Evaluation of thyroid profile among children aged 1-15 years with nephrotic syndrome: An observation study.

BACKGROUND: The interaction between the kidney and the thyroid is important for normal function of both organs. In nephrotic syndrome, proteinuria leads to loss of several proteins, which in turn causes hypothyroidism. AIM: To assess the thyroid function in children with nephrotic syndrome. METHODS: This cross-sectional study was conducted in a tertiary center, Bhopal, from February 2020 to January 2021. Consecutive children aged 1-15 years admitted with nephrotic syndrome (first-time diagnosed and all relapse cases) were included in the study. A thyroid profile was sent along with routine investigations, and thyroid hormone status was assessed in nephrotic syndrome children. RESULTS: Of the 70 patients, 39 (55.7%) showed abnormal thyroid profiles; 19 (27.1%) had overt hypothyroidism, and 20 (28.6%) had subclinical hypothyroidism. Overt hypothyroidism was seen in 16.1% of newly diagnosed cases, 40% of second relapses, and 2.7% of frequently relapsed cases (P < 0.001). The mean serum free T3 and free T4 levels in frequent relapses were 2.50 ± 0.39 ng/dL and 0.78 ± 0.12 ng/dL, respectively, which were significantly lower than in newly diagnosed cases (2.77 ± 0.37 ng/dL and 0.91 ± 0.19 ng/dL, respectively). The mean thyroid-stimulating hormone (TSH) level was significantly higher in frequent relapses 5.86 ± 1.56 µIU/mL) and second relapse (5.81 ± 1.78 µIU/mL) than in newly diagnosed cases (4.83 ± 0.76 µIU/mL) and first relapse cases (4.74 ± 1.17 µIU/mL), (P < 0.01). CONCLUSION: An abnormal thyroid profile was commonly observed in children with nephrotic syndrome, and overt hypothyroidism was more common in frequent relapse cases. Therefore, thyroid screening should be a part of the management of nephrotic syndrome so that hypothyroidism can be detected and managed at an early stage.

Spectrum of Alport syndrome in an Indian cohort.

BACKGROUND: Next-generation sequencing has enabled non-invasive diagnosis of type IV collagen disease in clinical settings other than the typical presentation of Alport syndrome (AS). METHODS: We reviewed the clinical and histological records of children diagnosed with Alport syndrome based on next-generation sequencing. Variants on clinical exome sequencing were categorized using ACMG 2015 criteria. RESULTS: During 2015-2023, we found 43 patients (34 boys) with 39 variants in COL4A5 (n = 27), COL4A4 (n = 7), and COL4A3 (n = 5). Thirty, 8, and 5 patients had X-linked, autosomal recessive, and autosomal dominant disease, respectively. The median (IQR) age and eGFR at diagnosis were 10 (7-13) years and 100.1 (59-140) ml/min/1.73 m2, respectively. Fifteen patients were initially diagnosed with steroid-resistant nephrotic syndrome. Alport syndrome was suspected in these patients due to persistent microscopic hematuria, eGFR < 90 ml/min/1.73 m2, characteristic histology, and/or non-response to immunosuppression. Of 26 patients who underwent kidney biopsy, light microscopy revealed focal segmental glomerulosclerosis, minimal change disease, and mesangial proliferative glomerulonephritis in 9, 9, and 8 patients, respectively. Electron microscopy (n = 18) showed characteristic glomerular basement membrane changes and/or foot process effacement in 12 and 16 cases, respectively. Twenty-one patients (48.8%) had high-frequency sensorineural hearing loss, while two had lenticonus. Twelve patients progressed to chronic kidney disease stages 4-5. Median survival (IQR) with eGFR > 30 ml/min/1.73 m2 was 15.6 (13-18) years. CONCLUSIONS: The phenotype of Alport syndrome varies from asymptomatic urinary abnormalities to hematuria, proteinuria and/or low eGFR, and steroid-resistant nephrotic syndrome. Adverse outcomes are common, especially in boys with X-linked disease.

Effective calcineurin inhibitor treatment in adult-onset steroid-resistant nephrotic syndrome with a novel splice donor site variant of TRPC6: a case report.

Transient receptor potential canonical 6 (TRPC6) variants, which were initially detected in adult-onset familial focal segmental glomerulosclerosis (FSGS), were also identified in pediatric-onset one. Here, we present a patient with adult-onset steroid-resistant nephrotic syndrome (SRNS) who harbored a likely pathogenic TRPC6 variant and partially responded to calcineurin inhibitors (CNIs). A 44-year-old woman with stable rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome was presented with nephrotic syndrome. Her renal biopsy results showed minor glomerular abnormalities. Upon admission, she was treated with steroids for around 4 weeks, but it was ineffective. After 1-2 weeks of cyclosporine A (CyA) administration, urine output increased, renal function improved without a decrease in proteinuria, and she was discharged. Her renal function was maintained for 2 months, but after a CyA dose reduction, she was again admitted to the hospital due to relapsing edema, decreased urine output, and worsening renal function. CyA was replaced by tacrolimus (TAC). A second renal biopsy showed nearly the same findings as the first except for tubulointerstitial lesions. After 1-2 weeks of TAC administration, urine output increased, and renal function improved. However, urinary protein levels did not decrease as before. After discharge, a whole exome analysis revealed a heterozygous splice donor site variant NM_004621.6;c.2644 + 1G > A in TRPC6. Genetic testing identified a novel splice donor site variant of TRPC6 in a patient with adult-onset SRNS, which prevented unnecessary steroid continuation. The safety and efficacy of CNI in TRPC6 glomerulopathy must be evaluated in future larger studies with longer follow-up.

Nucleoporin-associated steroid-resistant nephrotic syndrome.

Nucleoporins (Nups) are a class of proteins that assemble to form nuclear pore complexes, which are related to nucleocytoplasmic transport, gene expression, and the cell cycle. Pathogenic variants in six genes encoding Nups, NUP85, NUP93, NUP107, NUP133, NUP160, and NUP205, cause monogenic steroid-resistant nephrotic syndrome (SRNS), referred to as nucleoporin-associated SRNS. In this paper, we review the epidemiology, structure and function of Nups, pathogenesis, phenotypes and genotypes, and management of nucleoporin-associated SRNS as well as implications for genetic counseling. Affected individuals exhibit autosomal recessive isolated and syndromic SRNS, whose extrarenal manifestations include neurological disorders, growth and development disorders, cardiovascular disorders, and congenital malformations. The median ages at onset of NUP85-, NUP93-, NUP107-, NUP133-, NUP160-, and NUP205-associated SRNS are 7, 3, 4.1, 9, 7, and 2 years, respectively. Kidney biopsies reveal focal segmental glomerulosclerosis in 89% of patients. Most affected individuals are resistant to immunosuppressants. For the six subtypes of nucleoporin-associated SRNS, patients show progression to kidney failure at median ages of 8.5, 3.7, 6.9, 13, 15, and 7 years, respectively. Only two patients with NUP93-associated SRNS with nephrotic syndrome relapse post-transplant have been reported, and the recurrence rate is 12.5%. Next-generation sequencing using a targeted gene panel is recommended in cases of suspected nucleoporin-associated SRNS for genetic diagnosis. Renin-angiotensin-aldosterone system inhibitors are recommended for patients with nucleoporin-associated SRNS. Once genetic diagnosis is confirmed, immunosuppressant discontinuation should be considered, and kidney transplant is preferred when patients progress to kidney failure. Genetic counselling should be provided for asymptomatic siblings and future siblings of an affected individual. Further studies on the pathogenesis of nucleoporin-associated SRNS are needed to seek new therapeutic interventions.

Seroprevalence of SARS-CoV-2 antibodies in children with nephrotic syndrome and chronic kidney disease: a cross-sectional study from India.

BACKGROUND: There is a paucity of literature on the seroprevalence of SARS-CoV-2 antibodies among pediatric patients with underlying kidney disorders; few serosurveys among healthy children have shown seropositivity of 20-65% after different waves of infections. METHODS: The study had a cross-sectional design and was conducted between January 2023 and July 2023; 163 children and adolescents (1-18 years) with nephrotic syndrome and chronic kidney disease (CKD) were screened for Anti-Spike SARS-COV-2 IgG antibodies as detected by a quantitative chemiluminescence immunoassay. Children with nephrotic syndrome, both steroid sensitive (SSNS) and steroid resistant (SRNS) were enrolled during disease remission. Correlation of SARS-CoV-2 seropositivity status was done with age, gender, disease type, treatment duration, immunosuppressants, previous SARS-CoV-2 infection, and immunization status. RESULTS: Of 163 children (63.8% boys) with median age of 9 years; 101 (62%) had underlying nephrotic syndrome (61 SSNS and 40 SRNS), and 62 (38%) children had CKD. Seroprotective titers for SARS-COV2 antibodies were present in 100 (61.3%) children. The median titers for all patients were 37.1 BAU/mL; for nephrotic syndrome they were 27.1 BAU/mL and for CKD they were 76.7 BAU/mL (p = 0.0033). A total of 43 (26.4%) children had high positive antibody levels (> 200 BAU/ml). Among those with nephrotic syndrome 60.7% with SSNS and 43.5% SRNS had seropositive titers. Only 4 (2.5%) children had a history of previous COVID infection and 6 (3.7%) were vaccinated. CONCLUSIONS: In a largely unvaccinated population of children with nephrotic syndrome and CKD, 61.3% were seropositive for SARS-CoV-2 IgG antibody indicating a past asymptomatic infection; titers were significantly higher in CKD compared to nephrotic syndrome.

Integrated Multi-Omics Analysis Reveals Mountain-Cultivated Ginseng Ameliorates Cold-Stimulated Steroid-Resistant Asthma by Regulating Interactions among Microbiota, Genes, and Metabolites.

Steroid-resistant asthma (SRA), resisting glucocorticoids such as dexamethasone (DEX), is a bottleneck in the treatment of asthma. It is characterized by a predominantly neutrophilic inflammatory subtype and is prone to developing into severe refractory asthma and fatal asthma. Currently, there is a lack of universally effective treatments for SRA. Moreover, since cold stimulation does increase the risk of asthma development and exacerbate asthma symptoms, the treatment of cold-stimulated SRA (CSRA) will face greater challenges. To find effective new methods to ameliorate CSRA, this study established a CSRA mouse model of allergic airway inflammation mimicking human asthma for the first time and evaluated the alleviating effects of 80% ethanol extract of mountain-cultivated ginseng (MCG) based on multi-omics analysis. The results indicate that cold stimulation indeed exacerbated the SRA-related symptoms in mice; the DEX individual treatment did not show a satisfactory effect; while the combination treatment of DEX and MCG could dose-dependently significantly enhance the lung function; reduce neutrophil aggregation; decrease the levels of LPS, IFN-γ, IL-1ß, CXCL8, and IL-17; increase the level of IL-10; alleviate the inflammatory infiltration; and decrease the mucus secretion and the expression of MUC5AC. Moreover, the combination of DEX and high-dose (200 mg/kg) MCG could significantly increase the levels of tight junction proteins (TJs), regulate the disordered intestinal flora, increase the content of short-chain fatty acids (SCFAs), and regulate the abnormal gene profile and metabolic profile. Multi-omics integrated analysis showed that 7 gut microbes, 34 genes, 6 metabolites, and the involved 15 metabolic/signaling pathways were closely related to the pharmacological effects of combination therapy. In conclusion, integrated multi-omics profiling highlighted the benefits of MCG for CSRA mice by modulating the interactions of microbiota, genes, and metabolites. MCG shows great potential as a functional food in the adjuvant treatment of CSRA.

Urine-derived podocytes from steroid resistant nephrotic syndrome patients as a model for renal-progenitor derived extracellular vesicles effect and drug screening.

BACKGROUND: Personalized disease models are crucial for evaluating how diseased cells respond to treatments, especially in case of innovative biological therapeutics. Extracellular vesicles (EVs), nanosized vesicles released by cells for intercellular communication, have gained therapeutic interest due to their ability to reprogram target cells. We here utilized urinary podocytes obtained from children affected by steroid-resistant nephrotic syndrome with characterized genetic mutations as a model to test the therapeutic potential of EVs derived from kidney progenitor cells (nKPCs). METHODS: EVs were isolated from nKPCs derived from the urine of a preterm neonate. Three lines of urinary podocytes obtained from nephrotic patients' urine and a line of Alport syndrome patient podocytes were characterized and used to assess albumin permeability in response to nKPC-EVs or various drugs. RNA sequencing was conducted to identify commonly modulated pathways after nKPC-EV treatment. siRNA transfection was used to demonstrate the involvement of SUMO1 and SENP2 in the modulation of permeability. RESULTS: Treatment with the nKPC-EVs significantly reduced permeability across all the steroid-resistant patients-derived and Alport syndrome-derived podocytes. At variance, podocytes appeared unresponsive to standard pharmacological treatments, with the exception of one line, in alignment with the patient's clinical response at 48 months. By RNA sequencing, only two genes were commonly upregulated in nKPC-EV-treated genetically altered podocytes: small ubiquitin-related modifier 1 (SUMO1) and Sentrin-specific protease 2 (SENP2). SUMO1 and SENP2 downregulation increased podocyte permeability confirming the role of the SUMOylation pathway. CONCLUSIONS: nKPCs emerge as a promising non-invasive source of EVs with potential therapeutic effects on podocytes with genetic dysfunction, through modulation of SUMOylation, an important pathway for the stability of podocyte slit diaphragm proteins. Our findings also suggest the feasibility of developing a non-invasive in vitro model for screening regenerative compounds on patient-derived podocytes.

In steroid-resistant nephrotic syndrome that meets the strict definition, monogenic variants are less common than expected.

BACKGROUND: In patients with steroid-resistant nephrotic syndrome (SRNS), the presence of monogenic variants influences therapeutic strategies. Large cohort studies reported the detection of monogenic variants in approximately 30% of patients with SRNS. However, these cohorts included many patients, such as those with symptomatic proteinuria, who did not meet the strict diagnostic criteria for pediatric nephrotic syndrome (NS). Therefore, we investigated the proportion of causative monogenic variants detected in patients who strictly met the diagnostic criteria of SRNS and explored their clinical characteristics. METHODS: We examined pediatric SRNS cases with genetic analysis conducted in our hospital. Cases satisfying all of the following criteria were included: (1) age at onset 1-18 years, (2) serum albumin at onset ≤ 2.5 g/dl, (3) persistent heavy proteinuria, and (4) no complete remission after 4 weeks of steroid monotherapy. RESULTS: The proportion of detected monogenic variants was 12% (22/185) among all patients. The proportion was only 7% (9/129) in patients with edema at disease onset compared with 38% (9/24) in those without (p < 0.0001). Monogenic variants were rare in patients with acute kidney injury associated with NS (1% (1/11)) or a history of complete remission (4% (2/51)). CONCLUSIONS: Our study revealed a monogenic cause in 12% of individuals with strictly defined SRNS, a much smaller proportion than previously reported. The presence or absence of edema at the onset was an important factor to distinguish SRNS with monogenic cause from SRNS without. Our results provide further evidence of the SRNS types attributable to monogenic causes.

Unravelling the Acute, Chronic and Steroid-Refractory Management of High-Grade Neurological Immune-Related Adverse Events: A Call to Action.

Rare side effects of immune-checkpoint inhibitors (ICIs) are known as neurological immune-related adverse events (n-irAEs). Typically, n-irAEs affect the peripheral nervous system, primarily presenting as myositis, polyradiculoneuropathy, or cranial neuropathy. Less commonly, they impact the central nervous system, resulting in encephalitis, meningitis, or myelitis. High-grade n-irAEs managing and recognizing remains challenging, considering the risk of mortality and long-term disability. To date, strong scientific data are lacking to support the management of high-grade clinical forms. We performed a systematic literature search, selecting all articles describing high-grade steroid-resistance n-irAEs. and we reported them in a practical review. Specifically, current recommendations advise stopping ICI use and beginning corticosteroid treatment. Our findings highlighted that in steroid-resistant n-irAEs, it should be recommended to quickly escalate to plasma exchange (PLEX) and/or intravenously immunoglobulins (IVIg), usually in association with other immunosuppressants. Furthermore, newer evidence supports the use of drugs that may specifically block inflammation without reducing the anti-tumour effect of ICIs. In this practical review, we provide new evidence regarding the therapeutic approach of high-grade n-irAEs, particularly in steroid-resistant cases. We would also stress the importance of informing the scientific community of the discrepancy between current guidelines and clinical evidence in these rare forms of pathology.

Long-Term Clinical, Radiological, and Mortality Outcomes Following Pneumonitis in Nonsmall Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors: A Retrospective Analysis.

AIMS: Despite known short-term mortality risk of immune checkpoint inhibitor (ICI) pneumonitis, its impact on 1-year mortality, long-term pulmonary function, symptom persistence, and radiological resolution remains unclear. METHODS: We retrospectively analyzed 71 nonsmall cell lung cancer (NSCLC) patients treated with anti-PD(L)1 monoclonal antibodies between 2018-2021, who developed pneumonitis. Clinical and demographic covariates were collected from electronic medical record. Cox regression assessed associations with mortality, while logistic regression evaluated associations with persistent symptoms, hypoxemia, and radiological resolution. RESULTS: Steroid-refractory pneumonitis (hazard ratio [HR] = 15.1, 95% confidence interval [95% CI]:3.9-57.8, P < .0001) was associated with higher 1-year mortality compared to steroid-responsive cases. However, steroid-resistant (odds ratio [OR] = 1.4, 95% CI: 0.4-5.1, P = .58) and steroid-dependent (OR = 0.4, 95% CI: 0.1-1.2, P = .08) pneumonitis were not. Nonadenocarcinoma histology (OR = 6.7, 95% CI: 1.6-46.6, P = .01), grade 3+ pneumonitis (OR = 4.6, 95% CI: 1.3-22.7, P = .03), and partial radiological resolution (OR = 6.3, 95% CI: 1.8-23.8, P = .004) were linked to increased pulmonary symptoms after pneumonitis resolution. Grade 3+ pneumonitis (OR = 8.1, 95% CI: 2.3-31.5, P = .001) and partial radiological resolution (OR = 5.45, 95% CI: 1.29-37.7, P = .03) associated with residual hypoxemia. Nonadenocarcinoma histology (OR = 3.6, 95% CI: 1.01-17.6, P = .06) and pretreatment ILAs (OR = 4.8, 95% CI: 1.14-33.09, P = .05) were associated with partial radiological resolution. CONCLUSIONS: Steroid refractory pneumonitis increases 1-year mortality in NSCLC patients. Pretreatment ILAs may signal predisposition to fibrosis-related outcomes, seen as partial resolution, which in turn is associated with postresolution symptoms and residual hypoxemia. These findings offer insights for identifying patients at risk of adverse outcomes post-pneumonitis resolution.

Better clinical outcomes and lower triggering of inflammatory cytokines for allogeneic hematopoietic cell transplant recipients treated in home care versus hospital isolation - the Karolinska experience.

After allogeneic hematopoietic cell transplantation (Allo-HCT) and conditioning, patients are typically placed in isolated hospital rooms to prevent neutropenic infections. Since 1998, we've offered an alternative: home care for patients living within a one to two-hour drive of the hospital. In Sweden this approach includes daily visits by an experienced nurse and daily phone consultations with a unit physician. When necessary, patients receive transfusions, intravenous antibiotics, and total parenteral nutrition at home. Our initial study report compared 36 home care patients with 54 hospital-treated controls. Multivariate analysis found that home care patients were discharged earlier to outpatient clinics, required fewer days of total parenteral nutrition, had less acute graft-versus-host disease (GVHD) grade II-IV, and lower transplantation-related mortality (TRM) and lower costs. Long-term follow-up showed similar chronic GVHD and relapse rates in both groups, with improved survival rates in the home care group. A subsequent comparison of 146 home care patients with hospital-treated controls indicated that home care and longer home stays were associated with lower grades of acute GVHD. Home care was found to be safe and beneficial for children and adolescents. Over two decades, 252 patients received home care post-Allo-HCT without any fatalities at-home. Ten-year outcomes showed a 14% TRM and a 59% survival rate. In 2020, an independent center confirmed the reduced risk of acute GVHD grades II-IV for patients treated in home care. Here, we report for the first time that home care patients also demonstrate a less inflammatory systemic cytokine profile. We found higher levels of IFN-γ, IL-2, IL-5, IL-13, GM-CSF, and G-CSF, but lower VEGF in hospital-treated patients, which may contribute to acute GVHD grades II-IV. In conclusion, home-based treatment following Allo-HCT yields multiple promising clinical outcomes and improved systemic inflammatory markers, which may contribute to less development of life-threatening GVHD.

Recent advances in acute gastrointestinal graft versus host disease (aGvHD): aspects of steroid-resistant disease.

Acute Graft versus Host Disease (aGvHD) is a common immunological complication occurring in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Moreover, aGvHD is associated with a higher risk of infections and metabolic complications, affecting non-relapse mortality. Progress in transplantation has changed the prophylactic and therapeutic strategies of aGvHD and improved patient outcomes. The standard first-line therapy remains steroids, with a response rate of about 50%. The Janus Kinase 2 (JAK2) inhibitor, ruxolitinib, is an effective second-line therapy. The management of patients who developed a disease that is refractory to steroids and ruxolitinib, especially in the severe gastrointestinal forms of aGvHD, is not validated and remains an unmet medical need. In the article, we present the current clinical practice, as well as the latest advances targeting pathophysiological pathways of GvHD and gut microbiota, which may be a potential future of aGvHD therapy.

Association of PLCE1 (rs7922612) and COL4A3 (rs375290088) Genetic Variants with the Risk of Nephrotic Syndrome in Egyptian Pediatric Patients.

Nephrotic syndrome is one of the most prevalent pediatric kidney illnesses seen in pediatric nephrology clinics. Steroid resistance in children with nephrotic syndrome is a primary cause of renal failure and is characterized by nephrotic range proteinuria that does not respond to conventional steroid therapy. The current work was intended to investigate the possible role of the Phospholipase C epsilon 1 (rs7922612) and collagen4 alpha 3 (rs375290088) single nucleotide polymorphisms as risk factors for developing nephrotic syndrome among Egyptian children. The study was conducted on 100 children with nephrotic syndrome and 100 age- and sex-matched healthy individuals. Geno typing was performed by two methods of polymerase chain reaction for the analysis of PLCE1 (rs7922612) and COL4A3 (rs375290088) variants. We observed a higher percentage of the heterozygous and homozygous variant genotypes of PLCE1 (rs7922612) SNP in NS patients in comparison with the controls (P < 0.001 for both). The frequencies of the PLCE1 (rs7922612) variant showed a statistically significant elevated risk of NS using several genetic models, including the dominant (OR = 9.12), recessive (OR = 2.31), and allelic (OR = 1.62) models (P < 0.001 for each). In addition, the PLCE1 (rs7922612) genotypes and alleles frequencies did not differ significantly between SRNS compared to SSNS cases. Furthermore, there was no significant difference regarding COL4A3 (rs375290088) polymorphism, neither between the NS and control groups nor between SDNS and SRNS. PLCE1 (rs7922612) is considered an independent risk factor for nephrotic syndrome in Egyptian pediatrics.COL4A3 (rs375290088) polymorphism is not correlated to Egyptian NS patients.

Clinical characteristics and favorable treatment responses of recurrent focal segmental glomerulosclerosis or steroid-resistant nephrotic syndrome in children after kidney transplantation.

BACKGROUND: Recurrence of focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) after kidney transplant leads to significant morbidity and potentially earlier allograft loss. To date however, reported rates, risk factors and treatment outcomes have varied widely. METHODS: We applied computational phenotypes to a multicenter aggregation of electronic health records data from 7 large pediatric health systems in the USA, to identify recurrence rates, risk factors, and treatment outcomes. We refined the data collection by chart review. RESULTS: From > 7 million patients, we compared children with primary FSGS/SRNS who received a kidney transplant between 2009 and 2020 and who either developed recurrence (n = 67/165; 40.6%) or did not (n = 98/165). Serum albumin level at time of transplant was significantly lower and recipient HLA DR7 presence was significantly higher in the recurrence group. By 36 months post-transplant, complete remission occurred in 58.2% and partial remission in 17.9%. Through 6 years post-transplant, no remission after recurrence was associated with an increased risk of allograft loss over time (p < 0.0001), but any remission showed similar allograft survival and function decline to those with no recurrence. Since treatments were used in non-random fashion, using spline curves and multivariable non-linear analyses, complete + partial remission chance was significantly higher with greater plasmapheresis sessions, CTLA4-Ig doses or LDL-apheresis sessions. Only treatment with anti-CD20, CTLA4-Ig agents, or LDL-apheresis sessions were associated with complete remission. Excluding 25 patients with mutations did not significantly change our results. CONCLUSIONS: Our contemporary high-risk cohort had higher favorable response rates than most prior reports, from combinations of agents.

Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset steroid-resistant nephrotic syndrome: a multicenter study.

BACKGROUND: The efficacy of rituximab in steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown. METHODS: This retrospective study included 45 patients with childhood-onset SRNS treated with rituximab across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. The primary outcome was the rate of CR, PR, and NR. Risk factors for non-CR were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were also evaluated. RESULTS: The rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. The median follow-up period after rituximab administration was 7.4 years. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively (p < 0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5. CONCLUSION: Early administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with SRNS.

Short stature and dysmorphic features in Asian Indian siblings with DAAM2-associated steroid-resistant nephrotic syndrome: Expansion of the phenotypic spectrum or a blended phenotype?

Variants in more than 60 different genes, most of which code for podocyte-related proteins, have been found to be associated with monogenic forms of nephrotic syndrome (NS). Biallelic variants in DAAM2, a member of the formin family, were recently identified to cause autosomal recessive (AR) NS type 24 in four unrelated families with steroid-resistant nephrotic syndrome (SRNS). This case report represents only the fifth reported family of DAAM2-associated NS and the first from India, with two sibs who presented with a complex phenotype characterized by steroid-resistant nephrotic syndrome, short stature, dysmorphic facial features, deep-set toenails, myopia, increased thickness of the calvarium of the skull, and sloping ribs. Both sibs were found to have a homozygous likely pathogenic nonsense variant c.196C>T (p.Arg66Ter; NM_001201427.2) in exon 3 of the DAAM2 gene through whole exome sequencing. The dysmorphic features could possibly be part of the DAAM2-related phenotype which has hitherto not been reported or could represent a blended phenotype, with the extrarenal manifestations resulting from a yet to be identified coexisting genetic condition.

Efficacy of rituximab in treating steroid-resistant Graves' orbitopathy in active moderate-to-severe and sight-threatening forms: A retrospective observation from China.

Background and objectives: The efficacy of rituximab (RTX) in treating steroid-resistant Graves' orbitopathy (GO) has been limitedly studied in Asians. Moreover, RTX has been considered even less for patients with steroid-resistant dysthyroid optic neuropathy (DON) who failed to undergo orbital decompression surgery for physical or financial reasons, or who responded poorly to the procedure. This study aimed to investigate the efficacy of RTX in treating steroid-resistant active moderate-to-severe and sight-threatening GO in a Chinese population. Methods: Data from 28 patients with steroid-resistant GO prescribed a single dose of 500 mg RTX were retrospectively retrieved. Treatment responses and contributing factors were analyzed. Results: The median follow-up time was 22 (8-34) weeks. 23 (82.1 %) patients had a positive objective outcome recommended by the European Group on Graves' Orbitopathy (EUGOGO), while 25 (92.6 %) had a decrease in 7-item clinical activity score (CAS) by at least 2. Diplopia, visual dysfunction, and MRI-detected T2 relaxation time of the involved extraocular muscles improved significantly at the last follow-up compared to baseline (81.0 % vs. 47.6 %, 38.9 % vs. 16.7 %, and 87.8 (8.64) vs. 75.8 (10.9) ms, respectively; all p values < 0.05). No significant improvement was seen in terms of proptosis and eye muscle duction. Notably, a higher baseline IgG4 to IgG ratio was a predictor for RTX-induced positive EUGOGO outcomes. After RTX treatment, all 8 patients with DON demonstrated inactivation, and 4 improved in visual acuity by ≥ 1 line. No patient with DON experienced obvious deterioration. Conclusion: A single dose of 500 mg RTX seemed to be an effective and tolerable treatment for steroid-resistant GO. However, larger-scale studies with a control group are required for a more solid conclusion. The role of RTX in steroid-resistant DON management where surgery is unavailable or ineffective should be further explored.

Recessive variants in MYO1C as a potential novel cause of proteinuric kidney disease.

BACKGROUND: Steroid-resistant nephrotic syndrome is the second leading cause of chronic kidney disease among patients < 25 years of age. Through exome sequencing, identification of > 65 monogenic causes has revealed insights into disease mechanisms of nephrotic syndrome (NS). METHODS: To elucidate novel monogenic causes of NS, we combined homozygosity mapping with exome sequencing in a worldwide cohort of 1649 pediatric patients with NS. RESULTS: We identified homozygous missense variants in MYO1C in two unrelated children with NS (c.292C > T, p.R98W; c.2273 A > T, p.K758M). We evaluated publicly available kidney single-cell RNA sequencing datasets and found MYO1C to be predominantly expressed in podocytes. We then performed structural modeling for the identified variants in PyMol using aligned shared regions from two available partial structures of MYO1C (4byf and 4r8g). In both structures, calmodulin, a common regulator of myosin activity, is shown to bind to the IQ motif. At both residue sites (K758; R98), there are ion-ion interactions stabilizing intradomain and ligand interactions: R98 binds to nearby D220 within the myosin motor domain and K758 binds to E14 on a calmodulin molecule. Variants of these charged residues to non-charged amino acids could ablate these ionic interactions, weakening protein structure and function establishing the impact of these variants. CONCLUSION: We here identified recessive variants in MYO1C as a potential novel cause of NS in children.

Steroid-Resistant Nephrotic Syndrome due to NPHS2 Variants Is Not Associated With Posttransplant Recurrence.

Introduction: Unlike idiopathic nephrotic syndrome (NS), hereditary podocytopathies are not expected to recur after kidney transplantation. However, some reports of posttransplant recurrence of NS in patients carrying variants in the NPHS2 gene have been described, notably with the p.Arg138Gln variant, which is more prevalent in Europe. The objective of this study was to assess the risk of recurrence after kidney transplantation in a large cohort of patients with biallelic NPHS2 pathogenic variants. Methods: Since January 2010, 61 patients identified at Necker-Enfants Malades Hospital and 56 enrolled in the PodoNet Registry with biallelic variants in the NPHS2 gene were transplanted and were compared with 44 transplanted children with steroid-resistant NS (SRNS) without any identified pathogenic variant. Results: Of the 117 patients, 23 carried the p.Arg138Gln variant in the homozygous state and 16 in the compound heterozygous state. The other 78 patients carried different variants in the homozygous (n = 44) or compound heterozygous state. Only 1 patient with NPHS2-related SRNS experienced posttransplant recurrence (median follow-up of cohort 8.5 years [2.5-15]). Conversely, 7 of 44 patients (16%) without any identified pathogenic variant recurred within a maximum of 7 days after transplantation (median follow-up 8.9 years [0.6-13.9]). Conclusion: In this large cohort, the risk of patients with causative variants in the NPHS2 gene to develop NS recurrence after kidney transplantation was extremely low. This is coherent with the pathophysiology of intrinsic slit-diaphragm disease. These data are reassuring and should be considered when counselling patients, making living kidney donation, whether related or not, a safe choice.

A Review of Focal Segmental Glomerulosclerosis Classification With a Focus on Genetic Associations.

Focal segmental glomerulosclerosis (FSGS) defines a distinct histologic pattern observed in kidney tissue that is linked to several distinct underlying causes, all converging on the common factor of podocyte injury. It presents a considerable challenge in terms of classification because of its varied underlying causes and the limited correlation between histopathology and clinical outcomes. Critically, precise nomenclature is key to describe and delineate the pathogenesis, subsequently guiding the selection of suitable and precision therapies. A proposed pathomechanism-based approach has been suggested for FSGS classification. This approach differentiates among primary, secondary, genetic, and undetermined causes, aiming to provide clarity. Genetic FSGS from monogenic mutations can emerge during childhood or adulthood, and it is advisable to conduct genetic testing in cases in which there is a family history of chronic kidney disease, nephrotic syndrome, or resistance to treatment. Genome-wide association studies have identified several genetic risk variants, such as those in apolipoprotein L1 (APOL1), that play a role in the development of FSGS. Currently, no specific treatments have been approved to treat genetic FSGS; however, interventions targeting underlying cofactor deficiencies have shown potential in some cases. Furthermore, encouraging results have emerged from a phase 2 trial investigating inaxaplin, a novel small molecule APOL1 channel inhibitor, in APOL1-associated FSGS.