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At which range should blood pH stay? Why are so many systems dedicated to defending that?

Several systems are involved in the defense of systemic pH, since any protracted increase or decrease in pH can lead to a broad array of organ perturbations. For example, extracellular pH modulates bone turnover, muscle protein synthesis, cardiac contractility, cognitive function, and gastrointestinal motility. Therefore, the blood pH in mammals is narrowly defended between 7.38 and 7.42. Indeed, life for humans is not supportable at a blood pH of 7.70.


What is the volatile acid in the body? Explain how it is produced and excreted.

The daily acid production in humans consists of two classes of acid, volatile and nonvolatile. Volatile acid consists of gaseous carbon dioxide (Pco2), and is disposed of by the lungs. Organic compounds are the primary substrates that produce CO2. Glucose, fatty acids, and ketones are oxidized to CO2, which generates carbonic acid (H2CO3) (Eq. [13.1]).
elMetabolismCOHCOHHCO2+HO23+2→→↔+− 3 (13.1)
Carbonic acid dissociates into a hydrogen ion (H+) and bicarbonate (HCO3). The increase in hydrogen ion concentration reduces the systemic pH, since the pH is equal to the –log [H+]. The oxidation of fuel produces 200 mmol of volatile acid per kg/BW per day or 14,000 mmol per day for the average
70 kg adult.


How are non-volatile acids produced and excreted?

The kidneys provide the only route of elimination for nonvolatile acids. Amino acids such as cysteine and methionine, which contain sulfur, are catabolized to sulfuric acid; nucleic acids and phosphoproteins are metabolized to phosphoric acid; and the basic amino acids lysine and arginine are catabolized to hydrochloric acid. Sulfuric, phosphoric, and hydrochloric acid production in a normal adult produces ~25-50 mEq of acid per day. In addition, incomplete metabolism of organic acids, such as lactic acid and ketoacids, accounts for an additional 25-50 mEq of acid per day. Finally, loss of bicarbonate in the stool generates 20-30 mEq of protons per day. Since bicarbonate generation necessitates production of a hydrogen ion, bicarbonate loss manifestly results in acid retention. The total generation of nonvolatile acid each day is approximately 1-1.5 mEq/kg body weight, or 70-100 mEq per day in the typical 70 kg adult.


What are the 3 primary systems that maintain blood pH?

The maintenance of a stable blood pH depends on threeprimary systems:
1. Chemical buffer systems, which are passive and operate within minutes
2. The respiratory system, which is an active system, that operates over a time scale of hours
3. The renal system, which requires several days to exert its maximal effect
The importance of these systems in the defense of blood pH is illustrated in Fig. 13.1.


What increases buffer capacity? What are the buffers in the blood? What are the buffers outside of the blood (both extracellular and intracellular)?

When the concentration of acid and conjugate base are equal, often described as half-neutralization, the pH equals the pKa. Importantly, the buffer capacity of a weak acid reaches its maximum value when the pH is equal to its pKa. In addition, the buffer capacity is directly proportional to the concentration of the acid. Titration curves for various blood buffers are shown in Fig. 13.3.
The blood buffering system consists of plasma buffers and red blood cell buffers. The plasma contains the following compounds that can serve as effective buffers: phosphate, bicarbonate, and proteins (mostly albumin). The red blood cells buffer hydrogen ions via histidine side groups on hemoglobin. Table 13.1 lists endogenous chemical buffers, their concentration, pKa, and their performance as passive chemical buffers or active physiological buffers.

In addition to the blood buffer system, large capacity buffers exist in the body, which are both intracellular and extracellular in nature. Intracellular fluid buffers consist of proteins and organic phosphates, whereas, extracellular fluid buffering occurs via the carbonate present in the inorganic matrix of bone. The buffering capacity of bone is considerable, by virtue of its large mass.


What happens to bone in chronic metabolic acidosis?

Chronic metabolic acidosis is commonly accompanied by bone disease. As hydrogen ions are buffered by bone, they effectively displace calcium from bone matrix, producing dissolution and osteopenia.


Why does CO2/bicarb make the best buffer pair?

It is quantitatively the most abundant extracellular buffer.
• The products and reactants are under physiological control (carbon dioxide is regulated by the lungs, whereas, the plasma bicarbonate is regulated by the kidneys).
• Carbon dioxide and bicarbonate are quickly and reliably measured using standard laboratory techniques.
• The pKa (6.1) of this buffer system is relatively close to the systemic pH.


How are met. alk/met.acid/resp acid/resp alk. compensated for?

In metabolic acidosis, the primary derangement reduces the bicarbonate concentration. The appropriate compensation involves a parallel decrease in the Pco2. Thus, both the numerator and denominator of Eq (13.5) are decreased. Since the ratio of Pco2 to bicarbonate governs the hydrogen ion concentration, the change in pH is minimized by compensation. In metabolic alkalosis the primary derangement leads to an increase in plasma bicarbonate concentration. The compensatory increase in Pco2 is the result of a decrease in ventilatory drive (which is pH dependent), thus preserving the ratio and minimizing the pH change. In respiratory acidosis the primary derangement is a decrease in ventilatory drive allowing Pco2 to rise. The compensation involves an increase in bicarbonate concentration. Because the induction of enzymes required to generate bicarbonate in the distal nephron requires several days, there are two phases of metabolic/renal compensation, acute and chronic. The acute phase of compensation, in the first
24 hours, depends predominately on the chemical buffer systems. The chronic phase that occurs after 48 hours relies on renal adjustments. Similar arguments can be made for respiratory alkalosis.


Where in the CNS is ventilation controlled? How is it regulated?

Ventilation is controlled by central chemoreceptors located in the medullary raphe. Cerebrospinal fluid pH regulates seritonergic neurons in the raphe, which project to all of the main respiratory nuclei (Fig. 13.4). Since, hydrogen ions and bicarbonate do not readily pass through the cerebrospinal fluid (CSF) barrier, the arterial Pco2 is the primary determinant of CSF pH. An increase in arterial Pco2 reduces CSF pH because CO2 diffuses across the blood-brain barrier and ultimately generates a hydrogen ion (see Eq. [13.5]). A fall in CSF pH increases respiratory activity, thereby reducing the arterial Pco2 and restoring the systemic pH. Several other factors also modulate respiratory activity in the medulla, including:
• State of alertness
• Exercise
• Metabolic rate
• Fever
• Oxygen tension

Therefore, the prevailing Pco2 reflects the effects of a variety of effectors of respiratory activity. Regardless, the respiratory system provides an important defense against changes in systemic pH since minute ventilation can be rapidly increased or decreased. Conversely, impairment of ventilatory drive can result in life-threatening changes in arterial pH.


What are the two things renal regulation of pH require?

Renal regulation of acid-base homeostasis requires the execution of two largely independent processes:
1. Reclamation of the filtered load of bicarbonate.
2. Excretion of the daily acid load. Daily acid excretion occurs in tandem with regeneration of plasma bicarbonate. Bicarbonate is consumed during the buffering of acid produced from metabolism. Importantly, individuals who are on a strict vegetarian diet generate bicarbonate rather than acid.


How is bicarb filtered at the glomerulus? What percent is reabsorbed in the different parts of the nephron? How is it reabsorbed? Explain in detail the mechanism.

Plasma bicarbonate is freely filtered at the glomerulus and must be reclaimed to preserve acid-base homeostasis. The majority of bicarbonate is reabsorbed in the proximal tubule (85%-90%). The remainder is reabsorbed in the thick ascending limb of the Loop of Henle (5%-10%) and the cortical collecting duct (5-10%). Assuming a GFR of 125 mL/min and a plasma bicarbonate concentration of 24 mEq/L, more than 4000 mEq of bicarbonate are filtered and subsequently reabsorbed each day.

The reabsorption of bicarbonate in the proximal tubule requires active hydrogen ion secretion (Fig. 13.5). Secreted hydrogen ions instantly combine with filtered bicarbonate and generate carbonic acid. Carbonic anhydrase IV, present on the brush border of the proximal tubule, converts carbonic acid into carbon dioxide and water. Luminal carbon dioxide diffuses freely into the proximal tubular epithelial cell and is converted to carbonic acid with the aid of cytosolic carbonic anhydrase II. Carbonic acid dissociates into a hydrogen ion and bicarbonate. Intracellular hydrogen ions are secreted into the lumen via NHE-3 and H-ATPase. The intracellular bicarbonate is extruded from the basolateral membrane via a sodium/bicarbonate cotransporter (NBC-1). Thus, filtered bicarbonate is not simply reabsorbed in the proximal tubule but is rather regenerated. In other words, each bicarbonate that is produced in the cell is accompanied by parallel consumption of bicarbonate in the lumen (after hydrogen ions combine with bicarbonate). Accordingly, there is no net change in plasma bicarbonate concentration.
Bicarbonate can also exit the basolateral membrane via a chloride/bicarbonate anion exchanger (AE-1). This transport system appears to play a less important role in bicarbonate reabsorption than NBC-1. The remaining 15-20% of bicarbonate is reabsorbed in more distal nephron segments using nearly identical transport proteins.


Describe the mechanisms by which hydrogen ion is secreted in the PT.

Hydrogen ion secretion in the proximal tubule is mediated by two transport systems. Approximately 60% of the hydrogen ion secreted in the proximal tubule occurs via NHE-3 (see Fig. 6.5). NHE-3 is an electroneutral, secondary active transport pump, which exchanges one sodium ion for one hydrogen ion. This transport system does not directly utilize ATP as a source of energy but is energized by the concentration gradient of sodium across the luminal membrane of the proximal tubular cells. The ten-fold lower sodium concentration in the tubular cells favors sodium entry into cells. The sodium concentration inside the proximal tubular cells is kept low by Na/K-ATPase that is located on the basolateral membrane.

NHE-3 can transport other cations such as ammonium (which displaces hydrogen ions) and lithium (which displaces sodium). NHE-3 is the major transport system responsible for ammonium secretion in the proximal tubule.

Hydrogen ion secretion in the proximal tubule can also occur via a vacuolar type H-ATPase (V-type H-ATPase). V-type H-ATPases belong to a superfamliy of ATPases that are subdivided into three categories (P-type ATPases include H/K-ATPase, mitochondrial ATPases, and V-type or vacuolar ATP-ases). The V-type H-ATPases comprises 14 subtypes. They are widely distributed among mammalian intracellular organelles (clathrin-coated vesicles, endosomes, lysosomes, Golgi membrane, and endoplasmic reticulum), referred to collectively as the vacuolar system. The V-type H-ATPases are also present in the plasma membrane of many cell types, including osteoclasts, macrophages, and renal epithelial cells. Acidification of intracellular compartments is important for several cellular processes, including receptor-mediated endocytosis and degradation of proteins. Conversely, acidification of the extracellular environment is involved in bone turnover (osteoclasts dissolve bone matrix) and killing microorganisms (macrophages). In renal epithelial cells, the V-type H-ATPase is responsible for 40% of the hydrogen ion secreted in the proximal tubule.


Which parts of the nephron are responsible for daily excretion of the nonvolatile acid load? In which forms are acids excreted (percentages)?

The distal nephron is responsible for the excretion of the daily nonvolatile acid load. Several segments are involved in the elimination of nonvolatile acid (often referred to as fixed acid), including the distal convoluted tubule, connecting segment, cortical collecting duct, outer medullary collecting duct, and inner medullary collecting duct. Acid excretion generates new bicarbonate, which replenishes the blood bicarbonate consumed by acids produced during metabolism. In the steady state, the net acid excreted in a 24-hour period is equal to the daily acid load, or ~70-100 mEq.

Since less than 1% of the nonvolatile acid generated per day can be excreted as free hydrogen ions, urinary buffering of acid is critical to permit excretion of the daily load. Hydrogen ions excreted into the urine exist in three states (Fig. 13.7): (1) <1% are unbound or free, however, the concentration of free hydrogen ions governs the urine pH, since pH = −log [H+], (2) 30% are bound to conjugate base buffers that are present in normal urine; predominately phosphate and sulfate, and (3) the majority of acid in the urine is excreted as ammonium (NH4+).


What is the major non-ammonia urinary buffer? How is it regulated?

Because of its favorable acid dissociation constant (pKa = 6.8), and relatively high concentration, inorganic phosphate is the major nonammonia urinary buffer. Other urinary buffers include sulfate, creatinine, and uric acid. Unlike, ammonia, the concentration of these urinary buffers is not actively regulated. Collectively, these urinary buffers are quantitated using a technique referred to as titratable acidity. Titratable acidity is measured by titrating the urine pH to 7.4 with alkali, specifically sodium hydroxide. The mEq of sodium hydroxide required to titrate the urine back to physiologic pH is equal to the mEq of hydrogen ion buffered by nonammonia urinary buffers. The excretion of titratable acids averages 300 mEq/d. Although, acid loading decreases proximal phosphate reabsorption and, therefore, increases urinary phosphate concentration, the ability to enhance net acid excretion by this phosphaturic response is limited. Rather it is the ability of the kidney to increase urinary ammonia concentration that constitutes the major adaptation to an acid load (see Renal Ammonia Synthesis later in this chapter.).


What are some proteins in distal nephron cells that influence acid-base homeostasis? How do principal cells influence acid secretion? Where are intercalated cells found? What is their function? Compare and contrast the different types.

Several cell types in the distal nephron express proteins (H-ATPase, AE-1, pendrin) that are directly involved in acid-base homeostasis. In addition, principal cells indirectly influence hydrogen ion secretion because they generate a negative transepithelial potential (see Fig. 8.5). The intercalated cell, which consists of several subtypes, is the primary cell responsible for urinary acidification. Intercalated cells are distributed along the distal convoluted tubule, connecting segment, cortical collecting duct, and initial third of the inner medullary collecting duct. Intercalated cells are distinguished from the principal cells by a darker cytoplasm that is rich in carbonic anhydrase II. They are subclassified based on the presence or absence of AE-1 and the subcellular location of H-ATPase into type-A (Fig. 13.8) and type-B (Fig. 13.9), or non-A and non-B cells. Type-A cells express V-type H-ATPase on the luminal membrane and AE-1 on the basolateral membrane. The V-type H-ATPase in type-A cells is similar, but not identical, to the H-ATPase in the proximal tubule. Type-B intercalated cells express V-type H-ATPase on the basolateral membrane and pendrin on the luminal membrane. Type-B cells are the mirror image of type-A cells. Type-B cells are believed to play an important role in bicarbonate excretion following an alkali load or in the setting of a metabolic alkalosis.

Recent evidence suggests that type-B cells can switch to type-A cells after an acid load. This conversion appears to involve a matrix protein known as Hensin. Non-A, non-B cells express both pendrin and V-type H-ATPase on the luminal membrane.


What is the cellularity like in the IMCD? What are these cells like? What is HK? Wher is it expressed?

The outer and inner third of the inner medullary collecting duct is composed of type-A intercalated cells. In addition, about 40% of the cells express aquaporin-2 and, therefore, are believed to be principal cells. However, potassium secretion has not been demonstrated at this site, suggesting that these cells are a variation of the classic principal cell described in the cortical collecting duct. The remaining two-thirds of the inner medullary collecting duct is composed of IMCD cells, which also express aquaporin-2 and V-type H-ATPase.
Finally, a hydrogen ion transporter identical to that described in colonic and gastric mucosa has been characterized in the distal nephron. This protein utilizes ATP to secrete hydrogen ions in exchange for potassium (H/K-ATPase or HK). HK is expressed predominately in the collecting duct. Intercalated cells appear to be the dominant cell type that expresses HK. Type-A intercalated cells express HK in the apical membrane, and type-B intercalated cells express it in the basolateral membrane. HKs role in acid-base homeostasis is controversial. However, recent studies indicate that HK deficient mice have impaired acid secretion. The importance of HK in potassium conservation was previously discussed (see Transport in the Outer Medullary Duct in Chap. 8, ).


How of the acid that is renally excreted is excreted as ammonia? Describe ammoniagenesis in the PT.

More than 70% of the acid excreted in the urine is bound to ammonia as ammonium. In addition, the synthesis andexcretion of ammonia by the kidney can increase severalfold in response to an acid load. In biological systems, ammonia (NH3) exists predominately as ammonium (NH4+), since the pKa for the ammonia buffer system is >9.0 (Eq. [13.7]).
NHHNH43+=++ (13.7)
Ammoniagenesis occurs exclusively in the proximal tubule (Fig. 13.11). Several steps are involved in renal ammoniagenesis. Glutamine, which is transported across the epithelial cell membrane, is shuttled into the mitochondria, where it is converted to glutamate and ammonium via the enzyme glutaminase. Glutamate is then converted to a second ammonium ion and a-ketoglutarate via the action of glutamate dehydrogenase. Metabolism of a-ketoglutarate produces two bicarbonate ions. Thus, the net effect of glutamine metabolism in the proximal tubule is the production of 2 moles of ammonium and 2 moles of bicarbonate. The bicarbonate is absorbed into the blood via NBC-1. The ammonium is secreted into the lumen via NHE-3, which can function as a sodium ammonium antiporter.


Describe ammonia transport in the various parts of the nephron.

More than 75% of the ammonia that enters the loop of Henle is recycled in the medulla so that very little enters the distal cortical nephron segments. The primary step in medullary recycling involves ammonium reabsorption in the thick ascending limb, perhaps by displacing potassium on NKCC2. Passive transport of ammonium may also occur through potassium channels in the luminal membrane, since the physicochemical properties of ammonium and potassium are nearly identical. In the less acidic medullary interstitium the relative concentration of ammonia increases. Ammonia in the interstitium diffuses into the straight segment of the proximal tubule. The net effect of this recycling process is maintenance of a high medullary interstitial ammonia concentration (Fig. 13.12). The secretion of ammonia by the collecting duct accounts for the majority of ammonium in the final urine. When the urine pH is low, the collecting duct favors conversion of ammonia to ammonium and essentially traps hydrogen ions in the lumen.


Describe how ammonia transport is mediated in the collecting duct. What factors regulate ammoniagenesis in the PT?

Recent studies suggest that ammonia transport in the collecting duct is mediated by passive diffusion (especially ammonia) as well as active secretion. The secretory mechanism appears to involve the Rh glycoprotein family, since these proteins are highly expressed in the kidney collecting duct and are well established mammalian ammonia transporters. Three Rh glycoproteins have been described, RhAG, RhBG, and RhCG. Importantly, acid loading increases the expression of RhCG in the medullary collecting duct indicating that it is the predominant transport system for ammonium in the collecting duct. The increased expression of RhCG appears to be specific to the intercalated cell and IMCD cell.
Acid loading increases proximal tubule ammoniagenesis. Several other factors have been shown to stimulate ammoniagenesis in the proximal tubule including aldosterone, angiotensin II, and potassium depletion.


What are the principal factors that influence acid excretion in the kidney?

The principal factors that influence acid excretion in the kidney include:
• Extracellular pH
• Extracellular volume
• Aldosterone
• Extracellular potassium concentration


How does extracellular pH regulate acid excretion?

Parallel changes in the renal tubular cell pH are thought to constitute the signal by which the extracellular pH alters acid excretion. Acidosis promotes an increase in NHE-3 activity and V-type H-ATPase expression in proximal tubular epithelial cells and intercalated cells, respectively. In addition, renal glutaminase activity is inversely proportional to pH. Therefore, intracellular acidosis promotes ammonia synthesis. Alkalosis induces an opposite effect on renal acid transport systems.


What normally happens to filtered bicarb? What happens in volume contraction? What are the mechanisms by which this happens?

Virtually all of the filtered bicarbonate is reabsorbed in the renal tubule within the physiologic range of 24-26 mEq/L. However, when the bicarbonate concentration exceeds ~28 mEq/L, bicarbonate is excreted in the urine. This normal physiologic response maintains the serum bicarbonate concentration within a narrow range. However, volume contraction promotes bicarbonate reabsorption even if the plasma levels exceed 28 mEq/L. The mechanisms responsible for increased bicarbonate reabsorption include increased sodium reabsorption via NHE-3 and diminished chloride delivery to type-B (bicarbonate-secreting) intercalated cells. In addition, volume contraction increases plasma aldosterone, which promotes acid excretion in the urine (see Aldosterone).


How does aldosterone affect acid excretion? How do hyper and hypo aldosteronism affect blood pH and potassium levels?

Aldosterone directly increases distal hydrogen ion secretion through stimulation of the V-type H-ATPase transport system. In addition, aldosterone promotes ammonia synthesis in the proximal tubule, and, therefore, increases urinary ammonium excretion. Aldosterone indirectly mediates acid excretion by increasing the negative transepithelial potential in the cortical collecting duct (see Fig. 8.5).

Hyperaldosteronism is commonly associated with hypokalemia and metabolic alkalosis. Conversely, hypoaldosteronism is accompanied by hyperkalemia and metabolic acidosis.


Describe how EC potassium levels affect acid excretion.

The plasma potassium concentration influences renal hydrogen ion secretion. Hypokalemia promotes a shift of potassium from the intracellular to extracellular compartment in exchange for hydrogen ions and, therefore, reduces renal epithelial cell pH. A fall in cellular pH increases V-type H-ATPase expression, NHE-3 activity, and ammonia synthesis. The opposite effects occur with an increase in the plasma potassium concentration. Potassium can also effect hydrogen ion secretion via changes in HK activity. For example, potassium depletion increases HK activity and, therefore, increases hydrogen ion secretion.