1. Lecture 3. Secondary glomerular diseases and diseases of large blood vessels

2. Crescentic Glomerulonephritis and Vasculitis VASCULITIS: Inflammation and necrosis of blood vessels Large vessel vasculitis eg Giant cell (Temporal) arteritis Medium sized vessel arteritis eg Polyarteritis Nodosa Small vessel vasculitis* –*Capillaries, venules, arterioles +/- small arteries –Skin only e.g. drugs –Multiple organs, tissues, kidney: systemic vasculitis Crescentic glomerulonephritis is typical of systemic vasculitis involving the kidney (renal-limited crescentic GN also occurs)

3. Vasculitis

4. Vasculitis - artery in Polyarteritis Nodosa Lumen

5. Crescentic Glomerulonephritis, vasculitis Crescent: Proliferation of cells inside Bowman’s capsule - obliterates urinary space Glom CRESCENTCRESCENT

6. Systemic small vessel Vasculitis Microscopic polyangiitis (micro PAN) –Vasculitis in small, med blood vsls; glomerulonephritis Wegener’s granulomatosis –Necrosis and granulomas in upper/lr resp tract –Vasculitis in small, med blood vsls; glomerulonephritis Henoch-Schlonlein purpura Cryoglobulinemia Goodpasture’s syndrome and anti-GBM nephritis –Anti-GBM, anti-alveolar BM antibodies –Pulmonary haemorrhage, glomerulonephritis

7. Wegener’s granulomatosis Multinucl Giant cell Granulomas, necrosis, vasculitis in respiratory tract Crescents, focal necrosis in glomeruli

8. Vasculitis - clinical Clinical signs vary: Fever, rash, arthralgias, pulmonary infiltrates or nodules, haemorrhage, ENT, GI, musculoskel or neurological symptoms, Acute renal failure, oliguria over wks, months (dialysis); hypertension, haematuria, proteinuria Investigations: Renal function, imaging, ESR, serology, ANCA

9. Anti-neutrophil cytoplasmic antibodies (ANCA) Serum antibodies to enzymes in neutrophil granules, monocyte lysosomes Immunofluorescence: Cytoplasmic or Perinuclear P-ANCA (anti-myeloperoxidase) in 80% of micro polyangiitis; more often indolent, renal limited C-ANCA (anti-proteinase 3) in 90% of Wegener’s Very useful in diagnosis; follow up of disease activity in Wegener’s with C-ANCA

10. Crescentic GN, vasculitis Crescent Necrosis and crescent N Cr

11. Crescentic GN, vasculitis: Immunofluorescence findings 65% “pauci-immune” –pauci = few or no IC 20% immune complex 15% anti-GBM...,.

12. Crescentic GN, vasculitis - pathology LM: Glomerular crescents, inflammation and necrosis Crescent: Proliferation of cells inside Bowman’s capsule - obliterates urinary space (-> oliguria) Focal glomerular inflammation, necrosis –Immune complex deposits FM & EM 20% e.g. SLE, cryoglob –anti-GBM 15% Goodpature’s syndrome, anti-GBM nephritis –pauci-immune 65% (in ANCA+ microscopic polyangiitis, Wegener’s) –Adverse prognosis: >80% crescents, anti-GBM Summary: Crescentic GN typical of systemic small vessel vasculitis; sometimes limited to kidney

13. Secondary glomerular diseases Glomerular disease an important feature of multisystem diseases - vasculitis, diabetes, SLE, amyloidosis DIABETES MELLITUS –Relative/absolute deficiency of insulin secretory response; leading cause of end-stage renal disease in US, Europe (40%) –Type 1: autoimmune destruction of insulin secreting beta cells –Type 2 (90%) decreased insulin secretion; insulin resistance Gradual onset of proteinuria, glycosylation of proteins, microangiopathy thick leaky GBM, and increased mesangial matrix synthesis; also suscept to pyelonephritis

14. Glomerular and vascular lesions in Diabetes Art KW Art

15. SLE (Lupus) nephritis

16. Chronic auto-immune disease; females 20-30 yrs Rash, connective tissues, kidney etc Antinuclear (e.g. anti-ds DNA), anticytoplasmic & antiphospholipid antibodies Lupus nephritis in 90% - variable proteinuria, haematuria Immune Complex Glomerulonephritis ranges from very mild to severe Glomerulonephritis a major cause of morbidity, mortality

17. Lupus nephritis

18. Amyloidosis Abnormal beta-fibrillar protein (15 classes) (A-beta in Alzheimer’s) AA amyloid (chronic infection, inflammation) or AL amyloid (Ig derived) deposited in glomeruli, renal vessels Proteinuria Poor prognosis

19. Amyloidosis

20. Clinical Presentations of glomerular disease

21. CRESCENTIC GN and VASCULITIS (“Rapidly progressive GN”) HAEMATURIA –IgA nephropathy PROTEINURIA & NEPHROTIC SYNDROME –Minimal change disease –Membranous glomerulonephritis –SLE, diabetes, renal amyloidosis ACUTE NEPHRITIS –Post-streptococcal glomerulonephritis - Haematuria, hypertension, raised serum creatinine, oedema Immune complexes to streptococcal antigen Most patients recover fully CHRONIC RENAL FAILURE –Abnormal renal function tests. Raised se Cr, reducd Cr Cl & clinical signs –Develops slowly, chronically over years –Glomerular disease not the only cause (nephrosclerosis, APCKD)

22. Lesions of large blood vessels

23. Lesions of Renal Blood Vessels Thrombi, emboli, infarcts –Renal artery thrombosis –Left heart, heart valves e.g. mitral vegetations –Atheroemboli from aorta -> interlobular arteries in kidneys

24. Lesions of Renal Blood Vessels Vasculitis (other than small vessel vasculitis) –Large and medium sized blood vessels, small arteries. –Temporal (Giant cell) arteritis - head and neck –Takayasu’s - coronaries –(Vasculitis a/w infection include fungal) Polyarteritis Nodosa –aneurysms in coeliac, mesenteric, coronary and renal arteries; hepatitis B in 30%; ANCA negative

25. Lesions of Renal Blood Vessels Renal artery stenosis –Proximal renal artery atherosclerosis –Fibromuscular dysplasia – GFR afferent arteriole pressure -> Renin, BP Nephrosclerosis –Age change worsened by hypertension –Thick arterioles (“hyaline” arteriolosclerosis) & thickened small, medium sized arteries –Small kidneys, granular suface +/- larger scars Malign BP and thrombotic microangiopathies –Endothelial injury, necrosis of media, thrombi

26. Nephrosclerosis Granular renal cortical surface & scars Thickened artery