Haemodynamic and renal effects of felodipine in young and elderly subjects

OBJECTIVE: To study the influence of age on renal and haemodynamic effects of the calcium antagonist felodipine. METHODS: Eight young (mean age 27 years) and eight elderly (mean age 75 years) healthy normotensive subjects were given felodipine intravenously for 120 min aiming at close to therapeutic plasma level concentration. Renal blood flow (RBF) and renal vascular resistance (RVR) was estimated from para-aminohippuric acid (PAH) clearance 51CrEDTA clearance was used to measure glomerular filtration rate (GFR) and used in the calculations of fractional excretion (FE) of electrolytes. Impedance cardiography was performed to assess stroke volume and for the calculation of cardiac output and ejection fraction. RESULTS: At the end of felodipine infusion, the concentration of felodipine was on average 10.0 nmol x l(-1) in young and 12.0 nmol x l(-1) in elderly subjects (NS). During felodipine infusion blood pressure (BP) decreased from 138/76 to 120/68 in elderly subjects. The BP in young subjects was 126/74 at basal and 125/70 after infusion of felodipine. The systemic and renal vascular resistance decreased to a similar extent in young and elderly subjects after felodipine infusion. Felodipine caused a decrease in systemic vascular resistance from 25.6 to 23.3 in elderly and from 23.8 to 21.8 in the young subjects. Mean values for RVR at baseline and during infusion of felodipine were significantly higher in the elderly (10.1-15.1) than in the young subjects (5.4-6.7). Felodipine reduced RVR by 10% in the young and by 12% in the elderly at the end of infusion. The young subjects had 31% higher GFR than the elderly subjects at the start of infusion. Felodipine infusion did not affect GFR. There were no effects on stroke volume and ejection fraction. An initial natriuretic effect was found after infusion of felodipine in the young subjects. The fractional excretion of all electrolytes tended to increase after both felodipine and placebo, more in the elderly than in the young subjects. CONCLUSION: The effects of felodipine on central and renal haemodynamics previously observed in young and middle-aged subjects also seem to exist in the elderly. Volume expansion seems to increase the excretion of electrolytes more in elderly than in young people, and therefore the effect of felodipine on natriuresis is more evident in young subjects.     

Cyclosporin does not inhibit the tubular secretion of creatinine

BACKGROUND: The immunosuppressive drug cyclosporin is known to impair renal function. The degree of renal dysfunction is usually estimated from the clearance of creatinine (CCr). Theoretically however, a fall in CCr can be caused by a decrease of GFR, an inhibition of the tubular secretion of creatinine, or the combination of both. CsA has convincingly been shown to decrease GFR, but detailed information on the effects of CsA on tubular secretion of creatinine is lacking. METHODS: We performed two studies to investigate the influence of CsA on tubular creatinine secretion. In study A we simultaneously measured CCr and GFR (using inulin) immediately before and 4 weeks after cessation of CsA therapy in 17 renal transplant patients. In study B, the rise in serum creatinine after administration of cimetidine, which blocks the tubular secretion of creatinine, was compared in renal transplant patients treated with either CsA (in whom secretion might already be inhibited) or azathioprine. RESULTS: Study A: After cessation of CsA there was an increase of GFR (54+/-15 vs 63+/-16 ml/min/1.73 m2, PCr (71+/-21 vs 82+/-23 ml/min/1.73 m2; PCr and GFR (a measure of the relative contribution of tubular secretion to the clearance of creatinine) did not change significantly (1.33+/-0.21 vs 1. 32+/-0.30). Study B: In nine couples of patients matched for GFR the relative rises in serum creatinine after administration of cimetidine were 26+/-21% and 22+/-7% for CsA and azathioprine treated patients respectively (NS). CONCLUSION: CsA does not substantially inhibit the tubular secretion of creatinine. A rise in serum creatinine after administration of CsA can thus be attributed completely to a fall in GFR.     

Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome

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 washout (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.     

Acute effects of nifedipine in renal transplant recipients treated with cyclosporine or azathioprine

Cyclosporine (CsA) impairs renal function, probably by preglomerular vasoconstriction. Vasodilating substances may therefore be of benefit to ameliorate CsA-induced renal dysfunction. We studied the acute effects on blood pressure and renal function of the dihydropyridine calcium antagonist nifedipine (10 mg orally) in 20 CsA-treated renal transplant patients. In addition, we compared the effects of nifedipine when given immediately before and 4 weeks after elective conversion from CsA to azathioprine. Compared with placebo (n = 14), administration of nifedipine led to a significant decrease in blood pressure and a strong natriuretic and diuretic response. Despite the reduction in blood pressure, glomerular filtration rate improved from 60 +/- 20 (mean +/- SD) to 69 +/- 24 mL/min/1.73 m2 (P < 0.001) and renal plasma flow (RPF) increased from 260 +/- 87 to 338 +/- 120 mL/min/1.73 m2 (P < 0.001). The combination of a decreased blood pressure with an increased RPF was reflected in a sharp decrease in renal vascular resistance (0.34 +/- 0.18 units v 0.23 +/- 0.10 units; P < 0.001). The conversion from CsA to azathioprine by itself led to significant increases in glomerular filtration rate (62 +/- 15 mL/min/1.73 m2 v 76 +/- 18 mL/min/1.73 m2; P < 0.05) and RPF (280 +/- 86 mL/min/1.73 m2 v 334 +/- 66 mL/min/1.73 m2; P < 0.05). During treatment with azathioprine an effect of nifedipine on glomerular filtration rate and RPF was no longer observed, although the natriuretic effect was similar on both occasions. The decrease in renal vascular resistance was larger during treatment with CsA than during treatment with azathioprine (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Production of less chronic nephrotoxicity by cyclosporine G than cyclosporine A in a low-salt rat model

Chronic tubulointerstitial nephropathy during long-term cyclosporine A (CsA) use has led to a search for equally effective but safer analogues. In this study we evaluated one of these analogues, cyclosporine G (CsG), in a rat model of chronic cyclosporine nephrotoxicity. CsG has immunosuppressive effects equivalent to CsA when dosed on a weight basis. Pair-fed Sprague-Dawley rats kept on a low-salt rice diet were given CsA 15 mg/kg, CsG 15 mg/kg, CsG 25 mg/kg, or vehicle subcutaneously. After 21 days, CsA animals had a lower glomerular filtration rate, measured by inulin clearance (0.16 +/- 0.04 ml/min/100 g) and higher serum creatinine (0.94 +/- 0.06 mg/dl) than CsG 15 mg/kg (GFR: 0.41 +/- 0.10 ml/min/100 g and serum creatinine: 0.68 +/- 0.09 mg/dl), CsG 25 mg/kg (GFR: 0.39 +/- 0.16 ml/min/100 g) or control rats (GFR: 0.62 +/- 0.06 ml/min/100 g; serum creatinine: 0.56 +/- 0.03 mg/dl), respectively (P < 0.05). The CsA group had considerable cortical and medullary injury (interstitial fibrosis and tubular atrophy), whereas both groups of CsG animals had more limited changes. Despite the same or larger doses of CsG on a weight basis, cyclosporine blood levels were significantly lower in CsG than CsA rats. We conclude that CsG, an analogue of cyclosporine with immunosuppressive activity equivalent to that of CsA, produced less nephrotoxicity in a model of chronic renal injury in rats, using both functional and structural parameters.     

Low-dose cyclosporine and mycophenolate mofetil in renal allograft recipients with suboptimal renal function

BACKGROUND: Cyclosporine (CsA) nephrotoxicity can be identified by functional changes and chronic renal damage. CsA-associated renal fibrosis has been related to the overproduction of transforming growth factor (TGF)-beta1, a fibrogenic cytokine. Mycophenolate mofetil (MMF) may allow CsA dose reduction without increasing the risk of rejection. METHODS: We studied the impact of CsA dose reduction in association with MMF on renal function and TGF-beta1, production in 16 long-term renal allograft recipients with suspected CsA nephrotoxicity. Two grams/day of MMF were introduced, and CsA dose was reduced to reach whole-blood levels between 40 and 60 ng/ml within 1 month. CsA dose and levels, renal function parameters, and platelet-poor plasma TGF-beta1 levels were evaluated before and 6 months thereafter. RESULTS: MMF allowed a decrease in both the mean dose of CsA (3.8+/-1.35 vs. 2.2+/-0.73 mg/kg/day; P<0.01) and CsA levels (148+/-36 vs. 53+/-19 ng/ml; P<0.001). The reduction of CsA was associated with a decrement of serum creatinine levels (210+/-46 vs. 172+/-41 micromol/L; P<0.001) and an increase in both the glomerular filtration rate (32.9+/-12 vs. 39.1+/-14 ml/min/1.73 m2; P<0.02) and renal plasma flow (195+/-79 to 218.6+/-74.02 ml/min/1.73 m2; P<0.02). There was a reduction in plasma TGF-beta1 levels (4.6+/-4.2 vs. 2.0+/-1.4 ng/ml; P=0.003) and CsA levels correlated with TGF-beta1 (r=0.536, P=0.002). No rejection episodes occurred, and an improvement in both systolic (149+/-13 vs. 137+/-12 mmHg; P<0.01) and diastolic blood pressure (89+/-14 vs. 83+/-10 mmHg; P<0.04) were observed. CONCLUSIONS: These short-term results show that MMF introduction allows a CsA dose reduction, which improves renal function, reduces TGF-beta1 production, and improves the control of hypertension, without increasing the incidence of acute rejection.     

Modulation of renal kallikrein production by dietary protein in streptozotocin-induced diabetic rats

Renal kallikrein levels and excretion rates are increased in insulin-treated diabetic rats with hyperfiltration, and inhibition of kallikrein or blockade of kinin receptors reduces GFR and RPF. In contrast, insulin-deprived severely (SD) diabetic rats that display renal vasoconstriction show reduced levels and excretion rates of renal kallikrein. In these two models, dietary protein manipulation was utilized to study further the relationships between renal kallikrein and renal hemodynamic regulation. Insulin-deprived SD and insulin-treated moderately diabetic (MD) rats were fed a low (9%), normal (25%), and a high (50%) protein diet. In SD rats fed the 50% protein diet, GFR, RPF, and kallikrein excretion rate were increased compared with SD rats fed the 25% protein diet (GFR, 2.66 +/- 0.16 versus 1.74 +/- 0.30 mL/min; RPF, 7.78 +/- 0.58 versus 5.14 +/- 1.03 mL/min; total kallikrein, 248 +/- 24 versus 120 +/- 30 micrograms/24 h, SD 50% versus SD 25%, respectively; P < 0.005). In MD rats fed the 9% protein diet, GFR, RPF, and kallikrein excretion rate were significantly reduced compared with MD 25% protein-fed rats (GFR, 1.54 +/- 0.07 versus 1.95 +/- 0.09 mL/min; RPF, 5.58 +/- 0.35 versus 7.81 +/- 0.35 mL/min; total kallikrein, 119 +/- 8.3 versus 219 +/- 15 micrograms/24 h, MD 9% versus MD 25%, respectively; P < 0.005). Protein restriction in normal nondiabetic rats resulted in a twofold decrease in kallikrein mRNA levels. These findings suggest that the renal hemodynamic response to dietary protein manipulation in diabetic rats could be mediated via changes in renal kallikrein-kinin system activity.     

Pentoxifylline reduces nephrotoxicity associated with cyclosporine in the rat by its rheological properties

BACKGROUND: The goals of this study were to evaluate whether administration of pentoxifylline (POF) reduces the nephrotoxicity associated with cyclosporine (CsA) in the rat, and whether the effect of POF is related to its rheological properties. METHODS: Mean arterial pressure was measured by an intraarterial catheter. Glomerular filtration rate and renal plasma flow were determined by measuring inulin and para-aminohippurate clearances, after double-blind coadministration for 10 days of CsA (25 mg/kg/day) with either vehicle or POF (45 mg/kg every 12 hr). These results were compared with those obtained in control rats. Blood viscosity and erythrocyte deformability were also evaluated after treatment using a cone plate viscometer and a filtration method, respectively. RESULTS: No changes were observed in mean arterial pressure in both groups compared with controls. Glomerular filtration rate was significantly lower in CsA-treated rats (0.3+/-0.1 ml/min/100 g) than in control animals (0.6+/-0.1 ml/min/100 g, P<0.02). The coadministration of CsA with POF normalized the glomerular filtration rate (0.6+/-0.1 ml/min/100 g). A parallel decrease in renal plasma flow was observed in CsA-treated rats compared with controls (CsA+vehicle: 1.5+/-0.2 vs. control: 2.2+/-0.1 ml/min/100 g, P<0.02), this effect completely reversed by cotreatment with POF (3.1+/-0.2 ml/min/100 g). Blood viscosity was significantly higher in CsA-treated rats than in the control group (CsA+vehicle: 5.6+/-0.7 vs. control: 5.0+/-0.4 m x Pa x s, P<0.05). This effect was associated with a lower erythrocyte deformability (CsA+vehicle: 1.2+/-0.2 vs. control: 1.5+/-0.3 ml/min, P<0.05). These rheological abnormalities were normalized by coadministration with POF (blood viscosity: 4.9+/-0.7 m x Pa x s and erythrocyte deformability: 1.9+/-0.4 ml/min, P<0.05). CONCLUSIONS: Our results show that administration of POF prevents the nephrotoxicity associated with CsA. This beneficial effect could be related to its rheological properties.     

Cholinergic receptor-mediated responses in the arteriolar and venous vascular beds of the human forearm

Different antihypertensive treatment regimes were studied in rats during long-term inhibition of nitric oxide synthesis. Male Munich Wistar rats (weight 150-200 g) were put on oral L-nitro-arginine methyl ester (L-NAME, 50 mg/l drinking water) for 12 weeks. The control group (n = 16) received only tap water. Six weeks after starting L-NAME administration rats were divided into 7 groups (n = 13 in each group: group 1, no treatment; group 2, l-arginine 1 g/l drinking water; group 3, doxazosin 30 mg/kg/day; group 4, felodipine 25-30 mg/kg/day; group 5, losartan 40 mg/kg/day; group 6, metoprolol 300-350 mg/kg/day, and group 7, ramipril 1 mg/kg/day. Systolic blood pressure (sBP) was measured in the conscious rat 1, 6, and 12 weeks after study begin. After a treatment period of 6 weeks albuminuria, glomerular filtration rate (GFR) and renal plasma flow (RPF; inulin and p-aminohippuric acid clearance) were analyzed. All rats showed a significant increase in sBP under 6 weeks of L-NAME administration. Control rats remained normotensive during the whole study period. Rats receiving L-NAME without antihypertensive treatment showed a further increase in sBP after 12 weeks. Blood pressure was lowered in all treated animals, except in rats receiving l-arginine. Values for GFR were lowest in the placebo group, the l-arginine group and in rats receiving felodipine (p < 0.05 compared to the control group). RPF was lowest in the placebo group, the l-arginine group, the felodipine group and the ramipril group (p < 0.05 compared to the control group).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclosporine-induced hypertension and decline in renal function in healthy volunteers

OBJECTIVE: To investigate the effect of cyclosporine A (CsA; Sandimmun Neoral) on systemic and renal hemodynamics, tubular function, and sodium excretion in healthy volunteers. Furthermore, we studied whether CsA enhances the systemic and renal hemodynamic sensitivity to norepinephrine. METHODS: Eighteen healthy volunteers were administered 10 mg/kg CsA or placebo capsules in a double-blind fashion. The mean arterial blood pressure (MAP), renal vascular resistance (RVR), glomerular filtration rate (GFR), and renal clearances of lithium (CLi) and sodium (CNa) were measured for 8 h after ingestion of the capsules. Norepinephrine (2 microg/kg per h) was infused intravenously for 1.5 h into nine subjects. RESULTS: CsA increased the MAP by 17+/-2 mmHg. The GFR decreased by 18+/-2% (P < 0.001) and the RVR increased by 37+/-4% (P< 0.001) after ingestion of CsA. The CsA-induced increase in MAP preceded the CsA-induced fall in GFR. The rise in MAP was followed by an early 35+/-8/0 increase in CNa (P < 0.001). At the end of the 8 h study period, CNa decreased by 25+/-7% (P < 0.001). Using CLi, it was found that the initial natriuresis had been caused by a relative decrease both in proximal and in distal tubular reabsorption of sodium, whereas the late sodium retention was secondary to the CsA-induced fall in GFR. Infusion of norepinephrine increased the MAP, RVR, and filtration fraction, and decreased the renal plasma flow, without CsA having any additional effect. CONCLUSION: It was demonstrated that a single oral dose of CsA caused a rise in blood pressure and transient natriuresis, followed by a fall in GFR and antinatriuresis. Thus, the present study confirms and extends earlier observations that renal dysfunction and sodium retention are not the initiating events in CsA-induced hypertension. The study also affords evidence suggesting that such rises in blood pressure are not mediated by an increased sensitivity to norepinephrine.     

Low dosages of felodipine ER once daily as monotherapy in elderly hypertensive patients: effect on ambulatory blood pressure and quality of life

OBJECTIVE: To establish the efficacy of 24-h ambulatory and casual blood pressure (BP) reduction, and the tolerability of once daily felodipine extended release (ER) 2.5 mg and felodipine ER 5 mg as monotherapy. DESIGN: Randomised, double-blind placebo controlled 6 weeks parallel study. SETTING: From 15 general practices centres (with 19 GPs) in the region of the University of Maastricht, The Netherlands. SUBJECTS: A total of 129 subjects aged 50-80 years with primary hypertension were screened; 27 men and 61 women with a casual diastolic BP of 100-115 mm Hg and/or a systolic BP of less than 200 mm Hg entered the study. MAIN OUTCOME MEASURES: Casual and 24-h ambulatory BP and a subjective symptom assessment (SSA) questionnaire after 6 weeks of therapy. RESULTS: After correlation for placebo response the mean casual systolic/diastolic BP (SBP/DBP) reduction was 10/5 mm Hg (NS) and 12/10 mm Hg (P < 0.05) for felodipine ER 2.5 and 5 mg, respectively. By using 24-h ambulatory BP measurements these reduction were 6/4 mm Hg (NS) and 13/8 mm Hg (P < 0.05), respectively. No significant difference for SBP and DBP was found during the night time between felodipine 2.5 and placebo (-1/0). Felodipine ER 5 mg lowered the BP load significantly during both daytime and night time but felodipine ER 2.5 mg only for DBP during the daytime. There was a significant difference for the number of responders between placebo (28%) vs felodipine ER 2.5 mg (55%) and ER 5.0 mg (59%). Both felodipine dosages and placebo were comparable in (a low) number of adverse events and results of the SSA. CONCLUSIONS: During daytime felodipine ER 2.5 mg and 5 mg are effective in BP lowering in elderly hypertensive patients. However, only felodipine ER mg is effective in reducing BP during night time (22.00-7.00). Only felodipine ER 5 mg has a significant reducing effect on BP load during day and night time. Both felodipine ER 2.5 and ER 5.0 have a significant effect on the responder rate. It appeared from this study that compared to placebo, and in contrast with felodipine ER 5 mg, the ER form of felodipine 2.5 mg has no BP lowering effect during night time in elderly patients. To assess the effectivity during night time of felodipine ER 2.5 mg in an individual patient it is recommendable to measure the BP at the end of the dose interval.     

Systemic and renal effects of an ET(A) receptor subtype-specific antagonist in healthy subjects

1. Endothelins (ETs) might play a pathophysiological role in a variety of vascular diseases. The aim of the present study was to characterize the effects of BQ-123, a specific ET(A) receptor antagonist on systemic and renal haemodynamics in healthy subjects. This was done at baseline and during infusion of exogenous ET-1. 2. The study was performed in a balanced, randomized, placebo-controlled, double blind 4 way cross-over design in 10 healthy male subjects. Subjects received co-infusions of ET-1 (2.5 ng kg(-1) min(-1) for 120 min) or placebo and BQ-123 (15 microg min(-1) for 60 min and subsequently 60 microg min(-1) for 60 min) or placebo. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate (PAH) and the inulin plasma clearance method, respectively. 3. BQ-123 alone had no renal or systemic haemodynamic effect. ET-1 significantly reduced RPF (-24%, P<0.001) and GFR (-12%, P=0.034). These effects were abolished by co-infusion of either dose of BQ-123 (RPF: P=0.0012; GFR: P=0.020). 4. BQ-123 reversed the renal haemodynamic effects induced by exogenous ET-1 in vivo. This indicates that vasoconstriction in the kidney provoked by ET-1 is predominantly mediated by the ET(A) receptor subtype.     

Long-term improvement in renal function after cyclosporine reduction in renal transplant recipients with histologically proven chronic cyclosporine nephropathy

BACKGROUND: Chronic cyclosporine (CsA) nephropathy, which has been unequivocally documented in recipients of heart, heart-lung, liver, or bone marrow transplants, as well as in nontransplant situations, usually results in a progressive deterioration of renal function. In this study, we assessed the potential reversibility of chronic CsA nephropathy in renal transplant recipients. PATIENTS AND METHODS: Twenty-three renal transplant patients with biopsy-proven CsA nephropathy associated with long-term CsA administration (27+/-4 months) were followed up for more than 2 years after CsA reduction (18/23 patients) or withdrawal (5/23 patients) and addition of azathioprine. Changes in effective renal plasma flow and glomerular filtration rate were assessed before and 2 years after CsA reduction, whereas serum creatinine, proteinuria, blood pressure, and CsA concentrations were monitored up to 5 years. RESULTS: At 2-year follow-up, glomerular filtration rate increased from 40+/-3 to 47+/-4 (P<0.05) and effective renal plasma flow from 217+/-23 to 244+/-24 ml/min/1.73 m2 (NS). Mean arterial pressure significantly decreased from 98.7+/-2.9 to 93.1+/-2.7 mmHg (P<0.05). There was no significant change in renal vascular resistance, filtration fraction, or albumin excretion. A significant decrease in serum creatinine was also observed during the whole follow-up (73+/-6.5 months). CsA reduction was followed by only one episode of acute reversible rejection; chronic rejection developed in three patients 2 years or later after CsA reduction. CONCLUSIONS: These data suggest that CsA nephropathy participates in graft dysfunction in a small group of renal transplant recipients. In addition, graft dysfunction may be reversible when CsA dosage is reduced early after diagnosis of chronic CsA nephropathy.     

Role of the donor in post-transplant renal function

BACKGROUND: The donor, i.e. adult or paediatric, might influence the outcome of the graft function. METHODS: The glomerular filtration rate (GFR) of 120 transplanted children (47 girls) aged 10.4+/-4.6 years (0.7-17.2) was prospectively assessed over a 5-year period. The patients were divided into two groups according to the age of donor: adult (donor age > 18 years; n=33) and paediatric (donor age < 18 years; n=87). GFR was assessed by inulin clearance at 3, 6 and 12 months and yearly thereafter. RESULTS: The average GFR was stable in the range of 70 ml/min/1.73 m2 for the whole follow-up period. The adjusted GFR in adult graft recipients was significantly higher at 3 months post-transplantation: 80.6+/-36.9 vs 65.1+/-22.0, P=0.02. However, from the second year post-transplantation, the adjusted GFR in paediatric graft recipients became significantly higher than that of adult graft recipients. Such results could be due to an improvement in the absolute GFR (ml/min) of paediatric graft recipients with time (P=0.0001) whereas that of the adult graft recipients remained stable despite the children's growth. CONCLUSIONS: The adjusted GFR of adult graft recipients was significantly higher than that of paediatric graft recipients in the early post-transplant period. In the long-term, a progressive decrease in adjusted GFR was noted in adult graft recipients. On the one hand, this may be due to a functional adaptation and/or inadequate compensatory growth of the graft. On the other hand, the absolute GFR of paediatric graft recipients increased, suggesting an ongoing capacity for growth and/or compensatory hypertrophy after child-to-child renal transplantation.     

Effects of smoking on renal hemodynamics in healthy volunteers and in patients with glomerular disease

Patients with renal disease who smoke have a poor renal functional prognosis, but the mechanisms involved have not been explored. In this controlled study, the effects of smoking and sham smoking were compared in 15 healthy normotensive volunteers. All were occasional smokers and abstained from smoking for 48 h as documented by urinary cotinine measurements. These data were compared with those of seven patients with biopsy-confirmed IgA glomerulonephritis, also occasional smokers. Renal clearance examinations were obtained after hydration in the supine position before and while smoking two cigarettes or sham cigarettes in random order on 2 consecutive days. GFR and effective renal plasma flow were determined using In111-diethylenetriamine penta-acetic acid and 131I-hippurate with a dual tracer infusion clearance technique. In an ancillary study with six volunteers, the effect of smoking was compared with the effect of nicotine-containing chewing gum. In healthy volunteers, sham smoking caused a minor but significant increase of mean arterial pressure (MAP) and GFR with no significant change of effective renal plasma flow, filtration fraction (FF), or renovascular resistance. Smoking caused a significant and more marked increase of MAP (from baseline 92.8+/-8.98 to 105+/-7.78 mmHg) and heart rate (from 61.7+/-7.52 to 86.4+/-9.87 min(-1)), accompanied by a significant increase in arginine vasopressin (from 1.27+/-0.72 to 19.9+/-27.2 pg/ml) and epinephrine (from 37+/-13 to 140+/-129 pg/ml). During smoking, GFR decreased in all but one volunteer (from 120+/-17.7 to 102+/-19.3 ml/min per 1.73 m2), and this was accompanied by a significant decrease of FF (from 21.3+/-4.24 to 17.4+/-3.41%) and an increase in renovascular resistance (from 97.6+/-27.2 to 108+/-30.4 mmHg x min/ml per 1.73 m2). These findings were reproduced with nicotine-containing chewing gum. In contrast, when patients with IgA glomerulonephritis smoked, a similar increment in MAP was noted, the changes of FF were not uniform, and a small but consistent increase of urinary albumin/creatinine ratio was observed. An additional 20 volunteers were subjected to the smoking arm of the study for statistical evaluation of the GFR change in patients. The difference between the change of GFR between all volunteers (n = 35) and patients (n = 7) was significant (P < 0.005). It is concluded that the known effects of smoking and nicotine on the sympathetic nervous system and on systemic hemodynamics are accompanied by significant acute changes in renal hemodynamics and albuminuria. These findings are of interest because of the known effects of smoking on progression of renal disease.     

Fiber growth initiation in hair follicles of goats treated with melatonin

Amphotericin B (AmB) is the drug of choice for most systemic fungal infections, but doses are frequently reduced because of nephrotoxicity. We investigated the role of thromboxane as a mediator for this nephrotoxicity. Vehicle or amphotericin (0.60 mg/kg) was infused into the left renal artery in four groups of rats, and renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured. Group 1 received vehicle for 90 min. Group 2 received vehicle followed by a 30 minute AmB infusion which caused a significant and reversible fall in the RPF and GFR. Group 3 received vehicle followed by AmB infusion, but were infused with a bolus of ibuprofen (20 mg/kg) 45 minutes before AmB. This group exhibited an insignificant attenuation in the fall in RPF and GFR. Group 4 received vehicle followed by AmB, but were infused with a bolus and continuous infusion of the thromboxane receptor antagonist SQ29,548. This group demonstrated an attenuation in the fall in RPF and a significant decrease in GFR compared to AmB control rats. In addition, the rat glomeruli were incubated with AmB (4 ug/ml). Supernatant levels of thromboxane B2 were significantly elevated in the presence of AmB vs buffer alone. We conclude that the reduction in RPF and GFR observed with AmB infusion in the rat is partially mediated by release of thromboxane.     

Donor age and graft function

We evaluated survival and renal function of cadaveric donor grafts according to donor age. The median age of the pediatric donors was 7.0 (0.7-16) years in 46 patients [median age 11.8 years (range) 3-16.8 years]. The median age of the adult donors was 34.4 (19-54) years in 59 patients [median age 12.1 years (range) 7-17.3 years]. Thirty patients were treated with azathioprine and prednisolone and 75 with cyclosporine A and prednisolone. The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) were determined by the clearances of 51chromium-EDTA and 125iodine-hippurate 1-48 months after kidney transplantation. There was no difference in graft survival between pediatric and adult grafts. There were also no differences in GFR in patients receiving grafts from pediatric or adult donors; 2-3 months after transplantation the GFR in recipients of pediatric grafts was 62 +/- 20 ml/min per 1.73 m2 compared with 61 +/- 21 in those receiving adult grafts. The ERPF in recipients of adult grafts was significantly higher in the 1st month after transplantation: 486 +/- 239 versus 362 +/- 158 ml/min per 1.73 m2. From the 4th to the 6th month after transplantation this difference disappeared: the ERPF of grafts from pediatric donors was 279 +/- 131 ml/min per 1.73 m2 compared with 273 +/- 123 ml/min per 1.73 m2 in grafts from adult donors. Using the single-kidney GFR and ERPF on an age-matched group of probands with minor diseases as references, 2-3 months after transplant the mean GFR of grafts from pediatric donors increased to 118% +/- 51%, whereas the GFR of adult donor grafts fell to 60% +/- 22% over the same period. After 4-6 months the ERPF in pediatric grafts was 96% +/- 55% compared with 50% +/- 22% in adult grafts. We conclude that graft survival and function in children with either a pediatric or an adult graft may not differ because graft function adapts to the requirement of the recipient.     

Myocardial viability. Concept, physiopathology. Methods and diagnostic value]

This study was designed to investigate the effect of tacrolimus (FK506) and of cyclosporine (CsA) on tubular function in renal graft recipients. Patients were randomised after renal transplantation to immunosuppressive treatment with FK506 (n = 8) or CsA (n = 8). Patients had a mean age of 45.7 +/- 3.4 yr; there was no difference in age, sex, HLA status or CMV mismatches. Neither was there any difference in the frequency of episodes of acute kidney failure between the groups, nor was there a significant difference in the frequency of episodes of kidney rejection within the first year. The mean FK506 level at the time lay at 14.7 +/- 14.4 ng/mL whole blood, and the mean CsA level at the time of study was 162 +/- 25 ng/mL whole blood. We performed renal function studies 6 months after transplantation: CIn, CPAH, NaHCO3 loading, and Na2SO4 loading. There was no significant impairment of GFR in patients treated with FK506 with 53.6 +/- 2.5 mL/min as compared to 58 +/- 6 mL in group 2. Plasma renin activity (0.6 +/- 0.4 ng/mL vs 2.3 +/- 3; p < 0.01) and aldosterone (69 +/- 17 vs 157 +/- 28.2 pg/mL; p < 0.05) were significantly decreased during treatment with FK506. Fractional HCO3 excretion was low in both groups, indicating that bicarbonate reabsorption in the proximal nephron was unimpaired. Distal renal tubular acidosis was demonstrated in 4 patients of group 1 but in only 1 of group 2. Potassium levels were slightly increased in patients treated with FK506 (5.4 +/- 0.2 mmoL/L) as compared to cyclosporine (4.9 +/- 0.3 mmoL/L; p < 0.05). Distal hydrogen ion secretion, evaluated by the ability to increase urinary pCO2 in a highly alkaline urine, was impaired in patients treated with FK506 (U-B pCO2: 16.1 +/- 4 vs 36 +/- 5.8; p < 0.05) as compared to patients treated with CsA. The maximum acidification capability (NAE) was slightly lowered during therapy with FK506 (67.5 +/- 11.8 versus 86.6 +/- 16.5 mumoL/min, ns). We conclude that FK506 administration results in a decrease in the rate of hydrogen ion secretion by the collecting tubules. This defect was disclosed by the finding of a subnormal pCO2 in a highly alkaline urine. These results show that FK506 is able to induce distal tubular acidosis. Distal tubular acidosis is part of FK506 induced nephrotoxicity, the pathogenesis of this type of hyperkalemic metabolic acidosis found in patients treated with FK506 after renal transplantation has to be further elucidated.     

Progression of nephropathy in long-term diabetics with proteinuria and effect of initial anti-hypertensive treatment

The rate of progression of nephropathy was studied in 6 young male diabetics with intermittent proteinuria (Albustix) and in 10 young male diabetics with constant proteinuria by measuring glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary albumin excretion by exact techniques. Albumin excretion was elevated in both the recumbent and the erect position in patients with intermittent proteinuria. GFR and RPF were at the same level as in diabetics without proteinuria, and no deterioration in renal function was noted during a mean control period of 32 months. In the patients with constant proteinuria the fall rate during a mean period of 33.6 months for GFR and RPF was 0.91 ml/min/month +/- 0.68 (S.D.) and 4.38 ml/min/month +/- 3.23 (S.D.) respectively. Initial fall rate in GFR correlated well with long-term fall rate, both of which were studied in 7 patients. In the same patients there was a positive correlation between the fall rate in GFR and diastolic blood pressure as well as albumin clearance. In 8 patients with constant proteinuria and mean blood pressure of 159/101 mmHg, antihypertensive treatment was started with propranolol alone or combined with hydralazine and furosemide. During a treatment period of 47 days blood pressure was reduced to 143/93 mmHg, and in the same period urinary albumin excretion was reduced significantly from a mean value of 3547 mug/min to 2414 mug/min (P less than 0.01). Further control studies will clarify whether end-stage of renal insufficiency will be postponed by antihypertensive treatment.     

Mechanism of the diabetogenic action of cyclosporin A

To investigate the mechanism of diabetogenic action of cyclosporin A (CsA), 7 male Wistar albino rats received 10 mg/kg/day of the drug for 4 weeks (CsA). The results were compared with controls (C); blood CsA levels measured weekly remained stable throughout the experiment (mean +/- SEM) (X = 2657.9+/-155.1 ng/ml). Intravenous glucose load (0.75 g/kg) performed after 2 weeks of CsA therapy showed glucose intolerance in treated animals as evaluated by the glucose area under the curve (CsA = 409.2+/-17.8 vs. C = 313.3+/-12.6 umol x ml(-1) x min(-1)) (p < 0.05) with insulin levels being similar in the two groups (CsA = 8603.9+/-1645.5 vs. C = 9571.9+/-828.5 pmol x ml(-1) x min(-1)). After 4 weeks of CsA administration, glucose intolerance was maintained (CsA = 398.6+/-35.6 vs. C = 301.7+/-23.0 umol x ml(-1) x min(-1)) (p < 0.05) associated with a significant decrease in insulin secretion (CsA = 4404.9+/-2392.0 vs. C = 10075.9+/-2861.0 pmol x ml(-1) x min(-1) (p < 0.05). These results suggest that CsA induced a state of insulin resistance preceding the failure of insulin secretion. After 4 weeks, the pancreatic insulin content was also decreased (CsA = 0.7+/-0.1 vs. C = 1.4+/-0.5 mU/mg) (p < 0.05). Maximal insulin binding to isolated adipocytes was not affected by CsA (CsA = 7.4+/-2.6 vs. C = 6.4+/-2.0%), although glucose transport and oxidation decreased after CsA treatment (p < 0.05). In conclusion, glucose intolerance induced by CsA in Wistar albino rats is due to decreased insulin production and impaired insulin action by a post-binding mechanism.