Effects of the calcium antagonist felodipine on renal haemodynamics, tubular sodium handling, and blood pressure in cyclosporin-treated dermatological patients

BACKGROUND: Deterioration of renal function and rise in blood pressure are clinically important side-effects of cyclosporin (CsA) treatment. Calcium antagonists may have a renoprotective effect against CsA nephrotoxicity. PURPOSE: To investigate the effect of the dihydropyridine calcium-channel blocker felodipine on renal haemodynamics, tubular sodium handling, and blood pressure in CsA- treated patients with no primary renal disease, 18 patients with various CsA-treated dermatological diseases were allocated to receive either felodipine 5 mg (extended release tablets) once daily for 4 weeks followed by placebo for 4 weeks, or vice versa, in a prospective, randomized, double-blind study. The patients were investigated before treatment and at the end of each treatment period. RESULTS: After felodipine, both glomerular filtration rate (GFR) and renal plasma flow (RPF) were significantly higher compared to placebo (89.4 +/- 17.5 (mean +/- SD) vs 79.0 +/- 15.9 ml/min and 412.0 +/- 107.6 vs 326.1 +/- 78.0 ml/min respectively, P < 0.001 for both), and filtration fraction (FF) was lower (0.22 +/- 0.03 vs 0.25 +/- 0.03, P < 0.001). Both systolic and diastolic blood pressure were lower after felodipine compared to placebo (116 +/- 11/71 +/- 7 vs 133 +/- 18/83 +/- 10 mmHg, P < 0.001 for both). Furthermore, proximal output of sodium, i.e. fractional excretion of lithium, was higher after felodipine (26.9 +/- 7.3% vs 20.4 +/- 5.5%, P < 0.001) as well as total sodium excretion (0.33 +/- 0.19 vs 0.19 +/- 0.08 mmol/min, P < 0.001). CONCLUSIONS: It is concluded, that felodipine 5 mg once daily for 4 weeks increased GFR, RPF, and sodium excretion in cyclosporin-treated dermatological patients with no primary renal disease. Furthermore, felodipine lowers blood pressure in these patients. The effects of felodipine may be due to an antagonizing effect against CsA-induced nephrotoxicity.      

Renal and systemic effects of atenolol and tertatolol in renal transplant recipients on cyclosporine A

Background. Hypertension and nephrotoxicity are well-known side-effects of cyclosporine A (CsA). CsA-induced vasoconstriction of the afferent glomerular arteriole probably plays a role in at least the nephrotoxicity. Frequently renal transplant recipients on CsA have to be treated with antihypertensive drugs and for this purpose also {beta}-blockers are used. Tertatolol is a new {beta}-blocker with specific vasodilatory properties, and thus might be particularly useful in CsA-treated transplant recipients. Methods. We studied the systemic and renal haemodynamic effects of atenolol and tertatolol in 12 hypertensive renal transplant recipients on cyclosporine A (CsA). In a cross-over way, all patients were treated with atenolol and tertatolol for 4 weeks each, separated by a wash-out period also of 4 weeks. At the end of each period, the mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured. Results. The mean arterial pressure was lower (P<0.05) during atenolol (124±2 mm Hg) and tertatolol (125±2 mm Hg) treatment compared with wash out (132±4 mm Hg). Also the heart rate was lower (P<0.01) during atenolol and tertatolol (54±3 and 55±2 beats/min respectively) than in the wash-out period (65±3 beats/min). GFR and RPF were not changed by either {beta}-blocker. Conclusion. In CsA treated renal transplant recipients both atenolol and tertatolol effectively reduced blood pressure. In these patients we found no evidence of a specific vasodilatory effect of tertatolol. Both {beta}-blockers had no negative influence on renal function. Hence, these cardioprotective agents are an attractive and safe choice for the treatment of hypertension in such patients.     

Effect of 6 weeks of vitamin E administration on renal haemodynamic alterations following a single dose of neoral in healthy volunteers.

BACKGROUND: A single oral dose of cyclosporin-A (CsA) transiently reduces renal plasma flow (RPF) and glomerular filtration rate (GFR) in transplant patients and, in some patients, chronic administration of CsA leads to renal impairment and fibrosis. Based on experimental studies, several mediators including free radicals have been proposed to account for CsA-nephrotoxicity. We have previously reported that administration of the antioxidant vitamin E in a rat model of chronic CsA-nephrotoxicity reduces renal fibrosis and maintains renal function. METHODS: In the present study, the effect on renal haemodynamics of a single dose of the new oral formulation of CsA (neoral) was assessed before and after 6 weeks of vitamin E (800 IU/day, 2-fold increase in serum vitamin E). GFR (inulin clearance) and RPF (para-amino hippuric acid clearance) were measured before and after a single dose of 5 mg/kg of neoral in 12 healthy subjects under standardised conditions. RESULTS: Although the mean area under the curve of the CsA levels was 21% lower after the vitamin E period, the peak CsA level at 120 min after neoral was similar both before and after vitamin E administration. At 120 min after neoral, a transient reduction in RPF and GFR was noted both before and after vitamin E administration. The nadir of the reductions in RPF (-81 +/-27 ml/min) and GFR (-14 +/- 6 ml/min) at 120 min compared with baseline tended to be lower before than after the treatment with vitamin E (-51 +/- 33 ml/min of RPF and -12 +/- 8, ml/min of GFR, respectively). Plasma and urine levels of F2-isoprostanes (free radical-catalysed vasoconstrictive prostanoids (F2-iso) at 120 min after the administration of neoral were not different from the pre-neoral levels. CONCLUSION: The findings demonstrate that a single oral dose of neoral causes transient, yet significant, reductions in RPF and GFR, and suggest that F2-iso might not be involved in the CsA-induced acute renal vasoconstriction. The tendency for a lower reduction in RPF and GFR following CsA during the vitamin E period in healthy humans warrants additional studies in transplant patients.     

Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity.

Endothelin (Et) has been implicated in cyclosporine A (CsA) nephrotoxicity. We have previously shown that CsA treatment in rats results in up-regulation of Et receptors specifically within the kidney. The role of Et in vivo CsA nephrotoxicity was therefore studied further with a new competitive antagonist, BQ-123, specific for Et(A) receptors (EtRA). Systemic administration of CsA in Munich-Wistar rats resulted in marked glomerular hypoperfusion and hypofiltration, with RPF in left and right kidneys falling by some 40% to 1.60 +/- 0.25 and 1.73 +/- 0.38 ml/min and GFR decreasing by some 20% to 0.61 +/- 0.05 and 0.67 +/- 0.11 ml/min, respectively. Selective infusion of EtRA into the left renal artery following systemic CsA treatment had no effect on this hemodynamic pattern (RPF 1.58 +/- 0.29 and 1.92 +/- 0.34 ml/min and GFR 0.60 +/- 0.09 and 0.70 +/- 0.08 ml/min in left and right kidneys, respectively, P = NS vs. CsA period). By contrast, intrarenal infusion of EtRA prior to systemic administration of CsA resulted in a strikingly different pattern of renal hemodynamics. Thus, EtRA pretreatment in the left kidney protected against glomerular dysfunction following CsA: RPF was maintained, 3.23 +/- 0.28 ml/min versus 2.96 +/- 0.31 (P = NS EtRA vs. EtRA + CsA), as was the GFR, 1.04 +/- 0.16 ml/min versus 1.12 +/- 0.09 (P = NS). However, the contralateral right kidneys of these rats, not pretreated with EtRA, showed no protective effect: RPF decreased from 3.15 +/- 0.34 ml/min to 2.39 +/- 0.19 and GFR from 1.04 +/- 0.10 ml/min to 0.85 +/- 0.07 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cyclosporin A on renal function and kidney growth in the uninephrectomized rat

This study was designed to characterize the effect of cyclosporin A (CsA) on renal function and compensatory kidney growth in a rat model of uninephrectomy (Ux). The infusion of CsA (12.5 mg/k body wt) after acute Ux resulted in a fall in glomerular filtration rate (GFR) and renal plasma flow (RPF) and a marked increase in renal vascular resistance (RVR). Three weeks following Ux, GFR was also reduced in CsA treated animals as compared to pair-fed controls (0.39 +/- 0.03 vs. 0.67 +/- 0.06 ml/min/100 g, P less than 0.001), but RPF was not (1.97 +/- 0.14 vs 2.19 +/- 0.34 ml/min/100 g). The reduction in GFR seen in rats treated with CsA was fully reversible two weeks after discontinuation of the drug. Three weeks after Ux, kidney weight in CsA-treated animals increased to the level of pair-fed controls (1.50 +/- 0.05 vs. 1.57 +/- 0.06 g) but renal cortical RNA (39.4 +/- 4.3 vs. 49.3 +/- 1.3 micrograms/ml, P less than 0.05), DNA (26.4 +/- 1.7 vs. 34.7 +/- 2.1 micrograms/ml, P less than 0.01), and protein content (6.4 +/- 0.3 vs. 7.8 +/- 0.2 mg/dl, P less than 0.001) were all markedly reduced. Unilateral renal denervation in CsA-treated rats resulted in an increase in GFR and RPF as compared to that of pair-fed sham-denervated animals also treated with CsA (0.57 +/- 0.06 vs. 0.39 +/- 0.03 ml/min/100 g, P less than 0.025 and 2.14 +/- 0.14 vs. 1.63 +/- 0.20 ml/min/100 g, P less than 0.025, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of felodipine on renal haemodynamics and tubular sodium handling in cyclosporin-treated renal transplant recipients.

The effect of a single oral dose of 10 mg of the calcium antagonist felodipine or placebo was investigated in 10 cyclosporin-treated renal transplant recipients before, during, and after an acute intravenous infusion of cyclosporin in a randomised, single-blind cross-over study. Renal plasma flow (RPF), glomerular filtration rate (GFR), renal tubular sodium and water handling as judged by the lithium clearance technique, and plasma concentrations of angiotensin II (AngII), aldosterone (Aldo), atrial natriuretic factor (ANF), and arginine vasopressin (AVP) were measured. Both RPF and GFR increased after felodipine (mean increase: RPF, 38.7%; GFR, 16.2%; P less than 0.01 for both) in spite of a significant decrease in both systolic and diastolic blood pressure (mean decrease 10.6% and 16.0% respectively, P less than 0.02 for both). Estimated by the lithium clearance technique felodipine induced a decrease in fractional reabsorption in the proximal tubules (mean 72.0% vs 63.0%, P less than 0.01), an increase in proximal output of fluid (mean 11.0 ml/min vs 16.0 ml/min, P less than 0.01), and a decrease in distal fractional reabsorption of sodium (mean 90.5% vs 83.9%, P less than 0.05) resulting in a significant natriuresis and diuresis. Ang II, Aldo, ANF, or AVP did not change. Intravenous infusion of cyclosporin per se did not influence any of the parameters. It is concluded that a single dose of felodipine in cyclosporin treated renal transplant recipients has beneficial effects on blood pressure, renal haemodynamics, and renal tubular sodium and water handling, which seems to compensate for some of the adverse effects of cyclosporin. It is suggested that these effects result from a direct vasodilatation and an effect on proximal tubular function.     

Inhibition of mineralocorticoid receptors with eplerenone alleviates short-term cyclosporin A nephrotoxicity in conscious rats

BACKGROUND: Recent data indicate that aldosterone aggravates cyclosporin A (CsA)-induced nephrotoxicity. We examined whether the mineralocorticoid receptor (MR) blocker eplerenone (EPL) antagonized early deterioration of renal function and blood pressure (BP) increase in CsA-treated rats. METHODS: Male Sprague-Dawley rats received CsA (15 mg/kg/day i.p.) and/or EPL (100 mg/kg/day p.o.) for 21 days. After 2 weeks, arterial, venous and urinary bladder catheters were implanted and the rats were trained to accept a restraining device allowing arterial blood sampling and direct measurement of BP and renal function. BP was measured on-line in conscious rats. RESULTS: CsA significantly increased systolic BP: 139 +/- 4 versus 134 +/- 2 mmHg, reduced body weight gain: -5 +/- 6 versus 36 +/- 7 g, glomerular filtration rate (GFR): 1.02 +/- 0.16 versus 2.64 +/- 0.27 ml/min, renal blood flow (RBF): 5.3 +/- 2.4 versus 13.5 +/- 2.1 ml/min and lithium clearance (C(Li+)): 0.16 +/- 0.04 versus 0.26 +/- 0.07 ml/min compared to controls. These changes were prevented by simultaneous EPL treatment: systolic BP, 130 +/- 4 mmHg; weight gain, 53 +/- 7 g; GFR, 1.67 +/- 0.26 ml/min; RBF, 12.3 +/- 2.1 ml/min and C(Li+), 0.27 +/- 0.03 ml/min. Analysis of kidney morphology after the CsA treatment showed hyaline vacuolization in tubules and vascular depositions in arterioles; these changes were less pronounced after combination therapy. No significant changes were seen regarding haemoglobin, haematocrit, plasma renin and vasopressin, plasma and urinary sodium, potassium, or osmolality. CONCLUSIONS: MR blockade by EPL prevented short-term alterations in GFR, RBF and hypertension associated with CsA nephrotoxicity. We conclude that the aldosterone-MR pathway contributes markedly to the renal toxicity induced by this calcineurin inhibitor.     

L-arginine supplementation in young renal allograft recipients with chronic transplant dysfunction.

AIMS: L-arginine (LA), the precursor of nitric oxide (NO), was suggested to be beneficial in many forms of renal disease: hypertension, ureteral obstructive nephropathy and cyclosporin A (CsA) nephrotoxicity. METHODS: Thus, we investigated the effects of LA supplementation on renal function, proteinuria and blood pressure (BP) in young renal allograft recipients with chronic renal transplant dysfunction treated with CsA. Eleven CsA-treated renal allograft recipients with chronic transplant dysfunction, aged 11-22 years, were randomly assigned to a 6-week treatment period with placebo (P), followed by 2 subsequent 6-week periods with LA supplementation (0.1 g/kg body weight/day) or a 6-week treatment period with LA, followed by 2 subsequent 6-week periods with P. At the end of each treatment period 24-hour BP recordings were made, and GFR (Inutest), RPF (PAH clearance) and the urinary excretion of protein, albumin, nitrate, cGMP and urea were evaluated. RESULTS: In comparison to placebo, LA treatment did not significantly change GFR, RPF, proteinuria and albuminuria, mean systolic or diastolic BP. The urinary excretion of urea and NO3 increased after LA supplementation (uUrea: LA 26.3 +/- 4.6 compared to P 23.5 +/- 4.7 g/day/1.73 m3, p < 0.05, uNO3: LA 514 +/- 152 compared to P 95 +/- 41 mM/day/1.73 m3, p < 0.05), whereas urinary excretion of cGMP remained unchanged. CONCLUSION: LA supplementation did not improve renal function and did not decrease proteinuria in CsA-treated renal allograft recipients with chronic transplant dysfunction possibly because of inhibition of NO-cGMP forming mechanism.     

Advantages of cyclosporin A using 2-h levels in pediatric kidney transplantation

Clinical trials in adult liver and heart recipients have shown that management of cyclosporine (CsA) dose with 2-h levels (C2) leads to lower rejection rates and serum creatinine levels compared with C0 monitoring. Therefore, we investigated whether C2 monitoring might also improve late graft survival after kidney transplantation in children. To date, no results in adult renal transplantation and in pediatric transplantation have been published. Forty-nine stable pediatric kidney recipients with a minimum time of 1 year after transplantation (mean=7±5 years) entered the study. None of the patients had experienced an acute rejection up to 6 months before entering the study. CsA dosing was based on C0 monitoring for the first 6 months and then based on C2 monitoring for the following 6 months. C0 and C2 levels were measured at 4-weekly intervals. Percentage decline in glomerular filtration rate (GFR) and mean coefficients of variation of CsA levels (C_var) were calculated and compared during the 6-months periods. At the beginning of the study, the mean calculated GFR was 53±15 ml/min per 1.73 m². During the 6 months of C0 monitoring, the mean GFR decreased to 49±12 m/min per 1.73 m² (P=0.001, paired t-test). Six months after switching to C2 monitoring, the mean GFR remained stable, at 49±15 ml/min per 1.73 m² (P=0.3 paired t-test). The largest increase in GFR (3.9±7.9%) was found in patients with a decrease of their CsA dose of more than 5% under C2 monitoring. C_var was significantly lower under C2 than under C0 monitoring (0.24±0.10 vs. 0.30±0.15, P=0.02, unpaired t-test). We conclude that the switch to C2 monitoring helped to identify patients with CsA overdosing as well as to reduce variation in CsA level, which resulted in a halt in GFR decline.     

Correlation between glomerular morphology and renal haemodynamic response to amino-acid administration in patients with IgA nephropathy

RATIONALE.: To establish relationship, if any, between renal morphologyand renal haemodynamic response to amino acids. DESIGN AND METHODS.: We investigated the correlation between renal haemodynamic regulationand morphology in a group of 15 patients with primary IgA nephropathy(IgAN) (age 26±2 years, BMI 24.4±1, GFR 64±5ml/min, RPF 377±34 mI/mm, FF 0.17±0.02). Twelvenormal subjects (age 30±3 years, BMI 24±1, GFR82±6 ml/min, RPF421±42 ml/min, FF 0.19±0.02)were studied as controls. IgA patients were divided into twogroups according to the histological staging of glomerular lesions:group I (n=7) stage II, and group II (n=8) stage III–IV. RESULTS.: In the basal state GFR was similar in the two groups and averaged64±9 and 64±6 ml/mm respectively. In contrast,FF was significantly lower in group II(0.14±0.01) (P<0.05)in comparison to group I (0.21±0.03) and controls (0.19±0.02).In order to evaluate the renal functional reserve, all studygroups underwent to an intravenous amino-acid infusion designedto increase plasma amino acid levels twofold (total from 2096±145to 4301±221 µmol/l in IgA nephropathy patientsand from 2272±83 to 3844±238 µmol/l in controls).In response to amino-acid infusion, GFR rose significantly ingroup I (GFR 20±2% and RPF 37±4% versus basal)and controls (GFR 20±2% and RPF 20±3% versus basal)(both P<0.01 vs basal). In contrast, in patients with moresevere glomerular lesions (group II) neither GFR nor RPF rosesignificantly (GFR –1±4% and RPF –8±6%versus basal) (P NS versus basal, P<0.01 versus group I andcontrols). CONCLUSIONS.: The data show that in IgA nephropathy: severe forms of glomerularlesions are associated with a complex alteration of glomerularhaemodynamic regulation, characterized by lower basal FF andloss of haemodynamic response to hyperaminoacidaemia.     

Cyclosporine-induced transient renal hypoperfusion in adolescent transplant recipients

We investigated the acute hemodynamic effect of a single oral dose of cyclosporine A (CsA) given as part of the immunosuppressive schedule in six adolescents with renal transplants. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined by continuous infusion of inulin and amino-hippuric acid for 12 h. A fall in both GFR and RPF was observed 4–6 h after peak plasma CsA levels. No significant correlation was found with CsA dosage or any pharmacokinetic parameters. This study demonstrates that CsA also has a vasoconstrictory effect in adolescent recipients; this could be one of the causes of its nephrotoxicity.     

Renal haemodynamic responses to a chicken or beef meal in normal individuals

Background: In normal subjects, protein loading with soybean meal does not produce the same renal haemodynamic effects as those observed with a beefy meal. The renal responses of an acute protein load in the form of chicken meal is unknown. Methods: To examine whether the renal response to a chicken meal differs from that to beef, we studied the renal function of eight normal healthy volunteers before and after a protein load with each of these meals. In a crossover randomized study, we measured the glomerular filtration rate (GFR; inulin clearance), renal plasma flow (RPF; para-aminohippurate clearance and, plasma amino acid and glucagon levels. We also determined the amino acid content of a sample of chicken and beef. Results: GFR and RPF increased significantly 2 h after both the chicken and beef meals (chicken, 98±13 vs 119±18 and 476±123 vs 570±99 ml/min/1.73 m²; beef, 107±14 vs 122±16 and 501±118 vs 560±97 ml/min/1.73 m², for GFR and RPF at basal and 2 h respectively, P<0.05). Renal vascular resistance decreased and the filtration fraction remained unchanged after both protein loads. The changes induced by the protein challenges in the plasma amino acid and glucagon levels were not different between the two protein sources. The amino acid contents of chicken and beef samples were similar. Conclusion: In normal subjects, chicken and beef meals induced a similar degree of hyperfiltration. Key words: beef; chicken; diabetic nephropathy; glomerular hyperfiltration; protein load; renal haemodynamics      

Renal fibrosis in cyclosporin A-treated renal allograft recipients: morphological findings in relation to renal hemodynamics

Nineteen nondiabetic kidney graft patients treated with cyclosporin A for 2 years underwent percutaneous renal allograft biopsy as well as renal hemodynamic examination. Renal allograft fibrosis was quantitatively evaluated as the relative volume of the renal cortical interstitium (V_v%) and as the intersttium/tubuli ratio (I/T ratio). The histological changes were then classified into four groups, depending on the degree of interstitial fibrosis. The glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF), filtration fraction (FF), and fractional clearance of sodium, potassium, phosphate, chloride, osmoles, and free water clearance were determined in all patients and in 13 healthy controls. Kidney graft recipients had significantly lower GFR, lower RPF, and lower RBF than the healthy controls (P<0.001 for all comparisons) while FF was similar in patients and controls. Transplant recipients had a significantly higher fractional excretion of sodium, potassium, chloride, and phosphate than controls. All except one patients had clearly increased V_v values, indicating increased interstitial fibrosis. The mean V_v in renal allograft patients was 35%±10% (normal <16%±5%) and the I/T ratio was 1.07±0.60 (normal <0.24±0.08). No correlation was found between the quantitative or semiquantitative biopsy analysis and any renal hemodynamic parameter measured. We conclude that renal function is significantly decreased in kidney graft recipients, but that adaptive tubular changes occur in the graft. Interstitial renal fibrosis was common but did not correlate to any renal functional parameter.     

Effects of the prostacyclin analogue iloprost on cyclosporin-induced renal hypoperfusion in stable renal transplant recipients

BACKGROUND.: The synthetic prostacyclin analogues have been proposed to protectagainst cyclosporin A (CsA) nephrotoxicity. The present studyinvestigated the effect of infusion of the prostacyclin analogueiloprost on the acute CsA-induced renal hypoperfusion and hypofiltrationin stable renal-transplant recipients. METHODS.: The study included 10 stable renal-transplant recipients withgood graft function (s-creatinine 90–170 umol/1). Renalfunction and the acute renal haemodynamic and tubular responseto an oral CsA-dose (Sandimmun Neoral, 3 mg.kg^–1) wereinvestigated with an infusion of iloprost (1 ng.kg^–1.min^–1)or placebo on 2 separate days. After an overnight fast, seven30-min renal clearance periods were performed, two before infusion,three during infusion, and two recovery periods. An additionalcontrol clearance study without CsA intake or iloprost/placeboinfusion was done in eight of the patients. RESULTS.: CsA ingestion decreased ERPF and GFR significantly with a maximumdecline at the end of the clearance study. Iloprost infusionabolished the CsAinduced decrease in ERPF, but had no effecton the CsA-induced decrease in GFR, leading to a significantdecline in FF. Renal clearance of lithium (CLi), used as anindex of proximal tubular outflow, decreased in parallel withGFR after CsA intake, with no additional effects of iloprost.Iloprost infusion decreased blood pressure and increased heartrate. CONCLUSION.: Infusion of iloprost causes systemic and renal vasodilatation,but has no effect on the CsA-induced decrease in GFR and C_Liin stable renal transplant recipients.     

Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A

Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A. BACKGROUND: Endothelins may play an important role in cyclosporine A (CsA)-induced renal vasoconstriction. Therefore, the effects of a mixed endothelin A and B receptor antagonist, bosentan (BO), on CsA were studied. METHODS: BO was given either alone or combined with CsA to healthy subjects in a double-blind, placebo-controlled, cross-over study. Standardized renal hemodynamics took place after a single dose of BO or placebo and after seven days of regular intake of CsA + BO or CsA + placebo. CsA was administered as a dose-adjusted regimen to achieve predetermined target trough levels. A pharmacokinetic study of CsA and BO was performed. RESULTS: A single dose of BO did not affect renal hemodynamics. After seven days of coadministration with CsA, BO significantly attenuated both the overall CsA-induced fall of renal plasma flow (RPF; placebo, 594 +/- 85; CsA + placebo, 490 +/- 93; CsA + BO, 570 +/- 106* mL/min, *P < 0.01) and the maximal RPF fall (P < 0.01) observed five hours after CsA intake. The CsA-induced rise of blood pressure and the decrease of glomerular filtration rate (GFR) were not influenced by comedication with BO. After seven days of CsA + BO, the area under the curve (AUC) of BO was nearly doubled compared with the AUC after a single dose of BO (P < 0.05). To reach the CsA target trough levels after seven days, the average CsA dose was increased by 35% when given with BO, as compared with placebo (P = 0.01). CsA exposure (trough levels, AUC) was not statistically different after CsA + placebo and after CsA + BO. CONCLUSIONS: Assuming CsA nephrotoxicity is mainly due to vasoconstriction, BO has the potential to attenuate the CsA renal toxicity by markedly blunting the renal hypoperfusion effect of CsA. A complex drug interaction between BO and CsA was observed.     

Antagonist capacity of felodipine on cyclosporin A nephrotoxicity in the rat.

Functional and morphological cyclosporin A (CsA) nephropathy has been attributed to a CsA-induced constriction of the afferent glomerular arteriole. Calcium-channel blockade with nifedipine prevented the development of short-term functional nephrotoxicity in CsA-treated rats. This study investigated whether the calcium antagonist felodopine, a structural analogue of nifedipine, which reduces renal tubular fractional sodium reabsorption, could prevent both short- and long-term functional and long-term morphological CsA nephropathy. In short-term experiments, four groups of Spraque-Dawley rats (n = 39) were given CsA (either 0 or 12.5 mg/kg per day by daily gastric intubation for 2 weeks), and felodipine (0 or 30 mg/kg per day) in the diet. In long-term experiments, rats (n = 39) were given CsA (12.5 mg/kg per day for 16 weeks), and felodipine (0 or 30 mg/kg per day in the diet). Renal function was investigated with clearance methods (inulin, lithium, and sodium), and kidney morphology was studied by light-microscopy. In short-term experiments, CsA treatment reduced GFR (730 versus 1181 microliters/min per g kidney weight (KW), P < 0.05) and CLi (130 versus 271 microliters/min per gKW, P < 0.02). Felodipine decreased proximal fractional reabsorption (PFR) (67.5% versus 71.4%, P < 0.05) and increased CNa (15.9 versus 8.4 microliters/min per gKW, P < 0.02) as compared to controls. In CsA-treated rats felodipine increased C in (1260 versus 730 microliters/min per gKW, P < 0.05) and CLi (319 versus 130 microliters/min per gKW, P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute cyclosporine renal dysfunction reversed by dopamine infusion in healthy subjects

Up to now, no studies have been performed in normal humans to investigate the role of renal hemodynamic abnormalities in relation to acute-cyclosporin A (CsA) renal dysfunction and to verify whether the specific renal vasodilator, dopamine, can counteract these abnormalities. Eight normal subjects were examined both (A) after oral CsA (12 mg/kg body wt) and (B) after oral CsA + dopamine infusion (2 mg/kg body wt/min), under water diuresis. Both in protocols A and in B, four basal renal clearances were performed before CsA and every twenty minutes for four hours after CsA administration. In protocol A, after CsA, inulin (GFR) and PAH clearance (RPF) fell by up to 27% and to 41%, respectively, so that filtration fraction (FF) increased (P less than 0.01). A slight (not significant) hypertension occurred while renal resistances were markedly raised (P less than 0.001). Fractional urine and Na+ excretion as well as CH2O decreased, while UOsm increased (P less than 0.01). In protocol B, dopamine was infused from 120 to 180 minutes after CsA (that is, when the maximal adverse effects of CsA on renal hemodynamics had been observed in A). Dopamine infusion could reverse completely the effects of CsA on RPF, GFR, fractional urine output and CH2O; only UOsm remained higher than normal in conclusion with an increased fractional excretion of sodium (P less than 0.01). No changes were observed in plasma renin activity, aldosterone and in urinary epinephrine and norepinephrine excretion both in protocols.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of felodipine on renal function and vasoactive hormones in infrarenal aortic surgery

We have examined the possible renoprotective effect of felodipine 5 mg orally, given daily for 5 days before operation, in 29 patients undergoing elective infrarenal aortic surgery in a randomized, blinded and placebo-controlled study. Effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urine output, fractional sodium clearance and plasma concentrations of angiotensin II, aldosterone, arginine vasopressin and atrial natriuretic peptide did not differ between the felodipine and placebo groups. ERPF and GFR were not reduced after operation in the placebo group. In the felodipine group, GFR was higher 24 h after operation compared with before operation. We conclude that increased GFR in the felodipine group, measured 24 h after operation, may indicate a beneficial effect of felodipine but in the present context this was not clinically important. Felodipine had no significant effect on vasoactive hormones.      

Renal hemodynamic effects of L-arginine and sodium nitroprusside in heart transplant recipients

BACKGROUND: Long-term treatment with cyclosporine A (CsA) induces vasoconstriction in the kidney and causes renal impairment. An altered L-arginine (L-Arg)/nitric oxide (NO) pathway may play a key role in CsA nephrotoxicity. METHODS: We studied the effect of L-Arg (dosage, 17 mg/kg/min over 30 min), the precursor of NO synthesis, and sodium nitroprusside (SNP; dosage, 1.0 microgram/kg/min over 30 min) on renal hemodynamics in a double-blind, placebo-controlled, randomized, three-way cross-over study comprising 12 stable cardiac transplant recipients on long-term CsA treatment, 10 patients with chronic nephropathy not receiving CsA, and 13 healthy controls. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured by paraaminohippurate (PAH) and the inulin clearance method, respectively. RESULTS: In healthy subjects, L-Arg induced an increase in RPF (P = 0.009) and GFR (P = 0.001). By contrast, L-Arg did not induce renal hemodynamic effects in heart transplant patients or patients with chronic nephropathy. SNP reduced RPF (P = 0.050) and GFR (P = 0.005) in patients with chronic nephropathy but did not affect renal hemodynamics in heart transplant recipients or in healthy subjects. CONCLUSIONS: These data indicate that L-Arg cannot be used to reverse CsA-induced renal vasoconstriction in heart transplant recipients under long-term CsA treatment, although these patients have a normal renal response to SNP.     

Losartan reduces proteinuria and preserves renal function in hypertensive patients with IgA nephropathy

Background. The objectives of this study were to evaluate the effects of the angiotensin II receptor antagonist losartan on blood pressure (BP), proteinuria, and renal function in hypertensive patients with IgA nephropathy. Method. The study subjects comprised 18 patients with biopsy-proven IgA nephropathy with mild hypertension. Patients were classified into three groups (good/relatively good, relatively poor, poor) according to renal histologic findings and treated once a day with losartan 50 mg for 12 months. Changes in BP, proteinuria, renal function, and biochemical parameters were prospectively evaluated before and after the treatment. Results. BP began to fall after 1 month and proteinuria decreased significantly after 9 months of therapy. Glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF) did not change throughout the observation period. There was no significant difference between the three different histologic groups in relation to the effects of losartan on BP, proteinuria, and renal function. We found that in patients with a proteinuria reduction rate of more than 50%, RPF increased and FF decreased significantly. Although it has been reported that losartan has a uric acid lowering effect, this study could not confirm such an effect. Conclusions. Losartan lowers blood pressure and decreases proteinuria in hypertensive patients with IgA nephropathy. These effects appear to be independent of renal histologic findings. This study suggests that the antiproteinuric effect of losartan is primarily mediated by changes in glomerular hemodynamics. Received: April 13, 2001/Accepted: July 15, 2002 Correspondence to:H. Ohashi