16

Renal System and

4 /e
y,

Its Disorders
og
ol
th

Key Points..........................................................
Pa

 Hematuria is excretion of intact RBCs > 3/ hpf in urine

 Sterile pyuria: presence of elevated numbers of pus cells (WBCs) in sterile urine (seen
in Tuberculosis)
 Most common cause of isolated glomerular hematuria is IgA nephropathy
 Mesangial cells are mesenchymal origin, are contractile, phagocytic, and capable of
proliferation
 Crescents are seen in RPGN and suggest poor prognosis
 Microalbuminuria: Excretion of 30–300 mg/day of albumin in urine or 30–300 mg/g of
creatinine in urine
 Focal Segmental Glomerulosclerosis (FSGS) is the most common cause of nephrotic
syndrome in adults
 Minimal change disease is the most frequent cause of nephrotic syndrome in children
 Most specific histological lesion in diabetic nephropathy is Kimmelsteil -Wilson lesions
 Thyroidization of tubules is a feature of Chronic pyelonephritis
 Major Causes of Papillary Necrosis is analgesic nephropathy
 Clear cell Ca is the most common histological subtype of Renal cell Carcinoma (RCC)
 Polycythemia and Hypertension is the most common paraneoplastic feature of RCC
 Michaelis-Gutmann bodies are seen in Malacoplakia

Key Recent Updates.........................................

 MPGN type II is now classified as C3 glomerulopathy
 Fibronectin glomerulopathy occurs due to mutation of FN1 gene on chromosome 2q34
 Complete Review of Pathology

CLINICAL MANIFESTATIONS OF RENAL ƒƒ Width of the cast depends on the size of the tubuleQ in which
it was formed
DISEASES
ƒƒ Cast formation increases with lower pH, increased ionic
ƒƒ Hematuria: Excretion of intact RBCs > 3/ hpf in urineQ concentration and stasis in nephronsQ
ƒƒ Pyuria: Presence of > 5 pus cells/hpfQ in urine, typically from
bacterial infection
ƒƒ Sterile pyuriaQ: Presence of elevated numbers of pus cells High Yield Facts
(WBCs) in urine which is sterile using standard culture •• Eosinophils in the urine suggests allergic interstitial
techniques nephritis or atheroembolic renal disease.Q
ƒƒ Sterile pyuria is seen in Renal tuberculosis •• Urinary Dipsticks detect only albumin as urinary proteinQ
ƒƒ OliguriaQ: 24-h urine output <400 mLQ, usually due to •• Dipstick gives false-positive results for:
underlying renal failure. ƒƒ Albumin: when pH >7.0, urine is very concentrated or
ƒƒ Anuria: Complete absence of urine formation(<100 mL).Q contaminated with blood.Q
It can be caused by total urinary tract obstruction, total ƒƒ Hematuria: when myoglobinuria is present, as in
renal artery or vein occlusion, shock, cortical necrosis, rhabdomyolysis.Q
ATN and RPGN.Q •• RBCs of glomerular origin are often dysmorphicQ
ƒƒ Polyuria: 24-h urine output >3 LQ •• Most common cause of isolated glomerular hematuria is
ƒƒ Azotemia: Increased serum levels of nitrogenous waste IgA nephropathyQ
products like urea and creatinineQ

/e
ƒƒ Uremia: Azotemia along with clinical manifestationsQ due
to deranged renal function.
GLOMERULUS AND GLOMERULAR
4 DISEASES
y,
Structure of Glomerular Filtering Membrane
og

ƒƒ Mesangium
ƒƒ Visceral epithelial cells (podocytes)Q:
20-30-nm–wide filtration slits → size selective barrier
ol

{{

{{ Responsible for synthesis of GBM components

th

ƒƒ Glomerular basement membrane (GBM):

{{ Composed of collagen type 4 (or COL4 α1 to α6)Q
Normal urine microscopy
Pa

{{ Each molecule consists of a 7S domain at the N terminus,

a triple-helical domain in the middle, and a globular

Urinary Casts (Refer annexures for images and types) noncollagenous domain (NC1) at the C terminus.
ƒƒ Formed elements of urineQ that have kidney as their sole {{ Other components are: Laminin, polyanionicproteo-

site of originQ glycans (negatively charged), mostly heparan sulfate,

ƒƒ Tamm-Horsfall protein, secreted from the thick ascending fibronectin, entactin and several other glycoproteins.
loop of HenleQ forms the matrix of all castsQ ƒƒ Fenestrated endothelial cells (70-100 nm)Q.

T
H
E
O
R
Y

578 Structure of glomerulus Types of glomerular deposits

 Renal System and Its Disorders

PATHOLOGIC RESPONSES OF THE GLOMERULUS TO INJURY

Site of glomerular deposits Type of Glomerulonephritis Terminologies used in Kidney Biopsy:

Subepithelial deposits •• PSGN Terminology Description
•• Membranous GN
•• RPGN Diffuse Involving >50% of the glomeruli in the kidneyQ
•• Heymann Nephritis Global Involving the glomerulus completelyQ
Subendothelial deposits •• L upus nephritis
Focal Involving <50% of the glomeruli in the kidney
•• MPGN-I
Membranous deposits •• MPGN II Segmental Affecting a part of each glomerulusQ

Mesangial deposits •• I gA nephropathy Capillary loop Affecting predominantly capillary or mesangial

•• HSP Mesangial regionsQ

High Yield Facts

•• Mesangial cellsQ- mesenchymal origin, are contractileQ, phagocyticQ, and capable of proliferationQ
•• Mesangial cells and mesangial matrix support the glomerular tuft
•• Glomerular filtering membrane is a size- and charge-dependent barrier

/e
•• Neutral substance ≤ 4A can get freely filtered through GBM
•• GBM is negatively charged due to sialo-glycoprotein
••
•• 4
All proteins (negatively charged) are normally repelled by GBM
y,
Albumin (smallest molecular wt, 70 kD) is the 1st protein to appear in urine in glomerulonephritis
•• ANionic antigens form subENdothelial deposits
og

•• Cationic antigens form subepithelial deposits

•• Neutral antigens form mesangial deposits
ol

PATHOGENESIS OF GLOMERULAR INJURY

th
Pa

T
H
E
O
R
Y

579
 Complete Review of Pathology

Electron Microscopy
Subepithelial Intramembranous Subendothelial Mesangial Combined Subendothe-
lial, Subepithelial and
Mesangial
Membranous GN Dense-deposit disease MPGN IgA nephropathy Lupus (WHO classes III
C3GN and IV) C3GN
Lupus GN related to endocarditis, Lupus (WHO class III Henoch-Schonlein MPGN type III
(WHO class V) deep-seated abscesses and IV) purpura
Postinfectious GN Other infections Cryoglobulinemic Lupus (WHO class II) GN related to infections.
GN (microglobular Clq nephropathy Proliferative GN with
structure) Rare other forms of monoclonal IgG deposit

/e
mesangioproliferative GN

4
y,
og
ol
th
Pa

Electron microscopy findings

Immunofluorescence
Deposition Pattern Granular (Probably Immune Complex) Linear (classic Antiglomerular Basement Membrane
[anti-GBM] Antibodies)

T
H
E
O
R
Y Region of deposition Capillary wall—membranous nephropathy Mesangium-Berger disease (IgA nephropathy)
Class of Ig and fraction Full house of Igs-systemic lupus erythematosus (SLE) IgA-Berger disease (IgA nephropathy)
of complement
580
 Renal System and Its Disorders

NEPHRITIC SYNDROME
ƒƒ Definition: Sudden onset of gross hematuria, oliguria, nephritic range proteinuria, mild edema, hypertension, and renal
insufficiencyQ
ƒƒ Characterized by inflammation in the glomeruliQ

Difference between nephritic and nephrotic syndrome

Characteristic Nephritic Syndrome Nephrotic Syndrome
Hematuria and RBC casts Present Absent/few
Proteinuria Nephritic range (<3.5g/day)Q Nephrotic range (>3.5g/day)Q (>40 mg/m2/hr)
Hypertension PresentQ Uncommon
Uremia PresentQ
Absent
Oliguria PresentQ
Absent

POSTSTREPTOCOCCAL

/e
GLOMERULONEPHRITIS (PSGN)
ƒƒ Time course:1 to 4 weeks after a streptococcal infection
(sore throat or pyoderma)Q
4
y,
ƒƒ Age group: most frequently, children 6 -10 yearsQ
ƒƒ Inciting agent: group A β-hemolytic streptococciQ –
og

nephritogenic strains (12, 4, and 1)Q

ƒƒ Complement levels C3 decrease Anti-Streptococcal-O
(ASO) increases, normal levels of C4
ol

High Yield Facts

th

EM: Showing Humps in PSGN

•• In PSGN, Serum complement levels (C3): transiently lowQ
Pa

•• Principal antigen in PSGN: streptococcal pyogenic

exotoxin B (Spe B)Q
•• Early treatment of sore throat/pyoderma with antibiotics Prognosis
does notQ prevent PSGN
•• Deposits seen in PSGNQ: Subepithelial humps, Suben- In children:
dothelial, mesangial •• Self-recovery is seen in 95% (Good prognosis)Q
•• 1% become severely oliguric, and develop RPGNQ
•• 5% undergo slow progression to chronic glomerulonephritisQ
Morphology
Light Microscopy Immunofluores- Electron
cence Microscopy Microscopy RAPIDLY PROGRESSIVE
•• Hypercellular Granular deposits Discrete, GLOMERULONEPHRITIS (RPGN) T
glomeruli of IgG, and C3 in amorphous,
•• Infiltration by WBCs, mesangiumQ and electron-dense ƒƒ Characterized by severe glomerular injury (crescents) lead- H
•• Proliferation of along GBM SUBEPITHELIAL ing to rapid and progressive loss of renal function associ-
deposits ated with severe oliguria and signs of nephritic syndrome.Q
E
endothelial and
mesangia cells: Endo- (“Humps”)Q ƒƒ If untreated, death from renal failure occurs within weeks to O
and exocapillary months.Q
proliferationQ
R
•• Crescents: Severe Y
casesQ

581
 Complete Review of Pathology

Types of RPGN
Entity Type I (20%) Type II (25%) Type III (55%)
Mechanism Anti-GBM Antibody Immune Complex Pauci-immune,
c-ANCA/p-ANCA mediated
Etiology Renal limited •• Postinfectious ANCA-associated
Good pasture syndromeQ ƒƒ Poststreptococcal glomerulonephritisQ •• Idiopathic
(Serum antibodies against alpha 3 ƒƒ Bacterial endocarditisQ •• Granulomatosis with
NC1 domain of collagen – IV) •• Noninfectious polyangiitis (Wegener
ƒƒ SLEQ, HSPQ granulomatosis)Q
ƒƒ Mixed cryoglobulinemiaQ •• Microscopic polyangiitisQ
•• Primary Renal Disease •• Hypersensitivity vasculitisQ
ƒƒ MPGNQ
ƒƒ IgA nephropathyQ
Grossly Kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surfaces. (FLEA-BITTEN KIDNEY)Q
Light m/e •• Glomeruli: Crescents are HallmarkQ
•• Focal and segmental necrosisQ, endothelial and mesangial proliferationQ
•• Pauci-immune: Segmental glomerular necrosis is characteristicQ

/e
Crescents- Formed by

4 •• Proliferation of parietal cellsQ

•• Infiltration by WBCsQ
y,
•• Fibrin strands.Q
Crescents obliterate the urinary space
og

and compress the glomerular tuft, hence

More the number of crescents →
poorer the prognosisQ
ol

Cresentic glomerulonephritis
th

Immunofluores- Linear GBM fluorescenceQ Granular immune depositsQ No deposition of immune

cence m/e reactantsQ
Pa

No Deposits seen

(Pauci-immune)
Type I RPGN (Linear) Type II RPGN (Granular)
Electron m/e Ruptures in the GBMQ may be present, Type II shows immune complex deposits
T
H Clinical Course NEPHROTIC SYNDROME
E ƒƒ Hematuria with RBC casts in the urine, variable proteinuria,
Q
The Manifestations of Nephrotic Syndrome Include
O hypertension and edema.
ƒƒ Progressive over weeks and ends in severe oliguria/renal ƒƒ Massive proteinuria (> 3.5 gm/day)Q (>40 mg/m2/hr)
R failure.Q ƒƒ HypoalbuminemiaQ (plasma albumin< 3 gm/dL)
Y ƒƒ Goodpasture syndrome: Recurrent hemoptysis or even ƒƒ Generalized edema (due to loss of oncotic pressureQ >
life-threatening pulmonary hemorrhage (Necrotizting hem- sodium and water retention)Q
orrhagic interstitial pneumonitis).Q
582
 Renal System and Its Disorders

ƒƒ Hyperlipidemia:Q-Increased synthesis of lipoproteins in the {{ Secondary: 25%

liver, abnormal transport of circulating lipid particles, and yy Infections: Chronic hepatitis B, hepatitis C, Syphilis,
decreased lipid catabolism. Schistosomiasis, MalariaQ
ƒƒ Lipiduria (free fat or as oval fat bodies in urine)Q yy Drugs: Penicillamine, Captopril, Gold, NSAIDsQ
yy Carcinoma lung, colon, and melanoma
Remember: Proteinuria can be yy Autoimmune diseases: SLE (10–15%), Rheumatoid
ƒƒ Selective proteinuria: → Initially; consists mostly of low- Arthritis, Primary biliary cirrhosis, Dermatitis herpeti-
molecular-weight proteins (albumin, 70 kD; transferrin, formis
76 kD) yy Systemic diseases: Fanconi’s syndrome, sickle cell
ƒƒ Nonselective proteinuria: → Later, in advanced disease, anemia, diabetes, Crohn’s disease, Sarcoidosis,
consists of higher molecular-weight globulins and albumin. ƒƒ Morphology:
{{ Light microscopy: Uniform, diffuse thickening of the

Causes of Nephrotic Syndrome glomerular capillary wall.Q

{{ Immunofluorescence microscopy: Granular/Lumpy
Primary Glomerular Disease Systemic Diseases bumpyQ electron dense immune complexes deposits
•• Membranous •• Diabetes mellitusQ, {{ Electron microscopy: Granular deposits, (Ig + comple-
glomerulonephropathy (MGN)Q AmyloidosisQ ment)
•• Minimal-change disease (MCD)Q •• Systemic lupus yy Effacement of podocyte foot processesQ
•• Focal segmental erythematosus (SLE)Q {{ On Silver methenamine stain- prominent “spikes” and
glomerulosclerosis (FSGS)Q •• Drugs (NSAIDs, “domes”Q of silver-staining matrix

/e
•• Membranoproliferative penicillamine, Lithium,
glomerulonephritis (MPGN) Pamidronate, heroin
•• IgA nephropathyQ injection)Q
•• Infections (hepatitis 4
y,
B and C, HIV, malaria,
toxoplasmosis, syphilis)Q
og

•• Malignant disease
(carcinoma, lymphoma)Q
•• Hereditary nephritis,
ol

Renal vein thrombosis)

th

Normal capillary wall

High Yield Facts
Pa

•• Microalbuminuria: Excretion of 30–300 mg/dayQ of

albumin in urine or 30–300 mg/g of creatinine in urineQ
•• Macroalbuminuria: Excretion of 300–3500 mg/day of
albumin in urineQ
•• Nephrotic range proteinuria: Excretion of > 3.5 g/dayQ of
albumin in urine
•• Selective proteinuria: Selective excretion of low-
molecular-weight proteins like albumin and transferrinQ
by the kidney.
Thickened capillary wall

MEMBRANOUS NEPHROPATHY T
ƒƒ Characterized by: Diffuse thickening of glomerular capillary
H
wall due to accumulation of deposits containing immune E
complex deposits along sub-epithelial side of basement
membrane.Q
O
ƒƒ Etiology: R
{{ Primary: 75%: Associated with HLA-DQA1Q, Autoantigen:
Y
phospholipase A2 receptorQ Spikes and domes on silver stain

583
 Complete Review of Pathology

ƒƒ Clinical course: {{ Electron microscopy: Diffuse effacement of foot pro-

{{ Persistent proteinuria in 60% of patientsQ cesses of podocytes (“podocytopathy”)Q
{{ 40% develop severe CKD or ESRDQ yy No electron-dense depositsQ
{{ 40% recurs in patients who undergo transplantationQ {{ Proximal tubules cells get laden with lipid and protein due

to tubular reabsorption of lipoproteins: Lipoid nephrosisQ

ƒƒ Clinical course:
High Yield Facts {{ Excellent prognosis: >90% respond rapidly to steroidsQ
{{ Renal function remains normalQ
•• Membranous nephropathy is the most frequent cause {{ No hypertension or hematuria.Q
of nephrotic syndrome in elderlyQ {{ Selective proteinuria is seen
•• Focal segmental glomerulosclerosis (FSGS) is the most
common cause of nephrotic syndrome in adultsQ
•• Minimal change disease is the most frequent cause of FOCAL SEGMENTAL
nephrotic syndrome in childrenQ
•• Mutation in NPHS2 is the most common cause of Steroid
GLOMERULOSCLEROSIS (FSGS)
Resistant Nephrotic syndromeQ ƒƒ Hallmark Disruption of visceral epithelial cells with
effacement of foot processes (podocytopathy)Q
ƒƒ Genetic basis: APOL1 gene on chr 22 is strongly associated
MINIMAL CHANGE DISEASE ƒƒ Etiology
Primary: Idiopathic (10% in children and 35% in adults)Q

/e
{{
ƒƒ Characterized by: Absence of immune deposits but has an
{{ Secondary: Due to underlying etiology
immunologic basis.Q
yy Reflux nephropathyQ
ƒƒ Epidemiology: Most common age group involved: 2 to 6
yearsQ 4 yy Hypertensive nephropathy
yy HIV infection (HIV-associated nephropathy)Q
y,
ƒƒ Etiology: Idiopathic
yy Heroin addiction (heroin nephropathy)Q
ƒƒ Morphology:
og

yy Sickle-cell diseaseQ
{{ Light microscopy: Glomeruli appear normalQ
{{ Immunofluorescence microscopy: No Ig/ complement
yy Massive obesity
yy Secondary event to focal glomerulonephritis (e.g. IgA
deposits
ol

nephropathy)Q
yy Renal ablation/surgeryQ
th

Podocyte
Pa

Foot process GBM

FSGS: Renal biopsy showing sclerosis of a part of glomerulus

T ƒƒ Congenital anomalies (unilateral renal agenesis or renal

H dysplasia)
ƒƒ Inherited forms of nephrotic syndrome : mutation in
E podocin, α-actinin 4, and TRPC6 (transient receptor potential
O calcium channel-6)Q
ƒƒ Morphology
R {{ Light microscopy

Y yy Collapse of capillary loops in sclerotic areas

Effacement of foot process yy Deposition of plasma proteins along capillary wall
(hyalinosis)
584
 Renal System and Its Disorders

{{ Immunofluorescence microscopy MEMBRANOPROLIFERATIVE

yy IgM + C3 deposition in sclerotic areas and/or in GLOMERULONEPHRITIS (MPGN)
mesangium.
{{ Electron microscopy Etiology
yy Diffuse effacement of foot processes of podocytes Primary Idiopathic
yy Focal detachment of the epithelial cells Secondary Invariably type I: More common in adultsQ
yy Denudation of the underlying GBM. . Autoimmune diseases SLEQ
ƒƒ Clinical course Infections Hep C infection,
{{ 20% of patients follow rapid course, with massive protein- usually with
uria ending in renal failure within 2 years. cryoglobulinemiaQ,
{{ Histologic subtype (collapsing variant → unfavorable Hep B, HIV,
course; tip variant → good prognosis) SchistosomiasisQ
{{ 25–50 % recurs in patients who undergo transplantation Other causes α1-Antitrypsin
deficiencyQ, CLL
Nephrotic Syndrome in Children Due to Genetic
Disorders of the Podocytes MPGN I MPGN II
(Now called C3
Gene Name Chr Inheritance Renal glomerulopathy)

/e
Disease
Complement acti- Both classical and Only alternate
STEROID-RESISTANT NEPHROTIC SYNDROME vation alternate pathway pathway

NPHS1Q
(most
NephrinQ 19q RecessiveQ
4
Finnish-typeQ
Complement levels All factors reduced C1, C2 and C4 nor-
mal; C3 Nephritic
y,
factor seen;
common)
Light Microscopy Mesangial and GBM Dense deposits
og

NPHS2Q PodocinQ 1q RecessiveQ FSGSQ proliferation (tram

track appearance)
FSGS1 α-actinin-4 19q Dominant FSGSQ Type of deposits Subendothelial Electron dense
ol

(αACTN4) intramembranous
WT1 Wilms tumor- 11p Dominant Denys-Drash
th

suppressor syndrome ISOLATED GLOMERULAR DISEASES

gene Frasier’s
Pa

syndromeQ IgA Nephropathy (Berger’s Disease)

ƒƒ Most common type of glomerulonephritis in adults, worldwide.
HIV-associated Nephropathy (HIVAN) ƒƒ Most common cause of gross hematuria
ƒƒ Associated with 5–10% of HIV-infected individuals
Characterized by: Recurrent hematuria and presence of IgA de-
posits in the mesangium.Q
Morphology
Pathogenesis
Light microscopy Electron microscopy ƒƒ Aberrantly glycosylated IgA-1deposition in mesangiumQ or
Collapsing variant of FSGS: •• Focal cystic dilation of Autoimmune response to IgA-1
ƒƒ Most characteristic tubule segments filled with Mesangial immune deposits activate mesangial cellsQ to
lesionQ proteinaceous material, and proliferate, produce increased amounts of extracellular matrix,
ƒƒ Poor prognosisQ inflammation and fibrosis and secrete numerous cytokines and growth factors. T
Characterized by collapse of •• Tubuloreticular inclusionsQ Etiology H
entire glomerular tuft along within endothelial cells (also
with proliferation and hyper- seen in SLE)
ƒƒ Primary: Idiopathic E
ƒƒ Secondary IgA nephropathy: Due to underlying causes-
trophy of glomerular visceral O
{{ Gluten enteropathy (celiac disease): Intestinal mucosal
epithelial cellsQ (also seen in R
defectsQ
pamidronate toxicity). {{ Liver disease: Defective hepatobiliary clearance of IgAQ Y

585
 Complete Review of Pathology

ƒƒ 15–40% cases progress to ESRD in 20 years.Q

ƒƒ 15% recurs in patients who undergo transplantationQ

High Yield Facts

•• Collapsing type of FSGS has worst prognosis
•• Types II and III MPGN are associated with complement
factor H deficiency, presence of C3 nephritic factor, partial
lipodystrophy (type II MPGN) or complement receptor
deficiency (type III MPGN)
•• Kidney changes in AIDS patient include Collapsing vari-
IgA Nephropathy showing mesangial deposits ant of FSGS, MPGN, DPGN, IgA nephropathy (Mesangio-
proliferative glomerulonephritis), MCD and MGN
•• Most specific histological lesion in diabetic nephropathy
Morphology (see chapter 18 Endocrine system) is Nodular glomerulo-
Light microscopy Immunofluorescence Electron sclerosis or Kimmelsteil-Wilson lesions
microscopy microscopy •• Most common pathological lesion in diabetes nephropa-
thy is diffuse GBM thickening>diffuse glomerulosclerosis
•• Mesangioprolif- •• Mesangial Electron-dense
erative glomeru- deposition of IgA+ deposits in

/e
lonephritis: C3 and properdin, mesangiumQ
mesangial widen- IgG, IgM+/-Q Hereditary Nephritis
ing and endocapil-
lary proliferationQ
•• Early complement
components are 4 Diseases with mutations in collagen genes that manifest primarily
y,
with glomerular injury.
•• Focal proliferative absent
glomerulone- Includes: Alport syndrome and Thin basement membrane
og

phritis lesion (MC cause of benign familial hematuria)Q

Alport Syndrome
ol

ƒƒ Triad of
th

{{ Hematuria, sensorineural deafness, Eye disorders: lens

dislocation, posterior cataracts, and corneal dystrophyQ
Pa

ƒƒ Inheritance:
{{ X-linked dominantQ (85%, MC mode of inheritence) >

Autosomal
ƒƒ Pathogenesis: Mutations in subunits of collagen → Defective
GBM synthesis
{{ COL4A5 (X-linked)Q, COL4A3/4 (Autosomal)Q

ƒƒ Morphology:
{{ Light microscopy: Mesangial proliferation, Capillary wall

thickening,
Immunofluorescence showing mesangial deposition of IgA yy Foam cellsQ: Lipid containing tubular or interstitial
cells
T {{ Immunofluorescence microscopy, Absence of staining
Clinical Course with COL4A5Q (Not diagnostic)
H ƒƒ Two most common presentations of IgA nephropathy are: {{ Electron microscopy

E {{ Recurrent episodes of macroscopic hematuria 1–2 yy GBM: Irregular foci of thickening alternating with
days following an upper respiratory infection often thinningQ
O accompanied by proteinuria or yy Pronounced splitting and lamination of the lamina
R {{ Persistent asymptomatic microscopic hematuria. densa: distinctive basket-weave appearance (diag-
ƒƒ Nephrotic syndrome, however, is uncommon nostic feature of Alport syndrome)Q.
Y

586
 Renal System and Its Disorders

THIN BASEMENT MEMBRANE LESION SLE Kidney

(BENIGN FAMILIAL HEMATURIA) Classification of Lupus Nephritis (International Society of
Nephrology)
ƒƒ Inheritance: Autosomal inheritance with defective collagen
4 α3/4 (COL4A3/4)Q ƒƒ Class I : Minimal MesangialQ
ƒƒ Class II : Mesangial Proliferative
ƒƒ Morphology on Light microscopy: Diffuse thinning of the
ƒƒ Class III :  Focal Lupus NephritisQ
GBM to widths between 150 and 225 nm (compared with
Q

300 to 400 nm in healthy adults) ƒƒ Class IV :  Diffuse Lupus NephritisQ

ƒƒ Class V :  Membranous Lupus NephritisQ
ƒƒ Prognosis: Excellent
ƒƒ Class VI : Advanced Sclerotic Lupus Nephritis

CHRONIC GLOMERULONEPHRITIS
It is end-stage glomerular disease as a result of glomerulone-
phritis.
Following primary glomerular diseases commonly lead to
chronic glomerulonephritis:
ƒƒ Rapidly progressive (Crescentic) GN (90%) (most

/e
common)Q
ƒƒ Focal segmental glomerulosclerosis (50% to 80%)
Alports’ Syndrome (GBM showing splitting and lamination) arrow

4 ƒƒ Membranoproliferative GN (50%), Membranous, IgA nephrop-

athy, Post-streptococcal
y,
TWO SPECIAL CONDITIONS
og

NEED MENTION
ol

Diabetic Nephropathy
Glomerular Lesions
th

A. Capillary Basement Most characteristic lesionQ, GBM

Pa

Membrane thickening & mesangial wideningQ

Thickening Along with thickening of tubular
basement membranesQ
B. Diffuse Mesangial Most common changeQ, Diffuse
Sclerosis increase in mesangial matrix
(PAS-positive);Q correlates with
deteriorating renal function like
proteinuriaQ
C. Nodular or •• Spherical, laminated, nodules
Intercapillary of matrix at the periphery of Granular contracted kidney
Glomerulosclerosis glomerulus, which are PAS-positiveQ
or Kimmelstiel- •• Capillary microaneurysms
Morphology
Wilson diseaseQ •• Fibrin capsQ- Accumulation of hyaline T
material in capillary loops ƒƒ Symmetrically contracted kidneysQ with diffusely granular
•• Capsular dropsQ - hyaline material cortical surfaces H
adherent to Bowman's capsules ƒƒ On section, the cortex is thinned,Q and there is an increase E
Renal Vascular Lesions in peripelvic fat.
ƒƒ Replacement of glomeruli by blue-staining collagen
O
Arteriolosclerosis affecting both afferent & efferent arteriole. Q
(Masson trichrome stain)Q R
Pyelonephritis, Including Necrotizing Papillitis ƒƒ Tubular atrophy, irregular interstitial fibrosis, and mono-
Starts in interstitial tissue & spreads to tubules; called
Y
nuclear leukocytic infiltration of the interstitium.
necrotizing papillitis (papillary necrosis)Q
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 Complete Review of Pathology

Causes of Granular Contracted Kidney Two Forms

Acute tubulointerstitial Chronic interstitial nephritis
nephritis

Rapid clinical onsetQ Insidious onsetQ

Histologically: Histologically:

•• Interstitial edemaQ •• Infiltration with

mononuclear WBCs

•• Neutrophillic infiltration in •• Prominent interstitial fibrosis

interstitium and tubulesQ

•• Tubular injury •• Tubular atrophyQ

NEM O N
M
IC

Distinguished Clinically from the Glomerular Diseases by the

Following Hallmarks:
Flea-bitten kidney is seen in
“World Health PSM” ƒƒ Absence of nephritic or nephrotic syndromeQ
• World - Wegener’s granulomatosis ƒƒ Presence of defects intubular functionQ

/e
• Health - Henoch Schonlein purpura {{ E.g.: Impaired ability to concentrate urine (polyuria or
• P-Post-streptococcal Glomerulonephritis (PSGN). nocturia)
Polyarteritis nodosa
• S-Sub acute bacterial endocarditis (SABE), SLE, Good
Pasteur syndrome 4 {{

{{
Salt wasting
Diminished ability to excrete acids (metabolic acidosis)
y,
{{ Isolated defects in tubular reabsorption or secretion
• M-Malignant hypertension
og

PYELONEPHRITIS AND URINARY

TUBULOINTERSTITIAL NEPHRITIS TRACT INFECTION
ol

Characterized by Characterized by: Inflammation of tubules, interstitium, and

th

ƒƒ Inflammatory injuries to tubules and interstitium Insidious

Q renal pelvis
in onset Pathogenesis of Acute Pyelonephritis: Ascending infection is
Pa

ƒƒ Principally manifested by azotemiaQ the most common cause.

Characteristics Acute pyelonephritis Chronic pyelonephritis

Definition Acute suppurative inflammation of Chronic tubulointerstitial inflammation and scarring involve the calyces
the kidney and pelvis
Etiology Ascending urinary tract infection Bacterial infection plays a dominant role; 2 forms:
MC: E. coli (MC)Q, Proteus, Klebsiella, •• Reflux nephropathyQ: Urinary infection on congenital vesicoureteral reflux
and Enterobacter •• Chronic obstructive pyelonephritisQ
Morphology: Gross •• Discrete focal abscesses •• Coarse, discrete,
•• Large wedge like areas Corticomedullary scarsQ (Hallmark) overlying dilated, blunted, or
T deformed calyces
H •• Flattening of the papillaeQ

E Light •• Patchy interstitial suppurative •• Involves tubules and interstitium

Microscopy inflammation (hallmark) •• Thyroidization of tubulesQ: Dilated tubules filled with casts resembling
O •• Intratubular aggregates of thyroid colloid
R neutrophils •• Chronic interstitial inflammation and fibrosis
•• Neutrophilic tubulitisQ •• Vessels demonstrate obliterative intimal sclerosis
Y
•• Tubular necrosisQ •• Hyaline arteriolo sclerosisQ
•• Periglomerular fibrosisQ
588 •• Secondary FSGSQ may be seen.
Contd...
 Renal System and Its Disorders

Characteristics Acute pyelonephritis Chronic pyelonephritis

Complications •• Papillary Necrosis •• Xanthogranulomatous pyelonephritis:
ƒƒ Major Causes ƒƒ A rare form of chronic pyelonephritisQ
ŠŠ Analgesic nephropathy (Most ƒƒ Often associated with Proteus infectionsQ and obstruction
common)Q ƒƒ M.C age group: 5th -6th decadeQ
ŠŠ Sickle cell nephropathy ƒƒ Females are most commonly affected
ŠŠ Diabetes with urinary tract ƒƒ Associated features: Large staghorn calculiQ and hydronephrosisQ
infection ƒƒ Gross morphology: large, yellowish orange nodules that may be
•• PyonephrosisQ grossly confused with renal cell carcinoma.
•• Perinephric abscessQ ƒƒ Microscopy: Accumulation of foamy (lipid laden) macrophages
(Xanthoma cells)Q with plasma cells, lymphocytes.

Pyelonephritis can occur in following steps

High Yield Facts
ƒƒ ColonizationQof the distal urethra and introitus (in the
•• Most important factor in pyelonephritis: Vesicoureteral female) by coliform bacteria
refluxQ
ƒƒ Retrograde spreadQfrom the urethra to the bladder
•• In the absence of vesicoureteral reflux, infection usually
ƒƒ Further spread from bladder to kidneys by the following
remains localized in the bladder

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mechanisms:
•• An emerging viral pathogen causing pyelonephritis in
{{ Urinary tract obstruction and stasis of urineQ
kidney transplantation is Polyomavirus (> 6 months
post-transplant)
•• Analgesic nephropathy is a high risk for development of 4 {{ Vesicoureteral refluxQ-Incompetence of the vesicoureter-

al valve that allows bacteria to ascend the ureter into the

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transitional cell Carcinoma kidney renal pelvis.
{{ Open ducts at the tips of the papillae (intrarenal reflux)Q
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Normal tubule
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Colloid like
deposition

Papillary necrosis Thyroidization of tubules

INHERITED CYSTIC KIDNEY DISEASES

Disease Gene Protein Renal Abnormality Extrarenal Abnormality T
Autosomal dominant AD PKD1 Polycystin-1 Cortical and medullary cysts Cerebral aneurysms;Q liver
polycystic kidney diseaseQ AD PKD2 Polycystin-2 and spleen cystsQ
H
Autosomal recessive polycystic AR PKHD1  Fibrocystin Distal tubule and collecting Hepatic fibrosis;Q Caroli’s E
kidney diseaseQ (polyductin) duct cysts diseaseQ O
Nephronophthisis I (juvenile/ AR NPHP1  Nephrocystin Small fibrotic kidneys; Retinitis pigmentosa
adolescent) medullary cysts R
Nephronophthisis II (infantile) AR NPHP2 Inversin Large kidneys;Q widespread Situs inversusQ Y
(INVS)  cysts
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Disease Gene Protein Renal Abnormality Extrarenal Abnormality

Nephronophthisis III (juvenile/ AR NPHP3  Nephrocystin-3 Small fibrotic kidneys; Retinitis pigmentosa; hepat-
adolescent) medullary cysts ic fibrosis
Medullary cystic kidney disease AD MCKD1 /2 Uromodulin Small fibrotic kidneys; Hyperuricemia and goutQ
medullary cysts
Tuberous sclerosis AD TSC1/2  Hamartin/ Renal cysts;Q Facial angiofibromas;Q CNS
Tuberin angiomyolipomas;Q Renal cell hamartomasQ
carcinomaQ
Von Hippel-Lindau disease AD VHL  pVHL Renal cysts;Q Renal cell car- Retinal angiomas;Q CNS
cinomaQ hemangioblastomas;Q
pheochromocytomasQ

RENAL TUMORS
Benign Neoplasms
ƒƒ Renal Papillary Adenoma

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{{Small, discrete adenomas
{{Arises from the renal tubular epitheliumQ

4 ƒƒ Angiomyolipoma
{{ Benign neoplasmQ consisting of vessels, smooth muscle,
y,
and fat
{{ Originates from perivascular epithelioidQcells.
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ƒƒ Oncocytoma
{{ Epithelial neoplasm composed of large eosinophilic

cellsQ having small, round, benign-appearing nuclei that

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Autosomal dominant Autosomal recessive have large nucleoli.

polycystic kidney disease polycystic kidney disease
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{{ Arise from the intercalated cells of collecting ducts

showing distorted outline showing smooth outline {{ E/M: eosinophilic cells have numerous mitochondria.Q
Pa

Malignant Tumors
High Yield Facts Renal Cell Carcinoma (RCC)
ƒƒ Age group: most commonly in 6th and 7th decadeQ
•• In ADPKD, patients with PKD1 mutation have higher risk ƒƒ Male: Female ratio= 2:1.Q
of ESRDQ than those with PKD2 mutation
•• Extra-renal sites of cysts in ADPKD are: Liver (most Risk Factors
common)Q> CNS (berry aneurysm) > Spleen > Pancreas •• Cigarette smoking (most important)Q There is also an increased
> Lung •• Obesity (particularly in women)Q risk in patients with:
•• Familial juvenile Nephronophthisis is the most common •• HypertensionQ
variant of Nephronophthisis •• End-stage renal diseaseQ
•• Unopposed estrogen therapy
•• Nephronophthisis complex is the most common genetic •• Chronic kidney diseaseQ
•• Exposure to asbestos
T cause of ESRD in childrenQ •• Acquired cystic diseaseQ
•• Petroleum productsQ •• Tuberous sclerosis.Q
H •• Heavy metals.

E Acquired (Dialysis-Associated) Cystic Disease Classification of RCC

O ƒƒ Cystic degeneration in ESRD after prolonged dialysis. ƒƒ Sporadic: Most common type
ƒƒ Increased risk of renal cell carcinoma ƒƒ Hereditary forms: Autosomal dominant, Young age affected
R
Y

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R9th latest updates

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4 Types of Familial Variants •• Hereditary papillary carcinoma: AD

•• Von-Hippel-Lindau (VHL) syndrome: AD ƒƒ Mutation in MET proto-oncogene papillary cell Ca
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ƒƒ Sporadic and familial forms of clear cell carcinoma •• Birt-Hogg-Dubé syndrome: AD

•• Hereditary leiomyomatosis and renal cell cancer syndrome: AD ƒƒ Mutations in BHD gene, which expresses folliculin.
Pa

ƒƒ Caused by mutations of the FH gene which expresses fumarate ƒƒ Constellation of skin (fibrofolliculomas, trichodiscomas, and
hydratase acrochordons), pulmonary (cysts or blebs), and renal tumors
ƒƒ Characterized by cutaneous and uterine leiomyomata and
an aggressive type of papillary carcinoma with increased
tendency for metastatic spread.

Clinical Features Paraneoplastic Feature of RCC

ƒƒ Costovertebral pain, palpable mass, hematuria (Most reliable ƒƒ Hypertension (most common)Q
sign) Q
ƒƒ Polycythemia, Hypercalcemia
Metastasis ƒƒ Hepatic dysfunction (Stauffer’s syndrome)Q
ƒƒ Feminization or masculinizationQ
Most common locations of metastasis are: lungs (50%)Q and T
bones (33%)Q ƒƒ Cushing syndrome (Rare)Q, Eosinophilia, Leukemoid reac-
tions, Amyloidosis. H
R9th latest updates Urothelial Carcinoma of the Renal Pelvis E
ƒƒ Originate from the urothelium of the renal pelvisQ O
Xp11 translocation
•• Rare and seen in young Patients
ƒƒ Range from Benign papillomas to invasive urothelial R
(transitional cell) carcinomas.Q
•• Tumor cells with clear cytoplasm and papillary structure
ƒƒ Multiple lesions involving the pelvis, ureters, and bladder.
Y
•• Translocation of TFE3 on Chr Xp11.2 ƒƒ Often associated with bladder urothelial tumor.
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 Complete Review of Pathology

ƒƒ Increased incidence with Lynch syndrome and analgesic macrophages are called Michaelis Gutmann bodies. These
nephropathy.Q histiocytes have pink-cytoplasm called as-von Hansemann
ƒƒ Infiltration of the wall of the pelvis and calyces indicative of histiocytes
poor prognosis.Q

BLADDER CARCINOMA
DISEASES OF URINARY BLADDER
ƒƒ Epidemiology: More common in men than in women,
MALACOPLAKIA common age group affected: 50–80 years old
ƒƒ A vesical inflammatory reaction is characterized macro-
Q ƒƒ Types:
scopically by soft, yellow, slightly raised mucosal plaques {{ Epithelial tumors include Urothelial or transitional cell
3 to 4 cm in diameter type (most common)Q, SquamousQ and GlandularQ
ƒƒ It is a granulomatous disease with defective intracellular ƒƒ Precursor lesions:
{{ Noninvasive papillary tumors, Flat noninvasive urothelial
lysosomal digestion of bacteria in histiocytes. It is mostly
caused by E. coli.Q carcinomaQ
ƒƒ Risk factors:
{{ Cigarette smoking: Most importantQ
{{ Industrial exposure to arylaminesQ like 2-naphthylamine,
Benzidine, Acrolein

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{{ Schistosoma haematobiumQ infections (Squamous
Carcinoma > Transitional Cell Ca)

4 {{

{{
Long-term analgesic use (Phenacetin)Q
Long-term exposure to cyclophosphamide, Exposure
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of bladder to irradiation, Urolithiasis (predisposes to
Squamous Cell Ca)
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ƒƒ Genetic alterations:
{{ Monosomy 9 or del 9p or 9q (most common)
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ƒƒ Clinical feature:
{{ Painless hematuria, Frequency, urgency, and dysuria
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may be present
ƒƒ Prognosis:
Pa

{{ Depends on the histologic gradeQ of the papillary tumor

and the stage at diagnosis.

{{ Involvement of muscularis mucosa (detrusor muscle)Q

is associated with worst prognosis

- Nucleus
-M ichoelis-Gutmonn body
High Yield Facts
•• Noninvasive high grade urothelial carcinoma: Loss of
TP53 and RB genes, noninvasive low grade papillary
Microscopy urothelial Carcinoma: Gain of function FGFR3 and HRAS
ƒƒ Infiltration with large, foamy macrophagesQ with a mutations
Michaelis-Gutmann bodiesQ with multinucleate giant cells •• Squamous cell carcinoma and adenocarcinomaQ are
T associated with a worse prognosisQ
and lymphocytes.
•• “Polychronotropism”Q: The tendency to recur over time
H ƒƒ Laminated mineralized concretions resulting from deposition
and in new locations in the urothelial tract
of calcium in enlarged lysosomes, typically present within the
E
O
R
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 Renal System and Its Disorders

High Yield Facts

Assessment of Glomerular Filtration Rate (GFR)
•• Direct measurement: By Inulin clearanceQ (Inulin is
filtered at the glomerulus but neither reabsorbed nor
secreted throughout the tubule)
•• Serum Creatinine: Used as a surrogate to estimate GFR. It
is the most widely used marker for GFR. Commonly used
formulae used to calculate GFR from serum creatinine
are:
ƒƒ Cockcroft-GaultQ
ƒƒ Schwartz FormulaQ
•• Creatinine clearanceQ: An approximation of GFR; CrCl =
(Uvol × UCr)/(PCr × Tmin).
•• Cystatin CQ: More sensitive marker of early GFR decline
Transitional cell carcinoma than plasma creatinine

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R10th latest updates
C3 Glomerulopathy
Encompasses the following: 4
y,
1. Dense-deposit disease (formerly known as type II MPGN) where dense glomerular intramembranous deposits are present in the glomerular
capillary loops, which stain for C3 only by IF.
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2. C3GN, a proliferative GN resembling MPGN type I without Ig deposits.

3. Rare diseases such as familial MPGN type III and complement factor H–related protein 5 abnormality–associated familial GN cases
ƒƒ Immunofluorescence Characteristics: C3 shows double-linear appearance of the glomerular capillary wall and a ring appearance
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around the mesangial deposits (mesangial rings)

ƒƒ IgG deposition should not be present
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ƒƒ Type II MPGN is now classified under C3 glomerulopathy

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 Complete Review of Pathology

Image-Based Questions
1. 5-year old male presented with mild hematuria, pedal 3. The morphological finding of kidney shown in the figure is
edema and frothy urine. BP 110/70 mm of Hg. Subsequently associated with which of the following conditions?
he was treated with steroid but he did not improve. The
renal biopsy was carried out. The electron microscopy
finding has been shown. What is your diagnosis?

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a. Chronic glomerulonephritis
b. Renal amyloidosis
a. Minimal Change disease b. FSGS
4

c.
d.
Malignant hypertension
Acute pyelonephritis
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c. MPGN d. PSGN
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2. 55 yr old diabetic male found to have microalbuminuria. 4. Identify the kidney disease?
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Identify the lesion shown in renal biopsy of this patient.

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a. Amyloidosis a. Polycystic disease

b. Kimmelstiel- wilson lesion b. Hydronephrosis
c. Wire loop lesions c. Pyelonephritis
d. Crescentric glomerulonephritis d. Chronic pyelonephritis

I
B
Qs

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 Renal System and Its Disorders

5. Which of the following conditions usually leads to the 6. Most common histology of this gross lesion is?
finding given below:

a. Benign hypertension
b. Malignant hypertension
c. Chronic pyelonephritis
d. Acute pyelonephritis a. Clear cell type b. Papillary Cell Ca
c. Belini duct Ca d. Anaplastic Ca

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Answers of Image-Based Questions
og
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1. Ans. (a) Minimal Change disease

•• History given here is that of nephrotic syndrome and electron microscopy shows flattening of foot processes of podocytes, a
th

feature of minimal change disease.

Pa

2. Ans. (b) Kimmelstiel-Wilson lesion

•• In this case kidney biopsy from a patient suffering from diabetic nephropathy shows Nodular glomerulosclerosis suggested by
diffuse increase in mesangial matrix and characteristic acellular PAS-positive nodules.
3. Ans. (c) Malignant hypertension
•• The given kidney gross shows small, pinpoint petechial hemorrhages may appear on the cortical surface from rupture ofarterioles
or glomerular capillaries, giving the kidney a peculiar“flea-bitten” appearance. The kidney size varies depending on the duration
and severity of the hypertensive disease.
4. Ans. (b) Hydronephrosis
•• Marked dilation of the pelvisand calyces and thinning of the renal parenchyma.
5. Ans. (c) Chronic pyelonephritis
•• Gross surface is irregularly scarred. Microscopically shows changes involve predominantly tubules and interstitium. The tubules
show atrophy in some areas and hypertrophy or dilation in others. Dilated tubules with flattened epithelium may be filled with
casts resembling thyroid colloid (thyroidization)
6. Ans. (a) Clear cell type
•• The given gross shows Renal cell Carcinoma, the most common histology of which is clear cell type.

I
B
Qs

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