Renal Pathology Review Medical Diseases of the Kidney Karlene Hewan-Lowe, MD Brody School of Medicine at East Carolina University

Amyloidosis Immunofluorescence Microscopy Renal Pathology The Osler Institute Review Course Amyloidosis Immunofluorescence Microscopy May stain for monoclonal light chains Electron Microscopy Randomly arranged, rigid, nonbranching filaments 7 – 10 nanometers Prognosis Uniformly poor Colchicine limits progression of AA amyloidosis in Familial Mediterranean Fever

Fibrillary Glomerulopathy Renal Pathology The Osler Institute Review Course Fibrillary Glomerulopathy Clinical Features Associated with chronic lymphocytic leukemia, B- cell lymphoma Renal insufficiency Hematuria Hypertension Pathogenesis Monotypical IgG may have role in fibrillogenesis

Fibrillary Glomerulopathy Renal Pathology The Osler Institute Review Course Fibrillary Glomerulopathy Light Microscopy Mesangial hypercellularity Mesangial expansion Immunofluorescence Microscopy Linear staining staining with IgG, C3, kappa and lambda

Fibrillary Glomerulopathy Renal Pathology The Osler Institute Review Course Fibrillary Glomerulopathy Electron Microscopy Randomly distributed fibrils Diameter – 20 to 30 nm

Light Chain Deposition Disease Renal Pathology The Osler Institute Review Course Light Chain Deposition Disease Second most common plasma cell related disorder Nephrotic syndrome or heavy proteinuria MPGN type pattern of glomerular injury Monoclonal deposision – kappa light chains Finely granular, ribbon-like subendothelial deposits in GBM Myeloma Cast Nephropathy Acute renal failure Refractile, angular intraluminal casts and multinucleated giant cells

Glomerular Diseases Associated with the Nephritic Syndrome Renal Pathology The Osler Institute Review Course Glomerular Diseases Associated with the Nephritic Syndrome Acute postinfectious glomerulonephritis Crescentic (rapidly progressive) glomerulonephritis IgA Nephropathy/Henoch Schonlein purpura

Acute Post Infectious Glomerulonephritis Renal Pathology The Osler Institute Review Course Acute Post Infectious Glomerulonephritis Clinical Features Beta hemolytic Streptococcus Type 1, 4, 12, 49 Skin, pharyngitic infections and deep seated abscesses Nephritic Syndrome Elevated ASO titre Decreased serum complement, C3 Pathogenesis Immune complex mediated glomerular injury

Acute Post Infectious Glomerulonephritis Renal Pathology The Osler Institute Review Course Acute Post Infectious Glomerulonephritis Light Microscopy Large, hypercellular glomerular tuft Neutrophilis infiltrate the glomerular tuft Immunofluorescence Microscopy Lumpy-bumpy, granular mesangial and peripherat capillary wall deposits for IgG and C3 Electron Microscopy Subepithelial humps Scattered mesangial and subendothelial deposits

Crescentic (Rapidly Progressive) Glomerulonephritis Renal Pathology The Osler Institute Review Course Crescentic (Rapidly Progressive) Glomerulonephritis Precipitous renal failure 50% or greater loss of renal function within three months Crescentic GN is defined as glomerulonephritis in which there are >50 % crescents A severe morphologic expression of glomerular injury Immunologic mechanisms, fibrin and inflammatory mediators have a role in the formation of crescents

Crescentic (Rapidly Progressive) Glomerulonephritis Renal Pathology The Osler Institute Review Course Crescentic (Rapidly Progressive) Glomerulonephritis Anti-GBM disease Immune complex mediated glomerulonephritis Pauci immune glomerulonephritis

Crescentic (Rapidly Progressive) Glomerulonephritis Renal Pathology The Osler Institute Review Course Crescentic (Rapidly Progressive) Glomerulonephritis ANCA Related Diseases ANCA are serologic markers for pauci immune crescentic GN In the presence of ANCA an associated systemic vasculitis should be considered PR3-ANCA (C-ANCA) – more frequent in Wegener’s granulomatosis PR3-ANCA (C-ANCA) and MPO-ANCA (P-ANCA) occur in patients with polyarteritis nodosa MPO-ANCA (P-ANCA) more frequent in Churg-Strauss, ANCA-GN (idiopathic crescentic GN)

IgA Nephropathy/Henoch Schonlein Purpura Renal Pathology The Osler Institute Review Course IgA Nephropathy/Henoch Schonlein Purpura Clinical Features Most common glomerular disease in the world Hematuria Nephritic Syndrome Variable Proteinuria HSP – abdominal pain, joint pain and purpura Pathogenesis Inadequate clearance of an abnormally glycosylated IgA

IgA Nephropathy/Henoch Schonlein Purpura Renal Pathology The Osler Institute Review Course IgA Nephropathy/Henoch Schonlein Purpura Pathology Mesangial proliferation IgA in mesangium Mesangial and paramesangial immune complex, electron dense deposits Prognosis Slow progression to ESRD HSP in children – complete resolution

Thin Basement Membrane Disease Renal Pathology The Osler Institute Review Course Thin Basement Membrane Disease Clinical Features and Pathology Asymptomatic hematuria No immune complexes by immunofluorescence or electron microscopy Basment membrane < 300 nanometers No progression to ESRD Pathogenesis Abnormal gene that controls formation of alpha chain Type IV

Renal Pathology The Osler Institute Review Course Secondary Diseases

Systemic Lupus Erythematosus Renal Pathology The Osler Institute Review Course Systemic Lupus Erythematosus Clinical Features African American women, age 20 Systemic disease Arthralgia, arthritis, skin rashes, inflammation of serous surfaces Clinical evidence of renal disease is present in 50 to 70% of patients with SLE Renal disease is less common in drug related SLE – chlorpromazine, hydralazine. Methlyldopa, procainamide

Systemic Lupus Erythematosus Renal Pathology The Osler Institute Review Course Systemic Lupus Erythematosus Pathogenesis Immune complex – antibody to a variety of nuclear constituents Increased apoptosis in lupus patients induces excessive autoantibody against nuclear proteins and nucleic acid sequences

Systemic Lupus Erythematosus Renal Pathology The Osler Institute Review Course Systemic Lupus Erythematosus ISN/RPS Classification of Lupus Nephritis CClass I Minimal mesangial lupus nephritis Mesangial ICD by IF and EM CClass II Mesangial Proliferative lupus nephritis Mesangial hypercellularity CClass III Focal proliferative lupus nephritis Focal and segmental glomerular lesions Focal interstitial inflammation Mesangial, subepithelial and subendothelial deposits

Systemic Lupus Erythematosus Renal Pathology The Osler Institute Review Course Systemic Lupus Erythematosus ISN/RPS Classification of Lupus Nephritis CClass IV Diffuse proliferative lupus nephritis Hypercellular glomerular tuft Membranoproliferative type pattern “Wire loop” lesions, hyaline thrombi CClass V Membranous lupus nephritis Mesangial hypercellularity Refractile, thick glomerular basement membranes Mesangial deposits CClass VI Chronic sclerosing lupus nephritis

Systemic Lupus Erythematosus Renal Pathology The Osler Institute Review Course Systemic Lupus Erythematosus Renal Symptoms correlate with morphologic classification Class I and II lupus nephritis Hematuria Mild proteinuria Class II and IV lupus nephritis Nephritic syndrome Nephrotic syndrome Low serum complement Class V lupus nephritis

Systemic Lupus Erythematosus Renal Pathology The Osler Institute Review Course Systemic Lupus Erythematosus Immunofluorescence “Full house” Mesangial deposits – Class I and II Mesangial and capillary wall deposits – Class II and IV Capillary wall deposits – Class IV Electron Microscopy Mesangial electron dense deposits are always present Subendothelial deposits – Class III and IV Supepithelial deposits – Class V Tubuloreticular structures in endothelial cells

Thrombotic Microangiopathy Renal Pathology The Osler Institute Review Course Thrombotic Microangiopathy HUS TTP FK506 Cyclosporine Systemic lupus Anti-phospholipid syndrome Malignant hypertension Acute phase of scleroderma Cancer and chemotherapy Renal transplantation - recurrent and de-novo Bone marrow transplantation HIV infection

Renal Pathology The Osler Institute Review Course Hereditary Nephritis

Alport’s Syndrome X-linked inheritance in 80% of cases Renal Pathology The Osler Institute Review Course Alport’s Syndrome X-linked inheritance in 80% of cases Other patterns – autosomal recessive, autosomal dominant Clinical features Microscopic hematuria Proteinuria Early progression to end stage renal failure (males, 30) Ocular lesions Sensoneuronal deafness

Alport’s Syndrome Light Microscopy Electron Microscopy Pathogenesis Renal Pathology The Osler Institute Review Course Alport’s Syndrome Light Microscopy Glomerulosclerosis Tubular atrophy and interstitial fibrosis Interstitial foam cells Electron Microscopy Moth eaten glomerular basement membrane Foci of thickening and thinning Pathogenesis One or more mutations in COL4A5 gene Long arm of X - chromosome

Other Renal Diseases Tubulointerstitial Diseases Renal Pathology The Osler Institute Review Course Other Renal Diseases Tubulointerstitial Diseases Acute tubular necrosis Acute pyelonephritis Interstitial nephritis Cast nephropathy Myeloma Myoglobin Analgesic nephropathy

Pathology of Renal Transplants Renal Pathology The Osler Institute Review Course Pathology of Renal Transplants

Pathology of Renal Transplants Renal Pathology The Osler Institute Review Course Pathology of Renal Transplants Banff 97 Classification of Renal allograft Rejection Updated 2001 Lake Louise, Banff, CA

Pathologic Markers of Antibody/Humoral Rejection Renal Pathology The Osler Institute Review Course Pathologic Markers of Antibody/Humoral Rejection Neutrophils in peritubular capillaries Neutrophils in glomerular capillaries Neutrophilic tubulitis Fibrinoid necrosis of arteries and capillaries Fibrin thrombi Infarction Acute tubular injury C4d in peritubulqr cqpillaries

Pathologic Markers of Cellular Rejection Renal Pathology The Osler Institute Review Course Pathologic Markers of Cellular Rejection Swollen, pale kidney Tubules - Tubulitis Interstitium - interstitial infiltrate of inflammatory cells Vessels - Endarteritis Immunofluorescence Fibrinogen and increased C3 along the tubular basement membranes

Markers of Chronic Rejection Renal Pathology The Osler Institute Review Course Markers of Chronic Rejection Transplant glomerulopathy Tubular atrophy and fibrosis Vessels Intimal proliferation Subintimal foam cells Vessel in vessel

1. Normal Banff 97 Classification of Renal allograft Rejection Renal Pathology The Osler Institute Review Course Banff 97 Classification of Renal allograft Rejection Updated 2001 1. Normal

2. Antibody Mediated Rejection Renal Pathology The Osler Institute Review Course Banff 97 Classification of Renal allograft Rejection Updated 2001 2. Antibody Mediated Rejection Rejection due, at least in part, to documented anti-donor antibody Report as ‘Suspicious for’ if NO anti-donor antibody Type (Grade) ATN like, minimal inflammation C4d+ Capillary margination +/- thromboses C4d + Arterial (v3) C4d+

Borderline changes: Suspicious for acute cellular rejection Renal Pathology The Osler Institute Review Course Banff 97 Classification of Renal allograft Rejection Updated 2001 Borderline changes: Suspicious for acute cellular rejection Foci of mild tubulitis 1 – 4 mononuclear cells per tubular cross section No significant interstitial inflammation

4. Acute/Active Cellular Rejection T-cell mediated rejection Renal Pathology The Osler Institute Review Course Banff 97 Classification of Renal allograft Rejection Updated 2001 4. Acute/Active Cellular Rejection T-cell mediated rejection Type (Grade) IA. Significant interstitial infiltration, foci of moderate tubulitis IB. Significant interstitial infiltration, foci of severe tubulitis IIA. Mild to moderate intimal arteritis IIB. Severe intimal arteritis III. Transmural arteritis and or fibrinoid necrosis

5. Chronic/sclerosing allograft nephropathy Renal Pathology The Osler Institute Review Course Banff 97 Classification of Renal allograft Rejection Updated 2001 5. Chronic/sclerosing allograft nephropathy Fibrosing changes in the allograft +/- features of alloimmune injury Grade Histopathological findings I. Mild interstitial fibrosis and tubular atrophy +/- changes suggesting chronic rejection II. Moderate interstitial fibrosis and tubular atrophy +/- changes suggesting chronic rejection III. Severe interstitial fibrosis and tubular loss +/- changes suggesting chronic rejection

Other Banff 97 Classification of Renal allograft Rejection Renal Pathology The Osler Institute Review Course Banff 97 Classification of Renal allograft Rejection Updated 2001 Other Changes not due to rejection Polyoma virus infection De-novo and recurrent renal disease

Polyoma VN vs. Acute Cellular Rejection Renal Pathology The Osler Institute Review Course Polyoma VN vs. Acute Cellular Rejection Widespread infiltrates and focal viral infection Expression of MHC Class II antigen on tubular epithelial cells C4d deposition in the peritubular capillaries

Renal Pathology The Osler Institute Review Course

Renal Diseases that Recur in Transplant Kidney Renal Pathology The Osler Institute Review Course Renal Diseases that Recur in Transplant Kidney Usual Dense deposit D Immunotactoid/Fibrillary Diabetes Mellitus Common IgAN HUS HSP FSGS - Primary MPGN Type I Amyloid Pauci-immune

Renal Diseases that Recur in Transplant Kidney Renal Pathology The Osler Institute Review Course Renal Diseases that Recur in Transplant Kidney Rare Anti-GBM disease Systemic Lupus No Recurrence Classical HUS Postinfectious GN Secondary and familial FSGS Hereditary nephritis