INTRODUCTION

• Diabetic nephropathy is a clinical syndrome

characterized by persistent albuminuria (>300
mg/d or >200 mcg/min) that is confirmed on at
least 2 occasions 3-6 months apart, a relentless
decline in the glomerular filtration rate (GFR),
and elevated arterial blood pressure
• Proteinuria was first recognized in diabetes
mellitus in the late 18th century. In the 1930s,
Kimmelstiel and Wilson described the classic
lesions of nodular glomerulosclerosis in diabetes
associated with proteinuria and hypertension.
 Pathophysiology
• The earliest morphologic abnormality in diabetic
nephropathy is the thickening of the glomerular
basement membrane (GBM) and expansion of the
mesangium due to accumulation of extracellular
matrix
• Light microscopy findings show an increase in
the solid spaces of the tuft, most frequently
observed as coarse branching of solid (positive
periodic-acid Schiff reaction) material (diffuse
diabetic glomerulopathy). Large acellular
accumulations also may be observed within these
areas. These are circular on section and are
known as the Kimmelstiel-Wilson lesions/nodules
• The glomeruli and kidneys are typically normal or
increased in size initially, thus distinguishing
diabetic nephropathy from most other forms of
chronic renal insufficiency, wherein renal size is
reduced (except renal amyloidosis and polycystic
• The severity of diabetic glomerulopathy is
estimated by the thickness of the peripheral
basement membrane and mesangium and matrix
expressed as a fraction of appropriate spaces (eg,
volume fraction of mesangium/glomerulus,
matrix/mesangium, or matrix/glomerulus).
• Three major histologic changes occur in the
glomeruli of persons with diabetic nephropathy.
First, mesangial expansion is directly induced by
hyperglycemia, perhaps via increased matrix
production or glycosylation of matrix proteins.
Second, GBM thickening occurs. Third, glomerular
sclerosis is caused by intraglomerular
hypertension (induced by renal vasodilatation or
from ischemic injury induced by hyaline
narrowing of the vessels supplying the glomeruli).
These different histologic patterns appear to have
similar prognostic significance.
• The exact cause of diabetic nephropathy is
unknown, but various postulated mechanisms are
hyperglycemia (causing hyperfiltration and renal
injury), advanced glycosylation products, and
activation of cytokines.
• Hyperglycemia increases the expression of
transforming growth factor-beta (TGF-beta) in the
glomeruli and of matrix proteins specifically
stimulated by this cytokine. TGF-beta may
contribute to both the cellular hypertrophy and
enhanced collagen synthesis observed in persons
with diabetic nephropathy.
• Hyperglycemia also may activate protein kinase
C, which may contribute to renal disease and
other vascular complications of diabetes.
Figure 1. General features of hyperglycemia-
induced tissue damage.
Figure 2. Hyperglycemia increases flux through the polyol
pathway. From Brownlee M: Biochemistry and molecular
cell biology of diabetic complications. Nature 414:813-820,
2001.
Figure 3. Increased production of AGE precursors and its pathologic
consequences. From Brownlee M: Biochemistry and molecular cell
biology of diabetic complications. Nature 414:813-820, 200
Figure 4. Consequences of hyperglycemia-induced
activation of PKC.
 Figure 5. Hyperglycemia increases flux through the hexosamine
pathway. From Brownlee M: Biochemistry and molecular cell biology of
diabetic complications. Nature 414:813-820, 2001.
Figure 6. Hyperglycemia-induced production of superoxide
by the mitochondrial electron transport chain.
 Figure 8. Mitochondrial overproduction of superoxide activates four
major pathways of hyperglycemic damage by inhibiting GAPDH. From
Brownlee M: Biochemistry and molecular cell biology of diabetic
complications. Nature 414:813-820, 2001.
Figure 9. ROS-induced DNA damage activates PARP and
modifies GAPDH
Figure 10. The unifying mechanism of hyperglycemia-
induced cellular damage
 Figure 11. Insulin resistance causes mitochondrial overproduction of ROS in
macrovascular endothelial cells by increasing FFA flux and oxidation. From Hofmann S,
Brownlee M: Biochemistry and molecular cell biology of diabetic complications: a unifying
mechanism. In Diabetes Mellitus: A Fundamental and Clinical Text . 3rd ed. LeRoith D,
Taylor SI, Olefsky JM, Eds. Philadelphia, Lippincott Williams & Wilkins, p. 1441-1457,
2004.
Figure 12. Excess superoxide independently inhibits activity of two
critical antiatherogenic enzymes without involvement of the four
pathways of hyperglycemic damage. From refs.[51] and [52]
 Frequency:
• In the US: Diabetic nephropathy rarely
develops before 10 years' duration of
IDDM. Approximately 3% of newly
diagnosed NIDDM patients have overt
nephropathy. The peak incidence rate
(3%/y) is usually found in persons who
have had diabetes for 10-20 years, after
which the rate progressively declin. The
risk for the development of diabetic
nephropathy is low in a normoalbuminuric
patient with diabetes' duration of greater
than 30. The peak onset of nephropathy in
those with IDDM is 10-15 years after
disease onset. Patients who have no
proteinuria after 20-25 years have a risk of
developing overt renal disease of only
• Internationally: Striking epidemiologic
differences exist even among European
countries. In some European countries,
particularly Germany, the proportion of
patients admitted for renal replacement
therapy exceeds the figures reported from
the United States. In Heidelberg (southwest
Germany), 59% of patients admitted for
renal replacement therapy in 1995 had
diabetes and 90% of those had NIDDM. An
increase in ESRD from NIDDM has been
noted even in countries with notoriously low
incidences of NIDDM, such as Denmark and
Australia. Exact incidences and prevalences
from Asia are not readily available.
 Mortality/Morbidity:
• Diabetic nephropathy accounts for
significant morbidity and mortality.
The fraction of patients with IDDM
who develop renal failure seems to
have declined over the past several
decades. However, 20-40% still have
this complication. On the other hand,
only 10-20% of patients with NIDDM
develop uremia due to diabetes. Their
nearly equal contribution to the total
number of patients with diabetes who
develop kidney failure results from
the higher prevalence of NIDDM (5- to
10-fold).
 Race
• In white persons, the prevalence of
progressive renal disease is generally lower
in those with NIDDM than in those with
IDDM. This does not apply to persons of all
racial groups who have NIDDM, and some
have a more ominous renal prognosis. For
example, nephropathy develops in as many
as 50% of Pima Indians with diabetes at 20
years, with 15% having progressed to ESRD
by this time. Additionally, the Pima Indians,
among certain other racial or ethnic groups,
have a high incidence of diabetic
nephropathy, suggesting familial clustering.
• Sex: Diabetic nephropathy affects males
and females.
• Age: Diabetic nephropathy rarely develops
before 10 years' duration of IDDM. The peak
 CLINICAL
• History:
• Diabetes
• Passing of foamy urine
• Otherwise unexplained proteinuria in a
patient with diabetes
• Diabetic retinopathy
• Fatigue and foot edema secondary to
hypoalbuminemia (if nephrotic syndrome
is present)
• Other associated disorders such as
peripheral vascular occlusive disease,
hypertension, or coronary artery disease
 Physical examination
• Generally, diabetic nephropathy is considered after a
routine urinalysis and screening for
microalbuminuria in the setting of diabetes. Patients
usually have physical findings associated with long-
standing diabetes mellitus.
• Hypertension
• Evidence of diabetic retinopathy after funduscopy or
fluorescin angiography
• Peripheral vascular occlusive disease (decreased
peripheral pulses, carotid bruits)
• Evidence for diabetic neuropathy (evidenced by
decreased fine sensations, diminished tendon
reflexes)
• Evidence for fourth heart sound during cardiac
auscultation
• Nonhealing skin ulcers/osteomyelitis
 DIFFERENTIALS
• Nephritis, Interstitial
Nephrosclerosis
Nephrotic Syndrome
Renal Artery Stenosis
Renal Vein Thrombosis
Renovascular Hypertension
multiple myloma
Other Problems to be Considered:
Diabetic nephropathy must be
differentiated from cholesterol
embolization, amyloidosis, and other
glomerulopathies affecting patients
with diabetes.
 WORKUP
• Lab Studies
• Urinalysis
– Regular annual urinalysis is recommended for screening for
microalbuminuria Typically, the urinalysis results from a
patient with established diabetic nephropathy show
proteinuria varying from 150 mg/dL to greater than 300
mg/dL, glucosuria, and occasional hyaline casts.
– Microalbuminuria is defined as albumin excretion of more
than 20 mcg/min. This phase indicates incipient diabetic
nephropathy and calls for aggressive management, at
which stage the disease may be potentially reversible.
– A 24-hour urinalysis for urea, creatinine, and protein is
extremely useful in quantifying protein losses and
estimating the GFR.
– Perform microscopic urinalysis to help rule out a potentially
nephritic picture, which may lead to a workup to rule out
other primary glomerulopathies, especially in the setting of
rapidly deteriorating renal function (eg, rapidly progressive
glomerulonephritis).
Imaging Studies:
• Renal ultrasound
– Observe for kidney size, which is usually normal to increased
in the initial stages and, later, decreased or shrunken with
chronic renal disease.
– Rule out obstruction.
– Perform echogenicity studies for chronic renal disease.
• Procedures:
Serum and urinary electrophoresis is performed
mainly to help exclude multiple myeloma (in the
appropriate setting) and to classify the proteinuria
(which is predominantly glomerular in diabetic
nephropathy).
• Renal biopsy is not routinely indicated in all cases of
diabetic nephropathy, especially in persons with a
typical history and a progression typical of the
disease. It is indicated if the diagnosis is in doubt, if
other kidney disease is suggested, or if atypical
features are present.
 TREATMENT
• Medical Care: Several issues are key in the medical care of
patients with diabetic nephropathy
• Glycemic control
• In persons with either IDDM or NIDDM, hyperglycemia has
been shown to be a major determinant of the progression
of diabetic nephropathy. The evidence is best reported for
type 1 diabetes mellitus.
• It has been shown that intensive therapy can partially
reverse glomerular hypertrophy and hyperfiltration, delay
the development of microalbuminuria, and stabilize or even
decrease protein levels in patients with microalbuminuria.
• Results from pancreatic transplant recipients in which true
euglycemia is restored suggest that strict glycemic and
metabolic control may slow the progression rate of
progressive renal injury even after overt dipstick-positive
proteinuria has developed.
• In type 2 diabetes, reduction in microvascular
complications in patients receiving intensive
insulin therapy was of a smaller magnitude
than in patients with type 1 diabetes in the
Diabetes Control and Complications Trial. In
an outcome and cost-effective analysis of the
United Kingdom Prospective Diabetes Study,
the authors concluded that intensive blood
glucose control in patients with type 2
diabetes significantly increased treatment
costs but substantially reduced the cost of
complications and increased the time free of
complications
 Antihypertensive treatment
• In general, antihypertensive therapy, irrespective of
the agent used, slows the development of diabetic
glomerulopathy; however, ACE inhibitors confer
superior long-term protection even compared with
triple therapy with reserpine, hydralazine, and
hydrochlorothiazide or a calcium (Ca+) channel
blocker (nifedipine). In addition to beneficial
cardiovascular effects, ACE inhibition has also been
demonstrated to have a significant beneficial effect
on the progression of diabetic retinopathy and the
development of proliferative retinopathy.
• ACE inhibition delays the development of diabetic
nephropathy. In the ACE inhibition arm of a large
trial, only 7% of patients with microalbuminuria
experienced progression to overt nephropathy;
however, in the placebo-treated group, 21% of
patients experienced progression to overt
nephropathy. The beneficial effect of ACE inhibition
on preventing progression from microalbuminuria to
overt diabetic nephropathy is long-lasting (8 y) and
is associated with the preservation of a normal GFR.
• The impact of ACE inhibition in patients with microalbuminuric
NIDDM has also been evaluated. Treatment with an ACE inhibitor
for 12 months has significantly reduced mean arterial blood
pressure and the urinary albumin excretion rate in NIDDM patients
who have microalbuminuria.
• Normotensive patients with microalbuminuric NIDDM received
enalapril or placebo for 5 years. Of the patients, 12% in the actively
treated group experienced diabetic nephropathy, with a rate of
decline in kidney function of 13%, and 42% of the patients
receiving placebo experienced nephropathy.
• From a therapeutic standpoint, preventing the progression of
kidney disease is better achieved with a nonglycemic intervention,
such as treatment with ACE inhibition. The antiproteinuric effect of
ACE inhibition in patients with diabetic nephropathy varies
considerably. Individual differences in the renin-angiotensin
system may influence this variation. A potential role may exist for
an insertion/deletion polymorphism of the ACE gene on this early
antiproteinuric responsiveness in young patients with
hypertension and IDDM who have developed diabetic nephropathy.
• Angiotensin receptor blocking (ARB) agents are also believed to
exert similar or even additive beneficial effects to the ACE
inhibitors, and trials are underway to study this issue.
•
• Long-term treatment with ACE inhibitors, usually
combined with diuretics, reduces blood pressure
and albuminuria and protects kidney function in
patients with hypertension, IDDM, and nephropathy.
Beneficial effects on kidney function have also been
reported in patients with normotension, IDDM, and
nephropathy.
• Meta-analysis has shown that ACE inhibitors are
superior to beta-blockers, diuretics, and calcium
channel blockers in reducing urinary albumin
excretion in normotensive and hypertensive IDDM
and NIDDM patients. This superiority is pronounced
in the normotensive state, whereas it is diminished
progressively with progressive blood pressure
reduction. Reduced glomerular capillary hydraulic
pressure in combination with diminished size- and
charge-selective properties of the glomerular
capillary membrane are the most likely mechanisms
involved in the antiproteinuric effect of ACE
inhibitors
• Dietary protein intake: A meta-analysis
examining the effects of dietary protein
restriction (0.5-0.85 g/kg/d) in diabetic
patients suggested a beneficial effect on the
GFR, creatinine clearance, and albuminuria.
However, a large, long-term prospective
study is needed to establish the safety,
efficacy, and compliance with protein
restriction in diabetic patients with
nephropathy. Limitations include ensuring
compliance in the patients.
• Specific therapies: This includes
modification and/or treatment of associated
risk factors such as hyperlipidemia, smoking,
and hypertension.
 Renal replacement therapies
• As for any other patient with ESRD, diabetic patients
with ESRD can be offered hemodialysis, peritoneal
dialysis, kidney transplantation, or combined kidney-
pancreas transplantation.
• In patients with uremia of any cause, starting at a
creatinine clearance of 10-15 mL/min is wise. In
diabetic patients, starting earlier is useful when
hypervolemia renders blood pressure
uncontrollable, when the patient experiences
anorexia and cachexia or other uremic symptoms,
and when severe vomiting is the combined result of
uremia and gastroparesis.
• Carefully explain the therapeutic options and
modalities of renal replacement therapy to patients,
their partners, and their families in an early stage of
renal failure. In chronically ill patients with diabetes,
this tends to be much more important than in those
renal patients who do not have diabetes.
• As for any other patient with ESRD, diabetic patients
with ESRD can be offered hemodialysis, peritoneal
dialysis, kidney transplantation, or combined kidney-
pancreas transplantation.
• In patients with uremia of any cause, starting at a
creatinine clearance of 10-15 mL/min is wise. In
diabetic patients, starting earlier is useful when
hypervolemia renders blood pressure
uncontrollable, when the patient experiences
anorexia and cachexia or other uremic symptoms,
and when severe vomiting is the combined result of
uremia and gastroparesis.
• Carefully explain the therapeutic options and
modalities of renal replacement therapy to patients,
their partners, and their families in an early stage of
renal failure. In chronically ill patients with diabetes,
this tends to be much more important than in those
renal patients who do not have diabetes.
 Diet:
• The American Diabetic Association suggests diets of
various energy intake (caloric values), depending on
the patient. With advancing renal disease, protein
restriction of as much as 0.8-1 g/kg/d may retard the
progression of nephropathy.
• When nephropathy is advanced, the diet should
reflect the need for phosphorus and potassium
restriction, with the use of phosphate binders.
• Activity:
• No restriction in activity is necessary for persons
with diabetic nephropathy, unless warranted by
other associated complications of diabetes, such as
associated coronary disease or peripheral vascular
disease.
• Further Inpatient Care:

• Inpatient care is usually restricted to managing

complications of diabetic nephropathy, such as
volume overload, renal vein thrombosis, uremia
complications (eg, pericarditis), and problems
related to access.
• Further Outpatient Care:

• Regular outpatient follow-up is key in managing

diabetic mellitum nephropathy successfully, with
screening regularly for microalbuminuria, ensuring
optimal glucose control, optimizing blood pressure,
and screening for other associated complications of
diabetes (eg, retinopathy, diabetic foot,
cardiovascular disease).
• Pre-ESRD clinic referral is appropriate if the patient
has overt diabetic nephropathy
 Deterrence/Prevention
• Optimal blood glucose control
• Control of hypertension
• Avoidance of potentially nephrotoxic
substances such as nonsteroidal anti-
inflammatory medications and
aminoglycosides
• Early detection and optimal management
of diabetes, especially in the setting of
family history of diabetes
 Complications:
• Diabetic retinopathy is present in virtually all persons with IDDM who
have nephropathy, whereas only 50-60% of patients with proteinuric
NIDDM have retinopathy. An absence of retinopathy requires further
investigation for nondiabetic glomerulopathies. Blindness due to
severe proliferative retinopathy or maculopathy is approximately 5
times more common in persons with IDDM or NIDDM and nephropathy
than in persons who are normoalbuminuric.
• Macroangiopathy (eg, stroke, carotid artery stenosis, coronary heart
disease, peripheral vascular disease) is 2-5 times more common in
patients who are nephropathic.
• Peripheral neuropathy is present in almost all patients with advanced
nephropathy. Foot ulcers with associated sepsis, which leads to
amputation, occur frequently (>25%), probably because of a
combination of neural and arterial disease.
• Autonomic neuropathy may be asymptomatic and simply manifest as
abnormal cardiovascular reflexes, or it may result in debilitating
symptoms.
• Nearly all patients have grossly abnormal results from autonomic
function tests, with more than half the patients with advanced
nephropathy having symptoms of autonomic neuropathy (ie, gustatory
sweating, impotence, postural hypotension, and diarrhea in one
study).
• Diabetic cystopathy is also a frequent (>30%) problem in these
patients.
 Prognosis:
• The overall prevalence of microalbuminuria and macroalbuminuria in both
types of diabetes is approximately 30-35%. Diabetic nephropathy rarely
develops before patients have had IDDM for at least 10 years, whereas
approximately 3% of patients with newly diagnosed NIDDM have overt
nephropathy.
• The peak incidence rate (3%/y) is usually found in persons who have had
diabetes for 10-20 years, after which the rate progressively declines.
• Microalbuminuria independently predicts cardiovascular morbidity, and both
microalbuminuria and macroalbuminuria increase mortality from any cause in
diabetes mellitus. Microalbuminuria also predicts coronary and peripheral
vascular disease and death from cardiovascular disease in the general
nondiabetic population.
• Patients in whom proteinuria did not develop have a low and stable relative
mortality rate, whereas patients with proteinuria have a 40-fold higher relative
mortality rate. Patients with IDDM and proteinuria have the characteristic bell-
shaped relationship between diabetes duration/age and relative mortality, with
maximal relative mortality in the age interval of 34-38 years (as reported in 110
females and 80 males).
• ESRD is the major cause of death, accounting for 59-66% of deaths in patients
with IDDM and nephropathy. The cumulative incidence rate of ESRD in patients
with proteinuria and IDDM is 50% 10 years after the onset of proteinuria,
compared with 3-11% 10 years after the onset of proteinuria in European
patients with NIDDM.
• Cardiovascular disease is also a major cause of death (15-25%) in persons with
nephropathy and IDDM, despite their relatively young age at death.
 Patient Education:
• Patient education is key in trying to prevent
diabetic nephropathy. Appropriate education,
follow-up, and regular doctor visits are
important in prevention and early recognition
and management of diabetic nephropathy.
• Pregnancy in a patient with diabetic
nephropathy does not seem to accelerate
functional loss. More overt bacteruria,
increased range of proteinuria, and
hypertension may occur after mid gestation