Diabetic nephropathy pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The hallmark of diabetic nephropathy is mesangial expansion. Nonetheless, diabetic nephropathy is characterized by the presence of abnormalities in the glomeruli, such as glomerular hypertrophy, in the tubules and interstitium, such as tubular atrophy and interstitial fibrosis, and in the blood vessels, such as arteriosclerosis in both the afferent and the efferent renal arteries. Findings on histopathological analysis may be evident very early in diabetes, but are often clinically present approximately 15 years after the onset of metabolic abnormalities. A 2010 classification has been proposed that correlated the histopathological findings with the severity of disease.

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. This process is called "GBM thickening", a linear process that is caused by the accumulation of extracellular matrix. 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. While an increase in cellularity is often observed early in the disease, mesangial expansion without hypercellularity is common as the disease further progresses. 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.

Advanced diabetic nephropathy is typically seen approximately 15 years after the onset of diabetes type I. It is characterized by the abundant sclerosis of the mesangium and mesangial expansion in an irregular nodular (round/oval) pattern, called Kimmelstiel-Wilson nodules. These nodules are acellular or pauci-cellular nodules with a lamellated appearance that stain positively by silver methenamine stain. 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.

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

• 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. 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. Podocyte injury first starts with widening of the podocyte foot processes with consequent detachment from the GBM.24) As podocytes are lost, glomerulotubular junctions are exposed to further injury and formation of atubular glomeruli. 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.

The following table distinguishes renal findings in type I vs. type II diabetes mellitus:

Distinguishing Type I vs. Type II Diabetic Nephropathy

Type of Diabetes	Frequency	Heterogeneity	Severity of Glomerulopathy
Type I	*20% of diabetes-related ESRD *Renal lesions more frequently attributed to diabetes	Usually less heterogenous lesions	*More severe *Clinical severity associated with renal findings
Type II	*80% of diabetes-related ESRD *Renal lesions may often be non-diabetic	Usually more heterogeneous lesions	*Less severe *Clinical severity and association with renal findings is variable

^{Adapted from Najafian B, Alpers CE, Fogo AB. Pathology of human diabetic nephropathy. Contrib Nephrol. 2011;170:36-47}

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). 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.

The following table summarizes a classification system proposed in 2010 that correlates histopathological findings with severity of diabetic nephropathy:

Classification of Diabetic Nephropathy According to Histopathological Findings (2010)

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:

Glomerular Lesions

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

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

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