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Renal Pathology: Tubulointerstitial Nephritis and Granulomatous Diseases
- 1. Presenter : Dr. Pallavi Prasad Senior Resident, SGPGIMS
- 2. • Involvement of the renal interstitium and tubules by inflammatory cells + edema or fibrosis + tubular atrophy • Tubulointerstitial nephritis= tubulointerstitial nephropathy
- 4. • Gross: kidneys are pale, edematous, enlarged • External surface is smooth
- 5. • M/F : cellular infiltration and edema (neutrophils, mononuclear cells, macrophages) • Drug reactions- lymphocytes, eosinophils • Late stages : monocytes/macrophages >> • Plasma cells, histiocytes • Granuloma formation
- 9. 1) Tubular cell regeneration: flattening of the epithelial lining cytoplasmic basophilia enlarged nuclei with prominent nucleoli 2) Interstitial fibrosis 3) Presence of monocytes/macrophages 4) Granulomas
- 10. • Linear deposits of antibody and complement along the TBM - antibody directed to/cross-reactive with TBM • Granular deposits - immune complex pathogenesis • Granular or linear TBM staining for complement (C3) • Nonspecific (basement membrane of atrophic tubules)
- 11. Electron-dense immune-type deposits along the TBM/in interstitium SLE Crystalline inclusions in tubular epithelial cells or finely granular electron-dense deposits along the TBM MIDD Viral particles in infected tubular epithelial cells Viral etiology
- 13. Infections Drug reactions Urinary tract obstruction and sterile reflux of urine Immune-mediated Plasma cell dyscrasias Metabolic disorders Exposure to heavy metals Hereditary diseases Various chronic nephropathies, including idiopathic TIN Progressive chronic primary glomerular disease Systemic autoimmune diseases, monoclonal gammopathies, metabolic diseases Vasculitis Chronic TMA Ischemia secondary to atherosclerosis and hypertension
- 14. • Gross : small, contracted, and pale, Scarred or finely granular • Variable papillary involvement: necrosis, sclerosis, calcification • Corticomedullary junction - poorly demarcated
- 15. • M/F : lymphocytes, monocytes/macrophages, plasma cell • Granulomas • Tubular atrophy and interstitial fibrosis - histologic hallmarks • Deposited extracellular matrix – collagen types I, III, and V, (interstitial fibroblasts) and type IV (endothelial and tubular epithelial cells)
- 17. compensatory hypertrophy of tubules Microcystic dilatation
- 18. • Granular deposits of immunoglobulin and complement along the TBM and interstitium - immune complexes • C3 deposition-nonspecific finding in the basement membrane of atrophic tubules
- 19. Thickened lamellated basement membrane Deposits of granular to microspherical material..
- 21. • Native renal biopsy-45y/F
- 27. Drugs Infections : Tuberculosis, fungal, brucellosis, parasites Sarcoidosis Tubulointerstitial nephritis and uveitis syndrome (TINU) Granulomatous vasculitis (Wegener's) Oxalosis Gout Cholesterol granuloma Idiopathic
- 28. • M/C interstitial nephritis • Urinanalysis : pyuria,(eosinophils- specific marker for allergic IN) • Eosinophils -Hansel stain • Microscopic hematuria, mild proteinuria
- 29. Glomeruli spared Ischemic collapse and sclerosing changes Periglomerular fibrosis Tubular cell injury (vacuolation, loss of brush border, exfoliation and loss of tubular cells) Tubulitis Eosinophils = penicillins, sulfonamides, and rifampicin Neutrophils –rare Basophils 1-2% Granuloma- noncaseating Vessels - uninvolved Few- vasculitis In chronic TIN: interstitial fibrosis Mild II-nodular and localized to fibrotic areas
- 30. • No/minor LM changes • Acute tubular necrosis , interstitial nephritis • Granuloma • Glomeruli: MCD, membranous glomerulopathy
- 31. • Contracted kidneys • Subcapsular surface shows irregularly alternating depressed and raised areas • papillary necrosis yellow stripes confluent lying free
- 32. a) Chronic pyelonephritis/reflux nephropathy b) Diabetic nephropathy (no capillary sclerosis beneath the urothelium ) c) Sickle cell disease d) Vasculitis e) SLE
- 33. Earliest : sclerosis of capillaries beneath the urothelial mucosa capillary sclerosis involves the ptc in the papilla and inner medulla Thickened basement membranes are PAS+ and contain lipid & calcium Ultrastructurally this basement membrane thickening =numerous thin layers of basement membrane material
- 34. • Peculiar tubular lesion - cytoplasmic ballooning or vacuolation with strands of PAS+ material in the vacuolated cytoplasm • Microcystic dilatation of tubules
- 35. • Interstitial nephritis • Eosinophils ** • Granulomas • Rifampicin • Interstitial edema with variable numbers of mononuclear cells • Granulomas • Tubular necrosis • Pigmented casts • Glomeruli and vessels are usually normal
- 36. • Crystalluria-early complication • Acute interstitial nephritis (indinavir) • Morphologic findings do not differ from other forms of drug-induced interstitial nephritides. Proton-Pump Inhibitors
- 37. • Native renal biopsy -15y/F
- 43. • Gross : white nodules (i.e., tubercles) • Cortex > medulla
- 44. • Interstitial nephritis and epithelioid or caseating granulomas • Stains for acid-fast bacilli : usually negative • Immunocompromised patients- atypical mycobacterial infections (m. Avium-intracellulare) which does not form typical granulomas • Abundant mycobacteria - in foamy-appearing macrophages
- 45. • Gross : enlarged or decreased size • Irregular scarring • On cut section, the calyces and the pelvis are dilated or deformed, parenchymal atrophy and foci of calcification • Involvement of the papilla by caseating necrosis • Segmental ureteral strictures (ureteral involvement) • “Cement,” “putty,” or “chalk” kidney
- 46. • M/F : tubercle
- 47. • Granulomas = abundant, sharply delineated with many epithelioid cells and many giant cells • Noncaseating epithelioid granulomas (positive correlation between serum ACE levels and granuloma formation) • Nephrocalcinosis • Interstitial nephritis • Hypercalciuria
- 49. TINU Oxalosis/Gout Wegener’s Idiopathic Cholesterol granulomas Proximal tubule dysfunction-Fanconi's syndrome, renal insufficiency, proteinuria, renal failure, uveitis Afer small intestine bypass surgery With sarcoid features Isolated renal sarcoidosis Mononuclear inflammatory infiltrate Eosinophils ++ Few granuloma Foreign body type No of granuloma varies granuloma Acute tubular injury and flattening of the tubular epithelium Localised around crescent damage and involve arteries Noncaseating granulomas- bone marrow, lymph nodes, kidneys
- 50. Infections : Tuberculosis, fungal, brucellosis, parasites Drugs Sarcoidosis Tubulointerstitial nephritis and uveitis syndrome (TINU) Granulomatous vasculitis (Wegener's) Oxalosis Gout Cholesterol granuloma Idiopathic
- 51. • 23 y/F • C/O fever x 1 month; nausea and vomiting; right flank pain x 20 days • No H/O hematuria or lithuria • No medical comorbidities • Evaluation outside reported : TLC - 46400 • Urine R/M - 40 - 50 WBC /HPC • S creat - 1.40 mg/dl CECT KUB ( 27/9/16): Rt kidney enlarged Wedge-shaped large non enhancing area in upper pole & mid pole
- 52. HE 10 X
- 53. HE 20 X
- 54. CSM 20 X
- 55. 10X6X4 cm
- 58. HE 20 X
- 59. HE 40 X
- 60. CSM 40 X
- 61. PAS 40 X
- 62. • Fungal infection S/O Mucormycosis
- 63. Candida Aspergillosis Cryptococcus Histoplasmosis Mucormycosis Opportunistic Mucosal surfaces A. Fumigatus Pigeon droppings Resp tract Bird/bat dropping-soil Opportunistic Inhalation of spores Candida casts in urine Respiratory tract, mucosal surfaces, i/v Urine sediment:india ink+culture Fungal balls- Pelvis, calyces Abscess surr by red rim Vascular thrombi, infarction Well- circumscribed nodules to diffuse necrosis Rarely isolated renal involvement Vessel thrombosis- infarction Little/no inflammation Ext necrosis Miliary abscess Papillary necrosis Mycotic aneurysms Extensive abscess formation Vacular invasion, thrombosis Infarction inflammation Abscesses Granuloma Necrosis Papillary necrosis Tubular destruction Aggregates of yeast-laden macrophages Suppurative, necrotising inflammation with thrombosis Granuloma Giant cells fibrosis Broad, non- septate, right angled branching 2-4 µ pseudohyphae 3-5µ hyphae 4-20µ spherical (capsule) 5µ yeast forms
- 64. • 47y/F • Renal allograft recepient [Date of transplantation 27/7/16] • ABO-compatible renal transplantation • Admitted for acute graft dysfunction • Rise in creatinine to 2.7 from 1.5 mg/dl • H/o decreased urine output x 1week • No h/o dysuria , urgency , frequency, haematuria , • No h/o obstruction • No c/o dysuria,flank pain,pain abdomen
- 71. • Renal graft biopsy : Acute combined humoral and cellular rejection with viral cytopathic changes
- 72. In renal transplant pts Others Polyoma and BK virus CMV Adenovirus EBV Hantavirus Dengue Parvovirus Coxsackie HIV
- 74. Polyoma virus nephropathy Type 1 Type 4Type 3 Type 2
- 76. 1) PVN grade 1 (early phase) : few intranuclear inclusion bodies , minimal tubular injury 2) PVN grade 2 (florid phase) :marked viral replication , severe tubular injury, tubulitis, focal denudation of TBMs, diffuse inflammatory cell infiltrate in the interstitium 3) PVN grade 3 (sclerosing phase) : marked IFTA
- 77. Cytomegalovirus Endothelial swelling, hypertrophy/ necrosis Obliteration of capillary lumen Fibrillar deposits in glomeruli Mild segmental mesangial hypercellularity
- 78. Adenovirus
- 79. Frank tubular destruction necrosis granuloma Interstitial hemorrhage When to suspect adenovirus ??
- 80. Early lesions Reactive plasmacytic hyperplasia Infectious mononucleosis-like Polymorphic posttransplant lymphoproliferative disorders Monomorphic posttransplant lymphoproliferative disorders B-cell neoplasms : DLBCL, Burkitt/Burkitt-like lymphoma, Plasma cell myeloma, Plasmacytoma-like lesions T-cell neoplasms : Peripheral T-cell lymphoma, other types Hodgkin lymphoma
- 82. • Interstitial inflammation with mononuclear cells • Plasma cells may occasionally be abundant
- 83. • Increased number of IgG4-positive interstitial plasma cells • Interstitial fibrosis • >10 IgG4-positive plasma cells/HPF
- 84. • Croatia, Bosnia, Serbia, Bulgaria, and Romania • GSTM-1 allele of the glutathione S-transferase • Aristolochic acid = nephrotoxin and carcinogenic agent present in Aristolochia • Contaminants of wheat grains in endemic regions • DNA adducts
- 85. • Finely granular or smooth,cortex is thin • Abundant interstitial fibrosis, inflammation tumors pelvis & ureter TCC, SCC, papillomas
- 86. • aristolochic acid [Chinese herb Stephania tetrandra] • DNA adducts • Extensive IFTA, sparse II • Interlobular arteries - fibromucoid intimal thickening • Glomerular global sclerosis, collapse & ischemic changes
- 88. • Obstructive acute pyelonephritis - enlarged kidney with a bulging cut surface • Cortex : scattered, small, discrete, whitish-yellow abscesses with a hemorrhagic rim; medulla - whitish-yellow streaks
- 89. • Papillary necrosis • Pelvis and calices are dilated (obstruction) and the mucosal surfaces congested • severe obstruction thinned renal parenchyma blunted papillae pelvis filled with pus pyonephrosis
- 90. White cell casts microabscess neutrophils in ptc Destruction of tubules
- 92. • Parenchymal abscesses, infarction, gas formation in the necrotic areas • Papillary necrosis + vascular thromboses
- 93. • With the renal capsule stripped, coarse, depressed scars are evident on the cortical surface • Dilated pelvicalyceal systems, pelvic wall is thickened and granular • Stones • Blunting of the papillae
- 95. • Xanthogranulomatous Pyelonephritis • Malakoplakia • Megalocytic Interstitial Nephritis • Mycobacterial Infections • Fungal Infections • Viral Nephropathies • Syphilis • Actinomycosis • Nocardiosis • Parasitic Infections
- 96. Xanthogranulomatous Pyelonephritis Malakoplakia Megalocytic Interstitial Nephritis Enlarged kidney Adhesions to surrounding renal tissue, perirenal fibrosis Dilated pelvis , cortical thinning staghorn stones necrotic material and pus Yellowish parenchyma yellowish or tan nodules Diffuse involvement with multiple grayish foci of various sizes finely granular foam cells (PAS+) Lipid=neutral fat+cholesterol ester Inflammation Fibrosis , foreign-body giant cells polygonal cells-foamy eosinophilic cytoplasm PAS+ granules inclusions, 4 -10 µ (Michaelis-Gutmann bodies) Inflammation Damaged tubules Interstitial fibroblastic & collagenous reaction Polygonal cells with a coarsely granular eosinophilic cytoplasm (PAS+) D/D malakoplakia Prediagnostic phase of malakoplakia Focal variant: D/D clear cell RCC
Editor's Notes
- Because interstitial nephritis is commonly accompanied by variable tubular damage,
- with the degree of enlargement proportional to the extent of involvement.
- Eosinophils are common in drug-induced cases, but their absence does not exclude a drug-induced form of interstitial nephritis
- Tubular rupture with expulsion of Tamm-Horsfall protein from the tubule into the interstitium. Note the interstitial inflammatory cell infiltrate around the Tamm-Horsfall protein. This is a nonspecific finding that can occur in any renal injury with tubular disruption and secondary interstitial Tamm-Horsfall protein deposits
- Biopsies taken several days after the initial insult show features of
- and immunohistochemical techniques are rarely helpful in determining the underlying cause.
- inflammatory cells may be scarce or absent.
- The “endocrineâ€-type atrophic tubule has a narrow lumen or no lumen at all, is usually prominently reduced in diameter, and has simplified epithelium and a thin basement membrane. These endocrine-type atrophic tubules usually occur in clusters.
- hypertrophic tubules are lined usually with tall proximal-appearing tubular epithelial cells. The lumen is dilated and commonly irregular (microcystic tubules usually have a thin simplified epithelium and are filled by proteinaceous homogeneous material. Sometimes the microcysts may have a scalloped outline
- result of repeated tubular epithelial injury and regeneration. The regenerating renal epithelium probably creates newer and newer thin layers of basement membrane material, which will lend a lamellated pattern ). This material should not be misinterpreted as immune complex deposition.
- In contrast to acute tubulointerstitial nephritis, in which glomeruli are usually spared, secondary to poor glomerular blood perfusion Arterial and arteriolar changes - usually present, aging, HT
- 33/48 sclerosed
- moderate tubular atrophy and moderate interstitial fibrosis.
- Drug/idio
- similar to those of other interstitial nephritides, mononuclear interstitial infiltrate Mild interstitial edema and inflammation, associated with acute tubular injury, in a patient following NSAID administration. The glomerulus is unremarkable. This patient had nephrotic syndrome and acute renal failure. The renal failure and proteinuria reversed after discontinuation of NSAIDs
- Portion of a kidney with advanced analgesic nephropathy. Note the pale grey-white papilla, representing papillary sclerosis/necrosis The depressed areas correspond to atrophic, scarred portions of the cortex above a necrotic papilla. The nodular areas correspond to the hypertrophic areas of the cortex above the columns of Bertini. no inflammatory reaction around a necrotic/sclerotic papilla. The ghost structure of the renal papilla is still recognizable Interstitial fibrosis and tubular atrophy
- The irregular bumpy cortical contours with underlying papillary necrosis and sclerosis are distinct from the medullary and cortical scarring with caliceal deformities in
- At a more advanced stage (in early stages of papillary necrosis), the
- One has to remember, however, that microcystic dilatation of the tubules is a nonspecific finding and is commonly seen in any chronic tubulointerstitial disorder.
- may be contained and heal, or the infection may expand.
- When this occurs, the renal parenchyma is replaced by caseous material, leaving rims of fibrous tissue imparting a loculated appearance to the organ. This condition is also known as
- Microscopically, these lesions show central caseous debris surrounded by a peripheral granulomatous reaction (see Fig. 24.28). Mycobacteria are found in peripheral areas of caseation or cavitary lesions. Less involved areas may show variable interstitial inflammation with lymphocytes and plasma cells amidst calcific foci, probably representing calcified tubercles.
- granulomas may be missed in a kidney biopsy specimen and sometimes just an interstitial mononuclear cell infiltrate is seen
- Sarcoidosis, which may be engulfed by giant cells.
- The interstitial infiltrate is mostly mature lymphocytes. Only rare immunoblasts are seen The number of transformed cells is increased, with many immunoblasts. Focal necrosis is seen
- Many plasma cells in an acute and chronic interstitial nephritis, in a patient with Sjögren syndrome.
- These discrete cortical abscesses are indicative of a secondary blood-borne infection, because obstructive pyelonephritis in the acute stage very commonly gives rise to bacteremia Cortical abscesses produce discrete or confluent, raised, yellowish-white, rounded nodules with surrounding hyperemia on the subcapsular surface Abscesses are apparent on the cut surface of the cortex, and there are straight yellow streaks and hyperemia in the medulla
- The kidney is converted into a pus-filled sac, with little identifiable parenchyma. The mucosa of the collecting system is focally hemorrhagic and covered by creamy exudate; it contains several calculi.
- Acute pyelitis; neutrophils erode the lining epithelium forming microabscesses. (H&E; neutrophils appear first in peritubular capillaries ( White cell casts in acute pyelonephritis. (H
- The medullary infiltrate has a typical linear distribution, and collecting ducts are filled with polymorphonuclear leukocytes The necrotic papilla has the usual intense inflammatory border
- as formation in necrotic tissue produces circular spaces resembling pulmonary emphysema. (H&E; ×200
- Chronic pyelonephritis. A: Tubule thyroidization composed of atrophic or dilated tubules with flattened epithelium containing eosinophilic, waxy casts. B: The cortex is thin above the dilated calyx. Lymphoid follicles in the cortex and in the pericalicial region, tubular atrophy and pericalicial fibrosis are present. (
- von Kossa for calcium, and the Prussian blue reaction for iron