Transcript Renal role in acid-base balance, factors that determine H+ excreted

This lecture was conducted during the Nephrology
Unit Grand Ground by Medical Student rotated under
Nephrology Division under the supervision and
administration of Prof. Jamal Al Wakeel, Head of
Nephrology Unit, Department of Medicine and Dr.
Abdulkareem Al Suwaida, Chairman of Department of
Medicine. Nephrology Division is not responsible for
the content of the presentation for it is intended for
learning and /or education purpose only.
Presented by:
Dr. Rinda Mousa
Medical Student
August 2008
Objectives
1-RENAL ROLE IN ACID-BASE
BALANCE
Reabsorption of bicarbonate
Acid excretion
2-PROXIMAL RTA
3-DISTAL RTA
4-TYPE 4 RENAL TUBULAR
ACIDOSIS



The lungs and the kidneys are
responsible for the maintenance of acidbase balance within the body.
Alveolar ventilation removes carbon
dioxide.
while the kidneys reabsorb filtered
bicarbonate and excrete a daily quantity
of hydrogen ion equal to that produced
by the metabolism of dietary protein.
Dietary acid load increases ammonium excretion
Ammonium excretion increased almost four-fold despite a minimal fall in the
plasma bicarbonate concentration.
RENAL ROLE IN ACID-BASE
BALANCE
Reabsorption of bicarbonate
And Acid excretion
the factors that determine H+ excreted
and HCO3- reabsorption.
1- The extracellular pH (ABG) is the major
physiologic regulator .
2- the effective circulating volume and
Aldosterone
3- the plasma K+ concentration
4- other less important factors such as
parathyroid hormone, Hypochloremia
and nonreabsorbable anion
1-The extracellular pH
The intracellular pH changes either due to.


An elevation in the PCO2
will induce rapid acidification in the cells, because
CO2 can freely cross cell membranes.
Alterations in the plasma HCO3- concentration
are less direct, since transcellular diffusion of this
anion is limited by the lipid bilayer of the cell
membrane.
However, the carrier-mediated HCO3- exit steps in
the basolateral membrane of the proximal tubule
(Na+-3HCO3- cotransport) and in the distal nephron
(Cl--HCO3- exchange) are affected by the
transmembrane HCO3- gradient.
Acidemia is manifested in the
proximal tubule by 3 changes

Enhanced luminal Na+-H+ exchange .
It is sensitive to inhibition by the diuretic drug amiloride, and has affinity for Li+ in
addition to Na+ and H+ .


Increased activity of the Na:3HCO3cotransporter in the basolateral membrane
.
Increased NH4+ production from
glutamine .
Acidemia is manifested In the
collecting tubules
H+-ATPase pumps
the increase in acidification appears to
involve the insertion of preformed
cytoplasmic.
 the diffusion of interstitial NH3 into the
lumen
where it will be trapped as NH4+ .
 Cl--HCO3- exchange
The net effect of increase in acid excretion is
enhanced generation of HCO3- by the tubules
that is returned to the peritubular capillary.

In the proximal tubule, glutamine is taken up by the cells and metabolized into NH4+ and
alpha-ketoglutarate. Utilization of the latter results in the generation of HCO3-, whereas
NH4+ substitutes for H+ on the Na+-H+ exchanger and is then secreted directly into the
lumen. The mechanism is different in the collecting tubules; nonpolar, lipid-soluble NH3
diffuses from the interstitial fluid into the lumen, where it combines with secreted H+ to
form NH4+. Ammonium is lipid-insoluble and is therefore unable to back-diffuse out of
the lumen. Note that each NH4+ ion that is excreted is associated with the generation of
a new HC03- ion that is returned to the peritubular capillary.
These adaptive changes in cell pH
are determined by the extracellular pH itself, not by
the HCO3- concentration or PCO2 alone. Thus, there
is no alteration in the cell pH if both the HCO3concentration and PCO2 are lowered or raised to a
similar degree, so that the extracellular pH remains
constant . I
The importance of this local effect,
which is independent of other circulating factors, is
though to be mediated by activation of pH-sensitive
proteins .
2-the effective of circulating
volume and Aldosterone
Ion transport in collecting tubule cell.
Aldosterone, leads to enhanced Na reabsorption and potassium secretion by
increasing both the number of open Na channels and the number of Na-K-ATPase
pumps in the intercalated cells in the cortical collecting tubule, and the cells in the
outer and inner medullary collecting tubule† . Atrial natriuretic peptide inhibits
sodium reabsorption by closing the Na channels. The potassium-sparing diuretics
act by closing Na channels, amiloride and triamterene directly and spironolactone by
competing with aldosterone.
Ion transport in thick ascending limb of the loop of Henle
•The entry of filtered NaCl into the cells is mediated by a neutral Na-K-2Cl
cotransporter in the apical (luminal) membrane. Reabsorbed Na is pumped out of
the cell by the Na-K-ATPase pump in the basolateral (peritubular) membrane.
Although K plays an important role in this process, the concentration of K in the
filtrate and tubular fluid is much less than that of Na and Cl; thus, K must recycle
back into the lumen through K channels in the apical membrane to allow
continued NaCl reabsorption.
•The ensuing lumen electropositivity creates an electrical gradient that promotes
the passive reabsorption of cations - Na, and, to a lesser degree, Ca, and Mg - via
the paracellular pathway between the cells.
The loop diuretics inhibit Na, K, and Cl (and Ca and Mg) reabsorption by
competing for the Cl site on this transporter.
3-the plasma K+ concentration
Reciprocal cation shifts of K, H, and Na between the cells, (including renal
tubular cells) and the extracellular fluid.
In the presence of hypokalemia K moves out of the cells down a concentration
gradient. Since the cell anions (primarily proteins and organic phosphates) are
unable to cross the cell membrane, electroneutrality is maintained by the entry
of Na and H into the cell(alkalosis). The increase in renal cell H concentration
may be responsible for the increased H secretion and HCO3 reabsorption (
alkalosis) seen with hypokalemia.
hyperkalemia K moves in causes H and Na to leave the cells( acidosis), in
renal cell resulting in a fall in H secretion and HCO3 reabsorption.
4-Hypochloremia and
nonreabsorbable anion

both H+ and Cl- ions are lost in most
patients,
such as those with vomiting or diuretic therapy.

The reduction in the filtered Clconcentration,
can enhance H+ secretion and HCO3reabsorption
Effect of nonreabsorbable anion on potassium and hydrogen secretion
Events occurring after Na reabsorption across the luminal membrane in
the cortical collecting tubule. the presentation of Na with a
nonreabsorbable anion such as SO4(2-) enhances H and K secretion. In
contrast, if NaCl is presented to this segment, Na will be reabsorbed with
Cl, with little effect on H and K secretion
5-parathyroid hormone
Parathyroid hormone (PTH) diminishes proximal HCO3reabsorption by
 reducing the activity of Na+-H+ exchanger in the
luminal membrane and the Na+-3HCO3cotransporter in the basolateral membrane .
 However, the extra HCO3- delivered out of the
proximal tubule is mostly picked up in the loop of
Henle and more distal segments. Although there may
be a slight increase in HCO3- excretion, this is
generally counteracted by enhanced excretion of
phosphate which can increase net acid excretion .





Refers to the development of metabolic acidosis
because of a defect in the ability of the renal tubules
to perform their functions .
Impaired hydrogen ion secretion is the primary
defect in distal RTA while impaired ammoniagenesis
is the primary defect in type 4 RTA and renal failure
All forms of RTA are characterized by a normal anion
gap (hyperchloremic) metabolic acidosis.
This form of metabolic acidosis usually results from
either
1-the net retention of hydrogen chloride .
2-the net loss of sodium bicarbonate .
However, The major cause of a normal anion gap
acidosis in patients without renal failure is diarrhea
Type 1 or distal RTA
It is associated with a defect in
distal hydrogen ion excretion
Major causes of type I (distal)
renal tubular acidosis
In the proximal tubule, glutamine is taken up by the cells and metabolized into NH4+ and
alpha-ketoglutarate. Utilization of the latter results in the generation of HCO3-, whereas
NH4+ substitutes for H+ on the Na+-H+ exchanger and is then secreted directly into the
lumen. The mechanism is different in the collecting tubules; nonpolar, lipid-soluble NH3
diffuses from the interstitial fluid into the lumen, where it combines with secreted H+ to
form NH4+. Ammonium is lipid-insoluble and is therefore unable to back-diffuse out of
the lumen. Note that each NH4+ ion that is excreted is associated with the generation of
a new HC03- ion that is returned to the peritubular capillary.
Distal RTA results from one of several defects
in distal hydrogen ion secretion.
1-Decreased proton pump (H-ATPase) activity
2-Increased luminal membrane permeability
with backleak of hydrogen ions
3-Diminished distal tubular sodium reabsorption
which reduces the electrical gradient for
proton secretion
 The most common causes in adults are
autoimmune disorders, such as Sjögren's
syndrome, and other conditions associated
with chronic hyperglobulinemia. In children,
type 1 RTA is most often a primary,
hereditary condition





Several patients with Sjögren's syndrome have been described
in whom immunocytochemical analysis of tissue obtained by
renal biopsy showed complete absence of H-ATPase pumps in
the intercalated cells . How immunologic injury leads to this
change is not known.
Mutations in the gene for the chloride-bicarbonate exchanger
(AE1 or band 3) have been described in autosomal dominant
(most common) and autosomal recessive type 1 RTA . Other
mutations in AE1 can lead to hereditary spherocytosis.
Mutations have also been described in the genes encoding the
B1 and alpha4 subunits of the H-ATPase pump defects of either
subunit may be associated with sensorineural deafness,
suggesting that the pump is required for normal function of the
inner ear .
The presence of high titers of an autoantibody directed against
carbonic anhydrase II as observed in patients with Sjögren's
syndrome ; inhibition of this enzyme would reduce the number
of hydrogen ions generated within the cell for secretion into the
lumen .


Increased luminal membrane
permeability amphotericin B i enhance membrane
permeability lead to both the fall in hydrogen
secretion and increased membrane permeability to
potassium.
Diminished sodium reabsorption in the
adjacent principal cells indirectly influences net
hydrogen secretion by the intercalated cells. The
transport of sodium makes the lumen
electronegative, an effect that promotes the secretion
both of potassium and hydrogen. Thus, impairing
sodium reabsorption will tend to induce both
metabolic acidosis and hyperkalemia . urinary tract
obstruction sickle cell disease , lupus nephritis , and
with any cause of marked volume depletion
Hyperkalemic type 1 RTA can be
differentiated from type 4 RTA in which
hypoaldosteronism leads to a rise in the
plasma potassium concentration.
In type 1 RTA, however, aldosterone
levels are normal and the acidifying
defect is more severe, leading to a
urine pH that is above 5.30 and a
plasma bicarbonate concentration that
is often below 15 meq/L. In
comparison, the urine pH is typically
below 5.3 and the plasma bicarbonate
concentration is generally above 17
meq/L in type 4 RTA .
Major causes of type I (distal) renal tubular acidosis
Primary
1-Idiopathic, sporadic
2-Familial
3-Autosomal dominant
3-Autosomal recessive
Secondary
Sjögren's syndrome , Rheumatoid arthritis , SLE
Hypercalciuria
Hyperglobulinemia
Ifosfamide
Amphotericin B
Cirrhosis
Renal trasplant
Sickle cell anemia (may be hyperkalemic)
Obstructive uropathy (may be hyperkalemic)
Lithium carbonate
DIAGNOSIS




high urine pH (greater than 5.5 in the
presence of acidosis).
plasma bicarbonate concentration that may
fall below 10 meq/L.
hypercalciuria due to the effects of chronic
acidosis on both bone resorption and the
renal tubular reabsorption of calcium.
Hypercalciuria contributes to the development
of nephrolithiasis and nephrocalcinosis.
Hypokalemia, sometimes severe, is frequently
seen in distal RTA and may produce muscle
weakness, potassium secretion must be
enhanced to maintain electroneutrality as
sodium is reabsorbed.
treatment



correction of the acidemia has the advantages of
minimizing new stone formation and nephrocalcinosis
and lowering inappropriate urinary potassium losses.
The aim of alkali therapy is to achieve a relatively
normal plasma bicarbonate concentration (22 to 24
meq/L). Bicarbonate wasting is negligible in adults
who can generally be treated with 1 to 2 meq/kg of
sodium bicarbonate or sodium citrate (Bicitra™,
which is usually better tolerated). Children, however,
may require as much as 4 to 8 meq/kg per day in
divided doses because the urine pH and fixed
bicarbonate losses may be higher than in adults .
Potassium citrate, alone or with sodium citrate
(Polycitra™), is indicated for persistent hypokalemia
or for calcium stone disease.
Type 2 or proximal RTA
It is characterized by a reduction
in proximal bicarbonate
reabsorption capacity




Inherited defects in the gene for the sodium
bicarbonate cotransporter (SLC4A4) results in
autosomal recessive type 2 RTA (with concurrent
ocular abnormalities) .
while mutations in the gene for one of the plasma
membrane sodium-hydrogen exchangers may be
responsible for autosomal dominant disease .
Defective carbonic anhydrase activity and, in
cystinosis, ATP depletion have been described among
patients with type 2 RTA .
The distal nephron has substantial bicarbonate
reabsorptive capacity; thus, even if proximal function
is severely impaired, the plasma bicarbonate
concentration does not fall below 12 meq/L.
In the proximal tubule, glutamine is taken up by the cells and metabolized into NH4+ and
alpha-ketoglutarate. Utilization of the latter results in the generation of HCO3-, whereas
NH4+ substitutes for H+ on the Na+-H+ exchanger and is then secreted directly into the
lumen. The mechanism is different in the collecting tubules; nonpolar, lipid-soluble NH3
diffuses from the interstitial fluid into the lumen, where it combines with secreted H+ to
form NH4+. Ammonium is lipid-insoluble and is therefore unable to back-diffuse out of
the lumen. Note that each NH4+ ion that is excreted is associated with the generation of
a new HC03- ion that is returned to the peritubular capillary.


Proximal (type 2) RTA may occasionally
present as an isolated defect, but is more
commonly associated with generalized
proximal tubular dysfunction called the
Fanconi syndrome. In addition to
bicarbonaturia, generalized proximal
dysfunction may be associated with one or
more of the following: glucosuria,
phosphaturia, uricosuria, aminoaciduria, and
tubular proteinuria.
The most common causes of Fanconi
syndrome in adults are the excretion of light
chains due to multiple myeloma (which may
be occult) and the use of a carbonic
anhydrase inhibitor (such as acetazolamide)
or the anticancer drug ifosfamide .
Idiopathic, sporadic
Acquired disorders
Multiple myeloma
Familial disorders
Ifosfamide
Carbonic anhydrase inhibitors
Cystinosis
Amyloidosis
Tyrosinemia
Heavy metals
Hereditary fructose intolerance
Galactosemia
Glycogen storage disease (type I)
Lead
Cadmium
Mercury
Copper
Vitamin D deficiency
Wilson's disease
Renal transplantation
Lowe's syndrome
Paroxysmal nocturnal
hemoglobinuria
Potassium balance —
depending whether the patient is being treated with alkali
therapy.
Once there has been a sufficient reduction in the filtered
bicarbonate load in untreated patients, all of the filtered
bicarbonate can again be reabsorbed as in normal subjects. At
this time, the plasma bicarbonate concentration is stable
(usually between 12 and 20 meq/L), the urine pH may be
normally acid, and the plasma potassium concentration is
relatively normal. There may still be some tendency to
potassium wasting , since metabolic acidosis alone diminishes
proximal sodium reabsorption . As a result, there is increased
distal delivery of sodium and sodium-wasting-induced secondary
hyperaldosteronism, both of which promote potassium
secretion.

The findings are dramatically different once alkali therapy is
begun to correct the acidemia. The ensuing marked elevation in
distal sodium and water delivery can substantially enhance
distal potassium secretion . Thus, many patients must be
treated with a combination of potassium and sodium
bicarbonate (or citrate).
The diagnosis of proximal RTA



measurement of the urine pH
fractional bicarbonate excretion
during a bicarbonate infusion.
The hallmark is a urine pH above 7.5
and the appearance of more than 15
percent of the filtered bicarbonate in
the urine when the serum bicarbonate
concentration is raised to a normal level
treatment



Correction of the acidemia will allow normal
growth to occur and will promote healing of
rickets or osteomalacia.
phosphate and vitamin D supplementation
may be necessary to normalize the plasma
phosphate concentration.
bicarbonaturia also enhances urinary
potassium losses by increasing sodium and
water delivery to the distal potassium
secretory site .
Type 3 RTA
The term is now most often applied to a
rare autosomal recessive syndrome
(resulting from carbonic anhydrase II
deficiency) with features of :

Both type 1 and type 2 RTA

Oesteopetrosis

cerebral calcification

mental retardation.
Type 4 RTA or
hypoaldosteronism
It is associated with hyperkalemia
and a mild metabolic acidosis



Estimation of the transtubular potassium
concentration gradient (TTKG) is often of greater
value in hyperkalemic patients, since it may
distinguish hypoaldosteronism from other causes of
hyperkalemia.
The TTKG can be calculated using the following
formula:
TTKG = [Urine K ÷ (urine osmolality /
serum osmolality)] ÷ serum K
Hyperkalemia should be associated with increases in
aldosterone release and distal potassium secretion,
leading to a high TTKG above 10 in normal subjects.
A value below 7 and particularly below 5 is highly
suggestive of hypoaldosteronism. The TTKG is
relatively accurate as long as the urine osmolality
exceeds that of serum and the urine sodium
concentration is above 25 meq/L (to ensure adequate
distal distal sodium delivery).
Major causes of hypoaldosteronism
1-Aldosterone deficiency
2-Aldosterone resistance
Aldosterone deficiency
Primary
1-Primary adrenal insufficiency
2-Congenital adrenal hyperplasia, particularly 21-hydroxylase
deficiency
3-Isolated aldosterone synthase deficiency
4-Heparin and low molecular weight heparin
Hyporeninemic hypoaldosteronism
1-Renal disease, most often diabetic nephropathy
2-Volume expansion, as in acute glomerulonephritis
3-Angiotensin converting enzyme inhibitors
4-Nonsteroidal antiinflammatory drugs
5-Cyclosporine HIV infection
6-Some cases of obstructive uropathy
Aldosterone resistance
1-Drugs which close the collecting tubule sodium
channel
Amiloride
Spironolactone
Triamterene
Trimethoprim (usually in high doses)
Pentamidine
2-Tubulointerstitial disease
3-Pseudohypoaldosteronism
4-Distal chloride shunt
In the proximal tubule, glutamine is taken up by the cells and metabolized into NH4+ and
alpha-ketoglutarate. Utilization of the latter results in the generation of HCO3-, whereas
NH4+ substitutes for H+ on the Na+-H+ exchanger and is then secreted directly into the
lumen. The mechanism is different in the collecting tubules; nonpolar, lipid-soluble NH3
diffuses from the interstitial fluid into the lumen, where it combines with secreted H+ to
form NH4+. Ammonium is lipid-insoluble and is therefore unable to back-diffuse out of
the lumen. Note that each NH4+ ion that is excreted is associated with the generation of
a new HC03- ion that is returned to the peritubular capillary.
DIAGNOSIS OF
HYPOALDOSTERONISM


1.
2.
3.
4.
Patients suspected to have
hypoaldosteronism should be questioned
about the use of any drug or the presence
of a disease that can impair aldosterone
release,
If none of these findings is present, then
evaluation for some other causes of
hypoaldosteronism :
hyporeninemic hypoaldosteronism
primary adrenal insufficiency
adrenal enzyme defect
the rare genetic disorders type 1 and type 2
pseudohypoaldosteronism.
These disorders can be differentiated by measurement of
plasma renin activity (PRA)and serum aldosterone and cortisol




Hyporeninemic hypoaldosteronism most often occurs in
patients 50 to 70 years of age with diabetic nephropathy
or chronic interstitial nephritis who have mild to
moderate renal insufficiency . It is associated with low
PRA , a low serum aldosterone concentration, and a
normal serum cortisol concentration.
primary adrenal insufficiency have low serum
aldosterone and cortisol concentrations, but high PRA
due to volume depletion and hypotension.
adrenal enzyme deficiency , adrenal androgen synthesis
increased, leading to virilization
syndrome of aldosterone resistance
(pseudohypoaldosteronism) have high PRA and serum
aldosterone concentration
The cortical collecting tubule contains two
cell types with very different functions
principal cells
increased function in Liddle's syndrome and
decreased function in
pseudohypoaldosteronism
The intercalated cells
Treatment
Treat the cause
In the proximal tubule, glutamine is taken up by the cells and metabolized into NH4+ and
alpha-ketoglutarate. Utilization of the latter results in the generation of HCO3-, whereas
NH4+ substitutes for H+ on the Na+-H+ exchanger and is then secreted directly into the
lumen. The mechanism is different in the collecting tubules; nonpolar, lipid-soluble NH3
diffuses from the interstitial fluid into the lumen, where it combines with secreted H+ to
form NH4+. Ammonium is lipid-insoluble and is therefore unable to back-diffuse out of
the lumen. Note that each NH4+ ion that is excreted is associated with the generation of
a new HC03- ion that is returned to the peritubular capillary.