Elevated Plasma Creatinine Concentration Research Articles

Therapeutic drug monitoring of β-lactams in critically ill patients: proof of concept

The extreme pharmacokinetic behaviour of drugs sometimes observed in critically ill patients poses a significant threat to the achievement of optimal antibiotic treatment outcomes. Scant information on β-lactam antibiotic therapeutic drug monitoring (TDM) is available. The objective of this prospective study was to evaluate the practicality and utility of a β-lactam TDM programme in critically ill patients. TDM was performed twice weekly on all eligible patients at a 30-bed tertiary referral critical care unit. Blood concentrations were determined by fast-throughput high-performance liquid chromatography (HPLC) assays and were available within 12 h of sampling. Dose adjustment was instituted if the trough or steady-state blood concentration was below 4–5× the minimum inhibitory concentration (MIC) or above 10× MIC. A total of 236 patients were subject to TDM over an 11-month period. The mean ± standard deviation age was 53.5 ± 18.3 years. Dose adjustment was required in 175 (74.2%) of the patients, with 119 of these patients (50.4%) requiring dose increases after the first TDM. For outcome of therapy, 206 (87.3%) courses resulted in a positive treatment outcome and there were 30 (12.7%) treatment failures observed including 14 deaths and 15 courses requiring escalation to broader-spectrum agents; 1 course was ceased due to an adverse drug reaction. Using binomial logistic regression, only an elevated Acute Physiology and Chronic Health Evaluation (APACHE) II score ( P < 0.01) and elevated plasma creatinine concentration ( P = 0.05) were found to be predictive of mortality. In conclusion, further research is required to determine definitively whether achievement of optimal β-lactam pharmacodynamic targets improves clinical outcomes.

Potential roles of erythropoietin in the management of anaemia and other complications diabetes

Erythropoietin (EPO) is a haematopoietic cytokine, mainly generated in the renal cortex, and its secretion and action is impaired in chronic kidney disease (CKD). Early renal damage in diabetes mellitus (DM) is usually not detected because diabetes-induced nephron hypertrophy maintains glomerular filtration rate (GFR) and an elevated plasma creatinine concentration is a relatively late manifestation of diabetic nephropathy. However, anaemia occurs more frequently in subjects with DM when compared with those with non-DM renal disease. While reduced production and a blunted response to EPO occurs in DM with early renal damage, other factors including chronic inflammation, autonomic neuropathy and iron deficiency are also important. Although recombinant human erythropoietin (rhEPO) has been an effective therapeutic agent in CKD anaemia, it appears to be more effective in patients with DM, even in earlier stages. Nevertheless, patients with DM are also more likely to be iron deficient, a barrier to effective rhEPO therapy. The effect of treatment on the reliability of haemoglobin A(1c) as an index of glycaemic control must be remembered. It is proposed that anaemia and its causes must be important components of care in subjects with early diabetic renal damage.

Determinants of hyperhomocysteinemia in patients with chronic liver disease and after orthotopic liver transplantation

Homocysteine metabolism may be impaired in chronic liver disease, possibly contributing to fibrogenesis and disease complications. The goal was to investigate the prevalence and determinants of basal and postprandial hyperhomocysteinemia in patients with chronic liver disease and after orthotopic liver transplantation (OLT). This was a cross-sectional study of 323 patients with chronic liver disease (93 with hepatitis, 8 with fatty liver, 168 with cirrhosis, and 54 after OLT) and 25 healthy control subjects. Portohepatovenous gradients of total homocysteine (tHcy) and methionine and postload methionine and tHcy kinetics before and after 10 d of supplementation with folate plus vitamin B-6 were investigated in subgroups. Basal hyperhomocysteinemia was observed in all patient groups (34% of patients with hepatitis, 50% with fatty liver, 54% with cirrhosis, and 52% after OLT). It was more frequently seen in patients with elevated plasma creatinine concentrations and at advanced stages of liver disease. Mean plasma folate was normal in patients with liver disease, but vitamin B-12 was elevated in cirrhosis and vitamin B-6 was low after OLT. There were significant negative associations between tHcy and folic acid or vitamin B-12 concentrations in control subjects and in patients with hepatitis and after OLT. No systematic association between portohepatovenous differences in tHcy and methionine concentrations was found. Cirrhosis was accompanied by impaired methionine clearance. After vitamin supplementation, the area under the tHcy curve improved in cirrhosis at nearly unchanged basal tHcy concentrations. Basal hyperhomocysteinemia is seen in approximately 50% of patients with cirrhosis and after OLT. Basal tHcy concentrations do not change significantly after supplementation with folate and vitamin B-6, but postprandial Hcy metabolism improves.

Elevated plasma 4-pyridoxic acid in renal insufficiency

Renal insufficiency is associated with altered vitamin B-6 metabolism. We have observed high concentrations of 4-pyridoxic acid, the major catabolite of vitamin B-6 metabolism, in plasma during renal insufficiency. The objective was to evaluate the renal handling of 4-pyridoxic acid and the effects of renal dysfunction on vitamin B-6 metabolism. We measured the renal clearance of 4-pyridoxic acid and creatinine in 17 nonpregnant, 17 pregnant, and 16 lactating women. We then examined the influence of vitamin B-6 or alkaline phosphatase activity on the ratio of 4-pyridoxic acid to pyridoxal (PA:PL) in plasma in 10 men receiving a low (0.4 mg pyridoxine.HCl/d) or high (200 mg pyridoxine.HCl/d) vitamin B-6 intake for 6 wk, in 10 healthy subjects during a 21-d fast, in 1235 plasma samples from 799 people screened for hypophosphatasia, and in 67 subjects with a range of serum creatinine concentrations. Renal clearance of 4-pyridoxic acid was 232 +/- 94 mL/min in nonpregnant women, 337 +/- 140 mL/min in pregnant women, and 215 +/- 103 mL/min in lactating healthy women. These values were approximately twice the creatinine clearance, indicating that 4-pyridoxic acid is at least partially eliminated by tubular secretion. Elevated plasma creatinine concentrations were associated with marked elevations in 4-pyridoxic acid and PA:PL. PA:PL was not affected by wide variations in vitamin B-6 intake or by the wide range of pyridoxal-P concentrations encountered while screening for hypophosphatasia. Plasma 4-pyridoxic acid concentrations are markedly elevated in renal insufficiency. Plasma PA:PL can distinguish between increases in 4-pyridoxic acid concentrations due to increased dietary intake and those due to renal insufficiency.

Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room

To determine whether a course of low-dose indomethacin therapy, when initiated within 24 hours of birth, would decrease ductal shunting in premature infants who received prophylactic surfactant in the delivery room. Ninety infants, with birth weights of 600 to 1250 gm, were entered into a prospective, randomized, controlled trial to receive either indomethacin, 0.1 mg/kg per dose, or placebo less than 24 hours and again every 24 hours for six doses. Echocardiography was performed on day 1 before treatment and on day 7, 24 hours after treatment. A hemodynamically significant patent ductus arteriosus (PDA) was confirmed with an out-of-study echocardiogram, and the nonresponders were treated with standard indomethacin or ligation. Forty-three infants received indomethacin (birth weight, 915 +/- 209 gm; gestational age, 26.4 +/- 1.6 weeks; 25 boys), and 47 received placebo (birth weight, 879 +/- 202 gm; gestational age, 26.4 +/- 1.8 weeks; 22 boys) (P = not significant). Of 90 infants, 77 (86%) had a PDA by echocardiogram on the first day of life before study treatment; 84% of these PDAs were moderate or large in size in the indomethacin-treated group compared with 93% in the placebo group. Nine of forty indomethacin-treated infants (21%) were study-dose nonresponders compared with 22 (47%) of 47 placebo-treated infants (p < 0.018). There were no significant differences between both groups in any of the long-term outcome variables, including intraventricular hemorrhage, duration of oxygen therapy, endotracheal intubation, duration of stay in neonatal intensive care unit, time to regain birth weight or reach full caloric intake, incidence of bronchopulmonary dysplasia, and survival. No significant differences were noted in the incidence of oliguria, elevated plasma creatinine concentration, thrombocytopenia, pulmonary hemorrhage, or necrotizing enterocolitis. The prophylactic use of low doses of indomethacin, when initiated in the first 24 hours of life in low birth weight infants who receive prophylactic surfactant in the delivery room, decreases the incidence of left-to-right shunting at the level of the ductus arteriosus.

Hypertension in pregnancy: the incidence of underlying renal disease and essential hypertension.

The objective of this study was to ascertain the likelihood of underlying renal disease or essential hypertension in women diagnosed antepartum as having pre-eclampsia. One hundred eighty-six women (antepartum diagnosis of pre-eclampsia in 87 women and gestational hypertension, also known as "mild pre-eclampsia" by other definitions, in 99 women) in whom no underlying disorder was apparent during pregnancy or the early puerperium were entered into the study. Women were reviewed between 3 and 60 months postpartum. All patients were assessed by measurement of blood pressure, urinalysis, and phase-contrast urine microscopy, and those with pre-eclampsia also had plasma urea, electrolyte, and creatinine concentrations determined and underwent renal imaging with either intravenous pyelography or ultrasound. The kidneys were also imaged in the gestational hypertension group if there was any clinical suspicion of underlying renal disease on review. Essential hypertension was diagnosed if systolic blood pressure was higher than 140 mm Hg and/or diastolic blood pressure was higher than 90 mm Hg after 3 months postpartum and the results of other investigations were normal. Renal disease was diagnosed in the presence of abnormal findings on urinalysis, urine microscopy, or renal imaging, or by elevated plasma creatinine concentration. Seven (8%) of the 87 women with pre-eclampsia had underlying disease (essential hypertension, five patients; renal disease, two patients [one with reflux nephropathy and one with medullary sponge kidney]), as did 16 (16%) of the 99 women with gestational hypertension (essential hypertension, 14 patients (14%); renal disease, two patients (2%) [one with medullary sponge kidney and one with thin basement membrane disease]).(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of Drug Action in Disease States. 45. Effect of Elevated Plasma Creatinine Concentrations on the Hypnotic Action of Phenobarbital in Normal Rats

Kinetics of Drug Action in Disease States. 45. Effect of Elevated Plasma Creatinine Concentrations on the Hypnotic Action of Phenobarbital in Normal Rats

Plasma Lipid Profile in Rats with Gentamicin-Induced Nephrotoxicity

1. Administration of gentamicin to rats at doses of 20, 40 or 80 mg kg-1 d-1 for 6 days induced nephrotoxicity exhibited by elevated plasma creatinine concentration and a decrease in alkaline phosphatase activity in rat kidney cortex. 2. Gentamicin treatment produced significant elevation in plasma total cholesterol amounting to 70% at the 80 mg kg-1 dose. At this dose, the combined cholesterol fractions of low density and very low density lipoproteins increased by more than two-fold. 3. Gentamicin treatment also caused significant increase in plasma triglyceride concentration, while plasma phospholipid levels showed dose-dependent reductions. 4. In another experiment recovery of the aforementioned parameters was assessed 7 and 14 days after the withdrawal of gentamicin, administered at a dose of 40 mg kg-1 d-1 for 6 days. After 7 days from drug discontinuation, both plasma creatinine and total cholesterol concentrations returned to the control levels, while triglyceride concentration was still significantly higher than control 14 days after stoppage of treatment. 5. Plasma phospholipid concentration and the activity of cortical alkaline phosphatase were still significantly lower than control 14 days after cessation of the treatment.

Reflux Nephropathy and Primary Vesicoureteric Reflux in Adults

We have studied the clinical features and course of adults with reflex nephropathy and/or primary vesicoureteric reflux, paying particular attention to the differences between males and females, and the presenting features that influence prognosis. In our series of 293 patients, females outnumbered males in the ratio 5:1 and most presented with urinary infection, whereas males most commonly presented with features of renal damage such as proteinuria, hypertension or renal failure. Males more commonly had bilateral scarring and persistent reflux. One hundred and forty-seven patients were followed for two years or more (range 2-19 years); deterioration in renal function occurred in 55 (37 per cent). Risk factors for a rise in plasma creatinine were, in descending order, the presence of proteinuria, an elevated plasma creatinine concentration, bilateral scarring, male sex and the presence of hypertension. Stepwise multiple regression analysis showed that the independent risk factors were proteinuria, elevated plasma creatinine concentration and hypertension; gender and the presence of persistent reflux had no independent influence on the course of renal failure.

Glomerular alterations in uranyl acetate-induced acute renal failure in rabbits

The study was performed to elucidate the progression and regression of superficial and inner glomerular alterations in uranyl acetate-induced renal failure in rabbits. Fifteen hours after the drug injection, creatinine clearance (CCr) decreased to 55% of controls with slightly elevated plasma creatinine concentration (initiation stage). After 5 days, urine flow and CCr decreased to approximately zero, with severe azotemia (maintenance stage). Scanning electron microscopic observations in these stages revealed a flattening and spreading of podocyte cell bodies associated with loss of epithelial foot processes, and reduction in the density of endothelial fenestrae. These changes were more advanced in the maintenance stage. Glomerular and fenestral diameters did not significantly change in the initiation stage but increased in the maintenance stage. There was no significant difference in these morphologic alterations, however, between the superficial and inner glomeruli. Glomerular alterations reverted to normal within 14 days, with good recovery of glomerular function. The findings show no significant difference in the progression or regression of the glomerular changes between the superficial and deep cortex. These morphologic changes may play a role in the reduction of CCr observed in this model.