In chronic kidney disease, vascular calcification, renal osteodystrophy, and phosphate contribute substantially to cardiovascular risk and are components of CKD-mineral and bone disorder (CKD-MBD). The cause of this syndrome is unknown. Additionally, no therapy addresses cardiovascular risk in CKD. In its inception, CKD-MBD is characterized by osteodystrophy, vascular calcification, and stimulation of osteocyte secretion. We tested the hypothesis that increased production of circulating factors by diseased kidneys causes the CKD-MBD in diabetic mice subjected to renal injury to induce stage 2 CKD (CKD-2 mice). Compared with non-CKD diabetic controls, CKD-2 mice showed increased renal production of Wnt inhibitor family members and higher levels of circulating Dickkopf-1 (Dkk1), sclerostin, and secreted klotho. Neutralization of Dkk1 in CKD-2 mice by administration of a monoclonal antibody after renal injury stimulated bone formation rates, corrected the osteodystrophy, and prevented CKD-stimulated vascular calcification. Mechanistically, neutralization of Dkk1 suppressed aortic expression of the osteoblastic transcription factor Runx2, increased expression of vascular smooth muscle protein 22-a, and restored aortic expression of klotho. Neutralization of Dkk1 did not affect the elevated plasma levels of osteocytic fibroblast growth factor 23 but decreased the elevated levels of sclerostin. Phosphate binder therapy restored plasma fibroblast growth factor 23 levels but had no effect on vascular calcification or osteodystrophy. The combination of the Dkk1 antibody and phosphate binder therapy completely treated the CKD-MBD. These results show that circulating Wnt inhibitors are involved in the pathogenesis of CKD-MBD and that the combination of Dkk1 neutralization and phosphate binding may have therapeutic potential for this disorder. CKD is a pandemic affecting 26 million Americans in its early stages. 1 CKD is associated with high rates of cardiovascular mortality, making it much more likely that affected individuals will sustain cardiovascular morbidity, including death, than reach end stage kidney disease that requires RRT.

The causes of cardiovascular mortality associated with chronic kidney disease (CKD) are partly attributed to the CKD-mineral bone disorder (CKD-MBD). The causes of the early CKD-MBD are not well known. Our discovery of Wnt (portmanteau of wingless and int) inhibitors, especially Dickkopf 1, produced during renal repair as participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical. In the search for such factors, we studied the effects of activin receptor type II A (ActRIIA) signaling by using a ligand trap for the receptor, RAP-011 (a soluble extracellular domain of ActRIIA fused to a murine IgG-Fc fragment). In a mouse model of CKD that stimulated atherosclerotic calcification, RAP-011 significantly increased aortic ActRIIA signaling assessed by the levels of phosphorylated Smad2/3. Furthermore, RAP-011 treatment significantly reversed CKD induced vascular smooth muscle dedifferentiation as assessed by smooth muscle 22α levels, osteoblastic transition and neointimal plaque calcification. In the diseased kidneys, RAP-011 significantly stimulated αklotho levels and it inhibited ActRIIA signaling and decreased renal fibrosis and proteinuria. RAP-011 treatment significantly decreased both renal and circulating Dickkopf 1 levels showing that Wnt activation was downstream of ActRIIA. Thus, ActRIIA signaling in CKD contributes to the CKD-MBD and renal fibrosis. ActRIIA signaling may be a potential therapeutic target in CKD.

The implementation of surveillance biopsies in pediatric kidney transplantation remains controversial. Surveillance biopsies detect subclinical injury prior to clinical dysfunction, which could allow for early interventions that prolong allograft survival. We conducted a single-center retrospective cohort study of 120 consecutive pediatric kidney recipients, of whom 103 had surveillance biopsies ≤6 months posttransplant. We tested the hypothesis that subclinical inflammation (borderline or T cell-mediated rejection without clinical dysfunction) is associated with a 5-year composite endpoint of acute rejection and allograft failure. Overall, 36% of subjects had subclinical inflammation, which was associated with increased hazard for the composite endpoint (adjusted hazard ratio 2.89 [1.27, 6.57]; P < .01). Subjects with treated vs untreated subclinical borderline rejection had a lower incidence of the composite endpoint (41% vs 67%; P < .001). Subclinical vascular injury (subclinical inflammation with Banff arteritis score > 0) had a 78% incidence of the composite endpoint vs 11% in subjects with no major surveillance abnormalities (P < .001). In summary, we showed that subclinical inflammation phenotypes were prevalent in pediatric kidney recipients without clinical dysfunction and were associated with increased acute rejection and allograft failure. Once prospectively validated, our data would support implementation of surveillance biopsies as standard of care in pediatric kidney transplantation.

Background The Patient Reported Outcomes Measurement Information System (PROMIS) II is a prospective study that evaluates patient reported outcomes in pediatric chronic diseases as a measure of health-related quality of life (HRQOL). We have evaluated the influence of disease duration on HRQOL and, for the first time, compared the findings of the PROMIS measures to those of the PedsQL™ 4.0 Generic Scales (PedsQL) from the PROMIS II nephrotic syndrome (NS) longitudinal cohort. Methods This was a prospective study in which 127 children (age range 8–17 years) with active NS from 14 centers were enrolled. Children with active NS defined as the presence of nephrotic range proteinuria (>2+ urinalysis and edema or urine protein/creatinine ratio >2 g/g) were eligible. Comparisons were made between children with prevalent (N=67) and incident (N=60) disease at the study enrollment visit. Results The PROMIS scores were worse in prevalent patients in the domains of peer relationship (p=0.01) and pain interference (p < 0.01). The PedsQL showed worse scores in prevalent patients for social functioning (p < 0.01) and school functioning (p = 0.03). Multivariable analyses showed that prevalent patients had worse scores in PROMIS pain interference (p=0.02) and PedsQL social functioning (p<0.01). Conclusion The PROMIS measures detected a significant impact of disease duration on HRQOL in children, such that peer relationships were worse and pain interfered with daily life to a greater degree among those with longer disease duration. These findings were in agreement with those for similar domains in the PedsQL legacy instrument.