A patient has kidney failure. how may this affect the patient’s ability to compensate for acidosis?
Causes and diagnostic considerationsMetabolic acidosis is typically classified according to whether the anion gap (AG) is normal (ie, non-AG) or high. Non-AG metabolic acidosis is also characterized by hyperchloremia and is sometimes referred to as hyperchloremic acidosis. Calculation of the AG is thus helpful in the differential diagnosis of metabolic acidosis. [3, 5] Show
Normal anion gap metabolic acidosis Hyperchloremic or non-AG metabolic acidosis occurs principally when HCO3- is lost from either the GI tract or the kidneys or because of a renal acidification defect. Some of the mechanisms that result in a non-AG metabolic acidosis are the following:
Causes of non-AG metabolic acidosis can be remembered with the mnemonic ACCRUED:
Conditions that may cause a non-AG metabolic acidosis are as follows:
Causes of non-AG metabolic acidosis are discussed in more detail below. High anion gap metabolic acidosis High AG metabolic acidosis warrants consideration of the following:
Several mnemonics are used to help recall of the differential diagnosis of high anion gap acidosis. Three are as follows:
A more current mnemonic is GOLD MARK, which incorporates newly recognized forms of metabolic acidosis and eliminates P for paraldehyde as that is now rarely seen. [10]
Plasma osmolality and the osmolar gap can be helpful in determining the cause of high AG acidosis. Plasma osmolality can be calculated using the following equation: Posm = [2 × Na+]+[glucose in mg/dL]/18+[BUN in mg/dL]/2.8 Posm can also be measured in the laboratory, and because other solutes normally contribute minimally to serum osmolality, the difference between the measured and the calculated value (osmolar gap) is no more than 10-15 mOsm/kg. In certain situations, unmeasured osmotically active solutes in the plasma can raise the osmolar gap (eg, mannitol, radiocontrast agents). The osmolar gap can also be a clue to the nature of the anion in high-AG acidosis because some osmotically active toxins also cause a high-AG acidosis. Methanol, ethylene glycol, and acetone are classic poisons that increase the osmolar gap and AG; measuring the osmolar gap can help narrow the differential diagnosis of high-AG acidosis. Causes of AG metabolic acidosis are discussed in more detail below. Specific causes of hyperchloremic or non-AG metabolic acidosisLoss of HCO3- via the GI tract The secretions of the GI tract, with the exception of the stomach, are relatively alkaline, with high concentrations of base (50-70 mEq/L). Significant loss of lower GI secretions results in metabolic acidosis, especially when the kidneys are unable to adapt to the loss by increasing net renal acid excretion. Such losses can occur in diarrheal states, fistula with drainage from the pancreas or the lower GI tract, and sometimes vomiting if it occurs as a result of intestinal obstruction. When pancreatic transplantation is performed, the pancreatic duct is sometimes diverted into the recipient bladder, from where exocrine pancreatic secretions are lost in the final urine. Significant loss also occurs in patients who abuse laxatives, which should be suspected when the etiology for non-AG metabolic acidosis is not clear. Urine pH will be less than 5.3, with a negative urine AG reflecting normal urine acidification and increased NH4+ excretion. However, if distal Na+ delivery is limited because of volume depletion, theurine pH cannot be lowered maximally. Replacing the lost HCO3- on a daily basis can treat this form of metabolic acidosis. Distal RTA (type 1) (see the Table below) The defect in this type of RTA is a decrease in net H+ secreted by the A-type intercalated cells of the collecting duct. As mentioned previously, H+ is secreted by the apical H+–ATPase and, to a lesser extent, by the apical K+/H+–ATPase. The K+/H+–ATPase seems to be more important in K+ regulation than in H+ secretion. The secreted H+ is then excreted as free ions (reflected by urine pH value) or titrated by urinary buffers, phosphate, and NH3. A decrease in the amount of H+ secreted results in a reduction in its urinary concentration (ie, increase in urine pH) and a reduction in total H+ buffered by urinary phosphate or NH3. Type 1 RTA should be suspected in any patient with non-AG metabolic acidosis and a urine pH greater than 5.0. Patients have a reduction in serum HCO3- to various degrees, in some cases to less than 10 mEq/L. They are able to reabsorb HCO3- normally, and their fractional excretion (FE) of HCO3- is less than 3%. The disorder has been classified into 4 types—secretory, rate dependent, gradient, and voltage dependent—based on the nature of the defect. Several different mechanisms are implicated in the development of distal RTA. These include a defect in 1 of the 2 proton pumps, H+–ATPase or K+/H+–ATPase, that can be acquired or congenital. This may lead to loss of function (ie, secretory defect) or a reduction in the rate of H+ secretion (ie, rate-dependent defect). Another mechanism is a defect in the basolateral Cl-/HCO3- exchanger, AE1, or the intracellular carbonic anhydrase that can be acquired or congenital. This also causes a secretory defect. Back-diffusion of the H+ from the lumen via the paracellular or transcellular space is another mechanism; this occurs if the integrity of the tight junctions is lost or permeability of the apical membrane is increased (ie, permeability or gradient defect). With a urine pH of 5.0 and an interstitial fluid pH of 7.4, the concentration gradient facilitating back-diffusion of free H+, under conditions of increased permeability of the collecting duct epithelia, is approximately 250-fold. A defect in Na+ reabsorption in the collecting duct would decrease the electrical gradient favoring the secretion of H+ into the tubular lumen (ie, voltage-dependent defect). This can occur, for instance, in severe volume depletion with decreased luminal Na+ delivery to this site. The serum potassium level typically is low in patients with distal RTA because defects in H+ secretion or back-diffusion of H+ tend to increase urinary K+ wasting. Potassium wasting occurs from one or more of the following factors:
The serum K+ level can be high if the distal RTA is secondary to decreased luminal Na+ in the distal nephron. Na+ reabsorption in the principal cells of the collecting duct serves as the driving force for K+ secretion. In this case, the patient has hyperkalemia and acidosis; the disorder is also called voltage-dependent or hyperkalemic type 1 acidosis. Urine AG is positive and urine pH is high secondary to the renal acid secretion defect. Urine pH also can be high in patients with type 2 RTA if their serum HCO3- level is higher than the renal threshold for reabsorption, typically when a patient with type 2 RTA is on HCO3- replacement therapy. Administration of an HCO3- load leads to a marked increase in urine pH in those who have type 2 RTA, while those with type 1 RTA have a constant urine pH unless their acidosis is overcorrected. Patients with type 1 RTA may develop nephrocalcinosis and nephrolithiasis. This is thought to occur for the following reasons:
The causes of distal RTA are shown as follows. Type 1 RTA occurs sporadically, although genetic forms have been reported.
The genetic forms of type 1 RTA are the following:
Proximal (type 2) RTA The hallmark of type 2 RTA is impairment in proximal tubular HCO3- reabsorption. In the euvolemic state and in the absence of elevated levels of serum HCO3-, all filtered HCO3- is reabsorbed, 90% of which is in the proximal tubule. Normally, HCO3- excretion occurs only when serum HCO3- exceeds 24-28 mEq/L. Patients with type 2 RTA, however, have a lower threshold for excretion of HCO3-, leading to a loss of filtered HCO3- until the serum HCO3- concentration reaches the lower threshold. At this point, bicarbonaturia ceases and the urine appears appropriately acidified. Serum HCO3- typically does not fall below 15 mEq/L because of the ability of the collecting duct to reabsorb some HCO3-. Type 2 RTA can be found as a solitary proximal tubular defect, in which reabsorption of HCO3- is the only abnormality (rare) such as with homozygous mutations in SLC4A4. More commonly, it is part of a more generalized defect of the proximal tubule characterized by glucosuria, aminoaciduria, and phosphaturia, also called Fanconi syndrome. Dent disease or X-linked hypercalciuric nephrolithiasis is one example of a generalized proximal tubular disorder characterized by an acidification defect, hypophosphatemia, and hypercalciuria and arises from mutations in the renal chloride channel gene (CLCN5). Homozygous mutations in SCL34A1 also cause a genetic form of Fanconi syndrome. The proximal tubule is the site where bulk reabsorption of ultrafiltrate occurs, driven by the basolateral Na+/K+ –ATPase. Any disorder that leads to decreased ATP production or a disorder involving Na+ -K+ –ATPase can result in Fanconi syndrome. In principle, loss of function of the apical Na+/H+ antiporter or the basolateral Na+/3HCO3- cotransporter or the intracellular carbonic anhydrase results in selective reduction in HCO3- reabsorption. Patients with type 2 RTA typically have hypokalemia and increased urinary K+ wasting. This is thought, in part, to be due to an increased rate of urine flow to the distal nephron caused by the reduced proximal HCO3- reabsorption and, in part, to be due to activation of the renin-angiotensin-aldosterone axis with increased collecting duct Na+ reabsorption from the mild hypovolemia induced by bicarbonaturia. Administration of alkali in those patients leads to more HCO3- wasting and can worsen hypokalemia unless K+ is replaced simultaneously. The diagnosis of type 2 RTA should be suspected in patients who have a normal-AG metabolic acidosis with a serum HCO3- level usually greater than 15 mEq/L and acidic urine (pH < 5.0). Those patients have an FEHCO3- less than 3% when their serum HCO3- is low. However, raising serum HCO3- above their lower threshold and closer to normal levels results in significant HCO3- wasting and an FEHCO3 exceeding 15%. FEHCO3- = (urine [HCO3-] X plasma [creatinine] / plasma [HCO3-]) X urine [creatinine] X 100 Some patients with type 2 RTA tend to have osteomalacia, a condition that can be observed in any chronic acidemic state, although it is more common in persons with type 2 RTA. The traditional explanation is that the proximal tubular conversion of 25(OH)-cholecalciferol to the active 1,25(OH)2-cholecalciferol is impaired. Patients with more generalized defects in proximal tubular function (as in Fanconi syndrome) may have phosphaturia and hypophosphatemia, which also predispose to osteomalacia. The following are causes of proximal RTA:
Isolated proximal RTA occurs sporadically, although an inherited form has recently been described. Homozygous mutations in the apical Na+/3HCO3- cotransporter have been found in 2 kindred with proximal RTA, band keratopathy, glaucoma, and cataracts. A form of autosomal recessive osteopetrosis with mental retardation is associated with a mixed RTA with features of both proximal and distal disease (called type 3). The mixed defect is related to the deficiency of carbonic anhydrase (CA II isoform) normally found in the cytosol of the proximal tubular cells and the intercalated cells of the collecting duct. The most common cause of acquired proximal RTA in adults follows the use of carbonic anhydrase inhibitors. Type 4 RTA This is the most common form of RTA in adults and results from aldosterone deficiency or resistance. The collecting duct is a major site of aldosterone action; there it stimulates Na+ reabsorption and K+ secretion in the principal cells and stimulates H+ secretion in the A-type intercalated cells. Hypoaldosteronism, therefore, is associated with decreased collecting duct Na+ reabsorption, hyperkalemia, and metabolic acidosis. Hyperkalemia also reduces proximal tubular NH4+ production and decreases NH4+ absorption by the thick ascending limb, leading to a reduction in medullary interstitial NH3 concentration. This diminishes the ability of the kidneys to excrete an acid load and worsens the acidosis. Because the function of H+ –ATPase is normal, the urine is appropriately acidic in this form of RTA. Correction of hyperkalemia leads to correction of metabolic acidosis in many patients, pointing to the central role of hyperkalemia in the pathogenesis of this acidosis. Almost all patients with type 4 RTA manifest varying degrees of hyperkalemia, which commonly is asymptomatic. The etiology of hyperkalemia is multifactorial and related to the presence of hypoaldosteronism in conjunction with a degree of renal insufficiency. The acidosis and hyperkalemia, however, are out of proportion to the degree of renal failure. The following findings are typical of type 4 RTA:
Type 4 RTA should be suspected in any patient with a mild non-AG metabolic acidosis and hyperkalemia. The serum HCO3- level is usually greater than 15 mEq/L, and the urine pH is less than 5.0 because these patients have a normal ability to secrete H+. The primary problem is hyperkalemia from aldosterone deficiency or end organ (collecting duct) resistance to the action of aldosterone. This can be diagnosed by measuring the transtubular potassium gradient (TTKG). TTKG = urine K+ X serum osmolality/serum K+ X urine osmolality A TTKG greater than 8 indicates that aldosterone is present and the collecting duct is responsive to it. A TTKG less than 5 in the presence of hyperkalemia indicates aldosterone deficiency or resistance. For the test to be interpretable, the urine Na+ level should be greater than 10 mEq/L and the urine osmolality should be greater than or equal to serum osmolality. The hyperkalemia suppresses renal ammoniagenesis, leading to a lack of urinary buffers to excrete the total H+ load. The urine AG will be positive. Note that patients with hyperkalemic type 1 RTA have a urine pH greater than 5.5 and a low urine Na+. The following are causes of type 4 RTA:
Although type 4 RTA occurs sporadically, familial forms have been reported. The genetic forms are called PHA; PHA type 1 is characterized by hypotension with hyperkalemia and acidosis and includes an autosomal recessive and autosomal dominant form. PHA type 2 is characterized by hypertension with hyperkalemia and acidosis and is also known as Gordon syndrome and familial hyperkalemic hypertension. Note the following:
Table. Comparison of Types 1, 2, and 4 RTA (Open Table in a new window)
Early renal failure Metabolic acidosis is usual in patients with renal failure, and, in early to moderate stages of chronic kidney disease (glomerular filtration rate of 20-50 mL/min), it is associated with a normal AG (hyperchloremic). In more advanced renal failure, the acidosis is associated with a high AG. In hyperchloremic acidosis, reduced ammoniagenesis (secondary to loss of functioning renal mass) is the primary defect, leading to an inability of the kidneys to excrete the normal daily acid load. In addition, NH3 reabsorption and recycling may be impaired, leading to reduced medullary interstitial NH3 concentration. In general, patients tend to have a serum HCO3- level greater than 12 mEq/L, and buffering by the skeleton prevents further decline in serum HCO3-. Note that patients with hypobicarbonatemia from renal failure cannot compensate for additional HCO3- loss from an extrarenal source (eg, diarrhea) and severe metabolic acidosis can develop rapidly. Urinary diversion Hyperchloremic metabolic acidosis can develop in patients who undergo a urinary diversion procedure, such as a sigmoid bladder or an ileal conduit. This occurs through 1 of the following 2 mechanisms: The first is the intestinal mucosa has an apical Cl-/HCO3- exchanger. When urine is diverted to a loop of bowel (as in patients with obstructive uropathy), the chloride in the urine is exchanged for HCO3-. Significant loss of HCO3- can occur, with a concurrent increase in serum Cl- concentration. The second is intestinal mucosa reabsorbs urinary NH4+, and the latter is metabolized in the liver to NH3 and H+. This is particularly likely to occur if urine contact time with the intestinal mucosa is prolonged, as when a long loop of bowel is used or when the stoma is obstructed and when sigmoid rather than ileal loop is used. Presumably, the creation of a continent bladder also increases HCO3- loss. This disorder is not observed very frequently anymore because short-loop incontinent ureteroileostomies are used now. Infusion of acids The addition of an acid that contains Cl- as an ion (eg, NH4 Cl) can result in a normal-AG acidosis because the drop in HCO3- is accompanied by an increase in Cl-. The use of arginine or lysine hydrochloride as amino acids during hyperalimentation can have the same result. Specific causes of high-AG metabolic acidosisLactic acidosis Briefly, L-lactate is a product of pyruvic acid metabolism in a reaction catalyzed by lactate dehydrogenase that also involves the conversion of nicotinamide adenine dinucleotide (NADH) to the oxidized form of nicotinamide adenine dinucleotide (NAD+). This is an equilibrium reaction that is bidirectional, and the amount of lactate produced is related to the reactant concentration in the cytosol (pyruvate, NADH/NAD+). Daily lactate production in a healthy person is substantial (approximately 20 mEq/kg/d), and this is usually metabolized to pyruvate in the liver, the kidneys, and, to a lesser degree, in the heart. Thus, production and use of lactate (ie, Cori cycle) is constant, keeping plasma lactate low. The major metabolic pathway for pyruvate is to acetyl coenzyme A, which then enters the citric acid cycle. In the presence of mitochondrial dysfunction, pyruvate accumulates in the cytosol and more lactate is produced. Lactic acid accumulates in blood whenever production is increased or use is decreased. A value greater than 4-5 mEq/L is considered diagnostic of lactic acidosis. Type A lactic acidosis occurs in hypoxic states, while type B occurs without associated tissue hypoxia. D-lactic acidosis is a form of lactic acidosis that occurs from overproduction of D-lactate by intestinal bacteria. It is observed in association with intestinal bacterial overgrowth syndromes. D-lactate is not measured routinely when lactate levels are ordered and must be requested specifically when such cases are suspected. Metformin-associated lactic acidosis has been reported. [11, 12] Ketoacidosis Free fatty acids released from adipose tissue have 2 principal fates. In the major pathway, triglycerides are synthesized in the cytosol of the liver. In the less common pathway, fatty acids enter mitochondria and are metabolized to ketoacids (acetoacetic acid and beta-hydroxybutyric acid) by the beta-oxidation pathway. Ketoacidosis occurs when delivery of free fatty acids to the liver or preferential conversion of fatty acids to ketoacids is increased. This pathway is favored when insulin is absent (as in the fasting state), in certain forms of diabetes, and when glucagon action is enhanced. Alcoholic ketoacidosis occurs when excess alcohol intake is accompanied by poor nutrition. Alcohol inhibits gluconeogenesis, and the fasting state leads to low insulin and high glucagon levels. These patients tend to have a mild degree of lactic acidosis. This diagnosis should be suspected in alcoholic patients who have an unexplained AG acidosis, and detection of beta-hydroxybutyric acid in the serum in the absence of hyperglycemia is highly suggestive. Patients may have more than one metabolic disturbance (eg, mild lactic acidosis, metabolic alkalosis secondary to vomiting). Starvation ketoacidosis can occur after prolonged fasting and may be exacerbated by exercise. DKA is usually precipitated in patients with type 1 diabetes by stressful conditions (eg, infection, surgery, emotional trauma), but it can also occur in patients with type 2 diabetes. Hyperglycemia, metabolic acidosis, and elevated beta-hydroxybutyrate confirm the diagnosis. The metabolic acidosis in DKA is commonly a high-AG acidosis secondary to the presence of ketones in the blood. However, after initiation of treatment with insulin, ketone production ceases, the liver uses ketones, and the acidosis becomes a non-AG type that resolves in a few days (ie, time necessary for kidneys to regenerate HCO3-, which was consumed during the acidosis). Advanced renal failure Patients with advanced chronic kidney disease (glomerular filtration rate of less than 20 mL/min) present with a high-AG acidosis. The acidosis occurs from reduced ammoniagenesis leading to a decrease in the amount of H+ buffered in the urine. The increase in AG is thought to occur because of the accumulation of sulfates, urates and phosphates from a reduction in glomerular filtration and from diminished tubular function. In persons with chronic uremic acidosis, bone salts contribute to buffering, and the serum HCO3- level usually remains greater than 12 mEq/L. This bone buffering can lead to significant loss of bone calcium with resulting osteopenia and osteomalacia. Salicylate overdose Deliberate or accidental ingestion of salicylates can produce a high-AG acidosis, although respiratory alkalosis is usually the more pronounced acid-base disorder. The increase in AG is only partly from the unmeasured salicylate anion. Increased ketoacid and lactic acid levels have been reported in persons with salicylate overdose and are thought to account for the remainder of the AG. Salicylic acid ionizes to salicylate and H+ ion with increasing pH; at a pH of 7.4, only 0.004% of salicylic acid is nonionized, as follows: Salicylic acid (HS)↔salicylate (S) + H+ (H+) HS is lipid soluble and can diffuse into the CNS; with a fall in pH, more HS is formed. The metabolic acidosis thus increases salicylate entry to the CNS, leading to respiratory alkalosis and CNS toxicity. Methanol poisoning Methanol ingestion is associated with the development of a high-AG metabolic acidosis. Methanol is metabolized by alcohol dehydrogenase to formaldehyde and then to formic acid. Formaldehyde is responsible for the optic nerve and CNS toxicity, while the increase in AG is from formic acid and from lactic acid and ketoacid accumulation. Clinical manifestations include optic nerve injury that can be appreciated by funduscopic examination as retinal edema, CNS depression, and unexplained metabolic acidosis with high anion and osmolar gaps. Ethylene glycol poisoning Ingestion of ethylene glycol, a component of antifreeze and engine coolants, leads to a high-AG acidosis. Ethylene glycol is converted by alcohol dehydrogenase first to glycoaldehyde and then to glycolic and glyoxylic acids. Glyoxylic acid then is degraded to several compounds, including oxalic acid, which is toxic, and glycine, which is relatively innocuous. The high AG is primarily from the accumulation of these acids, although a mild lactic acidosis also may be present. Patients present with CNS symptoms, including slurred speech, confusion, stupor or coma, myocardial depression, and renal failure with flank pain. Oxalate crystals are usually observed in the urine and are an important clue to the diagnosis, as is an elevated osmolar gap. How does the kidney compensate for acidosis?The kidneys compensate for a respiratory acidosis by tubular cells reabsorbing more HCO3 from the tubular fluid, collecting duct cells secreting more H+ and generating more HCO3, and ammoniagenesis leading to increased formation of the NH3 buffer.
How does kidney failure cause acidosis?Healthy kidneys remove acid from the body through urine and they keep the right amount of bicarbonate (base) in the blood. But in CKD, the kidneys can't remove enough acid, which can lead to metabolic acidosis.
Is kidney failure associated with acidosis?Metabolic acidosis is commonly found in patients with chronic kidney disease (CKD), and its causes are: impaired ammonia excretion, reduced tubular bicarbonate reabsorption and insufficient renal bicarbonate production in relation to the amount of acids synthesised by the body and ingested with food.
How do kidneys compensate for acidosis and alkalosis?In respiratory acidosis, the kidney produces and excretes ammonium (NH4+) and monophosphate, generating bicarbonate in the process while clearing acid. In respiratory alkalosis, less bicarbonate (HCO3−) is reabsorbed, thus lowering the pH.
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