Role of TSP-1 and its receptor ITGB3 in the renal tubulointerstitial injury of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS), a common cause of primary glomerulonephritis, has a poor prognosis and is pathologically featured by tubulointerstitial injury. Thrombospondin-1 (TSP-1) is an extracellular matrix protein that acts in combination with different receptors in the kidney. Here, we analyzed the tubular expression of TSP-1 and its receptor integrin ß3 (ITGB3) in FSGS. Previously the renal interstitial chip analysis of FSGS patients with tubular interstitial injury showed that the expressions of TSP-1 and ITGB3 were up-regulated. We found that the level of TSP-1 and ITGB3 increased in the tubular cells of FSGS patients. The serum level of TSP-1 increased and was correlated to the degree of tubulointerstitial lesions in FSGS patients. THBS1/ITGB3 signaling induced renal tubular injury in HK-2 cells exposure to BSA and the ADR-induced nephropathy model. THBS1 knockout ameliorated tubular injury and renal fibrosis in ADR-treated mice. THBS1 knockdown decreased the expression of KIM-1 and caspase 3 in the HK-2 cells treated with BSA, while THBS1 overexpression could induce tubular injury. In vivo, we identified cyclo-RGDfK as an agent to block the binding of TSP-1 to ITGB3. Cyclo-RGDfK treatment could alleviate ADR-induced renal tubular injury and interstitial fibrosis in mice. Moreover, TSP-1 and ITGB3 were colocalized in tubular cells of FSGS patients and ADR-treated mice. Taken together, our data showed that TSP-1/ITGB3 signaling contributed to the development of renal tubulointerstitial injury in FSGS, potentially identifying a new therapeutic target for FSGS.

Artificial intelligence assists identification and pathologic classification of glomerular lesions in patients with diabetic nephropathy.

BACKGROUND: Glomerular lesions are the main injuries of diabetic nephropathy (DN) and are used as a crucial index for pathologic classification. Manual quantification of these morphologic features currently used is semi-quantitative and time-consuming. Automatically quantifying glomerular morphologic features is urgently needed. METHODS: A series of convolutional neural networks (CNN) were designed to identify and classify glomerular morphologic features in DN patients. Associations of these digital features with pathologic classification and prognosis were further analyzed. RESULTS: Our CNN-based model achieved a 0.928 F1-score for global glomerulosclerosis and 0.953 F1-score for Kimmelstiel-Wilson lesion, further obtained a dice of 0.870 for the mesangial area and F1-score beyond 0.839 for three glomerular intrinsic cells. As the pathologic classes increased, mesangial cell numbers and mesangial area increased, and podocyte numbers decreased (p for all < 0.001), while endothelial cell numbers remained stable (p = 0.431). Glomeruli with Kimmelstiel-Wilson lesion showed more severe podocyte deletion compared to those without (p < 0.001). Furthermore, CNN-based classifications showed moderate agreement with pathologists-based classification, the kappa value between the CNN model 3 and pathologists reached 0.624 (ranging from 0.529 to 0.688, p < 0.001). Notably, CNN-based classifications obtained equivalent performance to pathologists-based classifications on predicting baseline and long-term renal function. CONCLUSION: Our CNN-based model is promising in assisting the identification and pathologic classification of glomerular lesions in DN patients.

Clinicopathological Characteristics of Light and Heavy Chain Deposition Disease: A Case Series.

RATIONALE & OBJECTIVE: Light and heavy chain deposition disease (LHCDD) is a rare form of monoclonal immunoglobulin (Ig) deposition disease, and limited clinical data are available characterizing this condition. Here we describe the clinicopathological characteristics and outcomes of LHCDD. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 13 patients with biopsy-proven LHCDD diagnosed between January 2008 and December 2022 at one of 2 Chinese medical centers. FINDINGS: Among the 13 patients described, 6 were men and 7 were women, with a mean age of 52.6±8.0 years. Patients presented with hypertension (76.9%), anemia (84.6%), increased serum creatinine concentrations (84.6%; median, 1.7mg/dL), proteinuria (100%; average urine protein, 3.0g/24h), nephrotic syndrome (30.8%), and microscopic hematuria (76.9%). Serum immunofixation electrophoresis showed monoclonal Ig for 11 patients (84.6%). Serum free light chain ratios were abnormal in 11 patients (84.6%), and heavy/light chain ratios were abnormal in 9 of 10 patients (90%) with available data. Five patients were diagnosed with multiple myeloma. A histological diagnosis of nodular mesangial sclerosis was made in 10 patients (76.9%). Immunofluorescence demonstrated deposits of IgG subclass in 7 patients (γ-κ, n=4; γ-λ, n=3) and IgA in 5 patients (α-κ, n=2; α-λ, n=3). Six patients underwent IgG subclass staining (γ1, n=3; γ2, n=2; γ3, n=1). The deposits of IgD-κ were confirmed by mass spectrometry in 1 patient. Among 12 patients for whom data were available during a median of 26.5 months, 11 received chemotherapy and 1 received conservative treatment. One patient died, and disease progressed to kidney failure in 3 (25%). Among the 9 patients evaluable for hematological and kidney disease progression, 5 (56%) had a hematologic response and 1 (11%) exhibited improvement in kidney disease. LIMITATIONS: Retrospective descriptive study, limited number of patients, urine protein electrophoresis or immunofixation electrophoresis test results missing for most patients. CONCLUSIONS: In this case series of LHCDD, light and heavy chain deposition in kidney tissues were most frequent with monoclonal IgG1-κ. Among patients with evaluable data, more than half had a hematologic response, but a kidney response was uncommon.

The correlation between anti-phospholipase A2 receptor antibodies and hypercoagulability in patients with idiopathic membranous nephropathy.

BACKGROUND: Patients with idiopathic membranous nephropathy (IMN) are more likely to be complicated by venous thromboembolism (VTE). The aim of the study was to investigate the potential association between anti-phospholipase A2 receptor (PLA2R) antibodies and hypercoagulability in patients with IMN. METHODS: A total of 168 patients with biopsy-proven IMN and 36 patients with biopsy-proven minimal change disease (MCD) were enrolled in this study. The clinical data, serum anti-PLA2R antibodies and coagulation-related indices of the patients were retrospectively analyzed. RESULTS: Patients with IMN were categorized into glomerular PLA2R staining-positive (GAg+) IMN group and glomerular PLA2R staining-negative (GAg-) IMN group in the study. Patients with IMN who were GAg + had lower PT, APTT and R time than patients with IMN who were GAg-, while the CI value was higher in patients with IMN who were GAg+. Patients with IMN who were GAg + were divided into the SAb+/GAg + group and the SAb-/GAg + group. Patients with IMN who were SAb+/GAg + had higher Fib and MA values than patients with IMN who were SAb-/GAg+. Correlation analysis showed that serum anti-PLA2R antibodies were positively correlated with fibrinogen, D-dimer, K time, CI value, α-angle, and MA value. Multiple linear regression analysis indicated that anti-PLA2R antibodies were independently correlated with fibrinogen and MA value. CONCLUSION: Our study provides a new perspective on the underlying mechanisms of hypercoagulability in patients with IMN. Anti-PLA2R antibodies are associated with hypercoagulability in patients with IMN and may affect coagulation in patients with IMN by affecting platelet aggregation function and fibrinogen counts.

Advancing the application of the analytical renal pathology system in allograft IgA nephropathy patients.

BACKGROUND: The analytical renal pathology system (ARPS) based on convolutional neural networks has been used successfully in native IgA nephropathy (IgAN) patients. Considering the similarity of pathologic features, we aim to evaluate the performance of the ARPS in allograft IgAN patients and broaden its implementation. METHODS: Biopsy-proven allograft IgAN patients from two different centers were enrolled for internal and external validation. We implemented the ARPS to identify glomerular lesions and intrinsic glomerular cells, and then evaluated its performance. Consistency between the ARPS and pathologists was assessed using intraclass correlation coefficients. The association of digital pathological features with clinical and pathological data was measured. Kaplan-Meier survival curve and cox proportional hazards model were applied to investigate prognosis prediction. RESULTS: A total of 56 biopsy-proven allograft IgAN patients from the internal center and 17 biopsy-proven allograft IgAN patients from the external center were enrolled in this study. The ARPS was successfully applied to identify the glomerular lesions (F1-score, 0.696-0.959) and quantify intrinsic glomerular cells (F1-score, 0.888-0.968) in allograft IgAN patients rapidly and precisely. Furthermore, the mesangial hypercellularity score was positively correlated with all mesangial metrics provided by ARPS [Spearman's correlation coefficient (r), 0.439-0.472, and all p values < 0.001]. Besides, a higher allograft survival was noticed among patients in the high-level groups of the maximum and ratio of endothelial cells, as well as the maximum and density of podocytes. CONCLUSION: We propose that the ARPS could be implemented in future clinical practice with outstanding capability.

Resveratrol relieves chronic heat stress-induced liver oxidative damage in broilers by activating the Nrf2-Keap1 signaling pathway.

Heat stress (HS) affects poultry production and welfare, causing enormous damage to poultry. Resveratrol, an antioxidant and anti-inflammatory natural plant polyphenol, is widely used in agriculture for the prevention of oxidative stress-related diseases. This study aimed to explore the effects and potential mechanism of resveratrol on liver oxidative damage in heat-stressed broilers. Sixty SPF chickens were randomly divided into control, heat stress (HS) and HS+ resveratrol (resveratrol) groups. Broilers were exposed to 35 ± 2 â„ƒ (8 h/d) for 7 consecutive days to induce HS, and the other 16 h/d were kept at 23 ± 2 â„ƒ, similar to the control group. Broilers received 400 mg/kg resveratrol in the basic diet 2 days before exposure to HS and for the following 7 days. The results showed that resveratrol improved growth performance by increasing the average daily gain (ADG) and reducing the feed conversion ratio (FCR), compared with the HS group. Heat stress reduced liver weight and index, increased inflammatory cell infiltration in the liver, enhanced serum AST levels, and decreased TP and ALB II levels, which resulted in liver injury in broilers, and resveratrol effectively alleviated liver injury. Moreover, supplementation with resveratrol enhanced the activities of liver antioxidant enzymes resulting in higher GPX and SOD levels than those in the heat-stressed broilers, and decreased MDA levels. Furthermore, resveratrol alleviated liver oxidative stress by activating the gene and protein levels of Nrf2 and HO-1, enhancing NQO1 and SOD1 gene levels, and decreasing protein levels of HSP70, p62, and Keap1, and thereby alleviated the liver injury of heat-stressed broilers. Compared with the HS group, Nrf2 immunofluorescence was significantly up-regulated in the livers of resveratrol group. These results suggest that resveratrol can enhance the liver antioxidant function by activating the Nrf2-Keap1 signaling pathway to promote growth performance in broilers under HS.

Resveratrol inhibits oxidative damage in lungs of heat-stressed broilers by activating Nrf2 signaling pathway and autophagy.

The purpose of this study was to investigate the effects of resveratrol on heat stress-induced lung injury in broilers and the mechanism underlying this process. Sixty two-week-old SPF BWEL broilers were randomly divided into the heat stress group (HS), resveratrol group (heat stress + 400 mg/kg resveratrol), and the control group after one week of feeding, with 20 chickens in each group. Broilers in the control group were reared at 23 ± 2 â„ƒ. Those in the HS and resveratrol group were reared under heat stress (35 â„ƒ ± 2 â„ƒ) for 8 h/day for seven days. Broilers in the resveratrol group were fed a diet supplemented with 400 mg/kg resveratrol two days before the start of the experiment. The feeding was continued for nine days. The results showed that HS decreased body weight (BW), average daily feed intake (ADFI), average daily gain (ADG), and lung weight. It, however, increased the lung index, induced lung congestion, and promoted infiltration of inflammatory cells to the lung. Resveratrol improved growth performance and inhibited heat stress-induced lung damage. Compared with broilers in the control group, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), Beclin-1, LC3 Ⅰ, and LC3 Ⅱ genes in the lung of heat-stressed broilers was significantly lower. The levels of kelch-like ECH-associated protein 1 (Keap1), NQO1, and HO-1 showed a similar trend with gene expressions. Immunofluorescence indicated that HS inhibited the expression of Nrf2 and LC3B proteins. Finally, the ratio of LC3 Ⅱ/LC3 Ⅰ was also significantly lower in the HS group. Further analyses revealed that resveratrol supplements in feeds enhanced antioxidation in the lung by activating the Nrf2 signaling pathway and autophagy. In conclusion, HS causes oxidative damage and inhibits autophagy in broilers. However, resveratrol protects against lung injury by alleviating oxidative stress and enhancing autophagy.

Acetaminophen-induced hepatotoxicity predominantly via inhibiting Nrf2 antioxidative pathway and activating TLR4-NF-κB-MAPK inflammatory response in mice.

To explore the action time and molecular mechanism underlying the effect of acetaminophen (APAP) on liver injury. APAP was used to establish drug-induced liver injury (DILI) model in mice. Mice in the model group were intraperitoneally injected 300 mg/kg APAP for 6, 12, and 24 h respectively, and control group mice were given the same volume of normal saline. The mice were anesthetized through intravenous injection of sodium pentobarbital at 6, 12, and 24 h after APAP poisoning. Analysis of ALT, AST and ALP in serum, liver histopathological observation, oxidative damage and western blot were performed. The livers in APAP exposed mice were pale, smaller, with a rough texture, and poorly arranged cells. Lesions, large areas of hyperemia, inflammation, swelling, poorly cell arrangement, necrosis, and apoptosis of liver cells were obvious in the liver tissue sections. Serum ALT, AST and ALP levels were significantly enhanced at 12 h of APAP adminstration mice than that of in control group mice (P＜0.05). The histopathological alterations and proinflammatory cytokines (IL-1ß, TNF-α and IL-6) levels were most severe at 12 h of APAP-induced hepatotoxicity. APAP treatment induced oxidative stress by decreasing hepatic activities of superoxide dismutase (SOD) and glutathione (GSH) (P＜0.05), and enhancing malondialdehyde (MDA) content (P＜0.05). Moreover, APAP inhibited erythroid 2-related factor 2 (Nrf2) antioxidative pathway with decreased of Nrf2 and HO-1 proteins levels. Furthermore, APAP aggravated the activation of NLRP3 inflammasome by increasing of NLRP3, caspase-1, ASC, IL-1ß and IL-18 proteins levels. Finally, APAP further significantly activated the toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. This study demonstrated that APAP-induced hepatotoxicity by inhibiting of Nrf2 antioxidative pathway and promoting TLR4-NF-κB-MAPK inflammatory response and NLRP3 inflammasome activation.

Yinhuang oral liquid protects acetaminophen-induced acute liver injury by regulating the activation of autophagy and Nrf2 signaling.

This study aimed to investigate the protective effect and potential mechanism of Yinhuang oral liquid (YOL) against acetaminophen (APAP) induced liver injury in mice. C57BL/6 mice were randomly divided into control group, model group (300 mg/kg APAP), NAC group and YOL group. Mice were treated intragastrical with YOL (8 g/kg) and N-Acetylcysteine (NAC, 300 mg/kg) 6 h before and 6 h after the APAP (300 mg/kg) intraperitoneal injection. 12 h after APAP exposure, blood and liver samples were collected for subsequent testing. The results showed that APAP decreased liver index, induced liver pathological injury with hepatocytes swelling, necrosis and apoptosis and inflammatory cell infiltration. APAP exposure significantly increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels to 35 and 6 multiples than their original levels. YOL alleviated liver pathological damage, decreased the serum levels of ALT and AST in APAP exposure mice, and it worked better than NAC. Moreover, APAP promoted oxidative stress by increasing lipid peroxidation (MDA) and decreasing anti-oxidant enzyme activities of SOD and GSH, inhibited the mRNA levels of Nrf2, HO-1, Gclc and Gclm, and decreased the protein levels of Nrf2, HO-1 and Keap1, compared to control group. Furthermore, APAP exposure significantly down-regulated the mRNA and protein levels of autophagy related genes (Beclin-1, LC3-II, LC3-I, Atg4B, Atg5, Atg16L1 and Atg7). However, the gene levels of mTOR and p-mTOR increased, and p-ULK1 protein level decreased in liver of APAP treated mice. Additionally, YOL alleviated the oxidative injury by up-regulating Nrf2 pathway. The gene and protein levels of autophagy-related genes Beclin-1, LC3-II, LC3-I, Atg4B, Atg5, Atg16L1 and Atg7 reached the basal levels after YOL treatment. In conclusion, YOL had a protective and therapeutic role in APAP-induced liver injury in mice by activating Nrf2 signaling pathway and autophagy.

Focal Segmental Glomerulosclerosis Superimposed on Transplant Glomerulopathy: Implications for Graft Survival.

INTRODUCTION: Transplant glomerulopathy (TG) is a morphological lesion resulting from chronic glomerular endothelium injury, and it is strongly associated with poor graft survival. TG coexisting with focal segmental glomerulosclerosis (FSGS) can be found in renal allograft biopsies, but few related studies are available. METHODS: Consecutive kidney transplant recipients with biopsy-proven TG were studied retrospectively. Patients concomitant with FSGS were identified and compared with those without FSGS. The influence of FSGS on allograft outcomes was assessed using univariate and multivariate Cox regression models. RESULTS: Of the 66 patients with TG, 40 (60.6%) had concomitant FSGS. TG patients with FSGS had higher proteinuria (median, 2.6 vs. 0.8 g/24 h, p < 0.001) and serum creatinine levels (median, 2.5 vs. 2.1 mg/dL, p = 0.04), lower serum albumin levels, higher chronic glomerulopathy (cg) score, larger glomerular tuft area, lower number of podocytes, and higher incidences of podocyte hyperplasia, pseudotubule formation, and diffuse foot process effacement than those without FSGS (all p < 0.05). The kidney allograft loss rate of patients with FSGS was higher than that of patients without FSGS (65.7% vs. 37.5%, p = 0.03). The presence of FSGS was independently associated with allograft loss in TG (hazard ratio (HR) = 3.42, 95% confidence interval (CI): 1.30-8.98, p = 0.01). Other independent predictors were proteinuria (HR = 1.18, 95% CI: 1.02-1.37, p = 0.02), estimated glomerular filtration rate (HR = 0.94, 95% CI: 0.91-0.97, p < 0.001), and panel reactive antibody (HR = 3.99, 95% CI: 1.14-13.99, p = 0.03). Moreover, FSGS (odds ratio (OR) = 4.39, 95% CI: 1.29-14.92, p = 0.02) and cg (OR = 5.36, 95% CI: 1.56-18.40, p = 0.01) were independent risk factors for proteinuria. CONCLUSION: In this cohort of patients with TG, the presence of FSGS was strongly associated with more severe clinicopathological features and worse allograft survival.

Identification of glomerular lesions and intrinsic glomerular cell types in kidney diseases via deep learning.

Identification of glomerular lesions and structures is a key point for pathological diagnosis, treatment instructions, and prognosis evaluation in kidney diseases. These time-consuming tasks require a more accurate and reproducible quantitative analysis method. We established derivation and validation cohorts composed of 400 Chinese patients with immunoglobulin A nephropathy (IgAN) retrospectively. Deep convolutional neural networks and biomedical image processing algorithms were implemented to locate glomeruli, identify glomerular lesions (global and segmental glomerular sclerosis, crescent, and none of the above), identify and quantify different intrinsic glomerular cells, and assess a network-based mesangial hypercellularity score in periodic acid-Schiff (PAS)-stained slides. Our framework achieved 93.1% average precision and 94.9% average recall for location of glomeruli, and a total Cohen's kappa of 0.912 [95% confidence interval (CI), 0.892-0.932] for glomerular lesion classification. The evaluation of global, segmental glomerular sclerosis, and crescents achieved Cohen's kappa values of 1.0, 0.776, 0.861, and 95% CI of (1.0, 1.0), (0.727, 0.825), (0.824, 0.898), respectively. The well-designed neural network can identify three kinds of intrinsic glomerular cells with 92.2% accuracy, surpassing the about 5-11% average accuracy of junior pathologists. Statistical interpretation shows that there was a significant difference (P value < 0.0001) between this analytic renal pathology system (ARPS) and four junior pathologists for identifying mesangial and endothelial cells, while that for podocytes was similar, with P value = 0.0602. In addition, this study indicated that the ratio of mesangial cells, endothelial cells, and podocytes within glomeruli from IgAN was 0.41:0.36:0.23, and the performance of mesangial score assessment reached a Cohen's kappa of 0.42 and 95% CI (0.18, 0.69). The proposed computer-aided diagnosis system has feasibility for quantitative analysis and auxiliary recognition of glomerular pathological features. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Prognosis of severe drug-induced acute interstitial nephritis requiring renal replacement therapy.

OBJECTIVE: Drug-induced acute interstitial nephritis (DAIN) is often associated with improved outcomes, whereas some patients may still progress to chronic kidney disease (CKD). The aim of this study was to evaluate the prognosis of patients with severe DAIN requiring renal replacement therapy (RRT) at baseline, and to explore the risk factors of progression to CKD. METHODS: We performed a retrospective study of patients with severe DAIN confirmed by renal biopsies in our center over a 10 years period, all the patients received RRT at presentation. The clinical and pathological characteristics at baseline were recorded, and the outcomes (renal function recovered or progressed to CKD) during follow-ups were also evaluated. Univariate and multivariate logistic regression analysis were performed to identify the independent risk factors of progression to CKD. RESULTS: Seventy-two patients who met the inclusion criteria were enrolled, 13 patients (18.0%) progressed to CKD (GFR < 60 ml/min/1.73 m2) after at least 6 months of follow-up, the remaining 59 patients achieved a favorable renal function recovery. Compared with patients who achieved renal function recovery (recovery group), the patients progressed to CKD (progression group) were older and had longer interval from symptom onset to treatment with steroids. The peak serum cystatin C concentration was higher in progression group than recovery group. Higher score of interstitial fibrosis/tubular atrophy (IFTA) and more interstitial inflammatory cells infiltration were detected in renal tissue in progression group. According to multivariable analysis, higher peak cystatin C concentration (OR = 2.443, 95% CI 1.257, 4.746, p = 0.008), longer interval to treatment with corticosteroids (OR = 1.183, 95% CI 1.035, 1.352, p = 0.014) were independent risk factors of progression to CKD. The cutoff value of cystatin C concentration was 4.34 mg/L, at which the sensitivity and specificity were 76.9% and 89.3%, respectively; the cutoff value of interval to treatment with corticosteroids was 22.5 days, at which the sensitivity and specificity were 81.8% and 79.5%, respectively. CONCLUSION: Renal function was reversible in majority of patients with severe DAIN requiring RRT when early identification and treatment. Higher peak cystatin C concentration and longer interval to treatment with corticosteroids associated with worse renal prognosis.

Heavy Chain Deposition Disease: Clinicopathologic Characteristics of a Chinese Case Series.

RATIONALE & OBJECTIVE: Heavy chain deposition disease (HCDD) is a rare consequence of monoclonal immunoglobulin deposition disease that has not been well characterized in non-white populations. To explore the clinicopathologic characteristics and outcomes of HCDD in Chinese individuals, we report on a case series assembled in a single center in China. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 25 patients with biopsy-proven HCDD were studied retrospectively. RESULTS: 14 men and 11 women with an average age of 50.3 years were studied. The patients presented with hypertension (76%), edema (96%), anemia (84%), serum creatinine level > 1.2mg/dL (68%), nephrotic-range proteinuria (56%), and microscopic hematuria (80%). One (4%) patient had multiple myeloma diagnosed. Serum immunofixation electrophoresis showed that 10 of 21 (48%) patients were positive for monoclonal immunoglobulin. Hypocomplementemia of C3 was found in 68% of patients. Nodular mesangial sclerosis was identified in all patients by using light microscopy. Using immunofluorescence, all 25 patients had deposition of heavy chains of immunoglobulin G class (γ1, 13; γ2, 2; γ3, 6; γ4, 2; γ1 and γ4, 1; and γ2 and γ4, 1). During an average of 40.1 months of follow-up of 20 patients, 65% had improved kidney function, 10% had worsening kidney function, and 25% progressed to kidney failure. Mean values for kidney and patient survival were 37.8 and 40.1 months, respectively. Kidney survival was higher among patients who received chemotherapy. LIMITATIONS: Retrospective study, single-center experience. CONCLUSIONS: In this case series of HCDD in a single center in China, the heavy chain deposits seen in the kidney biopies of all individuals were of immunoglobulin G class. Chemotherapy improved kidney function, especially among individuals in an early stage of the disease.

Comparison of secondary IgA nephropathy in patients with ankylosing spondylitis and rheumatoid arthritis.

Objectives: The aim of the present study was to investigate the differences in clinic-pathological features of secondary IgA nephropathy (SIgAN) between patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA).Methods: Forty-six patients with SIgAN related to AS (SIgAN-AS) and 26 patients with SIgAN related to RA (SIgAN-RA) were enrolled in this retrospective study. The two groups were compared for their clinic-pathological characteristics.Results: The 10-year prevalence of SIgAN-AS and SIgAN-RA were 167 per 1000 and 51.3 per 1000, respectively. Compared with SIgAN-RA patients, SIgAN-AS patients had lower incidences of edema and nephrotic syndrome, but higher levels of eGFR, serum C3, and CD3- and CD8-positive T-cell counts, but less incidences of acute tubulointerstitial lesions and interlobular arterial lesions. IgM was the most familiar co-depositing immune complex on tissue with significantly different frequencies. In SIgAN-AS patients, those with positive HLA-B27 presented with lower levels of proteinuria, higher levels of serum IgG and C3, and less incidence of renal insufficiency, crescents >14.5%, glomerular sclerosis >32.6% and segmental sclerosis >5.2%.Conclusion: SIgAN was more prevalent in AS than in RA. SIgAN-AS patients differed from SIgAN-RA patients in certain clinic-pathological characteristics. HLA-B27 likely protected SIgAN-AS patients from renal insufficiency.

Prediction and Risk Stratification of Kidney Outcomes in IgA Nephropathy.

RATIONALE & OBJECTIVE: Immunoglobulin A nephropathy (IgAN) is common worldwide and has heterogeneous phenotypes. Predicting long-term outcomes and stratifying risk are important for clinical decision making and designing future clinical trials. STUDY DESIGN: Multicenter retrospective cohort study of 2,047 patients with IgAN. SETTING & PARTICIPANTS: Derivation and validation cohorts composed of 1,022 Chinese patients with IgAN from a single center and 1,025 patients with IgAN from 18 renal centers, respectively. PREDICTORS: 36 characteristics, including demographic, clinical, and pathologic variables. OUTCOMES: Combined event of end-stage kidney disease or 50% reduction in estimated glomerular filtration rate within 5 years after diagnostic kidney biopsy. ANALYTICAL APPROACH: A gradient tree boosting method implemented in the eXtreme Gradient Boosting (XGBoost) system was used to select the 10 most important variables from 36 candidate variables. Stepwise Cox regression analysis was used to derive a simplified scoring scale model (SSM) based on these 10 variables. Model discrimination and calibration were assessed using the C statistic and Hosmer-Lemeshow test. Risk stratification of the SSM was evaluated using Kaplan-Meier analysis. RESULTS: In the derivation and validation cohorts, 74 and 114 patients reached the outcome, respectively. XGBoost predicted the outcome with a C statistic of 0.84 (95% CI, 0.80-0.88) for the validation cohort. The SSM included 3 variables: urine protein excretion, global sclerosis, and tubular atrophy/interstitial fibrosis. Using Kaplan-Meier analysis, the SSM identified significant risk stratification (P < 0.001). LIMITATIONS: Retrospective study design, application for other ethnic groups needs to be verified. CONCLUSIONS: A prediction model using routinely available characteristics and based on the combination of a machine learning algorithm and survival analysis can stratify risk for kidney disease progression in the setting of IgAN. An online calculator, the Nanjing IgAN Risk Stratification System, permits easy implementation of this model.

The clinical and pathological features of adefovir dipivoxil-related renal impairment
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AIMS: To investigate the clinicopathological features and outcomes of adefovir dipivoxil (ADV)-related renal impairment in Chinese patients. MATERIALS AND METHODS: Clinical, pathological, and follow-up data from 15 patients with ADV-related renal impairment were studied. Proximal renal tubular dysfunction (PRTD) was defined by the presence of at least two of the following four abnormalities: hypophosphatemia, hypouricemia, nondiabetic glucosuria, and proteinuria. RESULTS: All patients were treated for 3 - 15 (mean 6.7) years with daily ADV of 10 mg. Renal impairment manifested as PRTD (12, 80%), elevated serum creatinine (12, 80%), and hematuria (2, 13.3%). Mild to moderate tubulointerstitial injury primarily affecting the proximal tubules by light microscopy, and enlarged, dysmorphic mitochondria with loss and disorientation of cristae by electron microscope were identified in all of our cases. Four patients had pathological evidence of IgA nephropathy. The phosphorus, serum uric acid, and creatinine levels were normalized after ADV cessation in 66.7% (8/12) of affected patients, 27.3% (3/11) of affected patients, and 25% (3/12) of affected patients, respectively; proteinuria was eliminated in 7 of 13 affected patients (53.8%); and glucosuria and hematuria both disappeared in all affected patients. These abnormalities had hardly any recovery, and even aggravated with new-onset glucosuria, new-onset hematuria in 3 patients who replaced ADV with tenofovir. CONCLUSION: Nephrotoxicity developed in patients undergoing long-term ADV treatment and was partially reversible after drug cessation. Tubulointerstitial lesions and heteromorphic mitochondria were the predominant pathological changes. Patients with ADV-induced renal impairment should replace ADV with other antiviral agents other than tenofovir.
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Urinary miR-196a predicts disease progression in patients with chronic kidney disease.

BACKGROUND: Urinary miRNAs may potentially serve as noninvasive biomarkers in various kidney diseases to reflect disease activity, severity and progression, especially those correlated with the pathogenesis of kidney diseases. This study demonstrates that urinary miR-196a, a kidney-enriched miRNA, can predict progression of chronic kidney disease (CKD). METHODS: Focal segmental glomerulosclerosis (FSGS) cohorts were used as the representative example of CKD. First, correlation of miR-196a with disease activity was analyzed using paired urine and plasma samples from FSGS patients with nephrotic-range proteinuria (FSGS-A), complete remission (FSGS-CR) and normal controls (NCs). Then, the value of urinary miR-196a in predicting disease progression was validated using another cohort of 231 FSGS patients who were followed-up until over 36 months or reaching end-stage renal disease (ESRD). MiR-196a levels were analyzed by quantitative reverse transcription-polymerase chain reaction. RESULTS: The results showed that urinary miR-196a significantly increased in FSGS-A compared with FSGS-CR and NCs, clearly distinguishing FSGS-A from FSGS-CR and NCs, whereas plasma miR-196a showed no difference among these groups. Moreover, urinary miR-196a, which was associated with proteinuria, estimated glomerular filtration rate (eGFR), interstitial fibrosis and tubular atrophy, significantly increased in patients progressed to ESRD compared to those not. Furthermore, patients with higher urinary miR-196a displayed poorer renal survival than those with lower urinary miR-196a. Multivariate Cox analysis confirmed urinary miR-196a as an independent risk factor for FSGS progression after adjusting for age, sex, proteinuria and eGFR. Prediction accuracy of ESRD was significantly improved by combining urinary miR-196a with other indicators including eGFR and proteinuria. CONCLUSION: Urinary miR-196a may serve as a biomarker for predicting CKD progression.

Clinic-Pathologic Features and Renal Outcome of Fabry Disease: Data from a Chinese Cohort.

BACKGROUND: Fabry disease (FD) with life-threatening complications occurs as a result of organ damage in kidneys, heart, and brain. Only a few studies, especially from Asia, report their long-term outcome. METHODS: In this monocentric study, patients with Fabry nephropathy confirmed by renal biopsy were clinically investigated in a comprehensive manner. The clinic-pathological features, progression, and risk factors for the outcome were analyzed. RESULTS: Thirty-one patients were recruited, after median 62 months (range 8-156 months) follow-up, 23 of them had stable renal function while 8 underwent renal function deterioration. Frequent presenting symptoms included acroparesthesia (58.1%), edema (51.6%), hypo- or anhidrosis (38.7%), and angiokeratoma (32.3%). Left ventricular hypertrophy was present in 62.5% patients with renal function deterioration and 17.4% patients with stable renal function (p = 0.03). The renal cumulative survival rate of all patients was 64.5% in 10 years. Mainz Severity Score Index (MSSI) and segmental sclerosis are independent predictive factors for a more rapid progression of Fabry nephropathy. The receiver operating characteristic analysis demonstrated that the area under the curve for the prediction of renal function progression on the basis of MSSI and segmental sclerosis levels in patients with FD was 0.845 and 0.780, respectively. MSSI score ≥18 or segmental sclerosis ≥3.9% in patients with FD positively correlated with poor renal prognosis. CONCLUSIONS: FD's clinical manifestations are heterogeneous and nonspecific. The -10-year cumulative renal survival rate was low in Chinese patients. MSSI score and segmental sclerosis levels predict the renal prognosis of patients with FD sensitively.

Clinicopathologic characteristics of light chain proximal tubulopathy with light chain inclusions involving multiple renal cell types
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Light chain proximal tubulopathy (LCPT) associated with plasma cell dyscrasias is a rare abnormality, especially cases involving multiple cell types. The aim of this study is to explore the characteristics and outcomes of these diseases. We comprehensively evaluated the clinical-pathological data, treatment, and outcomes of 6 LCPT patients with involvement of multiple cell types. In 3 cases, we found that the inclusions largely existed in tubular cells, while in 2 cases they coexisted in podocytes and tubular cells, and in 1 case they coexisted in histiocytes and tubular cells. The stain features and appearances of inclusions were specific and varied. Five patients displayed κ-light chains with crystal formation, while 1 patient displayed a λ subtype with increased lysosomes instead of crystals. Six patients presented with proteinuria, 4 with renal insufficiency, and 4 with complete or partial Fanconi syndrome. Our findings indicate that tubular cells are the most common location of cytoplasmic inclusions. Cases with κ-light chain storage are more common than λ, and the formation of crystals may be associated with the subtype of light chains. Immunoelectron microscopy could be used to increase sensitivity for the detection and location of monoclonal light chains. Therefore, these patients have some common clinical features with varied pathologic characteristics and prognoses but the same subtype of light chains.
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HLA-DRB1*15:01 and HLA-DRB3*02:02 in PLA2R-Related Membranous Nephropathy.

Idiopathic membranous nephropathy (MN) is associated with HLA; however, the HLA allele involved remains unknown. To identify the HLA risk alleles associated with phospholipase A2 receptor (PLA2R)-related MN in the Chinese population, we sequenced the entire MHC region in DNA samples from 99 patients with PLA2R-related MN, 50 patients with PLA2R-unrelated MN, and 100 healthy subjects. Two HLA risk alleles, HLA-DRB1*15:01 and HLA-DRB3*02:02, independently and strongly associated with an increased risk of PLA2R-related MN. After adjusting for HLA-DRB1*15:01 and HLA-DRB3*02:02, no other alleles showed significant association with PLA2R-related MN. A replication study in an independent cohort of 293 participants with PLA2R-related MN and 285 healthy controls validated these findings. In a joint analysis, a multivariate logistic regression model confirmed that HLA-DRB1*15:01 (odds ratio [OR], 24.9; 95% confidence interval [95% CI], 15.3 to 42.6; P=2.3×10-35) and HLA-DRB3*02:02 (OR, 17.7; 95% CI, 11.0 to 30.3; P=8.0×10-29) independently and strongly associated with PLA2R-related MN. As many as 98.7% of patients with PLA2R-related MN, compared with 43.9% of control subjects, carried at least one HLA risk allele. Subjects with either risk allele had higher odds of developing PLA2R-related MN than those without a risk allele (OR, 98.9; 95% CI, 44.4 to 281.7; P=2.5×10-23). These HLA risk alleles also associated with the age at disease onset in patients with PLA2R-related MN. In conclusion, our findings provide clear evidence that the HLA-DRB1*15:01 and HLA-DRB3*02:02 alleles independently and strongly associate with PLA2R-related MN in the Chinese population.