The effects of abrupt antipsychotic discontinuation in cognitively impaired older persons: a pilot study.

BACKGROUND: Antipsychotic use for behavioural and psychological symptoms of dementia (BPSD) is controversial. Guidelines advise to reduce antipsychotics given the adverse effects and limited efficacy, to limit dose and treatment duration as well as to undertake discontinuation. METHODS: A pilot study with 40 hospitalised geriatric cognitively impaired patients, in which the effects of abrupt antipsychotic discontinuation were investigated, using neuropsychiatric inventory (NPI) scores before and one month after discontinuation. Withdrawal symptoms were monitored thrice a day with a checklist during five consecutive days. RESULTS: Participants (n = 40) had a mean age of 84 years (range 67-95) and 53% were male. The total mean baseline NPI score was 21 (SD 12) with predominantly behavioural rather than psychological disturbances. After abrupt discontinuation, mild withdrawal symptoms were observed in 72% of the patients, with frequencies of symptoms peaking on day 2 (53%) and day 3 (48%). After one month, 31 patients (85%) were still off antipsychotics and improved on the majority of NPI domains, with a total mean NPI score decreasing from 18 (SD 13) to 12 (SD 8, p = 0.003). In the relapse group, there was no deterioration associated with the abrupt discontinuation and subsequent resumption of therapy with a total mean NPI score decreasing from 31 (SD 12) at baseline to 27 (SD 8) at one-month follow-up (p = 0.345). CONCLUSION: Abrupt antipsychotic discontinuation appears to be feasible in older individuals with BPSD. Systematically performed discontinuation efforts in clinical practice are needed to differentiate between patients where antipsychotics have no added value and patients where the benefits outweigh the risks.

Hospital consumption of antibiotics in 15 European countries: results of the ESAC Retrospective Data Collection (1997-2002).

OBJECTIVES: To collect reliable, comparable and publicly available data on hospital use of antibiotics in Europe aggregated at the national level (1997-2002). METHODS: Consumption data of systemic antibiotics in Anatomical Therapeutic Chemical (ATC) class J01 were collected and expressed in defined daily doses (DDD) per 1000 inhabitants per day. Valid data for 2002 were available for 15 countries, and 6 year trends for 10 countries. Comparison with ambulatory care (AC) consumption data was possible in 14 countries. RESULTS: In 2002, median national hospital antibiotic consumption in Europe was 2.1 DDD/1000 inhabitants/day in Europe, ranging from 3.9 in Finland and France to 1.3 in Norway and Sweden. Hospital care (HC) consumption as a proportion of total antibiotic consumption ranged from 17.8% to 6.4%. The consumption of hospital-specific antibiotics ranged from 0.43 DDD/1000 inhabitants/day in Greece and 0.08 in Sweden. Six-year trends in consumption were stable, except for rising co-amoxiclav exposure and more rapid market penetration of new antibiotics (e.g. levofloxacin) in some countries. There was a strong, positive correlation between the extent of antibiotic use in AC and in HC (Spearman coefficient 0.745; P = 0.002), both for overall use and for use of five main classes (not macrolides and 'others'). In contrast to AC consumption no substantial seasonal variation in consumption was observed. CONCLUSIONS: It was cumbersome but feasible to collect ecological data on hospital antibiotic consumption in a set of 15 European countries on a retrospective basis, illustrating substantial cross-national variations in the extent and distribution of exposure to antibiotics in hospital care.

European surveillance of antimicrobial consumption (ESAC): data collection performance and methodological approach.

BACKGROUND: Europe is a continent with strong public healthcare systems, but diverging antibiotic policies and resistance patterns. AIMS: To describe the performance and methodological approach in a retrospective data collection effort (1997-2001), through an international network of surveillance systems, aiming to collect publicly available, comparable and reliable data on antibiotic use in Europe. METHODS: A central multidisciplinary management team co-ordinated a network of national representatives, liasing with national data providers and bodies responsible for antibiotic policy. The data collected were screened for bias, using a checklist. We focused on detection bias in sample and census data; errors in assigning medicinal product packages to the Anatomical Therapeutic Chemical Classification (ATC); errors in calculations of defined daily doses (DDD) per package; bias by over-the-counter sales and parallel trade; and bias in ambulatory care (AC)/hospital care (HC) mix. Datasets were corrected after national feedback, and classified as valid; valid but with minor bias; not valid. RESULTS: Of the 31 participating countries, 21 countries delivered AC data suitable for cross-national comparison (14 for all 5 years). Of these, 17 countries provided data on a quarterly basis for at least 1 year. For HC, 14 countries were able to deliver valid data (nine for all 5 years). A valid estimate of the total exposure of national populations to human antibiotic consumption could be made in 17 countries. CONCLUSION: In cross-national comparisons of antibiotic consumption in Europe, methodological rigour in correcting for various sources of bias and checking the validity of ATC/DDD assignment is needed.

Re-evaluation and modification of the Stuivenberg Hospital Acute Renal Failure (SHARF) scoring system for the prognosis of acute renal failure: an independent multicentre, prospective study.

BACKGROUND: A prognostic scoring system for hospital mortality in acute renal failure (Stuivenberg Hospital Acute Renal Failure, SHARF score) was developed in a single-centre study. The scoring system consists of two scores, for the time of diagnosis of acute renal failure (ARF) and for 48 h later, each originally based on four parameters (age, serum albumin, prothrombin time and heart failure). The scoring system was now tested and adapted in a prospective study. METHODS: The study involved eight intensive care units. We studied 293 consecutive patients with ARF in 6 months. Their mortality was 50.5%. The causes of ARF were medical in 184 (63%) patients and surgical in 108 (37%). In the latter group, 74 (69%) patients underwent cardiac and 19 (18%) vascular surgery. RESULTS: As the performance of the original SHARF scores was much lower in the multicentre study than in the original single-centre study, we re-analysed the multicentre data to customize the original model for the population studied. The independent variables were the score developed in the original study plus all additonal parameters that were significant on univariate analysis. The new multivariate analysis revealed an additional subset of three parameters for inclusion in the model (serum bilirubin, sepsis and hypotension). For the modified SHARF II score, r(2) was 0.27 at 0 and 0.33 at 48 h, respectively, the receiver operating characteristic (ROC) values were 0.82 and 0.83, and the Hosmer-Lemeshow goodness-of-fit P values were 0.19 and 0.05. CONCLUSION: After customizing and by using two scoring moments, this prediction model for hospital mortality in ARF is useful in different settings for comparing groups of patients and centres, quality assessment and clinical trials. We do not recommend its use for individual patient prognosis.

Renal impairment in patients with inflammatory bowel disease: association with aminosalicylate therapy?

BACKGROUND: In recent years, several case reports have been published suggesting an association between the use of 5-aminosalicylic acid (5-ASA) in patients with inflammatory bowel disease (IBD) and the development of chronic tubulo-interstitial nephritis. Apart from lesions associated to 5-ASA treatment, however, it is clear that IBD itself may also induce renal impairment, albeit the frequency is unknown. METHODS: During 1 year, all IBD patients seen at the outpatient clinic of 27 European centres of gastro-enterology were registered and screened for renal impairment controlling for a possible association with 5-ASA therapy. Patients were questioned about their medical and drug history and their IBD disease activity. Renal screening (calculated creatinine clearance) was performed at baseline, after 6 and 12 months. RESULTS: Included patients (n = 1,529) had a mean age of 39 (range 14-98), 56% had Crohn's disease, 42% ulcerative colitis and 2% indeterminate colitis. Half of the patients used 5-ASA during the study period. Decreased creatinine clearance was observed in 34 patients, among them 13 with chronic renal impairment. Comparing patients with and without renal impairment, no difference could be observed in 5-ASA consumption. In contrast, patients with renal impairment were significantly older, had a lower body mass index and showed a higher frequency of male sex, bowel resection and stoma. CONCLUSION: Although the association between 5-ASA therapy and chronic tubulo-interstitial nephritis is clearly described in several case reports, this prospective study came to the reassuring conclusion that renal impairment in IBD patients is not frequently observed and is rarely associated with 5-ASA therapy.

What can nephrologists learn from epidemiology?

During the last decade, epidemiology has played an increasing role in the study of renal diseases. In the fields of drug-nephrotoxicity and occupational renal failure, epidemiological research has made an important contribution. In recent years, the specific role of epidemiology in outcome research has gained recognition. Epidemiology is based on observations under real-life conditions using a representative sample of renal patients. Methods range from simple clinical observations and cross-sectional studies to case-control and prospective cohort studies. Contributions and limitations of the different epidemiological approaches are illustrated using the example of the nephrotoxicity of 5-aminosalicylic acid in patients with inflammatory bowel disease.

Treating and monitoring water for dialysis in Europe.

The quality of water used for dialysis is not subject to any mandatory regulations in most European countries. A survey of haemodialysis facilities in 14 countries carried out by the European Dialysis and Transplant Nurses Association/European Renal Care Association (EDTNA/ERCA) showed that the majority of centres aimed to meet the requirements of the European Pharmacopoeia, but only 50% carried out tests to check compliance. The wide variation in policies for maintaining and monitoring the equipment and the distribution system indicates that guidelines for water treatment are urgently needed in Europe.

Morphometric analysis of renal vessels. Advantage of the multisector area approach to cross-sections.

OBJECTIVE: To determine the most accurate morphometric approach to overcoming the obstacles of limited number, angle of section and irregular contours of vascular structures in analyzing vascular sections of renal biopsies. STUDY DESIGN: The luminal area of 451 cortical arterioles in 65 Masson-trichrome-stained renal sections was assessed with a computer-assisted imaging system connected to a Leica DMR microscope (Mikroskopie und Systeme GmbH, Wetzlar, Germany). The luminal area measured by the imaging system was used as the gold standard, against which three mathematical sector approaches and one classical approach were evaluated. The accuracy of these approaches was evaluated by means of the relative deviation from the measured value and of the degree of overestimation or underestimation. Intraobserver and interobserver variability were determined for the most accurate mathematical approach. RESULTS: As compared to measured luminal area, the sector elliptical approach yielded the lowest relative deviation (13.4 +/- 12.5%), without significant overestimation or underestimation (-0.6 +/- 18.3%). The intraobserver and interobserver correlation coefficients for this method were 82.3% and 86.5%, respectively. CONCLUSION: The sector elliptical approach is the most accurate mathematical approach to vascular sections in renal biopsies.

Increased bone strontium levels in hemodialysis patients with osteomalacia.

BACKGROUND: In this study, we report on the association between increased bone strontium levels and the presence of osteomalacia in end-stage renal failure patients treated by hemodialysis. METHODS: We performed a histologic examination and determined the strontium content and strontium/calcium ratios in bone biopsies of 100 hemodialysis patients recruited from various centers all over the world. Aside from the bone strontium concentration, the bone aluminum content was assessed. The bone zinc concentration, a nonrelevant element for bone toxicity, was also measured. RESULTS: Bone strontium levels and bone strontium/calcium ratios were increased in subjects with osteomalacia when compared with those with the other types of renal osteodystrophy. Bone strontium and bone calcium levels correlated with each other. The slope of the linear regression curve correlating these parameters was much steeper in the osteomalacic group (Y = 2.22X - 120) as compared with the other types of renal osteodystrophy (Y = 0.52X - 5.7). Within the group of patients with osteomalacia, bone strontium levels also significantly correlated with the bone aluminum content (r = 0.72, P = 0.018). No such correlation was found for the other types of renal osteodystrophy. The bone zinc concentration of subjects with normal renal function did not differ significantly from the values noted for the various types of renal osteodystrophy taken as separate groups, nor could increased bone zinc concentrations be associated with a particular bone lesion. CONCLUSIONS: Our data demonstrate an association between osteomalacia and increased bone strontium concentrations in dialysis patients. Further studies are warranted to establish whether strontium plays either a primary, secondary, or contributive role in the development of the latter type of renal osteodystrophy.

Increased serum strontium levels in dialysis patients: an epidemiological survey.

BACKGROUND: We previously reported on increased bone strontium levels in dialysis patients with osteomalacia versus those presenting other types of renal osteodystrophy. A causal role of strontium in the development of osteomalacia was established in a chronic renal failure rat model. METHODS: To further elucidate the latter issue and to find out whether dialysis patients from particular centers/countries are at an increased risk for strontium accumulation, a worldwide multicenter study was established. In total, 834 patients from 34 dialysis centers in 23 countries were included. In each of the patients, a serum sample was taken for strontium determination, and water and dialysate samples were taken at the various steps of the water purification process. For each patient clinical data and for each center dialysis modalities were recorded. RESULTS: Strontium levels in serum of dialysis patients showed major differences between the various centers, ranging from mean values of 25 +/- 8 microgram/liter in the center with the lowest level up to 466 +/- 90 microgram/liter in the center with the highest concentration. It is of interest that these high levels were mainly found in developing countries. Furthermore, our data point toward a role of the final dialysate in the accumulation of the element, as indicated by the strong correlation (r = 0.74, P < 0.001) between mean serum and dialysate strontium levels. As the high tap water concentration of strontium was adequately reduced during the water purification process, contamination of the final dialysis fluid occurred by the addition of concentrates contaminated with strontium. Besides the dialysate, other factors, such as duration of dialysis, vitamin D supplements, or types of phosphate binders, played a less important role in the accumulation of the element. CONCLUSIONS: Data of this multicenter study indicate patients of particular dialysis centers to be at an increased risk for strontium accumulation, the clinical consequence of which is under current investigation.

Aluminum, iron, lead, cadmium, copper, zinc, chromium, magnesium, strontium, and calcium content in bone of end-stage renal failure patients.

BACKGROUND: Little is known about trace metal alterations in the bones of dialysis patients or whether particular types of renal osteodystrophy are associated with either increased or decreased skeletal concentrations of trace elements. Because these patients are at risk for alterations of trace elements as well as for morbidity from skeletal disorders, we measured trace elements in bone of patients with end-stage renal disease. METHODS: We analyzed bone biopsies of 100 end-stage renal failure patients enrolled in a hemodialysis program. The trace metal contents of bone biopsies with histological features of either osteomalacia, adynamic bone disease, mixed lesion, normal histology, or hyperparathyroidism were compared with each other and with the trace metal contents of bone of subjects with normal renal function. Trace metals were measured by atomic absorption spectrometry. RESULTS: The concentrations of aluminum, chromium, and cadmium were increased in bone of end-stage renal failure patients. Comparing the trace metal/calcium ratio, significantly higher values were found for the bone chromium/calcium, aluminum/calcium, zinc/calcium, magnesium/calcium, and strontium/calcium ratios. Among types of renal osteodystrophy, increased bone aluminum, lead, and strontium concentrations and strontium/calcium and aluminum/calcium ratios were found in dialysis patients with osteomalacia vs the other types of renal osteodystrophy considered as one group. Moreover, the concentrations of several trace elements in bone were significantly correlated with each other. Bone aluminum was correlated with the time on dialysis, whereas bone iron, aluminum, magnesium, and strontium tended to be associated with patient age. Bone trace metal concentrations did not depend on vitamin D intake nor on the patients' gender. CONCLUSIONS: The concentration of several trace elements in bone of end-stage renal failure patients is disturbed, and some of the trace metals under study might share pathways of absorption, distribution, and accumulation. The clinical significance of the increased/decreased concentrations of several trace elements other than aluminum in bone of dialysis patients deserves further investigation.

Analgesic nephropathy: is it caused by multi-analgesic abuse or single substance use?

Analgesic nephropathy is a slowly progressive renal disease, characterised by renal papillary necrosis. Recently, diagnostic criteria for this disease have been defined based on renal computed tomography scanning performed without contrast. The observation of a decreased renal mass of both kidneys, combined with either bumpy contours or papillary calcifications, has been found to have high diagnostic specificity and sensitivity. However, the question remains as to what kind of analgesics can cause analgesic nephropathy. In the majority of early reports about this condition, phenacetin was singled out as the nephrotoxic culprit. However, during the last decade the nephrotoxic potential of nonphenacetin-containing preparations has become apparent. It is clear that people who abuse analgesics prefer combination analgesics containing 2 analgesics combined with caffeine and/or codeine. In contrast, abuse of products containing only aspirin (acetylsalicylic acid) or paracetamol (acetaminophen) is seldom described and associated renal disease is only occasionally reported. Experimental evidence of the nephrotoxicity of analgesic preparations is not well established. The results of studies involving analgesic administration in animals remain contradictory. Clinical evidence linking high consumption of analgesic preparations with analgesic nephropathy is overwhelming. Most patients who admit to over-consuming analgesics have taken preparation containing more than one compound. In recent years, it has become more apparent that preparations not containing phenacetin also have the potential to cause nephrotoxicity manifesting as identical renal lesions. Further epidemiological evidence of the nephrotoxic potential of analgesic combinations has come from case-control studies published during the last decade and from 2 prospective cohort studies. Effective prevention of analgesic nephropathy consists of the prohibition of over-the-counter sales of preparation containing at least 2 analgesics associated with caffeine and/or codeine.

A meta-analysis and morphological review of cyclosporine-induced nephrotoxicity in auto-immune diseases.

BACKGROUND: The risk-benefit ratio of cyclosporine A (CsA) is much more critical in some auto-immune diseases in comparison to transplantation medicine, due to its renal toxic potential. The present meta-analysis is based on an a priori defined methodology, and is linked with a review of CsA-induced morphological lesions, in order to draw relevant conclusions with regard to CsA-induced nephrotoxicity in auto-immune diseases. METHODS: Only controlled, randomized trials with a treatment period of two months or more, published from January 1979 to August 1996, were selected for the evaluation of functional renal impairment due to CsA treatment. To assess the risk of developing nephrotoxicity during CsA therapy, individual peak rises in serum creatinine level were compared between the CsA-treated group and the control group. Nephrotoxicity was defined as an increase in serum creatinine level of 50% or more above baseline at least once during the study period. Papers reporting CsA-induced renal morphological lesions were reviewed. RESULTS: A risk difference of 20.9% for developing nephrotoxicity, between a therapy with CsA and an alternative therapy, was found. Already after a treatment period of 12 months with low dose CsA (< or = 5 mg/kg/day), de novo nonspecific morphological damage could be induced in patients with auto-immune diseases. CONCLUSIONS: From this analysis of the literature, it is obvious that a therapy with CsA in patients affected by auto-immune diseases is not without risk. A rigorous evaluation of the risk-benefit ratio is strongly recommended for each patient, with strict monitoring of serum creatinine and CsA trough levels during treatment. Renal biopsies during treatment must be seriously taken into consideration in patients who develop even a slight renal functional impairment, particularly when prolonged therapy of longer than one year, even with low dose CsA (< or = 5 mg/kg/day), is given.

Analgesic abuse in the elderly. Renal sequelae and management.

Nephropathy caused by the use of 'classical' analgesics [paracetamol (acetaminophen), salicylates and pyrazolone derivatives] and renal impairment associated with nonsteroidal anti-inflammatory drugs (NSAIDs) are important health problems in the elderly. Classical analgesic nephropathy is a chronic renal disease characterised by renal papillary necrosis and chronic interstitial nephritis. The nephropathy is caused by the excessive consumption of analgesic mixtures containing at least 2 antipyretic analgesics combined with caffeine and/or codeine. The use of NSAIDs is associated with a wide range of tubular, interstitial, glomerular and vascular renal lesions. Despite the well-characterised acute biological effects of NSAIDs on the kidney, there is only limited evidence that they are associated with an increased risk of chronic renal failure. Classical analgesic toxicity can be effectively prevented by limiting the availability of over-the-counter analgesic mixtures containing 2 analgesic compounds in combination with potentially addictive substances (e.g. caffeine and/or codeine). In the elderly in particular, the prolonged, regular use of NSAIDs should be discouraged. Patients starting NSAID therapy should be monitored regularly and drug interactions should be avoided.

The assessment of biomarkers to detect nephrotoxicity using an integrated database.

Groups of industrial workers exposed to heavy metals (cadmium, mercury, and lead) or solvents were studied together with corresponding control groups. The cohorts were collected from several European centers (countries). Eighty-one measurements were carried out on urine, blood, and serum samples and the results of these analyses together with questionnaire information on each individual were entered into a central database using the relational database package Rbase. After the completion of the database construction phase, the data were exported in a format suitable for analysis by the statistical package SAS. The potential value of each test as an indicator of nephrotoxicity was then assessed. Rigorous exclusion criteria were applied which resulted in the elimination of some tests and samples from the dataset. The measurable contributions of smoking, gender, metal exposure, and site were either singly or in combination assessed by biomarkers for nephrotoxicity. The parameters measured included three urinary enzymes, six specific proteins, total protein, two extracellular matrix markers, four prostaglandins and anti-GBM antibodies, and beta 2-microglobulin in serum. The most sensitive renal tests included the urinary enzymes N-acetyl-beta-D-glucosaminidase (NAG) and intestinal alkaline phosphatase (IAP), brush border antigens, and urinary low-molecular-weight proteins. Of the newer tests investigated the prostaglandins were the most promising. Different patterns of biomarker excretion were observed following exposure to lead, cadmium, or mercury. The dataset provides a unique repository of data which could provide the basis of an enlarging source of information on normal human reference ranges and on the effects of exposure to toxins and the use of biomarkers for monitoring nephrotoxicity.