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