Nephrolithiasis management and outcomes in pediatric patients with limited mobility.

INTRODUCTION AND OBJECTIVES: Pediatric patients with limited lower extremity mobility may be at increased risk of developing nephrolithiasis due to bone mineral metabolic derangements. This study sought to assess whether nephrolithiasis management and related outcomes differ between ambulatory versus non-ambulatory pediatric patients. METHODS: This was a retrospective review of ambulatory and non-ambulatory pediatric patients with nephrolithiasis from 2010 to 2021 from a single tertiary care center. Demographics, surgical history, stone compositions, and 24-h urine data were reviewed. Adjusted logistic and linear regression models were utilized to assess whether mobility status was associated with nephrolithiasis-related management and outcomes, including: age at first stone; requiring surgical intervention for stones; number of surgeries; stone compositions; urine culture results; and completion of 24-h urine studies. RESULTS: Among 339 pediatric patients with nephrolithiasis, 67 (19.8%) were non-ambulatory. In adjusted analyses, non-ambulatory patients had 3.24 times greater odds of requiring surgical intervention for stones (95% CI: 1.93-6.84; p < 0.0001); among those who required surgery, non-ambulatory patients required an average of 0.82 more surgical interventions (95% CI: 0.35-1.30; p = 0.0008) than ambulatory patients. Additionally, non-ambulatory patients had 5.28 times greater odds of having a positive urine culture at the time of surgery (95% CI: 2.35-14.08; p = 0.0001) and were significantly less likely to undergo 24-h urine studies (OR: 0.35; 95% CI: 0.15-0.83; p = 0.02). Stone composition significantly varied by mobility status, with non-ambulatory patients being significantly more likely to form calcium apatite (OR: 5.1; 95% CI: 2.18-11.93; p = 0.0002) or struvite (OR 3.72; 95% CI: 1.18-11.74; p = 0.03) stones, and significantly less likely to form calcium oxalate stones (OR: 0.19; 95 CI: 0.08-0.47; p = 0.0003). Among all patients, age at first stone occurred at a median age of 13.4 years (IQR: 8.2-16.4) and did not significantly differ by mobility status (p = 0.92). CONCLUSIONS: Patients with limited mobility required surgery for nephrolithiasis at significantly higher rates and had different stone compositions than ambulatory patients. Obtaining a 24-h urine study in patients with comorbidities affecting ambulation was uncommon, compared to ambulatory patients. Similarly to ambulatory patients, pediatric patients with limited mobility who develop nephrolithiasis tend to first present with stones in early adolescence.

Pathophysiology and treatment of cardiovascular disease in pediatric chronic kidney disease.

Life expectancy in patients with all stages of chronic kidney disease (CKD) falls far short of that in the general population. Cardiovascular disease is the leading cause of mortality in pediatric patients with CKD. In contrast to the intimal atherosclerotic lesions that characterize cardiovascular disease in the general population, vascular endothelial dysfunction, medial arterial calcification, and cardiac dysfunction contribute to cardiovascular pathological conditions in CKD. The pathogenesis of these lesions, the origins of which can be identified in the absence of traditional cardiovascular risk factors, is incompletely understood. CKD-mediated vascular calcification in CKD is characterized by a transition of vascular smooth muscle cells to an osteoblast-like phenotype and altered bone and mineral metabolism are strongly linked to progressive cardiovascular disease in this population. Renal osteodystrophy therapies, including phosphate binders, vitamin D analogs, and calcimimetics, have an impact on the progression of cardiovascular disease. However, cardiovascular disease has its origins before the development of secondary hyperparathyroidism, and optimal therapeutic regimens that minimize cardiac dysfunction, vascular calcification, and early mortality remain to be defined.

Primary osteoblast-like cells from patients with end-stage kidney disease reflect gene expression, proliferation, and mineralization characteristics ex vivo.

Osteocytes regulate bone turnover and mineralization in chronic kidney disease. As osteocytes are derived from osteoblasts, alterations in osteoblast function may regulate osteoblast maturation, osteocytic transition, bone turnover, and skeletal mineralization. Thus, primary osteoblast-like cells were cultured from bone chips obtained from 24 pediatric ESKD patients. RNA expression in cultured cells was compared with RNA expression in cells from healthy individuals, to RNA expression in the bone core itself, and to parameters of bone histomorphometry. Proliferation and mineralization rates of patient cells were compared with rates in healthy control cells. Associations were observed between bone osteoid accumulation, as assessed by bone histomorphometry, and bone core RNA expression of osterix, matrix gla protein, parathyroid hormone receptor 1, and RANKL. Gene expression of osteoblast markers was increased in cells from ESKD patients and signaling genes including Cyp24A1, Cyp27B1, VDR, and NHERF1 correlated between cells and bone cores. Cells from patients with high turnover renal osteodystrophy proliferated more rapidly and mineralized more slowly than did cells from healthy controls. Thus, primary osteoblasts obtained from patients with ESKD retain changes in gene expression ex vivo that are also observed in bone core specimens. Evaluation of these cells in vitro may provide further insights into the abnormal bone biology that persists, despite current therapies, in patients with ESKD.

The role of bone in CKD-mediated mineral and vascular disease.

Cardiovascular disease is the leading cause of death in pediatric patients with chronic kidney disease (CKD), and vascular calcifications start early in the course of CKD. Based on the growing body of evidence that alterations of bone and mineral metabolism and the therapies designed to treat the skeletal consequences of CKD are linked to cardiovascular calcifications, the Kidney Disease, Improving Global Outcomes (KDIGO) working group redefined renal osteodystrophy as a systemic disorder of mineral and bone metabolism due to CKD, and this newly defined disorder is now known as "chronic kidney disease-mineral bone disorder (CKD-MBD)". Elevated fibroblast growth factor 23 (FGF23), a bone-derived protein, is the first biochemical abnormality to be associated with CKD-MBD, and high FGF23 levels correlate with increased cardiovascular morbidity and mortality, suggesting that bone is central to both initiating and perpetuating the abnormal mineral metabolism and vascular disease in CKD. The current standard therapies for CKD-MBD affect FGF23 levels differently; non-calcium-based binders with or without concurrent use of dietary phosphate restriction reduce FGF23 levels, while calcium-based binders seem to either increase or have no effect on FGF23 levels. Active vitamin D sterols increase FGF23 levels, whereas therapy with calcimimetics decreases FGF23 levels. Thus, the appropriate therapy that will minimize the rise in FGF23 and prevent cardiovascular morbidity remains to be defined.