BASIC RESEARCH
Sphingosine Kinase 2 and Renal Fibrosis
The nuclear deacetylase inhibitor sphingosine 1-phosphate (S1P) has a critical role in AKI and renal fibrosis, but the importance of the S1P-producing sphingosine kinases 1 and 2 (SphK1 and SphK2) is unclear. In this issue, Bajwa et al. show that knockout of SphK2 in mice protects against AKI-induced renal fibrosis through the upregulation of IFN-γ. Moreover, daily administration of a moderately selective SphK2 inhibitor beginning 1 day after AKI protects against fibrosis in mice, suggesting the clinical potential of targeting SphK2 in renal disease. See Bajwa et al., pages 1145–1161.
The Function of Circulating αKlotho
Deficiency of the mineral metabolism regulator αKlotho (αKL) associates with hyperphosphatemia and vascular calcification. The membrane-bound form of αKL (mKL) functions as a receptor for fibroblast growth factor-23 (FGF23), but the function of the cleaved soluble form (cKL) is not well defined. Here, Hum et al. provide evidence from studies in diabetic mice and αKL-null mice suggesting that cKL increases serum FGF23 levels, reduces serum phosphate levels, and prevents aortic calcification associated with hyperphosphatemia. Thus, upregulating cKL-mediated pathways may restore proper mineral metabolism in diseases of hyperphosphatemia. See Hum et al., pages 1162–1174.
Mucosal Immune Dysregulation in IgA Nephropathy
The gene encoding a proliferation-inducing ligand (APRIL) has been identified as a susceptibility gene in patients with IgA nephropathy (IgAN), but the mechanisms involved remain unclear. Here, Muto et al. report the unusual upregulation of both cleavable and uncleavable APRIL in tonsillar germinal center B cells of patients with IgAN. A higher percentage of germinal centers with aberrant APRIL expression correlated with higher proteinuria before treatment and with improved outcomes after tonsillectomy. In vitro studies showed that repeated stimulation of Toll-like receptor 9 triggers the aberrant expression of APRIL. These findings advance our understanding of the role of mucosal immune dysregulation in the pathogenesis of IgAN. See Muto et al., pages 1227–1238.
CLINICAL EPIDEMIOLOGY
Fibroblast Growth Factor-23 and Infection Risk
Fibroblast growth factor-23 (FGF23) negatively regulates the production of 1,25-dihyroxyvitamin D. In this issue, Nowak et al. report on their prospective, longitudinal study of 3141 older community-dwelling adults without ESRD designed to determine the relationship between circulating FGF23 levels and infection risk. In this cohort, higher plasma FGF23 concentrations independently associated with risk of first infection-related hospitalization. Additional studies should be undertaken to confirm these findings and identify the molecular mechanisms involved. See Nowak et al., pages 1239–1246.
A Home-Based Exercise Program for Dialysis Patients
Patients on dialysis derive clear benefits from in-center exercise programs. Home-based programs could provide further options but have not been well studied. Manfredini et al. conducted a 6-month multicenter, randomized trial in 296 patients with stage 5D-CKD to evaluate a simple, personalized, low-intensity, home-based walking program managed by dialysis staff. Compared with the control group, the exercise group experienced significant improvement in physical capacity as well as cognitive function and quality of social interaction. Long-term trials should determine the effects of such exercise programs on clinical outcomes. See Manfredini et al., pages 1259–1268.
CLINICAL RESEARCH
Rituximab in IgA Nephropathy
IgA nephropathy (IgAN) is driven by autoantibodies against galactose-deficient IgA1 (Gd-IgA1). Lafayette et al. conducted an open label, multicenter, randomized, controlled study in 34 patients with IgAN at high risk of progression to evaluate the addition of rituximab, to deplete antibody-producing B cells, to standard of care. Addition of rituximab effectively depleted CD19+ B cells but did not reduce the serum levels of Gd-IgA1 or Gd-IgA1-specific IgG autoantibodies, reduce proteinuria, or improve renal function over 1 year of follow-up. Although effects in different disease stages and with different treatment protocols remain undetermined, these results do not support the use of rituximab in patients with IgAN. See Lafayette et al., pages 1306–1313.
