disease
2. Immunofluorescence stain: identifies the deposition patterns of various proteins (e.g., IgG, complement)
a. Linear pattern: characteristic finding in anti-GBM disease; antibodies form a line along the GBM (e.g., Goodpasture's syndrome) (Figure 19-2)
b. Granular ("lumpy-bumpy") pattern: usually indi- cates immunocomplex deposition in the glo- merulus (Figure 19-3)
3. Electron microscopy
a. Detects submicroscopic defects in the glomerulus (e.g., fusion of podocytes, damage to visceral epi- thelial cells)
b. Detects electron-dense immunocomplex deposits in subendothelial, intramembranous, subepithe- lial, or mesangial sites
D. Nephritic syndrome: clinical subtype of glomerular disease (Table 19-3)
1. Clinical and laboratory findings
244 Pathology
Figure 19-2 Goodpasture's syn- drome, linear immunofluores- cence. The uninterrupted smooth immunofluorescence along the glomerular basement membrane is caused by deposition of IgG antibodies directed against the membrane.
Figure 19-3 Acute postinfec- tious glomerulonephritis, granular immunofluorescence. Granular irregular deposits in the capillar- ies are caused by immuno- complex deposition.
a. Key finding: red blood cell (RBC) casts; white blood cell (WBC) casts may be present.
b. Hypertension: caused by sodium retention (also periorbital puffiness)
c. Oliguria (< 400 mL urine/day): caused by de- creased GFR from inflamed glomeruli
d. Hematuria with dysmorphic RBCs: abnormal cell shapes are caused by glomerular damage.
e. Neutrophils in the sediment: particularly in im- munocomplex types
f. Mild to moderate proteinuria: < 2 g/day g. Azotemia
2. IgA glomerulonephritis (Berger's disease)
a. Incidence of nephritic or nephrotic presentation occurs in children and adults at the same rate.
b. Increased mucosal synthesis and decreased clear- ance of IgA: immunocomplexes contain IgA; acti- vation of alternative complement pathway c. May have features in common with Henoch-
Schtinlein purpura
Most common glo- merulonephritis: IgA glomerulonephritis
Chapter 19 Kidney Disorders 245 TABLE 19-3 Glomerular Diseases
Disease Morphologic Characteristics
Mesangial IgA immunocomplex deposits, granular immunofluorescence
Subepithelial immunocomplex deposits, granular immunofluorescence
Subendothelial immunocomplex deposits, wire looping, granular immunofluorescence May have crescent formation
Goodpasture's syndrome: anti-GBM antibodies, linear immunofluorescence
Split GBM, lipid in visceral epithelial cells (foam cells), negative immunofluorescence
Sensorineural hearing loss, ocular abnormalities Fusion of podocytes, negative immunofluorescence Fusion of podocytes, negative immunofluorescence Fusion of podocytes, granular immunofluorescence,
subepithelial deposits ("spike and dome" pattern) Fusion of podocytes, granular immunofluorescence,
subendothelial deposits, tram tracks
Fusion of podocytes, granular immunofluorescence, intramembranous deposits, tram tracks, C3
nephritic factor
Fusion of podocytes, negative immunofluorescence, afferent and efferent hyaline arteriolosclerosis, nodular mesangial deposits
Fusion of podocytes, negative immunofluorescence, amyloid positive for Congo red stain, apple-green birefringence when polarized
Nephritic
IgA glomerulonephritis (Berger's disease) Poststreptococcal
glomerulonephritis Diffuse proliferative
glomerulonephritis (SLE) Rapidly progressive
glomerulonephritis Alport's syndrome (hereditary
nephritis) Nephrotic
Minimal change disease (lipoid nephrosis) Focal segmental
glomerulosclerosis Diffuse membranous glomerulonephritis Type I MPGN Type II MPGN Diabetic nephropathy
Renal amyloidosis
GBM, glomerular basement membrane; MPGN, membranoproliferative glomerulonephritis;
SLE, systemic lupus erythematosus
d. Granular immunofluorescence in the mesangium e. Clinical and laboratory findings
(1) Episodic bouts of hematuria, usually follow- ing an upper respiratory infection
(2) Slow progression to chronic renal failure (3) Increased serum IgA
3. Acute poststreptococcal glomerulonephritis
a. Usually follows group A streptococcal infection of the skin or pharynx (e.g., scarlet fever); immuno- complexes activate the alternative complement system.
b. Microscopic findings: diffuse proliferative pattern with neutrophil infiltration, granular im- munofluorescence, subepithelial deposits (Figure 19-4)
c. Clinical and laboratory findings
(1) Hematuria with smoky-colored urine (1-3 weeks after group A streptococcal infection)
Most common type of postinfectious glomerulonephritis:
acute poststrep- tococcal glomerulo- nephritis
246 Pathology
Figure 19-4 Subepithelial im- munocomplex deposits viewed with electron micros- copy. The arrows point to electron-dense deposits directly beneath the visceral epithelial cells Normal basement mem- brane has a light gray appearance
Figure 19-5 Subendothelial irnmunocomplex deposits viewed with electron microscopy. The band of electron-dense material extends around the glornerular basement membrane and hugs the interface of the membrane with the capillary lumen. The arrow points to immune deposits directly beneath the nucleus of the endothelial cell A thin rim of normal basement membrane (light gray) separates the deposits from the epithelial side of the membrane.
(2) Chronic renal failure is uncommon.
(3) High anti—streptolysin 0 (ASO) titers after pharyngeal infection; high anti-DNAase B titers after skin infection
4. Diffuse proliferative glomerulonephritis in SLE a. Most common type of glomerular disease in SLE b. Caused by deposition of DNA—anti-DNA immuno-
complexes, which activate the classic complement pathway
c. Microscopic findings: granular immunofluores- cence, wire-loop formation on capillaries caused by subendothelial deposits (Figure 19-5), neutrophil infiltration with fibrinoid necrosis
d. Clinical and laboratory findings
(1) Kidneys are the major target organ in SLE.
Renal disease occurs in approximately 90% of affected individuals, with eventual develop- ment of end-stage renal disease.
Chapter 19 Kidney Disorders 247
Figure 19-6 Crescentic glomer- ulonephritis. The arrows point to a proliferation of parietal epi- thelial cells in Bowman's capsule, occupying approxi- mately 50% of the entire urinary space The cells encase and eventually compress the glomer- ular tuft
(2) Serum antinuclear antibody (ANA) test:
usually a rim pattern indicating presence of anti—double-stranded DNA antibodies 5. Rapidly progressive glomerulonephritis
a. Rapid loss of renal function progressing to acute renal failure over days to weeks; poor prognosis b. May or may not be associated with crescent forma-
tion (crescentic glomerulonephritis; Figure 19-6) c. Clinical associations: Goodpasture's syndrome,
microscopic polyarteritis, Wegener's granulo- matosis
6. Goodpasture's syndrome
a. Occurs most often in young males
b. Caused by anti-GBM antibodies, which are di- rected against type IV collagen in both the glomer- ular and pulmonary capillaries
c. Crescentic glomerulonephritis; linear immunoflu- orescence; no electron-dense deposits
7. Alport's syndrome
a. X-linked dominant disease (85%): defect in the synthesis of type IV collagen in the GBM
b. Microscopic findings: negative immunofluores- cence; split GBM; lipid accumulation in visceral epithelial cells, producing foam cells
c. Clinical findings: sensorineural hearing loss, ocular abnormalities
E. Nephrotic syndrome: clinical subtype of glomerular disease (see Table 19-3)
1. Clinical and laboratory findings
a. Proteinuria (gold standard for diagnosis): > 3.5 g/day
b. Key finding: fatty casts with Maltese crosses c. Generalized pitting edema and ascites: caused by
hypoalbuminemia; risk of spontaneous peritoni- tis caused by Streptococcus pneumoniae
d. Hypertension: caused by sodium retention
Goodpasture's syn- drome begins with hemoptysis and ends with renal failure.
248 Pathology
Figure 19-7 Fusion of the podocytes in minimal change disease. The arrows show fusion of the podocytes, which should be separated by slit pores
e. Hypercholesterolemia: caused by hypoalbumin- emia, leading to increased synthesis of choles- terol by the liver
f. Hypogammaglobulinemia: caused by loss of y-globulins in the urine
2. Minimal change disease (lipoid nephrosis)
a. More common in girls; occurs in 20-25% of adults b. T-cell immune reaction against visceral epithe-
lial cells causes a loss in the negative charge of the GBM (polyanion loss), resulting in loss of
albumin.
c. Secondary causes: nonsteroidal anti-inflammatory drugs (NSAIDs), Hodgkin's disease, bee stings d. Microscopic findings: structurally normal glomer-
uli; positive fat stains in the glomerulus and tubules (become oval fat bodies); negative immu- nofluorescence; fusion of podocytes (Figure 19-7) e. Clinical and laboratory findings
(1) Often preceded by a respiratory infection or routine immunization
(2) Normal blood pressure (unlike other causes of nephrotic syndrome)
3. Focal segmental glomerulosclerosis
a. Occurs as primary or secondary disease; second- ary causes include HIV infection and intrave- nous heroin abuse.
b. Microscopic findings: normal immunofluores- cence; fusion of podocytes with detachment of vis- ceral epithelial cells
c. Clinical and laboratory findings
(1) Most common initial presentations: protein- uria, microscopic hematuria
Most common cause of nephrotic syndrome in chil- dren: minimal change disease
Chapter 19 Kidney Disorders 249
Figure 19-8 Diffuse membra- nous glomerulonephritis. The glo- merular basement membranes are uniformly thickened (arrow), and the number of nuclei is less than 100. There is no proliferative component.
(2) Progression to chronic renal failure; poor prognosis
4. Diffuse membranous glomerulonephritis
a. Occurs as primary or secondary disease; second- ary causes include:
(1) Drugs: captopril, ketoprofen
(2) Infections: Plasmodium malariae, hepatitis B, syphilis
(3) Malignancy: carcinoma, non-Hodgkin's lymphoma
(4) Autoimmune disease: SLE b. Microscopic findings
(1) Diffuse thickening of membranes; silver stains showing "spike and dome" pattern beneath visceral epithelial cells (subepithelial depos- its) (Figure 19-8)
(2) Granular immunofluorescence; fusion of podocytes and subepithelial deposits 5. Membranoproliferative glomerulonephritis (MPGN)
a. Type I MPGN: most common
(1) Immunocomplex disease; associated with hepatitis C and cryoglobulinemia
(2) Microscopic findings: subendothelial depos- its, "tram-track" appearance (splitting of GBM by an ingrowth of mesangium) b. Type II MPGN
(1) Associated with C3 nephritic factor; autoan- tibody causes low levels of C3.
(2) Microscopic findings: diffuse intramembra- nous deposits (entire GBM is dense; "dense deposit disease"); "tram-track" appearance 6. Diabetic nephropathy (nodular glomerulosclerosis,
Kimmelstiel-Wilson disease)
a. Risk factors: poor glycemic control, hypertension
Most common cause of nephrotic syndrome in adults: diffuse membranous glomerulonephritis
Most common cause of chronic renal failure in US:
diabetes mellitus
250 Pathology
Figure 19-9 Diabetic glomerulo- sclerosis The broken arrow points to an afferent or efferent arteriole that has hyaline arte- riolosclerosis, with an increase in proteinaceous material in the wall of the vessel. The solid arrow shows a mesangial nodule containing type IV collagen and trapped protein
b. Pathogenesis
(1) Nonenzymatic glycosylation of the GBM membranes and tubule basement membranes, increasing vessel and tubular cell permeabil- ity to proteins
(2) Nonenzymatic glycosylation of the afferent and efferent arterioles, causing hyaline arte- riolosclerosis of the efferent arterioles before the afferent arterioles
(3) Hyperfiltration damage to the mesangium caused by the selective hyaline arteriolosclero- sis of efferent arterioles, increasing GFR, which damages mesangial cells
(4) Increased deposition of type IV collagen in the GBM and mesangium
c. Microscopic findings
(1) Afferent and efferent hyaline arterioloscle- rosis: when the afferent arteriole becomes hy- alinized, GFR decreases (Figure 19-9).
(2) Nodular masses in the mesangial matrix:
caused by increased type IV collagen and trapped proteins
d. Clinical and laboratory findings (1) Microalbuminuria
Angiotensin-converting enzyme (ACE) inhibitors are prescribed when microal- buminuria is first detected. ACE inhibitors slow the progression of diabetic nephrop- athy by decreasing pressure in the glomer- ular capillaries.
(2) Other renal problems associated with diabe- tes mellitus: renal papillary necrosis, acute and chronic pyelonephritis
Initial laboratory finding in diabetic nephropathy:
microalbuminuria
Chapter 19 Kidney Disorders 251 7. Nephropathy associated with amyloidosis: associated
with both primary and secondary amyloidosis (see Chapter 3)