Yayoi Ogawa

Donor-specific antibody in chronic rejection is associated with glomerulopathy, thickening of peritubular capillary basement membrane, but not C4d deposition

Abstract:  The impact of post‐transplant donor‐specific antibody (DSA) on the development of chronic rejection has been focused recently. The aim of this study was to evaluate the significance of DSA, graft function and pathological factors of chronic rejection. Seventy‐three kidney recipients who underwent protocol biopsy were included in the study. The median follow‐up period after transplant was 40 months. The presence of anti‐HLA antibody (aHLAAb) and DSA was tested using flow beads analysis (FlowPRA®). The patients were divided into a group with DSA, a group with non‐donor‐specific aHLAAb and a group without aHLAAb. Protocol biopsy specimen were compared for transplant glomerulopathy (cg), vasculopathy (cv), C4d deposition at peritubular capillary (PTC), peritubular capillaritis (ptc score 0–3) and thickening of PTC basement membrane (ptcbm score 0–3) as recently proposed. The presence of DSA was significantly associated with the presence of cg, ptcbm. The group with non‐donor‐specific aHLAAb had ptcbm but did not have cg. The group without aHLAAb rarely showed ptcbm. The presence of DSA was associated with impaired graft function. C4d was not specific for the patients with DSA. These histopathological markers are useful in the detection of immunological chronic rejection. Early detection by screening tests will be important for treatment before irreversible change occurs.

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

Abstract:  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.

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

Abstract:  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.

Successful treatment with foscarnet for ganciclovir‐resistant cytomegalovirus infection in a kidney transplant recipient: A case report

Cytomegalovirus (CMV) infection is the most common infectious complication following solid organ transplantation. Ganciclovir (GCV)‐resistant CMV infection may be fatal, and is difficult to treat while avoiding allograft rejection. A 31‐year‐old woman received a second ABO‐incompatible kidney transplant, from her father. Induction therapy consisted of basiliximab and rituximab followed by maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and methylprednisolone. Her CMV serostatus was D+/R‐ at second transplant and she received prophylactic low‐dose valganciclovir (VGCV). BK polyoma virus nephropathy (BKVN) developed 7 months after transplant concurrent with CMV hepatitis and retinitis. VGCV was increased to a therapeutic dose combined with reduced immunosuppression with minimal methylprednisolone (2 mg/day) and everolimus (0.5 mg/day). However, pp65 antigenaemia continued to increase for 6 weeks. Her CMV was defined as ganciclovir (GCV)‐resistant. Foscarnet was therefore administered and her CMV disease resolved within 2 weeks. Kidney allograft dysfunction developed 9 months after transplant, and graft biopsy showed tubulointerstitial injury with crystal deposition suggesting foscarnet nephrotoxicity, with no findings of BKVN or rejection. Kidney function recovered after cessation of foscarnet and the patient had good graft function 18 months after transplant. This case demonstrates the successful use of foscarnet to treat GCV‐resistant CMV infection after ABO‐incompatible kidney transplant complicated with BKVN, without acute allograft rejection. This case further highlights the need to establish appropriate management for CMV D+/R‐ patients to avoid the acquisition of GCV‐resistant gene mutations.

Long-term clinicopathological impact of calcineurin inhibitor cessation without specific cytoreductive induction in kidney transplantation

Calcineurin inhibitors (CNIs) have considerably improved renal allograft survival. However, their chronic use has various adverse effects, including hypertension, hyperlipidemia, and nephrotoxicity. We conducted a retrospective study of kidney transplant recipients using a CNI withdrawal protocol. Eleven of 13 patients who had stable graft function on triple‐drug therapy including a cyclosporine (CsA) were enrolled in this study. The dose of CsA was reduced by 20% every two wks until complete withdrawal. The mean period between the baseline and last biopsies was 97 (range: 21–123) months. No patient had an acute rejection episode during follow‐up. Progression of interstitial fibrosis and tubular atrophy was seen in five and six cases, respectively. Arteriolar hyalinosis improved in three cases, but worsened in four. No patient lost his graft during the study. The mean serum creatinine level was 1.30 ± 0.26 mg/dL at baseline and stable for 10 yr after elimination (1.26 ± 0.11 mg/dL). At the end of the study, four of the eleven patients had reduced their antihypertensive drugs, and one patient had stopped hyperlipidemia treatment. CNI withdrawal can be implemented safely in stable renal transplant recipients and might lead to improved patient outcomes. Additional specific evidence of CNI nephrotoxicity should be elucidated.

Steroid-sensitive nephrotic syndrome associated with positive C1q immunofluorescence

A 21-year-old woman showed heavy proteinuria and edema. A light microscopic study of a renal biopsy specimen showed diffuse mild mesangial expansion, with borderline mesangial hypercellularity. An immunofluorescence study revealed dominant positive staining (3+) of C1q in the glomerular mesangium. Stainings for C3, C4, IgG, and IgM were weak or 1+. Staining for IgA was negative. Electron-dense deposits were present in the mesangial area. There was significant fusion of foot processes. There was no serological or clinical evidence of collagen disease. She was treated with oral prednisolone (initially, 40 mg/day). The proteinuria was alleviated and the patient remains in complete remission. The histopathological studies were compatible with C1q nephropathy, although the clinical outcome differed in a number of aspects. The clinical picture in the current patient appears to represent a very rare phenotype of nephritis.

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

Abstract:  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.

Severe acute‐hybrid rejection occurring nine months after kidney transplantation: a report of rescue by orchestration of antirejection therapies

Abstract:  Although a majority of acute rejection (AR) in non‐sensitized recipients is T‐cell‐mediated by primed T cells, recent studies have shown that antibody‐mediated acute rejection occurs in 20–30% of AR, and that it is often refractory to conventional antirejection therapy; possibly leading to graft loss. We report a case of severe acute‐hybrid rejection consisting of both features in a non‐sensitized kidney recipient, which was rescued by the orchestration of antirejection therapies. A 33‐yr‐old Japanese male, with advanced‐stage chronic kidney disease with an unknown etiology, underwent a HLA 3/6 mismatch and ABO‐compatible living‐related kidney transplantation preemptively. He had an excellent clinical course, except for initial cytomegalovirus infection, with good graft function [serum creatinine (sCr) 1.1 mg/dL]. Nine months later, his creatinine abruptly increased to 2.1 mg/dL, when graft biopsy revealed acute T cell‐mediated rejection (ATMR) grade IA, and simultaneous acute antibody‐mediated rejection (AAMR) grade I. Antirejeciton therapy, comprising methyl‐prednisolone pulse and 15‐deoxyspergualin, and second line rituximab and plasmapheresis, was ineffective. Moreover, histologically and clinically, the rejection status deteriorated (ATMR grade III and AAMR grade III, max sCr 4.0 mg/dL). Next, we administered muromonab CD3 and basiliximab, which could eradicate the complicated severe AR without opportunistic infection, even under the strong immunosuppression. The present case implies that high‐grade combined rejection can respond to anti‐CD 20 and anti‐CD25 mAbs, without serious complication; however, post‐operative, thorough appropriate monitoring of immunosuppression is important because its effects are limited.

A case of plasmacytic hyperplasia arising in a kidney allograft salvaged with immunosuppression reduction alone.

Abstract:  Post‐transplant lymphoproliferative disorder (PTLD) is a well‐known complication of organ transplantation. Plasmacytic hyperplasia (PH) is thought of as the mildest form of PTLD; however, a graftectomy is necessary in most situations. We experienced an interesting case of PH arising in a kidney allograft, which could be relieved with a reduction in immunosuppression. A 27‐year‐old female underwent a living‐related kidney transplantation. A 3‐month non‐episode protocol biopsy unexpectedly showed the devastating appearance of polymorphic plasma cell infiltration into the graft intersitium, compatible with PH. The PH was located in the graft by radiographic examinations. The infiltration of plasma cell disappeared completely on the 6‐month graft biopsy specimen following immunosuppression reduction and the graft is functioning, although it was damaged by a subsequent acute rejection. Our present case indicates that some PTLD can be completely cured with a reduction in immunosuppression alone. The diagnostic modality for the evaluation of PTLD cell extinction is necessary to maintain graft function with adequate immunosuppression thereafter.

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

Abstract: 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.