Melgar|Mendoza|Montenegro|Pascual|Santos, P. Kidney Pathology I: 2015B Page 1 of 10
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
Define/describe the different clinical manifestations/syndromes pertaining to renal diseases
Describe the pathologic mechanisms behind glomerular, tubulointerstitial and vascular diseases
Describe the morphologic changes
Discuss the clinical outcome/prognosis of the different diseases in the kidney LEGEND:
Powerpoint and lecture Robbins
Must remember
ANATOMY
2 MAJOR DIVISIONS
Upper urinary tract (kidney)
Lower urinary tract (pelvicalcyceal system, ureters, bladder and urethra)
PHYSIOLOGIC FUNCTIONS OF THE KIDNEY__
Excretes the waste products of metabolism
Serves to convert more than 1,700 liters of blood per day into about 1 liter of a highly specialized concentrated fluid called urine
Regulates the body’s concentration of water and salt With the lungs, it maintains the acid-base balance Serves as an endocrine organ—secreting hormones
such as erythropoietin, renin and prostaglandins
The study of kidney diseases is facilitated by dividing them into those that affect the four basic morphologic components: glomeruli, tubules,
interstitium, blood vessels.
This approach is useful since the early manifestations of disease
affecting each of these components tend to be distinct.
GROSS FEATURES OF THE KIDNEY
Fig. 1. Normal Kidney
150 g - average weight of adult kidney 1 -1.5 cm - cortical thickness
Normal to have a minimal amount of fat
Major parts:
Cortex—outer region Medulla—inner region
Collecting system—which consists of the proximal portion of the ureter that is connected to the renal pelvis, which branches inward to the kidney towards the major calices and branches further to the minor calices
RENAL PATHOLOGY
Definition of Terms: *Azotemia
Biochemical abnormality that refers to an elevation of the blood urea nitrogen (BUN) and creatinine levels
Related largely to a decreased glomerular filtration rate (GFR)
Consequence of many renal disorders, but it also arises from extrarenal disorders
Prerenal Azotemia: encountered when there is hypoperfusion of the kidneys that impairs renal function without parenchymal damage (e.g. hemorrhage, shock, volume depletion, congestive heart failure)
Postrenal Azotemia: encountered whenever urine flow is obstructed beyond the level of the kidney, wherein relief of the obstruction is followed by the correction of the azotemia
*Uremia
When azotemia becomes associated with a constellation of clinical signs and symptoms and biochemical abnormalities Characterized by: failure of renal excretory function,
metabolic and endocrine alterations resulting from renal damage
Manifests secondary involvements of the GIT (uremic gastroenteritis), peripheral nerves (neuropathy), and heart (uremic fibrinous pericarditis)
Clinical Manifestations of Renal Diseases
NEPHRITIC SYNDROME
Acute onset of usually grossly visible hematuria, mild to moderate proteinuria, hypertension
Classic presentation of acute poststreptococcal glomerulonephritis
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 abnormalities
ACUTE RENAL FAILURE
Dominated by oliguria or anuria and recent onset of azotemia (see acute tubular necrosis)
RENAL TUBULAR DEFECTS
Dominated by polyuria, nocturia and electrolyte disorders
Result of diseases that either directly affect tubular structure or cause defects in specific tubular functions
URINARY TRACT INFECTION
Bacteriuria amd pyuria (bacteria and lymphocytes) May be symptomatic or not
May affect the kidney (pyelonephritis) or the bladder (cystitis)
Normal Glomerulus
NEPHROLITHIASIS
Renal stones
Manifested by severe spasms of pain (renal colic) and hematuria
Often with recurrent stone formation
URINARY TRACT OBSTRUCTION OR RENAL TUMORS
Varied clinical manifestations
CHRONIC RENAL FAILURE
Prolonged signs and symptoms of uremia
End result of all chronic renal parenchymal diseases
Stage I (Diminished Renal Reserve): GFR is 50% of
normal. Serum BUN and creatinine levels normal. Asymptomatic. More susceptible to develop azotemia with additional renal insult.
Stage II (Renal Insufficiency): GFR is 20-50% of
normal. Azotemia is present, with anemia and hypertension, as well as polyuria and nocturia. Sudden stress may precipitate uremia.
Stage III (Chronic Renal Failure): <20-25% of normal.
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
Hyperkalemia Dehydration Calcium Phosphate and Bone:
Hyper PP LowC RO Hyperphosphatemia Hyperparathyroidism (secondary) Hypocalcemia Renal Osteodystrophy Hematologic: AB Anemia Bleeding diathesis Cardiopulmonary: C-CHUP Cardiomyopathy
Congestive heart failure Hypertension
Uremic pericarditis Pulmonary edema Gastrointestinal: BEN Bleeding
Esophagitis, gastritis, colitis Nausea and vomiting Neuromuscular: PEM Peripheral neuropathy
Encephalopathy Myopathy
Dermatologic: PSD Pruritus
Sallow color Dermatitis
OVERVIEW: GLOMERULAR DISEASES
Normal Glomerulus
Most important functional unit of the kidney Histologically: an interconnection of capillary loops—
like a specialized vascular unit
Glomerulus consists of an anastomosing network of capillaries lined by fenestrated endothelium invested by two layers of epithelium.
The visceral epithelium is incorporated into and becomes an intrinsic part of the capillary wall, separated from endothelial cells by a basement membrane.
The parietal epithelium, situated on the Bowman’s capsule, lines the urinary space, the cavity in which plasma filtrate first collects.
Fig. 2. Components of Glomerulus
Comprises of:
Endothelial cells—attach inward to the capillary lumen
Visceral epithelial cell—outside the endothelial cell
Mesangial cells—supporting cells (together with the mesangial matrix: makes up the mesangium) *Mesangium—serves as the supporting framework of the interconnecting capillary lumen
Parietal epithelial cells—comprises of the Bowman’s capsule
Main function: maintains the integrity of
glomerular filtration barrier
Fig. 3. Histology of Glomerulus GLOMERULAR FILTRATION BARRIER
Composed of:
Fenestrated endothelial cells Basement membrane
Epithelial podocytes layer or visceral layer
2 Factors that will Determine Filtration
Size of the molecule - <70 kilodalton (molecular weight of albumin) will allow solutes to pass through. >70kd will not pass through.
*Responsible for the slit like diaphragm cells called your visceral epithelial cells or your podocytes.
Charge of the barrier - the more cationic the substance is, the more it is permeable to the filtrating membrane. Such that your albumin is anionic ----> can't pass.
*Responsible for this charged selective barrier is your
proteoglycans and sialoglycans proteins that coat the
membranes of your endothelial and visceral epithelial together with your basement membrane.
Glomerular Syndromes
1. Acute Nephritic Syndrome (inflammation in glomeruli)
Hematuria and red cell casts in urine
Associated with azotemia - increase in blood urea and BUN without signs and symptoms of CRF. Also accompanied with:
o Variable proteinuria non-nephrotic range o Oliguria
o Edema and hypertension
2. Rapid Progressive Glomerulonephritis
Characterized by a rapid/fast renal deterioration associated with
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.
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 Bowman’s 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 )
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. It’s 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
β-hemolytic Streptococci (types 12, 4 and 1)
Identified by typing of M protein of the cell wall
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 andprogressive 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.
Manifests as hemoptysis and nephritis
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 underlying disease)
Cellular proliferation in glomerular tuft and crescent formation
Granular pattern in immunoflourescence
(lumpy-bumpy appearance) Type3: PAUCI-IMMUNE TYPE
Lack of anti-GBM Ab or immune complexes by immunofluorescence and electron microscopy. Has circulating anti-neutrophil cytoplasmic Ab
(ANCAs) which attacks visceral epithelial cells ->
Thus associated with some vasculitis disease like microscopic polyangitis, Wegener granulomatosis.
MORPHOLOGY_______________________________
Gross: Enlarged, pale with cortical petechial hemorrhage
Light Microscopy
o Crescent formation by proliferation of
parietal epithelial cells o Obliterated Bowman’s space
o WBC migration and some fibrin strands seen between the cell layers in the crescents Immunofluorescence:
o Variable (granular or linear) Ex. Goodpasture’s syndrome – Linear
Postinfectious GN – Granular Electron Microscopy:
Subepithelial deposits & rupture of the GBM (all types)
Cause the fibrin to escape the glomerulus and settle in the space.
Fig. 12. RPGN: Left – Visible crescent shape, plus shrinkage of the glomerulus. Right – Immunoflourescence of type 1 RPGN
Disccusing Nephrotic Syndrome
Fig. 13. Pathophysiology of Nephrotic Syndrome. Insidious onset.
Derangement of capillary walls Increased permeability to plasma Allows proteins to escape plasma to glomerular filtrate Massive
proteinuria Depletes serum albumin levels at a rate beyond the
compensatory synthetic capacity of the liver AND increased catabolism of filtered albumin Hypoalbuminemia with a reversed
albumin-to-globulin ratio
Decreased colloid osmotic pressure Fluid accumulation in interstitial tissues AND sodium and water retention (due to compensatory secretion of aldosterone via the hypovolemia-enhanced renin secretion, stimulation of the sympathetic system, a reduction in the secretion of natriuretic factors such as atrial peptides) Generalized edema
Increased blood levels of cholesterol, triglyceride, VLDL, LDL, apoprotein and decreased concentration of HDL Increased synthesis of lipoproteins in the liver, abnormal transport of circulating lipid particles and decreased catabolism Hyperlipidemia Lipiduria
CAUSES______________________________________
Vary depending on age: Children (<15 y/o) – Primary glomerular disease
Adults (2nd glomerular disease like SLE)
most important Primary Glomerular Disease: 1. Lipoid Nephrosis : children
2. Membranous GN: adults 3. Focal Segmental GS: all ages
MANIFESTATIONS___________________________ 1. Massive proteinuria, with the daily loss of 3.5 gm or more of
protein (less in children)
2. Hypoalbuminemia, with plasma albumin levels less than 3
gm/dL
3. Generalized edema 4. Hyperlipidemia
5. Lipiduria – lipoprotein leak across the glomerular capillary
wall lipid in urine: free fat or oval fat bodies
Representing lipoprotein resorbed by tubular epithelial cells and then shed along with the 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 Characterized by diffuse thickening of the glomerular 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
Note from 2014B Trans:
What is common among these three? SEVERE GLOMERULAR INJURY, basta if we are talking about RPGN, think about severe, aggressive, very fast, complicated disorder.
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 nephritis—induced 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
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 acytokine-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 Hodgkin’s
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
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
cells—difference from MCD’s 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
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
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) are often present
Type II MPGN
Lamina densa of GBM becomes an irregular, ribbon-like, extremely electron-dense structure due to the
deposition of dense material
C3 is present in irregular granular or linear foci in
the BM on either side but not within the dense
deposits
C3 is also present in the mesangium in characteristic
circular aggregates (mesangial rings)
IgG absent
IgA Nephropathy (Berger Disease)
Isolated urinary abnormality
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 African-Americans)
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
MORPHOLOGY_______________________________
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 transplantationHereditary Nephritis
Refers to a group of heterogenous familial renal diseases associated primarily with glomerular injury.
ALPORT SYNDROME_________________________
Hematuria progressing to chronic renal failure,
accompanied by nerve deafness and various eye disorders (including lens dislocation, posterior
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)
Fig. 18. Alport Syndrome. GBM and tubular BM show irregular foci of
thickening alternating with attenuation (thinning) and pronounced splitting and lamination of the lamina densa, often producing a
distinctive basket-weave appearance.
THIN BASEMENT MEMBRANE DISEASE_______
a.k.a. Benign Familial Hematuria
Clinically manifested by familial asymptomatic hematuria discovered on routine urinalysis
Diagnosed morphologically through electron microscopy by thinning of GBM between 150-250 nm (Normal: 300-400 nm)
Mode of inheritance: Heterozygous
Pathogenesis:
Defective genes encoding α3 or α4 chains of Type IV collagen
Fig. 19. Thin Basement Membrane
Chronic Glomerulonephritis
Fig. 20. Chronic glomerulonephritis is more of an end-stage pool of the previously discussed glomerulopathies. If these diseases progress
further, they end up as chronic GM.
Fig. 21. Cross-section of kidney with chronic GM where you are able to appreciate several features: symmetrically contracted, diffusely granular cortical surface, thinned-out cortex, increased peripelvic fat.
With the ruler you can observe that these kidneys are small. Normal diameter is 10cm. Here it is 8cm (size reduction).
Fig. 22: In Chronic GM, there is difficulty stripping off the renal
capsule. If ever you are able to do so it will reveal a coarsely granular
cortical surface.
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_______________________________
Early cases: evidence of primary disease
Progression: obliteration of glomeruli acellular
eosinophilic masses (trapped plasma proteins,
increased mesangial matrix, BM-like material and collagen)
Arterial and arteriolar sclerosis may be conspicuous: 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)
GLOMERULAR LESIONS ASSOCIATED WITH
SYSTEMIC DISEASE
Systemic Lupus Erythematosus
Fig. 24. Pathogenesis of SLE. SLE is a multisystemic disorder: antibodies
against self-antigens. Since it is immune mediated, one of organs not spared is the kidneys.
W.H.O. CLASSIFICATION OF LUPUS NEPHRITIS BASED ON MORPHOLOGY
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 following criteria:
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 of the glomerular capillary walls.
Seen in 10-25% of SLE patients
Minimal renal manifestation in the form of mild hematuria or transient proteinuria.
Immunofluorescense: granular mesangial deposits of Ig and complement are present.
Fig. 25. Class II – Mesangial GN
Class III – Focal Proliferative Glomerulonephritis
20-25% of SLE cases
Focal = some glomeruli normal, some are not Proliferative = hypercellularity
Fig. 26: Class III – Focal Proliferative GN Class IV – Diffuse Proliferative GN
Most serious form of lupus nephritis 35-60% of SLE patient
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 continually forming these immune complexes. Need to treat with steroids.
Class V – Membranous GN
Clinical picture is similar to that of Idiopathic membranous GN.
Diabetic Nephropathy
Diabetes mellitus is now one of the most common causes of end-stage renal failure.
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.
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. Mesina’s lecture and powerpoint Robbins 2014B Trans
Hey 2015B HAPPY CHRISTMAS ;D
Since it’s Christmas break na, then New Year, we just wanna share stuff with you and baka it’s the end of the world, and this’ll be the last thing you’ll read (ASA) :p
Beeteedub, CONGRATULATIONS FAITH :D
P.S. EVERYONE, LET’S EOWS a.k.a. End of the World S.. ;)) Pag nilalandi ka ng crush mo, sabihin mo: WAAAAAAAAG…mong 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 don’t wanna be saved the trouble. Maybe I want the trouble. I haven’t wanted the trouble in a long time. But with you, the trouble doesn’t seem so troubling. I don’t 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, it’s a mistake. I know it’s a mistake. But there are certain things in life where you know it’s a mistake but you don’t really know it’s a mistake because the only way to really know it’s 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, I’ve made no mistakes! I’ve 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 (Berger’s Disease) 6. Diabetic Nephropathy
7. Membranoproliferative Glomerulonephritis 8. Group A β-hemolytic Streptococci (types 12, 4 and 1) 9. Chronic Glomerulonephritis
