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RENAL ACIDIFICATION
H+ and HCo3- • H+ ion , smallest ion• Million fold lesser in concentration than HCo3-
• H+ play a major role in ETC- generation of ATP• If their conc. exceeds a tight range, it can lead to
acidemia.• Binding of H + to proteins ( functioning as
enzymes, transporters, contractile elements, and structural compounds) can lead to their altered function
Body needs some mechanism to keep H + in check
Answer to this are buffers
EXTRACELLULAR BUFFER a) Bicarbonate buffer system (H+ )+ ( HCO3 -) ↔ (CO2)+(H20)
b) Plasma proteinsc) Phosphated) Bone apatite
INTRACELLULAR BUFFERa) Hemoglobinb) Cellular proteinsc) Organophosphate complexesd) HCO3
Excess acid or alkali generated needs to be removed from body……
Portals – LUNG & KIDNEY
RENAL REGULATION OF pHKidneys cause Net Acid Excretion (NAE) which is summation of a) Ammonium excretion (60 %)b) Titrable acid (PO4, UA, Cr)excretion (40 %)c) Bicarbonate excretion (0% in normal states)
Thus kidney should-• Reabsorb near total filtered bicarb by excreting
H +• Add new bicarb in acid load by excreting
Ammonium
Renal handling of acid bases at different levels of nephrons
GLOMERULUS –No significant role in regulation Only causes about 4500 mmol/day of HCo3 loss(GFR multiplied by bicarbonate concentration)
The major business of acid base regulation is in tubules
HCo3- absorption
Renal acid-base homeostasis may be broadly divided into 2 processes
1. Proximal urinary acidification i.e Proximal tubular absorption of HCO3
-
2. Distal urinary acidification.
Reabsorption of remaining HCO3- that escapes
proximally.
Excretion of fixed acids through buffering & Ammonia recycling and excretion of NH4
+.
Proximal tubular HCo3 - absorption
NHE – 2/3
H ATPase – 1/3
IV II
NA K ATPase
NA HCO3 COTRANSPORTER
Cl HCO3 ANTIPORTER
THICK ASCENDING LOOP OF HENLE
NA H ANTIPORTER
NA K ATPase
NA HCO3 COTRANSPORTER
Cl HCO3 EXC
COLLECTING DUCT The segments of the collecting duct includeA) Cortical collecting ductB) Outer medullary collecting ductC) Inner medullary collecting duct.
There are two distinct cell types in the cortical collecting duct histologically:a) The principal cell and b) The intercalated cell.
Principal cell- Reabsorbs Na+ and Secretes K+
Intercalated cells- secrete acid - α cells secrete base – β cells
H ATPase
H K ATPase CA II
Cl HCO3 EXCHGR
H ATPase
HCO3 Cl EXC
Ammonia metabolismThe proximal tubule is responsible for both a) Ammonia production (from glutamine metabolism resulting in production of two NH4+ and two HCO3 ions from each glutamine ion)
b ) Luminal secretion (NH4 + transport by the apical Na+-H+ antiporter NHE3)
Metabolic acidosis increases the mobilization of glutamine from skeletal muscle and intestinal cells. Glutamine is preferentially taken up by the proximal tubular cell through the Na+- and H+-dependent glutamine transporter SNAT3.
SNAT3 expression increases several fold in metabolic acidosis, and it is preferentially expressed on the
cell’s basolateral surface
Proximal tubule
Distal tubule
Net Acid Excretion
NH4 + Excretion
Titrable Acid Excretion
HCO3 Excretion
ACIDOSIS ↑ ↑ ↑ ↓
ALKALOSIS ↓ ↓ ↓ ↑
REGULATION OF RENAL ACIDIFICTION
CONDITION SITE OF NEPHRON
ECF VOLUME CONTRACTION ANGIOTENSIN II
PCT , DCT
HYPERALDOSTERONISM PCT , CD
HYPOKALEMIA PCT, CD – INTERCALATED CELLS
DECREASED ACID EXCRETION
REGULATION OF RENAL ACIDIFICTION
CONDITION SITE OF NEPHRON
ECF VOLUME EXPANSIONANGIOTENSIN II
PCT , DCT
HYPOALDOSTERONISM PCT , CD
HYPOKALEMIA PCT, CD – INTERCALATED CELLS
INCREASED ACID EXCRETION
Hormonal Regulation
• Endothelin-1
a) Acidosis causes increased ET-1 expression by proximal tubule
b) Increased transcription, translation and expression of NHE-3 and NBCe1
c) ET-1 may also be involved in distal nephron regulation
• Glucocorticoid
a) Acidosis triggers secretion
b) Increased transcription, translation and expression of NHE-3 and NBCe1
c) Stimulation of ammoniagenesis
Hormonal Regulation• Parathyroid Hormone (PTH)
a) Secretion stimulated by acidosis
b) PTH inhibits proximal Pi reabsorption
c) Pi delivered distally results in an increase in
titratable acid excretion