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2-uremia when azotemia progresses to clinical manifestations and systemic biochemical abnormalities. Uremia is characterized by: 1- failure of renal excretory function. 2- metabolic and endocrine alterations.
3
1- acute onset . 2- gross hematuria. 3- mild to moderate proteinuria (< 3.5 gm of protein/day in adults) 4- azotemia. 5- edema. 6- hypertension.
5
2-Nephrotic syndrome
it is a glomerular syndrome characterized by: 1- heavy proteinuria (excretion of >3.5 gm of protein/day in adults) 2- hypoalbuminemia 3- severe edema 4- hyperlipidemia 5- lipiduria (lipid in the urine).
6
10
8-Nephrolithiasis
Renal stones. It is manifested by: 1-renal colic. 2-hematuria. 3-recurrent stone formation.
12
GLOMERULAR DISEASES
chronic glomerulonephritis is one of the most common causes of chronic kidney disease in humans. the glomerulus consists of an anastomosing network of capillaries invested by two layers of epithelium. The visceral epithelium (podocytes) is an intrinsic part of the capillary wall. the parietal epithelium lines Bowman space (urinary space), the cavity in which plasma ultrafiltrate first collects.
13
The glomerular capillary wall is the filtration unit and consists of : 1-A thin layer of fenestrated endothelial cells, each fenestra 70 to 100 nm in diameter. 2-A glomerular basement membrane (GBM).
14
The capillary basement membrane consists of : 1- a thick electron-dense central layer (lamina densa) 2- thinner and electron-lucent peripheral layers ( lamina rara interna and lamina rara externa ).
15
The GBM consists of collagen (mostly type IV), laminin, polyanionic proteoglycans, fibronectin, and several other glycoproteins.
16
3-The visceral epithelial cells (podocytes), structurally complex cells that possess interdigitating processes embedded in and adherent to the lamina rara externa of the basement membrane.
17
Adjacent foot processes are separated by 20- to 30-nm-wide filtration slits which are bridged by a thin slit diaphragm composed in large part of nephrin.
18
4-Supportive cells (mesangial cells) lying between the capillaries. Basement membrane-like mesangial matrix forms a meshwork through which the mesangial cells are scattered.
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Normal glomerulus by LM. The glomerular capillary loops are thin and delicate. Endothelial and mesangial cells are normal in number. The surrounding tubules are normal.
21
EM-GLOMERULUS
CL-capillary lumen, End-endothelium, US-urinary space, B-basement membrane, Ep-epithelial cell, Mes-mesangial cell, Fp-foot process.
Fp
22
23
The selective permeability discriminates among protein molecules depending on: 1- their size (the larger the less permeable), 2- their charge (the more cationic the more permeable). 3-their configuration. Nephrin and its associated proteins, including podocin, have a crucial role in maintaining the selective permeability of the glomerular filtration barrier.
24
antigen-antibody complexes are formed in situ or in the circulation and are then trapped in the glomeruli activation of complement and the recruitment of leukocytes injury. the glomerular lesions usually consist of leukocytic infiltration (exudation) into glomeruli and variable proliferation of endothelial, mesangial, and parietal epithelial cells.
27
Electron microscopy reveals the immune complexes as electron-dense deposits or clumps that lie at one of three sites: 1-in the mesangium. 2-between the endothelial cells and the GBM (subendothelial deposits). 3-between the outer surface of the GBM and the podocytes (subepithelial deposits).
28
Deposits may be located at more than one site. The presence of Igs and complement in these deposits can be demonstrated by immunofluorescence microscopy. The pattern of immune complex deposition is helpful in distinguishing various types of GN.
29
IF-Granula deposition of immune complexes . characteristic of circulating and in situ immune complex deposition
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Planted antigens include: 1- DNA. 2- bacterial products 3-large aggregated proteins (e.g., aggregated IgG), which deposit in the mesangium because of their size 4- immune complexes themselves because they continue to have reactive sites for further interactions with free antibody, free antigen, or complement.
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The basement membrane antigen responsible for classic anti-GBM antibody GN is a component of the noncollagenous domain of the 3 chain of collagen type IV. The anti-GBM antibodies cross-react with basement membranes of lung alveoli resulting in simultaneous lung and kidney lesions (Goodpasture syndrome).
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Primary Glomerular Disease Membranous GN Minimal-change disease Focal segmental glomerulosclerosis Membranoproliferative GN IgA nephropathy
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Manifestations: Diabetes mellitus: Amyloidosis Systemic lupus erythematosus drugs (gold, penicillamine, "street heroin") Infections (malaria, syphilis, hepatitis B, HIV) Malignancy (carcinoma, melanoma) Miscellaneous (e.g bee-sting allergy)
39
Pathogenesis
The pathogenesis of proteinuria is still not clear. Based on some experimental studies, the proteinuria has been attributed to a T-cell derived factor that causes podocyte damage and effacement of foot processes. neither the nature of such a putative factor nor a causal role of T cells is established in the human disease.
41
Morphology
LM the glomeruli in minimal change disease appear normal. The cells of the proximal convoluted tubules are often heavily laden with protein droplets and lipids but this is secondary to tubular reabsorption of the lipoproteins passing through the diseased glomeruli (lipoid nephrosis).
42
EM
the GBM appears normal. The only obvious glomerular abnormality is the uniform and diffuse effacement of the foot processes of the podocytes . The cytoplasm of the podocytes thus appears flattened over the external aspect of the GBM obliterating the network of arcades between the podocytes and the GBM. There are also epithelial cell vacuolization microvillus formation and occasional focal detachments.
43
When the changes in the podocytes reverse (e.g., in response to corticosteroids) the proteinuria remits.
44
45
Minimal change disease. A Under the light microscope the PAS-stained glomerulus appears normal, with a delicate basement membrane B Schematic diagram illustrating diffuse effacement of foot processes of podocytes with no immune deposits.
MCD-EM the capillary loop in the lower half contains two electron dense RBC's. Fenestrated endothelium is present and the BM is normal. The overlying epithelial cell foot processes are fused (arrows).
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Clinical Course
insidious development of the nephrotic syndrome in an otherwise healthy child. There is no hypertension. renal function is preserved in most individuals. selective proteinuria (the protein loss is usually confined to albumin ) The prognosis is good.
47
More than 90% of cases respond to a short course of corticosteroid therapy. proteinuria recurs in more than 2/3 of the initial responders some of whom become steroid dependent. < 5% develop chronic renal failure after 25 years and it is likely that most persons in this subgroup had nephrotic syndrome caused by FSGS not detected by biopsy. Adults with minimal change disease also respond to steroid therapy but the response is slower and relapses are more common.
48
It can occur : (1)in association with other known conditions as AIDS or heroin abuse (HIV or heroin nephropathy). (2) as a secondary event in other forms of GN (e.g IgA nephropathy).
50
(3) as a maladaptation after nephron loss. (4) in inherited or congenital forms resulting from mutations affecting cytoskeletal or related proteins expressed in podocytes (e.g., nephrin). (5) as a primary disease( 20% to 30% of all cases of the nephrotic syndrome) .
51
MCD
hematuria -
FSGS
+
hypertension
proteinuria
selective
+
nonselective
good
poor
At least 50% of individuals with FSGS develop end-stage renal failure within 10 years of diagnosis. Adults do worse than children.
53
Pathogenesis
unknown . injury to the podocytes is thought to represent the
The recurrence of proteinuria after renal allografts transplantation sometimes within 24 hours of transplantation supports the idea that a circulating mediator is the cause of the damage to podocytes .
55
Morphology
The disease is "focal" and initially affects only the juxtamedullary glomeruli. With progression eventually all levels of the cortex are affected. LM-FSGS is characterized by lesions occurring in some tufts within a glomerulus and sparing of the others ( "segmental").
56
The affected glomeruli exhibit increased mesangial matrix, obliterated capillary lumens, and deposition of hyaline masses (hyalinosis) and lipid droplets. progression of the disease leads to global sclerosis of the glomeruli (global sclerosis) with pronounced tubular atrophy and interstitial fibrosis.
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focal and segmental glomerulosclerosis (PAS stain). a mass of scarred, obliterated capillary lumens with accumulations of matrix material
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IF microscopy nonspecific trapping of Igs usually IgM, and complement in the areas of hyalinosis. EM the podocytes exhibit effacement of foot processes as in MCD.
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Collapsing glomerulopathy
It is a morphologic variant of FSGS. It carries a particularly poor prognosis. It is characterized by collapse of the entire glomerular tuft and podocyte hyperplasia. It may be : 1-idiopathic . 2-associated with HIV infection. 3-drug-induced toxicities.
62
Clinical Course
Poor responses to corticosteroid therapy. about 50% of individuals suffer renal failure after 10 years.
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secondary to other disorders including: (1) infections (HBV, syphilis,schistosomiasis, malaria). (2) malignant tumors (carcinoma of the lung and colon and melanoma). (3) autoimmune diseases as SLE . (4) exposure to inorganic salts (gold, mercury). (5) drugs (penicillamine, captopril,NSAID).
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Pathogenesis
Membranous GN is a form of chronic immune complex nephritis. circulating complexes of 1- exogenous (e.g., hepatitis B virus) . 2- endogenous (DNA in SLE) antigen .
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Morphology
LM the basic change appears to be diffuse thickening of the GBM .
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LM- membranous glomerulonephritis in which the capillary loops are thickened and prominent, but the cellularity is not increased
69
Membranous nephropathy. A ,Diffuse thickening of the glomerular basement membrane . B ,Schematic diagram illustrating subepithelial deposits, effacement of foot processes, and the presence of "spikes" of basement membrane material between the immune deposits .
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A silver stain of the glomerulus highlights the proteinaceous basement membranes in black. There are characteristic "spikes" seen with membranous glomerulonephritis seen here in which the black basement membrane material appears as projections around the capillary loops.
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IF diffuse granular deposits of immunoglobulins and complement along the GBM . mainly IgG and complement.
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MGN IF-deposits of mainly IgG and complement collect in the basement membrane and appear in a diffuse granular pattern
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EM subepithelial deposits thickening of the GBM and are separated from each other by small, spikelike protrusions of GBM matrix that form in reaction to the deposits ("spike and dome" pattern). As the disease progresses, these spikes close over the deposits, incorporating them into the GBM.
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EM-the darker electron dense immune deposits are seen scattered within the thickened basement membrane .
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the podocytes show effacement of foot processes. the incorporated deposits may be catabolized and eventually disappear leaving cavities within the GBM. Continued deposition of basement membrane matrix leads to progressively thicker basement membranes. With further progression the glomeruli can become sclerosed.
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Clinical Course
insidious development of the nephrotic syndrome, usually without antecedent illness. some individuals with membranous nephropathy may have lesser degrees of proteinuria rather than the full-blown nephrotic syndrome. the proteinuria is nonselective. no response to corticosteroid therapy.
77
Membranous nephropathy follows a variable and often indolent course. Overall proteinuria persists in over 60% of cases. ~ 40% suffer progressive disease terminating in renal failure after 2 to 20 years. 10%-30% have a more benign course with partial or complete remission of proteinuria.
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Membranoproliferative Glomerulonephritis
MPGN is characterizedby alterations in the GBM and mesangium and by proliferation of glomerular cells. It accounts for 5% to 10% of cases of idiopathic nephrotic syndrome in children and adults. Some individuals present only with hematuria or proteinuria in the nonnephrotic range. others have a combined nephroticnephritic picture.
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Pathogenesis
Types of MPGN: 1-type I is (about 80% of cases). 2-type II.
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Type I MPGN
circulating immune complexes similar to chronic serum sickness but the inciting antigen is not known. It occurs in association with: 1- hepatitis B and C antigenemia. 2- SLE. 3- infected A-V shunts. 4- extra-renal infections with persistent or episodic antigenemia.
81
disease)
The fundamental abnormality
82
Some patients have an autoantibody against C3 convertase called C3 nephritic factor, which is believed to stabilize the enzyme and lead to uncontrolled cleavage of C3 and activation of the alternative complement pathway. Mutations in the gene encoding the complement regulatory protein Factor H have been described in some patients. These mutations may lead to a deficiency of plasma Factor H or defective function of the protein, again resulting in excessive complement activation
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Functional impairment of Factor H may also be caused by autoantibodies or abnormalities in the C3 protein that prevent its interaction with Factor H. Hypocomplementemia is more marked in type II due to: 1- excessive consumption of C3 2- reduced synthesis of C3 by the liver. It is still not clear how the complement abnormality induces the glomerular changes.
84
Morphology
LM
both types of MPGN are similar. The glomeruli are large with an accentuated lobular appearance and show proliferation of mesangial and endothelial cells as well as infiltrating leukocytes The GBM is thickened and the glomerular capillary wall often shows a double contour or "tram track," appearance especially evident in silver or PAS stains.
85
The tram track appearance is caused by "splitting" of the GBM due to the inclusion within it of processes of mesangial and inflammatory cells extending into the peripheral capillary loops (MPGN II).
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Membranoproliferative GN, showing mesangial cell proliferation, basement membrane thickening, leukocyte infiltration, and accentuation of lobular architecture.
87
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 by light microscopy.
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89
This silver stain demonstrates a double contour of the basement membranes("tram-tracking" )that is characteristic of (MPGN)(arrows).
90
IF C3 is deposited in an irregular granular pattern. IgG and early complement components (C1q and C4) are often also present (immune complex pathogenesis).
91
IF Granular deposition of immune complexes characteristic of circulating and in situ immune complex deposition
92
93
EM-MPGN type I a mesangial cell at the lower left that is interposing its cytoplasm at the arrow into the basement membrane leading to splitting" of the GBM (tram track).
94
In type II lesions the lamina densa and the subendothelial space of the GBM are transformed into an irregular, ribbon-like, extremely electron-dense structure, resulting from the deposition of material of unknown composition, giving rise to the term densedeposit disease. C3 is present in irregular chunky and segmental linear foci in the basement membranes and in the mesangium in characteristic circular aggregates (mesangial rings). IgG ,C1q and C4 are usually absent.
95
EM-dense deposits in the basement membrane of MPGN type II. There are dark electron dense deposits within the basement membrane that often coalesce to form a ribbon-like mass of deposits ) arrows)
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Clinical Course
Nephrotic syndrome (in 50% of cases). MPGN may begin as acute nephritis or mild proteinuria. The prognosis of MPGN is generally poor. No remission. 40% progressed to end-stage renal failure. 30% had variable degrees of renal insufficiency. the remaining 30% had persistent nephrotic syndrome without renal failure.
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Dense-deposit disease has a worse prognosis. It tends to recur in renal transplant recipients.
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Pathogenesis
proliferation of the cells within the glomeruli accompanied by a leukocytic infiltrate injures the capillary walls permitting escape of red cells into the urine GFR oliguria, reciprocal fluid retention, and azotemia. Hypertension is probably a result of both the fluid retention and some augmented renin release from the ischemic kidneys.
100
Acute Postinfectious (Poststreptococcal) Glomerulonephritis is typically caused by glomerular deposition of immune complexes resulting in diffuse proliferation and swelling of resident glomerular cells and frequent infiltration of leukocytes, especially neutrophils. The inciting antigen may be exogenous or endogenous.
101
Exogenous antigens: 1-poststreptococcal GN. 2-Infections by organisms as pneumococci and staphylococci 3-infections by several common viral diseases such as mumps, measles, chickenpox, and hepatitis B and C. Endogenous antigens as occur in SLE
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Poststreptococcal GN
It develops in a child 1-4 wks after the individual recovers from a group A streptococcal infection. Only certain "nephritogenic" strains of -hemolytic streptococci are capable of evoking glomerular disease. In most cases the initial infection is localized to the pharynx or skin.
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Pathogenesis
Ag-Ab complex deposition. Typical features of immune complex disease, such as hypocomplementemia and granular deposits of IgG and complement on the GBM are seen. The relevant antigens are probably streptococcal proteins but their identity is not established.
104
It is also not clear if immune complexes are formed in the circulation or in situ. Studies indicate that C3 may be deposited on the GBM before IgG ( the primary injury might be by complement activation).
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Morphology
LM
The most characteristic change in postinfectious GN is a fairly uniformly increased cellularity of the glomerular tufts that affects nearly all glomeruli( "diffuse" ). The increased cellularity is caused both by proliferation and swelling of endothelial and mesangial cells and by a neutrophilic and monocytic infiltrate. Sometimes there is necrosis of the capillary walls. "crescents" within the urinary space in response to the severe inflammatory injury.
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Post-streptococcal glomerulonephritis. This glomerulus is hypercellular and capillary loops are poorly defined.
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Post-streptococcal glomerulonephritis is due to increased numbers of epithelial, endothelial, and mesangial cells as well as neutrophils in and around the capillary loops (arrows)
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IF
reveals scattered granular deposits of IgG and complement within the capillary walls and some mesangial areas. These deposits are usually cleared over a period of about 2 wks.
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APGN immune deposits are distributed in the capillary loops in a granular, bumpy pattern because of the focal nature of the deposition process .
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EM
shows deposited immune complexes arrayed as subendothelial, intramembranous, or, most often, subepithelial "humps" nestled against the GBM. Mesangial deposits are also occasionally present.
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EM -immune deposits of PSGN are predominantly subepithelial, a large subepithelial "hump" at the right of the BM (arrows). The capillary lumen is filled with a PMN whose nuclear lobes (arrows)and cytoplasmic granules are visibl(arrows).
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Clinical Course
abrupt onset . malaise, a slight fever, nausea, and the nephritic syndrome. oliguria, azotemia, and hypertension are only mild to moderate. gross hematuria. Some proteinuria is a constant feature of the disease and it may occasionally be severe enough to produce the nephrotic syndrome. Serum complement levels are low during the active phase of the disease. serum anti-streptolysin O antibody titers.
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Recovery occurs in most children in epidemic cases. Some children develop rapidly progressive GN due to severe injury with crescents or chronic renal disease due to secondary scarring. The prognosis in sporadic cases is less clear. In adults 15% to 50% of individuals develop end-stage renal disease over the ensuing few years or 1 to 2 decades. in children the prevalence of chronicity after sporadic cases of acute postinfectious GN is much lower.
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the hematuria lasts several days and then subsides only to recur every few months. It is often associated with loin pain. The pathogenic hallmark is the
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nephropathy to be a localized variant of Henoch-Schnlein purpura, also characterized by IgA deposition in the mesangium.
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Henoch-Schnlein purpura is a
systemic syndrome involving the skin (purpuric rash), gastrointestinal tract (abdominal pain), joints (arthritis), and kidneys .
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Pathogenesis
1- It is associated with an abnormality in IgA production and clearance. IgA is increased in 50% of patients with IgA nephropathy due to increased production in the marrow. circulating IgA-containing immune complexes are present in some individuals. A genetic influence is suggested by the occurrence of this condition in families and in HLA-identical siblings, and by the increased frequency of certain HLA and complement phenotypes in some populations
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2-abnormality in glycosylation of the IgA immunoglobulin plasma clearance of IgA deposition in the mesangium. 3-the absence of C1q and C4 in glomeruli points to activation of the alternative complement pathway.
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4-increased IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents (e.g., viruses, bacteria, food proteins) may lead to deposition of IgA and IgA-Ag complexes in the mesangium, where they activate the alternative complement pathway and initiate glomerular injury.
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5-IgA nephropathy occurs with increased frequency in individuals with celiac disease and in liver disease where there is defective hepatobiliary clearance of IgA complexes (secondary
IgA nephropathy).
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Morphology
1-focal proliferative GN
The glomeruli may be normal or may show mesangial widening and segmental inflammation confined to some glomeruli .
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IF mesangial deposition of IgA often with C3 and properdin and smaller amounts of IgG or IgM . Early components of the classical complement pathway are usually absent.
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EM Electron-dense deposits in the mesangium. The deposits may extend to the subendothelial area of adjacent capillary walls in a minority of cases usually those with focal proliferation.
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Mesangial involvement is variable, but often characterized by a submembranous concentration of the electrondense deposits.(x 4600)
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Hereditary Nephritis
Hereditary nephritis refers to a group of hereditary glomerular diseases caused by mutations in GBM proteins. Alport syndrome, in which nephritis is accompanied by nerve deafness and various eye disorders, including lens dislocation, posterior cataracts, and corneal dystrophy.
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Pathogenesis
The GBM is largely composed of type IV collagen, which is made up of heterotrimers of 3, 4, and 5 type IV collagen. This form of type IV collagen is crucial for normal function of the lens, cochlea, and glomerulus. Mutation of any one of the chains results in defective heterotrimer assembly and thus the disease manifestations of Alport syndrome.
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Morphology
Histologically, glomeruli in hereditary nephritis appear unremarkable until late in the course when secondary sclerosis may occur. Interstitial cells take on a foamy appearance as a result of accumulation of neutral fats and mucopolysaccharides (foam cells) as a reaction to marked proteinuria.
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With progression, there is increasing glomerulosclerosis, vascular sclerosis, tubular atrophy, and interstitial fibrosis.
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LM-The renal tubular cells appear foamy (arrows)because of the accumulation of neutral fats and mucopolysaccharides. The glomeruli show irregular thickening and splitting of basement membranes.
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EM the BM of glomeruli appears thin and attenuated early in the course. Late in the course, the GBM develops irregular foci of thickening or attenuation with pronounced splitting and lamination of the lamina densa, yielding a "basket-weave" appearance.
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The diagrams below illustrate normal BM(LT) vs the thickened and 'falling apart' of Alport GBM(RT)
BM
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Clinical Course
X-linked as a result of mutation of the gene encoding 5 type IV collagen. Males > females and are more likely to develop renal failure. Rarely, inheritance is autosomal recessive or dominant, linked to defects in the genes that encode 3 or 4 type IV collagen.
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presentation at age 5-20 yrs with gross or microscopic hematuria and proteinuria. overt renal failure occurs between 2050 yrs of age.
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Female carriers of X-linked Alport syndrome or carriers of either gender of the autosomal forms usually present with persistent hematuria which is most often asymptomatic and follows a benign course. a heterozygous defect in the 3 or 4 chains is associated with persistent often familial hematuria and a benign course (benign familial hematuria, or thin basement membrane lesion).
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Pathogenesis
Primary kidney or systemic disease. In most cases the glomerular injury is immunologically mediated. CrGN is divided into 3 groups on the basis of immunologic findings.
146
Type I (Anti-GBM Antibody): Goodpasture syndrome (12%) characterized by linear deposits of IgG and, C3 on the GBM. The anti-GBM antibodies also bind to pulmonary alveolar capillary basement membranes to produce the clinical picture of pulmonary hemorrhages associated with renal failure (Goodpasture).
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Anti-GBM antibodies are present in the serum and are helpful in diagnosis. Plasmapheresis which removes pathogenic antibodies from the circulation is beneficial.
Type II (Immune Complex) (44%): Idiopathic Postinfectious/infection related Systemic lupus erythematosus(SLE) Henoch-Schnlein purpura/IgA nephropathy Type III (Pauci-Immune) ANCA Associated (44% ): Idiopathic Wegener granulomatosis Microscopic angiitis
Morphology
LM Glomeruli show segmental necrosis and GBM breaks with resulting proliferation of the parietal epithelial cells in response to the exudation of plasma proteins (fibrinogen) into Bowman's space. These distinctive lesions of proliferation are called crescents due to their shape as they fill Bowman's space.
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The crescents eventually obliterate Bowman's space and compress the glomeruli. Fibrin strands are prominent between the cellular layers in the crescents. Crescents may undergo scarring(fibrous crescents).
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Crescentic GN (PAS stain). the collapsed glomerular tufts and the crescent-shaped mass of proliferating cells and leukocytes internal to Bowman's capsule.
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IF strong linear staining of deposited IgG and C3 along the GBM Type I (Anti-GBM Antibody).
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EM
deposits are not visualized because the endogenous collagen IV antigen to which the antibody is reacting is diffusely distributed, and so the large lattices of antigens and antibodies that occur in deposited immune complexes are not formed. distinct ruptures in the GBM may be seen.
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Immune Complex-Mediated (Type II) Crescentic Glomerulonephritis immune complex-mediated disorders. it can be a complication of any of the immune complex nephritides including : 1-poststreptococcal GN 2-SLE 3-IgA nephropathy 4-Henoch-Schnlein purpura 5-idiopathic
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Morphology
LM
There is severe injury with segmental necrosis and GBM breaks with resultant crescent formation. in contrast to type I CrGN (anti-GBM antibody disease), segments of glomeruli without necrosis show evidence of the underlying immune complex GN (e.g., diffuse proliferation and leukocyte exudation in postinfectious GN or SLE, and mesangial proliferation in IgA nephropathy or HenochSchnlein purpura(.
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IF
reveal the characteristic granular ("lumpy bumpy") pattern of staining of the GBM and/or mesangium for immunoglobulin and/or complement.
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Morphology
Glomeruli show segmental necrosis and GBM breaks with resulting crescent formation. Uninvolved segments of glomeruli appear normal without proliferation or prominent inflammatory cell influx. IF& EM for immunoglobulin and complement are negative and there are no deposits detectable by electron microscopy.
160
Clinical Course
The onset of RPGN is by nephritic syndrome except that the oliguria and azotemia are more pronounced. Proteinuria sometimes approaching nephrotic range may occur. Some of these persons become anuric and require long-term dialysis or transplantation.
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The prognosis can be roughly related to the number of crescents. When No. of crescents in less than 80% of the glomeruli have a better prognosis than those with higher percentages of crescents.
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Chronic Glomerulonephritis
It is an important cause of end-stage renal disease presenting as chronic renal failure. Among all individuals who require chronic hemodialysis or renal transplantation, 30% to 50% have the diagnosis of chronic GN. It probably represents the end stage of a variety of entities: 1-CrGNs. 2-FSGS. 3-MGN. 4-IgA nephropathy. 5-MPGN. 6-Idiopathic( 20% of cases).
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Although chronic GN may develop at any age, it is usually first noted in young and middle-aged adults.
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Morphology
Classically, the kidneys are symmetrically contracted and their surfaces are red-brown and diffusely granular. LM scarring of the glomeruli sometimes to in the point of complete sclerosis (obliteration of the glomeruli).
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There is also marked interstitial fibrosis, associated with atrophy and dropout of many of the tubules in the cortex, and diminution and loss of portions of the peritubular capillary network. The small and medium-sized arteries are frequently thick walled, with narrowed lumina, secondary to hypertension. Lymphocytic and plasma cells are present in the fibrotic interstitial tissue. The markedly damaged kidneys are designated end-stage kidneys.
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Chronic GN. A MT stain shows complete replacement of virtually all glomeruli by blue-staining collagen.
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Tubulointerstitial Nephritis
Causes : 1- bacterial infection. 2- drugs. 3- metabolic disorders such as hypokalemia. 4- physical injury such as irradiation. 5- viral infections. 6- immune reactions.
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Acute Pyelonephritis
Acute pyelonephritis, a common suppurative inflammation of the kidney and the renal pelvis. It is caused by bacterial infection. It is an important manifestation of urinary tract infection (UTI) : 1- lower UT (cystitis, prostatitis, urethritis). 2- upper UT(pyelonephritis). 3- both.
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Pathogenesis
The principal causative organisms are : 1- Escherichia coli is the most common . 2- Proteus.
Routes of infection
1-hematogenous. 2-ascending infection (commonest). acute pyelonephritis may result from seeding of the kidneys by bacteria in the course of septicemia or infective endocarditis. Ascending infection from the lower urinary tract is the most important and common route by which the bacteria reach the kidney.
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bladder urine is sterile and remains so as a result of: 1- the antimicrobial properties of the bladder mucosa. 2- the flushing action associated with periodic voiding of urine.
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The first step is adhesion of bacteria to mucosal surfaces colonization of the distal urethra bladder by expansive growth of the colonies and by moving against the flow of urine.
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Predisposing factors
1-urethral instrumentation, including catheterization and cystoscopy 2-female sex because of the close proximity of the urethra to the rectum 3-trauma to the urethra
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4-outflow obstruction or bladder dysfunction Obstruction at the level of the urinary bladder results in incomplete emptying and increased residual volume of urine stasis bacteria introduced into the bladder multiplication without being flushed out or destroyed by the bladder wall the bacteria ascend along the ureters to infect the renal pelvis and parenchyma.
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UTI is particularly frequent among individuals with: - benign prostatic hyperplasia - uterine prolapse. - neurogenic bladder dysfunction
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5-Pregnancy. 4% to 6% of pregnant women develop bacteriuria sometime during pregnancy and 20% -40% of these eventually develop UTI. 6-UTI is increased in diabetes because of the increased susceptibility to infection. 7-vesicoureteral reflux An incompetent vesicoureteral orifice allows the reflux of bladder urine into the ureters &allows bacteria to ascend the ureter into the pelvis. .
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The normal ureteral insertion into the bladder is a competent one-way valve that prevents retrograde flow of urine, especially during micturition when the intravesical pressure rises.
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VUR is present in 20% to 40% of young children with UTI. 1- congenital defect that results in incompetence of the ureterovesical valve. 2-acquired in spinal cord injury and with neurogenic bladder dysfunction secondary to diabetes.
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Acute pyelonephritis. The cortical surface is studded with focal pale abscesses
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Acute TIN
1-most frequently occurs with synthetic penicillins (methicillin, ampicillin) 2- other synthetic antibiotics (rifampin), diuretics (thiazides) 3- nonsteroidal anti-inflammatory agents 4-other drugs (phenindione, cimetidine).
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Pathogenesis
Many features of the disease suggest an immune mechanism. Clinical evidence of hypersensitivity is not dose related. Serum IgE levels are increased in some persons suggesting type I hypersensitivity. The mononuclear or granulomatous infiltrate, together with positive skin tests to drugs, suggests a T cell-mediated (type IV) hypersensitivity reaction.
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the drugs act as haptens that covalently bind to some cytoplasmic or extracellular component of tubular cells and become immunogenic. The resultant tubulointerstitial injury is then caused by IgE- and cell-mediated immune reactions to tubular cells or their basement membranes.
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Morphology
the interstitium shows pronounced edema and infiltration by mononuclear cells, lymphocytes and macrophages . Eosinophils and neutrophils may be present, often in large numbers. With some drugs (e.g., methicillin, thiazides, rifampin), interstitial non-necrotizing granulomas with giant cells may be seen. The glomeruli are normal except in some cases caused by nonsteroidal antiinflammatory agents.
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Clinical course
The disease begins about 15 days (range 240 days) after exposure to the drug. It is characterized by fever, eosinophilia & rash in about 25% of persons, and renal
abnormalities.
Renal findings include hematuria, minimal or no proteinuria, and leukocyturia (sometimes including eosinophils).
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A rising serum creatinine or acute renal failure with oliguria develops in about 50% of cases, particularly in older patients. It is important to recognize drug-induced renal failure, because withdrawal of the offending drug is followed by recovery although it may take several months for renal function to return to normal.
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Analgesic Nephropathy
Consumption large quantities of analgesics may cause chronic interstitial nephritis often
Aspirin and acetaminophen While they can cause renal disease in apparently healthy individuals preexisting renal disease seems to be a necessary precursor to analgesicinduced renal failure.
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Pathogenesis
The pathogenesis of the renal lesions is not entirely clear. Papillary necrosis is the initial event, and the interstitial nephritis in the overlying renal parenchyma is a secondary phenomenon. Acetaminophen, a phenacetin metabolite, injures cells by both covalent binding and oxidative damage.
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The ability of aspirin to inhibit prostaglandin synthesis suggests that this drug may induce its potentiating effect by inhibiting the vasodilatory effects of prostaglandin and predisposing the papilla to ischemia. The papillary damage may be caused by a combination of direct toxic effects of phenacetin metabolites as well as ischemic injury to both tubular cells and vessels.
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Morphology
The papillae show coagulative necrosis Foci of dystrophic calcification may occur in the necrotic areas. The cortex drained by the necrotic papillae shows tubular atrophy, interstitial scarring, and inflammation. The small vessels in the papillae and urinary tract submucosa exhibit characteristic PASpositive basement membrane thickening.
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Clinical Course
Chronic renal failure, hypertension, and anemia. The anemia results in part from damage to red cells by phenacetin metabolites. A complication of analgesic abuse is the increased incidence of transitionalcell carcinoma of the renal pelvis or bladder in persons who survive the renal failure.
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failure.
In acute renal failure, urine flow falls within 24 hours to less than 400 mL/day (oliguria).
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Other causes of acute renal failure include : (1) severe glomerular diseases manifesting as RPGN. (2) diffuse renal vascular diseases such as microscopic polyangiitis and thrombotic microangiopathies. (3) acute papillary necrosis associated with acute pyelonephritis. (4) acute drug-induced interstitial nephritis. (5) diffuse cortical necrosis.
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nephrotoxic ATN poisons including heavy metals (e.g., mercury) organic solvents (e.g., carbon tetrachloride) drugs such as gentamicin and other antibiotics, and radiographic contrast agents.
Pathogenesis
(1) tubular injury (2) persistent and severe disturbances in blood flow resulting in diminished oxygen and substrate delivery to tubular cells. Tubular epithelial cells are particularly sensitive to anoxia and are also vulnerable to toxins. Ischemia causes numerous structural alterations in epithelial cells
Loss of cell polarity reversible early event. Redistribution of membrane proteins (e.g., Na+, [Kgr ]+ATPase) from the basolateral to the luminal surface of tubular cells Decreased sodium reabsorption by proximal tubules and hence increased sodium delivery to distal tubules. Vasoconstriction. Redistribution or alteration of integrins that anchor tubular cells to their underlying basement membranes results in shedding of tubular cells into the urine.
damage to the tubules and the resultant tubular debris can block urine outflow and eventually increase intratubular pressure decreasing GFR. fluid from the damaged tubules could leak into the interstitium resulting in increased interstitial pressure and collapse of the tubules. Ischemic tubular cells also express chemokines, cytokines, and adhesion molecules such as Pselectin that recruit and immobilize leukocytes that can participate in tissue injury.
Benign Nephrosclerosis
the term used for the renal changes in benign hypertension It is always associated with hyaline arteriolosclerosis. Some degree of mild benign nephrosclerosis is present at autopsy in many persons older than 60 years of age. The frequency and severity of the lesions are increased at any age when hypertension or diabetes mellitus are present.
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Pathogenesis
many renal diseases cause hypertension which in turn is associated with benign nephrosclerosis. this renal lesion is often seen superimposed on other primary kidney diseases. Similar changes in arteries and arterioles are seen in individuals with chronic thrombotic microangiopathies.
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Morphology
the kidneys are symmetrically atrophic, each weighing 110 to 130 gm, with a surface of diffuse, fine granularity that resembles grain leather. the basic anatomic change is hyaline thickening of the walls of the small arteries and arterioles known as hyaline arteriolosclerosis. This appears as a homogeneous, pink hyaline thickening at the expense of the vessel lumina with loss of underlying cellular detail .
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The narrowing of the lumen results in markedly decreased blood flow through the affected vessels and thus produces ischemia in the organ served All structures of the kidney show ischemic atrophy.
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Benign nephrosclerosis. arterioles with hyaline deposition, marked thickening of the walls and a narrowed lumen.
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In advanced cases of benign nephrosclerosis the glomerular tufts may become globally sclerosed. Diffuse tubular atrophy and interstitial fibrosis are present.
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The larger blood vessels (interlobar and arcuate arteries) show reduplication of internal elastic lamina along with fibrous thickening of the media and the subintima (fibroelastic hyperplasia).
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Clinical Course
rarely causes severe damage to the kidney except in susceptible populations, such as African Americans. all persons with this lesion usually show some functional impairment, such as loss of concentrating ability or a variably diminished GFR. A mild degree of proteinuria.
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Pathogenesis
vascular damage to the kidneys. most commonly results from long-standing benign hypertension with eventual injury to the arteriolar walls. The result is increased permeability of the small vessels to fibrinogen and other plasma proteins, endothelial injury, and platelet deposition. fibrinoid necrosis of arterioles and small arteries and intravascular thrombosis.
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Mitogenic factors from platelets (e.g., PDGF) and plasma cause intimal smooth hyperplasia of vessels, resulting in the hyperplastic arteriolosclerosis typical of malignant hypertension and of morphologically similar thrombotic microangiopathies
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The kidneys become markedly ischemic. Renin-angiotensin system is stimulated. angiotensin II causes intrarenal vasoconstriction renal ischemia renin secretion. Aldosterone levels are also elevated salt retention Bp.
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The consequences of the markedly elevated blood pressure on the blood vessels throughout the body are known as malignant arteriolosclerosis, and the renal disorder is referred to as
malignant nephrosclerosis.
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Morphology
The kidney is normal-slightly shrunken, depending on the duration and severity of the hypertensive disease. Small pinpoint petechial hemorrhages may appear on the cortical surface from rupture of arterioles or glomerular capillaries giving the kidney a peculiar, flea-bitten appearance.
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fibrinoid necrosis of the arterioles . In the interlobular arteries and larger arterioles, proliferation of intimal cells produces an onion-skin appearance . This lesion, called hyperplastic arteriolosclerosis, causes marked narrowing of arterioles and small arteries to the point of total obliteration. Necrosis may also involve glomeruli with microthrombi within the glomeruli as well as necrotic arterioles.
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Malignant hypertension.
Fibrinoid necrosis of afferent arteriole (PAS stain).
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Clinical Course
malignant hypertension is characterized by : 1-diastolic pressures > 120 mm Hg, 2-papilledema 3-encephalopathy 4-cardiovascular abnormalities 5-renal failure
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Early symptoms are related to increased intracranial pressure and include headache, nausea, vomiting, and visual impairment, particularly the development of scotomas, or spots before the eyes. At the onset of rapidly mounting blood pressure there is marked proteinuria and microscopic or macroscopic hematuria but no significant alteration in renal function. The syndrome is a true medical emergency that requires prompt and aggressive antihypertensive therapy before irreversible renal lesions develop.
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About 50% of patients survive at least 5 years. 90% of deaths are caused by uremia. 10% by cerebral hemorrhage or cardiac failure.
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1-Simple Cysts 2-Autosomal Dominant (Adult) Polycystic Kidney Disease 3-Autosomal Recessive (Childhood) Polycystic Kidney Disease 4-Medullary Cystic Disease
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1-Simple Cysts
Multiple or single cystic spaces that vary widely in diameter ( 1-5 cm in diameter ) filled with clear fluid. The cysts are usually confined to the cortex. Massive cysts as large as 10 cm in diameter are rare. Simple cysts are a common post-mortem finding that has no clinical significance. The main importance of cysts lies in their differentiation from kidney tumors when they are discovered either incidentally or because of hemorrhage and pain.
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Dialysis-associated acquired cysts occur in the kidneys of patients with end-stage renal disease who have undergone prolonged dialysis. They are present in both cortex and medulla and may bleed causing hematuria. renal adenomas or even adenocarcinomas arise in the walls of these cysts.
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Cystic change associated with chronic renal dialysis. These kidneys are about normal in size but have a few scattered cysts, none of which is over 2 cm in size. This is
1-In 85-90% of families, PKD1, the defective gene is on the short arm of chromosome 16. This gene encodes a large and complex cell membrane-associated protein called polycystin-1.
2-The PKD2 gene (10-15% of cases) on chromosome 4 and encodes polycystin 2. Polycystin 2 is thought to function as a calcium-permeable membrane channel. polycystins 1 and 2 are believed to act together by forming heterodimers. mutation in either gene gives rise to essentially the same phenotype although patients with PKD2 mutations have a slower rate of disease progression as compared with patients with PKD1 mutations.
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Clinical presentation
asymptomatic until the 4th decade by which time the kidneys are quite large although small cysts start to develop in adolescence. The most common presenting complaint is flank pain or a heavy dragging sensation. Acute distention of a cyst either by intracystic hemorrhage or by obstruction may cause excruciating pain. palpation of an abdominal mass. Intermittent gross hematuria commonly occurs. hemorrhage.
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Complications
1-hypertension (75% ). 2-urinary infection. 3-Saccular aneurysms of the circle of Willis are present in 10% to 30% of patients (subarachnoid hemorrhage ). 4-end-stage renal failure occurs at about age 50 .
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Mutations in a gene PKHD1 coding for a putative membrane receptor protein called fibrocystin, localized to chromosome 6p. Fibrocystin may be involved in the function of cilia in tubular epithelial cells .
Cysts are fairly small but uniformly distributed throughout the parenchyma so that the disease is usually symmetrical in appearance with both kidneys markedly enlarged.
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disease complex
is almost always associated with renal dysfunction.
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The juvenile form is the most common. Approximately 15-20% of individuals with juvenile nephronophthisis have extra-renal manifestations: 1- retinal abnormalities, including retinitis pigmentosa. 2- oculomotor apraxia. 3- mental retardation. 4- cerebellar malformations. 5- liver fibrosis.
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The initial manifestations are usually polyuria and polydipsia a consequence of diminished tubular function. Progression to end-stage renal disease ensues over a 5-10-year period. The disease is difficult to diagnose, since there are no serologic markers and the cysts may be too small to be seen with radiologic imaging. cysts may not be apparent on renal biopsy if the cortico-medullary junction is not well sampled. A positive family history and unexplained chronic renal failure in young patients should lead to suspicion of medullary cystic disease.
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Pathogenesis
Renal stones are composed of: 1-calcium oxalate or calcium oxalate mixed with calcium phosphate(80%) . 2-10% are composed of magnesium ammonium phosphate. 3-6%-9% are either uric acid or cystine stones.
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In all cases there is an organic matrix of mucoprotein that makes up about 2.5% of the stone by weight.
Causes
1-increased urine concentration of the
stone's constituents so that it exceeds their solubility in urine (supersaturation). 50% of patients who develop calcium stones have hypercalciuria that is not
associated with hypercalcemia.
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Hypercalciuria: A. absorptive hypercalciuria. B. renal hypercalciuria due to primary renal defect of calcium reabsorption.
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2-The presence of a nidus In 20% of this subgroup there is excessive excretion of uric acid in the urine which favors calcium stone formation. Urates provide a nidus for calcium deposition. Desquamated epithelial cells
3-urine pH High urine pH favors crystallization of calcium phosphate and stone formation. Magnesium ammonium phosphate (struvite) stones almost always occur with a persistently alkaline urine due to UTIs.
Uric acid stones formed in acidic urine (under pH 5.5). Cystine stones are more likely to form when the urine is relatively acidic.
4-infections The urea-splitting bacteria such as Proteus vulgaris and the staphylococci predispose the person to urolithiasis.
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5-lack of substances that normally inhibit mineral precipitation. Inhibitors of crystal formation in urine include Tamm-Horsfall protein, osteopontin, pyrophosphate, mucopolysaccharides, diphosphonates, and a glycoprotein called nephrocalcin No deficiency of any of these substances has been consistently demonstrated in individuals with urolithiasis.
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Stones are unilateral in about 80% of patients. Common sites of formation are renal pelves and calyces and the bladder. They tend to be small (average diameter 2-3 mm) and may be smooth or jagged. Progressive precipitation of salts leads to the development of branching structures known as staghorn calculi. These massive stones are usually composed of magnesium ammonium phosphate.
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Hydronephrosis
Refers to dilation of the renal pelvis and calyces, with accompanying atrophy of the parenchyma. The obstruction may be sudden or insidious and it may occur at any level of the urinary tract from the urethra to the renal pelvis.
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1-Congenital:
Atresia of the urethra Valve formations in either ureter or urethra Aberrant renal artery compressing the ureter Renal ptosis with torsion or kinking of the ureter
2-Acquired: Foreign bodies: Calculi, necrotic apillae Tumors: Benign prostatic hyperplasia, carcinoma of the prostate, bladder tumors (papilloma and carcinoma), contiguous malignant disease (retroperitoneal lymphoma, carcinoma of the cervix or uterus Inflammation: Prostatitis, ureteritis, urethritis, retroperitoneal fibrosis Neurogenic: Spinal cord damage with paralysis of the bladder Normal pregnancy: Mild and reversible
Hydronephrosis of the kidney, with marked dilation of the pelvis and calyces and thinning of renal parenchyma.
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