urinary excretion of the sodium and potassium salts of ketoanions and retention of chloride.^5,9

Treatment

The best treatment for the acidosis of uncontrolled diabetes mellitus is fluid therapy and insulin. Insulin administration allows glucose use by skeletal muscle and adipose tissue, decreases hepatic glucose production, prevents lipolysis and ketogenesis, and permits peripheral metabolism of ketoacids. Several regimens for administration of insulin to ketoacidotic dogs and cats have been described.⁸⁴ The particular protocol of insulin administration is probably less crucial to the ultimate outcome than the individualized care provided by the veterinarian during management of the diabetic animal.

Several factors may contribute to a delay in the repair of the HCO₃⁻ deficit in patients with diabetic ketoacidosis.¹⁰⁰ Ketoacid anions that have been excreted in the urine are lost to the body and cannot be metabolized to HCO₃⁻. After treatment with fluids and insulin, recovery may be faster in patients with a high anion gap because the retained ketoanions are metabolized, yielding HCO₃⁻.^7,9 Thus, withholding alkali may be more rational for diabetic patients with high anion gap metabolic acidosis than for those with hyperchloremic metabolic acidosis. Dilutional acidosis may occur if ECF volume (ECFV) is expanded with alkali-free solutions such as 0.9% saline. If hyperventilation persists, it may impair renal reabsorption of HCO₃⁻, and renal acid excretion may require several days to become fully augmented.

The use of NaHCO₃ to treat diabetic ketoacidosis is highly controversial, and clear benefits of its use have not been demonstrated in human patients. For example, there was no difference in recovery (based on rate of decrease of blood glucose and ketone concentrations and rate of increase of blood or cerebrospinal fluid [CSF] pH or HCO₃⁻ concentration) when NaHCO₃ was or was not administered to human patients with diabetic ketoacidosis who presented with blood pH values in the range of 6.90 to 7.14.¹⁶⁶ In another study, treatment with NaHCO₃ delayed resolution of ketosis in diabetic ketoacidosis.¹⁷⁸

There are several theoretical arguments against the use of NaHCO₃ in diabetic ketoacidosis. Acidosis in the CNS may develop after NaHCO₃ administration. The blood-brain barrier is permeable to CO₂ but less permeable to the charged HCO₃⁻ ion. If NaHCO₃ is administered, pH increases in ECF as the HCO₃⁻/ P_CO2 ratio increases, and compensatory hyperventilation decreases somewhat. As a result, P_CO2 increases and CO₂ diffuses into the CNS. However, bicarbonate diffusion into CNS lags behind that of CO₂. During this time, the HCO₃⁻ P_CO2 ratio and pH in the CNS may decrease. This has been referred to as paradoxical CNS acidosis.¹⁹² The frequency of occurrence of this complication and its clinical significance are uncertain.¹³⁵

The pathophysiology of diabetic ketoacidosis also affects oxygen delivery to tissues. Chronic acidosis shifts the oxygen-hemoglobin dissociation curve to the right, thus enhancing delivery of oxygen to the tissues. Conversely, phosphorus deficiency in diabetes decreases red cell 2,3-diphosphoglycerate concentration and causes a shift of the oxygen-hemoglobin dissociation curve back to the left. Correction of acidosis with NaHCO₃ shifts the curve farther to the left and potentially decreases oxygen delivery to tissues. However, administration of insulin and fluid therapy also lead to correction of the acidosis and should have a similar effect on the oxygen-hemoglobin dissociation curve.

Overzealous therapy with NaHCO₃ may contribute to late development of metabolic alkalosis because insulin promotes metabolism of retained ketoacid anions to HCO₃⁻. This excess HCO₃⁻ should be readily excreted in the urine if renal function is adequate. Other potentially detrimental effects of NaHCO₃ therapy include aggravation of hyperosmolality as a consequence of the obligatory sodium load, tetany resulting from a sudden decrease in ionized serum calcium concentration, and precipitation of severe hypokalemia as extracellular potassium ions move into cells during administration of insulin and correction of acidosis. For all these reasons, NaHCO₃ is not used unless severe acidosis (pH <7.1 to 7.2) is present and then only in small amounts (see the Treatment of Metabolic Acidosis section).

Pathophysiology

The metabolic acidosis of chronic renal failure is usually mild to moderate in severity (plasma HCO₃⁻ concentration, 12 to 15 mEq/L) and may be hyperchloremic early in the course of the disease process.²³⁹ Later in the course of the disease, the anion gap increases because of retention of phosphates, sulfates, and organic anions. Acid-base status is usually well preserved in chronic renal failure until GFR decreases to 10% to 20% of normal. In retrospective studies of small animal patients with chronic renal failure, plasma HCO₃⁻ concentrations were less than 16 mEq/L in 40% of dogs with chronic renal failure caused by amyloidosis⁷² and less than 15 mEq/L in 63% of cats with chronic renal failure of various causes.⁷¹ A high anion gap was observed in 43% of affected dogs (>25 mEq/L) and in 19% of affected cats (>35 mEq/L) in these studies. In acute renal failure, there has been insufficient time for the kidneys to adapt to the disease state, and the metabolic acidosis of acute renal failure is usually more severe than that observed in chronic renal failure. Complications such as sepsis and marked tissue catabolism may contribute to the severity of metabolic acidosis in acute renal failure.

Delivery of HCO₃⁻ from the proximal tubules to the distal nephron is increased in chronic renal failure.²³⁵ In dogs with experimentally induced unilateral renal disease, renal HCO₃⁻ reabsorption was not different in the diseased and control kidneys, but bicarbonaturia developed when the normal kidney was removed, and the contralateral diseased kidney was forced to function in a uremic environment.¹⁶⁵ The osmotic diuresis characteristic of uremia may thus contribute to the increased delivery of HCO₃⁻ to the distal tubules. Increased parathyroid hormone concentration as a result of renal secondary hyperparathyroidism does not seem to have important adverse effects on HCO₃⁻ reabsorption in experimentally induced renal disease in dogs.^12,206,207 The ability to lower urine pH maximally is preserved in chronic renal failure.

The main method by which the diseased kidney responds to chronic retention of fixed acid is by enhanced renal ammoniagenesis. Total ammonium excretion decreases during progressive chronic renal disease, but ammonium excretion is observed to be markedly increased when expressed per 100 mL GFR or per remnant nephron.^75,202 On a per nephron basis, the diseased kidney can increase its ammonium excretion threefold to fivefold.^219,235,238 This adaptive mechanism seems to be fully expended when the GFR decreases to less than 20% of normal. At this point, the diseased kidneys can no longer effectively cope with the daily fixed acid load, and a new steady state is established at a lower than normal plasma HCO₃⁻ concentration. The relatively mild decrease in plasma HCO₃⁻ concentration that is observed in chronic renal failure has been attributed to the contribution of the large reservoir of buffer (e.g., calcium carbonate) in bone. However, the capacity of the skeleton to buffer the amount of acid that accumulates in long-standing chronic renal failure has been questioned.¹⁷⁷ The decrease in total ammonium excretion that occurs in chronic renal failure may be counterbalanced by decreased urinary excretion of organic anions (e.g., citrate, lactate, pyruvate, ketoanions).⁵⁶ Metabolism of these retained organic anions would result in a net gain of HCO₃⁻ that would offset the decreased excretion of H⁺ in the form of NH₄⁺.

The amount of phosphate buffer available in urine in chronic renal failure is relatively fixed and likely to be at its maximum because of hyperphosphatemia and the effects of increased plasma parathyroid hormone concentration.^202,219 Furthermore, phosphorus binders and dietary phosphorus restriction are commonly used to treat chronic renal failure and may limit the amount of phosphate that can contribute to titratable acidity. When expressed on a per nephron basis, however, titratable acidity is increased in chronic renal failure.¹⁶⁴