Background: Microalbuminuria is an early sign of kidney disease in diabetes and indicates cardiovascular risk. We tested if a prespecified urinary proteomic risk classifier (CKD273) was associated with development of microalbuminuria and if progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone. Methods: Prospective multicentre study in people with type 2 diabetes, normal urinary albumin excretion and preserved renal function in 15 European specialist centres. High-risk individuals determined by CKD273 were randomised 1:1 (interactive web response system) in a double-blind randomised controlled trial comparing spironolactone 25 mg o.d. to placebo. Primary endpoint was development of confirmed microalbuminuria in all individuals with available data. Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone and association between CKD273 and impaired renal function defined as a glomerular filtration rate < 60 ml/min per 1•73 m 2. This study is registered with ClinicalTrials.gov: NCT02040441 and is completed. Findings: From March 25, 2014 to September 30, 2018 we followed 1775 participants, 12% (n=216) had high-risk urinary proteomic pattern of which 209 were included in the trial and assigned spironolactone (n=102) or placebo (n=107). Median follow-up time was 2•51 years (IQR 2•0-3•0). Progression to microalbuminuria was seen in 28•2% of high-risk and 8•9% of low-risk people (P< 0•001) (hazard ratio (HR), 2•48; 95% confidence interval [CI], 1•80 to 3•42 P<0•001, independent of baseline clinical characteristics). A 30% decline in eGFR from baseline was seen in 42 (19•4 %) high-risk participants compared to 62 (3•9 %) low-risk participants, HR 5•15; 95 % CI (3•41 to 7•76; p<0.0001). Development of microalbuminuria was seen in 35 (33%) randomised to placebo and 26 (25%) randomised to spironolactone treatment (HR 0•81, 95% CI, 0•49 to 1•34, P=0•41). Harms: hyperkalaemia was seen in 13 versus 4, and gynaecomastia in 3 versus 0 subjects on spironolactone and placebo, respectively. Interpretation: In people with type 2 diabetes and normoalbuminuria, the urinary proteomic classifier CKD273 was associated with a 2•5 times increased risk for progression to microalbuminuria over a median of 2•5 years, independent of clinical characteristics. Spironolactone did not prevent progression to microalbuminuria in high-risk subjects.

The SWI/SNF complex is a key element of the yeast CWI MAPK pathway, which mediates the chromatin remodeling necessary for an adequate transcriptional response to cell wall stress. The MAPK Slt2 mediates, through Rlm1, nucleosome rearrangements at cell wall stress–responsive genes by targeting the SWI/SNF complex.

Fungi are surrounded by an essential structure, the cell wall, which not only confers cell shape but also protects cells from environmental stress. As a consequence, yeast cells growing under cell wall damage conditions elicit rescue mechanisms to provide maintenance of cellular integrity and fungal survival. Through transcriptional reprogramming, yeast modulate the expression of genes important for cell wall biogenesis and remodeling, metabolism and energy generation, morphogenesis, signal transduction and stress. The yeast cell wall integrity (CWI) pathway, which is very well conserved in other fungi, is the key pathway for the regulation of this adaptive response. In this review, we summarize the current knowledge of the yeast transcriptional program elicited to counterbalance cell wall stress situations, the role of the CWI pathway in the regulation of this program and the importance of the transcriptional input received by other pathways. Modulation of this adaptive response through the CWI pathway by positive and negative transcriptional feedbacks is also discussed. Since all these regulatory mechanisms are well conserved in pathogenic fungi, improving our knowledge about them will have an impact in the developing of new antifungal therapies.Keywords: cell wall integrity; mitogen-activated protein kinase (MAPK); signal transduction; transcription; gene expression; antifungal Cell Wall Organization and Structure in S. cerevisiaeYeast cell integrity depends on the cell wall, an essential structure necessary not only for maintaining morphology but also for protecting cells against environmental stress conditions [1,2]. The cell wall is a macromolecular complex mainly composed of β-1,3-glucan, β-1,6-glucan, chitin and mannoproteins. Chitin, although a minor component, is essential for cell survival. β-1,3-glucan is the most abundant component of the yeast cell wall and serves as a backbone to which the other cell wall components are linked. The reducing ends of β-1,6-glucan and chitin are attached to the non-reducing end of β-1,3-glucan chains by an uncharacterized link and a β-1,4-linkage, respectively [3][4][5]. β-1,6-glucan is also attached to the chitin through β-1,3-linked oligogluco-residues that branch off the glucan. There is also a fraction of free chitin. Cell wall mannoproteins, including those involved in adhesion, cell wall remodeling, structural proteins and somatic antigens [6][7][8][9] can be linked directly to the β-1,3-glucan via alkali-labile bonds [9,10] and indirectly via β-1,6-glucan through a glycosylphosphatidylinositol (GPI) anchor [9,11]. The structure of the fungal cell wall is very well conserved among fungi despite several differences in cell wall composition exist [12]. Among fungal glucans, diversities in configuration, position of glyosidic bonds and branching have been reported [13]. β-1,3-glucan is the major cell wall component and is present in all the fungal species analyzed, whereas other polysaccharides including β-1,3/β-1,4-glucan, β-1,6-glucan or α-1,3-glucan a...