Podocyte

Visceral epithelial Cell

Parietal epithelial Cell
Mesangial Cell
Endothelial Cell
Proximal Tubules
Interstitial Cells
 Normal Glomerular Capillary

Endothelial cell – fenestrated – size restriction

Charge selectivity
Heparan
sulfate

Podocytes
Foot processes

Basement
Membrane

Filtration Pores in the Basement Membrane

 Physiology

• Filtration Fraction = RPF = PAH clearance RBF= RPF/1-HCT

GFR / RBF
GFR = inulin clearance

What happens to the filtration fraction?

AII ? Constricts Efferent

Increase GFR
Minimal decrease RPF
Increase FF
Postaglandins – PGE2 ?
Dilate afferent
Increase RPF
Increase GFR
No change FF
 Physiology

• Filtration Fraction
– ACEI
• Dilate efferent
• Decrease GFR
• Decrease FF
– NSAID
• Constrict afferent
• Decrease RBF
• Decrease GFR
• No change FF
 Importance of Prostaglandins
Juxtaglomerular Cells
Modified Smooth
Prostaglandins Renin muscle cells
Afferent arteriole
Macula Densa
Distal tubule
Senses Na
Angiotensin I

Aldosterone Angiotensin II
Adrenal
Autoregulation
Increased afferent
arteriolar vasodilation Autoregulation
PGE2 Increased efferent
PGE2
NO arteriolar constriction

PGI2 Angiotensin II
A c u te R e n a l F a ilu r e

P r e -r e n a l
R enal

A TN
I n te r s titia l N e p h r itis
G lo m e r u lo n e p h r itis
V a s c u la r
P ost - R en al
 Outpatient Acute Kidney Injury :
Etiologies

10%

14% Pre-renal azotemia

Obstructive Uropathy

Acute GN
10%
Acute Interstitial
66% Nephritis

Majority of Outpatient AKI is Pre-renal Azotemia

Etiology of Acute Kidney Injury in the
Hospital
5% 5%

9%

22%

11% Interstitial Nephritis

Pre-Renal Azotemia
ATN
Obstruction
Acute on Chronic
Glomerulonephritis

48%
 Renal Origin : AKI

ATN
(85%)

Ischemic Toxic
(50%) (35%)
 Pars
Convoluta

Pars Recta
 AKI – Site of Injury

• Ischemic
– Outer Medulla
• Proximal tubule
–Pars recta
• TALH (major site)
• Toxic
– Proximal tubule (pars convoluta) >>
Distal tubule
 Laboratory Evaluation of ARF
Pre- renal ATN
Azotemia
Urine Sodium < 20 > 40

Urine > 500 280

Osmolality
Specific gravity > 1.015 1.010

FENA < 1% > 2%

BUN/Cr > 20:1 10-15:1

 Laboratory Evaluation of AKI

Pre- renal ATN CKD CKD

Azotemia + AKI
RBCs ------ ----- ------ -----

WBCs ------ ----- ------ ------

RBC cast ------ ----- ------ ------

Waxy Cast ------- ------ +++ +++

Granular cast ------ +++ ------ +++

 Causes of ATN
• Radiology
– IV Contrast
– Gadolinium
• NO !!!! Causes a disease called nephrogenic systemic
fibrosis but it is not nephrotoxic – never use in a
patient with Stage 5 CKD or Dialysis
• Antibiotics
– Aminoglycosides
• Chemotherapy
– Cis platinum
• Muscle
– Rhabdomyolysis (statins / cocaine)
 Phases of AKI

• Initiating Phase
– Time of exposure to hemodynamic or
toxic insult
• Oliguric Phase
– Period of oliguria (67%)
• Urine volume < 400 cc/day
Duration of AKI at this point : 10 –14 days
 Phases of AKI

• Diuretic phase
– Increasing urine output (non-oliguric)
– No change in renal function
• Recovery phase
– May last 3 – 12 months before full
functional recovery occurs
• Acid base / Water homeostasis
 CKD
• Acidosis
– Impaired ammoniagenesis –inability to secret H+ -
initially non anion gap then in advanced CKD/ESRD –
high anion gap
• Supplement HCO3
• Anemia
– Lack of erythropoietin – made in interstitium
• Inject erythropoietin
• Hyperparathyroidism
– Trade off hypothesis – increased Phos, decreased calcium
(low vitamin D) followed by increased PTH=
osteodystrophy
• Treat with phos binders
 Initiation of RRT
• Laboratory indicators:
– Unmanageable hyperkalemia
– Severe Metabolic acidosis
– Uremic Symptoms / Encephalopathy
• (ie. nausea, vomiting, altered mental acuity,
seizures, anorexia)
– Pericaridal rub
– Unmanageable volume overload

– No specific BUN, creatinine or GFR

– (Usually GFR < 10 cc/min
 Urinalysis : Proteinuria
Nephrotic Syndrome
• hypoalbuminemia
• hypercholesterolemia (Type IIA)
• edema
• > 3.5 gm/protein/day or protein/creatinine > 3.5
(based on 1.73 sq m body surface area)
Caveat
• All the above clinical and laboratory findings
do not need to be present - nephrotic range
proteinuria is the most important finding to
identify
 Nephritic Syndrome : PHAROH

• P = Proteinuria (<3.5 gm in 24 hours)

• H = Hematuria (dysmorphic RBCS)
• A = Azotemia
• R = RBC casts
• O = Oliguria
• H = HTN
 Laboratory Evaluation of AKI
Pre- renal Glomerulonephritis ATN
Azotemia
RBCs ------ Dysmorphic -----

WBCs ------ +++ -----

RBC cast ------ ++++ -----

Waxy Cast ------- ---------- ------

Granular cast ------ ++++ +++

Telescopic Urine
 Nephrotic Syndrome

Adults Children

Minimal Change 10 - 15 75

Membranous 20 - 30 <5

Focal Sclerosis (FSGS) 40 - 50 10

Membranoproliferative 10 - 15 15 - 20

IgA Nephropathy 5 - 10 <5

 Normal Patient

The electron microscopy shows fusion (effacement) of the foot processes,

MINIMAL CHANGE DISEASE
Podocyte injury is thought to be the pathogenesis of Minimal Change Disease.
 Immunoflourescence
of Minimal Change Disease

Nothing !!!!!!!!!!!!!! No deposits

Here, the basement membrane looks thick and rigid.
 Here, the basement membrane looks thick and rigid.

Compare the patient’s (left) with the normal glomerulus (right).

Here, the basement membrane looks thick and rigid. A special stain for membranes called
(Jones’) silver stain shows spikes. These findings are typical for
MEMBRANOUS GLOMERULOPATHY
Immunofluorescence confirms the presence of deposits with the typical granular appearance
Sub-Epithelial Deposits
 Fun GN Facts

• Black patients get FSGS >>>> Caucasian

• HIV is associated with FSGS / Collapsing variant
• Hepatitis C is associated with MPGN –
cryoglobulinemia = low complements
• Hepatitis B is associated with Membranous
• IgA is found in Asians – with URI – hematuria
• Post Strep (Post Infectious) – 10-14 days AFTER onset
of infection – Proliferative GN – immune complexes –
low complement
• SLE is an immune complex disease – low complements
– diffuse proliferative GN- Sub endothelial deposits
 Diffuse Proliferative GN :
SLE/MPGN/Post infectious

NORMAL

Too many cells – Everywhere in the glomerulus

Crescentic Glomerulonephritis
Crescentic = Rapidly Progressive GN
Immunofluorescence shows linear staining of the glomerular basement membranes.
Anti-GBM – Goodpasture’s – Hemoptysis – Pulm/renal syndrome
Granular Staining Garland-type Staining Linear Staining
Membranous Post-streptococcal Goodpasture’s
 What if the Patient has RPGN – crescents
but this finding on immunoflourescence ???

On immunofluorescence, there is virtually no staining  pauci-immune.

ANCA positive !!! Remember 2 types C – ANCA and P - ANCA
Diabetic Nephropathy typically has a nodular appearance on light microscopy (Kimmelstiel-
Wilson nodules) that can occupy large parts of the glomerulus in the advanced stage.
Amyloid – looks just like Diabetes – stains with Congo Red
No immune deposits – only fibrils
 Generalized Proximal Tubular
Dysfunction : Fanconi’s Syndrome

• Bicarbonaturia (proximal RTA – Type II)

• Glucosuria (with normal serum glucose)
• Phosphaturia (hypophosphatemia)
• Tubular proteinuria (1-2 grams/24 hours)
• Uricosuria (hypouricemia)
• Hypokalemia
 Never Forget !!!

The Tubules Myeloma Kidney

Kappa Kills Fanconi’s Syndrome

Lambda lays down Amyloid

Bence Jones Proteins

Not measured by the dipstick : SSA test urine or Freelite in blood
 I Guarantee they will ask at least 2
questions from this table !!!!
ADPCKD ARPCKD Alports- Fabry’s
Hereditary
Nephritis
Inheritance Autosomal Autosomal X Linked X Linked
Dominant Recessive
Lesion Distal and Collecting duct Type IV collagen a galactosidase A
Proximal tubules a3 / a5 chains deficiency
Kidney size Very large Large/normal Normal Normal
Main extra-renal Cerebral (berry) Portal fibrosis- Ocular / hearing Premature ASHD
complications aneurysms liver failure loss LVH
MVP, Diverticula Skin lesions-
Angiokeratomas
Kidney disease Non nephrotic Non- nephrotic Nephrotic Nephrotic
Cyst bleeding / Progressive CKD syndrome syndrome
rupture / infection Micro/Macro Progressive CKD
progressive CKD Hematuria
Progressive CKD
 Urinalysis
Allergic Interstitial Pyelonephritis
Nephritis
Specific Gravity 1.010 1.010

RBCs Yes Yes

WBCs Yes Yes
RBC casts none none
WBC casts Occasional Yes (PMNs)
(lymphocytes)
Granular Casts Yes Yes-
FENA High > 2% High > 2%
Sepsis Syndrome No Often
Fever, Flank pain Occasional Common
Eosinophiluria Yes No
RCC: CLEAR CLEAR (Conventional)
Clear Cell
 Renal Cell Carcinoma ACTH = Cushings

• Often associated with Paraneoplastic Disease

Hypercalcemia Polycythemia Hepatic Dysfunction

No bone metastasis Increased erythropoietin
15% of patients production from the tumor
PTH related Peptide 1-5% of patients
produced by the tumor A result of a gene mutation
of the von-Hippel lindau
protein
No liver metastasis
21% of patients
Related to tumor
production of cytokines
(Stauffer’s Syndrome)
 RCC

Clear Cell Papillary Chromophobe Oncocytoma Medullary Collecting

(chromophil) Duct
Origin Proximal Proximal Intercalated Intercalated Collecting Collecting
(tubule) cell (distal) (distal) duct duct
Incidence 70% 10-15% 5% 5% <1% <1%
Presentation solitary multifocal solitary solitary solitary solitary
/bilateral
Risk VHL gene C-Met ----- ------ Sickle cell
(3p)
Behavior Malignant Malignant Malignant benign Malignant Malignant
Patient with Acute Kidney Injury in the ER : Metabolic Acidosis
Quick – Help him ?

Oxalate crystals
 Anion Gap Metabolic Acidosis:
Phases of Ethylene Glycol Toxicity
Ethylene Glycol Stage 1

Alcohol Dehydrogenase

Glycoaldehyde

Aldehyde Dehydrogenase

Glycolic Acid Stage 2

Glyoxylate Oxalate Stage 3

 Ethylene Glycol : Treatment
• Initial Goal
– Prevent the enzymatic conversion of Ethylene Glycol to
Glycolic Acid
• Osmolar gap
Competitive
Ethylene Glycol Stage 1 Alcohol
Inhibition

Alcohol Dehydrogenase

Glycoaldehyde Direct
Fomepizole
Inhibition
Aldehyde Dehydrogenase

Glycolic Acid Stage 2

 Ethylene Glycol Intoxication
Osmolar Gap
• Diagnosis
– Important clue to the diagnosis of any
organic alcohol intoxication
– Accumulation of the alcohol will increase the
plasma osmolarity
• Calculation
– Order a serum osmolarity
– Calculate the serum osmolarity yourself
from the key contributing molecules
• Na + Glucose + Urea
 Osmolar Gap
• A Gap > 10 mosm/L indicates the presence of some sort of
intoxicant such as :
– Ethylene Glycol
– Methanol
– Alcohol
Example :
Case 1
laboratory measurement of osmolarity = 295 mosm/L
Calculated osmolarity = 290 mosm/L
Osmolar Gap = 5 mosm/L = no significant “extra” compound
is present in the blood
Case 2
laboratory measurement of osmolarity = 315 mosm/L
Calculated osmolarity = 290 mosm/L
Osmolar Gap = 25 mosm/L = significant “extra” compound
is present in the blood
 Anion Gap Metabolic Acidosis

• Ethylene Glycol
AND Brand New !!!!!
• Methanol
• Salycylates
• Uremia
• Ketoacidosis
– Diabetic Iron overdose
– Alcoholic
Isoniazid
• Lactic Acid
Propylene glycol
 Methanol Overdose

Formic Acid

Anion Gap Vision Loss

Metabolic Acidosis Blurred vision
Central Scotoma
Hyperemia of the optic disk
Afferent pupilary defect
 Anion Gap Acidosis
Ethylene Methanol Aspirin DKA Alcoholic Lactic Uremia
Glycol Ketoacidosis Acidosis
Type of Acid Glycolic Formic Salicylic Ketones* Ketones* Lactic Sulfuric
Phosphoric
Lactic
Primary acid Metabolic Metabolic Mixed Metabolic Metabolic Metabolic Metabolic
base disorder Acidosis Acidosis Alkalosis Acidosis Acidosis Acidosis Acidosis
(Respiratory)
And
Metabolic
Acidosis
Source Anti-freeze Anti-freeze Pharmacy ---- ---- Tissue ----
Solvents Solvents hypoxia
Drugs :
biguanides**
RTI^, iron,
INH+ , PG^^
Osmolar Gap Yes Yes No No No No No
Urinalysis Calcium ----- ----- Positive Positive ketone ----- -----
oxalate ketone test test
crystals
Physical exam ----- Visual loss ---- ----- ----- ----- -----
Optic nerve
hyperemia
Treatment Alcohol Alcohol Urine Hydration Hydration Oxygen Bicarbonate
infusion infusion alkalinization Insulin Carbohydrates Volume Dialysis
Fomepizole Fomepizole
What is this ???
Staghorn Stones
 Triple Phosphate Stones
• Synonyms
– Triple Phosphate Stones
• 3 cations bind to phosphate
– Magnesium
– Ammonium
– Calcium
– Infection Stones
• Prerequisite - urinary tract infection
– Urease producing organisms
– Struvite Stones
Triple Phosphate

Urease
What is this ???

Cystine
 Cystinuria

• Autosomal recessive disorder of amino acid transport

– Dibasic amino acids
• COLA
– Cystine
– Ornithine
– Lysine
– Arginine
• Frequency
– Heterzygous 1 / 200
– Homozygous 1 / 20,000
 Radiologic Appearance of
Nephrolithiasis

Radio-opaque Radio-l ucent

Calcium Oxalate
Uric Acid
Cystine
Xanthine

Triple Phosphate
Triamterene

Calcium Phosphate
Ephedrine
 Calcium Oxalate Stones : Treatment

• Hypercalciuria
– Decrease sodium intake (< 150 meq/day)
– Do not decrease dietary calcium !!!
• Increased risk of stone disease with reduced
calcium intake
• Dietary calcium supplements decreased stone
formation
Rationale
– Calcium is necessary to bind dietary oxalate in the
intestines which prevents its absorption
– Reduced intestinal calcium allows enhanced oxalate
absorption
 Hypercalciuria

• Diuretics
– Thiazide diuretics reduce urinary
calcium
• Mild volume depletion
• Enhanced urinary sodium and
calcium absorption
– Do not use loop diuretics
• Increase urinary calcium
 Hyponatremia : YES or NO

Thiazides Loop Diuretics

Distal tubule TALH
Na-Cl channel Na-K - 2Cl channel
 Total Body Water
TBW = 60% of total body weight
Extracellular

Osmoles
Plasma

Interstitial Intracellular

3.5 L 11.5 L 28 L

14 L

Osmolality of Plasma = Osmolality of Interstitial Fluid = Osmolality of Intracellular Fluid

Exercises: IV fluid distribution
Total body water : 60% of body weight for a man
50% of body weight for a woman

TBW

Intracellular Extracellular
2/3 1/3

Interstitial Intravascular
3/4 1/4
 10% 2% Osmolality results in
Volume results
A linear increase in
in an exponential
ADH secretion
increase in ADH

Volume Control of ADH >>> Osmolality

 Key Principle

The Body Protects Volume over Tonicity

When the Change in Volume is > 10%
 I corrected my patient’s
hyponatremia from 115 meq/L all
the way to normal – 140 meq/L in
only 24 hours – but the patient is
incoherent and seizing –
why is this happening to me ?
what did I do wrong ???
Definition : Myelinolysis Syndromes

Central Pontine Myelinolysis (CPM)

Extra Pontine Myelinolysis (EPM)

Osmotic Demyelinating Syndrome

 Myelinolysis

• Correction rate of 1-2 meq/L/hr is acceptable in a patient

with severe symptoms

• Do not exceed > 10-12 meq/L increase in Na within a 24

hour period (0.5 meq/L/hr)

• Limit increase to a target Na = 120 meq/L

 Quick – Name the Association

• Carbonic Anhydrase • Type II RTA

inhibitor

• Lead • HTN / Gout / CKD

• Dihydropyridine • Edema
Calcium channel blockers
• Lithium • Nephrogenic DI

• Calcineurin inhibitor • CKD- CIN / Lymphoma

• Fibrinoid necrosis • Malignant HTN

 Quick – Name the Association

• Flushing , tachycardia • Pheochromocytoma

• Severe HTN
• Pregnant 30 wks /BP 130/90
• Upr/Ucr = .45 • Pre-eclampsia
• Big mass in my kidney filled with •
Xanthogranulomatous
yellow foamy macrophages
Pyelonephritis
• Transitional cell cancer of • Aristolochic acid/
the bladder cyclophosphamide/ smoking
• Cough – kinins / hyperkalemia /
• ACEI/ARB side effect AKI – renal artery stenosis /
teratogenic /