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Kidney non tumor

Superpage - Part 2

Revised: 10 January 2013
Copyright: (c) 2001-2013, PathologyOutlines.com, Inc.

Associated with systemic conditions

Amyloidosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 5 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Group of conditions with extracellular deposition of fibrillar proteins having an anti-parallel, beta-pleated sheet tertiary structure, leading to Congo Red staining and apple-green birefringence under polarized light
● Amyloid is composed of a fibrillary protein (types described below) and non-fibrillary glycoproteins (amyloid P component also called serum amyloid P [SAP], glycosaminoglycans and apolipoprotein E)
● Serum amyloid P may contribute to stability of amyloid deposits; radioactive iodine-labeled SAP is used in nuclear medicine studies to assess amyloid deposition
● Irrespective of molecular composition, amyloid always has the same characteristic histologic and ultrastructural appearance
● Amyloid is resistant to digestion, accumulates within tissue, interferes with function and destroys vital organs

Clinical features
=========================================================================

● Renal amyloidosis causes 5% of adult cases of nephrotic syndrome
● Suggestive of renal amyloidosis (Chinese study): middle-age, nephrotic syndrome, weight loss, organ enlargement, monoclonal light chains in serum or urine (Clin Lab 2011;57:947)
● Systemic or localized
● Duodenal biopsy is sensitive for diagnosing amyloidosis in chronic kidney disease patients, and highly correlates with renal amyloidosi (Clin Nephrol 2012;77:114)
● Can determine specific type based on immunohistochemistry / immunofluoresence; also laser microdissection and mass spectrometry (Kidney Int 2012;82:226)

AL type:
● Also called primary amyloidosis
● Most common cause of renal amyloidosis in US
● Due to plasma cell dyscrasias with systemic deposition of amyloid and mild increase in bone marrow plasma cells that are monoclonal
● 20% have myeloma or other lymphoproliferative disorders
● Deposits are more likely lambda (75%) light chains or fragments than kappa type, often from amino-terminal fragment of variable region of light chain
● Either vascular-limited or diffuse patterns (Nephrol Dial Transplant 2012;27:1097)
● 40% develop nephrotic syndrome
● Urinary exosomes may be useful to identify patients with AL amyloidosis (PLoS One 2012;7:e38061)
● Poor prognosis (Intern Med 2011;50:2511); patients may develop acute leukemia after alkylating agents, secondary malignancies after autologous transplantation

AA type:
● Also called secondary amyloidosis
● Associated with chronic inflammatory conditions such as osteomyelitis, bronchiectasis, decubitus ulcers, Crohn’s disease, rheumatoid arthritis, tuberculosis (Swiss Med Wkly 2012 May 31;142:w13580)
● Main amyloid component is protein A, derived from proteolytic cleavage of serum amyloid A protein, an acute phase reactant
● 90% have renal insufficiency or nephrotic syndrome at diagnosis
● Renal function is associated with amount of amyloid deposition (Rheumatol Int 2011 Sep 27 [Epub ahead of print])>
● Treatment: treat the underlying inflammatory condition

Beta 2 microglobulin type:
● Associated with long-term hemodialysis or peritoneal dialysis; also renal failure between treatments; increases with duration of dialysis
● Amyloid protein composed of intact and modified beta 2 microglobulin, an integral part of HLA class I antigen complex, that is usually eliminated by the kidney
● Amyloid deposits occur in blood vessel walls, perineural and periarterial tissue, bone, joint, skin, subcutaneous tissue, heart, GI and lungs
● May cause carpal tunnel syndrome, joint disease and bone cysts

ATTR type:
● Amyloid fibrils consist of transthyretin (Clin J Am Soc Nephrol 2012;7:1337)
● Associated with familial amyloidosis

Familial Mediterranean fever:
● Autosomal recessive, deposits consist of AA amyloid (Yonsei Med J 2012;53:454)

AH type:
● Due to heavy chains
● Very rare (predominantly lambda)

Case reports
=========================================================================

● 57 year old man with amyloid fibrils 3x usual size (Hum Pathol 1990;21:868)
● 59 year old man with IgM heavy chain amyloidosis (Am J Surg Pathol 2003;27:541)
● Patient developing lambda light chain deposition disease (treated with autologous peripheral blood stem cell transplant) and later IgG heavy chain amyloidosis (Am J Surg Pathol 2003;27:1477)
● Bilateral buttock tumors of beta 2 microglobulin after long term hemodialysis (Arch Pathol Lab Med 1994;118:651)
● AA-amyloid like deposits but fibrils twice the usual size (Arch Pathol Lab Med 1992;116:261)

Gross images
=========================================================================


   
Pale amyloid deposits in enlarged kidney

Micro description
=========================================================================

● Salmon orange amorphous, fluffy, extracellular deposits in mesangium and subendothelium that obliterate glomeruli
● Also deposits in blood vessel walls, interstitium and around tubules
● Also mast cells that lead to interstitial fibrosis in AA type (Mod Pathol 2000;13:1020 (mast cells and interstitial fibrosis))
● Proposed histopathologic classification system: Arch Pathol Lab Med 2010;134:532
● 10% of AL patients lack glomerular deposits
● Glomerular cell proliferations are uncommon

Micro images
=========================================================================


       

           

               
Various images

   
Patient with Amyloid AA due to hidradenitis suppurativa (H&E, PAS, Congo Red)


Patient with familial Mediterranean fever

       
Congo Red and amyloid immunostains


Interstitial mast cells accumulate around amyloid deposits

Virtual slides
=========================================================================



Amyloidosis

Positive stains
=========================================================================

● Congo Red: causes apple-green birefringence on polarization microscopy; staining lost in AA amyloidosis if pretreated with potassium permanganate
● Silver stain: may show spiking along glomerular capillary loops
● PAS: weak staining
● Thioflavine T: fluoresces; may be positive for anti-AA antibodies, light chain restriction

Electron microscopy description
=========================================================================

● 7.5-10 nm in diameter fibrils with randomly dispersed, non-branching arrangement in mesangium and subendothelium

Electron microscopy images
=========================================================================



10 nm haphazard fibrils


Mast cell (MC) within extracellular matrix of renal interstitial containing collagen fibers (C) and amyloid fibrils (A); inset-mast cells stained with anti-chymase

Differential diagnosis
=========================================================================

Fibrillary glomerulonephritis: fibrils are 15-30 nm, negative amyloid stains
Diabetic glomerulosclerosis: no deposits, intense silver staining
Immunotactoid glomerulonephritis: microtubules, 20–50nm



Associated with systemic conditions

Bone marrow transplant nephropathy


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 5 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● May be due to total body irradiation (similar to radiation nephropathy, (eMedicine), although controversial if total body irradiation is risk factor for renal dysfunction (Radiother Oncol 2009;90:242)
● Delayed renal insufficiency (occurs in 20%), hypertension and anemia out of proportion to azotemia; possibly hemolytic uremic syndrome
● May have a long latency period between exposure to radiation and the development of radiation nephritis
● Treatment with angiotensin-converting enzyme inhibitor may be useful (Clin Exp Nephrol 2006;10:78)

Treatment
=========================================================================

● Supportive therapy

Case reports
=========================================================================

● 27 year old man with renal impairment after bone marrow transplant for CML (Arch Pathol Lab Med 2004;128:233)

Micro description
=========================================================================

Early changes: related to acute tubular necrosis, infection, nephrotoxic drugs, graft versus host disease, tumor lysis syndrome, marrow infusion toxicity, hepatic venoocclusive disease or interstitial nephritis
Late changes (3 months after bone marrow transplant): prominent mesangiolysis, focal aneurysmal capillary dilation and variable increase in mesangial matrix; also swollen endothelial cells, widened subendothelial space, duplicated (double contour) glomerular basement membrane and focal fibrin thrombi within glomerular capillaries

Micro images
=========================================================================


   
Left: mesangiolysis and extreme widening between endothelium and glomerular basement membrane; right: hypocellular glomerulus, increased mesangial matrix


Nephropathy due to chemotherapy, not radiation therapy:
Figure 1: accentuation of glomerular lobules, narrowed capillary lumens, focal aneurysmal capillary dilation
Figure 2: prominent mesangiolysis and extreme widening of space between endothelium and glomerular basement membrane giving double-contour appearance (PAS-silver stain)
Figure 3: endothelial cell injury with separation of endothelial lining from basement membrane due to greatly expanded subendothelial space (arrowheads)


Immunofluorescence
=========================================================================

● Fibrin, IgM

Electron microscopy description
=========================================================================

● Endothelial injury with widened subendothelial space filled with loose, amorphous, granular material (fibrin) and new basement membrane material
● Variable red blood cell fragments

Electron microscopy images
=========================================================================



Extreme widening, endothelial swelling and irregularity, and no immune deposits

Differential diagnosis
=========================================================================

Hemolytic uremic syndrome



Associated with systemic conditions

Cryoglobulinemia


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 15 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Usually systemic disease in which deposits of IgG or IgM immune complexes cause glomerulonephritis (focal, diffuse), cutaneous vasculitis (skin rash) and synovitis (arthritis)
● Defined by presence of serum cryoglobulins, which are immunoglobulin complexes that precipitate at 4°C and become soluble again at 30°C
Type I: cryoglobulin is single monoclonal immunoglobulin class, usually due to myeloma, Waldenström macroglobulinemia or other lymphoma
Type II: mixture of 2+ immunoglobulins, one a monoclonal antibody against polyclonal IgG; usually IgG-IgM, in which IgM is monoclonal and has rheumatoid factor activity
Type III: both immunoglobulin components are usually polyclonal IgG and IgM

Clinical features
=========================================================================

● Symptoms of fatigue, purpura over lower extremities, arthralgias, hepatosplenomegaly, lymphadenopathy, Raynaud’s phenomenon, glomerulonephritis in 50% with proteinuria and hypertension, progressing to renal failure in 5%
● Usually women ages 30+ years
● Hepatitis C virus is major cause of mixed cryoglobulinemia
● Renal disease unrelated to Hepatitis C is often related to primary Sjögren Syndrome (Medicine (Baltimore) 2009;88:341)
● Cryoglobulinemia found in 83% of chronic hemodialysis patients, although not necessarily symptomatic (Ren Fail 2011;33:801)
● Types II and III associated with B cell lymphoma, chronic infection, chronic liver disease, SLE and hepatitis C

Case reports
=========================================================================

● 7 year old boy with glomerular rhomboid inclusions (Am J Kidney Dis 2009;53:866)
● 55 year old man with Hepatitis C (J Med Case Rep 2009;3:91.)
● 58 year old woman with ultrastructural diagnosis of cryoglobulinemic glomerulonephritis (Arch Pathol Lab Med 1981;105:474)
● 60 year old man with Hepatitis B virus associated type II cryoglobulinemia and severe multisystem disease, treated with Rituximab (J Med Case Rep 2012;6:39)
● 81 year old man with essential type II cryoglobulinemia unrelated to Hepatitis virus (Geriatr Gerontol Int 2009;9:92)

Treatment
=========================================================================

● Double filtration plasmapheresis; cryofiltration (Ther Apher Dial 2012;16:91)
● Possibly interferon for Hepatitis C related cases (Ren Fail 2009;31:149)
● Possibly Rituximab in nonviral patients age 70 years or less (Arthritis Care Res (Hoboken) 2010;62:1787, Autoimmun Rev 2011;11:48)

Micro description
=========================================================================

● Expanded mesangium with thickened capillaries
● Diffuse proliferative glomerulonephritis, often with membranoproliferative pattern
● Also focal and segmental glomerulonephritis and less often crescentic or membranous glomerulonephritis
● Acutely may produce wire loops or thrombi seen in lupus nephritis, vasculitis of interlobular arteries and afferent arterioles

Micro images
=========================================================================


               
Cryoglobulin-related glomerulonephritis-various images


With hepatitis C associated cryoglobulinemia


Chronic lymphocytic leukemia and cryoglobulinemic glomerulonephritis

Immunofluorescence
=========================================================================

● Immunoglobulins, strong C3; also C1q and C4

Immunofluorescence images
=========================================================================



Globular accumulations of cryoglobulin in the capillary lumens

Electron microscopy description
=========================================================================

● Large amounts of subendothelial immune complex deposits; lesser amounts of subendothelial deposits
● 50% have glomerular deposits with 25-35 nm microtubules forming bundles or arranged in fingerprint-like array

Electron microscopy images
=========================================================================


       
Various images

Differential diagnosis
=========================================================================

Fibrillary glomerulonephritis: 15-30 nm fibrils
Immunotactoid glomerulopathy



Associated with systemic conditions

Diabetic glomerulosclerosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 15 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Diffuse capillary basement membrane thickening, diffuse and nodular glomerulosclerosis
● Causes glomerular disease, arteriolar sclerosis, pyelonephritis, papillary necrosis; similar between type I and II patients
● Accounts for 30% of long term dialysis patients in US; causes 20% of deaths in patients with diabetes < age 40
● Changes may be related to nephronectin, which functions in the assembly of extracellular matrix (Nephrol Dial Transplant 2012;27:1889)

Clinical features
=========================================================================

● Proteinuria occurs in 50%, usually 12-22 years after onset of diabetes
● End stage renal disease occurs in 30% of type I patients
● Early increased GFR and microalbuminemia (30-300 mg/day) are predictive of future diabetic nephropathy
● Renal disease reduced by tight diabetic control; may recur with renal allografts; ACE inhibitors may reduce progression

Case reports
=========================================================================

● Five patients with acute post-staphylococcal glomerulonephritis complicating diabetic nephropathy, with IgA deposition in glomeruli (Hum Pathol 2003;34:1235)
● Insudative hyaline cap lesions (Hum Pathol 1989;20:388)

Micro description
=========================================================================

● Basement membrane thickening and increased mesangial matrix in ALL patients
● Diffuse glomerulosclerosis: increase in mesangial matrix associated with PAS+ basement membrane thickening, eventually obliterates mesangial cells
● Nodular glomerulosclerosis: also called intercapillary glomerulosclerosis or Kimmelstiel-Wilson disease; ovoid, spherical, laminated hyaline masses in peripheral of glomerulus, PAS+, eventually obliterates glomerular tuft; specific for diabetes and membranoproliferative glomerulonephritis, light-chain disease and amyloidosis (Hum Pathol 1993;24:77 (pathogenesis of Kimmelstiel-Wilson nodule))
● Profound hyalinization of afferent arterioles (insudative lesion-intramural): specific for diabetes in afferent arterioles, but non-specific if in periphery of glomerular loop, Bowman’s capsule or mesangium; insudative material composed of proteins, lipids and mucopolysaccharides
● Organizing fibroepithelial crescents: associated with aggressive clinical course
● Diffuse thickening of tubular basement membrane, tubular atrophy and interstitial fibrosis
● Isolated thickened glomerular basement membrane and proteinuria may be an early predictor of diabetic disease (Mod Pathol 2004;17:1506)

Micro images
=========================================================================


           

           

           


Various images

Immunofluorescence
=========================================================================

● Diffuse linear staining for IgG along capillary walls
● Also IgM, IgA and albumin (considered to be non-specific trapping of plasma proteins due to basement membrane or mesangial dysfunction)

Electron microscopy description
=========================================================================

● Diffuse thickening of basement membranes; increased mesangial matrix

Electron microscopy images
=========================================================================



Thick glomerular capillary basement membrane, uniform and homogenous

Differential diagnosis
=========================================================================

Amyloidosis
Cryoglobulinemia
Fibrillary glomerulonephritis
Immunotactoid glomerulonephritis



Associated with systemic conditions

Heavy chain deposition disease


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 27 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Lymphoplasmacytic neoplasm that produces an abnormally truncated immunoglobulin heavy-chain protein that lacks associated light chains (eMedicine)
● Less common than light chain deposition disease
● May have milder hematological disorders than in light chain deposition disease (Clin Nephrol 2009;71:9)
● Associated with various lymphoproliferative disorders, but usually has features overlapping with cases previously reported as "vaguely nodular, polymorphous" lymphoplasmacytic lymphoma (Am J Surg Pathol 2012;36:534)

Case reports
=========================================================================

● 51 year old man with linear deposits of gamma 4 heavy chains along glomerular, tubular and vascular basement membrane and in mesangial regions (Mod Pathol 1994;7:874)
● 68 year old woman with gamma 1 heavy chain disease (Intern Med 2010;49:1411)
● Monotypic mu heavy chain mesangial deposits causing nodular glomerulosclerosis in woman without evident hematopoietic malignancy (Hum Pathol 2000;31:122)
● Follow up biopsy post-chemotherapy showed remarkable diminution of both nodular glomerular lesions and IgG heavy-chain deposits (Clin Nephrol 2008;69:383)

Micro images
=========================================================================


       
Various images

Immunofluorescence
=========================================================================

● IgG heavy chains along glomerular, tubular and vascular basement membranes and in mesangium
● No light chain deposition

Electron microscopy images
=========================================================================



Subendothelial electron-dense deposits and mesangial expansion



Associated with systemic conditions

Henoch-Schonlein purpura


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 20 September 2012, last major update July 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.
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General
=========================================================================

● Purpuric skin lesions on extensor arms and legs and buttocks
● Also abdominal pain, vomiting, GI bleeding, arthralgias, hematuria, proteinuria and nephrotic syndrome
● Due to systemic small vessel leukocytoclastic vasculitis
● Most common systemic vasculitis in children
● Also called anaphylactoid purpura

Clinical features
=========================================================================

● Significant clinicopathological differences with IgA nephropathy (Zhongguo Dang Dai Er Ke Za Zhi 2012;14:506
● Renal symptoms in 30-70%; some adults develop rapidly progressive glomerulonephritis
● 70% are ages 2-11 years; rare in adults or infants 1 year or less
● Higher rate of renal involvement in children ages 10-18 (Iran J Kidney Dis 2012;6:269)
● Associated with atopy in 1/3; may follow respiratory infection
● Related to IgA nephropathy, due to elevated serum IgA, circulating immune complexes with IgA, similar kidney lesions (Arch Pathol Lab Med 1982;106:192), high serum galactose-deficient immunoglobulin A1 levels (Kidney Int 2011;80:79)
● Hypertension, serum creatinine, proteinuria, cellular crescents, glomerular necrotizing lesions and chronic renal lesions are associated with renal failure (Mod Pathol 2001;14:635)
● Variable recurrence rates (12-69%) after renal transplant, but usually not clinically important (Transplantation 2011;92:907, Clin J Am Soc Nephrol 2011;6:1768, Clin J Am Soc Nephrol 2011;6:2034)
Prognosis: excellent in children (50% have spontaneous remission); poorer in adults (Clin Nephrol 2011;76:49) or with nephrotic syndrome; often difficult to predict (Clin J Am Soc Nephrol 2011;6:679)

Case reports
=========================================================================

● 15 year old girl with prior onset of IgA nephropathy (Fukushima J Med Sci 2010;56:157)
● 72 year old man with coexisting IgG4-related tubulointerstitial nephritis (Allergy Asthma Clin Immunol 2011;7:5)
● 75 year old man with rectal bleeding and acute renal injury (J Med Case Rep 2011;5:364)

Treatment
=========================================================================

● Recommended to administer intensive therapy initially (Indian J Pediatr 2012;79:207)
● Corticosteroids, cytotoxic drugs
● Mycophenolate mofetil for children with nephrotic-range proteinuria (Pediatr Nephrol 2012;27:765)

Micro description
=========================================================================

Acute:
● Leukocytoclastic vasculitis of small vessels due to deposition of IgA immune complexes
● Diffuse proliferation of mesangial cells and matrix without significant involvement of capillary walls or lumina
● Also segmental necrotizing lesions (50%), endocapillary proliferation (13%), cellular crescents, glomerular acute and chronic inflammatory infiltrate

Chronic:
● Glomerular sclerosis, tubular loss, interstitial fibrosis and hyaline arteriolosclerosis

Skin:
● Hemorrhage and necrotizing vasculitis in dermal small vessels, which contain IgA
● Vasculitis is present in other organs but usually NOT kidney

Micro images
=========================================================================


                   
Various images

               
Silver stain

Immunofluorescence
=========================================================================

● IgA deposition in mesangium, resembling IgA nephropathy
● Variable IgG, IgM, C3 and properdin

Immunofluorescence images
=========================================================================


   
Henoch-Schönlein purpura nephritis

Electron microscopy description
=========================================================================

● Mesangial deposits, may extend into subendothelial areas
● May have subepithelial deposits



Associated with systemic conditions

Hemolytic uremia syndrome / thrombotic thrombocytopenic purpura (HUS/TTP)


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update November 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Thrombosis in capillaries and arterioles throughout the body, microangiopathic hemolytic anemia, thrombocytopenia, renal failure with platelet-fibrin thrombi in interlobular renal arteries and glomeruli, necrosis and thickening of vessel walls
● Morphologic changes resemble malignant hypertension, but usually no pre-existing hypertension
● HUS and TTP are usually considered part of clinical spectrum, in which disease manifestations depend on distribution of microangiopathy (but see Arch Pathol Lab Med 2003;127:834)
HUS: fibrin / red cell rich thrombi, largely confined to kidney and often severe; usually no pancreas, adrenal gland, brain or heart involvement
● Atypical HUS: due to excessive complement activation in microvasculature; inherited and acquired abnormalities affecting components of the alternative complement pathway are found in 60% (Hematology Am Soc Hematol Educ Program 2011;2011:15)
TTP: platelet rich thrombi in myocardial arteries; also pancreas, kidney, adrenal gland or brain; usually no permanent kidney damage
Pathophysiology: endothelial injury by toxins (certain strains of E. coli 0157:H7 producing shiga-like toxin, Hum Pathol 1988;19:1102)) or antibodies and activation cause intravascular thrombosis and platelet aggregation, which causes vascular obstruction and vasoconstriction, affects predominantly the renal vessels; TTP occurs due to enhanced platelet aggregation, e.g., metalloproteinase activity causing abnormal vWF-cleavage

Childhood HUS
=========================================================================

● 75% of cases occur after shiga-toxin producing E coli O157:H7 infection (also called verocytotoxin because it damages Vero cells in culture)
● Main cause of childhood acute renal failure
● Usually infants and young children, may occur at any age
Symptoms: sudden onset of influenza, bleeding (hematemesis or melena), severe oliguria, hematuria, microangiopathic hemolytic anemia, neurologic changes in 1/3 and hypertension in 50%
Pathogenesis: related to Shiga-like toxin, which promotes adhesion of white blood cells to endothelium; also increases endothelin and decreases nitrous oxide production, causing vasoconstriction

Adult HUS/TTP
=========================================================================

● Poor prognosis with high mortality due to CNS disease or uncontrollable bleeding; survivors develop chronic renal failure
Causes: typhoid fever, E. coli (enterohemorrhagic strains), viral infections, shigellosis, antiphospholipid syndrome (primary or secondary to SLE), postpartum or after placental hemorrhage, vascular renal diseases such as scleroderma or malignant hypertension, drugs (mitomycin C, cyclosporine, bleomycin, cisplatin) and various malignancies
● Lupus patients may have more severe disease (Am J Med Sci 2009;338:343, Nephron Clin Pract 2009;112:c177)

Idiopathic HUS/TTP
=========================================================================

● More common in women age 40 years or less; mortality 50%
Symptoms: CNS involvement dominant (fever, neurologic symptoms), hemolytic anemia, thrombotic thrombocytopenic purpura and renal involvement in only 50% (thrombi in glomerular capillaries and afferent arterioles)

Case reports
=========================================================================

● 17 year old girl with TTP and ANCA-associated vasculitis (Pediatr Nephrol 2011;26:1317)
● 18 year old man with C1q nephropathy with acute HUS (Saudi J Kidney Dis Transpl 2012;23:556)
● 23 year old man with TTP-HUS and post-ERCP pancreatitis (Eur J Gastroenterol Hepatol 2011;23:825)
● 32 year old pregnant woman with renal grant, acute T-cell-mediated rejection and TTP (Clin Transplant 2010;24 Suppl 22:66)
● 39 year old man with resistant TTP that presented with concomitant severe rhabdomyolysis (Int J Gen Med 2011;4:687)
● 48 year old woman presenting with myocardial infarction (J Cardiovasc Dis Res 2012;3:167)
● Association with mitomycin in four patients (Arch Pathol Lab Med 1984;108:959)
● Death due to diffuse myocardial necrosis (Arch Pathol Lab Med 1999;123:937)

Treatment
=========================================================================

● HUS: supportive therapy (Am J Kidney Dis 2009;53:259)
● TTP: plasmapharesis, steroids; possibly Rituximab (anti-CD20) or Eculizumab (anti-C5) in severe cases (Dtsch Med Wochenschr 2010;135:71, Hong Kong Med J 2009;15:201, Am J Kidney Dis 2012;59:707)
● TTP relapse occurs in 36%, death in 4% (Transfusion 2010;50:868)

Gross description
=========================================================================

● Patchy or diffuse renal cortical necrosis

Micro description
=========================================================================

Early:
● Fibrin deposits in capillary lumina
● Fibrinoid necrosis of larger vessels, thrombosis and endothelial cell proliferation in small arteries and arterioles
● Ischemic changes in glomeruli with endothelial swelling and capillary luminal narrowing
● Expanded mesangial thrombi appear red on trichrome stain, thrombi are not essential for a pathologic diagnosis

Later:
● Intense basophilic thickening in small arteries and arterioles which restricts lumen, aneurysmal dilatation and proliferation of arterioles at hilus of glomerulus
● May have double contour of glomerular basement membrane

Micro images
=========================================================================


   
HUS: kidney


Atypical HUS: kidney


TTP: kidney


TTP: lesions of myocardium, adrenal gland, CNS, pancreas, other

Virtual slides
=========================================================================



DIC and microthrombi

Immunofluorescence
=========================================================================

● Demonstrates fibrin and fibrinogen, irregular staining for IgM, C3 and C1q, negative for IgA and IgG

Electron microscopy description
=========================================================================

● Widening of subendothelial space, filled with pale, finely particulate or fibrillar material (fibrinogen) and intraluminal platelet microthrombi causing narrowing of capillary lumen
● Swollen mesangial cells with numerous phagolysosomes
Later: mucinous, onion skin-type obliterating endarteritis

Differential diagnosis
=========================================================================

Malignant hypertension: similar vascular lesions but different clinical presentation
Systemic sclerosis: similar vascular lesions but different clinical presentation
Antiphospholipid antibody syndrome: thrombosis in veins, arterioles, capillaries with glomerular subendothelial expansion



Associated with systemic conditions

Light chain deposition disease


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 21 November 2012, last major update November 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Monoclonal gammopathy characterized by overproduction and deposition of nonamyloid immunoglobulin light chains in various organs.(eMedicine)
● Uncommon; occasionally also heavy chains
● See also myeloma
● 80% male, usually older adults
● 60% have associated myeloma or other lymphoplasmacytic disorder, although it may not become apparent until years later
● Renal failure with heavy proteinuria; also Fanconi’s anemia with aminoaciduria, glucosuria and phosphaturia
● Also cardiac, hepatic and neural damage and deposition in soft tissues and other organs of histiocytes and fibroblasts containing crystals (Am J Surg Pathol 1993;17:461)
● May recur in renal transplants
● Variable 5 year survival; ~ 70%, less if coexisting myeloma

Case reports
=========================================================================

● 41 year old man with no clinical plasma cell dyscrasia (Ultrastruct Pathol 2012;36:134)
● 49 year old woman with biopsy proven resolution after autologous stem cell transplantation.(Nephrol Dial Transplant 2010;25:2020)
● 53 year old woman with recurrent light chain deposition disease post-renal transplantat (Clin Transplant 2012;26 Suppl 24:64)
● 66 year old man presenting with severe jaundice (Oman Med J 2012;27:56)
● Middle-aged woman with myeloma and type II diabetes (Arch Pathol Lab Med 1983;107:319)

Treatment
=========================================================================

● Chemotherapy with bortezomib, a proteasome inhibitor (Med Oncol 2012;29:1197), thalidomide (Int J Hematol 2011;93:673); also autologous stem cell transplantation (Int J Lab Hematol 2012;34:347, J Nephrol 2011;24:246)

Micro description
=========================================================================

● Enlarged glomeruli with PAS+ material in thickened capillary walls and mesangial nodules
● Occasional fibroepithelial crescents
● Thickened tubular basement membranes with glassy (crystalline) appearance
● Also crystals within histiocytes; weakly positive on silver stain

Micro images
=========================================================================


       
Various images

Immunofluorescence
=========================================================================

● Granular deposits of kappa (80%) or lambda (20%) light chains (not both) along glomerular and tubular basement membranes, in mesangium, vessel walls and interstitium

Negative stains
=========================================================================

● Congo red, thioflavin T and amyloid P protein

Electron microscopy description
=========================================================================

● Diffuse electron dense, finely granular material in glomerular basement membrane, mesangium, tubular and vascular basement membranes
● Immunoelectron microscopy may be useful for diagnosis (Hum Pathol 2003;34:270)

Differential diagnosis
=========================================================================

AL amyloidosis: fibrillar deposits, usually lambda light chains, Congo Red+, thioflavin T+, amyloid P protein+
Diabetes: severe arteriolar hyalinosis, fibrin caps, capsular drops, strongly positive with silver stain
● Drug related crystals



Associated with systemic conditions

Microscopic polyangiitis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 12 December 2012, last major update December 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Systemic, pauci-immune, small-vessel necrotizing vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA), often targeting myeloperoxidase (MPO), but without immune complex deposition or granulomas
● A type of pauci-immune vasculitis (necrotizing small-vessel vasculitis with no immune complex deposition by EM or immunofluorescence)
● Previously considered a type of polyarteritis nodosa (eMedicine)

Clinical features
=========================================================================

● Affects 1 per 100,000; any age but more common at age 50+ years
● 90% have renal involvement; lungs usually affected (may simulate Goodpasture’s syndrome)
● Also skin, ear, nose, throat, musculoskeletal, nervous system, GI
● Symptoms: hematuria, proteinuria, hemoptysis, palpable purpura, abdominal pain, myalgias, arthralgias, mild hypertension
● Birmingham Vasculitis Activity Score (BVAS, online calculator): useful for determining disease activity and outcome (Clin Rheumatol 2011;30:1499)
● Survival of 60-80% at 10 years, death mainly in first months after diagnosis (Rheumatology (Oxford) 2011;50:1414)
● Laboratory: PR3-ANCA (40%), MPO-ANCA (50%), negative (10%)
● Treatment: IV corticosteroids, immunosuppressants, transplant (Clin J Am Soc Nephrol 2010;5:445, Am J Nephrol 2011;33:185)

Case reports
=========================================================================

● 59 year old man with myeloperoxidase-ANCA negative microscopic polyangiitis with pulmonary hemorrhage and IgA nephropathy (Case Rep Dermatol 2011;3:22)

Micro description
=========================================================================

● Glomerulonephritis (focal and segmental to severe diffuse and crescentic)
● Arterial lesions usually all at same stage
● Usually tubulointerstitial infiltrate
● Sausage shaped microaneurysms of interlobular arteries
● No granulomas or asthma (Hum Pathol 1998;29:223)

Micro images
=========================================================================



Microscopic polyangiitis: A-acute focal segmental necrotizing glomerulonephritis; B-interstitial inflammation and arteritis


Patient with ANCA-associated microscopic polyangiitis and focal necrotizing glomerulonephritis



Glomerulus shows segmental fibrinoid necrosis with adjacent small cellular crescent; PAS shows focal dissolution of Bowman's capsule basement membrane (arrows); .glomerular basement membranes and mesangial matrix have been destroyed near the fibrinoid necrosis; note the periglomerular tubulointerstitial inflammation and edema


Mild mesangial cellular proliferation and expansion; mesangial and diffuse IgA deposits were observed but crescents were absent


Red blood cell cast (urine)

Virtual slides
=========================================================================



Microscopic polyangiitis (polyarteritis)

Immunofluorescence
=========================================================================

● No deposits

Electron microscopy description
=========================================================================

● No deposits

Differential diagnosis
=========================================================================

● Other pauci-immune glomerulonephritis including Wegener’s granulomatosis (necrotizing granulomas), Churg-Strauss syndrome / allergic granulomatosis and angiitis (eosiniophilia, asthma, granulomas)



Associated with systemic conditions

Myeloma


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 23 December 2012, last major update July 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● See also light chain deposition disease, Lymphoma and plasma cell neoplasms chapter
● Renal dysfunction / insufficiency occurs in 50% and renal disease is #2 cause of death in myeloma patients

Renal features
=========================================================================

● Various renal disorders (Arch Pathol Lab Med 2004;128:875, Am J Kidney Dis 2012;59:786):

Bence Jones nephropathy
● Also called myeloma cast nephropathy or myeloma kidney
● Occurs in 30-40% at autopsy
● Proteinuria consisting of light chains, which are normally filtered by glomeruli, reabsorbed and metabolized by proximal tubular cells
● In myeloma, proximal tubular cells are overwhelmed and light chains reach distal nephron, where they are directly toxic to epithelial cells; Bence Jones proteins combine with urinary glycoprotein (Tamm-Horsfall) under acidic conditions to form tubular casts that obstruct tubules

● AL amyloidosis (6-24% of myeloma patients)
● Hypercalcemia, hyperuricemia, urinary tract obstruction, vascular disease
● Light chain nephropathy: PAS+ mesangial deposits in glomeruli, lobular accentuation, mesangial hypercellularity
● Also acute and chronic renal failure induced by dehydration, acute infection, acute tubular necrosis (acute tubulopathy), fungal infection, infarction, monoclonal cryoglobulins in glomeruli, neprhotic syndrome, nephrotoxic antibiotics, plasma cell tumor nodules, thrombotic microangiopathy, tubulointerstitial nephritis

● Estimated GFR calculated using Modification of Diet in Renal Disease (MDRD) Study equation, which has prognostic impact (Eur J Haematol 2012;88:159)
Note: urinary beta 2 microglobulinemia can simulate Bence-Jones proteins in electrophoresis (Arch Pathol Lab Med 2001;125:555)
● Estimated GFR is calculated using Modification of Diet in Renal Disease (MDRD) Study equation, which has prognostic impact (Eur J Haematol 2012;88:159)

Case reports
=========================================================================

● 51 year old man presenting with rapidly progressive glomerulonephritis due to IgA myeloma (Nephron Extra 2011;1:69)

Treatment of renal disease
=========================================================================

● Treatment for underlying plasma cell neoplasm is discussed in Lymphoma and plasma cell neoplasms chapter
● Dialysis for acute renal failure (Nefrologia 2012;32:35, Ann Hematol 2012;91:729)

Micro description
=========================================================================

● Pink-blue amorphous masses fill and distend lumen, surrounded by giant cells and histiocytes; adjacent epithelium is necrotic
● Casts and histiocytes may contain rhomboid or needle shaped crystals (light chains)

Micro images
=========================================================================



Light chain cast nephropathy-various images


Plasma cell nodules


Left: thrombotic microangiopathy; right: abscess with fungal hyphae


Glomerular disease: various images

 
Glomerular disease: crescentic glomerulonephritis as presenting sign of IgA myeloma (rare)


Tubular disease: various images


Various images

Immunofluorescence
=========================================================================

● Granular dense material along basement membrane

Electron microscopy description
=========================================================================

● Peripheral and mesangial kappa or lambda light chains

Differential diagnosis
=========================================================================

● Diabetic nodules
Membranoproliferative glomerulonephritis



Associated with systemic conditions

Polyarteritis nodosa


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 24 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Primary vasculitis of unknown etiology that affects muscular arteries at branch points
● Produces lesions of varying stages of evolution, also aneurysms
● Usually affects kidney (80%) and GI tract

Clinical features
=========================================================================

● 2 cases per million, 2/3 male, ages 50+ years
● 1/3 of cases are hepatitis B carriers
● Causes renal infarct, hypertension (often severe or malignant)
● May present with rapidly progressive renal insufficiency (Clin Nephrol 2010;74:315)
● < 20% have positive p-ANCA

Case reports
=========================================================================

● 36 year old man with bilateral renal hemorrhage wrongly attributed to blunt trauma (Nat Rev Urol 2009;6:563)
● 80 year old woman with MPO-ANCA (p-ANCA), fever, malaise and weight loss (Clin Exp Nephrol 2011;15:281)
● Case limited to kidneys (Hum Pathol 1987;18:1074)

Gross images
=========================================================================



Fatal retroperitoneal hemorrhage (red arrow), pseudoaneurysms (black arrows), multiple pale infarcts (white arrows)

Micro description
=========================================================================

● Necrotizing vasculitis of renal, interlobar and arcuate arteries at branch points with aneurysmal dilatation, fibrinoid necrosis and neutrophilic infiltration of vessel wall, often with thrombosis
● Later have mononuclear infiltrate, fibrosis of media and perivascular tissue and recanalization of thrombosed vessel
● Often not detected in biopsy since lesions are focal
● Glomeruli show ischemic changes of collapse and sclerosis

Micro images
=========================================================================



Lymphocytic vasculitis of renal vessels


Neutrophilic infiltration of vessels


Inflammation and fibrinoid necrosis


Small artery has inflammation and red staining (fibrinoid) due to penetration of plasma into vessel wall


Zone of infarction with coagulative necrosis on left, acute inflammation in middle, congested cortical parenchyma on right

Immunofluorescence
=========================================================================

● No deposits

Immunofluorescence images
=========================================================================



Irregular circumferential transmural staining for fibrin

Electron microscopy description
=========================================================================

● No deposits

Differential diagnosis
=========================================================================

● Kawasaki's disease: more mural edema and infiltrating monocytes, less fibrinoid necrosis



Associated with systemic conditions

Preeclampsia


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 24 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Disorder of widespread vascular endothelial malfunction and vasospasm, occurs after 20 weeks' gestation (as late as 4-6 weeks postpartum); defined by hypertension and proteinuria (eMedicine, Wikipedia)
● Possible causes of systemic endothelial dysfunction include glomerular capillary endotheliosis, dysregulation of glomerular filtration apparatus, podocyte loss (Clin Nephrol 2012;78:241)
● Causes 50% of pregnancy related hypertension

Clinical features
=========================================================================

● 5-7% of first pregnancies, usually affects women at extremes of reproductive age
● In subsequent pregnancies, associated with multiple births, fetal hydrops
● Called eclampsia if convulsions develop
● May be caused by primary endothelial cell injury causing local intravascular coagulation
● Good prognosis; glomerular changes and blood pressure return to normal within weeks of delivery

Micro description
=========================================================================

● Enlarged, swollen and bloodless glomeruli with capillary lumina obliterated by swollen endothelial cells
● No / mild hypercellularity; may have herniation of capillary tuft into proximal tubule (tufting)
● Rare crescent formation in severe cases; normal afferent arterioles

Micro images
=========================================================================



Various images


Glomerular endotheliosis


Various images (scroll down)

Immunofluorescence
=========================================================================

● Fibrinogen deposits, occasionally IgM

Electron microscopy description
=========================================================================

● Lysosomal-like, single membrane lined vacuoles within cytoplasm of endothelium and mesangial cells
● Some vacuoles contain bland lipids or have myelin-like figures

Electron microscopy images
=========================================================================



Marked endothelial cell swelling and vacuolization and extensive epithelial foot-process effacement


Fig 14.1: swollen endothelial cell with epithelial foot processes intact (A), swollen endothelial and mesangial cells showing prominent vacuolization on capillary lumina


Glomerular capillary



Associated with systemic conditions

Sarcoidosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 23 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Often white men lacking skin, eye or lung involvement
● Often hypercalcemia and fever at presentation of renal sarcoidosis (Medicine (Baltimore) 2009;88:98)
● Renal failure in <3% (Rev Pneumol Clin 2011;67:342)
● Cases with renal involvement difficult to diagnose on renal biopsy due to focal nature (Int J Nephrol Renovasc Dis 2011;4:131)

Case reports
=========================================================================

● 19 year old woman who died of rapidly progressive renal and respiratory failure (Arch Pathol Lab Med 1989;113:1295)
● With nephrotic syndrome resistant to steroids and immunosuppression (Arch Pathol Lab Med 1978;102:572)

Treatment
=========================================================================

● Prednisone for renal insufficiency (Arch Pathol Lab Med 1990;114:488)
● Renal transplantation, recurrence in 27% (Clin J Am Soc Nephrol 2010;5:2101)

Micro description
=========================================================================

● Diagnosis of exclusion
● Interstitial non-caseating granulomatous nephritis, nephrocalcinosis, often segmental thickening and wrinkling of glomerular capillary walls
● Granulomas look fibrotic with minimal or no lymphocytic cuffing (naked nuclei)

Micro images
=========================================================================



Various images


Granulomatous interstitial nephritis


Renal biopsy shows nonspecific features, which is common


Recurrence after renal transplant

Immunofluorescence
=========================================================================

● No specific findings

Electron microscopy description
=========================================================================

● Numerous single and coalescent calcific microspherules within basement membrane, paramesangial zone and mesangium



Associated with systemic conditions

SLE / systemic lupus erythematosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 23 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Autoimmune disease of women (90%) with various clinical manifestations
● 40-80% have impaired renal function, due to in situ or circulating immune complexes

Etiology
=========================================================================

● Most cases idiopathic, but drug induced lupus-like disease is associated with chlorpromazine, hydralazine, isoniazid, methyldopa, procainamide, quinidine

Clinical features
=========================================================================

● Adults and children (2/3 present initially at ages 16-30 years)
● In children in US, prevance of 10 per 100K Medicaid-enrolled children (Arthritis Rheum 2012;64:2669)
● Most common renal symptoms are proteinuria and microscopic hematuria; also acute nephritis, acute and chronic renal failure, isolated abnormalities in urinary sediment, nephrotic syndrome
● Biopsy is necessary to determine subsequent clinical course and to assist with treatment
● Non-lupus nephritides occasionally present (Hum Pathol 2001;32:1125), including IgA nephropathy (Mod Pathol 1995;8:5)

WHO classification of lupus nephritis
=========================================================================

I: normal or minimal abnormality; no abnormalities identified by H&E, immunofluorescence or EM; asymptomatic; may not actually represent renal disease
II (10-20% of cases): pure mesangial lesions; mesangial expansion but mostly patent capillaries; mesangial immune deposits; mild proteinuria with variable hematuria, but normal renal function
IIA: minimal light microscopy changes, but immune deposits present in mesangium by immunofluorescence and EM
IB: glomerular mesangial hypercellularity present by light microscopy, involving center of lobules away from vascular pole; immune deposits only in mesangial region; no significant tubular, interstitial or vascular changes; good prognosis (5 year renal survival > 90%)
III (30-40% of cases): focal proliferative glomerulonephritis; focal and segmental proliferative intra- or extracapillary necrotizing or sclerosing lesions in < 50% of glomeruli; predominantly mesangial and subendothelial immune deposits (Ig, complement); nephritic urinary sediment; variable proteinuria but usually non-nephrotic
IV (40-60%): diffuse proliferative glomerulonephritis; predominantly global proliferative lesions, necrosis, crescents in > 50% of glomeruli, variable sclerosis, prominent inflammatory interstitial infiltrate, often wire loop lesions in thickened capillary walls; predominantly mesangial and subendothelial immune deposits of IgG, often IgM and IgA (all three is called a “full house”); also C3 and C1q, fibrin and fibrinogen; nephritic and nephrotic syndromes, hypertension, variable renal insufficiency; rapidly progresses to renal failure without treatment
V (10-15%): membranous glomerulonephritis; diffuse thickening of capillary walls, subepithelial and mesangial immune deposits (“spike and dome” pattern with silver stain); nephrotic syndrome or severe proteinuria
VI: advanced sclerosing glomerulonephritis; glomerular obsolescence and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis; few immune deposits; chronic renal failure that is unlikely to respond to therapy
● Overlap common in classes III and V, IV and V


Table

International Society of Nephrology (ISN) / Renal Pathology Society (RPS) classification of Lupus Nephritis (2004)
=========================================================================

Class I: Minimal Mesangial Lupus Nephritis:
● Glomeruli normal by light microscopy (LM), mesangial deposits by immunofluorescence (IF) / electron microscopy (EM)

Class II: Mesangial Proloferative Lupus Nephritis:
● Mesangial hypercelullularity and/or mesangial expansion by LM, immune deposits by IF / EM

Class III: Focal Lupus Nephritis:
● Active or inactive focal, segmental or global endo or extracapillary glomerulonephritis involving < 50% of glomeruli, immune deposits are subendothelial
● Subclassified as A (active lesions), A/C (active and chronic lesions), C (chronic lesions)

Class IV: Diffuse Lupus Nephritis:
● > 50% glomeruli with active / inactive diffuse, segmental, or global endo and/or extracapillary glomerulonephritis
● Diffuse subendothelial deposits can cause wire-loop appearance
● A (active lesions), A/C (active and chronic lesions), C (chronic lesions)
● Diffuse segmental if > 50% glomeruli show segmental lesions, diffuse global if > 50% show global lesions

Class V: Membranous Lupus Nephritis:
● Global or segmental involvement, subepithelial immune deposits
● May occur in combination with class III or IV

Class VI: Advanced Sclerosing Lupus Nephritis:
● > 90% globally sclerosed glomeruli

References: J Am Soc Nephrol 2004;15:241


Tables

Tubulointerstitial disease: observed in all classes, severe in classes III and IV; usually composed of lymphocytes, plasma cells and macrophages; severe cases have casts
Vascular lesions: common, associated with poor prognosis; includes vascular immune deposits, non-inflammatory necrotizing vasculopathy, true vasculitis, thrombotic microangiopathy and non-specific arteriolosclerosis
Hematoxylin bodies: focal areas of necrosis containing fragmented nuclei; specific for SLE, but only 1-2% sensitive
● Alveolar hemorrhage (bland alveolar wall changes) is similar to lupus microangiopathy of kidney; both are caused by immune complex deposition and induction of apoptosis (Arch Pathol Lab Med 2001;125:475)
Activity index: based on scoring (0-3) of (a) glomerular endocapillary proliferation, (b) glomerular neutrophilic infiltration, (c) wire-loop deposits and hyaline thrombi, (d) glomerular fibrinoid necrosis and karyorrhexis, (e) cellular crescents and (f) interstitial inflammation; double the fibrinoid necrosis / karyorrhexis (part d) and cellular crescent (part e) scores; add up (maximum 24)
Chronicity index: based on scoring (0-3) of (a) glomerular sclerosis, (b) fibrous crescents, (c) tubular atrophy and (d) interstitial fibrosis; add up (maximum 12)

Case reports
=========================================================================

● 12 year old girl with severe oliguric renal failure (ISN/RPS class IV-G(A)) and spontaneous remission (BMC Nephrol 2012;13:81)
● Two patients with alveolar hemorrhage and class IV lupus nephritis (Arch Pathol Lab Med 2001;125:475)

Treatment
=========================================================================

● Steroids, cyclosporine A (Clin Nephrol 2011;76:136), tacrolimus and other immunosuppressants (Tohoku J Exp Med 2012;227:281)

Gross images
=========================================================================



Diffuse proliferative lupus nephritis

Micro images
=========================================================================



Membranous lupus nephritis, class II


Membranous lupus nephritis, class III




Membranous lupus nephritis, class IV


Membranous lupus nephritis, classes II to IV


Membranous lupus nephritis, classes V


Membranous lupus nephritis, classes VI


Membranous lupus nephritiss, class IV to VI


WHO class III and IV


Membranous glomerulonephritis-various images


Platelet microthrombi, macrophagic infiltration, activated complement deposition.

Virtual slides
=========================================================================



Membranous glomerulonephritis with wire loops

Electron microscopy description
=========================================================================

● Granular glomerular electron-dense deposits; may be organized into curvilinear microtubular or fibrillar structures composed of bands 10–15 nm in diameter (‘fingerprinting’)

Electron microscopy images
=========================================================================



Class IV lesions


Various features common to lupus nephritis and Hepatis B related nephritis

Differential diagnosis
=========================================================================

● Class III lesions resemble Henoch-Schonlein purpura, pauci immune focal segmental necrotizing glomerulonephritis and IgA nephropathy
● Class IV needs to be distinguished from severe forms of IgA nephropathy, membranoproliferative glomerulonephritis and cryoglobulinemic glomerulonephritis
● IgG4 related kidney disease: see Intern Med 2012;51:1731



Associated with systemic conditions

Systemic sclerosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 21 December 2012, last major update December 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Connective tissue disorder of unknown etiology with multiple organ system involvement, symptoms due to excessive collagen deposition and vascular disease
● Also called scleroderma

Clinical features
=========================================================================

● 75% women, usually ages 30+, rare in children
● Symptoms: digital pulp atrophy, esophageal dysmotility, malabsorption, musculoskeletal involvement, Raynaud’s syndrome, skin thickening, telangiectasia
● Death due to pulmonary hypertension, interstitial fibrosis and cardiomyopathy

Sclerodermal renal disease
=========================================================================

● 60% have renal involvement, either (a) renal crisis / acute and rapidly progressive form of renal failure associated with malignant hypertension, systemic vasoconstriction, microangiopathic hemolytic anemia; or (b) slowly progressive chronic form with proteinuria, hypertension and azotemia
● Scleroderma renal crisis: malignant hypertension and oligo-anuric acute renal failure; occurs in 2-5%, particularly those with diffuse cutaneous systemic sclerosis in initial years of disease evolution (Nephrol Ther 2011;7:192)
● Risk factors for renal crisis: increased serum sCD147 levels (Clin Rheumatol 2012;31:835), RNA polymerase III antibodies (Scand J Rheumatol 2012;41:39), use of glucocorticoids (Clin Rev Allergy Immunol 2011;40:84)
● Increased risk of acute kidney injury with hematopoietic cell transplantation (Biol Blood Marrow Transplant 2011;17:674)

Gross images
=========================================================================



Finely granular, petechial hemorrhages beneath the capsule


Cortical hemorrhages

Micro description
=========================================================================

● Intimal thickening by loose myxoid fibrous tissue in interlobular arteries
● Subendothelial fibrin deposition and intimal hemorrhage
● Fibrinoid necrosis and thrombosis in arterioles
● Acute ischemic changes in glomeruli

Micro images
=========================================================================


   
Various images


Sclerodermal renal crisis


Medium sized renal cortical artery in patient with diffuse systemic sclerosis and renal crisis; note severe concentric, edematous myxoid intimal proliferation with almost total obliteration of lumen

   
Fig 16.25-mucoid intimal hyperplasia with prominent luminal narrowing; fig 16.26- small interlobular artery shows luminal narrowing, little collagen deposition

   
Fig 16.27-extensive (circumferential) fibrin insudation; fig 16.29-subendothelial fibrin deposition


Fig 16.30-significant chronicity, with extensive tubulointerstitial fibrosis, ischemic glomeruli and intimal fibroplasia of an interlobular size artery


Fibrinoid necrosis

Immunofluorescence
=========================================================================

● Fibrinogen, variable IgM and C3

Electron microscopy images
=========================================================================



Wide electron-lucent zone on the endothelial side of the capillary basement membrane is seen, with mesangial cell interposition

Differential diagnosis
=========================================================================

Malignant hypertension
HUS-TTP: different clinically, but similar renal lesions



Associated with systemic conditions

Wegener’s granulomatosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 23 December 2012, last major update December 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare autoimmune disease of unknown etiology with triad of (a) necrotizing granulomatous inflammation of upper respiratory tract or lungs, (b) necrotizing pauci-immune vasculitis of small / medium sized vessels in lungs, upper airways and other sites; and (c) focal necrotizing glomerulonephritis (eMedicine)
● “Limited” disease if only 1 or 2 of the above, usually spares kidneys

Clinical features
=========================================================================

● Incidence of 3 per 100,000, occurs at any age but more common at ages 30-49 years
● 80% have renal involvement, which progresses rapidly without treatment, leading to end stage renal disease (Scand J Rheumatol 2011;40:283) and death
● Serum c-ANCA is 90% specific, 50% sensitive initially, 100% sensitive if active and generalized disease; c-ANCA not present during remission

Case reports
=========================================================================

● 54 year old man with recovery of pulmonary involvement while renal disease progressed to end-stage.(Ren Fail 2011;33:1032)
● 73 year old man with fever, malaise, anorexia, 25 pound weight loss (University of Pittsburgh)

Treatment
=========================================================================

● Cyclophosphamide, corticosteroids (cause remission, but 50% relapse)
● Renal transplant for end stage renal disease (Clin Transplant 2011;25:380)

Micro description
=========================================================================

● Focal necrotizing glomerulonephritis, often with cellular crescents and usually with glomerular thrombosis (Hum Pathol 1984;15:943)
● Interstitial inflammation common, renal papillary necrosis in 20%
● Rare: granulomatous glomerulonephritis, necrotizing granulomas in biopsies

Micro images
=========================================================================



Positive c-ANCA (immunofluorescence pattern produced by binding of ANCA to ethanol-fixed neutrophils)


Various images

       
Glomerulonephritis (left to right): focal necrotizing, sclerosing, early crescent


Global cellular crescent


Crescents (left to right): partial cellular, fibrin present (direct immunofluoresence with antibody panel)

   
Vascular lesions (left to right): fibrinoid necrosis of interlobular artery; vasculitis

   
Necrotizing granulomatous vasculitis


Tubular disease: red blood cell castss

Immunofluorescence
=========================================================================

● Usually no immune complex deposits, but fibrinogen in glomeruli and vessel walls, small amounts of IgM, IgG or C3 in glomeruli and vessels (pauci-immune)

Electron microscopy description
=========================================================================

● Rarely sparse electron dense deposits in glomeruli

Differential diagnosis
=========================================================================

● Other pauci-immune glomerulonephritis, such as Churg-Strauss syndrome and microscopic polyangitis



Tubular and interstitial diseases

General


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 23 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Primary tubulointerstitial disease (nephritis) lacks significant glomerular or vascular injury; causes 20-40% of cases of end stage renal disease (eMedicine)
● Secondary tubulointerstitial nephritis is due to glomerular disease, systemic or vascular disorders
● Tubulointerstitial disease may be acute (interstitial edema, neutrophils, focal tubular necrosis) or chronic (mononuclear inflammation, interstitial fibrosis, tubular atrophy)
● Symptoms: inability to concentrate urine (polyuria, nocturia), salt wasting and diminished ability to excrete acids (metabolic acidosis)
● Causes: infections, jejunoileal bypass (Arch Pathol Lab Med 1980;104:112) metabolic disease, toxins, tumors, vascular diseases
● IgG4 staining recommended to identify subset with IgG4 related disease (Clin Nephrol 2011;76:440)

Case reports
=========================================================================

● 12 year old boy with Crohn's disease (Nat Clin Pract Nephrol 2008;4:693)
● 20 year old man with idiopathic tubulointerstitial nephritis and uveitis / TINU syndrome (Nephrol Dial Transplant 2008;23:771)

Micro images
=========================================================================



Tubulointerstitial nephritis


Idiopathic hypocomplementemic immune-complex-mediated tubulointerstitial nephritis

Virtual slides
=========================================================================



Interstitial nephritis

Electron microscopy images
=========================================================================



Idiopathic hypocomplementemic immune-complex-mediated tubulointerstitial nephritis



Tubular and interstitial diseases

Acute allergic tubulointerstitial nephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 23 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Drug reaction to beta lactam antibiotics, non-steroidal anti-inflammatory drugs, diuretics, other drugs; generally after 2–3 weeks after exposure
● May occur in renal allografts (Clin Nephrol 2009;72:331)
● Fever, hematuria, azotemia and eosinophilia
● Variable skin rash
● May be associated with inactive cytochrome P450 polymorphisms (Ren Fail 2009;31:749)
● Urinalysis: suggestive of infection (eosinophils, hematuria, proteinuria, pyuria), but culture negative

Micro description
=========================================================================

● Generalized interstitial edema and infiltration by lymphocytes, plasma cells, macrophages and eosinophils
● Tubular epithelial damage (tubulitis) with luminal white blood cells; variable degree of tubular injury
● Normal glomeruli and vessels

Micro images
=========================================================================



Various images



Tubular and interstitial diseases

Acute pyelonephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 23 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Acute suppurative (pus forming) infection of kidney collecting system as well as renal parenchyma
● Affects infants and young children with congenital lesions, women of childbearing age, men and women age 60+ years (due to nodular hyperplasia of prostate, cystoceles in women, cervical carcinoma, nephrolithiasis)
● Also associated with diabetes or immunocompromise

Clinical features
=========================================================================

Causes: urinary tract infection (UTI), instrumentation, obstruction, pregnancy (4-6% have bacteriuria, 20% have symptoms if untreated), vesicoureteral reflux
Bacterial UTI: due to colonization of distal urethra and introitus by coliform bacteria with adhesins on P-fimbriae (pili), plus upward spread via instrumentation or catheterization; more common in women than men due to short urethra, no anti-bacterial prostatic fluid, hormonal changes, sex-related trauma
● Usually gram negative rods from fecal flora (E. coli, Enterobacter, Klebsiella, Proteus, Streptococcus faecalis) or Staph
● Ascending route most common; also hematogenous spread of bacteria to kidney
Intrarenal reflux: via open ducts at tips of papillae; most common at poles of kidney where papillae have flat or concave tips; demonstrate via voiding cystourethrogram (seen in 50% of children with UTI)
Vesicoureteral reflux: due to short intravesical ureter, spinal cord injuries; some UTIs; independent risk factor for renal scar formation after acute pyelonephritis in infants (J Urol 2012;187:1032)
Signs / symptoms: sudden onset of costovertebral angle pain, symptoms of systemic infection or urinary tract infection, pyuria or white blood cell casts

Complications
=========================================================================

Papillary necrosis: more common with diabetes and urinary tract obstruction; usually bilateral; variable number of pyramids involved; coagulative necrosis of tubules; usually limited white blood cell response
Perinephric abscess: extension of pus through renal capsule into adjacent tissue
Pyonephrosis: total or almost complete obstruction prevents drainage of pus

Treatment
=========================================================================

● Antibiotics usually eliminate symptoms in a few days (Am Fam Physician 2011;84:519, Lancet 2012;380:484)
● Persistent bacteriuria is usually associated with obstruction, diabetes and immunocompromise

Gross description
=========================================================================

● Focal abscesses or wedge-shaped areas of suppuration

Gross images
=========================================================================



Acute pyelonephritis


Renal papillary necrosis

Micro description
=========================================================================

● Patchy suppurative inflammation, primarily cortical, with edema, neutrophils in interstitium and tubular lumina, and tubular necrosis
● Cortical abscesses and necrosis
● Glomeruli and vessels usually normal (Candida affects glomeruli)

Micro images
=========================================================================





Acute pyelonephritis

Virtual slides
=========================================================================


   
Acute and chronic pyelonephritis


Pseudomonas abscess



Tubular and interstitial diseases

Acute tubular necrosis (ATN)


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 24 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Reversible destruction of tubular epithelial cells with acute suppression of renal function
● Most common cause of acute renal failure

Etiology
=========================================================================

● Tubules are sensitive to injury due to vast electrically charged surface for reabsorption, active transport for ions and organic acids and the ability to concentrate
Ischemic: also called acute vasomotor nephropathy; due to inadequate renal blood flow, often from marked hypotension and shock (acute pancreatitis, severe trauma); ischemia causes vasoconstriction, which leads to reduced glomerular filtration rate and oliguria
Nephrotoxic: due to carbon tetrachloride, cisplatin, ethylene glycol, gentamycin, hemoglobin (transfusion reaction, malaria), lead, light chains (myeloma), mercury (Arch Pathol Lab Med 1991;115:56), methotrexate, myoglobin (from crush injury, myositis, muscle toxins), radiographic contrast agents; greatest injury is to proximal convoluted tubules

Clinical features
=========================================================================

Phases:
● Initiating: 0-36 hours, decreased urine output, elevated BUN and creatinine due to decreased blood flow
● Maintenance: 40-400 ml/day of urine, salt / water overload, hyperkalemia, acidosis and uremia; may need dialysis
● Recovery: increased urine volume up to 3 liters/day due to tubular damage, inability to concentrate and hypokalemia; vulnerable to infection
● Mortality: 5% if no damage to other organs, 50% if shock / sepsis

Non-oliguric acute tubular necrosis: increased or normal urine volumes, often associated with nephrotoxins and a more benign clinical course
Urinalysis: shows epithelial and granular casts

Micro description
=========================================================================

Ischemic ATN:
Early - varies from cell swelling to focal tubular epithelial necrosis and apoptosis with desquamation of cells into lumen; dilated proximal tubules with thinning or loss of PAS+ brush border; hyaline, granular and pigmented cases, particularly in distal and collecting ducts, eosinophilic hyaline casts of Tamm-Horsfall protein (urinary glycoprotein normally secreted by these cells); white blood cells in dilated vasa recta, interstitial edema
Later - epithelial regeneration (flattened epithelium, dilated tubular lumina, large nuclei with prominent nucleoli and mitotic activity)

Nephrotoxic ATN:
● Extensive necrosis of tubular cells along proximal tubule

Carbon tetrachloride: neutral lipid accumulation / fatty change in injured cells, followed by necrosis
Ethylene glycol: ballooning and hydropic changes of proximal tubules, calcium oxalate crystals in tubular lumina
Hemoglobin / myoglobin: numerous deeply pigmented, red-brown casts in distal and collecting ducts
Indinavir: intraluminal clear crystals with mononuclear reaction (Kidney Int 2009;75:428)
Lead: dark intranuclear inclusions and necrosis
Mercury: large acidophilic inclusions
Tenofovir: distinctive proximal tubular eosinophilic inclusions representing giant mitochondria (Kidney Int 2010;78:1171)
Vancomycin: acute interstitial nephritis with lymphocytic and eosinophilic infiltrate and ATN (Clin Exp Nephrol 2012;16:320)

Micro images
=========================================================================



Necrosis and sloughing of epithelial cells


Calcium oxalate crystals (various causes)


Denge fever: necrotic debris in tubular lumina (PAS)


Ethylene glycol poisoning


Indinavir toxicity


Post-transplant (24 hours): isografts and allografts (A and B)


Post-transplant (1 week): human cadaveric kidney


Tenofovir toxicity


Vancomycin toxicity

Virtual slides
=========================================================================



ATN: due to ethylene glycol poisoning, cause unspecified

Electron microscopy images
=========================================================================



Granulocytes and mononuclear cells aggregating in a peritubular capillary


Tenofovir toxicity

Differential diagnosis
=========================================================================

● Other causes of acute renal failure (urine output < 400 ml/24 hr): hemolytic-uremic syndrome, malignant hypertension, polyarteritis nodosa
Acute tubulointerstitial nephritis: severe interstitial inflammation and associated tubulitis
● DIC
Pyelonephritis with papillary necrosis
Rapidly progressive glomerulonephritis
● Urinary obstruction



Tubular and interstitial diseases

Chronic pyelonephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 24 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Chronic tubulointerstitial inflammation and renal scarring with severe involvement of calyces and pelvis
● Pyelocalyceal damage / blunting rules out other tubulointerstitial inflammation

Clinical features
=========================================================================

● Causes 10%-20% of end stage renal disease in transplant or dialysis units
● Associated with pyelitis and ureteritis cystica
● Some patients with pyelonephritic scars develop focal and segmental glomerulosclerosis with proteinuria in nephrotic range, perhaps due to renal ablation nephropathy

● Types: reflux (chronic reflux-associated pyelonephritis) and obstruction (chronic obstructive pyelonephritis)
Reflux: more common, usually arises in childhood, unilateral or bilateral; damage often due to infection; associated with calyceal dilation (usually upper pole); see tubular atrophy and thyroidization, interstitial fibrosis
Obstruction: associated with parenchymal scarring, usually not in children

Case reports
=========================================================================

● 68 year old woman with renal sinus mass by imaging (J Med Case Rep 2009;3:9054)

Gross description
=========================================================================

● Irregular scarred cortical surface usually at poles, dilated and blunted calyces
● Dilated ureter; retraction and destruction of papillae with “U” shaped scars

Gross images
=========================================================================



Dilated calyces, reduced renal parenchyma and scarring

Micro description
=========================================================================

● Tubular thyroidization (filled with colloid casts), tubular atrophy
● Interstitial fibrosis and inflammation (intense diffuse lymphoplasmacytic inflammatory infiltrate with germinal centers)
● Obliterative endarteritis of vessels, interstitial Tamm-Horsfall protein (amorphous, fibrillary, PAS+ material surrounded by inflammatory cells)
● Normal glomeruli early in disease course

Micro images
=========================================================================





Various images

Differential diagnosis
=========================================================================

Chronic glomerulonephritis: diffusely scarred cortex
● Vascular disease: can cause wedge-shaped cortical scars, but underlying medullary and calyceal areas are normal



Tubular and interstitial diseases

Drug toxicity-general


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 24 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

See also Acute tubular necrosis

General
=========================================================================

● Acute drug-induced interstitial nephritis, typically arises 15 days after exposure, non dosage related
● May be a delayed (type IV) hypersensitivity reaction, due to hapten like effect of drug, which binds to tubular epithelium, making it immunogenic
● Rash, fever, eosinophilia, hematuria, mild proteinuria
● 50% have rising creatinine or develop acute renal failure
● Common offending drugs are cimetidine, penicillin, phenylbutzaone, rifampin, thiazides

Treatment
=========================================================================

● Stop offending drug, but some patients have delayed recovery (Am J Med Sci 2012;343:36)

Micro description
=========================================================================

● Edematous interstitium containing abundant eosinophils and neutrophils, lymphocytes, macrophages
● Also basophils and plasma cells, occasionally granulomas after methicillin
● Tubular necrosis and regeneration present; glomeruli are normal

Micro images
=========================================================================



Urine may have white blood cell casts


Various images



Tubular and interstitial diseases

Granulomatous interstitial nephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare disorder, often due to drugs (aspirin, gentamycin), infections (E. coli, mycobacteria), sarcoidosis (Am J Kidney Dis 2012;59:303), Wegener’s granulomatosis, oxalosis secondary to intestinal bypass (Hum Pathol 1995;26:1347)

Case reports
=========================================================================

● 23 year old woman with tuberculosis (Clin Nephrol 2011;76:487)
● 42 year old man with rising serum creatinine 18 months after initiation of adalimumab therapy for ankylosing spondylitis (Am J Kidney Dis 2010;56:e17)
● 70 year old woman taking carbamazepine (Clin Exp Nephrol 2012;16:168)

Treatment
=========================================================================

● Steroids for idiopathic disease

Micro description
=========================================================================

● Usually granulomas, T cells and macrophages; rarely neutrophils

Micro images
=========================================================================


   
Various images


Adalimumab related


Carbamazepine related


Cryptococcus infection related


Nitrofurantoin related



Renal sarcoidosis


Tuberculosis infection related



Tubular and interstitial diseases

Karyomegalic nephropathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Marked enlargement and hyperchromatic nuclei (karyomegaly) in tubular cells with associated interstitial fibrosis surrounding atrophic tubules
● Due to mutations in FAN1 (Nat Genet 2012;44:910)
● Karyomegaly may also be present within GI tract, lungs, vessels
● Unknown etiology - may be genetic or associated with ochra toxin

Micro description
=========================================================================

● Focal marked enlargement of tubular cells with prominent nuclei and nucleoli
● Chronic interstitial nephritis, normal and sclerotic glomeruli

Micro images
=========================================================================





Striking nuclear enlargement and hyperchromasia of tubular cell nucleis




PathoPics: various images

Cytology description
=========================================================================

● Urine cytology contains large pleomorphic cells, resembling carcinoma (Diagn Cytopathol 2007;35:179)

Electron microscopy images
=========================================================================



PathoPics: various images

Differential diagnosis
=========================================================================

Lead toxicity



Tubular and interstitial diseases

Lead nephropathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update March 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Kidney is main route for lead removal from body; lead is absorbed by proximal tubular cells, binds to specific proteins; with acute lead nephrotoxicity in dose-response relationship (Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2010;28:170), these lead-protein complexes are seen as intracellular inclusions (eMedicine)
● Due to occupational (electric storage battery makers, foundrymen, jewelers, painters, welders, ) or environmental causes (children eating lead pain, water in lead pipe systems, lead earthenware, moonshine liquor)
● Lead exposure damages central and peripheral nervous system, GI tract and kidney

Micro description
=========================================================================

● Tubular atrophy and interstitial fibrosis
● Tubular inclusions are eosinophilic and intranuclear or cytoplasmic, acid-fast and red with Giemsa stain
● Arteriolar disease similar to nephrosclerosis
● Tubules disappear in chronic disease; no inflammation

Micro images
=========================================================================



Nonspecific tubular atrophy and interstitial fibrosis, absence of interstitial infiltrate


Lead inclusions in nucleus of tubular cells

Electron microscopy description
=========================================================================

● Inclusions are lead-protein complex that appear as compact cores surrounded by loose meshwork of fibrils



Tubular and interstitial diseases

Malakoplakia


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also spelled malacoplakia
● Foamy macrophages with PAS+ granular cytoplasm and Michaelis-Gutmann bodies (may be due to deposition of amorphous salts, Am J Surg Pathol 1984;8:151)
● Associated with transplants
● May be due to defective macrophage function that blocks lysosomal degradation of engulfed bacteria, filling up cytoplasm with undigested debris

Case reports
=========================================================================

● 65 year old woman with malakoplakia of kidney extending to descending colon (Korean J Fam Med 2011;32:367)

Gross description
=========================================================================

● Soft, yellow mucosal plaques

Gross images
=========================================================================



55 year old man with recurrent urinary tract infections

Micro description
=========================================================================

● Foamy macrophages with PAS+ granular cytoplasm due to phagosomes stuffed with bacterial debris and Michaelis-Gutmann bodies (laminated mineralized concretions)
● May have rare Michaelis-Gutmann bodies, late fibrous stage (Am J Surg Pathol 1989;13:225)

Micro images
=========================================================================



Various images


55 year old man with recurrent urinary tract infections

Positive stains
=========================================================================

● Calcium (von Kossa), iron (Prussian blue)

Electron microscopy description
=========================================================================

● Intracellular calcific inclusions

Electron microscopy images
=========================================================================



Tongue mass: A-Michaelis-Gutman body has electron-dense core surrounded by granular amorphous osmophilic protein; B-macrophage shows multiple intracellular electron-dense bacillary forms within a large vacuole (asterisk); small Michaelis-Gutman body is seen in an adjacent macrophage (arrow)

Differential diagnosis
=========================================================================

Xanthogranulomatous pyelonephritis: no Michaelis-Gutmann bodies



Tubular and interstitial diseases

Nephrocalcinosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Technically, disease of increased renal calcium levels (eMedicine), but usually refers to chronic tubulointerstitial nephropathy of tubular calcium phosphate deposition causing slowly progressive renal insufficiency
● Less common than nephrolithiasis
● Hypercalcemia can also cause glomerular calcium deposition and glomerulosclerosis (Arch Pathol Lab Med 2003;127:E80)
● Hyperphosphaturia and hypercalciuria types differ histologically (Nephrol Dial Transplant 2012;27:1122)
● Endoscopy may be required to distinguish nephrolithiasis (Urol Res 2010;38:421)

Causes
=========================================================================

● Conditions associated with chronic hypercalcemia, including primary hyperparathyroidism, myeloma or other malignancy; also distal renal tubular acidosis, hypercalciuria due to chronic furosemide use in premature infants (Hum Pathol 2000;31:1363), milk alkali syndrome, oral sodium phosphate as bowel preparation (Hum Pathol 2004;35:675), sarcoidosis, vitamin D intoxication

Treatment
=========================================================================

● Reduce urinary saturation of calcium by increasing fluid intake, crystallization inhibitors, disease-specific medication, (Kidney Int 2011;80:1278)

Micro description
=========================================================================

● Diffuse tubular injury with atrophy, interstitial fibrosis and abundant tubular deposition of calcium phosphate
● Over time, glomerulosclerosis and vascular disease

Micro images
=========================================================================



Various images


Grading system: from rat

Virtual slides
=========================================================================



Nephrocalcinosis

Electron microscopy images
=========================================================================



Calcium deposits (arrows) with glomerular capillary basement membrane and mesangium



Tubular and interstitial diseases

Urate nephropathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

Three types:
● Acute uric acid nephropathy due to precipitation of uric acid crystals in tubules, causing acute renal failure; associated with chemotherapy for leukemia / lymphoma
● Chronic urate nephropathy, associated with gout and lead exposure from drinking “moonshine”
● Uric acid stones, in 22% with gout and 42% with secondary hyperuricemia

● Gout causes deposition of monosodium urate crystals with tophus formation that obstructs tubules, leading to cortical atrophy and scarring (eMedicine)
● Kidney injury molecule-1 expression identifies proximal tubular injury in urate nephropathy (Ann Clin Lab Sci 2008;38:210)

Gross images
=========================================================================



Chronic urate nephropathy


Uric acid stones

Micro images
=========================================================================



Gouty nephropathy



Tubular and interstitial diseases

Xanthogranulomatous pyelonephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare, severe, atypical form of chronic pyelonephritis due to infection (E. coli, Proteus) or stones, but resembling renal cell carcinoma; correct preoperative diagnosis is unusual (Arch Pathol Lab Med 2011;135:671, Arch Dis Child 1999;81:483)
● Characterized by foamy histiocytes replacing renal parenchyma, due to
● High index of suspicion necessary for preoperative diagnosis (Int Urol Nephrol 2011;43:15), intraoperative urine culture may be helpful (Tunis Med 2010;88:427)

Clinical features
=========================================================================

● Destructive inflammatory process that may complicate chronic pyelonephritis
● Usually unilateral, ages 40+, 2/3 women
● Associated with pelvicalyceal obstruction and ulceration
● Rarely coexists with squamous cell carcinoma (J Cancer Res Ther 2010;6:339), renal cell carcinoma (ScientificWorldJournal 2009;9:5)

Case reports
=========================================================================

● 51 year old woman with Liesegang rings (Patholog Res Int 2010;2010:602523
● 68 year old woman with fever of unknown origin and renal mass (Heart Lung 2012 May 31 [Epub ahead of print])

Gross description
=========================================================================

● Multiple yellow nodules around calyces, may form a mass and be infiltrative

Gross images
=========================================================================





Various images

Micro description
=========================================================================

● Replacement of renal parenchyma with CD68+ foamy histiocytes, occasional multinucleated giant cells and inflammatory cells

Micro images
=========================================================================





Various images


Liesegang rings

Differential diagnosis
=========================================================================

Malakoplakia: Michaelis-Gutmann bodies
Renal clear cell carcinoma: cells with clear cytoplasm may resemble histiocytes, but are keratin+, CD68-; arranged in compact, tubulocystic, alveolar or rarely papillary patterns; often glassy hyaline globules; usually nuclear grade 2 or higher; chicken wire / delicate vasculature is common (sinusoids near each packet of cells)
Renal replacement lipomatosis: atrophic renal parenchyma is replaced by fatty tissue, not xanthoma cells (Rev Assoc Med Bras 2011;57:262)



Blood vessel disorders

Atherosclerotic renal disease


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 24 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Often bilateral, causes renal insufficiency; revascularization may help
● Stenting for renal artery stenosis benefits primarily those with rapid decline in GFR pre-stent (Ren Fail 2012;34:142)
● Embolic protection system may be useful post-angioplasty for renal artery stenosis (Catheter Cardiovasc Interv 2012;79:430)

Gross images
=========================================================================



Atherosclerosis of aorta


Renal atrophy due to narrowed renal artery

Micro images
=========================================================================



Renal arteriolosclerosis



Blood vessel disorders

Benign nephrosclerosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called hypertensive nephrosclerosis
● Sclerosis of renal arterioles and small arteries, particularly afferent arterioles, due to hypertension
● Causes focal ischemia, moderate reduction in glomerular filtration rate, moderate proteinuria
● Causes end stage renal disease (QJM 2007;100:113); higher risk if African-American, severe hypertension, diabetes mellitus

Gross description
=========================================================================

● Mildly shrunken kidneys, cortical surface resembles leather

Gross images
=========================================================================



Various images

Micro description
=========================================================================

● Thickened and hyalinized vessel walls, hyaline deposition in arterioles, fibroelastic hyperplasia in lobular / arcuate arteries
● Tubular atrophy, interstitial fibrosis, periglomerular fibrosis and glomerulosclerosis
Hyaline arteriolosclerosis: outer wall thickened by PAS+ eosinophilic and homogenous material, with atrophy of smooth muscle cells in vessel wall and uniform basement membrane thickening; more common in afferent arteriole and vessels lacking an internal elastic lamina; associated with diabetes, hypertension and increasing age; IgM and C3 deposition

Micro images
=========================================================================





Various images

Virtual slides
=========================================================================



Arterio- and arteriolosclerosis

Electron microscopy images
=========================================================================



Thickened glomerular capillary walls



Blood vessel disorders

Diffuse cortical necrosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Necrosis sharply limited to cortex and columns of Bertin
● Rare cause of acute renal failure secondary to ischemic necrosis of the renal cortex (eMedicine)
● May occur after obstetric emergency (J Ayub Med Coll Abbottabad 2010;22:74), due to disseminated intravascular coagulopathy; fatal if bilateral

Gross images
=========================================================================



Various images

Micro images
=========================================================================



Various images

Videos
=========================================================================






Blood vessel disorders

Emboli in kidney


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Occur after surgery for abdominal aortic aneurysm or aortography
● May cause acute renal failure if renal function already compromised
● Often have cholesterol crystals

Micro images
=========================================================================





Cholesterol crystal embolization from upstream coronary artery plaque after percutaneous transluminal coronary angioplasty

Virtual slides
=========================================================================



Multiple atheroemboli



Blood vessel disorders

Hemosiderosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Renal hemosiderosis due to hemolytic anemia is rare cause of renal failure (Am J Pathol 1966;48:409, Indian J Pathol Microbiol 2011;54:379)
● Defined as histologic equivalent of secondary iron overload, usually due to hemosiderin from hemoglobin breakdown, which may be focal
● Typically free serum hemoglobin is bound to haptoglobin, but in severe cases, haptoglobin is overwhelmed, free hemoglobin is filtered by kidney and deposited in proximal convoluted tubules, which may cause renal failure

Case reports
=========================================================================

● 52 year old man with unexplained renal failure (Case of Week #235)

Micro description
=========================================================================

● Hemosiderin is golden yellow to brown, granular cellular pigment

Micro images
=========================================================================





H&E and iron stains

Electron microscopy images
=========================================================================



Groups of dark granules likely made up of heme proteins (white arrows) and autophagolytic lysosomal vacuoles (black arrows) containing mitochondria



Blood vessel disorders

Infarct of kidney


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Usually due to emboli from left atrial mural thrombi or left ventricular myocardial infarction
● Also endocarditis, abdominal aortic aneurysm and atherosclerotic emboli
● Infarcts are "white" anemic type; ringed by intense hyperemia; wedge shaped with apex towards medulla

Gross images
=========================================================================



Wedge shaped hemorrhagic infarcts

Micro images
=========================================================================







Various images

Virtual slides
=========================================================================



Septic infarct



Blood vessel disorders

Malignant hypertensiony and accelerated nephrosclerosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 26 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called hypertensive emergency, malignant nephrosclerosis
● Severe hypertension with acute impairment of one or more organ systems (especially CNS, cardiovascular, renal) that may cause irreversible organ damage

Pathophysiology
=========================================================================

● Vascular damage (due to chronic hypertension, arteritis, coagulopathy) increases permeability of small vessels to fibrinogen and other plasma proteins
● This causes endothelial injury and platelet deposition, which causes fibrinoid necrosis
● Kidneys become ischemic, which stimulates renin-angiotensin system to produce angiotensin II, which causes renal vasoconstriction, as well as increased aldosterone secretion and salt retention, which elevate blood pressure even further
● May be related to increased TRPC3 expression in vascular endothelium (Dtsch Med Wochenschr 2009;134:2224)

Clinical features
=========================================================================

● Usually associated with pre-existing hypertension, glomerulonephritis or reflux nephropathy
● Rarely caused by juxtaglomerular cell tumor (J Med Assoc Thai 2012;95 Suppl 2:S251, J Hypertens 2012;30:974)
● 1-5% of patients with hypertension; higher frequency in young men, African-Americans
● Symptoms: diastolic blood pressure 130 mm or more, cardiac symptoms, encephalopathy, headache, nausea, vomiting, loss of consciousness, proteinuria and renal failure
● Treatment: antihypertensive therapy before irreversible renal lesions develop
● Renal survival has improved; mean proteinuria is important prognostic factor (Nephrol Dial Transplant 2010;25:3266)

Gross description
=========================================================================

● "Flea bitten" appearance of kidney due to pinpoint petechiae on cortical surface

Gross images
=========================================================================



Various images

Micro description
=========================================================================

● Fibrinoid necrosis of arterioles, hyperplastic arteriolitis (onion skinning) due to concentric layering of collagen
● May see necrotizing glomerulitis, wrinkling and collapse of capillary walls and small crescents
● Myointimal hyperplasia and hypertropy is associated with acute or persistent severe high blood pressure
● Necrotizing arteriolitis: fibrinoid necrosis of afferent arteriole, often superimposed on hyperplastic or hyaline lesions; media has deposits of deeply eosinophilic and fibrillar material containing fibrin and fibrinogen
Early changes: profound intimal thickening by myxoid connective tissue, reducing lumen
Late changes: scarring and concentric thickening of vessel wall by myointimal cells and deposition of basement membrane type material (onion skinning)

Micro images
=========================================================================





Various images


TRPC3 expression

Virtual slides
=========================================================================



Onion-skinning of vessels

Immunofluorescence
=========================================================================

● Occasional fibrin, fibrinogen, IgM and complement

Electron microscopy description
=========================================================================

● Swollen endothelium
● May be focally disrupted from glomerular basement membrane by accumulation of electron-dense material



Blood vessel disorders

Renal artery stenosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 26 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Hypertension that responds to ACE inhibitors, with stenosis by intravenous pyelogram or renal scans, bruit, elevated renin
● 2-5% of cases of hypertension, surgery curative in 70%

Causes
=========================================================================

Atheromatous plaque: more common in older men with diabetes, often at orifice of renal artery and associated with aneurysmal dilatation of aorta distal to renal arteries
Fibromuscular dysplasia: more common in younger women; may involve other vessels; not responsive to hypertensive drugs; 50% bilateral, often involve distal 2/3 of renal artery; due to intimal, medial, perimedial or periarterial fibroplasia, medial hyperplasia or medial dissection
Radiation injury: loss of muscle, intense fibrosis in all wall layers; usually after radiation treatment, including renal artery field years previous
Takayasu’s aortitis: also called pulseless disease; chronic sclerosing aortitis of unknown etiology

Case reports
=========================================================================

● 4 year old boy with segmental renal artery stenosis (Am J Surg Pathol 1994;18:512)
● 35 year old woman with aortic coarctation and renal artery stenosis due to fibromuscular dysplasia (Arch Pathol Lab Med 1989;113:809)
● Due to misplaced surgical clips post-nephrectomy (BMJ Case Rep 2012 Aug 13)

Treatment
=========================================================================

● Anti-hypertensive medications
● Angioplasty with stent placement may be effective, even in transplanted kidney (Nefrologia 2012;32:455)
● Revascularization is usually not effective for atherosclerotic renovascular disease (Nephrol Dial Transplant 2012;27:3843, Cardiol Rev 2012;20:189)

Gross description
=========================================================================

● Shrunken kidney

Gross images
=========================================================================



Renal artery stenosis with atrophic kidney

Micro description
=========================================================================

● Diffuse atrophy with crowded and smaller glomeruli, atrophic tubules and interstitial fibrosis (Lab Invest 1991;65:558)
● Arterioles usually normal
● Usually no hypertensive changes in small vessels, although opposite kidney may show hypertensive changes
Medial fibroplasia: multiple foci of stenosis alternate with microaneurysms to produce “string of beads”
Perimedial fibroplasia: normal outer half of media but hyperplasia of muscle causes uniform circumferential thickening of vessel wall with luminal narrowing
Intimal fibroplasia: hyperplasia of intima, resembling atherosclerosis, but without lipid deposition
Periarterial fibroplasia: rare, fibrosis of adventitia extends into adjacent adipose and connective tissue, causing constriction from without

Micro images
=========================================================================



Patient with central renal artery stenosis and persistent allograft dysfunction shows focal acute tubular injury and intratubular proteinaceous cast material (asterisk)



Blood vessel disorders

Sickle cell disease nephropathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Sickle cell trait or disease causes hematuria, decreased concentrating ability
● May be due to ischemia in hypertonic, hypoxic renal medulla due to plugging of vessels in vasa recta
● Mild proteinuria in 30%

Gross images
=========================================================================



Necrotizing papillitis

Micro description
=========================================================================

● Patchy papillary necrosis
● Occlusion of glomeruli by sickled cells
● Extensive congestion and sickling in peritubular capillaries

Micro images
=========================================================================



Sickle cell nephropathy


Case report of collapsing glomerulopathy

Electron microscopy images
=========================================================================



Sickle red cells inside glomerular capillary loop



Blood vessel disorders

Venous thrombi


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Due to trauma, tumor or membranous glomerulonephritis
● Chronic kidney disease is a risk factor (J Thromb Haemost 2010;8:2428)

Case reports
=========================================================================

● 53 year old man with bilateral renal vein thrombosis and subsequent acute renal failure due to IVC filter migration and thrombosis (Clin Nephrol 2010;73:408)
● 62 year old woman with acute bilateral renal vein thrombosis due to sepsis from pyelonephritis (Int Braz J Urol 2012;38:132)
● 74 year old man with renal actinomycosis with concomitant renal vein thrombosis (Clin Nephrol 2012;77:156)

Gross images
=========================================================================


       
Renal vein thrombus



Kidney transplantation

Kidney transplantation-general


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 26 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

Biopsies
=========================================================================

Determine
● (a) if graft failure is due to acute tubular necrosis, drug related nephrotoxicity (cyclosporin, tacrolimus), infections, outflow tract obstruction, primary glomerular disease, rejection, vascular obstruction
● (b) for rejection, intensity and nature, potential reversibility and thus most suitable therapy

Clinical features
=========================================================================

● First transplant performed in 1950 (Wikipedia)
● Better prognosis with living donors and younger donors (Transpl Int 2012;25:1150)
● ABO-incompatible kidney transplantation is effective (Transplant Rev (Orlando) 2012 Aug 14 [Epub ahead of print])
● Mismatches for HLA class II were more strongly associated with hospitalization and death with functionng graft than mismatches for HLA class I.(Am J Transplant 2012 Aug 17 [Epub ahead of print])

Gross images
=========================================================================



Kidney transplant

Micro images
=========================================================================



Post-transplant biopsies



Kidney transplantation

Acute rejection


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 26 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Can occur at any time after transplantation, although usually within months of transplant
● Either acute antibody mediated rejection (morphologic evidence of acute tissue injury, circulating donor-specific allo-antibodies, C4d+; variable cellular infiltrates) or acute cellular renal allograft rejection (infiltration of allograft by lymphocytes and other inflammatory cells)

Gross images
=========================================================================



Various images

Micro images
=========================================================================



Banff 97 classification


Acute antibody mediated rejection

General
=========================================================================

● Also called acute humoral rejection, acute tubulointerstitial rejection
● Associated with poor graft outcome

Micro description
=========================================================================

● Most severe changes are in small arteries, arterioles and veins
Vessels: early changes are neutrophil margination in peritubular interstitial capillaries, swelling and vacuolization of endothelial cells with ulceration, chronic inflammatory cells in intima and vacuolization of smooth muscle cells in media; thrombi are often small and non-occlusive, but in irreversible rejection, become obliterative and widespread with necrosis of vessel wall
Glomeruli: endothelial cell swelling, increased cellularity and occasional thrombosis
Tubules: focal necrosis
Interstitium: hemorrhage

Micro images
=========================================================================





Various images

Virtual slides
=========================================================================



Acute rejection

Immunofluorescence
=========================================================================

● Occasionally complement, IgM and IgG along with fibrin in vessel walls and glomeruli

Electron microscopy description
=========================================================================

● Endothelial cell swelling and separation of endothelium from basement membrane by fluffy fibrillar material, which may contain fibrin or platelet fragments


Acute cellular rejection

General
=========================================================================

● Most common form of rejection; T-lymphocyte mediated
● Usually reversible with therapy

Micro description
=========================================================================

Early: edema, lymphocytic infiltration of interstitium and peritubular capillaries (perivascular in very early stages) and dilation of peritubular capillaries
Late: tubulitis (lymphocytes on internal aspect of tubular basement membrane), increased infiltration by lymphocytes (60% CD8+), plasma cells, macrophages and mast cells, occasional granulocytes; tubulitis is more concentrated in cortex than medulla; phlebitis of arcuate and interlobular veins often present (Hum Pathol 2001;32:1388)

Micro images
=========================================================================





Various images

Immunofluorescence
=========================================================================

● Negative

Electron microscopy description
=========================================================================

● Tubular damage and regeneration, many inflammatory cells in interstitium
● Variable glomerular and vascular changes

Differential diagnosis
=========================================================================

● Urinary tract infection: neutrophilic tubulitis usually more severe than lymphocytic tubulitis, positive cultures


Acute vascular rejection

General
=========================================================================

● Intimal arteritis and transmural arteritis
● Usually mild; interstitial inflammation present, also peritublar capillaritis, usually transplant glomerulitis (Transplant Proc 2012;44:230)
● 40% have CD4d deposition, 25% have antibody mediated rejection
● Usually steroid resistant, requiring greater anti-rejection therapy

Micro images
=========================================================================



Various images



Kidney transplantation

Chronic rejection


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called chronic allograft nephropathy, interstitial fibrosis and tubular atrophy not otherwise specified
● Irreversible end stage of repeated episodes of acute vascular or interstitial rejection
● Occurs months to years after transplantation, independent of acute rejection and specific disease
● Incidence of 55% after 8 years post-transplant in one study (Nephrol Dial Transplant 2011;26:3750)
● Most common cause of graft failure after 6-12 months

Etiology
=========================================================================

● Transplant arteriopathy/capillaropathy and glomerulopathy are induced by alloantigens - systematic assessment of longitudinal changes in alloantibody levels can identify patients at greater risk (Kidney Int 2011;79:1131)
● Inflammation (due to various causes) and tissue remodeling may induce autoimmune responses against self-antigens, leading to chronic rejection (Discov Med 2010;9:229)

Gross images
=========================================================================



Enlarged kidney with surface hemorrhage

Micro description
=========================================================================

Chronic transplant nephropathy: non-specific sclerosing changes (no lesions indicative of immunologic injury, thus a diagnosis of exclusion)
● Resembles nephrosclerosis
● Severe obliterative fibrointimal proliferation or mucoid widening of intima
● Reduplication or disruption of elastic lamina and irregular fibrosis of media
● Variable distribution of vascular lesions; also occasional small thrombi
● Atrophic tubules, diffusely scarred interstitium
● Glomerulosclerosis with ischemic glomerular capillary collapse and thickened capillary walls
Transplant capillaropathy: peritubular capillary profile with 7+ circumferential basement membrane layers or 3 profiles with 5-6 circumferential layers; these findings are specific (except for obstructive uropathy or thrombotic microangiopathy) and sensitive (present in 80%) for chronic rejection; may be due to repeated episodes of endothelial cell damage or death and regeneration

Micro images
=========================================================================





Various images

Virtual slides
=========================================================================



Chronic rejection

Immunofluorescence
=========================================================================

● Negative, occasional linear or granular deposition of IgM, IgG or complement

Electron microscopy description
=========================================================================

● Thickened capillary walls due to widening of subendothelial space or mesangial interposition
● Electron microscopy better than light microscopy to identify microvascular changes (Mod Pathol 2001;14:1200)

Electron microscopy images
=========================================================================



Transplant capillaropathy: various images



Kidney transplantation

Hyperacute rejection


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 26 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Occurs within minutes to hours after revascularization, causing abrupt cessation of urine production
● Due to preformed circulating antibodies in recipient to donor endothelial cells, caused by prior pregnancies, blood transfusions or transplants
● Can perform ABO-incompatible transplants if low titers (Nephrol Dial Transplant 2010;25:3794)
● Rare currently due to routine screening and cross matches

Case reports
=========================================================================

● With negative pretransplantation T- and B-cell flow cytometric crossmatches and blood group identity (Transplant Proc 2008;40:2422)

Gross description
=========================================================================

● Mottled cyanosis and diminished turgor in renal graft

Gross images
=========================================================================



Cortex is blue, edematous and congested.

Micro description
=========================================================================

● Fibrin thrombi in glomerular capillaries, peritubular venules and other vessels leading to infarction and tubular necrosis
● Variable white blood cells within glomeruli, peritubular capillaries and interstitium

Micro images
=========================================================================



Various images

Immunofluorescence
=========================================================================

● Linear staining of IgM or IgG, as well as C3 and C4d along glomerular and peritubular capillaries
● At later stages Ig may not be detectable

Electron microscopy description
=========================================================================

● Capillary occlusion by degranulated platelets and endothelial denudation of glomerular basement membrane
● Also fibrin, sludged red blood cells

Differential diagnosis
=========================================================================

Other conditions that can cause primary graft failure include:
Acute tubular necrosis
● Perfusion injury
● Major vascular occlusion



Kidney transplantation

Banff classification of rejection


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

Banff '07 classifcation of Renal Allograft Pathology updated Banff '97 classification
● Adequate core biopsy must contain 10 glomeruli and 2 arteries (marginal if 7-10 glomeruli and 1 artery; unsatisfactory if < 7 glomeruli or no arteries)
● Every renal allograft biopsy should be stained for C4d

1. Normal

2. Antibody-mediated rejection: C4d deposition, acute antibody-mediated, chronic active antibody-mediated

3. Borderline changes: “suspicious” for acute T cell mediated rejection

4. T cell mediated rejection:
Acute T cell mediated rejection
Type IA: Cases with significant interstitial infiltration (> 25% of parenchyma affected, i2 or i3) and foci of moderate tubulitis (t2)
Type IB: Cases with significant interstitial infiltration (> 25% of parenchyma affected, i2 or i3) and foci of severe tubulitis (t3)
Type IIA: Cases with mild to moderate intimal arteritis (v1)
Type IIB: Cases with severe intimal arteritis comprising > 25% of luminal area (v2)
Type III: Cases with “transmural” arteritis or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3)
Chonic active T cell mediated rejection
'Chronic allograft arteriopathy' (arterial intimal fibrosis with mononuclear cell infiltration in fibrosis, formation of neo-intima)

5. Interstitial fibrosis and tubular atrophy, no evidency of any specific etiology
Grade I: Mild interstitial fibrosis and tubular atrophy (<25% of cortical area)
Grade II: Moderate interstitial fibrosis and tubular atrophy (26-50% of cortical area)
Grade III: Severe interstitial fibrosis and tubular atrophy/loss (>50% of cortical area)

6. Other: Changes not considered to be due to rejection

Quantitative criteria for mononuclear cell interstitial inflammation:
ti0: no or trivial interstitial inflammation (<10% of parenchyma)
ti1: 10-25% of parenchyma inflamed
ti2: 26-50% of parenchyma inflamed
ti3: >50% of parenchyma inflamed

References: Evolution of Banff schema (Indian J Nephrol 2010;20:2), no change in 2011, next meeting in 2013 (Am J Transplant 2012;12:563)

Micro images
=========================================================================



Histopathologic lesions of acute rejection as defined by Banff 97 classification


Borderline rejection


Intimal arteritis (v2)


Tubulitis (t3)


Extensive tubular atrophy and interstitial fibrosis (IFTA Grade III)



Miscellaneous

Dialysis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Artificial replacement for lost kidney function in people with renal failure (Wikipedia)
● Treatment may cause acquired cystic kidney disease, papillary adenoma, acquired cystic kidney disease related carcinoma, clear cell papillary renal cell carcinoma
● Associated with beta2 microglobulin amyloidosis, usually affecting bone or joints, occasionally viscera (J Am Soc Nephrol 1997;8:509)

Case reports
=========================================================================

● Rare fatal air embolism after dialysis (Am J Forensic Med Pathol 2012;33:110)

Micro description
=========================================================================

● Arterial intimal thickening, calcium oxalate crystals in tubules

Micro images
=========================================================================



Calcium oxalate crystals (various causes)



Miscellaneous

Obstructive uropathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 26 December 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Obstructive uropathy is structural or functional hindrance of normal urine flow, sometimes leading to renal dysfunction (obstructive nephropathy)
● Acute obstruction increases susceptibility to infection; chronic obstruction causes hydronephrosis
Causes: bladder neck obstruction, congenital (meatal stenosis, anterior/posterior urethral valves [Pediatr Surg Int 2009;25:613], ureteropelvic junction narrowing, urethral strictures, vesicoureteral reflux); cystocoele, inflammation, neurogenic ureter / bladder, pregnancy, prostatic hypertrophy, sloughed papillae or blood clots, stones, tumors, uterine prolapse
Symptoms: none if unaffected kidney maintains adequate function; pain due to distention of collecting system or renal capsule; early - nocturia, polyuria; after relief of obstruction, may get massive diuresis with sodium wasting
Hydronephrosis: cystic dilation of renal pelvis and calyces associated with progressive atrophy of kidney, due to obstructive uropathy

Gross description
=========================================================================

● Thin cortical rim due to atrophy
● More calyceal dilation if incomplete obstruction, since glomerular filtration is not suppressed

Gross images
=========================================================================



Various images

Micro description
=========================================================================

● Initial functional alterations are tubular, cause interstitial inflammatory infiltrate
● Chronic changes are cortical atrophy, diffuse interstitial fibrosis and blunting of calyces

Micro images
=========================================================================



Tubular atrophy, interstitial fibrosis and interstitial inflammation


Grading of obstructive uropathy



Miscellaneous

Radiation nephropathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 December 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

Acute radiation nephropathy: 6-12 months after radiation exposure, may occur quicker in children; gradual onset of edema, hypertension, dyspnea after exertion, pleural and peritoneal serous effusions, anemia, headaches, proteinuria and urinary casts; associated with reduction in glomerular filtration rate and renal failure in 50%; those who recover have persistent proteinuria and renal impairment; overall high mortality rate (eMedicine)
Chronic radiation nephropathy: either follows acute phase or develops insidiously; mild proteinuria and moderate hypertension years after radiation exposure
● Severity is related to dose, method of irradiation, age, amount of perirenal fat, presence of renal disease and use of chemotherapy

Micro description
=========================================================================

● Glomeruli: segmental fibrinoid necrosis, thickened glomerular capillary walls with double contour (silver stain), variable glomerulosclerosis and prominent mesangium
● Tubules: swelling of tubular epithelium with desquamation, basement membrane thickening and splitting, tubular loss and atrophy; often abnormal tubular regeneration; focally scarred interstitium without inflammation
● Vessels: fibrinoid necrosis of arterioles and small arteries with variable thrombosis

Micro images
=========================================================================



Nephropathy associated with bone marrow transplantation (PAS stain); glomerulus is relatively hypocellular, glomerular basement membranes are not thickened; but are separated from capillary lumens focally by a low-density, matrixlike material; increased mesangial matrix is present; interstitial fibrosis separates tubules from each other; arteriolar thickening and arteriolar hyalin are present


Bone marrow transplant related radiation nephropathy


Glomerular basement membrane splitting (arrowhead), mesangial expansion (asterisk), subendothelial accumulation of amorphous material, and focal intracapillary thrombi (arrow); interstitial expansion but only scant inflammatory infiltrates

Immunofluorescence
=========================================================================

● Focal IgM and fibrinogen

Electron microscopy description
=========================================================================

● Widened glomerular subendothelium due to fibrin or flocculent material (Arch Pathol Lab Med 1977;101:469)
● May have focal extension of mesangium into subendothelial space
● Swollen or focally detached endothelium

Electron microscopy images
=========================================================================



Bone marrow transplant related radiation nephropathy



Miscellaneous

Urolithiasis (stones)


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 26 December 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Stones within collecting system of kidney are present in 5-10% of Americans; most commonly in men ages 20-49
● Due to supersaturation of stone constituents, decreased urine volume or deficiency of crystal inhibitors in urine

Clinical features
=========================================================================

● 80% unilateral, usually in calyces, pelvis or bladder
● Usually only 2-3 mm, but with severe, abrupt flank pain and hematuria
● All stones contain an organic matrix of mucoprotein

Types of stones
=========================================================================

Calcium oxalate / phosphate (75%): due to hypercalciuria (idiopathic, 50%), hypercalcemia (infants may have high Vitamin D levels, Iran J Kidney Dis 2012;6:186), hyperoxaluria (in vegetarians with oxalate rich diet), hyperuricosuria (hyperparathyroidism, bone disease, sarcoidosis) and rarely primary hyperoxaluria (Arch Pathol Lab Med 2002;126:1250); oxalate crystals are highlighted by polarized light; are accompanied by foreign body giant cells and macrophages
Struvite (triple stones, magnesium ammonium phosphate, 15%): due to urea-splitting bacteria (Proteus, Staphylococcus); produce staghorn calculi
Uric acid (6%): due to hyperuricemia, chemotherapy for leukemia, uricosuric drugs or excess dietary proteins; 50% lack elevated uric acid in blood / urine; may be due to acidic pH; radiolucent; may become staghorn calculi if in renal pelvis; elongated and rectangular crystals in collecting tubules or doubly refractile crystals in interstitium with giant cell reaction
Cysteine (1%): due to genetic defects in cystine transport (Orphanet J Rare Dis 2012;7:19); autosomal recessive, affects 1 per 20,000; yellow-brown and radioopaque stones form at low urinary pH; crystals are flat hexagons in urine
Ammonium acid urate: rare, but more common in Asia (Kaohsiung J Med Sci 2012;28:259)
Stone granuloma: complication of ureteral stone fragmentation and instrumentation
Xanthinuria (rare): autosomal recessive, due to deficient xanthine oxidase, causing excessive xanthine levels and stones in 1/3 with this disorder

Diagrams
=========================================================================



Diagram

Case reports
=========================================================================

● 48 year old man with nephrectomy for renal mass due to urolithiasis caused by 2,8-dihydroxyadenine crystals (Hum Pathol 1992;23:1081)

Gross images
=========================================================================



Various images

End of Kidney non tumor > Superpage part 2


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