Yasuyuki Nakada

Plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation

We report a case of plasma cell‐rich rejection accompanied by acute antibody‐mediated rejection in a patient with ABO‐incompatible kidney transplantation. A 33‐year‐old man was admitted for an episode biopsy; he had a serum creatinine (S‐Cr) level of 5.7 mg/dL 1 year following primary kidney transplantation. Histological features included two distinct entities: (1) a focal, aggressive tubulointerstitial inflammatory cell (predominantly plasma cells) infiltration with moderate tubulitis; and (2) inflammatory cell infiltration (including neutrophils) in peritubular capillaries. Substantial laboratory examination showed that the patient had donor‐specific antibodies for DQ4 and DQ6. Considering both the histological and laboratory findings, we diagnosed him with plasma cell‐rich rejection accompanied by acute antibody‐mediated rejection. We started 3 days of consecutive steroid pulse therapy three times every 2 weeks for the former and plasma exchange with intravenous immunoglobulin (IVIG) for the latter histological feature. One month after treatment, a second allograft biopsy showed excellent responses to treatment for plasma cell‐rich rejection, but moderate, acute antibody‐mediated rejection remained. Therefore, we added plasma exchange with IVIG again. After treatment, allograft function was stable, with an S‐Cr level of 2.8 mg/dL. This case report demonstrates the difficulty of the diagnosis of, and treatment for, plasma cell‐rich rejection accompanied by acute antibody‐mediated rejection in a patient with ABO‐incompatible kidney transplantation. We also include a review of the related literature.

Successful treatment of recurrent Henoch–Schönlein purpura nephritis in a renal allograft with tonsillectomy and steroid pulse therapy

We report a case of recurrent Henoch–Schönlein purpura nephritis (HSPN) treated successfully with a tonsillectomy and steroid pulse therapy in a kidney transplant patient. A 29‐year‐old woman was admitted to our hospital for an episode biopsy; she had a serum creatinine (S‐Cr) of 1.0 mg/dL and 1.34 g/day proteinuria 26 months after kidney transplantation. Histological examination revealed increased amounts of mesangial matrix and mesangial hypercellularity with IgA deposition. Of note, one glomerulus showed focal endocapillary proliferation and tuft necrosis. We diagnosed active recurrent HSPN. Considering both the histological findings and refractory clinical course of the native kidney, she was treated for 3 consecutive days with steroid pulse therapy and a tonsillectomy. The patients proteinuria decreased gradually to less than 150 mg/day 6 months later. A second biopsy 6 years after kidney transplantation showed an excellent response to treatment and revealed a marked reduction in both the mesangial matrix and mesangial hypercellularity, with trace IgA deposition. We conclude that a tonsillectomy and steroid pulse therapy appeared to be useful in this patient with active recurrent HSPN. This paper is the first to report a tonsillectomy and steroid pulse therapy as a therapeutic option for active recurrent HSPN. Further studies are needed to elucidate the efficacy and mechanisms of tonsillectomy with recurrent HSPN in kidney transplant patients.

Subclinical antibody-mediated rejection due to anti-human-leukocyte-antigen-DR53 antibody accompanied by plasma cell-rich acute rejection in a patient with cadaveric kidney transplantation.

A 56‐year‐old man who had undergone cadaveric kidney transplantation 21 months earlier was admitted to our hospital for a protocol biopsy; he had a serum creatinine level of 1.2 mg/dL and no proteinuria. Histological features showed two distinct entities: (i) inflammatory cell infiltration, in the glomerular and peritubular capillaries and (ii) focal, aggressive tubulointerstitial inflammatory cell infiltration, predominantly plasma cells, with mild tubulitis (Banff 13 classification: i2, t1, g2, ptc2, v0, ci1, ct1, cg0, cv0). Immunohistological studies showed mildly positive C4d immunoreactivity in the peritubular capillaries. The patient had donor specific antibody to human‐leucocyte‐antigen‐DR53. We diagnosed him with subclinical antibody‐mediated rejection accompanied by plasma cell‐rich acute rejection. Both antibody‐mediated rejection due to anti‐ human‐leucocyte‐antigen ‐DR53 antibodies and plasma cell‐rich acute rejection are known to be refractory and have a poor prognosis. Thus, we started plasma exchange with intravenous immunoglobulin and rituximab for the former and 3 days of consecutive steroid pulse therapy for the latter. Three months after treatment, a follow‐up allograft biopsy showed excellent responses to treatment for both histological features. This case report considers the importance of an early diagnosis and appropriate intervention for subclinical antibody‐mediated rejection due to donor specific antibody to human‐leucocyte‐antigen‐DR53 and plasma cell‐rich acute rejection.

A refractory case of subclinical antibody‐mediated rejection due to anti‐HLA‐DQ antibody in a kidney transplant patient

We herein report a refractory case of subclinical antibody‐mediated rejection (AMR) due to anti‐HLA‐DQ antibody in a kidney transplant patient. A 45‐year‐old man was admitted for a protocol biopsy; he had a serum creatinine (S‐Cr) level of 1.8 mg/dL 3 years following primary kidney transplantation. Histological examination revealed moderate to severe inflammatory cell infiltration in the peritubular capillaries. Thorough laboratory examination showed that the patient had donor‐specific antibodies (DSAbs) to DR9 and DQ9. Considering both the histological and laboratory findings, we diagnosed acute antibody‐mediated rejection. The patient underwent 3 days of consecutive steroid pulse therapy, intravenous immunoglobulin (IVIG), and plasma exchange. We also administered rituximab (200 mg/body). Six months after the treatment, a second allograft biopsy revealed the progression of interstitial fibrosis and tubular atrophy and persistence of mild peritubular capillaritis. Further analysis showed that the anti‐DR9 antibodies had disappeared, but that the mean fluorescence intensity value of the anti‐DQ9 antibodies had increased. Therefore, we repeated the plasma exchange and IVIG. Allograft function was stable throughout the course of treatment, and the S‐Cr level remained at 1.8 mg/dL. This case report demonstrates the difficulty of treating AMR due to the presence of anti‐DQ DSAbs and the necessity for subsequent therapies in refractory cases.

Successful treatment of BK virus nephropathy using therapeutic drug monitoring of mycophenolic acid.

We report the successful management of BK virus nephropathy (BKVN) using therapeutic drug monitoring (TDM) of mycophenolic acid (MPA). A 40‐year‐old woman was admitted for a protocol biopsy 3 months following primary kidney transplantation. Histological features were distributed in mainly two sections: the corticomedullary junction and cortical area. In the former, massive interstitial mononuclear cell infiltration and mild to moderate tubulitis with nuclear inclusion bodies were found. SV40 staining was positive in the injured tubules. These findings were compatible with BKVN. In the latter, focal interstitial inflammation and severe tubulitis without cytopathic changes were identified outside of SV40‐positive areas. Based on the histological findings, we diagnosed BKVN and we also suspected of the complication with acute T‐cell‐mediated rejection. We started steroid pulse therapy and reduced the dosage of immunosuppressive therapy under careful monitoring, using not only a trough level of tacrolimus but also a 12‐h area under the curve (AUC0–12) of MPA. After the treatment, the patient maintained kidney function. This case report demonstrates the usefulness of MPA AUC0–12 for more accurate adjustment of immunosuppressive therapy and the difficulty of pathological differentiation of BKVN and acute cellular rejection.

Acute vascular rejection during antituberculosis therapy in a kidney transplant patient.

We report a case of acute vascular rejection occurring during antituberculosis therapy in a patient who had received a kidney transplant. A 29 year‐old man was admitted for a protocol biopsy; he had a serum creatinine (S‐Cr) level of 1.5 mg/dL 1 year after primary kidney transplantation. Histological examination yielded no evidence of rejection but a routine chest CT scan revealed typical lung tuberculosis and his serum was positive for QFT. We commenced antituberculosis therapy, including rifampicin, on June 29 2012. We paid close attention to the weekly trough tacrolimus (TAC) level but the S‐Cr concentration increased to 3.7 mg/dL on October 16 2012, and he was admitted for biopsy. Histological examination revealed, first, a diffuse aggressive infiltration of tubulointerstitial inflammatory cells accompanied by severe tubulitis and mild intimal arteritis and, second, peritubular capillary infiltration by inflammatory cells (including neutrophils). Laboratory data revealed that our patient did not express donor‐specific antibody and the peritubular capillaries did not exhibit C4d immunoreactivity. Upon consideration of both histological and laboratory findings, we diagnosed acute vascular rejection of Banff 2007 class ACR IIA. We commenced 3‐day sessions of intravenous steroid pulse therapy twice weekly and adjusted the trough TAC level to 5–8 ng/mL by varying the TAC dose. We next performed an allograft biopsy and found no evidence of rejection (the S‐Cr level was 2.7 mg/dL on April 1 2013). The present case report demonstrates the difficulties associated with management of TAC‐based regimens in kidney transplant patients undergoing antituberculosis therapy. We also review the relevant literature.

The prognostic values of Caveolin‐1 immunoreactivity in peritubular capillaries in patients with kidney transplantation

The low sensitivity of C4d immunoreactivity in peritubular capillaries (PTCs) hinders its use in the diagnosis of chronic active antibody‐mediated rejection (CAAMR). C4d‐negative CAAMR was defined in the 2013 Banff classification, which included the expression of endothelial‐associated transcripts (ENDATs). We previously showed that the ENDAT caveolin‐1 (CAV‐1) is a distinct feature of CAAMR. In this study, we investigated the prognostic value of CAV‐1 immunoreactivity in PTCs in kidney transplant patients. Ninety‐eight kidney transplant recipients were included in this study. The prognostic value of CAV‐1 immunoreactivity in PTCs was evaluated by double immunostaining for CAV‐1 and pathologische Anatomie Leiden endothelium (PAL‐E, a PTC marker) in the PTCs of kidney allograft biopsy samples. The patients were divided into two groups: CAV‐1/PAL‐E<50% and CAV‐1/PAL‐E≥50%. Kaplan‐Meier curves showed that CAV‐1/PAL‐E≥50% patients had a significantly worse prognosis than that of CAV‐1/PAL‐E<50% patients (log‐rank; P<.001). C4d staining of PTCs was not associated with the development of graft failure (log‐rank; P=.345), whereas in a multivariate Cox regression analysis, CAV‐1 immunoreactivity in PTCs was independently associated with graft failure (hazard ratio: 11.1; P=.0324). CAV‐1 immunoreactivity in PTCs may serve as a prognostic marker for kidney allograft survival.

Probable C4d‐negative accelerated acute antibody‐mediated rejection due to non‐HLA antibodies

We report a case of probable C4d‐negative accelerated acute antibody‐mediated rejection due to non‐HLA antibodies. A 44 year‐old male was admitted to our hospital for a kidney transplant. The donor, his wife, was an ABO minor mismatch (blood type O to A) and had Gitelman syndrome. Graft function was delayed; his serum creatinine level was 10.1 mg/dL at 3 days after transplantation. Open biopsy was performed immediately; no venous thrombosis was observed during surgery. Histology revealed moderate peritubular capillaritis and mild glomerulitis without C4d immunoreactivity. Flow cytometric crossmatching was positive, but no panel‐reactive antibodies against HLA or donor‐specific antibodies (DSAbs) to major histocompatibility complex class I‐related chain A (MICA) were detected. Taken together, we diagnosed him with probable C4d‐negative accelerated antibody‐mediated rejection due to non‐HLA, non‐MICA antibodies, the patient was treated with steroid pulse therapy (methylprednisolone 500 mg/day for 3 days), plasma exchange, intravenous immunoglobulin (40 g/body), and rituximab (200 mg/body) were performed. Biopsy at 58 days after transplantation, at which time S‐Cr levels were 1.56 mg/dL, found no evidence of rejection. This case, presented with a review of relevant literature, demonstrates that probable C4d‐negative accelerated acute AMR can result from non‐HLA antibodies.

Change in glomerular volume and its clinicopathological impact after kidney transplantation.

Both immunological and non‐immunological etiologies affect graft function after kidney transplantation, including acute rejection, calcineurin inhibitor toxicity, and a recurrence of glomerulonephritis. Glomerular enlargement or glomerular sclerosis due to glomerular hyperfiltration related to increased renal blood flow is another cause. Although the glomerular volume in baseline biopsies predicts late allograft function, the relationship between allograft function and the annual changes in glomerular volume after kidney transplantation are unclear.

Clinicopathological study of de novo membranous nephropathy of ‘stage 0’ after kidney transplantation: De novo membranous nephropathy stage 0

De novo membranous nephropathy (dnMN) contributes to graft failure, but the pathophysiology of the disease remains poorly understood. We defined cases exhibiting granular Immunoglobulin G (IgG) immunofluorescence staining but lacking dense deposits on electron microscopy as being of ‘dnMN stage 0’; we studied the associated clinicopathological features.