NAZMOON LAILANAZMOON LAILA

Normal Renal HistologyNormal Renal Histology

The normal renal cortex contains The normal renal cortex contains – glomeruliglomeruli– other vessels other vessels – tubules and tubules and – interstitiuminterstitium

Features in H&E : Features in H&E : – overall cellularity of the glomerulusoverall cellularity of the glomerulus– the symmetry of the glomerulus the symmetry of the glomerulus – the thickness of the capillary walls the thickness of the capillary walls

Normal HistologyNormal Histology

The renal cortex The renal cortex renal cortex is easily identified even at low renal cortex is easily identified even at low magnification by the presence of renal magnification by the presence of renal corpuscles, which are absent in the renal corpuscles, which are absent in the renal medulla. However, the bulk of the cortex is medulla. However, the bulk of the cortex is occupied by the proximal and distal occupied by the proximal and distal convoluted tubules. The arcuate arteries convoluted tubules. The arcuate arteries and veins help to demarcate the cortex and veins help to demarcate the cortex from the medulla. from the medulla.

These micrographs compare the appearances of the proximal and distal These micrographs compare the appearances of the proximal and distal convoluted tubules. The proximal convoluted tubule (PCT) is a coiled tube convoluted tubules. The proximal convoluted tubule (PCT) is a coiled tube measuring approximately 14mm in length and random sections of PCT thus measuring approximately 14mm in length and random sections of PCT thus occupy most of the renal cortex. Approximately 65% of the glomerular occupy most of the renal cortex. Approximately 65% of the glomerular filtrate is reabsorbed from the PCT, a function reflected in the structure of filtrate is reabsorbed from the PCT, a function reflected in the structure of the epithelial lining the epithelial lining

As seen in micrograph (c), distal convoluted tubules DCT may be differentiated from As seen in micrograph (c), distal convoluted tubules DCT may be differentiated from proximal convoluted tubules PCT by the absence of a brush border, a larger more proximal convoluted tubules PCT by the absence of a brush border, a larger more clearly defined lumen, more nuclei per cross-section (since DCT cells are smaller clearly defined lumen, more nuclei per cross-section (since DCT cells are smaller than PCT cells) and paler cytoplasm (due to fewer organelles). In addition, sections of than PCT cells) and paler cytoplasm (due to fewer organelles). In addition, sections of DCT are less numerous than sections of PCT since the DCT is much shorter than the DCT are less numerous than sections of PCT since the DCT is much shorter than the PCT. In micrograph (d) the prominent brush border of the PCT is contrasted with the PCT. In micrograph (d) the prominent brush border of the PCT is contrasted with the lack of brush border in the DCT lack of brush border in the DCT

The renal medulla :The renal medulla :

renal medulla consists of closely packed tubules renal medulla consists of closely packed tubules of two types: the loop of Henle and the collecting of two types: the loop of Henle and the collecting tubules and ducts as well as the vasa recta. The tubules and ducts as well as the vasa recta. The loop of Henle is a continuation of the proximal loop of Henle is a continuation of the proximal convoluted tubule. It dips down into the medulla, convoluted tubule. It dips down into the medulla, where it loops back on itself and returns to the where it loops back on itself and returns to the cortex to it's own renal corpuscle, becoming the cortex to it's own renal corpuscle, becoming the first part of the distal convoluted tubule. first part of the distal convoluted tubule.

Acute nephritic syndromeAcute nephritic syndrome is a glomerular syndrome dominated by is a glomerular syndrome dominated by the acute onset of usually grossly visible hematuria (red blood cells the acute onset of usually grossly visible hematuria (red blood cells in urine), mild to moderate proteinuria, and hypertension; it is the in urine), mild to moderate proteinuria, and hypertension; it is the classic presentation of acute poststreptococcal glomerulonephritis. classic presentation of acute poststreptococcal glomerulonephritis. The The nephrotic syndromenephrotic syndrome is characterized by heavy proteinuria (more is characterized by heavy proteinuria (more than 3.5 gm/day), hypoalbuminemia, severe edema, hyperlipidemia, than 3.5 gm/day), hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria (lipid in the urine). and lipiduria (lipid in the urine). Asymptomatic hematuria or proteinuria, or a combination of these Asymptomatic hematuria or proteinuria, or a combination of these two, is usually a manifestation of subtle or mild glomerular two, is usually a manifestation of subtle or mild glomerular abnormalities. abnormalities. Acute renal failureAcute renal failure is dominated by oliguria or anuria (reduced or no is dominated by oliguria or anuria (reduced or no urine flow), with recent onset of azotemia. It can result from urine flow), with recent onset of azotemia. It can result from glomerular, interstitial, or vascular injury or acute tubular necrosis. glomerular, interstitial, or vascular injury or acute tubular necrosis. Chronic renal failureChronic renal failure, characterized by prolonged symptoms and , characterized by prolonged symptoms and signs of uremia, is the end result of all chronic renal parenchymal signs of uremia, is the end result of all chronic renal parenchymal diseases. diseases.

Renal tubular defects are dominated by polyuria (excessive urine Renal tubular defects are dominated by polyuria (excessive urine formation), nocturia, and electrolyte disorders (e.g., metabolic formation), nocturia, and electrolyte disorders (e.g., metabolic acidosis). They are the result of either diseases that directly affect acidosis). They are the result of either diseases that directly affect tubular structure (e.g., medullary cystic disease) or defects in tubular structure (e.g., medullary cystic disease) or defects in specific tubular functions. The latter can be inherited (e.g., familial specific tubular functions. The latter can be inherited (e.g., familial nephrogenic diabetes, cystinuria, renal tubular acidosis) or acquired nephrogenic diabetes, cystinuria, renal tubular acidosis) or acquired (e.g., lead nephropathy). (e.g., lead nephropathy). Urinary tract infection is characterized by bacteriuria and pyuria Urinary tract infection is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). The infection may be (bacteria and leukocytes in the urine). The infection may be symptomatic or asymptomatic, and it may affect the kidney symptomatic or asymptomatic, and it may affect the kidney (pyelonephritis) or the bladder (cystitis) only. (pyelonephritis) or the bladder (cystitis) only. Nephrolithiasis (renal stone) is manifested by renal colic, hematuria, Nephrolithiasis (renal stone) is manifested by renal colic, hematuria, and recurrent stone formation. and recurrent stone formation. Urinary tract obstruction and renal tumors represent specific Urinary tract obstruction and renal tumors represent specific anatomic lesions with often varied clinical manifestationsanatomic lesions with often varied clinical manifestations

Glomerular Diseases Glomerular Diseases constitute some of the major problems in nephrology; indeed, chronic constitute some of the major problems in nephrology; indeed, chronic glomerulonephritis is one of the most common causes of chronic renal glomerulonephritis is one of the most common causes of chronic renal failure in humans.failure in humans. Glomeruli may be injured by a variety of factors and in the course of a Glomeruli may be injured by a variety of factors and in the course of a number of systemic diseases. number of systemic diseases. Systemic immunologic diseases such as systemic lupus erythematosus Systemic immunologic diseases such as systemic lupus erythematosus (SLE), vascular disorders such as hypertension and polyarteritis nodosa, (SLE), vascular disorders such as hypertension and polyarteritis nodosa, metabolic diseases such as diabetes mellitus, and some purely hereditary metabolic diseases such as diabetes mellitus, and some purely hereditary conditions such as Fabry disease often affect the glomerulus. These are conditions such as Fabry disease often affect the glomerulus. These are termed termed secondary glomerular diseasessecondary glomerular diseases to differentiate them from disorders to differentiate them from disorders in which the kidney is the only or predominant organ involved. in which the kidney is the only or predominant organ involved. The latter constitute the various types of The latter constitute the various types of primary glomerulonephritisprimary glomerulonephritis or, or, because some do not have a cellular inflammatory component, because some do not have a cellular inflammatory component, glomerulopathy. glomerulopathy. However, both the clinical manifestations and glomerular histologic changes However, both the clinical manifestations and glomerular histologic changes in primary and secondary forms can be similar.in primary and secondary forms can be similar.

Various types of glomerulonephritis are characterized by one or Various types of glomerulonephritis are characterized by one or more of four basic tissue reactions.more of four basic tissue reactions.Some Some inflammatory diseasesinflammatory diseases of the glomerulus are characterized by of the glomerulus are characterized by an increase in the number of cells in the glomerular tufts. This an increase in the number of cells in the glomerular tufts. This hypercellularity is characterized by one or more combinations of the hypercellularity is characterized by one or more combinations of the following: following: Cellular proliferationCellular proliferation of mesangial or endothelial cells of mesangial or endothelial cells Leukocytic infiltrationLeukocytic infiltration, consisting of neutrophils, monocytes, and, in , consisting of neutrophils, monocytes, and, in some diseases, lymphocytes some diseases, lymphocytes Formation of crescents.Formation of crescents. These are accumulations of cells composed These are accumulations of cells composed of proliferating parietal epithelial cells and infiltrating leukocytes. The of proliferating parietal epithelial cells and infiltrating leukocytes. The epithelial cell proliferation that characterizes crescent formation epithelial cell proliferation that characterizes crescent formation occurs following an immune/inflammatory injury (see later). Fibrin, occurs following an immune/inflammatory injury (see later). Fibrin, which leaks into the urinary space, often through ruptured basement which leaks into the urinary space, often through ruptured basement membranes, has been long thought to be the molecule that elicits membranes, has been long thought to be the molecule that elicits the crescentic response. such as interleukin-1, tumor necrosis the crescentic response. such as interleukin-1, tumor necrosis factor, and interferon-γ. factor, and interferon-γ.

Basement Membrane Thickening.Basement Membrane Thickening. By light microscopy, By light microscopy, this change appears as thickening of the capillary walls, this change appears as thickening of the capillary walls, best seen in sections stained with periodic acid-Schiff best seen in sections stained with periodic acid-Schiff (PAS).(PAS).By electron microscopy, such thickening can be resolved By electron microscopy, such thickening can be resolved as one of two alterations: (1) deposition of amorphous as one of two alterations: (1) deposition of amorphous electron-dense material, most often immune complexes, electron-dense material, most often immune complexes, on the endothelial or epithelial side of the basement on the endothelial or epithelial side of the basement membrane or within the GBM itself. Fibrin, amyloid, membrane or within the GBM itself. Fibrin, amyloid, cryoglobulins, and abnormal fibrillary proteins may also cryoglobulins, and abnormal fibrillary proteins may also deposit in the GBM; or (2) thickening of the basement deposit in the GBM; or (2) thickening of the basement membrane proper, as occurs in diabetic membrane proper, as occurs in diabetic glomerulosclerosis.glomerulosclerosis.. .

Hyalinization and Sclerosis.Hyalinization and Sclerosis. Hyalinization, or hyalinosis, as applied to the glomerulus, denotes Hyalinization, or hyalinosis, as applied to the glomerulus, denotes the accumulation of material that is homogeneous and eosinophilic the accumulation of material that is homogeneous and eosinophilic by light microscopy. by light microscopy. By electron microscopy, the hyalin is extracellular and consists of By electron microscopy, the hyalin is extracellular and consists of amorphous substance, made up of plasma proteins that have amorphous substance, made up of plasma proteins that have exuded from circulating plasma into glomerular structures.exuded from circulating plasma into glomerular structures.This change contributes to obliteration of capillary lumina of the This change contributes to obliteration of capillary lumina of the glomerular tuft (a feature of sclerosis). Hyalinosis is usually a glomerular tuft (a feature of sclerosis). Hyalinosis is usually a consequence of endothelial or capillary wall injury and typically is consequence of endothelial or capillary wall injury and typically is the end result of various forms of glomerular damage. Additional the end result of various forms of glomerular damage. Additional alterations include alterations include intraglomerular thrombosisintraglomerular thrombosis or or accumulation of accumulation of lipidlipid or other metabolic materials or other metabolic materials

All the glomerular capillaries should be about All the glomerular capillaries should be about the same thickness, which is very thin (almost the same thickness, which is very thin (almost wispy). wispy).

With normal cellularity, cell nuclei are not With normal cellularity, cell nuclei are not clustered or overlapping. Clusters of cells, clustered or overlapping. Clusters of cells, especially away from the hilum, indicate especially away from the hilum, indicate abnormal hypercellularity. Increased cells abnormal hypercellularity. Increased cells within the lumens of capillaries indicate within the lumens of capillaries indicate leukocyte infiltration or, rarely, an angiotrophic leukocyte infiltration or, rarely, an angiotrophic lymphoma.lymphoma.

In the cortex but not the medulla, the In the cortex but not the medulla, the tubules should be almost back to back, i.e. tubules should be almost back to back, i.e. the tubular basement membranes should the tubular basement membranes should be almost touching. There is very little be almost touching. There is very little interstitium in the cortex, therefore, if there interstitium in the cortex, therefore, if there is space between the tubules, there is is space between the tubules, there is something wrong in the tubulointerstitial something wrong in the tubulointerstitial compartment (e.g. edema or fibrosis).compartment (e.g. edema or fibrosis).

Intrarenal arteries have very little intima, Intrarenal arteries have very little intima, i.e. there is little or no space between the i.e. there is little or no space between the endothelium and the muscularis. endothelium and the muscularis. Pathologic processes expand the arterial Pathologic processes expand the arterial intima, e.g. collagen in arteriosclerosis and intima, e.g. collagen in arteriosclerosis and proteinaceous insudate in an acute proteinaceous insudate in an acute thrombotic microangiopathy. thrombotic microangiopathy.

(green = epithelial cells, yellow = endothelial cells, red = mesangial cells).

Visceral epithelial cells line the capillary walls. Visceral epithelial cells line the capillary walls. Parietal epithelial cells line Bowman's capsule, Parietal epithelial cells line Bowman's capsule, and are continuous with the proximal tubular and are continuous with the proximal tubular epithelial cells. Endothelial cells line capillary epithelial cells. Endothelial cells line capillary lumens. Mesangial cells are in the middle lumens. Mesangial cells are in the middle (meso) between the capillaries (angis). The (meso) between the capillaries (angis). The mesangial cells are modified smooth muscle mesangial cells are modified smooth muscle cells that are continuous with the vascular cells that are continuous with the vascular smooth muscle cells in the hilar arterioles. As smooth muscle cells in the hilar arterioles. As such, they have a contractile capability and can such, they have a contractile capability and can tug on the edges of the capillaries and thus tug on the edges of the capillaries and thus control blood flow through the glomeruluscontrol blood flow through the glomerulus

Mesangial cells also produce a variety of Mesangial cells also produce a variety of cytokines when stimulated, and are cytokines when stimulated, and are capable of phagocytosis. There is a route capable of phagocytosis. There is a route for trafficking of debris through the for trafficking of debris through the mesangium that begins in the mesangium that begins in the subendothelial zone and enters the subendothelial zone and enters the mesangium and then passes through mesangium and then passes through physiologic if not actual channels through physiologic if not actual channels through the matrix to the hilum. the matrix to the hilum.

PAS Trichrome H&E Jones silver stains

The silver stain accentuates collagenous The silver stain accentuates collagenous structures, e.g., in the glomerulus, the mesangial structures, e.g., in the glomerulus, the mesangial matrix and the glomerular basement membrane. matrix and the glomerular basement membrane. The PAS stain also accentuates matrix and The PAS stain also accentuates matrix and basement membrane constituents, as does the basement membrane constituents, as does the blue or green component on the trichrome stain. blue or green component on the trichrome stain. In certain circumstances the trichrome stain In certain circumstances the trichrome stain demonstrates immune deposits as fuchsinophilic demonstrates immune deposits as fuchsinophilic (red) structures. (red) structures.

The peripheral endothelial cell cytoplasm, The peripheral endothelial cell cytoplasm, which has pores through it, looks like a which has pores through it, looks like a little string of sausages on cross section. little string of sausages on cross section. This allows recognition of the lumenal side This allows recognition of the lumenal side of the capillary wall. The visceral epithelial of the capillary wall. The visceral epithelial cells, or podocytes, have foot processes cells, or podocytes, have foot processes that are intact in normal glomeruli and that are intact in normal glomeruli and often effaced in proteinuric conditions.often effaced in proteinuric conditions.

The glomerular basement membrane has The glomerular basement membrane has 3 ultrastructural zones that can be 3 ultrastructural zones that can be disturbed in various glomerular diseases: disturbed in various glomerular diseases: the lamina densa in the middle, the lamina the lamina densa in the middle, the lamina lucida (rara) externa and the lamina lucida lucida (rara) externa and the lamina lucida (rara) interna. (rara) interna.

The glomerular basement membrane does not The glomerular basement membrane does not completely enclose the lumen, unlike the completely enclose the lumen, unlike the endothelial basement membrance in most endothelial basement membrance in most vessels, but rather splays out over the vessels, but rather splays out over the mesangium to become the paramesangial mesangium to become the paramesangial basement membrane. This leaves a functional basement membrane. This leaves a functional gap where materials from the capillary lumen or gap where materials from the capillary lumen or subendothelial zone (having passed through the subendothelial zone (having passed through the endothelial pores) can directly enter the endothelial pores) can directly enter the mesangium without traversing the basement mesangium without traversing the basement membrane. This explains why the mesangium is membrane. This explains why the mesangium is a preferential sequestration point for some types a preferential sequestration point for some types of debris, including immune complexes.of debris, including immune complexes.

The endothelial cell nucleus sits over the The endothelial cell nucleus sits over the origin of the mesangium, which is where it origin of the mesangium, which is where it is usually found. A few pores through the is usually found. A few pores through the endothelial cytoplasm can be seen. The endothelial cytoplasm can be seen. The glomerular basement membrane lamina glomerular basement membrane lamina lucida externa is the thin lucent zone just lucida externa is the thin lucent zone just under the foot processes of the visceral under the foot processes of the visceral epithelial cell. The bulk of the basement epithelial cell. The bulk of the basement membrane is the lamina densa. membrane is the lamina densa.

The pores through the endothelial cell are below The pores through the endothelial cell are below the basement membrane. The thickness of the the basement membrane. The thickness of the glomerular basement membrane lamina densa glomerular basement membrane lamina densa is about 5-6 times thicker than the lamina lucida is about 5-6 times thicker than the lamina lucida externa in this particular electron micrograph. externa in this particular electron micrograph. The lamina lucida externa thickness is a useful The lamina lucida externa thickness is a useful landmark that can be used to assess the normal landmark that can be used to assess the normal thickness of the glomerular basement thickness of the glomerular basement membrane. The thickness of the lamina densa is membrane. The thickness of the lamina densa is important in making the diagnosis, for example, important in making the diagnosis, for example, of thin basement membrane nephropathy and of thin basement membrane nephropathy and diabetic glomerulosclerosis.diabetic glomerulosclerosis.

Another internal reference point for basement Another internal reference point for basement membrane thickness is an intact foot process. If membrane thickness is an intact foot process. If you average the width of intact foot processes you average the width of intact foot processes and then turn that 90 degrees, that is about the and then turn that 90 degrees, that is about the normal thickness of the laminar densa. normal thickness of the laminar densa. Therefore, if you compare the thickness of the Therefore, if you compare the thickness of the lamina densa to that of the lamina lucida externa lamina densa to that of the lamina lucida externa or to an intact foot process, you can determine or to an intact foot process, you can determine whether the basement membrane is normal or whether the basement membrane is normal or abnormal thickness. abnormal thickness.

Minimal Change GlomerulopathyMinimal Change Glomerulopathy

There are many synonyms for minimal change There are many synonyms for minimal change glomerulopathy, e.g., minimal change disease, glomerulopathy, e.g., minimal change disease, lipoid nephrosis, nill disease. lipoid nephrosis, nill disease. No abnormality. No abnormality. Sometimes there may be a little bit of mesangial Sometimes there may be a little bit of mesangial hypercellularity in a few segments. Otherwise, hypercellularity in a few segments. Otherwise, any scarring, any infiltration of leukocytes, any any scarring, any infiltration of leukocytes, any necrosis, or any other substantial structural necrosis, or any other substantial structural changes in glomeruli rule out a diagnosis of changes in glomeruli rule out a diagnosis of minimal change glomerulopathyminimal change glomerulopathy

Slide 13Slide 13 is a representative immunofluorescence micrograph of is a representative immunofluorescence micrograph of the immunohistology of minimal change glomerulopathy, i.e., the immunohistology of minimal change glomerulopathy, i.e., background staining. There are occasional specimens that will background staining. There are occasional specimens that will have small amounts of exclusively mesangial immunoglobulin have small amounts of exclusively mesangial immunoglobulin (especially IgM) or complement accumulation that can still be (especially IgM) or complement accumulation that can still be designated minimal change glomerulopathy. A little bit of designated minimal change glomerulopathy. A little bit of mesangial IgM and/or C3 without ultrastructural evidence for mesangial IgM and/or C3 without ultrastructural evidence for electron dense deposits is tolerable for a diagnosis of minimal electron dense deposits is tolerable for a diagnosis of minimal change glomerulopathy. When groups of patients with change glomerulopathy. When groups of patients with absolutely no immunofluorescence findings absolutely no immunofluorescence findings havehave been been compared to those that have low levels of IgM dominant compared to those that have low levels of IgM dominant mesangial deposits without electron dense deposits, they act mesangial deposits without electron dense deposits, they act no differently with respect to their clinical response to steroids no differently with respect to their clinical response to steroids and long term outcomes. Well defined mesangial electron and long term outcomes. Well defined mesangial electron dense deposits, however, worsen the prognosis for response dense deposits, however, worsen the prognosis for response to steroids or spontaneous remission. Thus, if there are to steroids or spontaneous remission. Thus, if there are electron dense deposits, minimal change glomerulopathy is not electron dense deposits, minimal change glomerulopathy is not an appropriate diagnoses.an appropriate diagnoses.

Effacement of visceral epithelial foot Effacement of visceral epithelial foot processes and epithelial microvillous processes and epithelial microvillous transformation. Microvillous transformation transformation. Microvillous transformation of epithelial cytoplasm often accompanies of epithelial cytoplasm often accompanies effacement. The effacement of foot effacement. The effacement of foot processes and microvillous transformation processes and microvillous transformation are not specific for minimal change are not specific for minimal change glomerulopathy.glomerulopathy.

Foot process effacement is characteristic for Foot process effacement is characteristic for minimal change glomerulopathy and is required minimal change glomerulopathy and is required for the pathologic diagnosis of this disease; for the pathologic diagnosis of this disease; however, this same change is present in any however, this same change is present in any patient with substantial proteinuria of any cause. patient with substantial proteinuria of any cause. Therefore, the diagnosis of minimal change Therefore, the diagnosis of minimal change glomerulopathy is one of exclusion, i.e., these glomerulopathy is one of exclusion, i.e., these ultrastructural changes should be present in the ultrastructural changes should be present in the absence of light microscopic, immunohistologic absence of light microscopic, immunohistologic or other ultrastructural features of any other or other ultrastructural features of any other cause of proteinuria. cause of proteinuria.

almost complete effacement of the visceral almost complete effacement of the visceral epithelial foot processes. There is condensation epithelial foot processes. There is condensation of the epithelial cytoskeleton near the basement of the epithelial cytoskeleton near the basement membrane. If you don't know what this is, you membrane. If you don't know what this is, you can mistake it for subepithelial electron dense can mistake it for subepithelial electron dense deposits, suggesting membranous deposits, suggesting membranous glomerulopathy. It is actin condensation that glomerulopathy. It is actin condensation that takes place inside of visceral epithelial cytoplasm takes place inside of visceral epithelial cytoplasm when there is effacement of foot processes, when there is effacement of foot processes, suggesting that there is movement of cytoplasmic suggesting that there is movement of cytoplasmic structures during the effacement event. structures during the effacement event.

Membranous Glomerulopathy Membranous Glomerulopathy

Membranous glomerulopathy is the most common cause for the Membranous glomerulopathy is the most common cause for the nephrotic syndrome in adults, whereas, minimal change nephrotic syndrome in adults, whereas, minimal change glomerulopathy is the most common cause for the nephrotic glomerulopathy is the most common cause for the nephrotic syndrome in children. Even though membranous glomerulopathy is syndrome in children. Even though membranous glomerulopathy is the most common cause in adults, it only accounts for about 1/3 of the most common cause in adults, it only accounts for about 1/3 of adults with nephrotic syndrome in my renal biopsy population. The adults with nephrotic syndrome in my renal biopsy population. The frequency of membranous glomerulopathy in other series ranges frequency of membranous glomerulopathy in other series ranges from around 20% to around 50%, and most series are under 50%. from around 20% to around 50%, and most series are under 50%. Thus, in an adult with the nephrotic syndrome, if you guess Thus, in an adult with the nephrotic syndrome, if you guess membranous glomerulopathy every time, you are going to be wrong membranous glomerulopathy every time, you are going to be wrong about 2/3 of the time. Therefore, in adults with nephrosis, most about 2/3 of the time. Therefore, in adults with nephrosis, most nephrologists will biopsy to identify the underlying diseasenephrologists will biopsy to identify the underlying diseaseFrom age 16 to 65, membranous glomerulopathy is rather frequent, From age 16 to 65, membranous glomerulopathy is rather frequent, but its highest frequency is in the 40-60 year old age group. but its highest frequency is in the 40-60 year old age group.

early stage: If you don't have a good early stage: If you don't have a good internal reference as to the thickness of internal reference as to the thickness of capillary loops, it is hard to look at a capillary loops, it is hard to look at a membranous glomerulopathy biopsy membranous glomerulopathy biopsy and be sure there is something wrong and be sure there is something wrong by light microscopy, especially during by light microscopy, especially during early stages to the diseaseearly stages to the disease

a late stage membranous glomerulopathy a late stage membranous glomerulopathy with markedly thickened capillary walls.with markedly thickened capillary walls.

the very thick capillary wall of an overt case of the very thick capillary wall of an overt case of membranous glomerulopathy can be recognized. On a membranous glomerulopathy can be recognized. On a trichrome stained section (middle panel), if you have a trichrome stained section (middle panel), if you have a good stain and if the stage of the disease is just right and good stain and if the stage of the disease is just right and there are big deposits, you can see the subepithelial there are big deposits, you can see the subepithelial immune complex deposits as fuchsinophilic (red) immune complex deposits as fuchsinophilic (red) granular deposits. The blue basement membrane is granular deposits. The blue basement membrane is beneath the deposits and there are projections of blue beneath the deposits and there are projections of blue between them. On a silver stained section, and between them. On a silver stained section, and sometimes on a well- stained PAS stained section, as sometimes on a well- stained PAS stained section, as shown in the panel on the right, you can see the so-shown in the panel on the right, you can see the so-called spikes of basement membrane that project called spikes of basement membrane that project between the deposits in certain stages of membranous between the deposits in certain stages of membranous glomerulopathy, in particular stage II. glomerulopathy, in particular stage II.

The characteristic lesion of membranous The characteristic lesion of membranous glomerulopathy is deposition of immune glomerulopathy is deposition of immune complexes in the subepithelial zone. In later complexes in the subepithelial zone. In later stages of the disease, the deposits are stages of the disease, the deposits are transformed into intramembranous deposits.transformed into intramembranous deposits.19diagrams a stage II lesion with regularly 19diagrams a stage II lesion with regularly distributed deposits with projections of basement distributed deposits with projections of basement membrane between them. There also is membrane between them. There also is effacement of foot processes in microvillous effacement of foot processes in microvillous transformation.transformation. ..

The electron micrograph The electron micrograph (Slide 20)(Slide 20) of a of a stage II membranous lesion demonstrates: stage II membranous lesion demonstrates: capillary lumen, endothelial cytoplasm, capillary lumen, endothelial cytoplasm, original basement membrane, original basement membrane, subepithelial deposits (with actin subepithelial deposits (with actin condensation in the overlying epithelium), condensation in the overlying epithelium), and projections of basement membrane and projections of basement membrane material between the depositsmaterial between the deposits

In stage I there are no basement membrane In stage I there are no basement membrane projections adjacent to deposits. In stage II there projections adjacent to deposits. In stage II there are GBM projections between deposits. In stage are GBM projections between deposits. In stage III, the deposits become incorporated in the III, the deposits become incorporated in the basement membrane. In stage IV, the deposits basement membrane. In stage IV, the deposits start to fade away leaving lucent gaps and a start to fade away leaving lucent gaps and a thickened basement membrane. The stage V thickened basement membrane. The stage V lesion, paradoxically, has a normal subepithelial lesion, paradoxically, has a normal subepithelial zone of the basement membrane, which has zone of the basement membrane, which has been repaired, and the disturbance has been been repaired, and the disturbance has been pushed to the subendothelial zone. pushed to the subendothelial zone.

demonstrates the typical immunofluorescence demonstrates the typical immunofluorescence microscopy pattern of membranous glomerulopathy, in a microscopy pattern of membranous glomerulopathy, in a panel adjacent to a low magnification electron panel adjacent to a low magnification electron micrograph. The grains seen by immunofluorescence micrograph. The grains seen by immunofluorescence microscopy correspond to the electron dense deposits. microscopy correspond to the electron dense deposits. Typically, the granular staining of membranous Typically, the granular staining of membranous glomerulopathy is diffuse and globalglomerulopathy is diffuse and global(Slide(Slide 22a) 22a). Diffuse . Diffuse means all of the glomeruli are involved, as opposed to means all of the glomeruli are involved, as opposed to focal, which means that some glomeruli are involved and focal, which means that some glomeruli are involved and some are not. Global means that all the glomerular some are not. Global means that all the glomerular segments and capillaries are involved in a given segments and capillaries are involved in a given glomerulus, as opposed to segmental, which means that glomerulus, as opposed to segmental, which means that only some of them are. only some of them are.

Typically, membranous glomerulopathy has Typically, membranous glomerulopathy has diffuse global granular staining of capillary diffuse global granular staining of capillary walls. walls. The composition of immune deposits is The composition of immune deposits is almost always IgG-dominant. Usually there is almost always IgG-dominant. Usually there is some IgM and IgA. C3 staining is usually very some IgM and IgA. C3 staining is usually very low intensity in idiopathic(primary) low intensity in idiopathic(primary) membranous glomerulopathy, membranous glomerulopathy, a post-infectious glomerulonephritis in which a post-infectious glomerulonephritis in which there is usually intense C3 staining along there is usually intense C3 staining along with very low intensity or absent IgG staining.with very low intensity or absent IgG staining.