Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PlGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PlGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PlGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted.

Placental growth factor (PlGF) contributes to atherogenesis through vascular inflammation and plaque destabilization. High levels of PlGF may be associated with mortality and cardiovascular disease, but the relationship between PlGF level and adverse outcomes in patients with CKD is unclear. We conducted a prospective cohort study of 1351 consecutive participants with CKD enrolled in the Novel Assessment of Risk management for Atherosclerotic diseases in CKD (NARA-CKD) study between April 1, 2004, and December 31, 2011. During a median follow-up of 3 years, 199 participants died and 383 had cardiovascular events, defined as atherosclerotic disease or heart failure requiring hospitalization. In adjusted analyses, mortality and cardiovascular risk increased in each successive quartile of serum PlGF level; hazard ratios (HRs) (95% confidence intervals [95% CIs]) for mortality and cardiovascular risk, respectively, were 1.59 (0.83 to 3.16) and 1.55 (0.92 to 2.66) for the second quartile, 2.97 (1.67 to 5.59) and 3.39 (2.20 to 5.41) for the third quartile, and 3.87 (2.24 to 7.08) and 8.42 (5.54 to 13.3) for the fourth quartile. The composite end point of mortality and cardiovascular events occurred during the study period in 76.4% of patients in both the highest PlGF quartile ($19.6 pg/ml) and the lowest eGFR tertile (,30 ml/min per 1.73 m 2 ). The association between PlGF and mortality or cardiovascular events was not attenuated when participants were stratified by age, sex, traditional risk factors, and eGFR. These data suggest elevated PlGF is an independent risk factor for all-cause mortality and cardiovascular events in patients with CKD.

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Results: Seven of 18 patients had pathogenic NPH-causing mutations in NPHP1, NPHP3, NPHP4, or CEP164. Compared with patients without pathogenic mutations, those with pathogenic mutations were significantly younger but did not significantly differ in the classic NPH pathologic findings, such as tubular cysts. On the other hand, the number of tubules with thick tubular basement membrane (TBM) duplication, which was defined as >10-mm thickness, was significantly higher in patients with genetically proven adult NPH than in those without pathogenic mutations. a-Smooth muscle actin (a-SMA)-positive myofibroblasts were detected inside thick TBM duplication. Conclusions:In adult patients with NPH, thick TBM duplication was the specific finding. Our analysis also suggested that older patients tended to have no pathogenic mutations, even when they were suspected to have NPH by renal biopsy. These findings could be the novel clinical clue for the diagnosis of NPH in adult patients.

Systemic reactive AA amyloidosis is a life-threatening complication of chronic inflammatory diseases. Anti-interleukin-6 receptor, tocilizumab (TCZ), has been shown to improve clinical symptoms of patients with AA amyloidosis, accompanied with regression of the amyloid deposition. We report a case of AA amyloidosis evaluated by histology of multiple organs before and after TCZ treatment. A woman in her 60s with rheumatoid arthritis was referred to our hospital because of cardiac and renal dysfunction. A gastric and renal biopsy revealed the deposition of AA amyloid, and echocardiography revealed concentric left ventricular hypertrophy. Her estimated glomerular filtration rate was decreased to 8.6 mL/min/1.73 m2, and B-type natriuretic peptide, C-reactive protein, and serum amyloid A protein were significantly elevated. TCZ treatments markedly decreased her serum amyloid A protein and C-reactive protein levels, but hemodialysis was required 1 year later. Endoscopic gastric rebiopsy 3 years after initiation of TCZ treatments revealed the regression of amyloid deposition and echocardiography revealed improvement of her left ventricular hypertrophy. However, a renal rebiopsy revealed that the amyloid deposition had not regressed. In conclusion, these observations suggest that the therapeutic effects of TCZ can vary among organs in patients with AA amyloidosis.