Paula O’Shea

Establishment of reference intervals for aldosterone and renin in a Caucasian population using the newly developed Immunodiagnostic Systems specialty immunoassay automated system

Background Measurement of aldosterone and/or renin is essential to aid the differential diagnosis of secondary hypertension, guide strategy for therapeutic management of hypertension and assess adequacy of mineralocorticoid replacement. Aim The objective was to establish normative data for aldosterone and renin using the Immunodiagnostic Systems specialty immunoassay system platform in a Caucasian population. Methods Following informed consent, 365 subjects were recruited to this study. Subjects were ambulatory and attended clinic for blood pressure measurement and phlebotomy between the hours of 7:00 and 11:00. Blood pressure was measured according to the 2013 European Society of Hypertension/Cardiology guidelines. The inclusion criteria: age ≥18 years, BMI <30 kg/m2, non-pregnant, blood pressure <140/90, normal electrolytes and kidney function and not taking prescribed/over the counter medications. Ninety-four subjects were excluded based on these criteria. A total of 271 volunteers (females n = 145), aged 18–65 years formed the reference cohort. Blood for aldosterone/renin was collected into ethylenediaminetetraacetic acid specimen tubes. Samples were kept at room temperature and transported within 30 min of blood draw to the laboratory for immediate processing (centrifugation, separation and freezing of plasma). Plasma was stored at −20℃ prior to analysis on the Immunodiagnostic Systems specialty immunoassay system instrument. Results The established reference intervals in an Irish Caucasian population for renin: females: 6.1–62.7 mIU/L, males: 9.0–103 mIU/L, for aldosterone: females: <138–1179 pmol/L, males: <138–670 pmol/L, respectively. Conclusion This study demonstrates that reference intervals for aldosterone and renin should be gender specific. These automated immunoassays offer rapid stratification of patients with refractory hypertension and will better facilitate the optimization of therapeutic management.

Screening for phaeochromocytoma and paraganglioma: impact of using supine reference intervals for plasma metanephrines with samples collected from fasted/seated patients.

Background The Endocrine Society Clinical Practice Guideline on Phaeochomocytoma and Paraganglioma recommends phlebotomy for plasma-free metanephrines with patients fasted and supine using appropriately defined reference intervals. Studies have shown higher diagnostic sensitivities using these criteria. Further, with seated-sampling protocols, for result interpretation, reference intervals that do not compromise diagnostic sensitivity should be employed. Objective To determine the impact on diagnostic performance and financial cost of using supine reference intervals for result interpretation with our current plasma-free metanephrines fasted/seated-sampling protocol. Methods We conducted a retrospective cohort study of patients who underwent screening for PPGL using plasma-free metanephrines from 2009 to 2014 at Galway University Hospitals. Plasma-free metanephrines were measured using liquid chromatography-tandem mass spectrometry. Supine thresholds for plasma normetanephrine and metanephrine set at 610 pmol/L and 310 pmol/L, respectively, were used. Results A total of 183 patients were evaluated. Mean age of participants was 53.4 (±16.3) years. Five of 183 (2.7%) patients had histologically confirmed PPGL (males, n=4). Using seated reference intervals for plasma-free metanephrines, diagnostic sensitivity and specificity were 100% and 98.9%, respectively, with two false-positive cases. Application of reference intervals established in subjects supine and fasted to this cohort gave diagnostic sensitivity of 100% with specificity of 74.7%. Financial analysis of each pretesting strategy demonstrated cost-equivalence (€147.27/patient). Conclusion Our cost analysis, together with the evidence that fasted/supine-sampling for plasma-free metanephrines, offers more reliable exclusion of PPGL mandates changing our current practice. This study highlights the important advantages of standardized diagnostic protocols for plasma-free metanephrines to ensure the highest diagnostic accuracy for investigation of PPGL.

Screening for primary aldosteronism using the newly developed IDS-iSYS® automated assay system

Background The recommended approach to screening for primary aldosteronism (PA) in at-risk populations is to determine the ratio of aldosterone concentration (serum (SAC)/plasma (PAC)) to renin measured in plasma as activity (PRA) or concentration (DRC). However, lack of assay standardisation mandates the need for method-specific decision thresholds and clinical validation in the local population. Aim The study objective was to establish method-specific aldosterone: renin ratio (ARR) cut-offs for PA in men and women using the IDS-iSYS® assay system (IDS plc). Methods A prospective cohort study design was used. PAC and DRC were measured immunochemically in ethylenediamine-tetraacetic acid (EDTA) plasma on the IDS-iSYS® instrument. Results A total of 437 subjects (218 men, 219 women) were recruited including: healthy normotensive volunteers (n=266) and women taking the oral contraceptive pill (OCP; n=15); patients with essential hypertension (EH; n=128); confirmed PA (n=16); adrenal cortical carcinoma (ACC; n=3); Addisons disease (AD; n=4) and phaeochromocytoma/paraganglioma (PPGL; n=5). In this population, an ARR cut-off at >37.4 pmol/mIU provided 100% diagnostic sensitivity, 96% specificity and positive likelihood ratio for PA of 23:1. When the ARR decision threshold was stratified according to gender, a cut-off of >26.1 pmol/mIU in men and >113.6 pmol/mIU in women resulted in diagnostic sensitivity and specificity of 100%. Conclusion This study demonstrates that decision thresholds for PA should not only be method-specific but also gender-specific. However, given the small number of PA patients (n=16), particularly women (n=4), further validation through a prospective study with a larger PA cohort is required before the thresholds presented here could be recommended for routine clinical use.

The prevalence of metabolic syndrome up to 5 years post-partum in patients with a history of gestational diabetes mellitus

Metabolic syndrome (MetS) is associated with cardiovascular mortality and increased risk of type 2 diabetes.

Defining reference intervals for a serum growth differentiation factor-15 (GDF-15) assay in a Caucasian population and its potential utility in diabetic kidney disease (DKD)

Abstract Background: Growth differentiation factor-15 (GDF-15), a stress responsive cytokine, is a promising biomarker of renal functional decline in diabetic kidney disease (DKD). This study aimed primarily to establish normative data and secondarily to evaluate the potential utility of GDF-15 in DKD using Roche Diagnostics electrochemiluminescence immunoassay (ECLIA) in an Irish Caucasian population. Methods: Following informed consent, 188 healthy volunteers and 128 participants with diabetes (72 with and 56 without DKD) were recruited to a cross-sectional study. Baseline demographics, anthropometric measurements and laboratory measurements were recorded. Blood for GDF-15 measurement was collected into plain specimen tubes kept at room temperature and processed (centrifugation, separation of serum, freezing at −80 °C) within 1 h of phlebotomy pending batch analyses. Reference intervals were determined using the 2.5th and 97.5th percentiles for serum GDF-15 concentration. Results: Of 188 healthy participants, 63 failed to meet study inclusion criteria. The reference interval for serum GDF-15 was 399 ng/L (90% confidence interval [CI]: 399–399) – 1335 ng/L (90% CI: 1152–1445). Receiver operator characteristics (ROC) curve analysis for DKD determined the area under the ROC curve to be 0.931 (95% CI: 0.893–0.959; p<0.001). The optimum GDF-15 cutoff for predicting DKD was >1136 ng/L providing a diagnostic sensitivity and specificity of 94.4% and 79%, respectively, and positive likelihood ratio of 4.5:1 (95% CI: 3.4–6.0). Conclusions: The reference interval for serum GDF-15 in a healthy Irish Caucasian population using Roche Diagnostics ECLIA was established and a preliminary determination of the potential of GDF-15 as a screening test for DKD was made. Further prospective validation with a larger DKD cohort will be required before the cutoff presented here is recommended for clinical use.

ATLANTIC DIP: The prevalence of pre-diabetes/type 2 diabetes in an Irish population with gestational diabetes mellitus 1-5 years post index pregnancy

The ATLANTIC-DIP (diabetes in pregnancy) programme showed 18% of women with gestational diabetes mellitus (GDM) screened with a 75g oral glucose tolerance test (OGTT) 12 weeks post-partum demonstrated glucose intolerance. However, long-term data on progression to type 2 diabetes (T2DM) post gestational diabetes (GDM) in an Irish population is lacking.

Validation of a diabetes risk score in identifying patients at risk of progression to abnormal glucose tolerance post partum

FINDRISC (Finnish Diabetes Risk Score) is a risk assessment tool widely used for the prediction of the development of type 2 diabetes (T2DM), combining a questionnaire with simple anthropometric measurements to identify patients at risk of developing diabetes, with increasing score (0-26) signifying increased risk. A cut off score of 9 has previously been proposed (with drug-treated DM as the endpoint) with a positive predictive value (PPV) of 0.12 and negative predictive value (NPV) of 0.99, area under receiver operating characteristic curve (AuROC)=0.80. It has been well validated in the general population.