Persistent albuminuria (>300 mg/24 hr or 200 g/min) is the

hallmark of diabetic nephropathy, which can be diagnosed

clinically if the following additional criteria are fulfilled: presence

of diabetic retinopathy and absence of clinical or laboratory

evidence of other kidney or renal tract disease. This

clinical definition of diabetic nephropathy is valid in both type

1 diabetes and type 2 diabetes.1

During the last decades several longitudinal studies have

shown that raised urinary albumin excretion (based on a single

measurement) that is below the level of clinical albuminuria

(by reagent strip), so-called microalbuminuria, strongly predicts

the development of diabetic nephropathy in both type 1

and type 2 diabetes.2-4 Microalbuminuria is defined as urinary

albumin excretion of more than 30 mg/24 hours (20 g/min)

and less than or equal to 300 mg/24 hr (200 g/min), irrespective

of how the urine is collected.

Nephropathy is a major cause of illness and death in diabetes.

Indeed, the excess mortality of diabetes occurs mainly

in proteinuric diabetic patients and results not only from

end-stage renal disease (ESRD) but also from cardiovascular

disease, with the latter being particularly common in type 2

diabetic patients.5-7 Diabetic nephropathy is the single most

common cause of ESRD in Europe, Japan, and the United

States, with diabetic patients accounting for 25% to 45% of all

patients enrolled in ESRD programs.

Pathology of the Kidney in

Diabetesdiabetes, followed by a
comparison of the similarities and
differences in renal pathology in type 2
diabetes. When its
features are taken together, diabetic
nephropathology in type
1 diabetes is unique to this disease
(Table 38-1)8-10 Thickening
of the glomerular basement membrane
(GBM) is the

Structural-Functional Relationships
in Type 1
Diabetic Nephropathy

Mesangial expansion is the major lesion of diabetic nephropathy

leading to renal dysfunction in type 1 diabetes patients.22

Mesangial expansion out of proportion to increases in glomerular

volumethat is, increased Vv(Mes/glom)is strongly correlated

with decreased peripheral GBM filtration surface density,

or Sv(PGBM/glom) (Figure 38-10),22 and filtration surface per

glomerulus is strongly correlated with GFR in type 1 diabetes.37

Vv(Mes/glom) is also closely related to urinary albumin excretion

rate (AER)22,23 (Figure 38-11A) and is a strong concomitant

of hypertension.22 Thus, all of the clinical manifestations of

diabetic nephropathy are associated with mesangial expansion

and the consequent restriction of the filtration surface.

Although GBM width is also directly correlated with blood

pressure and AER (Figure 38-12A) and inversely correlated

with GFR, the relationships are somewhat weaker than those

seen with Vv(Mes/glom).22,23 However, Vv(Mes/glom) and

GBM width, together, explain nearly 60% of AER variability

in type 1 diabetic patients over the full range of proteinuria

with AERs ranging from normoalbuminuria to proteinuria.23

As noted earlier, decreased glomerular podocyte number and

detachment has been related to glomerular permeability alterations

in diabetes. In addition, changes in podocyte shape, including

increases in foot process width and decreases in filtration

slit-length density, correlate with AER increases in type 1 and

type 2 diabetic patients.30,32,38,39 Heparin sulfate proteoglycans,

presumed to represent an epithelial cell product important in glomerular

chargebased permselectivity, are decreased in density in

the lamina rara externa in proportion to the increase in AER in

type 1 diabetic patients.40 Whether the addition of podocyte cell

structural variables would reduce the residual unexplained variability

in AER or GFR in diabetic nephropathy (see later) has not

yet been tested. If true, this would support the idea that podocyte

alterations contribute to proteinuria and renal insufficiency.

Moreover, confirmation that reduced podocyte number predicts

diabetic nephropathy development or progression41 would add

further credence to the importance of this cell in this disease.

The total peripheral capillary filtration surface is directly

correlated with GFR across the spectrum from hyperfiltration

to renal insufficiency.38,42 Nonetheless, as already noted, diabetic

glomerulopathy structural parameters, examined in linear

regression models, explain only a minority of GFR variability in

type 1 diabetic patients.23 Percent global sclerosis27 and interstitial

expansion9 are also linearly correlated with the clinical

manifestations of diabetic nephropathy and are, to some extent,

independent predictors of renal dysfunction and hypertension

in type 1 diabetes. In fact, some have argued that renal dysfunction

in diabetes is primarily consequent to interstitial rather than

glomerular lesions.43,44 However, the conclusion that the interstitium

is more closely related to renal dysfunction in diabetes

than glomerular changes has been derived from studies in which

most, if not all, patients already have elevated serum creatinine values and in which the interstitium is carefully measured but

the glomerular structure is only subjectively estimated.43,44

In fact, throughout most of the natural history of diabetic

nephropathy, glomerular parameters are more important

determinants of renal dysfunction, whereas interstitial changes

may become a stronger determinant of the rate of progression

from established renal insufficiency to terminal uremia.45 Furthermore,

as mentioned earlier, in the first decade of diabetes,

Vv(Int/cortex) is decreased, whereas Vv(Mes/glom) and

GBM width are already increased. Moreover, early interstitial

expansion in type 1 diabetes is mainly due to expansion of

the cellular component of this compartment, and increased

interstitial fibrillar collagen is seen in patients whose GFR is

already reduced.20 These and other findings suggest that the

interstitial and glomerular changes of diabetes have somewhat

different pathogenetic mechanisms and that advancing interstitial

fibrosis generally follows the glomerular processes in

type 1 diabetes.

Through much of the natural history of diabetic nephropathy,

lesions develop in complete clinical silence, and when

microalbuminuria and proteinuria initially manifest, lesions are

often far advanced and loss of GFR may then progress relatively

rapidly toward ESRD. This typical clinical story is best mirrored

by nonlinear analyses of structural-functional relationships.21

When piecewise regression models were used, glomerular structural

variables alone [Vv(Mes/glom), GBM width, and total filtration

surface per glomerulus] explained 95% of variability in

AER ranging from normoalbuminuria to proteinuria; this leaves

little room for improvement in predictive models by adding nonglomerular

structural variables to the parameters. These same

glomerular structures, however, explained only 78% of GFR variability.

With the addition of indices of glomerulotubular junction

abnormalities and Vv(Int/cortex), this increased to 92%.21

In summary, most of the AER and GFR changes in type

1 diabetes are explained by diabetic glomerulopathy changes.

These structural-functional relationships are largely driven by

more advanced lesions, however; structural changes are highly

variable (from virtually none to moderately severe) in patients

without functional abnormalities. Predictive tools for the first

decade of type 1 diabetes are needed

Reversibility of Diabetic
Nephropathy Lesions

Mesangial expansion present after 7 months of diabetes

reversed within 2 months after normoglycemia was induced

by islet transplantation in rats with streptozotocin-induced

diabetes.67 It was thus disappointing that no improvement in

diabetic nephropathy lesions in their native kidneys was found

after 5 years of normoglycemia following successful pancreatic

transplantation68 in type 1 patients with a diabetes duration

of approximately 20 years. After 10 years of normoglycemia,

however, these same patients showed marked reversal of diabetic

glomerulopathy lesions. Thus, GBM and TBM width

were reduced at 10 years compared with the baseline and

5-year values, with several patients having measures at 10

years that had returned to the normal range (Figure 38-13A

and B).69 Similar results were obtained for Vv(Mes/glom),

primarily due to a marked decrease in mesangial matrix fractional

volume (Figure 38-13C and D). Remarkable glomerular

architectural remodeling was seen by light microscopy,

including the complete disappearance of Kimmelstiel-Wilson

nodular lesions (Figure 38-14).69

The reason for the long delay in this reversal process is

not understood and could include epigenetic memory of the

diabetic state, the slow process of replacement of glycated by

nonglycated ECM, or other, as yet undetermined processes.

Regardless of the mechanism, relevant renal or circulating cells

must be able to recognize the abnormal ECM environment

and to initiate and sustain a state of imbalance in which the

rate of ECM removal exceeds that of ECM production. This

is clearly not the normal situation, because throughout adult

life GBM width and mesangial matrix remain quite constant,

consistent with balanced ECM production and removal.70

More recently, remodeling and healing in the tubulointerstitium

has also been demonstrated in these same patients.71

These studies demonstrated reduction in total cortical interstitial

collagen and underscore the remarkable potential for healing

of kidney tissue that has been damaged by long-standing

diabetes.71 Blockade of the renin-angiotensin system (RAS)

for 5 years did not lead to regression nor to slowing of the progression

of diabetic glomerulopathy lesions in young patients

with type 1 diabetes and normoalbuminuria.72 Whether healing

can be induced by treatments other than cure of the diabetic

state is currently unknown