Kidney non-tumor
Last revised 7 October 2009
Copyright (c) 2002-2008, PathologyOutlines.com, Inc.
Bold and underlined topics are hypertext links within this document or to references
Primary references, embryology, anatomy, glomeruli, tubules and interstitium, physiology, renal disease-general, congenital anomalies
Primary glomerular diseases: biopsy-general, glomerular disease-general, pathogenesis, C1q, chronic glomerulonephritis, congenital nephrotic syndrome, diffuse mesangial hypercellularity with nephrotic syndrome, fibrillary GN, focal proliferative and necrotizing GN, focal and segmental GS, 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, infantine nephropathic cystinosis, 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, granulomatous interstitial nephritis, karyomegalic nephropathy, lead, malakoplakia, nephrocalcinosis, urate nephropathy, xanthogranulomatous pyelonephritis
Blood vessel disorders: atherosclerotic, benign nephrosclerosis, diffuse cortical necrosis, emboli, 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
Go to Kidney tumors chapter
American Journal of Surgical Pathology (AJSP), March 1977 to November 2004
Archives of Pathology and Laboratory Medicine (Archives), January 1976 to November 2004
Human Pathology (Hum Path), March 1970 to October 2004
Modern Pathology (Mod Path), January 1988 to November 2004
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); 2004
University of Pittsburgh case studies: #1 to #60
www.WebPathology.com - source of numerous beautiful GU images
Journal search terms: kidney, renal
Please refer to these primary references for more detailed discussions and photographs
Stages of kidney development: pronephros (based on Wolffian duct, kidneys nonfunctional), mesonephros (appear at week 4, form nephron-like tubules but degenerate), metanephros (form at week 5, function by week 11)
Metanephric blastema: forms glomerulus, proximal convoluted tubules, loops of Henle, distal convoluted tubules, connective tissue of renal interstitium
Ureteric bud: forms cortical and medullary collecting tubules and medullary collecting ducts
Gross images: fetal kidneys at 25 weeks gestation; infant kidney with fetal lobulations
Posterior abdomen on either side of vertebral column, in retroperitoneum
Surrounded by fat and loose areolar tissue
Superior border is at T12, inferior border is at L3
11 cm long x 5-8 cm x 3 cm
Weighs 125-170 g in males, 115-155 g in females
Capsule: covers kidney, is surrounded by perirenal fat
Cortex: outer 1.2 cm of kidney, surrounds inner medulla containing pyramids and lacking glomeruli
Renal sinus: fatty compartment within confines of kidney not delineated from renal cortex by a fibrous capsule
Gerota’s fascia: fibromembranous tissue surrounding the kidney that separates it from adjacent musculature
Ureter ascends into renal pelvis, divides into calyces (2-3 major, 12 minor total)
Related to a calyx are renal pyramids with apices called papillae
Vasculature: receives 25% of cardiac output, 90% goes to cortex, via interlobar, arcuate, interlobular, afferent arterioles, then into glomeruli, efferent arterioles, peritubular vascular network
Deeper juxtamedullary glomeruli give rise to vasa recta, which supply outer and inner medulla
Since arteries are end vessels, their occlusion causes infarction
Glomerular disease causes tubular disease, since efferent arterioles supply tubules
Regional lymph nodes: renal hilar, paracaval, aortic, retroperitoneal
Diagrams: vertical section; relation to other organs - #1; #2; #3; #4; #5
Gross images: normal adult kidney; kidney cross section; close-up
Micro images: renal capsule
Virtual slides: normal kidney
Tuft-like vascular structure composed of lobules of specialized capillaries that arise from afferent arteriole and rejoin to drain into efferent arteriole
200 microns in diameter, 20% larger in juxtamedullary area
Layers (inner to outer) are: fenestrated endothelium, then glomerular basement membrane (lamina rare interna, lamina densa and lamina rare externa), then podocytes (visceral epithelium with foot processes); also parietal epithelium which lines Bowman’s space
Glomerular basement membrane (GBM): normally 310-380 nm, composed of type IV collagen, laminin, polyanionic proteoglycans (mostly heparan sulfate), fibronectin, entactin
Type IV collagen forms suprastructure to which other glycoproteins attach; composed of 3 alpha chains
Each alpha chain has amino 7S domain, middle triple helical domain and a carboxyl noncollagenous (NC1) domain; NC1 domain is site of anti-GBM nephritis and dimer formation
Mesangial cells: type of myofibroblast that supports glomerular tuft, regulates capillary width and blood flow; are phagocytic and can proliferate
Podocytes (visceral epithelium): their foot processes embed in lamina rare externa of glomerular basement membrane; the distal diffusion barrier to filtration of proteins is a filtration slit diaphragm between foot processes
Glomerular filtration: highly permeable to water and solutes through fenestrated endothelium, but impermeable to large proteins like albumin (proteins are more permeable if smaller and more cationic)
Diagrams: normal glomerulus #1; #2; #3; vessels surrounding glomeruli and tubules
Micro: hypercellularity - the presence of more than 3 cells in an individual glomerular mesangial region away from the vascular pole
Micro images: normal glomerulus #1; #2; #3; A: light microscopy; B: fluorescence microscopy with Hollande’s fixative distinguishes proximal (heavy star) and distal (asterisk) convoluted tubules; fluorescence microscopy shows thin and delicate glomerular loops, smooth mesangial matrices
EM images: glomerular basement membrane and podocytes
References: Mod Path 2002;15:988
Medullary rays: in cortex, contain cortical collecting tubules and loops of Henle of superficial nephrons
Renal columns of Bertin: cortical tissue extending into spaces between pyramids
Proximal tubules: long microvilli, numerous mitochondria and extensive intercellular interdigitations assist in reabsorption of sodium, water, proteins, glucose, potassium, phosphate, amino acids; vulnerable to toxins and ischemic damage
Juxtaglomerular apparatus: close to glomerulus where afferent arteriole enters it; consists of juxtaglomerular cells (modified smooth muscle cells) plus macula densa (region of distal tubule as it returns to vascular pole of parent glomeruli) plus lacis cells (nongranular cells that reside near afferent arteriole, macula densa and glomerulus and resemble mesangial cells); produces renin
Interstitium: contains fibroblast like cells and peritubular capillaries; expands due to edema and inflammation
Diagrams: renal tubule and its vascular supply; vessels surrounding glomeruli and tubules
Micro images: renal papillae; brush border of collecting duct; medullary rays; macula densa #1; #2; macula densa and juxtaglomerular apparatus; distal and proximal convoluted tubules; cytology of glomeruli (1A), tubules (1B)
Filters 1700L of blood to 1L of urine per day
Excretes metabolic waste; regulates water, salt, pH; secretes renin, prostaglandins, erythropoietin
Nephron: glomerulus filters blood, filtrate enters Bowman’s space, filtrate enters proximal convoluted tubule, to pars recta of proximal tubule, to thin descending limp of loop of Henle, to thick ascending limb of loop of Henle, to macula densa (adjacent to glomerulus), to distal convoluted tubule, to collecting tubule, to collecting duct of Bellini, to calyx
Nephrons: production ceases at birth, are 1.3 million/kidney
Clearance: amount of plasma cleared of a substance per minute to appear in urine
Renal hormones
Aldosterone: causes increased reabsorption of NaCl to increase blood volume
Antidiuretic hormone (vasopressin): stimulates water reabsorption by stimulating insertion of "water channels" or aquaporins into the membranes of kidney tubules; these channels transport solute-free water through tubular cells and back into blood, leading to a decrease in plasma osmolarity and an increased osmolarity of urine; in diabetes insipidus (without ADH), kidney tubules are virtually impermeable to water, which flows out as urine (up to 10 liters of dilute urine/day)
Erythropoietin: secreted in response to low serum pO2, promotes red blood cell production
Natriuretic hormones: cause increase in glomerular filtration rate after nephron destruction
Renin: produced by juxtaglomerular apparatus in response to hypotension, converts angiotensinogen to angiotensin I, which is converted to angiotensin II in the lung by angiotensin converting enzyme (ACE); angiotensin II increases aldosterone production and promotes vasoconstriction
20% of women get urinary tract infections
1% of Americans develop renal stones
Divided for analytical purposes into diseases of glomeruli, tubules, interstitium and vessels
Glomerular diseases tend to be immunologically mediated; tubular and interstitial disorders are often due to toxins/infections
Glomerular and tubular disease affect each other, because glomerular disease impairs the tubular blood supply and increases tubular toxins, and tubular disease causes increased intraglomerular pressure
Acute nephritic syndrome:
Grossly visible hematuria, hypertension, azotemia, oliguria, mild edema, red blood cell casts, variable proteinuria
Associated with postinfectious, diffuse crescentic and membranoproliferative glomerulonephritis
Acute renal failure:
Abrupt anuria or oliguria with rapidly progressive azotemia identified by increase in BUN or ammonia
Azotemia:
Increased serum BUN (blood urea nitrogen) and creatinine, due to reduced glomerular filtration rate (GFR); causes are prerenal (hemorrhage, shock, congestive heart failure, volume depletion), renal and postrenal (obstruction)
Chronic renal failure:
Azotemia progressing to uremia over a period of years
Stages of chronic renal failure: (1) diminished renal reserve (GFR 50% normal) with normal BUN/Cr, (2) renal insufficiency (azotemia, anemia, hypertension, polyuria, nocturia, (3) renal failure: GFR < 20% normal, kidneys cannot regulate volume of solutes and patient develops edema, metabolic acidosis and hypocalcemia, (4) end stage renal disease: GFR <5% normal
Represents the end stage of various renal diseases
Nephrotic syndrome:
Proteinuria > 3.5 g/day, hypoalbuminemia (serum level <3 g/dl), hyperlipidemia, lipiduria, severe edema (anasarca)
Due to derangement in glomerular capillary walls which leads to increased permeability to plasma proteins, causing massive proteinuria, hypoalbuminemia and generalized edema (pitting, periorbital and dependent edema)
Hyperlipidemia is due to increased lipoprotein synthesis and decreased catabolism
Lipiduria is due to leakage of lipoproteins with albumin
Patients are prone to staphylococcus and pneumococcal infections due to loss of immunoglobulins and factor B of complement; thrombosis and thromboemboli are due to loss of anticoagulants such as antithrombin III and antiplasmin
Associated with minimal change disease (more common in children), focal and segmental glomerulosclerosis, membranous glomerulonephritis (more common in adults), systemic disease (SLE, diabetes, amyloidosis), congenital nephrotic syndrome
Rapidly progressive glomerulonephritis:
Acute glomerulonephritis with proteinuria and acute renal failure
Uremia:
Azotemia plus clinical signs/symptoms (gastroenteritis, peripheral neuropathy, fibrinous pericarditis, secondary hyperparathyroidism); associated with chronic renal failure
Tubular defects cause polyuria, nocturia, electrolyte disorders; due to diseases directly or indirectly affecting tubular function
10% of individuals have urinary tract malformations, although many are asymptomatic
15% of congenital urogenital anomalies are secondary to an underlying chromosomal disorder
In children, 20% of chronic renal failure is due to renal dysplasia or hypoplasia
In adults, 10% of chronic renal failure is due to adult polycystic kidney disease
Absence of normal appearing proximal tubules
Associated with monochorionic twinning or renal hypoperfusion
References: Hum Path 1991;22:147; Hum Path 1986;17:1259
Agenesis
Bilateral agenesis is incompatible with life and is associated with pulmonary hypoplasia and limb defects
Incidence is 0.03% of newborns but 0.3% of stillborns
Unilateral renal agenesis is uncommon, not fatal
Compensatory hypertrophy in other kidney may cause glomerulosclerosis in adults
Case reports: associated with Klinefelter’s (47, XXY) syndrome (Archives 2004;128:e44)
Gross images: 1: posterior view of stillborn with no kidneys and downwardly displaced adrenal glands (arrows); 2: 47,XXY
Duplication of ureters
Occurs in <1% of individuals
Usually asymptomatic; may be associated with obstruction
Gross images: bilateral duplication
Ectopic (displaced) kidneys
Usually at pelvic brim, may have kinking of ureters
Horseshoe kidney
1/500 autopsies, 90% are fused at lower pole
Associated with obstruction
Gross images: fusion at lower pole
Hypoplasia
Failure of kidney to develop to normal size without scarring
Usually unilateral, with a reduced number of pyramids (6 or less)
Oligomeganephronia: a type of hypoplasia with a small kidney but hypertrophied nephrons
Gross images: hypoplastic and hypertrophic kidneys
PRIMARY GLOMERULAR DISEASES
Helps establish diagnosis and determine prognostic factors for renal disorders and transplant recipients
Needle core or open biopsies are relatively safe, and only rarely cause morbidity or mortality
Pathology should correlate complete clinical and laboratory information (using a clinical form is recommended) with light microscopy, immunofluorescence and electron microscopy; cannot diagnose certain diseases without immunofluorescence or EM
Must carefully evaluate glomeruli, tubules, interstitium, vessels
Specimen must be handled gently
Don’t: use forceps, pull or stretch tissue, place tissue on dry gauze or water-soaked gauze, freeze entire sample or place on ice-cold saline
Do: transport with tissue culture medium on saline-moistened gauze; cut with fresh scalpel
Dissecting microscope helps assess adequacy of glomeruli; place sample on glass slide with saline
Two cores recommended
Core #1: take samples 0.5 to 1.0 mm thick from each end with razor/scalpel and put in glutaraldehyde for EM; place remainder in saline, then fixative for light microscopy
Core #2: take samples for EM, snap freeze the remainder for immunofluorescence
Wrap light microscopy specimens in lens paper prewetted with fixative (avoid sponges or plastic embedding bags)
If only one core or a small specimen is obtained, use tissue for EM and immunofluorescence, because EM semi-thin sections can also provide light microscopic information
Fixative: mercury fixatives (Zenker’s, Bouin’s, other) provide optimal architectural and cytologic detail; ethanol fixation helps find glycogen or crystals of urate/uric acid
Recommended to section through entire specimen, put 3-4 sections on each slide; for every batch of 5 slides, stain 1 with H&E, 1 with PAS and keep 3 unstained slides for possible future use
Can detect immune complexes with antibodies or using fluorescence microscopy of H & E stained sections fixed in Hollande’s fixative (Mod Path 2002;15:988)
Immunofixation: best performed on unfixed, frozen sections; examine for IgG, IgM, IgA, C3, C1q, C4, fibrin, kappa, lambda; should include positive and negative controls for each run; immunoperoxidase may be a substitute (cheaper, can correlate with H&E, doesn’t fade), but complement antigens are difficult to detect, may have higher background staining
Gross images: (1) a: renal cortex with round red glomeruli; b: renal medulla without glomeruli; (2) diagram about dividing up core tissue if no dissecting microscope is present
Minimum glomeruli: 5-10 in general; 10 for crescentic disorders; 1 may be sufficient for diffuse lesions such as membranous glomerulonephritis
Immunohistochemistry: IgG, IgA, IgM, C1q, C3, C4, fibrinogen, fibrin
EM: uses osmium tetroxide or glutaraldehyde for fixation (cannot perform if tissue exposed to B5, Zenker’s or other mercury-based fixatives, can reprocess tissue from paraffin block); embed in epoxy resin, stain semi-thin (one micron thick) sections with toluidine blue or methylene blue; obtain thin sections for EM, stained with uranyl acetate and lead citrate
Frozen section: requested to determine adequacy (% sclerotic glomeruli) in donor kidney for transplant
Transplant biopsies: performed to assess rejection
References: Mod Path 2004;17:1555
Glomerulonephritis: inflammation of glomerulus
Glomerulopathy: any disorder affecting glomerulus
Primary: kidney is only or predominant organ involved
Changes can be diffuse (all glomeruli) or focal; global (entire glomerulus) or segmental (part of glomerulus) or mesangial
Minimal change disease, diffuse mesangial hypercellularity and focal and segmental glomerulosclerosis may be a continuum of the same disease.
Micro:
Hypercellularity: due to cellular proliferation (mesangial, endothelial, parietal epithelial cells); white blood cells (acute and chronic) or crescents (white blood cells and epithelial cells)
Basement membrane thickening is highlighted by PAS stain and electron microscopy; EM also shows electron-dense deposits (usually immune complexes) in or adjacent to basement membrane (subepithelial is most common)
Hyalinization and sclerosis of glomeruli are the end result of glomerular damage from various causes
Pathogenesis of glomerular injury
Usually immune mediated via antibody deposition, cell-mediated injury or activation of alternative complement pathway
Antibodies deposited are either to in situ antigen (intrinsic or planted) or are circulating immune complexes
Intrinsic: Goodpasture’s disease-antigens are in basement membrane; Heymann nephritis-antigens are on visceral epithelial cells; produce linear immunofluorescence patterns
Planted antigens are deposited in basement membrane; may be exogenous (drugs, infectious agents) or endogenous (DNA, immunoglobulin, immune complexes); their cationic proteins bind to glomerular anionic sites and produce granular lumpy staining by immunofluorescence
Circulating immune complexes may be endogenous (DNA, tumors) or exogenous (infectious products); they usually localize within glomeruli and activate complement; deposits are usually mesangial or subendothelial and resolve by macrophage phagocytosis, unless there are repeated cycles of formation (Hepatitis B/C, lupus)
Cell-mediated immune injury is by sensitized nephritogenic T cells
Progression to end stage renal disease occurs when the glomerular filtration rate (GFR) is 30-50% of normal, due to compensatory hypertrophy of remaining glomeruli and systemic hypertension (inhibited by angiotensin converting enzyme inhibitors), eventually causing glomerulosclerosis
Micro: injured epithelial cells have vacuoles, retract and detach from basement membrane, lose foot processes
Immunofluorescence patterns: granular deposits represent immune complexes that settle out of blood or form in situ; linear deposits are due to anti-basement membrane antibodies or light chain nephropathy
Can detect via fluorescent antibodies or using fluorescence microscopy of H & E stained sections fixed in Hollande’s fixative (Mod Path 2002;15:988)
Rare; causes proteinuria that responds poorly to steroids
Teenagers and young adults, higher incidence among blacks and males
Slow progression to renal failure
Micro: variable mesangial hypercellularity with increase in mesangial matrix; variable segmental glomerulopathy
Micro images: various images including EM
Immunofluorescence: prominent mesangial C1q deposition; also IgG, IgM, IgA and C3
EM: mesangial immune complex deposits
DD: lupus nephritis (may have prominent deposition of C1q, C3, immunoglobulins)
An end stage disease due to progression of various types of glomerulonephritis; occasionally is no prior history of kidney disease
Rates of progression: rapidly progressive (90%), post-streptococcal (1% kids, 5% adults), focal and segmental glomerulosclerosis (50-80%, rapid), membranous (50%), membranoproliferative (50%), IgA nephropathy (30-50%, slow)
Paradoxically, nephrotic syndrome decreases as glomeruli disappear
Gross: symmetrically small kidneys with thin granular cortex and increased peripelvic fat
Gross images: bilaterally small kidneys #1; #2; #3; #4 (cut surface)
Micro: glomerulosclerosis, tubular atrophy and thyroidization, interstitial fibrosis and lymphocytic inflammation; arterial and arteriolar sclerosis
Micro images: end stage kidney with sclerotic glomeruli, tubular thyroidization, interstitial fibrosis and thickened arterial walls #1; #2
Virtual slides: chronic glomerulonephritis
Heterogenous conditions with nephrotic syndrome in first 3 months of life
No response to steroids or immunosuppressive therapy
Treatment: renal transplant
DD: membranous glomerulonephritis (associated with congenital syphilis, mercury poisoning), toxoplasmosis, HIV, malaria, CMV, minimal change glomerulopathy
References: OMIM #600995
Finnish type
Autosomal recessive
Occurs in 1 per 10,000 newborns in Finland, lower incidence elsewhere
1.5% of cases of nephrotic syndrome in childhood
Nephrin protein at 19q13.1, normally at slit diaphragm of glomerular podocyte, is missing in patients with Finnish-type syndrome of gene mutations
Can diagnose in utero via genetic testing
Heavy proteinuria in utero
At birth, large placentas, proteinuria, edema, infections, premature birth, mild facial/limb abnormalities, poor development
Disease progresses to death without kidney transplant; dramatic improvement with transplant, but 20% have recurrence of nephrotic syndrome
Micro: proximal and distal tubular ectasia with flattening of tubular epithelium, microcysts, glomerulosclerosis, immature glomeruli
Immunofluorescence: nonspecific IgM and C3 in mesangium and capillaries
EM: obliteration of foot processes
References: OMIM #256300
Diffuse mesangial sclerosis
Early onset of severe proteinuria (within first 6 months of life), with rapid progression to end stage renal disease by age 3 years
May be associated with Denys-Drash syndrome (nephrotic syndrome, male pseudohermaphroditism, Wilms’ tumor) or be isolated
Normal placenta, no premature births, but is associated with cataracts and corneal clouding, aniridia, microencephaly, mental retardation, hypertelorism
Does not recur after transplantation
Micro: diffuse mesangial sclerosis; tubular atrophy and interstitial fibrosis
Immunofluorescence: mesangial deposits of IgM, C3, C1q
EM: obliteration of foot processes, basement membrane thickening, increase in mesangial matrix
References: OMIM #256370
Diffuse mesangial hypercellularity with nephrotic syndrome
2-10% of renal biopsies from patients with idiopathic nephrotic syndrome
Associated with steroid resistant or steroid dependent minimal change glomerulopathy, focal and segmental glomerulosclerosis
Note: minimal change disease, diffuse mesangial hypercellularity and focal and segmental glomerulosclerosis may be a continuum of the same disease.
Micro: mild mesangial hypercellularity
Immunofluorescence: IgM, variable C3
EM: obliteration of foot processes, sparse mesangial deposits
Deposition of extracellular nonamyloid fibrillary material in glomeruli and tubular basement membranes (“nephropathy” better term than glomerulonephritis)
Rare, <1% of renal biopsies
More common in whites and females
Patients present with heavy proteinuria, hematuria, and systemic hypertension
50% eventually develop end-stage kidney disease within 2 to 4 years from diagnosis
Associated with membranoproliferative glomerulonephritis
7% also have lymphoproliferative disorders
No evidence of extrarenal fibrillary deposits
Features overlap with hepatitis C virus induced cryoglobulinemic glomerulonephritis
Not a disease, but the morphologic expression of a diverse group of diseases incompletely defined (Hum Path 2001;32:660)
Diagnosis: based on ultrastructural (EM) findings; some authors require exclusion of cryoglobulins
Case reports: crescentic glomerulonephritis with linear IgG staining (Archives 2001;125:534), polyclonal gammopathy but IgG1 deposits (Mod Path 1998;11:103)
Micro: mesangial expansion with PAS-positive material, diffuse thickening of the glomerular basement membrane; variable proliferative lesions, 25% have crescents
Micro images: crescentic glomerulonephritis; various image including EM
Negative stains: Congo red, thioflavin T
Immunofluorescence: deposition of IgG4, C3, kappa and lambda light chains
EM: randomly arranged non-amyloid fibrils in the mesangium and glomerular capillary walls, 18-22 nm thick vs. 10 nm for amyloid and 30-50 nm thick and organized for immunotactoid glomerulopathy; usually extensive effacement of epithelial foot processes
EM images: randomly oriented subepithelial fibrils; 20 nm fibrils; series of images
References: AJSP 1991;15:632
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
Focal and segmental glomerulosclerosis
A histologic pattern of glomerulosclerosis (some glomeruli, part of capillary tuft) associated with heavy proteinuria and progressive renal failure
In normal adults ages 55 or less at autopsy, glomerulosclerosis affects <3% of glomeruli (Archives 1989;113:1253)
Primary (idiopathic) form: causes 10% of nephrotic syndrome in children (usually <5 years), 20% in adults (20-39 years); associated with hematuria, hypertension, nonselective proteinuria; rarely is familial
Secondary forms: heroin addiction, HIV, IgA nephropathy, renal ablation nephropathy, unilateral renal agenesis, hypertension, sickle cell disease, morbid obesity, obstruction, reflux, congenital (associated with 19q13 or nephrin alterations), glycogen storage disease, congenital heart disease, healed focal proliferative and necrotizing glomerulonephritis; have similar glomerular lesions as idiopathic forms
May be due to circulating mediator (proteinuria may recur with allografts in 24 hours, overall in 25-50% of allografts)
Children have better prognosis than adults, who often progress to renal failure (40-60% overall within 10-20 years)
Note: minimal change disease, diffuse mesangial hypercellularity and focal segmental glomerulosclerosis may be a continuum of the same disease.
Micro: focal and segmental glomerulosclerosis and mesangial sclerosis in lobules that appear to adhere to Bowman’s capsule (begins in corticomedullary region), hyaline deposits and foam cells or lipoid droplets in focal glomeruli, initially mild mesangial hypercellularity that becomes hypocellular in advanced lesions; focal tubular atrophy with interstitial fibrosis, hyaline thickening of afferent arterioles
Micro images: focal sclerosis of glomeruli #1; #2 (various images); focal sclerosis his highlighted by trichrome staining; increased glomerular size (left vs. right); perihilar sclerosis with hyalinosis, lipid vacuolization and adhesion to Bowman’s capsule; series of images; diffuse IgM staining
Immunofluorescence: IgM and C3 in sclerotic segments
EM: epithelial cell detachment from glomerular basement membrane; extensive foot process obliteration (even in non-sclerotic glomeruli), mesangial sclerosis with increased matrix, collapsed glomerular loops
EM images: series of images
Special form in IV drug abuse and AIDS
Rapid progression to end stage renal failure in AIDS (3-4 months) and IV drug abuse (2-4 years)
Note: HIV also causes acute renal failure, postinfectious, membranous or membranoproliferative glomerulonephritis (Hum Path 1987;18:1293)
Micro: often collapse and sclerosis of entire glomerular tuft with hypertrophic podocytes filling Bowman’s space; large tubular hyaline casts, flattened epithelium; also manifestations of severe tubulointerstitial injury such as epithelial degenerative changes, microcystic dilation of tubules, interstitial inflammatory infiltrate (primarily activated T cells)
Micro images: various images including EM
EM: tubuloreticular structures in endothelium (non specific for infection), induced by interferon alpha
EM images: tubuloreticular inclusions
References: Hum Path 1988;19:1060 (tubuloreticular inclusions)
Collapsing glomerulopathy
Resembles special form in IV drug abuse and AIDS (rapid progression to renal failure with severe proteinuria, poor response to treatment and similar microscopic changes), but HIV negative
Usually black men
Aggressive variant of focal segmental glomerulosclerosis
Similar changes in renal allografts
May be due to altered hemodynamics
Process may have different origin in renal allografts (Hum Path 2002;33:437)
Micro: accentuation of lobules due to widespread collapse of glomerular capillary loops with localized hyperplasia and hypertrophy of epithelial cells overlying sclerotic segment; cells are vacuolated and swollen, contain abundant resorption droplets; severe tubulointerstitial injury with degenerative changes, dilated tubules, tubular casts, lymphocytic infiltrate
Micro images: series of images; collapsing glomerulopathy
Immunofluorescence: segmental IgM and C3
Glomerular tip lesion
Appears to have similar response to therapy as classic type
Micro: sclerosis only in portion of glomerulus opposite the hilus, forming an adhesion near the opening of Bowman’s space into proximal tubule; capillary lumina of sclerotic loops may be obliterated by swollen endothelial cells with vacuoles and foam cells
Micro images: glomerular tip lesion (PAS); lesions of proximal tubular poles
Idiopathic nodular glomerulosclerosis
top
Resembles nodular diabetic glomerulosclerosis, but in nondiabetic patients
Mean age 68 years, 74% white, 78% men
Typically presents with renal insufficiency (83%, mean serum creatinine of 2.4 mg/dL), proteinuria > 3g/day (70%), nephrotic syndrome (22%)
Associated with hypertension (96%), smoking (91%, mean 53 pack-years), hypercholesterolemia (90%), extrarenal vascular disease (44%)
A diagnosis of exclusion
Poor prognostic factors for end stage renal disease: continued smoking, lack of angiotensin II blockage, degree of arteriosclerosis
Micro: prominent diffuse and nodular mesangial sclerosis, glomerular basement membrane thickening, arteriosclerosis and arteriolosclerosis; also neovascularization of glomeruli
Positive stains: CD34 highlights increased number of vascular channels within glomeruli compared with normal controls
References: Hum Path 2002;33:826
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)
Micro images: lipoprotein thrombi
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)
Gross images: flea bitten cortical surface in class IV lupus nephritis
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 #1; #2; papillary necrosis; wide streaks in medulla; large abscess
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
Gross images: irregularly scarred contracted kidney
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; recent infarct; old infarct with scarring
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)