THE OXFORD CLASSIFICATION OF IgA NEPHROPATHY: SINGLE CENTRE EXPERIENCE

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THE OXFORD CLASSIFICATION OF IgA NEPHROPATHY
SINGLE CENTRE EXPERIENCE

• Petrusevska G., Jasar G., Grcevska L.,
  Kostadinova S., Bogdanovska M., Nikolov V.,
  Polenakovic M.
• Macedonia

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INTRODUCTION

• The diagnosis of IgA nephropathy, the commonest
  glomerular disease worldwide, is defined by the
  presence of mesangial IgA-dominant immune
  deposits within glomeruli in the absence of
  systemic disorders1,2,3,4,6.
• This criterion is the reason for a wide range of
  histological changes in IgA nephropathy (IgAN)
  and a different outcome of the renal disease
  1,5,7.

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INTRODUCTION

• Biopsy appearances may range from
• normal glomeruli by optical microscopy
• severe crescentic glomerulonephritis
• sclerosing glomerulonephritis.
• Some biopsies present dominant diffuse mesangial
  proliferation and the other focal proliferative
  changes with different degrees of
  tubulointerstitial changes.

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INTRODUCTION

• Thus many authors in the past tried to make a
  usefull classification, comparing the
  histopathological findings with clinical features
  and the outcome of the disease7,8,9,10.
• None has achieved widespread acceptance, because
  of a lack of definitions, and inclusion of both
  active and chronic lesions in the definitions of
  single categories.
• There is continuing discussion as to wheather
  pathological features seen on renal biopsy
  contribute additional prognostic information in
  addition to the clinical features.

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INTRODUCTION

• The aim of the new Oxford classification 11,12,13
  was to identify specific pathological features
  that can predict the risk of progression of renal
  disease in IgAN.
• Six of the pathological variables were identified
  as having an independent value in predicting
  renal outcome 1) the mesangial hypercellularity
  score percentage of glomeruli showing, 2)
  segmental sclerosis, 3) endocapillary
  hypercelullarity or 4) cellular/fibrocellular
  crescents5) percentage of tubular
  atrophy/interstitial fibrosis and 6)
  arteriosclerosis score.
• These features were recommended to be taken into
  account for predicting an outcome independent of
  the clinical features both at the time of
  presentation and during follow-up.

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AIMS

• The aim of our study was
• To define the presence of the histopathological
  variables recommended by Oxford classification in
  Macedonian patients with diagnosed IgAN.
• To corelate the value of these pathologic
  variables and outcome of the disease in this
  group of patients with IgAN.
• To determine the survival in two groups of
  patients those with nephrotic syndrome (defined
  as proteinuriagt 3g/daily) and immunosupression
  and the other group of patients, with mild
  clinical features and without immunosupression.

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PATIENTS AND METHODS

• The study had a retrospective character on cases
  with biopsy-proven IgAN at the Institute of
  pathology and Laboratory for cytology and
  histopathology, Institute of oncology, Medical
  faculty in Skopje, admitted at the University
  Nephrology Department.
• Histological variables were analysed according to
  the histopathological reports because of long
  period survey analysis.
• The diagnosis of IgAN includded 1) demonstration
  of mesangial IgA deposition by DIF in isolation
  or as the predominant immunoglobulin and the lack
  of clinical or serological evidence of systemic
  lupus erythematosus, Henoch-Scoenlein purpura, or
  liver disease 2) standard histological analysis
  of the renal biopsies on HE, PAS, Trichrome
  Mason, Silvermethenamine-Jones stained sections
  and 3) Electron microscopy performed in 6 of the
  patients, and semithin sections in about 70.

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SELECTION OF THE PATIENTS

• Histopathological reports and the clinical data
  at the onset and during follow-up were obtained
  from the in-patient and out-patient files of the
  patients at the University Nephrology Department
  which covers renal disease patients in all area
  of R. Macedonia (about 2,000,000 people).
• Ninety eight adult patients were classified as
  having IgA nephropathy during the period
  1976-2006.
• 40 adult patients (25 male, 15 female,gt15 years)
  were selected for the study, patients with more
  than 10 glomeruli at optical microscopy and with
  a follow-up of more than 3 years.
• We used four pathological variables proposed by
  the Oxford Classification as it is presented in
  Table 1.

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Table 1. Definition of pathological variables
used in the classification of IgAN.
Variable Definition Score
Mesangial hypercelullarity The score is the mean score for all glomeruli M0lt5 M1gt5
Segmental glomerulosclerosis Any amount of the tuft involved in sclerosis, but not involving the whole tuft S0 absent S1 - present
Endocapillary hypercelullarity cellular/ /fibrocellular crescents Hypercelullarity due to increased number of cells within glomerular capillary lumina E0 absent E1 - present
Tubular atrophy/interstitial fibrosis Percentage of cortical area involved by th tubule atrophy or interstitial fibrosis, whichever is greater 0-25 T0 26-50 T1 gt50 T2
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Statistics

• Statistics included
• Students T test, Spearmans test and
  Mann-Whitney U Wilcoxon test to compare
  histological scoring and duration of follow-up
  without end-stage renal disease.
• Histopathological score and survival were
  compared separately 1) in all 40 patients,
  independently of clinical signs and treatment 2)
  12 patients with nephrotic syndrome (defined as
  proteinuriagt 3g/daily) and immunosupression were
  analysed separately, and 3) the other 28
  patients, with mild clinical features and without
  immuniosupression, were also analysed separately.
  
• The Kaplan-Mayer test was performed to determine
  the survival of the patients.

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Table 2 RESULTS Histological findings in whole
group of 40 pts
Histological changes in IgAN No. of ESRD ESRD
Mesangial hypercelullarity (MH) 4/8 8 years
Segmental glomerulosclerosis (SGS) 1/2 6 years
Endocapillary hypercelullarity (EH) 0/2 -
Tubular atrophy/interstitial fibrosis 0 -
MH SGS 6/9 5.2 years
MH SGS TA/IF 2/2 3 years
MH EH 2/4 6.5 years
MH SGS EH 2/2 7 years
MH SGS EH TA/IF 2/2 4.5 years
Slightly increased mesangial celullarity 1/9 12 years
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RESULTS Overall survival of the whole group of
40 pts)

• The average survival of the whole group was
  10.8/-7.47 years (M/-SD).
• Twenty from forty (50) of the patients
  experienced end stage renal disease after a
  period of 3-12 years.
• Pathological variables and follow-up of all 40
  patients according to the recommendation of the
  Oxford classification are presented at Table 3.
• Mesangial hypercelullarity was confirmed to be
  associated with the renal outcome (p0.047), as
  well as glomerular sclerosis (p0.009),
  endocapillary hypercellularity (p0.001) and
  tubular atrophy/interstitial fibrosis (p0.045)

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Table 3 Influence of the histological variables
to the renal outcome
Variable Score ESRD p
Mesangial hypercelullarity M0lt5 13 pts M1gt5 27pts 2 pts 18 pts P0.047
Segmental glomerulosclerosis S0 absent 23 pts S1 present 17 pts 7 pts 13 pts P0.009
Endocapillary hypercelullarity E0 absent 30 pts E1 present 10 pts 13 pts 6 pts P0.001
Tubular atrophy/interstitial fibrosis T0 0-25 36 pts T1 26-50 4 pts T2 gt50 0 pts 16 pts 4 pts 0 P0.045
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Results of Group I patients (without nephrotic
syndrome)

• This group consisted of 28 patients with
  clinically normal renal function, without
  hypertension and nephrotic syndrome at
  presentation. Thirteen from 28 (46.1) of these
  patients, in contrast to mild clinical features
  at presentation, presented end-stage renal
  disease during follow up.
• Mesanagial hypercelullarity didnt correlate with
  renal survival in this separated group of
  patients (p0.053 Mann Whitney, p0.49 Spearman
  test). Segmental glomerulosclerosis significantly
  correlated with the outcome of the disease
  (p0.007 Mann Whitney, p0.006 Spearman test).
  Endocapillary hypercelullariry (p0.351, p0.32)
  as well as tubular atrophy/interstitial fibrosis
  (p0.071, p0.105) did not correlated with the
  renal outcome.

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Table 3 Influence of the histological variables
to the renal outcome
Variable Score ESRD p
Mesangial hypercelullarity M0lt5 11pts M1gt5 17 pts 2 pts 11 pts p0.053 p0.49
Segmental glomerulosclerosis S0 absent 18 pts S1 present 10 pts 5 pts 8 pts p0.007 p0.006
Endocapillary hypercelullarity E0 absent 25 pts E1 present 3 pts 10 pts 2 pts p0.351 P0.032
Tubular atrophy/interstitial fibrosis T0 0-25 27 pts T1 26-50 1 pts T2 gt50 0 pts 12 pts 1 pts 0 p0.071 p0.105
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Results of Group II patients (with nephrotic
syndrome)

• Group II consisted of 12 patients with severe
  clinical features at presentation and necessary
  immunosuppression.
• Seven from 12 (58.3) developed terminal phase of
  chronic renal failure during follow-up.
• Renal survival was not associated with mesangial
  hypercelullarity (Man Whitney p0.606, Spearman
  test p0.607) with glomerular sclerosis
  (p0.343, p0.302) and endocapillary
  hypercelullarity (p0.53 p0.533),
• But it was associated with the degree of chronic
  tubulointerstitial changes (p0.018, p-0.016).

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Table 3 Influence of the histological variables
to the renal outcome
Variable Score ESRD p
Mesangial hypercelullarity M0lt5 2 pts M1gt5 10 pts 0 pts 7 pts p0.606 p0.607
Segmental glomerulosclerosis S0 absent 5 pts S1 present 7 pts 0 pts 7 pts p0.343 p0.302
Endocapillary hypercelullarity E0 absent 5 pts E1 present 7 pts 3 pts 4 pts p0.53 P0.533
Tubular atrophy/interstitial fibrosis T0 0-25 9 pts T1 26-50 3 pts T2 gt50 0 pts 4 pts 2 pts 0 p0.018 p0.016
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Survival of both groups of patients with IgA
nephropathy

• It can be seen that there was noted significant
  difference in survival between those two group of
  patients.
• Glomerular sclerosis was a poor prognostic
  pathologic variable in the patients without
  nephrotic syndrome, and tubulointerstitial
  changes in ones with nephrotic syndrome.

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DISCUSSION

• Many authors have tried to correlate clinical
  signs and histological features in IgAN7,8,9,10,
  14,15,16.
• Gross hematuria was frequently associated with
  mild glomerular lesions and a favourable clinical
  course on the other hand, the presence of heavy
  proteinuria at the onset was frequently
  associated with severe histology and progressive
  renal disease.

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DISCUSSION

• Severe histology was also associated with already
  decreased renal function and/or hypertension at
  the time of biopsy. Many authors believe that the
  histologic type of glomerular lesions appears to
  be the best predictive index in IgAN.
• The folowing factors were regarded as
  histological parameters of progressive damage in
  IgAN severe mesangial proliferation, frequent
  sclerotic glomeruli, crescents higher proportions
  of glomerular adhesions, vascular sclerosis and
  marked interstitial fibrosis (8,9,14). They are
  all causally correlated with each other in
  portending a poor prognosis.

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DISCUSSION

• Several histologic grading systems have been used
  in the past8,17,18. These pathological systems
  used to classify renal lesions in IgAN, can be
  divided into two groups lumped and split.
• The lumped systems assess the overall severity of
  histological lesions, found in glomerular,
  tubular, interstitial and arteriolar
  compartments, as in the widely-used
  classification of Lee and Haas8,18. The split
  systems use semiquantitative severity grading of
  lesions in each of the four compartments and
  permit the elaboration of a global or aggreagate
  score for each compartment

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DISCUSSION

• Lesions of focal and segmental hyalinosis and
  sclerosis were described as very specific for
  progression and so in our previous report we
  measured the sclerotic glomerular area and
  combined it with the semiquantitaive score of the
  tubulointerstitial changes in order to predict
  the progression19.
• In general, the agreement among various
  classifications is only reached when considering
  renal disease already progressed to sclerosis.

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DISCUSSION

• The new Oxford classification11,12,13 documented
  by univariate and multivariate analysis that the
  following lesions resulted as independently
  predictive of clinical outcome mesangial
  hypercelullarity score, endocapillary
  hypercelullarity, segmental glomerulosclerosis
  and tubular atrophy/interstitial fibrosis.
  Necrotizing and crescentic lesions were not
  evaluated because of their rarity. Our results
  taking into consideration only those four
  histological variables presented the same
  results, a higher total score a more
  progressive disease.
• Our group consisted of 40 patients of different
  age, different clinical presentations and
  different treatment depending on the presence of
  nephrotic syndrome, and these four variables
  proposed by the Oxford classification were
  important for the outcome of the disease.

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In memory to

• Prof.dr. Georgi Zografski, pathologist,
  Laboratory for cytology and histopathology,
  Institute of Oncology

Geographic position of R. Macedonia and the
church of St. Kaneo in Ohrid
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WELCOME in Ohrid, 12-16 October