Surgical reversal of two-kidney one clip hypertension during inhibition of the renin-angiotensin system.

Conscious rats with two-kidney one clip Goldblatt hypertension had the constricting clip removed during continuous infusion of either dextrose, saralasin, or captopril. Other dextrose-infused animals underwent removal of the ischemic kidney or a sham procedure. Direct arterial blood pressure (BP) was recorded throughout the 15-hour preoperative and subsequent 24-hour postoperative period. Rats were studied in the "early" phase (1-3 weeks duration) or "chronic" phase (greater than 4 months) of hypertension. Animals subjected to a sham procedure returned to preoperative BP values. The BP of animals unclipped or nephrectomized did not return to previous hypertensive levels. Instead, a biphasic response was seen where BP partially recovered from an operative fall and then slowly declined to normal at 24 hours; this effect occurred in both stages of hypertension. At 24 hours, removal of the ischemic kidney was as effective as removal of the constricting clip in the correction of both early and chronic phase hypertension. Rats infused with saralasin or captopril demonstrated an acute (within 2 hours) and sustained fall in BP, but not to normotensive levels. This fall was significant in all animals (p less than 0.01) apart from chronic phase rats infused with saralasin where no significant fall was seen. Although animals infused with saralasin or captopril commenced at a lower preoperative BP, the biphasic pattern of response to unclipping was identical to that of dextrose-infused unclipped rats. Thus, sustained inhibition of the renin-angiotensin system did not modify the correction of hypertension produced by removal of the constricting clip, and the response to surgical correction did not appear to be entirely mediated by changes in the activity of the renin-angiotensin system, particularly in the chronic stage. Equally, the rapidity of correction is not consistent with a role of vascular hypertrophy.

Vascular capacitance in rats subjected to chemical renal medullectomy.

Selective renal medullary destruction is produced in rats by a single injection of 2-bromoethylamine hydrobromide. The object of these studies was to investigate whether destruction of the renal medulla in normal rats would alter vascular capacitance. Conscious bromoethylamine-treated rats (n = 15) were compared with control saline-injected rats (n = 12). Mean circulatory filling pressure was measured during a brief circulatory arrest caused by inflation of a right atrial balloon. Blood volume was determined from plasma volume (iodine-125-labeled albumin) and hematocrit. Mean circulatory filling pressure was measured at resting blood volume and after rapid blood volume changes. Vascular compliance was derived from the mean circulatory filling pressure-blood volume curve. The bromoethylamine-treated rats were significantly hypertensive compared with control rats (mean arterial pressure 133 +/- 2 and 114 +/- 3 mm Hg, respectively, p less than 0.001) and had a significant tachycardia (475 +/- 8 and 443 +/- 10 beats/min, respectively, p = 0.02). Blood volume, plasma volume, hematocrit, and sodium excretion were no different. There was no significant difference in mean circulatory filling pressure (6.5 +/- 0.2 and 6.8 +/- 0.2 mm Hg, respectively, p = 0.4) or vascular compliance (3.64 +/- 0.20 and 3.53 +/- 0.12 ml/kg/mm Hg, respectively, p = 0.7). The position of the vascular pressure-volume curve was unchanged indicating no change in vascular capacity. This would suggest that the destruction of renal medullary vasodepressor mechanisms does not result in alterations in vascular capacitance.

Chemical renal medullectomy. Effect on urinary prostaglandin E2 and plasma renin in response to variations in sodium intake and in relation to blood pressure.

We have studied the possible vasodepressor role of the renal medulla by chemical medullectomy. Bromoethylamine hydrobromide (200 mg/kg) was injected to induce selective renal medullary necrosis in rats. The acute effects on sodium balance and long-term effects on blood pressure, plasma renin concentration (PRC) and urinary prostaglandin E2 (PGE2) were studied and compared with saline injected controls. There was an immediate and sustained increase in urine volume of low osmolality. Direct blood pressure in conscious free-moving animals was higher at 2 and 10 weeks after injection in medullary-damaged rats, although this was only significant at 10 weeks (136 +/- 3.3 vs 118 +/- 4.5 mm Hg, p less than 0.01). An initial negative sodium balance returned to normal by 7 days and rats with established medullary damage tolerated a wide range of sodium intakes. Although there was no evidence of sodium retention on the normal diet, with very high sodium loads some sodium retention was apparent since PRC was suppressed and body weight increased. Plasma creatinine and creatinine clearance were normal. PRC in rats with medullary damage was unchanged on normal diet and rose to similar levels as in control rats on low sodium intake. Urinary PGE2 was markedly reduced (148 +/- 54 vs 536 +/- 71 ng/day, p less than 0.01) in medullary damaged rats, consistent with the renal medulla being the major source of urinary PGE2. High salt intake increased urinary PGE2 in normal and proportionally in medullary damaged rats, whereas on a low sodium intake, urinary PGE2 was not different from that on the normal diet in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Better blood pressure control: how to combine drugs.

Prospective comparisons of different drug classes have shown that differences in blood pressure control, rather than differences between drug classes, have the over-riding influence on overall outcome. The same studies have also reinforced the need, in the majority of patients, to use combinations of drugs in order to achieve the target of <140/85 mmHg. By contrast, most patients in routine practice receive single agents and consequently fail to achieve target blood pressure. This failure reflects in part the emphasis in individual studies and subsequent guidelines on comparison of individual drugs. In this article we show how the consistency of both theory and a broad range of evidence permits a didactic approach to combination therapy. Our advice is based on the growing recognition that essential hypertension and its treatment fall into two main categories. Younger Caucasians usually have renin-dependent hypertension that responds well to angiotensin-converting-enzyme inhibition or angiotensin receptor blockade (A) or ss blockade (B). Most other patients have low-renin hypertension that responds better to calcium channel blockade (C) or diuretics (D). These latter drugs activate the renin system rendering patients responsive to the addition of renin suppressive therapy. Coincidence of the initials of these main drug classes with the first four letters of the alphabet permits an AB/CD rule, according to which recommended combinations are one drug from each of the "AB" and "CD" categories of drugs. However, the diabetogenic potential of the older "B" and "D" classes leads us to advise against combining "B" and "D" in older patients, and to recommend "A" + "C" + "D" as standard triple therapy for resistant hypertension.

Evaluation of the intravenous fat tolerance test in chronic renal disease.

The intravenous fat tolerance test (IVFTT) was performed on 17 controls, 25 patients with non dialyzed, non nephrotic chronic renal failure and 32 patients on hemodialysis. The fractional removal rate of triglyceride (K2) from plasma is decreased to the same degree in renal disease whether treated by hemodialysis or not. There was an inverse relationship between K2 and both serum triglyceride and fasting blood sugar, which were significantly increased compared to controls. The IVFTT also separated patients with renal disease and hypertriglyceridemia into two groups. One, where there was a low K2, suggesting that defective clearance of triglyceride was the major etiological factor in the hypertriglyceridemia and two, those patients with a normal K2 value, where other factors appear to be more important.

Use of the Tesio catheter for hemodialysis in patients with end-stage renal failure: a 2-year prospective study.

BACKGROUND: The Tesio catheter system has been proposed to be a reliable source of vascular access for the dialysis patient with low rates of infection and other complications. Whether such catheters provide reliable short- and long-term access remains undetermined. METHODS: This study prospectively examined all Tesio lines inserted over a 2-year period in patients with end-stage failure with careful recording of all catheter complications and reasons for catheter loss. RESULTS: 100 catheters were inserted in 82 patients giving a total experience of 13,749 catheter days; 74 catheters were inserted into the jugular veins, the remainder into the femoral veins; 82 insertions were covered with antibiotics. At the end of the study, 29 catheters remained in situ. Of the remaining 71 catheters, 27 catheters were removed because of fashioning of definitive access. Nine catheters were lost due to infection and 10 were lost due to non-function; 19 patients died with a functioning catheter. Episodes ofnon-function were the major complications, although catheter patency was restored in 90% of cases utilizing urokinase and warfarin. Overall 80% of femoral and 16% of jugular catheters required anticoagulation. CONCLUSIONS: Tesio catheters inserted into the jugular or femoral veins can provide excellent access whilst awaiting definitive dialysis access. They are well-tolerated with a low complication rate compared to standard temporary central venous catheters. Non-function remains a significant problem, especially in femoral catheters, which should be anticoagulated following insertion. Because of our results we suggest that these catheters be used as part of the co-ordinated approach to the management of vascular access in end-stage renal failure patients without definitive access.

Impact of peritoneal absorption of glucose on appetite, protein catabolism and survival in CAPD patients.

Dietary protein and calorie intake, protein catabolism and peritoneal kinetics were measured in 97 CAPD patients to establish the effect of peritoneal glucose absorption on appetite and survival. There was a large variability in the number of calories obtained from the dialysate, mean 5.89 cal/kg (median 5.43 cal/kg), with a skewed distribution, due to the increased requirement for hypertonic solutions by patients with more rapid glucose absorption and poor ultrafiltration. On average calories derived from peritoneal absorption accounted for 19% of the total energy intake which in itself was well below that recommended. Patients with > 6 cal/kg, obtained from the dialysate (top 20th percentile, n = 19) were compared with those with < 6 cal/kg, but no significant differences in oral protein or calorie intake, protein catabolism or total calorie intake were found. Age, body mass index (BMI) and KT/V were also similar in both groups. Patients were followed-up prospectively for a minimum of 24 months and a comparison made of actuarial survival. Patients with high peritoneal calorie intake tended to survive longer but this was not significantly different (p = 0.25). This study suggests that calories derived from the peritoneum in CAPD patients do not suppress appetite, provide a useful and significant proportion of the total energy intake, that does not cause excessive obesity or have a negative effect on patient survival.

Renal vasodepressor mechanism: characterization by chemical medullectomy.

The features of hypertension produced in the rat by chemical medullectomy with 2-bromoethylamine hydrobromide are described. This procedure partially prevents the fall in blood pressure that occurs when the constriction is removed from the renal artery of rats with two-kidney one-clip Goldblatt hypertension. In normal rats, chemical medullectomy causes a moderate but consistent blood pressure elevation that is dose related and associated with elevation of peripheral resistance; the venous side of the circulation is normal. The hypertension is not associated with sodium retention or with activation of the renin angiotensin system. Although vasopressin levels are elevated, the rise is only modest, and blood pressure is not reduced by a vascular AVP antagonist. It is concluded that chemical medullectomy removes the source of a humoral substance that has been shown by other workers to carry out a vasodepressor role. The chemical medullectomy model therefore offers new insights into the renomedullary vasodepressor system.

The predictive value of KT/V and peritoneal solute transport in CAPD patients is dependent on the type of comorbidity present.

Comorbidity, age, dialysis dose (KT/V(urea)), plasma albumin, and peritoneal function (D/P(creat) were measured cross-sectionally in 228 continuous ambulatory peritoneal dialysis (CAPD) patients, who were then followed up for a mean of two years. Comorbidity, utilizing a semi-quantitative score described previously, was the most powerful predictor of mortality in both univariate and multivariate analysis. Using univariate analysis, all the variables predicted outcome with statistical significance, mortality being associated with lower KT/V and plasma albumin and a higher D/P(creat). On multivariate analysis only comorbidity, age, and KT/V remained independent predictors. Data was further analyzed on the basis of type of comorbid condition. In those patients without comorbid disease (n = 127) neither KT/V, albumin nor D/P(creat) predicted outcome. In patients with clinical evidence of ischemic heart disease the KT/V was a significant predictor of favorable outcome. In those with clinical evidence of left ventricular function, mortality was significantly and independently associated with low plasma albumin, high D/P(creat), and KT/V. It is suggested that the concept of treatment adequacy in CAPD patients must include both measures of dialysis dose and peritoneal function, particularly in the context of the patient's comorbidity.

Impact of peritoneal membrane function on long-term clinical outcome in peritoneal dialysis patients.

It is increasingly clear that peritoneal membrane transport status has clinical implications. The role of the peritoneum in dialysis delivery becomes paramount once residual renal function is lost, particularly as the membrane characteristics may change for the worse with time on treatment. These findings have several important implications: Clinicians need to take solute transport characteristics into account as they assess their patients. Adverse effects of high solute transport include reduced ultrafiltration, solute removal (in particular, sodium), and increased peritoneal protein losses. A need exists to replace lost residual renal function, not just with enhanced solute removal, but also with adequate salt and water removal. The interpretation of urea and creatinine clearances in anuric PD patients needs further consideration and validation. Hypoalbuminemia in PD patients will result from the combined effects of high protein losses, over-hydration, comorbidity, and malnutrition.

Functional status of CAPD patients and their mood state, dialysis dose, comorbidity and quality of life.

Whilst Continuous Ambulatory Peritoneal Dialysis (CAPD) has sustained the lives of thousands of patients with End Stage Renal Disease (ESRD), renal team members are increasingly confronted with concerns about quality of life. Uraemic symptoms in patients with ESRD are reported to be a source of functional and psychosocial problems, thus diminishing quality of life (1).

Vasodepressor mechanisms in experimental hypertension: studies using chemical medullectomy.

There is evidence that neither activation of the renin-angiotensin system nor changes in sodium balance can fully explain the maintenance of blood pressure in Goldblatt hypertension. Thus, in Goldblatt two-kidney, one clip hypertension in the rat sodium balance is negative and in hypertension of a few months' duration plasma renin initially elevated has returned to normal. When hypertension is reversed by removal of the constricting clip from the renal artery, blood pressure falls within a matter of hours even when hypertension has been present for many months, suggesting that the effect of structural changes in vascular resistance vessels has been overcome. In addition, blockade of the renin-angiotensin system during renal artery declipping does not influence the pattern of the blood pressure fall. We investigated the role of the renomedullary vasodepressor system by inducing medullary necrosis with 2-bromo-ethylamine hydrobromide. This causes a moderate blood pressure increase in normal rats, and partly inhibits the fall of blood pressure in Goldblatt two-kidney, one clip hypertension when the renal clip is removed. Chemical medullectomy is associated with a slightly negative sodium balance, plasma volume contraction, a reduction in plasma renin activity and urinary PGE2, and a minimal elevation in plasma vasopressin. Blood pressure elevation appears to be attributable to inhibition of a vasodepressor system based on the renal medulla. Chemical medullectomy offers a valuable tool for investigating the role of this medullary vasodepressor system.

Chemical renal medullectomy: effect on blood pressure in normal rats.

The renal medulla may have a vasodepressor function in blood pressure control. We have studied the effect of selective ablation of the medulla produced with 2-bromoethylamine hydrobromide on blood pressure in the rat. Increasing doses of bromoethylamine produced a corresponding degree of histological damage. Five weeks after medullary ablation intra-arterial blood pressure was elevated only in those groups of animals which had confluent necrosis of the papilla. The degree of hypertension was not related to plasma renin concentration but showed a significant correlation with urinary prostaglandin E2 excretion. Hypertension in medullectomized animals is probably due to a loss of a medullary vasodepressor function.

Influence of dietary protein on glomerular angiotensin II-receptor binding in normotensive and spontaneously hypertensive rats.

1. The binding of angiotensin II to glomerular receptors was studied in spontaneously hypertensive and normotensive Wistar-Kyoto rats in response to 7, 16 and 32% isocaloric, isonatraemic protein diets. 2. Increased dietary protein elevated the systemic angiotensin II levels of both spontaneously hypertensive and Wistar-Kyoto rats [F0.05(2,26) = 4.758, P less than 0.05; n = 36], and this was not associated with changes in either systemic blood pressure or cortical renin activity. 3. Furthermore, no significant changes in the affinity or density of angiotensin II receptors were associated with changes of dietary protein intake in either strain. 4. These results indicate a dissociation between the system renin-angiotensin system and the tissue renin-angiotensin system in response to protein intake.

A comparison between oral ciprofloxacin and intra-peritoneal vancomycin and gentamicin in the treatment of CAPD peritonitis.

Fifty-one patients were included in a prospective, randomized comparison of oral ciprofloxacin and intraperitoneal vancomycin/gentamicin in the treatment of CAPD peritonitis. Staphylococcal species accounted for 40% of the isolates with an equal incidence of Staphylococcus aureus and coagulase negative staphylococci. Although, overall, there was no significant difference between the regimens in outcome, ciprofloxacin was significantly less effective when peritonitis was due to coagulase negative staphylococci.

Vascular capacitance and reversal of 2-kidney, 1-clip hypertension in rats.

Vascular capacitance was studied in conscious early-phase (less than 6 wk) 2-kidney, 1-clip (2K, 1C) hypertension and compared with sham-clipped control rats. Two other groups of 2K, 1C rats were studied before and 6 h after unclipping or a sham operation. Mean circulatory filling pressure (MCFP) was measured during a brief circulatory arrest caused by inflation of a right atrial balloon. Blood volume (BV) was determined from plasma volume (125I-labeled albumin) and hematocrit. MCFP was measured at resting BV and after rapid BV changes. Vascular compliance was derived from the MCFP-BV curve. Hypertensive 2K, 1C rats had an increase in hematocrit (46 +/- 1.3 vs. 42 +/- 0.4%, P less than 0.01) and no difference in BV compared with controls. MCFP was increased (8.6 +/- 1.0 vs. 7.2 +/- 0.2 mmHg, P less than 0.01) with no difference in compliance, indicating decreased unstressed vascular volume in the 2K, 1C group. After unclipping, there was a significant fall in mean arterial pressure to normal, with a fall in MCFP (8.14 +/- 0.32 to 6.78 +/- 0.11 mmHg, P less than 0.01), but there was no difference in BV or compliance compared with the 2K, 1C group, indicating an increase in unstressed vascular volume after unclipping. These studies for the first time show an important role for vascular capacitance in modulating the circulatory changes accompanying the fall in blood pressure in surgical reversal of 2K, 1C hypertension.

A protocol of urokinase infusion and warfarin for the management of the thrombosed haemodialysis catheter.

BACKGROUND: Catheter dysfunction remains a significant cause of catheter loss and interrupted haemodialysis sessions. A number of regimens utilizing urokinase have been used but the optimum management of this common problem remains undetermined. METHODS: The study took place over 2 years and evaluated a protocol of urokinase infusion (25,000 U in 48 ml saline run at 4 ml/h via each limb of the catheter) followed by warfarin for restoration of catheter patency. RESULTS: Forty-eight urokinase infusions were used for 41 episodes of catheter dysfunction. Catheter patency was restored in 95% and only one catheter was lost. Recurrent thrombosis occurred in eight of 10 catheters not anticoagulated. Once anticoagulated, catheters worked well. Further episodes of non-function were related to a sub-therapeutic INR. CONCLUSIONS: Our results show a high success rate for our protocol. We suggest an aggressive approach to the management of catheter thrombosis with urokinase used by infusion and carefully controlled anticoagulation to maintain the INR in the range 2-2.5.

The effect of renal transplantation with a minimal steroid regime on uraemic hypertriglyceridaemia.

We have studied the lipid and associated biochemical indices in 18 renal transplant patients maintained on an alternate day prednisolone regime. At an average 27 months following transplantation serum lipids were not significantly different from normals despite some renal impairment in the transplant recipients. In addition the blood sugar and plasma immunoreactive insulin levels were elevated in transplanted patients. The intravenous fat tolerance test (IVFTT) was not found to be different from that of normals. In some patients IVFTT was performed before and after transplantation and it was shown that K2 (fractional removal rate of Intralipid) improved from abnormal to normal values. Thus, it has been demonstrated that previously abnormal lipid levels can return to normal after transplantation and this may be related to alternate day steroid regimes. Impaired removal of triglyceride seen in chronic renal failure is improved by transplantation.