Abstract Background The diagnosis and treatment of nephrotic syndrome (NS) dates back to Hippocrates. The treatment has undergone a significant transition from the use of intramuscular injections of cortisone to the use of oral prednisolone and a group of other immunosuppressive medications. Nevertheless, despite intense investigations into the etiologies and targeted treatments, the full potential for precision medicine as it applies to pediatric glomerular diseases remains unfilled. A literature search was completed of all randomized clinical trials in pediatric NS. The International Study of Kidney Disease in Children (ISKDC) conducted the first international collaborative randomized blinded controlled trial in pediatric nephrology in the 1960s, which provided the framework to this day of all subsequent randomized controlled trials (RCT) of NS in children. Optimal therapy of patients with frequent relapsing steroid-sensitive NS and steroid-resistant primary focal segmental glomerulosclerosis (FSGS) has remained challenging with treatment failures, complications, and impairment in the quality of life of the patients. Summary The discovery of biomarkers associated with NS has led to the innovation of precision medicine in the management of glomerular disease, which is tailored to individual patients. This review tracked the life course trajectory of RCTs in the treatment of NS, including steroid-sensitive, steroid-resistant NS and FSGS, and advanced therapies to provide individualized therapies which are based on biomarkers from Neptune Match Clinical Trials, FONT, DUET, and APOL1 studies to improve treatment outcomes and minimize side effects of unnecessary immunosuppressants (precision medicine). Key Messages The treatment of NS in pediatric patients has advanced significantly from the early use of corticosteroids to the current promise of new targeted non-immunosuppressant therapies. A review of the major RCTs in the field, from the seminal ISKDC to the present, provides new insights into the mechanisms responsible for glomerular conditions, including FSGS, and the application of advances in targeted therapies using unique biomarkers to implement the potential of precision medicine in alleviating the burden of chronic glomerular kidney disease in children and adolescents.
Background Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and kidney failure worldwide. Although renin–angiotensin–aldosterone system (RAAS) blockade and newer disease-modifying therapies have improved outcomes, substantial residual kidney and cardiovascular risks remain because of the complex and multifactorial pathogenesis of DKD. Summary This review summarizes current and emerging evidence supporting combination kidney-protective therapy in DKD, including RAAS inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, finerenone, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), endothelin receptor antagonists, and aldosterone synthase inhibitors. RAAS inhibitors remain the cornerstone of kidney protection, while SGLT2 inhibitors, finerenone, and GLP-1 RAs provide complementary effects by targeting glomerular hyperfiltration, inflammation, fibrosis, metabolic abnormalities, and cardiovascular risk. Clinical trials and real-world evidence support the additive benefits of combining therapies with distinct mechanisms of action. The integration of these agents has established a multidrug approach centered on the four pillars of kidney protection: RAAS blockade, SGLT2 inhibition, mineralocorticoid receptor antagonism with finerenone, and GLP-1 receptor activation. Emerging therapies targeting endothelin and aldosterone pathways may further enhance individualized treatment strategies. Key Messages Multidrug therapy targeting complementary pathogenic pathways represents the current paradigm for DKD management. Phenotype-guided treatment selection may optimize kidney and cardiovascular protection, minimize residual risk, and advance precision nephrology approaches.
Purpose: GM1 gangliosidosis is a rare autosomal recessive lysosomal storage disorder caused by variants in the GLB1 gene, leading to β-galactosidase deficiency and the accumulation of glycolipids and oligosaccharides. While neurological and systemic complications are well-documented, renal involvement remains poorly understood and largely unreported. This report aims to present the first detailed description of clinical and histopathologic renal findings in GM1-gangliosidosis, supported by comprehensive microscopic and ultrastructural analysis. Case Report: We describe a male infant with infantile-onset GM1-gangliosidosis, diagnosed based on clinical features, including developmental regression, severe hypotonia, macular cherry-red spots, and molecular confirmation of GLB1 variants. Throughout his clinical course, the patient developed hypoalbuminemia, nephrotic-range proteinuria, and pseudohyponatremia. Postmortem kidney biopsy revealed widespread vacuolization in glomerular podocytes, mesangial cells, and renal tubular cells. Vacuoles were negative for periodic acid-Schiff and methenamine silver stains. Ultrastructural analysis confirmed cytoplasmic vacuolization containing membranous and lamellar material. These findings are consistent with lysosomal storage pathology. Conclusion: This report highlights the severe histopathological and clinical renal manifestations of GM-1 gangliosidosis. This case underscores the need for further studies to better understand the mechanisms of renal pathology and their clinical implications in GM1-gangliosidosis, broadening the systemic understanding of this disease.
ALECT2 amyloidosis is a systemic amyloidosis derived from the precursor protein leukocyte cell–derived chemotactic 2 (LECT2), which is primarily produced by hepatocytes. ALECT2 has emerged as a prevalent non-AL renal amyloid subtype, especially in older patients of Mexican/Hispanic ancestry, as well as in Punjabi, First Nations, Native American, Egyptian, Sudanese, and Chinese populations. Renal involvement by ALECT2 can clinically mimic other nephritides, primarily with worsening renal function, and has been reported in patients presenting with pulmonary-renal syndromes and systemic lupus erythematosus (SLE). However, concurrent ALECT2 and biopsy proven ANCA-associated crescentic glomerulonephritis (GN)is exceedingly rare. Here we present an 80-year-old Persian male with a previous history of renal dysfunction attributed to urologic issues who presented with rapid deterioration of renal function. Renal biopsy revealed a focal pauci-immune necrotizing and crescentic GN with dual MPO & PR3 antibody positivity superimposed on an unexpected finding of early ALECT2 amyloidosis with atypical glomerular-limited involvement. Here, we discuss treatment responses and considerations of assessment of contributions of each disease to his renal dysfunction.
Background: The association between hypertension and accelerated deterioration in kidney function is well-established, yet inadequate blood pressure control persists in patients with chronic kidney disease. We investigated if the updated guidelines for hypertension management led to improved blood pressure control in patients after 2017 compared to pre-2017. Methods: Data were used from the Kidney Research Network electronic health record registry. Hypertension was defined using blood pressure measurements, ICD-9/10 codes, and medication records. Follow-up was split into two eras, pre-2017 and post-2017, however post-2017 guidelines on hypertension were applied to both eras. Blood pressure control was defined as observing healthy blood pressure for 75% of follow-up after hypertension diagnosis. We used logistic regression with a logit link and an unstructured correlation matrix to evaluate the effect of era on blood pressure control, adjusting for sex, race, glomerular disease diagnosis, medication usage, pre-diagnosis blood pressure, kidney function, proteinuria, and weight. Sequential regression was used to determine which variables were mediating the effect of era on blood pressure control. Results: A total of 725 adult patients were eligible for this analysis. Prior to 2017, 14% of patients demonstrated normal blood pressures compared to 10% in the post-2017 cohort. However, following adjustment, the post-2017 era had better blood pressure control. Blood pressure medication usage, particularly calcium channel blockers, increased after the guideline change. Conclusions: Blood pressure control in patients with glomerular disease remains poor. Publication of updated blood pressure management guidelines has not yet led to substantial improvement in blood pressure control in this patient population, though it has led to an increase in the number of medications prescribed.
