INTERNATIONAL IgA NEPHROPATHY NETWORK
&
RENAL PATHOLOGY SOCIETY
In collaboration with the International Society of Nephrology
CONSENSUS ON PATHOLOGY OF IgA NEPHROPATHY
 

Introduction

The group of nephrologists and renal pathologists began its work to develop a consensus on the pathological classification of IgA nephropathy in November 2005.

  Our main goals can be summarised as:

  1Development of a pathological classification that discriminates patients with IgA nephropathy into classes which correspond to categories based on their presenting clinical and laboratory data
2 Development and validation  of a pathological classification that discriminates patients by significantly different outcome out to 5 years as estimated by renal survival or by rate of deterioration in renal function (slope of estimated GFR).

  It is likely that the elements of the pathological classification will include disease activity, chronicity, and severity. A secondary goal will be to identify the relative predictive value of each of these elements and their discriminatory value when added to clinical outcome data. It may also be possible to identify pathological features which predict response to therapy

   

Worldwide Consultation

 

The Consensus Group now wishes to receive the views of nephrologists and renal pathologists all over the world on the plans that have been made.

  Documents are being posted which have been prepared by the nephrology and renal pathology groups working within the Consensus.

They are being  posted on the websites of the International IgA Nephropathy Network and the Renal Pathology Society.

Please copy  your comments on the Nephrologists’ Proposals to:

John Feehally                  jf27@le.ac.uk

Daniel Cattran                daniel.cattran@uhn.on.ca

YasuhikoTomino            yasu@juntendo.ac.jp

Rosanna Coppo              nefrologia@oirmsantanna.piemonte.it

Please copy your comments on the Pathologists’ proposals to:

Terry Cook                     t.h.cook@imperial.ac.uk

Mark Haas                      mhaas@jhmi.edu

Fernand Lai                    fmlai@cuhk.edu.hk

 

NEPHROLOGISTS PROPOSALS

To achieve our goals will require the study of large cohorts of patients of different ages from different areas of the world.

  We have reached agreement on:

•       The mandatory parameters in the clinical datasets, both at clinical presentation and during follow up.
•       Where there may be uncertainty, the definitions for each of these parameters.
•       The number of data time points minimum duration of follow up from time of first biopsy  necessary for a case to be useful in the evaluation of the classification.
•       The earliest date of biopsy for a case to be included in the evaluation

  The full datasets [see Tables 1&2] are ‘ideal’. We need to recognise that some of these data may not be readily available in cohorts which otherwise provide excellent information. One example may be smoking status which we know has not been collected in all cohorts; another may be height. We propose a minimum dataset [shown in bold in Tables 1&2] which we may need to use in some cohorts.

We will need large patient cohorts from centres willing to commit to involvement in the project. When  we have received comments from the wider renal community on our proposals, we will approach a number of centres throughout the world to establish whether they have sufficient suitable cases for analysis, and to confirm their willingness to participate.  

   

Inclusion criteria

o      Biopsy-proven IgA nephropathy

o      Diagnosis 1980 or more recent [1]

o      No clinical features of HSP

o      Dataset available for time of diagnosis [see Table 1]

o      Follow up dataset [see Table 2] available on a minimum of five occasions over a minimum of five years [2]   

o      Biopsy slide/blocks available for review of light microscopic appearances [at least ten glomeruli].

o      Outcome at 5 years in one of three categories:

o      Remission – no haematuria or proteinuria, e GFR > 90 mL/min/1.73m²

o      Non-progressive – persistent haematuria and/or proteinuria, serum creatinine increased < 25% from diagnosis

o      Progressive - persistent haematuria and/or proteinuria serum creatinine at least  twice value at diagnosis, eGFR < 60 mL/min/1.73m²

 

PATHOLOGIST’S PROPOSALS

Proposed Definitions in IgA Nephropathy

IgA nephropathy: IgA nephropathy in the native kidney is defined as dominant or co-dominant staining with IgA in glomeruli by immunofluorescence or immunoperoxidase. Not all glomeruli need show this positivity. SLE-related nephritis should be excluded. The intensity of IgA staining should be more than trace.  The distribution of IgA staining should include presence in the mesangium, with or without capillary loop staining, excluding a pure membranous, diffuse, global granular GBM staining pattern or linear GBM staining pattern. IgG and IgM may be present, but not in greater intensity than IgA, except that IgM may be prominent in sclerotic areas. Complement C3 may be present. The presence of C1q staining in more than trace intensity should bring up consideration of lupus nephritis.

Glomerular definitions

Diffuse: a lesion involving most (≥ 50%) glomeruli.

Focal: a lesion involving <50% of glomeruli.

Global: a lesion involving more than half of the glomerular tuft.

Segmental: a lesion involving less than half of the glomerular tuft  (i.e. at least half of the glomerular tuft is spared). N.B. see below for definitions of segmental and global sclerosis

Endocapillary hypercellularity: hypercellularity due to increased number of cells within glomerular capillary lumina causing narrowing of the lumina”.

Extracapillary proliferation or cellular crescent: extracapillary cell proliferation of more than two cell layers occupying one-fourth or more of the glomerular capsular circumference.

Localized extracapillary hypercellularity:  is defined as < 25% of the glomerular capsular circumference involved by extracapillary hypercellularity, >2 cell layers thick, excluding podocyte hyperplasia.

Karyorrhexis: presence of apoptotic, pyknotic and fragmented nuclei.

Necrosis: is defined as disruption of the glomerular basement membrane with fibrin exudation and karyorrhexis. At least two of these three lesions need to be present to meet the criteria for necrosis.

GBM duplication: is defined as a double contour of the GBM with or without endocapillary hypercellularity.

Increased mesangial matrix: is defined as an increase in the extracellular material in the mesangium such that the width of the interspace exceeds two mesangial cell nuclei in at least two glomerular lobules.

 Sclerosis: is defined as obliteration of the capillary lumen by increased extracellular matrix with or without hyalinosis, with or without foam cells.

An adhesion: is defined as a local, < 25% of the circumference of Bowman's capsule, area of continuity between the glomerular tuft  and Bowman's capsule with associated extracellular matrix.

Crescents are sub-classified as follows: 

A fibrocellular crescent: is defined as >25% of the circumference of Bowman's capsule covered by a combination of cells and extracellular matrix, with <50% cells and <90% matrix. This lesion is often associated with disruption of Bowman's capsule.  Ischemic, obsolescent glomeruli should be excluded.

Fibrous crescent: if >90% of the crescent is occupied by extracellular matrix.

Cellular crescent:  if >50% of the crescent is occupied by cells.

Mesangial hypercellularity: is sub-classified as follows: 

If <3 mesangial cells/mesangial area = normal,

3-4 mesangial cells/mesangial area = mild mesangial hypercellularity,

5-7 mesangial cells/mesangial area = moderate mesangial hypercellularity,

8 or more mesangial cells/mesangial area = severe mesangial hypercellularity.

Note: This is scored for each glomerulus by assessing the most cellular lobule

Segmental sclerosis: is defined as any amount of the tuft involved with sclerosis, but not involving the whole tuft.

Global sclerosis:  is defined as the entire glomerular tuft involved with sclerosis.  Note: This should not include obsolescent glomeruli felt to be sclerotic on the basis of an etiology other than chronic glomerulonephritis (e.g., long-standing hypertension).

Active glomerular lesions

Endocapillary hypercellularity

Karyorrhexis

Fibrinoid necrosis                                                             

Rupture of glomerular basement membrane                                   

Crescents, cellular or fibrocellular

Chronic glomerular lesions

Glomerular sclerosis (segmental, global)

Fibrous adhesions

Fibrous crescents

Tubulointerstitial definitions

Tubular atrophy: is defined by thick irregular tubular basement membranes with decreased diameter of tubules. It is scored according to the percent of cortical area involved, excluding the subcapsular area.  The categories are <10%, 10-25%, 26-50%, and >50% tubular atrophy.

Interstitial fibrosis: is defined as increased extracellular matrix separating tubules in the cortical area, excluding the subcapsular area. It is scored as follows: <10%, 10-25%, 26-50%, and >50% of area occupied by interstitial fibrosis.

Interstitial inflammation: is defined as inflammatory cells within the cortical interstitium in excess, excluding the subcapsular area.  It is scored according to the area involved with interstitial inflammation, as follows:  <10%, 10-25%, 26-50%, >50%.

Additional tubular lesions are noted as follows: The presence of numerous red blood cells, defined as tubules completely filled with red blood cells with or without casts, is noted as a lesion when it involves >20% of tubules.

Acute tubular injury of the proximal tubular epithelium is defined by simplification of the epithelium without tubular basement membrane thickening.

Vascular definitions

Arterial lesions are scored based on the most severe lesions.  The following lesions are assessed: intimal fibrosis: none, or lesions occupying the following percentage of lumen, <10%, 10-25%, 26-50%, >50%.

Arteriolar lesions are scored as follows: Non-hyaline arteriolar sclerosis is noted as present or absent.  Arteriolar hyaline is noted as present or absent. 

Of note: Other vascular lesions can be noted on the scoring form.

Table 1: Dataset at time of renal biopsy [data collected within 3 months of biopsy]

‘Minimum’ dataset shown in bold

		Notes
Demographics/Clinical
Centre/Patient Identifier
Date of birth	dd/mm/yyyy
Ethnicity	White/Black/Asian/Indo-Asian/Other	Black = Black African origin Asian = Chinese, Japanese, South East Asian Indo-Asian = Indian, Pakistani, Bangladeshi
Gender	Male/female
Date of first clinical  presentation	dd/mm/yy
Date of renal biopsy	dd/mm/yy
Presenting clinical features [single category]	Macroscopic haematuria Asymptomatic microhaematuria Asymptomatic microhaematuria and proteinuria Nephrotic syndrome Acute renal failure Chronic renal failure [eGFR< 60mL/min]
Height	metres
Weight	Kg
Body Mass Index	Kg/m2
Smoker	Yes/No
Systolic blood pressure	mm Hg	Hypertension defined as >130/80 or need for antihypertensive medication For children - use high-adjusted reference ranges
Diastolic blood pressure	mm Hg
Laboratory data
Serum creatinine	µmol/L or mg/dL	Values will be converted to μmol/L before analysis
Estimated GFR	mL/min/1.73 m2	Adults - Modified MDRD formula Children – Schwartz formula
Serum albumin	mmol/L or mg/dL	Values will be converted to mmol/L before analysis
Serum cholesterol	mmolL or mg/dL	Values will be converted to mmol/L before analysis
Serum triglycerides	mmol/L or mg/dL	Values will be converted to mmol/L before analysis
Urine protein	g/24hr/1.73m2 or  albumin/creatinine ratio or protein/creatinine ratio	Values will be expressed in g/24hr before analysis [using accepted conversion factors]
Microscopic haematuria	0-3+ on dipstick analysis
Medications	Treatments before diagnosis
Number of blood pressure medications prescribed	0-5
ACE inhibitors	Yes/No
ARBs	Yes/No
Non dihydropyridine calcium channel blockers	Yes/no
Dihydropyridine calcium channel blockers	Yes/No
Statins	Yes/No
Diuretics	Yes/No
Fish oil	Yes/No
Corticosteroids	Yes/No
Cyclophosphamide	Yes/No
Mycophenolate	Yes/No
Azathioprine	Yes/No
Platelet aggregation inhibitors	Yes/No
Tonsillectomy	Yes/No Date of Surgery – dd/mm/yyyy

 

Table 2: Follow up dataset  [data collected on at least five occasions over 5 years]

‘Minimum’ dataset shown in bold

 

Centre/Patient Identifier
Clinical data
Height	metres
Weight	Kg
Body Mass Index	Kg/m2
Smoker	Yes/No
Systolic blood pressure	mm Hg
Diastolic blood pressure	mm Hg
Laboratory data
Serum creatinine	µmol/L or mg/dL
Estimated GFR	mL/min /1.73 m2
Serum albumin	mmol/L or mg/dLDont think this should be obligatory Most IGA have normal albubins and nephrologists will not monitor regularly Same with using MDRD should consider Cockcroft –Gault where its not necessary to haveit
Serum cholesterol	mmolL or mg/dL
Serum triglycerides	mmol/L or mg/dL
Urine protein	g/24hr/1.73 m2 or  albumin/creatinine ratio or protein/creatinine ratio
Microscopic haematuria	0-3+ on dipstick analysis
Medications	During time  period since last observations point
Number of blood pressure medications prescribed	0-5
ACE inhibitors	Yes/No
ARBs	Yes/No
Non dihydropyridine calcium channel blockers	Yes/No
Dihydropyridine calcium channel blockers	Yes/No
Statins	Yes/No
Fish oil	Yes/No
Corticosteroids	Yes/No
Cyclophosphamide	Yes/No
Mycophenolate	Yes/No
Azathioprine	Yes/No
Platelet aggregation inhibitors	Yes/No
Tonsillectomy	Yes/No Date of Surgery – d/mm/yyyy