Categorization of the diabetic nephropathy by Tervaert classification in

clinical settingFilipa 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 syndromeClinical syndrome• Persistente proteinuria • Hypertension• Progressive decline in renal function

Pathologic renallesions

Pathologic renallesions

• 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

Glomerular-Thickening of glomerular basement membrane (GBM)-Mesangial expansion-Nodular glomerulosclerosis (Kimmelstiel-Wilson lesions)

Interstitial-Thickening of tubular basement membrane (TBM)-Arteriolar hyalinosis

Diagnostic histopathologic lesionsDiagnostic histopathologic lesions

Tervaert’s Pathologic Classification of Diabetic Nephropathy

Similar histologic lesionsSimilar renal complications

Type I DN Type I DN Type II DN Type II DN

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

• GBM, measured with EM is, on average• Thicker than 430 nm in males • Thicker than 395 nm in females

Class I – H & E 400x

Class II Mesangial Expansion

II a – MildII b – Severe

• Mild or severe mesangial expansion, not meeting the criteria for class II or IV

• 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 a – PAS 400x

Class II b – PAS 400x

Class III Nodular Sclerosis – Kimmelstiel-Wilson lesions.

• At least one convincing Kimmelstiel-Wilson lesion is found

• The biopsy specimen does not have more than 50% global glomerulosclerosis (Class III)

• Kimmelstiel-Wilson lesion – focal, lobular, round to oval mesangial lesions with an acellular, hyaline/matrix core, rounded peripherally by sparse, crescent-shaped mesangial nucleiClass III – PAS 400x

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

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

Objective

Methods

Senior Pathologist>10 years experience(A – Gold standard)

Senior Pathologist>10 years experience(A – Gold standard)

Intermediate Pathologist3 years experience

(B)

Intermediate Pathologist3 years experience

(B)

Junior Pathologist1st year of practice

(C)

Junior Pathologist1st year of practice

(C)

Blinded inter-observer and blinded for clinical outcome categorization of DM biopsies

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

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)

Global Kappa – 0.82

Table 3 Senior Pathologist (A – Gold standard) vs Junior Pathologist experience (C)

(A)Classes II III IV

(B) II 9 1 1III 1 14 -IV - 1 3

kappa= 0.85

(A)Classes II III IV

(C) II 8 1 1III 2 13 -IV - 2 3

kappa=0.79

Results Renal survival

At 5 years follow-up

Renal survival•II= 98.4% •III= 54.3% •IV= 36.2%

Figure 1 Kaplain Meier curves by Tervaert Classification DN

Discussion

1. Recruitment

2. Allocation

3. Maintenance

4. Blind or objective assessment of outcomes

5. Results analysis

Study validity

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

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

Recruitment

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

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

Allocation

Problems

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

Allocation

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

• No adjusted analyses was needed for confounders

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)

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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