Pediatric Transplantation in the United States, 1996–2005

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73448/1/j.1600-6143.2007.01780.x.pd

Cyclosporine absorption profiles in pediatric kidney and liver transplant patients

Cyclosporine absorption profiling uses either the area under the concentration curve in the first 4 h post dose, AUC(0–4), or the concentration 2 h post dose (C2) to optimize immunosuppression in adult kidney and liver transplantation. We characterized C2 versus AUC(0–4) relationships over time after transplant and across transplant indications in 56 pediatric transplant patients. There were 36 kidney transplant patients aged 9.7±3.9 years. Nineteen of these patients were studied in the de novo period on day 7 post transplant and 17 in the maintenance phase more than 1 year post transplant. In addition, 20 liver transplant patients aged 8.9±4.2 years were studied in the maintenance phase. All patients had five blood samples collected over the 12-h dose interval that were analyzed by validated assay methods at a central laboratory. Pediatric C2 values were 1,463±658 ng/ml for de novo kidney, 954±322 ng/ml for maintenance kidney, and 619±339 ng/ml for maintenance liver transplant patients. C2 was a strong predictor of AUC(0–4) in all three pediatric groups, with coefficients of determination ( r 2 ) ranging from 0.861 to 0.936. Although data were limited from the de novo period, the C2 versus AUC(0–4) regression was consistent over time after transplant and between transplant indications, with a regression slope of 2.50 in de novo kidney, 2.54 in maintenance kidney, and 2.76 in maintenance liver transplant recipients. These slopes were also comparable to that in adult maintenance kidney transplant patients (2.60). In conclusion, C2 versus AUC(0–4) relationships demonstrated consistency over time (de novo vs. maintenance phase), between transplant indications (kidney vs. liver), and across age groups (pediatric vs. adult patients). Average C2 values achieved with current pediatric cyclosporine dosing practices cluster around the target C2 ranges recommended for adults.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47821/1/467_2003_Article_1260.pd

Species-Specific Structural Requirements of Alpha-Branched Trehalose Diester Mincle Agonists

Despite the ever present need for an effective Mycobacterium tuberculosis (Mtb) vaccine, efforts for development have been largely unsuccessful. Correlates of immune protection against Mtb are not wholly defined, but Th1 and likely Th17 adaptive immune responses have been demonstrated to be necessary for vaccine-mediated protection. Unfortunately, no approved adjuvants are able to drive a Th17 response, though recent clinical trials with CAF01 have demonstrated proof of concept. Herein we present the discovery and characterization of a new class of potential Th17-inducing vaccine adjuvants, alpha-branched trehalose diester molecules (αTDE). Based off the Mtb immunostimulatory component trehalose dimycolate (TDM), we synthesized and evaluated the immunostimulatory capacity of a library of structural derivatives. We evaluated the structure activity relationship of the compounds in relation to chain length and engagement of the Mincle receptor, production of innate cytokines from human and murine cells, and a pro-Th17 cytokine profile from primary human peripheral blood mononuclear cells. Murine cells displayed more structural tolerance, engaging and responding to a wide array of compound chain lengths. Interestingly, human cells displayed a unique specificity for ester chains between 5 and 14 carbons for maximal immune stimulating activity. Evaluation of two distinct αTDEs, B16 and B42, in concert with a recombinant Mtb antigen demonstrated their ability to augment a Th17 immune response against a Mtb antigen in vivo. Collectively this data describes the species-specific structural requirements for maximal human activity of alpha-branched trehalose diester compounds and demonstrates their capacity to serve as potent Th17-inducing adjuvants

Trabecular bone volume and osteoprotegerin expression in uremic rats given high calcium

Calcium (Ca)-containing phosphate binders have been recommended for the treatment of hyperphosphatemia in children with chronic kidney disease. To study the effects of high Ca levels on trabecular bone volume (BV) and osteoprotegerin (OPG) expression in uremic young rats, a model of marked overcorrection of secondary hyperparathyroidism was created by providing a diet of high Ca to 5/6 nephrectomized young rats (Nx-Ca) for 4 weeks. The results of chondrocyte proliferation and apoptosis, osteoclastic activity, OPG expression and BV were compared among intact rats given the control diet, intact rats given a high Ca diet and 5/6 nephrectomized rats given the control diet (Nx-Control) and the high Ca diet (Nx-Ca). Ionized Ca levels were higher and parathyroid hormone levels were lower in Nx-Ca rats than in the other groups. Final weight, final length and final tibial length of Nx-Ca rats were significantly less than those of the other groups, although the length gain did not differ among the groups. The hypertrophic zone width was markedly enlarged in Nx-Ca rats. Chondrocyte proliferation rates did not differ among the groups, whereas osteoclastic activity was decreased in Nx-Ca rats compared with the Nx-Control animals. The OPG expression and BV were increased in Nx-Ca rats compared with the Nx-Control rats. Increased BV should improve bone strength, whereas disturbance of osteoclastogenesis interferes with bone remodeling. Bone quality has yet to be determined in high Ca-fed uremic young rats

The use of mycophenolate mofetil suspension in pediatric renal allograft recipients

Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m 2 b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m 2 b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC 0–12 ) of 27.2 µg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m 2 b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42304/1/467-16-12-978_10160978.pd

De novo lupus-like glomerulonephritis after pediatric non-kidney organ transplantation.

BACKGROUND: We propose a novel clinically significant finding, de novo lupus-like glomerulonephritis (DNLLGN), in patients with autoantibodies and kidney abnormalities in pediatric liver transplant (LT) and intestinal inclusive transplants (ITx). METHODS: We describe the clinical, serologic, and histopathologic presentation and kidney outcomes in eight patients from our center found to have DNLLGN on kidney biopsy. RESULTS: Pediatric recipients of non-kidney solid organ transplants developed an unusual de novo immune complex glomerulonephritis with morphologic similarity to lupus nephritis. Six had isolated LT (0.9% of all pediatric LT at our center) and two had ITx (2.1% of all ITx). Five (63%) presented with nephrotic syndrome. Five patients had autoantibodies. Patients underwent kidney biopsy at a mean of 11.5 years in LT and 2.8 years in ITx after the index transplant. Biopsies demonstrated changes similar to focal or diffuse active lupus. Follow-up eGFR at a mean of 6 years after biopsy showed a mean decrease of 30 ml/min/1.73 m2 in all patients (p = 0.11). CONCLUSIONS: DNLLGN has not been previously recognized in this clinical setting, yet 8 kidney biopsies from pediatric recipients of LT and ITx at our center in 25 years demonstrated this finding. DNLLGN appears to be an under-reported phenomenon of clinical significance. A higher resolution version of the Graphical abstract is available as Supplementary information