Diabetic nephropathy pathophysiology

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Pathophysiology

The onset of diabetic nephropathy generally takes place at least 15 years after the onset of diabetes mellitus. The pathogenesis of diabetic nephropathy occurs in distinct stages. Early pathogenesis - which may start as early as 2 years after the onset of diabetes - may include no visible lesions with mild global and diffuse hypertrophy of the renal glomeruli only.[1] This process is called "GBM thickening", a linear process that is caused by the accumulation of extracellular matrix.[1][2] These changes may not be detectable by light microscopy and require electron microscopy to identify. When the accumulation of the extracellular matrix becomes significant, pathological changes on light microscopy will be evident, typically first seen 5 years after onset of type 1 diabetes and usually occurs at a faster frequency after 15 years of onset.[3][4][5] While an increase in cellularity is often observed early in the disease, mesangial expansion without hypercellularity is common as the disease further progresses.[6] Disorganized mesangial expansion - the hallmark of diabetic nephropathy - is not a linear process and is in fact the result of a vicious circle that is characterized by the presence of frequently mesangiolysis followed by the formation of micro-aneurysms and balloon formation of glomeruli, hyaline accumulation, and mesangial repair with concomitant thickening of the GBM lamina densa.[7]

Advanced diabetic nephropathy is typically seen approximately 15 years after the onset of diabetes type I.[8] It is characterized by the abundant sclerosis of the mesangium and mesangial expansion in an irregular nodular (round/oval) pattern, called Kimmelstiel-Wilson nodules.[6] These nodules are acellular or pauci-cellular nodules with a lamellated appearance that stain positively by silver methenamine stain.[6] They are a non-specific finding in diabetic nephropathy but are frequently found in glomerular tufts in up to 25% of patients with advanced diabetic nephropathy.[6]

Of note, Kimmelsteil-Wilson nodules may be found in several disease entities, as listed below[9][10]:

  • Diabetic nephropathy
  • Multiple myeloma and other gammopathies
  • Membranoproliferative glomerulopathies
  • Post-infectious glomerulonephritis
  • Amyloidosis
  • Idiopathic nodular glomerulosclerosis in patients with no renal disease

Hyalinosis, defined as the exudation of hyaline material (usually lipid particles) between the basement membrane of Bowman's capsule and the parietal epithelium.[6] Meanwhile, the irreversible loss of podocytes plays a crucial role in the disease pathogenesis and the clinical finding of proteinuria in patients with diabetic nephropathy.[11] Podocyte injury first starts with widening of the podocyte foot processes with consequent detachment from the GBM.[11]24) As podocytes are lost, glomerulotubular junctions are exposed to further injury and formation of atubular glomeruli.[12][13] Typically, patients with diabetic nephropathy do not demonstrate any specific findings on immunofluorescence, but IgG deposition is common in these patients. The presence of IgG is not believed to be a cause of the disease, but rather as a by-product due to the presence of an abnormal sticky GBM.[6]

Histopathological findings directly correlate with clinical signs and symptoms. The extent of mesangial expansion is inversely associated with the estiamted glomerular filtration rate (GFR) and albumin excretion rate (AER).[14][15][16] Podocyte injury is also correlated with the degree of proteinuria in diabetic patients; proteinuria is frequently seen when more than 20% of podocytes are denuded from the GBM.[11]


Classification of Diabetic Nephropathy According to Histopathological Findings (2010)[8]
Class Findings Inclusion Criteria
I *Thickening of GBM on electron microscopy
*Mild or no changes on light microscopy		 *Biopsy does not meet criterial mentioned for class II, III, or IV
*GB width by electron microscopy measuring > 395 nm in female and > 430 nm in male patients aged 9 years and above
IIa Mild mesangial expansion *Biopsy does not meet criteria for class III or IV
*Mild mesangial expansion in > 25% of observed mesangium
IIb *Severe mesangial expansion *Biopsy does not meet criteria for class III or IV
*Severe mesangial expansion in > 25% of observed mesangium
III Nodular sclerosis (Kimmelstiel-Wilson nodules) *Biopsy does not meet criteria for class IV
*At least one Kimmelstiel-Wilson nodule
IV Advanced diabetic glomerulosclerosis *Global glomerular slerosis in > 50% of glomeruli
*Lesions from classes I through III
Adapted from Tervaert TW, Mooyaart AL, Amann K, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010;21(4):556-63



In summary, a list of renal abnormalities may ensue following the metabolic abnormalities in diabetes[6]:

Glomerular Lesions[6]

Light Microscopy

  • Glomerular hypertrophy and possible hypercellularity
  • Thickened capillary basement membranes
  • Diffuse irregular mesangial expansion and sclerosis
  • Nodular mesangial sclerosis
  • Mesangiolysis
  • Capillary micro-aneurysms
  • Hyaline deposition

Immunofluorescence

  • Linear staining of capillary basement membrane for IgG
  • Linear staining of capillary basement membrane for albumin

Electron Microscopy

  • Thickened basement membranes
  • Increased mesangial extracellular matrix and possible hypercellularity
  • Non-amyloidotic extracellular matrix
  • Podocyte loss

Lesions of Tubules & Interstitium[6]

Light Microscopy

  • Atrophy
  • Thickened tubular basement membrane
  • Interstitial fibrosis

Immunofluorescence

  • Linear staining of tubular basement membrane for IgG
  • Linear staining of tubular basement membrane for albumin

Electron Microscopy

  • Thickened tubular basement membranes
  • Increased presence of interstitial collagen
  • Tubular atrophy

Blood Vessels[6]

Light Microscopy

  • Hyalinosis of afferent and efferent arterioles
  • Intimal sclerosis

Immunofluorescence

  • No specific changes

Electron Microscopy

  • Subendothelial and transmural hyaline arterial deposition in small arteries and arterioles
  1. ↑ 1.0 1.1 Drummond K, Mauer M, International Diabetic Nephropathy Study Group (2002). "The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes". Diabetes. 51 (5): 1580–7. PMID 11978659.
  2. ↑ Hørlyck A, Gundersen HJ, Osterby R (1986). "The cortical distribution pattern of diabetic glomerulopathy". Diabetologia. 29 (3): 146–50. PMID 3699305.
  3. ↑ østerby R (1974). "Early phases in the development of diabetic glomerulopathy". Acta Med Scand Suppl. 574: 3–82. PMID 4533587.
  4. ↑ Mauer SM, Sutherland DE, Steffes MW (1992). "Relationship of systemic blood pressure to nephropathology in insulin-dependent diabetes mellitus". Kidney Int. 41 (4): 736–40. PMID 1513095.
  5. ↑ Drummond KN, Kramer MS, Suissa S, Lévy-Marchal C, Dell'Aniello S, Sinaiko A; et al. (2003). "Effects of duration and age at onset of type 1 diabetes on preclinical manifestations of nephropathy". Diabetes. 52 (7): 1818–24. PMID 12829652.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 Najafian B, Alpers CE, Fogo AB (2011). "Pathology of human diabetic nephropathy". Contrib Nephrol. 170: 36–47. doi:10.1159/000324942. PMID 21659756.
  7. ↑ Alpers CE, Hudkins KL (2011). "Mouse models of diabetic nephropathy". Curr Opin Nephrol Hypertens. 20 (3): 278–84. doi:10.1097/MNH.0b013e3283451901. PMC 3658822. PMID 21422926.
  8. ↑ 8.0 8.1 Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB; et al. (2010). "Pathologic classification of diabetic nephropathy". J Am Soc Nephrol. 21 (4): 556–63. doi:10.1681/ASN.2010010010. PMID 20167701.
  9. ↑ Kimmelstiel P, Wilson C (1936). "Intercapillary Lesions in the Glomeruli of the Kidney". Am J Pathol. 12 (1): 83–98.7. PMC 1911022. PMID 19970254.
  10. ↑ Alpers CE, Biava CG (1989). "Idiopathic lobular glomerulonephritis (nodular mesangial sclerosis): a distinct diagnostic entity". Clin Nephrol. 32 (2): 68–74. PMID 2766585.
  11. ↑ 11.0 11.1 11.2 Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M (2007). "Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy". Diabetes. 56 (8): 2155–60. doi:10.2337/db07-0019. PMID 17536064.
  12. ↑ Najafian B, Crosson JT, Kim Y, Mauer M (2006). "Glomerulotubular junction abnormalities are associated with proteinuria in type 1 diabetes". J Am Soc Nephrol. 17 (4 Suppl 2): S53–60. doi:10.1681/ASN.2005121342. PMID 16565248.
  13. ↑ Najafian B, Kim Y, Crosson JT, Mauer M (2003). "Atubular glomeruli and glomerulotubular junction abnormalities in diabetic nephropathy". J Am Soc Nephrol. 14 (4): 908–17. PMID 12660325.
  14. ↑ Mauer SM, Steffes MW, Ellis EN, Sutherland DE, Brown DM, Goetz FC (1984). "Structural-functional relationships in diabetic nephropathy". J Clin Invest. 74 (4): 1143–55. doi:10.1172/JCI111523. PMC 425280. PMID 6480821.
  15. ↑ Ellis EN, Steffes MW, Goetz FC, Sutherland DE, Mauer SM (1986). "Glomerular filtration surface in type I diabetes mellitus". Kidney Int. 29 (4): 889–94. PMID 3712971.
  16. ↑ Caramori ML, Kim Y, Huang C, Fish AJ, Rich SS, Miller ME; et al. (2002). "Cellular basis of diabetic nephropathy: 1. Study design and renal structural-functional relationships in patients with long-standing type 1 diabetes". Diabetes. 51 (2): 506–13. PMID 11812762.
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