Acute kidney injury requiring kidney replacement therapy in childhood lupus nephritis: a cohort study of the Pediatric Nephrology Research Consortium and Childhood Arthritis and Rheumatology Research Alliance.

BACKGROUND: Acute kidney injury (AKI) is common in lupus nephritis (LN) and a risk factor for development of chronic kidney disease. In adults with LN, AKI severity correlates with the incidence of kidney failure and patient survival. Data on AKI outcomes in children with LN, particularly those requiring kidney replacement therapy (KRT), are limited. METHODS: A multicenter, retrospective cohort study was performed in children diagnosed between 2010 and 2019 with LN and AKI stage 3 treated with dialysis (AKI stage 3D). Descriptive statistics were used to characterize demographics, clinical data, and kidney biopsy findings; treatment data for LN were not included. Logistic regression was used to examine the association of these variables with kidney failure. RESULTS: Fifty-nine patients (mean age 14.3 years, 84.7% female) were identified. The most common KRT indications were fluid overload (86.4%) and elevated blood urea nitrogen/creatinine (74.6%). Mean follow-up duration was 3.9 ± 2.9 years. AKI recovery without progression to kidney failure occurred in 37.3% of patients. AKI recovery with later progression to kidney failure occurred in 25.4% of patients, and there was no kidney recovery from AKI in 35.6% of patients. Older age, severe (> 50%) tubular atrophy and interstitial fibrosis, and National Institutes of Health (NIH) chronicity index score > 4 on kidney biopsy were associated with kidney failure. CONCLUSIONS: Children with LN and AKI stage 3D have a high long-term risk of kidney failure. Severe tubular atrophy and interstitial fibrosis at the time of AKI, but not AKI duration, are predictive of kidney disease progression. A higher resolution version of the Graphical abstract is available as Supplementary information.

Gain-of-function, focal segmental glomerulosclerosis Trpc6 mutation minimally affects susceptibility to renal injury in several mouse models.

Mutations in TRPC6 are a cause of autosomal dominant focal segmental glomerulosclerosis in humans. Many of these mutations are known to have a gain-of-function effect on the non-specific cation channel function of TRPC6. In vitro studies have suggested these mutations affect several signaling pathways, but in vivo studies have largely compared wild-type and Trpc6-deficient rodents. We developed mice carrying a gain-of-function Trpc6 mutation encoding an E896K amino acid change, corresponding to a known FSGS mutation in TRPC6. Homozygous mutant Trpc6 animals have no appreciable renal pathology, and do not develop albuminuria until very advanced age. The Trpc6E896K mutation does not impart susceptibility to PAN nephrosis. The animals show a slight delay in recovery from the albumin overload model. In response to chronic angiotensin II infusion, Trpc6E896K/E896K mice have slightly greater albuminuria initially compared to wild-type animals, an effect that is lost at later time points, and a statistically non-significant trend toward more glomerular injury. This phenotype is nearly opposite to that of Trpc6-deficient animals previously described. The Trpc6 mutation does not appreciably impact renal interstitial fibrosis in response to either angiotensin II infusion, or folate-induced kidney injury. TRPC6 protein and TRPC6-agonist induced calcium influx could not be detected in glomeruli. In sum, these findings suggest that a gain-of-function Trpc6 mutation confers only a mild susceptibility to glomerular injury in the mouse.

Using a Multi-Institutional Pediatric Learning Health System to Identify Systemic Lupus Erythematosus and Lupus Nephritis: Development and Validation of Computable Phenotypes.

BACKGROUND AND OBJECTIVES: Performing adequately powered clinical trials in pediatric diseases, such as SLE, is challenging. Improved recruitment strategies are needed for identifying patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Electronic health record algorithms were developed and tested to identify children with SLE both with and without lupus nephritis. We used single-center electronic health record data to develop computable phenotypes composed of diagnosis, medication, procedure, and utilization codes. These were evaluated iteratively against a manually assembled database of patients with SLE. The highest-performing phenotypes were then evaluated across institutions in PEDSnet, a national health care systems network of >6.7 million children. Reviewers blinded to case status used standardized forms to review random samples of cases (n=350) and noncases (n=350). RESULTS: Final algorithms consisted of both utilization and diagnostic criteria. For both, utilization criteria included two or more in-person visits with nephrology or rheumatology and ≥60 days follow-up. SLE diagnostic criteria included absence of neonatal lupus, one or more hydroxychloroquine exposures, and either three or more qualifying diagnosis codes separated by ≥30 days or one or more diagnosis codes and one or more kidney biopsy procedure codes. Sensitivity was 100% (95% confidence interval [95% CI], 99 to 100), specificity was 92% (95% CI, 88 to 94), positive predictive value was 91% (95% CI, 87 to 94), and negative predictive value was 100% (95% CI, 99 to 100). Lupus nephritis diagnostic criteria included either three or more qualifying lupus nephritis diagnosis codes (or SLE codes on the same day as glomerular/kidney codes) separated by ≥30 days or one or more SLE diagnosis codes and one or more kidney biopsy procedure codes. Sensitivity was 90% (95% CI, 85 to 94), specificity was 93% (95% CI, 89 to 97), positive predictive value was 94% (95% CI, 89 to 97), and negative predictive value was 90% (95% CI, 84 to 94). Algorithms identified 1508 children with SLE at PEDSnet institutions (537 with lupus nephritis), 809 of whom were seen in the past 12 months. CONCLUSIONS: Electronic health record-based algorithms for SLE and lupus nephritis demonstrated excellent classification accuracy across PEDSnet institutions.

Principles of pediatric lupus nephritis in a prospective contemporary multi-center cohort.

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.

Late Kidney Effects of Childhood Cancer and Cancer Therapies.

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.

Cosmc-dependent mucin-type O-linked glycosylation is essential for podocyte function.

Mucin-type O-linked glycosylation, a posttranslational modification affecting the stability and biophysical characteristics of proteins, requires C1GalT1 (T synthase) and its obligate, X-linked chaperone Cosmc. Hypomorphic C1GalT1 mutations cause renal failure via not yet established mechanisms. We hypothesize that impaired Cosmc-dependent O-glycosylation in podocytes is sufficient to cause disease. Podocyte-specific Cosmc knockout mice were generated and phenotyped to test this hypothesis. Female heterozygous mice displaying mosaic inactivation of Cosmc in podocytes due to random X-linked inactivation were also examined. Mice with podocyte-specific Cosmc deletion develop profound albuminuria, foot process effacement, glomerular sclerosis, progressive renal failure, and impaired survival. Glomerular transcriptome analysis reveals early changes in cell adhesion, extracellular matrix organization, and chemokine-mediated signaling pathways, coupled with podocyte loss. Expression of the O-glycoprotein podoplanin was lost, while Tn antigen, representing immature O-glycans, was most abundantly found on podocalyxin. In contrast to hemizygous male and homozygous female animals, heterozygous female mosaic animals developed only mild albuminuria, focal foot process effacement, and nonprogressive kidney disease. Ultrastructurally, Cosmc-deficient podocytes formed Tn antigen-positive foot processes interdigitating with those of normal podocytes but not with other Cosmc-deficient cells. This suggests a cell nonautonomous mechanism for mucin-type O-glycoproteins in maintaining podocyte function. In summary, our findings demonstrated an essential and likely cell nonautonomous role for mucin-type O-glycosylation for podocyte function.

Acute kidney injury in hematopoietic stem cell transplantation.

PURPOSE OF REVIEW: Acute kidney injury (AKI) in the setting of hematopoietic stem cell transplantation (HSCT) is common in pediatric and adult patients. The incidence ranges from 12 to 66%, and development of AKI in the posttransplant course is independently associated with higher mortality. RECENT FINDINGS: Patients who undergo HSCT have many risk factors for developing AKI, including sepsis, use of nephrotoxic medications, graft versus host disease (GVHD), and veno-occlusive disease (VOD). In addition, engraftment syndrome/cytokine storm, transplant-associated thrombotic microangiopathy (TA-TMA), and less common infections with specific renal manifestations, such as BK and adenovirus nephritis, may lead to kidney injury. There has been significant advancement in the understanding of TA-TMA in particular, especially the role of the complement system in its pathophysiology. The role of early dialysis has been explored in the pediatric population, but not well studied in adult HSCT recipients SUMMARY: This review provides an update on the risk factors, causes, and treatment approaches to HSCT-associated AKI.

Transmembrane insertases and N-glycosylation critically determine synthesis, trafficking, and activity of the nonselective cation channel TRPC6.

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 ß-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.

Should ACE inhibitors and ARBs be used in combination in children?

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in a host of renal and cardiovascular functions. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), drugs that disrupt RAAS function, are effective in treating hypertension and offer other renoprotective effects independent of blood pressure (BP) reduction. As our understanding of RAAS physiology and the feedback mechanisms of ACE inhibition and angiotensin receptor blockade have improved, questions have been raised as to whether combination ACEI/ARB therapy is warranted in certain patients with incomplete angiotensin blockade on one agent. In this review, we discuss the rationale for combination ACEI/ARB therapy and summarize the results of key adult studies and the limited pediatric literature that have investigated this therapeutic approach. We additionally review novel therapies that have been developed over the past decade as alternative approaches to combination ACEI/ARB therapy, or that may be potentially used in combination with ACEIs or ARBs, in which further adult and pediatric studies are needed.