Results of the Case-Control Study on Analgesics and Nephropathy

The results are in the publication process. A link to the publication will be created as soon as the article appeared. Meanwhile, for the sake of transparency, a summary is provided in the following paragraphs.


Description of cases and controls

Starting with initially identified 1831 suspected cases with first dialysis due to chronic renal failure. Reasons for exclusion reduced to 907 analyzable cases; these were acute dialysis or re-dialysis after transplantation, outside study period, seriously poor health/death before interview, wrong age, interview rejected, and history of phenacetin use.
Similarly, the number of identified controls decreased from initially contacted 6587control addresses to 3892 interviewed controls. : Some were in too bad condition for an interview (n=154), others out of the age range or other reasons for non-eligibility (n=204).
Out of the remaining 6236 eligible controls 1878 refused their consent to participate in the study and 466 had other or undeclared reasons not to undergo an interview. Finally 3892 controls were interviewed and 3622 were available for analyses.

Users of phenacetin – having used mainly during childhood or early youth - were excluded from all analyses: 71 cases and 270 controls presented at least some reasonable evidence/suspicion of phenacetin use, usually a long time ago.
The response rates of eligible persons were acceptable according to the study protocol (74.9% for eligible cases and – as predicted - lower (62.4%) in controls). No serious heterogeneity of response rates across subgroups of age, gender, or case/control status was observed. However, non-responders are always a point of concern even if the rate is in the internationally acceptable range for case-control studies.

Glomerulonephritis (34.5%), pyelonephritis/ interstitial nephritis (7.6%) had the highest prevalence as underlying diseases of ESRD, but polycystic kidney disease (12%) and diabetic nephropathy (15.8%) were also prevalent causes of ESRD. In 18.5% of cases other diseases were mentioned (such as lupus erythematosus, tuberculosis, vasculopathy, infarction, alport syndrome, amyloid nephrosis) or the cause was unclear for the treating physician in 10.9%.

It was the decision of the SAC to include all cases irrespective of the suspected underlying disease, because no published evidence was found that one of the disease-categories leading to terminal renal failure is particularly susceptible to the exposure under study.
Thus analyses stratified by “causal disease” of ESRD were foreseen to check for differences of risk impact - but they were not observed.
Very little suspicion of “analgesic nephropathy” (AN) as cause of ESRD was found, i.e. only in 5 out 907 cases (0.6%) such a diagnosis were considered at all, however, without reliable diagnostic confirmation (e.g., histology) in the patients’ files. No single case with a medical diagnosis of “AN” was observed among the cases with uppermost cumulative lifetime use of analgesics (see further down).

Overall risk of ESRD, ever use, and cumulative lifetime dose

The analysis for ever use of phenacetin-free analgesics at index date 3 (last 5 years prior to ESRD not considered) compared with no/rare use showed no increased risk (unmatched adjusted OR: 0.84; 95% CI: 0.71 to 0.98). The risk estimates were virtually identical using the matched and unmatched logistic regression analysis.

The use of high cumulative lifetime dose of analgesics (upper dose tertile) was not associated with later ESRD either for all phenacetin-free analgesics together or for analgesics with a single component (Monos), or for analgesics with multiple components (Combis). Most risk estimates were under unity (1.0). Risk estimates calculated for lifetime doses of the 2nd and 1st tertile (=medium use) were mainly significantly decreased. The lifetime-use of different sub-categories of analgesics are not mutually exclusive.

The adjusted comparison of high users of all phenacetin-free analgesics together with no/rare 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), and if aspirin and paracetamol were excluded from mono-preparations the risk did not change: 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 no/rare use is 1.05 (95% CI: 0.77 to 1.44). Similarly, combination analgesics with or without paracetamol showed risk estimates in the same order of magnitude.

The alleged high risk of nephropathy of combined analgesics including those with or without caffeine is not substantiated by the data of our study and the association of caffeine does not increase the risk of ESRD.
Specifically, the ESRD risk associated with the 3rd tertile of the cumulated lifetime dose of the combination ASA, Paracetamol, Caffeine – compared with no/rare use - was not significantly increased (Adj. OR= 0.98; 95% confidence interval 0.62 – 1.55).
We observed no meaningful evidence of an increased or different risk of ESRD associated with cumulated lifetime dose of analgesics (all analgesics, monos, or combis) depending on the underlying disease of ESRD; the risk varied around unity across all disease subgroups with sufficient numbers.

Combined effect of dose and duration

The results of low/high lifetime dose combined with short/long duration of analgesic use presented a rather arbitrary risk pattern with no significantly increased or decresed risk estimates (Ors).

Adjustment for confounding by other analgesic formulations

Attempts were made to adjust for overlapping of the use of different analgesic formulation during lifetime by taking all other analgesic subgroups into the equation.
ESRD showed no significant association for any formulations containing ASA, paracetamol or other analgesics, i.e. the ESRD risk associated with high use (3rd tertile of cumulated lifetime dose) vs. no/rare use varied around unity.
Also, no increased risk was observed in those participants who had used only one single analgesic formulation or combination category during lifetime.

Dose-response: categorical & continuous perspective

Dose-response analyses showed that analgesic use was not associated with an increased risk for ESRD up to 3.5 kg cumulative lifetime dose (98 % of the cases with ESRD). While the large subgroup of users with a lifetime dose up to 0.5 kg (278 cases and 1365 controls) showed a significantly decreased risk, a tiny subgroup of extreme users with over 3.5 kg lifetime use (19 cases and 11 controls) showed a significant risk increase.
The detailed evaluation of 22 cases and 19 controls with over 2.5 kg lifetime use recommended by the regulatory advisors showed an excess of conditions triggering the evolution of ESRD in cases compared with controls.
95% of the cases in this group of users of uppermost lifetime dose of analgesics showed 2-6 diseases/conditions predisposing for chronic renal failure, whereas all members of the control group with such high analgesic use a history of 0 -2 such conditions were found.

The interpretation is, that a real (direct) contribution of analgesics to ESRD risk in the high-end dose user group is not convincing. Our study was not designed for an epidemiological analysis of such a small subgroup.
The user of uppermost dose of analgesics of our case-controls study needed clinical judgment at the individual level compatible with an “adverse event assessment”.

It was decided to ask an “expert-nephrologist” for an individual assessment of the upper-most user of analgesics
Outside our case-control-study, all cases with a cumulative lifetime dose of more than 2.5 kg analgesics were individually evaluated concerning the likelihood that analgesics could have played a causal role in the pathogenesis of development of the disease toward renal failure, i.e. the causal contribution over and above the medical history and development of the renal disease itself. This was done by an independent expert-nephrologist following the rules of classical “adverse event evaluation”.

The expert came to the opinion that
(1) “It was concluded that “analgesic nephropathy” can be excluded as a significant cause of ESRD in this group of “extreme users” (22 cases)”, and
(2) “ The type of original renal disease with a prevalence of diabetes as well as the presence of a number of additional risk factors can sufficiently explain the evolution to end-stage renal failure. Hints pointing towards an additional role of analgesics and NSAID consumption were not found in this clinical study.” The full expert report is attached.

Conclusions

This initial research question of an increased risk of analgesic nephropathy associated with use of combination analgesics was specified & re-defined by the SAC and Drug Regulators to be investigated in a case-control study, i.e. with an improved methodological design never applied before in this research field.

We found no clinically meaningful evidence for an increased risk of ESRD associated with the cumulated lifetime use of phenacetin-free analgesics in single or combined formulations with and without caffein.

The apparent risk increase shown in a small subgroup with extreme lifetime dose of analgesics is most likely an indirect, non-causal association. This hypothesis, however, cannot be confirmed or refuted within our case-control study.
Overall, our results lend support to the mounting evidence that phenacetin-free analgesics do not induce ESRD and that the notion of “analgesic nephropathy” needs to be re-evaluated. No single case with a “medical diagnosis of AN” was found among the group with uppermost lifetime dose of analgesics.

Individual risk assessment (classical adverse event report assessment) of the tiny subgroup of users of uppermost doses was performed outside the case-control study, i.e. leading to a separate report.
This individual assessment of cases/controls with a cumulative lifetime use of more than 2.5 kg analgesics showed that a causal contribution by analgesics to causation or progression of ESRD is not likely.
There is no reason anymore to use the diagnosis "analgesic nephropathy", either from the viewpoint of this study or from the new pathomorphological findings of the Basel II autopsy study by Mihatsch.

The prevalence of pathognomic patterns of “analgesic nephropathy” continuously declined over the years in the autopsy statistics of Basel and have now virtually disappeared in contrast to the high prevalence in the Basel I autopsy study (1978-80) using identical methods.

Meanwhile an Editorial Comment by Michielsen appeared in NDT, i.e. not directly related to this case-control study: “In memoriam “analgesic nephropathy” (circa 1972-2006)”.