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Cited by 173Organ Transplantation Techniques and OutcomesReproductive Biology and FertilityTransplantation: Methods and Outcomes

The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index; none of the 47 sources its claims cite is checked for support yet.

Vitrification and nanowarming enable long-term organ cryopreservation and life-sustaining kidney transplantation in a rat model

Open access
Han, Zonghu, Rao, Joseph Sushil, Gangwar, Lakshya, Namsrai, Bat-Erdene, Pasek-Allen, Jacqueline L., Etheridge, Michael L., Wolf, Susan M., Pruett, Timothy L., Bischof, John C., Finger, Erik B.·2023·Nature Communications
DOI 10.1038/s41467-023-38824-8PMC PMC10256770
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Abstract

Banking cryopreserved organs could transform transplantation into a planned procedure that more equitably reaches patients regardless of geographical and time constraints. Previous organ cryopreservation attempts have failed primarily due to ice formation, but a promising alternative is vitrification, or the rapid cooling of organs to a stable, ice-free, glass-like state. However, rewarming of vitrified organs can similarly fail due to ice crystallization if rewarming is too slow or cracking from thermal stress if rewarming is not uniform. Here we use “nanowarming,” which employs alternating magnetic fields to heat nanoparticles within the organ vasculature, to achieve both rapid and uniform warming, after which the nanoparticles are removed by perfusion. We show that vitrified kidneys can be cryogenically stored (up to 100 days) and successfully recovered by nanowarming to allow transplantation and restore life-sustaining full renal function in nephrectomized recipients in a male rat model. Scaling this technology may one day enable organ banking for improved transplantation.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This study reports vitrification and nanowarming of rat kidneys stored for 1–100 days at −150 °C, followed by transplantation into nephrectomized male rats. Nanowarmed kidneys restored life-sustaining renal function, and all recipients survived the 30-day endpoint, with function normalizing after 2–3 weeks.

Key findings

  • Vitrified kidneys were stored for 1–100 days at −150 °C and rewarmed by nanowarming at 72.0 ± 8.0 °C/min, faster than the ~50 °C/min critical warming rate of VMP in kidney tissue; cooling was 20.5 ± 8.1 °C/min versus a 2 °C/min critical cooling rate.
  • In syngeneic Lewis-to-Lewis transplants with both native kidneys removed, all fresh control and nanowarmed kidney recipients survived the full 30-day study; serum creatinine in nanowarmed recipients peaked on days 2–3, fell below 2.0 mg/dL by day 19, reached normal rat range by day 23 (0.4–0.8 mg/dL), and from day 14 onward was not statistically different from controls.
  • At 30 days, eGFR was 2.2 ± 0.8 mL/min in nanowarmed recipients versus 2.7 ± 0.7 mL/min in controls (P = 0.421), and serum/urine parameters were statistically similar and essentially normal; no correlation was found between preservation time and peak creatinine, time to creatinine <2.0, or terminal creatinine (all P > 0.5).
  • During normothermic machine perfusion, nanowarmed kidneys made urine immediately and had vascular resistance of 31.3 ± 3.6 mmHg/mL/min × g, not statistically different from fresh control (18.8 ± 4.1, P = 0.9), 24-h cold stored (24.9 ± 2.6, P = 1.0), or VMP-only (27.5 ± 3.4, P = 1.0), but much lower than VS55-only (372 ± 131, P < 0.001).

Methods

  • Male Lewis and Sprague Dawley rats (450–525 g) were used; kidneys were recovered, flushed with UW solution, perfused with VMP CPA plus silica/PEG-coated iron oxide nanoparticles, cooled in a controlled-rate freezer to −150 °C, stored for 1–100 days, and rewarmed in a 15 kW RF coil at 63 kA/m and 180 kHz.
  • Assessments included micro-CT, histology, differential scanning calorimetry, normothermic machine perfusion with oxygenated acellular Krebs–Henseleit buffer, and syngeneic Lewis-to-Lewis kidney transplantation with bilateral native nephrectomy and daily laboratory follow-up to 30 days; limited allogeneic transplants and a 60-h cold-stored comparison were also performed.
  • Statistical analysis used R version 4.2.1 with ANOVA/Tukey HSD or Games–Howell, Wilcoxon/Kruskal–Wallis, and Pearson’s Chi-squared tests; biological replicates were n = 4–8 per group.

Limitations

  • Stated by the paper: the study was performed in a rat model with limited sample size (n = 4–8 per group), not human or human-sized porcine kidneys; storage was studied only up to 100 days; transplant recipients were followed only to 30 days; only a limited number of allogeneic transplants were performed and host immune response was not characterized; mechanisms of initial transplant dysfunction were not determined; comparison to other transplant categories such as 36–48 h cold storage was incomplete; and nanowarmed organs experienced 2–3 weeks of initial graft dysfunction.
  • Evident from the text: all transplant experiments used male rats only, and no long-term survival or chronic allograft outcomes beyond 30 days were assessed.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41467-023-38824-8

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

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Verification

Claims the paper makes

0 of 47 cited sources checked · 0 supported · 0 flagged

Verify all 22 references — free account
  • Findingown data

    The 60-h cold stored kidney transplants demonstrated mesangial hypercellularity and diffuse proximal convoluted tubule necrosis with congestion in the glomerulus and tubules in the medulla.

    “The 60-h cold stored kidney transplants demonstrated mesangial hypercellularity and diffuse proximal convoluted tubule necrosis with congestion in the glomerulus and tubules in the medulla.”
    Quote in the paperNot a substantial claim
  • Findingown data

    From day 14 onward, serum creatinine in nanowarmed recipients was not statistically different from that in control kidney recipients.

    “From day 14 onward, the creatinine in nanowarmed recipients was not statistically different from that in control kidney recipients.”
    Quote in the paperSubstantial claim
  • Findingown data

    No vascular thrombosis was observed in nanowarmed kidney transplants.

    “We did not observe any vascular thrombosis.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Nanowarmed kidney urine and venous electrolytes (Na+, K+, Cl−) were very similar to fresh control.

    “Nanowarmed kidney urine and venous electrolytes (Na+, K+, Cl−) were very similar to fresh control (Fig. 5).”
    Quote in the paperSubstantial claim
  • Findingown data

    The authors demonstrated stable storage of vitrified kidneys for up to 100 days.

    “whereas we demonstrated stable storage for up to 100 days.”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one. 54
  • Probably not a substantial claim. 27

  • It may state two separate claims as one.

    Findingown data

    Intraoperatively, all nanowarmed kidneys reperfused rapidly and homogeneously upon restoration of blood flow and appeared similar to fresh control organ transplants.

    “Intraoperatively, all nanowarmed kidneys reperfused rapidly and homogeneously upon restoration of blood flow and appeared similar to fresh control organ transplants (Fig. 6).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In the transplant experiments, nanowarmed kidneys had higher peak creatinine and took longer to achieve normal levels than fresh control transplants, but both groups performed much better than 60-h cold stored ones.

    “In the transplant experiments, nanowarmed kidneys had higher peak creatinine and took longer to achieve normal levels than fresh control transplants, but both groups performed much better than 60-h cold stored ones.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Histologically, nanowarmed kidneys appeared similar to VMP-only treated ones and much better than VS55-only.

    “Histologically, nanowarmed kidneys appeared similar to VMP-only treated ones and much better than VS55-only (Fig. 3).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    After an initial drop in hemoglobin in both groups due to surgical blood loss, hemoglobin rose steadily in the postop period, suggesting intact renal erythropoietin production and/or potentially hemoconcentration.

    “After an initial drop in hemoglobin in both groups due to surgical blood loss, hemoglobin rose steadily in the postop period, suggesting intact renal erythropoietin production and/or potentially hemoconcentration (Fig. 7h).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    A 60-h cold stored kidney transplant reperfused poorly with patchy ecchymosis and hilar congestion, failed to make urine, and the rat was euthanized.

    “The 60-h cold stored kidney reperfused poorly with patchy ecchymosis over the surface and hilar congestion (Fig. 6). Failing to make urine, the rat was euthanized, and the gross appearance of the bisected kidney demonstrated congested medulla and ecchymosis in the cortex.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    VMP-only treated kidneys were histologically similar to fresh control kidneys and much better than VS55-treated kidneys.

    “VMP-only treated kidneys (loading and unloading only but no nanoparticles or vitrification) were histologically similar to fresh control kidneys and much better than those treated with the prior CPA, VS55 (Fig. 3).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Creatinine clearance of nanowarmed kidneys was slightly reduced compared to fresh control and cold-stored kidneys, but similar to VMP-only.

    “Creatinine clearance, a measure of overall renal function, was slightly reduced compared to fresh control and cold-stored kidneys, but similar to VMP-only (Fig. 4c).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The kidney extravascular space had a mean radiodensity of 507 ± 30 HU, while the adherent fat outside the kidney was 267 ± 104 HU.

    “The kidney extravascular space had a mean radiodensity of 507 ± 30 Hounsfield Units (HU), while the adherent fat outside the kidney was 267 ± 104 HU.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The organs eventually recovered fully but experienced a period of 2-3 weeks of initial graft dysfunction.

    “And finally, while the organs eventually recovered fully, they experienced a period of 2–3 weeks of initial graft dysfunction”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The estimated glomerular filtration rate for nanowarmed kidney recipients was 2.2 ± 0.8 mL/min, not statistically different from control kidney transplant recipients (2.7 ± 0.7 mL/min, P = 0.421) and in the range for normal rats.

    “The estimated glomerular filtration rate (eGFR) for nanowarmed kidney recipients was 2.2 ± 0.8 mL/min, which was not statistically different from control kidney transplant recipients (2.7 ± 0.7 mL/min, P = 0.421) and in the range for normal rats (median: 1.5 mL/min, interquartile range: 1.0–2.2 mL/min28).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Besseling, P. J. et al. A plasma creatinine- and urea-based equation to estimate glomerular filtration rate in rats. Am. J. Physiol. Ren. Physiol. 320, F518–f524 (2021). source

  • It may state two separate claims as one.

    Findingown data

    During normothermic machine perfusion, nanowarmed kidneys made urine immediately and at rates not statistically different from fresh control or cold-stored kidneys and similar to VMP-only, but much better than VS55-only.

    “Nanowarmed kidneys made urine immediately upon perfusion (Fig. 4b) and at rates that were not statistically different than fresh control or cold-stored kidneys and very similar to VMP-only treated organs, but much better than VS55-only.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    All fresh control and nanowarmed kidney transplants continued to produce urine, and all animals survived the full 30-day study period.

    “Postoperatively, all fresh control and nanowarmed kidney transplants continued to produce urine, and all animals survived for the full 30-day study period.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The measured nanowarming rate adjacent to the kidney was 72.0 ± 8.0 °C/min, faster than the ~50 °C/min CWR of VMP in kidney tissue.

    “The measured warming rate adjacent to the kidney was 72.0 ± 8.0 °C/min (Fig. 2c), which is faster than the ~50 °C/min CWR of VMP in kidney tissue (Supplementary Methods).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingcitation

    No extra white space was seen within the extravascular space of nanowarmed kidneys, which would have been seen if ice had formed during the process.

    “No extra “white space” was seen within the extravascular space of the nanowarmed kidneys, which would have been seen if ice had formed during the process14.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Manuchehrabadi, N. et al. Improved tissue cryopreservation using inductive heating of magnetic nanoparticles. Sci. Transl. Med. 9, eaah4586 (2017). source

  • It may state two separate claims as one.

    Findingown data

    Normal liver function tests and creatinine kinase levels suggested a lack of systemic toxicity, but there was a mild elevation in serum amylase in nanowarmed organ recipients.

    “Normal liver function tests and creatinine kinase levels suggested a lack of systemic toxicity, but there was a mild elevation in serum amylase in the nanowarmed organ recipients.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The venous pH of nanowarmed kidneys was initially somewhat acidic but normalized by 20 min of normothermic machine perfusion.

    “Initially, the venous pH of nanowarmed kidneys was somewhat acidic, suggesting anaerobic metabolism, but the pH normalized by 20 min of NMP (Fig. 4f).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Venous lactate rose slowly for all groups, with minor differences between groups.

    “Venous lactate, which correlates with organ quality in perfused organ systems25,26, rose slowly for all groups, but the differences between groups were minor (Fig. 4h).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Nasralla, D. et al. A randomized trial of normothermic preservation in liver transplantation. Nature 557, 50–56 (2018). source
    • cites [26] Dhital, K. K. et al. Adult heart transplantation with distant procurement and ex-vivo preservation of donor hearts after circulatory death: a case series. Lancet 385, 2585–2591 (2015). source

  • It may state two separate claims as one.

    Findingown data

    VS55-only treated kidneys demonstrated increased Bowman's space, diffuse tubular necrosis, and hyaline changes, but no vascular compromise.

    “In contrast, VS55-only treated kidneys demonstrated increased Bowman’s space, diffuse tubular necrosis, and hyaline changes (but with no vascular compromise).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Nanowarmed kidney graft dysfunction lasted 2-3 weeks, following which renal function normalized in all nanowarmed kidney transplant recipients.

    “In this study, we found an initial period of nanowarmed kidney graft dysfunction lasting 2–3 weeks, following which renal function normalized in all nanowarmed kidney transplant recipients.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Transplanted nanowarmed kidneys at day 30 demonstrated some focal tubular necrosis and hyaline change but intact basement membranes and vasculature, with no microthrombi or infarcts.

    “Histologic examination of transplanted nanowarmed kidneys demonstrated some focal tubular necrosis and hyaline change but intact basement membranes and vasculature (Fig. 6c, d). Microthrombi and infarcts were absent.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Nanowarmed organs restored renal function and solely sustained the lives of nephrectomized transplant recipients for 30 days post transplant.

    “Nanowarmed organs restored renal function and solely sustained the lives of nephrectomized transplant recipients for 30 days post transplant.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The mean cooling rate was 20.5 ± 8.1 °C/min, which was much faster than the 2 °C/min CCR of VMP in kidney tissue.

    “The mean cooling rate was 20.5 ± 8.1 °C/min (Fig. 2b), which was much faster than the 2 °C/min CCR of VMP in kidney tissue.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In syngeneic nanowarmed kidney recipients, serum creatinine was higher on postop day 1 than in control transplants, continued to rise, peaked between days 2-3, and then gradually declined to control levels over 2-3 weeks.

    “In syngeneic (Lewis to Lewis) nanowarmed kidney recipients, serum creatinine levels (a principal measure of renal function) were higher on postop day 1 than in the control transplants (Fig. 7b). Creatinine in the nanowarmed kidney recipients continued to rise, peaking between days 2–3, and then gradually declined to reach control levels over 2–3 weeks.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Nanowarmed kidneys made urine within 40-45 min following reperfusion, whereas fresh control transplants made urine within a few minutes.

    “Nanowarmed kidneys made urine within 40–45 min following reperfusion. In contrast, fresh control transplants made urine within a few minutes.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    From the normothermic perfusion experiments, nanowarmed kidneys produced the same amount of urine as fresh control kidneys, albeit with a slightly reduced creatinine clearance, and performed similarly to the 24-h cold stored control group for all measures.

    “From the normothermic perfusion experiments, we found that nanowarmed kidneys produced the same amount of urine as fresh control kidneys (albeit with a slightly reduced creatinine clearance) and performed similarly to the 24-h cold stored control group for all measures.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Vitrified rat kidneys can be cryogenically stored for up to 100 days and successfully recovered by nanowarming to allow transplantation and restore life-sustaining full renal function in nephrectomized male rat recipients.

    “We show that vitrified kidneys can be cryogenically stored (up to 100 days) and successfully recovered by nanowarming to allow transplantation and restore life-sustaining full renal function in nephrectomized recipients in a male rat model.”
    • Also stated in: § Discussion · plain
      “Nanowarmed organs restored renal function and solely sustained the lives of nephrectomized transplant recipients for 30 days post transplant.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    At the 30-day endpoint, renal function of nanowarmed kidney recipients was statistically similar to fresh control transplants, as measured by serum chemistries and urinalyses, and both groups were in the normal range for healthy control rats.

    “At the 30-day endpoint, renal function of nanowarmed kidney recipients was statistically similar to fresh control transplants, as measured by serum chemistries and urinalyses, and both groups were in the normal range for healthy control rats.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In the authors' nanowarmed kidney transplants, nadir creatinine was 0.4 mg/dL and terminal creatinine was 0.6 mg/dL, each in the normal range for rats.

    “which was much higher than what we observed (nadir 0.4 mg/dL and terminal 0.6 mg/dL, each in the normal range for rats).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Serum creatinine in nanowarmed recipients fell below 2.0 mg/dL by day 19 and into the normal range for healthy rats on day 23, remaining between 0.4 and 0.8 mg/dL until the end of follow-up.

    “The creatinine fell below 2.0 mg/dL by day 19 and into the normal range for healthy rats on day 23, remaining between 0.4 and 0.8 mg/dL until the end of follow-up.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    There were no areas of low HU attenuation suggesting ice crystallization or linear transitions suggesting cracking in the IONP-loaded vitrified kidneys.

    “However, there were no areas of low HU attenuation that would suggest ice crystallization or linear transitions suggesting cracking (see Supplementary Data for micro-CT calibration of vitrified materials).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Both control and nanowarmed kidney recipients increased body weight; nanowarmed recipients initially had greater weight gain, presumably due to hypervolemia, with ~10% excess resolving by days 10-12.

    “Following transplant, both control and nanowarmed kidney recipients increased body weight. Initially, nanowarmed organ recipients experienced greater weight gain, presumably due to hypervolemia. This ~10% excess weight gain resolved by days 10–12, after which body mass increased in parallel to control transplants (Fig. 7i).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The mean vascular resistance of nanowarmed kidneys after 40 min of perfusion was 31.3 ± 3.6 mmHg/mL/min × g, not statistically different from fresh control, 24-h cold stored, or VMP-only, but much lower than VS55-only.

    “The mean vascular resistance of nanowarmed kidneys after 40 min of perfusion was 31.3 ± 3.6 mmHg/mL/min × g, which was slightly higher but not statistically different than fresh control (18.8 ± 4.1, P = 0.9), 24-h cold stored (24.9 ± 2.6, P = 1.0) or VMP-only (27.5 ± 3.4, P = 1.0), but much lower than VS55-only (372 ± 131, P < 0.001).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Inadequate tissue CPA concentration combined with suboptimal rewarming led to ice formation, particularly in the renal medulla, and failure in almost all transplants.

    “Inadequate tissue CPA concentration, combined with suboptimal rewarming, led to ice formation, particularly in the renal medulla, and failure in almost all transplants21,31.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Fahy, G. M. et al. Cryopreservation of organs by vitrification: perspectives and recent advances. Cryobiology 48, 157–178 (2004). source
    • cites [31] Fahy, G. M. et al. Physical and biological aspects of renal vitrification. Organogenesis 5, 167–175 (2009). source

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationreasoning

    Successful banking and relief from time constraints will invite a transformation in the system to address these problems and benefit patients.

    “Successful banking and relief from time constraints will invite a transformation in the system to address these problems and benefit patients.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The current organ transplantation system is based on severe time constraints from organ acquisition to transplant, typically measured in hours.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductown data

    The authors only followed transplant recipients to a 30-day endpoint and did not assess longer-term survival.

    “Third, we only followed transplant recipients to our 30-day endpoint and did not assess longer-term survival.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Another group attempted nanowarming in rat hearts but did not test for viability or function after rewarming.

    “Another group attempted nanowarming in rat hearts but did not test for viability or function after rewarming20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Chiu-Lam, A., Staples, E., Pepine, C. J. & Rinaldi, C. Perfusion, cryopreservation, and nanowarming of whole hearts using colloidally stable magnetic cryopreservation agent solutions. Sci. Adv. 7, eabe3005 (2021). source

  • It may state two separate claims as one.

    Interpretationcitation

    Nanowarmed kidney recipients had normal creatinine at the end of the 30-day follow-up, which in clinical transplantation predicts good long-term graft function in human kidney recipients.

    “Our nanowarmed kidney recipients had normal creatinine at the end of the 30-day follow-up, which in clinical transplantation predicts good long-term graft function in human kidney recipients30.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Koh, S. M., Ju, M. K., Huh, K. H., Kim, Y. S. & Kim, M. S. Serum creatinine level at 1-month posttransplant can independently predict long-term graft survival and functional status. Korean J. Transplant. 34, 244–248 (2020). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    A range of other technologies are in use or being studied to prolong preservation times for kidneys and other organs, including hypothermic machine perfusion, normothermic machine perfusion, subnormothermic machine perfusion, high subzero supercooling, and partial freezing.

    “Further, a range of other technologies are in use or are being studied to prolong preservation times for kidneys and other organs, including hypothermic machine perfusion37, normothermic machine perfusion25, subnormothermic machine perfusion38, high subzero supercooling39,40, and partial freezing41.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] Moers, C. et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N. Engl. J. Med 360, 7–19 (2009). source
    • cites [25] Nasralla, D. et al. A randomized trial of normothermic preservation in liver transplantation. Nature 557, 50–56 (2018). source
    • cites [38] Bruinsma, B. G. et al. Subnormothermic machine perfusion for ex vivo preservation and recovery of the human liver for transplantation. Am. J. Transplant. 14, 1400–1409 (2014). source

  • It may state two separate claims as one.

    Premisecitation

    In past work, nanowarming could rewarm vitrified organs including kidneys from animal models with physical success, but only partial biological recovery and no transplant data.

    “In the past, we and others have shown that nanowarming can rewarm vitrified organs (including kidneys) from animal models with physical success, but only partial biological recovery and no transplant data17–20.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [17] Gao, Z. et al. Vitrification and rewarming of magnetic nanoparticle‐loaded rat hearts. Adv. Mater. Technol. 7, 2100873 (2021). source
    • cites [18] Sharma, A. et al. Vitrification and Nanowarming of Kidneys. Adv. Sci. (Weinh.) 8, e2101691 (2021).

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [19] Sharma, A. et al. Cryopreservation of whole rat livers by vitrification and nanowarming. Ann. Biomed. Eng. 51, 566–577 (2022). source
    • cites [20] Chiu-Lam, A., Staples, E., Pepine, C. J. & Rinaldi, C. Perfusion, cryopreservation, and nanowarming of whole hearts using colloidally stable magnetic cryopreservation agent solutions. Sci. Adv. 7, eabe3005 (2021). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The current U.S. organ transplantation system is characterized by wide variations in organ availability by region and transplant center, inefficient matching of organs and recipients, significant inequities in organ availability, and excessive organ nonuse.

    “This has contributed to a U.S. system characterized by wide variations in organ availability by region and transplant center, inefficient matching of organs and recipients, significant inequities in organ availability, and excessive organ nonuse42.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] National Research Council. Realizing the Promise of Equity in the Organ Transplantation System (The National Academies Press, Washington, DC, 2022).

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisereasoning

    Reducing the loading temperature to −22 °C slowed CPA delivery due to increased viscosity and decreased diffusivity and membrane permeability.

    “To overcome that toxicity, they reduced the loading temperature to −22 °C, which slowed CPA delivery due to increased viscosity and decreased diffusivity and membrane permeability.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Histologic interpretation was performed in a blinded fashion by a clinical pathologist.

    “histologic interpretation was performed in a blinded fashion by a clinical pathologist.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    The authors set prospective exclusion criteria wherein the perfusion flow rate during unloading had to be >45% of the observed flow rate during loading.

    “we set prospective exclusion criteria wherein the perfusion flow rate during unloading had to be >45% of the observed flow rate during loading.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Fahy and colleagues first demonstrated vitrification of rabbit kidneys in 1984.

    “We note that Fahy and colleagues first demonstrated vitrification of rabbit kidneys in 198411”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Fahy, G. M., MacFarlane, D. R., Angell, C. A. & Meryman, H. T. Vitrification as an approach to cryopreservation. Cryobiology 21, 407–426 (1984). source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisenone given

    Rewarming of vitrified organs can fail due to ice crystallization if rewarming is too slow or cracking from thermal stress if rewarming is not uniform.

    “However, rewarming of vitrified organs can similarly fail due to ice crystallization if rewarming is too slow or cracking from thermal stress if rewarming is not uniform.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductnone given

    All measurements represent distinct biological replicates taken from individual kidneys or rats, except for time series data, where kidneys/rats were resampled at each time point.

    “All measurements represent distinct biological replicates taken from individual kidneys or rats, except for time series data, where kidneys/rats were resampled at each time point.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationnone given

    The approach is translatable to other organs, and the intrinsic scalability of nanowarming suggests clinical translation is feasible.

    “While we demonstrate success in the rat kidney, our approach is translatable to other organs, and the intrinsic scalability of nanowarming suggests clinical translation is feasible.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    Statistical testing was two-sided, and a P value of <0.05 was considered significant.

    “Statistical testing was two-sided, and a P value of <0.05 was considered significant.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Directional freezing was tested for liver cryopreservation with partial success, but with only limited biologic outputs (including no survival transplants) and absent follow-on study.

    “Another approach called “directional freezing” was tested for liver cryopreservation with partial success, but with only limited biologic outputs (including no survival transplants) and absent follow-on study36.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Gavish, Z., Ben-Haim, M. & Arav, A. Cryopreservation of whole murine and porcine livers. Rejuvenation Res. 11, 765–772 (2008). source

  • Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.

    Premisereasoning

    IONPs remain in the organ vasculature and can be washed out during CPA perfusion unloading.

    “Importantly, since the IONPs remain in the organ vasculature, they can be washed out during CPA perfusion unloading.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationreasoning

    Nanowarming uniquely would improve donor/recipient matching by increasing the number of organs available for consideration at one time, whereas other approaches continue one-at-a-time decision making for every potential organ offer.

    “However, nanowarming uniquely would improve donor/recipient matching by increasing the number of organs available for consideration at one time, whereas other approaches continue the practice of one at a time decision making for every potential organ offer.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Nanowarming is independent of size.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    The authors have not fully characterized how nanowarmed organs perform compared to other categories of transplants, such as 36-48 h of cold storage.

    “Sixth, we have not fully characterized how nanowarmed organs perform compared to other categories of transplants, such as 36–48 h of cold storage.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisereasoning

    Due to limitations in convective warming rates, a higher concentration of CPA (9.3 M M22) was required with more significant toxicity than VMP.

    “Due to limitations in the convective warming rates, a higher concentration of CPA was required (9.3 M M22) with more significant toxicity than VMP.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationown data

    A trace amount of yellowish-brown material in some thin-walled capillaries of most nanowarmed kidneys could represent a small amount of retained IONPs.

    “There was a trace amount of yellowish-brown material in some of the thin-walled capillaries of most of the nanowarmed kidneys, best seen at the cortico-medullary junction and medulla but absent in glomeruli, which could represent a small amount of retained IONPs.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    The authors performed only a limited number of allogenic transplants and have not characterized any changes to the host immune response.

    “Fourth, we performed only a limited number of allogenic transplants and have not characterized any changes to the host immune response.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Fahy et al.'s transplant recipient had a nadir creatinine of ~4 mg/dL and a terminal creatinine of ~6 mg/dL.

    “Further, their transplant recipient had a nadir creatinine of ~4 mg/dL and a terminal creatinine of ~6 mg/dL”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Fahy, G. M. et al. Physical and biological aspects of renal vitrification. Organogenesis 5, 167–175 (2009). source

  • It may state two separate claims as one.

    Premisecitation

    Fahy et al.'s transplant sustained the life of the recipient but with significantly impaired renal function and the need for repeated blood transfusion.

    “While their transplant did sustain the life of the recipient, it did so with significantly impaired renal function and the need for repeated blood transfusion.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Fahy, G. M. et al. Physical and biological aspects of renal vitrification. Organogenesis 5, 167–175 (2009). source

  • It may state two separate claims as one.

    Premisecitation

    These other technologies extend preservation for broader organ sharing but only increase preservation by hours to a few days and do not achieve prolonged banking for months and potentially years.

    “While these extend preservation for broader organ sharing, they only increase preservation by hours to a few days and do not achieve prolonged banking for months and potentially years.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [37] Moers, C. et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N. Engl. J. Med 360, 7–19 (2009). source
    • cites [25] Nasralla, D. et al. A randomized trial of normothermic preservation in liver transplantation. Nature 557, 50–56 (2018). source
    • cites [38] Bruinsma, B. G. et al. Subnormothermic machine perfusion for ex vivo preservation and recovery of the human liver for transplantation. Am. J. Transplant. 14, 1400–1409 (2014). source

  • Probably not a substantial claim. It may state two separate claims as one.

    Interpretationreasoning

    These approaches, and the authors' approach, allow for national organ sharing, more time to perform cross-matching, and converting transplants to daytime events.

    “These approaches, and ours, allow for national organ sharing, more time to perform cross-matching, and converting transplants to daytime events.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationreasoning

    Nanowarming would allow better patient preparation prior to surgery, enable tolerance protocols that take days to weeks of conditioning or preparation, and increase organ utilization by banking organs even if an appropriate recipient has not yet been identified.

    “Further, nanowarming would allow better patient preparation prior to surgery, enable tolerance protocols that take days to weeks of conditioning or preparation, and increase organ utilization by banking organs even if an appropriate recipient has not yet been identified.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Nanowarming is independent of size.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    P values were adjusted for multiple comparisons.

    “P values were adjusted for multiple comparisons.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Recovery of hemoglobin levels suggested intact renal erythropoietin production, and normal calcium levels suggested preserved renal conversion of vitamin D to its active form.

    “Further, recovery of hemoglobin levels suggested intact renal erythropoietin production (and potentially hemoconcentration), and normal calcium levels suggested preserved renal conversion of vitamin D to its active form (1,25-dihydroxyvitamin D).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationreasoning

    The initial graft dysfunction might have been treated with dialysis in some clinical settings.

    “which might have been treated with dialysis in some clinical settings.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    The study was performed in a rat model with limited sample size (n = 4-8 per group) rather than in human or human-sized (e.g., porcine) kidneys.

    “First, it was performed in a rat model with limited sample size (n = 4–8 per group) rather than in human or human-sized (e.g., porcine) kidneys.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The Institutional IACUC committee from the University of Minnesota (protocol #2204-39970 A) approved all animal studies.

    “The Institutional IACUC committee from the University of Minnesota (protocol #2204-39970 A) approved all animal studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The authors have not determined which mechanisms and modes of injury led to the observed initial transplant dysfunction in the nanowarmed kidneys.

    “Fifth, we have not determined which mechanisms and modes of injury (e.g., apoptosis vs. necrosis, protein denaturation from high concentration CPA solutions) led to the observed initial transplant dysfunction in the nanowarmed kidneys.”
    Quote in the paperNot a substantial claim
66 of 66

  • The paper relies on this without support.

    Organ banking via cryopreservation would make organ transplantation elective and improve donor/recipient matching, equity in access, patient preparation, tolerance protocols, organ utilization, and graft and patient survival.

    “Organ banking via cryopreservation would make organ transplantation an elective rather than an urgent/emergent procedure and revolutionize how organs are used to treat human disease. Better donor/recipient matching, improved equity in access, better patient preparation, better transplant tolerance protocols, increased organ utilization, and enhanced graft and patient survival could all be enabled”

  • The paper relies on this without support.

    Vitrification followed by long-term transplant success with a kidney or any organ has never been reproducibly achieved.

    “Indeed, vitrification followed by long-term transplant success with a kidney (or any organ) has never been reproducibly achieved.”

  • The paper relies on this without support.

    Perfusion within capillaries allows sufficiently uniform delivery of CPAs and IONPs regardless of organ size.

    “In addition, perfusion within the capillaries allows sufficiently uniform delivery of CPAs and IONPs regardless of organ size.”

  • The authors state this as an assumption.

    The transport from the capillary vasculature into the extravascular space occurs across a membrane (composite basement and cell membrane) that can be described by coupled solute/solvent flow using irreversible thermodynamics as described by the Kedem-Katchalsky equations.

    “The transport from the capillary vasculature into the extravascular space is assumed to occur across a membrane (composite basement and cell membrane) that can be described by coupled solute/solvent flow using irreversible thermodynamics as described by the Kedem-Katchalsky (KK) equations.”

  • The authors state this as an assumption.

    The kidney can be represented by many parallel identical cylindrical/hexagonal prism units, each consisting of a central capillary surrounded by tissue.

    “In the Krogh model, the kidney is represented by many parallel identical cylindrical/hexagonal prism units, each consisting of a central capillary surrounded by tissue.”

  • The authors state this as an assumption.

    The processes in one Krogh unit are typical and representative of the processes in the whole organ.

    “The mass transfer in the whole kidney is analyzed by considering the processes in such a unit to be typical and representative of the processes in the whole organ.”

  • The paper relies on this without support.

    Nanowarming is independent of size.

    “In contrast, nanowarming is independent of size.”

  • The paper relies on this without support.

    Fahy and colleagues have never reproduced their finding of a successful rabbit kidney transplant.

    “but have never reproduced that finding.”

  • The paper relies on this without support.

    The current organ transplantation system is based on severe time constraints from organ acquisition to transplant, typically measured in hours.

    “The current system is based on severe time constraints from organ acquisition to transplant, typically measured in hours.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The IONP required for a single human kidney is ~0.8-1.6 gFe when the estimated amount is multiplied by ~2-4 times the vascular volume to ensure complete perfusion loading.

    “This amount should be multiplied by ~2 to 4 times the vascular volume to ensure complete perfusion loading14,15, elevating the IONP required for a single kidney to ~0.8–1.6 gFe.”

    From Physical vitrification and nanowarming at liter-scale CPA volumes: toward organ cryopreservation (2025) · cites this paper as [15]

    The Methods section, “Loading of nanoparticles” (page unavailable), describes perfusing IONPs into rat kidneys at 10 mg Fe/mL for 4–5 minutes. It does not give a 2–4-times-vascular-volume loading rule or estimate 0.8–1.6 gFe for a human kidney, so the quantitative extrapolation is not supported by this source. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Nanowarming of volumes up to 80 mL CPA and 30 mL biological at rates up to 50-100 °C/min has been published.

    “So far, we and others have published on nanowarming of volumes up to 80 mL CPA mL and 30 mL biological nanowarming at rates up to 50–100 °C/min14–19 (see Table S1).”

    From Physical vitrification and nanowarming at liter-scale CPA volumes: toward organ cryopreservation (2025) · cites this paper as [15]

    The Results section, “Kidney nanowarming and post-nanowarming assessment” (page not supplied), reports nanowarming a rat kidney at 72.0 ± 8.0 °C/min, within the claimed rate range. The Methods section, “Nanowarming of kidneys” (page not supplied), describes an approximately 80 mL coil bore, not 80 mL of CPA; our copy does not establish a 30 mL biological sample either. Thus this paper supports the nanowarming rate and biological-organ example, but not the claimed volumes. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • During CPA perfusion loading of organs, successfully perfused tissues may only equilibrate to ~92-94% concentration of full-strength CPA.

    “during CPA perfusion loading of organs, successfully perfused tissues may only equilibrate to ~92-94% concentration of full-strength CPA15,34”

    From Physical vitrification and nanowarming at liter-scale CPA volumes: toward organ cryopreservation (2025) · cites this paper as [15]

  • The predicted nanowarming rate for adult human kidneys (40 °C/min) is lower than previously reported rates achieved in rat kidneys (>60 °C/min).

    “the predicted nanowarming rate for adult human kidneys is lower than previously reported rates achieved in rat kidneys (40 °C/min versus >60 °C/min)15.”

    From Physical vitrification and nanowarming at liter-scale CPA volumes: toward organ cryopreservation (2025) · cites this paper as [15]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Serum protein components do not add up to total protein

    Minor

    In the control group, mean albumin plus globulin is 6.38 g/dL, not the reported total protein of 6.22 g/dL. The V-N group has the same discrepancy: 4.04 + 2.84 = 6.88 g/dL, rather than 6.76 g/dL.

    Reported 6.22 · recomputed 6.38

1 of 1

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. National Research Council. Realizing the Promise of Equity in the Organ Transplantation System (The National Academies Press, Washington, DC, 2022).

Cited by

Sorted by citations

Related

Metadata

Authors
Han, Z., Rao, J. S., Gangwar, L., Namsrai, B.-E., Pasek-Allen, J. L., Etheridge, M. L., Wolf, S. M., Pruett, T. L., Bischof, J. C., & Finger, E. B.
Affiliations
University of Minnesota (US)
Corresponding author
  • Bischof, John C.
  • Finger, Erik B.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-06-09
Volume
14
Issue
1
Pages
3407-3407
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-38824-8
PMC
PMC10256770
OpenAlex
W4380090567
Semantic Scholar
1b5960dcdad05e1bf3b7ca39b716e564aba64703
Cited by
173
References
51
Citations by year
2026: 58 · 2025: 53 · 2024: 46 · 2023: 16
FWCI
38.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (DK117425, DK131209, DK132211)
  • Biostasis Research Institute
  • U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (HL135046)
  • National Science Foundation (EEC-1941543)
Topics
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
  • Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
  • Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
Keywords
organ cryopreservation, vitrification, nanowarming, kidney transplantation, organ banking, alternating magnetic field heating, magnetic nanoparticles, ice crystal formation, thermal stress, renal function recovery, rat model
MeSH terms
Animals, Kidney, Male, Organ Preservation, Cryopreservation, Kidney Transplantation, Rats, Vitrification

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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