Renal Study Guide Notes

Renal Study Guide Notes
Chapter 1 – Normal Development and congenital Anomalies
 Urinary and genital systems originate from Intermediate mesoderm.
 The intermediate mesoderm pinches off from the paraxial mesoderm to
form the nephrogenic cord
o Nephrogenic cord gives rise to the urinary system
 Three major developmental excretory units
o Prosnephros
o Mesonephros
o Metanephros
 Sequence of development is
o Prosnephros
o Mesonephros
o Metanephros
 The metanephros becomes the definitive adult kidney
 The prosnephros becomes nonfunctional
 The prosnephros develops in the cervical region.
o Three sets of kidneys develop from cranial to caudal
 Prosnephros is degenerate, but
o Prosnephric duct becomes the mesonephric duct.
 Mesonephric duct AKA Wolffian duct
 Mesonephric duct empties into cloaca
 Mesonephros develops caudal with respect to the prosnephros
 Structures of the mesonephros include
o Glomeruli
o Mesonephric tubules
o Tubules empty into mesonephric ducts
 Caudal mesonephric segmented tubules persist to become efferent
ductules of testes in adult males
 Elimination of waste in the embryo is done by the placenta
 Urine from the metanephros contributes to the amniotic fluid in the
amniotic cavity
 When baby cannot make urine or urine can’t drain into the amniotic cavity
–→ oligohydramnios
 Oligohydramnios is when there is a deficiency of amniotic fluid
 Oligohydramnios is diagnosed by ultrasound
 Reciprocal induction is when the ureteric bud and metanephric blastema
produce signals that regulate each other’s development
 The adult renal collection system develops from the ureteric bud and
metanephric blastema
 The ureteric bud comes from the mesonephric duct near its entrance into
the cloaca
 The ureteric bud penetrates the metanephric blastemal to make the
 Metanephric blastema is derived from the nephrogenic cord
o Intermediate mesoderm pinches off from paraxial mesoderm
o Intermediate mesoderm –→ nephrogenic cord –→ Metanephric
 The ureteric bud forms:
o Ureter
o Renal Pelvis
o Major/minor calyces
o Collecting ducts
 The stalk of the ureteric bud becomes the adult ureter
 The metanephric blastema gives rise to the adult
o Proximal convoluted tubule
o Loop of Henle
o Distal convoluted tubules
o Connecting tubule
 The ureteric bud divides into arched collecting tubules
o These tubules induce clusters of cells in the metanephric blastema to
form metanephric vesicles
o Metanephric vesicles elongate and form
 Metanephric tubules
 The glomerular capillary tuft receives blood from afferent arteriole
o Afferent arteriole arises originally from the
o Dorsal aorta
In the last trimester, the kidney grows by
o Hypertrophy of the existing nephrons
The kidney initially develops in the
o Pelvis
Kidneys ascend to their adult position in the abdomen (T12-L3) by
o Growth and straightening of the body
Branches of the common iliac arteries feed the kidney while it is in the
25% of people have 2 or more accessory renal arteries because
o As kidneys ascend –→ new renal arteries arise from the cephalic
o Inferior arteries should degenerate in patients with 2 or more renal
o More inferior arteries fail to degenerate –→ numerous accessory
renal arteries
During 6th week of gestation
o Urorectal septum divides the cloaca into posterior rectum and UG
UG sinus is continuous with the allantois
Segments of UG sinus and their adult structures
o Cephalic dilated vesical segment of UG sinus
 Bladder
o Middle narrow pelvic segment
 Urethra in females
 Membranous prostatic urethra in males
o Caudal phallic segment (AKA definite UG sinus)
 Covered by UG membrane
 Becomes small portion of urethra and vestibule in females
 Becomes penile urethra in males
CARUT (Congenital anomalies of Kidney and Urinary Tract) can be detected
in utero by Ultrasound
Failure of the ureteric bud to induce the metanephric blastema leads to
o Renal agenesis
 Bilateral renal agenesis leads to
o Potter syndrome:
 Flattened nose, epicanthal folds, low set ears
 Bilateral renal agenesis is more frequent in males
 Fetuses with renal agenesis have pulmonary hypoplasia
o Have reduced circumference of chest
 Bilateral renal agenesis includes other systems
o Pulmonary hypoplasia
o Reproductive tract abnormalities
o GI problems
o CV problems
o MSK problems
 Bilateral renal agenesis is compatible with prenatal life
o Because placenta is major excretory organ
 Bilateral renal agenesis is not compatible with postnatal life
o Because kidneys never developed
 Renal function/urine production in newborn with unilateral renal agenesis
is normal
o Unilateral renal agenesis usually incidental finding
o Contralateral kidney undergoes hyperplasia
 Renal hypoplasia –→ kidneys have fewer nephrons than expected
o May also have fewer papillae and calyces
 Severe bilateral renal hypoplasia leads to
o Renal failure in infancy
 Nephrons lost after birth are not replaced by new nephrons
o Nephron formation stops after second trimester
o Nephron loss after that is not replaced
o –↑ nephron loss –→ renal failure
o If injury is early on in life –→ renal hypertrophy to compensate
 Early and excessive branching of ureteric bud –→
o Accessory kidneys
 Accessory kidneys usually smaller than and separated from normal kidneys
 Renal ectopia
o When kidney is located outside normal position
 In renal ectopia –→ kidney usually found in
o Pelvis
 Crossed renal ectopia
o When both kidneys are located outside their usual position
 Renal ectopia can lead to
o Hydronephros
o Hydroureter
o Dysplastic changes
 In Turner syndrome
o XO female
o Webbed neck, wide chest
o Has horseshoe kidney
 Horseshoe kidneys
o Happens in 1/500 births, more common in Turner’s
o Usually found in pelvic brim
 Cause fused kidneys cannot ascend
 Blocked by inferior mesenteric artery
 Horseshoe kidney usually has 2 separate ureters
o Course ventrally
o Drain into bladder
 Horseshow kidney is usually asymptomatic
o Increased risk of infection/obstruction
 Renal Dysplasia
o Developmental cystic anomaly
o Disorganized architecture in cortex and medulla
o Small glomeruli
o Simple atrophic tubules
o Variable cyst formation
o Can involve any part of kidney
o Kidneys are large and dysfunctional
 Autosomal Dominant Polycystic Kidney Disease (AD-PKD)
o AD
o Pt gets symptoms in middle age
o Cysts are initially small
o Cysts not radially oriented
o Associated with at least 2 abnormal genes
 Most common is short arm of Chromosome 16
 Autosomal Recessive (infantile) Polycystic Kidney Disease (AR-PKD)
o AR
o Pt gets symptoms in childhood
o Enlarged kidneys
o Radially oriented cysts
o Numerous, elongated radially oriented cysts
 Duplex Ureter
o Caused by branching of ureteric bud before entering metanephric
o Can have separate pelvises and 2 proximal ureters
o Both ureters merge into a single ureter before they enter bladder
o Causes
 Hyronephrosis
 Dysplastic changes of kidney may occur
 Aplasia or hypoplasia of ureteric lumen as it enters the bladder may lead to
o Ureteral obstruction at uretero-vesicle junction
o Hydronephrosis
 Seen on US in fetal urinary tract
 Exstrophy of bladder
o Defect in lower abdominal wall and musculature
o Leads to exposure of mucosal surface of bladder
 Epispadias –→ Opening of urethra in dorsal side of penis
o Associated with exstrophy of bladder
 Hypospadias –→ Opening of urethra in ventral side of penis
 Posterior urethral valves
o Epithelial folds that project from urethral mucosa near base of
o Most common cause of lower urinary tract obstruction
o If complete obstruction –→ oligohydramnios
 Prune belly syndrome
o Due to lower urinary tract obstruction
 (from urethral atresia, stenosis, kinking, or posterior urethral
o Initially –→ distended abdomen
 Blocks formation of abdominal muscles
o Then urinary system ruptures
 Fluid drains into peritoneal cavity
 Then drains into amniotic cavity
o Seen in males
o Associated with
 Undescended testes
 Undeveloped prostate
Chapter 2 – Gross and Microscopic Anatomy with Functional
 The kidneys are located in the retroperitoneal space
o Right kidney is slightly lower than the left
o Due to liver being on top of right kidney
 Interlobal and arcuate arteries
o Surround the renal pyramid
 Base of renal pyramid faces the renal cortex at the Corticomedullary
o Arcuate arteries lie in the corticomedullary junction
 Tip of renal pyramid (papilla)
o Empties into minor calyx
 Collecting ducts empty through the papillary tip
o Papillary tip AKA area cribrosa
 Columns of Bertin –→ extensions of cortex, surround lateral sides of
o Columns of bertin located in medulla
 Even though they are cortical tissue
 Medullary rays
o Vertical striations in cortex
o Radiate from the medulla into the cortex
o Technically in cortex, not medulla
o Medullary rays include
 Straight parts of proximal and distal ascending tubules
 Collecting ducts
Cortical labyrinth
o Tissue adjacent to medullary rays
o Cortical labyrinth contains
 Glomeruli
 Proximal and distal convoluted tubules
 Interlobular vessels
 Capillaries
 Connecting tubules
 Initial collecting ducts
Medulla has 2 zones
o Inner and outer zone
o Outer zone is adjacent to cortex
o Inner medulla includes
 Collecting ducts –→ has striped appearance
Kidney lobe includes
o Single pyramid and surrounding cortex
o 8-12 lobes in each kidney
o Lobes are visible to naked eye
o Disappear after birth usually
Kidney lobule includes
o Medullary rays and surrounding cortical tissue
o Contains all nephrons draining into that collecting duct
2 major steps of urine formation
o Filtration of plasma
 Across renal corpuscle into Bowman’s space
o Reabsorption and secretion of water and solutes in tubules
3 major components of Renal Corpuscle
o Glomerulus
 Afferent arterioles bring blood into glomerulus
 Efferent arterioles take blood out of glomerulus
 One afferent and one efferent arteriole for each glomerulus
o Bowman’s capsule
 Has 2 poles:
 Vascular pole
 Where afferent and efferent arterioles enter capsule
 Urinary pole
 Where fluid in bowman’s space enters proximal tubule
o Bowman’s space
 Mesangium
o Matrix of connective tissue and cells
o In capillary network of glomerulus
o Seen on cross section of glomerulus
o Mesangium contains mesangial cells and mesangial matrix
o Mesangial cell functions include
 Synthesis of ECM (similar to GBM)
 Alter filtration surface area
 By closing capillaries in response to vasoactive
 Phagocytose and metabolize molecules in GBM that got
trapped in the mesangium
 Synthesize inflammatory and fibrogenic cytokines
 May contribute to pathogenesis of kidney disease
 3 layers of filtration barrier (glomerular capillary wall)
o Inner fenestrated capillary Endothelium
o Middle Glomerular Basement Membrane (GBM)
o Outer visceral epithelium (Podocytes)
o Podocytes and GBM cover only 75% of glomerular capillary
 Uncovered region has mesangium in direct contact with
 Inner Endothelium
o Endothelium has fenestrations –→ large pores that lack a diaphragm
(compared to capillary endothelial cells)
o Fenestrations are negatively charged
 Due to polyanionic glycoproteins
 Prevents filtration of blood elements (RBC, WBC, platelets)
Middle GBM
o Produced by podocytes, has 3 layers
 Lamina rara interna (inner, faces glomerular capillary)
 Lamina densa (middle)
 Lamina rara externa (outer, facing podocyte)
Outer Podocytes
o Podocytes have foot processes that extend from podocyte and
attach to GBM
o Space between podocytes are called slit pores
Course of Creatine molecule from glomerular capillary to urine:
o Glomerular capillary –→ fenestrations of endothelium–→ GBM –→
slit diaphragm of podocytes –→ bowman’s space –→
o Proximal tubule –→ loop of henle –→ distal tubule –→ collecting
duct –→
o Minor calyx –→ major calyx –→ renal pelvis –→
o Urethra –→ bladder for storage
Filtration does not require passage through cell walls
o Process would be slow if it did
Glomerular filtration has a heteroporous model
o Mostly small pores
 Don’t allow large molecules like albumin to get through
o Some large pores
 Allows small amount of large molecules to get through
o Glomerulus also has electrical barrier to filtration
 Positive molecules have higher permeability across glomerular
filtration barrier
 Because all 3 layers (endothelial, GBM, podocyte) are
negatively charged proteins
 Prevent negative molecules from being filtered easily
 Electrical barrier only prevents large negative molecules (like
albumin) from being filtered
 Small molecules can still get through
 Albumin has a negative charge
o When you put plasma in an electrical gradient (electrophoresis)
o Negatively charged albumin moves to positive cathode
o Positively charged gamma globulins move towards negative anode
 Filtration slit and foot processes primarily prevent loss of proteins
 Congenital nephrotic syndrome
o Proteinuria > 3.5g /day
o Mutation in nephrin –→ defect in podocyte slit diaphragm
o Changes in diaphragm architecture
 Fusion of foot processes
o Podocyte diaphragm necessary to prevent passage of plasma
 Tubular portions of nephrons (proximal, distal, loop of henle)
o Very thin layers
o Single epithelial cell layers
o Rest on basement membrane
 Tight junction
o Made up of
 Transmembrane proteins
 Claudins
 Occludins
 JAM – functional adhesion molecules
 Zona occludin –→ cytoplasmic anchors
 ZO-1, ZO-2, ZO-3
o Tight junctions allow solutes and water to move via
 Paracellular route
 Variable amounts of leakiness depending on tubular segment
o Mutation in claudin-16 transmembrane proteins
 Familial hypomagnesemia with hypercalciuria and
nephrocalcinosis –→ AR
 Lead to hypomagnesemia
 Claudin 16 found in thick ascending loop of henle
 Needed for paracellular resorption of Mg
 Loss of fxn mutation –→ cant resorb Mg (or Ca)
o –→ ↓ Mg, ↓ Ca
 Claudin-16 AKA Paracellin-1
Proximal Tubule
o Early proximal tubule –→ proximal convoluted tubule
 In cortex
 AKA pars convolute
o Late proximal tubule –→ proximal straight tubule
 In cortex and outer medulla
 AKA Thick descending limb
 AKA pars recta
Nephrons can be short looped (cortical) or long looped (juxtaglomerular)
o Short looped nephrons (cortical)
 Small glomeruli
 In superficial to mid-cortical region
 90% of nephrons
o Long looped nephrons (juxtaglomerular)
 Large glomeruli
 Deep cortex, near cortico-medullary junction
 10% of nephrons
 Long looped nephrons necessary for maximum urine
 Because they reach into medulla where there is highest
concentration gradient
Juxtaglomerular apparatus
o Includes
 Juxtaglomerular cells
 AKA JG cells, granular cells
 Extra-glomerular mesangial cells
 AKA Lacis cells, polkissen cells, Goormaghtigh cells
 Macula densa cells
Juxtaglomerular cells
o Contain and secrete renin
 Renin kept in cytoplasmic granules
o Located in afferent arteriole
 Macula densa
o Forms border between
 thick ascending limb of Henle and distal convoluted tubule
o Lies between afferent and efferent arterioles
o Detects changes in tubular concentration and/or flow rates
 Signals adjacent mesangial cells –→ regulatory effects on
 Glomerular filtration
 Renal blood flow
 AKA tubuloglomerular feedback
 Proximal Tubule
o Resorbs 60% of filtered water, Na, Cl
o Resorbs almost all glucose, bicarb, AAs
o Luminal/apical surface has brush border
 Long microvilli
 Increases surface area
o Transport possible by
 Ion channels, specialized channels
 Endocytosis
 Pinocytosis
o Capillary/basolateral surface has
 Basolateral membrane infolding
 Increases surface area on basolateral side
o Luminal microvilli is coated with glycocalyx
 Binds filtered proteins
 Proteins resorbed by pinocytosis
 Proteins broken down to AA and reabsorbed into circulation
o On histo
 Proximal tubule is longer than other segments
 More common in cortex samples
 Prominent brush border seen on inner lumen
 Brush border can slough off and be seen in lumen
 Big, cuboidal eosinophilic cells
 No clear separation between cells
o Early proximal tubule has leaky tight junctions
 Allows for passive paracellular transport of water and solute
o Late proximal tubule has well developed tight junctions
 Allows for complete absorption of AA and glucose
 No back leak of solutes
Thin descending and ascending loop of Henle on histo
o Simple flat epithelium
o Few luminal microprojections
o Has mitochondria in cells
o Lateral cell membrane interdigitations
Thick ascending loop of Henle on histo
o Large cuboidal cells
o Nucleus seen at apical portion of cell
 Cause cell to bulge into lumen
o Cant see lateral margins well
 Extensive basolateral cell membrane interdigitation
o Lightly stain with eosin
Distal tubule on histo
o Shorter than proximal tubule
o Simple cuboidal epithelium
o Short stubby microvilli
o Deep basilar infoldings
o More nuclei per cell area and less cytoplasm that proximal tubule
Collecting ducts
o Cortical collecting duct
 Found in medullary rays as it moves down into the medulla
 2 types of cells:
 Principal cells/Light cells
 40% of cells in cortical collecting duct
 Pale, single cilium, Few microvilli
 Active Na resorption/ K excretion
o Stimulated by Aldosterone
 Water resorption
o By ADH
 Intercalated cells/dark cells
 60% cells in cortical collecting duct
 Dense dark cytoplasm
 Apical folds and microvilli
 ↑ Carbonic anhydrase II
 Do acid base balance
o Medullary collecting duct
 Cells become columnar
 No invagination of basal cell membrane
 10% intercalated cells
 90% Inner Medullary Collecting Duct cells (IMCD cells)
 Final Na, Cl, H2O balance regulation
 Vasculature and Blood flow
o Peritubular fibroblasts in the cortex
 Produce EPO
o 20% of the cardiac output flows through renal arteries
o Course of RBC from Renal artery –→ Renal vein
 Renal art –→ segmental art–→ interlobar art –→ arcuate art –
→ interlobular art –→
 Afferent arteriole –→ glomerulus –→ efferent arteriole –→
 Peritubular capillary (cortical nephron) or vasa recta
(juxtamedullary nephron) –→
 Interlobular vein –→ arcuate vein –→ interlobar vein –→ renal
o Interlobar arteries are located between the renal pyramids
 in columns of Bertin
o Arcuate arteries are located between the cortex and medulla
 Urinary tract
o Pathway of urine from collecting ducts –→ bladder
 Collecting ducts –→ collecting ducts of bellini (at papillary tip
of renal pyramids) –→
 Minor calyx –→ major calyx –→ renal pelvis –→
 Ureter –→ bladder for storage
o Layers of wall of urinary tract from minor calyx down
 Mucosa (superficial)
 Transitional epithelium
 Muscularis
 Smooth muscle
 Adventitia or serosa
 Connective tissue
o Transitional epithelium only found in urinary tract
 Can accommodate stretching in urinary tract
 Large ovoid cells when normal/empty
 Stretched thin cells when full
o Minor calyx envelopes the tip of a renal pyramid
 Bladder
o Ureters enter the bladder at the Trigone
 Trigone is where you can find submucosal blood vessels
 Shape is an inverted triangle
 2 ureteral orifices at base
 Internal urethral orifice at apex
 Ureters enter bladder at posterior aspect
o Detrusor muscle is main muscle of bladder
 has middle circular layer
 Sandwiched between inner and outer longitudinal layers
o Internal sphincter of bladder
 Involuntary control
 Inherent tone prevents emptying until appropriate stimulus
o External sphincter of bladder
 Under voluntary control
Chapter 3 – Body Fluid Composition and Fluid administration
 Mass of a mole of a substance is the molecular weight
a. E.g. mass of 1 mole of carbon = 12 g
 30g of a substance with a MW of 120g = 0.25 moles of substance
 Molarity is the number of moles dissolved in 1L of solution
 30g of substance with a MW of 120g dissolved in 5L water is what molarity
a. 30/120 = .25 moles, 0.25 moles/5 L = 0.05 M/L
 How many moles in 1g urea (MW=60)
a. 1/60 = 0.0167 M = 16.7mM
 Molarity of 1g urea in 0.5L water
a. 0.0167M /0.5L = 0.0334 M/L
 How many moles in 4.575g Bicarb (MW=61)
a. 4.575/61 = 0.075 mol = 75 mmol
 Molarity of 4.575g bicarb in 3L water?
a. 0.075 mol/3L = 0.025 M = 25 mM
 Problem
 Molality
a. Independent of temp and pressure
b. Dependent on mass, not volume
c. Can ignore diff between molality and molarity since dilute solutions
 Osmotic pressure
a. Pressure exerted by water flow through semipermeable membrane
i. Between 2 solutes w/diff concentrations
 If you put cell into iso-osmolar urea solution
a. Urea –→ moves into cell
b. Brings water with it –→ cell bursts
c. Iso-osmolar, hypotonic
 Mannitol
a. Stays in extracellular compartment
b. Volume expander
 Albumin
a. –↓ albumin –→ ↓ oncotic pressure –→ ↑ fluid movement into
 Body water composition
 Kidney –→ highest % water in organ
 Deuterium (heavy water, D2O)
a. Used to measure Total Body water
 Inulin –→
a. Used to measure ECV
 Radiolabeled RBCs
a. Used to measure Interstitial/extravascular fluid
b. Cant use radiolabeled albumin
i. Some goes into interstitium
 ECF solutes
a. Na, Cl, HCO3
b. Very low concentrations of K, Ca, Mg
 Albumin
a. Most of it is in intravascular space
b. Albumin is negative charge –→ Attracts cations (Ca, Mg, K)
c. Cations attracted to intravascular space
d. Called Gibbs Donnan equilibrium
 Sources of water
a. Water intake from drinking
b. Water production from metabolism
 Sources of water loss
a. Evaporation (skin, breathing)
b. Urine and stool
 Transport
a. Facilitated diffusion
i. Diffusion down concentration gradient through channel
b. Coupled transport
i. At least 1 solute is transported uphill against electrochemical
c. Secondary active transport
i. 2 solutes moved
ii. One moved down electrochemical gradient, one moved up its
electrochemical gradient
d. Solvent drag
i. Water coming along with solute
 Crystalloids and colloids
a. Colloids more likely to stay in vascular space
b. Saline
i. Na –→ volume of equilibration is almost completely
extracellular space
c. D5W
i. Iso-osmolar –→ does not cause RBC lysis
d. D5NS
i. Dextrose gives some calories
ii. Prevents breakdown of muscles to form glucose via
e. LR not ideal
i. Pt normally require more K than in LR (25 vs 4)
ii. In hepatic dz
1. Lactacte cannot metabolize to bicarb
2. –↑ lactate –→ systemic vasodilation
iii. Ca infusion needs to be tailored
iv. LR doesn’t show better outcome than other crystalloids
f. 3% NaCl
i. Used to tx hyponatremia
ii. S/E
1. Volume overload –→ pulm edema
2. Osmotic demyelination syndrome
g. Hetastarch
i. S/E
ii. Bleeding
iii. Anyphylaxis
h. Add KCl to
i. Meet daily needs
ii. Treat losses
iii. Treat –↓ K
i. Add bicarb to treat acidosis
Chapter 4 – Glomerular Hemodynamics
 Large substances like cells, Ig, and –↑ MW proteins are not filtered at the
o Proteins w/ size > albumin –→ not filtered
 Starling Eq
o GFR = Kf [(Pgc-Pbs)-( 𝜋gc-𝜋bs)]
o Oncotic pressure of bowmans space –→ negligible, usually 0
o Determinants of Pgc
 BP
 Ratio of resistance of afferent and efferent arteriole
 Pgc = Ra/Re
 GFR decreases throughout capillary
o Protein free filtrate leaves
o Remaining plasma –→ ↑ protein concentration –→ ↑ 𝜋gc –→ ↓
o Pgc drops only 2-4 mm Hg
 Glomerular capillary is a low resistance vascular bed
 ↑ afferent and efferent resistance –→ ↓ RBF –→ ↓ GFR
 If –↑ Kf
o –↑ Kf –→ ↑ GFR
o No change on Pgc and RBF
 Pbs increases in urinary tract obstruction
o Cancer, stones, BPH
o –↑ Pbs –→ ↓ GFR
 Main factor opposing filtration is 𝜋gc –→
o Increases along the length of the capillary
o GFR decreases along the length of the capillary
 ↑ RBF –→ ↑ GFR
o Due to shift in oncotic pressure profile
 RBF = Renal perfusion pressure/renal vascular pressure
o Renal perfusion pressure = BP- Renal venous pressure
o Renal vascular pressure = afferent + efferent arteriolar resistance
o RBF = (BP-Renal venous pressure)/(afferent+efferent arteriolar
 Autoregulation
o If –↑ BP –→ balanced out by –↑ Renal vascular resistance
o Myogenic stretch reflex
 Local event on vascular beds
 If –↓ renal perfusion pressure –→ ↓ afferent arteriolar
resistance –→ minimized pressure change in capillary bed
 ↑ RBF, GFR
 If –↑ renal perfusion pressure –→ ↑ afferent arteriolar
resistance –→ minimized pressure change in capillary beds
 ↓ RBF, GFR
o Tubuloglomerular feedback
 ↑ Renal perfusion pressure –→ ↑ RBF –→ ↑ GFR
 ↑ GFR –→ ↑ flow to macula dena in distal tubule
 Macula densa –→ signal to afferent arteriole –→ ↑
constriction in AFFERENT Arteriole –→ ↓ GFR
 TGF protects against against fluctuations of pressure, GFR, RBF
and protects against solute loss
 Protects against changes that might occur with posture and
 Standing –→ ↓ BP –→ ↓ GFR –→ ↓ flow to macula
densa –→ signal to afferent arteriole –→ ↓ afferent
arteriole resistance –→ ↑ GFR
 In gentamicin use –→ proximal tubule damage
 Proximal tubule damage –→ ↑ flow to macula densa –
→ ↓ GFR (AKI) –→protects against fluid/solute loss
 Renin cleaves liver derived angiotensinogen –→ AT I
 By ACE from Pulm capillaries
 By chymase
 AT II –→ ↑ efferent vasoconstriction –→ ↓ RBF, ↑ GFR
 AT II –→ ↑ proximal Na and water resorption
 B adrenergic fibers
 Stimulated by sympathetics and norepi
o Vessels affected by autoregulation (and others)
 Myogenic reflex –→ afferent arteriole
 TGF –→ afferent arteriole
 RAAS –→ efferent arteriole
 Aldosterone –→ efferent vasoconstriction
 PGE2/PGI2 –→ afferent vasodilation
o Clinical conditions that override autoregulation
 Volume depletion
 Hemorrhage
 Heart failure
 Shock
 In these situation
 Vasoconstriction of renal vasculature –→ ↓ RBF, ↓ GFR
o PGE2, PGI2
 ↑ Afferent vasodilation –→ ↑ RBF, GFR
 RBF = renal perfusion pressure/(afferent + efferent arteriolar resistance)
Chapter 5 – Principles of Renal Clearance
1. Clearance is the volume of plasma completely cleared of a substance in a
specified interval of time
2. How is clearance equation derived
a. Mass filtered = mass excreted
b. Mass filtered = GFR x [substance] plasma concentration
c. Mass filtered = [substance] urine concentration x urine volume
d. GFR = [substance] urine * volume urine/ [substance] plasma
e. For a substance that isn’t secreted or absorbed and is freely filtered,
clearance = GFR
f. If substance if freely filtered and resorbed –→ Clearance < GFR
g. If substance is freely filtered and secreted –→ Clearance > GFR
3. To Calculate Clearance, need
a. Timed urine sample
b. Plasma concentration
4. The ideal properties of a substance used to calculate clearance are
a. Substance must be freely filtered at glomerulus
b. Substance must not be reabsorbed or secreted by the renal tubules
5. If ideal substance, clearance = GFR
6. Inulin is an ideal substance
a. Freely filtered, not resorbed or secreted at renal tubules
b. Is a polymer of fructose
7. Sodium is freely filtered and 99% reabsorbed, so
a. Sodium clearance is much less than GFR
b. So Na clearance not a good measure of GFR
8. Problem
9. Problem
11.Inulin clearance not used in clinical practice because
a. Difficult to do
b. Easier, but less accurate used to measure GFR
12.Creatinine clearance (CrCl) used to measure GFR
13.Creatinine comes from the metabolism of creatine in skeletal muscle
14.Advantages of using creatinine clearance to measure GFR
a. Creatinine released from muscle into blood at constant rate –→
provides steady state
b. Freely filtered at the glomerulus
c. Not reabsorbed by renal tubules
15.Disadvantages of using creatinine clearance to measure GFR
a. Creatinine Clearance overestimates GFR
b. Because 10% of CrCl is due to proximal tubular secretion of
c. Tubular secretion of creatinine becomes greater as GFR decreases
i. Tubular secretion of creatinine may account for 60% of urine
creatinine in patients with severely decreased GFR
d. Collecting 24 hr urine for CrCl is difficult
16.Drugs that interact with assay for creatinine include
a. Acetoacetate
b. Flucytosine
c. Cephalosporins
17.Cimetidine and Trimethroprim/TMP
a. –↓ tubular secretion of creatinine –→ ↑ serum creatinine
18.Can use cimetidine to –↓ tubular secretion of creatinine –→ CrCl becomes
more accurate estimate of GFR
19.Measurements of CrCl and GFR not accurate in acute kidney injury (AKI)
a. GFR calculations assume Creatinine concentration in plasma is
b. In AKI, plasma [creatinine] is rapidly changing
20.Relationship between plasma creatinine and GFR
a. Creatinine production = excretion (ignoring tubular secretion)
b. Large changes in GFR do not affect plasma [creatinine]
c. However, when GFR low (AKI) –→ plasma [creatinine] varies a lot
21.Relationship between GFR and creatinine
a. For every doubling of creatinine, GFR decreases by half
b. (GFR), Plasma [creatinine]
c. 100 , 1
d. 50 , 2
e. 25 , 4
f. 12.5 , 8
22.More muscular people have naturally higher GFRs
23.Better to use GFR calculations from serum creatinine rather than doing
24hr CrCl since that is cumbersome and difficult
24.Estimate CrCl with Cockcroft gault formula
a. For men
b. (140-age)*weight(kg)/(72*plasma[creatinine)
c. For women
d. (140-age)*weight(kg)*.85/(72*plasma[creatinine)
25.Estimate GFR with MDRD formula (don’t need to memorize)
a. Based on age, sex, race, plasma creatinine
26.MDRD formula underestimates GFR in pt with GFR >60
27.CKD EPI formula is another recent formula to estimate GFR
28.When calculating drug dosages, use Cockcroft Gault formula
29.When determining GFR/CrCl
a. Use Cockroft Gault or MDRD if plasma creatinine >2
b. Use Creatinine Clearance if plasma creatinine <2
30.No equations or estimations are valid in AKI
31.Para amino hippurate (PAH)
a. Used to estimate renal plasma flow
b. Used in research, not clinically
32.PAH is filtered by glomerulus and secreted by proximal tubule
a. Eliminates PAH from plasma when it passes through kidney
33.Clearance of PAH > GFR
a. Because there is glomerular filtration (GFR) and tubular secretion
34.If substance has clearance greater than GFR this means that
a. There must be tubular secretion
35.If substance has clearance less than GFR
a. Substance is not freely filtered and/or it is being reabsorbed
36.Clearance formula for PAH
a. [urine PAH]*urine volume/[plasma PAH]
Chapter 6 – Transport of Electrolyte and Water in the Proximal Tubule
1. How much fluid filtered by kidneys each day
a. GFR = 125 ml/min
b. 1440 min/day
c. .125L*1440min = 180L/day
2. Osmolarity of glomerular filtrate in Bowman’s capsule
a. Equal to plasma
3. Nephron is like an assembly line
a. Each part of it acts on fluid and passes it to the next portion
4. Major function of proximal tubule is to reabsorb the majority of the
glomerular filtrate
5. About 66% of filtered sodium and water is reabsorbed into the proximal
6. Proximal tubule reabsorbs almost all
a. Glucose
b. Amino Acids
c. Bicarb
7. Proximal tubule has brush border cells with microvilli
a. Microvilli –→ ↑ Surface area
b. Microvilli do most of the work of proximal tubule cells
c. Have –↑ mitochondria
8. Tm = transport maximum
a. Max threshold above which solutes will not be reabsorbed
b. Above this, solutes appear in urine
9. Will solute be excreted in urine if Tm is higher than plasma concentration?
a. No, Tm for reabsorption is greater than plasma concentration
10.Will solute be excreted if Tm is less than solute’s plasma concentration?
a. Yes, since more solute present in plasma than kidney can resorb
11.For a pt with a Tm of glucose of 375 mg/min, what would be filtered load of
glucose if serum concentration is 100 mg/dL and GFR is 125 ml/min
a. Filtered load = 125 ml/min* 100mg/100mL = 125 mg/min
12.Would glucose be found in urine?
a. No, pt Tm glucose is 375 mg/min, filtered load is 125 mg/min
13.If serum glucose was 400 mg/dL
a. 125ml/min *400mg/100mL = 500mg/min
b. 500 mg/min>375 mg/min
c. There will be glucose in the urine
14.Splay would be when a solute is found in the urine even though its Tm is
greater than its rate of filtration
a. Filtration due to GFR, plasma concentration, and glomerular
15.We see splay because
a. To calculate Tm, we add Tm’s of all nephrons
b. Some nephrons have higher Tm than others
c. Nephrons with higher GFR are more likely to exceed Tm –→
d. Incomplete absorption and excretion into urine
16.An example of splay
a. Tm of glucose is 375 mg/min
b. Despite this
c. Glucose found in urine when plasma glucose >200
17.Proximal tubule is longer than distal tubule
18.Apical tight junctions hold the cells together
19.Basolateral membranes extend up to the tight junctions in the complex
20.Six pack analogy
a. Beer cans –→ tubular epithelial cells
b. Plastic ring that binds them –→ tight junctions
c. Tops of cans –→ apical membranes
d. Remainder of cans –→ basolateral membranes
e. Spaces between the cans –→ lateral intercellular spaces
21.Unique channels and transporters allow unidirectional transport
22.During fluid transport, some moves between cells (paracellular)
a. Some moves through the cell (transcellular)
23.Transcellular transport is active
a. Paracellular transport is passive
b. Water transport always passive, even if transcellular
24.Proximal tubule is divided into
a. S1 - Early convoluted tubule (pars convolute)
b. S2 - Late convoluted tubule and early straight segment
c. S3 - Remainder of straight proximal tubule (pars recta)
25.Differences between segments of proximal tubule
a. Early segments do bulk transport
i. Low affinity, high capacity
b. Later segments do fine tuning
i. High affinity, low capacity
26.S1 – Early convoluted tubule is where bulk transport happens
a. Has
b. abundant energy supply (mitochondria)
c. –↑ Basolateral infoldings
d. –↑ surface area
27.S3 has tight junctions
a. Glucose and amino acids are not reabsorbed in proximal tubule
b. Minimizes paracellular back-leak of these solutes
c. From capillary down the concentration gradient
28.Differences between blood supply to cortical and juxtamedullary nephrons
a. Cortical nephrons are perfused by efferent arteriole of parent
b. Juxtamedullary nephrons are perfused by efferent arterioles of
several adjacent glomeruli
29.Na/K ATPase
a. Provides energy for transport of solute and water reabsorption
b. Maintains Na K gradient across cell membrane
c. Has catalytic alpha subunit
d. Beta subunit –→ inserts and localizes protein
e. FXYD subunit –→ regulates activity of transporter
30.Na/K ATPase located on basolateral membrane
31.100% of filtered glucose reabsorbed in early proximal tubule
a. Reabsorbed via SGLT2
i. SGLT2 is high capacity, low affinity
b. Distal convoluted tubule has SGLT1
i. SGLT1 is low capacity, high affinity
c. Early convoluted tubule SGLT2 does bulk glucose reabsorption
d. Distal convoluted tubule SGLT1 does leftover glucose reabsorption
e. Energy provided by Na/K ATPase
f. Keeps intracellular Na concentration low
g. Keeps inside of cell negatively charged
h. Allows Na to enter cell from lumen down its electrical chemical
i. Glucose exits the cell via basolateral membrane
j. Through glucose transporter (GLUT 2)
32.Canagliflozin is a SGLT2 inhibitor to treat T2DM
a. Inhibits SGLT2
b. Dose dependent glycosuria
c. Reduces plasma glucose, some weight loss
d. Canagliflozin increases splay
i. More glucose lost
33.Amino acids reabsorbed by SoLute Carrier group (SLC) transporters
a. On apical membrane
b. AA reabsorption coupled to Na+ reabsorption
c. Specific carriers for positive, neutral, and negative AA
a. AR
b. Mutation in anionic apical cysteine carrier protein
c. Inability to reabsorb filtered cysteine
d. Get hexagon shaped crystals in
i. Kidney
ii. Ureter
iii. Bladder
e. Cyanide nitroprusside test –→ screening
i. Add cyanide to urine
ii. Cyanide breaks disulfide bonds of cysteine
iii. Nitroprusside then binds cysteine –→ turns purple
35.Bicarb reabsorption
a. Bicarb combines with H+
b. H+ from Na/H exchanger
c. Forms carbonic acid
d. Carbonic acid –→ CO2
i. Catalyzed by carbonic anhydrase
e. CO2 resorbed
36.Phosphate resorption
a. Most reabsorbed in proximal tubule
b. Via apical Na/phosphate transporters
37.PTH effect on phosphate resorption
a. PTH binds receptor (PTH1R)
b. Induces endocytosis of NPT2a
c. Decreases phosphate reabsorption –→ phosphaturia
a. Inhibits phosphate reabsorption
b. Alters expression of NPT
c. –↓ NPT –→ ↑ phosphate reabsorption
39.Calcium reabsorption
a. 50% filtered Ca reabsorbed in proximal tubule
b. Through paracellular pathways
c. Similar to Na/H2O reabsorption
40.Magnesium reabsorption
a. 30% reabsorbed in proximal tubule
b. Through paracellular pathways
c. Depends on concentration and electrical gradients
d. Similar to Na/H2O reabsorption
41.Water reabsorption
a. 65% filtered water reabsorbed by AQP-1 (aquaporin)
b. AQP located in apical and basolateral membranes
c. Also travels by paracellular pathways
d. Goes down concentration gradient
42.Reabsorbed water goes from the lumen to the interstitium
43.Chloride reabsorption is via
a. Paracellular absorption or
b. Transcellular absorption
i. In apical membrane
ii. Filtered formate + H+ → formic acid
iii. Formic acid diffuses into cell
iv. Dissociates into formate + H+
v. Formate filtered back out into lumen by Cl-/formate exchanger
vi. Cl transported from basolateral membrane
1. By Cl/HCO3 exchanger
44.Na concentration doesn’t change much as fluid moves through proximal
a. Amount of Na however decreases a lot
b. Concentration of Cl increases because HCO3 is resorbed
c. Cl replaces HCO3 in lumen (to maintain electrical gradient)
45.Proteins can be filtered a bit
a. To resorb
b. Endocytosed by proximal tubule
c. Metabolized into AA
d. Secreted into basolater side to enter circulation
e. Megalin and Cubulin
i. Found on Apical membrane of proximal tubule
ii. Receptors for proteins
46.Vitamin D
a. Filtered Vit D is bound to Vit D binding protein
b. Resorption done by endocytosis by proximal tubular cells
c. Then convereted to 1, 25 OH-D via 1 alpha hydroxylase
d. 1 alpha hydroxylase highly expressed in
i. mitochondria of proximal tubular epithelial cells
Chapter 7: Transport of Electrolyte and Water in Loop of Henle
 Components of Loop of Henle
o Thin descending limb
o Thin ascending limb
o Thick ascending limb
 Medullary segment (mTAL)
 Cortical segment (cTAL)
 Resorption in Loop of Henle
o Causes filtrate to become hypotonic at the end of the loop
o Causes surrounding medullary tissue to become very concentrated
 Necessary so body can concentrate or dilute the urine
 Concentrated in presence of ADH
 Diluted in absence of ADH
o Descending limb
 Permeable to H2O, impermeable to NaCl
 H2O resorbed
 Filtrate becomes hyperosmolar
o Ascending limb
 Permeable to NaCl, impermeable to H20
 NaCl resorbed
 Filtrate becomes hypo-osmolar
 Has Na/K/2Cl cotransporter (NKCC2) on apical membrane
 Electroneutral, resorbs NaCl
 Inhibited by loop diuretics
o Furosemide, bumetanide, torsemide
o Bind Cl- receptor and induce conformational
change –→ inhibited cotransporter
 Other transporters
 Na/K ATPase
o Supplies energy to resorb Na
 ROMK Renal Outer Medullary K Channel
o K that is resorbed by NKCC2 is recycled out via
 CLC-KB Kidney specific Chloride Channel – B
o Cl exits cell on basolateral side
 Need to recycle K into lumen by ROMK
 Without K recycling –→ lumen –↓ K –→ cannot resorb
NaCl via NKCC2
 K recycling –→ positive lumen –→ promotes paracellular
resorption of cations
 Cation transport in Loop of Henle
o Na, K, Ca++, Mg++ resorbed paracellularly
 Passes through tight junction channels
 Claudin-16 AKA Paracellin-1
o Cl- exits the cell vial CLC-KB at the basolateral membrane
o Ascending loop is a diluting segment
 NaCl is reabsorbed w/out water
o NKCC2 cotransporter maintains acid base balance too
 NH4+ can substitute for K in cotransport
o Pt w/hypercalcemia usually present with hypovolemia
 ↑ Plasma Ca –→ activates CaSR (Ca sensing receptor) on the
basolateral membrane of ascending limb
 Activation of CaSR –→ ↓ NKCC2 activity –→ diuresis and
volume depletion
 Bartter Syndrome
o Impaired fxn of NKCC2
o –↓ Na, Mg
o Volume contraction, metabolic alkalosis
o Similar to patients on loop diuretics
 Water transport
o Via Aquaporins (AQP-1) in the descending limb
 Ascending limb lacks AQP –→ Impermeable to water
o Urine osmolality ranges from 50-1200 mOsm
o Interstitial osmolality ranges from 300-1200 mOsm from the
 Cortex to the papillary tip
o During diuresis, corticomedullary gradient decreases
 Due to less retention of urea
o During anti-diuresis (concentration), corticomedullary gradient
o Medullary interstitium becomes hypertonic due to
 Active transport of NaCl w/out water
o Single effect
 NaCl removed from ascending limb
 Deposited in surrounding interstitium
 Leads to steady concentration gradient
 200 mOsm gradient between lumen and interstitium at
each point
o Final concentration of urine
 Dependent on permeability of collecting duct
 Determined by ADH
 Absence of ADH –→ ↓ permeability to H2O –→ Dilute urine
 Presence of ADH –→ ↑ permeability to H2O –→ Concentrated
 NKCC2 in ascending limb and AQP-1 in descending limb dilute urine
o NaCl removed by ascending limb via NKCC2
 Single effect decreases osmolality of tubular fluid
 ↑ osmolality of surrounding interstitium
o Filtrate moves down descending limb
 H2O out via AQP-1
 ↑ osmolality of filtrate
o Peak osmolality is 1200 at hairpin turn
o Filtrate moves up ascending limb
 NKCC2 removes NaCl
 Concentration difference between filtrate and interstitium
only exists in ascending limb
 Due to NKCC2
o Net result
 Fluid leaving loop of henle has a lower osmolarity than fluid
entering loop
 Countercurrent multiplication
o In ascending limb
o Repeated use of single effect
o Allows filtrate to reach maximum osmolality at papillary tip
 Simultaneous dilution of filtrate that exits the loop
 Water Homeostasis
o If drink excess water
 Filtrate exiting ascending limb is 100 mOsm
 NaCl removal in distal nephron lowers osmolality to 50 mOsm
 Assumes absence of ADH
o If need water
 ↑ ADH –→ ↑ AQP in collecting duct –→ ↑ permeability of
collecting duct to water
 Water equilibrates with interstitium –→ ↑ concentration of
o ADH secretion depends on plasma osmolality
 Sensed by osmoreceptors in hypothalamus
 ↑ osmolality –→ ↑ osmoreceptor activity in HT –→ ↑ ADH
release from Post pituitary
o ADH mechanism
 Binds Vasopressin Receptor 2 (V2R –→ GpcR)
 On basolateral membrane of principal cells in collecting
 Stimulates adenylyl cyclase –→ ↑ cAMP
 cAMP –→ ↓ AQP-2 recruitment
 AQP-2 recycled back into cell via endocytosis
o AQP found in
 Proximal tubule, descending limb, and collecting duct
 Absent in ascending limb and distal convoluted tubule
 Diabetes insipidus
o Inability to concentrate urine
o Polyuria
o Central DI –→ defect in ADH release or synthesis
o Nephrogenic DI –→ dysregulation of AQP-2 (by lithium), or mutation
in AQP-2 (AR) or V2R (XLR)
 Urea
o Formed in liver from breakdown of proteins
o In protein deprivation
 ↓ urea formed –→ ↓ urinary concentration capacity –→
dilute urine
o –↑ ADH –→ ↑ Urea resorption in collecting duct
 Collecting duct usually has low permeability to urea
 ↓ urea resorption –→ ↑ luminal urea concentration in
collecting ducts
 ADH recruits UT-A1 (urea transporter A1) into apical side
 Urea –→ goes to interstitium down gradient –→ ↑ interstitial
o Loss of fxn mutation in UT-A1
 ↓ urea concentration in inner medulla
 ↑ osmotic diuresis
 ↓ urine concentration
o Urea recycled back into nephron via UT-A2
 Found in Descending loop of Henle
 Urea handling in nephron
o 50% of filtered urea resorbed by proximal tubule
 Increases in volume depletion –→ ↑ BUN/Creatinine –→
marker for hypovolemia
o Subsequently secreted into descending loop via UT A2
o 50% resorbed in inner medullary collecting duct
o In vasa recta
 UT-B expressed
 Similar to Kidd blood group Ag
 Urea leaves vasa recta –→ into interstitium
 ↑ concentration of inner medulla interstitium
 Pt lacking Kidd blood group Ag –→ ↓ urinary concentration
 Countercurrent exchange
o Countercurrent exchange is the exchange of water and solute
between vasa recta and interstitium
o Vasa recta is permeable to interstitium
o Vasa recta descends into medulla –→ ↑ osmolality
 ↓ osmolality as vasa recta ascends
o Prevents loss of osmoles
o Maintains –↑ osmolality in medulla
 Vasa recta
o –↑ flow rate in ascending vasa recta
 Fluid and electrolytes removed from loop –→ into interstitium
–→ into vasa recta –→ ↑ volume and faster flow in ascending
vasa recta
 Prevents swelling of medulla
 Oxygen gradient between cortex and medulla
o Partial pressure of O2 in cortex is 50-60
 10-20 in medulla
o Renal medullary hypoxia due to
 ↑ O2 consumption by ascending loop
 Countercurrent exchange –→ ↑ O2 diffusion from descending
vasa recta to ascending vasa recta
 ↓ oxygen tension
 ↓ blood supply to renal medulla
o Renal medulla susceptible to ischemic injury
 Acute tubular injury –→ leads to necrosis and apoptosis of
ascending loop
Chapter 8: Transport of Electrolytes and Water in the Distal Tubule
 Distal Tubule
o Segments
 Early Distal convoluted tubule (DCT1)
 Late Distal convoluted tubule (DCT2)
 Connecting segment (CS)
 Cortical Collecting Duct (CCD)
 Outer Medullary Collecting Duct (OMCD)
 Inner Medullary Collecting Duct (IMCD)
o Purpose
 To resorb last little filtrate that reaches it
 Only site that regulates final urinary concentration of
 Na, K, Ca, Mg, H2O, acid
o Has well developed tight junctions –→ No back leak
 Can reach high concentration
 NaCl Cotransporter (NCC)
o Na resorbed in distal tubule by apical NaCl cotransporters (NCC)
o NCC most expressed in early-mid DCT
o NCC inhibited by Thiazide diuretics
 Thiazide diuretics bind NCC at Cl site –→ ↓ NCC fxn
o Na K ATPase on basolateral side gives energy needed by NCC
o Cl exits on basolateral side by CLC-KB
o Regulation
 NCC regulated by WNK Kinase
 No lysine –→ no lysine kinase
 WNK 4 inhibits NCC
 WNK 1 inhibits WNK 4
 WNK 1 indirectly stimulates NCC
 Gitelman syndrome
o Hypokalemia, metabolic alkalosis, salt wasting, hypermagnesuria,
hypomanesemia, hypocalciuria
 Serum –→ ↓ K, Mg ↑ pH
 Urine –→ ↑ Na, Mg, ↓ Ca
o Caused by inactivating mutation of NCC
 Some have inactivating mutation of CLC-KB
 Ion exchange in DCT
o Filtrate –→ ↓ osmolality as it passes through DCT
 Osmolality reaches 50 mOsm
o DCT reabsorbs NaCl
 Impermeable to water –→ ↓ osmolality
o Mg in DCT
 Most Mg filtered passively in proximal tubule and Loop of
 Early DCT regulates final urinary concentration of Mg
 Mg resorbed in early DCT by TRPM6 (Transient Receptor
Potential channel Melastatin 6)
 Apical side
 Loss of fxn in TRPM6 –→ ↓ Mg, ↑ Mg wasting
o Ca in DCT
 90% of Ca resorbed in proximal tubule and loop of Henle
 Ca resorbed via TRPV5 (Transient Receptor Potential Vanilloid
 Apical side
 Ca channel only in DCT
 Binds intracellular Calbindin D28K
o Calbindin –→ moves Ca to basolateral side
 Ca moves into blood via
o NCX1 Na/Ca antiporter
o PMCA1b Ca ATPase transporter
 PTH and 1,25 OH D –→
 ↑ Calbindin D28K, NCX1, PMCA1b –→
 ↑ Ca resorption
 Collecting ducts
o In cortical, outer medullary, and initial inner medullary collecting
ducts, you find
 Intercalated cells
 Principal cells –→
 H2O Resorption
 K secretion via ROMK channels
 Na reabsorption via ENaC channels
o ENaC is blocked by Amiloride and Triamterene
o AKA Potassium sparing diuretics
o Nedd4-2 ligase tags ENac with ubiquitin –→
internalization and termination
o Rest inner medullary collecting duct has
 Inner medullary collecting duct cells (IMCD)
Liddle Syndrome AKA Pseudoaldosteronism
o AD
o Mutation in ENaC
 Mutation in Beta or gamma subunits –→
 ENaC becomes resistant to Nedd4-2 –→
 Remains active –→ ↑ Na resorption
o Na retention –→ severe HTN
o Suppression of plasma renin and aldosterone
o –↓ K and metabolic alkalosis
Negative potential in cortical collecting duct due to
o Na reabsorption
o Helps secretion of K+, H+
o Helps resorption of ClAldosterone
o Fxn
 ↑ activity/synthesis of Na K ATPase –→
 ↓ intracellular Na, ↑ K
 ↑ open ENaC –→ ↑ Na reabsorption
 ↑ open ROMK –→ ↑ K secretion
o Effect of hyperkalemia on aldosterone
 ↑ K –→ ↑ aldosterone secretion –→ ↑ K excretion
Intercalated cells
o Carbonic Anhydrase II expressed by all intercalated cells
Type A Intercalated cells
o Acid excretion, K resorption
o Apical side
 H ATPase –→ H secretion
 H K ATPase –→ K resorption, acid balance
o Basolateral side
 Anion exchanger 1 (AE1) –→ chloride, bicarb exchanger
o CAII forms carbonic acid
 Dissociates into H+ and HCO3 H+ → excreted by apical H ATPase
 HCO3- → exchanged for Cl at basolateral side
o Net result
 H+ secreted into urine –→ acidifying urine
 Bicarb added to circulation –→ alkalizing blood
o Loss of fxn in in any H ATPase would cause
 Distal renal tubular acidosis (dRTA)
 Due to inability to acidify the urine
 Type B Intercalated cells
o Bicarb excretion
o On apical side
 Pendrin –→ Cl bicarb exchanger
o On basolateral side
 H ATPase
o CA II forms carbonic acid
 Bicarb exchanged on apical side for Cl –→ alkalinizes urine
 H+ absorbed into blood –→ acidifies blood
o Important during metabolic alkalosis
 Inner Medullary Collecting Duct (IMCD)
 Binds basolateral receptors –→
 GTP –→ ↑ cGMP
 cGMP –→ ↓ amiloride sensitive Na channel –→
 (different from ENaC)
 Leads to natriuresis
 Found proximally in principle cells of collecting duct
o Aldosterone
 ↑ amiloride sensitive Na channel (different from ENaC)
 ↑ Na K ATPase on basolateral side
 Both lead to –↑ Na reabsorption
 Urinary Ca excretion
o Effects of Diuretics on Ca excretion
 Loop diuretics –→ ↑ Ca excretion
 Used to treat hypercalcemia
 Thiazide diuretics –→ ↓ Ca excretion
 Used to treat Ca nephrolithiasis (kidney stones)
 Lowers urinary Ca levels
o Effect of Bartter syndrome on Ca excretion
 Inhibited NKCC2 –→ like loop diuretics
 ↑ Ca excretion
 Hypercalciuria in Bartter can help differentiate it from
o Effect of Gitelman syndrome on Ca excretion
 Inhibition of NCC –→ like thiazide diuretics
 ↓ Ca excretion
 Hypocalciuria in Gitelman can help differentiate it from Bartter
Chapter 9: Renal Endocrinology
o CaSR measures extracellular Ca
o –↓ Ca –→ ↑ PTH secretion
o PTH binds PTH 1r
 ↓ NPT –→ ↓ PO4 resorption –→ ↑ PO4 excretion
 ↑ 1a OH-ase –→ ↑ 1,25 OH D
o PTH in DT
 ↑ TRPV5 –→ ↑ Ca resorption
o Synthesized in PVN and SON of HT
 Migrates down supraoptic-hypophyseal tract
 Released by PP
o Binds V1R in vascular smooth muscle
 ↑ resistance
o Binds V2R on basolateral side of CD
 ↑ cAMP –→ ↑ AQP-2 recruitment –→ ↑ water permeability
o ADH in IMCD (internal medullary collecting duct
 ADH –→ ↑ urea permeability in IMCD
o Stimuli for ADH release
 Plasma osmolality –→ measured by osmoreceptors
 Osmoreceptors found in brain –→ HT –→ lamina
 Osmoreceptors measure Na (determines osmolality)
 During mild hypovolemia
o ↑ osmolality more effect on ADH release than
 Intravascular volume –→ by volume receptors
 During severe hypovolemia (15% change)
o –↓ volume more effect on ADH release than –↑
o Hyperosmolality –→ ↑ thirst –→ ↑ water intake
o Stimulate ADH release
 ↑ osmolality, ↓ volume
 Nausea, Pain
 Pregnancy
 ↓ glucose
 Pneumonia, HIV
 Early brain injury
o Inhibit ADH release
 ↓ osmolality, ↑ volume
 Ethanol, opiates
 Late brain injury
 Norepi, Tolvaptan
o ADH in hyponatremia
 Would expect hyponatremia to decrease ADH
 Other factors –→ ↑ ADH, despite –↓ Na –→ ↓ ADH
 ↑ ADH maintains –↓ Na in hyponatremia
 Aldosterone
o Acts at Distal nephron
 Connecting segment and cortical collecting duct
o Aldosterone –→ ↑ Na reabsorption, ↓ K reabsorption
 Enters principal cells –→ cytosolic aldosterone Receptors
 Goes to nucleus –→ gene expression –→
 ↑ Na and –↑ K channels in apical membrane
 ↑ Na/K ATPase activity
o Aldosterone stimuli
 ↑ K –→ directly affects zona glomerulosa of adrenal
 ↑ AT II
o Aldosterone escape
 ↑ aldosterone –→ ↓ Na excretion –→ ↑ Na –→ ↑ water
retention, weight –→ ↑ BP
 ↑ BP –→ ↑ ANP, ↑ GFR
 ↑ ANP, GFR –→ ↓ Na retention –→ stops further weight gain
and increase in BP
 Aldosterone –→ ↑ volume –→ ↑ ANP release
 Aldosterone –→ ↑ BP –→ ↑ GFR –→ ↑ Na excretion
o –↑ ECV –→ ↑ Atrial stretch –→ ↑ ANP release
o ANP –→
 Direct vasodilation –→ ↓ BP
 ↑Na excretion
 ANP binds guanylate cyclase-A in IMCD (basolateral)
 ANP –→ GC-A –→ ↑ cGMP –→ blocks amiloride
sensitive Na channels (ASNaC) –→ ↑ diuresis
 Vit D
o From UV light –→ skin –→ non-enzymatic synthesis (90%)
 10% diet
o Transported in blood
 Bound to Vit D Binding Protein (DBP)
o Metabolism of vit D
 D3 –→ liver –→ 25-OH-ase –→ 25 OH D
 25 OH D bound to DBP –→ filtered at glomerulus –→
 resorbed in PT via endocytosis (megalin, cubulin) –→
 1a OH ase in cells –→ 1,25 OH D
Stimulates Vit D
 ↓ Ca, ↓ PO4, ↑ PTH
Inhibits Vit D
 ↑ Ca, ↑ PO4, ↓ PTH, ↑ Vit D
Can find –↑ extra renal production of Vit D
 In cancer and granulomatous dz (TB, sarcoidosis)
 M0 have 1a OH ase
 Pt presents w/↑ Ca
 Local regions,
 lots of cells express Vit D production for cell growth
Effects of Vit D
 Gut –→ ↑ Ca, ↑ PO4 resorption
 Bone –→ ↑ osteoclast activity
 DCT –→ ↑ TRPV5 activity –→ ↑ Ca resorption
o Produced by peritubular fibroblasts
o Stimulated by –↓ oxygen tension
o EPO acts on CFU-E cell
 EPO –→ binds EPO-R –→ ↑ JAK1 –→ ↑ STAT –→ goes to
 ↑ transcription –→ ↓ apoptosis
 Renin
o Produced by JG cells of afferent arteriole
o Acts on Angiotensinogen
 Angiotensinogen made in liver
 Renin –→ cleaves angiotensinogen –→ AT I
o Stimulate renin release
 ↑K
 ↑ Sympathetic NS
 ↓ renal perfusion pressure
o Inhibit renin release
 ↑ AT II
 ↑ renal perfusion pressure
 Angiotensin II
o ATI –→ AT II
 Conversion in heart and blood vessels done by chymase, not
o Effects of AT II (binding AT-R1)
 ↑ vasoconstriction
 ↑ EFFERENT ARTERIOLE vasoconstriction
 ↑ aldosterone release from adrenals
 ↑ thirst
 ↑ Na resorption in PT and distal nephron
o ACE-2
 Converts AT 1 –→ AT 1.7
 AT 1.7 –→ binds Mas –→
 ↑ vasodilation
 ↓ cell growth
o AT II can also bind AT-R2 (opposite effect)
 AT II –→ AT-R2
 ↑ apoptosis
 ↓ cell growth
 ↑ vasodilation
 Prostaglandins/NSAIDs
o PGE2, PGI2
 ↑ AFFERENT ARTERIOLE vasodilation
o NSAIDs –→ ↓ PGE2, PGI2
 ↓ RBF –→ ↓ AFFERENT ARTERIOLE vasodilation
 ↓ GFR
 Blunt effects of antihypertensives
 Because they –↑ Na resorption
o NSAIDs effect
 NSAIDs –→ ↓ COX 1, 2 –→ ↓ arachidonic acid cleavage
 Hormones degraded in kidneys
o Degraded at PT
o Degraded by receptor-mediated endocytosis
o –↓ kidney fxn –→ ↓ hormone clearance –→ ↑ hormone
Chapter 10: Water Disorders
 Hyper/hyponatremia –→ due to problems in water balance
o Hyper/hypovolemia –→ due to problem in sodium balance
o CHF pt
 Hypervolemic and hyponatremic
 Changes in plasma osmolality
o Determined by ADH
o Major solute is Na, Cl, HCO3
o –↑ Na resorption normally doesn’t cause hypernaturemia
 Transient –↑ Na –→ ↑ ADH/thirst
 ↑ resorption Na –→ volume expansion
o ↑ aldosterone
 –→ ↑ ENaC –→ ↑ Na resorption
 Causes –↑ water –→ HTN
o Hyponatremia
 Common in elderly
 ↓ Na –→ ↑ Intracranial pressure –→
 Need plasma osmolality to differentiate between
 Hypertonic hyponatremia
o Most common cause is hyperglycemia (DM)
o –↑ glucose –→ ↑ plasma osmolality –→ ↑ water
rushing into plasma –→ dilutional hyponatremia
o Overal osmolality is increased
 Pseudohyponatreumia
o Caused by –↑ lipids
o Normally, ↓ lipids
o If –↑ lipids –→ Na measured over volume of
plasma + lipid –→ ↓ Na reading (false)
 Cell size in hypertonic hyponatremia –→ Cells shrink
 Cell size in hypotonic hyponatremia –→ cells swell
 Hyponatremia
o Common in elderly
o Due to water intake > water excretion
o ↓ Na –→ ↑ Intracranial pressure –→
 N/V
 Behavior changes
 ↓ consciousness –→ coma
 Seizures
o Adaptations to minimize swelling
 Acute –→ salt water excretion from cells
 Chronic –→ organic compound excretion from cells –→ nl ICP
 Rate of –↓ Na causes sx more than absolute –↓ Na
o If correct Na too quickly –→ osmotic demyelination syndrome
 Brain cells shrink
o Due combination of
 ↑ water intake
 Unregulated –↑ ADH release
o Can tx w/ water restriction
o Occurs in elderly and alcoholic
 Eat little –→ ↓ solute intake –→ ↓ solute excretion –→ ↓
water excretion –→ ↑ water retention –→ ↑ dilutional
o In CHF, volume depletion
 ↑ proximal uptake of water
 Renal excretion of water
o Glomerular filtration
o PT resorption of water and solute –→ same osmolality
o Descending LH –→ water resorption –→ ↑ osmolality
o Ascending LH –→ NKCC2 solute resorption –→ ↓ osmolality below
o In CD
 ↑ ADH –→ ↑ water resorption –→ ↑ osmolality
 ↓ ADH –→ ↓ water resorption –→ ↓ osmolality
 TBW is all fluid componints
o ECV is only what is used ot perfuse vital organs
 Hyponatremia –→ etiology associated w/ ↓ ECV and nl ECV
o –↓ Na and ↓ ECV
 ↓ Na, ↓ ECV, ↑ TBW
 CHF, nephrotic syndrome, Cirrhosis
 ↓ ECV –→
o –↑ RAAS
o –↑ Sympathetic outflow
o –↑ ADH –→ ↑ water retention
 ↓ ECV –→ contraction effects –→
o –↑ PT/DT resorption of Na –→ ↓ Na available to
excrete water
o –↓ volume, ↑ osmolality, ↓ Na urine excreted
 ↓ Urine Na –→ marker for volume contraction
 Tx –→ tx underlying disorder
o Water restriction, Na restriction
o Difficult since CHF pt –→↓ ECV –→ ↑ AT II
 ATII –→ ↑ thirst
 ↓ Na, ↓ ECV, ↓ TBW
 Tx –→ volume correction w/ NS –→ ↓ stimulus for ADH
 ↓ ADH –→ ↑ water excretion –→ Na returns to normal
o –↓ Na and nl ECV
 ↑ ADH –→ ↑ Na excretion –→ ↑ urine Na concentration
 Causes
 TB, HIV, pneumonia, ARDS, fungal
 Drugs –→ psychoactive, carbamazepine,
 CNS trauma, infxn, tumor, Multiple sclerosis, stroke
 Ectopic ADH
o Carcinoma lung, pancreas, thyroid, lymphoma
 Drugs that potentiate ADH
o Chlorpromide, NSAIDs, antidepressants
 Tx for SIADH
 Fluid restriction
 NaCl tablets –→ ↑ solute –→ ↑ water excretion
 Declocycline
o Tetracycline –→ S/E is photosensitivity
o Antagonizes ADH
 ADH antagonists
o Conivaptan, tolvaptan (also can use for CHF and
o Compete for ADH to bind at V2R
o When working up hyponatremia, you want
 Serum and urine osmolality
 Serum Na
 Volume status (BP, edema, turgor)
o Differentiate pseudohyponatremia from hyponatremia
 Measure serum osmolality true –→ nl
 Calculated osmolality –→ low
o Causes of hyponatremia by pt labs
 ↓ Na, ↓ volume, ↓ serum osmolality, ↓ urine Na
 Volume contraction
 ↓ Na, ↓ volume, ↓ serum osmolality, ↑ urine Na
 Diuretic use
 ↓ Na, ↑ volume, ↓ serum osmolality, ↓ urine Na
 CHF, nephrotic syndrome, cirrhosis
 ↓ Na, nl volume, ↓ serum osmolality, ↑ urine Na, ↑ urine
 SIADH, Adrenal insufficiency, Hypothyroidism
 ↓ Na, nl volume, ↓ serum osmolality, ↓ urine osmolality
 Psychogenic polydipsia, ↓ solute intake
Urine Na
Diuretic use
nephrotic sd,
low solute
o Psychogenic polydipsia
 Young women on psych meds
 Thirst from anticholinergic drugs
 ↓ maximal dilution
o Adrenal insufficiency and hypothyroid
 Tx underlying problem –→ hypothyroid cured
 Diuretics
o Thiazide diuretics –→ ↓ Na
 Both thiazide and loop → volume contraction and –↑ ADH
 → ↑ AQP recruitment –→ water reuptake
 Thiazides –→ in early distal tubule
 ↓ urine dilution
 ↑ ADH –→ ↓↓ urine dilution
o Loop diuretics –→ volume contraction and –↑ ADH –→ ↑ AQP –→
↑ water reuptake
 Loop diuretics –→ ↓ NKCC in ascending limb
 ↓ interstitial osmolarity –→ ↓ water resorption in descending
 Reset osmostat
o –↓ threshold of osmolality for ADH release –→ ↑ ADH at normal
serum osmolality
o Keeps –↓ osmolality as nl –→ ↓ Na as nl
o May have –↓ urine osmolality
o If tx w/ fluid restriction
 ↑ ADH –→ ↑ water resorption –→
 ↓ serum Na, ↑ urine osmolality
 Vs psychogenic polydipsia
 Fluid restriction –→ ↓ urine osmolality
 Acute hyponatremia
o Tx w/ 3% saline,
o Loop diuretics –→ ↑ volume excretion
 Acutely –→ ↑ volume excretion, compensates for volume
overload by 3% saline
 Chronically –→ ↓ volume –→ ↑ thirst, ↑ ADH
 Osmotic demyelination syndrome
o From rapid correction of hyponatremia
o Presents w/
 Quadriplegia
 Cant speak/chew/swallow
 Weakness in face muscles –→ expressionless
 ↑ gag reflex
 Laughing and crying
o Tx –→ ↓ Na w/ D5W
o Risk groups
 Alcoholics
 Liver transplant, malnutrition, AIDS
o Prevent by correcting hyponatremia
 Asymptomatic –→ water restriction
 Symptomatic –→ ↑ Na by 5-7 max
 Don’t –↑ Na by more than 10
 Hypernatremia
o Due to imbalance in water homeostasis
o Needed:
 ↓ thirst (CNS disease, stroke, altered)
 ↓ accessibility to water (dementia, child, mental impairment)
o Hypernatremia secondary to impaired thirst
 ↑ ADH –→ ↑ urine osmolality (>800)
o If hypernatremia and –↓ urine osmolality
 Consider defective ADH
 Uncommon unless DI + impaired thirst or no access to water
o If hypernatremia and urine osmolality = 300
 Osmotic diuresis
 Hyperglycemia, mannitol
o If hypernatremia and urine osmolality 150-800
 DI
 Impaired countercurrent multiplication
 Tubule damage/aging kidney
 Diabetes Insipidus
o Central DI –→ ↓ ADH
 If ADH stim test –→ ↑ urine osmolality
o Nephrogenic DI –→ ↓ response to ADH
 If ADH stim test –→ no change in urine osmolality
o Uncommon to have DI w/hypernatremia
 ↑ Na –→ ↑ thirst –→ ↑ water intake
o DI presentation
 Polyuria, polydipsia
 NOT hypernatremia
o Causes of Central DI
 CNS trauma, infection, encephalopathy,
 Sarcoidosis, meningitis
o Causes of nephrogenic DI
 Lithium –→ interferes with AQP2 expression in CD
 Demeoclocycline –→ use to tx SIADH
 HIV meds
 ↑ Ca, CKD, TIN
 Pregnancy
 Polyuria
o Polyuria, ↓ urine osmolality
 Complete DI, psychogenic polydipsia
o Polyuria, ↑ urine osmolality, 2*(Na+K) < urine osmolality
 Osmotic diuresis from –↑ glucose, urea, or mannitol
o Polyuria, ↑ urine osmolality, 2*(Na+K) = urine osmolality
 Sodium diuresis
 Diuretic use, renal salt wasting, CNS salt wasting, ↑ Na intake
Water deficit = TBW*(serum Na/140 -1)
Tx of Central DI
Tx of nephrogenic DI
 mild volume depletion –→ ↑ water reabsorption in PT –→ ↓
water excretion in DT
 HCTZ –→ ↑ AQP2 in CD
Tx of hypernatremia
o Volume correction w/NS
o D5W to correct hypernatremia up to 12/day
o Replace losses of water and Na
002 – IV Fluid Administration
 Difference between Isosmotic and Isotonic
o Effective solute –→ NaCl
 Isosmotic Isotonic –→ no cell change
 Hyperosmotic Hypertonic –→ cells dehydrate
o Ineffective solute –→ Urea
 Isosmotic Hypotonic –→ cell swells
 Hyperosmotic Hypotonic –→ cell swells
o In Males, intravascular fluid is 5% weight,
o In females 4.167%
 Fluids
o Crystalloids
 Nl saline
 D5W
 Lactated Ringers
o Colloids
 Albumin
 Starches
 Dextrans
 Use hypertonic solution in
o Trauma where –↓ intracranial pressure
o Burns
o Symptomatic hyponatremia
 Sodium vs water
o –↓ Na –→ ↓ ECV
 Hypotension –→ Tx is saline
o –↑ Na –→ ↑ ECV
 CHF, Pulm edema, cirrhosis –→ Tx is diuretics
o –↓ water –→ ↓ TBW
 Hypernatremia –→ tx is water
o –↑ water –→ ↑ TBW
 Hyponatremia –→ tx is fluid restriction, 3% NaCl
003 – Glomerular Hemodynamics
 Renal processes
o Glomerulus –→ ↑ pressure –→ filtration
o Peritubular capillaries –→ ↓ pressure –→ reabsorption
 Filtered load = GFR*[P]
 Filtration coefficient
o –↑ K
 Relaxation of mesangial cells –→ ↑ glomerular surface area
 ↑ GFR
o –↓ K
 T2DM, HTN –→ thickening of basement membrane –→ ↓ fxnl
 ↓ GFR
 Efferent arteriole constriction
o As –↑ efferent resistance
 Initially –→ ↑ GFR as expect
o When –↑↑↑ efferent resistance
 ↑ pooling of proteins in glomerular capillaries –→ ↑ oncotic
pressure in blood vessels –→ ↓ GFR, FF
 Urine outflow obstruction/ureteral stone
o –↑ hydrostatic pressure in bowman’s capsule
o –↓ GFR,FF
 Regulation of RBF
o By SNS and humoral agents
o Myogenic Autoregulation local reflex
 ↑ blood perfusion –→ ↑ arterial wall stretch
 Opening stretch sensitive CaSR
o On smooth muscle of afferent arteriole
 ↑ contraction of SM –→ ↑ resistance –→ ↓ blood flow
 ↓ arterial wall stretch
 ↓ stretch sensitive CaSR –→ hyperpolarized SM cells
 ↓ contraction of SM –→ ↓ resistance –→ ↑ blood flow
o Tubuloglomerular feedback
 ↑ RBF –→ ↑ GFR
 ↑ NaCl delivery to Juxtaglomerular apparatus
 Sensed by macula densa –→ ↑ adenosine release
 Adenosine –→ ↑ vasoconstriction –→ ↑ resistance of
afferent arteriole
 ↓ RBF –→ ↓ GFR
 ↓ arterial resistance –→ ↓ glomerular pressure –→ ↓ GFR
 ↓ Macula densa NaCl
 ↓ Afferent arteriolar resistance –→ ↑ GFR
 ↑ renin –→ ↑ AT II –→ ↑ Efferent arteriolar resistance
–→ ↑ GFR
 Extrinsic regulation
o Vasoconstrictors
 Sympathetic nerves
 Endothelin
o Vasodilators
 PGE2, PGI2
 Bradykinin
 Dopamine
 Proximal tubule
o Na cotransported w/ Glucose, AAs, PO4
 Glucose
 SGLT2 in early PT –→ high capacity, low affinity
o Bulk resorption
 SGLT1 in mid-late PT –→ low capacity, high affinity
o Reclaims remaining glucose
 Glucose exits basolateral side via GLUT-2
 AA exits basolateral side via LAT/TAT
 PO4
 NPT2a in PT –→ Na/PO4 cotransporter
o PTH –→ binds PTH1R on basolateral side –→ ↓
 Mutation in NPT2c –→ rickets
o Acid-base
 NHE3 –→ Na/H antiporter
 Imp in anion exchange
 A- (formate) combine w/H+ from NHE3 in lumen
 HA –→ into cells –→ dissociates into A- and H+
 A- → leaves cell into lumen, exchange for Cl- in
 Cl absorbed
 CA IV –→ HCO3 –→ CO2 in lumen
 CA II –→ CO2 –→ HCO3 in cell
 NBC –→ HCO3 absorption into blood
Ca, Mg, H2O
 Mid PT
 Paracellular
Paracellular Cl transport via claudins
 Endocytosed by megalin and cubulin
Vit D
 Endocytosed by cells –→ converted to 1, 25 OH D by 1a OH-ase
Organic cations
 Enter cell via OCT on basolateral side
 OC+/H+ antiporter on apical size –→ OC+ secretion into urine
004 – Embryology, Histology, and Anatomy
 Intermediate mesoderm
o Prosnephros
o Mesonephros
 Gives rise to glomeruli
 Tubules and ducts
o Metanephros
 Definitive kidney
 Ureteric bud
 Metanephric blastema
 Kidney rotates –→ becomes retroperitoneal
 Anomalies
o Horseshoe kidney –→ IMA, turner
o Early bifurcation of ureteric bud –→ 2 ureters, 2 kidneys
 Urachus
o Remnant of allantois
o Supposed to obliterate
o Sometimes urachus remains patent –→ get pooling of urine in
 Nephrolithiasis
o Blocks calyx –→ leads to hydronephrosis
 Renal corpuscle
o Capsule is simple squamous
o Tubule is cuboidal
005 – Urine concentration, distal nephron, effect of hormones
006 – Pathology of Kidney and Urinary Tract
 Nephritic syndrome
o Mild proteinuria
o Gross hematuria –→ coca cola urine
o Azotemia, oliguria
o Mild edema
o Acute onset, rapid progressive, or chronic
o Inflammation
o Acute PSGN, Crescentic GN
 Nephrotic syndrome
o Severe proteinuria
o –↓ albumin
o –↑ lipids
o Oval fat bodies
o Severe edema
o Insidious
o MCD, FSGS, MPGN, amyloidosis
 Nephritic syndrome
 Nephritic pathology
o Glomerular cellular proliferation
 Glomerular capillary obstruction –→ ↓ blood flow –→
 Tubular epithelial damage
o –↑ fluid retention –→ edema
o RBC casts in urine
 ↓ filtration→
o –↑ fluid retention –→ edema
o Olivuria –→ ↑ blood urea –→ ↑ BUN
 Stimulation of JG apparatus –→ ↑ renin –→
o ↑ BP
o Glomerular endothelial inflammation –→ damage
 Focal –↑ permeability –→
 Proteinuria –→
o Edema
o Protein casts in urine
 ↑ escape of RBCs –→
 Hematuria –→ RBC casts in urine
 Acute Post-Streptococcal Post infectious Glomerulonephritis PSGN
o PSGN –→ camel hump
o From nephritogenic strep (pyo)
 M protein (type 12, 4, 1
 1-4 weeks after infection
o Or endogenous Ag
o Children –→ recover
 Adults –→ don’t recover well –→ get ESRD
o Clinical
 Abrupt onset
 Periorbital edema, coca cola urine, oliguria, fever, nausea
 Mild proteinuria
o Immune mediated
 ↑ titers of anti-streptolysin O Ab
 –↓ levels C3 due to overactivation and consumption
o On histo
 Diffusely enlarged hypercellular glomeruli
 Proliferation of endothelial and mesangial cells
 Neutrophilic infiltrate
 ↓ capillary lumen size –→ ↓ blood flow
o On EM
 Circulating immune complexes
 Discrete subepithelial deposits –→ camel humps
o IF
 Granular
 IgG and C3 complement
 Crescentic Rapidly Progressive Glomerulonephritis
o RPGN is a clinical syndrome, several etiologies
o Nephritic –→ severe oliguria
o Rapid loss of renal fxn –→ death in months
o Kidneys grossly
 Enlarged, pale,
 Petechial hemorrhages on cortical surfaces
o On histo
 Crescent formation
 GBM ruptures –→
 Fibrinogen and cytokines leak –→ parietal cells
proliferate –→ fibrin deposits –→ crescent formation
 Glomerular sclerosis and necrosis
 Proliferation of endothelial and mesangial cells
o Immunologic classification
 Type 1 –→ Anti-GBM Ab
 Etiologies
o Intrinsic (renal)
o Goodpasture syndrome (renal +pulmonary)
 Ab against a3 chain of type 4 collagen in GBM
 Goodpasture
o Cross reaction w/pulmonary alveolar basement
o Alveolar hemorrhage + renal failure
o HLA DRB1 +
 IF –→ Diffuse linear, IgG and C3
 Tx w/ plasmapheresis, immunosuppression
 Type 2 –→ Immune complex deposition
 Etiologies
o Lupus nephritis
o IgA nephropathy
o Henoch Schonlein purpura
 Segmental glomerular tuft proliferation
 Leukocyte infiltration
 Crescent formation
 EM –→ discrete immune complex deposits
 IF –→ Granular lumpy bumpy deposits
 Type 3 –→ pauci/no-immune
 Etiologies
o cANCA Wegners granulomatosis
o pANCA microscopic polyangiitis
o Churg strauss
 No immune deposits
 ANCA positive
 Older people w/ crescentic RPGN
 More frequent than Goodpasture
 Tx is immnuosuppressives,
 Nephrotic syndrome
 Nephrotic pathophysiology
o Impaired capillary walls, filtration barrier
 Massive proteinuria
o –↑ renal catabolism of albumin
 ↑ proteinuria > hepatic synthesis
 ↓ albumin
o –↓ colloid osmotic pressure –→ ↑ fluid in interstitium
 ↓ volume –→ ↓ renal blood flow –→ ↑ RAAS –→
 ↑ Na water retention –→ edema
o –↑ lipoprotein synthesis in liver –→ abnormal transport, ↓ lipid
 ↑ lipids in urine –→ oval fat bodies
 Oval fat bodies = lipoprotein resorbed by tubular
epithelial cells and shed w/ cells in urine
o Hyperlipidemia and lipiduria
 Minimal change disease
o Nephrotic syndrome in children
o Females
o Insidious
o Selective albumin proteinuria
o Good prognosis on steroids
o Path
 Immune T cell dysfxn → ↑ cytokines –→ podocyte damage –→
 effacement of foot processes –→ proteinuria
o histo
 shows no difference
 may show lipid oval fat bodies
o EM
 Uniform diffuse effacement of foot processes
 Retraction, flattening and swelling
 Not fusion
 Vacuolization of foot proesses
o IF
 Negative
 No immune complex involvement
 Focal Segmental Glomerulosclerosis
o Adults w/nephrotic
o Hispanic and African
o Podocyte mediated injury
 ↑ hematuria, ↓ GFR, ↑ HTN
o Non-selective proteinuria
o Etiology
 Primary
 Podocyte damage –→ lymphocyte mediated
 Secondary FSGS
 Malignancy, Hodgkin disease, lymphoma
 IV drugs, heroin, HIV
 Sickle cell dz
 Secondary to scarring from oter GN –→ IgA nephropathy
 Inappropriate response to renal tissue loss
 Inherited/genetic FSGS
 Mutation in slit diaphragm proteins
o Nephrin –→ NPHS1
o Podocn –→ NPHS2
o A actin 4, TRPC6, APOL1
 Focal and segmental glomerulosclerosis
 ↑ mesangial matrix
 Glassy nodular hyaline masses –→ hyalinosis
 Fiam cells, lipid droplets
 Collapsed capillary loops
 Segments of normal glomeruli
 Diffuse effacement of foot processes
 In sclerotic and non sclerotic ares
 Focal detachment of epithelial cells
 Denudation of GBM
 Non-specific deposits of IgM and C3 in sclerotic areas only
 Areas w/out sclerosis –→ negative in IF
Poor response to steroids –→ renal failure
Renal transplant doesn’t help
–↑ hematuria and HTN
HIV associated FSGS
 Collapsing variant of FSGS
 Blacks
 Collapsed glomerular capillaries on histo
 Swelling and hyperplasia of podocytes
 Tubuloreticular inclusions on EM
 Modified Endoplasmic reticulum by IFN-a
 Also seen in SLE
 Membranous Nephropathy
o Whites, Asians
o Chronic immune complex glomerulonephritis
o Eitiology
 Idiopathic
 Autoimmune linked to HLA DQA1
 Ab against podocyte Ag
o M type PLA2-R
o In-situ immune complex formation
 Secondary to systemic dz
 Hep B, C, SLE, Sickle cell anemia
 Drugs, malignancy, lymphoma,
o Clinical
 Full blown nephrotic syndrome –→ non selective proteinuria
 Slow progressive course
 Does not respond to steroids
o Complement activation
 Mesangial cell damage –→ capillary wall injury –→ proteinuria
o Histo
 Diffuse membranous capillary wall thickening
o EM
 Spikes and domes
 Spikes –→ thick GBM
 Domes –→ subepithelial immune deposits
 Effacement of podocyte foot processes
o IF
 Diffuse granular
 IgG and C3
 Make up black spikes
 Membranoproliferative Glomerulonephritis
o Young adults
o Unremitting progressive course
o Split train tracts
o Type 1
 Circulating immune complex formation
 Secondary
 Due to SLE
 Discrete sub-endothelial deposits
 IF –→ granular IgG and C3
 Subendothelial
 mesangium
o Type 2 –→ dense deposit disease –→ C3 glomerulonephritis
 Rare
 Worse prognosis
 Circulating IgG against C3 nephritic factor (C3NeF)
 Excessive activation of alternative complement pathway
 ↓ complement due to overconsumption
 Intramembranous
 Ribbon like deposits –→ C3
 IF –→ C3 staining
 Ribbon like capillary wall
 Coarse granular mesangium
o Histo
 Mesangium and capillary proliferation
 Enlarged hypersegmented glomeruli
 Leukocyte infiltration
 GBM thickening, splitting, duplication
 Tram track and double contours
 IgA Nephropathy
o IgA deposits
o Variant of Henoch Schonlein purpura
o Young men 20-30
o Recurrent gross hematuria every few months
o Sx appears 1-2 days after a resp, GI, or urinary tract infxn
o Risk of progression in
 ↑ age, heavy proteinuria, htn, glomerulosclerosis
o Primary
 Food proteins
 Celiac disease, gluten enteropathy
 Resp or GI agents
o Secondary
 Liver disease
 Defective hepatobiliary clearance of IgA
o Pathogenesis
 Abnormality in IgA production and clearance
 Abnormal glycosylation of hinge region of IgA –→ galactose
deficient IgA1 polymers –→ ↓ IgA plasma clearance
 Deposition of nephritogenic IgA in mesangium
 Glomerular injury
 Mesangial proliferation
 Normally
 IgA monomers present in mucosal secretions
 ↑ IgA –→ IgA1 immune complex formation –→
 –↓ clearance of nephritogenic IgA1 in glomerulus –→
 ↑ C3 complement pathway activation –→ deposition of
IgA1 immune complexes and C1 in mesangium
o On histo
 Mesangial expansion –→ immune complex deposits
o On EM
 Mesangial IgA dense deposits
o On IF
 Granular dense deposits in mesangium
o IgA, C3 deposits
 Hereditary nephritis –→ alport syndrome
o Men
o Children
o Hematuria
o Defect in a3 chain of type 4 collagen in GBM
o Hearing loss, eye defects, nephritic syndrome
 Mutation in COL 4A5 –→ a5 change of type 4 collagen
 Males express full syndrome
 Female carriers express some sx
o On histo
 Interstitial and tubular foam cells
 Failure of GBM to stain a3, a4, a5 collagen
o Early diagnosis only by EM
 Diffuse thinning of GBM
 Basket weave/moth eaten appearance
 Hereditary nephritis→ Thin basement membrane disease
o Benign familial hematuria
o Mutations in COL 4A3, COL 4A4
 A3 or a4 chains of type 4 collagen
o Autosomal
o Asymptomatic hematuria
o No hearing loss or ocular abnormalities
o On EM
 Diffuse thinning of GBM
 Lupus nephritis
Kidney Hormones:
o –↓ Ca –→ activates CaSR –→ GpcR on parathyroid –→ PTH release
o PTH –→ proximal tubule
 Binds PTH 1R –→ ↓ NPT
 ↓ PO4 resorption
 ↑ 1a OH-ase –→ ↑ 1,25 OH D
o PTH –→ distal tubule
 ↑ TRPV5
 ↑ Ca resorption
o Stimulated by –↑ plasma osmolality/↓↓↓ volume
o Made in PVN and SON of HT
o Secreted through PP
o ADH –→ collecting duct
 –↑ AQP-2 (apical)
 ↑ urea permeability
o Stimulators of ADH release
 Nausea/pain
 Pregnancy
 Hypoglycemia
 Pneumonia
o Inhibitors of ADH release
 Alcohol/opiates
 Norepi
 Tolvaptan
 Aldosterone
o Acts at connecting segment and cortical CD
o Stimulated by AT II and –↑ K
o Aldosterone escape
 Diuresis due to –↑ ANP and BP
o From atrial cells
o –↑ volume –→ ↑ stretch –→ ↑ ANP
o –↑ ANP –→ ↑ vasodilation
 → ↑ urinary Na excretion
 1,25 OH D
o D3 –→ liver –→ 25 OH D –→ kidney (1a OH ase) –→ 1,25 OH D
 25 OH D needs megalin and cubulin to be resorbed in PT
o 1,25 OH D stimulated by
 ↑ PTH, ↓ PO4, ↓ Ca
o 1,25 OH D –→
 ↑ Gut reabsorption of Ca
 ↑ TRPV5 in DCT –→ ↑ Ca
 ↑osteoclast activity
o Glycoprotein hormone
o –↑ EPO –→ CFU-E cells
o –↓ O2 –→ peritubular fibroblasts –→
 ↑ HIF-1 –→ EPO-R –→ JAK-2 phosphorylase –→ STAT –→
 EPO production
o EPO effects
 ↑ RBC
 ↓ apoptosis
o Renin secreted from granular JG cells of Afferent arteriole
o Renin stimulated by
 ↓ renal perfusion pressure
 ↑K
 ↑ Sympathetic
 ↓ AT II
 Angiotensin II
o Made by chymase more than ACE
o ACE 1 –→ AT II
o ACE 2 –→ AT 1.7
 AT 1.7 –→ MAS –→ opposite effects (vasodilation)
o AT II binding AT-R1
 Normal activity
 ↑ vasoconstriction
 ↑ thirst
 ↑ aldosterone release
 ↑ Na resorption
o AT II binding AT-R2
 Opposite activity
 ↑ vasodilation
 ↑ apoptosis
 Prostaglandins
o Made from FA precursors
o Dilate afferent arteriole
o –↑ PGE2 –→ ↑ Na excretion
o Blocked by NSAIDs
 NSAIDs –→ ↓ RBF, ↓ GFR
 NSAIDs –→ ↓ Na excretion
Hormone catabolism
o PT is main site of protein degradation
 Via receptor endocytosis
o Endocrine homeostasis –→ hormone catabolism
UTA-2 –→ in loop of Henle
UTA 1, 3 –→ in Collecting duct
BB notes:
Figures and tables from book:
Ch 1: Development and congenital anomalies
Ch 2: Functional anatomy
Ch 3: Body fluid composition and administration
Ch 4: Glomerular Hemodynamics
Ch 5: Renal Clearance
Ch 6: Proximal Tubule
Ch 7: Loop of Henle
Ch 8: Distal Tubule and Collecting Duct
Ch 9: Renal Endocrinology
Ch 10: Water Disorders