Pathology_Robbins

Pathology_Robbins. 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, and podocytes are also largely responsible for synthesis of GBM components. Nephrin, a transmembrane glycoprotein, is the major component of the slit diaphragms between adjacent foot processes. The intracellular part of nephrin interacts with several cytoskeletal and signaling proteins (see


Pathology_Robbins

Pathology_Robbins. Fig. 14.1 ). Nephrin and its associated proteins, including podocin, have a crucial role in maintaining the selective permeability of the glomerular filtration barrier. This is dramatically illustrated by rare hereditary diseases in which mutations of nephrin or its partner proteins lead to abnormal leakage of plasma proteins into the urine and the nephrotic syndrome. As might be expected, acquired defects in podocytes and slit diaphragms, which are seen in a number of renal diseases, also are associated with proteinuria of varying severity. Glomeruli may be injured by diverse mechanisms in the course of a number of systemic diseases ( Table 14.1 ). 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. The glomerular alterations in systemic diseases are discussed elsewhere.


Pathology_Robbins

Pathology_Robbins. Immune mechanisms underlie most types of primary glomerular diseases and many of the secondary glomerular diseases. Under experimental conditions, GN can be readily induced by antibodies, and glomerular deposits of immunoglobulins, often with various components of complement, are found frequently in patients with GN. 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, and (2) antibodies reacting in situ within the glomerulus, either with fixed (intrinsic) glomerular antigens or with extrinsic molecules that are planted in the glomerulus ( Fig. 14.3 ). These pathways are not mutually exclusive, and in humans all may contribute to injury. Abnormal activation and glomerular deposition of complement may be the sole culprit in some forms of GN. Cell-mediated immune mechanisms also may play a role in certain glomerular diseases.


Pathology_Robbins

Pathology_Robbins. Deposition of circulating immune complexes in the glomerulus initiates complement (and/or Fc receptor) mediated leukocyte activation, resulting in glomerular injury. The pathogenesis of immune complex diseases is discussed in detail in Chapter 5. Presented here is a brief review of the salient features that relate to glomerular injury in GN. In circulating immune complex–mediated diseases, the complexes may be formed with endogenous antigens, as in the GN associated with systemic lupus erythematosus, or the antigens may be exogenous, as is probable in the GN that follows certain bacterial (streptococcal), viral (hepatitis B), parasitic (Plasmodium falciparum malaria), and spirochetal (Treponema pallidum) infections. Often the inciting Table 14.1 Glomerular Diseases Glomerulopathies Secondary to Systemic Diseases IgA, ImmunoglobulinA. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Table 14.1 Glomerular Diseases Glomerulopathies Secondary to Systemic Diseases IgA, ImmunoglobulinA. http://ebooksmedicine.net Deposition of circulating immune complexes In situ binding of antibodies with or without immune complex formation Subepithelial (at outer surface of glomerular basement membranes) Subendothelial (at inner surface of glomerular basement membranes) Antibody against antigen on podocytes Anti-glomerular basement membrane antibody Subepithelial immune complex formation (membranous nephropathy) Anti-glomerular basement membrane glomerulonephritis (no immune complexes formed) Granular immunofluorescence Linear immunofluorescence Mesangial


Pathology_Robbins

Pathology_Robbins. Fig. 14.3 Antibody-mediatedglomerularinjury.Injurycanresulteitherfromthedepositionofcirculatingimmunecomplexesorfromantibody-bindingtoglomerularcomponentsfollowedbyformationofcomplexesinsitu.Depositionofcirculatingimmunecomplexesgivesagranularimmunofluorescencepattern.Anti-glomerularbasementmembrane(anti-GBM)antibodyglomerulonephritisischaracterizedbyalinearimmunofluorescencepattern;thereisnoimmunedepositformationinthisdisease. antigen is unknown, as in most cases of membranoproliferative GN.


Pathology_Robbins

Pathology_Robbins. Once antigen-antibody complexes are deposited or formed in the glomeruli, they produce injury by activating complement and recruiting leukocytes. Binding of immune complexes to Fc receptors on leukocytes also may contribute to activation of the cells and injury. Morphologically, affected glomeruli exhibit leukocytic infiltrates and variable proliferation of mesangial and parietal epithelial cells. Electron microscopy reveals electron-dense immune deposits in one or more of three locations: between the endothelial cells and the GBM (subendothelial deposits), between the outer surface of the GBM and the podocytes (subepithelial deposits), or in the mesangium. The localization of antigen, antibody, or immune complexes determines the glomerular injury response. Studies in experimental models have shown that complexes deposited in the endothelium or subendothelium elicit an inflammatory reaction in the glomerulus with infiltration of leukocytes and exuberant proliferation of glomerular


Pathology_Robbins

Pathology_Robbins. have shown that 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, antibodies directed to the subepithelial region of glomerular capillaries are often noninflammatory, as seen in primary membranous nephropathy (discussed later). The presence of immunoglobulins and complement in these deposits can be demonstrated by immunofluorescence microscopy. The pattern of immune complex deposition by immunofluorescence microscopy is granular, given the rather picturesque description of “lumpy-bumpy” by pathologists (


Pathology_Robbins

Pathology_Robbins. Fig. 14.4A 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, such as in hepatitis B virus infection and self nuclear antigens in systemic lupus erythematosus, but more often the antigen is unknown. Although immune complex deposition is a common mechanism of injury, circulating complexes are almost never identified in human disease, likely because of technical limitations.


Pathology_Robbins

Pathology_Robbins. 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” nonglomerular antigens, which deposit and become concentrated in the kidney through interaction with various glomerular components. Planted antigens include nucleosomal complexes, mainly derived from breakdown of apoptotic cells, in patients with systemic lupus erythematosus; bacterial products, such as endostreptosin, a protein expressed by group A streptococci; and large aggregated proteins (e.g., aggregated immunoglobulin G [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,


Pathology_Robbins

Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 14.4 Twopatternsofdepositionofimmunecomplexesasseenbyimmunofluorescencemicroscopy.(A)Granular,characteristicofcirculatingandinsituimmunecomplexdeposition.(B)Linear,characteristicofclassicanti-glomerularbasementmembrane(anti-GBM)antibodyglomerulonephritis.(A, Courtesy of Dr. J.Kowalewska,Department of Pathology,University of Washington,Seattle,Washington.) Antibody-mediated GN results from the glomerular deposition of autoantibodies directed against protein components of the GBM. The best-characterized disease in this group is anti-GBM antibody–mediated crescentic GN (see Fig. 14.3 ), also known as Goodpasture disease. In this type of injury, antibodies are directed against fixed antigens in the GBM, creating a linear pattern of staining when visualized with immunofluorescence microscopy (


Pathology_Robbins

Pathology_Robbins. Fig. 14.4B ). This pattern is useful in the diagnosis of glomerular disease. A known antigen that is the target of anti-GBM antibodies is the α3 chain of the type IV collagen of the GBM. Sometimes the anti-GBM antibodies cross-react with basement membranes of lung alveoli, resulting in simultaneous lung and kidney lesions (Goodpasture syndrome, Chapter 13).


Pathology_Robbins

Pathology_Robbins. The primary cause of these diseases is unregulated activation of the alternative complement pathway, which may be triggered by acquired autoantibodies against complement components or inherited abnormalities of complement regulatory proteins. Ensuing 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 this category. Although complement-mediated thrombotic microangiopathy is a systemic condition, renal manifestation represents the major morbidity of the disease. Mediators of Immune Injury


Pathology_Robbins

Pathology_Robbins. Mediators of Immune Injury A major pathway of antibody-initiated glomerular injury involves complement activation and recruitment of leukocytes. 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; and arachidonic acid metabolites, which contribute to reduction in GFR. In other types of GN in which neutrophils are not prominent, complement-dependent injury may occur through assembly of the C5b-C9 membrane attack complex. There is evidence that the membrane attack complex injures epithelial cells, inducing them to secrete various inflammatory mediators. The alternative and lectin pathways of complement can be activated by cell injury or apoptosis, and also perhaps by deposited IgA.


Pathology_Robbins

Pathology_Robbins. 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. Platelets may aggregate and release mediators, including prostaglandins. Resident glomerular cells (epithelial, mesangial, and endothelial) can be stimulated to secrete mediators such as cytokines (interleukin-1), arachidonic acid metabolites, growth factors, and nitric oxide. Thus, virtually all of the mediators described in the discussion of inflammation in Chapter 3 may contribute to glomerular injury. Non-immune Mechanisms of Glomerular Injury Mechanisms other than inflammation contribute to glomerular abnormalities in certain primary renal disorders. Two that deserve special mention are podocyte injury and nephron loss.


Pathology_Robbins

Pathology_Robbins. Mechanisms other than inflammation contribute to glomerular abnormalities in certain primary renal disorders. Two that deserve special mention are podocyte injury and nephron loss. Podocyte injury can be 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 (discussed later). Podocyte injury produces morphologic changes including effacement of foot processes, vacuolization, and retraction and detachment of cells from the GBM, and often results in the development of proteinuria. Of these changes, it is the loss of normal slit diaphragms that is most highly associated with proteinuria. Germline mutations in the structural components of slit diaphragms, such as nephrin and podocin, also are associated with functional alterations that lead to rare hereditary forms of the nephrotic syndrome. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. 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. Such progressive sclerosis is exacerbated by adaptive changes that occur in response to the loss of nephrons. Specifically, intact glomeruli undergo hypertrophy to maintain renal function, an alteration that is associated with hemodynamic changes, including increases in single-nephron GFR, blood flow, and transcapillary pressure (capillary hypertension). These alterations are ultimately “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 followed by capillary obliteration, increased deposition of mesangial matrix and plasma proteins, and


Pathology_Robbins

Pathology_Robbins. to proteins, and accumulation of proteins and lipids in the mesangial matrix. This is followed by capillary obliteration, increased deposition of mesangial matrix and plasma proteins, and finally segmental (affecting a portion) or global (complete) sclerosis of glomeruli. The latter results in further reduction of nephron mass, initiating a vicious cycle of progressive glomerulosclerosis.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Lessfrequently,complementmaybeactivatedintheabsenceofantibody,becauseofacquiredorhereditarydefectsinitsregulation. We now turn to a consideration of specific types of GN and the syndromes they produce ( Table 14.2 ). Many primary glomerular disease cause the nephrotic syndrome, but in adults this syndrome is most often secondary to diabetes, amyloidosis, and systemic lupus erythematosus ( Table 14.3 ). The renal lesions produced by lupus and amyloidosis are discussed in Chapter 5, and those caused by diabetes in Chapter 20. Minimal-change disease, a relatively benign disorder, is the most frequent cause of the nephrotic syndrome in children and is characterized by glomeruli that have a normal appearance by light microscopy. Diffuse effacement of podocyte foot processes is seen with electron microscopy. It may develop at any age, but is most common between 1 and 7 years of age.


Pathology_Robbins

Pathology_Robbins. A popular hypothesis for the pathogenesis of minimal-change disease is that some circulating molecules injure podocytes and cause proteinuria with effacement of foot processes. Although there are numerous reports of candidate serum “factors” produced by lymphocytes and other cells, none has been characterized biochemically or definitively established as being causative in the disease. Thus, the pathogenesis of minimal-change disease remains unknown. MORPHOLOGYUnderthelightmicroscope,theglomeruliappearnormal,thusgivingrisetothename( Fig.14.5A ).Thecellsoftheproximalconvolutedtubulesoftenareheavilyladenwithproteindropletsandlipidsduetotubularreabsorptionofthelipoproteinspassingthroughthediseasedglomeruli.Theonlyobviousglomerularabnormalityisthediffuse effacement of the foot processes of the podocytes (see


Pathology_Robbins

Pathology_Robbins. The disease typically manifests with abrupt 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 smaller plasma proteins, chiefly albumin (selective proteinuria). The prognosis for children with this disorder is favorable. More than 90% of children respond to a short course of corticosteroid therapy; however, proteinuria recurs in more than two-thirds of the initial responders, some of whom become steroid-dependent with proteinuria recurring when steroids are withdrawn. Less than 5% develop chronic kidney disease after 25 years, and it is likely that most individuals in this subgroup had nephrotic syndrome caused by focal segmental glomerulosclerosis http://ebooksmedicine.net Table 14.2 Summary of Major Primary Glomerular Diseases GBM, Glomerularbasementmembrane;IgA, immunoglobulinA;IgG, immunoglobulinG;IgM, immunoglobulinM.


Pathology_Robbins

Pathology_Robbins. Table 14.2 Summary of Major Primary Glomerular Diseases GBM, Glomerularbasementmembrane;IgA, immunoglobulinA;IgG, immunoglobulinG;IgM, immunoglobulinM. not detected by biopsy. Because of its responsiveness to therapy in children, minimal-change disease must be differentiated from other causes of the nephrotic syndrome in nonresponders. Adults with this disease also respond to steroid therapy, but the response is slower and relapses are more common. Focal segmental glomerulosclerosis (FSGS) is characterized by sclerosis of some (but not all) glomeruli that involves only a part of each affected glomerulus. FSGS may be primary (idiopathic) or secondary to one of the following conditions: HIV infection (HIV nephropathy). FSGS is seen in 5–10% of patients infected with HIV, but the incidence is decreasing with improved antiviral therapy. Secondary to other forms of GN (e.g., IgA nephropathy)


Pathology_Robbins

Pathology_Robbins. Secondary to other forms of GN (e.g., IgA nephropathy) As a maladaptation to nephron loss (as discussed earlier) • Inherited forms, including autosomal dominant forms associated with mutations in cytoskeletal proteins and podocin, both of which are required for the integrity of podocytes. 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. Injury to podocytes is thought to represent the initiating event of primary FSGS. However, what causes this injury remains unknown. Some investigators have suggested that FSGS and minimal-change disease are part of a continuum and that minimal-change disease may transform into FSGS, but others believe them to be distinct clinicopathologic entities from the outset. As with minimal-change disease, permeability-increasing factors produced http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Table 14.3 Causes of Nephrotic Syndrome Ingestionofdrugs(gold,penicillamine,“streetheroin”) Infections(malaria,syphilis,hepatitisB,HIV) Malignancy(carcinoma,melanoma) Miscellaneous(beestingallergy,hereditarynephritis) HIV, Humanimmunodeficiencyvirus.*Approximateprevalenceofprimarydiseaseis95%ofthecasesinchildrenand60%inadults.Approximateprevalenceofsystemicdiseaseis5%ofthecasesinchildrenand40%inadults. by lymphocytes are suspected but remain unproven. The deposition of hyaline in the glomeruli is caused by the entrapment of plasma proteins and lipids in foci of injury where sclerosis develops. The recurrence of proteinuria in patients underoing renal transplantion for FSGS, sometimes within 24 hours of transplantation, supports the idea that a circulating mediator leads to podocyte damage in some cases.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYPrimaryFSGSinitiallyaffectsonlythejuxtamedullaryglomeruli.Withprogression,eventuallyalllevelsofthecortexareaffected.Thelesionsoccurinsometuftswithinaglomeruluswhilesparingothers( Fig.14.6 ).Theaffectedglomeruliexhibitincreased mesangial matrix, obliterated capillary lumina, deposition of hyaline (hyalinosis) and foamy (lipid-laden) macrophages. Inaffectedglomeruli,immunofluorescencemicroscopyoftenrevealsnonspecifictrappingofimmunoglobulins,usuallyIgM,andcomplementintheareasofhyalinosis.Onelectronmicroscopy,thepodocytesexhibiteffacement of foot processes, asinminimal-changedisease. Withtime,progressionleadstoglobalsclerosisoftheglomeruli,pronouncedtubularatrophy,andinterstitialfibrosis.Thisadvancedpictureisdifficulttodifferentiatefromotherformsofchronicglomerulardisease,discussedlater.


Pathology_Robbins

Pathology_Robbins. Amorphologicvariantcalledcollapsing glomerulopathy ischaracterizedbycollapseoftheglomerulartuftandepithelialcellhyperplasia.ThismoreseveremanifestationofFSGSmaybeidiopathicormaybeassociatedwithHIVinfection,drug-inducedtoxicities,andsomemicrovascularinjuries.Itcarriesaparticularlypoorprognosis. 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. Also, 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.


Pathology_Robbins

Pathology_Robbins. Membranous nephropathy is characterized by 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 thickening of the capillary wall. It usually presents in adults between the ages of 30 and 60 years and follows an indolent and slowly progressive course. Up to 80% of cases of membranous nephropathy are primary, caused by autoantibodies against podocyte antigens. In the remainder, it occurs secondary to other conditions, including the following: A Podocyte with effaced foot processes Normal basement membrane B Fig. 14.5 Minimal-changedisease.(A)Whenviewedwithalightmicroscope,thesilvermethenamine–stainedglomerulusappearsnormal,withadelicatebasementmembrane.(B)Schematicdiagramillustratingdiffuseeffacementoffootprocessesofpodocyteswithnoimmunedeposits. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 14.6 Focalandsegmentalglomerulosclerosis(periodicacid–Schiffstain),seenasacollectionofscarred,obliteratedcapillariesandaccumula-tionsofmatrixmaterialinpartoftheaffectedglomerulus.(Courtesy of Dr. H. Rennke, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.) Infections (chronic hepatitis B, syphilis, schistosomiasis, malaria) Malignant neoplasms, particularly carcinoma of the lung and colon and melanoma Autoimmune diseases, particularly systemic lupus erythematosus 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 antibodies reacting in situ to endogenous or planted glomerular antigens.


Pathology_Robbins

Pathology_Robbins. Membranous nephropathy is a form of chronic immune complex glomerulonephritis induced by antibodies reacting in situ to endogenous or planted glomerular antigens. Antibodies against the podocyte antigen phospholipase A2 receptor (PLA2R) are frequently present but it is not established that they are causative. 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. MORPHOLOGYThemainhistologicfeatureofmembranousnephropathyisdiffuse thickening of the capillary wall onroutineH&Estains( Fig.14.7A ).Electronmicroscopyrevealsthatthisapparentthickeningiscausedinpartbysubepithelial deposits, whichnestleagainsttheGBMandareseparatedfromeachotherbysmall,spikelikeprotrusionsofGBMmatrixthatforminreactiontothedeposits(spike and dome pattern) (see


Pathology_Robbins

Pathology_Robbins. Fig.14.4A Most cases of membranous nephropathy are sudden in onset and present as full-blown 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.


Pathology_Robbins

Pathology_Robbins. Fig. 14.7 Membranousnephropathy.(A)Diffusethickeningoftheglomeru-larbasementmembrane(periodicacid–Schiffstain).(B)Schematicdiagramillustratingsubepithelialdeposits,effacementoffootprocesses,andthepres-enceofspikesofbasementmembranematerialbetweentheimmunedeposits.A B Podocyte with effaced foot processes Subepithelial deposits "Spikes" Thickened basement membrane http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. 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). Of the two types of disease, MPGN type I is far more common (about 80% of cases) and is discussed here. Dense deposit disease will be discussed later along with the related condition of C3 glomerulonephritis.


Pathology_Robbins

Pathology_Robbins. 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. MORPHOLOGYBylightmicroscopytheglomeruliarelarge,haveanaccentuatedlobularappearance,andshowproliferation of mesangial and endothelial cells as well as infiltrating leukocytes ( Fig. 14.8A ).TheGBMisthickened,andtheglomerularcapillarywalloftenshowsadoublecontour,or“tramtrack,”appearance,especiallyevidentwithuseofsilverorperiodicacid–Schiff(PAS)stains.This“splitting”oftheGBMisduetoextensionofprocessesofmesangialandinflammatorycellsintotheperipheralcapillaryloopsanddepositionofmesangialmatrixaswellassubepithelialimmunecomplexes(see Fig.14.8B ).Thecharacteristiclightmicroscopicglomerularmanifestationsareoftenreferredtoasmembranoproliferative pattern of glomerular injury. Byelectronmicroscopy,typeIMPGNischaracterizedbydiscrete subendothelial deposits (see


Pathology_Robbins

Pathology_Robbins. Byelectronmicroscopy,typeIMPGNischaracterizedbydiscrete subendothelial deposits (see Fig.14.8B ).Byimmunofluorescencemicroscopy,C3isdepositedinanirregulargranularpattern,andIgGandearlycomplementcomponents(C1qandC4)alsooftenarepresent,indicativeofanimmunecomplexpathogenesis.


Pathology_Robbins

Pathology_Robbins. Fig.14.8B ).Byimmunofluorescencemicroscopy,C3isdepositedinanirregulargranularpattern,andIgGandearlycomplementcomponents(C1qandC4)alsooftenarepresent,indicativeofanimmunecomplexpathogenesis. 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. In one study, none of the 60 patients followed for 1 to 20 years showed complete remission; 40% progressed to end-stage renal failure, 30% had variable degrees of renal insufficiency, and the remaining 30% had persistent nephrotic syndrome without renal failure. MPGN type I also 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 “idiopathic” cases are believed to be associated with hepatitis C and related cryoglobulinemia.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The term 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.


Pathology_Robbins

Pathology_Robbins. 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 auto-antibodies to Factor H, are the cause of unregulated activation of the alternative pathway of complement.


Pathology_Robbins

Pathology_Robbins. Both dense deposit disease and C3 GN carry a relatively poor prognosis and both tend to recur posttransplantation 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. 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.


Pathology_Robbins

Pathology_Robbins. The typical case of poststreptococcal GN develops in a child 1 to 4 weeks after he or she recovers from a group A streptococcal infection. Only certain “nephritogenic” strains of β-hemolytic streptococci evoke glomerular disease. In most cases, the initial infection is localized to the pharynx or skin. In rare cases, the disease can develop during the infection.


Pathology_Robbins

Pathology_Robbins. 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). MORPHOLOGYBylightmicroscopy,themostcharacteristicchangeinpostinfectiousGNisincreased cellularity oftheglomerulartuftsthataffectsnearlyallglomeruli—hencethetermdiffuse GN ( Fig.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYBylightmicroscopy,themostcharacteristicchangeinpostinfectiousGNisincreased cellularity oftheglomerulartuftsthataffectsnearlyallglomeruli—hencethetermdiffuse GN ( Fig. 14.9A ).Theincreasedcellularityiscausedbothbyproliferationandswellingofendothelialandmesangialcellsandbyinfiltratingneutrophilsandmonocytes.Sometimesthereisnecrosisofthecapillarywalls.Inafewcases,“crescents”(discussedlater)maybeobservedwithintheurinaryspace,formedinresponsetothesevereinjury.Electronmicroscopyshowsdepositedimmunecomplexesarrayedassubendothelial,intramembranous,or,mostoften,subepithelial “humps” nestledagainsttheGBM(see Fig.14.9B ).Mesangialdepositsalsoareoccasionallypresent.Immunofluorescencestudiesrevealscatteredgranular deposits of IgG and complement withinthecapillarywallsandsomemesangialareas,correspondingtothedepositsvisualizedbyelectronmicroscopy.Thesedepositsusuallyareclearedoveraperiodofabout2months.


Pathology_Robbins

Pathology_Robbins. 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, as mentioned earlier, 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. http://ebooksmedicine.net Fig. 14.9 Poststreptococcalglomerulonephritis.(A)Glomerularhypercellularityiscausedbyintracapillaryleukocytesandproliferationofintrinsicglomerularcells.Notetheredbloodcellcastsinthetubules.(B)Typicalelectron-densesubepithelial“hump”(arrow) andintramembranousdeposits.BM, Basementmembrane;CL, capillarylumen;E, endothelialcell;Ep, visceralepithelialcells(podocytes).


Pathology_Robbins

Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. IgA nephropathy is one of the most common causes of recurrent microscopic or gross hematuria and is the most common glomerular disease revealed by renal biopsy worldwide. This condition usually affects children and young adults and begins as an episode of gross hematuria that occurs within 1 or 2 days of a nonspecific upper-respiratory tract infection. Typically, the hematuria lasts several days and then subsides, but it recurs periodically, usually in the setting of a viral infection. It may be associated with local pain. 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 Henoch-Schönlein purpura, also characterized by IgA deposition in the mesangium. In contrast with IgA nephropathy, which is confined to the kidney, Henoch-Schönlein purpura is a systemic syndrome also involving the skin (purpuric rash), gastrointestinal tract (abdominal pain), and joints (arthritis).


Pathology_Robbins

Pathology_Robbins. An abnormally glycosylated IgA1 (i.e., galactose-deficient IgA1 [Gd-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. The presence of C3 in the mesangium and the absence of C1q and C4 points to activation of the alternative complement pathway in the pathogenesis. A genetic influence is suggested by the occurrence of IgA nephropathy in families and in HLA-identical siblings, and increased frequency of certain HLA and complement genotypes in some populations. Taken together, these data suggest that in genetically susceptible individuals, respiratory or gastrointestinal exposure to microbial or other antigens (e.g., viruses, bacteria, food


Pathology_Robbins

Pathology_Robbins. populations. Taken together, these data suggest that in genetically susceptible individuals, respiratory or gastrointestinal exposure to microbial or other antigens (e.g., viruses, bacteria, food proteins) may lead to increased IgA synthesis, some of which is abnormally glycosylated, and deposition of IgA and IgA-containing immune complexes in the mesangium, where they activate the alternative complement pathway and initiate glomerular injury. In support of this scenario, 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).


Pathology_Robbins

Pathology_Robbins. Histologically,thelesionsinIgAnephropathyvaryconsiderably. http://ebooksmedicine.net Fig. 14.10 IgAnephropathy.CharacteristicimmunofluorescencedepositionofIgA,principallyinmesangialregions,isevident.IgA, ImmunoglobulinA. proliferativeGN);diffusemesangialproliferation(mesangioproliferativeGN);or(rarely)overtcrescenticGN.Thecharacteristicimmunofluorescencepictureisofmesangial deposition of IgA, oftenwithC3andproperdinandsmalleramountsofIgGorIgM( Fig.14.10 ).Earlycomponentsoftheclassicalcomplementpathwayusuallyareabsent.Electronmicroscopyconfirmsthepresenceofelectron-densedepositsinthemesangium.


Pathology_Robbins

Pathology_Robbins. 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, and 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.


Pathology_Robbins

Pathology_Robbins. 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, posterior cataracts, and corneal dystrophy. Thin basement membrane disease is the most common cause of benign familial hematuria with no systemic manifestations. 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.


Pathology_Robbins

Pathology_Robbins. The majority of Alport syndrome patients have X-linked disease as a result of mutation of the gene on the X chromosome encoding the α5 chain of type IV collagen. Males therefore are affected more frequently and more severely than females and are more likely to develop end-stage renal disease and deafness. Rare autosomal recessive or dominant cases are linked to defects in the genes that encode α3 or α4 type IV collagen. Individuals with hereditary nephritis present at 5 to 20 years of age with gross or microscopic hematuria and proteinuria, and progress to overt renal failure by the ages of 20 to 50 years. Female carriers of X-linked Alport syndrome or carriers of either gender of the autosomal forms usually present with persistent asymptomatic hematuria and follow a benign nonprogressive clinical course. Heterozygous mutations in the genes encoding the α3 and α4 chains of type IV collagen are found in 40% of patients with thin basement membrane disease.


Pathology_Robbins

Pathology_Robbins. RPGN is 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. RPGN is characterized by rapid loss of renal function, laboratory findings typical of the nephritic syndrome, and often severe oliguria. If untreated, it can rapidly lead to renal failure within a period of weeks to months.


Pathology_Robbins

Pathology_Robbins. Crescentic GN may be caused by a number of different diseases, some restricted to the kidney and others systemic. RPGN may be associated with a number of diseases, as follows: • Anti-GBM antibody–mediated crescentic GN (Goodpasture disease) is characterized by 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. These patients are said to have Goodpasture syndrome. Anti-GBM antibodies are present in the serum and are helpful in diagnosis. It is important to recognize anti-GBM antibody–mediated crescentic GN, because affected individuals benefit from plasmapheresis, which removes pathogenic antibodies from the circulation. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Immune complex–mediated crescentic GN may complicate any of the immune complex nephritides, including post-streptococcal GN, systemic lupus erythematosus, IgA nephropathy, and Henoch-Schönlein purpura. In other cases, immune complexes are demonstrated but the underlying cause is undetermined. This type of RPGN frequently shows cellular proliferation and influx of leukocytes within the glomerular tuft, in addition to crescent 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. This disorder usually does not respond to plasmapheresis.


Pathology_Robbins

Pathology_Robbins. 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, which, as discussed in Chapter 10, have a pathogenic role in some vasculitides. In some instances, therefore, crescentic GN is a component of a systemic vasculitis such as microscopic polyangiitis or granulomatosis with polyangiitis. In many cases, however, pauci-immune crescentic GN is limited to the kidney.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. in the GBM, signifyingsevereglomerularinjurythatischaracteristicofthisformofGN.ThecrescentseventuallyobliterateBowman’sspaceandcompresstheglomeruli.Intime,crescentsmayundergoscarring,andglomerulosclerosisdevelops.


Pathology_Robbins

Pathology_Robbins. 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, as 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 pauciimmune crescentic GN. Minimal-change disease isthemostfrequentcauseofnephroticsyndromeinchildren.Itismanifestedbyproteinuriaandeffacementofglomerularfootprocesseswithoutantibodydeposits.


Pathology_Robbins

Pathology_Robbins. Minimal-change disease isthemostfrequentcauseofnephroticsyndromeinchildren.Itismanifestedbyproteinuriaandeffacementofglomerularfootprocesseswithoutantibodydeposits. Focal segmental glomerulosclerosis (FSGS)maybeprimaryorsecondary(e.g.,asaconsequenceofpreviousglomerulonephritis,hypertension,orinfectionsuchasHIV).Glomerulishowfocalandsegmentalobliterationofcapillaryluminaandlossoffootprocesses. Membranous nephropathy iscausedbyanautoimmuneresponse,mostoftendirectedagainstthePLA2Ronpodocytes.ItischaracterizedbygranularsubepithelialdepositsofantibodieswithGBM“spike”formation,thickeningandlossoffootprocessesbutlittleornoinflammation. Membranoproliferative glomerulonephritis type 1 isanimmunecomplex–mediateddiseasewithimmunedepositsinthesub-endotheliallocation. Fig. 14.11 Crescenticglomerulonephritis(silverstain).Arrowsindicateareasofnecrosisandcrescentformation.ThesegmentaldistributioninthiscaseistypicalofANCA(anti-neutrophilcytoplasmicantibody)–associatedcrescenticglomerulonephritis.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net •Dense deposit disease andC3 glomerulonephritis arecausedbyunregulatedactivationofthealternativecomplementpathway.ImmunofluorescenceispositiveforC3inbothconditions. •Acute postinfectious glomerulonephritis typicallyoccursafterstreptococcalinfectioninchildrenandyoungadultsbutmayoccurfollowinginfectionwithmanyotherorganisms.Itiscausedbydepositionofimmunecomplexes,mainlyinthesubepithelialspaces,withabundantneutrophilsandproliferationofglomerularcells. IgA nephropathy, characterizedbymesangialdepositsofIgAcontainingimmunecomplexes,isthemostcommonformofglomerulonephritisworldwide.Recurrentasymptomatichematuriaisthemostcommonclinicalpresentation.Itcommonlyaffectschildrenandyoungadultsandhasavariablecourse.


Pathology_Robbins

Pathology_Robbins. RPGNmaybemediatedbyautoantibodiestotheGBM(anti-GBMantibodydisease),byimmunecomplexdeposition,oritcanbepauci-immuneoftenassociatedwithanti-neutrophilcytoplasmicantibodies(pauci-immuneGN). Most forms of tubular injury also involve the interstitium, so the two are discussed together. Presented under this heading are diseases characterized by (1) inflammatory involvement of the tubules and interstitium (tubulointerstitial nephritis) and (2) ischemic or toxic tubular injury, leading to acute tubular injury and the clinical syndrome of acute kidney injury.


Pathology_Robbins

Pathology_Robbins. Tubulointerstitial nephritis (TIN) refers to a group of inflammatory kidney diseases that primarily involve the interstitium and tubules. The glomeruli may be spared altogether or affected only late in the course. In cases of TIN caused by bacterial infection, the renal pelvis is prominently involved—hence the more descriptive term pyelonephritis (from pyelo, “pelvis”). The term interstitial nephritis generally is reserved for cases of TIN that are nonbacterial in origin. These include tubular injury resulting from drugs, metabolic disorders such as hypokalemia, irradiation, viral infections, and immune reactions. On the basis of clinical features and the character of the inflammatory exudate, TIN can be divided into acute and chronic categories. Discussed next is acute pyelonephritis followed by consideration of other forms of interstitial nephritis.


Pathology_Robbins

Pathology_Robbins. Acute pyelonephritis, a common suppurative inflammation of the kidney and the renal pelvis, is caused by bacterial infection. It is an important manifestation of urinary tract infection (UTI), which can involve the lower (cystitis, prostatitis, urethritis) or upper (pyelonephritis) urinary tract, or both. As we will see, the great majority of cases of pyelonephritis are associated with infections of the lower urinary tract, which are very common. Fortunately, most infections of the lower urinary tract remain localized and do not spread to the kidney.


Pathology_Robbins

Pathology_Robbins. The principal causative organisms in acute pyelonephritis are enteric gram-negative bacilli. Escherichia coli is by far the most common. Other important organisms are Proteus, Klebsiella, Enterobacter, and Pseudomonas; these usually are associated with recurrent infections, especially in individuals who undergo urinary tract manipulations or have congenital or acquired anomalies of the lower urinary tract (see later). Staphylococci and Streptococcus faecalis also may cause pyelonephritis, but they are uncommon pathogens in this setting. Bacteria can reach the kidneys from the lower urinary tract (ascending infection) or through the bloodstream (hematogenous infection) (


Pathology_Robbins

Pathology_Robbins. Bacteria can reach the kidneys from the lower urinary tract (ascending infection) or through the bloodstream (hematogenous infection) ( Fig. 14.12 ). Ascending infection from the lower urinary tract is the most important and frequent route by which bacteria reach the kidney. Adhesion of bacteria to mucosal surfaces is followed by colonization of the distal urethra (and the introitus in females). Genetically determined properties of both the urothelium and the bacterial pathogens may facilitate adhesion to the urothelial lining by bacterial fimbriae (proteins that attach to receptors on the surface of urothelial cells), conferring susceptibility to infection. The organisms then reach the bladder, by expansive growth of the colonies and by moving against the flow of urine. This may occur during urethral instrumentation, including catheterization and cystoscopy.


Pathology_Robbins

Pathology_Robbins. In the absence of instrumentation, UTI most commonly affects females. Because of the close proximity of the female urethra to the rectum, colonization by enteric bacteria can occur more readily in females. Furthermore, the short urethra and trauma to the urethra during sexual intercourse facilitate the entry of bacteria into the urinary bladder. Normally, bladder urine is sterile, because of the anti-microbial properties of the bladder mucosa and the flushing mechanism associated with periodic voiding of urine. With outflow obstruction or bladder dysfunction, however, the natural defense mechanisms of the bladder are overwhelmed, setting the stage for UTI. In the presence of stasis, bacteria introduced into the bladder can multiply undisturbed, without being flushed out or http://ebooksmedicine.net Common agents: E. coli Pyelonephritis Foci of pyelonephritis Common agents: E. coli Proteus Enterobacter


Pathology_Robbins

Pathology_Robbins. Common agents: E. coli Pyelonephritis Foci of pyelonephritis Common agents: E. coli Proteus Enterobacter Fig.14.12 Pathwaysofrenalinfection.Hematogenousinfectionresultsfrom bacteremicspread.Morecommonisascendinginfection,whichresultsfrom acombinationofurinarybladderinfection,vesicoureteralreflux,andintra-renalreflux. destroyed by the bladder wall. Accordingly, UTI is particularly frequent among patients with urinary tract obstruction, as may occur with benign prostatic hyperplasia and uterine prolapse. From the contaminated bladder urine, the bacteria ascend along the ureters to infect the renal pelvis and parenchyma. The frequency of UTI also is increased in diabetes because of the increased susceptibility to infection and neurogenic bladder dysfunction, which predispose to urine stasis. Increased incidence of UTI during pregnancy is attributed to urine stasis due to pressure on the bladder and ureters from the growing uterus.


Pathology_Robbins

Pathology_Robbins. Incompetence of the vesicoureteral orifice, resulting in vesicoureteral reflux (VUR), is an important cause of ascending infection. The reflux allows bacteria to ascend the ureter into the pelvis. VUR is present in 20% to 40% of young children with UTI, usually as a consequence of a congenital defect that results in incompetence of the ureterovesical valve. VUR also can be acquired in individuals with a flaccid bladder resulting from spinal cord injury or with bladder dysfunction secondary to diabetes. VUR results in residual urine after voiding in the urinary tract, which favors bacterial growth. Furthermore, VUR affords a ready mechanism by which the infected bladder urine can be propelled up to the renal pelvis and further into the renal parenchyma through open ducts at the tips of the papillae (intrarenal reflux). Additional risk factors for UTI include preexisting renal conditions with renal scarring and intraparenchymal obstruction and also immunosuppressive therapy and


Pathology_Robbins

Pathology_Robbins. of the papillae (intrarenal reflux). Additional risk factors for UTI include preexisting renal conditions with renal scarring and intraparenchymal obstruction and also immunosuppressive therapy and immunodeficiency.


Pathology_Robbins

Pathology_Robbins. Although hematogenous spreadis far less common than ascending infection, acute pyelonephritis may result from seeding of the kidneys by bacteria in the course of septicemia or infective endocarditis. Oneorbothkidneysmaybeinvolved.Theaffectedkidneymay benormalinsizeorenlarged.Characteristically,discrete,yellowish, raised abscesses are grossly apparent on the renal surface ( Fig. 14.13 ).They may be widely scattered or limitedtooneregionofthekidney,ortheymaycoalescetoform asinglelargeareaofsuppuration. Thecharacteristichistologicfeatureofacutepyelonephritis is liquefactive necrosis and abscess formation within the renal parenchyma.Intheearlystages,pusformation(suppuration)is limited to the tubularlumina, but later abscessesruptureinto the interstitial tissue. Large masses of intratubular neutrophils frequentlyextendwithininvolvednephronsinto thecollecting ducts,givingrisetocharacteristicwhitebloodcellcastsinthe urine.Typically,theglomeruliarenotaffected.


Pathology_Robbins

Pathology_Robbins. When obstruction is prominent, the pus does not drain and may fill the renal pelvis, calyces, and ureter, producing pyonephrosis. Asecond(rare)formofpyelonephritisispapillary necrosis, which has three predisposing conditions: diabetes, urinary tractobstruction,andsicklecellanemia.Thislesionismarkedby ischemicandsuppurativenecrosisofthetipsoftherenalpyramids(renalpapillae).Thepathognomonicgrossfeatureissharply definedgray-whitetoyellownecrosisoftheapicaltwo-thirdsof Fig.14.13 Acutepyelonephritis.Thecorticalsurfaceisstuddedwithfocal paleabscesses,morenumerousintheupperpoleandmiddleregionofthe kidney;thelowerpoleisrelativelyunaffected.Betweentheabscesses,there isdarkcongestionoftherenalsurface. thepyramids.Onepapillaorseveralorallpapillaemaybeaffected.Microscopically,thepapillarytipsshowcoagulativenecrosissurroundedbyaneutrophilicinfiltrate. Involvementoftheprostatecangiverisetoacuteorchronicprostatitis,particularlyinoldermaleswithbenignprostatichyperplasia.


Pathology_Robbins

Pathology_Robbins. Involvementoftheprostatecangiverisetoacuteorchronicprostatitis,particularlyinoldermaleswithbenignprostatichyperplasia. Acute pyelonephritis often is associated with predisposing conditions, as described earlier in the discussion of pathogenetic mechanisms. After the first year of life (an age by which congenital anomalies in males commonly become evident) and up to approximately 40 years of age, infections are much more frequent in females. Up to 6% of pregnant women develop bacteriuria some time during pregnancy, and 20% to 40% of these eventually develop symptomatic urinary infection if not treated. With increasing age, the incidence in males rises as a result of the development of prostatic hyperplasia, which causes urinary outflow obstruction.


Pathology_Robbins

Pathology_Robbins. The onset of uncomplicated acute pyelonephritis usually is sudden, with pain at the costovertebral angle and systemic evidence of infection, such as chills, fever, nausea, malaise, and localizing urinary tract signs of dysuria, frequency, and urgency. The urine appears turbid due to the contained pus (pyuria). The disease usually is unilateral, and affected individuals thus do not develop renal failure. In cases in which predisposing factors are present, the disease may become recurrent or chronic and is more likely to be bilateral. The development of papillary necrosis is associated with a much poorer prognosis.


Pathology_Robbins

Pathology_Robbins. Chronic pyelonephritis is a clinicopathologic entity in which interstitial inflammation and scarring of the renal parenchyma are associated with grossly visible scarring and deformity of the pelvicalyceal system in patients with a history of UTI. Chronic pyelonephritis is an important cause of chronic kidney disease. It can be divided into two forms: chronic obstructive pyelonephritis and chronic reflux–associated pyelonephritis. As noted, obstruction predisposes the kidney to infection. Recurrent infections superimposed on diffuse or localized obstructive lesions lead to recurrent bouts of renal inflammation and scarring, which eventually cause chronic pyelonephritis. The disease can be bilateral, as with congenital anomalies of the urethra (e.g., posterior urethral valves), or unilateral, such as occurs with calculi and unilateral obstructive lesions of the ureter.


Pathology_Robbins

Pathology_Robbins. Chronic reflux–associated pyelonephritis is the most common cause of chronic pyelonephritis. It results from superimposition of a UTI on congenital vesicoureteral reflux and intrarenal reflux. Both the reflux and the attendant renal damage may be unilateral or bilateral, the latter potentially leading to chronic renal insufficiency. MORPHOLOGYOneorbothkidneysmaybeinvolved,eitherdiffuselyorinpatches.Evenwheninvolvementisbilateral,thekidneysarenotequallydamagedandthereforearenotequallycontracted.Thisuneven scarring isusefulindifferentiatingchronicpyelonephritisfromthemoresymmetricallycontractedkidneysassociatedwithvascularsclerosis(oftenreferredtoasbenign nephrosclerosis)andchronicGN.Thehallmarkofchronicpyelonephritisisscarring involving the pelvis or calyces, orboth,leadingtopapillarybluntingandmarkedcalyceal deformities ( Fig.14.14


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Many patients with chronic pyelonephritis come to medical attention relatively late in the course of the disease, because of the gradual onset of renal insufficiency or because signs of kidney disease are noticed on routine laboratory tests. In other cases, the renal disease is heralded by the development of hypertension. The radiologic image is characteristic: affected kidneys are asymmetrically contracted, with some degree of blunting and deformity of the calyceal system (caliectasis). The presence or absence of significant bacteriuria is not particularly helpful, as its absence does not rule out chronic pyelonephritis. If the disease is bilateral and progressive, tubular dysfunction leads to an inability to concentrate the urine (hyposthenuria), manifested by polyuria and nocturia. Fig. 14.14 Typicalcoarsescarsofchronicpyelonephritisassociatedwithvesicoureteralreflux.Thescarsareusuallylocatedattheupperorlowerpolesofthekidneyandareassociatedwithunderlyingbluntedcalyces.


Pathology_Robbins

Pathology_Robbins. Fig. 14.14 Typicalcoarsescarsofchronicpyelonephritisassociatedwithvesicoureteralreflux.Thescarsareusuallylocatedattheupperorlowerpolesofthekidneyandareassociatedwithunderlyingbluntedcalyces. http://ebooksmedicine.net As noted earlier, some individuals with chronic pyelonephritis or reflux nephropathy ultimately develop secondary glomerulosclerosis, associated with proteinuria; eventually, these injuries all contribute to progressive chronic kidney disease. 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, and numerous other drugs (phenindione, cimetidine, immune checkpoint inhibitors).


Pathology_Robbins

Pathology_Robbins. Many features of the disease suggest an immune mechanism. Clinical features consistent with a hypersensitivity reaction include latent period between drug exposure and development of lesions, eosinophilia and rash, the idiosyncratic nature of the drug reaction (i.e., the lack of dose dependence), and the recurrence of the reaction following reexposure to the same drug or others of similar structure. Serum IgE levels are increased in some individuals, suggesting immediate (type I) hypersensitivity. In other cases, the nature of the inflammatory infiltrate and the presence of positive skin tests to drugs suggest a T cell–mediated (type IV) hypersensitivity reaction.


Pathology_Robbins

Pathology_Robbins. The most likely sequence of pathogenic events is that the drugs act as haptens that, during secretion by tubules, covalently bind to some cytoplasmic or extracellular component of tubular cells and become immunogenic. The resultant tubulointerstitial injury is then caused by IgEor T cell–mediated immune reactions to tubular cells or their basement membranes. MORPHOLOGYTheabnormalitiesinacutedrug-inducednephritisareintheinterstitium,whichshowspronouncededemaandinfiltrationbymononuclearcells,principallylymphocytesandmacrophages( Fig.14.15 ).Eosinophilsandneutrophilsmaybepresent,ofteninlargenumbers.Withsomedrugs(e.g.,methicillin,thiazides,rifampin),Tcellmediatedreactionmaygiverisetointerstitialnonnecrotizinggranulomaswithgiantcells.Theglomeruliarenormalexceptinsomecasescausedbynonsteroidalanti-inflammatoryagents,inwhichthehypersensitivityreactionalsoleadstopodocytefootprocesseffacementandthenephroticsyndrome.


Pathology_Robbins

Pathology_Robbins. The disease begins about 15 days after exposure to the drug and is characterized by fever, eosinophilia (which may be transient), rash (in about 25% of individuals), and renal abnormalities. Urinary findings include hematuria, minimal or no proteinuria, and leukocyturia (sometimes including eosinophils). A rising serum creatinine or acute kidney injury with oliguria develops in about 50% of cases, particularly in older patients. Clinical recognition of drug-induced kidney injury is imperative, because withdrawal of the offending drug is followed by recovery, although it may take several months for renal function to return to normal. Fig. 14.15 Drug-inducedinterstitialnephritis,withprominenteosinophilicandmononuclearinfiltrate.(Courtesy of Dr. H. Rennke, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.) TINconsistsofinflammatorydiseaseprimarilyinvolvingtherenaltubulesandinterstitium.


Pathology_Robbins

Pathology_Robbins. Drug-induced interstitial nephritis isanIgE-orTcell–mediatedimmunereactiontoadrug;itischaracterizedbyinterstitialinflammation,oftenwithabundanteosinophils,andedema. 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 concurrent elevation of serum creatinine. ATI is the most common cause of acute kidney injury and may produce oliguria (defined as urine output of <400 mL/day). http://ebooksmedicine.net There are two forms of ATI that differ in the underlying causes.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net There are two forms of ATI that differ in the underlying causes. Ischemic ATI is most often 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 hypo-tension 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. 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.


Pathology_Robbins

Pathology_Robbins. Proximal tubular epithelial cells are particularly sensitive to hypoxemia and also are vulnerable to toxins ( Fig. 14.16 ). Several factors predispose these cells to toxic and ischemic injury, including elevated intracellular concentrations of various molecules that are resorbed or secreted across the proximal tubule, exposure to high concentrations of luminal solutes that are concentrated by the resorption of water from the glomerular filtrate, and a high rate of oxygen consumption, which is required to generate the ATP that is needed for transport and reabsorption functions.


Pathology_Robbins

Pathology_Robbins. Ischemia causes numerous structural alterations in epithelial cells. Loss of cell polarity is an early reversible event caused by ischemia. It leads to the redistribution of membrane proteins (e.g., Na+,K+-ATPase) from the basolateral to the luminal surface of tubular cells, resulting in decreased sodium reabsorption by proximal tubules and hence increased sodium delivery to distal tubules. The latter, through a tubuloglomerular feedback mechanism, contributes to afferent arteriolar vasoconstriction and a decrease in GFR, further worsening the perfusion (discussed below). Injury to the epithelial cells causes detachment of the damaged cells from the basement membranes, and their shedding into the urine. If sufficient tubular debris builds up, it can block the outflow of urine (obstruction by casts), increasing intratubular pressure and thereby exacerbating the decline in GFR. Additionally, fluid from the damaged tubules may leak back into the interstitium, resulting in decreased urine


Pathology_Robbins

Pathology_Robbins. by casts), increasing intratubular pressure and thereby exacerbating the decline in GFR. Additionally, fluid from the damaged tubules may leak back into the interstitium, resulting in decreased urine output, increased interstitial pressure, and collapse of the tubules. Ischemic tubular cells also express chemokines, cytokines, and adhesion molecules such as P-selectin that recruit leukocytes (interstitial inflammation) and can participate in tissue injury. Necrotic tubular cells also may elicit an inflammatory reaction that contributes to the tubular injury and functional derangements.


Pathology_Robbins

Pathology_Robbins. Tubular injury is exacerbated by severe hemodynamic alterations that cause reduced GFR. The major one is intra-renal vasoconstriction, which results in both reduced glomerular plasma flow and reduced oxygen delivery to the tubules in the outer medulla (thick ascending limb and straight segment of the proximal tubule) (see Fig. 14.16 ). Although a number of vasoconstrictor pathways have been implicated in this phenomenon (e.g., renin-angiotensin, thromboxane A2, sympathetic nerve activity), the current opinion is that vasoconstriction is mediated by sublethal endothelial injury, leading to increased release of the endothelial vasoconstrictor endothelin and decreased production of vasodilatory nitric oxide and prostaglandins. Finally, some evidence points to a direct effect of ischemia or toxins on the glomerulus, causing a reduced effective glomerular filtration surface.


Pathology_Robbins

Pathology_Robbins. 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. This repair is dependent on the capacity of reversibly injured epithelial cells to proliferate and differentiate. Fig. 14.16 Postulatedsequenceinischemicortoxictubularinjury. http://ebooksmedicine.net MORPHOLOGYIschemic ATI ischaracterizedbylesionsinthestraightportionsoftheproximaltubuleandtheascendingthicklimbs,butnosegmentoftheproximalordistaltubulesisspared.Thereisoftenavarietyoftubular injuries, includingattenuationofproximaltubularbrushborders,blebbingandsloughingofbrushborders,vacuolizationofcells,anddetachmentoftubularcellsfromtheirunderlyingbasementmembraneswithsloughingofcellsintotheurine(


Pathology_Robbins

Pathology_Robbins. The clinical course of ischemic ATI initially is dominated by the inciting medical, surgical or obstetric event. Affected patients often present with manifestations of acute kidney injury, including oliguria and decreased GFR. Not all patients have oliguria; both anuric and non-oligouric forms are seen. The clinical picture is often dominated by electrolyte abnormalities, acidosis, and the signs and symptoms of uremia and fluid overload. The prognosis varies depending upon the severity and nature of the underlying injury and comorbid conditions. In the absence of supportive treatment or dialysis, patients may die. When the cause of acute kidney injury is ATI, repair and tubular regeneration lead to gradual clinical improvement. With supportive care, patients who survive have a good chance of recovering renal function, but a single severe episode of ATI also may result in chronic kidney disease. In those with preexisting chronic kidney disease, complete recovery is less frequent, and


Pathology_Robbins

Pathology_Robbins. of recovering renal function, but a single severe episode of ATI also may result in chronic kidney disease. In those with preexisting chronic kidney disease, complete recovery is less frequent, and progression to end-stage renal disease is unfortunately common.


Pathology_Robbins

Pathology_Robbins. ATIischaracterizedmorphologicallybyinjuryornecrosisofsegmentsofthetubules(typicallytheproximaltubules),proteinaceouscastsindistaltubules,andinterstitialedema. Nearly all diseases of the kidney affect the renal blood vessels secondarily. Systemic vascular diseases, such as various forms of vasculitis, also involve renal blood vessels, and often produce clinically important effects on renal function (Chapter 10). Conversely, the kidney is intimately involved in the pathogenesis of both essential and secondary hypertension. This section covers the renal lesions associated with hypertension.


Pathology_Robbins

Pathology_Robbins. Nephrosclerosis refers to sclerosis of small renal arteries and arterioles that is strongly associated with hypertension. The characteristic morphologic alterations of the small arterioles are called hyaline arteriolosclerosis, while the arteries show fibrous intimal and medial thickening often resulting in luminal narrowing. The vascular changes cause ischemia, which leads to various combinations of interstitial fibrosis, tubular atrophy, and focal global glomerulosclerosis. Some degree of nephrosclerosis, albeit mild, is present in many individuals older than 60 years of age. The frequency and severity of the lesions are increased at any age when hypertension or diabetes are present. Of note, many renal diseases cause hypertension, which in turn is associated with nephrosclerosis. Thus, this renal lesion often is superimposed on other primary kidney diseases.


Pathology_Robbins

Pathology_Robbins. The arterial lesions associated with hypertension are the result mainly of endothelial dysfunction and platelet activation (Chapter 10). Two processes participate in the arterial lesions of nephrosclerosis: http://ebooksmedicine.net Medial and intimal thickening, as a response to hemodynamic changes, aging, genetic defects, or some combination of these Hyalinization of arteriolar walls, caused by extravasation of plasma proteins through injured endothelium and by increased deposition of basement membrane matrix MORPHOLOGYGrossly,thekidneysaresymmetrically atrophic. Typicallytherenalsurfaceshowsdiffuse,finegranularitythatresemblesgrainleather.Microscopically,themostprominentchangeishyalinethickeningofthewallsofthearterioles,knownashyaline arteriolosclerosis. Thisappearsasahomogeneous,pinkhyalinethickening,attheexpenseofthevessellumina,withlossofunderlyingcellulardetail(


Pathology_Robbins

Pathology_Robbins. Fig.14.18 ).Thenarrowingofthelumenresultsinmarkedlydecreasedbloodflowthroughtheaffectedvessels,withconsequentischemiaandrenalatrophy.Inadvancedcasesofarterionephrosclerosis,theglomerulartuftsmaybecomesclerosed.Diffusetubularatrophyandinterstitialfibrosisarepresent,butinflammatoryinflltratesareabsentorscant.Thelargerbloodvessels(interlobarandarcuatearteries)showintimalthickeningwithreplicationofinternalelasticlaminaalongwithfibrousthickeningofthemedia(fibroelastic hyperplasia). This renal lesion alone rarely causes damage severe enough to produce renal failure, except in individuals from some, possibly genetically susceptible, groups, such as African Americans, in whom it may lead to uremia and death. However, all patients usually show some functional impairment, such as loss of concentrating ability or a variably diminished GFR. A mild degree of proteinuria is a frequent finding.


Pathology_Robbins

Pathology_Robbins. Fig. 14.18 Benignnephrosclerosis.High-powerviewoftwoarterioleswithhyalinedeposition,markedthickeningofthewalls,andanarrowedlumen. (Courtesy of Dr. M.A.Venkatachalam, Department of Pathology, University of Texas Health Sciences Center, San Antonio,Texas.) Malignant hypertension, defined as blood pressure usually greater than 200/120 mm Hg, is far less common in the United States than essential hypertension and occurs in only about 5% of hypertensive individuals. It may arise de novo (i.e., without preexisting hypertension), or it may appear suddenly in an individual who had mild hypertension. 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. The renal changes are related to hypertension and the reactions to it.


Pathology_Robbins

Pathology_Robbins. The renal changes are related to hypertension and the reactions to it. 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 Mitogenic factors from platelets (e.g., platelet-derived growth factor) and plasma cause intimal hyperplasia of vessels, resulting in hyperplastic arteriosclerosis. Because of the luminal narrowing, the kidneys become markedly ischemic, which leads to further elevation of blood pressure via the renin-angiotensin system. MORPHOLOGYThekidneymaybenormalinsizeorshrunken,dependingonthedurationandseverityofthehypertensivedisease.Small,pinpoint petechial hemorrhages mayappearonthecorticalsurfacefromruptureofarteriolesorglomerularcapillaries,givingthekidneyapeculiar,flea-bitten appearance.


Pathology_Robbins


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Pathology_Robbins. The full-blown syndrome of malignant hypertension is characterized by papilledema, encephalopathy, cardiovascular abnormalities, and renal failure. Most often, the early symptoms are related to increased intracranial pressure and include headache, nausea, vomiting, and visual impairment, particularly the development of scotomas, or “spots” before the http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 14.19 Malignanthypertension.(A)Fibrinoidnecrosisofafferentarteriole(periodicacid–Schiffstain).(B)Hyperplasticarteriolosclerosis(onion-skinlesion).(Courtesy of Dr. H. Rennke, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.) eyes. At the onset of rapidly mounting blood pressure, there is marked proteinuria and microscopic, or sometimes macroscopic, hematuria but no significant alteration in renal function. Soon, however, acute kidney injury develops. The syndrome represents a true medical emergency that requires prompt and aggressive anti-hypertensive therapy before irreversible renal lesions develop. About 50% of patients survive at least 5 years; 90% of deaths are caused by uremia, and the other 10% are caused by cerebral hemorrhage or cardiac failure.


Pathology_Robbins

Pathology_Robbins. As discussed in Chapter 10, the term thrombotic microangiopathy (TMA) refers to lesions seen in various clinical syndromes characterized by microvascular thrombosis accompanied by microangiopathic hemolytic anemia, thrombocytopenia, and, in certain instances, renal failure. The primary forms of TMA include those with a known etiology, while the secondary forms develop in the background of other diseases or conditions without well-defined etiology. Common primary forms of TMA include Shiga toxin– mediated hemolytic uremic syndrome (HUS); atypical HUS, also called complement-mediated TMA because excessive complement activation is an important pathogenic mechanism; thrombotic thrombocytopenic purpura (TTP); and some of the drug-mediated TMAs. Malignant hypertension and scleroderma-associated TMA represent examples of the secondary forms.


Pathology_Robbins

Pathology_Robbins. The major pathogenetic factors in the thrombotic microangiopathies are endothelial cell injury and platelet activation and aggregation. They can be caused by diverse insults, including external toxins, drugs, autoantibodies, and inherited mutations, which can lead to excessive small vessel thrombosis in the capillaries and arterioles in various organs. Vascular compromise results in ischemic injury and organ dysfunction. The classic laboratory manifestations of thrombotic microangiopathy are thrombocytopenia caused by excessive platelet consumption, and microangiopathic hemolytic anemia due to mechanical injury (shearing) of red cells as they pass through vascular channels narrowed by thrombi. In the primary forms of thrombotic microangiopathies, the etiology is well-defined (


Pathology_Robbins

Pathology_Robbins. Table 14.4 ), while the secondary forms are associated with various underlying conditions and diseases, such as malignant hypertension, scleroderma, pregnancy, chemotherapy, anti-phospholipid antibodies, and transplant rejection, with less well-defined etiology and pathogenesis. Only the three major forms of primary thrombotic microangiopathies are sufficiently common to merit discusson. Shiga toxin–mediated HUS. As many as 75% of cases follow intestinal infection with Shiga toxin–producing E.


Pathology_Robbins

Pathology_Robbins. Shiga toxin–mediated HUS. As many as 75% of cases follow intestinal infection with Shiga toxin–producing E. coli, such as occurs following ingestion of contaminated ground meat (e.g., in hamburgers) and infections with Shigella dysenteriae type I. The pathogenesis is related to the effects of Shiga toxin. The basis for thrombus formation in small vessels, particularly in the kidney, is complex, but most studies suggest endothelial damage has a central role. Renal glomerular endothelial cells are vulnerable because they express the membrane receptor for Shiga toxin. At low doses, the toxin activates endothelial cells, leading to leukocyte adhesion, Table 14.4 Etiologic Classification of the Major Forms of Primary Thrombotic Microangiopathy ADAMTS13, vonWillebrandfactorcleavingprotease;HUS, hemolyticuremicsyndrome;TMA, thromboticmicroangiopathy;TTP, thromboticthrombocytopenicpurpura.


Pathology_Robbins

Pathology_Robbins. ADAMTS13, vonWillebrandfactorcleavingprotease;HUS, hemolyticuremicsyndrome;TMA, thromboticmicroangiopathy;TTP, thromboticthrombocytopenicpurpura. http://ebooksmedicine.net increased endothelin production and decreased nitric oxide production (both favoring vasoconstriction), as well as other changes that may promote platelet adhesion and activation. At high doses, the toxin causes endothelial cell death. All of these alterations may contribute to the formation of thrombi, which tend to be most prominent in glomerular capillaries, afferent arterioles, and interlobular arteries.


Pathology_Robbins

Pathology_Robbins. Atypical HUS is caused by acquired or hereditary abnormalities of factors that dampen activation of complement by the alternative pathway. Their absence leads to excessive activation of complement, with ensuing microvascular injury and microvascular thrombosis. The C5-9 membrane attack complex appears to have a central role, as a therapeutic antibody that inhibits this complex turns off platelet consumption and improves renal function. Interestingly, abnormalities of the alternative pathway of complement activation also may lead to C3 glomerulonephritis and dense deposit disease, as discussed earlier.


Pathology_Robbins

Pathology_Robbins. TTP is caused by acquired or inherited deficiencies in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin-like motifs), a plasma protease that cleaves von Willebrand factor (vWF) multimers into smaller sizes. Acquired defects in ADAMTS13 are caused by inhibitory autoantibodies directed against ADAMTS13, while inherited deficiencies stem from mutations in the ADAMTS13 gene. Deficiencies of ADAMTS13 result in the formation of abnormally large vWF multimers that activate platelets spontaneously, leading to platelet aggregation and thrombosis in multiple organs, including the kidney.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYThemorphologiclesionsareverysimilarinallformsofTMAregardlessoftheetiology.Thrombiareseeninglomerularcapillariesandalsothearteriolesandsometimesthelargerarteriesinmoreseverecases.Additionalglomerularchangesresultingfromendothelialinjuryincludewideningofthesubendothelialspace,duplicationorsplittingofGBMs,andlysisofmesangialcells.Corticalnecrosisalsomayoccurinseverecases.IfTMApersists,scarringofglomerulimaydevelop.Exceptforvaryingamountsoffibrinogenintheglomeruliandarterioles,immunofluorescencestudiesaretypicallynegative. The clinical course varies according to the etiology and the severity of the morphologic changes. More severe vascular changes are typically associated with a less favorable outcome.


Pathology_Robbins

Pathology_Robbins. The clinical course varies according to the etiology and the severity of the morphologic changes. More severe vascular changes are typically associated with a less favorable outcome. Shiga toxin–associated HUS is characterized by the sudden onset, usually after a gastrointestinal or flulike prodromal episode, of bleeding manifestations (especially hematemesis and melena), severe oliguria, hematuria, microangiopathic hemolytic anemia, and (in some individuals) prominent neurologic changes. This disease is one of the main causes of acute kidney injury in children. If the acute kidney injury is managed properly with dialysis, most patients recover in a matter of weeks. The long-term prognosis (over 15–25 years), however, is not uniformly favorable, as about 25% of affected children eventually develop renal insufficiency.


Pathology_Robbins

Pathology_Robbins. The onset of atypical HUS is usually sudden, without prodromal diarrhea. The outcome is significantly poorer than in Shiga toxin–mediated HUS. The case-fatality ratio is approximately 20%, and only 60% to 70% of patients recover renal function. Plasma exchange can be used to temporarily restore missing factors (in those with inherited disease) or remove pathogenic antibodies. Since most complement factors are produced in the liver, liver transplantation can be curative. More recently, antibody inhibitors of the membrane attack complex have been shown to be effective in reducing thrombosis and improving renal function, and are now considered to be the first-line therapy in “complement-mediated” forms of HUS.


Pathology_Robbins

Pathology_Robbins. The typical onset of TTP is also sudden, with a dominant involvement of the central nervous system, and the kidneys are less commonly involved than in Shiga toxin and atypical HUS. Without therapy, TTP typically follows a rapidly fatal course, with survival rates of approximately 10%. With the advent of plasma exchange therapy that replaces ADAMTS 13, the prognosis has improved dramatically. In those patients who survive, residual renal abnormalities are rare. Arterionephrosclerosis: Progressive,chronicrenaldamageassociatedwithhypertension.Characteristicfeaturesarehyalinearteriolosclerosisandnarrowingofvascularluminawithresultantcorticalatrophy. Malignant hypertension: Acutekidneyinjuryassociatedwithsevereelevationofbloodpressure.Arteriesandarteriolesshowfibrinoidnecrosisandhyperplasiaofsmoothmusclecells;petechialhemorrhagesappearonthecorticalsurface.


Pathology_Robbins

Pathology_Robbins. Thrombotic microangiopathies: Disorderscharacterizedbyfibrinthrombiinglomeruliandsmallvesselsresultinginacutekidneyinjury.TypicalHUSisusuallycausedbyendothelialinjurybyanE. coli toxin;TTPisoftencausedbyabnormalitiesinvonWillebrandfactorleadingtoexcessivethrombosis,withplateletconsumption.ThemostcommoncauseofatypicalHUSiscomplement-mediatedendothelialinjuryduetocomplementdysregulation. Chronic kidney disease is a broad term that describes the final common pathway of progressive nephron loss resulting from any type of kidney disease. Alterations in the function of remaining intact nephrons are ultimately maladaptive and cause further scarring. This eventually results in an end-stage kidney with sclerosed glomeruli, tubules, interstitium and vessels, regardless of the anatomic site of the original injury. Unless the disorder is treated with dialysis or transplantation, death from uremia, electrolyte disturbances, or other complications of end-stage renal disease results.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net As progressive renal damage destroys more and more nephrons, adaptive mechanisms are initated that try to maintain renal function. Among such adaptive mechanisms, glomerular hyperfiltration tends to compensate for decreased glomerular filtration rate resulting from the loss of nephrons. An increase in the rate of excretion of solutes per nephron via increased plasma concentrations (for creatinine), decreased tubular reabsorption (for sodium, phosphate, and calcium), or increased tubular secretion (for potassium and hydrogen ions) helps to maintain homeostasis until the late stages of chronic kidney disease. The rate of functional decline varies based on the original disease; however, renal function often deteriorates progressively even when the original insult is controlled. Uncontrolled hypertension, regardless of the etiology, results in more rapid renal functional decline.


Pathology_Robbins

Pathology_Robbins. Chronic kidney disease may develop insidiously and be discovered late in its course, because it is often asymptomatic. Frequently, renal disease is first detected by the discovery of proteinuria, hypertension, or azotemia on routine medical examination. Disease-specific findings may precede development of chronic kidney disease. In patients with glomerular disease resulting in nephrotic syndrome, as the glomeruli undergo sclerotic changes and result in nephron loss, the avenue for protein loss is progressively lessened, and the nephrotic syndrome thus becomes less severe with advanced disease. Some degree of proteinuria, however, is present in almost all cases. Hypertension is very common. Although microscopic hematuria is usually present, grossly bloody urine is infrequent at this late stage. Without treatment, the prognosis is poor; relentless progression to uremia and death is the rule. The rate of progression is extremely variable.


Pathology_Robbins

Pathology_Robbins. Without treatment, the prognosis is poor; relentless progression to uremia and death is the rule. The rate of progression is extremely variable. Fig. 14.20 Chronicglomerulonephritis.AMassontrichromepreparationshowscompletereplacementofvirtuallyallglomerulibyblue-stainingcollagen.(Courtesy of Dr. M.A. Venkatachalam, Department of Pathology, University of Texas Health Sciences Center,San Antonio,Texas.) Cystic diseases of the kidney are a heterogeneous group comprising hereditary, developmental, and acquired disorders. They often present diagnostic problems for clinicians, radiologists, and pathologists and can occasionally be confused with malignant tumors. Some forms, such as adult polycystic disease, constitute major causes of chronic kidney disease.


Pathology_Robbins

Pathology_Robbins. An emerging theme in the pathophysiology of the hereditary cystic diseases is that the underlying defect is in the cilia-centrosome complex of tubular epithelial cells. Such defects may interfere with fluid absorption or cellular maturation, resulting in cyst formation. A brief overview of simple cysts, the most common form, is presented next, followed by a more detailed discussion of polycystic kidney disease. Renal dysplasia, the most common form of cystic renal disease in childhood, is discussed under congenital and developmental anomalies later in the chapter.


Pathology_Robbins

Pathology_Robbins. Simple cysts are generally innocuous lesions that occur as multiple or single cystic spaces of variable size. Commonly, they are 1 to 5 cm in diameter; translucent; lined by a gray, glistening, smooth membrane; and filled with clear fluid. On microscopic examination, these membranes are seen to be composed of a single layer of cuboidal or flattened cuboidal epithelium, which in many instances may be completely atrophic. The cysts usually are confined to the cortex. Rarely, massive cysts as large as 10 cm in diameter are encountered. Simple cysts are a common postmortem finding that has no clinical significance. The main importance of cysts lies in their differentiation from kidney tumors, when they are discovered either incidentally or during evaluation of hemorrhage and pain. Radiographic studies show that in contrast with renal tumors, renal cysts have smooth contours, are almost always avascular, and produce fluid rather than solid tissue signals on ultrasonography.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Acquired cystic kidney disease occurs in patients with end-stage renal disease who have undergone dialysis for many years. Multiple cysts may be present in both the cortex and the medulla and may bleed, causing hematuria. The risk for renal neoplasms, particularly cystic ones, in this setting is over 100 times greater than in the general population. Adult polycystic kidney disease is characterized by multiple expanding cysts affecting both kidneys that ultimately destroy the intervening parenchyma. It is seen in approximately 1 in 500 to 1000 individuals and accounts for 10% of cases of chronic kidney disease. This disease is genetically heterogeneous. It can be caused by inheritance of one of at least two autosomal dominant genes of very high penetrance.


Pathology_Robbins

Pathology_Robbins. In 85% to 90% of families, PKD1, on the short arm of chromosome 16, is the defective gene. This gene encodes a large (460-kDa) and complex cell membrane–associated protein called polycystin-1. The polycystin-1 protein has a large extracelluar domain and multiple transmembrane regions. The extracellular domains have regions that can bind to extracellular matrix. Polycystin-1 localizes to the primary cilium of tubular cells (as do nephrocystins linked to medullary cystic disease, discussed later), giving rise to the concept of renal cystic diseases as a type of ciliopathy. Cilia are hairlike organelles that project into the lumina from the apical surface of tubular cells, where they serve as mechanosensors of fluid flow. Current evidence suggests that polycystin mutations produce defects in mechanosensing (


Pathology_Robbins

Pathology_Robbins. Fig. 14.21 ). This, in turn, alters downstream signaling events involving calcium influx, leading to dysregulation of cell polarity, proliferation, and cell–cell and cell–matrix adhesion. The increase in intracellular calcium is thought to stimulate proliferation and secretion from the tubular epithelial cells, which together lead to the formation of cysts, which progressively enlarge over time. Mediators in cyst fluid derived from the epithelial cells can further enhance fluid secretion and induce inflammation. In addition, the calcium-induced signals alter the interaction of epithelial cells with extracellular matrix, and this too is thought to contribute to the cyst formation and interstitial fibrosis that are characteristic of progressive polycystic kidney disease. It is interesting to note that whereas germ-line mutations of the PKD1 gene are present in all renal tubular cells of affected individuals, cysts develop in only some tubules. This is most likely due to loss of both


Pathology_Robbins

Pathology_Robbins. to note that whereas germ-line mutations of the PKD1 gene are present in all renal tubular cells of affected individuals, cysts develop in only some tubules. This is most likely due to loss of both alleles of PKD1. Thus, as with tumor suppressor genes, a second “somatic hit” is required for cyst development.


Pathology_Robbins

Pathology_Robbins. The PKD2 gene, implicated in 10% to 15% of cases, resides on chromosome 4 and encodes polycystin-2, a smaller, 110-kDa protein. Polycystin-2 is thought to function as a calcium-permeable membrane channel, and is also localized to cilia. Although structurally distinct, polycystins 1 and 2 are believed to act together by forming heterodimers. Thus, mutation in either gene gives rise to essentially the same phenotype, although patients with Mutations in polycystin 1, 2 or fibrocystin or nephrocystins Altered mechanosensation by tubular cilia Altered calcium flux Altered tubular epithelial growth and differentiation Fig. 14.21 Possiblemechanismsofcystformationincystickidneydiseases(seetext). Glomerular, PKD2 mutations have a slower rate of disease progression compared to patients with PKD1 mutations.


Pathology_Robbins

Pathology_Robbins. Fig. 14.21 Possiblemechanismsofcystformationincystickidneydiseases(seetext). Glomerular, PKD2 mutations have a slower rate of disease progression compared to patients with PKD1 mutations. MORPHOLOGYInautosomaldominantadultpolycystickidneydisease,thekidneymayreachenormoussize;weightsofupto4kgforeachkidneyhavebeenrecorded.Theseverylargekidneysarereadilypalpableabdominallyasmassesextendingintothepelvis.Ongrossexamination,thekidneyseemstobecomposedsolelyofcystsofupto3or4cmindiameterwithnointerveningparenchyma.Thecystsarefilledwithfluid,whichmaybeclear,turbid,orhemorrhagic( Fig.14.22


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Polycystic kidney disease in adults usually does not produce symptoms until the fourth decade of life, by which time the kidneys are quite large. The most common presenting complaint is flank pain or a heavy, dragging sensation. Acute distention of a cyst, either by intracystic hemorrhage or by obstruction, may cause excruciating pain. Sometimes attention is first drawn to the lesion on palpation of an abdominal mass. Intermittent gross hematuria commonly occurs. The most important complications, because of their deleterious effect on already marginal renal function, are hypertension and urinary infection. Hypertension of variable severity develops in about 75% of individuals with this http://ebooksmedicine.net Fig. 14.22 Autosomaldominantadultpolycystickidney,viewedfromtheexternalsurface(A)andbisected(B).Thekidneyismarkedlyenlarged(centimeter ruleisshownforscale),withnumerousdilatedcysts.


Pathology_Robbins

Pathology_Robbins. Fig. 14.22 Autosomaldominantadultpolycystickidney,viewedfromtheexternalsurface(A)andbisected(B).Thekidneyismarkedlyenlarged(centimeter ruleisshownforscale),withnumerousdilatedcysts. disorder. Saccular aneurysms of the circle of Willis (Chapter 23) are present in 10% to 30% of patients and are associated with a high incidence of subarachnoid hemorrhage. Although the disease is ultimately fatal, the outlook is generally more favorable than with most chronic kidney diseases. The condition progresses very slowly. End-stage renal disease occurs at about 50 years of age, but there is wide variation in the course, and nearly normal life spans are reported. Patients in whom the disease progresses to renal failure are treated by renal transplantation. Death usually results from uremia or hypertensive complications.


Pathology_Robbins

Pathology_Robbins. The childhood form of polycystic kidney disease is a rare autosomal recessive disorder that is genetically distinct from adult polycystic kidney disease. It occurs in approximately 1 in 20,000 live births. Perinatal, neonatal, infantile, and juvenile subcategories have been defined, depending on age at presentation and the presence of associated hepatic lesions. All types result from mutations in the PKHD1 gene, coding for a putative membrane receptor protein called fibrocystin. Fibrocystin is found in cilia in tubular epithelial cells, but its function remains unknown.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYInautosomalrecessivepolycystickidneydisease,numerous small cysts inthecortexandmedullagivethekidneyasponge-likeappearance.Dilated,elongatedchannelsatrightanglestothecorticalsurfacecompletelyreplacethemedullaandcortex.Thecystshaveauniformliningofcuboidalcells,reflectingtheiroriginfromthecollectingtubules.Thediseaseisinvariablybilateral.Inalmostallcases,findingsincludemultipleepithelium-linedliver cysts andproliferationofportalbileducts. Perinatal and neonatal forms are most common; serious manifestations usually are present at birth, and young infants may die quickly from hepatic or renal failure. Patients who survive infancy develop liver cirrhosis (congenital hepatic fibrosis).