Aki Mafune

Distinct effects of alcohol consumption and smoking on genetic alterations in head and neck carcinoma.

Background Tobacco and alcohol consumption are risk factors for head and neck squamous cell carcinoma (HNSCC). Recently, whole-exome sequencing clarified that smoking increased TP53 and other mutations in HNSCC; however, the effects of alcohol consumption on these genetic alterations remain unknown. We explored the association between alcohol consumption and somatic copy-number alterations (SCNAs) across the whole genome in human papillomavirus (HPV)-negative HNSCCs, and compared with the effects of smoking on genetic alterations. Methods SCNA and TP53 mutations in tumor samples were examined by high-resolution comparative genomic hybridization microarray 180K and by direct sequencing, respectively, and statistically analyzed for associations with alcohol consumption and smoking during the 20 years preceding diagnosis of HNSCC. Probes with a corrected p-value (=q-value) less than 0.05 and fold change greater than 1.2 or less than -1.2 were considered statistically significant. Results A total of 248 patients with HNSCC were enrolled. In the HPV-negative patients (n=221), heavy alcohol consumption was significantly associated with SCNAs of oncogenes/oncosuppressors that were previously reported to occur frequently in HNSCCs: CDKN2A (q=0.005), FHIT (q=0.005), 11q13 region including CCND1, FADD and CTTN (q=0.005), ERBB2 (HER2) (q=0.009), 3q25-qter including CCNL1, TP63, DCUN1D1 and PIK3CA (q=0.014), and CSMD1 (q=0.019). But, TP53 mutations were not affected. In contrast, smoking was associated with increased risk of TP53 mutations, but did not induce any significant SCNAs of oncogenes/oncosuppressors. Conclusion These results suggest that both alcohol consumption and smoking had distinct effects on genetic alterations in HNSCCs. Heavy alcohol consumption may trigger previously known and unknown SCNAs, but may not induce TP53 mutation. In contrast, smoking may induce TP53 mutation, but may not trigger any SCNAs.

Proton Pump Inhibitor Use and Magnesium Concentrations in Hemodialysis Patients: A Cross-Sectional Study

Magnesium concentration is a proven predictor of mortality in hemodialysis patients. Recent reports have indicated that proton pump inhibitor (PPI) use affects serum magnesium levels, however few studies have investigated the relationship between PPI use and magnesium levels in hemodialysis patients. This study aimed to clarify the association between PPI use and serum magnesium levels in hemodialysis patients. We designed this cross sectional study and included 1189 hemodialysis patients in stable condition. Associations between PPI and magnesium-related factors, as well as other possible confounders, were evaluated using a multiple regression model. We defined hypomagnesemia as a value < 2.0 mg/dL, and created comparable logistic regression models to assess the association between PPI use and hypomagnesemia. PPI use is associated with a significantly lower mean serum magnesium level than histamine 2 (H2) receptor antagonists or no acid-suppressive medications (mean [SD] PPI: 2.52 [0.45] mg/dL; H2 receptor antagonist: 2.68 [0.41] mg/dL; no acid suppressive medications: 2.68 [0.46] mg/dL; P = 0.001). Hypomagnesemia remained significantly associated with PPI (adjusted OR, OR: 2.05; 95% CI: 1.14–3.69; P = 0.017). PPI use is associated with an increased risk of hypomagnesemia in hemodialysis patients. Future prospective studies are needed to explore magnesium replacement in PPI users on hemodialysis.

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.

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.

Successful treatment of monomorphic primary central nervous system post‐transplantation lymphoproliferative disorder 5 years after kidney transplantation

A 31‐year‐old man underwent living‐related kidney transplantation in 2004 as a consequence of primary focal segmental glomerulosclerosis (FSGS). Four years after the transplantation, we confirmed nephrotic syndrome caused by recurrent FSGS. We performed plasmapheresis and low‐density lipoprotein adsorption. We also combined steroid therapy with a reduction in the dose of tacrolimus and an increased dose of mycophenolate mofetil. The nephrotic syndrome improved dramatically with this combined therapeutic approach.

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.

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.

A case of BK virus nephropathy and cytomegalovirus infection concurrent with plasma cell–rich acute rejection

The BK virus is a double‐stranded DNA virus to which 90% of adults have been exposed. BK virus infections typically result in an oral or respiratory infection; however, BK virus reactivation is an infectious disease of concern in kidney transplant recipients. The prevalence of BK virus nephropathy (BKN) in kidney transplant recipients is approximately 5%, and most cases occur within one yr after kidney transplantation. Graft survival of BKN is reported to be 30–60%, and the standard treatment strategy for BKN is reducing immunosuppressive therapy and close monitoring for rejection. Viral infection is most common in the early post‐transplantation phase, and BKN or acute rejection is one of the major factors involved in graft loss. However, in this report, we describe the successful management of BKN and cytomegalovirus infection concurrent with plasma cell–rich acute rejection.