Peter Topham Consultant Nephrologist John Walls Renal Unit Leicester United Kingdom

Peter TophamConsultant Nephrologist

John Walls Renal UnitLeicester

United Kingdom

Classification in Nephropathology:A Clinician’s Point of View

A clinical case

19 year old man – 1st year sports science student at Loughborough University

Visible haematuria

Upper respiratory tract infection

No further episodes

Persistent non-visible haematuria

Dipstick positive proteinuria

Referred to the renal unit for evaluation

Asymptomatic

No significant past medical history

No family history

Non smoker

Binge alcohol

Occasional cannabis use

No other drug use

Examination

Fit and well

BMI 22kg/m2

BP 118/72mmHg

Investigations

serum creatinine 68µmol/L (60–110) eGFR >90ml/minserum C-reactive protein 5mg/L (<10)

Urinalysis:blood 3+protein 1+

Urine PCR 71mg/mmol (<30)

anti-nuclear antibody negativeANCA negativeserum complement C3 74mg/dL (65–190)serum complement C4 28mg/dL (15–50) serum immunoglobulin G 11.2g/L (6.0–13.0) serum immunoglobulin A 3.3g/L (0.8–3.0) serum immunoglobulin M 2.1g/L (0.4–2.5) antistreptolysin titre 102IU/mL (<200)

Investigations

serum creatinine 68µmol/L (60–110) eGFR >90ml/minserum C-reactive protein 5mg/L (<10)

Urinalysis:blood 3+protein 1+

Urine PCR 71mg/mmol (<30)

anti-nuclear antibody negativeANCA negativeserum complement C3 74mg/dL (65–190)serum complement C4 28mg/dL (15–50) serum immunoglobulin G 11.2g/L (6.0–13.0) serum immunoglobulin A 3.3g/L (0.8–3.0) serum immunoglobulin M 2.1g/L (0.4–2.5) antistreptolysin titre 102IU/mL (<200)

Renal tract ultrasound:Lt kidney 10.2cmRt kidney 10.0cmNormal appearanceNo stones

KUB X-ray:No renal tract calcification

Cystoscopy:No intravesical pathology

Clinical diagnosis of IgA nephropathy

Clinical diagnosis of IgA nephropathy

What next?

Clinical diagnosis of IgA nephropathy

What next?

?? Kidney biopsy

What do we want to know?

What is the diagnosis ?

What is his individual prognosis?

How should he be treated?

What is his risk of transplant recurrence?

Does it help us understand disease mechanisms?

Is he suitable for recruitment to clinical trials?

What would a biopsy add to what we already (think we) know?

Clinical predictors of outcome in IgA nephropathy

Poor prognosis•Proteinuria•Hypertension•Baseline renal function•Increased body mass index•Increasing age

Good prognosis•Recurrent visible haematuria

No impact on outcome•Gender•Geography•Ethnicity•Serum IgA level

Reich H N et al. JASN 2007;18:3177-3183

What would a biopsy add to what we already (think we) know?

Reich H N et al. JASN 2007;18:3177-3183

Time-average proteinuria1 - < 1g/24h2 – 1-2 g/24h3 – 2-3g/24h4 - >3g/24h

What would a biopsy add to what we already (think we) know?

Renal biopsy findings

IgA

Renal biopsy findings

IgA nephropathy

IgA

Oxford MEST Classification

Mesangial hypercellularity - in < or >50% of glomeruli M0 or M1

Endocapillary hypercellularity – absent/present E0 or E1

Segmental sclerosis/adhesions – absent/present S0 or S1

Tubular atrophy/interstitial fibrosis – 0-25%, 26-50%, >50% T0 or T1 or T2

Cellular/fibrocellular crescents were not predictive of outcome

Oxford MEST Classification

Mesangial hypercellularity - in < or >50% of glomeruli M0 or M1

Endocapillary hypercellularity – absent/present E0 or E1

Segmental sclerosis/adhesions – absent/present S0 or S1

Tubular atrophy/interstitial fibrosis – 0-25%, 26-50%, >50% T0 or T1 or T2

Cellular/fibrocellular crescents were not predictive of outcome

Each adds predictive value to ….Initial clinical featuresFollow up clinical features In all agesIn white Europeans and East Asians

Oxford MEST Classification

VALIDATION STUDIES FOR THE OXFORD CLASSIFICATION OF IgAN?

M E S T

Macedonia2010

98 + + + +

USA2011

54 + + - +

Japan2011

161 children + + - +

France2011

183 - + + +

USA, Canada2011

187 adults & children

+ + + +

China2011

410 - + + +

Japan 2011

702 - - + +

Sweden2012

99 + + - +

Korea2012

197 + - + +

6/10 7/10 6/10 10/10

Oxford MEST Classification:M0 E0 S0 T0

How does this help?

Oxford MEST Classification: M0 E0 S0 T0

How does this help?

Slope:

ml/min/1.73m2/yr

Minimal mesangial without segmental sclerosis M0,E0,S0 12 0.7 ± 2.5

with segmental sclerosis M0,E0,S1 22 -1.5 ± 2.7

Mesangial hypercellularity without segmental sclerosis M1,E0,S0 31 -2.2 ± 4.3

with segmental sclerosis M1,E0,S1 88 -4.7 ± 7.6

Endocapillary proliferation without segmental sclerosis M0/1,E1,S0 21 1.2 ± 1.2

with segmental sclerosis M0/1,E1,S1 90 -4.9 ± 10.0

CriteriaNo. of

patients

PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONSCombining glomerular patterns

Oxford MEST Classification: M0 E0 S0 T0

PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONSCombining glomerular and tubulointerstitial lesions

Slope:

ml/min/1.73m2/yr

Minimal mesangial ≤25% M0,E0,T0 30 -0.6 ± 3.0

> 26% M0,E0,T1-2 5 -1.0 ± 1.2

Mesangial hypercellularity ≤25% M1,E0,T0 89 -2.7 ± 5.5

> 26% M1,E0,T1-2 30 -7.9 ± 9.1

Endocapillary proliferation ≤25% M0/1,E1,T0 88 -3.0 ± 1.9

> 26% M0/1,E1,T1-2 23 -6.9 ± 1.2

Glomerular lesions TA/IF CriteriaNo. of

patients

How does this help?

Oxford MEST Classification: M0 E0 S0 T0

PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONSCombining glomerular and tubulointerstitial lesions

Slope:

ml/min/1.73m2/yr

Minimal mesangial ≤25% M0,E0,T0 30 -0.6 ± 3.0

> 26% M0,E0,T1-2 5 -1.0 ± 1.2

Mesangial hypercellularity ≤25% M1,E0,T0 89 -2.7 ± 5.5

> 26% M1,E0,T1-2 30 -7.9 ± 9.1

Endocapillary proliferation ≤25% M0/1,E1,T0 88 -3.0 ± 1.9

> 26% M0/1,E1,T1-2 23 -6.9 ± 1.2

Glomerular lesions TA/IF CriteriaNo. of

patients

These are just examples

NotNot enough evidence yet to directly sum risks

How does this help?

Oxford MEST Classification: M0 E0 S0 T0

Oxford MEST Classification:M1 E1 S0 T0

Slope:

ml/min/1.73m2/yr

Minimal mesangial ≤25% M0,E0,T0 30 -0.6 ± 3.0

> 26% M0,E0,T1-2 5 -1.0 ± 1.2

Mesangial hypercellularity ≤25% M1,E0,T0 89 -2.7 ± 5.5

> 26% M1,E0,T1-2 30 -7.9 ± 9.1

Endocapillary proliferation ≤25% M0/1,E1,T0 88 -3.0 ± 1.9

> 26% M0/1,E1,T1-2 23 -6.9 ± 1.2

Glomerular lesions TA/IF CriteriaNo. of

patients

PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONSCombining glomerular and tubulointerstitial lesions

How does this help?

Oxford MEST Classification: M1 E1 S0 T0

Immunosuppression had no influence on relationship between pathology variables and the rate

of renal function decline

…..except for endocapillary lesions

Patients with endocapillary proliferation

Immunosuppression -1.5+/-8.3 ml/min/1.73m2 /yr

No immunosuppression -5.4+/-1.1 ml/min/1.73m2 / yr

Immunosuppression had no influence on relationship between pathology variables and the rate

of renal function decline

…..except for endocapillary lesions

Relationship between pathology variables and the rate of renal function decline

was notnot influenced by immunosuppression

…..except for endocapillary lesions

Patients with endocapillary proliferation

Immunosuppression -1.5+/-8.3 ml/min/1.73m2 /yr

No immunosuppression -5.4+/-1.1 ml/min/1.73m2 / yr

Retrospective dataCaution against overinterpretation

What is the diagnosis ? IgA nephropathy

What is his individual prognosis? Some insight

How should he be treated? Little clarity

What is his risk of transplant recurrence? Unhelpful

Does it help us understand disease mechanisms? No

Is he suitable for recruitment to clinical trials? Probably

What do we want to know?

Why were crescents not related to outcome in this classification?

Why were crescents not related to outcome in this classification?

There were few cases with crescents

No case had more than 30% of glomeruli with crescents

These were slowly progressive cases

WHEN ARE CRESCENTS SIGNIFICANT IN IgA NEPHROPATHY ?

Katafuchi R et al. CJASN 2011; 6: 2806

Patients meeting ‘Oxford’ criteria

Patients outside ‘Oxford’ criteria

Why is the classification based just on light microscopy?

Would the addition of immunohistochemistry and/or EM data add any value?

Why is the classification based just on light microscopy?

Would the addition of immunohistochemistry and/or EM data add any value?

IgA DEPOSITS IN IgA NEPHROPATHYMesangial deposits Capillary wall deposits

Bellur SS et al. NDT 2011; 26: 2533

IgA & IgG DEPOSITS IN IgA NEPHROPATHY

Bellur SS et al. NDT 2011; 26: 2533

Mesangial vs. capillary wall IgA

NoNo difference in 5 year outcome

Presence or absence of IgG deposits

NoNo difference in 5 year outcome

Another clinical case

49 year-old-man presents with progressive leg swelling

Noted that his urine had become frothy

No cardiorespiratory symptoms

Previously fit and well

No medication apart from occasional ibuprofen for headache

No family history of renal disease

Smokes 10 cigarettes per day

30-40 units of alcohol per week

Estate agent

Examination

Not acutely unwell

Afebrile

Oedema to upper thighs and sacrum

JVP not elevated

Normal heart sounds – no murmurs or gallop rythmn

Clear lung fields

Detectable ascites – no organomegaly

Dipstick urinalysis:blood 1+protein 4+

Investigations

serum creatinine 172µmol/L (60–110) eGFR 47ml/minserum albumin 19g/L (35-45)Serum cholesterol 9.8mmol/Lserum C-reactive protein 5mg/L (<10)

Urine PCR 781mg/mmol (<30)

anti-nuclear antibody negativeserum complement C3 74mg/dL (65–190)serum complement C4 28mg/dL (15–50) serum immunoglobulin G 4.2g/L (6.0–13.0) serum immunoglobulin A 1.3g/L (0.8–3.0) serum immunoglobulin M 2.1g/L (0.4–2.5)serum protein electrophoresis negative

Investigations

serum creatinine 172µmol/L (60–110) eGFR 47ml/minserum albumin 19g/L (35-45)Serum cholesterol 9.8mmol/Lserum C-reactive protein 5mg/L (<10)

Urine PCR 781mg/mmol (<30)

anti-nuclear antibody negativeserum complement C3 74mg/dL (65–190)serum complement C4 28mg/dL (15–50) serum immunoglobulin G 4.2g/L (6.0–13.0) serum immunoglobulin A 1.3g/L (0.8–3.0) serum immunoglobulin M 2.1g/L (0.4–2.5)serum protein electrophoresis negative

Renal tract ultrasound:Lt kidney 10.6cmRt kidney 10.9cmNormal appearanceNo stones

KUB X-ray:No renal tract calcification

Kidney biopsy

Renal tract ultrasound:Lt kidney 10.6cmRt kidney 10.9cmNormal appearanceNo stones

KUB X-ray:No renal tract calcification

Investigations

serum creatinine 172µmol/L (60–110) eGFR 47ml/minserum albumin 19g/L (35-45)Serum cholesterol 9.8mmol/Lserum C-reactive protein 5mg/L (<10)

Urine PCR 781mg/mmol (<30)

anti-nuclear antibody negativeserum complement C3 74mg/dL (65–190)serum complement C4 28mg/dL (15–50) serum immunoglobulin G 4.2g/L (6.0–13.0) serum immunoglobulin A 1.3g/L (0.8–3.0) serum immunoglobulin M 2.1g/L (0.4–2.5)serum protein electrophoresis negative

Renal biopsy

Focal segmental glomerulosclerosis

Renal biopsy

Focal segmental glomerulosclerosisNot Otherwise Specified

Renal biopsy

Focal segmental glomerulosclerosisHistological pattern – comprises a group of clinico-pathologic syndromes that

share a common glomerular lesionMediated by a variety of insults that target the podocyte

Focal segmental glomerulosclerosisHistological pattern – comprises a group of clinico-pathologic syndromes that

share a common glomerular lesionMediated by a variety of insults that target the podocyte

D’Agati V et al. N Engl J Med 2011;365:2398

Focal segmental glomerulosclerosis

80% have primary FSGS

50-60% of adults present with nephrotic syndrome

Histological pattern – comprises a group of clinico-pathologic syndromes that share a common glomerular lesion

Mediated by a variety of insults that target the podocyte

D’Agati V et al. N Engl J Med 2011;365:2398

PATHOLOGICAL CLASSIFICATION OF FSGS

D’Agati V et al. AJKD 2004

Perihilar variant Tip lesion variant

NOS

Collapsing variant Cellular variant

Thomas DB et al. KI 2006; 69: 920

Demographics, clinical presentation, and outcomes of FSGS variants

What do we want to know?

What is the diagnosis ?

What is his individual prognosis?

How should he be treated?

What is his risk of transplant recurrence?

Does it help us understand disease mechanisms?

Is he suitable for recruitment to clinical trials?

What do we want to know?

What is the diagnosis ?

What is his individual prognosis?

How should he be treated?

What is his risk of transplant recurrence?

Does it help us understand disease mechanisms?

Is he suitable for recruitment to clinical trials?

What’s the diagnosis?

D’Agati V et al. AJKD 2004

Perihilar variant Tip lesion variant

NOS

Collapsing variant Cellular variant

What’s the diagnosis?

D’Agati V et al. AJKD 2004

NOS

What do we want to know?

What is the diagnosis ?

What is his individual prognosis?

How should he be treated?

What is his risk of transplant recurrence?

Does it help us understand disease mechanisms?

Is he suitable for recruitment to clinical trials?

PREDICTING OUTCOME FROM PATHOLOGY IN FSGS

Thomas DB et al. KI 2006; 69: 920

Collapsing

All other ‘variants’

P = 0.0016

PREDICTING OUTCOME FROM PRESENTATION IN FSGS

Non-nephrotic 20% ESRD at 10 years

Nephrotic >50% ESRD at 5-10 years

Nephrotic >10g/day ~100% ESRD at 5-10 years ‘Malignant FSGS’

REMISSION & ESRD IN FSGS

Troyanov S. et al. JASN 2005; 16:1061Stirling C et al– QJM 2005; 98: 443

No Remission vs. Partial remission

with a relapse

Time to RRT or death(yrs)

1086420

Perc

enta

ge S

urvi

val

1.0

.8

.6

.4

.2

0.0

Remission (partial or complete)vs. No remission

Thomas DB et al. KI 2006; 69: 920

Demographics, clinical presentation, and outcomes of FSGS variants

What do we want to know?

What is the diagnosis ?

What is his individual prognosis?

How should he be treated?

What is his risk of transplant recurrence?

Does it help us understand disease mechanisms?

Is he suitable for recruitment to clinical trials?

D’Agati V et al. N Engl J Med 2011;365:2398-411

TREATMENT OF FSGS

D’Agati V et al. N Engl J Med 2011;365:2398-411

TREATMENT OF FSGS

D’Agati V et al. N Engl J Med 2011;365:2398-411

TREATMENT OF FSGS

PREDICTING OUTCOME IN FSGSWho will respond to steroids

PREDICTING OUTCOME IN FSGSWho will respond to steroids

Histological variant predicts steroid responsiveness

Stokes MB et al. KI 2006; 70: 1676

Histological variant does not does not predict steroid responsiveness

Chun M et al. JASN 2004; 15: 2169

Stokes MB et al. KI 2006; 70: 1676

Treatment and outcomes of FSGS

Classic FSGS Cellular Lesion Tip Lesion P

n 36 40 11Treated 17 (47%) 25 (63%) 9 (82%) NS

remission 9 (53%)c 16 (64%) 7 (78%) NS

complete 6 6 5partial 3 10 2No treatment 19 15 2remissionb 2 2 0 NS

Total remission 11 18 7 NS

No remission 25 22 4Follow-up from biopsy (mo) 73 ± 94 52 ± 45 99 ± 94 NS

ESRD 9 (25%) 17 (43%) 3 (27%) NSremission 1 1 0no remission 8 16 3treated 4 6 2no treatment 5 11 1

Chun M et al. JASN 2004; 15: 2169

Treatment and outcomes of FSGS

Characteristics

What do we want to know?

What is the diagnosis ?

What is his individual prognosis?

How should he be treated?

What is his risk of transplant recurrence?

Does it help us understand disease mechanisms?

Is he suitable for recruitment to clinical trials?

Recurrence of FSGS after kidney transplantation

FSGS recurs in 30-40% of first kidney transplants (nearly 100% in 2nd Tx if recurrence in 1st)

Recurrence of FSGS after kidney transplantation

Risk factors for recurrence:

•young age •mesangial proliferation in the native kidneys •rapid progression to ESRD •pretransplant bilateral nephrectomy •white ethnicity •specific aspects of genetic background

FSGS recurs in 30-40% of first kidney transplants (nearly 100% in 2nd Tx if recurrence in 1st)

Recurrence of FSGS after kidney transplantation

Risk factors for recurrence:

•young age, •mesangial proliferation in the native kidneys,

•rapid progression to ESRD, •pretransplant bilateral nephrectomy,

•white ethnicity, •specific aspects of genetic background

The histologic variant type of FSGS in native kidneys does not reliably predict recurrence in the allograft

FSGS recurs in 30-40% of first kidney transplants (nearly 100% in 2nd Tx if recurrence in 1st)

In summary

The histologic classification can be helpful in defining diagnosis / cause

Provides some level of prognostic information but ? more than from clinical parameters

It provides no guidance in terms of steroid-responsiveness

It provides no guidance about risk of transplant recurrence

Obliged to treat with steroids – no a priori idea about likelihood of response

In summary

The histologic classification can be helpful in defining diagnosis / cause

Provides some level of prognostic information but ? more than from clinical parameters

It provides no guidance in terms of steroid-responsiveness

It provides no guidance about risk of transplant recurrence

ANCA-associated vasculitis

Berden AE et al. JASN 2010; 21: 1628

Validated

European population

PREDICTING OUTCOME FROM PATHOLOGY IN ANCA-ASSOCIATED GN

Berden AE et al. JASN 2010; 21: 1628

PREDICTING OUTCOME FROM PATHOLOGY IN ANCA-ASSOCIATED GN

Berden AE et al. JASN 2010; 21: 1628

Chang D et al. Nephrol Dial Transplant (2012) 27: 2343

Chinese population

Independent validation

Renal response to treatment of the four classifications

Chang D et al. Nephrol Dial Transplant (2012) 27: 2343

Largely a (valuable) research tool

Extremely valuable in stratifying subjects recruited to clinical trials

Clinical utility limited

Patients will tend to be treated aggressively anyway irrespective of the pathologic class

One exception: frail patient with renal-limited disease and sclerotic phenotypeMay provide reassurance that avoiding immunosuppression is justifiable

PREDICTING OUTCOME FROM PATHOLOGY IN ANCA-ASSOCIATED GN

THE FUTURE

INDIVIDUAL PROGNOSIS AND TREATMENT PLAN FOR PATIENTS WITH GLOMERULONEPHRITIS

Histopathology

THE FUTURE

Clinical Immune mechanisms Genetics Biomarkers

INDIVIDUAL PROGNOSIS AND TREATMENT PLAN FOR PATIENTS WITH GLOMERULONEPHRITIS

PATHOLOGICAL CLASSIFICATION OF MEMBRANOUS NEPHROPATHY

ELECTRON MICROSCOPY

Stage 1: subepithelial EDDs, no BM reaction

Stage II: ‘spikes’

Stage III: EDDs surrounded by BM

Stage IV: lucency of deposits

Ehrenreich & Churg, 1968

PATHOLOGICAL CLASSIFICATION OF MEMBRANOUS NEPHROPATHY

Ehrenreich & Churg, 1968

• Logical & systematic

• Covers ‘progression’ of lesions

BUT

11 reports 1979-1992

8/11 suggested this classification did not predict outcome or duration of disease

Hofstra JM et al. CJASN 2011;6:1286

The relationship between anti-PLA2R and proteinuriain membranous nephropathy

Beck LH et al. JASN 2011;22:1543

The relationship between anti-PLA2R and proteinuriain membranous nephropathy following treatment

INDIVIDUAL PROGNOSIS INIgA NEPHROPATHY

CLINICALProteinuria

Hypertension

PATHOLOGYMEST

IgA glycosylation ?

Other ?

Classification in Nephropathology:My Point of View

Renal biopsy will remain a crucial part of the evaluation of patients with glomerular disease

In some situations it may become less important (eg membranous nephropathy)

Classification systems are crucial for clinical research studies

In day-to-day clinical practice in general, they are currently less helpful

The future will involve more integrated classification systems

This may result in more diagnostic clarity (rather than descriptions of histological patterns)

Thank you

Questions?

PATHOLOGICAL CLASSIFICATION OF GN

A classification must be

• evidence-based• clinically relevant• simple• precise in its definitions• reproducible