Diabetic Nephropathy: What is Best Therapeutic Option?
Authored by Maryam Zain
Keywords
Keywords:
Blood pressure; Diabetes; Kidneys; Sodium; Microalbuminuria;
Macroalbuminuria; Oxidative stress; Management; Treatment; Reactive
oxygen speceis
Introduction
The present review focused on the most important
metabolic disorder which is affecting every fourth of the diabetic, and
is known as diabetic nephropathy. This review focused on the
hypertension in diabetic nephropathy, its clinical aspects, management
and guidelines. Hypertension is the most common phenomenon in diabetics.
It increases the risk of kidney diseases and diabetes and increases the
chances for morbidity and mortality. Diabetic nephropathy is the most
common cause of Chronic Kidney Disease (CKD) in those with diabetes and
is the leading cause for incident end stage renal disease (ESRD). The
mechanism of hypertension in diabetic nephropathy is complex, not
completely understood, and includes excess accumulation of sodium,
sympathetic nervous system (SNS) and renin-angiotensin-aldosterone
system (RAAS) activation and increased oxidative stress. Both
non-pharmacological and pharmacological interventions, including RAAS
antagonists are critically important in the management of hypertension
in diabetic nephropathy.
The purpose of this article is to examine the
pathophysiology which leads to hypertension in diabetic nephropathy and
the clinical trials that support the implementation of strategies aimed
at these pathophysiological mechanisms.
Diabetic Nephropathy and Hypertension
The hypertension is the condition which is found to be twice in diabetics as compared to the general population [1]. The hypertensive patient's prevalence is also twice as compared to normal patients with respect to diabetes [2].
However, the prevalence of hypertension varies in type 1 and type 2
diabetic subjects according to the micro albuminuria and macro
albuminuria levels due to infiltration in kidneys [1]. In type 1 diabetic subjects the hypertension is prevalent in the patients of micro albuminuria and overt nephropathy [2]. While, in case of normoalbuminuric patients the prevalence was found to be somewhat different i.e., 19% [3].
According to one Danish report including 1700 diabetics and 10,000
controls, the prevalence of hypertension (160/95mmHg) was found to be
similar to that of the control subjects [2]. The proteinuria and microalbuminuria is considered to be a potential biomarker for diabetic and non-diabetic renal disease [4,5].
In addition to this, the hemodynamic metabolic and genetic parameters
which are common in the diabetic patients. Some genes are found to
enhance the progression of disease while others are found to be
renoprotective [6,7].
Factors Enhancing Hypertension and Diabetic Nephropathy
Multiple factors contributes to the development of
hypertension in type 1 and type 2 diabetic subjects, which results in
the dysregulation of the systems that regulate the vascular balances in
the body. Various factors like activation of RAAS (Renin Angiotensin
Aldosterone pathway), increased Reactive Oxygen Species (ROS), increase
in the activity of endothelial dysfunction and decreased activity of
nitric oxide are involved in these derangements. These factors actually
increase the activity of non hemodynamic factors that increases the risk
of cardiovascular and kidney diseases. The details of these factors are
given below:
Renin angiotensin aldosterone system (raas) pathway
RAAS pathway has been extensively studied with
reference to the cardiovascular diseases and hypertension. As there are
various enzymes and genes which contribute to the occurrence of not only
diabetic nephropathy but also cardiovascular diseases in most of the
patients of type 1 and type 2 diabetes. The action of Angiotensin II is
mainly responsible for the increase in the vasoconstriction and sodium
reabsorption which ultimately increases the blood pressure [8].
The pharmacological drugs are available in the market which inhibits
the production of angiotensin II and block AT1R and thus it targets the
RAAS pathway.
Sodium balance
The increase in the sodium plays a very important in
hypertension in diabetics and renal disease patients. It has been
documented that the people with the renal disease have an increase level
of sodium even in the absence of the activity of RAAS pathway [2].
As Glomerular Filtration Rate (GFR) declines, the kidneys ability to
filter some important metabolites decreases which continuously increased
the level of the sodium thus damage to the glomerular cells [9].
Thus in diabetic nephropathy patients the care must be given with
reference to sodium intake and low doses of sodium in diet must be
preferred.
Sympathetic nervous system (SNS) activity
Increased SNS activity results in the increased
pathogenesis of diabetic and nephropathy complications. It increases the
microalbuminuria and other complications related to diabetes. An
increased adregenic activity with high nocturnal blood pressure was also
observed in the diabetic nephropathy patients [10-12].
Nitric oxide
Although the exact role of the nitric oxides are not
well documented for hypertensive and diabetic patients. According to
some reports the nitric oxide levels are increased in the hyper
filtration kidney stages of diabetes. The diabetic rats induced by
streptozotocin showed an increased blood pressure by the inhibition of
nitric oxide, thus proved that nitric oxide is also one of the factor
for hypertension in diabetics [13].
Oxidative stress
Hyperglycemia is considered to be one of the factors for increased oxidative stress in type 2 diabetic patients [14]. In chronic kidney diseases also there is an increased oxidative stress and decrease antioxidant defenses [3,4]. Reduction in oxidative stress correlates with the albuminuria in the diabetic patients [5].
Through various experimental evidences it was also proved that the
reduction in oxidative stress results when the angiotensin II levels
becomes low [6].
Nitric oxide in combination with Reactive Oxygen Species (ROS) produces
peroxynitrite which is responsible for increase in oxidative stress [7].
Autoregulatory impairment
In healthy and normal kidneys the auto regulatory
functions of the afferent arterioles and juxtaglomerular apparatus are
responsible for maintaining the blood pressure. When these mechanisms
are impaired as in diabetic nephropathy elevated blood pressure is
transmitted to the renal vasculature and it results in the increase in
the blood pressure, inflammation, fibrosis, injury and other kidney
related impairments. These mechanisms also induced the transport of
glucose transporter 1 that is responsible for hyperglycemia in diabetic
patients [8].
Management of Hypertension in Diabetic Nephropaty
Guidelines
The essential target for the treatment of the
diabetic nephropathy is the reduction in the hypertension and
albuminuria, as these two parameters are found to be raised in diabetic
patients. In type 1 diabetic patients however it was found that 80% of
the type 1 diabetic subjects developed due to microalbuminuria and later
to macroalbuminuria. Out of these 80% patients about 50-75% of them
will develop to End Stage Renal Disease (ESRD) in their next twenty
years of life [9].
However for untreated type 2 diabetes mellitus subjects the conditions
are somewhat different and about 40% of the patients develop to the
overt nephropathy condition whereas the 20% of the type 2 diabetic
subjects developed ESRD [10].
Hypertension is considered as the main factor which is responsible for
the occurrence of the nephropathy and cardiovascular diseases in both of
the type 1 and type 2 diabetic subjects. One drug as the captopril is
found to decrease the craetinine levels in diabetic patients with the
average decline in creatinine clearance of about 11mL/min/y [11].
For type 2 diabetic patients however the irbesartan resulted in
creatinine clearance of 5.5mL/ min/yr as compared to 6.8mL/min/yr in the
placebo group or in the persons having the treatment of amlodipine [12].
Some Angiotensin Converting Enzyme (ACEi) inhibitors and Angiotensin
Receptors Blockers (ARBs) are also found to be more effective in the
treatment of diabetic nephropathy which is discussed below.
ACE inhibitors and ARB blocker as monotherapy
The ACE inhibitors and Angiotensin receptor blockers
are considered as the first line of treatment against diabetic
nephropathy. The ACE inhibitors are considered as the best treatment for
the decrease of the GFR and prevention of albuminuria in type 1
diabetic patient [11,12].
Various types of ACE inhibitor drugs are available for example,
enalapril, ramipril, captopril, benzapril etc which in combination with
renin inhibitors as aliskiren and angiotensin receptor blockers as
telmisartin and volsartin are used for controlling diabetic nephropathy [13-15].
Angiotensin receptor blockers (ARB)
Angiotensin Receptor Blockers (ARBs) are also
effective in controlling the hypertension. The mechanism of their action
is that they block the Angiotensin II type 1 receptor (AT1R). The AT1R
blockade results Angiotensin II to bind to Angiotensin type 2 receptor
(AT2R) and it results in the decrease of the blood pressure and also
reduced renal interstitial fibrosis [15].
Combination therapy of ARB and ACE inhibitors has been proved in some
of the studies to be more beneficial and useful in terms of reducing the
hypertension, proteinuria, blood pressure and cardiovascular
complications [16].
Direct renin inhibitors (DRIs)
One of the drugs which is used commonly for the
reduction in albuminuria and hypertension in the diabetic nephropathy
patients is the Direct Renin Inhibitors (DRIs) pharmacologically named
as Aliskiren [17].
For this drug the combination therapy proved to be effective. The
losartan and Aliskiren in combination found to be much effective for the
reduction of the albuminuria and albuminuria along with albumin to
creatinine ratio in type 2 diabetic patients [18].
So, a number of therapeutic trials confers that when the
pharmacologically blocking agents block the RAAS pathway, it reduces the
risk of progression of diabetes by 20% to 25% and improving
cardiovascular conditions [19-25].
Target Blood Pressure in Diabetic Nephropathy
There were certain retrospective and follow up
studies which were conducted to study the effect of blood pressure on
renal and cardiovascular diseases. One large study 'The Action in
Diabetes and Vascular Disease (ADVANCE) study included 11,140 patients
with diabetes and cardiovascular diseases. They were given the ACE
inhibitors and thiazide drugs. The incidence of microalbuminuria and
creatinine levels were found to be decreased in the patients along with
the improvement in systolic blood pressure [26].
This large study thus provide the evidence that the RAAS inhibitors are
favourable for the decrease in systolic blood pressure in ESRD and DN
patients.
General Guidelines
Improved blood pressure control and reduction in
albuminuria is considered as the main targets when treating the patients
of diabetic nephropathy. The Renin Angioten Aldosterne System is one
ofthe major pathway which is involved in the control of the blood
pressure. There are certain drugs known as the loop diuretics which are
considered as encouraging in reducing the GFR<50mL/min and
hyperkalemia. Certain experiments of low sodium diet as well as RAAS
inhibitors are also considered as an effective strategy in controlling
the progression of chronic kidney diseases in diabetics. The emphasis on
the control of salt intake is given because the salt retention is
considered as the main reason for enhancement of the glomerulosclerosis
and chronic kidney diseases in diabetics. The beta blockers and calcium
channel blockers should be recommended for the patients of hypertension.
Some drugs like clonidine, vasodilators (hydralazine and minoxodil) and
alpha blockers are found to be more effective in patients having the
persistent hypertension. The hyperkalemia is found to be effective in
patients who are having the thiazide drug treatment [27].
The control of BP below 130/85mmHg in addition to the low sodium
intake, with daily dosage of <200mg daily while the persons are on
RAAS inhibition is found to be more effective.
Conclusion
The Diabetic nephropathy is the most common cause of
the kidney diseases in the patients with diabetes. Hypertension is
highly prevalent in the patients of type 1 and type 2 diabetes. The
mechanism which is involved in hypertension in diabetic nephropathy
subjects are the activation of the local and renal RAAS, systemic
nervous system activity, increased oxidative stress and abnormal no
production etc. These mechanisms are responsible for the onset and even
worsening of the condition of diabetic nephropathy and they also
contributes to the increased risk of cardiovascular diseases. The
management for the hypertension and diabetic nephropathy includes the
therapies that block the angiotensin production. The blood pressure and
treatment goals includes the reduction in blood pressure to 130/80mmHg.
For achieving this control the non pharmacological drugs as well as
antihypertensive treatment is considered to be more beneficial. However,
the overall results of the combination therapies of various drugs of
RAAS pathway are still under experimentation.
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