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Abstract Background Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown. Methods We reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients. Results Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression. Conclusions This first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.

Abstract Takayasu arteritis (TA) is a large vessel vasculitis that usually affects young female patients during the second and third decades of life, but has been reported in children as young as 24 months of age. Aim of this report was to describe four children (two girls) with TA, as well as summarizing main published studies. The mean age at presentation of our cases was 11 years (range 8–15). Three patients were Caucasians and one Asian. Arterial hypertension was the commonest mode of presentation followed by systemic symptoms. Other related symptoms were due to ischemia and consisted of abdomen, chest, and limb pain. An abdominal bruit was noted in only one patient. Inflammation markers were always abnormal. Angiography was performed in all cases; left subclavian artery and common carotid artery were more frequently involved. Renal artery stenosis was observed in two patients. One boy was diagnosed as having an associated immune deficiency (Wiskott-Aldrich syndrome). Treatment modalities included prednisone (n = 4), methotrexate (n = 3), and mycophenolate mofetil (MMF) (n = 1). Surgery was required in two patients. Follow-up ranged from 3 to 10 years since diagnosis. In three cases antihypertensive drugs and methotrexate were stopped, and prednisone was reduced to 7.5 mg/day.

Introduction: In primary hyperoxaluria type 1 (PH1), oxalate overproduction frequently causes kidney stones, nephrocalcinosis, and kidney failure. As PH1 is caused by a congenital liver enzyme defect, combined liver–kidney transplantation (CLKT) has been recommended in patients with kidney failure. Nevertheless, systematic analyses on long-term transplantation outcomes are scarce. The merits of a sequential over combined procedure regarding kidney graft survival remain unclear as is the place of isolated kidney transplantation (KT) for patients with vitamin B6-responsive genotypes. Methods: We used the OxalEurope registry for retrospective analyses of patients with PH1 who underwent transplantation. Analyses of crude Kaplan–Meier survival curves and adjusted relative hazards from the Cox proportional hazards model were performed. Results: A total of 267 patients with PH1 underwent transplantation between 1978 and 2019. Data of 244 patients (159 CLKTs, 48 isolated KTs, 37 sequential liver–KTs [SLKTs]) were eligible for comparative analyses. Comparing CLKTs with isolated KTs, adjusted mortality was similar in patients with B6-unresponsive genotypes but lower after isolated KT in patients with B6-responsive genotypes (adjusted hazard ratio 0.07, 95% CI: 0.01–0.75, P = 0.028). CLKT yielded higher adjusted event-free survival and death-censored kidney graft survival in patients with B6-unresponsive genotypes (P = 0.025, P < 0.001) but not in patients with B6-responsive genotypes (P = 0.145, P = 0.421). Outcomes for 159 combined procedures versus 37 sequential procedures were comparable. There were 12 patients who underwent pre-emptive liver transplantation (PLT) with poor outcomes. Conclusion: The CLKT or SLKT remains the preferred transplantation modality in patients with PH1 with B6-unresponsive genotypes, but isolated KT could be an alternative approach in patients with B6-responsive genotypes.

Abstract Primary hyperoxaluria (PH) is a group of diseases due to mutations in genes coding for enzymes involved in oxalate metabolism. Three types of PH are identified depending on the gene mutated. Type 1 is the most frequent with 80% of the cases, while PH2 and PH3 are rarer. The severity of renal involvement varies between the three types. Indeed, between 60% and 80% of PH1 but only 20% of PH2 patients will reach end‐stage kidney disease. In PH3 patients, dialysis is uncommon. Because oxalate clearance is impaired in CKD patients, oxalate can precipitate in various organs leading to systemic oxalosis. We report an uncommon presentation of bone oxalosis associated with hypercalcemia in a dialyzed patient. This report emphasizes the difficulties to diagnose primary hyperoxaluria and the challenge of treating dialyzed patients.

Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

BackgroundEstimating kidney glomerular filtration rate (GFR) is of utmost importance in many clinical conditions. However, very few studies have evaluated the performance of GFR estimating equations over all ages and degrees of kidney impairment. We evaluated the reliability of two major equations for GFR estimation, the CKD-EPI and Schwartz equations, with urinary clearance of inulin as gold standard.Methods and findingsThe study included 10,610 participants referred to the Renal and Metabolic Function Exploration Unit of Edouard Herriot Hospital (Lyon, France). GFR was measured by urinary inulin clearance (only first measurement kept for analysis) then estimated with isotope dilution mass spectrometry (IDMS)-traceable CKD-EPI and Schwartz equations. The participants' ages ranged from 3 to 90 y, and the measured GFRs from 3 to 160 ml/min/1.73 m2. A linear mixed-effects model was used to model the bias (mean ratio of estimated GFR to measured GFR). Equation reliability was also assessed using precision (interquartile range [IQR] of the ratio) and accuracy (percentage of estimated GFRs within the 10% [P10] and 30% [P30] limits above and below the measured GFR). In the whole sample, the mean ratio with the CKD-EPI equation was significantly higher than that with the Schwartz equation (1.17 [95% CI 1.16; 1.18] versus 1.08 [95% CI 1.07; 1.09], p < 0.001, t-test). At GFR values of 60-89 ml/min/1.73 m2, the mean ratios with the Schwartz equation were closer to 1 than the mean ratios with the CKD-EPI equation whatever the age class (1.02 [95% CI 1.01; 1.03] versus 1.15 [95% CI 1.13; 1.16], p < 0.001, t-test). In young adults (18-40 y), the Schwartz equation had a better precision and was also more accurate than the CKD-EPI equation at GFR values under 60 ml/min/1.73 m2 (IQR: 0.32 [95% CI 0.28; 0.33] versus 0.40 [95% CI 0.36; 0.44]; P30: 81.4 [95% CI 78.1; 84.7] versus 63.8 [95% CI 59.7; 68.0]) and also at GFR values of 60-89 ml/min/1.73 m2. In all patients aged ≥65 y, the CKD-EPI equation performed better than the Schwartz equation (IQR: 0.33 [95% CI 0.31; 0.34] versus 0.40 [95% CI 0.38; 0.41]; P30: 77.6 [95% CI 75.7; 79.5] versus 67.5 [95% CI 65.4; 69.7], respectively). In children and adolescents (2-17 y), the Schwartz equation was superior to the CKD-EPI equation (IQR: 0.23 [95% CI 0.21; 0.24] versus 0.33 [95% CI 0.31; 0.34]; P30: 88.6 [95% CI 86.7; 90.4] versus 29.4 [95% CI 26.8; 32.0]). This study is limited by its retrospective design, single-center setting with few non-white patients, and small number of patients with severe chronic kidney disease.ConclusionsThe results from this study suggest that the Schwartz equation may be more reliable than the CKD-EPI equation for estimating GFR in children and adolescents and in adults with mild to moderate kidney impairment up to age 40 y.