The Expression of C4d and HLA-DR in Renal Allografts with the Histologic Features of Antibody-Mediated Rejection

박문향,송영수 대한병리학회 2008 Journal of Pathology and Translational Medicine Vol.42 No.5

Background : Deposition of C4d along the peritubular capillaries is generally associated with an antibody-mediated response. We evaluated, with performing C4d immunostaining, the diagnostic accuracy of the cases that were previously diagnosed as antibody-mediated rejection (ABMR) when based only on the histologic findings, and we examined possible correlation of C4d with HLA-DR. Methods : Forty-five renal transplantation biopsies, which showed ABMR-like histology, were obtained. The expressions of C4d and HLA-DR in the transplant rejection cases were investigated using immunofluorescent and/or immunohistochemical staining. Results : There were 14 discordant cases among a total of 45 cases when C4d was used as a diagnostic marker and the original slides were reviewed. These total cases consisted of the C4d negative cases in two cases of hyperacute rejection and all the cases of ABMR and ABMR with chronic/sclerosing allograft nephropathy (CAN) and two C4d positive cases (one each of acute cellular rejection (ACR) and CAN according to their original diagnosis) and all these cases were then revised according to Banff 07. The expression of HLA-DR tended to be correlated with the log-transformed duration of grafts until three years after the transplantation. Conclusions : This study demonstrates that C4d together with the histologic findings should be used for making the diagnosis of ABMR. The tubular HLA-DR expression over time should be studied to further understand the mechanism of graft rejection. Background : Deposition of C4d along the peritubular capillaries is generally associated with an antibody-mediated response. We evaluated, with performing C4d immunostaining, the diagnostic accuracy of the cases that were previously diagnosed as antibody-mediated rejection (ABMR) when based only on the histologic findings, and we examined possible correlation of C4d with HLA-DR. Methods : Forty-five renal transplantation biopsies, which showed ABMR-like histology, were obtained. The expressions of C4d and HLA-DR in the transplant rejection cases were investigated using immunofluorescent and/or immunohistochemical staining. Results : There were 14 discordant cases among a total of 45 cases when C4d was used as a diagnostic marker and the original slides were reviewed. These total cases consisted of the C4d negative cases in two cases of hyperacute rejection and all the cases of ABMR and ABMR with chronic/sclerosing allograft nephropathy (CAN) and two C4d positive cases (one each of acute cellular rejection (ACR) and CAN according to their original diagnosis) and all these cases were then revised according to Banff 07. The expression of HLA-DR tended to be correlated with the log-transformed duration of grafts until three years after the transplantation. Conclusions : This study demonstrates that C4d together with the histologic findings should be used for making the diagnosis of ABMR. The tubular HLA-DR expression over time should be studied to further understand the mechanism of graft rejection.

C4d 강 양성을 보인 BK 바이러스 신병증 1예

이은영 ( Eun Young Lee ),박선희 ( Sun Hee Park ),최지영 ( Ji Young Choi ),조지형 ( Ji Hyung Cho ),김찬덕 ( Chan Duck Kim ),김용림 ( Yong Lim Kim ),김용진 ( Yong Jin Kim ) 대한신장학회 2010 Kidney Research and Clinical Practice Vol.29 No.2

C4d deposition in peritubular capillaries in renal allograft biopsies is a significant marker for diagnosis of antibody-mediated rejection. However, it is unclear whether C4d deposition could be derived from BK virus infection. We present a case of BK virus nephropathy with strong C4d deposition 10 months after kidney transplantation. The diagnosis of BK virus nephropathy was missed out, whereas strong C4d deposition was noted in the first biopsy and therefore anti-rejection therapy was started. The deterioration of renal function led to a evaluate the possibility of BK virus nephropathy with second graft biopsy and further studies of BK virus replication status. Second graft biopsy revealed BK virus nephropathy without rejection. Finally, discontinuation of immunosuppressants and addition of anti-viral therapy for BK virus resulted in recovery of renal function, despite development of pancytopenia and subsequent fungal infection after leflunomide therapy. As in this case, initial focal pathologic changes from BK virus nephropathy could be overlooked by light microscopy. In addition, even though C4d positivity in peritubular capillaries is a good marker for diagnosis of antibody-mediated rejection, the meticulous examinations of the localization of C4d is needed, considering BK virus activates complement pathways and therefore leads to deposition of C4d mainly in tubular basement membrane. Based on our case of BK virus nephropathy with strong C4d deposition, we suggest that C4d deposition could be derived from BK virus nephropathy and therefore, it should be differentiated from acute antibodymediated rejection in a renal allograft recipient.

Characterization of Burkholderia glumae BGR1 4-Hydroxy-3-methylbut-2-enyl Diphosphate Reductase (HDR), the Terminal Enzyme in 2-C-Methyl-Derythritol 4-Phosphate (MEP) Pathway

Kwon, Moonhyuk,Shin, Bok-Kyu,Lee, Jaekyoung,Han, Jaehong,Kim, Soo-Un The Korean Society for Applied Biological Chemistr 2013 Applied Biological Chemistry (Appl Biol Chem) Vol.56 No.1

4-Hydroxy-3-methylbut-2-enyl diphosphate reductase (HDR) is the ultimate enzyme in 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway converting (E)-4-hydroxy-3-methylbut-2-enyl pyrophosphate (HMBPP) into isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Burkholderia glumae, a Gram-negative rice-pathogenic bacterium, harbors 2 hdr genes and lacks isopentenyl diphosphate isomerase (idi). Both HDR enzymes could complement E. coli hdr deletion mutant (DYTL1). Both of the recombinant HDR proteins, BgHDR1 and BgHDR2, catalyzed reduction of HMBPP into IPP and DMAPP at a ratio of 2:1, in contrast to 5:1 ratio of other bacterial HDRs so far characterized. The $k_{cat}$ and $K_m$ values of BgHDR1 and BgHDR2 were 187.0 $min^{-1}$ and 6.0 ${\mu}M$ and 66.6 $min^{-1}$ and 21.2 ${\mu}M$, respectively. Physiological significance of the kinetic properties was discussed.

Molecular Cloning, Characterization and Functional Analysis of a 2C-methyl-D-erythritol 2, 4-cyclodiphosphate Synthase Gene from Ginkgo biloba

Gao, Shi,Lin, Juan,Liu, Xuefen,Deng, Zhongxiang,Li, Yingjun,Sun, Xiaofen,Tang, Kexuan Korean Society for Biochemistry and Molecular Biol 2006 Journal of biochemistry and molecular biology Vol.39 No.5

2C-methyl-D-erythritol 2, 4-cyclodiphosphate synthase (MECPS, EC: 4.6.1.12) is the fifth enzyme of the non-mevalonate terpenoid pathway for isopentenyl diphosphate biosynthesis and is involved in the methylerythritol phosphate (MEP) pathway for ginkgolide biosynthesis. The full-length mecps cDNA sequence (designated as Gbmecps) was cloned and characterized for the first time from gymnosperm plant species, Ginkgo biloba, using RACE (rapid amplification of cDNA ends) technique. The full-length cDNA of Gbmecps was 874 bp containing a 720 bp open reading frame (ORF) encoding a peptide of 239 amino acids with a calculated molecular mass of 26.03 kDa and an isoelectric point of 8.83. Comparative and bioinformatic analyses revealed that GbMECPS showed extensive homology with MECPSs from other species and contained conserved residues owned by the MECPS protein family. Phylogenetic analysis indicated that GbMECPS was more ancient than other plant MECPSs. Tissue expression pattern analysis indicated that GbMECPS expressed the highest in roots, followed by in leaves, and the lowest in seeds. The color complementation assay indicated that GbMECPS could accelerate the accumulation of $\beta$-carotene. The cloning, characterization and functional analysis of GbMECPS will be helpful to understand more about the role of MECPS involved in the ginkgolides biosynthesis at the molecular level.

Molecular Cloning, Characterization and Functional Analysis of a 2C-methyl-D-erythritol 2, 4-cyclodiphosphate Synthase Gene from Ginkgo biloba

( Shi Gao ),( Juan Lin ),( Xue Fen Liu ),( Zhong Xiang Deng ),( Ying Jun Li ),( Xiao Fen Sun ),( Ke Xuan Tang ) 생화학분자생물학회 2006 BMB Reports Vol.39 No.5

Characterization of Burkholderia glumae BGR1 4- Hydroxy-3-methylbut-2-enyl Diphosphate Reductase (HDR), the Terminal Enzyme in 2-C-Methyl-Derythritol 4-Phosphate (MEP) Pathway

권문혁,신복규,Jaekyoung Lee,한재홍,김수언 한국응용생명화학회 2013 Applied Biological Chemistry (Appl Biol Chem) Vol.56 No.1

4-Hydroxy-3-methylbut-2-enyl diphosphate reductase (HDR) is the ultimate enzyme in 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway converting (E)-4-hydroxy-3-methylbut-2-enyl pyrophosphate (HMBPP) into isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Burkholderia glumae, a Gram-negative rice-pathogenic bacterium, harbors 2hdr genes and lacks isopentenyl diphosphate isomerase (idi). Both HDR enzymes could complement E. coli hdr deletion mutant (DYTL1). Both of the recombinant HDR proteins, BgHDR1 and BgHDR2, catalyzed reduction of HMBPP into IPP and DMAPP at a ratio of 2:1, in contrast to 5:1 ratio of other bacterial HDRs so far characterized. The kcat and Km values of BgHDR1 and BgHDR2 were 187.0 min−1 and 6.0 μM and 66.6 min−1 and 21.2μM, respectively. Physiological significance of the kinetic properties was discussed.

증례 : 신장 ; 신이식 환자의 항체매개성 거부반응에서 Bortezomib으로 치료한 1예

박세정 ( Se Jeong Park ),유훈 ( Hoon Yu ),강성희 ( Sung Hee Kang ),백승돈 ( Seung Don Baek ),백충희 ( Chung Hee Baek ),정재호 ( Jae Ho Jeong ),박수길 ( Su Kil Park ) 대한내과학회 2011 대한내과학회지 Vol.81 No.6

공여자 특이 항체는 이식신 부전의 주요 원인이 되며 이를 효과적으로 제거하는 것은 이전의 치료 방법을 통해서는 충분히 달성되지 못했다. 저자들은 39세 여자 환자로 신기능저하로 입원하여 신조직 검사에서 C4d 미만성 양성 소견 및 혈중 공여자 특이 항체의 존재로 항체 매개 거부 반응을 진단받았고, 프로테아좀 억제제인 bortezomib을 통해 조직학적소견의 호전 및 혈중 공여자 특이 항체의 감소와 이식신 기능회복을 가져온 증례를 경험하였기에 이를 보고한다. Donor-specific anti-human leukocyte antigen antibodies (DSA) following kidney transplantation predict the evolution of humoral rejection and reduced graft survival. Rapid, complete elimination of DSA during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. We report the case of a 39-year-old female who was admitted for increasing azotemia and diagnosed with AMR based on diffusely positive histological changes on C4d immunostaining. In this case, bortezomib reversed the histological changes and induced a reduction in DSA. Proteasome-inhibitor-based combination therapy is a potential means for rapid DSA elimination in antibody-mediated rejection in renal transplant recipients. (Korean J Med 2011;81:780-785)

A new pathological perspective on thrombotic microangiopathy

김용진 대한신장학회 2022 Kidney Research and Clinical Practice Vol.41 No.5

Thrombotic microangiopathy (TMA) refers to a condition caused by microvascular injury that includes thrombosis, hemolytic anemia, and thrombocytopenia. There are two classic TMAs, hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura, as well as an atypical HUS (aHUS). aHUS includes a broad spectrum of disorders with diverse etiologies and shares clinical manifestations with classic TMA; however, it frequently lacks typical clinical and laboratory findings. These traits can confuse clinicians and pathologists in terms of renal pathologic diagnosis, especially in cases where TMA is associated with other glomerulopathies or hypertensive renal disease. In this review, new paradigms for classifying TMA and the diversity of histopathologic changes including associated renal diseases are discussed. Renal biopsy is an important and useful diagnostic tool for diagnosing TMA and identifying TMA changes in other renal diseases, including hypertension. Adopting the term “TMA features” for TMA-like changes in glomerulus or artery/ arteriole in addition to the pathological diagnosis of glomerulopathy would be informative to clinicians for a prompt diagnosis and treatment of aHUS.