Neil Dalton - Academia.edu (original) (raw)

Papers by Neil Dalton

Research paper thumbnail of 199 the Effects of Disease Stage and Acute-On-Chronic Liver Failure on the Profile of Plasma Dimethylarginines in Cirrhosis

J Hepatol, 2010

POSTERS and safety of ACEi/ARB in compensated patients may be secondary to a targeted effect on t... more POSTERS and safety of ACEi/ARB in compensated patients may be secondary to a targeted effect on the locally activated hepatic RAAS system, as compared to decompensated patients who show activation of the systemic RAAS. Further studies with clinical end-points should determine the clinical potential of these drugs.

Research paper thumbnail of Effect of acute variations of insulin and glucose on plasma concentrations of asymmetric dimethylarginine in young people with Type I diabetes

Clinical Science, 2008

1 concentrations of asymmetric dimethylarginine in young people with 2 type 1 diabetes. 3 4 5 Abs... more 1 concentrations of asymmetric dimethylarginine in young people with 2 type 1 diabetes. 3 4 5 Abstract: 248 22 23 24 Tables: 4 25 Figures: 2 26 27 28 Keywords: asymmetric dimethylarginine, symmetric dimethylarginine, type 1 diabetes, 29 insulin, glycemia, cardiovascular disease 30 31 32 33 34 35

Research paper thumbnail of Creatine deficiency syndromes: diagnostic pearls and pitfalls

The Canadian Journal of Neurological Sciences Le Journal Canadien Des Sciences Neurologiques, Sep 1, 2011

Research paper thumbnail of Abstract 16297: The Relationship Between Albumin Excretion and Early Markers of Cardiovascular Disease Risk in Adolescents with Type-1 Diabetes: The AdDIT Study

Circulation, Nov 20, 2012

Research paper thumbnail of Hyperglycemia with and without glycosuria: Effect on inulin and para-amino hippurate clearance

Kidney International, Dec 1, 1987

The response of the clearance of inulin (Cin) and para-amino hippurate (CPAH) to acute hyperglyce... more The response of the clearance of inulin (Cin) and para-amino hippurate (CPAH) to acute hyperglycemia with and without glycosuria was investigated in ten, healthy non-diabetic subjects. Standard methodology (UV/P) was used, with a mean clearance calculated from three, 15-minute urine collection periods. Each subject was studied at three levels of blood glucose (mmol/liter) concentration, mean (SE): Level 1, fasting, 4.5 (0.1); Level 2, hyperglycemia below renal threshold for glucose, 7.2 (0.1); Level 3, hyperglycemia with glycosuria, 12.6 (0.5). There was a significant rise in mean Cin (ml/min/1.73 m2) when changing from Level 1 (112[3]) to Level 2 (121[5]), with no further increase on changing to Level 3 (122[4]). With glycosuria Cin fell in some subjects. Mean CPAH (ml/min/1.73 m2) increased through Level 1 (560[27]) to Level 3 (603[34]), with consequently no change in mean filtration fraction at the three levels of glycemia. Our observations show a rise in glomerular filtration rate with mild hyperglycemia below renal threshold, with no further increase during hyperglycemia sufficient to produce glycosuria.

Research paper thumbnail of A1C Variability as an Independent Risk Factor for Microalbuminuria in Young People With Type 1 Diabetes

Diabetes Care, Feb 1, 2011

OBJECTIVE-To assess the potential association between A1C variability (A1C-SD) and microalbuminur... more OBJECTIVE-To assess the potential association between A1C variability (A1C-SD) and microalbuminuria in young people with type 1 diabetes.

Research paper thumbnail of An infant with methylmalonic aciduria and homocystinuria (cbIC) presenting with retinal haemorrhages and subdural haematoma mimicking non-accidental injury

European Journal of Pediatrics, 2004

In this article, we report an infant with methylmalonic aciduria and homocystinuria in whom retin... more In this article, we report an infant with methylmalonic aciduria and homocystinuria in whom retinal haemorrhages together with subdural and intraventricular cerebral haemorrhage were the prominent initial presenting features.

Research paper thumbnail of Biomarkers of rapid chronic kidney disease progression in type 2 diabetes

Kidney international, Jan 22, 2015

Here we evaluated the performance of a large set of serum biomarkers for the prediction of rapid ... more Here we evaluated the performance of a large set of serum biomarkers for the prediction of rapid progression of chronic kidney disease (CKD) in patients with type 2 diabetes. We used a case-control design nested within a prospective cohort of patients with baseline eGFR 30-60 ml/min per 1.73 m(2). Within a 3.5-year period of Go-DARTS study patients, 154 had over a 40% eGFR decline and 153 controls maintained over 95% of baseline eGFR. A total of 207 serum biomarkers were measured and logistic regression was used with forward selection to choose a subset that were maximized on top of clinical variables including age, gender, hemoglobin A1c, eGFR, and albuminuria. Nested cross-validation determined the best number of biomarkers to retain and evaluate for predictive performance. Ultimately, 30 biomarkers showed significant associations with rapid progression and adjusted for clinical characteristics. A panel of 14 biomarkers increased the area under the ROC curve from 0.706 (clinical d...

Research paper thumbnail of Validation of a continuous infusion of low dose Iohexol to measure glomerular filtration rate: randomised clinical trial

Journal of Translational Medicine, 2015

Introduction: There is currently no accurate method of measuring glomerular filtration rate (GFR)... more Introduction: There is currently no accurate method of measuring glomerular filtration rate (GFR) during acute kidney injury (AKI). Knowledge of how much GFR varies in stable subjects is necessary before changes in GFR can be attributed to AKI. We have designed a method of continuous measurement of GFR intended as a research tool to time effects of AKI. The aims of this crossover trial were to establish accuracy and precision of a continuous infusion of low dose Iohexol (CILDI) and variation in GFR in stable volunteers over a range of estimated GFR (23-138 mL/min/1.73 m 2 ). Methods: We randomised 17 volunteers to GFR measurement by plasma clearance (PC) and renal clearance (RC) of either a single bolus of Iohexol (SBI; routine method), or of a continuous infusion of low dose Iohexol (CILDI; experimental method) at 0.5 mL/h for 12 h. GFR was measured by the alternative method after a washout period (4-28 days). Iohexol concentration was measured by high performance liquid chromatography/electrospray tandem mass spectrometry and time to steady state concentration (Css) determined. Results: Mean PC was 76.7 ± 28.5 mL/min/1.73 m 2 (SBI), and 78.9 ± 28.6 mL/min/1.73 m 2 (CILDI), p = 0.82. No crossover effects occurred (p = 0.85). Correlation (r) between the methods was 0.98 (p < 0.0001). Bias was 2.2 mL/min/1.73 m 2 (limits of agreement −8.2 to 12.6 mL/min/1.73 m 2 ) for CILDI. PC overestimated RC by 7.1 ± 7.3 mL/min/1.73 m 2 . Mean intra-individual variation in GFR (CILDI) was 10.3% (p < 0.003). Mean ± SD Css was 172 ± 185 min.

Research paper thumbnail of An independent effect of parental lipids on the offspring lipid levels in a cohort of adolescents with type 1 diabetes

Genetic factors modulate lipid levels and an intrafamilial aggregation of abnormal lipid profiles... more Genetic factors modulate lipid levels and an intrafamilial aggregation of abnormal lipid profiles has been reported in the general population. As dyslipidemia is common among people with diabetes and has been related to diabetic nephropathy, we investigated whether parental lipid levels were related to lipids and albumin excretion in young offspring with childhood-onset type 1 diabetes (T1D). Non-fasting blood samples were collected from 895 offspring, 808 mothers and 582 fathers. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and non-HDL-C were measured. Three early morning urinary albumin-creatinine ratios (ACR), hemoglobin A1C (HbA1c) and anthropometric parameters were also assessed. The offspring&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s mean age (±SD) was 14.5 ± 2.2 yr, mean diabetes duration 5.5 ± 3.7 yr; the fathers&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; age was 45.7 ± 6.1 yr and the mothers&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; age was 42.8 ± 5.5 yr. After adjusting for the offspring age, gender, body mass index, HbA1c, maternal (TC: β = 0.242; TG: β = 0.152; HDL-C: β = 0.285; LDL-C: β = 0.278; non-HDL-C: β = 0.253; all p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and paternal lipid levels (TC: β = 0.188; TG: β = 0.108; HDL-C: β = 0.253; LDL-C: β = 0.187; non-HDL-C: β = 0.173; all p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) were significantly associated with the offspring&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lipid parameters. In contrast, no significant association was found between parental lipid levels and the offspring&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s ACR. In the present study, parental lipid levels were independently associated with the same traits in the offspring, suggesting a role of genetic influences and/or shared environmental factors in modulating the metabolic profile of adolescents with T1D. In contrast, there was no significant association between parental lipid levels and the offspring&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s albumin excretion.

Research paper thumbnail of Glomerular and tubular function in glycogen storage disease

Pediatric Nephrology, 1995

Urinary protein and calcium excretion were assessed in 77 patients with the hepatic glycogen stor... more Urinary protein and calcium excretion were assessed in 77 patients with the hepatic glycogen storage diseases (GSD): 30 with GSD-I (median age 12.4 years, range 3.2-32.9 years), 25 with GSD-III (median age 10.5 years, range 4.2-31.3 years) and 22 with GSD-IX (median age 11.8 years, range 1.2-35.4 years). Inulin (Cinulin) and para-aminohippuric acid (CPAH) clearances were also measured in 33 of these patients. Those with GSD-I had significantly greater albumin (F=15.07, P< 0.001), retinolbinding protein (RBP) (F=14.66, P < 0.001), N-acetyl-[3-o glucosaminidase (NAG) (F=9.41, P<0.001) and calcium (F=7.41, P=0.001) excretion than those with GSD-III and GSD-IX. GSD-I patients (n=18) also had significantly higher Cinulin (F=5.57, P=0.009), but Ceart did not differ (F=0.77, NS). Renal function was normal in GSD-III and GSD-IX patients. In GSD-I, Cinulin @=-0.51, P=0.03) and NAG excretion (r=--0.40, P=0.03) were inversely correlated with age, whereas albumin excretion was positively correlated with age (r=-+0.41, P=0.03). RBP and calcium excretion were generally high throughout all age groups. Hyperfiltration in GSD-I is associated with renal tubular proteinuria that occurs before the onset of significant albuminuria. Deficiency of glucose-6-phosphatase within the proximal renal tubule may primarily cause tubular dysfunction, glomerular hyperfiltration being a secondary phenomenon.

Research paper thumbnail of The contribution of glycemic control to impaired growth during puberty in young people with type 1 diabetes and microalbuminuria

Pediatric Diabetes, 2013

The contribution of glycemic control to impaired growth during puberty in young people with type ... more The contribution of glycemic control to impaired growth during puberty in young people with type 1 diabetes and microalbuminuria Marcovecchio ML, Heywood JJN, Dalton RN, Dunger DB. The contribution of glycemic control to impaired growth during puberty in young people with type 1 diabetes and microalbuminuria. Pediatric Diabetes 2014: 15: 303-308.

Research paper thumbnail of Inflammation is an important determinant of levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in acute liver failure

Liver Transplantation, 2007

Acute liver failure (ALF) is characterized by rapid progressive organ failure and poor outcome. T... more Acute liver failure (ALF) is characterized by rapid progressive organ failure and poor outcome. The pathophysiology of multiorgan dysfunction in ALF remains unclear but increased systemic inflammatory response is believed to be an important determining factor. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, results from proteolysis and the liver is a major site for its metabolism. ADMA has been shown to independently predict outcome in multiorgan failure associated with severe liver dysfunction. In this study, we tested the hypothesis that proinflammatory cytokine driven responses are important in modulating ADMA levels in patients with acetaminophen-induced ALF. Blood samples were collected from 10 ALF patients (grade IV encephalopathy) from admission until the time of transplantation or death, and assayed for cytokines and ADMA. A total of 8 patients required treatment for raised intracranial pressure and all patients were managed with standard of care, including full mechanical ventilation and veno-venous hemofiltration. ADMA levels were markedly higher in ALF patients compared to age-matched controls (P Ͻ 0.001) and correlated with the levels of proinflammatory cytokines. In pretransplantation patients undergoing hepatic venous catheterization, we demonstrated no significant uptake of ADMA across the failing liver. However, following liver transplantation, ADMA levels reduced acutely. A timed study of ADMA levels during transplantation demonstrated a slight increase during the anhepatic phase but a marked and sustained reduction in ADMA following liver reperfusion. In conclusion, our data show a significant correlation between ADMA levels and proinflammatory cytokines, supporting a hypothesis that proinflammatory cytokines may regulate ADMA metabolism in ALF. Liver Transpl 13: 400-405, 2007.

Research paper thumbnail of The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic subjects: The Oxford Regional Prospective Study

Kidney International, 2005

The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic... more The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic subjects: The Oxford Regional Prospective Study.

Research paper thumbnail of Oral essential aminoacid and ketoacid supplements in children with chronic renal failure

Kidney International, 1983

Oral essential aminoacid and ketoacid supplements in children with chronic renal failure. The eff... more Oral essential aminoacid and ketoacid supplements in children with chronic renal failure. The effects on growth, body composition, and metabolism of a protein-restriced diet supplemented with essential aminoacids, the calcium-ketoacids of valine, leucine, isoleucine, and phenylalanine, and the calcium-hydroxyacid of methionine, were inves-

Research paper thumbnail of Hyperglycemia with and without glycosuria: Effect on inulin and para-amino hippurate clearance

Kidney International, 1987

The response of the clearance of inulin (Cin) and para-amino hippurate (CPAH) to acute hyperglyce... more The response of the clearance of inulin (Cin) and para-amino hippurate (CPAH) to acute hyperglycemia with and without glycosuria was investigated in ten, healthy non-diabetic subjects. Standard methodology (UV/P) was used, with a mean clearance calculated from three, 15-minute urine collection periods. Each subject was studied at three levels of blood glucose (mmol/liter) concentration, mean (SE): Level 1, fasting, 4.5 (0.1); Level 2, hyperglycemia below renal threshold for glucose, 7.2 (0.1); Level 3, hyperglycemia with glycosuria, 12.6 (0.5). There was a significant rise in mean Cin (ml/min/1.73 m2) when changing from Level 1 (112[3]) to Level 2 (121[5]), with no further increase on changing to Level 3 (122[4]). With glycosuria Cin fell in some subjects. Mean CPAH (ml/min/1.73 m2) increased through Level 1 (560[27]) to Level 3 (603[34]), with consequently no change in mean filtration fraction at the three levels of glycemia. Our observations show a rise in glomerular filtration rate with mild hyperglycemia below renal threshold, with no further increase during hyperglycemia sufficient to produce glycosuria.

Research paper thumbnail of Measurement of plasma very long-chain fatty acids as a preliminary screening procedure for the diagnosis of peroxisomal disorders

Journal of Inherited Metabolic Disease, 1994

Research paper thumbnail of 199 the Effects of Disease Stage and Acute-On-Chronic Liver Failure on the Profile of Plasma Dimethylarginines in Cirrhosis

Journal of Hepatology, 2010

POSTERS and safety of ACEi/ARB in compensated patients may be secondary to a targeted effect on t... more POSTERS and safety of ACEi/ARB in compensated patients may be secondary to a targeted effect on the locally activated hepatic RAAS system, as compared to decompensated patients who show activation of the systemic RAAS. Further studies with clinical end-points should determine the clinical potential of these drugs.

Research paper thumbnail of Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis

Hepatology, 2007

Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes t... more Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylargininedimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P ‫؍‬ 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylaminohydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function. Conclusion: Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis. (HEPATOLOGY 2007;45:62-71.) Abbreviations: AH, alcoholic hepatitis; HVPG, hepatic venous pressure gradient; ADMA, asymmetric dimethylarginine; SDMA, symmetric dimethylarginine; DDAH, dimethylarginine dimethylaminohydrolase; PRMT, protein arginine methyltransferase; eNOS, endothelial nitric oxide synthase; NO, nitric oxide. From the

Research paper thumbnail of An infant with methylmalonic aciduria and homocystinuria (cblC) presenting with retinal haemorrhages and subdural haematoma mimicking non-accidental injury

European Journal of Pediatrics, 2004

In this article, we report an infant with methylmalonic aciduria and homocystinuria in whom retin... more In this article, we report an infant with methylmalonic aciduria and homocystinuria in whom retinal haemorrhages together with subdural and intraventricular cerebral haemorrhage were the prominent initial presenting features.

Research paper thumbnail of 199 the Effects of Disease Stage and Acute-On-Chronic Liver Failure on the Profile of Plasma Dimethylarginines in Cirrhosis

J Hepatol, 2010

POSTERS and safety of ACEi/ARB in compensated patients may be secondary to a targeted effect on t... more POSTERS and safety of ACEi/ARB in compensated patients may be secondary to a targeted effect on the locally activated hepatic RAAS system, as compared to decompensated patients who show activation of the systemic RAAS. Further studies with clinical end-points should determine the clinical potential of these drugs.

Research paper thumbnail of Effect of acute variations of insulin and glucose on plasma concentrations of asymmetric dimethylarginine in young people with Type I diabetes

Clinical Science, 2008

1 concentrations of asymmetric dimethylarginine in young people with 2 type 1 diabetes. 3 4 5 Abs... more 1 concentrations of asymmetric dimethylarginine in young people with 2 type 1 diabetes. 3 4 5 Abstract: 248 22 23 24 Tables: 4 25 Figures: 2 26 27 28 Keywords: asymmetric dimethylarginine, symmetric dimethylarginine, type 1 diabetes, 29 insulin, glycemia, cardiovascular disease 30 31 32 33 34 35

Research paper thumbnail of Creatine deficiency syndromes: diagnostic pearls and pitfalls

The Canadian Journal of Neurological Sciences Le Journal Canadien Des Sciences Neurologiques, Sep 1, 2011

Research paper thumbnail of Abstract 16297: The Relationship Between Albumin Excretion and Early Markers of Cardiovascular Disease Risk in Adolescents with Type-1 Diabetes: The AdDIT Study

Circulation, Nov 20, 2012

Research paper thumbnail of Hyperglycemia with and without glycosuria: Effect on inulin and para-amino hippurate clearance

Kidney International, Dec 1, 1987

The response of the clearance of inulin (Cin) and para-amino hippurate (CPAH) to acute hyperglyce... more The response of the clearance of inulin (Cin) and para-amino hippurate (CPAH) to acute hyperglycemia with and without glycosuria was investigated in ten, healthy non-diabetic subjects. Standard methodology (UV/P) was used, with a mean clearance calculated from three, 15-minute urine collection periods. Each subject was studied at three levels of blood glucose (mmol/liter) concentration, mean (SE): Level 1, fasting, 4.5 (0.1); Level 2, hyperglycemia below renal threshold for glucose, 7.2 (0.1); Level 3, hyperglycemia with glycosuria, 12.6 (0.5). There was a significant rise in mean Cin (ml/min/1.73 m2) when changing from Level 1 (112[3]) to Level 2 (121[5]), with no further increase on changing to Level 3 (122[4]). With glycosuria Cin fell in some subjects. Mean CPAH (ml/min/1.73 m2) increased through Level 1 (560[27]) to Level 3 (603[34]), with consequently no change in mean filtration fraction at the three levels of glycemia. Our observations show a rise in glomerular filtration rate with mild hyperglycemia below renal threshold, with no further increase during hyperglycemia sufficient to produce glycosuria.

Research paper thumbnail of A1C Variability as an Independent Risk Factor for Microalbuminuria in Young People With Type 1 Diabetes

Diabetes Care, Feb 1, 2011

OBJECTIVE-To assess the potential association between A1C variability (A1C-SD) and microalbuminur... more OBJECTIVE-To assess the potential association between A1C variability (A1C-SD) and microalbuminuria in young people with type 1 diabetes.

Research paper thumbnail of An infant with methylmalonic aciduria and homocystinuria (cbIC) presenting with retinal haemorrhages and subdural haematoma mimicking non-accidental injury

European Journal of Pediatrics, 2004

In this article, we report an infant with methylmalonic aciduria and homocystinuria in whom retin... more In this article, we report an infant with methylmalonic aciduria and homocystinuria in whom retinal haemorrhages together with subdural and intraventricular cerebral haemorrhage were the prominent initial presenting features.

Research paper thumbnail of Biomarkers of rapid chronic kidney disease progression in type 2 diabetes

Kidney international, Jan 22, 2015

Here we evaluated the performance of a large set of serum biomarkers for the prediction of rapid ... more Here we evaluated the performance of a large set of serum biomarkers for the prediction of rapid progression of chronic kidney disease (CKD) in patients with type 2 diabetes. We used a case-control design nested within a prospective cohort of patients with baseline eGFR 30-60 ml/min per 1.73 m(2). Within a 3.5-year period of Go-DARTS study patients, 154 had over a 40% eGFR decline and 153 controls maintained over 95% of baseline eGFR. A total of 207 serum biomarkers were measured and logistic regression was used with forward selection to choose a subset that were maximized on top of clinical variables including age, gender, hemoglobin A1c, eGFR, and albuminuria. Nested cross-validation determined the best number of biomarkers to retain and evaluate for predictive performance. Ultimately, 30 biomarkers showed significant associations with rapid progression and adjusted for clinical characteristics. A panel of 14 biomarkers increased the area under the ROC curve from 0.706 (clinical d...

Research paper thumbnail of Validation of a continuous infusion of low dose Iohexol to measure glomerular filtration rate: randomised clinical trial

Journal of Translational Medicine, 2015

Introduction: There is currently no accurate method of measuring glomerular filtration rate (GFR)... more Introduction: There is currently no accurate method of measuring glomerular filtration rate (GFR) during acute kidney injury (AKI). Knowledge of how much GFR varies in stable subjects is necessary before changes in GFR can be attributed to AKI. We have designed a method of continuous measurement of GFR intended as a research tool to time effects of AKI. The aims of this crossover trial were to establish accuracy and precision of a continuous infusion of low dose Iohexol (CILDI) and variation in GFR in stable volunteers over a range of estimated GFR (23-138 mL/min/1.73 m 2 ). Methods: We randomised 17 volunteers to GFR measurement by plasma clearance (PC) and renal clearance (RC) of either a single bolus of Iohexol (SBI; routine method), or of a continuous infusion of low dose Iohexol (CILDI; experimental method) at 0.5 mL/h for 12 h. GFR was measured by the alternative method after a washout period (4-28 days). Iohexol concentration was measured by high performance liquid chromatography/electrospray tandem mass spectrometry and time to steady state concentration (Css) determined. Results: Mean PC was 76.7 ± 28.5 mL/min/1.73 m 2 (SBI), and 78.9 ± 28.6 mL/min/1.73 m 2 (CILDI), p = 0.82. No crossover effects occurred (p = 0.85). Correlation (r) between the methods was 0.98 (p < 0.0001). Bias was 2.2 mL/min/1.73 m 2 (limits of agreement −8.2 to 12.6 mL/min/1.73 m 2 ) for CILDI. PC overestimated RC by 7.1 ± 7.3 mL/min/1.73 m 2 . Mean intra-individual variation in GFR (CILDI) was 10.3% (p < 0.003). Mean ± SD Css was 172 ± 185 min.

Research paper thumbnail of An independent effect of parental lipids on the offspring lipid levels in a cohort of adolescents with type 1 diabetes

Genetic factors modulate lipid levels and an intrafamilial aggregation of abnormal lipid profiles... more Genetic factors modulate lipid levels and an intrafamilial aggregation of abnormal lipid profiles has been reported in the general population. As dyslipidemia is common among people with diabetes and has been related to diabetic nephropathy, we investigated whether parental lipid levels were related to lipids and albumin excretion in young offspring with childhood-onset type 1 diabetes (T1D). Non-fasting blood samples were collected from 895 offspring, 808 mothers and 582 fathers. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and non-HDL-C were measured. Three early morning urinary albumin-creatinine ratios (ACR), hemoglobin A1C (HbA1c) and anthropometric parameters were also assessed. The offspring&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s mean age (±SD) was 14.5 ± 2.2 yr, mean diabetes duration 5.5 ± 3.7 yr; the fathers&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; age was 45.7 ± 6.1 yr and the mothers&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; age was 42.8 ± 5.5 yr. After adjusting for the offspring age, gender, body mass index, HbA1c, maternal (TC: β = 0.242; TG: β = 0.152; HDL-C: β = 0.285; LDL-C: β = 0.278; non-HDL-C: β = 0.253; all p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and paternal lipid levels (TC: β = 0.188; TG: β = 0.108; HDL-C: β = 0.253; LDL-C: β = 0.187; non-HDL-C: β = 0.173; all p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) were significantly associated with the offspring&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lipid parameters. In contrast, no significant association was found between parental lipid levels and the offspring&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s ACR. In the present study, parental lipid levels were independently associated with the same traits in the offspring, suggesting a role of genetic influences and/or shared environmental factors in modulating the metabolic profile of adolescents with T1D. In contrast, there was no significant association between parental lipid levels and the offspring&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s albumin excretion.

Research paper thumbnail of Glomerular and tubular function in glycogen storage disease

Pediatric Nephrology, 1995

Urinary protein and calcium excretion were assessed in 77 patients with the hepatic glycogen stor... more Urinary protein and calcium excretion were assessed in 77 patients with the hepatic glycogen storage diseases (GSD): 30 with GSD-I (median age 12.4 years, range 3.2-32.9 years), 25 with GSD-III (median age 10.5 years, range 4.2-31.3 years) and 22 with GSD-IX (median age 11.8 years, range 1.2-35.4 years). Inulin (Cinulin) and para-aminohippuric acid (CPAH) clearances were also measured in 33 of these patients. Those with GSD-I had significantly greater albumin (F=15.07, P< 0.001), retinolbinding protein (RBP) (F=14.66, P < 0.001), N-acetyl-[3-o glucosaminidase (NAG) (F=9.41, P<0.001) and calcium (F=7.41, P=0.001) excretion than those with GSD-III and GSD-IX. GSD-I patients (n=18) also had significantly higher Cinulin (F=5.57, P=0.009), but Ceart did not differ (F=0.77, NS). Renal function was normal in GSD-III and GSD-IX patients. In GSD-I, Cinulin @=-0.51, P=0.03) and NAG excretion (r=--0.40, P=0.03) were inversely correlated with age, whereas albumin excretion was positively correlated with age (r=-+0.41, P=0.03). RBP and calcium excretion were generally high throughout all age groups. Hyperfiltration in GSD-I is associated with renal tubular proteinuria that occurs before the onset of significant albuminuria. Deficiency of glucose-6-phosphatase within the proximal renal tubule may primarily cause tubular dysfunction, glomerular hyperfiltration being a secondary phenomenon.

Research paper thumbnail of The contribution of glycemic control to impaired growth during puberty in young people with type 1 diabetes and microalbuminuria

Pediatric Diabetes, 2013

The contribution of glycemic control to impaired growth during puberty in young people with type ... more The contribution of glycemic control to impaired growth during puberty in young people with type 1 diabetes and microalbuminuria Marcovecchio ML, Heywood JJN, Dalton RN, Dunger DB. The contribution of glycemic control to impaired growth during puberty in young people with type 1 diabetes and microalbuminuria. Pediatric Diabetes 2014: 15: 303-308.

Research paper thumbnail of Inflammation is an important determinant of levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in acute liver failure

Liver Transplantation, 2007

Acute liver failure (ALF) is characterized by rapid progressive organ failure and poor outcome. T... more Acute liver failure (ALF) is characterized by rapid progressive organ failure and poor outcome. The pathophysiology of multiorgan dysfunction in ALF remains unclear but increased systemic inflammatory response is believed to be an important determining factor. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, results from proteolysis and the liver is a major site for its metabolism. ADMA has been shown to independently predict outcome in multiorgan failure associated with severe liver dysfunction. In this study, we tested the hypothesis that proinflammatory cytokine driven responses are important in modulating ADMA levels in patients with acetaminophen-induced ALF. Blood samples were collected from 10 ALF patients (grade IV encephalopathy) from admission until the time of transplantation or death, and assayed for cytokines and ADMA. A total of 8 patients required treatment for raised intracranial pressure and all patients were managed with standard of care, including full mechanical ventilation and veno-venous hemofiltration. ADMA levels were markedly higher in ALF patients compared to age-matched controls (P Ͻ 0.001) and correlated with the levels of proinflammatory cytokines. In pretransplantation patients undergoing hepatic venous catheterization, we demonstrated no significant uptake of ADMA across the failing liver. However, following liver transplantation, ADMA levels reduced acutely. A timed study of ADMA levels during transplantation demonstrated a slight increase during the anhepatic phase but a marked and sustained reduction in ADMA following liver reperfusion. In conclusion, our data show a significant correlation between ADMA levels and proinflammatory cytokines, supporting a hypothesis that proinflammatory cytokines may regulate ADMA metabolism in ALF. Liver Transpl 13: 400-405, 2007.

Research paper thumbnail of The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic subjects: The Oxford Regional Prospective Study

Kidney International, 2005

The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic... more The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic subjects: The Oxford Regional Prospective Study.

Research paper thumbnail of Oral essential aminoacid and ketoacid supplements in children with chronic renal failure

Kidney International, 1983

Oral essential aminoacid and ketoacid supplements in children with chronic renal failure. The eff... more Oral essential aminoacid and ketoacid supplements in children with chronic renal failure. The effects on growth, body composition, and metabolism of a protein-restriced diet supplemented with essential aminoacids, the calcium-ketoacids of valine, leucine, isoleucine, and phenylalanine, and the calcium-hydroxyacid of methionine, were inves-

Research paper thumbnail of Hyperglycemia with and without glycosuria: Effect on inulin and para-amino hippurate clearance

Kidney International, 1987

The response of the clearance of inulin (Cin) and para-amino hippurate (CPAH) to acute hyperglyce... more The response of the clearance of inulin (Cin) and para-amino hippurate (CPAH) to acute hyperglycemia with and without glycosuria was investigated in ten, healthy non-diabetic subjects. Standard methodology (UV/P) was used, with a mean clearance calculated from three, 15-minute urine collection periods. Each subject was studied at three levels of blood glucose (mmol/liter) concentration, mean (SE): Level 1, fasting, 4.5 (0.1); Level 2, hyperglycemia below renal threshold for glucose, 7.2 (0.1); Level 3, hyperglycemia with glycosuria, 12.6 (0.5). There was a significant rise in mean Cin (ml/min/1.73 m2) when changing from Level 1 (112[3]) to Level 2 (121[5]), with no further increase on changing to Level 3 (122[4]). With glycosuria Cin fell in some subjects. Mean CPAH (ml/min/1.73 m2) increased through Level 1 (560[27]) to Level 3 (603[34]), with consequently no change in mean filtration fraction at the three levels of glycemia. Our observations show a rise in glomerular filtration rate with mild hyperglycemia below renal threshold, with no further increase during hyperglycemia sufficient to produce glycosuria.

Research paper thumbnail of Measurement of plasma very long-chain fatty acids as a preliminary screening procedure for the diagnosis of peroxisomal disorders

Journal of Inherited Metabolic Disease, 1994

Research paper thumbnail of 199 the Effects of Disease Stage and Acute-On-Chronic Liver Failure on the Profile of Plasma Dimethylarginines in Cirrhosis

Journal of Hepatology, 2010

POSTERS and safety of ACEi/ARB in compensated patients may be secondary to a targeted effect on t... more POSTERS and safety of ACEi/ARB in compensated patients may be secondary to a targeted effect on the locally activated hepatic RAAS system, as compared to decompensated patients who show activation of the systemic RAAS. Further studies with clinical end-points should determine the clinical potential of these drugs.

Research paper thumbnail of Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis

Hepatology, 2007

Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes t... more Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylargininedimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P ‫؍‬ 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylaminohydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function. Conclusion: Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis. (HEPATOLOGY 2007;45:62-71.) Abbreviations: AH, alcoholic hepatitis; HVPG, hepatic venous pressure gradient; ADMA, asymmetric dimethylarginine; SDMA, symmetric dimethylarginine; DDAH, dimethylarginine dimethylaminohydrolase; PRMT, protein arginine methyltransferase; eNOS, endothelial nitric oxide synthase; NO, nitric oxide. From the

Research paper thumbnail of An infant with methylmalonic aciduria and homocystinuria (cblC) presenting with retinal haemorrhages and subdural haematoma mimicking non-accidental injury

European Journal of Pediatrics, 2004

In this article, we report an infant with methylmalonic aciduria and homocystinuria in whom retin... more In this article, we report an infant with methylmalonic aciduria and homocystinuria in whom retinal haemorrhages together with subdural and intraventricular cerebral haemorrhage were the prominent initial presenting features.