Pharmacokinetic Profile of Twice- and Once-daily Tacrolimus in Pediatric Kidney Transplant Recipients.

BACKGROUND: The aim of this study was to assess the differences in pharmacokinetic (PK) profiles after the 1:1 ratio-based conversion from a twice-daily to a once-daily tacrolimus formulation (TD-TAC and OD-TAC, respectively) in pediatric recipients of kidney transplants. METHODS: TD-TAC was initially administered to 29 pediatric patients who underwent kidney transplantations between April 2010 and September 2015 and were then subsequently switched to OD-TAC. The switch dose ratio was 1:1, and the 24-hour complete PK parameter assessment was performed before and after the regimen was changed from TD-TAC to OD-TAC. RESULTS: The mean total daily dose at baseline was 5.5 ± 2.9 mg (0.18 ± 0.10 mg/kg body weight). Consecutive PK studies revealed no significant difference in the mean time to achieve maximum concentrations and the area under the concentration-time curve from 0 to 24 hours (AUC0-24) of both drug formulations. However, the mean trough concentration (Cmin) and the maximum concentration of OD-TAC were 22% and 6% lower and higher, respectively, than those of TD-TAC. Therefore, a better correlation was observed between the AUC0-24 and Cmin of OD-TAC than between those of TD-TAC. CONCLUSIONS: After the change from TD-TAC to OD-TAC, the AUC0-24 values were equivalent despite a 22% reduction in Cmin. Cmin may therefore be an excellent predictor in the therapeutic drug monitoring of OD-TAC because of its superior correlation with AUC0-24.

Association Between the Fertile Period and Live Birth Post-Kidney Transplantation: A Retrospective Single-Center Cohort Study.

BACKGROUND: Despite restoration of fertility after kidney transplantation, the benefit is limited in female kidney recipients. Our objective is to determine the reasons for this discrepancy. METHODS: We evaluated 315 women who underwent kidney transplantation from 1983 to 2015 (a median of age at transplantation [10th-90th percentile] of 32 years [7-55 years]); 230 recipients between the ages of 15 to 49 years old as of March 2016 were observed. RESULTS: We experienced 10 abortions and 21 live births from our 23 recipients and 2 abortions and 7 live births in 7 recipients from other transplant center. The live birth rate was 8.9 per 1000 female transplant recipients of childbearing age. Seven recipients received either treatments of artificial insemination or in vitro fertilization. Average age at pregnancy was 33.2 ± 3.2 years old, and the fertile period post-transplantation was longer in recipients with live births than those without live births (14.1 ± 7.1 vs 9.9 ± 7.3 years, P < .05). In 42.9% of recipients with live birth, pregnancy-induced hypertension was observed in the last trimester. The gestational age and the average birth weight were 32.8 ± 5.0 months and 2184 ± 632 g, respectively. During follow-up of 14.5 years, there was one case of graft loss, which is a rate of 2.5 per 1000 female recipients. CONCLUSION: Although pregnancy complications are often observed in kidney recipients, graft survival is less influenced by pregnancy. Importantly, kidney disease at childbearing age disrupts pregnancy even after kidney transplantation.

Molecular epidemiologic analysis of a Pneumocystis pneumonia outbreak among renal transplant patients.

Between 18 November and 3 December 2011, five renal transplant patients at the Department of Nephrology, Toho University Omori Medical Centre, Tokyo, were diagnosed with Pneumocystis pneumonia (PCP). We used molecular epidemiologic methods to determine whether the patients were infected with the same strain of Pneumocystis jirovecii. DNA extracted from the residual bronchoalveolar lavage fluid from the five outbreak cases and from another 20 cases of PCP between 2007 and 2014 were used for multilocus sequence typing to compare the genetic similarity of the P. jirovecii. DNA base sequencing by the Sanger method showed some regions where two bases overlapped and could not be defined. A next-generation sequencer was used to analyse the types and ratios of these overlapping bases. DNA base sequences of P. jirovecii in the bronchoalveolar lavage fluid from four of the five PCP patients in the 2011 outbreak and from another two renal transplant patients who developed PCP in 2013 were highly homologous. The Sanger method revealed 14 genomic regions where two differing DNA bases overlapped and could not be identified. Analyses of the overlapping bases by a next-generation sequencer revealed that the differing types of base were present in almost identical ratios. There is a strong possibility that the PCP outbreak at the Toho University Omori Medical Centre was caused by the same strain of P. jirovecii. Two different types of base present in some regions may be due to P. jirovecii's being a diploid species.

Angiocentric immunoproliferative lesion associated with chronic active Epstein-Barr virus infection in an 11-year-old boy. Clonotopic proliferation of Epstein-Barr virus-bearing CD4+ T lymphocytes.

We report a pulmonary angiocentric immunoproliferative lesion (AIL) in an 11-year-old boy with chronic active Epstein-Barr virus (EBV) infection. The phenotypes of the proliferating lymphoid cells in the biopsied pulmonary lesion were CD2+, CD3+, CD4+, CD5+, CD7+, and HLA-DR+. EBV DNA was detected in the tumorous and the nontumorous tissue by Southern-blotting studies. Dual immunostains and combined immunohistochemistry/in situ hybridization showed the simultaneous presence of EBV-determined nuclear antigen or EBV-encoded small RNAs and T-cell markers in the lymphoid cells. Molecular genetic analysis of the tumorous lesion diagnosed as AIL grade III showed no clonal rearrangement of the T-cell receptor beta gene but a single type of fused terminal band of EBV. No such evidence of monoclonality was identified in the surrounding nontumorous tissue diagnosed as AIL grade I or II. The present case was a rare example of AIL in childhood and provides further histopathologic and molecular biological evidence supporting the concept of AIL as a continuous spectrum from premalignant lymphoproliferative disorders to monoclonal, overt malignant lymphoma.

[Home parenteral nutrition for patients with gastrointestinal malignancy--consideration of adequate timing for the introduction, with emphasis on the mental aspects of patients and family members].

Home parenteral nutrition (HPN) is a useful method for the management of patients with gastrointestinal malignancy in that it enables them to resume their life at home even when they have become incapable of oral food ingestion. The appropriate time to start HPN may vary according to the background of the patients. Through an audit of 15 patients in whom HPN was initiated at Ward 7 West, and an analysis of a few representative cases, an assessment was made regarding the appropriate timing for the initiation of HPN. Whether the patients feel capable of leading a new and modified life at home depends on how well they have accepted the concept of HPN. After explaining to the patients their physical condition and the reason HPN is needed, medical professionals must evaluate how well patients have mentally and technically adapted themselves to the requirements of the HPN. It is also mandatory to assess whether the familial and medical environments around the patient are sufficient to provide whatever assistance is needed. The decision regarding the initiation of HPN should be based on these assessments. It is also important to evaluate the extent of the contribution that can be expected from the family members and to minimize the burden on the patient.

Outcomes of pediatric ABO-incompatible kidney transplantations are equivalent to ABO-compatible controls.

BACKGROUND: Due to the profound shortage of suitable deceased allografts, much effort has been made to investigate whether successful kidney transplantation (KT) is possible across the ABO blood group barrier even for pediatric recipients. METHODS: We reviewed 52 consecutive ABO incompatible (ABOic) transplantation performed between September 1989 and March 2011. The mean age at transplantation was 10.6 ± 3.9 years (range, 4.4-19.7), with 35 boys and 17 girls. The donor-to-recipient ABO blood antigen incompatibility was as follows: A1/O (n = 17); B/O (n = 13); A1/B (n = 6); B/A1 (n = 1); A1B/B (n = 9); and A1B/A (n = 6). As a control group, data were collected from 271 pediatric ABO compatible (ABOc) living donor KT in the same period. RESULTS: Overall acute rejection episodes (ARE) among the ABOic group were significantly higher than those of the ABOc group (44% vs 26%; P < .02). However, there was no difference in glomerular filtration rate (GFR) at 1 year after transplantation: 86 ± 31 mL/min for ABOic vs 99 ± 37 mL/min for ABOic, respectively. The 1-y, 5-y, and 10-year patient survival rates were 98%, 92%, and 92% in the ABOic group, respectively, and 99%, 98%, and 97% in the ABOc group, respectively (P = not significant [NS]). The overall 1-, 5-, 10-, and 15-year graft survival rates were 94%, 88%, 86%, and 86% in the ABOic group, respectively, and 95%, 92%, 88%, and 78% in the ABOc group, respectively. CONCLUSION: ABOic KT provided long-term allograft and patient survivals equivalent to ABOc live donor transplantations.

C3 activator in agammaglobulinemia.

C3 activator in sera of patients with agammaglobulinemia shows higher levels compared with age-matched healthy controls. This fact may be due to a compensatory function of the alternative pathway of the complement system to make up for the defect of production of antibody in these patients.

[A case of hypogammaglobulinemia associated with polyarteritis nodosa presenting a variety of symptoms in childhood].

A case of polyarteritis nodosa (PN) in childhood involving various organs such as the gastrointestinal tract, skin, CNS, kidneys and liver with hypogammaglobulinemia is reported. This 6 month old girl was admitted to our hospital with vomiting, diarrhea, bloody stools with mucous and weight loss. For the past 5 months she had these abdominal symptoms. She was diagnosed as having PN of the Kussmaul-Maier variety on the grounds of the biopsy of skin lesion where a necrotizing vasculitis was found. Prednisolone and methylprednisolone pulse treatment were not effective in suppressing the progress of the disease. At the age of 1 year 7 month a combination therapy of prednisolone and immunosuppressants (cyclophosphamide) was started and this was found to be effective. She was discharged when she was 2 year and 2 month. The dosage of prednisolone was tapered as the activity of the PN decreased and she did well with a maintainance dosage of 9.5 mg/day. At 3 year 6 month of age she suddenly developed hypertension (the plasma renin activity was found to be 16.6 ng/m/hr. and the aldosterone 220 ng/dl). CNS involvement such as spinal cord dysfunction, left sided convulsions, cerebral hemorrhage developed 5 months later. Methylprednisolone pulse therapy was performed 3 times and 2 mg/kg/day of prednisolone was administered. In spite of this therapy she passed away with a massive cerebral hemorrhage at the age of 4 year 8 month. Unfortunately an autopsy was not performed. Results of the immunological tests proved that the hypogammaglobulinemia was a common variable immunodeficiency (CVI). It has been reported that primary immuno-deficiency syndrome is often associated with collagen disease and auto-immune disease. This lack of the defense mechanism against the virus or extra antigen could be related to the onset of collagen and auto-immune disease. As the correlation between CVI and PN has not been clarified this case is of interest as concerns the cause of PN.

Kawasaki disease complicated with mitral insufficiency. Autopsy findings with special reference to valvular lesion.

A case of mucocutaneous lymph node syndrome (Kawasaki disease, MCLS) complicated with mitral insufficiency is reported. This patient showed severe valvulitis, which was thought to be the main cause of mitral regurgitation. Two other patients with MCLS who did not present clinical signs of mitral insufficiency revealed the presence of mild valvulitis. The morphological alterations of cardiac valves were non-specific and mainly consisted of inflammatory infiltration, increment of fibrous connective tissue, and proliferation of small capillaries. In addition to the coronary aneurysms, the involvement of cardiac valves should receive attention as the sequelae of MCLS.

Clinical evaluation of a teleradiology system utilizing personal computers and public telephone line.

Practical usefulness of a teleradiology system using CCD camera, personal computer and telephone line was evaluated in a daily clinical practice. Image quality of this system is diagnostic for the majority of abnormalities on radiological images including plain radiographs. Radiological consultation between hospitals in the same city as well as between distant cities using this moderately priced system was thought to be useful in 90% of cases. Teleradiology using compact systems like ours is expected to be useful in the urban clinical environment as well as in distant areas.

Homozygous C3 deficiency associated with IgA nephropathy.

A 23-year-old male patient with homozygous C3 deficiency who developed asymptomatic proteinuria and hematuria was reported. Renal biopsy disclosed typical IgA nephropathy with deposition of early- and late-complement components except for C3 deposition. C9 and membrane attack complex were detected in the glomeruli despite the absence of C3. It was suggested that there might be some unknown complement activation mechanism which does not require C3 component.

IL-18 accounts for both TNF-alpha- and Fas ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury in mice.

When LPS is administered to heat-killed Propionibacterium acnes-primed BALB/c nude mice, they develop endotoxin-induced liver injury. As previously reported, this liver injury can be prevented by treatment with an Ab against IL-18, a novel cytokine with the ability to induce IFN-gamma production and up-regulate functional Fas ligand (FasL) expression. To identify the pathologic role of IL-18 in this liver injury, we investigated the hepatic cytokine network and FasL induction after LPS challenge. After LPS challenge to BALB/c nude mice, their livers expressed IL-12 mRNA, followed by the induction of IFN-gamma and FasL mRNA and then by the late elevation of TNF-alpha mRNA, but stably expressed IL-18 mRNA. The TNF-alpha induction curve had two peaks. The first peak was the result of the direct reaction to LPS, and the late peak might have been induced, since P. acnes-elicited Kupffer cells showed one-peak TNF-alpha kinetics in response to LPS stimulation in vitro. LPS-activated P. acnes-elicited Kupffer cells secreted both IL-12 and IL-18, as determined by ELISA and bioassay, respectively. The in vivo administration of anti-IL-18 just before an LPS challenge suppressed not only the induction of IFN-gamma and the late TNF-alpha elevation, but also the FasL induction, resulting in the total prevention of liver injury, whereas such an anti-IL-12 treatment did not. Anti-IFN-gamma treatment reduced the late increase in TNF-alpha, but not FasL, resulting in a partial prevention of the liver injury. The administration of anti-TNF-alpha just before elevation of the late TNF-alpha peak also markedly, but incompletely, suppressed the LPS-induced liver injury. These data suggested that IL-18 activates both TNF-alpha- and FasL-mediated hepatocytotoxic pathways in endotoxin-induced liver injury.

Propionibacterium acnes treatment diminishes CD4+ NK1.1+ T cells but induces type I T cells in the liver by induction of IL-12 and IL-18 production from Kupffer cells.

LPS injection into normal mice does not induce liver injury, while the same treatment of Propionibacterium acnes-primed mice induces severe liver injury, indicating that P. acnes treatment renders the mice susceptible to LPS. Since IFN-gamma sensitizes macrophages to LPS, we investigated the mechanism of induction and activation of IFN-gamma-producing (type 1) T cells by P. acnes. Twenty percent of liver lymphocytes of C57BL/6 mice are CD4+ NK1.1+ T cells that promptly produce IL-4 in response to anti-CD3 in vitro. However, P. acnes treatment diminished these lymphocytes. Therefore, liver lymphocytes from P. acnes-primed mice showed reduced IL-4 production. Furthermore, P. acnes treatment induced CD4- type 1 T cells in the liver. Isolated P. acnes-elicited Kupffer cells produced IL-12 and to a lesser degree IL-18 in vitro. Injection of anti-IL-12 Ab totally abrogated these actions of P. acnes, while injection of anti-IL-18 Ab caused only partial abrogation. Thus, administration of P. acnes diminished CD4+ NK1.1+ T cells, but induced type 1 T cells in the liver by induction of IL-12 and IL-18 production. Injection of IL-12 (approximately 1,000 ng) dose dependently diminished CD4+ NK1.1+ T cells, but induced type 1 T cells. In contrast, injection of IL-18 (approximately 1,000 ng) failed, although injection of a much larger dose of IL-18 (10,000 ng) or IL-18 (approximately 1,000 ng) with suboptimal doses of IL-12 (1-100 ng) diminished CD4+ NK1.1+ T cells in a dose-dependent manner. Thus, P. acnes treatment renders the mice highly susceptible to LPS by induction and activation of type 1 T cells.

BK virus nephropathy in a patient with ABO-incompatible renal transplantation.

A 43-year-old woman with end-stage renal disease originating from IgA nephropathy entered chronic haemodialysis therapy. She then received an ABO-incompatible living related renal transplantation. Initial immunosuppression consisted of azathioprine, methylprednisolone and tacrolimus. At 155 days after transplantation, the azathioprine was changed to mycophenolate mofetil for continuous graft dysfunction. Furthermore, a total of three courses of anti-rejection therapy was given. At 665 days after transplantation, diagnosis of BK-virus nephropathy was made by immunohistochemical analysis and viral DNA assay. Therefore the immunosuppression therapy was reduced for graft dysfunction. All five renal biopsy specimens were examined retrospectively in order to determine when the BK virus nephropathy had developed. The expressions of SV40 large T antigens were detected from the third (117 days) to the fifth (665 days) biopsies, with increasing numbers of SV40 large T antigen positive cells. In addition, many cells contained inclusion bodies which were already present in the urinary sediment for 3 months post-transplantation. Although it is difficult to make a diagnosis of early stage of BKVN, we have to consider with caution if urinary cells with inclusion body are seen. Awareness of BKVN at the earliest opportunity is important in order to avoid over-immunosuppression.

IL-18 up-regulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor.

IL-18 is a powerful inducer of IFN-gamma production, particularly in collaboration with IL-12. IL-18, like IL-12, also augments NK activity. Here we investigated the molecular mechanism underlying the up-regulation of killing activity of NK cells by IL-18. IL-18, like IL-12, dose dependently enhanced NK activity of splenocytes. This action was further enhanced by costimulation with IL-12. Treatment with anti-IL-2R Ab did not affect IL-18- and/or IL-12-augmented NK activity, and splenocytes from IFN-gamma-deficient mice showed enhanced NK activity following stimulation with IL-12 and/or IL-18. Splenocytes from the mice deficient in both IL-12 and IL-18 normally responded to IL-18 and/or IL-12 with facilitated NK activity, suggesting that functional NK cells develop in the absence of IL-12 and IL-18. IL-18R, as well as IL-12R mRNA, was constitutively expressed in splenocytes from SCID mice, which lack T cells and B cells but have intact NK cells, and in those from IL-12 and IL-18 double knockout mice. NK cells isolated from SCID splenocytes expressed IL-18R on their surface. IL-18, in contrast to IL-12, did not enhance mRNA expression of perforin, a key molecule for exocytosis-mediated cytotoxicity. However, pretreatment with concanamycin A completely inhibited this IL-18- and/or IL-12-augmented NK activity. Furthermore, IL-18, like IL-12, failed to enhance NK activity of splenocytes from perforin-deficient mice. These data suggested that NK cells develop and express IL-12R and IL-18R in the absence of IL-12 or IL-18, and that both IL-18 and IL-12 directly and independently augment perforin-mediated cytotoxic activity of NK cells.

Kupffer cells from Schistosoma mansoni-infected mice participate in the prompt type 2 differentiation of hepatic T cells in response to worm antigens.

Infection with Schistosoma mansoni, a portal vein-residing helminth, is well known to generate life cycle-dependent, systemic immune responses in the host, type 1 deviation during the prepatent period, and type 2 polarization after oviposition. Here we investigated local immunological changes in the liver after infection. Unlike splenocytes, hepatic lymphocytes from infected mice during the prepatent period already produced a higher amount of IL-4 and a lesser amount of IFN-gamma than those from uninfected mice. Hepatic lymphocytes, particularly conventional T cells, but not NK1.1+ T cells, promptly produced IL-4 in response to worm products, soluble worm Ag preparation (SWAP), whenever presented by Kupffer cells from infected mice. The hepatic lymphocytes that had been stimulated with SWAP presented by infected mice-derived Kupffer cells produced a huge amount of IL-4, IL-13, and IL-5 as well as little IFN-gamma in response to immobilized anti-CD3 mAb. Kupffer cells from uninfected mice produced IL-6 and IL-10, but not IL-12 or IL-18, in response to SWAP stimulation and gained the potential to additionally produce IL-4 and IL-13 after the infection. These results suggested that prompt type 2 deviation in the liver after the infection might be due to the alteration of Kupffer cells that induces SWAP-mediated type 2-development of hepatic T cells.