Presence of retinopathy and incident kidney and cardiovascular events in type 2 diabetes with normoalbuminuria - A post-hoc analysis of the PRIORITY randomized clinical trial.

AIMS: Baseline diabetic retinopathy (DR) and risk of development of microalbuminuria, kidney function decline, and cardiovascular events (CVEs) in type 2 diabetes. 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. DR diagnosis included non-proliferative and proliferative abnormalities, macular oedema, or prior laser treatment. Cox models were fitted to investigate baseline DR presence with development of persistent microalbuminuria (urinary albumin-creatinine ratio > 30 mg/g); chronic kidney disease (CKD) G3 (eGFR <60 ml/min/1.73m2); and CVE. 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 < 0.001), and higher HbA1c (62 ± 13 vs. 56 ± 12 mmol/mol, p < 0.001). The adjusted hazard ratios of DR at baseline for development of microalbuminuria (n = 197), CKD (n = 166), and CVE (n = 64) were: 1.50 (95%CI: 1.07, 2.11), 0.87 (95%CI: 0.56, 1.34), and 2.61 (95%CI: 1.44, 4.72), compared to without DR. CONCLUSIONS: Presence of DR in normoalbuminuric type 2 diabetes was associated with an increased risk of developing microalbuminuria and CVE, but not with kidney function decline.

Early detection of diabetic kidney disease by urinary proteomics and subsequent intervention with spironolactone to delay progression (PRIORITY): a prospective observational study and embedded randomised placebo-controlled trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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<0·0001, after adjustment for baseline variables of age, sex, HbA1c, systolic blood pressure, retinopathy, urine albumin-to-creatinine ratio [UACR], and eGFR). Development of impaired renal function (eGFR <60 mL/min per 1·73 m2) was seen in 48 (26%) of 184 high-risk participants and 119 (8%) of 1423 low-risk participants (HR 3·50; 95% CI 2·50-4·90, after adjustment for baseline variables). A 30% decrease in eGFR from baseline (post-hoc endpoint) was seen in 42 (19%) of 216 high-risk participants and 62 (4%) of 1559 low-risk participants (HR 5·15, 95% CI 3·41-7·76; p<0·0001, after adjustment for basline eGFR and UACR). In the intention-to-treat trial cohort, development of microalbuminuria was seen in 35 (33%) of 107 in the placebo group and 26 (25%) of 102 in the spironolactone group (HR 0·81, 95% CI 0·49-1·34; p=0·41). In the safety analysis (intention-to-treat trial cohort), events of plasma potassium concentrations of more than 5·5 mmol/L were seen in 13 (13%) of 102 participants in the spironolactone group and four (4%) of 107 participants in the placebo group, and gynaecomastia was seen in three (3%) participants in the spironolactone group and none in the placebo group. One patient died in the placebo group due to a cardiac event (considered possibly related to study drug) and one patient died in the spironolactone group due to cancer, deemed unrelated to study drug. INTERPRETATION: In people with type 2 diabetes and normoalbuminuria, a high-risk score from the urinary proteomic classifier CKD273 was associated with an increased risk of progression to microalbuminuria over a median of 2·5 years, independent of clinical characteristics. However, spironolactone did not prevent progression to microalbuminuria in high-risk patients. FUNDING: European Union Seventh Framework Programme.

A new method of color Doppler perfusion measurement via dynamic sonographic signal quantification in renal parenchyma.

OBJECTIVE: Perfusion quantification of tissues is an important goal to evaluate the state of blood supply of an organ. We developed a method to quantify tissue perfusion via color Doppler signal quantification from sonographic videos and applied this to describe renal parenchymal perfusion in healthy kidneys. METHOD: Color Doppler sonographic videos of renal perfusion from both kidneys of 87 healthy children (age 2 weeks to 16 years) were recorded under defined conditions. Perfusion data (color hue, color area) were measured in a standardized region of interest automatically. Signal intensity was calculated as whole ROIs (regions of interest) mean flow velocity (cm/s) encoded by color Doppler signals during one full heart cycle. RESULTS: Normal signal intensity values are: 1.86 cm/s in the region encompassing central 50% of the renal cortex and 0.56 cm/s in the peripheral 50% of the renal cortex. These differences are significant. Signal intensity of both kidneys did not differ. CONCLUSION: Signal intensity of cortical tissue in healthy kidneys was quantified noninvasively from color Doppler signal data in an easily accomplishable manner with new measurement software. Normal values for this technique have been calculated. Possible further applications might be all situations, where perfusion changes could be expected like inflammation, renal insufficiency, vascular diseases and tumors.