Heart rate variability and n-3 fatty acids in patients with chronic renal failure--a pilot study.

Patients with chronic renal failure (CRF) often have autonomic cardiac dysfunction, which can be assessed by measuring heart rate variability (HRV). This dysfunction prediposes the patients to sudden cardiac death. This study describes 24-hour HRV in patients with CRF compared to HRV in patients with a previous myocardial infarction (MI). Furthermore, associations between HRV in patients with CRF and the content of n-3 polyunsaturated fatty acids (PUFA) in cell membranes were examined, because n-3 PUFA may improve HRV. Twenty-nine patients with CRF treated with dialysis were enrolled. A 24-hour Holter recording was obtained at baseline and the HRV variables, RR (= mean of all normal RR intervals during the 24-hour recording) and SDNN (= standard deviation of all normal RR intervals in the entire 24-hour recording) were analyzed. Also, granulocyte fatty acid composition was determined. The patients were allocated to dietary supplementation with either 5.2 g of n-3 PUFA or a placebo oil (olive oil) daily for 12 weeks in a double-blind design. At the end of the supplementation period the Holter recording and blood sampling were repeated. At baseline the CRF patients' mean SDNN ws 86 ms compared to 118 ms (p < 0.01) in patients with a previous MI. After supplementation with either n-3 PUFA or placebo a highly significant correlation was observed between the content of n-3 PUFA in cell membranes and HRV (r = 0.71, p < 0.01). Furthermore, when the patients were dichotomized according to their mean SDNN, it was found, that those with the highest SDNN had a higher content of n-3 PUFA in cell membranes compared to those with the lowest SDNN (7.8% vs 4.2%, p < 0.05). In conclusion, HRV was decreased in CRF patients indicating a cardiovascular autonomic dysfunction. The positive correlation between the n-3 PUFA content in cell membranes and HRV suggests that the effects of an increased intake of n-3 PUFA in CRF patients should be further studied.

A comparison of the effect of ramipril, felodipine and placebo on glomerular filtration rate, albuminuria, blood pressure and vasoactive hormones in chronic glomerulonephritis. A randomized, prospective, double-blind, placebo-controlled study over two years.

The effects of an ACE-inhibitor (ramipril), a calcium antagonist (felodipine) and placebo on glomerular filtration rate (GFR), urinary albumin/creatinine ratio, blood pressure (BP) and vasoactive hormones were investigated in a randomized, prospective, double-blind, placebo-controlled study of patients with chronic glomerulonephritis and hypertension, with measurements at entrance and after 12 and 24 months. In total, 33 patients were included: 21 completed the study with 7 patients in each group. GFR was measured as 51Cr-EDTA clearance and the vasoactive hormones with radioimmunoassays. The reduction in GFR was significantly more pronounced in the felodipine group (-7 ml/min) than in the ramipril group (0 ml/min) but the same as in the placebo group (-6 ml/min). The urinary albumin/creatinine ratio was significantly more reduced in the ramipril group (-74 mg/mmol) than in the placebo group (-11 mg/mmol), which did not deviate from the felodipine group (-10 mg/mmol). BP was significantly reduced by ramipril and felodipine, but not by placebo. Angiotensin II and aldosterone in plasma increased or tended to increase in the felodipine and placebo groups, but were unchanged in the ramipril group. Endothelin increased only in the placebo group, and vasopressin, atrial natriuretic peptide, and brain natriuretic peptide were not significantly changed in any of the groups. It is concluded that ramipril seems to be superior to felodipine in chronic glomerulonephritis owing to better preservation of GFR.

Effect of felodipine on renal haemodynamics and tubular sodium handling after single-dose cyclosporin infusion in renal transplant recipients treated with azathioprine and prednisolone.

A total of 25 renal transplant recipients, treated solely with prednisolone and azathioprine, were investigated in a randomized, double-blind, placebo-controlled, cross-over study. The effect of a single oral dose of felodipine 5 mg or placebo on: glomerular filtration rate (GFR); renal plasma flow (RPF); renal vascular resistance (RVR); renal tubular sodium and water handling, measured by the lithium clearance technique; plasma levels of angiotensin II (AngII), aldosterone (Aldo), atrial natriuretic factor (ANF) and arginine vasopressin (AVP); blood pressure (BP), and heart rate (HR) was studied before, during, and after an intravenous infusion of cyclosporin (CyA). Three consecutive clearance periods were performed, each lasting 1 h. During the second period, CyA (0.75 mg kg-1 body weight) was infused. Before infusion of CyA, felodipine caused a significant rise (6.7%) in RPF and lowered RVR, but did not change GFR significantly. The rise in RPF was abolished by infusion of CyA. After infusion, both GFR (7.8%) and RPF (9.4%) were significantly higher and RVR lower after felodipine than after placebo. Proximal tubular output and total sodium excretion were higher on the felodipine day before and after, but not during CyA infusion. In all three periods felodipine reduced both systolic and diastolic BP. In conclusion, a single dose of felodipine increases RPF and decreases blood pressure in renal transplant recipients not treated with CyA. Although some of these changes are abolished by an acute intravenous infusion of CyA, the effects of felodipine are present again also during the 1st hour after the infusion and thereby indicate at least in part some renal protective effect of felodipine. It is suggested that a higher dose of felodipine might also have been preventive against CyA renal side-effects during the acute infusion.

Mineralization defect but no effect on hypercalcemia during clodronate treatment in secondary hyperparathyroidism.

In four patients with severe secondary hyperparathyroidism, treatment with clodronate caused no decrease in serum calcium. In one of the patients treatment for seven months was associated with a severe mineralization defect which was not caused by aluminium. This lesion was reversible upon termination of clodronate treatment. In a single patient without hyperparathyroidism, a precipitous decrease in serum calcium was observed due to clodronate. However, long-term treatment with clodronate did not ameliorate ectopic calcification in this patient. It is concluded that in severe secondary hyperparathyroidism, clodronate does not always decrease serum calcium. Our experience suggest that clodronate like other bisphosphonates may inhibit bone mineralization.

Calcium acetate versus calcium carbonate as phosphorus binders in patients on chronic haemodialysis: a controlled study.

The first reported double-blind cross-over comparison between the phosphorus binders calcium carbonate and calcium acetate was undertaken in 15 stable patients on chronic maintenance haemodialysis. Detailed registration of diet and analysis of the protein catabolic rate suggested an unchanged phosphorus intake during the study. It was found that predialytic serum phosphate concentration was significantly decreased by 0.11 mmol/l (0.34 mg/dl) (P = 0.021, 95% confidence limits 0.02-0.21 mmol/l; 0.06-0.65 mg/dl) during calcium acetate treatment. The calcium phosphate product was insignificantly decreased during treatment with calcium acetate whereas we could not exclude the possibility that calcium concentration had increased.

Long-term graft survival after conversion from cyclosporin to azathioprine 1 year after renal transplantation. A prospective, randomized study from 1 to 6 years after transplantation.

Cyclosporin has improved graft survival after renal transplantation, but cyclosporin nephrotoxicity is a severe clinical problem. Conversion from cyclosporin to azathioprine 1 year after transplantation might improve long-term graft survival by avoidance of cyclosporin nephrotoxicity. After treatment with cyclosporin and prednisolone during the first year after renal transplantation, 106 patients were consecutively randomized to treatment with either azathioprine and prednisolone or cyclosporin and prednisolone in a prospective, controlled study during the following 5 years, i.e. 6 years after transplantation. Actuarial estimates of graft survival rates after inclusion in the study were obtained by the product-limit method of Kaplan-Meier, and the Mantel-Cox log rank test was used to compare the two treatment regimens. When the end-points in the analyses were cessation of graft function or withdrawal of immunosuppressive treatment due to side-effects, and when patients alive with graft function or who had died with a functioning graft were treated as censored observations, graft survival 5 years after inclusion in the study was 57.7 +/- 5.2% in the total material and was the same in both the azathioprine group (52.4 +/- 7.7%) and the cyclosporin group (63.3 +/- 6.7%) (log rank = 0.40, P = 0.53). When cessation of graft function was the only end-point, graft survival 5 years after inclusion in the study was 73.7 +/- 5.2% for the total material with no significant differences between the two groups (log rank = 0.58, P = 0.45).(ABSTRACT TRUNCATED AT 250 WORDS)

Quality of life, side effects and efficacy of lisinopril compared with metoprolol in patients with mild to moderate essential hypertension.

In a double-blind, parallel-group multicentre study in general practice, lisinopril (10-20 mg once daily) was compared with metoprolol (100-200 mg once daily) in 360 patients whose diastolic blood pressure (DBP) was in the range 91-115 mmHg despite diuretic treatment. Following a three week run-in period during which the diuretic was withdrawn, monotherapy with either lisinopril or metoprolol was given for two months with dose doubled after one month if DBP remained greater than 90 mmHg. Quality of life was assessed using established and validated questionnaires at the time of cessation of diuretic treatment and again after two months's active treatment. Both metoprolol and lisinopril achieved statistically significant BP reduction relative to baseline (P less than 0.001). Significantly fewer adverse events were experienced on lisinopril and metoprolol than on diuretic treatment. Frequency of withdrawals due to adverse events were statistically significantly lower on lisinopril than metoprolol P = 0.01. Before treatment approximately 35% of the patients had quality of life problems measured by General Health Questionnaire (GHQ), which was reduced to 17% on lisinopril and 23% on metoprolol. Thus both metoprolol and lisinopril were effective and safe in the treatment of mild to moderate essential hypertension with lisinopril being better tolerated. From patients' self-assessments of quality of life, lisinopril was found to be superior to metoprolol in some aspects of emotional, cognitive and social functioning.

The effect of n-3 polyunsaturated fatty acids on lipids, platelet function, coagulation, fibrinolysis and monocyte chemotaxis in patients with hypertension.

We have studied the effect of dietary supplementation with 4 g of n-3 polyunsaturated fatty acids (n-3 PUFA) daily for 6 wk on plasma lipids, haemostasis and monocyte chemotaxis in 10 patients with untreated hypertension. Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides did not change, but the ratio of total to HDL-cholesterol was significantly reduced after the fish oil supplement. Platelet function was unaltered by intake of n-3. Plasma fibrinogen and fibronectin decreased after supplementation with n-3 PUFA, while the effects on fibrinolysis were equivocal. Monocyte chemotaxis was reduced by the supplement. These data lend support to a role for an increased intake of n-3 PUFA in the management of patients with hypertension.

[The effects of captopril and metoprolol on blood pressure and side effects in patients with mild to moderate hypertension]. / Effekten af captopril og metoprolol på blodtryk og forekomst af bivirkninger hos patienter med mild til moderat hypertension.

A material of 76 patients from general practice treated with diuretics for mild to moderate hypertension were randomized to supplementary treatment with captopril (39 patients) and metoprolol (37 patients), respectively, on account of diastolic blood pressure greater than or equal to 95 mmHg. Satisfactory regulation of the blood pressure (diastolic blood pressure less than or equal to 90 mmHg) and acceptable wellbeing was obtained in 29 patients in the captopril group and in 23 patients in the metoprolol group. Six patients in the captopril group were excluded on account of absence of effect on the blood pressure and four dropped out on account of side effects. In the metoprolol group, nine patients were excluded on account of absence of effect on the blood pressure and five on account of side effects. This difference was not significant. In the captopril group, 14 side effects were registered in eight patients while 23 side effects were observed in 15 patients in the metoprolol group. This difference was not statistically significant, p greater than 0.05 (risk for type 2 error = 60%). It is concluded that captopril + a diuretic is just as effective a form of treatment of slight to moderate hypertension as metoprolol + a diuretic and that treatment with captopril + a diuretic is associated with so few side effects that it may be considered as an alternative first choice of treatment in cases of slight to moderate hypertension.

Haemostatic aspects of renal transplantation.

Platelet function and protein C activity and antigen level was studied in 31 renal transplant recipients and 10 healthy controls. The patients were divided into three groups: (I) cyclosporin treated, (II) azathioprine treated, and (III) azathioprine treated patients with chronic rejection. The platelet function in the renal transplant patients was normal and there was no difference between groups I and II. The specific activity of protein C was decreased in patients after renal transplantation and decreasing protein C activity and progressive renal failure was found to be positively correlated in the azathioprine treated groups.

Relationship between urinary prostaglandin E2 and F2 alpha excretion and plasma arginine vasopressin during renal concentrating and diluting tests in renal transplant recipients.

Urinary excretion of prostaglandin E2 (PGE2 and F2 alpha (PGF2 alpha) and plasma concentration of arginine vasopressin (AVP) were determined during urinary concentrating and diluting tests in renal transplant recipients and control subjects. During the concentrating test PGE2 and PGF2 alpha remained unchanged in the renal transplant recipients, whereas both PGE2 and PGF2 alpha were significantly reduced in the control subjects. During the diluting test PGE2 and PGF2 alpha increased in both groups but, contrary to PGF2 alpha, PGE2 was significantly higher in all periods in the transplant recipients compared to the controls. However, the prostaglandin excretion rates per kidney were significantly higher in the renal transplant recipients than control subjects, for all periods during both the concentrating and the diluting test. Arginine vasopressin was significantly higher in renal transplant recipients than control subjects during basal conditions, increased to a significantly higher level in the transplant recipients after thirst, but was reduced to the same levels in the two groups during the diluting test. It is concluded that the increased excretion of prostaglandins in renal transplant recipients may be a compensatory phenomenon representing an adaptation to a reduced renal mass in order to maintain adequate renal water excretion. Although a direct relationship between the prostaglandin excretions of PGE2 and PGF2 alpha and AVP does not seem to exist, it is possible that the higher prostaglandin excretion in the renal transplant recipients may be a counterbalancing mechanism to the higher AVP level, which most likely is secondary to a decreased responsiveness to vasopressin of the renal collecting ducts in the transplanted kidney.

Exaggerated natriuretic response to isotonic volume expansion in hypertensive renal transplant recipients: evaluation of proximal and distal tubular reabsorption by simultaneous determination of renal plasma clearance of lithium and 51Cr-EDTA.

In fourteen hypertensive and fourteen normotensive renal transplant recipients, and in a group of thirteen healthy controls, changes in natriuresis, glomerular filtration rate (GFR), and tubular reabsorption of sodium were determined in relation to intravenous infusion of 2 mmol isotonic sodium chloride per kg body weight. An exaggerated natriuresis was demonstrated in the hypertensive renal transplant recipients. This new finding indicates that the augmented natriuresis following plasma volume expansion, which is a characteristic finding in subjects with arterial hypertension, is not mediated by the renal nerves. Investigation of the tubular reabsorption rates of sodium by simultaneous determination of the renal clearance of 51Cr-EDTA and lithium showed that in the hypertensives the changes in tubular handling of sodium were different from those registered in the normotensive subjects. The increased sodium excretion in the hypertensive renal transplant recipients was caused by an increased output of sodium from the proximal tubules which was not fully compensated for by an increased distal reabsorption. Whether this increased delivery of sodium to the distal segments was caused by changes in GFR or in the proximal tubular reabsorption of sodium could not be clarified in the present study and warrants further investigations.

Urinary excretion of albumin and beta-2-microglobulin in hypertensive and normotensive renal transplant recipients during urinary diluting and concentrating tests.

Urinary excretion of albumin and beta-2-microglobulin was measured in nine hypertensive and nine normotensive renal transplant recipients and 10 healthy control subjects before and after an oral water load of 20 ml (kg body weight)-1 (study 1) and in eight hypertensive and 11 normotensive renal transplant recipients and 11 healthy control subjects during 24-h water deprivation (study 2). In both studies 1 and 2 urinary albumin excretion was significantly higher (p less than 0.01) in the hypertensive renal transplant recipients that in the normotensive patients and the control subjects (levels before loading; hypertensives: 23.9 micrograms/min (median), range 7.5-58.7; normotensives: 3.4 micrograms/min, range 1.0-49.3; controls: 2.9 micrograms/min, range 1.3-10.3). Urinary albumin excretion was significantly positive correlated to both systolic, diastolic and mean blood pressure (for mean blood pressure: rho = 0.625, n = 18, p less than 0.01) in transplanted patients. Albumin excretion tended to increase after water loading and to decrease during water deprivation in all groups. Beta-2-microglobulin excretion was approximately the same in all groups in both studies 1 and 2 and was not correlated to blood pressure. During a follow-up period of at least 18 months, none of the renal transplant recipients developed signs of chronic graft failure. Increased urinary albumin excretion in hypertensive renal transplant recipients thus appears to be caused by increased glomerular permeability that may be due to glomerular damage induced by arterial hypertension corresponding to the findings in essential hypertension.

Post-renal-transplant hypertension. Urine volume, free water clearance and plasma concentrations of arginine vasopressin, angiotensin II and aldosterone before and after oral water loading in hypertensive and normotensive renal transplant recipients.

Urine volume (V), free water clearance (CH2O) and plasma concentrations of arginine vasopressin (AVP), angiotensin II (A II) and aldosterone (Aldo) were determined before and three times during the first 5 h after an oral water load of 20 ml/kg body wt in 19 patients with post-renal-transplant hypertension (group I), in 13 normotensive renal transplant recipients (group II) and in 20 control subjects (group III). Both V and CH2O increased significantly in all groups, but considerably less in groups I and II than in group III. When CH2O was related to glomerular filtration rate no differences existed between patients and control subjects. Basal AVP was the same in groups I (3.3 pmol/l, median) and II (3.0 pmol/l), but significantly (p less than 0.01) higher than in group III (1.9 pmol/l). Basal A II was significantly (p less than 0.01) elevated in group I (18 pmol/l) when compared to both groups II (10 pmol/l) and III (11 pmol/l), and the level was independent of the presence of native kidneys. Basal Aldo was the same in all groups. During loading, AVP was reduced in all groups, A II was almost unchanged, and Aldo was increased in groups I and II and reduced in group III depending on alterations in serum potassium. Thus urinary diluting ability is reduced in renal transplant recipients due to a reduced glomerular filtration rate. The enhanced A II in hypertensive renal transplant recipients gives further evidence for the point of view that hypertension is angiotensin-dependent in most of these patients.

Effect of exercise on plasma concentrations of arginine vasopressin, angiotensin II and aldosterone in hypertensive and normotensive renal transplant recipients.

Plasma concentrations of angiotensin II (A II), aldosterone (Aldo) and arginine vasopressin (AVP), and serum osmolality (Sosm) were determined before and after gradually increasing exercise loads on a bicycle ergometer in 10 hypertensive (group I) and 10 normotensive renal transplant recipients (group II), and in 15 healthy control subjects (group III). Working capacity was reduced in groups I and II. The A II, Aldo, AVP, Sosm increased in all groups after exercise. The A II was higher in group I than II and the percentage changes were significantly lower in groups I and II than in group III. There were no significant differences in Aldo between the groups either before or after exercise. The AVP was the same in groups I and II, and AVP in these groups was higher than in group III. The Sosm and AVP were significantly correlated in all groups. Neither A II, Aldo nor AVP were significantly correlated to systolic blood pressure (BP). Alterations in AVP, but not in A II or Aldo, were correlated to the degree of exercise load. It can be concluded that the renin-angiotensin-aldosterone system and the osmoregulatory system are stimulated during exercise in renal transplant recipients. The A II is elevated in post-renal transplant hypertension, but the responsiveness is reduced in both hypertensive and normotensive recipients. The alterations in AVP are probably secondary to changes in Sosm, and the higher AVP levels in recipients could be due to a decreased responsiveness of the renal tubules to AVP. Our findings are in good agreement with the hypothesis that hypertension after renal transplantation is angiotensin II-dependent.

Expansion of extracellular volume in early polycystic kidney disease.

Blood volume (BV), extracellular volume (ECV), blood pressure (BP), creatinine clearance (CCr), plasma levels of angiotensin II (AII), aldosterone (Aldo) and arginine vasopressin (AVP), and serum osmolality (Sosm) were determined in 18 patients with adult polycystic kidney disease, 8 normotensive (group I), 10 hypertensive (group II), and in 11 control subjects (group III). ECV but not BV was increased in group I compared with group III, whereas BV and ECV did not differ significantly between groups II and III. In group II, Aldo and AVP were increased and AII tended to be increased, while in group I the hormone levels did not differ significantly from those in group III. Sosm did not differ significantly between the groups. In the combined patient group, CCr correlated positively with BV and ECV and negatively with BP. In the patients, AII and AVP were positively correlated with BP but not with CCr. The results suggest that both the renin-angiotensin system and AVP might be involved in the BP elevation, whereas expansion of ECV can be found without an increase in BP.

Renovascular hypertension. Ability to renal vein ratio to predict the blood pressure level 18-24 months after surgery.

Fourteen patients with severe hypertension and renal artery stenosis were treated surgically. One patient died 4 days after surgery due to a cerebral thrombosis. The other 13 patients were followed for 18-24 months. Five were considered cured since the diastolic blood pressure (DBP) was less than or equal to 90 mm Hg without therapy. Five were improved since DBP was less than or equal to 100 mm Hg during treatment with only one or two antihypertensive agents. There were unchanged. Renal vein renin ratio (RVRR) was greater than or equal to 1.5 either before or after furosemide in all patients who were cured or improved and less than or equal to 1.5 in 2 of 3 who were unchanged. It can be concluded that surgical treatment cured or improved 77% of the patients, and that a RVRR greater than or equal to 1.5 is a good predictor of the blood pressure lowering effect of surgery.