Analgesics Use And ESRD In Younger Age: A Case-control Study

Fokke J van der Woude; Lothar AJ Heinemann; Helmut Graf; Michael Lewis; Sabine Moehner; Anita Assmann; Doerthe Kühl-Habich


BMC Nephrology 

In This Article


The study was designed as a population-based case-control study to investigate the risk of phenacetin-free analgesics with regard to the occurrence of ESRD in Germany and Austria between January, 2001 and December, 2004. The study protocol was reviewed and agreed to by the Scientific Advisory Committee, was accepted by the regulatory authorities of Germany, Austria, and Switzerland, and was reviewed and approved by the Kidney Foundation of Germany. It was supported by the three Nephrological Societies in Germany and the Nephrological Association of Austria, published in BMC Nephrology,[11] shown on an open-access website,[12] registered as clinical study in the FDA website (Protocol Registration Receipt NCT00302835),[13] and approved as a study protocol by the Lancet.

Cases were recruited from 170 dialysis centers and were defined as patients with end-stage renal disease (ESRD) newly admitted to a chronic dialysis program (incident dialysis) and aged up to 50 years. Rapid case ascertainment systems were used to identify all eligible cases. Cases were excluded if they had acute or recurrent renal failure, were out of age range, died before the interview could be done, were in poor physical or mental condition, or refused informed consent to participate in the study. Four neighborhood controls were randomly selected from the same geographic regions as the cases and were matched by age (5-year age group) and sex. Cases and controls documented their willingness to participate in the study by signing an informed consent form.

All study participants completed a standardized in-person interview, during which a trained interviewer collected information on lifetime use of analgesics documented by brand name as well as details and dates of lifetime use, on co-morbidity (renal, circulatory, metabolic, psychiatric, other medical conditions, headache or other painful conditions), treatment history (treatments with potential relation to outcome and risk factors), job exposure (occupation & industrial branch; exposure in selected occupational categories; exposure to groups of certain chemicals and minerals), and other demographic data such as age, sex, area of residence, and health care contacts. Participants were shown a book of color photographs and other descriptions of analgesics (mixed with other common drugs to blind the interviewee) marketed from the 1950s, organized by brand, name, dose, and the period during which the drugs were available to elicit an accurate lifetime history of analgesic use. Training and re-training of interviewers as well as briefing and re-briefing of study centers were standard quality control measures. Detailed logbooks were maintained in all participating dialysis centers for all new dialysis patients. The procedures to minimize potential bias included complete coverage of new dialysis patients (to address selection bias), use of index dates in the analysis (reverse causality bias), blinding of interviewers to the main research question (interviewer bias), and the restriction to phenacetin-free analgesics and adjustment for co-variables to reduce confounding. The data were collected locally, transferred to the central Data Management and Coordination Centre Berlin at the ZEG Berlin, and then to EPES Berlin for data analysis.

The SAC approved a detailed analysis plan for the "core analyses" which included a review of center performance and response rates. Frequency distributions of exposure with analgesics by case/control status and by index dates were calculated.

A fixed reference group defined as individuals who had been exposed to less than one table or unit dose of any phenacetin-free analgesic compound per month across all 12-months periods in their lifetimes was used for all analyses. This group is comprised of all participants who indicated no or very low use of analgesics, and is called "low use" in text and tables. This strategy was adopted to account for the potential differential recall of trivial use in cases and controls, based on the notion that controls may have poorer recall of irregular and low use than cases despite all standard memory aids used (cf. protocol published in this journal[11]). The decision was approved by the SAC after discussion of intermediate analyses and became integral part of the analysis plan. All persons suspected to have ever taken phenacetin in their lifetime were excluded.

Several index dates were defined and examined to determine the most appropriate lag time between exposure to analgesics and the start of dialysis. The decision was made that exposures in the 5 years prior to start of dialysis should not be used in analyses concerning ESRD risk[11] because analgesic use may have been initiated due to incipient kidney disease during that time.

Logistic regression analyses were used to estimate the association between ESRD and analgesic exposure. Crude and adjusted odds ratios with 95% confidence interval were calculated. The decision was made a priori to use unmatched analysis if the risk estimates of matched analysis did not materially differ.[11] This is because less information is lost in unmatched analyses and these are therefore better suited for subgroup analyses.

Many possible risk factors for ESRD (cf. Table 1 ) were assessed for confounding. Logistic regression with backwards elimination was used to define the adjustment variables for the analytic model. The final set of adjustment variables were age (5-year group), sex (male, female), country (Germany, Austria), first degree family history of chronic renal diseases (yes, no), and self-reported exposure with welding/soldering fumes, solvents (yes, no), and education(over/under 10 years). Following the recommendation of the study's statistical advisory committee, co-variables assumed to be intermediates in the causal pathway of ESRD -such as hypertension or diabetes – were excluded from the list of possible confounders for the final analysis to avoid over-adjustment.

The analyses focused on the association between high cumulative lifetime dose (grams) and ESRD across various subgroups of analgesic formulations. The primary comparison was that of the top tertile of cumulative lifetime dose with no or very low use for users of all phenacetin-free analgesics and for users of analgesic subgroups.

Due to the small numbers in many analgesic formulation subgroups, the SAC recommended using only a minimum of adjustment variables and to refrain from calculating or reporting odds ratios if any of the cells for a comparison contained less than 10 subjects. Doses per duration of use were analyzed as well as dose-response analyses. More detailed dose-response analyses will be published at a later time in a methodology paper. Because matched and unmatched analyses showed virtually identical results, the SAC decided that this publication should show the results of unmatched analyses.

All statistical analyses were performed with the commercial statistical software Stata 8.1.


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