Categorization of the diabetic nephropathy by Tervaert classification in clinical setting

1. Categorization of the diabetic nephropathy by Tervaertclassification 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

2. 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

3. What is the Diabetic Nephropathy? • 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 Clinical syndrome Pathologic renal lesions

4. Diabetic Nephropathy Diagnostic histopathologic lesions • Glomerular • Thickening of glomerular basement membrane (GBM) • Mesangial expansion • Nodular glomerulosclerosis (Kimmelstiel-Wilson lesions) • Interstitial • Thickening of tubular basement membrane (TBM) • Arteriolar hyalinosis

5. 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

6. Tervaert’s Pathologic Classification of Diabetic Nephropathy

7. 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

8. Mesangial Expansion II a – Mild II b – Severe Class II • 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

9. 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 nuclei Class III – PAS 400x

10. 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

11. Tervaert’s Pathologic Classification of Diabetic Nephropathy

12. 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

13. 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) Junior Pathologist 1st year of practice (C) Blinded inter-observer and blinded for clinical outcome categorization of DM biopsies

14. Methods Categorization with Tervaert Classification

15. 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

16. Results Characterization of the Population Table 1 Baseline data at the moment of biopsy** ** All patients had Type II diabetes mellitus

17. Results Reproducibility Table 2 Senior Pathologist (A – Gold standard) vs Intermediate Pathologist experience (B) Table 3 Senior Pathologist (A – Gold standard) vs Junior Pathologist experience (C) Global Kappa – 0.82

18. 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%

19. Discussion Study validity Recruitment Allocation Maintenance Blind or objective assessment of outcomes Results analysis

20. 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

21. Problems Recruitment Biopsies are performed only when clinical course is not typicalfor 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

22. 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

23. 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

24. 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 IIband III may only be due to different pathogenic processes and not progression of disease

25. 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

26. Assessment of outcomes • The outcome assessors were unaware of participants categorization with Tervaert Classification (Blind assessment of outcomes) • The assessmentof outcomes was objective (start dialysis date) • The death not related with diabetic disease was censored

27. 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)

28. 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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