Ji Hyun Yu

Decrease of immature B cell and interleukin-10 during early-post-transplant period in renal transplant recipients under tacrolimus based immunosuppression

B lymphocytes are known to play a role in kidney transplantation (KT) outcomes. Here, we evaluated the proportion of B cell subsets before and after KT. Twenty-one patients, who showed stable allograft function without acute rejection in the month following the KT, were included in this study. Peripheral blood samples were obtained from these patients before transplantation as well as 1month after transplantation. Changes in the proportion of B cell subsets after transplantation were investigated using multi-color flow cytometry. The proportion of lymphocytes in the peripheral blood mononuclear cells (PBMCs) and of CD19(+) B cells in the total leukocyte population did not change after KT. Similarly, the proportions of CD19(+)CD24(+) lymphocytes, mature B cells (CD24(Int)CD38(Inter)/CD19(+)), and memory B cells (CD24(+)CD38(-)/CD19(+)) did not change post-KT. However, the proportion of immature B cells (CD24(+)CD38(+)/CD19(+) B cells) decreased significantly after transplantation (P<0.01). The levels of IL-10, and IL-21, and expression of the B cell marker BLNK also decreased significantly after transplantation. Incubation of PBMCs with tacrolimus (0.1, 1, and 10ng/mL) and mycophenolate mofetil (200μg/mL) an immunosuppressant, resulted in significant reduction in the percentage of immature B cells. In contrast, the proportion of memory and mature B cells was not affected. Taken together, these results show that while the total B lymphocyte count and the proportion of memory/mature B cell subsets do not change after KT, the proportion of immature B cells and the associated cytokines that they secrete decrease significantly.

Effects of metformin on hyperglycemia in an experimental model of tacrolimus- and sirolimus-induced diabetic rats

Background/Aims Metformin (MET) is a first-line drug for type 2 diabetes mellitus (DM); its effect on new-onset diabetes after transplantation caused by immunosuppressant therapy is unclear. We compared the effects of MET on DM caused by tacrolimus (TAC) or sirolimus (SRL). Methods DM was induced by injection of TAC (1.5 mg/kg) or SRL (0.3 mg/kg) for 2 weeks in rats, and MET (200 mg/kg) was injected for 2 more weeks. The effects of MET on DM caused by TAC or SRL were evaluated using an intraperitoneal glucose tolerance test (IPGTT) and by measuring plasma insulin concentration, islet size, and glucose-stimulated insulin secretion (GSIS). The effects of MET on the expression of adenosine monophosphate-activated protein kinase (AMPK), a pharmacological target of MET, were compared between TAC- and SRL-treated islets. Results IPGTT showed that both TAC and SRL induced hyperglycemia and reduced plasma insulin concentration compared with vehicle. These changes were reversed by addition of MET to SRL but not to TAC. Pancreatic islet cell size was decreased by TAC but not by SRL, but addition of MET did not affect pancreatic islet cell size in either group. MET significantly increased GSIS in SRL- but not in TAC-treated rats. AMPK expression was not affected by TAC but was significantly decreased in SRL-treated islets. Addition of MET restored AMPK expression in SRL-treated islets but not in TAC-treated islets. Conclusions MET has different effects on hyperglycemia caused by TAC and SRL. The discrepancy between these drugs is related to their different mechanisms causing DM.

Cytomegalovirus (CMV) immune monitoring with ELISPOT and QuantiFERON-CMV assay in seropositive kidney transplant recipients

Although cytomegalovirus (CMV) specific cell-mediated immunity (CMI) has been suggested as a predictive marker for CMV infection, proper CMI monitoring strategy in CMV-seropositive recipients and optimal method are not defined. The aim of this study was to evaluate two interferon gamma release assays during early post-transplant period as a predictor of the development of CMV infection in CMV-seropositive patients. A total of 124 CMV-seropositive recipients who received kidney transplantation from CMV-seropositive donor were prospectively examined. At pre-transplant and post-transplant 1 and 3 months, CMV-CMIs were tested using QuantiFERON-CMV assay (QF-CMV) and CMV specific T cell ELISPOT against CMV pp65 and IE-1 antigens (pp65-ELISPOT, IE-1-ELISPOT). CMV DNAemia occurred in 16 (12.9%) patients within 3 months after transplant. Post-transplant pp65 or IE-1 ELISPOT response, but not QF-CMV, was significantly associated with CMV DNAemia. The pp65 ELISPOT (cut-off; 30 spots/200,000 cells) and IE-1 ELISPOT (10 spots/200,000 cells) at post-transplant 1 month predicted the risk of post-transplant CMV DNAemia (P = 0.019). Negative predictive values (NPV) for protection from CMV DNAemia in case of positive ELISPOT results were 94.5% (95% CI: 86.9–97.8%) and 97.6% (95% CI: 86.3–99.6%) in pp65-ELISPOT and IE-1-ELISPOT assays, respectively. These results suggest that the variability may exist between CMV ELISPOT assays and QF-CMV, and CMV ELISPOT at post-transplant 1 month can identify the risk of CMV DNAemia in seropositive kidney transplant recipients.

Safety and immunologic benefits of conversion to sirolimus in kidney transplant recipients with long-term exposure to calcineurin inhibitors

Background/Aims: Sirolimus (SRL) is a promising immunosuppressant replacingcalcineurin inhibitors (CNIs). This study was performed to evaluate the safetyand immunologic benefits of conversion to SRL in stable kidney transplant (KT)recipients exposed to CNIs for long periods. Methods: Fourteen CNI-treated KT recipients with stable renal function for morethan 10 years were included. Either 2 or 3 mg per day of SRL was administeredwhile CNIs were reduced by half starting on day 1, and then stopped 2 weeks afterSRL introduction. The safety of SRL conversion was assessed considering thegraft function, acute rejection, and graft loss. Immunologic alterations were measuredvia serial changes of T cell and B cell subsets after SRL conversion. Adverseeffects of SRL conversion were also evaluated. Results: Conversion to SRL was successful in nine patients (64.2%). Conversionto SRL preserved graft function as compared to the baseline value (p = 0.115). Noacute rejection or allograft loss was observed during the follow-up period. Immunemonitoring of T and B cells revealed a regulatory T cells increase after SRL conversion (p = 0.028). Most adverse events developed within 6 weeks after SRLconversion, and oral mucositis was the main cause of SRL withdrawal. Conclusions: Conversion to SRL can be safe and has immunologic benefits in KTrecipients with long-term CNI exposure. Close monitoring of mucocutaneous adverseevents is, however, required in the early period after SRL conversion.

Clinical outcomes of ABO- and HLA-incompatible kidney transplantation: A nationwide cohort study

This was a nationwide cohort study to investigate the impact of anti‐A/B and donor‐specific anti‐HLA (HLA‐DSA) antibodies on the clinical outcomes in kidney transplant recipients (KTRs). We classified a total of 1964 KTRs into four groups: transplants from ABO‐incompatible donors (ABOi, n = 248); transplants in recipients with HLA‐DSA (HLAi, n = 144); transplants from combined ABOi and HLAi donors (ABOi + HLAi, n = 31); and a control group for whom neither ABOi nor HLAi was applicable (CONT, n = 1541). We compared the incidence of biopsy‐proven acute rejection (BPAR), allograft and patient survival rates. The incidence of BPAR was higher in the HLAi and ABOi + HLAi groups relative to the CONT group; in contrast, it was not higher in the ABOi group. Death‐censored graft survival rates did not differ across the four groups. However, relative to the CONT group, patient survival rate was reduced in the ABOi and ABOi + HLAi groups, and with infection being the most common cause of death. Further, multivariable analysis revealed that desensitization therapy because of ABOi or HLAi was independent risk factors for patient mortality. HLAi was a more important risk factor for BPAR compared with ABOi. However, pretransplant desensitization therapy for either ABOi or HLAi significantly increased the risk of infection‐related mortality.

Impact of ABO incompatible kidney transplantation on living donor transplantation

Background ABO incompatible kidney transplantation (ABOi-KT) is an important approach for overcoming donor shortages. We evaluated the effect of ABOi-KT on living donor KT. Methods Two nationwide transplantation databases were used. We evaluated the impact of ABOi-KT on overall living donor transplant activity and spousal donation as subgroup analysis. In addition, we compared the clinical outcome between ABOi-KT and ABO compatible KT (ABOc-KT) from spousal donor, and performed a Cox proportional hazards regression analysis to define the risk factors affecting the allograft outcomes. Result The introduction of ABOi-KT increased overall living donor KT by 12.2% and its portion was increased from 0.3% to 21.7% during study period. The ABOi-KT in living unrelated KT was two times higher than that of living related donor KT (17.8 vs.9.8%). Spousal donor was a major portion of living unrelated KT (77.6%) and ABOi-KT increased spousal donation from 10% to 31.5% in living donor KT. In addition, increasing rate ABOi-KT from spousal donor was 10 times higher than that of living related donor. The clinical outcome (incidence of acute rejection, allograft function, and allograft and patient survival rates) of ABOi-KT from spousal donor was comparable to that of ABOc-KT. Neither ABO incompatibility nor spousal donor was associated with acute rejection or allograft failure on multivariate analysis. Conclusions ABOi-KT increased overall living donor KT, and ABOi-KT from spousal donor is rapidly increasing with favorable clinical outcomes.

Usefulness of valacyclovir prophylaxis for cytomegalovirus infection after anti-thymocyte globulin as rejection therapy

Background/Aims Anti-thymocyte globulin (ATG) treatment for acute T-cell mediated rejection (TCMR) can increase the risk of cytomegalovirus (CMV) infection. We aimed to evaluate the effect of valacyclovir prophylaxis against CMV infection after ATG administration as anti-rejection therapy. Methods We retrospectively analyzed 55 kidney transplant recipients (KTRs) receiving ATG for steroid resistant TCMR. In all KTRs, we used intravenous ganciclovir during ATG injection. In 34 KTRs treated before July 2013, we performed preemptive therapy for CMV infection after ATG therapy. They were regarded as the historic control group (CONT). After July 2013, we used valacyclovir maintenance for 1 month after ATG therapy in 21 patients (VAL). The primary outcome was the incidence of CMV infection, and the secondary outcomes were subsequent acute rejection, and graft and patient outcome. Results Valacyclovir prophylaxis significantly reduced the incidence of CMV infection (VAL, 9.6% vs. CONT, 67.6%; p < 0.001), and CMV-free survival rate was higher in the VAL group compared to the CONT group (p = 0.009). In the VAL group, two cases of CMV infection were limited to CMV viremia, but CMV disease or syndrome (n = 3) was detected in the CONT group. There was no difference in graft failure (CONT, 70.5% vs. VAL, 47.6%; p = 0.152), incidence of subsequent rejection after ATG treatment (CONT, 41.1% vs. VAL, 33.3%; p = 0.776), and graft or patient survival between the two groups. There were no major adverse events associated with valacyclovir prophylaxis. Conclusions In conclusion, valacyclovir prophylaxis is effective in the prevention of CMV infection after ATG treatment for steroid resistant TCMR.

Clinical Outcome of Rituximab and Intravenous Immunoglobulin Combination Therapy in Kidney Transplant Recipients with Chronic Active Antibody-Mediated Rejection

BACKGROUND We previously reported that rituximab (RIT) and intravenous immunoglobulin (IVIg) combination therapy is effective in deterring the progression of chronic active antibody-mediated rejection (CAMR), but that report was based on the assessment of a small number of cases for a short period. MATERIAL AND METHODS Forty-three patients with CAMR were recruited during the study period after 2010. The patients were divided into high (n=17, 39.5%) and low proteinuria groups (n=26, 60.5%) based on spot urine protein-to-creatinine ratio of > or <3.5 g/g. We compared clinical outcomes between the two groups in terms of allograft survival rate, decrease in estimated glomerular filtration rate (ΔeGFR), change in proteinuria level, and infectious complications. We also evaluated the risk factors of allograft failure. RESULTS The 3-year allograft survival rate after combination treatment was 60.5% overall, but was higher in the low proteinuria group than in the high proteinuria group (69.2% versus 47.1%; log rank p<0.05). The combination treatment reduced the eGFR slope in both groups, and this effect was more definite in the low proteinuria group. No significant differences in the amount of proteinuria and infectious complication rate were found between the two groups. Proteinuria and eGFR at treatment were independent predictive factors of allograft failure (p<0.01 and p<0.001, respectively). CONCLUSIONS RIT and IVIg combination therapy was effective in reducing the progression of CAMR, and this effect was more definite in the patients with low proteinuria.

Limited immune tolerance induced by transient mixed chimerism.

To the Editor, The short-term clinical outcomes of kidney transplantation (KT) have been improved significantly with advances in drugs for the induction and maintenance of immunosuppression and the development of immune-monitoring methods for sensitization and rejection [1]. However, chronic use of immunosuppressive agents can result in infection, malignancy, and metabolic derangement associated with cardiovascular complications [2]. Moreover, currently used immune suppressants do not prevent chronic rejection, which is the most important cause of late allograft loss [3]. Over the last several years, immune tolerance induction to overcome such complications or limitations of immune suppressants has been attempted in solid organ transplantation. Indeed, successful cases of immune tolerance induction through mixed chimerism after combined hematopoietic stem cell transplantation (HSCT) and KT have been reported in a few centers [4,5]. However, there are still many obstacles and limitations to the combined HSCT and KT protocols in current use, and long-term immune tolerance was found only in a minor proportion of the patients in those trials. Here, we introduce our experiences with a method to achieve immune tolerance through the formation of mixed chimerism after combined HSCT and KT from a human leukocyte antigen (HLA)-haploidentical sibling donor. This trial was approved by the Institutional Review Board of Seoul St. Mary’s Hospital (KC12EISE0635). A 40-year-old woman with end-stage renal disease caused by focal segmental glomerulosclerosis was admitted for KT. Her potential donor was an HLA-haploidentical brother. Panel reactive antibody was 0% for both class I and II, and crossmatch tests were negative for T and B cells. Our center’s protocol for immune tolerance induction is shown in Fig. 1. Briefly, beginning 18 days before transplantation, the donor received granulocyte-colony stimulating factor at 10 μg/kg subcutaneously for 5 days. CD34+-enriched peripheral blood stem cells were harvested, and peripheral T cells were depleted using a Clini-MACS bead kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and cryopreserved until they were infused. The recipient was admitted 7 days before transplantation, and fludarabine was started at a dose of 30 mg/m2 for 4 days (days –6 to –3). Antithymocyte globulin was infused at 2.5 mg/kg for 2 days (days –4 to –3), and total nodal irradiation (750 cGy) was performed on day –2. For infection prophylaxis, fluconazole, sulfamethoxazole/trimethoprim, and acyclovir were used from day –5 to 6 months posttransplantation. Immunosuppressants, namely tacrolimus (target trough blood level of 8 to 12 ng/mL), mycophenolate mofetil (1.5 g/day), and steroids were started 2 days before KT (as in conventional KT). The collected donor peripheral blood stem cells were infused the following day. Figure 1. Immune tolerance induction protocol. The conditioning regimen consisted of fludarabine (30 mg/m2) administered intravenously for 4 days (from day –5 to –2), antithymocyte globulin (2.5 mg/kg) administered intravenously for 2 days (on day ... Our immune monitoring protocol was as follows. First, chimerism was measured every week for 1 month and every 3 months thereafter by DNA genotyping of simple sequence-length polymorphic markers that encoded short tandem repeats. Second, the mixed lymphocyte reaction (MLR), an ImmuKnow study, and immune cell monitoring were performed before transplantation, every week for 1 month posttransplantation, and every 3 months thereafter. Third, protocol kidney biopsies were scheduled 3 and 6 months after KT and just before cessation of the immunosuppressive agent. We planned to taper the immunosuppressant dose beginning 3 months after KT and to discontinue the immunosuppressants within 1 year after KT. After transplantation, the renal allograft and bone marrow function recovered well (Fig. 2). Additionally, multilineage mixed chimerism developed successfully and was maintained until 8 weeks after KT (Fig. 3A). Even after the disappearance of chimerism, a one-way MLR still showed a low response to the donor, implying sustained suppression of donor-specific allo-immune responses (Fig. 3B). During the follow-up period, the patient did not experience graft-versus-host disease or any serious infectious complication, except for an episode of cytomegalovirus viremia accompanied by transient pancytopenia 2 months after transplantation. Figure 2. Clinical course of the patient. The serum creatinine level (red) decreased immediately after kidney transplantation (KT) and was maintained below 1 mg/dL until 127 days after discontinuation of the immunosuppressants (ISs) (arrow, discontinuation of immunosuppression; ... Figure 3. Results of immune monitoring. (A) The percentage of donor chimerism in the total peripheral blood mononuclear cells (PBMCs, red), T cells (blue), B cells (green), and natural killer (NK) cells (black) indicates that successful mixed chimerism was achieved, ... Beginning 3 months after KT, we gradually reduced the dose of the immunosuppressant and discontinued it at 229 days after noticing a low donor-specific response in the MLR. We did not perform protocol biopsies because of thrombocytopenia. However, a kidney biopsy performed 44 days after discontinuation of immunosuppression (i.e., 273 days after KT) showed no evidence of acute rejection. At that time, the MLR still showed a low response to the donor. At 127 days after discontinuation of immunosuppressant (356 days after KT), the serum creatinine level increased abruptly from 0.85 to 2.94 mg/dL, and a kidney biopsy showed acute T cell-mediated rejection, type IIA. Donor-specific anti-HLA antibody was not detected. We began steroid pulse therapy followed by antithymocyte globulin administration and initiated maintenance immunosuppression again 366 days after KT (137 days after discontinuation of immunosuppression). After the antirejection treatment, the serum creatinine level decreased to 1.41 mg/dL and was maintained stably until 407 days after KT. In this case, mixed chimerism was achieved successfully and lasted for 8 weeks after combined KT and HSCT. The MLR showed a sustained low response to the donor even after mixed chimerism disappeared, lasting for 12 months. Additionally, an allograft biopsy performed 44 days after discontinuation of the immunosuppressant showed no evidence of rejection, and the allograft function was stable until 4 months after immunosuppression was stopped. During the follow-up period, the patient had no donor-specific anti-HLA antibodies. Taken together, all of these findings suggest that immune tolerance was successfully induced temporarily. However, this state was not permanent, and the patient required maintenance immunosuppression again 4 months after the discontinuation of immunosuppressants. The failure to maintain long-term immune tolerance in this case requires consideration of two issues. The first is the role of mixed chimerism in the maintenance of immune tolerance. It is evident that development of mixed chimerism is essential for the induction of early-stage immune tolerance in solid organ transplantation. However, whether durable mixed chimerism is necessary for permanent immune tolerance is still debated. In a previous report from Massachusetts General Hospital [5], an immune-tolerant state was maintained despite transient mixed chimerism. The proposed mechanism for that was the upregulation of a regulatory T cell population with suppressive capacity and peripheral deletion of donor-specific T cells by the transplanted renal allograft. In contrast, another group proposed that durable mixed chimerism was essential for the long-term maintenance of immune tolerance [4]. Thus, in this case, whether the disappearance of mixed chimerism was significantly associated with the loss of immune tolerance or other unknown mechanisms are involved remains unclear. Indeed, the underlying mechanism for the maintenance of immune tolerance remains to be fully determined. The second issue that needs to be considered is whether a monitoring tool to measure immune tolerance is needed. As described above, detection of mixed chimerism does not always coincide with an immune-tolerant state because immune tolerance may persist after the disappearance of macrochimerism [5]. However, there is no available method to confirm the state of immune tolerance after the disappearance of mixed chimerism. In this case, we suspected that immune tolerance was maintained for 9 months, even after the disappearance of mixed chimerism. However, the patient required maintenance immunosuppression again due to allograft rejection, despite the fact that the MLR still showed a low donor-specific allo-immune response. If we possessed a tool to accurately measure immune tolerance, we could have determined the time point at which the tolerance state was broken and thus could have started immunosuppressive therapy before the development of rejection. In summary, we have reported a case in which immune tolerance was successfully induced by the development of mixed chimerism using combined HSCT and KT. However, the mixed chimerism and immune tolerance were not durable, and the patient returned to maintenance immunosuppression 137 days after discontinuation of the initial immunosuppression therapy. This case suggests that future studies should focus on the development of an effective induction protocol for more stable immune tolerance and monitoring methods to accurately measure immune tolerance.

Recurrent neutropenia induced by rifabutin in a renal transplant recipient.

To the Editor, Tuberculosis (TB) is one of the most common opportunistic infections and is associated with high morbidity and mortality. Rifampicin is an essential first-line anti-TB drug; however, it sometimes induces acute rejection by decreasing the blood levels of calcineurin inhibitors via the induction of cytochrome P450 in renal transplant recipients. Therefore, rifabutin, a weaker inducer of cytochrome P450 enzymes, is recommended as an alternative to rifampicin [1,2]. We report herein a case of rifabutin-related recurrent neutropenia in a renal transplant recipient. A 48-year-old woman was admitted because of fever and increased urinary frequency. She had undergone two kidney transplantations: the first in 1989 and the second in 2012. No TB prophylaxis was performed during these two kidney transplantations. The patient was treated with tacrolimus (1 mg/day) and prednisolone (5 mg/day). Mycophenolic mofetil administration was stopped 2 months after the second transplantation because of gastrointestinal discomfort. The clinical course after the second transplantation was uneventful until a palpable mass was detected in her neck. She was diagnosed with TB lymphadenitis based on biopsy findings 14 months after the second transplantation. One month before admission, TB treatment was initiated with a combination of isoniazid (300 mg/day), ethambutol (600 mg/day), and rifabutin (300 mg/day). To maintain an appropriate serum concentration of tacrolimus, which is metabolized by cytochrome P450, we chose rifabutin instead of rifampicin because rifabutin has a weaker potency of cytochrome P450 induction than does rifampicin. Moreover, pyrazinamide, which can precipitate gout flares by decreasing renal excretion of uric acid, was not used because the patient was taking the uricosuric agent benzbromarone to treat persistent hyperuricemia. On admission, the patients complete blood count (CBC) showed a white blood cell (WBC) count of 2,200 cells/mm3 and an absolute neutrophil count (ANC) of 1,780 cells/mm3. Urinalysis revealed an increased leukocyte count and nitrite positivity, suggesting a urinary tract infection. Intravenous antibiotic therapy was initiated to treat the urinary tract infection. A CBC performed the next day revealed persistent neutropenia (ANC, 860 cells/mm3); therefore, granulocyte colony-stimulating factor (G-CSF) was subcutaneously injected. Thereafter, the ANC recovered to the reference range and the patient was discharged after completion of a 5-day antibiotic treatment. Three weeks later, she was readmitted because of fever and urinary incontinence, symptoms suggestive of a recurrent urinary tract infection. To treat both the first and second urinary tract infections, we intravenously administered 1 g of meropenem every 8 hours, based on the previous urine culture in which extended-spectrum beta lactamase-producing Escherichia coli was found. The next day, a sharp decrease in the WBC count (3,530 to 1,470 cells/mm3) and ANC (2,930 to 410 cells/mm3) occurred. On day 3, the patients symptoms improved, and the urinalysis findings normalized; however, the WBC count and ANC remained low (1,460 and 650 cells/mm3, respectively). G-CSF was administered, and the ANC temporarily increased to 4,880 cells/mm3; however, it decreased to < 1,000 cells/mm3 2 days later, as shown in Fig. 1. Figure 1 Serial follow-up of absolute neutrophil count (ANC) during antituberculosis treatment. Note prompt improvement in ANC after changing from rifabutin to levofloxacin. The arrows indicate the timing of granulocyte colony-stimulating factor injection. The serum trough level of tacrolimus, which had remained stable at 8.0 to 10.0 ng/mL with 1 mg/day of tacrolimus after the transplantation, decreased gradually after administration of TB medication to 3.0 to 3.7 ng/mL. We assumed that the rifabutin had influenced this change. Because a second transplantation increases the risk of rejection, we did not taper the dose of tacrolimus, but instead increased it to 2 mg/day to achieve the target trough level. The serum creatinine level ranged from 0.74 to 1.02 mg/dL and showed little difference from before administration of the TB medication. In the present case, the recurrent neutropenia temporarily responded to G-CSF therapy. Recurrence of neutropenia despite amelioration of the urinary tract infection suggests that the drugs administered to the patient caused the neutropenia. Therefore, we reviewed the patients medication and selected fexofenadine, meropenem, and rifabutin as the possible causative drugs. Fexofenadine was excluded after considering that the patient had taken this drug for several months before the development of neutropenia. Meropenem was also suspected; however, withdrawal of this drug did not improve the neutropenia. Therefore, rifabutin was suspected as the cause of neutropenia in the present case, and a review of the literature supports our presumption of a close association between rifabutin and neutropenia [3,4,5]. Our suspicion was confirmed by the replacement of rifabutin with levofloxacin. One week after switching to levofloxacin, the WBC count increased to 5,400 cells/mm3, and no further neutropenia was observed during the 6-month follow-up period (Fig. 1). To date, rifabutin-induced neutropenia is not a well-known adverse effect, and it has only been described in case reports. However, in a multicenter study performed to evaluate the tolerance and potential pharmacokinetic interactions between azithromycin and rifabutin, the incidence of neutropenia ranged from 10% to 26%, and a significant decrease in the ANC was observed during the initial 14 days of monotherapy with rifabutin [5]. These findings suggest that rifabutin-induced neutropenia is not a rare event, and it is recommended that the WBC count be monitored for 1 week after the initiation of therapy and at 2- to 4-week intervals thereafter to avoid life-threatening neutropenia [3]. In summary, we have reported a case of neutropenia caused by rifabutin during the treatment of TB in a renal transplant recipient. Rifabutin-induced severe neutropenia can lead to serious consequences in renal transplant recipients. Hence, early and frequent monitoring of the hematologic profile is needed in patients receiving rifabutin during renal transplantation.