Contrasting results have been reported regarding the prevalence of hypertension in insulin-dependent diabetes mellitus (IDDM), showing a slightly higher.
Insulin-Dependent Diabetes Mellitus and Hypertension
Contrasting results have been reported regarding the prevalence of hypertension in insulin-dependent diabetes mellitus (IDDM), showing a slightly higher or normal percentage of IDDM patients with elevated blood pressure levels than in the general population. Most of the cross-sectional and prospective studies on the prevalence of hypertension in IDDM show an association between microalbuminuria and elevated blood pressure levels. However, it is not clear whether hypertension is simply secondary to kidney damage or whether hypertension occurs with or even before the development of impaired kidney function. Patients with IDDM have a higher exchangeable body Na + pool. Na + retention in IDDM is accounted for by several metabolic and hormonal abnormalities such as hyperglycemia, hyperketonemia, hyperinsulinemia, altered secretion, and resistance to atrial natriuretic peptide. High blood pressure appears to be dependent, at least at some phase, on expansion of extracellular fluid volume as a consequence of defects in the renal secretion of Na + and water. On the other hand, a tendency toward Na" retention characterizes all patients with IDDM, whereas hypertension develops only in a subgroup of diabetic patients. One possible explanation for these findings is that a genetic predisposition plays a role in creating susceptibility to hypertension and perhaps to diabetic nephropathy independent of diabetes, even if Na + retention can further deteriorate this susceptibility to hypertension. With regard to this issue, it has recently been suggested that the risk of kidney disease in patients with IDDM is associated with a genetic predisposition to hypertension. Furthermore, diabetic nephropathy occurs in familial clusters, because diabetic siblings of nephropathic diabetic patients show a higher frequency of diabetic nephropathy than the diabetic From the Institute of Internal Medicine, University Medical Center, Padua, Italy. Address corresondence and reprint requests to Romano Nosadini, MD, Instituto di Medicina Interna, Policlinico Universitario, Via Ciustiniani 2, 35128 Padua, Italy.
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Romano Nosadini, MD Paola Fioretto, MD Roberto Trevisan, MD Gaetano Crepaldi, MD
siblings of nonnephropathic diabetic patients. One of the possible genetic markers that could be useful to identify the diabetic patients with susceptibility to hypertension and diabetic nephropathy is the N a - L i + countertransport activity in erythrocytes. Diabetes Care 14:210-19, 1991
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iabetic nephropathy has been shown to reach a peak of incidence between the 15th and the 20th yr of diabetes duration (1,2). Patients with diabetic nephropathy often have elevated blood pressure, which has been presumed to be a consequence of kidney damage. However, blood pressure in patients with insulin-dependent diabetes mellitus (IDDM) and microalbuminuria are often raised before there is evidence of impaired kidney function (3-5). It is not clear which of these variables precedes the other in the development of nephropathy. Increased blood pressure levels in the parents of IDDM patients who develop diabetic nephropathy has been reported, suggesting that a genetic predisposition to hypertension is a mechanism capable of developing renal complications in IDDM patients (6,7). At variance with these findings, no difference in blood pressure level or prevalence of hypertension was found between the parents of diabetic patients with and without nephropathy at the Steno Memorial Hospital in Copenhagen (8,9). However, the hypothesis that elevated blood pressure should be a primary event in the development of clinical nephropathy received further support from a large-scale retrospective study by Borch-johnsen et al. (10). They found that the blood pressure of IDDM patients who had survived >40 yr was significantly lower than in the background population (10), suggesting that a predisposition
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R. NOSADINI AND ASSOCIATES
to low blood pressure might protect against development of diabetic nephropathy. Cross-sectional and prospective studies could be useful to clarify the relationships between the progression of microalbuminuria and the increase in blood pressure level in IDDM. Christlieb et al. (11) reported that, in white diabetic patients >24 yr old, the prevalence of hypertension was higher than in either the Framingham population or the general United States population. Further information provided by studies performed at the Joslin Clinic (Boston, MA) showed that patients with IDDM who later died from kidney failure usually developed both hypertension and proteinuria approximately at the same time between 20 and 30 yr of age, indicating that hypertension is of renal origin in these cases (11). At variance with these reports, hypertension was found by Kelleher et al. (12) among IDDM patients (15%) as frequently as among control subjects (16%). The discrepancy in the prevalence of hypertension in IDDM patients could be at least partially accounted for by differences in the criteria used to recruit the diabetic population. For example, Parving et al. (13) determined the prevalence of microalbuminuria and hypertension in adults with >5 yr duration of IDDM that had started before the 41st yr of age. The prevalence of arterial hypertension increased with increased albuminuria, being 19, 30, and 65% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively. A different approach to analyze the relationships between hypertension and diabetic nephropathy is that provided by the studies done mainly in young IDDM subjects with a relatively short duration of disease, when it is reasonable to assume that kidney function is not yet impaired. Moss et al. (14), in children from adolescence on, showed elevated systolic blood pressure in diabetic patients compared with nondiabetic control subjects. Cruickshanks et al. (15) also reported higher systolic and diastolic blood pressure levels in 149 diabetic patients 9-16 yr of age compared with 45 unaffected siblings. On the other hand, Kaas-lbsen et al. (16) found no difference in systolic blood pressure levels between diabetic and nondiabetic girls, whereas the diastolic blood pressure level tended to be even lower in diabetic girls. Tarn and Drury (17) examined blood pressure levels in 97 male and 66 female patients with IDDM 4-32 yr of age and in 137 male and 95 female nondiabetic siblings. There were no significant differences in systolic blood pressure levels between diabetic and nondiabetic siblings of either sex, but phase IV diastolic blood pressure was significantly higher in male diabetic patients, and the mean difference in diastolic blood pressure between male diabetic patients and nondiabetic subjects was 2.8 mmHg. Altogether, 19% of male patients with IDDM had relative hypertension (mean blood pressure >90th percentile for age, derived from values of siblings for each sex separately) compared to 9% of nondiabetic siblings. For females, the figures were 14 and 13%, respectively. Age did not account for the rise in diastolic
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blood pressure in male diabetic subjects, and it was not solely explained by early diabetic nephropathy. The duration of diabetes showed no significant effect on blood pressure in either sex. Contrasting reports on this issue have also been provided by recent studies performed in different areas of Europe, with different genetic background and environmental factors possibly influencing the occurrence of IDDM, hypertension, and the development of diabetic nephropathy. Indeed, Mathiesen et al. (18) prospectively followed 209 consecutive normotensive patients with IDDM from 1982 to 1988 in the Steno Memorial Hospital and found that only 15 of the 209 patients had developed persistent microalbuminuria 5 yr later and that a significant elevation in urinary albumin excretion rate precedes the increase in systemic blood pressure. A similar prospective approach has been used at Guy's Hospital in London to elucidate the relationships between microalbuminuria and hypertension in IDDM. At variance with the previous reports from Steno Memorial Hospital, blood pressure level was found to be significantly higher in diabetic patients who subsequently developed microalbuminuria than in those who remained normoalbuminuric (19). More recently, the Italian Microalbuminuria Study Group reported that the prevalence of hypertension among 4040 IDDM patients was 12% compared to 19% in the general population (20) and that blood pressure levels were already slightly but significantly increased in patients with an early increase in the urinary albumincreatinine ratio between 2 and 3.5 (mg/mM, albumin/ creatinine), although the albumin excretion rate was still normal (e.g.,
