Degenerative and Metabolic Mechanisms of Renal Damage Glomerular Permeability to Protein is influenced by: • Protein factors o MW and radius o Electrical charge o Molecular structure – “rigidity” • Glomerular factors o Pore size o Haemodynamics o Integrity of permeability barrier Pathological Classifications • Primary: GN • Secondary: metabolic and degenerative diseases • Both end in End Stage Kidney Disease (ESKD) Diabetes • Pathogenesis o Hyperglycaemia  AGEs formation  Protein kinase C activation NADPH depletion o Proinflammatory o Profibrogenic o Endothelial injury o Oxidative stress  • Principle effects o Atherosclerosis of renal arteries and branches o Arteriolosclerosis: hyalinisation of arterioles o Microangiopathy: diffuse BM thickening of glomerular capillaries o Mesangiosclerosis: ↑mesangial matrix o Infection  Pyelonephritis  Renal medullar necrosis • Diabetic glomerular sclerosis o CL: nephrotic syndrome: proteinuria, HT, renal failure o LM: nodular and/or diffuse mesangial expansion, exudative lesions (fibrin caps, capsular drops), AA and EA arteriolosclerosis o IF: non-specific o EM: thick GBM Amyloidosis • Systemic disorder • Abnormal fibrillar protein  deposition • Same physical structure (β-pleated sheet) and morphology on LM • Different chemical composition and aetiologies Investigations • CL: Proteinuria, nephrotic syndrome, renal failure, extra-renal • LM: Thick GBM and mesangium, Congo red positive • IF: Variable (occasionally positive for Ig light chains) • EM: Characteristic beaded fibrils Fabry’s Disease • Renal findings often 1st clue to diagnosis (this is a rare condition) • Subtype of lysosomal storage disorder • Genetic defect in particular lysosomal enzyme  build-up of specific insoluble partially degraded metabolites • Deficient enzyme is α-galactosidase A • Metabolite is lipid globotriaosylceramid • Accumulates in endothelial cells, podocytes and distal tubular cells Investigations • CL: early onset renal dysfunction, proteinuria, dialysis • LM: podocytes expanded by lipid deposits, FSGS • IF: N/A • EM: laminated electron dense lipid deposits Hypertensive Renal Disease • 95% of HTN is idiopathic o Risk Factors: obesity, dietary sodium, low birth weight, race • 5% of HTN is secondary o Renal artery stenosis  RAAS activation o Neoplasia e.g. phaeochromocytoma, adrenal cortical tumours o Chronic renal disease • Malignant hypertension o Escalating RAAS activation and vascular injury Investigations • CL: Asymptomatic, proteinuria, renal failure • LM: Cortical scars (seen with naked eye) , atheroslcerosis, hyalinosis, global or segmental GS, compensatory hypertrophy in others, tubular changes (atrophy, interstitial fibrosis and inflammation); acute vessel damage (necrosis, thrombus) with malignant hypertension • IF: Variable • EM: Thickened or wrinkled GBM Cortical scarring Global sclerosis, atherosclerosis, hyalinosis, tubular atrophy FSGS Can be primary (idiopathic) or secondary (e.g. HT, obesity) Investigations: • CL: Proteinuria • LM: Focal and segmental sclerosis of glomeruli • IF: Segmental IgM and C3 deposition • EM: Loss of podocyte foot processes