L6 Renal Physiology 6 (and stuff from 5

Overview

This lecture completes acid-base balance and then introduces potassium homeostasis. It starts from the two daily acid challenges (CO2 from cells and non-volatile acid from metabolism), shows why buffering alone is insufficient and why the kidney must regenerate bicarbonate, then uses the Henderson-Hasselbalch equation as the framework for classifying the four primary disturbances and for understanding compensation. The anion gap is used to split metabolic acidosis into two patterns, and two clinical cases (an NG-drainage metabolic alkalosis with paradoxical aciduria, and a diabetic ketoacidosis) apply the whole scheme. The final section covers potassium: its distribution, short-term internal shifts between ICF and ECF, and long-term external balance by the kidney.

The daily acid challenge

Two day-to-day challenges to pH regulation:

1. CO2 produced by cells, which hydrates to carbonic acid: $C{O}_2+H_{2}O\leftrightarrow H_{2}C{O}_3\leftrightarrow H^{+}+HC{O}_3^{-}$
2. Acid produced from metabolism, the “non-volatile acids”: phosphoric, sulfuric, lactic acid, ketone bodies.

CO2 load: about 13000 mmol CO2/day (10 mmol/min), i.e. potentially 13000 mmol of acid. This is not normally a problem because CO2 can be removed via the lungs. But two caveats: CO2 is not produced in the lungs, so it has to be buffered in transit; and you need to keep breathing.

Non-volatile acid load (NEAP): metabolism produces 50 to 80 mmol/day.

• $H_{2}S{O}_4$ from sulfur-containing amino acids
• $H_{3}P{O}_4$ from phosphoproteins and phospholipids
• Organic acids, e.g. lactate and pyruvate from anaerobic exercise
• Ketoacids from fat metabolism

The H+ from these acids must be both buffered and excreted.

Buffering and why the kidney is required

There are multiple buffering mechanisms, with three main buffers:

• Bicarbonate
• Protein
• Phosphate

Plus dilution and exchange with bone minerals, together termed “whole body buffering”. This prevents pH falling to dangerous levels.

Buffering only hides the H+; it still has to be removed. Using the bicarbonate and respiratory route, buffered H+ reacts with bicarbonate: $H^{+}+HC{O}_3^{-}\to H_{2}C{O}_3\to C{O}_2+H_{2}O$. The CO2 is exhaled and the H+ is now part of a water molecule, so it is no longer an acid threat. The catch is that the process has consumed a bicarbonate ion, which must be replaced by the kidney.

Renal handling of bicarbonate has two components:

1. Replacement of filtered HCO3 (“reabsorption”): “new” HCO3 is synthesised by proximal tubule cells to replace the filtered ions.
2. Replacement of bicarbonate consumed in buffering and excretion of non-volatile acids, or excretion of excess bicarbonate.

The Henderson-Hasselbalch framework

$pH=6.1+\log \frac{[HC{O}_3^{-}]}{0.03\times pC{O}_2}$

• CO2 is under respiratory control; HCO3 levels are under renal control.
• Normal pH therefore requires appropriate respiratory function to maintain CO2, and appropriate renal function: the kidney must be able to function at all, handle HCO3 appropriately, and secrete acid appropriately.
• The normal ratio $[HC{O}_3^{-}]:(0.03\times pC{O}_2)$ is 20 : 1. If one variable changes, pH can be brought back towards normal by changing the other variable to restore the 20 : 1 ratio. That is compensation.

The four primary disturbances

Respiratory disturbances (primary change in CO2):

• Too much CO2: hypoventilation (e.g. chronic bronchitis) or high inspired CO2, giving respiratory acidosis.
• Too little CO2: hyperventilation (e.g. anxiety, high altitude, hypoxia), giving respiratory alkalosis.

Metabolic disturbances (primary change in HCO3):

• Too much HCO3, an acid deficit: excess bicarbonate by ingestion or renal overproduction, or loss of acid secretions (gastric contents), giving metabolic alkalosis.
• Too little HCO3, an acid excess: loss of bicarbonate (gut), inadequate renal bicarbonate production, or addition/excessive production of organic acids, giving metabolic acidosis.

Compensation

Compensation is an integrated response in which lungs and kidneys work together to correct pH abnormalities:

• Respiratory compensation of metabolic acidosis/alkalosis: a primary metabolic change in HCO3 is followed by a secondary change in pCO2.
• Renal compensation of respiratory acidosis/alkalosis: a primary respiratory change in pCO2 is followed by a secondary change in HCO3.

The lecture’s recurring diagram places the Henderson-Hasselbalch equation at the centre, with primary metabolic changes leading to secondary respiratory changes and primary respiratory changes leading to secondary renal changes, the two linked as a reciprocal lung-kidney loop.

Worked example, renal compensation of respiratory acidosis: hypoventilation causes excess CO2 and therefore excess H+ ($C{O}_2+H_{2}O\to H_{2}C{O}_3\to H^{+}+HC{O}_3^{-}$). The kidneys compensate by excreting more H+ and synthesising more HCO3.

How the kidney adjusts bicarbonate production to need:

• If HCO3 must be lost (alkalosis): do not “reabsorb” all filtered HCO3; secrete HCO3 in the distal tubule/collecting duct; reduce acid secretion, which makes less HCO3.
• If more HCO3 is needed (acidosis): maximise “reabsorption” of filtered HCO3; excrete more titratable acid and ammonium in the urine, which means more “new” HCO3 is made by the kidney.

Quantitative picture (mmol/day; metabolic alkalosis / normal / metabolic acidosis):

	Metabolic alkalosis	Normal	Metabolic acidosis
[HCO3-] plasma	33	25	17
HCO3- filtered	6000	4500	3000
HCO3- replaced	5600	4500	3000
HCO3- excreted	400	0	0
Total H+ secreted	5600	4580	3400
Titratable acid excreted	0	30	100
NH4+ excreted	0	50	300
Total titratable acid + NH4+	0	80	400

The total titratable acid plus NH4+ excreted equals the additional HCO3 synthesised by the kidney and added to plasma.

Metabolic alkalosis: causes

• Ingestion of bicarbonate
• Loss of acid secretions: gastric contents, through vomiting or naso-gastric drainage
• Kidneys making too much bicarbonate: hypokalaemia, excess aldosterone

Metabolic acidosis and the anion gap

Two types: normal anion gap and abnormally high anion gap (> 16 mmol/L).

$AG=([N{a}^{+}]+[K^{+}])-([HC{O}_3^{-}]+[C{l}^{-}])$

Normal is up to 15 mmol/L (quoted as roughly 8 to 15 in the worked case). The anion gap is a crude estimate of the plasma concentration of “unmeasured” anions, namely phosphates and proteins.

The two patterns, from the bar-chart diagram (mmol/L):

• Normal: Na+ + K+ = 145; HCO3- 25 and Cl- 105 on the other side; anion gap 15.
• Pattern A, normal anion gap, arising from H+Cl- gain or HCO3- loss: HCO3- falls to 15, Cl- rises to 115, Na+/K+ still 145, AG unchanged at 15.
• Pattern B, increased anion gap, arising from H+A- gain (an unmeasured anion A-): HCO3- falls to 15, Cl- unchanged at 105, Na+/K+ still 145, AG rises to 25.

Normal anion gap metabolic acidosis:

• Loss of bicarbonate from gut (diarrhoea) or kidney
• Inadequate renal bicarbonate production
• Addition of HCl or precursors of HCl (e.g. NH4Cl)
• HCO3- falls and Cl- rises to maintain electroneutrality, so $([N{a}^{+}]+[K^{+}])-(\downarrow [HC{O}_3^{-}]+\uparrow [C{l}^{-}])$ is unchanged
• Therefore a normal anion gap and a normal concentration of “other” anions

High anion gap metabolic acidosis:

• Excessive organic acid production (e.g. lactate, ketones) or ingestion (methanol, ethylene glycol)
• The acids dissociate into organic anions plus H+
• H+ is buffered by bicarbonate, so HCO3- falls
• No rise in Cl-, because the anions from the acid make up for the fall in HCO3-, giving $([N{a}^{+}]+[K^{+}])-(\downarrow [HC{O}_3^{-}]+[C{l}^{-}])$
• Therefore an increased anion gap and an increased concentration of “other” anions, namely the organic anions

Case: Douglas, metabolic alkalosis with paradoxical aciduria

Douglas has a paralytic ileus following GI surgery. A naso-gastric tube is in place with high losses (> 2 litres/day).

Initial results:

• Blood: Na 135, K 3.5, Cl 100, HCO3 30, pH 7.48
• Urine: pH 7.0, Na 45, Cl 30

Mechanism: H+ synthesis in gastric parietal cells adds HCO3 to plasma. In the absence of gastric secretions reaching the gut, that bicarbonate cannot be removed from plasma, so it accumulates and causes alkalosis.

Compensation at this stage:

• Respiratory: hypoventilation
• Renal: minimise new HCO3 by reducing titratable acid and NH4 excretion, so urine pH becomes less acidic; and secrete HCO3 in the distal tubule/collecting duct in exchange for Cl, which reduces urine Cl

Three days later, with ongoing NG fluid losses:

• Blood: Na 136, K 3.4, Cl 98, HCO3 35, pH 7.5
• Urine: pH 5.3, Na 10, Cl 10

Why it worsens: with persistent volume loss the renal priorities change to volume retention. Na retention is maximised, taking any anion with it (Cl or HCO3) or exchanging with H+, which adds HCO3 to plasma. Renal removal of excess HCO3 is therefore reduced and the alkalosis persists, while the urine reverts to a normal acid pH, known as paradoxical aciduria.

Case: Frankie, diabetic ketoacidosis

Frankie (11) was admitted with dehydration. Over the last few months his parents said he had seemed tired and lacking in energy and, despite eating well and drinking large quantities of fluids, had lost about 9 kg. He was also going to the toilet a lot, during the day and at night.

On examination: evidence of dehydration, pulse 115/min, BP 95/55 mmHg, respiratory rate 20 breaths/min, breath smelling of acetone.

Results: Na 138, Cl 98, K 7.6, glucose 35; pCO2 25, pH 7.22, HCO3 10.

What disturbance? pH down, CO2 down, HCO3 down: metabolic acidosis with respiratory compensation. Cause: probable ketoacidosis.

Anion gap: $(138+7.6)-(10+98)=37.6$ (normal roughly 8 to 15), so extra anions are present, most likely ketoacids in diabetes mellitus.

Why is plasma [K] raised, and is there a potassium excess?

• H+ moves into cells in exchange for K+, raising plasma [K]
• Insulin deficiency reduces K entry into cells, raising plasma [K]
• There is no whole body K excess. Osmotic diuresis increases renal tubule K secretion, so K is lost in the urine and there is actually a whole body K deficit

Management: rehydration, insulin, potassium.

Potassium homeostasis: roles and distribution

Potassium is the main cell cation, and it:

• Maintains the cell environment and enzyme function
• Contributes to volume regulation
• Contributes to acid-base balance
• Sets the resting membrane potential through the ratio of K inside to K outside, and so governs nerve, muscle and cardiac function

Three things must be maintained simultaneously: plasma [K], the plasma/cell ratio, and total body K.

Distribution and turnover:

• 98% of K is in the ICF at 140 to 150 mmol/L, with 80% of body K in muscle
• 2% of K is in the ECF at 3.5 to 5 mmol/L
• Plasma K must be kept relatively constant: both hyper- and hypokalaemia are bad, with nerve, muscle and cardiac consequences, up to death
• Intake is about 100 mmol/day; output is about 100 mmol/day (the slide first shows this value blank and fills it in as 100 on the next build), about 10% in faeces and about 90% in urine
• The kidney is the major organ for long term K balance

Internal balance: shifts between ECF and ICF

Short term regulation of plasma K is by shifting K into and out of cells. The reason this matters: a meal containing 40 mmol K entering 14 litres of ECF would raise [K] by 3 mmol/L, i.e. from 4.5 mmol/L to 7.5 mmol/L.

Factors affecting K shifts into and out of cells:

• Raised plasma K itself, increased Na/K ATPase activity, increased insulin, increased adrenaline and increased aldosterone all increase K uptake by cells
• ECF pH: in acidosis H+ moves into cells and K+ out; in alkalosis K+ moves into cells and H+ out
• Increased ECF osmolarity: K moves out of cells
• Exercise: K moves out of cells into the ECF

External balance: the kidney

Long term regulation is by the kidneys. About 700 mmol/day is filtered:

• 66% reabsorbed in the proximal tubule
• 20% reabsorbed in the loop of Henle
• Distal tubule/collecting duct: secrete K if there is excess (principal cells), or reabsorb K if there is a deficit (intercalated cells)
• Net result: 14% of filtered K reaches the urine

The kidney can secrete large amounts of K if necessary, so GFR is rarely a limiting factor in K excretion; that requires substantial glomerular damage and/or tubule damage.

Self-test

1. State the two day-to-day challenges to pH regulation and the reaction that links CO2 to acid.
2. How much CO2 is produced per day, and why is it not normally an acid problem?
3. Give two reasons why CO2 still has to be buffered despite being removed by the lungs.
4. How much non-volatile acid does metabolism produce per day, and what are its four sources?
5. List the three main buffers, and name two further components of “whole body buffering”.
6. Explain why buffering alone does not solve the acid load, and write the reaction by which buffered H+ is finally disposed of.
7. Describe the two ways the kidney handles bicarbonate.
8. Write the Henderson-Hasselbalch equation and state which organ controls each variable.
9. What is the normal ratio of [HCO3-] to 0.03 x pCO2, and how does compensation use it?
10. Distinguish respiratory acidosis from respiratory alkalosis by cause, with one example of each.
11. Distinguish metabolic acidosis from metabolic alkalosis by cause, listing the mechanisms given for each.
12. Describe the steps by which the kidney compensates for a respiratory acidosis caused by hypoventilation.
13. List the three things the kidney does when it needs to lose bicarbonate, and the two things it does when it needs more.
14. In the acid-base table, what happens to titratable acid and NH4+ excretion in metabolic acidosis compared with normal, and what does their total represent?
15. List the causes of metabolic alkalosis.
16. Write the anion gap formula, give the normal value, and say what the gap estimates.
17. Distinguish Pattern A from Pattern B metabolic acidosis in terms of what happens to HCO3-, Cl- and the gap, using the diagram’s numbers.
18. Explain why chloride rises in a normal anion gap acidosis but not in a high anion gap acidosis.
19. Explain why prolonged naso-gastric losses cause an alkalosis, and why the urine becomes acidic after several days.
20. A child presents with dehydration, weight loss, polyuria and acetone on the breath; pH 7.22, pCO2 25, HCO3 10, Na 138, K 7.6, Cl 98, glucose 35. Classify the disturbance, calculate the anion gap, and give the likely cause.
21. In that child, explain the raised plasma potassium and state whether total body potassium is high or low, with the reason.
22. State the ICF and ECF potassium concentrations and the percentage of body K in each compartment.
23. List the factors that drive potassium into cells and those that drive it out.
24. Describe the tubular handling of filtered potassium, segment by segment, and give the fraction excreted.
25. Integrative: a patient in metabolic acidosis has a plasma [K] of 6.0 mmol/L. Using the internal-balance and renal mechanisms from this lecture, explain how the acidosis raises plasma K and how the kidney’s response to acidosis differs from its response to alkalosis.

Answers

Reveal answers

1. CO2 produced by cells and acid produced from metabolism (non-volatile acids). The link reaction is $C{O}_2+H_{2}O\leftrightarrow H_{2}C{O}_3\leftrightarrow H^{+}+HC{O}_3^{-}$.
2. About 13000 mmol/day (10 mmol/min), potentially 13000 mmol of acid; it is not normally a problem because CO2 can be removed via the lungs.
3. CO2 is not produced in the lungs, so it must be buffered in transit; and you need to keep breathing for the lung route to work.
4. 50 to 80 mmol/day (NEAP): H2SO4 from sulfur-containing amino acids, H3PO4 from phosphoproteins and phospholipids, organic acids such as lactate and pyruvate from anaerobic exercise, and ketoacids from fat metabolism.
5. Bicarbonate, protein and phosphate; plus dilution and exchange with bone minerals.
6. Buffering only hides the H+, it does not remove it. Disposal is $H^{+}+HC{O}_3^{-}\to H_{2}C{O}_3\to C{O}_2+H_{2}O$, with CO2 exhaled and the H+ now part of water, at the cost of one consumed HCO3-.
7. Replacement of filtered HCO3 (“reabsorption”), where new HCO3 is synthesised by proximal tubule cells to replace the filtered ions; and replacement of the bicarbonate consumed in buffering and excreting non-volatile acids, or excretion of excess bicarbonate.
8. $pH=6.1+\log ([HC{O}_3^{-}]/(0.03\times pC{O}_2))$. CO2 is under respiratory control, HCO3 under renal control.
9. 20 : 1. If one variable changes, pH can be returned towards normal by changing the other variable to restore the 20 : 1 ratio.
10. Respiratory acidosis is too much CO2, from hypoventilation (e.g. chronic bronchitis) or high inspired CO2. Respiratory alkalosis is too little CO2, from hyperventilation (e.g. anxiety, high altitude, hypoxia).
11. Metabolic alkalosis is too much HCO3 (acid deficit): excess bicarbonate from ingestion or renal overproduction, or loss of acid secretions such as gastric contents. Metabolic acidosis is too little HCO3 (acid excess): loss of bicarbonate from the gut, inadequate renal bicarbonate production, or addition/excessive production of organic acids.
12. Hypoventilation gives excess CO2, which via $C{O}_2+H_{2}O\to H_{2}C{O}_3\to H^{+}+HC{O}_3^{-}$ gives excess H+; the kidneys then excrete more H+ and synthesise more HCO3.
13. To lose HCO3: do not reabsorb all the filtered HCO3, secrete HCO3 in the DT/CD, and reduce acid secretion so less HCO3 is made. To gain HCO3: maximise reabsorption of filtered HCO3, and excrete more titratable acid and ammonium so more new HCO3 is made.
14. Titratable acid rises from 30 to 100 mmol/day and NH4+ from 50 to 300 mmol/day. Their total (80 normal, 400 in acidosis) equals the additional HCO3 synthesised by the kidney and added to plasma.
15. Ingestion of bicarbonate; loss of acid secretions, i.e. gastric contents through vomiting or NG drainage; and kidneys making too much bicarbonate, seen with hypokalaemia and with excess aldosterone.
16. $AG=([N{a}^{+}]+[K^{+}])-([HC{O}_3^{-}]+[C{l}^{-}])$, normally up to 15 mmol/L (about 8 to 15). It is a crude estimate of the plasma concentration of unmeasured anions, namely phosphates and proteins.
17. Pattern A (normal gap) follows H+Cl- gain or HCO3- loss: HCO3- falls from 25 to 15, Cl- rises from 105 to 115, gap stays 15. Pattern B (increased gap) follows H+A- gain: HCO3- falls from 25 to 15, Cl- stays 105, gap rises from 15 to 25 with the unmeasured anion A- present. Na+ + K+ remains 145 in both.
18. In a normal gap acidosis Cl- rises to maintain electroneutrality as HCO3- falls. In a high gap acidosis the organic anions liberated by the dissociating acid make up for the fallen HCO3-, so Cl- does not need to rise.
19. H+ synthesis in gastric parietal cells adds HCO3 to plasma; without gastric secretions that bicarbonate cannot be removed and accumulates, causing alkalosis. After several days persistent volume loss shifts renal priorities to volume retention, so Na retention is maximised, taking Cl or HCO3 with it or exchanging with H+ (which adds more HCO3), removal of excess HCO3 falls and the urine becomes acid again: paradoxical aciduria.
20. Metabolic acidosis with respiratory compensation (pH down, CO2 down, HCO3 down). Anion gap $(138+7.6)-(10+98)=37.6$, well above normal, so extra anions are present. Likely cause is ketoacidosis in diabetes mellitus.
21. H+ enters cells in exchange for K+, and insulin deficiency reduces K entry into cells, so plasma [K] rises. Total body potassium is actually low, because osmotic diuresis increases renal tubule K secretion and K is lost in the urine.
22. ICF 140 to 150 mmol/L holding 98% of body K (80% of body K in muscle); ECF 3.5 to 5 mmol/L holding 2%.
23. Into cells: raised plasma K, increased Na/K ATPase activity, insulin, adrenaline, aldosterone, and alkalosis (K+ in, H+ out). Out of cells: acidosis (H+ in, K+ out), increased ECF osmolarity, and exercise.
24. About 700 mmol/day is filtered; 66% is reabsorbed in the proximal tubule and 20% in the loop of Henle; the DT/CD then secrete K if there is excess (principal cells) or reabsorb it if there is a deficit (intercalated cells), leaving 14% of the filtered load in the urine.
25. In acidosis H+ moves into cells in exchange for K+ moving out, raising plasma [K] without necessarily raising total body K. The kidney’s response to acidosis is to maximise reabsorption of filtered HCO3 and excrete more titratable acid and ammonium, generating more new HCO3; in alkalosis it does the opposite, leaving filtered HCO3 unreabsorbed, secreting HCO3 in the DT/CD and reducing acid secretion so less HCO3 is made.