Caspase-11/GSDMD contributes to the progression of hyperuricemic nephropathy by promoting NETs formation.

Hyperuricemia is an independent risk factor for chronic kidney disease (CKD) and promotes renal fibrosis, but the underlying mechanism remains largely unknown. Unresolved inflammation is strongly associated with renal fibrosis and is a well-known significant contributor to the progression of CKD, including hyperuricemia nephropathy. In the current study, we elucidated the impact of Caspase-11/Gasdermin D (GSDMD)-dependent neutrophil extracellular traps (NETs) on progressive hyperuricemic nephropathy. We found that the Caspase-11/GSDMD signaling were markedly activated in the kidneys of hyperuricemic nephropathy. Deletion of Gsdmd or Caspase-11 protects against the progression of hyperuricemic nephropathy by reducing kidney inflammation, proinflammatory and profibrogenic factors expression, NETs generation, α-smooth muscle actin expression, and fibrosis. Furthermore, specific deletion of Gsdmd or Caspase-11 in hematopoietic cells showed a protective effect on renal fibrosis in hyperuricemic nephropathy. Additionally, in vitro studies unveiled the capability of uric acid in inducing Caspase-11/GSDMD-dependent NETs formation, consequently enhancing α-smooth muscle actin production in macrophages. In summary, this study demonstrated the contributory role of Caspase-11/GSDMD in the progression of hyperuricemic nephropathy by promoting NETs formation, which may shed new light on the therapeutic approach to treating and reversing hyperuricemic nephropathy.

Biodegradable double-network GelMA-ACNM hydrogel microneedles for transdermal drug delivery.

As a minimally invasive drug delivery platform, microneedles (MNs) overcome many drawbacks of the conventional transdermal drug delivery systems, therefore are favorable in biomedical applications. Microneedles with a combined burst and sustained release profile and maintained therapeutic molecular bioactivity could further broaden its applications as therapeutics. Here, we developed a double-network microneedles (DN MNs) based on gelatin methacrylate and acellular neural matrix (GelMA-ACNM). ACNM could function as an early drug release matrix, whereas the addition of GelMA facilitates sustained drug release. In particular, the double-network microneedles comprising GelMA-ACNM hydrogel has distinctive biological features in maintaining drug activity to meet the needs of application in treating different diseases. In this study, we prepared the double-network microneedles and evaluated its morphology, mechanical properties, drug release properties and biocompatibility, which shows great potential for delivery of therapeutic molecules that needs different release profiles in transdermal treatment.

Crystalline appearance in light chain cast nephropathy is associated with higher early mortality in patients with newly diagnosed multiple myeloma.

BACKGROUND: Light chain cast nephropathy (LCCN) is the most common kidney lesion in multiple myeloma patients. LCCN may exhibit a crystalline appearance. The frequency and clinical significance of crystalline LCCN are not well understood. Here, we report the first retrospective study of crystalline LCCN. METHODS: Twenty-six patients with LCCN were enrolled. We studied the clinicopathological features and outcomes of LCCN patients and compared ordinary LCCN patients (n = 18) with crystalline LCCN patients (n = 8). RESULTS: Crystalline LCCN was not rare (8/26, 30.8%) in our study. The median age of LCCN patients was 57.5 (range, 41-75) years. No patients presented with nephrotic syndrome. No significant differences in clinical features were observed between the two groups. All crystalline LCCN patients suffered from advanced multiple myeloma and acute kidney injury. There was a dominance of the λ isotype (7/8, 87.5%) in patients with crystalline LCCN. Patients with ordinary LCCN had significantly higher scores of tubular atrophy and acute tubular injury than those with crystalline LCCN. The crystalline casts of 5 crystalline LCCN patients stained negative with antihuman Tamm-Horsfall glycoprotein. There were no significant differences in the median overall survival between the crystalline LCCN group and the ordinary LCCN group (6.0 months vs. 35.0 months, p = 0.173). However, crystalline LCCN patients had higher early mortality than ordinary LCCN patients (50.0% vs 11.1%, p = 0.03). CONCLUSION: Crystalline LCCN patients had higher early mortality than ordinary LCCN patients. Thus, for patients with LCCN, crystalline appearance should be screened carefully.

Clinicopathological features and outcomes of coexistent light chain cast nephropathy and light chain deposition disease in patients with newly diagnosed multiple myeloma.

AIMS: A varying proportion of patients with multiple myeloma suffer from more than one type of kidney disease simultaneously, of which the most common pattern is coexistent light chain cast nephropathy and light chain deposition disease (LCCN+LCDD). We investigated clinicopathological characteristics and outcomes of LCCN+LCDD in comparison with pure LCCN and pure LCDD. METHODS: We retrospectively analysed 45 newly diagnosed multiple myeloma patients with pure LCCN (n=26), LCCN +LCDD (n=9) and pure LCDD (n=10) between 2000 and 2019 at Peking University First Hospital. RESULTS: Pathologically, patients with LCCN+LCDD were more likely to have λ light chain isotype and presented atypical features of LCDD including less nodular glomerulosclerosis and less deposit distribution than patients with pure LCDD. In clinical characteristics, patients with LCCN +LCDD and patients with pure LCCN shared similar features. The death-censored renal survival in patients with LCCN +LCDD was similar to patients with pure LCCN but worse than patients with pure LCDD, but the overall survival was much better than patients with LCCN alone and similar to patients with pure LCDD. For patients with pure LCCN, the independent predictor of death-censored renal survival was lactate dehydrogenase, and the independent predictors of overall survival were the mean number of casts and serum albumin. CONCLUSIONS: Patients with LCCN+LCDD had similar renal outcome compared with patients with pure LCCN but the overall survival is much better. Thus, for patients with LCCN, especially those with λ restriction, pathologists should carefully evaluate the kidney specimens to exclude the possibility of combined LCDD.

Monoclonal Immunoglobulin-Associated Renal Lesions in Patients with Newly Diagnosed Multiple Myeloma: A Report from a Single Center.

BACKGROUND: Monoclonal immunoglobulin-associated renal lesions in patients with newly diagnosed myeloma vary. We aimed to determine the pathological spectrum and analyze associated prognostic factors. METHODS: Fifty-six patients with newly diagnosed multiple myeloma and biopsy-proven renal lesions were enrolled. Kidney biopsies were reanalyzed, and the baseline clinical characteristics, treatments and outcomes were recorded. RESULTS: Fifty-one patients had monoclonal immunoglobulin-associated renal lesions, with myeloma cast nephropathy (MCN) being the most common pattern. We divided our cohort into pure MCN, MCN+ other pathologies and non-MCN. Patients with MCN had more severe renal injury than those with non-MCN. In our cohort, none of the patients with pure MCN or MCN + other pathologies presented with nephrotic syndrome. Patients with non-MCN had better renal and overall survival than those with pure MCN but similar survivals to those with MCN + other pathologies. Number of myeloma casts (HR 1.08, p = 0.012) was the only independent prognostic factor for renal survival. Male sex (HR: 3.64; p = 0.015) and number of casts (HR: 1.17; p = 0.001) were independent prognostic factors for overall survival. CONCLUSION: Patients with MCN had more severe renal injury than those with non-MCN. Patients with non-MCN had better renal and overall outcomes than those with pure MCN, but their outcomes were similar to those with MCN + other pathologies. The independent predictors of overall survival were male sex and number of myeloma casts.

Comparison of Ultrastructural Features Between Patients with Mercury-associated Membranous Nephropathy and Idiopathic Membranous Nephropathy.

BACKGROUND: Prolonged exposure to mercury can cause membranous nephropathy. Mercury-associated membranous nephropathy (M-MN) and idiopathic membranous nephropathy (I-MN) have similar clinical manifestations, making misdiagnoses likely. We compared the clinicopathological and ultrastructural features of M-MN and I-MN. METHODS: We retrospectively analyzed the clinicopathological data of 13 M-MN patients and 13 I-MN patients. Electron micrographs of glomerular capillaries were taken, and foot process width (FPW) and the number of foot processes per 10 µm glomerular basement membrane (GBM) were calculated. The presence and location of electron-dense deposits were recorded. RESULTS: Compared with I-MN patients, M-MN patients were younger (38.7 ±â€¯8.5 versus 45.8 ±â€¯5.7 years, P = 0.020), achieved complete remission more quickly (9.0 ±â€¯6.1 versus 20.3 ±â€¯9.8 months, P = 0.004), and had a lower relapse rate (0 versus 45.5%, P = 0.014). Patients with M-MN also had lower FPW (974.3 [interquartile range or IQR, 791.2-1504.4] nm versus 2370.6 [IQR, 2219.4-2559.1] nm, P = 0.001), more foot processes per 10 µm GBM (8.1 [IQR, 5.2-10.0] versus 3.3 [IQR, 3.1-3.5], P = 0.001), and a higher rate of mesangial electron-dense deposits (41.7% versus 0, P = 0.015). A cut-off FPW of <1654 nm differentiated M-MN from I-MN with high sensitivity (92.3%) and specificity (83.3%). CONCLUSIONS: Foot process effacement was less severe in M-MN than in I-MN. In patients with mercury toxic exposure, MN with less severe foot processes effacement suggested mercury could be the cause. Better prognosis in patients with M-MN may be associated with minor podocyte damage.

Myeloma cast nephropathy with diffuse amyloid casts without systemic amyloidosis: two cases report.

BACKGROUND: Multiple myeloma (MM) is a plasma-cell derived hematologic malignant disease. The malignant proliferating plasma cells secrete massive monoclonal immunoglobulins which lead to various pathologic types of renal injury. Myeloma cast nephropathy (MCN) is the most common histopathologic lesion with the worst renal prognosis. Rarely, the free light chains in the protein casts can form amyloid fibrils. Here, we reported two rare cases of MCN with diffuse amyloid casts. CASE PRESENTATION: Case 1: A 54-year-old Chinese man presented with a 4-year history of multiple myeloma, proteinuria and hematuria. He had monoclonal IgAλ plus free λ spike in both serum and urine. He had been on chemotherapy for 4 years and maintained normal serum creatinine until 11 months ago. Then, his renal function deteriorated and he went on hemodialysis 4 months before admission. Renal biopsy showed diffuse amyloid casts in the tubular lumens, without any obvious amyloid deposits in other kidney compartments or signs of extra-renal amyloidosis. The amyloid fibrils formed around mononuclear cells which were CD68 negative. According to the morphology and location, these mononuclear cells were considered as tubular epithelial cells. The patient was maintained on chemotherapy and hemodialysis. He died 8 months after renal biopsy. Case 2: A 58-year-old Chinese man presented with a one-and-a-half-year history of proteinuria and slowly rising serum creatinine. He had monoclonal IgDλ spike in both serum and urine. Amyloid casts were observed in the tubular lumens and mononuclear cells could be identified in the center of some casts. There were no amyloid deposits in other kidney compartments and no sign of systemic amyloidosis. The patient also had fine granular deposits along the tubular basement membrane with λ linear staining along tubular basement membrane suggesting light chain deposition disease. He was treated with bortezomib-based chemotherapy followed by lenalidomide-based chemotherapy and achieved very good partial remission (VGPR). After 27 months of follow-up, the patient still showed no signs of systemic amyloidosis. CONCLUSIONS: These 2 cases of MCN with diffuse amyloid casts have different histopathologic characteristics from the usual myeloma casts and tubular epithelial cells might play important roles in the pathogenesis.

A non-invasive differential diagnostic model for light chain cast nephropathy in newly diagnosed multiple myeloma patients with renal involvement: a multicenter study.

OBJECTIVE: Light chain cast nephropathy is the most common form of renal lesion in multiple myeloma. Kidney impairment caused by light chain cast nephropathy can be reversed and survival can be improved if early diagnosis is available. It is thus of imperative importance to develop a non-invasive method to diagnose light chain cast nephropathy once the kidney biopsy is not always applicable. METHODS: We consecutively screened newly diagnosed multiple myeloma patients with kidney biopsies from 4 centers in China. Kidney pathologies were reviewed and clinical presentations were recorded. Then a diagnostic model was established by logistic regression and the predictive values were assessed. RESULTS: Between 1 June 1999 and 30 June 2019, a kidney biopsy was performed in 94 patients with newly diagnosed multiple myeloma, and light chain cast nephropathy was the most common pattern, seen in 52% of biopsied patients. The diagnostic model was established by multivariate logistic regression analysis as P(z) = 1/(1 + e-z) and z = - 0.093 Hemoglobin (g/L) + 0.421 Serum albumin (g/L) + 3.463 Acute kidney injury (0/1) - 9.207 High-density lipoprotein (mmol/L). If P(z) ≥ 0.55, the diagnosis pointed to light chain cast nephropathy; if P(z) < 0.55, the diagnosis favored non-light chain cast nephropathy. The area under the receiver operating characteristic curves was 0.981 (95% CI 0.959, 1.000). The model had a sensitivity of 93.9%, a specificity of 95.6%, a positive predictive value of 96.0%, a negative predictive value of 94.0%, and a total consistency of 95.0%. CONCLUSION: We built a novel, non-invasive diagnostic model through a multicenter study, which may be helpful in the diagnosis of light chain cast nephropathy in newly diagnosed multiple myeloma patients.

Measurement of Particle Size of Loose Accumulation Based on Alpha Shapes (AS) and Hill Climbing-Region Growing (HC-RG) Algorithms.

The loose accumulation CAUSED by landslide, collapse, debris flow, and mine blasting, exerts considerable negative influence to human activities. Besides, it can easily trigger secondary disaster under inner and outer geological conditions. Extraction and measurement of the particle of loose accumulation is of importance for prediction of slope stability and mine blasting. In this paper, the 3D laser scanning is utilized to collect the point clouds of granular materials in physical model (three types of materials) and landslide accumulation in field, respectively. Then, the alpha shapes (AS) and hill climbing-region growing (HC-RG) algorithms are introduced for identifying particles and finding their dimensions (e.g., particle number and radii). Comparison between the recognition results and reality shows that both algorithms can provide a good performance in laboratory physical model, and acceptable results can be obtained when applying two algorithm to field survey. AS algorithm needs less time to process data than HC-GR algorithm; however, the recognition from HC-RG algorithm is more accurate than that by AS algorithm.

Acute tubulointerstitial nephritis with germinal centers in antineutrophil cytoplasmic antibody-associated vasculitis: A case report and literature review.

RATIONALE: Occasionally, tubulointerstitial lesions can be found in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, significantly isolated tubulointerstitial nephritis (TIN) with germinal centers is rare. PATIENT CONCERNS: A 17-year-old Chinese Han patient showed rapidly progressive glomerulonephritis, anuria, and serum creatinine of 19.4 mg/dL. DIAGNOSIS: He had positive ANCA targeting myeloperoxidase (55.0 RU/mL). The renal biopsy showed crescent formation in 100% of glomeruli. Of special note, the glomerular crescents were surrounded by granulomatous inflammation, extensive tubular destruction or disappearance, and massive interstitial infiltration. A diagnosis of AAV was thus made with the involved organ restricted to the kidney. INTERVENTIONS: The patient underwent 7 rounds of plasmapheresis, 3 pulses of methylprednisolone therapy (500 mg per pulse), and oral prednisolone (50 mg/d). Rituximab (500 mg) was used after the plasma exchange treatment. OUTCOMES: ANCA was negative, while anti-modified C-reactive protein (anti-mCRP) antibodies remained positive. The patient was dependent on hemodialysis. We found anti-mCRP antibody in the serum of the patient, with the major epitope on amino acids 35 to 47 of mCRP. LESSONS: We proposed that the anti-mCRP antibody might play an important role in this case of acute TIN in AAV.

Deformation Monitoring of Earth Fissure Hazards Using Terrestrial Laser Scanning.

Deformation monitoring is a powerful tool to understand the formation mechanism of earth fissure hazards, enabling the engineering and planning efforts to be more effective. To assess the evolution characteristics of the Yangshuli earth fissure hazard more completely, terrestrial laser scanning (TLS), a remote sensing technique which is regarded as one of the most promising surveying technologies in geohazard monitoring, was employed to detect the changes to ground surfaces and buildings in small- and large-scales, respectively. Time-series of high-density point clouds were collected through 5 sequential scans from 2014 to 2017 and then pre-processing was performed to filter the noise data of point clouds. A tiny deformation was observed on both the scarp and the walls, based on the local displacement analysis. The relative height differences between the two sides of the scarp increase slowly from 0.169 m to 0.178 m, while no obvious inclining (the maximum tilt reaches just to 0.0023) happens on the two walls, based on tilt measurement. Meanwhile, global displacement analysis indicates that the overall settlement slowly increases for the ground surface, but the regions in the left side of scarp are characterized by a relatively larger vertical displacement than the right. Furthermore, the comparisons of monitoring results on the same measuring line are discussed in this study and TLS monitoring results have an acceptable consistency with the global positioning system (GPS) measurements. The case study shows that the TLS technique can provide an adequate solution in deformation monitoring of earth fissure hazards, with high effectiveness and applicability.