Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population
van Waateringe RP, Fokkens BT, Slagter SN, van der Klauw MM, van Vliet-Ostaptchouk JV, et al. Diabetologia 2019; 62(2): 269–280
AIMS/HYPOTHESIS: Earlier studies have shown that skin autofluorescence measured with an AGE reader estimates the accumulation of AGEs in the skin, which increases with ageing and is associated with the metabolic syndrome and type 2 diabetes. In the present study, we examined whether the measurement of skin autofluorescence can predict 4-year risk of incident type 2 diabetes, cardiovascular disease (CVD) and mortality in the general population.
METHODS: For this prospective analysis, we included 72 880 participants of the Dutch Lifelines Cohort Study, who underwent baseline investigations between 2007 and 2013, had validated baseline skin autofluorescence values available and were not known to have diabetes or CVD. Individuals were diagnosed with incident type 2 diabetes by self-report or by a fasting blood glucose ≥7.0 mmol/L or HbA1c ≥48 mmol/mol (≥6.5%) at follow-up. Participants were diagnosed as having incident CVD (myocardial infarction, coronary interventions, cerebrovascular accident, transient ischaemic attack, intermittent claudication or vascular surgery) by self-report. Mortality was ascertained using the Municipal Personal Records Database.
RESULTS: After a median follow-up of 4 years (range 0.5–10 years), 1056 participants (1.4%) had developed type 2 diabetes, 1258 individuals (1.7%) were diagnosed with CVD, while 928 (1.3%) had died. Baseline skin autofluorescence was elevated in participants with incident type 2 diabetes and/or CVD and in those who had died (all P< 0.001), compared with individuals who survived and remained free of the two diseases. Skin autofluorescence predicted the development of type 2 diabetes, CVD and mortality, independent of several traditional risk factors, such as the metabolic syndrome, glucose and HbA1c.
CONCLUSIONS/INTERPRETATION: The non-invasive skin autofluorescence measurement is of clinical value for screening for future risk of type 2 diabetes, CVD and mortality, independent of glycaemic measures and the metabolic syndrome.
A renal genetic risk score (GRS) is associated with kidney dysfunction in people with type 2 diabetes
Zusi C, Trombetta M, Bonetti S, Dauriz M, Boselli ML, et al. Diabetes Res Clin Pract 2018; 144: 137–143
This study aims to investigate whether renal and cardiovascular phenotypes in Italian patients with type 2 diabetes (T2D) could be influenced by a number of disease risk SNPs recently found in genome-wide association studies (GWAS). In 1591 Italian subjects with T2D: (1) 47SNPs associated to kidney function and/or chronic kidney disease (CKD) and 49SNPs associated to cardiovascular disease (CVD) risk were genotyped; (2) urinary albumin/creatinine (A/C) ratio, glomerular filtration rate (eGFR) and lipid profile were assessed; (3) a standard electrocardiogram was performed; (4) two genotype risk scores (GRS) were computed (a renal GRS calculated selecting 39 SNPs associated with intermediate traits of kidney damage and a cardiovascular GRS determined selecting 42 SNPs associated to CVD risk phenotypes). After correction for multiple comparisons, the renal GRS was not associated to A/C ratio (P=0.33), but it was significantly related to decreased eGFR (P=0.005). No association between the cardiovascular GRS and electrocardiogram was detected. Thus, in Italian patients with T2D a renal GRS might predict the decline in glomerular function, suggesting that the clock of diabetes associated CKD starts ticking long before hyperglycemia. Our data support the feasibility of gene-based prediction of complications in people with T2D.
Protein markers and risk of type 2 diabetes and prediabetes: a targeted proteomics approach in the KORA F4/FF4 study
Huth C, von Toerne C, Schederecker F, de Las Heras Gala T, Herder C, et al. Eur J Epidemiol 2018: doi: 10.1007/s10654-018-0475-8 [Epub ahead of print]
The objective of the present study was to identify proteins that contribute to pathophysiology and allow prediction of incident type 2 diabetes or incident prediabetes. We quantified 14 candidate proteins using targeted mass spectrometry in plasma samples of the prospective, population-based German KORA F4/FF4 study (6.5-year follow-up). 892 participants aged 42–81 years were selected using a case-cohort design, including 123 persons with incident type 2 diabetes and 255 persons with incident WHO-defined prediabetes. Prospective associations between protein levels and diabetes, prediabetes as well as continuous fasting and 2 h glucose, fasting insulin and insulin resistance were investigated using regression models adjusted for established risk factors. The best predictive panel of proteins on top of a non-invasive risk factor model or on top of HbA1c, age and sex was selected. Mannan-binding lectin serine peptidase (MASP) levels were positively associated with both incident type 2 diabetes and prediabetes. Adiponectin was inversely associated with incident type 2 diabetes. MASP, adiponectin, apolipoprotein A-IV, apolipoprotein C-II, C-reactive protein, and glycosylphosphatidylinositol specific phospholipase D1 were associated with individual continuous outcomes. The combination of MASP, apolipoprotein E (apoE) and adiponectin improved diabetes prediction on top of both reference models, while prediabetes prediction was improved by MASP plus CRP on top of the HbA1c model. In conclusion, our mass spectrometric approach revealed a novel association of MASP with incident type 2 diabetes and incident prediabetes. In combination, MASP, adiponectin and apoE improved type 2 diabetes prediction beyond non-invasive risk factors or HbA1c, age and sex.
Association between circulating tumor necrosis factor-related biomarkers and estimated glomerular filtration rate in type 2 diabetes.
Kamei N, Yamashita M, Nishizaki Y, Yanagisawa N, Nojiri S, et al. Sci Rep 2018; 8(1): 15302
Chronic inflammation plays a crucial role in the development/progression of diabetic kidney disease. The involvement of tumor necrosis factor (TNF)-related biomarkers [TNFα, progranulin (PGRN), TNF receptors (TNFR1 and TNFR2)] and uric acid (UA) in renal function decline was investigated in patients with type 2 diabetes (T2D). Serum TNF-related biomarkers and UA levels were measured in 594 Japanese patients with T2D and an eGFR ≥30 mL/min/1.73 m2. Four TNF-related biomarkers and UA were negatively associated with estimated glomerular filtration rate (eGFR). In a logistic multivariate model, each TNF-related biomarker and UA was associated with lower eGFR (eGFR <60 mL/min/1.73 m2) after adjustment for relevant covariates (basic model). Furthermore, UA and TNF-related biomarkers other than PGRN added a significant benefit for the risk factors of lower eGFR when measured together with a basic model (UA, ΔAUC, 0.049, P<0.001; TNFα, ΔAUC, 0.022, P=0.007; TNFR1, ΔAUC, 0.064, P<0.001; TNFR2, ΔAUC, 0.052, P<0.001) in receiver operating characteristic curve analysis. TNFR ligands were associated with lower eGFR, but the associations were not as strong as those with TNFRs or UA in patients with T2D and an eGFR ≥30 mL/min/1.73 m2.
Plasma endostatin predicts kidney outcomes in patients with type 2 diabetes
Chauhan K, Verghese DA, Rao V, Chan L, Parikh CR, et al. Kidney Int 2019; 95(2): 439–446
Novel biomarkers are needed to predict kidney function decline in patients with type 2 diabetes, especially those with preserved glomerular filtration rate (GFR). There are limited data on the association of markers of endothelial dysfunction with longitudinal GFR decline. We used banked specimens from a nested case-control study in the Action to Control Cardiovascular Disease (ACCORD) trial (n=187 cases; 187 controls) and from a diverse contemporary cohort of type 2 diabetic patients from the Mount Sinai BioMe Biobank (n=871) to assess the association of plasma endostatin and kidney outcomes. We measured plasma endostatin at enrolment and examined its association with a composite kidney outcome of sustained 40% decline in estimated GFR or end-stage renal disease. Baseline plasma endostatin levels were higher in participants with the composite outcome. Each log2 increment in plasma endostatin was associated with approximately 2.5-fold higher risk of the kidney outcome (adjusted odds ratio [OR] 2.5; 95% confidence interval [CI] 1.5–4.3 in ACCORD and adjusted hazard ratio [HR] 2.6; 95% CI 1.8-3.8 in BioMe). Participants in the highest versus lowest quartile of plasma endostatin had approximately fourfold higher risk for the kidney outcome (adjusted OR 3.6; 95% CI 1.8-7.3 in ACCORD and adjusted HR 4.4; 95% CI 2.3-8.5 in BioMe). The AUC for the kidney outcome improved from 0.74 to 0.77 in BioMe with the addition of endostatin to a base clinical model. Plasma endostatin was strongly associated with kidney outcomes in type 2 diabetics with preserved eGFR and improved risk discrimination over traditional predictors
Relation of serum and urine renal biomarkers to cardiovascular risk in patients with type 2 diabetes mellitus and recent acute coronary syndromes (from the EXAMINE Trial)
Vaduganathan M, White WB, Charytan DM, Morrow DA, Liu Y, et al. Am J Cardiol 2019; 123(3): 382–391
A deeper understanding of the interplay between the renal axis and cardiovascular (CV) disease is needed in type 2 diabetes mellitus (T2DM). We aimed to explore the prognostic value of a comprehensive panel of renal biomarkers in patients with T2DM at high CV risk. We evaluated the prognostic performance of both serum (Cystatin C) and urine renal biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 protein, and indices of urinary protein excretion) in 5380 patients with T2DM and recent acute coronary syndromes in the EXAMINE trial. Patients requiring dialysis within 14 days were excluded. Single- and multimarker covariate-adjusted Cox proportional hazards models were developed to predict times to events. Primary endpoint was composite nonfatal myocardial infarction, nonfatal stroke, or CV death. Median age was 61 years, 68% were men, and mean baseline estimated glomerular filtration rate (eGFR) was 74 mL/min/1.73 m2. During median follow-up of 18 months, 621 (11.5%) experienced the primary endpoint and 326 (6.1%) patients had died. All renal biomarkers were robustly associated with adverse CV events in step-wise fashion, independent of baseline eGFR. However, in the multimarker prediction model, only Cystatin C (per 1 SD) was associated with the primary endpoint (hazard ratio [HR] 1.28 [1.14 to 1.45]; P≤0.001), death (HR 1.51 [1.30 to 1.74]; P≤0.001), and heart failure hospitalization (HR 1.20 [0.96 to 1.49]; P=0.11). Association between Cystatin C and the primary endpoint was similar in baseline eGFR above and below 60 mL/min/1.73 m2 (Pinteraction >0.05). In conclusion, serum and urine renal biomarkers, when tested alone, independently predict long-term adverse CV events in high-risk patients with T2DM. In an integrative panel of renal biomarkers, only serum Cystatin C remained independently associated with subsequent CV risk. Renal biomarkers informing various aspects of kidney function may further our understanding of the complex interplay between diabetic kidney disease and CV disease.
A plasma circulating miRNAs profile predicts type 2 diabetes mellitus and prediabetes: from the CORDIOPREV study
Jiménez-Lucena R, Camargo A, Alcalá-Diaz JF, Romero-Baldonado C, Luque RM, et al. Exp Mol Med 2018; 50(12): 168
We aimed to explore whether changes in circulating levels of miRNAs according to type 2 diabetes mellitus (T2DM) or prediabetes status could be used as biomarkers to evaluate the risk of developing the disease. The study included 462 patients without T2DM at baseline from the CORDIOPREV trial. After a median follow-up of 60 months, 107 of the subjects developed T2DM, 30 developed prediabetes, 223 maintained prediabetes and 78 remained disease-free. Plasma levels of four miRNAs related to insulin signalling and beta-cell function were measured by RT-PCR. We analysed the relationship between miRNAs levels and insulin signalling and release indexes at baseline and after the follow-up period. The risk of developing disease based on tertiles (T1-T2-T3) of baseline miRNAs levels was evaluated by Cox analysis. Thus, we observed higher miR-150 and miR-30a-5p and lower miR-15a and miR-375 baseline levels in subjects with T2DM than in disease-free subjects. Patients with high miR-150 and miR-30a-5p baseline levels had lower disposition index (P=0.047 and P=0.007, respectively). The higher risk of disease was associated with high levels (T3) of miR-150 and miR-30a-5p (HRT3-T1 = 4.218 and HRT3-T1=2.527, respectively) and low levels (T1) of miR-15a and miR-375 (HRT1-T3 = 3.269 and HRT1-T3=1.604, respectively). In conclusion, our study showed that deregulated plasma levels of miR-150, miR-30a-5p, miR-15a, and miR-375 were observed years before the onset of T2DM and pre-DM and could be used to evaluate the risk of developing the disease, which may improve prediction and prevention among individuals at high risk for T2DM.
Emerging biomarkers, tools, and treatments for diabetic polyneuropathy
Bönhof GJ, Herder C, Strom A, Papanas N, Roden M, Ziegler D. Endocr Rev. 2019; 40(1): 153–192
Diabetic neuropathy, with its major clinical sequels, notably neuropathic pain, foot ulcers, and autonomic dysfunction, is associated with substantial morbidity, increased risk of mortality, and reduced quality of life. Despite its major clinical impact, diabetic neuropathy remains underdiagnosed and undertreated. Moreover, the evidence supporting a benefit for causal treatment is weak at least in patients with type 2 diabetes, and current pharmacotherapy is largely limited to symptomatic treatment options. Thus, a better understanding of the underlying pathophysiology is mandatory for translation into new diagnostic and treatment approaches. Improved knowledge about pathogenic pathways implicated in the development of diabetic neuropathy could lead to novel diagnostic techniques that have the potential of improving the early detection of neuropathy in diabetes and prediabetes to eventually embark on new treatment strategies. In this review, we first provide an overview on the current clinical aspects and illustrate the pathogenetic concepts of (pre)diabetic neuropathy. We then describe the biomarkers emerging from these concepts and novel diagnostic tools and appraise their utility in the early detection and prediction of predominantly distal sensorimotor polyneuropathy. Finally, we discuss the evidence for and limitations of the current and novel therapy options with particular emphasis on lifestyle modification and pathogenesis-derived treatment approaches. Altogether, recent years have brought forth a multitude of emerging biomarkers reflecting different pathogenic pathways such as oxidative stress and inflammation and diagnostic tools for an early detection and prediction of (pre)diabetic neuropathy. Ultimately, these insights should culminate in improving our therapeutic armamentarium against this common and debilitating or even life-threatening condition.
Detection of urinary microRNAs as biomarkers of diabetic kidney disease
, /in Featured Articles /by 3wmediaCurrent measures for diagnosis and therapy of chronic kidney disease are limited. Better biomarkers are required to improve treatment by directing therapeutic intervention, tracking responses to therapy and providing greater understanding of the underlying mechanisms driving renal disease progression. We describe here the development of microRNAs as biomarkers for diabetic kidney disease, the most common etiology leading to chronic kidney disease and end-stage renal failure.
by Dr Tanya A. Smith, Dr Kate Simpson, Prof Donald J. Fraser and Dr Timothy Bowen
Diabetes, complications and biomarkers
Diabetes is a major global health challenge, with 23.1 million cases diagnosed in the US alone [1]. As described below, our laboratory is currently developing urinary microRNAs as biomarkers for diabetic kidney disease. These transcripts may also have utility as biomarkers for other complications of type 2 diabetes mellitus including diabetic retinopathy, neuropathy, cardiovascular disease, stroke, ulceration and amputation [2].
Diabetic kidney disease
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease in the United States. Clinical presentation is characterized by proteinuria, hypertension, and progressive reduction in kidney function. DKD is a progressive condition associated with around 35% of patients with type 1 and type 2 diabetes mellitus [3]. A highly significant public health concern, DKD is currently managed by targeting cardiovascular risk reduction, blood pressure management, glycemic control (hemoglobin A1c concentration), nutritional counselling, weight loss, smoking cessation, and pharmacological inhibition of the renin–angiotensin system using angiotensin-converting enzyme inhibitors or angiotensin-2 receptor blockers [4].
Despite the stabilization of the incidence of diabetes over the past 15 years, the United States Renal Data System has demonstrated increased prevalence of end-stage renal disease attributed to diabetes. However, the disease burden is such that patients often do not survive to end-stage renal disease. There is a broad spectrum of cardiovascular complications associated with DKD of which the underlying etiology remains unclear. Cardiovascular disease is the leading cause of death in this patient group, manifesting as cerebral vascular event, sudden cardiac death, myocardial infarction and diabetic cardiomyopathy. It is, therefore, essential to identify and treat patients before irreversible organ damage to reduce the medical and economic burden of disease [4].
Existing DKD biomarkers
DKD is associated with both glomerular hyperfiltration leading to progressive albuminuria, and declining glomerular filtration rate.
Albuminuria
Proteinuria is a biomarker used widely as a proxy to assess the integrity of the glomerular filtration barrier (for detailed glomerular and nephronal physiology see [5]). Quantification of urinary albuminuria excretion is a non-invasive and inexpensive method to monitor disease. Microalbuminuria is currently the primary predictive clinical DKD marker and occurs when urinary albuminuria excretion rate reaches 30–300 mg/24 h, macroalbuminuria is reached when this rate exceeds 300 mg/24 h. In the presence of diabetes mellitus, confirmation of microalbuminuria in two separate samples taken 3–6 months apart is diagnostic of DKD. Screening for albuminuria is more commonly performed using urinary albumin-to-creatinine ratio on an isolated urine sample, and is defined as >30 mg/g.
However, albuminuria is a non-specific biomarker measurable only after kidney injury has occurred and correlates poorly with clinical disease. In addition, albuminuria may be a transient DKD feature, or may occur only when widespread glomerular damage is already present [6, 7]. Recent reports have noted that up to 25% of patients with type 2 diabetes mellitus and diminished kidney function have little or no proteinuria, despite having biopsy-proven DKD [8]. There is, therefore, a need to find sensitive and specific biomarkers to predict DKD susceptibility and progression.
Estimated glomerular filtration rate
The Kidney Disease: Improving Global Outcomes (KDIGO) [4] classification is directed at adults and children over the age of 2 years old with evidence of kidney disease. Glomerular filtration rate (GFR) is considered the best measure of kidney function. Normal GFR is quantified as 100–150 ml/min and can be determined by creatinine clearance or an estimated GFR (eGFR) calculation basis on serum creatinine, age, sex and ethnicity (Table 1).
Histological features of renal biopsies, eGFR and DKD
Histological features (see [5]) correlate with functional alterations in DKD. The Renal Pathological Society system, based on glomerular changes observed in the development of DKD, groups both type 1 and type 2 diabetes mellitus patients into the four classes described below [9].
Class I: Glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild, non-specific changes by light microscopy that do not meet the criteria of classes II–IV.
Class II: Mesangial expansion, mild (class IIa) or severe (class IIb). Glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel–Wilson lesions) or global glomerulosclerosis in >50% of glomeruli.
Class III: Nodular sclerosis (Kimmelstiel–Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel–Wilson) without changes described in class IV.
Class IV: Advanced diabetic glomerulosclerosis. Over 50% global glomerulosclerosis with other clinical or pathologic evidence showing that sclerosis is attributable to DKD.
The need for newer biomarkers
Current biomarkers do not relate well to the above pathological classification. Many potential novel biomarkers have been tested in an attempt to improve our ability to discern underlying renal pathology non-invasively, with the aim of guiding therapy. These include urinary transferrin, serum osteopontin, urinary retinol-binding protein (RBP), serum interleukin-18, serum cystatin C, serum resistin, serum TNF-α, serum interleukin-6 and urinary neutrophil gelatinase-associated lipocalin (NGAL) [reviewed in 6]. In patients with albuminuria these markers increase significantly, but their relationships with histopathological changes, eGFR, HBA1C and blood pressure is complex.
Detection and identification of microRNAs in body fluids as kidney disease biomarkers
Members of the short single-stranded endogenous RNA transcript family known as microRNAs (miRNAs) modulate the expression of most mammalian protein coding genes, thereby influencing developmental and metabolic processes, and disease phenotypes [10]. Disease-associated changes in miRNA expression profiles have been observed in cancer, cardiovascular disease, diabetes and chronic kidney disease that is treated by dialysis or transplantation [reviewed in 11–14].
To date, the majority of miRNA biomarker analyses have focused on detection of circulating transcripts [11, 13]. By contrast, the adoption into existing treatment pathways of a miRNA biomarker test on biofluid samples that can be obtained without venipuncture promises attractive reductions in time and cost [15].
We have developed RT-qPCR-based methods for precise quantification of miRNAs in urine, peritoneal dialysis effluent and renal transplantation perfusate [15–19]. The robust recovery of miRNAs from these complex analytical matrices highlights their potential utility both as non-invasive biomarkers of occurrence and/or progression of kidney disease, and as potential targets for therapeutic intervention. We have shown association of increased miR-21 with peritoneal fibrosis [17] and transplantation outcomes [18, 19]. Analysis of the renal transplantation perfusate with which the organ is supplied between donor and recipient also identified elevated miR-21 [18].
Utility of urinary miR-29b, miR-126 and miR-155 to test for DKD
Disease biomarkers are useful only when they can inform our potential to change patient treatment. The US Food and Drug Administration recommends that a reduction in eGFR of 40% over 2–3 years is a broadly acceptable effective surrogate for confirmation of CKD [20]. However, since eGFR decline is typically very gradual over the first decade or so of disease and more rapid thereafter, a biomarker that can differentiate between later stages of CKD maybe more cost-effective in detecting quantifiable responses to therapy in clinical trials [20, 21].
We have recently shown association of elevated urinary miR-29b, miR-126 and miR-155 detection predominantly in patients with type 2 diabetes mellitus and DKD [15]. We observed upregulation of these three miRNAs in two disease cohorts, obtaining an area under the curve of 0.8 in combined receiver operating characteristic curve analysis [15]. Our markers are clustered in late-stage disease (Fig. 1) and at an 80% relative quantification threshold for each miRNA, identified 48% of DKD patients with a 3.6% false positive detection rate [15]. We are currently investigating the significance of this apparent DKD patient stratification.
Utility of urinary miR-29b, miR-126 and miR-155 to investigate DKD mechanisms
We detected increased miR-29b and miR-126 in conditioned medium from cultured glomerular endothelial cells exposed to disease-related cytokines transforming growth factor-β1 and tumour necrosis factor-α, respectively [15]. It is thus conceivable that miRNAs may travel down the nephron [5] to mediate disease-related and functional effects [22]. Our data also included evidence for decreased urinary miR-192 in DKD [15], supporting our previous finding showing downregulated miR-192 expression in renal biopsies from DKD patients [23].
Conclusion
DKD is one of the most important global health challenges. Existing biomarkers provide a non-invasive approach to diagnosis and, in late-stage disease, identify the extent of kidney damage. However, there is a lack of non-invasive measures of active disease processes. New biomarkers are, therefore, required to measure risk of progressive kidney damage and to measure responses to treatment in the individual. Successful development of such biomarkers would help to individualize treatment using existing approaches, and would greatly accelerate testing of new treatments. MicroRNAs tested in urine show promise in this area.
Acknowledgments
Supported by the National Institute for Health Research Invention for Innovation (i4i) Programme grant II-LA-0712-20003 and Kidney Research UK Project grant award RP44/2014. The Wales Kidney Research Unit is funded by core support from Health and Care Research Wales.
Disclosure
TB and DF are inventors for patent WO/2017/129977 Chronic Kidney Disease Diagnostic.
References
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2. Wang J, Chen J, Sen S. MicroRNAs as biomarkers and diagnostics. J Cell Physiol 2016; 231(1): 25–30.
3. de Boer IH, et al. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 2011; 305(24): 2532–2539.
4. Levin A, et al. Kidney disease: improving global outcomes (KDIGO) CKD work group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Supplements 2013; 3(1): 1–150.
5. Pollak MR, et al. The glomerulus: the sphere of influence. Clin J Am Soc Nephrol 2017; 9(8): 1461–1469.
6. Al-Rubeaan K, et al. Assessment of the diagnostic value of different biomarkers in relation to various stages of diabetic nephropathy in type 2 diabetic patients. Sci Rep 2017; 7(1): 2684.
7. Alicic RZ, et al. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol 2017; 12(12): 2032–2045.
8. Dwyer JP, Lewis JB. Nonproteinuric diabetic nephropathy: when diabetics don’t read the textbook. Med Clin North Am 2013; 97(1): 53–58.
9. Tervaert TW, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol 2010; 21(4): 556–563.
10. Bartel DP. Metazoan microRNAs. Cell 2018; 173(1): 20–51.
11. Simpson K, et al. MicroRNAs in diabetic nephropathy: from biomarkers to therapy. Curr Diab Rep 2016; 16(3): 35.
12. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 2016; 16(3): 203–222.
13. Wonnacott A, et al. MicroRNAs as biomarkers in chronic kidney disease. Curr Opin in Nephrol and Hypertens 2017; 26(6): 460–466.
14. Zhao H, et al. MicroRNAs in chronic kidney disease. Clin Chim Acta 2019; 491(4): 59–65.
15. Beltrami C, et al. Association of elevated urinary miR-126, miR-155 and miR-29b with diabetic kidney disease. Am J Pathol 2018; 188(9): 1982–1992.
16. Beltrami C, et al. Stabilization of urinary microRNAs by association with exosomes and argonaute 2 protein. Noncoding RNA 2015; 1(2): 151–165.
17. Lopez Anton M, et al. MicroRNA-21 promotes fibrogenesis in peritoneal dialysis. Am J Pathol 2017; 187(7): 1537–1550.
18. Khalid U, et al. MicroRNA-21 (miR-21) expression in hypothermic machine perfusate may be predictive of early outcomes in kidney transplantation. Clinical Transplant 2016; 30(2): 99–104.
19. Khalid U, et al. A urinary microRNA panel that is an early predictive biomarker of delayed graft function following kidney transplantation. Sci Rep 2019; 9: 3584.
20. Levey AS, et al. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis 2014; 64(6): 821–835.
21. Stevens LA, et al. Surrogate end points for clinical trials of kidney disease progression. Clin J Am Soc Nephrol 2006; 1(12): 874–884.
22. Thomas MJ, et al. Biogenesis, stabilization and transport of microRNAs in kidney Health and Disease. Noncoding RNA 2018; 4(4): E30.
23. Krupa A, et al. Loss of microRNA-192 promotes fibrogenesis in diabetic nephropathy. J Am Soc Nephrol 2010; 21(3): 438–447.
The authors
Tanya A. Smith MB ChB; Kate Simpson PhD; Donald J. Fraser MB ChB, PhD; Timothy Bowen* PhD
Wales Kidney Research Unit, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
*Corresponding author
E-mail: bowent@cardiff.ac.uk
Scientific literature review: Diabetes
, /in Featured Articles /by 3wmediaSkin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population
van Waateringe RP, Fokkens BT, Slagter SN, van der Klauw MM, van Vliet-Ostaptchouk JV, et al. Diabetologia 2019; 62(2): 269–280
AIMS/HYPOTHESIS: Earlier studies have shown that skin autofluorescence measured with an AGE reader estimates the accumulation of AGEs in the skin, which increases with ageing and is associated with the metabolic syndrome and type 2 diabetes. In the present study, we examined whether the measurement of skin autofluorescence can predict 4-year risk of incident type 2 diabetes, cardiovascular disease (CVD) and mortality in the general population.
METHODS: For this prospective analysis, we included 72 880 participants of the Dutch Lifelines Cohort Study, who underwent baseline investigations between 2007 and 2013, had validated baseline skin autofluorescence values available and were not known to have diabetes or CVD. Individuals were diagnosed with incident type 2 diabetes by self-report or by a fasting blood glucose ≥7.0 mmol/L or HbA1c ≥48 mmol/mol (≥6.5%) at follow-up. Participants were diagnosed as having incident CVD (myocardial infarction, coronary interventions, cerebrovascular accident, transient ischaemic attack, intermittent claudication or vascular surgery) by self-report. Mortality was ascertained using the Municipal Personal Records Database.
RESULTS: After a median follow-up of 4 years (range 0.5–10 years), 1056 participants (1.4%) had developed type 2 diabetes, 1258 individuals (1.7%) were diagnosed with CVD, while 928 (1.3%) had died. Baseline skin autofluorescence was elevated in participants with incident type 2 diabetes and/or CVD and in those who had died (all P< 0.001), compared with individuals who survived and remained free of the two diseases. Skin autofluorescence predicted the development of type 2 diabetes, CVD and mortality, independent of several traditional risk factors, such as the metabolic syndrome, glucose and HbA1c.
CONCLUSIONS/INTERPRETATION: The non-invasive skin autofluorescence measurement is of clinical value for screening for future risk of type 2 diabetes, CVD and mortality, independent of glycaemic measures and the metabolic syndrome.
A renal genetic risk score (GRS) is associated with kidney dysfunction in people with type 2 diabetes
Zusi C, Trombetta M, Bonetti S, Dauriz M, Boselli ML, et al. Diabetes Res Clin Pract 2018; 144: 137–143
This study aims to investigate whether renal and cardiovascular phenotypes in Italian patients with type 2 diabetes (T2D) could be influenced by a number of disease risk SNPs recently found in genome-wide association studies (GWAS). In 1591 Italian subjects with T2D: (1) 47SNPs associated to kidney function and/or chronic kidney disease (CKD) and 49SNPs associated to cardiovascular disease (CVD) risk were genotyped; (2) urinary albumin/creatinine (A/C) ratio, glomerular filtration rate (eGFR) and lipid profile were assessed; (3) a standard electrocardiogram was performed; (4) two genotype risk scores (GRS) were computed (a renal GRS calculated selecting 39 SNPs associated with intermediate traits of kidney damage and a cardiovascular GRS determined selecting 42 SNPs associated to CVD risk phenotypes). After correction for multiple comparisons, the renal GRS was not associated to A/C ratio (P=0.33), but it was significantly related to decreased eGFR (P=0.005). No association between the cardiovascular GRS and electrocardiogram was detected. Thus, in Italian patients with T2D a renal GRS might predict the decline in glomerular function, suggesting that the clock of diabetes associated CKD starts ticking long before hyperglycemia. Our data support the feasibility of gene-based prediction of complications in people with T2D.
Protein markers and risk of type 2 diabetes and prediabetes: a targeted proteomics approach in the KORA F4/FF4 study
Huth C, von Toerne C, Schederecker F, de Las Heras Gala T, Herder C, et al. Eur J Epidemiol 2018: doi: 10.1007/s10654-018-0475-8 [Epub ahead of print]
The objective of the present study was to identify proteins that contribute to pathophysiology and allow prediction of incident type 2 diabetes or incident prediabetes. We quantified 14 candidate proteins using targeted mass spectrometry in plasma samples of the prospective, population-based German KORA F4/FF4 study (6.5-year follow-up). 892 participants aged 42–81 years were selected using a case-cohort design, including 123 persons with incident type 2 diabetes and 255 persons with incident WHO-defined prediabetes. Prospective associations between protein levels and diabetes, prediabetes as well as continuous fasting and 2 h glucose, fasting insulin and insulin resistance were investigated using regression models adjusted for established risk factors. The best predictive panel of proteins on top of a non-invasive risk factor model or on top of HbA1c, age and sex was selected. Mannan-binding lectin serine peptidase (MASP) levels were positively associated with both incident type 2 diabetes and prediabetes. Adiponectin was inversely associated with incident type 2 diabetes. MASP, adiponectin, apolipoprotein A-IV, apolipoprotein C-II, C-reactive protein, and glycosylphosphatidylinositol specific phospholipase D1 were associated with individual continuous outcomes. The combination of MASP, apolipoprotein E (apoE) and adiponectin improved diabetes prediction on top of both reference models, while prediabetes prediction was improved by MASP plus CRP on top of the HbA1c model. In conclusion, our mass spectrometric approach revealed a novel association of MASP with incident type 2 diabetes and incident prediabetes. In combination, MASP, adiponectin and apoE improved type 2 diabetes prediction beyond non-invasive risk factors or HbA1c, age and sex.
Association between circulating tumor necrosis factor-related biomarkers and estimated glomerular filtration rate in type 2 diabetes.
Kamei N, Yamashita M, Nishizaki Y, Yanagisawa N, Nojiri S, et al. Sci Rep 2018; 8(1): 15302
Chronic inflammation plays a crucial role in the development/progression of diabetic kidney disease. The involvement of tumor necrosis factor (TNF)-related biomarkers [TNFα, progranulin (PGRN), TNF receptors (TNFR1 and TNFR2)] and uric acid (UA) in renal function decline was investigated in patients with type 2 diabetes (T2D). Serum TNF-related biomarkers and UA levels were measured in 594 Japanese patients with T2D and an eGFR ≥30 mL/min/1.73 m2. Four TNF-related biomarkers and UA were negatively associated with estimated glomerular filtration rate (eGFR). In a logistic multivariate model, each TNF-related biomarker and UA was associated with lower eGFR (eGFR <60 mL/min/1.73 m2) after adjustment for relevant covariates (basic model). Furthermore, UA and TNF-related biomarkers other than PGRN added a significant benefit for the risk factors of lower eGFR when measured together with a basic model (UA, ΔAUC, 0.049, P<0.001; TNFα, ΔAUC, 0.022, P=0.007; TNFR1, ΔAUC, 0.064, P<0.001; TNFR2, ΔAUC, 0.052, P<0.001) in receiver operating characteristic curve analysis. TNFR ligands were associated with lower eGFR, but the associations were not as strong as those with TNFRs or UA in patients with T2D and an eGFR ≥30 mL/min/1.73 m2.
Plasma endostatin predicts kidney outcomes in patients with type 2 diabetes
Chauhan K, Verghese DA, Rao V, Chan L, Parikh CR, et al. Kidney Int 2019; 95(2): 439–446
Novel biomarkers are needed to predict kidney function decline in patients with type 2 diabetes, especially those with preserved glomerular filtration rate (GFR). There are limited data on the association of markers of endothelial dysfunction with longitudinal GFR decline. We used banked specimens from a nested case-control study in the Action to Control Cardiovascular Disease (ACCORD) trial (n=187 cases; 187 controls) and from a diverse contemporary cohort of type 2 diabetic patients from the Mount Sinai BioMe Biobank (n=871) to assess the association of plasma endostatin and kidney outcomes. We measured plasma endostatin at enrolment and examined its association with a composite kidney outcome of sustained 40% decline in estimated GFR or end-stage renal disease. Baseline plasma endostatin levels were higher in participants with the composite outcome. Each log2 increment in plasma endostatin was associated with approximately 2.5-fold higher risk of the kidney outcome (adjusted odds ratio [OR] 2.5; 95% confidence interval [CI] 1.5–4.3 in ACCORD and adjusted hazard ratio [HR] 2.6; 95% CI 1.8-3.8 in BioMe). Participants in the highest versus lowest quartile of plasma endostatin had approximately fourfold higher risk for the kidney outcome (adjusted OR 3.6; 95% CI 1.8-7.3 in ACCORD and adjusted HR 4.4; 95% CI 2.3-8.5 in BioMe). The AUC for the kidney outcome improved from 0.74 to 0.77 in BioMe with the addition of endostatin to a base clinical model. Plasma endostatin was strongly associated with kidney outcomes in type 2 diabetics with preserved eGFR and improved risk discrimination over traditional predictors
Relation of serum and urine renal biomarkers to cardiovascular risk in patients with type 2 diabetes mellitus and recent acute coronary syndromes (from the EXAMINE Trial)
Vaduganathan M, White WB, Charytan DM, Morrow DA, Liu Y, et al. Am J Cardiol 2019; 123(3): 382–391
A deeper understanding of the interplay between the renal axis and cardiovascular (CV) disease is needed in type 2 diabetes mellitus (T2DM). We aimed to explore the prognostic value of a comprehensive panel of renal biomarkers in patients with T2DM at high CV risk. We evaluated the prognostic performance of both serum (Cystatin C) and urine renal biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 protein, and indices of urinary protein excretion) in 5380 patients with T2DM and recent acute coronary syndromes in the EXAMINE trial. Patients requiring dialysis within 14 days were excluded. Single- and multimarker covariate-adjusted Cox proportional hazards models were developed to predict times to events. Primary endpoint was composite nonfatal myocardial infarction, nonfatal stroke, or CV death. Median age was 61 years, 68% were men, and mean baseline estimated glomerular filtration rate (eGFR) was 74 mL/min/1.73 m2. During median follow-up of 18 months, 621 (11.5%) experienced the primary endpoint and 326 (6.1%) patients had died. All renal biomarkers were robustly associated with adverse CV events in step-wise fashion, independent of baseline eGFR. However, in the multimarker prediction model, only Cystatin C (per 1 SD) was associated with the primary endpoint (hazard ratio [HR] 1.28 [1.14 to 1.45]; P≤0.001), death (HR 1.51 [1.30 to 1.74]; P≤0.001), and heart failure hospitalization (HR 1.20 [0.96 to 1.49]; P=0.11). Association between Cystatin C and the primary endpoint was similar in baseline eGFR above and below 60 mL/min/1.73 m2 (Pinteraction >0.05). In conclusion, serum and urine renal biomarkers, when tested alone, independently predict long-term adverse CV events in high-risk patients with T2DM. In an integrative panel of renal biomarkers, only serum Cystatin C remained independently associated with subsequent CV risk. Renal biomarkers informing various aspects of kidney function may further our understanding of the complex interplay between diabetic kidney disease and CV disease.
A plasma circulating miRNAs profile predicts type 2 diabetes mellitus and prediabetes: from the CORDIOPREV study
Jiménez-Lucena R, Camargo A, Alcalá-Diaz JF, Romero-Baldonado C, Luque RM, et al. Exp Mol Med 2018; 50(12): 168
We aimed to explore whether changes in circulating levels of miRNAs according to type 2 diabetes mellitus (T2DM) or prediabetes status could be used as biomarkers to evaluate the risk of developing the disease. The study included 462 patients without T2DM at baseline from the CORDIOPREV trial. After a median follow-up of 60 months, 107 of the subjects developed T2DM, 30 developed prediabetes, 223 maintained prediabetes and 78 remained disease-free. Plasma levels of four miRNAs related to insulin signalling and beta-cell function were measured by RT-PCR. We analysed the relationship between miRNAs levels and insulin signalling and release indexes at baseline and after the follow-up period. The risk of developing disease based on tertiles (T1-T2-T3) of baseline miRNAs levels was evaluated by Cox analysis. Thus, we observed higher miR-150 and miR-30a-5p and lower miR-15a and miR-375 baseline levels in subjects with T2DM than in disease-free subjects. Patients with high miR-150 and miR-30a-5p baseline levels had lower disposition index (P=0.047 and P=0.007, respectively). The higher risk of disease was associated with high levels (T3) of miR-150 and miR-30a-5p (HRT3-T1 = 4.218 and HRT3-T1=2.527, respectively) and low levels (T1) of miR-15a and miR-375 (HRT1-T3 = 3.269 and HRT1-T3=1.604, respectively). In conclusion, our study showed that deregulated plasma levels of miR-150, miR-30a-5p, miR-15a, and miR-375 were observed years before the onset of T2DM and pre-DM and could be used to evaluate the risk of developing the disease, which may improve prediction and prevention among individuals at high risk for T2DM.
Emerging biomarkers, tools, and treatments for diabetic polyneuropathy
Bönhof GJ, Herder C, Strom A, Papanas N, Roden M, Ziegler D. Endocr Rev. 2019; 40(1): 153–192
Diabetic neuropathy, with its major clinical sequels, notably neuropathic pain, foot ulcers, and autonomic dysfunction, is associated with substantial morbidity, increased risk of mortality, and reduced quality of life. Despite its major clinical impact, diabetic neuropathy remains underdiagnosed and undertreated. Moreover, the evidence supporting a benefit for causal treatment is weak at least in patients with type 2 diabetes, and current pharmacotherapy is largely limited to symptomatic treatment options. Thus, a better understanding of the underlying pathophysiology is mandatory for translation into new diagnostic and treatment approaches. Improved knowledge about pathogenic pathways implicated in the development of diabetic neuropathy could lead to novel diagnostic techniques that have the potential of improving the early detection of neuropathy in diabetes and prediabetes to eventually embark on new treatment strategies. In this review, we first provide an overview on the current clinical aspects and illustrate the pathogenetic concepts of (pre)diabetic neuropathy. We then describe the biomarkers emerging from these concepts and novel diagnostic tools and appraise their utility in the early detection and prediction of predominantly distal sensorimotor polyneuropathy. Finally, we discuss the evidence for and limitations of the current and novel therapy options with particular emphasis on lifestyle modification and pathogenesis-derived treatment approaches. Altogether, recent years have brought forth a multitude of emerging biomarkers reflecting different pathogenic pathways such as oxidative stress and inflammation and diagnostic tools for an early detection and prediction of (pre)diabetic neuropathy. Ultimately, these insights should culminate in improving our therapeutic armamentarium against this common and debilitating or even life-threatening condition.
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, /in Featured Articles /by 3wmediaMolecular Diagnostics Literature Review
, /in Featured Articles /by 3wmediaGenome-wide analysis of circulating cell-free DNA copy number detects active melanoma and predicts survival
Silva S, Danson S, Teare D, Taylor F, Bradford J, et al. Clin Chem 2018; 64(9): 1338–1346.
BACKGROUND: A substantial number of melanoma patients develop local or metastatic recurrence, and early detection of these is vital to maximize benefit from new therapies such as inhibitors of BRAF and MEK, or immune checkpoints. This study explored the use of novel DNA copy-number profiles in circulating cell-free DNA (cfDNA) as a potential biomarker of active disease and survival.
PATIENTS AND METHODS: Melanoma patients were recruited from oncology and dermatology clinics in Sheffield, UK, and cfDNA was isolated from stored blood plasma. Using low-coverage whole-genome sequencing, we created copy-number profiles from cfDNA from 83 melanoma patients, 44 of whom had active disease. We used scoring algorithms to summarize copy-number aberrations and investigated their utility in multivariable logistic and Cox regression analyses.
RESULTS: The copy-number aberration score (CNAS) was a good discriminator of active disease (odds ratio, 3.1; 95 % CI, 1.5–6.2; P=0.002), and CNAS above or below the 75th percentile remained a significant discriminator in multivariable analysis for active disease (P=0.019, with area under ROC curve of 0.90). Additionally, mortality was higher in those with CNASs above the 75th percentile than in those with lower scores (HR, 3.4; 95 % CI, 1.5–7.9; P=0.005), adjusting for stage of disease, disease status (active or resected), BRAF status, and cfDNA concentration.
CONCLUSIONS: This study demonstrates the potential of a de novo approach utilizing copy-number profiling of cfDNA as a biomarker of active disease and survival in melanoma. Longitudinal analysis of copy-number profiles as an early marker of relapsed disease is warranted.
Microbiological diagnostics of bloodstream infections in Europe – An ESGBIES survey
Idelevich EA, Seifert H, Sundqvist M, Scudeller L, Amit S, et al. Clin Microbiol Infect 2019; doi: 10.1016/j.cmi.2019.03.024 [Epub ahead of print].
OBJECTIVES: High-quality diagnosis of bloodstream infections (BSIs) is important for successful patient management. As knowledge on current practices of microbiological BSI diagnostics is limited, this project aimed to assess its current state in European microbiological laboratories.
METHODS: We performed an online questionnaire-based cross-sectional survey comprising 34 questions on practices of microbiological BSI diagnostics. The ESCMID Study Group for Bloodstream Infections, Endocarditis and Sepsis (ESGBIES) was the primary platform to engage national coordinators who recruited laboratories within their countries.
RESULTS: Responses were received from 209 laboratories in 25 European countries. While 32.5 % (68/209) of laboratories only used the classical processing of positive blood cultures (BCs), two-thirds applied rapid technologies. Of laboratories that provided data for respective question, 42.2 % (78/185) were able to start incubating blood cultures in automated BC incubators around-the-clock, and only 13 % (25/192) had established a 24-hour service to start immediate processing of positive BCs. Only 4.7 % (9/190) of laboratories validated and transmitted the results of identification and antimicrobial susceptibility testing (AST) of BC pathogens to clinicians 24 hours/day. MALDI-TOF MS from shortly incubated sub-cultures on solid media was the most commonly used approach to rapid pathogen identification from positive BCs, and direct disk diffusion was the most common rapid AST method from positive BCs.
CONCLUSIONS: Laboratories have started to implement novel technologies for rapid identification and AST for positive BCs. However, progress is severely compromised by limited operating hours such that current practice of BC diagnostics in Europe complies only partly with the requirements for optimal BSI management.
An integrated next-generation sequencing system for analyzing DNA mutations, gene fusions, and RNA expression in lung cancer
Haynes BC, Blidner RA, Cardwell RD, Zeigler R, Gokul S, et al. Transl Oncol 2019; 12(6): 836–845.
We developed and characterized a next-generation sequencing (NGS) technology for streamlined analysis of DNA and RNA using low-input, low-quality cancer specimens. A single-workflow, targeted NGS panel for non-small cell lung cancer (NSCLC) was designed covering 135 RNA and 55 DNA disease-relevant targets. This multiomic panel was used to assess 219 formalin-fixed paraffin-embedded NSCLC surgical resections and core needle biopsies. Mutations and expression phenotypes were identified consistent with previous large-scale genomic studies, including mutually exclusive DNA and RNA oncogenic driver events. Evaluation of a second cohort of low cell count fine-needle aspirate smears from the BATTLE-2 trial yielded 97 % agreement with an independent, validated NGS panel that was used with matched surgical specimens. Collectively, our data indicate that broad, clinically actionable insights that previously required independent assays, workflows, and analyses to assess both DNA and RNA can be conjoined in a first-tier, highly multiplexed NGS test, thereby providing faster, simpler, and more economical results.
Molecular diagnosis of asparagine synthetase (ASNS) deficiency in two Indian families and literature review of 29 ASNS deficient cases
Devi ARR, Naushad SM. Gene 2019; doi: 10.1016/j.gene.2019.04.024 [Epub ahead of print].
In the current study, we report three cases of asparagine synthetase (ASNS) deficiency from two consanguineous families. Family 1 had two early neonatal deaths due to a novel mutation in the ASNS gene c.788C > T (p.S263F) and both the children presented with microcephaly and one of them had severe intracranial hemorrhage. The proband from the second family was homozygous for c.146G > A (p.R49Q) and manifested myoclonic seizures, developmental delay, coarse hair and diffuse cortical atrophy. Molecular docking studies of both the mutations revealed alteration in the ligand binding site. To date, 26 mutations were reported in ASNS gene in 29 affected children indicating high degree of genetic heterogeneity and high mortality. Although asparagine depletion is not of diagnostic utility, multiple linear regression model suggested that asparagine levels vary to the extent of 20.6 % based on glutamine and aspartate levels and ASNS deficiency results in depletion of arginine synthesis. ASNS deficiency should be suspected in any neonate with microcephaly and epileptic encephalopathy.
Placental growth factor testing reduces time to diagnosis for women with suspected pre-eclampsia
, /in Featured Articles /by 3wmediaPre-eclampsia is a condition that affects approximately 2–8% pregnancies worldwide and, although the cause is not really understood, is thought to be due to poor function of the placenta. Early signs that create suspicion of pre-eclampsia in the mother typically include hypertension, proteinuria and edema (particularly of the pitting type) of the ankles. Symptoms of more severe pre-eclampsia can include pulmonary edema, headaches, visual disturbance, epigastric/right upper quadrant abdominal pain and vomiting, before the development of seizures (eclampsia). Symptoms in the fetus include fetal growth restriction.
Left untreated, pre-eclampsia is associated with a high risk of adverse outcome for both the mother and fetus. The only treatment is delivery of the baby and the placenta. Diagnosis of pre-eclampsia is challenging because of the vagueness of the symptoms, but becomes suspected with new onset hypertension after 20 weeks’ gestation. The management of women presenting with pre-eclampsia from 37 weeks of gestation is through planned delivery. However, the management of patients with suspected pre-eclampsia earlier in pregnancy involves careful surveillance, and therefore increased use of health resources, balancing the risk to maternal health against the risk of preterm delivery for the fetus. Angiogenic factors, such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) have shown potential for the diagnosis of pre-eclampsia in cohort studies. Recently, however, the results of study using a stepped-wedge cluster-randomized controlled trial measuring PlGF levels alongside the use of a clinical management algorithm have been published in The Lancet (Duhig KE, et al. Lancet 2019; pii: S0140-6736(18)33212-4). The study involved more than 1000 women with suspected pre-eclampsia and the women were divided into two groups – where the PlGF levels were either made known (revealed PlGF) or not (concealed PlGF). The results showed that in the revealed PlGF group, time to diagnosis fell from 4.1 to 1.9 days compared with the concealed PlGF group and that serious maternal complications fell from 5.3% (24 of 447 women) to 4% (22 of 573 women). The findings from the study, have resulted in NHS England deciding to make the test more widely available, allowing more timely patient management and more appropriate use of resources in high-risk women, so helping to avoid life-threatening complications for both mother and baby as well as providing reassurance when
pre-eclampsia is ruled out.