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BACKGROUNDMineralocorticoid receptor (MR) activation induces fibrosis. Urinary proteomic profiling (UPP) detects thousands of sequenced peptides, mainly derived from collagen. No previous study applied UPP to generate insights in the antifibrotic actions of MR antagonism.METHODSBased on urine sample availability, subsets of the open HOMAGE trial (n=290; 23.8% women; median age: 73 years) and the double-blind PRIORITY trial (n=110; 21.8% women; 64 years) were analyzed as discovery and replication data sources. In the open HOMAGE trial, patients at risk of heart failure were randomized to usual therapy or usual therapy combined with spironolactone 25-50 mg/d. In the double-blind PRIORITY trial, type-2 diabetic patients with normal renal function were randomized to placebo or spironolactone 25 mg/d, both given on top of usual therapy. UPP relied on capillary electrophoresis coupled with mass spectrometry. In HOMAGE, the PICP/CITP ratio was calculated from serum PICP and serum CITP, which are markers of type-1 collagen synthesis and degradation, respectively. After rank-normalization of the biomarker distributions, between-group differences in the biomarker changes were analyzed by multivariable models. Correlations between the changes in urinary peptides and in serum CITP, derived from mature type-1 collagen, were compared between groups, using Fisher Z transform.RESULTSIn the HOMAGE and PRIORITY analytical subsets, patients had detectable signals of 1498 urinary peptides. Follow-up totaled 9 months in HOMAGE and was 30 months (median) in PRIORITY. All changes in urinary peptides that remained significantly different (PP≤0.0129). Correlations between changes from baseline to follow-up in urinary type-1 collagen fragments and CITP were positive often reaching significance if fragments increased during follow-up, but were nonsignificant if fragments decreased during follow-up. There were no between-group differences in these correlations.CONCLUSIONSMR antagonism predominantly reduces collagen-derived urinary peptides. Inhibition of collagen synthesis by lowering the amount available for breakdown may be a contributing mechanism.Clinical PerspectiveWhat Is New?Few studies addressed the association between urinary and serum markers of fibrosis and how MR antagonism influences urinary peptides derived from collagen.MR antagonism reduces collagen-derived urinary peptides. Inhibition of type-1 collagen synthesis by lowering the amount available for breakdown may be a contributing mechanism.Correlations between changes from baseline to follow-up in type-1 collagen and in CITP were positive if fragments increased during follow-up and nonsignificant if fragments decreased.What Are the Clinical Implications?Spironolactone inhibits fibrosis, supporting the use of MRAs in patients at risk of heart failure or chronic kidney disease.UPP profiling opens new research perspectives in documenting the antifibrotic properties of novel drug classes, such as nonsteroidal MR antagonists or sodium-glucose cotransporter-2 inhibitors.The development of novel medicines that would promote collagen degradation in addition to MRAs would strengthen the therapeutic armamentarium to modify fibrosis.GRAPHICAL ABSTRACT

Background Diabetic retinopathy (DR) is a microvascular complication of diabetes highly associated to cardiovascular disease and diabetic kidney disease. However, these associations are not thoroughly investigated at an early type 2 diabetes disease stage. This study therefore evaluated the association between baseline DR status and development of cardiovascular events (CVEs), microalbuminuria, and kidney function decline and in persons with type 2 diabetes and normal urinary albumin excretion. Methods Post-hoc analysis of the PRIORITY study including 1758 persons with type 2 diabetes and normoalbuminuria followed for a median of 2.5 (IQR: 2.0–3.0) years. The study was originally designed to investigate a urinary proteomic risk classifier predictor of microalbuminuria development. DR at baseline was defined as non-proliferative and proliferative abnormalities, macular oedema, or history of laser treatment. Cox models were fitted to investigate the association of DR status with development of 1) a CVE composite defined as non-fatal myocardial infarction, stroke, coronary artery bypass graft, percutaneous coronary intervention, hospitalization for heart failure, or all-cause mortality; 2) persistent microalbuminuria (urinary albumin-creatinine ratio > 30mg/g); and 3) chronic kidney disease (CKD) G3 (eGFR 2). Models were adjusted for relevant risk factors. Results At baseline, 304 (17.3%) had DR. Compared to persons without DR, they were older (mean ± SD: 62.7 ± 7.7 vs 61.4 ± 8.3 years, p = 0.019), had longer diabetes duration (17.9 ± 8.4 vs. 10.6 ± 7.0 years, p 1c (62 ± 13 vs. 56 ± 12 mmol/mol, p

BackgroundCeramides are lipid molecules involved in inflammation-related signaling. Recent studies have shown that higher amounts of specific circulating ceramides and ceramide ratios are associated with future development of cardiovascular (CV) disease (CVD). In persons with longstanding type 1 diabetes (T1D), we investigated if serum ceramide levels and ratios predicted CVD, kidney failure and all-cause mortality.MethodsWe included 662 participants with T1D from 2009-2011. Health registry data was obtained at a 6-year follow-up. Baseline serum samples were analyzed using liquid chromatography-mass spectrometry. Six predefined ceramide levels were measured and ratios calculated. Adjusted Cox regression analyses were carried out to investigate ceramide levels in relation to future CV events (CVE), kidney failure and all-cause mortality.ResultsCeramide ratio cer(d18:1/18:0)/cer(d18:1/24:0) was significantly associated with risk of CVE (HR = 1.33, P = 0.01) and all-cause mortality (HR = 1,48, P = 0.01) before and after adjustments. All five investigated ceramide ratios were associated with kidney failure, before adjusting for the kidney markers estimated glomerular filtration rate and urinary albumin excretion rate.ConclusionsSpecific ceramides and ratios associated with 6-year cardiovascular risk and all-cause mortality in a T1D cohort. The ratio of cer(d18:1/18:0)/cer(d18:1/24:0) was an especially robust indicator. This highlights the strength of ceramide association with vascular complications and presents a new potential tool for early risk assessment if validated in other cohorts.Trial RegistrationClinicalTrial.govidentifier:NCT01171248

Background Plasma copeptin is a surrogate of arginine vasopressin (AVP) secretion and is associated with a risk of renal and cardiovascular disease. We investigated associations between copeptin and renal events, cardiovascular events and mortality in type 1 diabetes (T1D). Methods We conducted a prospective cohort study on 658 individuals with T1D from Steno Diabetes Center Copenhagen. Plasma copeptin concentrations and conventional risk factors were assessed at baseline. The five endpoints were traced through national registries and electronic laboratory records. Results Baseline mean age was 55 ± 13 years and estimated glomerular filtration rate (eGFR) was 81 ± 26 mL/min/1.73 m2. The median follow-up was 6.2 years (interquartile range 5.8–6.7); 123 participants reached a combined renal endpoint [decline in eGFR ≥30%, end-stage kidney disease (ESKD) or all-cause mortality], 93 had a decrease in eGFR ≥30%, 21 developed ESKD, 94 experienced a combined cardiovascular endpoint and 58 died from all causes. Higher copeptin was associated with all endpoints in unadjusted Cox regression analyses. Upon adjustment for baseline eGFR, the associations were attenuated and remained significant only for the combined renal endpoint and decrease in eGFR ≥30%. Results were similar upon further adjustment for other risk factors, after which hazard ratios for the two renal endpoints were 2.27 (95% confidence interval 1.08–4.74) and 4.49 (1.77–11.4), respectively, for the highest versus the lowest quartile of copeptin. Conclusions Higher copeptin was an independent risk marker for a combined renal endpoint and decline in renal function. AVP may be a marker of renal damage or a factor whose contribution to renal and cardiovascular risk is partially mediated by renal damage.

OBJECTIVE Few studies have compared midregional proatrial natriuretic peptide (MR-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP). We compared their value as risk markers for all-cause mortality and cardiovascular (CV) and renal complications in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS MR-proANP and NT-proBNP were measured in 664 individuals. Hazard ratios (HRs) were assessed per doubling of NT-proBNP or MR-proANP for risk of a composite of ischemic events, heart failure (HF), a combined renal end point of end-stage kidney disease (ESKD), decline in estimated glomerular filtration rate (eGFR) ≥30%, and all-cause mortality or individual end points. Adjustments included CV risk factors and addition of MR-proANP or NT-proBNP. RESULTS Median follow-up was 5.1–6.2 years. MR-proANP was associated with higher risk of all-cause mortality (n = 57; HR 1.7, 95% CI 1.1–2.7), combined CV end point (n = 94; 1.6, 1.1–2.2), HF (n = 27; 2.8, 1.5–5.2), combined renal end point (n = 123; 1.6, 1.2–2.1), and ESKD (n = 21; 3.1, 1.2–7.8) independent of CV risk factors (P ≤ 0.02). After addition of NT-proBNP, significance for all end points was lost. A doubling of NT-proBNP was associated with higher risk of all-cause mortality (HR 1.5, 95% CI 1.2–1.8), the combined CV end point (1.3, 1.1–1.5), HF (1.7, 1.3–2.1), and the combined renal end point (1.3, 1.1–1.4) independent of CV risk factors (model 2 [P < 0.001]) and MR-proANP (model 3 [P ≤ 0.03]). There was no association with decline in eGFR ≥30% (n = 93). CONCLUSIONS Higher NT-proBNP was independently associated with all-cause mortality, CV disease, HF, and the combined renal end point. MR-proANP was associated with all end points but decline in eGFR, although not independent of NT-proBNP. MR-proANP may contribute to the predictive value of NT-proBNP for risk stratification in type 1 diabetes.

The use of "omics" is increasing in research areas looking to identify biomarkers or early preclinical signs of disease or to increase understanding of complex pathological processes that determines prognosis of the disease. Diabetic kidney disease is no exception as it is an area in need of further improvement of both understanding and prognosis. In addition, there is a notion that pretreatment investigations using techniques like proteomics, lipidomics and metabolomics can help individualize therapy thus fulfilling the wish for personalized medicine. An increasing number of cohort studies using these techniques are published, but only few have been validated in external cohorts or even replicated by other groups. In essence, to achieve clinical impact and usefulness, prospective validation is needed. So far, only the urinary proteomics based PRIORITY study has tried to do this, as discussed in this review. Other areas are promising, but are currently lacking such efforts. In this review we report and discuss the current status of urinary proteomics as well as plasma metabolomics and lipidomics with an overview of the results so far, and with some comments and perspectives regarding future developments and implementation. As is evident, these techniques are promising, but there is still some way before widespread clinical use can be foreseen.

People with type 1 diabetes have increased risk of cardiovascular (CV) and kidney disease. A 24-hour ambulatory blood pressure (BP) measurement (ABPM) examines diurnal variations in BP. We aimed to determine the prognostic significance of blunted decrease in nocturnal systolic BP of10 % (non-dipping of nocturnal BP) for CV- and kidney disease and all-cause mortality in type 1 diabetes.From 2009 to 2011, at Steno Diabetes Center Copenhagen, 654 participants with type 1 diabetes had 24-hour ABPM obtained with a tonometric wrist-watch device (BPro, HealthStats, Singapore). In 2017, outcomes (composite CV endpoint; all-cause mortality; decline in estimated glomerular filtration rate (eGFR) ≥30 %; end-stage kidney disease (ESKD); and a composite kidney endpoint including decline in eGFR ≥30 %, ESKD and all-cause mortality) were registered. Hazard Ratios (HR) were calculated using Cox regressions.Participants were mean ± SD 55 ± 13 years old and had median (IQR) 35 (24-44) years diabetes duration. Mean daytime and nocturnal systolic BP were 133 ± 16 and 121 ± 16 mmHg while 337 (52 %) participants demonstrated non-dipping. After CV risk factor adjustments, non-dipping was associated with all-cause mortality (HR 2.12 (1.09-4.11), p = 0.03) and the composite kidney endpoint (HR 1.92 (1.23-3.00), p = 0.004).Non-dipping entailed increased risk of all-cause mortality and kidney disease in type 1 diabetes.

OBJECTIVE Trimethylamine N-oxide (TMAO) is suggested as an independent gut microbiota–derived risk factor for cardiovascular and renal disease. We investigated associations between plasma TMAO concentrations and cardio-renal outcomes in a prospective study of individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS Plasma TMAO was measured at baseline in 1,159 individuals with type 1 diabetes (58% male, mean ± SD age 46 ± 13 years). End points were all-cause and cardiovascular mortality, cardiovascular disease (CVD), and renal events tracked from national registries. Associations between TMAO and end points were tested using Cox regression models. RESULTS After 15.0 (6.7–19.3) (median [interquartile range]) years of follow-up, we recorded all-cause and cardiovascular mortality (n = 363 and 120, respectively), combined CVD (n = 406), coronary outcome (myocardial infarction and coronary intervention) (n = 163), stroke (n = 115), hospitalization for heart failure (n = 81), and end-stage renal disease (n = 144). In univariate analyses, higher TMAO concentrations were associated with all end points (P ≤ 0.005). Except for stroke and heart failure, all end points remained significantly associated with higher TMAO concentrations after adjustment for conventional cardiovascular risk factors (P ≤ 0.003). After further adjustment for baseline estimated glomerular filtration rate (eGFR), results became insignificant for all end points. TMAO was inversely associated with baseline eGFR (R2 = 0.29; P < 0.001). CONCLUSIONS In individuals with type 1 diabetes, higher concentrations of plasma TMAO were associated with mortality, CVD events, and poor renal outcome, independent of conventional risk factors. However, the association became insignificant after further adjustment for baseline eGFR. This could reflect TMAO as a renal function marker or a risk factor for micro- and macrovascular complications mediated through impaired renal function.

BACKGROUND Clinical characteristics such as HbA1c , systolic blood pressure (SBP), albuminuria and estimated glomerular filtration rate (eGFR) are important when treating type 1 diabetes. We investigated the variability in these measures as risk markers for micro- and macrovascular complications. METHODS This prospective study included 1062 individuals with type 1 diabetes. Visit-to-visit variability of HbA1c , SBP, albuminuria and eGFR was calculated as the SD of the residuals in individual linear regression models using all available measures in a specified period of 3 years (VV). Endpoints included were as follows: cardiovascular events (CVE) defined as myocardial infarction, non-fatal stroke, or coronary or peripheral arterial intervention; end-stage kidney disease (ESKD) defined as eGFR

Objective Few studies have compared Midregional Proatrial Natriuretic Peptide (MR-proANP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). We compared their value as risk markers for all-cause mortality, cardiovascular (CV) and renal complications in persons with type 1 diabetes.Research design and methods MR-proANP and NT-proBNP were measured in 664 individuals. Hazard ratios (HR) were assessed per doubling of NT-proBNP or MR-proANP for risk of a composite of ischemic events, heart failure (HF), a combined renal endpoint of end-stage kidney disease (ESKD), decline in estimated glomerular filtration rate (eGFR) ≥30% and all-cause mortality or individual endpoints. Adjustments included CV risk factors and addition of MR-proANP or NT-proBNP.Results Median follow-up was 5.1-6.2 years. MR-proANP was associated with higher risk of all-cause mortality n=57; HR 1.7, 95% CI 1.1-2.7, combined CV endpoint (n=94; 1.6(1.1-2.2)), HF (n=27; 2.8(1.5-5.2)), combined renal endpoint (n=123; 1.6(1.2-2.1)) and ESKD (n=21; 3.1(1.2-7.8)) independent of CV risk factors (p≤0.02). After addition of NT-proBNP significance for all endpoints was lost. A doubling of NT-proBNP was associated with higher risk of all-cause mortality (1.5(1.2-1.8)), the combined CV endpoint (1.3(1.1-1.5)), HF (1.7(1.3-2.1)) and the combined renal endpoint (1.3(1.1-1.4)) independent of CV risk factors (model 2;pConclusions Higher NT-proBNP was independently associated with all-cause mortality, CV disease, HF and the combined renal endpoint. MR-proANP was associated with all endpoints but decline in eGFR, although not independent of NT-proBNP. MR-proANP may contribute to the predictive value of NT-proBNP for risk-stratification in type 1 diabetes.

Context There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease. Objective To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D). Design 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts. Main outcome measures Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. Results In total, 125 metabolites were significantly associated (PFDR = 1.5×10–32 − 0.046; β = −11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after. Conclusions This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation.

OBJECTIVE Previous studies have provided inconclusive results on the role of uric acid (UA) in risk prediction. Here we aimed to improve the power and precision of the predictive value of UA for the risk of decline in kidney function, cardiovascular events (CVEs), and mortality in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Plasma UA was measured in 670 patients with T1D and various degrees of albuminuria, ranging from normoalbuminuria to macroalbuminuria. Associations of UA with an estimated glomerular filtration rate (eGFR) decline of ≥30%, CVEs, and mortality were analyzed. The median follow-up time was 5.3 years [interquartile range (IQR) 2.7–6.2 years] for a decline in eGFR of ≥30%, 5.8 years (2.5–6.4 years) for progression in albuminuria status, 5.1 years (4.7–5.6 years) for CVE, and 6.2 years (5.8–6.7 years) for mortality. Both univariable and multivariable associations of UA with relevant outcomes and variables were reported. Hazard ratios (HRs) were calculated per doubling of the UA level. RESULTS A doubling in UA level was associated with a higher risk of decline in eGFR of ≥30% (n = 89) (HR 3.18 [IQR 1.71–5.93]; P < 0.001), CVE (n = 94) (HR 2.25 [IQR 1.20–4.21]; P = 0.011), and mortality (n = 58) (HR 2.58 [IQR 1.12–5.90]; P = 0.025) in adjusted analyses. Adding UA to the adjusted model including conventional risk factors improved the relative integrated discrimination index by 12.6% for a decline in eGFR of ≥30% (P < 0.001), 6.5% for CVE (P = 0.010), and 11.8% (P = 0.003) for mortality. A doubling in UA level was also associated with a steeper decline in eGFR (P < 0.0026) and a steeper increase in urine albumin-to-creatinine ratio (P < 0.0027) in adjusted analysis. CONCLUSIONS In individuals with T1D, a higher UA level is associated with a higher risk of decline in kidney function, CVE, and mortality, independently of other risk factors. Our results suggest that UA has a promising role in risk stratification among individuals with T1D.

Background and Aims In the PRIORITY study, it was recently demonstrated that the urinary peptidome-based classifier CKD273 was associated with increased risk for progression to microalbuminuria. In this sub-study, we aim to evaluate whether glucose-lowering and antihypertensive medications, many of which have been demonstrated to have albuminuria-lowering effects, may interfere with the predictive value of CKD273. Method A post hoc analysis of a prospective observational study with embedded randomised placebo-controlled trial. Setting 1775 subjects from 15 European sites with a mean follow-up time of 2.6 years (minimum of 7 days and a maximum of 4.3 years). Patients Subjects with T2D, normoalbuminuria and estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73m2. Participants were stratified into high- or low-risk groups based on their CKD273 score in a urine sample at screening (high-risk defined as score > 0.154). Main outcome measures Baseline medication or initiation during the study was assessed for the following medications: glitazones, glucagon-like peptide-1 receptor agonists (GLP1-RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), angiotensin-converting-enzyme inhibitors (ACEi), angiotensin-II-receptor blockers (ARB), calcium channel blockers (CCB) and beta blockers (BB). The main outcome was development of confirmed microalbuminuria (urinary albumin to creatinine ratio (UACR) >30 mg/g and with ≥30% increase from baseline) in 2 of 3 consecutive samples. Results The hazard ratio (HR (95% CI)) for development of microalbuminuria (high vs. low-risk) was 3.9 (2.9-5.3) in a crude Cox-model; and 2.4 (1.8-3.4; p Conclusion Although several glucose-lowering and antihypertensive medications were more frequently prescribed in high-risk subjects, the CKD273 classifier prospectively predicted confirmed microalbuminuria, independent of baseline co-medications and medication initiated during the study. Moreover, initiated medications during the study could not explain the inability of spironolactone to delay progression to microalbuminuria.

Background and Aims In the PRIORITY study, it was recently demonstrated that the urinary peptidome-based classifier CKD273 was associated with increased risk for progression to microalbuminuria. As a prespecified secondary outcome, we aim to evaluate the classifier CKD273 as a determinant of relative reductions in eGFR (CKD-EPI) of 30% and 40% from baseline, at one timepoint without requirements of confirmation. Method The ‘Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria trial’ (PRIORITY) is the first prospective observational study to evaluate the early detection of diabetic kidney disease in subjects with type 2 diabetes (T2D) and normoalbuminuria using the CKD273 classifier. Setting 1775 subjects from 15 European sites with a mean follow-up time of 2.6 years (minimum of 7 days and a maximum of 4.3 years). Patients Subjects with T2D, normoalbuminuria and estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73m2. Participants were stratified into high- or low-risk groups based on their CKD273 score in a urine sample at screening (high-risk defined as score > 0.154). Results In total, 12 % (n = 216) of the subjects had a high-risk proteomic pattern. Mean (SD) baseline eGFR was 88 (15) ml/min/1.73m2 in the low-risk group and 81 (17) ml/min/1.73m2 in the high-risk group (p < 0.01). Baseline median (interquartile range) urinary albumin to creatinine ratio (UACR) was 5 (3-8) mg/g and 7 (4-12) mg/g in the low-risk and high-risk groups, respectively (p < 0.01). A 30 % reduction in eGFR from baseline was seen in 42 (19.4 %) subjects in the high-risk group as compared to 62 (3.9 %) in the low-risk group (p < 0.0001). In an unadjusted Cox-model the hazard ratio (HR) for the high-risk group was 5.7, 95 % confidence interval (CI) (3.9 to 8.5; p A 40 % reduction in eGFR was seen in 15 (6.9 %) subjects in the high-risk group whereas 22 (1.4 %) in the low-risk group developed this endpoint (p Conclusion In normoalbuminuric subjects with T2D, the urinary proteomic classifier CKD273 predicts renal function decline of 30 % and 40 %, independent of baseline eGFR and albuminuria.

Background: \ud Microalbuminuria is an early sign of kidney disease in people with diabetes and indicates increased risk of cardiovascular disease. We tested whether a urinary proteomic risk classifier (CKD273) score was associated with development of microalbuminuria and whether progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone.\ud \ud Methods: \ud In this multicentre, prospective, observational study with embedded randomised controlled trial (PRIORITY), we recruited people with type 2 diabetes, normal urinary albumin excretion, and preserved renal function from 15 specialist centres in ten European countries. All participants (observational cohort) were tested with the CKD273 classifier and classified as high risk (CKD273 classifier score >0·154) or low risk (≤0·154). Participants who were classified as high risk were entered into a randomised controlled trial and randomly assigned (1:1), by use of an interactive web-response system, to receive spironolactone 25 mg once daily or matched placebo (trial cohort). The primary endpoint was development of confirmed microalbuminuria in all individuals with available data (observational cohort). Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone (trial cohort, intention-to-treat population) and association between CKD273 risk score and measures of impaired renal function based on estimated glomerular filtration rate (eGFR; observational cohort). Adverse events (particularly gynaecomastia and hyperkalaemia) and serious adverse events were recorded for the intention-to-treat population (trial cohort). This study is registered with the EU Clinical Trials Register (EudraCT 20120-004523-4) and ClinicalTrials.gov (NCT02040441) and is completed.\ud \ud Findings: \ud Between March 25, 2014, and Sept 30, 2018, we enrolled and followed-up 1775 participants (observational cohort), 1559 (88%) of 1775 participants had a low-risk urinary proteomic pattern and 216 (12%) had a high-risk pattern, of whom 209 were included in the trial cohort and assigned to spironolactone (n=102) or placebo (n=107). The overall median follow-up time was 2·51 years (IQR 2·0–3·0). Progression to microalbuminuria was seen in 61 (28%) of 216 high-risk participants and 139 (9%) of 1559 low-risk participants (hazard ratio [HR] 2·48, 95% CI 1·80–3·42; p

Aim: \ud To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273.\ud \ud Methods: \ud We conducted a prospective, randomized, double‐blind, placebo‐controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high‐ or low‐risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis.\ud \ud Results: \ud A total of 1777 participants from 15 centres were included, with 12.3% of these having a high‐risk proteomic pattern. Participants in the high‐risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low‐risk group (n=1559, P

Background: Clinical characteristics such as HbA1c, systolic blood pressure (SBP), albuminuria and estimated glomerular filtration rate (eGFR) are important when treating type 1 diabetes (T1D). We investigated the variability in these measures as risk markers for micro- and macrovascular complications. Methods: This prospective study included 1062 individuals with T1D. Visit-to-visit variability (VVV) of HbA1c, SBP, albuminuria, and eGFR was calculated as the SD of the residuals in individual linear regression models using all available measures in a specified period of 3 years (SVVV) as well as the entire follow-up (CVVV). Endpoints included: composite cardiovascular events (CVE) defined as myocardial infarction, non-fatal stroke, coronary arterial intervention, or peripheral arterial intervention; end-stage kidney disease (ESKD) defined as chronic kidney disease stage 5, chronic dialysis, or kidney transplantation; eGFR-decline ≥30%; and mortality. Adjustment included age, sex, cholesterol, HbA1c, SBP, body mass index, smoking, albuminuria, eGFR, and intercept and slope of respective regression models. Findings: SVVV and CVVV for every exposure associated significantly with each other (p

Aims To investigate levels and changes in diabetes distress over the course of the PRIORITY (Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In people with TYpe 2 diabetes and normoalbuminuria) randomised controlled trial of screening for diabetic kidney disease (DKD) risk among people with type 2 diabetes (T2D) at a specialist diabetes clinic in Denmark. Methods Of 436 trial participants with T2D, 216 were invited to complete the 17-item diabetes distress scale at the time of screening (T1, n = 180), immediately after receiving the screening results at 6–8 weeks (T2, n = 169), and at 12 months follow up (T3, n = 107). Linear mixed models were used to explore changes in diabetes distress. Results No significant changes in diabetes distress were observed between the time of screening, receiving results, and at 12 months. Changes in diabetes distress were not influenced by diabetes empowerment, sense of coherence, or perceived support for diabetes self-management. Conclusions In contrast to previous studies demonstrating that screening programmes can have negative psychological consequences, our findings indicate that participating in this screening programme for DKD does not influence emotional burden or physician-related distress among people with T2D.

There is an urgent need for a better molecular understanding of the pathophysiology underlying development and progression of diabetic nephropathy. The aim of the current study was to identify novel associations between serum lipidomics and diabetic nephropathy. Non-targeted serum lipidomic analyses were performed with mass spectrometry in 669 individuals with type 1 diabetes. Cross-sectional associations of lipid species with estimated glomerular filtration rate (eGFR) and urinary albumin excretion were assessed. Moreover, associations with register-based longitudinal follow-up for progression to a combined renal endpoint including ≥30% decline in eGFR, ESRD and all-cause mortality were evaluated. Median follow-up time was 5.0–6.4 years. Adjustments included traditional risk factors and multiple testing correction. In total, 106 lipid species were identified. Primarily, alkyl-acyl phosphatidylcholines, triglycerides and sphingomyelins demonstrated cross-sectional associations with eGFR and macroalbuminuria. In longitudinal analyses, thirteen lipid species were associated with the slope of eGFR or albuminuria. Of these lipids, phosphatidylcholine and sphingomyelin species, PC(O-34:2), PC(O-34:3), SM(d18:1/24:0), SM(d40:1) and SM(d41:1), were associated with lower risk of the combined renal endpoint. PC(O-34:3), SM(d40:1) and SM(d41:1) were associated with lower risk of all-cause mortality while an SM(d18:1/24:0) was associated with lower risk of albuminuria group progression. We report distinct associations between lipid species and risk of renal outcomes in type 1 diabetes, independent of traditional markers of kidney function.

OBJECTIVE Patients with type 1 diabetes (T1D) have a higher risk of developing chronic kidney disease, cardiovascular events (CVEs), and mortality than the general population. We hypothesized that two previously published biomarkers, namely PRO-C6, a biomarker of collagen type VI formation, and C3M, a biomarker of collagen type III degradation, may be associated with impaired renal function and have prognostic value for adverse renal, CVE, and mortality in patients with T1D. RESEARCH DESIGN AND METHODS PRO-C6 and C3M in serum (sPRO-C6, sC3M) and urine (uPRO-C6, uC3M) were measured by ELISA in 663 patients with T1D ranging from normoalbuminuric to macroalbuminuric. Association of the biomarkers with mortality, CVEs, heart failure, decline in estimated glomerular filtration rate (eGFR) ≥30%, and end-stage renal disease (ESRD) were tested in Cox proportional hazards models after log2 transformation and adjusted for relevant clinical characteristics. Hazard ratios (HRs) were reported per doubling of biomarker levels. RESULTS High levels of sPRO-C6 were independently associated with a higher risk of all-cause mortality (HR 2.26 [95% CI 1.31–3.87], P < 0.0031). There was an association with higher risk of CVEs (n = 94) and heart failure (n = 28) but not after adjustment (P ≥ 0.58). In relation to renal outcomes, adjusted sPRO-C6 was associated with a higher risk of eGFR decline ≥30% in T1D, with eGFR >45 and >30 mL/min/1.73 m2, and with a higher risk of ESRD (all P ≤ 0.03). Higher uPRO-C6 was associated with a lower risk of decline in eGFR. CONCLUSIONS In patients with T1D, higher sPRO-C6 was an independent predictor of both decline in eGFR and development of ESRD and of all-cause mortality. Higher uPRO-C6 was also associated with a lower risk of decline in eGFR.

Purpose: The prognostic significance of carotid-femoral pulse wave velocity (cfPWV) remains to be determined in patients with type 1 diabetes (T1D). We investigated the predictive value of cfPWV for various endpoints in T1D. Methods: At baseline, cfPWV was measured using the SphygmoCor device in 652 patients with T1D and various degrees of albuminuria. Endpoints were traced through National Registers and patient records and comprised: composite CVE, mortality, progression in albuminuria, and decline in estimated glomerular filtration rate (eGFR) ≥30%. Median follow-up ranged from 5.2 to 6.2 years. Slope estimates of eGFR and urinary albumin creatinine rate (UACR) were calculated for a median of 5.5 years. Adjustment included sex, age, mean arterial pressure, LDL cholesterol, smoking, HbA1c, UACR and eGFR at baseline. Hazard ratios (HR) were calculated per 1 standard derivation (SD) increase in cfPWV. Results: Of the 652 participants (56% male); mean±SD age was 54 ± 13 years and cfPWV 10.5 ± 3.38 m/s2. After adjustment, higher cfPWV was significantly associated with all endpoints: composite CVE (n = 81; HR:1.31; p = 0.045); mortality (n = 48; HR:1.39; p = 0.033); progression in albuminuria (n = 31; HR:1.16; p = 0.012); and decline in eGFR ≥ 30% (n = 90; HR: 1.39; p = 0.015).Higher cfPWV was associated with a steeper decline in eGFR and a steeper increase in UACR after adjustments (p ≤ 0.009). Conclusions: In patients with T1D, higher arterial stiffness was consistently associated with a higher risk of CVE, mortality and decline in renal function, independent of other risk factors. Measurement of cfPWV may have a promising role in risk stratification in T1D.

Background: Screening for future risk of diabetic kidney disease (DKD) in people with type 2 diabetes (T2D) and normal kidney function was conducted in the clinical multicenter intervention trial PRIORITY (Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria). Risk screening was based on a urinary proteomic analysis categorizing the patients at high or low risk for DKD. Little is known about how risk-assessments affect patients. However, screening for DKD is likely to increase diabetes distress (DD), as DD is linked to specific diabetes stressors such as worrying about complications. Aim: To investigate to what extent DD was affected by screening and individualized information about future risk of DKD. Methods: Of 436 participants in the Danish part of PRIORITY, 217 were asked to complete a full diabetes distress scale (DDS) and 139 completed DDS at screening visit (T1) and after provision of screening results (T2, 6 weeks after T1). DDS was repeated in 84 at a follow-up visit (T3, 12 months after T2). DD differences were explored with wilcoxon signed-rank test and subgroup differences with paired t-test. Results: Participants’ mean age was 61 years, 37 % women, mean diabetes duration 10 years, mean HbA1c 54mmol/mol, 4 % had high overall DD and 12 % were categorized as having high risk of DKD. No significant changes were found in DD between T1, T2 and T3. Mean DD differences [SD] between T1 to T2 was 0.02 [0.38], p=0.65 and between T2 and T3 0.01 [0.35], p=0.88. No significant differences in DD changes were found when comparing participants with high vs. low initial DD or when comparing participants in high vs. low risk of DKD. However, few participants had high DD at T1 and few had high risk of DKD. Conclusions: The study indicated that screening for future risk of DKD does not increase DD in people with T2D. Future studies should explore potential subgroup differences further as well as the mechanisms behind the results. Disclosure L.E. Joensen: None. K.P. Madsen: None. M. Frimodt-Moller: None. N. Tofte: None. I. Willaing: None. M. Lindhardt: None. P. Rossing: Advisory Panel; Self; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim GmbH. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Advisory Panel; Self; Astellas Pharma US, Inc.. Stock/Shareholder; Self; Novo Nordisk A/S. Advisory Panel; Self; Bayer AG.

Patients suffering from spinal cord injuries resulting in complete or incomplete paraplegia or tetraplegia are highly disposed to frequent, recurrent or even chronic urinary tract infections (UTIs). The reason for the increased risk of acquiring UTIs is multifactorial, including reduced sensation of classical UTI symptoms, incomplete bladder emptying, frequent catheterizations or chronic urinary tract catheters. Biofilms in relation to UTIs have been shown both on catheters, on concrements or as intracellular bacterial communities (IBCs). Due to the increased risk of acquiring recurrent or chronic UTIs and frequent antibiotic treatments, patients experience an increased risk of being infected with antibiotic-resistant bacteria like extended-spectrum β-lactamase–producing Escherichia coli or Klebsiella spp., but also bacteria like Pseudomonas aeruginosa inherently resistant to several antibiotics. Diagnosing the UTI can also be challenging, especially distinguishing harmless colonization from pathogenic infection. Based on a previous study showing activation of humoral immune response toward UTI pathogens in patients with spinal cord lesions (SCL), the present mini review is an evaluation of using antibody response as an indicator of chronic biofilm UTI. In addition, we evaluated the effect of long-term treatment with antibiotics in patients with SCLs and chronic UTI, defined by culturing of a uropathogen in the urine and elevated specific precipitating antibodies against the same uropathogen in a blood sample. Elimination of chronic UTI, decrease in specific precipitating antibody values and avoiding selection of new multidrug-resistant (MDR) uropathogens were the primary markers for effect of treatment. The results of this evaluation suggest that the long-term treatment strategy in SCL patients with chronic UTI may be effective; however, randomized prospective results are needed to confirm this.

This was a retrospective study analyzing the mortality and incidence of Aspergillus infection and invasive disease, comparing patients given voriconazole for 3 months following transplantation to patients not given prophylaxis.All consecutive patients (n = 147) transplanted at Copenhagen University Hospital, Rigshospitalet from 2002 to 2006 were included in the study; the study period included the 2 years before the initiation of fungal prophylaxis (88 patients) and the 2 years after (59 patients). Eight patients transplanted in this period were excluded leaving 139 patients in the study.No effect of voriconazole on the incidence of Aspergillus infection (colonization, or superficial or invasive infection) or on the time from transplantation to the first sign of infection was seen when the 2 groups of patients were compared. The cumulated incidence of infection was 45% without and 49% with prophylaxis, and in both groups approximately half of the infections occurred in the first 3 months, the time during which prophylaxis was given. There were significantly more cystic fibrosis (CF) patients among the Aspergillus-infected patients compared to other diagnoses, and the effect of prophylaxis was the same as in non-CF patients. There was a significantly lower mortality in the voriconazole-treated group compared to the non-prophylaxis group, but in an isolated analysis of Aspergillus-infected patients this difference no longer existed; hence, the difference in mortality must be attributable to a time effect and not to voriconazole prophylaxis.Routine use of voriconazole treatment for prophylaxis against Aspergillus infection in lung transplant recipients does not appear to be warranted.

OBJECTIVE Soluble urokinase plasminogen activator receptor (suPAR) is an important inflammatory biomarker implicated in endothelial and podocyte dysfunction. However, suPAR’s predictive qualities for complications in type 1 diabetes have yet to be determined. We investigated the prognostic value of suPAR for the development of cardiovascular events, decline in renal function, and mortality in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS We included 667 patients with type 1 diabetes with various degrees of albuminuria in a prospective study. End points were cardiovascular events (cardiovascular death, nonfatal acute myocardial infarction, nonfatal stroke, or coronary or peripheral arterial interventions), estimated glomerular filtration rate (eGFR) decline ≥30%, progression from lower to higher albuminuric state, development of end-stage renal disease (ESRD), and mortality. Follow-up was 5.2–6.2 years. Results were adjusted for known risk factors. Hazard ratios (HRs) are presented per doubling of suPAR with 95% CI. Relative integrated discrimination improvement (rIDI) was calculated. RESULTS Quantification of suPAR was available in all participants; median (interquartile range) was 3.4 ng/mL (2.7–4.5). The adjusted HR (95% CI) for cardiovascular events (n = 94), progression in albuminuria (n = 36), eGFR decline (n = 93), ESRD (n = 23), and mortality (n = 58) were 3.13 (1.96–5.45, P < 0.001), 1.27 (0.51–3.19, P = 0.61), 2.93 (1.68–5.11, P < 0.001), 2.82 (0.73–11.9, P = 0.13), and 4.13 (1.96–8.69, P < 0.001), respectively. rIDI was significant for cardiovascular events (22.6%, P < 0.001), eGFR decline (14.4%, P < 0.001), and mortality (23.9%, P < 0.001). CONCLUSIONS In patients with type 1 diabetes and a broad range of albuminuria, a higher level of suPAR is a significant and independent risk factor for cardiovascular events, decline in eGFR ≥30%, and mortality. In addition, suPAR contributes significantly to discrimination for the end points.