Trimethoprim and acute kidney injury in the elderly

Trimethoprim used to treat UTIs in the elderly is associated with excessive hyperkalemia and acute kidney injury (see trimethoprim AKI bmj2018 in dropbox, or https://doi.org/10.1136/bmj.k341 ).

Details:
--UK electronic primary care records were data-mined for adults >65yo who had at least one urinary tract infection (UTI) treated with antibiotics, from 1997-2015
--178,238 individuals were identified from their Clinical Practice Research Datalink of 1,191,904 people; 422,514 had had UTIs
--79% female, median 3 UTIs, evenly spread with about  85,000 UTIs for each 5-year age group from 65 to >85yo, DM 21%/ischemic heart disease 34%/heart failure 12%/htn 61%
--baseline renal function: eGFR>60 in 42%/45-59 in 23%/30-44 in 12%/<30 in 4%
--exposure to RAS blocker or potassium-sparing diuretic in 35%
--antibiotics used for UTIs:
    --amoxacillin 5% (n=22,543)
    --trimethoprim 59% (n=215,193)
    --cefalexin 15% (n=64,885)
    --ciprofloxacin 5% (n=21,946)
    --nitrofurantoin 15% (n=61,947)

Results:
--within 14 days of antibiotic prescription, total number of cases of acute kidney injury (AKI): 1345; hyperkalemia: 648; deaths: 2214
--more amox or cipro used in men; slightly more amox in those >85yo;more trimethoprim in those with fewer comorbidities; more nitrofurantoin if better renal function; more cipro if history BPH or renal calculi
--acute kidney injury leading to hospitalization within 14 days after antibiotic therapy, as compared to amoxacillin:
    --trimethoprim:  72% higher, adjusted odds ratio 1.72 (1.31-2.24)
    --ciprofloxacin:  48% higher, adjusted odds ratio 1.48 (1.03-2.13)
--hyperkalemia within 14 days after antibiotic therapy, as compared to amoxacillin:
    --trimethoprim:  127% higher, adjusted odds ratio 2.27 (1.49-3.45)
--death within 14 days after antibiotic therapy, as compared to amoxacillin:
    --trimethoprim: no difference either for whole group or for those on RAS blockers
--absolute differences: for 1000 UTIs treated with trimethoprim vs amoxacillin:
    --1-2 additional cases of hyperkalemia
    --2 hospital admissions for acute kidney injury
    --BUT, for those on RAS blockers and spironolactone: 18 more cases of hyperkalemia and 11 more admissions for AKI (taking only one of these would led to 2 additional cases of both hyperkalemia and AKI, not much difference from taking neither)
--subgroup analyses:
    ​--AKI: the fully adjusted odds ratios were even higher (OR=2.36 for trimethoprim) in those given antibiotics for any indication (ie, it was not just the presence of a UTI itself that led to more AKI); also slight increase in those on RAS blocker (adjusted for potassium-sparing diuretics) with OR=1.92 for trimethoprim.  as above, OR for the whole group on trimethoprim was 1.72
    --hyperkalemia: also somewhat higher (OR=2.52 for trimethoprim) in those given antibiotics for any indication. difference if on RAS blocker (adjusted for potassium-sparing diuretic). as above OR for the whole group on trimethoprim was 2.27


Commentary:
-- trimethoprim/sulfamethoxazole (TMP/SMX) is the 4th most commonly prescribed antibiotic in the US; several studies have associated its use with developing hyperkalemia, especially in those taking ACE-I/ARB or spironolactone. Not so surprising since trimethoprim is known to reduce distal renal tubule excretion of potassium.  Several studies have found that TMP/SMX can be associated with interstitial nephritis, impaired renal function, acute tubular necrosis, as well as hyperkalemia. creatinine may be mildly increased but not reflecting a change in GFR because trimethoprim decreases tubular secretion of creatinine (though this is unlikely the problem in the above study, since these were all patients admitted to the hospital with AKI). cipro has also been found to be associated  with AKI.
--in the UK trimethoprim is more commonly used than TMP/SMX, the former with 3.7 million prescriptions in 2015, and is still the most used antibiotic for UTIs (though resistance is increasing)
--current UK guidelines are to use nitrofurantoin as first-line therapy, except if CKD present, or trimethoprim if area of low resistance. ciprofloxacin and cefalexin are not recommended, other than cipro for pyelonephritis. though all of these antibiotics are actually used in practice. not sure how to explain the curious finding that only 15% in the above study got nitrofurantoin, but perhaps the UK guidelines changed over the course of this data collection
--prior studies have found that TMP/SMX has been associated with sudden death in those on RAS blockers. ??relation to AKI or hyperkalemia
--?confounding by indication: were those put on cipro different from those on trimethoprim? and who got amox? were those put on trimethoprim less likely to have baseline hyperkalemia or urologic pathology (though both of these would lead to underestimation of trimethoprim risk)? was UTI the sole indication for antibiotics (?prostatitis in men, ?concern of upper tract infection in women?)
--one advantage of this study is that it involves a huge database of outpatients put on antibiotics for UTIs. ​

so, this study adds to the literature on adverse effects of TMP/SMX regarding hyperkalemia and renal outcomes, but significantly showed that trimethoprim by itself seems to be the culprit. given these issues, it seems prudent to avoid trimethoprim or TMP/SMX in those with baseline hyperkalemia (though i personally have felt comfortable using it even in those on RAS blocker plus spironolactone if their baseline potassium were under 4.3 or so) for short course therapies. in our case in Boston, given the pretty high resistance of e. coli to TMP/SMX for UTIs, its most common indication is probably for skin infections (eg MRSA)​