Thyroid hormones for acute kidney injury: Cochrane systematic review

Abstract

Background

Acute kidney injury (AKI), which is common in hospitalised patients, is associated with significant morbidity and mortality. Despite recent advances in treatment, AKI outcomes have not changed substantially during the past four decades, and incidence is increasing. There is an urgent need to explore novel therapeutic agents and revisit some older drugs to review their roles in the management of AKI. Although thyroid hormone therapy has shown promise in experimental animal studies, clinical efficacy and safety have not been systematically assessed for the management of people with AKI.

Objectives

To evaluate the benefits and harms of thyroid hormones for the treatment of hospitalised adults with AKI of any aetiology.

Search methods

We searched the Cochrane Renal Group's Specialised Register, CENTRAL, MEDLINE, and EMBASE. We also checked the reference lists of retrieved studies and articles.

Date of search: November 2012

Selection criteria

Randomised controlled trials (RCTs) and quasi-RCTs (in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) that compared any dose or form of thyroid hormone therapy alone or in combination with other agents compared with placebo or supplemental treatment (such as furosemide, dopamine, or atrial natriuretic peptide) in adult AKI patients.

Data collection and analysis

Two authors independently assessed study quality and extracted data. The quality of included studies was assessed using the Cochrane Collaboration's risk of bias assessment tool. For dichotomous outcomes (death, need for renal replacement therapy (RRT), progression to end-stage kidney disease (ESKD)), we planned to express results as risk ratios (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (length of hospital stay, durations of AKI and RRT), we planned to use the mean difference (MD).

Main results

Two studies, enrolling 97 participants, met our inclusion criteria. The studies differed significantly in terms of study populations, natural history of AKI (multifactorial AKI in patients with native kidneys versus delayed graft function associated with acute tubular necrosis in transplant recipients), and study interventions; hence, data were not meta-analysed. One study reported a significant increase in the risk of all-cause mortality associated with thyroid hormone interventions compared with placebo (59 participants, RR 3.32, 95% CI 1.21 to 9.12); no deaths were reported in the other study. Both studies reported no significant difference in the need for RRT associated with thyroid hormone therapy when compared to placebo. Neither study reported incidence of progression to ESKD. There was a significantly longer duration of AKI (MD 2.00 days, 95% CI 0.18 to 3.82) and RRT (5.00 days, 95% CI 2.05 to 7.95) associated with thyroid hormone therapy compared with placebo in one study; no differences in durations of AKI (MD 2.00 days, 95% CI -3.53 to 7.53) and RRT (MD 2.00 days, 95% CI -2.36 to 6.36) were noted in the other study. One study reported similar lengths of stay in the intensive care unit and hospital in both intervention and control arms (MD -0.20 days, 95% CI -8.17 to 7.77); the other did not report this outcome. No adverse events were noted to be associated with thyroid hormone therapy in either study. Adequate data were not available to assess changes in kidney function or numbers of RRT sessions. Both included studies were small and methodological quality was suboptimal.

Authors' conclusions

We found a paucity of large, high quality studies to inform analysis of thyroid hormone interventions for the treatment of people with AKI. Current evidence suggested that thyroid hormone therapy may be associated with worse outcomes for patients with established AKI; therefore, its use for these patients should be avoided. The role of thyroid hormone therapy in preventing AKI has not been adequately investigated and may be considered in future clinical studies.

Author(s)

Nigwekar Sagar U, Strippoli Giovanni FM, Navaneethan Sankar D

Summary

Thyroid hormones for acute kidney injury

Acute kidney injury (AKI) has a number of causes including infection, trauma, kidney stones, toxic drugs, or acquired during hospital treatment. People with AKI suddenly lose kidney function leading to poor urine output and retention of body wastes. In every 1000 people who are discharged from hospital about 30 are diagnosed with AKI; about 6% of all critically ill patients have AKI. Many people with AKI will die from the disease.

AKI treatment aims to restore kidney function using drugs, kidney dialysis, or both. Experimental animal studies of thyroid hormone therapy (a drug treatment) held promise, but uncertainty existed about its effectiveness and safety for people.

We searched the medical literature to investigate the benefits and harms of thyroid hormone therapy for adults with AKI of any cause who were in hospital and found two studies that involved 97 people. There were many differences between study populations, particularly participants' kidney history (some had their own kidneys; others had transplants); and the drugs that were investigated. These differences meant that we were unable to statistically evaluate (meta-analyse) study data.

We found that risk of death from any cause was much higher among people with AKI who received thyroid hormone therapy compared with those who received placebo in one study; no deaths were reported in the second study. Thyroid hormone therapy was found to be no better or worse than placebo in changing patients' needs for kidney dialysis or transplant. People with AKI who received thyroid hormone therapy needed dialysis for longer than those who received placebo in one study, but no differences in AKI and dialysis durations were noted in the other. Lengths of stay in intensive care units and hospital were similar in both those who received thyroid hormone therapy and placebo in one study; but not reported in the other study. Neither study reported if any participants progressed to end-stage kidney disease. We had planned to analyse changes in kidney function and numbers of dialysis sessions, but data reporting was insufficient to make assessments.

The included studies were few in number, small in size, and low in methodological quality. The available evidence suggested that use of thyroid hormone therapy was associated with worse outcomes in patients with established AKI, and therefore, use of these therapies should be avoided for these people.

Reviewer's Conclusions

Implications for practice

There are no large, high quality studies that address the role of thyroid hormone treatment for people with AKI. Current available evidence suggests that use of thyroid hormone therapy could be associated with worse outcomes in patients with established AKI. This effect may be mediated by the sustained suppression of serum thyroid stimulating hormone levels caused by administering thyroid hormone therapy. Thus, thyroid hormone therapy for the treatment of people with AKI should be avoided.

Implications for research

Given that evidence has not been identified to indicate that thyroid hormone therapy for people with AKI confers beneficial effects, future studies should consider investigation of other interventions. If attempted, future studies of thyroid hormone therapy for people with established AKI should carefully examine end-points of harm. The role of thyroid hormone therapy in preventing AKI was not assessed in this review. Future investigators may consider assessing the safety and efficacy of thyroid hormone therapy in this capacity. Given the results from intervention studies conducted in people with AKI, any future prevention studies should pay particular attention to safety issues. Mortality and RRT can be competing outcomes in the critically ill population, and it is possible that some patients with AKI may not survive to need RRT. A composite outcome such as dialysis-free survival may therefore be more meaningful and should be considered. Investigators should consider building the collaborative networks that are needed to adequately power definitive results. Furthermore, future studies should consider populations who are at high risk of AKI such as people with chronic kidney disease. Novel biomarkers such as neutrophil gelatinase-associated lipocalin, interleukin-18 and others may help to identify high risk populations (Coca 2008; Parikh 2006). Furthermore, these biomarkers may be applied as enrolment criteria for future clinical trials aimed at prevention of AKI.

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