Dexmedetomidine Prevents Acute Kidney Injury After Adult Cardiac Surgery


Abstract

Background Dexmedetomidine has been shown to confer direct renoprotection by stabilizing the sympathetic system, exerting anti-inflammatory effects and attenuating ischemia/reperfusion (I/R) injury in preclinical studies. Results from clinical trials of dexmedetomidine on acute kidney injury (AKI) following adult cardiac surgery are controversial.

Methods We searched EMBASE, PubMed, and Cochrane CENTRAL databases for randomized controlled trials (RCTs) comparing the renal effect of dexmedetomidine versus placebo or other anesthetic drugs in adult patients undergoing cardiac surgery. The primary outcome was the incidence of AKI. The secondary outcomes were mechanical ventilation (MV) duration, intensive care unit (ICU) stay and hospital length of stay(LOS), and postoperative mortality (in-hospital or within 30 days).

Results Ten trials with a total of 1575 study patients were selected. Compared with controls, dexmedetomidine significantly reduced the incidence of postoperative AKI [68/788 vs 97/787; odds ratio(OR), 0.65; 95% confidence interval (CI), 0.45–0.92; P = 0.02; I2 = 0.0%], and there was no difference between groups in postoperative mortality (4/487 vs 11/483; OR, 0.43; 95% CI, 0.14–1.28; P = 0.13; I2 = 0.0%), MV duration [in days; n = 1229; weighted mean difference(WMD), −0.22; 95% CI, −2.04 to 1.70; P = 0.81], ICU stay (in days; n = 1363; WMD, −0.85; 95% CI, −2.14 to 0.45; P = 0.20), and hospital LOS (in days; n = 878; WMD, −0.24; 95% CI, −0.71 to 0.23; P = 0.32).

Conclusions Perioperative administration of dexmedetomidine in adult patients undergoing cardiac surgery may reduce the incidence of postoperative AKI. Future trials are needed to determine the dose and timing of dexmedetomidine in improving outcomes, especially in patients with decreased baseline kidney function.

Trimethoprim Is Associated with Excess Risk for Acute Kidney Injury in Elders


In this cohort study, higher odds of hyperkalemia and kidney injury with TMP weren’t dependent on drug interactions.

 

Trimethoprim/sulfamethoxazole (TMP/SMX) use is associated with excess risk for hyperkalemia and related adverse events in patients who take angiotensin-converting–enzyme inhibitors, angiotensin-receptor blockers (NEJM JW Gen Med Sep 1 2010 and JAMA Intern Med 2010; 170:1045; NEJM JW Gen Med Dec 15 2014 and BMJ 2014; 349:6196), or spironolactone (NEJM JW Gen Med Nov 1 2011 and BMJ 2011; 343:5228). However, whether TMP confers risk for hyperkalemia when it is used without SMX and in the absence of renin-angiotensin system blockers is unknown. In the U.K., TMP often is prescribed without SMX, giving researchers an opportunity to clarify this issue in a cohort of 180,000 patients (age, ≥65) who experienced at least one urinary tract infection (UTI) and received antibiotics.

After adjustment for numerous potential confounders (including use of renin-angiotensin system blockers and potassium-sparing diuretics), odds of acute kidney injury during the 14 days following antibiotic initiation were 72% higher with TMP and 48% higher with ciprofloxacin than with amoxicillin. Odds of hyperkalemia occurrence during the 14 days following antibiotic initiation were 127% higher with TMP than with amoxicillin. TMP, compared with amoxicillin, was not associated with increased odds of death. Trimethoprim was associated with 1 to 2 additional cases of hyperkalemia and 2 admissions for acute kidney injury per 1000 treated patients; for people taking renin-angiotensin system blockers and spironolactone, 18 additional cases of hyperkalemia and 11 additional admissions for acute kidney injury occurred.

Comment

TMP use alone was associated with excess risk for hyperkalemia and acute kidney injury, but not death, compared with amoxicillin use for primary care treatment of UTIs among elders. This hyperkalemia finding is unsurprising, as TMP reduces potassium excretion in the distal renal tubule. Although TMP can raise serum creatinine concentration (by reducing tubular secretion of creatinine), which could result in overestimation of “true” kidney injury, the authors provide several reasons to believe that kidney injury in their study was real — a novel observation for TMP. Antibiotics other than those that contain TMP should be used in patients at risk for hyperkalemia and acute kidney injury.

Risk of acute kidney injury associated with the use of fluoroquinolones


Abstract

Background: Case reports indicate that the use of fluoroquinolones may lead to acute kidney injury. We studied the association between the use of oral fluoroquinolones and acute kidney injury, and we examined interaction with renin–angiotensin-system blockers.

Methods: We formed a nested cohort of men aged 40–85 enrolled in the United States IMS LifeLink Health Plan Claims Database between 2001 and 2011. We defined cases as men admitted to hospital for acute kidney injury, and controls were admitted to hospital with a different presenting diagnosis. Using risk-set sampling, we matched 10 controls to each case based on hospital admission, calendar time (within 6 wk), cohort entrance (within 6 wk) and age (within 5 yr). We used conditional logistic regression to assess the rate ratio (RR) for acute kidney injury with current, recent and past use of fluoroquinolones, adjusted by potential confounding variables. We repeated this analysis with amoxicillin and azithromycin as controls. We used a case-time–control design for our secondary analysis.

Results: We identified 1292 cases and 12 651 matched controls. Current fluoroquinolone use had a 2.18-fold (95% confidence interval [CI] 1.74–2.73) higher adjusted RR of acute kidney injury compared with no use. There was no association between acute kidney injury and recent (adjusted RR 0.87, 95% CI 0.66–1.16) or past (RR 0.86, 95% CI 0.66–1.12) use. The absolute increase in acute kidney injury was 6.5 events per 10 000 person-years. We observed 1 additional case per 1529 patients given fluoroquinolones or per 3287 prescriptions dispensed. The dual use of fluoroquinolones and renin–angiotensin-system blockers had an RR of 4.46 (95% CI 2.84–6.99) for acute kidney injury. Our case-time–control analysis confirmed an increased risk of acute kidney injury with fluoroquinolone use (RR 2.16, 95% CI 1.52–3.18). The use of amoxicillin or azithromycin was not associated with acute kidney injury.

Interpretation: We found a small, but significant, increased risk of acute kidney injury among men with the use of oral fluoroquinolones, as well as a significant interaction between the concomitant use of fluoroquinolones and renin–angiotensin-system blockers.

Fluoroquinolones are commonly prescribed broad-spectrum antibiotics.1 Although highly effective, they are known to cause cardiac arrhythmia, hypersensitivity reactions and central nervous system effects including agitation and insomnia.2,3 Recent reports of tendon rupture4 and retinal detachment5 suggest that these drugs may damage collagen and connective tissue. Case reports of acute kidney injury with the use of fluoroquinolones have been published,6 and the product label includes renal failure in a list of potential, but uncommon, adverse reactions.2 In clinical practice, when oral fluoroquinolones are prescribed, the potential for acute kidney injury is generally not a clinical consideration. We aimed to quantify the risk of acute kidney injury with the use of oral fluoroquinolones among men. This study population was limited to men because the cohort we studied was formed to investigate health issues that affect older men.

Methods

Data source

The IMS LifeLink Health Plan Claims Database contains paid claims from US health care plans. Compared with the US Census, the database captures 17% of men aged 45–54 years, 13% of men aged 55–64 years and 8% of men aged over 65 years. Data for men over 65 years are captured through Medicare Advantage programs. These privatized health care plans combine medical and prescription services, providing more inclusive health care data.7

The IMS LifeLink database contains fully adjudicated medical and pharmacy claims for over 68 million patients, including inpatient and outpatient diagnoses (via International Classification of Diseases, 9th revision, clinical modification [ICD-9-CM], codes) in addition to retail and mail-order prescriptions. The data are representative of US residents with private health care in terms of geography, age and sex. The IMS LifeLink database is subject to quality checks to ensure data quality and minimize errors,7 and it has been used in previous pharmacoepidemiologic studies.810

This study was approved by the University of Florida’s Institutional Review Board. All coding used in this study can be found in Appendix 1 (available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.121730/-/DC1).

Cohort formation

We used a nested case–control design for our primary analysis. Our cohort was formed to study health issues that affect older men. This population is at the greatest risk of acute kidney injury and is commonly prescribed fluoroquinolones. We extracted data for 2 million men from the IMS LifeLink database who had both prescription and medical coverage. We included men aged 40–85 years who met the inclusion criteria between Jan. 1, 2001, and June 30, 2011, and who had 365 days of enrolment with no acute kidney injury. We excluded men with a history of chronic kidney disease or dialysis because these men may be more prone to acute kidney injury. Censoring was performed at a study outcome, the end of enrollment and end of the study. The cohort was nested within inpatient hospital records, which were used to select cases and controls.

Cases and controls

Multiple studies have validated algorithms to determine acute kidney injury using ICD-9-CM coding. Several were not applicable because they were published only in abstract form,11 included ICD-10-CM coding,12 did not define acute kidney injury at hospital admission,13 included cases before 1990,14 assessed acute kidney injury that occurred after admission to hospital15 or included unspecified (nonacute) renal failure (ICD-9-CM 586.x).16 Two studies validated ICD-9-CM coding against a reference standard that required doubling of serum creatinine and found poor positive predictive values; however, this algorithm does not account for differences in baseline serum creatinine levels.17,18 A second algorithm was developed that identified acute kidney injury based on baseline serum creatinine level: acute kidney injury was defined by a change in serum creatinine of 0.5 mg/dL (44.2 μmol/L) for a nadir serum creatinine of 1.0 mg/dL (88.4 μmol/L) or lower, a change in serum creatinine of 1.0 mg/dL for a nadir serum creatinine between 2.0–4.9 mg/dL (176.8–433.2 μmol/L), or a change in serum creatinine of 1.5 mg/dL (132.6 μmol/L) for a nadir serum creatinine of 5.0 mg/dl (44.2 μmol/L).19 Two studies validated acute kidney injury using ICD-9-CM coding for all hospital discharges against this reference, finding positive predictive values of 80.2%17 and 87.6%.20

We defined acute kidney injury as ICD-9-CM 584.0 (acute renal failure, unspecified), 584.5 (acute tubular necrosis), 584.6 (cortical acute renal failure), 584.7 (medullary acute renal failure), 584.8 (acute renal failure with other specified pathologic lesion) and 584.9 (acute renal failure, not otherwise specified). We further restricted cases to the primary hospital discharge diagnosis, a diagnostic code that identifies the main reason for hospital admission. This is known to increase the positive predictive values and identify the primary reason for admission. We excluded cases if they had been admitted to hospital during the 6 months before the admission for acute kidney injury. Previous hospital admissions could indicate a greater degree of morbidity (confounding by disease severity) and prevent us from measuring prescription use (immeasurable time bias).21 We did not differentiate between subtypes of acute kidney injury because ICD-9-CM coding has not been validated to show this distinction.

We considered men who were admitted to hospital with a diagnosis other than acute kidney injury and who had not been admitted to hospital in the previous 6 months to be eligible for the control group. We used risk-set sampling to select the controls, whereby for each case, a pool of potential controls was formed that met the following criteria: were eligible for matching only on the day of hospital admission; were admitted to hospital within 6 weeks (calendar-time matching); entered the nested cohort no more than 6 weeks apart; and were within 5 years of age. From this risk set, 10 controls, who were still eligible to have an acute kidney injury, were randomly selected and matched for each case. This allows formation of an odds ratio equivalent to the rate ratio (RR).22 Matching on hospital admissions (a strong proxy for health status) was done to provide controls of more similar comorbidity and to reduce residual confounding.

Drug exposure

We included exposure to oral fluoroquinolones: ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin and norfloxacin. We excluded ophthalmic and topical fluoroquinolones because they have minimal systemic absorption. We excluded intravenous fluoroquinolones because our focus was on outpatient-dispensed preparations. We excluded prescriptions dispensed on the day of hospital admission to prevent reverse causality bias.

We defined a current user as someone who had an active supply of fluoroquinolone at hospital admission or had stopped taking a fluoroquinolone (prescription termination; final day of drug supply) in the 1–7 days before admission. Recent users were those who had a prescription termination 8–60 days before admission and had no active supply within the 7 days before admission. We defined past users as those who had a prescription termination 61–180 days before admission and who had no active prescriptions during days 0–60.

We selected 2 common oral antibiotics (amoxicillin and azithromycin) as control drugs. Although both have been implicated in rare cases of interstitial nephritis,2326 we hypothesized that the burden of acute kidney injury with these drugs would be insufficient to produce a positive association.

Statistical analysis

Primary analysis: nested case–control

We used conditional logistic regression to determine the RR for acute kidney injury with fluoroquinolone use. The model was adjusted by fluoroquinolone indication (genitourinary, respiratory or gastrointestinal tract infection; skin infection; and joint or bone infection in the past 6 mo), diseases associated with acute kidney injury (cancer, chronic obstructive pulmonary disease, congestive heart failure, diabetes mellitus, HIV and hypertension in the past year), potentially nephrotoxic drugs with high use (loop diuretics, nonsteroidal anti-inflammatory drugs and renin–angiotensin-system blockers at hospital admission) and markers of health care use (number of medications, billing codes and physician visits in the past 6 mo). We stratified the subsequent analyses by fluoroquinolone product (ciprofloxacin, levofloxacin and moxifloxacin).

We examined drug–drug interactions between fluoroquinolones (current use) and renin–angiotensin-system blockers (at admission) through the addition of an interaction term to our fully adjusted model. We defined renin–angiotensin-system blockers as angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers. We did not include aldosterone antagonists based on low use and concern for confounding based on the many indications for these medications. Although we hypothesized drug–drug interactions between fluoroquinolones and loop diuretics or nonsteroidal anti-inflammatory drugs, we did not have sufficient power for these analyses. We computed a number needed to harm (absolute risk increase × 100) in which the absolute risk increase equaled the estimated incidence among users (RR × incidence among nonusers) minus the incidence among nonusers.

Secondary analysis: case-time–control

A case-crossover design allows patients to serve as their own controls, using within-patient comparisons of drug exposure to assess the RR for the study outcome.27 This technique has the advantage of having no residual confounding from time-invariant covariates. Two cardinal requirements for a case-crossover study are an acute outcome and a transient exposure. Acute kidney injury is an acute outcome, and fluoroquinolones are typically prescribed for 7–14 days,2 meeting the assumption of transient exposure. Because most fluoroquinolone prescriptions are for 14 or fewer days, we chose the 14 days immediately before admission to hospital as the case-time. Four control-times were selected, each immediately following the previous 14 day window (days 15–28, 29–42, 43–56 and 57–71). We used conditional logistic regression to determine the RR for acute kidney injury with fluoroquinolone exposure. We sensitized the case-crossover by the distribution of fluoroquinolone use from these time windows in the 10 matched control patients from the main analysis. This analysis, referred to as a “case-time–control,” adjusts for a potential trend toward increased use of all antibiotics before hospital admission.28

Sensitivity analysis

We were concerned that patients taking fluoroquinolones would be more likely to have a genitourinary infection (compared with patients taking one of the control medications), which could make them more likely to have acute kidney injury. We conducted a sensitivity analysis in which we removed patients who had experienced a genitourinary infection during the 6 months before admission, and we repeated the study analysis.

Because the sensitivity of excluding people with chronic kidney disease using ICD-9-CM coding is unknown, we repeated our analyses without excluding patients with previous claims for chronic kidney disease; from this analysis, the changes in the study RRs can be used to assess whether residual confounding from unmeasured chronic kidney disease is a potential concern.

Results

Our nested cohort contained 767 209 patients (162 608 hospital admissions) eligible for matching. We identified 1292 cases with acute kidney injury and 12 651 matched controls. The characteristics of the cases and controls are shown in Table 1. Ciprofloxacin (44.5%) and levofloxacin (43.9%) were the most commonly used fluoroquinolones (Table 2); the most common indications were respiratory (45.6%) or genitourinary infections (27.0%) (Table 3).

Table 1:

Characteristics of cases and controls

Table 2:

Use of oral fluoroquinolones among cases and controls

Table 3:

Indication for the use of antibiotics among cases and controls

We observed an increased risk of acute kidney injury with current use of fluoroquinolones (adjusted RR 2.18, 95% CI 1.74–2.73) and no change in risk with either recent (adjusted RR 0.87, 95% CI 0.66–1.16) or past (adjusted RR 0.86, 95% CI 0.66–1.12) use. There was no association between the use of amoxicillin or azithromycin and acute kidney injury (Table 4).

Table 4:

Nested case–control analysis of the risk of acute kidney injury with the use of fluoroquinolones

When we stratified our analysis by fluoroquinolone product, the largest RR was found for ciprofloxacin (RR 2.76, 95% CI 2.03–3.76), followed by moxifloxacin (RR 2.09, 95% CI 1.04–4.20) and levofloxacin (RR 1.69, 95% CI 1.20–2.39). When levofloxacin was used as a reference, ciprofloxacin had a significantly increased RR (RR 1.73, 95% CI 1.08–2.77), whereas moxifloxacin did not (RR 1.20, 95% CI 0.54–2.65).

The case-time–control analysis confirmed the results from the nested case–control study: we found an increased risk of acute kidney injury with fluoroquinolone use (RR 2.16, 95% CI 1.52–3.18) but not with amoxicillin (RR 0.65, 95% CI 0.38–1.05) or azithromycin (RR 1.06, 95% CI 0.62–1.90) (Table 5). The absolute increase in the incidence of acute kidney injury was 6.5 events per 10 000 person-years with use of fluoroquinolones. We observed 1 additional case of acute kidney injury per 1529 patients who used fluoroquinolone or per 3287 prescriptions dispensed.

Table 5:

Case-time–control analysis of the risk of acute kidney injury with the use of fluoroquinolones or other antibiotics

The addition of a drug–drug interaction to the “current use” models for study drugs found similar main effects. Although renin–angiotensin-system blockers can increase serum creatinine levels, we did not find an increased risk of acute kidney injury with renin–angiotensin-system blocker monotherapy (RR 1.00, 95% CI 0.84–1.18). We did find, however, an interaction between the combined use of fluoroquinolones and renin–angiotensin-system blockers (interaction RR 2.19, 95% CI 1.30–3.69). An interaction can be defined as the additional risk for acute kidney injury from the concomitant use of 2 drugs that is beyond the additive risk of each individual drug. This interaction resulted in a greater than fourfold increase in the RR for acute kidney injury (RR 4.46, 95% CI 2.84–6.99) with active use of both drugs. When we analyzed the data by drug class, a similar increased risk was found with the dual use of fluoroquinolones and either angiotensin-converting-enzyme inhibitors (RR 4.54, 95% CI 2.74–7.52) or angiotensin-receptor blockers (RR 3.80, 95% CI 1.72–8.41).

Adjustment for a genitourinary infection had a negligible effect on all point estimates for fluoroquinolone use and acute kidney injury (< 2% change). When we restricted the nested cohort to only patients with no history of genitourinary infection and repeated the nested case–control analysis, we found similar RRs as in the main analysis between fluoroquinolones and acute kidney injury (current use: RR 2.48, 95% CI 1.92–3.23; recent use: RR 0.95, 95% CI 0.65–1.37; past use: RR 0.98, 95% CI 0.75–1.29). When we included patients with a previous claim for chronic kidney disease, we found similar RRs for all user types (current use: RR 2.08, 95% CI 1.67–2.59; recent use RR 0.95, 95% CI 0.73–1.26; past use RR 0.88, 95% CI 0.67–1.13).

Interpretation

We found a twofold increased risk of acute kidney injury with current use of fluoroquinolones. There were nonsignificant associations between fluoroquinolone use and acute kidney injury among recent and past users (point estimates less than 1.0). The twofold differential in risk between current and both recent and past fluoroquinolone use suggests that acute kidney injury is an acute adverse effect of fluoroquinolones. These results were replicated in the case-time–control analysis, which increases our confidence in these associations because of better control of time-invariant confounding.

Previous evidence of acute kidney injury with fluoroquinolone use comes from case reports. Most case reports result from an allergic or hypersensitivity reaction termed acute interstitial nephritis.29,30 Fluoroquinolones have also been reported to cause granulomatous interstitial nephritis, characterized by infiltration of the renal tissue by histiocytes and T lymphocytes, leading to the formation of granulomas.31,32 Crystalluria has been reported to occur when urine pH is above 6.8,33 and several cases of acute kidney injury from crystal formation secondary to fluoroquinolone use have been documented.34,35 More severe cases of acute tubular necrosis have also been linked to fluoroquinolone use.36,37

Although most published case reports are of ciprofloxacin use,6 this may be an artifact of its high use. Nephrotoxicity may not be entirely dependent on renal elimination,6 and one patient with ciprofloxacin-induced nephrotoxicity did not experience a positive rechallenge after switching to ofloxacin.38 We observed a larger risk of acute kidney injury with ciprofloxacin use, compared with the use of levofloxacin; however, this differential finding was not an a priori hypothesis and should be interpreted with caution until further investigation.

Although fluoroquinolones are thought to induce acute kidney injury through acute hypersensitivity reactions, renin–angiotensin-system blockers affect renal hemodynamics through dilation of the efferent arteriole, reducing intra-glomerular pressure and increasing serum creatinine levels.39 The risk of acute kidney injury with the use of renin–angiotensin-system blockers is thought to increase after a superimposed renal insult, such as that with dehydration or the use of other prescription medications.5,6 Physician monitoring of serum creatinine levels, particularly after starting renin–angiotensin-system blocker therapy, and ascertainment of severe cases of acute kidney injury that require admission to hospital may explain the lack of a signal with renin–angiotensin-system blocker monotherapy.

Limitations

Because of the transient nature of fluoroquinolone use, we used 3 distinct and nonoverlapping definitions of drug exposure, allowing recent and past users to serve as negative controls. We found similar results after removing patients with genitourinary infections from the nested cohort analysis, thereby reducing concerns about confounding by indication.

We used admission to hospital to ascertain cases of severe acute kidney injury; however, we could not assess milder cases that resulted in mild or asymptomatic kidney injury. This could potentially result in an underestimation of the risk of acute kidney injury. We did not have information about the severity of acute kidney injury, nor did we have sufficient power to assess the risk by dosage or duration of use.

Although we conducted a self-controlled analysis, which has implicit control for unmeasured time-invariant confounders, residual confounding, particularly by time-varying covariates, is always a potential concern in observational research.

There is no reason to think that the proposed mechanism for increased risk of acute kidney injury with fluoroquinolone use is specific only to middle-aged and elderly men; however, this limited population is a key limitation of this study. It is possible that these medications may have different associations in other populations, and verifying this will require further study.

Conclusion

We found a twofold increased risk of acute kidney injury requiring hospital admission with the use of fluoroquinolone antibiotics among adult men, using 2 analytic techniques. We did not find increased risk of acute kidney injury with other antibiotics, supporting the hypothesis that this potential adverse association of fluoroquinolones with acute kidney injury is not a class effect of all antibiotics. We found a strong interaction with concomitant use of fluoroquinolones and renin–angiotensin-system blockers, cautioning against the concomitant use of these 2 drug classes. Although it is clear that the risk of death due to serious infections outweighs the risks associated with the use of fluoroquinolones, the potential for acute kidney injury raises the importance of vigilant prescribing.

 

Source:http://www.cmaj.ca

 

Can Fluoroquinolones Cause Acute Kidney Injury?


A case-control study suggests a modest, but significant, association.

 

Case reports have suggested that fluoroquinolone antibiotics occasionally cause acute kidney injury. In this case-control study, researchers used a claims database of 767,000 men (age range, 40–85) to compare fluoroquinolone exposure in 1300 men hospitalized for acute kidney injury (cases) and 13,000 similarly aged men hospitalized for other reasons (controls).

Cases were twice as likely as controls to have received oral fluoroquinolones during the week before hospital admission (8.4% vs. 3.9%); in analyses adjusted for comorbidities, other medications, and indication for fluoroquinolone use, the association between acute kidney injury and current fluoroquinolone use was significant (rate ratio, 2.18). The RR was similar when patients with urinary infections were excluded. In contrast, less-recent fluoroquinolone use and current use of amoxicillin or azithromycin were not associated with acute kidney injury. One additional case of acute kidney injury occurred per 1529 fluoroquinolone users. Excess risk was noted for all three commonly prescribed fluoroquinolones: ciprofloxacin, levofloxacin, and moxifloxacin (Avelox). Combined use of quinolones and renin–angiotensin-system blockers elevated risk further.

Comment

Even if this association between fluoroquinolones and acute kidney injury represents cause and effect, the very small absolute risk should not preclude appropriate prescribing of quinolones. But we should keep the association in mind, particularly when a fluoroquinolone-treated patient unexpectedly is feeling poorly.

Reducing acute kidney injury due to vancomycin in trauma patients


Supratherapeutic vancomycin trough levels are common after trauma and associated with both increased acute kidney injury (AKI) and mortality. We sought to limit the adverse effects of vancomycin in trauma patients through more frequent trough monitoring.

METHODS: Beginning in January 2011, trauma patients treated with vancomycin had trough levels (VT) monitored daily until steady state was reached. Trauma patients admitted from January 2011 to May 2015 (POST) were compared with those admitted from January 2006 to December 2010 (PRE). Inclusion criteria required administration of intravenous vancomycin, admission serum creatinine (SCr), and SCr within 72 hours of highest VT. Acute kidney injury was defined as an increase in SCr of at least 0.3 mg/dL or 50% from admission to post–vancomycin administration. Those in the POST group were prospectively followed up until discharge or death.

RESULTS: Two hundred sixty-three patients met inclusion criteria in the PRE-phase and 115 in the POST-phase. The two groups were similar in age, gender, race, body mass index, pre-existing comorbidities, admission systolic blood pressure, Glasgow Coma Scale, and head Abbreviated Injury Scale. Injury Severity Score was higher in the POST cohort (18 PRE vs. 25 POST, p < 0.001). Compared with PRE, the POST cohort had lower rates of supratherapeutic VT (>20 mg/L) (34.6% PRE vs. 22.6% POST, p = 0.02) and AKI (30.4% PRE vs. 19.1% POST, p = 0.026). After adjusting for confounders, the POST group had a significantly lower risk of AKI with an adjusted odds ratio of 0.457 (p = 0.027). There was a trend toward decreased mortality in the POST cohort, but this did not reach significance (10% PRE vs. 5.2% POST, p = 0.162).

CONCLUSIONS: A reduction in AKI was observed in trauma patients with daily vancomycin trough levels monitored until steady state. Increased awareness regarding closer surveillance of VT in trauma patients may limit the incidence of vancomycin-related nephrotoxicity.

Renal Replacement Therapy — Sooner or Later?


Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit

 

Summary

Acute kidney injury (AKI) is a common and challenging condition to manage in critically ill patients, with many studies over the past decade attempting to better define, characterize, and optimize treatment. In particular, the timing of renal replacement therapy (RRT) in critically ill patients with AKI remains contentious.[1,2]

Gaudry and colleagues sought to determine whether earlier or later initiation of RRT would result in better outcomes in patients who were either mechanically ventilated or on vasopressors (or both) but without an acute indication for dialysis.[3] They randomly assigned 620 patients to initiate RRT either earlier (at randomization) or later (when an acute indication for dialysis arose).

There was no overall difference in 60-day mortality (48.5% vs 49.7%), and 49% of patients in the delayed group never initiated RRT. Catheter-related bloodstream infections were more frequent in the early RRT group (10% vs 5%; P=.03), and diuresis occurred earlier in the delayed RRT group.

The authors concluded that there was no difference in mortality with earlier RRT and that a delayed strategy often averted the need for RRT.

Viewpoint

The major finding of this study is there are no differences in major clinical outcomes attributable to the timing of RRT initiation in critically ill patients, at least in those with the most severe AKI (Kidney Disease: Improving Global Outcomes [KDIGO] classification stage 3)[4] who are mechanically ventilated or on vasopressors (or both). Although those qualifiers could make a difference, it seems unlikely that the timing of RRT initiation would produce substantially better outcomes in different intensive care unit populations, such as patients with less severe AKI or those not on vasopressors.
Regardless, it appears that delayed initiation of RRT is superior in some respects. For example, at the individual patient level, delayed RRT resulted in earlier and more significant urine output (shown in this study particularly as a greater probability of adequate urine output). And from the perspective of providers and health systems, delayed RRT resulted in less use of dialysis by half. For critically ill patients with severe AKI, delayed initiation of RRT is appropriate, pending the development of an indication for more acute initiation.

Acute Kidney Injury May Not Preclude Transplant


In light of reasonable 6-month graft function, clinicians should consider kidney transplant from deceased donors with acute kidney injury (AKI), according to a multicenter study published online March 11 in the American Journal of Transplantation. However, there are risks for kidney discard and delayed graft function (DGF), defined as the need for continued dialysis support in the first week after transplantation.

“There appears to be room to attempt more transplants using these AKI kidneys rather than throwing them away,” senior author Chirag R. Parikh, MD, director of the Program of Applied Translational Research at Yale University School of Medicine, New Haven, Connecticut, said in a university news release.
“The waiting list has grown to over 100,000 patients as thousands more people are wait-listed each year than actually receive a transplant. In addition, the median time it takes for an adult to receive a transplant in the United States increased from 2.7 to 4.2 years between 1998 and 2008, and more than 5,000 people die each year while waiting for a kidney,” Dr Parikh continued.

Using a sample of 1632 donors, Isaac E. Hall, MD, from the Program of Applied Translational Research, Department of Medicine, Yale University School of Medicine, and colleagues examined associations of AKI, defined as increasing admission-to-terminal serum creatinine, with kidney discard, DGF, and 6-month estimated glomerular filtration rate (eGFR).

Compared with donor kidneys with no AKI, kidneys with AKI Network stages 1, 2, and 3 had increased kidney discard risk. Adjusted relative risks were 1.28 (95% confidence interval [CI], 1.08 – 1.52), 1.82 (95% CI, 1.45 – 2.30), and 2.74 (95% CI, 2.00 – 3.75), respectively.

Donor AKI stage was also linked to risk for DGF, with adjusted relative risks of 1.27 (95% CI, 1.09 – 1.49) for stage 1, 1.70 (95% CI, 1.37 – 2.12) for stage 2, and 2.25 (95% CI, 1.74 – 2.91) for stage 3.

Surprisingly, however, AKI was not linked to poor kidney transplant function 6 months later, and AKI stages did not differ significantly in terms of 6-month eGFR. However, recipients with DGF had significantly lower 6-month eGFR (48 mL/minute per 1.73 m2; interquartile range, 31 – 61 mL/minute per 1.73 m2) than those without DGF (58 mL/minute per 1.73 m2; interquartile range, 45 – 75 mL/minute per 1.73 m2; P < .001).
There was a significant, favorable interaction between donor AKI stage and DGF. Six-month eGFR increased in tandem for DGF kidneys with increasing donor AKI (P for interaction = .05).

“What we saw was, with worsening AKI in the donor, the six-month outcome was actually better for recipients who experienced DGF,” Dr Hall said in the news release.

A possible explanation offered by Dr Hall was that kidneys acutely injured in the donor may develop ischemic preconditioning, which could protect the organs from later injury. Alternatively, the successfully transplanted kidneys with AKI may have been of better quality otherwise than the rejected kidneys with AKI, despite adjustment for donor age, comorbidity, and other clinical factors.

The authors note several study limitations, including its observational design with possible residual confounding and lack of complete follow-up data beyond 6 months. Nonetheless, the study authors suggest considering cautious expansion of the donor pool to deceased donors with AKI.

“Even if it only means a few dozen more kidney transplants each year, those are patients who would come off of the waiting list for transplants sooner and have much better survival than continuing on dialysis in hopes of seemingly higher-quality kidney offers, which may never come in time,” Dr Parikh said in the release.

Acute Kidney Injury May Not Preclude Transplant


In light of reasonable 6-month graft function, clinicians should consider kidney transplant from deceased donors with acute kidney injury (AKI), according to a multicenter study published online March 11 in the American Journal of Transplantation. However, there are risks for kidney discard and delayed graft function (DGF), defined as the need for continued dialysis support in the first week after transplantation.

“There appears to be room to attempt more transplants using these AKI kidneys rather than throwing them away,” senior author Chirag R. Parikh, MD, director of the Program of Applied Translational Research at Yale University School of Medicine, New Haven, Connecticut, said in a university news release.

 “The waiting list has grown to over 100,000 patients as thousands more people are wait-listed each year than actually receive a transplant. In addition, the median time it takes for an adult to receive a transplant in the United States increased from 2.7 to 4.2 years between 1998 and 2008, and more than 5,000 people die each year while waiting for a kidney,” Dr Parikh continued.

Using a sample of 1632 donors, Isaac E. Hall, MD, from the Program of Applied Translational Research, Department of Medicine, Yale University School of Medicine, and colleagues examined associations of AKI, defined as increasing admission-to-terminal serum creatinine, with kidney discard, DGF, and 6-month estimated glomerular filtration rate (eGFR).

Compared with donor kidneys with no AKI, kidneys with AKI Network stages 1, 2, and 3 had increased kidney discard risk. Adjusted relative risks were 1.28 (95% confidence interval [CI], 1.08 – 1.52), 1.82 (95% CI, 1.45 – 2.30), and 2.74 (95% CI, 2.00 – 3.75), respectively.

 Donor AKI stage was also linked to risk for DGF, with adjusted relative risks of 1.27 (95% CI, 1.09 – 1.49) for stage 1, 1.70 (95% CI, 1.37 – 2.12) for stage 2, and 2.25 (95% CI, 1.74 – 2.91) for stage 3.

Surprisingly, however, AKI was not linked to poor kidney transplant function 6 months later, and AKI stages did not differ significantly in terms of 6-month eGFR. However, recipients with DGF had significantly lower 6-month eGFR (48 mL/minute per 1.73 m2; interquartile range, 31 – 61 mL/minute per 1.73 m2) than those without DGF (58 mL/minute per 1.73 m2; interquartile range, 45 – 75 mL/minute per 1.73 m2; P < .001).

There was a significant, favorable interaction between donor AKI stage and DGF. Six-month eGFR increased in tandem for DGF kidneys with increasing donor AKI (P for interaction = .05).

“What we saw was, with worsening AKI in the donor, the six-month outcome was actually better for recipients who experienced DGF,” Dr Hall said in the news release.

A possible explanation offered by Dr Hall was that kidneys acutely injured in the donor may develop ischemic preconditioning, which could protect the organs from later injury. Alternatively, the successfully transplanted kidneys with AKI may have been of better quality otherwise than the rejected kidneys with AKI, despite adjustment for donor age, comorbidity, and other clinical factors.

The authors note several study limitations, including its observational design with possible residual confounding and lack of complete follow-up data beyond 6 months. Nonetheless, the study authors suggest considering cautious expansion of the donor pool to deceased donors with AKI.

“Even if it only means a few dozen more kidney transplants each year, those are patients who would come off of the waiting list for transplants sooner and have much better survival than continuing on dialysis in hopes of seemingly higher-quality kidney offers, which may never come in time,” Dr Parikh said in the release.

Modest’ Increased Adverse-Event Risk With Clarithromycin Plus Some Statins


Combining a statin not metabolized by cytochrome P450 3A4 (CYP3A4) with the antibiotic clarithromycin is associated with an increased risk of adverse events, according to the results of a new analysis. Individuals taking rosuvastatin (Crestor, AstraZeneca), pravastatin, or fluvastatin with clarithromycin had a 65% increased risk of hospitalization for acute kidney injury, a more than twofold increased risk of hyperkalemia, and a 43% increased risk of all-cause mortality compared with individuals taking non-CYP3A4-metabolized statins and azithromycin[1].

The absolute increase in the risk of adverse events was small—less than 1%. Still, researchers say the “modest increase” in the number of deaths and hospital admissions among the older adults studied may reflect statin toxicity.

“The population impact of this preventable drug–drug interaction can be considered in the context of the high frequency of clarithromycin and statin co-prescription,” write Dr Daniel Li (University of Western Ontario, London) and colleagues December 22, 2014 in CMAJ. In Canada, rosuvastatin was the second most commonly prescribed drug in 2010.

Co-Prescription of Clarithromycin and Rosuvastatin

In their report, the researchers explain that clarithromycin is an antibiotic that can inhibit organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3). “Several haplotypes of commonly occurring genetic polymorphisms in the liver-specific OATP1B1 were associated with increased concentrations of rosuvastatin and pravastatin,” they note.

In total, 51 523 individuals were prescribed clarithromycin and 52 518 were prescribed azithromycin, an antibiotic that does not inhibit CYP3A4, OATP1B1, or OATP1B3. Regarding statin therapy, 76% were treated with rosuvastatin, 21% with pravastatin, and 3% with fluvastatin.

30-Day Adverse-Event Outcomes

Outcome Number of events, clarithromycin) Number of events, azithromycin Absolute risk difference, % Adjusted relative-risk (95% CI)
Hospitalization for rhabdomyolysis 13 6 0.02 2.27 (0.86–5.96)
Hospitalization for acute kidney injury 175 122 0.11 1.65 (1.31–2.09)
Hospitalization for hyperkalemia 33 18 0.03 2.17 (1.22–3.86)
All-cause mortality 200 155 0.09 1.43 (1.15–1.76)

Li et al’s finding of increased risk with rosuvastatin, pravastatin, and fluvastatin when taken with clarithromycin can’t be explained by the inhibition of CYP3A4, as the drugs are not metabolized by this pathway. “A growing body of evidence highlights the role of transporter-mediated mechanisms in such interactions, notably the inhibition of human OATPs,” they write.

The US Food and Drug Administration recommends the use of non-CYP3A4-metabolized statins in patients taking drugs that inhibit CYP3A4. However, “unintended adverse events may still occur, possibly because of additional mechanisms of drug interactions independent of the CYP3A4 pathway,” say Li and colleagues. “To prevent toxicity, the use of azithro­mycin or another antibiotic that does not interact with statins can be considered.”

CRP Levels Tied to Statin Effects on Contrast Nephropathy in PRATO-ACS Analysis


In patients with non–ST-segment-elevation ACS (NSTE-ACS) who are about to undergo cardiac catheterization, early administration of high-dose rosuvastatin protects against contrast-induced acute kidney injury (AKI), especially in those with higher baseline levels of C-reactive protein (CRP), new research shows[1].

“In this series of NSTE-ACS patients, our study confirms previous clinical and experimental studies [showing that] high levels of systemic and/or local (renal) inflammation may contribute to the development of acute kidney injury after contrast medium exposure,” Dr Anna Toso (Santo Stefano Hospital, Italy) told heartwire in an email.

Moreover, it “adds another piece of information—that is, that ‘the higher the baseline CRP levels, the higher the [contrast-induced] AKI and adverse renal and cardiovascular event rates and the higher the benefits of on-admission rosuvastatin administration.’ ”

Measuring baseline CRP levels—and correlating this with other comorbidities, levels of other inflammatory markers, and the extent of myocardial damage—can identify the NSTE-ACS patients who have a higher risk of contrast-induced nephropathy, she noted.

The findings, based on data from the Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Nephropathy and Myocardial Damage in Patients With Acute Coronary Syndrome Undergoing Coronary Intervention (PRATO-ACS) study, were published online December 16, 2014 in JACC: Cardiovascular Interventions.

Looking at CRP Levels in PRATO-ACS

Previously in the PRATO-ACS randomized study, the researchers showed that statin-naive patients with NSTE-ACS who were about to undergo coronary angiography, in addition to receiving standard preventive measures (intravenous hydration, use of low- or iso-osmolar contrast media, and reduced dosages of contrast agents), early high-dose rosuvastatin reduced the risk of contrast-induce AKI and improved short- and mid-term clinical outcomes.

Other studies have suggested that systemic inflammation (evidenced by elevated CRP levels) could make the kidneys more vulnerable to local inflammation caused by iodinated contrast medium, which contributes to the development of contrast-induced acute kidney injury.

Thus, the researchers aimed to investigate how inflammation might explain the pathogenesis of AKI in the PRATO-ACS population.

PRATO-ACS had randomized 504 statin-naive patients scheduled for early invasive angiography to a statin group (40-mg rosuvastatin on admission followed by 20 mg/day) or a control group with no statins. The primary outcome was contrast-induced AKI, defined as an increase in serum creatinine of >0.5 mg/dL or >25% over the baseline value within 72 hours after the administration of contrast agent.

The study participants were stratified into tertiles according to their baseline CRP levels: <2.7 mg/L; 2.7 to <7.5 mg/L; and >7.5 mg/L.

Overall, 55 patients developed contrast-induced AKI: 17 of 252 patients (6.7%) in the statin group and 38 of 252 patients (15.1%) in the control group (odds ratio after adjustment for CRP 0.41, 95% CI 0.22–0.77; P=0.005).

Contrast-induced AKI increased with increasing tertiles of baseline CRP. Of the 55 patients who developed this complication, nine patients had the lowest CRP levels; 14 patients had intermediate CRP levels; and 32 patients had the highest levels (P=0.0001).

The beneficial effect of rosuvastatin was significant for patients in the highest CRP tertile (odds ratio 0.20, 95% CI 0.07–0.54; P=0.002).
Rosuvastatin treatment was followed by improved short-term outcomes at 30 days (acute renal failure requiring dialysis, persistent renal damage, all-cause mortality, MI, or stroke) and mid-term outcomes (death or MI at 6 months), especially in patients with high systemic inflammation at baseline.

Among patients who were in the highest baseline tertile of CRP, compared with control patients, those who received early rosuvastatin had a significantly lower rate of adverse events at 30 days (7.2% vs 17.4%, P=0.043); there was also a trend toward better outcomes at 6 months (6.02% vs 13.04%, P=0.12).

The group concludes: “Whether or not these benefits are due to the anti-inflammatory properties of rosuvastatin cannot be established on the basis of this study, but our findings represent a further reason in favor of early use of high-dose statin therapy and assessment of [CRP] in ACS patients.”