Phenolic compounds induce ferroptosis-like death by promoting hydroxyl radical generation in the Fenton reaction.

Phenolic compounds are industrially versatile chemicals, also the most ubiquitous pollutants. Recently, biosynthesis and biodegradation of phenols has attracted increasing attention, while phenols' toxicity is a major issue. Here, we evolved phloroglucinol-tolerant Escherichia coli strains via adaptive evolution, and three mutations (ΔsodB, ΔclpX and fetAB overexpression) prove of great assistance in the tolerance improvement. We discover that phloroglucinol complexes with iron and promotes the generation of hydroxyl radicals in Fenton reaction, which leads to reducing power depletion, lipid peroxidation, and ferroptosis-like cell death of E. coli. Besides phloroglucinol, various phenols can trigger ferroptosis-like death in diverse organisms, from bacteria to mammalian cells. Furthermore, repressing this ferroptosis-like death improves phloroglucinol production and phenol degradation by corresponding strains respectively, showing great application potential in microbial degradation or production of desired phenolic compounds, and phloroglucinol-induced ferroptosis suppresses tumor growth in mice, indicating phloroglucinol as a promising drug for cancer treatment.

Simultaneous pancreas and kidney transplantation for end-stage kidney disease patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

PURPOSE: The indications for patients with type 2 diabetes mellitus (T2DM) combined with end-stage kidney disease (ESKD) undertaking simultaneous pancreas and kidney transplantation (SPK) remain an unresolved issue. This study aimed to systematically review the survival outcomes of SPK among T2DM-ESKD patients. METHODS: Online databases including PubMed, MEDLINE, EMBASE, and the CENTRAL Library, CNKI, Chinese Biomedical Literature Database, and Wan-Fang database were used to locate the studies of ESKD patients with T2DM undertaking SPK up to May 2021. A third reviewer was consulted if there were disagreements. Data were analyzed with STATA (15.0). RESULTS: Nine cohort studies were identified. The pooled 1-year, 3-year, and 5-year patient survival rates of patients with T2DM and ESKD after SPK were 98%, 95%, and 91% respectively. Comparing the treatment effect of SPK between type 1 diabetes mellitus (T1DM) and T2DM, the survival estimates were comparable. For T2DM patients, SPK had a survival advantage compared with KTA. CONCLUSIONS: The synthesized clinical outcomes of T2DM patients with ESKD after SPK were relatively better than KTA, but a subset of T2DM-ESKD patients who would benefit the most from SPK was to be defined. PROSPERO registration number CRD42019118321. Date of registration: 14 Jan 2019 (retrospectively registered).

Suture ligation for submucosal hemostasis during hand-sewn side-to-side duodeno-ileostomy in simultaneous pancreas and kidney transplantation.

BACKGROUND: Enteric anastomotic (EA) bleeding is a potentially life-threatening surgical complication associated with enteric anastomosis during simultaneous pancreas and kidney transplantation (SPKT). AIM: To investigate whether suture ligation (SL) for submucosal hemostasis during hand-sewn enteric anastomosis could decrease the morbidity of early EA bleeding in SPKT. METHODS: We compared the outcomes of 134 patients classified into SL (n = 44) and no SL (NSL) groups (n = 90). This study adheres to the declarations of Istanbul and Helsinki and all donors were neither paid nor coerced. RESULTS: During the first postoperative week, the EA bleeding rate in the SL group was lower than that in the NSL group (2.27% vs 15.56%; P = 0.021); no relationship was found between EA bleeding and donor age, mean pancreatic cold ischemia time, platelet count, prothrombin time international normalized rate, activated partial thromboplastin time, and thrombin time. Anastomotic leakage was observed in one case in the SL group at postoperative day (POD) 14 and in one case at POD 16 in the NSL group (P = 0.754). No significant difference was found between the two groups in the patient survival, pancreas graft survival, or kidney graft survival. CONCLUSION: SL for submucosal hemostasis during hand-sewn enteric anastomosis in SPKT can decrease the morbidity of early EA bleeding without increasing the anastomotic leakage rate.

Safety and Efficacy of Anti-CD19-Chimeric Antigen Receptor T Cell Combined With Programmed Cell Death 1 Inhibitor Therapy in a Patient With Refractory Post-Transplant Lymphoproliferative Disease: Case Report and Literature Review.

Post-transplant lymphoproliferative disease (PTLD) often exhibits poor prognosis and high mortality, and there are no uniform guidelines for the treatment of this disease. Anti-CD19 chimeric antigen receptor (CAR) T cells show significant efficacy in treatment of relapse/refractory diffuse large B-cell lymphoma (DLBCL). Treatment using anti-CD19-CAR T-cell therapy in PTLD has been limited by immunosuppressants and has not been widely employed. In this study, a refractory post kidney transplant DLBCL patient with a high tumor burden was enrolled in a clinical trial of anti-CD19-CAR T-cell therapy. The tacrolimus dose was not decreased during combination chemotherapy, as the creatinine level of the patient increased. To improve the function of autologous T cells, combination therapy with anti-CD19-CAR T cells and programmed cell death 1 (PD-1) inhibitors was selected. After treatment with the combination therapy, the patient was diagnosed with grade 1 cytokine release syndrome and grade 3 immune effector cell-associated neurotoxicity syndrome. The amplification peak of anti-CD19-CAR T cells reached 9.01% on day 7. With PD-1 inhibitor maintenance therapy, his disease was maintained in partial remission for 18 weeks. However, his tumor suddenly increased in size, and he discontinued the treatment, including radiation therapy. The anti-CD19-CAR T cell and PD-1 inhibitors have a combined effect on PTLD, and this combination therapy needs to be further explored.

Kidney re-transplantation after living donor graft nephrectomy due to de novo chromophobe renal cell carcinoma: A case report.

BACKGROUND: There are few reported cases of allograft nephrectomy due to malignancy followed by successful renal re-transplantation two years later. In this paper, we report a patient who underwent kidney re-transplantation after living donor graft nephrectomy due to de novo chromophobe renal cell carcinoma (ChRCC) involving the allograft kidney. CASE SUMMARY: A 34-year-old man underwent living kidney transplantation at the age of 22 years for end-stage renal disease. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil (MMF), and prednisone. Six years post-transplantation, at another hospital, ultrasonography revealed a small mass involving the upper pole of the graft. The patient declined further examination and treatment at this point. Seven years and three months post-transplantation, the patient experienced decreasing appetite, weight loss, gross hematuria, fatigue, and oliguria. Laboratory tests showed anemia (hemoglobin level was 53 g/L). Contrast-enhanced computed tomography revealed a large heterogeneous cystic-solid mass involving the upper pole of the renal allograft. Graft nephrectomy was performed and immunosuppressants were withdrawn. Histological and immunohistochemical features of the tumor were consistent with ChRCC. One year after allograft nephrectomy, low doses of tacrolimus and MMF were administered for preventing allosensitization. Two years after allograft nephrectomy, the patient underwent kidney re-transplantation. Graft function remained stable with no ChRCC recurrence in more than 2-years of follow-up. CONCLUSION: De novo ChRCC in kidney graft generally has a good prognosis after graft nephrectomy and withdrawal of immunosuppression. Kidney re-transplantation could be a viable treatment. A 2-year malignancy-free period may be sufficient time before re-transplantation.

PSMP Is Discriminative for Chronic Active Antibody-Mediated Rejection and Associate With Intimal Arteritis in Kidney Transplantation.

Chronic active antibody-mediated rejection (CAAMR) is an intermediate process that occurs during the development of chronic antibody-mediated rejection (CAMR), which is a key problem associated with the long-term kidney grafts survival. This study investigated the role played by PC3-secreted microprotein (PSMP) in the progression of CAAMR and CAMR. We showed that CAAMR and CAMR patients' allografts dysfunction with declined survival rate, which suggested that earlier diagnosis and treatment of CAAMR might be important to prevent irreversible chronic injury of CAMR progression. We found PSMP was an important factor in the development of chronic antibody-mediated rejection. The PSMP expression increased significantly in CAAMR biopsy samples but not in CAMR and control patients, which distinguished CAAMR patients from CAMR and non-rejection patients. Moreover, our results showed that infiltration of CD68+ macrophages in CAAMR increased, and the correlation between CD68+ macrophages and PSMP expression in CAAMR patients was significant. Additionally, our data also revealed that intimal arteritis (v-lesion) accompanied by increased macrophage infiltration might have contributed to more graft loss in CAAMR, and PSMP expression was significantly associated with the v-lesion score. These results indicated that PSMP played an important role in the recruitment of macrophages and promote intimal arteritis inducing allograft lost in CAAMR progression. In future study PSMP could be a potential histopathological diagnostic biomarker and treatment target for CAAMR in kidney transplantation.

Human parvovirus B19-associated early postoperative acquired pure red cell aplasia in simultaneous pancreas-kidney transplantation: A case report.

BACKGROUND: Acquired pure red cell aplasia (aPRCA) related to human parvovirus B19 (HPV B19) is rarely reported in simultaneous pancreas-kidney transplantation (SPKT) recipients; there has yet to be a case report of early postoperative infection. In this current study, we report the case of a Chinese patient who experienced the disease in the early postoperative period. CASE SUMMARY: A 63-year-old man, with type 2 diabetes and end-stage renal disease, received a brain dead donor-derived SPKT. Immunosuppression treatment consisted of tacrolimus, prednisone, enteric-coated mycophenolate sodium (EC-MPS), and thymoglobulin combined with methylprednisolone as induction. The hemoglobin (Hb) level declined due to melena at postoperative day (POD) 3, erythropoietin-resistant anemia persisted, and reticulocytopenia was diagnosed at POD 20. The bone marrow aspirate showed decreased erythropoiesis and the presence of giant pronormoblasts at POD 43. Metagenomic next-generation sequencing (mNGS) of a blood sample identified HPV B19 infection at POD 66. EC-MPS was withdrawn; three cycles of intravenous immunoglobulin (IVIG) infusion therapy were administered; and tacrolimus was switched to cyclosporine. The HPV B19-associated aPRCA resolved completely and did not relapse within the 1-year follow-up period. The diminution in mNGS reads was correlated with Hb and reticulocyte count improvements. CONCLUSION: HPV B19-associated aPRCA can occur at an early period after SPKT. An effective therapy regimen includes IVIG infusion and adjustment of the immuno-suppressive regimen. Moreover, mNGS can be used for the diagnosis and to reflect disease progression.

Epstein-Barr virus-associated monomorphic post-transplant lymphoproliferative disorder after pediatric kidney transplantation: A case report.

BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) is the most common malignant tumor that occurs after kidney transplantation in children, and is associated with Epstein-Barr virus (EBV). CASE SUMMARY: We report a case of PTLD that occurred in a 17-year-old female patient at 5 mo post-transplant. The first symptom was abdominal pain accompanied by fever, nausea, and vomiting. EBV-associated monomorphic PTLD with multiple abdominal nodules was diagnosed by pathology, clinical manifestations, imaging results, and the presence of EB-DNA. After successful treatment with rituximab, the abdominal nodules in the spleen and liver disappeared. CONCLUSION: Early pathological biopsy to confirm the diagnosis is critical to treatment and prognosis. Reducing immunosuppression and rituximab therapy are effective methods for treating PTLD, but need to be initiated as early as possible.

Single-Center Retrospective Analysis of Prophylaxis and Treatment of Pneumocystis carinii Pneumonia in Patients with Renal Dysfunction After Renal Transplantation.

BACKGROUND Pneumocystis carinii is an opportunistic pathogen that can cause severe lung infections after renal transplantation. Trimethoprim-sulfamethoxazole (TMP-SMX) has been recognized as a first-line treatment for chemoprophylaxis of Pneumocystis carinii pneumonia (PCP). This study aimed to establish a personalized chemoprophylaxis prescription specifically for those recipients with renal insufficiency. MATERIAL AND METHODS This retrospective study included 68 patients with confirmed PCP after renal transplantation. Patients were divided into 2 groups: an abnormal renal function (ARF) group (creatinine ≥1.5 ng/dl; n=37) and a normal renal function (NRF) group (creatinine <1.5 ng/dl; n=31). Clinical characteristics and prognosis of PCP in both groups were compared and analyzed. RESULTS Patients in the ARF group had more prophylaxis after transplantation (15 [40.5%] vs. 2 [6.5%], p=0.047), had more biopsy-proven rejections (10 [27%] vs. 1 [3.2%], p=0.008), and had lower lymphocyte counts (0.6 [05-0.9] vs. 1.1 [0.7-1.6], p<0.01). Renal function after treatment was obviously improved in the ARF group, which had a significant decrease rate in creatinine (-13.2% [-22~4.8%] vs. -4.4% [-12.6~20.9%], p=0.043). CONCLUSIONS PCP prophylaxis regimens for recipients after renal transplantation are still needed regardless of whether the renal functions were normal or abnormal, especially for recipients with persistent lymphopenia or rejection after transplantation.

Pelvic lipomatosis and renal transplantation: A case report.

BACKGROUND: Pelvic lipomatosis is a rare disease of unknown etiology, characterized by the overgrowth of pelvic adipose tissue that causes compression of the urinary tract including the bladder and ureters, rectum and blood vessels. The patient may progressively develop obstructive uropathy which could subsequently lead to renal failure. At present, there are no reports of renal transplantation due to uremia caused by pelvic lipomatosis. The ideal management of patients with pelvic lipomatosis after renal transplantation is not yet well-established due to the lack of literature and follow-up data. CASE SUMMARY: We report a 37-year-old male patient with pelvic lipomatosis who received a successful living donor renal transplantation on July 22, 2015. The operation was complicated as the iliac vessels and bladder were wrapped entirely in excessive abnormal fat. The external iliac artery and vein were located using ultrasonographic guidance. The adipose tissue around the right bladder was removed as far as possible, and the graft ureter was reimplanted into the bladder, using the Lich-Gregoir technique. At 22 mo after transplantation, graft percutaneous nephrostomy was performed under ultrasonographic guidance for urinary diversion due to hydronephrosis of the graft kidney. Follow-up at four years showed that the renal allograft function was stable. CONCLUSION: When patients with pelvic lipomatosis develop renal failure, renal transplantation could be a feasible treatment strategy.

Exploration of symptom experience in kidney transplant recipients based on symptoms experience model.

PURPOSE: Kidney transplant recipients suffer from a variety of symptoms, and symptom management is crucial in improving their quality of life (QOL). Accordingly, this study aims to identify the symptoms experienced by kidney transplant recipients and examine the relationship amongst antecedents, symptom experience and QOL of recipients in China. METHODS: A total of 300 kidney transplant recipients were investigated in one of the most first-rate hospitals in China by asking them to fill out a self-designed general questionnaire, the Symptom Experience Scale, the Sense of Coherence Scale (Chinese version), the Revised Life Orientation Test (Chinese version) and the 36-item Short Form Health Survey (Chinese version). RESULTS: Kidney transplant recipients experienced multiple symptoms that were frequent, severe and bothersome. The final model showed significant consistency with the data. In the QOL model, post-transplant time, complications, immunosuppressive agents and sense of coherence explained 30.7% of the variance of symptom experience. Moreover, habitual residence, economic burden, post-transplant time, kidney function, optimism and symptom experience accounted for 70.6% of the variance on QOL. CONCLUSIONS: We can explain the relationship between antecedents, symptom experience and QOL amongst Chinese kidney transplant recipients by using Symptoms Experience Model. Clinicians and caregivers can manage the recipient's symptoms during follow-up from psychological, physical and medication management perspectives. Improving sense of coherence, maintaining optimism and managing symptoms are essential for enhancing QOL.

Disappearance of GFP-positive hepatocytes transplanted into the liver of syngeneic wild-type rats pretreated with retrorsine.

BACKGROUND AND AIM: Green fluorescent protein (GFP) is a widely used molecular tag to trace transplanted cells in rodent liver injury models. The differing results from various previously reported studies using GFP could be attributed to the immunogenicity of GFP. METHODS: Hepatocytes were obtained from GFP-expressing transgenic (Tg) Lewis rats and were transplanted into the livers of wild-type Lewis rats after they had undergone a partial hepatectomy. The proliferation of endogenous hepatocytes in recipient rats was inhibited by pretreatment with retrorsine to enhance the proliferation of the transplanted hepatocytes. Transplantation of wild-type hepatocytes into GFP-Tg rat liver was also performed for comparison. RESULTS: All biopsy specimens taken seven days after transplantation showed engraftment of transplanted hepatocytes, with the numbers of transplanted hepatocytes increasing until day 14. GFP-positive hepatocytes in wild-type rat livers were decreased by day 28 and could not be detected on day 42, whereas the number of wild-type hepatocytes steadily increased in GFP-Tg rat liver. Histological examination showed degenerative change of GFP-positive hepatocytes and the accumulation of infiltrating cells on day 28. PCR analysis for the GFP transgene suggested that transplanted hepatocytes were eliminated rather than being retained along with the loss of GFP expression. Both modification of the immunological response using tacrolimus and bone marrow transplantation prolonged the survival of GFP-positive hepatocytes. In contrast, host immunization with GFP-positive hepatocytes led to complete loss of GFP-positive hepatocytes by day 14. CONCLUSION: GFP-positive hepatocytes isolated from GFP-Tg Lewis rats did not survive long term in the livers of retrorsine-pretreated wild-type Lewis rats. The mechanism underlying this phenomenon most likely involves an immunological reaction against GFP. The influence of GFP immunogenicity on cell transplantation models should be considered in planning in vivo experiments using GFP and in interpreting their results.

OX40 mRNA in peripheral blood as a biomarker of acute renal allograft rejection.

BACKGROUND: Acute rejection remains an important cause of renal allograft dysfunction and the need for accurate diagnosis is essential to successfully treat transplant recipients. The purpose of this study was to determine the costimulatory molecules OX40 and OX40L messenger RNA (mRNA) levels in peripheral blood mononuclear cells (PBMCs) to predict acute renal transplant rejection. METHODS: The whole blood samples from 20 recipients with biopsy-confirmed acute rejection (rejection group), 20 recipients with stable graft function and normal biopsy results (stable group) after kidney transplantation, and 20 healthy volunteers (control group) were collected. The mRNA levels of OX40 and OX40L were analyzed with TaqMan real-time reverse transcriptase polymerase chain reaction (RT-PCR). The association of OX40 and OX40L mRNA levels with disease severity was investigated. RESULTS: There was no significant difference of OX40, OX40L mRNA levels in PBMCs between the stable group and control group (P > 0.05). The levels of OX40 and OX40L mRNA were significantly higher in the rejection group than in the control group (P < 0.01 and P < 0.05, respectively). Non-significantly higher OX40L mRNA and significantly higher OX40 mRNA in PBMCs were observed in subjects in the rejection group compared with the stable group (P > 0.05 and P < 0.01, respectively). Receiver operating characteristic (ROC) curve analysis demonstrated that OX40 mRNA levels could discriminate recipients who subsequently suffered acute allograft rejection (area under the curve, 0.908). OX40 and OX40L mRNA levels did not significantly correlate with serum creatinine levels in the rejection group (P > 0.05). Levels of OX40 mRNA after anti-rejection therapy were lower than those at the time of protocol biopsy in the rejection group (P < 0.05). CONCLUSION: Our data suggest that measurement of OX40 mRNA levels after transplant might offer a noninvasive means for recognizing recipients at risk of acute renal allograft rejection.

[The effect of the different immunosuppression therapy on CD4(+)Foxp3(+) Treg cells in kidney recipients].

OBJECTIVE: To investigate the effect of the different immunosuppression therapy on CD4(+)Foxp3(+)regulatory T cells (CD4(+)Foxp3(+)Treg cells) in the peripheral blood monocytes of kidney transplantation recipients. METHODS: A Closed Cohort study was conducted in 50 primary living kidney transplant recipients between January 2006 and January 2008, who had been followed up for 1 year. The recipients divided into calcineurin inhibitors group (CNI + MMF + Pred) (19 recipients, including cyclosporin group 10 recipients and tacrolimus group 9 recipients), rapamycin group (RAPA + MMF + Pred) (31 recipients). Twenty end-stage renal disease patients were in control group. The frequency of CD4(+)Foxp3(+)Treg cells in total CD4(+)T cells was analyzed by flow cytometry in peripheral blood from three groups, results were compared. RESULTS: The clinical variables of recipients such as age, sex, cold ischemia time, human leucocyte antigen mismatch, panel reaction antibody, rejection episode were no significant difference. The percentage of CD4(+)Foxp3(+)Treg cells in total CD4(+) cells was significantly higher in rapamycin group and end-stage renal disease group than calcineurin inhibitors group (P < 0.01). The level of CD4(+)Foxp3(+)Treg cells between cyclosporin group and tacrolimus group was no significant difference (P > 0.05). CONCLUSION: The level of CD4(+)Foxp3(+)Treg was significantly higher in patients receiving RAPA + MMF + Pred than the patients receiving CNI + MMF + Pred, which suggested that RAPA may be play a more important role in immune tolerance induction.