Review Reports

Round 1

Reviewer 1 Report

In the manuscript entitled “Past, Current and Future Perspective on Transplanting Acute Kidney Injury Kidneys”, the authors summarized the current studies and referenced to the clinical experience at their center on the AKI kidneys transplantation. They concluded that by employing procurement biopsies, machine perfusion and DGF management, the outcomes of AKI kidneys transplant can be improved. Overall, it’s an interesting study and is meaningful to expand the donor pool and meet the need for the kidney transplantation. However, there are some issues need to be addressed:

 

Major Concerns:

 

1.     What is the criteria for the mild chronic change mentioned in Figure 1? All criteria for examining the kidney biopsies should be specified.

2.     The screenshot for Figure 2 is not appropriate. The form version is recommended.

3.     It would be better if the authors can discuss the current basic research on the factors which can influence the outcomes of kidney transplantation and AKI-CKD progression. For example, macrophage polarization (Cells. 2021 Nov 6;10(11):3057) and hypertension (J Cell Physiol. 2022 Jan;237(1):983-991).

4.     The magnification in Figure 3 should be uniformed and specified. Scale bar should be added.

 

Minor Concerns:

 

1.     Some “]” are missing in Page 4.

Author Response

1. Define criteria for mild chronic changes in Figure 1. And all criteria for examining the kidney biopsies.

Thank you for this question. Chronic changes are as defined by the Banff criteria with mild referring to <25% glomerulosclerosis, fibrosis (ci), tubular atrophy (ct), arterial sclerosis (cv), arteriolar hyaline (ah). The percentages for chronic changes are also outlined in Figure 2.

2. Figure 2 – get the form version, not screenshot.

We have updated the manuscript with the form version.

3. Discuss current basic research on factors which can influence the outcomes of kidney transplantation and AKI-CKD progression.

Thank you for the suggestion. Kidney fibrosis is a notable finding on biopsy in patients with chronic kidney disease and repeated and severe acute kidney injury events can also yield similar findings.  The molecular mechanisms responsible for these histologic changes remain to be fully understood however recent studies have focused on understanding these pathways. The identification of these mechanisms has the potential to yield therapeutic strategies in both chronic kidney disease and acute kidney injury and be applied to further expand the use of AKI kidneys in transplant. We have added this into our manuscript (p. 4) [ref 1-2/updated manuscript references 21-22].

References

1. Jiao B, An C, Du H, et al. STAT6 Deficiency Attenuates Myeloid Fibroblast Activation and Macrophage Polarization in Experimental Folic Acid Nephropathy. Cells. 2021;10(11):3057. Published 2021 Nov 6. doi:10.3390/cells10113057
2. An C, Jiao B, Du H, Tran M, Zhou D, Wang Y. Myeloid PTEN deficiency aggravates renal inflammation and fibrosis in angiotensin II-induced hypertension. J Cell Physiol. 2022;237(1):983-991. doi:10.1002/jcp.30574
3. Magnification in Figure 3 should be uniformed and specified. Scale bar should be added.

We have updated the Figure 3 legend to include the magnification; a) 20x, b) 20x, c) 20x, d) 20x, e) 20x, f) 10x but were unable to add scale bars.

 

 

Minor Concerns:

 

5. Some “]” are missing in Page 4.

Thank you, we have corrected this.

Reviewer 2 Report

Thank you for reviewing this exciting manuscript. Although the authors do not report their results, it is still an attention-grabbing narrative review. It is well known that the quality and quantity of available transplant organs are a problem worldwide, so the search for additional potential opportunities is of utmost importance. The inclusion of donors with biopsy-proven acute kidney injury sounds promising. However, this can also be a limitation since a kidney biopsy requires an experienced pathologist to evaluate it properly.

The manuscript is well-written and has a logical structure, but it also has limitations:

1- There are too many abbreviations. I would like to advise reducing it. It helps reading if you solve abbreviations only used a few times. It may not be necessary to use so many abbreviations.

2- In Line 66, there is an irrelevant abbreviation.

3- Tables and Figure 1 have no abbreviations.

After these corrections, this manuscript is suitable for publication.

Author Response

Reviewer 2:

 

• too many abbreviations, advise reducing it. It helps reading if you solve abbreviations only used a few times.

We agree and have removed the following abbreviations: BMI, OPTN, OPO, PNF, CKD, HgbA1c, CVA, RRT, IRI, CNI, US, and NMP.

• In Line 66, there is an irrelevant abbreviation.

We have removed this abbreviation.

• Tables and Figure 1 have no abbreviations.

We have removed most abbreviations as requested.

Reviewer 3 Report

The authors aim to add additional opportunities to further expand the donor pool by using AKI kidneys. Here are outlines from this article: (1) the condition of underutilization of AKI graft; (2) Current AKI kidney practices: Mayo Clinic Algorithm for Assessing AKI Kidneys with Biopsy; (3) Role of procurement biopsies for AKI kidneys: Mayo Clinic Standardized Form for Preimplantation Biopsy Review; (4) Use of machine perfusion to evaluate AKI kidney; (5) Management of DGF. There are several comments and concerns that need to be addressed before the conclusion is justified.

 

(1)  For procurement biopsy, is there a standardized approach to the biopsy process (who recovers the sample, how it is processed/ stained, read and reported)?

(2)  Some OPOs oppose implementation of the proposed policy that mandates renal biopsy at time of procurement as they believe the additional requirements for kidney biopsies will adversely impact kidney utilization. How do the authors debate for this point of view?

(3)  As the content from Figure 1 Mayo clinic algorithm for assessing AKI kidney and biopsy, if the graft meets criteria for pre-transplant biopsy and external biopsy is not available, plan to import kidney and biopsy/re-biopsy upon arrival. Does the center evaluate the average time cost from initiation biopsy to final report of biopsy report? Is it stipulated that the biopsy process should be completed within the time limit in the author’s center?

(4)  From line 143 to 145, “The success our transplant center program has had in utilizing severe AKI kidneys is multifactorial beginning with careful consideration of the donor’s clinical history and cause of death. The etiology of the donor’s AKI and indications for RRT is also pertinent”.  Does the authors analyze the association of different cause of AKI with graft outcome?

(5)  From line 185 to 188, the authors mentioned “Wedge biopsies are considered inferior to core needle biopsies due to their tendency to overestimate the degree of glomerulosclerosis and fibrosis due to their proximity with the renal capsule”. Please list the references. And do the authors suggest core biopsy for procurement procedures?

(6)  From line 193 to 195, the authors mentioned “the procurement biopsy should not be used for decline but rather to guide decision making on recipient selection as well as potential need for dual versus single adult kidney transplantation”. What are the common pathological features or are there pathologic scores that are related to worse graft outcomes that cause the decision of graft discard? In the article “Discard Conference research priorities (reference 13)”, the Commonly cited reasons for kidney discards include abnormal biopsy findings, and this is vague.

 

(7)  In line 242 “Use of machine perfusion to evaluate AKI kidney”, this sentence is confusing and seems not related to the affiliated paragraph. Please refine this sentence to convey the authors’ point.

(8)  In Line 259 “HMP also allows for additional kidney allograft assessment based on perfusion parameters” How to access allograft based on perfusion parameters? please elaborate this point.

(9)  From line 253-266, the authors explained the study from MIT transplant group. Do the authors group could share their own experiences/protocol and outcome of HMP on deceased AKI kidney transplants?

(10)  Can the authors summarize the benefit of HMP from current evidences that support its clinical implications? (Because HMP seems to show non-inferior outcome compared with SCS) Is HMP used to prolong CIT for logistic reasons (and convert KT into a planned procedure) in deceased donor kidney transplantation? What do the authors recommend for the clinical indications of HMP in kidney transplantation?

(11)  Studies comparing the effect of SCS and HMP were available. Are there current clinical trials of deceased donor kidney transplant comparing HMP and NMP devices?

 

Minor comments:

(1)  Typo errors:

Line 115: “Even with out of 115 sequence allocation” > with out or without?

Line 135: “DBD” > please add full name

Line 250, “incidence of IRI, improve drug delivery” > incidence of IRI and improve drug delivery.

(2)  The reference [33] couldn't be found on the INTERNET.

(3)  The authors may consider add up below paper: Matthew Garner , Colleen L Jay , Berjesh Sharda. Long-term outcomes of kidney transplantation from deceased donors with terminal acute kidney injury: Single center experience and literature review. Clin Transplant. 2023 Mar;37(3):e14886. doi: 10.1111/ctr.14886. Epub 2022 Dec 28.

Comments for author File: Comments.pdf

The quality of English Language is good. 

Author Response

Reviewer 3:

• For procurement biopsy, is there a standardized approach to the biopsy process (who recovers the sample, how it is processed/ stained, read, and reported)?

In the United States, procurement biopsies are performed by the recovering kidney surgeon. Recovery surgeons include surgeons who work for transplant centers and Organ Procurement Organizations, surgeons undergoing advanced fellowship training, as well as recovery technicians who do not have medical degrees. Procurement biopsies in the United States are most commonly wedge biopsies that are processed as frozen sections due to time constraints, often using a single stain. They are frequently read by an on-call pathologist at who may not specialize in kidney pathology or kidney transplant. Until recently, procurement biopsies were reported in various ways at the discretion of the on-call pathologist. Within the past year, the Organ Procurement and Transplantation Network, approved a policy to standardize kidney biopsy reporting and data collection. This policy requires that biopsy data be reported in a typed (not handwritten) report, with consistent kidney biopsy information, and using a standardized pathology report. We have added this information to our manuscript and added references number 32.

1. https://optn.transplant.hrsa.gov/policies-bylaws/public-comment/standardize-kidney-biopsy-reporting-and-data-collection/

• Some OPOs oppose implementation of the proposed policy that mandates renal biopsy at time of procurement as they believe the additional requirements for kidney biopsies will adversely impact kidney utilization. How do the authors debate for this point of view?

The value of procurement biopsies remains controversial. We do not recommend routinely using procurement biopsy in younger, low risk donor kidneys. The quality and reliability of procurement biopsies can be questionable due to processing issues and the experience of the pathologist.  However, in our center’s experience with transplanting kidneys from AKI donors, we have found that the procurement biopsy can be valuable.  In this setting, we would avoid transplanting kidneys with either severe chronic changes or severe cortical necrosis.  However, we do not have comparison data to quantify the value of the procurement biopsy.  For example, if we have a donor with severe acute kidney injury, we would assess the procurement biopsy to rule out significant cortical necrosis (greater than 10%) because of the concern for primary nonfunction or suboptimal renal function.  In addition, for donors with a higher KDPI and acute kidney injury, we would use the procurement biopsy to assess for chronic changes.  We assess the chronic changes in all the compartments of the biopsy including glomerular sclerosis, interstitial fibrosis, tubular atrophy, intimal vascular thickening or arterial hyaline changes.  If the biopsy shows moderate-to-severe changes in several of these compartments, we might not use this kidney or perhaps use it as a dual organ transplant. Our job as a transplant center is to try to safely utilize all available organs, pair the right organ with the right recipient and ensure that we are attaining appropriate short- and long-term quality goals (e.g., patient and graft survival). The principal metric for OPOs is to increase placement of donor organs. The metrics by which transplant centers and OPOs are held are unfortunately not always congruent. We have added this discussion into our manuscript.

 

• As the content from Figure 1 Mayo clinic algorithm for assessing AKI kidney and biopsy, if the graft meets criteria for pre-transplant biopsy and external biopsy is not available, plan to import kidney and biopsy/re-biopsy upon arrival. Does the center evaluate the average time cost from initiation biopsy to final report of biopsy report? Is it stipulated that the biopsy process should be completed within the time limit in the author’s center?

If a kidney meets biopsy criteria and the external biopsy is unavailable, we communicate the plan to re-biopsy with the OPO and request kidney biopsy waivers. Re-biopsies are performed at the time of kidney arrival at our transplant center and coordinated with our transplant center on-call kidney pathologist. This process usually adds about 30 minutes to anticipated CIT.

• From line 143 to 145, “The success our transplant center program has had in utilizing severe AKI kidneys is multifactorial beginning with careful consideration of the donor’s clinical history and cause of death. The etiology of the donor’s AKI and indications for RRT is also pertinent”. Does the authors analyze the association of different cause of AKI with graft outcome?

This is an interesting question although we have never assessed outcomes based on AKI etiologies. Below is unpublished data from 230 AKI kidney allografts transplanted at Mayo Clinic Arizona from donors that were on renal replacement therapy at the time of donation. Anoxia was the most common cause of death and the most common mechanisms of injury were drug intoxication (47.8%) followed by cardiovascular events (23.9%). In our experience, findings on procurement biopsy are the main predictors of outcomes for AKI donors. Other factors such as CIT likely also play an incremental role. Unfortunately, data on indications for renal replacement therapy are not consistently documented.

Cause of Death -          Anoxia -          Head Trauma -          CV/Stroke -          Other	185 (80.4%) 31 (13.5%) 8 (3.5%) 6 (2.6%)
Mechanism of Injury -          Cardiovascular -          Blunt trauma -          Drowning -          Drug intoxication -          Asphyxiation -          GSW -          Intracranial bleed -          Other	55 (23.9%) 18 (7.8%) 5 (2.2%) 110 (47.8%) 5 (2.2%) 15 (6.5%) 8 (3.5%) 14 (6.1%)

 

• From line 185 to 188, the authors mentioned “Wedge biopsies are considered inferior to core needle biopsies due to their tendency to overestimate the degree of glomerulosclerosis and fibrosis due to their proximity with the renal capsule”. Please list the references. And do the authors suggest core biopsy for procurement procedures?

There are advantages and disadvantages to both core needle and wedge biopsies. The quality of both biopsy types is dependent on the technique in which they are completed. Deeper wedge biopsies are often avoided at organ recoveries due to concerns for post-transplant complications. As a result, most wedge biopsies sample only the subcapsular region and may not accurately represent the true renal architecture (1). With aging, there is a predominance of sclerosis in the kidney’s subcapsular region, and in this context, wedge biopsies can overestimate the amount of glomerulosclerosis the area.

Good wedge biopsies not restricted to the subcapsular cortex can however in fact be superior to needle biopsies (2).  In the “Banff histopathologic consensus criteria for preimplantation kidney biopsies” authors Liapis et al. found a better agreement among pathologist when reading wedge biopsies compared to needle biopsies (2). Good to fair reproducibility was observed in semiquantitative scores for percentage of glomerulosclerosis, arterial intimal fibrosis and interstitial fibrosis on frozen wedge biopsies. Evaluation of frozen wedge and core biopsies was comparable for number of glomeruli, but needle biopsies showed worse interclass correlation for glomerulosclerosis, interstitial fibrosis and tubular atrophy. In this context, there are advantages and disadvantages to both core needle and wedge biopsies. It is important to anticipate what these limitations might be when interpreting biopsies and adjust interpretation accordingly. A strategy to counteract these limitations is to have these biopsies reviewed by an experienced renal pathology team that can comment on quality and sample adequacy. We have updated our discussion to reflect this information and added the below references (#30-31).

1. Muruve NA, Steinbecker KM, Luger AM. Are wedge biopsies of cadaveric kidneys obtained at procurement reliable? Transplantation. 2000 Jun 15;69(11):2384-8. doi: 10.1097/00007890-200006150-00029. PMID: 10868645.
2. Liapis H, Gaut JP, Klein C, et al. Banff Histopathological Consensus Criteria for Preimplantation Kidney Biopsies. Am J Transplant. 2017;17(1):140-150. doi:10.1111/ajt.13929

 

• From line 193 to 195, the authors mentioned “the procurement biopsy should not be used for decline but rather to guide decision making on recipient selection as well as potential need for dual versus single adult kidney transplantation”. What are the common pathological features or are there pathologic scores that are related to worse graft outcomes that cause the decision of graft discard? In the article “Discard Conference research priorities (reference 13)”, the Commonly cited reasons for kidney discards include abnormal biopsy findings, and this is vague. 

The value of procurement biopsy remains controversial, as highlighter in the discussion from question 13 above, primarily because of quality issues in processing and in the experience of the pathologist.  In our practice, we use the procurement biopsy to help with recipient selection.  For example, if the biopsy shows moderate chronic changes, we do not offer this organ to a young recipient.  We might even decide to transplant that kidney as a dual adult transplant.  At our transplant center, we take into consideration all biopsy components biopsy including glomerular sclerosis, interstitial fibrosis, tubular atrophy, arterial intimal fibrosis, and arteriole hyalinosis.

• In line 242 “Use of machine perfusion to evaluate AKI kidney”, this sentence is confusing and seems not related to the affiliated paragraph. Please refine this sentence to convey the authors’ point.

We have updated this title of this subsection to read “Preservation Methods for AKI Kidneys: Static Cold Storage vs. Machine Perfusion.”

• In Line 259 “HMP also allows for additional kidney allograft assessment based on perfusion parameters” How to access allograft based on perfusion parameters? please elaborate this point.

Most transplant centers establish internal machine perfusion criteria that they use to assess kidneys allografts. These criteria vary by center and also by the type of allograft being perfused. As an example, the Miami Transplant Institute (author G.G.) aims to limit static cold storage to <24 hours but with acceptable total ischemia times, including that of machine perfusion, exceeding 40 hours. Machine perfusion parameters for their center, at the time of transplant, generally include flows >100 mL and RI of <0.40.

• From line 253-266, the authors explained the study from MIT transplant group. Do the authors group could share their own experiences/protocol and outcome of HMP on deceased AKI kidney transplants?

We do not have easy access to HMP at our transplant center (Mayo Clinic Arizona) and, as a result we do not routinely use it. We included the MTI experience (author G.G.) in this review paper to provide this perspective.

• Can the authors summarize the benefit of HMP from current evidence that support its clinical implications? (Because HMP seems to show non-inferior outcome compared with SCS). Is HMP used to prolong CIT for logistic reasons (and convert KT into a planned procedure) in deceased donor kidney transplantation? What do the authors recommend for the clinical indications of HMP in kidney transplantation?

In an international randomized controlled trial that randomized one kidney to HMP and the other kidney to SCS, kidneys undergoing HMP had reduced risk and duration of DGF and higher one-year graft survival (1). Other studies have shown similar results utilizing HMP, along with reduced economic burden due to reduced DGF rates (2-4). HMP potentially has the most benefit in kidney allografts with the most at-risk characteristics. In the MTI experience, use of HMP allows for increased utilization of kidneys with a higher KDPI and longer CIT (4).  Although there are no standard indications for HMP, it has shown clinical benefit in extended-criterion donor kidneys, DCD kidneys and other marginal kidneys (4-5). Recently, the Netherlands implemented HMP as their national standard preservation method to preserve deceased donor kidneys and have observed a significant reduction in DGF (6). We have added this to our discussion and also updated our references.

 

Table: Comparison of Kidney Transplant Outcomes Using HMP Compared to SCS

 

Study	Study Design	Risk of DGF	Duration of DGF	PNF	Acute Rejection	Graft Survival	Economic Burden
Moers 2009 1	Paired RCT	↓	↓	«	«	↑	-
Tingle 20202	Meta-analysis of HMP vs SCS RCT’s	↓	-	«	-	↑	↓
Gasteiger 20203	Retrospective propensity score matched analysis	↓	-	-	-	«	-
Brat 20216	Prospective HMP arm, historic retrospective SCS arm	↓	↓	-	-	«	-

 

 

1. Moers C, Smits JM, Maathuis MH, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med. 2009;360(1):7-19. doi:10.1056/NEJMoa0802289
2. Tingle SJ, Figueiredo RS, Moir JA, Goodfellow M, Thompson ER, Ibrahim IK, Bates L, Talbot D, Wilson CH. Hypothermic machine perfusion is superior to static cold storage in deceased donor kidney transplantation: A meta-analysis. Clin Transplant. 2020 Apr;34(4):e13814. doi: 10.1111/ctr.13814. Epub 2020 Mar 5. PMID: 32031711.
3. Gasteiger S, Berchtold V, Bösmüller C, Dostal L, Ulmer H, Bogensperger C, Resch T, Rudnicki M, Neuwirt H, Oberhuber R, Cardini B, Scheidl S, Mayer G, Öfner D, Weissenbacher A, Schneeberger S. A Retrospective Propensity Score Matched Analysis Reveals Superiority of Hypothermic Machine Perfusion over Static Cold Storage in Deceased Donor Kidney Transplantation. J Clin Med. 2020 Jul 21;9(7):2311. doi: 10.3390/jcm9072311. PMID: 32708180; PMCID: PMC7408946.
4. Goggins MO, Gaynor JJ, Mattiazzi A, Figueiro J, Burke G, Ciancio G, et al. Machine Perfusion Allows Use of High KDPI and Prolonged Cold Ischemia Time in Deceased Donors: A Single Center Effort to Decrease Discard Rates. Am J Transplant [Internet]. 2019;19(suppl 3). Available from: cold-ischemia-time-in-deceased-donors-a-single-center-effort-to-decrease-discard-rates/
5. De Deken J, Kocabayoglu P, Moers C. Hypothermic machine perfusion in kidney transplantation. Curr Opin Organ Transplant. 2016 Jun;21(3):294-300. doi: 10.1097/MOT.0000000000000306. PMID: 26945319.
6. Brat A, de Vries KM, van Heurn EWE, Huurman VAL, de Jongh W, Leuvenink HGD, van Zuilen AD, Haase-Kromwijk BJJM, de Jonge J, Berger SP, Hofker SH. Hypothermic Machine Perfusion as a National Standard Preservation Method for Deceased Donor Kidneys. Transplantation. 2022 May 1;106(5):1043-1050. doi: 10.1097/TP.0000000000003845. Epub 2021 Jun 23. PMID: 34172648; PMCID: PMC9038234.

 

• Studies comparing the effect of SCS and HMP were available. Are there current clinical trials of deceased donor kidney transplant comparing HMP and NMP devices?

Data on normothermic machine perfusion in kidney transplantation remains limited. Early data from Rijkse et al. shows there to be a phase 2 RCT comparing NMP and HMP in human kidneys with an estimated completion in 2023 (1). To our knowledge, there is no commercially available normothermic device for kidney transplantation in the United States.

 

1. https://classic.clinicaltrials.gov/ct2/show/NCT04882254

 

Rijkse E, Bouari S, Kimenai HJAN, de Jonge J, de Bruin RWF, Slagter JS, van den Hoogen MWF, IJzermans JNM, Hoogduijn MJ, Minnee RC. Additional Normothermic Machine Perfusion Versus Hypothermic Machine Perfusion in Suboptimal Donor Kidney Transplantation: Protocol of a Randomized, Controlled, Open-Label Trial. Int J Surg Protoc. 2021 Oct 6;25(1):227-237. doi: 10.29337/ijsp.165. PMID: 34708171; PMCID: PMC8499718.

 

Minor comments:

 

• Typo errors:

Line 115: “Even with out of 115 sequence allocation” > without or without?

 

This should have read out-of-sequence. We have replaced this verbiage with “expedited allocation.”

 

Line 135: “DBD” > please add full name.

 

We have made this correction.

 

Line 250, “incidence of IRI, improve drug delivery” > incidence of IRI and improve drug delivery.

 

Thank you, we have made this correction.

• The reference [33] couldn't be found on the INTERNET.

This is a talk that was given by author G.G. at our transplant center. Guerra G. (February 23, 2023) Kidney Transplant Success: Strategic Organ Selection/Optimization and Patient Selection – To Infinity and Beyond. Mayo Clinic Arizona, Phoenix, Arizona. We have updated the reference to reflect this.

• The authors may consider add up below paper: Matthew Garner, Colleen L Jay, Berjesh Sharda. Long-term outcomes of kidney transplantation from deceased donors with terminal acute kidney injury: Single center experience and literature review. Clin Transplant. 2023 Mar;37(3):e14886. doi: 10.1111/ctr.14886. Epub 2022 Dec 28.

Thank you for the suggestion, we have updated our manuscript to include this reference, #18.

Round 2

Reviewer 1 Report

No comment.

Reviewer 3 Report

Thank you for the additive information and the work is perfect.