Recurrence of granulomatous interstitial nephritis in transplanted kidney.

Sarcoidosis is a multisystemic disease of unknown etiology. Minor renal involvement is not rare but kidney failure is uncommon and only rare cases of recurrent disease in a kidney transplant have been published. We report a patient who at age 10 yr developed ESRD secondary to renal sarcoidosis with GIN. Her disease subsequently recurred in the transplanted kidney despite standard immunosuppression with prednisone, tacrolimus, and mycophenolate mofetil. The recurrent disease appeared to respond to increased immunosuppression, which included infliximab. However, the patient died of disseminated histoplasmosis three yr post-transplant.

Effect of age, ethnicity, and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients.

Tacrolimus has become an effective alternative to cyclosporine as a component of primary immunosuppression in pediatric renal transplant patients, but the information on the pharmacokinetic characteristics of tacrolimus in young patients is still limited. The primary objective of this study was to determine the effect of patient age, ethnicity, and concurrent steroid administration on tacrolimus pharmacokinetics in pediatric renal transplant patients. The study population consisted of 30 pediatric patients, age 1.5-18.6 yr, who received a kidney transplant between July 1999 and February 2004. After twice daily dosing was stabilized based on clinical judgment, at least 5 days postoperatively, tacrolimus levels were drawn prior to, and 1, 2, 4, 8, and 12 h after the morning dose. The mean dose of tacrolimus was 0.12 mg/kg/dose. Mean trough level was 11.9 +/- 5.0 ng/mL. Mean area under the curve (AUC) was 192 +/- 84 with a range of 78-360 h x (ng/mL). The correlation between trough level and AUC was only fair (r = 0.74); later time points correlated better with AUC, and an excellent correlation (r = 0.96) was obtained between the mean of trough and 2-h level (C(2)) and AUC. There was a negative correlation between age and dose per body weight (r = -0.68). African-American patients had marginally lower drug exposure with similar dosing. Three age groups (<5, 5-12, and >12 yr) were compared with respect to dosing and AUC. Despite similar AUC in all three groups, the mean dose per kg required to achieve the AUC was 2.7- and 1.9-fold higher in the <5 and 5-12-yr groups, respectively, compared with the >12-yr group. Nine of the 30 patients were on a totally steroid-free regimen. Their tacrolimus dose and trough levels were similar to those of steroid-exposed patients, but their mean AUC was 41% higher. Our results show an inverse correlation between age and required tacrolimus dose, wide interindividual variation, and greater exposure with steroid-free regimen despite no change in trough level.

Decreased expression of T-cell NF-kappaB p65 subunit in steroid-resistant nephrotic syndrome.

BACKGROUND: Although the etiology of childhood nephrotic syndrome is unclear, there is evidence to suggest an important role for T cells in the pathogenesis. Steroid resistance is considered a poor prognostic sign but the mechanism of the resistance is unknown. The study examined the potential role of T-cell nuclear transcription factors in the steroid resistance. METHODS: The expression of the nuclear transcription factors activating protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) as well as that of lymphokines interleukin (IL)-2, IL-4, and interferon-gamma (IFN-gamma) were compared in T cells obtained from normal subjects, children with steroid-sensitive nephrotic syndrome (SSNS) and children with steroid-resistant nephrotic syndrome (SRNS) before any treatment was given. Changes in expression and binding of the nuclear transcription factors were studied with electrophoretic mobility shift assay (EMSA) and Western blot, whereas mRNA cytokine expression were evaluated by enzyme-linked immunosorbent assay (ELISA)-linked reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: A significant decrease of the p65 subunit protein of NF-kappaB but not in p50 was documented by both EMSA (N= 7) and Western blotting (N= 5) in five of five SRNS patients but not in control subjects or SSNS patients; there was a decrease in mRNA expression as shown by ELISA-linked RT-PCR. In contrast, there were no significant differences in AP-1 expression by EMSA. IL-2 mRNA level was higher in T cells from SRNS patients than in T cells from either SSNS or control subjects. IL-4 and IFN-gamma were equally decreased in both groups of patients. CONCLUSION: The results show differences in T cells between untreated SSNS and SRNS patients. The decrease of NF-kappaB p65 subunit and up-regulation of IL-2 are potential mechanism of glucocorticoid resistance in SRNS.