A Heated Debate in Organ Preservation
The future of organ transplantation is not just about finding more donors, but also about preserving their precious gifts in the perfect environment.
Imagine a life-saving kidney journeying from donor to recipient not in a cooler packed with ice, but in a miniature incubator that keeps it warm, pumping, and alive. This isn't science fiction—it's the forefront of transplant medicine, where the simple question of temperature is revolutionizing how we save lives.
For decades, the gold standard for preserving donor kidneys has been static cold storage (SCS), a simple method where organs are placed on ice to slow their metabolism and reduce oxygen demand 1 4 . However, as the global organ shortage forces transplant teams to use organs from older, sicker donors, this one-size-fits-all approach is showing its limits. In the United States alone, nearly 20% of recovered kidneys were discarded in 2023, often due to quality concerns exacerbated by cold storage 2 .
Enter the dynamic world of machine perfusion, a technology that actively pumps preservation solutions through the organ's blood vessels. This field is now divided into a heated debate: should we "keep it cool" with advanced hypothermic techniques, or "warm things up" with normothermic approaches? The answer could determine whether thousands of waitlisted patients receive their life-changing transplant.
Slowing metabolism to reduce oxygen demand and extend preservation time.
Maintaining physiological conditions for assessment and repair capabilities.
Hypothermic Machine Perfusion (HMP) preserves organs at 4-10°C while maintaining a continuous, pulsatile flow of preservation solution 4 8 . Unlike simple cold storage, this method helps flush out toxic metabolites and reduces inflammation.
The benefits are well-established. A landmark European trial demonstrated that HMP significantly reduced delayed graft function (DGF)—the need for dialysis shortly after transplant—compared to SCS, with an adjusted odds ratio of 0.57 1 . For vulnerable kidneys from extended criteria or circulatory death donors, this can be the difference between immediate function and prolonged recovery.
The latest innovation in this cold arena is the addition of oxygen, known as Hypothermic Oxygenated Machine Perfusion (HOPE). By introducing oxygen to the cold perfusion, HOPE aims to restore mitochondrial function and generate small amounts of cellular energy (ATP), further reducing injury when blood flow is restored 4 6 . The European COMPARE trial showed that in older donation after circulatory death (DCD) kidneys, HOPE resulted in fewer severe complications and lower rates of graft loss compared to standard HMP 4 .
Normothermic Machine Perfusion (NMP) represents a paradigm shift. Instead of slowing down metabolism, it maintains the kidney at near-physiological temperatures (around 37°C) with an oxygen- and nutrient-rich perfusate, often based on red blood cells 1 3 . The organ remains in a functionally active state, potentially allowing for real-time viability assessment and active repair before transplantation 2 .
This warm approach offers several theoretical advantages. By maintaining normal metabolic activity, NMP enables transplant teams to objectively assess kidney function—measuring urine production, nutrient consumption, and waste product clearance—before deciding to transplant 2 . This could dramatically reduce discard rates of potentially usable organs.
Furthermore, NMP serves as an excellent platform for targeted therapies. Researchers are exploring its use to deliver stem cells, gene therapies, and pharmacological agents directly to the kidney without systemic effects on the recipient 8 . A groundbreaking 2025 study even demonstrated that NMP could efficiently distribute kidney tubuloids (miniature lab-grown kidney structures) throughout a human kidney, opening possibilities for regenerative medicine .
NMP is technically more complex than cold preservation. Maintaining metabolic viability ex-situ is demanding, particularly for already injured kidneys 2 . The technology requires careful management of perfusate composition, oxygenation, and waste removal, especially during prolonged perfusions.
| Technique | Temperature | Principle | Key Advantages | Key Challenges |
|---|---|---|---|---|
| Static Cold Storage (SCS) | 0-4°C | Slows metabolism to reduce oxygen demand | Simple, cost-effective, widely available 1 | Limited preservation time, no functional assessment 4 |
| Hypothermic Machine Perfusion (HMP) | 4-10°C | Continuous cold perfusion with solution | Reduces DGF, better early function vs. SCS 1 4 | Limited metabolic activity, assessment capabilities |
| Hypothermic Oxygenated Perfusion (HOPE) | 4-10°C | Adds oxygen to HMP to support energy production | May improve outcomes in high-risk kidneys 4 | Protocol standardization, optimal oxygen dosing 4 |
| Normothermic Machine Perfusion (NMP) | 33-37°C | Maintains near-physiological function | Enables viability assessment and targeted repair 1 2 | Technical complexity, cost, perfusate management 2 |
The NKP1 trial, a phase 1 study published in Nature Communications in 2025, represents one of the most ambitious clinical investigations of prolonged warm perfusion to date 5 . This single-center study pushed the boundaries of how long a kidney could be maintained outside the body while remaining transplantable.
Deceased donor kidneys were recovered using standard clinical techniques and initially preserved with static cold storage during transport.
Upon arrival at the transplant center, kidneys were transferred to a custom-designed NMP device that included an organ chamber, perfusion pump, oxygenator, and heat exchanger.
The renal artery was connected to the device via a PTFE vascular graft, with careful cannulation of the renal vein.
Kidneys were perfused at 37°C with a leukocyte-depleted, oxygenated red-cell-based solution. The mean arterial pressure was maintained at approximately 75 mmHg.
The perfusate contained nutrients (glucose, amino acids), antibiotics, insulin, and other components to support metabolic function.
Perfusion continued for 2.2 to 23.4 hours (median 5.8 hours) with continuous monitoring of vascular flow, resistance, and urine output 5 .
The primary outcome—30-day graft survival—was 100% in all 36 transplanted kidneys, matching the control group 5 . This safety profile was remarkable given the extended preservation times.
Perhaps most impressively, despite significantly longer total preservation times (15.7 hours for NMP vs. 8.9 hours for controls), clinical outcomes were equivalent. The delayed graft function rate was 36% in the NMP group versus 38% in controls, and graft function at 12 months was comparable (eGFR 46.3 vs. 49.5 mL/min/1.73m²) 5 .
The study also identified strong correlations between biomarkers measured during ex-situ perfusion and post-transplant outcomes. For instance, changes in glutathione S-transferase (GST) levels during NMP correlated with 12-month graft function (R=0.54, p=0.001), suggesting NMP could provide valuable predictive information about long-term kidney performance 5 .
| Outcome Measure | NMP Cohort (n=36) | Control Cohort (n=72) | Statistical Significance |
|---|---|---|---|
| 30-Day Graft Survival | 100% | 100% | Not significant |
| Delayed Graft Function (DGF) | 36% | 38% | Not significant |
| 12-Month eGFR (mL/min/1.73m²) | 46.3 | 49.5 | p = 0.44 |
| Total Preservation Time (hours) | 15.7 | 8.9 | p < 0.0001 |
| Patient Survival at 12 Months | 97% | 99% | Not significant |
| Tool | Function | Examples & Notes |
|---|---|---|
| Perfusion Devices | Provides mechanical platform for perfusion | LifePort (HMP), Kidney Assist (HMP/NMP), OrganOx Metra (NMP) 4 6 |
| Preservation Solutions | Maintains cellular integrity during preservation | KPS-1 (HMP), Belzer MPS, Custodiol, HTK 8 |
| Oxygen Carriers | Delivers oxygen to organ tissues during perfusion | Red blood cell-based solutions, artificial hemoglobin solutions, acellular solutions 3 |
| Biomarker Assays | Assesses organ viability and injury | Lactate dehydrogenase (LDH), Neutrophil gelatinase-associated lipocalin (NGAL), Kidney Injury Molecule-1 (KIM-1) 1 |
| Vascular Cannulas | Connects organ vasculature to perfusion device | Various sizes for arterial and venous connection 5 |
| Metabolic Supports | Provides nutrition during normothermic perfusion | Glucose, amino acids, insulin 5 |
Mechanical platforms that simulate physiological conditions for organ preservation.
Specially formulated solutions that maintain cellular integrity during preservation.
Tools to assess organ viability, injury, and function during perfusion.
As research progresses, the question is increasingly shifting from "which temperature is better" to "which temperature is right for this specific kidney" 2 . The future likely holds a more nuanced approach where perfusion strategies are tailored to each organ's unique needs and injury profile.
Sequential perfusion strategies show particular promise—beginning with HMP for transport and initial protection, followed by end-ischemic NMP for assessment and repair before transplantation 1 3 . This hybrid approach leverages the strengths of both temperatures while mitigating their individual limitations.
The ongoing development of perfusate biomarkers that can accurately predict post-transplant function during NMP represents another exciting frontier 5 . As these tools mature, they could provide transplant teams with unprecedented confidence in assessing marginal organs, potentially adding thousands of viable kidneys to the donor pool.
Furthermore, NMP's potential as a therapeutic platform continues to expand beyond simple preservation. From delivering stem cells to modulate immunogenicity 8 to using gene therapies to repair damaged tissues , the ability to treat organs ex vivo could transform transplantation outcomes.
The temperature debate in kidney preservation is more than academic—it represents a fundamental shift from viewing donor organs as static commodities to treating them as living, responsive entities that can be assessed, improved, and personalized for their recipients. As these technologies evolve, the hope is that fewer patients will die waiting for a transplant, and more transplanted kidneys will provide decades of life-sustaining function.
The optimal temperature for kidney preservation may not be a single number, but a carefully orchestrated sequence—a symphony of cold and warm—that honors the incredible gift of donation by ensuring every viable organ reaches someone in need.