Comparison of Humoral Response in Kidney Transplant Recipients and Donors and Healthy Volunteers Following Second Dose of SARS-CoV-2 mRNA Vaccine.

PURPOSE: To investigate the kinetics and durability of anti-spike glycoprotein (S) immunoglobulin G (IgG) after the second dose of mRNA-based SARS-CoV-2 vaccine in kidney transplant recipients (recipients) compared with those in kidney donors (donors) and healthy volunteers (HVs) and identify factors negatively associated with SARS-CoV-2 vaccine effectiveness in recipients. METHODS: We enrolled 378 recipients with no history of COVID-19 and no anti-S-IgG before the first vaccine and who received a second mRNA-based vaccine dose. Antibodies were detected using an immunoassay more than 4 weeks after the second vaccine dose. Anti-S-IgG <0.8, ≥0.8 to 15, and ≥15 U/mL were considered negative, weak positive, and strongly positive, respectively, whereas anti-nucleocapsid protein IgG was negative. Anti-S-IgG titer was determined in 990 HVs and 102 donors. RESULTS: Anti-S-IgG titers were 154, 2475, and 1181 U/mL in the recipient, HV, and donor groups, respectively, with values significantly lower in recipients. The anti-S-IgG-positivity rate of recipients gradually increased following the second vaccination, suggesting that recipients had a delayed response compared with the HV and donor groups, who had a 100% positivity rate at an earlier time point. Anti-S-IgG titers decreased in donors and HVs, whereas they remained stable in recipients, although at a significantly lower level. Independent negative factors associated with anti-S-IgG titers in recipients were age >60 years and lymphocytopenia (odds ratio: 2.35 and 2.44, respectively). CONCLUSIONS: Kidney transplant recipients demonstrate delayed and attenuated responses, with lower SARS-CoV-2 antibody titers after the second dose of the mRNA-based COVID-19 vaccine.

CaMK phosphatase (CaMKP/POPX2/PPM1F) inhibitors suppress the migration of human breast cancer MDA-MB-231 cells with loss of polarized morphology.

CaMK phosphatase (CaMKP/POPX2/PPM1F) is a Ser/Thr protein phosphatase that belongs to the PPM family. Accumulating evidence suggests that CaMKP is involved in the pathogenesis of various diseases, including cancer. To clarify the relationship between CaMKP activity and human breast cancer cell motility, we examined the phosphatase activity of CaMKP in cell extracts. CaMKP activity assays of the immunoprecipitates prepared from the cell extract revealed that cells exhibiting higher motility had higher CaMKP activity, with no significant differences in the specific activity being observed. Two CaMKP-specific inhibitors, 1-amino-8-naphthol-4-sulfonic acid (ANS) and 1-amino-8-naphthol-2,4-disulfonic acid (ANDS), inhibited the migration of highly invasive MDA-MB-231 breast cancer cells without significant cytotoxicity, while an inactive analog, naphthionic acid, did not. Furthermore, the cells lost their elongated morphology and assumed a rounded shape following treatment with ANS, whereas they retained their elongated morphology following treatment with naphthionic acid. Consistent with these findings, ANS and ANDS significantly enhanced the phosphorylation level of CaMKI, a cellular substrate of CaMKP, while naphthionic acid did not. The present data suggest that CaMKP could be a novel therapeutic target for cancer metastasis.

Successful immunomodulation in kidney transplant recipients with cytokine release syndrome after coronavirus disease.

Introduction: Patients with coronavirus disease, especially solid organ transplant recipients, are more susceptible to developing cytokine release syndrome than those with other viral infections. However, currently, treatment methods for such patients have not been established. Here, we describe two cases of successful immunomodulation in Japanese kidney transplant recipients with cytokine release syndrome following coronavirus disease. Case presentation: Two patients who had been receiving long-term immunosuppressant therapy developed coronavirus disease-associated pneumonia caused by cytokine release syndrome, following immunosuppressant dosage reduction. However, they recovered immediately after administration of tocilizumab with or without dexamethasone. Conclusion: The immunosuppressant dosage should be reduced to restore host immunity; however, immunomodulation should be considered in cases of suspected cytokine release syndrome.

Associations Between Recipients' Feelings of Guilt for Donor and Depressive Symptoms Before Living Kidney Transplantation.

BACKGROUND: Recipient depression before kidney transplantation needs to be treated to reduce poor posttransplant outcomes. For recipients who receive living kidney transplantation, feelings of guilt for potential donors may be factors related to the presence of depressive symptoms. This study aimed to examine the association between recipients' feelings of guilt for the donor and depressive symptoms before living kidney transplantation. METHODS: Participants included 178 patients in Sapporo City General Hospital, Hokkaido, Japan, who completed a questionnaire before having living kidney transplantation from April 2009 to May 2016. Feelings of guilt for the donor, depressive symptoms using the Beck Depression Inventory-II (BDI-II), relationship to the donor, dialysis period, and socio-demographic characteristics were assessed via a questionnaire. Multivariate regression analyses were performed to examine the association between feelings of guilt for the donor and BDI-II score after multiple imputations. RESULTS: The results showed that feelings of guilt for donors were associated with depressive symptoms, especially cognitive factors. CONCLUSIONS: These findings indicate that medical staff needs to address recipients' feelings of guilt for donors before living kidney transplantation.

Long noncoding RNA CCDC26 as a modulator of transcriptional switching between fetal and embryonic globins.

The CCDC26 gene is considered to encode a functional noncoding RNA associated with acute myeloid leukemia and other cancers. However, investigations into the physiological roles of CCDC26 are rare. Previously, we reported that CCDC26 regulated proliferation and cell death of leukemia cells through KIT, a receptor tyrosine kinase, by using K562 leukemia cells and their derivative CCDC26-knockdown (KD) cells. Here we propose a new role of CCDC26 in the differentiation of erythroid cells. We showed that expression of embryonic (ε- and ζ-) globins was markedly upregulated in CCDC26-KD cells compared with K562 control cells during hemin-induced differentiation. In contrast, expression of fetal-type γ-globin, a major globin expressed in original K562 cells, was decreased. These changes in the expression of globin genes mainly took place at the transcriptional level, with significant suppression of transcription of adult (ß-, δ-) globins in CCDC26-KD cells. Re-introduction of exogenous CCDC26 into the CCDC26-KD cells recovered low-level expression of the embryonal globins. These results suggest CCDC26 has a role in switching transcription of globin genes in the differentiation of erythroid cells. The expression profile of the CCDC26-KD cells and control cells suggests FOG-2, a transcriptional modulator, as a candidate for a mediator of the CCDC26-associated regulation. We showed that both embryonic globins were transcriptionally activated in FOG-2-KD K562 cells. The KIT inhibitor ISCK03 suppressed the production of hemoglobin in K562 cells but did not affect transcription of globin genes. To summarize, FOG-2, but not KIT, is responsible for globin transcriptional regulation by CCDC26.

Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP/PPM1F) interacts with neurofilament L and inhibits its filament association.

Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP/PPM1F) is a Ser/Thr phosphatase that belongs to the PPM family. Growing evidence suggests that PPM phosphatases including CaMKP act as a complex with other proteins to regulate cellular functions. In this study, using the two-dimensional far-western blotting technique with digoxigenin-labeled CaMKP as a probe, in conjunction with peptide mass fingerprinting analysis, we identified neurofilament L (NFL) as a CaMKP-binding protein in a Triton-insoluble fraction of rat brain. We confirmed binding of fluorescein-labeled CaMKP (F-CaMKP) to NFL in solution by fluorescence polarization. The analysis showed that the dissociation constant of F-CaMKP for NFL is 73 ± 17 nM (n = 3). Co-immunoprecipitation assay using a cytosolic fraction of NGF-differentiated PC12 cells showed that endogenous CaMKP and NFL form a complex in cells. Furthermore, the effect of CaMKP on self-assembly of NFL was examined. Electron microscopy revealed that CaMKP markedly prevented NFL from forming large filamentous aggregates, suggesting that CaMKP-binding to NFL inhibits its filament association. These findings may provide new insights into a novel mechanism for regulating network formation of neurofilaments during neuronal differentiation.

Long noncoding RNA, CCDC26, controls myeloid leukemia cell growth through regulation of KIT expression.

BACKGROUND: Accumulating evidence suggests that some long noncoding RNAs (lncRNAs) are involved in certain diseases, such as cancer. The lncRNA, CCDC26, is related to childhood acute myeloid leukemia (AML) because its copy number is altered in AML patients. RESULTS: We found that CCDC26 transcripts were abundant in the nuclear fraction of K562 human myeloid leukemia cells. To examine the function of CCDC26, gene knockdown (KD) was performed using short hairpin RNAs (shRNAs), and four KD clones, in which CCDC26 expression was suppressed to 1% of its normal level, were isolated. This down-regulation included suppression of CCDC26 intron-containing transcripts (the CCDC26 precursor mRNA), indicating that transcriptional gene suppression (TGS), not post-transcriptional suppression, was occurring. The shRNA targeting one of the two CCDC26 splice variants also suppressed the other splice variant, which is further evidence for TGS. Growth rates of KD clones were reduced compared with non-KD control cells in media containing normal or high serum concentrations. In contrast, enhanced growth rates in media containing much lower serum concentrations and increased survival periods after serum withdrawal were observed for KD clones. DNA microarray and quantitative polymerase chain reaction screening for differentially expressed genes between KD clones and non-KD control cells revealed significant up-regulation of the tyrosine kinase receptor, KIT, hyperactive mutations of which are often found in AML. Treatment of KD clones with ISCK03, a KIT-specific inhibitor, eliminated the increased survival of KD clones in the absence of serum. CONCLUSIONS: We suggest that CCDC26 controls growth of myeloid leukemia cells through regulation of KIT expression. A KIT inhibitor might be an effective treatment against the forms of AML in which CCDC26 is altered.

An active C-terminally truncated form of Ca (2+) /calmodulin-dependent protein kinase phosphatase-N (CaMKP-N/PPM1E).

Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP/PPM1F) and its nuclear homolog CaMKP-N (PPM1E) are Ser/Thr protein phosphatases that belong to the PPM family. CaMKP-N is expressed in the brain and undergoes proteolytic processing to yield a C-terminally truncated form. The physiological significance of this processing, however, is not fully understood. Using a wheat-embryo cell-free protein expression system, we prepared human CaMKP-N (hCaMKP-N(WT)) and the truncated form, hCaMKP-N(1-559), to compare their enzymatic properties using a phosphopeptide substrate. The hCaMKP-N(1-559) exhibited a much higher V(max) value than the hCaMKP-N(WT) did, suggesting that the processing may be a regulatory mechanism to generate a more active species. The active form, hCaMKP-N(1-559), showed Mn(2+) or Mg(2+)-dependent phosphatase activity with a strong preference for phospho-Thr residues and was severely inhibited by NaF, but not by okadaic acid, calyculin A, or 1-amino-8-naphthol-2,4-disulfonic acid, a specific inhibitor of CaMKP. It could bind to postsynaptic density and dephosphorylate the autophosphorylated Ca(2+)/calmodulin-dependent protein kinase II. Furthermore, it was inactivated by H2O2 treatment, and the inactivation was completely reversed by treatment with DTT, implying that this process is reversibly regulated by oxidation/reduction. The truncated CaMKP-N may play an important physiological role in neuronal cells.

A case of pregnancy-induced thrombotic thrombocytopenic purpura with a kidney allograft recipient.

A 32-yr-old female patient, who had been suffering from diffuse crescentic glomerulonephritis and a consequent end-stage renal disease, successfully underwent living-related ABO-incompatible kidney transplantation after a desensitization therapy including anti-CD20 monoclonal antibody. Forty-six months after the transplantation, the recipient became pregnant. At the 17th gestational week, the patient was admitted for the management of pregnancy-induced hypertension and aggressive deterioration of kidney graft function. At the 21st gestational week, the patient lost her kidney graft and was re-induced into regular hemodialysis. The patient was also suffering from progressive hemolytic anemia, thrombocytopenia, and neurologic symptoms with decreased activity of von Willebrand factor-cleaving protease, a disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13 (ADAMTS13). From these findings and a kidney allograft biopsy, the patient was diagnosed as thrombotic thrombocytopenic purpura concurrent with acute T-cell-mediated rejection. The patient immediately underwent plasma exchange as well as steroid pulse therapy. Despite these treatments, thrombocytopenia and intrauterine growth retardation progressed. The patient underwent a caesarian section at the 24th gestational week. Consequently, her platelet count recovered drastically. However, the patient lost her neonate five d after giving a birth, and the patient's graft function had never recovered.

(99m)Tc-DTPA dynamic SPECT and CT volumetry for measuring split renal function in live kidney donors.

OBJECTIVES: Split renal function (SRF) estimated from the posterior view of (99m)Tc-diethylenetriaminepentaacetic acid planar scintigraphy (DTPA/P) is not sufficiently accurate even after correction for kidney depth by computed tomography (CT). To obtain more accurate SRF using (99m)Tc-DTPA, dynamic SPECT method was carried out for the initial 5 min after bolus injection of (99m)Tc-DTPA (DTPA/SPECT). Also SRF was evaluated from the renal volume measured by CT. We compared the results with (99m)Tc-dimercaptosuccinic acid SPECT (DMSA/SPECT). METHODS: In 60 consecutive live kidney donors, 30 DTPA/P, 30 DTPA/SPECT, 60 (99m)Tc-DMSA/SPECT, and 60 CT studies were performed. In the DTPA/P studies, SRF was calculated from the posterior image recorded during 2-3-min postinjection with attenuation correction for kidney depth measured by CT. In the DTPA/SPECT studies, SPECT images were acquired continuously for 5 min with a dual-headed gamma camera. In (99m)Tc-DMSA scintigraphy, DMSA/SPECT images were acquired 3-h postinjection. The SRF on both SPECT studies was calculated from the total counts of each kidney. In the DTPA/SPECT study, SRF was evaluated on the three images summed for 1 min: 1-2 min (DTPA/SPECT1-2), 2-3 min (DTPA/SPECT2-3), and 1-3 min (DTPA/SPECT1-3). In the CT examination, to assess the global renal volume, the axial images in the excretory phase were chosen. Renal contours were identified on each image, and the areas (cm(2)) of these regions were summed and multiplied by the slice thickness (10 mm) to yield global renal volume (ml). Right renal function from DTPA/P, DTPA/SPECT, and CT were compared with that from DMSA/SPECT as a reference. RESULTS: Correlation coefficients of the right renal function between DMSA/SPECT and DTPA/P, DTPA/SPECT2-3, and CT were 0.663, 0.849 and 0.907, respectively (P < 0.0001). The differences between DMSA/SPECT and DTPA/P, DTPA/SPECT2-3 and CT were 2.42 +/- 3.878, 0.867 +/- 1.672, and -0.421 +/- 1.077% (mean +/- SD), respectively. CONCLUSION: SRF derived from DTPA/SPECT showed a better correlation with DMSA/SPECT and significantly fewer errors (P < 0.05) than DTPA/P. A significant strong correlation was observed between SRF from DMSA/SPECT and CT, indicating the utility of CT renal volumetry for evaluating SRF.

Clinicopathologic evaluation of short-term outcome after early corticosteroid discontinuation in kidney transplantation.

OBJECTIVES: Steroids have been a gold-standard drug of immunosuppressive regimens in kidney transplantation. Steroid minimization protocols have been applied to minimize the adverse effects of steroids. We have evaluated the short-term outcomes of our early steroid discontinuation regimen. METHODS: A total of 128 recipients who received kidney from ABO-compatible, flow crossmatch-negative living-related donors were included in this study. Immunosuppressive regimens consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), and basiliximab. In a cohort of recipients, designated as a steroid early discontinuation (ESD) group, only three doses of methylprednisolone (MP) were given (500, 250, 125 mg). In the other cohort of recipients, designated as a chronic steroid (CS) group, MP was given chronically, being tapered to 4 mg at one month post-transplant. TAC and mycophenolic acid (MPA) blood levels were monitored. The following data were retrospectively compared between the two groups at 1, 3, 6, 9, 12 months post-transplant: serum creatinine (sCr), urine protein per gCr (uP/Cr), the incidence of biopsy-proven acute rejection (BPAR), graft survival (GS), area-under-the-curve of blood levels of tacrolimus (TAC-AUC(0-12), ng h/mL) and mycophenolic acid (MPA-AUC(0-12), mug h/mL), MMF dose (mg), the incidence of opportunistic infection, post-transplant diabetes mellitus (PTDM), and histopathologic findings of protocol biopsy according to the Banff '07 classification. RESULTS: sCr and uP/Cr were comparable between the two groups up to 12 months except for sCr at one month (ESD group > CS group). TAC-AUC(0-12) was significantly higher in ESD group at one month but was equivalent thereafter, while the prevalence of biopsy-proven tubulotoxicity was not different. MMF dose was comparable throughout the period between two groups. The incidence of BPAR until 12 months was equivalent. Of note, 60% of BPAR cases in ESD group occurred within one month. Prevalence of opportunistic infection or PTDM was equivalent. Graft survival was 100% in both groups. The following histopathologic scores up to 12 months were also equivalent: t, i, g, v, ci, ct, cg, cv, mm, ah, and ptc. CONCLUSIONS: Favorable short-term outcomes were achieved both clinically and histologically using our early steroid discontinuation protocol compared with the conventional protocol with chronic steroid treatment.

Successful rescue of late-onset acute T-cell mediated rejection with anti-CD25 antibody: a case report.

Japan A 56-yr-old Japanese male with a history of diabetic nephropathy underwent a HLA 5/6 mismatch and ABO-compatible living-related kidney transplantation (donor: his 49-yr-old wife). A pre-transplant standard NIH complement-dependent cytotoxicity cross-match (Xm) test, a flow-cytometric T-cell Xm, and a FlowPRA test were totally negative. Inductionimmunosuppressive protocol consisted of tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab (BAS). The patient's post-operative course was almost uneventful, and the graft was functioning well (sCr 1.1 mg/dL). He developed general fatigue, and his sCr was elevated to 2.2 mg/dL 792 d after transplant. A graft biopsy showed acute T-cell mediated rejection Banff grade IB (i3, t3, g0, v0, ptc0, C4d staining negative). The conventional anti-rejection therapy could not improve his graft function; therefore, we added BAS to eliminate activated graft-infiltrating T-cells. He responded to the rescue therapy, and the improvement in graft function was confirmed by a subsequent graft biopsy. He enjoyed his health without any opportunistic infections.

Genes encoded within 8q24 on the amplicon of a large extrachromosomal element are selectively repressed during the terminal differentiation of HL-60 cells.

Human acute myeloblastic leukemia HL-60 cells become resistant to differentiation during long-term cultivation. After 150 passages, double minute chromosomes (dmins) found in early-passaged cells are replaced by large extrachromosomal elements (LEEs). In a DNA library derived from a purified fraction of LEEs, 12.6% (23/183) of clones were assigned to 8q24 and 9.2% (17/183) were assigned to 14q11 in the human genome. Fluorescence in situ hybridization (FISH) revealed a small aberrant chromosome, which had not been found in early-passaged cells, in addition to the purified LEEs. We determined that each LEE consisted of six discontinuous segments in a region that extended for 4.4Mb over the 8q24 locus. Five genes, namely, Myc (a proto-oncogene), NSMCE2 (for a SUMO ligase), CCDC26 (for a retinoic acid-dependent modulator of myeloid differentiation), TRIB1 (for a regulator of MAPK kinase) and LOC389637 (for a protein of unknown function), were encoded by the amplicon. Breaks in the chromosomal DNA within the amplicon were found in the NSMCE2 and CCDC26 genes. The discontinuous structure of the amplicon unit of the LEEs was identical with that of dmins in HL-60 early-passaged cells. The difference between them seemed, predominantly, to be the number (10-15 copies per LEE versus 2 or 3 copies per dmin) of constituent units. Expression of the Myc, NSMCE2, CCDC26 and LOC389637 and TRIB1 genes was constitutive in all lines of HL-60 cells and that of the first four genes was repressed during the terminal differentiation of early-passaged HL-60 cells. We also detected abnormal transcripts of CCDC26. Our results suggest that these genes were selected during the development of amplicons. They might be amplified and, sometimes, truncated to contribute to the maintenance of HL-60 cells in an undifferentiated state.

Late corticosteroid withdrawal can be safely performed for kidney recipients with stable graft function under pathological confirmation.

Corticosteroid withdrawal (CSWD) protocols to minimize the risk of cardiovascular events after kidney transplantation have been reported. However, most of them were within one year post-transplant, and the pathological survey after CSWD was poorly done. We conducted the present retrospective study to elucidate the usefulness and safety of late-steroid withdrawal more than one year after transplantation in kidney recipients with pathological evaluation. Twenty kidney recipients with stable graft function more than one year post-transplant, and whose corticosteroid (CS) was withdrawn were enrolled in this study. The change in their clinical parameters of graft function (sCr and uP/Cr), metabolic profiles, and histological graft status (Banff 97 scoring system) were studied pre- and post-CSWD, and compared with a control cohort taking continuous CS. The dose of CS was tapered gradually and has been maintained with the minimal dose of CS (1.25-5 mg of prednisone) by three months after transplant. CS was furthermore reduced thereafter, if graft function had been stable more than one year and a patient wanted CS to be withdrawn, then a graft biopsy was undertaken. CSWD was accomplished between 16 and 195 (median 41.5) months post-transplant, if there was no significant histological graft damage or on-going acute rejection. A repeat biopsy was carried out two to 21 months after CSWD. In contrast, the observation point of the control cohort was 24 to 49 (median 36.5) months after transplant, and the second biopsy was done five to 30 months after the initial biopsy. The control cohort took 2.5 to 5 (median 2.5) mg of prednisone daily. There were no significant alterations of graft function between pre- and post-CSWD (sCr: 1.14 +/- 0.1 and 1.17 +/- 0.1 mg/dL, respectively, p = 0.3299, uP/Cr: 0.12 +/- 0.01 and 0.21 +/- 0.06, respectively, p = 0.0574). The hypertension rate between both groups was not different between double biopsy points. In addition the rates of glucose intolerance and hyperlipidemia were comparable between two points in both cohorts. There was no significant change in the acute/active lesion scoring (2 t1 and 3 i1 were only positive factors before CSWD and they all returned to t0 and i0 after CSWD). Moreover, chronic/sclerosing allograft nephropathy scorings were minimal and similar between pre- and post-CSWD compared with the control. CSWD for more than one year is safe for patients whose graft functions are stable with pathological confirmation; however, a longer follow-up study is warranted.

Positive pre-transplant flow-panel reactive antibody detected after accelerated acute rejection with negative pre-transplant flow crossmatch.

A 30-yr-old woman underwent kidney transplantation from a flow cytometric lymphocyte crossmatch-negative donor. Immunosuppression consisted of tacrolimus, mycophenolate mofetil, basiliximab and three days of steroid. On day 5 post-transplant, she developed acute rejection and underwent anti-rejection therapy consisting of steroid pulse and deoxyspurgualin. Retrospective analyses of anti-human leukocyte antigen antibody revealed high flow panel reactive antibody (PRA) in the pre-transplant serum without donor specific antibody (DSA) and positive DSA at the time of rejection. Anti-rejection therapy was successful in treating cellular rejection but her graft function further deteriorated after three months post-transplant and graft biopsy revealed chronic allograft nephropathy with positive staining for C4d in peritubular capillary, suggesting the presence of chronic antibody-mediated rejection. Pre-transplant positive flow PRA without DSA may also be a risk for acute and chronic rejection.

Epididymo-orchitis caused by intravesically instillated bacillus Calmette-Guérin: genetically proven using a multiplex polymerase chain reaction method.

The intravesical instillation of bacillus Calmette-Guérin (BCG) is a standard therapy for superficial bladder carcinoma. Tuberculosis-like inflammation in the genitourinary tract is a serious complication of BCG. It can occur after a long interval from the cessation of the intravesical BCG therapy. If inflammation occurs, it is necessary to test whether the BCG strain has caused it or another mycobacterium species has. However, there has never been a report that proves BCG causes the inflammation, because BCG is difficult to differentiate from other strains of Mycobacterium bovis and other members of the Mycobacterium tuberculosis complex by conventional tests, including regular polymerase chain reaction (PCR). We first present a case of epididymo-orchitis, which developed 31 months after the cessation of BCG therapy, detected using a multiplex PCR method as having been caused by BCG. Our report illustrates the efficacy of this method to detect the responsible microbe that is thought to be transmitted from the instillated BCG strain.

Quadruple immunosuppression with basiliximab, tacrolimus, mycophenolate mofetil and prednisone is safe and effective for renal transplantation.

INTRODUCTION: Recent immunosuppression with tacrolimus and mycophenolate mofetil has improved the results of renal transplantation. In this study, we analyzed the effect and safety of basiliximab as an induction therapy. MATERIAL AND METHODS: Forty-nine kidney recipients were given tacrolimus, mycophenolate mofetil and prednisone (non-Bas group), and 31 recipients were given basiliximab as an induction therapy in addition to the triple immunosuppressants (Bas group). Graft function, incidence of acute rejection (AR), findings of protocol graft biopsy and adverse effects were compared. RESULTS: Serum creatinine within 1 yr post-transplant was comparable between the two groups. Incidence of biopsy-proven AR within 6 months post-transplant was less in the Bas group than in the non-Bas group. Borderline change at 3 months post-transplant was less in the Bas group when compared to the non-Bas group. The frequency and severity of tubulitis were higher in the non-Bas group than in the Bas group. The addition of basiliximab did not increase opportunistic infection, but reduced tacrolimus nephrotoxicity. CONCLUSION: The addition of basiliximab to the tacrolimus-based triple immunosuppressive regimen enabled us to reduce the doses of immunosuppressants and tacrolimus nephrotoxicity without increasing early rejection or infection. This regimen is safe and effective for application during the early period after renal transplantation.

[Relationship between dose of mycophenolate mofetil and the occurrence of cytomegalovirus infection and diarrhea in renal transplant recipients].

To establish guidelines for avoiding the side effects of mycophenolate mofetil (MMF) in renal transplant recipients with tacrolimus (TAC)-based immunosuppression, the relationship between the daily dose of MMF and the occurrence of side effects was analyzed in this study. The frequency of side effects was investigated retrospectively in 28 renal transplant recipients treated with immunosuppression (men 14 : women 14, age: 33.0+/-12.4 years, weight: 50.9+/-10.7 kg). Cytomegalovirus (CMV) infection and diarrhea were the most frequent side effects in the early transplant phase (from transplantation to 3-month biopsy) in the recipients. In 18 recipients, excluding the recipients with risk factors for CMV infection (ABO-incompatible transplantation, donor (+)/recipient (-) CMV serostatus, etc.), no significant correlation was shown between the daily dose of MMF and the occurrence of CMV infection in the two-sample t-test. On the other hand, the daily dose in the diarrhea group (33.2+/-4.3 mg/kg/day, n = 5) was significantly higher than that in the no-diarrhea group at 30 days (28.4+/-3.7 mg/kg/day, n = 23, p < 0.05) and 90 days (25.7+/-4.4 mg/kg/day, n = 21, p < 0.005) after transplantation, respectively. The receiver-operating characteristic (ROC) curve also revealed that the risk of diarrhea increased with a daily MMF dose higher than 30 mg/kg/day. In conclusion, to decrease the risk of diarrhea in the early transplant phase in renal transplant recipients with TAC-based immunosuppression, the daily dose of MMF should not be more than 30 mg/kg/day.

Squamous metaplasia mimicking papillary carcinoma in the upper urinary tract.

We experienced a case of squamous metaplasia mimicking papillary urothelial cell carcinoma in the upper urinary tract. A 69-year-old woman, who complained of gross hematuria and intermittent left flank dull pain underwent nephrectomy with the clinical diagnosis of papillary urothelial carcinomas in the left upper urinary tract according to positive split urine cytology and tumorous filling defects of contrast media by the abdominal CT scan. Pathological diagnosis was squamous metaplasia and concomitant foreign body granuloma. Those changes were judged due to a tiny calculus in the ureter. Our presented case implies that a tiny calculus can cause the metaplastic change in the urothelial epithelium and the combination of radiographical and cytological diagnoses would not be enough to lead the correct diagnosis and the definitive surgical treatment against protruding lesions in the upper urinary tract requires more reliable diagnostic modalities.

Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistance-associated protein 2 in rats.

The onset of diarrhea after the administration of mycophenolate mofetil (MMF) is possibly associated with the biliary excretion of its metabolite, mycophenolic acid glucuronide (MPAG). This study was undertaken to clarify the mechanism underlying the biliary excretion of MPAG. Intravenously administered mycophenolic acid (MPA, 5 mg/kg) rapidly disappeared from plasma and was efficiently excreted as MPAG in the bile of Wistar (26% of dose) and Sprague-Dawley rats (21% of dose) over 1 h. On the other hand, in spite of the rapid disappearance of MPA from plasma, the biliary excretion of MPAG was very limited in Eisai hyperbilirubinemic rats (EHBRs), which display mutations in multidrug resistance-associated protein 2 (Mrp2)/canalicular multispecific organic anion transporter, and constituted only 0.5% of dose. Instead, high levels of MPA were noted in the plasma of EHBRs. Intravenous administration of CsA (5 mg/kg) to Wistar rats significantly lowered the biliary excretion of MPAG. However, intravenously administered tacrolimus (0.1 mg/kg) failed to produce such effect. In conclusion, it is suggested that there is an efficient MPAG transport mediated by Mrp2 on the bile canalicular membrane of rat hepatocytes and that the therapeutic range of CsA potentially interferes with Mrp2. However, the therapeutic range of tacrolimus does not inhibit the transporter. Thus, it should be noted that MMF coadministered with tacrolimus instead of CsA might increase the occurrence of diarrhea related to the biliary excretion of MPAG in transplant recipients.