Renal Week 1 Flashcards Preview

CVPR > Renal Week 1 > Flashcards

Flashcards in Renal Week 1 Deck (287):

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

main componenets

aggregate intracellular volume of all cells

⅔ of total body fluid (27 L)

Main ICF = K+, PO4 3-, Mg2+, proteins


Extracellular compartment

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



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


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


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)



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



-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 =

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


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)


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



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


--> 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



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?


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

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



Chloride and water transport across tubular epithelium

-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 >>>> 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


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



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)



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)



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



build up of nitrogenous wastes in the blood (e.g. BUN and creatinine)



Urine volume less than 500 ml/24 hours in a normal sized adult



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


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


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?

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)

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

+/- blood
no protein
Microscopic --> Granular casts, RTEs (renal tubular epithelial cells)


UA pattern of obstructive (post-renal azotemia)

-no blood
-no protein
-normal microscopic


Chemistries for pre-renal azotemia

-urine Na

-urine Na less than 20
-Ucr/Pcr > 20
-Uosm increased
-FENa less than 1


Chemistries for Acute tubular necrosis

-urine Na

-urine Na > 20
-Ucr/Pcr less than 10
-Uosm = isosmotic
-FENa > 2



filtering units of kidney, take 20% of CO - essentially a ball of capillaries

-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)



create most important barrier to size with slit diaphragm extending between cells and GBM via long “foot processes”



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


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



5 defining features of nephritic syndrome

Decreased renal function
RBC and RBC casts (hematuria)
Proteinuria (


Nephrotic Syndrome

major glomerular abnormality causing excessive leak of protein through the glomerular capillary wall into the urinary space



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: +/-
-ACEi (decrease proteinuria)
-Vit D replacement
-Normal or slightly low protein diet


Hereditary Nephrotic Syndrome

-what mutation?
-most common in who?

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)

1) Peak incidence 2-8 yrs
2) Edema, ascites, weight gain
3) Normal BP

1) Normal/slightly depressed renal function

Urinalysis →
2) 4+ protein
3) hyaline casts
4) microscopic hematuria


Minimal change disease:

Associations? (3)

Hodgkin’s lymphoma


Minimal change disease:


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)

Peak incidence between 20-40yrs
Most common in African Americans

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


-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


mediated by antibodies to phospholipase A2 receptor on podocytes


Membranous Nephropathy

treatment (2)

corticosteroids and cyclophosphamide (cytoxan)
Some progress to ESRD


Membranoproliferative Glomerulonephritis (MPGN) Type I


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)




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)


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


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 = >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)



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



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)

1. Hematuria
2. Proteinuria
3. Hypertension
4. Edema
5. Reduced GFR
6. 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



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

1.Subendothelial space → can generate things and easily dump then in the blood → lots of inflammation

2.Subepithelial space → less inflammatory (e.g. membranous disease)

3.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

1.Segmental = part of one glomerulus

2.Focal = only some glomeruli involved

3.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:


Plasma exchange: only done in severe autoantibody disease


Clinical syndromes of glomerular disease: (5)

1. asymptomatic hematuria/proteinuria
2. acute nephritic syndrome
3. Rapidly progressive nephritic syndrome
4. Nephrotic syndrome
5. Chronic renal failure


Acute nephritic syndrome

(hematuria/proteinuria + ARF)

1.Increase glomerular capillary permeability

a.Hematuria, proteinuria

2.Decrease GFR

a.Na+, H2O retention → edema, CHF, HTN


Rapidly progressive nephritic syndrome (RPGN)

occurs over hours to days

1.Increase glomerular capillary permeability

a.Hematuria, proteinuria

2.Big decrease in GFR
a.More fluid retention
b.More azotemia
d. Serum creatinine disorders


RPGN is associated with (3)

a. Anti-GBM disease
b.ANCA associated vasculitis


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

1. Nephron loss → decreased GFR

a.Glomerular disease
b.Vascular disease (HTN)
e.Urinary tract obstruction


4 morphologic glomerular changes that accompany glomerular injury

1. Cell proliferation
2. Leukocyte infiltration
3. Basement membrane thickening/changes
4. Sclerosis


Cell proliferation in glomerular injury

1. Mesangial

2.Endocapillary (occlusion of capillary loops)

3.Epithelial (podocyte → crescents)

a.Reaction to severe injury to glomerular capillaries

4.Inflammatory cells


9 nephritic diseases

1. Benign familial hematuria
2. Alport's Disease
3. IgA nephropathy
4. Anti-GBM disease
5. Postinfectious GN
6. Focal necrotizing/crescentic GN
7. Lupus GN
8. Pauci-immune renal vasculitis
9.. Cryoglobulinemia


Benign familial hematuria

(thin BM disease)

1.Mutation in genes encoding collagen IV

2.Need to differentiate from Alport’s syndrome

3.Dx based on electron microscopy


Alport's disease

triad = nephritis, deafness, ocular lesions

1.Mutation in alpha-5 chain of collagen IV → can’t form normal BM


3.Dx based on electron microscopy (basket-weave pattern)

4.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

1.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


a.Self-limited disease

b.Very small risk of some irreversible renal damage


Focalnecrotizing/crescentic GN

not a specific disease, a histological pattern

1.Crescents = histologic sign of severe acute glomerular disease

2.Caused by fibrinoid necrosis of capillaries

3.Clinically present as RPGN

4.% of glomeruli with crescents correlates with serum creatinine and prognosis

5.Glomeruli usually heal with a scar

6.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



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