Clinical characteristics and prognosis of pregnancy-related acute kidney injury: a case series study.

OBJECTIVE: Acute kidney injury (AKI) seriously affects the health of both pregnant women and fetuses. This study aimed to investigate the clinical characteristics and prognosis of pregnancy-related AKI (PR-AKI). METHODS: This case series study enrolled pregnant women with PR-AKI admitted to the surgical intensive care unit of Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine between January 2010 and December 2020. RESULTS: Thirty-one PR-AKI patients were enrolled with a mean age of 29.16 ± 4.97 years. Seventeen pregnant women (54.84%) had complete recovery of renal function, 5 (16.13%) had partial recovery of renal function, 2 (6.45%) patients had no renal function improvement, and 7 (22.58%) died. Among the 31 patients with 35 fetuses, 25 (80.6%) pregnant women had poor fetal outcomes, including 5 cases of stillbirths, 5 neonatal asphyxia, 18 premature births, 10 low birth weight, and 8 deficient birth weight infants. Compared to cases with good fetal outcomes, cases with poor fetal outcomes had significantly shorter gestational weeks (39.26 ± 1.53 vs. 31.62 ± 5.50, P = 0.002), lower platelet count (217.13 ± 122.87 vs. 90.24 ± 84.88, P = 0.005), lower hemoglobin (94.19 ± 13.21 vs. 74.48 ± 20.78, P = 0.036), higher blood urea nitrogen (11.87 ± 4.28 vs. 19.47 ± 10.98, P = 0.013), and higher uric acid (262.41 ± 167.00 vs. 586.87 ± 144.52, P < 0.001). CONCLUSIONS: The maternal renal function of women with PR-AKI might improve after treatment, but occurrence rates of adverse fetal outcomes were still high.

ASH2L Controls Ureteric Bud Morphogenesis through the Regulation of RET/GFRA1 Signaling Activity in a Mouse Model.

SIGNIFICANCE STATEMENT: Causes of congenital anomalies of the kidney and urinary tract (CAKUT) remain unclear. The authors investigated whether and how inactivation of Ash2l -which encodes a subunit of the COMPASS methyltransferase responsible for genome-wide histone H3 lysine K4 (H3K4) methylation-might contribute to CAKUT. In a mouse model, inactivation of Ash2l in the ureteric bud (UB) lineage led to CAKUT-like phenotypes. Removal of ASH2L led to deficient H3K4 trimethylation, which slowed cell proliferation at the UB tip, delaying budding and impairing branching morphogenesis. The absence of ASH2L also downregulated the expression of Ret , Gfra1 , and Wnt11 genes involved in RET/GFRA1 signaling. These findings identify ASH2L-mediated H3K4 methylation as an upstream epigenetic regulator of signaling crucial for UB morphogenesis and indicate that deficiency or dysregulation of these processes may lead to CAKUT. BACKGROUND: Ureteric bud (UB) induction and branching morphogenesis are fundamental to the establishment of the renal architecture and are key determinants of nephron number. Defective UB morphogenesis could give rise to a spectrum of malformations associated with congenital anomalies of the kidney and urinary tract (CAKUT). Signaling involving glial cell line-derived neurotrophic factor and its receptor rearranged during transfection (RET) and coreceptor GFRA1 seems to be particularly important in UB development. Recent epigenome profiling studies have uncovered dynamic changes of histone H3 lysine K4 (H3K4) methylation during metanephros development, and dysregulated H3K4 methylation has been associated with a syndromic human CAKUT. METHODS: To investigate whether and how inactivation of Ash2l , which encodes a subunit of the COMPASS methyltransferase responsible for genome-wide H3K4 methylation, might contribute to CAKUT, we inactivated Ash2l specifically from the UB lineage in C57BL/6 mice and examined the effects on genome-wide H3K4 methylation and metanephros development. Genes and epigenome changes potentially involved in these effects were screened using RNA-seq combined with Cleavage Under Targets and Tagmentation sequencing. RESULTS: UB-specific inactivation of Ash2l caused CAKUT-like phenotypes mainly involving renal dysplasia at birth, which were associated with deficient H3K4 trimethylation. Ash2l inactivation slowed proliferation of cells at the UB tip, delaying budding and impairing UB branching morphogenesis. These effects were associated with downregulation of Ret , Gfra1 , and Wnt11 , which participate in RET/GFRA1 signaling. CONCLUSIONS: These experiments identify ASH2L-dependent H3K4 methylation in the UB lineage as an upstream epigenetic regulator of RET/GFRA1 signaling in UB morphogenesis, which, if deficient, may lead to CAKUT.

A novel CLCN5 frame shift mutation responsible for Dent disease 1: Case report.

Background: Dent disease is a group of inherited X-linked recessive renal tubular disorders. This group of disorders is characterized by low molecular weight proteinuria (LMWP), nephrocalcinosis, hypercalciuria and renal failure. Case presentation: Here we report one 11-year-old Chinese boy (proband) and one 13-year-old Chinese boy who was proband's cousin, both presented with massive proteinuria. Further laboratory examinations revealed a lack of nephrocalcinosis, nor any other signs of tubular dysfunction, but only LMWP and hypercalciuria. There was no abnormality in growth, renal function or mineral density of the bones. A novel deletion (c.1448delG) in the CLCN5 gene was identified, resulting in a frame shift mutation (p.Gly483fs). The proband's and his cousin's mothers were found to be the carrier of this mutation. Conclusions: In this study, we have found a novel frameshift mutation (c. 1448delG) at exon 11 of the CLCN5 gene which leads to Dent disease 1, expanding the spectrum of CLCN5 mutations.

Identification and functional characterization of the first deep intronic GLA mutation (IVS4+1326C>T) causing renal variant of Fabry disease.

BACKGROUND: Fabry disease (FD, OMIM #301500) is an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A (α-GalA), encoded by the GLA gene. Among more than 1100 reported GLA mutations, few were deep intronic mutations which have been linked to classic and cardiac variants of FD. METHODS AND RESULTS: We report a novel hemizygous deep intronic GLA mutation (IVS4+1326C>T) in a 33-year-old Chinese man with a mild α-GalA deficiency phenotype involving isolated proteinuria and predominant globotriaosylceramide deposits in podocytes. IVS4+1326C>T, which appears to be the first deep intronic GLA mutation associated with renal variant of FD, was identified by Sanger sequencing the entire GLA genomic DNA sequence of the patient's peripheral mononuclear blood lymphocytes (PBMCs). Further sequencing of cDNA from PBMCs of the patient revealed a minor full-length GLA transcript accounting for about 25% of total GLA transcript, along with two major aberrantly spliced GLA transcripts encoding mutant forms of α-GalA with little enzyme activity characterized by in vitro α-GalA overexpression system in the HEK293T cells. Thus, the combined clinical phenotype, genetic analysis and functional studies verified the pathogenicity of IVS4+1326C>T. CONCLUSIONS: The identification of IVS4+1326C>T establishes a link between deep intronic GLA mutation and the renal variant of FD, which extends the mutation spectrum in GLA gene and justifies further study of how IVS4+1326C>T and potentially other deep intronic GLA mutations contribute to Fabry podocytopathy through aberrant splicing. Future studies should also assess the true incidence of IVS4+1326C>T in patients with different variants of FD, which may improve early genetic diagnosis to allow timely treatment that can prevent disease progression and improve survival.

Tissue Proteome of 2-Hydroxyacyl-CoA Lyase Deficient Mice Reveals Peroxisome Proliferation and Activation of ω-Oxidation.

Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of ß-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is 2-hydroxyacyl CoA lyase (HACL1), which is responsible for the cleavage of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA. Hacl1 deficient mice do not present with a severe phenotype, unlike mice deficient in other α-oxidation enzymes such as phytanoyl-CoA hydroxylase deficiency (Refsum disease) in which neuropathy and ataxia are present. Tissues from wild-type and Hacl1-/- mice fed a high phytol diet were obtained for proteomic and lipidomic analysis. There was no phenotype observed in these mice. Liver, brain, and kidney tissues underwent trypsin digestion for untargeted proteomic liquid chromatography-mass spectrometry analysis, while liver tissues also underwent fatty acid hydrolysis, extraction, and derivatisation for fatty acid gas chromatography-mass spectrometry analysis. The liver fatty acid profile demonstrated an accumulation of phytanic and 2-hydroxyphytanic acid in the Hacl1-/- liver and significant decrease in heptadecanoic acid. The liver proteome showed a significant decrease in the abundance of Hacl1 and a significant increase in the abundance of proteins involved in PPAR signalling, peroxisome proliferation, and omega oxidation, particularly Cyp4a10 and Cyp4a14. In addition, the pathway associated with arachidonic acid metabolism was affected; Cyp2c55 was upregulated and Cyp4f14 and Cyp2b9 were downregulated. The kidney proteome revealed fewer significantly upregulated peroxisomal proteins and the brain proteome was not significantly different in Hacl1-/- mice. This study demonstrates the powerful insight brought by proteomic and metabolomic profiling of Hacl1-/- mice in better understanding disease mechanism in fatty acid α-oxidation disorders.

Absolute negative mobility of active polymer chains in steady laminar flows.

We investigate the transport of active polymer chains in steady laminar flows in the presence of thermal noise and an external constant force. In the model, the polymer chain is worm-like and is propelled by active forces along its tangent vectors. Compared with inertial Brownian particles, active polymer chains in steady laminar flows exhibit richer movement patterns due to their specific spatial structures. The simulation results show that the velocity-force relation is strongly dependent on the system parameters such as the chain length, bending rigidity, active force and so on. The polymer chain may move in some preferential movement directions and exhibits absolute negative mobility within appropriate parameter regimes, i.e., the polymer chain can move in a direction opposite to the external constant force. In particular, we can observe giant negative mobility in a broad range of parameter regimes.

Diagnostic yield of additional exome sequencing after the detection of long continuous stretches of homozygosity (LCSH) in SNP arrays.

Long continuous stretches of homozygosity (LCSH) are associated with risk of recessive disorders. Though LCSH can be detected by SNP microarrays, additional testing is necessary to clarify the clinical significance. This study is to assess the yield of additional exome sequencing (ES) after LCSH detection and inform the likelihood of eventual diagnosis. In 2226 patients referred to SNP microarrays, 35 patients met the criteria of indicative LCSH. These patients were recruited and went through additional ES. The diagnostic yield was analyzed, and the LCSH pattern was compared between eventually diagnosed cases and those undiagnosed. The results showed additional ES attained a diagnostic yield of 31.4% (11/35), but only one-third of the yield (11.4%, 4/35) was relevant to LCSH. In contrast, two-thirds of the diagnostic variants (20%, 7/35) were de novo or dominantly inherited, irrelevant to the original LCSH finding. No particular LCSH pattern, including the chromosomal coverage or LCSH size, was found to associate with the diagnostic outcome. We concluded that additional ES after LCSH detection could reveal diagnostic variants, but it is strongly recommended to consider all possible inheritance mode, as the diagnostic variants may be irrelevant to the original LCSH finding.

Separation and alignment of chiral active particles in a rotational magnetic field.

We propose a method for the chiral separation and alignment of active paramagnetic particles in a two-dimensional square box with periodic boundary conditions. In a rotational magnetic field, the dynamic behavior of magnetized particles is strongly determined by the competition between the magnetic interaction and differing chirality. By suitably tailoring the parameters, active particles with different chirality can be aggregated into different clusters and separated. However, when either the magnetic interaction or chirality difference is dominant, the particles are prone to mixing. In addition, the external rotational magnetic field plays a decisive role in aligning particles. The numerical results show that there exists an optimal strength and rotation frequency of the magnetic field, as well as a rotational diffusion coefficient, self-propulsion velocity, and packing fraction, at which the separation coefficient takes its maximal value. The proposed method can be exploited to separate naturally occurring chiral active particles.

Extracellular vesicle-derived circ_SLC19A1 promotes prostate cancer cell growth and invasion through the miR-497/septin 2 pathway.

The occurrence and development of prostate cancer (PCa) is complex, and the related mechanism is not fully understood. Current studies have found that extracellular vesicles (EVs) and circular RNAs (circRNAs) have important functions in various tumours and other diseases. In this study, the detection of circRNAs in PCa showed that circ_SLC19A1 was increased in PCa cells and their secreted EVs. EVs with high expression of circ_SLC19A1 could be taken up by PCa cells, which promoted cell proliferation and invasion. The sequence of circ_SLC19A1 contained multiple binding sites for miR-497, and circ_SLC19A1 could bind directly to miR-497 in cells. The expression of miR-497 was downregulated in PCa cells, while the expression of its target gene septin 2 (SEPT2) was upregulated significantly. Transfection of circ_SLC19A1 small interfering RNA (siRNA) or miR-497 mimics could significantly inhibit the expression of SEPT2 and the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2). After co-transfection of circ_SLC19A1 siRNA and miR-497 inhibitors or SEPT2 overexpression vector, the expression of SEPT2 and ERK1/2 phosphorylation levels showed no significant changes. Similar results were obtained with co-transfection of miR-497 mimics and the SEPT2 overexpression vector. Therefore, cancer cells can regulate the expression of SEPT2 through miR-497 by secreting EVs with high expression of circ_SLC19A1, thus affecting the activation of the downstream ERK1/2 pathway and ultimately regulating PCa cell growth and invasion. Therefore, EV-derived circ_SLC19A1 plays an important regulatory role in PCa and may be an important target for PCa prevention and treatment.

Circ_KATNAL1 regulates prostate cancer cell growth and invasiveness through the miR-145-3p/WISP1 pathway.

Prostate cancer (PCa) is the second leading cause of death in men, and current studies have shown that circular RNAs (circRNAs) play important roles in its occurrence and development. Detection of circRNAs in PCa cells showed that circ_KATNAL1 is down-regulated, mainly located in the cytoplasm, and contains multiple binding sites of miR-145-3p, which is an anticancer miRNA. RNA immunoprecipitation with anti-AGO2 antibody, RNA pull-down assays with biotin-labeled circ_KATNAL1 probe or an miR-145-3p mimic, and dual luciferase reporter gene assays confirmed that circ_KATNAL1 binds directly to miR-145-3p in cells, and that WISP1, which is highly expressed in many types of tumors, is an important target gene of miR-145-3p. Circ_KATNAL1 and miR-145-3p promote each other's expression, and down-regulate the expression of the target gene WISP1. Both circ_KATNAL1 and miR-145-3p inhibit cell proliferation, invasiveness, and migration, down-regulate the expression of MMP-2 and MMP-9, promote cell apoptosis and the activation of caspase-3, caspase-8, caspase-9, and PARP, whereas WISP1 has the opposite effect, and the above-mentioned functions of circ_KATNAL1 were achieved through the miR-145-3p/WISP1 pathway. Therefore, circ_KATNAL1 plays an anticancer role in PCa cells through the miR-145-3p/WISP1 pathway, which could be an important target for the diagnosis and treatment of PCa.

SPOP suppresses pancreatic cancer progression by promoting the degradation of NANOG.

Speckle-type POZ domain protein (SPOP), an adaptor in the E3 ubiquitin ligase complex, recognizes substrates and promotes protein degradation via the ubiquitin-proteasome system. It appears to help regulate progression of several cancers, and we show here that it acts as a tumor suppressor in pancreatic cancer. Our analysis of patient tissues showed decreased SPOP expression, which was associated with poor prognosis. SPOP knockdown in SW1990 (in vitro/vivo) and PANC-1 (in vitro) cells led to significantly greater proliferation, migration, and invasion. Co-immunoprecipitation experiments in SW1990 cells showed that SPOP interacted with the stem-cell marker NANOG, and this interaction has recently been shown to play a critical role in regulating progression of prostate cancer. We showed that, in one patient with pancreatic cancer, the expression of a truncated form of SPOP (p.Q360*) lacking the nuclear localization signal led to nuclear accumulation of NANOG, which promoted growth and metastasis of pancreatic cancer cells. Our results suggest that SPOP suppresses progression of pancreatic cancer by promoting the ubiquitination and subsequent degradation of NANOG. These results identify the SPOP-NANOG interaction as a potential therapeutic target against pancreatic cancer.

MiR-424 is over-expressed and attenuates ischemia-reperfusion kidney injury via p53 and death receptor 6 pathway.

BACKGROUND: Ischemic reperfusion injury of kidney is major cause for renal failure, however the involved pathogenesis remains unclear creating an void for its effective treatment. Here we studied involvement of microRNA-424 in renal injury. METHODS: For the study, p53 or HIF-1α mice were used, ischemic renal injury was induced using clamping of renal pedicles bilateraly. Proximal kidney tubular cells were used for in vitro studies. Hoechst 33342 analysis was done for apoptosis. Blood urea nitrogen (BUN) and serum creatinine was done for renal function, Hematoxylin-eosin tissue damage and Terminal transferase-dUTP nick-end labeling assay for apoptosis. RT-PCR was done for miRNA and ChIP assay to identify the binding of p53 to miR-424. TargetScan and miRanda data base were scanned to find targets of miR-424. Protein expression was done by western blot analysis. RESULTS: We discovered that, miR-424 was over-expressed in ischemic renal injury mice and in hypoxia exposed renal cells. In cells, miR-424 suppressed the expression levels of death receptor 6 (DR6) and halted the apoptosis mediated by hypoxia. Blocking of miR-424 halted the inhibition of DR6 and caused apoptosis and activation of caspase. In mice, miR-424 mimic inhibited expression of DR6 and attenuated ischemic renal injury. We established that, up-regulation of miR-424 in ischemic reperfusion injury was p53 dependent, also inhibition of p53 caused repression of miR-424 levels in hypoxia induced cells in vitro. The p53 knockout mice showed attenuation in levels of miR-424 confirming role of p53 behind up-regulation of miR-424 in vivo. CONCLUSION: The study confirmed p53/miR-424/DR6 as a protective cascade during ischemic-reperfusion injury.

Survival Motor Neuron (SMN) Protein Insufficiency Exacerbates Renal Ischemia/Reperfusion Injury.

The survival of motor neuron (SMN) protein is ubiquitously involved in spliceosome assembly and ribonucleoprotein biogenesis. SMN protein is expressed in kidney and can affect cell death processes. However, the role of SMN in acute kidney injury (AKI) is largely unknown. In the current study, we found that the expression of SMN in the kidney was significantly reduced in both clinical ischemic AKI and a mouse model of renal ischemia-reperfusion injury (IRI). We then used SMN heterozygous knockout (SMN+/-) mice and found that the declines in renal function, tubular injury, and tubular cell apoptosis after experimental IRI were significantly more severe in SMN+/- mice than those in their wild-type littermates. Concomitantly, the canonical transcription factor nuclear factor-κb (NFκb) signaling was enhanced in ischemic SMN+/- mice. In vitro, cobalt dichloride (CoCl2) treatment reduced SMN expression in proximal tubular epithelial cells. In addition, CoCl2-induced apoptosis and activation of NFκb signaling pathway were enhanced by transient transfection of a small-interfering RNA (siRNA) against SMN while attenuated by transient transfection of a full-length SMN plasmid. Taken together, this study for the first time supported the protective role of SMN in ischemic AKI.

De novo Cardiac Valve Calcification after Hemodialysis in End-Stage Renal Disease Patients Predicts Future Cardiovascular Events: A Longitudinal Cohort Study.

BACKGROUND: Cardiac valve calcification (CVC) in maintenance hemodialysis patients is associated with adverse cardiovascular outcomes. However, whether de novo CVC in incident hemodialysis patients predicts future cardiovascular events is unknown. METHODS: This study included 174 patients newly receiving hemodialysis without CVC as reflected by echocardiography between January 2005 and December 2014. De novo CVC was determined with echocardiography once every 6 months until December 2016. RESULTS: The median follow-up was 66 months (range, 19-141). De novo CVC developed in 80 out of 174 (45.98%) subjects: 58 developed aortic valve calcification (AVC) alone, 42 developed mitral valve calcification (MVC) alone, and 20 developed both AVC and MVC. The median time from baseline to de novo CVC was 46 months (range, 3-120) for AVC and 50 months (range, 13-127) for MVC. Patients who developed CVC had a higher major adverse cardiovascular events (MACE) rate than those who did not (AVC: 30/58 [51.72%] vs. 23/116 [19.83%]; MVC: 25/42 [59.52%] vs. 28/132 [21.21%]). Multivariate time-dependent Cox regression showed an association between MACE with both de novo AVC and MVC (AVC: hazard ratio [HR] 3.2, 95% confidence interval [CI] 1.55-6.63; MVC: HR 5.95, 95% CI 2.90-12.20). CONCLUSIONS: De novo CVC is an independent risk factor for MACE in hemodialysis patients, and regular CVC screening among hemodialysis patients without preexisting CVC may be helpful to identify patients at increased risk of adverse cardiovascular outcomes.

First identification of PODXL nonsense mutations in autosomal dominant focal segmental glomerulosclerosis.

Recently, a novel heterozygous missense mutation c.T1421G (p. L474R) in the PODXL gene encoding podocalyxin was identified in an autosomal dominant focal segmental glomerulosclerosis (AD-FSGS) pedigree. However, this PODXL mutation appeared not to impair podocalyxin function, and it is necessary to identify new PODXL mutations and determine their causative role for FSGS. In the present study, we report the identification of a heterozygous nonsense PODXL mutation (c.C976T; p. Arg326X) in a Chinese pedigree featured by proteinuria and renal insufficiency with AD inheritance by whole exome sequencing (WES). Total mRNA and PODXL protein abundance were decreased in available peripheral blood cell samples of two affected patients undergoing hemodialysis, compared with those in healthy controls and hemodialysis controls without PODXL mutation. We identified another novel PODXL heterozygous nonsense mutation (c.C1133G; p.Ser378X) in a British-Indian pedigree of AD-FSGS by WES. In vitro study showed that, human embryonic kidney 293T cells transfected with the pEGFP-PODXL-Arg326X or pEGFP-PODXL-Ser378X plasmid expressed significantly lower mRNA and PODXL protein compared with cells transfected with the wild-type plasmid. Blocking nonsense-mediated mRNA decay (NMD) significantly restored the amount of mutant mRNA and PODXL proteins, which indicated that the pathogenic effect of PODXL nonsense mutations is likely due to NMD, resulting in podocalyxin deficiency. Functional consequences caused by the PODXL nonsense mutations were inferred by siRNA knockdown in cultured podocytes and podocalyxin down-regulation by siRNA resulted in decreased RhoA and ezrin activities, cell migration and stress fiber formation. Our results provided new data implicating heterozygous PODXL nonsense mutations in the development of FSGS.

Impact of hemoglobin variability on cardiovascular mortality in maintenance hemodialysis patients.

PURPOSE: Although the association between anemia and cardiovascular mortality in hemodialysis patients is well established, whether hemoglobin variability (Hgb-Var) affects the prognosis remains unclear. We aimed to evaluate the association between Hgb-Var and cardiovascular mortality in Chinese hemodialysis patients. METHODS: This retrospective study included 252 patients starting hemodialysis in Xin Hua Hospital between January 2009 and December 2015. Patients were divided into three tertiles based on Hgb-Var, as reflected by SD Hgbmean, SD Hgbrange, and Hgbdeflection during a 12-month evaluation period after hemodialysis initiation. Left ventricular ejection fraction (EF) and left ventricular mass index (LVMI) were evaluated by echocardiography. Information on cardiovascular deaths occurred by December 2017 was collected. Multivariate Cox regression models were constructed to evaluate the association between Hgb-Var and cardiovascular mortality. RESULTS: A total of 75 deaths and 52 cardiovascular deaths occurred during the 47-month follow-up (range 29.5-70). Under multivariate regression, the subgroup with the highest Hgb-Var had a higher risk of cardiovascular mortality after adjusting for relevant factors (HR vs. lowest SD Hgbmean: 9.15, 95% CI 2.82, 29.693, P < 0.0001; HR vs. lowest SD Hgbrange: 3.81, 95% CI 1.40, 10.38, P = 0.005). Per 1 SD of Hgbmean and Hgbrange elevations were both related to a 10% increase in the cardiovascular mortality risk. Baseline EF% and LVMI did not differ across the Hgb-Var subgroups. EF% upon the last patient visit to the clinic was lower in the subgroup with the highest SD Hgbmean (P = 0.02). CONCLUSIONS: High Hgb-Var is an independent risk factor for cardiovascular mortality in hemodialysis patients and might influence the cardiac function.

Clinical and Histological Features of Phospholipase A2 Receptor-Associated and Thrombospondin Type-I Domain-containing 7A-Associated Idiopathic Membranous Nephropathy: A Single Center Retrospective Study from China.

BACKGROUND M-type phospholipase A2 receptor (PLA2R) was identified as the major target antigen in idiopathic membranous nephropathy (IMN). Another target antigen, namely thrombospondin type-1 domain-containing 7A (THSD7A), was recently detected in approximately 10% of non-PLA2R-associated IMN. In this single center retrospective study, clinical and histological features of PLA2R-associated and THSD7A-associated IMN patients were evaluated. MATERIAL AND METHODS A total of 192 IMN patients, who were receiving no glucocorticoids or immunosuppressant before renal biopsy, were enrolled in this study and followed for a median duration of 25.5 months. IMN with enhanced glomerular PLA2R and THSD7A staining by immunohistochemistry (IHC) were designated as PLA2R-associated IMN and THSD7A-associated IMN respectively. Serum anti-PLA2R and anti-THSD7A antibodies levels were assessed by enzyme linked immunosorbent assay and indirect immunofluorescence testing in PLA2R-associated and THSD7A-associated IMN. RESULTS Of 192 IMN patients, 164 patients (85.4%) had PLA2R-associated IMN and 3 patients (1.6%) had THSD7A-associated IMN. Compared with non-PLA2R-associated IMN patients, the 24-hour urinary protein levels were significantly higher (P=0.008), whereas, the proteinuria remission rates were significantly lower (P=0.03) in PLA2R-associated IMN patients. No pathological differences were found between PLA2R-associated IMN and non-PLA2R-associated IMN. Among 3 THSD7A-associated IMN patients, 1 patient had elevated serum anti-THSD7A antibody levels, which was below detectable levels after achieving partial proteinuria remission with combined glucocorticoid and cyclosporine treatment. CONCLUSIONS Compared with non-PLA2R-associated IMN patients in our cohort, PLA2R-associated IMN patients presented with more severe proteinuria and lower remission rates after treatment, with no distinct histological differences. Glomerular expression of PLA2R could be a useful marker to indicate the severity, treatment response, and prognosis of IMN.

THSD7A-associated membranous nephropathy in a patient with neurofibromatosis type 1.

Target antigens in idiopathic membranous nephropathy (MN) include the phospholipase A2 receptor (PLA2R), and in some cases, the thrombospondin type 1 domain-containing 7A (THSD7A). A notable phenomenon is the high rate of cancer (reported to be as high as 20%) in patients with THSD7A-associated MN. Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by NF1 gene mutation, and clinically characterized by multiple cutaneous neurofibromas and café-au-lait spots. In this article, we report a patient with NF1 who developed THSD7A-associated MN when the NF1 skin lesions deteriorated. The patient, a 62-year-old male, was referred to us for nephrotic syndrome for 6 months. Physical examination revealed multiple cutaneous nodules throughout the entire body, and the patient noted recent increase in the numbers of these skin lesions. Cutaneous nodules excisional biopsy suggested NF1 and Sanger sequencing using genomic DNA extracted from peripheral blood revealed a previously reported heterozygous frameshift NF1 mutation (c.1541_1542delAG, p. Gln514fs). Renal biopsy revealed MN and immunohistochemistry (IHC) showed enhanced staining of THSD7A as well as PLA2R along the glomerular basement membrane whereas the serum level of THSD7A and PLA2R were both within normal range. The neurofibroma tissues were positive for THSD7A but not for PLA2R on IHC. The patient did not respond to 6-month treatment with glucocorticosteroid and cyclophosphamide. In this exceptional case, strong positive staining of THSD7A in both skin and renal biopsy samples, together with the temporal association between nephrotic syndrome and skin lesions and lack of treatment response, suggested the possibility that MN could be the result of immune response to THSD7A in NF1. This report may improve understanding of the mechanistic link between MN and cancer.

Micro RNA-155 inhibitor as a potential therapeutic strategy for the treatment of acute kidney injury (AKI): a nanomedicine perspective.

In this study, we have prepared miR-155 inhibitor-loaded liposome vesicles for the effective treatment of acute kidney injury. The efficacy of liposomal miR-155 inhibitor in the expression of miR-155, mortality in animals, the expression of TNF-α-IL6, and the expression of SOCS1-STAT1 were evaluated. The loading of miR-155 inhibitor into liposomes conferred the much needed colloidal stability and efficient delivery to the renal tissues. The study clearly shows that miR-I-LV significantly decreases the expression of miR-155 in kidneys compared to LPS. Administration of miR-I-LV remarkably reduced the pathological concerns of the kidneys with a marked decrease in inflammatory cell infiltration. Scrambled miR-155 did not have any effect on the expression of these markers; however miR-I-LV showed a remarkable ability to decrease the expression of TNF-α and IL-6 in kidney tissues indicating an ability to treat acute kidney infections. Overall, administration of miR-155 inhibitor effectively alleviated LPS-induced kidney injury by significantly suppressing TNF-α and IL-6 in kidney tissue and by remarkably increasing the expression of mRNA of SOCS1 and STAT1. The present results suggest that miR-155 inhibitor could be used in an effective targeting strategy for the treatment of acute kidney injury (AKI).

Inhibition of Reticulon-1A-Mediated Endoplasmic Reticulum Stress in Early AKI Attenuates Renal Fibrosis Development.

Several animal studies have shown an important role for endoplasmic reticulum (ER) stress in AKI, whereas human studies are lacking. We recently reported that Reticulon-1A (RTN1A) is a key mediator of ER stress and kidney cell injury. Here, we investigated whether modulation of RTN1A expression during AKI contributes to the progression to CKD. In a retrospective study of 51 patients with AKI, increased expression of RTN1A and other ER stress markers were associated with the severity of kidney injury and with progression to CKD. In an inducible tubular cell-specific RTN1A-knockdown mouse model subjected to folic acid nephropathy (FAN) or aristolochic acid nephropathy, reduction of RTN1A expression during the initial stage of AKI attenuated ER stress and kidney cell injury in early stages and renal fibrosis development in later stages. Treatment of wild-type mice with tauroursodeoxycholic acid, an inhibitor of ER stress, after the induction of kidney injury with FA facilitated renoprotection similar to that observed in RTN1A-knockdown mice. Conversely, in transgenic mice with inducible tubular cell-specific overexpression of RTN1A subjected to FAN, induction of RTN1A overexpression aggravated ER stress and renal injury at the early stage and renal fibrosis at the late stage of FAN. Together, our human and mouse data suggest that the RTN1A-mediated ER stress response may be an important determinant in the severity of AKI and maladaptive repair that may promote progression to CKD.