Systematic pathology Kidney and urinary tract pathology Kidney diseases Congenital diseases û Renal agenesis (bilateral) ð incompatible with life û Renal dysplasia (uni-, bilateral) ð developmental disorder due to abnormal morphogenesis and differentiation. Parenchyma with foci of immature renal tissue. ðClinically: diff.dg. x renal tumors of childhood Congenital diseases û Horseshoe kidney (ren arcuatus) ð both kidneys fused by their lower poles û Cysts and cystosis 2 main forms : ð autosomal recessive polycystic kidney disease • Infantile, microcystic • death commonly soon after birth, kidneys completely replaced by multiple cysts < 2mm Congenital diseases ð Adult polycystic kidney disease • common congenital disease, ↓of renal function in the 3.- 4. dec., autosomal dominant - gen usually on the short arm of chromosome 16 • gross: symmetrical kidney enlargement – lenght to 30 cm, multiple cysts 0,5-50mm Congenital diseases ð Solitary kidney cysts • accidental finding . Important diff. dg x cystic renal carcinoma Polycystic kidney Vascular kidney disorders û Renal artery stenosis ð renovascular hypertension (Goldblatt‘s) ð pressure ↓ in afferent arterioles ð↓ of filtration pressure in the glomerulus ð juxtaglomerular apparatus hyperplasia + renin overproduction ð blood pressure ↑ - by longer duration - vascular atrophy. Vascular kidney disorders û Benign nephrosclerosis ð by benign (compensated) hypertension • gross : symmetrical decrease in size, fine granulated surface • micro : hyalinne insudates in arteriolar walls, median hypertrophy + intimal sclerosis, ischemic changes +/- glomerular loss, vascular atrophy of the tubules, adjacent interstitial fibrosis. Benign nephrosclerosis Ischemic glomerular chamges, „wrinkling“ of the GBM Benign nephrosclerosis Vascular kidney disorders û Malignant nephrosclerosis ð due to accelerated arterial hypertension (diastole >130mmHg), endothelial damage •gross : renal oedema, infarctions possible •micro: oedema, intimal mucoid seepage in arteries, fibrinoid necrosis of the arteriolar wall, possible trombi Malignant nephrosclerosis Singificant arteriolar luminal narrowing, endothelial oedema Malignant hypertension Fibrinoid necrosis of the hilar arteriole Malignant nephrosclerosis Oedema, mucoid intimal seepage, luminal narrowing in a muscular artery Vascular kidney disorders û Thrombotic microangiopathy (HUS, TTP) ð endothelial damage + platelet trombi formation in the systemic microcirculation ð platelets consumption •gross: renal oedema, infarctions possible •micro: intimal oedema, endothelial distention, platelet trombi, infarctions Thrombotic microangiopathy Luminal thrombi in glomerular capillaries Vascular kidney disorders û renal infarction ð ischemic coagulative necrosis due to blockage of peripherale branches of the renal artery •gross: yellowish conical necrosis •micro: necrosis with haemorragic rim Renal infarction Renal infarction coagulativeí necrosis Glomerular diseases û Glomeral damage caused by various factors ð vascular changes ð metabolic diseases ð familiar diseases ð immune-mediated disorders Normal glomerulus Mechanism of the glomerular damage û Immune-mediated damage ð circulating immune complexes ð in situ immune complexes ð anti-GBM antibodies ð antineutrophilic antibodies Mechanism of the glomerular damage û Non-immunological damage ð haemodynamic factors ð hypertension ð ischemia Glomerular reaction to the damage û proliferation: ðhyperplasia of mesangial, endothelial, epithelial cells – hypercellularity. Epithelial cells (podocytes) may be a part of crescents filling the Bowman‘s capsule. û exudation: ðleukocytes + fibrin û thickening of the glomerular capillary wall ðusually due to deposition of immune complexes and/or GBM reaction Glomerular reaction to the damage û sclerosis: ð eosinophilic material consisting of the mixture of collapsed membranes, mesangial matrix and plasmatic proteins. PAS + silver impregnation highly positive û hyalinosis: ð foci of refractive amorphous material comprising insudated plasmatic proteins and lipoproteins (PAS intensive positivity, silver impregnation negative) Clinical presentation of the glomerular disorders ð According to the number of affected glomeruli • diffuse changes (> 50% of gl.) • focal changes ðAccording to the extent of glomerular lesion • global changes (the whole gl.) • segmental changes Clinical presentation of the glomerular disorders û nephritic syndrome: ð acute gl. damage, hematuria, proteinuria, oligouria, oedema, hypertension û nephrotic syndrome: ð severe proteinuria with protein loss> 3,5g/24h, hypoalbuminemia, decrease of production of concentrated urine, oligouria → anuria, ↑ azotemia Clinical presentation of the glomerular disorders û acute renal failure: ð sudden decrease of production of concentrated urine, oligouria → anuria, ↑ azotemia û chronic renal failure: ð gradual loss of renal functions Glomerular diseases classification û Mostly according to the clinical signs ð Glomerulopathy with proteinuria or nephrotic syndrome ð Glomerulopathy with isolated or predominant hematuria Glomerular diseases classification ð Glomerulopathy with acute nephritic syndrome ð Glomerular/kidney involvment by SLE ð Chronic glomerulonephritis Glomerular diseases classification û primary x secondary GN ð primary GN – disorder limited to the kidney, without systemic disease ð secondary GN – part of other disease ( SLE, hepatitis C, neoplasia, … ) Glomerulopathies manifestated by proteinuria/nephrotic sy Glomerulopathies with proteinuria/nephrotic sy û Minimal glomerular change disease ð mostly in children‘s age ð heavy selective proteinuria (albuminuria) ð nefrotic syndrome responsive to steroid therapy ð normal renal functions • LM: normal glomerular morphology • IMF: negative, without immunodeposits • EM: diffuse fusion of podocytes‘ foot processes Minimal glomerular change disease Normal glomerular morphology Minimal glomerular change disease (EM) diffuse fusion of podocytes‘ foot processes Glomerulopathies with proteinuria/nephrotic sy û Focal segmental glomerulosclerosis (FSGS) ð children, adults (↑ incidence) ð non-selective proteinuria up to nephrotic type ð nephrotic syndrome, steroid-resistant ð gradual progression to the renal failure • LM: Focal segmental sclerotic and hyalinne gl. changes due to capillary loops collapse and mesangial expansion • IMF: negative, without immune deposits • EM: fusion of podocytes‘ foot processes and podocytes‘ detachment from the GBM FSGS Segmental sclerosis of the capillary tuft Glomerulopathies with proteinuria/nephrotic sy û Membranous glomerulopathy ð immune complex-mediated glomerulopathy, mostly in adults. ð proteinuria of nephrotic type, hematuria. • LM: diffuse and global gl. involvment, normocellular. Deposition of immune complexeson the outer aspect of the glomerular basal membrane (GBM), thickened in futher stages. • IMF: granular deposits along GBM (IgG, C3) • EM: subepithelial electron-dense immune deposits Membranous glomerulopathy Diffuse GBM thickening Glomerulus without inflammation or proliferation Membranous glomerulopathy (IMF) Granular deposits along the GBM in IgG Membranous glomerulopathy (EM) Diffuse subepithelial (outer aspect of the GBM) immune deposits Glomerulopathies with proteinuria/nephrotic sy û Amyloidosis ð extracellular deposition of pathological fibrilary protein with typical staining features ð systemic amyloidoses most clinically important ð 4 main groups: • AA amyloidosis (SAA protein precursor) in chronic diseases (RA, IBD, …) Amyloidosis • AL amyloidosis (precursor - plasma cell product) in monoclonal plasma cell disorders • hereditary amyloidosis: genetically determinated protein defect ( transthyretin) • amyloidosis associated with haemodialysis Amyloidosis ð proteinuria with nephrotic syndrome • LM: structure-less eosinophilic masses in the glomeruli, tubules, intersticium and vessels Positive Congo red staining, green dichroism in polarisation • IMF: positivity of AA amyloid, light chains • EM: non-branching, randomly orientated fibrils, size of 6-13nm Amyloidosis Amyloid deposition in the glomerulus Amyloidosis Congo red-positive amyloid deposition in the glomerulus Glomerulopathies with proteinuria/nephrotic sy û Diabetic glomerulopathy ð renal involvment by diabetic microangiopathy ð proteinuria of nephrotic type • LM: thickening of GBM, mesangial expansion by PAS positive mesangial matrix, mildly increased cellularity, glomerular enlargement – diffuse diabetic glomerulosclerosis Diabetic glomerulopathy • later homogennous eosinophilic nodular formations, mesangial cells pushed to the periphery – nodular diabetic glomerulosclerosis . Hyalinne insudations in arterioles • IMF: without immune deposits • EM: thickening of GBM Diabetic glomerulopathy Mesangial nodules Glomerulopathies with haematuria Glomerulopathies with haematuria û IgA nephropathy (Berger´s disease) ð immune complex-mediated disorder with raised levels of circulating IgA ð IgA mesangial deposits by chronic GIT, respiratory tract mucosal inflammations, liver cirrhosis ð episodic macroscopic haematuria in coincidence with respiratory infection Glomerulopathies with haematuria • LM: mesangial proliferation • IMF: mesangial IgA granules • EM: Mesangial and paramesangial ID û Henoch-Schönlein purpura ð extensor skin vasculitis with purpuric rash, GIT manifestations, arthralgia ð renal involvment - IgA nephropathy IgA nephropathy IMF Mesangial IgA immune deposits Glomerulopathies with haematuria û Alport syndrome/ thin basement membrane lesion ð mutation in genes for collagen IV, part of basement membranes, (mostly gene COL4A5 encodedon the X. chromosome). ð gradual progression of renal failure ð in the fully evolved Alport sy – bilateral hearing disorders, ocular abnormities Alport syndrome/ thin basement membrane lesion û thin basement membrane lesion ð without progression into renal failure, mild clinical signs (benign familiar haematuria) ð typical morphology possible in female carriers of X-linked Alport syndrome Alport syndrome/ thin basement membrane lesion ELMI Characteristic picture of lamellar glomerular basement membrane in hereditary nephropathy. Glomerulopathies with acute nephritic syndrome Glomerulopathies with acute nephritic syndrome ð usually proliferative glomerulonephritis with increased mesangial and endocapillary cellularity, commonly with crescent formation. û Acute diffuse endocapillary proliferative GN ð syn. acute post-infective, acute proliferative, exudative GN ð immune complex-mediated disorder Acute diffuse endocapillary proliferative GN ð usually post-infective glomerulonephritis ( beta-hemolytic streptococcus, staph., G-bacteria, viruses, parasites ) ð systemic disorders (SLE, infective endocarditis, nectorising arteritis) may be accompanied by this GN ð most commonly children , 1-4 wks. after streptococcal infection Acute post-infective GN ð haematuria, proteinuria , hypertension, oedemas, renal failure ð possible asymptomatic course ð raised ASLO titre and drop of C3 ,C4 complement in serum Acute post-infective GN ð benign course in children ð protracted course in adults, with hypertension,variable grade of renal failure • LM : ↑ endocapillary and mesangial cellularity, capillary lumen compression Acute post-infective GN •IMF: diffuse segmental IgG and C3 granules in capillary loops, in mesangium •EM: humphs – electron-dense subepithelial immune deposits Acute post-infective GN hypercellularity, neutrophils Acute post-infective GN (IMF) Granular IgG deposits on GBM and in mesangium Acute post-infective GN (EM) Granular subepithelial deposits Glomerulopathies with acute nephritic syndrome û Membrano-proliferative GN (mesangio-capillary) ð Type I.-III. according morphology ð Type I. – immune complex-mediated, cryoglobulinemia (esp. hepatitis C), other causes - more common in children, teens ð ↓ serum complement, nephritic syndrome, nephrotic sy possible. • LM: diffuse glomerulopathy, endocapillary and mesangial hypercellularity, accentuation of capillary tuft lobular architecture, GBM duplication („tram track“) in PAS, silver impregnation. Membrano-proliferative GN • EM: subendothelial immune deposits + mesangial interposition (inclusion of mesangium + new layer of BM inbetween the immune deposits and original BM – duplication, „splitting“), subendothelial + mesangial ID. ð Type II. ð > 60% of patients with antibody C3nephritic factor (NeFa) binding to C3 convertase → stabilisation (no enzymatic degradation), → permanent C3 activation of alternative pathway of complement cascade Membrano-proliferative GN • EM: dense-deposit disease (DDD). Ribbon-like immune deposits in the GBM and mesangium, ð Typ III. rare • LM: same findings as in the type I. • EM: + subepithelial ID. Membrano-proliferative GN Lobulisation of the capillary tuft, hypercellularity in mesangium + endocapillary Membrano-proliferative GN (EM) 1.Subendothelial immune deposits 2. podocyte foot processes fusion 3. mesangial interposition Glomerulopathies with acute nephritic syndrome û Rapidly progressive GN (RPGN), crescentic ð Hematuria, proteinuria ð Rapid loss of renal functions ð Extensive crescentic formation RPGN ð Variable group of diseases: ð pauci-immune GN (part of systemic vasculitis, sm. ANCA+) ð Anti-GBM disease ð immune-complex mediated GN complication of other GN (IgA, post-infectious GN, SLE) RPGN Cellular crescents within the Bowman capsule RPGN 1. Fibrin in the crescent 2. Cellular crescent (incipient) RPGN Fibrinoid necrosis of capillaries Vascular kidney/glomerular diseases Vascular kidney/glomerular diseases û Systemic vasculitis û Anti-GBM glomerulonephritis ð antibodies against Goodpasture antigen (part of noncollagenous portion of the GBM) Vascular kidney/glomerular diseases ð binding of anti-GBM antibody→ complement + proteases activation → GBM destruction ðLM: RPGN appearance • IMF: diffuse linear IgG deposits positivity of GBM Immune complex-mediated vasculitis ð Henoch-Schönlein purpura • IgA nephropathy morphology Vascular kidney/glomerular diseases û ANCA-associated vasculitis (antineutrophil cytoplasmic antibodies) ð Granulomatosis with polyangiitis (Wegener granulomatosis) ð Microscopic polyangiitis • RPGN morphology Anti - GBM 1. Cellular compressive crescent 2. Collapsing capillary tuft Anti-GBM (IMF) Linear peripheral IgG positivity ( on the GBM) Vascular kidney/glomerular diseases ûThrombotic microangiopathy ð Haemolytic uremic syndrome, Thrombotic thrombocytopenic purpura – formation of platelet thrombi in small vessels of systemic circulation, platelets consumption, endothelial damage and haemolysis ð Intimal and endothelial oedema, fibrinoid necrosis of the arteriolar wall, fibrin thrombi in capillaries ðtypes: • epidemic (E.coli – shiga-like toxin) • other – drugs, irradiation, infection • TTP – hereditary/acquired excessive activation of platelets Chronic glomerulonephritis û gl. disease in the end-stage (significant renal lesion) •gross: kidney contracted, granulated • micro: high percentage of globally obliterated glomeruli, interstitial fibrosis, tubular atrophy, vascular changes. Chronic glomerulonephritis 1. Obliterated glomeruli 2. Vascular changes Tubulo-interstitial disorders ð both parts (tubules + interstitium) affected û Two main categories: ð Ischemic and toxic lesion (acute tubular necrosis ATN) ð Inflammatory (tubulointerstitial nephritis TIN) Tubulo-interstitial disorders ûAcute tubular necrosis ð etiology: ischemic , toxic ð acute renal failure with oligouria/anuria, hemodialysis necessary • gross: kidney edema, markedly pale cortex • micro: variable grade of tubular cells injury, from loss of brush border to necrosis. ðIschemic – segmental lesions along the whole tubular lenght ðtoxic – proximal tubules Acute tubular necrosis Tubular dilatation, simple flat epithelium Acute tubular necrosis Tubulo-interstitial disorders û Acute tubulo-interstitial nephritis ð Etiology: infectious bacterial (acute pyelonephritis) ð toxic drug-induced ( post ATB) ð metabolic (diseases with crystal formation) ð viral (hantaviruses) • micro: interstitial inflammatory infiltrate, variable grade of tubular epithelium injury Tubulo-interstitial disorders û Acute pyelonephritis ð acute pelvis + kidney inflammation - mostly ascennding - bacterial infection – i.e. E. coli ð descending - in sepsis ð febrile ilness, lumbal pain, dysuria + urging, pyuria with numerous neutrophils Tubulo-interstitial disorders • gross : swollen kidney, yellow subcapsular abscesses. • edematous, hyperemic pelvis, sm. with pus, progression of purulent inflammation to the adjacent tissues - paranephritic abscess • micro: interstitial + tubular neutrophils Acute pyelonephritis Tubulo-interstitial disorders û Chronic pyelonephritis ð one of the most common causes of renal failure ð possible insidious start, manifestation due to hypertension, commonly after multiple attacks of acute pyelonephritis. Tubulo-interstitial disorders û gross: irregular shrunken kidney, flat scars, commonly + nephrolithiasis, progressive atrophy - end-stage kidney û micro: interstitial fibrosis, tubular atrophy, dilatation + casts (follicular colloid-like), glomerular hyalinisation Tubulo-interstitial disorders û Drug-induced TIN ð Antibiotics, NSAIDs • micro: interstitial oedema, mixed interstitial inflammatory infiltrate with eosinophils TIN Eosinophils in inflammatory infiltrate Oxalate nephropaty Oxalate crystals/deposits in tubules Tubulo-interstitial disorders û Myeloma nephropathy ð renal damage due to myeloma ð excretion of light chains (BJ protein) into primary urine, toxic to epithelia ð + casts formation→ nephrohydrosis, blockage of urine outflow within renal parenchyme. ð tubular epithelial damage, multinucleated macrophages Myeloma nephropathy 1. Protein casts 2. Giant multinucleated macrophages Renal tumors û Benign x malignant û Benign ð angiomyolipoma • Mesenchymal (perivascular epithelioid cell – PEComa) more common in patients with tuberous sclerosis ð cortical adenoma •micro: papillary structure •gross: ochre colour, size< 5mm • accidental finding Benign tumors ð renal oncocytoma •gross: demarcated tumor of red-brown colour, variable size central scar •micro: eosinophilic, granular cytoplasm, cells in acinar, tubular, solid nests; central hyalinne scar Renal oncocytoma Renal cell carcinoma (RCC) û More common in males; middle-older age û Smoking as major risk factor û mostly sporadic tumors, 4% part of hereditary syndromes Clear cell RCC ð 70-80% of all RCC •gross : demarcated tumor, yellowish colour commonly with haemorrhagic, necrotic, fibrotic foci • angioinvasive tendency – direct grow into renal vein, vena cava; • invasion into pelvis - haematuria Clear cell RCC •Metastases via blood mostly (lungs, bones, brain) •micro : large cells with clear granular cytoplasm (glycogen + lipids) Clear cell RCC Clear cell RCC ð clinical : local symptoms late, haematuria. Fever, paraneoplastic syndromes ð prognosis according to the tumor size/stage ð ca< 3 cm quite good Papillary RCC ð 15% of all RCC •gross: well-demarcated, regressive changes, commonly multifocal and bilateral •micro: malignant epithelial cells covering stromal papillae, with stromal foam macrophages Papillary RCC Chromophobe RCC ð 5% of RCC. •gross: well demarcated, partial lobulisation, brown colour •micro: eosinophilic granular cytoplasm, distinctive cell membranes, shrunken („raisin“) nucleus Chromophobe RCC Nephroblastoma ð 3rd most common malignant pediatric tumor ð Diagnosed mostly in the 3rd-4th year of age ð Sporadic, or part of some syndromes •gross: large, well demarcated tumor, greyish colour, regressive changes Nephroblastoma •micro: structures attempting to recapitulate variable stages of nephrogenesis – Triphasic combination of blastemal, stromal and epithelial cell types in variable percentage – Highly cellular foci resembling embryonal blastema divided by strands of immature mesenchyme Nephroblastoma ð clinical: large tumor, palpable, complications due to compression of adjacent organs, hematuria ð prognosis: good, CHT (RT carefully, second malignancies possible) Nephroblastoma Nephroblastoma Nephroblastoma Urinary tract disorders Urinary tract ð Calices ð Pelvis ð Ureters ð Urinary bladder ð Urethra Inflammations ð Mostly ascending infection ð urethritis ð urocystitis ð possible progression into kidney ð etiology: E.coli, Proteus, Klebsiella, Enterococcus,Neisseria gonorrhoeae, etc. ðCandida, Schistosoma, Inflammations ð dysuria, polakisuria (urging), raised temperature •gross: haematuria, pyuria – Hypeaemic mucosa, possible pseudomembrane, ulceration ð complications : progression of inflammation into adjacent structures: glands, interstitium – phlegmona, periurethral abscess » Inflammations • micro: – acute inflammation with prevalence of neutrophils, regressive changes of transitional cell epithelium – chronic inflammations - reactive changes of transitional cell epithelium, squamous/glandular metaplasia. Brunn nests – cystitis cystica ð urethra – caruncula urethrae – pseudotumorous hyperplastic polyp in the region of urethral orifice. Hydronephrosis ûPathological dilatation of the renal pelvis and calyces • Causes: – Impacted stone, … – Tumors – External compression (pregnancy, prostatic hyperplasia, …) Tumors û benign x low malignant potential x frankly malignant û flat x papillary lesions ð Mostly urothelial Precursor lesions: ð Urothelial dysplasia ð risk factors: • M:F 3:1 • smoking • professional exposure (aromatic amines, etc.) • long-term use of phenacetin, irradiation, … Urothelial dysplasia •Micro: flat lesion, cytologic atypia with loss of cell polarity, ↑ mitotic activity in upper layers of urothelium, ↑ N/C ratio, coarse chromatin ûLG (low grade) IUN (intraurothelial neoplasia) x HG IUN (CIS) Urothelial ca in situ Papillary urothelial neoplasm û urothelial papilloma •Solitary papillary lesion covered by normal urothelium without cytological or architectonic atypias. Papillary urothelial neoplasm ð papillary urothelial neoplasm of low malignant potential (PUNLMP) • recurrent tumor • papillae covered by hyperplastic urothelium with preserved stratification, minimal cytonuclear atypia, sporadic mitoses. Papillary urothelial neoplasm ð non-invasive papillary urothelial carcinoma • low grade • high grade ð Papillary neoplasia without signs of invasion into stroma (suburothelial mesenchymal tissue) ð LG ð altered papillary architectonics, ð mild cytonuclear atypia ð basal layer mitoses Low grade non-invasive papillary urothelial carcinoma Non-invasive papillary urothelial carcinoma ð HG ð papillary fusion, solid foci ð loss of cell polarity ð moderate – high grade of anisocytosis and anisokaryosis ð atypical mitoses in upper layers of neoplastic epithelium High grade urothelial carcinoma Bladder carcinoma Invasive (infiltrating) urothelial carcinoma ð ca invasion into sub-urothelial fibrotic tissue or deeper (muscle, …) Invasive urothelial carcinoma Bladder carcinoma û Less common carcinomas ð squamous cell carcinoma (schistosomiasis) ð adenocarcinoma ð neuroendocrine carcinoma Mucinous adenocarcinoma