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E A Burdmann

Publications and source records attributed to E A Burdmann.

31 records · Page 2Linked to original sources
PubMed1995

FK506 nephrotoxicity: morphologic and physiologic characterization of a rat model.

BACKGROUND: FK506 is a useful agent in the prevention of allograft rejection but has recently been shown to be nephrotoxic. EXPERIMENTAL DESIGN: Sprague-Dawley rats (n = 40) were divided into four groups: control (C); low-salt (LS); FK506, 3 mg/kg daily by gavage (FK); and FK506-low-salt (FK-LS). After 6 weeks, the animals underwent physiologic studies and were sacrificed with perfusion fixation of the kidneys. Semiquantitative analysis of morphologic injury was performed as well as grading of juxtaglomerular apparatus (JGA) granularity (1-micron plastic sections). Computer-assisted morphometry was used to measure medullary thick ascending limb (mTAL) size within the inner stripe. RESULTS: Serum creatinine and plasma renin activity were significantly elevated only in the FK-LS group, but both FK groups had significantly increased fractional excretion of Mg. Tubular atrophy and fibrosis involving medullary rays and inner stripe (areas of low oxygen availability) was minimally present in FK, but prominent in FK-LS (P < 0.001). Injury correlated with decreased function (P < 0.001). Variance of mTAL size, an expression of co-existent tubular atrophy and hypertrophy was significantly greater in FK-LS and correlated with decreased renal function and urine osmolality (P < 0.001). JGA granularity was increased by FK506 (P < 0.006) with the highest values in FK-LS (P < 0.001), and strongly correlated with injury (P < 0.001). JGA granularity did not correlate with circulating renin activity levels, suggesting local activation of a renin-angiotensin system. CONCLUSIONS: FK506 compromises renal parenchymal zones which are known to have limited oxygen availability (medullary ray and inner stripe), a pattern that has been observed with other nephrotoxins. The injury is potentiated by salt depletion and may be mediated by the renin-angiotensin system. Furthermore, these findings illustrate the close correlation between the medullary injury that was observed and the impaired function that was documented.

Animals↗
PubMed1994

Enhancement of FK506 nephrotoxicity by sodium depletion in an experimental rat model.

FK506 can show efficacy in transplant rejection even after other immunosuppressive drugs have been ineffective. However, the lack of a suitable animal model has hindered the study of FK nephrotoxicity, which has been noted as a common adverse effect in human trials. In this paper, we report a model of chronic FK nephrotoxicity in which renal structure and function are worsened by sodium depletion. Pair-fed male Sprague-Dawley rats were given FK (6 mg/kg p.o.) or vehicle for 21 days on a low-salt or normal diet. There was no significant difference in body weight between FK and vehicle groups. The FK whole-blood trough levels (3-10 ng/ml) in rats are similar to those in FK treated transplant patients. In sodium-depleted rats, FK clearly decreased GFR (0.09 +/- 0.03 ml/min/100 g vs. 0.94 +/- 0.06 ml/min/100 g in the vehicle group, P < 0.01), urinary osmolarity (UOsm, P < 0.01) and plasma magnesium (P < 0.01) and increased plasma creatinine (Pcr, P < 0.01), fractional excretion of magnesium (P < 0.01), urine volume (P < 0.01), plasma renin activity (PRA, P < 0.05), and alanine aminopeptidase (AAP, P < 0.05) as compared with those in the vehicle group. Salt depletion significantly potentiated these functional changes as compared with those in the normal salt group (GFR, UOsm, Pcr, PRA, and AAP of the low salt group vs. those of the normal salt group, P < 0.05 by ANOVA). In the sodium-depleted rats, the main lesion in the rat kidneys was focal collapse and vacuolization in proximal tubules, but there was also significant interstitial fibrosis. In contrast, no injury was observed in the sodium-replete rat kidneys. In conclusion, an experimental model of FK nephrotoxicity in sodium-depleted rats has been developed that is characterized by reduced GFR and structural damage to the proximal tubule accompanied by interstitial fibrosis. Sodium depletion appears to potentiate these changes at blood levels similar to those achieved in patients receiving FK.

Animals↗
PubMed1994

Experimental nephrotoxicity, hepatotoxicity and pharmacokinetics of cyclosporin G versus cyclosporin A.

Cyclosporin G (CsG) is an analogue of cyclosporin A (CsA) with strong immunosuppressive activity. We compared these two drugs in a rat model in which salt depletion promotes irreversible renal interstitial fibrosis with renal dysfunction in animals given CsA for three weeks. When both drugs were given in the same dosage on a weight basis (15 mg/kg/day, subcutaneously), CsA blood levels were higher than CsG (3305 vs. 1824 ng/ml, P < 0.001). This could be explained by a higher CsG clearance (6.4 vs. 4.3 ml/min/kg in CsA, P < 0.0001) resulting in smaller CsG area under the curve. There was also lower renal and hepatic CsG tissue concentrations. CsA induced a dramatic decrease in GFR, 0.14 in CsA versus 0.67 ml/min/100 g in control, P < 0.001, and increased urinary excretion of N-acetyl beta-D-glucosaminidase (NAG), 21 in CsA versus 13 IU/gCr in control rats, P < 0.001. CsG-treated and control rats had similar GFR and urinary NAG. When CsA dosage was decreased to 7.5 mg/kg blood levels were similar to those found with CsG 15 mg/kg. CsA at this dose caused a reduced GFR (0.29 ml/min/100 g) and an increased urinary NAG (20 IU/gCr) (P < 0.01 vs. control for both). Both dosages of CsA induced considerable cortical and medullary injury (interstitial fibrosis and tubular atrophy), more severe than the histological damage found in CsG-treated rats. Neither drug promoted significant changes in liver function or histology.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylglucosaminidase↗
PubMed1994

Urinary enzymes as biomarkers of renal injury in experimental nephrotoxicity of immunosuppressive drugs.

Urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and of alanine-aminopeptidase (AAP) was studied after administration of cyclosporine A (CSA A), FK 506, or the corresponding vehicles to salt-depleted rats. On days 7, 14, and 28 after treatment for CSA and day 14 after treatment for FK 506, measurements of the urinary enzymes, serum creatinine (SCr), creatinine clearance (ClCr), and blinded renal histology were done. After 1 week on CSA there was a dramatic increase of 489% in the urinary excretion of AAP (162.6 IU/g Cr, CSA vs. 27.6 IU/g Cr control, p < .03), a significant decrease of 32% in ClCr, a significant increase of 41% in SCr, and mild proximal tubular atrophy and vacuolization. After 2 or 4 weeks of CSA treatment there were no more differences in the urinary AAP between CSA and control rats, but the urinary excretion of NAG was increased: 29.6 IU/g Cr, CSA vs. 20.9 IU/g Cr, control, p < .03 on day 14 and 26.9 IU/g Cr, CSA vs. 21.5 IU/g Cr, control, p < .008 on day 28. At the same time there was a progressive decline of the ClCr, a progressive increase in the SCr, and an increase in the severity of the histological lesion. After 14 days of treatment with FK 506 we observed a striking elevation in urinary AAP (62.6 IU/g Cr, FK 506 vs. 36.0 IU/g Cr, control, p < .01) consistent with a significant decrease in ClCr, a significant increase in SCr, and a moderate proximal tubular vacuolization and atrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylglucosaminidase↗
PubMed1994

Nephrotoxicity of immunosuppressive drugs.

Acute and chronic nephrotoxicity frequently limits the therapeutic benefits of immunosuppressive therapy for transplant and autoimmune indications. The clinical aspects, pathophysiology, and relevant pharmacology of current and future immunosuppressive drugs are reviewed in this paper. Insights gained from experimental models of chronic nephrotoxicity associated with tubulointerstitial fibrosis are presented.

Acute Kidney Injury↗
PubMed1994

Effects of oral magnesium supplementation on acute experimental cyclosporin nephrotoxicity.

Hypomagnesaemia with magnesuria are common findings in cyclosporin-(CsA)-treated patients and have been proposed as both a cause and a consequence of nephrotoxicity. To investigate the role of Mg depletion in the pathogenesis of acute CsA nephrotoxicity, rats kept on a low-salt diet were maintained on plain water (Mg(-)group) or water supplemented with 2% MgCl2 (Mg(+)group) and randomly assigned to treatment with CsA 15 mg/kg (CsA) or vehicle (VH) s.c. for 7 days. Water and food ingestion in VH animals was adjusted to the intake of CsA animals. CsAMg(-) group showed a significant plasma magnesium (PMg) reduction as compared to baseline (1.13 versus 1.53 mg/dl, P < 0.001) or VH values (versus 1.60 mg/dl, P < 0.001) and a significantly greater posttreatment fractional excretion of magnesium (FeMg) as compared to VH (9.4 versus 5.4%, P < 0.01). Magnesium supplementation increased PMg (2.11 versus 1.57 mg/dl P < 0.001) and FeMg (13.6 versus 6.2%, P < 0.001) but did not prevent a reduction in GFR with CsA treatment. Alanine aminopeptidase (AAP) excretion at 7 days was significantly greater than baseline (130 versus 44 IU/gCr, P < 0.05) or VH (36 IU/gCr, P < 0.05) values only in the CsAMg(-) rats. No differences were observed in intraerythrocyte Mg, blood pressure, and urinary excretion of N-acetyl-beta-D-glucosaminidase among groups. Renal histology was similar in CsA rats independent of magnesium supplementation: mild vacuolization and tubular collapse in proximal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

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.

Animals↗
PubMed1993

Snakebite-induced acute renal failure: an experimental model.

Acute renal failure (ARF) has been frequently reported after bites from the Viperidae snake family. The lack of a reproducible animal model has hampered the study of renal damage mechanisms. Intravenous injection of rats with 0.4 mg/kg of Bothrops jararaca venom produced functional and morphologic changes similar to those observed in human snakebite-induced ARF. There was an acute and significant decrease in the glomerular filtration rate, diuresis, and renal plasma flow. Serum fibrinogen levels decreased significantly. There was intravascular hemolysis, as shown by a significant decrease in hematocrit, and an increase in plasma lactate dehydrogenase levels and free hemoglobin. Blood pressure and serum creatine phosphokinase levels were not affected. Light and electron microscopy showed massive fibrin deposition in glomerular capillaries, proximal and distal tubular necrosis, and hemolyzed red blood cell casts in renal tubules. Based on these findings, a model of snakebite-induced ARF was achieved. Ischemia related to glomerular coagulation and intravascular hemolysis were the most important pathogenic factors causing a decrease in the glomerular filtration rate, although a direct venom nephrotoxicity cannot be excluded.

Acute Kidney Injury↗
PubMed1985

Abruptio placentae following snake bite.

A case in which, besides the clinical complications that commonly follow snake biting, abruptio placentae occurred is reported here. None of the factors that are frequently associated with abruptio placentae were present. The laboratory tests performed showed that renal function was impaired and that a dramatic hypercoagulability was present. The relationship of the latter to the abruptio placentae is discussed.

Abruptio Placentae↗
PubMedDate not supplied

FTY720 prevents renal T-cell infiltration after ischemia/reperfusion injury.

Ischemia/reperfusion (I/R) injury, a common early feature in renal transplantation, results from both free radical species generation and local inflammatory responses that attract different types of cells. The interaction with infiltrating leukocytes could promote damage and death of resident renal cells contributing to worsening of renal function. It has been shown that depletion of host T cells protects against kidney damage after I/R injury, although the mechanism is not fully understood. FTY720, a synthetic analog of a natural product extracted from Isaria sincclairii has shown modulatory properties in experimental models of autoimmune disease, transplantation, and I/R injury. FTY720 alters lymphocyte responses to chemokine homing signals, thereby decreasing the number of lymphocytes in inflammatory sites. We evaluated renal function in mice at 3, 5, and 7 days after I/R injury in the presence or absence of FTY720 treatment. FTY720 treatment promoted earlier recovery of renal function associated with a lower number of renal-infiltrating lymphocytes. These findings confirm previous results showing a protective effect of FTY720 in I/R injury models.

Animals↗
PubMedDate not supplied

Prolonged administration of FTY720 does not cause renal toxicity in mice.

Prevention of allograft rejection without renal toxicity caused by calcineurin-inhibitor immunosuppression is a major goal for transplantation. FTY720 is a synthetic drug that modulates immune responses of transplantation in many animal models. FTY720 modulating mechanisms relate to lymphocyte migration to peripheral lymph nodes instead of inflammatory sites. The drug has no effect on T-cell proliferation or cytokine production, and therefore prevents generalized immunosuppression. However, it is still to be confirmed that FTY720 has no nephrotoxic effects when administered continuously. In the present study FTY720 was administered orally for 21 days to C57BL/6 mice that underwent weekly evaluations. FTY720 (1 mg/kg per day) impaired body weight gain, but had no significant effect on either renal function or structure. Our findings suggest that FTY720 may provide a reasonable add-on therapy in calcineurin-inhibitor-treated transplant recipients.

Animals↗
PubMedDate not supplied

Prednisone alters the histopathology of chronic cyclosporine nephropathy.

The effects of prednisone (Pred) and azathioprine (Aza) on a rat model of chronic cyclosporine (CsA) nephropathy were studied. Twenty-four salt-depleted Sprague-Dawley rats were randomized to four groups: (1) control; (2) CsA 15 mg/kg; (3) CsA/Aza 5 mg/kg, and (4) CsA/Pred 1 mg/kg. After 4 weeks, functional measurements, including urinary N-acetyl-beta-D-glucosaminidase (NAG) levels, were determined. Semiquantitative grading of cortical and medullary damage was done. Cross-sectional areas of medullary thick ascending limbs (mTAL) and collecting ducts (CD) were determined. Tubulointerstitial injury was equivalent in all CsA groups, but tended to be lowest in the CsA/Pred group. Mean mTAL size in the CsA/Pred group was significantly greater than controls (p = 0.035). In contrast, mean CD size was not different among all groups. All CsA-treated animals had significantly larger hypertrophic mTAL than controls. The degree of hypertrophy was even greater in the CsA/Pred group (p = 0.006 vs. the other CsA-treated groups). Mean mTAL size was found to correlate with creatinine clearance, free water reabsorption, and urinary NAG. The percent of hypertrophic mTAL was found to correlate with creatinine clearance, free water reabsorption, and urinary NAG. This report shows that Pred alters the nephrotoxic effect of CsA, permitting a predominantly hypertrophic, rather than atrophic, medullary response. The extent of hypertrophy, in all CsA-treated groups, correlated with improved functional parameters, suggesting that at least in one phase of CsA nephropathy compensatory responses preserve renal function.

Animals↗