On 2016 May 20, Preben Berthelsen commented:

A grant application is not a clinical trial registration. The content of such an application is not a blueprint of the research but merely an indication of what the researchers contemplate. What counts scientifically is the pre-trial registration of the study with ClinicalTrials. To finalise the discussion on the question of the aim of the study, I have copy pasted below the Primary Outcome Measure from the ClinicalTrials registration (NCT01680744).

Primary Outcome Measures: • Renal Function [ Time Frame: 12 hours of mild hypothermia ] [ Designated as safety issue: No ] The primary outcome measures are renal function as determined by creatinine and cystatin c between declaration of neurological death and organ recovery in each of the two treatment groups. Delta creatinine and terminal creatinine are important predictors of graft quality and function, as demonstrated in the present data (HRSA study and Region 5 DMG/DGF study), and will be compared between the control and treatment group.

Ethical Problem. If the authors planned - as the thorny lifeline thrown by Dr. Greenwald (HRSA) seems to suggest - to study recipient graft function all along, the kidney recipients should have been informed that they took part in a randomized clinical trial and they should have given their consent before being enrolled in the investigation. This did not happen.

Preben G. Berthelsen, M.D. Charlottenlund, Denmark.

On 2016 Apr 25, Preben Berthelsen commented:

None

On 2016 Mar 09, Melissa Greenwald commented:

The United States Health Resources and Services Administration (HRSA) is the federal agency that awarded the grant funding for this research proposal. Grant awards were based on ranking after applications were reviewed by an external Technical Review Committee. “Delayed graft function” (DGF) was clearly stated as one of the goals of this research study as noted in the original grant application submitted in March 2011: “The goals of the this intervention are to demonstrate that TH [Therapeutic Hypothermia]: 1) better preserves deceased donor renal function while awaiting organ recovery when compared to normothermia; 2) increases the number of suitable organs for transplantation; and 3) improves recipient renal function after transplantation as measured by a reduction in DGF [Delayed Graft Function] and SGF [Slow Graft Function].” The grant application listed “Initial graft function” one of four variables to be measured for assessment of the first of two specific objectives of this research study. This is further specified in the Methods section of the grant application as: “The primary outcome measure will be number of patients in each group showing DGF/ SGF.” The parameters for information about research grants that is included and displayed on the Clinical Trials.gov website is under oversight of the U.S. National Institutes of Health.

Melissa Greenwald MD, Acting Director, Division of Transplantation, Health Resources and Services Administration, Rockville, Maryland, USA

On 2016 Jan 04, Preben Berthelsen commented:

According to the ClinicalTrials registration (NCT01680744) for this study, the primary outcome measure was renal function as determined by changes in creatinine and cystatin c between declaration of neurological death and organ recovery in donors randomised to normothermia or hypothermia. No secondary outcome measures were stipulated.

When Niemann et al report the results of their investigation, the primary outcome measure has been radically altered from changes in donor renal function to delayed graft function in the kidney recipients. This change in end-point - mirabile dictu – resulted in a positive outcome of the authors’ intervention.

In my view, the paper does not present evidence for a benefit of induced hypothermia in brain death donors prior to kidney transplantation. As the paper falsely suggests such a benefit the only safe option is a retraction of the paper - either by the authors or by the New Engl J Med where the review process seems to have been substantially substandard.

P.G.Berthelsen, M.D. Charlottenlund, Denmark

On 2015 Dec 04, Claus U Niemann commented:

Thank you for reviewing the study. I agree that the ethics and logistics of this study were exceedingly complex. This is further complicated by the complete lack of regulatory oversight for this type of research. Some of our efforts to alleviate this lack of oversight are described in the supplement. Two specific comments: 1.) Recipient covariates were included. Table S4 in the supplementary appendix provide important recipient variables that are known to be associated with renal allograft function. In fact, these variables are validated in several studies and are provided to the transplant community by the Scientific Registry of Transplant Recipients (SRTR),http://www.srtr.org/ 2.) Creatinine levels and GFR ( last determination prior organ recovery) appeared be lower in the hypothermia group. However, we are unsure of the effect of hypothermia on creatinine production itself and therefore cannot state with certainty that hypothermia actually resulted in an improvement. Nevertheless, the last creatinine prior organ recovery has been demonstrated to be a significant predictor of delayed graft function in the recipient.

On 2015 Nov 15, NephJC - Nephrology Journal Club commented:

This study was discussed on Sep 22nd and 23rd in the open online nephrology journal club, #NephJC, on twitter. Introductory comments are available at the NephJC website.

The discussion was quite detailed, with about 40 participants, including nephrologists, fellows and residents.

A transcript and a curated (i.e. Storified) version of the tweetchat are available from the NephJC website.

The highlights of the tweetchat were:

• The authors were to commended for designing and conducting this trial, using a relatively safe and low risk intervention, which may have potentially important implications for care of potential donors and outcomes in transplant recipients.

• A considerable discussion occurred around the ethics of doing a clinical trial without needing to obtaining consents from the recipients, which admittedly would have been logistically challenging.

• Though the results on delayed graft function were dramatic, as also were biologically plausible with a greater benefit observed in extended criteria donor organs, most discussants thought the results needed replication and also would like to see benefit in longer term clinical outcomes. Some key issues also brought up included the lack of covariates (especially related to recipient characteristics) and the pre-transplant improvement in kidney function seen in the intervention arm.

Interested individuals can track and join in the conversation by following @NephJC or #NephJC, or visit the webpage at NephJC.com.

On 2015 Nov 15, NephJC - Nephrology Journal Club commented:

This study was discussed on Sep 22nd and 23rd in the open online nephrology journal club, #NephJC, on twitter. Introductory comments are available at the NephJC website.

The discussion was quite detailed, with about 40 participants, including nephrologists, fellows and residents.

A transcript and a curated (i.e. Storified) version of the tweetchat are available from the NephJC website.

The highlights of the tweetchat were:

• The authors were to commended for designing and conducting this trial, using a relatively safe and low risk intervention, which may have potentially important implications for care of potential donors and outcomes in transplant recipients.

• A considerable discussion occurred around the ethics of doing a clinical trial without needing to obtaining consents from the recipients, which admittedly would have been logistically challenging.

• Though the results on delayed graft function were dramatic, as also were biologically plausible with a greater benefit observed in extended criteria donor organs, most discussants thought the results needed replication and also would like to see benefit in longer term clinical outcomes. Some key issues also brought up included the lack of covariates (especially related to recipient characteristics) and the pre-transplant improvement in kidney function seen in the intervention arm.

Interested individuals can track and join in the conversation by following @NephJC or #NephJC, or visit the webpage at NephJC.com.

On 2015 Dec 04, Claus U Niemann commented:

Thank you for reviewing the study. I agree that the ethics and logistics of this study were exceedingly complex. This is further complicated by the complete lack of regulatory oversight for this type of research. Some of our efforts to alleviate this lack of oversight are described in the supplement. Two specific comments: 1.) Recipient covariates were included. Table S4 in the supplementary appendix provide important recipient variables that are known to be associated with renal allograft function. In fact, these variables are validated in several studies and are provided to the transplant community by the Scientific Registry of Transplant Recipients (SRTR),http://www.srtr.org/ 2.) Creatinine levels and GFR ( last determination prior organ recovery) appeared be lower in the hypothermia group. However, we are unsure of the effect of hypothermia on creatinine production itself and therefore cannot state with certainty that hypothermia actually resulted in an improvement. Nevertheless, the last creatinine prior organ recovery has been demonstrated to be a significant predictor of delayed graft function in the recipient.

On 2016 Jan 04, Preben Berthelsen commented:

According to the ClinicalTrials registration (NCT01680744) for this study, the primary outcome measure was renal function as determined by changes in creatinine and cystatin c between declaration of neurological death and organ recovery in donors randomised to normothermia or hypothermia. No secondary outcome measures were stipulated.

When Niemann et al report the results of their investigation, the primary outcome measure has been radically altered from changes in donor renal function to delayed graft function in the kidney recipients. This change in end-point - mirabile dictu – resulted in a positive outcome of the authors’ intervention.

In my view, the paper does not present evidence for a benefit of induced hypothermia in brain death donors prior to kidney transplantation. As the paper falsely suggests such a benefit the only safe option is a retraction of the paper - either by the authors or by the New Engl J Med where the review process seems to have been substantially substandard.

P.G.Berthelsen, M.D. Charlottenlund, Denmark

On 2016 Mar 09, Melissa Greenwald commented:

The United States Health Resources and Services Administration (HRSA) is the federal agency that awarded the grant funding for this research proposal. Grant awards were based on ranking after applications were reviewed by an external Technical Review Committee. “Delayed graft function” (DGF) was clearly stated as one of the goals of this research study as noted in the original grant application submitted in March 2011: “The goals of the this intervention are to demonstrate that TH [Therapeutic Hypothermia]: 1) better preserves deceased donor renal function while awaiting organ recovery when compared to normothermia; 2) increases the number of suitable organs for transplantation; and 3) improves recipient renal function after transplantation as measured by a reduction in DGF [Delayed Graft Function] and SGF [Slow Graft Function].” The grant application listed “Initial graft function” one of four variables to be measured for assessment of the first of two specific objectives of this research study. This is further specified in the Methods section of the grant application as: “The primary outcome measure will be number of patients in each group showing DGF/ SGF.” The parameters for information about research grants that is included and displayed on the Clinical Trials.gov website is under oversight of the U.S. National Institutes of Health.

Melissa Greenwald MD, Acting Director, Division of Transplantation, Health Resources and Services Administration, Rockville, Maryland, USA

On 2016 Apr 25, Preben Berthelsen commented:

None

On 2016 May 20, Preben Berthelsen commented:

A grant application is not a clinical trial registration. The content of such an application is not a blueprint of the research but merely an indication of what the researchers contemplate. What counts scientifically is the pre-trial registration of the study with ClinicalTrials. To finalise the discussion on the question of the aim of the study, I have copy pasted below the Primary Outcome Measure from the ClinicalTrials registration (NCT01680744).

Primary Outcome Measures: • Renal Function [ Time Frame: 12 hours of mild hypothermia ] [ Designated as safety issue: No ] The primary outcome measures are renal function as determined by creatinine and cystatin c between declaration of neurological death and organ recovery in each of the two treatment groups. Delta creatinine and terminal creatinine are important predictors of graft quality and function, as demonstrated in the present data (HRSA study and Region 5 DMG/DGF study), and will be compared between the control and treatment group.

Ethical Problem. If the authors planned - as the thorny lifeline thrown by Dr. Greenwald (HRSA) seems to suggest - to study recipient graft function all along, the kidney recipients should have been informed that they took part in a randomized clinical trial and they should have given their consent before being enrolled in the investigation. This did not happen.

Preben G. Berthelsen, M.D. Charlottenlund, Denmark.