Renal effects of S10036 in man.

The renal hemodynamic and tubular effects of S10036 (fotemustine) were evaluated in seven patients with advanced malignancy. Initial evaluation carried out prior to treatment and repeated 1 day after the first fotemustine infusion and 7 days after the second included clinical, haematological parameters, liver-function tests, and determination of the glomerular filtration rate, renal blood flow and enzymuria. The glomerular filtration rate was 108 +/- 3.7 ml/min before treatment and remained stable after the first (117 +/- 5 ml/min) and second (124 +/- 6 ml/min) fotemustine infusions. Renal blood flow and urinary beta 2-microglobulin and N'-acetylglucosaminidase excretion were also not modified by fotemustine administration. We conclude that fotemustine does not acutely alter renal haemodynamics, nor does it have direct tubular toxicity.

Renal vasoconstriction after low and high osmolar contrast agents in ischemic and non ischemic canine kidney.

We have assessed the effect of contrast media on renal blood flow before and after inducing renal ischemia. Diatrizoate, iopamidol and ioxaglate were injected within 15 seconds at 20 min intervals, at the dose of 1 ml/kg during a control period and 15 min after applying an aortic clamp to reduce the renal perfusion pressure to 70 mmHg. During the control period iopamidol, ioxaglate (17 +/- 13%) and diatrizoate (16 +/- 2%) induced a comparable decrease in renal blood flow (RBF). During the ischemic period the effects of diatrizoate on renal hemodynamic were dramatically enhanced. Ioxaglate andiopamidol induced a 20 +/- 12 and a 32 +/- 9% decrease in RBF at 1 minute, respectively. Iopamidol induced an increase in renal vascular resistance (RVR) from 0.8 +/- 0.08 to 1.46 +/- 0.26 mmHg min/ml (p less than 0.05). Ioxaglate induced an increase in RVR from 0.8 +/- 0.09 to 1.36 +/- 0.38 (p less than 0.05). Diatrizoate induced a 77 +/- 10% decrease in RBF and a maximum increase in RVR at 1 minute from 0.9 +/- 0.09 to 26 +/- 12 mmHg min/ml. There was still a 36 +/- 14% and a 23 +/- 13% decrease in RBF 10 and 20 min after diatrizoate administration. These changes were significantly higher than those observed with all contrast media during the control period and low osmolar contrast media during the ischemic period. We have thus shown that ischemia potentiates the renal vascular effect of contrast media.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the safety and efficacy of telmisartan and enalapril, with the potential addition of frusemide, in moderate-renal failure patients with mild-to-moderate hypertension.

The effect on renal function and efficacy of the angiotensin II AT1-receptor blocker (ARB), telmisartan, were compared with those of the angiotensin-converting enzyme inhibitor, enalapril, for the treatment of mild-to-moderate hypertension (diastolic blood pressure [DBP] 95-114 mmHg) in the presence of moderate renal failure (creatinine clearance [Ccr] 30-80 ml/minute). The study was multicentre, double-blind, double-dummy and active-controlled in design, with patients randomised in a 2:1 ratio to receive telmisartanor enalapril. After a two-week placebo run-in period, the 71 eligible patients received either telmisartan, 40 mg, orenalapril, 10 mg, once-daily for four weeks. Thereafter, doses were titrated to telmisartan 80 mg or enalapril 20 mg once-daily if supine trough DBP was still > or =90 mmHg. After a further four weeks, dose titration was again performed, as required, to telmisartan, 80 mg,or enalapril, 20 mg, or frusemide was given in addition if the double dose was already being administered. Mean Ccr decreases of 4.6% for telmisartan and 2.8% forenalapril were not clinically significant. Adverse events occurred in 12 (26.7%) telmisartan-treated patients and in 12 (46.2%) patients receiving enalapril. The mean reduction in supine trough DBP from baseline to the last available value was 12.5 mmHg for telmisartan,compared with 11.9 mmHg for enalapril. A full (reduction of >or=10 mmHg) or partial (reduction of 7-9 mmHg) response occurred in 78% of telmisartanpatients and 65% of enalapril patients. In the enalapril group, 43% of patients required frusemide, compared with 29% of those in the telmisartan group. In conclusion, telmisartan lacks detrimental effect on renal function, is effective in the treatment of mild-to-moderate hypertension in patients with moderate renal failure,and is comparable to enalapril.

A role for adenosine calcium and ischemia in radiocontrast-induced intrarenal vasoconstriction.

These studies were designed to test the hypothesis that adenosine and calcium are important in mediating radiocontrast-media-associated reduction in renal blood flow (RBF) in the dog. Intravenous verapamil (V) and diltiazem (DTZ) infusion significantly attenuated the magnitude of the vasoconstrictor response observed after each intrarenal contrast media (CM) injection. (First injection: -47 +/- 8% control vs. -14 +/- 3% V, p less than 0.03; -38 +/- 4% control vs. -19 +/- 3% DTZ, p less than 0.02. Second injection: -33 +/- 6% control vs. -12 +/- 1% V, p less than 0.03; -32 +/- 5% control vs. -17 +/- 2% DTZ, p less than 0.03. Third injection: -32 +/- 6% control vs. -11 +/- 5% V, p less than 0.03; -38 +/- 5% control vs. -10 +/- 5% DTZ, p less than 0.02). Furthermore, V and DTZ almost completely abolished the increase in renal vascular resistance (RVR) induced by each CM administration. Theophylline also significantly attenuated the magnitude of the vasoconstrictor response observed after CM injection (first injection: -31 +/- 3% control vs. -12 +/- 3% theophylline, p less than 0.05; second injection: -26 +/- 3% control vs. -12 +/- 3% theophylline, p less than 0.03). Similarly, theophylline blunted the increase in RVR induced by CM injection. In addition, theophylline inhibited exogenous adenosine-induced decrease in RBF (-61 +/- 10% and -26 +/- 1% decrease in RBF without and with theophylline, respectively). In contrast, dipyridamole significantly enhanced the vasoconstriction induced by CM (first injection: 25 +/- 3% control vs. 49 +/- 4% dipyridamole; second injection: 31 +/- 3% control vs. 48 +/- 4% dipyridamole p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal effects of radiocontrast agents in rats: a new model of acute renal failure.

The objectives of this study were first to develop a reproducible and reversible model of acute renal failure following contrast medium infusion in the rat; second to use that method to compare the nephrotoxicity of low- and high-osmolar contrast agents. Contrast media or saline were perfused in the aorta while a clamp was applied on the aorta just above the renal artery. Three minutes of renal ischemia with or without infusion of isotonic saline induced no change in serum creatinine and a slight and transient decrease in creatinine clearance at 24 h. Urinary N-acetyl glucosaminidase (NAG) excretion was not modified in this control group. All 17 kidneys which were examined were normal. 2,100 mosm/kg hypertonic saline induced a significant increase in serum creatinine and a significant decrease in creatinine clearance (from 1.8 +/- 0.1 to 0.8 +/- 0.1 and 1.0 +/- 0.2 ml/min at 24 and 48 h, respectively). Urinary NAG excretion increased from 23 +/- 18 to 48 +/- 20 and 8 +/- 4 mumol h-1/mmol creatinine at 24 and 48 h, respectively (p less than 0.05). Histologic analysis of 5 kidneys revealed acute tubular necrosis (n = 3) and no histologic abnormalities (n = 2). Diatrizoate induced an acute and reversible renal failure. Creatinine clearance decreased from 1.6 +/- 0.1 to 0.4 +/- 0.1 and 0.8 +/- 0.1 ml/min at 24 and 48 h, respectively (p less than 0.01). Urinary NAG excretion increased also significantly from 43 +/- 9 to 352 +/- 79 and 64 +/- 23 mumol h-1/mmol creatinine at 24 and 48 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Nephrotoxicity of contrast media in high-risk patients with renal insufficiency: comparison of low- and high-osmolar contrast agents.

We have compared the renal effects of ioxitalamate, ioxaglate, and iopamidol in patients with chronic renal failure. Sixty consecutive patients with an estimated creatinine clearance (ECRCl) less than 60 ml/min were randomly assigned to receive either ioxitalamate, iopamidol, or ioxaglate. All patients received 500 cm3 isotonic saline before the procedure. Serum creatinine and ECRCl were estimated before, 1 and 2 or 3 days after the procedure. There was no statistical difference between the three groups with respect to age, sex, weight, renal function, amount of iodine, and type of procedure. Mean serum creatinine and ECRCl remained unchanged after administration of contrast media. No patient had nephrotoxicity or acute oliguria requiring dialysis as a result of the administration of contrast material. The number of patients with an increase in the serum creatinine level greater than 10% from the basal value did not differ in the treatment groups. The maximal increases in serum creatinine were 52 mumol/l (29%) in the ioxitalamate group, 56 mumol/l (18%) in the ioxaglate group, and 57 mumol/l (23%) in the iopamidol group (p = NS). Using a population carefully randomized and matched for renal insufficiency, we could not show any differences in nephrotoxicity between these three contrast agents. Clinically serious renal impairment was uncommon in our study, regardless of the contrast agent used. However, the interpretation of these favorable findings requires a cautionary note. All patients in this study were well hydrated before and after uro-/angiography, and none had a recent renal injury or a treatment with a nephrotoxic agent that would predispose to injury from contrast material.(ABSTRACT TRUNCATED AT 250 WORDS)