Co-administration of Co-trimoxazole Does Not Augment Tacrolimus-Induced Impairment in Kidney Function in Rats

Co-trimoxazole is an antibiotic that is frequently used in organ transplant patients. Our objective was to determine the effect of co-trimoxazole on tacrolimus-mediated functional impairment of the kidney in rats. Sprague Dawley rats were divided into three groups. Group 1 (dextrose) received 5% dextrose and Group 2 (tacrolimus) received tacrolimus (1 mg/kg/day) as a continuous intravenous infusion for seven days. Group 3 (combination) received tacrolimus as above and co-trimoxazole (30 mg/kg/day trimethoprim and 150 mg/kg/day sulfamethoxazole) intraperitoneally for six or seven days. Biochemical and functional parameters were measured pre- and post-drug infusion. On day 7, glomerular filtration rate (GFR) was evaluated using ³H-inulin. while the effective renal plasma flow (ERPF)/cationic tubular secretion was assessed using ¹⁴C-tetraethylammoniumbromide (TEA).

GFR (mL/min/kg) as measured by inulin clearance was higher (p ≤ 0.05) in the dextrose (12.0 ± 1.4) group as compared to tacrolimus group (6.0 ± 1.3) and combination group (6.4 ± 1.6), but there was no difference between the tacrolimus and combination group. ERPF/cationic tubular secretion (mL/min/kg) was also significantly higher in the dextrose group (62.6 ± 10.3) as compared to the other two groups. ERPF/cationic tubular secretion was not different between the combination (33.3 ± 5.9) and the tacrolimus (35.1 ± 6.7) groups when there was no co-trimoxazole in the body. However, in the presence of co-trimoxazole ERPF/cationic tubular secretion was significantly reduced in the combination (23.1 ± 3.5) group as compared to the tacrolimus group (35.1 ± 6.7).

These results indicate that co-trimoxazole does not further potentiate tacrolimus induced impairment in kidney Junction but is likely to further inhibit cationic tubular secretion in patients on tacrolimus therapy.     

Role of growth hormone in the amino acid-induced acute rise in renal function in man

To examine whether plasma growth hormone is necessary for the amino acid-induced rise in effective renal plasma flow (ERPF, PAH clearance) and GFR (inulin clearance), arginine HCl, 500 mg/kg, was infused for 30 minutes into eight normal and six growth hormone-deficient individuals. During infusion, ERPF increased in the normal and growth hormone-deficient subjects by 28.9 +/- 11.4 SD-% (P less than 0.01) and 46.5 +/- 14.4% (P less than 0.001). GFR rose by 23.7 +/- 5.9% (P less than 0.05) and 42.7 +/- 29.1% (P less than 0.001) in the two groups. Plasma growth hormone rose only in the normal subjects, while glucagon increased in both groups. Infusion of arginine HCl, 200 mg/kg, into normals increased ERPF and GFR without increasing plasma osmolality. Lower arginine doses essentially did not affect ERPF, GFR, growth hormone, or glucagon. Infusion of D-glucose into normals raised plasma osmolality as high as with arginine HCl, 500 mg/kg, but increased ERPF only slightly and not GFR; D-glucose infusion caused a delayed rise in growth hormone that was unassociated with an increase in ERPF or GFR. An infusion of ammonium chloride with sodium chloride, which provided an amount of chloride similar to the 500 mg/kg arginine HCl dose, did not change ERPF and GFR; this suggests that the chloride load did not cause the altered renal hemodynamics stimulated by arginine HCl. These findings indicate that neither normal plasma growth hormone levels nor a rise in growth hormone mediates the arginine-induced acute increase in ERPF or GFR. This effect is also not due to the osmolar load but could be caused by the rise in plasma glucagon.     

Characterization of tubular functional capacity in humans using para-aminohippurate and famotidine

BACKGROUND: Renal drug excretion by glomerular filtration and active tubular secretion may be altered by factors such as acute and chronic renal disease, nephrotoxins, and drug interactions. Thus, accurate and reproducible methods for quantitation of glomerular filtration rate (GFR) and tubular functional capacity are critical. METHODS: We utilized a four-step sequential infusion method to characterize anionic [para-aminohippurate (PAH)] and cationic (famotidine) tubular functional capacity in healthy volunteers. Filtration and secretion rates were quantitated from renal clearance and iothalamate-derived GFR determinations. RESULTS: Concentration-dependent renal clearance of PAH was observed at plasma concentrations> 100 mg/L; renal clearances were 442 +/- 131 (mean +/- SD), 423 +/- 94, 233 +/- 45, and 152 +/- 18 mL/min/1.73 m2 at plasma concentrations of 18 +/- 2, 92 +/- 5, 291 +/- 47 and 789 +/- 28 mg/L, respectively. The apparent affinity (Km) and maximum secretory capacity (TmPAH) were 141 +/- 70 mg/L and 71 +/- 16 mg/min/1.73 m2, respectively. The unbound renal clearance and tubular secretory clearance of famotidine were 384 +/- 70 and 329 +/- 78 mL/min/1.73 m2, respectively, and were not significantly correlated with the unbound plasma concentrations, which ranged from 126 to 2659 ng/mL. The rate of tubular secretion was linear at unbound plasma concentrations up to 2659 ng/mL. CONCLUSIONS: These data indicate that a sequential infusion method using PAH may be used to characterize the anionic secretory component of proximal tubular function. The tubular clearance of famotidine may be a suitable index of the cationic secretory capacity of the proximal tubule in humans. Saturation of the cationic secretory pathway was not observed, and further investigation into parallel pathways of cationic secretion, such as p-glycoprotein, may be warranted.     

Relative glomerular hyperfiltration in primary aldosteronism

Experimental and clinical data suggest that primary aldosteronism (PA) may be associated with cardiovascular hypertrophy and fibrosis, in part independent of the BP level. Whether PA may also result in specific deleterious effects on the kidneys was less studied. In 25 patients with tumoral PA, renal studies (urinary excretion of proteins, GFR, and effective renal plasma flow [ERPF], as clearances of technetium-labeled diethylene triaminopentaacetic acid and 131I-ortho iodohippurate, respectively) were performed both before and 6 mo after surgical cure. A control group consisting of patients with essential hypertension (EH) was studied before and after 6 mo of antihypertensive therapy. At baseline, PA and EH patients were similar with respect to demographic data, duration and level of hypertension, and GFR and ERPF. Urinary excretion of albumin and beta2 microglobulin were higher in PA than EH (88 +/- 26 versus 39 +/- 12 and 0.91 +/- 0.23 versus 0.26 +/- 0.19 mg/24 h, respectively; both P < 0.05). Adrenalectomy was followed by a decrease in arterial BP (by 28 +/- 3/13 +/- 2 mmHg), urinary excretion of albumin and beta2 microglobulin (by 48 +/- 19 and 0.53 +/- 0.21 mg/24 h, respectively), and GFR and ERPF (by 15 +/- 3 and 54 +/- 15 ml/min per 1.73 m(2), respectively). In EH, a similar decrease in pressure was associated with a decrease in albuminuria but no change in GFR or ERPF. In 17 of the 25 PA patients who received a 6-mo treatment of spironolactone, both GFR and ERPF decreased in parallel with BP, similar to what was observed after surgery. These data suggest that PA was associated with relative hyperfiltration, unmasked after suppression of aldosterone excess.     

Effects of prostacyclin infusion on renal function during cardiopulmonary bypass

Infusion of prostacyclin inhibits platelet activation during cardiopulmonary bypass (CPB) but also results in systemic arterial hypotension. Therefore, the effects of CPB and prostacyclin on renal function were studied in 36 male patients undergoing aortocoronary bypass. Nineteen patients (Group 1) received prostacyclin, 50 ng per kilogram of body weight per minute, during CPB, and 17 patients (Group 2) served as controls. There was pronounced hypotension in Group 1 only. Urine production during CPB averaged 88 +/- 140 ml and 2,306 +/- 1,112 ml in Groups 1 and 2, respectively. No patient had renal failure. Glomerular filtration rate (GFR), as measured by clearance of chromium 51-labeled ethylenediaminetetraacetic acid, was increased in Group 1 from 86 +/- 14 to 99 +/- 22 ml/1.73 m2/min (p less than 0.05) the day after operation, but remained unchanged in Group 2 (81 +/- 15 to 82 +/- 21 ml/1.73 m2/min). The increased GFR in Group 1 can be regarded as an expected adaptation to the change in body fluids after CPB. Therefore, the unchanged GFR in Group 2 must be regarded as caused by insufficient adaptation or impaired renal function. Proximal tubular function was evaluated by determination of beta 2-microglobulin in urine. In both groups, urinary beta 2-microglobulin and the ratio of urinary beta 2-microglobulin to urinary creatinine were increased the day after operation. The hypotension in Group 1 did not exacerbate the damage to tubular function.     

Does choice of the anesthetic influence renal function during infrarenal aortic surgery?

Reconstructive infrarenal aortic surgery is associated with impairment of renal function owing to vasoconstriction during and after aortic cross-clamping. To assess the influence of anesthetic technique on renal hemodynamics during aortic surgery, 34 patients received one of four anesthetics: isoflurane (n = 10), halothane (n = 9), droperidol (n = 8), and flunitrazepam (n = 7). Supplemental anesthesia consisted of midazolam, fentanyl, nitrous oxide in oxygen (50%), and pancuronium. Before aortic cross-clamping, effective renal plasma flow (ERPF) (131iodohippuran clearance) and glomerular filtration rate (GFR) (99technetium-DTPA clearance) were low in the halothane and flunitrazepam groups (118.4 +/- 25.6 and 170 +/- 35 mL/min for ERPF; 19.7 +/- 5.2 and 26.9 +/- 5.8 mL/min for GFR, respectively) and better preserved in the isoflurane group (253.4 +/- 51.5 and 44.9 +/- 8.4 mL/min, respectively; P less than 0.05 between isoflurane and halothane groups) or in the droperidol group as regards GFR (75.4 +/- 9.4 mL/min, P less than 0.05). During clamping, both renal variables were not markedly affected in any group except in the droperidol group in whom GFR significantly decreased from preclamp value. The GFR was then significantly higher in the isoflurane group (49.5 +/- 9.2 mL/min) than in the halothane and flunitrazepam groups (14.8 +/- 3.7 and 26.5 +/- 10.1 mL/min, respectively; P less than 0.05). After aortic declamping, ERPF and GFR increased markedly in the halothane group, and there was no significant difference between the groups. These results suggest that renal hemodynamics are less altered with droperidol-fentanyl anesthesia during abdominal surgery but not during aortic cross-clamping.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal tubular function in cirrhotic patients with ascites: special reference to lithium clearance following the human atrial natriuretic peptide administration]

Synthetic alpha-human atrial natriuretic peptide (alpha-hANP), 1 micrograms/kg, was intravenously given to 16 cirrhotic patients with ascites and 9 control subjects (CS) to investigate major factors responsible for sodium retention and refractory ascites. The following parameters were measured before and after alpha-hANP administration; such as lithium clearance (CLi) as an index of fluid delivery to the distal tuble, mean arterial pressure (MAP), urinary sodium excretion rate (UNaV), urine volume (V), glomerular filtration rate (GFR), effective renal plasma flow (ERPF), plasma renin activity (PRA), plasma aldosterone concentration (PAC), urinary excretion of prostaglandin (PG)E2, 6-keto-PGF1 alpha (6-k-PGF1 alpha), and thromboxane B2 (TxB2). Patients were divided following alpha-hANP administration into 2 groups as "good responders (GR)" and "poor responders (PR)", in which GR was defined as the group showing 2-fold-increase in UNaV. In contrast, PR had significant lower MAP (71.8 +/- 5.04 mmHg), GFR (21.3 +/- 3.90 ml/min), ERPF (158.0 +/- 43.8 ml/min), FELi (CLi/GFR; 12.6 +/- 1.26%), and higher PRA (8.72 +/- 0.99 ng/ml/h) and PAC (12.2 +/- 3.13 ng/dl) than GR. GR demonstrated almost same natriuretic response as CS with an increase of GFR and renal PGs synthesis, and a decrease of FELi despite reduction in blood pressure. However, alpha-hANP did not suppress PRA, PAC, and distal tubular reabsorption of sodium (FDRNa = 1-FENa/FELi) in cirrhotic patients, whereas suppressed in CS. UNaV correlated with FELi (r = 0.687, p = 0.01) and GFR (r = 0.777, p = 0.01). PRA correlated with FELi r = 0.669, p = 0.015), GFR (r = -0.634, p = 0.018), and MAP (r = 0.858, p = 0.001) only in cirrhosis. These results therefore indicated that hypotension caused by hemodynamic alteration and extremely stimulated renin release might effect on proximal tubular sodium reabsorption and GFR, leading to sodium retention and diuretic resistance in cirrhosis.     

Body mass index is associated with altered renal hemodynamics in non-obese healthy subjects

BACKGROUND: Weight excess is associated with increased renal risk. Data in overt obesity suggest a role for altered renal hemodynamics. Whether body mass index (BMI) is also relevant to renal function in non-obese subjects is unknown. METHODS: We studied the relation between BMI and renal hemodynamics in 102 healthy, non-obese (BMI <30 kg/m2) subjects [59 males, 43 females, mean age 39 (18-69) years] in a post-hoc analysis of subjects evaluated as prospective kidney donors or as healthy volunteers in renal hemodynamic studies. RESULTS: Mean (+/-SD) BMI was 24.0 +/- 2.8 kg/m2, mean arterial pressure (MAP) 93 +/- 11 mm Hg, glomerular filtration rate (GFR, iothalamate clearance) 111 +/- 19 mL/min/1.73 m2, effective renal plasma flow (ERPF, hippuran clearance) 458 +/- 108 mL/min/1.73 m2, FF (GFR/ERPF) 0.25 +/- 0.04. On univariate analysis, BMI correlated negatively with ERPF/1.73 m2 body surface area (BSA) (r=-0.46; P < 0.001), GFR/1.73 m2 BSA (r=-0.24, P= 0.013) and positively with FF (r= 0.45, P < 0.001), and age (r= 0.47, P < 0.001). On multivariate analysis both BMI and age were independent predictors of ERPF/1.73 m2 BSA (negative) and FF (positive, all P < 0.05). Age was the only predictor of GFR/1.73 m2 BSA (negative). Analyzed for renal function indexed for height (h), BMI correlated negatively with ERPF/h (r=-0.274, P= 0.005), but not with GFR/h (r= 0.13, P= 0.899). On multivariate analysis both BMI (positive) and age (negative) were independent predictors for GFR/h (both P < 0.001). Age was the only predictor for ERPF/h (negative). Predictors for FF (BMI and age, both positive) were by definition unaltered. CONCLUSION: The impact of BMI on renal function is not limited to overt obesity, as in subjects with BMI <30 kg/m2 a higher BMI is associated with higher FF, that is, a higher GFR relative to ERPF. This suggests an altered afferent/efferent balance and higher glomerular pressure (i.e., a potentially unfavorable renal hemodynamic profile) that may confer enhanced renal susceptibility when other factors, such as hypertension or diabetes are superimposed.     

Renal function and tubular phosphate handling in long-term cyclosporine- and tacrolimus-based immunosuppression in kidney transplantation

The aim of the study was to assess impaired tubular phosphate reabsorption and renal function among patients on cyclosporine- or tacrolimus-based immunosuppression for 2 years after kidney transplantation. Among 60 cadaveric kidney allograft recipients observed for 48 months, 40 received cyclosporine, azathioprine, and prednisone (group A and B). Group C consisted of 20 patients receiving tacrolimus with steroid withdrawal at 3 months after transplantation. Renal function and calcium-phosphate metabolism-iPTH, 25-OHD, 1,25(OH)(2)D concentration, phosphate reabsorption (TRP; mmol/L), and tubular maximum phosphate reabsorption per glomerular filtration rate (TmPO(4)/GFR; mmol/L)-were assessed at 1, 6, 12, 18, and 24 months (groups A and C) or 24, 30, 36, 42, and 48 months (group B). Renal function after 24 months of observation was significantly better among tacrolimus-treated patients (serum creatinine concentration mumol/L; C: 94.6 +/- 16.8 vs A: 110.5 +/- 22.1 vs B: 121.1 +/- 30.9; P < .05). Among tacrolimus-treated recipients, TRP and TmPO(4)/GFR remained within normal values during the whole observation period. In groups A and B, TRP improved during the first year of observation; after 2 years it reached values observed in group C (TRP: A: 0.67 +/- 0.1; B: 0.72 +/- 0.13; C: 0.76 +/- 0.07; P = NS), whereas TmPO(4)/GFR remained low in group A after 2 years (A: 0.78 +/- 0.19; B: 0.91 +/- 0.25; C: 0.94 +/- 0.15; P < .05). Tacrolimus-treated patients exhibit significantly faster recovery from tubular phosphate reabsorption impairment compared with cyclosporine-treated recipients. Tacrolimus-based immunosuppression led to better kidney allograft function during 2-year observation.     

Tacrolimus and nonsteroidal anti-inflammatory drugs: an association to be avoided

BACKGROUND: Tacrolimus (FK) and nonsteroidal anti-inflammatory drugs (NSAIDs) can cause acute nephrotoxicity. The expanding use of tacrolimus and the intense consumption of NSAIDS increase the chances of their simultaneous use. METHODS: Rats receiving a nonselective COX inhibitor (diclofenac, D) and FK or a selective COX-2 inhibitor (rofecoxib, RO) and FK were treated with FK (2 mg/kg/day), D (10 mg/kg/day), RO (3 mg/kg/day), FK+D, FK+RO and vehicle for 7 days on low-salt diet. RESULTS: Both associations significantly impaired glomerular filtration rate (GFR; 0.63 +/- 0.06 ml/min/100 g in FK+D, 0.83 +/- 0.06 ml/min/100 g in FK+RO) which did not occur with single drug therapy (0.98 +/- 0.03 ml/min/100 g in D, 1.06 +/- 0.04 ml/min/100 g in RO, 0.99 +/- 0.05 ml/min/ 100 g in FK) or vehicle (1.10 +/- 0.05 ml/min/100 g). GFR decrease was significantly higher with FK+D. GFR impairment occurred without RBF or RVR major changes. Mild tubular vacuolization and dilatation and acute degenerative changes were observed in tubular cells. FK+D animals showed a marked weight loss, not observed in the other groups. FK+NSAIDs association decreased FK blood levels (1.73 +/- 0.3 ng/ml in FK+D, 1.8 +/- 0.3 ng/ml in FK+RO, 3.2 +/- 0.4 ng/ml in FK, p < 0.05). CONCLUSIONS: The association of FK and nonselective or COX-2 selective NSAIDs in salt-depleted animals caused a significant GFR impairment and decreased FK blood levels.     

Renal function in patients with cadaveric kidney transplants treated with tacrolimus or cyclosporine

INTRODUCTION: Renal function predicts graft survival in kidney transplant patients. This study compared the 2-year evolution of renal function in patients treated with cyclosporine or tacrolimus in combination with mycophenolate mofetil (MMF) and prednisone. METHODS: We studied 1558 cadaveric renal transplant recipients from 14 Spanish hospitals between January 2000 and December 2002. Of these, 1168 were treated with tacrolimus and 390 with cyclosporine. The primary efficacy endpoint was long-term renal function. Renal function was measured by serum creatinine and glomerular filtration rate (GFR) by creatinine clearance calculated from the Cockcroft-Gault formula. This report summarizes the 2-year results. RESULTS: At 24 months the tacrolimus group showed significantly better serum creatinine (1.5 +/- 0.7 vs 1.8 +/- 0.8 mg/dL, P < .001) and GFR (60.5 +/- 20.9 mL/min vs 47.9 +/- 10.0, P < .001) than the cyclosporine group. Additionally, recipients with ideal graft donors (23.5 +/- 2.8 vs 24.0 +/- 2.9 years) had a better serum creatinine at 2 years (1.23 +/- 0.2 vs 1.5 +/- 0.4 mg/dL, P < .05). Multivariate analysis showed that tacrolimus was an independent factor associated with better renal function: odds ratio 1.6, 95% confidence interval (1.2 to 2.2), P < .001. CONCLUSIONS: Patients with a renal transplant treated with tacrolimus in combination with MMF and prednisone displayed better renal function at 2 years than those who received cyclosporine.     

Short-term protein restriction in healthy volunteers: effects on renal hemodynamics and renal response to a meat meal

We have studied the renal hemodynamic effects of short-term protein restriction and short-term protein loading in 12 healthy volunteers, who adhered to a low protein diet (0.6 g/kg/day) for three weeks and then switched to a high protein diet (1.8 g/kg/day) for another three weeks. Baseline glomerular filtration rate (GFR) was not influenced by dietary protein intake. Effective renal plasma flow (ERPF), however, was significantly lower on the low protein diet (491 +/- 23 ml/min; mean +/- SEM) as compared to values on the high protein diet (538 +/- 19 ml/min; p less than 0.01). The increase of GFR after a meat meal (providing 1.8 g protein/kg body weight) was higher on the high protein diet (GFR: +23.6 +/- 5.1 ml/min) than on the low protein diet (GFR: +13.0 +/- 2.4 ml/min; p less than 0.05). We conclude that three weeks of dietary protein restriction do not decrease glomerular filtration rate and do not enhance the renal response to a meat meal. Therefore, it seems doubtful that dietary protein restriction decreases glomerular capillary pressure through vasoconstriction of the afferent glomerular arteriole. Furthermore, measurement of the renal hemodynamic response to an acute protein load seems of doubtful physiological significance.     

Renal hemodynamic effects of captopril and doxazosin during slight physical activity in hypertensive patients with type-1 diabetes mellitus

Angiotensin-converting enzyme inhibitors are renoprotective in diabetes mellitus through their intrarenal hemodynamic effects. Alpha-1 blockade has variable pre- and postglomerular vasodilatory effects dependent upon the stimulation of the sympathetic nervous system. We tested the hypothesis that the two different classes of drugs have similar renal hemodynamic effects when the patients are examined in an upright position where the sympathetic nervous system is activated. Mean blood pressure (MAP), glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were examined in 28 hypertensive type-1 diabetic patients with variable degree of nephropathy treated for a mean period of 7.6 +/- 0.4 months with captopril (n = 13) or doxazosin (n = 15). Average treatment doses were 112 +/- 7 mg/day in the captopril group and 8 +/- 1 mg/day in the doxazosin group. Sitting MAP decreased from 118 +/- 3 to 106 +/- 4 mm Hg after captopril (p < 0.05), and from 117 +/- 4 to 110 +/- 3 mm Hg after doxazosin (p = 0.07). GFR and ERPF were unchanged in both groups. The filtration fraction (FF) decreased from 0.27 +/- 0.02 to 0.25 +/- 0.02 after captopril (p < 0.05) and from 0.26 +/- 0.01 to 0.25 +/- 0.01 after doxazosin (p = 0.08). Calculation of 95% confidence intervals of the difference between the post-treatment values as well as the difference between pre- and post-treatment values of MAP, GFR, ERPF and FF of the two drugs indicates no difference in renal hemodynamic response between the drugs. In conclusion, captopril and doxazosin have similar renal hemodynamic responses when the patients are examined in a situation where the sympathetic nervous system is stimulated, and this suggests that doxazosin has a renoprotective effect beyond the blood pressure-lowering effect.     

Nifedipine improves immediate,and 6- and 12-month graft function in cyclosporin A (CyA) treated renal allograft recipients

To investigate the effect of oral nifedipine, a calcium channel blocker known not to modify cyclosporin A (CyA) pharmacokinetics, on immediate transplant function and CyA nephrotoxicity, 68 adult renal transplant recipients were pre-operatively randomized to one of three regimes: A (high-dose CyA, initial dose 17 mg/kg per day, maintenance dose 7 mg/kg per day); B (regime A plus oral nifedipine); C low-dose CyA, initial dose 10 mg/kg per day, maintenance 4 mg/kg per day plus azathioprine 1 mg/kg per day). All three groups received identical steroid regimes. Calcium channel blockers of all types were avoided in groups A and C. Delayed graft function (dialysis dependence by day 4) was seen least frequently in group B (P < 0.02). Group B had improved graft function at 6 months compared with group A, identified by differences in serum creatinine (P < 0.05), GFR (P < 0.01) and ERPF (P < 0.05). Similar differences in serum creatinine (P < 0.05) and GFR (P < 0.05) were also identified at 12 months. Group C also had better 6- and 12-month GFR values than group A (P < 0.05 each). The three groups did not differ in donor or recipient age, HLA matching, ischaemic or anastomosis times, frequency of early rejection or whole-blood CyA levels. These results indicate that nifedipine significantly improves immediate and medium-term graft function.     

The effect of a shift in sodium intake on renal hemodynamics is determined by body mass index in healthy young men

A body mass index (BMI)>or=25 kg/m2 increases the risk for long-term renal damage, possibly by renal hemodynamic factors. As epidemiological studies suggest interaction of BMI and sodium intake, we studied the combined effects of sodium intake and BMI on renal hemodynamics. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured in 95 healthy men (median age 23 years (95% confidence interval: 22-24), BMI: 23.0+/-2.5 kg/m2) on low (50 mmol Na+, LS) and high (200 mmol Na+, HS) sodium intake. Mean GFR and ERPF significantly increased by the change to HS (both P<0.001). During HS but not LS, GFR and filtration fraction (FF) positively correlated with BMI (R=0.32 and R=0.28, respectively, both P<0.01). Consequently, BMI correlated with the sodium-induced changes in GFR (R=0.30; P<0.01) and FF (R=0,23; P<0.05). The effects of HS on GFR and FF were significantly different for BMI>or=25 versus <25 kg/m2, namely 7.8+/-12.3 versus 16.1+/-13.1 ml/min (P<0.05) and -0.1+/-2.2 and 1.1+/-2.3% (P<0.05). FF was significantly higher in BMI>or=25 versus <25 kg/m2, (22.6+/-2.9 versus 24.6+/-2.4%, P<0.05) only during HS. ERPF was not related to BMI. Urinary albumin excretion was increased by HS from 6.0 (5.4-6.7) to 7.6 (6.9-8.9). Results were essentially similar after excluding the only two subjects with BMI>30 kg/m2. BMI is a determinant of the renal hemodynamic response to HS in healthy men, and of GFR and FF during HS, but not during LS. Consequently, HS elicited a hyperfiltration pattern in subjects with a BMI>or=25 kg/m2 that was absent during LS. Future studies should elucidate whether LS or diuretics can ameliorate the long-term renal risks of weight excess.     

Dietary arginine supplementation attenuates renal damage after relief of unilateral ureteral obstruction in rats

BACKGROUND: Progression of renal injury after relief of unilateral ureteral obstruction (UUO) has been demonstrated. Nitric oxide (NO) may be an effective intervention due to its vasodilatory, antifibrotic, and anti-apoptotic effects. Herein, we used dietary L-arginine (ARG) supplementation in a UUO relief model. METHODS: This study comprised group 1, control (no treatment). All other rats were subject to 3-day UUO, which was then relieved, and the rats maintained for 7 additional days. Group 2, no additional treatment; group 3, L-ARG; group 4, L-NAME, NO synthase inhibitor; group 5, ARG and L-NAME. Urinary NO(2/3) was quantified. GFR and ERPF were measured at day 10. Interstitial fibrosis and fibroblast expression, macrophage infiltration, tubular apoptosis, and proliferation, NOS expression, and the levels of tissue TGF-beta were evaluated. RESULTS: Urinary NO(2/3) was significantly increased by ARG treatment and decreased by L-NAME. GFR and ERPF measured 7 days following relief were not significantly different in the previously obstructed kidneys (POK) of groups 2 and 3. L-NAME significantly reduced GFR and ERPF in the POK. ARG significantly reduced apoptosis, macrophage infiltration, and fibroblast expression in the POK. L-NAME exacerbated the effects on apoptosis and fibroblasts. Fibrosis was minimal in groups 1 through 3, but was significantly increased by L-NAME. ARG did not affect renal NOS expression and tissue TGF-beta1 levels. CONCLUSION: Dietary ARG supplementation during UUO relief did not improve ERPF or GFR. However, renal damage, including fibrosis, apoptosis, and macrophage infiltration was significantly improved by ARG treatment. This suggests that increasing NO availability could be beneficial in the setting of UUO relief.     

Renal hemodynamics and segmental tubular reabsorption in early type 1 diabetes

To investigate mechanisms underlying GFR control in diabetes mellitus, renal hemodynamics and segmental tubular handling of sodium, using lithium clearance, were assessed in 41 insulin-dependent diabetics (IDD) treated by insulin for 11 +/- 8 days, and in 19 normal controls. Average GFR and effective renal plasma flow (ERPF) were slightly but not significantly higher (136 +/- 22 vs. 123 +/- 16 ml/min.1.73 m2) in IDD than in normal subjects. GFR and ERPF were positively and strongly correlated in controls (r = 0.61, P less than 0.001) and in diabetics (r = 0.72, P less than 0.0001) indicating the marked flow dependency of GFR in both populations. After adjustment for ERPF, GFR was significantly higher in diabetics, suggesting a role of increased glomerular capillary pressure and ultrafiltration coefficient in the subset of "hyperfiltering" patients. Both fractional (FPRNa) and absolute (APRNa) proximal sodium reabsorption were significantly higher in IDD and significantly correlated with GFR. The ensuing decrease in sodium distal delivery could deactivate the tubuloglomerular feedback response and thus favor sustained vasodilation and high GFR in some diabetics. The renal effects of acute administration of drugs acting predominantly at either the pre- or the postglomerular resistance using nicardipine (N = 16) or captopril (N = 25) were further evaluated in IDD. The renal response to captopril or nicardipine was different in IDD. Whereas both drugs induced a marked decrease in renal vascular resistance, GFR was slightly decreased by captopril and was unchanged after nicardipine; these results are similar to those observed in normotensive non-diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal hemodynamics during pregnancy in chronically catheterized, conscious rats

Two types of experiments were performed, cross-sectional and longitudinal. In the cross-sectional studies, rats were mated, later prepared surgically, and then 5 or more days after surgery, each examined twice during days 11 to 15 or days 18 to 20 of gestation. Nonpregnant rats matched for age and prepregnant weight served as controls. In the longitudinal studies, rats were catheterized and, starting 6 days later, examined twice; then the same rats were mated and each was studied on days 5, 8, 12, 16, and 20 of gestation, as well as on day 5 postpartum. In the cross-sectional studies, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were elevated by approximately 26% and 20%, respectively, above nonpregnant controls at 11 to 15 days of gestation (GFR, 2739 +/- 94 vs. 2181 +/- 134 microliters . min-1, P less than 0.005; ERPF, 9367 +/- 295 vs. 7785 +/- 422 microliters . min-1, P less than 0.01). By 18 to 20 days of gestation, GFR and ERPF had returned to levels that were not significantly different from nonpregnant values. The longitudinal studies confirmed these findings in every respect and further revealed that GFR and ERPF were elevated above nonpregnant values as early as day 5 of gestation (P less than 0.005). Thereafter, they rose to peak values, at 12 and 16 days of gestation, of 3122 +/- 144 and 10,584 +/- 541 microliters . min-1, and then returned to nonpregnant levels by day 20 of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal effects of hypotensive anaesthesia in combination with acute normovolaemic haemodilution with hydroxyethyl starch 130/0.4 or isotonic saline

BACKGROUND: Hypotensive anaesthesia (HA) and acute normovolaemic haemodilution (ANH) are used separately to decrease per-operative blood loss. Reducing blood viscosity by adding ANH to HA may appear profitable in a situation with lowered perfusion pressure and concern about organ ischemia. The aim of this study was to clarify the influence of HA in combination with ANH using crystalloid or colloid as replacement fluid on renal function. METHODS: Hypotensive anaesthesia was induced in 11 patients referred to major spine surgery using sevoflurane in combination with fentanyl/remifentanil. Acute normovolaemic haemodilution was carried out by drawing venous blood into standard blood bags and replacing it by isotonic saline 0.9% (Group S) or HES 130/0.4 (Group V). Renal function was evaluated before, during and up to 8 h after hypotension as the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) by means of 51Cr-EDTA and 125I-Hippuran clearances. RESULTS: Lowering mean arterial blood pressure decreased GFR and ERPF in both groups. During hypotension ERPF was lower in Group S (n = 5) than Group V (n = 6). Renal function was normalized postoperatively. We found a positive but non-significant correlation between the relative GFR change and the duration of hypotension. CONCLUSION: In conclusion, our study demonstrated that renal function, assessed by GFR and ERPF, is transiently reduced during the combination of hypotensive anaesthesia and acute normovolaemic haemodilution. A colloid-based fluid regime (HES 130/0.4) used for haemodilution may preserve renal function to a greater extent than a crystalloid-based regime (0.9% saline).     

Low-dose cyclosporin nephrotoxicity in the rat

The nephrotoxicity of cyclosporin (CsA) continues to be a clinicalproblem that detracts from its obvious benefits as an immunosuppressiveagent. Animal models designed to study the problem have generallyrelied either on chronic administration of high doses of thedrug or acute administration of single i.v. doses. The presentstudy establishes a model of CsA nephrotoxicity using dosesof the drug comparable to those used in man administered overa time period sufficient for haemodynamic and structural changesto become evident. The technique used measures glomerular filtration rate (GFR)and effective renal plasma flow (ERPF) by the plasma clearanceof chromium EDTA and iodohippuran respectively. This has theadvantage of allowing sequential measurements in individualanimals. Significant impairment of GFR was seen in animals treated intraperitoneallywith doses of CsA as low as 5 mg/kg/day. CsA 7.5 mg/kg/day causeda significant reduction in ERPF, and at 10 mg/kg/day and greaterfiltration fraction also declined significantly. Detailed histologicalexamination of the kidneys from these animals also revealedsignificant tubular dilatation at 10 mg/kg/day and above. This model of CsA toxicity circumvents many of the problemsassociated with other models. The animals can be studied longitudinallyand the period of administration has relevance to clinic practice.This work provides the basis for further studies which can closelymimic the clinical situation using doses similar to those usedfor human maintenance immunosuppression.