Year 2004 Paper one: Questions supplied by Megan
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1 QUESTION 53 Endothelial cell pathology on renal biopsy is most characteristic of which one of the following diagnoses? A. Pre-eclampsia B. Haemolytic uraemic syndrome C. Lupus nephritis D. Immunoglobulin A (IgA) disease E. Wegener s granulomatosis PRE-ECLAMPSIA - Pre-eclampsia = new onset of hypertension and proteinuria after 20 weeks gestation in a previously normotensive woman - Eclampsia = development of GTCS in woman with gestational HT or pre-eclampsia - Gestational HT = HT without proteinuria developing in the latter part of pregnancy, should resolve by 12 weeks post-partum Clinical Features - Gradual development of HT, proteinuria and oedema - Usually after 20 weeks - Tends to worsen as pregnancy progresses - Due to maternal responses to generalised endothelial dysfunction (with increased vascular permeability oedema, proteinuria and increased vascular tone HT) - Can also develop ischaemia of target organs due to endothelial dysfunction which can be exacerbated by lowering BP - Abnormal expression of procoagulants can lead to coagulopathy Renal Abnormalities - Kidney most likely organ to manifest endothelial injury - Proteinuria due in part to impaired integrity of the glomerular barrier and altered tubular handling of filtered proteins - Glomerular endotheliosis has been found in women with normal pregnancy as well as in both nonproteinuric and proteinuric HT not pathognomonic for pre-eclampsia as previously thought
2 Light micrograph in preeclampsia showing glomerular endotheliosis. The primary changes are swelling of damaged endothelial cells, leading to partial closure of many of the capillary lumens (large arrows). Mitosis within an endothelial cell (small arrow) is a sign of cellular repair. Courtesy of Helmut Rennke, MD Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows). Courtesy of Helmut G Rennke. HUS-TTP - Thrombocytopaenia - Microangiopathic anaemia (non-immune haemolysis with prominent red cell fragmentation or schistocytes) - Neurological abnormalities - Renal abnormalities usually mild proteinuria only - Fever - Often idiopathic - Can be associated with shiga toxin from E.coli, drugs or pregnancy Renal Histology - Thrombi in glomeruli and arterioles - Subendothelial widening of glmoerular capillary wall - During healing, intimal thickening and onion-skin hypertrophy of the interlobular arteries - All a consequence of endothelial cell injury
3 Light micrograph showing multiple intracapillary glomerular thrombi (arrows) typical of a thrombotic microangiopathy as can be seen in any of the forms of the hemolytic-uremic syndrome. Courtesy of Helmut Rennke, MD. LUPUS NEPHRITIS - Renal involvement in SLE common (40-75%) - Usually occur soon after or at diagnosis - There are a number of different types of renal disease - Immune complex-mediated glomerular disease most common (anti-dna): o Immune complexes complement activation focal or diffuse proliferative GN o ie. proliferation of mesangium and subendothelium - Pathological finding specific for lupus = presence of numerous tubuloreticular structures in glomerular endothelial cells - Subendothelial or GBM proliferationleads to membranous nephropathy (nephrotic syndrome) Electron micrograph in diffuse proliferative lupus nephritis shows massive subendothelial deposits (D) and characteristic tubuloreticular structures (arrow) in the endothelial cells (En). The subendothelial deposits cause marked thickening of the glomerular capillary wall, leading to a wire loop appearance on light microscopy.
4 Ep: epithelial cell; GBM: glomerular basement membrane. Courtesy of Helmut Rennke, MD. Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin and no electron dense deposits are present. Two normal platelets are seen in the capillary lumen. Courtesy of Helmut Rennke, MD. - Other forms of renal disease in lupus include tubulointerstitial nephritis, vascular disease and drug-induced renal disease IgA NEPHROPATHY - Most common lesion causing primary GN - Peaks 2 nd to 3 rd decades - M>F - IgA molecules react to unknown antigen - Immune complexes inflammatory response, cytokines mesangial cell proliferation and mesangial matrix expansion - Diagnosis by renal biopsy only: o Immunofluorescence microscopy demonstrates prominent globular deposits of IgA in the mesangium and less so along glomerular capillary wall o Indistinguishable from Henoch-Schonlein purpura o Light microscopy: focal or diffuse mesangial proliferation and matrix expansion, segmental crescents relatively common o Later in disease may develop glomerulosclerosis (chronic finding) - Usually present with macroscopic haematuria (often following URTI) or microscopic haematuria +/- mild proteinuria
5 Light micrograph of a mesangial glomerulonephritis showing segmental areas of increased mesangial matrix and cellularity (arrows). This finding alone can be seen in many diseases, including IgA nephropathy and lupus nephritis. Courtesy of Helmut Rennke, M Low power electron micrograph in IgA nephropathy. The primary finding is electron dense deposits that are limited to the mesangial regions (D). The glomerular basement membrane (GBM) is normal and there are no glomerular capillary wall deposits. Endo: endothelial cell nucleus. WEGENER S GRANULOMATOSIS - Systemic vasculitis of small and medium arteries and venules - Classically involves respiratory and renal systems - Can have other symptoms such as arthralgia, myalgia, eye symptoms - Renal disease = ARF with red cell +/- casts and proteinuria and rapidly progressive GN - Clinical criteria: o Nasal or oral inflammation o Abnormal CXR with nodules, infiltrates or cavities o Abnormal urinary sediment o Granulomatous inflammation on biopsy of an artery or perivascular area - ANCA, ESR elevated - Renal biopsy = segmental necrotising GN that is usually pauci-immune on IM or EM
6 Light micrograph showing fresh segmental necrotizing lesions with bright red fibrin deposition (arrows). A necrotizing glomerulonephritis can be seen in a variety of inflammatory disorders including vasculitis and lupus nephritis. The latter has prominent immune complex deposition which is generally absent in vasculitis. Courtesy of Helmut Rennke, MD. Both pre-eclampsia and HUS have features of endothelial injury but there are a number of other prominent findings in HUS (micro-thrombi etc). The correct answer is therefore A although endotheliosis is now considered a normal finding in pregnancy.
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