Clinical trial NCT06374121: Kidney Perfusion With or Without Absorption
Official title: A Single-center, Pilot, Prospective, Randomized Clinical Study of Hypothermic Oxygenated Perfusion With or Without Adsorption in Histologically Evaluated Kidneys Retrieved From Marginal Donors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Kidney Replacement
Keywords: Kidney perfusion
Absorption
Marginal donors
Lead sponsor: Mario Negri Institute for Pharmacological Research
Sponsor class: OTHER
First posted: 2024-04-18
Enrollment: 10
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: To compare the biochemical profiles of the perfusate obtained from 5 kidneys treated with perfusion and concomitant adsorption, with that of the perfusate obtained from 5 kidneys treated with perfusion without adsorption.
Primary purpose: TREATMENT

Brief summary: In this single-center, pilot, prospective, randomized study, the investigators will compare the biochemical profiles of the perfusate and the functional parameters of five kidneys perfused with Integrated PerLife® system and "PerSorb ECOS-300CY ™" sorbent (adsorption groups) with the profiles of the perfusate and functional parameters of five matched kidneys perfused with Integrated PerLife® system only (non-adsorption group). Kidneys from marginal donors with a clinical indication to pre-transplant histological evaluation (donor \>70-years-old or aged 60 to 69 years but with hypertension, diabetes and/or clinical proteinuria) will be allocated to perfusion with or without adsorption using a 1:1 randomization ratio. When both donor kidneys will have a score from 0 to 4, the two kidneys will be used for two single transplants. When one kidney will have a score from 0 to 4 and the other kidney will have a score of 5 or more, and when both kidneys will have a score from 5 to 7, the two kidneys will be transplanted together into the same recipient. If one kidney will have a score from 5 to 7 and the other kidney will have a score of 8 or greater, the two kidneys will be discarded. With the use of the minimization method, the randomization will be planned in order to have the same number of single or dual transplants in the perfusion kidney groups with or without adsorption. Donor selection, kidney evaluation and allocation and recipient management will be based on per center practice.

Detailed description: In recent years, growing interest has been addressed to the use of dynamic preservation of the kidneys as a tool to improve graft function and survival. Retrospective analyses and a randomized controlled trial showed that pre-transplant machine perfusion (MP) is associated with a lower incidence of delayed graft function (DGF) and improved one-year graft survival as compared with static cold storage. However, the overall beneficial effect of MP on transplant outcomes is largely driven by treatment effect in recipients of grafts from marginal donors.

Hypothermic oxygenated perfusion has been found to reduce early allograft injury and to improve post-transplant outcomes in a randomized controlled trial of liver transplantation from older donors. In vitro studies show that perfusion reduces endothelial damage to the sinusoidal capillaries and increases adenosine triphosphate production. As far as kidney transplantation is concerned, little data is available on the outcomes of grafts treated with perfusion. In rat models of allogeneic kidney transplant, perfusion-treated grafts displayed better short-term function, less tubular injury, fewer interstitial infiltrates of immune cells and milder endothelial activation than the untreated counterparts.

MP is not only beneficial per se. It can also be exploited as a means to deliver additional treatment to the graft. For instance, there is in vivo evidence that hemoadsorption improves renal blood flow during perfusion and reduces the release of cytokines and prostaglandins at reperfusion in a porcine model of kidney transplantation. Beneficial effects of hemoadsorption have been documented in the setting of continuous renal replacement treatment for septic shock. In the setting of pre-transplant organ conditioning, cytokine adsorption paired to normothermic perfusion has been found to reduce inflammatory gene expression and increase oxidative phosphorylation pathway gene expression in human kidneys. Whether adsorption paired to perfusion reduces the inflammatory response and whether this is of clinical relevance in transplantation of histologically evaluated kidneys from marginal donors, is worth investigating.

Eligibility criteria: Inclusion Criteria:

* Males and females older than 50 years eligible for single or dual kidney transplant from marginal donors identified according to the NITp criteria (\>70-year-old or 60 to 70 years with hypertension and/or diabetes and/or clinical proteinuria)
* Pre-transplant histological evaluation
* Histological score ≤ 7
* Written informed consent.

Exclusion Criteria:

* Any factor that represents a contraindication to receive a deceased donor kidney transplant according to the NITp criteria,
* Need for specific desensitization protocols because of a high immunological risk according to the NITp criteria,
* Active enrollment in concomitant intervention studies,
* Macroscopic vascular abnormalities that preclude the possibility of machine perfusion.

Primary outcomes:
measure: Oxidative stress markers
timeFrame: Every 30 minutes during clinical perfusion
measure: Acute kidney injury markers
timeFrame: Every 30 minutes during clinical perfusion
measure: Inflammatory cytokine markers
timeFrame: Every 30 minutes during clinical perfusion
measure: Complement activation markers
timeFrame: Every 30 minutes during clinical perfusion
measure: Vascular resistances
timeFrame: Every 30 minutes during clinical perfusion
measure: Perfusate sample collection
timeFrame: At clinical perfusion start, after 1 hour, then after 4 hours from start and every 2 hours thereafter, up to perfusion end
Secondary outcomes:
Other outcomes:
Locations:
city: Bergamo
country: Italy
facility: ASST - Papa Giovanni XXIII - U.O. Nefrologia e Dialisi/ Mario Negri Institute for Pharmacological Research - Clinical Research Center for Rare Diseases Aldo e Cele Daccò
state: BG
Study officials:
affiliation: Istituto Di Ricerche Farmacologiche Mario Negri
name: Giuseppe Remuzzi, MD
role: STUDY_CHAIR
References:
citation: Remuzzi G, Grinyo J, Ruggenenti P, Beatini M, Cole EH, Milford EL, Brenner BM. Early experience with dual kidney transplantation in adults using expanded donor criteria. Double Kidney Transplant Group (DKG). J Am Soc Nephrol. 1999 Dec;10(12):2591-8. doi: 10.1681/ASN.V10122591.
citation: Hosgood SA, Moore T, Kleverlaan T, Adams T, Nicholson ML. Haemoadsorption reduces the inflammatory response and improves blood flow during ex vivo renal perfusion in an experimental model. J Transl Med. 2017 Oct 25;15(1):216. doi: 10.1186/s12967-017-1314-5.
citation: Brouwer WP, Duran S, Kuijper M, Ince C. Hemoadsorption with CytoSorb shows a decreased observed versus expected 28-day all-cause mortality in ICU patients with septic shock: a propensity-score-weighted retrospective study. Crit Care. 2019 Sep 18;23(1):317. doi: 10.1186/s13054-019-2588-1.
citation: Hosgood SA, Hoff M, Nicholson ML. Treatment of transplant kidneys during machine perfusion. Transpl Int. 2021 Feb;34(2):224-232. doi: 10.1111/tri.13751. Epub 2020 Oct 19.
citation: Ferdinand JR, Hosgood SA, Moore T, Ferro A, Ward CJ, Castro-Dopico T, Nicholson ML, Clatworthy MR. Cytokine absorption during human kidney perfusion reduces delayed graft function-associated inflammatory gene signature. Am J Transplant. 2021 Jun;21(6):2188-2199. doi: 10.1111/ajt.16371. Epub 2020 Nov 22.