Etiology and Pathogenesis.

Membranous glomerulopathy is a form of chronic immune complex-mediated disease. In secondary membranous glomerulopathy, particular antigens can sometimes be identified in the

immune complexes. For example, membranous glomerulopathy in SLE is associated with deposition of autoantigen-antibody complexes. Exogenous (hepatitis B, Treponema antigens) or

endogenous (thyroglobulin) antigens have been identified within deposits in some patients.

The lesions bear a striking resemblance to those of experimental Heymann nephritis, which, as you might recall, is induced by antibodies to a megalin antigenic complex. A similar but still

unidentified antigen is presumed to be present in most cases of idiopathic membranous glomerulopathy in humans. Susceptibility to Heymann nephritis in rats and membranous

glomerulopathy in humans is linked to the MHC locus, which influences the ability to produce antibodies to the nephritogenic antigen. Thus, idiopathic membranous glomerulopathy, like

Heymann nephritis, is considered an autoimmune disease linked to susceptibility genes and caused by antibodies to a renal autoantigen.

How does the glomerular capillary wall become leaky in membranous glomerulopathy? There is a paucity of neutrophils, monocytes, or platelets in glomeruli and the virtually uniform

presence of complement, and experimental work suggests a direct action of C5b-C9, the pathway leading to the formation of the membrane attack complex. C5b-C9 causes activation of

glomerular epithelial and mesangial cells, inducing them to liberate proteases and oxidants, which cause capillary wall injury and increased protein leakage.

Morphology.

By light microscopy, the glomeruli either appear normal in the early stages of the disease or exhibit uniform, diffuse thickening of the glomerular capillary wall( Fig. 20-19A ). By

electron microscopy, the thickening is seen to be caused by irregular dense deposits between the basement membrane and the overlying epithelial cells, the latter

Figure 20-19Membranous glomerulonephritis. A, PAS stain. Note the marked diffuse thickening of the capillary wall without an increase in the number of cells. B, Electron micrograph

showing electron-dense deposits (arrow) along the epithelial side of the basement membrane (B). Note the obliteration of foot process overlying deposits. CL, capillary lumen; End,

endothelium; Ep, epithelium. C, Characteristic granular immunofluorescent deposits of IgG along GBM. D, Diagrammatic representation of membranous glomerulonephritis.

Figure 20-20Minimal change disease. Glomerulus stained with PAS. Note normal basement membrane and absence of proliferation. Compare with membranous glomerulopathy in Figure

20-19A .

Figure 20-21 A, Ultrastructural characteristics of minimal change disease: effacement of foot processes (double arrows), absence of deposits, vacuoles (V), and microvilli in visceral

epithelial cells (single arrow). B, Schematic representation of minimal change disease, showing diffuse effacement of foot processes.

Figure 20-22Focal segmental glomerulosclerosis, PAS stain. A, Low-power view showing segmental sclerosis in one of three glomeruli (at 3 o'clock). B, High-power view showing

hyaline insudation and lipid (small vacuoles) in sclerotic area.

Figure 20-23Membranoproliferative glomerulonephritis, showing mesangial cell proliferation, increased mesangial matrix (staining black with silver stain), basement membrane

thickening and focal splitting, accentuation of lobular architecture, swelling of cells lining peripheral capillaries, and influx of leukocytes.

Figure 20-24 A, Membranoproliferative glomerulonephritis, type I. Note the large subendothelial deposit (arrow) incorporated into mesangial matrix (M). E, endothelium; EP, epithelium;

CL, capillary lumen. B, Type II membranoproliferative glomerulonephritis, dense-deposit disease. There are markedly dense homogeneous deposits within the basement membrane proper.

CL, capillary lumen. C, Schematic representation of patterns in the two types of membranoproliferative GN. In type I there are subendothelial deposits; type II is characterized by

intramembranous dense deposits (dense-deposit disease). In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope.

Figure 20-25The alternative complement pathway. Note that C3NeF, present in the serum of patients with membranoproliferative glomerulonephritis, acts at the same step as properdin,

serving to stabilize the alternative pathway C3 convertase, thus enhancing C3 breakdown and causing hypocomplementemia.

Figure 20-26IgA nephropathy. A, Light microscopy showing mesangial proliferation and matrix increase. B, Characteristic deposition of IgA, principally in mesangial regions, detected by

immunofluorescence.

Figure 20-27Hereditary nephritis. Electron micrograph of glomerulus with irregular thickening of the basement membrane, lamination of the lamina densa, and foci of rarefaction. Such

changes may be present in other diseases but are most pronounced and widespread in hereditary nephritis. CL, capillary lumen; Ep, epithelium.

Figure 20-28Primary glomerular diseases leading to chronic glomerulonephritis (GN). The thickness of the arrows reflects the approximate proportion of patients in each group who

progress to chronic glomerulonephritis: poststreptococcal (1% to 2%); rapidly progressive (crescentic) (90%), membranous (30% to 50%), focal glomerulosclerosis (50% to 80%),

membranoproliferative glomerulonephritis (50%), IgA nephropathy (30% to 50%).

Figure 20-29Chronic glomerulonephritis. A Masson trichrome preparation shows complete replacement of virtually all glomeruli by blue-staining collagen. (Courtesy of Dr. M.A.

Venkatachalam, Department of Pathology, University of Texas Health Sciences Center, San Antonio, TX.)

Figure 20-30Electron micrograph of advanced diabetic glomerulosclerosis. Note the massive increase in mesangial matrix (Mes) encroaching on the glomerular capillary lumina (CL).

The GBM and Bowman capsule (C) are markedly thickened. Ep, epithelium; E, endothelium.

Figure 20-31Diffuse and nodular diabetic glomerulosclerosis (PAS stain). Note the diffuse increase in mesangial matrix and characteristic acellular PAS-positive nodules.

Ischemia causes numerous structural and functional alterations in epithelial cells, as discussed in Chapter 1 . The structural changes include those of reversible injury (such as cellular

swelling, loss of brush border, blebbing, loss of polarity, and cell detachment) and those associated with lethal injury (necrosis and apoptosis). Biochemically, there is depletion of

adenosine triphosphate; accumulation of intracellular calcium; activation of proteases (e.g., calpain), which cause cytoskeletal disruption, and phospholipases, which damage membranes;

generation of reactive oxygen species; and activation of caspases, which induce apoptotic cell death. One early reversible result of ischemia is loss of

cell polarity due to redistribution of membrane proteins (e.g., the enzyme Na+ K+ -ATPase) from the basolateral to the luminal surface of the tubular cells, resulting in abnormal ion

transport across the cells, and increased sodium delivery to distal tubules. The latter incites vasoconstriction via tubuloglomerular feedback, which will be discussed below.[82] In addition,

ischemic tubular cells express cytokines and adhesion molecules (such as ICAM-1), thus recruiting leukocytes that appear to participate in the subsequent injury.[83] In time, injured cells

detach from the basement membranes and cause luminal tubule obstruction, increased intratubular pressure, and decreased GFR. In addition, fluid from the damaged tubules can leak into

the interstitium, resulting in interstitial edema, increased interstitial pressure, and further damage to the tubule. All these effects, as shown in Figure 20-32 , contribute to the decreased

GFR.

• Disturbances in blood flow: Ischemic renal injury is also characterized by hemodynamic alterations that cause reduced GFR. The major one is intrarenal vasoconstriction, which

results in both reduced glomerular plasma flow and reduced oxygen delivery to the functionally important tubules in the outer medulla (thick ascending limb and straight segment of the

proximal tubule). A number of vasoconstrictor pathways have been implicated, including the renin-angiotensin mechanism, stimulated by increased distal sodium delivery (via

tubuloglomerular feedback), and sublethal endothelial injury, leading to increased release of the vasoconstrictor endothelin and decreased production of the vasodilators nitric oxide and

PGI2 . Finally, there is also some evidence of a direct effect of ischemia or toxins on the glomerulus, causing a reduced glomerular ultrafiltration coefficient, possibly due to mesangial

contraction.

The patchiness of tubular necrosis and maintenance of the integrity of the basement membrane along many segments allow ready repair of the necrotic foci and recovery of function if the

precipitating cause is removed. This repair is dependent on the capacity of reversibly injured epithelial cells to proliferate and differentiate. Re-epithelialization is mediated by a variety of

growth factors and cytokines produced locally by the tubular cells themselves (autocrine stimulation) or by inflammatory cells in the vicinity of necrotic foci (paracrine stimulation).[84] Of

these, epidermal growth factor (EGF), TGF-a, insulin-like growth factor type I, and hepatocyte growth factor have been shown to be particularly important in renal tubular repair. Growth

factors, indeed, are being explored as possible therapeutic agents to enhance re-epithelialization in ATN.[84]

Figure 20-32Possible pathogenetic mechanisms in ischemic acute renal failure (see text).

Figure 20-33Patterns of tubular damage in ischemic and toxic acute tubular necrosis. In the ischemic type, tubular necrosis is patchy, relatively short lengths of tubules are affected, and

straight segments of proximal tubules (PST) and ascending limbs of Henle's loop (HL) are most vulnerable. In toxic acute tubular necrosis, extensive necrosis is present along the proximal

tubule segments (PCT) with many toxins (e.g., mercury), but necrosis of the distal tubule, particularly ascending Henle's loop, also occurs. In both types, lumens of the distal convoluted

tubules (DCT) and collecting ducts (CD) contain casts.

Figure 20-34Acute tubular necrosis. Some of the tubular epithelial cells in the tubules are necrotic, and many have become detached (from their basement membranes) and been sloughed

into the tubular lumina, whereas others are swollen, vacuolated, and regenerating. (Courtesy of Dr. Agnes Fogo, Vanderbilt University, Nashville, TN.)

TABLE 20-9-- Causes of Tubulointerstitial Nephritis

Infections

Acute bacterial pyelonephritis

Chronic pyelonephritis (including reflux nephropathy)

Other infections (e.g., viruses, parasites)

Toxins

Drugs

Acute hypersensitivity interstitial nephritis

Analgesic nephropathy

Heavy metals

Lead, cadmium

Metabolic Diseases

Urate nephropathy

Nephrocalcinosis (hypercalcemic nephropathy)

Hypokalemic nephropathy

Oxalate nephropathy

Physical Factors

Chronic urinary tract obstruction

Radiation nephropathy

Neoplasms

Multiple myeloma (cast nephropathy)

Date: 2016-04-22; view: 872