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Peter Topham Consultant Nephrologist John Walls Renal Unit Leicester United Kingdom Classification in Nephropathology: A Clinician’s Point of View.

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Presentation on theme: "Peter Topham Consultant Nephrologist John Walls Renal Unit Leicester United Kingdom Classification in Nephropathology: A Clinician’s Point of View."— Presentation transcript:

1 Peter Topham Consultant Nephrologist John Walls Renal Unit Leicester United Kingdom Classification in Nephropathology: A Clinician’s Point of View

2 A clinical case

3 19 year old man – 1 st 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

4 Asymptomatic No significant past medical history No family history Non smoker Binge alcohol Occasional cannabis use No other drug use Examination Fit and well BMI22kg/m 2 BP118/72mmHg

5 Investigations serum creatinine68µmol/L (60–110) eGFR>90ml/min serum C-reactive protein5mg/L (<10) Urinalysis: blood3+ protein1+ Urine PCR71mg/mmol (<30) anti-nuclear antibodynegative ANCAnegative serum complement C374mg/dL (65–190) serum complement C428mg/dL (15–50) serum immunoglobulin G11.2g/L (6.0–13.0) serum immunoglobulin A3.3g/L (0.8–3.0) serum immunoglobulin M2.1g/L (0.4–2.5) antistreptolysin titre102IU/mL (<200)

6 Investigations serum creatinine68µmol/L (60–110) eGFR>90ml/min serum C-reactive protein5mg/L (<10) Urinalysis: blood3+ protein1+ Urine PCR71mg/mmol (<30) anti-nuclear antibodynegative ANCAnegative serum complement C374mg/dL (65–190) serum complement C428mg/dL (15–50) serum immunoglobulin G11.2g/L (6.0–13.0) serum immunoglobulin A3.3g/L (0.8–3.0) serum immunoglobulin M2.1g/L (0.4–2.5) antistreptolysin titre102IU/mL (<200) Renal tract ultrasound: Lt kidney 10.2cm Rt kidney 10.0cm Normal appearance No stones KUB X-ray: No renal tract calcification Cystoscopy: No intravesical pathology

7 Clinical diagnosis of IgA nephropathy

8 What next?

9 Clinical diagnosis of IgA nephropathy What next? ?? Kidney biopsy

10 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?

11 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

12 Reich H N et al. JASN 2007;18: What would a biopsy add to what we already (think we) know?

13 Reich H N et al. JASN 2007;18: Time-average proteinuria 1 - < 1g/24h 2 – 1-2 g/24h 3 – 2-3g/24h 4 - >3g/24h What would a biopsy add to what we already (think we) know?

14 Renal biopsy findings IgA

15 Renal biopsy findings IgA nephropathy IgA

16 Oxford MEST Classification

17 Mesangial hypercellularity - in 50% of glomeruli M0 or M1 Endocapillary hypercellularity – absent/presentE0 or E1 Segmental sclerosis/adhesions – absent/presentS0 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

18 Mesangial hypercellularity - in 50% of glomeruli M0 or M1 Endocapillary hypercellularity – absent/presentE0 or E1 Segmental sclerosis/adhesions – absent/presentS0 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 features Follow up clinical features In all ages In white Europeans and East Asians Oxford MEST Classification

19 VALIDATION STUDIES FOR THE OXFORD CLASSIFICATION OF IgAN? MEST Macedonia USA Japan children++-+ France USA, Canada adults & children ++++ China Japan Sweden Korea /107/106/1010/10

20 Oxford MEST Classification: M0 E0 S0 T0

21 How does this help? Oxford MEST Classification: M0 E0 S0 T0

22 How does this help? PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONS Combining glomerular patterns Oxford MEST Classification: M0 E0 S0 T0

23 PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONS Combining glomerular and tubulointerstitial lesions How does this help? Oxford MEST Classification: M0 E0 S0 T0

24 PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONS Combining glomerular and tubulointerstitial lesions These are just examples Not Not enough evidence yet to directly sum risks How does this help? Oxford MEST Classification: M0 E0 S0 T0

25 Oxford MEST Classification: M1 E1 S0 T0

26 PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONS Combining glomerular and tubulointerstitial lesions How does this help? Oxford MEST Classification: M1 E1 S0 T0

27 Immunosuppression had no influence on relationship between pathology variables and the rate of renal function decline …..except for endocapillary lesions

28 Patients with endocapillary proliferation Immunosuppression -1.5+/-8.3 ml/min/1.73m 2 /yr No immunosuppression -5.4+/-1.1 ml/min/1.73m 2 / yr Immunosuppression had no influence on relationship between pathology variables and the rate of renal function decline …..except for endocapillary lesions

29 Relationship between pathology variables and the rate of renal function decline not was not influenced by immunosuppression …..except for endocapillary lesions Patients with endocapillary proliferation Immunosuppression -1.5+/-8.3 ml/min/1.73m 2 /yr No immunosuppression -5.4+/-1.1 ml/min/1.73m 2 / yr Retrospective data Caution against overinterpretation

30 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?

31 Why were crescents not related to outcome in this classification?

32 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

33 WHEN ARE CRESCENTS SIGNIFICANT IN IgA NEPHROPATHY ? Katafuchi R et al. CJASN 2011; 6: 2806 Patients meeting ‘Oxford’ criteria Patients outside ‘Oxford’ criteria

34 Why is the classification based just on light microscopy? Would the addition of immunohistochemistry and/or EM data add any value?

35 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 NEPHROPATHY Mesangial deposits Capillary wall deposits Bellur SS et al. NDT 2011; 26: 2533

36 IgA & IgG DEPOSITS IN IgA NEPHROPATHY Bellur SS et al. NDT 2011; 26: 2533 Mesangial vs. capillary wall IgA No No difference in 5 year outcome Presence or absence of IgG deposits No No difference in 5 year outcome

37 Another clinical case

38 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 units of alcohol per week Estate agent

39 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: blood1+ protein 4+

40 Investigations serum creatinine172µmol/L (60–110) eGFR47ml/min serum albumin19g/L (35-45) Serum cholesterol9.8mmol/L serum C-reactive protein5mg/L (<10) Urine PCR781mg/mmol (<30) anti-nuclear antibodynegative serum complement C374mg/dL (65–190) serum complement C428mg/dL (15–50) serum immunoglobulin G4.2g/L (6.0–13.0) serum immunoglobulin A1.3g/L (0.8–3.0) serum immunoglobulin M2.1g/L (0.4–2.5) serum protein electrophoresisnegative

41 Investigations serum creatinine172µmol/L (60–110) eGFR47ml/min serum albumin19g/L (35-45) Serum cholesterol9.8mmol/L serum C-reactive protein5mg/L (<10) Urine PCR781mg/mmol (<30) anti-nuclear antibodynegative serum complement C374mg/dL (65–190) serum complement C428mg/dL (15–50) serum immunoglobulin G4.2g/L (6.0–13.0) serum immunoglobulin A1.3g/L (0.8–3.0) serum immunoglobulin M2.1g/L (0.4–2.5) serum protein electrophoresisnegative Renal tract ultrasound: Lt kidney 10.6cm Rt kidney 10.9cm Normal appearance No stones KUB X-ray: No renal tract calcification

42 Kidney biopsy Renal tract ultrasound: Lt kidney 10.6cm Rt kidney 10.9cm Normal appearance No stones KUB X-ray: No renal tract calcification Investigations serum creatinine172µmol/L (60–110) eGFR47ml/min serum albumin19g/L (35-45) Serum cholesterol9.8mmol/L serum C-reactive protein5mg/L (<10) Urine PCR781mg/mmol (<30) anti-nuclear antibodynegative serum complement C374mg/dL (65–190) serum complement C428mg/dL (15–50) serum immunoglobulin G4.2g/L (6.0–13.0) serum immunoglobulin A1.3g/L (0.8–3.0) serum immunoglobulin M2.1g/L (0.4–2.5) serum protein electrophoresisnegative

43 Renal biopsy

44 Focal segmental glomerulosclerosis Renal biopsy

45 Focal segmental glomerulosclerosis Not Otherwise Specified Renal biopsy

46 Focal segmental glomerulosclerosis 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

47 Focal segmental glomerulosclerosis 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

48 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

49 PATHOLOGICAL CLASSIFICATION OF FSGS D’Agati V et al. AJKD 2004 Perihilar variant Tip lesion variant NOS Collapsing variant Cellular variant

50 Thomas DB et al. KI 2006; 69: 920 Demographics, clinical presentation, and outcomes of FSGS variants

51 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?

52 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?

53 What’s the diagnosis? D’Agati V et al. AJKD 2004 Perihilar variant Tip lesion variant NOS Collapsing variant Cellular variant

54 What’s the diagnosis? D’Agati V et al. AJKD 2004 NOS

55 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?

56 PREDICTING OUTCOME FROM PATHOLOGY IN FSGS Thomas DB et al. KI 2006; 69: 920 Collapsing All other ‘variants’ P =

57 PREDICTING OUTCOME FROM PRESENTATION IN FSGS Non-nephrotic20% ESRD at 10 years Nephrotic >50% ESRD at 5-10 years Nephrotic >10g/day~100% ESRD at 5-10 years ‘Malignant FSGS’

58 REMISSION & ESRD IN FSGS Troyanov S. et al. JASN 2005; 16:1061 Stirling C et al– QJM 2005; 98: 443 No Remission vs. Partial remission with a relapse Remission (partial or complete) vs. No remission

59 Thomas DB et al. KI 2006; 69: 920 Demographics, clinical presentation, and outcomes of FSGS variants

60 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?

61 D’Agati V et al. N Engl J Med 2011;365: TREATMENT OF FSGS

62 D’Agati V et al. N Engl J Med 2011;365: TREATMENT OF FSGS

63 D’Agati V et al. N Engl J Med 2011;365: TREATMENT OF FSGS

64 PREDICTING OUTCOME IN FSGS Who will respond to steroids

65 PREDICTING OUTCOME IN FSGS Who will respond to steroids Histological variant predicts steroid responsiveness Stokes MB et al. KI 2006; 70: 1676 does not Histological variant does not predict steroid responsiveness Chun M et al. JASN 2004; 15: 2169

66 Stokes MB et al. KI 2006; 70: 1676 Treatment and outcomes of FSGS

67 Classic FSGSCellular LesionTip LesionP n Treated 17 (47%)25 (63%)9 (82%)NS remission 9 (53%) c 16 (64%)7 (78%)NS complete 665 partial 3102 No treatment remission b 220NS Total remission 11187NS No remission Follow-up from biopsy (mo) 73 ± 9452 ± 4599 ± 94NS ESRD 9 (25%)17 (43%)3 (27%)NS remission 110 no remission 8163 treated 462 no treatment5111 Chun M et al. JASN 2004; 15: 2169 Treatment and outcomes of FSGS Characteristics

68 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?

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

70 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 2 nd Tx if recurrence in 1 st )

71 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 2 nd Tx if recurrence in 1 st )

72 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

73 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

74 ANCA-associated vasculitis Berden AE et al. JASN 2010; 21: 1628 Validated European population

75 PREDICTING OUTCOME FROM PATHOLOGY IN ANCA-ASSOCIATED GN Berden AE et al. JASN 2010; 21: 1628

76 PREDICTING OUTCOME FROM PATHOLOGY IN ANCA-ASSOCIATED GN Berden AE et al. JASN 2010; 21: 1628

77 Chang D et al. Nephrol Dial Transplant (2012) 27: 2343 Chinese population Independent validation

78 Renal response to treatment of the four classifications Chang D et al. Nephrol Dial Transplant (2012) 27: 2343

79 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 phenotype May provide reassurance that avoiding immunosuppression is justifiable PREDICTING OUTCOME FROM PATHOLOGY IN ANCA-ASSOCIATED GN

80 THE FUTURE INDIVIDUAL PROGNOSIS AND TREATMENT PLAN FOR PATIENTS WITH GLOMERULONEPHRITIS

81 Histopathology THE FUTURE Clinical Immune mechanisms Genetics Biomarkers INDIVIDUAL PROGNOSIS AND TREATMENT PLAN FOR PATIENTS WITH GLOMERULONEPHRITIS

82 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

83 PATHOLOGICAL CLASSIFICATION OF MEMBRANOUS NEPHROPATHY Ehrenreich & Churg, 1968 Logical & systematic Covers ‘progression’ of lesions BUT 11 reports /11 suggested this classification did not predict outcome or duration of disease

84 Hofstra JM et al. CJASN 2011;6:1286 The relationship between anti-PLA2R and proteinuria in membranous nephropathy

85 Beck LH et al. JASN 2011;22:1543 The relationship between anti-PLA2R and proteinuria in membranous nephropathy following treatment

86 INDIVIDUAL PROGNOSIS IN IgA NEPHROPATHY CLINICAL Proteinuria Hypertension PATHOLOGY MEST IgA glycosylation ? Other ?

87 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)

88 Thank you Questions?

89 PATHOLOGICAL CLASSIFICATION OF GN A classification must be evidence-based clinically relevant simple precise in its definitions reproducible


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