Long-term renal survival of γ3-heavy-chain deposition disease complicated by heart failure: A case report.

Key Clinical Message: Heavy-chain deposition disease (HCDD), a rare monoclonal immunoglobulin deposition disease, involves truncated heavy-chain deposition in kidneys. Limited long-term data exist. We report a case of renal and cardiac failure with favorable outcomes post bortezomib-based therapy. Stable renal function observed over 4 years suggests efficacy in HCDD with multisystem involvement. Abstract: Heavy-chain deposition disease (HCDD) is an extremely rare form of monoclonal immunoglobulin deposition disease (MIDD) that involves the deposition of truncated immunoglobulin heavy chains in the kidneys. Only a few cases of HCDD with a favorable long-term renal prognosis have been reported, resulting in limited long-term follow-up data for this patient population. In this report, we present the case of a 52-year-old patient with nephrotic syndrome who experienced renal failure and cardiac failure. Renal biopsy confirmed the presence of γ3-HCDD and monoclonal Immunoglobulin G (IgG)κ in the serum. The patient exhibited low voltage on electrocardiogram (ECG) and unexplained left ventricular hypertrophy on cardiac ultrasound. The patient underwent eight cycles of bortezomib-based chemotherapy, which led to hematological remission. After 4 years of follow-up, the patient's renal function remained stable, with serum creatinine levels ranging from 0.7 to 0.9 mg/dL and proteinuria of 0.3-0.5 g/24 h. Our findings suggest that bortezomib-based chemotherapy is equally effective in HCDD patients with combined multisystem damage.

Evaluation of malnutrition and inflammation after total parathyroidectomy in patients on maintenance dialysis.

PURPOSE: To evaluate the effect of total parathyroidectomy (tPTx) on malnutrition and inflammation in patients on maintenance dialysis (MHD) having secondary hyperparathyroidism (SHPT). METHODS: Twenty-five patients on MHD having SHPT who were being treated with tPTx were selected, and changes in their general condition (dry body mass), parathyroid hormone (PTH) and calcium levels, nutrition state (hemoglobin, hematocrit, serum albumin, and total iron binding capacity), and inflammatory status [serum C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and the malnutrition-inflammation score (MIS)] were observed at 12, 24, and 36 months postoperatively. RESULTS: Compared with the preoperative period, the dry body mass increased at 12, 24, and 36 months postoperatively (P < 0.01), hemoglobin, hematocrit, and serum albumin increased significantly (P < 0.01), whereas calcium, phosphorus, and PTH levels decreased significantly (P < 0.01). Serum CRP, IL-6, and TNF-α levels were significantly decreased at 12, 24, and 36 months after surgery (P < 0.01). Furthermore, MIS was reduced as well but to a lesser extent (P < 0.01). CONCLUSION: tPTx effectively reduced MIS in maintenance dialysis patients, and the alleviated malnutrition and improved inflammatory status may contributed to improving the quality of life of patients on MHD with SHPT.

Astragalus-Saffron-Rhubarb Mixture Delays the Progress of Diabetic Nephropathy in db/db Mice.

OBJECTIVE: This study aimed to investigate the protective effect of astragalus-saffron-rhubarb mixture (Bao'shen recipe, BSR) on diabetic nephropathy (DN) in db/db mice and preliminarily explore the possible underlying mechanism. METHODS: A total of 125 8-week-old male db/db mice with DN were randomly divided into five groups: model group, irbesartan group and high-, medium- and low doses of BSR group, while 25 male db/m mice were used as a blank control. At 8, 12, 16, 20, and 24 weeks of feeding, the animals were sacrificed and blood as well as urine samples were collected for blood glucose, urea nitrogen, creatinine and urinary albumin excretion rate (UAER) measurement via blood glucose meter or corresponding detection kits, respectively. The renal tissues of each mouse underwent hematoxylin and eosin (H&E), Masson, periodic acid Schiff (PAS) staining. Renal homogenate was used to detect IL-6, TNF-α, TNF-1R and TNF-2R by enzyme-linked immunosorbent assay. Additionally, the data obtained was statistically analyzed via one-way analysis of variance. RESULTS: BSR could effectively reduce the body weight, blood glucose, UAER, blood urea nitrogen and creatinine levels, relieve the proliferation of mesangial tissue, and lower the levels of IL-6, TNF-α, TNF-1R, and TNF-2R in renal tissue of db/db mice with DN. Of note, the high-dose BSR treatment group has advantages over irbesartan treatment group in improving above-mentioned aspects. CONCLUSION: BSR could effectively delay the progress of DN, partly related to its anti-inflammation effect.

Obstructive sleep apnea hypopnea syndrome: Protocol for the development of a core outcome set.

BACKGROUND: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a common, chronic sleep disease. As the incidence of OSAHS increases, it has seriously threatened people's health. There have been an increasing number of clinical trials of OSAHS in recent years. However, the clinical trials of OSAHS have heterogeneous outcomes, surrogate outcomes, subjective outcomes, and composite outcomes, as well as the lack of endpoints or patient perspectives. The best method is to develop a core outcomes sets (COSs) for OSAHS's clinical trials. METHODS: The development of COSs of OSAHS will include 5 stages: RESULTS:: The results of our study will be published in a peer-reviewed journal. DISCUSSION: The development of the COSs of OSAHS will improve the design and operation of OSAHS clinical trials to conform to international standards and ensure the credibility of the outcomes. In addition, this study will involve different stakeholder groups to help ensure that the developed COSs will be suitable and well accepted. TRIAL REGISTRATION NUMBER: 1544.

Expression Profiling and Clinical Significance of Plasma MicroRNAs in Diabetic Nephropathy.

AIMS: MicroRNAs (miRNAs) stably and abundantly exist in body fluids and have been considered as novel and noninvasive biomarkers for several diseases. The present study is aimed at investigating the expression profiling and clinical significance of plasma miRNAs in the pathogenesis and progression of diabetic nephropathy (DN). METHODS: Plasma samples were obtained from 66 DN patients (36 had microalbuminuria and 30 had macroalbuminuria), 36 diabetic patients with normoalbuminuria, and 40 healthy controls. The plasma miRNA profiles were obtained by miRNA low-density array chip and validated by quantitative real-time polymerase chain reaction. The correlations between the differential expression of plasma miRNAs and clinicopathological parameters were explored. RESULTS: miR-150-5p, miR-155-5p, miR-30e, miR-320e, and miR-3196 were found to be differentially expressed in plasma samples among these three groups: diabetic patients with microalbuminuria, diabetic patients with normoalbuminuria, and healthy controls (P < 0.05). The expression levels of miR-150-5p and miR-155-5p in patients with macroalbuminuria were 2.3-fold (P = 0.001) and 1.5-fold (P = 0.033) higher than patients with microalbuminuria, respectively. However, the expression levels of miR-30e, miR-3196, miR-320, and let-7a-5p were not significantly different between these two groups (P > 0.05). Furthermore, plasma miR-150-5p (P = 0.016, r = -0.460) and miR-155-5p (P = 0.014, r = -0.467) were negatively correlated with the albuminuria excretion rate, while plasma miR-150-5p (P = 0.01, r = 0.318) and miR-155-5p (P = 0.030, r = 0.271) were positively correlated with the estimated glomerular filtration rate. CONCLUSION: miR-150-5p, miR-155-5p, miR-30e, miR-320e, and miR-3196 are potentially new diagnostic biomarkers for early DN. miR-150-5p and miR-155-5p may be involved in the pathogenesis and progression of DN. Further research is required to verify these findings and clarify the specific molecular mechanisms.

Toll-like Receptor 9 Can be Activated by Endogenous Mitochondrial DNA to Induce Podocyte Apoptosis.

Toll-like receptor 9 (TLR9) senses bacterial DNA characteristic of unmethylated CpG motifs to induce innate immune response. TLR9 is de novo expressed in podocytes of some patients with glomerular diseases, but its role in podocyte injury remains undetermined. Since TLR9 activates p38 MAPK and NFkB that are known to mediate podocyte apoptosis, we hypothesized that TLR9 induces podocyte apoptosis in glomerular diseases. We treated immortalized podocytes with puromycin aminonucleosides (PAN) and observed podocyte apoptosis, accompanied by TLR9 upregulation. Prevention of TLR9 upregulation by siRNA significantly attenuated NFκB p65 or p38 activity and apoptosis, demonstrating that TLR9 mediates podocyte apoptosis. We next showed that endogenous mitochondrial DNA (mtDNA), whose CpG motifs are also unmethylated, is the ligand for TLR9, because PAN induced mtDNA accumulation in endolysosomes where TLR9 is localized, overexpression of endolysosomal DNase 2 attenuated PAN-induced p38 or p65 activity and podocyte apoptosis, and DNase 2 silencing was sufficient to activate p38 or p65 and induce apoptosis. In PAN-treated rats, TLR9 was upregulated in the podocytes, accompanied by increase of apoptosis markers. Thus, de novo expressed TLR9 may utilize endogenous mtDNA as the ligand to facilitate podocyte apoptosis, a novel mechanism underlying podocyte injury in glomerular diseases.

The effects of PK11195 on meningioma was associated with allopregnanolone biosynthesis, which was mediated by translocator protein 18 KDa.

Meningioma is one of the common brain tumors in adults. It had been shown that the allopregnanolone biosynthesis was associated with tumorigenesis and PK11195, the translocator protein 18 KDa (TSPO) antagonist, had the effects of the allopregnanolone biosynthesis. However, little is known about the association between the effects of PK11195 on meningioma and the allopregnanolone biosynthesis. To evaluate this, the meningioma cell line IOMM-LEE was applied. Cell viability and proliferation were determined by CCK-8 assay. The IC50 of PK11195 on the IOMM-LEE was 1.505 ± 0.08 nM. The cell viability and proliferation of AC-5216 (TSPO selective ligand, 2 and 4 nM) was blocked by PK11195 (1.5 nM). Further, we evaluated the role of allopregnanolone biosynthesis in the effects of TSPO on meningioma. Enzyme-Linked ImmunoSorbent Assay (ELISA) was used in the measurement of the allopregnanolone level. It showed that the allopregnanolone level was increased by AC-5216 (2 and 4 nM) and the increase was reversed by PK11195 (1.5 nM). Collectedly, it firstly indicated that the effects of PK11195 on meningioma were relevant to the decrease of allopregnanolone biosynthesis, which was mediated by TSPO.

Foci of Entotic Nuclei in Different Grades of Noninherited Renal Cell Cancers.

We report here an intriguing pattern in nuclear appearance of renal clear cell cancer. In low grade clear cell cancer, detailed examination showed that in many cells, two or more nuclei were within the confines of a single cell membrane. This likely resulted from a cell being contained within its neighboring cell. Consequently, this resulted in appearance of multicellularity. This appearance of the nuclei were not associated with mitotic figures, suggesting that these did not result from nuclear fission. Additionally, the cells containing this nuclei did not show any evidence of cytokinesis including equatorial tapering, suggesting that the process may have resulted from cytokinesis failure. In some sections of higher grade clear cell cancer, these appearance were higher, though we did not observe any frank syncytium formation. On careful observation, there were isolated events of fusion of nuclei within a single cell in different grades of renal cell cancers. There occurrence was more frequent in higher grades of clear cell renal cancer and metastatic clear cell carcinoma. These features were also demonstrable in multiple fields of lower grades of clear cell carcinoma. This phenomenon of entosis may contribute to aneuploidy and tumor progression to dysplastic stages and genomic instability in renal cancers. Future studies are aimed at delineating the cell-cell boundaries and the mechanism contributing to this observation, either from peripheral cell engulfing or failure of cytosolic division for cell separation.

Circulating Mitochondrial DAMPs Are Not Effective Inducers of Proteinuria and Kidney Injury in Rodents.

Mitochondria in eukaryotic cells are derived from bacteria in evolution. Like bacteria, mitochondria contain DNA with unmethylated CpG motifs and formyl peptides, both of which have recently been shown to be damage associated molecular patterns (DAMPs) and induce immune response and cell injury. Based on the facts that circulating mitochondrial DAMPs (mtDAMPs) are increased in the patients of trauma or burn injury who also have proteinuria, that mtDAMPs can activate immune cells which in turn secrete glomerular permeability factors, that renal intrinsic cells express a variety of DAMP receptors, and that mtDAMPs can directly increase endothelial cell permeability in vitro, we hypothesized that mtDAMPs may be novel circulating factors inducing proteinuria and kidney injury. We tested this hypothesis by directly injecting mtDAMPs into rodents and examining urinary protein and kidney histology. We prepared mtDAMP samples, including mitochondrial DNA (mtDNA) and mitochondrial debris (MTD), from rodent liver. In mice, injection of mtDNA for 20 µg/ml initial concentration in circulation (much higher than the clinical range), did not cause any renal manifestations. However, an increased dose leading to 45 µg/ml initial concentration in circulation resulted in a transient, slight increase in urinary albumin. In rats, MTD injection resulting in 450 µg/ml initial concentration of MTD protein in circulation, which was much higher than the clinical range, caused mild, transient proteinuria and lung lesions. Multiple injections of such large amount of either mtDNA or MTD into rodents on 3 consecutive days also failed in inducing proteinuria and kidney injury. In summary, clinical levels of circulating mtDAMPs do not induce proteinuria and clinically irrelevant high levels of mtDAMPs cause only a transient and slight increase in urinary protein in rodents, suggesting that circulating mtDAMPs may not be responsible for the proteinuria and kidney injury in patients with trauma, burn injury, and other diseases.

Clinicopathological and prognostic role of MMP-9 in esophageal squamous cell carcinoma: a meta-analysis.

OBJECTIVE: Many studies reported that matrix metalloproteinase-9 (MMP-9) participated in the development of esophageal squamous cell carcinoma (ESCC) and resulted in poor prognosis, however, they all included few patients and had inconsistent results. So we conducted a meta-analysis to explore the correlation between overexpression of MMP-9 and the clinicopathological characteristics and overall survival (OS) of ESCC. METHODS: PubMed, EMBASE, Web of Science, Chinese Biomedical Literature Database, Google Scholar and other databases were searched for relevant studies. The Newcastle-Ottawa quality assessment scale was used to assess the methodological quality of included study and RevMan 5.2 software was used to conduct meta-analysis. RESULTS: A total of 35 studies were included, and the results of meta-analysis showed that overexpression of MMP-9 was associated with grade of differentiation [well/moderate vs. poor: odds ratio (OR): 0.39, 95% confidence interval (CI): 0.29-0.52; P<0.00001], lymph node metastasis (negative vs. positive: OR: 0.24, 95% CI: 0.16-0.34; P<0.00001), TNM stage (T1/T2 vs. T3/T4: OR: 0.28, 95% CI: 0.14-0.54; P=0.0002), the depth of invasion (T1/T2 vs. T3/T4: OR: 0.29, 95% CI: 0.17-0.49; P<0.00001), and vascular invasion of ESCC (negative vs. positive: OR: 0.35, 95% CI: 0.21-0.58; P<0.0001), and also associated with poor overall survival of ESCC (HR: 2.17, 95% CI: 1.32-3.57; P=0.002). Subgroup analysis showed that more than 10% of carcinoma cell staining was associated with significant increase of mortality risk (HR: 2.44, 95% CI: 1.16-5.15; P=0.02), and sensitive analysis suggested that MMP-9 was an independent prognostic factor in ESCC (HR: 1.49, 95% CI: 1.16-1.91; P=0.002). CONCLUSIONS: On the basis of limited evidence, overexpression of MMP-9 may be a potential independent prognosis factor of ESCC patients in Asia, and high-quality studies assessing the prognostic significance of MMP-9 for ESCC patients are still needed.

Expression of JAKs/STATs pathway molecules in rat model of rapid focal segmental glomerulosclerosis.

The objective of this study was to investigate the role of the Janus kinase-signal transducers and activators of transcription (JAKs/STATs) pathway in focal segmental glomerulosclerosis. Sixty specific pathogen-free male Wistar rats were randomly divided into two groups: a model group (MG) and a control group (CG). In the MG group, nephropathy was induced by unilateral nephrectomy and a single tail vein injection of adriamycin (5 mg/kg). Ten rats were sacrificed every 2 weeks in each group. The expressions of smooth muscle alpha actin (alpha-SMA), collagen (COL)-IV, STAT1, and STAT3 were examined using histochemical techniques, and Western blotting was used to examine the protein levels of STAT1, STAT3, phosphorylated (P)-STAT1, P-STAT3, and transforming growth factor beta1 (TGFbeta(1)). The expressions of JAK1, JAK2, STAT1, STAT3, suppressors of cytokine signaling (SOCS)1, SOCS3, protein inhibitors of activated STAT (PIAS)1, and PIAS3 were also measured by real-time quantitative reverse transcriptase-PCR. A steady and significant increase in the expressions of alpha-SMA, COL-IV and TGFbeta(1) were observed in MG rats over the whole experimental course. Increased STAT1 and P-STAT1 levels in MG rats were observed by week 6, whereas increased levels of STAT3 and P-STAT3 were noted by week 2. At the mRNA levels, JAK1, STAT1, and PIAS1 were significantly increased in MG rats in week 2, whereas JAK2 mRNA showed a significant decrease by weeks 2 and 4, followed by an significant increase in week 6. Significantly increased STAT3 levels were noted in week 2, followed by a steady and significant decrease in weeks 4 and 6. Significantly reduced levels of SOCS1, SOCS3, and PIAS3 mRNA were noted at all time points. We conclude that the JAKs/STATs signaling pathway may play an important role in the pathological process of rapid focal segmental glomerulosclerosis in the rat model.