Captopril related kidney damage: renal afferent arteriolar responses to angiotensin II and inflammatory signaling.

Captopril can have nephrotoxic effects, which are largely attributed to accumulated renin and "escaped" angiotensin II (Ang II). Here we test whether angiotensin converting enzyme-1 (ACE1) inhibition damages kidneys via alteration of renal afferent arteriolar responses to Ang II and inflammatory signaling. C57Bl/6 mice were given vehicle or captopril (60 mg/kg per day) for four weeks. Hypertension was obtained by minipump supplying Ang II (400 ng/kg per min) during the second 2 weeks. We assessed kidney histology by periodic acid-Schiff (PAS) and Masson staining, glomerular filtration rate (GFR) by FITC-labeled inulin clearance, and responses to Ang II assessed in afferent arterioles in vitro. Moreover, arteriolar H2O2 and catalase, plasma renin were assayed by commercial kits, and mRNAs of renin receptor, transforming growth factor-ß (TGF-ß) and cyclooxygenase-2 (COX-2) in the renal cortex, mRNAs of angiotensin receptor-1 (AT1R) and AT2R in the preglomerular arterioles were detected by RT-qPCR. The results showed that, compared to vehicle, mice given captopril showed lowered blood pressure, reduced GFR, increased plasma renin, renal interstitial fibrosis and tubular epithelial vacuolar degeneration, increased expression of mRNAs of renal TGF-ß and COX-2, decreased production of H2O2 and increased catalase activity in preglomerular arterioles and enhanced afferent arteriolar Ang II contractions. The latter were blunted by incubation with H2O2. The mRNAs of renal microvascular AT1R and AT2R remained unaffected by captopril. Ang II-infused mice showed increased blood pressure and reduced afferent arteriolar Ang II responses. Administration of captopril to the Ang II-infused mice normalized blood pressure, but not arteriolar Ang II responses. We conclude that inhibition of ACE1 enhances renal microvascular reactivity to Ang II and may enhance important inflammatory pathways.

Maternal and neonatal outcomes of pregnancy complicated by urolithiasis: a systematic review and meta-analysis.

BACKGROUND: The effect of urolithiasis on pregnancy-related outcomes remains unknown. The aim of this study was to determine the risk of adverse maternal and neonatal outcomes. METHODS: We searched PubMed, Embase, and the Cochrane Library through December 2020 for studies reporting on adverse maternal and neonatal outcomes in patients with urolithiasis. Risk ratios (ORs) with 95% confidence intervals (CIs) were calculated for these outcomes in pregnant mothers with urolithiasis and compared to healthy controls. RESULTS: Eight studies comprising 26,577 mothers with urolithiasis were included in our analysis. Preterm birth (OR = 1.63; 95% CI 1.37-1.95, p < 0.001) or very preterm birth risk (OR = 1.49, 95% CI 1.06-2.11, p = 0.02) was more common in patients with urolithiasis compared to healthy controls. Mothers with urolithiasis had an increased incidence of preeclampsia (OR = 1.75, 95% CI 1.33-2.3, p < 0.001), hypertension (OR = 2.97, 95% CI 1.31-6.71, p = 0.009), caesarean section (OR 1.31, 95% CI 1.11-1.55, p = 0.001), and gestational diabetes mellitus (OR 1.84, 95% CI 1.37-2.46, p < 0.001). CONCLUSION: Patients with urolithiasis may be at increased risk of developing adverse maternal or neonatal outcomes.

Predictive value of aberrant right subclavian artery for fetal chromosome aneuploidy in women of advanced maternal age.

BACKGROUND: In the entire population, an aberrant right subclavian artery (ARSA) is closely associated with chromosomal abnormalities. ARSA with additional ultrasonic findings would increase risk of chromosomal abnormalities. The risk of fetal chromosomal abnormalities increased exponentially with the maternal age. These risks in the advanced maternal age (AMA) group are uncertain. This study aimed to determine the incidence of ARSA in Chinese AMA and non-AMA women and the frequency of aneuploidy among AMA and non-AMA women with ARSA. METHODS: This retrospective study included 13,690 singleton pregnancies, were divided into AMA and non-AMA groups. Integrated obstetric ultrasonic screening, biochemical screening, noninvasive prenatal screening, and fetal karyotype analysis were analyzed. RESULTS: The overall incidence of ARSA was 0.69%, with no difference between age groups. The incidence of chromosomal abnormalities in the AMA group (37 / 2860) was much higher than that of the non-AMA group. The risk of chromosomal abnormalities significantly increased with both ARSA detected and additional ultrasound findings. With combined ARSA and AMA, the likelihood of the incidence of chromosomal abnormalities increased. Chimerism (45X / 46XX) was found with isolated ARSA in AMA pregnancies. CONCLUSION: There is a high prevalence of chromosomal abnormalities in fetuses of AMA women. ARSA increases the risk of chromosomal abnormalities in both age groups, especially combined with ARSA. When ARSA occurs in AMA women, it confers a high likelihood of chromosomal abnormalities.

Gene expression profiling of sepsis-associated acute kidney injury.

Sepsis accounts for more than 50% of all acute kidney injury (AKI) cases, and the combination of sepsis and AKI increases the risk of mortality from sepsis alone. However, to the best of our knowledge, the specific mechanism by which sepsis causes AKI has not yet been fully elucidated, and there is no targeted therapy for sepsis-associated AKI (SA-AKI). The present study investigated gene expression profiles using RNA sequencing (RNA-Seq) and bioinformatics analyses to assess the function of differentially expressed genes (DEGs) and the molecular mechanisms relevant to the prognosis of SA-AKI. From the bioinformatics analysis, 2,256 downregulated and 3,146 upregulated genes were identified (false discovery rate <0.1 and fold-change >2). Gene Ontology analysis revealed that the genes were enriched in cellular metabolic processes, cell death and apoptosis. The enriched transcription factors were v-rel reticuloendotheliosis viral oncogene homolog A and signaling transducer and activator of transcription 3. The enriched microRNAs (miRNAs or miRs) among the DEGs were miR-30e, miR-181a, miR-340, miR-466d and miR-466l. Furthermore, the enriched pathways included toll-like receptor signaling, nod-like receptor signaling and the Janus kinase/STAT signaling pathway. In conclusion, the present study identified certain prognosis-related genes, transcription factors, miRNAs and pathways by analyzing gene expression profiles of SA-AKI using RNA-Seq, which provides some basis for future experimental studies.

Genome-wide identification of WD40 genes reveals a functional diversification of COP1-like genes in Rosaceae.

KEY MESSAGE: Genome-wide identification of WD40-like genes reveals a duplication of COP1-like genes, one of the key players involved in regulation of flowering time and photomorphogenesis, with strong functional diversification in Rosaceae. WD40 proteins play crucial roles in a broad spectrum of developmental and physiological processes. Here, we conducted a systematic characterization of this family of genes in Rosa chinensis 'Old Blush' (OB), a founder genotype for modern rose domestication. We identified 187 rose WD40 genes and classified them into 5 clusters and 15 subfamilies with 11 of RcWD40s presumably generated via tandem duplication. We found RcWD40 genes were expressed differentially following stages of vegetative and reproductive development. We detected a duplication of CONSTITUTIVE PHOTOMORPHOGENIC1-like genes in rose (RcCOP1 and RcCOP1L) and other Rosaceae plants. Featuring a distinct expression pattern and a different profile of cis-regulatory-elements in the transcriptional regulatory regions, RcCOP1 seemed being evolutionarily conserved while RcCOP1L did not dimerize with RcHY5 and RcSPA4. Our data thus reveals a functional diversification of COP1-like genes in Rosacaeae plants, and provides a valuable resource to explore the potential function and evolution of WD40-like genes in Rosaceae plants.

Executive Summary: Clinical Practice Guideline for Autosomal Dominant Polycystic Kidney Disease in China.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, with a prevalence of 1/2,500-1/1,000, and it affects 1.25 million people in China. ADPKD is responsible for nearly 5% of end-stage renal disease cases, which leads to a major burden on public health. In 2016, the Chinese working group developed guidelines for the diagnosis and treatment of ADPKD, which promoted the clinical management of ADPKD in China. In the last 3 years, Chinese clinicians have deepened their understanding and standardized the management of ADPKD, and several basic and clinical studies on ADPKD have been conducted. In combination with international guidelines and research results, the working group updated the ADPKD guidelines in China. This guideline includes 5 chapters: introduction, diagnosis, kidney disease progression monitoring, treatment, and family planning. We highlight the main recommendations and suggestions of the ADPKD guidelines in this summary.

Preoperative Serum Fibrinogen is Associated With Acute Kidney Injury after Cardiac Valve Replacement Surgery.

Acute kidney injury (AKI) after open cardiac surgery is associated with a longer hospital stay and higher risk of mortality. We aimed to explore the association between preoperative serum fibrinogen level and risk of postoperative AKI in patients with open cardiac surgery. 3459 patients who underwent cardiac valve replacement surgery from January 2011 to September 2015 were recruited. The primary outcome was AKI, defined as AKI stage-1 or higher based on the Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines. Synthetic Minority Oversampling Technique (SMOTE) was used to subsample minority groups to eliminate classification bias. 510 (14.74%) patients developed postoperative AKI. Serum fibrinogen was independently associated with AKI (OR = 1.211, 95% CI 1.080 to 1.358, p = 0.001) after adjustment of covariates. The receiver operator characteristic (ROC) curve for the outcome of AKI, after the addition of serum fibrinogen, had a c-statistic increasing from 0.72 to 0.73 (p < 0.001). This translated to a substantially improved AKI risk classification with a net reclassification index of 0.178 (p < 0.001). After SMOTE subsampling, serum fibrinogen was still independently associated with AKI grade 1 or higher (OR = 1.212, 95% CI 1.1089 to 1.347, p = 0.003). Preoperative serum fibrinogen levels were associated with the risk of postoperative AKI after cardiac valve replacement surgery.

Severe mental disorders following anti-retroviral treatment in a patient on peritoneal dialysis: A case report and literature review.

BACKGROUND: Antiviral drugs are widely used in populations with viral infection caused by immunologic inadequacy. Because these drugs are mainly metabolized by the kidneys, patients with renal failure undergoing renal replacement therapy are prone to drug adverse effects and poisoning. Severe neurotoxicity caused by antiviral drugs is a rare but life-threatening complication. CASE SUMMARY: This study reported one male patient on peritoneal dialysis who suffered from severe mental disorders after receiving an overdose of acyclovir and valacyclovir for the treatment of herpes zoster. The literature review suggested that hemodialysis is better than peritoneal dialysis to clear acyclovir from the circulation. The patient died after his consciousness deteriorated despite peritoneal dialysis and continuous blood purification. CONCLUSION: This case emphasizes cautiousness when using anti-retroviral drugs in patients with uremia. Hemodialysis is optimal method to remove the drugs.

A positively charged tight UF membrane and its properties for removing trace metal cations via electrostatic repulsion mechanism.

The development of highly efficient membranes technology using low-pressure driven filtration process, is one of the principal challenges in the wastewater treatment field, especially those aimed at the removal of trace heavy metals. In this work, a novel positively charged tight ultrafiltration (PCTUF) membrane was developed to remove heavy metal cations (Mn2+, Co2+, Ni2+, Zn2+ and Cd2+) from contaminated waters via electrostatic repulsion mechanism. The PCTUF membrane was fabricated from a new polymer with poly (vinyl chloride co dimethylaminoethyl methacrylate), P (VC-co-DMA) via a nonsolvent induce phase separation (NIPS) process and following facile surface quaternization. The quaternization conditions, the pore structures and chemical properties of the membranes were investigated in detail. The optimally quaternized membrane possessed a positively charged surface and 3.27 nm charged channel with the water permeability of 84 L m-2 h-1 bar-1. The rejections of heavy metal cations surpassed 95% for feed solutions containing 10 ppm heavy metal. Moreover, the influences of feed concentrations and the operating condition with pressure and pH on the membrane performances were also investigated. The results revealed that the prepared PCTUF membrane with its high perm-selectivity performance provides a worthy reference for highly efficient removal of heavy metal cations.

Correction to: Basiliximab versus rabbit antithymocyte globulin as induction therapy for living-related renal transplantation: a single-center experience.

In the original publication, incorrect grant number was included in the Acknowledgements text as 'This study (article) was supported by Natural Science Foundation Y16H050011 of Zhejiang Province, China'. The correct acknowledgement section is given here.

Intradialytic blood pressure pattern recognition based on density peak clustering.

End-stage renal disease (ESRD) is the final stage of chronic kidney disease (CKD) and requires hemodialysis (HD) for survival. Intradialytic blood pressure (IBP) measurements are necessary to ensure patient safety during HD treatments and have critical clinical and prognostic significance. Studies on IBP measurements, especially IBP patterns, are limited. All related studies have been based on a priori knowledge and artificially classified IBP patterns. Therefore, the results were influenced by subjective concepts. In this study, we proposed a new approach to identify IBP patterns to classify ESRD patients. We used the dynamic time warping (DTW) algorithm to measure the similarity between two series of IBP data. Five blood pressure (BP) patterns were identified by applying the density peak clustering algorithm (DPCA) to the IBP data. To illustrate the association between BP patterns and prognosis, we constructed three random survival forest (RSF) models with different covariates. Model accuracy was improved 3.7-6.3% by the inclusion of BP patterns. The results suggest that BP patterns have critical clinical and prognostic significance regarding the risk of cerebrovascular events. We can also apply this clustering approach to other time series data from electronic health records (EHRs). This work is generalizable to analyses of dense EHR data.

Kidney disease models: tools to identify mechanisms and potential therapeutic targets.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are worldwide public health problems affecting millions of people and have rapidly increased in prevalence in recent years. Due to the multiple causes of renal failure, many animal models have been developed to advance our understanding of human nephropathy. Among these experimental models, rodents have been extensively used to enable mechanistic understanding of kidney disease induction and progression, as well as to identify potential targets for therapy. In this review, we discuss AKI models induced by surgical operation and drugs or toxins, as well as a variety of CKD models (mainly genetically modified mouse models). Results from recent and ongoing clinical trials and conceptual advances derived from animal models are also explored.

Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury.

Interstitial fibrosis is an important contributor to graft loss in chronic renal allograft injury. Inflammatory macrophages are associated with fibrosis in renal allografts, but how these cells contribute to this damaging response is not clearly understood. Here, we investigated the role of macrophage-to-myofibroblast transition in interstitial fibrosis in human and experimental chronic renal allograft injury. In biopsy specimens from patients with active chronic allograft rejection, we identified cells undergoing macrophage-to-myofibroblast transition by the coexpression of macrophage (CD68) and myofibroblast (α-smooth muscle actin [α-SMA]) markers. CD68+/α-SMA+ cells accounted for approximately 50% of the myofibroblast population, and the number of these cells correlated with allograft function and the severity of interstitial fibrosis. Similarly, in C57BL/6J mice with a BALB/c renal allograft, cells coexpressing macrophage markers (CD68 or F4/80) and α-SMA composed a significant population in the interstitium of allografts undergoing chronic rejection. Fate-mapping in Lyz2-Cre/Rosa26-Tomato mice showed that approximately half of α-SMA+ myofibroblasts in renal allografts originated from recipient bone marrow-derived macrophages. Knockout of Smad3 protected against interstitial fibrosis in renal allografts and substantially reduced the number of macrophage-to-myofibroblast transition cells. Furthermore, the majority of macrophage-to-myofibroblast transition cells in human and experimental renal allograft rejection coexpressed the M2-type macrophage marker CD206, and this expression was considerably reduced in Smad3-knockout recipients. In conclusion, our studies indicate that macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. Moreover, the transition of bone marrow-derived M2-type macrophages to myofibroblasts in the renal allograft is regulated via a Smad3-dependent mechanism.

Mycophenolate Mofetil Combined With Prednisone Versus Full-Dose Prednisone in IgA Nephropathy With Active Proliferative Lesions: A Randomized Controlled Trial.

BACKGROUND: Observational studies suggest that patients with immunoglobulin A nephropathy (IgAN) with active proliferative lesions show a good response to immunosuppressive treatment. STUDY DESIGN: Multicenter, prospective, randomized, controlled trial. SETTING & PARTICIPANTS: 176 patients with IgAN with active proliferative lesions (cellular and fibrocellular crescents, endocapillary hypercellularity, or necrosis), proteinuria with protein excretion ≥ 1.0g/24h, and estimated glomerular filtration rate > 30mL/min/1.73m2. INTERVENTION: Mycophenolate mofetil (MMF) group: MMF, 1.5g/d, for 6 months and prednisone, 0.4 to 0.6mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months; prednisone group: prednisone, 0.8 to 1.0mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months. All patients were followed up for another 6 months. OUTCOMES: The primary end point was complete remission rate at 6 and 12 months. RESULTS: At baseline, median estimated glomerular filtration rates were 90.2 and 94.3mL/min/1.73m2 and mean proteinuria was protein excretion of 2.37 and 2.47g/24h in the MMF and prednisone groups, respectively. At 6 months, complete remission rates were 37% (32 of 86 patients) and 38% (33 of 88 patients); the between-group difference was not statistically significant (P=0.9). At 12 months, complete remission rates were 48% (35 of 73 patients) and 53% (38 of 72 patients) in the MMF and prednisone groups, respectively; the between-group difference was not statistically significant (P=0.6). Incidences of Cushing syndrome and newly diagnosed diabetes mellitus were lower in the MMF group than in the prednisone group. LIMITATIONS: Not all participants were treated with renin-angiotensin system blockers, relatively short follow-up. CONCLUSIONS: MMF plus prednisone versus full-dose prednisone did not differ in reducing proteinuria, but patients treated with the former had fewer adverse events in patients with IgAN with active proliferative lesions.

Biomarkers for Early Diagnosis of Acute Kidney Injury: Current Progress and Clinical Prospects.

Acute kidney injury (AKI) is one of the most common complications in critically ill patients, resulting in high morbidity and mortality. AKI usually occurs after major surgery, severe infection or drug-induced nephrotoxicity and is associated with prolonged hospital stays, increased costs and adverse clinical outcomes. The diagnosis of AKI is currently based on decreased glomerular filtration rate (GFR) and urine output, and increased serum creatinine. Novel biomarkers are required for early identification of patients with AKI to allow timely therapy and improve patient outcomes. With the advent of proteomics and genomics techniques, a vast array of biomarkers are now available in clinical practice.

Effect of uric acid-lowering therapy on blood pressure: systematic review and meta-analysis.

BACKGROUND: The purpose of this meta-analysis was to determine if uric acid-lowering therapy is associated with a decrease in blood pressure (BP) and serum creatinine levels. MATERIALS AND METHODS: Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 29 June 2016, with keywords: uric-acid-lowering therapy, allopurinol, febuxostat, uricosuric, and BP. Only randomized controlled trials were included. The primary outcomes were reduction in systolic BP (SBP) and diastolic BP (DBP), and secondary was reduction in serum creatinine level. RESULTS: Patients treated with allopurinol had greater reduction in SBP (standardized difference in means [SDM] = 0.321, 95% confidence interval [CI]: 0.145-0.497, p < 0.001), DBP (SDM = 0.260, 95% CI: 0.102 to 0.417, p = 0.001), and creatinine level (SDM = 0.312, 95% CI: 0.008 to 0.615, p = 0.044) than control patients. Subgroup analysis showed that allopurinol significantly decreased SBP whether or not antihypertensive drugs were being administered; a decrease in DBP was only seen in patients receiving antihypertensive drugs. Low-dose allopurinol (≤300 mg/day) was more effective at reducing SBP than high-dose (>300 mg/day) in patients receiving antihypertensive drugs. CONCLUSIONS: These results support that allopurinol decreases BP and creatinine levels in patients with hyperuricemia. KEY MESSAGES Allopurinol decreases SBP and DPB, and creatinine levels in patients with hyperuricemia. Allopurinol resulted in a significant decrease in SBP in patients with or without treatment of antihypertensive drugs. A dose of allopurinol of ≤300 mg per day might be more effective than a higher dose.

Downregulation of DOCK1 sensitizes bladder cancer cells to cisplatin through preventing epithelial-mesenchymal transition.

During the past several decades, resistance to single or multiple anticancer agents has posed a great challenge in cancer therapy. Dedicator of cytokinesis 1 (DOCK1), the first identified member in DOCK family, plays diverse roles in cellular processes, including tumorigenesis. In this study, we explored the biological role of DOCK1 in the chemotherapeutic resistance in bladder cancer and its underlying mechanism. Our results showed that the bladder cancer cell lines UM-UC-3 and J82 with higher DOCK1 are more resistant to cisplatin, whereas B87 cells with the lowest expression of DOCK1 exhibited the highest sensitivity to cisplatin. Down-regulation of DOCK1 with small interfering RNA (siRNA) increased the cisplatin sensitivity in bladder cancer cells. Moreover, treatment with cisplatin induced epithelial-mesenchymal transition (EMT), while transfection with Twist siRNA restored the chemosensitivity to cisplatin. In addition, we found that downregulation of DOCK1 reversed EMT program in bladder cancer cells. However, cotransfection with DOCK1 siRNA could not further enhance the cisplatin sensitivity and cellular phenotypic changes in tumor cells. Taken together, these results demonstrate that downregulation of DOCK1 could increase the chemosensitivity in bladder cancer cells via preventing cisplatin-induced EMT, suggesting that DOCK1 may serve as a potential therapeutic target in bladder cancer.

Basiliximab versus rabbit antithymocyte globulin as induction therapy for living-related renal transplantation: a single-center experience.

PURPOSE: To compare the long-term effects of the interleukin-2 receptor antagonist basiliximab versus rabbit antithymocyte globulin as an induction therapy for living-related renal transplantation. METHODS: This is a prospective, open-label, nonrandomized, controlled study including 213 cases of renal transplant. Immunosuppressive therapy containing calcineurin inhibitors, mycophenolate mofetil and steroids was applied in all cases. The interleukin-2 receptor antagonist group (IL2Ra group) included 108 cases with 20 mg basiliximab induction on Day 0 and Day 4. The other 105 cases comprised the rabbit antithymocyte globulin group (rATG group) with 1.0 mg/kg/day ATG induction from Day 0 to Day 4. The primary endpoint was biopsy-proven acute rejection. Other endpoints included delayed graft function (DGF), graft loss and death. RESULTS: All patients were followed up for 3 years. Acute rejection rates in the IL2Ra group and the ATG group were 5.6 and 3.8 % (P = 0.781), and the differences in the DGF rates, graft loss and death were insignificant between groups. All-cause infection rates in the IL2Ra and rATG groups were 26.9 and 43.8 % (P = 0.010). Urinary tract infections were more common in the rATG group than in the IL2Ra group (15.2 vs 6.5 %, P = 0.040). Specific viral infection rates were significantly different (18.1 % in rATG group vs 8.3 % in IL2Ra group, P = 0.035). CONCLUSIONS: IL2Ra and rATG had no significant differences as induction therapies during the perioperative period of living-related renal transplantation, according to acute rejection rates, DGF rates, graft loss, 1- and 3-year patient/graft survival rates. However, the incidence of infection, especially of urinary tract infection and specific viral infection, was higher in rATG-induced patients.