Renal Pathology part 1 Flashcards
Most glomerular diseases are
immunologically mediated
Tubular and interstitial disorders are
frequently caused by toxic or infectious agents
Severe glomerular damage impaires
flow through the peritubular vascular system
Tubular destruction
-may induce glomerular injury by increasing intraglomerular pressure
Azotemia
- biochemical abnormality that refers to an elevation of BUN and creatinine levels and is related largely to a decreased glomerular filtration rate (GFR)
- consequence of renal and external disorders
- typical feature of both acute and chronic injury
Prerenal azotemia
Encountered where there is hypoperfusion of the kidneys (hypertension or excessive fluid losses from any cause, or if the effective intravascular volume is decreased due to shock, volume depletion, congestive heart failure or cirrhosis of the liver) that impairs renal function in the absence of parenchymal damage
Postrenal azotemia
- seen whenever renal flow is obstructed distal to kidney
- relief of obstruction followed by correction of the azotemia
Uremia
- when azotemia becomes associated with clinical signs/symptoms and biochemical abnormalities
- failure of excretory function and a host of metabolic and endocrine alterations resulting from renal damage
Uremic patients frequently have secondary involvement of
- GI system (uremic gastroenteritis)
- peripheral nerves (peripheral neuropathy)
- heart (uremic fibrinous pericarditis)
Nephritic syndrome
- clinical entity caused by glomerular disease and is dominated by the acute onset of either grossly visible hematuria (RBCs in urine) or microscopic hematuria with dysmorphic red cells and red cell casts on urinalysis, diminished GFR, mild to moderate proteinuria, and hypertension
- classic presentation of acute post streptococcal glomerulonephritis
Rapidly progressive glomerulonephritis
-nephritic syndrome with rapid decline in GFR (within hours to days)
Nephrotic syndrome
- due to glomerular disease
- heavy proteinuria, hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria
Asymptomatic hematuria/proteinuria
usually a manifestation of subtle or mild glomerular abnormalities
Acute kidney injury
- Rapid decline in GFR (within hours to days), with concurrent dysregulation of fluid and electrolyte balance, and retntion of metabolic waste products normally excreted by the kidney including urea and creatinine
- In most severe forms, manifested by oliguria or anuria (reduced or no urine flow)
Acute kidney injury can result from
-glomerular, interstitial, vascular or acute tubular injury
Chronic kidney disease
- the presence of a diminished GFR that is persistently less than 60mL/min/ 1.73 m2 for at least 3 months, from any cause, and/or persistent albuminuria
- may present with clinically silent decline in renal excretory function in milder forms and in more severe cases by prolonged symptoms and signs of uremia
- end result of all chronic renal parenchymal diseases
end stage renal disease (ESRD)
-GFR less than 5% of normal; terminal state of uremia
Renal tubular defects are dominated by
polyuria (excessive urine formation), nocturia, and electrolyte disorders (metbolic acidosis)
-result of diseases that with either directly affect tubular structures or cause defects in specific tubular functions (can be inherited or acquired)
Urinary tract infection
- bacteriuria and pyuria
- may be symptomatic or asymptomatic, may affect the kidney or the bladder
Nephrolithiasis
- renal stones
- spasms of severe pain (renal colic) and hematuria,often with recurrent stone formation
Secondary glomerular disease causes
-systemic immunologic diseases such as systemic lupus erythmatous, vascular disorders such as hypertension, metabolic diseases such as diabetes mellitus, and some heriditary conditions such as Fabry disease often affect glomerulus
The glomerulus consists of
- an anastomosing network of capillaries lined by fenestrated endothelium invested by 2 layers of epithelial cells
- visceral epithelial cells (podocytes) are incorporated into and become an intrinsic part of the capillary wall, separated from endothelial cells by a basement membrane
Glomerulus parietal epithelium
- situated on Bowman’s capusule
- lines the urinary space, the cavity in which plasma filtrate first collects
The glomerular capillary wall is
-the filtering membrane and consists of a thin layer of fenestrated endothelial cells, a glomerular basement membrane (GBM) with a thick electron-dense layer, the lamina densa, and thinner electron-lucent peripheral layers, the lamina rara internal and lamina rara external
GBM consists of
-collagen type IV, laminin, polyanionic proteoglycans (mostly heparin sulfate), fibronectin, entactin, and several other glycoproteins
Type IV collagen forms
- a network suprastructure to which other glycoproteins attach
- building block of this network is a triple-helical molecular composed of one or more of 6 types of alpha chains
- each molecule consists of a 7s domain at the N terminus, a triple-helical domain in the middle, and a globular non collagenous domain (NC1) at the C terminus
NC1 domain
- importain for helix formation and for assembly of collagen monomers into the basement membrane superstructure
- glycoproteins and proteoglycans attach to the collagenous superstructure
Antigens in the NC1 domain are
the targets of Abs in the anti-GBM nephritis; genetic defects in the alpha chains underly some forms of heriditary nephritis; and the proteoglycans content of the GBM may contribute to its permeability characteristics
Visceral epithelial cells (podocytes)
- possess interdigitating processes embedded in and adherent to the lamina rara externa of the basement membrane
- adjacent foot processes are separated by filtration slits, which are bridged by a thin diaphragm
Glomerular tuft is supported by
mesangial cells lying between the capillaries
Basement membrane like mesangila matrix forms
a meshwork in which the mesangial cells are embedded
-these cells, of mesangial origin are contractile, phagocytic and capable of proliferation of laying down both matrix collagen and of secreting several biologically active mediators
Normal glomerulus is highly permeable to
water and small solutes because of the fenestrated nature of the endothelium and impermeable to proteins of the size of albumin or larger
Permeability characteristics of the glomerular filtration barrier allow
discrimination among various protein molecules, depending on their size (the larger, the less permeable) and charge (the more cationic, the more permeable)
Visceral epithelial cell is important for
maintenance of glomerular barrier function; its slit diaphragm presents a size-selective distal diffusion barrier to the filtration of proteins, and it is the cell type that is largely responsible for synthesis of GBM components
Nephrin
- a transmembrane protein with a large extracellular portion made up of immunoglobulin like domains
- molecules extend toward each other from neighboring foot processes and dimerize across the slit diaphragm
Within the cytoplasm of the foot processes, nephrin forms
molecular connections with podocin, Cd-2 associated protein, and ulitmately the actin cytoskeleton of the visceral epithelial cells
Mutations in genes encoding slit diaphragm proteins lead to
defects in protein permeability and the nephrotic syndrome
Some inflammatory diseases of the glomerulus are characterized by
an increase in the number of cells in the glomerular tufts
Hypercellularity of glomerular tufts results from
- proliferation of mesangial or endothelial cells
- infiltration of leukocytes, including neutrophils, monocytes, and in some diseases, lymphocytes
- formation of crescents
Endocapillary proliferation
-combination of infiltration of leukocytes and swelling and proliferation of mesangial and/or endothelial cells
Crescents
- accumulations of cells composed of proliferating glomerular epithelial cells and infiltrating leukocytes
- epithelial cell proliferation that characterizes crescent formation occurs following an immune/inflammatory injury involving capillary walls
- plasma proteins leak into the urinary space, where it is believed that exposure to procoagulants leads to fibrin deposition
Suspected of being a trigger for crescent formation
activation of coagulation factors such as thrombin
By light microscopy, basement membrane thickening appears as
thickening of capillary walls, best seen in sections with PAS
By electron microscopy, basement membrane thickening takes one of these forms
- deposition of amorphous electron dense material, most often immune complexes, on the endothelial or epithelial side of the membranes or within the GBM itself. Fibrin, amyloid, cryoglobulins, and abnormal fibrillary proteins may also deposit in the GBM
- increased synthesis of the protein components of the basement membrane as occurs in diabetic glomerulosclerosis
- formation of addiional layers of BM matrices, which most often occupy subendohelial locations and may range from poorly organized matrix to duplicated lamina densa, as occurs in membranoproliferative glomerulonephritis
Hyalinosis
- the accumulation of material that is homogenous and eosinophilic by light microscopy
- usually a consequence of endothelial or capillary wall injury and typically the end result of various forms of glomerular damage
Hyalin
- an extracellular, amorphous material composed of plasma proteins that have insulated from the circulation into glomerular structures
- when extensive, these deposits may obliterate the capillary lumens of the glomerular tuft
Sclerosis
- characterized by deposition of extracellular collagenous matrix
- may be confined to mesangial areas as is often the case in diabetic glomerulosclerosis, involve the capillary loops, or both
Sclerosing process may also result in
obliteration of some or all of the capillary lumens in affected glomeruli
Histologic glomerular change categories
- diffuse, involving all of the glomeruli in the kidney
- global, involving the entirety of individual glomeruli
- focal, involving only a fraction of the glomeruli in the kidney
- segmental affecting a part of each glomerulus
- capillary loop or mesangial affecting predominantly capillary or mesangial regions
Glomerulonephritis can be readily induced experimentally by
Ag-Ab reactions
Found in the majority of individuals with glomerulonephritis
-glomerular deposits of immunoglobulins often with components of complement
Two forms of antibody associated injury in glomerulonephritis have been estabilshed
- injury by Abs reacting in situ within the glomerulus, either binding to insoluble fixed glomerular Ags or extrinsic molecules planted within the glomerulus
- injury results from deposition of circulating Ag-Ab complexes in the glomerulus
The major cause of glomerulonephritis resulting from formation of Ag-Ab complexes is the consequence of
in situ immune complex formation
in glomerular injury from in situ formation of immune complexes
immune complexes are formed locally by Abs that react with intrinsic tissue Ag or with extrinsic Ags “planted” in the glomerulus from the circulation
Membranous nephropathy
-classic example of glomerular injury resulting from local formation of immune complexes
Heymann Nephritis rat model of glomerulonephritis
- induced by immunizing rats with an Ag, megalin that is present in epithelial cell foot processes
- rats develop Abs to this Ag and disease develops from the reaction of Ab with the megalin-containing protein complex located on the basal surface of visceral epithelial cells, leading to localized immune complex formation
Ag that underlies most cases of primary human membranous nephropathy
-M-type phospolipase A2 receptor (PLA2R)
Ab binding to PLA2R present in the glomerular epithelial cell membrane is followed by
complement activation and then shedding of the immune aggregates from the cell surface to form characterisitic deposits of immune complexes along with the sub epithelial aspect of the BM
On EM, glomerulopathy is characterized by
presence of numerous discrete subepithelial electron dense deposits (made up largely of immune reactants)
In glomerulopathy the pattern of immune deposition by IF microscopy is
granular rather than linear, reflective of the very localized Ag-Ab interaction
In glomerulopathy, sub-epithelial complexes with resultant host responses can result in
a thickened basement membrane apearance by LM–membranous nephropathy
In humans, primary membranous nephropathy is
an autoimmune disease caused by Abs to endogenous tissue componenets
Secondary forms of membranous nephropathy can be experimentally induced by
drugs (mercuric chloride) and graft vs host disease
In some situations of membranous nephropathy
there may be uncontrolled B cell activation leading to the production of autoantibodies that react with renal Ags
