Tubulointerstitial Score Research Articles

Dynamics of CD4+ and CD8+ Lymphocytic Inflammatory Infiltrates in Lupus Nephritis.

Lupus nephritis (LN) is a common clinical manifestation of systemic lupus erythematosus (SLE). Our study aims to quantitatively analyze CD4+ and CD8+ lymphocytes in different areas and LN classes and describe a specific distribution pattern that is correlated with the severity of LN-specific lesions. In total, 53 LN renal biopsies were immunohistochemically investigated using anti-CD4 and anti-CD8 antibodies. T lymphocytes were counted in 3 areas, including intraglomerular, periglomerular, and interstitial regions. The severity of glomerular and tubulo-interstitial lesions was assessed using an original semi-quantitative algorithm based on the renal corpuscle score (RC_S) and the tubulo-interstitial score (TI_S). The number of CD8+ T lymphocytes was higher than that of CD4+ T lymphocytes in each of the three areas and in each LN class, showing statistically significant differences. ANOVA analysis of all LN classes showed significant differences between periglomerular and interstitial CD4+ and CD8+ T lymphocytes, respectively. Irrespective of location, the number of CD8+ T lymphocytes statistically correlates with the RC_S and the TI_S; no significant correlations were found between the number of CD4+ T lymphocytes and the RC_S and the TI_S for all three considered areas. Our data provide strong evidence supporting the major role of CD8+ lymphocytes in LN lesion progression, with CD4+ lymphocytes playing a limited role.

Clinical and histopathological characteristics of acute kidney injury in a cohort of brain death donors with procurement biopsies.

Kidney biopsies are routinely used for diagnostic and prognostic purposes but their utility in the intensive care unit (ICU) setting is limited. We investigated the associations of clinical and histopathological risk factors with ICU-acute kidney injury (AKI) in donors with brain death (DBD) with kidneys of lower quality and procurement biopsies. Overall,221 donors with brain death, 239 biopsies and 197 recipients were included. The biopsies were reread and scored according to the Banff recommendations. Clinical and histopathological data were compared between donors with and without AKI defined by serum creatinine and by urine output. Logistic regression analysis was applied to identify independent clinical and histopathological risk factors for both phenotypes. Lastly, the impact of each AKI phenotype on outcome was explored.AKI was diagnosedbased on the RIFLE (Risk, Injury, Failure, Loss of function, End-stage kidney disease)AKIN (Acute Kidney Injury Network) orKDIGO (Kidney Disease Improving Global Outcomes) criteria. Acute kidney injury occurred in 65% of donorsbased both uponserum creatinine and by urine output. Serum creatinine was able to better discriminate AKI. Multiorgan failure and severe AKI were captured by serum creatinine, and hemodynamic instability by urine output. Donors with serum creatinine-AKI showed lower chronic macrovascular scores, while donors with urine output-AKI had higher chronic microvascular and tubulointerstitial scores. Tubular injury was similar between the subgroups. Except for delayed graft function and one-year death-censored graft survival, the other short-term recipient outcomes were similar for both AKI phenotypes. Serum creatinine is more suitable than urine output for defining AKI in donors with brain death. There are distinct clinical risk factors for each AKI-ICU phenotype. Donor AKI phenotype does not predict the recipient´s prognosis. Kidney biopsies do not seem to confer any tangible benefit in defining AKI indonors with brain death.

Interstitial fibrosis increases the risk of end-stage kidney disease in patients with lupus nephritis.

To evaluate the risk of end-stage kidney disease (ESKD) in LN patients using tubulointerstitial lesion scores. Clinical profiles and histopathological presentations of 151 biopsy-proven LN patients were retrospectively examined. Risk factors of ESKD based on characteristics and scoring of their tubulointerstitial lesions [e.g. interstitial inflammation (II), tubular atrophy (TA) and interstitial fibrosis (IF)] were analysed. The mean age of 151 LN patients was 36 years old, and 136 (90.1%) were female. The LN cases examined included: class I/II (n = 3, 2%), class III/IV (n = 119, 78.8%), class V (n = 23, 15.2%) and class VI (n = 6, 4.0%). The mean serum creatinine level was 1.4 mg/dl. Tubulointerstitial lesions were recorded in 120 (79.5%) patients. Prior to receiving renal biopsy, nine (6.0%) patients developed ESKD. During the follow-up period (mean, 58 months), an additional 47 patients (31.1%) progressed to ESKD. Multivariate analyses identified serum creatinine [hazard ratio (HR): 1.7, 95% CI: 1.42-2.03, P < 0.001] and IF (HR: 3.2, 95% CI: 1.58-6.49, P = 0.001) as independent risk factors of ESKD. Kaplan-Meier analysis further confirmed a heightened risk of ESKD associated with IF. Tubulointerstitial involvement is commonly observed in the histopathological presentation of LN. However, IF, rather than II or TA, was found to increase the risk of ESKD in our cohort. Therefore, to predict renal outcome in LN patients prior to adjusting immunosuppressive treatment, the degree of IF should be reviewed.

Value of original and modified pathological scoring systems for prognostic prediction in paraffin-embedded donor kidney core biopsy

Background No study has validated, compared and adapted scoring systems for prognosis prediction based on donor kidney core biopsy (CB), with less glomeruli than wedge biopsy. Methods A total of 185 donor kidney CB specimens were reviewed using seven scoring systems. The association between the total score, item scores, score-based grading, and allograft prognosis was investigated. In specimens with less than ten glomeruli (88/185, 47.6%), scoring systems were modified by adjusting weights of the item scores. Results The Maryland aggregate pathology index (MAPI) score-based grading and periglomerular fibrosis (PGF) associated with delayed graft function (DGF) (Grade: OR = 1.59, p < 0.001; PGF: OR = 1.06, p = 0.006). Total score, score-based grading and chronic lesion score in scoring systems associated with one-year and 3-year eGFR after transplantation. Total-score-based models had similar predictive capacities for eGFR in all scoring systems, except MAPI and Ugarte. Score of glomerulosclerosis (GS), interstitial fibrosis (IF), tubular atrophy (TA), and arteriolar hyalinosis (AH) had good eGFR predictive capacities. In specimens with less than ten glomeruli, modified scoring systems had better eGFR predictive capacities than original scoring systems. Conclusions Scoring systems could predict allograft prognosis in paraffin-embedded CB with ten more glomeruli. A simple and pragmatic scoring system should include GS, IF, TA and AH, with weights assigned based on predictive capacity for prognosis. Replacing GS scores with tubulointerstitial scores could significantly improve the predictive capacity of eGFR. The conclusion should be further validated in frozen section.

Renal resistive index as a marker of histopathological damage in diabetic and non-diabetic chronic kidney disease

BackgroundChronic kidney disease is a worldwide public health problem with diabetes being the leading cause. Renal resistive index derived by Duplex Doppler sonography, has been in use clinically to examine intrarenal hemodynamic abnormalities. However, renal biopsy remains the gold standard for the evaluation of intrarenal damage. In this study we correlated the renal resistive index in diabetic and non-diabetic kidney disease patients with the established parameters of renal dysfunction i.e. histopathological changes.ResultsThe conducted study was a cross-sectional comparative study on 114 patients (58 diabetic and 56 non-diabetic patients) over a period of 18 months. Evaluated histopathological indices and renal resistive index had a statistically significant positive correlation (glomerulosclerosis, arterial damage and tubulo-interstitial damage scores) in both diabetic and non-diabetic patients. The highest correlation was observed with tubulo-interstitial score in our study.ConclusionsRenal resistive index could be considered a marker of histological damage in both diabetic and non-diabetic kidney disease. Inclusion of resistive index in the routine diagnostic protocol of chronic kidney disease can help in the accurate assessment of intrarenal damage. Hence, it is of utmost importance as a radiologist to determine resistive index in chronic kidney disease patients and guide the clinicians for efficient management.

Abstract P3190: Renal Tubular Mitochondrial Akt1 Modulates Cardiorenal Metabolic Syndrome

Metabolic syndrome-induced cardiomyopathy is a significant risk factor for cardiovascular diseases (CVDs). The proximal tubular cells of the kidney play a crucial role in regulating glucose and lipid metabolism. Mitochondrial dysfunction in these cells has been linked to the development of metabolic syndrome-induced cardiac dysfunction. AKT1, a serine/threonine protein kinase, regulates mitochondrial function. In this study, we investigated the effects of renal proximal tubular mitochondrial AKT1 on metabolic syndrome-induced cardiomyopathy in transgenic mice. We generated transgenic mouse lines, KMioxCAKT, with inducible overexpression of mitochondrial AKT1, specifically in renal proximal tubular cells. One line was induced with tamoxifen, while the other was with corn oil. Both lines were fed a high-fat diet (HFD) for 16 weeks to provoke metabolic syndrome. For renal function, although serum BUN ( p= 0.728 ) and creatinine ( p=0.622 ) were not changed, the proteinuria ( p=0.031 ) and the urine KIM-1 ( p=0.012 ) were decreased in tamoxifen-induced KMioxCAKT. The glomerulosclerosis index ( p =0.027), tubulointerstitial fibrosis score ( p =0.032), tubular dilatation score ( p =0.032), tubular vacuolation score ( p =0.031), and tubular casts ( p =0.018) of renal histology were amended in tamoxifen-induced KMioxCAKT. The fasting glucose level ( p =0.015); the 15 to 120 minutes glucose levels ( p =0.020); the fasting insulin level ( p=0.037 ), and insulin resistance measured by Homeostatic Model Assessment for Insulin Resistance ( p=0.005 ) were reduced in metabolic syndrome with augmentation of renal tubular mitochondrial AKT1. In addition, tamoxifen-induced KMioxCAKT mice had significantly attenuated cardiac hypertrophy in the heart compared to corn oil-induced KMioxCAKT. Our results suggest that enhancing renal proximal tubular mitochondrial AKT1 could ameliorate the cardiorenal metabolic syndrome.

#3314 DIURETIC AND RENOPROTECTIVE EFFECTS OF GOREISAN IN A RAT MODEL OF NEPHROTIC SYNDROME

Abstract Background and Aims Goreisan, a traditional Chinese medicine composed of five herbs, is commonly used for the purpose of control of edema and gastrointestinal symptoms. However, the detailed mechanisms have not been fully elucidated. In clinical settings, nephrotic syndrome often causes edema, mainly due to hypoalbuminemia and sodium retention. Thus, we investigated the effects of Goreisan on the kidney using a rat model of nephrotic syndrome. Method A model of nephrotic syndrome was created by a right nephrectomy and subsequent administration of adriamycin using Sprague Dawley rats. Nephrotic rats were randomly divided into three groups at 10 weeks of age as follows; vehicle (control), Goreisan 0.5 g/kg (GL), and Goreisan 1.0 g/kg (GH) groups. Goreisan was administered once a day for 4 weeks. At 14 weeks of age, the rats were sacrificed for the evaluation of blood, urine, mRNA expressions, and kidney histopathology. Results Urine volume was significantly increased in the GL and GH groups than in the control group (Δurine volume: control; −1.25±2.48 mL, GL group; 9.83±4.16 mL, GH group; 10.00±2.62 mL). The GH group showed significantly lower urine osmotic pressure compared to the control group. There were no significant differences in urinary sodium excretion and serum arginine-vasopressin levels among the three groups. Subsequently, we assessed the expression of aquaporin (AQP) in kidney tissue using real-time PCR and immunohistochemical staining. The mRNA expression of AQP1, AQP2, AQP3, and AQP4 did not differ among the three groups. However, immunohistochemical staining showed that the localization of AQP2 at the apical plasma membrane of the collecting ducts was decreased by treatment with Goreisan. Furthermore, deterioration of kidney function was prevented by treatment with Goreisan. Histological analysis revealed that glomerular and tubulointerstitial damages were ameliorated in the GL and GH groups compared to the control group (glomerular damage score: control; 2.19±0.05, GL group; 1.71±0.05, GH group; 1.10±0.05, tubulointerstitial damage score: control; 2.55±0.09, GL group; 2.28±0.10, GH group; 2.12±0.10). In addition, urinary 8-OHdG, which is an oxidative stress marker, was significantly lower in the GL and GH groups than in the control group. Conclusion Our results suggested that Goreisan may have diuretic and renoprotective effects by suppressing the trafficking of AQP2 to the apical plasma membrane of the collecting ducts and possibly reducing systemic oxidative stress.

Evaluating the renal mild tubulointerstitial damage and renal function in IgAN patients: a comparative study based on diffusion kurtosis imaging and diffusion tensor imaging.

To compare the performance of 3.0T magnetic resonance diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in evaluation of the degree of tubulointerstitial damage and renal function in Immunoglobulin A Nephropathy (IgAN) patients. Both DKI and DTI were performed in 40 IgAN patients and 17 healthy volunteers. IgAN patients were divided into two groups according to tubulointerstitial lesion score: Mild injury group, n = 24; Moderate-severe injury group, n = 16. DKI characteristic parameters [mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr)] and DTI parameters [fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), radial diffusivity (Dr)] of renal cortex and medulla were measured and compared among different groups. Correlations between DKI, DTI parameters and clinicopathological characteristics were assessed. Diagnostic performance of DKI and DTI to evaluate tubulointerstitial damage of IgAN was compared. Cortical MK, Kr, Da and parenchymal Ka significantly differed among three groups (P < 0.05). Cortical MK, Kr, Ka were negatively correlated with estimated glomerular filtration rate (eGFR) (MK: r = - 0.613; Kr: r = - 0.539; Ka: r = - 0.664) and positively correlated with tubulointerstitial lesion score (MK: r = 0.655; Kr: r = 0.577; Ka: r = 0.661) (all P < 0.001). Lower correlation coefficient was found among cortical FA, MD, Dr and eGFR, tubulointerstitial lesion score (all|r|< 0.350). The AUCs of DKI and DTI parameters for differentiating Mild injury group from control group were (cortical MK 0.822, cortical Ka 0.816; cortical FA 0.515, cortical MD 0.714) and for differentiating Mild injury group from Moderate-severe injury group were (cortical MK 0.813, cortical Ka 0.831; medulla FA 0.784, medulla MD 0.586). Compared with DTI, DKI was more sensitive and accurate to probe the renal function and the tubulointerstitial damage of IgAN, especially the mild tubulointerstitial damage.

Noninvasive assessment of clinical and pathological characteristics of patients with IgA nephropathy by diffusion kurtosis imaging

ObjectivesTo explore the diagnostic performance of diffusion kurtosis imaging (DKI) in evaluating the clinical and pathological characteristics of patients with immunoglobulin A nephropathy (IgAN) compared with conventional DWI.Materials and methodsA total of 28 IgAN patients and 14 healthy volunteers prospectively underwent MRI examinations including coronal T2WI, axial T1WI, T2WI, and DWI sequences from September 2020 to August 2021. We measured mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC) by using MR Body Diffusion Toolbox v1.4.0 (Siemens Healthcare). Patients were divided into three groups according to their estimated glomerular filtration rate (eGFR) (Group1, healthy volunteers without kidney disease or other diseases that affect renal function; Group2, IgAN patients with eGFR > 60 mL/min/1.73 m2; Group3, IgAN patients with eGFR < 60 mL/min/1.73 m2). One-way analysis of variance, Pearson or Spearman correlation, and receiver operating characteristic curves were applied in our statistical analysis.ResultsMKCortex and ADCCortex showed significant differences between the Group1 and Group2. MKCortex, MDCortex, ADCCortex, MKMedulla, and ADCMedulla showed significant differences between Group2 and Group3. MKCortex had the highest correlation with CKD stages (r = 0.749, p < 0.001), and tubulointerstitial lesion score (r = 0.656, p < 0.001). MDCortex had the highest correlation with glomerular lesion score (r = − 0.475, p = 0.011). MKCortex had the highest AUC (AUC = 0.923) for differentiating Group1 from Group2, and MDCortex had the highest AUC (AUC = 0.924) for differentiating Group2 from Group3, followed by MKMedulla (AUC = 0.923).ConclusionsDKI is a feasible and reliable technique that can assess the clinical and pathological characteristics of IgAN patients and can provide more valuable information than conventional DWI, especially MKCortex.

Sex-specific effects of metformin and liraglutide on renal pathology and expression of connexin 45 and pannexin 1 following long-term high-fat high-sugar diet

The comparative effects of the two commonly used antidiabetic drugs metformin and liraglutide on renal pathology and expression of connexin 45 (Cx45) and pannexin 1 (Panx1) in adult obese rats fed high-fat high-sugar diet (HFHSD) were studied. Considering recent data on the profound influence of sex on metformin and liraglutide effects, we compared the effects of both drugs between male and female animals. 44-week-old Sprague-Dawley rats were separated into 4 groups that were fed: standard diet, HFHSD, HFHSD treated with metformin (s.c., 50 mg/kg/day) and HFHSD treated with liraglutide (s.c., 0.3 mg/kg/day). Treatment with metformin or liraglutide lasted for 14 weeks. Histology and immunohistochemistry were performed to quantify renal pathological changes and Cx45 and Panx1 expression. HFHSD caused thickening of the Bowman’s capsule (BC). Both metformin and liraglutide failed to ameliorate the BC thickening; metformin even worsened it. Effects on the tubulointerstitial fibrosis score, BC thickness and Cx45 and Panx1 expression were sex-dependent. We found a 50% increase in mitochondria in proximal tubules of metformin- and liraglutide-treated HFHSD-fed rats, but these effects were not dependent on the sex. This is a first study showing that the effects of metformin and liraglutide on kidney pathology in rats fed HFHSD are mostly sex-dependent and that these effects are not necessarily beneficial. Both drugs changed the Cx45 and Panx 1 expression; hence their effects could be related to amelioration of disruptions in intercellular communication.

Rituximab Is Preferable to Cyclophosphamide for Treatment of Membranous Nephropathy: CON.

This is an Early Access article. Please select the PDF button, above, to view it. Be sure to also read the PRO: 10.34067/KID.0001842021 and the COMMENTARY: 10.34067/KID.0002492021

Early Renoprotective Effect of Ruxolitinib in a Rat Model of Diabetic Nephropathy.

Diabetic kidney disease (DKD) is still one of the unresolved major complications of diabetes mellitus, which leads ultimately to end-stage renal disease in both type 1 and type 2 diabetes patients. Available drugs that suppress the renin–angiotensin system have partially minimized the disease impact. Yet, there is an unmet need for new therapeutic interventions to protect the kidneys of diabetic patients. In DN, glomerular sclerosis and tubulointerstitial fibrosis are mediated through several pathways, of which JAK/STAT is a key one. The current study explored the potential renoprotective effect of the JAK1/JAK2 inhibitor ruxolitinib (at doses of 0.44, 2.2, and 4.4 mg·kg−1) compared to that of enalapril at a dose of 10 mg·kg−1, in a rat model of streptozotocin-induced diabetes mellitus over 8 weeks. The effect of ruxolitinib was assessed by determining urinary albumin/creatinine ratio, serum level of cystatin, and levels of TGF-β1, NF-κB, and TNF-α in renal tissue homogenates by biochemical assays, the glomerular sclerosis and tubulointerstitial fibrosis scores by histological analysis, and fibronectin, TGF-β1, and Vimentin levels by immunohistochemical staining with the respective antibodies. Our results revealed a significant early favorable effect of a two-week ruxolitinib treatment on the renal function, supported by a decline in the proinflammatory biomarkers of DKD. This pre-clinical study suggests that the renoprotective effect of ruxolitinib in the long term should be investigated in animals, as this drug may prove to be a potential option for the treatment of diabetic kidney disease.

Jian-Pi-Yi-Shen Formula Ameliorates Oxidative Stress, Inflammation, and Apoptosis by Activating the Nrf2 Signaling in 5/6 Nephrectomized Rats

Chronic kidney disease (CKD) is an increasing global public health problem, with high morbidity and mortality. Jian-Pi-Yi-Shen (JPYS) formula is a representative traditional Chinese medicine formula in the treatment of CKD, which is widely used in clinical practice in China. However, the underlying mechanism has not been well elucidated. In the present study, we measured the markers of apoptosis, inflammation, oxidative stress, and nuclear factor erythroid 2–related factor 2 (Nrf2) signaling to investigate the effects of JPYS formula on renal function and fibrosis and its molecular mechanism in an established animal model of 5/6 nephrectomized (5/6Nx) rats. The results demonstrated that the JPYS formula exerted a significant preventive effect on renal dysfunction and fibrosis, based on analysis of correlative parameters such as urinary protein, SCr, BUN, glomerular sclerosis index, and tubulointerstitial fibrosis score and renal histopathology and ultrastructural pathology of CKD rats. JPYS formula also induced downregulation of gene expression associated with fibrosis, such as TGF-β and type I, III, and IV collagen. Moreover, the JPYS formula showed a significant protective effect in suppressing cell apoptosis according to the results of apoptotic indexes, including increased gene expression of Bcl-2, decreased gene expression of Bax, caspase 3, caspase 9, and the number of TUNEL-positive cells. JPYS formula also ameliorated the activation of the NF-κB-mediated inflammatory pathway, as manifested by the downregulation of gene expression of TNF-α, IL-1β, IκBα, NF-κB p65, MCP-1, CXCL1, COX-2, and iNOS in the kidney. Our evidence also suggested that the JPYS formula ameliorates oxidative stress by promoting antioxidant function according to antioxidant index indicators as an indicator of GSH, SOD, CAT, and GPx and abating excessive accumulation of the reactive oxygen species biomarkers, including ROS, TBARS, 8-oxo-dG, and MDA. The data also suggested that the JPYS formula reversed the downregulation of HO-1 and Nrf2 level and upregulation of Keap1 expression. Together, our data highlighted that the JPYS formula relieved renal oxidative injury mediated by activation of Nrf2 signaling by inhibiting inflammation and apoptosis in CKD rats.

Spectrum of cancer patients receiving renal biopsy

The frontier of onco-nephrology, particularly renal complications of cancer and treatment, remains unexplored. We revisit the fundamental tool of diagnosing kidney disease, renal biopsy, in cancer patients with renal manifestation. Patients who received renal biopsy from July 2015 to July 2019 were analyzed. Primary outcomes included end-stage renal disease (ESRD), mortality, and catastrophic outcome defined as either ESRD or mortality. A Cox proportional hazards model and Kaplan-Meier technique were used to assess the association with outcome measurements and survival analyses. Immunosuppression after renal biopsy and response to the treatment were evaluated. Among the 77 patients, the median age was 66 years (interquartile range [IQR] 59-73 years) and 46 (59.7%) were male. At the time of renal biopsy, 57 patients (74%) had various degrees of renal insufficiency. Tubulointerstitial damage score, quantified by renal pathology, were associated with higher hazards of ESRD (hazard ratio [HR], 1.77; 95% confidence interval [95% CI], 1.20 to 2.61; P=0.004) and catastrophic outcome (HR, 1.30; 95% CI, 0.99 to 1.70; P=0.058). The response rate to immunosuppression was lower in those diagnosed with tubulointerstitial nephritis (1 of 4 patients, 25%) than those with glomerulopathy (10 of 20 patients, 50%). Renal biopsy may improve diagnostic accuracy and assist in treatment guidance of cancer patients with renal manifestation. Renal biopsy should be encouraged with clinical indication. Collaboration between oncologists and nephrologists is of paramount importance to provide more comprehensive care for caner patients.

Evaluation of the nephrotoxicity and safety of low-dose aristolochic acid, extending to the use of Xixin (Asurum), by determination of methylglyoxal and d-lactate

Ethnopharmacological relevanceMost Aristolochiaceae plants are prohibited due to aristolochic acid nephropathy (AAN), except Xixin (Asarum spp.). Xixin contains trace amounts of aristolochic acid (AA) and is widely used in Traditional Chinese Medicine. Methylglyoxal and d-lactate are regarded as biomarkers for nephrotoxicity. Aim of the studyThe use of Xixin (Asarum spp.) is essential and controversial. This study aimed to evaluate tubulointerstitial injury and interstitial renal fibrosis by determining urinary methylglyoxal and d-lactate after withdrawal of low-dose AA in a chronic mouse model. Materials and methodsC3H/He mice in the AA group (n = 24/group) were given ad libitum access to distilled water containing 3 μg/mL AA (0.5 mg/kg/day) for 56 days and drinking water from days 57 to 84. The severity of tubulointerstitial injury and fibrosis were evaluated using the tubulointerstitial histological score (TIHS) and Masson's trichrome staining. Urinary and serum methylglyoxal were determined by high-performance liquid chromatography (HPLC); urinary d-lactate were determined by column-switching HPLC. ResultsAfter AA withdrawal, serum methylglyoxal in the AA group increased from day 56 (429.4 ± 48.3 μg/L) to 84 (600.2 ± 99.9 μg/L), and peaked on day 70 (878.3 ± 171.8 μg/L; p < 0.05); TIHS and fibrosis exhibited similar patterns. Urinary methylglyoxal was high on day 56 (3.522 ± 1.061 μg), declined by day 70 (1.583 ± 0.437 μg) and increased by day 84 (2.390 ± 0.130 μg). Moreover, urinary d-lactate was elevated on day 56 (82.10 ± 18.80 μg) and higher from day 70 (201.10 ± 90.82 μg) to 84 (193.28 ± 61.32 μg). ConclusionsMethylglyoxal is induced after AA-induced tubulointerstitial injury, so methylglyoxal excretion and metabolism may be a detoxification and repair strategy. A low cumulative AA dose is the key factor that limits tubulointerstitial injury and helps to repair. Thus, AA-containing herbs, especially Xixin, should be used at low doses for short durations (less than one month).

Enhanced Bruton\u2019s tyrosine kinase activity in the kidney of patients with IgA nephropathy

PurposeBruton’s tyrosine kinase (BTK) is a vital biological molecule that contributes to immune regulation. Previous studies have showed that BTK can be detected in patients with lupus nephritis and rheumatoid arthritis. However, the role of BTK in IgA nephropathy (IgAN) has not yet been elucidated. The purpose of this research was to investigate the role of BTK activation in macrophages in IgAN.MethodsPeripheral blood and renal tissue samples were collected from 63 patients with IgAN, and peritumoral normal tissues were collected from 20 patients after surgical resection of renal tumor for use as control. Additionally, 20 healthy volunteers were recruited as control. The levels of BTK, CD68, phosphorylated BTK (pBTK), phosphorylated NF-κB (p-NF-κB p65), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and monocyte chemotactic protein (MCP)-1 were measured by immunohistochemistry (IHC), real-time polymerase chain reaction (RT-PCR), western blotting, and enzyme-linked immunosorbent assay (ELISA).ResultsCompared to peritumoral normal tissues, the expression levels of CD68 and BTK were significantly increased in IgAN group (p < 0.001) and the differences between M0 and M1, E0 and E1, S0 and S1, T0 and T1-2, C0 and C1-2 were statistically significant in the updated Oxford Classification (p < 0.05). Also, CD68 and BTK were positively correlated with Katafuchi semi-quantitative glomerular and tubulointerstitial scores (r = 0.580, 0.637 and 0.442, 0.489, respectively, p < 0.05). The expression of BTK was significantly higher in C3b- and C4d-positive renal tissues of patients with IgAN (p < 0.05). In addition, BTK was positively correlated with 24-h urine protein, serum creatinine levels (r = 0.456 and 0.453, respectively, p < 0.001), and negatively correlated with serum albumin (r = 0.357, p < 0.05). The intensity of expression of pBTK and p-NF-κB p65 was observably increased in renal tissues and monocytes of patients with IgAN compared to the control group. The results of IHC, RT-PCR, and ELISA indicated that the levels of TNF-ɑ, IL-1β, and MCP-1 were markedly increased in the IgAN group (p < 0.05).ConclusionThe results of this study indicate that activation of BTK in macrophages may play an important role in promoting the progression of renal inflammation in IgAN.

Shear wave elastography accurately detects chronic changes in renal histopathology.

Renal biopsy is the gold standard for the histological characterization of chronic kidney disease (CKD), of which renal fibrosis is a dominant component, affecting its stiffness. The aim of this study was to investigate the correlation between kidney stiffness obtained by shear wave elastography (SWE) and renal histological fibrosis. Shear wave elastography assessments were performed in 75 CKD patients who underwent renal biopsy. The SWE-derived estimates of the tissue Young's modulus (YM), given as kilopascals (kPa), were measured. YM was correlated to patients' renal histological scores, broadly categorized into glomerular, tubulointerstitial and vascular scores. Young's modulus correlates significantly with tubulointerstitial score (ρ = 0.442, P < .001) and glomerular score (ρ = 0.375, P = .001). Patients with no glomerular sclerosis showed lower mean YM measurements compared to those with glomerular sclerosis. The mean YM increased as the percentage of interstitial fibrosis and tubular atrophy increased. The area under the receiver operating characteristic curve (ROC) for SWE in differentiating between mildly and moderately impaired kidneys was 0.702. Shear wave elastography accurately detects chronic renal damage resulting from glomerular sclerosis, interstitial fibrosis and tubular atrophy, using the optimal cut-off YM value of ≥5.81 kPa.

Biopsy-Controlled Non-Invasive Quantification of Collagen Type VI in Kidney Transplant Recipients: A Post-Hoc Analysis of the MECANO Trial

The PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal associations between plasma and urine PRO-C6 and proven histological changes after kidney transplantation. The current study is a post-hoc analysis of 94 participants of the MECANO trial, a 24-month prospective, multicenter, open-label, randomized, controlled trial aimed at comparing everolimus-based vs. cyclosporine-based immunosuppression. PRO-C6 was measured in plasma and urine samples collected 6 and 24 months post-transplantation. Fibrosis was evaluated in biopsies collected at the same time points by Banff interstitial fibrosis/tubular atrophy (IF/TA) scoring and collagen staining (Picro Sirius Red; PSR); inflammation was evaluated by the tubulo-interstitial inflammation score (ti-score). Linear regression analyses were performed. Six-month plasma PRO-C6 was cross-sectionally associated with IF/TA score (Std. β = 0.34), and prospectively with 24-month IF/TA score and ti-score (Std. β = 0.24 and 0.23, respectively) (p < 0.05 for all). No significant associations were found between urine PRO-C6 and any of the biopsy findings. Fibrotic changes and urine PRO-C6 behaved differentially over time according to immunosuppressive therapy. These results are a first step towards non-invasive fibrosis detection after kidney transplantation by means of collagen VI synthesis measurement, and further research is required.

The Histological Picture of Indication Biopsies in the First 2 Weeks after Kidney Transplantation.

In preclinical studies, ischemia-reperfusion injury and older donor age are associated with graft inflammation in the early phase after transplantation. In human kidney transplantation, impaired allograft function in the first days after transplantation is often adjudicated to donor- and procedure-related characteristics, such as donor age, donor type, and ischemia times. , setting, participants, & measurementsIn a cohort of 984 kidney recipients, 329 indication biopsies were performed within the first 14 days after transplantation. The histologic picture of these biopsies and its relationship with alloimmune risk factors and donor- and procedure-related characteristics were studied, as well as the association with graft failure. Multivariable Cox models were applied to quantify the cause-specific hazard ratios for early rejection and early inflammatory scores, adjusted for potential confounders. For quantification of hazard ratios of early events for death-censored graft failure, landmark analyses starting from day 15 were used. Early indication biopsy specimens displayed microvascular inflammation score ≥2 in 30% and tubulointerstitial inflammation score ≥2 in 49%. Rejection was diagnosed in 186 of 329 (57%) biopsies and associated with the presence of pretransplant donor-specific HLA antibodies and the number of HLA mismatches, but not nonimmune risk factors in multivariable Cox proportional hazards analysis. In multivariable Cox proportional hazards analysis, delayed graft function, the graft dysfunction that prompted an early indication biopsy, HLA mismatches, and pretransplant donor-specific HLA antibodies were significantly associated with a higher risk for death-censored graft failure, whereas early acute rejection was not. Indication biopsies performed early after kidney transplantation display inflammatory changes related to alloimmune risk factors. Nonimmune risk factors for ischemia-reperfusion injury, such as cold and warm ischemia time, older donor age, and donor type, were not identified as strong risk factors for early inflammation after human kidney transplantation.

Research on the Application Value of Serum and Urine β2-Microglobulin in Immunoglobulin a Nephropathy.

To compare the application value of serum and urinary β2-microglobulin in immunoglobulin A nephropathy (IgAN). Two hundred thirteen patients were hospitalized at the First Affiliated Hospital of Bengbu Medical College in China because of physical abnormalities and diagnosed with IgAN by means of renal biopsy between January 2010 and December 2018. β2-MG levels in serum and urine were detected through immunoturbidimetric methods. The renal histopathology was quantified according to Katafuchi semi-quantitative standards and Lee's grading. One hundred twenty-four patients were male and 89 cases were female, for a 1.39:1 male to female ratio. The average age was 38.25 ± 12.48 years old when patients received their first renal biopsy. The levels of serum β2-MG and urine β2-MG increased gradually with the aggravation of tubulointerstitial lesions. Results of correlation analysis showed that serum β2-MG had higher application value. Serum β2-MG levels were positively correlated with SCr and tubulointerstitial lesions (r = 0.840, 0.652, p = 0.000), negatively correlated with CG-eGFR (r = -0.680, p = 0.000). The results of multivariate logistic regression analysis showed that serum β2-MG was a marker of independent risk factor for the score of tubulointerstitial lesions ≥ 3 (OR = 6.649, p = 0.000). ROC analysis showed better diagnostic performance for serum β2-MG, with the optimal cutoffs in predicting tubulointerstitial score ≥ 1, score ≥ 4 and score ≥ 7 of 1.905 mg/L, 2.13 mg/L, and 4.49 mg/L, respectively. Serum β2-MG is valuable in evaluating renal function and pathological lesions in IgAN patients and has significant predictive value in evaluating tubulointerstitial lesions. Serum β2-MG may be used as a non-invasive diagnostic indicator for predicting renal function and tubulointerstitial lesions in IgAN.