DIABETIC NEPHROPATHY
Diabetic
nephropathy (DN) reflects renal injury in response to chronic long-standing
hyperglycemia. It may occur in patients with type I or II diabetes mellitus,
and it manifests as progressive albuminuria followed by a decline in the
glomerular filtration rate (GFR).
Recent data
from the Centers for Disease Control and Prevention estimate that 23.6 million
individuals in the United States, or roughly 7.8% of the population, suffer
from diabetes mellitus. Because of this rising epidemic, DN is now the leading
cause of chronic kidney disease and end stage renal disease (ESRD) in the United
States and other countries (both developed and developing).
Among those
with type 1 diabetes, the incidence of overt nephropathy (defined as
dipstick-positive proteinuria) has declined over recent years, from
approximately 30% to 10% at 25 years. Among those with type 2 diabetes,
approximately 12% develop overt nephropathy over the same timeframe.
The risk of
nephropathy increases with patient age, duration of diabetic disease,
hypertension, and poorer glycemic control. Genetic factors also play an important
role, insofar as a patient with diabetes mellitus is more likely to develop
nephropathy if a sibling or parent has this complication as well. In addition,
blacks and certain minority populations (such as Pima Indians) are more likely
to develop DN than Caucasians.
PATHOPHYSIOLOGY
The sequence
of events that leads to DN is largely unknown. Proposed mechanisms include
hyperglycemia-induced hyperfiltration, accumulation of advanced glycation end
products, and activation of proinflammatory/profibrotic pathways.
An increase
in the glomerular filtration rate is the earliest demonstrable abnormality,
reflecting afferent arteriolar vasodilation and efferent arteriolar
vasoconstriction. The exact link between hyperglycemia and hyperfiltration,
however, is not fully understood and probably reflects multiple mechanisms,
including abnormalities in tubuloglomerular feedback induced by increased
proximal reabsorption of glucose and sodium, effects of advanced glycation end
products, and changes in hormonal input (such as from the renin-angiotensin
axis). In the long term, increased intraglomerular pressure can lead to
glomerulosclerosis. Systemic hypertension can accelerate this process by
further increasing intraglomerular pressure.
Meanwhile,
hyperglycemia causes increased production of mesangial matrix proteins, leading
to mesangial expansion. Angiotensin II and transforming growth factor-(TGF-)
are important factors in this process, and variations in the genes encoding
angiotensin II and its receptors have been found to account for some of the
inherited risk for nephropathy. It appears that hyperglycemia stimulates
angiotensin II synthesis, which in turn stimulates TGF- secretion. TGF-then
increases the synthesis and decreases the degradation of matrix proteins, leading
to their accumulation. Another hormone known to be involved in this process is
vascular endothelial growth factor (VEGF). In animal models of diabetic
nephropathy, blockade of TGF- and VEGF has been shown to have beneficial
effects.
Advanced
glycation end products (AGEs) also play an important role in promoting mesangial matrix accumulation. These
compounds are formed nonenzymatically when proteins are exposed to glucose.
They then cross link with normal matrix proteins, such as collagen, and render
them resistant to proteolysis. Binding of AGEs to a specific receptor (RAGE)
triggers production of reactive oxygen species and subsequent inflammation.
In type 1
diabetes, the pathologic changes to the glomerulus occur in a somewhat
predictable sequence, with hypertrophy of the glomeruli and thickening of the
basement membrane seen early in the disease course. Expansion of the mesangium
then follows and leads to the clinical manifestation of proteinuria. As the
disease progresses, there is progressive glomerular damage and increasing
amounts of albuminuria, with eventual reduction of the GFR and, ultimately,
ESRD.
In type 2
diabetes, these events may be temporally compressed, with impaired renal
function appearing as an early manifestation. To some extent this difference
may reflect the fact that diagnosis often does not occur until later in the
disease course; however, it may also reflect increased patient age in this
population and the frequent presence of comorbid hypertension.
PRESENTATION
AND DIAGNOSIS
The earliest
clinical manifestation of diabetic nephropathy is known as microalbuminuria,
defined as 30 to 300 mg of albumin per gram of creatinine in a spot urine sample, a quantity of protein that cannot reliably be detected on
a urine dipstick. As the disease progresses, macroalbuminuria ensues ( 300
mg/g of creatinine in a spot sample), which can be detected on a dipstick and
is a marker of overt nephropathy. In some cases, proteinuria may be severe
enough to cause the full nephrotic syndrome. The final stages of DN are
characterized by a progressive decline in renal function, which can lead to
ESRD.
To assess
for the presence and degree of proteinuria, all patients with known diabetes
mellitus should be evaluated on an annual basis with a quantitive spot urine
albumin to creatinine ratio. Such testing should begin 5 years from diagnosis
in patients with type 1 diabetes, and at the time of diagnosis in patients with
type 2 diabetes. The screening should also include a serum creatinine concentration
to evaluate for renal insufficiency and, in patients with overt nephropathy,
measurement of serum albumin and lipid concentrations. Monitoring blood
pressure is also essential.
In patients
with overt nephropathy, other renal diseases should always be ruled out
before diabetes is assumed to be the cause. A renal ultrasound should be
performed as part of the workup. Although most renal diseases cause the kidneys
to appear shrunken, DN causes them to appear normal-sized or even enlarged.
(This finding is not specific, however, because a small number of other diseases
such as amyloidosis, also cause enlarged kidneys.)
Renal biopsy
is not routinely indicated, but it may be performed if another diagnosis is
suspected on clinical or serologic grounds, or if the rate of progression is
atypical. For example, a biopsy would be indicated in a patient with an active,
cellular urine sediment or a rapid decline in filtration function over the
course of weeks or months. Conversely, a diabetic patient with retinopathy,
long-standing proteinuria, a bland urine sediment, and a slow decline in renal
function can be reasonably assumed to have diabetic nephropathy without a
biopsyproven diagnosis.
Upon biopsy,
the pathologic lesion of DN may be classified into one of four classes. Class I
features isolated thickening of the glomerular basement membrane; class II
features mesangial expansion; class III (also known as nodular
glomerulosclerosis or the “Kimmelstiel-Wilson” lesion) features intercapillary
nodules resulting from severe mesangial expansion, with compression of adjacent
capillary lumina; and class IV features advanced glomerulosclerosis ( 50% of
glomeruli have global sclerosis). The correlation between clinical and
pathologic findings is often weak, however, and patients with minimal clinical
manifestations may undergo biopsies that reveal established diabetic lesions,
or vice versa.
TREATMENT
DN is both
prevented and treated by rigorously controlling serum glucose concentrations
(goal hemoglobin A1C 7.0)
and lowering blood pressure. In the United Kingdom Prospective Diabetes Study, for example, each 10 mm Hg reduction
in systolic pressure was associated with a 12% reduction in the risk for
diabetic complications, with the lowest risk occurring in patients with a
systolic blood pressure under 120 mm Hg.
ACE
inhibitors and angiotensin receptor blockers (ARBs) are the preferred antihypertensive agents because they also reduce
proteinuria and slow the inflammatory processes that drive further renal
dysfunction. They should be offered to all diabetics with hypertension, as well
as to all normotensive diabetics with microalbuminuria or macroalbuminuria.
Available evidence indicates that these agents may also be effective for
delaying the onset of microalbuminuria in patients with no albuminuria.
It is
unclear if dietary protein restriction has any role in retarding progression of
renal insufficiency. Renal replacement therapy, including dialysis or renal
trans- plantation, is indicated once patients approach ESRD.
PROGNOSIS
A large
study of type 2 diabetics found that the annual risk of progression from no
albuminuria to microalbuminuria was 2.0%, from microalbuminuria to
macroalbuminuria was 2.8%, and from macroalbuminuria to impaired filtration
function was 2.3%. Overall, at 10 years after diagnosis, 25% had
microalbuminuria or worse, 5% had macroalbuminuria or worse, and 1% had
elevated plasma creatinine or were undergoing renal replacement therapy.
