Avoiding insufficient therapies and overdosing with co-reporting eGFRs (estimated glomerular filtration rate) for personalized drug therapy and improved outcomes - a simulation of the financial benefits.

Patients with impaired renal function are at high risk for morbidity and mortality. Chronic kidney disease (CKD) even in the early stages can be associated with significant side effects of drug therapy, longer length of stay, and high costs. Correct assessment of renal function in the hospital is important to detect CKD, to avoid further damage to the kidneys, and to optimize pharmacological therapy. Current protocols for renal function testing in drug dosing are only creatinine based, are not robust enough, and can wrongly classify certain patients. Goal of our simulation study is to optimize noninvasive renal function estimates and to allow for optimal dosing of pharmacological treatment without further renal damage. Co-reporting of creatinine- and of cystatin C-derived estimated glomerular filtration rates (eGFR) allows a personalized approach for patients with large discrepancies in eGFR and it enabled us in detecting patients at high risk for side effects due to incorrect drug dosing. This approach might be highly effective for patients as well as for clinicians. In addition, we simulated the efficiency by estimating savings for the hospital administration and the payor with a benefit cost ratio of 58 to 1.

Hippocampal volume differences between healthy young apolipoprotein E ε2 and ε4 carriers.

The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for the development of late-onset Alzheimer's disease (AD), whereas the presence of the APOE ε2 allele seems to confer protection. Here, we report that healthy young APOE ε4 carriers have statistically significantly smaller hippocampal volumes than APOE ε2 carriers, while no differences were detected between the two groups in memory performance. The difference in hippocampal morphology is cognitively/clinically silent in young adulthood, but could render APOE ε4 carriers more prone to the later development of AD possibly due to lower reserve cognitive capacity.

Influence of brain-derived neurotrophic-factor and apolipoprotein E genetic variants on hippocampal volume and memory performance in healthy young adults.

Unravelling the impact of genetic variants on clinical phenotypes is a challenging task. Apolipoprotein E (ApoE) and brain-derived neurotrophic factor (BDNF) play an important role in cell growth, regeneration, synaptic plasticity, learning and memory processes. The aim of the present study was to examine the impact of BDNF Val66Met- and ApoE-polymorphisms and their interactions on hippocampal morphology and memory functions in healthy young adults. Hippocampal volume and memory performance of 135 healthy individuals, aged 24.6 ± 3.2 years, were assessed, using magnetic resonance imaging and the Inventory for Memory diagnostics. The performance of BDNF-Met66 carriers was significantly lower in working memory (P = 0.03) compared with non carriers, whereas no further differences were observed either in cognitive performance or in hippocampal volumes between the groups. Age, BDNF Val66 Met polymorphism and the interaction factor BDNF genotype x age were significantly associated with the variation of working memory scores (P = 0.01, 0.01, 0.02 respectively). No statistically significant differences were detected in the volumes of hippocampi and in memory phenotypes between individuals carrying the ApoE E4 allele and those without it. The analysis did not reveal an impact of gene-gene interaction between BDNF and ApoE genes on hippocampal volumes or memory performance. BDNF Val66Met polymorphism seems to influence working memory function and modulate the effects of ageing on working memory in healthy young adults.

[Questionnaire surveying nephrologists on drug dose adjustment in patients with impaired kidney function]. / Umfrage zur Arzneimitteldosierung bei Niereninsuffizienz unter nephrologisch tätigen Arzten.

OBJECTIVE: Our intention was to assess knowledge and requirements related to drug dose adjustment in patients with impaired kidney function. METHOD: In 2005, we sent a questionnaire containing 22 questions to nephrologists in Germany and Austria. With 77 responses, the study was not representative. However, it was probably of importance for the target group of practising physicians and potential users of a future drug information system. RESULTS: Only 28% of the responding colleagues use the package inserts; these are obviously not considered to be an obligatory guideline for dose adjustment. The most common dosing problems (p < 0.05) were associated with anti-infective (48%) and anti-cancer drugs (25%). The greatest problems with dosing were encountered within intensive care units (29%). The risk of excessive dosing is estimated significantly more serious than the risk of underdosing (51% vs. 23%, p = 0.02). There was support for the statement that for cephalosporin antibiotics the trough levels are more important than peak levels (58% vs. 27%, p < 0.01). However, only 8% knew that in patients with impaired kidney function, trough concentrations of aminoglycosides and vancomycin need to be higher than in patients with normal kidney function for adequate peak levels to be obtained. Forty-five percent of respondents erroneously presumed that ceftriaxone must be adjusted to the kidney function. Half of the respondents were incorrect in assuming that ceftriaxone or moxifloxacin would be removed by dialysis. CONCLUSIONS: We see the need for more knowledge-based information on drug dosing in patients with kidney impairment and those in the intensive care unit. The risk to life posed by underdosage might be underestimated, especially for anti-infective drugs.

Review on pharmacokinetics and pharmacodynamics and the aging kidney.

In people who are aged >65 years, pharmacokinetics are influenced more by the loss of kidney function than by the aging process of any other organ. A GFR of 30 to 60 ml/min, suggestive of stage 3 kidney disease, is observed in 15 to 30% of elderly people. Drug dosing must be adjusted to both changing pharmacokinetics and pharmacodynamics; the pharmacodynamics might be influenced by the aging of other organs, too. Using our NEPharm database, we extracted abstracts with pharmacokinetic parameters since 1999 from a weekly PubMed search. The recorded data were analyzed and compared with published recommendations on drug dosage and use in the elderly. Purely age-related changes in pharmacokinetic parameters were recorded from publications on 127 drugs. The analysis of our NEPharm records revealed an average (mean +/- SD) age-related prolongation of half-life of 1.39-fold (corresponding to +39 +/- 61%). Contrasting to common opinion, mean changes in clearance (-1 +/- 54%) and volume of distribution (+24 +/- 56%) were even less. The modest changes in pharmacokinetics do not suggest general dosage modifications in the elderly for most drugs. Changes in pharmacodynamics justify the common medication rule in the elderly-"start low + go slow"-especially for drugs that act on the central nervous system; however, in the case of anti-infective and anticancer therapy, the rule should be "hit hard = start high + go fast" to produce the target effect also in the elderly.