The Kidneys and Regulation of Water and

Inorganic Ions

Human Kidneys and Vascular Supply

Paired retroperitoneal organsIn humans, upper pole lies opposite T12 vertebra and lower pole lies opposite L3 vertebraWeight: 125-170 g in adult man and 115-155 g in adult womanLength: about 11-12 cmHilum, through which the renal pelvis, renal artery and vein, the lymphatics and a nerve plexusRenal artery enters the hilar region and divided into anterior and posterior branch

Bisected Kidney Showing Difference between the

Light-staining Cortex and Dark-staining Outer Medulla

Cortex

(about 1 cm in thickness in humans)

Outer medulla

(contains 8 to 18 striated conical masses, the renal pyramids)

Bellini terminate

(10 to 25 small openings on the tip of each papilla that represent distal ends of collecting ducts)

Renal columns of Bertin

(Renal cortex extends downward between the individual pyrimads)

Medullary rays of Ferrein

(They are actually considered a part of cortex and formed by collecting ducts and the straight segments of proximal and distal tubules)

The Nephron Renal Corpuscle (Glomerulus)

Light micrograph of a normal glomerulus Scanning electron micrograph of a cast of a glomerulus with its capillary loops

The Nephron Renal Corpuscle (Glomerulus)

Electron micrograph of a portion of a glomerulus from normal kidney

Transmission electron micrograph illustrating a segment of glomerular basement membrane (GBM) from normal rat kidney

The Nephron Renal Tubule

Nephron segments in a juxtamedullary nephron (left) and a superficial nephron (right)

The Nephron Proximal Tubule Cell

The endocytic-lysosomal system in a proximal tubule cell

The Nephron Collecting Duct

Immunolocalization of the vasopressin-sensitive aquaporin CD water channel in the rat collecting duct. A. Light micrography of cryosection from outer medulla. B. Electron micrograph of ultrathin cryosection of principal cells in the inner medullary collecting duct

Renal Transport of Sodium and Water

Schematic Representation of Renal Epithelial Cell

Schematic Representation of Renal Epithelial Cell

Na+ Reabsorption at Proximal tubule (1) Na+ Reabsorption at Proximal tubule (1)

Two mechanisms for Na+ transport from lumen to the cell

(1) Na+/H+ antiporter: H+ secretion & HCO3- reabsorption: account for 2/3 amount

(2) with Cl-, H2 PO4-, glucose, amino acid & other anions: account for 1/3 amount greater in the early (pars convoluta) than in the late (pars recta) proximal nephron

Proximal tubule (2)Proximal tubule (2)

Na+ exits out of the cell at the basolateral surface is coupled with

(1) Na+/K+ ATPase: accounting for 80%

(2) HCO3- reabsorption: 20%

Ascending limb of Henles Loop (1)Ascending limb of Henles Loop (1)

NaCl & KCl are reabsorbed together in a secondary active, electroneutral mannerNa-K-2Cl cotransporter is driven by the electrochemical gradient for Na by Na/K ATPase in the peritubular membraneCl- exits out of the cell at the basolateral surface via KCl symporter and Cl conductance channel

ROMK channel

Ascending limb of Henles Loop (2)Ascending limb of Henles Loop (2)

Resulting in excretion of 20~25% of filtered Na+ load due to

(1) act at a site with substantial Na reabsorption

(2) Na+ escaped transport in the loop have limited opportunities to be reabsorbed later in the nephron

Early Distal Convoluted Tubule

Early Distal Convoluted Tubule

Electroneutral NaCl reabsorptionThiazide group (including metolazone and indapamide): compete with Cl- binding site of Na-Cl cotransporterExcretion of 5-8% of filtered Na loadBasolateral 3Na+/Ca2+ exchanger: Na+ into and Ca2+ out of the cell of DCT

3

Comparison of Stoichiometric Relationship between TNa + and either

QO2 or ATP Utilization

Comparison of Stoichiometric Relationship between TNa+ and either

QO2 or ATP Utilization

Distribution of Body Fluid

Total Body Water (TBW) : 60% of body weightIntracellular fluid: 40% of TBWExtracellular fluid: 20% of TBW 15% interstitial fluid 5% plasma water

Body Fluid Composition

ECF volume: renal Na+ regulationICF volume: effective osmolality

KK++ NaNa++2828

140140

1414

140140

ICFICF ECFECF

Plasma Osmolality

Plasma Osmolality (mOsm/Kg H2 O) = 2 x [Na] (mEq/L) + [glucose]/18 (mg/dl)

+ [BUN]/2.8 (mg/dl)

Effective Posm = 2 x [Na] (mEq/L) + [glucose]/18 (mg/dl)

Osmolar vs Volume Regulation (1)

1. Osmotic threshold : the level of Posm when serum ADH is detectable (usually about 280 mOsm/Kg)

2. Threshold for thirst , Posm about 2-5 mOsm/Kg higher than Osmotic threshold

3. Under steady state ( [Na] 137mEq/L, Osm 285mOsm/Kg), ADH is average 2.5 pg/ml

4. Serum Osm < 280, ADH is unmeasurable; urine is maximally dilure ( 50 mOsm/Kg)

5. When serum Osm >295mOsm/kg, ADH is 5 pg/ml; urine is maximally concentrated ( about 1200 mOsm/Kg)

Regulation of thirst

Osmoreceptor: at anterolateral hypothalamus

Factors stimulate thirst: Increase in serum osmolality (tonicity) Decrease in blood volume Hypokalemia Hypercalcemia

6. Volume regulation of ADH: Hypotension or 8-10% reduction of blood volume=> release of ADH

7. Osmoregulation of ADH: 1-2% increase of Posm will stimulate release of ADH

8. Osmoregulation is more sensitive than volume regulation

9. Volume regulation has higher priority to osmoregulation ( Persistent ADH secretion will be noted in hypotensive and hypovolemic patients in spite of hyponatremia)

Osmolar vs Volume Regulation (2)

Body Fluid Composition

ECF volume: renal Na+ regulationICF volume: effective osmolality

KK++ NaNa++2828

140140

1414

140140

ICFICF ECFECF

Prevalence Rate of Hyponatremia

If hyponatremia is defined as Plasma [Na] < 135 mEq/L => 15~22%Plasma [Na] < 130 mEq/L => 1~4%

Symptoms of Hyponatremia

Acute: headache, hypertension, coma, seizure, blurred vision, etc.Chronic: non-specific symptoms such

as general malaise, weakness, leg cramps, memory loss, altered mental status or personality, insomnia, etc.

Defense Mechanism in Hyponatremia

First line: outward shift of intracellular and interstitial fluid of brain into CSFSecond line: loss of intracellular osmogenic particles such as K+, Na+, Cl-, etc

K+, Na+

Osmolytes /H2 O

NaNa++/H/H22 OO

NaNa++/H/H22 OO

NaNa++/H/H22 OO

NormonatremiaNormonatremia

AcuteAcuteHyponatremiaHyponatremia

ChronicChronicHyponatremiaHyponatremia

11

22

K+, Na+

Osmolytes/H2 O

K+, Na+

Osmolytes /H2 O

33

Renal Transport of Potassium

Total Body K+ Content (mmol/kg)

Age (years) Male Female10 37 3720 58 4540 52 4060 48 3780 45 33

Pierson et al. Am J Physiol 1984: 246, 234-9

Distribution of Total Body K+

Muscle 2650 mmolLiver 250 mmolRed blood cells 250 mmol[K+] 150 mmol/L

Bone 33 mmolInterstitialfluid 35 mmol

Plasma 15 mmol[K+] 4 mmol/L

Intracellular fluid (ICF)

Extracellular fluid (ECF)

Physiologic Roles of K+Physiologic Roles of K+

Roles of intracellular K+: * Cellular volume maintenance * Intracellular pH regulation * Cell enzyme function * DNA/protein synthesis * Cell growthRoles of transcellular K+ ratio: * Resting cell membrane potential * Neuromuscular excitability * Cardiac pacemaker rhythmicity

Resting Membrane Potential

Vm = - k

ln {[ K+]i

[ K+]o } ----- (1)This equation can be expressed at 37C as follows:Vm = -61.5 mV x log [ K+]i /[ K+]o ----- (2)Vt = - ln {k1x [Mg2+]i+k2x[Na+]i+k3x[Ca2+]i+

+k4x[H+]o}

{k5x[Mg2+]o+k6x[Na+]o +k7 x[Ca2+]o +k8 x[H+]i } -- (3)

Ki is the K+ activity of the intracellular fluid Ko is the K+ activity of the extracellular fluid

Components of K+ Homeostasis

Internal balance ( ICF and ECF K+ distribution)External balance ( Renal excretion of K+)

Distribution of K+ in the Body: routes of acquisition and

excretion

Factors Influencing K+ Shift from ICF to ECF (1)

Factors Influencing K+ Shift from ICF to ECF (1)

Hormones: 2 -adrenergic antagonist, lack of insulin or aldosterone, Acid-base disturbances: acute acid gain or bicarbonate lossICF anion change: catabolism, loss of organic phosphatesCell necrosis

Renal Regulation of K+ Excretion

Renal Regulation of K+ Excretion

Overview of the renal handling of K+

Cellular mechanisms ( Principal cells in CCD)

Cortical collecting duct ( CCD)

Factors Modifing K+ Secretion by the Distal Nephron

FactorsK+ secretionPlasma [K+ ] Flow rate, glucocorticoidsLumen [Na+] Transepithelial potential difference Anions (except Cl-)AlkalemiaVasopressin2- agonists Dietary K+ intakeAldosterone

FactorsK+ secretionPlasma [K+ ] Dietary K+ intakeAcidemiaAmmoniaLumen [Cl-] at DCTInsulin1- agonists

Components of K+ ExcretionComponents of K+ ExcretionGenerate a lumen-negative transepithelial potential difference (TEPD) in CCD

Movement of K+ via specific K+ channel

Flow rate through the CCD

Bartter SyndromeHypokalemia: Cl reabsorption at TAHL=> JGA hyperplasia & Na +,K +,Cl - to the distal nephron (CCD) => H+,K+ secretion at CCDCl--resistant metabolic alkalosis, High urine [Na+], [K+],[Cl-], [Ca+ +]; mimicking furosemide effect Hyperreninic hyperaldosteronismHyperprostaglandin due to[K+] & RAAHyporesponsiveness of BP to angiotensin II infusionAutosomal recessive inheritance with malfunction of NKCC2, ROMK, ClC-kb channel at TAHLTreatment: KCl supplement, K+-sparing agent ( Spironolactone, Triamterene, Amiloride), NSAID

(ROMK channel)

Gitelman SyndromeHypokalemiaCl--resistant metabolic alkalosisHyperreninic hyperaldosteronismHypocalciuria: urine Ca2+ < 100 mg/dayRenal Mg wasting and hypomagnesemiaBiochemical data similar to thiazide effectAutosomal recessive inheritance with mutation of Na+/Cl- cotransporter at distal convoluted tubule

Renal Transport of Hydrogen Ion (H+)

Stages of Acid-Base BalanceAcid synthesis:1. S-containing AA:

H2SO42. Phosphoesters:

H3PO43. Oxid. foods:

organic acids* Total production1~1.5 mEq/kg/day

Buffering1. HCO3-

/H2CO32. Albumin3. Hemoglobin

* Loss of alkali1~1.5 Eq/kg/day

Renal acid Excretion

1.H+ secretion

2. Titration of urinary buffers

* Total excretion:

1~1.5mEq/kg/dayHA H+A-

+NaHCO3

CO2+ Na+A- Kidney

H+A-Resynthesis

excretion

Acid BalanceAcid Balance

In: acid production

Out: net acid excretion (NAE) = NH4+ + TA (H2 PO4-) HCO3-

Medullary Metabolism of NH3+ & H+

Classical Distal RTA

Back Leakage & Hypokalemic Distal RTA

H+K+

Voltage Defect & Hyperkalemic Distal RTA

Renal Transport of Calcium (Ca2+) &

Magnesium (Mg2+)

47% Ionized47% Ionized

37% Albumin37% Albumin

ECF 1%

Distribution and Normal Ranges of Calcium inDistribution and Normal Ranges of Calcium inA 70 Kg Healthy AdultA 70 Kg Healthy Adult

0

20

40

60

80

100

10% Globulin10% Globulin

FilterableFilterable

Body content 1300 g Plasma level

8.4-10.2 mg/dl(2.1-2.55 mmol/L)

Tissue 1%

ECF 1%

Skeleton 98%

6% Complexed6% Complexed

BoundBound

Typical daily calcium intake and output for a normal adult in neutral Ca2+ balance

Intestinal Calcium Transport

Renal Calcium Reabsorption

Segmental Handling of CaSegmental Handling of Ca2+2+

along the Renal Tubule along the Renal Tubule

NEPHRON SEGMENT

FRACTIONAL REABSORPTION

(%)

CELLULAR TRANSPORT MECHANISM

Proximal tubule 5060 Passive, paracellular

Thin descending & ascending limbs

0

TAL (Thick ascending limb of Henles loop)

15 Passive, paracellularActive component stimulated by PTH

DCT/CNT 1015 Active, transcellular

Collecting duct Unknown

Renal Tubule Handling of CaRenal Tubule Handling of Ca2+2+

Parathyroid Hormone (PTH)

Net effectBlood calcium Blood phosphateUrine calcium: increase in filtered Ca load >> increase in tubular reabsorption

Calcium Sensing Receptor

Parathyroid gland: G protein-coupled receptor Abundant expression Central role in PTH secretion:

Ca2+ decreases PTH secretionKidney: mRNA present along entire nephron Protein: proximal tubulebrush border

IMCD brush border cTAL,mTAL-basolateral surface DCT-basolateral surface

Action of 1,25 (OH)2 D3

Kidney: * effect on Ca and P reabsorption is not

clearBone: * necessary to maintain Sca and Sp for

proper mineralization * administration mobilizes Ca and PIntestine: Ca and P absorption in small intestine

Hypercalcemia due to Thiazide

The mechanism of thiazide action is complexChronic thiazide administration sodium depletion

proximal tubular resorption of

sodium and calcium hypocalciuria

Urine [Ca2+]

MgMg2+2+ MetabolsimMetabolsim in in Normal AdultsNormal Adults

Renal Tubule Handling of MgRenal Tubule Handling of Mg2+2+

Thank You for Your Attention

The Kidneys and Regulation of Water and Inorganic IonsHuman Kidneys and Vascular SupplyBisected Kidney Showing Difference between the Light-staining Cortex and Dark-staining Outer Medulla 4The NephronRenal Corpuscle (Glomerulus)The NephronRenal Corpuscle (Glomerulus)The NephronRenal TubuleThe NephronProximal Tubule CellThe NephronCollecting DuctRenal Transport of Sodium and WaterSchematic Representation of Renal Epithelial Cell Na+ Reabsorption at Proximal tubule (1) 13 14Proximal tubule (2) 16Ascending limb of Henles Loop (1) 18Ascending limb of Henles Loop (2)Early Distal Convoluted Tubule 21 22Comparison of Stoichiometric Relationship between TNa+ and either QO2 or ATP Utilization 24 25 26Distribution of Body FluidBody Fluid CompositionPlasma OsmolalityOsmolar vs Volume Regulation (1) 31Regulation of thirstOsmolar vs Volume Regulation (2)Body Fluid CompositionPrevalence Rate of HyponatremiaSymptoms of HyponatremiaDefense Mechanism in Hyponatremia 38Renal Transport of PotassiumTotal Body K+ Content (mmol/kg)Distribution of Total Body K+Physiologic Roles of K+ 43Resting Membrane Potential 45Components of K+ HomeostasisDistribution of K+ in the Body:routes of acquisition and excretionFactors Influencing K+ Shift from ICF to ECF (1) Renal Regulation of K+ Excretion 50Factors Modifing K+ Secretion by the Distal Nephron Components of K+ ExcretionBartter Syndrome 54Gitelman Syndrome 56Renal Transport of Hydrogen Ion (H+)Stages of Acid-Base BalanceAcid Balance 60 61Medullary Metabolism of NH3+ & H+ 63 64Voltage Defect & Hyperkalemic Distal RTARenal Transport of Calcium (Ca2+) & Magnesium (Mg2+) 67 68Intestinal Calcium Transport 70Renal Calcium Reabsorption 72 73 74 75Parathyroid Hormone (PTH)Calcium Sensing Receptor 78 79 80Action of 1,25 (OH)2D3Hypercalcemia due to Thiazide 83 84 85 86 87