Effects of Sodium Intake on Albumin Excretion in Patients with Diabetic Nephropathy Treated with Long-Acting Calcium Antagonists

Methods

All patients were recruited from the Rush University Hypertension Clinic. We selected 15 of the 22 patients screened. These patients met the following inclusion criteria: They 1) had had non–insulin-dependent diabetes mellitus for more than 5 years, 2) had blood pressure greater than 140/90 mm Hg, 3) were older than 45 years of age, and 4) had albumin excretion greater than 500 mg/d. All patients signed an informed consent form approved by the institutional review board of Rush-Presbyterian-St. Luke's Medical Center before entering the study.

All 15 patients had a complete history and physical examination and an ophthalmologic evaluation to test for proliferative retinopathy. Initial laboratory tests included a complete blood count; measurements of serum electrolyte, calcium, magnesium, blood urea nitrogen, creatinine, hemoglobin A_1c, and fasting blood glucose levels; liver function studies; electrocardiography; and microscopic analysis of the spun urine. Patients were then formally counseled by a registered dietitian about diets consisting of 50 mEq and 250 mEq of sodium per day.

The study protocol is outlined in Figure 1. All patients began receiving a diet of 50 mEq of sodium per day, and antihypertensive medications were withheld for 2 weeks. Therapy with all other medications, including oral hypoglycemic agents, was continued. Patients then began receiving oral clonidine, because studies have shown that antihypertensive medications of this class do not significantly reduce albumin excretion [11]. After 4 weeks, two consecutive 24-hour urine collections were used to measure baseline creatinine clearance, albumin excretion, and sodium levels. All patients then received once-daily nifedipine for 1 month, after which the measures were repeated. A diet of 250 mEq of sodium per day was subsequently initiated, and, after another 4 weeks, measures were again repeated. Patients received clonidine during the 4-week washout period, and the protocol was then repeated with once-daily diltiazem (Figure 1). Furosemide was given to all patients in the initial phase of the study after the clonidine dose was titrated to 0.3 mg twice daily. This was done to control both edema and arterial pressure.

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Figure 1. Asterisks indicate weeks during which blood pressure, creatinine clearance, albumin excretion, and sodium excretion (2 consecutive days) were measured. For weeks marked with daggers, only blood pressure was measured. Study protocol.

We measured blood pressure by the cuff method using a standard mercury column-filled sphygmomanometer and a properly sized cuff. Systolic pressure was recorded when the initial sound was heard (Korotkoff, phase I), and diastolic pressure was recorded when the sound disappeared (Korotkoff, phase V). Weight, blood pressure, and pulse were measured monthly, the latter two measures at 10-minute intervals between 8:00 a.m. and 10:00 a.m. while the patient was in the sitting position.

We independently designed and did this study with no input or influence from the funding source in gathering, analyzing, or interpreting the data. The statistical analysis was done by investigators blinded to the data.

All data are expressed as the mean ±SD and were analyzed using a paired t-test. A two-factor repeated-measure analysis of variance was done to assess the effect of sodium intake on the ability of each calcium antagonist to alter albumin excretion. Side effects were evaluated using a McNemar test. Statistical significance was denoted as a P value less than 0.05.

Results

The baseline patient demographic and metabolic characteristics included a history of non–insulin-dependent diabetes of 11 ± 3 years and a history of hypertension of 6 ± 4 years. Fifty-three percent of patients were black, and 87% had a family history of cardiovascular disease. The baseline hemoglobin A (_1c) level was 9.9% ± 0.3%, and the baseline cholesterol level was 6.49 ± 0.36 mmol/I.

Patients reached the blood pressure goal of less than 140/90 mm Hg with either calcium antagonist (Table 1). The mean dose of once-daily nifedipine required to achieve this goal was 83 ± 9 mg; for once-daily diltiazem, the dose was 392 ± 27 mg. Albumin excretion was not reduced when patients received a diet of 250 mEq of sodium per day, regardless of the antihypertensive medication used (Table 1). A diet of 50 mEq of sodium per day in combination with once-daily diltiazem reduced albumin excretion (2967 ± 784 mg/d at baseline compared with 1294 ± 679 mg/d after diltiazem therapy; P < 0.05). Albumin excretion was not reduced after a similar period of blood pressure reduction with once-daily nifedipine (Table 1). Changes in creatinine clearance and arterial pressure did not contribute to reductions in albumin excretion with high sodium intake (Table 1).

The most common side effects were headaches (37%) and pedal edema (50%) with once-daily nifedipine and mild nausea (7%) and flushing (15%) with once-daily diltiazem.

Conclusion

Our data support previous reports that showed no reduction in albumin excretion with nifedipine and a decrease in albumin excretion with diltiazem [5, 6, 12-15]. We further show that reductions in albumin excretion were only noted when patients received a low-sodium diet during diltiazem therapy. Thus, arterial pressure reduction without a low-sodium diet will not maximally decrease albumin excretion in patients with diabetic nephropathy.

Sodium may alter albumin excretion through its effect on intrarenal hemodynamics and glomerular permeability [10]. Reductions in sodium intake decrease albumin excretion in hypertensive patients receiving converting enzyme inhibitors [9]. Calcium antagonists and converting enzyme inhibitors have different hemodynamic profiles [5, 15]. However, the overall renal hemodynamic profiles of diltiazem and nifedipine are similar. Moreover, nifedipine does not alter glomerular permeability with blood pressure reduction [12, 13]. Thus, our data support the observation that a low-sodium diet expresses a diltiazem-associated change in glomerular permeability [14].

Antihypertensive agents that reduce both arterial pressure and albumin excretion in patients with insulin-dependent or non–insulin-dependent diabetes may yield better renal survival over agents that only reduce arterial pressure [1-616, 17]. Thus, low sodium intake may be an important therapeutic intervention that expresses optimal benefit of certain calcium antagonists.

Our conclusions, however, must be viewed within the confines of our study's limitations, including a nonrandomized study design and a small sample of patients with diabetic nephropathy receiving loop diuretics. Despite these problems, we still noted differences between the calcium antagonists. Thus, although these data are not generalizable to patients without diabetic nephropathy, they express important differences in sodium-mediated drug effects on the kidney.