RESUMEN
PURPOSE: Autosomal dominant polycystic kidney disease (ADPKD) is a common adult-onset monogenic disorder, with prevalence of 1/1000. Population databases including ExAC have improved pathogenic variant prioritization in many diseases. Due to pseudogene homology of PKD1, the predominant ADPKD disease gene, and the variable disease severity and age of onset, we aimed to investigate the utility of ExAC for variant assessment in ADPKD. METHODS: We assessed coverage and variant quality in the ExAC cohort and combined allele frequency and age data from the ExAC database (n = 60,706) with curated variants from 2000 ADPKD pedigrees (ADPKD Mutation Database). RESULTS: Seventy-six percent of PKD1 and PKD2 were sequenced adequately for variant discovery and variant quality was high in ExAC. In ExAC, we identified 25 truncating and 393 previously reported disease-causing variants in PKD1 and PKD2, 6.9-fold higher than expected. Fifty-four different variants, previously classified as disease-causing, were observed in ≥5 participants in ExAC. CONCLUSION: Our study demonstrates that many previously implicated disease-causing variants are too common, challenging their pathogenicity, or penetrance. The presence of protein-truncating variants in older participants in ExAC demonstrates the complexity of variant classification and highlights need for further study of prevalence and penetrance of this common monogenic disease.
Asunto(s)
Riñón Poliquístico Autosómico Dominante/genética , Análisis de Secuencia de ADN/métodos , Canales Catiónicos TRPP/genética , Alelos , Estudios de Cohortes , Femenino , Frecuencia de los Genes/genética , Variación Genética/genética , Genética de Población/métodos , Humanos , Masculino , Mutación/genética , LinajeRESUMEN
AIMS: Metformin may have clinical benefits in dialysis patients; however, its safety in this population is unknown. This systematic review evaluated the safety of metformin in dialysis patients. METHODS: MEDLINE, Embase, CENTRAL, PsycINFO and the Cochrane Library were searched for randomised controlled trials and observational studies evaluating metformin use in dialysis patients. Three authors reviewed the studies and extracted data. The primary outcomes were mortality, occurrence of lactic acidosis and myocardial infarction (MI) in patients taking metformin during dialysis treatment for ≥12 months (long term). Risk of bias was assessed using Risk Of Bias In Nonrandomised Studies of Interventions (ROBINS-1). Overall quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Fifteen observational studies were eligible; 7 were prospective observational studies and 8 were case reports/case series. No randomised controlled trials were identified. The 7 prospective observational studies (n = 194) reported on cautious metformin use in patients undergoing maintenance dialysis. Only 3 provided long-term follow-up data. In 2 long-term studies of metformin therapy (≤1000 mg/d) in patients undergoing peritoneal dialysis (PD), 1 reported 6 deaths (6/83; 7%) due to major cardiovascular events (3 MI) and the other reported no deaths (0/35). One long-term study of metformin therapy (250 mg to 500 mg thrice weekly) in patients undergoing haemodialysis reported 4 deaths (4/61; 7%) due to major cardiovascular events (2 MI). These findings provide very low-quality evidence as they come from small observational studies. CONCLUSION: The evidence regarding the safety of metformin in people undergoing dialysis is inconclusive. Appropriately designed randomised controlled trials are needed to resolve this uncertainty.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Enfermedades Renales/sangre , Riñón/metabolismo , Metformina/efectos adversos , Diálisis Renal , Acidosis/sangre , Acidosis/inducido químicamente , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Monitoreo de Drogas , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Enfermedades Renales/complicaciones , Enfermedades Renales/terapia , Ácido Láctico/sangre , Metformina/administración & dosificación , Metformina/farmacocinética , Metformina/uso terapéuticoRESUMEN
AIMS: To compare the pharmacokinetics of metformin between diabetic Indigenous (Aboriginal and Torres Strait Islander) and non-Indigenous patients. METHODS: An observational, cross-sectional study was conducted on type 2 diabetic Indigenous and non-Indigenous patients treated with metformin. Blood samples were collected to determine metformin, lactate, creatinine and vitamin B12 concentrations and glycosylated haemoglobin levels. A population model was used to determine the pharmacokinetic parameters. RESULTS: The Indigenous patients (median age 55 years) were younger than the non-Indigenous patients (65 years), with a difference of 10 years (95% confidence interval 6-14 years, P < 0.001). The median glycosylated haemoglobin was higher in the Indigenous patients (8.5%) than in the non-Indigenous patients (7.2%), with a difference of 1.4% (0.8-2.2%, P < 0.001). Indigenous patients had a higher creatinine clearance (4.3 l h(-1) ) than the non-Indigenous patients (4.0 l h(-1) ), with a median difference of 0.3 l h(-1) (0.07-1.17 l h(-1) ; P < 0.05). The ratio of the apparent clearance of metformin to the creatinine clearance in Indigenous patients (13.1, 10.2-15.2; median, interquartile range) was comparable to that in non-Indigenous patients (12.6, 9.9-14.9). Median lactate concentrations were also similar [1.55 (1.20-1.88) vs. 1.60 (1.35-2.10) mmol l(-1) ] for Indigenous and non-Indigenous patients, respectively. The median vitamin B12 was 306 pmol l(-1) (range 105-920 pmol l(-1) ) for the Indigenous patients. CONCLUSIONS: There were no significant differences in the pharmacokinetics of metformin or plasma concentrations of lactate between Indigenous and non-Indigenous patients with type 2 diabetes mellitus. Further studies are required in Indigenous patients with creatinine clearance <30 ml min(-1) .
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/análisis , Hipoglucemiantes/farmacocinética , Ácido Láctico/sangre , Metformina/farmacocinética , Nativos de Hawái y Otras Islas del Pacífico , Anciano , Australia , Creatinina/sangre , Estudios Transversales , Diabetes Mellitus Tipo 2/sangre , Humanos , Hipoglucemiantes/sangre , Hipoglucemiantes/uso terapéutico , Tasa de Depuración Metabólica , Metformina/sangre , Metformina/uso terapéutico , Persona de Mediana Edad , Grupos de PoblaciónRESUMEN
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of kidney failure and is primarily associated with PKD1 or PKD2. Approximately 10% of patients remain undiagnosed after standard genetic testing. We aimed to utilise short and long-read genome sequencing and RNA studies to investigate undiagnosed families. Patients with typical ADPKD phenotype and undiagnosed after genetic diagnostics were recruited. Probands underwent short-read genome sequencing, PKD1 and PKD2 coding and non-coding analyses and then genome-wide analysis. Targeted RNA studies investigated variants suspected to impact splicing. Those undiagnosed then underwent Oxford Nanopore Technologies long-read genome sequencing. From over 172 probands, 9 met inclusion criteria and consented. A genetic diagnosis was made in 8 of 9 (89%) families undiagnosed on prior genetic testing. Six had variants impacting splicing, five in non-coding regions of PKD1. Short-read genome sequencing identified novel branchpoint, AG-exclusion zone and missense variants generating cryptic splice sites and a deletion causing critical intron shortening. Long-read sequencing confirmed the diagnosis in one family. Most undiagnosed families with typical ADPKD have splice-impacting variants in PKD1. We describe a pragmatic method for diagnostic laboratories to assess PKD1 and PKD2 non-coding regions and validate suspected splicing variants through targeted RNA studies.
RESUMEN
A 10-year-old boy from Papua New Guinea with multidrug-resistant tuberculosis and multibacillary leprosy developed acute glomerulonephritis while being treated as an inpatient at Thursday Island Hospital in the Torres Strait, Queensland. This is the first such case to be reported in Australia, where these diseases are uncommon and the combination is extremely rare, and it outlines important learning points regarding the aetiology of renal disease among patients with tuberculosis and leprosy.
Asunto(s)
Glomerulonefritis/complicaciones , Lepra Multibacilar/complicaciones , Tuberculosis Resistente a Múltiples Medicamentos/complicaciones , Enfermedad Aguda , Antituberculosos/uso terapéutico , Australia , Niño , Eritema Nudoso/tratamiento farmacológico , Eritema Nudoso/etiología , Humanos , Leprostáticos/uso terapéutico , Lepra Multibacilar/tratamiento farmacológico , Masculino , Papúa Nueva Guinea/etnología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.
Asunto(s)
Frecuencia de los Genes , Pruebas Genéticas/métodos , Enfermedades Renales Poliquísticas/genética , Secuenciación Completa del Genoma/métodos , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Pruebas Genéticas/normas , Glucosidasas/genética , Proteínas del Choque Térmico HSP40/genética , Factor Nuclear 1-alfa del Hepatocito/genética , Humanos , Lactante , Masculino , Persona de Mediana Edad , Enfermedades Renales Poliquísticas/diagnóstico , Receptores de Superficie Celular/genética , Sensibilidad y Especificidad , Canales Catiónicos TRPP/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Secuenciación Completa del Genoma/normasRESUMEN
BACKGROUND: The aim of this study was to identify the current evidence regarding the risk of acquiring viral infections from gases or plumes during intra-abdominal surgery. Peritoneal fluids may contain cellular material and virus particles. Electrocautery smoke and plumes from energy devices may aerosolize harmful substances and viral particles. Insufflation and desufflation during laparoscopic surgery may also aerosolize and distribute biological material. A systematic scoping review was performed to assess the evidence and inform safe surgical practice. METHODS: A systematic search of the PubMed and Medline databases was undertaken until June 2020, observing Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology, to identify articles associating viral infection of operating room staff from surgical gases and plumes. All evidence levels were included. The search strategy utilized the search terms 'surgery', 'laparoscopy', 'laparoscopic' 'virus', 'smoke', 'risk', 'infection'. RESULTS: The literature search identified 74 articles. Eight articles relevant to the subject of this review were included in the analysis, two of which specifically related to intra-abdominal surgery. Of the remaining six, four involved gynaecological surgery and two were in-vitro studies. No evidence that intra-abdominal surgery was associated with an increased risk of acquiring viral infections from exsufflated gas or smoke plumes was identified. CONCLUSION: There is currently no evidence that respiratory viruses can be found in the peritoneal fluid. Whilst there is currently no evidence that desufflated carbon dioxide or surgical smoke plumes present a significant infectious risk, there is not a wealth of literature to inform current practice. Further clinical research in this area is required.
Asunto(s)
Insuflación , Laparoscopía , Virosis , Femenino , Gases , Procedimientos Quirúrgicos Ginecológicos , Humanos , Insuflación/efectos adversos , Virosis/epidemiología , Virosis/etiologíaAsunto(s)
Alopurinol/análogos & derivados , Alopurinol/sangre , Alopurinol/envenenamiento , Supresores de la Gota/envenenamiento , Gota/tratamiento farmacológico , Fallo Renal Crónico/inducido químicamente , Oxipurinol/sangre , Ribonucleósidos/sangre , Adulto , Cromatografía Líquida de Alta Presión/métodos , Sobredosis de Droga , Femenino , Humanos , Fallo Renal Crónico/sangre , Factores de Riesgo , TransexualidadAsunto(s)
Diverticulitis del Colon , Diverticulitis , Enfermedades del Sigmoide , Colon Sigmoide/diagnóstico por imagen , Diverticulitis/complicaciones , Diverticulitis del Colon/complicaciones , Diverticulitis del Colon/diagnóstico por imagen , Humanos , Venas Mesentéricas/diagnóstico por imagen , Vena Porta/diagnóstico por imagen , Enfermedades del Sigmoide/complicaciones , Enfermedades del Sigmoide/diagnóstico por imagenRESUMEN
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disorder and is due to disease-causing variants in PKD1 or PKD2. Strong genotype-phenotype correlation exists although diagnostic sequencing is not part of routine clinical practice. This is because PKD1 bears 97.7% sequence similarity with six pseudogenes, requiring laborious and error-prone long-range PCR and Sanger sequencing to overcome. We hypothesised that whole-genome sequencing (WGS) would be able to overcome the problem of this sequence homology, because of 150 bp, paired-end reads and avoidance of capture bias that arises from targeted sequencing. We prospectively recruited a cohort of 28 unique pedigrees with ADPKD phenotype. Standard DNA extraction, library preparation and WGS were performed using Illumina HiSeq X and variants were classified following standard guidelines. Molecular diagnosis was made in 24 patients (86%), with 100% variant confirmation by current gold standard of long-range PCR and Sanger sequencing. We demonstrated unique alignment of sequencing reads over the pseudogene-homologous region. In addition to identifying function-affecting single-nucleotide variants and indels, we identified single- and multi-exon deletions affecting PKD1 and PKD2, which would have been challenging to identify using exome sequencing. We report the first use of WGS to diagnose ADPKD. This method overcomes pseudogene homology, provides uniform coverage, detects all variant types in a single test and is less labour-intensive than current techniques. This technique is translatable to a diagnostic setting, allows clinicians to make better-informed management decisions and has implications for other disease groups that are challenged by regions of confounding sequence homology.
Asunto(s)
Pruebas Genéticas/métodos , Genoma Humano , Riñón Poliquístico Autosómico Dominante/genética , Seudogenes , Homología de Secuencia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Eliminación de Gen , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Riñón Poliquístico Autosómico Dominante/diagnóstico , Análisis de Secuencia de ADN/métodos , Canales Catiónicos TRPP/genéticaRESUMEN
Leiomyomas are smooth muscle tumours that are rarely found in the kidney. There is one report of a leiomyoma in a kidney transplant in a paediatric recipient. Here, we report an adult renal transplant recipient who developed an Epstein-Barr virus-positive leiomyoma in his allograft 15 years after transplantation. The patient was converted to everolimus for posttransplant immunosuppression management and there was no sign of progression over a year.
RESUMEN
BACKGROUND: Lactic acidosis is an adverse event associated with metformin usage. Patients with metformin-associated lactic acidosis (MALA), however, often have other conditions contributing to the event. The relative contribution of metformin is often unclear. MALA is usually diagnosed without measuring the plasma concentrations of metformin. OBJECTIVES: The objectives of this study were, first, to examine the plasma concentrations of metformin, lactate and creatinine and the arterial pH of patients with suspected MALA and, second, to review critically the mechanisms of MALA. METHODS: Patients who were suspected of having MALA were identified during the period October 2008-September 2011. Repeated blood samples were collected to determine the plasma concentrations of lactate, metformin and creatinine. The pH of arterial blood was also measured on several occasions in each patient. RESULTS: Patients (n = 15; 9 female, 6 male) were 70 ± 12 years of age. There was one acute metformin overdose (estimated dose 5 g). Metformin was undetectable in one patient and one patient had therapeutic concentrations of metformin on admission (<5 mg/L). There were ten patients with chronic kidney disease, whereby the estimated glomerular filtration rate (eGFR) was less than 60 mL/min/1.73 m(2) before the acidotic event. Metformin doses ranged from 1 to 3 g daily (excluding the deliberate overdose). On admission, the mean plasma concentration of metformin on admission was 29.8 ± 19.1 mg/L (mean ± SD), the mean lactate concentration was 12.9 ± 6.1 mmol/L and the mean pH was 7 ± 0.2. The mean creatinine concentration on admission was 481 ± 225 µmol/L. The main pre-admission symptoms were vomiting and diarrhoea (n = 12). There were linear relationships between venous lactate, venous creatinine and arterial pH, with the venous plasma concentrations of metformin in most patients. Three patients died but metformin was unlikely to have been a significant factor. DISCUSSION AND REVIEW: Most patients with MALA presented to the hospital with high metformin concentrations. The following factors appear to have been involved in the development of MALA in these patients: vomiting and diarrhoea, acute kidney injury, high doses or excessive accumulation of metformin, and acute disease states leading to tissue hypoxia. The extent of metformin accumulation in patients with MALA can be determined by investigating the concentrations of metformin. We suggest that the development of MALA is due to a positive feedback system involving one or more of these factors. While nausea is a common adverse effect of metformin, vomiting and diarrhoea out of the ordinary is a clear first sign of MALA. In this condition, dosage with metformin should be stopped and patients should receive urgent medical attention.
Asunto(s)
Acidosis Láctica/sangre , Metformina/sangre , Acidosis Láctica/inducido químicamente , Acidosis Láctica/patología , Anciano , Creatinina/sangre , Femenino , Humanos , Concentración de Iones de Hidrógeno , Ácido Láctico/sangre , Masculino , Metformina/efectos adversosRESUMEN
BACKGROUND AND OBJECTIVE: Metformin is contraindicated in patients with renal impairment; however, there is poor adherence to current dosing guidelines. In addition, the pharmacokinetics of metformin in patients with significant renal impairment are not well described. The aims of this study were to investigate factors influencing the pharmacokinetic variability, including variant transporters, between healthy subjects and patients with type 2 diabetes mellitus (T2DM) and to simulate doses of metformin at varying stages of renal function. METHODS: Plasma concentrations of metformin were pooled from three studies: patients with T2DM (study A; n = 120), healthy Caucasian subjects (study B; n = 16) and healthy Malaysian subjects (study C; n = 169). A population pharmacokinetic model of metformin was developed using NONMEM(®) version VI for both the immediate-release (IR) formulation and the extended-release (XR) formulation of metformin. Total body weight (TBW), lean body weight (LBW), creatinine clearance (CLCR; estimated using TBW and LBW) and 57 single-nucleotide polymorphisms (SNPs) of metformin transporters (OCT1, OCT2, OCT3, MATE1 and PMAT) were investigated as potential covariates. A nonparametric bootstrap (n = 1,000) was used to evaluate the final model. This model was used to simulate 1,000 concentration-time profiles for doses of metformin at each stage of renal impairment to ensure metformin concentrations do not exceed 5 mg/l, the proposed upper limit. RESULTS: Creatinine clearance and TBW were clinically and statistically significant covariates with the apparent clearance and volume of distribution of metformin, respectively. None of the 57 SNPs in transporters of metformin were significant covariates. In contrast to previous studies, there was no effect on the pharmacokinetics of metformin in patients carrying the reduced function OCT1 allele (R61C, G401S, 420del or G465R). Dosing simulations revealed that the maximum daily doses in relation to creatinine clearance to prescribe to patients are 500 mg (15 ml/min), 1,000 mg (30 ml/min), 2,000 mg (60 ml/min) and 3,000 mg (120 ml/min), for both the IR and XR formulations. CONCLUSION: The population model enabled doses of metformin to be simulated for each stage of renal function, to ensure the concentrations of metformin do not exceed 5 mg/l. However, the plasma concentrations of metformin at these dosage levels are still quite variable and monitoring metformin concentrations may be of value in individualising dosage. This study provides confirmatory data that metformin can be used, with appropriate dosage adjustment, in patients with renal impairment.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metformina/farmacocinética , Modelos Biológicos , Insuficiencia Renal/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Preparaciones de Acción Retardada , Diabetes Mellitus Tipo 2/fisiopatología , Relación Dosis-Respuesta a Droga , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Malasia , Proteínas de Transporte de Membrana/genética , Metformina/administración & dosificación , Persona de Mediana Edad , Dinámicas no Lineales , Polimorfismo de Nucleótido Simple , Distribución Tisular , Población Blanca , Adulto JovenAsunto(s)
Fármacos Anti-VIH/efectos adversos , Enfermedades Renales/inducido químicamente , Oxazinas/efectos adversos , Podocitos/efectos de los fármacos , Alquinos , Benzoxazinas , Ciclopropanos , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Humanos , Glomérulos Renales/ultraestructura , Masculino , Persona de Mediana EdadRESUMEN
We report the case of a man with chronic tophaceous gout who had end-stage renal failure secondary to the Alport syndrome. Following a failed kidney transplant, where urate deposition was a suspected contributor, the patient responded positively to consistent allopurinol therapy and regular haemodialysis sessions. Extensive and destructive tophi receded in size remarkably and the almost constant incidence of acute attacks of gout subsided. The patient has recently received a new kidney transplant and his plasma concentrations of urate are controlled well with allopurinol and he no longer experiences acute attacks of gout. While efficacious, adherence is critical for achieving the therapeutic effects of allopurinol even in end-stage renal disease.
Asunto(s)
Alopurinol/uso terapéutico , Gota/tratamiento farmacológico , Fallo Renal Crónico/terapia , Diálisis Renal , Estudios de Seguimiento , Gota/complicaciones , Supresores de la Gota/uso terapéutico , Humanos , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana EdadRESUMEN
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 (t(½)) 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 (CL(R)) 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 CL(R) and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CL(CR)). As the CL(R) and CL/F decrease approximately in proportion to CL(CR), the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CL(CR). 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.