Dealing With Delayed Graft Function.

During deceased donor kidney transplantation, the transplanted kidney is subjected to repeated insults of variable severity. Donor death may entail hypotension, hypertension, microvascular thrombosis, sepsis, obstruction, drug toxicity, and in the case of donation after circulatory determination of death (DCDD), cessation of kidney blood flow. Retrieval surgery adds physical trauma and a brief period of kidney ischemia at body temperature, followed by instillation of preservation fluid and a period of cold storage, with or without machine perfusion. Implantation surgery imparts further insults, including exposure to a second period of warm ischemia during rewarming. Upon reperfusion, the kidney is exposed to recipient factors including uremic serum, foreign immune system, and variable blood pressures. Consequently, transplanted kidneys inevitably develop ischemia-reperfusion injury (IRI). The clinical manifestations of kidney IRI depend on its severity, ranging from immediate function with polyuria and clearance of creatinine, through “slow” graft function where urine output is achieved without significant reduction in serum creatinine, to delayed graft function (DGF). DGF is characterized by increasing serum creatinine, with or without oliguria, despite adequate graft perfusion. For clinical, registry and trial purposes, DGF is defined by the requirement for 1 or more dialysis treatments beginning the first week posttransplant.1 This definition is somewhat subjective because indications for dialysis may vary between clinicians and may include factors not directly resulting from IRI, including volume overload or hyperkalemia. The definition also does not incorporate the severity of injury. However, this definition is simple, binary, relevant to patients, clinicians, payers and registries, and has therefore been endorsed by the Food and Drug Administration for use in clinical trials.2 DGF is a significant and increasing problem, affecting 20%–40% of recipients of a donation after neurological determination of death kidney and 40%–60% of those receiving a DCDD kidney. With increasing use of kidneys from older and more marginal donors, DGF incidence will likely increase. For patients, requiring dialysis posttransplant causes anxiety, discomfort, need for additional tests, and prolonged hospitalization. Increased costs, surveillance scans and biopsies, and increased risks of acute rejection and graft failure are major problems for care providers. Addressing DGF, therefore, remains an important unmet need in kidney transplantation. Substantial efforts to prevent DGF are underway and can be categorized as donor based, preservation based, or recipient based. Donor-based interventions include donor hypothermia and, for DCDD kidneys, regional perfusion. Donor hypothermia showed initial promise as a preventive strategy3 but was not found to be useful in a recent large clinical trial.4 Regional perfusion may provide substantial protection5,6; however, clarification of this procedure is required within legal, ethical, and clinical contexts. Preservation-based strategies have shown benefits, particularly machine perfusion of organs ex vivo. A Cochrane review7 of 14 studies found high-certainty evidence that hypothermic machine perfusion reduces the risk of DGF compared with standard of care cold storage (relative risk, 0.77; 95% confidence interval, 0.67-0.90; I2 = 33%). Despite initial success in a nonrandomized study,8 a recent multicenter randomized trial9 of normothermic perfusion of DCDD kidneys with a warmed, oxygenated red-cell based perfusate did not demonstrate a reduction in DGF. Further trials exploring different approaches including pulsatility, solution (oxygen carrying or not), and duration of normothermia are planned or underway. Machine perfusion has been progressively adopted into clinical practice, although its high cost, labor requirements, and practicality have limited uptake in a global context. Recipient-based interventions include strategies to block graft and/or recipient-mediated immune responses and interventions designed to improve kidney perfusion. Induction therapy with steroid and polyclonal T-cell depleting antibodies are primarily used to inhibit alloimmunity but likely reduce IRI by inhibiting immune cell activation and migration into the kidney, respectively. Studies specifically addressing capacity to prevent DGF are few.10 Other inhibitors of innate and adaptive immunity, including complement inhibition, have not as yet demonstrated compelling efficacy in clinical trials. Perioperative fluid management has been acknowledged for decades as critical to maintaining perioperative BP and graft perfusion. Fluids are cheap and widely available and are therefore appealing. How much fluid and what type have been open to question. Standard clinical practice has been to administer larger volumes of fluids than in nontransplant surgery, targeting a high central venous pressure to ensure adequate graft perfusion. However, excessive volume expansion is a common consequence and may contribute to adverse outcomes, including delayed wound healing and pulmonary edema. Whether use of central venous pressure monitoring or more invasive and/or dynamic measures of blood pressure responsiveness to volume loading can be used to optimize fluid therapy and prevent DGF remains uncertain.11 Traditionally, potassium-containing fluids have been avoided because of perceived risks of posttransplant hyperkalemia and consequently normal saline (0.9% sodium chloride) has been the fluid of choice for many units. Albumin appeared beneficial in early studies; however, larger multicenter studies failed to confirm efficacy.11 Small studies of limited quality suggested balanced crystalloids may have advantages over saline, avoiding the hyperchloremic metabolic acidosis that occurs with large volume infusions of saline and has been associated with reduced blood flow and hypoperfusion in mechanistic studies.12 Hyperkalemia was not more common than with saline, attributed to the lack of acidosis. The BEST-Fluids trial, published this month in The Lancet,13 has provided clear answers to the question of whether choice of IV fluid can prevent DGF. In this pragmatic, double-blind, registry-embedded, randomized trial of 808 deceased donor kidney transplant recipients in Australia and New Zealand, the incidence of DGF was 30% among participants receiving Plasma-Lyte 148 (Plasmalyte), a balanced crystalloid, compared with 40% among those who received saline. The adjusted relative risk of 0.74 (95% confidence interval, 0.66-0.84) and absolute risk reduction of 10% are highly clinically meaningful, indicating that 1 case of DGF was prevented for every 10 patients treated with Plasmalyte. Treatment effects were consistent across a range of subgroups, including DCDD and donation after neurological determination of death, all tertiles of kidney donor risk index, and shorter or longer ischemic times. Plasmalyte use was associated with lower serum chloride and higher bicarbonate and pH than saline, and was safe and well tolerated. Hyperkalemia was similar in both groups. Given the study’s quality and generalizability,14 and Plasmalyte’s low cost and widespread availability, this should now become standard of care for peritransplant intravenous fluid therapy. Beyond the BEST-Fluids trial results, several issues remain. Cost savings remain to be proven but are likely substantial given the low differential and overall costs of Plasmalyte over saline in many parts of the world, including Australia, New Zealand, United States, and the United Kingdom,15 and the much larger costs of dialysis. The proposed mechanism of Plasmalyte in avoiding hyperchloremia may be applicable to other balanced crystalloids; however, subtle differences in tonicity and electrolyte content exist between Plasmalyte and others such as Lactated Ringers solution. Broader applicability should ideally be demonstrated rather than assumed. Use of machine perfusion was infrequent in BEST-Fluids and given the effectiveness of this technology at preventing DGF,7 further studies are needed to determine the relative benefits of Plasmalyte in patients receiving machine perfused kidney transplants. Identifying an IV fluid therapy that prevents DGF represents a significant advance for the kidney transplant field. However, the residual 30% incidence of DGF seen with Plasmalyte in this study indicates much room for improvement before we can conclude that we have dealt with DGF.