Tight glucose control versus intermediate glucose control: a quasi-experimental study.

Intensive insulin treatment is associated with an increased risk of hypoglycaemia. The purpose of this study was to evaluate two different strategies: tight glucose control (TGC) versus intermediate glucose control (IGC). In this quasi-experimental study, 130 critically ill patients were assigned to receive either the TGC protocol (n=65), according to which blood glucose levels were maintained between 4.4 and 6.1 mmol/l, or the IGC protocol (n=65), according to which blood glucose levels were maintained between 4.4 and 8.0 mmol/l. A total of 52 subjects (40%) were diabetic and 63 (49%) were septic. In the IGC group, glucose levels were stabilised in the target range for a longer period of time when compared to the TGC group (63 vs. 41%, P < 0.001). The median capillary blood glucose level was 6.7 mmol/l in the TGC group (6.2 to 7.2) and 7.9 mmol/l (7.0 to 8.5) in the IGC group (P < 0.001). The incidence of hypoglyacemia less than 2.2 mmol/l was 21.5% in the TGC group and 1.5% in the IGC group (P < 0.001), and the incidence of hypoglycaemia less than 3.3 mmol/l was 67.7 and 26.2% (P < 0.001) in the two groups, respectively. Diabetes (odds ratio 2.88, CI 1.22 to 6.84) and the TGC protocol (odds ratio 7.39, CI 3.15 to 1735) were identified as independent risk factors for hypoglycaemia less than 3.3 mmol/l. Mechanical ventilation (odds ratio 4.33, CI 1.16 to 16.13), medical illness (odds ratio 2.88, CI 1.20 to 6.99) and hypoglycaemia (< 3.3 mmol/l) (odds ratio 299, CI 1.21 to 7.41) were independent factors associated with mortality. TGC is difficult to accomplish in routine intensive care unit settings and is associated with a significant increase in the incidence of hypoglycaemia. Hypoglycaemia < 3.3 mmol/l is an independent risk factor for in-hospital mortality.

Effect of cyclooxygenase inhibitors on gentamicin-induced nephrotoxicity in rats.

The frequent use of nonsteroidal anti-inflammatory drugs (NSAID) in combination with gentamicin poses the additional risk of nephrotoxic renal failure. Cyclooxygenase-1 (COX-1) is the main enzyme responsible for the synthesis of renal vasodilator prostaglandins, while COX-2 participates predominantly in the inflammatory process. Both are inhibited by non-selective NSAID such as indomethacin. Selective COX-2 inhibitors such as rofecoxib seem to have fewer renal side effects than non-selective inhibitors. The objective of the present study was to determine whether the combined use of rofecoxib and gentamicin can prevent the increased renal injury caused by gentamicin and indomethacin. Male Wistar rats (250-300 g) were treated with gentamicin (100 mg/kg body weight, ip, N = 7), indomethacin (5 mg/kg, orally, N = 7), rofecoxib (1.4 mg/kg, orally, N = 7), gentamicin + rofecoxib (100 and 1.4 mg/kg, respectively) or gentamicin + indomethacin (100 and 5 mg/kg, respectively, N = 8) for 5 days. Creatinine clearance and alpha-glutathione-S-transferase concentrations were used as markers of renal injury. Animals were anesthetized with ether and sacrificed for blood collection. The use of gentamicin plus indomethacin led to worsened renal function (0.199 +/- 0.019 ml/min), as opposed to the absence of a nephrotoxic effect of rofecoxib when gentamicin plus rofexicob was used (0.242 +/- 0.011 ml/min). These results indicate that COX-2-selective inhibitors can be used as an alternative treatment to conventional NSAID, especially in situations in which risk factors for nephrotoxicity are present.

Effect of cyclooxygenase inhibitors on gentamicin-induced nephrotoxicity in rats

The frequent use of nonsteroidal anti-inflammatory drugs (NSAID) in combination with gentamicin poses the additional risk of nephrotoxic renal failure. Cyclooxygenase-1 (COX-1) is the main enzyme responsible for the synthesis of renal vasodilator prostaglandins, while COX-2 participates predominantly in the inflammatory process. Both are inhibited by non-selective NSAID such as indomethacin. Selective COX-2 inhibitors such as rofecoxib seem to have fewer renal side effects than non-selective inhibitors. The objective of the present study was to determine whether the combined use of rofecoxib and gentamicin can prevent the increased renal injury caused by gentamicin and indomethacin. Male Wistar rats (250-300 g) were treated with gentamicin (100 mg/kg body weight, ip, N = 7), indomethacin (5 mg/kg, orally, N = 7), rofecoxib (1.4 mg/kg, orally, N = 7), gentamicin + rofecoxib (100 and 1.4 mg/kg, respectively) or gentamicin + indomethacin (100 and 5 mg/kg, respectively, N = 8) for 5 days. Creatinine clearance and alpha-glutathione-S-transferase concentrations were used as markers of renal injury. Animals were anesthetized with ether and sacrificed for blood collection. The use of gentamicin plus indomethacin led to worsened renal function (0.199 ± 0.019 ml/min), as opposed to the absence of a nephrotoxic effect of rofecoxib when gentamicin plus rofexicob was used (0.242 ± 0.011 ml/min). These results indicate that COX-2-selective inhibitors can be used as an alternative treatment to conventional NSAID, especially in situations in which risk factors for nephrotoxicity are present.

Métodos dialíticos utilizados nos cardiopatas graves / Dialysis modalities for the treatment of patients with severe cardiac disease

Nas últimas três décadas, os avanços tecnológicos permitiram a disponibilização de diversas modalidades dialíticas, as quais oferecem vantagens e desvantagens, que devem ser levadas em conta quando da prescrição e escolha da modalidade para determinado paciente. Isso é particularmente importante nos pacientes que apresentam instabilidade hemodinâmica. Na sepse, discute-se hoje a dose de diálise e o uso de terapias contínuas de reposição da função renal. Grandes progressos têm sido feitos nessa área nos últimos anos. Dados recentes sugerem que a diálise peritoneal e a ultrafiltração lenta podem beneficiar pacientes com insuficiência cardíaca terminal. Nesta revisão, abordaremos os aspectos básicos e técnicos, e a aplicação clínica dos métodos dialíticos no paciente criticamente enfermo, particularmente na sepse e na insuficiência cardíaca.

Effect of the antiglucocorticoid RU-486 on glomerular hemodynamics in remnant nephrons.

Endogenous glucocorticoid (GC) has been proposed to play a role in the adaptive functions of remnant nephron and participates in the progression of renal disease. The effect of GC blockade by RU-486 (20 mg/kg), an anti-GC agent, on the progression of chronic renal failure (CRF) was evaluated in Munich-Wistar rats. CRF was induced by 5/6 nephrectomy. Global renal function, glomerular hemodynamics, proteinuria and renal histopathology studies were performed after 60 days of CRF induction. RU administration in control or CRF groups did not induce significant changes in total renal function, mean arterial or intraglomerular hydraulic pressures, 24-hour proteinuria or sclerosis index. However, RU induced a significant reduction in single-nephron glomerular filtration rate in the superficial nephrons in both groups' control (decreases 20%) and CRF (decreases 57%), without changing total glomerular filtration rate, when compared with vehicle administration. These reductions were due to a decline in glomerular plasma flow rate (QA) and in glomerular ultrafiltration coefficient (Kf). These data suggest that GC played a role in the adaptive hyperfiltration associated with the compensatory mechanism but did not participate in the genesis of proteinuria or glomerulosclerosis in this experimental model.

Neurohumoral systems in patients with cirrhosis.

In order to evaluate the activation of the sympathetic nervous and renin-angiotensin systems and antidiuretic hormone release in the setting of chronic liver disease, we studied 30 patients with cirrhosis who presented normal renal function. The cirrhotic patients were divided into two groups according to Child's score: 20 were Child A and 10 Child B. The control group consisted of 10 normal subjects. Blood samples were collected for determination of norepinephrine (NE), dopamine (DA), angiotensin I and II (AI and AII), and antidiuretic hormone (ADH), using the method of high-performance liquid chromatography (HPLC). No significant differences (p < 0.05) were found in the plasma levels of NE, DA, AI, and AII between the cirrhotic patients and the controls, although the absolute values observed in both groups of cirrhotics were clearly higher than in controls. The ADH levels were higher in Child B in comparison to Child A patients and controls, though this difference was not significant as well. Our results suggest a hormonal activation in cirrhotic patients, even in the early stages of hepatic disease (without ascites). We also noted an increase in ADH levels in Child B patients in relation to Child A and controls, although there was no difference in osmolality, suggesting a non-osmotic ADH release.

Nephrotoxicity of acyclovir and ganciclovir in rats: evaluation of glomerular hemodynamics.

Whole-kidney function and glomerular hemodynamics were evaluated after acute (50 mg/kg, iv, in bolus) and short-term chronic (50 mg mg/kg, ip, 5 days) acyclovir (ACV) and short-term chronic ganciclovir (Gan; 30 mg/kg, ip, 5 days) treatment in envolemic Munich-Wistar rats. The evaluation of whole-kidney function of the ACV groups showed a significant reduction in total GFR (0.96 +/- 0.10 to 0.28 +/- 0.02 mL/min in the acute group, P < 0.05, and 1.04 +/- 0.09 to 0.33 +/- 0.04 mL/min in the chronic group, P < 0.05) with a marked increase in total renal vascular resistance (TRVR) (33 +/- 5 to 122 +/- 26 mm Hg.min/mL in the acute group and 28 +/- 3 to 74 +/- 18 mm Hg.min/mL in the chronic group, P < 0.05) and a reduction in RPF (2.29 +/- 0.25 to 0.81 +/- 0.15 mL/min in the acute group and 2.57 +/- 0.36 to 1.30 +/- 0.40 mL/min in the chronic group, P < 0.05). Conversely, urinary flow (V') was unchanged (3.6 +/- 0.4 to 3.6 +/- 0.2 microL/min in the acute group) or elevated (3.7 +/- 0.6 to 6.6 +/- 1.4 microL/min in the chronic group, P < 0.05). The evaluation of glomerular hemodynamics after ACV treatment showed a reduction in single-nephron GFR (SNGFR) (46.4 +/- 5.3 to 26.2 +/- 3.4 nL/min in the acute group and 38.7 +/- 5.7 to 21.1 +/- 5.7 nL/min in the chronic group, P < 0.05), a significant elevation in total arteriolar resistance (RT) (2.90 +/- 0.44 to 4.94 +/- 0.77 x 10(10) dyn.s.cm-5 in the acute group and 3.72 +/- 0.45 to 9.00 +/- 2.40 x 10(10) dyn.s.cm-5 in the chronic group, P < 0.05) and a severe reduction in glomerular plasma flow rate (QA) (152.6 +/- 29.5 to 103.8 +/- 27.8 nL/min in the acute group and 149.1 +/- 29.8 to 68.5 +/- 10.0 nL/min in the chronic group, P < 0.05). However, the glomerular ultrafiltration coefficient, Kf, was changed only in the chronic group (0.1002 +/- 0.0165 to 0.0499 +/- 0.0090 nL/(s.mm Hg), P < 0.05). After Gan treatment, no changes were observed in GFR (1.04 +/- 0.09 to 0.96 +/- 0.08 mL/min, with the maintenance of RPF (2.57 +/- 0.36 to 2.66 +/- 0.34 mL/min) and a nonsignificant reduction in TRVR (28 +/- 3 to 20 +/- 3 mm Hg.min/mL. The short-term Gan treatment also showed a different pattern in glomerular hemodynamics by inducing an elevation in SNGFR (38.7 +/- 5.7 to 50.3 +/- 2.8 nL/min, P < 0.05) with no changes in QA (150 +/- 30 to 135 +/- 22 nL/min) and a mild vasodilation, RT (3.7 +/- 0.5 to 2.7 +/- 0.3 x 10(10) dyn.s.cm-5, P < 0.05) associated with an increment in Kf (0.1002 +/- 0.0165 to 0.2400 +/- 0.0700 nL/(s.mm Hg), P < 0.05). Thus, ACV induced acute renal failure by reducing GFR and SNGFR by an increase in TRVR and RT with a reduction in RPF and QA. Also, after short-term treatment with ACV, a reduction in Kf led to a reduction of SNGFR. On the other hand, Gan treatment did not induce acute renal failure by the adopted techniques.

Fructose-1,6-diphosphate: potential protection in cyclosporine-induced renal impairment.

There is evidence that fructose-1,6-diphosphate (FDP) provides protection from hepatic and cardiac toxic-induced damage and ischemic renal insult. To determine if FDP also protects against cyclosporine (CsA)-induced nephrotoxicity, two groups of adult male Wistar rats were studied for whole kidney clearance rates. After two initial control periods, group 1 received only CsA (CsA, n = 8). Group 2 received FDP 350 mg/kg, followed by CsA 50 mg/kg (FDP-CsA, n = 6). In both groups, after a 30-min equilibration period, two additional clearance rates were measured (Post 1 and Post 2). A significant reduction in clearance rates was observed after drug infusion in both groups (approximately 58 and 64% in CsA and FDP-CsA groups, respectively, p < 0.05) with a recovery to control values in the Post 2 period in the FDP-CsA group. These data suggest a protective effect of FDP on CsA-induced renal impairment.

Differential tubulogenic and branching morphogenetic activities of growth factors: implications for epithelial tissue development.

At least two kidney epithelial cell lines, the Madin-Darby canine kidney (MDCK) and the murine inner medullary collecting duct line mIMCD-3, can be induced to form branching tubular structures when cultured with hepatocyte growth factor (HGF) plus serum in collagen I gels. In our studies, whereas MDCK cells remained unable to form tubules in the presence of serum alone, mIMCD-3 cells formed impressive branching tubular structures with apparent lumens, suggesting the existence of specific factors in serum that are tubulogenic for mIMCD-3 cells but not for MDCK cells. Since normal serum does not contain enough HGF to induce tubulogenesis, these factors appeared to be substances other than HGF. This was also suggested by another observation: when MDCK cells or mIMCD-3 cells were cocultured under serum-free conditions with the embryonic kidney, both cell types formed branching tubular structures similar to those induced by HGF; however, only in the case of MDCK cells could this be inhibited by neutralizing antibodies against HGF. Thus, the embryonic kidney produces growth factors other than HGF capable of inducing tubule formation in the mIMCD-3 cells. Of a number of growth factors examined, transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) were found to be tubulogenic for mIMCD-3 cells. Whereas only HGF was a potent tubulogenic factor for MDCK cells, HGF, TGF-alpha, and EGF were potent tubulogenic factors for mIMCD-3 cells. Nevertheless, there were marked differences in the capacity of these tubulogenic factors to induce tubulation as well as branching events in those tubules that did form (HGF >> TGF-alpha > EGF). Thus, at least three different growth factors can induce tubulogenesis and branching in a specific epithelial cell in vitro (though to different degrees), and different epithelial cells that are capable of forming branching tubular structures demonstrate vastly different responses to tubulogenic growth factors. The results are discussed in the context of branching morphogenesis during epithelial tissue development.

Involvement of hepatocyte growth factor in kidney development.

Using PCR, hepatocyte growth factor (HGF) and c-met (HGF receptor) expression were analyzed in the developing mouse kidney. Both HGF and c-met were expressed from Gestational Day 11.5 onward, the time at which branching morphogenesis of ureteric bud occurs. Coculturing the embryonic kidney with MDCK cells seeded in Type I collagen induced branching morphogenesis of the MDCK cells. When a monospecific antiserum against HGF was included in the culture medium, the branching morphogenesis induced by the embryonic kidney was markedly inhibited (73%). This anti-HGF serum also inhibited metanephric growth when incubated with 11.5- to 12.5-day embryonic kidneys in an organ culture assay. No inhibition was observed by nonimmune serum. Perturbation of ureteric duct development as well as extraductal metanephric development was observed in embryonic kidneys incubated with the anti-HGF serum. Together, our data indicates an important role for HGF in kidney development.

HGF-induced tubulogenesis and branching of epithelial cells is modulated by extracellular matrix and TGF-beta.

Beginning with the observation that hepatocyte growth factor (HGF) induces the formation of branching tubular structures in Madin-Darby canine kidney (MDCK) cells cultured in Type I collagen gels but not in basement membrane Matrigel, we examined the individual components within this complex basement membrane extract to determine the effect of these proteins on the morphogenetic changes mediated by HGF. After extraction of several growth factors from Matrigel, HGF was still unable to induce process formation, an early event in tubulogenesis, indicating that one or more of the remaining extracellular matrix (ECM) proteins or growth factors were exerting the inhibitory effect. By individually adding back these components to MDCK cells grown in Type I collagen gels in the presence of HGF, we were able to establish that: (1) certain ECM proteins, such as laminin, entactin, and fibronectin, actually facilitated the formation of branching tubular structures and increased their complexity; (2) other ECM proteins, such as Type IV collagen, heparan sulfate proteoglycan, and vitronectin, caused marked inhibition of HGF-induced morphogenesis; and (3) not only did transforming growth factor-beta (TGF-beta) inhibit the formation of tubular structures, but those which did form exhibited little branching, thereby suggesting that TGF-beta modulates tubulogenesis as well as branching. These results suggest that a tubulogenic morphogen such as HGF and a tubulogenesis-inhibitory morphogen such as TGF-beta can, in the context of the dynamic matrix known to exist during epithelial tissue development, modulate the degree of tubule (or ductal) formation, the length of these tubules, and the extent of their arborization. The relevance of these findings to tubulogenesis and branching during kidney development is discussed.

Modulation of HGF-induced tubulogenesis and branching by multiple phosphorylation mechanisms.

MDCK cells cultured in Type I collagen gels can be induced to develop branching tubular structures with demonstrable lumens in the presence of hepatocyte growth factor (HGF). As we have now shown by immunofluorescent localization of specific marker proteins, these tubules retain apical-basolateral polarity. However, the secondary signaling events which lead to these characteristic morphogenetic changes induced by HGF remain largely unelucidated. In order to examine these signaling events, particularly the role of protein phosphorylation in the formation of branching tubular structures, Madin-Darby canine kidney (MDCK) cells in collagen gels were treated with HGF plus well-characterized agents that affect protein phosphorylation. We quantified the formation of branching processes, an early step in the development of tubular structures in this model. Protein kinase C (PKC) inhibition resulted in more complex branching processes in the presence of HGF, when compared with HGF alone. In contrast, treatment with activators of protein kinase A (PKA), as well as calmodulin antagonists, caused a marked decline in process formation. Consistent with an important role for protein phosphorylation in HGF-induced morphogenesis, protein phosphatase inhibition by okadaic acid or calyculin A was found to markedly inhibit process formation. Tyrosine kinase (TK) inhibition also decreased the percentage of processes. This is consistent with data indicating that one of the HGF receptors is identical to the c-met protooncogene product, which is known to possess TK activity. Our results suggest that the HGF-mediated induction of branching processes in MDCK cells, an early step in the development of branching tubular structures, can be modulated by multiple phosphorylation mechanisms including those mediated by PKC, PKA, and Ca2+/calmodulin-dependent kinase(s). We discuss how these phosphorylation events may play crucial roles in determining the degree of tubule formation and their length, as well as the extent of their arborization during the early development of epithelial tissues.

Nephrotoxicity of cyclosporine: the role of platelet-activating factor and thromboxane.

Cyclosporine (CsA), an immunosuppressive agent, is potentially nephrotoxic. We had previously observed that acute administration of CsA to Munich-Wistar rats induced a decrease in single nephron glomerular filtration rate, due to a decline in glomerular plasma flow, and in the glomerular ultrafiltration coefficient. Moreover, these alterations were prevented when an antagonist of platelet-activating factor (PAF) was administered. In the present study we examined whether the protective effect of the PAF blocker in CsA nephrotoxicity could have been mediated by thromboxane (TxA2). Our data show that the PAF effects were not mediated by TxA2, since administration of dazmegrel, a thromboxane synthetase inhibitor, did not ameliorate the acute renal failure caused by CsA. Thus, PAF appears to be a direct mediator of acute CsA nephrotoxicity, while TxA2 is not significantly involved in this process.

Effect of platelet-activating factor antagonist BN 52063 on the nephrotoxicity of cisplatin.

Cisplatin (DDP) is an effective anticancer agent that has been successfully applied against various solid tumors. However, DDP commonly causes nephrotoxicity. We observed that DDP led to significant alterations in renal microcirculation when administered to Munich-Wistar rats, with a concomitant decrease in single nephron glomerular filtration rate due to reduction in glomerular plasma flow and transcapillary hydraulic pressure difference. BN 52063, a platelet-activating factor antagonist, caused a striking change in acute renal failure induced by DDP leading toward normalization of all parameters of renal function. The results suggest that BN 52063 could be used as a novel drug to control DDP nephrotoxicity.

Role of platelet activating factor in gentamicin and cisplatin nephrotoxicity.

The present study was undertaken to evaluate the effects of platelet activating factor (PAF) antagonists on nephrotoxicity induced by gentamicin (GENTA) and cisplatin (DDP) in rats. PAF infusion provoked a 56% decline in single nephron (SN) GFR due to a decrease in glomerular plasma flow (QA, 55%), glomerular transcapillary hydraulic pressure (delta P, 13%), and glomerular ultrafiltration coefficient (Kf, 37%). Four days after a single dose of DDP (6 mg/kg, i.p.) we observed non-oliguric acute renal failure (ARF) with reduced SNGFR (45%), QA (46%) and delta P (10%) and unchanged Kf. GENTA administration for 10 days (40 mg/kg, i.p. daily) induced a decline in SNGFR (40%), QA (41%) and Kf (41%). Chronic treatment with a GENTA + PAF antagonist (BN 52021) partially prevented the decline in SNGFR (22%) by an amelioration in QA (25%) and Kf (13%). However, simultaneous treatment with DDP and BN 52063 completely prevented the ARF induced by DDP, normalizing all parameters of renal function. Thus, PAF may be a potential mediator involved in the nephrotoxicity induced by GENTA and DDP.

Effects of systemic hypertension, antidiuretic hormone, and prostaglandins on remnant nephrons.

Renal function was evaluated in normal and after 30 days of 5/6 renal mass reduction (CRF) in Munich-Wistar (MW) rats, spontaneously hypertensive rats with superficial glomeruli (EPM), and in Brattleboro rats with congenital diabetes insipidus (DI). Mean arterial pressure was higher in EPM-Control and EPM-CRF rats as compared with MW and DI rats. MW and EPM rats with CRF showed increases of 120% and 196%, respectively, in single nephron glomerular filtration rate as compared with their controls. However, DI rats with CRF did not show any increase in single nephron glomerular filtration rate as compared with the control group. Therefore, the data suggest that the presence of hypertension enhances the adaptive mechanisms on remnant kidney's function. Conversely, in the absence of antidiuretic hormone, adaptive mechanisms of remnant nephrons did not occur. In addition, it was observed that rats with CRF submitted to prostaglandin blockade with indomethacin showed for MW rats a 55% and 20% reduction in ultrafiltration coefficient and in single nephron glomerular filtration rate, respectively. Decreases of 60% and 30% in ultrafiltration coefficient and single nephron glomerular filtration rate, respectively, were observed for EPM rats. In contrast, DI rats did not show any alteration on renal function after indomethacin. It seems, therefore, that prostaglandins play a role in remnant nephron function of MW and EPM rats, but in the absence of antidiuretic hormone, prostaglandins do not affect remnant glomerular hemodynamics.

Effect of platelet-activating factor antagonist on cyclosporine nephrotoxicity. Glomerular hemodynamics evaluation.

In order to evaluate the effect of platelet-activating factor (PAF) antagonist BN 52021 (5 mg/kg i.v.) on cyclosporine (50 mg/kg i.v.) nephrotoxicity, euvolemic Munich-Wistar rats were submitted to micropuncture studies. BN 52021 alone did not change the total (1.08 +/- 0.07 vs. 1.04 +/- 0.06 ml/min) or single nephron (SN) (29.1 +/- 50 vs. 31.3 +/- 4.0 nl/min) and glomerular filtration rate. The CsA administration caused a decline on GFR (0.47 +/- 0.07 vs. 0.96 +/- 0.04 ml/min, P less than 0.05) and on SNGFR (14.0 +/- 3.5 vs. 27.9 +/- 3.4 ml/min, P less than 0.05). An increase in afferent (RA) and efferent (RE) arteriolar resistances, 180% and 360%, respectively, that caused a decrease on glomerular plasma flow rate (QA) from 100.99 +/- 17.09 to 44.37 +/- 13.37 nl/min (P less than 0.05) was observed. Moreover, the glomerular ultrafiltration coefficient (Kf) declined by 70% (0.096 +/- 0.003 to 0.031 +/- 0.10 ml/sec mmHg, P less than 0.05). The previous BN 52021 administration on rats treated with CsA blunted its effects on superficial nephrons. The SNGFR (22.3 +/- 3.0 vs. 28.0 +/- 25 nl/min), QA (72.2 +/- 5.9 vs. 91.7 +/- 12.1 nl/min) and KF (0.038 +/- 0.009 vs. 0.048 +/- 0.005 nl/s mmHg) remained unaltered. By contrast, the total renal function was not prevented by BN 52021 treatment: GFR 0.45 +/- 0.12 vs. 0.94 +/- 0.05 ml/min (P less than 0.05). Thus, this study suggests that PAF may participate in CsA nephrotoxicity. Furthermore, the protective effect of BN 52021 on superficial nephrons may indicate that BN 52021 is a drug that can minimize the impairment of renal function induced by CsA.

Effect of cisplatin on glomerular hemodynamics.

1. The effects of cisplatin on renal microcirculation were evaluated in euvolemic Munich-Wistar rats submitted to micropuncture. Nine rats received a single dose of cisplatin (6 mg/kg, ip), and 6 control rats received the same volume (0.3 ml) of 150 mM NaCl 4 days before the measurements. 2. Cisplatin administration induced non-oliguric acute renal failure by decreasing glomerular filtration rate (GFR) from 0.96 +/- 0.05 to 0.33 +/- 0.04 ml/min (P less than 0.05) and by increasing urinary volume from 3.3 +/- 0.3 to 12.4 +/- 2.2 microliters/min (P less than 0.05). 3. Cisplatin administration decreased single nephron GFR from 34.2 +/- 2.1 to 20.1 +/- 2.3 nl/min (P less than 0.05) due to a reduction in both glomerular plasma flow from 106 +/- 9 to 61 +/- 6 nl/min (P less than 0.05) and transcapillary hydraulic pressure difference from 31 +/- 1 to 27 +/- 1 mmHg (P less than 0.05). An increase in arteriolar resistances, mainly afferent arteriolar resistance from 2.5 +/- 0.2 to 4.7 +/- 0.5 x 10(10) dyn.s.cm-5 (P less than 0.05), was observed. The glomerular ultrafiltration coefficient was unchanged.

Effect of cisplatin on glomerular hemodynamics

The effects of cisplatin on renal microcirculation were evaluated in euvolemic Munich-Wistar rats submitted to micropuncture. Nine rats received a single dose of cisplatin (6 mg/kg,ip), and 6 control rats received the same volume (0.3 ml) of 15 mM NaCl 4 days before the measurements. Cisplatin administration induced non-oliguric acute renal failure by decreasing glomerular filtration rate (GFR) from 0.96 + or- 0.5 to 0.33 + or - 0.04 ml/min (P<0.05) and by increasing urinary volume from 3.3 + or - 0.3 to 12.4 + or - 2.2 micronl/min (P<0.05). Cisplatin administration decreased single nephron GFR from 34.2 + or - 2.1 to 20.1 + or - 2.3 nl/min (P<0.05) due to a reduction in both glomerular plasma flow from 106 + or - 9 to 61 + or - 6 nl/min (P<0.05) and transcapillary hydraulic pressure difference from 31 + or - 1 to 27 + or - 1 mmHg (P<0.05). An increase in arteriolar resistances, mainly afferent arteriolar resistance from 2.5 + or - 0.2 to 4.7 + or - 0.5 x 10**10 dyn.s.cm**-5 (P<0.05), was observed. The glomerular ultrafiltration coefficient was unchanged