Antibody-mediated rejection due to anti-HLA-DQ antibody after pregnancy and delivery in a female kidney transplant recipient.

Herein, we report a case of antibody-mediated rejection (ABMR) due to anti-HLA-DQ antibody after pregnancy and delivery in a female kidney transplant recipient. A 34-year-old female recipient was admitted at 2 years after delivery for an examination of an elevated serum creatinine (S-Cr) level. The patient had received a living kidney transplantation from her mother at 22 years of age, and her kidney graft function was almost stable. The episode biopsy showed peritubular capillaritis and transplant capillaropathy with C4d immunoreactivity in the peritubular capillaries. Additional examination revealed expression of a donor-specific antibody (DSA) against HLA-DQ5, leading to the diagnosis of chronic active ABMR. Intravenous immunoglobulin, plasma exchange, and rituximab were administered, and her S-Cr level was maintained stable. This case demonstrates a possible relationship between pregnancy/delivery and development of ABMR due to a de novo DSA in a female kidney transplant recipient.

Recurrence and graft loss after renal transplantation in adults with IgA vasculitis.

BACKGROUND: IgA vasculitis, a rare condition resulting in end-stage renal disease, is a small-vessel vasculitis that affects the kidney in 49-83 % of adults. The reported recurrence rate of IgA vasculitis in renal transplant recipients is 11.5-60 %, leading to graft loss in 0-50 % of these patients. However, limited data are available on recurrence and graft loss after renal transplantation. METHODS: We evaluated renal transplant recipients seen from 1987 to 2015 at the Jikei University School of Medicine and the Department of Urology, Tokyo Women's Medical University. Using a 1:2 match, 21 patients with IgA vasculitis and 42 controls were selected. The mean post-transplant follow-up was 121 ± 69 months for IgA vasculitis and 147 ± 66 months for the controls. RESULTS: The 15-year patient survival was 100 % in IgA vasculitis and 97.6 % in the controls (p = 0.22). The 5-, 10-, and 15-year graft survival rates were 95.2, 90.5, and 81 % in IgA vasculitis and 100, 90.5, and 88.1 % in the controls, respectively (p = 0.63). The recurrence rate was 28.6 % (6 of 21 cases) and half of them (3 of 6 cases) showed histological activity (ISKDC III). We treated them with methylprednisolone pulse therapy and/or tonsillectomy. None of the recurrence cases lost the allograft. CONCLUSION: The long-term patient and graft survival of IgA vasculitis in renal transplantation were comparable with the previous reports. The recurrence rate was 28.6 %, but none of the recurrent cases showed allograft loss in this study. We speculate that methylprednisolone pulse therapy and/or tonsillectomy prevent the progression of recurrent IgA vasculitis.

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.

Associations among serum trimethylamine-N-oxide (TMAO) levels, kidney function and infarcted coronary artery number in patients undergoing cardiovascular surgery: a cross-sectional study.

BACKGROUND: Trimethylamine-N-oxide (TMAO) is a metabolite of phosphatidylcholine generated by gut microbiota and liver enzymes, and has recently been recognized as contributing to atherosclerosis. Elevated serum TMAO levels have been shown to increase the risk of cardiovascular disease (sudden death, myocardial infarction, or stroke) in patients undergoing elective coronary angiography. We aimed to clarify whether TMAO levels are associated with the number of infarcted coronary arteries as a measure of the severity of atherosclerosis, with adjustment using a priori-defined covariates such as kidney function. METHODS: By conducting a cross-sectional study of 227 patients who underwent cardiovascular surgery for coronary artery disease, valvular heart disease, or aortic disease, the association between serum TMAO levels as measured by HPLC-APCI-MS/MS and the number of infarcted coronary arteries was evaluated using ordered logistic regression models with adjustment of 10 covariates, including chronic kidney disease (CKD) stage. Unadjusted and adjusted odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were determined. RESULTS: Significantly higher TMAO levels were observed in advanced-stage CKD (p ≤ 0.001). In fully adjusted models with the 10 covariates, a significantly increased number of infarcted coronary arteries was identified in the highest quartile and quintile of TMAO compared to the lowest quartile (OR 11.9; 95 % CI 3.88-36.7, p ≤ 0.001) and quintile (OR 14.1; 95 % CI 3.88-51.2; p ≤ 0.001), respectively, independent of dyslipidemia. CONCLUSIONS: Higher serum TMAO levels may be associated with advanced CKD stages and with an increased number of infarcted coronary arteries in patients who undergo cardiovascular surgery.

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 patient's 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.

Homozygous deletions of UGT2B17 modifies effects of smoking on TP53-mutations and relapse of head and neck carcinoma.

BACKGROUND: Smoking induces oncogenic TP53-mutations in head and neck squamous cell carcinomas (HNSCCs). Disruptive mutations of TP53-gene and expression of p16 protein [p16 (+)] in tumor tissue associate with worse and better prognosis, respectively. UDP-glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) detoxifies smoking-related metabolites. Differences among ethnic groups in UGT2B17 are extremely high. Homozygous deletions of UGT2B17 gene (UGT2B17-deletion) are a common copy number variant (CNV) among Japanese, but not a common CNV among Africans and Europeans. Thus, we examined Japanese patients with HNSCC to explore if UGT2B17-deletion and/or p16 (+) modify effects of smoking on TP53-mutations and affect relapse. METHODS: We conducted a posthoc analysis of a prospective cohort. Polymerase chain reaction, immunohistochemistry, and direct sequencing were used to determine UGT2B17-deletion, p16 (+), and detailed TP53-mutations, respectively. RESULTS: UGT2B17-deletion was observed in 80% of this study population. For this 80%, TP53-mutations were significantly more common among smokers than non-smokers (P = 0.0016), but this difference between smokers and nonsmokers was not significant for the 20% with UGT2B17. In patients with UGT2B17-deletion and p16 (+), simultaneously, TP53-mutations were much more common among smokers than among non-smokers (81% versus 17%; P = 0.0050). Patients with both UGT2B17-deletion and disruptive TP53-mutations had higher relapse rates than other patients (hazard ratio, 2.22; 95% confidence interval, 1.30 to 3.80, P = 0.004) in a stepwise method. CONCLUSIONS: These results suggest that UGT2B17-deletion interacting with p16 (+) may modify effects of smoking on TP53-mutations and may further interact with the disruptive TP53-mutations to raise relapse rates among Japanese patients with HNSCC.

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

BACKGROUND: 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. AIM: We investigated changes in glomerular volume after kidney transplantation and their clinicopathological relationship. METHODS: We enrolled 23 patients with stable kidney function without an episode of rejection or any complication resulting in a functional decrease in the graft. We measured glomerular volume (GV) using the Weibel-Gomez method and glomerular density (GD) using 0,1 h biopsy samples as baseline controls and 1 yr biopsy samples and investigated the association between the changes in them and clinical parameters, including graft function, proteinuria, and renal hemodynamic markers, including effective renal plasma flow (ERPF) and filtration fraction (FF). The ERPF was calculated from a 99mTc-mercaptoacetyltriglycine (MAG3) renogram. RESULTS: The GV and ERPF increased significantly 1 yr after kidney transplantation. In contrast, proteinuria decreased significantly and Δproteinuria (1 yr - 1 month after transplantation) was correlated with ΔGV (P < 0.05, rs = -0.467). CONCLUSION: Glomerular enlargement 1 yr after transplantation may be related to improved proteinuria. It is possible that glomerular enlargement serves as a renal adaptation after kidney transplantation.

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

BACKGROUND: 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. AIM: To address the mechanisms, we compared the pathological and physiological features between patients with a donor/recipient body weight mismatch and those without a mismatch 1 yr after kidney transplantation. Furthermore, we investigated the correlation with the donor/recipient body weight ratio. METHODS: We examined allograft biopsy specimens from 10 recipients with stable kidney function, with body weight mismatch (donor/recipient body weight ratio [D/R BWR] < 0.9), and compared them with samples from 13 patients without mismatch. We measured glomerular volume (GV) using the Weibel-Gomez method and glomerular density (GD) defined by nonsclerotic glomerular number/renal cortical area as pathological findings. The physiological parameters included estimated glomerular filtration rate and proteinuria (mg/day). These data were evaluated to identify a correlation with D/R BWR. RESULTS: The pathological features showed that GV and GD were identical in the two groups. However, when glomerular enlargement was defined by ΔGV (GV at the 1-yr biopsy minus GV at baseline biopsy), ΔGV was higher in mismatch cases compared with that in cases without a mismatch (10.6 ± 4.6 vs. 5.5 ± 7.1 × 10(5) µm(3) ; P = 0.049). Furthermore, D/R BWR was significantly correlated with ΔGV (P = 0.03, r = -0.436). eGFR values were physiologically identical between the two groups, but the mismatch cases had significantly higher proteinuria levels than that of the cases without a mismatch at 1 yr after kidney transplantation. CONCLUSION: A donor/recipient body weight mismatch could affect glomerular enlargement and increased proteinuria 1 yr after kidney transplantation. How these two features affect long-term graft survival and function must be addressed in the future.

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.

Acute T cell-mediated rejection accompanied by C4d-negative acute antibody-mediated rejection and cell debris in tubulus: A case report.

Herein, we report a complicated case of acute T-cell-mediated rejection (ACR) accompanied by C4d-negative acute antibody-mediated rejection (AMR) and cell debris in tubulus. A 32 year-old male was admitted for an episode biopsy with a serum creatinine (S-Cr) level of 1.83 mg/dL and pyuria (20-29 white blood cells per high power field) 49 days following kidney transplantation. Histological features included three distinct entities, mainly, in one of the three specimens: 1) focal aggressive tubulointerstitial inflammatory cell infiltration with moderate tubulitis, 2) inflammatory cell infiltration in peritubular capillaries (including neutrophils) and glomerular capillaries, and 3) cell debris consisting mainly of neutrophils in tubulus. Laboratory examination revealed evidence of non-human leukocyte antigen donor-specific antibodies. However, urinary culture and gram staining were negative. Considering both the histological and laboratory findings, the patient was diagnosed with ACR accompanied by C4d-negative AMR and suspicion of a urinary tract infection (UTI). The patient was treated for three consecutive days with steroid pulse therapy. The patient's S-Cr level decreased to ~1.5 mg/dL following treatment and did not increase thereafter. A second biopsy 133 days following kidney transplantation showed an excellent response to treatment and revealed no evidence of rejection. This case report demonstrates the difficulty in the diagnosis of, and therapy for, the complicated pathological findings of ACR, AMR and suspicion of a UTI.

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.

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.

Associations among smoking, MGMT hypermethylation, TP53-mutations, and relapse in head and neck squamous cell carcinoma.

BACKGROUND: Epigenetic silencing of the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair enzyme via promoter hypermethylation (hmMGMT) may increase mutations in the TP53 oncosuppressor gene and contribute to carcinogenesis. The effects of smoking, which is a risk factor for head and neck squamous cell carcinoma (HNSCC), were investigated to determine whether they up- or down-regulate hmMGMT. Additionally, the impact of hmMGMT and disruptive TP53-mutations on relapse was investigated in patients with HNSCC. METHODS: This study included 164 patients with HNSCC who were negative for both p16 protein expression and human papilloma virus infection. The association of smoking and hmMGMT was investigated using multiple logistic regression analysis. Competing risk regression was used to evaluate the effects of hmMGMT and TP53-mutations in exon 2 to 11 on relapse of HNSCC. RESULTS: hmMGMT was observed in 84% of the 164 patients. TP53-mutations, specifically, G:C>A:T transition, were more frequent in patients with hmMGMT (32%) than in those without hmMGMT (8%). The frequency of disruptive TP53-mutations was not significantly different between groups. Compared with nonsmoking, heavy smoking of 20 pack-years or more was significantly associated with decreased hmMGMT (adjusted odds ratio, 0.08; 95% CI, 0.01 to 0.56; P = 0.01). Patients who had both hmMGMT and disruptive TP53-mutations showed a significantly higher relapse rate than all other patients (subdistribution hazard ratio, 1.77; 95% CI, 1.07 to 2.92; P = 0.026). CONCLUSIONS: It was found that hmMGMT was suppressed by heavy smoking, and hmMGMT combined with disruptive TP53-mutations may indicate a poor prognosis in patients with HNSCC.

A Case of Transplant Nephrectomy due to Chronic Graft Intolerance Syndrome.

We report a case of graft intolerance syndrome in which transplant nephrectomy was performed 11 years after kidney transplantation. A 46-year-old man was admitted to our hospital in February 2018 with a mild fever, left lower abdominal pain, and gross hematuria with enlargement of the transplanted kidney. Urinary tract infection was ruled out. Because the symptoms developed after the immunosuppressants had been stopped after kidney graft loss, graft intolerance syndrome was suspected. He had lost his graft in 2016 and had stopped all immunosuppressants since January of 2017. Immunosuppressive therapy was intensified, and steroid half-pulse therapy was added for 3 days. After the steroid pulse therapy, the C-reactive protein (CRP) decreased from 6.47 mg/dL to 0.76 mg/dL, but there was little improvement in the symptoms, and the CRP then increased to 4.44 mg/dL. Transplant nephrectomy was performed in March 2018. Postoperatively, the symptoms disappeared without the administration of immunosuppressants, and the CRP decreased. Pathologically, the resected kidney graft showed persistent active allograft rejection with severe endarteritis, transplant glomerulopathy, and diffuse interstitial fibrosis. Massive thrombi occluded the large arteries, and there was extensive hemorrhagic cortical necrosis. Transplant nephrectomy is uncommon in patients >6 months after transplantation. However, even if more time has passed since transplantation, as in this case, transplant nephrectomy may be a valid option in some cases of severe graft intolerance syndrome.

Associations Between Low Serum Testosterone and All-Cause Mortality and Infection-Related Hospitalization in Male Hemodialysis Patients: A Prospective Cohort Study.

INTRODUCTION: Infectious diseases are the second highest cause of death in patients on dialysis. In addition, testosterone deficiency or hypogonadism is prevalent in dialysis patients. However, to our knowledge, no studies have investigated the association between testosterone levels and infectious events. We aimed to evaluate whether serum testosterone levels are associated with infection-related hospitalization in male hemodialysis patients in a prospective cohort study. METHODS: We divided the study population into 3 groups based on serum testosterone levels. Associations between testosterone levels and clinical outcomes of infection-related hospitalization, all-cause mortality, and cardiovascular disease (CVD) events were analyzed using the Cox proportional hazard model. RESULTS: Nine hundred two male patients were enrolled and followed up for a median of 24.7 months. Their mean ± SD age was 63.4 ± 11.8 years, and their median (interquartile range) of total testosterone was 11.7 nmol/l (7.9-14.9 nmol/l). During follow-up, 123 participants died. Infection-related hospitalization and CVD events occurred in 116 and 151 patients, respectively. Infection-related hospitalization was more frequent in the lower testosterone tertile than in the higher testosterone tertile (hazard ratio [HR]: 2.12; 95% confidence interval [CI]: 1.18-3.79; P = 0.01) in adjusted models. Moreover, all-cause mortality was significantly greater in the lower testosterone tertile than in the higher testosterone tertile in adjusted analysis (HR: 2.26; 95% CI: 1.21-4.23; P = 0.01). In contrast, there were no significant differences in CVD events by testosterone level. DISCUSSION: Low levels of testosterone may be associated with higher rates of infection-related hospitalization and all-cause mortality in male hemodialysis patients.

Helicobacter cinaedi bacteremia with cellulitis in a living-donor kidney transplant recipient identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry: a case report.

BACKGROUND: Helicobacter cinaedi causes bacteremia and cellulitis, mainly in immunocompromised patients. We report a rare case of H. cinaedi bacteremia with cellulitis in a living-donor kidney transplant recipient identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). A 54-year-old Asian man with IgA nephropathy underwent living-donor kidney transplantation 14 years previously. He was admitted to our hospital for evaluation of fever and multifocal cellulitis. H. cinaedi was isolated and identified from the patient's blood using matrix-assisted laser desorption ionization time-of-flight mass spectrometry and gyrase subunit B-targeted polymerase chain reaction assays. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry has proven over the years to be a rapid and accurate universal method for the identification of microorganisms. CONCLUSIONS: The combined use of these detection methods enabled the appropriate administration of 6 weeks of antibiotic therapy. The patient recovered completely, with no recurrence.

Successful Treatment of Plasma Cell-Rich Acute Rejection Using Pulse Steroid Therapy Alone: A Case Report.

Despite the recent development of immunosuppressive agents, plasma cell-rich acute rejection (PCAR) has remained refractory to treatment. Herein, we report an unusual case of PCAR that responded well to pulse steroid therapy alone. A 47-year-old man was admitted for a protocol biopsy three months after kidney transplantation, with a stable serum creatinine level of 1.6 mg/dL. Histological examination showed focal aggressive tubulointerstitial inflammatory cell infiltration of predominantly polyclonal mature plasma cells, leading to our diagnosis of PCAR. Three months following three consecutive days of high-dose methylprednisolone (mPSL) therapy, an allograft biopsy performed for therapy evaluation showed persistent PCAR. We readministered mPSL therapy and successfully resolved the PCAR. Although PCAR generally develops more than six months after transplantation, we diagnosed this case early, at three months after transplantation, with focally infiltrated PCAR. This case demonstrates the importance of early diagnosis and prompt treatment of PCAR to manage the development and severity of allograft rejection.

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.

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.