The first case of lipoprotein glomerulopathy complicated with collagen type III glomerulopathy and literature review.

Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant kidney disease caused by pathogenic mutations in the APOE gene. Collagen type III glomerulopathy (CG) is a sporadic condition in adults characterized by abnormal accumulation of type III collagen in the subendothelial space and mesangium of the glomerulus. We report the first case of both LPG and CG in a 21-year-old male. A search of the literature found no confirmed reports of these two concomitant nephropathies. The patient presented with hypertension, proteinuria, hematuria and hyperlipidemia. Renal pathology showed lipid vacuoles in the enlarged glomerular capillary loops and type III collagen in the segmental mesangial area and on the inner side of the glomerular basement membrane by electron microscopy. Whole-exome sequencing revealed a heterozygous mutation (c.127C>T; p. Arg43Cys) in exon 3 of the APOE gene, known as the APOE-Kyoto of LPG. In addition, two heterozygous COL4A4 mutations (c.4715C>T in exon 47 and c.5065 T>C in exon 48) were observed, the first one was suspected pathogenic and the other one was uncertain significant. There is no special treatment for these diseases. The patient was treated with lipid-lowering agents, renin-angiotensin-aldosterone system inhibition and tripterygium glycosides. The patient received double-filtration plasmapheresis and immunoadsorption therapy when renal function deteriorated dramatically. Immunoadsorption was beneficial for this patient.

Recent Advances in Epigenetics of Age-Related Kidney Diseases.

Renal aging has attracted increasing attention in today's aging society, as elderly people with advanced age are more susceptible to various kidney disorders such as acute kidney injury (AKI) and chronic kidney disease (CKD). There is no clear-cut universal mechanism for identifying age-related kidney diseases, and therefore, they pose a considerable medical and public health challenge. Epigenetics refers to the study of heritable modifications in the regulation of gene expression that do not require changes in the underlying genomic DNA sequence. A variety of epigenetic modifiers such as histone deacetylases (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors have been proposed as potential biomarkers and therapeutic targets in numerous fields including cardiovascular diseases, immune system disease, nervous system diseases, and neoplasms. Accumulating evidence in recent years indicates that epigenetic modifications have been implicated in renal aging. However, no previous systematic review has been performed to systematically generalize the relationship between epigenetics and age-related kidney diseases. In this review, we aim to summarize the recent advances in epigenetic mechanisms of age-related kidney diseases as well as discuss the application of epigenetic modifiers as potential biomarkers and therapeutic targets in the field of age-related kidney diseases. In summary, the main types of epigenetic processes including DNA methylation, histone modifications, non-coding RNA (ncRNA) modulation have all been implicated in the progression of age-related kidney diseases, and therapeutic targeting of these processes will yield novel therapeutic strategies for the prevention and/or treatment of age-related kidney diseases.

SARS-CoV-2 Causes Acute Kidney Injury by Directly Infecting Renal Tubules.

Acute kidney injury (AKI) is one of the most prevalent complications among hospitalized coronavirus disease 2019 (COVID-19) patients. Here, we aim to investigate the causes, risk factors, and outcomes of AKI in COVID-19 patients. We found that angiotensin-converting enzyme II (ACE2) and transmembrane protease serine 2 (TMPRSS2) were mainly expressed by different cell types in the human kidney. However, in autopsy kidney samples, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein was detected in ACE2+ or TMPRSS2+ renal tubular cells, whereas the RNAscope® Assay targeting the SARS-CoV-2 Spike gene was positive mainly in the distal tubular cells and seldom in the proximal tubular cells. In addition, the TMPRSS2 and kidney injury marker protein levels were significantly higher in the SARS-CoV-2-infected renal distal tubular cells, indicating that SARS-CoV-2-mediated AKI mainly occurred in the renal distal tubular cells. Subsequently, a cohort analysis of 722 patients with COVID-19 demonstrated that AKI was significantly related to more serious disease stages and poor prognosis of COVID-19 patients. The progressive increase of blood urea nitrogen (BUN) level during the course of COVID-19 suggests that the patient's condition is aggravated. These results will greatly increase the current understanding of SARS-CoV-2 infection.

Biomarkers for detecting and improving AKI after liver transplantation: From diagnosis to treatment.

Orthotopic liver transplantation (OLT) is a well-established treatment for patients with liver failure. The shortage of donor organs and postoperative complications remain major obstacles for improving patient survival. Among these complications, acute kidney injury (AKI) is one of the most frequent types, contributing to graft loss. The timely detection and reversal of AKI can reduce its adverse influences on graft and patient outcomes. Traditional markers for detecting AKI are often limited with regard to their accuracy and specificity, and the discovery of better AKI markers and therapeutic targets assumes great importance. During past decades, studies directed toward early detection and treatment of AKI in OLT have been available. This review summarizes the evidence of these biomarkers for the prediction, diagnosis, treatment and prognosis stratification of AKI associated with OLT.

Angiopoietin-Tie signaling in kidney diseases: an updated review.

Angiopoietins (Angs) are a family of vascular growth factors that share multiple cellular functions related to cell survival, proliferation, and migration. Angs play physiological and pathological roles through the Tie tyrosine kinase receptors. The Ang-Tie signaling pathway participates in the developmental and tumor-induced angiogenesis and is also involved in many disease settings, such as vascular diseases, systemic inflammation, and cancers. Since Angs are widely expressed in the kidney, an enormous amount of research focuses on their roles in the kidney. In this review, we describe the biological functions of the Ang-Tie signaling pathway and summarize their roles in kidney development and maturation, acute and chronic kidney diseases, diabetic nephropathy, lupus nephropathy, hemolytic uremic syndrome, end-stage renal diseases, and renal cell carcinoma. Understanding the molecular mechanisms of Ang-Tie signaling may reveal potential therapeutic targets for preventing or alleviating kidney diseases.

A New Pathogenesis of Albuminuria: Role of Transcytosis.

Transcytosis is an important intracellular transport process by which multicellular organisms selectively move cargoes from apical to basolateral membranes without disrupting cellular homeostasis. In kidney, macromolecular components in the serum, such as albumin, low-density lipoprotein and immunoglobulins, pass through the glomerular filtration barrier (GFB) and proximal tubular cells (PTCs) by transcytosis. Protein transcytosis plays a vital role in the pathology of albuminuria, which causes progressive destruction of the GFB structure and function. However, the pathophysiological consequences of protein transcytosis in the kidney remain largely unknown. This article summarizes recent researches on the regulation of albumin transcytosis across the GFB and PTCs in both physiological and pathological conditions. Understanding the mechanism of albumin transcytosis may reveal potential therapeutic targets for prevention or alleviation of the pathological consequences of albuminuria.

Identification of a Novel COL4A4 Variant in Compound-Heterozygous State in a Patient With Alport Syndrome and Histological Findings Similar to Focal Segmental Glomerulosclerosis (FSGS).

Alport syndrome (AS) is a rare and inherited renal disorder with an autosomal recessive mode of inheritance. AS patients usually manifest with hematuria and progressive renal disorder also occasionally accompanied by hearing loss and ophthalmic disease. Germline variants in collagen type IV α-4 (COL4A4) gene lead to autosomal recessive Alport syndrome. In the present study, we investigated a Chinese family with Alport syndrome. The index patient is a 24-year-old Chinese woman who has been suffering from proteinuria. Renal biopsy and renal pathology were performed and found focal segmental glomerulosclerosis (FSGS) like lesion in the index patient. The index patient also presented with binocular edema and blurred vision. However, binocular edema dissipated gradually without any further treatment. Unlikely, the index patient was not diagnosed with hearing impairment. Index patient's parents are phenotypically normal. Targeted next generation sequencing and Sanger sequencing was performed. A novel heterozygous single nucleotide insertion, c.4760_4761insC and a previously reported likely pathogenic variant, c.1323_1340delTGGCTTGCCTGGAGCACC in the COL4A4 gene were identified in the index patient. The novel heterozygous single nucleotide insertion (c.4760_4761insC) leads to a frameshift which eventually results in the formations of a truncated COL4A4 protein. In addition, the other heterozygous likely pathogenic variant, c.1323_1340delTGGCTTGCCTGGAGCACC, has been already identified with causing AS an autosomal recessive mode of inheritance. Sanger sequencing confirmed that these two variants were inherited in the index patient from her father and mother, respectively. These two variants were not found in 100 normal control individuals. In conclusion, our present finding emphasizes the significance of high throughput targeted next generation sequencing technology for rapid and cost-effective genetic screening which allows us easy and accurate clinical diagnosis of AS patients.

Efficacy and safety of tacrolimus vs. cyclophosphamide for idiopathic membranous nephropathy: A meta-analysis of Chinese adults.

The efficacy and safety of tacrolimus (TAC) and cyclophosphamide (CTX) in the treatment of idiopathic membranous nephropathy (IMN) were compared in Chinese adult patients using a meta- analysis of the available literatures. Randomized controlled clinical trials (RCTs) of the treatment of primary IMN with TAC or CTX combined with corticosteroids in the English databases PubMed, Embase and Cochrane, as well as Chinese databases, were searched. Qualified studies were subjected to quality assessment and meta-analysis. A total of 8 RCTs, including 359 Chinese patients, were included in the meta-analysis. The complete remission rate and overall remission rate in the TAC treatment group after 6 months of treatment were higher than those in the CTX treatment group. No significant difference in remission rate was found after 12 months of treatment. There was no significant difference in the adverse reaction between the two groups at the 6th or 12th months. TAC-based treatment was associated with a faster response than CTX at the 6th month, but there was no significant difference between the two groups at 12th month in Chinese adults. Further study is needed to evaluate the long-term efficacy and safety of this treatment regimen.

Urinary angiopoietin-2 is associated with albuminuria in patients with type 2 diabetes mellitus.

Aims. To evaluate the levels of angiopoietin-1 (Ang-1), Ang-2, and vascular endothelial growth factor (VEGF) in serum and urine, and their association with albuminuria in patients with type 2 diabetes mellitus. Methods. In 113 type 2 diabetic patients with normoalbuminuria, microalbuminuria, and macroalbuminuria and 30 healthy controls, the levels of Ang-1, Ang-2, and VEGF in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). Results. Urinary and serum levels of Ang-2 were significantly higher in diabetic patients with normoalbuminuria than in healthy controls. Increased urinary Ang-2 level was positively associated with the degree of albuminuria. Urinary Ang-1 levels were significantly higher in normoalbuminuria patients and lower in macroalbuminuria patients than in controls. The levels of urinary VEGF increased in the albuminuria subgroup, though serum levels of Ang-1 and VEGF did not change. Urinary Ang-2 levels were correlated positively with albuminuria and negatively with glomerular filtration rate (GFR). Stepwise multiple regression analysis identified albuminuria (P < 0.001) and GFR (P = 0.001) as significant predictors of urinary Ang-2. Conclusions. Our data suggest that urinary Ang-2 is stepwise increased with renal damage in patients with type 2 diabetes mellitus and is associated with albuminuria.

Clinicopathological features of renal amyloidosis: a single-center study on 47 cases.

The correlations between the clinicopathological features and the long-term outcomes of renal amyloidosis (RA) were analyzed with a view to develop strategies for improving diagnosis and prognosis of RA. We retrospectively reviewed the clinicopathological characteristics of 47 patients diagnosed with RA between 2004 and 2014 at the Wuhan Union Hospital. The data on the renal histology, clinical manifestations, and prognosis of RA patients were retrieved from the hospital records and characteristic patterns were identified. The histological changes in the kidneys were correlated with the clinical manifestations of RA. Additionally, most RA patients in this study had decreased serum levels of κ light chain and increased urine levels of κ and λ light chains as well as presence of M-protein in the urine and serum. Patients with early RA showed no specific pathognomonic symptoms. Bleeding associated with diagnostic renal biopsy was rare. We recommend that the routine work-up of patients aged over 40 years and presenting with non-diabetic nephropathy includes the non-invasive tests for the measurement of serum and urine levels of κ and λ light chains as well as protein electrophoresis tests for the presence of urinary and serum M-protein. Additionally, such patients should undergo renal biopsy screening with Cong-red staining to ensure early diagnosis of RA and improve their survival, since the risk of hemorrhage related to renal biopsy screening is low at early stages of RA.

Therapeutic effect of alprostadil in diabetic nephropathy: possible roles of angiopoietin-2 and IL-18.

BACKGROUND/AIMS: To investigate the role of angiopoietin-2 (Ang-2) and IL-18 in the pathogenesis of diabetic nephropathy (DN) and the molecular mechanisms through which alprostadil protects renal function. METHODS: DN was induced by streptozotocin and intraperitoneal injection of alprostadil was given to diabetic mice. After 2, 4 and 8 weeks of alprostadil treatment, the mRNA and protein expression of kidney Ang-2 and IL-18 were detected by reverse transcription PCR, Western blot and immunohistochemistry analyses. Mouse glomerular endothelial cells (GEnCs) were cultured in high glucose and treated with alprostadil. After transfection with an Ang-2-pcDNA and Ang-2-siRNA, both Ang-2 and IL-18 expression were measured by Western blot analyses. RESULTS: Alprostadil treatment caused a significant decrease in the renal damage parameters. Both Ang-2 and IL-18 were significantly increased in DN mice and in GEnCs cultured in high glucose; however, their expression was greatly reduced by alprostadil treatment. Ang-2 could also increase IL-18 expression in cultured endothelial cells under high glucose, and this response was partially blocked by Ang-2 siRNA. CONCLUSIONS: Ang-2 and IL-18 may be associated with the development and progression of DN in mice. Alprostadil treatment can protect renal function by reducing proteinuria. These effects are mediated, at least in part, through down-regulation of Ang-2 and IL-18 expression.

Variation of serum monocyte chemoattractant protein-1 in patients with diabetes and metabolic syndrome.

This study investigated the variation of serum monocyte chemoattractant protein-1 (MCP-1) in patients with both diabetes mellitus (DM) and metabolic syndrome (MS). Based on the International Diabetes Federation (IDF) diagnostic criteria, 93 patients enrolled in this study were divided into four groups: normal control (NC), simple DM, simple MS, and DM plus MS (DM-MS) groups. The main measures included height, weight, waist circumference (WC), hip circumference, blood pressure, fasting blood glucose, insulin resistance index (HOMA-IR), serum triglyceride (TG), HDL-ch, LDL-ch, and MCP-1. The results showed that the serum levels of MCP-1 in the DM-MS group were significantly increased as compared with those in the DM and MS groups (P<0.05), and the increase in the MCP-1 level in the DM group was much higher than in the MS group (P<0.05). The DM-MS group had the highest HOMA-IR levels, followed by MS, DM and NC groups (P<0.05). Correlation tests showed that the association of MCP-1 with age, HDL-ch, or LDL-ch was insignificant, whereas that of MCP-1 with body mass index (BMI), waist hip rate (WHR), WC, systolic blood pressure (SBP), diastolic blood pressure (DBP), TG, and HOMA-IR was significantly positive. It was concluded that circulating MCP-1 was substantially increased in patients with both DM and MS as compared with that in the patients with DM or MS alone, and the central obese state may contribute to a more vicious proinflammatory condition and insulin resistance in patients with diabetes.

Role of protease activated receptor-2 expression in renal interstitial fibrosis model in mice.

The role of protease activated receptor-2 (PAR-2) in the renal tubulointerstitial lesion induced by unilateral ureteral obstruction (UUO) was explored. Mice were sacrificed on the day 1, 3, 5, 7, 10, 14 and 21 after UUO. The expression of PAR-2 mRNA and protein and alpha-smooth muscle actin (alpha-SMA) protein in tubulointerstitium was detected by RT-PCR and immunohistochemistry at each time point, respectively. The results showed that the PAR-2 expression in renal tubulointerstitium was increased progressively starting from 24 h to the day 14 post-ligation, and it was significantly associated with the relative volume of interstitium and the positive area of alpha-SMA. PAR-2 was mainly expressed in renal tubule epithelial cells, especially in proximal tubular cells. It also located in renal capillary ansa, interstitial infiltrate cells and fibroblasts. It was concluded that PAR-2 was active in interstitial and tubular cells in the early phase of fibrotic process and played an important role in mediating the tubulointerstitial lesion after UUO.