Vitamin D and proteinuria: a critical review of molecular bases and clinical experience.

Proteinuria is the main predictor of chronic kidney disease progression. Drugs that block the renin-angiotensin-aldosterone (RAA) system reduce proteinuria and slow down the progression of the disease. However, their effect is suboptimal, and residual proteinuria persists as an important predictor of renal impairment. Vitamin D has pleiotropic effects that could have an impact on these parameters. In this study, we critically review the molecular and experimental bases that suggest an antiproteinuric effect of vitamin D receptor (VDR) activation and the available evidence on its antiproteinuric effect in clinical practice. In animal models, we have observed the antiproteinuric effect of VDR activation, which could be due to direct protective action on the podocyte or other pleiotropic effects that slow down RAA system activation, inflammation and fibrosis. Clinical trials have generally been conducted in patients with a vitamin D deficiency or insufficiency and the main trial (VITAL) did not demonstrate that paricalcitol improved the study's primary endpoint (decrease in the urine albumin to creatinine ratio). In this sense, the information available is insufficient to advise the use of native vitamin D or VDR activators as renoprotective antiproteinuric drugs beyond the experimental level. Two Spanish clinical trials and one Italian trial attempted to determine the effect of paricalcitol and vitamin D on residual proteinuria in various clinical circumstances (PALIFE, NEFROVID and PROCEED).

Acute kidney injury transcriptomics unveils a relationship between inflammation and ageing.

There are no pathophysiolgical therapeutic approaches to acute kidney injury (AKI) and the mortality remains high. In addition chronic kidney disease (CKD) predisposes to AKI and AKI contributes to progression of CKD. Recently a transcriptomics approach unveiled a relationship between AKI, inflammation and the regulation of ageing. A transcriptomics analysis of experimental AKI revealed increased kidney expression of Fn14 and transmembrane chemokine CXCL16, as well as a decreased expression of the kidney-secreted anti-ageing hormone Klotho. Fn14 is the receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily. In AKI kidneys there was a positive correlation between Fn14 and CXCL16 mRNA expression and an inverse correlation between Fn14 and Klotho mRNA. Tubular cells were the site of Fn14, CXCL16 and Klotho expression in vivo. Research on the relationships between these three molecules disclosed that TWEAK activation of Fn14 promoted inflammation through secretion of chemokines such as CXL16 in tubular cells in culture and in vivo. Furthermore, TWEAK activation of Fn14 decreased expression of Klotho mRNA and protein in culture and in vivo. Interestingly, both TWEAK activation of CXCL16 mRNA transcription and suppression of Klotho mRNA transcription were mediated by the NFκB transcription factor. In conclusion, TWEAK engagement of Fn14 is a central event promoting NFκB-mediated activation of inflammation pathways and suppression of anti-inflammatory/anti-ageing pathways. This information may influence future therapeutic approaches to AKI and inflammation/aging.