Role of The Kidneys in The Regulation of Acid-Base Balance

Richard Thomas P. Lim, MD Assistant Professor I Department of Physiology Jonelta Foundation School of Medicine January 22, 2013

Outline
I. The Bicarbonate Buffer System II. Overview of Acid-Base Balance III. Net Acid Excretion by The Kidneys
A. Bicarbonate Reabsorption Along the Nephron B. Regulation of H Secretion C. Formation of New Bicarbonate

IV. Response to Acid-Base Disorders

A. Extracellular and Intracellular Buffers B. Respiratory Compensation C. Renal Compensation

V. Simple Acid-Base Disorders

A. Types of Acid-Base Disorders
1. 2. 3. 4. Metabolic Acidosis Metabolic Alkalosis Respiratory Acidosis Respiratory Alkalosis

B. Analysis of Acid-Base Disorders

Acids and Bases

Diet Cellular metabolism Kidney, lungs, liver

Acid adds H to body fluids Alkali removes H from body fluids

Each day, we ingest a variety of acidic and basic substances. Also, cellular metabolism produces acids and bases. Without proper regulation of the pH of the body, many biochemical reactions necessary for life might not occur. For this lecture, we will be focusing on how the kidneys regulate the bodys pH. However, aside from the kidneys, the lungs and liver also help in maintaining a normal pH of the body. An acid is defined as any substance that adds H to body fluids while alkali or bases remove H from the body fluids.

Bicarbonate Buffer System

Buffer of ECF Regulated by both kidneys and the lungs
Carbonic anhydrase
Rate-limiting step

The bicarbonate buffer system is an important buffer of ECF. It can potentially buffer up to 350meq of H. It is different from the other buffer systems in the body, such as the phosphate, because it is regulated by both the kidneys and the lungs. The first reaction is slow, and is the rate-limiting step. The enzyme carbonic anhydrase speeds up this reaction. The dissociation of carbonic acid occurs instantaneously.

Change in bicarbonate metabolic acid-base disorder Change in PCO2 respiratory acid-base disorder Kidneys bicarbonate Lungs PCO2
This equation is derived from the HH equation. Suffice it to say at this point that any change in PCO2 or any change in bicarbonate will alter the pH or the H concentration of the body. When the alteration in pH is due to a change in bicarbonate, this is called a metabolic acid-base disorder. When the alteration in pH is due to a change in PCO2, this is called a respiratory acid-base disorder. The kidneys are responsible for regulating the bicarbonate while the lungs regulate the PCO2

Acid Balance
Acid production/ingestion = acid excretion Acidosis addition > excretion Alkalosis addition < excretion
As we have discussed repeatedly in the past, regulation of any compound in the body depends on the amount ingested or produced and the amount excreted. Ingestion of acidic comounds, or the production of acids from cellular metabolism must be equal to the amount of acid excreted in order to maintain a normal body pH. If addition of H is greater than the excretion, acidosis results. If excretion is more than the addition of H, aklasis will occur.

Volatile and Non-volatile

Volatile acid derived from CO2; eliminated immediately; does not impact acid-base balance Non-volatile acid not derived from CO2s
Carbon dioxide is eliminated immediately from the lungs. Because of this, CO2 does not impact acid-base balance. It is the only volatile acid. It is called as such because it has the potential to generate H from the hydration of CO2. All the other acids produced in the body are non-volatile acids. These are acids not derived from CO2.

 Dietary intake meat Cellular metabolism Feces bicarbonate loss Net addition of nonvolatile acid

Normally, the body gets a net addition of nonvolatile acids from different processes. These nonvolatile acids are immediately neutralized by bicarbonate. Intake of meat, composed of protein amino acids yield a net production of acids. Metabolism of certain amino acids yield acids, while only a few result to production of a basic compound. Thus dietary intake of meat yield acids. Cellular metabolism also result to a net production of acids. Bicarbonate is also lost in the feces. All of these processes result in a net addition of volatile acids. Remember that volatile acids are acids not derived from the hydration of carbon dioxide. The acids formed from these processes are neutralized by bicarbonate, thereby forming Na salts and consuming bicarbonate in the process. To continually neutralize these acids, the kidneys must be able to replenish the bicarbonate needed. Our bicarbonate stores, if not replenished would only last us 5 days.

Net Acid Excretion by Kidneys

Acid excretion = acid production Prevent bicarbonate loss in urine 4320 meq HCO3 filtered load 100meq HCO3 needed for nonvolatile acids
Normally, the acid excreted by the kidneys is equual to the amount of acid production. In addition, the kidneys must also prevent loss of bicarbonate in the urine, because we need the bicarbonate to neutralize the production of nonvolatile acids. The filtered load of bicarbonate is about 4320 meq/day, while only 100meq of HCO3 are needed to neutralize the production of nonvolatile acids. The reabsorption of HCO3 is quantitately more important because we can potentially lose so much HCO3 from the urine.

Titratable Acids
Way of excreting H Urinary buffers phosphate, creatinine
Maximum urine pH 4.0 Way of excreting excess H beyond maximum pH
The kidneys are unable to excrete urine with a pH of less than 4.0. Therefore, if the urine has a pH of 4.0 already, how will the kidneys excrete the excess H? Another way of excreting H, aside from being secreted as H in the urine is via titratable acids. These collective term refer to compounds found in the urine which bind H and serve as another means of excreting H. These include phosphate, creatinine and other urine constituents.

Ammonium
Way of excreting H Ammonium lost = bicarbonate returned
Remember that there is an overall excess of H in the body produced from the processes discussed earlier. We talked about titratable acids earlier as one way of excreting H. However, this method is not enough to handle the load from production of nonvolatile acids. Ammonium serves another way of excreting H in the urine.

Net Acid Excretion NEA

Rate of ammonium excretion Rate of titratable acid excretion Amount of bicarbonate lost in urine

Maximized when little bicarbonate lost Bicarbonate freely filtered and almost entirely reabsorbed
This is the equation for net acid excretion. Net acid excretion is equal to the rates of excretion of ammonium and titratable acid minus the amount of bicarbonate lost in the urine. From the equation, we can see that NAE is maximized when little or no bicarbonoate is lost in the urine. This is actually normally the case because bicarbonate is freely filtered is almost entirely reabsorbed.

This figure shows how much bicarbonate is reabsorbed by the different segments of the nephron. The PT reabsorbs most of the bicarbonate and the other segments are able to reabsorb what is left of the filtered bicarbonate. Almost no bicarbonate is lost in the urine.

Bicarbonate Reabsorption

Proximal Convuluted Tubule

H is actively tranported out of the tubular cell via a NaH antiporter or a H ATPase. The NaK ATPase maintains the intracellular concentration of Na low. This creates a gradient for Na to be transported from the tubular fluid into the tubular cell. As Na gets in, H goes out via the NaH antiporter. This is the predominant pathwya for H secretion. The H ATPase directly uses ATP to transport H out of the tubular cell.once in the tubular fluid, H will combine with bicarbonate to form carbonic acid. CA present in the brush border catalyzes the dehydration reaction to yield CO2 and H2O which then diffuse back to the tubular cell. Inside the cell, they again react via carbonic anhydrase which will yield H and bicarbonate. H is secreted out via the mechanisms discussed earlier while bicarbonate is reabsorbed back to the blood via either a Na3HCO3 symporter or a Cl-HCO3 antiporter.

DT and CD
Two types of intercalated cells
Alpha secrete H/reabsorb bicarbonate Beta secrete bicarbonate

Distal tubule and collecting duct

H is secreted from the alpha cell via two pathways: HK antiporter and an HATPase. Movement of K into the cell is coupled with the movement of H out of the cell. For the other protein, ATP is used to pump H out of the cell. The secreted H combines with bicarbonate to form carbonic acid which then dissociates to CO2 and H2O. These then diffuse back to the cell. Carbonic anhydrase form bicarbonate and H. H is secreted again via the two mechanisms described above while bicarbonate is reabsorbed back to the blood via a Cl-HCO3 antiporter.

Distal tubule and collecting duct

The beta cells, instead of reabsorbing bicarbonate, secrete bicarbonate. The key difference in this cell compared to the alpha or H secreting/ bicarbonate reabsorbing cell is the location of the H ATPase and the Cl HCO3 antiporter. The Cl-HCO3 antiporter is located at the apical side while the H ATPase is located in the basolateral side.

Most acidic of them all

PT has higher permeability to H and HCO3 than DT and CD. Which segment is the most acidic of them all?
The segments of the nephron have different permeabilities to H and bicarbonate. The proximal tubule is the most permeable to H and bicarbonate, thus it is able to reabsorb more H and bicarbonate. The urine in this segment will then be less acidic pH 6.5 because H is reabsorbed. The DT and CD are not very permeable to H. Thus the urine at this segment will be very acidic, ph 4.0, because H is not reabsorbed and persists in the urine.

Regulation of H Secretion
Acidosis stimulate H secretion Alkalosis reduce H secretion

Acidosis or an excess of H will promote secretion of H while alkalosis will reduce the secretion of H. O di ba etong part na to madali lang intindihin. Gets agad.

Metabolic Acidosis
Immediate decrease in intracellular pH
Cell-to-tubular fluid H gradient Allosteric changes in transport proteins More transporters shuttled to the membrane

Long term
Increased synthesis of transport proteins

Hormones
Endothelin Cortisol

Depending on how long metabolic acidosis has been occuring, there may be immediate and long term changes occurring in the cells of the nephron. Metabolic acidosis causes the pH inside the tubular cell to decrease. This will create a more favorable cell-to-tubular fluid gradient for H secretion. The increase in acidity also causes allosteric changes in the transport proteins in these cells, which result to enhancing their ability to secrete more H. Another immediate result of a decrease in pH is the transport of more transport proteins into the membranes of these cells. More transport proteins means more H can be secreted out of the cell.

When metabolic acidosis becomes prolonged, the tubual cells synthesize more transport proteins for H secretion. Hormones also mediate these changes in H transport proteins. These are endothelin and cortisol.

Endothelin
Produced from endothelial and proximal tubule cells Stimulated by acidosis Insertion of NaH and Na-3HCO3 into the apical and basolateral membranes
Endothelin is produced from the endothelial cells and in the proximal tubule cells. Secretion of this hormone is stimulated by acidosis. This hormones promotes insertion of transport proteins in the tubular cells which facilitate secretion of H

Cortisol
Produced from adrenal cortex Stimulated by acidosis Increases transcription and translation of NaH antiporter and Na-3HCO3 symporter genes
Secretion of coritsol is also stimulated by acidosis from the adrenal cortex. This homone increases the transcription and translation of genes coding for transport proteins which will facilitate H secretion

Alkalosis
Increase in intracellular pH Inhibits H secretion Mechanisms reversed for acidosis
In alkalosis, the changes we have discussed are reversed. Alkalosis will increase intracellular pH. A decrease in the H concentration inside the tubular cells will inhibit secretion of H because of a less favorable gradient for H transport out of the cell.

Na affects H and HCO3

Na affects H secretion NaH antiporter

Glomerulotubular balance GFR and PCT reabsorption GFR - filtered Na and HCO3 - more bicarbonate reabsorbed
In the proximal tubule and the loop of Henle, the NaH antiporter is involved in H secretion. Since this is an antiporter, change in Na will also affect H secretion. This will also translate to a change in bicarbonate reabsorption since H secretion is also linked to bicarbonate reabsorption. Glomerulotubular balance matches the reabsorption at the PCT with the GFR. Thus when the GFR increases, there will be more fluid reaching the PCT, and thus it will also reabsorb more fluid, containing Na and HCO3.

Volume Contraction
Negative Na balance H secretion is enhanced via activation of RAAS Peritubular capillary hydrostatic pressure
H secretion is also enhanced when there is volume contraction, or a Na deficit. This condition activates the RAAS, whose overall effect is to retain water by reabsorbing more Na. In our previous lecture, we talked about the changes occuring in volume contraction. There is a decrease in peritubular capillary hydrostatic pressure, which enhances Na and water reabsorption.

Volume Contraction
Angiotensin II PCT Stimulate NaH antiporter and Na-HCO3 symporter Insertion of more transporters Aldosterone DT and CD Hyperpolarizes transepithelial voltage Stimulate Na reabsorption in principal cells Stimulate H secretion by intercalated cells
Angiotensin II acts on the PCT. It stimulates the NaH antiporter and Na-HCO3 symporter. Increasing the activity of these proteins will reabsorb more Na and secrete more H. It also inserts more of these transport proteins in the cells of the PT. Aldosterone on the other hand acts on the DT and CD. When it stimulates Na reabsorption in the principal cells, the lumen becomes more electro negative or it hyperpolarizes the transepithelial voltage. This will then facilitate the secretion of positively charged H into the lumen.

Proximal Convuluted Tubule

H is actively tranported out of the tubular cell via a NaH antiporter or a H ATPase. The NaK ATPase maintains the intracellular concentration of Na low. This creates a gradient for Na to be transported from the tubular fluid into the tubular cell. As Na gets in, H goes out via the NaH antiporter. This is the predominant pathwya for H secretion. The H ATPase directly uses ATP to transport H out of the tubular cell.once in the tubular fluid, H will combine with bicarbonate to form carbonic acid. CA present in the brush border catalyzes the dehydration reaction to yield CO2 and H2O which then diffuse back to the tubular cell. Inside the cell, they again react via carbonic anhydrase which will yield H and bicarbonate. H is secreted out via the mechanisms discussed earlier while bicarbonate is reabsorbed back to the blood via either a Na3HCO3 symporter or a Cl-HCO3 antiporter.

Late distal tubule and collecting duct

H2O Cl Cl H2O

The late distal tubule is composed of two cells, the principal cell and the intercalated cell. Lets first discuss what the principal cell does. The reabsorption of Na, and secretion of K depends on the activity of the NaK ATPase. Again, it maintains a low intracellular sodium, creating a gradient which allows Na to be reabsorbed passively through Epithelial Na-selective channels or ENaC in the apical membrane. Sodium then enters the blood via the action of the NaKATPase. The reabsorption of sodium, creates a relative negative charge on the tubular fluid, since positively charged sodium ions are removed from it. This will then form a gradient for Chloride to be passively reabsorbed through the gap junctions via the paracellular pathway. Aside from sodium, and chloride, water is also reabsorbed in the principal cells via aquaporin channels located both in the apical and basolateral membranes of the tubular cells. We have now discussed how sodium, chloride and water are reabsorbed by the principal cells.

Now we move on to how potassium is secreted in the principal cell. Potassium uptake from the blood is done by the NaKATPase. This increases the K inside the principal cells. K then moves out of the cell via diffusion, down its concentration gradient via apical cell membrane K channels. In the intercalated cell, K is reabsorbed via a K-H ATPase. It secretes either bicarbonate or H, thus it is important in regulating acid-base balance. This will be further discussed in the succeeding lectures.

Volume Expansion
Positive Na balance H secretion is reduced Low angiotensin and aldosterone Peritubular capillary hydrostatic pressure

During volume expansion, or positive Na balance, H secretion is reduced. Less Na is reabsorbed from the tubules thus less H will be secreted via the NaH antiporter. The RAAS will not be activated thus there will be low angiotensin and aldosterone which promote Na reabsorption and H secretion in the tubules. An increase in peritubular capillary hydrostatic pressure will inhibit Na reabsorption during volume expansion. Inhibition of Na reabsorption will also inhibit secretion of H.

PTH
Acute inhibits H secretion
Inhibits NaH antiport Endocytosis

Chronic stimulates H secretion

TAL, DT Renal response to acidosis
PTH has both as stimulatory and an inhibitory role in secretion of H. During acute acidosis, PTH will inhibit secretion of H by inhibiting the action of the NaH antiporter and promoting endocytosis of transport proteins in the apical membranes. During chronic acidosis, PTH will stimulate the kidney to secrete H. This constitutes the renal response to acidosis which is to secrete H.

K
Hypokalemia acidifies tubular cells promotes H secretion; increased HKATPase expression in intercalated cells Hyperkalemia alkalinizes tubular cells - inhibts H secretion K-induced cellular changes
Changes in K also alter H secretion. K-induced cellular changes are thought to influence the secretion of H from the tubular cells. Hypokalemia acidifies the cells of the tubules, which promote H secretion. Aside from this mechanism, hypokalemia also increases the experssion of HKATPase at the intercalated cells. Hyperkalemia, on the other hand, alkalinizes the tubular cells, which inhibits H secretion.

Formation of New Bicarbonate

Reabsorption of HCO3 not enough Formation of HCO3 needed Excretion of titratable acid Excretion of NH4
To maintain acid-base balance, the kidneys reabsorb bicarbonate. However, this is not enough to replenish the bicarbonate lost from neutralizing the nonvolatile acids. The kidneys must form new bicarbonate to replenish the bicarbonate lost, and also to maintain acid-base balance. Generation of new bicarbonate is done by excreting titratable acid and excretion of ammonium.

Titratable Acid
HCO3 reabsorbed in PT and loop of Henle Little HCO3 reach DT and CD Secreted H combines with nonHCO3 buffers (P)

Insufficient to generate required amount of HCO3

The proximal tubule and the loop of Henle reabsorb bicarbonate. Thus the tubular fluid reaching the DT and CD have very little amounts of bicarbonate available to neutralize the secreted H. Instead of combining with bicarbonate, H will combine with non-HCO3 compounds, or urinary buffers such as phosphate. Since the secreted H is formed inside the cell, formation of H also forms bicarbonate which is reabsorbed back into the blood. Formation of titatable acid is not sufficient to generate the appropriate amount of bicarbonate. This is augmented by the formation and excretion of ammonium.

This slide shows how the formation of a titratable acid is able to generate bicarbonate, which is needed to neutralize the formation of nonvolatile acids. Since the tubular fluid reaching the DT and CD have low amount of bicarbonate, the secreted H will combine with urinary buffers such as phosphate. The combined H-buffer is then excreted into the urine. The generation of H, which occurred inside the cell, also generates bicarbonate via the action of CA. This bicarbonate is reabsorbed back into the blood.

Ammonium
Synthesis and excretion result to addition of bicarbonate to ECF Produced from glutamine ammoniagenesis Secreted from PCT, reabsorbed in TAL, secreted in the CD 1 ammonium excreted = 1 bicarbonate returned
The synthesis and excretion of ammonium result to addition of bicarbonate to the ECF. Ammonium comes from the breakdown of glutamine, a process called ammoniagenesis. Ammonium is synthesized and secreted from the PCT. It is then reabsorbed in the TAL, secreted again in the CD before getting excreted into the urine. Excretion of 1 molecule of ammonium will result to a return of 1 molecule of bicarbonate to the ECF.

This slide shows the complicated synthesis and excretion of ammonium, and how this process is able to generate bicarbonate. First lets look at the cell of the PCT. This is where ammoniagenesis occurs. Glutamine is degraded into ammonium and an anion (2-oxoglutarate). Metabolism of this anion will yield 2 molecules of bicarbonate which will be reabsorbed back into the peritubular capillary. At this point, we already have returned molecules of bicarbonate back to the ECF. Now, lets talk about how ammonium is excreted and why it is important.

Excretion of Ammonium
Complex If not excreted, NH4+ urea
Generates H Consumes bicarbonate
The excretion of ammonium involves a complex process, as we will discuss later. The formation of bicarbonate and ammonium from glutamine is not enough. Ammonium still has to be excreted, because if not, it will be reabsorbed. When it is reabsorbed, it will be converted to urea by the liver. This process will yield an additional H, which will then be needed to be neutralized by consuming another bicarbonate. Thus if ammonium is not excreted or is reabsorbed, we will not be able to generate bicarbonate but instead will consume another bicarbonate.

Ammonium secreted from the PT

Now lets discuss how ammonium is excreted. We have formed ammonium from the metabolism of glutamine. Ammonium can be secreted from the PT by a NaH antiporter, with ammonium substituting for H. It may also be deprotonated to ammonia, which can then diffuse out of the PT. Once in the tubular fluid, ammonia is then protonated again because of the secreted H from the PT. We have now secreted ammonium from the PT.

Majority of the ammonium secreted from the PT gets reabsorbed in the TAL. The reabsorption of ammonium at this segment is mediated by the NaK2Cl symporter and a positive transepithelial luminal voltage. From the TAL, the ammonium moves to the medullary interstitium.

Ammonium reabsorbed in the TAL

-Na-K-2Cl symporter -Positive transepithelial luminal voltage

Secretion of Ammonium from CD

From interstitium to CD First mechanism
Nonionic diffusion NH3 diffuses into CD Diffusion trapping CD less permeable to NH4+

Second mechanism
NH4-H antiporters
Secretion of ammonium moves ammonium from the interstitium back into the lumen of the CD. Secretion of ammonium involves two mechanisms: noniondic diffusion and diffusion trapping and via NH4-H antiporters.

Secretion of NH4+ in the CD

-nonionic diffusion -diffusion trapping

The first mechanism for the secretion of ammonium involves two processes: nonionic diffusion and diffusion trapping. From the medullary interstitium, ammonium diffused into the CD as ammonia. This is nonionic diffusion. Once in the tubular fluid, ammonia will be protonated by H secreted from the intercalated cell of the CD. This will then form ammonium again. The CD is les permeable to ammonium than ammonia because ammonium has a charge. Once inside the lumen of the CD, ammonium will not be reabsorbed back into the interstitium. This is diffusion trapping. Once trapped in the tubular lumen, ammonium is excreted out into the urine.

Secretion of NH4+ in the CD

NH4-H antiporters
The second mechanism for the secretion of ammonium in the CD involves this antiporter. This antiporter secretes ammonium out of the cell and transfer H back into the cell. The secreted ammonium is then excreted in the urine.

Response to Acid base Disorders

pH 7.35 to 7.45 Extracellular and intracellular buffering Respiratory compensation Adjustments in renal net acid secretion Minimize change in pH
The bodys pH is maintained at a very narrow range, at pH 7.35 to 7.45. The body pH changes when there is any alteration in either the pCO2 or the bicarbonate. When there is a change in the bodys pH, the body employs several mechanisms to defend against the changes in pH. These mechanisms do not correct the pH but just minimizes the change in pH imposed the a certain condition.

Buffers
First line of defense Extracellular instantaneous Intracellular slower, minutes
Intracellular and extracellular buffers are the first line of defense against any changes in pH. Effects of extracellular buffers are instanteneous while intracellular buffers are slower, buffering pH in minutes.

Buffer Mechanism
Extracellular Acid added neutralized by HCO3 HCO3 consumed Alkali added neutralized by H more HCO3 produced from H2CO3 Intracellular acid added H moves into the cell alkali added H moves out of the cell
In extracellular buffers, when acid is produced or added into the body, this acid is neutralized by bicarbonate in the ECF. This consumes the bicarbonate thus lessening the bicarbonate concentration in the ECF. When alkali is added, it will be neutralized by H, which is produced from carbonic acid. This process will consume H, but will also produce more bicarbonate as well. In intracellular buffering, when acid is added, this will promote movement of H into the cells. The H inside the cell will then be buffered by bicarbonate, phosphate, or proteins inside the cell. When alkali is added, this will promote H to move out of the cell so it can buffer the H outside.

Bida ang Bicarbonate

Bicarbonate buffer system principal buffer of ECF Phosphate and plasma proteins provide additional ECF buffering
The principal buffer in the ECF is the bicarbonate buffer system. Phosphate and plasma proteins provide additional buffering capacity. B- bicarbonate = Bida

HCO3 in Respiratory acid-base

PCO2 CO2 inside cell PCO2 CO2 moves inside cell

bicarbonate goes out ECF bicarbonate

bicarbonate goes out ECF bicarbonate

This is how bicarbonate buffers the ECF during respiratory acid-base disturbances. When there is an increase in PCO2 or respiratory acidosis, more CO2 will move inside of the cell. This will shift the reaction towards the formation of more H and HCO3. The formed H is buffered intracellularly while the bicarbonate goes out of the cell. This will then increase the ECF bicarbonate and thus decrease the change in pH induced by the increase in pCO2.

On the other hand, if the pCO decreases, less CO2 will be inside the cell. This will shift the reaction towards the dissociation of carbonic acid to CO2 and H2O. Thus, there will be less bicarbonate which will go out of the cell. And the ECF bicarbonate will decrease.

Respiratory Compensation

2nd line of defense Response occurs in hours Chemoreceptors in brainstem, carotid, aortic bodies sense changes in pCO2 and H H - pH - RR H - pH - RR

Based on the HH equation, any change in pCO2 will alter the bodys pH. Chemoreceptors found in the brainstem, carotid and aortic bodies sense changes in pCO2 and H. These will then determine the ventilatory rate. When there is metabolic acidosis, or an increase in H, the respiratory rate is increased so that more CO2 will be blown off and the pCO2 will decrease. This will then decrease the H. If there is metabolic alklaosis, or a decrease in H, the respiratory rate will be decreased so that more CO2 will be retained. This will then increase the H. Adjustments in ventilatory may be initiated immediately but full compensation might require several hours to complete.

Renal Adjustment
3rd line of defense Response takes several days to complete
Renal adjustment to acid base disorders is the 3rd line of defense. It takes several days for the kidneys to adjust so that the pH is maintained at normal values.

Renal Adjustment
Acidosis
H secretion entire filtered HCO3 reabsorbed excretion of titratable acid, production and excretion of NH4, bicarbonate production ECF bicarbonate
When there is acidosis, the tubules will secrete more H. The entire filtered load of bicarbonate is also reabsorbed. Since there is excess of H, excretion of titratable acid and NH4 will increase as well. When these compounds are formed, bicarbonate is also formed and is reabsorbed into the blood. This will then increase the ECF bicarbonate and restore the pH back to normal.

Renal Adjustment
Alkalosis
filtered load of HCO3, H secretion HCO3 excretion, titratable acid and NH4 excretion HCO3 in urine, net acid excretion ECF bicarbonate
When there is alkalosis, there will be an increase in the filtered load of bicarbonate since there is an excess of bicarbonate in the blood. Secretion of H in the collecting duct will be inhibited. Bicarbonate excretion will increase and thus bicarbonate will be found in the urine. A decrease in H secretion will also decrease synthesis and excretion of titratable acid and ammonium resulting a decrease in net acid excretion. All these processes will decrease ECF bicarbonate to restore pH back to normal.

Acid Base Disorders

Compensation only reduces the change in pH, but does not correct the underlying cause of the acid base disorder

Acid base disorders include the following 4 disorders. When you have acidosis, there is a decrease in pH. If you have alkalosis, you have an increase in your pH. In metabolic acidosis, the primary problem is a deficiency in bicarbonate in the ECF. To compensate for this, the 3 defense mechanisms we discussed earlier are used. There is hyperventilation to decrease the pCO2 and increase in renal net acid excretion to balance out the increase in pH. In metabolic alkalosis, the primary problem is an excess of bicarbonate. Again, same mechanisms are involved to decrease the change in pH. There will be hyperventilation and a decrease in net acid excretion to compensate for the increase in pH. In respiratory acid base balance, only two mechansims are involved for compensation, since the respiratory system is already the problem. In respiratory acidosis, there is an increase in pCO2. this is buffered by the ICF and the kidneys by increasing net acid excretion. In respiratory alkalosis, there is a decrease in pCO2. this is buffered by the ICF and the kidneys by decreasing net acid excretion. The compensations we discussed only reduce the change in pH, to try to maintain the pH at values which will still allow for life to continue without any problems.. The compensation does not correct the underlying cause of the acid base disorder. Once these mechanisms are overwhelmed, the acid base disorder will still persist unless the underlying cause has been resolved.

 Causes Addition of acid - diabetic ketoacidosis Loss of base diarrhea Failure to excrete H renal failure

Metabolic Acidosis

Compensation Buffering in ICF and ECF pH stimulates respiratory center - RR - PCO2 NEA
The causes of metabolic acidosis include addition of acid such as in diabetic ketoacidosis, loss of base as in diarrhea and failure to excrete H when you have renal failure. The primary problem here is a deficiency in bicarbonate, and the compensation for the change in pH is mediated by the buffers, decreasing the pCO2 by increasing the RR, and increasing secretion of H by the kidneys.

Metabolic Alkalosis
Causes Addition of base ingestion of antacids Volume contraction hemorrhage Loss of acid vomiting

Compensation Decreased HCO3 reabsorption pH inhibits respiratory center - RR - PCO2

Metabolic alkalosis is caused by addition of base such as in ingestion of antacids, volume contraction such as in hemorrhage and loss of acid during vomiting. The primary problem here is an excess of bicarbonate. To offset this, this is buffered by the ICF and ECF, the respiratory rate is decreased to increase the pCO2 and the kidneys decrease the secretion of H.

 Decreased gas exchange Inadequate ventilation (drug induced depression of respiratory center) Impaired gas diffusion (pulmonary edema)
Compensation Acute ICF buffering Chronic renal - Stimulate HCO3 reabsorption and excretion of titratable acid, NH4 - NEA
Respiratory acidosis is primarily caused by a decrease in gas exchange. This is usually caused by inadequate ventilation, probably from depression of the respiratory center, or impairment in gas diffusion such as in pulmonary edema. The compensation in respiratory acidosis is done by the kidneys by reabsorbing more HCO3 and excretion of more titratable acid and NH4. however, this response will take several days so in the acute setting, the buffering of the ICF maintain the pH at accetable levels.

Respiratory Acidosis

Respiratory Alkalosis
Increased gas exchange Increased ventilation (stimulation of respiratory centers, hyperventilation)

Compensation Acute ICF buffering Chronic inhibit HCO3 reabsorption, reduce excretion of titratable acid, NH4 - NEA
Respiratory alkalosis is caused by an increase in gas exchange. This may occur when there is increase in ventilation, such as when the respiratory centers are stimulated or by hyperventilation caused by fear, anxiety or pain. In the acute phase, the ICF does the buffering while in the chronic phase, the reabsorption of HCO3 is inhibited, and the excretion of titratable acid and NH4 are also reduced. These events will lead to a decrease in net acid excretion to compensate for the alkalosis.

Analysis of Acid-Base Disorders

pH 7.35 (7.35-7.45) HCO3 = 16 (24) PCO2 = 30 (40)
Interpret this ABG result.

Answer
1. acidosis 2. metabolic 3. compensated

Key Concepts
The kidneys maintain acid-base balance through the excretion of an amount of acid equal to the amount of nonvolatile acid produced by metabolism and the quantity ingested in the diet. The kidneys also prevent the loss of HCO3- in urine by reabsorbing virtually all the HCO3filtered at the glomeruli. Both reabsorption of the filtered HCO3- and excretion of acid are accomplished via secretion of H+ by nephrons

Key Concepts
.Acid is excreted by the kidneys in the form of titratable acid (primarily as Pi) and NH4+. Excretion of both titratable acid and NH4+ results in the generation of new HCO3-, which replenishes the ECF HCO3- lost during the neutralization of nonvolatile acids.

Key Concepts
The body uses three lines of defense to minimize the impact of acid-base disorders on body fluid pH: (1) ECF and ICF buffering, (2) respiratory compensation, and (3) renal compensation.

Key Concepts
Metabolic acid-base disorders are caused by primary alterations in ECF [HCO3-], which in turn result from the addition of acid to or loss of alkali from the body. In response to metabolic acidosis, pulmonary ventilation is increased, which decreases PCO2, and renal net acid excretion is increased. An increase in ECF [HCO3-] causes alkalosis. This decreases pulmonary ventilation, which elevates PCO2. The pulmonary response to metabolic acid-base disorders occurs in a matter of minutes. Renal net acid excretion is also decreased. This response may take several days.

Key Concepts
Respiratory acid-base disorders result from primary alterations in PCO2. Elevation of PCO2 produces acidosis, and the kidneys respond with an increase in net acid excretion. Conversely, a reduction in PCO2 produces alkalosis, and renal net acid excretion is reduced. The kidneys respond to respiratory acid-base disorders over a period of several hours to days.