G. K. van der Hem

Prevention of relapses in Wegener's granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre

58 patients with biopsy-proven Wegeners granulomatosis (WG) were prospectively screened for clinical evidence of the disease 3-monthly, with antineutrophil cytoplasmic antibody (ANCA) measurements every month. Over 24 months, ANCA rose in 20 patients, 9 of whom were randomly assigned to receive combined 9 and 3 month courses of cyclophosphamide and prednisolone, respectively, at the time of ANCA rise; and 11 patients who were untreated except if there was a clinical relapse. 6 of 11 untreated patients relapsed within 3 months of ANCA rise. 3 of the remaining 5 patients relapsed after 3 months. There were no early or late relapses in patients randomised to treatment. Patients receiving no treatment at the time of ANCA rise took more cyclophosphamide and prednisolone than patients who were treated. Side-effects did not significantly differ between the two groups.

NEPHROPTOSIS AND HYPERTENSION

The degree of renal mobility was measured in patients with and without hypertension to evaluate a suggested causal relation between nephroptosis and hypertension. In contrast to men, women often showed pronounced renal mobility and the degree of renal mobility correlated positively with the blood-pressure. Fibromuscular dysplasia of the renal artery was always accompanied by a considerable degree of renal mobility on the side involved. The results of this study indicate that in women there may be an association between abnormal renal mobility and the development of high blood-pressure.

Antihypertensive effect of a 5-day infusion of atrial natriuretic factor in humans.

Atrial natriuretic factor was infused in a low dose (0.2 μg/min) during 5 days in six patients with essential hypertension. Atrial natriuretic factor infusion caused plasma levels of atrial natriuretic factor to increase from 49±10 to 106±19 pg/ml. Within 4 hours after the start of the atrial natriuretic factor infusion, urinary sodium excretion increased hi all subjects. Sodium balance was regained after 24 hours with a net loss of 72.3±14.6 mmol. However, systolic as well as diastolic blood pressure started to decrease gradually in all subjects only after 12 hours of atrial natriuretic factor infusion, reaching a stable level after 36 hours with a decrease of 11.5±1.5% and 10.3±0.8%, respectively. Heart rate increased in parallel by 12.6±3.1%. Hematocrit rose 7.1±2.3%. After cessation of atrial natriuretic factor infusion, plasma atrial natriuretic factor levels, sodium balance, and hematocrit returned to baseline within 24 hours, whereas blood pressure slowly returned toward baseline values over 3 days. These data show that chronic atrial natriuretic factor infusion in patients with essential hypertension causes a negative sodium balance and a rise in hematocrit, followed by a smooth decrease in blood pressure with a rise in heart rate until a new equilibrium is reached after approximately 2 days. Thus, atrial natriuretic factor in low doses appears intimately involved in the regulation of sodium balance and blood pressure in humans. Moreover, these data suggest that atrial natriuretic factor-like substances will eventually become useful antihypertensive drugs.

EFFECT OF HUMAN ATRIAL-NATRIURETIC-PEPTIDE ON BLOOD-PRESSURE AFTER SODIUM DEPLETION IN ESSENTIAL-HYPERTENSION

Human atrial natriuretic peptide was infused over four hours in three patients with essential hypertension. When the patients had a sodium intake of 200 mmol (mEq) daily an infusion of 0.5 micrograms atrial natriuretic peptide/min caused no significant change in blood pressure, whereas an infusion of 1.0 micrograms/min caused a gradual decrease in blood pressure and an increase in heart rate. After two to three hours of infusion with the higher dose two patients showed a sudden decrease in heart rate, with symptomatic hypotension. When the same patients had an intake of 50 mmol sodium daily their blood pressure was more sensitive to infusion of atrial natriuretic peptide; one patient again developed symptomatic hypotension, this time during an infusion of 0.5 micrograms/min. During all infusions distinct natriuresis occurred irrespective of whether blood pressure was affected. Prolonged, relatively low dose infusions of atrial natriuretic peptide can cause unwanted symptomatic hypotension. The effect on blood pressure is enhanced after sodium depletion, and blood pressure should be monitored carefully during longer infusions of atrial natriuretic peptide in patients with essential hypertension.

Immune Response to Two Different Hepatitis B Vaccines in Haemodialysis Patients: A 2-Year Follow-Up

Formalin-inactivated hepatitis B vaccine was given at 0, 1 and 6 months to 22 medical staff members and to 37 haemodialysis patients. After vaccination with 20 micrograms surface antigen (HBsAg), seroconversion occurred in 95% of the staff members. Following immunisation with a double dose, only 74% of the haemodialysis patients developed antibodies against HBsAg (anti-HBs). Anti-HBs levels were lower in the patient group and 6 responders (23%) became anti-HBs-negative within 2 years. 40 other haemodialysis patients were immunised at monthly intervals with either three doses of 3 micrograms or three doses of 27 micrograms heat-inactivated hepatitis B vaccine. Seroconversion was achieved in 60% of the patients in the 3-micrograms group and in 95% of the patients in the 27-micrograms group. Anti-HBs levels increased significantly when the high dose was used. Although the study design does not allow a definite conclusion, it appears that the immunogenicity per microgram HBsAg is higher for the heat-inactivated vaccine than for the formalin-inactivated vaccine. The findings further indicate that decreased immune response to hepatitis B vaccination in haemodialysis patients can be improved by increasing the dose of the vaccine. A booster injection should be considered in these patients within 2 years after the first vaccination.

Changes in Renal Function Induced by ACE-lnhibition in the Conscious Two-Kidney, One-Clip Goldblatt Hypertensive Dog

In order to study why the diagnostic sensitivity of 123I-hippurate renography for a renal artery stenosis is improved by angiotensin converting enzyme (ACE-) inhibition we used the model of the conscious chronically instrumented two-kidney, one-clip Goldblatt hypertensive dog. Urine flow (UV), renal blood flow (RBF), glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured (with constant infusion of 125I-iothalamate and 131I-hippurate, respectively) for both kidneys separately before and after a bolus injection of a mild unilateral renal artery stenosis (approximately 30% reduction of RBF). During ACE-inhibition, there were remarkable falls in poststenotic GFR (from 37 +/- 5 to 4 +/- 2 ml/min, p less than 0.05), ERPF (from 111 +/- 13 to 21 +/- 10 ml/min, p less than 0.05) and UV (from 0.86 +/- 0.15 to 0.075 +/- 0.045 ml/min, p less than 0.05), whereas RBF of the poststenotic kidney slightly increased (from 193 +/- 18 to 237 +/- 27 ml/min, p less than 0.05). The concentration of hippurate and thalamate in the blood remained remarkably constant while the excretion of the tracers by the poststenotic kidney diminished and renal retention of 123I-hippurate was seen on the renogram. In 2 dogs, the experiments were repeated during mannitol infusion. In that situation, there was a much smaller decrease of poststenotic UV and GFR whereas ERPF even showed a small increase comparable to the RBF changes.(ABSTRACT TRUNCATED AT 250 WORDS)

IS THE ANTIPROTEINURIC EFFECT OF DIPYRIDAMOLE HEMODYNAMICALLY MEDIATED

We studied the acute antiproteinuric and renal hemodynamic effect of dipyridamole 30–60 mg intravenously in 13 salt-depleted patients with the nephrotic syndrome of different etiology. Whereas mean arterial pressure did not change, a small fall in glomerular filtration rate with a concomitant fall in filtration fraction and a decrease in urinary protein loss occurred. The fall in filtration fraction was positively correlated with the fall in proteinuria. This suggests that the antiproteinuric effect of dipyridamole is at least partly due to an efferent vasodilation with a fall in intraglomerular capillary pressure.

ANGIOTENSIN CONVERTING ENZYME-INHIBITION IMPROVES DIAGNOSTIC PROCEDURES FOR RENOVASCULAR HYPERTENSION IN DOGS

In renovascular hypertension adaptive mechanisms in the poststenotk kidney are a probable cause of the 20 to 25% false-negative findings during rapid sequence urography or [123I]oiodohippurate renography. We blocked the renin-angiotensin system in an effort to increase the yield of these diagnostic procedures. Chronically instrumented, salt-depleted conscious dogs were used in which a light (n = 5), moderate (n = 4), or severe (n = 2) renal artery stenosis was induced. Before stenosis 10 of the dogs showed no left-right differences with either diagnostic procedure, and angiotensin converting enzyme (ACE) inhibition did not change this result. Two to 3 weeks after induction of a renal artery stenosis, all dogs showed signs of renovascular hypertension. However, only 50% of the renograms and 22% of the urograms showed differences between the two kidneys indicative of the presence of stenosis. After ACE inhibition, all previously negative test results became positive (abnormal) and previously existing left-right differences became more evident. Ekctromagnetically measured renal blood Bow on the stenotic side did not change during ACE inhibition (146 ± 13 vs 145 ± 21 ml/mm), whereas contralateral blood flow showed a distinct increase (207 ± 18 vs 282 ± 20 ml/min, p < 0.01). In conclusion, ACE Inhibition markedly improves the sensitivity of rapid sequence urography and hlppurate renography in the diagnosis of renovascular hypertension in the two-kidney, one clip Goldblatt hypertensive dog. The effects of ACE inhibition on the handling of the different tracers do not appear to be related to its effects on renal blood flow or systemic blood pressure.

Atrial natriuretic factor influences renal diurnal rhythm in essential hypertension.

We investigated in six patients with essential hypertension the effect of a low dose atrial natriuretic factor infusion for 5 days on the diurnal rhythm of renal electrolyte excretion. Atrial natriuretic factor infusion increased the net excretion of sodium and caused a delay in its time of maximal diurnal urinary excretion. Similarly, atrial natriuretic factor caused an increase in the net excretion of chloride, calcium, and magnesium and also changed the diurnal rhythms of these electrolytes. In contrast, atrial natriuretic factor did not change the net excretion of potassium, phosphate, and uric acid, nor did atrial natriuretic factor change the diurnal rhythms of these solutes. During baseline, the time points of maximal urinary excretion of sodium and potassium overlapped, whereas atrial natriuretic factor infusion caused sodium excretion to peak 2.2 +/- 0.3 hours (p less than 0.02) after the potassium excretion peak. During baseline, the time of maximal urinary excretion of sodium did not correlate with the time of highest blood pressure, whereas it correlated negatively with mean plasma aldosterone concentration. In contrast, during atrial natriuretic factor infusion the time of maximal urinary excretion of sodium correlated positively with the time of highest blood pressure, whereas it did not correlate with mean plasma aldosterone concentration. These data suggest that atrial natriuretic factor is involved with the diurnal rhythm of the urinary excretion of sodium and that atrial natriuretic factor-induced natriuresis is mediated in part by blood pressure and plasma aldosterone.

BLOOD-PRESSURE RESPONSE TO ENALAPRILIC ACID IN ESSENTIAL-HYPERTENSION - DOSE-RESPONSE AND EFFECT OF PRE-TREATMENT WITH FUROSEMIDE

SummaryEnalaprilic acid (MK 422), the active metabolite of enalapril, has recently become available for intravenous administration. In order to establish the proper dose for rapid blood pressure reduction, 9 patients with moderate to severe essential hypertension on a constant sodium intake of 100 mmol/24 h were studied. They received four single doses of MK 422 according to an up-and-down titration schedule. Doses between 5 and 80 mg resulted in effective blood pressure reduction with an onset of action of about 10 minutes. Within this dose range the response was flat. No symptomatic hypotension was observed. The fall in blood pressure was less pronounced in patients with low initial plasma renin activity (PRA). Accordingly, a study was done to show whether the blood pressure response could be augmented by preceding stimulation of PRA by injection of 40 mg furosemide 15 minutes before the administration of MK 422. PRA increased after furosemide, but the blood pressure response to MK 422 was not augmented.