Renal Week 1 Flashcards
Describe the role of the kidney in a single sentence
The main physiological function of the kidney is the maintenance of the composition and volume of the extracellular fluid
Intracellular compartment
volume
main componenets
aggregate intracellular volume of all cells
⅔ of total body fluid (27 L)
Main ICF = K+, PO4 3-, Mg2+, proteins
Extracellular compartment
volume
main component
2 parts
⅓ of total body fluid (15 L)
Plasma + interstitial fluid (space between cells) → both constantly mixing across capillary membrane, so have same concentration
Main ECF = Na+, Cl-, HCO3-, Ca2+
(GI fluids, urine, lung fluids NOT considered ECF)
Major components and volumes of daily water intake and loss
Input: Total = 2.5 L
- Ingestion in fluids and food = 2.0 L
- Metabolic processes = 0.5 L (e.g. glucose → H2O and CO2)
Output: Total = 2.5 L
- Sweat and feces = 0.1 L
- Respiration, skin “leaks” = 0.9 L
- Urine = 1.5 L
What does the renal system regulate? (3)
1) ECF characteristic: volume, osmolarity, electrolyte composition (e.g. Na+, K+, Ca2+, PO4-), pH (via bicarbonate)
2) Excretion: metabolic wastes (urea, nonvolatile acids, etc.), foreign substances (drugs and their metabolites, etc.)
3) Blood pressure: water and Na+ regulation and renin-angiotensin system
The nephron
- basic unit of renal structure and function
- 2 million nephrons in the renal system
- made up of blood supply (glomerular and peritubular capillaries) and epithelial tubules
function: blood filtration and selective reabsorption
Pathway of blood through the nephron
Blood enters through afferent artery → passes through glomerular capillaries → some fluid filtered into tubules → rest of blood leaves efferent capillaries → peritubular capillaries (surround tubules) → blood then leaves through renal veins
Four process in a nephron
1) Glomerular Filtration
2) Tubular Reabsorption
3) Excretion
4) Tubular secretion
Glomerular filtration
filter plasma into tubule = NONSPECIFIC
Free passage of H2O and solutes into tubule, but retains larger colloids (proteins, lipid aggregates, etc.) and circulating blood cells in blood
-GFR held relatively constant → rates of tubular handling of each regulated substance varied as needed
Tubular Reabsorption
once in tubule, kidney recaptures some filtered components
Transport of substances across epithelial layer
Highly selective transporters
Regulated by kidney - Selective regulation of rate of reabsorption of individual ECF components → just enough ECF components returned to circulating plasma
Excretion
substances in excess of those required to maintain ECF balance pass through tubule and are excreted as urinary output
tubular secretion
movement of substances from peritubular blood capillaries into the tubule
Regulated
Involves specific molecular transporters
Some substances undergo both reabsorption and secretion within the tubule
Normal values for: assuming CO = 5.2 L/min in 70 kg person
Renal Blood Flow
Renal Plasma Flow
Glomerular Filtration Rate
Filtration Fraction
Renal blood flow = 1.3 L/min
-Kidneys get 25% of CO! More blood than any other organ (except lungs)
Renal plasma flow = 0.65 L/min, 650 ml/min
Glomerular filtration rate = 130 ml/min
-Daily rate of 190 L!
Filtration fraction = 0.2 (20%)
-20% of RPF undergoes glomerular filtration
Non-ECF functions of the renal system
EPO production
Glucogenesis
Produce active vitamin D (calcitriol 1,25-dihydroxyvitamin D)
Renin Angiotensin Axis
Decrease in BP sensed by baroreceptors → kidney increases secretion of renin
→ cleaves angiotensinogen to angiotensin I (biologically inactive)
- Renin level is rate-limiting for production of AgII
- Primary regulatory event is a decrease in BP
AgI → lungs where it is cleaved by ACE to Angiotensin II → arteriolar smooth muscle contraction → increased peripheral resistance → rise in MAP
Function of arterioles of filtration apparatus and special cells there
- on either side of glomerular capillary bed
- Serve as valves that control flow of plasma and blood through the filtration apparatus (and kidney) while regulating GFR
Granular cells: specialized smooth muscle cells of afferent arteriole
-Secrete renin - part of juxtaglomerular apparatus (JGA)
Filterability
concentration of filtrate in Bowman’s capsule vs. concentration in plasma
1 = freely filtered 0 = not filtered
Molecular size cut off of glomerular filtration
size of substances that don’t pass through filter (60,000 D)
Just lower than serum albumin size (67,000 daltons)
How does the ultrafiltrate pass from the glomerular capillaries into the urinary space? (3 things it goes through)
1) Glomerular capillary endothelium (fenestrated holes)
2) Basement membrane
3) Podocytes
Glomerular capillary endothelium
Fenestrated holes in epithelium don’t present resistance to movement of plasma through them - stop RBCs from entering
Podocytes
- sheet of tubular epithelial cells on other side of filter
- visceral epithelium of Bowman’s capsule
- Rounded cell bodies with “feet” (pedicles) projected toward endothelial layer - feet of adjacent podocyte intimately intertwine
- Act as molecular sieves
- most important filter for size
Basement membrane
basement membrane secreted by endothelial and epithelial cells
Important molecular sieve
Composed of mucoproteins (acidic sugars + protein cores), negatively charged → near molecular size cutoff, + charge macromolecules filter much better
What drives filtration in the glomerulus?
Hydrostatic pressure within glomerular capillary
osmotic force in tubule considered to be zero
What opposes filtration in the glomerulus?
1) Pt (hydrostatic backpressure in bowmans capsule)
- caused by filtrate flowing through narrow confines of the tubule
2) Osmotic force in glomerular capillary (πgc)
What generates the osmotic force in the glomerular capillary?
Small ions and solutes filter freely, and are equal on both sides
Large dissolved proteins in plasma (albumin, immunoglobulins) do not filter → water extracted from plasma by filtration → protein concentration rises = Colloid osmotic pressure (COP)
Starling equation for GFR
GFR = K (Pgc - Pt - πgc)
will be tested
What is K
total hydraulic conductivity of kidneys (how much fluid will flow across glomerulus per unit time for each unit of pressure)
Large K due to large GF surface area
What is the Net Filtration pressure (NFP)
Sum of the forces (Pgc - Pt - πgc)
NFP is changing across the glomerular capillary
Why does GFR change? (3)
1) GFR falls in urinary obstruction due to increased Pt
2) GFR falls in severe hypovolemia due to decreased RPF (increased gc)
3) GFR falls in glomerular disease (diabetes, lupus, etc.) due to decreased K
Typical magnitude of starling forces
Pgc =
Pt =
πgc =
NFP =
Pgc = 46 mm Pt = 10 mm πgc = 30 mm NFP = 6 mm
Implications of small NFP: means K is relatively large (large surface area)
Mesangial Cells
cover glomerular capillaries
-Contract and decrease filtration area and thus GFR
Purpose of Autoregulation
If Pgc wasn’t regulated, 15% increase in MAP would cause doubling of NFP → enormous increase in urine flow rate, and electrolyte/metabolite excretion
Changes in MAP do NOT cause proportionate changes in glomerular capillary pressure - Pgc is tightly regulated = autoregulation
Myogenic response
autoregulation
MAP increases → smooth muscle cells of afferent arteriole constrict or dilate to keep downstream flow constant, and maintain Pgc and GFR constant
Intrinsic to vascular SM cells in afferent arteriole
What happens to the myogenic response in malignant HTN
MAP exceeds autoregulatory range, causing dramatic change in RPF/GFR and Pgc as well as damage to delicate glomerular capillaries
What happens to the body during times of hypovolemia?
Hypovolemia → increases resistance of peripheral circulation, shunt blood to essential organs (heart, brain, lungs) → kidney must reduce blood flow, while maintaining function of plasma processing
Complete kidney filtration shutdown can occur if volume loss leads to hypotension and a MAP drop below autoregulatory range
How is GFR maintained during hypovolemia?
GFR maintained by coordinated constriction of afferent and efferent arterioles
Constriction of efferent arteriole → flow diverter, restoring Pgc to normal value, and GFR resumes a normal flow
-Also increases renal vascular resistance → decrease RBF further
Usual baroreceptors in main arteries and effect on GFR
Sense decline in MAP that is significant and long lasting → increase renal sympathetic nerve activity → cause arteriolar muscle to contract → decreases RBF, keep GFR constant
External baroreceptor reflex and effect on GFR
-hormone constriction of arterioles
Neural stimulation of afferent arteriole → increase renin release from granular cells of JG apparatus → increase AgII
→ directly constricts arterioles (afferent and efferent) of kidney
**AgII acts more strongly on efferent arteriole
Intrarenal baroreceptors and effect on GFR
reside in granular cells, stimulate renin-angiotensin axis by detection of reduced arteriolar pressure
A decrease in MAP causes stimulation of what two pathways
1) Arterial baroreceptor reflex –> increase firing rate of renal sympathetic nerve –> JGA renin secretion and constriction of afferent/efferent arterioles
2) JGA baroreceptor stimulation –> renin and angiotensin II
Angiotensin II and hypovolemia
AgII production stimulated by two limbs of hypovolemic response (causes afferent/efferent arteriole constriction)
AND
Essential to systemic circulatory response because AgII causes ALL arterioles to constrict → raise central perfusion and pressure
Filtration equilibrium
point at which NFP = 0 before plasma exits the capillary → no further filtration takes place until end of glomerular capillary
Filtration equilibrium in hypovolemia
During hypovolemia…GFR takes a “double hit” - filtration starts off with a lowered NFP due to hypotension AND effective area for filtration is reduced (equilibrium reached sooner)
What happens if you increase efferent constriction too much?
decrease RBF, increase pressure in glomerular capillary (increase FF) BUT if efferent arteriole constricted too much, πgc increases → decrease GFR
This is what happens in severe hypovolemia
What happens if you increase afferent constriction too much?
decrease RBF, decrease pressure in glomerular capillary (decrease FF), πgc increases → decrease GFR
Renal prostaglandins
-produced by renal interstitial cells in response to AgII
- Local dilatory effect on renal arterioles - antagonizes AgII!
- Pgs maintain adequate renal blood flow by blunting affect of AgII on renal arteriolar constriction
- Provide protection against acute renal failure in hypovolemia
**Dilatory effect of Pgs is selective for AFFERENT arteriole
**DOES NOT eliminate hypovolemic mechanisms, merely blunt them a bit so RBF and GFR reductions aren’t purely vasoconstrictive
Medullary Pyramids
conical functional units, consist of series of tubular elements of nephrons and their associated collecting ducts)
Collecting ducts
empty urine at tip of each cone or pyramid (papilla) into a calyx
Calices
urinary drainage conduits that connect sections of kidney together at the renal pelvis –> ureter at hilum
Blood flow into and within the kidney finishing with entry into glomeruli
Abdomina aorta –> Renal arteries –> anterior and posterior branches –> interlobar arteries (between medullary pyramids)
–> Arcuate arteries (parallel to outer capsule) –> interlobular arteries (towards capsule) –> afferent arterioles
–> glomeruli
Blood flow out of the glomeruli finishing with exit in renal vein
glomeruli –> efferent arterioles
–> interlobular veins –> arcuate veins –> interlobar veins –> renal vein
OR
–> VASA RECTA (capillary plexus where important shit happens)
Renal corpuscles
- initial blood filtering component of nephron
- glomerulus (capillaries) + bowman’s capsule (epithelial capsule)
- located in the cortex
Proximal convoluted and straight tubule
- Cuboidal epithelium, extensive brush border of tall microvilli on luminal side
- Connected by tight junctions
-Basolateral side → extensive basal and lateral infolds with Na+K+ ATPase for pumping Na+ out basolateral side
→ drive uptake of Na+, glucose, and amino acids by facilitated diffusion at microvilli luminal side
-75-85% of filtrate volume absorbed by the time it enters thin portion of loop of henle
Thin descending loop of Henle and thin ascending loop of henle are composed of what cell type?
simple squamous epithelium
Ascending thick loop of henle
Cuboidal epithelium
Active transporters of sodium, numerous mitochondria, extensive basolateral infolds
Distal convoluted tubule
Continuation of thick ascending loop after it enters cortex
Cuboidal epithelium
Short microvilli on luminal side
Major role in acid/base balance
Respond to aldosterone and ADH (?? - not sure if this is right)
Numerous mitochondria, basolateral infolds with Na+K+ ATPase
Collecting tubules and ducts
Collecting tubules of several nephrons join collecting ducts
- ADH acts on cells to increase permeability to water of collecting ducts and tubules via increase in aqua-pores → more concentrated urine
- Columnar
Principal clear cells
active transporters
Couple Na+ uptake with K+ secretion
Function: Na+ reabsorption, K+ secretion, H2O reabsorption
Intercalated cells
stain more darkly
- Secrete H+, reabsorb bicarbonate
- Acid-base balance
A-intercalated cells: H+ secretion, HCO3- synthesis, K+ absorption
B-Intercalated cells: HCO3- secretion, Cl- absorption
Epithelium of ureters and bladder
Transitional epithelium - contains unique lamina propria with folded elastic CT that enables marked stretch of entire epithelium
Highly elastic basal lamina
Range of Water and Salt Handling by the Kidneys
Max excretion of either salt or water is only a small fraction of the filtered load
→ MOST of filtered load of water and salt is obligatorily reabsorbed, with only a small fraction under homeostatic control
At least 92% of filtered water and 98% of filtered NaCl MUST be reabsorbed
- Nearly all obligatory recapture in proximal segments (proximal tubule and loop of Henle)
- Homeostatically varied reabsorption takes place in “fine tuning” segments (distal tubule and collecting duct)
Possible to overwhelm excretory abilities?
salt
water
Water:
Difficult to ingest large volume of water sufficient to overwhelm excretory abilities of kidneys in maintaining water balance
-Water intoxication - possible with drugs like ecstasy
Salt:
Upper limit of salt excretion can be exceeded with high salt diet
Epithelial transport of sodium
Na+ actively extruded from interior of tubular epithelium by basolateral Na+/K+ ATPase ion pump = primary energetic event
→ reduce [Na+] inside cell, increase [K+] in cell
-Na+ moved to serosal side of epithelium
-Na+ passes from tubular lumen into cell through Na+ channels on apical membrane (passive) - large driving gradient due to pumping
_______, _________, and _________ are coupled to the active reabsorption of ______
chloride, water, and other solutes
Na+
Chloride and water transport across tubular epithelium
Chloride:
- paracellular - through tight junctions
- moves with Na+ gradient
- accumulates with Na+ and serosal side of membrane
→ osmotic gradient across epithelium → WATER then moves from lumen to serosal side (paracellular/tight junctions or transcellular/aquaporins)
Transport of glucose across tubular epithelium
reabsorbed in “secondary” active transport
Na+/glucose co transporter → concentrate glucose in the cell → passive movement from cell into serosa
Role of Proximal tubule in NaCl and water reabsorption
-“big bite” of filtered load of water and NaCl, and recapture important metabolites in filtrate
- Obligatorily reabsorbs 65% of filtered water and NaCl regardless of homeostatic requirements
- Aquaporins allow H2O passage transcellularly
- Absorption of essentially ALL filtered glucose and amino acids
- Via Na+ co transporters
*Absorption of filtered bicarb/H+ secretion
Capacity for reabsorption is finite (mediated by discrete transporters)
Loop of Henle role in NaCl and water reabsorption
creates hypertonic interstitium, hypotonic tubular fluid (urine dilution)
- more NaCl than water is reabsorbed
- Obligatory processes
- Crucial for water reabsorption in fine tuning segments
Descending limb of the loop of Henle role in NaCl and water reabsorption
highly permeable to H2O, impermeable to NaCl
Osmotic gradient established in ascending limb brings H2O in at descending limb
Ascending limb of the loop of Henle role in NaCl and water reabsorption
NaCl reabsorption (25% of original filtered load from lumen) → highly hypertonic interstitium
- Impermeable to water
- Increases medullary osmolarity
- Calcium and magnesium ion reabsorption
- Apical membrane: Na/K/2Cl cotransporter for reabsorption
Role of distal convoluted tubule and collecting ducts in NaCl and water reabsorption
“fine tuning” segments
Na/K pump Na+ into serosa → Na+ channels on lumen side bring Na+ down gradient into the cell
Na/Cl cotransporter - Thiazide diuretic site of action
Ca and Mg reabsorption (Ca2+-Mg2+-ATPase)
Aldosterone and ADH active here
Aldosterone actions in collecting ducts
upregulates sodium reabsorption on principal cells in collecting duct
Mechanism by which aldosterone upregulates sodium reabsorption
Aldosterone enters principal cell (lipid soluble) → bind intracellular receptor → hormone/receptor complex diffuses to nucleus → turns on genes to increase synthesis of transporter proteins
-Takes an hour or more
Rapid insertion of pre-existing pools of transporters within vesicles near cell membrane
-Occurs in tens of minutes
Why is there such a high driving osmotic force for water reabsorption at distal tubule and collecting duct?
Addition of more solute to interstitium around fine tuning segments by loop of henle process → increasing osmotic gradient between lumen and interstitium
→ HIGH driving force of water reabsorption
ADH/Vasopression action on collecting duct and mechanism
dramatically increases water permeability of segments
Small vesicles with aquaporins fuse to apical membrane of epithelial cells in presence of ADH
-ADH binds V2 receptor on basolateral membrane of epithelial cells of collecting duct→ initiate intracellular cAMP phosphorylation cascade → initiate de novo synthesis of aquaporins
In absence of vasopressin, collecting duct relatively impermeable to water
RAPID response
Countercurrent multiplication
- generates medullary osmotic gradient
- Deeper from cortex into medulla, osmotic gradient in kidney increases
- Established by U-shaped loop of Henle and Vasa recta
Descending permeability: H2O > NaCl
Ascending permeability: NaCl»_space;» H2O (impermeable)
–> Concentrates the interstitium
Allows for fine tuning of water excretion distally in collecting ducts
Vasa recta in countercurrent multiplication
U shaped - maintain osmotic gradient
Passive movement of H2O and solute
Blood in Vasa recta becomes more concentrated as it descend deeper into the medulla
As blood ascends, water will return into blood vessel and solutes will move from blood vessel into interstitium
Descending vs. ascending capillaries of vasa recta
Descending capillaries:
-Blood enters hypertonic interstitium → H2O movies out of blood into interstitium and solute moves from interstitium into blood
Ascending capillaries:
-Blood enters less hypertonic interstitium → H2O moves back into blood, solute moves back into interstitium
Starling forces for bulk recapture flow - why do we need it?
Huge amount of water and NaCl pumped across tubular epithelium re-enters capillaries to be returned to the ECF via bulk flow of interstitial fluid into the peritubular capillaries - governed by Starling’s principles
What is the main driving force for flow of reabsorbed fluid back into capillaries?
high osmotic pressure of capillary plasma
Due to colloid osmotic pressure of plasma: High because plasma had lots of H2O extracted from it upstream when it was subjected to glomerular filtration → only cells and big things left in blood
Starling forces for bulk recapture flow (equation + normal values)
Fic = K (Pint + πcap - Pcap - πint)
Pint = 7 mm πcap = 35 mm Pcap = 11 mm πint = 6mm
→ NFP = 25
How does flow rate effect reabsorption
Proportional reabsorption changes with flow RATE:
Increased tubular flow → allow more tubular substance to escape reabsorption → increase excretion rate with tubular flow
Opposite is true for reduced tubular flow
How do diuretics effect tubular flow and excretion?
Diuretics: increase tubular flow and excretion of most substances
Increase urine output by decreasing water reabsorption → more water in tubule → increased tubular flow → increased excretion of all solutes
Glomerulotubular Balance
ability of obligatory reabsorption mechanisms in proximal tubule to compensate for changes in filtered load
Fixed proportion of filtered load of water and NaCl is ALWAYS reabsorbed (65%)
**There will still be a surplus
Increased GFR → Higher volume of ultrafiltrate
→ oncotic pressure in capillary increases → more water and solute reabsorbed
Tubuloglomerular Feedback
direct regulation of GFR of each nephron in response to changes in NaCl concentration at macula densa
-done by macula densa
Macula densa
specialized epithelial cells in direct contact with cells of afferent arteriole (Can cause arteriole to constrict or dilate)
Placed at start of distal tubule → monitor status of obligatory reabsorption just before the tubular fluid enters fine tuning segments
How does tubuloglomerular feedback work? 4 steps
1) Rise in GFR → initial rise in tubular fluid flow → compensated by glomerular tubular balance in proximal tubule, but uncompensated part causes fluid to move faster in loop of Henle
2) → reduction in proportion of NaCl reabsorbed in ascending limb → NaCl concentration increases in lumen of ascending limb
3) → fluid exits loop and encounters macula densa → sense rise in NaC concentration → signal afferent arteriole to contract
4) → Pgc drops to return GFR to normal level
ECF volume is determined more by _______ than _______
ECF osmolarity is determined more by _______ than ________
ECF volume is determined more so by sodium balance than water balance
ECF osmolarity is determined more so by water balance than sodium balance
ECF volume is sensed by _______ via what receptors?
What is the response?
effective vascular volume
Sensors: stretch receptors
EABV increases → increase renal excretion of Na, “natriuresis”
EABV decreases → decrease renal excretion of Na (increase reabsorption of Na)
Response: renal Na absorption/excretion
ECF osmolarity is sensed by _______ via what receptors?
What is the response?
plasma osmolarity
osmoreceptors
Response: urine osm/H2O excretion, thirst/H2O intake
What happens to ECF volume and sodium concentration when you eat a big salty meal?
EX) eat big salty meal → increase ECF osmolarity → water flows rapidly from cells to ECF to balance osmolarity between the two compartments
→ decrease osmolarity of ECF and increase osmolarity of cellular compartment as water leaves
NO change in sodium concentration, just pure increase in ECF volume
Why do *Losses or gains in ECF sodium cause greater changes in ECF VOLUME than they do in sodium concentration? consequences?
Two-fold greater volume of cellular over ECF compartment → gains (or losses) of sodium in ECF result in TWO-FOLD greater changes in ECF volume than they do in ECF sodium concentration
→ sensors of sodium regulation monitor changes in ECF volume NOT sodium concentration
4 types of sensors of sodium regulation
1) High pressure baroreceptors
2) Low pressure baroreceptors
3) Intra-renal sensors (JGA - glomerular afferent arteriole, macula densa)
4) Hepatic and CNS sensors
High pressure baroreceptor sensors of Na+ regulation
sense effective arterial blood volume (EABV) in aortic arch and carotid sinus by monitoring MAP
-EABV does not always correspond to ECF volume
E.g. heart failure → high ECF volume, low EABV
Low pressure baroreceptor sensors of Na+ regulation
in cardiac atria, LV, and pulmonary vasculature
Sense stretch in cardiac chamber walls or pulmonary vessels caused by increased ECF volumes
Renin-angiotensin-aldosterone system effect on renal absorption of sodium
Activated by low ECF fluid volume –> activate ECF volume sensors
Angiotensinogen → AgI → AgII → adrenal gland (zona glomerulosa) → increase secretion of ALDOSTERONE → MR in collecting duct (principal cells) → SODIUM RETENTION and increased BP
SNS effect on renal absorption of sodium
Reduced arterial pressure and vascular volume → VASOCONSTRICTION, release of renin, decreased RBF and GFR, and increased RENAL REABSORPTION of NaCl
Direct innervation of renin secreting cells in JGA and catecholamines → stimulate renin release and RAAS → increased RENAL REABSORPTION of sodium
What effector molecules are activated during times of high ECF volume (help renal excretion of sodium and vasodilation)
Natriuretic peptides, prostaglandins, bradykinin, and dopamine
Act directly on tubules or indirectly via renal vasculature to change glomerular hemodynamics
Feedback Loop: Renal Control of ECF Volume (Na Balance)
Negative sodium balance –>
Positive sodium balance –>
Negative sodium balance = more sodium leaving the body than entering (sweat, diarrhea, diuretics)
-Body is volume contracted → volume sensors → renal effector mechanisms → anti-natriuresis
Positive sodium balance = more sodium entering the body than leaving
-Body volume is expanded → volume sensors → renal effector mechanisms → natriuresis
Mechanisms of Na and H2O regulation are ______ of one another
INDEPENDENT
Feedback mechanisms of water balance:
Negative water balance
Negative water balance (H2Oin less than H2Oout) = hypertonicity
Negative water balance → ECF osmolarity increases (hypertonic)
1) → osmostat (hypothalamus) → stimulate SON to produce ADH and release ADH from posterior pituitary, stimulate thirst
→ increase water reabsorption from collecting duct
→ increase H2O intake
Feedback mechanisms of water balance:
Positive water balance
Positive water balance (H2Oin > H2Oout) = hypotonicity
Positive water balance → Hypotonic ECF
1) → osmostat (hypothalamus) → suppress ADH synthesis (decrease renal H2O excretion) and decrease thirst and water intake
2) → stretch of atrial cells → release proANP → increase ANP in plasma → block ADH, decrease secretion of ADH → decrease water reabsorption, and increase excretion
* *Only active when volume less than 10%
Changes in ECF tonicity are reflected by changes in _________
[Na] plasma
What is the target serum osmolarity?
Goal is to maintain serum osmolarity (Sosm) between 280-290 mOsm/kg
What effectors control water balance (3)
1) Thirst
2) Vasopressin
3) ANP
When is thirst typically stimulated?
Thirst is stimulated when maximal effective vasopressin levels have been reached (urine osmolarity of about 1200)
Vasopressin
synthesized in hypothalamus, packaged into vesicles, and transmitted via axons to posterior pituitary where it is stored and released
When ECF osmolarity increases, or ECF volume decreased → vasopressin released from posterior pituitary
Stimuli for release of vasopressin
osmotic vs. non-osmotic
Osmotic → hypertonicity (elevated PNa)
Non-osmotic → unrelated to tonicity
- Decreased EABV (overrides tonicity)
- Pain, nausea, medications, drugs (ecstasy), etc. → Syndrome of inappropriate ADH (SIADH)
Osmoreceptors in the hypothalamus
(Neurons in supraoptic nucleus (SON) of hypothalamus)
Sense serum osmolarity, which is primarily determined by [Na]plasma
-[Na]plasma is determined by water content and sodium content
ECF volume receptors
- Sense filling pressure in LA of heart
- Sense ECF osmolarity through changes in their cell volume
**Triggered when EABV declines by > 10%
With low EABV, ADH release stimulated even if Sosm/SNa low
ECF sensors for water (osmolarity)
1) Osmoreceptors in the hypothalamus
2) ECF volume receptors (sense filling pressures in LA)
what determines ECF water regulation under normal physiologic conditions vs. more severe conditions?
ECF osmolarity determines renal regulation of water balance (osmoregulatory loop is VERY sensitive)
When ECF volume is significantly decreased (>10%) → ECF volume overrides osmotic control of renal water handling
**ECF water regulation is primarily an osmoregulatory system with an emergency low-volume override
What happens to your water regulation during severe sweating
→ decrease in blood volume, increase osmolarity of ECF
Decreased ECF volume → low filling pressure in LA of heart (sensitive indication of circulating volume/preload) → baroreceptor reflex → ADH-synthesizing hypothalamic neurons release ADH from terminals in posterior pituitary → kidney → aquaporins and water reabsorption
Hypotonic composition of sweat → hypertonic ECF → activate osmoreceptors in hypothalamus → ADH synthesis activated
What happens when you have severe diarrhea and lose 3L of volume
Decrease in blood volume (3 L)→ ADH synthesis and secretion
Diarrhea is isotonic, so does NOT change osmolarity and thus does NOT activate osmoreceptors in hypothalamus
When patient recovers:
-Patient drinks 2 L of water → decrease osmolarity of blood, but total blood volume is still down by 1 L
→ inhibit ADH secretion
**ECF volume has little effect on ADH levels, except when ECF volume falls severely
What happens when you give someone 1L of pure water IV
osmolarity of ICF = ECF → 2x more water distributes intracellularly (ICF expands by 666 ml, ECF expands by 333 ml)
What happens when you give someone 1L of isotonic saline IV
it all stays extracellular (ECF expands by 1L, but only ¼ will stay in intravascular space, the rest in interstitium)
No stimulus for water to shift because it is isotonic
What effector regulates volume overload?
Atrial natriuretic peptide (ANP)
Atrial Natriuretic Peptide
potent diuretic peptide that also increases sodium excretion
What happens with ANP when you have increased blood volume
Increased ECF volume → increased distention of atria → release of ANP granules of atrial cardiocytes (contain pro-ANP, which is cleaved to Active ANP)
→ active ANP reaches targets throughout body which increase production of urine
Effects of ANP
1) decrease ADH secretion
→ decrease water reabsorption
2) block ADH action on tubules → decrease water reabsorption
3) decrease renin release –> decrease AgII and aldosterone
4) block aldosterone action on tubules → decrease Na+ reabsorption
5) selectively dilate both afferent and efferent arteriole → more fluid in tubule (increased GFR)
**All of the above cause…
→ increase excretion of water and sodium (through flow effects, decreased water reabsorption and decreased Na+ reabsorption)
Uremia
constellation of signs/symptoms of multiple organ dysfunction caused by retention of “uremic toxins” and lack of renal hormones due to acute or chronic kidney injury
Azotemia
build up of nitrogenous wastes in the blood (e.g. BUN and creatinine)
Oliguria
Urine volume less than 500 ml/24 hours in a normal sized adult
Anuria
Urine volume less than 50 ml/24 hours in a normal sized adult
Fractional Excretion of Sodium (FENa)
FENa = (UNa/PNa)/(UCr/PCr) x 100 (expressed in %)
Ratio of clearance of sodium to creatinine
Single Nephron GFR Starling Force Equation
SNGFR = [(PGC - PT)-(πGC-πT)] x Kf
_______ is proportional to hydrostatic pressure of glomerular capillary
why?
single nephron GFR
SNGFR = [(PGC - PT)-(πGC-πT)] x Kf
- πGC and PT only have small variations
- πT is assumed to be zero
Effect of prostaglandins on afferent and efferent arteriolar tone
Effect of NSAIDS?
Prostaglandins → vasodilation of afferent arteriole
NSAIDS → inhibit PGs can cause renal failure
Effect of Angiotensin II on afferent and efferent arteriolar tone
Effect of ACEI/ARBs?
Angiotensin II → constrict efferent arteriole
ACEI/ARBs block AgII → can cause renal failure
If you decrease afferent arteriole constriction you _____ GFR
If you increase afferent arteriole constriction you ______ GFR
If you decrease efferent arteriole constriction you _____ GFR
If you increase efferent arteriole constriction you ______ GFR
decrease afferent arteriole –> increase GFR
increase afferent arteriole –> decrease GFR
decrease efferent arteriole –> decrease GFR
increase efferent arteriole –> increase GFR
Equation for GFR
GFR (ml/min) = [UX (mg/100ml) x V (ml/min)] / PX (mg/100ml)
X = plasma concentration of X V = urine flow rate
Equation for clearance of substance X
CLX= Xe/PX
or CLX = UX x V / PX
Xe = amount of X eliminated PX = mean plasma concentration of X in plasma
Ideal substance for GFR
Freely filtered, not reabsorbed, and not secreted
and endogenous
Why is Urea bad for estimating GFR
Plasma urea concentrations (BUN) only give INDIRECT estimate of GFR
Freely filtered, not secreted, but is reabsorbed so its clearance can underestimate GFR
creatinine and estimating GFR
freely filtered by glomerulus, NOT reabsorbed
Used for serum-based estimates of GFR
Can overestimate GFR by 10-20% because its secretion is variable
Rising creatinine indicates worsening renal function
**All GFR estimating methods require steady state creatinine
Cockroft and Gault formula for creatine clearance
Creatinine clearance = [A x (140-age) x weight] / (72xSCr)
A = 1.0 for males and 0.85 for females
Age is in years, weight is in kg
Serum creatinine is in mg/dL
Urine based estimates of GFR
requires 24-hour urine collection (urine creatinine), plasma creatinine, and urine flow rate (volume/1440 min)
**ClCr = UCr x V/PCr
Acute Kidney Injury can be divided into 3 categories
1) Pre-renal causes
2) Renal Causes
3) Post-renal causes
Acute kidney injury
rapid reduction in GFR, manifested by a rise in plasma creatinine concentration, urea, and other nitrogenous waste products → state called azotemia
Pre-Renal Azotemia
decrease in GFR due to decreases in renal plasma flow and/or renal perfusion pressure
- Defect between heart and afferent arteriole
- Most common cause of abrupt fall in GFR in hospitalized pt
Causes of pre-renal azotemia
1) Hypovolemia (renal losses, third space losses, GI losses, hemorrhage)
2) Hypervolemia
- decreased CO (CHF, MI, valvular disease, pericardial tamponade)
- Systemic arterial vasodilation (cirrhosis, sepsis, meds, autonomic, neuropathy)
Physical exam findings in pre-renal azotemia
Intravascular volume depletion → decreased weight, flat neck veins, postural changes in BP and/or pulse
Cardiac dysfunction → edema, pulmonary rales, S3 gallop
Lab and urinalysis findings in pre-renal azotmeia
FENa = ?
FENa less than 1% (urine sodium driven down, urine creatinine up → smaller number)
Urinalysis: High tonicity (kidney water retention due to increased ADH)
Post-renal azotemia
(obstructive nephropathy): decrease in GFR due to obstruction of urine flow
Increases in intratubular pressure → low GFR
If obstruction is prolonged → renal vasoconstriction and persistent decrease in GFR
Obstruction must be bilateral for significant kidney injury
Causes of post-renal azotemia
1) Obstruction of ureters:
- Extraureteral (carcinoma of cervix, endometriosis, retroperitoneal fibrosis, ureteral ligation)
- Intraureteral (stones, blood clots, sloughed papilla)
2) Bladder outlet obstruction (bladder carcinoma, urinary infection, neuropathy)
3) Urethral obstruction (posterior urethral valves, prostatic hypertrophy, carcinoma)
Physical exam findings in post-renal azotemia
Evidence of urinary obstruction → anuria, intermittent anuria, or large swings in urine flow rate
Labs/Test findings in post-renal azotemia
FENa = ?
Renal US?
Catheterization?
FENa>2% (high Na+ concentrations and impairment of water reabsorption → low urine creatinine concentrations)
Renal Ultrasound: shows obstruction as an expansion of collecting system (hydronephrosis)
Catheterization:
Placement of catheter following voiding can confirm dx
Intrinsic Renal Disease
decrease in GFR due to direct injury to kidneys
Causes of intrinsic renal disease (4)
1) Vascular Disease
2) Glomerular Disease
3) Interstitial Disease
4) Tubular Disease
Acute Tubular Necrosis
Form of tubular disease causing intrinsic renal disease
caused by ischemia or nephrotoxins causing decreased GFR
Vascular factor = decrease in RBF, decrease in glomerular permeability (Kf)
Tubular Factors = tubular obstruction, backleak of glomerular filtrate
Treatment of pre-renal azotemia
optimize renal perfusion
Improve CO, replace intravascular volume
Treatment of post-renal azotemia
relieve obstruction
Treatment of Acute Tubular Necrosis
- stop it before it happens
- Avoid risk factors (prerenal azotemia, nephrotoxins)
Treat medically
If medication fails → renal replacement therapy (dialysis)
Dialysis: fluid electrolytes, and nitrogenous wastes removed from plasma by external devices
UA pattern of prerenal azotemia
HIGH specific gravity
- no blood
- no protein
- normal microscopic
UA pattern of glomerulonephritis
normal/high specific gravity
+ blood
+ protein
Microscopic –> RBC casts and RBCs
UA pattern of AIN
Isosmotic urine
+/- blood
+/- protein
Microscopic –> WBC casts, eosinophils (with allergic interstitial nephritis)
UA pattern of vasculitis
normal/high specific gravity
+ blood
+ protein
Microscopic –> RBC casts and RBC
UA pattern of acute tubular necrosis
Isosmotic
+/- blood
no protein
Microscopic –> Granular casts, RTEs (renal tubular epithelial cells)
UA pattern of obstructive (post-renal azotemia)
- isosmotic
- no blood
- no protein
- normal microscopic
Chemistries for pre-renal azotemia
- urine Na
- Ucr/Pcr
- Uosm
- FENa
- urine Na less than 20
- Ucr/Pcr > 20
- Uosm increased
- FENa less than 1
Chemistries for Acute tubular necrosis
- urine Na
- Ucr/Pcr
- Uosm
- FENa
- urine Na > 20
- Ucr/Pcr less than 10
- Uosm = isosmotic
- FENa > 2
Glomeruli
filtering units of kidney, take 20% of CO - essentially a ball of capillaries
Anatomy:
- Glomerular capillary wall uniquely permeable to salt, water, and metabolic waste products (creatinine, urea)
- Cells and proteins not normally filtered at glomerulus
- Negative charge of GBP and podocytes → charge-charge repulsion with most proteins
Glomerular filtration barrier = ________ + __________ + _________
Glomerular filtration barrier = endothelial cell layer (fenestrations) + basement membrane + glomerular epithelial cells (aka podocytes)
Glomerular basement membrane (composition, 4 things)
1) Type IV collagen (backbone)
2) Lamin and entactin
3) Glycoproteins (for endothelial and epithelial attachment)
4) Heparan sulfate proteoglycan (gives - charge to GBM)
Podocytes
create most important barrier to size with slit diaphragm extending between cells and GBM via long “foot processes”
Nephrin
protein is primary protein of slit diaphragm
Mutation → congenital nephrotic syndrome (Finish type)
Mesangial cells
Secrete basement membrane matrix
Smooth muscle-like properties (contractile), effect capillary surface area and filtration
Macrophage-like properties
Normal protein excretion
500 mg of albumin (most reabsorbed in proximal tubule)
Tamm-Horsfall protein
IgA
Abnormal protein excretion
Albumin >?
Microalbuminuria = ?
> 300 mg/day →
300 mg-2 gm/day →
> 3 gm/d →
> 3-3.5 gm/d →
Albumin > 30 mg/day
Microalbuminuria = 30-300 mg/day
-Suggestive of early glomerular damage
> 300 mg/day → identified by dipstick
300 mg-2 gm/day → glomerular/tubular disease
-Can be “functional” (high fever, severe exercise, CHF, and other acute conditions)
> 3 gm/d → defect in glomerular permeability
> 3-3.5 gm/d → decreased serum albumin, edema = nephrotic range-proteinuria (Nephrotic Syndrome)
Nephritic Syndrome
active inflammation within glomerulus leading to damage to the glomerulus with subsequent loss of filtration and reduction in GFR
GLOMERULAR INJURY
5 defining features of nephritic syndrome
Decreased renal function Hypertension RBC and RBC casts (hematuria) Edema Proteinuria (
Nephrotic Syndrome
major glomerular abnormality causing excessive leak of protein through the glomerular capillary wall into the urinary space
PROTEIN LEAK
Defining features of nephrotic syndrome (5)
1) Proteinuria, albuminuria > 3.5 g/d (due to disruption of slit diaphragm - injury/mutation)
2) Hypoalbuminemia (less than 3.0g/dl)
3) Edema
4) Hyperlipidemia
5) Lipiduria (fat globules in urine)
Why is there Hypoalbuminemia in nephrotic syndrome?
proteinuria and increased catabolism of reabsorbed protein in renal tubules
Synthesis by liver cannot keep up with urinary losses
hypoalbuminemia (
What are the two causes of edema in nephrotic syndrome
1) Decrease in serum albumin → decreased plasma oncotic pressure → filtration of fluid into interstitial space, decrease intravascular volume → stimulate RAAS and vasopressin → salt and water retention
* Typically only in kids
2) Primary renal defect in sodium excretion (activate epithelial sodium channel (eNAC) in collecting duct → increase Na reabsorption → volume expansion → fluid moves into interstitium due to low oncotic P and high hydrostatic P
Other complications of nephritic syndrome (4)
1) Increased risk for bacterial infections (urinary loss of IgG and complement factor B)
2) Increased risk for thrombosis
3) Poor growth in children and osteomalacia
- Decreased vitamin D levels (loss of vitD binding protein)
4) Protein malnutrition
Why is there an increased risk for thrombosis in nephrotic syndrome?
Increased coagulation factors (fibrinogen, 5,8,9,10)
Decreased antithrombin III
Increased platelet aggregation to stimuli
Treatment of Nephrotic Syndrome
1) Low salt diet
2) Diuretics
3) BP control
Other measures: +/-
- Statin
- ACEi (decrease proteinuria)
- Vit D replacement
- Normal or slightly low protein diet
Hereditary Nephrotic Syndrome
- what mutation?
- most common in who?
- treatment?
mutations in slit diaphragm proteins
Present in infant or child - edema, ascites, failure to thrive
Resistant to steroids, transplantation is curative
Minimal change disease:
Presentation (3)
Labs (4)
Presentation:
1) Peak incidence 2-8 yrs
2) Edema, ascites, weight gain
3) Normal BP
Labs:
1) Normal/slightly depressed renal function
Urinalysis →
2) 4+ protein
3) hyaline casts
4) microscopic hematuria
Minimal change disease:
Associations? (3)
Allergy/atopy
Hodgkin’s lymphoma
NSAIDs
Minimal change disease:
Pathophysiology
circulating permeability factor → podocyte injury (foot process fusion, expression of CD80 dendritic cell marker in podocytes) → proteinuria
Minimal change disease:
Treatment (2)
Corticosteroids (prednisone)
Short course of oral cytoxan (12wks) for frequent relapse
Minimal change disease:
Histology (3)
Normal light microscopy
Negative immunofluorescence
EM with foot process fusion
Focal Glomerular Sclerosis:
Presentation: age and race
Labs (4)
Presentation:
Peak incidence between 20-40yrs
Most common in African Americans
Labs:
1) Normal/slightly depressed renal function
Urinalysis →
2) 4+ protein
3) hyaline casts
4) microscopic hematuria
Causes of focal glomerular sclerosis (4)
1) Idiopathic (most common)
2) HIV associated
3) Heroin nephropathy
4) Secondary FGS - obesity, sickle cell disease
HIV associated nephropathy
- Nephrotic syndrome
- Focal and segmental glomerulonephritis
- 5-10% of all AIDS patients (assoc. with low CD4 counts)
- Responds to anti-retroviral agents
Pathology: Focal sclerosis, tubular dilation, reticuloendothelial inclusions
Pathophysiology of focal glomerular sclerosis
circulating factor unknown
APOL1 polymorphisms (genetic mutation) in African Americans
Membranous Nephropathy
Presentation (6)
1) edema
2) BP variable
3) 4+ proteinuria
4) microhematuria
5) Most often in adults and is associated with other diseases (cancer)
6) Often has hilar mass
Membranous Nephropathy
associations?
- idiopathic, cancer (GI, lung, breast), Lupus, HepB, heavy metals (mercury), drugs (rheumatoid meds), infections
- Cancer present in 6-11% of cases
“Bugs, drugs, tumors, and rheum”
Membranous Nephropathy
Renal biopsy findings (2)
1) thickening of GBM (“spikes”)
2) normocellular, and granular immune complex deposits in subepithelial region
Membranous Nephropathy
Pathogenesis
mediated by antibodies to phospholipase A2 receptor on podocytes
Membranous Nephropathy
treatment (2)
progression
corticosteroids and cyclophosphamide (cytoxan)
Some progress to ESRD
Membranoproliferative Glomerulonephritis (MPGN) Type I
presentation
labs
9 things
1) Elevated creatinine (mildly reduced renal function)
2) proteinuria
3) palpable purpura
3) liver disease (Elevated LFTs)
4) Acute glomerulonephritis or nephritic syndrome
5) HTN frequent early on
6) Chronic hepC with HCV and RNA in circulation
7) Cryoglobulins
8) RF+
9) low complement levels (C3 and C4)
MPGN Type I
Associations
1) HepC
2) Low grade systemic infection: ventriculoatrial shunts, subacute endocarditis
3) Idiopathic: rare, mostly in children
MPGN type I pathology
light microscopy –>
IF –>
EM –>
Light microscopy → thickening of GBM, mesangial cell proliferation, lobulated glomerulus
IF → C3 deposits in capillary walls and mesangium, IgG deposits
EM → subendothelial/mesangial deposits (immune complexes)
Treatment of MPGN type 1 (2)
prognosis?
Poor prognosis, some progress to end stage renal disease
- Treat HepC
- Steroids if progressing rapidly (idiopathic also)
MPGN Type II: Complement Disorder
Typically presents in childhood
Nephrotic syndrome, HTN
Low C3 and NORMAL C4 (C3 → alternative, C4 → classical)
Typically respond to therapy (complement blocking drugs)
Primary renal causes of nephrotic syndrome (5)
1) Hereditary Nephrotic syndrome
2) Minimal change disease
3) Focal Segmental Glomerulosclerosis
4) Membranous Nephropathy
5) Membranoproliferative GN (MPGN)
Primary renal causes of nephritic syndrome (3)
1) Post-strep GN
2) IgA nephropathy
3) RPGN
- Anti-GBM
- idiopathic
Secondary renal causes of nephrotic syndrome (3)
1) Diabetes
2) Amyloid and light chain disease
3) SLE (membranous)
Secondary renal causes of nephritic syndrome (2)
1) Vasculitis
2) Immune complex (SLE, HSP)
Non-inflammatory mechanisms of nephrotic syndrome (2)
1) Circulating factors or Igs bind to glomerular epithelial cell (GEC) membranes and/or GBM without fixing complement
→ loss of polyanion (charge selective)
→ GEC detachment from GBM (size selective)
EX) Minimal change disease, focal sclerosis
2) Complement fixing anti-GEC Abs
-Alternative pathway
-C5-9 → increased permeability of GBM (size selective)
EX) membranous nephropathy
Renal amyloidosis (5)
- Kidney involved in 85% of cases
- AA vs. AL (light chain types)
- Usually present with proteinuria
- Histology shows amorphous fluffy pink material in glomeruli and vessels
- Positive on Congo red stain with apple green birefringence
Chronic Renal Failure can occur secondary to what diseases? (3)
1) Diabetes
2) Vascular disease
3) Hypertension
Diabetic renal failure
1) Hyaline arteriolar disease
2) Diabetic glomerulosclerosis
- Diffuse or nodular expansion of mesangium
- Mesangial “lysis”
- BM thickening
Hypertensive renal failure
Finely granular surface (scarred glomeruli)
Blood vessels → medial and intimal thickening + hyaline deposition
Malignant hypertensive renal disease
Initial event is renal vasculature injury
Result is fibrinoid necrosis and hyperplastic arteriolitis
Kidneys respond by secreting more renin and perpetuating the problem
What do you look for on the macroscopic “visual” exam of urinalysis (4)
1) Volume
2) Color
3) Clarity
4) Odor
Polyuria
Oliguria
Anuria
Polyuria = >2000ml/24hr
Oliguria = less than 500 ml/24hr
Anuria = less than 50 ml/24 hr
Color of urine, means what?
Yellow-green-brown → ?
Orange-red-brown → ?
Pink-Red → ?
Dark brown/black → ?)
Yellow-green-brown → bile pigments
Orange-red-brown → excreted urobilinogen
Pink-Red → hematuria, hemoglobinuria, myoglobinuria, porphyrias, beet ingestion
Dark brown/black → methemoglobin, rhabdomyolysis, L-dopa, homogentisic acid (alkaptonuria)
Specific Gravity
- indicates kidney’s concentrating ability
- Relative proportion of dissolved solid components to total volume of specimen
Decreased = less than 1.010 –> less concentrated
Increased > 1.035 → more concentrated
(Dehydration, DM, proteinuria, CHF, Addison’s disease, SIADH)
Osmolality
number of particles of solute per volume of solution
Usually increases in parallel with specific gravity unless there is an abnormal solute (e.g. glucose, protein)
pH of urine
what does acidic or alkaline urine indicate?
varies from 4.6 to 8.0 (mean = 6.0)
Acidic urine → metabolic or respiratory acidosis, drugs, diet high in protein, cranberries
Alkaline urine → renal tubular acidosis, UTIs, excess bicarb ingestion, respiratory or metabolic alkalosis, foods (citrus, large meal)
Proteinuria dipstick
normally 150mg/dl
Increases → postural proteinuria, proteinuria in elderly, overflow (multiple myeloma), glomerular disease (nephrotic syndrome = >3.5 g/24hrs)
Reads 0 to 4+ - rough correlation to amount of protein
Cannot detect microalbuminuria
Glucose on urinalysis dipstick
with hyperglycemia, glucose appears in urine when blood glucose > 180-200 mg/dL
Other sugars not detected by this
Ketones on urinalysis dipstick
product of lipid metabolism (normally undetectable)
Positive in DM, alcoholism, cirrhosis, prolonged fast, heavy exercise
Acetoacetic acid and acetone react with nitroprusside → colored compound (does not detect hydroxybutyrate)
Blood on urinalysis dipstick
tests for peroxidase-like activity of hemoglobin
Must differentiate (+) based on history and other tests (hemoglobinuria, myoglobinuria, hematuria)
No RBCs on microscopic analysis→ free hemoglobin or myoglobin, indicative of intravascular hemolysis
Nitrite on urinalysis
Indirect test for UTI: nitrate reduced to nitrite by some bacteria
+ → gram negative bacteria, high specificity
- → not helpful (low sensitivity)
Leukocyte Esterase on urinalysis
indirect test for UTI
Made by neutrophils = indirect measure of # of neuts in sample
Casts
Congealed form in tubule, incorporates whatever is also in tubule at the time of formation
Two smooth parallel edges + blunt ends
Hyaline Casts
clear, colorless, rounded ends, parallel edges
Increased in dehydration, physical exertion, fever, renal injury (only if large quantity)
Nonspecific (a few are normal)
Waxy casts
sharp margins, blunt ends, cracks in lateral margins
Associated with advanced chronic renal failure
Red Cell Casts
lumpy edges, slightly reddish
Establishes kidney as source of bleeding not lower urinary tract
Signify glomerular disease
White blood cell casts
contain lobed nuclei of neutrophils
Signify inflammation within the kidney (pyelonephritis, interstitial nephritis, allergic interstitial nephritis)
Tubular casts
entirely renal tubular cells, singular round nuclei
Suggest acute tubular necrosis, viral disease, drug/toxin exposure
Granular casts
trapped cellular debris or protein aggregates
Immune complexes, fibrinogen
Nephritic syndrome
inflammatory injury of glomeruli, can progress very rapidly and often responds well to treatment
i.Glomerulonephritis may involve: mesangium, podocytes, capillaries/endothelium or parietal epithelial cells
Clinical features of nephritic syndrome (6)
- Hematuria
- Proteinuria
- Hypertension
- Edema
- Reduced GFR
- Active urine sediment
Proteinuria in nephritic syndrome
(usually sub-nephrotic)
a.Due to direct damage to glomerular capillary wall, induced by immunologic mechanisms → increased protein filtration
b.Typically
Hypertension in nephritic syndrome
Consequence of salt and water retension
Edema in nephritic syndrome
Increase in tubular reabsorption of salt and water due to reduced glomerular perfusion → expansion of extracellular fluid volume
Reduced GFR in nephritic syndrome
Due to acute inflammatory process within glomerulus → glomerular vasoconstriction, occlusion, or thrombosis of glomerular capillary loops → reduction in filtrated SA
Active urine casts in nephritic syndrome
(RBC, WBC, and RBC casts)
a.Due to glomerular inflammation and disruption of GBM
Physical exam of nephritic syndrome
rashes, lung disease, neurologic abnormalities, evidence of viral or bacterial infections, MSK/hematologic abnormalities
Labs: nephritic syndrome
CBC, electrolyte panel, 24 hour urine collection (protein and creatinine clearance), liver function tests
Seriologies: nephritic syndrome
Complement C3, ASO titer, ANA, ANCA, cryoglobulins, anti-GBM ab
Importance of tissue diagnosis in nephritic syndrome
required to confirm clinical findings
Immune complex deposition in glomerulonephritis
in mesangium or subendothelial space → inflammatory mediators into circulation → influx of inflammatory cells
- Subendothelial space → can generate things and easily dump then in the blood → lots of inflammation
- Subepithelial space → less inflammatory (e.g. membranous disease)
- Mesangial → intermediate
Gloemerular Emdothelial injury in nephritic syndrome
caused by abs to glomerular basement membrane (anti-GBM) → necrotizing injury to glomerular capillaries (ANCA-mediated vasculitis)
Light microscopy in nephritic syndrome
glomeruli examined for cellularity, scarring
- Segmental = part of one glomerulus
- Focal = only some glomeruli involved
- Crescents = proliferation of cells in Bowman’s capsule, associated with severe disease
a. Usually associated with: ANCA, Lupus and anti-GBM
Immunofluorescense in nephritic syndrome
look for presence of immunoglobulins (IgA, IgG, IgM, or complement) and pattern of staining (capillary vs. mesangial)
Electron microscopy of nephritic syndrome
morphology of BM
1.Fusion of podocyte foot processes, presence and location (mesangial, subendothelial, subepithelial) of any immune deposits
Treatment of nephritic syndrome
Drugs that block the immune response:
- Prednisone
- Rituximab
- IVIG
- Cyclophosphamide
Plasma exchange: only done in severe autoantibody disease
Clinical syndromes of glomerular disease: (5)
- asymptomatic hematuria/proteinuria
- acute nephritic syndrome
- Rapidly progressive nephritic syndrome
- Nephrotic syndrome
- Chronic renal failure
Acute nephritic syndrome
(hematuria/proteinuria + ARF)
- Increase glomerular capillary permeability
a. Hematuria, proteinuria - Decrease GFR
a. Na+, H2O retention → edema, CHF, HTN
b. Azotemia
c. Hyperkalemia
Rapidly progressive nephritic syndrome (RPGN)
occurs over hours to days
- Increase glomerular capillary permeability
a. Hematuria, proteinuria - Big decrease in GFR
a. More fluid retention
b. More azotemia
c. Oliguria
d. Serum creatinine disorders
RPGN is associated with (3)
a. Anti-GBM disease
b. ANCA associated vasculitis
c. Lupus
Tx of RPGN
Requires more aggressive therapy (cytotoxic drugs, plasma exchange)
Nephrotic syndrome
Massive proteinuria (>3.5 g/d) not compensated by hepatic albumin synthesis
Decreased oncotic pressure → H2O and Na+ retention → massive edema, hypercholesterolemia, etc.
Chronic renal failure
- Nephron loss → decreased GFR
- Uremia
- Etiology:
a. Glomerular disease
b. Vascular disease (HTN)
c. Infections
d. Drugs/Toxins
e. Urinary tract obstruction
4 morphologic glomerular changes that accompany glomerular injury
- Cell proliferation
- Leukocyte infiltration
- Basement membrane thickening/changes
- Sclerosis
Cell proliferation in glomerular injury
- Mesangial
- Endocapillary (occlusion of capillary loops)
- Epithelial (podocyte → crescents)
a. Reaction to severe injury to glomerular capillaries - Inflammatory cells
9 nephritic diseases
- Benign familial hematuria
- Alport’s Disease
- IgA nephropathy
- Anti-GBM disease
- Postinfectious GN
- Focal necrotizing/crescentic GN
- Lupus GN
- Pauci-immune renal vasculitis
- . Cryoglobulinemia
Benign familial hematuria
(thin BM disease)
- Mutation in genes encoding collagen IV
- Need to differentiate from Alport’s syndrome
- Dx based on electron microscopy
Alport’s disease
triad = nephritis, deafness, ocular lesions
- Mutation in alpha-5 chain of collagen IV → can’t form normal BM
- X-linked
- Dx based on electron microscopy (basket-weave pattern)
- Usually progress to end stage renal disease
IgA nephropathy
mesangial proliferative glomerulonephritis with predominance of IgA immune deposits in mesangium (rare in subendothelial)
Epidemiology of IgA nephropathy
most common type of acute glomerulonephritis
a.Males 15-35 years old
Clinical presentation of IgA nephropathy
usually asymptomatic microhematuria, non-nephrotic proteinuria, and normal/mildly reduced renal function
a. Occasional gross hematuria (red cell casts) due to viral illness
b. Systemic syndrome sometime in kids (fever, rash, GI problems, renal disease) = Henoch-Schonlein Purpura
- Skin biopsy → IgA deposits
c. Coincides with URI or GI infection, liver disease
Pathogenesis of IgA nephropathy
deposition of IgA immune complexes to mesangium → activation of mesangial cells via Fc alpha receptors → cell proliferation, matrix expansion
Light microscopy, EM, and IF of IgA nephropathy
Light microscopy → increase in mesangial cell # and matrix
EM → Mesangial deposits
IF → Mesangial IgA , IgG, and C3 in a mesangial pattern
Treatment of IgA nephropathy
steroids, ACEi
a.25-50% of patient progress to slowly to renal failure
Henoch-Schonlein purpura
systemic IgA vasculitis
a. Systemic deposition of IgA immune complexes
b. Involves kidneys, skin, joints, GI tract
c. Renal biopsy looks like IgA nephropathy
d. Usually in kids younger than 10 yrs
- Post URI (strep)
e.Purpuric rash on arms and legs
Anti-GBM disease
severe, rapidly progressing GN +/- pulmonary hemorrhage
- Goodpasture’s Syndrome: pulmonary hemorrhage, iron deficiency anemia, GN with circulating ab to GBM
a. Rare, mostly young males
Pathology of Anti-GBM diseased
Ab binding antigens in type IV collagen within GBM → linear IgG deposits, complement activation, neutrophil infiltration
b. Extensive crescent formation
c. Rapid loss of renal function (RPGN)
Clinical presentation of anti-GBM disease
Pulmonary hemorrhage precedes renal involvement (if pulm involved)
b. ELISA assay detection of anti-GBM ab
c. Anti-GBM kidney biopsy
Treatment of anti-GBM disease
a. Untreated anti-GBM disease rapidly progresses to ESRD
b. Steroids, immunosuppressive agents, plasma exchange
c. Common recurrence of disease in transplanted kidneys too
Postinfectious GN
Acute nephritic syndrome
1.Post Group A streptococcus infections - occurs 14 days after throat infection 21 days after skin infection
Epidemiology of postinfectious GN
most common in children of developing countries
a.Most kids recover completely, 60% of adults recover
Pathogenesis of postinfectious GN
exogenous immune complex
a.Ab response to strep antigens → circulating immune complexes lodge in glomeruli and activate complement
Light microscopy, IF, and EM of ppostinfectious GN
a. Light microscopy → Diffuse, proliferative, exudative GN with infiltrative neutrophils and monocytes
b. Immunofluorescence → granular deposits of IgG and C3 in subendothelial, mesangial and subepithelial locations
- “Starry Sky” Pattern
c. EM → subendothelial and mesangial deposits
- Classic “subepithelial humps”
Clinical presentation post-infectious GN
a. Sudden weight gain
b. Hematuria, nephrotic proteinuria, GFR decreased
c. Severe HTN
d. Elevated abs and ASO (Strep antigens), decreased complement (C3), normal C4
Treatment of postinfectious gn
supportive
a. Self-limited disease
b. Very small risk of some irreversible renal damage
Focalnecrotizing/crescentic GN
not a specific disease, a histological pattern
- Crescents = histologic sign of severe acute glomerular disease
- Caused by fibrinoid necrosis of capillaries
- Clinically present as RPGN
- % of glomeruli with crescents correlates with serum creatinine and prognosis
- Glomeruli usually heal with a scar
- Diverse etiologies
Lupus glomerulonephritis pathogenesis
loss of tolerance to self-antigens, generation of autoantibodies
a.Immune complex deposition in kidney (ANA and anti-dsDNA)
Epidemiology of lupus GN
Renal involvement in 70% of SLE patients
Pathology of Lupus GN
immune complexes in mesangium, subendothelial space, and subepithelial space
a. “Full house” on IF → granular immune complex pattern with + IgG, IgA, IgM, C1q, and C3
b. Deposits are “Lumps and bumps” pattern (different from linear seen on anti-GBM disease)
Treatment of Lupus GN
high dose steroids, cytotoxics
Pauci-immune renal vasculitis
Small vessel vasculitis without evidence of immune complex deposition
a.Includes GPA, MPA, Eosinophilic granulomatosis with polyangitis
Pathology of Pauci-immune renal vasculitis
fibrinoid necrosis, crescents
a.NO immune complexes
Clinical presentation of pauci-immune renal vasculitis
a. +ANCA (MPO or PR3): Cytoplasmic-ANCA or Perinuclear-ANCA
b. Multiple organ systems (skin, lungs, GI)
- Alveolar capillaritis, pulmonary hemorrhage
c.Nephritic pattern of renal disease
Treatment of pauci-immune renal vasculitis
a. Immunosuppressive drugs (high dose steroids, cyclophosphamide)
b. Plasma exchange
Cryoglobulinemia
Abs that precipitate in cold - in vivo cause immune-complex precipitation in small vessels → vasculitis)
Pathogenesis of cryoglobulinemia
a. Commonly associated with HepC
b. Also associated with lymphoproliferative disorders, autoimmune disease (Sjogrens) and other infections
Pathology of cryoglobulinemia
a. Immune complex glomerulonephritis
b. Membranoproliferative pattern of injury and subendothelial immune deposits
c. Microtubular structures with deposits with “fingerprint” appearance
Clinical presentation of cryoglobulinemia
a. Effect numerous different tissues throughout body → palpable purpura, arthralgias, generalized weakness
b. Proteinuria, hematuria, slowly progressive disease
c. Low C4 level
Treatment of cryoglobulinemia
a. Antiviral therapy for HepC
b. Rituximab for lymphoproliferative disease
c. Plasmapheresis to remove cryoglobulins
