URINARY CONCENTRATION AND DILUTION
o When Plasmaosm is not :: plasma [Na]
 ↑ = excess , ↓ = deficit
 Sodium
o main cation in ECF = Na
o Size of ECF volume :: Total body Na content
 ECF volume ↓ = ECV ↓ = Total body Na ↓
 Assessed by HTN, Edema, Pulm crackles, Ascites
 ECF volume ↑ = ECV ↑ = Total body Na ↑
 Assessed by Hypotension, Tachycardia, Orthostasis
 So Assessed by physical exam (Not by Na concentration)
 Or by intravascular monitoring
 Water
o In ICF and ECF
o Osmolality = # of particles/kg H2O
o ICFosm ≈ ECFosm (ECF includes Plasmaosm)
o Plasmaosm :: Plasma [Na] :: (1/Total Body Water)
o TBW ↑  ↓ Posm  ↓ Plasma [Na]
o TBW ↓  ↑ Posm  ↑ Plasma [Na]
o TBW assessed by serum/plasma [Na]
 Calculated Plasma Osmolality (when no measuring device available)
o = (2*Na(mmol/L)) + (Glucose(mg/dL)/18) + (BUN(mg/dL)/2.8)
o ≈ 290 usually
o Can be different from measured Plasma Osmolality b/c of
presence of other unknown solutes
 Assessment
o Total body Na content assessed by physical exam/intravasc
o Total body H2O content assessed by Plasma [Na]
o Plasma [Na] = (Total Body Na) / (Total body H2O)
 Example 1 = ↓ = ↑/↑
 If pt has edema, crackles, etc = ↑Total body Na content
 Then if lab values show ↓plasma [Na]
 This means  Relative to Na content, TBW is High
 Example 2 = ↓ = ↓/↑
 If pt has hypotension, dry mucous = ↓Total body Na content
 Then if lab values show ↓plasma [Na]
 This means  Relative to Na content, TBW is High
 Example 3 = ↑ = ↓/↓
 If pt w/ hypotension, dry mucous = ↓Total body Na
 Then if lab values show ↑plasma [Na]
 This means  Relative to Na content, TBW is Very Low
 TBW content is described relative to Na content
 Giving Isotonic NaCl fluid, or just H20 or just NaCl
o Caveats –
 Any NaCl given(w/ or w/o H2O) will remain in ECF
 Any H2O given will distribute into ECF and ICF
o Example 1 = Give Isotonic NaCl
 NaCl will remain in ECF and b/c its isotonic to ICF, H2O will
also stay in ECF
 ECF will ↑
 No change in osmolality
o Example 2 = Give just H2O
 H2O will spread to both ECF and ICF
 ECF will gain 1/3 of the H20 given and ICF 2/3
 ECF↑ and ICF↑
 Osmolality↓ b/c no solutes given
o Example 3 = Just NaCl given
 NaCl will stay in ECF
 H2O will move from ICF to ECF
 ECF will ↑ and ICF ↓ in size
 Osmolality ↑ and stabilize at new equilibrium
 Pseudohyponatremia
o 2 types of situations
o 1) Artifactual hyponatremia
 Na only dissolves in H2O
 Plasma also contains solids like lipids and proteins
 So Plasma [Na] will be measured as 140 instead of 150
 2 conditions make this fake decrease even worse
 Hyperlipidemia
 Hypergammaglobulinemia (seen in Multiple Myeloma)
o 2) Hyperosmolal Hyponatremia
 In uncontrolled diabetes  pt is in hyperglycemia
 So ↑glucose in ECF  H2O moves from ICF to ECF
 [Na] ↓  so pt is Hyperosmolal but Hyponatremic
 [Na] is not proportional to Plasmaosm
 After pt is treated w/ insulin  what will be new plasma [Na] ?
 For every 100mg/dL that blood glucose was above 200, add
1.6 mM to the old plasma [Na] value
 So if pt had glucose of 1100, add 1.6*9 to get new [Na] = 139
 But if new [Na] = 150 = ↑Plasmaosm = TBW deficit possibly
due to osmotic diuresis due to original hyperglycemia
 Thirst
o ↑Plasmaosm(main), or ↓blood volume or ↓BP will cause thirst
o Osmoreceptor (TRPV1 channel) in hypothalamus detects plasma
osmolality and is also stimulated Angiotensin II
o Sensation of thirst and ADH secretion stop by act of drinking
o ↑Plasmaosm + TRPV1  magnocellular neuron  ADH
secretion  Water reabsorb by kidney  ↓Plasmaosm
 ADH threshold and sensitivity
o A small ↑ in Osm from normal = set point or threshold (x
intercept)  ADH release
o As Osm↑, the slope of the rise = sensitivity
o These both can be affected by drugs, preg, BP, diseases etc
 Control of ADH secretion
o Osmoreceptors (mentioned above)
o Baroreceptors – respond to stretch
 Low Pressure receptors = Atria, Pulm vessels detect ↓volume
 High Pressure receptors = Aortic Arch and Carotid Sinus
 Signals sent to brain via CN 9 and 10
 ↑Pressure  nerve fires  signal ADH secretion inhibition
 Normal condition = ADH under tonic inhibition
 ↓Pressure  Nerves stop firing  disinhibition
o Other factors – pO2, pCO2, pain, nausea, NTs
 ADH Effect on Kidney
o Site of Action
 ↑Reabsorb of solutes @ Thick Asc Loop of Henle
 ↑Perm to H2O and Urea @ Collecting Duct
o Result
 ↑Medullary osmotic gradient
 ↑Urinary Conc
o Mode of Action
 Stim the Na/K/2Cl transporter @ TALH
 Stim H2O reabsorb by principal cells @ CD
 Stim Urea reabsorb @ inner medullary CD
o Molecular Mechanism of ADH on principal cells @ CD
 1) ADH binds V2 receptor on basolateral side of principal cell
 Basolateral side = side bordering interstitium not CD
 2) V2 receptor + AC  ↑cAMP + protein kinase A 
 3) insertion of AQP2 channels into apical (luminal) side
 4) H2O enters principal cell and leaves cell to blood via AQP3
or AQP4
o Removal of ADH 
 Internalize/shed AQP2  apical side impermeable to H2O
 Countercurrent Multiplication - Henle Loop  Calculation of Body H2O Content
o Fluid leaving PCT = isotonic to plasma o TBW = 0.6 * kg
o Desc Loop = H20 Perm o ICF = TBW * 2/3
o Thick Asc Loop = H2O Imperm, Active Solute Reabsorb o ECF = TBW * 1/3
 aka diluting segment  Interstitial Volume = ECF * ¾
 Na/K/2Cl cotransporter reabsorbs solutes from tube to cell  Plasma volume = ECF * ¼
 Na/K ATPase on basolat side needed for cotransporter fxn o If given hypoosmotic plasma + Low plasma [Na]
o Medullary interstitium = Solutes reabsorbed from TALH sits here  Calculate the TBW excess
and creates a high Osm in interstitium as you go deeper down o If given hyperosmotic plasma + High plasma [Na]
o So as the fluid comes down Desc loop, H2O reabsorb into  Calculate TBW deficit
interstitium to equilibrate  This ↑Osm in tube o To do this use the formula – M1V1 = M2V2 
o As this high osm fluid goes to Asc loop, the solute is reabsorbed  TBWideal * Posm normal = TBWabnormal * Posm abnormal
 this ↓osm in tube as it goes up.  When TBWabnormal calculated  do TBWabnormal - TBWideal
o The high osm at bottom of interstitum provides H2O to be
reabsorbed at the CD (in presence of ADH)  concentrating urine
 Countercurrent Exchange – vasa recta
o Perm to Solutes + H2O URINARY CONCENTRATION AND DILUTION
o Provides nutrients and O2 for tubules
o Maintains the interstitial gradient Demonstrate ability to calculate free water clearance
 Medullary interstitial gradient Demonstrate ability to calculate free water deficit/excess
o Contains Na, Cl, Urea 2 Identify mechanisms and treatments in urinary concentrating
o Steepness of gradient = defect
 Directly related to rate of solute reabsorb by TALH Identify causes of hyperosmoial hyponatremia
 Inversely related to tubular flow rate (pseudohyponatremia)
 Inversely related to vasa recta flow rate Identify symptoms of hyponatremia
 Urea Identify the stimuli that result in vasoperession secretion
o Freely filtered at glomerulus Identify urinary concentrating defect
o Reabsorb by prox tubule To understand factors effecting GFR
o Secreted by prox straight tubule, Desc limb, Thin Asc limb To understand factors effecting urinary concentration
o Reabsorbed by inner medullary of CD (deepest part) Understand the changes in ECF volume resulting from infusion of
o Urea excretion need for different types of fluids
 Removal of Nitrogen waste
 ↑urinary concentration
o Urea Recycling mechanism
 Urea reabsorb @ terminal CD  into Asc Vasa Recta 
diffuse to Desc Vasa Recta and also secreted into prox straight
tubule  Desc loop  Asc loop  Reabsorbed into
interstitium
 Rest of urea continues to CD  as H2O is reabsorb in cortex
and outer medulla, Urea ↑conc  urea at innermost medulla
reabsorbed and some excreted
 Max Urinary Dilution done w/ -
o Normal GFR and Prox Tub fxn
o Normal TALH fxn
o NO ADH
 Max Urinary Concentration done w/ -
o Normal GFR and Prox Tub fxn
o Normal TALH fxn
o YES ADH
 Quantitation of Dilution and Concentration
o Single Effect – of separating solute from H2O  allows kidney to
make a volume of water in urine that is Free of solute – Solute
Free Water
o Free water clearance = volume of urine that is solute free after
removal of volume of urine that is iso-osmotic to plasma
 It is not like a classic “clearance” definition
o Osmolal Clearance (Cosm) = (Uosm * V) / Posm
o Free water Clearance (CH2O) = V - Cosm
o Uosm/Posm < 1, CH2O > 0  Urine is dilute (hypoosmotic)
o Uosm/Posm = 1, CH2O = 0  Urine is isosmotic to plasma
o Uosm/Posm > 1, CH2O < 0  Urine is concen. (hyperosmotic)
 When CH2O < 0  water was reabsorbed
o See Page 25 for example calculations****
o CH2O calculated b/c need to estimate speed/magnitude of loss of
water when correcting someone w/ hypoosmolal hyponatremia b/c
too rapid or too great ↑Plasma [Na]  Permanent Brain damage
 Disorders of Body Fluid Osmolality  2 approaches
o Look at Urine = mechanistic view
 Problem in dilution or concentration?
o Look at plasma [Na] and physically examine patient
 Is there excess or deficit in body water?
 Disorders of Urinary Concentration
o Signs
 If H2O available Polyuria/Polydipsia
 If H2O not avail  ↑Posm/confusion/coma
 If very severe  ECF depletion signs  ↓BP, ↑HR, etc
o Causes of Urinary Concentration Defect
 ↓PCT fluid reabsorb b/c of
 osmotic diuresis (Diabetes)
 ↓TALH solute reabsorb b/c of
 NaK2Cl transporter inhibition (loop diuretics)  can’t absorb
solutes into interstitium to create gradient for CD to
concentrate the urine
 Or damage to TALH (acute tubular necrosis, obstruction,
sickle cell, NSAIDS/aspirin)
 ↓Medullary interstitial gradient b/c of
 ↑flow rate (osmotic diuresis, polydipsia)
 Lack of Urea (protein malnutrition)
 NaK2Cl inhibition (loop diuretics)
 V2 receptor defect
 Damage to vasa recta (obstruction, sickle cell,
NSAIDS/aspirin)
 ADH related problems
 Lack of ADH = Central Diabetes Insipid (damage to pit stalk)
 Principal cell unresponsive to ADH = Nephrogenic DI
(genetic problems in V2 or AQP2, or acquired problems like
↑Ca, ↓K that cause abnormal # of AQP2)
o Causes of Inadequate H2O intake
 Thirst deficiency (tumor/infarct of brain)
 Can’t obtain water (Baby, not conscious, desert, paralysis)
 Intake of hypertonic salt w/o water (sea water, IV solution)
 Impaired ADH synthesis (DI)
o Clinical approach to the hyperosmolality (hypernatremia)
 First evaluate if pt has low/normal/high ECV  Physical Exam
 Low ECV (↓BP, dry mucous membrane, poor skin turgor, etc)
 Diarrhea/vomit, osmotic diuresis, can’t access water/food,
excess sweating (cystic fibrosis)
 Tx – isotonic saline until BP improves, then switch to
hypotonic saline (because lack H2O more than Na)
 Normal ECV – maybe central or nephrogenic DI
 If Normal  Tx – H2O w/ dextrose (D5W)
 If central DI  Tx – ADH analogue (dDAVP)
 If Nephrogenic DI  Tx – Hydrochlorothiazide (prevents
reabsorb of solute at DCT, which is imperm to H2O)
 High ECV (↑BP, edema, pulm crackles, ascites) – Rare/iatrog
 Na bicarb injections, hypertonic breast milk
 Tx – D5W
 Disorders of Urinary Dilution
o Signs – due to brain cell edema
 Headache/nausea/vomit/Confusion/muscle cramps
 Focal neuro signs/seizures/coma
 Death from brain herniation
o Causes of impaired urinary dilution
 ↓GFR (renal fail, low Cardiac output)
 ↑PCT fluid reabsorb (↑Angiotensin II due to Heart/liver failure)
 ↓TALH solute reabsorb
 NaK2Cl transporter inhibition (loop diuretics)  can’t
reabsorb solutes so can’t dilute the urine
 Inhibition of NaCl transporter in cortex TALH or DCT
(thiazide diuretics)
 Glucocorticoid deficiency (adrenal problem)
 ↑H2O perm @ CD
 Presence of ADH even during hypoosmolality
(CHF/baroreceptor problem, cirrhosis, hypoxia, hypercapnia,
SIADH)
 ↑ADH action on CD (many drugs)
o Causes of Hypoosmolality Hyponatremia
 H2O intake greater than Kidney’s ability to excrete
 Pure H2O intake w/ losses in Na and H2O
 Diuretics, Diarrhea, Vomiting
 H2O intake + ADH secretion  ecstasy
 Abnormal osmoreceptor fxn - reset osmol threshold to lower
 Stim of baroreceptors even during ↓Plasma os
 Hemorrhage/hypotension
 Insensitivy of baroreceptors to volume/pressure stimuli
 CHF/liverliver fail
 ADH secretion despite hypoosmolality
 (CHF/baroreceptor problem, cirrhosis, hypoxia, hypercapnia,
SIADH)
 ↑ADH action on CD (many drugs)
o Clinical approach to the hypoosmolality (hyponatremia)
 First evaluate if pt has low/normal/high ECV  Physical Exam
 Low ECV (total body Na deficit) – Hypotension/Tachy/↓BP
 GI, skin burns, mineralocorticoid deficit (addison’s)
 Normal ECV
 Hypothyroid, glucocorticoid def, hypoxia, hypercapnia,
SIADH
 High ECV (Total body Na excess)
 CHF, cirrhosis, renal fail, nephrotic syndrome
o Tx for hyponatremia
 H2O restriction
 Normal isotonic saline (for low ECV)
 Drugs for chronic hyponatremia = Demeclocycline, Aquaretics
(vaptans)
 Death assoc w/ osmolality disorders
o Hyperosmol disorders  brain volume ↓
 High mortality
 Death from underlying comorbid state
o Hypoosmol disorders  brain volume ↑
 Low mortality
 Death from brainstem herniation
 Correction of hypoosmolal  demyelination
 Too rapid correction (>6mM/24hrs)
 Too great a correction (to >125 mM on day 1)
 Leads to vegetative state, locked in syndrome, death
CHRONIC KIDNEY DISEASE  Potassium Problems
o Normally all K filtered gets reabsorbed  any K in urine is by
 Markers secretion @CD principal cells
o BUN = no tubular secretion , only filtration o CKD  ↑Aldo levels
 Affected by diet, liver dz, urine flow rate  ↑uptake by muscles + excretion by GI + ↑Renal excretion
 Not sensitive  ↑K only seen in late CKD (GFR <20)
o Creatinine = Mainly filtered, some secreted  ↑K in Early CKD due to
 Considered  Amount filtered = Amount excreted  Lack of Aldo
 Secretion ↓ (so serum level ↑) w/ Trimethoprin, cimetidine o Diabetics  ↓Renin and ↓Aldo
 SCr ↑ from 1 to 2 ( GFR↓ 120 to 60) is worse than 2 to 4 o Drugs that affects Aldo
 Not sensntive o Alter Aldo = ACEi/ARB, Spironolactone, Heparin
o GFR o Alter Na channel = Triamterene, Amiloride, Pentamidine
 Measured = 24 hr urine for creatinine excretion o Alter K distribution = Non-select BB, Digoxin, NSAIDs
 Estimated (See notes for formulas)  Low flow states = Pre-Renal Azotemia
 Cockroft Gault – memorize  Excessive K intake
 MDRD (Modification of diet in renal dz)  Tissue breakdown – seizure, hemolysis
o PCr, Age, gender, race  Leads to Metab Acidosis, ↓sensitivity to insulin (↓influx to
o Good estimate when low GFR muscles)
 CKD-EPI = Good estimate in low and high GFR o Treatment
 Categories  Limit K intake and stop Drugs that ↑K
 G1 >90  normal  Treat Acidosis
 G3 = 44-60  Mod to severely decreased  Insulin + D5W
 G5<15 kidney failure  Beta-Agonist to cause K shift into cell (only used acutely)
 Risk of mortality and CV event not till GFR<60  Lasix (Furosemide) = Excrete more K
o Albuminuria (Albumin excretion rate)  Keyexealate = bowel mvmt and ion exchanger
 A1 <30  normal  Calcium/Vit D problems
 A2 >30  microalbuminuria o ↑P and ↓Active Vit D  ↓Ca  ↑PTH (↑P solely can ↓Ca)
 A3 >300  macroalbuminuria  Bone resorption of Ca + P
 Risk of mortality and CV event not till >30  Kidney reabsorb Ca, excrete P, ↑Calcitriol synth
o Labs and Sx only seen after 50 kidney loss  As time prog  GFR↓  P Peak + Ca Dip  PTH ↑
 Definition of CKD o Renal Osteodystrophy
o Kidney damage > 3 months w/ or w/o GFR↓  Osteitis Fibrosa Cystica = ↑Bone resorption
 Damage seen by patho or markers/imaging  Salt and pepper skull, thinning of distal clavicle, phalynx
 GFR <60 >3 months w/ or w/o kidney damage  Rugger Jersey Spine  Kyphosis, Scoliosis
o Causes  Excess P and Ca deposit in Soft tissue and arteries (Aorta*)
 1 = Diabetes Dialysis when  Volume Overload, o Treatment
 2 = HTN Persistent ↑K, Acidosis, ↑P, GFR <10 (<12  ↓P via diet restrict (↓Seeds, nuts, dry fruits, dairy, eggs)
 3 = Glomerulonephritis in diabetics), Uremic Sx  P Binders when using P rich food
 Blacks have ↑Risk  Active Vit D Supp = Calcitriol
o Progression to CKD  Chemical Changes in CKD w/ time (Seen when GFR 30-40)
 Early = ↑SNGFR 2-3x (to compensate for loss of nephrons) o ↑Creatinine, BUN  ↑P  ↑Uric Acid  ↓BiCarb  ↑K (late)
 Later = Hyperfiltration  Hormonal Changes
 Eventually = Hyperfiltration injury w/ more loss of nephrons o Hormones ↓
 Salt and Water problems  Active Vit D  Osteomalacia, OFC
o Isothenuria = inability to concentrate and dilute urine  EPO  Anemia
o Management  Somatomedin (GH)  ↓Growth in children (Tx w/ exo GH)
 Restrict Salt + Fluid Intake  Testosterone, Estrogen  Impotence, ↓Libido, Infertility
 Use of Loop diuretics (add thiazides if not enough response) o Hormones ↑
 Acid Base problems  Insulin  Pt req ↓ but insulin resistance
o Normally  Prolactin  Lactation
 Carbs and Fat  CO2 + H2O  Lungs  Gastrin  Gastritis  Bleeding  Anemia
 Proteins  Sulfate, Phosphorous, Nitric Acid  Kidneys  Renin-Aldo (to get rid of K)  HTN
o Early CKD (stage 3b, 4) = Non Gap Acidosis  PTH  Osteitis fibrosis, Pruritis
 Due to ↓NH4 excretion = ↓Renal Mass  Symptoms of CKD mainly due to ↑Urea/Guanidino compounds
 GI Bicarb loss, TIN o NM = Asterixis
 ↑NH4 production by tubules  tubule inflamm  prog CKD o CV = HTN, LVH, coronary A. calcification
o Late CKD (Stage 5) = Gap Acidosis  Pericarditis (Serositis) seen in late CKD (Friction Rub)
 Gap due to retention of anions like phosphate, sulfate, urate o GI = Can’t taste food, full easily, halitosis
 Bicarb made by kidneys gets affected so Bone used as a source  Stages
for Bicarb to buffer o 1 = Damage w/ normal GFR of >90
o Alkalosis can also be seen in vegetarians o 2 = damage w/ GFR 60-90  HTN
o Treatment = Oral Bicarb + Low protein diet o 3 = Mild Kidney dz GR 30-60  ↑BUN, Cr / ↓ Ca / nocturia
 Prevents prog of CKD (↑NH4 damages tubules) o 4 = Moderate GFR 15-30  Lots of Sx, ↑P, ↓K, LVH, anemia
 Prevents bone dz (↑Bicarb released causes bone Ca release) o 5 = Kidney failure GFR <15  Azotemia, 2*↑PTH, Acidosis
 Prevents muscle breakdown
Urinalysis  Microscopic Examination
o Cells
 Should be examined within an hour, other put in fridge  RBC = 1-2/hpf = normal
 Clean catch midstream  Monomorphic RBC = Anywhere in UT
 Appearance  Dysmorphic RBC = blood from glomerulus 
o Smoky/Tea/Cola colored (b/c of RBCs) glomerulonephritis
 acute glomerulonephritis  WBC <3-5/hpf = normal
o Foamy = Proteinuria (Nephrotic)  Mainly PMNs
 Specific Gravity  From anywhere in UT
o Dep on # of particles + weight of particles  Granular cytoplasm + nuclei + bigger than RBC
o ↓Conc of urine = ↓SG  Epithelial Cells = 0-2/hpf = normal, >5 = abnormal
 fluid intake is high  Anywhere from PCT to end
 Diabetes Insipidus  Renal tubular cells (tubular injury)
o ↑Conc of urine = ↑SG o Larger than WBC + round nuclei
 Fluid intake is low
 Transitional cells
 Particle w/ high molecular wt (glucose or radio dye)
o 2-4 times bigger than WBC
 SG↑ disproportionately o Anywhere from Renal pelvis to upper part of urethra
 Urine Osmolality o Seen in inflamm states of ureter or bladder
o Dep only on # of particles  Squamous cells
o More accurate than SG to estimate Conc/dilute ability o Large cytoplasm sheets w/ small nuclei
o More difficult test to do than SG o From Urethra and Vagina (seen in vag contamination)
 Dipstick  Oval Fat Bodies
o Protein o Renal tubular epithelial cells w/ fat droplets in cytoplasm
 TALH secretes Tamm-Horsfall Protein  normally most of o Polarized light  Maltese cross of cholesterol and ester
urine protein is by this and not from filtered protein o Sign of Nephrotic syndrome
 Abnormal proteinuria >150 mg/day o Casts
 Dipstick is (+) when >250 mg/day  Formed when tamm horsfall prtein gels
 Very sensitive to Albumin  Material in tubules get trapped in this
 Less sensitive to gamma globulin, bence jones, or tamm-  ALWAYS Renal origin
horsfall  Hyaline Cast
 (-) does not rule out presence of bence jones in a pt w/ MM  Acellular, transparent cast made up of tamm-horsfall
 Tubular disorder = <1.5g/day or 1+ to 2+  Seen during dehydration or after exercise
 Less of normally filtered protein is reabsorbed  RBC Cast
 Glomerular dz = >3.5g/day or 3+ to 4+  Strong sign of glomerulonephritis*
 More protein filtered o Usually seen w/ dysmporphic RBCs
 Overflow states  Even one cast is a sign
 Ig light chain (bence jones) in MM over produced  Rarely a tubular source and a sign of pyelonephritis or renal
 Exceeds reabsorptive capacity infarct
 Contamination by semen, blood, pus, vaginal discharge, mucus  WBC Cast
o Blood  Mainly from PMNs
 Test for intact RBCs, Hemoglobin, Myoglobin  From inflamed interstitium around tubules
 If stick (+) but no RBC under microscope  possibly Rhabdo
 Interstitial Nephritis* or Pyelonephritis
(myoglobin) or intravascular hemolysis (hemoglobin)
 Not seen in bladder infection b/c of renal origin
o Glucose
 Epithelial cell cast
 Seen in uncontrolled DM or if PCT cannot reabsorb glucose
due to a dz (so positive even w/ normal blood glucose)   Renal tubular epithelial cells that slough off and embed in
 Renal Glycosuria (normal blood glucose) hyaline cast
 PCT dz (Fanconi)  Acute tubular necrosis
 Granular cast
 Interstitial Nephritis
 Finely granular cast = debris from all the casts said above
 Pregnancy
 Coarsely granular cast = Muddy brown casts
 Crystals
o Acute tubular necrosis (will also have epith cell cast)
o Acidic urine = Crystals of uric acid, calcium oxalate and
 Waxy Casts
amorphous urate crystals
 Highly refractile and end result of degen of granular cast
 Calcium oxalate due to Ethylene Glycol ingestion
o Alkaline urine = Crystals of amorphous phosphate, triple  Broad Cast = Renal Failure cast in Late CKD
phosphate, ammonium biurate and calcium carbonate o Formed in dilated or hypertrophied tubules
o Calcium Oxalate crystal = envelope or dumbbell shape o 2 to 6 times wider than other casts
 Ethylene glycol ingestion  Fatty Cast
o Uric Acid crystals  Casts w/ lipid, polarized light  maltese cross
o Tripple phosphate cystals = coffin box  Oval fat bodies + free fat droplets + fatty casts  Nephrotic
o Cystine crystal = only one that is pathognomonic
 Cysteinuria and cysteine stones
GLOMERULAR DISEASE  Minimal Change Disease - Child
o After Resp Infxn or vaccination
NephrOtic Syndrome o Pathogen
 Usually a 1° dz
 Sx  2° to NSAIDs, Lymphoprolif dz (Hodgkin’s)
o Heavy Proteinuira >3.5g/day (effacement of Foot Processes)  Immunologic dz – Assoc w/ Hx of allergic reactions
o ↓Albumin (due to urinary loss of protein)  Cytokines  damage visc epithelial (Podocyte) and worsened
o Generalized Edema (Esp periorbital) by loss of Anionic barrier  heavy proteinuria (SELective
 ↓albumin  ↓oncotic pressure for Albumin)
 Worsened by intravasc volume depletion  Renal hypoperfuse o Glomerulus
 (+) RAA  retain Na/H2O  Vicious cycle  LM – Normal
o ↑Lipid  Lipiduria (free fat droplets or oval fat bodies on UA)  IF – Normal
o ↑Risk of infection (due to urinary loss of Ig)  EM – Effacement of foot processes
o ↑Risk of Thromboembolism (loss of AT 3 + ↑fibrinogen) o Px = Very Good! Fast response to CS tx
 Membranous glomerulonephropathy - Adults
o Chronic IC mediated dz NephrItic Syndrome
o *1° Membranous = Ag is Podocyte PLA2 receptor)
 Autoimmune dz  Sx
 Px = Not responsive to CS and slowly prog o Hematuria + RBC casts (b/c complement/Macs make holes in
o 2° Membranous = Circulating Ag planted at foot process GMB)
 Medications - Captopril, Li, Gold, Penicillamine o Azotemia = ↑BUN (due to ↓GFR)
 Chronic infxn - Hep B and C, Treponema, malaria o Oliguria
 Cancers (lung, breast, colon) o HTN
 Autoimmune dz’s (Nuclear components in SLE) o Mild to Mod Proteinuria (b/c glom HYPERcellular so protein not
 Px = dep on inciting Ag easily filtered)
o Pathogen o Edema
 IC form/deposit  (+) MAComplex (C5b-9) Complement   Acute Proliferative Post Streptococcal Glomerulonephritis – Child
epithel and mesangial (+) to produce proteolytics/cytokines o Sudden (Hours to days) onset few weeks after GAS infxn of
capillary wall damage  Heavy Proteinuria (NONselective) pharynx or skin
o Glomerulus o Pathogen = Type 3 HS
 LM – NORMocellular w/ thickening of capillary wall  Infxn w/ nephritogenic strain Ab to microbial Ag (pyogenic
 IF – granular of IgG and complement exotoxin B – SpeB)  form/deposit IC w/in glom 
 EM – SubEPI deposits  Spikes of GBM (Silver stain stains (+)Complement WBC infil + Prolif of Glom cells
GBM w/o IC)  Thick GBM o Glomerulus
 Focal Segmental Glomerulosclerosis (FSGS) – AA/Hispanic Adult  LM – Enlarged, HYPERcellular Glom w/ PMNs/Macs + Prolif
o NONselective proteinuria and Hematuria and HTN of Endothel and Mesangial cells
o 1° FSGS = Idiopathic  IF – Granular of IgG and C3 in GBM and mesangium
 Like severe form of MCD  EM – Very Large SubEPI electron dense deposits – Humps
 Damage to Visc epith (podocytes) Signif plasma protein leak (Few but very very big compared to Membranous)
Massive Proteinuria (NONselective) + Protein accum in o Serum
glomeruli (Hyalinosis)  ↑ECM (Sclerosis)  ↑Antistrept Antibody titers=Anti-Streptolysin O, Anti-DNase B
o 2°  ↓Complement C3 level
 Signif loss of renal tissue  Hyperfiltration o Px
 Reflux Nephropathy and Morbid obesity  Child = Recover w/ conservative Mx (some may  RPGN or
 Previously active focal glomerulonephritis (IgA Nephropathy) Chronic Glomerulonephritis)
 Heroin Addiction  Adults = Less than child
 HIV Infxn directly of glomerulus and tubules  Post Infectious Non Post Strept Acute Glomerulonephritis
 Collapsing Variant (see below)  Non Post Infectious Acute Glomerulonephritis – SLE
o Inherited form (Uncommon)
 Mutation in Podocin/Nephrin protein used for slit diaphragm
o LM –Hyalinosis, Lipid Vacuolization and Sclerosis of glom and
AFF arteriole
 Interstitial Fibrosis and Tubular Atrophy seen (↓blood in AFF)
o IF - +/- IgM and C3 due to leakage from plasma (Not IC med)
o EM – focal detach of visc epith (podo) from BM, ↑ECM
o Collapsing Variant – Assoc w/ HIV
 LM = Retraction of Glom tuft w/ prolif and enlarge of podocyte
+/- FSGS patho
 Tubule = Focal cystic dilatation w/ pink hyaline in tubule
 EM – Same as above + Endothelial cell tubuloreticular
inclusions (alpha-IFN modified ER)
 Px = Very Poor!
o Px – Child>Adults
 Poor response to CS and prog to CKD
 Freq recurs after renal transplant
Nephrotic/Nephritic Syndrome = Membranoproliferative
Glomerulonephritis (MPGN)
 Adolescent/Young Adults
 IC mediated or Complement mediated
 *Type 1 = IC mediated
o Glom IC form/deposit  (+) Classic + Alternative Complement
 WBC infil + Prolif of Glom cells (last part same as strep one)
o 1° Type 1 = Idiopathic
o 2° Type 1
 Autoimmune dz (SLE), Chronic infxn (Hep C), Cancers
o IF
 Granular of IgG, C3, C1q, C4 in periph capillary/mesangium
o EM
 SubENDO deposits + duplication of GBM due to mesangial
cytoplasmic process
 Type 2 = Dense Deposit Dz
o AutoAb – C3 Nephritic factor (C3NeF) binds Alternative Comp
C3 Convertase (C3bBb) and protects it from degradation 
Persistent C3 (+) + Consumption in serum
o IF
 C3 in GBM (next to dense deposits) + in mesangium (as
circular rings) + No IgG, C1q or C4!
o EM
 Extremely Electron Dense material (this is not C3) w/ in
Lamina Densa of GBM  splitting it
 LM – Same for Type 1 + 2
o Lobulated + thick GBM (Nephrotic part)
o Double Contour/TramTrack/Split of capillary wall
o Enlarged, HYPERcellular Glom w/ WBC infil +
Endothel/Mesangial prolif (Nephritic part)
 IF = Different for Type 1 and 2
 EM = Different for Type 1 and 2
 Px
o Unresponsive! w/ prog to CKD (some prog to RPGN)
o Recurs after renal transplant
Rapidly Progressive (Crescentic) Glomerulonephritis (RPGN)
 Severe Glom capillary damage  Fibrinogen leakage into Bowman
space  form Crescent (due to prolif of PARIETAL epith cells)
 NephrItic clinical presentation = hematuria w/ RBC casts, HTN,
proteinuria, edema) but occurs Weeks to Months
 + Rapid loss of Renal fxn w/ Severe Oliguria
 Kidney
o Gross = Swollen, pale, w/ Petechial hemorrhages
o LM = Same for all 3 types
 Crescents of prolif PARIETAL epith cells, Fibrin and WBC
infil w/ in Bowman Space  Compress Glom Tuft
 Endothel/Mesangial prolif
 FSGNecrosis +Tubule injury
o EM = Same for all 3 types
 Wrinkled GBM w/ focal discontinuities (Big holes fibrin
leakage)
 Type 2 = Electron Dense deposits
 Type 1 (Anti-GBM Antibody) = Young Adult Men (Not IC med)
o AutoAb to noncollagen peptide w/ in Type 4 Collagen (exposed
due to environ. insult like Hydrocarbons or Tobacco smoke)
o IF - Linear of GBM for IgG (less intense for C3) and tubule BM
o Limited to Kidney or if w/ Lungs  Good Pasture Syndrome
(Pulm hemorrhage)
o Tx = Plasmapheresis + Immunosupp
 Type 2 = IC Mediated Nephritic presentation
o Complication of IC Glomerulonephritis (Post strep, SLE-
AntiDsDNA, IgA nephropathy) or any of those that deal w/ IC can
become this or cryoglobulinemia
o IF - Granular of IC
o Tx = Tx underlying dz
 *Type 3 (Pauci-Immune) = Small vessel vasculitis
o Circulating ANCA = p-ANCA (Myeloperoxidase-MPO) or
c-ANCA (Proteinase-3 – PR3)
o Limited to Kidney or part of a systemic vasculitis
 p-ANCA = Microscopic polyangitis
 c-ANCA = Granulomatosis w/ Polyangitis (Wegener’s)
o IF – Negative
o Tx = Immunosupp
 Px
o Steady loss of renal fxn  Irreversible Renal Fail
 Serum Complement Levels to Dx AGN and RPGN
o Low level
 Systemic dz = SLE class 3 or 4, Subacute bacterial
endocarditis, “Shunt” nephritis, Cryoglobulinemia
 Renal dz = PSGN, MPGN
o Normal level
 Systemic dz = Wegener’s, Goodpasture’s
 Renal dz = IgA nephropathy, Anti-GBM dz
Isolated Urine Abnormalities Glomerular Pathology Assoc w/ Systemic Dz

 *IgA Nephropathy (Berger dz) – Children/Young Adult  Henoch Schonlein Purpura – Child* Male or Adults (severe renal dz)
o Most common glom dz in world – seen in SE Asia o Form of IgA nephropathy
o Sx o Seen after Upper Resp Infxn
 Microhematuria + Episodic Macrohematuria o Anatomical
 +/- proteinuria  Small BV in skin and GI due to necrotizing vasculitis w/
o Days after a Mucosal Infection (esp Resp) deposition of IgA IC and C3
o Pathogen  Mesangial Deposits of IgA1 IC + Hypercellular
 In suscept pts (genetics)  ↑IgA synth (due to resp infxn in o Sx
setting of Celiac dz, or ↓IgA clearance in hepatobiliary dz)   Palpable purpura on but and dorsal legs/arms, arthralgias,
plasma polymeric IgA↑ (nephritogenic IgA glycosylated)  abdominal pain, GI bleed
form/deposit IgA IC in mesangium  (+) Alternative Comp   Hematuria, proteinuria, HTN, edema
Mesangial injury  Lupus – SLE Glomerulonephritis
o Glomerulus o Renal patho mainly due to IC mediated damage
 LM - Mesangial expansion  Mesangium  Subendo  Subepi
 IF – Granular for IgA and C3 in mesangium o Class 1 = minimal mesangial (normal appearance)
 +/- IgG or IgM (No C1q or C4) o Class 2 = Prolif mesangium
 EM – electron dense deposits in Mesangium + ↑ECM o Class 3 = Focal Prolif
o Prognosis  Scattered glom w/ ↑cellularity + fibrinoid necrosis/thrombosis
 Indolent (some prog to CKD and RPGN) o Class 4 = Diffuse Proliferative (Looks like Post Strep GN)
 Recur after renal transplant  Most glomeruli w/ ↑cellularity + fibrinoid necrosis/thrombosis
 Alport Syndrome = X linked  Tx w/ steroids
o Sx  Class 3 and Class 4 are Type 3 HS aka Nephritic
 Renal = Hematuria w/ RBC casts o Class 5 = Membranous (2° membranous glomerulonephropathy)
 Dev of proteinuria @ childhood and prog to CKD @ adult  Widespread thickening of BM aka Nephrotic
 Auditory  CANNOT Tx w/ steroids
 Sensoryneural hearing loss o Class 6 = Advanced Sclerosing
 Ocular o LM – Thickening of capillary wall = Wire Loops
 Retinal flecks, Anterior lenticonus, cataracts, corneal o IF – Granular of IgA, IgG, IgM, C3, C1q in mesangium +/-
dystrophy capillary wall
o Pathogen o EM – Electron dense deposits in mesangium +/- deposit in
 Genetic mutation  alpha chain problem  defective SubENDO (Class 3 and 4)or SubEPI(Class 5)
assembly of type 4 collagen  dysfxn of GBM, Cochlea and  IC deposits w/in Tubule BM
Eye structures
o LM – Interstitial foam cells
o IHC – No normal BM using Collagen alpha chain Ab
o EM – Irreg BM (glom/tubule) w/ alternating areas of Thick and
Thin + Lamination of Lamina Densa (Basket Weave appearance)
 Thin Basement Membrane Lesion
o Most common cause of benign familial hematuria
o Spectrum of disorders due to genetic mutation of type 4 collagen
alpha chain but most are heterozygotes (carriers)
o EM – diffuse thinning of GBM
o Px = ASx hematuria w/ Normal Renal fxn  Excellent!
 Diagnosis
o Hematuria w/ or w/o proteinuria
 IgA nephropathy, MPGN, Alport, Thin basement membrane
lesion, PSGN
o Non-NephrOtic proteinuria = Orthostatic proteinuria, FSGS, DM,
amyloidosis

Chronic Glomerulonephritis

 ESRD due to 1) RPGN, 2) FSGS, 3) MPGN

 Can also be caused by DM, HTN
 Gross = symmetric, diffusely granular SMALL kidneys w/ thinned
cortices
 Uremic Pericarditis, Sx of 2° HyperPTH, LVH due to HTN
 Slow loss of renal fxn over 5 to 10 years
 Urine sediment = variable w/ proteinuria and/or hematuria and/or
granular(waxy/broad) casts
 Widespread glomerular destruction w/ scarring + tubular atrophy +
interstitial fibrosis
CLINICAL ASPECTS OF GLOMERULAR DISEASE

 GFR Measurement
o Measure urine clearance of a marker
 Inulin is gold standard but is used mainly in research
 Freely filtered, not reabsorbed, not secreted, not synthesized,
and not metabolized during excretion
 Creatinine = less accurate than inulin but easier
 Endogenously made
 Will over estimate GFR b/c also secreted in tubule
 Creatinine Clearance = Ccr = (Ucr x V ) / Pcr
o Estimation of GFR
 Cockcroft Gault
 [(140-age)x(body wt in kg)] / [72 x serum creatinine]
 X 0.85 for Female
 2 patients w/ same serum creatinine concentration but pt that
is older or weighs less will have lower creatinine clearance
 MDRD = accurate if GFR <60
 Variables = Pcr, Age, BUN, [Albumin], gender, race
 CKD-EPI = accurate for any GFR
o In order to use serum Cr to estimate GFR, serum Cr must be stable
 Proteinuria
o Normal kidney = most of the protein excreted in urine is due to
secreted Tamm horsfall protein by TALH
o Protein has to go through fenestrated endothelium, GBM and slit
pores/diaphragm of foot processes of podocytes
 Size selective = GBM + Slit diaphragm
 Charge selective = GBM + Endothelial fenestrae ( Positive
charge is more easily filtered)
o Glomerular disease
 Change in charge selective  (-) protein like Albumin more
easily filtered but larger proteins like IgG still cannot pass
 Change in size selective  filter Albumin and large IgG’s
 Hematuria
o RBC normally does not pass filter
o In glom dz  dysmorphic RBC and RBC casts are hallmark
 Presence ofdysmorphic RBC or RBC casts are due to bleeding
from glomerulus
 HTN and Edema
o Acute glom dz = variable ↓GFR but initially normal tubule
function. The ↓GFR leads to ↑Na and H2O reabsorption leading to
edema if Na intake is not restricted
o Advanced glom dz = severe ↓GFR + tubule damage and so the
↓GFR is causing the Na and H2O retention
 Nephritic UA = WBCs, RBCs, RBC casts and non nephrotic
proteinuria
 Nephrotic UA = nephrotic proteinuria, oval fat bodies, fatty casts and
maltese cross in polarizing light
TUBULOINTERSTITIAL DISEASES

 Acute Tubular Necrosis (ATN)

o Common cause of ARF
o ↑K, ↓Na,

TUBULOINTERSTITIAL DISEASES