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:

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:

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. FOR THE OXFORD CLASSIFICATION OF IgAN?
VALIDATION STUDIES
FOR THE OXFORD CLASSIFICATION OF IgAN? M E S T
Macedonia
2010 98 +
USA
2011 54 -
Japan
161 children
France
183
USA, Canada
187 adults & children
China
410
702
Sweden
2012 99
Korea
197
6/10
7/10
10/10

20. Oxford MEST Classification:

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. These are just examples Not enough evidence yet to directly sum risks
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
Not enough evidence yet to directly sum risks

25. Oxford MEST Classification:

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 /-8.3 ml/min/1.73m2 /yr
No immunosuppression /-1.1 ml/min/1.73m2 / yr

29. …..except for endocapillary lesions
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 /-8.3 ml/min/1.73m2 /yr
No immunosuppression /-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. Kidney biopsy 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. Focal segmental glomerulosclerosis
Renal biopsy
Focal segmental glomerulosclerosis

45. Focal segmental glomerulosclerosis Not Otherwise Specified
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
Collapsing variant
Cellular 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

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? Cellular variant Collapsing variant NOS
Tip lesion variant
Perihilar variant
D’Agati V et al. AJKD 2004

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

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
All other ‘variants’
P =
Collapsing
Thomas DB et al. KI 2006; 69: 920

57. 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’

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

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

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

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

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

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
Histological variant does not
predict steroid responsiveness
Chun M et al. JASN 2004; 15: 2169

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

67. Treatment and outcomes of FSGS
Characteristics
Classic FSGS
Cellular Lesion
Tip Lesion P n 36 40 11
Treated
17 (47%)
25 (63%)
9 (82%) NS
remission
9 (53%)c
16 (64%)
7 (78%) NS
complete 6 6 5
partial 3 10 2
No treatment 19 15 2
remissionb 2 2 NS
Total remission 11 18 7 NS
No remission 25 22 4
Follow-up from biopsy (mo)
73 ± 94
52 ± 45
99 ± 94 NS
ESRD
9 (25%)
17 (43%)
3 (27%) NS
remission 1 1
no remission 8 16 3
treated 4 6 2
no treatment 5 11 1
Chun M et al. JASN 2004; 15: 2169

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 2nd Tx if recurrence in 1st)

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

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

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. In summary Obliged to treat with steroids –
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

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

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

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

79. PREDICTING OUTCOME FROM PATHOLOGY
IN ANCA-ASSOCIATED GN
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

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

81. THE FUTURE INDIVIDUAL PROGNOSIS AND TREATMENT PLAN
Histopathology
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
Logical & systematic
Covers ‘progression’ of lesions
BUT
11 reports
8/11 suggested this classification
did not predict outcome or duration of disease
Ehrenreich & Churg, 1968

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

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

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

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