Medical School · Year 2 · Renal · includes a quiz and discussion video

Lecture 7: Renal Acid-Base Regulation

Unit 2.1: Renal System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the role of the kidney in acid-base homeostasis
2. Explain bicarbonate reabsorption along the nephron
3. Describe the mechanisms of net acid excretion
4. Explain the pathophysiology of renal tubular acidoses
5. Describe the renal response to respiratory and metabolic acid-base disorders
6. Apply renal acid-base concepts to clinical scenarios

Overview of Acid-Base Balance

Maintaining blood pH within the narrow range of 7.35 to 7.45 is essential for cellular function, enzyme activity, and oxygen delivery. The body continuously generates acid from metabolism and must eliminate it to prevent progressive acidemia.

Daily acid production occurs through two distinct pathways. Volatile acid, in the form of carbon dioxide, is produced in massive quantities, approximately 15,000 mmol daily, from cellular oxidative metabolism. This CO2 dissolves in water to form carbonic acid but is efficiently eliminated through pulmonary ventilation and therefore does not accumulate. Fixed (non-volatile) acids are produced in smaller but still significant quantities, approximately 50 to 100 mEq per day. The metabolism of sulfur-containing amino acids (methionine, cysteine) generates sulfuric acid. Phospholipid and nucleotide metabolism produces phosphoric acid. Incomplete oxidation of carbohydrates and fats generates organic acids. Unlike CO2, these fixed acids cannot be exhaled and must be eliminated by the kidney.

The body defends against acidemia through three successive lines of defense operating on different time scales. Chemical buffers provide immediate defense within seconds, minimizing pH change as acid is added. The bicarbonate buffer system is most important in extracellular fluid, while proteins and phosphates buffer intracellularly. Respiratory compensation operates over minutes to hours, adjusting ventilation to alter CO2 elimination and thus the denominator of the Henderson-Hasselbalch equation. Renal compensation is the slowest but ultimately most complete mechanism, operating over hours to days to regenerate consumed bicarbonate and excrete acid.

The kidney's acid-base tasks are twofold. First, it must reclaim the bicarbonate filtered at the glomerulus, preventing loss of this crucial buffer. Second, it must generate new bicarbonate to replace that consumed in buffering the daily fixed acid load, excreting the hydrogen ions in the process.

<image>Panel A: Daily acid production showing volatile acid (CO2, ~15,000 mmol/day) directed to lungs and fixed acid (~50-100 mEq/day) from sulfur amino acids, phospholipids, and incomplete oxidation directed to kidneys. Panel B: Buffer defense (immediate) with the bicarbonate buffer equation H+ + HCO3- ↔ H2CO3 ↔ CO2 + H2O. Panel C: Respiratory defense (minutes-hours) showing lungs adjusting CO2 elimination to alter pH. Panel D: Renal defense (hours-days) showing kidney reclaiming filtered HCO3- and excreting H+ as the slowest but most complete mechanism.</image>

Bicarbonate Reabsorption

The glomerulus freely filters bicarbonate, with approximately 4500 mEq filtered daily at normal plasma bicarbonate concentration of 24 mEq/L and GFR of 180 L/day. Virtually all of this bicarbonate must be reclaimed to prevent catastrophic buffer loss. Normally, less than 2 mEq of bicarbonate appears in the final urine.

The proximal tubule reabsorbs 80 to 85 percent of filtered bicarbonate through a well-coordinated mechanism. Bicarbonate itself cannot cross the apical membrane directly. Instead, hydrogen ions are secreted into the lumen via the sodium-hydrogen exchanger NHE3, which uses the inward sodium gradient established by the basolateral sodium-potassium ATPase. In the lumen, hydrogen ions combine with bicarbonate to form carbonic acid, which rapidly dissociates to CO2 and water catalyzed by carbonic anhydrase type IV anchored to the brush border. The CO2 diffuses freely across the apical membrane into the tubular cell. Inside the cell, carbonic anhydrase type II catalyzes the reverse reaction, forming carbonic acid that dissociates to regenerate hydrogen ions and bicarbonate. The hydrogen ions are recycled back to the lumen via NHE3, while bicarbonate exits the basolateral membrane via the NBC1 sodium-bicarbonate cotransporter (carrying 3 bicarbonate ions with each sodium).

The thick ascending limb reabsorbs an additional 10 to 15 percent of filtered bicarbonate through similar mechanisms involving apical hydrogen ion secretion and basolateral bicarbonate exit.

Several factors regulate bicarbonate reabsorption. Acidosis stimulates NHE3 activity and increases reabsorption. Volume depletion activates angiotensin II, which directly stimulates NHE3. Elevated PCO2 increases intracellular carbonic acid formation and hydrogen ion availability for secretion. Hypokalemia shifts hydrogen ions into cells, increasing their availability for secretion. Parathyroid hormone inhibits proximal tubule NHE3, reducing bicarbonate reabsorption. Carbonic anhydrase inhibitors like acetazolamide block both the luminal and intracellular enzymes, causing bicarbonaturia.

<image>Panel A: Luminal reactions showing filtered HCO3- combining with secreted H+ from NHE3 to form H2CO3, converted by carbonic anhydrase IV to CO2 + H2O, with CO2 diffusing across the apical membrane. Panel B: Intracellular reactions showing CO2 + H2O converted by carbonic anhydrase II to H2CO3, dissociating to H+ (recycled to NHE3) and HCO3- (exits basolaterally via NBC1 carrying 1 Na+ and 3 HCO3-). Panel C: Basolateral membrane showing Na+/K+-ATPase maintaining the sodium gradient that drives NHE3 activity. Panel D: Regulatory factors listing stimulators of reabsorption (acidosis, volume depletion/AII, elevated PCO2, hypokalemia) and inhibitors (PTH, carbonic anhydrase inhibitors).</image>

Net Acid Excretion

While bicarbonate reclamation prevents buffer loss, the kidney must additionally generate new bicarbonate to replace that consumed buffering the daily fixed acid load. This occurs through net acid excretion, quantified by the formula: Net Acid Excretion (NAE) = Titratable Acid + Ammonium - Bicarbonate. Normally, bicarbonate excretion is negligible, so NAE approximately equals titratable acid plus ammonium, which together total 50 to 100 mEq/day, matching fixed acid production.

Titratable acid represents hydrogen ions bound to urinary buffers other than bicarbonate. The primary urinary buffer is phosphate; as hydrogen ions are secreted into the lumen, they protonate HPO42- to form H2PO4-. Because phosphate has a pKa of 6.8, it buffers effectively as urine acidifies. Titratable acid typically contributes 20 to 40 mEq/day to net acid excretion. This component is limited by the rate of phosphate excretion, which cannot increase substantially even during acidosis.

Ammonium (NH4+) represents the major adaptive pathway for acid excretion, contributing 30 to 60 mEq/day at baseline but capable of increasing 5 to 10-fold during chronic acidosis. This flexibility makes ammonium the key mechanism for responding to increased acid loads.

Understanding why ammonium excretion represents new bicarbonate generation is essential. In the proximal tubule, glutamine metabolism produces both ammonium and α-ketoglutarate. The α-ketoglutarate is further metabolized to bicarbonate, which enters the bloodstream as new buffer. For each molecule of glutamine metabolized, two ammonium ions and two bicarbonate ions are produced. If the ammonium is excreted in the urine, the new bicarbonate is retained, representing net acid excretion. If the ammonium instead returns to the liver and is converted to urea, the bicarbonate is consumed in the process and no net acid excretion occurs. The kidney's ability to route ammonium to excretion rather than hepatic return is therefore crucial.

<image>Panel A: Net acid excretion equation NAE = Titratable Acid + NH4+ - HCO3- with typical values (20-40 + 30-60 - 0 = 50-100 mEq/day). Panel B: Titratable acid showing HPO42- + H+ forming H2PO4- in the tubular lumen, pKa 6.8, contributing 20-40 mEq/day and limited by phosphate excretion rate. Panel C: Ammonium production showing glutamine metabolized to 2 NH4+ and 2 alpha-ketoglutarate yielding 2 new HCO3- to blood, with 5-10x increase possible in acidosis as the major adaptive mechanism. Panel D: Critical concept illustrating that NH4+ excreted in urine equals new HCO3- retained, whereas NH4+ returned to liver for urea synthesis results in no net bicarbonate gain.</image>

Ammonium Production and Excretion

The production, transport, and ultimate excretion of ammonium involves all segments of the nephron working in concert.

In the proximal tubule, glutamine enters cells from both the peritubular blood and tubular lumen. Mitochondrial glutaminase cleaves glutamine to glutamate plus ammonium. Glutamate dehydrogenase then converts glutamate to α-ketoglutarate plus a second ammonium. The α-ketoglutarate enters the metabolic pathways that generate new bicarbonate, which exits across the basolateral membrane to the blood. The ammonium produced substitutes for hydrogen ions on NHE3 or diffuses directly into the tubular lumen.

In the loop of Henle, ammonium is reabsorbed in the thick ascending limb. Ammonium has similar ionic properties to potassium and substitutes for potassium on the NKCC2 transporter. This reabsorbed ammonium accumulates in the medullary interstitium, creating an ammonium concentration gradient parallel to the osmolar gradient.

In the collecting duct, ammonium is "trapped" in the urine. Ammonia (NH3), the uncharged form, diffuses from the medullary interstitium into the collecting duct lumen down its concentration gradient. Type A intercalated cells secrete hydrogen ions via apical H+-ATPase. In the acidic lumen, NH3 combines with H+ to form NH4+, which is charged and therefore trapped and excreted. The more acidic the urine, the more complete the trapping. This explains why the ability to acidify urine is important for ammonium excretion.

Ammonium production is strongly regulated by acid-base status. Chronic acidosis increases glutaminase and glutamate dehydrogenase expression, increasing ammonium production 5 to 10-fold over several days. This adaptation explains why patients with chronic metabolic acidosis can excrete much larger acid loads than those with acute acidosis. Reduced GFR impairs ammonium production because there are fewer tubular cells to synthesize it. Hyperkalemia inhibits ammonium production and trapping, contributing to the acidosis of hyperkalemic states.

<image>Panel A: Proximal tubule showing glutamine entering the cell, glutaminase and GDH reactions producing 2 NH4+ and 2 new HCO3- exiting to blood, with NH4+ secreted into lumen via NHE3 or direct diffusion. Panel B: Thick ascending limb showing NH4+ reabsorbed via NKCC2 (substituting for K+) and accumulating in the medullary interstitium. Panel C: Collecting duct showing NH3 (uncharged) diffusing from interstitium into lumen, Type A intercalated cell secreting H+, and NH3 + H+ forming trapped NH4+ (charged) in acidic urine. Panel D: Regulation showing increased NH4+ production with chronic acidosis via enzyme induction and decreased production with hyperkalemia.</image>

Collecting Duct Acid-Base Handling

The collecting duct provides the final adjustment of urine acid-base content through two specialized cell types with opposing functions that can shift their predominance based on systemic acid-base status.

Type A intercalated cells mediate acid secretion and bicarbonate reabsorption. The apical membrane contains the H+-ATPase, a proton pump that secretes hydrogen ions into the tubular lumen using ATP hydrolysis. Some type A cells also express the H+/K+-ATPase, which exchanges a secreted hydrogen ion for a reabsorbed potassium ion. The basolateral membrane contains the AE1 anion exchanger (the same protein found in red blood cells), which exchanges bicarbonate for chloride. As hydrogen ions are secreted apically, bicarbonate generated intracellularly exits basolaterally, representing new bicarbonate delivered to the blood. Type A cells predominate during acidosis when acid secretion is needed.

Type B intercalated cells perform the opposite function, secreting bicarbonate and reabsorbing acid. The polarity of transporters is reversed: the H+-ATPase is located basolaterally, while pendrin, a chloride-bicarbonate exchanger, is located apically and secretes bicarbonate into the lumen. Type B cells become more active during alkalosis when excess bicarbonate must be eliminated.

The ratio of type A to type B intercalated cells shifts with chronic acid-base disturbances. During prolonged acidosis, type B cells can actually convert to type A phenotype through a process of polarity reversal, increasing acid secretion capacity. This plasticity provides long-term adaptation to acid-base demands.

Aldosterone stimulates type A intercalated cell function, increasing H+-ATPase activity and acid secretion. This effect explains the metabolic alkalosis seen with hyperaldosteronism and the metabolic acidosis seen with hypoaldosteronism. Acidosis directly stimulates hydrogen ion secretion. The minimum urine pH achievable is approximately 4.5, limited by the gradient against which the H+-ATPase can pump. Urinary buffers, particularly ammonia, allow continued acid secretion despite low pH by accepting hydrogen ions.

<image>Panel A: Type A intercalated cell showing apical H+-ATPase and H+/K+-ATPase secreting H+ into lumen, intracellular CA II generating H+ and HCO3-, and basolateral AE1 (Cl-/HCO3- exchanger) sending HCO3- to blood, predominating in acidosis. Panel B: Type B intercalated cell showing reversed polarity with apical pendrin (Cl-/HCO3- exchanger) secreting HCO3- into lumen and basolateral H+-ATPase, predominating in alkalosis. Panel C: Polarity reversal with arrows indicating Type B to Type A interconversion during chronic acidosis, illustrating cellular plasticity. Panel D: Regulatory factors showing aldosterone stimulating Type A activity, minimum urine pH of approximately 4.5, and the role of NH3 buffering to allow continued acid secretion beyond the pH gradient limit.</image>

Renal Tubular Acidoses

The renal tubular acidoses (RTAs) are disorders of renal acidification that produce hyperchloremic (normal anion gap) metabolic acidosis despite relatively preserved glomerular filtration. They are classified by the site and nature of the defect.

Type 1 (distal) RTA results from impaired hydrogen ion secretion in the collecting duct. Because acid cannot be excreted effectively, the urine cannot be acidified below pH 5.5 even in the presence of systemic acidosis, the hallmark diagnostic feature. Net acid excretion is reduced, leading to progressive metabolic acidosis that can be severe, with bicarbonate falling below 10 mEq/L. Potassium wasting occurs because sodium that would normally be reabsorbed in exchange for hydrogen ions is instead exchanged for potassium. Complications include nephrolithiasis and nephrocalcinosis from the alkaline urine (which reduces citrate excretion and increases calcium phosphate precipitation), osteomalacia from chronic buffering of acid by bone mineral, and hypokalemia. Causes include hereditary H+-ATPase mutations, autoimmune diseases (Sjögren syndrome, systemic lupus), drugs (amphotericin B, lithium), and obstructive uropathy. Treatment with alkali replacement at relatively low doses (1-3 mEq/kg/day) is effective because the administered bicarbonate is not lost in urine.

Type 2 (proximal) RTA results from impaired bicarbonate reabsorption in the proximal tubule. The proximal tubule has a reduced threshold for bicarbonate reabsorption, so bicarbonate is lost in the urine until plasma bicarbonate falls to a new steady state, typically 15 to 18 mEq/L. Below this threshold, the reduced filtered load can be reclaimed, and urine can be appropriately acidified (pH less than 5.5). This self-limiting nature distinguishes proximal from distal RTA. However, if bicarbonate is administered therapeutically, it will be lost in the urine until levels exceed the threshold. Hypokalemia occurs because bicarbonaturia obligates sodium and potassium losses. Proximal RTA often occurs as part of Fanconi syndrome, with additional losses of glucose, amino acids, phosphate, and uric acid reflecting generalized proximal tubule dysfunction. Causes include multiple myeloma (light chain deposition), carbonic anhydrase inhibitors, and hereditary conditions. Treatment requires high-dose alkali because much is lost in urine, plus potassium supplementation; thiazide diuretics can be helpful by inducing mild volume depletion that stimulates proximal reabsorption.

Type 4 RTA results from aldosterone deficiency or resistance. Unlike types 1 and 2, the kidney can acidify the urine appropriately (pH less than 5.5). The problem is reduced ammonium production and excretion, caused by the hyperkalemia that accompanies hypoaldosteronism. Hyperkalemia inhibits renal ammoniagenesis, so even though hydrogen ions can be secreted, the lack of ammonia buffer limits total acid excretion. The acidosis is typically mild (bicarbonate 17-22 mEq/L). Causes include diabetic nephropathy (the most common cause, through hyporeninemic hypoaldosteronism), adrenal insufficiency, and medications (potassium-sparing diuretics, ACE inhibitors, ARBs). Treatment focuses on correcting hyperkalemia; fludrocortisone replaces aldosterone if deficient.

<image>Panel A: Type 1 (Distal) RTA showing collecting duct H+ secretion defect, urine pH greater than 5.5, hypokalemia, severely low HCO3-, complications of nephrolithiasis and nephrocalcinosis, and causes including Sjogren syndrome and amphotericin B. Panel B: Type 2 (Proximal) RTA showing proximal tubule HCO3- reabsorption defect, urine pH less than 5.5 once threshold reached, hypokalemia, HCO3- approximately 15-18 (self-limited), and causes including Fanconi syndrome, myeloma, and CA inhibitors. Panel C: Type 4 RTA showing aldosterone deficiency or resistance, urine pH less than 5.5, hyperkalemia, HCO3- approximately 17-22, and causes including diabetic hyporeninemic hypoaldosteronism and K+-sparing diuretics. Panel D: Nephron schematic identifying the site of defect for each type with the collecting duct for Type 1, proximal tubule for Type 2, and collecting duct aldosterone signaling for Type 4.</image>

Renal Compensation for Acid-Base Disorders

The kidney provides definitive correction for respiratory acid-base disorders and contributes to compensation for metabolic disorders.

In response to metabolic acidosis, the kidney increases net acid excretion to regenerate consumed bicarbonate. Immediately, hydrogen ion secretion and bicarbonate reabsorption increase as intracellular acidosis stimulates transporters. Over hours, titratable acid excretion rises as more phosphate is protonated in the urine. Over days, ammonium production increases dramatically through enzyme induction, allowing net acid excretion to increase 5 to 10-fold. The time required for maximal adaptation (3-5 days) explains why acute metabolic acidosis may show incomplete renal compensation.

In response to metabolic alkalosis, the kidney should excrete excess bicarbonate by reducing bicarbonate reabsorption and increasing bicarbonate secretion via type B intercalated cells. However, several factors often maintain alkalosis by preventing appropriate bicarbonate excretion. Volume depletion stimulates proximal sodium and bicarbonate reabsorption through angiotensin II. Chloride depletion limits the chloride-bicarbonate exchange needed for bicarbonate secretion. Hypokalemia stimulates hydrogen ion secretion and ammonium production. Aldosterone excess stimulates acid secretion. Understanding these maintaining factors is crucial because treating metabolic alkalosis requires addressing them.

In response to respiratory acidosis (elevated PCO2), the kidney increases bicarbonate reabsorption to raise plasma bicarbonate and partially correct pH. This compensation takes 3 to 5 days to fully develop. The expected chronic compensation is an increase in bicarbonate of 3.5 mEq/L for each 10 mmHg rise in PCO2. Acute respiratory acidosis shows less compensation (approximately 1 mEq/L per 10 mmHg) because full adaptation requires time.

In response to respiratory alkalosis (low PCO2), the kidney reduces bicarbonate reabsorption and decreases ammonium production, lowering plasma bicarbonate. The expected chronic compensation is a decrease in bicarbonate of 5 mEq/L for each 10 mmHg fall in PCO2. Acute respiratory alkalosis shows minimal renal compensation.

<image>Panel A: Metabolic acidosis renal response showing timeline from immediate (increased H+ secretion) to hours (increased titratable acid) to days (increased NH4+ production as the major adaptive response), with net effect of HCO3- regeneration. Panel B: Metabolic alkalosis showing impaired HCO3- excretion maintained by volume depletion, Cl- depletion, hypokalemia, and aldosterone excess. Panel C: Respiratory acidosis showing increased HCO3- reabsorption with acute compensation of approximately 1 mEq/L per 10 mmHg rise in PCO2 and chronic compensation (3-5 days) of approximately 3.5 mEq/L per 10 mmHg. Panel D: Respiratory alkalosis showing decreased HCO3- reabsorption and decreased NH4+ production with chronic compensation of approximately 5 mEq/L decrease per 10 mmHg fall in PCO2.</image>

Maintenance of Metabolic Alkalosis

Metabolic alkalosis poses a unique conceptual challenge: why doesn't the kidney simply excrete the excess bicarbonate? Understanding the distinction between generation and maintenance of alkalosis is clinically essential.

Generation of alkalosis occurs through loss of acid (vomiting, nasogastric suction) or addition of base (bicarbonate administration, citrate from transfusions). These events create the initial alkalosis but cannot sustain it indefinitely if the kidney functions normally.

Maintenance of alkalosis requires factors that prevent appropriate renal bicarbonate excretion. Volume depletion activates the renin-angiotensin system, increasing proximal tubular bicarbonate reabsorption via angiotensin II stimulation of NHE3. Chloride depletion limits chloride-bicarbonate exchange; without chloride, bicarbonate cannot be secreted via pendrin in type B intercalated cells. Hypokalemia increases hydrogen ion secretion (as potassium exits cells, hydrogen enters) and stimulates ammonium production, generating new bicarbonate rather than excreting it. Aldosterone excess (primary or secondary) stimulates collecting duct acid secretion. Reduced GFR decreases the filtered load of bicarbonate, limiting what can be excreted.

Clinical classification of metabolic alkalosis uses urine chloride to distinguish chloride-responsive from chloride-resistant forms. Chloride-responsive alkalosis (urine chloride less than 20 mEq/L) results from vomiting, nasogastric suction, or prior diuretic use. These patients are volume-depleted and chloride-depleted; treatment with saline and potassium chloride corrects the maintaining factors and allows bicarbonate excretion. Chloride-resistant alkalosis (urine chloride greater than 20 mEq/L) results from primary hyperaldosteronism, Cushing syndrome, or severe ongoing potassium depletion. Volume repletion does not correct these; treatment targets the underlying cause.

Urine chloride is more reliable than urine sodium for assessing volume status in alkalotic patients because obligate bicarbonaturia (when bicarbonate exceeds the reabsorptive threshold) carries sodium with it, making urine sodium elevated even in volume-depleted patients.

<image>Panel A: Generation versus maintenance distinction showing acid loss or base gain creating initial alkalosis, with maintenance factors preventing renal HCO3- excretion. Panel B: Maintaining factors at the kidney including volume depletion (increased proximal reabsorption via AII), Cl- depletion (no exchange partner for HCO3-), hypokalemia (increased H+ secretion), aldosterone excess (increased H+ secretion), and low GFR (less HCO3- filtered). Panel C: Diagnostic algorithm using urine Cl- with less than 20 mEq/L indicating Cl--responsive alkalosis (vomiting, NG suction, prior diuretics) and greater than 20 mEq/L indicating Cl--resistant alkalosis (hyperaldosteronism, Cushing syndrome, severe K+ depletion). Panel D: Treatment approach showing saline plus KCl for Cl--responsive forms and treatment of the underlying cause for Cl--resistant forms, with note that urine Na+ may be misleading due to bicarbonaturia.</image>

Clinical Assessment Tools

Several urine tests help evaluate renal acid-base handling and identify the cause of acid-base disorders.

The urine anion gap, calculated as (UNa + UK - UCl), provides an indirect estimate of ammonium excretion. In metabolic acidosis, an appropriately responding kidney increases ammonium excretion. Because ammonium is excreted with chloride (as NH4Cl), urine chloride rises relative to sodium and potassium, making the urine anion gap negative. A negative urine anion gap (typically -20 to -50 mEq/L) indicates increased ammonium excretion, appropriate for a systemic acidosis with an extrarenal cause such as diarrhea. A positive urine anion gap in the setting of metabolic acidosis indicates impaired ammonium excretion, suggesting renal tubular acidosis or renal failure. This test helps differentiate gastrointestinal bicarbonate loss from renal acidification defects.

Urine pH interpretation requires clinical context. In metabolic acidosis, urine pH should be maximally acidic (below 5.5). A urine pH above 5.5 during metabolic acidosis suggests distal RTA (type 1), urinary tract infection with urea-splitting organisms that raise pH, or very early proximal RTA before the threshold has been reached. In metabolic alkalosis, urine pH should be alkaline if the kidney is appropriately excreting bicarbonate. Paradoxical aciduria (acid urine during alkalosis) indicates that maintaining factors are preventing bicarbonate excretion and suggests chloride-responsive alkalosis that should be treated with saline.

The fractional excretion of bicarbonate, calculated as (UHCO3 × PCr) / (PHCO3 × UCr) × 100%, helps identify proximal RTA. Normally, fractional excretion should be less than 5 percent. In proximal RTA, more than 15 percent of filtered bicarbonate may be excreted, though this is only seen when bicarbonate is administered to raise plasma levels above the reduced threshold.

The ammonium chloride loading test can diagnose distal RTA when urine pH is equivocal. After administering an acid load (ammonium chloride or furosemide with fludrocortisone), a normal kidney acidifies urine below pH 5.3. Failure to acidify confirms type 1 RTA.

<image>Panel A: Urine anion gap formula (UNa + UK - UCl) explaining that NH4+ excreted with Cl- makes the gap negative, with negative gap indicating appropriate NH4+ excretion (extrarenal acidosis such as diarrhea) and positive gap indicating impaired NH4+ excretion (RTA or renal failure). Panel B: Urine pH interpretation as a 2x2 grid showing metabolic acidosis with pH less than 5.5 (appropriate) versus greater than 5.5 (distal RTA or UTI), and metabolic alkalosis with alkaline urine (appropriate) versus acidic urine (paradoxical aciduria from maintaining factors). Panel C: Fractional excretion of bicarbonate formula with greater than 15% suggesting proximal RTA when plasma bicarbonate is raised above the reduced threshold. Panel D: Ammonium chloride loading test for equivocal cases, where failure to acidify urine below pH 5.3 after acid load confirms Type 1 RTA.</image>

Summary

• The kidney reclaims filtered bicarbonate (greater than 99%) and generates new bicarbonate by excreting hydrogen ions
• Bicarbonate reabsorption occurs 80% in the proximal tubule via NHE3 and carbonic anhydrase
• Net acid excretion equals titratable acid (phosphate buffer) plus ammonium
• Ammonium is produced from glutamine in the proximal tubule, reabsorbed in the TAL, and trapped in the collecting duct
• Ammonium production increases 5 to 10-fold during chronic acidosis, representing the major adaptive response
• Type A intercalated cells secrete hydrogen ions; type B cells secrete bicarbonate
• Type 1 (distal) RTA: impaired hydrogen ion secretion, urine pH greater than 5.5, hypokalemia, nephrolithiasis
• Type 2 (proximal) RTA: impaired bicarbonate reabsorption, self-limited acidosis, associated with Fanconi syndrome
• Type 4 RTA: hypoaldosteronism causing hyperkalemia and reduced ammonium production
• Metabolic alkalosis is maintained by volume depletion, chloride depletion, hypokalemia, and aldosterone excess
• The urine anion gap estimates ammonium excretion; negative indicates appropriate response to acidosis

Key Terms

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