Renal Pathology

Dr Muhammed Azam Part 1 FRCPath Course Manchester January 2020

The beauty of a multiple-choice question is that all the information you will need is given to you.

The drawback is that the additional information given to you is designed to confuse you.

How to approach questions?

Read the stem carefully.

Process the stem:

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Underline key words.

Translate the question into your own words.

Watch for small but important words, such as not or always.

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Predict an answer.

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Read all the alternatives carefully, even if the first choice seems correct.

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Identify the best response.

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In which of the following clinical situations is a needle biopsy of the kidney most useful?

A. Long standing diabetes with elevated serum creatinine  B. Ureteric stones with suspected hydronephrosis  C. Reflux nephropathy  D. Isolated symptomless haematuria  E. Systemic lupus erythematosus with impaired renal function  F. Chronic renal failure and reduced kidney size 

E. Systemic lupus erythematosus with impaired renal function.

Renal biopsies are for diagnosis, grading and staging of the disease. Therapy may depend upon determination of the severity and nature of the renal involvement with SLE.

A.

Diabetes and renal biopsy

Indications: New onset nephritic signs Nephrotic syndrome Rapidly deteriorating renal function Persistent haematuria No obvious signs of other target organ damage

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B. Hydronephrosis C. Reflux nephropathy

Imaging better for diagnosis

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D. Isolated (no proteinuria, hypertension, renal impairment, ..) symptomless haematuria takes an overwhelmingly benign course in both children and adults.

“F. Chronic renal failure and reduced kidney size”  F. Renal biopsy might not give accurate assessment of chronic lesions  Biopsy in chronic renal failure with small kidneys is risky, difficult and usually unrewarding  Limited treatment options in many cases  However biopsy on CRF with normal sized kidneys is worthwhile. Often progressive form of glomerular disease will be found  In older age groups, the diagnosis of unsuspected amyloid, light chain disease or cast nephropathy can be made.

Common indications for renal biopsy:

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Proteinuria over 2g/24h or nephrotic syndrome Persistent proteinuria plus haematuria Rapidly progressive glomerulonephritis SLE Suspected interstitial nephritis Acute renal failure of obscure origin Acute renal failure without resolution in 3-4 weeks Chronic renal failure with normal-sized kidneys Renal allograft dysfunction

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1.

2.

3.

4.

5.

Which of the following is NOT a relative contraindication to renal biopsy?

Uncontrolled hypertension Kidney size <8cm on scan Morbidly obese patient HIV positive patient Elevated prothrombin time

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HIV positive patient

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Reporting involves assessing H&E stains  Special stains  Immunofluorescence or immunohistochemistry  Electron microscopy 

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Areas being examined Glomeruli  Tubules  Interstitium  Vessels 

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H&E

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PAS- GBM thickening, hyalinosis, sclerosis, mesangial cellularity and matrix increase, Tubular BM, arteriolar hyalinosis

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Methenamine silver- GBM spikes, double contours, breaks in GBM/Bowman’s capsule

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Congo red- amyloid

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(Masson Trichrome- interstitial fibrosis, fibrin, platelets EVG- Blood vessels)

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IgG IgA IgM C3 C1q (Fibrinogen) Kappa Lambda

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Which of the following statements are incorrect?

1.

Focal involvement means less than 50% of a glomerular tuft is affected.

Mesangiocapillary (AKA membranoproliferative) pattern is characterised by capillary wall thickening due to mesangial interposition and duplication of glomerular BM. Mesangial hypercellularity is defined as presence of 3 or more mesangial cells per mesangial area.

Crescent formation occurs due to build up of more than 2 layers of proliferating endothelial cells in the Bowman’s space

2.

3.

4.

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Which of the following statements are incorrect.

1.

Focal involvement means less than 50% of a glomerular tuft is affected.

Membranoproliferative pattern is characterised by capillary wall thickening due to mesangial interposition and duplication of glomerular BM. Mesangial hypercellularity is defined as presence of 3 or more mesangial cells per mesangial area.

Crescent formation occurs due to build up of more than 2 layers of proliferating endothelial cells in the Bowman’s space

2.

3.

4.

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Focal - involving less than 50% of glomeruli.

Diffuse - Involving 50% or more of glomeruli.

Segmental- Involving a portion of the glomerular tuft Global- Involving the entire glomerular tuft.

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Build up of more than 2 layers of cells within Bowman’s space caused by proliferation of parietal cells, podocytes and infiltrating inflammatory cells.

Classified as cellular, fibrocellular and fibrous.

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Nephrotic syndrome and proteinuria Nephritic ‘syndrome’ and/or RPGN = rapidly progressive glomerulonephritis (NB This is a clinical term!)

Asymptomatic/gross haematuria Acute kidney injury Chronic kidney disease

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Which of the following is not part of the definition of nephrotic syndrome.

1.Proteinuria >3.5gm/24 hours 2. Active urinary sediments 3. Hypoalbuminaemia 4. Oedema 5. Hyperlipidemia

Active urinary sediment Hyperlipidaemia

A 25 year old female presented with fatigue, weight gain and puffiness of eyes. Investigations revealed proteinuria of 4gm/24 hours, no haematuria, normal renal function and normal sized kidneys.

Which of the following changes are unlikely on a renal biopsy.

1.

Diffuse thickening of basement membranes with spikes 2.

Crescents involving > 50% of glomeruli 3.

Segmental sclerosis of glomeruli 4.

Normal light microscopic appearance of glomeruli. 

2. Crescents involving >50% of glomeruli

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Primary idiopathic Minimal Change Disease FSGS Membranous GN

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Systemic diseases Diabetes SLE Dysproteinemias

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Primary glomerular diseases presenting typically with nephritic features MPGN IgA nephropathy

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Commonest cause of nephrotic syndrome in children Usually idiopathic, has been associated with viruses, drugs, lymphoid malignancies Often presents with selective proteinuria Glomeruli normal on LM IMF- negative Foot process effacement on EM Responds to steroid therapy

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Primary (idiopathic)

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Secondary FSGS 1.Familial/Genetic 2.Virus associated 3.Drug induced 4.Adaptive structural- functional responses

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Clinico-pathological syndrome

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Nephrotic syndrome or heavy proteinuria.

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More likely to have haematuria, hypertension, renal insufficiency and progression, compared to minimal change disease.

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Pathological findings of FSGS in the absence of known secondary causes.

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1. NOS 2. Glomerular Tip lesions 3.Cellular 4.Perihilar 5.Collapsing

IMF- Segmental lesions often stain for IgM and C3. This is NOT true staining, merely nonspecific adherence to sclerotic areas EM- extensive effacement of foot processes.

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Common in 4th- 5th decade Most cases now known to be the result of antibodies to M-type phospholipase A2 receptor (PLA2R) (60-80%) Secondary causes- autoimmune diseases, neoplasia, infection.

Histology- Diffuse thickening of capillary basement membranes, spikes on silver stain.

IMF- granular staining for IgG and C3 along capillary basement membranes.

EM- subepithelial deposits

Which statement is correct: A.

B.

C. D.

E.

Minimal change disease accounts for 20% of cases of primary nephrotic syndrome in children Spikes in membranous GN are best seen with a Masson’s trichrome stain.

FSGS shows selective proteinuria.

‘Kimmelstein-Wilson’ lesions are seen in diabetic nephropathy Stage 4 membranous has recognizable deposits.

Correct is D. “Diabetic nephropathy shows ‘Kimmelstein Wilson’ lesions

Diabetic Nephropathy The leading cause of end stage renal disease in Europe, Japan, USA. IDDM and NIDDM Histological hallmarks: KW lesions, capsular drop and fibrin caps EM –Thickened basement membranes Kimmelstiel-Wilson lesions are PAS positive, silver positive and Congo red negative

Which statement is correct: A.

B.

C. D.

E.

Minimal change disease accounts for 20% of cases of primary nephrotic syndrome in children- 80% Spikes in membranous GN are best seen with a Masson’s trichrome stain.- Silver stain FSGS shows selective proteinuria.- non selective ‘Kimmelstein-Wilson’ lesions are seen in Diabetic nephropathy Stage 4 membranous has recognizable deposits.resolved deposits

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Typically abrupt onset Haematuria (often with red cell casts in urine) Mild to moderate proteinuria Hypertension Renal insufficiency (increased serum creatinine)

RPGN- >50% decline in glomerular filtration rate within 3 months of clinical presentation.

1.Acute Diffuse Proliferative GN (DPGN) 2. Membranoproliferative GN 3.Dense Deposit Disease 4.Crescentic GN

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Immune complex mediated injury, seen most commonly following transient/persistent infections.

- pharyngitis or skin infections (Streptococcus) - infectious endocarditis - bacterial infection of CSF shunts -osteomyelitis - deep seated abscesses

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Diffuse- all or nearly all glomeruli affected Glomerular tufts are hypercellular and capillary lumina obliterated.

Hypercellularity due to proliferation of mesangial cells, endothelial cells and filling of capillary lumina by leukocytes.

IMF- Coarse granular ‘lumpy-bumpy’ staining of glomerular capillary loops with IgG and C3 EM- Electron dense subepithelial ‘hump’ like deposits, resolve in 6 weeks.

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Primary Secondary- important association with chronic hepatitis C infection.

Histology-Global hypercellularity -Lobular accentuation -Thickening of capillary loops with double contours or tram track appearance.

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Type 1 Type 2- dense deposit disease, now known to be the result of homozygous complement factor H deficiency Type 3 – does it really exist? Probably not. May be variety of different conditions, including C3 glomerulopathy

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Consistent, usually intense staining for C3 along glomerular capillary loops as well as mesangium.

Similar staining may be seen with IgG and IgM

EM- type1 subendothelial deposits

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Presence of crescents in >50% of glomeruli (WHO definition)

3 types- based on immunofluorescence 1. Pauci-immune crescentic GN 2. Immune complex associated crescentic GN 3. Anti- GBM antibody associated crescentic GN

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A 20-year-old previously healthy man has been feeling tired for few days and passes ‘coca cola’ urine. On physical examination his blood pressure was 155/90 mm Hg. Laboratory studies showed his serum creatinine 4.4 mg/dL and high titre of CANCA. Which of the following pathologic findings on renal biopsy is most likely to be present in this man?     

A. Lack of staining on immunofluorescence B. Mesangial IgA positivity on immunofluorescence C. Thickness of basement membrane more than 600nm.

D. Effacement of foot processes E. Vasculitis of medium sized arteries

“Lack

of staining on immunofluorescence”

Renal vasculitis ~ 90 % are ANCA related  Wegener’s granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome are all associated with circulating anti-neutrophilic cytoplasmic antibody (ANCA).  Characteristically cause a necrotising glomerulonephritis with crescents Pauci-immune glomerulonephritis with absent staining for immunoglobulins by immunofluorescence 

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A. Lack of fluorescence B. Mesangial IgA positivity on immunofluorescence – HSP, IgA nephropathy C. Thickness of basement membrane more than 600nm - DM D. Effacement of foot processes – Minimal change E. Vasculitis of medium sized artery- ANCA vasculitis affects small vessels (capillaries), bigger vessels affected very rarely.

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IgA nephropathy Henoch Schonlein purpura Alport Syndrome Thin basement membrane nephropathy

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Which of the following is not true of IgA nephropathy?

1.Highest prevalence reported in southeast Asia.

2. The most common glomerular pattern is mesangioproliferative GN 3. IgA should be dominant or co-dominant immunoglobulin on immunofluorescence to make this diagnosis.

4. The vast majority (80%) of cases have a benign clinical course, with little or no progression to end stage renal disease.

4. The vast majority (80%) of cases have a benign clinical course, with little or no progression to end stage renal disease.

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IgA nephropathy Henoch Schonlein purpura Alport Syndrome Thin basement membrane nephropathy

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Which is the correct statement?

A. Fibrin caps are seen in membranous nephropathy.

B. “Collapsing variant’ of FSGS shows proliferation of endothelial cells.

C. Mesangial IgA deposits are seen in Henoch Schonlein purpura nephritis.

D. IgA nephropathy is frequently associated with Hodgkin’s lymphoma.

E. Goodpasture syndrome is more common than Wegener’s syndrome in renal biopsies.

C. Mesangial deposits are seen in HenochSchonlein purpura nephritis.

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Which is the correct statement?

Fibrin caps are seen in membranous nephropathyDiabetic nephropathy B. “Collapsing variant’ of FSGS shows proliferation of endothelial cells.- visceral epithelial cells C. Mesangial deposits are seen in HSP- CORRECT D. IgA nephropathy is associated with Hodgkin’s lymphoma.- no such association E. Goodpasture syndrome is more common than Wegener’s syndrome in renal biopsies.- rare A.

Match the topic ( A,B....) with the appropriate conditions ( 1,2,3...)  The conditions can be used on more than one occasion 

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A. Subepithelial IgG humplike positivity B. Linear membranous IgG positivity C. Subepithelial granular IgG deposits D. IgA mesangial positivity E. C1q peripheral and mesangial positivity

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1. Anti GBM 2. IgA nephropathy 3. Membranous nephropathy 4. Lupus nephritis 5. Post-infectious nephropathy

1. Anti GBM

B. Linear membranous IgG positivity

2. IgA nephropathy

D. IgA mesangial positivity C. Subepithelial granular IgG deposits

3. Membranous nephropathy 4. Lupus nephritis

E. C1q peripheral and mesangial positivity

5. Post-infectious nephropathy

A. Subepithelial IgG hump-like positivity

A-5 B-1 C-3 D-2 E-4

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A. Subepithelail IgG humplike positivity B. Linear membranous IgG positivity C. Subepithelial granular IgG deposits D. IgA mesangial positivity E. C1q peripheral and mesangial positivity

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1. Anti GBM 2. IgA nephropathy 3. Membranous nephropathy 4. Lupus nephritis 5. Post-infectious nephropathy

Post-infectious granular IgG

Anti GBM linear IgG

A. In this condition the pathologist sees ‘fractured casts’ B. Clusters of neutrophils within tubular lumina is indicative of this condition C. The underground abnormality in this renal disease can be IBD, TB, osteomyelitis or RA. D. Onion skinning is seen in this renal condition.

E. Accumulation of nucleated cells in the vasa recta of the medulla, is a clue to this diagnosis.

1. Acute Tubular Necrosis 2. Fibromuscular dysplasia 3. Hyaline arteriosclerosis 4. Hyperplastic arteriosclerosis 5. Myeloma cast nephropathy 6. Amyloidosis 7. Pelvic lipomatosis 8. Acute allergic nephritis 9. Analgesic nephropathy 10. Acute pyelonephritis.

11. Chronic pyelonephritis 12. Acute tubular necrosis

A-5 B-10 C-6 D-4 E-1

A. In this condition the pathologist sees ‘fractured casts’ B. Clusters of neutrophils within tubular lumina is indicative of this condition C. The underground abnormality on this renal disease can be IBD, TB, osteomyelitis or RA. D. Onion skinning is seen in this renal condition.

E. Accumulation of nucleated cells in the vasa recta of the medulla, is a clue to this diagnosis.

1. Acute Tubular Necrosis 2. Fibromuscular dysplasia 3. Hyaline arteriosclerosis 4. Hyperplastic arteriosclerosis 5. Myeloma cast nephropathy 6. Amyloidosis 7. Pelvic lipomatosis 8. Acute allergic nephritis 9. Analgesic nephropathy 10. Acute pyelonephritis.

11. Chronic pyelonephritis 12. Acute tubular necrosis

The expression ‘acute renal failure’ has been replaced by ‘acute kidney injury (AKI)’. There are 3 main patterns:  as an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons (pre-renal).  in response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage (glomerular, tubulointerstitial and vascular).  with obstruction to the passage of urine (post-renal).

Prerenal AKI is the most common. Volume loss from GI, cutaneous (e.g., burns), and internal or external haemorrhage.

Can also result from decreased renal perfusion in patients with heart failure or shock (e.g., sepsis, anaphylaxis).

Arteriolar vasoconstriction leading to ARF can occur in hypercalcemic states, with the use of radiocontrast agents and NSAIDs.

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A. This renal disease contains fibrils 8 to 10nm in diameter.

B. In this renal disease the EM identified fibrils are 20nm in diameter.

C. This renal disease contains fibrils 30 to 50nm in diameter.

D. Tubulo- reticular inclusions are seen in this condition E. Myeloid or ‘Zebra bodies’ are seen in lysosomes

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1. Minimal change GN 2. Mesangiocapillary GN 3. IgA nephropathy 4. Membranous GN 5. Diabetic nephropathy 6. Amyloidosis 7. Light chain deposition disease 8. Fibrillary GN 9. Immunotactoid GN 10. Congenital nephrotic syndrome 11. Alport syndrome 12. Rapidly progressive GN 13. Thin basement membrane syndrome 14. Lupus nephritis 15. Fabry’s disease 16. Myeloma cast nephropathy

A-6 B-8 C-9 D-14 E-15

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A. This renal disease contains fibrils 8 to 10nm in diameter.

B. In this renal disease the EM identified fibrils are 20nm in diameter.

C. This renal disease contains fibrils 30 to 50nm in diameter.

D. Tubulo- reticular inclusions are seen in this condition E. Myeloid or ‘Zebra bodies’ are seen on lysosomes

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1. Minimal change GN 2. Mesangiocapillary GN 3. IgA nephropathy 4. Membranous GN 5. Diabetic nephropathy 6. Amyloidosis 7. Light chain deposition disease 8. Fibrillary GN 9. Immunotactoid GN 10. Congenital nephrotic syndrome 11. Alport syndrome 12. Rapid progressive GN 13. Thin membrane syndrome 14. Lupus nephritis 15. Fabry’s disease 16. Myeloma cast nephropathy

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Almost impossible EMQ but there are interesting data in Ackermann’s book about these diseases. Be anyway familiar with the normal thickness of the basement membrane and its increase in thickness in diabetes.

Silver negative and PAS negative (Sirius red and) Congo red positive

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AA AL…..etc Hereditary and acquired Systemic and localised

http://www.virtualpathology.leeds.ac.uk/teaching/collections/renal/