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


Of 1,831 cases identified, 1,305 met the study entry criteria, 978 were interviewed, and 907 phenacetin-free cases were included in the analysis. The reasons for exclusion are shown in Figure 1. Similarly, of 6,587 potential neighborhood -controls, 6.236 were eligible, 3,892 were interviewed after 1,878 were excluded due to refusal to participate and 466 for undeclared reasons, and 3,622 controls without history of phenacetin use finally entered the analysis (Fig. 1). There were 71 cases and 270 controls with reasonable evidence for past phenacetin use mainly during childhood or early youth who were excluded from analysis. In terms of the study protocol, response rates of 74.9% for cases (978 of 1,305 eligibles) and 62.4 % (3,892 interviewed of 6,236 eligible) were considered acceptable. No important heterogeneity was observed for response rates across subgroups of age, gender, or case/control status (data not shown).

Flow chart: inclusion and exclusion of possible cases and controls.

Table 1 provides an overview of baseline characteristics for all cases and their controls. As expected from the matching process, there was no difference between cases and controls with regard to age, sex, and country. Compared with cases, controls had a proportionately higher educational level (defined as more than 10 years of school), smoked less, but consumed more alcohol. Cases more frequently reported conditions suspected to play a role in ESRD development such as diabetes, hypertension, renal diseases, urinary tract infections, and a first-degree family history of chronic renal conditions. There was a higher proportion of painful conditions such as headache, migraine, chronic back or arthritic pain as well as use of specific medications (anti-rheumatic, immune-suppressive, or long-term therapy with antibiotics) among cases than among controls. Relative to their age group, controls more frequently voiced minor subjective physical and psychological complaints than did cases, which were more prone to major complaints ( Table 1 ). Cases more often reported worksite exposure to heavy metals, other metal dust (such as aluminum, copper, chromium, tin), certain silicates (such as sand, cement, coal, rock, grain dust), solvents (such as varnish & paints, glue, crude oil, fuel, diesel, toluene), and welding and soldering fumes. These descriptive differences were taken into account for the determination of the adjustment factors for the main analysis.

The most frequently named underlying conditions leading to ESRD were glomerulonephritis (34.5%), pyelonephritis/interstitial nephritis (7.6%), polycystic kidney disease (12%), and diabetic nephropathy (15.8%), Other diseases such as lupus erythematosus, tuberculosis, vasculopathy, infarction, alport syndrome, and amyloid nephrosis were named in 18.5% of cases. The cause of kidney disease was unclear for the treating physician in 10.9%. "Analgesic nephropathy" was considered to be the cause of ESRD in only 5 of 907 cases (0.6%).

The main research question defined in the study protocol addressed the risk of ever use of phenacetin-free analgesics at index date 3 (the status 5 years before first dialysis) compared with no or low use of such substances. This standard reference group of individuals with no or very low use was defined as including those with exposure to less than one tablet or unit of any phenacetin-free analgesic compound per month across all 12-months periods of the participant's lifetime. The adjusted odds ratio (OR) for this analysis is 0.84, 95% confidence interval (CI): 0.71 to 0.98. The crude and adjusted risk estimates were virtually identical.

The association between cumulative lifetime dose of analgesics and ESRD is shown in Table 2 . The sub-categories of lifetime analgesic use are not mutually exclusive. The use of higher cumulative lifetime dose (tertile 3) of analgesics up to five years before dialysis was not associated with later ESRD either for all phenacetin-free analgesics together (All), or for analgesics with a single substance (monos), or for analgesics with multiple components (combis). Most risk estimates were below unity (1.0). Risk estimates calculated for medium lifetime doses (= tertile 2 and 1 combined) compared with the reference group of low use showed significantly decreased estimates. The adjusted comparison of high users of all phenacetin-free analgesics together with no or very low use showed a risk of 1.02 (95% CI: 0.81 to 1.28), the same estimate for all mono-analgesics was 0.98 (95% CI: 0.77 to 1.24). This estimate did not change when aspirin and paracetamol were excluded from the mono-preparations (OR 0.90; 95% CI: 0.61 to 1.31.). The overall estimate for the ESRD risk of high use of any combination analgesic compared with the reference group of no or very low use was 1.05 (95% CI: 0.77 to 1.44). Combination analgesics with or without paracetamol showed risk estimates in the same order of magnitude (cf. Table 2 ). Finally, no differences were found for the comparison between high versus low use when examining compounds with and without caffeine in this younger population with no prior use of phenacetin. We observed no evidence of an increased or different risk of ESRD associated with analgesic use (all analgesics, single substances, or combination products) with regard to the underlying disease of ESRD. The risk varied around unity across all disease subgroups containing sufficient numbers for analysis. These data will be presented at a later time in a clinical publication.

The relationship of analgesic dose and duration of use and their potential impact on ESRD development was examined extensively. Table 3 shows the analyses for all analgesics, mono-substance and combination preparations separately for lower and higher user of analgesics and for shorter and longer durations, where the cut-off points for each class are based on the respective median value found in controls. Although no significant increase is found, the table indicates that there may be a weak positive association with higher doses of analgesics used for shorter duration (left lower corner of Table 3 ) On the other hand, lower user of analgesics for longer durations (upper right corner) showed statistically significant lower risks for 2 of 3 analgesic types analyzed. Finally, lower use and shorter duration showed a statistically significant inverse association for all 3 analgesic types. There was an inverse association (not statistically significant) for 2 of 3 types for higher dose and longer duration of use. The numbers were too small for stable risk estimates of formulation subgroups.

In order to account for overlapping of the use of different analgesic formulation during the participant's lifetime, all other analgesic subgroups were taken into the equation ( Table 4 ). No significant association with ESRD was shown for any formulations containing ASA, paracetamol or containing neither of these two substances, i.e. the ESRD risk associated with high use (3rd tertile of cumulated lifetime use) vs. low use varied around unity.

The cumulative lifetime dose of analgesics (in grams) was stratified in eight sub-categories in steps of 500 grams up to 3.5 kg in order to show the risk distribution up to the uppermost dose groups ( Table 5 ). There was no increased risk for ESRD up to 3.5 kg cumulative lifetime dose (98 % of the cases with ESRD). A significantly increased risk was found for the tiny subgroup of upper-most lifetime dose of more than 3.5 kg in this young age group (19 cases and 11 controls, 2% of all cases and 0.3% of all controls). Conversely, the risk was significantly reduced for the large subgroup of user with a lifetime dose up to 0.5 kg. In a second approach we examined the risk of ESRD contributed per gram at various levels of use compared with "no or very low use". This essentially confirms the above mentioned results, as each gram of use is associated with lowered risk for the group below 0.6 kg lifetime analgesics consumption, it is associated with no risk in the group up to 4.6 kg, and only in the group over 4.6 kg is there a significantly increased risk of ESRD per dose (table not shown). This threshold applies to 12 cases (= 1.3% of all cases) and 3 controls (= 0.08%) in this study. None of these were categorized as analgesic nephropathy by their treating physicians.

A detailed review of the characteristics of the 22 cases (2.4 % of all cases) and 19 controls (0.5 % of all controls) who reported at least 2.5 kg or more cumulative lifetime dose of analgesics was conducted. This cut-off point was recommended by the SAC and approved by the German Drug Authority. No difference in the reason for analgesic use for the cases and controls in this subgroup, or in their subjective complaints was determined. However, conditions associated with the causal pathway of ESRD such as hypertension, diabetes, gout, arterial diseases (cardiac, cerebral, peripheral), renal diseases, other serious diseases or operations, and family history of chronic renal diseases were much more prevalent in cases than in controls with upper-most, extreme use of analgesics. Cumulatively, 70% of the 22 cases had three and more of these seven conditions and 70% of the 19 controls had 0–1 of these conditions related to the evolution of ESRD ( Table 6 ).


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