GLOMERULAR DISEASES. Dr. de Châtel Rudolf. Semmelweis Egyetem ÁOK, I.Sz.Belgyógyászati Klinika, Budapest

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1 GLOMERULAR DISEASES Dr. de Châtel Rudolf Semmelweis Egyetem ÁOK, I.Sz.Belgyógyászati Klinika, Budapest

2 The CIBA Collection of Medical Illustrations Volume 6: Kidney, ureters and urinary bladder CIBA Medical Education Division Summit, New Yersey USA

3 The CIBA Collection of Medical Illustrations Volume 6: Kidney, ureters and urinary bladder CIBA Medical Education Division Summit, New Yersey USA

4 The CIBA Collection of Medical Illustrations Volume 6: Kidney, ureters and urinary bladder CIBA Medical Education Division Summit, New Yersey USA

5 IMMUNOLOGICAL MECHANISMS Antigens 1. Renal: glomerular basement membrane (GBM) (laminin, type IV collagen etc.) Antibody: anti-gbm antibody linear deposit on immunfluorescence 2. Non-renal: - exogenous - viral (HBV) - bacterial (Streptococcus) - fungal (candida) - parasites (malaria) - drugs (haptenes) - tumour-derived (lymphoma), etc. - endogenous - DNA

6 Antibody and antigen form immune complexes - in situ - in the circulation granular deposits on immun fluorescence - subepithelial (complement dependent) - subendothelial (cell-dependent) - mesangial Immune complex deposition leads to: A: membrane thickening and fusion of foot processes B: proliferation - macrophag binding cytokines, leukotrienes - leukocyte adhesion proteolytic enzymes - platelet activation microthrombi fibrin The results of these are destruction, cell proliferation, fibrosis

7 The CIBA Collection of Medical Illustrations Volume 6: Kidney, ureters and urinary bladder CIBA Medical Education Division Summit, New Yersey USA

8 THE CLINICAL SYNDROMES I. Nephrotic syndrome Pure membrane abnormality without cell proliferation (loss of negative membrane charge) Proteinuria > 3.5 g/day serum albumin < 25 g/l - decreased colloid osmotic pressure of plasma - hypovolaemia - sodium retention - oedema - thromboembolism (antithrombin loss) - hypercholesterolaemia May respond to steroids and cytotoxic drugs

9 THE CLINICAL SYNDROMES 1. Minimal change disease (lipoid nephrosis) no light microscoplc changes, fusion of foot processes on electron microscopy, no immune deposits T-cell abnormality? cellular immune mechanisms) most frequent in childhood excellent response to steroids (1 mg/kg for 8 weeks, then tapering) relapses may occur - steroid dependent cases

10 2. Focal segmental glomerular sclerosis podocyte destruction adhesion of capillary loops hyalin deposition glomerular function it is also a T-cell mediated disorder however, it responds pooriy to steroids after 10 years, > 90% of patients will have end-stage renal failure cytotoxic drugs, cyclosporin A may result in remission, and prevent recurrence after transplantation

11 3. Membranous glomerulopathy GBM is thickened due to subepithelial deposition of immune complexes ("humps") it is the underiying abnormality in the majority of adult nephrotic syndrome steroid treatment may favourably influence the clinical course; spontaneous remission is possible, but appr. 30% of cases will proceed to end-stage renal failure

12 Symptomatic treatment of the nephrotic patient Diet: - reduce sodium intake - high protein intake is useless, because it increases proteinuria Diuretic treatment: - furosemide - spironolactone Antithrombotic treatment: - aspirin - anticoagulation (if necessary) Antiatherosclerotic treatment: cholesterol lowering drugs Prevention and treatment of infections: antibiotics (if necessary)

13 The CIBA Collection of Medical Illustrations Volume 6: Kidney, ureters and urinary bladder CIBA Medical Education Division Summit, New Yersey USA

14 II. Glomerulonephritis THE CLINICAL SYNDROMES Cell proliferation in the glomerulus is the predominant microscopic (biopsy) abnormality: focal or diffuse - endothelial cell (endocapillary) proliferation - podocytes = epithelial cell (extracapillary) proliteration - mesangial cell proliferation (also: matrix ) - capsular cell proliferation crescents Inflammation leads to: - GBM injury (rupture) haematuria proteinuria ( g/d) cellular casts fibrosis, scarring GFR azotaemia Clinical course may be: - spontaneous resolution (ev. with some scarring) - persisting abnormality (usually oligosymptomatic) - progression chronic nephritis uraemia Response to treatment practically nil. microscopic gross

15 1. Acute glomerulonephritis Aetiology: usually post-streptococcal (14-18 days) (b-haemolytic, group A Streptococci, types 12, 4, 18) Histology: - mesangial and endothelial proliferation - compression of glomerular capillaries - leukocytes ("exudative" lesion) Symptoms: - gross haematuria, proteinuria - oliguria - oedema (facial; non-nephrotic) Na + retention - hypertension

16 The CIBA Collection of Medical Illustrations Volume 6: Kidney, ureters and urinary bladder CIBA Medical Education Division Summit, New Yersey USA

17 Acute glomerulonephritis Complications (rare): Clinical course: Treatment: - anuria, azotaemia - hypertensive encephalopathy - acute left ventricular failure usually spontaneous remission occurs - fluid and food restriction - bed rest, hospitalisation if necessary: - diuretics - antihypertensive drugs - dialysis prevention: antibiotics

18 2. Rapidly progressive glomerulonephritis (RPGN) Aetiology: Histology: Symptoms: - immune complexes - anti-gbm-antibodies (may also attack alveolar basement membrane: Goodpasture's syndrome with pulmonary haemorrhage) extensive proliferation and crescent formation (> 80% of glomeruli) - proteinuria, haematuria, casts ("telescopic" sediment) - haemoptysis Clinical course: - rapidly deteriorating renal function (within a few months) Treatment: "pulse" steroids + plasma exchange

19 3. Essential (benign) haematuria ("Berger's IgA mesangial nephropathy") Aetiology: usually post-viral infection (1-2 days) Histology: - mesangial expansion and proliferation - IgA deposits in mesangium Symptoms: - gross haematuria, without proteinuria - microscopic haematuria between episodes Clinical course: episodes ofhaematuria usually become less and less conspicuous, subsequently becoming microscopic with absence of haematuria between the episodes; in 20-30% of cases progression to chronicity and uraemia Treatment: nil

20 4. Membrano-proliferative glomerulonephritis (MPGN) (mesangio-capillary glomerulonephritis) Aetiology: Histology: Symptoms: - immune complexes (type 1; subendothelial deposits) - "C3 nephritogenic factor" (type II; dense deposits, hypocomplementaemia) - capillary membrane thickened ("doubiing") - mesangial proliferation - nephrotic-ievel proteinuria (> 3.5 g/d) - microscopic haematuria, casts Clinical course: - the nephrotic syndrome subsides as renal function is deteriorating, - signs of chronicity (hypertension, increased serum creatinine and BUN appear within a few years Treatment: symptomatic (diuretics)

21 The CIBA Collection of Medical Illustrations Volume 6: Kidney, ureters and urinary bladder CIBA Medical Education Division Summit, New Yersey USA

22 5. Orthostatic proteinuria Aetiology: compression of renal vein by lordosis Histology: mild focal proliferation in a few glomeruli Symptoms: proteinuria absent in nocturnal urine Clinical course: - appears in adolescence - resolution before the age of 25 - proteinuria may become persisting ("minor urinary abnormality")

23 THE CLINICAL SYNDROMES III. Glomerular lesions in systemic diseases Characteristic histologie lesions may be present, but usually the glomeruli exhibit non-specific proliferation, mesangial or membrane abnormalities, hyalinosis and fibrosis Severity of the glomerular injury depends on the activity of the underlying systemic disease Progression to end-stage renal disease is common The clinical picture is indistinguishable from chronic glomerulonephritis (with or without nephrosis)

24 1. Diabetic nephropathy Aetiology: - impaired glucose metabolism glycosylation of proteins polyol pathway - growth factors (IGF-1) organomegaly hyperfiltration (GFR) - hypervolaemia (sodium retention?) intraglomerular pressure hypertension Histology: "intercapillary glomerulosc1erosis - mesangial expansion - thickening of capillary membrane - Kimmelstiel - Wilson nodule - arteriolar hyalinosis - exudative lesions (" capsular drop", "fibrin cap")

25 The CIBA Collection of Medical Illustrations Volume 6: Kidney, ureters and urinary bladder CIBA Medical Education Division Summit, New Yersey USA

26 1. Diabetic nephropathy Clinical course: runs parallelly with retinopathy - early stage with increased GFR - microalbuminuria ( mg/d) - "macroalbuminuria", proteinuria nephrosis - hypertension - GFR, azotaemia - end-stage renal failure Treatment: only the rate of decline in renal function can be decreased - intensified insulin treatment - antihypertensive drugs (ACE-inhibitors) - dietary Na+ and protein restriction (0.7 g/kg/d) - early dialysis treatment

27 2. Systemic lupus erythematosus (SLE) Aetiology: - "prototype" of immune complex disease - nuclear and cytoplasmic proteins serve as antigens (DNA, laminin etc.) Histology: pathognomic lesion is the "wire-ioop" (rare) - polymorphy and pleomorphy - WHO classification (Classes I-VI): - I: normal glomeruli - II: pure mesangial lesion - III: focal proliferation - IV: diffuse proliferation - V: membranosus glomerulopathy - VI: sclerosing glomerulonephritis

28 The CIBA Collection of Medical Illustrations Volume 6: Kidney, ureters and urinary bladder CIBA Medical Education Division Summit, New Yersey USA

29 The CIBA Collection of Medical Illustrations Volume 6: Kidney, ureters and urinary bladder CIBA Medical Education Division Summit, New Yersey USA

30 2. Systemic lupus erythematosus (SLE) Clinical manifestations: - remissions and exacerbations - findings range from no abnormality (Class I) to: - minor urine abnormalities (Class II) - non-nephrotic proteinuria «3.5 g/d) with haematuria, mild hypertension (Class III) - heavy proteinuria, haematuria, severe hypertension, rapid dec line of kidney'function (Class IV) - pure nephrotic syndrome (Class V) - slight changes with long lasting remission (Class VI) Treatment: - depends also on systemic manifestations - ranges from nil to vigorous - alternate day steroids - immunosuppression (azathioprine) - cytotoxic agents (cyclophosphamide) - plasma exchange

31 The CIBA Collection of Medical Illustrations Volume 6: Kidney, ureters and urinary bladder CIBA Medical Education Division Summit, New Yersey USA

32 Proteinuria Reabsorbed 90% Filtered 2g/d Excreted < 200 mg/d Small globulin molecules Urinary protein excretion depends - size, charge, shape of protein - permeability of glom. capillary - tubular reabsorption of proteins

33 Glomerular barrier: pores (60.000D) charge (neg.) - Overfow proteinuria (Bence-Jones) - Glomerular proteinuria >3.5 g = nephrosis - Tubular proteinuria < 2 g/d Tamm-Horsfall protein Transient proteinuria - fever - excess (physical) - burns - heart failure - seizures Orthostatic proteinuria selective (albumin) nonselective

34 Hutt MP, Glassrock RJ: Proteinuria and the nephrotic syndrome. In: Schrier RW(ed): Renal and Electrolyte Disorders. Boston, Little, Brown and Company 1980.

35 1. Vasculitis Vascular diseases of the kidney Vasculitis: inflammation of vessei wall, with or without granulomatous lesions (pure inflammation - pure granulomatosis) Hypersensitivity reaction, usually with ANCA positivity (antineutrophilcytoplasmic antibody) Precipitating factors: Histology: Clinical manifestations: Treatment: - infection - drug-, food-allergy - malignant disease - perivascular infiltration: - lymphocytic (angiitis) - monocytic, giant cells (granuloma) - glomerular lesions: - proliferations (focai or diffuse), often with crescents - necrosis - systemic symptoms (fever, myalgia) - proteinuria, haematuria, casts - rapid deterioration of renal function - pulse steroids (up to 1 g/d for 3 days) - cyclophosphamide (1-2 mg/kg b.w.) - plasmapheresis

36 2. Thrombo-embolic disorders Small and medium arteries: infarction severe pain haematuria rapid decline in renal function Main sources of emboli: - atheromatous plaque (ulcerating) - mitral stenosis with atrial thrombus - atrial fibrillation - bacterial endocarditis - myocardial infarction (mural thrombus) Diagnosis: - serum lactic dehydrogenase (LDH) - CT, renal arteriography Treatment: - anticoagulants - surgical embolectomy

37 Renal vein thrombosis (RVT) renal swelling pain infarction collaterals around the pelvis and ureter may develop indentation on IVP nephrotic syndrome (particularly that caused by membranous glomerulopathy) is usually the underlying disorder pulmonary embolism is a frequent complication anticoagulant therapy is mandatory, but rarely restores renal function

38 Vascular diseases of the kidney The vasculitides Polyarteritis nodosa small and medium arteries are affected: narrowing of lumina ( infarction) granulomas segmental aneurysms ("pearl string") proliferative / necrotic lesions in the glomeruli with fibrosis renal failure hypertension is usually severe (malignant)

39 Vascular diseases of the kidney The vasculitides Wegener's granulomatosis upper respiratory tract involvement dominates the clinical picture (sinusitis, destructing granulomas in the nasal cavity, pulmonary nodular infiltrates) glomeruli show focal-segmental or diffuse necrotizing lesions, distinguished from other kinds of vasculitis only if granulomas are present Allergic granulomatous angiitis (Churg-Strauss) Giant cell arteritis Hypersensitivity angiitis (microscopic polyarteritis) (Glomerular involvement is rare in these forms of vasculitis)