Idiopathic nephrotic syndrome (INS) is among the most common glomerular diseases in children with standard first line treatment of glucocorticoids. However, there has been no definitive treatment that can completely cure disease with few side effects for steroid resistant INS patients. Voclosporin (VCS) is a second generation calcineurin inhibitor (CNI) approved in multiple countries for the treatment of adults with active lupus nephritis. VCS does not require therapeutic drug monitoring due to an improved pharmacokinetic profile compared to other CNIs. Based on this, we assessed the ability of VCS to ameliorate proteinuria and hypoalbuminemia in a non-inflammatory glomerular disease using an animal model of NS. Rats received 50 mg/kg puromycin aminonucleoside (PAN) IV to induce NS. Rats were gavaged BID with vehicle or VCS (4 mg/kg/dose), a clinically relevant dose. Outcome measures included proteinuria, hypoalbuminemia, serum lipid profiles, glomerular podocyte injury, renal tubular injury, and hypercoagulopathy. Human podocytes were also treated with PAN +/- VCS and assessed for cell viability and stress using XTT and LDH release assays. VCS treatment significantly ameliorated PAN-induced proteinuria (61% median reduction; P < 0.05) and tubular injury (P < 0.05) in rats. VCS also numerically but insignificantly improved hypoalbuminemia (P = 0.16), hypercoagulopathy (P = 0.099), and glomerular podocyte injury (P = 0.11). VCS did not exacerbate serum lipid profiles of rats with PAN-induced disease. In vitro, VCS significantly protected podocyte viability from PAN-induced toxicity and reduced PAN-induced stress, though not significantly. VCS significantly ameliorated proteinuria in a non-inflammatory model of glomerular disease, and compared favorably regarding improvements in hypoalbuminemia, hypercoagulopathy, dyslipidemia, and podocyte injury. These findings suggest that VCS could be clinically efficacious in patients with primary or secondary NS, without need for drug level testing and with decreased risk of exacerbation of known CNI-related dyslipidemia. Not applicable.

The primary objective of this study was to assess urinary vitamin D binding protein (uVDBP) levels in idiopathic nephrotic syndrome. Secondary objectives were to evaluate the ability of uVDBP to differentiate between steroid resistant nephrotic syndrome (SRNS) and steroid sensitive nephrotic syndrome (SSNS), and between minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) of SRNS. Sixty-three cases of idiopathic nephrotic syndrome were included; 23 were first episode nephrotic syndrome (FENS), 24 were relapsing nephrotic syndrome (RNS), and 16 were steroid resistant. Eleven subjects were used as controls and 17 cases were under remission. ELISA kit was used to assay uVDBP. Median uVDBP levels were increased across FENS, RNS, SRNS groups as compared to controls (P < 0.001). Median uVDBP was significantly higher in SRNS (32.2 ng/mL) than in SSNS (4.0 ng/mL, P < 0.001). Similarly, the median level was also significantly higher in FSGS (56.6 ng/mL) than in MCD (20.8 ng/mL, P = 0.005). The uVDBP was significantly lower during remission (1.2 ng/mL) than in the active (5.1 ng/mL) phase of the disease (P < 0.001). At the 12-ng/mL cut-off value, uVDBP had higher sensitivity, specificity, and area under the curve (100%, 97.9% and 0.983, respectively) for distinguishing steroid-resistant from steroid-sensitive patients. Significant positive correlation was found between uVDBP and urine protein/creatinine ratio (r = 0.441, P < 0.001) and negative correlation between uVDBP and serum albumin (r = -0.303, P = 0.019). uVDBP level is related to disease activity and can distinguish not only steroid-resistant from steroid-sensitive, but also FSGS from MCD histological subtypes of steroid-resistant NS. Objetivo principal - avaliar níveis de proteína de ligação à vitamina D urinária (uVDBP) na síndrome nefrótica idiopática. Objetivos secundários - determinar a capacidade da uVDBP de diferenciar síndrome nefrótica resistente a esteroides (SNRE) da sensível a esteroides (SNSE) e, no contexto da SNRE, distinguir doença de lesão mínima (DLM) de glomeruloesclerose segmentar focal (GESF). Estudo com 63 casos: 23 de primeiro episódio (SNPE), 24 recorrentes (SNR) e 16 resistentes a esteroides; 11 indivíduos serviram como controles e 17 estavam em remissão. O kit ELISA foi empregado para analisar uVDBP. Níveis medianos de uVDBP foram maiores em SNPE, SNR, SNRE versus controles (P < 0,001). A mediana foi significativamente maior na SNRE (32,2 ng/ml) em relação à SNSE (4,0 ng/ml; P < 0,001). De forma semelhante, a mediana também foi significativamente maior na GESF (56,6 ng/ml) do que na DLM (20,8 ng/ml; P = 0,005). A uVDBP foi significativamente menor durante a remissão (1,2 ng/ml) versus fase ativa (5,1 ng/ml) da doença (P < 0,001). No valor de corte 12 ng/ml, a uVDBP apresentou maior sensibilidade, especificidade e área sob a curva (100%, 97,9%, 0,983, respectivamente) para distinguir pacientes resistentes daqueles sensíveis a esteroides. Observou-se correlação positiva significativa com relação proteína/creatinina urinária (r = 0,441; P < 0,001) e negativa com albumina sérica (r = −0,303; P = 0,019). O nível de uVDBP relaciona-se à atividade da doença e pode distinguir resistência de sensibilidade a esteroides, além de diferenciar os subtipos histológicos da SNRE, GESF e DLM.

Background Nephrotic syndrome (NS) is a common renal ailment among children, typically manifesting as a relapsing-remitting pattern. Most of the cases are managed on an outpatient basis, but a subset of patients experience complications, e.g., acute kidney injury (AKI). Although historically more prevalent in secondary NS, AKI is now occurring increasingly in children with idiopathic NS. However, the literature on AKI in this population consists of case reports and retrospective studies, particularly from India, so the study was planned to identify various risk factors that precipitate AKI in a child with NS. The secondary objective was to assess the hydration status of children having NS and its association with the development of AKI. Materials and methods This longitudinal study was conducted in the Department of Pediatrics at the All India Institute of Medical Sciences, Raipur, Chhattisgarh, from October 2021 to April 2023. Children of both genders and age groups between three months and 15 years, satisfying the International Society for Pediatric Neurosurgery 2021 guideline for the diagnosis of NS, were included in the study. Children having chronic kidney disease were excluded. Using the non-probability convenient sampling technique, 57 patients with NS were enrolled in the study. The patients without AKI were evaluated daily for the development of AKI using the Kidney Disease Improving Global Outcomes 2012 guideline until day 14 or discharge and followed up for six months. Records of those children who were admitted with AKI were reviewed for possible risk factors of AKI. Data was analyzed on Epi Info software enUS version 7.3.2 (Centers for Disease Control and Prevention, Atlanta, GA, USA). Categorical data were expressed as a percentage and/or 95% confidence interval (CI) of the estimate and compared using Chi-square or Fisher's exact test. A p-value ≤0.05 was considered statistically significant. The odds ratio (OR) for risk factors for AKI was determined using logistic regression. Results The mean age of the study subjects at the onset of the disease was 5.34 ± 3.66 years. The common presentations were edema (94.74%) and oliguria (80.7%). The majority (89.2%) showed a response to steroid therapy. About 56.14% of children developed AKI, and stages 2 and 3 AKI were more common, 37.5% each. About 53.12% and 46.88% of children developed pre-renal AKI and intrinsic AKI, respectively; 45.61% had hypertension at admission, with the majority having stage 1 hypertension (38.46%). Only six (10.5%) children had sickle cell trait, and all developed AKI during follow-up. Forty-two (73.68%) children had nephrotoxic drug exposure, with the most common drug being enalapril, followed by nephrotoxic antibiotics. Out of 10 children with AKI who underwent renal biopsy, focal segmental glomerulosclerosis was the most common entity (60%). The notable parameters that were found to have statistical significance for AKI were low eGFR at admission, hypertension, nephrotoxic drug exposure, inadequate water intake, fractional excretion of sodium (FeNa), and urine potassium index as markers of renal hypoperfusion, infections, steroid-resistant nephrotic syndrome, and significant glomerular lesions. Conclusion The present study demonstrates an association between traditional risk factors and the causation of AKI. However, high urine osmolality, raised urine K+ index, and FeNa suggestive of raised aldosterone levels had a significant association with AKI.

Predicting the risks of progression to chronic kidney disease (CKD) stage 5 in idiopathic nephrotic syndrome (NS) and recurrence of the disease (rNS) following kidney transplantation (KT) is a key assessment to provide essential management information. NS has been categorized etiologically as genetic and immune-based. A genetic cause can be identified in ~ 30% of children with steroid-resistant NS (SRNS), a finding associated with a very low risk of rNS following KT. In immune-based NS, clinical overlap is observed among steroid-sensitive NS, secondary-resistant NS, and SRNS not associated with disease-causing genetic variants (non-monogenic SRNS). While ~ 50% of SRNS patients with no identified monogenic disease respond to intensified immunosuppressive treatments, the ones that do not respond to this therapy have a high risk of progression to CKD stage 5 and post-KT rNS. Secondary-resistant patients who progress to CKD stage 5 display the highest risk of post-KT rNS. The proposed shared underlying mechanism of the immune-based NS associated with post-KT rNS is based on a systemic circulating factor (CF) that affects glomerular permeability by inducing foot process effacement and focal segmental glomerulosclerosis. However, identifying patients without a detected genetic form who will recur post-KT is a major challenge. Extensive efforts, therefore, have been made to identify CFs and biomarkers potentially capable of predicting the risk of progression to CKD stage 5 and post-KT rNS. This review discusses the in vitro and in vivo approaches employed to date to identify and characterize potential CFs and CF-induced biomarkers of recurrent NS and offers an assessment of their potential to improve outcomes of KT in this patient population.

Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. Treatment with steroids is usually successful; however, in a small percentage of patients, steroid resistance is observed. The most frequent histologic kidney feature of steroid-resistant nephrotic syndrome (SRNS) is focal segmental glomerulosclerosis (FSGS). Genetic testing has become a valuable diagnostic tool in defining the etiology of SRNS, leading to the identification of a genetic cause. The TRIM8 gene is expressed in various tissues, including kidney cells and the central nervous system (CNS). An association between a mutation in the TRIM8 gene and an early onset of FSGS has been proposed but is not well described. We present a 17-year-old boy with epilepsy, early mild developmental delay, a low IgG serum level, and proteinuria, secondary to FSGS. A Next-Generation Sequencing (NGS)-based analysis revealed a heterozygous de novo pathogenic variant in the TRIM8 gene (c.1200C>G, p.Tyr400Ter). TRIM8 gene sequencing should be considered in individuals with early onset of FSGS, particularly accompanied by symptoms of cortical dysfunction, such as epilepsy and intellectual disability.