Immune-mediated mesangial cell injury—Biosynthesis and function of prostanoids

Immune-mediated mesangial cell injury—Biosynthesis and function of prostanoids. We studied the formation of cyclo-oxygenase products in a rat model of mesangial cell injury, in order to determine a possible role of prostaglandin E2 (PGE2), prostaglandin I2 (determined as 6-keto-PGF1α and thromboxane A2 (TxA2) in immune-mediated glomerular disease. Selective immune-mediated mesangial cell injury was induced by i.v. administration of a rabbit anti-rat thymocyte antiserum (ATS). Intravenous ATS leads to immune deposits in the mesangium followed by mesangiolysis and the infiltration of polymorphonuclear granulocytes and monocytes. Glomerular TxB2 formation two hours (292 ± 27 pg/mg/min) and 48 hours (396 ± 69 pg/mg/min) following antibody was significantly (P < 0.05) higher compared to animals receiving non-antibody rabbit IgG (TxB2: 2hr 143 ± 13; 48hr 171 ± 32 pg/mg/min). Treatment with cobra venom factor (CVF) and the reduction of glomerular monocyte infiltration inhibited the increase of glomerular TxB2 formation significantly. Depletion of granulocytes with a rabbit anti-rat granulocyte serum had no effect on glomerular prostanoid formation following ATS. Glomerular PGE2 and 6-keto PGF1α production was not altered following ATS. Inulin clearance in rats with immune-mediated mesangial cell injury was significantly (P < 0.001) lower at two hours (456 ± 24 µl/min/100g body wt) and 48 hours (433 ± 54 µl/min/lOO g body wt) compared to their corresponding control animals which were treated with non-antibody IgG (2 hr: 914 ± 51; 48 hr: 694 ± 79 µl/min/100g body wt). Pretreatment of rats with indomethacin (Indo) or with the thromboxane synthetase inhibitor UK 38485 prevented the decrease in inulin clearance following ATS at two hours (Indo: 800 ± 67; UK 38485: 923 ± 115) and at 48 hours (Indo: 697 ± 60; UK 38485: 654 ± 99). The data demonstrate that selective, immune-mediated mesangial cell injury in rats is associated with increased glomerular TxB2 formation. Complement and monocyte/macrophage depletion reduces TxB2 production. The fall in inulin clearance following ATS is ameliorated when the rats receive indomethacin or the Tx synthetase inhibitor UK 38485. Thus, elevated TxB2 formation might mediate the reduction in GFR in this model of glomerular immune injury

Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplant recipients

Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplant recipients. To delineate the pathogenesis of the reduction in hemoglobin occurring in renal transplant patients treated with angiotensin converting enzyme inhibitors (ACEI) and azathioprine (AZA) a controlled, prospective trial of ACEI withdrawal was conducted. The ACEI was replaced by nifedipine or clonidine in 15 kidney transplant patients immunosuppressed with AZA and prednisone (enalapril in 14 and captopril in 1). Before and during 10 to 12 weeks after withdrawal of the ACEI, AZA metabolites, renal function parameters and hematological parameters including erythropoietin and reticulocytes were evaluated. Enalaprilat levels were measured and compared with 15 similar patients matched for transplant function and enalapril dosage immunosuppressed with cyclosporine and prednisone. AZA metabolites did not differ significantly in the presence or absence of the ACEI. Enalaprilat levels also showed no significant difference between the two patient groups treated with AZA or cyclosporine. Hematocrit and hemoglobin increased significantly from 37.5 ± 6.4 to 39.7 ± 3.6% (mean ± SD, P = 0.02) and 12.8 ± 2.2 to 13.5 ± 1.2 g/dl, P = 0.04, respectively, 10 to 12 weeks after ACEI treatment had been discontinued. Simultaneously numbers of reticulocytes and erythropoietin concentrations rose significantly after 2, 4 and 10 weeks, with a peak at two weeks (from 14.1 ± 3.8 to 20.6 ± 8.0%, P < 0.05 and from 14.3 ± 12.4 to 29.3 ± 54.5 mU/ml, P < 0.05, respectively). In conclusion, ACEI-related anemia in renal transplant recipients seems to be due to the erythropoietin-lowering effect of this group of drugs. A pharmacokinetic interaction between AZA and enalapril is not likely since plasma enalaprilat levels were independent of the immunosuppressive regimen and AZA metabolite levels were unchanged in the presence and absence of the ACEI. Several mechanisms by which angiotensin converting enzyme blockade may cause a decrease in circulating erythropoietin are discussed

Improving anemia by hemodialysis: Effect on serum erythropoietin

Improving anemia by hemodialysis: Effect on serum erythropoietin. Serum erythropoietin (SEP) concentration was measured on two occasions in 42 patients with terminal renal failure (1) immediately before the first hemodialysis, and (2) 3 to 27 months following the onset of regular hemodialysis treatment. Although the hematocrit (Hct) showed an increase in every patient, the SEP concentration decreased in every patient. The mean Hct rose from 21.7 to 28.6% (volume per volume) (P < 0.001), and the SEP dropped from 509 to 182 mU/ml (P < 0.001). This shows that anemia improvement is not a consequence of increased erythropoietin production but that it is most likely due to elimination of an inhibitor of the bone marrow by hemodialysis treatment. The decrease of SEP concentration has to be interpreted as a response to the improved tissue oxygenation that correlates with the higher hematocrit or as a consequence of further reduction of renal mass with progress of the renal disease.L'amélioration de l' anémie de l'insuffisance rénale: Effet sur Pérythropoïétine sérique. La concentration d'érythropoïétine sérique (SEP) a été mesurée chez 42 malades atteints d'insuffisance rénale terminale, à deux reprises: (1) immédiatement avant la première hémodialyse et (2) 3 à 27 mois après le début de l'hémodialyse intérative. Alors que l'hématocrite (Hct) augmentait chez tous les malades, SEP diminuait. L'hématocrite moyen est passé de 21,7 à 28,6% (P < 0,001), SEP moyen a baissé de 509 à 182 mU/ml (P < 0,001). Cela montre que l'amélioration de l'anémie n'est pas la conséquence d'une augmentation de la production d'érythropoïétine, mais plus probablement liée à l'élimination par l'hémodialyse d'un inhibiteur de la moelle osseuse. La diminution de SEP doit être interprétée comme la réponse à une meilleure oxygénation tissulaire du fait de l'augmentation de l'hématocrite ou la conséquence d'une diminution de la masse rénale liée à l'évolution de l'affection