Santiago Rodríguez-Segade

Carnitine Concentrations in Dialysed and Undialysed Patients with Chronic Renal Insufficiency

Free carnitine, acylcarnitine and total carnitine serum concentrations have been measured in chronic renal insufficiency patients under conservative treatment, in patients under regular haemodialysis treatment and in healthy controls. In the undialysed patients the levels of free carnitine, acylcarnitine and total carnitine were all clearly higher than those of the control group. The free carnitine and total carnitine levels of undialysed subjects were also higher than in regularly haemodialysed patients, showing that dialysis produces plasma carnitine losses that are not compensated for by endogenous synthesis of carnitine (this finding supports published reports of tissue carnitine deficiency in patients undergoing regular haemodialysis). The acylcarnitine levels of dialysed and undialysed patients were not significantly different, however; both were very much higher than that of control group. The hypercarnitinaemia of the patients under conservative treatment suggests that the impairment of renal function causes a reduction in the elimination of carnitine via the kidney.

Progression of Nephropathy in Type 2 Diabetes: The Glycation Gap Is a Significant Predictor After Adjustment for Glycohemoglobin (Hb A1c)

BACKGROUND The glycation gap has been proposed as an index of nonglycemic determinants of glycated hemoglobin (Hb A(1c)). We investigated whether it predicts progression of nephropathy in type 2 diabetic patients. METHODS We recorded albumin excretion rate, Hb A(1c), and serum fructosamine in 2314 patients over an average of 6.5 years. Hb A(1c) was regressed on fructosamine by using a repeated-measures longitudinal regression model and data for all visits of all patients; the raw glycation gap gg was calculated at each visit, as measured by Hb A(1c) minus the value predicted by the regression; and the mean glycation gap (GG) was defined for each patient as the mean of the values for the raw glycation gap (gg) calculated at each visit. The study group was divided into high-, medium- and low-GG groups of equal sizes, which were compared for progression of nephropathy by Cox regression analyses controlling for age, sex, duration of diabetes, initial nephropathy status, therapy, baseline Hb A(1c), mean Hb A(1c), and mean fructosamine. The design of the study was a retrospective cohort study with follow-up for 6.5 (SD 4.2) years. RESULTS The gg exhibited considerable stability over time. In the high- and medium-GG groups, the risk of progression of nephropathy was respectively 2.5 and 1.6 times that of the low-GG group (P < 0.0001 and P = 0.001, respectively) after adjustment as described above. CONCLUSIONS GG predicts the progression of nephropathy in type 2 diabetic patients independently of fructosamine and even after adjustment for Hb A(1c). The joint use of the glycation gap and fructosamine as measures of nonglycemic and glycemic determinants of glycation, respectively, may improve evaluation of the risk of nephropathy and of the glycemic control desirable for the individual patient.

Carnitine deficiency associated with anticonvulsant therapy

Valproic acid therapy is known to be associated with carnitine deficiency in adult as well as young epileptic patients. In a study of the possible existence of such side-effects with other anticonvulsants, 76.5% of adult patients treated with valproate were deficient in serum free carnitine, with acylcarnitine levels significantly higher than in controls (p less than 0.01), while the carnitine deficiency rate in a group of patients treated with anticonvulsants other than valproate was 21.5%. Since in clinical practice only about one fifth of patients are treated with valproate, this means that about 15% of epileptics are carnitine deficient because of valproate treatment and 17% because of other anticonvulsants. The mechanisms and clinical and biological consequences of the carnitine deficiency associated with antiepileptic drugs other than valproate are not known.

SERUM CARNITINE LEVELS IN EPILEPTIC CHILDREN BEFORE AND DURING TREATMENT WITH VALPROIC ACID, CARBAMAZEPINE, AND PHENOBARBITAL

Serum levels of free, acyl, and total carnitine were determined in 32 patients with seizures, before and after 3, 6, and 12 months of treatment with valproic acid (17 patients), carbamazepine (10 patients), or phenobarbital (5 patients). In all three treated groups, both free and total carnitine levels showed a significant decline with respect to pretreatment levels. This decline was most marked and most consistent in patients treated with valproic acid. In 35% of the patients in this group, carnitine deficiency (ie, total camitine < 30 μmol/L) was observed by month 12. In none of the three groups were serum carnitine levels significantly correlated with the serum concentration of the drug. These findings suggest a need to monitor serum carnitine levels in children treated with any of these drugs. (J Child Neurol 1998;13:546-549).

Carnitine deficiency in haemodialysed patients.

Free carnitine, acylcarnitine and total carnitine concentrations have been determined in the sera of chronic renal insufficiency patients undergoing regular haemodialysis treatment and in those of healthy controls. The most striking difference was found to be the high proportion of acylated carnitine (23.4 mumol/l) in the haemodialysed patients. Free carnitine and acylcarnitine levels were not completely restored between successive dialysis treatments, making levels measured immediately before the third weekly sessions significantly lower than those measured before the first session (p less than 0.01). In patients monitored throughout 25 wk of treatment, there was an exponential decay of both total serum carnitine levels (Spearmans r = -0.993, p less than 0.001) and free carnitine levels (Spearmans r = -0.972, p less than 0.001). It is suggested that in the absence of exogenous supplies of carnitine, endogenous synthesis is unable to make up for losses due to dialysis treatment, and that carnitine deficiency consequently ensues.

Evolution of Serum Lipids and Lipoprotein (a) Levels in Epileptic Children Treated With Carbamazepine, Valproic Acid, and Phenobarbital

The concentration levels of serum lipids and lipoprotein (a) were measured in 20 children receiving carbamazepine, 25 children receiving valproic acid, and 5 children receiving phenobarbital at the following times: (1) during chronic treatment while eating a normal diet, (2) during chronic treatment while eating a low-fat diet (children treated with carbamazepine and phenobarbital with high levels of total choleserol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), and (3) 3 months after the end of treatment with antiepileptic drugs. Patients during chronic treatment and eating a normal diet revealed significant changes in lipids, but when we reevaluated the groups of children treated with carbamazepine and phenobarbital when they were eating a low-fat diet and reevaluated the three groups of children 3 months after the end of treatment, a complete return to normal of all parameters was observed. These data demonstrate that the changes induced by these drugs are transient, reversible, and influenced by a low-fat diet. (J Child Neurol 2006;21:48—53).

Intrapersonal HbA1c variability and the risk of progression of nephropathy in patients with Type 2 diabetes

Diabet. Med. 29, 1562–1566 (2012)

Neuron-specific enolase, nucleotides, nucleosides, purine bases, oxypurines and uric acid concentrations in cerebrospinal fluid of children with meningitis

To determine the effects of meningitis on cerebral energy metabolism, cerebrospinal fluid concentrations of adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and urate were determined by high-performance liquid chromatography, and neuron-specific enolase by an enzyme immunoassay method, in 100 children with meningitis (45 bacterial, 46 viral and nine tuberculous), aged between 1 month and 13 years, and in 160 age-matched controls. Compared with controls, patients with bacterial meningitis showed high concentrations of hypoxanthine, xanthine and urate; patients with viral meningitis showed high concentrations of inosine, guanosine, xanthine, urate and neuron-specific enolase; and patients with tuberculous meningitis showed very high concentrations of inosine, xanthine and urate. Xanthine and urate concentrations were significantly higher in patients with tuberculous meningitis than in patients with viral or bacterial meningitis. These results suggest that in the acute stage of bacterial, viral and tuberculous meningitis, neuronal energy metabolism may be altered. The measurement of cerebrospinal xanthine and uric acid concentrations may be useful for the early diagnosis of a tuberculous origin.

Estimation of the Glycation Gap in Diabetic Patients With Stable Glycemic Control

OBJECTIVE The glycation gap (the difference between measured A1C and the value predicted by regression on fructosamine) is stable and is associated with microvascular complications of diabetes but has not hitherto been estimated within a clinically useful time frame. We investigated whether two determinations 30 days apart suffice for a reasonably reliable estimate if both A1C and fructosamine exhibit stability. RESEARCH DESIGN AND METHODS We studied 311 patients with type 1 or type 2 diabetes for whom simultaneous measurements of A1C and serum fructosamine had been made on at least two occasions separated by 1 month (t0 and t1). Glycemia was deemed stable if A1C(t1) – A1C(t0) and fructosamine(t1) − fructosamine(t0) were both less than their reference change values (RCVs). Instantaneous glycation gaps [gg(t0) and gg(t1)] and their mean (GG), were calculated using the data from all stable patients for the required regression. RESULTS Stable glycemia was shown by 144 patients. In 90% of unstable case subjects, a change in medication was identified as the cause of instability. Among 129 stable patients with an average of eight gg determinations prior to t0, GG correlated closely with the mean of these prior determinations (r2 = 0.902, slope 1.025, intercept −0.038). CONCLUSIONS The glycation gap can be calculated reliably from pairs of A1C and fructosamine measurements taken 1 month apart if these measurements satisfy the RCV criteria for glycemic control.

Purine and carnitine metabolism in muscle of patients with Duchenne muscular dystrophy

We determined levels of purines, purine metabolites, related enzymes and carnitine in muscle of 8 untreated Duchenne muscular dystrophy (DMD) patients, 12 allopurinol-treated DMD patients and 12 age-matched controls. Muscle of DMD patients was found to be deficient in ATP, ADP, adenylsuccinate, hypoxanthine, guanine and adenylsuccinate synthetase. In allopurinol-treated DMD patients, mean total adenylate level was only three times less than in controls (versus 14 times less in untreated DMD patients). Mean inosine monophosphate (IMP), adenine, adenosine, inosine, xanthine, guanine, guanosine and uric acid levels were higher in allopurinol-treated patients than in controls, while mean adenylsuccinate levels were higher than in untreated patients. Allopurinol also restored acylcarnitine levels to normal and significantly increased free carnitine levels. These findings strongly support the hypothesis that Duchenne muscular dystrophy involves alterations leading to blockage of the IMP-->purine pathway and that allopurinol treatment favours restoration of purine levels by this route. Furthermore, our results suggest that the observed deficiencies in cell components unrelated to purine metabolism are long-term secondary effects.