Alex Kolesar Diabetes Information

The nodular lesion

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As the volume of the mesangial matrix increases, some mesangial regions become more prominent than others and may take on a globular shape (figure 2). The mesangial nodule is thus created by a gradual increase of the diffuse lesion and the distinction between them is arbitrary. Several nodules may be present in each glomerulus, but usually only a few of the mesangial regions are affected in this way

The nodules are distributed in a horseshoe-shaped area corresponding to the peripheral mesangium [12]. The other mesangial regions present the diffuse lesion. Small nodules contain evenly distributed mesangial cells, but in medium-sized or large nodules, the central areas are almost always acellular.

The periphery of the nodule contains one or a few layers of mesangial cells. Around the nodule, a ring of capillaries is present and they may be dilated. It has been suggested that the formation of the nodule is preceded by focal mesangiolysis [13,14].

Fig. 2. Diabetic glomerulopathy. The diffuse component is more marked than in figure 1 and a nodule has been formed from a particulary voluminous region. PAS-haematoxylin.

The fibrinous cap

Insudative or exudative lesions consists of deposits of plasma proteins and lipids within renal arterioles (arteriolar hyalinosis), glomerular capillaries (fibrinoid or fibrin cap) and Bowman's capsule (capsular drop). The fibrin cap [8,9,15-17] is situated in the peripheral capillary wall and has a crescentic shape (figure -3).

If the basement membrane is stained by silver methenamine, the cap appears to be situated between this and the endothelium. Its structure is homogeneous although small vacuoles may be seen in which lipids can be demonstrated in frozen sections stained by oil-red.

Fig. 3. Fibrinoid cap in diabetic glomerulopathy. Totally obsolescent glomerulus with several fibrinoid caps, one of them indicated by an arrow. The crescent-shaped pale area to the left is subcapsular, fibrotic tissue. The PAS-positive glomerular basement membranes form a solid, retracted tuft. PAS-haematoxylin.

The capsular drop

This lesion [1,3] is situated on the inner side of the capsule of Bowman. It sometimes looks like a drop (figure 4), but it may also be more extended, as a slender, fusiform deposit. Its outer border is formed by the capsule of Bowman; its inner projects toward the urinary space.

Arteriolar hyalinosis

In the early stage of arteriolar hyalinosis (or hyaline arteriolosclerosis), small drops of strongly eosinophilic material accumulate in the wall of the juxtaglomerular arterioles. They may be situated in the intima or in the media. They gradually increase in size and eventually involve the whole arteriolar wall, which then appears as a strongly thickened, homogeneous structure. Arteriolar hyalinosis in diabetes involves the afferent arteriole as well as the efferent arteriole (figure 5).

Fig. 4. Capsular drop in diabetic glomerulopathy. A large, drop-shaped deposit (arrow). PAS-haematoxylin.

Fig. 5. Arteriolosclerosis in diabetes. There is moderate hyaline arteriolosclerosis in both the afferent (double arrow) and the efferent (arrow) arterioles. A, interlubular artery. PAS-haematoxylin.

Staining characteristics and histochemistry

Histochemical studies have been published by several authors [10,17,18]. The most important results are presented in table 1. The fibrinoid cap, capsular drop, and arteriolar hyalinosis are identical in staining characteristics, which is why some authors have included them in one group.

Immunoflourescence microscopy (IF) shows often IgG in a fine linear pattern along the glomerular capillary walls [19-21]. This reaction is considered to be unspecific since albumin can also be detected in the same location and IgG cannot be eluded. The nodules are negative. Exudative lesions are positive for C3, ^-lipoprotein and (weakly) for IgG [21]. Insulin or anti-insulin is not detectable by IF in the glomeruli [20,21].

Table 1 Staining characteristics of diabetic glomerular lesions

Stain	Diffuse	Nodular	Exudative3
Haematoxylineosin	+red	+red	++red
V Gieson-Hansen	+red	+red	++yellow
Masson-trichrome	++blue	++blue	+++red
Phosphotungstic	0	0	+++deep blue
acid-haematoxylin
PAS after diastase	++	++	+++
Silver-	++black	+/- black fibrils	0
methenamine		in pale matrix
Alcian-blue	+	0	0
Congo red, other
amyloid stains	0	0	0
Neutral fat	0	occasionally	+ fat vacuoles

aExudative lesions are fibrinoid caps, capsular drops, and arteriolar hyalinosis aExudative lesions are fibrinoid caps, capsular drops, and arteriolar hyalinosis

Ultrastructure

A wealth of important morphometric data have been published on glomerular ultrastructural lesions in DM and their relation to duration of disease, presence of micro- or macroalbuminuria and other clinical parameters. A review of these are presented in other chapters in this book. The following is a brief discussion of the main glomerular lesions seen on electron microscopy [22 - 24].

Glomerular ultrastructure is normal at the onset of IDDM. After about two years, widening of the glomerular basement membrane and expansion of mesangial matrix (increased volume fraction of matrix per mesangium) can be demonstrated by morphometry. The fraction of the glomerular tuft occupied by mesangium, which is normal at the beginning of the disease, begins to increase and this becomes marked after 5 - 10 years in patients with microalbuminuria. Most of this expansion is due to matrix accumulation, but there is some participation of cell volume. A decrease of capillary filtration surface can be demonstrated later on. Nodules are composed of mesangial matrix containing very few clefts with cytoplasm of mesangial cells. Foot process width is increased in microalbuminuric compared with normoalbuminuric diabetics and the width of filtration slits is increased in normo- as well as microalbuminuric diabetics compared with control subjects.

Development of the lesions by time

The most powerful determinant for the appearance and development of glomerular and vascular lesions in diabetes is duration of the diabetic state [2]. Diffuse glomerulopathy can be demonstrated by ultrastructural morphometry after a few years of diabetes [26], but is usually not distinct light-microscopically until 5-10 years after the onset of the disease. Nodular glomerulosclerosis demands at least 15 years of diabetes to develop. The nodules tend to disappear with marked glomerular obsolescence. Whereas the precise onset of the diabetic disease is known in insulin dependent diabetes (IDDM) this is not the case with non-insulin dependent diabetes (NIDDM) in which the disease may have been present several years before diagnosis. This is why glomerular nodules may occasionally be seen in patients with a known duration of diabetes of less than 15 years, and they may even occur at the time diagnosis is made. The diffuse lesion and arteriolosclerosis occur in 20% of patients before 5 years have elapsed from the apparent onset [2]. These lesions are non-specific, and thus their presence in a patient suffering from diabetes may be unrelated to the diabetic state.

The fibrinoid cap occurs most frequently in the later stages of glomerulopathy, but, in contradistinction to all other glomerular lesions in this disease, the capsular drop is found almost as often in earlier as in later stages [2].

A peculiar and as yet unexplained fact is that about 60% of patients with longstanding diabetes do not develop clinical nephropathy or diabetic glomerular changes.

The development of glomerulopathy is associated with increasing albuminuria. At the onset of microalbuminuria there is on electron microscopy significant increase in peripheral basement membrane thickness and mesangial volume in relation to glomerular volume. In the stage of macroalbuminuria there is usually distinct light-microscopic glomerular changes. While this is the normal sequence, macroalbuminuria may occur in spite of normal glomerular structure. The situation is not rare, we found it in 13 % of our NIDDM patients with macroalbuminuria [25]. So far no explanation has been given for the increased glomerular capillary permeability in these patients, but endothelial dysfunction or biochemical glomerular basement membrane changes caused by sustained hyperglycemia are obvious candidates

Glomerular structure in the terminal phase

The appearance of glomeruli in advanced diabetic glomerulopathy presents a broad spectrum ranging from totally occluded to almost normal glomeruli. Glomeruli, which are still open, may be hypertrophic and often present global mesangial hypercellularity. Totally occluded glomeruli are not evenly distributed, but tend to be concentrated in radiating stripes parallel to the medullary rays [28]. There is no difference in the severity of glomerular involvement between deep and superficial cortical zones. The total number of glomeruli decreases with progression of the diabetic nephropathy, at least in IDDM [29].

It is important to realize that this terminal pattern is not exclusively due to glomerular alterations specific for diabetes. Ischemic scarring and focal glomerular sclerosis occur and may indicate that causes other than progression of diabetic glomerular lesion may be partially responsible for the development of renal failure, such as vascular constriction with glomerular ischemia and lesions due to hyperfunction of remaining glomeruli.

Specificity of the lesions

The diffuse lesion is completely non-specific and may be present in older people without diabetes. The combination of arteriolosclerosis and the diffuse lesion often occurs in hypertension, but involvement of both the afferent arteriole and the efferent arteriole is regarded as a strong indication of diabetes [6, 30, 31] although even this combination is not entirely specific [15].

All insudative lesions are much more numerous and/or larger in diabetics than in controls but they are not specific. Even capsular drops and hyalinosis of efferent arterioles which have traditionally been regarded as specific lesions may be seen in small numbers in some non-diabetic controls [15].

The nodular lesion is often regarded as pathognomonic for diabetes. It is true that numerous reports of nodular lesions in non-diabetic patients have been published [for a list, see ref. 3]. Most of these reports can be criticized, however, either because of doubt as to absence of diabetes or to lack of application of precise criteria for the morphologic diagnosis. There are, however, well documented cases on record with typical nodular glomerulopathy without diabetes [32, 33].

Although the typical nodular lesion is very strongly associated with diabetes, there exist nevertheless other conditions in which glomerular nodules may occur. Since these may present diagnostic difficulties, they will be briefly mentioned here. For a detailed report and illustrations, the reader is referred to an earlier publication [34].

In renal amyloidosis, abnormal homogeneous substance is deposited in the peripheral as well as mesangial parts of the glomerular capillary walls. In rare cases, the deposits may take on the shape of typical diabetic nodules with an acellular center. They can be correctly classified by the use of amyloid stains and by demonstration of typical fibrils on electron microscopy.

Some types of advanced glomerulonephritis (mesangial proliferative, membrano-proliferative) have a histology that resembles nodular glomerulosclerosis. In glomerulonephritis, however, there is a distinct hypercellularity and the central, acellular area that is so characteristic for diabetes is not present. Nodules in glomerulonephritis involve all mesangial areas and are of almost equal size. Immunodeposits are usually present, but are faint or absent in diabetes.

Glomerular nodules may also be present in various dysproteinemias (e.g. multiple myeloma and heavy-chain disease [35-40].

The clinical picture may often solve the diagnostic problem, but the occurrence of glomerular nodules in these diseases should be a reminder to the pathologist not to postulate the presence of diabetes on the prima facie detection of nodular structures in the glomeruli.

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