Categorization of the diabetic
nephropathy by Tervaert
classification in clinical setting
Filipa Moreno*, Ana Pinho**, Renata Dias*,
Ramon Vizcaino*
*Anatomic Pathology Department – Santo Antonio Hospital, Oporto, Portugal
**Nephrology Department – Faro Hospital, Faro, Portugal
Diabetic Nephropathy
Diabetic Nephopathy (DN) is the most common cause of end-stage
renal disease (ESRD)
The percentage of patients with ESRD who have Diabetes Mellitus,
specially Type II patients, have increseased over the past decade
The incidence of Diabetes Mellitus is rising world wide
It is estimated that 20-40% of all diabetic patients will develop diabetic
nephropathy
What is the Diabetic Nephropathy?
Clinical syndrome
Pathologic renal
lesions
• Persistente proteinuria
• Hypertension
• Progressive decline in renal function
• Diabetic microangiopathy –  of basement
membrane (BM) material
• Difuse glomerulosclerosis – difuse  in mesangial
matrix and thickening of the capillary walls
• Nodular glomerulosclerosis – Kimmelstiel-Wilson
lesions
• Insudative lesions – hyalinosis
• Atubular glomeruli
• Difuse linear reaction for IgG along the BM
Diabetic Nephropathy
Diagnostic histopathologic lesions
Glomerular
- Thickening of glomerular basement
membrane (GBM)
- Mesangial expansion
- Nodular glomerulosclerosis (KimmelstielWilson lesions)
Interstitial
- Thickening of tubular basement membrane
(TBM)
- Arteriolar hyalinosis
Tervaert’s Pathologic Classification of
Diabetic Nephropathy
“Our aim, commissioned by the Research Committee of the Renal
Pathology Society, was to develop a consensus classification
combining type I and type II diabetic nephropathies”
Jornal of the American Society of Nephrology, 21: 556-563, 2010
Type I DN
Type II DN
Similar histologic lesions
Similar renal complications
Tervaert’s Pathologic Classification of
Diabetic Nephropathy
Class I
Glomerular Basement Membrane
Thickening
• Biopsy shows no or only mild, nonspecific
changes by light microscopy
• Changes do not meet the criteria of
classes II through IV
• Absence of mesangial expansion,
nodular KW lesions and
glomerulosclerosis
Class I – H & E 400x
• GBM, measured with EM is, on average
• Thicker than 430 nm in males
• Thicker than 395 nm in females
Class II
Mesangial Expansion
II a – Mild
II b – Severe
• Mild or severe mesangial expansion, not
meeting the criteria for class II or IV
Class II a – PAS 400x
• Mesangial expansion – increase in
extracellular material in the mesangium
such that the width of the interspace
exceeds two mesangial cell nuclei in at
least two glomerular lobules
• Mild – expanded mesangial area <
mean area of a capillary lumen
• Severe - expanded mesangial area
mean area of a capillary lumen
Class II b – PAS 400x
>
Class III
Nodular Sclerosis – KimmelstielWilson lesions.
• At least one convincing Kimmelstiel-Wilson
lesion is found
• The biopsy specimen does not have more
than 50% global glomerulosclerosis (Class III)
Class III – PAS 400x
• Kimmelstiel-Wilson lesion – focal, lobular,
round to oval mesangial lesions with an
acellular, hyaline/matrix core, rounded
peripherally by sparse, crescent-shaped
mesangial nuclei
Class IV
Advanced Diabetic
Glomerulosclerosis
• Advanced DN
• More than 50% global glomerulosclerosis
• The is clinical or pathological evidence
that the sclerosis is attributable to DN
Class IV – PAS 400x
Tervaert’s Pathologic Classification of
Diabetic Nephropathy
Objective
To assess the reliability and prognostic value of
the Tervaert’s pathologic classification of
diabetic nephropathy in renal biopsies
performed on type 2 diabetes mellitus patients
with an atypical clinical presentation of renal
disease
Methods
Study design
Population
•
•
•
Single-center study in a tertiary referral hospital for renal
pathology
Retrospective evaluation of 710 consecutive renal biopsies
Selection of Diabetic Nephropathy (DM) positive biopsies
Exposure & Comparison
Senior Pathologist
>10 years experience
(A – Gold standard)
Intermediate Pathologist
3 years experience
(B)
Blinded inter-observer and blinded for clinical
outcome categorization of DM biopsies
Junior Pathologist
1st year of practice
(C)
Methods
Categorization with Tervaert
Classification
Methods
Study analysis
Outcomes
•
Primary: Start dialysis
•
Secondary: Death (censored death not related with diabetic disease)
Time
•
Between biopsy data and outcome (Cohort retrospective)
Results
•
Testing of the different baseline characteristics among classes
•
Evaluation of Tervaert’s classification reproducibility
•
Survival analysis by classes - Kaplan Meier
Results
Characterization of
the Population
Table 1 Baseline data at the moment of biopsy**
** All patients had Type II diabetes mellitus
Results
Reproducibility
Table 2 Senior Pathologist (A – Gold standard) vs Intermediate Pathologist experience (B)
(A)
(B)
Classes
II
III
IV
II
9
1
-
III
1
14
1
IV
1
3
kappa= 0.85
Table 3 Senior Pathologist (A – Gold standard) vs Junior Pathologist experience (C)
(A)
(C)
Classes
II
III
IV
II
8
2
-
III
1
13
2
IV
1
3
kappa=0.79
Global Kappa – 0.82
Results
Renal survival
Figure 1 Kaplain Meier curves by Tervaert Classification DN
At 5 years follow-up
Renal survival
• II= 98.4%
• III= 54.3%
• IV= 36.2%
Discussion
Study validity
1. Recruitment
2. Allocation
3. Maintenance
4. Blind or objective assessment of outcomes
5. Results analysis
Recruitment
• The setting was appropriate, given the study goals.
• The participants were at a similar stage in terms of progression of
their disease.
• The participants were not representative of all Tervaert’s
Pathologic Classification of Diabetic Nephropathy with pure
nephropathy diabetic
Problems
Recruitment
Biopsies are performed only when clinical course is not
typical for diabetic nephropathy
• The biopsies do not represent the pathologic range of DN in
type II diabetic patients
• The biopsies only represent patients with atypical clinical course
• A wide range of non-diabetic renal disease may be present
Allocation
• The participants were consistently allocated to Tervaert’s classes
• The measurements of baseline data were accurate and similar for
the different classes
• The differences between classes were documented
at the biopsy date
Problems
Allocation
The pathologic findings in diabetic nephropathy differ
substantially between type I and type II diabetic patients
• Kidney lesions underlying renal dysfunction are more
heterogeneous in type II patients
• In Type I patients, the most important renal structure changes
occur in the glomeruli
• Type II patients are more complex and only a minority have
histopathological patterns similar to the typical DN of Type I
patients
Problems
Allocation
The mechanisms underlying the associations between
cause, natural history and histopathological pattern in the
DN of Type II patients are inadequately defined
• Only a percentage of samples from type II diabetic patients with
proteinuria have typical diabetic glomerulopathy
• The association between the clinic and pathologic findings is
not always linear in Type II patients
• Differences found between class IIb and III may only be due to
different pathogenic processes and not progression of disease
Maintenance
• The participants remained in the groups they were initially allocated to
• The participants / investigators were blind to participants categorization
with Tervaert Classification /clinical baseline data, respectively
• Clinical co-intervention during the follow-up period was unknown
• Completeness of follow-up was high and similar in allocated groups
• Compliance and contamination problems were probably absent
Assessment of outcomes
• The outcome assessors were unaware of participants
categorization with Tervaert Classification (Blind assessment of
outcomes)
• The assessment of outcomes was objective (start dialysis date)
• The death not related with diabetic disease was censored
Results
• Survival analyses include all participants allocated by exposure
factor
• Reasonable precision (low confidence limits)
• There was consistency with other studies
Mazzucco, G. et al. Different patterns of renal damage in type 2 diabetes melitus: a multicentric
study on 393 biopsies. AJKD 39 (4), 713-720 (2002)
Se Won Oh et al. Clinical implications of pathologic diagnosis and classification for diabetic
nephropathy. Diabetes research and clinical practice 97 418–424 (2012)
• No adjusted analyses was needed for confounders
Conclusions
• In our study, Tervaert classification proved to be user friendly,
accurate and clinically useful
• There was a good inter-observer reproducibility
• A uniform and consistent classification of DN will improve the
communication between renal pathologists and clinicians, allowing
better clinical management.
• Our findings corroborate the results from experimental centers
• Larger and more significant trials are therefore recommended
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