A.Richard Christlieb

The changing natural history of nephropathy in type I Diabetes

Events in the natural history of diabetic nephropathy (including the onset of persistent proteinuria and end-stage renal failure) were studied in a cohort of 292 patients with juvenile-onset type I diabetes who were followed for 20 to 40 years. The risk of persistent proteinuria increased rapidly between the fifth and 15th years of diabetes and declined thereafter. This pattern suggests that susceptibility to this complication was limited to a subset of patients and was exhausted over time. Patients with the most frequent severe hyperglycemia (the highest quartile) during the first 15 years of diabetes had a risk of persistent proteinuria that was four and a half times higher than that for those with the least frequent hyperglycemia (the lowest quartile). Patients whose diabetes was diagnosed in the 1930s had twice the risk of persistent proteinuria as those in whom the condition was diagnosed in later decades. Once persistent proteinuria appeared, progression to renal failure almost always followed. Half reached this stage within 10 years, and the interval for progression did not vary according to sex, frequency of hyperglycemia, or calendar year of diagnosis of diabetes. This period, however, was significantly shorter (eight versus 14 years) for patients whose diabetes was diagnosed after puberty than for those who were younger at onset. In conclusion, the development of diabetic nephropathy consists of at least two stages. The onset of proteinuria, although related to the level of exposure to hyperglycemia, appears to be influenced by genetic and/or environmental factors. The second stage, progression to renal failure, seems to be influenced by processes related to maturation or aging.

Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus

The risk of premature coronary artery disease (CAD) and its determinants were investigated in a cohort of 292 patients with juvenile-onset, insulin-dependent diabetes mellitus (IDDM) who were followed for 20 to 40 years. Although patients with juvenile-onset IDDM had an extremely high risk of premature CAD, the earliest deaths due to CAD did not occur until late in the third decade of life. After age 30 years, the mortality rate due to CAD increased rapidly, equally in men and women, and particularly among persons with renal complications. By age 55 years the cumulative mortality rate due to CAD was 35 +/- 5%. This was far higher than the corresponding rate for nondiabetic persons in the Framingham Heart Study, 8% for men and 4% for women. Angina and acute nonfatal myocardial infarction followed a similar pattern, as did asymptomatic CAD detected by stress test, so that their combined prevalence rate was 33% among survivors aged 45 to 59 years. Age at onset of IDDM and the presence of eye complications did not contribute to risk of premature CAD. This pattern suggests that juvenile-onset diabetes and its renal complications are modifiers of the natural history of atherosclerosis in that although they profoundly accelerate progression of early atherosclerotic lesions to very severe CAD, they may not contribute to initiation of atherosclerosis.

Evolving natural history of coronary artery disease in diabetes mellitus

White diabetic patients are at high risk of developing coronary artery disease (CAD). The natural history of CAD in insulin-dependent (ID) and noninsulin-dependent (NID) diabetes mellitus (DM) is reviewed to gain insight into the mechanisms responsible for the development of premature or accelerated atherosclerosis in diabetic patients. In both IDDM and NIDDM, the risk of CAD increases with lengthening duration of diabetes; the risk, however, does not grow as a constant multiple of the nondiabetic risk of CAD, suggesting that the cumulative exposure to diabetes plays a significant role as a risk factor for CAD only in a subset of patients. This is consistent with the hypothesis that the diabetic milieu has an impact on the progression of atherosclerotic lesions but not on their initiation. This hypothesis is corroborated further by the observation that CAD does not occur in diabetic patients in populations with a low risk of CAD among nondiabetic patients. The component of the diabetic milieu responsible for promotion of atherosclerotic lesions is unknown. There is evidence, however, of a direct or indirect role of hyperinsulinemia in this process.

Acute myocardial infarction in diabetes mellitus and significance of congestive heart failure as a prognostic factor

Diabetes mellitus has been associated with high mortality rates in patients with acute myocardial infarction (AMI). To better define prognosis in this population, the clinical course of 183 diabetics with AMI was studied. In-hospital mortality for all patients was 28% (52 of 183 patients). Mortality was significantly higher in patients with prior AMI than in patients without prior AMI (41 vs 18%, p less than 0.01) and was significantly higher in women than in men (37 vs 19%, p less than 0.01). The 2-fold increase in mortality among diabetic women was observed both in patients with and without prior AMI. The excess mortality among diabetic women was attributable to their increased risk for severe congestive heart failure (CHF) and cardiogenic shock. Death due to CHF occurred in 22% of all diabetic women with AMI compared with 6% of the diabetic men (p less than 0.01). Death resulting from complications other than CHF was similar for both sexes. There were no male-female differences in the history of prior AMI, systemic hypertension, obesity, nephropathy, frequency of Q-wave AMI, anterior AMI or peak creatine kinase levels to account for the high risk for CHF in diabetic women. It is therefore concluded that diabetic women with AMI are at increased risk for death due to CHF, and that this risk is not readily attributable to known conditions associated with CHF.

Renal vein renin activity in the prognosis of surgery for renovascular hypertension

Abstract Twenty-four hypertensive patients underwent corrective surgery for renal hypertension. The postoperative follow-up period was one year or more in all. In twelve patients the results were classified as excellent (five patients) or good (seven patients). Type of surgery (nephrectomy, thirteen patients; vascular repair, eleven patients) was not a factor in the clinical results. Renal vein renin activity ratio and absolute renal vein renin activity from the involved kidney provided the most accurate means of predicting surgical results. The ratio correctly predicted the surgical result in eleven of fourteen patients, and the absolute level correlated correctly in all but one of fourteen patients. Divided ureteral function tests did not distinguish between patients whose condition was and was not improved by surgery, and the intravenous pyelogram, although adequate for screening for the presence of functional renovascular disease, included a high proportion of false-positive tests. Aortography, although revealing the arterial stenosis in all instances, emphasized the need for confirmation of the functional significance of the lesion since half the patients with stenosis did not respond to surgery. On the basis of our experience, renal vein renin determinations appear to be a highly reliable means of selecting patients for corrective renal surgery.

Hypertension, orthostatic hypotension and the microvascular complications of diabetes

Prevalences of hypertension and orthostatic hypotension and their relationship to the microvascular complications of diabetes were assessed in 702 individuals aged 18-74 years, who had been selected as a representative sample of surviving patients with diabetes diagnosed at the Joslin Clinic between 1939 and 1965. In diabetes of short, long and very long duration, hypertension was 1.7, 1.9 and 2.1 times more frequent, respectively, than in the white U.S. population, regardless of gender. The excess frequency of hypertension in short duration diabetes suggests that some etiologic factor is shared by both conditions, while the magnification of the excess with increasing duration could be explained by an effect of diabetes on the kidney. Hypertension without accompanying proteinuria was not associated with retinopathy. Orthostatic hypotension was observed in 12% of the males and 13% of the females. The magnitude of the fall in systolic blood pressure was correlated with age, postprandial blood glucose, supine diastolic blood pressure, and the presence of retinopathy. Patients with proliferative retinopathy had the largest fall in systolic blood pressure.

Plasma renin activity in children with coarctation of the aorta

Abstract Peripheral plasma renin activity was studied in 16 children, aged 2 to 13 years, with coarctation of the aorta and in 11 normal children. There was no significant difference in plasma renin activity between the two groups. Seven of the patients with coarctation of the aorta had angiotensin infusion tests, all of which were negative. In a group of patients with renovascular hypertension, a significant proportion had elevated peripheral plasma renin activity. These findings suggest that the hypertension associated with coarctation of the aorta is not associated with increased activity of the reninangiotensin system. The hypertension may, however, be renal in origin without operating through the reninangiotensin system. It is also possible that kidney renin secretion may be elevated to a degree that could lead to hypertension but not produce a detectable increase in peripheral plasma renin activity.

Renin: A Risk Factor for Cardiovascular Disease?

Abstract Sixty-seven of 80 patients with essential hypertension were prospectively studied for a mean 5 years. The prevalence of well-known risk factors had no apparent association with renin level...

The pattern of plasma renin activity and aldosterone secretion in normal and hypertensive subjects before and after saline infusions

Abstract The pattern of plasma renin activity and aldosterone secretion was studied in 56 unselected patients with essential hypertension and in 10 hypertensive patients with renal complications. The results were compared to responses found in 17 normal subjects and 6 patients with verified primary aldosteronism. In all cases, plasma renin activity and aldosterone secretion rates were measured under precise conditions of metabolic balance, initially during dietary salt restriction and then after physiologic saline infusions. Abnormally low responses in plasma renin activity to salt restriction were found in 13 patients with essential hypertension (25 percent), and in 4 there was no significant increase with standing. The expected increase in aldosterone secretion also failed to occur in 9 patients, 6 of whom demonstrated low plasma renin activity. The great majority of patients with essential hypertension responded normally to saline infusions with decreased plasma renin activity and aldosterone secretion, but in 4 patients the latter was greater than 300 μg/day after saline infusion. The response of hypertensive patients with renal complications was not different from that seen in uncomplicated cases. Although there was great variation in the responses seen in individual patients with essential hypertension, the combination of suppressed plasma renin activity and autonomous, excessive aldosterone secretion was found in only 1 patient. In this unselected series, the maximal incidence of primary aldosteronism (using the currently accepted criteria) was less than 5 percent.

RENAL ARTERY STENOSIS IN HYPERTENSIVE DIABETICS

The incidence of atherosclerotic renal artery stenosis was compared in consecutive renal angiography of 28 hypertensive diabetics and 104 hypertensive non-diabetics. Mean age and sex distribution were comparable. Angiographic evidence of atherosclerotic renal artery stenosis was present in 10 diabetics (36 per cent) and 50 non-diabetics (48 per cent). Stenosis was considered hemodynamically significant if the renal vein renin ratio of the involved to uninvolved side was 1.4:1.0 or more. A renal vein renin ratio equal to or more than 1.4 was observed in 4 of 7 diabetics (57 per cent) and 31 of 47 non-diabetics (67 per cent). Fibromuscular hyperplasia was not seen in diabetics but was present in 12 per cent of the non-diabetics. Hypertension was treated surgically and improved in 2 of 3 diabetics (67 per cent) and in 17 of 19 non-diabetics (89 per cent) with angiographic and hemodynamic evidence of renal artery stenosis. In this series the incidence of atherosclerotic renal artery stenosis of physiologic consequence was not significantly different in hypertensive diabetics when compared to hypertensive non-diabetics.