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.

Effective Treatment of a Post-renal Transplantation Patient with Early Recurrent Focal Segmental Glomerulosclerosis and Concomitant Hemolytic Uremic Syndrome, a Case Report

While recurrence of primary Focal Segmental Glomerular Sclerosis (FSGS) is common post renal transplantation (30%-80%), a concomitant presentation of hemolytic uremic syndrome (HUS) and recurrent FSGS has never been reported. In addition, treatment of recurrent FSGS and HUS post-renal transplantation is challenging; and usually individualized based on center's experience. Here, we reported a case of a pediatric patient with early recurrence of FSGS and concomitant HUS post-renal transplantation. This patient had a complete hematological and renal response following the administration of Eculizumab and Rituximab, respectively. Withdrawal of Tacrolimus as well as plasmapheresis did not improve kidney function. Therefore, we concluded that both Eculizumab and Rituximab could achieve remission in comparable cases when administered at fixed intervals.

Proteomic profile of mesothelial exosomes isolated from peritoneal dialysis effluent of children with focal segmental glomerulosclerosis

Peritoneal dialysis (PD) is the worldwide recognized preferred dialysis treatment for children affected by end-stage kidney disease (ESKD). However, due to the unphysiological composition of PD fluids, the peritoneal membrane (PM) of these patients may undergo structural and functional alterations, which may cause fibrosis. Several factors may accelerate this process and primary kidney disease may have a causative role. In particular, patients affected by steroid resistant primary focal segmental glomerulosclerosis, a rare glomerular disease leading to nephrotic syndrome and ESKD, seem more prone to develop peritoneal fibrosis. The mechanism causing this predisposition is still unrecognized. To better define this condition, we carried out, for the first time, a new comprehensive comparative proteomic mass spectrometry analysis of mesothelial exosomes from peritoneal dialysis effluent (PDE) of 6 pediatric patients with focal segmental glomerular sclerosis (FSGS) versus 6 patients affected by other primary renal diseases (No FSGS). Our omic study demonstrated that, despite the high overlap in the protein milieu between the two study groups, machine learning allowed to identify a core list of 40 proteins, with ANXA13 as most promising potential biomarker, to distinguish, in our patient population, peritoneal dialysis effluent exosomes of FSGS from No FSGS patients (with 100% accuracy). Additionally, the Weight Gene Co-expression Network Analysis algorithm identified 17 proteins, with PTP4A1 as the most statistically significant biomarker associated to PD vintage and decreased PM function. Altogether, our data suggest that mesothelial cells of FSGS patients are more prone to activate a pro-fibrotic machinery. The role of the proposed biomarkers in the PM pathology deserves further investigation. Our results need further investigations in a larger population to corroborate these findings and investigate a possible increased risk of PM loss of function or development of encapsulating peritoneal sclerosis in FSGS patients, thus to eventually carry out changes in PD treatment and management or implement new solutions.

Clinical Characteristics and Outcomes of Idiopathic Membranous Nephropathy with Glomerular Igm Deposits

BackgroundGlomerular IgM deposition is commonly shown in idiopathic membranous nephropathy (IMN), but the clinicopathological features and outcomes of IMN with IgM deposition are unclear.MethodsThis single-center prospective cohort study enrolled 210 patients with biopsy-proven IMN from January 2016 to December 2018. Clinicopathological features, treatment responses, and kidney outcomes were compared between patients with and without IgM deposition.Results76 (36.2%) patients shown glomerular IgM deposition. Patients with IgM deposition were younger (45±13.296 vs. 50.59±13.65 years, P=0.006), had a higher estimated glomerular filtration rate (eGFR) (100.03 [81.31–111.37] vs. 92.67 [74.71–106.63] mL/min/1.73 m2, P=0.041), and had a lower proportion of nephrotic syndrome (60.5% vs. 75.4%, P=0.024) at the time of kidney biopsy. Patients with IgM deposition had a significantly higher proportion of focal segmental glomerular sclerosis (FSGS) lesions (27.6% vs. 13.4%, P=0.011) and C1q deposition (72.4% vs. 57.5%, P=0.032). Although the treatments and initial treatment responses were comparable, patients with glomerular IgM deposition had a significantly greater proportion of eGFR decline of ≥5 mL/min/1.73 m2 per year (log-rank test, P<0.001) and eGFR decrease of ≥10% from baseline (log-rank test, P=0.003). Cox regression analysis showed that IgM deposition was an independent risk factor of eGFR decline of ≥5 mL/min/1.73 m2 per year (HR, 2.442; 95% CI, 1.550–3.848, P<0.001) and eGFR decline by ≥10% from baseline (HR, 2.629; 95% CI, 1.578–4.385, P<0.001) during follow-up.ConclusionsGlomerular IgM deposition is associated with younger age, more severe FSGS lesions and C1q deposition, and worse renal outcomes in IMN.

A Novel Model for Nephrotic Syndrome Reveals Associated Dysbiosis of the Gut Microbiome and Extramedullary Hematopoiesis

Glomerular kidney disease causing nephrotic syndrome is a complex systemic disorder and is associated with significant morbidity in affected patient populations. Despite its clinical relevance, well-established models are largely missing to further elucidate the implications of uncontrolled urinary protein loss. To overcome this limitation, we generated a novel, inducible, podocyte-specific transgenic mouse model (Epb41l5fl/fl*Nphs1-rtTA-3G*tetOCre), developing nephrotic syndrome in adult mice. Animals were comprehensively characterized, including microbiome analysis and multiplexed immunofluorescence imaging. Induced knockout mice developed a phenotype consistent with focal segmental glomerular sclerosis (FSGS). Although these mice showed hallmark features of severe nephrotic syndrome (including proteinuria, hypoalbuminemia and dyslipidemia), they did not exhibit overt chronic kidney disease (CKD) phenotypes. Analysis of the gut microbiome demonstrated distinct dysbiosis and highly significant enrichment of the Alistipes genus. Moreover, Epb41l5-deficient mice developed marked organ pathologies, including extramedullary hematopoiesis of the spleen. Multiplex immunofluorescence imaging demonstrated red pulp macrophage proliferation and mTOR activation as driving factors of hematopoietic niche expansion. Thus, this novel mouse model for adult-onset nephrotic syndrome reveals the significant impact of proteinuria on extra-renal manifestations, demonstrating the versatility of this model for nephrotic syndrome-related research.

Effective cholesterol lowering after myocardial infarction in patients with nephrotic syndrome may require a multi-pharmacological approach: a case report

Background Nephrotic syndrome causes severe hypercholesterolaemia due to increased production and altered clearance of lipoproteins from the liver. It is challenging for patients with nephrotic syndrome and coronary heart disease to meet LDL-cholesterol (LDL-C) goals for secondary prevention with conventional lipid-lowering therapy. Case summary We present a man with nephrotic syndrome caused by focal segmental glomerular sclerosis (FSGS) and hypercholesterolaemia. He presented at the emergency room (ER) with an ST-elevation myocardial infarction at the age of 26. On follow-up, the patient had persistent hypercholesterolaemia [LDL-C 3.9 mmol/L and lipoprotein(a) 308 nmol/L] despite a combination of lipid-lowering therapy with atorvastatin 80 mg/day and ezetimibe 10 mg/day. Addition of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitory antibody evolocumab 140 mg bi-monthly did not improve cholesterol levels. However, after addition of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin 10 mg/day on top of other anti-proteinuric treatments, the patient’s proteinuria was reduced and a dramatic drop in LDL-C level by 3.2–0.6 mmol/L (−81%) was observed when evolocumab was re-introduced. Discussion We show that target LDL-C levels were obtained in this patient with therapy-resistant FSGS and hypercholesterolaemia following multi-pharmacological treatment with SGLT2 and PCSK9 inhibitors on top of conventional lipid-lowering therapy. The SGLT2-inhibitor reduced proteinuria and, speculatively, also reduced urinary loss of PCSK9-antibody. Therefore, in patients with nephrotic syndrome and cardiovascular disease novel therapeutic options to manage proteinuria could be considered to improve the efficacy of the lipid-lowering therapy, especially when the protein-based PCSK9 inhibitors are used.

MO289IS THERE A ROLE OF INTERSTITIAL CHANGES ON THERAPY OUTCOME AMONG PATIENTS WITH FOCAL-SEGMENTAL GLOMERULAR SCLEROSIS AND MINIMAL CHANGE DISEASE?

Background and Aims It is well-known that interstitial changes in patients with focal-segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are linked with disease chronicity and progression. The aim of this study was to analyze is there any connection between interstitial changes and outcome after “first line” therapy in patients with FSGS/MCD. Method From 2014 till 2019, biopsy proven diagnosis of FSGS/MCD was established in 40 patients. Interstitial changes were classified in three groups as following: 0-w/o changes; 1-mild changes; 2-severe changes. Patients with nephrotic syndrome (No=29) were treated with prednisolone (1mg/kg) and after six months we have registered therapy outcome as: CR-complete remission; PR-partial remission; EX-death; NO-no effect. Results Among treated patients (age 50.4±15.3 years, 15 men), CR was achieved in 10 patients (34.5%) and 6 out of these 10 (60%) had no interstitial changes. Partial remission was observed in 11 patients (37.9%), in 4 patients (13.8%) therapy did not have any effect, and 4 patients (13.8%) deceased (table 1). All patients in EX and NO group had interstitial changes. There were no significant difference in age, gender, proteinuria, albuminaemia, creatinine and glycaemia levels between groups except for hemoglobin levels that were significantly lower in EX group than in others (∑ 15.144; p=0.002) and urea levels that were significantly higher in EX group (∑ 138.057; p=0.024). Conclusion Patients with FSGS/MCD respond well on standard immunosuppressive protocol, particularly in absence of interstitial changes what may increase the chance for achieving complete remission.