Establishing pragmatic estimated GFR thresholds to guide metformin prescribing.

AIMS: Renal impairment is a contraindication to metformin treatment because of the perceived increased risk of lactic acidosis. Current guidelines define renal impairment according to the serum creatinine of the individual, but this measure is being supplanted by the use of estimated glomerular filtration rate (eGFR) as it gives a closer estimate to true GFR. This study aimed to establish pragmatic eGFR limits for use in patients being considered for metformin treatment. METHODS: Estimated GFR measurements corresponding to currently used metformin creatinine limits of 130 and 150 micromol/l were derived and then applied to 12 482 patients with diabetes in Hull and East Yorkshire. RESULTS: Few patients with a serum creatinine of 130 or 150 micromol/l have an eGFR of < 30 ml/min/1.73 m(2)[chronic kidney disease (CKD) stage 4 or greater], while most are between 30 and 59 ml/min/1.73 m(2) (CKD stage 3). When applied to the 12 482 patients (median age 67 years, interquartile range 56-75), males predominated when using creatinine cut-offs (13.6% of males and 8.3% of females had creatinine > 130 micromol/l; 8.2% males and 5.2% females > 150 micromol/l), but not using eGFR CKD thresholds (3.3% males and 4.7% females < 30 ml/min/1.73 m(2); 20.8% males and 28.1% females eGFR 30-59 ml/min/1.73 m(2)). Similar proportions of patients as currently would have metformin withheld if using eGFR cut-offs between 30 and 49 ml/min/1.73 m(2). CONCLUSIONS: We have proposed pragmatic eGFR limits to guide metformin prescribing in patients with renal impairment. CKD stage 4 or greater should be an absolute contraindication to metformin, while CKD stage 3 should alert clinicians to consider other risk factors before initiating or continuing treatment.

Genetic linkage mapping of allozyme loci in even- and odd-year pink salmon (Oncorhynchus gorbuscha).

We constructed genetic linkage maps of allozyme loci in even- and odd-year pink salmon (Oncorhynchus gorbuscha), using the total of 320 families (each female was crossed with two different males, and 80 females and 160 males were used for each of even year and odd year). The maps include eight linkage groups involving 22 loci. We observed substantial variation in recombination frequencies among different families within broodline and between sexes within broodlines. In the linkage analysis between sAAT-3* and sMDH-B1,2*, two even-year families and one odd-year family exhibited evidence of association, but two even-year and one odd-year families did not. Recombination rate tends to be reduced in males in pink salmon. The ratio of recombination rate (female/male), which ranged from 1.7 to infinity, averaged 2.8 in the even-year crosses and 3.2 in the odd-year crosses. The linkage groups (LG) I and II involving sAAT and mAH loci, which probably duplicated in the recent tetraploidization event, and the orders of loci in the LGs I (sAAT-3* --> mAH-4*) and II (mAH-3* --> sAAT-4*) were reversed, suggesting the possible paracentric inversion during salmonid evolution after the duplication.

Gene-centromere distances of allozyme loci in even- and odd-year pink salmon, (Oncorhynchus gorbuscha).

We produced gynogenetic progeny families to estimate gene-centromere (G-C) distances of allozyme loci in even-year and odd-year pink salmon (Oncorhynchus gorbuscha). G-C distances of 37 loci distributed on a chromosome ranged from 1 cM at LDH-A1* to 49 cM at ADA-2*, DIA-2*, and sMDH-B1,2*. The distribution of the G-C distances along the chromosome arm was not even and appears telomeric. Eight loci in even-year and seven in odd-year showed high G-C distances (>45 cM), indicating that one crossover per chromosome arm is usual in pink salmon. Variation was observed in the results from different families; 14 loci out of 21 tested, showed heterogeneity. At mAH-3*, G-C distances from five odd-year families ranged from 6 to 37 cM; the widest range observed in this study. At isoloci such as sMDH-A 1,2* and sMDH-B1,2* the distances from different families were grouped into statistically discrete distributions, suggesting that it may be a reflection polymorphism at both isoloci. It appears G-C distances in salmonid species are well conserved with some minor differences.

Antenatal detection of placental steroid sulphatase deficiency by measurement of urinary 16 alpha-hydroxydehydroepiandrosterone sulphate.

A simple gas chromatographic technique for the measurement of 16 alpha-hydroxydehydroepiandrosterone sulphate in urine from pregnant women is described. An assessment was made of the effectiveness of the measurement of this oestriol precursor for the antenatal diagnosis of placental steroid sulphatase deficiency. Twenty-two patients whose pregnancies were complicated by subnormal oestrogen excretion for gestation were studied. In nine of these, where placental steroid sulphatase activity was found subsequently in vitro to be normal, the excretion of 16 alpha-hydroxydehydroepiandrosterone sulphate was less than 27 mumol/24 h. In the remaining 13 patients, in whom postnatal in vitro assay demonstrated absence of placental steroid sulphatase activity, urinary excretion of 16 alpha-hydroxydehydroepiandrosterone sulphate was 59-360 mumol/24 h. The excretion of this metabolite was below the limit of detection (20 mumol/24 h) in 30 uncomplicated pregnancies. It is concluded that urinary excretion of 16 alpha-hydroxydehydroepiandrosterone sulphate greater than 50 mumol/day or a ratio of urinary 16 alpha-hydroxydehydroepiandrosterone sulphate to urinary oestrogen greater than 2.0 correctly identifies, before delivery, those pregnancies in which fetus and placenta are deficient in steroid sulphatase activity.