Drug-related Kidney Injury and Safe Pharmacotherapy in the Elderly

__Abstract__ The kidney performs two functions that are essential for life. First, it participates in the homeostasis of the extracellular environment that is required for adequate functioning of the cells. This is achieved by excretion of some of the waste products of metabolism and by specifically adjusting the urinary excretion of water and electrolytes to match net intake and endogenous production. Second, it secretes hormones that participate in the regulation of systemic and renal hemodynamics, red blood cell production, and bone metabolism. Many medicines have nephrotoxic potential, either by direct damage of tubular cells or by glomerular or interstitial damage following immune-complex formation. Well-known examples of nephrotoxicity include cytotoxic chemotherapeutic agents such as cisplatin and aminoglycoside antibiotics such as gentamycin. Despite the risk of nephrotoxicity, use of these drugs is justified in case no safer alternatives are available and if the underlying condition is more serious than the risk of renal damage. However, history provides several examples where these conditions were not met. Examples are the chronic nephropathy caused by non-steroidal anti-inflammatory drugs (NSAIDs) and related analgesics, most notably phenacetin, that was ultimately withdrawn in 1983, and the acute renal failure associated with lactic acidosis from phenformin that was ultimately withdrawn in 1976. A more recent example is the combined use of drugs affecting the renin-angiotensin system. In relation to this, the Pharmacovigilance Risk Assessment Committee (PRAC) issued a negative advice against combined use of these drugs in 2014

Improving sensitivity of machine learning methods for automated case identification from free-text electronic medical records

Background: Distinguishing cases from non-cases in free-text electronic medical records is an important initial step in observational epidemiological studies, but manual record validation is time-consuming and cumbersome. We compared different approaches to develop an automatic case identification system with high sensitivity to assist manual annotators. Methods. We used four different machine-learning algorithms to build case identification systems for two data sets, one comprising hepatobiliary disease patients, the other acute renal failure patients. To improve the sensitivity of the systems, we varied the imbalance ratio between positive cases and negative cases using under- and over-sampling techniques, and applied cost-sensitive learning with various misclassification costs. Results: For the hepatobiliary data set, we obtained a high sensitivity of 0.95 (on a par with manual annotators, as compared to 0.91 for a baseline classifier) with specificity 0.56. For the acute renal failure data set, sensitivity increased from 0.69 to 0.89, with specificity 0.59. Performance differences between the various machine-learning algorithms were not large. Classifiers performed best when trained on data sets with imbalance ratio below 10. Conclusions: We were able to achieve high sensitivity with moderate specificity for automatic case identification on two data sets of electronic medical records. Such a high-sensitive case identification system can be used as a pre-filter to significantly reduce the burden of manual record validation

Brand and generic use of inhalation medication and frequency of switching in children and adults: A population-based cohort study

Background: The expiration of patents of brand inhalation medications and the ongoing pressure on healthcare budgets resulted in a growing market for generics. Aim: To study the use of brand and generic inhalation medication and the frequency of switching between brand and generic and between devices. In addition, we investigated whether switching affected adherence. Methods: From dispensing data from the Dutch PHARMO Database Network a cohort aged ≥ 5 years, using ≥ 1 year of inhalation medication between 2003 and 2012 was selected. Switching was defined as changing from brand to generic or vice versa. In addition, we studied change in aerosol delivery device type (e.g., DPI, pMDI, and nebulizers). Adherence was calculated using the medication possession ratio (MPR). Results: The total cohort comprised 70,053 patients with 1,604,488 dispensations. Per calendar year, 5% switched between brand and generic inhalation medication and 5% switched between devices. Median MPRs over the first 12 months ranged between 33 and 55%. Median MPR over the total period was lower after switch from brand to generic and vice versa for formoterol (44.5 vs. 42.1 and 63.5 vs. 53.8) and beclomethasone (93.8 vs. 59.8 and 81.3 vs. 55.9). Conclusion: Per year, switching between brand and generic inhalation medication was limited to 5% of the patients, switching between device types was observed in 5% as well. Adherence to both generic and brand inhalation medication was low. Effect of switching on adherence was contradictory; depending on time period, medication and type, and direction of switching. Further research on reasons for switching and potential impact on clinical outcomes is warranted

Reply to R. Ferraldeschi et al

Development and application of statistical models for medical scientific researc

Overanticoagulation is associated with renal function decline

Background: Recent studies suggest that overanticoagulation impairs renal function in patients on warfarin therapy, due to renal tubular obstruction from glomerular hemorrhage. Methods: Data from the Rotterdam Study (The Netherlands), a prospective population-based cohort study of patients 55 years and older, were used for this study. Information on vitamin K antagonist (VKA) therapy was obtained from the regional anticoagulation clinic, where prothrombin times were monitored every 1-6 weeks depending on target level and stability of the international normalized ratio (INR). Linear regression was performed to study the association between the cumulative number of instances of overanticoagulation (defined as a measurement of an INR >6.0) and the change in renal function between baseline and third examination round based on estimated glomerular filtration rate (CKD-EPI equation). Age, sex, baseline renal function, baseline and incident heart failure, and indication for VKA therapy were included as potential confounders. Results: Information was available for analysis on 2,802 study participants in whom overanticoagulation was significantly associated with a decline in renal function, after adjustment for confounding by age, sex, heart failure, baseline glomerular filtration rate and indication for VKA therapy (-0.180 ml/min per 1.73 m2 per year per event for INR >6.0, p = 0.030). Conclusions: Overanticoagulation (INR >6.0) is associated with a decline in renal function. Further studies are needed to evaluate the causal role of different degrees of overanticoagulation, including transient effects, in high-risk groups, and the association with the new oral anticoagulants