This Month's Highlights

doi:10.1681/ASN.2010090989

BRIEF COMMUNICATION

Renal RGS2 Modulates BP

Mice deficient in RGS2, a protein that modulates G protein signaling, develop hypertension. Gurley et al. used a kidney cross-transplantation strategy with genetically modified mice to investigate the mechanism underlying this observation. They report that the loss of renal RGS2 induces hypertension but the sole loss of extrarenal RGS2 does not. Their results support an intrarenal role for RGS2 in the modulation of arterial BP. Whether the renal epithelium, the renal vasculature, or both are the target of RGS2 requires further study. See Gurley et al., pages 1847–1851.

BASIC RESEARCH

Distinct Roles of Cubilin and Megalin

The proximal tubule reabsorbs protein that successfully passes the glomerular basement membrane, but this reabsorptive process is not completely understood. In this issue, Amsellem et al. extend our understanding of the roles of the two interacting receptors megalin and cubilin, which play a critical role in protein reabsorption by the kidney. Using genetically modified mice, they found that cubilin is essential for albumin reabsorption and that megalin drives the internalization of cubilin–albumin complexes. These results help to explain renal protein trafficking, derangement of which may contribute to proteinuric chronic kidney disease. See Amsellem et al., pages 1859–1867.

SPAK Deficiency Recapitulates Gitelman Syndrome

SPAK is a downstream substrate of the WNK kinases, which regulate the Na-K-2Cl and Na-Cl co-transporters (NKCC and NCC, respectively), but the role of SPAK in vivo is unknown. Yang et al. report that SPAK-null mice recapitulate Gitelman syndrome and are hypotensive. Explaining this phenotype, they demonstrate that SPAK deficiency impairs NCC in the kidney and NKCC1 in the aorta, leading to sodium wasting and vasodilation, respectively. Their data not only provide knowledge of the role of SPAK in the regulation of these ion transporters but also suggest that pharmacologic inhibition of SPAK could have potential in the treatment of hypertension. See Yang et al., pages 1868–1877.

CLINICAL EPIDEMIOLOGY

Rate of CKD Progression Independently Predicts Mortality

Chronic kidney disease (CKD) independently predicts mortality, but does rate of CKD progression exhibit a similar association? Al-Aly et al. explored this question by analyzing longitudinal data from >4000 U.S. veterans with rheumatoid arthritis and stage 3 CKD. They found that black race, hypertension, diabetes, cardiovascular disease, and peripheral artery disease predict severe progression (estimated GFR decline >4 ml/min per y), which increases risk for mortality by 54% compared with those with mild (1 to 4 ml/min per y) progression. Assessing disease progression may improve risk stratification for patients with CKD. See Al-Aly et al., pages 1961–1969.

Age, Race, Diabetes Modify BP–Mortality Association

Observational studies of heterogeneous cohorts of hemodialysis patients suggest a U-shaped relationship between BP and mortality, but whether this association is consistent among subgroups is incompletely understood. Here, Myers et al. analyzed data from a cohort of >16,000 incident hemodialysis patients and found that the increased mortality associated with low systolic BP is most pronounced among older patients and those with diabetes. Conversely, higher systolic BP associates with increased mortality among younger patients. In addition, they observed a survival advantage for black patients but predominantly among older patients. This analysis suggests that the optimal BP among hemodialysis patients may not follow a one-target-fits-all paradigm. See Myers et al., pages 1970–1978.

CLINICAL RESEARCH

Fibrosis with Inflammation Predicts Graft Loss

Identifying potential mechanisms of allograft failure could ultimately improve outcomes of kidney transplantation. Park et al. performed protocol biopsies one year after transplantation in 151 living-donor recipients at low risk for graft failure. They found that the combination of fibrosis and inflammation predicts graft loss, whereas normal histology or fibrosis without inflammation predicts stable graft function. Furthermore, in grafts with both fibrosis and inflammation, they observed overexpression of transcripts that compose potentially damaging immunologic pathways. These data suggest that developing therapeutic agents to target early inflammation may improve long-term graft survival. See Park et al., pages 1987–1997.