Reference intervals for clinical biochemistry and haematology tests during normal pregnancy.

BACKGROUND: Pregnancy induces physiological changes which affect biochemical and haematological parameters. As the significance of laboratory test results change throughout pregnancy, the reference interval (RI) or key result interpretive guide should be specific to pregnancy. This study sought to establish trimester-specific-RIs for routine biochemical and haematological tests in healthy white European women with singleton pregnancies with comparison to RIs for non-pregnant European adults. METHODS: A retrospective analysis of a prospective longitudinal single-centre study of healthy pregnant women conducted between November 2018 and December 2020 in a tertiary academic hospital with approximately 3000 births annually. Inclusion criteria: signed informed consent, age ≥18 years, white European, body mass index (BMI) <25 kg/m2, blood pressure <140/90mmHg, non-smoker, no previous pathology or gestational diabetes. Trimester defined as T1: up to 13 weeks + 6 days, T2: 14-27 weeks + 6 days and T3: ≥28-41 weeks + 6 days. Baseline demographics, anthropometric and laboratory measurements were recorded. In total, 31 biochemical and 10 haematological ISO15189:2012 accredited tests were measured using Roche Cobas® and Sysmex XN-9100™ analysers, respectively. RIs were established according to the International Federation of Clinical Chemistry (IFCC) recommended method. RESULTS: Apparently healthy pregnant women (n = 124) with bio-banked serum samples in each trimester were recruited. At the booking visit, 49.2% (n = 61) of participants were nulliparous, with median age of 34.4 (IQR: 31.3-37.3) years, gestational age of 89 (IQR: 84-93) days, BMI of 22.5 (IQR: 21.0-23.7) kg/m2 and systolic and diastolic blood pressure of 116 (110-125) mmHg and 67 (61-75) mmHg, respectively. CONCLUSIONS: Normative trimester-specific biological intervals for routinely requested biochemical and haematological medical laboratory tests were established. These RIs will be invaluable to result interpretation and the management of pregnant women.

Reference intervals for commonly requested biochemical and haematological parameters in a healthy Irish adult Caucasian population.

INTRODUCTION: In laboratory medicine, reference intervals (RIs) are key decision support tools used to guide the clinical interpretation of numerical test results. Best practice suggests each laboratory establishes RIs in the local population prior to introducing an assay into routine clinical practice. AIM: The aim of this study was to define RIs for frequently requested biochemical/haematological parameters in a healthy adult Irish Caucasian population. METHODS: A cross-sectional study of non-pregnant apparently healthy volunteers was conducted. Baseline demographics, anthropometric and laboratory measurements were recorded. In total, 37 commonly requested biochemical (serum, n = 26) and haematological (venous blood, n = 11) ISO15189:2012 accredited tests were analysed, using the Roche Cobas® Sebia Capillarys 3 Tera and Siemens Advia® 2120i platforms following standard operating procedures. RIs were defined according to the International Federation of Clinical Chemistry (IFCC) recommended method. RESULTS: Of 208 apparently healthy volunteers, 76 failed to meet the study inclusion criteria. The reference population comprised of 132 participants (males: n = 65, 49.2%) with a median age of 29.7 (18.1-62.2) years. RIs for the majority of biochemical/haematological parameters were broadly in accord with those provided by Pathology Harmony (UK)/Irish RI Harmonisation Project and the manufacturer Roche Diagnostics. However, the established RI defined for HbA1c: 27-37 mmol/mol was markedly different from that quoted nationally, HbA1c: 20-42 mmol/mol. CONCLUSION: Normative biological intervals established in a healthy adult Irish population for 37 commonly requested biochemical/haematological parameters will be a valuable aid to result interpretation in clinical laboratories after appropriate verification in accordance with ISO 15189: 2012.

Burden of chronic kidney disease and rapid decline in renal function among adults attending a hospital-based diabetes center in Northern Europe.

INTRODUCTION: This study aimed to determine the prevalence of diabetic kidney disease (DKD) and rapid renal function decline and to identify indices associated with this decline among adults attending a diabetes center in Northern Europe. RESEARCH DESIGN AND METHODS: This is a retrospective cohort study of 4606 patients who attended a diabetes center in Ireland between June 2012 and December 2016. Definition/staging of chronic kidney disease used the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 classification based on data from the most recently attended appointment. Relevant longitudinal trends and variabilities were derived from serial records prior to index visit. Rapid renal function decline was defined based on per cent and absolute rates of estimated glomerular filtration rate (eGFR) change. Multiple linear regression was used to explore the relationships between explanatory variables and per cent eGFR change. RESULTS: 42.0% (total), 23.4% (type 1 diabetes), 47.9% (type 2 diabetes) and 32.6% (other diabetes) had DKD. Rapid decline based on per cent change was more frequent in type 2 than in type 1 diabetes (32.8% vs 14.0%, p<0.001). Indices independently associated with rapid eGFR decline included older age, greater number of antihypertensives, higher log-normalized urine albumin to creatinine ratio (LNuACR), serum alkaline phosphatase, thyroid stimulating hormone, variability in systolic blood pressure and variability in LNuACR, lower glycated hemoglobin, high-density lipoprotein cholesterol and diastolic blood pressure, and lack of ACE inhibitor/angiotensin receptor blocker prescription. CONCLUSIONS: DKD (using the KDIGO 2012 classification) and rapid eGFR decline were highly prevalent among adults attending a hospital-based diabetes clinic in a predominantly Caucasian Northern European country. The burden was greater for adults with type 2 diabetes. Expected as well as potentially novel clinical predictors were identified.

Influence of Referral to a Combined Diabetology and Nephrology Clinic on Renal Functional Trends and Metabolic Parameters in Adults With Diabetic Kidney Disease.

OBJECTIVE: To examine the impact of a diabetes renal clinic (DRC) on renal functional and metabolic indices in adults who have diabetes mellitus (DM) and chronic kidney disease (CKD). PATIENTS AND METHODS: All patients evaluated at a DRC in a single tertiary referral center from January 1, 2008, to December 31, 2012, were identified. Serial renal and metabolic indices from January 1, 2004, to December 31, 2014, were recorded, and trends over time were analyzed by linear mixed-effects models. RESULTS: A total of 200 patients who had DM and CKD were identified and subdivided into 3 categories based on presumptive CKD etiology: 43 (21.5%) with type 1 DM (T1D) only, 127 (63.5%) with type 2 DM (T2D) only, and 30 (15.0%) with DM and an additional CKD etiology. Average annual absolute (mL/min per body surface area per year) and percentage (%/year) changes, respectively, in Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate before vs after first DRC attendance were: -1.59 vs -3.10 (P=.31) and -1.22 vs -9.39 (P=.06) for T1D; -5.64 vs -3.07 (P=.004) and -10.88 vs -9.94 (P=.70) for T2D; and -6.50 vs +0.91 (P<.001) and -13.28 vs -2.29 (P=.001) for DM with an additional CKD etiology. Glycemic control worsened in those who had T2D, whereas trends in total cholesterol levels improved in those who had T1D. CONCLUSION: After first DRC attendance, the absolute rate of estimated glomerular filtration rate decline remained similar for those who had T1D, but it slowed for those who had T2D or DM with additional CKD etiology. Thus, benefits of combined diabetology and nephrology consultation may vary for different diabetic subpopulations.

Characterisation of risk factors for stones in hyperuricosuric men attending a stone clinic.

Hyperuricosuria is common among stone formers, but its significance is uncertain. To progress our understanding and target treatment, we need to identify and characterise patients with uniform underlying pathology. We aimed to identify hyperuricosuric patients with a primary defect in renal urate reabsorption (renal hyperuricosuria) and to look for associated risk factors for stones. We undertook a retrospective cross-sectional database study of 666 male stone formers attending the Southampton stone clinic. We estimated filtered urate from plasma urate and 24-h creatinine clearance, and the net percentage reabsorbed. 153 men had hyperuricosuria (urine urate >4.80 mmol/24 h); 513 had normouricosuria. Hyperuricosuric men filtered more urate (median 68.1 and 52.5 mmol/24 h) but the ranges overlapped. Thirty hyperuricosuric men with filtered urate below the median for normouricosuria were selected as the renal hyperuricosuria group. Their normal plasma urate and high urate clearance substantiated this classification. In comparison with 60 normouricosuric stone formers matched for filtration, they had a higher incidence of hypercalciuria (67 versus 40%), but similar, high, frequencies of hyperoxaluria (25 and 11%) and phosphaturia (40 and 27%).There were no differences in age at first stone, incidence of stone recurrence or positive family history (20 and 25%). The findings demonstrate multiple risk factors for stones in this subgroup. In comparison, the 30 hyperuricosuric men with the highest filtration had a higher incidence of hyperoxaluria (58%) but fewer (7%) had a positive family history. Creatinine clearance was raised in 73%. An excessive protein intake might be a major correctable factor underlying these abnormalities.

Male hypercalciuric stone formers with low renal calcium reabsorption.

AIMS: Hypercalciuria is a common poorly understood abnormality among stone formers. We aimed to identify hypercalciuric male stone formers with a primary defect in renal calcium reabsorption and to look for associated risk factors. METHODS: A retrospective cross-sectional database study of 623 male idiopathic calcium stone formers with normal plasma ultrafilterable calcium levels attending the Southampton stone clinic. Filtered calcium was estimated from plasma ultrafilterable calcium (60% of total plasma calcium) and 24 h creatinine clearance. Reabsorbed calcium was the difference between filtered and excreted calcium. RESULTS: 276 men had hypercalciuria (urine calcium >7.50 mmol/24 h); 347 had normocalciuria. Hypercalciuric men filtered more calcium than normocalciuric men: median values 247 and 227 mmol/24 h, but the ranges overlapped (175-371 and 153-316 mmol/24 h). However, across the entire filtration range, hypercalciuric men reabsorbed less of the filtered calcium. Among the hypercalciuric men, we noticed differences between those with high and low filtration. We therefore compared data for hypercalciuric men in the highest and lowest filtration quintiles (n=55). Men with high filtration were younger at their first stone episode and had significantly higher plasma ultrafilterable calcium and calcium reabsorption, urinary calcium, oxalate, urate and creatinine excretion and creatinine clearance. 35% with high filtration and 40% with low filtration had recurrent stones; 27% and 20%, respectively, had an affected first-degree relative. CONCLUSIONS: Hypercalciuric men reabsorbed proportionately less filtered calcium than normocalciuric men. Among hypercalciuric men, the risks for stones were higher in those with a high than a low filtered calcium load and presentation was earlier.

Who makes uric acid stones and why--observations from a renal stones clinic.

AIMS: Excessively acidic urine is the dominant factor in uric acid stone formation. Recent evidence implicating insulin resistance has revived interest in its causation. We reviewed data on uric acid stone formers attending a general stones clinic to find out whether this supports and adds to current concepts. METHODS: A retrospective database study of 1504 stone formers investigated at the Southampton renal stones clinic from 1990 to March 2007. Uric acid stone formers and idiopathic calcium stone formers were compared using non-parametric tests. RESULTS: Fifty-nine patients (3.9%; 43 men) had uric acid stones. In men the commonest associated conditions were diabetes (20%), gout (20%) and an ileostomy (15%); in women, diabetes (33%), urinary infections (27%) and hyperparathyroidism (20%). Most patients with diabetes (85% of men, 75% of women), however, produced calcium stones. Risk factors did not differ significantly between calcium and uric acid stone formers with diabetes, gout or ileostomies. The median urine pH of men with idiopathic calcium stones was 6.20, idiopathic uric acid stones 5.47, diabetes 5.68, gout 6.05, diabetes and gout 5.20 and ileostomy 5.10. Plasma urate was higher with gout and idiopathic uric acid stones. Urate excretion was increased in gout. Oxalate excretion was lower with idiopathic uric acid stones (new finding). Urine volume decreased and oxalate concentration increased with ileostomy. CONCLUSIONS: Uric acid stones are increased in diabetes, but most patients with diabetes make calcium stones. Different mechanisms may explain low pH with diabetes, gout and idiopathic stones. Low oxalate excretion with idiopathic urate stones needs confirmation.

Demography and biochemistry of 2800 patients from a renal stones clinic.

BACKGROUND: Because the causes of stones are uncertain, interventions to prevent recurrence have an insecure foundation. Progress depends on careful evaluation of stone formers. METHODS: A descriptive retrospective database study of 1983 men and 816 women from the Southampton stones clinic from 1990 to March 2007. Anonymized data from the first attendance were analysed using non-parametric statistical tests. RESULTS: Sex ratio (2.43:1), age (median 49 y, 2.5th-97.5th percentiles, 23-77 y men, 20-79 y women), recurrent stone formers (30%) and type of stone were similar to other centres. Women more often had a positive family history (24% versus 19% men), previous urinary infection (31% versus 5%) and structural urinary tract abnormality (14% versus 7%); more men had gout (5% versus 1%) and bladder outlet obstruction (3% versus <1%). Calcium, oxalate and uric acid excretion were increased in 43%, 17% and 22% respectively of men and 31%, 7% and 10% of women. Urinary calcium, oxalate and uric acid correlated significantly, r ranging from 0.149 to 0.311 for 24 h excretion and 0.510 to 0.695 for concentrations per litre. Twenty-two percent of men and 8% of women with normal parathyroid hormone had phosphaturia (excretion of phosphate corrected for glomerular filtration rate (TmPO4/GFR) < 0.70 mmol/L); 6% men and 1.6% women also had low plasma phosphate. Many variables correlated significantly but often weakly with age. Creatinine clearance, pH and (men) TmPO4/GFR decreased from 50 y, urine creatinine, calcium and citrate from 60 y. CONCLUSIONS: Risk factors for stones differ between men and women, change with ageing and in some may have a genetic basis. The role of phosphaturia merits further exploration.

Systemic chemokine levels in breast cancer patients and their relationship with circulating menstrual hormones.

INTRODUCTION: The chemokines Stromal Cell-Derived Factor-1alpha (SDF-1alpha/CXCL12) and Monocyte Chemotactic Protein-1 (MCP-1/CCL2) have been implicated in breast cancer progression. We recently reported elevated systemic MCP-1 in breast cancer patients. This study investigated circulating levels of SDF-1alpha in breast cancer patients, and addressed potential hormonal regulation of these two potent chemokines. METHODS: SDF-1alpha levels were determined by ELISA in 114 breast cancer patients and 85 controls, and correlated with clinical data. Blood samples were collected from 36 healthy premenopausal volunteers weekly for four weeks to measure Luteinising Hormone (LH), Follicular Stimulating Hormone (FSH), Oestradiol and Progesterone using a Bayer ADVIA Centaur Immunoassay system, in parallel with SDF-1alpha and MCP-1. CXCL12 expression was determined using RQ-PCR in primary tumour stromal cells (n = 16) harvested at surgery. RESULTS: Plasma SDF-1alpha was significantly higher in breast cancer patients than age-matched controls and had a significant correlation with tumour grade and epithelial subtype. Investigation of menstrual variations of these chemokines revealed lower SDF-1alpha levels in the mid-luteal phase of the menstrual cycle and a significant positive correlation with circulating Oestradiol. MCP-1 levels showed no correlation with menstrual hormones. There was a trend towards increased CXCL12 expression in tumour compared to normal stromal cells. CONCLUSIONS: The elevated level of SDF-1alpha detected in breast cancer patients, and it's correlation with prognostic indicators, highlights the importance of this chemokine in disease progression. Elucidation of factors influencing chemokine secretion supports clarification of their role in tumourigenesis.