Takafumi Yamakawa

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.

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.

Rare case of nephrocalcinosis in the distal tubules caused by hereditary renal hypouricaemia 3 months after kidney transplantation

We report a rare case of nephrocalcinosis caused by hereditary renal hypouricaemia 3 months after kidney transplantation. A 41‐year‐old man who underwent living‐related kidney transplantation from his father was admitted to our hospital for a protocol biopsy; he had a serum creatinine (S‐Cr) of 1.37 mg/dL and no proteinuria. Histologically, there was no evidence of rejection or calcineurin inhibitor toxicity, although scattered nephrocalcinosis was observed in the distal tubules. Perioperatively, the patient had a serum uric acid (S‐UA) of 1.9 mg/dL with a fractional excretion of uric acid (FEUA) of 29% (normal, <10%) and UA clearance of 26.8 mL/min (normal, 7.3–14.7 mL/min) 3 days after kidney transplantation. The donor also had a relatively low S‐UA of 2.4 mg/dL and high FEUA of 10.3%. Subsequent DNA direct sequencing followed by restriction fragment length polymorphism revealed that both the recipients and donors urate transporter 1 (URAT1) gene had a heterozygous nonsense mutation in exon 5 (C889T). Further, the immunoreactivity of antibodies for the C terminus of URAT1 revealed a partial deletion. De Galantha and von Kossa staining revealed that the nephrocalcinosis was due to urate crystals and calcium stones. Therefore, we diagnosed hereditary renal hypouricaemia. We directed the patient to avoid hard exercise, drink plenty of water, and alkalize the urine. The 1‐year follow‐up allograft biopsy showed no evidence of nephrocalcinosis in the distal tubules. This is the first report of nephrocalcinosis in the distal tubules as a diagnostic clue to hereditary renal hypouricaemia. We also review the related literature.

Clinical and pathological features of donor/recipient body weight mismatch after kidney transplantation

Previous studies have shown that a donor/recipient body weight mismatch affects long‐term graft survival and graft function after kidney transplantation. However, the mechanisms are not fully understood.

Recurrence of native kidney disease after kidney transplantation: Recurrence of native GN after KTx

The extent of recurrence of original kidney disease after kidney transplantation has been underestimated for several reasons. First, the duration of observation varies among studies. Second, the criteria used to schedule protocol and episode biopsies differ among institutions. And third, diagnostic modalities used for early detection of recurrent original kidney disease also vary. Thus, rates of graft loss attributable to a recurrence of original kidney disease vary among institutions and are often underestimated. However, the recurrence of original disease is often thought to be less important than chronic rejection followed by loss of a functioning allograft. It is important to note that recent data have shown that in patients with certain limited primary kidney diseases (e.g., membranous proliferative glomerulonephritis [MPGN], IgA nephritis [IgAN], focal segmental glomerulonephritis [FSGS], and membranous nephropathy [MN]), the predominant (60%) cause of graft loss is the recurrence of original kidney disease. In addition, the rate of 5‐year graft survival in patients with recurrent original kidney disease averages 45%. Thus, research must address the recurrence of original kidney disease. Here we focus on this recurrence and discuss diagnoses, preventive strategies, treatments, and future research directions.

Clinicopathological features and outcomes of kidney allografts in plasma cell-rich acute rejection: A case series: Cases of plasma cell-rich acute rejection

Plasma cell‐rich acute rejection (PCAR) is a rare type of acute rejection in renal transplantation. Despite aggressive immunotherapy, approximately 40–60% of patients develop graft loss within 1 year after an episode of PCAR. However, the reason for this outcome remains obscure. This study retrospectively identified six patients with PCAR diagnosed between 2009 and 2015 at a single university hospital. Clinicopathological data were collected. Five of the six patients were male, and mean age at the onset of PCAR was 49.0 ±14.5 years. None of the patients showed overall poor adherence to medication. Mean time to diagnosis was 302 ±234 days post‐transplantation. All patients had preceding or concurrent viral infection. Four patients developed PCAR alone and two patients developed PCAR with antibody‐mediated rejection. One of the six patients showed both severe tubulointerstitial and microvascular inflammation (total of Banff tubulitis ‘t’ + interstitial inflammation ‘i’ + glomerulitis ‘g’ + peritubular capillaritis ‘ptc’ scores >10). This patient had progressive worsening of graft function and re‐initiated dialysis at 74 months after a PCAR episode. In addition, three of the six patients had long‐term recurrence of PCAR. With the recurrence of PCAR, patients with both moderate tubulointerstitial and microvascular inflammation (total of Banff ‘t’ + ‘i’ + ‘g’ + ‘ptc’ scores >6) had progressive worsening of graft function. In summary, the present results suggest that concurrent moderate to severe tubulointerstitial and microvascular inflammation may lead to poor outcomes of graft function after a PCAR episode.