Renal Pathology Flashcards
What is azotemia ? Why will GFR be decreased? What is prerenal azotemia and post renal azotemia? What is uremia? What is uremia characterized by ? In addition,name three systems that are involved in uremia damage
What does nephrotic syndrome result from?What is the classic presentation of acute poststreptococcal glomerulonephritis? What is Nephrotic syndrome ? What is a manifestation of subtle or mild glomerular abnormalities? Rapidly progressive glomerulonephritis is associated with what and how is it manifested? Acute kidney injury is dominated by what and can result from what? Chronic kidney disease is characterized by what and is the result of what? UTI is characterized by what? Nephrolithiasis is manifested by what ?
Azotemia is an elevation of blood urea nitrogen and cre- atinine levels and usually reflects a decreased glomerular filtration rate (GFR).
GFR may be decreased as a conse- quence of intrinsic renal disease or extrarenal causes. Prer- enal azotemia is encountered when there is hypoperfusion of the kidneys, which decreases GFR in the absence of paren- chymal damage.
Postrenal azotemia results when urine flow is obstructed below the level of the kidney. Relief of the obstruction is followed by correction of the azotemia.
When azotemia gives rise to clinical manifestations and systemic biochemical abnormalities, it is termed uremia. Uremia is characterized not only by failure of renal excre- tory function but also by a host of metabolic and endocrine alterations incident to renal damage. There is, in addition, secondary gastrointestinal (e.g., uremic gastroenteritis); neuromuscular (e.g., peripheral neuropathy); and cardio- vascular (e.g., uremic fibrinous pericarditis) involvement.
We now turn to a brief description of the major renal syndromes:
• Nephritic syndrome results from glomerular injury and is dominated by the acute onset of usually grossly visible hematuria (red blood cells and red cell casts in urine), proteinuria of mild to moderate degree, azotemia, edema, and hypertension; it is the classic presentation of
acute poststreptococcal glomerulonephritis.
• Nephrotic syndrome is a glomerular syndrome character- ized by heavy proteinuria (excretion of greater than 3.5 g of protein/day in adults), hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria (lipid in
the urine).
• Asymptomatic hematuria or non-nephrotic proteinuria, or
a combination of these two, is usually a manifestation of
subtle or mild glomerular abnormalities.
• Rapidly progressive glomerulonephritis is associated with
severe glomerular injury and results in loss of renal function in a few days or weeks. It is manifested by microscopic hematuria, dysmorphic red blood cells and red cell casts in the urine sediment, and mild to moder- ate proteinuria.
• Acute kidney injury is dominated by oliguria or anuria (no urine flow), and recent onset of azotemia. It can result from glomerular injury (such as rapidly proges- sive glomerulonephritis), interstitial injury, vascular injury (such as thrombotic microangiopathy), or acute tubular injury.
• Chronickidneydisease,characterizedbyprolongedsymp- toms and signs of uremia, is the result of progressive scarring in the kidney from any cause and may culmi- nate in end-stage kidney disease, requiring dialysis or transplantation.
• Urinary tract infection is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). The infection may be symptomatic or asymptomatic, and it may affect the kidney (pyelonephritis) or the bladder (cystitis) only.
• Nephrolithiasis (renal stones) is manifested by renal colic, hematuria (without red cell casts), and recurrent stone formation.
In addition to these renal syndromes, urinary tract obstruc- tion and renal tumors also commonly present with signs and symptoms related to renal dysfunction and are discussed later.
The glomerulus consists of what? What is visceral epithelium and parietal epithelium? The glomerular capillary wall consists of which structures? What is the normal for the glomerular filtration system? What is glomerular barrier function? Characteristics of the normal barrier depend on what? What is the function of the podocytes? What is nephrin? What is the function of nephrin and podocin? What is the hallmark of nephrotic syndrome ? Name five diseases that often affect the glomerulus? What are these diseases termed as?
. The glomerulus con- sists of an anastomosing network of capillaries invested by two layers of epithelium. The visceral epithelium (com- posed of podocytes) is an intrinsic part of the capillary wall, whereas the parietal epithelium lines Bowman space (urinary space), the cavity in which plasma ultrafiltrate first collects. The glomerular capillary wall is the filtration unit and consists of the following structures (Figs. 13–1 and 13–2):
• A thin layer of fenestrated endothelial cells
• A glomerular basement membrane (GBM) with a thick, electron-dense central layer
• Podocytes, which are structurally complex cells. Adjacent foot processes are separated
• The glomerular tuft is supported by mesangial cells lying between the capillaries. Basement membrane–like mesangial matrix forms a meshwork through which the mesangial cells are scattered.
Normally, the glomerular filtration system is extraordi- narily 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, called glomerular barrier function, discriminates among protein molecules according to their size (the larger, the less permeable), their charge (the more cationic, the more permeable), and their configuration. The characteristics of the normal barrier depend on the complex structure of the capillary wall, the integrity of the GBM, and the many anionic molecules present within the wall, including the acidic proteoglycans of the GBM and the sialoglycoproteins of epithelial and endothelial cell coats. The podocyte is also crucial to the maintenance of glomerular barrier function. Podocyte slit diaphragms are important diffusion barriers for plasma proteins, and podocytes are also largely responsible for synthesis of GBM components.
Nephrin, a transmembrane glycoprotein, is the major com- ponent of the slit diaphragms between adjacent foot pro- cesses. The intracellular part of nephrin interacts with several cytoskeletal and signaling proteins .Nephrin and its associated proteins, including podocin, have a crucial role in maintaining the selective permeability of the glomerular filtration barrier. This role is dramatically illustrated by rare hereditary diseases in which mutations of nephrin or its partner proteins are asso- ciated with abnormal leakage into the urine of plasma pro- teins, giving rise to the nephrotic syndrome (discussed later). This observation suggests that acquired defects in the function or structure of slit diaphragms constitute an important mechanism of proteinuria, the hallmark of the nephrotic syndrome.
Glomeruli may be injured by diverse mechanisms and in the course of a number of systemic diseases (Table 13–1). Immunologically mediated diseases such as sys- temic lupus erythematosus, vascular disorders such as hypertension and hemolytic uremic syndrome, metabolic diseases such as diabetes mellitus, and some purely heredi- tary conditions such as Alport syndrome often affect the glomerulus. These are termed secondary glomerular diseases to differentiate them from those in which the kidney is the only or predominant organ involved. The latter constitute the various types of primary glomerular diseases, which are discussed later in this section.
What are the mechanisms of glomerular injury and disease?
Glomerulonephritis can be readily induced by what? What kind of immune mechanisms may also play a role in certain glomerular diseases? What are the two forms of antibody-associated injury?
Name the kinds of diseases that can injure the glomeruli?(primary glomerular diseases, glomerulopathies secondary to systemic diseases, hereditary disorders)
it is clear that immune mechanisms underlie most types of primary glomerular diseases and many of the secondary glomerular diseases. Under
experimental conditions, glomerulonephritis (GN) can be readily induced by antibodies, and deposits of immuno- globulins, often with various components of complement, are found frequently in patients with GN. Cell-mediated immune mechanisms may also play a role in certain glo- merular diseases.
Two forms of antibody-associated injury have been established:
(1) injury resulting from deposition of soluble circulating antigen-antibody complexes in the glomerulus and (2) injury by antibodies reacting in situ within the glomerulus, either with insoluble fixed (intrinsic) glomerular antigens (antigens of glomerular origin) or with molecules planted within the glomerulus from circulation.
In addition, antibodies directed against glomerular cell components may cause glomerular injury. These pathways are not mutually exclusive, and in humans all may contribute to injury.
Primary Glomerular Diseases:
Minimal-change disease
Focal segmental glomerulosclerosis Membranous nephropathy
Acute postinfectious GN Membranoproliferative GN
IgA nephropathy
Glomerulopathies Secondary to Systemic Diseases:
Lupus nephritis (systemic lupus erythematosus) Diabetic nephropathy
Amyloidosis
GN secondary to multiple myeloma Goodpasture syndrome
Microscopic polyangiitis
Wegener granulomatosis Henoch-Schönlein purpura Bacterial endocarditis–related GN Thrombotic microangiopathy
Hereditary Disorders:
Alport syndrome
Fabry disease
Podocyte/slit-diaphragm protein mutations
Why can the glomerulus be considered as an innocent bystander? Where is the antigen from in circulating immune complex mediated disease? And name one disease associated w each place it may be from. In which disease is the inciting antigen unknown? Where do these antibody antigen complexes produce injury and how do they cause injury? Regardless of the mechanism, the glomerular lesions usually consist of what? Electron microscopy reveals the immune complexes as electron-dense deposits or clumps that lie at one of three sites. Name these sites?
The pattern and location of immune complex deposition are helpful in distinguishing among various types of GN. True or false? Once deposited in the kidney, immune complexes may eventually be what? What may lead to chronic glomerulonephritis (GN)?
In some cases the source of chronic antigenic exposure is clear, such as in hepatitis B virus infection and self nuclear antigens in systemic lupus erythematosus. In other cases, however, the antigen is unknown. True or false
What is a major pathway of glomerular injury? Antibodies in this form of injury react with what antigens?
Name some planted antigens . Most of these planted antigens induce what kind of pattern? What factors affect glomerular localization of antigen, antibody, or immune complexes? The localization of antigen, antibody, or immune complexes in turn determines what? complexes deposited in the endothelium or subendothelium elicit what? anti- bodies directed to the subepithelial region of glomerular capillaries elicit what?
With circulating immune complex–mediated disease, the glomerulus may be considered an “innocent bystander” because it does not incite the reaction. The antigen is not
of glomerular origin. It may be endogenous, as in the GN associated with systemic lupus erythematosus, or it may be exogenous, as is probable in the GN that follows certain bacterial (streptococcal), viral (hepatitis B), parasitic (Plas- modium falciparum malaria), and spirochetal (Treponema pal- lidum) infections. Often the inciting antigen is unknown, as in most cases of membranoproliferative glomerulonephritis (MPGN).
Whatever the antigen may be, antigen–antibody complexes are formed in situ or in the circulation and are then trapped in the glomeruli, where they produce injury, in large part through the activation of complement and the recruitment of leukocytes. Injury also may occur through the engagement of Fc receptors on leukocytes independent of complement activation, as cross-linking of Fc receptors by IgG antibod- ies also results in leukocyte activation and degranulation. Regardless of the mechanism, the glomerular lesions usually consist of leukocytic infiltration (exudation) into glomeruli and variable proliferation of endothelial, mesan- gial, and parietal epithelial cells. Electron microscopy reveals the immune complexes as electron-dense deposits or clumps that lie at one of three sites: in the mesangium, between the endothelial cells and the GBM (subendothelial deposits), or between the outer surface of the GBM and the podocytes (subepithelial deposits). Deposits may be located at more than one site in a given case. The presence of immunoglobulins and complement in these deposits can be demonstrated by immunofluorescence microscopy .
Once deposited in the kidney, immune complexes may eventually be degraded or phagocytosed, mostly by infil- trating leukocytes and mesangial cells, and the inflamma- tory changes may then subside. Such a course occurs when 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 over time, repeated cycles of immune complex formation, deposition, and injury may occur, leading to chronic GN.
Glomerulonephritis Caused by In Situ Immune Complexes
Antibody deposition in the glomerulus is a major pathway of glomerular injury. As noted, antibodies in this form of injury react directly with fixed or planted antigens in the glomerulus. Immune reactions in situ, trapping of circulat- ing complexes, interactions between these two events, and local hemodynamic and structural determinants in the glomerulus all contribute to the morphologic and func- tional alterations in GN. Antibodies also may react in situ with previously “planted” nonglomerular antigens, which may localize in the kidney by interacting with various intrinsic components of the glomerulus.
Planted antigens include nucleosomal complexes (in patients with systemic lupus erythematosus); bacterial products, such as endostroptosin, a protein expressed by group A streptococci; large aggregated proteins (e.g., aggregated immunoglobulin G [IgG]), which tend to deposit in the mesangium; and immune complexes themselves, because they contain reactive sites for further interactions with free antibody, free antigen, or complement. Most of these planted antigens induce a granular pattern of immuno- globulin deposition as seen by immunofluorescence microscopy.
The following factors affect glomerular localization of antigen, antibody, or immune complexes: the molecular charge and size of the reactants; glomerular hemodynam- ics; mesangial function; and the integrity of the charge- selective glomerular barrier. The localization of antigen, antibody, or immune complexes in turn determines the glomerular injury response. complexes deposited in the endothelium or subendothelium elicit an inflammatory reaction in the glomerulus with infiltration of leukocytes and exuberant
proliferation of glomerular resident cells. By contrast, anti- bodies directed to the subepithelial region of glomerular capillaries are largely noninflammatory and elicit lesions similar to those of Heymann nephritis or membranous nephropathy .
The best-characterized disease in Anti-Glomerular Basement Membrane Antibody–Mediated
Glomerulonephritis is what ? In this type of injury what happens to the antibodies? What is its counterpart in nephritis of rodents? Antibody–mediated GN in humans results from what? Deposition of these antibodies created what pattern ? What is goodpasture syndrome ? anti-GBM antibody–mediated crescentic GN are characterized by what ?
In summary,what is an important mechanism of glomerular damage ? And how? What are the most common forms of antibody mediated GN caused by ? These immune complexes may contain what kind of antigens? Immune complexes show what pattern of deposition? What are the cause of anti-GBM-antibody–mediated disease? What is the pattern of antibody deposition in anti-GBM-antibody–mediated disease? How do immune complexes and antibodies cause injury?
The best-characterized disease in this group is classic anti- GBM antibody–mediated crescentic GN . In this type of injury, antibodies are directed against fixed antigens in the GBM. It has its experimental counterpart in the nephritis of rodents called nephrotoxic serum nephritis. Antibody–mediated GN in humans results from the formation of autoantibodies directed against the GBM. Deposition of these antibodies creates a linear pattern of staining when the bound antibodies are visualized with immunofluorescence microscopy, in contrast with the granular pattern described for other forms of immune complex–mediated nephritis .This distinction is useful in the diagnosis of glomerular disease.
A confor- mational change in the α3 chain of the type IV collagen of the GBM appears to be key in inciting autoimmunity. Sometimes the anti-GBM antibodies cross-react with base- ment membranes of lung alveoli, resulting in simultaneous lung and kidney lesions (Goodpasture syndrome). Although anti-GBM antibody–mediated GN accounts for less than 1% of human GN cases, the resulting disease can be very serious. Many instances of anti-GBM antibody–mediated crescentic GN are characterized by very severe glomerular damage with necrosis and crescents and the development of the clinical syndrome of rapidly progressive GN
Glomerular Injury
• Antibody-mediated immune injury is an important mecha- nism of glomerular damage, mainly by way of complement- and leukocyte-mediated pathways. Antibodies also may be directly cytotoxic to cells in the glomerulus.
• The most common forms of antibody-mediated GN are caused by the formation of immune complexes, whether occurring in situ or by deposition of circulating immune complexes. These immune complexes may contain exog- enous (e.g. microbial) circulating antigens or endogenous antigens (e.g. in membranous nephropathy). Immune com- plexes show a granular pattern of deposition.
• Autoantibodies against components of the GBM are the cause of anti-GBM-antibody–mediated disease, often associated with severe injury. The pattern of antibody deposition is linear.
• Immune complexes and antibodies cause injury by com- plement activation and leukocyte recruitment, with release of various mediators, and sometimes by direct podocyte damage.
Once immune reactants are localized in the glomerulus, how does glomerular damage ensue? Why does This mechanism applies only to some types of GN? In these cases what happens? Antibodies against glomerular cell antigens also may directly damage glomerular cells or slit diaphragms. Such antibodies are suspected of what? Name five other mediators of glomerular damage?
Mediators of Immune Injury
A major pathway of antibody-initiated injury involves complement activation and recruitment of leukocytes .Activation of complement via the classical pathway leads to the genera- tion of chemotactic agents (mainly C5a) for neutrophils and monocytes. Neutrophils release proteases, which cause GBM degradation; oxygen-derived free radicals, which cause cell damage; and arachidonic acid metabolites, which contribute to reduction in GFR.
This mechanism applies only to some types of GN, however, because many types show few neutrophils in the damaged glomeruli. In these cases neutrophil-independent but complement-dependent injury may occur, possibly caused by the C5b-C9 mem- brane attack complex, which is formed on the GBM and may induce sublytic epithelial cell injury and stimulate the secretion of various inflammatory mediators from mesangial and epithelial cells. The alternative and mannose- binding lectin pathways of complement can be activated by cell injury or apoptosis, also leading to glomerular injury (Fig. 13–5).
. Such antibodies are suspected of being involved in certain disorders in which immune complexes are not found. Other mediators of glomerular damage include the following:
• Monocytesandmacrophages,whichinfiltratetheglomeru- lus in antibody- and cell-mediated reactions and, when activated, release diverse mediators
• Sensitized T cells, formed during the course of a cell- mediated immune reaction, can cause experimental glomerular injury. In some forms of experimental GN, the disease can be induced by transfer of sensitized T cells. T cell–mediated injury may account for the instances of GN in which either there are no deposits of antibodies or immune complexes or the deposits do not correlate with the severity of damage. However, it has been difficult to establish a causal role for T cells or cell- mediated immune responses in human GN.
• Platelets, which aggregate in the glomerulus during immune-mediated injury and release prostaglandins and growth factors
• Resident glomerular cells (epithelial, mesangial, and endothelial), which can be stimulated to secrete mediators such as cytokines (interleukin-1), arachidonic acid metabolites, growth factors, nitric oxide, and endothelin
• Thrombin, produced as a consequence of intraglomerular thrombosis, which causes leukocyte infiltration and glo- merular cell proliferation by triggering protease-acti- vated receptors (PARs)
Other mechanisms contribute to glomerular damage in certain primary renal disorders. Two mechanisms are important here, name them.
How are these mechanisms induced? What morphologic changes are reflected in these mechanisms? In most forms of glomerular injury what is key in development of proteinuria
Func- tional abnormalities of the slit diaphragm may result from what?
Renal disease that destroys sufficient nephrons to reduce GFR to what percentage of fifty percent of the normal causes progression to end stage kidney disease to proceed fast? Remaining glomeruli undergo what to maintain renal function? This change they undergo is associated with what hemodynamic changes ? These alterations lead to what?
What is nephrotic syndrome?
What is the common pathophysiology of causes of nephrotic syndrome? What causes the signs seen in nephrotic syndrome? In children 1 to 7 years of age nephrotic syndrome is almost always caused by what ? What is the most frequent systemic abuses of nephrotic syndrome in adults ?
What are the The most important of the primary glomeru- lar lesions that characteristically lead to the nephrotic syn- drome? Which of them are more important in kids and which is more important in adults? Which two other primary lesions commonly produce the nephrotic syndrome ?
Other mechanisms contribute to glomerular damage in certain primary renal disorders. Two that deserve special mention due to their importance are podocyte injury and nephron loss.
Podocyte Injury
Podocyte injury can be induced by antibodies to podocyte antigens; by toxins, as in an experimental model of protein- uria induced by the ribosome poison puromycin; conceiv- ably by certain cytokines; or by still poorly characterized circulating factors, as in some cases of focal segmental glo- merulosclerosis (see later). Podocyte injury is reflected by morphologic changes, which include effacement of foot processes, vacuolization, and retraction and detachment of cells from the GBM, and clinically by proteinuria. In most forms of glomerular injury, loss of normal slit diaphragms is key in the development of proteinuria (Fig. 13–5). Func- tional abnormalities of the slit diaphragm also may result from mutations in its structural components, such as nephrin and the associated podocin. Such mutations cause rare hereditary forms of the nephrotic syndrome.
Nephron Loss
Once renal disease, glomerular or otherwise, destroys sufficient nephrons to reduce the GFR to 30% to 50% of normal, progression to end-stage kidney disease proceeds inexorably at varying rates. Affected persons have protein- uria, and their kidneys show widespread glomerulosclerosis. Such progressive sclerosis may be initiated, at least in part, by the adaptive changes that occur in the remaining glom- eruli not destroyed by the initial disease. These remaining glomeruli undergo hypertrophy to maintain renal func- tion. This hypertrophy is associated with hemodynamic changes, including increases in single-nephron GFR, blood flow, and transcapillary pressure (capillary hypertension). These alterations ultimately become “maladaptive” and lead to further endothelial and podocyte injury, increased glomerular permeability to proteins, and accumulation of proteins and lipids in the mesangial matrix. This is fol- lowed by capillary obliteration, increased deposition of mesangial matrix and plasma proteins, and ultimately by segmental (affecting a portion) or global (complete) sclero- sis of glomeruli. The latter results in further reductions in nephron mass and a vicious circle of progressive glomerulosclerosis.
The nephrotic syndrome refers to a clinical complex that includes
• Massive proteinuria, with daily protein loss in the urine of 3.5 g or more in adults
• Hypoalbuminemia, with plasma albumin levels less than 3 g/dL
• Generalized edema, the most obvious clinical mani- festation
• Hyperlipidemia and lipiduria.
The nephrotic syndrome has diverse causes that share a common pathophysiology .In all there is a derangement in the capillary walls of the glomeruli that results in increased permeability to plasma proteins. Any increased permeability resulting from either structural or physicochemical alterations in the GBM allows protein to escape from the plasma into the glomerular filtrate. With long-standing or extremely heavy proteinuria, serum albumin is decreased, resulting in hypoalbuminemia and a drop in plasma colloid osmotic pressure. As discussed in Chapter 3, the resulting decrease in intravascular volume and renal blood flow triggers increased release of renin from renal juxtaglomerular cells. Renin in turn stimulates the angiotensin-aldosterone axis, which promotes the retention of salt and water by the kidney. This tendency is exacerbated by reductions in the cardiac secretion of natri- uretic factors. In the face of continuing proteinuria, these alterations further aggravate the edema and if unchecked may lead to the development of generalized edema (termed anasarca). At the onset, there is little or no azotemia, hema- turia, or hypertension.
The genesis of the hyperlipidemia is more obscure. Pre- sumably, hypoalbuminemia triggers increased synthesis of lipoproteins in the liver or massive proteinuria causes loss of an inhibitor of their synthesis. There is also abnormal transport of circulating lipid particles and impairment of peripheral breakdown of lipoproteins. The lipiduria, in turn, reflects the increased permeability of the GBM to lipoproteins.
In children 1 to 7 years of age, for example, the nephrotic syndrome is almost always caused by a lesion primary to the kidney, whereas among adults it often is due to renal manifestations of a systemic disease. The most frequent systemic causes of the nephrotic syndrome in adults are diabetes, amyloidosis, and systemic lupus erythematosus.The most important of the primary glomeru- lar lesions that characteristically lead to the nephrotic syn- drome are focal and segmental glomerulosclerosis and minimal-change disease. The latter is more important in children; the former, in adults. Two other primary lesions, membranous nephropathy and membranoproliferative glomerulonephritis, also commonly produce the nephrotic syndrome.
Name five systemic diseases with renal manifestations
What is minimal change disease as a primary glomeru- lar lesion that characteristically leads to the nephrotic syn- drome? Minimal change disease is the most frequent cause of nephrotic syndrome in which age group? Characteristically, what appearance do the glomeruli have? What is the pathogenesis of proteinuria in minimal-change disease?
Why is the disease called minimal change disease? What feature is is secondary to tubular reabsorption of the lipopro- teins passing through the diseased glomeruli? Under electron microscope in minimal change disease , what is the appearance of the GBM? What is the only obvious glomerular abnormality?
Diabetes mellitus
Amyloidosis
Systemic lupus erythematosus
Ingestion of drugs (gold, penicillamine, “street heroin”)
Infections (malaria, syphilis, hepatitis B, HIV infection)
Malignancy (carcinoma, melanoma)
Miscellaneous (bee sting allergy, hereditary nephritis)
Minimal-change disease, a relatively benign disorder, is the most frequent cause of the nephrotic syndrome in children. Characteristically, the glomeruli have a normal appearance by light microscopy but show diffuse effacement of podocyte foot processes when viewed with the electron microscope. Although it may develop at any age, this condition is most common between the ages of 1 and 7 years.
The pathogenesis of proteinuria in minimal-change disease remains to be elucidated. On the basis of some experimental studies, the proteinuria has been attributed to a circulating, possibly T cell–derived, factor that causes podocyte damage and effacement of foot processes. Neither the nature of such a putative factor nor a causal role of T cells, however, is established in the human disease.
Under the light microscope, the glomeruli appear normal, thus giving rise to the name “minimal-change disease” (Fig. 13–6, A). The cells of the proximal convoluted tubules often are heavily laden with protein droplets and lipids, but this feature is secondary to tubular reabsorption of the lipopro- teins passing through the diseased glomeruli. Even under the electron microscope, the GBM appears normal. The only obvious glomerular abnormality is the uniform and diffuse effacement of the foot processes of the podocytes .The cytoplasm of the podocytes thus appears flattened over the external aspect of the GBM, obliterating the network of arcades between the podocytes and the GBM. There are also epithelial cell vacuolization, microvillus formation, and occasional focal detachments, suggesting some form of podocyte injury. With reversal of the changes in the podocytes (e.g., in response to corticosteroids), the proteinuria remits.
What are the clinical manifestations of minimal change disease (the signs that are there and the signs that aren’t)
What is the prognosis for kids w this disorder ? Name two complications of this disease . What will cause ckd as a complication
What is focal segmental Glomerulosclerosis characterized by histologically ? This histologic picture is often associated with what? FSGS may be primary (idiopathic) or secondary to which diseases? Autosomal dominant forms are associated with mutations in what? Primary FSGS accounts for approximately 20% to 30% of all cases in which syndrome? And is a common cause of this syndrome in which people?
Clinical Course
The disease manifests with the insidious development of the nephrotic syndrome in an otherwise healthy child. There is no hypertension, and renal function is preserved in most of these patients. The protein loss usually is confined to the smaller plasma proteins, chiefly albumin (selective proteinuria). The prognosis for children with this disorder is good.
Recurrent proteinuria
Chronic kidney disease
most persons in this subgroup had nephrotic syndrome caused by focal and segmental glomerulosclero- sis not detected by biopsy.
Focal Segmental Glomerulosclerosis
Focal segmental glomerulosclerosis (FSGS) is character- ized histologically by sclerosis affecting some but not all glomeruli (focal involvement) and involving only segments of each affected glomerulus (segmental involve- ment). This histologic picture often is associated with the nephrotic syndrome. FSGS may be primary (idiopathic) or secondary to one of the following conditions:
• In association with other conditions, such as HIV infection (HIV nephropathy) or heroin abuse (heroin nephropathy)
• As a secondary event in other forms of GN (e.g., IgA nephropathy)
• Asamaladaptationtonephronloss(asdescribedearlier)
• In inherited or congenital forms. Autosomal dominant forms are associated with mutations in cytoskeletal pro- teins and podocin, both of which are required for the integrity of podocytes. In addition, a sequence variant in the apolipoprotein L1 gene (APOL1) on chromosome 22 appears to be strongly associated with an increased risk of FSGS and renal failure in individuals of African
descent.
Primary FSGS accounts for approximately 20% to 30% of all cases of the nephrotic syndrome. It is an increasingly common cause of nephrotic syndrome in adults and remains a frequent cause in children.
What is the pathogenesis of primary FSGS? In FSGS the disease first affects some of the glomeruli and in case of primary FSGS, initially only which part of the glomeruli? With progression which part of the glomeruli is affected? On histological exam ,FSGS is characterized by what? Affected glomeruli exhibit what? In affected glomeruli, immunofluorescence microscopy often reveals what? On electron microscopy, the podo- cytes exhibit what? With time,progression of the disease leads to what? This advanced picture is difficult to differentiate from what? What morphologic variant is increasingly being reported and what is it characterized by? What diseases or injuries can it be associated w ?
I’m kids, it’s important to distinguish FSGS as a cause of what? From what disease? And why ? In FSGS patients the incidence of which to signs is higher than in those w minimal change disease? At least fifty percent of patients with FSGS develop what within ten years of diagnosis
The pathogenesis of primary FSGS is unknown. Some inves- tigators have suggested that FSGS and minimal-change disease are part of a continuum and that minimal-change disease may transform into FSGS. Others believe them to be distinct clinicopathologic entities from the outset. In any case, injury to the podocytes is thought to represent the initiating event of primary FSGS. As with minimal- change disease, permeability-increasing factors produced by lymphocytes have been proposed. The deposition of hyaline masses in the glomeruli represents the entrapment of plasma proteins and lipids in foci of injury where sclerosis develops. IgM and complement proteins commonly seen in the lesion are also believed to result from nonspecific entrapment in damaged glomeruli. The recurrence of proteinuria and sub- sequent FSGS in a renal transplant in some patients who had FSGS, sometimes within 24 hours of transplantation, sup- ports the idea that a circulating mediator is the cause of the podocyte damage in some cases.
In FSGS, the disease first affects only some of the glomeruli (hence the term focal) and, in the case of primary FSGS, initially only the juxtamedullary glomeruli. With progression, eventually all levels of the cortex are affected. On histologic examination, FSGS is characterized by lesions occurring in some tufts within a glomerulus and sparing of the others (hence the term segmental). Thus, the involvement is both focal and segmental (Fig. 13–7). The affected glomeruli exhibit increased mesangial matrix, obliterated capillary lumina, and deposition of hyaline masses (hyalinosis) and lipid droplets.
In affected glomeruli, immunofluorescence microscopy often reveals nonspecific trapping of immunoglobulins, usually IgM, and complement n the areas of hyalinosis. On electron microscopy, the podo- cytes exhibit effacement of foot processes, as in minimal- change disease.
In time, progression of the disease leads to global sclerosis of the glomeruli with pronounced tubular atrophy and inter- stitial fibrosis. This advanced picture is difficult to differentiate from other forms of chronic glomerular disease, described later on.
A morphologic variant called collapsing glomerulopa- thy is being increasingly reported. It is characterized by col- lapse of the glomerular tuft and podocyte hyperplasia. This is a more severe manifestation of FSGS that may be idiopathic or associated with HIV infection, drug-induced toxicities, and some microvascular injuries. It carries a particularly poor prognosis.
Clinical Course
In children it is important to distinguish FSGS as a cause of the nephrotic syndrome from minimal-change disease, because the clinical courses are markedly different. The incidence of hematuria and hypertension is higher in persons with FSGS than in those with minimal-change disease; the 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 kidney disease within 10 years of diagnosis. Adults typically fare even less well than children.
What is membranous Nephropathy? What is it characterized morphologic ally by? Early in the disease how do the glomeruli appear by light microscopy? And I’m well developed cases how do the glomeruli appear by light microscopy? In about 85% of cases MN is caused bu what? In secondary MN it occurs secondary to which disorders?
What induces MN? Which antigen is most recognized by causative antibodies in MN? What is the experimental model of MN and how is it induced in animals? What happens to the antibodies produced and what’s the result? What is a puzzling aspect of MN and why? Complement activation in MN leads to what?
Membranous Nephropathy
Membranous nephropathy is a slowly progressive disease, most common between 30 and 60 years of age. It is char- acterized morphologically by the presence of subepithelial immunoglobulin-containing deposits along the GBM. Early in the disease, the glomeruli may appear normal by light microscopy, but well-developed cases show diffuse thicken- ing of the capillary wall.
In about 85% of cases, membranous nephropathy is caused by autoantibodies that cross-react with antigens expressed by podocytes. In the remainder (secondary membranous nephropathy), it occurs secondary to other disorders, including
• Infections(chronichepatitisB,syphilis,schistosomiasis, malaria)
• Malignant tumors, particularly carcinoma of the lung and colon and melanoma
• Systemic lupus erythematosus and other autoimmune conditions
• Exposure to inorganic salts (gold, mercury)
• Drugs (penicillamine, captopril, nonsteroidal anti- inflammatory agents)
Membranous nephropathy is a form of chronic immune complex glomerulonephritis induced by anti- bodies reacting in situ to endogenous or planted glomerular antigens. An endogenous podocyte antigen, the phospholi- pase A2 receptor, is the antigen that is most often recognized by the causative autoantibodies.
The experimental model of membranous nephropathy is Heymann nephritis, which is induced in animals by immuniza- tion with renal tubular brush border proteins that also are present on podocytes. The antibodies that are produced react with an antigen located in the glomerular capillary wall, resulting in granular deposits (in situ immune complex formation) and proteinuria without severe inflammation.
A puzzling aspect of the disease is how antigen-antibody complexes cause capillary damage despite the absence of inflammatory cells. The likely answer is by activating comple- ment, which is uniformly present in the lesions of membra- nous nephropathy. It is hypothesized that complement activation leads to assembly of the C5b-C9 membrane attack complex, which damages mesangial cells and podocytes directly, setting in motion events that cause the loss of slit filter integrity and proteinuria.
Histologically the main feature of MN is what? Electron microscopy reveals that the main feature is caused by what? As the disease progresses what happens?
What happens to the podocytes in MN? What causes cavities in the GBM? What leads to progressive thickening of basement membrane? Immunofluores- cence microscopy shows what?
Most cases of MN present as what? What’s the difference between MN and minimal change disease w regards to proteinuria?
Histologically, the main feature in membranous nephropathy is diffuse thickening of the capillary wall .Electron microscopy reveals that 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.
In addition, as in other causes of nephrotic syndrome, the podocytes show efface- ment of foot processes. Later in the disease, the incor- porated deposits may be broken down and eventually disappear, leaving cavities within the GBM. Continued deposi- tion of basement membrane matrix leads to progressive thickening of basement membranes. With further progres- sion, the glomeruli can become sclerosed. Immunofluores- cence microscopy shows typical granular deposits of immunoglobulins and complement along the GBM
Clinical Course
Most cases of membranous nephropathy present as full- blown nephrotic syndrome, usually without antecedent illness; other individuals may have lesser degrees of pro- teinuria. In contrast with minimal-change disease, the pro- teinuria is nonselective, with urinary loss of globulins as well as smaller albumin molecules, and does not usually respond to corticosteroid therapy. Secondary causes of membranous nephropathy should be ruled out.
Membranoproliferative Glomerulonephritis if manifested histologically bu what? It accounts for 5% to 10% of cases of what kind of nephrotic syndrome? Some patients present w what signs in the non nephrotic range and others exhibit what? Two major types of MPGN (I and II) have traditionally been recognized on the basis of? Which of the types are more common
What are the pathogenic mechanisms involved in development of MPGN and dense deposit disease?
Principal mode of presentation in MPGN is what? MPGN or dense deposit disease may begin as what? What’s the prognosis of MPGN type I? Complications of MPGN include,end-stage renal failure, renal insufficiency, and persis- tent nephrotic syndrome without renal failure. True or false ?
Dense deposit disease tends to occur more frequently in which patients?
MPGN type I may occur in associated w other disorders(secondary MPGN) name them.
Membranoproliferative GN (MPGN) is manifested histo- logically 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 non-nephrotic range; others exhibit a combined nephrotic–nephritic picture. Two major types of MPGN (I and II) have traditionally been recognized on the basis of distinct ultrastructural, immunofluorescence, microscopic, and pathogenic findings, but these are now recognized to be separate entities, termed MPGN type I and dense deposit disease (formerly MPGN type II). Of the two types of disease, MPGN type I is far more common (about 80% of cases).
Different pathogenic mechanisms are involved in the devel- opment of MPGN and dense deposit disease.
• Some cases of type I MPGN may be caused by
circulating immune complexes, akin to chronic serum sickness, or may be due to a planted antigen with subsequent in situ immune complex formation. In either case, the inciting antigen is not known. Type I MPGN also occurs in association with hepatitis B and C antigenemia, systemic lupus erythematosus, infected atrioventricular shunts, and extrarenal infections with persistent or epi- sodic antigenemia.
• The pathogenesis of dense deposit disease is less clear. The fundamental abnormality in dense deposit disease appears to be excessive complement acti- vation. Some patients have an autoantibody against C3 convertase, called C3 nephritic factor, which is believed to stabilize the enzyme and lead to uncontrolled cleavage of C3 and activation of the alternative complement pathway. Mutations in the gene encoding the complement regulatory protein factor H or autoantibodies to factor H have been described in some patients. These abnor- malities result in excessive complement activation. Hypo- complementemia, more marked in dense deposit disease, is produced in part by excessive consumption of C3 and in part by reduced synthesis of C3 by the liver. It is still not clear how the complement abnormality induces the glomerular changes.
Clinical Course
The principal mode of presentation (in approximately 50% of cases) is the nephrotic syndrome, although MPGN or dense deposit disease may begin as acute nephritis or mild proteinuria. The prognosis of MPGN type I generally is poor.
Dense deposit disease carries an even worse prognosis, and it tends to recur more frequently in renal transplant
recipients. MPGN type I may occur in association with other disorders (secondary MPGN), such as systemic lupus erythematosus, hepatitis B and C, chronic liver disease, and chronic bacterial infections. Indeed, many so-called idio- pathic cases are believed to be associated with hepatitis C and related cryoglobulinemia
By light microscopy do many cases of type 1 MPGN and dense deposit disease appear similar? What is seen in light microscopy that’s similar? Splitting of GBM is due to what? Type 1 MPGN is characterized by what? By immuno- fluorescence microscopy, C3 is deposited in what pattern and what are components are present? What does this indicate? In dense deposit disease what is seen by immuno fluorescence microscopy? C3 is present in what pattern? The components present in type 1 are absent in dense deposit disease true or false
In summary, nephrotic syndrome is characterized by? What is the underlying mechanism of proteinuria and this may be the result of what two things as in which two diseases for each thing? What is the most frequent cause of nephrotic syndrome? How is it manifested? FSGS may be what or what? State what they may be due to. Glomeruli show what morphologically?
MN is caused by what ? Most often directed against what? MN is characterized by what? What causes MPGN? Dense deposit disease is a consequence of what? Both may present with what features?
By light microscopy, type I MPGN and many cases of dense deposit disease are similar. The glomeruli are large, with an accentuated lobular appearance, and show prolifera- tion of mesangial and endothelial cells as well as infil- trating 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 “split- ting” of the GBM is due to extension of processes of mesangial and inflammatory cells into the peripheral capillary loops and deposition of mesangial matrix . Type I MPGN is characterized by discrete subendothe- lial electron-dense deposits .By immuno- fluorescence microscopy, C3 is deposited in an irregular granular pattern, and IgG and early complement components (C1q and C4) often are also present, indicative of an immune complex pathogenesis.
By contrast, in the aptly named dense deposit disease the lamina densa and the subendothelial space of the GBM are transformed into an irregular, ribbon-like, extremely electron-dense structure, resulting from the deposition of material of unknown composition. C3 is present in irregular chunky and segmental linear foci in the basement membranes and in the mesangium. IgG and the early components of the classical complement pathway (C1q and C4) are usually absent.
The Nephrotic Syndrome
• The nephrotic syndrome is characterized by proteinuria, which results in hypoalbuminemia and edema.
• Podocyte injury is an underlying mechanism of proteinuria, and may be the result of nonimmune causes (as in minimal- change disease and FSGS) or immune mechanisms (as in membranous nephropathy).
• Minimal-change disease is the most frequent cause of nephrotic syndrome in children; it is manifested by pro- teinuria and effacement of glomerular foot processes without antibody deposits; the pathogenesis is unknown; the disease responds well to steroid therapy.
• FSGS may be primary (podocyte injury by unknown mech- anisms) or secondary (e.g., as a consequence of previous glomerulonephritis, hypertension, or infection such as with HIV); glomeruli show focal and segmental oblitera- tion of capillary lumina, and loss of foot processes; the disease often is resistant to therapy and may progress to end-stage renal disease.
• Membranous nephropathy is caused by an autoimmune response, most often directed against the phospholipase A2 receptor on podocytes; it is characterized by granular subepithelial deposits of antibodies with GBM thickening and loss of foot processes but little or no inflammation; the disease often is resistant to steroid therapy.
• MPGN and dense deposit disease are now recognized to be distinct entities. MPGN is caused by immune complex deposition; dense deposit disease is a consequence of complement dysregulation. Both may present with nephrotic and/or nephritic features.
Nephritic syndrome is a clinical complex usually of acute onset characterized by what three things? Which two other signs may be present though not as severe as in nephrotic syndrome? What do The lesions that cause the nephritic syndrome have in common and what are they often accompanied by? This results in what?
Reduced GFR is manifested clinically by what three things? What is the cause of hypertension in nephritic syndrome?
The acute nephritic syndrome may be produced by sys- temic disorders such as ? Or it may be secondary to primary glomerular disease. The latter is exemplified by what? Acute postinfectious GN, one of the more frequently occurring glomerular disorders, is caused by what? Inciting antigens may be what or what? What pattern is seen in this acute PGN?
Infections by organisms other than streptococci may also be associated with postinfectious GN. These include?
Endogenous antigens as occur in SLE also may cause proliferation GN but more commonly result in what thereby lacking what characteristic of acute PGN ? What is a classic cause of PGN?
Only certain “nephritogenic” strains of β-hemolytic streptococci evoke glomerular disease. In most cases, the initial infection is localized to the pharynx or skin true or false
The Nephritic Syndrome
The nephritic syndrome is a clinical complex, usually of acute onset, characterized by (1) hematuria with dysmor- phic red cells and red cell casts in the urine; (2) some degree of oliguria and azotemia; and (3) hypertension.
Although proteinuria and even edema also may be present, these usually are not as severe as in the nephrotic syndrome. The lesions that cause the nephritic syndrome have in common proliferation of the cells within the glo- meruli, often accompanied by an inflammatory leukocytic infiltrate. This inflammatory reaction severely injures the capillary walls, permitting blood to pass into the urine and inducing hemodynamic changes that lead to a reduction in the GFR. The reduced GFR is manifested clinically by oliguria, fluid retention, and azotemia. Hypertension probably is a result of both the fluid retention and some augmented renin release from the ischemic kidneys.
The acute nephritic syndrome may be produced by sys- temic disorders such as systemic lupus erythematosus, or it may be secondary to primary glomerular disease. The latter is exemplified by acute postinfectious GN.
Acute postinfectious (post streptococcal)GN, one of the more frequently occurring glomerular disorders, is caused by glomerular deposition of immune complexes resulting in proliferation of and damage to glomerular cells and infiltration of leukocytes, especially neutro- phils. The inciting antigen may be exogenous or endoge- nous. The prototypic exogenous pattern is seen in poststreptococcal GN. Infections by organisms other than streptococci may also be associated with postinfectious GN. These include certain pneumococcal and staphylococ- cal infections as well as several common viral diseases such as mumps, measles, chickenpox, and hepatitis B and C. Endogenous antigens, as occur in systemic lupus erythe- matosus, also may cause a proliferative GN but more com- monly result in a membranous nephropathy (see earlier) lacking the neutrophil infiltrates that are characteristic of postinfectious GN. The classic case of poststreptococcal GN develops in a child 1 to 4 weeks after they recover from a group A strep- tococcal infection. .
