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Peter Topham Consultant Nephrologist John Walls Renal Unit Leicester United Kingdom

Classification in Nephropathology: A Clinician’s Point of View. Peter Topham Consultant Nephrologist John Walls Renal Unit Leicester United Kingdom. A clinical case. 19 year old man – 1 st year sports science student at Loughborough University Visible haematuria

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Peter Topham Consultant Nephrologist John Walls Renal Unit Leicester United Kingdom

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

  2. A clinical case

  3. 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

  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 BMI 22kg/m2 BP 118/72mmHg

  5. Investigations serum creatinine 68µmol/L (60–110) eGFR >90ml/min serum C-reactive protein 5mg/L (<10) Urinalysis: blood 3+ protein 1+ Urine PCR 71mg/mmol (<30) anti-nuclear antibody negative ANCA negative serum 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)

  6. Investigations serum creatinine 68µmol/L (60–110) eGFR >90ml/min serum C-reactive protein 5mg/L (<10) Urinalysis: blood 3+ protein 1+ Urine PCR 71mg/mmol (<30) anti-nuclear antibody negative ANCA negative serum 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 10.2cm 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. Clinical diagnosis of IgA nephropathy 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. What would a biopsy add to what we already (think we) know? Reich H N et al. JASN 2007;18:3177-3183

  13. What would a biopsy add to what we already (think we) know? • Time-average proteinuria • 1 - < 1g/24h • 2 – 1-2 g/24h • 3 – 2-3g/24h • 4 - >3g/24h Reich H N et al. JASN 2007;18:3177-3183

  14. Renal biopsy findings IgA

  15. Renal biopsy findings IgA IgA nephropathy

  16. Oxford MEST Classification

  17. 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

  18. 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 features • Follow up clinical features • In all ages • In white Europeans and East Asians

  19. VALIDATION STUDIES FOR THE OXFORD CLASSIFICATION OF IgAN?

  20. Oxford MEST Classification: M0 E0 S0 T0

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

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

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

  24. Oxford MEST Classification: M0 E0 S0 T0 How does this help? PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONS Combining glomerular and tubulointerstitial lesions These are just examples Notenough evidence yet to directly sum risks

  25. Oxford MEST Classification: M1 E1 S0 T0

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

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

  28. 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

  29. Relationship between pathology variables and the rate of renal function decline was not 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 data Caution against overinterpretation

  30. What do we want to know? 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

  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 ? Patients meeting ‘Oxford’ criteria Patients outside ‘Oxford’ criteria Katafuchi R et al. CJASN 2011; 6: 2806

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

  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 30-40 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: blood 1+ protein 4+

  40. Investigations serum creatinine 172µmol/L (60–110) eGFR 47ml/min serum albumin 19g/L (35-45) Serum cholesterol 9.8mmol/L serum C-reactive protein 5mg/L (<10) Urine PCR 781mg/mmol (<30) anti-nuclear antibody negative serum 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

  41. Investigations serum creatinine 172µmol/L (60–110) eGFR 47ml/min serum albumin 19g/L (35-45) Serum cholesterol 9.8mmol/L serum C-reactive protein 5mg/L (<10) Urine PCR 781mg/mmol (<30) anti-nuclear antibody negative serum 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 10.6cm Rt kidney 10.9cm Normal appearance No stones KUB X-ray: No renal tract calcification

  42. Investigations serum creatinine 172µmol/L (60–110) eGFR 47ml/min serum albumin 19g/L (35-45) Serum cholesterol 9.8mmol/L serum C-reactive protein 5mg/L (<10) Urine PCR 781mg/mmol (<30) anti-nuclear antibody negative serum 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 10.6cm Rt kidney 10.9cm Normal appearance No stones KUB X-ray: No renal tract calcification Kidney biopsy

  43. Renal biopsy

  44. Renal biopsy Focal segmental glomerulosclerosis

  45. Renal biopsy Focal segmental glomerulosclerosis Not Otherwise Specified

  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 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 80% have primary FSGS 50-60% of adults present with nephrotic syndrome D’Agati V et al. N Engl J Med 2011;365:2398

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

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

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