Robert J. Hamburger

SINGLE-DRUG THERAPY FOR HYPERTENSION IN MEN A Comparison of Six Antihypertensive Agents with Placebo

BACKGROUND Characteristics such as age and race are often cited as determinants of the response of blood pressure to specific antihypertensive agents, but this clinically important issue has not been examined in sufficiently large trials, involving all standard treatments, to determine the effect of such factors. METHODS In a randomized, double-blind study at 15 clinics, we assigned 1292 men with diastolic blood pressures of 95 to 109 mm Hg, after a placebo washout period, to receive placebo or one of six drugs: hydrochlorothiazide (12.5 to 50 mg per day), atenolol (25 to 100 mg per day), captopril (25 to 100 mg per day), clonidine (0.2 to 0.6 mg per day), a sustained-release preparation of diltiazem (120 to 360 mg per day), or prazosin (4 to 20 mg per day). The drug doses were titrated to a goal of less than 90 mm Hg for maximal diastolic pressure, and the patients continued to receive therapy for at least one year. RESULTS The mean (+/- SD) age of the randomized patients was 59 +/- 10 years, and 48 percent were black. The average blood pressure at base line was 152 +/- 14/99 +/- 3 mm Hg. Diltiazem therapy had the highest rate of success: 59 percent of the treated patients had reached the blood-pressure goal at the end of the titration phase and had a diastolic blood pressure of less than 95 mm Hg at one year. Atenolol was successful by this definition in 51 percent of the patients, clonidine in 50 percent, hydrochlorothiazide in 46 percent, captopril in 42 percent, and prazosin in 42 percent; all these agents were superior to placebo (success rate, 25 percent). Diltiazem ranked first for younger blacks (< 60 years) and older blacks (> or = 60 years), among whom the success rate was 64 percent, captopril for younger whites (success rate, 55 percent), and atenolol for older whites (68 percent). Drug intolerance was more frequent with clonidine (14 percent) and prazosin (12 percent) than with the other drugs. CONCLUSIONS Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of a drug.

Community-acquired acute renal failure

Acute renal failure usually occurs during hospitalization, but may also be present on admission to the hospital. To define the causes and outcomes of community-acquired acute renal failure, we undertook a prospective study of patients admitted to the hospital with acute elevations in serum creatinine concentrations. Over a 17-month period, all admission serum creatinine determinations were screened for patients with values greater than 177 mumol/L (2 mg/dL). These values were compared with baseline creatinines to select patients with an acute elevation in serum creatinine occurring outside the hospital. One hundred patients were entered into the study, with an overall incidence of 1% of hospital admissions. Seventy percent of the patients had prerenal azotemia, 11% had intrinsic acute renal failure, 17% had obstruction, and 2% could not be classified. Mean peak serum creatinine (318 +/- 18 mumol/L [3.6 +/- 0.2 mg/dL]) and mortality (7%) was lowest in the group with prerenal azotemia. In this group, volume contraction due to vomiting, decreased fluid intake, diarrhea, fever, glucosuria, or diuretics was the most common underlying cause. The group with intrinsic acute renal failure had the most severe renal failure and the highest mortality (55%). Although ischemic acute tubular necrosis is the most common cause of hospital-acquired intrinsic acute renal failure, this etiology was seen in only one patient. Drug-induced nephrotoxicity and infection-related causes were the most common underlying etiologies of intrinsic acute renal failure. Obstructive renal failure had a mortality of 24% and was most commonly due to benign prostatic hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

The natural history of incidental renal artery stenosis in patients with aortoiliac vascular disease

PURPOSE To examine the association between incidentally discovered renal artery stenosis and deterioration of renal function as determined by the change in serum creatinine concentration over time. SUBJECTS AND METHODS We performed a retrospective review of consecutive patients who underwent aortography for aortoiliac vascular disease. Angiograms were reviewed for renal artery stenosis, defined as a narrowing of at least 20% compared with adjacent normal renal artery. For patients with at least 180 days of subsequent follow-up, the change in serum creatinine concentration per year was compared in patients who had or did not have renal artery stenosis. RESULTS Of the 201 patients, 96 (48%) had some degree of renal artery stenosis in one or both renal arteries, including 53 (26%) who had at least one stenosis > or= 50% and 40 (20%) who had bilateral stenoses. The only clinical predictor of renal artery stenosis was a history of coronary artery disease (odds ratio = 2.0, 95% confidence interval: 1.2 to 3.8, P = 0.001). Among the 174 patients with > or =180 days of follow-up, there was no statistically significant difference (P = 0.88) in the mean change in serum creatinine concentration per year in the 78 patients with renal artery stenosis (0.06+/-0.33 mg/dL per year) as compared with the 96 patients without renal artery stenosis (0.06+/-0.22 mg/dL per year). Grouping the patients by the maximal percentage of stenosis did not reveal any difference in the mean changes in serum creatinine concentration per year. CONCLUSIONS Although renal artery stenosis is a common incidental finding in patients with atherosclerotic vascular disease, it is an uncommon cause of progressive renal disease.

Alterations in hemostatic parameters during hemodialysis with dialyzers of different membrane composition and flow design: Platelet activation and factor VIII-related von willebrand factor during hemodialysis

The effect of dialyzer membrane and design on hemostatic parameters during hemodialysis were evaluated in a prospective controlled study. This study demonstrated that hemodialysis is associated with significant platelet activation and loss, which are influenced by both dialyzer configuration and membrane composition. In addition, use of the cuprophan membrane is associated with greater perturbations of the vascular endothelium, as reflected in changes in factor VIII-related von Willebrand factor and 6-keto-prostaglandin F1 alpha concentrations not seen with the polyacrylonitrile membrane. Of the dialyzers studied, the polyacrylonitrile membrane in a hollow-fiber configuration appears to minimize platelet loss and activation, and to minimize increases in factor VIII-related von Willebrand factor and 6-keto-prostaglandin F1 alpha.

Emphysematous cystitis and pyelitis in a diabetic renal transplant recipient

Emphysematous cystitis is a rare complication of urinary tract infection. Patients with diabetes mellitus, neurogenic bladder, bladder outlet obstruction, and recurrent urinary tract infection are at increased risk for the disease. We present a case of emphysematous cystitis and pyelitis in a diabetic renal transplant recipient. He was treated with antibiotics alone with complete clinical and radiologic resolution. The clinical course was benign, as described in most patients. The prognosis of emphysematous cystitis is good after early diagnosis and prompt treatment with appropriate antibiotics, blood glucose control, and adequate urinary drainage.

Superficial and Deep Juxtaglomerular Apparatus Renin Activity of the Rat Kidney EFFECT OF SURGICAL PREPARATION AND NaCl INTAKE

The intrarenal gradient of renin activity was determined in rats by using superficial (S) and deep (D) cortical juxtaglomerular apparatuses (JGAs), identified and microdissected after silicone-rubber compound injection. Angiotensin generated from single JGAs using partially purified sheep renin substrate was quantified by rat bioassay. When, in rats on a normal NaCl diet, silicone-rubber was injected into a carotid artery, alone or with abdominal aorta catheterization, S:D renin activity ratios were 1.18+/-0.08 (SEM) and 1.21+/-0.12, respectively. The S:D renin activity ratios obtained when silicone-rubber was injected into the abdominal aorta (2.52+/-0.09) or a chronic carotid artery catheter (3.44+/-0.40) were significantly higher (P < 0.001). The lower S:D renin activity ratios after carotid artery manipulation were due to significantly higher D-JGA renin activities. This increased D-JGA renin activity and the lack of a renin gradient appear to be related to acute carotid artery manipulation. Alterations in JGA renin activity were examined relative to NaCl intake. 2 wk after high-NaCl diet the absolute net renin activity decreased (P < 0.001) more in S (5.84+/-0.11 ng AI.JGA(-1).h(-1)) than D (1.73+/-0.06 ng AI.JGA(-1).h(-1)) JGAs, and the intrarenal renin gradient was lost (S:D-JGA renin activity, 1.00+/-0.07), as compared to the regular NaCl diet. 2 wk of a low-NaCl diet resulted in a greater (P < 0.01) increase in S (14.28+/-1.47 ng AI.JGA(-1).h(-1)) than D (9.62+/-1.19 ng AI.JGA(-1).h(-1)) JGA renin activity and a renin gradient (S:D-JGA renin activity) of 1.75+/-0.12. These results demonstrate that NaCl intake clearly influences total JGA renin content and may also affect the relative intrarenal distribution of renin activity.

Distal tubule [Na+] and juxtaglomerular apparatus renin activity in uranyl nitrate induced acute renal failure in the rat

SummaryIt has been previously demonstrated that single nephron filtration rate, whole kidney glomerular filtration rate and total renal blood flow decreased by 30–35% 6 h after uranyl nitrate induced acute renal failure in the rat. In order to evaluate a role of the renin-angiotensin system in the initiating phase (0–6 h) of this model of acute renal failure, determinations of plasma renin activity, superficial (S) and deep (D) juxtaglomerular apparatus (JGA) renin activity and distal nephron [Na+] were obtained. Plasma renin activity increased from the control value of 1.5±0.3 (S.E.M.) to 2.9±0.4 ng/ml/h (P<0.005) at 6 h. Mean renin activity in S- and D-JGAs of control rats was 6.99±0.41 and 2.67±0.21 ng/JGA/h, respectively. After uranyl nitrate, renin activity in S-JGAs increased to 13.62±0.80 ng/JGA/h (P<0.001) at 2 h and remained elevated, 12.56±0.90 and 12.75±0.87 ng/JGA/h at 4 and 6 h. D-JGA renin activity increased (P<0.05) to 7.04±0.53, 6.23±0.31 and 3.44±0.33 ng/JGA/h at 2, 4 and 6 h after uranyl nitrate. Distal tubule [Na+], 27 samples in 6 rats, increased from a mean control value of 53.7±1.2 mEq/l to 116.9±2.5 mEq/1, 24 samples in 6 rats (P<0.001).Prompt increases in JGA renin activity were observed in the initiating phase of acute renal failure, suggesting a role for the renin-angiotensin system in the pathophysiology of this nephrotoxic model. The association of increased JGA renin activity and increased distal [Na+] is consistent with a role for the tubuloglomerular feedback mechanism in the initiating phase of uranyl nitrate induced acute renal failure in the rat.

Effects of reduction in drugs or dosage after long-term control of systemic hypertension

The possibility of discontinuing--compared to reducing--antihypertensive drug treatment was investigated in 606 male hypertensive patients with entry diastolic blood pressure (BP) in the range of 90 to 114 mm Hg. Diastolic BP was controlled at less than 90 mm Hg with 1 of 4 regimens: low dose hydrochlorothiazide (HCTZ), 25 mg twice daily; high dose HCTZ, 50 mg twice daily; or high dose HCTZ plus a low or high dose of a step II drug (propranolol, clonidine or reserpine). After 6 months of treatment that controlled BP, dosages were reduced in two-thirds of the patients. In those patients receiving low dose HCTZ and randomized to dose reduction, antihypertensive drugs were completely discontinued. Although approximately half of these patients remained normotensive for the first 6 months, a significantly greater proportion had elevation of BP compared to the control group, which continued to receive treatment (p less than 0.0001). In the high dose HCTZ drug group, the proportion of patients remaining normotensive did not differ among those stepped down to low dose HCTZ and the fully treated control group. While not achieving significance the trend was similar with the step II regimens. Although some patients remained normotensive after discontinuation of step II drugs, a greater proportion returned to elevated BP than when step II dosage was unchanged. Therefore, while stopping therapy may be effective in some patients, a decreased dosage is significantly more effective as a method for maintaining an antihypertensive effect. Decreasing drug dosages offers the dual benefit of minimizing side effects and reducing drug costs.

Comparison of plasma lipid and lipoprotein profiles in hypertensive black versus white men

An abnormal plasma lipid and lipoprotein profile is an independent and strong predictor of mortality and morbidity from coronary artery disease (CAD). We report on plasma lipid and lipoprotein profiles with respect to race, age, obesity, blood pressure (BP), smoking, and drinking history in 1,292 male veterans with a diastolic BP of 95 to 109 mm Hg while off antihypertensive medications. Blacks had 24% (p <0.001) lower triglycerides than whites. In contrast, the following parameters were higher in blacks than in whites by the indicated percentages: high-density lipoprotein (HDL) cholesterol, 16% (p <0.001); HDL2 cholesterol, 36% (p <0.001); apolipoprotein (Apo) A1, 8% (p <0.001); HDL/low-density lipoprotein (LDL), 18% (p = 0.018); HDL2/LDL, 36% (p = 0.031); HDL2/HDL3, 21% (p <0.001); and Apo A1/Apo B, 15% (p <0.001). Triglycerides were unchanged up to age 60, but were lower by 24% (p <0.001) in those aged > or = 70. Apo A1 levels were higher (p <0.001), whereas LDL cholesterol was lower (p <0.008) in moderate alcohol consumers versus abstainers. Triglycerides were higher (p <0.001), whereas HDL, HDL2 cholesterol, and Apo A1 were lower (p <0.001) with increasing obesity. Moderate alcohol consumption had a strong favorable effect on HDL, HDL2, and HDL3 cholesterol among subjects of normal weight, but this effect was diminished in obese subjects. Total and LDL cholesterol were higher by 6.4% (p = 0.001) and 9.4% (p <0.003), respectively, whereas HDL cholesterol remained unchanged in those with diastolic BP of 105 to 109 mm Hg versus those with diastolic BP of 95 to 99 mm Hg. We conclude that hypertensive black men have lipid and lipoprotein profiles indicative of less CAD risk than white men. Chronic moderate alcohol consumption correlates with a favorable plasma lipid and lipoprotein profile in normal, but not obese, men. Obesity is associated with an adverse plasma lipid and lipoprotein profile. Thus, race, alcohol intake, and obesity may be important modifiers of CAD in untreated hypertensive men.

Tubuloglomerular feedback response after hypotensive hemorrhage.

The tubuloglomerular feedback (TGF) response was studied in control rats and after either hypotensive hemorrhage or aortic clamping (AC). TGF was assessed both by differences in proximally and distally determined single nephron glomerular filtration rate (SNGFR) and by proximally determined SNGFR responses to orthograde microperfusion at 0 or 36 nl/min. Hypotensive hemorrhage was induced by the removal of blood equivalent to 0.5-1% of body weight. In control rats, proximal SNGFR was 29.74 +/- SE 0.87 nl/min and distal SNGFR was 28.64 +/- 0.82 nl/min, values not significantly different from each other. After moderate hemorrhagic hypotension (MH: BP = 86 +/- 1 mm Hg) or AC (BP = 70 +/- 4 mm Hg), both proximal and distal SNGFR decreased, with no significant differences between the values in either group. After severe hemorrhagic hypotension (SH; BP = 70 +/- 1 mm Hg), proximal SNGFR was 25.23 +/- 2.07 nl/min and distal SNGFR was 19.69 +/- 1.50 nl/min, values significantly different from each other and consistent with an enhanced feedback response. Using orthograde microperfusion, a significant reduction in SNGFR at a perfusion rate of 36 nl/min was observed under all circumstances. However, with SH hypotension the percent change in SNGFR at the two perfusion rates was significantly increased to 35.0 +/- 5.5%, compared to 21.6 +/- 6.6% in controls. In contrast, AC with reduction in renal perfusion pressure to a degree comparable to SH hypotension did not augment the relative decrease in SNGFR, the percentage change being 22.2 +/- 7.2%. Neither was TGF enhanced after MH hypotension when similar volumes of blood were removed but a similar decrease in BP was not obtained. These results suggest that some factor related to severe systemic hypotension enhanced the TGF response.