Shen Shuai II recipe improves renal hypoxia to attenuate renal injury in 5/6 renal ablation/infarction rats and effect evaluation using blood oxygenation level-dependent functional magnetic resonance imaging.

Background: Renal hypoxia plays a key role in the progression of chronic kidney disease (CKD). Shen Shuai II Recipe (SSR) has shown good results in the treatment of CKD as a common herbal formula. This study aimed to explore the effect of SSR on renal hypoxia and injury in CKD rats. Methods: Twenty-five Wistar rats underwent 5/6 renal ablation/infarction (A/I) surgery were randomly divided into three groups: 5/6 (A/I), 5/6 (A/I) + losartan (LOS), and 5/6 (A/I) + SSR groups. Another eight normal rats were used as the Sham group. After 8-week corresponding interventions, blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) was performed to evaluate renal oxygenation in all rats, and biochemical indicators were used to measure kidney and liver function, hemoglobin, and proteinuria. The expression of fibrosis and hypoxia-related proteins was analyzed using immunoblotting examination. Results: Renal oxygenation, evaluated by BOLD-fMRI as cortical and medullary T2* values (COT2* and MET2*), was decreased in 5/6 (A/I) rats, but increased after SSR treatment. SSR also downregulated the expression of hypoxia-inducible factor-1α (HIF-1α) in 5/6 (A/I) kidneys. With the improvement of renal hypoxia, renal function and fibrosis were improved in 5/6 (A/I) rats, accompanied by reduced proteinuria. Furthermore, the COT2* and MET2* were significantly positively correlated with the levels of creatinine clearance rate (Ccr) and hemoglobin, but negatively associated with the levels of serum creatinine (SCr), blood urea nitrogen (BUN), serum cystatin C (CysC), serum uric acid (UA), 24-h urinary protein (24-h Upr), and urinary albumin:creatinine ratio (UACR). Conclusion: The degree of renal oxygenation reduction is correlated with the severity of renal injury in CKD. SSR can improve renal hypoxia to attenuate renal injury in 5/6 (A/I) rats of CKD.

Identification of novel pathogenic variants of CUBN in patients with isolated proteinuria.

BACKGROUND: Although proteinuria is long recognized as an independent risk factor for progressive chronic kidney diseases, not all forms of proteinuria are detrimental to kidney function, one of which is isolated proteinuria caused by cubilin (CUBN)-specific mutations. CUBN encodes an endocytic receptor, initially found to be responsible for the Imerslund-Gräsbeck syndrome (IGS; OMIM #261100) characterized by a combined phenotype of megaloblastic anemia and proteinuria. METHODS: After analyzing their clinical and pathological characterizations, next-generation sequencing for renal disease genes or whole-exome sequencing (WES) was performed on four patients with non-progressive isolated proteinuria. CUBN biallelic pathogenic variants were identified and further analyzed by cDNA-PCR sequencing, immunohistochemistry, minigene assay, and multiple in silico prediction tools, including 3D protein modeling. RESULTS: Here, we present four patients with isolated proteinuria caused by CUBN C-terminal biallelic pathogenic variants, all of which showed no typical IGS symptoms, such as anemia and vitamin B12 deficiency. Their urine protein levels fluctuated between +~++ and estimated glomerular filtration rate (eGFR) were normal or slightly higher. Mild mesangial hypercellularity was found in three children's renal biopsies. A homozygous splice-site variant of CUBN (c.6821+3 (IVS44) A>G) was proven to result in the exon 44 skipping and premature translation termination by cDNA sequencing and immunohistochemistry. Compound heterozygous mutations were identified among the other three children, including another novel splice-site variant (c.10764+1 (IVS66) G>A) causing the retention of first 4 nucleotides in intron 66 by minigene assay, two unreported missense mutations (c.4907G>A (p.R1636Q); c. 9095 A>G (p.Y3032C)), and two reported missense mutations in China (c.8938G>A (p.D2980N); c. 9287T>C (p.L3096P)), locating behind the vitamin B12-binding domain, affecting CUB11, CUB16, CUB22, CUB23, and CUB27 domains, respectively. CONCLUSION: These results demonstrate that above CUBN mutations may cause non-progressive and isolated proteinuria, expanding the variant spectrum of CUBN and benefiting our understanding of proteinuria and renal function.

Proteomics-Based Identification of Potential Therapeutic Targets of Artesunate in a Lupus Nephritis MRL/lpr Mouse Model.

This study aimed to identify potential therapeutic targets of artesunate in an MRL/lpr lupus nephritis mouse model by quantitative proteomics. We detected serum autoimmune markers and proteinuria in 40 female mice that were divided into 4 groups (n = 10): normal C57BL/6 control group; untreated MRL/lpr lupus; 9 mg/kg/day prednisone positive control MRL/lpr lupus; and 15 mg/kg/day artesunate-treated MRL/lpr lupus groups. Renal pathology in the untreated MRL/lpr lupus and artesunate groups was examined by Periodic acid-Schiff (PAS) staining. Artesunate treatment in lupus mice decreased serum autoantibody levels and proteinuria while alleviating lupus nephritis pathology. Through tandem mass tag-tandem mass spectrometry (TMT-MS/MS) analyses, differentially expressed proteins were identified in the artesunate group, and subsequent functional prediction suggested associations with antigen presentation, apoptosis, and immune regulation. Data are available via ProteomeXchange with the identifier PXD046815. Parallel reaction monitoring (PRM) analysis of the top 19 selected proteins confirmed the TMT-MS/MS results. Immunohistochemistry, immunofluorescence, and Western blotting of an enriched protein from PRM analysis, cathepsin S, linked to antigen presentation, highlighted its upregulation in the untreated MRL/lpr lupus group and downregulation following artesunate treatment. This study suggests that artesunate holds potential as a therapeutic agent for lupus nephritis, with cathepsin S identified as a potential target.

Childhood-onset IgA nephropathy: is long-term recovery possible?

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. While studies have primarily focused on identifying risk factors for disease progression, very few data exist on the likelihood of achieving complete recovery from the disease. METHODS: We conducted a single-center retrospective study on all consecutive patients with biopsy-proven IgAN diagnosed between 1986 and 2018 in our pediatric center. Biopsies were classified according to the MEST-C Oxford classification score. "Complete clinical remission" was defined as the absence of proteinuria, hematuria, and hypertension in patients with normal kidney function who had been off therapy for more than 2 years. RESULTS: Overall, 153 patients with age at onset of 10.6 ± 4 years were enrolled in the study. Of these, 41 achieved "complete clinical remission." The estimated probability of complete clinical remission at 10 years was 43% (95%CI 33-54). However, seven patients relapsed within 10 years. Multivariable analysis showed that higher age at onset (HR 0.89, 95%CI 0.80-0.98, p = 0.017) and segmental glomerulosclerosis lesions (HR 0.28, 95%CI 0.10-0.79, p = 0.017) decreased significantly the chances of achieving complete clinical remission. Immunosuppressive therapy was not significantly associated with clinical outcomes. CONCLUSIONS: Approximately one-third of patients with pediatric-onset IgAN achieve prolonged remission, in particular, very young children at disease onset without sclerotic glomerular lesions. Longer term follow-up is needed to assess if these patients have achieved permanent remission.

Early-Onset Myopia and Retinal Detachment without Typical Microcoria or Severe Proteinuria due to a Novel LAMB2 Variant.

PURPOSE: To describe the ocular and renal features, as well as outcomes of retinal detachment repair, in patients with a novel, homozygous laminin ß-2 (LAMB2) pathogenic variant. DESIGN: Single-center retrospective chart review of patients with a homozygous variant, c.619T>C p.(Ser207Pro), in the LAMB2 gene. SUBJECTS: Eleven patients (22 eyes) from 4 families. METHODS: Demographic data and ocular findings were recorded. Patients were recalled for a detailed renal evaluation. MAIN OUTCOME MEASURES: Ocular features, renal features, and outcomes of retinal detachment repair. RESULTS: The mean age at presentation was 6.0 (range, 1-26) years. None of the study eyes had microcoria, and none of the patients had nephrotic-range proteinuria. The mean refraction and axial length were -7.9 diopters (range, -4.0 to -12.0 diopters) and 25.3 (range, 22.7-27.7) mm, respectively. Eleven eyes (50%) had cataract at presentation. Fifteen eyes had a clear view to the fundus and all showed tessellated myopic fundus, avascular peripheral retina evident clinically or on fluorescein angiography, and rudimentary fovea. Optic disc pallor was observed in 10 eyes (66.7%). Straightened retinal vessels, abnormal vascular emanation (situs inversus) from the optic disc, supernumerary vascular branching at the optic disc, and vascular tortuosity were observed in 10 (66.7%), 2 (13.4%), 2 (13.4%), and 2 (13.4%) eyes, respectively. Discrete areas of punched-out chorioretinal atrophy were observed in 4 (26.7%) eyes. Spectral-domain OCT showed retinal and choroidal thinning in 13 eyes (86.7%), retinoschisis temporal to the fovea in 2 eyes (13.4%), and rudimentary fovea in 15 eyes (100%). Among the 22 eyes, 14 eyes (63.6%) developed rhegmatogenous retinal detachment (RRD), mostly during childhood, of which 5 patients had bilateral RRD. Eight eyes were operated on and 6 (75%) achieved retinal reattachment at the last follow-up. The mean preoperative visual acuity was 20/300 and the mean postoperative visual acuity at the last follow-up was 20/400. CONCLUSIONS: This study describes a distinct phenotype of LAMB2-related disease with a novel, homozygous LAMB2 variant, and further expands the spectrum of ophthalmic and renal features, and the molecular genetic basis, of LAMB2-related disease. Because the typical microcoria and nephrotic-range proteinuria might be absent, the retinal features can guide the diagnosis. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Renal Implications of Long-Term Systemic Bevacizumab for Recurrent Respiratory Papillomatosis.

BACKGROUND: Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor that is used off-label for select cases of recurrent respiratory papillomatosis (RRP) that are severe, involve the distal airway or lung parenchyma, and refractory to other forms of adjuvant therapy. However, there is limited safety data for the use of bevacizumab in children and VEGF inhibitors are reported to have a range of adverse renal effects, including hypertension, proteinuria, and thrombotic microangiopathy (TMA). CASE-DIAGNOSIS/TREATMENT: This report describes a case of severe juvenile-onset RRP that had an exceptionally high operative burden that was refractory to several adjuvant treatment strategies (including intralesional cidofovir and subcutaneous pegylated interferon). Bevacizumab treatment resulted in a dramatic and sustained improvement in disease control over a 5-year period. However, after 3 years of treatment, the patient developed hypertension and proteinuria and was found to have evidence of a glomerular TMA on kidney biopsy. These complications were successfully managed with a reduction in bevacizumab frequency and angiotensin-converting enzyme inhibitor initiation. CONCLUSIONS: Clinicians caring for children treated with VEGF inhibitors should be aware of the potential renal complications and their management.

External validation of the pediatric International IgA Nephropathy Prediction Tool in a central China cohort.

BACKGROUND: This study aimed to externally validate the pediatric International IgA Nephropathy (IgAN) Prediction Tool updated from the adult IgAN Prediction Tool. METHODS: 439 children with biopsy-confirmed idiopathic IgAN were enrolled in this external validation study. The primary outcome was a 30% decline in eGFR or end-stage kidney disease. We evaluated the discrimination using Harrell's C-index, the receiver operating characteristic (ROC) curve, and Kaplan-Meier curves for four risk groups (< 16th [low risk], ∼16 to < 50th [intermediate risk], ∼50 to < 84th [high risk], and ≥ 84th percentiles [highest risk] of linear predictor). Calibration was assessed using calibration plots. RESULTS: The median follow-up time of the 439 patients was 4.5 (2.7-6.8) years, and 27 patients reached the primary outcome. Compared with the reported cohorts, our cohort was more contemporary, with milder proteinuria at biopsy, and had lower proportions of S1 and T1 lesions. Harrell's C-index and area under the ROC curve at 5 years were < 0.7 for both the models with and without race. The Kaplan-Meier curves of the risk groups were not well separated for the two models, only separated completely between the highest-risk group and the others for the model without race. The two models generally overestimated the risk of the primary outcome, CONCLUSION: The model without race could accurately distinguish the highest-risk patients from patients with low, intermediate, and high risk for kidney progression. Discrimination and calibration for the full model with or without race were unsatisfactory in this contemporary cohort in central China.

IgA nephropathy in children with minimal proteinuria: to biopsy or not to biopsy?

BACKGROUND: Tubulointerstitial lesions and glomerular inflammation severity have been shown to correlate with proteinuria in children with IgA nephropathy (cIgAN). However, there is a lack of data regarding severity of histopathologic findings in cIgAN in patients with minimal to absent proteinuria since kidney biopsy indications are not well defined in these cases. METHODS: Twenty-eight cIgAN patients with kidney biopsy from 4 different centers in Paris (France) and Montreal (Canada) with a urine protein/creatinine ratio (UPCr) ≤ 0.03 g/mmol and a normal estimated glomerular filtration rate (eGFR > 90 ml/min/1.73 m2) on the day of kidney biopsy prior to treatment were included. RESULTS: Median age was 11.82 (9.32-13.45) years, and median follow-up was 4 years (2.87-6.53). At time of biopsy, median eGFR was 116 (102.3-139.7) ml/min/1.73 m2, and median UPCr was 0.02 (0.011-0.03) g/mmol. Microscopic or macroscopic hematuria was present in 35.7% and 64.3% of cases, respectively. Kidney biopsy microscopy analysis showed mesangial (M1), endocapillary (E1), or extracapillary (C1) hypercellularity in 53.5%, 32.1%, and 7.1% of patients, respectively. Chronic histological lesions were also present: glomerulosclerosis (S1) in 42.8% and tubular atrophy/interstitial fibrosis in 7.1%. Podocytopathic features were detected in 21.4%. An ACE inhibitor or immunosuppressive therapy (IS) was prescribed in 42.8% and 21.4% of these patients respectively. One-third (35.7%) received no treatment. At last follow-up, median eGFR was 111.9 (90.47-136.1) ml/min/1.73 m2, and median UPCr was 0.028 (0.01-0.03) g/mmol. CONCLUSION: cIgAN with minimal proteinuria at time of biopsy might be linked with acute and chronic glomerular lesions.

Chronic kidney disease in a murine model of non-alcoholic steatohepatitis (NASH).

Clinical studies suggest that non-alcoholic steatohepatitis (NASH) is an independent risk factor for chronic kidney disease (CKD), but causality and mechanisms linking these two major diseases are lacking. To assess whether NASH can induce CKD, we have characterized kidney function, histological features, transcriptomic and lipidomic profiles in a well-validated murine NASH model. Mice with NASH progressively developed significant podocyte foot process effacement, proteinuria, glomerulosclerosis, tubular epithelial cell injury, lipid accumulation, and interstitial fibrosis. The progression of kidney fibrosis paralleled the severity of the histologic NASH-activity score. Significantly, we confirmed the causal link between NASH and CKD by orthotopic liver transplantation, which attenuated proteinuria, kidney dysfunction, and fibrosis compared with control sham operated mice. Transcriptomic analysis of mouse kidney cortices revealed differentially expressed genes that were highly enriched in mitochondrial dysfunction, lipid metabolic process, and insulin signaling pathways in NASH-induced CKD. Lipidomic analysis of kidney cortices further revealed that phospholipids and sphingolipids were the most significantly changed lipid species. Notably, we found similar kidney histological changes in human NASH and CKD. Thus, our results confirm a causative role of NASH in the development of CKD, reveal potential pathophysiologic mechanisms of NASH-induced kidney injury, and established a valuable model to study the pathogenesis of NASH-associated CKD. This is an important feature of fatty liver disease that has been largely overlooked but has clinical and prognostic importance.

Kidney biopsy findings in children with diabetes mellitus.

BACKGROUND: Diabetic nephropathy may begin in childhood, but clinical kidney disease ascribable to this is uncommon in children with type 1 (insulin dependent) diabetes mellitus. METHODS: We reviewed our experience of kidney biopsies in children with type 1 diabetes mellitus. RESULTS: Between 1995 and 2022, there were biopsies in 17 children, with various clinical indications for kidney biopsy, making this the largest series of biopsies in diabetic children with clinical kidney abnormalities. Four biopsies showed diabetic nephropathy, three showed the combination of diabetic nephropathy and IgA nephropathy, and ten showed a variety of conditions other than diabetic nephropathy: minimal change disease (2), membranous nephropathy (2), thin glomerular basement membrane lesion (2), non-glomerular chronic damage in Wolcott-Rallison syndrome (2), acute pauciimmune necrotizing crescentic glomerulonephritis (1) and IgA nephropathy (1). Clinical clues of something other than diabetic nephropathy included acute kidney injury, microscopic haematuria or chronic kidney impairment with little or no proteinuria and the nephrotic syndrome after a short duration of diabetes. CONCLUSIONS: We confirm that changes better known in adults with either type 1 or type 2 diabetes mellitus can occur in children with type 1 diabetes mellitus: overt diabetic nephropathy either on its own or combined with other conditions and kidney disorders other than diabetic nephropathy.

Levels of Proteinuria and Renal Pathology in Systemic Lupus Erythematosus Patients.

According to the current guidelines, renal biopsies are performed in systemic lupus erythematosus (SLE) patients for proteinuria of 0.5 g/24 h or higher. Renal pathology may be present in patients with lower-level proteinuria (<0.5 g/24 h). We aimed to review the renal histopathology in SLE patients, with lower levels of proteinuria. In this retrospective study, we retrieved SLE patients' data, including 24-h urinary protein excretion and renal histopathology results. We compared various parameters in different lupus nephritis (LN) classes and in different levels of proteinuria (urinary protein <0.5 g, 0.5 to <1 g, and ≥1 g per 24 h). Out of 476 patients, 274 (57.6%) had proteinuria of <0.5 g, 44 (9.2%) had 0.5 to <1 g, and 158 (33.2%) had ≥1 g per 24 h. SLE patients with proteinuria of <0.5 g/24 h were found to have LN, including the proliferative classes. Of the 299 LN cases confirmed by a renal biopsy, low-level proteinuria (<0.5 g) was found in 39.8% of all LN patients, in 50% of patients with Class III LN, 33.3% of those with Class IV LN, 31.4% of those with Class V LN, and 41.4% of those with other LN classes (II/V, III/V, and IV/V). Overall, 35.9% (87/242) of patients with the proliferative LN classes (III, IV, V, II/V, III/V and IV/V) had low-level proteinuria of <0.5 g/24 h. SLE patients with low-level proteinuria had significant renal pathology. Our study suggests there is a need to perform renal biopsies at lower levels of proteinuria.

[The efficiency of pre-administration of a peptide mimicking the spatial structure of erythropoietin -chain B in modeling experimental post-contrast acute kidney injury].

AIM: To study the efficiency of pre-administration of a peptide mimicking the spatial structure of erythropoietin -chain B in modeling experimental post-contrast acute kidney injury. MATERIALS AND METHODS: In this study, an experimental model of post-contrast acute kidney injury was created using a non-steroidal anti-inflammatory drug, a nitric oxide synthase inhibitor, and injection of iopromide to mature male mice. After 48 hours, a comprehensive assessment of the concentration of creatinine, urea, glomerular filtration rate, the ratio of urea/albumin in the serum, as well as the level of proteinuria and interleukin 6 in the urine was carried out. RESULTS: A peptide mimicking the spatial structure of erythropoietin -chain B, administered at a dose of 100 g/kg 30 minutes before modeling of pathologic process, contributes to a significant decrease in creatinine and urea concentrations by 2.5 and 1.8 times, respectively, with an increase in glomerular filtration rate 4.4 times. In addition, in the group with pharmacological correction, there was a significant decrease in the ratio of urea/albumin by 2.2 times, a decrease in the level of proteinuria by 61.9% and a decrease in the concentration of pro-inflammatory interleukin-6 in the urine by 2.1 times. CONCLUSION: Thus, the preliminary administration of a peptide that mimics the spatial structure of the erythropoietin -chain B helps to reduce the severity of post-contrast acute kidney injury in the experiment, due to anti-inflammatory properties.

A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats.

In proteinuric renal diseases, the serine protease (SP) plasmin activates the epithelial sodium channel (ENaC) by cleaving its γ subunit. We previously demonstrated that a high-salt (HS) diet provoked hypertension and proteinuria in Dahl salt-sensitive (DS) rats, accompanied by γENaC activation, which were attenuated by camostat mesilate (CM), an SP inhibitor. However, the effects of CM on plasmin activity in DS rats remain unclear. In this study, we investigated the effects of CM on plasmin activity, ENaC activation, and podocyte injury in DS rats. The DS rats were divided into the control diet, HS diet (8.0% NaCl), and HS+CM diet (0.1% CM) groups. After weekly blood pressure measurement and 24-h urine collection, the rats were sacrificed at 5 weeks. The HS group exhibited hypertension, massive proteinuria, increased urinary plasmin, and γENaC activation; CM treatment suppressed these changes. CM prevented plasmin(ogen) attachment to podocytes and mitigated podocyte injury by reducing the number of apoptotic glomerular cells, inhibiting protease-activated receptor-1 activation, and suppressing inflammatory and fibrotic cytokine expression. Our findings highlight the detrimental role of urinary plasmin in the pathogenesis of salt-sensitive hypertension and glomerular injury. Targeting plasmin with SP inhibitors, such as CM, may be a promising therapeutic approach for these conditions.

Pregnancy in women with autosomal recessive Alport syndrome caused by novel compound heterozygous mutations of COL4A3 gene: Two cases reports.

RATIONALE: Autosomal recessive Alport syndrome (ARAS) is an hereditary heterogeneous disease that poses a serious risk to pregnant women. PATIENT CONCERNS: We reported 2 cases of pregnancy with progressive proteinuria. The case 1 was a 21-year-old woman with 24-h proteinuria increased from 2.03 to 11.72 g at 13 to 35 weeks of gestation, and the case 2 was a 28-year-old woman with 24-h proteinuria increased from 2.10 to 9.32 g at 8 to 36 weeks of gestation. In advanced stage of pregnancy, the fetal development was smaller than the gestational age. DIAGNOSES: Sanger sequencing showed that novel compound heterozygous mutations [c.1315 G>T (p.G439C) and c.4847 G>A (p.C1616Y)] of the collagen type IV alpha 3 chain (COL4A3) gene were found in the 2 cases. Renal puncture pathology confirmed the diagnosis of ARAS. INTERVENTIONS: The 2 cases were treated with albumin, compounded amino acids, calcium, vitamin D, and low molecular weight heparin in addition to conventional treatment during pregnancy. Pregnancy was terminated by cesarean section at 36 to 37 weeks of gestation. After delivery, the patients were treated with Losartan for anti-proteinuric therapy for 1 year. OUTCOMES: The neonatal weights and Apgar scores were normal. The patients recovered well and 24-h proteinuria decreased to pre-pregnancy level. LESSONS: When pregnant women present with a persistent increasing proteinuria, ARAS needs to be considered. Sanger sequencing is useful to assist in the diagnosis of ARAS. Multidisciplinary treatments from nephrologists and gynecologists are needed to ensure the safety of pregnancy and the fetus.

Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases.

The progression of proteinuric kidney diseases is associated with podocyte loss, but the mechanisms underlying this process remain unclear. Podocytes reenter the cell cycle to repair double-stranded DNA breaks. However, unsuccessful repair can result in podocytes crossing the G1/S checkpoint and undergoing abortive cytokinesis. In this study, we identified Pfn1 as indispensable in maintaining glomerular integrity - its tissue-specific loss in mouse podocytes resulted in severe proteinuria and kidney failure. Our results suggest that this phenotype is due to podocyte mitotic catastrophe (MC), characterized histologically and ultrastructurally by abundant multinucleated cells, irregular nuclei, and mitotic spindles. Podocyte cell cycle reentry was identified using FUCCI2aR mice, and we observed altered expression of cell-cycle associated proteins, such as p21, p53, cyclin B1, and cyclin D1. Podocyte-specific translating ribosome affinity purification and RNA-Seq revealed the downregulation of ribosomal RNA-processing 8 (Rrp8). Overexpression of Rrp8 in Pfn1-KO podocytes partially rescued the phenotype in vitro. Clinical and ultrastructural tomographic analysis of patients with diverse proteinuric kidney diseases further validated the presence of MC podocytes and reduction in podocyte PFN1 expression within kidney tissues. These results suggest that profilin1 is essential in regulating the podocyte cell cycle and its disruption leads to MC and subsequent podocyte loss.

tRF-003634 alleviates adriamycin-induced podocyte injury by reducing the stability of TLR4 mRNA.

Podocyte injury plays a key role in the production of proteinuria and is closely related to the progression of chronic kidney disease (CKD). Alleviating podocyte injury is beneficial to prevent the occurrence and development of CKD. tRNA-derived RNA fragments (tRFs) are associated with podocytes injury processes such as protein binding, cell adhesion, synapses, the actin cytoskeleton. Our previous data showed that tRF-003634 tightly correlated with podocyte injury, while its effect remains unclear. This study aimed to investigate the role of tRF-003634 in podocyte injury and the potential mechanisms. The expression level of tRF-003634, nephrin, podocin and tRF-003634 targeted toll-like receptor 4 (TLR4) in podocytes and kidney tissues were examined by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. The biochemical indices were monitored and renal pathological changes were assessed by hematoxylin and eosin PAS staining. Furthermore, potential target genes of tRF-003634 were screened using high-throughput mRNA sequencing, and then confirmed by RNA pulse-chase analysis. The results showed that tRF-003634 was downregulated in adriamycin (Adr)-induced podocyte injury. Overexpression of tRF-003634 increased the expression of nephrin and podocin in vivo and in vitro and alleviated podocyte injury. Meanwhile, overexpression of tRF-003634 alleviated proteinuria and renal pathological damage. In addition, high-throughput sequencing after overexpression of tRF-003634 showed that TLR4 might be a downstream target gene. tRF-003634 can alleviate podocyte injury by reducing the stability of TLR4 mRNA, possibly by competing with TLR4 mRNA to bind to YTH domain-containing protein 1 (YTHDC1). In conclusion, tRF-003634 was underexpressed in Adr-induced podocyte injury, and its overexpression alleviated podocyte injury in vitro and in vivo by reducing the stability of TLR4 mRNA.

Cellular senescence in kidney biopsies is associated with tubular dysfunction and predicts CKD progression in childhood cancer patients with karyomegalic interstitial nephropathy.

Karyomegalic interstitial nephropathy (KIN) has been reported as an incidental finding in patients with childhood cancer treated with ifosfamide. It is defined by the presence of tubular epithelial cells (TECs) with enlarged, irregular, and hyperchromatic nuclei. Cellular senescence has been proposed to be involved in kidney fibrosis in hereditary KIN patients. We report that KIN could be diagnosed 7-32 months after childhood cancer diagnosis in 6/6 consecutive patients biopsied for progressive chronic kidney disease (CKD) of unknown cause between 2018 and 2021. The morphometry of nuclear size distribution and markers for DNA damage (γH2AX), cell-cycle arrest (p21+, Ki67-), and nuclear lamina decay (loss of lamin B1), identified karyomegaly and senescence features in TECs. Polyploidy was assessed by chromosome fluorescence in situ hybridization (FISH). In all six patients the number of p21-positive TECs far exceeded the typically small numbers of truly karyomegalic cells, and p21-positive TECs contained less lysozyme, testifying to defective resorption, which explains the consistently observed low-molecular-weight (LMW) proteinuria. In addition, polyploidy of TEC was observed to correlate with loss of lysozyme staining. Importantly, in the five patients with the largest nuclei, the percentage of p21-positive TECs tightly correlated with estimated glomerular filtration rate loss between biopsy and last follow-up (R2 = 0.93, p < 0.01). We conclude that cellular senescence is associated with tubular dysfunction and predicts CKD progression in childhood cancer patients with KIN and appears to be a prevalent cause of otherwise unexplained CKD and LMW proteinuria in children treated with DNA-damaging and cell stress-inducing therapy including ifosfamide. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The E3 ligase Trim63 promotes podocyte injury and proteinuria by targeting PPARα to inhibit fatty acid oxidation.

Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα) plays a key role in podocyte fatty acid oxidation (FAO). However, the underlying regulatory mechanisms remain unresolved. Trim63 is an E3 ubiquitin ligase that has been shown to inhibit PPARα activity; however, its role in fatty acid metabolism in the kidney has not been elucidated to date. In this study, we investigated the effects of overexpression and knockdown of Trim63 in Adriamycin (ADR)-induced nephropathy and diabetic nephropathy models and a podocyte cell line. In both rodents and human patients with proteinuric CKD, Trim63 was upregulated, particularly in the podocytes of injured glomeruli. In the ADR-induced nephropathy model, ectopic Trim63 application aggravated FAO deficiency and mitochondrial dysfunction and triggered intense lipid deposition, podocyte injury, and proteinuria. Notably, Trim63 inhibition alleviated FAO deficiency and mitochondrial dysfunction, and markedly restored podocyte injury and renal fibrosis in ADR-induced and diabetic nephropathy (DN) models. Additionally, Trim63 was observed to mediate PPARα ubiquitination and degradation, leading to podocyte injury. We demonstrate the pathological role of Trim63, which was previously unrecognized in kidney tissue, in FAO deficiency and podocyte injury. Targeting Trim63 may represent a viable therapeutic strategy for podocyte injury and proteinuria.

Histological transition from minimal change disease to THSD7A-associated membranous nephropathy in a patient receiving long-term steroid treatment: A case report.

RATIONALE: A predominant Th2 immune response is suggested in the pathogenesis of both minimal change disease (MCD) and membranous nephropathy (MN); however, consecutive development of the 2 diseases in a patient is extremely rare. PATIENT CONCERN: A Japanese man, who developed nephrotic syndrome in his 50s and was diagnosed with MCD by renal biopsy, experienced a relapse of proteinuria approximately 3 years later during long-term steroid treatment. Since the proteinuria was resistant to increase in steroid dosage, repeat renal biopsy was performed, which revealed a small amount of glomerular subepithelial immune deposits containing immunoglobulin (Ig)G (dominantly IgG4). Immunostaining for thrombospondin-type-1-domain-containing-7A (THSD7A) was positive on the glomerular capillary walls, whereas that for other causative antigens of MN, such as phospholipase A2 receptor or neural epidermal growth factor-like 1 protein, was negative. Detailed examination found no associated condition, including malignancies and allergic diseases. DIAGNOSIS: The diagnosis of THSD7A-associated idiopathic MN was made. INTERVENTIONS AND OUTCOMES: He received further increased dose of steroids. Thereafter he maintained clinical improvement because his urinary protein level was decreased. LESSONS: The present case suggested that histological transition from MCD to MN is possible and repeat biopsy would be crucial for accurate diagnosis.