Michio Nojima

INTRA‐ AND INTERINDIVIDUAL VARIATION IN THE PHARMACOKINETICS OF TACROLIMUS (FK506) IN KIDNEY TRANSPLANT RECIPIENTS—IMPORTANCE OF TROUGH LEVEL AS A PRACTICAL INDICATOR

Background:Tacrolimus (FK506) is currently used as the primary immunosuppressant in clinical kidney transplantation in some centers. The purpose of this study was to evaluate the pharmacokinetics of this drug and to see if trough level, which has been used widely in therapeutic drug monitoring, can be used as an appropriate substitute for other pharmacokinetic measurement tests.

The significant effect of HLA-DRB1 matching on long-term kidney graft outcome.

Serotyping and genotyping (polymerase chain reaction with sequence-specific oligonucleotide probes method) were conducted on 520 unrelated individuals to determine the linkage disequilibrium of HLA-B and HLA-DRB1. Analyses of 511 kidney transplants (300 related and 211 cadaver recipients) were carried out at 4 transplant centers using the linkage disequilibrium of HLA-B and HLA-DRB1 established previously. All transplant recipients received CsA immunosuppression and were transplanted from June 1983 to December 1991. There were 51 significant linkages formed between HLA-B and HLA-DRB1 alleles (P<0.05). DRB1-compatible transplants experienced a comparable 5-year graft success rate of 94% as did the HLA-identical recipients with a 100% 5-year success rate. However DRB1-incompatible recipients displayed a significantly reduced 5-year graft survival rate of 73% (73% vs. 94% P<0.01). The 5-year graft survival rate of HLA-DR-incompatible recipients of 71% was compatible to the 73% for HLA-DRBl-incompatible recipients. No variation of rejection rate for DRB1-compatible grafts was seen in any of the 4 transplant centers. The results also indicated that HLA-DRB1 compatibility was essential for optimal success rate, regardless of HLA class I mismatches. The overall conclusion was that matching for HLA-DR was important to achieve optimal kidney graft survival on the molecular level but not on the serotyping level.

Lower Urinary Tract Problems in Patients with Enuresis

Objective(s): Two hundred and thirty-eight children (170 males, and 68 females) with nocturnal enuresis were retrospectively studied for lower urinary tract problems. Surgical correction of subclinical organic obstruction in the lower urinary tract was evaluated for the improvement of bed-wetting. Methods: One hundred and fifty-five micturating cystourethrography (MCU), and 89 urodynamic studies were performed. Optic internal urethrotomy was done in a boy, and meatoplasty in a girl for urethral ‘ring’ stenosis (URS). Results: Nocturnal enuresis was found in 153 cases and nocturnal enuresis associated with daytime enuresis in 67 cases. Vesicoureteral reflux was found in 30, URS in 42, and posterior urethral valve in 3 cases on MCU. Detrusor instability was recognized in 39.4% of 38 cases of nocturnal enuresis associated with daytime enuresis and in 25.0% of 51 cases of nocturnal enuresis. Surgery brought 73.8% improvement of bed-wetting in 42 cases. Conclusions: Surgical correction of subclinical obstruction in the lower urinary tract might contribute to the earlier resolution of bed-wetting in children with nocturnal and/or diurnal enuresis.

Current therapy of acute uncomplicated cystitis

Acute uncomplicated cystitis (AUC) is one of the most common bacterial urinary tract infections. AUC frequently occurs in young sexually active, as well as postmenopausal, women. According to the guidelines published by the Infectious Diseases Society of America in 1999, the standard antimicrobial regimen for treatment of AUC is 3 days with trimethoprim–sulfamethoxazole (TMP/SMX); however, today the most popular antibiotics are the fluoroquinolones because of the emergence of uropathogens that are resistant to TMP/SMX. Fluoroquinolone resistance is also increasing worldwide, although the resistance rates have not been as high as those for TMP/SMX. Extended‐spectrum β‐lactamase (ESBL)‐producing strains are another problem because most nosocomial ESBL producers are also resistant to non‐β‐lactams, such as the fluoroquinolones. Under such circumstances, 3 days of therapy with fluoroquinolones or 7 days with β‐lactams is recommended for empirical therapy, although these regimens should be re‐evaluated in the next decade. Low‐dose fluoroquinolones should no longer be used because of the potential for emergence of resistance.

Primary carcinoid tumor of the urinary bladder.

A polyp of about 1.0 cm diameter was incidentally found at the center of theposterior wall of the urinary bladder in a 73-year-old man on cystoscopicexamination. A polyp was resected through a transurethral route withoutrecurrence for 22 months. A polyp consisted of a tumor covered with mucosaof the bladder. Tumor cells have round or oval nuclei with fine chromatinand one or two nucleoli per nucleus, and finely granular eosinophiliccytoplasm, being arranged in a trabecular or tubular pattern. Furthermore,they showed positive staining for chromogranin-A and with Grimelius stain,indicating that the tumor is a carcinoid tumor. Since there was no evidenceof carcinoid tumors in organs other than the urinary bladder, the presentcase is a primary carcinoid tumor (well differentiated endocrine tumor) ofthe urinary bladder which is extremely rare.

Ocular complications after renal transplantation

Seventy-two post-renal transplant patients were studied for ocular complications. Of 72 patients, 56 (77.8%) showed some ocular abnormality. Steroid cataract was the most common complication, occurring in 45 patients (62.5%). Eleven patients (18 eyes) had undergone operations for cataract. The average of their ages was 39.7 years and the period from renal transplantation to cataract operation was 3.3 years. Postoperative visual acuity was over 20/20 in most cases. Increased intraocular pressure was encountered in 9 patients (12.5%), cytomegalovirus ocular infection in 2 (2.8%), hypertensive retinopathy in 2 (2.8%), branch retinal vein occlusion in 1 (1.4%), and subconjunctival hemorrhage in 15 (20.8%). A new immunosuppressant, cyclosporine, increased renal graft survival more than azathioprine. However, ocular complications such as steroid cataract occurred frequently in spite of the use of cyclosporine, as in the azathioprine era. In conclusion, it is necessary for renal transplant patients to receive a periodical ophthalmological check-up.

Salvage therapy trial for erectile dysfunction using phosphodiesterase type 5 inhibitors and vitamin E: preliminary report.

We report our initial experience with salvage therapy for low responders to PDE-5 inhibitors by adding vitamin E. Of 89 patients with ED who visited our clinic between January 2004 to August 2006, 9 were unable to obtain a full response to a PDE-5 inhibitor and included in the present study. After providing informed consent, each was given 300 mg per day of α-tocophenol at least 1 month and completed IIEF-5 questionnaires to assess its efficacy while also taking a PDE-5 inhibitor. With α-tocophenol administration, the average IIEF-5 score increased from 13.8 ± 3.2 to 17.1 ± 3.6. Four of seven patients who completed the questionnaire each time showed improved IIEF-5 scores, with a maximum elevation of 9 points. Further, eight of the nine patients experienced favourable subjective changes, the majority being increased penile rigidity. The present clinical trial results are, to our knowledge, the first known to show the effects of vitamin E for enhancing the efficacy of a PDE-5 inhibitor.

Apoptosis of bladder cancer by sodium butyrate and cisplatin

The effects of sodium butyrate (SB), a histone deacetylase inhibitor, in combination with cisplatin (CDDP), for inhibition of cell growth and induction of apoptosis were investigated in bladder cancer cell lines in vitro. Bladder cancer cell lines T24, 253J, and UMUC3 were treated with different concentrations of CDDP or SB. Cell proliferation was studied by XTT assay. Cell-cycle analysis and induction of apoptosis were analyzed by laser scanning cytometry (LSC). Western blot analysis was used to determine expression of p21, p27, TRADD, FADD, caspase-2, and caspase-7. We observed that SB in combination with CDDP induced significant inhibition of cell growth in a dose-dependent manner through G1 arrest and apoptosis, as determined by LSC. When bladder cancer cell lines were treated with SB plus CDDP, Western blotting showed increased expression of p21 but not p27 in T24 cells, whereas both p21 and p27 increased in 253J and UMUC3 cells. All cell lines exhibited a moderate increase in TRADD and decrease in procaspase-2 but no significant change in FADD and procaspase-7. The results showed the synergistic anticancer effect of SB in combination with CDDP, their potential for treatment of bladder cancer, and their mechanism of action in terms of cell signal transduction and induction of apoptosis.

Extramedullary relapse of acute lymphoblastic leukemia in childhood to the prostate.

Abstract:  A 6‐year‐old boy presented with the chief complaints of miction pain and pollakisuria. He had a past history of acute lymphoblastic leukemia (ALL), which subsided in response to chemotherapy at 3 years of age. Ultrasonography revealed urinary retention associated with bilateral hydronephrosis secondary to the prostate enlargement. Computed tomography and magnetic resonance imaging showed no other abnormal finding. Transrectal needle biopsy showed infiltration of leukemic cells in the prostate. Bone marrow puncture and cerebrospinal fluid aspiration revealed no leukemic cells, resulting in a diagnosis of extramedullary relapse of ALL in the prostate. Although he was successfully treated by chemotherapy, irradiation and his voiding function was improved, ALL relapsed in the left testis 1 year later. In spite of left orchiectomy, irradiation and additional chemotherapy, he died of bone marrow relapse and multiple organ failure. Extramedullary relapse of ALL in the prostate is very rare. To our knowledge, our case is the first well‐documented report in the published work.

Excellent Results of Immunocomplex Capture Fluorescence Analysis-I for Cross-Match Test in Renal Transplantation

A flow cytometry cross-match (FCXM) test is the gold standard for detection of human leukocyte antigen (HLA) antibodies in renal transplantation because of its high sensitivity. However, this technique can produce false-positive results when non-HLA antibodies or low-titer donor-specific antibodies (DSA) are detected. To determine the clinical relevance of the recently introduced novel cross-match test termed immunocomplex capture fluorescence analysis (ICFA), we retrospectively compared the results of ICFA and FCXM, including a single-antigen bead test for detection of DSA in renal transplant recipients. We found a correlation of 71.4% (235/329) between the results of ICFA-I and FCXM-T, whereas that between ICFA-II and FCXM-B was 41.1% (134/326). Ninety-four patients were ICFA-I negative and FCXM-T positive, and 188 were ICFA-II negative and FCXM-B positive, whereas 46.8% (44/94) and 61.7% (116/188) were found to be DSA-I and DSA-II negative, respectively, which classified them into the non-HLA antibody and low-titer DSA groups, respectively. The mean value of molecules of equivalent soluble fluorochrome for DSA-I was 22,994 in the ICFA-I-positive group, which was significantly higher than 2117 in the negative group (P < .0001), whereas there was no significant difference for DSA-II between the ICFA-II-positive and ICFA-II-negative groups. Graft survival in the ICFA-I-negative group was significantly higher than that in the ICFA-I-positive group (P = .0058). Our results indicate that ICFA-I does not respond to non-HLA antibodies or low-titer DSA, which have influence on graft survival. Therefore, this novel hybrid test, which combines cross-match testing and HLA antibody detection functions, may be useful for clinical pretransplantation evaluation of renal transplantation patients.