Renal

1
Renal

• ??? ??? PhD, RPh
• hsumj_at_mail.cmu.edu.tw
• Office hours
• ?????(8-12),

2
Contents

• Overviews of Renal function
• Assessment of renal function
• Regulation of Renal blood flow (RBF) Glomerular
  filtration rate (GFR)
• Solutes and water homeostasis
• Acid-base balance

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• Body fluid osmolality volume
• Maintain the normal cell volume is essential for
  cardiovascular system (through regulation of NaCl
  and H2O)
• Electrolyte balance Na, K, Cl- , HCO3-, H,
  Ca, PO43-(intake excretion)Positive balance
  (intake gt excretion)?Negative balance
• Acid-balance balance Lung kidneys
• Excreteion (metabolites, foreign substances)
  Urea(aa),Uric acid (nucleic acid),
  Creatinine(muscle creatine), end product of
  hemoglobin , drugs, pesticides, chemical ingested
• Endocrine organ
• Renin(RAAS) ????, ??Na, K??,
• calcitriol(Vitamin D3 ???? ?GI??????
  ?????deposition)
• Erythropoietin (when? erythrocyte production)
  ??????????anemia

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??????-1

• Decreased ability to excrete Na ? ?ECF ?
  hypertension(occasionally, the patients have high
  plasma renin and angiotensin level ? produce even
  further ??ECF, and arteriolar vasoconstriction ?
  HP)
• Inability of kidney to produce NH4 ??capacity
  to excrete H in urine ? metabolic acidosis

5
??????-2

• ?K (become excessive)? hyperkalemia(acidosis
  ??hyperkalemia)??
• Acidosis in renal failure patients further
  ?hyperkalemia
• Patients with renal failure can produce membrane
  depolarization and cardiac failure

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??????-3

• Renal failure causes ?ECF ionic calcium
  concentration(hypocalcemia)??
• ?ECF calcium(hypocalcemia)
• ?excrete PO4-3 ?ECF PO4-3 ? ?ECF Ca(Ca x
  PO4-3 35-45)
• Reduce the ability of the kidney to active
  vitamin D ??absorb calcium from GI
• Reduced Ca2ECF promotes increased release of
  Parathyroid hormone(PTH),

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?
????NH4
?
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Diseases related with construction
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Nephrotic syndrome

• Causes Increased permeability of the glomerular
  capillaries to proteins
• Incidence Proteinuria protein excretion
• Indicting kidney disease (protein in urine)
• Develop edema and hypoalbuminemia

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Nephrin

• A transmembrane protein, a major component of the
  slit diaphragm
• Gene mutation leads to the abnormal or absent
  slit diaphragms
• Develop massive proteinuria and renal failure
• So, Nephrin plays essential role in the formation
  of the normal glomerular filtration barrier

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Alports syndrome

• Hematuria (blood in the urine) and progressive
  glomerulonephritis (inflammation of glomerular
  capillaries)
• 1-2 of cases of end-stage renal failure
• Cause defects in type IV collagen, a major
  component of the glomerular basement membrane
• Result basement membrane fails to serve as the
  barriers.

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Nephrolithiasis (kidney stone)

• 80-90 calcium salts
• Uric acid, magnesium-ammonium acetate
• Cysteine
• Formed by crystalization in a supersaturated
  urinary milieu.
• ??ureter is blocked with kidney stone, reflex
  constriction of the ureter around the stone
  elicits severe flank pain.

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Micturition

• Process of emptying the urinary bladder
• Progressive filling of the bladder
• Stretches the bladder wall and triggers a reflex
  initiated by stretch receptors
• Micturition reflex

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Assessment of renal function
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Renal clearance

• Based on Fick principle

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Pxa Pxv ?? substance X in renal artery and
renal vein plasma ??? RPFa RPFv renal plasma
flow rates In artery and vein UxX in
urine Vurine flow rate Pxa (mg/ml) Cx Ux
(mg/ml) V (ml/min) Cx clearance of
substance X Cx (Ux V)/ Pxa
Fick Principle Mass balance
Pxa Ux x V????
17
Assessment of renal functionRenal Clearance (Cx)
???

• A volume of plasma from which all the substance
• (substance x) has been removed and excreted into
  the
• urine per unit of time

(Unit volume/time)
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Renal Clearance (Cx) ???
?? 1 2 3 4
Urea excretion ?M/min 200 400 200 20
Plasma Urea ?M /min 3 6 30 3
Ratio 67 67 7 7
3 and 4 are patients with kidney diseases
Ratio Urea in Urine/Plasma Urea concentration
Ratio is a reliable index as renal function
(normal 70)
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Assessment of renal function ??Inulin Clearance
(Cin) ?? GFR
Inulin polymer of fructose neither reabsorbed,
secreted nor metabolized by the cells of
nephron ??????? Amt filtered amt excreted Pin
x GFR Uin x V GFR Uin x V/Pin
Determine Cin determine GFR
20
Assessment of renal function Creatinine
Clearance (Ccr)

• Creatinine
• By product of sketeal muscle creatine metabolism
• Produced at a constant rate
• Endogenous, not reabsorbed but small amount of
  secretion in urine

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Glomerular Filtration Rate( GFR )

• Index of kidney function
• Essential in evaluating the severity and course
  of kidney diseases
• GFR the sum of filtration rate of all
  functioning nephrons
• ?GFR
• ??????????????
• ??????
• ?GFR(recovery)

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• GFR????????????Pcr??
• GFR 120-100 ml/min
• Pcr 1.0-1.2 mg/dl

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Glomerular filtration

• GFR 90-140 ml/min, female (80-125) after 30
  GFR declines with age
• The first step in the formation of urine is the
  production of an ultrafiltrate of the plasma at
  the glomerulus
• The ultrafiltrate is devoid of cellular
  components and protein free.
• Salt, organic molecules (glucose, aa), are
  similar as plasma

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• Ultrafiltration is driven by Starling forces
  across the glomerular capillaries, and changes in
  these factors alter the GFR. GFR and RPF are
  regulated by autoregulation
• The force responsible for the glomerular
  filtration of plasma are the same as those
  involved in fluid exchange across all capillariry
  beds

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Hydrostatic and oncotic pressure
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Hydrostatics of glomerular filtration
Filtration coefficient(Kf) intrinsic
permeability of the glomerular capillary and the
glomerular surface area available for filtration
27
Determinants of glomerular filtration rate(GFR)

• Starling equation
• GFR Kf (PGC - PBS)- pGC
• Changes in Kf
• Drugs, hormones could dilate the glomerular
  arterioles also increase Kf
• A reduction in PGC is caused by
• Decline in renal arterial pressure
• Increase in afferent arteriolar resistance
• Decrease in efferent arteriolar resistance
• Increased PBS reduces GFR. Acute obstruction
  (kidney stone) of the urinary tract increase PBS

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Regulation of renal blood flow and GFR
29
Renal Blood Flow (RBF) 1.25 L/min

• ? GFR ?????
• ?????????????????????
• Participate in the concentration and dilution of
  the urine
• Deliver O2, nutrients and hormones to renal cells
  and returning CO2 and reabsorbed fluid and
  solutes to the general circulation
• Deliver substrates for excretion in the urine

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Renal blood flow (RBF)

• Q (blood flow) ?P (arterial pressure venous
  pressure of ea organ) / R (resistance)
• RBF aortic pressure renal venous pressure/
  renal vascular resistance

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Autoregulation

• Regulate the tone of afferent arteriole
• Change in arterial pressure
• Myogenic mechanism ????, renal afferent
  arterioles is stretched, the smooth muscle
  contract, increase in the resistance of the
  arteriole offsets the increase in pressure, RBF
  and GFR remains constant
• Change in NaCl concentration of tubular fluid
• Tubuloglomerular feedback ??GFR, ??NaCl in the
  tubule fluid in the loop of Henle, increases
  resistance of afferent arteriole, ???decrease GFR

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Myogenic mechanism
Autoregulation -???????????RBF?GFR -achieved by
changes in vascular resistance
Vascular R Precisely responds to changes of
arterial pressure 90-180 mmHg
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Tubuloglomerular feedback
NaCl ?tubular fluid ?? JGA???,
??JGA???? Afferent arteriole ?? Resistance ??GFR?
??, NaCl? Tubular fluid??, --------
34
N
AP ?
1
RBF ?P/R R k/r4 PGC hydrostatic pressure in
the glomerular capillary
2
3
4
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???????? RBF and GFR

• Sympathetic nerve binds to ?1 receptor, which
  are located mainly on the afferent arterioles
• Angiotensin II ??????????, ???? RBF ?? GFR
  (????AgII???, ?????????, ????????????)
• Angiotensin-converting enzyme (ACE)
• ACE inhibitors increase RBF and GFR
• Prostaglandins
• NO
• Endothelin
• bradykinin

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Regulation of GFR and RBF

• Extrinsic(??????)
• Renal sympathetic nerves(?????? ? NE ? ???? ?
  ?GFR)
• a1 receptor(??????????afferent artreioles)
• ?Effective circulating volume(ECV) hemorrhage
• Fear, pain ? ? RBF GFR
• Angiotensin II(?GFR)
• Prostaglandins
• PGE2,PGI2 ? ?? ? ?GFR
• NSAID ?
• Intrinsic
• Autoregulation

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Regulation of renal blood flow and GFR

• NO(endothelium-derived relaxing factor)
• Counteracts vasoconstriction produced by
  angiotensin II and catecholamines
• An increase in shear force acting on endothelial
  cells in arterioles
• Acetylcholine, histamine, bradykinin, ATP ?
  increase production of NO
• Abnormal production of NO
• Diabetes Mellitus, HP Excess of NO production ?
  glomerulat hyperfiltration and damage of the
  glomerulus
• Salt intake triggers NO production

• Prostaglandins
• ???????? May not regulate RBF and GFR in normal
  healthy person
• PGI2 PGE2 are produced locally within the kidney,
  and ?RBF w/o changes of GFR---????
• Prevent severe and harmful vasoconstriction and
  renal ischemia
• Prostaglandin synthesis is stimulated by
  decreased ECV and stress, angiotensin II, and
  sympathetic nerves

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Regulation of renal blood flow and GFR

• Endothelin
• A potent vasoconstrictor
• Secreted by
• Endothelial cell of renal vessels,
• Mesangial cells
• Distal tubular cells in response to angiotensin
  II, bradykinin, epinephrine, and shear stress
• Elevated in number of disease states(renal
  diseases with DM)

• Bradykinin
• Kallikrein is a proteolytic enzyme produced in
  the kidney
• Kallikrein cleaves circulating kininogen to
  bradykinin, a vaodilator
• Bradykinin is a vasodilator that acts by
  stimulating the release of NO and prostaglandins

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Regulation of renal blood flow and GFR

• Adenosine
• Produced in the kidney
• Cause vasoconstriction of the afferent arterioles
• Reduce RBF and GFR

• Atrial Natriuretic peptide ( ANP )
• Secreted by the heart rises with HP and expansion
  of extracellular fluid volume
• Cause vasodilation of afferent arteriole and
  vasoconstriction of efferent arterioles
• The net effect of ANP is therefore to produce a
  modest increase in GFR with little change in RBF

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Hemorrhage

• Hemorrhage ? ?arterial pressure ? baroreceptor
  reflex ? ?sympathetic nerve to the kidney ?
  Intensive constriction of afferent and efferent
  arterioles ??RBF and GFR ?
• ? Sympathetic ? ?release of epinephrine and
  angiotensin II ? further vasoconstriction and
  ?RBF GFR
• Rise of vascular resistance of the kidney ??TPR
• ?BP offset the fall in MAP caused by hemorrhage

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Regulation of renal blood flow and GFR
42
Regulation of renal blood flow and GFR
43
Solutes and water homeostasis
44

• Types of cellular transport pathway

??? Na ??? ???Na ??blood
Na 12 mEq/L
Na 145 mEq/L
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Collecting duct Principal cell
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Key
Acetazolamide Diamox
Solute and H2O reabsorption along the nephron 1.
Proximal tubule early segment ??HCO3-? glucose
, amino acids, Pi, lactate?????
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Solute and H2O reabsorption along the nephron 2.
Proximal tubule late segment ??Cl-
????? ?????Cl-??? ?? Na?early proximal
tubule?? ??????
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Proximal Tubule Na transport

• Early PT
• Glucose and amino acid
• Hydrogen iondriving the reabsorption of HCO3-,
• In the early PT, HCO3- is the major anion
  reabsorbed with Na, and luminal HCO3- falls
• ????????
• Phlorhizin(block Na - glucose cotransporter)
• Digoxin(? Na K- - ATPase )
• Acetazolamide (?H- Na counter transporter ? H
  ???? ? ????)?CAI block bicarbonate reabsorption

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Protein in the urine

• Nephrotic syndrome
• Fanconis syndrome????aa, glucose,
  low-molecular-weight proteins.??????????, so..
• Synthesis by thick ascending limb of Henles loop
  (Tamm-Horsfall glycoprotein????????????Tamm-Horsf
  all????????????PMN????? )

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Renal excretion of anions
Glutamate??
??organic anions????? transporter,
????PAH?? ??penicillin?secretion
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Renal excretion of cations (OC)
Cimetidine-H2 blocker, ??organic cation
pathway??secretion. ???procainamide
(antiarrhythmic) ?secretion.
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Renal excretion of cytotoxic drugs
Tubular fluid
blood
P-glycoprotein
Mrp1
Mrp2
Multidrug resistance (MDR)-associated protein
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Thick ascending limb Na Cl- transport( mainly of
the reabsorption in Loop of Henle)

• Basolateral membrane
• Key element in solute reabsorption by the thick
  ascending limb is the Na/K ATPase in the
• Lumen positive potential
• Electrogenic 2 Cl- for each Na that exit
  lumen(K diffuse back out via channel)
• Positive lumen potential difference is an
  important force for driving Na K Ca Mg
  reabsorption
• Inhibited by Furosemide
• ????PT?????????
• ???HL???,????? Na ???

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Thick ascending limb Na Cl- transport
Loop diuretics Furosemide ??NaCl??? ??K, Ca???,
??K, Ca, excretion ????excretion
Symporter
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Bartters syndrome

• Autosomal recessive genetic disease
• mutations in the gene coding for the
  1Na-2K-2Cl- symporter, apical K channel, or
  baslateral Cl- channel in tick ascending limb
• ?? NaCl, K???
• ??hypokalemia, decrease in effcetive circulating
  volume (ECV), ??aldosterone???
• Metabolic alkalosis
• hyperaldosteronism

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Distal tubule
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Early distal tubule Na Cl- transport

• Reabsorbs 5 of filtered NaCl
• Na enters cell via a Na/Cl- cotransporter
• Inhibited by thiazide diuretics
• Relatively little water reabsorption, not
  responsive to ADH

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Early distal tubule Na Cl- transport
Thiazide Diuretics
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Late distal tubule

• Principal cells
• Na reabsorption, K secretion
• Aldosterone
• ?number of open Na - channels at the apical
  membranes
• ?Na/K ATPase and open apical K channels
• Intercalated cells

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Solute and H2O reabsorption along the
nephron Distal tubule-last segments
Amiloride ???? Cl-??? ????K ??, ?? ?????
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Liddles syndrome

• Genetic disorder characterized by an increase in
  extracellular fluid volume (ECFV) ??????
• ?? Na channel? ????-subunit??mutation??????apica
  l cell membrane?Na-channel??? (overactive), ??,
  Na???????, ??ECFV???

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Pseudohypoaldosteronism type I (PAH1)

• Increase in Na excretion
• A reduction in ECFV
• Hypotension

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Hormones regulate NaCl reabsorption
Angiotensin-II renin? PT ?Na, H2O
aldosterone Ag-II ? TAL, DT/CT ?Na, H2O
ANP ECFV ? CD ?Na, H2O
Urodilatin ECFV ? CD ? Na, H2O
???? ECFV ? PT ?Na, H2O
Dopamine ECFV ? PT ? Na, H2O
ADH ECFV ? CT/DT ? H2O
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??angiotensin-converting enzyme (ACEI)

• ?? angiotensin II
• ?PT? NaCl and water reabsorption
• Aldosterone????, ????NaCl???
• Systemic arteriole?dilation, ?????? (TPR??)

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Collecting tubule

• Water reabsorption
• Relatively impermeable to water in the basal
  state, and is responsive to ADH, with the
  insertion of water channels

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Collecting tubule

• Intercalated cells
• Hydrogen ion secretion
• Bicarbonate reabsorption
• Hydrogen and bicarbonate formed from water and
  CO2 in the cell in the presence of carbonic
  anhydrase. Bicarbonate returns to the circulation
  by Cl-/HCO3- exchanger at basolateral membrane,
  and H secreted into the lumen by a H/ATPase.
  Process is stimulated by acidemia
• K reabsorption
• Although cortical collecting tubule normally
  secretes K under circumstances of K depletion,
  net reabsorption occurs by the K - ATPase of the
  intercalated cells

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Control of body fluid osmolality and volume

• ???????NaCl?????????osmolality?????

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Plasma osmolality

• ?????extracellular fluid (ECF)??????, ????Cl-,
  HCO3-
• So, Na is the major determinant of the
  osmolality of the ECF
• Rough estimate
• 2 (plasma Na) 285-295 mOsm/kg H2O
• In clinical set
• 2 (plasma Na) glucose/18 urea/2.8
• ???????????????????

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Control of body fluid osmolality urine
concentration dilution

• Renal excretion of water is regulated to maintain
  water balance

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Water reabsorption along the nephron

• PT
• 65-70 filtered water reabsorbed isoosmotically
• Na concentration and osmolality remains constant
  along PT. remember that although 65-70 of the
  filtered Na is rebasorbed in PT, water follows
  readily(because of the high water permeability of
  PT), and therefore the concentration of Na is
  essentially unchanged along PT
• HL
• Descending limb is always water permeable(20 of
  filtered water reabsorbed)
• Ascending limb is always water impermeable
• Late distal and collecting tubule
• Water reabsorption only in the presence of ADH

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Water reabsorption along the nephron
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Antidiuretic Hormone(ADH)

• ADH determines
• The concentration of urine
• The amount of water reabsorbed
• The volume of urine produced
• ADH binds to receptor on basolateral surfaces of
  principal cells
• Activate guanulate cyclase
• Lead to produce of water channels, and insert
  them into the luminal membranes of principal
  cells
• Water is reabsorbed passively down its
  concentration gradient into the interstitium of
  both cortex and medulla

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Antidiuretic Hormone(ADH)

• A 9 amino acid peptide
• Synthesized in supraotic and paraventricular
  hypothalamic nuclei
• ADH release is regulated by
• More sensitive to changes in osmotic pressure
• Osmotic regulation
• Osmoreceptor in anterior hypothalamus in the
  regions of the supraoptic nuclei
• Hemodynamic regulation
• volume(stretch-sensitive neurons in the cardiac
  atria and great veins)
• Arterial pressure(stretch-sensitive neurons in
  the carotid sinuses and aortic arch)

75
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76
PKA
77
ADH action on kidney
Collecting duct
lumen
Blood
Activate Gi
cAMP
H2O channel
PKA
H2O
H2O
??? UT-A1
UT-4
Aquaporin 2 gene
urea
urea
Aquaporin 2/H2O channel
H2O
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Inadequate secretion of ADH

• Central diabetes insipidus
• Inherited ????
• Head trauma, brain neoplasm, brain infection
• Corrected by administration of exogenous ADH

• Nephrogenic diabetes insipidus
• Collecting duct do not respond to ADH (????)
• Defects in ADH receptors
• Failure to insert water channel to apical
  membrane
• ?????hypercalcemia, Lithium,

80
??(lithium)

• ????????? (bipolar disorder) ???????
• ??????????????(0.6-1.2 meq/L) ??????,?????????????
  ????
• ???????????????,?????? (nephrogenic diabetes
  insipidus ),??????????????????

81

• ??????????60?????????,20????????????????????????
  ???,???????????????????????????
• ????????????????????????????????

82
??????????????????????
???????CAMP??????Arginine vasopressin?????(hydro-o
smotic effect)???(????????????????????????????????
?)
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Syndrome of inappropriate ADH secretion (SIADH)

• ????
• Infection and neoplasms of brain
• Drugs (antitumor agents)
• Pulmonary disease
• Plasma ADH is elevated
• Retain water
• Urine is more concentrated

84
Renin-angiotensin-aldosterone
Captopril
85

• Efferent is more sensitive to A-II than afferent
• Low concentration of A-II, constriction of
  efferent arteriole predominates
• High concentration of A-II, constriction of both
  afferent and efferent arterioles occurs

86
Phosphatidyl choline Arachidonic acid
NSAID
Cyclooxygenase
Lipooxygenase
PAF NO
Leukotrienes
Prostaglandin Thromboxanes
Neutrophil function Phagocytosis Bacterial
killing
Vasodilation
Permeability Leukocyte trapping
87
Potassium homeostasis
88
K homeostasis
K distribution
?????? ???K???? ???plasma K
98 in cell 2 in ECF Normal K 4mEq/L
K balance
???K????? ???
89
?? K distribution

• Insulin
• after K ingestion increase K uptake into cell
• Epinephrine
• Exercise ? K out of cell increase by 2-4 mEq/L
  (????? ?-adrenergic blockers, ??????hyperkalemia)
• Stress ? K uptake into cell
• Aldosterone ????
• Plasma K is increased ?increase K uptake into
  cell and excreted by kidney ? decrease plasma K

90
Factors ?? K distribution

• Acid-base balance
• Plasma osmolality
• Cell lysis
• Exercise
• Drug-induced hyperkalemia

91
Two processes of cellular K secretion
92
Factors regulate renal K secretion

• Plasma K
• Aldosterone
• Glucocorticoids
• Antidiuretic hormone(ADH)

Tubular flow
K excretion
GFR
93
K and aldosterone regulate renal K secretion
Hyperkalemia
Aldosterone
Na/K-ATPase
Permeability of apical m. to K
Flow rate of tubular fluid
Driving force for K across apical m.
K secretion??
94
Control of aldosterone and its effect on Na
reabsorption and K secretion
95
ADH maintain constant K balanceEven when H2O
excretion is fluctuated
Na uptake from apical m. ? electrochemical
driving force for K
96
Hyperkalemia
Hyperkalemia

• Low aldosterone
• GFR below 20 of the normal
• ??
• Insulin
• Epinephrine
• Aldosterone

• Burns
• Tumor lysis syndrome
• Rhabdomyolysis ??????
• Gastric ulcer blood cells are digested, and the
  K released from the cells

97
???

• ??????????,???????????,??????????????????????????,
  ?????????????????,????????1000??,???????????????
• ??????????,??????????????????????????????????????
  ?????????????
• ??????????ACEIs?Cyclosporine?Digitalis
  overdose?Heparin?Lithium?NSAIDs?Spironolactone?Suc
  cinylcholine?Trimethoprim?