1. The Oxford classification of IgA-nephropathy: A review based on the Polish renal biopsy registry
Agnieszka Perkowska-Ptasińska1, Małgorzata Węgrowska-Danilewicz, Marian Danilewicz, Agnieszka Hałoń, Anna Andrzejewska, Krzysztof Okoń, Henryk Karkoszka.
1Medical University of Warsaw

2. Non-specific clinical manifestation.
IgA nephropathy is the most common type of chronic glomerulonephritis in the world.
Up to 30% of clinically affected patients develop progressive renal failure, typically through a slow progression of CKD.
Non-specific clinical manifestation.
Diagnosis based on biopsy finding: the recognition of diffuse mesangial deposits of IgA in glomeruli.
Kidney biopsy is necessary to recognize IgA-N, but how much does it tell about the individual patient’s risk of kidneys insufficiency ?
But there is a question that still has not been unequivocally answered: how much does the biopsy tell

3. Several studies devoted to the identification of histopathologic features that most accurately predict adverse outcome
Boyce NW et al.,
1986, 112 patients
Morphological evaluation based on WHO classification for LN, progression to ESRD correlated with crescentic disease.
Radford MG et al., 1997, 148 patients
Glomerular, tubulo-interstitial, vascular scoring.
An independent histopathological predictor of ESRD: total glomerular
score: sum of 6 components scored 0-3 each: mesangial celullarity,
mesangial matrix increase, capillary narrowing or disruption,
glomerulosclerosis, cellular crescents, adhesions
Haas M,
1997, 240 patients
Strong correlation between histologic subclass and renal survival,
with an order I, II (best survival) >III > IV,V.
D’Amico G,
2004, analysis of the results of 23 studies
Glomerular sclerosis and interstitial fibrosis - the strongest, most reliable predictors of unfavourable prognosis. More controversial was the role of crescents and capsular adhesions.
Wakai K et al.,
2006, 2269 patients
Advanced histological changes independently increased the risk of ESRD
in IgA nephropathy patients.
Prognostic score composed of individual scores for clinical characteristics
and histopathological grading (I-IV).
In a work by Boyce morphological evaluation was based on WHO class for lupus nephropathy. IN this study ….
In 1997 Radford’s group published the results of the study in which they examined the predictive value of G, V, T-I scoring. They proved an independent predictive value of total G SCORE which was a sum of 6 components:….
The same year Mark Haas has published his classification of IgA nephropathy, the classification that stratified IgA patients to 5 groups with the 1st and 2nd having the best kidneys survivals, and the 4th and 5th the worst.
In 2004 D’AMico published the results of the analysis that encompassed 23 studies devoted to the relation between the morphological presentation of IgAN and kidneys survival. ….
In 2006 the Japanese group has published the biggest study so far, where they analysed a group of 2269 pts with IgA nephropathy. They developed a prognostic score …………

4. In a majority of studies tubulointerstitial scarring was found to be an independent predictor of progression to ESRD in a multivariate analysis.
Glomerular lesions were usually found to correlate significantly with disease progression by univariate analysis, but rarely were they found to be independent predictors of such progression by a multivariate analysis.
The introduction of composite scoring systems (such as in Radford’s study) was associated with an enhancement of the negative predictive value of the glomerular lesions.
But these published results demand some additional comment.
The question arises: do the results of these studies truly reflect the strenght of the impact of glomerular lesions on the clinical outcome?
Is it possible, that some methodological problems, such as poor inter-observer reproducibility of glomerular changes may caused an underestimation of the predictive value of these lesions

5. Haas classification Grade Glomerular findings I
Mild increase in mesangial matrix no proliferation, sclerosis, necrosis II
FSGS-like,
no proliferation
III
Focal proliferative GN (< 50% glomeruli affected),
with or without necrosis and crescent formation IV
Diffuse proliferative GN (> 50% glomeruli affected), with or without necrosis and crescent formation V
Presence of >40% globally sclerotic glomeruli and/or estimated tubular loss of >40%,
irrespective of the presence of active glomerular lesions
Now I would like to take a closer look at a couple of classifications.
As it was mentioned Haas class. was published in 1997, and become the most popular histopathological classification system of IgA nephropathy. It distinguishes 5 grades defined by the type of glomerular injury and the stage of the advancement of chronic lesions.

6. Interstitial and vascular findings
IgA-N histological grading according to the Joint Committee of the Research Group on Progressive Renal Disease and the Japanese Society of Nephrology ( ”the Japanese classification”, Wakai 2006)
Grade
Glomerular findings
Interstitial and vascular findings I
Slight mesangial cell proliferation and increased
matrix. No glomerulosclerosis, crescent formation
or adhesion to Bowman’s capsule.
Prominent changes are not seen
in the interstitium, renal tubules
or blood vessels. II
matrix. Glomerulosclerosis, crescent formation or
adhesion to Bowman’s capsule seen in <10% of
glomeruli.
Same as above.
III
Moderate, diffuse mesangial cell proliferation and
increased matrix.
Glomerulosclerosis, crescent formation or adhesion
to Bowman’s capsule seen in 10–30% of glomeruli.
Cellular infiltration is slight in the
interstitium except around some
sclerosed glomeruli. Slight tubular
atrophy, mild vascular sclerosis. IV
Severe, diffuse mesangial cell proliferation and
increased matrix. Glomerulosclerosis, crescent
formation or adhesion to Bowman’s capsule seen in
>30% of all biopsied glomeruli. When sites of
sclerosis are totalled and converted to global
sclerosis, the glomerulosclerosis rate is >50%.
Presence of interstitial cellular
infiltration and tubular atrophy, as
well as fibrosis.
Hyperplasia or degeneration of
arteriolar walls
Published in 2006 by Wakai the Japanese classification distinguishes 4 histological grades of IgA N depending on the severity of glomerular as well as interstitial and vascular pathological findings and the stage of the advancement of chronic lesions.

7. Oxford classification of IgA-N
The aim of the Oxford study: to develop a reproducible pathological classification of IgAN that would predict the clinical outcome.
Developed by renal pathologists and nephrologists from the international IgA nephropathy network and the RPS.
A study based on 265 patients with at least 1 year of follow-up.
Initially: selection of pathological variables that had high interobserver reproducibility and reliability.
Subsequently: identification of 4 pathological features which, independently of one another and of the patient’s clinical parameters, predicted the outcome.
The newest proposed classification was published in 2009 in KI. Oxford class. was developed as a result of the study that was aimed at the creation of a simple, reproducible pathological classification of IgAN that would predict the clinical outcome.
The group of pathologists engaged in this project initially selected ………
The study resulted in the identification………
KI (2009) 76

8. The aim of the PHIGANS study
To discern the prognostic values of histological IgA-N characteristics defined by: Oxford, Haas, Japanese classifications, and PHIGANS – the Polish histological IgA nephropathy system).
The last year’s presentation of the Oxford classification by Dr Roberts and the publication of the Oxford study in KI inspired us - as a direct stimulus - to conduct our own study. We wanted not only to validate the results of the Oxford study, but also to compare this classification with other histological scoring systems including the one that we had worked out ourselves.

9. Pathologists from the Polish nephropathological working group
Selection of IgA-N cases:
dataset of the Polish Registry of Nephropathies
Pathologists from the Polish nephropathological working group
Agnieszka Perkowska-Ptasińska
Małgorzata Danilewicz
Marian Danilewicz
Agnieszka Hałoń
Anna Andrzejewska
Krzysztof Okoń
Henryk Karkoszka
Nephrologists
Ewa Komuda-Leszek
Ilona Kurnatowska
Monika Kraśnicka
Tomasz Hryszko
Mariusz Kusztal
The PHIGAS study was a project conducted by pathologists from a Polish nephropath. working group in a cooperation with a group of nephrologists. The selection of IgA-N cases was based on the datasets of the Polish Registry of Nephropaties that currently contains about 7000 records from the years , as well as on datasets of individual nephropath. Labs participating in a study.

10. PHIGANS STUDY Study design: retrospective Inclusion criteria:
biopsy-proven IgA nephropathy recognized not later than in December 2008 with histological slides available for current re-evaluation,
patients’ age >18 years,
at least 12 months post-biopsy follow-up,
clinical data available:
- at the time of the biopsy
- 3-6 months after the biopsy
- 1 year after the biopsy
- at the end of the observation
It was a retrospective study, to which we included IgAN cases from adult patients’ population, with at least 1 year of post-biopsy FU, and clinical data available.

11. Clinical end points: Oxford study:
Rate of loss of renal function (ml/min/1.73 m2 per year),
≥50% loss of renal function or ESRD (<15 ml/min/1.73 m2) by the end of the follow-up,
Additional end point in PHIGANS study:
3. eGFR (MDRD) < 60 ml/min/1.73 m2 by the end of
the follow-up.
Two out of 3 end-points were taken after the Oxford study, an additional end point was defined as a level of calculated GFR below 60 ml/min by the end of FU.

12. Histopathological analysis
PHIGANS
Oxford classification
Parameters that describe acute/active lesions:
increased mesangial cellularity (0-3) (GM)
increased endocapillary cellularity (0-3) (GE)
glomerular necrosis (%,) (0; 1-25%; 26-50%; >50%)(GN)
cellular crescents (%,) (0; 1-25%; 26-50%; >50%)(GCC)
total interstitial inflammation (0-3) (Ti)
G sum: GM+GE+GN+GC
CG index: G sum/4
Endocapillary hypercellularity (absent/present)
Mesangial hypercellularity (≤0,5; >0,5)
Segmental GS (absent/present)
Tubular atrophy/interstitial fibrosis (0-25%; 26-50%; >50%)
Parameters that describe chronic lesions:
global GS (%), (0; 1-25%; 26-50%; >50%) (GGS)
segmental GS (%,) (0; 1-25%; 26-50%; >50%) (SGS)
fibrotic crescents (%) (0; 1-25%; 26-50%; >50%) (GCF)
tubular atrophy (0-3) (ct)
interstitial fibrosis (0-3) (ci)
ST sum: GGS+SGS+GCF+ci+ct
ST index: ST sum/5
Biopsy index: G index+ Ti +ST index (0-9)
This busy slide presents the histopathological parameters from both studies, that were defined in a semiquantitative manner. In PHIGANS we distinguished acute/active and chronic lesions. We introduced additional parameters that were defined as a sum of scores of individual glomerular lesions: „glomerular lesions sum” and „glomerular lesions index”. As for chronic lesions we introduced analogical composite scores of „staging sum” and „staging sum index”. In a attempt to express in one variable the information concerning the presence and severity of all the lesions analysed in a biopsy we also introduced calculated score named „biopsy index” .
As for the Oxford classification it includes 4 parameters …….

13. Characteristics of patient groups
PHIGANS study
Oxford study (KI (2009) 76)
Number of patients
118
265
Female
47.5%
28 %
Age at the Bx (years)
35 ± 12.4
35 ± 15
Duration of FU (years)
median 4.6 ( )
78% followed > 3 years
median 5 (1-22)
90% followed > 3 years
Proteinuria (g/d)
1.6 (0-16.7)
1.7 ( )
MAP (mmHg)
98 ± 9.3
98 ± 18
BMI
26 ± 7
25 ± 5
The PHIGANS study was performed on the group of 118 patients, with almost equal representation of both sexes, mean patients’ age of 35, mean MAP of 98 and median proteinuria of 1.6 g/d.
The Oxford study encompassed 265 patients, with the domination of men. Oxford study was also characterized by higher percentage of patients observed longer than 3 years. It is also worth mentioning that the Oxford study included both adults and children, whereas the PHIGANS study – only adults.

14. At the end of the follow-up Serum creatinine concentration (mg/dL)
PHIGANS study - patients’ clinical characteristics at different time points
Clinical parameters
At the time of Bx
3-6 months after Bx
1 year after Tx
At the end of the follow-up
Serum creatinine concentration (mg/dL)
1.1 ± 0.5
1.2 ± 0.5
GFR
84.4 ± 33.2
81.8 ± 30.7
82.9 ± 33.8
77.8 ± 30.9
Proteinuria:
2.1 ± 2.3
1.5 ± 2.6
0.8 ± 1.1
0.6 ± 0.7
Nephrotic syndrome:
20.3%
10.2%
3.4%
4.2%
Erytrocyturia:
94.9%
82.2%
75.4%
78.8%
Hematuria:
11.9%
2.54%
2.5%
0,9%
Nephritic syndrome:
33.1%
17.8%
BPS
130.4 ± 15
127.9 ± 15
126.8 ± 18.5
127.3 ± 15.9
BPR
81.4 ± 8.7
80.8 ± 9.3
81 ± 10.3
80.5 ± 9.8
MAP
97.7 ± 9.3
96.5 ± 10.1
96.2 ± 11.2
96.1 ± 10.9
BMI
26 ± 6.7
25.8 ± 5.4
26.3 ± 6.8
27.8 ± 11.6
As for the clinical characteristics of our patients, pathological findings in urinalysis were mostly pronounced at the time of Bx, also the blood pressure was the highest at this time. There was a mild increase in serum creatinine concentration at the end of FU as compared with the values established at the time of Bx.

15. Before or at the time of Bx At the end of the follow-up
PHIGANS study: pharmaphological supportive treatment during the time of observation
Before or at the time of Bx
Within 3-6 months
after Bx
Within 1 year
At the end of the follow-up
AEI
71.2%
82.2%
83.1%
74.6%
ARB
14.4%
22.9%
31.4%
44.9%
Statins
25.4%
36.4%
39%
As for supportive treatment the vast majority of our pts were treated with AEI and/or ARB.
Up to almost 40% of pts received statins.

16. PHIGANS study: pharmaphological treatment during the time of observation - immunosuppression
IS therapy
Before or at the time of Bx
Within 3-6 months after Bx
Within 1 year
after Bx
At the end of the follow-up
SM boluses
13. 6%
28.8%
5.9%
2.5%
Prednison
29.7%
58.5%
46.6%
Cyclophosphamide
7.6%
Azathioprine
3.4%
11.0%
15.6%
5.1%
Cyclosporine
0.9%
As for the IS therapy, more than 50% of pts were at some stage of their disease course treated with prednisone, almost 1/3 with SM boluses, about 15% with AZA, and fewer than 10% with cyclophosphamide or CsA.

17. Results PHIGANS study Oxford study Oxford study end points: 7.6% 4.24%
≥50% loss of renal function by the end of the FU
ESRD by the end of the FU
7.6%
4.24%
PHIGANS study
PHIGANS study end point:
eGFR (MDRD) < 60 ml/min/1.732 m
by the end of the FU
30.51 %
In our study 7.6% of pts reached the Oxford end point defined as loss of at least 50% of renal function and 4.2% the end point defined as ESRD at the end of FU. If you look at the respective percentages in the Oxford patients, you see that these two groups of patients are different in terms of the outcome.
1/3 of PHIGANS pts have reached the end point defined as eGFR of below 60 ml/min by the end of FU.
Oxford study end points:
≥50% loss of renal function by the end of the FU
ESRD by the end of the FU
22%
13%
Oxford study

18. Distribution of CKD stages among patients studied at the time of BX
PHIGANS study
Oxford study (KI (2009) 76)
54.7%
28.2%
16.2%
0.9%
35%
57%
28%
16% 1%
35%
49%
22% 4%
The comparison of the distribution of CKD between Oxford and PHIGANS groups shows, that in the Oxford study the proportion of pts in the 3d and 4th CKD stages was higher.

19. Distribution of acute/active lesions
PHIGANS study
Oxford study (KI (2009) 76)
Endocapillary hypercellularity (OX-E, GE)
71.2%
42%
Median of glomeruli involved: 12%
Mesangial hypercellularity (OX-M, GM)
56.8%
Approximately 93%
Necrosis in glomerular tufts (GN st)
8.47% (0.47±1.9)
2.3%
Cellular crescents (GCC st)
28.8% (2.8±7.6)
median of glomeruli involved: 0
45%
median of glomeruli involved: 9%
Interstitial inflammation (ti)
55.94%
(TI 1: %
TI 2: %) ?
There were also differences between groups that concerned the distribution of active/acute lesions, with more common occurrence of endocapillary hypercellularity, and foci of necrosis of glomerular tufts in the PHIGANS study, and more common presence of mesangial hypercellularity and cellular crescents in the Oxford pts.

20. Distribution of chronic lesions
PHIGANS study: Mean number of glomeruli per biopsy: 21 ± 11.1
Oxford study: Mean number of glomeruli per biopsy: 18
-20 20 40 60 80
frequency
Segmental GS
KI (2009) 76:
frequency
-20 20 40 60 80
Global GS
The published results of the Oxford study only allow for a rough comparison of chronic lesions distribution between the two discussed studies.
As you can see on the upper graphs the distribution of segmental GS seems to be quite similar in both studied groups. About 22-23% of pts in both groups were free of any segmental glomerular tufts sclerotisation.
However, I did not find any data concerning the distribution of global GS in the Oxford group. As you can see, in the PHIGANS study in more than 40% of patients there was no sclerosed glomeruli in the biopsy.

21. Distribution of chronic lesions
PHIGANS study
1-25% of cortex area with ci/ct
26-50% of cortex area with ci/ct
>50% of cortex area with ci/ct
no ci/ct 80 60 40 20
frequency 3 50 30 10 in 1 -
25% of
glomeruli
In 25
50%
In >50%
Oxford study
interstitial fibrosis/ tubular atrophy
KI (2009) 76:
Fibrotic crescents
As for the interstitial fibrosis and tubular atrophy, they seem to be more common in the Oxford study, with the prevalence of almost 90%, whereas in PHIGANS study they were detected in about 65% of cases.
As for the presence of fibrotic crescents in glomeruli in the PHIGANS study they were found in fewer than 50% of patients, and the percentage of the affected glomeruli did not exceed 25%.

22. Japanese classification
PHIGANS study: distribution of pathological grades according to the Haas and Japanese classifications
Haas classification
Frequency
Japanese classification
Frequency
The evaluation of our biopsies according to the Haas and Japanese classifications has shown that the vast majority of cases fulfiled the criteria for the grade 3 or 4 in each of these scoring systems.

23. Results of the statistical analysis
Correlations between the clinical parameters (at Bx) and histopathological variables defined according to the Oxford, Hass, Japanese, PHIGANS classifications.
Relation between the clinical (at Bx) as well as histopathological variables and the outcome defined as eGFR<60 ml/min by the end of the observation (Cox regression analysis).
Relation between histopathological parameters and progression defined as eGFR loss≥20% by the end of the observation in pts with initial eGFR<60 ml/min (univariate analysis).
Relation between the clinical (at Bx) as well as histopathological variables and the outcome defined as≥50% of eGFR loss or ESRD by the end of the observation (Cox regression analysis).
Relation between clinical (at Bx) as well as histopathological variables and the rate of GFR loss (dGFR) (linear regression).
The subsequent slides present the results of the statistical analysis.

24. Results of the statistical analysis
Correlations between the clinical parameters (at Bx) and histopathological variables defined according to the Oxford, Hass, Japanese, PHIGANS classifications.
Relation between the clinical (at Bx) as well as histopathological variables and the outcome defined as eGFR<60 ml/min by the end of the observation (Cox regression analysis).
Relation between histolopathogical parameters and progression defined as eGFR loss≥20% by the end of the observation in pts with initial eGFR<60 ml/min (univariate analysis).
Relation between the clinical (at Bx) as well as histopathological variables and the outcome defined as≥50% of eGFR loss or ESRD by the end of the observation (Cox regression analysis).
Relation between clinical (at Bx) as well as histopathological variables and the rate of GFR loss (dGFR) (linear regression).
I will start by presenting the correlations ……..

25. Correlations between the clinical parameters (at Bx) and histopathological variables defined according to Oxford class.
PHIGANS study
MAP
Proteinuria
eGFR
Mesangial hypercellularity (OX-M) P
0.04, NS
0.16
P=0.008
0.03
Endocapillary hypercellularity (OX-E)
0.04
0.11
0.12
Segmental glomeruloscelrosis (OX-S)
0.07
0.18
-0.22
P=0.016
Tubular atrophy/interstitial fibrosis (OX-T) p
0.17
P=0.05
-0.43
p<0.001
Oxford study
MAP
Proteinuria
eGFR
Mesangial hypercellularity (OX-M) NS
P=0.001
Endocapillary hypercellularity (OX-E)
P=0.008
P=0.01
Segmental glomeruloslclerosis (OX-S)
P=0.04
P=0.004
P=0.003
Tubular atrophy/interstitial fibrosis (OX-T)
P=0.03
<0.001
The analysis of datasets in the PHIGANS study revealed the correlation only between the extent of ct defined by the Oxford class. and GFR. These results are different from what was established in the Oxford study, in which, as you can see in the lower table, the same parameters were found to be correlated with clinical variables, although the correlation coefficient was not given.
KI (2009) 76:

26. Active lesions/grading
Correlations between the clinical parameters (at Bx) and histopathological variables according to PHIGANS
Active lesions/grading
MAP
Proteinuria
eGFR
Mesangial hypercellularity p
0.21
0.03
0.06 NS
-0.04
Endocapillary hypercellularity
-0.008
0.1
0.14
Glomerular necrosis (0-3)
-0.03
0.005
-0.12
Cellular crescents (0-3)
0.08
0.33
0.0003
-0.24
0.009
G sum
0.27
0.003
G index
0.0031
Total inflammation
0.02
0.25
0.006
-0.27
W oxfordzie tez była korelacja między półksiężycami a białkomoczem (uwaga dla mnie, tego nie gadam)
As for the correlation between the parameters from the PHIGANS system and the clinical presentation of the disease among the acute/active lesions, the only association that we have found was between the extent of crescenting GN and the proteinuria.

27. Chronic lesions/staging
Correlations between the clinical parameters (at Bx) and histopathological variables according to PHIGANS
Chronic lesions/staging
MAP
Proteinuria
eGFR
Global glomerulosclerosis (0-3) P
0.2
0.03
0.23
0.01
-0.43
<0.0001
Segmental glomerulosclerosis (0-3)
0.16 NS
0.36
-0.3
0.001
Fibrotic crescents (0-3)
0.12
0.19
0.04
-0.09
Interstitial fibrosis p
0.21
0.02
0.27
0.0035
Tubular atrophy
0.25
0.0058
-0.44
St sum
0.26
0.006
0.37
-0.48
St index
Biopsy index
0.35
-0.35
More distinct clinico-histopathological associations were found among chronic morphological lesions, with global GS being correlated with the loss of GFR, and the extent of segmental GS with proteinuria.
Composite scores such as …. were found to be correlated with both proteinuria and loss of GFR.

28. Japanese classification
PHIGANS study: correlations between the clinical parameters (at Bx) and histopathological variables defined according to the Haas and Japanese classifications
MAP
Proteinuria
eGFR
HAAS classification p
0.15 NS
0.24
0.01
-0.31
0.0007
Japanese classification
0.23
0.33
0.0002
-0.37
<0.0001
When defined according to the Haas and Japanese class. the morphological picture turned out to be correlated with GFR (the Haas class) and with both: GFR and the extent of proteinuria.

29. Results of the statistical analysis
Correlations between the clinical parameters (at Bx) and histopathological variables defined according to the Oxford, Hass, Japanese, PHIGANS classifications.
Relation between the clinical (at Bx) as well as histopathological variables and the outcome defined as eGFR<60 ml/min by the end of observation (Cox regression analysis).
Relation between the histopathological parameters and progression defined as eGFR loss≥20% by the end of observation in pts with initial eGFR<60 ml/min (univariate analysis).
Relation between the clinical (at Bx) as well as histopathological variables and the outcome defined as≥50% of eGFR loss or ESRD by the end of the observation (Cox regression analysis).
Relation between the clinical (at Bx) as well as histopathological variables and the rate of GFR loss (dGFR) (linear regression).
The next couple of slides are devoted to the results of the analysis concerning the relation …..

30. Relation between the clinical variables (at Bx) and the outcome defined as eGFR<60 ml/min by the end of FU - univariate analysis
Variables
Cox Regression Model HR
CI 95% p
Nephrotic syndrome
3.3
0.006
Nephritic syndrome
2.0
0.036
Age
33-71 vs 15-32
2.5
0.025
Serum creatinine
1-4 vs 0.5-1
10.2
3,6-28.6
<0.001
GFR
16-84 vs
12.7
Proteinuria
vs 0-1.5
0.1-10
0.003
BMI
27-64 vs 17-22 5
1.4-10
27-64 vs 23-26
1.3-10
0.015
BPS vs
1.7-10
0.001
MAP
vs 80-93
0.007
Among clinical variables those found to be associated with an increased risk of the occurrence of kidneys insufficiency with GFR below 60 ml/min in the univariate analysis were:

31. Relation between histopathological variables and the outcome defined as eGFR<60 ml/min by the end of FU - a univariate analysis
Variables
Cox Regression Model HR
CI 95% p
OX-T
1 vs 0
5.7
3-11
<0.001
Stage of global GS
2 vs 0
9.2
2-40
0.003
Stage of segmental GS
10.3
2-48 ct
36.6
5-290
0.001
8.4
1.1-64
0.041 ci
36.7
1.1-65 Ti
3.3
1.3-8
0.011
ST index
vs 0-0.6 10
3.3-50
vs 0.7-1 5
2.5-10
Biopsy index
vs 0-1.6
1.7-10
vs 1.6-3
2.5
1.3-5
Among the Oxford parameters only the extent of tubular atrophy was found to be associated with an increased risk of reaching such defined end-point.
As for the PHIGANS variables, a couple of them were found to be related to this outcome, with the highest risk associated with tubular atrophy, interstitial fibrosis and glomerulosclerosis.

32. Relation between the clinical (at Bx) as well as Oxford hist
Relation between the clinical (at Bx) as well as Oxford hist. variables and the outcome defined as eGFR<60 mil/min by the end of FU - a multivariate analysis
Cox regression model
frequency
OX-T GFR GFR 70-94
vs vs
PARAMETERS included in the multivariate regression model
(AIC: )
Multivariate analysis,
Cox regression model HR
95% CI p
OX-T 1 vs 0
3.3
0.001
GFR vs
22.7
0.002
GFR vs
4.9
0.144
In the multivariate analysis of the Oxford parameters and clinical variables the best model found included tubular atrophy and the initial GFR.
Due to the fact that there were very few cases with the severe degree of tubular atrophy that would correspond to the second grade in the semiquatitative estimation, we decided to express the scoring of this parameter as either absent or present.

33. Multivariate analysis,
Relation between clinical (at Bx) as well as PHIGANS variables and the outcome defined as a eGFR<60 mil/min by the end of FU - a multivariate analysis
Ct2 vs ct ct1 vs ct GFR GFR 70-94
vs vs
Cox regression model HR
PARAMETERS included in the multivariate regression model (AIC: )
Multivariate analysis,
Cox regression model HR
95% CI p
Ct 2 vs 0
49.2
0.007
Ct 1 vs 0 19
0.04
GFR vs
32.1
0.002
GFR vs
7.0
0.1
In the multivariate analysis of PHIGANS parameters and clinical variables the best model found was very similar to the previous one and included the tubular atrophy and the initial GFR.

34. Results of the statistical analysis
Correlations between the clinical parameters (at Bx) and histopathological variables defined according to the Oxford, Hass, Japanese, PHIGANS classifications.
Relation between the clinical (at Bx) as well as histopathological variables and the outcome defined as eGFR<60 ml/min by the end of observation (Cox regression analysis).
Relation between histopathological parameters and progression defined as eGFR loss≥20% by the end of the observation in pts with the initial eGFR<60 ml/min (univariate analysis).
Relation between the clinical (at Bx) as well as histopathological variables and the outcome defined as≥50% of eGFR loss or ESRD by the end of observation (Cox regression analysis).
Relation between the clinical (at Bx) as well as histopathological variables and the rate of GFR loss (dGFR) (linear regression).
Among patients with initial GFR below 60 ml/min we wanted to distinguished those that by the end of FU would experience further GFR loss of at least 20%. We called this subgroup „progressors”

35. Relation between histopathological parameters and progression defined as eGFR loss≥20% by the end of the observation in pts with the initial eGFR<60 mil/min - a univariate analysis
OX-T:
OX-T: (absent/present)
Among the Oxford parameters again tubular atrophy was found to be related to such defined outcome.

36. Relation between histopathological parameters and progression defined as eGFR loss≥20% by the end of the observation in pts with the initial eGFR<60 mil/min - a univariate analysis
ci:
GC st:
Among PHIGANS those variables that turned out to be related to progressive loss of GFR during the time of o the observation were interstitial fibrosis and the presence of cellular crescents.

37. Results of the statistical analysis
Correlations between the clinical parameters (at Bx) and histopathological variables defined according to the Oxford, Hass, Japanese, PHIGANS classifications.
Relation between clinical (at Bx) as well as histopathological variables and the outcome defined as eGFR<60 ml/min by the end of the observation (Cox regression analysis).
Relation between histopathological parameters and progression defined as eGFR loss≥20% by the end of the observation in pts with the initial eGFR<60 ml/min (univariate analysis).
Relation between clinical (at Bx) as well as histopathological variables and the outcome defined as≥50% of eGFR loss or ESRD by the end of observation (Cox regression analysis).
Relation between clinical (at Bx) as well as histopathological variables and the rate of GFR loss (dGFR) (linear regression).
The next slides will be devoted to the results of the analysis concerning the relation …..

38. Relation between the clinical (at Bx) as well as PHIGANS variables and the outcome defined as≥50% of eGFR loss or ESRD by the end of the observation - a univariate analysis
Variables
Cox Regression Model HR
CI 95% p
Nephrotic syndrome
7.2
0.001
Serum creatinine
1-4 vs 10
0.015
GFR vs
5.5
0.031
IS therapy (present vs absent)
3.9
0.033
Biopsy index
vs 0-1.6
9.1 1,
0.02
In the univariate analysis clinical variables found to be associated with an increased risk of at least 50% loss of GFR were……..
Among pathological parameters studied only the biopsy index was found to have a significantly negative impact on the outcome.

39. Relation between clinical (at Bx) and Oxford histopathological variables and the outcome defined as ≥50% loss of eGFR or ESRD by the end of the observation - a multivariate analysis
Cox regression model HR
OX-T GFR GFR 70-94
vs vs
PARAMETERS included in the multivariate regression model
(AIC: 76, )
multivariate analysis,
Cox regression model HR
95% CI p
OX-T 1 vs 0
1.9
0.37
GFR vs
8.4
0-70
0.05
GFR vs
0.6
IN none of the multivariate models studied were we able to confirm a significant, independent negative impact of any of Oxford parameters on the outcome defined as at least 50% of GRF loss or ESRD by the end of FU, which had been documented by the Oxford study.

40. Relation between Haas as well as Japanese classifications
and the outcome – univariate analysis
variables
Cox Regression Model
≥50% of eGFR loss or ESRD (p)
GFR< 60 mil/min
(p)
Haas
Class 5 vs 1 NS
Class 4 vs 1
Class 3 vs 1
Class 2 vs 1
Japanese
0.05
In univariate analysis Cox regression analysis revealed an association between the 4th stage of the disease according to Japanese classification and an end point defined as GFR< 60 mil/min.
As for the relation between the Haas and Japanese classifications and the outcome, an univariate analysis revealed an association between the highest histological grade according to the Japanese class. and the outcome defined as GFR of less than 60 ml/min at the and of FU.

41. Results of the statistical analysis
Correlations between clinical parameters (at Bx) and histopathological variables defined according to Oxford, Hass, Japanese, PHIGANS classifications.
Relation between clinical (at Bx) as well as histopathological variables and the outcome defined as eGFR<60 ml/min by the end of observation (Cox regression analysis).
Relation between histopathological parameters and progression defined as eGFR loss≥20% by the end of observation in pts with initial eGFR<60 ml/min (univariate analysis).
Relation between clinical (at Bx) as well as histopathological variables and the outcome defined as≥50% of eGFR loss or ESRD by the end of observation (Cox regression analysis).
Relation between clinical (at Bx) as well as histopathological variables and the rate of GFR loss (dGFR) (linear regression).
The final part of my presentation will be devoted to the results of the analysis concerning the relation …………………………..which was the second end-point defined by Oxford study.

42. Relation between clinical parameters (at Bx) and the rate of GFR loss (dGFR) - linear regression, univariate analysis
dGFR
GFR at the time of Bx
Cellular crescents
dGFR
In the univariate analysis the linear regression has shown an association between the rate of the GFR loss and the initial GFR as well as the presence of cellular crescents and the rate of the GFR loss.
P=0.06
P<0.0001

43. Relation between clinical parameters (at Bx) and the rate of GFR loss (dGFR) - linear regression, univariate analysis
P=0.03
IS therapy
dGFR
The analysis has also shown the strong relation between the fact that the patient was treated with IS and the rate of GFR loss.
Most probably the decision of the introduction of the IS treatment reflects the severity of patients’ status, both clinical and morphological, and that’s why -paradoxically – it constitutes a negative prognostic factor.

44. Relation between the activity/stage of the IgAN according to Haas class. and the rate of GFR loss (dGFR) - linear regression, multivariate analysis
Haas classification
0.002
IS therapy
<0.001
GFR
0.04
Haas classification p
Parameters in the best model (AIC: ) with Haas classification
dGFR
In the multivariate analysis the best model that included the grading of biopsy lesions according to Haas classification was the one that also included the initial GFR and the fact, that patient was treated with IS.
P=0.04

45. Japanese classification
Relation between the activity/stage of the IgAN according to Japanese classification and the rate of GFR loss (dGFR) - linear regression, multivariate analysis
Japanese classification
dGFR
0.004
IS therapy
<0.001
GFR
0.02
Japanese classification p
Parameters in the best model (AIC: 787.8) with the Japanese classification
THe analogical model was found for the Japanese class.
P=0.02

46. Parameters in the best model (AIC: 795 )
Relation between clinical as well as Oxford’s histop. variables and the rate of GFR loss (dGFR) linear regression, multivariate analysis
Parameters in the best model (AIC: 795 ) p
Endocapillary hypercellularity (OX-E)
0.113
Mesangial hypercellularity (OX-M)
0.182
Ttubular atrophy/interst. fibrosis (OX-T)
0.039
IS therapy
0.004
GFR
<0.0001
OX-T
dGFR
The only Oxford histopathological parameter that was found to be significantly associated with the rate of the GFR loss was again the tubular atrophy.
P=0.04

47. Parameters in the best model (AIC: 792 )
Relation between clinical as well as PHIGANS variables and the rate of GFR loss (dGFR) linear regression, multivariate analysis
dGFR
Biopsy index
Parameters in the best model (AIC: 792 ) p
Biopsy index
0.002
IS therapy
0.004
GFR
<0.0001
As for the PHIGANS parametrs the one that was significantly associated with the rate of the GFR loss in multivariate analysis was biopsy index.
P=0.002

48. Summary
eGFR at the time of Bx is the strongest clinical predictor of poor outcome in IgA nephropathy.
Among histopathological parameters defined by Oxford classification only tubular atrophy was found to be a negative prognostic factor in both univariate and multivartiate analysis with the end-point defined as eGFR <60 mil/min at the end of FU.
Among PHIGANS parameters the ones most distinctly associated with the clinical outcome were those that scored chronic lesions, with the strongest negative impact of tubulointerstitial scarring and composite scores, including biopsy index. Those scores have also correlated with the clinical manifestation of IgA at the time of biopsy (proteinuria and eGFR).
Japanese and Haas classifications were proved to have a significant negative impact on dGFR in the multivariate analysis.

49. Conclusions
The PHIGANS study has not confirmed the independent predictive value of glomerular lesions (segmental sclerosis, mesangial and endocapillary hypercellularity) that was documented by the Oxford study.
The usage of composite scores makes the impact of glomerular lesions on the clinical outcome more distinct.
There were differences in both clinical and pathological characteristics of patients’ groups in PHIGANS and Oxford studies – to what extent have these differences caused the results’ discrepancies?