Diabetic nephropathy (DN) caused by diabetes mellitus is one of the major causes of end-stage renal failure worldwide. Microalbuminuria is an important index to assess the progression of DN. But it is not accurate to evaluate the severity or prognosis simply based on the degree of proteinuria (not all diabetic patients who develop renal function failure have massive albuminuria). Nondiabetic renal disease (NDRD) may also complicate the clinical picture. Therefore, nephrologists and endocrinologists should be aware of the significance of pathological changes of DN in their clinical practice. (NDRD), which might commonly be superimposed with diabetic renal lesions in some patients with type 2 diabetes, could only be confirmed and excluded by biopsy.

1. Changing Histology in Diabetic
Kidney Disease
Dr. Pallavi Prasad
Assistant Professor
Department of Pathology
SGPGIMS, Lucknow

2. Outline
Pathologic Classification of Diabetic Nephropathy
Latest updates
Trajectories of kidney function in DN
Changes in renal histology in non-classical DN
Non-diabetic Kidney Disease

3. Introduction: Diabetic nephropathy
• Diabetic nephropathy (DN) caused by diabetes mellitus is one of
the major causes of end-stage renal failure worldwide.
• Microalbuminuria- important index to assess the progression of
DN.
• Not accurate to evaluate the severity or prognosis simply based
on the degree of proteinuria (not all diabetic patients who
develop renal function failure have massive albuminuria).
• Nondiabetic renal disease (NDRD)
pathological changes of DN

4. Pathologic Classification of Diabetic
Nephropathy
• A patient should carry a clinical diagnosis of diabetes mellitus to
apply the classification.
Renal biopsy (H&E, PAS,
MT & PSM stains for
LM)
at least 10 glomeruli
Immunofluorescence:
IgA, IgG, IgM, C3, C1q,
kappa and lambda light
chains
Electron microscopy

5. Pathologic Classification of Diabetic
Nephropathy
The Research Committee of the Renal Pathology Society
developed a consensus classification (2010) combining type 1 and
type 2 DN.
Discriminate lesions by various degrees of severity- easy to use
internationally in clinical practice.
Four hierarchical glomerular lesions, separate evaluation for
degrees of interstitial and vascular involvement.

6. Flow chart for classifying DN

7. Class I: Glomerular Basement Membrane
Thickening
• Characteristic early change in type 1 and type 2 DN
• “prediabetic” lesion
• Long-term glucose control
correlate strongly with GBM thickness
• urinary albumin excretion

8. Class I: Glomerular Basement Membrane
Thickening
increased
production
decreased
degradation
increased deposition
of normal
extracellular matrix
components
(collagen types IV
& VI, laminin, and
fibronectin)
ECM
accumulation

9. Class I: Glomerular Basement Membrane
Thickening
• No/only mild, nonspecific changes by LM that do not meet the
criteria of classes II-IV.
• GBM measurement (EM): average >430 nm (males >9 yrs); >395
nm in females.
• Mild chronic and other reactive
changes (e.g.,arterionephrosclerosis,
ischemic changes, or interstitial fibrosis) ✔️
hypertension
DN
ageing

10. Class II: Mesangial Expansion, Mild (IIa)
or Severe (IIb)
• “diffuse diabetic
glomerulosclerosis”
• Mild or severe mesangial
expansion; not meeting
inclusion criteria for class III
or IV.
• Restricts and distorts
glomerular capillaries and
diminishes the capillary
filtration surface.
IIa
mild mesangial
expansion in >25% of
the total mesangium
IIb
severe mesangial
expansion in > 25%
of total mesangium
observed throughout
the biopsy
Mesangial expansion

11. Class III: Nodular Sclerosis (Kimmelstiel–
Wilson lesions)
• One convincing Kimmelstiel– Wilson lesion (KW lesion)
• Not > 50% global glomerulosclerosis

12. microvascular injury
lytic changes in the mesangial
area [mesangiolysis]
destroys normal structure of
glomerular tuft+decrease in
mesangial cells (central area)
microvascular injury
detachment of endothelial cells
from the GBM
disrupt the connections
between mesangial area and
GBM
expansion of KW lesion
early or moderately
advanced stage
more advanced stage

14. Nodular sclerotic lesions also found in
hypertension smoking
hypercholesterolemia
extrarenal vascular
disease

15. Prognostic significance of Kimmelstiel–
Wilson lesions
at least one
KW lesion
• longer duration of diabetes
• less favourable clinical parameters
36 patients
with type 2
diabetes
• more severe overall retinopathy
• higher serum creatinine
study of
124
Chinese
patients
with type 2
diabetes
• longer duration of DM
• frequent evidence of retinopathy

16. Class IV: Advanced Diabetic Glomerulo-
sclerosis
• >50% global glomerulosclerosis in which there is clinical or
pathologic evidence that the sclerosis is attributable to DN.
accumulation
of
extracellular
matrix
proteins
mesangial
expansion
KW lesions
global
glomeruloscle
rosis

18. Other Glomerular Lesions
Fibrin cap: Capsular drops: in advanced
DN; associated with disease
progression
Glomerular hyalinosis:
Not specific {FSGS and
lupus nephritis}.
Tip lesion: abnormalities in
the glomerulotubular junctions
with focal adhesions
Atubular glomeruli: atrophic
tubules with no observable
glomerular opening.
Typically found in more
advanced stages of nephropathy
a/w overt proteinuria

19. Mesangiolysis
Vascular
endothelial
injury
Mesangiolysis
nodular
lesions (type
VI collagen in
glomeruli )
reduction in the glomerular filtration surface area

20. Polar vasculosis
• Characteristic of DN
• In >50% of patients with microalbuminuria
• by facilitating efferent blood flow from the glomeruli through the
small additional efferent arterioles
preserves GFR in type 2 diabetes

21. Immunofluorescence findings
• Linear staining of GBMs and TBMs (with IgG, IgM, complement
C1q, fibrinogen, and albumin)
• Hyalinotic lesions in glomeruli and arterioles: IgM and C1q+
• Electron microscopy: thickened GBMs, variable foot-process
effacement (podocytes), and increase in the mesangial matrix.

22. Tubular Lesions
• Concomitant tubular basement membrane thickening of non-
atrophic tubules
• > in class III and IV [PAS or silver stains].
• IFTA follow glomerular changes ESRD.

23. Interstitial Lesions
• Presence of mononuclear cells in the interstitium ✓
• T-lymphocytes and macrophages

24. Vascular Lesions
Arteriolar hyalinosis
• Score 0 to 2
• a/w more severe glomerular
disease.
Large vessel arteriosclerosis
• Isolated or significant medial
thickness may be associated
with concurrent hypertension.

28. Trajectories of kidney function in DKD
Nature reviews | Nephrology, https://doi.org/10.1038/ s41581-021-00462-y

29. ↑Mesangial expansion and
GBM thickening
↑Nodular lesions with
mesangiolysis
↑IFTA
↑Arteriosclerosis
↓Polar vasculosis
eGFR decline
(Classical DKD)

30. ↑Reduced
GBM thickening
mesangial matrix
expansion and glomerular
sclerosis
↑clearance of nodular
lesions
regression of
albuminuria

31. Histological features in rapid decliners
• Arteriolar hyalinosis was highest in the patients with accelerated
eGFR decline (≥3%/year)
• Nodular lesions
• Mesangiolysis
• IFTA

32. Renal histology in non-proteinuric
DKD

33. Histology of DKD without albuminuria
• Mixed histological findings have been reported.
• Histopathological findings: ~hypertensive nephrosclerosis
[glomerular sclerosis, IFTA and arteriosclerosis].

34. ↑Atypical glomerular
changes
↑Increase in GBM width
and mesangial expansion
↑Diffuse and nodular
lesions
tubulointerstitial and
vascular lesions
Non-proteinuric
or non-
albuminuric
DKD

35. Non-proteinuric or non-albuminuric DKD
1. Absence of classic diabetic glomerulosclerosis.
2. Tubulointerstitial changes: interstitial fibrosis, ischemic vascular
disease, tubulointerstitial nephritis & cholesterol emboli.
(Retnakaran R, Boronat M , Kramer et al. 39,21,36% no
albuminuria)
3. *Well-preserved tubules (Budhiraja et al): significant
reabsorption of albumin from the glomerular filtrate

36. Non-diabetic Kidney Disease (NDKD)
• Independent of, or superimposed on DN.
• Glomerular causes:
(IgA) nephropathy, membranous nephropathy, MPGN, acute
interstitial nephritis (AIN), hypertensive renal disease, FSGS,
crescentic glomerulonephritis [ANCA-associated disease and anti-
GBM glomerulonephritis].
• Prevalence and type of NDKD reported in the literature is highly
variable.
In China, IgA nephropathy>MN, mesangial proliferative
glomerulonephritis, hypertensive nephrosclerosis, MCD, FSGS
and crescentic glomerulonephritis.
In United States, FSGS, ATN and IgA nephropathy; hypertensive
nephrosclerosis, MCD, and MN also.

37. DM accompanied with Nondiabetic Renal
Disease (NDRD)
• Proliferative changes, tubulointerstitial disease
• Granular/chunky patterns of immunoglobulin by IF or
electron-dense deposits by EM - superimposed nondiabetic renal
disease.

38. Diabetic nephropathy with superimposed MPGN

39. Diabetic nephropathy with IgA nephropathy

40. Diabetic nephropathy with membranous nephropathy

41. DKD in Renal Allograft
• Recurrent or de-novo (10% and 46%).
• Pathologic findings similar to those in native kidneys.
• + vascular and tubulointerstitial changes caused by allograft
rejection, viral infection, or calcineurin inhibitor nephrotoxicity.
thickening of GBM and TBM- 1st sign of DKD
ECM accumulates - nodular mesangial changes-
compression of glomerular capillaries
glomerular sclerosis and obliteration of capillary
lumina
mesangial matrix expansion
Hyalinosis+ chronic tubulointerstitial changes

42. Key-messages
Renal biopsy is of immense utility for nephrologists and
endocrinologists.
The renal tissue may exhibit any of the wide spectrum of
histologies.
Morphological findings largely correlate with clinical severity and
disease progression.