ACID-BASE PATHOPHYSIOLOGY

The imidazole nitrogen of histidine, and the nitrogen of the N-terminal amino acid of proteins titrate ver the physiologic range of pH. These titrations change the structure, and therefore the function of these proteins. The proteins involved may be structural, transport protents, receptors, hormones, enzymes, hemoglobin, etc. pH therefore affects essentially every aspect of cell

Function by altering the structure of proteins and in some instances substrates, cofactors etc.

THE HCO₃/CO₂ BUFFER SYSTEM Acid-base homeostasis centers around the regulation of the HCO₃^-/CO₂ buffer system. Three key features of this buffer make it ideal for this purpose:

1) It is the buffer present at the highest concentrations in the body;

2) It’s pK value of 6.1 is close enough the physiologic pH to make it a good buffer; and

3) The major components of the buffer can be independently regulated by the lungs (CO₂) or Kidneys (HCO₃^-)

Because acid-bas regulations centers on the HCO₃^-/CO₂ buffer pair, all acid-base disorders are classified as being either respiratory (too much/too little CO₂) or metabolic (too much/too little HCO₃^-). The equations relating the components of the HCO₃^-/CO₂ buffer system are shown. With these equations you can calculate one parameter knowing the other two.

ACID-BASE BALANCE Acid-base balance means that the net quantity of acid or base we ingest is quantitatively excreted by the lungs and kidney. In this case we are in balance, the systemic pH will be stable, and the body buffers preserved. These are the major physiologic acid/bases:

	Acid	Base

MINERAL	H⁺	OH^-
	HCl	NH₃^--
	H₂SO₄	SO₄^-
	H₂PO₄	HPO₄^-

ORGANIC	CO₂	HCO₃^-
	LACTIC ACID	LACTATE^-
	b-HYDROXYBUTYRIC ACID	b-HYDROXYBUTYRATE^-

With a normal caloric intake of a meat-based diet the average person will generate approximately 20,000 mEq of acid/day in the form of CO₂ as the end-product of carbohydrate and fat metabolism. This CO₂ will be excreted by the lungs. Protein catabolism produces about1 mEq/kg (50-60 mEq/day) of inorganic acids (like sulfuric, phosphoric, or hydrochloric acids) which must be excreted by the kidney. To excrete this 50-60 mEq/day of acid into the final urine the kidney has to actually secrete 4370 mEq/day of acid: Most of this is used to titrate the filtered load of base (24 mEq/L HCO₃^- x 180 L/day = 4320 mEq/day), and only after this base has been titrated can net acid excretion be accomplished. Net acid excretion (NAE) is defined as:

NET ACID EXCRETION = NH₄Cl + titratable acid – HCO₃^-

The titrable acid is the amount of base needed to return the urine pH back to the systemic pH, and represents mostly the amount of H₂PO₄ in the urine. In general, whenever the urine pH is > 7 NAE will be zero or even negative because HCO₃^- will be present, all of the NH₄Cl will have been titrated to NH₃ and reabsorbed, and H₂PO₄ will have been titrated to HPO₄^-. If the urine pH is <6, NAE will always be positive because the HCO₃^-concentration at this pH is <1 mEq/L.

The Four Primary Acid-Base Disturbances

Type of Disturbance	Primary Alteration	Secondary Response	Mechanism of Secondary Response
Metabolic acidosis	Decrease in plasma [HCO₃^-]	Decrease in Pa CO₃	Hyperventilation
Metabolic alkalosis	Increase in plasma [HCO₃^-]	Increase in PaCO₃	Hypoventilation
Respiratory acidosis	Increase in PaCO3	Increase in plasma [HCO₃^-]	Acid titration of tissue buffers; transient increase in acid excretion and sustained enhancement of HCO₃^- reabsorption by kidney
Respiratory alkalosis	Decrease in Pa CO₃	Decrease in plasma [HCO₃^-]	Alkaline titration of tissue buffers; transient suppression of acid excretion and sustained reduction in bicarbonate reabsorption by kidney

Urine pH is usually acid, in the range of 5-6.5. This reflects the ongoing secretion of H⁺ by the kidney to excrete the daily acid load. The urine pH should always be checked in patients with acid-base disorders to be sure if the renal response is appropriate. With normal renal function, anyone with metabolic acidosis should have a very low urine pH, unless the kidneys are the cause of the acidosis as in renal tubular acidosis. Likewise, the urine should be maximally alkaline after infusing HCO₃^- to produce metabolic alkalosis, unless the kidneys are the cause of the alkalosis, as happens very commonly in the alkalosis associated with vomiting or volume depletion.

An alkaline urine pH is seen in several circumstances: This may occur physiologically whenever the filtered load of HCO3 exceeds the renal threshold. This happens after eating, as the “alkaline tide” from gastric acid secretion raises blood HCO3- enough to produce a urine pH around 8 due to NH3 formation. Urine left sitting usually has an alkaline pH due to CO2 loss. Strict vegetarians also have an alkaline urine.

The acid-base nomogram The acid-base nomogram illustrates the blood gas pattern that are seen when the various primary acid-base disorders are reproduced in otherwise normal patients. A simple acid-base disorder will produce a blood-gas pattern that falls in the shaded areas, and these responses reflect normal buffering and compensation. Another way of judging whether the buffering and compensatory responses are appropriate is to use the rules of thumb which have been derived from the nomogram.

Rules of Thumb for Bedside Interpretation of Acid-Base Disorders

Metabolic acidosis	PaCO₂ should fall by 1.0 to 1.5 X the fall in plasma HCO₃^- concentration
Metabolic alkalosis	PsCO₂ should rise by 0.25 to 1.0 X the rise in plasma HCO₃^- concentration
Acute respiratory acidosis	Plasma HCO₃^- concentration should rise by about 1 mmole per liter for each 10 mm Hg increment in PaCO₂ (± 3 mmoles per liter).
Chronic respiratory acidosis	Plasma HCO₃^-concentration should rise by about 4 mmoles per liter for each 10 mm Hg increment in PaCO₂ (± 4 mmoles per liter).
Acute respiratory alkalosis	Plasma HCO₃^-concentration should fall by about 1 to 3 mmoles per liter for each 10 mm Hg decrement in the PaCO₂, usually not to less than 18 mmoles per liter.
Chronic respiratory alkalosis	Plasma HCO₃^- concentration should fall by about 2 to 5 mmoles per liter per 10 mm Hg decrement in PaCO₂ but usually not to less than 14 mmoles per liter.

PLASMA ELECTROLYTES AND THE ANION GAP Plasma electrolytes are essential in unraveling acid-base disorders for two reasons. First, they reveal characteristic electrolyte patterns: a good example is the hypokalemia that accompanies many types of metabolic alkalosis. The second piece of useful information from the plasma electrolytes is the anion gap, which normally has a value of 12 ± 2 mEq/L.

The gap reflects unmeasured anions, mostly the negative charge on albumin. The gap is used to differentiate metabolic acidosis caused by loss of HCO₃^- (normal gap) from acidosis caused by organic acids like ketoacids, lactic acid, or toxins like ethylene glycol, or methanol.

In the case of HCO₃^- loss from RTA, HCO₃^- is lost in the urine in exchange for Cl. This results in hyperchloremia, the sum of Cl⁺ HCO₃ stays normal, as does the anion gap. In contrast, when metabolic acidosis is due to ingestion or production of any acid other than HCl, the anion gap will increase. This is because the H⁺ is accompanied by an unmeasured anion (lactate, acetoacetate , etc.) which replaces the HCO₃^- lost from titration. The sum of Cl + HCO₃ will therefore fall, causing the anion gap to increase.

RESPIRATORY ACIDOSIS represents CO₂ retention by the lungs. We generally divide this process into an acute phase (<24 hours) and more chronic phases. During the acute phase you will see the buffering response (HCO₃^- will increase about 1 mm for every 10 mm Hg increase in CO₂) but there has not yet been time for a renal response. Over the next few days renal acidification is stimulated by the increased pCO₂, and by about the 4^th day the fully-compensated picture emerges with HCO₃^- rising u to 4mm/10mm Hg increase in pCO₂.

RESPIRATORY ALKALOSIS represents hyperventilation and a primary reduction in pCO₂. The acute buffering response will drop HCO₃^- by about 1-3 mM/10 mm Hg change in pCO₂. The more chronic renal response is not well developed, but there is usually a small depression is renal acidification, which will lead to HCO₃^- wasting and a further decline in blood HCO₃^- so that the total change is 2-5 mM/10 mm Hg fall in pCO₂.

CHARACTERISTICS OF RENAL ACID-BASE HANDLING

To simplify our thinking about renal acidification we view it as a coordinated 2-step process: The first step is the reclamation of filtered bicarbonate. The second step is “net acid excretion”. As the last diagram illustrates, under normal conditions over 90% of the filtered load of HCO₃^- has been absorbed by the end of the proximal tubule, and the small amount remaining is reclaimed early in the distal nephron. Reclamation of HCO₃^- is therefore mostly the function of proximal acidification. Once HCO₃^- reclamation has taken place and HCO₃^- concentrations are low enough in the nephron, secreted H⁺ can be used to titrate NH₃ and HPO₄^- to form “net acid excretion”. This process requires very high luminal H⁺ concentrations, which are only obtainable in the collecting duct.

The proximal system behaves as if there were a threshold for HCO₃^- reabsorption, as shown in the following figure. The kidney can reabsorb filtered HCO₃^- up to plasma values of approximately 24-27 mEq/L, at which point the proximal system is saturated and all filtered HCO₃^- is excreted quantitatively. There are 3 important corrolaries that follow from this:

The U-B pCO₂ gradient Even though there can be no “net acid excretion”, it is important to realize that distal H⁺ secretion is still taking place at times when plasma HCO₃^- is elevated and large amounts of HCO₃^- are being excreted in the urine. The ongoing distal acidification can be detected and quantitated by measuring the pCO₂ tensions in the urine. These pCO₂ levels will rise substantially above plasma pCO₂ as the secreted H⁺ reacts with HCO₃^- in the tubular fluid, forming carbonic acid and hence CO₂ and H₂O.

Acidification takes place along the proximal and distal tubules, the thick ascending loop of Henle and the collecting duct. The thin loop of Henle doesn’t acidify that we know of and in fact may allow a bit of HCO₃^- backleak. An overview of the entire process is shown below, along with the pH and HCO₃^- at the various sites determined by micropuncture measurements, and the calculated net acid value. This net acid value starts out with a very large negative value, reflecting the amount of filtered HCO₃^-. We generally think of renal acidification as being divided into “proximal” and “distal” systems, each with unique features and mechanisms of proton secretion. This is a major oversimplification because the precise mechanism of acidification is different in the loop, the convoluted distal tubule, and in the cortical , outer and inner medullary collecting ducts. In fact, parts of cortical collecting duct can be shown to secrete HCO₃^- instead of acid if metabolic alkalosis is induced!

PROXIMAL ACIDIFICATION The high-capacity system responsible for over 90% of renal acidification is located in the proximal tubule. Proximal cells possess a large luminal surface area provided by the brush border. This membrane contains both carbonic anhydrase and the Na/H exchange protein which acidifies the lumen. This exchanger is driven by the sodium gradient from lumen (140 mM) to cell (10 mM). The very low values of cell Na arise from the actions of the basolateral Na/K ATPase which is constantly pumping Na out of the cell and K in. For each Na entering the cell from the urine, one H⁺ is exchanged into the urine. This H⁺ titrates one HCO₃^- to carbonic acid, which under the catalysis of carbonic anhydrase present on the brush border dissociates to CO₂. The CO₂ is freely permeable, and diffuses from the lumen to the cell. The reaction here runs in reverse, to produce H⁺ (which can recycle across the luminal membrane) and HCO₃^-, which leaves the cell through the basolateral membrane to enter the blood and regenerate the blood HCO₃^- levels. The proximal tubule is considered a “leaky” epithelium, and cannot sustain large transtubular gradients of electrical potential or pH. In fact, if the tubular fluid is artificially acidified to values below 6.5 acidification ceases because there are now higher H⁺ concentrations in the lumen than in the cell, offsetting the chemical driving force generated by the Na gradient. The primary function of the luminal carbonic anhydrase is to prevent the accumulation of carboinic acid; buildup of this H₂CO₃ would tend to shut off acidification by this effect.

DISTAL ACIDIFICATION After proximal acidification has effectively reabsorbed >90% of the filtered load of HCO₃^- the distal nephron can effectively secrete the final 50-60 mEq/day of acid needed to maintain balance. This is accomplished by the low-capacity but very potent H⁺ - ATPase present in the luminal membrane of a-type intercalated cells which is capable of secreting H⁺ to form up to a 1000 – fold H⁺ gradient from cells to urine (= 3 pH units). This secreted H⁺ titrates HPO₄⁼ to H₂PO₄^- and traps NH₃ as NH₄⁺. Net renal acidification is therefore quantitated as the sum of excreted NH₄⁺ and titratable acid (H₂PO₄^-) minus HCO₃^- and the latter term in acid urine is essentially zero. Distal acidification can therefore be measured in acid urine as the NAE, and in alkaline urine as the pCO₂ gradient between urine and blood. Recently, an H⁺ pump resembling the electroneutal gastric H/K – ATPase has been identified in some parts of the collecting duct, and this pump may contribute to renal H⁺ secretion. HCO₃^- secreting b-cells also exist in the distal nephron, but their role in renal acid/base secretion is not clear.

The distal H⁺pump is electrogenic, in contrast to the proximal Na/H exchanger which is electroneutral. This makes the distal system sensitive to electrical potential gradients, which can have important effects on urinary acidification. For example, active Na reabsorption at this site carries positive charge into the cell which will tend to augment H⁺ secretion by making the cell more positive, the lumen more electronegative. Likewise nonreabsorbable anions tend to augment distal H⁺ secretion by making the lumenal PD more negative relative to the cell interior. H⁺ secretion can also be stimulated by aldo or K depletion.

REGULATION OF PROXIMAL ACIDIFICATION

ECF volume: As outlined in previous lectures, the proximal nephron is very sensitive to the ECF volume state. In general, ECF volume depletion augments proximal reabsorption of practically all electrolytes, while ECF expansion depresses reabsorption. This seems to be true for the electrolytes handled by the Na/H exchanger: ECF depletion seems to augment both Na reabsorption and H⁺ secretion. This will augment acidification and HCO₃^- reabsorption. ECF expansion conversely depresses proximal acidification and HCO₃^- will be dumped in the urine because it will escape the proximal nephron and overwhelm the low-capacity distal system.

CO₂: Proximal acidification is also increased by CO₂, as seen in the figure below on the left. This mediates the renal compensation for respiratory acidosis. Likewise, the renal response to respiratory alkalosis is mediated by a decline in proximal neprhon acidification in response to the low pCO₂.

K⁺: As shown in the figure on the right, proximal acidification is also sensitive to K⁺. This may be relevent to metabolic alkalosis, in which proximal acidification is commonly increased, in part because of coexisting hypokalemia.

Misc. Proximal acidification is also affected by PTH, angiotensin, and systemic pH.

REGULATION OF DISTAL ACIDIFICATION Distal acidification is primarily thought to be regulated by aldosterone, which augments both H⁺ and K⁺ secretion. The distal system is also sensitive to systemic pH, pCO₂, and K⁺. The electrogenicity of distal H⁺ secretion, as discussed above, makes acidification sensitive to Na handling: anything which increases distal delivery of Na or nonreabsorbable anions will tend to increase H⁺ secretion. Finally, the diuretic furosemide is a potent stimulator of the distal system, and in fact a standard test of how well the kidney acidifies is to measure net acid exretion after a dose of furosemide.

METABOLIC ACIDOSIS

Metabolic acidosis is defined as a primary reduction in plasma HCO₃. This will produce acidemia in the arterial blood gas (unless there is another primary disorder which is more dominant!). The response to metabolic acidosis is outlined below. The addition of acid is first buffered by HCO₃ and other buffers. If the respiratory response is appropriate, ventilation will be stimulated. Overall, the pCO₂ will be reduced by 1-1.5 mm Hg per mEq/L fall in HCO₃. The renal response is to begin augmenting renal H⁺ secretion to clear the acid load and restore the normal body buffer composition. Note that in metabolic acidiosis the plasma HCO₃ is low, and therefore the filtered load of HCO₃ will be reduced. We therefore believe that the renal response involves primarily the distal acidification system, because if anything the proximal system has less of an H⁺ load to secrete. Renal H⁺ excretion will increase from normal values to 50-60 mEq/day to values an order of magnitude higher over several days. Because the renal excretion of phosphate is essentially stable, this increased NAE is largely in the form of NH₄⁺.

RESPONSE TO METABOLIC ACIDOSIS

BUFFERING: HCO₃^-

NON-HCO₃^- BUFFERS: PROTEINS

H⁺ + HCO₃^- « CO₂

PROTEIN « H-PROTEIN⁺

RESPIRATORY RESPONSE:

CNS ENTRY OF CO₂® ¯ pH

STIMULATION OF VENTILATION

CO2 FALLS BY 1-1.5 MM Hg / mEq/L CHANGE IN HCO₃^-

RENAL RESPONSE:

DISTAL ACIDIFICATION ® NET ACID EXCRETION

URINE pH MAXIMALLY ACID (<5.5

Chronic metabolic acidosis is dangerous because of progressive bone lysis and in children, growth retardation. Chronic metabolic acidosis should always be treated to prevent the resulting osteomalacia and restore growth. Acute metabolic acidosis is dangerous because it produces vasodilation and hypotension, and lowers the myocardial threshold for ventricular fibrillation. Treatment is necessary when the plasma HCO₃ falls below 15 mEq/L, and levels below10 should be considered an emergency. Remember that at HCO₃ levels below 10 very small changes of HCO₃ or pCO₂ levels will produce very drastic reductions in pH. Keep in mind that certain types of metabolic acidosis result in the accumulation of organic anions which can be metabolized to HCO₃ if the underlying problem is treated (DKA lactic acidosis in particular). Treatment with HCO₃ should not be overly aggressive in these cases, or it will produce an overshoot alkalosis.

INCREASED GAP METABOLIC ACIDOSIS represents the addition of some acid other than HCl to the body, and should be considered a medical emergency because the differential diagnosis includes the ingestion of toxins that can result in severe organ damage if the diagnosis is missed. In all these disorders the anion gap is increased because HCO₃ is titrated by the acid’s proton but the accompanying anion is usually not measured on the routine set of electrolytes. To make the diagnosis therefore requires trying to exclude renal failure, measuring ketoacids in urine and blood, and doing a thorough urinalysis and fundoscopic exam to detect ethylene glycol ingestion (produces oxalate crystals) or methanol ingestion (produces optic nerve hyperemia than ischemia). The ingestion of toxins can be assumed if there is a substantial osmolar gap. This is the difference between the osmolarity you calculated from the standard formula (estimated osm = 1.9 Na + Glu/18 + BUN/2.8 + 9) and the measured osmolality. Ingested ethanol, methanol, or ethylene glycol will result in a large osmolar gap, and the specific diagnosis can then be established by requesting an emergency screen of the urine for volatile toxins. (Please remember the “volatile” part – if you simply request a “toxic sceen” all you’ll get is testing for sedatives /narcotics!).

Some specific details on the various types of increased gap acidosis are presented below:

The acidosis of renal failure represents the inability to generate the required 1 mEq/kg of H⁺ NAE because there simply aren’t enough nephrons. The remaining nephrons work well, and the urine will therefore be maximally acid (pH < 6). The patient cannot maintain acid-base balance and will progressively titrate bone buffers until dialysis is started.

Diabetic ketoacidosis represents the accumulation of eta-hydroxybutyric acid and aceto-acetic acids. As diagrammed below chese accumulate as a result of the metabolic effects of insulin deficiency: there is increased lipolysis with release of fatty acids, and the acetyl-CoA endproducts cannot be effectively utilized in the Krebs cycle. The acetyl-CoA is therefore shunted to produce the ketoacids, which accumulate because of an associated defect in utilizing these substrates.

The diagnosis of DKA can be made by finding metabolic acidosis in the setting of hyperglycemia and an elevated anion gap. The dagnosis should always be confirmed by demonstrating “ketones” in the blood or urine using standard bedside tests. These tests use nitruprusside to detect ketone bodies and react substantially with acetone and acetoacetate but negligibly with beta-hydroxybutyrate. The test for ketones can actually be negative in some patients who have a severely deranged redox state and are producing predominantly beta-hydroxybutyrate.

Ethylene glycol ingestion produces acidosis by metabolism of the compound to oxalic acid (producing envelope-like crystals in the urine), and other acids. Ingestion is a true medical emergency because the kidney is rapidly and irreversibly damaed by the metabolites of ethylene glycol, and because the treatment is extremely effective in preventing this. Ethanol is given to produce legally drunk levels of 100 mg/ml, and at these concentrations ethanol serves as the preferred substrate for the alcohol dehydrogenase enzyme that otherwise would convert the ethylene glycol to the more toxic breakdown products. This allows enough time for hemodialysis to be performed which directly removes the ethylene glycol. The diagnosis should be suspected in every patient with an unexplained increased-gap metabolic acidosis, especially alcoholics. The diagnosis should be pursued (by obtaining a stat urinary screen for volatile toxins) if the urine contains oxalate crystals, or if there is an osmolar gap in the plasma.

EHYLENE GLYCOL POISONING

SOURCE: ANTIFREEZE

PATIENT: ALCOHOLIC, RAN OUT OF ETOH

TOXICITY: 100 ml LETHAL; METABOLIZED TO OXALIC ACID, OTHER ACIDS

CLINICAL: EARLY: CRYSTALURIA, CNS (DRUNK, SOMMOLENT, COMA)

METABOLIC ACIDOSIS WITH ELEVATED ANION GAP

MID: PULMONARY EDEMA OR CONGESTION

LATE: ACUTE RENAL FAILURE

TREATMENT: ETOH

IMMEDIATE DIALYSIS

Methanol ingestion is equally toxic because the metabolites (formic acid) damage the optic nerve producing blindness. Suspect methanol ingestion if there is the characteristic odor on the breath, if there are any compliants of visual disturbances or any fundoscopic abnormalities, or if there is an osmolar gap. As in the case of ethylene glycol poisoning, the toxicity is entirely preventable if treatment (ETOH, dialysis) is started early.

HYPERCHLOREMIC METABOLIC ACIDOSIS represents the loss of HCO₃ from either the kidney (renal tubular acidosis = RTA) or the GI tract. In either case the HCO₃ is lost in exchange for Cl^-. This results in hyperchloremia, and a normal gap because each lost HCO₃ is replaced by Cl^-. Keep in mind that diarrhea is probably several thousand times more common than RTA and that the diagnosis of diarrhea should be clear from the patient’s history! If for some reason the history could not be obtained, the urinary findings should clearly distinguish whether the HCO₃ loss is from the kidney or GI tract: with GI loss of HCO₃, the normal kidney sees a systemic metabolic acidosis and will augment both proximal and distal acidification to increase net acid acid excretion. This will tend to correct the acidemia, because each additional h+ excreted returns one HCO₃ to the blood to restore the deficit. The urine should therefore be acid (pH < 6) with generous amounts of NH₄Cl. Urinary NH₄ can be estimated by calculating the urinary anion gap as Na + K – Cl. Because of the high concentrations of the unmeasured caton NH₄⁺, the urinary anion gap is negative in patients with metabolic acidosis due to acid ingestion or from GI loss of HCO₃. In contrast, in distal RTA the urine is usually not as acid (pH is > 6.0) and the anion gap is near 0 or positive because of the inability to trap NH3 in the urine. The urinary anion gap will not be much help in detecting proximal RTA, and you will get a clue if this is the problem when you correct the acidosis with HCO₃ and see massive HCO₃ wasting as you approach normal levels of plasma HCO₃.

RENAL TUBULAR ACIDOSISMetabolic acidosis can originate from renal defects in acid secretion, resulting in renal tubular acidosis (RTA). All types of RTA produce a systemic metabolic acidosis with a normal anion gap. Serun k+ is often high or low, depending on the type of RTA. Remember that the normal function of the renal acidificaiton system is to first reclaim all of the filtered HCO₃, and to then form the 50-60 mEq/day of net acid that will keep us in balance. In RTA one of these systems is defective.

There are many subtypes of RTA. You are welcome to consult texts for more details on these various types, but we will only expect you to be familiar with proximal RTA and three other RTA’s: Type 4 RTA, classical distal RTA, and hyperkalemic distal RTA. In proximal RTA there is a defect in HCO₃ reclamation. In the other three disorders metabolic acidosis results because we are unable to form the necessary amounts of NAE. You can distinguish the various types of RTA by measuring the plasma K, by observing the urine pH at the time of acidosis, and then by observing the response to a HCO₃ infusion sufficient to normalize the plasma HCO₃ concentration

Proximal acidification: is tested by measuring the HCO₃ threshold. At what level of plasma HCO₃ do you start to see bicarbonaturia? The normal threshold is at the normal plasma concentration of 22-26 mEq/l. Patients with proximal RTA have reduced thresholds, and if their HCO₃ is artificially raised to normal levels they will have massive HCO₃ wasting, usually around 10% of filtered load. Patients with other types of RTA will only waste 1-3% when plasma HCO₃ is normal.

Distal acidification: is tested by checking the urinary pCO₂ at a time when the urine is highly alkaline during the HCO₃ infusion. A normal person with intact distal H+ secretion will generate a urinary pCO₂ of 60-100 mm Hg. Patients with proximal RTA will do the same, but patients with classical or hperkalemic types of distal RTA will have a urinary pCO₂ equal to plasma levels. Patients with Type 4 RTA generally elevate urinary pCO₂ as well as normal

PROXIMAL RTA = TYPE II RTA In proximal RTA there is a defect in HCO₃ reclamation. This defect causes a reduction in the renal HCO₃ threshold. Recall that a normal individual secretes over 4000 mEq/day of H⁺ proximally to reclaim filtered HCO₃. A patient with proximal RTA may only be able to reclaim 3000 mEq/day. There will be HCO₃ wasting in the urine ( the distal system has very limited reserve and will be swamped by this large HCO₃load) producing a systemic acidosis. Blood HCO₃ concentration will continue to fall until the new threshold value is reached. At this point, the proximal nephron can handle the reduced filtered load normally, which sets the stage for normal distal acidification as well. It is therefore handy to think of proximal RTA as having two stages