Arterial hypertension

In Type 1 DM, hypertension is usually a result of diabetic nephropathy and manifests at the stage of microalbuminuria. In Type 2 DM, hypertension is present at the time of diagnosis of diabetes in a third of the patients and may coexist with other parameters of the metabolic syndrome X, a common pathogenetic mechanism which is insulin resistant. It may also be due to diabetic nephropathy, coexistent idiopathic arterial hypertension, renal vascular disease or other causes.

Systolic and diastolic hypertension promote diabetic nephropathy to a significant degree. Aggressive antihypertensive treatment in Type 1 diabetic patients with already overt diabetic nephropathy, not only decreases albumin excretion rate (AER) but may also essentially delay decline of glomerular filtration rate (GFR) and decelerate progression to end stage renal disease. The UKPDS study also showed that BP control in Type 2 DM may decrease nephropathy risk (by 29 percent) irrespective of the kind of antihypertensive regimen (with a beta-blocker or an inhibitor of angiotensin converting enzyme).

The target is to achieve BP values < 130/80 mmHg. When urinary protein excretion is larger than 1 g/24 h, then BP control target should be lower (< 120/75 mmHg).

Both types of medicines that block the rennin-angiotensin system (i.e., ACE inhibitors and angiotensin receptors blockers [ARBs]) can be used with priority in the treatment of albuminuria/nephropathy. This has been proven in many studies and is explained by the special action of these medicines in the renal glomerulus and from a wide range of other actions that will be mentioned later. If intolerance to one category develops, the other can be used instead.

In hypertensive and non-hypertensive Type 1 diabetic patients with microalbuminuria, it has been proven that ACE inhibitors delay progression of nephropathy (that is, they decrease albumin excretion rate and progression to macroalbuminuria).

Furthermore, in hypertensive and non-hypertensive Type 2 diabetic patients with microalbuminuria, the beneficial effect of ARBs on delay of nephropathy deterioration and progression to macroalbuminuria has been proven (IRMA II and MARVAL studies). In studies specifically performed on Type 2 diabetic patients with hypertension, macroalbuminuria (albumin excretion rate > 300 mg/24 h) and mild renal insufficiency, ARBs were proven to delay progression of nephropathy (IDNT and RENAAL studies).

The basic mechanisms through which ACE inhibitors cause a reduction in BP are as follows: i) inhibition of angiotensin II formation; and ii) inhibition of bradykinin degradation resulting in its accumulation, nitric oxide (NO) and prostacyclin formation and subsequent vasodilatation.

Renoprotective mechanisms of ACE inhibitors, apart from a decrease in systemic blood pressure - a common feature of all antihypertensives -include many other actions, the majority of which refer to the category of ARBs as well. These include:

• A decrease in intraglomerular hypertension due to relaxation of the constricted efferent glomerular arteriole. A characteristic pathologic lesion in DM is an increase in intraglomerular pressure through vasodilatation of the afferent arteriole (due to effects of prostaglandin, bradykinin, atrial natriuretic peptide, etc.) and transmission of pressure from systemic circulation. Furthermore, there is constriction of the efferent arteriole due to an angiotensin II effect, which apart from its known systemic vasoconstrictive effect, contributes to the progression of renal disease through a variety of mechanisms. These include an increase in the formation of various cytokines in the kidney, such as transforming growth factor-b (TGF-b), collagen type IV, laminin, fibronectin and others. Evolving intraglomerular hypertension is considered responsible for the excretion of albumin and increase in basement membrane thickness. Thus, medicines of this category are considered as first line treatment of diabetic nephropathy due to their selective action on renal glomerulus.

• An increase in renal perfusion.

• A decrease in glomerular membrane permeability and decrease in proteinuria.

• A decrease in peripheral insulin resistance.

• A decrease in transforming growth factor-b (TGF-b) and other cytokines, resulting in a decrease in extracellular matrix deposition.

Therapy with ACE inhibitors has also been associated with a decrease in cardiovascular mortality and incidence of stroke and myocardial infarction, in patients with a high risk of cardiovascular disease, including patients with DM (HOPE study). In a recent comparative study of the renoprotective action of ACE inhibitors and ARBs (telmisartan versus enalapril) in Type 2 diabetic patients with incipient nephropathy, no clinical superiority of one versus the other was proven. This fact proves the equivalence of these two categories of medicines for use in diabetic patients at high risk of deterioration of renal function and cardiovascular events. A recent study in hypertensive Type 2 diabetic patients without nephropathy, showed that an ACE inhibitor or a combination of an ACE inhibitor with verapamil (a non-dihydropyridine calcium channel blocker) delayed onset of microalbuminuria compared with verapamil alone or placebo (that is, use of other antihypertensive medicines for blood pressure control). This is the first indication of a preventive renoprotective effect of ACE inhibitors compared to other antihypertensives in DM. These findings should be considered preliminary, however, and we need to wait for the results of other similar studies before a reliable conclusion for the use of ACE inhibitors as preventive renoprotective therapy in Type 2 DM can be drawn. It should be also noted that the group that received ACE inhibitor (or combination with verapamil) in that particular study, had a slightly better BP control (by 3 mmHg).

In the other categories of antihypertensive medications that have been used in diabetic nephropathy, dihydropyridine calcium channel blockers (nifedipine, etc.), when used in comparison to ACE inhibitors at doses that produced a similar antihypertensive result, had unpredictable effects on microalbuminuria (they can decrease, increase, or leave it unchanged). Furthermore, differences in the actions of the various calcium channel blockers have been observed. This denotes that they should not be considered as a uniform group regarding their action in diabetic nephropathy. Thus, in two studies, enalapril and captopril significantly decreased AER, whereas nitrendipine and nifedipine increased it, despite the fact that they had a similar antihypertensive effect to the ACE inhibitors. In other studies, verapamil and diltiazem (non-dihydropyridine calcium channel blockers) decreased AER regardless of their antihypertensive action.

As regards beta-blockers, they also inhibit renin secretion, resulting in a decrease in angiotensin II, relaxation of efferent arteriole and, consequently, an action similar to ACE inhibitors at the level of the kidney. If there is an indication, therefore (for example, ischaemic heart disease), they can be combined with other antihypertensive medicines for treatment of hypertension accompanying diabetic nephropathy.

The same is true for diuretics and the other antihypertensive categories (centrally acting, etc.) which have no proven selective action on the nephron. In advanced stages of CRF, however, the use of loop diuretics and calcium channel blockers (or another antihypertensive category) is preferred for BP treatment, while ACE inhibitors (or ARBs) are to be used carefully, with serum K+ monitoring, due to the fear of hyperkalaemia.

Diet

At the stage of clinical proteinuria, a relative restriction of food protein at a level of 0.8 g/kg body weight per day is recommended, i.e. almost the usually recommended level of intake for adults (10 percent of daily caloric intake). At the stage of CRF, a further restriction of protein intake is recommended (to the level of 0.6 g/kg body weight per day), as well as of sodium and phosphorus, with administration of phosphorus binding medicines, if necessary.

Furthermore, cessation of smoking is recommended, due to its well known association with macro- and micro-vascular complications. At every stage of diabetic nephropathy, therapy is supplemented with strict lipid control (target an LDL-cholesterol level < 100 mg/dl [2.6mmol/L], triglycerides < 150 mg/dl [1.7mmol/L] and HDL-cholesterol > 40 mg/dl [1.03 mmol/L]), initially with hypolipidaemic therapy and then with antilipidaemic factors (preferably with statins aiming at LDL and total cholesterol decrease). Additionally, regular monitoring of the haemato-crit should be performed (for the possibility of anaemia development), as well as monitoring of 24-hour urine protein excretion and serum electrolytes (sodium, potassium, calcium and phosphorus) which, due to the coadministration of diuretics and ACE inhibitors (or ARBs), can have many variations.

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