Meta-Analysis

Evaluation of Short-Term Changes in Serum Creatinine Level as a Meaningful End Point in Randomized Clinical Trials

Steven G. Coca, Azadeh Zabetian, Bart S. Ferket, Jing Zhou, Jeffrey M. Testani, Amit X. Garg and Chirag R. Parikh
JASN August 2016, 27 (8) 2529-2542; DOI: https://doi.org/10.1681/ASN.2015060642

Abstract

Observational studies have shown that acute change in kidney function (specifically, AKI) is a strong risk factor for poor outcomes. Thus, the outcome of acute change in serum creatinine level, regardless of underlying biology or etiology, is frequently used in clinical trials as both efficacy and safety end points. We performed a meta-analysis of clinical trials to quantify the relationship between positive or negative short–term effects of interventions on change in serum creatinine level and more meaningful clinical outcomes. After a thorough literature search, we included 14 randomized trials of interventions that altered risk for an acute increase in serum creatinine level and had reported between–group differences in CKD and/or mortality rate ≥3 months after randomization. Seven trials assessed interventions that, compared with placebo, increased risk of acute elevation in serum creatinine level (pooled relative risk, 1.52; 95% confidence interval, 1.22 to 1.89), and seven trials assessed interventions that, compared with placebo, reduced risk of acute elevation in serum creatinine level (pooled relative risk, 0.57; 95% confidence interval, 0.44 to 0.74). However, pooled risks for CKD and mortality associated with interventions did not differ from those with placebo in either group. In conclusion, several interventions that affect risk of acute, mild to moderate, often temporary elevation in serum creatinine level in placebo–controlled randomized trials showed no appreciable effect on CKD or mortality months later, raising questions about the value of using small to moderate changes in serum creatinine level as end points in clinical trials.

AKI, a current consensus definition of acute mild to moderate rapid change in serum creatinine, is independently associated with incident and progressive CKD and long-term mortality.1–3 Multiple studies have shown that AKI is a potent risk factor for these outcomes and that there is a dose-response relationship between the degree of change in serum creatinine and the risk for subsequent CKD.1–3 These clinical findings support the extensive data from experimental animals that show that isolated episodes of AKI caused by ischemia-reperfusion injury lead to chronic kidney fibrosis, salt-sensitive hypertension, and CKD.4–8

Although not all changes in creatinine represent true kidney injury, changes in creatinine are still used as the primary way to diagnose AKI in 2015. Moreover, although some recent observational studies with more granular data have shown that patients with acute increases in creatinine can experience better outcomes and large efforts have emerged to incorporate and use urinary biomarkers of kidney injury in current diagnostic criteria, the outcome of acute or subacute changes in serum creatinine is still frequently used in clinical trials as both efficacy and safety end points. Its use as an end point continues, despite the fact that changes in creatinine do not reflect the underlying biology and do not directly represent or influence how a patient feels, functions, or survives. Consistent with this concept, the Food and Drug Administration (FDA) has stated that a successful intervention for ARF/AKI must, in addition to reducing in-hospital AKI, improve long–term kidney function or hard end points, such as CKD or mortality.9 Thus, the key step in validating this outcome of acute or subacute changes in creatinine as a surrogate is to examine in randomized, controlled trials (RCTs) whether interventions that alter the risk of the surrogate outcome also have similar directional effects on more meaningful outcomes, which in this case, would include CKD (permanent versus temporary reductions in kidney function) and mortality.

We performed a systematic review and meta-analysis of RCTs to determine whether interventions that significantly changed serum creatinine resulted in a commensurate reduction or increase in the risk for CKD and death.

Results

Our search identified 1003 citations for the initial screening. On the basis of title and abstract review, we excluded 370 citations. After a detailed review of these citations, we further excluded 629 studies for various reasons (Figure 1). We also screened the potential relevant articles that were found through browsing the reference lists of the related articles and reviews and identified 10 additional articles eligible for our systematic review. After a careful and thorough screening process, we included 14 trials in our systematic review. The characteristics of these trials are listed in Tables 1 and 2.

Figure 1.
Figure 1.

Flow diagram of systematic trial selection process. The final selection resulted in 14 trials.

View this table:
Table 1.

Summary of trials of interventions that either increased or decreased the risk for acute elevation in serum creatinine

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Table 2.

Renal end points and baseline characteristics of study subjects in the trials of interventions that either increased or decreased the risk for acute elevations in serum creatinine

Trials were grouped on the basis of the type of intervention. First, we grouped the interventions that increased the risk for AKI (all were trials of dual or add–on renin-angiotensin-aldosterone system [RAAS] blockade).10–20 In total, 48,436 patients were enrolled in seven trials in this group. The mean follow-up time in these trials was 30 months, with a range of 11–56 months, and all were multicenter. Four trials were exclusively in patients with heart failure (the ASTRONAUT,13,14 EMPHASIS-HF,17,18 TOPCAT,11 and Val-HEFT15,16 Trials), one was exclusively in patients with diabetic nephropathy (the NEPHRON-D10 Trial), and two studied high–risk cardiovascular populations (the ALITITUDE12 and ONTARGET19,20 Trials). Second, we grouped the interventions that decreased the risk of AKI (off–pump cardiac surgery, vasodilators [atrial natriuretic peptide],21–23 N-acetylcysteine,24 higher mean arterial pressure in septic shock,25 nonchloride-containing fluids,26 and left ventricular end diastolic pressure–guided fluid administration).27 In total, 5817 patients were enrolled in these trials, and duration of follow-up was 12 months for four trials, 9 months for the N-Acetylcysteine Trial, 6 months for the POSEIDON Trial, and 3 months for the SEPSISPAM Trial. Only two of seven trials that reduced AKI were multicenter.

Across all trials, the criteria for meeting the categorical definition of AKI by acute changes in serum creatinine varied in terms of the magnitude from mild increases in serum creatinine (e.g., ≥0.3 mg/dl) to severe (need for acute RRT) (Table 2). CKD definitions for each trial varied as well (Table 2).

In terms of assessing risk of bias among included studies, most trials had good methodologic quality (Supplemental Figures 1 and 2). All trials had low risk of selection bias because of random sequence generation, although the majority did not mention any specific methods for allocation concealment. Three trials did not ensure blinding of subjects and/or study staff; however, because of the nature of the interventions, double blinding seemed impossible in these trials (off-pump surgery, higher mean arterial pressure target, and low chloride fluids). Blinding of outcome assessment was reported in all included studies, except the study by Yunos et al.26 None of the included trials seemed to have selective reporting bias. Although we did not have access to the original protocol for most of these trials, we found that they reported the results on all of the outcomes listed in their methods sections.

Interventions that Increased Risk of AKI

Trials with dual or add–on RAAS blockade as the intervention increased the risk for acute increase in serum creatinine by 52% (n=7 trials; pooled relative risk [RR], 1.52; 95% confidence interval [95% CI], 1.22 to 1.89). CKD was assessed as a categorical end point in four of seven trials in this group (Table 2). The pooled risk for CKD in the intervention arm was not different from that of placebo after 2.6 years of follow-up (pooled RR, 0.98; 95% CI, 0.82 to 1.18). Likewise, there was no difference in the risk for death in seven trials that assessed long–term mortality outcome after 2.5 years of follow-up (pooled RR, 0.99; 95% CI, 0.92 to 1.06) (Figure 2).

Figure 2.
Figure 2.

Pooled risk ratios for categorical end points of (A) AKI, (B) CKD, and (C) mortality between intervention and control groups in trials that increased the risk for AKI. The pooled risk for AKI was increased by 52%, while the subsequent pooled risks for CKD and mortality were not influenced. ALTITUDE, Aliskiren Trial in type 2 diabetes using cardiorenal end points; ASTRONAUT, Aliskiren Trial on acute heart failure outcomes; EMPHASIS-HF, Eplerenone in Mild Patients Hospitalization and Survival Study in hart failure; M-H, Mantel–Haenszel; NEPHRON-D, Veterans Affairs Nephropathy in diabetes; ONTARGET, ongoing telmisartan alone and in combination with Ramipril Global End point Trial; TOPCAT, treatment of preserved cardiac function heart failure with an aldosterone antagonist; Val-HEFT, Valsartan Heart Failure Trial.

Interventions that Lowered Risk of AKI

We were able to identify seven trials that showed a statistically significant reduction in the proportion with AKI defined by acute increase in serum creatinine with a preventive therapy and also, reported on CKD or death outcomes at 3 months or beyond (Table 2). AKI was reduced from 24.8% with control to 17.1% with the interventions (pooled RR, 0.57; 95% CI, 0.44 to 0.74). Despite the 43% reduction in the incidence of acute increase in serum creatinine, the outcome of CKD subsequent to randomization was not different between the intervention and control groups after an average of 11 months follow-up (pooled RR, 0.87; 95% CI, 0.52 to 1.46). Likewise, there was no difference in all-cause mortality (pooled RR, 0.97; 95% CI, 0.82 to 1.16) (Figures 2 and 3).

Figure 3.
Figure 3.

Pooled risk ratios of (A) AKI, (B) CKD, and (C) mortality between intervention and control groups in trials with therapies that reduced the risk of AKI. The pooled risk for AKI was decreased by 43%, while the subsequent pooled risks for CKD and mortality were not concomitantly reduced sufficiently to reach statistical significance. CORONARY, coronary artery bypass grafting surgery off- or on-pump revascularisation study; M-H, Mantel–Haenszel; NIU-HIT CKD, Nihon University Working Group Study of low-dose hANP infusion therapy during cardiac surgery for CKD; NU-HIT LVD, Nihon University Working Group Study of low-dose hANP infusion therapy during cardiac surgery for left ventricular dysfunction; POSEIDON, prevention of contrast renal injury with different hydration strategies; SEPSISPAM, Sepsis and Mean Arterial Pressure Trial.

Sensitivity Analyses

We performed sensitivity analyses by subgroup analyses on five study-level variables: the length of follow-up, the baseline proportion of subjects with CKD (eGFR≥60 versus <60 ml/min per 1.73 m2), sample size (>3000 and <3000 subjects), the type of study setting (hospitalized versus ambulatory), and the type of add–on RAAS antagonist drug (angiotensin–converting enzyme inhibitor/angiotensin II receptor blockers versus aldosterone antagonists versus renin inhibitors) (Table 3). These subgroup analyses were only performed on the trials of agents that increased serum creatinine, because there was not enough variation in any of these variables in trials of the kidney-protective agents. There was no meaningful difference in the overall outcomes when assessing the effects by any of five subgroups (Table 3). The bivariate meta-analysis showed a nonsignificant relationship between the size of the treatment effect on AKI and CKD in the trials of agents that increased serum creatinine (correlation coefficient, −0.42; 95% CI, −0.94 to 0.67) (Supplemental Figure 2A). However, there was a positive association between the treatment effects on AKI and CKD in trials of agents that decreased serum creatinine (correlation coefficient, 0.88; 95% CI, 0.61 to 0.97) (Supplemental Figure 2B). Finally, when we excluded one study with low quality26 from our analysis, the results were not changed significantly.

View this table:
Table 3.

Pooled RRs by prespecified subgroups for acute increase in serum creatinine, CKD, and mortality in trials of agents that increased risk for AKI (acute elevation in serum creatinine)

Discussion

In this meta-analysis of 14 RCTs that used interventions that influenced the incidence of AKI or acute changes in serum creatinine, we were unable to detect differences in the outcomes of CKD or mortality on follow-up, despite large effect sizes of a ≥50% increase or 40% decrease in the AKI end point. These findings challenge the use of acute or subacute changes in serum creatinine as a safety end point and are consistent with the viewpoint by the FDA to not approve new therapies that solely ameliorate or reduce the proportion of patients with acute changes in creatinine but do not provide evidence for benefit for long–term kidney function or mortality.

Although the changes in creatinine were of mild to moderate degree in the trials, these results contradict those from observational studies that nearly universally show strong dose–dependent independent associations between even very small changes in serum creatinine with CKD and long-term mortality.1,28,29 Moreover, the findings here may not represent the ultimate fate for other potential interventions to prevent AKI; they do place the burden of proof on future investigations to show that a drug or strategy that influences the incidence or severity of changes in creatinine will also affect clinical outcomes, such as CKD and mortality.

Several studies in experimental animals have shown that a single isolated episode of ischemia-reperfusion injury that leads to transient elevations in serum creatinine leads to chronic fibrosis, salt-sensitive hypertension, and CKD in these animals.4–8 Moreover, observational studies, even examining changes in serum creatinine changes as small as 0.1 mg/dl29 or 1%–24% increase,28 show a 40%–100% increased risk, even after adjusting for multiple demographic, clinical, and laboratory variables, of both ESRD and long-term mortality. Increases in serum creatinine of greater magnitude generally have a stronger association with these end points30–32; thus, it is a widely held belief that acute declines in kidney function/AKI are almost certainly causally related with these outcomes.33

Translation of these findings from experimental animals and observational studies to trials in humans is difficult. First, it is unethical to randomize humans to suffer from AKI, like one does to rodents in the laboratory. Second, RCTs of widely accepted nephrotoxic agents (e.g., aminoglycosides, amphotericin, hetastarch, and cisplatin) have not followed participants to obtain data on long–term renal function or survival. However, the recent publication of several large RCTs of dual RAAS blockade allows for examination of a larger body of evidence for several interventions that may induce acute increases in serum creatinine. Despite the potential for largely hemodynamic–induced changes in kidney function, these episodes of clinical AKI while on an RAAS inhibitor are still worrisome to the scientific community. In fact, the NEPHRON-D Trial was terminated, in part, for safety concerns because of the 70% increased risk for AKI with dual RAAS blockade, despite the fact that post hoc analyses showed that the risk for clinical end points was indeed lower in those with AKI.10 Also, in this regard, we have shown that the propensity for experiencing increase in serum creatinine postcardiac surgery was increased when RAAS antagonists were administered perioperatively; however, there was not a commensurate increase in the kidney injury as measured by several urinary biomarkers.34,35

In contrast, although no agent has been FDA approved to prevent or ameliorate AKI, there are at least seven trials published over the past 10 years included in this review that administered agents or strategies to prevent clinical AKI that not only decreased the proportion of participants with acute increase in serum creatinine but also, evaluated CKD and mortality at least 3 months after enrollment. Some of the trials did not show a large effect size on the proportion with elevations in serum creatinine (e.g., the CORONARY Trial: 17% RR reduction).23 However, despite a pooled decrease of 43% for the acute decline in the kidney function end point by these various agents/strategies, there was readily detectable reduction in the pooled incidence for CKD and mortality. Because most reasonable effect sizes that can be expected for any new agent would be more in the realm of 20%–25% reduction,36 the scientific and clinical community would generally be very satisfied if any single agent was able to decrease AKI by this degree in a phase 2 trial. The lack of commensurate movement of the hard outcomes in the direction of the intervention that acutely influenced serum creatinine has implications for the design of future clinical trials of agents/strategies that consider end points, such as AKI, that are solely on the basis of changes in serum creatinine. This would be true whether the end point is used as either a safety or stopping outcome or a phase 2 end point of agents meant to prevent or treat AKI, because it does not seem that inducing changes in serum creatinine influences future outcomes. In addition, these finding suggest that the independent associations shown in the observational studies between acute change in serum creatinine decline and CKD/ESRD/death were largely because of confounding or various biases. The degree of confounding that is present in observational studies is most evident from the analyses of the CORONARY Trial,23 which showed the tremendous difference in the risk for future CKD when treated as an observational cohort instead of as an RCT.

It should be noted, however, that it is very difficult to show that affecting AKI with an intervention will affect long-term outcomes. For prevention trials, where the incidence of AKI averaged about 25%–30% in the control group, the RR reduction of 25% would mean an 18%–20% incidence in the treatment group. This 7%–10% absolute risk reduction, in the best case scenario, translates into a 3%–5% difference in the incidence of CKD or death, assuming that the etiologic fraction of AKI for these outcomes is approximately 50%. However, the true etiologic fraction or proportion of treatment effect is likely much lower (<30%), meaning that the 7%–10% absolute risk reduction in AKI will only translate into a 2%–3% difference in hard outcomes and a massive trial would be required to detect this signal with statistical significance. The point estimate for CKD in the trials that reduced AKI was 0.87, meaning that it is possible that there is a 13% relative risk reduction. In addition, bivariate meta-analysis revealed the presence of a strong positive correlation between the individual treatment effects of agents that acutely decreased serum creatinine on the categorical outcomes of AKI and CKD (r=0.88). Despite this robust correlation, however, the pooled 95% CI for CKD still clearly crossed one, despite the inclusion of >5000 participants in these trials. Assuming the study of a total population with a similar 24% incidence of AKI in the control groups, then one would need to intervene with an agent that reduced AKI by ≥43% in a total of 17,578 participants to witness a statistically significant difference in CKD (assuming a proportion of treatment effect of 30%). A trial of this size is unlikely to be easily accomplished. The discrepancy between the bivariate analysis and the overall pooled results shows how challenging it is to have a statistically significant effect when an intervention is applied to >75% of patients who do not experience the initial primary event (AKI) and how there is additional dilution in contribution over time of the intervention for the final multifactorial outcome of CKD.

There are some limitations to these analyses. First, there were insufficient numbers of trials of AKI reducers to pool by type of intervention; thus, various renoprotective agents and strategies had to be grouped together, despite the vastly different mechanisms of action. Second, the definitions for AKI and CKD varied across studies, and moreover, we did not have data on CKD as a categorical outcome in three of seven trials of dual RAAS blockade (Val-HEFT, EMPHASIS-HF, and TOPCAT Trials). However, post hoc analysis of the Val-HEFT and EMPHASIS-HF Trials showed that, after the early decline in eGFR with dual RAAS blockade, there was no increased rate of eGFR decline over time as a continuous end point in the dual RAAS group to 3 years.16,17 The data on long–term kidney function from the TOPCAT Trial will likely be forthcoming in the near future (the study was only recently published). Third, all interventions in the trials that were examined have multiple pathways of potential efficacy and harm. It is possible that the effect on AKI by the agent has other effects on CKD or mortality that result in the final sum of effect seeming to be null (when in fact, a pure AKI inducer or reducer without any other effects may have influence on CKD or mortality). Fourth, the AKI reducers were generally studied in small trials that have not been reproduced by several multicenter large trials. Thus, the signals for efficacy for AKI may have been spurious. Fifth, we had hoped to examine CKD and long–term mortality end points associated with true nephrotoxic agents, such as hetastarch, aminoglycosides, and amphotericin; however, we could not find any trials that examined the CKD and mortality end points beyond 3 months for these agents. Thus, we could only examine trials of add–on RAAS therapy, in which it was unclear how much true kidney injury was present. None of the trials assessed biomarkers of kidney injury to help discern the degree of functional declines in kidney function versus the amount of true tubular injury prevented/induced by the interventions. Sixth, the mean length of follow-up of these 13 trials was only 2.5 years (and was ≤12 months for the trials that aimed to improve kidney function). This may seem to be a somewhat short time period for the acute episode to translate into the increased risk for CKD and death. However, in observational studies, the increased risk for these sequelae is seen within 3–6 months after the initial change in kidney function.1 Moreover, in the CORONARY Trial population,23 when the association between acute change in creatinine and 1-year eGFR was assessed as a cohort and not in the arms of the randomization, the adjusted odds ratio 3.4 (95% CI, 2.7–4.3) for developing a chronic decline in eGFR (i.e., CKD) in those with versus without AKI was 3.1. Thus, length of follow-up does not seem to be responsible for lack of detection of a signal.

Going forward, clinical trials that examine agents that either protect or harm the kidney can be improved in several ways. Other measures of kidney injury, such as serum and urinary biomarkers of kidney injury, inflammation, and fibrosis, should be considered concomitantly along with acute changes in serum creatinine. These biomarkers can detect subclinical kidney injury, despite lack of change in kidney function as assessed by serum creatinine.37–39 We and others have shown dissociation between measures of function (serum creatinine) and kidney injury (urinary biomarkers).34,40 In addition, instead of one peak value of creatinine serving as the input for the AKI–related end point, use of measures of kidney function that better summate the overall burden of acute decline in function, such as the duration of rise in serum creatinine,41,42 or continuous metrics, such as the average change in creatinine relative to baseline,43 may improve the ability to detect efficacy or harm signals from the agents.

In summary, this systematic review identified seven trials that collectively increased the risk for acute increase in serum creatinine by 52% and seven additional trials that collectively decreased the risk for acute increase in serum creatinine by 43%, yet there were no tangible differences in the end points of subsequent CKD or death despite the immediate impact of the interventions on AKI in both directions. These findings have implications for drug development as well as early stoppage of trials that may induce acute changes in serum creatinine but otherwise, have potential long–term benefits for the kidney or other organs in terms of injury and fibrosis.

Concise Methods

We conducted a systematic review and meta-analysis of RCTs that reported on both the incidence of acute change in serum creatinine and subsequent CKD (or change in GFR) or mortality between the treatment and control groups. We searched Medline (Pubmed), the Cochrane Central Register of Controlled Trials, Embase (Ovid), and the McMaster Acute Kidney Injury Filter44 from inception of each of the databases to May of 2014. We used search terms and filters that included the MeSH terms of AKI, CKD, mortality, and RCTs (Supplemental Table 1).44 We also searched the reference lists of potentially relevant systematic reviews and trials. The search was limited to studies on human subjects without language restriction.

Study Selection

We included trials that reported the incidence of those with acute change in serum creatinine along with CKD and mortality end points as primary, secondary, or adverse outcomes. Inclusion criteria included the following: (1) RCT or quasi-randomized trial, (2) a statistically significant difference in the incidence of acute change in serum creatinine between the arms of the trial (either higher or lower depending on the intervention), (3) a biologically plausible direct acute effect on kidney function, and (4) assessment of CKD or GFR and/or death at least 3 months after the initiation of the intervention. We excluded trials with a sample size of <100 total participants and trials in kidney transplant recipients (because of problems of AKI definitions in those with ESRD and falling creatinine post-transplant) as well as duplicate reports, observational studies, and review articles. We used a standardized protocol to screen the literature and identify trials for our analysis. Two authors (S.G.C. and A.Z.) independently reviewed the articles and resolved disagreements by discussion.

Data Extraction and Risk of Bias Assessment

We used a standardized data abstraction form for description of the trials that included the title of the study, authors, year of publication, trial design, number of participants, and their baseline characteristics. We also abstracted the type of intervention and the incidence of primary and secondary outcomes of interest in the control and treatment groups. We analyzed the quality of the studies and used the Cochrane Collaboration’s tool for assessing risk of bias: randomization method; allocation concealment; blinding of participants, staff, and assessors; selective reporting (for renal end points); and description of withdrawals.

Data Synthesis and Analyses

The pooled RRs for acute change in serum creatinine, CKD, and mortality for treatment versus control were computed using Mantel–Haenszel statistics.21–26 For the SEPSISPAM Trial, we examined only the incidence of AKI and mortality in the prespecified subgroup of patients with hypertension, and it was stated in the introduction that it was those with chronic hypertension who would most likely benefit from a higher BP target.25 Interstudy heterogeneity was calculated using the chi-squared test and the I2 statistic. Statistical calculations and graphs were made using the Review Manager, version 5.1 (The Nordic Cochrane Center; The Cochrane Collaboration, Copenhagen, Denmark). We further explored the diversity in study results and possible association of study-level factors by performing subgroup analyses. We performed a bivariate random effects meta–analysis to evaluate the correlation between treatment effects on AKI and CKD for trials that increased risk for AKI and trials that decreased this risk. Because within-study correlations were unknown, we used an alternative model as suggested by Riley et al.45 as implemented in Stata 12.1 (StataCorp., College Station, TX).

Disclosures

None.

Acknowledgments

S.G.C. was supported by National Institutes of Health (NIH) Career Development Award K23DK080132 and NIH Grant R01DK096549. S.G.C., A.X.G., and C.R.P. are members of the Assess, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury Consortium sponsored by NIH Grant U01DK082185. C.R.P. is supported by NIH Grant K24DK090203. C.R.P. was also supported by O’Brien Kidney Center Grant P30 DK079310-07.

Footnotes

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Evaluation of Short-Term Changes in Serum Creatinine Level as a Meaningful End Point in Randomized Clinical Trials
Steven G. Coca, Azadeh Zabetian, Bart S. Ferket, Jing Zhou, Jeffrey M. Testani, Amit X. Garg, Chirag R. Parikh
JASN Aug 2016, 27 (8) 2529-2542; DOI: 10.1681/ASN.2015060642
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