Recurrent Nephrotic Plasma Activates Pro-fibrotic Signalling Pathways Downstream of Protease-activated Receptor 1

Recurrence of steroid-resistant nephrotic syndrome (SRNS) is thought to be due to an unknown “circulating factor”, the identity of which has so far remained elusive. Our previous work suggests a signaling role for protease-activated receptor-1 (PAR-1), leading to impaired podocyte function. Here, we show that relapse nephrotic plasma (NP), but not paired remission plasma, induced a pro-fibrotic response. This change was inhibited by PAR-1 inhibitors, but not by TGF-β1 inhibition. Four PAR-1 inhibitors demonstrated distinct antagonistic properties. The phosphorylation of VASP and JNK in a 3D spheroid model (GlomSpheres) and kidney organoids corroborated the finding from a 2D ciPods model. Functionally, relapse NP induced podocyte motility, and podocyte loss from spheroids both of which were also selectively rescued by PAR-1 inhibitors. Also, it induced the loss of podocyte-specific markers in kidney organoids. We propose that the circulating factor acts as a pro-fibrotic effector by activating PAR-1, leading to increased podocyte injury.

COPD is associated with increased pro-inflammatory CD28null CD8 T and NKT-like cells in the small airways

We previously showed increased steroid resistant CD28null CD8+ senescent lymphocyte subsets in peripheral blood from COPD patients. These cells expressed decreased levels of the glucocorticoid receptor (GCR), suggesting their contribution to the steroid resistant property of these cells. COPD is a disease of the small airways. We therefore hypothesized that there would be a further increase in these steroid resistant lymphocytes in the lung, particularly in the small airways. We further hypothesized that the pro-inflammatory/cytotoxic potential of these cells could be negated using prednisolone with low-dose cyclosporin A. Blood, bronchoalveolar lavage, large proximal and small distal airway brushings were collected from 11 COPD patients and 10 healthy aged-matched controls. The cytotoxic mediator granzyme b, pro-inflammatory cytokines IFNγ/TNFα, and GCR were determined in lymphocytes subsets before and after their exposure to 1µM prednisolone and/or 2.5ng/mL cyclosporin A. Particularly in the small airways, COPD subjects showed an increased percentage of CD28null CD8 T-cells and NKT-like cells, with increased expression of granzyme b, IFNγ and TNFα and a loss of GCR, compared with controls. Significant negative correlations between small airway GCR expression and IFNγ/TNFα production by T and NKT-like cells (eg, T-cell IFNγ R= -.834, p=.031) and with FEV1 (R= -890) were shown. Cyclosporine A and prednisolone synergistically increased GCR expression and inhibited pro-inflammatory cytokine production by CD28null CD8- T and NKT-like cells. COPD is associated with increased pro-inflammatory CD28null CD8+ T and NKT-like cells in the small airways. Treatments that increase GCR in these lymphocyte subsets may improve efficacy of clinical treatment.

Biomarkers Predicting Treatment-Response in Nephrotic Syndrome of Children: A Systematic Review

Purpose: Nephrotic syndrome (NS) is the most common form of glomerulopathy in children. Most pediatric patients respond to glucocorticosteroid treatment (steroid-sensitive NS, SSNS), while approximately 10–15% will remain unresponsive or later become steroid-resistant. There has been a long-standing effort to find biomarkers that may predict steroid responsiveness.Methods: We systematically reviewed current studies which investigated clinically relevant biomarkers for predicting steroid responsiveness in pediatric NS. We performed a PubMed and EMBASE search to identify eligible articles. We collected data on urinary markers, blood/serum markers (including cellular phenotypes and mRNA expression), genotypes and HLA allele frequency.Results: A total of 659 articles were identified following electronic and manual searches. After reviewing the titles, abstracts, and full texts, 72 eligible articles were finally included. Vitamin D-binding protein (VDBP) seemed to be significantly elevated in SRNS than in SSNS, in both serum and urine specimen, although further validation is required.Conclusions: The present paper narratively illustrates current understandings of potential biomarkers that may help predict steroid responsiveness. Further investigation and collaboration involving a larger number of patients are necessary.

Therapeutic Response and Long-Term Renal Outcomes in Childhood Idiopathic Steroid-Resistant Nephrotic Syndrome: A Single-Center Study

<b><i>Purpose:</i></b> We aimed to evaluate therapeutic response and long-term renal outcomes of childhood idiopathic steroid-resistant nephrotic syndrome (iSRNS). <b><i>Methods:</i></b> We retrospectively reviewed treatment regimens, especially calcineurin inhibitor (CNI), pathologic diagnoses, and long-term renal outcomes of iSRNS patients for 30 years. <b><i>Results:</i></b> Of 516 patients with idiopathic NS, 52 (10.1%) had iSRNS. Renal biopsies from 48 patients showed minimal change disease (MCD) in 23 (47.9%), focal segmental glomerulosclerosis in 24 (50.0%), and mesangioproliferative glomerulonephritis in 1 (2.1%). The median follow-up period was 66.5 (range, 4–275) months, and 90.4% of them were treated with a CNI. CNI induced remission in 70.2% within 50.4 ± 43.5 days. Of the patients with MCD and focal segmental glomerular sclerosis (FSGS), 86.4% (19/22) and 45.0% (9/20) (<i>p =</i> 0.005) responded to CNI, respectively. Mean time until remission after using CNI was longer with FSGS (90.4 ± 54.0 days) than with MCD (29.6 ± 26.3 days) (<i>p =</i> 0.010). CNI-responsive patients with FSGS or MCD showed preserved renal function, and CNI nonresponsive MCD patients also showed preserved renal function during follow-up. However, end-stage renal disease (ESRD) progressed in 8 out of 11 patients with FSGS nonresponsive to the CNI for an average of 44.9 ± 18.4 months after diagnosis. <b><i>Conclusion:</i></b> Different response rates and times for remission were achieved with the CNI according to the pathology of iSRNS. All MCD patients regardless of CNI response and all CNI-responsive patients with FSGS showed excellent renal outcomes, while almost all FSGS patients nonresponsive to CNI eventually progressed to ESRD.

Guidelines for Genetic Testing and Management of Alport Syndrome

Genetic testing for pathogenic COL4A3–5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3–COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.

CLINICAL CASE: STEROID-RESISTANT NEPHROTIC SYNDROME

Описан клинический случай пациент с нефротическим синдромом, стероид резистентный вариант, с артериальной гипертензией, осложненный полисерозитом (гидроторакс, асцит, плеврит). Пациент поступил в клинику в состоянии средней степени тяжести, с массивными отеками, полисерозитом, артериальной гипертензией и выраженным нефротическим синдромом. Диагноз: Гломерулярная болезнь. Нефротический синдром, стероид резистентный вариант. Функция почек снижена (СКФ- 84мл/мин по Шварцу). Двухсторонний экссудативный плеврит. Гидроторакс. Полисерозит (в рамках нефротического синдрома) был установлен на основании выраженного нефротического синдрома. Пациенту была проведена патогенетическая терапия. Отмечено улучшение состояния больного, в виде снижения отеков, нормализаций артериального давления, что в свою очередь поспособствовало сохранению и улучшению качества жизни пациента. A clinical case of a patient with nephrotic syndrome, steroidresistant variant, with arterial hypertension complicated by polyserositis (hydrothorax, ascites, pleurisy) is described. The patient was admitted to the clinic in a state of moderate severity, with massive edema, polyserositis, arterial hypertension, and severe nephrotic syndrome. Diagnosis: Glomerular disease. Nephrotic syndrome, steroidresistant variant. The kidney function is reduced (GFR - 84 ml/min according to Schwartz). Bilateral exudative pleurisy. Hydrothorax. Polyserositis (within the framework of nephrotic syndrome) was established based on the severe nephrotic syndrome. The patient underwent pathogenetic therapy. An improvement in the patient's condition was noted, in the form of a decrease in edema, normalization of blood pressure, which in turn contributed to the preservation and improvement of the patient's quality of life.

A novel biomimetic nanomedicine system with anti-inflammatory and anti-osteoporosis effects improves the therapy efficacy of steroid-resistant nephrotic syndrome

Clinically, steroid-resistant nephrotic syndrome (SRNS) is always prolonged and difficult to treat and easily develops into end-stage renal disease, resulting in a low survival rate. Strategies to reverse steroid resistance and reduce the long-term use of high doses of steroid medicines are urgently needed. In this study, a novel nanoparticle drug system (Pm-GCH) with a core–shell structure was designed. Metal–organic frameworks, synthesized by glycyrrhizic acid (G) and calcium ions (Ca2+) loaded with hydrocortisone (H) were the core of the nanoparticles. Platelet membrane vesicles were the shells. The natural platelet membrane endows Pm-GCH with good biocompatibility and the ability to promote immune escape. In addition, under the chemotaxis of inflammatory factors, platelet membranes assist Pm-GCH in nonspecific targeting of the inflammatory sites of the kidney. Under an inflammatory acid environment, GCH slowly degrades and releases glycyrrhizic acid and hydrocortisone. Glycyrrhizic acid inhibits the inactivation of hydrocortisone, jointly inhibits the activity of phospholipase A2 (PLA2) and the classic activation pathway of complement C2, blocks the production of inflammatory factors, plays an anti-inflammatory role, and enhances the efficacy of hydrocortisone in the treatment of SRNS. Moreover, glycyrrhizic acid alleviates osteoporosis induced by long-term use of glucocorticoids. These results indicate that Pm-GCH is a promising treatment strategy for SRNS. Graphical Abstract

Steroid-resistant intestinal aGVHD and refractory CMV and EBV infections complicated by haplo-HSCT were successfully rescued by FMT and CTL infusion

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) produces similar survival outcomes as HLA-matched sibling donor allogeneic HCST in younger patients with acquired severe aplastic anemia (SAA). This study reported a 29-years-old man with SAA and intracranial hemorrhage who underwent haplo-HSCT with a modified BU/CY + ATG conditioning regimen. Neutrophil and platelet engraftment were both achieved on day 14 after HSCT. The patient developed grade IV acute graft-versus-host disease (aGVHD) on day 20 and acquired cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infections on day 47. After the failure of methylprednisolone, basiliximab, ruxolitinib, and antiviral treatment, the patient was diagnosed with steroid-resistant grade IV aGVHD and refractory CMV and EBV infections. We performed fecal microbiota transplantation and infused CMV- and EBV-specific cytotoxic T lymphocytes. After that the stool volume and frequency gradually decreased, and viral DNA was undetectable on day 80. This report provides helpful clinical experience for treating steroid-resistant aGVHD and refractory viral infections.