Hypertension and diabetic nephropathy: relationship, significance and management - abstract

ABSTRACT

During the past 10 years, several investigators have accumulated evidence for defining the relationship between systematic blood pressure levels and diabetic nephropathy. Studies showing the presence of insulin resistance in obese normotensive individuals, non-obese hypertensives, and in non-insulin-dependent diabetes mellitus (NIDDM) raise the possibility of shared pathogenic mechanisms in essential hypertension and diabetes mellitus. It is accepted that control of hypertension retards the progress of renal functional impairment in Diabetic Nephropathy (DN); what remains unknown is the class of antihypertensive agent best suited to this clinical situation. A case has been made for the angiotensin-converting enzyme inhibitors (ACE-Is) which have been demonstrated to have a renoprotective effect greater than can be attributed to lowering systemic blood pressure levels alone. Microalbuminuria is accepted as being an index of glomerular damage and a prognostic indicator for the development of DN and dip-stick detectable proteinuria. The ACE-I enalapril was shown to be more effective in reducing proteinuria than metoprolol, although both drugs reduced systemic blood pressure levels to a similar degree in the patients studied. On the other hand, the dihydropyridine calcium channel blocking agent (CCB), nifedipine, increased albuminuria whereas non-dihydropyridine CCBs did not. The animal experimental evidence suggesting glomerular hypertension as the mechanism through which albuminuria and subsequent glomerulosclerosis develop is persuasive. The differential renoprotective effects of the various hypertensive agents have therefore been related to their differing abilities to modulate both afferent and efferent glomerular arteriolar tone in a manner which produces net reduction in intraglomerular pressure. In clinical circumstances, selection of antihypertensive agents will be guided by the metabolic neutrality of the agent among other attributes, and ACE-Is and CCBs appear to have the most favourable profiles. Finally, the questions of how soon and how far to treat systemic hypertension in diabetics remain to be answered. Does one use ACE-iS to treat microalbuminuric and proteinuric patients who are still normotensive? To what level does one reduce the blood pressure in order to achieve optimal renoprotection in DN? There are now several survival studies of hypertensive patients which purport to show declining mortality with reduction of Diastolic Blood Pressure (DBP) levels to certain end-points, with a subsequent rise in mortality when DBP has been further reduced below approximately 85 mm Hg. The caveat of the "J-shaped" curve applies primarily to those patients with associated ischaemic heart disease, a condition which is frequently encountered in diabetes mellitus. Presumably, in those patients with associated left ventricular hypertrophy, reduction of DBP below a critical level compromises the coronary artery reserve and the blood supply to a mismatched ventricular mass. The ideal blood pressure lowering agent in DN is therefore one which reduces intraglomerular as well as systemic blood pressures, reduces albuminuria, is metabolically neutral, and reduces left ventricular mass. The ACE-Is and the CCBs fulfil these requirements but only ACE-Is decrease insulin resistance. Whether this latter "plus" will be shown to be critical is yet to be demonstrated (AU)