Diabetic Renal Disease: The Quest for Normotension—and Beyond

Over the past two decades there has been an increasing interest in hypertension as a risk factor for diabetic renal disease and in particular for the possibility of early antihypertensive intervention. Therefore, it would seem timely to review the history of hypertension in diabetes, with special reference to renal disease and the need for normotension, in a manner resembling glycaemic control. Elevated blood pressure (BP) associated with diabetes mellitus has been recognized since the beginning of the century and was initially particularly documented in association with the demonstration of the striking histological lesion in glomeruli, starting with the observation of Kimmelstiel and Wilson in 1936. These patients in many cases also showed hypertension, as confirmed in several subsequent reports, very similar to the studies of Kimmelstiel and Wilson. However, the development was hampered by the lack of effective antihypertensive agents and also by some who believed that elevated BP could be of importance to preserve renal function in these individuals. Indeed, it was suggested that reduction of BP could mean permanent deterioration in renal function. BP remained very high in the standard care of diabetic patients up to the middle 1970s. At this time it was documented that elevated BP was very closely related to development of diabetic renal disease in Type 1 (insulin‐dependent) diabetic (IDDM) patients, and studies also showed a correlation between blood pressure and rate of progression. This correlation stimulated research in intervention, and indeed in the 1980s and 1990s several long‐term studies reported that antihypertensive treatment can reduce the rate of decline in glomerular filtration rate (GFR) from about 12ml min ‐1 yr ‐1 down to about 2ml min ‐1 yr ‐1 in the most optimistic reports; usually a mean level of 2–5 ml min ‐1 yr ‐1 is achievable by antihypertensive treatment, in clinical situations where glycaemic control often is far from perfect. Many studies have also documented that BP starts to rise in the early phase of incipient diabetic nephropathy characterized by microalbuminuria. This is a stage with well‐preserved GFR and therefore probably an ideal stage for intervention in these at risk patients. Many studies, in particular those employing angiotensin converting enzyme (ACE) inhibitors based on important pathophysiological concepts proposed by Brenner, have shown that microalbuminuria can be reduced or stabilized by early antihypertensive treatment, just as we see with optimized glycaemic control. ACE inhibitors have also been widely used in patients with overt nephropathy and the rate of decline in GFR has been reduced considerably. However, it seems likely that an equal rate of decline in GFR may be achieved also by other BP‐reducing agents, but there is some disagreement in the literature. With respect to strong end‐points such as mortality and development of uraemia, retrospective studies suggest a beneficial effect of antihypertensive treatment with beta‐blockers and diuretics. Importantly, there is, however, only one formal randomized study showing effects on these end‐points, namely by ACE inhibitors, as compared to other antihypertensive agents, but still BP was more extensively reduced with the former treatment. Thus, the history of hypertension in diabetes in IDDM patients documents that BP is now being intensively treated in comparison to 15–20 years ago. Also the indication for prescription of treatment has been modified downwards and it has even been proposed that microalbuminuria should be an indication for treatment irrespective of BP. Parental hypertension or pre‐diabetic or pre‐nephropathy BP has been suggested to play a role for progression in renal disease, but there is still some controversy in this area, although this concept has gained strong support in the Pima‐Indian studies. A new development is the use of ambulatory 24‐h BP recordings (comparable to HbA 1c measurements) which must be used when a correlation between BP (and glycaemia) and progression of renal disease and intervention is in focus. Documentation of white‐coat hypertension is important to avoid unnecessary treatment in the normoalbuminuric IDDM patients. Generally speaking, the quest for normotension is just as strong or stronger (and better achievable) as a quest for near‐normoglycaemia, at least in IDDM patients and in particular in patients with incipient or overt renal disease.