Biomedical subjects

Robert M Langer

Publications and source records attributed to Robert M Langer.

4 recordsLinked to original sources

PubMed2005

Methoxyethyl-modified intercellular adhesion molecule-1 antisense phosphorothiateoligonucleotides inhibit allograft rejection, ischemic-reperfusion injury, and cyclosporine-induced nephrotoxicity.

BACKGROUND: The addition of phosphorothioate (PS) groups to natural phosphodiester (PD) antisense oligodeoxynucleotides (oligo) prevents their in vivo hydrolysis by nucleases allowing an RNase-dependent elimination of targeted mRNA. To further improve oligo function 2'-methoxyethyl (ME) groups were attached to selected nucleotides at the 3'-end because ME groups block RNase activity. METHODS/RESULTS: ME modification of PS- or PD/PS-oligo targeting human intracellular adhesion molecule (ICAM)-1 mRNA significantly increased the degree and duration of the in vitro inhibitory effects without compromising selectivity and specificity. A 7-day intravenous or oral therapy with rat ME/PS-modified ICAM-1 antisense oligo extended the survivals of kidney allografts. In addition, ME/PS-modified ICAM-1 antisense oligo reduced ischemic-reperfusion injury in kidneys, as measured by glomerular filtration rate, creatinine levels, and infiltration with leukocytes. Finally, a 14-day treatment with cyclosporine (CsA)-induced nephrotoxicity in syngeneic kidney transplants correlated with both increased ICAM-1 protein expression and infiltration with leukocytes. Graft perfusion and treatment of recipients with ICAM-1 antisense ME/PS-oligo alleviated the nephrotoxic effect and decreased ICAM-1 expression and leukocyte infiltration. CONCLUSIONS: ME/PS-modified ICAM-1 antisense oligo is very effective in inhibiting the ICAM-1-dependent mechanism of graft infiltration and tissue damage involved in allograft rejection, ischemic-reperfusion injury, and CsA-induced nephrotoxicity.

Animals↗

PubMed2003

Sirolimus does not increase the risk for postoperative thromboembolic events among renal transplant recipients.

BACKGROUND: Deep venous thrombosis (DVT) tends to occur in greater frequency among cyclosporine (CsA)-treated renal-transplant recipients. Because administration of sirolimus may increase the whole-blood concentrations of CsA, we sought to assess the impact of the combination regimen on the incidence, predisposing factors, and consequences of postoperative DVT, transplant renal-vein or artery thrombosis, and pulmonary embolus. METHODS: We retrospectively evaluated two cohorts of renal transplant recipients: CsA/prednisone (Pred)+/-azathioprine (n=136, group A) or sirolimus+CsA+Pred (n=354, group B) using Fisher's exact t and chi-square tests, as well as Kaplan-Meier analyses, odds ratios, and multiple logistic regression methods. RESULTS: The 7 of 136 (5.1%) incidence of thrombotic events in group A was similar to the 20 of 354 (5.6%) incidence in group B (P=0.513; NS) and occurred no more frequently ipsilateral to the transplant. Although the occurrence of an acute-rejection episode was not associated with the DVT diagnosis, all affected patients displayed elevated serum creatinine (Scr) values, which remained slightly higher than baseline following recovery (group A 1.63+/-1.22-1.95+/-0.93 mg/dL; group B 1.70+/-1.11-2.01+/-0.88 mg/dL). Renal biopsies failed to show evidence of intrarenal coagulopathy. No patient lost a graft as a complication of DVT, nor did these events produce other lasting adverse effects. Patients in the sirolimus group showed a strong correlation between the occurrence of DVT and the previous existence of an ipsilateral or contralateral lymphocele. CONCLUSION: Addition of sirolimus to a CsA+Pred regimen does not increase the incidence of postoperative thrombotic events among renal transplant recipients.

Adult↗

PubMed2002

Incidence, therapy, and consequences of lymphocele after sirolimus-cyclosporine-prednisone immunosuppression in renal transplant recipients.

BACKGROUND: In a retrospective study we sought to dissect the factors associated with an increased occurrence of clinically significant perinephric fluid collections and lymphoceles among sirolimus-treated renal transplant recipients. METHODS: We compared the incidence, predisposing factors, and consequences of these fluid collections among patients treated with sirolimus-cyclosporine (CsA)-prednisone (Pred) (n=354, group I) versus CsA-Pred with or without azathioprine (n=136, group II). RESULTS: More group I patients (135/354; 38.1%) displayed perinephric fluid collections (denoted as group III) then group II patients (24/136; 17.6%) (denoted as group IV) (P <0.001). In both subgroups the serum creatinine levels were elevated at the time of diagnosis from a nadir of 2.04+/-1.61 to 4.09+/-2.95 mg/dL (group III) and from 2.53+/-2.34 to 4.36+/-2.90 mg/dL (group IV). A significantly greater number of patients required treatment for lymphoceles among group I (56/354; 15.8%) versus group II recipients (6/136; 4.4%; P<0.001). Single or repeated percutaneous drainage procedures successfully treated 35 group I patients versus all 6 group IV patients (P =0.033). No patients in group II versus 21 patients in group I underwent surgical procedures (P <0.001). A significantly higher rate and higher histologic grade of acute rejection episodes, particularly proximate to the onset of the lymphocele, occurred among group IV patients, namely 54.2% (13/24) versus 21.4% (29/135) group III patients (P <0.001). CONCLUSIONS: Addition of sirolimus to a CsA-Pred regimen resulted in both a higher incidence and a requirement for more aggressive treatment of perinephric fluid collections and lymphoceles.

Adult↗

PubMed2002

De novo hemolytic uremic syndrome after kidney transplantation in patients treated with cyclosporine-sirolimus combination.

OBJECTIVE: We sought to examine factors that predisposed 1.5% (10/672) of renal transplant recipients treated with a cyclosporine (CsA)/sirolimus (SRL)/steroid immunosuppressive regimen to develop hemolytic uremic syndrome (HUS). METHODS: Two cohorts of recipients were treated for 1-212 months (mean: 25.0+/-26.4, median: 18.1) with concentration-control CsA regimens based upon either area under the concentration-time curve (AUC; n=412 patients) or trough measurements (C0; n=260 patients). RESULTS: The only demographic feature more common to affected patients was an original glomerulopathic disease in 7 patients, 4 of whom had displayed IgA glomerulonephritis. All 10 affected patients showed a clinical picture of hemolysis with schistocytes, thrombocytopenia (nadir: 35,000+/-19,600 platelets/mm3), as well as elevated serum levels of lactate dehydrogenase (1697+/-1427 IU) and creatinine (Scr; 2.05+/-1.52 mg/dL prediagnosis to 5.13+/-2.43 mg/dL at diagnosis). Seven patients experienced adverse events concomitant with the bout of HUS, namely, acute rejection episodes prior to (n=2) or during (n=3), and 2 patients, infections (Herpes simplex and pancolitis). The mean values of daily steroid dose and the immunosuppressive drug C0 values were above the putative therapeutic targets: namely, CsA C0=294.9+/-153.2 ng/ml versus 150+/-50 ng/ml and SRL C0=20.1+/-14.0 ng/ml versus 10+/-5 ng/ml, respectively. The therapeutic approach included discontinuation of CsA in 9/10, which was transient in 6/9; discontinuation of SRL in all 10, which was transient in 3, OKT3 for concurrent rejection in 3, and plasmapheresis in 5 patients. At 24 weeks postdiagnosis 9/10 patients have well-functioning kidneys with a mean Scr value of 1.6+/-0.59 mg/dL. One patient who underwent transplant nephrectomy subsequently succumbed due to a cluster of refractory thrombocytopenia, Aspergillus infection, and multiorgan failure. CONCLUSION: This initial experience suggests that a time-limited and reversible de novo HUS syndrome may be less frequent and milder among renal transplant recipients treated with SRL-based immunosuppression.

Adult↗