Kidneys and Regulation for Students pdf

The Kidneys and Regulation of Water and Inorganic Ions 唐德成 國立陽明大學 生理學科暨研究所 臺北榮民總醫院 內科部腎臟科

Human Kidneys and Vascular Supply Paired retroperitoneal organs In humans, upper pole lies opposite T12 vertebra and lower pole lies opposite L3 vertebra Weight: 125-170 g in adult man and 115-155 g in adult woman Length: about 11-12 cm Hilum, through which the renal pelvis, renal artery and vein, the lymphatics and a nerve plexus Renal 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

Outer medulla

(about 1 cm in thickness in humans)

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

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

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)

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

Electron micrograph of a portion of a glomerulus from normal 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

Na+ Reabsorption at Proximal tubule (1) Two mechanisms for Na+ transport from lumen to the cell (1) Na+/H+ antiporter: H+ secretion & HCO3reabsorption: account for 2/3 amount (2) with Cl-, H2PO4-, 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) 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 Henle’s Loop (1) NaCl & KCl are reabsorbed together in a secondary active, electroneutral manner Na-K-2Cl cotransporter is driven by the electrochemical gradient for Na by Na/K ATPase in the peritubular membrane Cl- exits out of the cell at the basolateral surface via KCl symporter and Cl conductance channel

ROMK channel

Ascending limb of Henle’s 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 Electroneutral NaCl reabsorption Thiazide group (including metolazone and indapamide): compete with Clbinding site of Na-Cl cotransporter Excretion of 5-8% of filtered Na load Basolateral 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

Distribution of Body Fluid Total Body Water (TBW) : 60% of body weight Intracellular fluid: 40% of TBW Extracellular fluid: 20% of TBW 15% interstitial fluid 5% plasma water

Body Fluid Composition ICF

ECF

28

14

K+

Na+

140

140

ECF volume: renal Na+ regulation ICF volume: effective osmolality

Plasma Osmolality Plasma Osmolality (mOsm/Kg H2O) = 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

Osmolar vs Volume Regulation (2) 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)

Body Fluid Composition ICF

ECF

28

14

K+

Na+

140

140

ECF volume: renal Na+ regulation ICF volume: effective osmolality

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 CSF Second line: loss of intracellular osmogenic particles such as K+, Na+, Cl-, etc

Normonatremia K+, Na+ Osmolytes/H2O

Na+/H2O

3

Acute Hyponatremia Na+/H2O Chronic Hyponatremia Na+/H2O

2

K+, Na+ Osmolytes

/H2O

1

K+, Na+ Osmolytes /H2O

Renal Transport of Potassium

Total Body K+ Content (mmol/kg) Age (years) 10 20 40 60 80

Male 37 58 52 48 45

Female 37 45 40 37 33

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

Distribution of Total Body K+ Intracellular fluid (ICF) Muscle 2650 mmol Liver 250 mmol Red blood cells 250 mmol [K+] 150 mmol/L

Extracellular fluid (ECF) Bone Interstitial fluid Plasma [K+]

33 mmol 35 mmol 15 mmol 4 mmol/L

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

+ K

Resting Membrane Potential Vm = - k × ln {[ K+]i ÷ [ K+]o} ----- (1) This equation can be expressed at 37°C 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+k7x[Ca2+]o +k8x[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) Hormones: Ă&#x;2-adrenergic antagonist, lack of insulin or aldosterone, Acid-base disturbances: acute acid gain or bicarbonate loss ICF anion change: catabolism, loss of organic phosphates Cell necrosis

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 Factors↑K+ secretion Plasma [K+ ] ↑ Flow rate, glucocorticoids Lumen [Na+] ↑ Transepithelial potential difference ↑ Anions (except Cl-) Alkalemia Vasopressin α2- agonists ↑Dietary K+ intake Aldosterone

Factors↓K+ secretion Plasma [K+ ] ↓ ↓ Dietary K+ intake Acidemia Ammonia Lumen [Cl-] at DCT Insulin β1- agonists

Components of K+ Excretion Generate a lumen-negative transepithelial potential difference (TEPD) in CCD Movement of K+ via specific K+ channel Flow rate through the CCD

Bartter Syndrome Hypokalemia: ↓ Cl reabsorption at TAHL=> JGA hyperplasia &↑ Na +,K +,Cl - to the distal nephron (CCD) => ↑ H+,K+ secretion at CCD Cl--resistant metabolic alkalosis, High urine [Na+], [K+],[Cl-], [Ca+ +]; mimicking furosemide effect Hyperreninic hyperaldosteronism Hyperprostaglandin due to↓[K+] &↑ RAA Hyporesponsiveness of BP to angiotensin II infusion Autosomal recessive inheritance with malfunction of NKCC2, ROMK, ClC-kb channel at TAHL Treatment: KCl supplement, K+-sparing agent ( Spironolactone, Triamterene, Amiloride), NSAID

(ROMK channel)

Gitelman Syndrome Hypokalemia

Cl--resistant metabolic alkalosis Hyperreninic hyperaldosteronism Hypocalciuria: urine Ca2+ < 100 mg/day Renal Mg wasting and hypomagnesemia Biochemical data similar to thiazide effect Autosomal recessive inheritance with mutation of Na+/Cl- cotransporter at distal convoluted tubule

Renal Transport of + Hydrogen Ion (H )

Stages of Acid-Base Balance Acid synthesis: Buffering 1. S-containing AA: 1. HCO3H2SO4 2. Phosphoesters: H3PO4 3. Oxid. foods: organic acids * Total production 1~1.5 mEq/kg/day

HA

Renal acid Excretion

/H2CO3 2. Albumin 3. Hemoglobin

1.H+ secretion 2. Titration of urinary buffers

* Total excretion: * Loss of alkali 1~1.5 Eq/kg/day 1~1.5mEq/kg/day

H+A-

+ NaHCO3

CO2+

Na+A-

Resynthesis

excretion

Kidney

H+A-

Acid Balance In: acid production Out: net acid excretion (NAE) = NH4+ + TA (H2PO4-) â&#x20AC;&#x201C; HCO3-

Medullary Metabolism of NH3+ & H+

Classical Distal RTA

Back Leakage & Hypokalemic Distal RTA

K+ H+

Voltage Defect & Hyperkalemic Distal RTA

Renal Transport of 2+ Calcium (Ca ) & 2+ Magnesium (Mg )

Distribution and Normal Ranges of Calcium in A 70 Kg Healthy Adult 100

6% 6%Complexed Complexed

Tissue 1%

Filterable Filterable 47% 47%Ionized Ionized

80

ECF 1% Skeleton 98%

ECF 1%

60 40 37% 37%Albumin Albumin

20 Body content 1300 g

Bound Bound 10% 10%Globulin Globulin

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

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

Intestinal Calcium Transport

Renal Calcium Reabsorption

Segmental Handling of Ca2+ along the Renal Tubule NEPHRON SEGMENT Proximal tubule

FRACTIONAL REABSORPTION (%) 50–60

Thin descending & ascending limbs

0

TAL (Thick ascending limb of Henle’s loop)

15

DCT/CNT Collecting duct

CELLULAR TRANSPORT MECHANISM Passive, paracellular

Passive, paracellular Active component stimulated by PTH

10–15 ±

Active, transcellular Unknown

Renal Tubule Handling of Ca2+

Parathyroid Hormone (PTH) Net effect ↑Blood calcium ↓Blood phosphate ↑Urine 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 secretion

Kidney: mRNA present along entire nephron Protein: proximal tubule—brush border IMCD –brush border cTAL,mTAL-basolateral surface DCT-basolateral surface

Action of 1,25 (OH)2D3 Kidney: * effect on Ca and P reabsorption is not clear Bone: * necessary to maintain Sca and Sp for proper mineralization * administration mobilizes Ca and P Intestine: â&#x2020;&#x2018; Ca and P absorption in small intestine

Hypercalcemia due to Thiazide

The mechanism of thiazide action is complex Chronic thiazide administration sodium depletion ↑proximal tubular resorption of sodium and calcium  hypocalciuria

↓Urine [Ca2+]

Mg2+ Metabolsim in Normal Adults

Renal Tubule Handling of Mg2+

Thank You for Your Attention