Plasma levels of endothelin in chronic renal failure and after renal transplantation: impact on hypertension and cyclosporin A-associated nephrotoxicity.

1. Plasma levels of endothelin were measured in 30 patients with chronic renal failure, 32 patients on chronic haemodialysis treatment and 25 renal graft recipients with stable renal graft function. 2. In patients with chronic renal failure as well as in patients on regular haemodialysis treatment, mean plasma levels of endothelin were significantly increased (4.59 +/- 2.09 pg/ml, 10.08 +/- 3.12 pg/ml, respectively) when compared with normal subjects (1.88 +/- 0.6 pg/ml, P less than 0.01, P less than 0.001, respectively). 3. In the group with chronic renal failure a positive correlation between the plasma level of endothelin and the plasma concentration of creatinine was observed (P less than 0.003). 4. Renal graft recipients on cyclosporin A with stable renal graft function had a normal plasma level of endothelin suggesting that cyclosporin A nephrotoxicity is not mediated by endothelin. 5. Hypertensive patients with chronic renal failure or on regular haemodialysis and hypertensive renal graft recipients did not differ from the corresponding normotensive population with regard to the plasma level of endothelin, demonstrating that an increased plasma level of endothelin does not play a major role in the pathogenesis of renal hypertension.     

Treatment of severe nephrotic syndrome with meclofenamate: an uncontrolled pilot study

The effect of meclofenamate on urinary protein excretion, level of serum albumin, and renal function was studied prospectively in 30 patients with corticosteroid-resistant severe nephrotic syndrome: 16 with focal segmental glomerulosclerosis, 12 with membranous glomerulopathy, and 2 with minimal-lesion nephropathy. Seventeen patients had a 40% or more reduction in urinary protein excretion ("responders"), and the decrease continued during long-term treatment. Meclofenamate therapy was discontinued after 2 months in eight "nonresponders" and in five other patients because of side effects (progressive increase in the level of serum creatinine in two, diarrhea in two, and pruritus in one). In responders, we recorded the following findings (mean +/- SD): urinary protein excretion decreased from 13.0 +/- 5.2 g/24 h to 7.2 +/- 3.5 g/24 h in 2 to 4 weeks and continued to decrease to 4.1 +/- 1.4 g/24 h at the time of the last follow-up study (median duration, 12 months; range, 6 to 36 months; P less than 0.01, 2 to 4 weeks versus later follow-up); the level of serum albumin increased from 1.9 +/- 0.5 g/dl to 2.9 +/- 0.7 g/dl (P less than 0.001) in 2 to 4 weeks; the level of serum cholesterol decreased from 413 +/- 125 mg/dl to 346 +/- 114 mg/dl (P less than 0.005) at the time of the last follow-up examination; and renal function remained unchanged from the baseline study to the follow-up study (serum creatinine 1.5 +/- 0.5 mg/dl versus 1.6 +/- 0.4 mg/dl and glomerular filtration rate 60.5 +/- 29.2 ml/min per 1.7 m2 versus 64.1 +/- 25.5 ml/min per 1.7 m2).(ABSTRACT TRUNCATED AT 250 WORDS)     

Is skeletal response to parathyroid hormone abnormal in experimental renal failure?

It is widely believed that skeletal resistance is the mechanism of impaired calcemic response to parathyroid hormone (PTH) in renal failure. The action of PTH not only involves skeletal mobilization of Ca, it may also stimulate intestinal absorption of Ca and renal conservation of Ca. We have examined each of these factors and studied the calcemic response to PTH in renal failure. PTH, 3 U/hr/100 gm, was infused for 5 hours in rats with renal failure 3 weeks after a five-sixths nephrectomy. In nonfasted animals, the post-PTH increments of total plasma Ca (0.71 +/- 0.06 mg/dl) and ionized Ca (0.37 +/- 0.06 mg/dl) of control sham-operated rats were significantly greater than those of rats with renal failure (plasma Ca 0.37 +/- 0.02 mg/dl and plasma ionized Ca 0.17 +/- 0.01 mg/dl both p less than 0.001). Urinary Ca excretion rate remained unchanged during PTH infusion despite the increase in plasma Ca. Plasma levels of calcitriol after PTH injection were higher in control rats (257 +/- 18 pg/ml) than in rats with renal failure (162 +/- 5 pg/ml, p less than 0.001). Pretreatment of rats with renal failure with 50 ng calcitriol intravenously corrected the abnormal calcemic response to PTH. To exclude the PTH effect on intestinal Ca absorption, PTH infusion was carried out in animals fasted for 18 hours. The post-PTH increments of Ca were no longer different between rats with renal failure (plasma Ca 0.37 +/- 0.04 mg/dl, plasma ionized Ca 0.20 +/- 0.01 mg/dl) and control rats (plasma Ca 0.37 +/- 0.03 mg/dl, plasma ionized Ca 0.19 +/- 0.01), suggesting that skeletal mobilization of Ca was similar between the two groups of animals. We conclude that lack of intestinal response to PTH rather than skeletal resistance was the mechanism of impaired calcemic response to PTH in this model of renal failure.     

Association between increased atrial natriuretic peptide and reduced cisplatin nephrotoxicity in rats.

Plasma atrial natriuretic peptide (ANP) concentrations were monitored in two experimental models of protection from cisplatin nephrotoxicity. Sprague-Dawley rats made diabetic with streptozotocin (65 mg/kg) were protected from cisplatin-induced nephrotoxicity when compared to control rats as indicated by reduced plasma creatinine (0.49 +/- 0.02 vs. 0.9 +/- 0.06 mg/dl; P less than .001) and blood urea nitrogen concentrations (18.51 +/- 1.4 vs. 43.08 +/- 2.1 mg/dl; P less than .001). Plasma ANP was also increased with experimental diabetes (76.5 +/- 8.98 fmol/ml) vs. normoglycemic controls (43.8 +/- 8.9 fmol/ml; P less than .02). When diabetic rats were treated with insulin, the renal protection observed with the diabetic state was reversed (creatinine, 0.70 +/- .05 mg/dl); plasma ANP concentrations were also reduced (52.2 +/- 15.2 fmol/ml). Renal platinum concentrations were significantly lower in the diabetic group and the reversal of diabetic-induced renal protection with insulin was associated with increased renal platinum concentrations. In rats given a single i.p. dose of cisplatin (5 mg/kg), a reduction in cisplatin-induced nephrotoxicity was observed when 5% NaCl was the vehicle of choice compared to that seen in rats given the same dose of drug in 0.9% saline (creatinine, 0.43 +/- 0.07 with 5% NaCl vs. 0.63 +/- 0.03 with 0.09% NaCl). NaCl (5%) administration also resulted in increased plasma ANP concentrations when compared to rats receiving equivalent volumes of 0.9% NaCl (88.4 +/- 6.2 vs. 50.5 +/- 5.6 fmol/ml, respectively). These data suggest that increased endogenous ANP may be a mechanism of renal protection common to both experimental diabetes and hypertonic saline administration. Chronically increased ANP may prevent renal accumulation of platinum in the kidney.     

Immunoreactive N-terminal pro-atrial natriuretic peptide in human plasma: plasma levels and comparisons with alpha-human atrial natriuretic peptide in normal subjects, patients with essential hypertension, cardiac transplant and chronic renal failure

1. Plasma levels of immunoreactive N-terminal pro-atrial natriuretic peptide (N-terminal ANP) have been measured in 25 normal subjects, 29 patients with essential hypertension, six cardiac transplant recipients, seven patients with dialysis-independent chronic renal failure and 11 patients with haemodialysis-dependent chronic renal failure. Plasma was extracted on Sep-Pak cartridges and N-terminal ANP immunoreactivity was measured using an antibody directed against pro-ANP (1-30). 2. Plasma levels of N-terminal ANP (means +/- SEM) were 235.3 +/- 19.2 pg/ml in normal subjects and were significantly raised in patients with essential hypertension (363.6 +/- 36.3 pg/ml), in cardiac transplant recipients (1240.0 +/- 196.2 pg/ml), in patients with chronic renal failure not requiring dialysis (1636.6 +/- 488.4 pg/ml) and patients with chronic renal failure on maintenance haemodialysis (10336.1 +/- 2043.7 pg/ml). 3. There were positive and significant correlations between the plasma levels of N-terminal ANP and alpha-human ANP (alpha-hANP) with individual correlation coefficients of 0.68 within the normal subjects, 0.47 in patients with essential hypertension, 0.78 in patients with dialysis-independent chronic renal failure and 0.68 in patients with haemodialysis-dependent chronic renal failure (P less than 0.05 in every case).(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide in human essential hypertension

We measured the circulating levels of atrial natriuretic peptide (ANP) in 62 patients with untreated uncomplicated essential hypertension and in 30 normotensive subjects. In the hypertensive patients, mean systolic and diastolic blood pressures were 148 and 101 mm Hg, respectively, and the mean heart rate was 73 beats/min. ANP concentrations were not elevated in the hypertensive group but were actually decreased slightly over those of the control group (27.4 +/- 1.8 pg/ml versus 35.3 +/- 2.4 pg/ml [P less than 0.02]). No relationship was found between ANP levels and diastolic blood pressure, plasma renin activity, urinary sodium excretion, or serum creatinine level. In 8 of the 62 patients with essential hypertension, 6 weeks of treatment with a dihydropyridine calcium channel blocker, nitrendipine, significantly reduced plasma ANP levels from 28.6 +/- 4.3 pg/ml to 18.7 +/- 1.8 pg/ml (P less than 0.05). In 17 additional patients treated with the hypotensive agent ketanserin, ANP levels were not significantly reduced after treatment. Thus, this study demonstrates that circulating plasma ANP levels are not increased but are slightly decreased in patients with uncomplicated essential hypertension in comparison with normotensive subjects. Furthermore, antihypertensive treatment with a calcium channel antagonist reduced plasma levels of ANP.     

Plasma concentrations of atrial natriuretic peptide in various diseases

Using a radioimmunoassay for atrial natriuretic peptide (ANP) we studied plasma concentrations of immunoreactive ANP in order to investigate the pathophysiological role of ANP in patients with various diseases. Plasma ANP levels were elevated in patients with congestive heart failure (394 +/- 260 pg/ml, n = 8) and chronic renal failure (219 +/- 86 pg/ml, n = 11). In patients undergoing hemodialysis plasma ANP levels were markedly high and decreased after hemodialysis from 433 +/- 166 pg/ml to 204 +/- 92 pg/ml (n = 11). ANP was removed from blood to dialysate (21 +/- 13 pg/ml of dialysate, n = 6, dialysate flow: 500 ml/min). Plasma ANP level was conversely correlated with creatinine clearance (r = -0.812, p less than 0.001) in patients with renal diseases (n = 29). In patients with atrial fibrillation, pace maker implantation, lung disease, chronic glomerulonephritis, nephrotic syndrome, essential hypertension, liver disease and cerebrovascular disease, plasma ANP levels were not significantly different from those in normal subjects (70 +/- 32 pg/ml, n = 28). These results suggest that ANP may be a circulating hormone playing pathophysiological roles in congestive heart failure and chronic renal failure.     

Comparison of vancomycin- and teicoplanin-induced histamine release and "red man syndrome".

Twelve healthy adult males participated in a double-blind, randomized, two-way crossover study to determine histamine release and the frequency and severity of "red man syndrome" (RMS) following intravenous administration of vancomycin (15 mg/kg of body weight over 60 min) and teicoplanin (15 mg/kg over 30 min). Concentrations of vancomycin and teicoplanin in serum and concentrations of histamine in plasma were measured at baseline and during and after each infusion. Erythema and pruritus were classified a priori as mild, moderate, or severe. The extent of erythema was determined by the use of a burn chart, and pruritus was assessed by the subject with a rank scale. Global severity of RMS was determined by summation of the individual scores for pruritus and erythema. Baseline areas under the concentration-time curve for histamine were not significantly different for the vancomycin and teicoplanin treatments. Vancomycin caused RMS in 11 of 12 subjects (9 severe and 2 moderate cases) and was associated with a significant increase in plasma histamine (46.7 +/- 31.3 ng.min/ml, P less than 0.05). In contrast, teicoplanin did not cause RMS or elicit significant histamine release (8.7 +/- 13.2 ng.min/ml). Peak concentrations of vancomycin and teicoplanin in serum were 58.8 +/- 8.4 and 148.0 +/- 31.8 micrograms/ml, respectively (P less than 0.05). Assuming equal efficacy, these data suggest that teicoplanin may be a safe alternative agent in subjects experiencing severe RMS due to vancomycin; however, further studies in the clinical setting are needed.     

Age-related differences in renal function at onset of renal replacement therapy in chronic kidney disease stage 5 patients

BACKGROUND: Guidelines for initiating renal replacement therapy (RRT) are based on renal function and not age, so renal function at onset of RRT is expected to be similar across age groups. AIM: To evaluate renal function at initiation of RRT across age groups. DESIGN: Observational cross-sectional study. METHODS: We extracted data for all incident chronic kidney disease (CKD) stage 5 patients (n = 322 064) commenced on chronic dialysis (haemodialysis and peritoneal) and renal transplant in the US from 1995 to 1999 from the US Renal Data Systems (USRDS). Subjects (n = 662) with incomplete data were excluded. The reminder (n = 321 402) were classified into five age groups: 0-19 years; 20-44 years; 45-64 years; 65-74 years; >/=75 years. Mean values of serum creatinine (Cr, mg/dl), creatinine clearance (CrCl, ml/min), body weight (kg) and body mass index (BMI, kg/m(2)) at onset of RRT were computed. Mean daily urinary creatinine excretion per kg body weight (CrCl x Cr/0.07/weight) was also calculated. RESULTS: Progressively lower serum creatinine levels were found in adult patients with increasing age (10.70, 8.56, 7.38 and 6.88 mg/dl in those aged 20-44 years, 45-64 years, 65-74 years, >/=75 years, respectively). CrCl was also lower in the same groups (14.76, 13.38, 11.63 and 11.60 ml/min, respectively). DISCUSSION: Older patients have a greater reduction in renal function than younger patients at onset of RRT, suggesting a delay in initiation of therapy.     

Inadequate aldosterone response to hyperkalemia during angiotensin converting enzyme inhibition in chronic renal failure

To assess the mechanism involved in hyperkalemia during angiotensin converting enzyme inhibition with captopril in chronic renal failure, captopril, 150 mg/day, was administered to 16 patients with hypertension with plasma creatinine levels between 1.6 and 12.4 mg/dl. After 4 weeks of therapy, plasma potassium levels increased from 3.9 +/- 0.1 to 5.5 +/- 0.2 mEq/L (P less than 0.001) and the final plasma potassium levels correlated with plasma creatinine levels (r = 0.67; P less than 0.01). In six patients with plasma creatinine levels greater than or equal to 3 mg/dl, aldosterone excretion decreased after 4 weeks of captopril, from 7.5 +/- 3.1 to 1.8 +/- 0.5 micrograms/24 hr, whereas plasma renin activity increased from 0.6 +/- 0.2 to 4.4 +/- 1.1 ng/ml/hr (P less than 0.05). This was associated with increases in plasma potassium levels from 3.9 +/- 0.2 to 5.4 +/- 0.4 mEq/L (P less than 0.005) and a significant reduction in fractional excretion of potassium from an average of 34% to 25%. No significant changes in plasma creatinine levels were observed during therapy. There was a significant positive correlation between aldosterone excretion and the potassium excretion fraction (r = 0.53; P less than 0.01). Increases in plasma potassium levels were not able to increase aldosterone excretion, although the greater the plasma potassium level attained, the smaller the reduction in aldosterone excretion (r = 0.47; P less than 0.05). Our results indicate that adequate aldosterone production is essential to preserve potassium homeostasis in chronic renal failure. Moreover, angiotensin II appears necessary for an adequate aldosterone response to potassium stimulation.     

Urinary levels of immunoreactive NH2-terminal of pro-opiomelanocortin in patients with malignant pulmonary disease

Urinary levels of immunoreactive (IR) human NH2-terminal (hNT) of pro-opiomelanocortin were measured in 43 patients with various cell types of lung cancer (19 squamous cells, 12 oat cells, 2 large cells, and 10 adenocarcinoma), 32 patients with benign lung disease, two patients after hypophysectomy, and in 23 healthy volunteers. Lung cancer patients were divided into two subgroups according to the stage of the disease: 22 patients had "limited", and 21 patients "extensive" disease. Urinary and plasma levels were measured in 9 patients with lung cancer before and after radio- and chemotherapy or surgery. Urine samples were dialyzed and IR hNT material was extracted by Sep Pak C-18 cartridges using a propanol-2/TFA solvent system. The plasma and urinary IR hNT levels of the normal controls were 124 +/- 25 pg/ml and 47.8 +/- 14.5 pg/mg creatinine, respectively. The plasma levels of IR hNT were elevated (greater than mean + 2SD) in 65% of our patients with histologically proven lung cancer (422 +/- 775, mean +/- SD, pg/ml). The highest incidence of an elevated plasma level of IR hNT was found in oat cell carcinoma (83%). Elevated plasma IR hNT occurred in 66% of the patients with benign pulmonary disease (246 +/- 141 pg/ml, N.S.). In cancer patients with "limited" disease we found levels of 226 +/- 143 pg/ml and in patients with "extensive" disease 627 +/- 1074 pg/ml (N.S.). The urinary IR hNT level in lung cancer patients was 186 +/- 337 pg/mg creatinine and 81% of our patients had elevated levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of nesiritide on renal function in patients admitted for decompensated heart failure

BACKGROUND: Studies addressing the effect of nesiritide on renal function in patients hospitalized for decompensated heart failure (HF) are limited, with conflicting results. AIM: To study the effect of nesiritide on renal function in patients admitted for acute decompensated HF. METHODS: We retrospectively reviewed charts of patients admitted with decompensated HF, comparing those who received nesiritide along with conventional therapy vs. those who received conventional therapy alone. Serum creatinine levels and body weight were measured on admission, and were compared with levels at day 3 to estimate deterioration in renal function. Worsening renal function (WRF) was defined as a rise in serum creatinine of > or =0.3 mg/dl from baseline, with final creatinine level >1.5 mg/dl. RESULTS: We reviewed 206 charts (116 controls, 90 nesiritide group). WRF developed in 28/90 (31.1%) in the nesiritide group and 37/116 (31.9%) controls (p = 1.0). Mean change in creatinine in the nesiritide group was 0.15 +/- 0.37 mg/dl, compared to 0.17 +/- 0.25 mg/dl in controls (p = 0.75). Using an alternative cut-off increase in serum creatinine of > or =0.5 mg/dl, 16/90 (17.7%) patients in the nesiritide group developed WRF compared to 18/116 (15.5%) controls (p = 0.80). If WRF was defined as elevation in serum creatinine levels by > or =0.3 mg/dl anytime during hospitalization, the incidence of WRF in the nesiritide group remained similar to that of controls (42.2% vs. 41.3%, p = 0.90). On multivariate analysis, nesiritide therapy was not associated with WRF (OR 0.8, 95% CI 0.4-1.6, p = 0.48). DISCUSSION: We failed to detect any significant risk of WRF in patients treated with nesiritide compared to conventional therapy in patients with decompensated HF during index hospitalization. Larger randomized, placebo-controlled trials are required to further elucidate the effect of nesiritide on renal function in these patients.     

Continuous arteriovenous hemofiltration in critically ill children with acute renal failure

Last year, five critically ill children with acute renal failure were treated by continuous arteriovenous hemofiltration. Mean treatment duration was 326 +/- 89 (SD)h, for a total of 1632 h. Mean ultrafiltration rates of 5.4 +/- 1.7 ml/min X m2 achieved mean serum urea levels of 150 +/- 25 mg/dl and a decline of mean prehemofiltration serum creatinine level of 3.5 +/- 3.6 to 2.9 +/- 2.0 mg/dl posthemofiltration. Continuous arteriovenous hemofiltration allowed adequate parenteral nutrition with a mean caloric intake of 79.6 +/- 9.2 kcal/kg X day. In the four surviving patients, urinary output started between 12 and 42 days after the onset of acute renal failure. Continuous arteriovenous hemofiltration is a very effective extracorporeal therapeutic system to control azotemia, fluid, and electrolyte balance in critically ill children with acute renal failure and hemodynamic instability.     

Steady-state dopamine clearance in critically ill infants and children

Little is known about dopamine pharmacokinetics in pediatric patients, especially in critically ill infants and children who often receive treatment with dopamine. Arterial plasma concentrations of dopamine were measured in 27 patients who were hemodynamically stable and received dopamine for at least one hour. The dopamine levels were measured using liquid chromatography with electrochemical detection. Dopamine clearance averaged 96.2 +/- 55.4 ml/kg.min in 13 patients in the neonatal ICU, and 58.8 +/- 51 ml/kg.min in 14 patients in the pediatric ICU. Six patients had renal (BUN greater than 25 mg/dl, or creatinine greater than 1.2 mg/dl) or hepatic (liver enzymes greater than 3 times normal) dysfunction. Dopamine clearance in these patients (25.1 +/- 17.2 ml/kg.min) was substantially lower than in the other patients (p less than .01). Neither postnatal nor gestational age correlated with dopamine clearance. Substantial interindividual variation was observed in steady-state dopamine clearance in critically ill infants and children, and plasma dopamine could not be predicted accurately from the dopamine infusion rate. Because of the more than three-fold prolongation of dopamine clearances in patients with hepatic or renal dysfunction, these patients may be more likely to suffer toxic effects of dopamine at the usual drug infusion rates.     

Beneficial effect of beta-adrenergic blockade on left ventricular function in haemodialysis patients

Congestive heart failure is a common and serious complication in patients undergoing chronic dialysis. However, there have been no studies on preferential medical therapies to improve left ventricular function in haemodialysis patients. Beta-blocker treatment is known to improve left ventricular function in patients with dilated cardiomyopathy; moreover, plasma levels of noradrenaline and natriuretic peptides are sensitive markers of left ventricular dysfunction. The present study investigated whether beta-blocker treatment could improve left ventricular function in haemodialysis patients with a dilated left ventricle. Our study group comprised 14 haemodialysis patients with a dilated left ventricle, who had undergone maintenance haemodialysis for a mean of 11 years. The following haemodynamic parameters were evaluated before and after 4 months of treatment with the beta-blocker metoprolol: left ventricular dimension at end-systole and end-diastole, and fractional shortening. Plasma levels of noradrenaline, atrial natriuretic peptide and brain natriuretic peptide were also determined. Dry body weight and haemoglobin concentration showed no significant change after compared with before treatment with metoprolol. Heart rate decreased significantly, from 79+/-9 beats/min to 69+/-9 beats/min, but systolic blood pressure remained unchanged. The left ventricular dimension both at end-systole and at end-diastole was decreased, and fractional shortening increased significantly. Plasma levels of noradrenaline did not change significantly, but those of atrial natriuretic peptide and brain natriuretic peptide decreased markedly [from 100+/-89 pg/ml to 46+/-29 pg/ml (P=0.0051) and from 549+/-516 pg/ml to 140+/-128 pg/ml (P=0.0035) respectively]. In conclusion, beta-blocker therapy with metoprolol can markedly attenuate left ventricular remodelling and decrease the plasma levels of natriuretic peptides in haemodialysis patients with a dilated left ventricle.     

Untoward effects of chronic dual renin-angiotensin system blockade: influence of previous chronic renal failure

Dual blockade of the renin-angiotensin system (RAS) has increased antiproteinuric effects and so a higher incidence of secondary effects can be expected when this kind of treatment is administered. The aim of this study was to assess the safety of dual blockade of RAS. Seventy-five (54 men and 21 women) patients has been treated in our unit with dual RAS blockade due to proteinuria higher than 1 g/24 h. Mean age was 57.1 +/- 14.0 years. Fifty-three patients had chronic renal failure (CRF) at baseline. Analytical data of 6 months visit and last follow-up visit were recorded. A small reduction of systolic blood pressure and diastolic blood pressure was observed in both treatment groups throughout the study. Neither the CRF patients nor those with normal renal function showed any reduction in mean plasma haemoglobin levels, but differences between groups were significant at the second and third visits (anova). No change was detected in haematocrit. Mean K+ significantly increase at the second visit in the CRF group (from 4.80 +/- 0.64 to 5.23 +/- 0.81 mmol/l, p < 0.001, Student's t-test). There were no changes in normal kidney function group (4.58 +/- 0.37 vs. 4.63 +/- 0.44). At baseline plasmatic creatinine was higher in the CRF group (2.09 +/- 0.60 0.20 mg/dl vs. 0.99 +/- 0.20 mg/dl, p < 0.001, Student's t-test) and creatinine clearance was lower (48.6 +/- 20.7 ml/min vs. 107.0 +/- 0.30 ml/min, p < 0.001, Student's t-test). There was a small increase in creatinine along the follow-up when compared with the normal renal function group (p < 0.001, anova). Conversely, creatinine clearance remain unchanged in the normal renal function group, and there was a decrease in creatinine in CRF patients (p < 0.001). Dual RAS blockade seems to be safe in renal patients even when mild to moderate renal failure is present. Severe hyperkalaemia is uncommon. Small increments in plasmatic creatinine can be seen but they are hardly dangerous. Combined treatment does not significantly influence erythropoiesis.     

Association between renal and sympathetic responses to nonhypotensive systemic sepsis

We investigated the association between plasma catecholamines and the renal response to nonhypotensive sepsis. Arterial plasma catecholamines were measured in 16 sheep, before and 24 h after surgical induction of peritonitis. Animals were volume loaded with lactated Ringer's solution (8 L/24 h) before and after surgery; non became hypotensive. For analysis, animals were retrospectively divided into those with increased serum creatinine after 24 h of sepsis (group 1, n = 8) and those without (group 2, n = 8). Group 1 showed increased cardiac index and decreased systemic vascular resistance typical of severe sepsis, with decreased glomerular filtration rate (GFR), oliguria, sodium retention, increased plasma renin activity (PRA), decreased urinary kallikrein excretion, and increased urinary 6-keto-prostaglandin-F1 alpha excretion. Group 2 showed insignificant hemodynamic disturbance, and no significant renal response. Plasma catecholamines were equal in both groups at baseline. In group 1, there were uniform increases after 24 h in plasma norepinephrine (474 +/- 115 to 1183 +/- 158 [SEM] pg/ml; p less than .01) and plasma epinephrine (108 +/- 8 to 309 +/- 70 pg/ml; p less than .05). In group 2, neither plasma norepinephrine (343 +/- 59 to 330 +/- 56 pg/ml) nor plasma epinephrine (116 +/- 16 to 116 +/- 13 pg/ml) changed significantly. Plasma norepinephrine correlated inversely with GFR; plasma epinephrine correlated with PRA. The sympathetic nervous system may be involved in the renal response to nonhypotensive sepsis, both directly and via effects on other vasoactive hormone systems.     

Plasma immunoreactive somatostatin response to arginine after glycemic control with continuous subcutaneous insulin infusion in type I diabetics

The effects of 3 wk of near normoglycemia by continuous subcutaneous insulin infusion (CSII) on plasma immunoreactive somatostatin (IRS) responses to arginine (0.5 g X kg-1 X 30 min-1) in seven patients with insulin-dependent diabetes mellitus (IDDM) were compared with the same patients in poor glycemic control during conventional insulin therapy (CIT) and with seven normal controls. After 3 wk of CSII treatment, mean daily blood glucose and HbA1 decreased to mean (+/- SE) values of 129 +/- 6 mg/dl and 8.0 +/- 0.1%, respectively. Plasma free-insulin levels in IDDM patients 30 min before a meal during CSII were significantly higher than those during CIT or in normal controls. Fasting mean plasma IRS levels of the IDDM patients during CSII (7.3 +/- 1.4 pg/ml) were not different from those during CIT (8.4 +/- 1.3 pg/ml) and in normal controls (5.9 +/- 0.8 pg/ml). Arginine elicited a rise in plasma IRS during CIT in all seven IDDM patients during CIT and in the normal controls, with peak values of 18.2 +/- 4.1 and 12.5 +/- 1.8 pg/ml, respectively. However, no significant increase in plasma IRS was observed in all seven IDDM patients during CSII. The integrated values of plasma IRS during the arginine-infusion study of the IDDM patients treated with CIT were significantly higher than those of the normal controls. The increased integrated values of plasma immunoreactive glucagon response to arginine observed during CIT became normalized after CSII. These results suggest that glycemic control with CSII in IDDM patients suppresses the increased plasma IRS response to arginine that occurs during CIT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between serum urate and plasma oxypurinol in the management of gout: determination of minimum plasma oxypurinol concentration to achieve a target serum urate level

The treatment of gout requires a lowering of serum urate (SU) levels, and allopurinol is the drug that is most commonly used for this purpose. The objectives of this study were to define the relationships between allopurinol dose on the one hand and plasma oxypurinol, renal function, and SU levels on the other and to determine the minimum plasma oxypurinol concentration that would result in a target level of <6?mg/dl (0.36?mmol/l) of SU. For this purpose, 82 patients who had been receiving allopurinol for at least 1 month were recruited. Patients with SU <6?mg/dl were followed up quarterly for 12 months. In patients with SU ≥6?mg/dl, the dose of allopurinol was increased to bring the level of SU to <6?mg/dl. These patients were followed up once a month until the SU level remained at <6?mg/dl for 3 consecutive months; thereafter they were seen quarterly. SU, creatinine, and plasma oxypurinol were measured 6-9 hours after administration of the allopurinol dose. There were significant inverse correlations between creatinine clearance (CrCl) and plasma oxypurinol (P = 0.002), between allopurinol dose and SU (P < 0.0001) and between plasma oxypurinol and SU (P < 0.0001). Using receiver operating characteristic analysis, the target SU of <6?mg/dl was achieved in 75% of serum samples with plasma oxypurinol levels of >100?μmol/l (15.2 mg/l). Increasing the allopurinol dose resulted in increased plasma oxypurinol and reduced SU concentrations. Plasma oxypurinol concentrations >100?μmol/l were required to achieve SU <6?mg/dl.     

Pharmacokinetics of cefonicid in uraemic patients

Eight subjects with normal renal function and 20 uraemic patients with various degrees of renal insufficiency were given a single iv dose of 1.0 g cefonicid, as a bolus injection. Five groups of subjects were studied: group I, GFR greater than 80 ml/min, group II 30 less than GFR less than 80 ml/min, group III 10 less than GFR less than 30 ml/min, group IV GFR less than or equal to 10 ml/min and group V, haemodialysis patients. Cefonicid concentrations in plasma and urine were measured by microbiological assay (MA) and HPLC method. Results were similar with the two techniques. The mean peak plasma levels were 200-300 mg/l and the apparent volume of distribution was 0.18-0.20 1/kg for all patients. The elimination half-life (T 1(2) beta) increased as renal function decreased: 5.31 +/- 1.30 h in healthy subjects and 58.92 +/- 12.38 h in patients with end-stage renal disease. Urinary elimination of cefonicid was inversely related to the degree of renal impairment: 83% of the dose in 24 h in normal subjects and 13.6% of the dose in patients with severe renal failure. Total body clearance decreased from 23.9 +/- 3.4 ml/min/1.73 m2 (group I) to 1.9 +/- 0.2 ml/min/1.73 m2 (group V). Renal clearance fell from 19.0 +/- 4.9 ml/min/1.73 m2 (group I) to 1.0 +/- 0.4 ml/min/1.73 m2 (group IV). The fractional clearance and the non renal clearance were similar in normal subjects and in uraemic patients. Cefonicid is not haemodializable because of its high protein binding. Dosage of cefonicid should be adjusted according to the degree of renal impairment. Supplemental doses are not necessary after haemodialysis.