How Can the Kidney Be Protected During Liver Transplantation?

 

Kidneys are at risk during and after liver transplantation. How can they be better protected? The prescription for intraoperative care is simple to state, if difficult to achieve.

“The bottom line is that if we avoid hypertension, avoid severe blood loss, and avoid reperfusion injury, the kidney will be fine,” said Michael Ramsay, MD, chief of service for the department of anesthesiology and pain management at Baylor University Medical Center in Dallas, in a forum held in Boston at the American Transplant Congress. “But the question is, how do you do that?”

To give a sense of the scope of the problem, Ramsay said that at his own center, acute renal dysfunction occurs in as many as 78 percent of patients intraoperatively. “So it happens, and it happens because of all the rigors we have to put the patients through during transplantation.” Factors that increase the risk of renal injury include preexisting renal impairment, hemodynamic instability, perioperative bleeding, inflammation, and abdominal compartment syndrome.

Changes in operative technique may or may not have helped. The “piggyback” technique is typically used to preserve the patient’s own vena cava while controlling blood flow during transplantation, and it has largely supplanted the older technique of venovenous bypass. The latter technique “is controversial, and is used less these days,” Ramsay said. He noted that a recent analysis of clinical trials in one center where these options were used concluded that piggyback alone resulted in less transfusion, shorter stay in the intensive care unit, and less acute renal failure. However, that analysis compared sequential, not concurrent, outcomes, and a Cochrane review concluded that there was no evidence to support or refute venovenous bypass.

“It may be that once we get good biomarkers, that in those patients with significant hepatorenal dysfunction, some form of bypass may be better for them, but until we get that onsite, immediate marker, I think it is going to be hard to show,” he said.

Reperfusion syndrome can be a major problem during surgery as well, increasing the risk of renal failure. “Severe hypotension, arrhythmia, cardiac arrest, acidosis, fibrinolysis: this is a result of all those bad things that are inside that liver graft,” which accumulate during its explantation, hitting the heart when flow is restored through the implanted liver. It occurs in about 25 percent of liver transplant recipients. The risk can be reduced by flushing the graft out with saline before restoring flow to the heart, and also by the prophylactic use of vasopressors, Ramsay recommended.

Choice of immune suppression therapy matters

Immune suppression can also lead to kidney injury, and the choice of agents may have a big effect, said James Trotter, MD, medical director of liver transplantation at Baylor University Medical Center in Dallas.

“By any measure, a substantial number of patients come into liver transplant with renal dysfunction, and 30 percent have renal insufficiency,” meaning that many patients are already at risk for posttransplant renal complications. Twenty-eight percent of liver recipients experience renal failure within 10 years of transplantation, and one quarter of those, he noted, do so within the first year. This “front-loaded effect implicates the possibility of immunosuppression as a potential cause,” he said.

Calcineurin inhibitors (CNIs), including cyclosporine and tacrolimus, are probably the most important nephrotoxic agents used. Cyclosporine can cause ischemia, scarring, and fibrosis. As a result, “We’ve had an evolution of how we handle immunosuppression over the past 20 years,” he said. “To a large extent, avoidance of CNIs” is a mainstay of protecting the kidney in the context of liver transplantation.

Trotter noted that it is important to distinguish between immunosuppression in the induction phase, or the first few weeks after transplantation, and the maintenance phase, many months to years afterward.

The field is now moving toward biologic agents for induction, with such agents as daclizumab and alemtuzumab, and today about a quarter of patients receive these. There is also a movement toward using mycophenolates as CNI-sparing agents, he said.

“Right now, the most common immunosuppressive regimen at the time of discharge is mycophenolate plus CNIs,” he said, accounting for 70 percent of patients, rather than using a CNI as monotherapy. Although the number of patients never receiving a CNI is still small, that number is growing as well.

“Liver transplant patients undergo multiple hits to the kidney, on top of likely having underlying kidney dysfunction,” which often ultimately leads to chronic kidney disease, explained Josh Levitsky, MD, of Northwestern University in Illinois.

“It would be extremely valuable to have a biomarker that could identify who is at increased risk of posttransplant kidney disease,” he said, in order to tailor therapy to that risk. But such a biomarker has been slow in coming.

He noted the important distinction between diagnostic and predictive biomarkers. “Creatinine is not a good biomarker because injury has already occurred,” he said, and the same goes for epidermal growth factor receptor and proteinuria. “These are diagnostic, but the goal is to push it ahead to prediction.” A good biomarker, he said, should improve with successful intervention to prevent progressive kidney injury. “That would be a slam dunk.”

For acute kidney injury, the most promising markers are neutrophil gelatinase–associated lipocalin, interleukin-18, renal liver-type fatty acid binding protein, cystatin C, and kidney injury molecule-1. “But none provide a clear advantage beyond traditional clinical serum creatine,” according to a recent review, he said.

And for predicting chronic kidney disease, “There is actually less data, and at the present time, none are ready for use.”

In the search for such a predictive marker, Levitsky and colleagues are first looking retrospectively using serial collections of plasma, and comparing those who experience chronic kidney disease after transplantation with those whose long-term renal function is stable. Ultimately, he said, this might help determine whether a liver transplant patient would be better off with a simultaneous liver-kidney transplant.


August 2012 (Vol. 4, Number 8)