Depleting profibrotic macrophages using bioactivated in vivo assembly peptides ameliorates kidney fibrosis.

Managing renal fibrosis is challenging owing to the complex cell signaling redundancy in diseased kidneys. Renal fibrosis involves an immune response dominated by macrophages, which activates myofibroblasts in fibrotic niches. However, macrophages exhibit high heterogeneity, hindering their potential as therapeutic cell targets. Herein, we aimed to eliminate specific macrophage subsets that drive the profibrotic immune response in the kidney both temporally and spatially. We identified the major profibrotic macrophage subset (Fn1+Spp1+Arg1+) in the kidney and then constructed a 12-mer glycopeptide that was designated as bioactivated in vivo assembly PK (BIVA-PK) to deplete these cells. BIVA-PK specifically binds to and is internalized by profibrotic macrophages. By inducing macrophage cell death, BIVA-PK reshaped the renal microenvironment and suppressed profibrotic immune responses. The robust efficacy of BIVA-PK in ameliorating renal fibrosis and preserving kidney function highlights the value of targeting macrophage subsets as a potential therapy for patients with CKD.

The relationship between diabetic retinopathy and diabetic nephropathy in type 2 diabetes.

Context: Diabetic retinopathy (DR) and diabetic nephropathy (DN), are major microvascular complications of diabetes. DR is an important predictor of DN, but the relationship between the severity of DR and the pathological severity of diabetic glomerulopathy remains unclear. Objective: To investigate the relationship between severity of diabetic retinopathy (DR) and histological changes and clinical indicators of diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM). Methods: Patients with T2DM (n=272) who underwent a renal biopsy were eligible. Severity of DR was classified as non-diabetic retinopathy, non-proliferative retinopathy, and proliferative retinopathy (PDR). Relationship between DN and DR and the diagnostic efficacy of DR for DN were explored. Results: DN had a higher prevalence of DR (86.4%) and DR was more severe. The sensitivity and specificity of DR in DN were 86.4% and 78.8%, while PDR was 26.4% and 98.5%, respectively. In DN patients, the severity of glomerular lesions (p=0.001) and prevalence of KW nodules (p<0.001) significantly increased with increasing severity of DR. The presence of KW nodules, lower hemoglobin levels, and younger age were independent risk factors associated with more severe DR in patients with DN. Conclusion: DR was a good predictor of DN. In DN patients, the severity of DR was associated with glomerular injury, and presence of KW nodules, lower hemoglobin levels and younger age were independent risk factors associated with more severe DR. Trial registration: ClinicalTrails.gov, NCT03865914.

The Effect and Mechanism of Fufang Banbianlian Injection in the Treatment of Mesangial Proliferative Glomerulonephritis.

OBJECTIVE: Mesangial proliferative glomerulonephritis (MsPGN) is an important cause of chronic kidney disease. Abnormal proliferation of mesangial cells and immune-inflammatory response are its important pathological manifestations. Currently, there is no ideal treatment for this disease. Fufang Banbianlian Injection (FBI) has anti-inflammatory, antioxidant, and immuneenhancing effects, and is mostly used for the treatment of bronchitis, pneumonia, and respiratory tract infections in children. METHODS: A rat model of MsPGN was established and treated with FBI. The efficacy was tested through pathological experiments and urine protein quantification. Network pharmacology methods were used to predict the signaling pathways and key proteins that exert the efficacy of FBI, and were screened through molecular docking experiments. The active substances that work were verified through cell experiments. RESULTS: The results confirmed that intervention with FBI can inhibit the proliferation of glomerular cells and reduce the infiltration of macrophages, thereby reducing the pathological damage of rats with mesangial proliferative nephritis; it has been found to have an obvious therapeutic effect. Molecular docking results have shown kaempferol (Kae), the main component of FBI, to have a good affinity for key targets. The results of in vitro verification experiments showed that FBI and its active ingredient Kae may play a therapeutic role by regulating the NF-κB signaling pathway in mesangial cells, inhibiting its activation and the secretion of proinflammatory cytokines. CONCLUSION: Through network pharmacology, molecular docking, and experimental verification, it was confirmed that FBI and its active ingredient Kae can reduce the molecular mechanism of pathological damage of MsPGN by regulating the NF-κB signaling pathway and providing potential therapeutic drugs for the treatment of this disease.

Pyruvate kinase M2 regulates kidney fibrosis through pericyte glycolysis during the progression from acute kidney injury to chronic kidney disease.

We aimed to investigate the role of renal pericyte pyruvate kinase M2 (PKM2) in the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). The role of PKM2 in renal pericyte-myofibroblast transdifferentiation was investigated in an AKI-CKD mouse model. Platelet growth factor receptor beta (PDGFRß)-iCreERT2; tdTomato mice were used for renal pericyte tracing. Western blotting and immunofluorescence staining were used to examine protein expression. An 5-ethynyl-2'-deoxyuridine assay was used to measure renal pericyte proliferation. A scratch cell migration assay was used to analyse cell migration. Seahorse experiments were used to examine glycolytic rates. Enzyme-linked immunoassay was used to measure pyruvate kinase enzymatic activity and lactate concentrations. The PKM2 nuclear translocation inhibitors Shikonin and TEPP-46 were used to alter pericyte transdifferentiation. In AKI-CKD, renal pericytes proliferated and transdifferentiated into myofibroblasts and PKM2 is highly expressed in renal pericytes. Shikonin and TEPP-46 inhibited pericyte proliferation, migration, and pericyte-myofibroblast transdifferentiation by reducing nuclear PKM2 entry. In the nucleus, PKM2 promoted downstream lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1) transcription, which are critical for glycolysis. Therefore, PKM2 regulates pericyte glycolytic and lactate production, which regulates renal pericyte-myofibroblast transdifferentiation. PKM2-regulated renal pericyte-myofibroblast transdifferentiation by regulating downstream LDHA and GLUT1 transcription and lactate production. Reducing nuclear PKM2 import can reduce renal pericytes-myofibroblasts transdifferentiation, providing new ideas for AKI-CKD treatment.

Serum levels of sonic hedgehog in patients with IgA nephropathy are closely associated with intrarenal arteriolar lesions.

BACKGROUND: Intrarenal arteriolar disease is a major risk factor for poor prognosis in immunoglobulin A nephropathy (IgAN). The morphologic factor sonic hedgehog (SHH) plays an important role in a variety of vascular diseases, so it may be directly or indirectly involved in the process of renal arteriolar disease. The purpose of this study was to investigate the correlation between serum SHH levels and renal arteriole disease in patients with IgAN. METHODS: Subjects with primary IgAN diagnosed by renal biopsy performed between October 2018 and August 2019 at the First Medical Center of the Chinese PLA General Hospital were recruited. Blood specimens were collected from the patients within 1 week before renal biopsy after they signed an informed consent form, and healthy controls were recruited for blood specimen collection during the same period. The concentration of serum SHH was measured by enzyme-linked immunosorbent assay in this population. RESULTS: Serum SHH levels were significantly lower in the IgAN group than in the control group. 41 of the 94 subjects diagnosed with IgAN had severe renal arteriolosclerosis and, compared to their less severely affected counterparts, were older, more hypertensive, and characterized by lower levels of SHH, higher levels of tubular atrophy/interstitial fibrosis and a higher Lee's classification. Serum SHH concentration was found to be an independent predictor of severe intrarenal arteriolosclerosis in IgAN subjects after correction using multivariate analysis. CONCLUSION: In this study, serum SHH levels were found to be significantly lower in patients with IgAN than in healthy subjects. Serum SHH may serve as a noninvasive biomarker of intrarenal arteriolosclerosis in patients with IgAN.

The therapeutic effect of Shenhua tablet against mesangial cell proliferation and renal inflammation in mesangial proliferative glomerulonephritis.

Shenhua tablet (SH), a formulation of traditional Chinese medicine, exerts renoprotective effect on chronic kidney diseases, and it has been found to restrain inflammation, but the mechanism is still unclear. Here, we explored the potential renoprotection of SH in mesangial proliferative glomerulonephritis (MsPGN) rat model induced by anti-Thy1 antibody. Administration of SH reduced urinary albumin/creatinine ratio (UACR) and significantly attenuated mesangial cell proliferation and renal inflammation. Notably, SH protected rats against renal inflammation, which was associated with decreasing macrophage infiltration and promoting macrophage anti-inflammatory activity. Network analysis combined with arrays identified the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway as the main pathways of SH could target inflammation. Furthermore, it was confirmed that mesangial cell proliferation, which response to inflammation, were alleviated by ASS1 expression enhanced after SH administration both in vivo and in vitro. Collectively, SH has the beneficial on relieving the progression of MsPGN to alleviate inflammation and mesangial proliferation by inhibiting STAT3 phosphorylation and maintains the expression level of ASS1, might be an effective strategy for treating MsPGN.

14-3-3ζ inhibits maladaptive repair in renal tubules by regulating YAP and reduces renal interstitial fibrosis.

Acute kidney injury (AKI) refers to a group of common clinical syndromes characterized by acute renal dysfunction, which may lead to chronic kidney disease (CKD), and this process is called the AKI-CKD transition. The transcriptional coactivator YAP can promote the AKI-CKD transition by regulating the expression of profibrotic factors, and 14-3-3 protein zeta (14-3-3ζ), an important regulatory protein of YAP, may prevent the AKI-CKD transition. We established an AKI-CKD model in mice by unilateral renal ischemia-reperfusion injury and overexpressed 14-3-3ζ in mice using a fluid dynamics-based gene transfection technique. We also overexpressed and knocked down 14-3-3ζ in vitro. In AKI-CKD model mice, 14-3-3ζ expression was significantly increased at the AKI stage. During the development of chronic disease, the expression of 14-3-3ζ tended to decrease, whereas active YAP was consistently overexpressed. In vitro, we found that 14-3-3ζ can combine with YAP, promote the phosphorylation of YAP, inhibit YAP nuclear translocation, and reduce the expression of fibrosis-related proteins. In an in vivo intervention experiment, we found that the overexpression of 14-3-3ζ slowed the process of renal fibrosis in a mouse model of AKI-CKD. These findings suggest that 14-3-3ζ can affect the expression of fibrosis-related proteins by regulating YAP, inhibit the maladaptive repair of renal tubular epithelial cells, and prevent the AKI-CKD transition.

Renal primary cilia lengthen in the progression of diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, and its early pathogenesis is critical. Shear stress caused by glomerular hyperfiltration contributes to the initiation of kidney injury in diabetes. The primary cilium of renal tubular epithelial cells (RTECs) is an important mechanical force sensor of shear stress and regulates energy metabolism homeostasis in RTECs to ensure energy supply for reabsorption functions, but little is known about the alterations in the renal cilium number and length during the progression of DKD. Here, we demonstrate that aberrant ciliogenesis and dramatic increase in the cilium length, the number of ciliated cells, and the length of cilia are positively correlated with the DKD class in the kidney biopsies of DKD patients by super-resolution imaging and appropriate statical analysis methods. This finding was further confirmed in STZ-induced or db/db diabetic mice. These results suggest that the number and length of renal cilia may be clinically relevant indicators and that cilia will be attractive therapeutic targets for DKD.

Clinicopathological features and short outcomes of oliguric acute tubular injury.

PURPOSE: To explore the clinicopathological features and analyze the relevant risk factors and short-term renal outcomes of acute tubular injury (ATI) patients. MATERIALS AND METHODS: A total of 83 patients with biopsy-proven ATI were included in this retrospective cohort study. Clinical characteristic and histological feature data were collected, and renal recovery at 1 month postbiopsy was recorded. RESULTS: The severity of renal dysfunction, percentage of acute tubular lesions, interstitial inflammation and fibrosis of oliguric ATI patients were all significantly higher than those of nonoliguric patients. In the subgroup analysis of the oliguric patients, the serum creatinine and urinary microalbumin levels, severity of epithelial cell degeneration and cast formation of patients in the polyuric phase at biopsy were significantly lower than those of patients in the oliguric phase. A total of 59 patients had 1-month follow-up records, and complete renal recovery was observed in 42 patients. In the multivariate analysis, the total acute tubular injury area at biopsy was the most important independent risk factor for poor renal outcomes. CONCLUSIONS: Oliguric ATI patients had severe clinicopathological conditions. The severity of tubular lesions seriously influenced renal function recovery, demonstrating the importance of renal biopsy in assessing the prognosis of patients with kidney disease.

Single Cell Dissection of Epithelial-Immune Cellular Interplay in Acute Kidney Injury Microenvironment.

Background: Understanding the acute kidney injury (AKI) microenvironment changes and the complex cellular interaction is essential to elucidate the mechanisms and develop new targeted therapies for AKI. Methods: We employed unbiased single-cell RNA sequencing to systematically resolve the cellular atlas of kidney tissue samples from mice at 1, 2 and 3 days after ischemia-reperfusion AKI and healthy control. The single-cell transcriptome findings were validated using multiplex immunostaining, western blotting, and functional experiments. Results: We constructed a systematic single-cell transcriptome atlas covering different AKI timepoints with immune cell infiltration increasing with AKI progression. Three new proximal tubule cells (PTCs) subtypes (PTC-S1-new/PTC-S2-new/PTC-S3-new) were identified, with upregulation of injury and repair-regulated signatures such as Sox9, Vcam1, Egr1, and Klf6 while with downregulation of metabolism. PTC-S1-new exhibited pro-inflammatory and pro-fibrotic signature compared to normal PTC, and trajectory analysis revealed that proliferating PTCs were the precursor cell of PTC-S1-new, and part of PTC-S1-new cells may turn into PTC-injured and then become fibrotic. Cellular interaction analysis revealed that PTC-S1-new and PTC-injured interacted closely with infiltrating immune cells through CXCL and TNF signaling pathways. Immunostaining validated that injured PTCs expressed a high level of TNFRSF1A and Kim-1, and functional experiments revealed that the exogenous addition of TNF-α promoted kidney inflammation, dramatic injury, and specific depletion of TNFRSF1A would abrogate the injury. Conclusions: The single-cell profiling of AKI microenvironment provides new insight for the deep understanding of molecular changes of AKI, and elucidates the mechanisms and developing new targeted therapies for AKI.

Role of NOD-Like Receptors in a Miniature Pig Model of Diabetic Renal Injuries.

Activation of NOD-like receptor (NLR) signaling pathway can promote downstream cytokine and proinflammatory cytokines release, and inflammation induced by excess nutrients leads to renal metabolic injury. How the NLRs influence metabolic progress and then lead to the renal injury remains poorly investigated. Compared with rodents, minipigs are more similar to humans and are more ideal animal models for human disease research. In this study, we established a diabetic minipig model through a high-sugar and high-fat diet combined with streptozotocin (STZ) injection. Blood biological markers and renal pathological markers, expression of NLRP subfamily members (NLRP1 and NLRP3) and their downstream cytokines (precursors of IL-1ß and IL-18 and mature forms of IL-1ß and IL-18), expression of NLRC subfamily members (NLRC1, NLRC2, and NLRC5) and their downstream nuclear factor-κB (NF-κB) signaling pathway molecules (IKKß, IκBα, and NF-κB p65), and inflammatory cytokines (TNF-α and interleukin-6 (IL-6)) were systematically evaluated. The expression of NLRP3 and its downstream cytokine signaling molecules, the precursors of IL-1ß and IL-18, and the mature forms of IL-1ß and IL-18 was significantly upregulated. The expression levels of NLRC1, NLRC2, and NLRC5 and activation of the downstream NF-κB pathway molecules phospho-IKKß, phospho-IκBα, NF-κB p65, and phospho-NF-κB p65 were significantly increased. The TNF-α and IL-6 levels were significantly increased in diabetic pig kidneys. The TGF-ß/Smad signaling molecules, TGF-ß and P-SMAD2/3, were also increased. These results suggested that the metabolic inflammation activated by NLRs might play an important role in diabetic renal injuries.

A Study on Correlation between Contrast-Enhanced Ultrasound Parameters and Pathological Features of Diabetic Nephropathy.

The objective of this study was to evaluate the correlation between contrast-enhanced ultrasound (CEUS) parameters and histopathological features in patients with diabetic nephropathy (DN). Sixty-two patients with DN (44 men, mean age: 52.61 ± 10.63 y) were enrolled. They underwent renal biopsy for DN at the Department of Ultrasound, PLA Hospital, between May 2017 and February 2020. Renal tissue was obtained by ultrasound-guided percutaneous needle biopsy. CEUS was performed, and time-intensity curves (TICs) and renal perfusion parameters were analyzed. Differences in CEUS parameters were analyzed according to the glomerular classification and interstitial fibrosis-tubular atrophy (IFTA) score. Continuous variables were evaluated using the analysis of variance or Mann-Whitney U-test. Discontinuous variables were compared with the χ2-test. Spearman correlation analyses evaluated associations among quantitative ultrasound perfusion parameters and histopathological characteristics. Peak enhancement (PE), wash-in rate (WiR), wash-in perfusion index (WiPI) and wash-out rate (WoR) of the cortex, and their cortex/medulla ratios, decreased with increasing glomerular classification grade (p < 0.05). The fall time (FT) of the cortex, and their cortex/medulla ratios, increased with increasing glomerular classification grade (p < 0.05). There were no significant differences in the CEUS parameters for different IFTA scores. The perfusion volume-relevant parameters (such as PE, WiR and WiPI) had a negative correlation (p < 0.05), while the perfusion time-relevant parameters (such as RT and FT) had a positive correlation (p < 0.05), with the severity of glomerular lesions, glomerulosclerosis rate and number of Kimmelstiel-Wilson lesions. The CEUS parameters of the cortex could reflect pathological characteristics, especially changes in glomerular lesions.

Multi-Task Learning-Based Immunofluorescence Classification of Kidney Disease.

Chronic kidney disease is one of the most important causes of mortality worldwide, but a shortage of nephrology pathologists has led to delays or errors in its diagnosis and treatment. Immunofluorescence (IF) images of patients with IgA nephropathy (IgAN), membranous nephropathy (MN), diabetic nephropathy (DN), and lupus nephritis (LN) were obtained from the General Hospital of Chinese PLA. The data were divided into training and test data. To simulate the inaccurate focus of the fluorescence microscope, the Gaussian method was employed to blur the IF images. We proposed a novel multi-task learning (MTL) method for image quality assessment, de-blurring, and disease classification tasks. A total of 1608 patients' IF images were included-1289 in the training set and 319 in the test set. For non-blurred IF images, the classification accuracy of the test set was 0.97, with an AUC of 1.000. For blurred IF images, the proposed MTL method had a higher accuracy (0.94 vs. 0.93, p < 0.01) and higher AUC (0.993 vs. 0.986) than the common MTL method. The novel MTL method not only diagnosed four types of kidney diseases through blurred IF images but also showed good performance in two auxiliary tasks: image quality assessment and de-blurring.

[Value of Contrast-enhanced Ultrasound Parameters in Evaluating K-W Nodule Formation in Diabetic Nephropathy].

Objective To discuss the value of contrast-enhanced ultrasound(CEUS)parameters in evaluating the formation of Kimmelstiel-Wilson(K-W)nodules in diabetic nephropathy(DN).Methods Sixty-two patients pathologically diagnosed with DN and undergoing CEUS in the First Medical Center of Chinese PLA General Hospital from March 2017 to January 2020 were assigned into two groups according to whether K-W nodules were formed.The cortical CEUS parameters and the ratios of cortical to medullary CEUS parameters were compared between the two groups.Results The 62 patients included 19 patients without K-W nodules(group A)and 43 patients with K-W nodules(group B).The median rise time(U=209,P=0.013)and fall time(U=197,P=0.007)in group B were significantly longer than those in group A.The median wash-in rate(WiR)(U=228,P=0.031)and wash-out rate(WoR)(U=229,P=0.032)in group B were significantly lower than those in group A.The median peak enhancement(PE)1/PE2(U=224,P=0.026),WiR1/WiR2(U=235,P=0.041),and WoR1/WoR2(U=230,P=0.043)ratios in group B were significantly lower than those in group A.The median FT1/FT2 ratio in group B was significantly higher than that in group A(U=227,P=0.038).Conclusion CEUS parameters can be used to quantitatively evaluate renal cortical microperfusion in DN patients with K-W nodules.

Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway.

Cardiorenal syndrome type 3 (CRS-3) is damage to the heart following acute kidney injury (AKI). Although many experiments have found that inflammation, oxidative stress, and cardiomyocyte death are involved in cardiomyocyte pathophysiological alterations during CRS-3, they lack a non-bias analysis to figure out the primary mediator of cardiac dysfunction. Herein proteomic analysis was operated in CRS-3 and growth factor receptor-bound protein 2 (Grb2) was identified as a regulator involving AKI-related myocardial damage. Increased Grb2 was associated with cardiac diastolic dysfunction and mitochondrial bioenergetics impairment; these pathological changes could be reversed through the administration of a Grb2-specific inhibitor during AKI. Molecular investigation illustrated that augmented Grb2 promoted cardiomyocyte mitochondrial metabolism disorder through inhibiting the Akt/mTOR signaling pathway. Besides that, Mouse Inflammation Array Q1 further identified IL-6 as the upstream stimulator of Grb2 upregulation after AKI. Exogenous administration of IL-6 induced cardiomyocyte damage and mitochondrial bioenergetics impairment, whereas these effects were nullified in cardiomyocytes pretreated with Grb2 inhibitor. Our results altogether identify CRS-3 to be caused by the upregulations of IL-6/Grb2 which contribute to cardiac dysfunction through inhibiting the Akt/mTOR signaling pathway and inducing cardiomyocyte mitochondrial bioenergetics impairment. This finding provides a potential target for the clinical treatment of patients with CRS-3.

GLA missense and promoter variants co-segregating in a Chinese family with Fabry disease.

BACKGROUND: Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder due to mutations in the GLA gene leading to deficiency of lysosomal α-galactosidase A (α-Gal A) and has a wide range of clinical presentations. Over 900 GLA gene mutations are currently known and of those most are thought not to be clinically significant, some with doubtful clinical significance, posing diagnostic and prognostic difficulties for the clinician. METHODS: Whole-exome sequencing (WES) was performed to detect the mutation in family members with Fabry disease. The function of g.1170C>T mutation was confirmed by dual luciferase system. RESULTS: A total of 1,375 variants were found in a Chinese family with FD. A missense variants c.1025C>T (p.Arg342Gln) which have been previously reported in association with FD and g.1170C>T single-nucleotide polymorphism (SNP) in the GLA gene were found in five patients. The g.1170C>T SNP affects transcription of GLA gene, presumably the transcription start site. Female patients only have hypohidrosis and neuropathic pain, while male patients have severe symptoms with simultaneous renal impairment. CONCLUSIONS: Two simultaneous variants in cis of the GLA gene, c.1025C>T (p.Arg342Gln) and g.1170C>T, were verified in Chinese individuals, and the corresponding clinical symptoms were described. The disease severity in male patients is worse than in female patients. These results may be helpful for genetic counseling, diagnosis and prognosis of patients with FD.

Ganab Haploinsufficiency Does Not Cause Polycystic Kidney Disease or Polycystic Liver Disease in Mice.

BACKGROUND: Heterozygous GANAB mutations that can cause autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD) have been described previously, but their roles in ADPKD and PLD are largely unknown. With the increase in polycystic kidney disease caused by GANAB gene mutations in recent years, a suitable animal model is still needed to further explore the pathogenic role of this gene. METHODS: To construct a mouse model of Ganab gene deletion, we analyzed the Ganab gene structure and designed two CRISPR-/Cas9-based targeting strategies. The Cas9/sgRNA we constructed was microinjected into fertilized mouse eggs to obtain chimeric F0 mice. Mice with stable genotypes were selected from offspring born after mating F0 mice with wild-type mice. RESULTS: We found that homozygous mutation of the Ganab gene in C57BL/6 mice resulted in early embryonic lethality, and there were no cysts in the kidneys or livers of Ganab +/- mice. Additionally, Ganab protein expression was reduced by at least 50%, while the expression of ADPKD proteins (PC1 and PC2) and acetylated tubulin was not affected in the Ganab +/- kidney. However, the Ganab +/- mice did not show any abnormal clinical phenotypes after birth and failed to reveal renal tubule dilatation or any abnormalities of the glomeruli in the Ganab +/- kidney. CONCLUSIONS: Homozygous Ganab mutations are lethal in the fetal stage, and Ganab haploinsufficiency does not cause kidney or liver cysts in mice, suggesting that it may not be the causative gene in polycystic kidney disease.

Analysis of clinical and laboratory characteristics and pathology of lupus nephritis-based on 710 renal biopsies in China.

OBJECTIVES: This study aimed to analyse the clinical and laboratory characteristics of different pathologic classifications of lupus nephritis (LN) patients in terms of age at systemic lupus erythematosus (SLE) diagnosis and nephritis onset. METHOD: Clinical, laboratory, and pathological data of 710 LN patients diagnosed by renal biopsy at our institution between 2000 and 2018 were retrospectively analysed. Patients were divided into the different pathological classification groups; childhood-, adult- and elderly-onset SLE groups and early- and late-onset LN groups. RESULTS: Class IV occurred most frequently and had the lowest complement C3 level. There was an obvious increase in active index in class IV and class V + IV. Patients with class VI showed some clinical characteristics similar to end-stage renal disease. Patients with proliferative nephritis were younger at SLE diagnosis and had higher blood pressure, higher frequency of proteinuria and urinary erythrocyte and lower haemoglobin and complement C3. Pathologic classification between childhood-, adult- and elderly-onset SLE patients or between early- and late-onset LN patients was not significantly different. Elderly-onset SLE patients had the highest chronic index (CI), IgA, IgG and Sjögren's syndrome A antibodies and Sjögren's syndrome B antibodies rates, whereas late-onset LN patients showed significantly higher CI, haemoglobin, complement C3 and C4 but lower uric acid, IgM and IgG. CONCLUSIONS: LN patients present with different clinical and laboratory characteristics according to pathological classification, age at SLE diagnosis and nephritis onset. These results might be valuable for estimating the pathology and guiding treatment and prognosis. Key Points • Patients with proliferative nephritis have more severe immune disorders, worse renal function and stronger inflammatory state. • The elderly-onset SLE patients showed a poorer condition. • The late-onset LN patients might have a more stable status.

Predictive Capabilities of Three Widely Used Pathology Classification Systems and a Simplified Classification (Beijing Classification) in Primary IgA Nephropathy.

BACKGROUND/AIMS: Several pathological classification systems were commonly used in clinical practice to predict the prognosis of IgA nephropathy (IgAN). However, how prognostic value differs between these systems is unclear. The aim of this study was to compare the Lee grade, the Oxford classification, and the Haas classification and to find a simplified classification. METHODS: We retrospectively analyzed IgAN cases diagnosed between January 2002 and December 2007. The endpoints were progression to end-stage renal disease (ESRD) or a ≥50% decline in estimated glomerular filtration rate (eGFR). The predictive capabilities were evaluated by comparing the ability of discrimination (continuous net reclassification) and calibration (Akaike information criterion [AIC]). RESULTS: A total of 412 IgAN patients were included in the study. The average follow-up period was 80.62 ± 23.63 months. A total of 44 (10.68%) patients progressed to ESRD, and 70 (16.99%) patients showed a ≥50% decline in eGFR. All multivariate Cox regression models had limited power for high AIC values. The prognostic values of the Lee grade and the Oxford classification were higher than those of models containing only established baseline clinical indicators for progression to ESRD or a ≥50% decline in eGFR (Lee grade 0.50, 95% CI 0.21-0.74; Oxford classification 0.48, 95% CI 0.28-0.71). The prognostic value of the Haas classification was lower than that of the other pathological classification systems for progression to ESRD or a ≥50% decline in eGFR (Lee grade 0.53, 95% CI 0.23-0.92; Oxford classification 0.59, 95% CI 0.10-0.74). The prognostic value of hierarchical classification (Beijing classification) using M and T lesion was similar to the Oxford classification. CONCLUSIONS: Both the Lee grade and the Oxford classification showed incremental prognostic values beyond established baseline clinical indicators. The Haas classification was slightly inferior to the Lee grade and the Oxford classification. The hierarchical classification (Beijing classification) using less pathological parameters does not lose predictive efficiency.