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Pathology of Renal System

Glomeruli and associated blood vessels in the kidney (colorized scanning electron micrograph). From
Widmaier EP, Raff H , Strang KT. Vander’s Human Physiology : The Mechanisms of Body Function, 14th ed.
New York, NY: McGraw-Hill, 2016.
Marc Imhotep Cray, M.D.
Overall Goal
The overall goal of this lecture series is to provide the learner with a
basic scientific understanding of the patterns, causes, mechanisms
and effects of the most clinically common renal disorders; including:
 Acute renal failure (AKI) and chronic renal failure (CKD)
 Glomerular diseases
 Urinary Tract Infections
 Tubulointerstitial diseases
 Obstructive uropathy, hydronephrosis & urolithiasis
 Vascular diseases
 Renal neoplasms
 Congenital and cystic diseases of kidney Covered elsewhere
 Volume regulation & electrolyte disorders within the sequence.
 Acid-base disorders
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Learning objectives (abridged*)
1.Describe the causes, mechanisms and effects of acute kidney
injury.
2.Describe the causes, mechanisms and effects of chronic kidney
disease.
3. Classify glomerular diseases based on acute vs chronic,
histopathologic features and clinical presentation.
4. Explain the pathogenesis (ie, immune-mediated Injury) and
pathophysiology of the most common glomerulonephritidies.
5. Describe the clinicopathologic features of the nephrotic vs
nephritic syndrome
*See Renal Pathology Learning Objectives, unabridged version.pdf

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Learning objectives cont’d.
6. Describe the characteristic light microscopy (LM),
immunofluorescence (IF), and electron microscopy (EM) findings
glomerular diseases.
7. Describe the renal features of systemic diseases (eg., HTN, DM,
SLE, amyloidosis, vasculitides) that involve the kidney.
8. Describe the major causes and pathologic mechanisms of
tubulointerstitial diseases.
9. Explain in the classification, etiology and pathogenesis of
urinary tract infections.

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Learning objectives cont’d.
10. Describe the gross and microscopic changes in acute
pyelonephritis (PN) and chronic PN.
11. List the causes of renal papillary necrosis.
Explain the causes and complications of obstructive uropathy,
and hydronephrosis.
12. Describe the composition of the most common forms,
favored sites for formation and complications of urolithiasis.
13. Describe the gross and microscopic features and typical
pathologic and clinical findings of commonest benign and
malignant tumors of the kidney.
14. List the congenital and cystic anomalies of the kidney.

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Topics Discussion Outline
 Scope of Problem
 Anatomy, Histology and Cell Biology
 Functions of kidney and lower urinary tract
 Overview of Renal Pathology
 Clinical Manifestations of Renal Diseases
 Glomerular Diseases
 Tubulointerstitial Diseases
 Vascular Diseases
 Obstructive uropathy, hydronephrosis & urolithiasis
 Renal Neoplasia
 Congenital and Cystic Diseases of Kidney

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Scope of Problem
Centers for Disease Control and Prevention estimates in U.S.
more than 10% of people 20 years and older (or more than 20
million individuals) have chronic kidney disease
 many more suffer from acute kidney injury annually
thus,
Clinicians of all specialties will encounter patients w renal
disorders behooves all to be aware of various risk factors and
causes of kidney disease (eg. hypertension and DM)
 Important b/c w early detection and appropriate management may
be able to prevent or at least slow rate of progression to kidney
failure or other complications
NB: Diagnosing kidney disease is particularly challenging, as patients are
typically asymptomatic until relatively advanced kidney failure is present.
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Lecture 1:
Scope of Problem
Anatomy, Histology and Cell Biology
Functions of kidney and lower urinary tract
Overview of Renal Pathology
Clinical Manifestations of Renal Diseases

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Anatomy, Histology and Cell Biology
Basic structural and functional unit of kidney function is nephron
 A structure consisting of a tuft of capillaries termed glomerulus and a
tubule

Each human kidney has approx. 1 million nephrons
 Each nephron is composed of an initial filtering component (renal
corpuscle [glomerulus& Bowman's capsule]) and a tubule specialized for
reabsorption and secretion (renal tubule)

NB: Understanding the complex functional organization of glomerulus is
crucial for understanding both normal renal function and characteristics
of different glomerular diseases.

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Schematic of Gross Anatomy
Cross-section of kidney showing gross structures. Cross-section of kidney showing arterial blood supply

Mohan H. Textbook of Pathology, 7th Ed. New Delhi: Jaypee Brothers Medical Publishers, 2015.

Renal blood flow: renal artery  segmental artery interlobar artery 
arcuate artery interlobular artery  afferent arteriole  glomerulus 
efferent arteriole  vasa recta/ peritubular capillaries  venous outflow
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Kidney and lower urinary tract
Kidney (upper urinary tract) &
lower urinary tract are
functionally connected
abnormalities in one component
can affect function of other
components of system

Bladder, urethra, ureters, & renal
pelvis (lower urinary tract) are
lined by transitional epithelium
Widmaier EP, Raff H , Strang KT. Vander’s Human Physiology : The
(urothelium) subject to similar Mechanisms of Body Function, 14th ed. New York, NY: McGraw-Hill, 2016.

types of disease processes
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Normal Kidney, Gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
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Normal Kidney, Gross cross section

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
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Normal Kidney, CT image

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. 14
Normal Kidney, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
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Normal Kidney, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Normal Kidney, microscopic HP

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Structure & histology of renal corpuscle
Four layers make up filtering
apparatus of glomerulus each
of these can be affected in renal
disease with effects on filtration:
• basement membrane
• blood vessel lining (endothelial
cells)
• podocytes (epithelial cells)
• mesangium (smooth muscle-like
cells with phagocytes)

See: Histology of the glomerular filtration
barrier.pdf Kelly CR, Landman J (Eds.). The Netter Collection of Medical Illustrations, 2Ed.
Vol 5- Urinary System. Philadelphia: Saunders- Elsevier, 2012;21.

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Glomerulus and glomerular capillary

Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease: An Introduction to Clinical Medicine, 7th Ed. New York, NY:
McGraw-Hill Education, 2014; 457.

A glomerulus consists of an afferent and an efferent arteriole and an intervening tuft of capillaries lined by
endothelial cells and covered by epithelial cells that form a continuous layer with those of Bowman capsule
and renal tubule. Space between capillaries in glomerulus is called mesangium. Material comprising a
basement membrane is located between capillary endothelial cells and epithelial cells.
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Detailed structure of glomerulus and glomerular filtration membrane
composed of endothelial cell, basement membrane, and podocyte.

Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease: An Introduction to Clinical Medicine, 7th Ed.
New York, NY: McGraw-Hill Education, 2014; 457.

Glomerular capillaries have unique features not found in most peripheral capillaries. First, glomerular capillary
endothelium is fenestrated. However, because endothelial cells have a coat of negatively charged glycoproteins and
glycosaminoglycans, they normally exclude plasma proteins such as albumin. On other side of glomerular basement
membrane are epithelial cells. Termed “podocytes” because of their numerous extensions or foot processes, these
cells are connected to one another by modified desmosomes. Mesangium is an extension of GBM.
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(Shown on left) Anatomy of a normal glomerular capillary.
Note fenestrated endothelium (EN), glomerular
basement membrane (GBM), and epithelium with its foot
processes (EP). Mesangium is composed of mesangial cells
(MC) surrounded by extracellular matrix (MM) in direct
contact with endothelium. Ultrafiltration occurs across
glomerular wall and through channels in mesangial matrix
into urinary space (US).

(Shown on right) Typical localization of immune deposits
and other pathologic changes.
(1) Uniform subepithelial deposits as in membranous
nephropathy. (2) Large, irregular subepithelial deposits or
“humps” seen in acute postinfectious glomerulonephritis.
(3) Subendothelial deposits as in diffuse proliferative lupus
glomerulonephritis. (4) Mesangial deposits characteristic of
immunoglobulin A nephropathy. (5) Antibody binding to
glomerular basement membrane (as in Goodpasture
syndrome) does not produce visible deposits, but a smooth
Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease: An Introduction to
linear pattern is seen on immunofluorescence. Clinical Medicine, 7th Ed. New York, NY: McGraw-Hill Education, 2014; 462.
(6) Effacement of epithelial foot processes is common in all
forms of glomerular injury with proteinuria. 21
Normal glomerular capillary electron micrograph
 This EM depicts a single capillary loop and
adjacent mesangium. Capillary wall portion of
lumen (L) is lined by a thin layer of fenestrated
endothelial cytoplasm (high magnification
next slide) that extends out from endothelial
cell body (E)
 Endothelial cell body is in direct contact with
mesangium, which includes the mesangial cell
(M) and adjacent matrix

 Outer aspect of basement membrane (B) is
covered by foot processes (F) from podocyte
(P) that line urinary space (U)
Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations of Medicine,
6th ed. Baltimore: Wolters Kluwer Health, 2012.
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Electron micrograph of glomerular filter
Molecules that pass from capillary lumen
(CL) to urinary space (US) traverse
fenestrations (F) of endothelial cell (E)
trilaminar basement membrane (BM) (lamina
rara interna [LRI], lamina densa [LD] and
lamina rara externa [LRE]) and slit pore
diaphragm (D) that connects podocyte foot
processes (FP)
REMEMBER: Endothelial cells have a coat of negatively
charged glycoproteins and glycosaminoglycans, they
normally exclude plasma proteins such as albumin.
Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations of
Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.

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Bowman’s capsule podocytes with foot
processes and filtration slits.
Note the filtration slits between adjacent
foot processes. The podocytes and their foot
processes encircle the glomerular capillaries.

Cell body of podocyte

Foot processes

Filtration slits

Photo: Glomerulus in a human kidney scanning electron micrograph. From: Widmaier EP, Raff H & Strang
KT. Vander’s Human Physiology: The Mechanisms Of Body Function, 13th Ed. New York, NY: McGraw-Hill 24
Companies, 2014; 490. [Labeling mine]
Functions of kidney and urinary tract
 Kidney participates in whole-body homeostasis via 4
main functions:
1. Excretion:
 of waste products and drugs this involves
selective reabsorption and excretion of substances
as they pass through nephron

2. Regulation:
 of body fluid volume and ionic composition
kidneys have a major role in homeostasis and
 are also involved in maintaining acid–base balance
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Functions of kidney cont’d.
3. Endocrine:
 kidneys are involved in synthesis of renin (which generates
angiotensin I from angiotensinogen) thus has a role in
blood pressure and sodium balance)
 Erythropoietin  controls erythrocyte production; and
 Prostaglandins  involved in regulation of renal function
 ADH retain water in body and constrict blood vessels
4. Metabolism:
 Vitamin D is metabolized to its active form
 kidney is a major site for the catabolism of low-molecular-
weight proteins including several hormones such as insulin,
PTH and calcitonin
 has
Marc Imhotep Cray, MDability to produce glucose through gluconeogenesis
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Overview of Renal Pathology
 Kidney consists of glomerular, vascular, tubular &
interstitial anatomic compartments
 Renal diseases are best understood in relation to
compartments affected & assoc. functional impairment
thus,

 Pathology of kidney can be organized into four
anatomic categories= diseases of
1. glomeruli
2. tubules and
3. interstitium
4. vessels
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Overview (2)
 Diseases that affect glomeruli most often have an
immunologic etiology
 Glomerular function disrupted by diseases that alter
glomerular structural arrangements seen w structural
damage to basement membrane, endothelium, epithelium
or mesangium
whereas,
 Diseases that affect tubules and interstitium usually
have an infectious or toxic (drugs) etiology
 Tubular function disrupted by metabolic insult to tubular
cells  hypoxia or toxins
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Overview (3)
 Early in disease process, predominantly affect one of
four anatomic structures over time, however, entire
kidney becomes diseased b/c of close structural &
functional relationships in nephron
 tubules & interstitium usually affected together

 As both glomerular and tubular functions are highly
dependent on adequate perfusion by blood if bld
perfusion disrupted, both functions are impaired

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Overview (4)
 b/c of large physiologic reserve of kidneys, many diseases do
not become clinically apparent until majority of organ is
affected subtle abnormalities in laboratory findings* are
only early indication of renal disease

 Recognition of patterns of abnormalities, pathologic findings,
and clinical presentation are arguably more important to renal
pathology than in any other organ system

N.B. *Chronic kidney disease can be detected at an early
stage by measuring GFR (nml 90–140 mL/ min men, and
80–125 mL/ min for women).
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Overview(5)Types of renal failure syndromes
Partial renal failure syndromes affect only some elements of
renal function
 There are four main types of partial renal failure:
1. Asymptomatic hematuria
2. Persistent proteinuria
3. Nephrotic syndrome
4. Nephritic syndrome
Total renal failure syndromes all functions of nephron are
impaired
 There are two types of total renal failure syndromes:
1. Acute renal failure (=AKI) sudden cessation of nephron function,
affecting all nephrons at same time
2. Chronic renal failure (=CKD) nephrons are destroyed one by one
over a long period
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QUESTION: How does someone with a partial renal failure syndrome,
such as a nephrotic syndrome, eventually develops total renal failure
syndrome(CKD)? Steps in pathological progression follow…
In most glomerular diseases damage causing nephritic or nephrotic
syndrome also eventually causes glomeruli to become completely
scarred (hyalinized) leading to loss of individual nephrons

Glomerular hyalinization is  result of excessive production of mesangial
matrix by mesangial cells over a long period of time

Expanding mesangial matrix mass slowly but progressively crushes
glomerular architecture out of existence until no blood flows through
glomerular capillaries and no oxygenated blood passes into efferent
arterioles and peritubular capillary systems

Tubules are deprived of oxygenated blood, and tubular epithelial cells die
Marc irrevocably
Imhotep Cray, MD and become atrophic…cont’d. on next slide
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Partial renal failure to complete renal failure explained cont’d.


Thus destruction of glomerulus  leads to destruction of
entire nephron unit

As more and more nephrons are destroyed partial renal
failure syndrome (nephritic or nephrotic)  develops into
total renal failure syndrome of chronic renal failure (CKD)

This is associated with progressive shrinkage of kidney to form
a small, scarred organ termed end-stage kidney

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Kibble J , Cannarozzi ML. Pathophysiology Flash Cards. New York: McGraw-Hill, 2013. 34
Overview (5) Renal Function Tests (RFT)
 To assess renal function, tests are available to give information
regarding following parameters:
 Renal blood flow
 Glomerular filtration (next slide)
 Renal tubular function
 Urinary outflow unhindered by any obstruction
 RFT divided into 4 groups:
1. Urinalysis
2. Concentration & dilution tests
3. Blood chemistry
4. Renal clearance tests
NB: Urinalysis and measurement of serum creatinine are
initial steps in evaluation of renal disorders.
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Overview (6) Glomerular Filtration
Filtration Barrier
 Composed of 1) fenestrated capillary endothelium, 2) fused
glomerular basement membrane, and 3) podocyte foot
processes epithelial layer
o capillary endothelium serves as a size barrier, while basement
membrane contains heparan sulfate leads to a negative charge
barrier preventing protein (albumin) filtration (=primary barrier)

Glomerular Filtration Rate and Filtration Fraction
 GFR can be estimated by clearance of creatinine (CCr)
 Effective renal plasma flow (RPF) can be estimated by clearance of para-
aminohippuric acid (CPAH)
 Filtration fraction(FF) = fraction of RPF filtered across glomerular
capillaries
Marc Imhotep Cray, MD  GFR/RPF=FF 36
GFR estimated by CCr
True picture of status of renal function can be obtained by
measuring GFR achieved clinically by measuring CCr, using a
calculation based on Cr content of a 24-hour collection of urine
and a single bld Cr estimation
 GFR nml range: 90–140 mL/ min men & 80–125 mL/ min women

Blood levels of urea and creatinine do not rise above nml until
GFR (CCr) has fallen below 50% nml
 thus , for many years of a chronic progressive kidney disease pt. may be
asymptomatic or show only minor Sx or Sn
o important to detect these early stages and to investigate cause and
monitor rate of progression
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Overview (7) Urinalysis & Urine Microscopy
 Understanding basic urinalysis (UA) and urine microscopy
helps interpret pathology of kidney, for instance…
…Urine microscopy:
 Presence of casts indicates that hematuria/pyuria is of
glomerular or renal tubular origin
 Bladder cancer and kidney stones→hematuria, no casts
 Acute cystitis → pyuria, no casts
 RBC casts → glomerulonephritis, malignant hypertension
(See Urinalysis & Urine Microscopy. Pdf notes)

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Overview (9) Renal Biopsy
 In addition to RFT, renal biopsy is performed on selected pts w
kidney disease to confirm Dx Indications include: hematuria,
proteinuria, renal failure, transplant kidney surveillance…more
 Renal biopsy tissue sample is fixed in alcoholic solution and examined
morphologically supported by special stains…
1. Light microscopy (LM)
o Periodic acid-Schiff (PAS) stain for highlighting GBM
o Silver impregnation to outline glomerular & tubular BM

2. Immunofluorescence (IF) to localize antigens, complements and
immunoglobulins type of immunologic injury is assessed

3. Electron microscopy (EM) to see ultrastructure of glomerular
changes exact site of immune-complex deposition is visualized
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Overview (10) Definitions of key terms
Nephrotic syndrome: A kidney disorder affecting
glomerulus, leading to proteinuria >3.5 g/day,
hypoalbuminemia, generalized edema, and
hyperlipidemia
 Nephrosis: nephropathy without inflammation or neoplasia

Nephritic syndrome: A kidney disorder of oliguria,
hematuria, edema, and hypertension, resulting from
glomerulonephritis (also sub-nephrotic proteinuria)
 Nephritis: nephropathy with inflammation

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Definitions of key terms cont’d.
Primary glomerular disease: A condition of kidney that
leads to
 nephrosis, such as membranous glomerulopathy, minimal
change disease, and focal segmental glomerulosclerosis or
 nephritis, such as postinfectious glomerulonephritis, rapidly
progressive glomerulonephritis and IgA nephropathy (Berger
disease)
Secondary glomerular disease: Conditions that are
systemic, infectious, and (or) toxic & affect kidney,
leading to nephrosis or nephritis
 Some of causes are DM, SLE, amyloidosis, penicillamine,
chronic hepatitis B infection, HIV, SBE…
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Definitions of key terms cont’d.
 Azotemia is a biochemical abnormality that refers to
an elevation of blood urea nitrogen (BUN) and
creatinine (Cr) levels, and is related to a ↓ glomerular
filtration rate (GFR)

 Uremia is when azotemia becomes assoc. w a
constellation of clinical signs (Sn) and symptoms (Sx)
and biochemical abnormalities

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Definitions of key terms cont’d.
Glomerulosclerosis versus glomerulonephritis:
 In glomerulosclerosis (sclerosis means hardening) there are
sclerotic, scarred areas that lose ability to filter, secondary to
capillary collapse
 In glomerulonephritis (-itis means inflammation), there is
ongoing glomerular inflammation (=hypercellularity and
leukocytosis)

Crescentic: Used to describe appearance when inflammatory
cells fill Bowman’s space leading to a crescent appearance
 NB: always indicative of a rapidly progressive
glomerulonephritis (RPGN)=bad disease
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Definitions of key terms cont’d.
Glomerulopathy: can include processes that are inflammatory
or noninflammatory, however
 b/c term glomerulitis exists for inflammatory conditions,
glomerulopathy sometimes carries a noninflammatory
implication

 Regarding location of glomerular lesions:
 Subepithelial: between podocyte and GBM (on epithelial
side of GBM)
 Subendothelial: between endothelium and GBM (on
endothelial side of GBM)

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Clinical Manifestations of Renal Diseases
 Following is a discussion of clinical manifestations and syndromes of renal
diseases with their defining features two most common syndromes assoc.
w glomerular diseases, nephrotic and nephritic, are given most attention
 Azotemia and uremia (defined above)
 Asymptomatic hematuria or proteinuria
 Acute kidney injury
 Chronic kidney disease
 End-stage renal disease (ESRD)
 Renal tubular defects
 Urinary tract obstruction and renal tumors
 Nephrolithiasis (renal stones)
 Nephrotic syndrome
 Nephritic syndrome

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Clinical Manifestations (2)
 Azotemia =↑of BUN & Cr levels  reflects a ↓ (GFR)
 GFR may be ↓ as a consequence of intrinsic renal disease or
extrarenal causes

 Azotemia has three classifications, depending on causative origin
o Prerenal azotemia is encountered when there is hypoperfusion of
kidneys  usually due to reduced extracellular fluid volume 
usually reversible if hypoperfusion is corrected in time
o Primary renal azotemia (ARF [AKI]) typically leading to uremia
intrinsic disease of kidney resultant of renal parenchymal damage
• Causes include renal failure, glomerulonephritis, acute tubular necrosis, or
any other kind of renal disease
o Postrenal azotemia results when urine outflow is obstructed
relief of obstruction is followed by correction of azotemia

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Clinical Manifestations (3)
 When azotemia gives rise to clinical manifestations and
systemic biochemical abnormalities it becomes uremia=
 failure of renal excretory function + a host of metabolic & endocrine
alterations

 In addition, uremia is characterized by secondary GI (e.g.,
uremic gastroenteritis), neuromuscular (e.g., peripheral
neuropathy), and cardiovascular (e.g., uremic pericarditis)
involvement

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Renal Failure and
Uremia Manifestations
Inability to make urine & excrete nitrogenous
wastes:
Consequences (MAD HUNGER):
Metabolic Acidosis
Dyslipidemia (especially ↑triglycerides)
Hyperkalemia
Uremia—clinical syndrome marked by ↑ BUN:
 Nausea and anorexia
 Pericarditis
 Asterixis
 Encephalopathy
 Platelet dysfunction
Na+/H2O retention (HF, pulmonary edema,
hypertension)
Growth retardation and developmental delay
Erythropoietin failure (anemia)
Renal osteodystrophy Buja LM, Krueger GR. Netter’s Illustrated Human Pathology 2nd Ed. Philadelphia:
Saunders-Elsevier, 2014. 48
Clinical Manifestations (5)
 Asymptomatic hematuria or proteinuria, or a combination
of these two represents a manifestation of subtle or mild
glomerular abnormalities

 Acute kidney injury is characterized by rapid decline in
GFR (within hours to days), w concurrent dysregulation of fluid
& electrolyte balance, and retention of metabolic waste
products normally excreted by kidney including urea and
creatinine
 In its most severe forms it is manifested by oliguria or anuria
(reduced or no urine flow)
 AKI can result from glomerular, interstitial, vascular or acute tubular
injury
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Clinical Manifestations (6)
 Chronic kidney disease (chronic renal failure) is defined as:
presence of a diminished GFR that is persistently <60 mL /minute
for at least 3 months, from any cause, and/or persistent
albuminuria
 CKD may present w clinically silent decline in renal excretory
function in milder forms, and
 in more severe cases, by prolonged Sx and Sn of uremia

 It is end result of all chronic renal parenchymal diseases

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Etiologies of CKD
Main groups of causes are:
 Chronic vascular disease (e.g. long-standing
hypertension
 Disease of glomeruli, e.g. glomerulonephritis
and diabetic glomerular disease
 Disease of tubules and interstitium
infective, toxic and obstructive damage to
tubules and renal papillae
 Some congenital kidney diseases, e.g.
autosomal dominant polycystic kidney
disease (ADPKD)

Note: A kidney in which virtually all nephrons
have been destroyed is called an end-stage
kidney Buja LM, Krueger GR. Netter’s Illustrated Human Pathology 2nd Ed.
46
Philadelphia: Saunders-Elsevier, 2014.
Clinical Manifestations (8)
 End-stage renal disease (ESRD)  GFR is less than 5%
of normal this is terminal stage of uremia

NDD-CKD vs. ESRD
 The term "non-dialysis-dependent chronic kidney disease" (NDD-CKD)
is used to encompass status of those persons w established chronic
kidney disease (CKD) who do not yet require life-supporting treatments
for kidney failure known as renal replacement therapy RRT, including
maintenance dialysis or kidney transplantation

 Condition of individuals w CKD, who require either of two types of RRT
(dialysis or transplant) referred to as the end-stage kidney disease
(ESKD)

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Staging of chronic kidney disease

Stevens A, Lowe J, Scott I. Core Pathology, 3rd Ed. St. Louis: Mosby-Elsevier, 2009. Note: Stages 4 and 5 are considered to equate to irreversible CKD.

NB: Patients with CKD should be prescribed medication with care,
as renal disease impairs excretion of certain drugs.
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End-stage renal disease, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Clinical Manifestations (11)
 Renal tubular defects are dominated by nocturia,
and electrolyte disorders (e.g., metabolic acidosis)
 A result of diseases that either directly affect tubular
structures (e.g., nephronophthisis-medullary cystic disease
complex) or cause defects in specific tubular functions
o Latter can be inherited (e.g., familial nephrogenic diabetes,
cystinuria, renal tubular acidosis [RTA]) or
o acquired (e.g., lead nephropathy)

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Clinical Manifestations (12)
 Urinary tract obstruction and renal tumors have varied
clinical manifestations based on specific anatomic
location and nature of lesion
 Urinary tract infection (UTI) is characterized by bacteriuria
and pyuria (bacteria and leukocytes in urine)
 Infection may be symptomatic or asymptomatic, and
 it may affect kidney (pyelonephritis) or bladder (cystitis)

 Nephrolithiasis (renal stones) is manifested by spasms of
severe pain (renal colic) and hematuria, often w recurrent
stone formation

Marc Imhotep Cray, MD
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Question
A patient with acute renal failure is referred for dialysis.
The following are all indications for dialysis EXCEPT?
A. Severe metabolic acidosis
B. Uncontrollable hyperkalemia
C. Pulmonary edema
D. Pericarditis
E. Anemias

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Answer
Anemia in a pt. w ARF is not an indication for dialysis.
Indications for dialysis include:
 Uncontrollable hyperkalemia
 Severe metabolic acidosis
 Pulmonary edema
 Overload of fluid not expected to respond to Tx w diuretics
 Uremic complications (pericarditis, encephalopathy,
GI bleeding, platelet dysfunction…) and
 Intoxication, that is, acute poisoning w a dialyzable substances
(eg. SLIME: salicylic acid, lithium, isopropanol, magnesium-
containing laxatives, and ethylene glycol)
Marc Imhotep Cray, MD
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Nephrotic vs Nephritic Syndrome Capsule
 Nephrotic Syndrome
 Proteinuria: b/c of disruption of glomerular charge barrier
 Hypoalbuminemia: b/c of proteinuria
 Edema: b/c of decreased plasma oncotic pressure from
proteinuria
 Hyperlipidemia & hypercholesterolemia: b/c of ↑ in
lipoprotein synthesis

 Nephritic Syndrome
 Oliguria & Azotemia: b/c of renal inflammation
 Hypertension: results from ↓clearance of sodium & water
 Hematuria: b/c of leakage of blood into Bowman capsule
Marc Imhotep Cray, MD
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Nephrotic syndrome pathophysiology
Heavy proteinuria, exceeds 3.5 g/day in nephrotic syndrome

Nephrotic syndrome has diverse causes that share a common
pathophysiology a derangement in capillary walls of glomeruli
results in ↑ permeability to plasma proteins

↑ permeability of GBM may result from structural or physicochemical
alterations

With long-standing or heavy proteinuria, serum albumin is ↓ giving rise
to hypoalbuminemia  a drop in plasma colloid osmotic pressure
which in turn leads to leakage of fluid from bld into extravascular
spaces…cont’d next slide

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Nephrotic syndrome cont’d.
 … resulting ↓in intravascular volume and renal blood flow triggers ↑
release of renin from renal juxtaglomerular cells renin in turn
stimulates angiotensin-aldosterone axis which promotes retention of
salt and water by kidney

 This tendency is exacerbated by reductions in cardiac secretion of
natriuretic factors ( ANP & BNP) attributed to ↓ intravascular volume

 In face of continuing proteinuria, salt and water retention further
aggravates edema  if unchecked may lead to development of
generalized edema (termed anasarca)

 At onset, there is little or no azotemia, hematuria, or hypertension occurs

Marc Imhotep Cray, MD
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Nephrotic syndrome cont’d.
 Genesis of hyperlipidemia is more murky
 presumably, hypoalbuminemia triggers ↑ synthesis of lipoproteins in
liver, or
 massive proteinuria causes loss of an inhibitor of lipoprotein
synthesis

 There is also is abnormal transport of circulating lipid particles
and impairment of peripheral breakdown of lipoproteins
 associated lipiduria reflects ↑ permeability of GBM to lipoproteins

Marc Imhotep Cray, MD
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Nephrotic syndrome cont’d.
 Hypercoagulability is a clinically significant manifestation of
nephrotic syndrome  caused by renal losses of proteins C &
S and antithrombin III , as well as elevated serum fibrinogen
and lipid levels

Note: Thyroid-binding globulin is also lost, however, this does not
appear to be clinically significant, as pts are euthyroid when free T4
is measured

Marc Imhotep Cray, MD
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Pathophysiology of
nephrotic syndrome
In nephrotic syndrome, RAS
is activated, leading to salt
and water retention and
edema

Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations
Marc Imhotep Cray, MD of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012. 64
Nephrotic syndrome cont’d.
Most important of primary glomerular lesions that lead to
nephrotic syndrome are focal segmental glomerulosclerosis
and minimal-change disease
 minimal-change disease is more important in children
 segmental glomerulosclerosis is more important in adults

Nephrotic syndrome is also commonly seen in two other
primary kidney diseases membranous nephropathy and
membranoproliferative glomerulonephritis, and as a
complication of systemic disease diabetes mellitus

Marc Imhotep Cray, MD
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Nephritic syndrome
 Nephritic syndrome is a clinical entity caused by glomerular
disease and is dominated by acute onset
 either grossly visible hematuria (RBCs in urine) or microscopic
hematuria w dysmorphic red cells and red cell casts on urinalysis
 diminished GFR
 mild to moderate proteinuria (< 3.0 g/day), and
 Mild hypertension
 It is classic presentation of acute poststreptococcal
glomerulonephritis

 Rapidly progressive glomerulonephritis (RPGN) is
characterized as a nephritic syndrome with rapid decline in
GFR (within hours to days)
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Nephritic syndrome cont’d
 Nephritic syndrome usually has an acute onset and is
caused by inflammatory lesions of glomeruli
 lesions that cause nephritic syndrome have in common
proliferation of cells within glomeruli, often accompanied
by an infiltrate of leukocytes

 inflammatory reaction injures capillary walls permitting
blood to pass into urine, and induces hemodynamic
changes that lead to a reduction in GFR

Marc Imhotep Cray, MD
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Nephritic syndrome cont’d
 Reduced GFR is manifested clinically by oliguria (or anuria),
fluid retention, and azotemia
 Hypertension is a result of both fluid retention and
augmented renin release from ischemic kidneys

 acute nephritic syndrome may be caused by primary
glomerular diseases, such as
 postinfectious glomerulonephritis GN and
 various forms of crescentic GN, or

 as a result of systemic disorders such as systemic lupus
erythematosus, amyloidosis, diabetes, hypertension
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Etiologies of most common two renal syndromes
Syndrome Common Etiologies Uncommon Etiologies
Nephrotic Minimal change disease, focal Membranous glomerulonephritis
syndrome segmental glomerulosclerosis, (GN)75% of cases are idiopathic, but
diabetic nephropathy 2° causes include SLE, penicillamine,
gold, NSAIDs, HBV, HCV, syphilis, and
malignancy
Renal amyloidosis, SLE WHO Class V
(membranous form)
Nephritic Postinfectious GN; IgA nephropathy; Membranoproliferative GN, HCV,
syndrome RPGN, ANCA-associated, pauci- cryoglobulinemia, Goodpasture’s
immune GN; SLE syndrome, vasculitides, TTP, HUS,
hereditary nephritis (Alport’s syndrome)
Redrawn after: Le T and Bhushan V. First Aid for the Wards, 5th Ed. New York: McGraw-Hill, 2013.

69
Lecture 2: Glomerular Diseases

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Glomerular Diseases
 Many renal disorders are caused by injury to glomerulus
 Glomeruli may be only major site of disease (1° glomerular disease;
e.g., immunoglobulin [Ig]A nephropathy) or
 Part of a disease affecting several organs (2° glomerular disease; e.g.,
lupus glomerulonephritis)
 Signs (Sn) & symptoms (Sx) of fall into one of following categories:
 Asymptomatic proteinuria
 Asymptomatic hematuria
 Nephrotic syndrome
 Acute nephritic syndrome
 Rapidly progressive nephritic syndrome
 Chronic kidney injury
 ESRD
Terminology use to describe syndromes is explained in next 4 slides.
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Terminology describing glomerular syndromes
All are histologic determinations after a renal biopsy:

Focal vs diffuse: Defines number of glomeruli on biopsy affected
 If less than half glomeruli are affected it is focal
 If more than half are affected it is diffuse

Segmental vs global: Defines how much of each individual
glomerulus is affected, for each affected glomerulus
 If only part is affected then it is segmental
 If entire glomerulus is affected it is global

Therefore, focal segmental glomerulosclerosis means  less than
half of glomeruli are affected [focal] and, of those affected, only
part
Marc of Cray,
Imhotep eachMD glomerulus is affected [segmental]
72
Patterns of glomerular disease

Segmental: affecting one glomerular segment, leaving
Global: affecting the whole of the glomerulus uniformly. other segments unaffected.

Diffuse: affecting all glomeruli in both kidneys. Focal: affecting a proportion of glomeruli, others unaffected.
Modified from: Stevens A, Lowe J, Scott I. Core Pathology, 3rd Ed. St. Louis: Mosby-Elsevier, 2009; 367.
73
Terminology describing glomerular syndromes
 Membranous vs proliferative vs membranoproliferative:

Membranous, glomerular basement membrane (GBM) becomes
thickened in parts thickenings appear as spikes & domes on
microscopy b/c of bulging membrane

Proliferative indicates cells are proliferating & numerous nuclei
seen on microscopy from added cell count

Membranoproliferative indicates membranous thickening &
proliferation  leads to a so-called tram track appearance b/c
GBM is rebuilt on top of damaged deposits
Marc Imhotep Cray, MD
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Summary of glomerular disorders nomenclature
TYPE CHARACTERISTICS EXAMPLE
Focal < 50% of glomeruli are involved Focal segmental glomerulosclerosis
Diffuse > 50% of glomeruli are involved Diffuse proliferative glomerulonephritis
Proliferative Hypercellular glomeruli Membranoproliferative glomerulonephritis

Membranous Thickening of glomerular basement Membranous nephropathy
membrane(GBM)
Primary 1° disease of kidney specifically Minimal change disease
glomerular impacting glomeruli
disease
Secondary Systemic disease or disease of SLE, diabetic nephropathy
glomerular another organ system that also
disease impacts glomeruli
Redrawn after: Le T, Bhushan V, et al. First Aid for the USMLE Step 1 2017. McGraw-Hill Education, 2017.

 If only part is affected then it is segmental
 If entire glomerulus is affected it is global
Marc Imhotep Cray, MD
Clinical features of glomerulonephritis relate
broadly to histological findings.
 There are four general rules of thumb which, albeit not
absolute, explain vast majority of clinical patterns of disease
that relate to each of several types of glomerulonephritis.

1. Structural change in glomerular basement membrane
(GBM) (usually thickening) or deposition of excessive
mesangial matrix leads to increased loss of protein in urine,
which if severe leads to the nephrotic syndrome.

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Clinical features of glomerulonephritis relate
to histological findings cont’d.
2. Glomerular damage associated with proliferation of
endothelial or mesangial cells is associated with the
development of microscopic hematuria or nephritic
syndrome.

3. If there is both damage to GBM and cell proliferation, a
mixed nephritic/ nephrotic syndrome is likely.

4. If damage to glomeruli is rapid and widespread, features of
acute renal failure develop.

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Acute versus Chronic Glomerulonephritis
Acute (and Rapidly Progressive) Glomerulonephritis
 There are several ways to classify acute GN
 Light microscopy (LM) essential for establishing areas of injury
 Circulating autoantibodies and measures of complement deposition
combined w Immunofluorescence (IF) studies and
 Electron microscopy (EM)
 LM, EM & IF allow GN to be categorized into subgroups
correlating w other features of disease  three patterns emerge:
1. Antiglomerular basement membrane ( anti-GBM ) antibody disease
2. Immune complex glomerulonephritis
3. Anti-neutrophil cytoplasmic antibody (ANCA) disease or pauci-immune
GN
 A brief description of each pattern with disease examples follows…
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Acute versus Chronic GN cont’d.
1. Anti-GBM antibody disease (eg, Goodpasture syndrome):
 This disease results from development of circulating
antibodies to an antigen intrinsic to GBM

 Binding of these pathologic anti-GBM antibodies to GBM
causes a cascade of inflammation

 Light microscopy shows crescentic GN, and characteristic
linear immunoglobulin deposition in glomerular capillaries
is seen on immunofluorescence

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Acute versus Chronic GN cont’d.
2. Immune complex glomerulonephritis:
 Immune complex deposition are seen in a variety of diseases

 On renal biopsy, granular immunoglobulin deposits are suggestive
of immune complexes from underlying systemic disease

 A classic example is postinfectious GN in which there is cross-
reactivity betw. an antigen of infecting organism and a host
antigen resulting in deposition of immune complexes and
complement in glomerular capillaries and mesangium
o Resolution of glomerular disease typically occurs weeks after Tx of original
infection

 Other examples include IgA nephropathy, lupus nephritis, &
membranoproliferative GN
Marc Imhotep Cray, MD
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Acute versus Chronic GN cont’d.
3. Anti-neutrophil cytoplasmic antibody (ANCA) disease
or pauci-immune GN:
 Characterized by a necrotizing GN but few or no immune deposits
(hence, pauci-immune) seen on immunofluorescence or electron
microscopy

 This pattern is typical of granulomatosis with angiitis, microscopic
polyangiitis, or Churg-Strauss syndrome

 ANCA-negative pauci-immune necrotizing GN occurs less frequently
but is also a well-described clinical entity

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Acute versus Chronic GN cont’d.
 Rapidly progressive glomerulonephritis (RPGN)
 A subset of acute GN in which there is a progressive and dramatic
decline (weeks to months) in renal function often leading to
complete renal failure and oliguria
o It is a nonspecific final pathway in a variety of glomerular diseases
 Early disease can be subtle, but is marked by proteinuria and
hematuria followed by ↓ GFR

 Often called “crescentic GN,” as characteristic finding on biopsy is
cellular crescents in Bowman space

 Cellular crescents, visible on light microscopy, form in response to
severe damage to glomerular capillaries
N.B. Recovery without specific treatment is rare
Marc Imhotep Cray, MD
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Acute versus Chronic GN cont’d.
Chronic Glomerulonephritis
 Some patients with acute GN develop CKD slowly over a period
of 5–20 years pathogenesis includes:
 Cellular proliferation, in either mesangium or capillary, is a pathologic
structural hallmark in some of these cases
whereas,
 others are notable for obliteration of glomeruli = sclerosing chronic
GN includes both focal and diffuse subsets
and yet,
 others display irregular subepithelial proteinaceous deposits w
uniform involvement of individual glomeruli (membranous GN)

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Chronic glomerulonephritis, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

84
Diagnostic features of glomerular diseases
I. Light microscopic (LM) features
A. Increased cellularity
Infiltration by leukocytes (e.g., neutrophils, monocytes, macrophages)
Proliferation of “endocapillary” cells (i.e., endothelial and mesangial cells)
Proliferation of “extracapillary” cells (i.e., epithelial cells) (crescent formation)
B. Increased extracellular material
Localization of immune complexes
Thickening or replication of GBM
Increases in collagenous matrix (sclerosis)
Insudation (collection) of plasma proteins (hyalinosis)
Fibrinoid necrosis
Deposition of amyloid

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Dx features of glomerular diseases (2)
II. Immunofluorescence (IF) features
A. Linear staining of GBM
Anti-GBM antibodies
Multiple plasma proteins (e.g., in diabetic glomerulosclerosis)
Monoclonal light chains (Amyloid nephropathy )
B. Granular immune complex staining
Mesangium (e.g., IgA nephropathy)
Capillary wall (e.g., membranous glomerulopathy)
Mesangium and capillary wall (e.g., lupus glomerulonephritis)
C. Irregular (fluffy) staining
Monoclonal light chains (AL amyloidosis) AA protein (AA amyloidosis)

Marc Imhotep Cray, MD
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Dx features of glomerular diseases (3)
III. Electron microscopic features
A. Electron-dense immune complex deposits
Mesangial (e.g., IgA nephropathy)
Subendothelial (e.g., lupus glomerulonephritis)
Subepithelial (e.g., membranous glomerulopathy)
B. GBM thickening (e.g., diabetic glomerulosclerosis)
C. GBM replication (e.g., membranoproliferative glomerulonephritis)
D. Collagenous matrix expansion (e.g., focal segmental glomerulosclerosis)
E. Fibrillary deposits (e.g., amyloidosis)

To view plates see: LM, IF and EM of Select Glomerular Diseases_pdf.

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Mechanisms of Glomerular Injury & Disease
 Immune mechanisms underlie most primary glomerular
diseases & many secondary glomerular diseases
 Two mechanisms of antibody deposition in glomerulus have
been established:
1. deposition of circulating antigen-antibody complexes in glomerular
capillary wall or mesangium, and
2. antibodies reacting in situ within glomerulus either with fixed
(intrinsic) glomerular antigens or with extrinsic molecules that are
planted in glomerulus
o Deposition of circulating immune complexes gives a granular
immunofluorescence pattern
o Anti-GBM antibody GN is characterized by a linear immunofluorescence
pattern there is no immune deposit formation in this disease

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Mechanisms of Glomerular Injury & Disease
cont’d.
Once antigen-antibody complexes are deposited or formed in
glomeruli they produce injury by activating complement and recruiting
leukocytes
 Binding of immune complexes to Fc receptors on leukocytes also may contribute to
activation of cells and injury

 Morphologically, affected glomeruli exhibit leukocytic infiltrates and
proliferation of mesangial and parietal epithelial cells

 Electron microscopy reveals electron-dense immune deposits in one or
more of three locations:
1. Betw. endothelial cells and GBM (subendothelial deposits)
2. Betw. outer surface of GBM and podocytes (subepithelial deposits),
3. In the mesangium
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Antibody-mediated glomerular injury. Injury can result either from deposition of
circulating immune complexes or from antibody-binding to glomerular components
followed by formation of complexes in situ

Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology, 10th ed. Philadelphia: Elsevier, 2018.
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Two patterns of deposition of immune complexes as seen by
immunofluorescence microscopy.
(A) Granular, characteristic of circulating and in situ immune complex deposition.
(B) Linear, characteristic of classic anti-glomerular basement membrane (anti-GBM) antibody
glomerulonephritis.

Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology, 10th ed. Philadelphia: Elsevier, 2018

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Localization of immune complexes in glomerulus:
1. Subepithelial humps as in acute
glomerulonephritis

2. Epimembranous deposits as in
membranous nephropathy

3. Subendothelial deposits as in lupus
nephritis & membranoproliferative
glomerulonephritis

4. Mesangial deposits as in IgA
nephropathy
EN, Endothelium; EP, epithelium; GBM, glomerular basement membrane;
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of
LD, lamina densa; LRE, lamina rara externa; LRI, lamina rara interna; MC, Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.
mesangial cell; MM, mesangial matrix.
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Clinical presentations of glomerulopathy /
glomerulonephritis(GN)
Clinical presentation of all various types of GN can take
one of six forms:
1. Nephritic syndrome: characterized by oliguria, hematuria,
edema, and hypertension
2. Nephrotic syndrome: characterized by massive proteinuria,
edema, hypoalbuminemia, and hyperlipidemia
3. Acute renal failure (now called acute kidney injury [AKI])
4. Chronic renal failure (now called chronic kidney disease[CKD])
5. Isolated (asymptomatic) proteinuria Asymptomatic meaning no functional
abnormalities assoc. w reduced GFR,
6. Isolated (asymptomatic) hematuria edema, or hypertension.
Marc Imhotep Cray, MD
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Suggested approach to reading/studying the data
that follows.
The discussions of glomerular disorders that follow are presented in
a concise and consistent format. Data for each disease commences
by presenting a trigger case illustrating the clinical relevance of the
pathologic disorder under consideration. Then the etiology and
epidemiology, pathology and pathogenesis, clinical manifestations,
treatment options and prognosis are presented.
Learners are encouraged read the trigger case with close attention
and extract all data thought to be relevant to the diagnosis before
proceeding to the knowledge-base.
This approach should make for good practice in appreciating the
intimate relationship of basic science pathology to clinical medicine.
Marc Imhotep Cray, MD
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Trigger Case 1
A 5-year-old boy presents to the emergency room with a 1-week
history of generalized edema and fatigue. Your history reveals that
he suffered from a viral URI 1 week before this visit. Serum and
urine studies reveal massive proteinuria, hyperlipidemia, and
hypoalbuminemia. You suspect that a renal biopsy would show
normal-appearing glomeruli on electron microscopy except for
fusion of the epithelial foot processes and you begin the child on
prednisone.
What is the Diagnosis?

Marc Imhotep Cray, MD
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Minimal Change Disease (Lipoid Nephrosis)
Etiology & Epidemiology
 Etio. unknown, but usually occurs following a viral URI
 also assoc. w Hodgkin disease & hypersensitivity reactions
 Most often seen in young children, but can occur in older
children and adults

Pathology
 LM: Normal-appearing glomeruli can see lipid
accumulation in renal tubular cells
 EM: Fusion of epithelial foot processes

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MCD cont’d.
Clinical Manifestations Nephrotic syndrome
 Complications include infection by gram-positive organism,
thromboembolism, and protein malnutrition

Treatment (Tx) & Prognosis (Px) Prednisone;
cyclophosphamide or chlorambucil for steroid-resistant cases
 Response is excellent

Note: Minimal change disease is the prototype of nephrotic
syndrome

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MCD
(A) When viewed with a LM, silver methenamine–stained glomerulus appears
normal, w a delicate basement membrane.
(B) Schematic diagram illustrating diffuse effacement of foot processes of
podocytes with no immune deposits.

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

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MCD, Electron micrograph

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

99
Trigger Case 2
A 40-year-old woman with a history of SLE presents to your office
with a chief complaint of increased swelling in her legs. She had
been referred by her primary care physician, who suspected a
secondary illness to her lupus. Recent laboratory studies show
proteinuria, hypoalbuminemia, hyperlipidemia, and
hypercholesterolemia. You suspect that a renal biopsy would
demonstrate immune complex deposition on electron
microscopy as well as a “spike and dome” appearance on silver
methenamine stain.
What is the Diagnosis?

Marc Imhotep Cray, MD
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Membranous Glomerulonephritis (also called
M. Glomerulopathy or M. Nephropathy)
Etio. & Epidem.
 An immune complex disease of unknown etiology
 Secondary disease seen in 10% of SLE patients (type V Lupus Nephritis)
 is sometimes assoc. w infections (eg, hepatitis B and C, syphilis, malaria), drugs
(eg, gold salts, penicillamine, NSAIDs), or malignancy
 Incidence is highest in adults
Pathology
 LM: Diffuse capillary wall thickening & basement membrane (BM) thickening
 IF: Granular pattern of IgG or C3 deposits (lumpy-bumpy)
 EM: Electron dense immune complex deposition in subepithelial locations
within BM of glomerular capillary walls
 Silver methenamine stain: A spike-and-dome appearance resulting from
extension of BM betw. and around immune deposits (spikes = basement
membrane, domes = immune complex deposits) 101
Membranous Glomerulopathy cont’d.
Clinical Manifestations Nephrotic syndrome accompanied
by azotemia
 Complications include renal vein thrombosis and higher incidence of
occult neoplasms of lung, stomach, and colon

Tx Cyclophosphamide or steroids
 ACE inhibitors (reduce urinary protein loss)
 renal transplantation for severe cases

Note: Membranous glomerulopathy is second most common cause of
nephrotic syndrome in adults, w focal segmental glomerulosclerosis
(FSGS) recently becoming most common

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Membranous nephropathy
A. Silver methenamine stain. Note marked diffuse
thickening of capillary walls without an increase in
number of cells. There are prominent “spikes” of
silver-staining matrix (arrow) projecting from
basement membrane lamina densa toward urinary
space, which separate and surround deposited
immune complexes that lack affinity for silver stain.
B. EM showing electron-dense deposits(arrow)
along epithelial side of basement membrane (B).
Note effacement of foot processes overlying
deposits. CL, Capillary lumen; End, endothelium; Ep,
epithelium; US, urinary space.
C. Characteristic granular immunofluorescent
deposits of IgG along glomerular basement
membrane.
D. Diagrammatic representation of membranous
nephropathy.
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of
Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015. 103
Trigger Case 3
A 40-year-old HIV-positive man is admitted to the hospital
complaining of generalized edema and fatigue. A complete
history reveals that he is a habitual IV drug user. Laboratory
studies show hypoalbuminemia, hyperlipidemia, proteinuria,
and microscopic hematuria. You suspect that his current
presentation is related to his HIV and you prepare the patient
for a renal biopsy to determine the exact diagnosis.
What is the Diagnosis?

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Focal Segmental Glomerulosclerosis (FSGS)
Etio. & Epidem.
 Often idiopathic; has been assoc. w heroin use, HTN, prior GN
and HIV infection (=collapsing glomerulopathy)
 Most often occurs in older patients

Pathology
 LM: Sclerosis within capillary tufts of deep juxtaglomerular
glomeruli w focal and segmental distribution
 hyalinosis (deposition of hyaline masses) also seen
 IF: granular mesangial fluorescence for IgM and C3
 EM: Fusion of epithelial foot processes

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FSGS cont’d.
Clinical Manifestations nephrotic syndrome
 more severe disease in HIV and IV drug users
 Lab findings: 80% have microscopic hematuria at presentation

Tx & Px Prednisone
 Most patients progress to ESRD in 5–10 years

Notes:
 FSGS most common cause of nephrotic syndrome in adults in U.S.
 b/c of focal nature of FSGS, early cases can be difficult to distinguish from
MCD (How might one differentiate the two clinically?)
 FSGS, w no cellular proliferation, is different from focal segmental
glomerulonephritis (FSGN), which involves cellular proliferation
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FSGS, microscopic (PAS stain)
A Low-power view showing segmental sclerosis in one of three glomeruli
(at 3 o’clock)
B High-power view showing hyaline insudation (arrow) and lipid (small
vacuoles) in sclerotic area

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

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Collapsing Glomerulopathy
Visible are retraction of glomerular tuft (arrows), narrowing of
 A morphologic variant of FSGS, capillary lumens, proliferation and swelling of visceral epithelial cells
(double arrows), and prominent accumulation of intracellular protein
characterized by retraction absorption droplets in the visceral epithelial cells (arrowheads).

and/or collapse of entire
glomerular tuft

 May be idiopathic, but it also has
been assoc. w some drug
toxicities (e.g., pamidronate)

 Most characteristic lesion of
HIV-associated nephropathy

 Typically assoc. w prominent
tubular injury
 It has a very poor prognosis
Marc Imhotep Cray, MD Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of
Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015. 108
Trigger Case 4
A 60-year-old African Americans man with a 20-year history of
type II DM presents for a nephrology consult after his primary
care physician found a progressive increase of proteinuria in
recent laboratory studies. These laboratory studies also showed
hyperlipidemia and hypercholesterolemia. On physical
examination, the patient has bilateral diabetic retinopathy and 2+
edema in both legs. You start the patient on an ACE inhibitor and
you suspect that a renal biopsy would show Kimmelstiel-Wilson
nodules.
What is the Diagnosis?

Marc Imhotep Cray, MD
109
Diabetic Nephropathy
Etio. & Epidem. Assoc. w long-standing diabetes
 T1DM carries 30%–40% chance of diabetic nephropathy after 20 years
 T2DM carries 15%–20% chance after 20 years however, b/c there
are more pts w type II diabetes ESRD is more prevalent among
type II diabetics
 higher risk of developing diabetic nephropathy among men, African
Americans and Native Americans w DM

Pathology LM: Increase in mesangial matrix, resulting in either
 diffuse glomerulosclerosis (diffusely distributed ↑ in mesangial
matrix) or
 nodular glomerulosclerosis (Kimmelstiel- Wilson nodules—nodular
accumulations of mesangial matrix material)
 EM: Striking ↑ in GBM thickening
Marc Imhotep Cray, MD
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Diabetic Nephropathy cont’d.
Clinical Manifestations  Nephrotic syndrome
 diabetic retinopathy is invariably present
 Lab findings: Microalbuminuria (early sign), proteinuria (late sign)

Tx & Px
 Strict glycemic control
 Treatment of hypertension and microalbuminuria w ACE inhibitors
during early stages to slow progression
 Often progresses to ESRD and dialysis

Note: Diabetic nephropathy is most common cause of ESRD in U.S.

Marc Imhotep Cray, MD
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Nodular glomerulosclerosis, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

112
Diffuse glomerulosclerosis, microscopic

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Question
A 60-year-old man complains of chronic back pain and fatigue,
excessive urination, and increased thirst. X-ray examination
reveals numerous lytic lesions in the lumbar vertebral bodies.
Laboratory studies show hypoalbuminemia, mild anemia, and
thrombocytopenia. Urinalysis displays 4+ proteinuria. A
monoclonal immunoglobulin light-chain peak is demonstrated
on serum electrophoresis. A bone marrow biopsy discloses
foci of plasma cells, which account for 20% of all
hematopoietic cells. A kidney biopsy is obtained (shown in
image). Which of the following is the most likely cause of
nephrotic syndrome in this patient?
A. Amyloid nephropathy
B. Crescentic glomerulonephritis
C. IgA nephropathy (Berger disease)
D. Membranous glomerulonephritis
E. Nodular glomerulosclerosis (Kimmelstiel-Wilson disease)

114
Diagnosis (A) , Amyloid nephropathy, multiple myeloma

Neoplastic plasma cells typically secrete a homogeneous immunoglobulin
chain, which can be detected in serum or urine by electrophoresis.

Amyloid nephropathy is caused by the deposition of secreted light chains in
the glomerular basement membranes and mesangial matrix. Amorphous
acellular material expands the mesangium and obstructs the glomerular
capillaries. Deposits of AL amyloid may also appear in the tubular basement
membranes and in the walls of renal vessels.
Renal amyloidosis usually presents with nephrotic syndrome.
The deposits of amyloid may take on a nodular appearance, reminiscent of
Kimmelstiel-Wilson lesion of diabetic glomerulosclerosis (choice E).
However, amyloid deposits are not PAS positive and are identifiable by Congo
red staining with characteristic apple-green birefringence.
IgA nephropathy (choice C) and membranous glomerulonephritis (choice D) are
unrelated to light-chain disease.
Marc Imhotep Cray, MD
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Renal Amyloidosis
 Etiology:
 Amyloidosis is complication of chronic Amyloid nephropathy. In a section stained w Congo
red and examined under polarized light, amyloid
inflammatory disorders, such as RA, deposits in glomerulus and adjacent arteriole show
osteomyelitis or CA= multiple myeloma etc. a characteristic apple-green birefringence
 kidneys, liver, spleen, and adrenals most
common organs involved
 accumulation of proteins in form of
abnormal, insoluble fibers=amyloid fibrils
 Pathology:
 Amyloidosis leads to nephrotic syndrome
and renal failure
 LM-Congo red stain shows apple-green
birefringence under polarized light due to
amyloid deposition in mesangium Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations of
 Diagnosis: Congo red staining or tissue biopsy Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.

gold standard methods of Dx 116
Amyloid nephropathy
Disorder is initially assoc. w accumulation of characteristic fibrillar deposits in mesangium. These inert masses, which are
fibrillar by EM, extend along inner surface of basement membrane (BM), frequently obstructing capillary lumen. Focal
extension of amyloid through BM may elevate epithelial cell, in which case irregular spikes are seen along outer surface of BM

Amyloid nephropathy, EM
Deposits of fibrils (10 nm diameter) in a
glomerulus adjacent to podocyte
cytoplasm with effaced foot processes.

Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations of Medicine, 6th ed.
Baltimore: Wolters Kluwer Health, 2012. 117
Trigger Case 5
A 45-year-old white woman with a 15-year history of SLE presents
to the nephrologist after her primary care physician found
hematuria and proteinuria on a routine urinalysis. The patient has
edema of the ankles on physical examination and she is
experiencing a SLE flare-up with an extensive malar rash visible
over her face. A renal biopsy is obtained and examination by light
microscopy reveals wire-loop abnormalities. You examine the
patient’s current immunosuppressive therapy to see what
additional therapies should be added.
What is the Diagnosis?

Marc Imhotep Cray, MD
118
Lupus Nephropathy
Etiology Renal component of systemic lupus erythematosus

Pathology Five distinct renal histologic patterns:
 (1) Type I: normal
 (2) Type II (mesangial form): focal & segmental glomerular involvement w
↑ in mesangial matrix
 (3) Type III (focal proliferative form): involves less than half of glomeruli,
causing extensive damage to individual glomeruli
 (4) Type IV (diffuse proliferative form): most severe form involving all
glomeruli w marked inflammation, mesangial proliferation, and scarring
o LM: wire-loop abnormality caused immune complex deposition and gross
thickening of GBM
o EM: endothelial cell proliferation
o IF: marked subendothelial immune complex deposition= granular pattern
 (5) Type V (membranous form): similar to membranous glomerulonephritis
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Lupus Nephropathy cont’d.
 Clinical Manifestations
 Type I: No clinical findings
 Types II and III: Mild to moderate proteinuria and hematuria
 Type IV: Combination of nephrotic and nephritic syndromes
 Type V: Nephrotic syndrome
 Tx
 Types I and II: No treatment required
 Types III, IV, and V: Immunosuppression (corticosteroids,
cyclophosphamide, and/or azathioprine)

Note: Renal lesion severity often determines overall prognosis of SLE
patients

Marc Imhotep Cray, MD
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Lupus nephritis
A, Focal proliferative glomerulonephritis, with two focal necrotizing lesions at the 11 0'clock
and 2 0'clock positions (H&E stain). Extracapillary proliferation is not prominent in this case.
B, Diffuse proliferative glomerulonephritis. Note marked increase in cellularity throughout
glomerulus (H&E stain).

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.
121
Lupus nephritis
C, Lupus nephritis showing a glomerulus w several 'Wire loop" lesions representing
extensive subendothelial deposits of immune complexes (PSA stain).
D, EM of a renal glomerular capillary loop from a patient w SLE nephritis. Subendothelial
dense deposits (arrowheads) correspond to "wire loops" seen by light microscopy.
B (with arrow) refers to the basement membrane.

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015. 122
Lupus nephritis
E, Deposition of lgG antibody in a granular pattern, detected by immunofluorescence.

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease,
9th ed. Philadelphia: Saunders-Elsevier, 2015.
123
Trigger Case 6
A 10-year-old girl presents to the clinic complaining of eye
swelling. You note that the child was seen 3 weeks ago in clinic for
a chief complaint of sore throat. Upon taking a history and
performing a physical, you find that the patient has pronounced
periorbital edema, has been urinating very little despite adequate
fluid intake, and has a blood pressure of 150/90. Laboratory
findings include azotemia, hematuria, red cell casts in the urine,
and an elevated ASO antibody titer. You reassure the parents that
their child’s condition will likely resolve on its own.
What is the Diagnosis?

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Poststreptococcal Glomerulonephritis
(Acute Proliferative GN/ Acute GN)
Etio. & Epidem. Most frequently seen in children (6-10 yrs.)
following infection w nephritogenic strains of group A β-hemolytic
streptococci
 decreasing in frequency in U.S but, fairly common disorder worldwide
Pathology
 Gross : Characterized by intense inflammatory reaction involving all
glomeruli in both kidneys resulting in punctate hemorrhages on kidney
surfaces
 LM: Enlarged, hypercellular, swollen glomeruli w proliferation of
mesangial and endothelial cells; normal GBM thickness
 EM: Electron-dense humps on the epithelial side of the basement
membrane (subepithelial localization)
 IF: Coarse granular immunofluorescence for IgG or C3 (lumpy-bumpy)
Marc Imhotep Cray, MD
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Poststreptococcal GN cont’d.
Clinical Manifestations Nephritic syndrome & periorbital
edema; pulmonary congestion not uncommon
 Lab findings: UA RBCs and/or red cell casts, decreased serum C3,
elevated ASO antibody titer (evidence of recent streptococcal infection)
Tx & Px
Resolves spontaneously
 More than 95% of affected children eventually recover renal function
w conservative therapy aimed at maintaining sodium and water balance
 In adults disease is less benign in up to 40% affected in epidemics fail
to resolve quickly

Note: Poststreptococcal glomerulonephritis is an immune complex disease w
antigen-antibody complex of streptococcal origin and is prototype of nephritic
syndrome
Marc Imhotep Cray, &
MDprototypical glomerular disease of immune complex etiology
126
Nonstreptococcal Acute Glomerulonephritis
(Postinfectious Glomerulonephritis)
A similar form of glomerulonephritis occurs sporadically in assoc. w other
infections, including those of bacterial (e.g., staphylococcal endocarditis,
pneumococcal pneumonia, and meningococcemia), viral (e.g., hepatitis B,
hepatitis C, mumps, HIV infection, varicella, and infectious mononucleosis),
and parasitic (malaria, toxoplasmosis) origin

 In these settings, granular immunofluorescent deposits and subepithelial
humps characteristic of immune complex nephritis are present

 Postinfectious glomerulonephritis due to staphylococcal infections differs
by sometimes producing immune deposits containing IgA rather than IgG
127
Acute proliferative
glomerulonephritis
A Normal glomerulus.

B Glomerular hypercellularity is
due to intracapillary leukocytes and
proliferation of intrinsic glomerular
cells.

C Typical electron-dense
subepithelial “hump” and a
neutrophil in lumen.

D Immunofluorescent stain
demonstrates discrete, coarsely
granular deposits of complement
protein C3 (stain for IgG was
similar), corresponding to “humps”
illustrated in part C.
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia:
Saunders-Elsevier, 2015. 128
Trigger Case 7
A 40-year-old man is admitted to the hospital with complaints of
blood in his sputum and urine. A thorough history also reveals
fever, malaise, and a 10-pound weight loss over the past month.
On physical examination, you find that his blood pressure is
160/95 and that he has several abnormal lung sounds. A urine
dipstick demonstrates hematuria. CXR reveals several nodular
lesions and blood tests show the presence of C-ANCA and an
elevated ESR. You start the patient on a high dose of
corticosteroids and you suspect that a renal biopsy would
demonstrate crescent moon shapes between the Bowman
capsule and the glomerular tuft.
What is the Diagnosis?
Marc Imhotep Cray, MD
129
Rapidly Progressive (Crescentic) Glomerulonephritis
 RPGN is a clinical syndrome assoc. w severe glomerular injury, but does
not denote a specific etiologic form of GN
 Type 1=20% (Anti-GBM antibody-mediated disease); Idiopathic or Goodpasture
syndrome (=Ab against BM lung alveoli hemoptysis)
 Type 2=25% (immune complexes): Idiopathic; postinfectious GN; SLE; IgA
nephropathy; Henoch- Schönlein purpura
 Type 3=55% (pauci-immune type): Idiopathic; ANCA-assoc. vasculitides= Wegener
granulomatosis; microscopic polyangiitis etc.

Pathology
 LM: Formation of crescent-moon shape betw. Bowman capsule and glomerular tuft
resulting from deposition of fibrin in Bowman space and proliferation of parietal
epithelial cells of Bowman capsule
 IF: Type 1, linear pattern deposits of IgG & C3; Type 2=granular deposits IgG &C3
130
RPGN cont’d.
Clinical Manifestations
 Nephritic syndrome progressing rapidly to renal failure
within months
 Sn & Sx specific to each etiology (eg, hemoptysis and anti-
GBM antibodies in Goodpasture syndrome)
Tx & Px
 Treat w diuretics and often eventual dialysis
 immunosuppression if appropriate for underlying cause
 may require transplantation
 Rapid course to renal failure

Note: RPGN refers to a syndrome assoc. w severe and progressive glomerular
injury It encompasses many different etiologies
Marc Imhotep Cray, MD
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RPGN Schematic
 Rapidly proliferating epithelial
crescent crushes glomerular
tuft, which may show a range
of changes including
o focal proliferative GN,
o segmental tuft necrosis,
o mesangiocapillary GN, or
o acute proliferative GN

Note: An epithelial crescent is result of
breaks in GBM permitting leak of fibrin,
blood proteins and WBCs (particularly
monocyte/ macrophages) into urinary space
Stevens A, Lowe J, Scott I. Core Pathology, 3rd Ed. St. Louis: Mosby-
Elsevier, 2009.
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Rapidly progressive glomerulonephritis, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

133
RPGN, Electron EM showing characteristic wrinkling of GBM w focal
disruptions (arrows).

micrograph

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of
Marc Imhotep Cray, MD Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.
134
RPGN, immunofluorescence

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Trigger Case 8
A 10-year-old boy brought to the clinic by his mother
complaining of a red tinge to his urine. A more detailed history
reveals that he was diagnosed with mild nerve deafness 2 years
earlier and also developed posterior cataracts 1 year ago.
Laboratory studies confirm hematuria as well as the presence of
erythrocyte casts. You begin to wonder if his conditions may be
related to a genetic disorder.
What is the Diagnosis?

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Alport Syndrome
 Etiology: Genetic disorder w heterogenous inheritance (usually
X-linked dominant) results in mutation of α-5 chain of type IV
collagen
 caused by mutations in COL4A3, COL4A4, and COL4A5, three of six
genes involved in basement membrane (type IV) collagen biosynthesis
 Pathology EM: Irregular foci of thickening or attenuation in
GBM with longitudinal splitting of lamina densa

 Clinical Manifestations: Triad of nephritis, nerve deafness, and
various eye disorders (cataracts, lens dislocation, corneal
dystrophy)
 often initially presents w hematuria and RBC casts
 Treatment ACE inhibitors; renal transplantation
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Alport syndrome, microscopic

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Trigger Case 9
A 25-year-old woman with a history of SLE is admitted to the
hospital with generalized edema, malaise, and fatigue. You take a
thorough history, which reveals that she had cold symptoms
2 weeks earlier. Laboratory studies show hypoalbuminemia,
hypercholesterolemia, proteinuria, and low complement levels.
When a renal biopsy shows reduplication of the basement
membrane on electron microscopy, you adjust the patient’s
current corticosteroid dose and decide to add an antiplatelet
drug to her regimen.
What is the Diagnosis?

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Diffuse Membranoproliferative GN
(Mesangiocapillary GN)
Etio. and Epidem. Assoc. w inherited complement component
deficiency
 Type I MPGN (90%) is seen in SLE, hepatitis B and C, and involves classic
& alternative pathway activation
 Type II MPGN (10%) (dense deposit disease) dysregulation of alternative
complement pathway
 Most patients are under the age of 30
 Pathology Types I and II:
 LM: reduplication of basement membrane (splitting) and
lobular proliferation of mesangial matrix into capillary loops
(tram track appearance)
 Type I: EM: subendothelial electron-dense deposits
 Type II: EM: dense deposit of homogeneous material within GBM
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Membranoproliferative GN cont’d.
Clinical Manifestations
 Type I: Commonly presents w nephrotic syndrome
 Type II: Commonly presents w hematuria and chronic renal failure
 Lab Findings: Low complement levels (↓ C3) , ↑BUN and Cr, RBCs
and/or RBC casts in urine

 Tx & Px: Corticosteroids (poor response) and
immunosuppression if appropriate for underlying cause
 Type II, particularly, poor prognosis slowly progresses to CKD 
50% develop CKD within 10 year
 Both types have high incidence of recurrence of disease in
transplanted kidneys

Marc Imhotep Cray, MD
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Schematic representation of MPGN
Patterns in two types of MPGN
 In type I there are subendothelial
deposits

 Type II is characterized by
intramembranous dense deposits
(=dense-deposit disease)

 In both, BM appear split when
viewed in light microscope

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of
Marc Imhotep Cray, MD Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015. 142
MPGN, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

143
A MPGN, type I. Note discrete electron-dense deposits (arrows) incorporated into glomerular capillary
wall betw. duplicated (split) basemen membranes (double arrows), and in mesangial regions (M); CL,
Capillary lumen.
B Dense-deposit disease (type II MPGN). There are dense homogeneous deposits within basement
membrane. In both, mesangial interposition gives appearance of split BM when viewed in LM

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.
Marc Imhotep Cray, MD
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Question
A 26-year-old woman with a history of mitral valve prolapse
comes in with 1 week of fever that started 3 days after a dental
procedure. Her urine contains red cells and her rheumatoid
factor is elevated. Which of the following serologic abnormalities
is expected to be present?
A. Anti-GBM antibody
B. Low serum complement levels
C. Antineutrophil cytoplasmic antibody
D. Elevated IgA levels

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145
Answer
The answer is B. (Robbins, 9th/e, p 926.) This clinical description is
classic for membranoproliferative glomerulonephritis, which is
associated with bacterial endocarditis. Low complement levels are
typically found in membranoproliferative glomerulonephritis, but
not in the other disorders listed.

Choice A. describes anti-GBM antibody disease or Goodpasture’s
syndrome when the lung is involved.
Choice C. describes pauci-immune glomerulonephritis, such as
Wegener’s.
Choice D. describes IgA nephropathy.
Marc Imhotep Cray, MD
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Trigger Case 10
A 15-year-old Asian boy presents to the emergency room
complaining of blood in his urine. Upon taking a complete history,
you learn that he has also been suffering from fevers, myalgias,
and arthralgias for the last 2 days. Serum studies reveal increased
serum IgA levels and normal serum complement levels. You begin
him on prednisone and you suspect that he is afflicted with the
most common form of acute glomerulonephritis in the United
States.
What is the Diagnosis?

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147
IgA Nephropathy (Berger Disease)
Etio. & Epidem. Primary renal disease of IgA deposition in
glomerular mesangium  can manifest after infection (viral
URI, GI infection, flu-like syndrome) or can be a component of
Henoch-Schönlein purpura
 Most commonly seen in children and young adults w men
affected more often than women

Pathology
 LM: mesangial widening and focal and segmental
inflammation
 EM: Mesangial deposits of IgA

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IgA Nephropathy (Berger Disease) cont’d.
Clinical Manifestations Presents w recurrent
hematuria (red or cola-colored urine) 1–2 days after an
infection
 Lab findings: ↑ serum IgA level (50% of cases), nml serum
complement levels

Tx & Px Prednisone
 Can progress to chronic renal failure 25-50% go on to
develop CKD within 20 yrs.

Note: Berger disease is most common form of acute GN in U.S. and
worldwide
Marc Imhotep Cray, MD
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IgA nephropathy (Berger disease), microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

150
IgA nephropathy, immunofluorescence

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
151
Algorithm demonstrating integration of pathologic findings with clinical data to
make a diagnosis of a specific form of primary or secondary glomerulonephritis.

Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012. 152
Glomerular diseases capsule
Nephrotic syndrome—podocyte disruption
Nephritic syndrome—due to GBM disruption. → charge barrier impaired. Massive proteinuria
Hypertension, ↑ BUN and creatinine, oliguria, (> 3.5 g/day) with hypoalbuminemia,
hematuria, RBC casts in urine. Proteinuria often hyperlipidemia, edema.
in the subnephrotic range (< 3.5 g/day) but in May be 1° (eg, direct podocyte damage) or 2° (podocyte
severe cases may be in nephrotic range. damage from systemic process [eg, diabetes]).
• Acute poststreptococcal glomerulonephritis • Focal segmental glomerulosclerosis (1° or 2°)
• Rapidly progressive glomerulonephritis • Minimal change disease (1° or 2°)
• IgA nephropathy (Berger disease) • Membranous nephropathy (1° or 2°)
• Alport syndrome • Amyloidosis (2°)
• Membranoproliferative glomerulonephritis • Diabetic glomerulonephropathy (2°)

Nephritic-nephrotic syndrome—severe nephritic syndrome
with profound GBM damage that damages the glomerular
filtration charge barrier → nephrotic-range proteinuria (> 3.5
g/day) and concomitant features of nephrotic syndrome. Can
occur with any form of nephritic syndrome, but is most
commonly seen with:
• Diffuse proliferative glomerulonephritis
• Membranoproliferative glomerulonephritis
• Lupus Nephropathy Type IV

GRAMS OF PROTEIN EXCRETED PER DAY (g/day)
0.25 3.5 > 3.5
Lecture 3:
Urinary Tract Infections
Tubulointerstitial diseases
Obstructive uropathy, hydronephrosis &
urolithiasis

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Urinary Tract Infections
 A urinary tract infection (UTI) is an infection that affects
part of urinary tract
 When it affects lower urinary tract it is known as a bladder
infection (cystitis)
 When it affects upper urinary tract it is known as kidney
infection (pyelonephritis [discussed under tubulointerstitial
diseases] )

 Cystitis
 Clinical features: dysuria in absence of vaginal discharge and
significant pain, frequency, urgency, suprapubic pain
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UTI, Cystitis cont’d.
Etio-pathogenesis:
 Bacteria gain access to urinary tract via urethra

 Cystitis most frequently involves normal colonic flora
o Escherichia coli is most common cause (approx. 80%)
o Proteus, Klebsiella, and Enterobacter are also implicated
o Staphylococcus saprophyticus causes 10% to 15% of
infections in young women
o Nosocomial cystitis is frequently caused by
Pseudomonas or Staphylococcus aureus

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UTI, Cystitis cont’d.
 Epidemiology
 Women have a higher incidence of infection b/c they have
shorter urethras
 Other risk factors include sexual activity, pregnancy, urinary
obstruction, neurogenic bladder, and vesicoureteral reflux-8
Diagnostic findings
 Characteristic clinical features are present
 Pyuria (more than 8 leukocytes/high-power field)
 Bacterial culture yields >105 organisms/mL
Treatment
 antibiotics
 Recurrent cystitis may require prophylactic antibiotics
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Acute cystitis
Patient died 2 days after surgery, and
cystitis was caused by an indwelling
catheter
A. Several foci of hemorrhage are
seen on hyperemic bladder mucosa

B. Foci of mucosal hemorrhage

C. Acute cystitis. Polymorphonuclear
leukocytes infiltrate mucosa

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine,
6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012. 158
Tubulointerstitial Diseases
Most forms of tubular injury also involve interstitium so they
are discussed together= tubulointerstitial diseases

Diseases involving tubules and interstitium may have clinical
manifestations of nephritic syndrome, or of specific defects in
tubular function, or of acute or chronic kidney disease without
more specific defining features

In this section we will discuss diseases characterized by:
1. Inflammatory involvement of tubules and interstitium (tubulointerstitial
nephritis)
 Acute and chronic pyelonephritis (Upper UTI)
2. Ischemic and toxic tubular injury leading to acute tubular injury and
clinical
Marc Imhotep Cray, MD syndrome of acute kidney injury (ARF)
159
Tubulointerstitial Diseases cont’d.
 Acute tubular necrosis (ATN)-now called acute tubular injury
(ATI)- is usually due to profound hypotension causing
ischemic damage to tubular epithelial cells

 Infections include pyelonephritis, renal abscesses & TB

 Drug toxicity usually causes tubulointerstitial nephritis due to
a hypersensitivity reaction, but
 other patterns may occur, including direct toxicity to tubular
epithelial cells giving an appearance similar to ATN

 Mechanical obstruction of ureters or bladder may lead to
hydronephrosis and recurrent infection
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Tubulointerstitial Nephritis
Tubulointerstitial nephritis (TIN) refers to a group of
inflammatory kidney diseases that primarily involve interstitium
& tubules
 glomeruli may be spared altogether or affected only late in
course

In cases of TIN caused by bacterial infection renal pelvis is
prominently involved hence a more descriptive term is
pyelonephritis (from pyelo, “pelvis”)

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Tubulointerstitial Nephritis cont’d.
Term interstitial nephritis is reserved for cases of TIN that are
nonbacterial in origin includes
 tubular injury resulting from drugs
 metabolic disorders such as hypokalemia
 irradiation
 viral infections, and
 immune reactions
o For example, acute drug-induced interstitial nephritis caused by
penicillin derivatives (eg, methicillin), NSAIDs, and diuretics

On basis of clinical manifestations & character of inflammatory
exudate TIN can be divided into acute and chronic categories

Marc Imhotep Cray, MD
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Trigger Case 11
A 25-year-old woman presents to the emergency room with
fever, severe flank pain, and costovertebral angle tenderness.
After taking a complete history, you find that she is sexually
active and has had a 2-week history of burning pain while
urinating and increased urinary frequency. Urinalysis reveals
white cell casts in the urine and a urine sample is sent for culture.
While you await the culture results, you start her on broad
spectrum antibiotics.
What is the Diagnosis?

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Pyelonephritis (Acute and Chronic)
 Etio. & Epidem.
 Acute: Caused by infection of renal parenchyma more frequent
among women
 Chronic: Results from chronic urinary tract obstruction & recurrent UTIs

 Pathology
Acute: Affects renal cortex w sparing of glomeruli
 neutrophilic infiltration and abscess formation within renal interstitium
o abscesses may rupture introducing WBCs into tubular lumen

Chronic: Asymmetric corticomedullary scarring
 tubules contain eosinophilic, proteinaceous casts resulting in gross
appearance reminiscent of thyroid follicles (thyroidization of kidneys)
 in later stages results in tubular atrophy and interstitial fibrosis
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Acute pyelonephritis, gross
 Note in this plate that cortical surface is
studded w focal pale abscesses, more
numerous in upper pole and middle
region of kidney, lower pole is relatively
unaffected

 Betw. abscesses, there is dark
congestion of renal surface

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic
Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

Marc Imhotep Cray, MD
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Acute pyelonephritis, microscopic
 An extensive infiltrate of neutrophils
is present in collecting tubules and
interstitial tissue

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
Marc Imhotep Cray, MD of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.
166
Pyelonephritis cont’d.
Pathogenesis Principal causative organisms in acute
pyelonephritis are enteric gram-negative bacilli
 Escherichia coli is most common
 Other important organisms are Proteus, Klebsiella, Enterobacter, and
Pseudomonas these usually are assoc. w recurrent infections,
especially in individuals who undergo urinary tract manipulations or
have congenital or acquired anomalies of lower urinary tract

Bacteria can reach kidneys from lower urinary tract (ascending
infection) or through bloodstream (hematogenous infection)
 N.B. Ascending infection from lower urinary tract is most important
& frequent route by which bacteria reach kidney
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Pathways of renal infection
 Hematogenous infection results
from bacteremic spread

 ascending infection results from
a combination of
o urinary bladder infection,
o vesicoureteral reflux, and
o intrarenal reflux

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic
Marc Imhotep Cray, MD Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.
168
Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed. Philadelphia: Saunders-Elsevier, 2014.
Marc Imhotep Cray, MD
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Vesicoureteral reflux demonstrated
by a voiding
 Dye injected into bladder refluxes
into both dilated ureters, filling
pelvis and calyces

 In absence of vesicoureteral
reflux, infection remains localized
in bladder
o majority of individuals w repeated
or persistent bacterial colonization
of urinary tract suffer from cystitis
and urethritis (lower UTI) rather
than pyelonephritis
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic
Marc Imhotep Cray, MD Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015. 170
Pyelonephritis cont’d.
 Clinical Manifestations
 Acute: Fever; flank pain with CVA tenderness; polyuria
and dysuria; nausea, vomiting, and diarrhea
 Chronic: Recurrent episodes of acute pyelonephritis can
lead to renal hypertension and ESRD
 Lab findings: Leukocytosis, WBC and/or WBC casts in urine

Treatment
Acute: IV antibiotics
Chronic: Renal transplantation if progresses to ESRD

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Chronic pyelonephritis, gross
 A Cortical surface contains many
irregular, depressed scars
(reddish areas)

 B marked dilation of calyces
(caliectasis) caused by
inflammatory destruction of
papillae, w atrophy and scarring
of overlying cortex

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine,
6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.
172
Chronic pyelonephritis, microscopic
 A LM shows tubular
dilation & atrophy, w many
tubules containing
eosinophilic hyaline casts
resembling colloid of
thyroid follicles (so-called
thyroidization)

 interstitium is scarred and
contains a chronic Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.
inflammatory cell infiltrate
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Two major types of chronic pyelonephritis:
Left. Vesicoureteral reflux causes infection of peripheral papillae and, therefore,
scars in poles of kidney
Right. Obstruction of urinary tract leads to high pressure backflow of urine,
causes infection of all papillae, diffuse scarring of kidney & thinning of cortex

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed.
Marc Imhotep Cray, MD Baltimore: Lippincott Williams & Wilkins, 2012. 174
Reflux nephropathy [vesicoureteral reflux]
N.B. Most common mechanism in pathogenesis of chronic
pyelonephritis is reflux nephropathy

 Reflux nephropathy is kidney damage (nephropathy) due to urine
flowing backward (reflux) from bladder toward kidneys also called
vesicoureteral reflux (VUR)
 Longstanding VUR can result in small and scarred kidneys during first five years of
life in affected children
 End results of reflux nephropathy can include high blood pressure, excessive
protein loss in urine, and eventually kidney failure

 When reflux nephropathy is suspected as a cause of kidney disease,
other conditions to consider include chronic pyelonephritis, obstructive
uropathy, and analgesic overuse
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Renal papillary necrosis & Diffuse cortical
necrosis
Important notes:
 Renal papillary necrosis is a complication of acute
pyelonephritis in diabetics or analgesics particularly those
ingested at least 2 kg in past (=analgesic nephropathy)
 risk is higher for phenacetin (withdrawn from market in U.S.) and
acetaminophen compared to aspirin and other NSAIDs

 Diffuse cortical necrosis is an acute generalized infarction of
renal cortices (medulla is spared)usually b/c of a
combination of DIC and end-organ vasospasm in assoc. w
obstetric catastrophes or septic shock

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Papillary necrosis
 Bisected kidney shows a
dilated renal pelvis and dilated
calyces secondary to urinary
tract obstruction

 Papillae are all necrotic and
appear as sharply demarcated,
ragged, yellowish areas
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

Mnemonic for causes of renal papillary necrosis is POSTCARDS:
pyelonephritis, obstruction of urogenital tract, sickle cell disease,
tuberculosis, cirrhosis, analgesia/alcohol abuse, renal vein
thrombosis, diabetes mellitus, and systemic vasculitis
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Renal cortical necrosis
 Cortex of kidney is pale yellow and
soft due to diffuse cortical necrosis
 Usually caused by significantly
diminished arterial perfusion of
kidneys due to spasms of feeding
arteries, microvascular injury, or DIC

 Renal cortical necrosis is the
pathological progression of acute
tubular necrosis
Rubin R , Strayer DS Eds. Rubin’s Pathology:
Clinicopathologic Foundations of Medicine, 6th Ed.
Baltimore: Lippincott Williams & Wilkins, 2012.
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Case Trigger 12
A 68-year-old man presents to the emergency room because he is
unable to urinate. After taking a detailed history, you learn that
he has had increasing urinary hesitancy and decreased force of
his urine stream for several months. He also complains of a
sensation of incomplete bladder emptying. On rectal
examination, you find a smooth, firm, elastic enlargement of the
prostate. Examination of the lower abdomen reveals signs of a
distended bladder. You order laboratory studies that show
increased urinary sodium excretion and an elevated BUN and
creatinine. You determine that the patient requires prompt
urethral catheterization to help reverse his renal failure.
What is the Diagnosis?
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Acute Renal Failure (Prerenal, Intrarenal, and
Postrenal Azotemia)
 Etiology
 Prerenal: Caused by decreased effective arterial volume (ie, CHF,
hypovolemia, systemic vasodilation [sepsis]), or renal vasoconstriction
(NSAIDs, ACE inhibitors, RAS)
 Intrarenal: Caused by acute tubular necrosis, acute interstitial nephritis,
glomerulonephritis, and thrombotic microangiopathy
 Postrenal: Caused by kidney stones, BPH, neurogenic bladder, and
neoplasia
 Pathology and Pathophysiology
 Prerenal: Renal hypoperfusion leads to decreased GFR resulting in
sodium and water retention
 Intrarenal: Characterized by patchy tubular necrosis leads to tubule
obstruction and fluid backflow across necrotic tubule and a resulting
decrease in GFR
 Postrenal:
Marc Imhotep Cray, MD Only develops w bilateral outflow obstruction 180
Acute Kidney Injury (AKI) [previously ARF]
 An acute rise in serum Cr has been called ARF
 It is classified as: prerenal, intrarenal, postrenal azotemia

Clinical Manifestations:
 oliguria; azotemia; hyperkalemia

 Intrarenal ARF is now called acute kidney injury (AKI) AKI is
categorized by portion of kidney that is primarily injured:
 glomeruli (e.g., acute glomerulonephritis)
 vessels (e.g., vasculitis),
 tubules (e.g., ischemic acute tubular injury (previously ATN) or
 interstitium (acute interstitial nephritis)

 most common cause intrarenal AKI is ischemic acute tubular injury
Marcmost
Imhotepcommon
Cray, MD cause of AKI overall is therapeutic drugs
181
AKI cont’d.
 acute tubular necrosis (ATN) is severe, but potentially
reversible, renal failure (RF) due to impaired tubular
epithelial function caused by ischemia or toxic injury
 b/c necrosis often is not a prominent feature of ATN
process also is called acute kidney injury (AKI)
 Ischemia and toxins can cause injury to tubules that results in
ARF
o Ischemic prerenal ARF is reversible pathophysiologic ARF w no
structural tubular epithelial changes
o If ischemia is severe enough to cause histologic tubular epithelial
injury it is becomes intrarenal ARF or ischemic AKI

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Laboratory Diagnosis of ARF (AKI)
Prerenal failure: BUN/Cr ratio> 20:1
Intrinsic failure: BUN/Cr ratio < 20:1

BUN/Cr ratio: Principle behind this ratio is fact that both urea
(BUN) and creatinine are freely filtered by glomerulus; however,
urea reabsorbed by tubules can be regulated (increased or
decreased), whereas creatinine reabsorption remains same
(minimal reabsorption)
 >20:1 BUN reabsorption is increased. BUN is disproportionately elevated
relative to creatinine in serum. Dehydration or hypoperfusion is
suspected.
 <10:1 Renal damage causes reduced reabsorption of BUN, therefore
lowering the BUN: Cr ratio.

Marc Imhotep Cray, MD
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Laboratory Diagnosis of AKI cont’d.
Urine sodium level
 In prerenal failure: < 20 mEq/L
 In intrinsic renal failure: > 20 mEq/L, b/c kidney cannot absorb Na+

Urine osmolality and specific gravity
 In prerenal failure: Urine osmolality is>500 mOsm/kg; Urine specific
gravity is> 1.020, b/c kidney is absorbing as much water as possible
 In intrinsic renal failure: Urine osmolality is <400 mOsm/kg, and urine
specific gravity is <1.010

 Fractional excretion of sodium (a very sensitive test)
 Prerenal failure: <1%
 Intrinsic renal failure: > 1% b/c of impaired tubular function
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Laboratory Diagnosis of AKI cont’d.

Laboratory Test Prerenal ARF Intrinsic Renal Failure
FENa < 1% > 1%
BUN/Cr ratio >20:1 < 20:1
Urine sodium < 20 mEq/L > 20 mEq/L
Urine osmolality > 500 mOsm/kg < 400 mOsm/kg
Specific gravity > 1.020 < 1.010
FENa, fractional excretion of sodium; BUN, blood urea nitrogen; Cr, creatinine.
Redrawn after: Kemp WL, Dennis K. Burns, Brown TG. The Big Picture : Pathology. New York: McGraw-Hill, 2008.

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Question
A 71-year-old man has had decreased urine output <500 mL per day for the
past 3 days. Physical examination shows vital signs with temperature 37° C,
pulse 88/min, respiratory rate 18/min, and blood pressure 85/60 mm Hg.
He has peripheral edema and diffuse rales on auscultation of the chest.
Urinalysis shows specific gravity 1.019 and no protein, blood, glucose,
ketones, WBCs, RBCs, or casts. His serum creatinine is 3.3 mg/dL, and urea
nitrogen is 67 mg/dL. The fractional excretion of sodium (FENa) is <1%.
Which of the following underlying conditions is he most likely to have?
A. Dilated cardiomyopathy
B. Membranous nephropathy
C. Prostatic hyperplasia
D. Systemic lupus erythematosus
E. Urothelial carcinoma

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Answer is A (PBD9 898–899)
He has azotemia, and the BUN-to-Cr ratio is >20:1, the low FENa, high urine
specific gravity, and hypotension suggest prerenal azotemia, and with
peripheral edema and diffuse rales on auscultation cardiac failure is the most
likely cause.

Incorrect answers explanations:
B. Membranous nephropathy is a renal cause with BUN-to-Cr ratio of 10:1 or
less and likely proteinuria at nephrotic levels.
C. Prostatic hyperplasia with urinary tract obstruction may produce postrenal
azotemia with BUN-to-Cr ratio between 10:1 and 20:1.
D. Systemic lupus erythematosus is likely to produce nephritic syndrome with
RBCs and RBC casts, and BUN-to-Cr ratio of 10:1 or less.
E. Urothelial carcinoma is likely to be unilateral, with sufficient reserve renal
function in the remaining kidney to prevent azotemia.
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Urinalysis in Acute Renal Failure (AKI)
Causes of Acute Renal Failure Urinalysis Sediment Findings
Acute tubular injury Granular (“muddy brown”) casts and
epithelial cells
Acute glomerulonephritis Red blood cell casts and proteinuria
Acute tubulointerstitial White blood cell casts and pyuria nephritis
Granular cast WBC cast RBG cast

Le T, Bhushan, et al. First Aid for the USMLE Step 1 2017. McGraw-Hill Education, 2017.

See: Urinalysis & Urine Microscopy. pdf
Marc Imhotep Cray, MD
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Pathogenesis of ARF caused by acute tubular injury (ATN)
 Sloughing & necrosis of epithelial
cells result in cast formation
presence of casts leads to
obstruction and ↑ intraluminal
pressure which reduces
glomerular filtration

 Afferent arteriolar vasoconstriction,
caused in part by tubuloglomerular
feedback, results in↓ glomerular
capillary filtration pressure

 Tubular injury and ↑ intraluminal
pressure  cause fluid back-leakage Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine,
from lumen into interstitium 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.
189
Consequences of renal failure
Inability to make urine and excrete nitrogenous wastes
Consequences (MAD HUNGER):
Metabolic Acidosis
Dyslipidemia (especially ↑triglycerides)
Hyperkalemia
Uremia—clinical syndrome marked by ↑ BUN:
 Nausea and anorexia
 Pericarditis
 Asterixis
 Encephalopathy
 Platelet dysfunction
Na+/H2O retention (HF, pulmonary edema,hypertension)
Growth retardation and developmental delay
Erythropoietin failure (anemia)
Renal osteodystrophy

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AKI Chronic Kidney Disease
 Chronic renal failure (CKD) [discussed in previous
lecture] develops gradually and shows compensation
that results in normal urine osmolality and volume
until ESRD occurs
 Common causes include hypertension and diabetes
 clinical manifestations include azotemia, anemia, and renal
osteodystrophy

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Trigger Case 13
A 60-year-old man is admitted to the intensive care unit with
hypotension and severe sepsis. His hypotension gradually
resolves with aggressive fluid resuscitation and pressor support.
Over the next couple of days, he becomes progressively oliguric.
Laboratory studies reveal worsening renal failure and
hyperkalemia. His urine sediment demonstrates muddy brown
casts. You worry that this patient may become progressively
fluid overloaded and hyperkalemic and eventually need dialysis.
What is the Diagnosis?

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Acute Tubular Necrosis (ATN)
Etiology Precipitated by renal ischemia (eg, prolonged
hypertension, shock), crush injury (eg, intense exercise,
myoglobinuria), contrast or nephrotoxic drugs (eg,
aminoglycosides)

Pathology
 Kidney: Focal tubular epithelial necrosis
 rupture of basement membranes
 eosinophilic hyaline casts in collecting ducts
 interstitial edema
 evidence of epithelial regeneration (flattened epithelial
cells w mitotic figures)
Marc Imhotep Cray, MD
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Causes of “ATN” and Acute Tubular Injury
 Ischemic Prerenal Acute Renal Failure (or Ischemic Acute Tubular Injury)
 Massive hemorrhage
 Septic shock
 Severe burns
 Dehydration
 Prolonged diarrhea
 Congestive heart failure
 Volume redistribution (e.g., pancreatitis, peritonitis)
 Nephrotoxic Acute Tubular Injury
 Antibiotics (e.g., aminoglycosides, amphotericin B)
 Radiographic contrast agents
 Heavy metals (e.g., mercury, lead, cisplatin)
 Organic solvents (e.g., ethylene glycol, carbon tetrachloride)
 Poisons (e.g., paraquat)
 Heme Protein Cast Nephropathies
 Myoglobin (from rhabdomyolysis, e.g., with crush injury)
 Hemoglobin (from hemolysis, e.g., with transfusion reaction)
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Postulated sequence in ischemic or toxic
tubular injury (Acute Tubular Injury/ATI)

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia:
Saunders-Elsevier, 2015.

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Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

196
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
197
Obstructive uropathy, hydronephrosis &
urolithiasis
 Obstructive lesions of urinary tract ↑susceptibility to infection
& stone formation (urolithiasis) unrelieved obstruction leads
to permanent renal atrophy, termed obstructive uropathy and
hydronephrosis
 Caused by pathologic changes produced by obstruction to flow
of urine results in hydronephrosis = distension & dilation of
renal pelvis & calyces
 A hydronephrotic kidney is more susceptible to pyelonephritis adds
injury to insult
 Acute urinary tract obstruction is often assoc. w obvious clinical
symptoms, whereas
 Chronic obstruction may be insidious or clinically silent
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Common causes of obstructive
lesions of urinary tract
 Obstruction may be sudden or
insidious, partial or complete,
unilateral or bilateral

 May occur at any level of
urinary tract  from urethra to
renal pelvis

 It can be caused by intrinsic
lesions of urinary tract or
extrinsic lesions that compress
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic
ureter Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.
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Urinary Tract Obstruction cont’d.
 Clinical features:
 Bilateral acute urinary tract obstruction causes acute
renal failure (=postrenal ARF)
 Unilateral obstruction is often asymptomatic

 As many causes of acute obstruction are reversible
prompt recognition is important

 Left untreated, an obstructed kidney undergoes atrophy

 If obstruction is bilateral CKD ensues

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Hydronephrosis
 Hydronephrosis of kidney, with
marked dilation of pelvis and
calyces and thinning of renal
parenchyma

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic
Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

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Urolithiasis
Calculi (stones) in urinary tract is a very common problem,
especially in men
 Calcium stones (composed of calcium oxalate or calcium
phosphate, or both) account for 80% to 85% of urinary
stones
o Such stones are assoc. w hypercalciuria in turn is caused by ↑
intestinal absorption of calcium, ↑ primary renal excretion of
calcium, or hypercalcemia

 Ammonium magnesium phosphate stones are assoc. w
ammonia-producing (urease-positive) bacteria, such as
Proteus vulgaris or Staphylococcus (Infection stones)
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Urolithiasis cont’d.
 Uric acid stones are assoc. w hyperuricemia in 50% of
patients and can occur secondary to gout or ↑ cell
turnover (leukemias or myeloproliferative syndromes)
o Radiolucent stones, others are radiopaque

 Cystine stones are almost always assoc. w cystinuria a
genetic aminoaciduria

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Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed. Philadelphia: Saunders-Elsevier, 2014.

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Urolithiasis cont’d.
 Clinically significant complications of urinary calculi involve
up to 10% of population
 Etiology is poorly defined although factors leading to
highly concentrated urine predispose to stone formation
 Certain metabolic diseases (hyperoxaluria and disorders of amino
acid metabolism) predispose to stone formation
 Renal calculi may remain in pelvis of kidney (staghorn
calculus) or pass down the ureter which produces severe
pain of renal colic
 Destruction of renal parenchyma may result from progressive
growth of calculus, obstruction, or infections

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Staghorn calculi
Infection stones:
 Infection, often w urea-splitting bacteria like
Proteus vulgaris , cause about 15% of
stones Resulting alkaline urine favors
magnesium ammonium phosphate
(struvite) and calcium phosphate (apatite)
precipitation

 Infection stones occasionally fill pelvis and
calyces to form a cast of these spaces, a
staghorn calculus

 Image: Kidney shows hydronephrosis &
stones that are casts of dilated calyces
Marc Imhotep Cray, MD
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Lecture 4:
Vascular diseases
Renal neoplasms
Congenital and cystic diseases of kidney

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Vascular Diseases of Kidney
Renal Vasculitis May Affect Vessels of All Sizes
 Small Vessel Vasculitis
 Medium-Sized Vessel Vasculitis
 Large Vessel Vasculitis

 Many types of systemic vasculitis affect kidney
 In a sense, glomerulonephritis is a local form of vasculitis
that involves glomerular capillaries
 Glomeruli may be only site of vascular inflammation, or
renal disease may be a component of a systemic vasculitis

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Small Vessel Vasculitis
 Sm. vessel vasculitis affects small arteries, arterioles,
capillaries and venules any of these may lead to
glomerulonephritis

 Other common manifestations include purpura, arthralgias,
myalgias, peripheral neuropathy and pulmonary hemorrhage

 Immune complexes, anti–basement membrane antibodies
or Anti-neutrophil cytoplasmic antibodies (ANCAs) can
cause small vessel vasculitides

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Small Vessel Vasculitis cont’d.
Henoch-Schönlein purpura is most common
childhood vasculitis
 It is caused by vascular localization of immune complexes
containing mostly IgA
 Glomerular lesion is identical w that of IgA nephropathy
(Berger’s disease)

Cryoglobulinemia vasculitis causes proliferative
glomerulonephritis, usually type I MPGN
 By light microscopy, aggregates of cryoglobulins (“hyaline
thrombi”) are often seen within capillary lumina

Marc Imhotep Cray, MD
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Small Vessel Vasculitis cont’d.
ANCA vasculitis involves vessels outside kidneys in 75%
of pts. w ANCA glomerulonephritis
 Based on clinical and pathologic features, patients w
systemic ANCA vasculitis are classified as follows:
o Wegener granulomatosis, if there is necrotizing
granulomatous inflammation, usually in respiratory tract
o Churg-Strauss syndrome, if there is eosinophilia and
asthma
o Microscopic polyangiitis, if there is no asthma or
granulomatous inflammation

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Medium-Sized Vessel Vasculitis
Medium-sized vessel vasculitides affect arteries, but
NOT arterioles, capillaries or venules

Necrotizing arteritides, such as
 Polyarteritis nodosa, which occurs mainly in adults, and
 Kawasaki disease, which principally afflicts young
children,
rarely cause renal dysfunction however,
 they may involve renal arteries and cause
pseudoaneurysm formation and renal thrombosis,
infarction and hemorrhage
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Large Vessel Vasculitis
Large vessel vasculitides, such as
 Giant cell arteritis and
 Takayasu arteritis, affect the aorta and its major branches

 These disorders may cause renovascular hypertension
by involving main renal arteries or aorta at origin of
renal arteries
 Narrowing or obstruction of these vessels results in renal
ischemia, which stimulates ↑renin production
consequent hypertension

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Nephrosclerosis
 Nephrosclerosis is term used for renal pathology assoc. w
sclerosis of renal arterioles and small arteries strongly
assoc. w hypertension can be both a cause and a
consequence of nephrosclerosis
Affected vessels have thickened walls and consequently
narrowed lumens result in focal parenchymal ischemia
 Ischemia leads to glomerulosclerosis and chronic tubulointerstitial
injury, and produces a reduction in functional renal mass

At autopsy is assoc. w advanced age, is more frequent in blacks
than whites, and may be seen in absence of hypertension
HTN and DM, however, ↑incidence and severity of the lesion

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Nephrosclerosis cont’d.
Pathogenesis
Two processes participate in arterial lesions:
 Medial and intimal thickening, as a response to hemodynamic
changes, aging, genetic defects, or some combination of these
 Hyalinization of arteriolar walls, caused by extravasation of plasma
proteins through injured endothelium and by ↑deposition of
basement membrane matrix

Clinical features
 Benign nephrosclerosis is most prevalent and aggressive
among blacks
 Among blacks, hypertension with no malignant phase is leading
cause of end-stage renal disease
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Close-up of gross appearance of cortical surface Hyaline arteriolosclerosis. High-power view of two arterioles with hyaline
in benign nephrosclerosis illustrating fine, deposition, marked thickening of walls, and a narrowed lumen.
leathery granularity of surface.
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015. 216
Hypertensive nephrosclerosis.
A. Three arterioles with hyaline sclerosis
(periodic acid–Schiff stain).
B. Arcuate artery with fibrotic intimal
thickening causing narrowing of the
lumen (silver stain).
C. One glomerulus with global sclerosis
and one with segmental sclerosis. Note
also tubular atrophy, interstitial fibrosis
and chronic inflammation (silver stain)
RubinCray,
Marc Imhotep R, Strayer
MD D (eds.) Rubin’s Pathology. Clinicopathologic Foundations of Medicine, 6th ed. Baltimore: Wolters Kluwer
Health, 2012. 217
Malignant Hypertensive Nephropathy
Malignant hypertensive nephropathy is a potentially fatal renal
disease

Etiologic factors:
No specific blood pressure defines malignant hypertension, but
 diastolic pressures over 130 mm Hg,
 retinal vascular changes,
 papilledema and
 renal functional impairment
are usual criteria.

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Malignant Hypertensive Nephropathy cont’d.
 Pathology:
 Gross, size of kidneys varies from small to enlarged,
depending on duration of preexisting benign
hypertension cut surface is mottled red and yellow, w
occasional small cortical infarcts
 Microscopically, malignant hypertensive nephropathy is
often superimposed on hypertensive nephrosclerosis, w
edematous (myxoid, mucoid) intimal expansion in
arteries and fibrinoid necrosis of arterioles
 Glomerular changes vary from capillary congestion
to consolidation to necrosis
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MHN, Glomerular changes

 Red fibrinoid necrosis in wall
of arteriole on right and clear
edematous expansion in
intima of interlobular artery
on left from a pt. w malignant
hypertension (Masson
trichrome stain)

Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations
of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.

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Malignant Hypertensive Nephropathy
cont’d.
 Clinical Manifestations:
 Malignant hypertension is more common in men than in
women, typically around age of 40 yrs.
 Patients suffer headache,
dizziness and visual disturbances  may develop overt
encephalopathy
 Hematuria and proteinuria are frequent
 Progressive renal deterioration develops if condition persists

 Aggressive antihypertensive therapy often controls
disease
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Renovascular Hypertension Follows
Narrowing of a Renal Artery
Molecular Pathogenesis:
 Stenosis or total occlusion of a main renal artery produces hypertension
that is potentially curable if arterial lumen is restored thus, termed
secondary HTN

 In pts w renal artery stenosis hypertension reflects ↑ production of renin,
angiotensin II and aldosterone
 Renal vein renin from an ischemic kidney is ↑, but nml in contralateral kidney

 Most (95%) cases are caused by atherosclerosis explains why disorder is
twice as common in men as in women and is primarily seen at older ages
(average age, 55 years)

 Fibromuscular dysplasia and vasculitis are less common causes overall but
Marcare most
Imhotep frequent causes in children
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Renovascular hypertension cont’d.
Clinical Features:
 Renovascular hypertension characterized by mild to moderate
blood pressure elevations
 A bruit may be heard over renal artery
 Diagnosis requires some type of imaging such as
angiography
 In over half of patients, surgical revascularization, angioplasty
or nephrectomy cures hypertension
 When there is long-standing renovascular hypertension
uninvolved kidney may become damaged by hypertensive
nephrosclerosis

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Renal artery stenosis, CT angiogram

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Renal Atheroembolism May Complicate
Aortic Atherosclerosis
In pts w severe aortic atherosclerosis atheromatous debris
may embolize into renal arteries and vascular tree as far as
glomerular capillaries and cause acute renal failure

may occur spontaneously or be initiated by trauma such as
angiographic procedures

 Cholesterol clefts are seen in vessel lumina

Early lesions are surrounded by atheromatous material or
thrombus may later elicit a foreign body reaction and may
stimulate fibrosis in adjacent vessel wall
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Atheroembolic renal disease, microscopic

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Renal infarct, gross

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Renal infarct, microscopic

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Microangiopathic Hemolytic Anemia
and Renal Failure
 Thrombotic Microangiopathies  Cause Microangiopathic
Hemolytic Anemia and Renal Failure
Molecular Pathogenesis:
 Thrombotic microangiopathy has a variety of causes and at
least two distinct pathogenic pathways
 One pathogenic pathway that causes typical and atypical
hemolytic–uremic syndrome (HUS) produces endothelial damage
that allows plasma constituents to enter intima of arteries, walls of
arterioles and subendothelial zone of glomerular capillaries
narrowing vessel lumina and causing ischemia
 Injured endothelial surfaces promote thrombosis worsens
ischemia and may cause focal ischemic necrosis

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Microangiopathic Hemolytic Anemia
and Renal Failure cont’d.
Typical HUS follows diarrhea due to toxin-producing bacteria,
most often Escherichia coli (usually O157:H7 strain), in
contaminated food
 Toxin injures endothelial cells in glomerular capillaries, initiating
sequence described above

Atypical HUS is unrelated to diarrhea and is caused by different
mechanisms, including genetic abnormalities in complement
regulatory proteins
 (mostly factor H but also factor I and membrane
cofactor protein), autoantibodies to complement regulatory
proteins (anti–factor H) or both
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Microangiopathic Hemolytic Anemia
and Renal Failure cont’d.
Thrombotic thrombocytopenic purpura (TTP) is caused by a genetic or
acquired deficiency of a protease that cleaves multimers of von
Willebrand factor on surface of endothelial cells

 large uncleaved multimers promote platelet aggregation and
microvascular thrombosis

 Passage of blood through vessels injured by either HUS or TTP  leads to
a nonimmune (Coombs-negative) hemolytic anemia, w misshapen
and disrupted erythrocytes (schistocytes) and thrombocytopenia
 This hematologic syndrome is termed microangiopathic hemolytic
anemia (MAHA)

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MAHA and Renal Failure cont’d.
 HUS and TTP can be very difficult to
distinguish clinically b/c they both
present w MAHA

 Thrombotic microangiopathies that
resemble HUS and TTP also can occur
secondary to drugs, autoimmune
diseases and malignant hypertension

Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations
Marc Imhotep Cray, MD of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.
232
MAHA and Renal Failure cont’d.
Pathology:
 renal pathology of HUS is comparable to that of malignant hypertensive
nephropathy which is a form of thrombotic microangiopathy
 Basic renal lesions are:
 Arteriolar fibrinoid necrosis
 Arterial edematous intimal expansion
 Glomerular consolidation, necrosis or congestion
 Vascular platelet-rich thrombosis
 EM of glomeruli shows electronlucent expansion of subendothelial due to
insudation of plasma proteins under injured endothelial cells
 By fluorescence microscopy, fibrin and insudated plasma proteins are seen
in injured vessel walls
Note: TTP may have vascular lesions that resemble HUS, but is characterized by
more numerous platelet-rich thrombi in glomerular capillaries as well as in
capillaries, arterioles and small arteries in many tissues of body.
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HUS microscopic, schematic
 A wide band of subendothelial
electron-lucent material causes
narrowing of the capillary
lumen
 Endothelial cell swelling also
contributes to narrowing of the
lumen

Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations
Marc Imhotep Cray, MD of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012. 234
Thrombotic microangiopathy, micro

 An electron micrograph
shows a wide band of lucent
material in subendothelial
zone(arrows), which causes
marked narrowing of lumen

Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations of
Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.

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MAHA and Renal Failure cont’d.
Clinical Features:
HUS and TTP share MAHA, thrombocytopenia, HTN and RF, although these
features are present to different degrees.

Hemolytic–Uremic Syndrome
 Typical postdiarrheal HUS features MAHA and acute renal failure, w little or no
significant vascular disease outside kidneys
 Typical HUS is one of the most common causes of acute renal failure in children
Thrombotic thrombocytopenic purpura
 In TTP systemic microvascular thrombosis is characterized clinically by
thrombocytopenia, purpura, fever and changes in mental status
 Unlike HUS, renal involvement is often absent or less important than other organ
disease
 Bleeding caused by consumptive thrombocytopenia, is also more severe in TTP
than it is in HUS
 TTP is more common in adults than children
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Renal Neoplasia
Capsule
 Clear cell renal cell carcinoma is most common subtype of
malignant renal neoplasms, which often involves VHL, a tumor
suppressor gene
 Papillary renal cell carcinoma is second most common subtype
of malignant renal neoplasms, which may involve MET proto-
oncogene
 Hereditary forms of renal cell carcinoma have led to discovery of
important genes (e.g., VHL, BHD) in renal carcinogenesis
 Urothelial tumors resembling similar tumors in urinary bladder
can also originate in renal pelvis- have a poor prognosis
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Case Trigger
A 60-year-old man presents to the clinic with cola-colored urine
and flank pain. After taking a careful history, you find that the man
has had a low-grade fever and has lost 10 pounds over the past
month. He is a chronic smoker (a pack of cigarettes a day for the
last 30 years). On physical
examination, you feel a large mass in the left kidney. Laboratory
findings demonstrate secondary polycythemia. You suspect that
an abdominal CT scan will show a solid renal mass and possible
metastasis to regional lymph nodes.
What is the Diagnosis?

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Renal cell carcinoma (older name
hypernephroma)
Etio. & Epidem
 Associated w von Hippel-Lindau disease, deletion on chr 3 and
cigarette smoking
 Most common among men (2:1 M:FM ratio) in sixth decade of
life (usually age 50–70)
 tumor originate from epithelium of proximal renal tubules
Pathology
 Kidney: Characterized by polygonal clear cells (demarcated
only by cell membranes, nuclei pushed to sides)
 Invades IVC and spreads hematogenously to lungs, bones,
and other sites
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Renal cell carcinoma cont’d
 Clinical Manifestations
 Hematuria (single most common presenting sign),
palpable mass, 2° polycythemia, flank pain, fever, weight
B
loss
o Invades renal vein (may develop varicocele if left sided)
 IVC and spreads hematogenously
 Treatment:
 Radical nephrectomy/ablation for localized disease
 Immunotherapy or targeted therapy for metastatic disease,
rarely curative
 Resistant to chemotherapy and radiation therapy

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Clear Cell RCC [Clear cell carcinoma is most common type of kidney tumor]
Clear cell renal cell carcinoma. The kidney contains a
large irregular neoplasm with a variegated cut surface.
Yellow areas correspond to lipid-containing cells. Clear cell renal cell carcinoma. Photomicrograph showing islands of
neoplastic cells with abundant clear cytoplasm.

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012. 241
Other histologic types of RCC, microscopic
Papillary renal cell carcinoma. Photomicrograph showing Chromophobe renal cell carcinoma. Photomicrograph
papillary fronds covered by neoplastic cells showing pale acidophilic granular cells with prominent cell borders.

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

242
Case Trigger
A 3-year-old boy is brought to the emergency room by his
mother because he is experiencing abdominal pain after
accidentally falling onto a toy truck that hit his abdomen. On
physical examination, you can feel a huge, palpable flank mass
on his left side. Urinalysis reveals microscopic hematuria. When
a CT scan reveals a large mass originating from the kidney, you
begin to suspect that this child’s condition is related to a gene
deletion on chromosome 11.
What is the Diagnosis?
6

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Wilms Tumor (nephroblastoma)
 Etio. and Epidem.
 Caused by deletion of WT-1 gene (tumor suppressor) on
short arm chromosome 11 (11p13)
 Most commonly seen in early childhood (ages 2–4)

 Pathology
 Gross: Large, solitary, well-circumscribed renal mass;
originates from primitive metanephric tissue
 Microscopic: Immature stroma with primitive tubules and
glomeruli; presence of mesenchymal elements (eg, bone,
cartilage, connective tissue)

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Wilms Tumor cont’d.
 Clinical Manifestations
 Presents as a huge, palpable flank mass in a young child
 may also initially present as pain in abdomen after some traumatic
incident, intestinal obstruction, or hypertension
 can be assoc. w unilateral muscular hypertrophy (hemihypertrophy)
 Lab findings: microscopic hematuria
 Tx and Px
 Surgery to remove tumor
 radiotherapy and chemotherapy w actinomycin D and vincristine
 There is an excellent survival rate

N.B. Wilms tumor can be assoc. w WAGR complex (Wilms tumor,
aniridia [absence of iris], genitourinary malformation, mental-
motor retardation)
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Wilms Tumor, micro
 Photomicrograph of tumor
shows highly cellular areas
composed of undifferentiated
blastema, loose stroma
containing undifferentiated
mesenchymal cells and
immature tubules

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
Marc Imhotep Cray, MD of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012. 246
Wilms Tumor, gross
 A cross-section of a pale tan
neoplasm attached to a residual
portion of kidney

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
Marc Imhotep Cray, MD of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012. 247
Case Trigger
A 62-year-old man presents to the clinic with painless hematuria.
A full history reveals that he worked in a factory that used aniline
dyes for 20 years before retiring 10 years ago and that he also
has smoked a pack of cigarettes per day for the last 30 years. You
order serum and urine studies that demonstrate hematuria,
exfoliated normal and abnormal urothelial cells in the urine, and
anemia. You fear that this patient may be suffering from a
neoplastic condition.
What is the Diagnosis?

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Transitional Cell Carcinoma (Urothelial
carcinoma/UCC) or TCC
 Etiology Betw. 5% and 10% of primary kidney cancers are
transitional cell carcinomas of pelvis or calyces
 morphologically identical to more common transitional cell
carcinomas of urinary bladder, and are assoc. w them in half of cases
 A malignant tumor assoc. w smoking, exposure to aniline dyes,
cyclophosphamide treatment, and phenacetin abuse

 Pathology
 Gross: Varies from flat to papillary & noninvasive to invasive
 can occur anywhere in urinary tract system (renal calyces, renal pelvis,
ureters, bladder) and may spread by local extension to adjacent tissue
 Microscopic: Multiple grades of carcinoma; histopathology varies from
well-differentiated tumor cells resembling normal transitional cells to
anaplastic tumor cells w giant cells and multiple mitoses
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Transitional Cell Carcinoma cont’d.
 Clinical Manifestations
 Presents w painless hematuria
 bladder transitional cell carcinoma may also present w irritative
voiding symptoms, palpable mass on bimanual examination,
hepatomegaly, or supraclavicular lymphadenopathy (if metastasized)
 Tx and Px
 Chemotherapy, radiotherapy, and transurethral resection for bladder
cancer (often recurs after removal)
 Prognosis is dependent on stage and grade
Notes:
Squamous cell carcinoma of bladder accounts for 3%–7% of bladder
cancers in U.S and is assoc. w schistosomiasis and other causes of chronic
bladder infection
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Urothelial carcinoma
 Urothelial carcinoma of renal pelvis
 Pelvis has been opened to expose
nodular irregular neoplasm, just
proximal to ureter

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic
Marc Imhotep Cray, MD Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.
251
Congenital and Cystic Diseases
 Potter Sequence
 Potter sequence (oligohydramnios sequence) is
syndrome of pathologic abnormalities that are
caused by markedly
reduced intrauterine urine production
o Reduced urine production results in less amniotic fluid
(oligohydramnios) amniotic fluid normally cushions
fetus with less fluid, fetus is compressed by
uterus this causes low-set ears, small receding chin,
beak-like nose and abnormally bent lower extremities
o Most life-threatening component of Potter sequence is
pulmonary hypoplasia  caused by inadequate
maturational stimuli from amniotic fluid and by
compression of chest wall by uterus
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Pulmonary hypoplasia, gross

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253
Renal agenesis
 Complete or bilateral renal agenesis
 Rare condition(1 in 4500 births) not compatible with life
 Both kidneys are absent (next slide)
 At birth there is severe pulmonary hypoplasia from
oligohydramnios sequence

 Unilateral renal agenesis
 One kidney is missing
 Still rear, but more common than complete renal agenesis
 survivable opposite kidney develops to about twice
size of a normal kidney from compensatory hyperplasia

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Renal agenesis, gross
Kidneys are absent from retroperitoneum no ureteric bud
induced metanephros

Marc Imhotep Cray, MD Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. 255
Horseshoe kidney
 Horseshoe kidney is a single, large,
midline organ
 kidneys are fused, usually at lower
poles
 anomaly ↑risk for obstruction and
renal infection (pyelonephritis) b/c
ureters must cross over junction
betw. two kidneys when organ is
fused at lower pole

Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations
Marc Imhotep Cray, MD of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.
256
Trigger Case
A 25-year-old man presents with blood in his urine. After taking a
complete history, you learn that his father had died of kidney
failure in his late 30s and that the patient is very concerned
about having the same fate. Physical examination reveals a blood
pressure of 170/110 mm Hg and bilateral, palpable renal masses.
A murmur is heard on the chest examination that is consistent
with a mitral valve prolapse. You order an abdominal CT to
confirm the diagnosis.
What is the Diagnosis?

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Congenital cystic diseases
ADPKD is most common of a group of
congenital diseases characterized by
numerous cysts in renal parenchyma

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Adult and Infantile Polycystic Kidney Disease
 Etiology
 APKD: Autosomal dominant (ADPKD) 90% resulting from
mutation of APKD1 gene on chr 16
 IPKD: Autosomal recessive (ARPKD)

 Pathology
 APKD: Replacement of renal parenchyma bilaterally with
multiple, large, variably sized cysts
 IPKD: Closed, small, homogenous cysts that are not in
continuity with collecting system

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Polycystic Kidney Disease cont’d.
 Clinical Manifestations
 APKD: Hypertension, hematuria, and palpable renal masses;
CT shows multiple cysts in both kidneys; assoc. w secondary
polycythemia, polycystic liver disease, berry aneurysms, and
mitral valve prolapse
 IPKD: CT shows multiple cysts at birth

 Treatment & Prognosis
 APKD: No therapy can prevent renal failure, although HTN Tx
w ACE inhibitors and low-protein diet may slow progression
of ESRD
 IPKD:
Marc Imhotep Cray, MD Results in death shortly after birth
260
A and B, Autosomal dominant adult polycystic kidney disease (ADPKD) viewed from the external surface and
bisected. Kidney is markedly enlarged and contains numerous dilated cysts.C, Autosomal recessive childhood PKD,
showing smaller cysts and dilated channels at right angles to the cortical surface. D, Liver cyst in adult PKD.

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.
261
Normal fetal kidney and autosomal recessive polycystic kidney disease (ARPKD), gross
The normal term infant kidneys in the left panel reveal typical fetal lobulations and smooth cortical surfaces with
some attached adipose tissue. Note the well-defined corticomedullary junctions on cut section. In the right panel,
note the bilaterally massively enlarged kidneys that nearly fill the abdomen below the liver, consistent with ARPKD
in this fetus at 23 weeks’ gestation whodied from pulmonary hypoplasia as a result of oligohydramnios.

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. 262
Cystic Diseases of Renal Medulla
Medullary sponge kidney is a poorly characterized condition
presenting in adulthood with multiple collecting duct cysts, 
lead to an increased risk of complications, including infection,
nephrolithiasis, and hemorrhage

Nephronophthisis-medullary cystic disease complex
 a genetic disorder (autosomal recessive) of kidneys most
commonly in childhood cysts are typically concentrated at
corticomedullary junction
 typically present with polyuria), polydipsia and after several
months to years, end-stage kidney disease

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Medullary sponge kidney (MSK), gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
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Acquired renal cystic disease, gross

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265
THE END

See next slide for hypermedia to further study tools and resources.
266
Study tools and resources
Module tools:
 Renal System Pathology Outline
 Renal Pathology Learning Objectives
 Acid-Base Imbalance_ A Case-based Oerview.ppt
 Fluid and Electrolyte Disorders.ppt
 Histology of the glomerular filtration barrier_Illusturations
 LM, IF and EM of Select Glomerular Diseases_Ferri Color Atlas…
 Renal Pathology Key Concepts_pdf notes
 Renal Pathology Rapid Review_pdf notes
Textbooks:
 Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed.
Philadelphia: Saunders-Elsevier, 2015, 898-957.
 Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations of Medicine,
6th ed. Baltimore: Wolters Kluwer Health, 2012; 754-807.

Additional eLearning tools:
 Renal System Cloud Folder
 Scientific Foundation Pathology Cloud Folder
Marc Imhotep Cray, MD
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