5.1.

KIDNEY PATHOLOGY I:
GLOMERULAR DISEASES
Ma. Josefa D. Mesina, M.D., F.P.S.P. December 13, 2012

Objectives:
Review the normal gross and microscopic features of the kidney
RENAL PATHOLOGY
Define/describe the different clinical manifestations/syndromes pertaining to Definition of Terms:
renal diseases
*Azotemia
Describe the pathologic mechanisms behind glomerular, tubulointerstitial and
vascular diseases Biochemical abnormality that refers to an elevation of the
Describe the morphologic changes blood urea nitrogen (BUN) and creatinine levels
Discuss the clinical outcome/prognosis of the different diseases in the kidney
Related largely to a decreased glomerular filtration rate
(GFR)
LEGEND:
Powerpoint and lecture Consequence of many renal disorders, but it also arises from
Robbins extrarenal disorders
Must remember Prerenal Azotemia: encountered when there is
hypoperfusion of the kidneys that impairs renal function
ANATOMY without parenchymal damage (e.g. hemorrhage, shock,
volume depletion, congestive heart failure)
2 MAJOR DIVISIONS Postrenal Azotemia: encountered whenever urine flow is
Upper urinary tract (kidney) obstructed beyond the level of the kidney, wherein relief of
Lower urinary tract (pelvicalcyceal system, ureters, the obstruction is followed by the correction of the azotemia
bladder and urethra)
*Uremia
When azotemia becomes associated with a constellation of
PHYSIOLOGIC FUNCTIONS OF THE KIDNEY__ clinical signs and symptoms and biochemical abnormalities
Excretes the waste products of metabolism Characterized by: failure of renal excretory function,
Serves to convert more than 1,700 liters of blood per day into metabolic and endocrine alterations resulting from renal
about 1 liter of a highly specialized concentrated fluid called damage
urine Manifests secondary involvements of the GIT (uremic
Regulates the bodys concentration of water and salt gastroenteritis), peripheral nerves (neuropathy), and heart
With the lungs, it maintains the acid-base balance (uremic fibrinous pericarditis)
Serves as an endocrine organsecreting hormones
such as erythropoietin, renin and prostaglandins
Clinical Manifestations of Renal Diseases
The study of kidney diseases is facilitated by dividing them into those that NEPHRITIC SYNDROME
affect the four basic morphologic components: glomeruli, tubules, Acute onset of usually grossly visible hematuria, mild
interstitium, blood vessels. to moderate proteinuria, hypertension
This approach is useful since the early manifestations of disease Classic presentation of acute poststreptococcal
affecting each of these components tend to be distinct.
glomerulonephritis

GROSS FEATURES OF THE KIDNEY RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

Nephritic syndrome with rapid decline (hours to
days) in GFR
NEPHROTIC SYNDROME
Heavy proteinuria (>3.5 gm/day), hypoalbuminemia,
severe edema, hyperlipidemia, lipiduria

ASYMPTOMATIC HEMATURIA OR PROTEINURIA

OR COMBINATION
Manifestation of subtle or mild glomerular
Fig. 1. Normal Kidney abnormalities

150 g - average weight of adult kidney

ACUTE RENAL FAILURE
1 -1.5 cm - cortical thickness
Dominated by oliguria or anuria and recent onset of
Normal to have a minimal amount of fat
azotemia (see acute tubular necrosis)
Major parts:
Cortexouter region RENAL TUBULAR DEFECTS
Medullainner region Dominated by polyuria, nocturia and electrolyte
Collecting systemwhich consists of the proximal disorders
portion of the ureter that is connected to the renal Result of diseases that either directly affect tubular
pelvis, which branches inward to the kidney towards structure or cause defects in specific tubular functions
the major calices and branches further to the minor
calices URINARY TRACT INFECTION
Bacteriuria amd pyuria (bacteria and lymphocytes)
May be symptomatic or not
May affect the kidney (pyelonephritis) or the bladder
(cystitis)

Melgar|Mendoza|Montenegro|Pascual|Santos, P. Kidney Pathology I: 2015B Page 1 of 10

NEPHROLITHIASIS
Renal stones
Manifested by severe spasms of pain (renal colic) and
hematuria
Often with recurrent stone formation

URINARY TRACT OBSTRUCTION OR

RENAL TUMORS Fig. 2. Components of Glomerulus
Varied clinical manifestations Comprises of:
Endothelial cellsattach inward to the capillary
CHRONIC RENAL FAILURE lumen
Prolonged signs and symptoms of uremia Visceral epithelial celloutside the endothelial
End result of all chronic renal parenchymal diseases cell
Stage I (Diminished Renal Reserve): GFR is 50% of Mesangial cellssupporting cells (together with
normal. Serum BUN and creatinine levels normal. the mesangial matrix: makes up the mesangium)
Asymptomatic. More susceptible to develop azotemia *Mesangiumserves as the supporting
with additional renal insult. framework of the interconnecting capillary
Stage II (Renal Insufficiency): GFR is 20-50% of lumen
normal. Azotemia is present, with anemia and Parietal epithelial cellscomprises of the
hypertension, as well as polyuria and nocturia. Bowmans capsule
Sudden stress may precipitate uremia. Main function: maintains the integrity of
Stage III (Chronic Renal Failure): <20-25% of normal. glomerular filtration barrier
Edema, metabolic acidosis and hyperkalemia present.
Overt uremia may ensue, with neurologic, GIT and
CV complications.
Stage IV (End-Stage Renal Disease): <5% GFR of
normal. Terminal stage of uremia.

Table 1: Principal Systemic Manifestations of Chronic Kidney

Disease and Uremia:
Fluid and Electrolytes: MEHD Metabolic acidosis
Edema Normal Glomerulus
Hyperkalemia
Dehydration Fig. 3. Histology of Glomerulus
Calcium Phosphate and Bone: Hyperphosphatemia
Hyper PP LowC RO Hyperparathyroidism GLOMERULAR FILTRATION BARRIER
(secondary)
Hypocalcemia Composed of:
Renal Osteodystrophy Fenestrated endothelial cells
Hematologic: AB Anemia Basement membrane
Bleeding diathesis Epithelial podocytes layer or visceral layer
Cardiopulmonary: C-CHUP Cardiomyopathy
Congestive heart failure 2 Factors that will Determine Filtration
Hypertension Size of the molecule - <70 kilodalton (molecular
Uremic pericarditis
weight of albumin) will allow solutes to pass through.
Pulmonary edema
>70kd will not pass through.
Gastrointestinal: BEN Bleeding
Esophagitis, gastritis, colitis *Responsible for the slit like diaphragm cells called your
Nausea and vomiting visceral epithelial cells or your podocytes.
Neuromuscular: PEM Peripheral neuropathy
Encephalopathy Charge of the barrier - the more cationic the substance
Myopathy is, the more it is permeable to the filtrating
Dermatologic: PSD Pruritus membrane. Such that your albumin is anionic ---->
Sallow color can't pass.
Dermatitis
*Responsible for this charged selective barrier is your
proteoglycans and sialoglycans proteins that coat the
OVERVIEW: GLOMERULAR DISEASES membranes of your endothelial and visceral epithelial together
Normal Glomerulus with your basement membrane.
Most important functional unit of the kidney
Histologically: an interconnection of capillary loops Glomerular Syndromes
like a specialized vascular unit 1. Acute Nephritic Syndrome (inflammation in glomeruli)
Glomerulus consists of an anastomosing network of Hematuria and red cell casts in urine
capillaries lined by fenestrated endothelium invested Associated with azotemia - increase in blood urea and
by two layers of epithelium. BUN without signs and symptoms of CRF. Also
The visceral epithelium is incorporated into and accompanied with:
becomes an intrinsic part of the capillary wall, o Variable proteinuria non-nephrotic range
separated from endothelial cells by a basement o Oliguria
membrane. o Edema and hypertension
The parietal epithelium, situated on the Bowmans 2. Rapid Progressive Glomerulonephritis
capsule, lines the urinary space, the cavity in which Characterized by a rapid/fast renal deterioration
plasma filtrate first collects. associated with

Melgar|Mendoza|Montenegro|Pascual|Santos, P. Kidney Pathology I: 2015B Page 2 of 10

 o Oliguria
o Nephritic syndrome
3. Nephrotic Syndrome
4. Chronic Renal Failure (CRF)
Increase in BUN and creatinine with
development of uremia in time
Uremia - can cause systemic manifestation
With isolated cases of hematuria and proteinuria.
5. Asymptomatic hematuria or proteinuria
6. Isolated Urinary Abnormalities
Glomerular hematuria and/or subnephrotic
proteinuria
Histologic Alterations
HYPERCELLULARITY_________________________
Increase in number of cells in the glomerular tufts.
Characterized by one or more combinations of the following:
Cellular Proliferation of mesangial and
endothelial cells.
Leukocytic infiltration of neutrophils, monocytes
and lymphocytes.
Formation of crescents - these are accumulations
of cells composed of proliferating parietal
epithelial cells + leukocytes.
This epithelial cell proliferation occurs
following an immune/inflammatory injury.
The molecule that elicits this crescentic
response is fibrin.
Fig. 4. Hypercellular Pattern. Hypercellularity = proliferation. Glomeruli
are enlarged. Cannot appreciate capillary because it is enlarged.
BASEMENT MEMBRANE THICKENING________
Thickening of the capillary walls.
Best seen with periodic acid-Schiff (PAS) stain
Takes one or two forms:
Thickening of basement membrane due to increased
synthesis of its protein components e.g diabetic
glomerulosclerosis
Deposition of amorphous electron-dense material,
most often immune complexes,on the endothelial and
epithelial side of the basement membrane or within
GBM itself.
Fig. 5. Basement Membrane Thickening Pattern due to deposition of
immune complexes. BM thickening = equates to the word membranous
HYALINOSIS AND SCLEROSIS_______________
Hyalinosis
Denotes accumulation of material that is
homogenous and eosinophilic by light microscopy.
Melgar|Mendoza|Montenegro|Pascual|Santos, P.
Common feature of focal segmental
glomerulosclerosis.
By electron microscopy, the hyaline is extracellular
and amorphous. It is made up of plasma proteins that
have insudated from the circulation into glomerular
structures.
When extensive, it contributes to obliteration of the
capillary lumens of the glomerular tuft.
Usually a consequence of endothelial or capillary wall
injury.
Fig. 6. Hyalinization Pattern. Due to accumulations of plasma proteins
from the capillary loops.
Sclerosis
Characterized by accumulations of extracellular
collagenous matrix, either confined to mesangial
areas or involving the capillary loops, or both.
May also result to capillary lumen obliteration, which
could lead to the formation of fibrous adhesions
between the sclerotic portions of the glomeruli and
the nearby parietal epithelium and Bowmans
capsule.
Fig. 7. Sclerosis Pattern. Increase or accumulation of ECM that will
eventually obliterate the lumen of the capillary.
Classification according to Histologic Patterns
DIFFUSE - all glomeruli involved
FOCAL - some glomerulus are affected, some are not
(only a proportion are involved)
GLOBAL - one whole glomerulus
SEGMENTAL - only portions of the glomerulus are
injured.
Pathogenesis of Glomerular Injury
Note: In general, glomerular diseases are immune-mediated in that it
requires a reaction between the Ag and Ab.
Fig. 8. Pathogenesis of Glomerular Disease (Robbins has a good
discussion on this topic. Please read )
Kidney Pathology I: 2015B Page 3 of 10
MECHANISM 1:
CIRCULATING IMMUNE COMPLEXES_________
Ag can either be endogenous (self Ag e.g SLE) or
exogenous (invading pathogens)
These circulating immune complexes are trapped and
activate your alternate complement system -->
activating MAC --> glomerular disease
MECHANISM 2:
IN SITU IMMUNE COMPLEX DEPOSITION____
Ab reacts directly with an intrinsic tissue Ag that is
found already or native in your glomerular B.M. Its
comparable to your auto-immune mechanism.
Or an Ag circulating that gets planted in the
glomerulus.
Other mechanisms that can damage your glomerulus:
Desensitization of your T-cells
Activation of your Alternate Complement Pathway
Fig. 9. Immune Complex Deposition would be described as a granular
appearance because of the random deposition of the immune complexes within
the BM. As compared to your In situ in which your Ag is within the BM
itself and is distributed uniformly projecting a linear pattern.
PRIMARY GLOMERULAR DISEASES
These diseases show characteristic:
Acute Nephritis
o Acute diffuse glomerulonephritis
o Rapid progressive/crescentic glomerulonephritis
Nephrotic Presentation
o Minimal change disease
o Focal segmental glomerulosclerosis
o Membranous glomerulonephritis
o Membranoproliferative glomerulonephritis
Primary Hematuria
o IgA neuropathy
Acute Diffuse Glomerulonephritis
Prototype: Postinfectious / Poststreptococcal
Glomerulonephritis
Inflammation of the glomerulus causing histologic
alterations in the form of hypercellularity and
clinically present as nephritic syndrome
Appears 1 4 weeks after a streptococcal infection of
the pharynx or skin (impetigo)
Most frequently affected are children 6-10 yrs. old
Manifests with hematuria, edema, hypertension
Proteinuria is also manifested but not that severe.
Can be endogenous (like SLE) or exogenous (post-
infection)
Skin infections are commonly associated with
overcrowding and poor hygiene.
Antigenic determinants: Strep pyogenic exotoxin B
(SpeB) and its zymogen precursor (zSpeB)
Etiologic agent: nephritogenic strains of group A -
hemolytic Streptococci (types 12, 4 and 1)
Identified by typing of M protein of the cell
wall
Melgar|Mendoza|Montenegro|Pascual|Santos, P.
PATHOGENESIS______________________________
Immune complex-mediated mechanism:
Circulating Ab-Ag complexes Entrapped in the glomeruli
Glomerular injury by activation of complement by the immune
complexes
MORPHOLOGY_______________________________
In Light Microscopy:
Fig. 10. Histology of Poststrep GN. Enlarged Hypercellularity
(leukocytic infiltration, endothelial & mesangial cell proliferation; in severe =
crescent formation) Diagnostic feature of Acute Diffuse Proliferative GN.
Diffuse: All glomeruli are affected.
In Immunofluorescence:
Fig. 11. Granular pattern due to focal and sparse deposition of IgG,
IgM and C3 (Ab-Ag complex deposition) in the mesangium and along
the GBM. Because of the deposition, there will be a decreased level of IgG,
IgM and C3 in the serum
In Electron Microscopy:
Discrete amorphous electron dense deposit on the
epithelial side of the membrane: humps appearance
CLINICAL COURSE___________________________
Overall prognosis is good in both children (95%) and
adults
Classic case: Young child develops malaise, fever,
nausea, oliguria and hematuria (smoky or cola-
colored urine) 1-2 weeks after recovery from sore
throat.
Since it is proliferative, it is nephritic syndrome.
Other Postinfectious (Non-Streptococcal) GN:
Seen in other bacterial disease (staphylococcal endocarditis,
pneumococcal pneumonia & meningococcemia), viral diseases
(Hep, B & C, mumps, varicella, HIV infection & infectious
mononucleosis) and parasitic infection (malaria,
toxoplasmosis)
Rapid Progressive Glomerulonephritis
Severe glomerular injury resulting to rapid and
progressive decline in renal function.
Manifests with severe oliguria and nephritis
Main histologic feature: epithelial proliferation -
Crescent formation
Proliferation obliterates the glomerular tuft, making it
one of the dreaded diseases
Not a specific disease entity, more of a sequelae or
complication.
3 GROUPS BASED ON IMMUNO MECHANISM_
Type1: ANTI-GBM ANTIBODY-INDUCED DISEASE (renal
limited)
Its antibodies attack the glomerular basement
membranes intrinsic antigen.
Kidney Pathology I: 2015B Page 4 of 10
 Manifests as hemoptysis and nephritis Disccusing Nephrotic Syndrome
If anti-GBM antibodies cross-react with the
pulmonary alveolar basement membranes: known as
the Goodpasture syndrome (pulmonary hemorrhage
with renal failure; clinical manifestation is recurrent
hemoptysis)
Linear pattern of IgG and C3 deposition in the GBM
in immunoflouresence
Treatment: plasmapheresis (to remove the pathogenic
circulating antibodies) or therapy to suppress the
immune response
Most severe and aggressive of the 3 types
Worst prognosis

Type2: IMMUNE COMPLEX MEDIATED

Complication of a previous GN such as Post-
infectious glomerulonephritis, lupus nephritis,
Henoch-Schonlein purpura (Treatment is for the Fig. 13. Pathophysiology of Nephrotic Syndrome. Insidious onset.
underlying disease)
Cellular proliferation in glomerular tuft and crescent Derangement of capillary walls Increased permeability to plasma
Allows proteins to escape plasma to glomerular filtrate Massive
formation
proteinuria Depletes serum albumin levels at a rate beyond the
Granular pattern in immunoflourescence (lumpy- compensatory synthetic capacity of the liver AND increased catabolism of
bumpy appearance) filtered albumin Hypoalbuminemia with a reversed albumin-to-
globulin ratio
Type3: PAUCI-IMMUNE TYPE
Lack of anti-GBM Ab or immune complexes by Decreased colloid osmotic pressure Fluid accumulation in interstitial
immunofluorescence and electron microscopy. tissues AND sodium and water retention (due to compensatory secretion of
aldosterone via the hypovolemia-enhanced renin secretion, stimulation of the
Has circulating anti-neutrophil cytoplasmic Ab
sympathetic system, a reduction in the secretion of natriuretic factors such as
(ANCAs) which attacks visceral epithelial cells ->
atrial peptides) Generalized edema
Thus associated with some vasculitis disease like
microscopic polyangitis, Wegener granulomatosis. Increased blood levels of cholesterol, triglyceride, VLDL, LDL, apoprotein and
decreased concentration of HDL Increased synthesis of lipoproteins in the
Note from 2014B Trans:
liver, abnormal transport of circulating lipid particles and decreased
What is common among these three? SEVERE GLOMERULAR
catabolism Hyperlipidemia Lipiduria
INJURY, basta if we are talking about RPGN, think about severe,
aggressive, very fast, complicated disorder. CAUSES______________________________________
Vary depending on age: Children (<15 y/o) Primary
glomerular disease
MORPHOLOGY_______________________________ Adults (2nd glomerular disease like SLE)
Gross: Enlarged, pale with cortical petechial most important Primary Glomerular Disease:
hemorrhage 1. Lipoid Nephrosis : children
Light Microscopy 2. Membranous GN: adults
o Crescent formation by proliferation of 3. Focal Segmental GS: all ages
parietal epithelial cells
o Obliterated Bowmans space MANIFESTATIONS___________________________
o WBC migration and some fibrin strands seen 1. Massive proteinuria, with the daily loss of 3.5 gm or more of
between the cell layers in the crescents protein (less in children)
2. Hypoalbuminemia, with plasma albumin levels less than 3
Immunofluorescence: gm/dL
o Variable (granular or linear) Ex.
3. Generalized edema
Goodpastures syndrome Linear
Postinfectious GN Granular 4. Hyperlipidemia
Electron Microscopy: 5. Lipiduria lipoprotein leak across the glomerular capillary
Subepithelial deposits & rupture of the GBM wall lipid in urine: free fat or oval fat bodies
(all types) Representing lipoprotein resorbed by tubular
Cause the fibrin to escape the glomerulus epithelial cells and then shed along with the
and settle in the space. degenerated cells
Globinuria: May also occur, making the patient
susceptible to infection (especially with staphylococci
and pneumococci)
Loss of anticoagulant factors (antithrombin III and
antiplasmins) May cause thrombotic and
thromboembolic complications

Membranous Glomerulonephritis/Nephropathy
Most common cause of nephrotic syndrome in adults
Fig. 12. RPGN: Left Visible crescent shape, plus shrinkage of the glomerulus. Characterized by diffuse thickening of the glomerular
Right Immunoflourescence of type 1 RPGN
capillary wall without an increase in number of cells
and the accumulation of electron-dense
immunoglobulin-containing deposits along the
subepithelial side of basement membrane

Melgar|Mendoza|Montenegro|Pascual|Santos, P. Kidney Pathology I: 2015B Page 5 of 10

PATHOGENESIS______________________________
Form of chronic immune complex-mediated disease
Immune complexes form in situ or circulating Ag
being trapped in the glomeruli and later on followed
by antibody deposition
Membrane damage due to attack of complements
Leakage of solutes, such as protein
Direct action of C5b-C9, which activates the
glomerular epithelial and mesangial cells Liberate
proteases and oxidants Capillary wall injury
Increased protein leakage
Lesions similar to those of experimental Heymann
nephritisinduced by Ab to a megalin antigenic complex
and is considered an autoimmune disease linked to
susceptibility genes and caused most likely by Ab to a renal
autoantigen
2 GROUPS BASED ON ETIOLOGY_____________
1. Idiopathic or Primary (85% of cases)
2. Secondary or in association with other systemic diseases
Development of immune complexes due to the
presence of abnormal circulating antigens
Infectious: Hepatitis B & C, syphilis, schistosomiasis
Drug-related: penicillamine, captopril, gold therapy,
NSAIDs
Tumor-associated: Lung cancer, colon, melanomas
SLE: 15% of GN in SLE is of the membranous type
MORPHOLOGY_______________________________
Light microscopy and immunofluorescence:
Fig. 13. Left: Silver methenamine stain. Note the uniform, diffuse
thickening of the capillary walls. There are prominent irregular
"spikes" of silver-staining matrix (arrow) projecting from the GBM
lamina densa toward the urinary space, which separate and surround
the deposited immune complexes that lack affinity for the silver stain.
Immune complexes are between the GBM and epithelial cells, the
latter having effaced foot processes.
Right: Characteristic granular immunofluorescent deposits of
IgG and C3 along GBM.
CLINICAL COURSE___________________________
Variable, irregular
Progression is associated with
Increase in sclerosis of glomeruli
Increase in BUN
Develop hypertension
Proteinuria is NONSELECTIVE
Any proteins are flushed out
Poor and unpredictable response to corticosteroid
therapy
Patients : Adults>children
Urine : poorly selective proteinuria
Course: Sudden presentation, usually only minimal
trace of hematuria
Treatment: poor response to steroid therapy
LM: thick capillary walls
IF: granular deposits of IgG & C3
EM: think SUBEPITHELIAL IMMUNE COMPLEX
DEPOSITS
Melgar|Mendoza|Montenegro|Pascual|Santos, P.
Minimal Change Disease
(Lipoid Nephrosis)
Most frequent cause of nephrotic syndrome in children
Characterized by diffuse effacement/flattening out of
foot processes of visceral epithelial cells (podocytes) that
appear normal under light microscopy
Mainly seen in children 2-6 years old
Sometimes follows a respiratory infection or routine
prophylactic immunization
Most characteristic feature: Dramatic response to
corticosteroid therapy
ETIOLOGY AND PATHOGENESIS_____________
Immunologic basis despite the absence of immune
complexes
Immune dysfunction elaboration of a cytokine-
like circulating substance affects visceral
epithelial cells Proteinuria
Proteinuria is selective to albumin only (since visceral
epithelial cells are the size-selective barrier of GBM);
therefore, there is good response to steroids
MORPHOLOGY_______________________________
Light microscopy: NORMAL
Immunofluorescence: NORMAL (No deposits)
Can only be detected with electron microscopy
Fig. 14. Normal podocytes
Fig. 15. Minimal Change Disease: visceral epithelial cells showing
uniform and diffuse flattened foot processes, these being replaced by
a rim of cytoplasm often showing vacuolization, swelling and
hyperplasia of villi.
CLINICAL FEATURES_________________________
Despite massive proteinuria, renal function remains good.
Commonly NO hypertension or hematuria
Highly-selective proteinuria (mostly albumin)
In adults, MCD can be associated with Hodgkins
lymphoma
Secondary MCD may follow NSAID therapy (usually
associated with acute interstitial nephritis)
Focal Segmental Glomerulosclerosis (FSGS)
Sclerosis of some, but not all, glomeruli (focal) and
affectation of a portion of the glomerular tuft (segmental)
Clinical presentation: Nephrotic syndrome or persistent,
heavy proteinuria
Most common form of glomerulosclerosis in adults
Various settings in which it occurs:
o Idiopathic or Primary FSGS
o Secondary associated with other disorders
Kidney Pathology I: 2015B Page 6 of 10
 Ex. Associated with HIV (HIV nephropathy),
heroin addiction, sickle cell diseases, and
massive obesity
o As a secondary event reflecting scarring of
previously active necrotizing lesions
Ex. IgA nephropathy
o
As a component of an adaptive response to loss
of renal tissue in advanced stages of other renal
disorders such as reflux nephropathy,
hypertensive nephropathy, or unilateral renal
agenesis
HALLMARK of FSGS Epithelial damage
Fig. 16. Degeneration and focal disruption of visceral epithelial
cellsdifference from MCDs diffuse epithelial cell change.
PATHOGENESIS______________________________
Circulating cytokines and genetically determined
defects affecting components of the slit diaphragm
complex (key factor: nephrin, which is the zipper-like
structure between podocyte foot processes that might
control glomerular permeability) Epithelial
damage
Entrapment of plasma proteins in extremely
hyperpermeable foci and increased ECM deposition
Hyalinosis and sclerosis
Circulating cytokine Recurrence of proteinuria
(sometimes within 24 hours of transplantation with
subsequent progression to overt lesions of FSGS)
MORPHOLOGY_____________________________
On light microscopy: focal and segmental lesions involve
only a minority of the glomeruli
Initially, involves only the juxtamedullary glomeruli
Then, it becomes more generalized
In the sclerotic segments: collapse of capillary loops,
increase in matrix, segmental deposition of plasma
proteins along the capillary wall (hyalinosis) which
could occlude the lumen
Lipid droplets and foam cells present
Glomeruli that do not show segmental lesions:
normal on LM but may show increased mesangial
matrix
On electron microscopy: both sclerotic and non-sclerotic areas
show diffuse effacement of foot processes
Focal detachment of epithelial cells
Denudation of underlying GBM
By immunofluorescence: IgM and C3 may be present in
sclerotic areas and/or mesangium
Pronounced hyalinosis and thickening of afferent
arterioles
In time: lead to global glomerulosclerosis with
pronounced tubular atrophy and interstitial fibrosis
Melgar|Mendoza|Montenegro|Pascual|Santos, P.
From Robbins (was not discussed in class):
Morphologic variant of FSGS: Collapsing Glomerulopathy
Retraction and/or collapse of the entire glomerular tuft
Proliferation and hypertrophy of glomerular visceral
epithelial cells
Idiopathic BUT is the most characteristic lesion of HIV-
associated nephropathy
Associated prominent tubular injury with formation of
microcysts; poor prognosis
Membranoproliferative Glomerulonephritis
(MPGN)
Also known as Mesangiocapillary GN
Clinical presentation: May be nephrotic (10-20% of cases)
or mixed nephrotic/nephritic with low C3
TYPES________________________________________1.
Primary or Idiopathic
Type I MPGN Immune complexes in the
glomerulus and activation of both classic and
alternative pathways
Type II MPGN Dense-deposit disease that has
abnormalities that suggest activation of the
alternative complement pathway
Consistently decreased serum C3 but normal C1
and C4 (the immune complex-activated early
components of the complement)
Diminished serum levels of factor B and
properdin (from alternative complement
pathway)
In the glomeruli, C3 and properdin are
deposited, but IgG is not. Recall: C3 is directly
cleaved by C3b upon contact with Ag and with the aid
of IgA aggregates in the presence of factors B and D
Generates the labile C3bBb, which is the alternative
pathway C3 convertase Stabilized by properdin
IN DENSE DEPOSIT DISEASE, C3 nephritic factor
(C3NeF; a circulating antibody that binds to C3bBb)
is present Binding of C3bBb and C3NeF
Stabilizes C3bBb Protected from enzymatic
degradation Favoring persistent C3 activation
Hypocomplementemia
Decreased C3 synthesis in the liver
2. Secondary MPGN
Chronic immune complex disorders like SLE, Hep B
and C infections
Alpha 1-antitrypsin deficiency
Malignant diseases (CLL, lymphoma)
Hereditary deficiencies of complement regulatory
proteins
Fig. 17. MPGN. Basement membrane thickening. Proliferation of
glomerular cells. Glomeruli are large and hypercellular. Leukocytic
infiltration especially in the mesangium. Enlarged glomeruli showing
mesangial cell proliferation. Lobular appearance of glomerular tuft.
MORPHOLOGY_______________________________
GBM thickened; often segmentally: most evident in
peripheral capillary loops
Kidney Pathology I: 2015B Page 7 of 10
 Capillary wall: double-contour or tram-track
appearance (especially evident in silver or PAS stains)
Caused by BM duplication/splitting
Split basement membrane: result of new BM
synthesis in response to subendothelial deposits of
immune complexes

Type I MPGN
Subendothelial electron-dense deposits
C3 is deposited in granular pattern
IgG and early complement components (C1q and C4) Fig. 18. Alport Syndrome. GBM and tubular BM show irregular foci of
are often present thickening alternating with attenuation (thinning) and pronounced
splitting and lamination of the lamina densa, often producing a
Type II MPGN distinctive basket-weave appearance.
Lamina densa of GBM becomes an irregular, ribbon-
like, extremely electron-dense structure due to the THIN BASEMENT MEMBRANE DISEASE_______
deposition of dense material a.k.a. Benign Familial Hematuria
C3 is present in irregular granular or linear foci in Clinically manifested by familial asymptomatic
the BM on either side but not within the dense hematuria discovered on routine urinalysis
deposits Diagnosed morphologically through electron
C3 is also present in the mesangium in characteristic microscopy by thinning of GBM between 150-250 nm
circular aggregates (mesangial rings) (Normal: 300-400 nm)
IgG absent Mode of inheritance: Heterozygous
Pathogenesis:
IgA Nephropathy (Berger Disease) Defective genes encoding 3 or 4 chains of
Isolated urinary abnormality Type IV collagen
Form of glomerulonephritis characterized by the presence
of prominent IgA deposits in the mesangial regions
detected ONLY by immunofluorescence microscopy
(immunocytochemical techniques)
Frequent cause of recurrent gross or microscopic
hematuria
Clinical presentation: Hematuria (gross/microscopic) and
mild proteinuria
Most common form of GN worldwide (except among Fig. 19. Thin Basement Membrane

African-Americans)
Chronic Glomerulonephritis
Course: 15-40% in a span of 20 years End-Stage Renal
Disease
Prognosis: Proteinuria > 1g/day and hypertension are bad

PATHOGENESIS______________________________
Polymeric IgA links with antigen and is carried into circulation
Deposition into mesangium Activates complement
Glomerular injury
Fig. 20. Chronic glomerulonephritis is more of an end-stage pool of the
previously discussed glomerulopathies. If these diseases progress
MORPHOLOGY_______________________________ further, they end up as chronic GM.
By immunofluorescence: mesangial deposition of
IgA, often with C3 and properdin and lesser
amounts of IgG or IgM
C1q and C4 absent

TREATMENT_________________________________
ACE inhibitors/Angiotensin receptor blockers (ARB)
If recurrent Renal transplantation

Hereditary Nephritis
Refers to a group of heterogenous familial renal diseases
associated primarily with glomerular injury.

ALPORT SYNDROME_________________________ Fig. 21. Cross-section of kidney with chronic GM where you are able to
Hematuria progressing to chronic renal failure, appreciate several features: symmetrically contracted, diffusely
accompanied by nerve deafness and various eye granular cortical surface, thinned-out cortex, increased peripelvic fat.
With the ruler you can observe that these kidneys are small. Normal diameter
disorders (including lens dislocation, posterior
is 10cm. Here it is 8cm (size reduction).
cataracts, corneal dystrophy)
Mode of inheritance: X-linked
Pathogenesis:
Mutation of gene encoding Type IV collagen
(main component of GBM) defective assembly
of Type IV collagen (seen in GBM, lens of the eye,
cochlea)

Melgar|Mendoza|Montenegro|Pascual|Santos, P. Kidney Pathology I: 2015B Page 8 of 10

 Class I - Minimal or no detectable abnormality
Seen in 5% of SLE patients

Class II Mesangial Lupus Glomerulonephritis

Mesangial cell proliferation and lack of involvement
Fig. 22: In Chronic GM, there is difficulty stripping off the renal of the glomerular capillary walls.
capsule. If ever you are able to do so it will reveal a coarsely granular
Seen in 10-25% of SLE patients
cortical surface.
Minimal renal manifestation in the form of mild
hematuria or transient proteinuria.
Immunofluorescense: granular mesangial deposits of
Ig and complement are present.

Fig. 23. Special stain showing hyalinosis of glomeruli in Chronic GM.

Hyalinosis of glomeruli indicates end-stage changes in glomeruli.
Tubular atrophy. Interstitial fibrosis.

MORPHOLOGY_______________________________ Fig. 25. Class II Mesangial GN

Early cases: evidence of primary disease
Progression: obliteration of glomeruli acellular
eosinophilic masses (trapped plasma proteins, Class III Focal Proliferative Glomerulonephritis
increased mesangial matrix, BM-like material and 20-25% of SLE cases
collagen) Focal = some glomeruli normal, some are not
Arterial and arteriolar sclerosis may be conspicuous: Proliferative = hypercellularity
because of co-morbid hypertension
Marked atrophy of associated tubules, irregular
interstitial fibrosis and mononuclear leukocytic
interstitial infiltration
Dialysis changes: arterial intimal thickening caused
by accumulation of smooth muscle-like cells and a
loose, proteoglycan-rich stroma, focal calcification,
extensive deposition of calcium oxalate crystals in
tubules and intersitium, acquired cystic disease,
increased numbers of renal adenomas and
adenocarcinomas
Uremic complications (see table on page 2)
Fig. 26: Class III Focal Proliferative GN
Class IV Diffuse Proliferative GN
GLOMERULAR LESIONS ASSOCIATED WITH Most serious form of lupus nephritis
SYSTEMIC DISEASE 35-60% of SLE patient
Systemic Lupus Erythematosus Diffuse = all glomeruli are abnormal
Fig. 27. Class IV Diffuse GN

Fig. 28. wire loop usually appreciated in Class IV because it is your

capillary basement membrane thickening. Usually when this lesion is
present in biopsy in SLE it connotes active disease. Individual is
Fig. 24. Pathogenesis of SLE. SLE is a multisystemic disorder: antibodies
continually forming these immune complexes. Need to treat with
against self-antigens. Since it is immune mediated, one of organs not spared is
steroids.
the kidneys.

W.H.O. CLASSIFICATION OF LUPUS NEPHRITIS Class V Membranous GN

Clinical picture is similar to that of Idiopathic
BASED ON MORPHOLOGY
membranous GN.
Usually if you have a patient visiting a nephrologist, the first thing
would like to note is the extent of kidney damage. Want to know
prognosis by doing renal biopsy then classifying based on the Diabetic Nephropathy
following criteria: Diabetes mellitus is now one of the most common causes of
end-stage renal failure.

Melgar|Mendoza|Montenegro|Pascual|Santos, P. Kidney Pathology I: 2015B Page 9 of 10

 Diabetes can affect the kidney in three forms:
1. Complications of diabetic vasculature
2. Diabetic glomerular damage
3. Increased susceptibility to infection and papillary
necrosis
CONTRIBUTORS TO RENAL TISSUE INJURY___
Glucose toxicity (hyperglycemia) -- metabolic effect causes
biochemical alterations in glomerular basement membrane
Non-enzymatic glycosylation of proteins AGE (advanced
glycosylation end products) that are toxic to the glomerulus
Hemodynamic changes (inc. GFR, inc. glomerular
capillary pressure, glomerular hypertrophy and inc.
glomerular filtration area)
MORPHOLOGIC CHANGES IN GLOMERULI___
Capillary basement membrane thickening
Diffuse mesangial sclerosis
Nodular sclerosis (pathognomonic lesion of diabetic
nephropathy) - intercapillary glomerulosclerosis or
Kimmelstiel Wilson disease
Fig. 29. Diffuse and nodular diabetic glomerulosclerosis. Sclerosis of
some of capillary loops. Sclerosis is due to accumulation of extracellular
collagenous matrix that eventually obliterates lumen of capillary loops.
Henoch-Schonlein
Purpuric skin lesions characteristically affecting the
extensor surface of the arms and legs and buttocks,
abdominal manifestation (abdominal pain, vomiting,
intestinal bleeding), non-migratory abnormalities and
urinary abnormalities.
Renal manifestation: gross or microscopic hematuria,
proteinuria, and nephrotic syndrome.
IgA is deposited in the glomerular mesangium,
sometimes with IgG and C3, similar to that of IgA
nephropathy.
Usually seen in children. If seen in adults, it carries a poor
prognosis.
Amyloidosis
Amyloid (a pathologic protein) is deposited in the GBM and
mesangium.
Permeability is increased proteinuria
Amyloid deposits may be found in the blood vessel wall
and interstitium
Fig. 30. Pink. How to differentiate from sclerosis and hyalinosis. Use congo
red stain to document as amyloidosis.
Melgar|Mendoza|Montenegro|Pascual|Santos, P.
POP QUIZ!
1. What glomerular syndrome manifests as hematuria,
azotemia, variable proteinuria, oliguria, edema and
hypertension?
2. At what value of proteinuria can one classify the case as
nephrotic syndrome?
3. What is the GFR associated with Stage II Renal Failure?
4. What condition are ANCAs associated with?
5. This condition can only be diagnosed through
immunoflurorescence testing.
6. What condition is associated with Kimmelstiel-Wilson
disease?
7. What condition has a characteristic tram-track appearance of
the capillary wall?
8. What are the most common etiologic agents of acute diffuse
glomerulonephritis?
9. What condition can be described grossly as symmetrically
contracted, diffusely granular cortical surface, thinned-out
cortex, increased peripelvic fat?
10. What condition manifests as hematuria progressing to
chronic renal failure, accompanied by nerve deafness and
various eye disorders?
REFERENCES
Dr. Mesinas lecture and powerpoint
Robbins
2014B Trans
Hey 2015B HAPPY CHRISTMAS ;D
Since its Christmas break na, then New Year, we just wanna share stuff with you
and baka its the end of the world, and thisll be the last thing youll read
(ASA) :p
Beeteedub, CONGRATULATIONS FAITH :D
P.S. EVERYONE, LETS EOWS a.k.a. End of the World S.. ;))
Pag nilalandi ka ng crush mo, sabihin mo: WAAAAAAAAGmong itigil
Kung may rabies ka, handa akong maulol..makahalik lang sa yo
Kung single ka, mahalin mo muna sarili mo. Tapos kapag ready ka na, isunod mo na ako
:D
Why do students choose to shade the wrong answer? Because we accept the grade we
think we deserve #PerksofBeingACrammer
Aabsent na lang ako sa lahat ng klase ko..makapasok lang sa puso mo
Buti pa ang mga aso, alam kung paano mag-STAY.
Kapag payat, COSPLAYER. Kapag mataba, MASCOT ;)))))
Sa panahon ngayon: uso na ang mag-move-on..kahit hindi nagiging kayo ;))
Baka kaya tayo iniiwan ng mga taong mahal natin, kasi baka merong bagong darating na
mas okay. Na mas mamahalin tayo. Yung taong hindi tayo sasaktan at paaasahin. Yung
nag-iisang taong magtatama ng mali sa buhay natin, nang lahat ng mali sa buhay mo.
P
Maybe I dont wanna be saved the trouble. Maybe I want the trouble. I havent wanted
the trouble in a long time. But with you, the trouble doesnt seem so troubling. I dont
know. I thought.. I guess I thought you felt the same way. B
T: Okay, I'm going to say something out loud that I've been doing a pretty good job of
not saying out loud lately. What you and Tony have, what I thought for a second you and
I had, what I know that Marshall and Lily have, I want that. I do. I keep waiting for it to
happen. I'm waiting for it to happen. I guess I'm just tired of waiting. And that is all I'm
going to say on that subject.
S: I know that you're tired of waiting. And you might have to wait a little while more
but, she's on her way, Ted. And she's getting here as fast as she can.
L: Okay, yes, its a mistake. I know its a mistake. But there are certain things in life
where you know its a mistake but you dont really know its a mistake because the only
way to really know its a mistake is to make the mistake, and look back, and say, Yep.
That was a mistake. So, really, the bigger mistake would be to not make the mistake,
because then you go your whole life not really knowing if something is a mistake or not.
And, damn it, Ive made no mistakes! Ive done all of this my life, my relationship, my
career mistake-free. Does any of this make sense to you?
ANSWER KEY:
1. Nephritic syndrome
2. >3.5 gm/day
3. 20-50% of normal
4. Type III Pauci Immune Type RPGN
5. IgA Nephropathy (Bergers Disease)
6. Diabetic Nephropathy
7. Membranoproliferative Glomerulonephritis
8. Group A -hemolytic Streptococci (types 12, 4 and 1)
9. Chronic Glomerulonephritis
10. Alport Syndrome
Kidney Pathology I: 2015B Page 10 of 10