Brief overview on pathogenesis and treatment of diabetic nephropathy

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ISSN Print: 2278 – 2648 IJRPP |Vol.3 | Issue 3 | July-Sep-2014
ISSN Online: 2278-2656 Journal Home page: www.ijrpp.com
Review article Open Access
Brief overview on pathogenesis and treatment of diabetic
nephropathy
*Harshada Langote, Vivek Mishra.
Sinhgad College of Pharmacy, Vadgaon (Bk.), Pune-411041 Maharashtra, India.
*Corresponding author: Harshada Langote.
E-mail id: harshadalangote@gmail.com
ABSTRACT
Diabetic nephropathy is a serious condition affecting the patients worldwide suffering from diabetes mellitus.
Diabetic nephropathy is the leading cause of Chronic Kidney Disease (CKD) in diabetic patients. About 25–40% of
patients with type 1 diabetes and 5–40% of patients with type 2 diabetes are more predisposed to develop diabetic
kidney disease. The current review focuses on the current statistical scenario of diabetic nephropathy, its causes and
the current treatment which is available for the treatment of this serious condition.
Keywords: Diabetic nephropathy, Treatment of diabetic nephropathy, Angiotensin Receptor blockers, ACE
Inhibitors.
INTRODUCTION
Increasing burden of Diabetes mellitus is giving a
wakeup call to all health care professionals and
common people as well. Increasing prevalence of
diabetes in nearly all countries is observed mainly
because of increase in sedentary lifestyle, reduced
physical activity and overconsumption of junk food.
From 2010 to 2030 the overall total predicted
increase in numbers of patients with diabetes is 54%,
at an annual growth of 2.2%. In India and China
alone absolute global increase of 154 million people
is anticipated to happen. In this way diabetes is
continuing to be an international health burden
[1]
.Type 1 Diabetes Mellitus (DM) is characterized by
an extensive and selective loss of pancreatic  cells
and a state of absolute insulin deficiency. In type 2
DM approximately (TTDM) 50% reduction in -cell
mass is observed resulting in a profound defect in
first-phase insulin secretion and insulin resistance. [2]
Diabetic nephropathy is the leading cause of Chronic
Kidney Disease (CKD) in diabetic patients. It is
estimated that 25–40% of patients with type
1diabetes and 5–40% of patients with type 2 diabetes
are more predisposed to develop diabetic kidney
disease. [3]
About one-third of patients with diabetic kidney
disease progress to End-Stage Renal Disease (ESRD)
and contributes in making TTDM as the single
leading cause of ESRD in the Western world as
incidence of nephropathy caused due to type 1
diabetes is declining. [4]
International Journal of Research in
Pharmacology & Pharmacotherapeutics

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Patients with TTDM undergoing maintenance
dialysis have a significant share in financial resources
than those with non-diabetic ESRD. In addition, type
2 diabetic patients show poor performance during
dialysis, leading to an excess mortality. [5]
Diabetic nephropathy is also known as Kimmelstiel-
Wilson syndrome or nodular diabetic
glomerulosclerosis or intercapillary glomerulo-
nephritis. British physician Clifford Wilson and
American physician Paul Kimmelstiel were the first
to describe diabetic nephropathy in 1936. [6]
Diabetic nephropathy (DN) is a clinical syndrome
characterized by the occurrence of persistent micro
albuminuria confirmed on atleast two occasions 3-6
months apart, permanent and irreversible decrease in
glomerular filtration rate (GFR) and arterial
hypertension with the concomitant type 1 or type 2
DM[7,8,9]
.
All patients with TTDM should be screened annually
for CKD, starting at diagnosis.
Urinary albumin excretion should be evaluated from
the albumin-to-creatinine ratio in a random spot
sample.
As some patients with TTDM can have advanced
stage nephropathy in the absence of albuminuria,
evaluation of urinary albumin excretion alone is not
sufficient to assess the presence and severity of CKD
therefore serum GFR estimated from serum
creatinine is also taken into consideration to decide
the level of CKD [10]
.
Table No. - 1 Stages of Diabetic Nephropathy.
Diabetic nephropathy has been didactically
categorized into stages based on the values of urinary
albumin excretion (UAE): micro albuminuria and
macro albuminuria. Micro albuminuria is defined as
urinary albumin excretion greater than 30 mg/24 h
(20 mg/min), and less than or equal to 300 mg/24 h
(200 mg/min) irrespective of how the urine is
collected. The natural course of DN is characterized
by a mean rate of decline in GFR of 10-15
mL/min/year ranging from 0 to 25 mL/min/year. [11]
After the phase of micro albuminuria, there is a
continued increase in urinary protein excretion with
declining glomerular-filtration rate. This results in the
development of Albustix-positive proteinuria and is
known as overt nephropathy or macro proteinuria. If
left untreated, uraemia will supervene and require
referral to end-stage renal-failure programmes such
as dialysis or transplantation.
The renin—angiotensin-aldosterone system in
diabetes [12-20]
Renin—angiotensin-aldosterone system (RAAS)
contributes significantly in pathogenesis of
hypertension and diabetes related complications. The
Suppression of the systemic RAAS is mostly
observed in DN. Renal haemodynamic factors are
thought to be involved in the development and
progression of diabetic kidney disease. Among these,
high intraglomerular pressure and hyperfilteration
coming under the influence of the RAAS system
plays an important role. Angiotensin II formed by the
cleavage of Angiotensin I is the main effector of the
renin–angiotensin–aldosterone system (RAAS).
Level/ Stage of GFR Description Criteria
1 Increased and optimal >90
2 Mild 60-89
3a Mild to moderate 45-59
3b Moderate to severe 30-44
4 Severe 15-29
5 Kidney Failure <15
Albuminuria Stage Description Criteria
1 Optimal and high normal <30
2 High 30-299
3 Very High >300

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Angiotensin II leads to number of rapid effects
including vasoconstriction (which reduces the
capacity of the vascular tree), increased aldosterone
secretion (which leads to salt retention), increased
thirst and release of antidiuretic hormone (which
leads to water conservation), increased myocardial
contractility (which increases cardiac output), and
increased activity of the sympathetic nervous system.
As a consequence of a greater effect of angiotensin II
on efferent than afferent arteriole, the glomerular
capillary pressure increases. These changes in
glomerular hemodynamics are responsible for injury
to visceral epithelial and glomerular endothelial cells
and mesangial expansion and these glomerular
hemodynamic adaptations then finally consequent
upon nephron loss ultimately proving to be
maladaptive and results in damage to remaining
nephrons, thereby establishing a vicious cycle of
progressive nephron loss.
The shear stress and mechanical strain, resulting from
altered glomerular hemodynamics and glomerular
hypertension, cause the release of autocrine and/or
paracrine cytokines and growth factors which in turn
plays a role in genesis of glomerulosclerosis and
interstitial fibrosis.
The generation of advanced glycation proteins occurs
as a result of chronic effects of glucose on tissues
leading to tissue injury. AGE tends to accumulate in
the kidney, particularly in people with diabetes or
declining renal function, or both. Another glucose-
dependent pathway, known as the polyol pathway has
been shown to play role in the pathogenesis of
diabetic nephropathy.
Along with the range of renal functional
abnormalities diabetic nephropathy involves
pathological changes like extracellular matrix
accumulation.
Glucose, AGE, and vasoactive hormones such as
angiotensin II and endothelin stimulates the release of
prosclerotic cytokine, transforming growth factor
(TGF)- in vitro which plays an important role in the
development of diabetic nephropathy. TGF- plays
an important part in mediating the interaction
between metabolic and haemodynamic factors
leading to extracellular matrix accumulation in the
diabetic kidney.
Genetic factors involved in the development
of diabetic nephropathy [21]
Genetic factors contribute significantly in the
susceptibility to diabetic nephropathy. A family
history of hypertension has also been associated with
an increased risk of diabetic nephropathy.
Association between red blood cell sodium-lithium
counter-transport activity and hypertension is noted
by some but not all investigators. Polymorphism of
genes relevant to the renin-angiotensin system such
as ACE and angiotensin type I receptor have been
evaluated.
Factors leading to diabetic nephropathy [22-35]
These changes are mostly caused by following
factors
1. Hyperglycemia
2. Systemic hypertension
3. Glomerular hyper filtration early, with onset of
diabetes late, with renal injury and nephron loss
4. Reduced nephron number
5. Genetic/racial
6. Proteinuria
7. AGEs
8. Anormalities of Renal RAS
9. Lipid abnormalities
The hyperglycemic state sensitizes the endothelium
to injury from elevated blood pressure. Therefore a
successful pancreas transplantation result in normal
insulin regulation and normoglycemia is associated
with a reversal of the lesions of diabetic nephropathy.
Systolic and diastolic hypertension accelerates the
progression of diabetic kidney disease.
The ‘compensatory’ haemodynamic changes
occurring due to hypertension were counter-
productive, leading to mesangial cell stretch,
extracellular matrix deposition and activation of
various autocrine and paracrine factors associated
with tissue injury and ultimately a decline in renal
function.
The role of lipids in progression of nephropathy is
not yet clear. It has been observed that with reduced
nephron number, dietary-induced hyper cholesterole-
mia worsens glomerular injury as well as
administration of Cholesterol-lowering drugs to
Zucker rats were associated with attenuation of
glomerular lesions.

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In diabetes and longstanding hyperglycemia,
nonenzymatic modification of free amino groups of
proteins by glucose and its metabolites leads to
formation of Schiff bases that leads to the AGEs
formation.
Functional changes are produced in kidney by
crosslinking of AGEs with the glomerular basement
membrane and other vascular membranes. It activates
cell signalling mechanisms which leads to increase in
transforming growth factor b (TGF-b) and vascular
endothelial growth factor (VEGF) expression, which
contributes to diabetes complications.
Pathological changes observed in diabetic
nephropathy [36]
Unique changes in kidney structure are observed with
diabetic nephropathy. Classic glomerulosclerosis is
observed with increased glomerular basement
membrane width, diffuse mesangial sclerosis,
hyalinosis, microaneurysm, and hyaline
arteriosclerosis. Tubular and interstitial changes are
also seen. In 40–50% of patients developing
proteinuria areas of extreme mesangial expansion
called Kimmelstiel-Wilson nodules or nodular
mesangial expansion are observed. Micro- and macro
albuminuric patients with type 2 diabetes have more
structural heterogeneity than patients with type 1
diabetes duration, degree of glycemic control, and
genetic factors. There is an important overlap in
mesangial expansion and glomerular basement
membrane thickening among normo albuminuric,
micro albuminuric, and proteinuric type 1 and type 2
diabetic patients with no clear cut off to distinguish
the groups.
Treatment of diabetic nephropathy [2, 37-48]
The increased activity of the renin–angiotensin–
aldosterone system (RAAS) plays an important role
in pathogenesis of nephropathy in diabetic patients.
Angiotensin II leads to vasoconstriction, increase of
aldosterone secretion, growth, fibrosis, thrombosis,
inflammation and oxidation. Therefore blockade of
the RAAS will lead to beneficial effect on the
development of diabetic nephropathy. Treatment of
diabetic nephropathy involves mainly control of the
glycaemic status and aggressive antihypertensive
therapy, primarily with RAAS-blocking agents.
RENAAL and IDNT trials demonstrated the
successful use of Angiotensin receptor blockers in
TTDM for prevention of diabetic nephropathy and
independent decrease in blood pressure.
ONTARGET investigates whether treatment with a
combination of an ACEI and an ARB has a more
potent beneficial effect on the nephropathy in type 2
diabetic patients as compared with separate treatment
with the two agents. Following agents are widely
used in the treatment of diabetic nephropathy.
Angiotensin-converting enzyme inhibitors
Angiotensin II is an important regulator of
cardiovascular function. The ability to reduce levels
of angiotensin II with orally effective inhibitors of
angiotensin-converting enzyme (ACE) represents an
important advance in the treatment of hypertension.
Captopril (CAPOTEN) was the first such agent to be
developed for the treatment of hypertension. Since
then, enalapril (VASOTEC), lisinopril (PRINIVIL),
quinapril (ACCUPRIL), ramipril (ALTACE),
benazepril (LOTENSIN), moexipril (UNIVASC),
fosinopril (MONOPRIL), trandolapril (MAVIK), and
perindopril (ACEON) also have become available.
These drugs have proven to be very useful for the
treatment of hypertension because of their efficacy
and their very favorable profile of adverse effects,
which enhances patient adherence.
1. Captopril (CAPOTEN)
Captopril was the first ACE inhibitor to be marketed
and is a potent ACE inhibitor with a Ki of 1.7 nM. It
is the only ACE inhibitor approved for use in the
United States that contains a sulfhydryl moiety.
Given orally, captopril is absorbed rapidly and has a
bioavailability of about 75%. Peak concentrations in
plasma occur within an hour, and the drug is cleared
rapidly with a half-life of approximately 2 hours.
Most of the drug is eliminated in urine, 40% to 50%
as captopril and the rest as captopril disulfide dimers
and captopril–cysteine disulfide. The oral dose of
captopril ranges from 6.25 to 150 mg two to three
times daily, with 6.25 mg three times daily or 25 mg
twice daily being appropriate for the initiation of
therapy for heart failure or hypertension,
respectively. Most patients should not receive daily
doses in excess of 150 mg. Since food reduces the

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oral bioavailability of captopril by 25% to 30%, the
drug should be given 1 hour before meals.
2. Enalapril (VASOTEC)
Enalapril maleate, the second ACE inhibitor
approved in the United States, is a prodrug that is
hydrolyzed by esterases in the liver to produce the
active dicarboxylic acid, enalaprilat. Enalaprilat is a
highly potent inhibitor of ACE with a Ki of 0.2 nM.
Although it also contains a "proline surrogate,"
enalaprilat differs from captopril in that it is an
analogue of a tripeptide rather than of a dipeptide.
Enalapril is absorbed rapidly when given orally and
has an oral bioavailability of about 60% (not reduced
by food). Although peak concentrations of enalapril
in plasma occur within an hour, enalaprilat
concentrations peak only after 3 to 4 hours. Enalapril
has a half-life of only 1.3 hours, but enalaprilat,
because of tight binding to ACE, has a plasma half-
life of about 11 hours. Nearly all the drug is
eliminated by the kidneys as either intact enalapril or
enalaprilat. The oral dosage of enalapril ranges from
2.5 to 40 mg daily (single or divided dosage), with
2.5 and 5 mg daily being appropriate for the initiation
of therapy for heart failure and hypertension,
respectively. The initial dose for hypertensive
patients who are taking diuretics, are water- or Na+
-
depleted, or have heart failure is 2.5 mg daily.
3. Lisinopril (PRINIVIL, ZESTRIL)
Lisinopril, the third ACE inhibitor approved for use
in the United States, is the lysine analogue of
enalaprilat; unlike enalapril, lisinopril itself is active.
In vitro, lisinopril is a slightly more potent ACE
inhibitor than is enalaprilat. Lisinopril is absorbed
slowly, variably, and incompletely (about 30%) after
oral administration (not reduced by food); peak
concentrations in plasma are achieved in about 7
hours. It is cleared as the intact compound by the
kidney, and its half-life in plasma is about 12 hours.
Lisinopril does not accumulate in tissues. The oral
dosage of lisinopril ranges from 5 to 40 mg daily
(single or divided dosage), with 5 and 10 mg daily
being appropriate for the initiation of therapy for
heart failure and hypertension, respectively. A daily
dose of 2.5 mg is recommended for patients with
heart failure who are hyponatremic or have renal
impairment.
4. Fosinopril (MONOPRIL)
Fosinopril is the only ACE inhibitor approved for use
in the United States that contains a phosphinate group
that binds to the active site of ACE. Cleavage of the
ester moiety by hepatic esterases transforms
fosinopril, a prodrug, into fosinoprilat, an ACE
inhibitor that in vitro is more potent than captopril yet
less potent than enalaprilat. Fosinopril is absorbed
slowly and incompletely (36%) after oral
administration (rate but not extent reduced by food).
Fosinopril is largely metabolized to fosinoprilat
(75%) and to the glucuronide conjugate of
fosinoprilat. These are excreted in both the urine and
bile; peak concentrations of fosinoprilat in plasma are
achieved in about 3 hours. Fosinoprilat has an
effective half-life in plasma of about 11.5 hours, and
its clearance is not significantly altered by renal
impairment. The oral dosage of fosinopril ranges
from 10 to 80 mg daily (single or divided dosage).
The dose is reduced to 5 mg daily in patients with
Na+
or water depletion or renal failure
5. Ramipril (ALTACE)
Cleavage of the ester moiety by hepatic esterases
transforms ramipril into ramiprilat, an ACE inhibitor
that in vitro is about as potent as benazeprilat and
quinaprilat. Ramipril is absorbed rapidly (peak
concentrations of ramipril achieved in 1 hour), and
the rate but not extent of its oral absorption (50% to
60%) is reduced by food. Ramipril is metabolized to
ramiprilat and to inactive metabolites (glucuronides
of ramipril and ramiprilat and the diketopiperazine
ester and acid) that are excreted predominantly by the
kidneys. Peak concentrations of ramiprilat in plasma
are achieved in about 3 hours. Ramiprilat displays
triphasic elimination kinetics with half-lives of 2 to 4
hours, 9 to 18 hours, and greater than 50 hours. This
triphasic elimination is due to extensive distribution
to all tissues (initial half-life), clearance of free
ramiprilat from plasma (intermediate half-life), and
dissociation of ramiprilat from tissue ACE (terminal
half-life). The oral dosage of ramipril ranges from
1.25 to 20 mg daily (single or divided dosage).

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Angiotensin antagonists (Angiotensin
receptor blockers)
Over the past 2 decades, several nonpeptide orally
active AT1 receptor antagonists have been developed
as alternative to ACE inhibitors. These include
losartan, candesartan, valsartan, telmisartan,
irbisartan, etc. Oral bioavailability of ARBs generally
is low (<50%, except for irbesartan, with 70%
available), and protein binding is high (>90%).
1. Candesartan Cilexetil (ATACAND)
Candesartan cilexetil is an inactive ester prodrug that
is completely hydrolyzed to the active form,
candesartan, during absorption from the
gastrointestinal tract. Peak plasma levels are obtained
3 to 4 hours after oral administration, and the plasma
half-life is about 9 hours. Plasma clearance of
candesartan is due to renal elimination (33%) and
biliary excretion (67%). The plasma clearance of
candesartan is affected by renal insufficiency but not
by mild to moderate hepatic insufficiency.
Candesartan cilexetil should be administered orally
once or twice daily for a total daily dosage of 4 to 32
mg.
2. Eprosartan (TEVETEN)
Peak plasma levels are obtained approximately 1 to 2
hours after oral administration, and the plasma half-
life ranges from 5 to 9 hours. Eprosartan is
metabolized in part to the glucuronide conjugate, and
the parent compound and its glucuronide conjugate
are cleared by renal elimination and biliary excretion.
The plasma clearance of eprosartan is affected by
both renal insufficiency and hepatic insufficiency.
The recommended dosage of eprosartan is 400 to 800
mg/day in one or two doses.
3. Irbesartan (AVAPRO)
Peak plasma levels are obtained approximately 1.5 to
2 hours after oral administration, and the plasma half-
life ranges from 11 to 15 hours. Irbesartan is
metabolized in part to the glucuronide conjugate, and
the parent compound and its glucuronide conjugate
are cleared by renal elimination (20%) and biliary
excretion (80%). The plasma clearance of irbesartan
is unaffected by either renal or mild to moderate
hepatic insufficiency. The oral dosage of irbesartan is
150 to 300 mg once daily.
4. Losartan (COZAAR)
Approximately 14% of an oral dose of losartan is
converted to the 5-carboxylic acid metabolite EXP
3174, which is more potent than losartan as an AT1-
receptor antagonist. The metabolism of losartan to
EXP 3174 and to inactive metabolites is mediated by
CYP2C9 and CYP3A4. Peak plasma levels of
losartan and EXP 3174 occur approximately 1 to 3
hours after oral administration, respectively, and the
plasma half-lives are 2.5 and 6 to 9 hours,
respectively. The plasma clearances of losartan and
EXP 3174 (600 and 50 ml/min, respectively) are due
to renal clearance (75 and 25 ml/min, respectively)
and hepatic clearance (metabolism and biliary
excretion). The plasma clearance of losartan and EXP
3174 is affected by hepatic but not renal
insufficiency. Losartan should be administered orally
once or twice daily for a total daily dose of 25 to 100
mg. In addition to being an ARB, losartan is a
competitive antagonist of the thromboxane A2
receptor and attenuates platelet aggregation (Levy et
al., 2000). Also, EXP3179, an active metabolite of
losartan, reduces COX-2 mRNA up-regulation and
COX-dependent prostaglandin generation (Krämer et
al., 2002).
5. Olmesartan Medoxomil (BENICAR)
Olmesartan medoxomil is an inactive ester prodrug
that is completely hydrolyzed to the active form,
olmesartan, during absorption from the
gastrointestinal tract. Peak plasma levels are obtained
1.4 to 2.8 hours after oral administration, and the
plasma half-life is between 10 and 15 hours. Plasma
clearance of olmesartan is due to both renal
elimination and biliary excretion. Although renal
impairment and hepatic disease decrease the plasma
clearance of olmesartan, no dose adjustment is
required in patients with mild to moderate renal or
hepatic impairment. The oral dosage of olmesartan
medoxomil is 20 to 40 mg once daily.
6. Telmisartan (MICARDIS)
Peak plasma levels are obtained approximately 0.5 to
1 hour after oral administration, and the plasma half-

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life is about 24 hours. Telmisartan is cleared from the
circulation mainly by biliary secretion of intact drug.
The plasma clearance of telmisartan is affected by
hepatic but not renal insufficiency. The
recommended oral dosage of telmisartan is 40 to 80
mg once daily.
7. Valsartan (DIOVAN)
Peak plasma levels occur approximately 2 to 4 hours
after oral administration, and the plasma half-life is
about 9 hours. Food markedly decreases absorption.
Valsartan is cleared from the circulation by the liver
(about 70% of total clearance). The plasma clearance
of valsartan is affected by hepatic but not renal
insufficiency. The oral dosage of valsartan is 80 to
320 mg once daily.
CONCLUSION
Increasing cases of Diabetic Nephropathy due to
consistently high TTDM patients has led to various
treatment complications and it has become
alarmingly difficult for the doctors to treat such
patients. There is a scope of development of more
advanced medicines for the treatment of diabetic
nephropathy. Continuous monitoring of the renal
performance and micro and macro albuminuria is
also necessary. Patients also need to take care of their
dietary habits to control the complications related to
diabetic nephropathy. Thus diabetic nephropathy is a
serious condition related to TTDM and needs a lot of
attention to be taken care of.
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