Matthew P. Doogue

Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: new developments and revised recommendations

The publication of the Australasian Creatinine Consensus Working Groups position statements in 2005 and 2007 resulted in automatic reporting of estimated glomerular filtration rate (eGFR) with requests for serum creatinine concentration in adults, facilitated the unification of units of measurement for creatinine and eGFR, and promoted the standardisation of assays. New advancements and continuing debate led the Australasian Creatinine Consensus Working Group to reconvene in 2010. The working group recommends that the method of calculating eGFR should be changed to the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) formula, and that all laboratories should report eGFR values as a precise figure to at least 90 mL/min/1.73 m2. Age‐related decision points for eGFR in adults are not recommended, as although an eGFR < 60 mL/min/1.73 m2 is very common in older people, it is nevertheless predictive of significantly increased risks of adverse clinical outcomes, and should not be considered a normal part of ageing. If using eGFR for drug dosing, body size should be considered, in addition to referring to the approved product information. For drugs with a narrow therapeutic index, therapeutic drug monitoring or a valid marker of drug effect should be used to individualise dosing. The CKD‐EPI formula has been validated as a tool to estimate GFR in some populations of non‐European ancestry living in Western countries. Pending publication of validation studies, the working group also recommends that Australasian laboratories continue to automatically report eGFR in Aboriginal and Torres Strait Islander peoples. The working group concluded that routine calculation of eGFR is not recommended in children and youth, or in pregnant women. Serum creatinine concentration (preferably using an enzymatic assay for paediatric patients) should remain as the standard test for kidney function in these populations.

Clinical Pharmacokinetics of Metformin

Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine.Metformin is excreted unchanged in urine. The elimination half-life (t1/2) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CLR) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CLR and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CLCR). AS the CLR and CL/F decrease approximately in proportion to CLCR, the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CLCR.The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical response are also limited. However, intersubject differences in the levels of expression of OCT1 and OCT3 in the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of metformin.Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in patients treated with metformin. We suggest that the mean plasma concentrations of metformin over a dosage interval be maintained below 2.5 mg/L in order to minimize the development of this adverse effect.

A Longitudinal Study of Plasma and Urinary Cortisol in Pregnancy and Postpartum

CONTEXT There is a paucity of longitudinal data on plasma and urinary cortisol levels during pregnancy using modern assays. Furthermore, conflicting data exist as to the effect of the low-dose oral contraceptive pill (OCP) on cortisol. DESIGN, SUBJECTS, AND MEASUREMENTS: We conducted a prospective longitudinal study on morning plasma cortisol (total and free), corticosteroid-binding globulin (CBG), and 24-h urinary free cortisol (UFC) levels in 20 pregnant women during the first, second, and third trimesters and 2-3 months postpartum compared with 12 subjects on low-dose OCP and 15 nonpregnant subjects not taking the OCP (control group). RESULTS A progressive rise in total plasma cortisol, CBG, and 24-h UFC was demonstrated during pregnancy, peaking during the third trimester (mean 3-fold rise compared with controls). Plasma free cortisol increased 1.6-fold by the third trimester. In the OCP group, total plasma cortisol and CBG were 2.9- and 2.6-fold elevated, respectively, whereas 24-h UFC and plasma free cortisol were not significantly different from controls. Compared with liquid chromatography-mass spectrometry, a commercial immunoassay underestimated mean total plasma cortisol concentrations by 30% during second and third trimesters and in OCP users and overestimated UFC levels by 30-35% during pregnancy. CONCLUSIONS Our study demonstrated elevations in total plasma cortisol and CBG concentrations during pregnancy and with low-dose OCP use. Pregnancy was also associated with significant increases in plasma free cortisol and UFC, suggesting that the rise in total plasma cortisol is contributed to by up-regulation of the maternal hypothalamic-pituitary-adrenal axis in addition to elevated CBG.

Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia

Iron-induced renal phosphate wasting, hypophosphataemia and osteomalacia have previously been reported in a small number of Japanese patients receiving parenteral iron sucrose. We report the case history of a European male who, as a result of regular intravenous iron polymaltose, developed prolonged hypophosphataemia complicated by widespread insufficiency fractures. The pathogenesis of this complication remains unknown however our novel finding of a marked elevation in fibroblast growth factor 23 (FGF23), which normalized after ceasing parenteral iron, suggests an important and previously unreported effect of iron on FGF23 homeostasis.

Clopidogrel Hypersensitivity Syndrome With Rash, Fever, and Neutropenia

We report a case of a severe hypersensitivity syndrome reaction to clopidogrel that resolved with dechallenge and recurred on rechallenge. The reaction included neutropenia, rash, fever, tachycardia, nausea, and vomiting. This presentation is very similar to the frequently reported hypersensitivity syndrome reactions to the structurally similar drug ticlopidine and is very similar to a case involving clopidogrel reported previously in this Journal. We could find no other reports of similar cases related to clopidogrel.

Detecting undiagnosed diabetes using glycated haemoglobin: an automated screening test in hospitalised patients

OBJECTIVE To assess the utility of glycated haemoglobin (HbA(1c)) level as an automated screening test for undiagnosed diabetes among hospitalised patients and to estimate the prevalence of undiagnosed diabetes among hospitalised patients. DESIGN, PARTICIPANTS AND SETTING A 3-month prospective study of all adult patients admitted to a tertiary hospital. An HbA(1c) test was automatically undertaken on admission for all patients with a random plasma glucose (RPG) level ≥ 5.5 mmol/L. Demographic, admission and biochemical data were obtained from hospital databases. A subset of patients was recruited for an oral glucose tolerance test (OGTT) after discharge. MAIN OUTCOME MEASURES Prevalence of undiagnosed diabetes (defined as HbA(1c) ≥ 6.5% in accordance with International Expert Committee and American Diabetes Association recommendations) and utility of automated HbA(1c) testing. RESULTS The prevalence of undiagnosed diabetes was 11% (95% CI, 9.8%-12.4%) (262/2360) during the study period. A further 312 patients with known diabetes were admitted. The prevalence of undiagnosed diabetes was highest in the 65-74-years age group. The HbA(1c) test cost was

An international initiative to create a collaborative for pharmacovigilance in hospice and palliative care clinical practice

152 per new diagnosis of diabetes. Conservatively assuming an annual incidence of undiagnosed diabetes of 0.8%, the ongoing cost of testing hospitalised patients would be

Pharmacovigilance in Hospice/Palliative Care: Net Effect of Haloperidol for Delirium

2100 per new diagnosis of diabetes. RPG testing was not sensitive or specific in diagnosing diabetes. Patients were poorly compliant with the post-discharge OGTT (27% completion rate). CONCLUSIONS HbA(1c) is a simple, inexpensive screening test that can be automated using existing clinical blood samples. Hospital screening for diabetes needs to be coupled with resources for management in the community.

Metformin increases plasma ghrelin in Type 2 diabetes.

BACKGROUND Medication registration currently requires evidence of safety and efficacy from adequately powered phase 3 studies. Pharmacovigilance (phase 4 studies, postmarketing data, adverse drug reaction reporting) provide data on more widespread and longer term use. Historically, voluntary reporting systems for pharmacovigilance have had low reporting rates, relying on ad hoc reporting and retrospective chart reviews, or prospective registries have often been limited to specific drugs or clinical conditions. Furthermore, these data are often irrelevant in hospice and palliative care due to the timeliness of which such data become available and the unique characteristics of our population and prescribing: compounding comorbidities, progressive organ failure, accumulation of symptom-specific medications, tendency to attribute toxicity to disease progression, use of old, off-patent medications, and incorporation of evolving evidence. There is a need for prospective, systematic pharmacovigilance in hospice and palliative care. METHOD Here we describe an international, Web-based, 128-bit secure initiative to collect pharmacovigilance data documenting net clinical benefit and safety of common medications. The intention is for a diverse and large group of clinical units to record data prospectively on a small deidentified consecutive cohort of patients started on the medication of interest. A new medication would be studied every 3 months. Three key time points (different for each medication) will be assessed for each patient, collecting easily codefiable data at baseline, a point at which clinical benefit should be experienced, and a point at which short- to medium-term toxicities may occur. Toxicities can additionally be recorded at any time they occur. Data collection will take a maximum of 10 minutes per patient. CONCLUSION The intention is to create an efficient, relevant system to improve hospice and palliative care with maximally generalizable results.

Antimicrobial Treatment Options for Granulomatous Mastitis Caused by Corynebacterium Species

INTRODUCTION Prescribing practice in hospice/palliative care is largely extrapolated from other areas of clinical practice, with few studies of net medication effects (benefits and harms) in hospice/palliative care to guide prescribing decisions. Hospice/palliative care patients differ in multiple ways from better studied participant groups, hence the applicability of studies in other participant groups is uncertain. Haloperidol, a butyrophenone derivative and dopamine antagonist, is commonly prescribed for nausea, vomiting, and delirium in hospice/palliative care. Its frequent use in delirium occurs despite little evidence of the effect of antipsychotics on the untreated course of delirium. The aim of this study was to examine the immediate and short-term clinical benefits and harms of haloperidol for delirium in hospice/palliative care patients. METHOD A consecutive cohort of participants from 14 centers across four countries who had haloperidol commenced for delirium were recruited. Data were collected at three time points: baseline, 48 hours (clinical benefits), and day 10 (clinical harms). Investigators were also able to report clinical harms at any time up to 14 days after it was commenced. RESULTS Of the 119 participants included, the average dose was 2.1 mg per 24 hours; 42 of 106 (35.2%) reported benefit at 48 hours. Harm was reported in 14 of 119 (12%) at 10 days, the most frequent being somnolence (n=11) and urinary retention (n=6). Seven participants had their medication ceased due to harms (2 for somnolence and 2 for rigidity). Approximately half (55/119) were still being treated with haloperidol after 10 days. CONCLUSION Overall, 1 in 3 participants gained net clinical benefit at 10 days.