Non-invasive monitoring of kidney allograft rejection through IDO metabolism evaluation.

The immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) is activated by interferon-gamma (IFN-gamma) and via tryptophan depletion, suppresses adaptive T cell-mediated immunity in inflammation, host immune defense, and maternal tolerance. Its role in solid organ transplantation is still unclear. Therefore, we investigated the usefulness of IDO-mediated tryptophan catabolism in the evaluation of kidney allograft rejection. Blood, urine, and tissue samples were collected from 34 renal transplant patients without rejection and from nine patients with biopsy-confirmed episodes of acute rejection (n=12). Concentrations of kynurenine and tryptophan in serum and urine were analyzed by high-pressure liquid chromatography. Kynurenine to tryptophan ratio (kyn/trp) was calculated to estimate IDO activity. Immunostaining for IDO was performed on renal biopsies. Neopterin was assessed using radioimmunoassay. Kyn/trp and neopterin were detectable at low levels in serum of healthy volunteers and were increased in non-rejecting allograft recipients. Serum levels of kyn/trp were higher in recipients with rejection compared to non-rejectors as early as by day 1 post-surgery. Rejection episodes occurring within 13+/-5.9 days after transplantation were accompanied by elevated kyn/trp in serum (114+/-44.5 micromol/mmol, P=0.001) and urine (126+/-65.9 micromol/mmol, P=0.02) compared to levels during stable graft function. Kyn/trp correlated significantly with neopterin suggesting an IFN-gamma-induced increase in IDO activity. Immunostaining showed upregulation of IDO in rejection biopsies, localized in tubular-epithelial cells. Non-rejected grafts displayed no IDO expression. Acute rejection is associated with simultaneously increased serum and urinary kyn/trp in patients after kidney transplantation. Thus, IDO activity might offer a novel non-invasive means of immunomonitoring of renal allografts.

Excellent results with calcineurin inhibitor-free initial immunosuppression in old recipients of old kidneys.

The ever increasing demand for donor organs has forced transplant surgeons to liberalize selection criteria. To avoid initial nephrotoxicity to kidneys from donors over 65 years of age, immunosuppression was begun with an IL-2 receptor antibody, mycophenolate mofetil, and steroids in a total of 38 recipients over 65 years. Calcineurin inhibitors (CI) were added after sufficient graft function was reached. After a mean cold ischemia time of 14:01 hours and a delayed function rate of 31%, patient survival, graft survival, and serum creatinine were 97.4%, 94.7%, and 1.5 mg/dL at 1 and 92.1%, 92.1%, and 1.7 mg/dL at 2 years, respectively. Thus, excellent results can be achieved in old recipients of old donor kidneys with CI-free initial immunosuppression.