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.

Bioequivalence evaluation and blood concentration estimation of generic and branded tacrolimus in healthy subjects under fasting: A randomized, four-periods, two-sequences, complete repeated, crossover study.

OBJECTIVE: The demand for generic tacrolimus is enormous. Our randomized trial was an open-label single-dose testing with four-periods and two-sequences; we aimed to evaluate the bioequivalence between a generic and branded tacrolimus by establishing their area under concentration-time curve (AUC) predictive equations. For better comparison, each tacrolimus served either as test vs. reference in sequence 1 or vice versa as reference vs. test in sequence 2. METHODS: Forty healthy subjects were randomized into two groups, namely a sequence 1 group (N = 20 in test-reference-test-reference) or sequence 2 (N = 20, reference-test-reference-test) received a test tacrolimus (Ruibeirong®; Chengdu Shengdi Medicine Co., Ltd.) and a reference tacrolimus (Astagraf XL®, Astellas Ireland Co., Ltd.) under the fasting condition with a wash-out period of ≥14 days between every two phases. Blood samples were collected sequentially until 120 h after oral administration of tacrolimus. RESULTS: A 95% upper confidence bound was -0.05% for the peak concentration (Cmax), -0.02% for the AUC from 0 to the last time point (AUC0-t), and - 0.02% for the AUC from 0 to infinity (AUC0-∞). The geometric least square means ratio (test/reference) with 90% of confidence interval (CI)) was 96.10% (90.58%-101.95%) for Cmax, 93.80% (88.52%-99.39%) for AUC0-t, and 94.34% (89.20%-99.77%) for AUC0-∞. Meanwhile, the ratio of within-subject standard deviation of test/reference (σWT/WR) with 90% CI was 0.66 (0.50-0.86) for Cmax, 0.73 (0.55-0.96) for AUC0-t, and 0.75 (0.57-0.98) for AUC0-∞. These results fulfilled the bioequivalence criteria by the Food and Drug Administration. Both products showed acceptable safety. Moreover, the AUC predictive equations (by linear regression plus limited sampling strategy) with 2-5 sampling time point showed the high performance (all R > 0.970, predictive error (PE) >0.5%, absolute PE <5.1%, which were interchangeable between test and reference products. CONCLUSION: Generic tacrolimus (Ruibeirong®) is bioequivalent to branded tacrolimus (Astagraf XL®) with tolerable safety, which AUC predictive equations work well and are interchangeable between the two products.

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.

The application of metagenomic next-generation sequencing in patients with infection or colonization caused by Lichtheimia species.

Background: Mucormycosis is considered the fourth most common invasive fungal disease after candidiasis, aspergillosis and cryptococcosis. Lichtheimia species accounted for 5%-29% of all mucormycosis. However, available data on species-specific analysis of Lichtheimia infections are limited. Methods: This study included nine patients hospitalized in five hospitals in two cities in south China with mucormycosis or colonization caused by Lichtheimia species, diagnosed mainly by metagenomic next-generation sequencing (mNGS). The corresponding medical records were reviewed, and the clinical data analyzed included demographic characteristics, site of infection, host factors and type of underlying disease, diagnosis, clinical course, management, and prognosis. Results: In this study, nine patients with Lichtheimia infections or colonization had a recent history of haematological malignancy (33.3%), solid organ transplants (33.3%), pulmonary disease (22.2%), and trauma (11.1%) and were categorized as 11.1% (one case) proven, 66.7% (six cases) probable mucormycosis and 22.2% (two cases) colonization. Pulmonary mucormycosis or colonization was the predominant presentation in 77.8% of cases and mucormycosis caused by Lichtheimia resulted in death in four out of seven patients (57.1%). Conclusion: These cases highlight the importance of early diagnosis and combined therapy for these sporadic yet life-threatening infections. Further studies on the diagnosis and control of Lichtheimia infection in China are required.

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.

Absence of TSC1 Accelerates CD8+ T cell-mediated Acute Cardiac Allograft Rejection.

Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by inactivating mutations in TSC1 or TSC2.Patients with TSC often require organ transplantation after organ failure. TSC1 serves as an important control node in immune cell development and responses; however, its effect on T cells in transplant immunity has not yet been explored. Here, we characterized the effect of TSC1 deficiency in T cells on acute allograft rejection using a mouse cardiac transplantation model. We observed compromised allograft survival in mice with TSC1-deficient T cells. Notably, the allografts in mice transferred with TSC1-deficient CD8+T cells showed accelerated acute allograft rejection. TSC1 deficiency triggered the increased accumulation of CD8+ T cells in allografts due to augmented infiltration caused by increased CXCR3 expression levels and elevated in-situ proliferation of TSC1-deficient CD8+ T cells. Compared to CD8+ T cells from wild-type (WT) mice, TSC1-deficient CD8+ T cells exhibited enhanced cell proliferation and increased expression levels of interferon-γ and granzyme B after alloantigen stimulation. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), is used to treat patients with TSC and prevent rejection after solid-organ transplantation. Although rapamycin induced most cardiac allografts to survive beyond 100 d in WT mice, rapamycin-treated cardiac allografts in TSC1-deficient mice were rejected within 60 d. These results suggest that TSC1-deficient recipients may be more resistant to rapamycin-mediated immunosuppression during organ transplantation. Collectively, TSC1 significantly accelerates acute allograft rejection by enhancing the alloreactivity of CD8+ T cells, making them more resistant to mTOR inhibitor-mediated immunosuppression.

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.

Higher incidence of neurotoxicity and skin hyperpigmentation in renal transplant patients treated with polymyxin B.

BACKGROUND: Toxicity is a major concern related to the clinical use of polymyxin B, and available safety data for renal transplant patients are limited. AIMS: We investigated the safety of polymyxin B and toxicity risk factors in renal transplant patients. METHODS: A prospective study was performed on a group of renal transplant patients who received intravenous polymyxin B between January 2018 and August 2021. Polymyxin B treatment was monitored to evaluate toxicity and risk factors. RESULTS: A total of 235 courses of polymyxin B were administered to 213 patients. Of these, 121 (51.5%) developed skin hyperpigmentation (SH), 149 (63.4%) developed neurotoxicity and 10 (5.5%) developed acute kidney injury of which 80% was reversible. Risk factors for developing SH included a high total dose by weight (odds ration [OR] 1.31, 95% confidence interval [CI] 1.08-1.60, P = .008) and the presence of neurotoxicity (OR 2.86, 95% CI 1.56-5.26, P = .001). Neurotoxicity manifested during the first 2 days of treatment. Neurotoxicity occurred most commonly in women (OR 3.84, 95% CI 1.82-8.10, P < .0001), and the presence of SH (OR 1.98, 95% CI 1.13-3.46, P = .016) was also an independent risk factor. CONCLUSIONS: Neurotoxicity and SH are the two major adverse effects of polymyxin B in renal transplant patients, which may limit its clinical use.

MiR-133b regulates the proliferation, colony formation, and invasion of bladder cancer cells via inhibiting SOX4. / MiR-133b通过抑制SOX4è°ƒèŠ‚è†€èƒ±ç™Œç»†èƒžçš„å¢žæ®–ã€å ‹éš†å½¢æˆå’Œä¾µè¢­èƒ½åŠ›.

OBJECTIVES: Bladder cancer is one of the most common urothelial tumors with high incidence and mortality rates. Although it has been reported that microRNA (miR)-133b can regulate tumorigenesis of bladder cancer, the mechanism remains unclear. Sex-determining region Y-box transcription factor 4 (SOX4) exhibits an important role in tumorigenesis, but it is unclear whether SOX4 and miR-133b are associated with regulation of pathogenesis of bladder cancer. This study aims to determine the expressions of SOX4 and miR-133b in bladder cancer tissues and cells, investigate their effects on the proliferation, colony formation, and invasion of bladder cancer cells, and to explore the association between miR-133b and SOX4 in regulating biological featurss of bladder cancer cells. METHODS: The bladder cancer and adjacent tissue samples of 10 patients who underwent surgical resection in the Second Xiangya Hospital of Central South Universty from Januray to June 2015 were obtained. The levels of miR-133b were tested by real-time PCR, and the protein levels of SOX4 were evaluated using Western blotting in bladder cancer tissues, matched adjacent tissues, and cell lines. The correlation between miR-133b expression and SOX4 expression in bladder cancer tissues was analyzed. Using the online database TargetScan, the relationship between SOX4 and miR-133b was predicted. MiR-133b mimics, miR-133b inhibitor, and short hairpin RNA (shRNA)-SOX4 were transfected into T24 cells by Lipofectamine 2000. The relationship between miR-133b and SOX4 was also verified by a dual-luciferase reporter assay. The proliferation of T24 cells cultured for 0, 12, 48, 72, and 96 h was evaluated by cell counting kit-8 (CCK-8) assay. The colony formation capacity of bladder cancer cells was tested after 14-day culture, and cell invasion capacity was evaluated with Transwell invasion assay. RESULTS: Bladder cancer tissue and bladder cancer cells had low level of miR-133b but high level of SOX4, compared with matched adjacent tissues and normal bladder epithelial cells. A negative correlation between miR-133b mRNA and SOX4 protein levels in bladder cancer tissues was also found (r=-0.84). The results of online database TargetScan showed that miR-133b targets at SOX4, and overexpression of miR-133b significantly attenuated the expression of SOX4 in T24 cells. Both overexpression of miR-133b and knockdown of SOX4 significantly inhibited the proliferation, colony formation, and invasion capacity of bladder cancer cells in vitro. SOX4 down-regulation restored the effects of miR-133b inhibitor on the proliferation, colony formation, and invasion capacity of T24 cells. CONCLUSIONS: The up-regulation of SOX4 contributes to the progression of bladder cancer, and miR-133b can regulate the proliferation, colony formation, and invasion of bladder cancer cells via inhibiting SOX4.

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 circulating T follicular helper cells in kidney transplantation.

Humoral rejection plays a crucial role in the chronic deterioration of kidney allografts, but there is no effective therapeutic strategy to prevent or treat it. T follicular helper (Tfh) cells provide help to B cells, subsequently contributing to humoral rejection. Investigation of Tfh cells may be a useful strategy for assessing the risk and level of humoral rejection. However, it is difficult to investigate Tfh cells from patient-derived lymphoid tissue. Recent studies have shown that circulating Tfh (cTfh) cells, working in parallel to Tfh cells, have the capacity to promote antibody-secreting B cell differentiation and antibody secretion. Here, we review recent studies of cTfh cells in kidney transplantation and discuss the characteristics and functions of cTfh cells in kidney transplant recipients.

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.

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

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.

Satisfactory usage of kidneys from pediatric donors with severe hand foot mouth disease.

No studies have reported making use of kidneys from pediatric donors with severe HFMD. Here, we retrospectively analyzed the feasibility and clinical effect of six cases of kidney transplantation from four pediatric donors with severe HFMD in our center between January 2014 and December 2016. The donors' age ranged from 6 months to 3 years and 11 months. The recipients' age ranged from 18 to 41 years. Single kidney transplantation was performed in four recipients, and dual splitting kidney transplantation and en bloc kidney transplantation were performed in two recipients, respectively. During the 1.5-4 years follow-up, all recipients maintained normal kidney allograft function except for one recipient whose allograft was removed due to the allograft artery thrombosis. The survival rates of recipient and allograft were 100% and 83.3%, respectively. None of the six recipients showed any symptoms associated with HFMD. In conclusion, it is feasible to perform kidney transplantation from pediatric donors with severe HFMD to adult recipients with immunity to the pathogens. The clinical effect is satisfactory.

CAV3.1 knockdown suppresses cell proliferation, migration and invasion of prostate cancer cells by inhibiting AKT.

BACKGROUND: Aberrant expression of CAV3.1, one of T-type Ca2+ channels, is reported to exert important functions in pathological processes, including carcinogenesis. However, its expression pattern and function in prostate cancer (PCa) remains unclear. MATERIALS AND METHODS: The expression pattern of CAV3.1 was analyzed in multiple ways, including online analysis in Oncomine database, experimental analyses in cell lines, and collected clinical specimens using immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and Western blot. Then, CAV3.1 was downregulated in PCa cells to explore its functions. RESULTS: Upregulated CAV3.1 in PCa tissues and cells was confirmed by analyzing mRNA expression datasets from Oncomine and quantitative reverse transcription polymerase chain reaction detection, respectively. Accordingly, significantly higher CAV3.1 protein level in PCa tissues specimens than that in benign prostatic hyperplasia tissues was indicated by immunohistochemical staining. In addition, CAV3.1 upregulation was positively associated with metastasis. Depletion of CAV3.1 impaired the proliferation, migration, and invasion ability of PCa cells demonstrating by cell functional experiments, such as CCK-8, cell cycle distribution, plate clone formation, scratch wound healing, and transwell invasion assays. Mechanistically, due to constrained Akt activity, CAV3.1 knockdown resulted in decreased level of CCND1, N-cadherin, and Vimentin, and increased level of E-cadherin whose expressions could be reversed by ectopic Akt expression. Similarly, ectopic Akt expression also rescued the inhibitory effects of CAV3.1 knockdown on cell functions like proliferation and migration in PCa cells. CONCLUSION: Upregulated CAV3.1 is positively associated with the development of PCa. CAV3.1 knockdown can inhibit PCa cell proliferation, migration, and invasion by suppressing AKT activity.

Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients.

AIMS: The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections. METHODS: A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed-effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model. RESULTS: A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l·h-1 , 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily. CONCLUSIONS: Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.

Cancer risks in recipients of renal transplants: a meta-analysis of cohort studies.

Renal transplantation is associated with an increased risk of cancers at multiple sites; however, the relationships between increased cancer risk and participant characteristics remain unclear. We searched PubMed, Embase, and the Cochrane Library to identify prospective observational studies performed up to July 2017. Totally 11 prospective studies reported data on 79,988 renal transplant recipients were included. Renal transplant recipients were found to display a higher risk of all cancers (standard incidence ratio [SIR]: 2.89; 95% CI: 2.13-3.91; P < 0.001), gastric cancer (SIR: 1.93; 95% CI: 1.60-2.34; P < 0.001), colon cancer (SIR: 1.85; 95% CI: 1.53-2.23; P < 0.001), pancreatic cancer (SIR: 1.53; 95% CI: 1.23-1.91; P < 0.001), hepatocellular carcinoma (SIR: 2.45; 95% CI: 1.63-3.66; P < 0.001), lung cancer (SIR: 1.68; 95% CI: 1.29-2.19; P < 0.001), thyroid cancer (SIR: 5.04; 95% CI: 3.79-6.71; P < 0.001), urinary bladder cancer (SIR: 3.52; 95% CI: 1.48-8.37; P = 0.004), renal cell cancer (SIR: 10.77; 95% CI: 6.40-18.12; P < 0.001), non-melanoma skin cancer (SIR: 12.14; 95% CI: 6.37-23.13; P < 0.001), melanoma (SIR: 2.48; 95% CI: 1.08-5.67; P = 0.032), Hodgkin's lymphoma (SIR: 4.90; 95% CI: 3.09-7.78; P < 0.001), non-Hodgkin lymphoma (SIR: 10.66; 95% CI: 8.54-13.31; P < 0.001), lip cancer (SIR: 29.45; 95% CI: 17.85-48.59; P < 0.001), breast cancer (SIR: 1.11; 95% CI: 1.00-1.24; P = 0.046), and ovarian cancer (SIR: 1.60; 95% CI: 1.23-2.07; P < 0.001). However, renal transplantation did not significantly influence the risks of uterine cancer (P = 0.171), and prostate cancers (P = 0.188). Our findings suggest that patients who receive renal transplantation have an increased risk of cancer at most sites, apart from uterine and prostate cancers patients.

A novel technique for en bloc kidney transplantation from infant donors with extremely low body weight by using the distal abdominal aorta as an outflow tract.

Pediatric kidney donors remain underutilized due to the high risk of postoperative thrombosis. To address this problem, we developed a novel en bloc kidney transplantation technique using donor thoracic aorta and the distal abdominal aorta as inflow and outflow tracts, respectively. Briefly, eight kidneys from deceased infant donors under five months old and with low body weight (1.9-4.9 kg) were transplanted en bloc into four pediatric and four adult patients. The donor's common iliac artery or external iliac artery was anastomosed to the recipient's distal external iliac artery or inferior epigastric artery, respectively, as an outflow tract. Recipients received basiliximab or antithymocyte globulin as induction therapy followed by tacrolimus, mycophenolate mofetil, and prednisone but without prophylactic anticoagulation. Delayed graft function was observed in one patient but was reversed at 90 days posttransplant. Two patients had urine leakage, which was cured by conservative treatment. Two recipients developed lung infections that eventually cleared. No patients experienced posttransplant vascular thrombosis. After 1-1.5 years of follow-up, all patients are well and have normal serum creatinine levels. In conclusion, this novel en bloc kidney transplantation technique using a modified arterial inflow and outflow tract can prevent vascular thrombosis and provide adequate graft function.