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Diabetic Nephropathy, Edited by Christoph Hasslacher

Copyright # 2001, John Wiley & Sons, Ltd

ISBNs: 0471489921 (Hardback); 0470846445 (Electronic)

Renal Structural Damage in
Functional Relationships

University of Newcastle upon Tyne, UK

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.


Natural Course, Pathogenesis, Morphology and Genetics


Whole kidney enlargement (nephromegaly) is an early feature of both
experimental and human diabetes (3, 4). In animals, nephromegaly occurs
within 4 days of diabetes onset and most IDDM patients have large kidneys
at diagnosis. This enlargement is mostly due to a combination of tubular
hypertrophy and hyperplasia and interstitial expansion, and is probably a
response to increased glucose and fluid filtration and their active reabsorption.
Glomeruli only account for 1% of total kidney volume, so their contribution to whole organ enlargement is insignificant.
Renal scarring and papillary necrosis are more common in diabetic
patients, especially women, and may result from an increased prevalence
of urinary tract infection (5). Rates of bacteriuria of up to 20% have been
reported in some hospital series.
Finally, atherosclerosis of the renal arteries severe enough to cause functional renal artery stenosis has been described in some NIDDM patients (6).

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

Renal Structural Damage






Natural Course, Pathogenesis, Morphology and Genetics





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

increases in mesangial volume have also been described. GBMT is

unchanged over this period, which implies a significant increase in the
production of matrix material in order to accommodate the observed change
in capillary dimensions (8).
Glomerular enlargement is also a feature of late diabetic nephropathy,
particularly in NIDDM patients (9). Mean values of up to 4  106 mm3 in
IDDM and > 6  106 mm3 in NIDDM have been reported. These contrast
with values of 12.3  106 mm3 reported in non-diabetic control subjects of
the same studies (9, 10). Why NIDDM patients with nephropathy should
demonstrate a greater capacity for glomerular enlargement is unclear.
Indeed, the mechanisms underpinning increases in glomerular size are
unknown. Early changes may be secondary to haemodynamic perturbations, whereas later enlargement may be a compensatory response to
capillary loss due to mesangial expansion and global glomerulosclerosis.
Diffuse mesangial expansion, with or without nodule formation, is the
hallmark of diabetic glomerulopathy (1). An accumulation of periodic acid

Renal Structural Damage


Figure 5.2 Scanning electron micrograph from a freeze-fractured rat glomerulus

revealing the endothelial lining of a capillary. Note fenestrated endothelium
(arrowed). E, endothelial cell

Schiff (PAS)-positive staining matrix material is seen to a greater or lesser

extent in all patients with nephropathy. In its early stages, the accumulation
tends to be in the centre of the glomerular tuft, and the capillary loops
become marginalized to the periphery (Figure 5.1b). Eventually, the remaining capillaries are also obliterated by mesangial tissue encroaching along the
endothelial surface.
The end result of advanced glomerulopathy is a hyalinized glomerulus
with no obvious capillary loops. This global sclerosis is probably secondary
to two processes that may occur in differing proportions in individual
glomeruli and different patients; these are ischaemia secondary to arteriolar
hyalinosis, and obliteration secondary to mesangial expansion (11). The
former process results in a collapsed-looking glomerulus with crenated
basement membranes, while the latter results in a larger, more amorphous
structure. Eventually, such glomeruli are completely reabsorbed.
Nodule formation is highly specific for diabetic glomerulopathy, but is
not an invariable finding and always occurs on the background of diffuse
mesangial expansion. Nodules appear as acellular, eosinophilic, lamellated


Natural Course, Pathogenesis, Morphology and Genetics



Figure 5.3 Scanning electron micrograph from a freeze-fractured rat glomerulus

showing interdigitating foot processes (arrowed) on the epithelial side of a capillary.
PC, podocyte

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

Renal Structural Damage




Figure 5.4 Low-power electron micrograph from a patient with nephropathy

showing a glomerular lobule comprising three capillaries with thickened glomerular
basement membrane (arrowed). Note the central mesangium (M) expanding into the
capillaries, reducing the available filtration surface area of the peripheral basement

prises predominantly type IV collagen, with smaller proportions of laminin,

fibronectin and entactin, and the proteoglycans chondroitin and dermatan
sulphate (1). This matrix is arranged around a dense mesh of microfibrils,
which form a plexus around the mesangial cells. At the mesangialendothelial cell interface and the attachment points of the capillary basement membrane, the microfibrils are much more tightly organized (14). This
arrangement lends itself to the various functions of the mesangium, such
as providing a support for the capillaries that is contractile and thus able to
adjust the tension in the basement membrane, and forming a mesh that can
entrap, neutralize and dispose of circulating macromolecules and pathogens. Matrix is produced by epithelial and endothelial cells on the surface of
the GBM, and also by the mesangial cells themselves (15). Degradation and
recycling is a function of the mesangium and also possibly macrophages.
In diabetes, the increase in matrix is secondary to a combination of excess
production and decreased degradation. In addition, its composition differs


Natural Course, Pathogenesis, Morphology and Genetics

from normal, with more type VI collagen and a reduction in proteoglycans,

particularly heparan sulphate (16). Moreover, matrix accumulation disrupts
the microfibrillar structure, altering the porous nature of the mesangium
and weakening the attachments to the endothelium and the GBM. In tissue
culture experiments, these changes can be induced by high ambient glucose,
growth factors such as TGF-b (17), prostanoids such as thromboxane (18),
and advanced glycation end products.
The other obvious feature of glomerulopathy visible using the electron
microscope is capillary basement membrane thickening (Figures 5.4, 5.5).
Normally, the GBM has an electron-dense middle (lamina densa) and less
dense inner (lamina rara interna) and outer (lamina rara externa) layers. It
comprises mainly matrix material of a similar composition to the mesangium and is continuous with it. The main proteoglycan constituent is
heparan sulphate, specifically perlecan. The type IV collagen chains are
arranged in a tight lattice, leaving a small number of pores with a functional
. Much of the permselectivity to circulating
size of approximately 60 A
macromolecules is dependent upon this structure.





Figure 5.5 High-power electron micrograph showing the thickened glomerular

basement membrane (GBM) adjacent to the thin segment (arrowed). Note the
contrasting electron density appearing as two distinct layers in the thin segment.
RBC, red blood cell; EC, endothelial cell

Renal Structural Damage


GBM thickening can be demonstrated in most patients with diabetes,

irrespective of their nephropathy status, although those with heavier proteinuria tend to have thicker membranes (19). It is therefore not as specific a
feature of glomerulopathy as mesangial expansion or nodule formation.
Most of the increase in matrix is due to type IV collagen accumulation.
There is, however, a net loss of proteoglycan, which is also more dispersed
throughout the thicker membranes (20). This loss is thought to result in a
loss of negative electrostatic charge and thus permit the passage of positively charged proteins such as albumin.
Mesangial matrix accumulation can be prevented and reversed in experimental animals treated with insulin or islet transplantation. GBM thickening
can certainly be prevented but resolution is much slower (21). In man,
mesangial expansion and GBMT have been shown to reverse after 10
years of normoglycaemia induced by pancreas transplantation (22). These
observations emphasize the slowness of the rate of turnover of matrix in
vivothe lesions take almost as long to resolve as they do to develop.
Studies of the impact of antihypertensive therapy on renal structure have
failed to show any impact on the lesions, perhaps because the duration
between biopsies was just 3 years (23, 24).
Very much thinner segments of GBM have been seen in some patients
with established nephropathy (25). (Figure 5.5). These segments occasionally appear ``lumpy'' and irregular and are lined with an abnormal endothelium. Their origin is obscure but they could represent micro-aneurysms or
even new capillary growth. They have been associated with asymptomatic
haematuria in non-diabetic subjects (26), but their significance in diabetes is
uncertain. They could provide an area of non-selective leakage of proteins.
There are no obvious changes in endothelial or epithelial cells in glomerulopathy, except that there is a widening of podocyte foot processes. This
development may be a ubiquitous response to increased protein passage
across the GBM, as it is seen in other proteinuric states. The total number of
epithelial cells may also be reduced in patients with glomerulopathy,
and this reduction does not appear to be amenable to glycaemic correction
Tubulo-interstitiumLight Microscopy
The tubular portion of the nephron arises from Bowman's capsule and
continues to the connecting ducts in the renal medulla. Glycogen-rich granules can be seen in the proximal tubular cells in acute diabetes and are the
result of massive glucose reabsorption. They do not occur in insulin-treated
animals (28) and are rarely seen in man. In experimental diabetes there is
an initial tubular hyperplasia of approximately 11%, but after 2 days of


Natural Course, Pathogenesis, Morphology and Genetics

hyperglycaemia hypertrophy predominates (29). These changes are

mediated via growth factors such as TGF-b and IGF1 . Hypertrophy is partly
reversible by insulin, but cell numbers remain increased. In man, it is likely
that similar processes underpin nephromegaly, but glycaemic correction
does not reverse long-standing, whole kidney enlargement (30). Tubular
cell atrophy is a feature of advanced nephropathy and is largely secondary
to glomerular loss, secondary to global glomerulosclerosis.
Arteriolar hyalinosis is a common feature and is particularly noticeable in
hypertensive patients (31). Involvement of the glomerular efferent arteriole
is said to be specific to diabetes, and this may play a role in increasing intraglomerular capillary pressure, which is thought to be of critical importance
in the pathophysiology of glomerulopathy.
The interstitial space is increased as a part of kidney enlargement in both
human and experimental diabetes. Apart from fluid, this space also contains
immunologically active cells and fibroblasts, and these cells are thought to
be responsible for the fibrotic changes seen in advanced nephropathy. There
is a clear link between the severity of these changes and those seen in the
glomeruli but it is not certain which occur first.
Tubulo-interstitiumElectron Microscopy
Subtle changes in the macula densa cells of the juxtaglomerular apparatus
(JGA) of the rat can be seen within hours of developing glycosuria (32). It is
hypothesized that they may represent a signalling pathway that could
control glomerular blood flow and thus GFR. Careful observation of the
JGA in diabetic man has also revealed changes from normal but their
significance is unclear.
Tubular basement membrane (TBM) is thought to have a similar composition and structure to GBM but is almost twice as wide. Diabetic patients
develop TBM thickening about two to three times the value seen in their
non-diabetic siblings (33) and it is common to see splitting under both light
and electron microscopy. The significance of this is unclear, but macromolecular penetration of the interstitial space may activate fibrosis and
would be facilitated by disruption of the TBM. Advanced glycation end
products have been shown to increase pore size in bovine TBM, which may
also result in increased protein permeation (34).
Arteriolar hyaline appears to be similar to mesangial matrix in its composition. It is present in significantly greater amounts in microalbuminuric
IDDM compared to normoalbuminuric controls, and is positively correlated
with GBM width.
Interstitial changes appear to be responsive to antihypertensive therapy
with angiotensin-converting enzyme inhibitors (ACEI), at least in NIDDM

Renal Structural Damage


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.


Clinical diabetic nephropathy is characterized by a steady, relentless
decline in GFR, increasing albuminuria and increasing systemic blood
pressure. There have been many attempts to relate the pathological changes
seen in the kidney at post mortem to the clinical features of the patient in
life (1). Latterly, percutaneous renal biopsy has meant that the progression
of the disease can be related to the progression of the lesions, and in this
way lead to a greater understanding of the pathophysiology of renal failure
in diabetes. The use of the electron microscope, and more precise quantitation of the pathology by morphometric measurement (35), has increased
our understanding of the structuralfunctional relationships in diabetic
nephropathy. This section will outline the determinants of GFR and albuminuria and describe the pathological correlates.
Glomerular Filtration Rate
GFR is determined by the product of the ultrafiltration pressure (Puf ),
capillary wall permeability (k), and the surface area of the capillary wall
available for filtration (s).
GFR Puf  k  s
The ultrafiltration pressure is determined by the hydrostatic pressure across
the capillary wall (P) and the osmotic pressure of the plasma proteins (p).
Furthermore, P is determined, in turn, by the difference between the hydrostatic pressure within the glomerular capillary (Pgc ) and the filtrate (Ptf ); and
p by the difference between the osmotic pressure in plasma pgc and the
filtrate (ptf ). Thus:
GFR k  sPgc




The product k.s is termed the ultrafiltration coefficient Kf .


Natural Course, Pathogenesis, Morphology and Genetics

The most important glomerular structure determining GFR is therefore

capillary surface area. It is possible to estimate this from photomicrographs
of the glomerular tuft by using morphometric techniques (35). In this way a
surface area per unit volume of glomerulus can be derived, and this measure is called surface density or Sv . The product of Sv and glomerular
volume (also able to be derived from micrographs) is the surface area of
capillary for that glomerulus. By estimating the surface areas in several
glomeruli, an average filtration surface per glomerulus can be estimated.
Positive correlations between this surface area and GFR (specifically creatinine clearance) have been reported, with r2 > 50% (Figure 5.6) (36,37).
The average filtration surface per glomerulus has been shown to be
determined by a combination of the mesangial and glomerular volumes,
giving a combined r of 0.93 (36). As mesangial expansion increases, filtration
surface declines, and this effect is ameliorated by glomerular enlargement.
Careful scrutiny of Figure 5.6, however, reveals that the relationship
between average filtration surface per glomerulus and GFR is not that


Creatinine clearance ml.min1








Capillary filtration surface area glomerulus x 103mm2

Figure 5.6 Relationship between creatinine clearance and capillary filtration

surface area per glomerulus in 37 type 1 diabetic patients with differing severities of
nephropathy (r 0.79; p 0.001). Note the wide range of filtration surface area per
glomerulus for any given creatinine clearance. Reproduced from (36), by permission
of the editor and publishers of Kidney International

Renal Structural Damage


precise. For example, for a given creatinine clearance of 80 ml/min, filtration

surface per glomerulus can vary three-fold (< 50150  103 mm2 ). Part of the
explanation lies in the fact that glomerular number also varies more than
three-fold between individuals, and it is, of course, the total available filtration surface per patient that determines GFR (i.e. the product of average
filtration surface per glomerulus and glomerular number). The final structural determinant of filtration surface in patients with nephropathy is the
percentage of globally sclerosed (and non-functioning) glomeruli. Negative
correlations of > 0.60 have been reported (36, 37).
Thus filtration surface area is itself affected by four main structural parameters:

Mean glomerular volume: possibly determined by haemodynamic factors,

at least in short-duration diabetes.
Mesangial volume: matrix accumulation related to glycaemia and
mediated via growth factors, such as TGF-b, and possibly mechanical
factors, such as stretch (38).
Total number of glomeruli: probably genetically determined (see below).
Percentage of sclerosed glomeruli: related to arteriolar hyalinosis (ischaemia) and mesangial volume (internal obliteration) (11).

The factors governing total glomerular number in man are unknown.

There is a great deal of debate surrounding the foetal programming hypothesis of Barker and others (39). These workers propose that foetal malnutrition leads to low birth weight and arrested development of key organs such
as renal glomeruli and pancreatic islets. Thus, the individual is ``programmed'' from birth to be at risk of developing renal disease, hypertension
and diabetes.
There are only limited published data on birth weight and glomerular
number in man and these have shown no significant relationship, although
none of the individuals in that study weighed < 2:5 kg at birth (40). The
same workers have also found no relationship between post mortem glomerular number in persons with and without diabetes, and with and without
nephropathy (41). A major difficulty in testing the foetal programming idea
lies in the problem of obtaining accurate estimates of glomerular number in
living man.
From the studies of structure and function, the following hypothesis has
been proposed. Patients with large numbers (more at birth, less global
sclerosis) or large glomeruli (greater inherent capacity for enlargement)
could accommodate an expanding mesangium and therefore have a greater
tendency to preserve GFR, compared to persons with smaller numbers of
smaller glomeruli. Thus, variability in glomerular number, structure and
adaptability could provide a structural basis for determining the clinical


Natural Course, Pathogenesis, Morphology and Genetics

course of nephropathy, and possibly the risk of developing it in the first

Most of these deductions have been made from cross-sectional studies in
IDDM patients. The few longitudinal repeat biopsy reports suggest that the
rate of GBM thickening slows in advanced nephropathy, but that mesangial
expansion continues, with a resulting loss in filtration surface (42). Longer
natural history studies of renal structure and function are ongoing and their
results eagerly awaited.
Two other factors that influence GFR have to be considered. Firstly, there
is a renal reserve of functional capacity, probably determined by limiting
blood flow to a population of glomeruli, and only recruiting them for active
filtration at times of need, e.g. diuresis, protein loading (43). Obviously,
pathological examination cannot take this into account and is reliant on the
estimate of GFR to be as close as possible to the maximum.
Secondly, the role of the tubulo-interstitium in determining GFR is only
just being explored (44). A positive correlation between serum creatinine
and interstitial volume was demonstrated years ago (45) and has been
confirmed since. However, the pathophysiology of tubulo-interstitial
nephritis and fibrosis is probably multifactorial and, until it is better understood, it is hard to draw firm conclusions about the nature of the relationship with progressive renal impairment in diabetes.
GFR is an important determinant of protein filtration but there are many
other factors that affect the amount of protein that appears in urine. Circulating macromolecules have to pass through the endothelial fenestrae, the
GBM and between the epithelial foot processes before appearing in the
filtrate, and each of these structures provides both a size and an electrostatic
barrier. Their combined selective property is termed ``the permselectivity of
the glomerulus''. Thereafter, proteins are subject to reabsorption by tubular
cells, and this process has a high degree of individual variability between
different tubules and different proteins (46). Some proteins can be secreted
by tubules, and finally, any process that leads to blood loss into, or inflammation of, the urinary tract and bladder can also increase proteinuria.
Experiments with electrically neutral dextran molecules of differing sizes
has shown that there is unrestricted permselectivity of the GBM for molecules < 60 000 molecular weight and which have an effective radius of < 24
(47). The physical characteristics of albumin (radius 36 A
) therefore make
albuminuria a sensitive marker of disordered permselectivity. There is
probably little effective prevention of protein filtration by the endothelial
fenestrae; however, the GBM provides both a size restriction in the form of

Renal Structural Damage


the collagen meshwork and a negatively charged electrostatic barrier of

proteoglycan molecules (48). The negative charge sites are concentrated in
the lamina rara interna and externa in normal man, but in the thickened,
diabetic GBM the number and density of these sites are reduced, leading to
an increased passage of positively-charged molecules, such as albumin.
Significant negative correlations between charge site number and albuminuria have been reported in IDDM patients.
Mathematical modelling in patients with heavy proteinuria has suggested
a heteroporous model of permselectivity (49). The increase in non-selective
proteinuria that is seen in progressive clinical nephropathy can be explained
by the development of a population of large pores < 10 nm diameter and
occupying just 2% of the total filtration surface area. No such pores have
been identified by the electron microscope, but this may be because they are
too small and too widely scattered. Some workers have suggested that the
thin segments of the GBM may act as the large pores, but there is no
confirmation of this and thin GBM does not cause heavy proteinuria in
non-diabetic subjects. There is a consistent but weak correlation, of the
order of 34%, between overall GBM width and proteinuria in both IDDM
and NIDDM (50), and it is likely that disruption of the collagen mesh by an
accumulation of excess matrix material creates functional wide pores
beyond the resolution of the electron microscope (51).
Epithelial cells change shape in response to proteinuria with widening of
the foot processes. This effectively shortens the length of the filtration slit
and thus reduces the available filtration path. Both mean foot process width
and filtration slit length correlate with albuminuria (52) and filtration slit
width with GFR (53). There are also charge sites on the podocyte cell surface, but no quantitative data on their density in diabetes.
Tubular reabsorption of albumin is thought to be fully saturated at physiological levels of albumin filtration (54). Thus, any excess caused by
altered permselectivity is likely to be detected in the urine. However,
there is no known method of estimating tubular reabsorption of proteins
in living man and, at low levels of albuminuria (1030 mg/min), it is possible
that some of the observed day-to-day variability of excretion is determined
by variable tubular function.
There are correlations between estimates of tubulo-interstitial disease and
albuminuria. Moreover, recent ideas about the pathophysiology of progressive nephropathies have proposed increased tubular protein trafficking as a
potential mechanism (54).
The relative lack of precision in the observed relationship between albuminuria and measures of structural damage (19) may therefore be due to a
number of factors. First, patients with ``normal'' albuminuria may develop
pathological changes prior to increasing albumin excretion. Second, the
variability in protein reabsorption may mean that, for a given severity of


Natural Course, Pathogenesis, Morphology and Genetics

glomerulopathy leading to excess albumin filtration, some patients will

show ``abnormal'' albuminuria while others will not. Third, the structural
basis for protein passage may be beyond the resolution of the electron
microscope. Fourth, demonstration and quantitation of charge sites in the
GBM remains technically difficult. Finally, the net result of albuminuria is
due to change in many structures at different parts of the nephron and their
relative importance is not known.
Despite these caveats, it is important to remember that the reason
why patients enter end stage renal failure is because of loss of nephrons.
Thus, a greater understanding of the pathological processes that lead to
nephron loss is essential if a reduction in the numbers of diabetic patients
requiring renal replacement therapy is to be achieved. To this end, carefully
controlled and planned studies of renal structure and function using
prospective kidney biopsy and unbiased quantitative analysis are necessary

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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