Histological appearance of Diabetic Nephropathy

The histological lesions of classical diabetic nephropathy (DN) have a characteristic pattern that can be identified by light and electron microscopy. Although much of the literature concentrates on the structural changes seen in the glomerulus, abnormalities are also found in the tubulointerstitium, particularly at later stages of disease. Early in DN there is thickening of the glomerular basement membrane and as disease progresses mesangial expansion occurs, resulting in the loss of available filtration surface. In more advanced DN, there is arteriolar hyalinosis, interstitial fibrosis and global glomerular sclerosis. In the majority of type 1 patients the clinical manifestations of diabetic nephropathy - the loss of protein into the urine (albuminuria), increasing blood pressure and a decline in renal function (measured by the glomerular filtration rate (GFR)), - correlate with the characteristic structural parameters of DN. However, many type 2 patients with progressive CKD do not have albuminuria and the histological pattern of renal injury follows a non-classical route.

Glomerular lesions

Glomeruli are composed of a network of capillaries supported by a framework of mesangial tissue. In diabetic nephropathy, the major structural abnormality seen by light microscopy is mesangial expansion. This increase in mesangial tissue is due to both cell proliferation and increased matrix deposition. As disease progresses however, matrix accumulation is the predominant mesangial change[1] The lesions can be identified as either diffuse or nodular. The diffuse glomerular lesion appears as an expansion of mesangial tissue that extends into the capillary loops, thus reducing the area available for filtration. The Kimmelsteil-Wilson (KW) nodule is a well demarcated structure located in the central regions of peripheral glomerular lobules. It is generally acellular but there may be a few mesangial cells located at the edge. The KW nodule is almost specific to diabetic nephropathy but is present in only 20 – 67% of patients with the diffuse lesion.

Mesangial expansion results in a loss of filtration surface and therefore could explain in part the fall in GFR. Glomerular enlargement is a recognised feature of DN and occurs both early and late in the disease process. It could be an adaptive response to loss of filtration surface or simply a direct result of expanding mesangium. If it is an adaptive response, it could mean that overall filtration surface remains stable and it has been suggested that loss of glomeruli to sclerosis and changes in the filtration capacity of the capillary wall are more likely to be responsible for GFR changes.

The filtration barrier

Each capillary loop consists of a glomerular basement membrane (GBM) lined by fenestrated endothelium and covered by visceral epithelial cells or podocytes. These three distinct layers - the inner endothelium, the central GBM, and the outer epithelial podocytes – form the glomerular filtration barrier. The podocytes possess interdigitating foot processes separated by filtration slits or pores. The filtration slit diaphragm is a specialised intercellular junction spanning the filtration slit. Filtration of plasma occurs via the endothelial fenestrae, across the basement membrane and through the filtration slits into the urinary space. The filtration barrier acts as a type of molecular sieve, allowing only small molecules that lack a high negative charge to pass through. It is likely that alterations to all components of the filtration barrier play a part in the development of DN.

Thickening of the GBM is present in almost all diabetic patients, irrespective of whether they have nephropathy, and can be demonstrated by electron microscopy as early as 2 years after diagnosis of type 1 diabetes[2]. There is a change in the composition of the GBM - there is an increase in type IV collagen and a decrease in both laminin and heparan sulphate proteoglycan (HSPG). The HSPGs provide the GBM with most of its anionic charge therefore the loss of this charge from the GBM is likely to be a major factor in allowing the permeation of albumin across the filtration barrier. However, recently the exact location of the charge-selective components has been questioned, with interest being directed at the endothelial cells. The fenestrae of the endothelial cells are coated in a 200-400nm thick endothelial surface layer, which comprises a membrane bound glycocalyx composed of proteoglycans and a loosely attached layer composed of proteoglycans, glycosaminoglycans and glycoproteins. These provide the endothelium with an anionic charge and thus a barrier to macromolecules[3]. Endothelial fenestration is decreased in type 1 diabetic patients[4] and there is indirect evidence that the glycocalyx could be involved[5].

Changes in the epithelial side of the glomerular filtration barrier have been demonstrated in patients with DN and correlate with proteinuria. There is widening or ‘effacement’ of the podocyte foot processes with a decrease in filtration slit length, a change that becomes more marked as the disease progresses[6]. Podocyte foot process effacement (FPE) is caused by changes in the actin cytoskeleton and this, together with structural alterations to the slit diaphragm, result in proteinuria. Podocyte FPE should be reversible as long as the podocytes themselves remain intact. Extensive podocyte damage however will eventually lead to podocyte loss and in diabetic patients there is a reduction in the number of podocytes as disease progresses[7]. There is evidence to suggest that podocytes are incapable of regenerative replication and loss of podocytes for any reason would not be replaced, resulting in areas of bare GBM. These areas of denuded GBM would then become attached to the parietal epithelial cells of Bowman’s capsule and thus open the glomerular tuft to the interstitium. Capillaries contained in this tuft adhesion would then deliver their filtrate directly into the interstitium, which could contribute to interstitial fibrosis[8].

Tubulointerstitial lesions

Studies have suggested that tubulointerstitial damage is not simply an aftermath of glomerular injury, but that tubular cells may be primary targets for various pathophysiological influences[9]. Pathological changes seen in diabetic nephropathy are thickening of the tubular basement membrane, tubular atrophy, interstitial fibrosis, and arteriolar sclerosis. Although there is a correlation between interstitial expansion and mesangial expansion, the impact of interstitial expansion is thought to be additive suggesting an independent effect on renal function.

Arteriolar lesions are prominent in diabetes, with hyaline material progressively replacing the entire wall. Accumulation of matrix results in fewer smooth muscle cells and therefore the arterioles may be less able to respond to changes in systemic pressure. This results in increased glomerular capillary pressure leading to glomerular injury. Arteriolar changes have been demonstrated in type 1 patients with microalbuminuria and without hypertension, and occur in both afferent and efferent arterioles[10]. Arteriolar hyalinosis correlates with the percentage of globally sclerosed glomeruli, suggesting a role for vascular lesions and ischaemia in their pathogenesis.

Heterogeneity of structural lesions in diabetic kidney disease with and without albuminuria

Microalbuminuria is the first clinical sign of DN. However, some type 1 diabetic patients with long-standing diabetes and normoalbuminuria have glomerular lesions similar to those with microalbuminuria[11]. In addition, some type 2 patients can have significant kidney dysfunction despite being normoalbuminuric. In these patients, glomerular lesions are less common – there is little mesangial expansion and the GBM width is within the normal range. Structural changes are more likely to be predominantly interstitial or vascular suggesting that other factors such as age, blood pressure and vascular disease play a role in declining renal function[12].

In patients with clinical proteinuria, structural–functional relationships are similar in type 1 and 2 diabetic patients. However, there is greater heterogeneity of both structural lesions and GFR in type 2 patients. The majority of type 1 patients with DN have typical glomerular lesions, with the severity of lesion relating to the level of albuminuria and the decline in GFR. However, some type 2 patients have a relatively well preserved GFR despite increased proteinuria and blood pressure. The renal structural changes in these patients can range from near-normal to typical DN with predominantly glomerular changes, or severe tubulointerstitial damage with little glomerular change[13].

References

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  2. ^ Østerby R. Morphometric studies of the peripheral glomerular basement membrane in early juvenile diabetes. I. Development of initial basement membrane thickening. Diabetologia 1972; 8:84-92.

  3. ^ Hjalmarsson C, Johansson BR, Haraldsson B. Electron microscopic evaluation of the endothelial surface layer of glomerular capillaries. Microvasc Res 2004; 67:9-17.

  4. ^ Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M. Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. Diabetes 2007; 56:2155-2160.

  5. ^ Broekhuizen LN, Lemkes BA, Mooij HL, Meuwese MC, Verberne H, Holleman F, Schlingemann RO, Nieuwdorp M, Stroes ES, Vink H. Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia 2010; 53:2646-2655.

  6. ^ Bjorn SF, Bangstad HJ, Hanssen KF, Nyberg G, Walker JD, Viberti GC, Osterby R. Glomerular epithelial foot processes and filtration slits in IDDM patients. Diabetologia 1995; 38:1197-1204.

  7. ^ White KE, Bilous RW, Marshall SM, El Nahas M, Remuzzi G, Piras G, De Cosmo S, Viberti G. Podocyte number in normotensive type 1 diabetic patients with albuminuria. Diabetes 2002; 51:3083-3089.

  8. ^ Kriz W, Gretz N, Lemley KV. Progression of glomerular diseases: Is the podocyte the culprit? Kidney Int 1998; 54:687-697.

  9. ^ Nath KA. The tubulointerstitium in progressive renal disease. Kidney Int 1998; 54:992-994.

  10. ^ Østerby R, Bangstad H-J, Nyberg G, Walker JD, Viberti GC. A quantitative ultrastructural study of juxtaglomerular arterioles in IDDM patients with micro- and normoalbuminuria. Diabetologia 1995; 38:1320-1327.

  11. ^ Chavers BM, Bilous RW, Ellis EN, Steffes MW, Mauer SM. Glomerular lesions and urinary albumin excretion in type I diabetes without overt proteinuria. N Engl J Med. 1989; 320:966-970.

  12. ^ Ekinci EI, Jerums G, Skene A, Crammer P, Power D, Cheong KY, Panagiotopoulos S, McNeil K, Baker ST, Fioretto P, Macisaac RJ. Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care. 2013; 36:3620-3626.

  13. ^ Nosadini R, Velussi M, Brocco E, Bruseghin M, Abaterusso C, Saller A, Dalla Vestra M, Carraro A, Bortoloso E, Sambataro M, Barzon I, Frigato F, Muollo B, Chiesura-Corona M, Pacini G, Baggio B, Piarulli F, Sfriso A, Fioretto P. Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes. 2000; 49:476-484.

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