CD5L up-regulates the TGF-ß signaling pathway and promotes renal fibrosis.

Renal fibrosis is the common final pathway of progressive renal diseases, in which the macrophages play an important role. ELISA was used to detect CD5 antigen-like (CD5L) in serum samples from end-stage renal disease (ESRD), as well as in mice serum with unilateral ureteral occlusion (UUO). Recombinant CD5L was injected into UUO mice to assess renal injury, fibrosis, and macrophage infiltration. The expression of CD5L was significantly upregulated in the serum of patients with ESRD and UUO mice. Histological analysis showed that rCD5L-treated UUO mice had more severe renal injury and fibrosis. Furthermore, rCD5L promoted the phenotypic transfer of monocytes from Ly6Chigh to LyC6low. RCD5L promoted TGF-ß signaling pathway activation by promoting Smad2/3 phosphorylation. We used Co-IP to identify HSPA5 interact with CD5L on cell membrane could inhibit the formation of the Cripto/HSPA5 complex, and promote the activation of the TGF-ß signaling pathway. The CD5L antibody could reduce the degree of renal fibrosis in UUO mice.

TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway in mice.

The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor that affects cellular phenotypes by modulating phagocytosis and metabolism, promoting cell survival, and counteracting inflammation. Its role in renal injury, in particular, unilateral ureteral obstruction (UUO) or ischemia-reperfusion injury (IRI)-induced renal injury remains unclear. In our study, WT and Trem2-/- mice were employed to evaluate the role of TREM2 in renal macrophage infiltration and tissue injury after UUO. Bone marrow-derived macrophages (BMDM) from both mouse genotypes were cultured and polarized for in vitro experiments. Next, the effects of TREM2 on renal injury and macrophage polarization in IRI mice were also explored. We found that TREM2 expression was upregulated in the obstructed kidneys. TREM2 deficiency exacerbated renal inflammation and fibrosis 3 and 7 days after UUO, in association with reduced macrophage infiltration. Trem2-/- BMDM exhibited increased apoptosis and poorer survival compared with WT BMDM. Meanwhile, TREM2 deficiency augmented M1 and M2 polarization after UUO. Consistent with the in vivo observations, TREM2 deficiency led to increased polarization of BMDM towards the M1 proinflammatory phenotype. Mechanistically, TREM2 deficiency promoted M1 and M2 polarization via the JAK-STAT pathway in the presence of TGF-ß1, thereby affecting cell survival by regulating mTOR signaling. Furthermore, cyclocreatine supplementation alleviated cell death caused by TREM2 deficiency. Additionally, we found that TREM2 deficiency promoted renal injury, fibrosis, and macrophage polarization in IRI mice. The current data suggest that TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway. These findings have implications for the role of TREM2 in the regulation of renal injury that justify further evaluation.

Role of triggering receptor expressed on myeloid cells-1 in kidney diseases: A biomarker and potential therapeutic target.

ABSTRACT: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.

Inhibition of interferon regulatory factor 4 orchestrates T cell dysfunction, extending mouse cardiac allograft survival.

BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of MAPK and mammalian target of Rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro, blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg-1·day-1) and Rapamycin (0.1 mg·kg-1·day-1) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS: Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.

Mouse kidney transplantation model: Three novel methods. / å°é¼ è‚¾ç§»æ¤æ¨¡åž‹ï¼š3种创新术式（英文）.

OBJECTIVES: The mouse kidney transplantation model presents challenges in terms of surgical difficulty and low success rate, making it difficult to master. This study aims to provide a crucial model for transplantation immunology research by modifying and developing novel techniques for mouse kidney transplantation. METHODS: A total of 57 pairs of mice were used to establish and compare the modified and innovative surgical techniques for mouse kidney transplantation. Three different surgical models were established, including the abdominal suture technique for orthotopic kidney transplantation, the abdominal cuff technique for orthotopic kidney transplantation, and the cervical cuff technique for ectopic kidney transplantation. BALB/c or C57BL/6 male mice, aged 8 to 12 weeks and weighed 20 to 25 g with specified pathogen free-grade were served as the donor mice or the recipient mice. The surgical technique characteristics, key surgical times, complications, and pathological examination in the early postoperative period were summarized and compared. RESULTS: Three different surgical models of mouse kidney transplantation were successfully established. The comparison of warm ischemic time for the 3 groups of mice showed no statistical significance (P=0.510 4). The abdominal suture group had the shortest total operation time of the donor compared with the abdominal cuff group and the cervical cuff group [(18.3±3.6) min vs (26.2±4.7) min and (22.8±2.5) min; both P<0.000 1]. There was a significant difference in cold ischemia time among the 3 groups (all P<0.000 1), with (60.8±4.1) min in the cervical cuff group, (43.3±5.0) min in the abdominal suture group, and (88.8±6.7) min in the abdominal cuff group. Due to different anastomosis methods, the cervical cuff group had the shortest time [(17.6±2.7) min], whereas the abdominal cuff group had the longest time [(38.8±5.4) min]. The total operation time for the recipients showed significant differences (P<0.000 1), with the abdominal suture group having the shortest time [(44.0±6.9) min], followed by the cervical cuff group [(64.1±5.2) min], and the abdominal cuff group [(80.0±6.0) min] being the longest. In the 32 mice of the abdominal suture group, there were 6 with intraoperative bleeding, including 1 arterial intimal injury bleeding and 5 with bleeding after vessel opening. Six mice had ureteral complications, including ureteral bladder anastomotic stenosis, necrosis, and renal pelvis dilation. Two mice had postoperative abdominal infections. In the abdominal cuff group, there was no intraoperative bleeding, but 6 mice showed mild arterial stenosis and 5 showed venous stenosis, 4 arterial injury, 4 arterial thrombosis, and 2 ureteral complications. No postoperative infections occurred in the mice. In the cervical cuff group, no intraoperative bleeding, arterial intimal injury, arterial/venous stenosis, or thrombosis were found in 13 mice. Five mice had ureteral complications, including ureteral necrosis and infection, which were the main complications in the cervical cuff group. The renal function in mice of the 3 groups remained stable 7 days after surgery. Hematoxylin and eosin staining and periodic acid-Schiff staining showed no significant differences in terms of acute rejection among the 3 surgical methods (all P>0.05). CONCLUSIONS: All 3 surgical methods are able to successfully establish mouse kidney transplantation models, with no significant differences observed in the short-term graft survival and acute rejection. The modified abdominal suture technique and abdominal cuff technique have their respective advantages in research applications. The novel cervical cuff technique for ectopic kidney transplantation model is relatively simple to be prepared and causes less trauma to the mice, providing more options for studies involving xenotransplantation, secondary transplantation, and local lymphatic drainage. However, the difficulty in harvesting the donor kidney and the high incidence of ureteral infections need further validation in long-term survival. This study holds important reference value for choosing the type of mouse kidney transplantation model for different research needs.

Dietary vitamin intake and cancer risk in patients with chronic kidney disease: results from the National Health and Nutrition Examination Survey (2007-2018).

PURPOSE: The relationship between vitamin intake and cancer risk in the chronic kidney disease (CKD) population is unknown. For this reason, we investigated the relationship between dietary vitamin intake and cancer risk in CKD patients and looked for effective vitamin dietary patterns. METHODS: This study included 3518 CKD patients from 2007 to 2018 National Health and Nutrition Examination Survey database. All participants were categorized into four groups based on vitamin intake by K-mean clustering. The data were collected and analyzed from June 2023 to December 2023. RESULTS: A total of 3518 CKD patients with a mean age of (61.8 ± 16.3) years were included in the study. During a median follow-up of 7.3 years, 137 participants died of cancer. In the multivariate adjusted cox proportional hazards model for single vitamin intake, vitamin E Q4 intake (reference Q1) reduced cancer mortality (HR (95% CI) = 0.45 (0.24-0.87), P = 0.018). Further plotting of the restricted cubic spline curve revealed a linearly decreasing relationship between vitamin E intake and cancer mortality (Poverall = 0.010 Pnon-linear = 0.163). In the multivariate adjusted cox proportional hazards model for multivitamin co-intake, the vitamin C/K intake group reduced cancer mortality compared to the low vitamin intake group (HR (95% CI) = 0.42 (0.20-0.88), P = 0.022). CONCLUSION: Increased vitamin C intake was independently associated with reduced cancer risk in CKD patients, and a vitamin dietary pattern with high vitamin C/K intake was also effective in reducing cancer risk.

Preexisting renal graft dysfunction as a major risk factor for SARS-CoV-2 Omicron variant pneumonia: A postinfection cross-sectional study of 312 immunosuppressed renal transplant recipients.

OBJECTIVES: SARS-CoV-2 pneumonia poses significant challenges to health systems worldwide, particularly, in severe and critical cases. Immunosuppressed renal transplant recipients appear to be at a particularly high risk for severe or critical COVID-19 illness. However, few studies elucidated the risk factors of SARS-CoV-2 pneumonia in renal transplant recipients with COVID-19. METHODS: A postinfection cross-sectional survey was conducted in 312 renal transplant recipients and 503 age- and sex-matched controls to explore risk factors for SARS-CoV-2 pneumonia in immunosuppressed renal transplant recipients. RESULTS: The results showed that renal transplant recipients had a much higher incidence of SARS-CoV-2 pneumonia (48.1%) after infection with the SARS-CoV-2 Omicron variant than controls (5.6%). The multivariate binary logistic regression analysis identified older age, lower creatinine clearance before infection, and higher dose of prednisone before infection as risk factors for SARS-CoV-2 pneumonia in renal transplant recipients. Preexisting renal dysfunction was a major risk factor for SARS-CoV-2 pneumonia, with an odds ratio of 3.27 (1.01-10.61). CONCLUSIONS: Preexisting renal graft dysfunction was a major risk factor for SARS-CoV-2 Omicron variant pneumonia. It is suggested that high-risk renal transplant recipients should undergo computed tomography scanning within 14 days after infection with SARS-CoV-2.

A murine groin site cardiac transplantation model-applicable tool for studying roles of peripheral lymph nodes in transplantation.

The murine heterotopic cardiac transplantation model has been widely used to study antigen-specific immune responses or new immunosuppressive agents, which have a strong correlation with peripheral lymph nodes. Thus, a new organ transplantation model that is applicable to related studies is needed. Here, we describe a groin-site murine heart transplantation model using a cuff technique, in which the donor aorta and pulmonary artery are anastomosed to the truncated femoral vessels of the recipient. The mean survival time (MST) of the grafts in BALB/c-to-C57BL/6 allo-transplant group was 7.2 ± 0.3 days, and 1.9 ± 0.2 days in BALB/c-to-Sprague-Dawley (SD) rat xeno-transplant group. H&E results show that donor hearts from both groups demonstrate typical pathological features at the endpoint. Evans Blue tracing revealed that the popliteal lymph nodes of the grafted side hindlimb are larger than those of the contralateral side. Moreover, IHC staining for CD3, CD20 shows that the germinal center and cortex region of the grafted side of popliteal lymph nodes is apparently increased than that of the contralateral side. To sum up, this model may serve as an ideal model to study the role of peripheral lymph nodes in organ transplant rejection. In addition, extra-peritoneal grafting makes a step forward in animal welfare under the 3Rs' principle (Replacement, Reduction, Refinement).

Homoharringtonine promotes heart allograft acceptance by enhancing regulatory T cells induction in a mouse model.

BACKGROUND: Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model. METHODS: Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan-Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation. RESULTS: HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo. Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days (P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4+ and CD8+ T cells in the spleen (P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes (CD4, H2-Eb1, TRAT1, and CD74) and upregulated the expression of IL-10 and transforming growth factor (TGF)-ß pathway-related genes and Treg signature genes (CTLA4, Foxp3, CD74, and ICOS). HHT increased CD4+ Foxp3+ cells and Foxp3 expression ex vivo, and it enhanced the inhibitory function of inducible Tregs. CONCLUSIONS: HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.

Clinical outcomes for kidney transplantation in 81 adults with IgA nephropathy. / 81例成人IgAè‚¾ç— è‚¾ç§»æ¤çš„ä¸´åºŠç–—æ•ˆï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Immunoglobulin A nephropathy (IgAN) is one of the most common types of kidney disease, and kidney transplantation is the most effective treatment for end-stage renal disease. This study aims to analyze the clinical curative effect of renal transplantation for adults with IgAN and to discuss the efficacy and safety of kidney transplantation for IgAN at the perioperative period and medium- and long-term follow-up. METHODS: This retrospective study included the clinical and follow-up data of 81 adult patients with IgAN who underwent kidney transplantation at the Second Xiangya Hospital, Central South University from January 2018 to January 2022. Of the 81 patients whose age at (34.1±9.9) years old, 47 (58.0%) were male. The body mass index was (20.8±3.2) kg/m2, and the human leukocyte antigen (HLA) mismatch number was 3.5±1.2. The estimated glomerular filtration rate (eGFR) and daily 24-hour urine output for the recipients on the 1st, 5th, and 7th day after kidney transplantation and when they were discharged were analyzed. The recovery of the transplanted kidney and occurrence of complications were comprehensively evaluated. The eGFR, urinary protein, and occult blood were evaluated at the 6th, 12th, 24th, 36th, and 48th month and at the last follow-up. RESULTS: The follow-up time was (25.7±15.8) months. No primary non-function occurred in any patient during the perioperative period time. Fifty-one (63.0%) patients had immediate graft function recovery, and 16 (19.8%) patients had slow graft function recovery. Delayed recovery of graft function was observed in 14 (17.3%) patients. A total of 19 perioperative complications occurred, including 9 patients with acute rejection, 5 patients with urinary fistula, 1 thrombosis in both lower limbs, and 4 lymphatic fistula. The eGFR at 6th, 12th, 24th, 36th, and 48th month of follow-up were (65.3±22.9), (67.6±23.0), (64.3±21.8), (65.9±24.7), and (68.7±31.2) mL/(min·1.73 m2), respectively. The eGFR remained high during the medium- and long-term follow-ups. At the longest follow-up of 56 months, eGFR fluctuation was still mild, and the positive rate of urine protein and occult blood was low. IgAN recurred in 4 transplanted kidneys, accounting for 4.94% of the total patients, without severe renal insufficiency. Three patients had kidney dysfunction due to severe pneumonia, rejection, and stone in the transplanted kidney. The overall survival rate of the transplanted kidney was higher than 95%, and the survival rate of all patients was 100% till Januray 2022. CONCLUSIONS: Renal transplantation for adults with IgAN had a remarkable short-term effect. The recipients can be beneficial significantly to favorable midium- and long-term outcomes. IgAN recurrence is infrequent and rarely causes severe renal function damage.

Hemophagocytic lymphohistiocytosis secondary to virus infection and followed by lupus nephritis recurrence in a renal transplantation pediatric recipient: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disorder characterized by systemic inflammation and organ failure as a result of dysregulated immune cell activation. HLH can be induced by a variety of factors including infection, tumours and autoimmune disease and can also occur in patients following solid organ transplantation. Occurrence of HLH and lupus nephritis (LN) successively within a short period of time after renal transplantation is uncommon. CASE PRESENTATION: We described an 11-year-old female post-transplant patient who presented with hemocytopenia, fever, elevated serum ferritin, splenomegaly, hyperlipidemia, and hypofibrinemia, and was clinically diagnosed with HLH. After comprehensive treatment with corticosteroids, intravenous immunoglobulin (IVIG), and reducing immunosuppressants, her condition improved, but then hematuria ensued. The transplant kidney biopsy showed LN. She was treated with hydroxychloroquine and methylprednisolone while intensive immunosuppressive agents were given. She has remained in remission for two years until now. CONCLUSIONS: The main inducing factors of HLH should be identified as early as possible, and accurate treatment plans should be taken. The long-course IVIG regimen may be one of the effective treatments for virus-induced HLH. After remission of HLH, we need to be alert to the recurrence of autoimmune diseases in patients with underlying diseases, and timely increase immunosuppressants.

DsbA-L deletion attenuates LPS-induced acute kidney injury by modulating macrophage polarization.

Disulfide bond A oxidoreductase-like protein (DsbA-L) drives acute kidney injury (AKI) by directly upregulating the expression of voltage-dependent anion-selective channels in proximal tubular cells. However, the role of DsbA-L in immune cells remains unclear. In this study, we used an LPS-induced AKI mouse model to assess the hypothesis that DsbA-L deletion attenuates LPS-induced AKI and explore the potential mechanism of DsbA-L action. After 24 hours of LPS exposure, the DsbA-L knockout group exhibited lower serum creatinine levels compared to the WT group. Furthermore, peripheral levels of the inflammatory cytokine IL-6 were decreased. Transcriptomic data analysis revealed a significant down-regulation in the IL-17 and tumor necrosis factor pathways in DsbA-L knockout mice following LPS induction. Metabolomic analysis suggested that arginine metabolism was significantly different between the WT and DsbA-L knockout groups after LPS treatment. Notably, the M1 polarization of macrophages in the kidneys of DsbA-L knockout AKI mice was significantly reduced. Expression of the transcription factors NF-κB and AP-1 was downregulated after DsbA-L knockout. Our results suggest that DsbA-L regulates LPS-mediated oxidative stress, promotes M1 polarization of macrophages, and induces expression of inflammatory factors via the NF-κB/AP-1 pathway.

Excellent clinical outcomes of renal transplant from pediatric deceased donors with acute kidney injury.

BACKGROUND: The use of kidneys from deceased donors with acute kidney injury (AKI) to expand the donor pool is an ongoing trend. Prior research on the utilization of AKI donor kidneys, especially from pediatric AKI donors, was limited and has been subject to small sample sizes. In this study, we aimed to evaluate the safety and effectiveness of early post-transplantation outcomes in pediatric deceased donors with AKI. METHODS: This retrospective study compared the clinical results (including delayed graft function [DGF], acute rejection, patient and death-censored graft survival rates and renal function post-transplant) of kidney transplantation from deceased donors who were categorized as pediatric donors and adult donors with or without AKI, as defined by the Kidney Disease: Improving Global Outcomes (KIDGO) criteria, at our center between January 2018 and December 2020. RESULTS: Of the 740 patients, 154 received kidneys from pediatric donors (with AKI group [n = 41]; without AKI group [n = 113]), and 586 received kidneys from adult donors (with AKI group [n = 218]; without AKI group [n = 368]). The baseline characteristics were similar in both cohorts. No significant difference was observed in 1-year patient survival, death-censored graft survival, or acute rejection between the AKI and non-AKI groups in both the pediatric and adult cohorts. However, compared with those transplanted with adult AKI kidneys, those transplanted with pediatric AKI kidneys showed a superior recovery of allograft function. In pediatric cohorts, no significant difference was found in serum creatinine/estimated glomerular filtration rate (SCr/eGFR) between the AKI and non-AKI groups, even in the first week post-transplant. In contrast, the post-transplant SCr/eGFR level of the AKI group recipients in adult cohorts did not recover to a level statistically similar to that of non-AKI recipients, even at 6-months post-transplant. Nonetheless, AKI kidney recipients were at an increased risk of DGF in both pediatric (34.1% vs. 16.8%) and adult (38.5% vs. 17.4%) cohorts. CONCLUSIONS: Kidney transplantation from deceased donors with AKI has short-term clinical outcomes comparable to those of non-AKI kidney transplantation. Pediatric AKI kidneys have a superior recovery of allograft function. The transplant community should utilize this donor pool to minimize waiting-list-related mortalities.

Association and prediction of red blood cell distribution width to albumin ratio in all-cause mortality of acute kidney injury in critically ill patients.

Aim: The progression of acute kidney injury (AKI) might be associated with systemic inflammation. Our study aims to explore the association and predictive value of the red blood cell distribution width (RDW) to human serum albumin (ALB) ratio (RDW/ALB ratio), an inflammation-related indicator, in the risk of all-cause mortality and renal replacement therapy (RRT) in AKI patients admitted in intensive care units (ICU). Methods: A retrospective cohort study was designed, and data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III). The primary outcome was the risk of all-cause mortality (1-month, 3-month, and 12-month), and the secondary outcome was the risk of RRT. The association between the RDW/ALB ratio and the risk of all-cause mortality and RRT was assessed using the Cox regression analysis, with results shown as hazard ratio (HR) and 95% confidence intervals (CIs). The relationship between the RDW/ALB ratio and crude probability of all-cause mortality or RRT was assessed using restricted cubic splines (RCS). The concordance index (C-index) was used to assess the discrimination of the prediction model. Results: A total of 13,856 patients were included in our study. In the fully adjusted Cox regression model, we found that a high RDW/ALB ratio was associated with an increased risk of 1-month, 3-month, and 12-month all-cause mortality and RRT (all p < 0.05). Moreover, RCS curves showed the linear relationship between the RDW/ALB ratio and the probability of all-cause mortality and RRT, and the probability was elevated with the increase of the ratio. In addition, the RDW/ALB ratio showed a good predictive performance in the risk of 1-month all-cause mortality, 3-month all-cause mortality, 12-month all-cause mortality, and RRT, with a C-index of 0.728 (95%CI: 0.719-0.737), 0.728 (95%CI: 0.721-0.735), 0.719 (95%CI: 0.713-0.725), and 0.883 (95%CI: 0.876-0.890), respectively. Conclusion: The RDW/ALB ratio performed well to predict the risk of all-cause mortality and RRT in critically ill patients with AKI, indicating that this combined inflammatory indicator might be effective in clinical practice.

Short-term outcome of kidney transplantation from deceased donors with nephrolithiasis. / 尸体供肾结石对肾移植短期疗效的影响（英文）.

OBJECTIVES: Shortage of kidney allografts is a major barrier to end-stage renal disease patients receiving kidney transplantation, and it is necessary to enlarge the donor pool and find better ways of using available allografts. The global incidence of nephrolithiasis is increasing, nephrolithiasis affects approximately 10% of adults worldwide, and it also affects the kidney donors. However, there is little information about the use of cadaveric kidney allografts with nephrolithiasis. This study aims to evaluate the safety and outcome of kidney transplantation with allografts from the deceased donors with nephrolithiasis. METHODS: A total of 520 deceased donors who was at least 10 years old, and 945 adult recipients with single kidney transplantation at the Department of Kidney Transplantation, the Second Xiangya Hospital from 2016 to 2020 were included in this study. The donors were divided into 2 groups according to nephrolithiasis diagnoses: The donors with nephrolithiasis (D + ) and the donors without nephrolithiasis (D - ). The recipients were assigned into 3 groups according to their donors and the allografts they received: The allografts from donors without nephrolithiasis (D - K - ), the allografts without nephrolithiasis from donors with nephrolithiasis (D + K - ), and the allografts with nephrolithiasis (D + K + ). The demographic and clinical data of enrolled subjects were retrospectively analyzed. The allograft discard ratio between different donors were analyzed. The one-year survival of allografts and recipients, as well as the allograft function and the complications of kidney transplantation were compared. RESULTS: Fifty out of 520 donors had nephrolithiasis, and the nephrolithiasis incidence was 9.6%. We recovered 1 040 kidneys, and total discard rate was 4.4% (46/1 040). The D + group had a rate of 7% discard. The donors with kidney discard accounted for 12% in the D + group, and this was higher than that of donors in the D - group (5.1%, P <0.05). The total incidence of delayed graft function (DGF) was 7.5%, and there were no significant differences in the incidence of DGF in recipients among the D - K - , D + K - , and D + K + group (7.5% vs 6.5% vs 8.2%, P> 0.05). During the one-year follow-up, 8 allografts lost function and 19 recipients died with a functional allograft. Recipients in the D - K - , D + K - ,and D + K + groups also had no significant difference between a one-year allograft and patient survival rate ( P >0.05). However, recipients in the D + K + group had a higher level of serum creatinine [(139.2±62.46) µmol/L vs (117.19±51.22) µmol/L, P <0.05] and lower estimated glomerular filtration rate [eGFR; (56.67±23.31) mL/(min·1.73 m -2 ) vs (66.86±21.90) mL/(min·1.73 m -2 ), P <0.05] compared with recipients in the D - K - group at 12 months after transplantation. During the first year after transplantation, 4 recipients developed urolithiasis, and recipients who received allografts from the D + group donors had a higher incidence of urolithiasis than those who received allografts from the D - group donors (2.2% vs 0.2%, P <0.05). There were no significant differences in the incidence of urinary tract infections and ureteral strictures at 1 year between recipients of D + and D - donors (both P >0.05). CONCLUSIONS: The cadaveric kidney allografts with nephrolithiasis could be safely used for transplantation, and the short-term outcome is acceptable. However, nephrolithiasis in donors may increase the rate of kidney discard, disturb the short-term function of allografts, and increase the risk of urolithiasis in recipients. Further research with a long-term study is needed to verify the long-term outcome of kidney transplantation using cadaveric kidney allografts with nephrolithiasis.

Drug-induced Fanconi syndrome in patients with kidney allograft transplantation.

Background: Patients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical. Methods: This retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis. Results: The onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A. Conclusions: For the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis.

Utilization of HCV Viremic Kidneys with Genotyping/Subtyping-Free Sofosbuvir/Velpatasvir Treatment Strategy: Experience from China.

Background: Owing to the advent of pangenotypic direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) treatment, utilization of HCV-infected deceased donor kidneys with simplified genotyping/subtyping-free sofosbuvir/velpatasvir (SOF/VEL) treatment strategy is now becoming a promising strategy for expanding the organ donor pool. Methods: This retrospective, comparative, single-center study included HCV viremic donor kidneys that were transplanted to 9 HCV-positive (HCV Ab-positive) recipients (D+/R+ group) and 14 HCV-negative recipients (D+/R- group) from May 2018 to January 2021. Both groups received prophylaxis with SOF/VEL treatment within 1-week posttransplant devoid of HCV genotyping/subtyping. The primary outcomes were sustained virologic response 12 weeks after completion of therapy (SVR12) and graft survival at 1-year posttransplant. Results: Baseline characteristics were similar between the HCV D+/R- and D+/R+ groups. The mean age of all recipients was 39.09 ± 9.65 (SD) years, and 73.9% were male. A total of 92.9% (13 out of 14) recipients had pretreatment HCV viremia in the D+/R- group. The pretreatment HCV viral load in the D+/R+ group (5.98, log 10 IU/mL; IQR, 5.28-6.53) was significantly higher than that in the D+/R- group (3.61, log 10 IU/mL; IQR, 2.57-4.57). After SOF/VEL treatment, SVR12 was achieved in all recipients, with a 100% 1-year patient and graft survival rates. The D+/R+ group had a higher incidence of abnormal liver function (44.4% vs. 7.1%). No significant difference was observed between the two groups in terms of DGF, acute rejection, ALT, serum creatinine, and eGFR within 1-year posttransplant. No severe adverse events associated with either HCV viremia or SOF/VEL were observed. Conclusions: Using a simplified genotyping/subtyping-free SOF/VEL treatment strategy, kidneys from hepatitis C viremic donors for both infected and uninfected recipients presented with safe, excellent, and comparable 1-year outcomes, which can safely expand the donor pool. HCV-positive donor kidneys should be utilized regularly, regardless of the recipient's HCV status.

Comparison of Outcomes of Kidney Transplantation From Extremely Low Body Weight ≤5kg Versus Larger Body Weight Pediatric Donors.

Background: Kidney transplantation from donors who weigh ≤5 kg is performed at only a few transplant centers owing to the high complication and low graft survival rates associated with this approach. Methods: We retrospectively compared the results of kidney transplantation at our center between January 2015 and December 2019 based on the following pediatric donor criteria: donor body weight ≤5 kg (n=32), 5 kg< donor weight ≤20 kg (n=143), and donor weight >20 kg (n=110). We also perform subgroup analysis of kidney transplantation outcomes from ≤5 kg donors, using conventional (dual separate and classic en-bloc KTx)/novel (en-bloc KTx with outflow tract) surgical methods and allocating to adult/pediatric recipients. Results: The death-censored graft survival rates from extremely low body weight ≤5kg at 1 month, and 1, 3, and 5 years were 90.6%, 80.9%, 77.5%, and 73.9%, respectively, which were significantly lower than that from larger body weight pediatric donors. However, the 3-, and 5-year post-transplantation eGFRs were not significantly different between the pediatric and adult recipient group. The thrombosis (18.8%) and urinary leakage (18.8%) rates were significantly higher in the donor weight ≤5 kg group. Compared with 5 kg< donor weight ≤20 kg group, donor weight ≤5kg group was at elevated risk of graft loss due to thrombosis (OR: 13.4) and acute rejection (OR: 6.7). No significant difference on the outcomes of extremely low body weight donor kidney transplantation was observed between adults and pediatric recipients. Urinary leakage rate is significantly lower in the novel operation (8.7%) than in the conventional operation group (44.4%). Conclusions: Although the outcomes of donor body weight ≤5kg kidney transplantation is inferior to that from donors with large body weight, it can be improved through technical improvement. Donors with body weight ≤5 kg can be considered as an useful source to expand the donor pool.

The Role of Regulatory B cells in Kidney Diseases.

B cells, commonly regarded as proinflammatory antibody-producing cells, are detrimental to individuals with autoimmune diseases. However, in recent years, several studies have shown that regulatory B (Breg) cells, an immunosuppressive subset of B cells, may exert protective effects against autoimmune diseases by secretion of inhibitory cytokines such as IL-10. In practice, Breg cells are identified by their production of immune-regulatory cytokines, such as IL-10, TGF-ß, and IL-35, however, no specific marker or Breg cell-specific transcription factor has been identified. Multiple phenotypes of Breg cells have been found, whose functions vary according to their phenotype. This review summarizes the discovery, phenotypes, development, and function of Breg cells and highlights their potential therapeutic value in kidney diseases.

Skills to Perform Vessel Eversion in Mouse Cervical Cardiac Transplantation with Cuff Technique

Abstract Introduction: The mouse heterotopic cardiac transplant model has been extensively used to explore transplant immunity. Although the cuff technique facilitates the operation, the procedure remains difficult, and vessel eversion is the most difficult step. Cuff movement and everted vessel wall slippage are the main adverse factors in vessel eversion. Traditional strategies to prevent these factors focus on cuff fixation, while more steps or surgical instruments would be required. Methods: According to the reported protocols and our experience, the vessel eversion skills were modified and used for transplantation. Cardiac grafts from C57BL/6(H-2b) or BALB/c(H-2d) mice were transplanted into C57BL/6(H-2b) mice. The operating times of recent 90 operations, which were divided into 9 groups according to their sequence, were summarized and analyzed. Results: The mouse cervical cardiac transplantation was successfully performed by using the modified vessel eversion skills. The cuff movement, which is the most important adverse factor to prevent vessel eversion, was effectively prevented. In the recent 90 operations, the total operating time was 47.3±7.9 min and the success rate was 98%. Conclusions: The modified surgical skills simplify the vessel eversion in mouse cervical cardiac transplantation with cuff technique, characterized by less cuff movement, fewer steps, and surgical instruments. Using these surgical skills, the transplant can be performed in a short time.