This Month’s Highlights

doi:10.1681/ASN.2013070789

BASIC RESEARCH

Inhibiting CDA1 Reduces Diabetic Nephropathy

Pathological activation of TGF-β signaling contributes to renal fibrogenesis in diabetic nephropathy, but direct inhibition of TGF-β or its receptors has adverse consequences. In this issue, Chai et al. report that genetic deletion of the gene encoding CDA1 attenuates, but does not completely block, TGF-β signaling and reduces diabetes-associated renal injury in mice. In contrast to TGF-β-deficient mice, CDA1-deficient mice were viable and healthy. Moreover, the authors identified elevated expression of CDA1 in sclerotic glomeruli of diabetic and non-diabetic patients. Overall, these results indicate that CDA1 warrants investigation as a target for reducing TGF-β-induced renal damage. See Chai et al., pages 1782–1792.

Soluble CR1 Restores Physiological Complement Activity

In dense deposit disease and C3GN, dysregulation of the alternative pathway of complement leads to glomerular accumulation of complement proteins and progressive kidney decline. Zhang et al. assessed the capacity of CR1, a cell surface glycoprotein that modulates the complement cascade, to restore complement regulation in these diseases. Soluble CR1 arrested complement activation in vitro, reduced glomerular deposition of complement fragments in mouse models, and normalized complement activity in a pediatric patient with dense deposit disease. Taken together, these results support the further exploration of soluble CR1 as a treatment for glomerulopathies associated with chronic activation of the alternative pathway of complement. See Zhang et al., pages 1820–1829.

LMX1B Regulates the Actin Cytoskeleton in Podocytes

Nail-patella syndrome, characterized by abnormal development of the kidneys and other organs, is caused by mutations in LMX1B. Studies in knockout mouse models implicated LMX1B in podocyte development, but the mechanisms involved remain controversial. Burghardt et al. developed an inducible podocyte-specific Lmx1b knockout mouse and report that LMX1B is required for both the acquisition and maintenance of podocyte differentiation. Additional studies performed in vitro and in zebrafish indicate that LMX1B controls these processes through regulation of the actin cytoskeleton, providing crucial insight into the mechanisms underlying renal complications in this ultra-rare disease. See Burghardt et al., pages 1830–1848.

Complement-Activating Microparticles Cause Renal Injury

Dysregulation of the alternative pathway of complement contributes to renal diseases, including atypical hemolytic uremic syndrome, and is exacerbated by treatment with calcineurin inhibitors. Renner et al. investigated the complement-activating potential of microparticles released by injured endothelial cells. In mice, cyclosporine treatment triggered microparticle release from endothelial cells, glomerular activation of the alternative pathway of complement, and vascular and renal damage. In renal transplant patients, the number of circulating microparticles increased after the start of tacrolimus. Together with in vitro study results, these data point to endothelial injury throughout the body as a cause of renal damage. See Renner et al., pages 1849–1862.

CLINICAL EPIDEMIOLOGY

Clinical Validation of Urinary Biomarkers of Incident CKD

Novel biomarkers capable of detecting subclinical kidney injury and identifying affected renal pathways remain elusive. Here, O’Seaghdha et al. report the results of a study examining the association of 14 urinary biomarkers with incident CKD and a broad range of adverse outcomes in a community-based setting. Individual markers within this panel associated with several adverse clinical outcomes, including outcomes not identified by existing clinical markers. While validation of these results in more diverse populations is necessary, clinical measurement of these biomarkers may predict CKD and other adverse outcomes, permitting therapeutic intervention. See O’Seaghdha et al., pages 1880–1888.

CLINICAL MEDICINE

Urine Metabolites Link Mitochondrial Metabolism and Diabetic Kidney Disease

Urine metabolomics offers the potential to identify molecular pathways involved in renal diseases. Sharma et al. used gas chromatography to quantify urine metabolites in patients with diabetes and found reduced levels of urinary organic acids, most of which are linked to mitochondrial metabolism. Consistent with this, kidney sections from patients with diabetes expressed less mitochondrial protein, and urine exosomes from patients with diabetes and CKD contained less mitochondrial DNA. These results support the prognostic value of urine metabolites in diabetic kidney disease and provide insight into the relationship between mitochondrial function and kidney disease. See Sharma et al., pages 1901–1912.