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5
Renal Structural Damage in
IDDM and NIDDM
Functional Relationships
RUDY BILOUS
INTRODUCTION
Although the classical glomerular pathological lesions of nodules and diffuse
mesangial expansion were recognized in patients with nephropathy in the
1930s and 1940s, structural abnormalities in the diabetic kidney had been
noted 50 years earlier (1). The first of these was glycogen deposition in the
tubules, reported in 1877, and this was quickly followed by descriptions of
glomerular and interstitial abnormalities long before the seminal observation
of nodules by Kimmelstiel and Wilson in 1936 (2). By 1960, early studies with
the electron microscope had revealed marked glomerular basement membrane thickening (GBMT) in diabetic patients, and this finding is now recognized as a sine qua non for diabetic glomerulopathy. For the most part, the
pathological changes in the diabetic kidney are similar for both IDDM (type
1) and NIDDM (type 2). Indeed, the first descriptions were in the pre-insulin
era and must of necessity have been in NIDDM patients. This chapter will
briefly outline the pathological changes in the diabetic kidney seen in both
types of diabetes, but will point out any contrasts between IDDM and
NIDDM where they occur. It will use the definitions of nephropathy, as a
clinical diagnosis based upon the finding of proteinuria, and glomerulopathy,
which describes the pathological changes occurring in the glomerulus.
Diabetic Nephropathy. Edited by C. Hasslacher.
# 2001 John Wiley & Sons, Ltd.
72
MICROSCOPIC CHANGES
GlomerulusLight Microscopy
There are 3501050 106 glomeruli in the normal kidney (7), and each
comprises a convoluted knot of capillaries supported on a scaffold of
mesangium, made up of cellular and matrix components (Figure 5.1a).
Blood enters the glomerulus via one or more afferent arterioles and leaves
via usually one efferent vessel. Each capillary comprises a basement membrane, which is continuous with the mesangium and is lined by a fenestrated endothelium (Figure 5.2). The outer surface of the basement
membrane is covered by an epithelium of interdigitating foot processes
(Figure 5.3). No two adjacent foot processes arise from the same epithelial
cell, and they are separated by a narrow filtration slit and membrane. The
glomerular tuft is surrounded by Bowman's capsule, which is continuous
with the basement membrane of the proximal convoluted tubule. Haemofiltration occurs from within the capillary, through the endothelial fenestrae,
across the basement membrane, through the filtration slits and across the
filtration membrane, into the urinary space defined by Bowman's capsule,
and thus into the tubular part of the nephron.
Like global nephromegaly, glomerular enlargement occurs within days of
onset of experimental diabetes (8). It is also a feature of IDDM patients with
short diabetes duration. Animal studies suggest that most of the enlargement is due to an increase in capillary length and diameter, although minor
73
50mm
CD
M
50mm
74
N
N
BC
50mm
Figure 5.1 PAS-stained light micrographs of semi-thin sections. (A) Normal renal
glomerulus. (B) Diffuse mesangial expansion (M). Note reduction in number of open
capillary loops. Also present is a capsular drop (CD). (C) KimmelstielWilson nodule
(N). Note also thickened Bowman's capsule (BC) and capillary basement membrane
(arrowed)
75
76
PC
PC
structures and are usually located at the periphery of the tuft (1, 2) (Figure
5.1c). This location is distinct from the pattern of lesion seen in other glomerulopathies, where most of the abnormalities are more central (12). The pathogenesis of nodules is unclear but they may represent obliterated capillary
micro-aneurysms. An alternative hypothesis is that mesangial expansion
disrupts endothelial cell attachment, resulting in them ballooning into the
capillary lumen, quickly followed by mesangial matrix material (13).
Finally, it is not uncommon to see accumulations of PAS-positive material
arranged in so-called ``capsular drops'' between the basement membrane
and parietal epithelial cells of Bowman's capsule (Figure 5.1b). Their presence is non-specific, however, and their pathological significance unclear.
GlomerulusElectron Microscopy
With the greater magnification possible with the electron microscope, much
of the mesangial expansion can be seen to be due to an accumulation of
amorphous matrix material (Figure 5.4). Normally, mesangial matrix com
77
M
M
5mm
78
EC
RBC
GBM
2mm
79
80
81
patients. Two small studies showed an increase in interstitium in conventionally treated patients that was not observed in those given ACEI (23, 24).
These results imply that an important pathological abnormality of nephropathy is able to be influenced by antihypertensive treatmentperhaps by
inhibition of growth factorsand may provide clues as to the pathophysiology of nephropathy.
Ptf
pgc
ptf
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0
0
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ACKNOWLEDGEMENTS
My thanks to Mrs K. White, of the Biomedical Electron Microscopy Unit of the
University of Newcastle upon Tyne, for providing the photomicrogaphs
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