Professional Documents
Culture Documents
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
Marc Imhotep Cray, MD
2
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
Mohan H. Textbook of Pathology, 7th Ed. New Delhi: Jaypee Brothers Medical Publishers, 2015.
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.
13
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.
15
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)
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.
Marc Imhotep Cray, MD
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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.
Marc Imhotep Cray, MD
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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).
23
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.
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
Marc Imhotep Cray, MD
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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,
↓
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
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
Marc Imhotep Cray, MD
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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)
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.
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
54
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)
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
69
Lecture 2: Glomerular Diseases
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:
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
Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology, 10th ed. Philadelphia: Elsevier, 2018.
Marc Imhotep Cray, MD
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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
2. Epimembranous deposits as in
membranous nephropathy
Pathology
LM: Normal-appearing glomeruli can see lipid
accumulation in renal tubular cells
EM: Fusion of epithelial foot processes
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.
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?
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
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
Marc Imhotep Cray, MD
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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.
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
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
112
Diffuse glomerulosclerosis, microscopic
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
113
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)
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Diagnosis (A) , Amyloid nephropathy, multiple myeloma
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?
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?
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
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
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
135
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?
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
138
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?
Type II is characterized by
intramembranous dense deposits
(=dense-deposit disease)
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
144
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
Pathology
LM: mesangial widening and focal and segmental
inflammation
EM: Mesangial deposits of IgA
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°)
Cystitis
Clinical features: dysuria in absence of vaginal discharge and
significant pain, frequency, urgency, suprapubic pain
Marc Imhotep Cray, MD
155
UTI, Cystitis cont’d.
Etio-pathogenesis:
Bacteria gain access to urinary tract via urethra
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
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
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
Clinical Manifestations:
oliguria; azotemia; hyperkalemia
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.
Le T, Bhushan, et al. First Aid for the USMLE Step 1 2017. McGraw-Hill Education, 2017.
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
193
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)
Marc Imhotep Cray, MD
194
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.
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
Marc Imhotep Cray, MD
198
Common causes of obstructive
lesions of urinary tract
Obstruction may be sudden or
insidious, partial or complete,
unilateral or bilateral
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
Marc Imhotep Cray, MD
215
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.
Fibromuscular dysplasia and vasculitis are less common causes overall but
Marcare most
Imhotep frequent causes in children
Cray, MD
222
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
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
224
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
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
226
Renal infarct, gross
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
227
Renal infarct, microscopic
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
228
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
An electron micrograph
shows a wide band of lucent
material in subendothelial
zone(arrows), which causes
marked narrowing of lumen
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
Marc Imhotep Cray, MD
236
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
Marc Imhotep Cray, MD
237
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?
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
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)
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
Marc Imhotep Cray, MD
249
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
Marc Imhotep Cray, MD
250
Urothelial carcinoma
Urothelial carcinoma of renal pelvis
Pelvis has been opened to expose
nodular irregular neoplasm, just
proximal to ureter
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
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
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
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
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
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
264
Acquired renal cystic disease, gross
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
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.