| How is histology of glomerulus? | ➢Anastomosing network of capillaries invested by two layers of epithelium :
The visceral epithelium (composed of podocytes) is part of the capillary wall Fenestrated endothelial cells.
➢ The glomerular basement membrane (GBM), has a thick, electron-dense central layer called the
lamina densa, and two thinner, electron-lucent peripheral layers, the lamina rara interna and externa.
➢The GBM consists of collagen (mostly type IV), laminin, polyanionic proteoglycans, fibronectin,
and several other glycoproteins.
➢Podocytes, cells that possess interdigitating foot processes that are embedded in and adherent to the
lamina rara externa.
➢Adjacent foot processes are separated by filtration slits, which are bridged by a thin slit diaphragm
➢Mesangial cells, lie in a mesangial matrix between the capillaries that supports the glomerular tuft.
➢Mesangial cells , of mesenchymal origin, are contractile and are capable of proliferation, of laying
down collagen and other matrix components, and of secreting a number of biologically active mediators in response to cytokines and other factors |
| What is glomerulus function? | ➢Normally, the glomerular filtration system is highly permeable to water and small solutes and almost completely impermeable to molecules of the size and molecular charge of albumin (a 70,000-kDa protein).
➢This selective permeability discriminates among protein molecules according to size (the larger, the less permeable), charge (the more cationic, the more permeable), and shape;
➢Podocyte slit diaphragms are important diffusion barriers for plasma proteins,
➢Nephrin and its associated proteins, including podocin, have a crucial role in maintaining the selective permeability of the glo- merular filtration barrier. |
| What are clinical features of kidneys? | ➢ Different clinical settings may be encountered
1. Nephrotic syndrome
2. Acute nephritic syndrome
3. Rapidly progressive glomerulonephritis syndrome
4. Hematuric syndrome,
5. Chronic renal disease
➢Performing a renal biopsy can provide therapeutic and prognostic information |
| What is dx approach for renal diseases? | ➢ Renal biopsy provides a specific pathological pattern or reveals non specific lesions (end stage kidney disease)
➢ To determine the disease (as a clinical entity) it will be essential to compare the anatomopathological report with the clinical and biological data.
➢ This correlation is a fundamental step which will allows us to distinguish primitive GP from secondary ones occuring in a more complexe disease
➢ Ex : crescentic pauci- immune GN can be seen in a variety of conditions including ANCA vacsulitis : in the case of an upper repsiratory tract syndrome is associated, with positive ANCA, we could propose the diagnosis of wegner granulomatosis |
| How is management of kidney disease in pathology? | ➢ It is necessary to obtain at least two fragments one for morphological study under light microscopy and the other for immunofluorescence tests
➢ The conventional study using paraffin-fixed tissue: Reveals elementary kidney lesion, but needs the Use of special stains in addition to the standard HE staining : Masson's trichrome : Hyaline deposits, fibrosis, …
Periodic Acid Schiff (PAS) : BM Silver Stain : Memranous deposits
➢Numerous cut sections are needed to highlight segmental and focal lesions
➢ Immunofluorescence studies :
✓Performed on frozen tissue
✓Reveals only extracellular deposits
✓Often gives precious information about the etiology of the disease
✓Antibodies used on every kidney biopsy :
Heavy Chain immunoglobulines (A,G,M)
Light Chain immunoglobulines (Kappa et lambda)
complement (C3 et C1q) Fibrinogene |
| What are glomerular diseases? | . |
| How is mechanism of glomerular injury and disease? | ➢ Immune mechanisms underlie most types of primary glomerular diseases and many of the secondary glomerular diseases.
➢ Two mechanisms of antibody deposition in the glomerulus have been established:
(1) Deposition of circulating antigen-antibody complexes in the glomerular capillary wall or mesangium
(2) Antibodies reacting in situ within the glomerulus, either with fixed (intrinsic) glomerular antigens or with extrinsic molecules that are planted in the glomerulus.
➢These pathways are not mutually exclusive, and in humans all may contribute to injury.
➢Abnormal activation and glomerular deposition of complement may be the only pathologic mecanism in some forms of GN.
➢Cell-mediated immune mechanisms also may play a role in certain glomerular diseases |
| What is glomerulonephritis caused by circulating immune complexes? | ➢ In circulating immune complex–mediated diseases, the complexes may be formed :
✓With endogenous antigens, as in the GN associated with systemic lupus erythematosus,
✓With exogenous antigens : GN that follows certain bacterial (streptococcal), viral (hepatitis B), parasitic (Plasmodium falciparum malaria), and spirochetal (Treponema pallidum) infections.
✓Often the inciting antigen is unknown, as in most cases of membranoproliferative GN.
➢Once antigen-antibody complexes are deposited or formed in the glomeruli, they produce injury by activating complement and recruiting leukocytes.
➢Morphologically, affected glomeruli exhibit leukocytic infiltrates and variable proliferation of mesangial and parietal epithelial cells
➢EM reveals electron-dense immune deposits in one or more of three locations:
1. Between the endothelial cells and the GBM (subendothelial deposits)
2. Between the outer surface of the GBM and the podocytes (subepithelial deposits),
3. In the mesangium.
➢The localization of antigen, antibody, or immune complexes determines the glomerular injury response |
| How is inflammation caused by immune complexes in glomerulus? | ➢Once deposited in the kidney, immune complexes may eventually be cleared by degradation or phagocytosis, mostly by infiltrating leukocytes and mesangial cells.
➢The inflammatory reaction may then subside if the exposure to the inciting antigen is short-lived and limited, as in most cases of poststreptococcal or acute infection–related GN.
➢However, if exposure to antigen is sustained, repeated cycles of immune complex formation, deposition, and injury occur, leading to chronic GN.
➢In some cases, the source of chronic antigenic exposure is clear (hepatitis B virus infection and SLE), but more often the antigen is unknown. |
| How is in situ glomerulonephritis caused by immune complexes? | ➢ Deposition of antibodies specific for fixed (intrinsic) or planted (from outside) antigens in the glomerulus is another major pathway of glomerular injury.
➢ Antigens expressed by podocytes have been implicated in membranous nephropathy.
➢ Antibodies also may react in situ with previously “planted” non glomerular antigens, which deposit and become concentrated in the kidney through interaction with various glomerular components.
➢ Planted antigens mainly derived from
1. breakdown of apoptotic cells, in patients with systemic lupus erythematosus;
2. bacterial products, such as endostreptosin, a protein expressed by group A streptococci;
3. large aggregated proteins [IgG], which tend to deposit in the mesangium.
➢Locally formed immune complexes may also grow in size through additional interactions with circulating free antibodies and antigens.
➢ Most of these planted antigens, as with circulating immune complexes deposited on the GBM, show a granular pattern of deposition by immunofluorescence microscopy |
| How is activation of glomerular diseases caused by complement activation? | ➢ unregulated activation of the alternative complement pathway, which may be triggered by acquired autoantibodies against complement components or inherited abnormalities of complement regulatory proteins.
➢complement-mediated injury may result in renal and systemic disease.
➢Two forms of GN (dense deposit disease and C3 GN) and one form of a systemic disease with significant renal manifestations (complement-mediated thrombotic microangiopathy [TMA] or atypical hemolytic uremic syndrome) belong to nthis category |
| What are mediators of immune injury in kidneys? | ➢ A major pathway of antibody-initiated glomerular injury involves complement activation and recruitment
➢Activation of complement via the classical pathway leads to the generation of
chemotactic agents (mainly C5a) for neutrophils and monocytes.
➢ Neutrophils release proteases, which cause GBM degradation;
➢ Oxygen-derived free radicals, which cause cell damage;
➢ Arachidonic acid metabolites, which contribute to reduction in GFR.
➢In addition to neutrophils and monocytes, which are recruited by antibodies and complement, T lymphocytes activated during the immune reaction also have been implicated in glomerular injury |
| What are non-immune mechanisms of glomerular injury? | ➢Podocyte Injury
induced by antibodies to podocyte antigens; by toxins; conceivably by certain cytokines; or by still poorly characterized circulating factors, as in some cases of focal segmental glomerulosclerosis
➢Nephron Loss Once renal disease, glomerular or otherwise, destroys sufficient nephrons to reduce the GFR to 30% to 50% of normal, symptoms appear and progression to end-stage renal disease proceeds at varying rates. Affected individuals have proteinuria, and their glomeruli show widespread scarring, called glomerulosclerosis |
| How is cellular proliferation histologic glomerular lesion? | Endocapillary proliferation = Increase in the number of cells in the endocapillarycompartment
➢ mesangial cells
➢ inflammatory cells of the circulating blood
➢ endothelial cells
Endocapillary proliferation is always linked to the presence of endomembrane deposit
Extracapillary proliferation = Increase in the number of parietal epithelial cells following glomerular necrosis
➢ Formation of a crescent in the urinary chamber
➢ Progression towards fibrosis |
| How is CT in glomerular histologic lesions? Distribution of lesions? | ➢Irregular thickening of GBM in response to the presence of extramembrane deposits
➢ Duplication of GBM (“MPGN").
➢Glomerulosclerosis: increase in the mesangial matrix ("Diabetes")
➢Focal/diffuse lesions :
Focal lesions affect only a minority of the glomeruli.
Diffuse lesions affect all glomeruli in the same way.
➢Segmental/global lesions:
The lesion is said to be Segmental when only part of the glomerular capillary is affected.
The lesion is said to be global when it affects the entire affected glomerulus |
| What are immunofluorescence findings for glomerular lesions? | 1. Location of deposits
a. Extramembrane deposits: immune complexes are located on the external side of the MBG (between the
MBG and the podocyte).
b. Endomembranous deposits: immune complexes are located within the MBG (mesangial,intercapillary) and
subendothelial.
c. Intramembranous deposits, immune complexes located in the basement membrane, are much rarer.
2. Appearance of immunofluorescence deposits
a. Granular: the most frequent, corresponding to immune deposits.
b. Linear: rarer (GN with anti-MBG antibodies, certain diseases with monoclonal Ig deposits).
c. Larger and more homogeneous deposits: "hyaline" deposits of HSF, diabetes / amyloidosis.
3. Nature of immunofluorescence deposits
a. Immunoglobulins (IgA, IgG, IgM, kappa, lambda).
b. Fraction of the complement |
| What is minimal chain disease? | LM : absence of glomerular abnormality (Normal glomeruli appearance on LM)
IF : No deposit of Ig or Complement.
ME : Diffuse effacement of podocyte foot processes
N.B : Most common cause of nephrotic syndrome in children youger than 10 years
Usually sudden onset of nephrotic syndrome in an otherwise healthy child
Relatively benign disorder, rarely if ever, leads to ESRD |
| What is focal segmental glomerulosclerosis? | ➢Primary Focal Segmental Glomerulosclerosis (idiopathic) characterized by :
Sclerosis of some (but not all) glomeruli
Sclerosis involves only a part of each affected glomerulus.
initially affects only the juxtamedullary glomeruli. With progression, eventually all levels of the cortex are affected.
Primary FSGS accounts for approximately 20% to 30% of all cases of the nephrotic syndrome.
➢ Secondary FSGS may occur in one of the following conditions:
• HIV infection (HIV nephropathy).
• Heroin abuse (heroin nephropathy)
• Secondary to other forms of GN (e.g., IgA nephropathy, diabetic GS, …)
• As a maladaptation to nephron loss
• Inherited forms, including autosomal dominant forms associated with mutations in cytoskeletal proteins and podocin, both of which are required for the integrity of podocytes. |
| How is pathogenesis of focal segmental glomerulosclerosis? | ➢Injury to podocytes is thought to represent the initiating event of primary FSGS. However, what causes this injury remains unknown.
➢FSGS and minimal-change disease are part of a continuum and that minimalchange disease may transform into FSGS,
➢It is important to distinguish FSGS from minimal-change disease, because the clinical courses and responses to therapy are markedly different.
➢Both are associated with nephrotic syndrome, but the incidence of hematuria and hypertension is higher in individuals with FSGS.
➢unlike minimal change disease, FSGS-associated proteinuria is nonselective, and in general the response to corticosteroid therapy is poor.
➢At least 50% of patients with FSGS develop end-stage renal disease within 10 years of diagnosis. |
| What are morphology of focal segmental glomerulosclerosis? | ➢ Increased mesangial matrix
➢ obliterated capillary lumina
➢ Deposition of hyaline (hyalinosis) and foamy (lipid-laden) macrophages.
➢ In affected glomeruli, IF microscopy often reveals nonspecific trapping of immunoglobulins, usually IgM, and C3 in the areas of hyalinosis. On EM, the podocytes exhibit effacement of foot processes, as in minimal-change disease.
➢ A morphologic variant : collapsing glomerulopathy
is characterized by collapse of the glomerular tuft and epithelialcell hyperplasia.
This more severe variant may be idiopathic or may be associated with HIV infection, drug-induced toxicities, and some microvascular injuries. It carries a particularly poor prognosis |
| What is membraneous nephropathy? | ➢ Characterized by subepithelial immunoglobulin-containing deposits along the GBM.
➢ Early in the disease, the glomeruli may appear normal by light microscopy,
➢ Well-developed cases show diffuse thickening of the capillary wall.
➢ Adults between 30 and 60 years; follows an indolent and slowly progressive course.
➢ Up to 80% of cases of MN are primary, caused by AB against podocyte antigens.
➢Pathogenesis : Membranous nephropathy is a form of chronic immune complex GN induced by AB reacting in situ to endogenous or planted glomerular antigens. AB against the podocyte antigen phospholipase A2 receptor (PLA2R) are frequently present.
➢Formation of subepithelial immune deposits leads to complement activation on the surface of podocytes and generates the membrane attack complex (C5-C9). This in turn causes podocyte injury and proteinuria |
| What is secondary membraneous nephropathy? | Occurs in many conditions, including the following :
➢ Infections (chronic hepatitis B, syphilis, schistosomiasis, malaria)
➢ Malignant neoplasms, particularly carcinoma of the lung and colon and melanoma (paraneoplastic syndrome)
➢ Autoimmune diseases, particularly systemic lupus erythematosus
➢ Exposure to inorganic salts (gold, mercury)
➢ Drugs (penicillamine, captopril, nonsteroidal anti-inflammatory agents) |
| What are clinical features of membraneous nephropathy? | ➢ Most cases of membranous nephropathy are sudden in onset and present as fullblown nephrotic syndrome, usually without antecedent illness;
➢ other individuals have lesser degrees of proteinuria.
➢ In contrast to minimal-change disease, the proteinuria is nonselective, and usually fails to respond to corticosteroid therapy.
➢ Secondary causes of membranous nephropathy should be ruled out.
➢ Membranous nephropathy follows a notoriously variable and often indolent course.
➢ Overall, although proteinuria persists in greater than 60% of patients, only about 40% progress to renal failure over a period of 2 to 20 years.
➢ An additional 10% to 30% of cases have a more benign course with partial or complete remission of proteinuria |
| What is MN morphology? | ➢LM : diffuse thickening of the capillary wall on routine stains
➢EM : this thickening is caused in part by subepithelial deposits, which nestle against 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.
➢With further progression, glomeruli may become sclerosed.
➢Immunofluorescence microscopy shows typical granular deposits of Ig and C3 along the GBM |
| What is membranoproliferative glomerulonephritis? | ➢ MPGN is manifested histologically by 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 patients present only with hematuria or proteinuria in the nonnephrotic range; others exhibit a combined nephroticnephritic picture.
➢ In the past, MPGN was subclassified into two types (I and II) on the basis of distinct ultrastructural, immunofluorescence, light microscopic, and pathogenic findings.
➢ These are now recognized to be distinct entities, termed MPGN type I and dense deposit disease (formerly MPGN type II).
➢ MPGN type I is far more common (about 80% of cases).
➢ Dense deposit disease is a related condition of C3 glomerulonephritis. |
| How is pathogenesis of membranoproliferative glomerulonephritis? | ➢ Type I MPGN may be caused by deposition of circulating immune complexes or by in situ immune complex formation with a planted antigen.
➢ The inciting antigen is not known.
➢ LM : glomeruli are large, have 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 with use of silver or periodic acid–Schiff (PAS) stains.
➢This “splitting” of the GBM is due to extension of processes of mesangial and inflammatory cells into the peripheral capillary loops and deposition of mesangial matrix as well as subepithelial immune complexes
➢The characteristic light microscopic glomerular manifestations are often referred to as membranoproliferative pattern of glomerular injury.
➢By electron microscopy, type I MPGN is characterized by discrete subendothelial deposits.
➢By immunofluorescence microscopy, C3 is deposited in an irregular granular pattern, and IgG and early complement components (C1q and C4) also often are present, indicative of an immune complex pathogenesis |
| What are clinical features of membranoproliferative glomerulonephritis? | ➢ cases are believed to be associated with hepatitis C and related cryoglobulinemia. The mode of presentation in approximately 50% of cases is the nephrotic syndrome, although it may begin as acute nephritis or mild proteinuria.
➢ The prognosis generally is poor.
➢ MPGN type I also may occur in association with other disorders (secondary MPGN), such as :
1. Systemic lupus erythematosus,
2. Hepatitis B and C,
3. chronic liver disease,
4. chronic bacterial infections.
➢ Often no etiology or association is found, the disease in called idiopathic |
| What is C3 glomerulopathy? | ➢C3 glomerulopathy encompasses two conditions, dense deposit disease (formerly MPGN, type II) and C3 glomerulonephritis.
➢These are relatively rare diseases with certain shared clinical, morphologic, and pathogenic features that may be part of a spectrum of injury.
➢They are set apart by differences in the electron microscopic appearance.
➢Patients may present with nephrotic or nephritic syndrome,
➢however, cases with only mild proteinuria also occur.
➢Patients with dense deposit disease are usually younger and more likely to have low serum C3 levels than patients with C3 GN, although these distinctions are subtle |
| How is pathogenesis of C3 glomerulopathy? | ➢Complement dysregulation due to acquired or hereditary abnormalities of the alternative pathway of complement activation is the underlying cause of dense deposit disease and C3 GN.
➢Some patients have an autoantibody against C3 convertase, called C3 nephritic factor (C3NeF), that causes uncontrolled cleavage of C3 by the alternative complement pathway.
➢ In other patients, mutations in various complement regulatory proteins, such as Factor H, Factor I, and membrane cofactor protein (MCP), or autoantibodies to Factor H, are the cause of unregulated activation of the alternative pathway of complement |
| How is morphology of C3 glomerulopathy? | ➢ Glomerular changes in dense deposit disease and C3 GN vary from relatively subtle to severe
➢ The classic light microscopic presentation is similar to that seen in MPGN, type 1 : hypercellular glomeruli, duplicated basement membranes in capillary walls , Increased mesangial matrix.
➢ By IF microscopy : bright mesangial and glomerular capillary wall staining for C3 in both dense deposit disease and C3 GN.
➢ In dense deposit disease, C3 staining also may be seen along the tubular basement membranes
➢IgG and the early components of the classical complement pathway
(C1q and C4) are usually absent in both conditions.
➢By electron microscopy, C3 GN features mesangial and subendothelial electron-dense “waxy” deposits; similar deposits also may be seen along the tubular basement membranes.
➢By contrast, in the dense deposit disease, the lamina densa and the subendothelial space of the GBM are transformed into an irregular, ribbonlike, extremely electrondense structure, resulting from the deposition of C3-containing material |
| What are clinical features of C3 glomerulopathy? | ➢Both dense deposit disease and C3 GN carry a relatively
poor prognosis
➢Both tend to recur post transplantation at a rate of up to 85%.
➢In a recent study of 70 patients with dense deposit disease or C3 GN, 29% of patients progressed to end-stage renal failure after a median of 28 months. |
| What is acute postinfectious glomeruloneprhtis? | ➢Acute postinfectious GN is caused by glomerular deposition of immune complexes resulting in proliferation of and damage to glomerular cells and infiltration of leukocytes, especially neutrophils.
➢ The classic pattern is seen in poststreptococcal GN.
➢Infections by organisms other than streptococci also may be associated with postinfectious GN.
➢These include certain pneumococcal and staphylococcal infections as well as several common viral diseases such as mumps, measles, chickenpox, and hepatitis B and C.
➢In most cases, the initial infection is localized to the pharynx or skin.
➢In rare cases, the disease can develop during the infection |
| How is pathogenesis of post infectious glomerulonephritis? | ➢Poststreptococcal GN is an immune complex disease in which tissue injury is primarily caused by complement activation by the classical pathway.
➢Typical features of immune complex disease, such as hypocomplementemia and granular deposits of IgG and complement on the GBM are seen.
➢The relevant antigens probably are streptococcal proteins.
➢Specific antigens implicated in pathogenesis include streptococcal exotoxin B (Spe B) and streptococcal glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
➢Both have an affinity for glomerular proteins and plasmin.
➢It is not clear if immune complexes are formed mainly in the circulation or in situ (the latter by binding of antibodies to bacterial antigens “planted” in the GBM) |
| How is morphology of post infectious glomerulonephritis? | ➢By light microscopy, the most characteristic change in postinfectious GN is increased cellularity of the glomerular tufts that affects nearly all glomeruli—hence the term diffuse GN.
➢The increased cellularity is caused both by proliferation and swelling of endothelial and mesangial cells and by infiltrating neutrophils and monocytes.
➢Sometimes there is necrosis of the capillary walls.
➢In a few cases, “crescents” may be observed within the urinary space, formed in response to the severe injury
➢Electron microscopy shows deposited immune complexes arrayed as subendothelial, intramembranous, or, most often, subepithelial “humps” nestled against the GBM.
➢Mesangial deposits also are occasionally present.
➢Immunofluorescence studies reveal scattered granular deposits of IgG and complement within the capillary walls and some mesangial areas, corresponding to the deposits visualized by electron microscopy.
➢These deposits usually are cleared over a period of about 2 months |
| What are clinical features of acute postinfectious glomerulonephritis? | ➢The most common clinical presentation is acute nephritic syndrome.
➢Edema and hypertension are common, with mild to moderate azotemia.
➢Characteristically, there is gross hematuria, the urine appearing smoky brown rather than bright red due to oxidation of hemoglobin to methemoglobin.
➢Some degree of proteinuria is a constant feature, and it occasionally may be severe enough to produce the nephrotic syndrome.
➢ Serum complement levels are low during the active phase of the disease, and serum anti–streptolysin O antibody titers are elevated in poststreptococcal cases.
➢ Recovery occurs in most children with poststreptococcal disease, but some develop rapidly progressive GN owing to severe injury with formation of crescents, or chronic renal disease from secondary scarring.
➢ The prognosis in sporadic cases is less clear.
➢ In adults, 15% to 50% of affected individuals develop end-stage renal disease over a few years or 1 to 2 decades, depending on the clinical and histologic severity.
➢ By contrast, in children with sporadic cases of acute postinfectious GN, the progression to chronicity is much lower |
| What is rapidly progressive glomerulonephritis? | ➢ Characterized by the presence of crescents (crescentic GN) and in most cases appears to be immunologically mediated.
➢ It is a clinical syndrome and not a specific etiologic form of GN.
➢ Clinically characterized by rapid loss of renal function
➢ laboratory findings are typical of the nephritic syndrome,
➢ Often severe oliguria.
➢ If untreated, it can rapidly lead to renal failure within a period of weeks to months. |
| How is pathogenesis of rapidly progressive glomerulonephritis? | ➢ RPGN may be associated with a number of diseases, as follows:
1. Anti-GBM antibody–mediated crescentic GN (Goodpasture disease) : linear deposits of IgG and, in
many cases, C3 in the GBM. In some patients, 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 syndrome
2. Immune complex–mediated crescentic GN may complicate any of the immune complex nephritis,
including post- treptococcal GN, systemic lupus erythematosus, IgA nephropathy, and HenochSchönlein purpura This type of RPGN frequently shows cellular proliferation and influx of leukocytes within the glomerular tuft, in addition to cres-cent formation. A consistent finding is the characteristic granular pattern of staining of the GBM and/or mesangium for immunoglobulin and/or
complement on immunofluorescence studies.
3. Pauci-immune type crescentic GN is defined by the lack of anti-GBM antibodies or significant
immune complex deposition. Anti-neutrophil cytoplasmic antibodies (ANCA) typically are found in the serum. In some instances crescentic GN is a component of a systemic vasculitis such as microscopic polyangiitis or granulomatosis with polyangiitis. |
| How is morphology of RPGN? | ➢ LM changes are similar although not identical in various forms of crescentic glomerulonephritis.
➢The glomeruli show :
✓Epithelial cellular proliferation outside the capillary loops (called crescents) with migration of
monocytes/macrophages into Bowman’s space
✓Cellular proliferation also is seen within the capillary loops and/or in the mesangial areas in
cases with immune complex-mediated pathogenesis
✓Sometimes association of a segmental capillary necrosis
✓Breaks in GBM
✓Deposition of fibrin in Bowman’s space.
➢The crescents eventually obliterate Bowman’s space and compress the glomeruli. In time, crescents may undergo scarring, and glo- merulosclerosis develops |
| What are clinical features of RPGN? | ➢ The onset of RPGN is much like that of the nephritic syndrome, except that the oliguria and azotemia are more pronounced.
➢ Proteinuria sometimes approaching the nephrotic range may occur.
➢ Some affected individuals become anuric and require long-term dialysis or transplantation.
➢The prognosis is roughly predicted by the fraction of involved glomeruli :
Patients in whom crescents are present in less than 80% of the glomeruli have a more favorable prognosis than those in whom the percentage of crescents is higher.
➢Plasma exchange may be of benefit in those with anti-GBM antibody GN and in some cases of ANCA-related pauci- immune crescentic GN |
| What is IgA nephropathy? | ➢ Ig A nephropathy is one of the most common causes of recurrent microscopic or gross hematuria
➢ The most common glomerular disease revealed by renal biopsy worldwide.
➢ Usually affects children and young adults
➢ Typically, the hematuria lasts several days and then subsides, but it recurs periodically, usually in the setting of a viral infection.
➢ The hallmark of the disease is the deposition of IgA in the mesangium.
➢ Some experts have considered IgA nephropathy to be a localized variant of HenochSchönlein purpura, also characterized by IgA deposition in the mesangium.
➢ In contrast with IgA nephropathy, which is confined to the kidney, HenochSchönlein purpura is a systemic syndrome also involving the skin (purpuric rash),
gastro- intestinal tract (abdominal pain), and joints (arthritis) |
| How is pathogenesis of IgA nephropathy? | ➢ An abnormally glycosylated IgA1 immunoglobulin is thought to play a central role in the pathogenesis.
➢ This abnormal IgA may elicit an autoimmune response, and autoantibodies may form large immune complexes with circulating IgA.
➢ These complexes deposit in the glomerular mesangium;
➢ This unusual location may be related to physicochemical features of the IgA and
may be facilitated by an IgA1 receptor (CD71) on mesangial cells.
➢ IgA nephropathy occurs with increased frequency in individuals with celiac disease, in whom intestinal mucosal defects are seen, and in liver disease, in which there is defective hepatobiliary clearance of IgA complexes (secondary IgA nephropathy) |
| How is morphology of IgA nephropathy? | ➢Histologically, the lesions in IgA nephropathy vary considerably.
➢The glomeruli may be normal or may show :
Mesangial widening and segmental inflammation confined to some glomeruli (focaproliferative GN); Diffuse mesangial proliferation (mesangiopro- liferative GN); Overt crescentic GN
➢The characteristic immunofluorescence picture is of mesangial deposition of IgA, often with C3 and properdin and smaller amounts of IgG or IgM
➢ Early components of the classical complement pathway usually are absent.
➢ Electron microscopy confirms the presence of electron-dense deposits in the mesangium. |
| What are clinical features of IgA nephropathy? | ➢ IgA nephropathy most often affects children and young adults.
➢ More than half of those affected present with gross hematuria after an infection of the respiratory or, less commonly, gastrointestinal or urinary tract;
➢ 30% to 40% have only microscopic hematuria, with or without proteinuria,
➢ 5% to 10% develop a typical acute nephritic syndrome.
➢ The hematuria typically lasts for several days and initially subsides, but then recurs periodically, usually in the setting of a viral infection. The course is highly variable.
➢ Many patients maintain normal renal function for decades.
➢Slow progression to end-stage renal disease occurs in 25% to 50% of cases over a period of 20 years.
➢Renal biopsy findings may help identify those with a poorer prognosis, as indicated by diffuse mesangial proliferation, segmental sclerosis, endocapillary proliferation, or tubulointerstitial fibrosis |
| What is hereditary nephritis? | ➢ Hereditary nephritis refers to a group of glomerular diseases caused by mutations in genes encoding GBM proteins.
➢ The most common of these rare diseases are Alport syndrome and thin basement membrane disease.
➢ In Alport syndrome, nephritis is accompanied by sensorineural deafness and various eye disorders, including lens dislocation, pos- terior cataracts, and corneal dystrophy.
➢ Thin basement membrane disease is the most common cause of benign familial hematuria with no systemic manifestations.
Pathogenesis:
➢ The GBM is composed largely of type IV collagen, which is made up of heterotrimers of α3, α4, and α5 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 α chains results in defective heterotrimer assembly and, consequently, the manifestations of Alport syndrome. |
| How is morphology of hereditary nephritis? | ➢ Glomeruli in hereditary nephritis appear unremarkable until late in the course.
➢ With progression, increasing glomerulosclerosis, vascular sclerosis, tubular atrophy, and interstitial fibrosis are typical changes
➢ Under the EM, the GBM is thin and attenuated early in the course, but over time develops irregular foci of thickening or attenuation with pronounced splitting and lamination of the lamina densa, yielding a “basketweave” appearance.
➢ In contrast to Alport syndrome, diffuse and uniform thinning of the glomerular basement membranes is the only morphologic finding in thin basement membrane disease |
| What are diseases affecting tubules and interstitium? | ➢Most forms of tubular injury also involve the interstitium, so the two are discussed together.
➢ Diseases characterized by
(1) inflammatory involvement of the tubules and interstitium
(tubulointerstitial nephritis)
(2) ischemic or toxic tubular injury, leading to acute tubular injury and the clinical syndrome of acute kidney injury |
| What is drug-induced tubuluinterstitial nephritis? | ➢Acute drug-induced TIN occurs as an adverse reaction to any one of an increasing number of drugs.
➢It is associated most frequently with :
Penicillins (methicillin, ampicillin),
Other antibiotics (rifampin), Diuretics (furosemide), Proton pump inhibitors (omeprazole), Nonsteroidal anti-inflammatory agents, Numerous other drugs (phenindione, cimetidine, immune checkpoint inhibitors).
Morphology: ➢ The abnormalities in acute drug-induced nephritis are in the interstitium, which shows pronounced edema and infiltration by mononuclear cells, principally lymphocytes and macrophages
➢ Eosinophils and neutrophils may be present, often in large numbers.
➢ With some drugs (e.g., methicillin, thiazides,rifampin), T cell mediated reaction may give rise to interstitial nonnecrotizing granulomas with giant cells.
➢The glomeruli are normal except in some cases caused by nonsteroidal anti-inflammatory agents, in which the hypersensitivity reaction also leads to podocyte foot process effacement and the nephrotic syndrome |
| What is acute tubular injury? | ➢ Acute tubular injury (ATI) is a clinicopathologic entity characterized by damage to tubular epithelial cells
and an acute decline in renal function, often associated with shedding of granular casts and tubular cells
into the urine.
➢ Clinicians use the term acute tubular necrosis, but frank necrosis is rarely observed in a kidney biopsy, so
pathologists prefer the term acute tubular injury.
➢ The constellation of changes, broadly termed acute kidney injury, manifests clinically as decreased GFR with
concurrentelevation of serum creatinine.
➢ ATI is the most common cause of acute kidney injury and may produce oliguria
➢ There are two forms of ATI that differ in the underlying causes.
• Ischemic ATI is most often the result of a period of inadequate
• Nephrotoxic ATI |
| What are two forms of ATI? | 1. Ischemic ATI
➢ Most often is the result of a period of inadequate Blood flow to all or some peripheral organs such as the kidney, sometimes in the setting of marked hypotension and shock.
➢This can be caused by a variety of conditions, including severe trauma, blood loss, acute pancreatitis and septicemia.
➢ Ischemia to tubules may also result from reduced intrarenal blood flow, as in microscopic polyangiitis, malignant hypertension, and thrombotic microangiopathies.
➢Mismatched blood transfusions and other hemolytic crises, as well as myoglobinuria, also produce a clinical picture resembling that of ischemic ATI.
2. Nephrotoxic ATI is caused by a variety of poisons, including heavy metals (e.g., mercury); organic solvents (e.g., carbon tetrachloride); and a multitude of drugs such as gentamicin and other antibiotics, and radiographic contrast agents |
| How is pathogenesis of ATI? | ➢ Proximal tubular epithelial cells are particularly sensitive to hypoxemia and also are vulnerable to toxins
➢ Ischemia causes numerous structural alterations in epithelial cells.
➢ Injury to the epithelial cells causes detachment of the damaged cells from the basement membranes.
➢ Necrotic tubular cells also may elicit an inflammatory reaction that contributes to the tubular injury
➢ The patchiness of tubular necrosis and maintenance of the integrity of the basement membrane along many segments allow repair of the injured foci and recovery of function if the precipitating cause is removed |
| What is vascular nephropathy? | ➢ The kidney is a target organ in vascular diseases.
➢ Clinically, high blood pressure is at the fore.
➢ Kidney failure is often severe while proteinuria and hematuria are usually moderate.
➢The renal biopsy is performed as part of the assessment of chronic renal failure (in the event of nephroangiosclerosis) or, more rarely, acute (in the event of thrombotic microangiopathy, cholesterol crystal emboli, etc.).
➢ Only a few current pathologies will be developed |
| What is benign nephroangiosclerosis? | ➢It is the renal impact of high blood pressure, leading to the onset of chronic renal failure
➢ Occurs after many years hypertension.
➢ It is a major cause of chronic kidney disease.
➢ Kidney biopsy is not always essential for diagnosis.
Light Microscopy :
➢Fibrous thickening of the intima of the arteries
➢Arteriolar hyaline deposits
➢Interstitial fibrosis
➢Absence of specific glomerular lesion.
IF: No specific deposit |
| What is malignant HTA? | ➢Malignant hypertension, defined as blood pressure usually greater than 200/120 mm Hg
➢The prevalence of malignant hypertension is higher in developing countries.
➢ It may present with severe acute kidney injury and renal failure.
➢Renal changes are confined to the vasculature and may include thrombotic microangiopathy.
➢ Injury resulting from long-standing hypertension causes\increased permeability of the vessels to fibrinogen and other plasma proteins,endothelial injury, and platelet deposition.
➢This leads to the appearance of fibrinoid necrosis of arterioles and small arteries and intravascular thrombosis
➢Because of the luminal narrowing, the kidneys become markedly ischemic, which leads to further elevation of blood pressure via the renin-angiotensin system |
| How is morphology of malignant HTA? | ➢ Damage to the small vessels is manifested as fibrinoid necrosis of the arterioles .
➢The vessel walls show a homogeneous, granular eosinophilic appearance.
➢In the interlobular arteries and larger arterioles, proliferation of intimal
cells after acute injury produces an onion-skin appearance : concentric arrangement of smooth muscle.
➢This lesion, called hyperplastic arteriolosclerosis, causes marked narrowing of arterioles and small arteries, to the point of total obliteration.
➢Necrosis also may involve glomeruli, with microthrombi within the glomeruli as well as necrotic arterioles. |
| What is thrombotic microangiopathy? | TMA is clinically revealed by a hemolytic uremic syndrome (HUS).
Causes:
➢ So-called "typical" HUS (postdiarrheal, especially in children): infection with enterobacteria producing "shiga-like toxins": E. Coli O157H7 ++;
➢Thrombocytopenic Thrombotic purpura;
➢ Drugs (cyclosporine, gemcitabine, quinine, etc.);
➢ HUS complicating an underlying disease : malignant hypertension, antiphospholipid syndrome, scleroderma, cancers;
➢ HELLP syndrome during pregnancy;
➢ Genetic origin: anomaly in the genes encoding the regulatory proteins of the alternate complement pathway (so-called “atypical” HUS).
➢ The initial lesion is endothelial, causing platelet aggregation and the formation of fibrino-platelet thrombi |
| How is morphology of TMA? | Light Microscopy :
➢ lesions affect arterioles and / or glomeruli
Plump Endothelial cells
Subendothelial edema;
fibrin and / or platelet thrombi
concentric hyperplasia of arteriolar myocytes ("onion bulb" appearance); chronic fibrous glomerular and arteriolar sequelae.
IF : Fibrine thrombi de fibrine
In children, Kidney biopsy is not mandatory in case of a typical clinical setting : HUS following a GI infection |
| What is chronic kidney disease? | ➢Term that describes the final common pathway of progressive nephron loss resulting from any type of kidney disease.
➢Classically, the kidneys are symmetrically contracted, and their surfaces are red-brown and diffusely granular when the underlying disorder affects blood vessels or glomeruli.
➢Kidneys damaged by chronic pyelonephritis are typically unevenly involved and have deep scars.
➢This obliteration of the glomeruli is the end point of many diseases, and it is impossible to ascertain from such kidneys the nature of the initial lesion
• Microscopically, the feature common to all cases is
advanced scarring of the glomeruli, sometimes to the
point of complete sclerosis.
• 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.
• Lymphocytic (and, rarely, plasma cell) infiltrates are
present in the fibrotic interstitial tissue.
• There also is The small- and medium-sized arteries
frequently are thick-walled, with narrowed lumina,
secondary to hypertension |
| What is ocnocytoma? | ➢ Oncocytoma, a benign neoplasm that arises from the intercalated cells of collecting ducts
➢ Represents about 10% of renal neoplasms.
➢ Associated with genetic changes—loss of chromosomes 1 and Y—that distinguish them from other renal neoplasms.
➢Characterized by a plethora of mitochondria, providing the basis for their tan color and their finely granular eosinophilic cytoplasm, seen histologically.
➢ A central stellate scar, which is another feature of oncocytomas, provides a characteristic appearance on imaging studies |
| What is renal cell carcinoma? | ➢Renal cell carcinomas are derived from the renal tubular epithelium, and hence they are located predominantly in the cortex.
➢These neoplasms represent 80% to 85% of all primary malignant neoplasms of the kidney and 2% to 3% of all cancers in adults.
➢ Most common from the sixth to seventh decades,
➢ Men are affected about twice as commonly as women.
➢The risk for developing these neoplasms is higher in smokers, hypertensive or obese patients, and those who have had occupational exposure to cadmium |
| What is clear cell carcinoma? | ➢ Clear cell cancers (the most common form of renal carcinomas) usually are solitary and large when symptomatic (spherical masses 3 to 15 cm in diameter).
➢They may arise anywhere in the cortex.
➢The cut surface of clear cell renal cell carcinomas is yellow to orange to graywhite, with prominent areas of cystic softening or of hemorrhage, either fresh or old
➢ The margins of the tumor are well defined.
➢ However, at times small processes project into the surrounding parenchyma and small satellite nodules are found, providing clear evidence of the aggressiveness of these lesions.
➢As the tumor enlarges, it may fungate through the walls of the collecting system, extending through the calyces and pelvis as far as the ureter.
➢ Even more frequently, the tumor invades the renal vein and grows as a solid column within this vessel, sometimes extending in serpentine fashion as far as the inferior vena cava and even into the right side of the heart.
➢ Occasionally, direct invasion into the perinephric fat and adrenal gland may be seen |
| What is papillary renal cell carcinoma? | ➢ Exhibit various degrees of papilla formation with fibrovascular cores.
➢ They tend to be bilateral and multiple.
➢ They also may show gross evidence of necrosis, hemorrhage, and cystic degeneration, but they are less vibrantly orange-yellow because of their lower lipid content.
➢ The cells may have a clear or, more commonly, pink cytoplasm |
| What is chromophobe renal carcinoma? | ➢ Tends to be grossly tan-brown.
➢ The cells usually have clear, flocculent cytoplasm with very prominent, distinct cell membranes.
➢ The nuclei are surrounded by halos of clear cytoplasm. |
