Integrative profiling of untreated primary membranous nephropathy at the single-cell transcriptome level.

Background: Primary membranous nephropathy (PMN) is an autoimmune kidney disease. Despite the identification of certain autoantigens, the etiology and pathophysiology of PMN are still largely unknown. Methods: Five patients with biopsy-proven PMN were enrolled in this study. Their blood, kidney and urine samples were collected respectively to profile cellular, molecular and immunological alterations by using single-cell RNA sequencing (scRNA-seq). Experimental verifications were also implemented in kidney tissue. Results: In the peripheral blood mononuclear cell (PBMC) samples, portions of B cells and plasma cells were increased in PMN patients. Cell-cell communication analysis suggests that APRIL (a proliferation-inducing ligand from B cells) might be a potential molecule that regulates the activity of plasma cells. In the kidney samples, scRNA-seq analysis showed that the infiltration of T cells, as well as the myeloid cells, appears abundant compared with healthy controls, suggesting that immune cells are actively recruited to kidney. Furthermore, we observed an enhanced interaction between inflammatory cells and podocytes, which might contribute to kidney injury. Accordingly, scRNA-seq analysis of urinary samples is partially reminiscent of the kidney cell landscape, especially T cells and myeloid cells, suggesting monitoring urinary samples is a promising method to monitor PMN development. Additionally, integrative analysis across the blood, kidney and urine identified LTB, HERP1, ANXA1, IL1RN and ICAM1 as common regulators of PMN. Finally, immune repertoire in PBMC also showed an elevated diversity of clonal type, implying the existence of autoreactive T-cell receptor/B-cell receptor. Conclusion: Our study comprehensively profiled the transcriptomic landscapes of blood, kidney and urine in patients with PMN using scRNA-seq. We depicted the alterations including cell compositions and cell-cell communication in PMN. These results offer important clues with regard to the diagnosis and pathogenesis of PMN and potential intervention of PMN progression.

Efficacy of growth factor gene-modified stem cells for motor function after spinal cord injury in rodents: a systematic review and meta­analysis.

The efficacy of growth factor gene-modified stem cells in treating spinal cord injury (SCI) remains unclear. This study aims to evaluate the effectiveness of growth factor gene-modified stem cells in restoring motor function after SCI. Two reviewers searched four databases, including PubMed, Embase, Web of Science, and Scopus, to identify relevant records. Studies on rodents assessing the efficacy of transplanting growth factor gene-modified stem cells in restoring motor function after SCI were included. The results were reported using the standardized mean difference (SMD) with a 95% confidence interval (95% CI). Analyses showed that growth factor gene-modified stem cell transplantation improved motor function recovery in rodents with SCI compared to the untreated (SMD = 3.98, 95% CI 3.26-4.70, I2 = 86.8%, P < 0.0001) and stem cell (SMD = 2.53, 95% CI 1.93-3.13, I2 = 86.9%, P < 0.0001) groups. Using growth factor gene-modified neural stem/histone cells enhanced treatment efficacy. In addition, the effectiveness increased when viral vectors were employed for gene modification and high transplantation doses were administered during the subacute phase. Stem cells derived from the human umbilical cord exhibited an advantage in motor function recovery. However, the transplantation of growth factor gene-modified stem cells did not significantly improve motor function in male rodents (P = 0.136). Transplantation of growth factor gene-modified stem cells improved motor function in rodents after SCI, but claims of enhanced efficacy should be approached with caution. The safety of gene modification remains a significant concern, requiring additional efforts to enhance its clinical translatability.

Detection of renal hypoxia configuration in patients with lupus nephritis: a primary study using blood oxygen level-dependent MR imaging.

BACKGROUND: Renal microstructure and function are closely associated with oxygenation homeostasis. Analyzing renal blood oxygen level‒dependent (BOLD) magnetic resonance imaging (MRI) examination results will provide information on the biological status of the kidneys. The current study was performed to explore the hypoxia mode of the entire renal parenchyma in patients with lupus nephritis (LN). METHODS: A total of 23 adult patients with LN and 18 healthy volunteers were recruited. R2* values were acquired using BOLD MRI analysis. The narrow rectangular region of interest was used to explore the hypoxia configuration in entire depths of renal parenchyma. Acquired sequential R2* data were fitted using four categories of mathematic functions. The tendency of R2* data in both patients with LN and healthy volunteers was also compared using repeated-measures analysis of variance. RESULTS: R2* data from the superficial cortex to deep medulla displayed two patterns called a sharp uptrend style and a flat uptrend style. After sequential R2* data were fitted individually with the use of four mathematic formulas, the multiple-compartment Gaussian function showed the highest goodness of fit. Compared with two categories of R2* value styles, the R2* tendency of entire parenchyma in patients with LN was different from that in healthy volunteers. CONCLUSIONS: Deep renal medullary oxygenation was not always overtly lower than oxygenation in the superficial renal cortical zone. The manifestation of renal parenchyma oxygenation could be described using a Gaussian function model. Deoxygenation tolerance was damaged in patients with LN.

Detection of water-molecular-motion configuration in patients with lupus nephritis: a primary study using diffusion-weighted imaging.

BACKGROUND: Lupus nephritis (LN) is one of most common types of secondary glomerulonephritis, which is characterized by longitudinal pathological changes. Microstructural lesions of LN will impact the motion of water molecules, which can be detected by diffusion-weighted imaging (DWI). There are few reported measurements of water diffusion in patients with LN, and the nature of water diffusion across the entire depth of the renal parenchyma remains largely unknown. METHODS: Twenty adult patients with LN and 11 healthy volunteers underwent DWI inspection. Renal biopsy samples were characterized based on the revised ISN/RPS 2003 classification. The apparent-diffusion coefficient (ADC) was calculated via fitting into a mono-exponential model. To compare the ADC level across the entire renal parenchyma between the two groups, repeated-measures analysis of variance (RM-ANOVA) was performed. ADC data derived from DWI pictures were transformed into tridimensional maps by MATLAB software. RESULTS: Compared with data from healthy volunteers, lower average ADC values with major undulatory magnitudes were found in patients with LN, especially in the cortical zone. Tridimensional maps of patients with LN displayed geographic terrain-like canyons and/or valleys that were different from the corresponding terrain-like flatlands and/or plateaus in healthy volunteers. A heterogeneity of ADC values was found in bilateral kidneys. Left kidneys predominated higher ADC values in patients with LN. The ADC values across the entire renal parenchyma exhibited statistically significant differences among the three identified pathological subclasses (P < 0.001). CONCLUSIONS: Analysis of the motion of water molecules across the entire renal parenchyma may be helpful for better understanding the pathological conditions of LN, for which microstructural and functional heterogeneity may be detected and visualized via DWI.

Clinical Significance of Galactose-Deficient IgA1 by KM55 in Patients with IgA Nephropathy.

BACKGROUND: Aberrant galactose-deficient IgA1 molecules (Gd-IgA1) are important causal factors in IgA nephropathy (IgAN); however, the detection of Gd-IgA1 in IgAN is complicated and instable. A monoclonal antibody, KM55, which specifically recognizes Gd-IgA1 has been developed. In the present study, we further explored the clinical significance of Gd-IgA1 using KM55. METHODS: In this study, we enrolled 75 patients with IgAN and 80 healthy controls and detected the plasma Gd-IgA1 levels using the KM55 ELISA method. We also stained -mesangial Gd-IgA1 deposition using KM55. RESULTS: We observed that the levels of plasma Gd-IgA1 in IgAN patients were elevated compared to the corresponding levels of healthy controls. Patients were divided into 2 groups based on the median of Gd-IgA1. Patients with high Gd-IgA1 levels had significantly higher levels of uric acid (UA) and IgA. The other clinical manifestations demonstrated that there were no differences in age, sex, blood pressure, initial proteinuria, hematuria, estimated glomerular filtration rate and Oxford pathological classification between the 2 groups of patients. In addition, positive correlations were observed between Gd-IgA1 and Bb, C3a, C4d and MAC. Mesangial Gd-IgA1 was positive in IgAN but negative in the normal renal tissue adjacent to neoplasm. We next analyzed the correlation between plasma Gd-IgA1 and mesangial Gd-IgA1 deposition. The results showed that a high level of plasma Gd-IgA1 was related to the deposition of mesangial Gd-IgA1, although the difference was not significant. CONCLUSION: We verified the elevated level of plasma and -mesangial Gd-IgA1 in patients with IgAN by KM55, which provided an alternative, easy, and reliable tool for diagnosis and activity assessment of IgAN. The level of plasma Gd-IgA1 positively correlated with levels of UA, total IgA levels, and complement activation products.

Severe acute interstitial nephritis induced by valsartan: A case report.

RATIONALE: Angiotensin receptor blocker (ARB) can increase serum creatinine or potassium levels in patients with renal insufficiency, renal artery stenosis, heart failure or hypovolemia, but hardly cause severe kidney injury in patients without any risk factors. A case of severe acute interstitial nephritis (AIN) induced by valsartan was reported here. PATIENT CONCERNS: A 62-year-old female with nausea for 1 month and acute deterioration of kidney function for 2 weeks was admitted. She had a history of hypertension for 5 months and had taken valsartan 40 mg daily for 4 months. Although the valsartan had been stopped for 2 weeks, the serum creatinine continuously increased after admission. Kidney biopsy demonstrated the eosinophils infiltration in interstitium. DIAGNOSES: AIN induced by valsartan. INTERVENTIONS: The patient was treated with glucocorticoid. OUTCOMES: The serum creatinine decreased gradually and got back to normal level 5 months later. Then therapy of glucocorticoid was stopped. Renal artery stenosis was excluded by computed tomography angiography (CTA). LESSONS: Although valsartan-induced allergy has been reported previously, AIN was firstly recognized as a severe complication of this drug. We suggest when there is a ARB-associated continuous deterioration of kidney function for patients without renal insufficiency, renal artery stenosis, heart failure or hypovolemia, AIN should be thought of and therapy with glucocorticoid should be considered if necessary.

Assessment of Renal Pathological Changes in Lupus Nephritis Using Diffusion Weighted Imaging: A Multiple Correspondence Analysis.

BACKGROUND/AIMS: Renal pathological changes affect the motion of water molecules, which can be detected using diffusion-weighted imaging (DWI). The current study was performed to explore the correlation between renal tissue pathological injuries and DWI iconographical parameters in lupus nephritis (LN). METHODS: Twenty adult patients with LN and 11 healthy volunteers were recruited. Patients with LN received renal biopsies and renal DWI-MRI inspections. The renal biopsy tissues were characterized based on the ISN/RPS 2003 classification. The volunteers, who were of comparable gender and age, only underwent renal DWI-MRI inspection. Four DWI parameters, namely, apparent diffusion coefficient (ADC), pure diffusion coefficient (Dt), pseudo-diffusion coefficient (Dp), and perfusion fraction (fp), were calculated using monoexponential and biexponential functions, respectively. Data from different renal areas and pathological pattern groups were compared. Multiple correspondence analysis (MCA) was performed to explore the correlation between each DWI index and multiple pathological features. RESULTS: ADC, Dt, and fp values were lower in the LN group compared to the controls (P < 0.001) regardless of the renal area in the cortex and medulla. Dp values were higher in the LN group (P = 0.004). A difference in mean DWI parameters was found between three LN subgroups and the healthy volunteers, with the exception of the Dp index in the renal cortex. MCA showed that serious proliferative pathological injuries and lower ADC and Dt values were located in the same quadrant. The MCA plots of Dp and fp provided similar results. Higher Dp and fp values were located in the MCA plot quadrant with more serious proliferative pathological changes. CONCLUSION: DWI is a noninvasive technique that may be used to detect renal pathophysiological changes. Renal cell proliferation and intestinal fibrosis may impact the movement of water in certain microenvironments. Enhanced perfusion may be a compensatory mechanism that is associated with renal pathological injuries.

Blood oxygen level dependent magnetic resonance imaging for detecting pathological patterns in lupus nephritis patients: a preliminary study using a decision tree model.

BACKGROUND: Precise renal histopathological diagnosis will guide therapy strategy in patients with lupus nephritis. Blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) has been applicable noninvasive technique in renal disease. This current study was performed to explore whether BOLD MRI could contribute to diagnose renal pathological pattern. METHODS: Adult patients with lupus nephritis renal pathological diagnosis were recruited for this study. Renal biopsy tissues were assessed based on the lupus nephritis ISN/RPS 2003 classification. The Blood oxygen level dependent magnetic resonance imaging (BOLD-MRI) was used to obtain functional magnetic resonance parameter, R2* values. Several functions of R2* values were calculated and used to construct algorithmic models for renal pathological patterns. In addition, the algorithmic models were compared as to their diagnostic capability. RESULTS: Both Histopathology and BOLD MRI were used to examine a total of twelve patients. Renal pathological patterns included five classes III (including 3 as class III + V) and seven classes IV (including 4 as class IV + V). Three algorithmic models, including decision tree, line discriminant, and logistic regression, were constructed to distinguish the renal pathological pattern of class III and class IV. The sensitivity of the decision tree model was better than that of the line discriminant model (71.87% vs 59.48%, P < 0.001) and inferior to that of the Logistic regression model (71.87% vs 78.71%, P < 0.001). The specificity of decision tree model was equivalent to that of the line discriminant model (63.87% vs 63.73%, P = 0.939) and higher than that of the logistic regression model (63.87% vs 38.0%, P < 0.001). The Area under the ROC curve (AUROCC) of the decision tree model was greater than that of the line discriminant model (0.765 vs 0.629, P < 0.001) and logistic regression model (0.765 vs 0.662, P < 0.001). CONCLUSIONS: BOLD MRI is a useful non-invasive imaging technique for the evaluation of lupus nephritis. Decision tree models constructed using functions of R2* values may facilitate the prediction of renal pathological patterns.

Blood oxygen level-dependent magnetic resonance imaging for detecting pathological patterns in patients with lupus nephritis: a preliminary study using gray-level co-occurrence matrix analysis.

Objective Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) is a noninvasive technique useful in patients with renal disease. The current study was performed to determine whether BOLD MRI can contribute to the diagnosis of renal pathological patterns. Methods BOLD MRI was used to obtain functional magnetic resonance parameter R2* values. Gray-level co-occurrence matrixes (GLCMs) were generated for gray-scale maps. Several GLCM parameters were calculated and used to construct algorithmic models for renal pathological patterns. Results Histopathology and BOLD MRI were used to examine 12 patients. Two GLCM parameters, including correlation and energy, revealed differences among four groups of renal pathological patterns. Four Fisher's linear discriminant formulas were constructed using two variables, including the correlation at 45° and correlation at 90°. A cross-validation test showed that the formulas correctly predicted 28 of 36 samples, and the rate of correct prediction was 77.8%. Conclusions Differences in the texture characteristics of BOLD MRI in patients with lupus nephritis may be detected by GLCM analysis. Discriminant formulas constructed using GLCM parameters may facilitate prediction of renal pathological patterns.

Detection of Renal Hypoxia in Lupus Nephritis Using Blood Oxygen Level-Dependent MR Imaging: A Multiple Correspondence Analysis.

BACKGROUND/AIMS: Nephrologists have pursued ideal, dynamic and noninvasive methods for assessing renal function and disease progression. Blood oxygen level dependent (BOLD) imaging is a useful technique for assessing renal disease. This current study was performed to explore the correlation between the hypoxia iconographical index and renal pathological features in lupus nephritis. METHODS: Adult patients with lupus nephritis (LN) and healthy volunteers were recruited for this study. Renal biopsy tissues were characterized based on the LNISN/RPS 2003 classification. R2* values of functional magnetic resonance parameters were acquired using the BOLD technique. The data characteristics of R2* values of different pathological patterns were calculated. Multiple correspondence analysis (MCA) was performed to explore the correlation between R2* values and clinical or pathological features. RESULTS: A total of twenty-three patients and eighteen healthy volunteers were examined with BOLD MRI. Renal pathological patterns included five class III (including 3 class III+V), eight class IV (including 4 class IV+V) and five class IV. The mean renal R2* values in LN patients were higher than those in healthy volunteers. R2* values in class V patients were higher than those in class IV and class III. The MCA showed that higher R2* values were associated with pathological features in class V patients. CONCLUSIONS: The extent of renal hypoxia in patients with LN was more serious compared with the healthy volunteers. Differentiated mechanisms of renal oxygenation are possibly involved in proliferative and non-proliferative LN patients. R2* values may be linked with multiple clinical and pathological indexes.

Myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis developed from ANCA negative renal limited vasculitis: A case report.

RATIONALE: The relationship between antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) and ANCA-negative vasculitis has not been elucidated. PATIENT CONCERNS: A 64-year-old female with edema and proteinuria was admitted. A kidney biopsy indicated focal proliferative nephritis with crescents in 25% of glomeruli. Serum ANCA was negative. Eighteen months later, systemic symptoms emerged and acute kidney injury occurred. Serum ANCA against myeloperoxidase (MPO) turned positive. Repeated kidney biopsy showed more severe lesion than last time. Immunoglobulin (Ig)G was purified from serum obtained before the first kidney biopsy. Weak ANCA which could not be detected in serum was found in IgG. DIAGNOSES: MPO-ANCA-associated AAV developed from ANCA-negative renal-limited AAV. INTERVENTIONS: The patient was treated with glucocorticoid. OUTCOMES: The serum creatinine decreased to 2.17 mg/dL a week later. MPO-ANCA turned negative when re-examined 3 weeks later. No relapse has been observed during follow-up for 6 months. LESSONS: This is the first reported case about the spontaneous transformation from ANCA-negative renal-limited AAV to ANCA-positive systemic vasculitis. There might be a slow process of epitope spreading in the pathogenesis of disease. Physicians should try their best to detect the ANCA in the diagnose and treatment of ANCA-negative AAV.

Tiopronin-induced membranous nephropathy: a case report.

BACKGROUND: Tiopronin, a glycine derivative extensively used to treat cystinuria and hepatic cell injury, can give rise to rare complications such as proteinuria and nephrotic syndrome. However, the pathological characteristics of this secondary nephropathy are poorly understood. Here, we report a case of tiopronin-induced nephrotic syndrome. CASE PRESENTATION: A 65-year-old Chinese man with a history of myasthenia gravis admitted tiopronin for hepatoprotection therapy. After 3 months later, he presented with rapid weight gain, massive peripheral edema, and proteinuria in the nephrotic range. Laboratory findings included serum albumin (20 g/L), total protein (38 g/L), and total cholesterol (11.78 mmol/L). A 24-hour urine protein collection contained 8620 mg. Percutaneous renal biopsy revealed a uniformly thickened glomerular and rigid basement membrane with immunoglobulin G (IgG) and complement C3 deposited along the glomerular capillary wall. Withdrawal of tiopronin-induced proteinuria complete remission and clinical resolution of nephrotic syndrome. CONCLUSIONS: Potential risk of kidney injury exists with long-term tiopronin treatment. Membranous nephropathy was a common renal pathologic feature. Proteinuria in the nephrotic range may spontaneously remit after tiopronin withdrawal. Periodic urine analysis and patient follow-up are recommended with tiopronin therapy.

Urinary kidney injury molecule-1 is related to pathologic involvement in IgA nephropathy with normotension, normal renal function and mild proteinuria.

BACKGROUND: IgA nephropathy (IgAN) may progress to renal failure for some patients without any clinical risk factors and it is not unusual to find severe pathologic damage in clinically mild IgAN. We therefore investigated whether urinary kidney injury molecule-1 (KIM-1) was related to pathologic involvement in clinically mild IgAN. METHODS: Urinary KIM-1/creatinine of 51 IgAN patients with normotension, normal renal function and proteinuria < 1.0 g/24 h were tested. Relationships between urinary KIM-1 and pathologic features were analyzed. RESULTS: Eighteen of the 51 patients had elevated urinary KIM-1. The tubular atrophy/interstitial fibrosis was more severe in patients with elevated urinary KIM-1 than that in patients with normal urinary KIM-1 (T0/T1/T2, 13/5/0 vs. 33/0/0, P = 0.004). Proportion of glomeruli containing cresecents was higher in patients with elevated urinary KIM-1 than that in patients with normal urinary KIM-1 (50% vs. 18%, P = 0.026). Urinary KIM-1 correlated with the proportion of total crescents (R = 0.303, p = 0.031) and fibrous crescents (R = 0.456, p = 0.001), but did not correlate with the proportion of cellular crescents or fibrocellular crescents. Although the proportion of vascular lesions was higher in patients with elevated urinary KIM-1 (44.4%) than that in patients with normal urinary KIM-1 (18.1%), the difference was not significant (p = 0.057). There was no difference of the response to treatment between patients with and without elevated urinary KIM-1 during a short-term follow-up. CONCLUSIONS: Urinary KIM-1 is a reflection of tubularinstitial injury. For patients with clinically mild IgAN, high urinary KIM-1 is related to relatively severe pathologic involvement on renal biopsy.

IgG4-related membranous nephropathy with high blood and low urine IgG4/IgG ratio: a case report and review of the literature.

Membranous nephropathy (MN) is a rare manifestation of IgG4-related disease. Interestingly, the significance of IgG4 has also been documented in idiopathic MN (IMN). Previous studies reported that urine IgG4/IgG ratios were significantly higher in IMN compared with other kinds of nephropathy, indicating that impairment of charge selectivity barrier seemed to be an obvious characteristic of IMN. Although high blood concentration of IgG4 is very common in IgG4-related MN, no study about the urine IgG4 has been described before. Here, we present a 55-year-old male with IgG4-related MN. Complete remission of proteinuria was promptly achieved by glucocorticoid treatment without immunosuppressant. Consistent with previous reports, the serum antibody against M-type phospholipase A2 receptor was negative. Surprisingly, although the blood concentration of IgG4/IgG reached as high as 36 %, the urine concentration of IgG4/IgG was only 5 %. The calculated ratio of the renal clearance of IgG4 to IgG of this patient (0.15) was obviously lower than that of five patients with IMN (0.53∼0.81). We speculated that this phenomenon might be a clue of the different pathogenesis between IgG4-related MN and IMN.

[Effects of hypercholesterolemia on contrast media-induced nephrotoxicity in rats].

OBJECTIVE: To explore the effects of short- and long-term dietary hypercholesterolemia on contrast media-induced nephrotoxicity in rats. METHODS: The male Wistar rats were fed either a normal rodent diet or a high cholesterol diet. At the end of 2 and 8 weeks, 8 rats from each group received a tail vein injection of either Iohexol injection (groups NC and HC) or vehicle (groups N and H). Blood lipid, renal function, renal hemodynamics, renal and urinary prostaglandin E2 (PGE2) and thromboxane B2 (TXB2), renal nitric oxide and malondialdehyde (MDA) were determined at Day 1 following the administration of contrast media. RESULTS: The dosing of contrast media induced obviously increased serum creatinine compared with normal rats ((185 ± 28) vs (53 ± 3) µmol/L, P < 0.01) and severe renal tubular necrosis in rats with a high cholesterol diet for 8 weeks but did not in normal-diet rats or rats with a high cholesterol diet for 2 weeks. The renal and urinary levels of PGE2 and TXB2 increased significantly in rats of groups H and HC at the end of 8 weeks. The renal production of nitric oxide decreased while the concentration of MDA increased markedly in groups HC and H at the end of 8 weeks. CONCLUSION: Long-term hypercholesterolemia appears to be a risk factor of contrast media-induced acute renal failure. And it may be associated with the disorder of intrarenal prostaglandins and the abnormality of renal nitric oxide system as induced by lipid peroxidation.

Effects of short- and long-term hypercholesterolemia on contrast-induced acute kidney injury.

BACKGROUND: Whether hypercholesterolemia is a risk factor for contrast-induced acute kidney injury (CI-AKI) remains unclear. In the present study, the effects of short- and long-term dietary hypercholesterolemia on contrast media-induced nephrotoxicity were evaluated. METHODS: Rats were fed either a normal rodent diet (N) or high-cholesterol diet (H). At the end of 2 and 8 weeks, 8 rats from each diet group were given a tail vein injection of either iohexol (group NC and group HC) or vehicle (group N and group H). Blood lipids, renal function and renal hemodynamics were evaluated 1 day after contrast media administration. Renal and urinary prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)) were detected by radioimmunoassay. Renal nitric oxide and malondialdehyde (MDA) were measured by the Griess reaction and thiobarbituric acid method, respectively. RESULTS: Contrast media administration increased serum creatinine levels and induced severe renal tubular necrosis in rats fed the high-cholesterol diet for 8 weeks but not in rats fed the normal diet or high-cholesterol diet for 2 weeks. The renal and urinary PGE(2) and TXB(2) levels increased significantly in rats in group H and group HC at the end of 8 weeks. Renal nitric oxide production decreased, and MDA levels increased markedly in group HC and group H at the end of 8 weeks. CONCLUSIONS: We conclude that long-term hypercholesterolemia appeared to be a risk factor for CI-AKI, which might be associated with disorders in intrarenal prostaglandins and abnormalities in renal nitric oxide system induced by lipid peroxidation.

[The histological changes in radial artery in uremia and their effects on arterial stiffness].

OBJECTIVE: To examine the changes of histological parameters of radial artery in uremia, and to explore their effects on arterial stiffness. METHODS: Sixty uremic patients underwent arteriovenous fistula surgery for hemodialysis and 20 healthy subjects received healthy examination were collected as uremia group and control group, respectively. Segments of radial arteries were obtained from all of uremic subjects and were evaluated by HE, Masson, van Kossa staining and electron microscopy. The expressions of osteopontin (OPN), α-SMA and elastin in arterial wall were detected by immunostaining, and apoptotic cells were determined by TUNEL assay. All of the subjects in the two groups received brachial ankle pulse wave velocity (baPWV) examination and the results were compared. The associations among histological parameters and baPWV were analyzed. RESULTS: More than one half (34/60) of artery samples presented uniformly thickening intima, in which most of cells expressed α-SMA and a few cells underwent apoptosis. The subendothelial matrix was abundant in collagen fibers, and no calcium deposition was found. The media thickened obviously, with increased collagen fibers, reduced elastin, unchanged α-SMA expression, and a few apoptotic smooth muscle cells. Two thirds uremic arteries expressed OPN, of which only one half had significant calcium deposition. The adventitia thickened and no calcium deposition was found. The baPWV level in uremic subjects was (18.5±3.2) m/s, far greater than that in control subjects (P<0.001). Statistical analysis showed that baPWV value was correlated with media thickness, calcification degree, and collagen content positively, and with elastin expression negatively. For diabetic uremic subjects, the OR values of vascular calcium deposition and remarkably-elevated baPWV value were 3.1, 2.3, respectively. CONCLUSIONS: Radial arterial intima often presents hyperplasia which is not related with baPWV increment in uremia. Arterial media calcification and collagen content incremental are the most two protuberant characteristics in uremia, especially in ones accompanied with diabetes. Medical calcification, collagen accumulation, and elastin reduction may contribute to the increased arterial stiffness in uremia.

Spironolactone ameliorates podocytic adhesive capacity via restoring integrin alpha 3 expression in streptozotocin-induced diabetic rats.

Podocyte responses to various injuries include detachment from the glomerular basement membrane (GBM) with impaired adhesion ability. Growing evidence suggests inappropriately enhanced aldosterone levels in glomeruli may contribute to podocytic injury and subsequently glomerulosclerosis in diabetic nephropathy (DN). In the present study, we aimed to investigate podocytic integrin alpha 3 expression and urinary podocyte excretion in streptozotocin (STZ)-induced diabetic rats, and to evaluate their responses to spironolactone (SPL). STZ-induced male diabetic Wistar rats were treated with vehicle (the STZ group, n=7), or spironolactone (the STZ+SPL group, n=6) for 12 weeks, six additional rats of similar body weight serving as control. Urine specimens were obtained for measurement of urine albumin concentration and urinary podocyte quantitation upon completion of the 12 weeks. Urinary podocyte excretion was quantified by immunofluorescence and expression of integrin alpha 3 was detected by immunohistochemistry and Western blotting. At 12 weeks, rats given STZ alone revealed an increase in blood glucose and were unaffected by spironolactone, whereas the STZ+SPL group showed considerable improvement in urine albumin and podocyte excretion, as well as up-regulation of integrin alpha 3. Our results suggest that spironolactone ameliorates impaired podocytic adhesion capacity and prevents STZ-induced DN progression.