Pathology 1 UGS PDF

Pathology Abdullah Ayyash & Laith Nawafleh Renal disease Not a major cause of death 70,00...

Pathology Abdullah Ayyash & Laith Nawafleh Renal disease Not a major cause of death 70,000 deaths / year (USA) congenital Agenesis after heart disease, cancer and strokes anomalies Hypoplasia renal diseases Ectopic kidney Horseshoe kidney Multicystic kidney Vascular diseases Tubulointerstitial diseases Glomerular diseases cystic Adult Polycystic Kidney Disease disease Childhood Polycystic Kidney Disease End Stage Renal Disease (ESRD) Simple Renal Cyst Small contracted kidney. Obsolete glomeruli, tubular & vascular changes. CRF Acquired Renal Cystic Disease Multicystic kidney disease Glomerulonephritis Primary GN Minimal change disease Acute Diffuse Proliferative GN Focal segmental glomerulosclerosis Minimal change disease Nephrotic Nephrotic syndrome syndrome Primary Glomerular Disease FSGS Membranous GN Membranoproliferative GN Membranoproliferative GN membranous GN Other proliferative GN (focal,mesangial,IgA-N ) IgA nephropathy DM, SLE, amyloidosis Systemic Diseases Crescentic (rapidly progressive) GN Drugs, malignancy,infections Secondary GN Lupus nephritis Miscellaneous (hereditary nephritis) Diabetic nephropathy postinfectious glomerulonephritis (GN) various forms of crescentic GN. Nephritic syndrome primary glomerular diseases Amyloidosis IgA nephropathy Membranoproliferative GN Goodpasture syndrome Dense deposit disease Secondary to systemic disorders systemic lupus erythematosus Hereditary Disorders Alport Syndrome Hereditary nephritis Alport syndrome Thin membrane disease 1 Pathology Abdullah Ayyash & Laith Nawafleh Congenital anomalies Adult Polycystic Kidney Disease AD + 10% of CRF Agenesis: a complete absence of one (unilateral) or both (bilateral) kidneys Common (1 per 500-1000) Unilateral Agenesis: Mutation in PKD1 (Chr 16/ POLYCSYTIN 1 ) 90% /PKD2 (Chr 4/POLYCYSTIN 2 Uncommon ) 10% / PKD3. Compatible with life. Pathophysiology ciliopathy. associated with other congenital disorders (e.g., limb defects, Mutation in polycystin mechanosensory defect loss hypoplastic lungs) of cilia function interferes with fluid absorption Bilateral Agenesis: cyst formation. Incompatible with life. stillborn infants Morphology : Bilateral enlarged kidney Hypoplasia Cortical or medullary numerous cyst (3-4 cm in Bilateral (CRF in childhood) or unilateral (common). diameter) A reduced number of renal lobes and pyramids. Cyst contains clear or hemorrhagic fluid clinical features: Ectopic kidney Gradual onset of CRF Lower than normal close to bladder Flank pain or dragging sensation tortuous ureter Intermittent gross hematuria. Increased incidence of infections, stones and Hypertension (75%) & UTI obstructive uropathy Associations: - Berry aneurysms in 10-30% Horseshoe kidney Liver cysts in 40% The most common congenital anomaly. Childhood Polycystic Kidney Disease Usually fusion of lower poles.. Autosomal recessive and causes CRF Usually located lower than normal (at pelvic brim) found in collecting duct Cause stagnation of urine risk of infections, Morphology: obstructive uropathy + stones. Smooth kidney surface Cortical or medullary numerous small cysts Cystic diseases Dilated channels perpendicular to surface Associations: Multicystic dysplasia Liver cysts in all cases The most common form of the renal cystic disease in children. Hepatic fibrosis (congenital) Due to non fusion between the secretory part (arise from Simple Renal Cyst metanephric cap) and and connecting part (ureteric bud). Collecting part Single or multiple cortical cysts( 1-5 cm in size) The kidneys are usually grossly distorted Common postmortem finding of no clinical significance the cysts range from microscopic to several Differentiate them from renal tumors centimeters in diameter. Can't develop into PKD associated with obstruction in the lower Acquired Renal Cystic Disease urinary tract Cortical & medullary cysts Microscopically: -ducts and tubules lined by In patients with CRF (undergone long-term dialysis) epithelium and surrounded by Cuffs of Main complication >> RCC in the cyst wall( 7% over 10 mesenchyme. years) 2 Pathology Abdullah Ayyash & Laith Nawafleh Pathogenesis of Glomerular Injury 1) Microbial Ag : bacterial product, viral ag (Hepatitis b / hepatitis c ), ag of treponemal pallidum and plasmodium falciparum Normal glomerulus Immunological Antibody reaction: Antibody (Fc portion) activate complement system Complement activate inflammatory cells release mediators and cytokines glomerular injury 1. Antibody-mediated (more frequent) in-situ immune complex deposition (ag-ab complex present in the glomerulus itself ) Ag types: Fixed intrinsic Ag : 1) a3 chain of Type IV collagen (basement membrane ) : no immune complex deposition (linear IF) seen in Goodpasture disease 2) PLA2R (podocyte ): subepithelial deposition (granular IF) seen in membranous nephropathy 3) Mesangial (mesangial cell ) Planted Ag : could be endogenous or exogenous Ex : Nucleosomal complexes (in SLE ), Bacterial products, ( endostreptosin) , aggregated proteins (e.g., [IgG] circulating immune complex deposition (ag-ab complex present everywhere in the body then deposit in the glomerulus ) Ag types: Endogenous: 1) SLE 2) IGA NEPHROPATHY Glomerular IF Linear IF Exogenous: 3 Pathology Abdullah Ayyash & Laith Nawafleh 2. Non-Antibody mediated (less frequent) 2. Hypoalbuminemia (plasma albumin 3.5 g/day ) 4 Pathology Abdullah Ayyash & Laith Nawafleh IF: often negative / may IgM, C3. Nephritic syndrome Associations HIV, heroin addiction. Diseases caused by inflammation, damage to glomeruli of kidney: become more sickle cell anemia, obesity, SLE. permeable lead to reduction in the GFR, allow red blood cells (RBCs) into urine Characteristics hematuria. hematuria, reduced GFR & HT. SIGNS & SYMPTOMS Non-selective proteinuria. 1. Hematuria (RBC casts in urine) (most indicative) (diagnostic test: Urine poor response to steroids analysis) poor prognosis 50% ESRF in 2. Proteinuria ( < 3.5 g/day) with or without edema 10Y 3. hypertension (by both the fluid retention and renin release from the There is sclerosis and hyalinosis ischemic kidney) of only one part of the glomerulus 4. oliguria, azotemia & Edema Azotemia: elevation of blood urea nitrogen and 5. Dysmorphic RBCs creatinine levels = decreased glomerular filtration Membranous glomerulonephritis rate (GFR) Adults 30% / Children 5% Uremia: is the buildup of urea in the blood subepithelial deposition uniform thickening of the capillary wall Pathogenesis 15% secondary (infectious) Acute Diffuse Proliferative GN (Post-streptococcal GN 85% idiopathic: 4 Autoantibodies have been recognized: (1-4) Weeks after a strep infection of the throat or skin 1. M-type phospholipase A2 receptor in 70% -hemolytic streptococci 2. Aldose reductase Pathogenesis 3. Maganese superoxide dismutase 2 Nephritogenic strains >90% 4. Membrane metalloendopeptidase Anti-streptolysin O titer increase non-selective proteinurea Immune complex deposition Morphology circulating or implanted Ag LM: BM thickening due to immune complex deposition /Spikes &domes apppearance Implicated Ags EM: Diffuse subepithelial deposits / spikes and domes appearance. Streptococcal exotoxin B (SpeB) IF: Granular IgG & C3. Strep glyceraldehyde-3-phosphate Prognosis: dehydrogenase (GAPDH) 33% spontaneously remit Clinical picture 33% stable proteinuria red cell casts (by Urine analysis) 33% progress to ESRF mild protein urea hypocomplementemia most commonly in children Morphology LM diffuse proliferation, leukocytic infiltration EM subepithelial humps (immune complex deposits subendothelial then go to subepithelial) IF: granular IgG & C3 in GBM & Mesangium Prognosis Children >95% recovery ,1% RPGN , 2% CRF. Adults 15-50% develop ESRD. 5 Pathology Abdullah Ayyash & Laith Nawafleh IgA nephropathy LM: crescents obliterating Bowman capsule (> 50 - 75% of glomeruli).Commonest type of GN EM: GBM rupture & sub-epithelial deposit Children & young adults IF: linear, granular, negative IgA deposits in the mesangium Prognosis: depend on glomerular involvement 1 to 2 days after URTI (mucosal infections) Crescent comprised of Fibrin and macrophages Episodic Microscopic or gross hematuria & Therapy: loin pain Plasmapheresis (Immune complex mediated crescentic GN usually Pathogenesis. alternative pathway of complement steroids. Genetic or acquired abnormality leading to cytotoxic drugs. 1. increase IgA synthesis by mucosa Circulating IgA aggregates or Some patients requires long term dialysis, and renal transplant. complexes deposit in mesangium complement activation Increase in celiac disease and liver disease (Secondary IgA nephropathy). Morphology Membranoproliferative GN Nephritic or Nephrotic LM: normal / mesangioproliferative basement membrane alterations , proliferation of glomerular cells and EM: dense deposits in the mesangium leukocyte infiltration IF: diffuse global mesangial IgA Children and young adults Bad prognostic features Primary or secondary Old age // Sclerosis //Heavy proteinuria //Hypertension Type I (more common) Prognosis Subendothelial slowly progressive RF Morphology 20 - 50% progress to CRF in 20 years LM: Enlarged glomeruli, proliferation, inflammatory cells 20-60% recur in transplants Tram-track appearance (due to Mesangial cell interposition) Rapidly progressive GN (crescentic GN) Crescents may be seen. not a single disease it is a syndrome (primary or secondary to systemic) EM: Subendothelial deposits sever oliguria Circumferential mesangial interposition If not treated: death from renal failure IF: C3, C1q, C4 in granular pattern in mesangial within weeks or months. Prognosis Classifications Generally poor 1. Anti-GBM AB mediated 40% progress to ESRF IF linear IgG,C3 (12%) 30% had persistent nephrotic syndrome without renal failure Alveolar BM involvement 30% had variable degrees of renal insufficiency Good pasture syndrome (hematuria+hemoptysis) 2. Immune complex-mediated IF >>Granular IgG, C3 (44%) PSGN , SLE, IgA nephropathy, HSP 3. Pauci-immune IF >> negative (44%) May be associated with systemic vasculitis most have ANCA in serum Morphology 6 Pathology Abdullah Ayyash & Laith Nawafleh Type II (Dense deposit disease) Intramembranous Pathogenesis Abnormality activates alternative complement >70% have C3 nephritic factor (auto-Ab stabilizes C3 convertase) Mutation or autoantibodies to factor H Low factor B & properdin Morphology LM: like type 1 EM: lamina densa transformation into an irregular, ribbon-like extremely electron dense structure IF: Granular mesangial short linear capillary loop deposits of C3 worse prognosis, and tends to recur in renal transplant recipients. hereditary Nephritis Alport syndrome eye disorders+ Nephritis + nerve deafness a bee) X-linked AR or AD Mutation in alpha-5 chain of collagen type IV defective GBM synthesis Gross hematuria mostly males 5 - 20 years Morphology LM: early normal later secondary sclerosis +Foam cells EM: irregular thickening, lamination, splitting basketweave appearance CRF in 20 years Thin membrane disease (benign familial hematuria) most common cause of benign familial hematuria Mutation in gene encoding alpha 3 & 4 chain Morphology EM: diffuse thinning of GBM. 7 Pathology. Abdullah Ayyash & Laith Nawafleh ✓ B: Antigen is part of normal structure. For unknown reason, body starts Extra sheet to form antibodies against this antigen lead to Ab-Ag complex along the basement membrane In slides ✓ C: Intrinsic fixed antigen is on the epithelial cells cause membranous nephropathy. ✓ Acute kidney injury : abrupt onset of renal dysfunction characterized by an acute increase in serum creatinine often associated with oliguria or anuria (decreased or no urine flow) ✓ Chronic kidney disease : progressive scarring in the kidney of any cause. It is characterized by various metabolic and electrolyte abnormalities such as hyperphosphatemia, dyslipidemia, and metabolic acidosis. However, it is often asymptomatic until the most advanced stages ✓ Multicystic dysplasia : The term dysplasia refers to a developmental rather than a preneoplastic lesion. ✓ In Congenital anomalies we have 2 types of ectopic kidney. ✓ It is contraindicated to do needle core biopsy for kidney mass (or cyst) because there is risk of dissemination of the tumor in case of malignancy. ✓ So if we have a kidney mass we need to do partial or total nephrectomy. ✓ Patients with Acquired Renal Cystic Disease may undergo prophylactic Doctor’s notes nephrectomy before renal cell carcinoma development. ✓ Test for protein in urine: ✓ Biopsy for studying glomeruli should be taken from cortex. Qualitative urine protein test ✓ Foot process fusion is not true fusion → The urine protein dipstick test measures the appears as they are fused but actually, they are presence of all proteins, including albumin, in a get flattened and hypertrophied so diaphragm urine sample (From 0 to 4+) slit become smaller.. ✓ Minimal change disease → In EM ( vacuolization) Quantitive urine protein test have vacules inside podocytes. Protein quantitation of a 24-hour urine ✓ In membranous GN silver stain is used in collection is the gold standard. histopathology to visualize and highlights the basement membrane of the glomeruli. ✓ In RPGN Plasmapheresis help with circulating Abs Immune Mechanisms of glomerular Injury only. ( Immune complex–mediate crescentic GN usually doesn’t respond) ✓ A: The circulating antigens exist the blood and get entrapped in sub- endothelial area And may cross sometimes to subepithelial. 1 Pathology. Abdullah Ayyash & Laith Nawafleh ❖ How are renal diseases diagnosed ? ✓ Usually by history, physical findings, Urinalysis and other laboratory data. Occasionally a renal biopsy must be performed ✓ The role of renal biopsy in the diagnosis of glomerular disease Percutaneous or open biopsy As we mentioned, Biopsy for studying glomeruli should be taken from cortex. To diagnose we need >12 glomeruli to have adequate samples Tissue divided into 3 parts: Stains Tissue types Microscope H&E, PAS, Jones Buffered formalin or Used in Light silver, trichrome. Bouin`s solution microscope Gluteraldehyde or Used in Electron Carson`s solution microscope Snap – frozen. Used in IF IgG, IgA, IgM, C3, C4, kappa, Lambda 2