Treatment of the acute respiratory distress syndrome with Keratinocyte growth factor: another failure to account
Editorial

Treatment of the acute respiratory distress syndrome with Keratinocyte growth factor: another failure to account

Marco Confalonieri, Francesco Fabiano, Francesco Salton

Department of Pulmonology, University Hospital of Trieste, Trieste, Italy

Correspondence to: Marco Confalonieri. Department of Pulmonology, University Hospital of Trieste, Trieste, Italy. Email: marco.confalonieri@asuits.sanita.fvg.it.

Provenance: This is a Guest Editorial commissioned by Editor-in-Chief Xi-Hua Liu, MD (Chinese Research Hospital Association, Beijing, China).

Comment on: McAuley DF, Cross LM, Hamid U, et al. Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Respir Med 2017;5:484-91.


Received: 04 October 2017; Accepted: 23 October 2017; Published: 09 November 2017.

doi: 10.21037/arh.2017.10.02


Acute respiratory distress syndrome (ARDS) is a life-threatening clinical syndrome defined as an acute and severe diffuse lung injury of known origin (1). The mortality rate for ARDS is still high, although it has decreased in the last decades (2). Current treatments are only supportive and there is no effective therapy interfering with the molecular basis of ARDS (3,4): in fact, despite extensive research, almost all promising potential therapies have proven unsuccessful in clinical trials. This is also the case of a randomized, double-blind, placebo-controlled phase II trial evaluating the keratinocyte growth factor (KGF) for the treatment of the ARDS (KARE trial), which has been recently published in the Lancet Respiratory Medicine (5).

The primary endpoint of the KARE trial was the improvement of oxygenation index (OI) at day 7, a parameter of severity which correlates with mortality in ARDS (6). Secondary endpoints were OI at days 3 and 14, and a change in respiratory system compliance, in PaO2/FiO2 ratio and/or in the SOFA score from baseline to days 3, 7 and 14. The KARE trial eventually failed in any primary or secondary endpoint, apart for OI at day 14 which resulted to be lower in the placebo group. The study had not enough power to assess other outcomes, such as duration of ventilation, intensive-care unit (ICU) stay, intensive care unit and in-hospital mortality, 28- and 90-day mortality. Nevertheless, all these measures were significantly higher in the KGF group compared with the placebo group, whereas there were fewer ventilator-free days in the KGF group and the study drug also carried a higher burden of adverse events. The Authors concluded that KGF might have been harmful with regards to clinical, not scheduled, outcomes.

KGF is an important biological modulator of alveolar epithelial cell phenotype during the re-epithelization phase which normally follows an acute lung injury (7-10): it has been shown to promote ATII cell proliferation both in vitro and in vivo and to enhance actin cytoskeletal function near the apical junctions, thus partially resolving paracellular permeability and protecting against epithelial cell damage (11). Therefore, the underlined hypothesis of the KARE trial was that KGF could have been able to accelerate epithelial repair in the injured lung, promoting a faster physiological and clinical recovery from ARDS. However, it should be noticed that alveolar repair and regeneration (or remodelling) is a very complex pathophysiological mechanism in which KGF probably doesn’t play the role of the conductor (12). For this reason, similarly to what happened with prostacyclin, statins, granulocyte-macrophage colony-stimulating factor (GM-CSF), surfactant and also KGF applied to sepsis in past years, the use of a single mediator of the regenerative cascade as a potential therapeutic agent might not have been sufficient to improve tissue regeneration in ARDS. Instead, recombinant KGF (Palifermin®) is approved and effectively used for the treatment of oral mucositis associated with radiotherapy or chemotherapy in patients affected by haematological disorders (13): in the KARE trial, indeed, the dose and duration of treatment was established according to the licensed and safe ones for oral mucositis. It is clear that the pathobiological and clinical features of ARDS are diverse and different from oral mucositis, but KGF had previously shown encouraging results also in animal and human models of ARDS (14). Unfortunately, though, there are no reliable models of ARDS reflecting the human syndrome with its high degrees of variability in baseline status, concomitant illnesses, rapidity and severity of lung injury and responses to supportive interventions to date. Moreover, several pulmonary and extrapulmonary precipitants such as sepsis, aspiration, pneumonia and transfusions are associated with the development of ARDS (15): even if these conditions share the same clinical manifestation, this only represents the epiphenomenon of very different pathways. For all these reasons, any clinical trial involving a potential drug which targets a single mediator of the ARDS pathogenetic mechanism risks to be at least underpowered to assess heavy outcomes such as duration of ventilation, ICU stay, ICU and in-hospital mortality, 28- and 90-day mortality.

The KARE trial finding of a higher mortality rate after 28 days in the KGF treated group compared to placebo is in contrast to pre-clinical data in experimental models of ARDS, which supported KGF as a potential therapy. As stated by the authors, it is shareable that the lower mortality in the placebo-treated group may have established a survivor bias explaining the failure of KGF to get the primary outcome, OI at day 7. One can also argue that KGF treatment might have been more harmful in some causative factor driving ARDS than others, but the KARE trial failed to identify any. The authors also claimed other possible theoretical explanations for the trial failure: first, KGF receptors might not be expressed on the target alveolar epithelial cells of patients whose epithelium is injured; second, the intravenous administration of KGF might have been less efficient than the intra-tracheal instillation or inhalation used in most preliminary experimental studies; third, a too short interval between doses might have contributed to a pro-inflammatory effect.

Nevertheless, and honestly speaking, even taking into account every possible bias of the KARE trial it would be easy to guess that there will not be another chance for KGF treatment in ARDS.


Acknowledgements

None.


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.


References

  1. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526-33. [PubMed]
  2. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005;353:1685-93. [Crossref] [PubMed]
  3. Confalonieri M, Salton F, Fabiano F. Acute respiratory distress syndrome. Eur Respir Rev 2017;26:160116. [Crossref] [PubMed]
  4. Boyle AJ, Mac Sweeney R, McAuley DF. Pharmacological treatments in ARDS; a state-of-the-art update. BMC Med 2013;11:166. [Crossref] [PubMed]
  5. McAuley DF, Cross LM, Hamid U, et al. Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Respir Med 2017;5:484-91. [Crossref] [PubMed]
  6. Seeley E, McAuley DF, Eisner M, et al. Predictors of mortality in acute lung injury during the era of lung protective ventilation. Thorax 2008;63:994-8. [Crossref] [PubMed]
  7. Ware LB, Matthay MA. Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair. Am J Physiol Lung Cell Mol Physiol 2002;282:L924-40. [Crossref] [PubMed]
  8. Barkauskas CE, Cronce MJ, Rackley CR, et al. Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 2013;123:3025-36. [Crossref] [PubMed]
  9. Confalonieri M, Buratti E, Grassi G, et al. Keratin14 mRNA expression in human pneumocytes during quiescence, repair and disease. PLoS One 2017;12:e0172130. [Crossref] [PubMed]
  10. Ficial M, Antonaglia C, Chilosi M, et al. Keratin-14 expression in pneumocytes as a marker of lung regeneration/repair during diffuse alveolar damage. Am J Respir Crit Care Med 2014;189:1142-5. [Crossref] [PubMed]
  11. Ulich TR, Yi ES, Longmuir K, et al. Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo. J Clin Invest 1994;93:1298-306. [Crossref] [PubMed]
  12. Tomashefski JF Jr. Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med 1990;11:593-619. [PubMed]
  13. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004;351:2590-8. [Crossref] [PubMed]
  14. Shyamsundar M, McAuley DF, Ingram RJ, et al. Keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury. Am J Respir Crit Care Med 2014;189:1520-9. [Crossref] [PubMed]
  15. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012;122:2731-40. [Crossref] [PubMed]
doi: 10.21037/arh.2017.10.02
Cite this article as: Confalonieri M, Fabiano F, Salton F. Treatment of the acute respiratory distress syndrome with Keratinocyte growth factor: another failure to account. Ann Res Hosp 2017;1:47.

Refbacks

  • There are currently no refbacks.