Dr Ian Roberts Oxford. Oxford Pathology Course 2010 for FRCPath Illustration-Cellular Pathology. Oxford Radcliffe NHS Trust

Transcription

1 Dr Ian Roberts Oxford Oxford Pathology Course 2010 for FRCPath

2 Present the basic diagnostic features of the commonest conditions causing proteinuria & haematuria Highlight diagnostic pitfalls

3 Nephrotic syndrome = heavy proteinuria, hypo-albuminaemia, oedema It reflects damage to the glomerular permeability barrier (podocyte or basement membrane) which may occur without inflammation. Nephritic syndrome = haematuria, proteinuria, oliguria, uraemia and hypertension It reflects glomerular inflammation (glomerular haematuria indicates breaks in the capillary wall).

4 Minimal change nephropathy Primary focal segmental glomerulosclerosis Membranous nephropathy Amyloidosis Diabetic nephropathy MIDD and myeloma kidney Lupus nephritis

5 Acute onset nephrotic syndrome Commonest in children but can occur at any age Usually steroid responsive Glomeruli normal by light microscopy IH negative (mesangial IgM allowed)

6 Normal EM: No deposits MCD Effacement of podocyte foot processes

7 A manifestation of heavy proteinuria. May be seen in association with minimal change disease, FSGS, membranous, diabetes, post-infectious GN, etc If it is the only glomerular abnormality, response to steroid treatment and prognosis is similar to minimal change disease.

8 is a lesion focal segmental sclerosis (actually multiple lesions that are often diffuse and may not show sclerosis ) is a clinicopathological entity, in which nephrotic syndrome is associated with focal segmental glomerular lesions the aetiologies are diverse and multiple the morphology to some extent reflects the aetiology and predicts prognosis

9 Idiopathic FSGS Known cause of podocyte injury 1. Genetic: eg. podocin, nephrin, WT-1, mutations 2. Infective: eg. HIV, parvovirus B19 3. Drug-induced: eg. Pamidronate, lithium, IFN- Glomerular hypertension/hyperfiltration 1. Reduced nephron mass: eg reflux nephropathy, nephrectomy, renal dysplasia, unilateral renal agenesis 2. Increased stress on normal nephron numbers: obesity, hypertension, sickle cell anaemia Non-specific scars following inflammatory injury eg. Vasculitic GN, IgAN/HSP nephritis, Lupus

10 Sclerosis and hyalinosis adjacent to the vascular pole. Associated with secondary (hyperfiltration) FSGS, eg obesity, hypertension. Non-sclerosed glomeruli are frequently enlarged (glomerulomegaly).

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13 May be primary or secondary to infections (HIVAN, parvovirus B19) or drugs (bisphosphonates) Carries a worse prognosis: % remission following steroid treatment: No cellular/collapsing lesion 52% Cellular/collapsing lesion in <20% glomeruli 53% Cellular/collapsing lesion in >20% glomeruli 23% Patients with >20% glomeruli with cellular lesion are black, have more severe proteinuria, less responsive to treatment and have an increased prevalence of ESRD. Schwartz et al. J Am Soc Nephrol 1999;10:

14 Idiopathic (80%): Autoimmune disease to podocyte antigen Secondary (20%): Drugs, eg gold, penicillamine SLE Malignancy, eg carcinoma bronchus, colon,stomach Infections, eg HBV, malaria

15 Stage I Normal by light microscopy Stage II-IV Thickened capillary walls Round capillary loops (increased rigidity) Increased mesangial cellularity (especially in lupus)

16 Stage I Normal silver Stage II Membrane spikes on silver Stain Stage III-IV Complex thickened chain-link membrane

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18 Stage II Stage III

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20 Beware! Congo red may be negative: Thin section Very little amyloid Poor stain

21 Immunohistochemistry Useful for detecting amyloid A Light chain stains usually unhelpful in AL amyloid

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29 Beware! The history of diabetes is often not provided by either clinician or examiner. There are other causes of nodular glomerulosclerosis, such as amyloidosis and light chain deposition disease. Patients with diabetic nephropathy aren t usually biopsied unless the clinical presentation is atypical - many have diabetic nephropathy plus something else eg IgA nephropathy Membranous nephropathy Oxalate nephropathy - especially if the diabetes is secondary to pancreatic failure atheroembolic disease

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36 LM: Can produce any pattern of proliferative GN. Membranous nephropathy +/- proliferation Wire loops and pseudothrombi (large immune deposits) IH: Full house immunoglobulins and complement Glomerular and tubular membrane deposits EM: Mesangial deposits +/- subendothelial & subepithelial deposits

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40 ISN/RPS Lupus Classification Class I Normal light microscopy, + IF/EM Class II Mesangial changes only Class III Focal lupus nephritis <50% of glomeruli, A/C Class IV Diffuse proliferative lupus nephritis >50% of glomeruli, S/G, A/C Class V Membranous lupus Class VI Advanced sclerosis (over 90%)

41 Common causes of isolated haematuria: IgA nephropathy Thin membrane nephropathy Common causes of nephritic syndrome: IgA nephropathy Post-infectious glomerulonephritis Mesangiocapillary glomerulonephritis

42 Commonest glomerulonephritis Variable clinical presentation (microscopic haematuria, nephrotic proteinuria, acute renal failure) Variable histology (normal by light microscopy to crescentic GN) Diagnosis based on the presence of IgApredominant immune deposits in glomeruli - usually mesangial

43 Proliferation: mesangial endocapillary

44 Mesangial deposits: Capillary wall- uncommon Common HSP, adverse prognostic factor

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46 Minimum prognostic data: Glomerular pattern : Mesangial hypercellularity in > or <50% of glomeruli (M 0/1) Endocapillary hypercellularity present/absent (E 0/1) Segmental sclerosis/adhesions present/absent (S 0/1) Tubular atrophy/interstitial fibrosis 0-25%, 26-50%, >50% (T 0/1/2) In addition: Total number of glomeruli Endocapillary proliferation - % Cellular/fibrocellular crescents - % Necrosis - % Global glomerulosclerosis - % Example summary line: There is an IgA nephropathy showing diffuse mesangial proliferation with focal segmental sclerosis and moderate chronic tubulointerstitial damage (M1,E0,S1,T1)

47 80% X-linked, mutations of COL4A5 gene Sensorineural deafness, ocular abnormalities Haematuria, proteinuria, renal failure Segmental mesangial proliferation & sclerosis, interstitial foam cells Diffuse thinning of lamina densa & areas of splitting

48 Benign microscopic haematuria - but not all benign Inheritance complicated - many carriers of Alport s mutations Normal by light microscopy Diffuse thinning of lamina densa of GBM (usually to <200nm, normal mean approx 300nm)

49 Streptococcol throat infections, deep abscesses Haematuria, proteinuria, nephrotic syndrome, renal failure Diffuse endocapillary GN - neutrophils in capillary loops Coarse granular deposits of IgG & C3 in capillary walls Subepithelial humps at EM

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51 MCGN is a morphology, not a diagnosis - mesangial cell proliferation + reduplication of GBM Immune-complex mediate GN Haematuria, proteinuria, nephrotic syndrome, renal failure IgG & C3 in capillary walls Subendothelial deposits at EM & mesangial cell interposition

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53 Haematuria (90%), nephrotic syndrome (50%), acute nephritic syndrome (20%) Mesangial cell proliferation and eosinophilic thickening of capillary walls C3 in capillary walls Replacement of basement membrane by linear masses of electron dense material

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55 C3