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Urinary system 4 Glomerular disease II

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1 Urinary system 4 Glomerular disease II
Professor John Simpson

2 The possible clinical presentations
acute nephritis (aka acute nephritic syndrome) rapidly progressive GN (acute nephritis with acute renal failure) nephrotic syndrome chronic renal failure proteinuria and/or haematuria but overlaps occur and the same patients can have different presentations at different stages of his/her disease and some of these presentations can also be due to non-glomerular disease

3 Last lecture on situations where filter clogs up or leaks a bit
This one mainly on what happens when the glomerular filter leaks a lot over a significant period of time, causing the nephrotic syndrome

4 Nephrotic syndrome The syndrome always consists of 3 things -
massive proteinuria (usually > 3.5 g/day) predominantly albuminuria hypoalbuminaemia (usually < 3 g/dl) oedema (often severe) and, usually also, hyperlipidaemia

5 Nephrotic syndrome (NS)
always the result of severe and prolonged damage to the glomerular filter that results in massive proteinuria which leads to hypoalbuminaemia and therefore reduced plasma colloid osmotic pressure and that causes (Starling equation) oedema, which may be severe (anasarca)

6 Other plasma proteins also leak
transferrin microcytic anaemia antithrombin III thrombosis IgG susceptibility to infection lipoprotein lipase altered lipoprotein metabolism, hyperlipidaemia

7 Why these proteins? it’s the smallest plasma proteins which leak most
(liver initially compensates by producing more albumen, but only for limited time) - and why hyperlipidaemia?

8 Causes of nephrotic syndrome
anything which causes severe prolonged filter damage glomerulonephritis (GN), including proliferative GN membranous GN minimal change GN FSGS membranoproliferative GN non GN glomerular disease, including diabetes mellitus amyloidosis myeloma

9 Proliferative GN any proliferative GN which does not resolve -
GN (streptococcal and other infections, autoimmune etc), whether diffuse, RPGN or focal but other GNs are more common causes of NS

10 Membranous GN commonest cause of NS in white adults, but also seen in all other races: mostly middle-aged/elderly Ag/Ab complexes again - long term deposition in most cases, Ag in complex is unknown (“idiopathic membranous GN”), but…

11 Known immune complex associations in membranous GN
infections (hepatitis B, quartan malaria, syphilis, schistosomiasis) drugs (e.g. penicillamine, NSAIDs) inorganic metals (gold, mercury) malignant tumours (e.g. lung, lymphoma, colon) autoimmune diseases (espec. SLE)

12 Membranous GN - uniform diffuse thickening of glomerular capillary wall

13 Membranous GN accumulation of electron-dense, immune complex deposits along outside of GBM paradoxically the thickened GBM is very leaky epithelial cell component of filter probably also damaged no cell proliferation – because Ag/Ab reactions are on outside of GBM, thus away from mesangial & endothelial cells and PMNs

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16 Membranous GN tends to have an indolent course
sometimes, proteinuria decreases for a time (so nephrotic syndrome will disappear) a few (mainly younger patients) resolve (espec. if “association” can be dealt with) but most drift into chronic renal failure (“chronic GN”) over 2-20 years

17 Minimal change GN most common cause of NS in children in the “west”, but also occurs in adults – also seen in Africa peak ages 2 – 10 NS sometimes accompanies URT infection or immunisation without lag time NS extremely responsive to steroids (almost diagnostic of the disease)

18 Minimal change GN little to see by light microscopy: may be fat in renal tubular cells (= lipoid nephrosis) EM shows loss of foot processes of epithelial cells no local immune reactants probably cytokine-like material from distant immune reaction targets the epithelial cells good prognosis

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21 Minimal change GN classically, recurrent episodes of NS
in children, often resolves by puberty if patient becomes steroid resistant, diagnosis probably wrong in a few adults, this type of GN associated with lymphomas or leukaemias

22 FSGS (focal and segmental glomerulosclerosis)
commonest cause of NS in blacks proteinuria often heavy enough to cause NS most cases progress to renal failure within months – year or two associations include HIV infection, heroin addiction, IgA GN etc but also “idiopathic”

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24 Focal GN in patients with HIV
HIVAN common often seen before AIDS probably due to anti-HIV Abs typical lesion is collapsing type of FSGS usually proteinuria, often severe enough for nephrotic syndrome prognosis, in terms of eventual renal failure, worse in adults

25 Other renal problems in patients with AIDS
post-infectious GN renal infection (pyelonephritis, TB etc) reactions to antiviral drugs – e.g. interstitial nephritis renal failure (acute or chronic) tumours

26 Back to causes of nephrotic syndrome

27 Membranoproliferative GN – mesangiocapillary GN in US textbooks
rare GN, but commonest one in hepatitis C – also not uncommon in schistosomiasis microscopically rather like a mixture of proliferative and membranous GNs i.e. both cellular proliferation and capillary wall thickening clinical presentation usually NS: often profound hypocomplementaemia (? role of nephritic factors) renal failure within 10 years

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29 Nephrotic syndrome also associated with non-GN disease
diabetes mellitus amyloid myeloma and other paraproteinaemias pathogeneses unclear, though all must be damaging GBM filter to cause chronic massive proteinuria.

30 Diabetic nephropathy diabetic glomerular disease
common after DM present 10 years+ especially in poorly controlled type 1 DM patients may also have diabetic retinopathy always proteinuria, sometimes bad enough to cause NS at least 50% cases will progress to end stage renal failure within 10 years

31 Diabetic nephropathy uniform thickening of GBM
diffuse global increase in mesangial matrix (connective tissue in mesangium) segmental nodular excess of mesangial matrix (Kimmelstiel-Wilson lesions) pathogenesis unclear, but probably related to degree of hyperglycaemia Pathogenesis of diabetic nephropathy ? Hyperglycaemia promoting non-enzymatic glycosylation of proteins, thus altering charge and permeability etc ? Growth factors ?cytokines

32 Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 14 July 2008 12:59 PM)
© 2007 Elsevier

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34 Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 29 January 2007 12:01 PM)
© 2005 Elsevier

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36 Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 29 January 2007 12:01 PM)
© 2005 Elsevier

37 Amyloid % patients with secondary amyloidosis (TB, chronic suppuration, rheumatoid arthritis, myeloma etc) get renal amyloidosis glomerular deposits of amyloid material cause proteinuria, again often heavy enough to cause nephrotic syndrome (amyloid also found in vessels) progression to chronic renal failure within 1-2 years

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39 Myeloma and other paraproteinaemias
glomeruli trap abnormal proteins (Bence-Jones and other paraproteins) GBM gets damaged and becomes leaky proteinuria, if severe and prolonged, causes nephrotic syndrome

40 It’s not always nephrotic syndrome!
patients with ALL of the diseases (GN and non-GN) causing nephrotic syndrome may at times have less severe proteinuria, so no nephrotic syndrome and, in some, the proteinuria sometimes disappears entirely

41 “Chronic” GN may result from ANY GN failing to resolve – but also may appear “de novo” glomeruli become fibrosed (global glomerulosclerosis) with secondary tubular loss, so kidneys shrink rate of glomerular loss determines how quickly renal function deteriorates GNs thus one cause of “end-stage” kidney (or “granular contracted kidney) and so chronic renal failure most patients hypertensive & require renal replacement therapy diabetes, amyloid and, less commonly hypertension can also cause chronic renal failure by gradually replacing functioning glomeruli

42 Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 14 July 2008 12:59 PM)
© 2007 Elsevier

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44 The possible clinical presentations
acute nephritis (aka acute nephritic syndrome) rapidly progressive GN (acute nephritis with acute renal failure) nephrotic syndrome chronic renal failure proteinuria and/or haematuria but overlaps occur and the same patients can have different presentations at different stages of his/her disease and some of these presentations can also be due to non-glomerular disease

45 - and finally

46 Systemic disease and the kidneys
(depends on how “systemic” is defined) SLE (and other non-organ specific autoimmune diseases) – glomerulonephritis DM, amyloid, myeloma – nephrotic syndrome infective endocarditis - GN Henoch-Schonlein purpura – IgA GN HIV, TB, schistosomiasis etc etc

47 - and many of these diseases affect the kidneys in more than one way

48 e.g. Diabetes and the kidney
In addition to diabetic nephropathy (glomerulosclerosis), diabetes also associated with pyelonephritis (bacterial infection of kidney) increased risk of atheroma and thus renal ischaemia increased risk of hypertension and thus arteriosclerotic renal disease (nephrosclerosis) increased risk of papillary necrosis (especially if pyelonephritis present)

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