Renal-Chemistry

Elizabeth Kim, MSN, ARNP, SRNA

March 2006

Anesthesiology Nursing ProgramFlorida International University

THE OUTLINE• Brief Review of Nephrology A&P

• Renal and Acid/Base Balance

• Review of Diuretics

Rapid Renal Blood Circulation

Weight of Kidneys = 0.5% body weight20-25% of CO goes to Kidneys

CO = 6 L/minRenal blood flow = 1.2-1.5 L/min

O2 consumption = 18 ml/min

• 1300 ml blood/min Renal Arteries• 1298-1299 ml Renal Veins• All that work for: 1-2 ml Ureter

Urine Formation

Renal Blood FlowAfferent Arteriole=>Glomerulus=>Efferent Arteriole =>Peritubular Capillaries=> Renal Vein

Phospholipid-Bilayer Membranes Not permeable to polar molecules

(interior lipid region/nonpolar)

Large hydrophilic molecules and ions do not diffuse through the lipid bilayer and need special channels to allow entrance and passage of polar species.

DefinitionsDefinitions

Polar molecules– Have no net charge. – Have a region with a cluster of positive charges and a

region with a cluster of negative charges. – Polar molecules are hydrophilic.

Nonpolar molecules: – Have a positive and negative charges uniformly

distributed throughout the molecule. – Nonpolar are hydrophobic.

Kidneys important in:

1) Regulation of ECF/ BP– When extracellular fluid volume ↓, BP ↓

– If ↓ ↓ blood volume and pressure=> ↓ flow to brain and other organs

– Kidneys work with CV system to maintain pressure in acceptable range

– ADH and aldosterone cause active reabsorption of more sodium and water = concentrate urine

2) Regulation of ionic composition

3) Electrolyte balance: Na+, K+, Ca++, Mg++, Cl-

4) Acid-base balance H+ and HCO3-

Kidney Function

•Na+: major cation (+) of ECF•Cl-: major anion (-) of ECF•Regulators of fluid balance•Hormonal regulation of Na+ balance:

–Mediated by aldosterone–Secreted when Na+ levels low– reabsorption in distal tubules

ECFIntravascular & Interstitial compartments

~20% of total body weight

Basic Nephron ProcessesBasic Nephron Processes

Glomerular FiltrationGlomerular FiltrationTubular ReabsorptionTubular Reabsorption

Tubular SecretionTubular Secretion

Renal Water HandlingRenal Water Handling

3 Important Components:Delivery of tubular fluid to diluting

segments of the nephron.Separation of solutes and water in the

diluting segment.Variable reabsorption of water in collecting

ducts (CDs)

Na+ RegulationNa+ Regulation

Defend against Na+ overload

Natriuretic peptides ANP (atria) BNP (brain) C-type natriuretic peptide

Defends against Na+ depletion & Hypovolemia

RAAS axis Aldosterone: Na+ excretion

– Baroreceptors (Ao Arch & Carotid Body)

– Stretch receptors (Great veins, pulmonary vasculature & atria)

Stretch: Sympathetic tone, Renal perfusion=> Renin.

The Kidney Has an Osmotic Gradient From Cortex to Medulla

• Cortex - Isotonic with the blood: ~300 mOsm/L

• Medulla - very Hypertonic: ~1200 mOsm /L

•Regulating osmolality = Regulating Na+ concentration (sodium salts represent 90% of total osmolality of ECF).

Loop of Henle (LOH)Loop of Henle (LOH)

Descending LOH Water reabsorbed Solute retained Osmolarity: ~1,200

mOsm/kg

Ascending LOH & Distal Tubule (DT)

Dilution of concentrated fluid

Relatively impermeable to water

Osmolarity leaving DT: ~ 50mOsm/kg

Where Sodium goes, Water follows

Sodium Out Dilution

Water:ADH

Sodium:Aldosterone

Water Out Concentration

DT Aldosterone (adrenal cortex): Na+ Reabsorption

CDWater Reabsorption: Mediated by ADH (Vasopressin) Stimulate aquaporin 2 water channels in CD

Segments of the Renal TubuleSegments of the Renal Tubule

Proximal tubule:Reabsorbs the bulk of filtered fluid Loop of Henle: Establishes and maintains an osmotic

gradient in the medulla of the kidney. Distal tubule and collecting duct: Final adjustments on

urine pH, osmolality and ionic composition. Reabsorption of water => ADH Reabsorption of Na+ and secretion of K+ => Aldosterone

HomeostasisHomeostasis

H+ ions are created and destroyed at all times.

H+ is controlled through:– 1. Buffers – 2. The Lungs– 3. The Kidneys

Acid-Base BalanceAcid-Base Balance3 Mechanisms for the regulation of acid-base balance:3 Mechanisms for the regulation of acid-base balance:

1. The Buffer system (secs)

2. Respiratory system (mins)

3. Renal system (hrs-day)

– Renal H+ excretion, which controls plasma HCO3

-

• For each HCO3- reabsorbed or

regenerated a H+ is secreted into the renal tubular fluid.

– Predominate buffers: phosphate (HPO42) & ammonia (NH3)

Acid-Base ReviewAcid-Base Review

Henderson-Hanselbalch EquationRelationship bt

– pH– PaCO2– NaHCO3-

Defines the above relationship but substitutes H+ concentrations for pH

Renal Acid-Base BalanceRenal Acid-Base BalanceHCOHCO

33--/H/H22COCO

33 Buffering System Buffering SystemMajor extracellular buffering systemMajor extracellular buffering system

To maintain normal pH, the kidneys must perform 2 physiological functions:

– 1st: Reabsorb all the filtered HCO3 (~85% at PT)– 2nd: Excrete the daily H+ load (CD)

HydrogenHydrogen HH22O + COO + CO

22HH22COCO33HH++ + HCO + HCO

33--

Adding acid load to the body fluids results in consumption of HCO3

- by H+ added and the

formation of carbonic acid, forms H2O & CO2

Only the urinary system can eliminate excess hydrogen ions, permanently and restore the bicarbonate buffering ions to the blood.

Hydrogen IonsHydrogen Ions

Continuously produced as substrates are oxidized in the production of ATP

Largest contribution of metabolic acids arises from the oxidation of carbohydrates, principally glucose.

Net production of hydrogen ions: ~60 mEq/day.

Hydrogen Ion RegulationHydrogen Ion Regulation

Metabolic reactions in the body are highly sensitive to pH or H+ ion concentration.

H+ ions change shapes of proteins, including enzymes (H+ changes can greatly effect the chemical reactions in your body.

Hydrogen Hydrogen Gains LossesGains Losses

1. CO2 + H20 H2CO3 HCO3- + H+

2. Protein breakdown.

3. Loss of HCO3- in GI tract. 

4. Loss of HCO3- in kidney. 

(3) and (4) result in a gain of plasma H+ because HCO3

- is no longer available to

bind H+.

1. Loss of H+ from stomach in vomiting.

2. Loss of H+ in urine.

3. Hypoventilation.

BuffersBuffers

Buffer: Any substance that can reversibly bind H+.

HCO3- : Important buffer. 

Buffer- + H+ Hbuffer When H+ increases, the reaction

is forced to the right and more H+ is bound to buffer.

CO2 + H20 H2CO3 HCO3- + H+

Homeostasis of HHomeostasis of H++ by the by the KidneysKidneys

HCO3- Excretion Free H+ in plasma. 

Alkalosis: Kidney excretes HCO3- to

free up H+ in the plasma. Acidosis: Kidney tubules produce

HCO3-

Bicarbonate Filtration and Bicarbonate Filtration and ReabsorptionReabsorption

HCO3-

Easily filtered Undergoes marked tubular reabsorption in the proximal

tubule and collecting ducts CO2 + H20 H2CO3 (CA) HCO3

- + H+ HCO3- diffuses down its concentration

gradient into the plasma. H+ : secreted into the tubule. This combines

with filtered HCO3- to form CO2 and H20.

Bicarbonate filtration and Bicarbonate filtration and reabsorptionreabsorption

If plasma HCO3- is low, the H+

combines with other buffers. HCO3

- is still produced in the renal tubules and diffuses into the plasma, raising plasma HCO3

-.

Kidney Response to AcidosisKidney Response to Acidosis H+ is secreted to reabsorb all the filtered

bicarbonate. More H+ is secreted to bind to other buffers in the

urine. More HCO3

- is created and diffuses into the plasma, to bind H+ and make the plasma more alkaline.

Glutamine metabolism and ammonium (NH4+) excretion increase. Ammonium grabs H+ and HCO3

- goes into the plasma, making it more alkaline.

Kidney responses to Kidney responses to AlkalosisAlkalosis

H+ secretion is down, so H+ cannot reabsorb all the bicarbonate. A significant amount of bicarbonate is excreted in the urine.

Glutamine metabolism and ammonium excretion are down, so little bicarbonate goes into the plasma.

Renal MechanismsAcid-Base Balance

CO2 + H2O H2CO3 HCO3- + H+

Carbonic anhydrase

•Kidneys alter/replenish H+ by altering plasma [HCO3-]

[H+] plasma (alkalosis) kidneys excrete lots of HCO3-

[H+] plasma (acidosis) kidneys produce new HCO3-

HCO3- Reabsorption

H2O + CO2 H2CO3HCO3- + H+

Lumen Blood

HCO3- + Na+

H+

Na+

H+

H2CO3

H20 + CO2CA

CO2 + H20

CA

HCO3- HCO3-

Na+K+

•Daily glomerular ultrafiltrate 180L (contains 4300 mEq of HCO3- )

•H+ in the tubular lumen combines w/ filtered HCO3-

•Body produces excess acids during normal metabolism

•To maintain balance: the kidneys excrete more H+ ions and the urine becomes more acidic.

Na+

H2CO3

Na+-H+ exchange•Permits HCO3- reabsorption/acid excretion

CA combines CO2 and water to form HCO3

- and H+

CA: Accelerates the dissociation of H2CO3

into H2O + CO2

HCO3- reabsorption: relies on

tubular secretion of H+,

Carbonic Anhydrase H2O + CO2 H2CO3HCO3

- + H+

Lumen Blood

HCO3- + Na+

H+

Na+

H+

H2CO3

H20 + CO2CA

CO2 + H20

CA

HCO3- HCO3-

Na+K+

Brush border

•Keeps the luminal H+ low

•Lumen: Filtered HCO3- is converted to CO2.

•Intracellular: Converted back to HCO3- to be returned to the systemic circulation, thus reclaiming the

filtered HCO3-.

Na+

H2CO3

1. Na+-H+ exchange•Permits HCO3- reabsorption/acid excretion

Rehydration

CA combines CO2 and water to form HCO3

- and H+

CA

Dehydration

CA: Accelerates the dissociation of H2CO3

into H2O + CO2

Recombine H+ with another buffer e.g. HPO4

2-

Excreted as H2PO42-

Net gain of HCO3- by

plasma

HPO4HPO42- 2- + H => H2PO4 + H => H2PO4--

•In the normal kidney about 1 mg/kg of acid must be cleared each day.  This is done by reclaiming filtered bicarb and excreting hydrogen ions with phosphate buffers and ammonium. Bicarb then diffuses into the blood and hydrogen into the urine, buffered by ammonium and phosphates.

NH3 = produced in renal tubular cell by glutaminase on amino acid glutamine. Unionized, rapidly crosses into the renal tubule down its concentration gradient.

• Renal production and secretion of ammonium (NH4

+)

• Urinary H+ excretion = renal addition of new HCO3

- to plasma

NH3 + H+ =>NH4

Lumen Blood

Glutamine

Glutaminase

NH3 + Glutamate

Na+ Na+

NH3 Glutamate

NH3 + H+ H+

NH4+

ATPaseNa+ Na+

K+ K+

DiureticsDiureticsWeak Organic AcidsWeak Organic Acids

Most diuretics inhibit sodium transport Interfere with the normal regulatory activity

of the kidney.Block the entry of Na+ from the urine into

the cell.

The Glomerulus•Glomerular filtration rate (GFR) can be changed by drugs affecting renal blood flow (RBF)

–Xanthine alkaloids (caffeine, theophylline, aminophylline)

–weak diuretic effect

–Increased cardiac output and vasodilation resulting in increased RBF, which increases GFR

The Proximal Convoluted Tubule•Majority 2/3 of filtered Na+ is reabsorbed at proximal tubules.

Lumen Blood

HCO3- + Na+ Na+

H+

H2CO3

H20 + CO2CA

CO2 + H20

CA

HCO3- HCO3-

Na+

K+

Carbonic anhydrase inhibitors–Blocks NaHCO3 reabsorption in the luminal membranes of the proximal tubule cells

•Causes sodium bicarbonate to be excreted in urine–-SO2NH2 (sulfonamide) group is essential for activity–Will increase urine pH within 30 minutes. Maximal increase in 2 hours.

Na+

H2CO3

H+

Increase Urine pH

CAI

Osmotic DiureticsOsmotic DiureticsProximal Convoluted TubuleProximal Convoluted Tubule

Thin descending limb Thin descending limb (Does not participate in salt reabsorption(Does not participate in salt reabsorptionWater reabsorption only)Water reabsorption only)

2 main mechanisms of action

1. Increase osmolarity in renal filtrate: Result: less water reabsorbed and more water excreted.

2. Increase in plasma osmolarity. Extracts water from intracellular compartment to the blood compartment. Decreases blood viscosity and increases renal blood flow.

Osmotic Diuretics– Mannitol (Osmitrol®)

• Monosaccharide not normally found in mammals• Nonreabsorbable solute – primarily undergoes glomerular filtration• Reduces Na+ reabsorption due to ↑ urine flow rates • Mannitol’s large size and its several hydroxyl groups give it a low

membrane permeability• No specialized transporters for this solute.

Na+-K+-2Cl- CotransportNa+-K+-2Cl- CotransportTAL Actively reabsorbs NaCl and KCl via the Na+-K+-2Cl-symport (35% TAL Actively reabsorbs NaCl and KCl via the Na+-K+-2Cl-symport (35% salt absorption). salt absorption).

TAL: not permeable to waterTAL: not permeable to water

2Cl-

K+

Na+

2Cl-

K+

Na+

K+

Na+

K+

K+

2Cl-

K+

2Cl-

Blood Urine

LASIX

– Inhibition of this transporter system leads to accumulation of K+ in the cell because of Na+/K+ ATPase bringing K+ into the cell also. This results in back diffusion of K+ into the tubular lumen which reduces the lumen positive potential and causes an increase in Mg++ and Ca++ excretion

Thick Ascending LimbMajor site of salt absorption and action of an important group of diuretics

~ 25 % of filtered Na+ is reabsorbed by these cells.

Loop diuretics–Most effective diuretics available

–Inhibits Na+/K+/2Cl- transport system to reduce the reabsorption of NaCl in the thick ascending limb of the loop of Henle

–Increase renal excretion of K+, Mg+–Not effective at low GFR

Early Distal Tubule

Thiazides: Inhibit Na+-Cl- symport

Late Distal TubuleSpironolactone:

Competitively inhibits aldosteroneInhibits Na+ reabsorption in the late distal tubule and collecting duct.

Decreases K+ secretion

ReferencesReferences

Craig, C.R & Stitzel, R.E. (1997). Modern pharmacology with clinical applications. 5th edition. Brown and Company Inc.

Devlin,T. M. (1997). Textbook of biochemistry. 4th edition.Wioley-Libss, Inc. New York, NY

Johnson, L.R. (1998). Essential medical physiology. 2nd edition. Lippincott-Raven

Lingappa, V.R. & Farey, K. (2000). Physiological medicine: a clinical approach to basic medical medical physiology. McGraw-Hill

Weldy, N.J. (1996). Body fluids and electrolytes. 7th edition. Mosby