Human mesenchymal stromal cells ameliorate cisplatin-induced acute and chronic kidney injury via TSG-6.

Cisplatin is widely used in tumor chemotherapy, but nephrotoxicity is an unavoidable side effect of cisplatin. Several studies have demonstrated that mesenchymal stromal cells (MSCs) ameliorate cisplatin-induced kidney injury, but the underlying mechanisms are unknown. In this study, the cisplatin-induced kidney injury mouse model was established by subjecting a single intraperitoneal injection with cisplatin. One hour before cisplatin injection, the mice received human bone marrow MSCs (hBM-MSCs) with or without siRNA-transfection, recombinant human tumor necrosis factor-α-stimulated gene/protein 6 (rhTSG-6), or PBS through the tail vein. In addition, cisplatin-stimulated HK-2 cells were treated with hBM-MSCs or rhTSG-6. Human BM-MSCs treatment remarkably ameliorated cisplatin-induced acute and chronic kidney injury, as evidenced by significant reductions in serum creatinine (Scr), blood urea nitrogen, tubular injury, collagen deposition, α-smooth muscle actin accumulation, as well as inflammatory responses, and by remarkable increased anti-inflammatory factor expression and Treg cells infiltration in renal tissues. Furthermore, we found that only a few hBM-MSCs engrafted into damaged kidney and that the level of human TSG-6 in the serum of mice increased significantly following hBM-MSCs administration. Moreover, hBM-MSCs significantly increased the viability of damaged HK-2 cells and decreased the levels of inflammatory cytokines in the culture supernatant. However, the knockdown of the TSG-6 gene in hBM-MSCs significantly attenuated their beneficial effects in vivo and in vitro. On the contrary, treated with rhTSG-6 achieved similar beneficial effects of hBM-MSCs. Our results indicate that systemic administration of hBM-MSCs alleviates cisplatin-induced acute and chronic kidney injury in part by paracrine TSG-6 secretion.

Treatment of Asymptomatic Bacteriuria after Kidney Transplantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background and Objectives: Asymptomatic bacteriuria (ASB) is prevalent in kidney transplant recipients (KTRs) and is hypothesized to heighten the risk of subsequent urinary tract infections (UTIs). Whether antibiotic treatment of ASB in KTRs is beneficial has not been elucidated. Materials and Methods: We carried out a systematic review and meta-analysis of all randomized controlled trials (RCTs) and quasi-RCTs that examined the merits of managing asymptomatic bacteriuria in KTRs. The primary outcomes were rates of symptomatic urinary tract infections (UTIs) and antimicrobial resistance. Results: Five studies encompassing 566 patients were included. No significant difference in symptomatic UTI rates was found between antibiotics and no treatment groups (relative risk (RR) 1.05, 95% confidence interval (CI) = 0.78-1.41), with moderate heterogeneity (I2 = 36%). Antibiotic treatment was found to present an uncertain risk for the development of drug-resistant strains (RR = 1.51, 95% CI = 0.95-2.40, I2 = 0%). In all trials, no significant difference between study arms was demonstrated regarding patient and graft outcomes, such as graft function, graft loss, hospitalization due to UTI, all-cause mortality, or acute rejection. Conclusions: The practice of screening and treating kidney transplant patients for asymptomatic bacteriuria does not curtail the incidence of future symptomatic UTIs, increase antimicrobial resistance, or affect graft outcomes. Whether early treatment of ASB after kidney transplantation (<2 months) is beneficial requires more RCTs.

Risk Factors and Pathogen Spectrum in Continuous Ambulatory Peritoneal Dialysis-Associated Peritonitis: A Single Center Retrospective Study.

BACKGROUND To investigate the incidence, risk factors, pathogen distribution, and drug resistance patterns in continuous ambulatory peritoneal dialysis-associated peritonitis (CAPDP). MATERIAL AND METHODS Clinical data for 248 patients who underwent continuous ambulatory peritoneal dialysis (CAPD) treatment in a single center in China from March 2018 to January 2021 were retrospectively collected. The patients were divided into the CAPDP group (n=40) and the non-CAPDP group (n=208) according to whether peritonitis occurred. The incidence rate, risk factors, bacterial distribution, and drug sensitivity of CAPDP were analyzed. RESULTS The incidence of CAPDP was 16.13%, and 87.5% of patients with CAPDP continued CAPDP treatment after anti-infection treatment. Patients with and without CAPDP were clearly distinguished, on the basis of their clinical characteristics, by using principal component analysis (PCA) methods. Logistic regression analysis found that body mass index (BMI; P=0.0095), albumin (P=0.016), albumin/globulin ratio (P=0.018), C-reactive protein (P=0.0001), and rapid transport (P=0.034) were independent risk factors for CAPDP. The main pathogens causing the CAPDP were Staphylococcus epidermidis (50.00%), Staphylococcus capitis (13.33%), and Escherichia coli (10.00%). Among the pathogenic bacteria, the main drugs to which gram-negative cocci were sensitive were imipenem, meropenem, piperacillin/tazobactam, cefoperazone/sulbactam, ceftazidime, and tigecycline. The main drugs to which gram-positive cocci were sensitive were vancomycin, teicoplanin, and linezolid. The drug resistance rate of pathogenic bacteria to penicillin G, ampicillin, compound trimethoprim, cefepime, ceftriaxone, and amoxicillin-clavulanic acid drugs was 36.26-100%. CONCLUSIONS BMI, albumin, albumin/globulin ratio, C-reactive protein, and rapid transport are independent risk factors for CAPDP. Gram-positive bacteria are the main pathogens of CAPDP and are sensitive to vancomycin, teicoplanin, and linezolid.

[Learning Curve of Retroperitoneal Laparoscopic Donor Nephrectomy and Risk Analysis of Intraoperative Complications].

OBJECTIVES: To investigate the learning curve of retroperitoneal laparoscopic donor nephrectomy (LDN) and evaluate the risk factors of intraoperative complications with data from a single center. METHODS: We evaluated perioperative data of 527 consecutive kidney donors who received retroperitoneal LDN between April 2009 and April 2014. The patients were divided into two groups according to the learning curve which was determined by the operation time:group 1 (on the learning curve) and group 2 (learning curve completed). RESULTS: The mean operation time was (88.4±38.07) min. The asymptote of the surgeon's learning curve for retroperitoneal LDN was achieved at the 100th case. The operation time and the incidence of intraoperative complications in group 1 were significantly higher than those of group 2. When cases completed, body mass index (BMI) and intraoperative complications were correlated to operative time. The incidence of intraoperative complications was 1.90% and BMI was correlated to the incidence of intraoperative complications. When the learning curve was completed, renal artery numbers and right kidney were found being correlated to operative time. CONCLUSIONS: Retroperitoneal LDN is a safe and effective operation method with a low incidence of complications. Technical proficiency in retroperitoneal LDN could be achieved after 100 surgeries.

Optimal Perioperative Antimicrobial Management Strategies of Kidney Transplant Recipients Guided by Metagenomic Next-Generation Sequencing of Deceased Donors' Microbiology Samples.

Background: There is no consensus on the optimal use of perioperative antibiotics prophylaxis after kidney transplantation, but there is a common trend to limit the duration of antibiotic use worldwide. Metagenomic next-generation sequencing (mNGS) has emerged as a novel technology for pathogen detection in clinical practice due to its noninvasive, rapid, precise and high susceptibility to detect infectious pathogens. However, data are lacking on whether mNGS analyses could be used to detect pathogens and guide anti-infection regimens in kidney transplant donors and recipients. Methods: We conducted a retrospective study to review all clinic data of mNGS and traditional laboratory methods (TMs) for pathogen detection in kidney transplant recipients and their corresponding deceased donors from August 1, 2021 to October 30, 2022 in our center. Results: A total of 57 donors and 112 of their corresponding recipients were included. The antimicrobial strategy mainly depended on mNGS results combined with traditional pathogen culture and clinical conditions. The percentages of positive pathogen detected by mNGS in blood, urine, bronchoalveolar lavage fluid (BALF) and preservation fluids (PFs) were 50.9% (29/57), 35.1% (20/57), 84.2% (48/57) and 54.4% (31/57) respectively, and were 24.6% (14/57), 15.8% (9/57), 57.9% (33/57) and 14.1% (8/57) respectively when using TMs. mNGS could detected all of pathogens which were detected by TMs. However, samples with negative TMs testing can be additionally detected as positive by mNGS (15/43 in blood, 11/48 in urine, 15/24 in BALF and 23/49 in PFs). Drug resistance genes were detected in 9 donors by mNGS,which were consistent with 6 donors by TMs. There was only one case of donor-derived infection in this study. Conclusion: This study showed that it is effective to combine mNGS with traditional pathogen detection methods and clinical features to develop optimal perioperative antimicrobial management strategies for deceased donor kidney transplantation.

LIGHT deficiency attenuates acute kidney disease development in an in vivo experimental renal ischemia and reperfusion injury model.

Ischemia-reperfusion (I/R), a leading risk factor of acute kidney injury (AKI), is associated with high mortality and risk of progression to chronic kidney disease. However, the molecular mechanism of I/R-AKI remains not fully understood, which hinders its efficient clinical treatment. In this study, we observed that LIGHT deficiency remarkably attenuated I/R-AKI, as evidenced by rescued renal function, ameliorated tubular cell apoptosis, and alleviated inflammatory responses. Consistently, blocking LIGHT signaling with its soluble receptor fusion proteins (HVEM-IgG-Fc or LTßR-IgG-Fc) improved I/R renal dysfunction. RNA-sequencing and corresponding results indicated that LIGHT promoted oxidative stress and inflammation triggered by ischemic injury. Moreover, LIGHT signaling augmented ischemic stress-induced mitochondrial dysfunction characterized by an imbalance in mitochondrial fission and fusion, decreased mtDNA copies, impaired mitophagy, and increased mitochondrial membrane potential (ΔΨm). Mechanistically, LIGHT promoted mitochondrial fission by enhancing Drp1 phosphorylation (Ser616) and its translocation to the mitochondria. In conclusion, these results suggest that LIGHT-HVEM/LTßR signaling is critical for the I/R-AKI pathogenesis and it is further confirmed to be related to the increase in I/R-induced oxidative stress and mitochondria dysfunction, which may be the underlying mechanism of LIGHT signaling-mediated I/R-AKI.

miR-17-92 ameliorates renal ischemia reperfusion injury.

There is limited information on the role of miR-17-92 in renal tubular pathophysiology. Therefore, the present study was performed to determine whether miR-17-92 plays a role in ischemia-reperfusion injury (IRI)-induced acute kidney injury. We originally demonstrated that miR-17-92 is up-regulated following IRI in vivo. To explore the roles of miR-17-92 in the IRI process, we first generated a renal proximal tubule-specific miR-17-92 deletion (PT-miR-17-92-/-) knockout mouse model with Cre driven by the Kap promoter. We found that PT-deficient miR-17-92 mice had more severe renal dysfunction and renal structures than their littermates. Compared with sham-operated mice, both wide-type (WT) mice and PT-miR-17-92-/- mice showed increased serum levels of creatinine and urea. However, the levels of serum urea and creatinine in PT-miR-17-92-/- mice after the IRI operation were significantly higher than the levels in WT mice. In addition, PT-miR-17-92-/- mice showed higher levels of serum potassium and phosphonium after the IRI operation. Histological analysis revealed that PT-miR-17-92-/- mice had substantial histopathologic changes, such as tubular dilation and tubular necrosis. Overexpression of miR-17-92 could partially reverse the side-effects of IRI on the proximal tubules in vivo. Furthermore, we employed a quantitative proteomic strategy and identified 16 proteins as potential targets of miR-17-92. Taken together, our findings suggested that miR-17-92 may ameliorates IRI-induced acute kidney injury. Our results indicate that pharmacologic modulation of these miRNAs may have therapeutic potential for acute kidney injury.

Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors.

To investigate whether the ratio of remnant kidney volume to body weight (V/W ratio) can impact renal function in donors, 45 living kidney donors were enrolled. Kidney volume was analyzed by magnetic resonance imaging. Renal function was compared between donors with a V/W ratio of < 2.0 mL/kg (n = 23) or ≥ 2.0 mL/kg (n = 22). Donors in both V/W groups showed similar serum creatinine levels and estimated glomerular filtration rates (eGFRs) at 7 days and 1 year, whereas donors with a V/W ratio of < 2.0 mL/kg had significantly higher 24-hour urine protein levels at 1 year (0.54 ± 0.23 g/d vs. 0.33 ± 0.19 g/d, p = 0.028). Multivariate analysis revealed no correlation between the V/W ratio and eGFR at 7 days or 1 year, and a V/W ratio of < 2 mL/kg was not associated with an increased incidence of eGFR < 60 mL/min/1.73 m(2) at 1 year (risk ratio 1.73, 95% confidence interval 0.10-29.47). The V/W ratio correlated inversely with 24-hour urine protein (r = -0.377, p = 0.021) at 1 year, and donors with a V/W ratio of < 2.0 mL/kg were more likely to show 24-hour urine protein >300 mg (risk ratio 1.70, 95% confidence interval 1.08-2.67) at 1 year. Donors with lower V/W ratios have higher 24-hour urinary protein levels at 1 year after transplantation. These findings suggest that the V/W ratio may be useful for kidney selection.

Calcineurin Inhibitors Associated Posterior Reversible Encephalopathy Syndrome in Solid Organ Transplantation: Report of 2 Cases and Literature Review.

Posterior reversible encephalopathy syndrome (PRES) is a rare neurologic side effect of calcineurin inhibitors (CNIs) with poorly understood clinical features.We report cases of 2 patients with PRES developing after kidney transplantation and summarize PRES clinical features through a literature review.The 1st case was a 28-year-old man who received a kidney transplant from a deceased donor. Initial immunosuppressive therapy consisted of tacrolimus/mycophenolate mofetil/prednisolone. He developed headache and blurred vision with visual field loss15 days after transplantation and generalized seizures 4 days later. The 2nd case was a 34-year-old man who received a living kidney transplant. His initial immunosuppressive therapy comprised tacrolimus/mycophenolate mofetil/prednisolone. Two months after transplantation, he developed seizures. Both patients were diagnosed with PRES based on neurological symptoms and magnetic resonance imaging (MRI) findings; they recovered after switching from tacrolimus to either a cyclosporine or a lower tacrolimus dose. CNI-associated PRES is an acute neurological syndrome with seizures, encephalopathy, visual abnormalities, headache, focal neurological deficits, and nausea/vomiting. It is always accompanied by hypertension. A fluid-attenuated inversion recovery signal MRI scan typically shows reversible subcortical white matter changes in the posterior cerebral hemisphere that usually occur within the 1st month after transplantation. CNI-associated PRES has a generally favorable prognosis with early diagnosis and prompt treatment including alternating or discontinuing CNIs and blood pressure control.CNI-associated PRES should be considered in patients exhibiting acute neurological symptoms after transplantation. Early diagnosis and immediate treatment are critical for a favorable prognosis.

Fluoroquinolone prophylaxis in preventing BK polyomavirus infection after renal transplant: A systematic review and meta-analysis.

Previous studies regarding the prevention of BK viremia following renal transplantation with fluoroquinolone have yielded conflicting results. The purpose of this systematic review was to examine the evidence regarding the efficacy of fluoroquinolone in preventing BK polyomavirus infection following renal transplantation. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for research articles published prior to January 2015 using keywords such as "fluoroquinolone," "BK viremia," and "renal transplantation." We extracted all types of study published in English. The primary outcome was BK viremia and viruria at 1 year post-transplantation. Secondary outcomes were BK virus-associated nephropathy (BKVN), graft failure, and fluoroquinolone-resistant infection. We identified eight trials, including a total of 1477 participants with a mean duration of fluoroquinolone prophylaxis of >1 month. At 1 year, fluoroquinolone prophylaxis was not associated with a decreased incidence of BK viremia [risk ratio (RR), 0.84; 95% confidence interval (95% CI), 0.58-1.20). No significant differences in BKVN (RR, 0.88; 95% CI, 0.37-2.11), risk of graft failure due to BKVN (RR, 0.68; 95% CI, 0.29-1.59), or fluoroquinolone-resistant infection (RR, 1.08; 95% CI, 0.64-1.83) were observed between the fluoroquinolone prophylaxis and control groups. The results of this study suggest that fluoroquinolone is ineffective in preventing BK polyomavirus infection following renal transplantation.

A lesson from kidney transplantation among identical twins: Case report and literature review.

There continues to be disagreement related to the appropriate therapeutic regimen to be used when the donor and the recipient in kidney transplant operations are identical twins. Here we present two cases of kidney transplantation between identical twins. Both recipients had end-stage renal disease (ESRD) caused by primary nephropathy. We also present information gleaned from a literature review of similar cases. The first recipient was a 26-year-old man who experienced biopsy-proven IgA nephropathy 10 months post-transplantation. Mycophenolate mofetil (MMF), angiotensin receptor blockers (ARBs), and steroids were used to reverse this pathologic condition. Till now, 76 months post-transplantation, the patient is stable, and the new kidney is functioning well. The second recipient was a 20-year-old woman who had hematuria and proteinuria 3 months post-transplantation, and crescent glomerulonephritis with mild to moderate interstitial injury was proven by biopsy 11 months postoperatively. This patient did not respond to various treatments and resumed hemodialysis 15 months post-transplantation. These case studies show that immunosuppressive therapy should be maintained in kidney transplant recipients who are identical twins with ESRD caused by initial nephropathy.

Post-renal transplantation anemia at 12 months: prevalence, risk factors, and impact on clinical outcomes.

PURPOSE: To investigate any association between post-transplantation anemia (PTA) and clinical outcomes following living donor kidney transplantation. METHODS: We retrospectively evaluated 887 patients who received living donor kidney transplantations at our medical center between January 2006 and December 2012 to evaluate whether PTA, defined as serum hemoglobin (Hb) levels of <130 g/l in men and <120 g/l in women, at 12 months is associated with post-transplant outcomes, including graft function, death-censored graft survival, or patient survival. RESULTS: The prevalence of PTA at 1, 3, 6, and 12 months was 84.3, 39.5, 26.2, and 21.6 %, respectively. Donor age [hazard ratio (HR), 1.03; 95 % confidence interval (CI) 1.01-1.05] and acute rejection (HR 2.13; 95 % CI 1.28-3.54) were found to be independent risk factors for PTA at 12 months. Recipient age (HR 0.98; 95 % CI 0.95-1.00), pre-transplantation Hb levels (HR 0.99; 95 % CI 0.98-1.00), and estimated glomerular filtration rates (eGFRs) at 12 months (HR 0.96; 95 % CI 0.94-0.97) were found to confer slight protection against PTA at 12 months. PTA at 12 months was associated with increased graft loss (HR 1.046; 95 % CI 1.045-1.046). For each increase in anemia degree, there was a 2.77-fold greater risk of graft loss (HR 2.77; 95 % CI 1.50-5.13). When stratified according to eGFR, PTA was found to be a predictor of graft loss in patients with an eGFR of <60 ml/min/1.73 m(2) (HR 4.57; 95 % CI 1.98-10.56) but not in patients with an eGFR of >60 ml/min/1.73 m(2) (HR 1.89; 95 % CI 0.13-27.78). PTA was not found to be a predictor of patient survival. CONCLUSIONS: Anemia is common after kidney transplantation, and its prevalence declines with time after transplantation. Presence of anemia at 12 months post-transplant was an independent predictor of graft loss, with higher risk of graft loss in patients with anemia and poorer kidney functions.

Kidneys from Older Living Donors Provide Excellent Short and Intermediate Outcomes--A Single China Center's Experience.

BACKGROUND: Transplantation with kidneys from older living donors is on the rise, yet controversy still exists over whether the outcomes are as satisfactory as with kidneys from younger donors. METHODS: We retrospectively analyzed 1009 living donor kidney transplants performed at our center between 2006 and 2013. Graft and patient outcomes were compared between transplants with kidneys from old living donors (OLD, 55-65 years) (n = 264) and from young living donors (YLD, <55 years) (n = 745). RESULTS: The age was 32.80 ± 9.71 years and 33.91 ± 5.98 years for recipient in YLD and OLD group, respectively. Death-censored graft survival at 1, 3, and 5 years was 98.8%, 97.1%, and 95.8% in patients receiving YLD kidneys, similar to the corresponding values of 97.6%, 95.5% and 95.5% in patients receiving OLD kidneys (P = 0.356). Patient survival at 1, 3, and 5 years after transplantation was also similar for patients receiving YLD kidneys (98.5%, 97.1%, and 96.7%) and for patients receiving OLD kidneys (99.6%, 99.6%, and 96.8%; P = 0.110). The OLD kidneys were not associated with increased risk of death-censored graft failure (hazard ratio, 2.5; 95% confidence interval, 0.57 to 11.11) and patient death (hazard ratio, 1.67; 95% confidence interval, 0.75 to 3.73). In addition, there is no increased graft loss or patient death for each 10-year increase in donor age. Transplantation with OLD kidneys was not associated with reduced patient or graft outcomes in the short term (≤ 12 months) or medium term (>1 year). CONCLUSIONS: Graft and patient outcomes after living-donor kidney transplantation are similar in the short-term and medium-term for donors aged 55 to 65 years and for younger donors. Therefore, the use of OLD kidneys should be encouraged in China.

Association of HHIP polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population.

The hedgehog signaling pathway plays an important role in lung morphogenesis and cellular responses to lung injury. Genome-wide association studies (GWAS) and integrative genomics approaches have demonstrated the associations between HHIP polymorphisms and chronic obstructive pulmonary disease (COPD) and in non-Asian populations. Here we investigated whether HHIP polymorphisms would also be associated with COPD susceptibility and COPD-related phenotypes in a Chinese Han population. In the present case-control study a total of 680 COPD patients and 687 healthy control subjects were recruited. Six single nucleotide polymorphisms (SNPs) (rs1828591, rs13118928, rs6817273, rs10519717, rs12504628, rs13147758) were selected for genotyping. Allele frequencies and genotype distributions were compared between patients and controls. To estimate the strength of association, odds ratios (OR) (with 95% CI) were calculated and potential confounding variables were tested by using logistic regression analysis. Association between haplotypes and COPD outcome was also assessed. We identified that SNP rs12504628 was associated with FEV1/FVC ratio among cases (P=0.0460). Moreover, the HHIP SNP rs10519717 was associated with the severity of disease (adjusted P-value=0.0300). The six SNPs showed strong linkage disequilibrium (r(2)≥ 0.9). Three major haplotypes were observed but showed no significant difference between case and control groups (P=0.4532, 0.0875, and 0.3484, respectively). In conclusion, our study suggests that the HHIP gene may be involved in COPD susceptibility in Chinese Han population.

Twenty-five cases of adult prostate sarcoma treated at a high-volume institution from 1989 to 2009.

OBJECTIVE: To analyze the clinical characteristics, treatment modalities, and outcomes of adult prostate sarcoma treated at our institution. MATERIALS AND METHODS: The medical records of 25 adult patients with prostate sarcoma were obtained from January 1989 to December 2009. The clinicopathologic parameters were evaluated to determine their effect on survival. RESULTS: The median age was 37 years (range 18-81). The median tumor size was 9.5 cm (range 4-25). The median serum prostate-specific antigen level was 1.39 ng/mL (range 0.39-33.20). The most common symptom was dysuria (72%). Transrectal ultrasound-guided needle biopsy was used to diagnose 22 sarcomas, transurethral resection of the prostate to diagnose 2, and open surgery to diagnose 1. The predominant histologic subtype was leiomyosarcoma (40%); 21 (88%) were high grade and 6 patients had metastatic disease. Surgical resection of curative intent was performed in 14 patients, with negative margins in 10. After a median follow-up of 21 months (range 5-63), 2 patients were disease free, 4 were alive with disease, and 19 had died of their disease. Overall, the 1-, 2-, 3-, and 5-year survival rate was 80.0%, 47.4%, 22.6%, and 11.3%, respectively, and the median survival time was 23 months. The median survival time after recurrence was 20 months (range 9-39) and that after metastasis was 10 months (range 3-23). Age >50 years, metastasis at presentation, and a lack of surgery with curative intent were independently predictive of an unfavorable outcome. CONCLUSION: Adult prostate sarcoma accounted for 0.7% of primary prostate malignancies and carried a poor prognosis. Early diagnosis and surgical resection with curative intent offer patients the best chance of survival.