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Kidney non-tumor
Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 6 May 2012, last major update May 2012 - IN PROGRESS
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.
Table of contents
Primary references, anatomy, congenital anomalies, embryology, glomeruli, physiology, tubules and interstitium, physiology, renal hormones, renal disease-general
Primary
glomerular diseases: biopsy-general, glomerular disease-general, pathogenesis, C1q, chronic glomerulonephritis, collapsing glomerulopathy, congenital nephrotic syndrome, diffuse mesangial hypercellularity with nephrotic syndrome, fibrillary GN, focal proliferative and necrotizing GN, focal and segmental GS, focal and segmental GS: HIV/IVDA, glomerular tip lesion, idiopathic nodular GS, IgA, immunotactoid, membranoproliferative GN, membranous GN, minimal change, post-infectious GN, rapidly progressive (crescentic) GN
Hereditary
renal disease: Alport’s syndrome, Bartter’s syndrome, collagen type III, Fabry’s disease, fibronectin, glutaric acidemia, glycogen storage disease, hereditary onycho-osteodysplasia, infantile nephropathic cystinosi, LCAT deficiency, lipoprotein, ochronosis, thin membrane disease
Infections/parasites: abscess, adenovirus, BK virus, CMV, Coccidioidomycosis, Dioctophyma renale, E coli, hantavirus, microsporidiosis, tuberculosis
Drug
related toxicity: adefovir, analgesics, chloroquine, cyclosporin A, gold, indinavir, NSAID, oxycodone, tacrolimus
Associated
with systemic conditions: amyloidosis, bone marrow transplant nephropathy, cryoglobulinemia, diabetic glomerulosclerosis, Henoch-Schonlein purpura, heavy chain deposition disease, HUS/TTP, light chain deposition disease, microscopic polyangiitis, myeloma, polyarteritis nodosa, preeclampsia, sarcoidosis, SLE/lupus, systemic sclerosis, Wegener’s granulomatosis
Tubular
and interstitial disease: general, acute allergic tubulointerstitial nephritis, acute pyelonephritis, acute tubular necrosis, chronic pyelonephritis, drug toxicity-general, , karyomegalic nephropathy, lead, malakoplakia, nephrocalcinosis, urate nephropathy, xanthogranulomatous pyelonephritis
Blood
vessel disorders: atherosclerotic, benign nephrosclerosis, diffuse cortical necrosis, emboli, hemosiderosis, infarct, malignant hypertension, renal artery stenosis, sickle cell, venous thrombi
Kidney
transplantation: general, hyperacute rejection, acute rejection, chronic rejection, Banff classification
Miscellaneous: dialysis, obstructive uropathy, radiation nephropathy, urolithiasis
top Primary Glomerular Diseases Focal proliferative and necrotizing
glomerulonephritis Only
parts of some glomeruli affected; proliferative, not sclerotic; also necrosis
and fibrin deposition Microscopic
to gross hematuria, occasionally with nephrotic syndrome Seen
early in systemic diseases (SLE, polyarteritis nodosa, Henoch-Schonlein
purpura, Goodpasture’s syndrome, endocarditis, Wegener’s granulomatosis); may
be part of IgA nephropathy or idiopathic Micro
images: focal
necrotizing and crescentic glomerulonephritis IgA nephropathy (Berger’s disease) A type
of diffuse mesangioproliferative glomerulonephritis (also Henoch-Schonlein
purpura, SLE, IgM nephropathy, resolving stage of postinfectious
glomerulonephritis) IgA in
mesangium and elevated serum IgA Most
common form of primary glomerulonephritis worldwide; causing 10% of cases of
end stage renal failure in many countries Common
at ages 10-29 years, usually males, who present with gross or microscopic
hematuria after respiratory infection, but no systemic disease More
common in southern Europe, Asia, Native Americans Slowly
progressive: 25%-50% have renal failure at 20 years; recurs in 20-60% of
allografts IgA
immune complexes are deposited in mesangium, activate alternative complement
pathway IgA
deposits also present in Henoch-Schonlein purpura; diseases may be related Secondary
disease: associated with gluten
enteropathy (celiac disease), liver disease, dermatitis herpetiformis (Archives
1983;107:324) Poor
prognosis: prominent arteriolar
hyalinization, older age, heavy proteinuria, hypertension Case
reports: death due to pulmonary
hemorrhage (Archives
1994;118:542) Micro: diffuse proliferation of mesangial cells and matrix
without significant involvement of capillary walls or lumina; mesangial
involvement is often uneven and resembles focal and segmental
glomerulosclerosis; normal or hypercellular glomeruli with diffuse necrotizing
crescentic glomerulonephritis Micro
images: (1) various images
including EM; (2) mild mesangial
expansion; (3) granular
mesangial staining for IgA Immunofluorescence: IgA, often IgG and C3 in mesangium; IgA also in
capillaries of dermis, lung, liver, intestine EM: electron dense deposits in mesangium of all
glomeruli EM
images: electron dense
deposits in mesangium DD: mesangial IgA deposition associated with obstructive
jaundice (Hum
Path 1987;18:1149) Rare,
<1% of renal biopsies More
common in whites and females Patients
have monoclonal immunoglobulin deposition in glomeruli and may have circulating
paraproteins Related
to fibrillary glomerulonephritis, but different fibril size and arrangement May
overlap with hepatitis C virus-induced cryoglobulinemic glomerulonephritis Associated
with nephrotic syndrome 33% of
patients with (vs. 7% without) circulating or urinary paraproteins have
lymphoproliferative disorders Poor
long term survival Diagnosis: based on EM findings Case
reports: 59 year old woman with
proteinuria, immunotactoid glomerulopathy, heavy chain disease and follicular
lymphoma (Archives
2004;128:689) Micro: mesangial widening and occasional hypercellularity,
capillary wall thickening; 25% have crescents Micro
images: (1) various
images including EM; (2) 1-basement
membrane thickening with focal and segmental glomerular hypercellularity; also
segmental endocapillary proliferation and expansion of mesangial matrix;
2-thickening of glomerular capillary walls (PAS); 3-basement membrane spikes in
some glomerular capillaries (silver stain); 4-monoclonal IgG band by serum
immunofixation; 5-EM shows 34 nm, randomly arranged subepithelial deposits;
6-EM shows subepithelial deposits Negative
stains: Congo red, thioflavin T Immunofluorescence:
variable IgG, C3; occasional IgM,
IgA EM: extracellular, nonamyloid deposits 30-50 nm wide,
focally arranged in parallel arrays and with a visible lumen (microtubules),
usually within mesangium but also involving basement membrane EM
images: 30-40 nm tubular arrays,
no cryoglobulinemia Membranoproliferative
glomerulonephritis Also
called hypocomplementemic (C3), lobular or mesangiocapillary / mesangiopathic
glomerulonephritis Alterations
in basement membrane and proliferation of mesangial cells Intermittent
remissions but overall downhill course Not a
pure entity, as type I and II appear to have different etiologies Type
I: CLASSICAL (2/3) 5% of
cases of glomerulonephritis affecting children and young adults Immune
complex deposition and activation of classical and alternative complement
pathway Typically
presents with nephrotic syndrome and hypertension in patients 8-16 years old;
less commonly nephritis Also
associated with Staphylococcus epidermidis infection with
ventriculoatrial or ventriculojugular shunts 2/3
have persistent decrease in serum C3 due to its hypercatabolism Secondary
disease occurs with chronic immune complex disorders (SLE, hepatitis B/C, HIV,
schistosomiasis), alpha-1-antitrypsin deficiency, malignancies May
cause high rates of non-diabetic end stage renal disease in Navajo Indians in
US (Archives
1989;113:158) Micro: large glomeruli with accentuation of lobules;
irregular thickening of glomerular basement membrane by interposition of
mesangial cells between endothelium and basement membrane; causes tram
track/double contour appearance (PAS or silver stain), crescents in 20%;
neutrophils often present; may have hyaline aggregates of immune complexes in
capillary lumina Micro
images: (1) hypercellular
glomeruli with accentuated lobules #1; #2; (3) tram track cappilary
loops with silver stain; (4) series
of images including EM #1; #2;
(6) IgG and C3
granular immunofluorescence of capillary loops and mesangium; (7) globular
immunofluorescence due to mixed cryoglobulinemia; (8) with
hepatitis B related disease, showing duplication of capillary wall and
tram-track appearance Immunofluorescence: lumpy bumpy (granular) for C3, IgG, early complement
(C1q, C4) EM: subendothelial and mesangial electron-dense
deposits, increased mesangial matrix, mesangialization of capillary loops, foot
process fusion EM
images: (1) splitting
and reduplication of basement membrane; (2) series of
images Type
II: DENSE DEPOSIT (1/3) Dense
deposits in glomerular basement membrane Familial
or associated with partial lipodystrophy (loss of subcutaneous fat from fat and
upper body) Apparent
activation of alternative complement pathway 60-70%
have antibody to C3 nephritic factor (stabilizes C3 convertase; promotes C3
degradation) Tends
to present with nephritis more than nephrotic syndrome Poorer
prognosis than type I; 50% have renal failure in 10 years 80-100%
recur after renal transplant Also
deposits in basement membranes of spleen, choroid, Bruch’s membrane of retina Micro: similar to type I, but less prominent cellular
proliferation; strongly PAS+, eosinophilic, refractile and ribbon-like
thickening of glomerular basement membrane, also basement membrane of Bowman’s
capsule and tubules Micro
images: moderate cellularity
and lobular accentuation (left), normal (right); thickening of basement
membrane (left) and capillary wall (right); various
images including EM Immunofluorescence: linear or double contoured C3 and properdin staining
of glomerular capillary walls and bright nodular or ringlike reaction in
mesangium, NOT in dense deposits; usually no immunoglobulins Immunofluorescence
images: (1) fluorescence
microscopy shows deposits corresponding to immune complexes along glomerular
basement membrane, (2) IgG
in glomerular capillary loops; (3) fluorescent
ribbons of variable thickness seen along glomerular capillary loops (arrows);
(4) intense C3
staining EM: dense deposits in lamina densa of glomerular
basement membrane, Bowman's capsule, spleen, causes long ribbon of hazy
material; also nodular deposits of similar material in mesangium EM
images: (1) ribbon-like
dense deposits within glomerular basement membrane #1; #2; (3) glomerular basement
membrane and mesangial deposits; (4) large
subendothelial electron dense deposit along glomerular basement membrane References: Mod
Path 2002;15:988 Type
III: MIXED (rare) Two
morphologic subtypes that are clinically similar to each other and to type I
membranous glomerulonephritis Type
III-Burkholder variant Combined
features of type I membranoproliferative glomerulonephritis and membranous
glomerulonephritis EM:
subendothelial and subepithelial
deposits and mesangial interposition associated with basement membrane spikes Type
III-Anders variant Hybrid
of type I and II membranoproliferative glomerulonephritis EM: massive accumulation of deposits within basement
membrane with membranous disruption, highlighted by silver stain Most
common cause of nephrotic syndrome in adults (40%); 5% of cases in children Diffuse
glomerular wall thickening due to in situ immune complexes (electron dense) in
glomerular basement membrane but NOT in mesangium 75% of
adult and 20% of childhood cases are idiopathic autoimmune disease linked to
HLA, caused by antibodies to a renal autoantigen Considered
the human model of Heymann nephritis, which in rats is produced by antibody to
megalin antigen complex on basal surface of visceral epithelial cells (megalin
is homologous to LDL receptor) Secondary
cases are associated with cancer (lung, colon, melanoma), hepatitis B/C,
malaria, schistosomiasis, drugs (penicillamine, captopril, gold, NSAID), heavy
metals, lupus, diabetes, thyroiditis, angiofollicular lymph node hyperplasia (Archives
1979;103:591) Proteinuria
may be due to C5b-C9 (MAC complex of complement) With
progression, get membrane thickening, narrow capillary lumina, mesangial
sclerosis, glomerulosclerosis Proximal
convoluted tubules contain hyaline droplets, reflecting protein reabsorption Rarely
tubulointerstitial nephritis due to anti-tubular basement membranes, usually
progressive to end stage renal failure, usually affects male children Hepatitis
B cases resemble lupus nephritis class V, but are HepB+ and lack SLE’s
extrarenal manifestations and autoantibodies (Mod
Path 2000;13:166) Clinical
course: insidious onset of nephrotic
syndrome, occasionally hematuria and hypertension; must rule out and treat
secondary causes; 10% die or develop renal failure in 10 years (40% eventually
develop renal failure); variable course of disease makes it difficult to
evaluate therapy; EM stages II-IV below have similar prognosis Micro: early-normal; later-uniform
diffuse capillary wall thickening without hypercellularity, without mesangial
sclerosis, without inflammatory cells Micro
images: thickened
glomerular capillary loops; (2) silver stain
shows basement membrane spikes; (3) diffuse
granular immunofluoresence for IgG; (4) early stage with subtle
changes; (5) later
stage with markedly thickened capillary walls; (6) series of
images, including EM; (7) early disease- A:
light microscopy shows slightly thickened glomerular capillary loops but no
immune complex deposits; B: fluorescence microscopy shows immune complex
deposits along glomerular basement membrane which appear as beads on a string;
(8) IgG
deposits; (9) late disease A:
light microscopy shows markedly thickened glomerular capillary loops, but no
immune complex deposits; B: fluorescence microscopy shows large deposits
corresponding to immune complexes Virtual
slides: membranous
glomerulonephritis Immunofluorescence: granular diffuse peripheral deposits, usually IgG
and C3, also C5b-C9, occasionally IgM or IgA EM
stages: Stage
I: Scattered subepithelial electron
dense deposits, normal glomeruli by light microscopy Stage
II: Spike and dome; deposits (dome)
covered by glomerular basement membrane material (spikes); extensive
obliteration of foot processes Stage
III: Deposits become intramembranous
as spikes close over immune deposits Stage
IV: Dissolution of deposits (by
macrophages, mesangial cells) with rarefaction and irregular glomerular
basement membrane thickening; associated with severe tubular atrophy and
vascular sclerosis EM
images: (1) stage II deposits;
(2) intramembranous
deposits; (3) other images;
(4) stage
I with electron dense deposits along glomerular basement membrane, (5) hepatitis
B with subepithelial and mesangial electron dense deposits (M) and fusion of
epithelial foot processes (arrows) References: Mod
Path 2002;15:988 Also
called minimal change disease, nil disease, lipoid necrosis, foot process
disease Causes
80% of cases of nephrotic syndrome in children (usually ages 2-6), 20% in
adults Extensive
foot process "fusion" appears to be due to epithelial injury with
loss of glomerular anionic charge "Fusion"
is actually simplification of epithelial architecture with flattening,
retraction and swelling of foot processes; also seen in membranous
glomerulopathy and diabetes; reverts to normal with remission Associated
with respiratory infections, immunizations, lead or mercury ingestion,
allergies, acute interstitial nephritis, Hodgkin’s lymphoma; in elderly,
associated with NSAIDs Clinical: nephrotic syndrome, selective for albumin, often
with severe edema or proteinuria, but with minimal microscopic glomerular
alterations and usually no hypertension, no hematuria, no azotemia Note:
minimal change disease, diffuse mesangial hypercellularity and focal and
segmental glomerulosclerosis may be a continuum of the same disease. Case
reports: intravascular B cell
lymphoma of kidney associated with minimal change disease (Hum
Path 1989;20:263), Treatment: 90% of children respond to steroids initially (foot
processes return to normal), may require immunosuppression, <5% develop
renal failure after 25 years; some children become steroid dependent/resistant,
but this usually resolves at puberty Older
adults with hypertension and severe proteinuria have a higher risk of
reversible renal failure May
develop nephrocalcinosis due to hypercalciuria from chronic furosemide use (Hum
Path 2000;31:1363) Micro: normal glomeruli, tubules have lipid droplets due to
reabsorption of lipoproteins that leak from glomeruli ("lipoid
nephrosis") Micro
images: normal
appearing glomeruli #1; #2 Positive
stains: albumin in proximal tubular
epithelial cells Immunofluorescence: negative EM: extensive foot process effacement (foot processes
retract into cell bodies, not actually fusion); microvillous transformation of
epithelial cells, cyst formation EM
images: foot
process effacement #1; #2; #3; #4 DD: focal and segmental glomerulosclerosis (tubular
atrophy and interstitial scarring) Post-infectious glomerulonephritis Also
called post-streptococcal or acute glomerulonephritis; a type of diffuse
endocapillary proliferative glomerulonephritis Deposition
of immune complexes from antibodies against organisms elicits acute
inflammatory response and nephritic syndrome Associated
with nephritogenic strains of Streptococcus pyogenes (beta hemolytic
Strep group A); similar histologic findings also associated with endemic
malaria, toxoplasmosis, hepatitis B/C, HIV, varicella, spirochetes,
staphylococci, meningococci, other bacteria Similar
process occurs in response to endogenous antigen in SLE Post-streptococcal
disease is decreasing in US, where post-Staphylococcal aureus infection
is more frequent, but is common elsewhere Children
age 6-10: abrupt onset of hematuria,
oliguria, fever, malaise and nausea 1-4 weeks after strep infection of pharynx
or skin (impetigo); RBC casts, proteinuria, periorbital edema, hypertension 95%
recover with conservative therapy; 1% develop rapidly progressive
glomerulonephritis, 1-2% develop chronic glomerulonephritis; poor prognosis
more likely if massive proteinuria and abnormal GFR; 2-5% die from pulmonary
edema, hypertensive encephalopathy, crescentic glomerulonephritis Adults: may have atypical presentation with sudden
hypertension, edema, elevated BUN; 60% recover, others develop rapidly
progressive glomerulonephritis Laboratory
(children and adults): high
antistreptococcal antibody titers, low C3 (due to consumption) Micro: glomeruli are globally and diffusely enlarged and
hypercellular due to neutrophils and macrophages and proliferation of mesangial
and endothelial cells; swelling of endothelial cells and presence of
inflammatory cells obstructs capillary lumina; returns to normal within months Micro
images: markedly
hypercellular glomeruli due to neutrophils #1; #2;
(3) lumpy
bumpy (granular) or starry scar immunofluoresence; (4) various
images including EM; (5) A:
light microscopy shows glomerular lobular accentuation, endocapillary cell
proliferation and neutrophils, but no immune complexes; B: fluorescence
microscopy shows deposits corresponding to immune complexes bulging from outer
surfaces of glomerular capillary loops (2002;15:988, #12) Immunofluorescence: lumpy-bumpy (granular) deposition of IgG, IgM and C3
in peripheral glomerular loops; also properdin; no C1q or C4 EM: subepithelial humps (finely granular, dome-shaped,
electron dense, representing immune complex deposits), obliteration of
epithelial cell foot processes Subclinical Typical
immune complex deposition of clinical disease, but with minimal symptoms or
urinary abnormalities Important
to recognize, since present in 10% of renal biopsies (Hum
Path 2003;34:3) Rapidly progressive (crescentic)
glomerulonephritis Also
called extracapillary proliferative glomerulonephritis, because cell
proliferation is primarily in Bowman’s space Crescents
are end result of damage to glomerular basement membrane or Bowman's capsule;
due to deposition of fibrin, epithelial cells and inflammatory cells; may have
various causes Crescents
affect 50% of glomerular circumference, 70% of glomeruli Rapid,
usually irreversible loss of renal function associated with severe oliguria and
hematuria, unresponsive to steroids Symptoms
of nephritic syndrome, nephrotic syndrome and renal failure Causes
death within weeks if untreated Case
reports: after Hepatitis B infection
(Mod
Path 1992;5:262) Gross: enlarged, pale kidneys with cortical petechial
hemorrhages Gross
images: (1) large
pale kidney with smooth surface; (2) pale
and swollen cortex Micro: crescents in glomeruli are proliferation of parietal
epithelium of Bowman’s capsule with macrophages, neutrophils, lymphocytes,
fibrin, collagen; also see glomerular capillary collapse, atrophic tubules,
interstitial inflammation Micro
images: cellular
crescent; (2) crescents
due to lupus; (3) immunofluorescence
demonstrates fibrinogen Virtual
slides: numerous
crescents EM: wrinkling and focal disruptions in glomerular
basement membrane DD: fibrillary glomerulonephritis (20-30 nm fibrils in
glomeruli by EM) 3 subtypes based on immunofluorescence and EM TYPE
1: Anti-glomerular basement membrane antibody crescentic glomerulonephritis
(15%) Goodpasture’s
syndrome: antibody to alpha 3 chain
of type 4 collagen (part of noncollagenous domain) in lung alveolar basement
membrane; associated with smoking and HLA-DRB1 Usually
young adult males with pulmonary involvement or age 50+ women limited to kidney Pulmonary
hemorrhage present, treated with plasmapheresis, steroids, cytotoxic agents Most
cases of Goodpasture’s are associated with rapidly progressive
glomerulonephritis; but only 50% have both renal and pulmonary syndromes Laboratory: 1/3 have circulating anti-neutrophil cytoplasmic
antibodies (ANCA), especially ANCA specific for myeloperoxidase Case
reports: coexisting vasculitis (Archives
1980;104:300) Micro: hypercellular glomeruli, crescents, variable
neutrophils, no/rare intracapillary cell proliferation Micro
images: (1) various
images; (2) diffuse
linear staining for IgG Immunofluorescence: diffuse linear staining of glomerular basement
membrane, IgG > IgM, also C3 and focal fibrin in capillary loops EM: no deposits; fibrin at glomerular basement membrane
breaks DD
(based on clinical presentation):
microscopic polyarteritis, Wegener’s granulomatosis; similar immunofluorescent
findings in diabetic nephropathy, SLE TYPE
2: Immune complex crescentic glomerulonephritis (35%) Immune
complex deposition with complement activation due to postinfectious
glomerulonephritis, types I and II membranoproliferative glomerulonephritis,
cryoglobulinemic glomerulonephritis, SLE, IgA nephropathy, Henoch-Schonlein
purpura, idiopathic Usually
children Must
treat underlying disease; plasmapheresis NOT helpful Micro: depends on underlying glomerular disease;
mild-moderate necrosis of glomerular segments adjacent to crescents, less than
types 1 or 3; various combinations of capillary wall thickening and
endocapillary cell proliferation Immunofluorescence: lumpy bumpy for IgG and C3 (like postinfectious) EM: immune complex deposits as subepithelial humps or
mesangial deposits, fibrin at glomerular basement membrane breaks TYPE
3: Pauci-immune crescentic glomerulonephritis (50%) No
anti-glomerular basement membrane antibodies, no immune complexes Usually
elderly Either
limited to kidney or associated with clinical vasculitis (Wegener’s
granulomatosis, microscopic polyarteritis) Often
have serum C-ANCA (against proteinase 3; associated with Wegener’s) or P-ANCA
(against myeloperoxidase; in those without extrarenal vasculitis); those with
microscopic polyarteritis have either Better
prognosis than type 1 Micro:
resembles type 1 Immunofluorescence: Ig negative, possibly C3 and fibrin/fibrinogen with
crescents EM: same as type 1 (no deposits, fibrin at glomerular
basement membrane breaks) Hereditary nephritis Also
called hereditary nephritis Nephritis,
subtle nerve deafness (55%, apparent in adults) and eye disorders in 15-30%
(anterior lens dislocation, posterior cataracts, corneal dystrophy) due to
defects in collagen IV synthesis affecting basement membranes Incidence
of 1 per 5-10,000 in US The
cause of end stage renal failure in 2.5% of children and 0.3% of adults in US Ages
5-20 years, usually males, with gross or microscopic hematuria, red blood cell
casts, often mild proteinuria, progressive loss of renal function; more likely
to progress to renal failure in males Rate
of progression to end stage renal disease and deafness are mutation dependent,
and each kindred reported has different mutations Juvenile
variant: end stage renal disease
develops in males before age 31 years; clinical course similar among all
patients Adult
variant: end stage renal disease
develops in males after 31 years; variable clinical course Pathogenesis: X linked form (80%) due to mutations in alpha 5 gene
at Xq22 coding collagen type IV, a component of glomerular basement membrane
which interferes with its suprastructure, reducing production of alpha 3
(Goodpasture’s antigen) and alpha 4; some X linked patients also have diffuse
leiomyomatosis Also
autosomal recessive (mutations in collagen type IV alpha 3 or alpha 4 genes,
males and females have similar prognosis), and possibly autosomal dominant
forms Screening: segmental glomerular basement membrane staining is
suggestive Case
reports: development of
anti-glomerular and anti-tubular basement membrane antibodies after renal
transplant (Archives
1994;118:728) Treatment: kidney transplant; 3-4% of males develop
anti-glomerular basement membrane nephritis, usually due to antibodies to NC1
domain of alpha 5 chain of type IV collagen Micro: early - segmental proliferation or
sclerosis of glomeruli, increased mesangial matrix; may see fetal type
glomeruli, foam cells in glomeruli or tubules; late -
glomerulosclerosis, tubular atrophy Micro
images: (1) foamy
renal tubular cells; (2) immunofluorescence
for alpha 3, 4 and 5; (3) various
images, including EM Immunofluorescence: negative or segmental staining for alpha 3, 4 and 5
collagen in glomerular basement membrane (normals have strong continuous
staining), negative for alpha 5 collagen in skin biopsies (positive in normals)
EM:
irregular thickening and thinning of glomerular basement membrane with
splitting and lamination of lamina densa and granular inclusions; children and
women may have only thin glomerular basement membranes without other
alterations DD:
resolving stages of membranous
glomerulonephritis, familial thin glomerular basement membrane (GBM) disease
(positive staining with anti-GBM antibodies, negative in Alport’s syndrome) References:
Hum
Path 2002;33:836; Hum
Path 1998;29:404 (alpha5 staining in X linked female patients); article
about Dr. Alport Rare,
<150 cases reported Hypokalemia,
metabolic alkalosis, hyperaldosteronism, growth retardation, normal blood
pressure but with blunted pressor response to exogenous angiotensin II; also
polyuria, impairment of concentrating ability, increased renin, angiotensin II
and prostaglandins Due to
primary molecular defect in NaCl reabsorption in thick ascending limb of
Henle’s loop; causes increased delivery of NaCl to distal and collecting
tubules, which promotes increased potassium and acid secretion in collecting
tubules; also associated with salt wasting and volume depletion, causing renin
secretion and increased serum angiotensin II and aldosterone, further
stimulating potassium and acid secretion, causing hypokalemia and acidosis;
lack of NaCl reabsorption is associated with lack of calcium reabsorption Neonatal
type: more severe, presents with
polyhydramnios due to intrauterine polyuria; also high urinary calcium,
nephrocalcinosis, severe failure to thrive, marked growth retardation Classic
type: develops during first months
or years with failure to thrive, dehydration, growth retardation, at most mild
hypercalciuria, no significant nephrocalcinosis Treatment: difficult, large doses of oral KCl with
spironolactone, possibly ACE inhibitors, indomethacin Micro: hyperplasia of juxtaglomerular apparatus EM: epithelioid cells associated with afferent and
sometimes efferent arterioles, with prominent Golgi complexes and secretory
granules, some rhomboidal; also immature glomeruli in children,
nephrocalcinosis DD: high dose loop diuretics, conditions causing severe
GI potassium chloride loss (have low chloride levels) References: EMedicine.com Collagen type III glomerulopathy Also
called primary glomerular fibrosis, collagenofibrotic
glomerulopathy Autosomal
recessive and sporadic, due to deposition of type III collagen, normally absent
in kidneys Either
gender, variable age Children
present with increasing proteinuria and nephrotic syndrome, hypertension,
progressive renal failure, and possibly hemolytic uremic syndrome Adults
have indolent course Micro:
diffuse increase in mesangial
matrix, generalized widening of glomerular capillary walls Micro
images: various
images including EM Immunofluorescence: strong anti-collagen type III staining in capillary
loops and mesangium (normally absent in kidneys); negative or focal IgM
deposition EM: large accumulation of collagen fibrils in
subendothelial glomerular basement membrane and mesangial matrix DD: hereditary onycho-osteodysplasia (has
ultrastructural similarities) References:
Pediatr
Nephrol 1993;7:354 Also
called alpha-galactosidase A deficiency, angiokeratoma corporis diffusum
universale X
linked (Xq22.1) recessive lysosomal storage disease that affects 1 per 40,000 Highly
penetrant in hemizygous males with symptoms at infancy or childhood; later age
of presentation in heterozygous females, who usually have more variable
severity due to variable lyonization of X chromosome and may have normal
leukocyte alpha-galactosidase A activity Due to
deficiency in lysosomal alpha-galactosidase A, which catabolizes neutral
glycosphingolipids Deficiency
causes intracellular accumulation of galabiosylceramide (ceramide trihexoside)
and digalactosyl ceramide within skin, renal glomeruli, renal tubular
epithelium, blood vessels, corneal epithelium, myocardium and ganglion cells Clinical
symptoms include angiokeratomas on skin of abdomen, buttocks, lips, genitalia,
upper thighs; also hematuria and proteinuria progressing to renal failure,
corneal dystrophy, recurrent shooting pains in legs Death
due to renal, cardiac or cerebrovascular disease at age 40+ Case
reports: atypical variant, limited
to heart or kidney abnormalities, diagnosed by renal biopsy for proteinuria (Archives
1996;120:86), 42 year old woman
with persistent proteinuria (Archives
1985;109:89), atypical variant
with accumulation in heart, not kidney or liver (Hum
Path 1990;21:1067), Diagnosis: low blood or urine levels of alpha-galactosidase by
enzymatic assay (may be normal in female heterozygotes), elevated ceramide
trihexoside in urine by thin layer chromatography and immunostains for ceramide
trihexoside; in women, must perform DNA mutation analysis of
alpha-galactosidase A gene to exclude carrier state Treatment: recombinant human alpha-galactosidase A replacement
therapy Micro
(kidney): enlarged and vacuolated
visceral epithelium, parietal epithelium, mesangial cells, endothelial cells, vascular
smooth muscle, distal tubular cells; narrowing and thrombosis of arteries and
arterioles Micro
images: (1) various
images including EM; (2) figure
1: vacuolar change in renal tubular cells with large nodular aggregates of foam
cells; 2: enlarged glomeruli due to segmental vacuolar changes in visceral
epithelial cells; 3: strong oil-red-O staining of vacuolated cells; 4: EM shows
abundant whorled lamellated electron dense myelin-like bodies lined by single
membranes; various images
including EM Positive
stains: PAS, oil red O, Sudan black,
Luxol fast blue (stain glycolipid and phospholipid-like material) Immunofluorescence: negative EM: characteristic single membrane bound intracellular
inclusions (myelin-like figures, zebra bodies), that are 0.1 to 10 microns in
diameter, round and lamellated with concentric electron dense layers, found in
endothelial and smooth muscle cells, myocardium, fibroblasts and glomerular
epithelium; also urine sediment (Archives
1981;105:361) EM
images: lamellated
lipid inclusions of visceral epithelial cells DD
(foam cell change): Gaucher’s
disease, gangliosidoses, fucosidosis, mucopolysaccharidoses (all have different
intracellular distribution and ultrastructural features of inclusions, can
detect by laboratory assays), treatment with chloroquine, amiodarone or
aminoglycosides (have similar myelin-like figures, Hum
Path 2003;34:285) References: Archives
1980;104:17 Massive
fibronectin deposition in glomeruli Autosomal
dominant, non sex linked, due to 1q32 abnormality (Am
J Hum Genet 1998;63:1724) Proteinuria,
often nephrotic syndrome, microhematuria, hypertension, progressive loss of renal
function May
recur after renal transplant Micro: lobular accentuation of glomeruli with minimal
hypercellularity; marked enlargement of mesangium and subendothelial space due
to massive deposition of fibronectin (PAS+, Congo red negative homogenous substance) Micro
images: lobular
accentuation of glomeruli Immunofluorescence: strongly positive for fibronectin, scanty
immunoglobulin or complement deposition EM: fibronectin has dense granular appearance with 12-16
nm fibrils References: OMIM %601894 Metabolic
disorder due to deficiency of flavoprotein or its oxyreductase Acidosis,
nonketotic hypoglycemia, hyperammonemia, dysmorphic facial features, urinary
organic acidemia, “sweat sock” odor May
have lipid accumulation in liver, heart and renal tubular epithelium Micro: subcortical renal glomerular cysts, renal medullary
dysplasia EM: cytoplasmic, homogenous, moderately electron dense
bodies with a limiting membrane References: Archives
1986;110:399, Archives
1988;112:1133 Type
I: thickening, lamellation and
glycogen deposition in glomerular basement membrane References:
Archives
1988;112:271 Hereditary onycho-osteodysplasia Also
called nail-patella syndrome, Turner-Keiser syndrome, Fog’s syndrome 1 per
50,000 live births Uncommon,
autosomal dominant Fingernail
aplasia or dysplasia (especially first fingers), patellar absence or
hypoplasia, subluxation of radial head and iliac horns Renal
involvement in 30-55%, usually asymptomatic proteinuria but may progress to
renal failure Due to
point mutations in LMX1B gene at 9q34, also 17q21-22 Treatment: transplant if severe kidney disease Micro: focal thickening of glomerular capillary walls,
variable sclerotic glomeruli EM: irregular thickening of glomerular basement membrane
with moth eaten electron-lucent areas; also collagen-like fibers in electron
lucent area and in mesangium Infantile nephropathic cystinosis Lysosomal
storage disease causing kidney disease Case
reports: crystalline histiocytosis
in patient post-kidney transplant (Archives
2002;126:1135), in renal
allograft, dark cells present in interstitium, rarely glomeruli or tubular
lumina, due to dark, granular material in cytoplasm, nucleus and cytoplasmic
inclusions of macrophages (Hum
Path 1989;20:472) Treatment: kidney transplant References: OMIM
#219800 Lecithin-cholesterol acyl
transferase deficiency Associated
with nephrotic syndrome Case
reports: two affected brothers (Mod
Path 1991;4:331) Micro: bubbly thickening of glomerular basement membrane in
membranous pattern, mesangial sclerosis, foamy macrophages in capillaries and
mesangium EM: small, solid, thread-like or lamellar dense
structures in empty-appearing lacunae Rare
genetic disorder of lipid metabolism 2/3
male, often Japanese, wide age range (2 weeks to 69 years) Present
with heavy proteinuria, usually in adults 50%
progress to renal failure Usually
no systemic manifestations of hyperlipidemia Treatment: none; often recurs in transplants Micro: lipoprotein thrombi (containing apolipoprotein apo
E, usually E2) EM: characteristic lamellar accumulations of variably
sized lipid droplets Autosomal
recessive disorder of increased urinary excretion of homogentisic acid
(alkaptonuria), with deposition of “ochre-colored” pigment in collagen-rich
regions Occurs
in 50% with alkaptonuria Due to
disorder of gene on #3q of homogentisic acid oxidase, intermediate component in
metabolism of tyrosine and phenylalanine, causing accumulation of benzoquinone
acetic acid, which binds to collagen irreversibly Clinically
black pigmentation of joints (arthritis with pigment deposition in cartilage
and intervertebral disks), cardiovascular system (valvular calcifications and
stenosis), kidney (black urine, pigmented stones) and skin (cutaneous
pigmentation); also involvement of sclera of eye Case
report of pigment in dura matter of brain (Archives
2001;125:961) Thin glomerular basement membrane
disease / lesion Also
called benign familiar hematuria Hereditary,
often autosomal dominant 5-9%
of general population, rare after age 50; 20-25% with isolated hematuria Asymptomatic,
hematuria discovered on routine urinalysis; mild proteinuria in 60% Normal
renal function, excellent prognosis, but up to 30% develop late-onset renal
insufficiency or hypertension A
diagnosis of exclusion Pathogenesis: associated with abnormalities in alpha 3 and alpha 4
genes for type IV collagen; most are heterozygous; in homozygotes, resembles
Alport’s disease and progresses to renal failure, even in women Micro: red blood cells in Bowman’s space and renal tubules,
but otherwise normal Micro
images: (1) various
images including EM; (2) strong
staining for alpha 3-5, in comparison to Alport’s syndrome IM: strong linear glomerular basement membrane staining
for alpha 3 and 4 protein (similar to normals), positive antibody staining to
NC1 domain of glomerular basement membrane from patients with thin basement
membrane disease; occasional IgM and IgG deposits EM: uniform thinning of lamina dense of glomerular
basement membrane to 200 nm; occasionally ruptures; no thickening, lamellation
or inclusions of glomerular basement membrane EM
images: diffusely
thin glomerular basement membranes DD: Alport’s syndrome in women without typical clinical
findings (has thick glomerular basement membrane, lamellation, granular
inclusions, loss of staining for alpha 3 and alpha 4 protein); IgA nephropathy References: Archives
2001;125:631, Hum
Path 2002;33:836, Archives
1988;112:794 Infections/parasites Due to
ascending infection (see acute pyelonephritis, below)
or hematogenous Gross
images: abscess; cortical
microabscesses; microabscesses
in cut surface May
cause necrotizing tubulointerstitial nephritis with hemorrhagic cystitis or
prostate involvement Associated
with bone marrow transplant recipients and chemotherapy Micro: hemorrhage and necrosis; tubulitis with intranuclear
inclusion bodies, either smudge cells, Cowry A intranuclear inclusions or
full-type intranuclear-containing cells EM: intranuclear crystalline arrays of 75-80 nm viral
particles References: Hum
Path 1991;22:1225 Polyomaviruses
are nonenveloped DNA viruses, 45 nm in diameter; members of papovavirus family,
which also contain papillomavirus Polyomavirus
BK is widely present in healthy individuals, but latent in kidneys, central
nervous system and B cells Other
polyoma viruses are JC (causes progressive multifocal leukencephalopathy) and
SV40 (causes subclinical infections) Immunosuppression
promotes reactivation of latent polyoma virus, leading to viral replication in
renal tubular epithelial cells; BKV strain of polyoma virus may cause renal
failure in AIDS patients (confirm by PCR), is reactivated in <8% of renal
transplant patients with heavy immunosuppression or rarely in other
immunosuppressed patients Associated
with interstitial nephritis, infection of glomerular epithelial cells and
crescents (minority of cases) JC
virus strain of polyoma virus usually not associated with renal damage (Hum
Path 2001;32:656), but present in renal tissue in 6% of AIDS patients (Mod
Path 2003;16:35) Case
reports: 14 year old boy with AIDS
and BK viral infection of lung and kidney causing diffuse alveolar damage and
death (AJSP
2000;24:145), 31 year old IV
drug user with AIDS and BK virus related renal failure (Archives
1999;123:807), 62 year old man
post-transplant for SLE induced renal disease (Archives
2001;125:973), 53 year old with
triple immunosuppressive therapy for transplant (Hum
Path 2001;32:656) Micro
(in non-transplanted kidney):
interstitial inflammation, atrophic tubules with large and eosinophilic nuclei Micro
(in allograft kidney): viral
cytopathic effect with large, homogenous, purple intranuclear inclusions,
primarily in tubular epithelium; no necrosis (as seen in HSV), no perinuclear
halo (as seen in CMV); also ischemic glomerulopathy (62%), aneurysmal dilation
of glomerular capillaries (28%), mild increase in mesangial matrix (23%), viral
cytopathic effect in parietal Bowman’s capsule (29%, including using BK
immunostains), crescents (12%), glomerulonephritis (3%) Micro
images: (1) various images;
(2) figure
1: tubulointerstitial nephritis with lymphocytes and enlarged tubular
epithelial cells; 2: tubular cells have large smudged nuclei and basophilic
chromatin; 3: EM shows distinct intranuclear inclusion; 4: inclusion consists
of crystalline arrays of nonenveloped, round, electron-dense particles, mean 45
nm in diameter, in loose crystalline lattices;
(3) A:
tubules with enlarged nuclei and inclusions (arrow); B/C: SV40+ tubules and
interstitium; (4) A:
intranuclear viral inclusions (arrowheads), regenerative changes of tubular
epithelium (arrow); B: anti-SV40 staining of infected cells and casts EM
images: tubular
cell with numerous viral particles (inset: anti-SV40 antibody) DD: rejection, other infection References:
Hum
Path 2004;35:367 Associated
with renal transplants Micro: large tubular cells with enlarged basophilic nuclei
with inclusions; also tubular injury Micro
images: various
images EM:
cytoplasmic virus has bulls-eye
appearance Virtual
slides: coccidioidomycosis Case
reports: 50 year old Chinese man
with cyst in upper kidney (AJSP
1986;10:508), 47 year old farmer
in Australia (AJSP
1983;7:281) Gross: hemorrhagic cyst, often thick walled Micro: cyst wall composed of granulomatous tissue with eggs
and cross striations of parasites; eggs have birefringent striated double wall See
HUS/TTP below Rodent
RNA virus that causes hemorrhagic fever with renal syndrome and hantavirus
pulmonary syndrome Renal
disease occurs outside US, severity depends on causative agent (severe -
Dobrava-Belgrade and Hantaan; moderate - Seoul; mild - Puumala virus) Overall
mortality rate is 7% Caused
significant mortality during Korean War Acute
flu-like febrile illness, then hemorrhage and sudden and extreme albuminuria,
then renal failure References:
Archives
2003;127:30 Case
reports: 45 year old woman with
living related donor transplant on high-dose steroids for acute rejection (Archives
2003;127:e224) Tuberculosis - Kidney nontumor chapter 9
million new cases of TB/year, causing 2 million annual deaths (WHO: Global
Tuberculosis Control 2008) GU
tract is #2 most common site of infection (after lungs) Renal
involvement may be indolent, may not become apparent until 20+ years from
detection of primary infection Urogenital TB is associated with unilateral non-functioning kidney in 27%
of cases, with renal failure present in 7% (Int J Urol 2008 Jul 10 [Epub
ahead of print]) In chronic kidney disease of all causes, one study from India
demonstrated a 4% incidence of TB,
which was usually tuberculin skin test negative (Clin Nephrol 2007;67:217) Case
reports: Case of the Week
#128 Gross: multiple cavities filled with yellow friable
material Gross
images: kidney Micro: extensive caseous necrosis, with occasional
granulomas composed of epithelioid cells and Langhans giant cells DD: xanthogranulomatous pyelonephritis (different
clinical picture, AFB negative, although AFB may be difficult to detect even in
TB patients, Int
J Urol 2006;13:67) Drug related nephrotoxicity Antiretroviral
agent used for HIV patients Causes
severe acute degenerative changes in proximal tubules, possibly mediated by
focal deficiency of cytochrome C oxidase EM: proximal tubular mitochondria are enlarged,
dysmorphic and disoriented with reduced cristae Reference: Hum
Path 2001;32:734 Bilateral
chronic renal disease due to excessive intake of analgesics, with papillary
necrosis and later chronic tubulointerstitial nephritis High
rates in Australia, southeast USA Due to
phenacetin plus aspirin, caffeine, acetaminophen (a metabolite of phenacetin),
codeine 80%
women; also people with chronic pain, factory workers Inability
to concentrate urine, renal stones, anemia due to red blood cell damage from
phenacetin metabolites; 50% have coexisting urinary tract infection May
have gross hematuria or renal colic due to sloughing of necrotic papillae Complication: papillary urothelial carcinoma of renal pelvis Gross: depressed cortex due to cortical atrophy overlying
necrotic papillae; papillae show varying stages of necrosis and sloughing Micro: early-papillae have patchy necrosis, later-papillae
are diffusely necrotic with ghost tubules and dystrophic calcification; renal
columns of Bertin are usually spared from tubular atrophy; small vessels have
basement membrane thickening Other
causes of papillary necrosis: (a)
diabetes mellitus: 75% women, usually 10+ years of disease, 80% have urinary
tract infection, all papillae affected similarly (b)
obstruction: 90% male, 90% have infection, frequent calcification (c)
sickle cell disease: M=F, few papillae affected Case
report mimicking Fabry’s disease (Hum
Path 2003;34:285) Cyclosporine
is extremely effective in controlling transplant rejection, but is nephrotoxic,
hepatotoxic and neurotoxic Also
causes gingival hyperplasia, hypertrichosis, lymphomas Nephrotoxicity
is dose related, occurs in 3% Functional
toxicity: mild decrease in renal
function and increase in serum creatinine, hypertension in 50%, reversible if
dosage lowered, no morphologic changes in kidney; toxicity due to alteration in
intrarenal hemodynamics Acute
toxicity: similar to functional
toxicity but more severe; microscopic changes are present, and include vacuoles
in proximal tubules (due to dilated endoplasmic reticulum) with giant
mitochondria, large lysosomes and microcalcifications; also arteriolar smooth
muscle cell degeneration, endothelial cell swelling, intimal thickening,
variable hyaline or mucoid deposits which narrow lumen; dose dependent and
reversible Thrombotic
microangiopathy: resembles hemolytic
uremic syndrome; occurs days to weeks after transplantation; glomeruli and
vessels show thrombotic microangiopathy with platelet and fibrin thrombi and
minimal inflammatory infiltrate; poor prognosis Chronic
toxicity: hypertension and slow
progression to renal failure; arterioles show nodular or diffuse hyalinosis of
vessel walls or mucoid thickening of intima, leading to luminal narrowing; also
interstitial fibrosis and tubular atrophy; early glomerular changes are aggregates
of platelets and fibrin; late changes are focal and segmental
glomerulosclerosis or global scarring; changes are irreversible Micro
images: various
images #1; #2 Case
reports: due to gold salts for
rheumatoid arthritis (Archives
1983;107:258, Archives
1981;105:373, Archives
1977;101:635) May
cause interstitial nephritis or nephrotic syndrome with gold deposits present
within tubular epithelium, interstitial macrophages and free within renal interstitium Treatment:
cessation of gold therapy Immunofluorescence: IgG or C3 deposits in granular pattern in glomerular
basement membrane, due to unknown immune complex May
cause tubulointerstitial nephritis Caused
by intratubular precipitation of indinavir crystals, with damage to tubular
epithelial cells and histiocytic reaction Micro
images: various
images Rare;
acute renal failure due to inhibition of vasodilatory prostaglandins May
cause an acute hypersensitivity interstitial nephritis, acute interstitial
nephritis and minimal change disease together, or membranous glomerulonephritis Intravenous
injection of suppositories may cause granulomatous glomerulonephritis and
subsequent renal failure (Hum
Path 1998;29:1246) May
also cause widespread tubulointerstitial involvement, with fibrillar deposits
in glomeruli and tubular basement membranes Positive
stains: PAS Negative
stains: Congo red, silver References:
Hum
Path 2002;33:783 Immunosuppressive
drug used frequently in renal transplants, effect may be mediated by binding to
FKBP12, a cytosolic protein FKBP12/FK506
binds to and inactivates calcineurin (a serine/threonine phosphatase), which
inhibits calcium and calmodulin dependent B and T cell responses by blocking
NFAT-mediated transcription Has
toxicity (in 1%) similar to cyclosporin A at level of renal vascular
endothelium, leading to fibrin thrombi in glomerular capillaries and afferent
arterioles; may also cause arteriolar hyalinosis and splitting / reduplication
of glomerular basement membrane Treatment: reduce dosage References:
AJSP
1996;20:306, AJSP
1993;17:60, AJSP
2003;27:58 (expression in vascular tumors) Renal disease associated with systemic conditions Group
of conditions with extracellular deposition of fibrillar proteins having a
beta-pleated sheet tertiary structure, which causes Congo red staining and
apple-green birefringence under polarized light Resistance
to digestion causes it to accumulate within tissue, interfere with function,
destroy vital organs Renal
amyloidosis causes 5% of adult cases of nephrotic syndrome Systemic
or localized Poor
survival in primary amyloidosis; patients may develop acute leukemia after
alkylating agents, also secondary malignancies after autologous transplantation Amyloid
is composed of a fibrillary protein (types described below) and nonfibrillary
glycoproteins (amyloid P component also called serum amyloid P [SAP],
glycosaminoglycans, apolipoprotein E) Serum
amyloid P may contribute to stability of amyloid deposits; radioactive iodine
labeled SAP is used in nuclear medicine studies to assess amyloid deposition AL
type: also called primary amyloidosis;
most common cause of renal amyloidosis in US; due to plasma cell dyscrasias
with systemic deposition of amyloid and mild increase in bone marrow plasma
cells that are monoclonal; 20% have myeloma or other lymphoproliferative
disorders; deposits are more likely lambda light chains or fragments than kappa
type, often from amino-terminal fragment of variable region of light chain; 40%
develop nephrotic syndrome AA
type: also called secondary
amyloidosis: associated with chronic inflammatory conditions such as
osteomyelitis, bronchiectasis, decubitus ulcers, Crohn’s disease, rheumatoid
arthritis or tuberculosis; main amyloid component is protein A, derived from
proteolytic cleavage of serum amyloid A protein, an acute phase reactant; 90%
have renal insufficiency or nephrotic syndrome at diagnosis Beta
2 microglobulin type: associated
with long-term hemodialysis or peritoneal dialysis; also renal failure between
treatment; increases with duration of dialysis; amyloid protein composed of
intact and modified beta 2 microglobulin, an integral part of HLA class I
antigen complex that is usually eliminated by the kidney; amyloid deposits
occur in blood vessel walls, perineural and periarterial tissue, bone, joint,
skin, subcutaneous tissue, heart, GI, lungs; may cause carpal tunnel syndrome,
joint disease, bone cysts ATTR
type: amyloid fibrils consist of
transthyretin; associated with familial amyloidosis Familial
Mediterranean fever: autosomal
recessive, deposits consist of AA amyloid AH
type: due to heavy chains; very rare Case
reports: patient developing lambda
light chain deposition disease (treated with autologous peripheral blood stem
cell transplant) and later IgG heavy chain amyloidosis (AJSP
2003;27:1477); 59 year old man
with IgM heavy chain amyloidosis (AJSP
2003;27:541), bilateral buttock
tumors of beta 2 microglobulin after long term hemodialysis (Archives
1994;118:651); AA-amyloid like
deposits but fibrils twice the usual size (Archives
1992;116:261), amyloid fibrils
3x usually size (Hum
Path 1990;21:868), associated
with sinus histiocytosis with massive lymphadenopathy and chronically elevated
C reactive protein (Hum
Path 2000;31:621) Gross
images: pale
amyloid deposits in enlarged kidney #1; #2
(normal kidney on far right) Micro: salmon orange amorphous deposits in mesangium and
subendothelium that obliterate glomeruli; also deposits in blood vessel walls,
interstitium and around tubules; also mast cells that lead to interstitial
fibrosis in AA type; 10% of AL patients lack glomerular deposits; glomerular
cell proliferations are uncommon Micro
images: (1) amorphous
material in mesangium and obliterating capillary loops; (2) various
images including EM; (3) interstitial
mast cells stained with anti-tryptase and accumulation around amyloid deposits
stained with anti-amyloid A Virtual
slides: amyloidosis Positive
stains: Congo red causes apple-green
birefringence on polarization microscopy; silver stain may show spiking along
glomerular capillary loops; thioflavine T fluoresces; may be positive for
anti-AA antibodies, light chain restriction EM:
7.5-10 nm in diameter fibrils with
randomly dispersed, nonbranching arrangement in mesangium and subendothelium EM
images: 10 nm haphazard
fibrils; mast
cell (MC) within extracellular matrix of renal interstitial containing collagen
fibers (C) and amyloid fibrils (A); inset-mast cells stained with anti-chymase DD:
fibrillary glomerulonephritis
(fibrils are 12-24 nm, negative amyloid stains) References:
Mod
Path 2000;13:1020 (mast cells and interstitial fibrosis) Bone marrow transplant nephropathy Due to
total body irradiation (similar to radiation nephropathy) Delayed
renal insufficiency (occurs in 20%), hypertension, anemia out of proportion to
azotemia; possibly hemolytic uremic syndrome Early
changes: related to acute tubular
necrosis, infection, nephrotoxic drugs, graft versus host disease, tumor lysis
syndrome, marrow infusion toxicity, hepatic venoocclusive disease or
interstitial nephritis Late
changes (3 months after bone marrow transplant): prominent mesangiolysis, focal aneurysmal capillary
dilation, variable increase in mesangial matrix; also swollen endothelial
cells, widened subendothelial space, duplicated (double contour) glomerular
basement membrane, focal fibrin thrombi within glomerular capillaries Treatment: supportive therapy Case
report: 27 year old with renal
impairment after bone marrow transplant for CML (Archives
2004;128:233) Immunofluorescence: fibrin, IgM EM: endothelial injury with widened subendothelial space
filled with loose, amorphous, granular material (fibrin) and new basement membrane
material; variable red blood cell fragments DD: hemolytic uremic syndrome Defined
by presence of serum cryoglobulins, which are immunoglobulin complexes that
precipitate at 4°C and become soluble again at 30°C Usually
systemic disease in which deposits of IgG or IgM immune complexes cause
glomerulonephritis (focal, diffuse), cutaneous vasculitis (skin rash),
synovitis (arthritis) Type
I: cryoglobulin is single monoclonal
immunoglobulin class, usually due to myeloma, Waldenström macroglobulinemia or
other lymphoma Type
II: mixture of 2+ immunoglobulins,
one a monoclonal antibody against polyclonal IgG; usually IgG-IgM in which IgM
is monoclonal and has rheumatoid factor activity Type
III: both immunoglobulin components
are usually polyclonal IgG and IgM Types
II and III associated with lymphoma, chronic infection, chronic liver disease,
SLE, hepatitis C; symptoms of variable fatigue, purpura over lower extremities,
arthralgias, hepatosplenomegaly, lymphadenopathy, Raynaud’s phenomenon,
glomerulonephritis in 50% with proteinuria and hypertension, progressing to
renal failure in 5%; usually women ages 30+ years Micro: diffuse proliferative glomerulonephritis, often with
membranoproliferative pattern; also focal and segmental glomerulonephritis and
less often crescentic or membranous glomerulonephritis; acutely may produce
wire loops or thrombi seen in lupus nephritis, vasculitis of interlobular
arteries and afferent arterioles Micro
images: various
images including EM Immunofluorescence: immunoglobulins, C3; also C1q and C4 EM: large amounts of subendothelial immune complex
deposits; lesser amounts of subendothelial deposits; 50% have glomerular
deposits with fibrillary or tubular structure forming bundles or arranged in
fingerprint-like array DD: immunotactoid glomerulopathy, fibrillary
glomerulonephritis References: Archives
1981;105:474 Accounts
for 30% of long term dialysis patients in US; causes 20% of deaths in those
with diabetes younger than age 40 End stage
renal disease occurs in 30% of type I patients Causes
glomerular disease, arteriolar sclerosis, pyelonephritis, papillary necrosis;
similar between type I and II patients Proteinuria
occurs in 50%, usually 12-22 years after onset of diabetes; associated with
diffuse capillary basement membrane thickening, diffuse and nodular
glomerulosclerosis Early
increased GFR and microalbuminemia (30-300 mg/day) are predictive of future
diabetic nephropathy Renal
disease reduced by tight diabetic control; may recur with renal allografts; ACE
inhibitors may reduce progression Isolated
thick glomerular basement membrane and proteinuria is associated with diabetes
(Mod
Path 2004;17:1506) Case
reports: acute post-staphylococcal
glomerulonephritis complicating diabetic nephropathy, with IgA deposition in
glomeruli (Hum
Path 2003;34:1235), insudative
hyaline cap lesions (Hum
Path 1989;20:388) Gross
images: small
kidney with finely granular surface Micro: (a)
basement membrane thickening and increased mesangial matrix, in ALL patients; (b)
diffuse glomerulosclerosis: increase in mesangial matrix associated with
basement membrane thickening, PAS positive, eventually obliterates mesangial
cells (c)
nodular glomerulosclerosis: also called intercapillary glomerulosclerosis or
Kimmelstiel-Wilson disease; ovoid, spherical, laminated hyaline masses in
peripheral of glomerulus, PAS positive, eventually obliterates glomerular tuft;
specific for diabetes and membranoproliferative glomerulonephritis, light-chain
disease, amyloidosis (d)
profound hyalinization of afferent arterioles (insudative lesion-intramural):
specific for diabetes in afferent arterioles, but nonspecific if in periphery
of glomerular loop, Bowman’s capsule or mesangium; insudative material composed
of proteins, lipids, mucopolysaccharides (e)
organizing fibroepithelial crescents: associated with aggressive clinical
course (f)
diffuse thickening of tubular basement membrane, tubular atrophy, interstitial
fibrosis Micro
images: sclerotic
nodules within glomeruli #1; #2 (PAS
highlights thickened arteriolar wall); #3;
various
images; normal
glomeruli; diabetic
glomerulosclerosis with mesangial sclerosis and Kimmelstiel-Wilson nodule
(arrow) Virtual
slides: diabetic
glomerulosclerosis Immunofluorescence:
diffuse linear staining for IgG
along capillary walls; also IgM, IgA, albumin (considered to be nonspecific
trapping of plasma proteins due to basement membrane or mesangial dysfunction) EM:
diffuse thickening of basement
membranes; increased mesangial matrix EM
images: thick
glomerular capillary basement membrane, uniform and homogenous References:
Hum
Path 1994;25:1213 (insudative lesions), Hum
Path 1993;24:77 (pathogenesis of Kimmelstiel-Wilson nodule) Also
called anaphylactoid purpura Purpuric skin lesions on extensor arms and legs and
buttocks; abdominal pain, vomiting, GI bleeding, arthralgias, hematuria,
proteinuria, nephrotic syndrome; due to systemic small vessel leukocytoclastic
vasculitis Renal
symptoms in 30-70%; some adults develop rapidly progressive glomerulonephritis 70%
are ages 2-11 years; rare in adults or infants 1 year or less Associated
with atopy in 1/3; may follow respiratory infection Related
to IgA nephropathy (both have elevated serum IgA, circulating immune complexes
with IgA, similar kidney lesions) Prognosis: excellent in children (50% have spontaneous
remission); poorer in adults or with nephrotic syndrome Hypertension,
serum creatinine, proteinuria, cellular crescents, glomerular necrotizing
lesions and chronic renal lesions are associated with renal failure (Mod
Path 2001;14:635) Treatment: corticosteroids, cytotoxic drugs Micro: acute - leukocytoclastic vasculitis of
small vessels due to deposition of IgA immune complexes; diffuse proliferation
of mesangial cells and matrix without significant involvement of capillary
walls or lumina; also segmental necrotizing lesions (50%), endocapillary
proliferation (13%), cellular crescents, glomerular acute and chronic
inflammatory infiltrate chronic - glomerular sclerosis, tubular loss, interstitial
fibrosis, hyaline arteriolosclerosis Skin - hemorrhage and necrotizing vasculitis in dermal
small vessels; vessels contain IgA; vasculitis present in other organs but
usually NOT kidney Micro
images: all with silver stain - (1) mild
mesangial hypercellularity with accentuated mesangial matrix; (2) endocapillary
proliferation; (3) segmental
necrotizing lesions; (4) cellular
crescent; (5) sclerosed
glomerulus with luminal collapse and crescent Immunofluorescence: IgA deposition in mesangium; resembles IgA
nephropathy; variable IgG, IgM, C3, properdin EM: mesangial deposits, may extend into subendothelial
areas; may have subepithelial deposits References:
Archives
1982;106:192 Heavy chain deposition disease Less
common than light chain deposition disease Due to
systemic deposition of truncated, monoclonal heavy chain Otherwise
similar to light chain deposition disease Case
reports: 51 year old man with linear
deposits of gamma 4 heavy chains along glomerular, tubular and vascular
basement membrane and in mesangial regions (Mod
Path 1994;7:874), monotypic mu
heavy chain mesangial deposits causing nodular glomerulosclerosis in woman
without evident hematopoietic malignancy (Hum
Path 2000;31:122) Immunofluorescence: IgG heavy chains along glomerular, tubular and
vascular basement membranes and in mesangium; no light chain deposition Hemolytic uremia syndrome /
thrombotic thrombocytopenic purpura (HUS/TTP) Thrombosis
in capillaries and arterioles throughout the body, microangiopathic hemolytic
anemia, thrombocytopenia, renal failure with platelet-fibrin thrombi in
interlobular renal arteries and glomeruli, and necrosis and thickening of
vessel walls Morphologic
changes resemble malignant hypertension, but usually no preexisting
hypertension HUS
and TTP are usually considered part of clinical spectrum in which disease
manifestations depend on distribution of microangiopathy HUS: fibrin/red cell rich thrombi, largely confined to
kidney, often severe; usually no pancreas, adrenal gland, brain or heart
involvement TTP: platelet rich thrombi in myocardial arteries; also
pancreas, kidney, adrenal gland, brain; usually no permanent kidney damage Pathophysiology: endothelial injury by toxins (certain strains of E.
coli) or antibodies and activation causes intravascular thrombosis and platelet
aggregation, which causes vascular obstruction and vasoconstriction Case
reports: death due to diffuse
myocardial necrosis (Archives
1999;123:937), association with
mitomycin (Archives
1984;108:959) Gross: patchy or diffuse renal cortical necrosis Micro: early - fibrin deposits in capillary
lumina; fibrinoid necrosis of larger vessels, thrombosis, endothelial cell
proliferation in small arteries and arterioles; ischemic changes in glomeruli,
with endothelial swelling and capillary luminal narrowing; expanded mesangium later - intense
basophilic thickening in small arteries and arterioles which restricts lumen,
aneurysmal dilatation and proliferation of arterioles at hilus of glomerulus;
may have double contour of glomerular basement membrane Micro
images: TTP related lesions – (1) various
images including EM; (2) 1A:
platelet thrombi in myocardial arteries; 1B: acute thrombus (arrow)
superimposed on organizing platelet thrombus; 1C: PTAH; 1D: factor VIII
highlight numerous TTP-related lesions; (3) adrenal
gland lesions are A: subcapsular; B: PTAH highlights fibrin in thrombi; (4)
A/B:
small thrombi in brainstem; (5) pancreatic
thrombi; (6) variable
renal involvement - A: moderately severe (PTAH stain); B: glomeruli with
minimal PTAH staining in thrombi Virtual
slides: DIC
and microthrombi EM: widening of subendothelial space, filled with pale,
finely particulate or fibrillar material (fibrinogen) and intraluminal platelet
microthrombi causing narrowing of capillary lumen; swollen mesangial cells with
numerous phagolysosomes; later - mucinous, onionskin-type obliterating
endarteritis DD: systemic sclerosis and malignant hypertension
(similar vascular lesions) References: Archives
2003;127:834 (HUS and TTP different clinical entities), Hum
Path 1988;19:1102 (E. coli related HUS) Childhood
HUS: 75% of
cases occur after E coli O157:H7 infection (also called verocytotoxin because
it damages Vero cells in culture) Main
cause of childhood acute renal failure Usually
infants and young children, may occur at any age Symptoms: sudden onset of influenza, bleeding (hematemesis or
melena), severe oliguria, hematuria, microangiopathic hemolytic anemia,
neurologic changes in 1/3, hypertension in 50% Pathogenesis: related to Shiga-like toxin, which promotes
adhesion of white blood cells to endothelium; also increases endothelin and
decreases nitrous oxide production, causing vasoconstriction Treatment: dialysis, with recovery in weeks Adult
HUS/TTP: Causes: typhoid fever, E. coli (enterohemorrhagic strains),
viral infections, shigellosis, antiphospholipid syndrome (primary or secondary
to SLE), postpartum or after placental hemorrhage, vascular renal diseases such
as scleroderma or malignant hypertension, drugs (mitomycin C, cyclosporine,
bleomycin, cisplatin), various malignancies Poor
prognosis with high mortality due to CNS disease or uncontrollable bleeding; survivors develop chronic renal failure Idiopathic
HUS/TTP: More
common in women age 40 years or less; mortality 50% Symptoms: CNS involvement dominant (fever, neurologic symptoms),
hemolytic anemia, thrombotic thrombocytopenic purpura, renal involvement in
only 50% (thrombi in glomerular capillaries and afferent arterioles) Treatment: exchange transfusions, steroids Light chain deposition disease Uncommon See
also myeloma below 80%
male, usually older adults; 60% have associated myeloma or other
lymphoplasmacytic disorder, although it may not become apparent until years
later Due to
overproduction and deposition of monoclonal light chains; occasionally also
heavy chains Renal
failure with heavy proteinuria; also Fanconi’s anemia with aminoaciduria,
glucosuria and phosphaturia Also
cardiac, hepatic and neural damage and deposition in soft tissues and other
organs of histiocytes and fibroblasts containing crystals (AJSP
1993;17:461) May
recur in renal transplants 5 year
survival is 70%, less if coexisting myeloma Immunoelectron
microscopy may be useful for diagnosis (Hum
Path 2003;34:270) Case
reports: light chain glomerulopathy
with numerous epithelial crescents and rapid progression to renal failure in
woman with myeloma and type II diabetes mellitus (Archives
1983;107:319) Micro: enlarged glomeruli with PAS+ material in thickened
capillary walls and mesangial nodules; occasional fibroepithelial crescents;
thickened tubular basement membranes with glassy (crystalline) appearance; also
crystals within histiocytes Micro
images: various
images including EM Negative
stains: Congo red, thioflavin T,
amyloid P protein Immunofluorescence: granular deposits of kappa (80%) or lambda (20%)
light chains (not both) along glomerular and tubular basement membranes, in
mesangium, vessel walls and interstitium EM: diffuse electron dense, finely granular material in
glomerular basement membrane, mesangium, tubular and vascular basement
membranes DD: AL amyloidosis (fibrillar deposits, usually lambda
light chains, Congo Red+, thioflavin T+, amyloid P protein+), diabetes (severe
arteriolar hyalinosis, fibrin caps, capsular drops), drug related crystals Formerly
called microscopic polyarteritis nodosa Necrotizing
systemic vasculitis affecting small vessels (capillaries, venules, arterioles),
without immune complexes Affects
1 per 100,000; any age but more common at age 50+ years 90%
have renal involvement; lungs usually affected also (may simulate Goodpasture’s
syndrome) Hematuria,
proteinuria, hemoptysis, palpable purpura, abdominal pain, myalgias,
arthralgias, mild hypertension 80%
have p-ANCA Micro: glomerulonephritis (focal and segmental to severe
diffuse and crescentic); arterial lesions usually all at same stage; usually
tubulointerstitial infiltrate; sausage shaped microaneurysms of interlobular
arteries (Hum
Path 1998;29:223) Virtual
slides: microscopic
polyangiitis (polyarteritis) Immunofluorescence: no deposits EM: no deposits See
also light chain deposition disease above Renal
dysfunction/insufficiency occurs in 50%; is #2 cause of death in myeloma
patients, due to: (1)
Bence Jones cast nephropathy; also called myeloma cast nephropathy or myeloma
kidney (in 30-40% at autopsy) Proteinuria
consisting of light chains, which are normally filtered by glomeruli,
reabsorbed and metabolized by proximal tubular cells In
myeloma, proximal tubular cells are overwhelmed, and light chains reach distal
nephron, where they are directly toxic to epithelial cells; Bence Jones
proteins combine with urinary glycoprotein (Tamm-Horsfall) under acidic
conditions to form tubular casts that obstruct tubules (2) AL
amyloidosis (6-24% of myeloma patients) (3)
Hypercalcemia, hyperuricemia, vascular disease, urinary tract obstruction (4)
Light chain nephropathy (PAS+ mesangial deposits in glomeruli, lobular
accentuation, mesangial hypercellularity) (5)
Also acute and chronic renal failure is induced by dehydration, acute
infection, nephrotoxic antibiotics, acute tubular necrosis (acute tubulopathy),
monoclonal cryoglobulins in glomeruli, tubulointerstitial nephritis, thrombotic
microangiopathy, renal infarction, fungal infection, plasma cell tumor nodules,
nephrotic syndrome Note: urinary beta 2 microglobulinemia can simulate
Bence-Jones proteins in electrophoresis (Archives
2001;125:555) Micro: pink-blue amorphous masses fill and distend lumen;
surrounded by giant cells and histiocytes; adjacent epithelium is necrotic;
casts and histiocytes may contain rhomboid or needle shaped crystals (light
chains) Micro
images: (1) light
chain cast nephropathy-various images; (2) figure
1A: casts in distal nephrons with inflammatory reaction; 1B: tubular casts with
occasional multinucleated tubular cells surrounding the casts; 1C: tubular
damage is indicated by vacuoles, apical blebs and desquamation; 1D: active
inflammation in tubules, typical of tubular interstitial nephritis; (3) figure
2A: eosinophilic amorphous amyloid in glomeruli; 2B: amyloid in interstitium;
2C/2D: light chain deposition disease with glomerular nodularity, amyloid
surrounding the tubules and thickened peripheral capillary walls in glomeruli;
(4) plasma
cell nodules, more atypical in B; (5) figure
4A: thrombotic microangiopathy; 4B: abscess with fungal hyphae (arrow) Immunofluorescence:
granular dense material along
basement membrane EM:
peripheral and mesangial kappa and
lambda light chains (either, not both) DD: diabetic nodules, membranoproliferative
glomerulonephritis References: Archives
2004;128:875 Primary
vasculitis of unknown etiology that affects muscular arteries at branch points Produces
lesions of varying stages of evolution, also aneurysms Usually
affects kidney (80%) and GI tract 2
cases per million, 2/3 male, ages 50+ years 1/3
are hepatitis B carriers <20%
have positive p-ANCA Causes
renal infarct, hypertension (often severe or malignant) Case
reports: limited to kidney (Hum
Path 1987;18:1074) Micro: necrotizing vasculitis of renal, interlobar and
arcuate arteries at branch points with aneurysmal dilatation, fibrinoid
necrosis and neutrophilic infiltration of vessel wall, often with thrombosis;
later have mononuclear infiltrate, fibrosis of media and perivascular tissue
and recanalization of thrombosed vessel; often not detected in biopsy since
lesions are focal; glomeruli show ischemic changes of collapse and sclerosis Micro
images: lymphocytic
vasculitis of renal vessel Immunofluorescence:
no deposits EM: no deposits Pregnancy
induced disease featuring hypertension, proteinuria and edema with variable
coagulation and liver disorders 5-7%
of first pregnancies, usually at gestational week 20+, usually affects women at
extremes of reproductive age In non
first pregnancies, associated with multiple pregnancies, fetal hydrops, renal
disease, essential hypertension Causes
50% of pregnancy related hypertension Called
eclampsia if convulsions develop May be
caused by primary endothelial cell injury causing local intravascular
coagulation Good
prognosis; glomerular changes and blood pressure return to normal within weeks
of delivery Micro: enlarged, swollen and bloodless glomeruli with
capillary lumina obliterated by swollen endothelial cells; no/mild
hypercellularity; may have herniation of capillary tuft into proximal tubule
(tufting); rare crescent formation in severe cases; normal afferent arterioles Micro
images: various
images Immunofluorescence: fibrinogen deposits, occasionally IgM EM: lysosomal-like, single membrane lined vacuoles
within cytoplasm of endothelium and mesangial cells; some vacuoles contain
bland lipids or have myelin-like figures Often
white men lacking skin, eye or lung involvement Case
reports: 19 year old woman who died
of rapidly progressive renal and respiratory failure (Archives
1989;113:1295), with nephrotic
syndrome resistant to steroids and immunosuppression (Archives
1978;102:572) Treatment: prednisone for renal insufficiency (Archives
1990;114:488) Micro:
interstitial non-caseating
granulomatous nephritis, nephrocalcinosis, often segmental thickening and
wrinkling of glomerular capillary walls Micro
images: various
images Immunofluorescence: no specific findings EM: numerous single and coalescent calcific microspherules
within basement membrane, paramesangial zone and mesangium References: Archives
1992;116:1221 SLE / systemic lupus erythematosis Autoimmune
disease with various clinical manifestations, 90% women, affects adults and
children (2/3 present at ages 16-30 years) Drug
induced lupus-like disease is associated with hydralazine, procainamide,
isoniazid, methyldopa, chlorpromazine and quinidine 40-80%
have impaired renal function, due to in situ or circulating immune complexes Most
common symptoms are proteinuria and microscopic hematuria; spectrum includes
acute nephritis, nephrotic syndrome, acute and chronic renal failure, isolated
abnormalities in urinary sediment Biopsy
is necessary to determine subsequent clinical course and to assist with
treatment Nonlupus
nephritides are occasionally present (Hum
Path 2001;32:1125; case report of IgA nephropathy, Mod
Path 1995;8:5) WHO
classification of lupus nephritis I - normal or minimal abnormality; no abnormalities
identified by H&E, immunofluorescence or EM; asymptomatic; may not actually
represent renal disease II (10-20% of cases) - pure mesangial lesions;
mesangial expansion but mostly patent capillaries; mesangial immune deposits;
mild proteinuria with variable hematuria but normal renal function IIA
- minimal light microscopy changes,
but immune deposits present in mesangium by immunofluorescence and EM IIB
- glomerular mesangial
hypercellularity present by light microscopy, involving center of lobules away
from vascular pole; immune deposits only in mesangial region; no significant
tubular, interstitial or vascular changes; good prognosis (5 year renal
survival >90%) III
(30-40% of cases) - focal
proliferative glomerulonephritis; focal and segmental proliferative intra- or
extracapillary necrotizing or sclerosing lesions in <50% of glomeruli;
predominantly mesangial and subendothelial immune deposits (Ig, complement); nephritic
urinary sediment; variable proteinuria but usually non-nephrotic IV (40-60%) - diffuse proliferative glomerulonephritis;
predominantly global proliferative lesions, necrosis, crescents in >50% of
glomeruli, variable sclerosis, prominent inflammatory interstitial infiltrate,
often wire loop lesions in thickened capillary walls; predominantly mesangial
and subendothelial immune deposits of IgG, often IgM and IgA (all three is
called a “full house”); also C3 and C1q, fibrin and fibrinogen; nephritic and nephrotic
syndromes, hypertension, variable renal insufficiency; rapidly progresses to
renal failure without treatment V (10-15%) - membranous glomerulonephritis; diffuse
thickening of capillary walls, subepithelial and mesangial immune deposits
(“spike and dome” pattern with silver stain); nephrotic syndrome or severe
proteinuria VI - advanced sclerosing glomerulonephritis; glomerular
obsolescence and segmental glomerulosclerosis, tubular atrophy, interstitial
fibrosis; few immune deposits; chronic renal failure that is unlikely to
respond to therapy Overlap
common in classes III and V, IV and V Tubulointerstitial
disease: observed in all classes,
severe in classes III and IV; usually composed of lymphocytes, plasma cells and
macrophages; severe cases have casts Vascular
lesions: common, associated with
poor prognosis; includes vascular immune deposits, noninflammatory necrotizing
vasculopathy, true vasculitis, thrombotic microangiopathy, nonspecific
arteriolosclerosis Hematoxylin
bodies: focal areas of necrosis
containing fragmented nuclei; specific for SLE, but only 1-2% sensitive Alveolar
hemorrhage (bland alveolar wall changes) is similar to lupus microangiopathy of
kidney; both are caused by immune complex deposition and induction of apoptosis
(Archives
2001;125:475) Activity
index: based on scoring (0-3) of (a)
glomerular endocapillary proliferation, (b) glomerular neutrophilic infiltration,
(c) wire-loop deposits and hyaline thrombi, (d) glomerular fibrinoid necrosis
and karyorrhexis, (e) cellular crescents and (f) interstitial inflammation;
double the fibrinoid necrosis/karyorrhexis (part d) and cellular crescent (part
e) scores; add up (maximum 24) Chronicity
index: based on scoring (0-3) of (a)
glomerular sclerosis, (b) fibrous crescents, (c) tubular atrophy, (d)
interstitial fibrosis; add up (maximum 12) Case
reports: alveolar hemorrhage and
class IV lupus nephritis (Archives
2001;125:475) Micro
images: (1) various
class IIb images including EM; (2) various
class III and IV images including EM; (3) various
class IV and V images including EM; (4) figure
1: renal biopsy shows hypercellular glomerulus and afferent arteriole whose
wall is effaced by smudgy eosinophilic material and contains pyknotic nuclear
material; 2: afferent arteriole shows nuclear pyknosis in media and
karyorrhexis (arrow); 3: IgG deposits in glomerulus and in underlying lupus
microangiopathy; 4: IgG deposits along alveolar walls; (5) class
V with spikes and honeycomb lesions (arrows); (6) class
V with beads on a string pattern of fluorescence corresponding to immune
complex deposits along glomerular basement membrane; membranous
glomerulonephritis #1; #2;
#3 Virtual
slides: membranous
glomerulonephritis with wire loops EM
images: class
IV lesions; class
V with subepithelial and mesangial electron dense deposits (M) and fusion of
epithelial foot processes (arrows) Also
called scleroderma Connective
tissue disorder of unknown etiology with multiple organ system involvement, 75%
women, usually ages 30+, rare in children Symptoms
due to excessive collagen deposition and vascular disease, includes Raynaud’s
syndrome, skin thickening, digital pulp atrophy, telangiectasia,
musculoskeletal involvement, esophageal dysmotility, malabsorption Death
due to pulmonary hypertension, interstitial fibrosis, cardiomyopathy 60%
have renal involvement, either (a) acute and rapidly progressive form of renal
failure associated with malignant hypertension, systemic vasoconstriction,
microangiopathic hemolytic anemia; or (b) slowly progressive chronic form with
proteinuria, hypertension and azotemia Micro: intimal thickening by loose myxoid fibrous tissue in
interlobular arteries; subendothelial fibrin deposition and intimal hemorrhage;
fibrinoid necrosis and thrombosis in arterioles; acute ischemic changes in
glomeruli Micro
images: various
images EM: intimal widening by amorphous electron-lucent
material corresponding to myxoid ground substance; basement membrane wrinkling
with focal subendothelial area containing fibrin strands Immunofluorescence: fibrinogen, variable IgM and C3 DD: malignant hypertension, HUS-TTP (similar renal lesions) Disease
of unknown etiology with triad of necrotizing granulomatous inflammation of
upper respiratory tract or lungs; necrotizing vasculitis of small/medium sized
vessels in lungs, upper airways and other sites; and focal necrotizing
glomerulonephritis “Limited”
disease if only 1 or 2 of the above, usually spares kidneys Incidence
of 3 per 100,000, any age but more common at ages 30-49 years 80%
have renal involvement, which progresses rapidly without treatment, leading to
death c-ANCA
is 90% specific, 50% sensitive initially, 100% sensitive if active and
generalized disease; c-ANCA not present during remission Case
history: University of Pittsburgh Treatment: cyclophosphamide, corticosteroids (cause remission,
but 50% relapse) Gross: necrosis of renal papillae in 20% (Hum
Path 1983;14:551) Micro: focal necrotizing glomerulonephritis, often with
crescents, usually with glomerular thrombosis; uncommonly granulomatous
glomerulonephritis; renal papillary necrosis in 20%; interstitial inflammation
common, necrotizing granulomas are rare in biopsies Micro
images: (1) various
images; (2) fibrinoid necrosis
of interlobular artery; (3) vasculitis
(low power); (4) necrotizing
granulomatous vasculitis #1; #2; (6) focal necrotizing
glomerulonephritis; (7) sclerosing
glomerulonephritis; (8) early crescent;
(9) partial
cellular crescent; (10) global cellular
crescent #1; #2;
#3; (13) tubular red blood
cell casts; (14) fibrin present in
crescents Immunofluorescence: usually no immune complex deposits, but fibrinogen
in glomeruli and vessel walls, small amounts of IgM, IgG or C3 in glomeruli and
vessels EM: rarely sparse electron dense deposits in glomeruli References: Hum
Path 1984;15:943 Tubular and interstitial diseases Primary
tubulointerstitial disease (nephritis) lacks significant glomerular or vascular
injury; causes 20-40% of cases of end stage renal disease Secondary
tubulointerstitial nephritis is due to glomerular disease, systemic or vascular
disorders May be
acute (interstitial edema, neutrophils, focal tubular necrosis) or chronic
(mononuclear inflammation, interstitial fibrosis, tubular atrophy) Tubular
defects: inability to concentrate
urine (polyuria, nocturia), salt wasting, diminished ability to excrete acids
(metabolic acidosis) Causes: infections, toxins, metabolic disease, tumors,
vascular diseases, jejunoileal bypass (Archives
1980;104:112). other Virtual
slides: interstitial
nephritis Acute allergic tubulointerstitial
nephritis Due to
beta lactam antibiotics, nonsteroidal anti-inflammatory drugs, diuretics,
others Fever,
hematuria, azotemia, eosinophilia Urinalysis: hematuria, pyuria, proteinuria, eosinophils, but
culture negative Variable
skin rash Micro: generalized interstitial edema by lymphocytes,
plasma cells, macrophages, eosinophils; tubular epithelial damage with luminal
white blood cells; normal glomeruli and vessels Acute suppurative (pus forming) infection of kidney collecting
system as well as renal parenchyma Causes: urinary tract infection (UTI), obstruction,
instrumentation, vesicoureteral reflux, pregnancy (4-6% have bacteriuria, 20%
have symptoms if untreated) Affects infants and young children with congenital
lesions, women of childbearing age, men and women age 60+ years (due to nodular
hyperplasia of prostate, cystoceles in women, cervical carcinoma,
nephrolithiasis) Also
associated with diabetes or immunocompromise Bacterial UTI: due to
colonization of distal urethra and introitus by coliform bacteria with adhesins
on P-fimbriae (pili) plus upward spread via instrumentation or catheterization;
more common in women due to short urethra, no anti-bacterial prostatic fluid,
hormonal changes, sex-related trauma; associated with urine stasis due to
obstruction Usually gram negative rods from fecal flora (E. coli,
Proteus, Klebsiella, Enterobacter, Streptococcus faecalis) or Staph Ascending
route most common; also hematogenous spread of bacteria to kidney Vesicoureteral
reflux: due to short intravesical
ureter, spinal cord injuries; some UTIs cause reflux Intrarenal
reflux: via open ducts at tips of
papillae; most common at poles of kidney where papillae have flat or concave
tips; demonstrate via voiding cystourethrogram (seen in 50% of children with
UTI) Signs/symptoms: sudden onset of costovertebral angle pain, symptoms
of systemic infection or urinary tract infection, pyuria, white blood cell
casts Complications: Papillary
necrosis: more common in
diabetes and urinary tract obstruction; usually bilateral; variable number of
pyramids involved; coagulative necrosis of tubules; usually limited white blood
cell response Perinephric
abscess: extension of pus
through the renal capsule into adjacent tissue Pyonephrosis: total or almost complete obstruction prevents
drainage of pus Treatment: antibiotics usually eliminate symptoms in a few
days; persistent bacteriuria is usually associated with obstruction, diabetes,
immunocompromise Gross: focal abscesses or wedge-shaped areas of suppuration Gross
images: multiple
abscesses; papillary
necrosis; wide
streaks in medulla Micro: patchy suppurative inflammation, primarily
cortical, with edema, neutrophils in interstitium and tubular lumina, and
tubular necrosis; cortical abscesses and necrosis; glomeruli and vessels
usually normal (Candida affects glomeruli) Micro
images: neutrophils
within tubules #1; #2; #3 Virtual
slides: acute
and chronic pyelonephritis #1; #2;
pseudomonas
abscess Reversible
destruction of tubular epithelial cells with acute suppression of renal
function Most
common cause of acute renal failure Tubules
are sensitive to injury due to vast electrically charged surface for
reabsorption, active transport for ions and organic acids and the ability to
concentrate Ischemic: also called acute vasomotor nephropathy; due to
inadequate renal blood flow, often from marked hypotension and shock (acute
pancreatitis, severe trauma, other); ischemia causes vasoconstriction, which
leads to reduced glomerular filtration rate and oliguria Nephrotoxic: due to gentamycin, methotrexate, cisplatin, radiographic
contrast agents, ethylene glycol, carbon tetrachloride, mercury (Archives
1991;115:56), lead, high levels
of hemoglobin (from transfusion reaction, malaria) or myoglobin (from crush
injury, myositis, muscle toxins); greatest injury is to proximal convoluted
tubules Nonoliguric
ATN: increased or normal urine
volumes, often associated with nephrotoxins, more benign clinical course Phases: Initiating:
0-36 hours, decreased urine output and elevated BUN and creatinine due to
decreased blood flow Maintenance:
40-400 ml/day of urine, salt/water overload, hyperkalemia, acidosis, uremia;
may need dialysis Recovery:
increased urine volume up to 3 liters/day due to tubular damage, inability to
concentrate, hypokalemia; vulnerable to infection Mortality:
5% if no damage to other organs, 50% if shock / sepsis Urinalysis: epithelial and granular casts Gross
images: sharply
demarcated cortex and medullary regions; pale
swollen kidney with congested medulla #1; #2;
diffusely
pale cortex Micro
(ischemic ATN): early
– varies from cell swelling to focal tubular epithelial necrosis and apoptosis
with desquamation of cells into lumen; dilated proximal tubules with thinning
or loss of PAS+ brush border; hyaline, granular and pigmented cases,
particularly in distal and collecting ducts, eosinophilic hyaline casts of
Tamm-Horsfall protein (urinary glycoprotein normally secreted by these cells);
white blood cells in dilated vasa recta, interstitial edema; later
- epithelial regeneration (flattened epithelium, dilated tubular lumina, large
nuclei with prominent nucleoli and mitotic activity) Micro
(nephrotoxic ATN): extensive
necrosis of tubular cells along proximal tubule Carbon
tetrachloride: neutral lipid
accumulation / fatty change in injured cells, followed by necrosis Ethylene
glycol: ballooning and hydropic
changes of proximal tubules, calcium oxalate crystals in tubular lumina Hemoglobin/myoglobin: numerous deeply pigmented, red-brown casts in distal
and collecting ducts Lead: dark intranuclear inclusions and necrosis Mercury:
large acidophilic inclusions Micro
images: (1) various
images #1; #2;
(3) diffuse
involvement of tubules with vacuolization and dilation in ethylene glycol
poisoning; (4) calcium
oxalate crystals (various causes) Virtual
slides: ATN
due to ethylene glycol poisoning; diffuse
tubular necrosis DD: other causes of acute renal failure (urine output
< 400 ml/24 hr) are vascular obstruction (polyarteritis nodosa, malignant
hypertension, hemolytic-uremic syndrome), rapidly progressive
glomerulonephritis, acute tubulointerstitial nephritis, pyelonephritis with
papillary necrosis, DIC, urinary obstruction Chronic
tubulointerstitial inflammation and renal scarring with involvement of calyces
and pelvis Calyceal
involvement (blunting) distinguishes chronic pyelonephritis from other
tubulointerstitial inflammation Causes
10%-20% of end stage renal disease in transplant or dialysis units Two
causes - chronic reflux-associated pyelonephritis and chronic obstructive
pyelonephritis Reflux: more common, usually arises in childhood,
unilateral or bilateral; damage often due to infection; associated with
calyceal dilation (usually upper pole), tubular atrophy and thyroidization,
interstitial fibrosis, usual cause of chronic pyelonephritis in children Obstruction: associated with parenchymal scarring Some
patients with pyelonephritic scars develop focal and segmental
glomerulosclerosis with proteinuria in nephrotic range, perhaps due to renal
ablation nephropathy Associated
with pyelitis and ureteritis cystica Gross:
irregular scarred cortical surface
usually at poles, dilated and blunted calyces; dilated ureter; retraction and
destruction of papillae with “U” shaped scars Micro: tubular thyroidization (filled with colloid casts)
and atrophy, interstitial fibrosis and inflammation (intense diffuse
lymphoplasmacytic inflammatory infiltrate with germinal centers), obliterative
endarteritis of vessels, interstitial Tamm-Horsfall protein (amorphous,
fibrillary, PAS+ material surrounded by inflammatory cells), normal glomeruli
early Micro
images: marked
inflammation sparing glomeruli #1; #2 with plasma
cells; #3
(various images, including EM) DD: chronic glomerulonephritis (diffusely scarred
cortex) Acute
drug-induced interstitial nephritis:
synthetic penicillin, rifampin, thiazides, phenylbutazone, cimetidine Onset
15 days after exposure (not dose related) Rash,
fever, eosinophilia, hematuria, mild proteinuria; 50% have rising creatinine or
acute renal failure Pathophysiology: possibly a delayed (type IV) hypersensitivity
reaction, due to hapten like effect of drug, which binds to tubular epithelium,
making it immunogenic Treatment: stop offending drug Micro: edematous interstitium containing abundant
eosinophils and neutrophils, lymphocytes, macrophage; also basophils and plasma
cells, occasionally granulomas after methicillin; tubular necrosis and
regeneration present; glomeruli are normal Micro
images: various
images Granulomatous interstitial nephritis Rare Causes: aspirin, gentamycin, combinations, E. coli
infection, other infections, sarcoidosis, Wegener’s granulomatosis, oxalosis
secondary to intestinal bypass Micro: usually granulomas, T cells and macrophages; rarely
neutrophils References: Hum
Path 1995;26:1347 Unknown
etiology – may be genetic or associated with ochra toxin Karyomegaly
may also be present within GI tract, lungs and vessels Micro: focal marked enlargement of tubular cells with
prominent nuclei and nucleoli; chronic interstitial nephritis, normal and
sclerotic glomeruli Micro
images: various
images DD: lead toxicity Occupational
(electric storage battery makers, painters, welders, foundrymen, jewelers) or
environmental causes (children eating lead pain, water in lead pipe systems,
lead earthenware, moonshine liquor) Lead
exposure damages central and peripheral nervous system, GI tract and kidney Micro: tubular atrophy and interstitial fibrosis; tubular
inclusions are eosinophilic and intranuclear or cytoplasmic, acid-fast and red
with Giemsa stain; arteriolar disease similar to nephrosclerosis; tubules
disappear in chronic disease; no inflammation EM: inclusions are lead-protein complex that appear as
compact cores surrounded by loose meshwork of fibrils Associated
with transplant patients May be
due to defective macrophage function that blocks lysosomal degradation of
engulfed bacteria, filling up cytoplasm with undigested debris Gross: soft, yellow, mucosal plaques Micro: foamy macrophages with PAS+ granular cytoplasm due to
phagosomes stuffed with bacterial debris; Michaelis-Gutmann bodies (laminated
mineralized concretions, positive with calcium and iron stains); may have late
fibrous stage Micro
images: various
images Positive
stains: calcium, iron EM: intracellular calcific inclusions DD: xanthogranulomatous pyelonephritis (no
Michaelis-Gutmann bodies) References: AJSP
1989;13:225, AJSP
1984;8:151 Chronic
tubulointerstitial nephropathy of tubular calcium phosphate deposition causing
slowly progressive renal insufficiency Less
common than nephrolithiasis Hypercalcemia
can also cause glomerular calcium deposition and glomerulosclerosis (Archives
2003;127:E80) Causes: conditions associated with chronic hypercalcemia,
including primary hyperparathyroidism, myeloma or other malignancy, vitamin D
intoxication, sarcoidosis, milk alkali syndrome, distal renal tubular acidosis,
hypercalciuria due to chronic furosemide use in premature infants (Hum
Path 2000;31:1363) May be
due to oral sodium phosphate as bowel preparation (Hum
Path 2004;35:675) Micro: diffuse tubular injury with atrophy, interstitial
fibrosis and abundant tubular deposition of calcium phosphate; over time,
develop glomerulosclerosis and vascular disease Micro
images: glomerular calcification in hypercalcemic patients (von Kossa stains
in all but D) - A:
mesangial calcium deposition; B: calcium fills Bowman’s space; C: sclerosed
glomerulus with global calcium deposits; D: segmental lesion with stippled
basophilia; E: same as D but with von Kossa stain; F: calcified cortical
tubules Virtual
slides: nephrocalcinosis EM
images: calcium
deposits (arrows) with glomerular capillary basement membrane and mesangium Three
types: (1)
acute uric acid nephropathy due to precipitation of uric acid crystals in
tubules causing acute renal failure; associated with chemotherapy for
leukemia/lymphoma (2)
chronic urate nephropathy, associated with gout and lead exposure from drinking
“moonshine” (3)
uric acid stones, occur in 22% with gout, 42% with secondary hyperuricemia Gout
causes deposition of monosodium urate crystals with tophus formation that
obstructs tubules, leading to cortical atrophy and scarring Micro
images: gouty
nephropathy Xanthogranulomatous pyelonephritis Rare;
usually unilateral, usually ages 40+, 2/3 women Usually
due to stones, Proteus, E. coli; associated with pelvicalyceal obstruction and
ulceration Destructive
inflammatory process that may complicate chronic pyelonephritis May
resemble renal cell carcinoma; correct preoperative diagnosis is unusual Gross: multiple yellow nodules around calyces, may form a
mass and be infiltrative Gross
images: destruction of parenchyma Micro: replacement of renal parenchyma with foamy
histiocytes, occasional multinucleated giant cells and inflammatory cells DD: malakoplakia References: AJSP
1992;16:522, Archives
1988;112:275 Blood vessel disorders Often
bilateral, causes renal insufficiency; revascularization may help Sclerosis
of renal arterioles and small arteries, particularly afferent arterioles;
causes focal ischemia Risk
factors for renal failure:
African-American, severe hypertension, diabetes mellitus Due to
hypertension; causes moderate reductions
in GFR or proteinuria Gross: mildly shrunken kidneys, cortical surface resembles
leather Gross
images: granular
cortical surface #1; #2;
#3;
#4 Micro: thickened and hyalinized vessel walls, hyaline
deposition in arterioles, fibroelastic hyperplasia in lobular/arcuate arteries,
tubular atrophy, interstitial fibrosis, periglomerular fibrosis,
glomerulosclerosis Hyaline
arteriolosclerosis: outer wall
is thickened by deposition of PAS+, eosinophilic, homogenous material, with
atrophy of smooth muscle cells in vessel wall and uniform basement membrane
thickening; more common in afferent arteriole and vessels lacking an internal
elastic lamina; associated with diabetes, hypertension, increasing age;
associated with IgM and C3 deposition Micro
images: various
images Virtual
slides: arterio-
and arteriolosclerosis EM
images: (1) thickened
glomerular capillary due to subendothelial expansion; (2) thickened
glomerular capillary wall with mesangial cell interposition (M), protein
insudation (circle), subendothelial basal lamina (arrowheads) (2001;14:1200) After
obstetric emergency; fatal if bilateral; may be due to DIC; necrosis sharply
limited to cortex and columns of Bertin Gross
images: multiple
small infarcts Micro
images: various
images Emboli in kidney After
surgery for abdominal aortic aneurysm or aortography; emboli have cholesterol
crystals; may cause acute renal failure if renal function already compromised Virtual
slides: multiple
atheroemboli Infarct of kidney Usually
due to emboli from left atrial mural thrombi or left ventricular myocardial
infarction; also endocarditis, abdominal aortic aneurysm, atherosclerotic
emboli Infarcts
are "white" anemic type; ringed by intense hyperemia; wedge shaped
with apex towards medulla Gross
images: wedge
shaped hemorrhagic infarct #1;
#2;
#3 Micro
images: cholesterol
emboli; recent
infarct Virtual
slides: septic
infarct Malignant hypertension and
accelerated nephrosclerosis Usually
associated with preexisting hypertension, glomerulonephritis or reflux
nephropathy Frequent
cause of death from uremia in patients with scleroderma 1-5%
of patients with hypertension; higher frequency in young men, African-Americans Pathophysiology: vascular damage (due to chronic hypertension,
arteritis, coagulopathy) increases permeability of small vessels to fibrinogen
and other plasma proteins and causes endothelial injury and platelet
deposition, which causes fibrinoid necrosis; kidneys become ischemic which
stimulates renin-angiotensin system, produces increased angiotensin II, which
causes renal vasoconstriction as well as increased aldosterone secretion and
salt retention, which elevate blood pressure even further Symptoms: diastolic blood pressure 130 mm or more,
encephalopathy, cardiac symptoms, headache, nausea, vomiting, renal failure,
loss of consciousness, proteinuria Treatment: antihypertensive therapy before irreversible renal
lesions develop; 5 year survival 75% with treatment vs. 1 year survival of 10%
without treatment Gross: "flea bitten" appearance due to pinpoint
petechiae on cortical surface Gross
images: focal
small hemorrhages #1; #2;
#3 Micro: fibrinoid necrosis of arterioles, hyperplastic
arteriolitis (onion skinning) due to concentric layering of collagen; may see
necrotizing glomerulitis, wrinkling and collapse of capillary walls, small
crescents Myointimal
hyperplasia and hypertrophy:
associated with acute or persistent severe high blood pressure; early -
profound intimal thickening by myxoid connective tissue reducing lumen; late -
scarring and concentric thickening of vessel wall by myointimal cells and
deposition of basement membrane type material (onion skinning) Necrotizing
arteriolitis: fibrinoid necrosis
of afferent arteriole, often superimposed of hyperplastic or hyaline lesions;
media has deposits of deeply eosinophilic and fibrillar material containing
fibrin and fibrinogen Micro
images: (1) fibrinoid necrosis
of small vessel; (2) onion skinning
of vessel wall; (3) various
images Virtual
slides: onion-skinning
of vessels Immunofluorescence: occasional fibrin, fibrinogen, IgM, complement EM: swollen endothelium; may be focally disrupted from
glomerular basement membrane by accumulation of electron-dense material 2-5%
of cases of hypertension, surgery curative in 70% Associated
with elevated renin levels; ACE inhibitors helpful Causes: Atheromatous
plaque: more common in older men
with diabetes, often at orifice of renal artery, associated with aneurysmal
dilatation of aortal distal to renal arteries Fibromuscular
dysplasia: more common in younger women; may involve other
vessels; not responsive to hypertensive drugs; 50% bilateral, often involve
distal 2/3 of renal artery; due to intimal, medial, perimedial or periarterial
fibroplasia, medial hyperplasia or medial dissection Radiation
injury: loss of muscle, intense
fibrosis in all wall layers; usually after radiation treatment including renal
artery field years previous Takayasu’s
aortitis: also called pulseless
disease; chronic sclerosing aortitis of unknown etiology Diagnosis: hypertension that responds to ACE inhibitors;
bruit, elevated renin; see stenosis by intravenous pyelogram or renal scans Gross: shrunken kidney Gross
images: shrunken
kidney Micro: diffuse atrophy with crowded and smaller glomeruli,
atrophic tubules, interstitial fibrosis; arterioles usually normal; usually no
hypertensive changes in small vessels, although opposite kidney may show
hypertensive changes Medial
fibroplasia: multiple foci of
stenosis alternate with microaneurysms to produce “string of beads” Perimedial
fibroplasia: normal outer half of
media but hyperplasia of muscle causes uniform circumferential thickening of
vessel wall with luminal narrowing Intimal
fibroplasia: hyperplasia of intima,
resembling atherosclerosis, but without lipid deposition; usually ages 20-39;
lower levels at autopsy in Mexico City (Mexico) than blacks and whites in New
Orleans (USA) (Archives
1996;120:261) Periarterial
fibroplasia: rare, fibrosis of
adventitia extends into adjacent adipose and connective tissue, causing
constriction from without Case
reports: 4 year old boy with severe
hypertension, cardiac failure, neurofibromatosis and renal artery stenosis due
to renal artery dysplasia and intimal hyperplasia (AJSP
1994;18:512), 35 year old woman
with aortic coarctation and renal artery stenosis due to fibromuscular
dysplasia (Archives
1989;113:809) Sickle cell disease nephropathy Sickle
cell trait or disease cause hematuria, decreased concentrating ability May be
due to ischemia in hypertonic, hypoxic renal medulla due to plugging of vessels
in vasa recta Mild
proteinuria in 30% Micro: patchy papillary necrosis; occlusion of glomeruli by
sickled cells; extensive congestion and sickling in peritubular capillaries Micro
images: various
images Due to
trauma, tumor, membranous glomerulonephritis Gross
images: renal
vein thrombus Kidney transplantation Kidney
transplantation-general Biopsies:
determine (a) if graft failure is
due to rejection, drug related nephrotoxicity (cyclosporin, tacrolimus), acute
tubular necrosis, infections, vascular obstruction, outflow tract obstruction,
primary glomerular disease; also (b) intensity and nature of rejection, potential
reversibility and thus most suitable therapy Prognostic
factors for success of graft: For
living kidneys with ABO-incompatibility, preoperative maximum levels of
anti-A/B IgG titers in recipient predict long-term results of transplantation
(humeral rejection in 71% with titers > 1:128 vs. 24% for those less than
1:32-1:64 Phlebitis of thin-walled or arcuate and interlobular veins (with
muscular walls) has no direct adverse affect, but is associated with borderline
changes suggestive of acute cellular rejection or acute rejection in 16% of
cases (Hum
Path 2001;32:1388) Intimal
arteritis in allograft has adverse effect on graft outcome Plasmacytic
infiltrates in renal allograft biopsies are uncommon; polyclonal
infiltrates are associated with acute rejection but with similar survival as
plasma cell negative biopsies; also associated with posttransplantation
lymphoproliferative disease (Hum
Path 2001;32:205) 10% of
transplants to adults from pediatric cadaveric donors < 6 years,
particularly infants, show diffuse irregular lamellation of glomerular basement
membrane and segmental glomerular sclerosis as early as 10 weeks after
transplant (AJSP
1999;23:437) Occurs
within minutes to hours after revascularization, causing abrupt cessation of
urine production Due to
preformed circulating antibodies in recipient to donor endothelial cells,
caused by prior pregnancies, blood transfusions or transplants Rare
due to routine screening and cross matches Gross: mottled cyanosis and diminished turgor in renal
graft Micro: fibrin thrombi in glomerular capillaries,
peritubular venules and other vessels leading to infarction and tubular
necrosis; variable white blood cells within glomeruli, peritubular capillaries
and interstitium Micro
images: various
images Immunofluorescence: linear staining of IgM or C3 along glomerular and
peritubular capillaries EM: capillary occlusion by degranulated platelets and
endothelial denudation of glomerular basement membrane; also fibrin, sludged
red blood cells Can
occur at any time after transplantation, although usually within months of
transplant Either
acute vascular rejection or acute interstitial allograft rejection Acute
vascular rejection Also
called acute humoral rejection Associated
with poor graft outcome Micro: most severe changes are in small arteries,
arterioles and veins Vessels: early changes are swelling and vacuolization of
endothelial cells with ulceration, chronic inflammatory cells in intima and
vacuolization of smooth muscle cells in media; thrombi are often small and
nonocclusive, but in irreversible rejection, become obliterative and widespread
with necrosis of vessel wall Glomeruli: endothelial cell swelling, increased cellularity and
occasional thrombosis Tubules: focal necrosis Interstitium: hemorrhage Micro
images: various
images #1; #2;
#3 Virtual
slides: acute
rejection Immunofluorescence:
occasionally complement in vessel
walls and glomeruli EM:
endothelial cell swelling and
separation of endothelium from basement membrane by fluffy fibrillar material,
which may contain fibrin or platelet fragments Acute
interstitial allograft rejection Also
called acute cellular rejection, acute tubulointerstitial rejection, acute
reversible rejection Usually
reversible with therapy, so important to quantitate % of rejection that is
interstitial Micro: early - edema, lymphocytic infiltration
of interstitium and peritubular capillaries, dilation of peritubular
capillaries; late - tubulitis (lymphocytes on internal aspect of
tubular basement membrane), increased infiltration by lymphocytes (60% CD8+),
plasma cells, macrophages and mast cells, occasional granulocytes; tubulitis is
more concentrated in cortex than medulla; phlebitis of arcuate and interlobular
veins often present (Hum
Path 2001;32:1388) Micro
images: various
images; neutrophilic
tubulitis and interstitial nephritis; atrophic
tubule containing proteinaceous cast containing fragmented inflammatory cells
(inset: neutrophils) Immunofluorescence:
negative EM: tubular damage and regeneration, many inflammatory
cells in interstitium; variable glomerular and vascular changes DD: urinary tract infection (neutrophilic tubulitis
usually more severe than lymphocytic tubulitis, positive cultures) References:
Mod
Path 2003;16:281 (versus urinary tract infection), Mod
Path 1996;9:1118 (mast cells), AJSP
2000;24:553 (severe tubulitis) Also
called chronic allograft nephropathy Uncommon,
months to years after transplantation, independent of acute rejection and
specific disease Irreversible;
end stage of repeated episodes of acute vascular or interstitial rejection Most
common cause of graft failure after 6-12 months Transplant
arteriopathy (capillaropathy) and transplant glomerulopathy are induced by
alloantigens May be
mediated by replicative senescence (failure of cells to divide at some point,
associated with telomere shortening and altered cell characteristics, Hum
Path 2003;34:924) Transplant
capillaropathy: peritubular
capillary profile with 7+ circumferential basement membrane layers or 3
profiles with 5-6 circumferential layers; these findings are specific (except
for obstructive uropathy or thrombotic microangiopathy) and sensitive (present
in 80%) for chronic rejection; may be due to repeated episodes of endothelial
cell damage or death and regeneration EM
better than light microscopy to identify microvascular changes (Mod
Path 2001;14:1200) Chronic
transplant nephropathy: nonspecific
sclerosing changes (no lesions indicative of immunologic injury, thus a
diagnosis of exclusion) Gross
images: enlarged
kidney with surface hemorrhage Micro: resembles nephrosclerosis; severe obliterative
fibrointimal proliferation or mucoid widening of intima; reduplication or
disruption of elastic lamina and irregular fibrosis of media; variable
distribution of vascular lesions; also occasional small thrombi; atrophic
tubules, diffusely scarred interstitium; glomerulosclerosis with ischemic
glomerular capillary collapse and thickened capillary walls Micro
images: (1) moderate fibrointimal
hyperplasia #1; #2; (3) severe interstitial
fibrosis; (4) severe vascular intimal
sclerosis; (5) chronic
transplant glomerulopathy-various images; (6) chronic
allograft nephropathy-various images; (7) a:
acute tubulointerstitial rejection (PAS stain); b: plasma cell infiltrate; c:
CD79a+ cells; d: C4d deposition in peritubular capillaries Virtual
slides: chronic
rejection Immunofluorescence: negative, occasional IgM, IgG or complement linear or
granular deposition Negative
stains: CMV EM:
thickened capillary walls due to
widening of subendothelial space or mesangial interposition EM
images: (1) transplant
glomerulopathy with accumulation of basement membrane material and well
developed subendothelial basal lamina along entire capillary circumference
(arrowheads); E-endothelial cell; P-podocyte, (2) transplant
glomerulopathy with duplication and splitting of basal lamina, (3) transplant
capillaropathy with a peritubular capillary profile with circumferential
multiplication and splitting of basement membrane and 7+ layers Banff classification of rejection Adequate core biopsy must contain 10 glomeruli and 2 arteries
(marginal if 7-10 glomeruli and 1 artery; unsatisfactory if <7 glomeruli or
no arteries) Normal Antibody-mediated rejection: immediate (hyperacute), delayed (accelerated acute) Borderline changes: “suspicious” for acute changes; cases with foci of mild tubulitis
(1-4 mononuclear cells/tubular cross section) and interstitial inflammation
(10-25% of parenchyma affected) Acute/active rejection Type IA:
significant interstitial inflammation (>25% of parenchyma affected) and foci
of moderate tubulitis (>4 mononuclear cells/tubular cross section or group
of 10 tubular cells) Type
IB: significant interstitial inflammation
(>25% of parenchyma affected) and foci of severe tubulitis (>10
mononuclear cells/tubular cross section or group of 10 tubular cells) Type
IIA: mild to moderate
intimal arteritis (v1) Type
IIB: severe intimal
arteritis comprising >25% of luminal area (v2) Type
III: “transmural”
arteritis or arterial fibrinoid change and necrosis of medial smooth muscle
cells (v3 with accompanying lymphocytic inflammation) Chronic/sclerosing
allograft nephropathy Grade I:
mild interstitial fibrosis and tubular atrophy without (a) or with (b) specific
changes suggesting chronic rejection Grade II:
moderate interstitial fibrosis and tubular atrophy without (a) or with (b)
specific changes suggesting chronic rejection Grade III:
severe interstitial fibrosis and tubular atrophy and tubular loss without (a)
or with (b) specific changes suggesting chronic rejection Changes unrelated to rejection Miscellaneous Associated
with cystic disease, adenomas (usually papillary), carcinomas (usually
papillary, small multiple bilateral tumors with cysts) Associated
with beta2 microglobulin amyloidosis, usually affecting bone or joints,
occasionally viscera (AJSP
2002;26:130) Micro: arterial intimal thickening, calcium oxalate
crystals in tubules Micro
images: calcium
oxalate crystals (various causes) Increases
susceptibility to infection; chronic obstruction causes hydronephrosis Causes:
congenital (posterior urethral
valves, urethral strictures, meatal stenosis, bladder neck obstruction,
ureteropelvic junction narrowing, vesicoureteral reflux); stones, prostatic
hypertrophy, tumors, inflammation, sloughed papillae or blood clots, normal
pregnancy, uterine prolapse or cystocoele, neurogenic ureter/bladder Symptoms: pain due to distention of collecting system or renal
capsule; none if unaffected kidney maintains adequate function; early
- nocturia, polyuria; after relief of obstruction, may get massive diuresis
with sodium wasting Hydronephrosis: cystic dilation of renal pelvis and calyces
associated with progressive atrophy of kidney due to obstructive uropathy Gross: more calyceal dilation if incomplete obstruction
since glomerular filtration is not suppressed; cortical rim thins out due to
atrophy Gross
images: (1) hydronephrosis;
(2) hydronephrosis
due to renal calculus; (3) advanced
hydronephrosis due to staghorn calculus; (4) marked
hydronephrosis and hydroureter Micro: initial functional alterations are tubular; cause
interstitial inflammatory infiltrate; chronic changes are cortical atrophy,
diffuse interstitial fibrosis, blunting of calyces Severity
is related to dose, method of irradiation, age, amount of perirenal fat,
presence of renal disease, use of chemotherapy Acute
radiation nephropathy: 6-12 months
after radiation exposure, may occur quicker in children; gradual onset of
edema, hypertension, dyspnea after exertion, pleural and peritoneal serous
effusions, anemia, headaches, proteinuria, urinary casts; associated with
reduction in GFR and renal failure in 50%; those who recover have persistent
proteinuria and renal impairment; overall high mortality rate Chronic
radiation nephropathy: either
follows acute phase or develops insidiously; mild proteinuria and moderate
hypertension years after radiation exposure Micro: variable glomerulosclerosis, segmental fibrinoid
necrosis, thickened glomerular capillary walls with double contour (silver
stain), may have prominent mesangium; fibrinoid necrosis of arterioles and
small arteries with variable thrombosis; swelling of tubular epithelium with
desquamation, basement membrane thickening and splitting, tubular loss and
atrophy; often abnormal tubular regeneration; focally scarred interstitium
without inflammation Immunofluorescence: focal IgM and fibrinogen EM: widened glomerular subendothelium due to fibrin or
flocculent material; may have focal extension of mesangium into subendothelial
space; swollen or focally detached endothelium References: Archives
1977;101:469 Stones
within collecting system of kidney are present in 5-10% of Americans, men ages
20-49 most common Due to
supersaturation of stone constituents, decreased urine volume or deficiency of
crystal inhibitors in urine 80%
unilateral, usually in calyces, pelvis, bladder All
stones contain an organic matrix of mucoprotein Usually
2-3 mm with severe, abrupt flank pain and hematuria Calcium
oxalate/phosphate (75%): due to
hypercalciuria (idiopathic, 50%), hypercalcemia, hyperoxaluria (in vegetarians
with oxalate rich diet), hyperuricosuria (hyperparathyroidism, bone disease,
sarcoidosis), rarely primary hyperoxaluria (Archives
2002;126:1250); oxalate crystals
are highlighted by polarized light Struvite
(triple stones, magnesium ammonium phosphate, 15%): due to urea-splitting bacteria (Proteus,
Staphylococcus); produce staghorn calculi Uric
acid (6%): due to hyperuricemia,
chemotherapy for leukemia, uricosuric drugs, excess dietary proteins; 50% lack
elevated uric acid in blood/urine; may be due to acidic pH; radiolucent; may
become staghorn calculi if in renal pelvis; elongated and rectangular crystals
in collecting tubules or doubly refractile crystals in interstitium with giant
cell reaction Cysteine
(1%): due to genetic defects in
cystine transport; autosomal recessive, affects 1 per 20,000; yellow-brown and
radioopaque stones form at low urinary pH; crystals are flat hexagons in urine Xanthinuria
(rare): autosomal recessive, due to
deficient xanthine oxidase, causing excessive xanthine levels and stones in 1/3
with this disorder Case
reports: nephrectomy for renal mass
due to urolithiasis caused by 2,8-dihydroxyadenine crystals (Hum
Path 1992;23:1081) Gross
images: (1) staghorn
calculus; (2) animation;
(3) various types of kidney stones Stone
granuloma: complication of ureteral
stone fragmentation and instrumentation Calcium
oxalate crystals plus foreign body giant cells and macrophages End of Kidney non tumor chapter
Go to Kidney tumors
chapter
American Journal of Clinical Pathology
American Journal of Surgical Pathology
Archives of Pathology and Laboratory Medicine
Human Pathology
Modern Pathology
Silva’s Diagnostic Renal Pathology 2009
Websites: Atlas of Renal Pathology, University of North Carolina, PathoPic, Webpathology.com
Virtual slides: University of Iowa, USCAP
Please refer to these primary references for more detailed discussions and photographs
