Sodium Levels and Age Predictive of Liver Transplant Mortality

CAMBRIDGE, England, Aug. 3 -- Adding serum sodium levels to the mix of factors considered when allocating donor livers may help improve graft and recipient survival, authors of two studies reported.

Among more than 5,100 liver transplant patients in the U.K. and Ireland, both severe hyponatremia and severe hypernatremia were independent predictors of death after surgery, wrote Muhammad F. Dawwas, M.D., of Addenbrooke's Hospital here, in the August issue of Transplantation.

A second study, by Angelo Luca, M.D., of the Mediterranean Institute for Transplantation and Advanced Specialized Therapies in Palermo, Italy, and colleagues, found that among patients with cirrhosis, both serum sodium and age were predictors for death, independent of the Model for End-Stage Liver Disease (MELD) score.

Together, they highlight both the clinical importance of sodium levels in patients with advanced liver disease, and the value of evidence-based approaches to the allocation of severely limited resources such as donor organs, wrote Scott W. Biggins, M.D., M.A.S., of the University of California in San Francisco, in an accompanying editorial.

"The articles by Luca et al. and Dawwas et al. solidify the importance of sodium as predictor of urgency for and risk from liver transplantation and fuel the debate over how to apply these risk assessments to rational improvements in liver graft allocation," he wrote.

In the first study, Dr. Dawwas and colleagues retrospectively reviewed the effect of donor recipient serum sodium concentrations on post-transplantation mortality.

In a risk-adjusted analysis, they looked at sodium levels and survival for all adults with chronic liver disease who received a first single-organ liver transplant in the U.K. and Ireland from March 1994 to April 2005.

They assessed survival of the 5,152 patients during and beyond the first 90 days after surgery, and at three years, adjusting for recipient, donor, and graft characteristics.

They found the 541 patients with severe hyponatremia (less than 130 meq/L sodium) had a higher risk-adjusted mortality at three years compared with the 3,066 patients in the normal reference range for sodium (135-145 meq/L, hazard ratio 1.28, 95% confidence interval, 1.04-1.59, P<0.02).

But they also found that all of the excess mortality in the severely hyponatremic patients occurred only in the first three months after surgery (hazard ratio 1.55, 95% CI, 1.18-2.04; P <0.002); after 90 days, there were no significant differences in mortality in this group.

On the other end of the Na spectrum, the 81 severely hypernatremic patients (those with serum sodium greater than 145 meq/L) were at an even greater risk for death compared with normonatremic patients (overall hazard ratio 1.85, 95% CI, 1.25-2.73; P<0.002).

As with the hyponatremic patients, the risk was greatest within the first 90 days (hazard ratio 2.29, 95% CI, 1.42-3.70, P<0.001) but was not significant thereafter (hazard ratio 1.12; 95% CI, 0.55-2.29, P=0.8).

In contrast, the 1,127 patients with mild hyponatremia (130-134 meq/L) had similar risk-adjusted mortality to those with normal sodium at corresponding time points.

The authors concluded that sodium "is an independent predictor of death following liver transplantation," and that "attempts to correct the sodium toward the normal reference range are an important aspect of pretransplantation management."

In the second study, Dr. Luca and colleagues studied whether adding objective variables could improve prognostic accuracy of the MELD score.

They retrospectively reviewed data on 310 consecutive patients with cirrhosis who underwent elective transjugular intrahepatic portosystemic shunt placement from July 1995 through March 2005.

The authors conducted bivariate and multivariate analyses and created proportional hazard Cox regression models. They evaluated the ability of various models to predict early death by calculation area under the receiver operating characteristic curve and likelihood ratios.

They then validated their finding by applying them to a second cohort of 451 consecutive patients with cirrhosis who were on the waiting list for liver transplantation.

They found that in bivariate age, serum bilirubin, serum creatinine, international normalized ratio of prothrombin time (INR), serum albumin, serum sodium, and MELD score all correlated with time to death.

In addition, multivariate analysis revealed that three factors -- MELD score, serum sodium, and age -- were independently associated with the risk of death.

When they evaluated an integrated MELD model that incorporated both serum sodium and patient age, they found that it was superior to the standard MELD at predicting 12-month mortality, as evidenced by an increase in the area under the curve of 13.4%, and an increase in the likelihood ratio from 23.5 to 48.2.

In his editorial, Dr. Biggins lauded the suggestions for improving the accuracy of predictive models for success or failure of liver transplantation, but cautioned that basing allocation on age, gender, or other immutable demographic characteristics is ethically unsound.

"The onus is on the transplant community to continuously refine the allocation system such that livers are targeted to patients who need them most without sacrificing the overall utility of this limited resource to society," he wrote.

"Application of outcome models to this laudable effort must continue to be held to this high standard. The bar is high and, clearly, when evaluating a candidate variable for use in organ allocation, the criteria of 'objective, reliable, and reproducible' are necessary but not sufficient," Dr. Biggins said.