RENAL PATHOLOGY leukocytes; trigger – activation of
I. Clinical Manifestations of Renal Diseases
 Azotemia
o Increased BUN and creatinine d/t decreased GFR
o Both in AKI and CKI
 Uremia
o Symptomatic azotemia
o Failure of renal excretory function
o Metabolic and endocrine changes
o Secondary involvement of the GIT, peripheral
nerves, and heart
 Nephritic syndrome
o Inflammatory glomerular disease
o Acute onset hematuria, diminished GFR, mild-
moderate proteinuria, hypertension
o Classic presentation of APSGN
 nephrotic syndrome
o Heavy proteinuria (> 3.5g/d), hypoalbuminemia,
severe edema, hyperlipidemia, lipiduria
 AKI
o Rapid decline in GFR (hours to days) with
dysregulation of fluid and electrolyte balance,
retention of metabolic wastes
o Most severe form: oliguria / anuria
 CKD
o Persistent GFR < 60 mL/min/1.73m 2 for > 3 mo
and/or persistent albuminuria
o End result of all chronic renal parenchymal
diseases (MC DM and HTN)
 ESRD
o GFR < 5% of normal
o Terminal stage of uremia
 Renal tubular defects
o Polyuria, nocturia, electrolyte disorders
II. Glomerular Diseases
 Pathologic Responses of the Glomerulus to Injury
o Hypercellularity
 Endocapillary proliferation: Proliferation of
mesangial or endothelial cells + Infiltration
of leukocytes
 Formation of crescents: proliferating
glomerular epithelial cells and infiltrating
coagulation factors
o Basement membrane thickening – seen in EM
 Deposition of immune complexes
 Increased synthesis of protein components
(eg diabetic glomerulosclerosis)
 Formation of additional matrix layers (eg
MPGN)
o Hyalinosis
 Accumulation of homogenous and
eosinophilic material
 Hyalin – extracellular amorphous,
composed of plasma proteins
o Sclerosis
 Deposition of extracellular collagenous
matrix
 Mesangial in diabetic glomerulosclerosis
 Pathogenesis - mainly immune mechanisms (most
commonly autoantibody-mediated)
1. In Situ Formation of Immune Complexes
o Antigens – intrinsic or extrinsic
o Classic example: membranous nephropathy
(local formation of immune complexes by
antibodies reactive with endogenous antigens)
o IF: Granular pattern of immune deposition –
localized Ag-Ab interaction
o EM: discrete subepithelial electron-dense
deposits (with resultant host responses, cause
thickened BM appearance)
2. Antibodies Directed Against Normal Components of
the GBM
o Intrinsic antigens homogenously distributed
along entire length of GBM
 IF: Diffuse linear pattern
o < 5% cases but causes severe necrotizing and
crescentic glomerular damage
o Clinical syndrome of RPGN
3. Deposition of Circulating Immune Complexes
o Localization because of physicochemical
properties of complexes and hemodynamic
factors peculiar to the glomerulus
o Antigens
 Endogenous – SLE, IgA nephropathy
 Exogenous – infections (streptococcal,
hepatitis B and C, Treponema pallidum,
Plasmodium falciparum)
 Mechanisms of Injury after Immune Complex
Formation
o Elicitation of a local inflammatory response
o Antibodies may activate complement and
engage Fc receptors on leukocytes and
mesangial cells
o Leukocytic infiltration and proliferation of
mesangial and endothelial cells
o EM: electron dense deposits (ICs)
o IF: granular deposits
o Once deposited, ICs may be degraded by
infiltrating neutrophils and
monocytes/macrophages, mesangial cells, and
endogenous proteases
  If repeatedly deposited for prolonged
periods however, it leads to membranous /
membranoproliferative GN
o Localization of ICs
Antigen Cross GBM Resultant IC
Cationic + Subepithelial
Anionic - Subendothelial
Neutral Mesangial
 Large ICs usually not nephritogenic –
cleared by phagocytes
 Influenced by glomerular dynamics,
mesangial function, and integrity of charge-
selective barrier of the glomerulus –
variable pattern in various forms of GN
 Subendothelial and mesangial – accessible
to circulation and > likely to be involved in
inflammatory processes requiring
interaction with WBCs
 Subepithelial – often non-inflammatory
 Other Possible Mechanisms of Injury
o T-cell mediated immune reactions
o Activation of alternative complement pathway
 Occurs in dense deposit disease (MPGN
type II) and C3 glomerulopathies
o Podocyte injury
 Mediators of Glomerular Injury
o Cells
 Neutrophils and monocytes – result of
activation of complement (C5a) and Fc
receptors; neutrophil release of proteases,
oxygen-derived free radicals, and
arachidonic acid metabolites
 Macrophages and T cells
 Platelets
 Resident glomerular cells (mesangial cells) –
produce inflammatory mediators; may
initiate inflammation even in the absence of
leukocyte infiltration
o Soluble mediators
 Complement activation – chemotactic
products, membrane attack complex (C5b-
C9); some diseases have defective
regulation (eg C3 glomerulopathies)
 Eicosanoids, nitric oxide, angiotensin,
endothelin
 Cytokines (IL-1 and TNF)
 Chemokines (eg monocyte chemoattractant
protein 1, growth factors)
 Coagulation system – fibrin often (+) in the
glomeruli and Bowman space in GN
 Mechanisms of Progression
o Once any renal disease destroys functioning
nephrons and reduces the GFR to 30-50% of
normal, progression to end-stage renal failure
proceeds at a steady rate, independent of the
original insult
1. Glomerulosclerosis
o Can lead to proteinuria and increasing functional
impairment
2. Tubular Injury and Interstitial Fibrosis
o Ischemia of tubular segments downstream from
sclerotic glomeruli, inflammation, od loss of
peritubular capillary blood supply
o Proteinuria can also cause direct injury to and
activation of tubular cells
 Activated tubular cells express adhesion
molecules and elaborate proinflammatory
cytokines, chemokines, and GFs,
contributing to interstitial fibrosis
A. Nephritic Syndrome
 Glomerular inflammation – injury of capillary walls
permits blood passage
 Hematuria, proteinuria (subnephrotic, +/- edema),
azotemia, and hypertension
 Typical presentation of most proliferative GN
 Reduced GFR – oliguria, fluid retention, azotemia
 Hypertension – fluid retention and renin release from
ischemic kidneys
1. Acute Proliferative (Post-infectious and Infection-
associated) GN
o Proliferation of glomerular cells + leukocytic
infiltrate
o Mainly caused by ICs
 Antigen exogenous (post-infectious) or
endogenous (SLE)
o Poststreptococcal GN – usually appears 1-4
weeks after streptococcal infection of the
pharynx or skin (impetigo); most common in
children 6-10 years old
 Group A beta-hemolytic streptococci (90%
types 12, 4, and 1) – identified by typing of
M protein of bacterial cell walls
 Latent period = time required for antibody
production and immune complex formation
 (+) serum antistreptococcal antibody titer
 Low serum complement (C3) because of
consumption of complement components
 Granular immune deposits in glomeruli
 Principal antigenic determinant:
streptococcal pyogenic exotoxin B (Spec B)
– humplike deposits
 Outset: inciting antigens are exogenously
planted from the circulation in the
subendothelium → in situ IC formation →
dissociate, migrate across the GBM, and
reform on the subepithelial side of the GBM
o Other infections with the same
pathomechanism:
 Bacterial – staphylococcal endocarditis,
pneumococcal pneumonia,
meningococcemia
 Viral – hepatitis B and C, mumps, HIV,
varicella, mononucleosis
 Parasitic – malaria, toxoplasmosis
o Morphology
 Enlarged hypercellular glomeruli
- Infiltration by neutrophils and
monocytes
 - proliferation of endothelial and  Produced predominantly by the
mesangial cells proliferation of epithelial cells lining the
- crescent formation (severe cases) Bowman capsule and by the infiltration of
 Proliferation and leukocyte infiltration – monocytes and macrophages (+/-
global and diffuse (all glomerular lobules neutrophils and lymphocytes)
involved) o Pathogenesis
 Swelling of endothelial cells  Anti-GBM Ab-mediated (1/5)
 Resultant obliteration of capillary lumen - Linear deposits of IgG and C3 in the
 +/- interstitial edema and inflammation, GBM
tubular RBC casts - May cross react with pulmonary
 IF: granular deposits of IgG and C3 alveolar BMs and cause pulmonary
(sometimes IgM) in the mesangium and hemorrhage (Goodpasture syndrome)
along the GBM – common antigen: non-collagenous
- ICs universally present but often focal portion of alpha-3 chain of collagen
and sparse type IV
 EM: discrete amorphous electron-dense - Tx: plasmapheresis, corticosteroids,
deposits on the epithelial side of the cytotoxic agents (can reverse
membrane (appear as humps) – ICs at the pulmonary hemorrhage and renal
subepithelial surface failure in Goodpasture syndrome)
- Subendothelial deposits common  Immune complex deposition (1/4)
especially in early disease course - Granular deposits of antibodies and
o Clinical Features complement
 Young child abruptly develops malaise, - May be idiopathic
fever, nausea, oliguria, and hematuria - IC nephritides: PSGN, lupus nephritis,
(smoky or cola urine) 1-2 weeks after sore IgA nephropathy, HSP
throat recovery - Tx: address underlying cause
- Dysmorphic RBCs [casts] in urine, mild  Pauci-immune crescentic GN
proteinuria (<1 g/d), periorbital - (-) anti-GBM Ab or IC
edema, and mild to moderate - Circulating antineutrophil cytoplasmic
hypertension antibodies (ANCAs) – cytoplasmic or
 Adults – onset atypical (sudden appearance perinuclear stain
of hypertension or edema with increased - May be a component of systemic
BUN) vasculitis but often limited to the
- may be subclinical (seen only on kidneys (idiopathic)
screening for microscopic hematuria in Formerly Now
epidemics) c-ANCA PR3-ANCA
 > 95% affected children recover – tx aimed p-ANCA MPO-ANCA
at maintaining sodium and water balance o Morphology
- < 1% develop RPGN  Kidneys enlarged and pale with petechial
- Remainder undergo slow progression hemorrhages on cortical surfaces
to chronic GN  Focal and segmental necrosis
- Poor prognostic factors: prolonged and  Variable proliferation
persistent heavy proteinuria and  Pauci-immune: segmental glomerular
abnormal GFR necrosis and crescents adjacent to
 Disease less benign in adults glomerular segments uninvolved by
- Only 60% of sporadic cases recover inflammatory or proliferative changes
promptly  Fibrin strands prominent between cellular
- Remainder experience persistence layers in the crescents
(may recover, develop chronic GN, or  IF
develop RPGN) - IC-mediated: granular immune
2. Crescentic (Rapidly Progressive) Glomerulonephritis deposits
(RPGN) - Goodpasture syndrome: linear GBM
o Severe glomerular injury without a specific fluorescence for Ig and complement
etiology denoted - Pauci-immune: little to no deposition
o Rapid and progressive loss of renal function of immune reactants
associated with severe oliguria and signs of  EM: GBM rupture
nephritic syndrome - Allows leukocytes, plasma proteins,
o If untreated, death from renal failure within and inflammatory mediators to reach
weeks to months the urinary space and trigger crescent
o (+) crescents in most of the glomeruli formation
  Crescents undergo organization with time
and foci of segmental necrosis resolve as
segmental scars (normalization only
possible with early aggressive tx)
o Clinical Features
 Hematuria with RBC casts
 Moderate proteinuria (occasionally
nephrotic)
 Variable hypertension and edema
 Renal involvement often progressive and
culminates in severe oliguria
 Tx: steroids, cytotoxic agents; however,
many patients later on require RRT
especially if disease is discovered at a late
stage
B. Nephrotic Syndrome
 Caused by a derangement in glomerular capillary
walls resulting in increased permeability to plasma
proteins
o Massive proteinuria (> 3.5 g / d)
o Hypoalbuminemia (< 3 g / dL) – urine loss > liver
production, increased renal catabolism of
filtered albumin
o Generalized edema – soft and pitting; most
marked in the periorbital region and dependent
portions of the body; if severe, may lead to
pleural effusion and ascites
 Decreased intravascular colloid osmotic
pressure
 Sodium and water retention
- hypovolemia-enhanced renin secretion
increases aldosterone production
- SNS activation
- Reduction in the secretion of
natriuretic factors
o Hyperlipidemia and lipiduria
 Increased lipoprotein synthesis in the liver,
abnormal transport of circulating lipid
particles, and decreased lipid catabolism
 Lipids appear in urine as free fat or oval fat
bodies (lipoprotein resorbed by tubular
epithelial cells then shed with injured cells
detached from BM)
Proteinuria selectivity Protein MW
High Low (albumin, transferrin)
Low Low and high (globulin)
 Vulnerable to infection
o Especially staphylococcal and pneumococcal
o Caused by loss of immunoglobulins in urine
 (+) thrombotic complications
o Caused by loss of anticoagulants in urine
o Consequence: renal vein thrombosis (particularly
with membranous nephropathy)
 Pathogenesis
o Children – often due to a primary kidney disease
o Adults – often associated with a systemic disease
(MC diabetes, amyloidosis, and SLE)
o Most important primary glomerular lesions:
minimal change disease, membranous
nephropathy, and FSGS
1. Membranous Nephropathy
o Diffuse thickening of the glomerular capillary
wall due to the accumulation of deposits
containing Ig along the subepithelial side of the
BM
o 75% primary; remainder secondary with the
following associations:
 Drugs: penicillamine, captopril, gold, NSAIDs
 Malignancy: carcinoma of the lung and
colon; melanoma
 SLE
 Infection: chronic hepatitis B and C, syphilis,
schistosomiasis, malaria
 Other autoimmune disorder: thyroiditis
o Pathogenesis
 Chronic immune-complex mediated disease
 Primary – antibodies to a renal autoantigen
- PLA2R (membrane protein at the basal
surface of the glomerular epithelial
cell) antigen in 60-70%
- ICs deposited at subepithelial BM
 Paucity of neutrophils, monocytes, or
platelets in the glomeruli
 MAC – activates glomerular epithelial and
mesangial cells – induced to liberate
proteases and oxidants that cause capillary
wall injury
 IgG4 – principal Ig deposited in most cases
of membranous nephropathy
o Morphology
 LM: glomeruli appear normal in early
disease or exhibit uniform diffuse thickening
of the glomerular capillary wall
 EM: thickening d/t electron-dense deposits
(ICs) between the BM and epithelial cells
with effacement of podocyte foot processes
- BM material laid down in between
deposits – appear as irregular spikes
protruding from the GBM (best seen by
silver stains which color the BM but
not the deposits black)
- Spikes thicken with time to produce
domelike protrusions and eventually
close over immune deposits – buried
 within a markedly thickened irregular - Changes completely reversible after
membrane corticosteroid tx (proteinuria
 IF: granular deposits of Ig and complement remission)
- Immunostain for PLA2R or THSD7a  PCT cells laden with lipid and protein d/t
 Segmental sclerosis with disease tubular reabsorption of lipoproteins that
advancement have passed through the diseased glomeruli
 Epithelial cells of PCT contain protein - “lipoid nephrosis”
reabsorption droplets  IF: (-) Ig or complement deposits
 Considerable interstitial mononuclear cell o Clinical Features
inflammation  Despite massive proteinuria, renal function
o Clinical Features remains good
 Insidious onset nephrotic syndrome  (-) hypertension or hematuria
 15% have non-nephrotic proteinuria  Proteinuria highly selective (MC albumin)
 Hematuria and mild hypertension in 15-35%  Dramatic response to corticosteroids (>90%
cases patients respond)
 Course generally indolent - Proteinuria may recur in some patients
 Non-selective proteinuria – non-responsive – may become steroid-dependent or
to corticosteroids resistant (but still resolves usually by
 Remission in 40% patients puberty)
- > in women and non-nephrotic range  Excellent long-term prognosis (even in
proteinuria adults who respond slower to steroids)
 Progression associated with increasing  May also follow NSAID tx usually in
glomeruli sclerosis, renal insufficiency, and association with acute interstitial nephritis
hypertension development 3. Focal Segmental Glomerulosclerosis (FSGS)
Clinical Progression % o Primary FSGS – MC cause of nephrotic syndrome
Persistent proteinuria 60 in the US
Renal failure, death 10 o MC manifests as acute or subacute onset
CKD, ESRD 40 nephrotic syndrome or non-nephrotic
 Recurs in 40% patients who underwent proteinuria
transplant  Hypertension, microscopic hematuria, and
2. Minimal Change Disease some degree of azotemia
o Benign disorder characterized by diffuse o Classification
effacement of foot processes (detected only on  Primary (idiopathic)
EM)  Associated with other known conditions
o MC cause of nephrotic syndrome in children (HIV, heroin, sickle cell disease, morbid
(peaks at 2-6 y/o) obesity)
o Pathogenesis – immunologic despite absence of  Secondary event (scarring of a previously
immune deposits active necrotizing lesion – eg focal GN (IgA
 Association with respiratory infection or nephropathy))
routine immunization  Component of adaptive response to renal
 Response to immunosuppressives tissue loss (renal ablation)
(corticosteroids) - Congenital (renal agenesis/dysplasia)
 Association with atopy (eczema, rhinitis) - Acquired (reflux nephropathy)
- Increased prevalence of certain HLA - Advanced disorders (hypertensive
haplotypes nephropathy)
 Increased incidence in Hodgkin lymphoma  Inherited – mutation in genes encoding slit
 Primary podocytopathy diaphragm proteins (podocin, alpha-actinin
o Morphology 4, TRPC6)
 LM: normal glomeruli o Clinical Features
 EM: GBM normal; principal lesion at visceral  > incidence of hematuria, reduced GFR, and
epithelial cells hypertension
- Uniform and diffuse effacement of foot  Non-selective proteinuria
processes – reduced to a rim of  Poor response to corticosteroids
cytoplasm with loss of recognizable  Progression to CKD (50% develop ESRD
intervening slit diaphragms within 10 years)
- D/dx (foot process effacement but o Pathogenesis
glomeruli appear abnormal):  Ultrastructural hallmark: epithelial damage
membranous glomerulopathy, diabetic  Degeneration and focal disruption of
nephropathy visceral epithelial cells with effacement of
foot processes (D/dx: MCD)
 - Caused by circulating factors and
genetic defects affecting the slit
diaphragm
 Hyalinosis and sclerosis – d/t entrapment of
plasma proteins in hyperpermeable foci and
increased ECM deposition
 Recurrence of proteinuria after transplant
(sometimes within 24 h) with subsequent
progression to overt lesions in some
patients – may be d/t an unknown
circulating factor
o Inherited forms
 NPHS1
- Chromosome 19q13
- Encodes nephrin (key component of
the slit diaphragm)
- Mutation - congenital nephrotic
syndrome (Finnish type)
 NPHS2
- AR; chromosome 1q25-q31
- Encodes podocin (also part of the slit
diaphragm)
- Mutation – steroid-resistant nephrotic
syndrome of childhood onset
 Gene encoder of podocyte actin-binding
protein alpha-actinin 4
- AD; insidious onset but high rate of
renal insufficiency progression
 Gene encoder of TRPC6
- Increased calcium flux in podocytes
- Some adult-onset FSGS
o Renal ablation FSGS
 A secondary form – complication of
[non]glomerular diseases (reflux
nephropathy, unilateral agenesis)
- May lead to progressive
glomerulosclerosis and renal failure
- Glomerulosclerosis initiated by the
adaptive change occurring in the
relatively unaffected glomeruli
(undergo hypertrophy – hypertension
both systemic and intraglomerular)
 Endothelial and visceral epithelial cell injury
- Denuding of foot processes → protein
permeability and accumulation in the
mesangial matrix
- Proliferation of mesangial cells,
infiltration by macrophages, increased
ECM accumulation
- Segmental and eventual global
sclerosis
 Prominent role: TGF-beta
 Tx: RAAS inhibitors
o Morphology
 LM: focal and segmental lesions may
involve only a minority of the glomeruli
(may be missed if the biopsy specimen
contains insufficient glomeruli)
- Sclerotic segments – collapse of
capillary loops, increased matrix, and
segmental deposition of plasma
proteins along the capillary wall
(hyalinosis)
- (+) lipid droplets and foam cells
 EM: diffuse effacement of foot processes
- Also focal detachment of epithelial
cells and denudation of underlying
GBM
 IF: IgM and C3 in sclerotic areas and/or
mesangium
 Disease progression – increasing sclerosis
with pronounced tubular atrophy and
interstitial fibrosis
 Morphologic variant: collapsing
glomerulopathy
- Retraction and/or collapse of the
entire glomerular tuft +/- FSGS lesions
- Proliferation and hypertrophy of
podocytes
- Idiopathic, drug-associated
(pamidronate)
- Most characteristic lesion of HIV-
associated nephropathy
- Associated with prominent tubular
injury with formation of microcysts and
interstitial inflammation
- Poor prognosis
o Clinical Features
 Little tendency for spontaneous remission
 Better prognosis in children
 Variable steroid response and progression
to renal failure
 25-50% recurrence in transplant patients
 Prognostic factors: degree of proteinuria,
renal insufficiency at diagnosis, histology
- Collapsing variant – poor prognosis
- Tip variant – good prognosis
4. HIV-Associated Nephropathy
o HIV – direct or indirect causation of renal
complications (eg with drugs or infection)
o 5-10% of patients with HIV
o Morphology
 Collapsing variant of FSGS
 Focal cystic dilation of tubule segments –
filled with proteinaceous material, inflamed
and fibrotic
 Tubuloreticular inclusions within
endothelial cells on EM (also seen in SLE) –
modifications of endoplasmic reticulum
induced by circulating interferon-alpha
o HIV-associated FSGD primarily due to G1/G2 risk
alleles for APOL1
5. Membranoproliferative Glomerulonephritis (MPGN)
o A pattern of immune-mediated injury (not a
specific disease)
o Types
I – deposition of ICs with IgG and complement
II – dense deposit disease – complement
activation; a form of C3 glomerulopathy (C3
present in GBM but not in dense deposits)
o Histology
 Alterations in GBM
 Accumulation of mesangial matrix
 Proliferation of glomerular cells
 Leukocyte infiltration
 Deposits in mesangial regions and
glomerular capillary walls
o 10% of nephrotic syndrome cases in children in
young adults; mostly associated other systemic
disorders
o Pathogenesis
 Type I – ICs in glomerulus and activation of
both classical and alternative complement
pathways
 Unknown antigens; believed to be from
hepatitis B and C
o Morphology
 Large and hypercellular glomeruli
 Hypercellularity from mesangial and
endocapillary proliferation
 Accentuated lobular appearance of
glomeruli due to the proliferating mesangial
cells and increased mesangial matrix
 GBM thickened – “double contour” or “tram
track” appearance especially in silver or PAS
stains
- Duplication / splitting of BM d/t new
BM synthesis in response to
subendothelial IC deposits
- Between duplicated BMs, (+) cellular
elements
- (+) crescents
 Type I – discrete subendothelial electron-
dense deposits
- Granular IgG and C3 deposition (also
C1q and C4)
o Clinical Features
 MC present in adolescence with nephrotic
syndrome and a nephritic component
 Few spontaneous remissions
 Slowly progressive but unremitting course
o Secondary MPGN
 Often type 1; arises from:
- Chronic IC deposition (SLE), hepatitis B,
hepatitis C with cryoglobulinemia,
endocarditis, infected ventriculoatrial
shunts, chronic visceral abscess, HIV,
schistosomiasis
- Alpha 1 antitrypsin deficiency
- Malignancy – chronic lymphocytic
leukemia
o Dense Deposit Disease
 Excessive activation of alternative
complement pathway
 Decreased serum C3, normal C1 and C4
 Decreased serum Factor B and properdin
 Glomerular deposits: C3 and properdin (not
IgG)
 > 70% patients have a circulating
autoantibody termed C3 nephritic factor
(C3NeF) that binds C3 convertase and
prevents its inactivation → persistent C3
activation and hypocomplementemia
 Decreased C3 synthesis by the liver
 +/- associated Factor H mutation
 Morphology
- Mesangial proliferative pattern – MC
- Defining feature in EM: permeation of
the lamina densa of the GBM by a
ribbonlike homogenous extremely
electron-dense material of unknown
composition
- IF: C3 (+) in irregular granular or linear
foci in BMs on either side but not
within dense deposits; also in
mesangium as circular aggregates
(mesangial rings)
- (-) IgG, C1q, C4
 Clinical Features
- Primarily affects children and young
adults
- Nephritic or nephrotic syndrome
- Poor prognosis (50% progress to ESRD)
- 90% recur in transplant patients
6. Fibrillary GN
o Fibrillary deposits in the mesangium and
glomerular capillary walls that resemble amyloid
fibrils superficially
 (-) staining however for Congo red
o LM: mesangioproliferative or
membranoproliferative
o IF: IgG4, C3, Ig-K and L light chains
o Nephrotic syndrome, hematuria, progressive
renal insufficiency
o Recurs in transplants
o Marker: DNAJB9
C. Other Glomerular Diseases
1. IgA Nephropathy (Berger Disease)
o Prominent IgA deposits in the mesangial regions
and hematuria
o MC type of GN worldwide
o Mild proteinuria; rarely may develop nephrotic
syndrome and present with crescentic GN
o Typically an isolated renal disease but IgA may
also be in other systemic disorders such as HSP
 Secondary IgA nephropathy may occur in
liver and intestinal disease
o Pathogenesis: multi-hit etiology
 Increased plasma polymeric IgA
- Aberrant glycosylation
- Defect in normal formation or
attachment of O-linked glycans to the
hinge region of IgA1
 Aberrantly glycosylated IgA either deposited
by itself in glomeruli or it forms ICs in the
circulation with IgG autoantibodies – later
on deposited in the mesangium
 Mesangial deposits activate mesangial cells
to proliferate, produce ECM, and secrete
cytokines and GFs
  Inflammatory cell recruitment
 Activation of alternate pathway – (+) C3 and
(-) C1q and C4 in glomeruli
 HLA genotypes may be linked
 Increased synthesis of abnormal IgA may
occur in response to RT/GIT exposure to
environmental agents
- Gluten enteropathy (celiac disease)
- Liver disease
o Morphology - varies
 Normal or mesangial widening and
endocapillary proliferation
 Focal proliferative GN
 Overt crescentic GN
 IF: characteristic mesangial deposition of
IgA
- Often with C3 and properdin, and less
IgG or IgM
- (-) early complement components
 EM: electron dense deposits in the
mesangium (sparse at capillary wall)
o Clinical Features
 MC in older children and young adults
 Mostly present with gross hematuria after
infection of RT > GIT or UT
- Lasts for several days, subsides, then
returns every few months
 Variable subsequent course
 Increased progression risk: old age of onset,
heavy proteinuria, hypertension, and
glomerulosclerosis
 Frequent recurrence in transplant
2. Hereditary Nephritis
o Mutations in collagen genes that manifest
primarily with glomerular injury
a. Alport Syndrome
 Mutations affecting type IV collagen (GBM,
eye lens, cochlea) resulting in hematuria
with progression to CRF
- Large deletions in alpha-5 chain
(COL4A5) associated with early stage
ESRD
 With nerve deafness (may require sensitive
testing) and eye disorders (lens dislocation,
posterior cataracts, and corneal dystrophy)
 X-linked (males – full syndrome, female
heterozygotes – hematuria) > AR and AD
 90% affected males progress to ESRD before
40 y/o
 Morphology
- GBM: irregular foci of thickening
alternating with thinning
- Pronounced splitting and lamination of
lamina densa → basket-weave
appearance
- Glomerulosclerosis with progression
 Clinical Features
- MC presenting sign: gross or
microscopic hematuria, with RBC casts
- May develop proteinuria later
- Sx appear at 5-20 y/o
- Overt renal failure in 20-50 y/o males
b. Thin Basement Membrane Nephropathy
(Benign Familial Hematuria)
 Familial asymptomatic hematuria – MC
uncovered on routine urinalysis
 Morphologic diffuse thinning of the GBM to
150-225nm (normal: 300-400 nm in healthy
adults)
 +/- mild-moderate proteinuria
 Renal function normal – excellent prognosis
 Affects 1% of the general population; MC
autosomal
 Mutation in genes encoding alpha 3 or 4
chains of collagen
D. Glomerular Lesions Associated with Systemic Diseases
1. Lupus Nephritis
o Hematuria, nephritic syndrome, RPGN<
nephrotic syndrome, ARF/CRF, hypertension
2. Henoch-Schonlein Purpura
o Purpura + abdominal pain and intestinal bleed +
arthralgia + renal abnormalities (not all needed
for diagnosis)
o Skin: arm and leg extensors, buttocks
o Abdomen: pain, vomiting, intestinal bleed
o Renal (1/3): hematuria, nephritic syndrome,
nephrotic syndrome
 Few adults develop RPGN with many
crescents
o MC in children 3-8 y/o – excellent prognosis
o 1/3 patients have atopy (onset after URTI)
o IgA deposition in mesangium (also C3)
o Morphology
 Mild to diffuse mesangial and endocapillary
proliferation to crescentic GN (vary)
 Pathognomonic on IF: IgA deposition
(sometimes with IgG and C3) in the
mesangium (sometimes to capillary loops)
 Skin lesions – subepidermal hemorrhages
and a necrotizing vasculitis of dermal
vessels (also with the same deposition)
- Vasculitis rare in the kidney
3. Diabetic Nephropathy
4. Other
a. Goodpasture syndrome, microscopic
polyangiitis, granulomatosis with
polyangiitis – foci of glomerular necrosis
and crescent formation
b. Essential mixed cryoglobulinemia –
cryoglobulins principally of IgG-IgM
complexes – induce cutaneous vasculitis,
synovitis, and MPGN type 1; often
associated with hepatitis C infection
c. Plasma cell neoplasms – secrete Ig that may
also induce glomerular lesions
III. Tubular and Interstitial Diseases
A. Acute Tubular Injury / Necrosis (ATI / ATN)
 Characterized by acute renal failure +/- tubular
epithelial cell necrosis
 Most common cause of AKI (50% in hospitalized
patients); reversible
 Causes
o Ischemia (Ischemic)
 Intrarenal blood vessel disease
(microangiopathies)
 Decreased effective circulating blood
volume (hypovolemic shock)
o Direct toxic injury to tubules (Nephrotoxic)
 Endogenous: myoglobin, hemoglobin,
monoclonal light chains, bile/bilirubin
 Exogenous: drugs (gentamicin),
radiocontrast dye, heavy metals (mercury),
organic solvents (carbon tetrachloride),
poison
o Combined ischemic and nephrotoxic: hemolytic
crises, skeletal muscle injuries
 Intratubular hemoglobin or myoglobin casts
 Toxic iron content
 Pathogenesis
o Tubular cell injury
 Tubular epithelial cells (especially those in
the PCT) are sensitive to ischemia and
vulnerable to toxins
 Predisposing factors
- Increased surface area for
reabsorption
- Active transport system for ions and
organic acids
- High rate of metabolism and oxygen
consumption
- Capability to resorb and concentrate
toxins
 Effects of Ischemia
- Loss of cell polarity due to
redistribution of membrane proteins
from the basolateral to the luminal
surface of the tubular cells →
abnormal ion transport → increased
sodium delivery to the distal tubules →
inciting vasoconstriction via
tubuloglomerular feedback (lowers the
GFR to maintain distal BF)
- Expression of cytokines and adhesion
molecules → leukocyte recruitment
- Injured cells detach from BM →
luminal obstruction, increased
intratubular pressure, and further
decreased GFR
 Glomerular filtrate in the lumen of damaged
tubules leak back into the interstitium →
interstitial edema
o Hemodynamic alterations that cause reduced
GFR
 Intrarenal vasoconstriction → reduced
glomerular BF and reduced oxygen delivery
to outer medulla (thick ascending limb and
straight segment of the proximal tubule)
 RAAS activation – stimulated by decreased
sodium in the tubules d/t decreased BP
 Sublethal endothelial injury → increased
release of endothelin and decreased
production of NO and PGI2
o Patchiness of necrosis and BM integrity allows
repair if the precipitating cause is removed
 Re-epithelialization mediated by growth
factors and cytokines from tubular and
inflammatory cells
 Morphology
o Tubular epithelial injury at multiple points along
the nephron with large skip areas in between
often with:
 BM rupture (tubulorrhexis)
 Occlusion of tubular lumen by casts
o Severity of morphologic findings doesn’t
correlate with severity of clinical manifestations
o Most vulnerable: straight portion of proximal
tubule and ascending thick limb in the renal
medulla
 Distal tubule may also show focal lesions
o Necrosis patchier in ischemic type and more
extensive in toxic type
o Other findings in ischemic ATI
 Interstitial edema
 Accumulation of leukocytes within dilated
vasa recta
 Epithelial regeneration – flattened epithelial
cells with hyperchromatic nuclei and mitotic
figures
o Toxic ATI
 Most obvious findings at PCT
Agent Morphology
Mercuric Large acidophilic inclusions; later
chloride necrotize, desquamate, and calcify
Ethylene Marked ballooning and
glycol hydropic/vacuolar degeneration;
calcium oxalate crystals in the lumen
 Clinical Course (Phases)
1. Initiation
o 36 hours; dominated by the inciting event
o Slight decline in urine output with increased BUN
o If with oliguria – d/t transient decrease in BF and
declining GFR
2. Maintenance
o Sustained decrease in UO 40-400mL/d (oliguria),
salt and water overload, increasing BUN,
hyperkalemia, metabolic acidosis, and other
manifestations of uremia
o Can be overcome with appropriate tx
3. Recovery
o Steady increase in urine volume that may reach
up to 3 L/d
o Tubules still damaged – large amounts of water,
Na, K lost in urine
o Development of hypokalemia
o Increased infection vulnerability
o Eventually, renal tubular function is restored and
concentrating ability improves (BUN and Cr
normalize)
 o
Subtle impairments may persist but most o Morphology
patients eventually recover completely  Hallmark: patchy interstitial suppurative
 Prognosis inflammation intratubular aggregates of
o Depends on magnitude and duration of injury neutrophils, neutrophilic tubulitis, and
o Recovery expected if no other organs are tubular injury
seriously damaged  Suppuration may occur as discrete focal
o 95% recover with supportive care abscesses or large wedge-like areas
o Mortality rate > 50% however if with multiorgan  Early: neutrophilic infiltration limited to
failure tubules; later on extend to interstitium and
B. Tubulointerstitial Nephritis produce abscesses
 Insidious onset; principally manifest by azotemia  Glomeruli are relatively resistant to
 Acute or Chronic infection (unless extensive)
o Acute  Fungal – granulomatous
 Interstitial edema with leukocytic  Complications
infiltration of the interstitium and tubules a. Papillary necrosis
 Tubular injury - Diabetics, sickle cell disease, UT
o Chronic obstruction
 Infiltration with predominant mononuclear - MC bilateral
leukocytes - Cut section: tips or distal 2/3 of the
 Prominent interstitial fibrosis pyramids have areas of gray-white to
 Widespread tubular atrophy yellow necrosis
 Differences from glomerular diseases - Microscopy: necrotic tissue shows
o Absence of nephritic / nephrotic syndrome characteristic ischemic coagulative
necrosis with preservation of tubule
o Defects in tubular function
outlines
 Polyuria / nocturia (impaired ability to
b. Pyonephrosis
concentrate urine)
- Seen with total obstruction, especially
 Salt wasting
if high in the UT
 Diminished ability to excrete acids
- Suppurative exudate unable to drain
(metabolic acidosis)
and fills the renal pelvis, calyces, and
ureter with pus
c. Perinephric abscess
- Extension of suppurative inflammation
through the renal capsule into the
perinephric tissue
 Healing occurs after the acute phase
- Neutrophilic infiltrate replaced by
macrophages, plasma cells, and
lymphocytes
- Inflammatory foci eventually replaced
by irregular scars seen on the cortical
surface as fibrous depressions
- Scars – tubular atrophy, interstitial
fibrosis, and lymphocytic infiltrate in a
characteristic patchy jigsaw pattern
with intervening preserved
parenchyma
- Pyelonephritic scar associated with
inflammation, fibrosis, and
deformation of underlying calyx and
pelvis
o Predisposing factors
 Urinary tract obstruction
 Instrumentation of UT
 VUR
 Pregnancy
 Gender and age
1. Pyelonephritis
 Acute 1 y/o Males (evident congenital
anomalies)
o Suppurative inflammation because of bacterial >
> 1 to 40 y/o Females
viral infection
 > 40 y/o Males (prostatic
hypertrophy,
instrumentation)
 Pre-existing renal lesions (scarring and
obstruction)
 Diabetes (infection, neurogenic bladder,
frequent instrumentation)
 Immunosuppression and immunodeficiency
o Clinical Features
 Presents as sudden onset pain at CVA and
systemic evidence of infection (malaise,
fever)
 Bladder and urethral irritation: dysuria,
frequency, urgency
 Pyuria – either upper or lower UT
involvement
 Leukocyte casts (rich in neutrophils – pus
casts) – renal involvement
 Benign course if uncomplicated (resolved in
a few days after antibiotic tx)
 If complicated, may lead to repeated
septicemic episodes
 If with papillary necrosis, may lead to ARF
o Polyomavirus Infection
 Latent infection widespread in the general
population
 Reactivates with immunosuppression of the
allograft recipient – causing transplant
failure in 5% patients
 “Polyoma nephropathy”
 Infection of tubular epithelial cell nuclei →
nuclear enlargement and intranuclear
inclusions – seen in LM (viral cytopathic
effect)
 Inclusions composed of virions arrayed in
distinctive crystalline-like lattices on EM
 Interstitial inflammatory response
 Tx: reduce immunosuppression
 Chronic
o Chronic tubulointerstitial inflammation and
scarring of the calyces and pelvis
 Only chronic PN and analgesic nephropathy
affect the calyces (clue to r/o other
differentials)
o Morphology
 Gross: kidneys irregularly scarred
(asymmetric if bilateral)
- D/dx: bilateral in chronic GN but
symmetric
 Hallmark: coarse discrete corticomedullary
scars overlying dilated blunted or deformed
calyces, and flattening of papillae
 Scars MC at upper and lower poles (reflux
MC in these sites)
 Tubules – atrophied in some areas,
hypertrophied/dilated in others
- Dilated tubules with flattened
epithelium may be filled with casts
resembling thyroid colloid
(thyroidization)
 Xanthogranulomatous pyelonephritis
- Rare form
- Accumulation of foamy macrophages
intermingled with plasma cells,
lymphocytes, polymorphonuclear
leukocytes, and occasional giant cells
- Often associated with Proteus infection
and obstruction
- Sometimes produce large yellow
orange nodules (D/Dx – RCC)
o Clinical Features
 Silent onset or acute recurrent PN s/sx
(back pain, fever, pyuria, bacteriuria)
 Late tx d/t gradual onset of renal
insufficiency and hypertension
 Loss of tubular function → polyuria and
nocturia
 Radiograph: asymmetrically contracted
kidneys with coarse scars and blunting /
Deformity of the calyceal system
 Proteinuria often mild but some develop
secondary FSGS
- Proteinuria onset – poor prognostic
sign – increases likelihood of ESRD
progression
C. TIN Induced by Drugs and Toxins
 2nd MC cause of AKI (after PN)
 Mechanism
o Trigger an interstitial immunologic reaction
(acute hypersensitivity nephritis induced by
methicillin)
o Cause ATI
o Cause subclinical but cumulative tubular injury,
taking years to result to CKD
1. Acute Drug-induced Interstitial Nephritis
o Most commonly occur with synthetic penicillins
(methicillin, ampicillin), other synthetic
antibiotics (rifampin), diuretics (thiazide),
NSAIDs, and other drugs (allopurinol, cimetidine,
checkpoint inhibitors)
o Analgesic nephropathy
 Chronic TIN caused by phenacetin-
containing analgesics
 Begins 2-40 days after drug exposure
 Fever, rash, and renal abnormalities
(hematuria, mild proteinuria, and
leukocyturia (often with eos))
- 50% have increased SCr or AKI with
oliguria
o Pathogenesis
 Idiosyncratic immune mechanism
 Hypersensitivity
- Latent period
- Eosinophilia and rash
- Nephropathy onset not dose-related
- Recurrence with re-exposure
- Some patients have increased serum
IgE (late phase reaction of type I
hypersensitivity)
 - Others have mononuclear / like crystals in the tubular lumens or in the
granulomatous reaction (type IV interstitium
delayed hypersensitivity)  Urate deposits evoke a mononuclear
 Drugs function as haptens and covalently response containing foreign body giant cells
bind to some plasma membrane or (tophus)
extracellular component of tubular cells  Tubular obstruction by the urates causes
- Modifed self-antigens become cortical atrophy and scarring
immunogenic  Clinically subtle
- Resultant injury due to IgE or cell- o Nephrolithiasis
mediated immunity  Uric acid stones are present in 22% patients
o Morphology with gout and 42% of those with secondary
 Interstitium: edema and infiltration by hyperuricemia
mononuclear cells (mainly lymphocytes and 2. Hypercalcemia and Nephrocalcinosis
macrophages) o Hyperparathyroidism, multiple myeloma, vitamin
 Inflammation more prominent in the D intoxication, metastatic cancer, or excess
medulla – inciting agent is concentrated calcium intake (milk-alkali syndrome) →
 With methicillin and thiazides, interstitial formation of calcium stones and deposition in
non-necrotizing granulomas may be seen the kidney (Nephrocalcinosis)
 Tubulitis (lymphocytic infiltration) o Defect: inability to concentrate urine
 Glomeruli normal (except in some cases  Other tubular defects may also occur
caused by NSAIDs – concurrent MCD and  CKD with progression
nephrotic syndrome) 3. Autosomal Dominant Tubulointerstitial Kidney
o Clinical Features Disease (ADTKD)
 Recovery after drug withdrawal expected o Previously Medullary Cystic Kidney Disease
but may take months o Genetic Mutations
 Occasionally, necrotic papillae are excreted MUC1 Mucin 1 Distal
and may cause gross hematuria or renal nephrons
colic due to ureteric obstruction UMOD Uromodulin Thick
Causes of Papillary Necrosis ascending
Analgesic nephropathy limb of LoH
DM REN Preprorenin JGA
Sickle cell disease HNF1-beta HNF1-beta
UT obstruction 4. Light Chain Cast Nephropathy (Myeloma Kidney)
- Caused by ischemia of medullary o Bence Jones proteinuria and cast nephropathy
vessels o Ig light chains are directly toxic to epithelial cells
o NSAID nephropathy o Bence Jones proteins combine with urinary
 d/t inhibition of COX-dependent PG- glycoprotein (Tamm Horsfall protein) under
synthesis acidic conditions to form large histologically
 Syndromes distinct tubular casts that obstruct the tubular
- AKI – decreased PG synthesis lumens and induce inflammation
(ischemia_ o Other associations
- Acute hypersensitivity interstitial
 AL Amyloidosis (MC lambda)
nephritis
 Light chain deposition disease (MC kappa)
- Acute interstitial nephritis and MCD
 Hypercalcemia and hyperuricemia
- Membranous nephropathy
o Morphology
D. Other Tubulointerstitial Diseases
 Bence Jones tubular casts appear as pink to
1. Urate Nephropathy
blue amorphous masses
o Acute uric acid nephropathy
- Sometimes concentrically laminated
 Precipitation of uric acid crystals (mainly at
and often fractured
collecting ducts due to its acidic pH) →
- Fill and distend the tubular lumens
nephron obstruction → AKI
- Some are surrounded by
 Occurs in patients with leukemia or
multinucleated giant cells
lymphoma undergoing chemo (tumor lysis
 Adjacent interstitial tissue shows
syndrome)
inflammation and fibrosis
o Chronic urate (gouty) nephropathy
 Occasionally, casts rupture the tubules,
 Rarely occurs in protracted forms of evoking a granulomatous inflammatory
hyperuricemia reaction
 Monosodium urate crystals deposit in the o Clinical Features
acidic milieu of distal tubules and collecting
 CKD or AKI
ducts → form distinct birefringent needle-
  Precipitating factors: dehydration,
hypercalcemia, acute infection, and
treatment with nephrotoxic antibiotics
 Bence Jones proteinuria in 70% individuals
with multiple myeloma
5. Bile Cast Nephropathy
o Impaired renal function in patients with severe
acute or advanced chronic liver disease
 Serum bilirubin markedly elevated → bile
cast formation (cholemic nephrosis) in distal
nephron segments
o Casts can extend to proximal tubules → direct
toxicity and obstruction
 Yellow-green to red-pink casts +/0 sloughed
cells or cellular debris
o Reversibility depends on severity and duration of
liver dysfunction
E. Vascular Diseases
1. Nephrosclerosis
o Sclerosis of renal arterioles and small arteries
o Strongly associated with hypertension (both a
cause and a consequence)
o Lesions
 Medial and intimal thickening
- Response to hemodynamic changes,
aging, genetic defects
 Hyalinization of arteriolar walls caused by
extravasation of plasma proteins through
injured endothelium and by increased
deposition of BM matrix
o Thickened walls → narrowed lumens → focal
parenchymal ischemia → glomerulosclerosis and
chronic tubulointerstitial injury → reduced
functional renal mass
o Morphology
 Normal or reduced kidney size (110-130 g)
- Due to cortical scarring and shrinking
 Cortical surfaces have a fine even
granularity resembling grain leather
- Subcapsular scars with sclerotic
glomeruli and tubular dropout
alternating with normal parenchyma
 Hyaline arteriolosclerosis → luminal
narrowing
 Interlobular and arcuate arteries show
medial hypertrophy, replication of internal
elastic lamina, and increased
myofibroblastic tissue in the intima
(fibroelastic hyperplasia)
 Vascular narrowing causes patchy ischemic
atrophy
- Foci of tubular atrophy and interstitial
fibrosis
- Glomerular alterations (collapse of
GBM, collagen deposition within the
Bowman space, periglomerular
fibrosis, and total sclerosis)
 Ischemic changes affecting large areas of
parenchyma can produce wedge-shaped
infarcts or regional scars with histologic
changes that may resemble renal ablation
injury
o Clinical Features
 Rarely cause renal insufficiency except in:
- African descent
- Severe BP elevation
- Other underlying diseases (DM)
 5% hypertensive patients experience
malignant hypertension
- Rapidly rising BP – if untreated, leads
to death within 1-2 years
- SBP > 200, DBP > 120
- Renal failure (malignant
nephrosclerosis)
- Retinal hemorrhages and exudates +/-
papilledema
- Some are associated with
microangiopathic hemolytic anemia
and hemolytic uremic syndrome
(common factor: endothelial injury)
2. Renal Artery Stenosis
o Pathogenesis
 Increased production of renin from the
ischemic kidney → RAAS activation
o Clinical Features
 Resemble essential hypertension
 A bruit may be heard
 Increased plasma or renal vein renin
 Response to ACEi
 Arteriography – needed for localization
o Morphology
 70% cases caused by narrowing of the renal
artery origin due to an atheromatous
plaque
- Men, advancing age, DM
- Concentric plaque with superimposed
thrombus
 Fibromuscular dysplasia
- Women, 3rd-4th decade
 Arteriolosclerosis: non-ischemic > ischemic
kidney (response to high pressure)
 Diffuse ischemic atrophy
- Reduced size
- Crowded glomeruli, atrophic tubules,
interstitial fibrosis, and focal
inflammatory infiltrates
3. Thrombotic Microangiopathies
o Thrombi
 RBC shear → microangiopathic hemolytic
anemia
 Occlusion → ischemia
 Platelet consumption → thrombocytopenia
o Includes Hemolytic Uremic Syndrome and
Thrombotic Thrombocytopenic Purpura
 Typical HUS (epidemic, classic, diarrhea-
positive)
- Consumption of food contaminated by
bacteria producing Shiga-like toxins
 Atypical HUS (non-epidemic, diarrhea-
negative)
 - Inherited mutations / autoantibodies
targeting complement-regulatory
proteins
- Endothelial injury
 TTP – inherited/acquired deficiency of
ADAMTS13 (vWF regulator)
o Pathogenesis
 Endothelial Injury (HUS)
- Platelet activation and thrombosis
within microvascular beds
- Decreased PGI2 and NO, increased
endothelin
 Platelet aggregation (HUS)
- Induced by very large multimers of
vWF accumulating due to deficient
ADAMTS13 – bind surface
glycoproteins and activate platelets
spontaneously
o Morphology
 Acute
- patchy / diffuse cortical necrosis and
subcapsular petechiae
- Glomerular capillaries are distended
and occluded by thrombi
- Mesangiolysis
- Interlobular arteries and arterioles
often show occlusive thrombi
 Chronic
- Common in atypical HUS
- Cortical scarring; similar to malignant
hypertension
- Glomeruli mildly hypercellular and
have marked thickening of capillary
walls associated with BM splitting
(double contour or tram track)
- Onion skinning – increased layers of
cells and connective tissue in artery
and arteriole walls
- Acute ischemic infarction
 Typical HUS
o Mostly occurs after intestinal infection with
strains of E. coli (O157:H7) that produce Shiga-
like toxins (also Shigella dysenteriae)
o Contaminated ground meat (also in drinking
water, raw milk, and person to person
transmission)
o Most at risk: children and older adults
o Prodrome of influenza or diarrhea → sudden
onset bleed (hematemesis, melena), severe
oliguria, hematuria
 Associated with microangiopathic hemolytic
anemia, thrombocytopenia, neurologic
changes, and hypertension
o Endothelial activation and apoptosis
 Atypical HUS
o >50% have an inherited deficiency of
complement regulatory proteins
 Most common: Factor H
- Breaks down C3 convertase to protect
cells from uncontrolled complement
activation
 Other: Factor I, CD46
o Other associated conditions
 Antiphospholipid syndrome
 Postpartum renal failure
 Renal vascular diseases
 Chemo and immunosuppressants
(mitomycin, cyclosporine, cisplatin,
gemcitabine, VEGF antagonists)
 Kidney irradiation
o Poorer prognosis due to underlying conditions
 TTP
o Pentad: fever, neurologic symptoms,
microangiopathic hemolytic anemia,
thrombocytopenia, and renal failure
o ADAMTS13 deficiency mostly due to
autoantibodies (some due to mutations)
o > in women, < 40 y/o
o Dominant feature: CNS involvement
 Renal involvement only in 50% patients
o Tx: plasma exchange
4. Other Vascular Disorders
o Atherosclerotic Ischemic Renal Disease
o Atheroembolic Renal Disease
 Embolization of atheromatous plaques from
aorta or renal artery into intrarenal vessels
 Occur especially after surgery
 Emboli – (+) cholesterol crystals appearing
as rhomboid clefts
 Commonly insignificant unless renal
function is already compromised
o Sickle Cell Nephropathy
 Disease – homozygous; trait – heterozygous
 Abnormalities: hematuria and decreased
concentrating ability (hyposthenuria)
 Sickling accelerated in the hypertonic
hypoxic milieu of the renal medulla
 Other possible findings: patchy papillary
necrosis, proteinuria
o Renal Infarcts
 Mostly due to embolism from mural
thrombosis in the LA and LV due to MI
(other sources: vegetative endocarditis,
aortic aneurysm, aortic atherosclerosis)
 Most often clinically silent, but sometimes
with CVA pain, RBC urine showers, and
hypertension if with arterial narrowing
 Morphology
- White anemic appearance due to lack
of collateral blood supply
- Within 24 h, infarcts become sharply
demarcated, pale yellow-white areas
that may contain small irregular foci of
hemorrhagic discoloration
- Usually ringed by a zone of intense
hyperemia
 - Wedge-shaped infarcts (base against
cortical surface and apex pointing
towards medulla)
- Progress to fibrous scarring →
depressed pale gray-white V-shaped
scars
IV. Congenital and Developmental Anomalies
 10% people are born with significant malformations
of the urinary system
 Hereditary or acquired during gestation
1. Agenesis of the Kidney
o Bilateral agenesis – incompatible with life; often
in stillborn infants and associated with other
congenital disorders
o Unilateral agenesis – rare; compatible with life if
without other abnormalities; undergoes
compensatory hypertrophy but some progress to
glomerular sclerosis, leading to CKD
2. Hypoplasia
o Failure of the kidneys to develop to a normal size
o Unilateral > bilateral
o True renal hypoplasia (no scars, < 6 pyramids)
observed in low-birth-weight infants and may
contribute to increased lifetime risk of CKD
3. Ectopic Kidneys
o Within the pelvis or just above the pelvic brim
o Usually normal or slightly smaller; otherwise
unremarkable except if with ureteral tortuosity
or kinking
 Obstruction to urinary flow → infection
predisposition
4. Horseshoe Kidneys
o Common (1 in 500-1000 autopsies); fusion of the
upper (10%) or lower (90%) poles – continuous
across the midline anterior to the great vessels
V. Cystic Diseases of the Kidney
A. Autosomal Dominant (Adult) Polycystic Kidney Disease
 Generalities
o Multiple expanding cysts of both kidneys that
ultimately destroy renal parenchyma and cause
renal failure
o 1 in 400-1000 live births
o 5-10% of ESRD cases – requiring RRT
o Both alleles of the involved genes have to be
nonfunctional for the disease to develop
o Bilateral; initially involve few nephrons (renal
function retained until 4th-5th decade of life)
 Genetics and Pathogenesis
o PKD1 and PKD2 mutation
 PKD1 gene
- Located on chromosome 16p13.3
- Encodes polycystin-1 – expressed in
tubular epithelial cells (distal nephron)
- Mutation in 85% cases
- Likelihood of developing renal failure
increases with aging
 PKD2 gene
- Located on chromosome 4q21
- < severe disease (older age of onset,
late development of renal failure)
- Polycystin-2 – expressed in all
segments of the renal tubules and in
many extrarenal tissues; Ca2+-
permeable cation channel
o Cilia-centrosome complex of tubular epithelial
cell defects (changes in mechanosensing, Ca 2+
flux, and signal transduction)
 Polycystin 1 and 2 are localized to the
primary cilium
 Altered tubular epithelial growth and
differentiation lead to abnormal ECM, cell
proliferation, and fluid secretion which
results to cyst formation
 Morphology
o Gross: kidneys are bilaterally enlarged (some can
weigh up to 4 kg)
o External surface appears to be composed solely
of a mass of cysts (3-4 cm d) with no intervening
parenchyma
 Microscopic exam reveals intervening
functional nephrons
o Cysts filled with clear serous fluid or turbid red-
brown hemorrhagic fluid
o Enlargement may lead to calyx and pelvis
encroachment, producing pressure defects
o Variable lining epithelia
 Clinical Features
o Asymptomatic until renal insufficiency develops
o In others, hemorrhage or dilation may produce
pain
o Blood clot excretion causes renal colic
o Enlarged kidneys on abdominal palpation –
dragging sensation
o Disease may begin with insidious onset
hematuria followed by other CKD features
o Progression > in blacks, sickle cell trait, males,
and hypertensives
o Extrarenal congenital anomalies
 40% have polycystic liver disease – often
asymptomatic; from biliary epithelium
 < cysts in spleen, pancreas, and lungs
 Intracranial berry aneurysms – altered
expression of Polycystin in vascular smooth
 muscle; at circle of Willis; SAH can cause
death
 Mitral valve prolapse in 20-25% patients
o Patients may survive for many years with
azotemia slowly progressing to uremia
Cause of Death % 
Heart disease 40
Infection 25
Ruptured berry aneurysm or 15
hypertensive ICH
B. Autosomal Recessive (Childhood) Polycystic Kidney
Disease
 Most commonly perinatal or neonatal presentation
o Serious manifestations MC present at birth
(death due to renal failure)
 Genetics and Pathogenesis
o MC PKHD1 mutation
 Chromosome 6p21-p23
 Highly expressed in adult and fetal kidney,
also liver and pancreas
 Encodes fibrocystin – also at primary cilium
of tubular cells
 Morphology
o Kidneys enlarged with a smooth external
appearance
o Cut section: numerous small cysts in the cortex
and medulla – spongelike appearance
o Dilated elongated channels are present at right
angles to the cortical surface
o Cylindrical > saccular dilation of collecting
tubules
o Cysts have a uniform lining of cuboidal cells
(originate from collecting ducts)
o Liver also has cysts – associated with portal
fibrosis and proliferation of portal bile ducts
 Clinical Features
o Patients who survive infancy may develop a
peculiar hepatic injury characterized by bland
periportal fibrosis and proliferation of well-
differentiated biliary ductules (congenital hepatic
fibrosis)
 Hepatic disease – predominant clinical
concern in older children (portal
hypertension with splenomegaly)
C. Cystic Diseases of the Renal Medulla
1. Medullary Sponge Kidney
o Multiple cystic dilations of the medullary
collecting ducts
o Occurs in adults; incidental finding
radiographically as renal function is normal
o Gross: papillary ducts dilated, +/- small cysts
 Lined by cuboidal > transitional epithelium
 (-) cortical scarring unless
superimposed pyelonephritis
2. Nephronophthisis
o Variable number of medullary cysts, MC
concentrated at corticomedullary junction
o Tubular BM disruption → tubular atrophy and
interstitial fibrosis
o Cause of eventual renal insufficiency: cortical
tubulointerstitial damage
o Variants
Sporadic non-familial
 Familial juvenile (MC) – AR
 Renal-retinal dysplasia
o MC genetic cause of ESRD in children and young
adults
o Present first with polyuria and polydipsia
 Also sodium wasting and tubular acidosis
o Can be syndromic
o Progresses to ESRD in 5-10 years
o Mutations: NPHP-1 to 11, JBTS-2, 3, 9, 11
 Proteins (+) in the primary cilia
 NPHP-2 – inversin – mediates L-R patterning
during embryogenesis
o Morphology
 Small kidneys – contracted granular
surfaces
 Medullary cysts
- Lined by flattened or cuboidal
epithelium
- Surrounded by inflammatory cells or
fibrous tissue
 Cortex: widespread atrophy and thickening
of tubular BM with interstitial fibrosis
 Glomerular structure preserved
D. Multicystic Renal Dysplasia
 Sporadic; kidney enlarged, irregular with varying cyst
size
o Lined by flattened epithelium
 Characteristic histology: presence of islands of
undifferentiated mesenchyme, often with cartilage,
and immature collecting ducts
 Most often associated with ureteropelvic obstruction,
ureteral agenesis or atresia
 Unilateral or bilateral
o Unilateral – mimic neoplasm; good prognosis
once removed as opposite kidney is normal
o Bilateral – renal failure later on
E. Acquired Cystic Disease
 Patients with ESRD who have undergone prolonged
dialysis develop numerous cortical and medullary
renal cysts
o 0.1-4 cm d, clear fluid, lined by hyperplastic or
flattened tubular epithelium, and contain
calcium oxalate crystals
o Form as a result of obstruction of tubules by
interstitial fibrosis or by oxalate crystals
o MC asymptomatic but seem bleed, causing
hematuria
o 100x increased risk of RCC
with F. Simple Cysts
 Single or multiple, MC at cortex; 1-5 cm but may
reach 10 cm
 Translucent, lined by gray glistening smooth
membrane and filled with clear fluid
 o Microscopic: membranes composed of 1 layer of
cuboidal or flattened cuboidal epithelium (may
be atrophic)
 Common post-mortem findings without clinical
significance
o Hemorrhage may cause sudden distension and
pain
o Calcification of hemorrhage may give rise to
bizarre radiographic shadows
 Difference from renal tumors: cysts have
smooth contours, often avascular, and give
fluid signals on UTZ
VI. Urinary Tract Obstruction (Obstructive Uropathy)
 Increased susceptibility to infection and stone
formation
o If unrelieved, leads to permanent renal atrophy
(hydronephrosis or obstructive uropathy)
o Often treatable
 Obstruction – sudden/insidious, partial/complete,
unilateral/bilateral, intrinsic/extrinsic, may occur at
any level; common causes:
o Congenital anomalies
o Urinary calculi
o BPH
o Tumors
o Inflammation
o Sloughed papillae / blood clots
o Pregnancy
o Uterine prolapse and cystocele
o Functional disorders
 Hydronephrosis – dilation of the renal pelvis and
calyces associated with progressive atrophy of the
kidney due to urine outflow obstruction
o Even with complete obstruction, GFR persists as
the filtrate subsequently diffuses back into the
renal interstitium and perirenal spaces –
VII.
returned to lymphatic and venous systems
 Continued filtration causes marked dilation
of affected calyces and pelvis
o High pressure at pelvis transmitted back through
collecting ducts into the cortex
 Renal atrophy
 Compression of medulla renal vasculature
o Tubular precedes glomerular defects
o Interstitial inflammation → fibrosis
 Morphology
o Sudden and complete obstruction → mild
dilation of the pelvis and calyces
o Subtotal or intermittent obstruction →
progressive dilation (hydronephrosis)
o Kidney may be slightly to massively enlarged
depending on degree and duration of
obstruction
o Progression
 Simple dilation of the pelvis and calyces
 Interstitial inflammation
 Cortical tubular atrophy with marked
diffuse interstitial fibrosis
 Progressive blunting of pyramidal apices
 Advanced: thin-walled cystic transformation
with striking parenchymal atrophy, total
obliteration of the pyramids, and cortical
thinning
 Clinical Features
o Acute obstruction – provoke pain attributed to
distention of the collecting system or renal
capsule
 Early sx MC d/t underlying cause (eg renal
colic with ureteral calculi, bladder sx with
BPH)
o Unilateral complete/partial hydronephrosis –
may remain silent for a long time as the
unaffected kidney can maintain adequate
function
 May be seen first on imaging incidentally
 UTZ – useful in the dx of obstructive
uropathy
o Bilateral partial obstruction
 Earliest manifestation: polyuria and
nocturia
 Some develop dTA, renal salt wasting,
secondary renal calculi, and chronic TIN
with scarring and atrophy of the papilla and
medulla
 Hypertension common
o Complete bilateral obstruction
 If rapid onset, results in oliguria/anuria –
incompatible with survival unless
obstruction is relieved
 With relief, post-obstructive diuresis occurs
(can be massive; urine rich in NaCl)
Urolithiasis
 Epidemiology
o Men > women, peak age of onset 20-30 y/o
o Familial predisposition (eg IEM – cystinuria,
primary hyperoxaluria)
 Etiology and Pathogenesis
o Main types of calculi
 Calcium (70%)
 Triple / struvite (15%) – magnesium
ammonium phosphate
 Uric acid (5-10%)
 Cystine (1-2%)
o An organic mucoprotein matrix is present in all
calculi (1-5% of stone weight)
o Most important determinant in stone formation:
urinary concentration of stone constituent –
exceed solubility (supersaturation)
 Other determinants: changes in urine pH,
decreased urine volume, presence of
bacteria, deficiency of inhibitors (eg
pyrophosphate, diphosphonate, citrate,
glycosaminoglycans, osteopontin,
nephrocalcin)
1. Calcium Oxalate stones
o 5%: hypercalcemia and hypercalciuria
(hyperparathyroidism, diffuse bone disease,
sarcoidosis)
o 55%: hypercalciuria without hypercalcemia
 Absorptive – hyperabsorption of calcium
from the intestine
 Renal – intrinsic impairment in renal tubular
reabsorption of calcium
 Idiopathic
o 20%: hyperuricosuric calcium nephrolithiasis
 Nucleation of calcium oxalate by uric acid
crystals in the collecting ducts
o 5%: hyperoxaluria
o Other associations
 Hypocitraturia
 Idiopathic calcium stone disease
o Radiopaque
2. Magnesium ammonium phosphate stones
o Formed mainly after infection by urea-splitting
bacteria (Proteus, staphylococci) – convert urea
to ammonia
o Alkaline urine causes precipitation of MAP salts
o Staghorn calculi formation common
3. Uric acid stones
o Common in hyperuricemia (gout, leukemia)
 However, > 50% patients with uric acid
calculi have neither hyperuricemia nor
increased urine excretion of uric acid
- Excrete urine at pH < 5.5
o Radiolucent
4. Cystine stones
o Genetic defects in renal reabsorption of amino
acids (including cystine) → cystinuria
o Form at low urine pH
 Morphology
o Unilateral in 80% patients
o Favored sites of formation: renal calyces, pelvis,
and in the bladder
o If formed in the renal pelvis, they tend to remain
small (2-3 mm)
o Smooth or irregular contour
o Often many stones are found within 1 kidney
o Rare: progressive accretion of salts lead to
development of branching structures – staghorn
calculi
 Create a cast of the pelvic and calyceal
system
 Clinical Features
o Asymptomatic or produce severe renal colic and
abdominal pain or may cause significant renal
damage
o Large stones – manifest as hematuria
o Stones predispose to superimposed infection
 Obstruction
 Trauma