Identification and validation of biomarkers in membranous nephropathy and pan-cancer analysis.

Background: Membranous nephropathy (MN) is an autoimmune disease and represents the most prevalent type of renal pathology in adult patients afflicted with nephrotic syndrome. Despite substantial evidence suggesting a possible link between MN and cancer, the precise underlying mechanisms remain elusive. Methods: In this study, we acquired and integrated two MN datasets (comprising a single-cell dataset and a bulk RNA-seq dataset) from the Gene Expression Omnibus database for differential expression gene (DEG) analysis, hub genes were obtained by LASSO and random forest algorithms, the diagnostic ability of hub genes was assessed using ROC curves, and the degree of immune cell infiltration was evaluated using the ssGSEA function. Concurrently, we gathered pan-cancer-related genes from the TCGA and GTEx databases, to analyze the expression, mutation status, drug sensitivity and prognosis of hub genes in pan-cancer. Results: We conducted intersections between the set of 318 senescence-related genes and the 366 DEGs, resulting in the identification of 13 senescence-related DEGs. Afterwards, we meticulously analyzed these genes using the LASSO and random forest algorithms, which ultimately led to the discovery of six hub genes through intersection (PIK3R1, CCND1, TERF2IP, SLC25A4, CAPN2, and TXN). ROC curves suggest that these hub genes have good recognition of MN. After performing correlation analysis, examining immune infiltration, and conducting a comprehensive pan-cancer investigation, we validated these six hub genes through immunohistochemical analysis using human renal biopsy tissues. The pan-cancer analysis notably accentuates the robust association between these hub genes and the prognoses of individuals afflicted by diverse cancer types, further underscoring the importance of mutations within these hub genes across various cancers. Conclusion: This evidence indicates that these genes could potentially play a pivotal role as a critical link connecting MN and cancer. As a result, they may hold promise as valuable targets for intervention in cases of both MN and cancer.

Unraveling DDIT4 in the VDR-mTOR pathway: a novel target for drug discovery in diabetic kidney disease.

Introduction: Diabetic kidney disease (DKD) necessitates innovative therapeutic strategies. This study delves into the role of DNA damage-inducing transcription factor 4 (DDIT4) within the VDR-mTOR pathway, aiming to identify a novel target for DKD drug discovery. Methods: Transcriptome data from the Gene Expression Omnibus Database were analyzed to assess the expression of mTOR and VDR expression in human renal tissues. Clinical samples from DKD patients and minimal change disease (MCD) controls were examined, and a DKD animal model using 20-week-old db/db mice was established. DDIT4 plasmid transfection was employed to modulate the VDR-mTOR pathway, with its components evaluated using immunohistochemistry, real-time quantitative PCR (qRT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). Results: Changes in the expression of the VDR-mTOR pathway were observed in both DKD patients and the animal model. Overexpression of DDIT4 increased VDR expression and decreased levels of mTOR, p70s6k, and 4E-BP1. Furthermore, DDIT4 treatment regulated autophagy by upregulating LC3I expression and downregulating LC3II expression. Notably, DDIT4 alleviated oxidative stress by reducing the levels of lipid peroxidation product MDA, while simultaneously increasing the levels of superoxide dismutase (SOD) and glutathione (GSH), underscoring the role of DDIT4 in the pathological process of DKD and its potential as a therapeutic target. Conclusion: Unraveling DDIT4's involvement in the VDR-mTOR pathway provides insights for innovative DKD drug discovery, emphasizing its potential as a therapeutic target for future interventions.

Membranous nephropathy with systemic light-chain amyloidosis of remission after rituximab therapy: A case report.

BACKGROUND: About 70%-80% of patients with primary membranous nephropathy (MN) have phospholipase A2 receptor (PLA2R) in renal tissue. Systemic light-chain (AL) amyloidosis is the most common type of amyloidosis. MN complicated with amyloidosis is rare. CASE SUMMARY: A 48-year-old Chinese male presented with nephrotic syndrome, positive serum PLA2R antibody, and positive serum and urine IgG-lambda type M-protein, with a normal ratio of serum-free light-chain level. The patient was diagnosed with MN accompanied by AL amyloidosis. He was treated with rituximab with glucocorticoids and CyBorD regimen of chemotherapy. After 21 mo of follow-up, the patient achieved complete remission regarding nephrotic syndrome without adverse effects of chemotherapy. CONCLUSION: We report a case of PLA2R-related MN complicated with primary AL amyloidosis only with renal involvement and successfully treated with rituximab, glucocorticoids and chemotherapy.

Clinical characteristics of membranous nephropathy with spontaneous remission: An analysis of 24 patients.

PURPOSE: To investigate the prognosis of patients with spontaneous remission (SR) of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN). PATIENTS AND METHODS: Patients diagnosed with MN were recruited after examining their renal biopsy in the Renal Department of China-Japan Friendship Hospital between January 2015 and September 2021. Among them, 24 patients with SR were included in this study and follow-up. RESULTS: Twenty-four patients diagnosed with SR of PLA2R-associated MN were recruited; 11 were male, and 13 were female, with a mean age of 49.5±14.5 years (range, 30-77 years). The initial 24-hour urinary total protein and serum albumin levels were 0.29±0.14g/d and 37.5±4.4g/L, respectively, and the initial serum creatinine was 65.0±15.8µmol/L. During the follow-up of 33.9±19.1 months (range, 6-73 months), 22 (91.7%) patients maintained remission; however, one patient had impaired renal function due to acute coronary syndrome and coronary angiography findings, and one patient experienced a repeated relapse caused by respiratory tract infection, at 50 and 70 months. A systematic review of the relevant literature was conducted, and records of patients with SR of PLA2R-associated MN were retrieved from 16 case reports or case series with a total of 97 cases. CONCLUSIONS: Most patients with SR of MN had a promising long-term prognosis, with only a few cases of relapse.

Acute kidney injuries induced by thrombotic microangiopathy following severe hemorrhage in puerperants: a case series and literature review.

BACKGROUND: Acute kidney injury in puerperants is generally caused by acute tubular necrosis and occasionally by thrombotic microangiopathy (TMA) following post-partum hemorrhage. However, TMA leads to worse clinical outcomes and is rarely reported in the literature. Therefore, this study aimed to evaluate the pathological mechanism behind the development of TMA in puerperants to improve the diagnosis and treatment of this condition. METHODS: Three patients diagnosed with severe postpartum hemorrhage and TMA from 2014 to 2017 at a nephrology center were retrospectively investigated. RESULTS: All patients had severe hemorrhage during delivery with a mean blood loss, 4.0 L (range, 2.7-5.0 L). AKI developed rapidly in these patients and was treated with hemodialysis. Following treatment, the mean volume of packed red blood cells was 2.3 L (range, 1.2-3.6 L), and the mean volume of resuscitation fluid was 3.7 L (range, 3.5-4.0 L). All patients had renal biopsy specimens with typical TMA and ATN changes on light microscopy. Two patients required a hysterectomy while another two patients received respiratory support. Only one patient received plasma exchange. None of the patients had recovered normal kidney function by the final follow-up (26-61 months), with two patients having stage 3 chronic kidney disease, and one patient having an end-stage renal disease requiring maintenance hemodialysis. CONCLUSION: Severe postpartum hemorrhage could lead to TMA, in addition to the common finding of ATN. Renal histology revealed that poor renal outcomes could be attributed to TMA coexisting with ATN. The potential mechanism was ischemia-reperfusion, which was followed by endothelial cell injury and activation of the alternative complement pathway.

Angiotensin II type 1 receptor blockers favorably affect renal angiotensin II and MAS receptor expression in patients with diabetic nephropathy.

INTRODUCTION: The aims of this study were to assess the renal expression of angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), and MAS receptor in human type 2 diabetic nephropathy (DN). MATERIALS AND METHODS: In total, 115 patients diagnosed with DN by renal biopsy were enrolled in this study. The protein expression levels of the AT1R, AT2R, and MAS receptors were assessed by immunohistochemistry. RESULTS: The protein expression levels of AT1R, AT2R, and MAS receptor in the renal biopsy tissue were correlated with the pathologic classification of DN. Tubulointerstitial AT1R expression in patients of class IIb was significantly stronger than control samples (p < 0.05). Expression of AT2R and MAS receptors were highest with class IIb DN patients. When DN patients were treated with AT1R blocker (ARB), the expression of AT1R was downregulated (p < 0.05), and the MAS receptor was upregulated in tubular interstitial (p < 0.05). CONCLUSIONS: Our results directly observed that renal expression levels of AT1R increase during the early stages of DN, ARB reducing AT1R while increasing MAS receptor. Therefore, ARB should be used as soon as possible in patients with DN.

Expression of the intrarenal angiotensin receptor and the role of renin-angiotensin system inhibitors in IgA nephropathy.

The critical role of the intrarenal renin-angiotensin system (RAS) in the development of kidney disease has been well demonstrated in animal and cell-culture experiments, but evidence from human kidney tissues is lacking. In this study, we screened 438 patients with IgA nephropathy (IgAN) and analyzed their clinical characteristics. Renal biopsy revealed the expression of angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), and MAS receptor (MASR) in the tissues of 260 patients not treated with RAS inhibitors, 32 patients treated with angiotensin-converting enzyme inhibitors (ACEIs), and 89 patients treated with angiotensin receptor blockers (ARBs). The correlations in expression among these three receptors and the results of Oxford typing were analyzed, together with the ability of ACEIs and ARBs to reduce proteinuria and the effects of ARBs on AT1R and AT2R expression. The results showed significantly higher AT1R, AT2R, and MASR expression in the M1 group (mesangial score > 0.5) than in the M0 group (mesangial score < 0.5), significantly higher AT1R expression in the S1 group (presence of segmental glomerulosclerosis) than in the S0 group (absence of segmental glomerulosclerosis); AT1R expression in the C2 group (crescent formation > 25%) was significantly higher than in the C0 (crescent formation = 0) and C1 (crescent formation < 25%) groups. Patients treated with an ARB for < 6 months had significantly lower urinary protein levels than those taking these drugs for > 6 months. These findings imply that overexpression of AT1R on the mesangial cells of IgAN patients is associated with mesangial cell proliferation, glomerular segmental sclerosis, and crescent formation. In addition, long-term administration of ARB may decrease the efficacy of these medications in terms of reducing proteinuria.

1,25-Dihydroxyvitamin D3 inhibits the proliferation of rat mesangial cells induced by high glucose via DDIT4.

1,25-Dihydroxyvitamin D3(1,25(OH)2 D3) is a secosteroid with antiproliferative property. It also plays a pivotal renoprotective role in diabetic nephropathy. We investigated whether 1,25(OH)2D3 could inhibit the proliferation of rat mesangial cells exposed to high glucose via the DNA-damage-inducible transcript 4/mammalian target of rapamycin(DDIT4/mTOR) pathway. The cell proliferation rate and cell cycle duration were measured using cell counting kit-8 assay and flow cytometry. Protein expression was assayed by Western blot. Glucose acted as a growth factor in rat mesangial cells, promoted cell proliferation. In parallel, the protein expression of DDIT4, TSC1/TSC2, and 4E-BP1 were decreased, and Rheb, mTOR, and p70S6K were increased. Acting via the DDIT4/mTOR signaling, 1,25(OH)2 D3 treatment reversed these pathological changes, upregulated DDIT4, TSC1/TSC2, and 4E-BP1, downregulated Rheb, mTOR, and p70S6K. The short-term overexpression of DDIT4 inhibited the proliferation of rat mesangial cells, similar to 1,25(OH)2 D3 treatment. siRNA knockdown of DDIT4 suppressed antiproliferative responses to 1,25(OH)2 D3. These results suggest that 1,25(OH)2 D3 inhibits the proliferation of rat mesangial cells induced by high glucose via the DDIT4/mTOR signaling pathway.

US-guided Microwave Ablation of Hyperplastic Parathyroid Glands: Safety and Efficacy in Patients with End-Stage Renal Disease-A Pilot Study.

Purpose To evaluate the safety and efficacy of microwave ablation (MWA) in patients with end-stage renal disease and secondary hyperparathyroidism. Materials and Methods The study protocol was approved by the human ethics review committee. Between March 1, 2014, and June 30, 2015, 51 patients (25 men, 26 women; mean age ± standard deviation, 53.1 years ± 12.9) were enrolled. All patients had at least one enlarged parathyroid gland and secondary symptomatic hyperparathyroidism, which was treated with ultrasonographically (US) guided MWA. The levels of intact parathyroid hormone, serum calcium, phosphorus, and alkaline phosphatase were compared before and after MWA. Paired-sample t tests and paired-sample Wilcoxon signed-rank tests were used to compare treatment outcomes before and after MWA. Results Complete ablation was achieved in all 96 glands in 51 of 120 patients with severe secondary hyperparathyroidism. The mean follow-up time was 11.1 months ± 3.3. The maximum diameter of the glands ranged from 0.5 cm to 4.8 cm (mean, 1.5 cm ± 0.6). The ablation time for each gland was 216.1 seconds ± 130.1. The mean serum intact parathyroid hormone, calcium, and phosphorus levels after MWA (400 pg/mL [400 ng/L; range, 151.3-629.0 ng/L], 2.33 mmol/L ± 0.23, and 1.54 mmol/L ± 0.43, respectively) were significantly lower than those before MWA (1203 pg/mL [1203 ng/L; range, 854.7-1694.5 ng/L], 2.53 mmol/L ± 0.24, and 1.97 mmol/L ± 0.50, respectively; P < .01), while the alkaline phosphatase levels did not change with MWA (P > .05). Ipsilateral recurrent laryngeal nerve injury was seen in one patient (2%). A hematoma developed during one procedure in one patient (2%) and was treated successfully with injection of thrombin. Conclusion US-guided MWA is safe and effective for destroying parathyroid gland tissue in patients with end-stage renal disease and severe secondary hyperparathyroidism. Further experience with the technique is clearly necessary. © RSNA, 2016.

A case report of varicella-zoster virus infection associated glomerulonephritis and encephalitis.

15-year-old boy was admitted with nephritic and nephrotic syndrome, renal dysfunction and decreased serum C3, who suffered from varicella for two months. His renal histopathology revealed endocapillary proliferative glomerulonephritis with podocytes proliferation and severe tubular injury by light microscopy. Direct immunofluorescence showed global granular deposition of IgG, IgA, IgM, C3, C1q and fibrinogen in mesangium and along glomerular capillary wall. Electron microscopic examination showed electron-dense deposits in multiple sites of glomeruli. Furthermore, specific serum IgM antibodies against varicella-zoster virus (VZV) were detected. VZV antigen and mRNA were demonstrated in glomerular and tubular epithelial cells by immunohistochemical staining and in-situ hybridization. Virus particles and virus inclusions were identified by electron microscopy and special staining (Methylene Blue and Eosion staining or Mann staining). The patient also experienced epileptic episodes and his brain MRI and electroencephalogram indicated herpes encephalitis with secondary epilepsy. Therefore, the diagnosis of VZV-associated glomerulonephritis and encephalitis was established. This is the first case of VZV-associated glomerulonephritis with renal histopathological evidence using in situ hybridization technique.

[The clinical and pathologic features of vascular amyloid deposits of amyloid nephropathy in 6 patients].

OBJECTIVE: To analyze clinical and pathologic features of a rare vascular amyloid deposits of amyloid nephropathy (VADAN) in 6 patients, so as to improve its diagnosis and treatment. METHODS: All patients received immunopathology, microscopy and electron microscopy examination, and amyloid types were analyzed. RESULTS: There were 3 males and 3 females with ages ranging from 52 to 73 years. Two patients suffered from multiple myeloma. Majority patients had slight albuminuria and hematuria. One patient combined with minimal change glomerular disease presented nephrotic syndrome. One patient combined with IgA nephropathy had albuminuria and hematuria. And one patient had myeloma cast nephropathy with acute renal failure. Kidney biopsy proved amyloid deposits along interlobular arterial wall only in all 6 patients. Two cases secondary from multiple myeloma were κ amyloid, and the rests were λ amyloid. CONCLUSIONS: VADAN is a rare type of amyloid nephropathy. Its clinical manifestation is different from common amyloid nephropathy. Kidney biopsy will benefit its differential diagnosis.