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Lupus nephritis (LN) is a life-threatening manifestation of systemic lupus erythematosus (SLE) and is more common in children than adults. The epidemiology and management of childhood-onset SLE (cSLE) have changed over time, prompting the need to reassess expected outcomes. The purpose of this study is to use the Childhood Arthritis and Rheumatology Research Alliance (CARRA) prospective registry to validate historical principles of LN in a contemporary, real-world cohort. After an extensive literature review, six principles of LN in cSLE were identified. The CARRA registry was queried to evaluate these principles in determining the rate of LN in cSLE, median time from cSLE diagnosis to LN, short-term renal outcomes, and frequency of rituximab as an induction therapy. Of the 677 cSLE patients in the CARRA registry, 32% had documented LN. Decline in kidney function was more common in Black cSLE patients than non-Black patients ( p = 0.04). Black race was associated with worse short-term renal outcomes. In short-term follow up, most children with LN had unchanged or improved kidney function, and end stage kidney disease (ESKD) was rare. Ongoing follow-up of cSLE patients in the CARRA registry will be necessary to evaluate long-term outcomes to inform risk, management, and prognosis of LN in cSLE.

Transient receptor potential cation channel subfamily C member 6 (TRPC6) is a widely expressed ion channel. Gain–of–function mutations in the human TRPC6 channel cause autosomal-dominant focal segmental glomerulosclerosis, but the molecular components involved in disease development remain unclear. Here, we found that overexpression of gain–of–function TRPC6 channel variants is cytotoxic in cultured cells. Exploiting this phenotype in a genome-wide CRISPR/Cas screen for genes whose inactivation rescues cells from TRPC6-associated cytotoxicity, we identified several proteins essential for TRPC6 protein expression, including the endoplasmic reticulum (ER) membrane protein complex transmembrane insertase. We also identified transmembrane protein 208 (TMEM208), a putative component of a signal recognition particle-independent (SND) ER protein-targeting pathway, as being necessary for expression of TRPC6 and several other ion channels and transporters. TRPC6 expression was also diminished by loss of the previously uncharacterized WD repeat domain 83 opposite strand (WDR83OS), which interacted with both TRPC6 and TMEM208. Additionally enriched among the screen hits were genes involved in N-linked protein glycosylation. Deletion of the mannosyl (α-1,3-)-glycoprotein β-1,2-N-acetylglucosaminyltransferase (MGAT1), necessary for the generation of complex N-linked glycans, abrogated TRPC6 gain–of–function variant-mediated Ca2+ influx and extracellular signal-regulated kinase activation in HEK cells, but failed to diminish cytotoxicity in cultured podocytes. However, mutating the two TRPC6 N-glycosylation sites abrogated the cytotoxicity of mutant TRPC6 and reduced its surface expression. These results expand the targets of TMEM208-mediated ER translocation to include multipass transmembrane proteins and suggest that TRPC6 N-glycosylation plays multiple roles in modulating channel trafficking and activity.

Childhood cancer therapy carries a high risk of treatment-related toxicities and complications that can impact kidney function. Although many of these adverse effects in the acute setting are well described, less is known about the latent effects of childhood cancer treatments on long-term kidney health. With decades of advancements in treatment protocols for many pediatric malignancies, more children than ever before are surviving into adulthood after being cured of their disease and with lower long-term morbidity. Although there is decreased prevalence of many chronic health conditions in cancer survivors, including gastrointestinal, endocrine, and musculoskeletal disorders, the long-term risk of kidney dysfunction has increased. In this review, we summarize the epidemiology of kidney disease in survivors of childhood cancer and describe the treatment-related risk factors associated with long-term impairment of kidney health. We organize this review by specific kidney disease-related outcomes of interest (chronic electrolyte abnormalities, CKD, proteinuria, and hypertension) to highlight what specific aspects of cancer treatment have been associated with these outcomes. Finally, we conclude by comparing different clinical practice guidelines that exist for long-term kidney function monitoring and include recommendations for when a childhood cancer survivor would benefit from long-term nephrology care.