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Recent Developments in |
Liver Transplantation | ||
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The success rate of liver transplantation has improved over the last decade, largely as a result of improvements in immunosuppression, surgical technique, and experience in the management of liver allograft recipients. Despite these advances, however, liver transplantation remains a formidable undertaking requiring a concerted team effort, tremendous resources, and deep institutional commitment. The role of appropriate renal care in the management of these patients is critical. Renal insufficiency often complicates the course of advanced liver disease and contributes significantly to posttransplant morbidity. One study of 102 liver allograft recipients revealed that 25% suffered from renal impairment prior to transplantation, and 67% had impaired posttransplant renal function.1 The same study identified pretransplant renal dysfunction as an independent predictor of postoperative mortality. A study from the University of Michigan reported similar findings.2
Numerous factors assault renal function as a result of liver disease pretransplant as well as during the perioperative, posttransplant recovery, and long-term follow-up periods. In these patients, renal dysfunction potentially results from hepatorenal syndrome, preexisting renal disease from other underlying medical problems, intraoperative complications, graft dysfunction, acute tubular necrosis (ATN) from postoperative sepsis, and toxic injury from the variety of therapeutic agents required to combat rejection and infection.3-6
Renal disease often coexists with liver disease in patients undergoing liver transplant evaluation. Although severe renal insufficiency was previously considered an absolute contraindication to liver transplantation, this is no longer the case. Reports of successful liver and kidney transplantation in patients with advanced disease of both organs have changed the assessment of renal disease in this population.7,8 The consultative evaluation should focus on identifying patients with advanced, fixed renal disease who may benefit from combined liver-kidney transplantation. The preoperative evaluation should characterize renal function individually, which may alter perioperative or postoperative care. Other problems that may contribute to problems during recovery include various acid-base abnormalities from liver disease, including respiratory alkalosis, metabolic alkalosis due to diuretics, lactic acidosis which may develop spontaneously or in the setting of spontaneous bacterial peritonitis, renal tubular acidosis, and Fanconi's syndrome.9-11 All liver transplant candidates should be screened for these problems which may affect preoperative and postoperative management.
Clinical evaluation of renal functional status in patients with advanced liver disease is not always straightforward. First, high levels of bilirubin can interfere with the measurement of serum creatinine in deeply jaundiced patients. In addition, falsely low serum creatinine levels in wasted individuals may mask underlying renal impairment. Severe nutritional depletion and deranged protein metabolism associated with advanced liver disease can produce a situation in which the serum creatinine reflects diminished protein stores and reduced hepatic function, rather than the true functional status of the kidneys.12
We have measured the glomerular filtration rate (GFR) pretransplant in over 400 patients and noted a lack of correlation of the pretransplant GFR with the serum creatinine. Furthermore, when we separated these patients into quartiles depending on their pretransplant GFR, we found that patients in the lowest quartile had an average serum creatinine of 1.4 ± 0.6 mg/dL, despite an average GFR of only 47 mL/min. Thus, the serum creatinine may be a highly unreliable index of renal function pretransplant. These results support the findings of Papadakis and Arieff,12 who noted a progressive decline in GFR without changes in serum creatinine in a series of cirrhotics. Serum creatinine failed to rise above normal even when the GFR declined to less than 25 mL/min. In fact, the creatinine clearance overestimated inulin clearance by a factor of 2. We therefore recommend assessing glomerular filtration rate by a method other than creatinine clearance. At present, we utilize the glofil technique performed with a single injection of I125-iothalamate. We have found that this method estimates the true glomerular filtration rate more reliably than does creatinine clearance.
The volume status of patients awaiting liver transplantation must be evaluated very carefully. Clinical assessment may be misleading, and central venous pressure monitoring including Swan-Ganz catheterization should be used whenever necessary. A reduction in the effective plasma volume may be devastating and can result in rapid and irreversible decline in renal function. Caution must be exercised in the prescription of diuretics or performance of paracentesis to relieve massive ascites. Furthermore, diarrhea, infection, or sepsis may lead to further deterioration of renal function prior to liver transplantation. Lactulose and other agents to treat hepatic encephalopathy must be used carefully, and gastrointestinal bleeding should be treated promptly before it leads to hypotension and renal failure. Use of nephrotoxic antibiotics and nonsteroidal antiinflammatory drugs should be avoided in the patient awaiting liver transplant.
Despite careful clinical management, some patients progress to hepatorenal syndrome. Hepatorenal syndrome (HRS), characterized anatomically by severe and nonresponsive constriction of the renal vasculature, is defined as the presence of renal failure in patients with hepatic failure in whom no other cause of renal failure can be diagnosed. Volume depletion must be ruled out. These patients exhibit pronounced sodium and water retention and fail to respond to volume expansion or other measures usually successful in correcting prerenal kidney failure. The diagnosis of HRS requires the following: severe liver disease, absence of a primary renal disease, benign urinary sediment, absence of proteinuria, inadequate urine output, elevated serum creatinine which usually rises over time, urinary sodium excretion less than 10 mEq/L or a fractional excretion of sodium less than 1%, absence of volume depletion as assessed by central hemodynamic monitoring, failure to respond to volume repletion, and the absence of any other cause of renal hypoperfusion such as heart failure or hypotension.13
Prior to the advent of liver transplantation, the outcome for patients with HRS was uniformly fatal. Nevertheless, kidneys from such patients could be successfully transplanted,14 indicating that HRS was a functional and reversible form of renal failure. If liver transplantation is anticipated, all efforts should be made to prevent patients from developing hepatorenal syndrome by attending to the factors listed above. A patient who develops hepatorenal syndrome despite all efforts to prevent it should be supported vigorously until liver transplantation can be performed. Renal function recovers following liver transplantation in patients with HRS.15,16
Patients awaiting liver transplantation may also have intrinsic renal disease, either in the form of preexisting renal damage from diabetes mellitus or obstructive uropathy, or preexistent end-stage renal disease (ESRD). In addition, ATN may develop as a result of hypotension, nephrotoxic drugs, or contrast media used in diagnostic studies. Glomerulonephritis may occur in patients with cirrhosis; most common is a form of IgA nephropathy which can produce mesangial deposits. Membranoproliferative glomerulonephritis and poststreptococcal glomerulonephritis have also been described in patients with liver disease. Hepatitis B is associated with various forms of renal disease, the most common of which is membranous nephropathy, but membranoproliferative glomerulonephritis and cryoglobulinemia have also been described. Finally, hepatitis B can cause kidney disease due to vasculitis in the form of polyarteritis nodosa, and hepatitis C has been associated with an increased incidence of cryoglobulinemia.17-25
The liver transplant procedure is an extremely difficult one, associated with major hemodynamic changes. In phase one or the preanhepatic phase, the liver is resected while the normal circulation is maintained. At the end of this phase, hemodynamics are altered with increased sympathetic nervous system activity and suboptimal renal perfusion. The anesthesiologist and the surgeon address intraoperative hemodynamic problems by adjusting operative technique and intraoperative fluid management in an attempt to decrease the impact on renal function. Just prior to the anhepatic phase of the operation, the vena cava is clamped. This by itself may influence renal function, but with the use of a venovenous bypass, the effects of increased caval pressures are usually ameliorated.5 Venovenous bypass reduces renal congestion, improves hemodynamic stability, and avoids the build up of toxic metabolites due to drainage of the portal circulation into the central circulation. When venovenous bypass is utilized, better urine output is maintained during all phases of the operation.26
Changes in calcium, glucose, and other electrolytes and alterations in acid-base balance must also be addressed by the anesthesiologist. Reduction in total ionized calcium is common in patients with severe liver disease. During surgery, ionized calcium may fall even further, but on occasion corrective measures overshoot the mark and lead to hypercalcemia. Hypercalcemia may also occur due to the production of a parathyroid-like hormone in patients with hepatocellular carcinoma. Calcium levels should be monitored carefully in patients undergoing transplantation for hepatocellular carcinoma.
During the preanhepatic phase, portal hypertension, coagulation defects, thrombocytopenia, and the liver resection itself may result in massive blood loss. If large volumes of citrated blood are transfused, calcium may be chelated rapidly and levels may drop abruptly. In addition, the ability of a newly transplanted liver to convert citrate to bicarbonate may be impaired. By the end of the preanhepatic phase, citrate levels have usually reached their peak. Vigorous calcium supplementation is not required at this point, even though mild hypocalcemia may be present. If the calculated free calcium deficit is replaced at this time, severe hypercalcemia can develop when the liver converts citrate to bicarbonate, releasing the chelated calcium. Careful attention to calcium fluxes during the intraoperative phase will avoid this problem.27-32
If hypocalcemia develops, myocardial depression and left ventricular dysfunction may follow as a consequence. Venovenous bypass may cause hemodilution with further reduction in ionized calcium. Once the new liver is implanted and the reperfusion phase has started, donor liver perfusion fluid is released into the circulation. This fluid is often hypothermic, acidic, and hyperkalemic. If the patient is hypocalcemic at this point, the risk of systemic hypotension and cardiac arrhythmias increases further.
Disturbances of other electrolyte levels, particularly potassium and sodium, are common during liver transplant surgery. Abnormal electrolyte levels may antedate the surgery, and careful attention must be paid to fluid and electrolyte management during surgery. Hypomagnesemia is also common in patients awaiting liver transplantation, possibly associated with the use of diuretics. If magnesium is not repleted, seizures may develop in patients treated with cyclosporine or tacrolimus. These drugs cause wasting of magnesium through renotubular effects and may exacerbate a mild underlying hypomagnesemia. Finally, various acid-base disturbances may be present in the liver transplant candidate. The most common is a mixed respiratory alkalosis with a mild metabolic acidosis, which occurs in patients with various degrees of functional renal failure preoperatively. Use of spironolactone in these patients commonly produces a mild renal tubular acidosis and hyperkalemia. Careful attention to acid-base status is critical in managing these patients.11,27
Although cyclosporine and tacrolimus have increased patient and graft survival following liver transplantation, this achievement has come at the price of nephrotoxicity. In an early report examining only serum chemistries, severe acute renal function occurred early in the postoperative course of 21% of adult and 22% of pediatric liver transplant recipients.6 An immediate fall in GFR may follow administration of the immunosuppressive drugs.
Table 1 shows our own series from Dallas utilizing iothalamate clearance studies in patients receiving cyclosporine. The GFR falls by almost 40% in the first six weeks postoperatively, and five-year follow-up demonstrates stability of renal function. Other studies have documented similar impairments in long-term renal function using various measurements of GFR.33-35 We have been unable to correlate the use of other nephrotoxic agents (such as amphotericin and aminoglycosides), septic shock, infection, ICU status, or any other factor known to affect renal function with the severity of the decline in posttransplant kidney function.36 Many therapeutic interventions aimed at reversing the nephrotoxicity of cyclosporine have been studied in kidney transplant patients; none has proved helpful in liver transplant patients.37-42
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Table 1.Long-term renal function in liver transplant recipients |
With the introduction of tacrolimus, transplanters hoped that renal dysfunction would present less of a problem. Initial studies from the University of Pittsburgh,43,44 however, demonstrated an almost invariable rise in serum creatinine, and a first-time dialysis requirement of approximately 5%. This acute nephrotoxicity was highly reversible, responding to downward adjustments of tacrolimus dosage. It is clear, however, that tacrolimus may produce nephrotoxicity similar to that caused by cyclosporine. In the recently completed U.S. multicenter trial of tacrolimus versus cyclosporine for immunosuppression of liver transplant recipients, there was no difference in effects on renal function, and this has been confirmed in reviews from three single centers.45-47
How then can one manage the immunosuppression in these patients to maximize therapeutic effect and minimize nephrotoxicity? In Dallas we utilize an individualized approach. In patients who present with a pretransplant GFR of less than 30 mL/min or oliguria, we withhold cyclosporine in the early postoperative period. Cyclosporine is not given until a brisk diuresis or an improvement in the serum creatinine occurs. In its place steroids and azathioprine are utilized. Studies utilizing OKT3 induction have demonstrated a preservation of renal function during the first 30 days posttransplant,48 but we do not use induction therapy with antilymphocyte agents unless the dysfunction persists for more than seven to ten days.
In patients with persistent nephrotoxicity or a decline in renal function, we utilize a cyclosporine-sparing protocol. Target levels of cyclosporine are dropped from our usual range of 300-400 ng/mL to 150-200 ng/mL by the TDX assay. In addition, azathioprine at 1.5-2 mg/kg is given along with steroids. This strategy has been very successful in preserving renal function. We have analyzed an initial group of 500 patients treated primarily with cyclosporine immunosuppression. We divided the patients into quartiles depending upon their pretransplant GFR. The lowest quartile had an average GFR prior to transplant of only 47 mL/min. The highest quartile had an average GFR of 140 mL/min. Despite an equal incidence of rejection and use of OKT3 throughout the study, there were more patients on azathioprine at all time points in the lowest quartile. We have also consciously decreased our cyclosporine dosage in these patients while increasing azathioprine. This strategy has succeeded in that patients in the lowest quartiles who had an average GFR of 47 mL/min pretransplant still maintain an average GFR of 49 mL/min at four years posttransplant. On the other hand, the patients with GFRs of 140 mL/min (the highest quartile) had an average GFR of only 75 mL/min at four years. Reliance on serum creatinine obviously led to an underestimation of nephrotoxicity of cyclosporine in this group of patients. However, in the entire group of 500 patients followed out to five years, we have had only seven documented cases of what was felt to be cyclosporine toxicity leading to end-stage renal disease. This is a rate of approximately 1.5%. This group of patients will be followed for a much longer period to determine if the seven- to ten-year exposure to cyclosporine or a reduced GFR for this length of time will lead to a higher incidence of end-stage renal disease. With a 70% five-year patient survival, however, we believe that this strategy is worth the trade-off.
Caution is advised in withdrawing cyclosporine totally in an attempt to improve renal function. A recently published study from the Mayo Clinic examined this approach in 12 liver transplant recipients.49 All 12 patients were stable at one year posttransplant with good allograft function but with serum creatinine greater than 2.1 mg/dL or renal clearance less than 35 mL/min. In attempt to improve renal function, cyclosporine was gradually withdrawn, and azathioprine and steroids were maintained. Sustained improvement in renal function did not occur in these patients; the serum creatinine decreased from 2.5 mg/dL to only 2.4 mg/dL. However, six of these 12 patients developed rejection after cyclosporine withdrawal. Two of these demonstrated chronic rejection. Therefore, total withdrawal of cyclosporine is not indicated in these patients. Our experience is that maintenance of cyclosporine at low levels will preserve graft function and preserve renal function even at levels of GFR less than 40 mL/min.
Patients with HRS are often excluded from liver transplantation because of high risk. This syndrome, however, is clearly functional and reversible.13-16 Our own experience in HRS leads us to offer liver transplantation to these patients. Although HRS patients are more likely to be ICU-bound and to require dialysis than non-HRS patients, results in our center have been good. In a group of 56 HRS patients, the four-year actuarial survival was 60%, compared to 70% in non-HRS patients. Furthermore, most patients recovered renal function, although 10% progressed to ESRD.50 Thus, although transplantation of HRS patients is more costly, a good outcome can be achieved.
We do not, however, recommend combined liver-kidney transplantation for HRS. Combined transplantation should be reserved for those patients with dual end-organ failure.7,8 We have performed combined liver-kidney transplants in 20 cases. The four-year survival of these patients is identical to that of HRS patients who received liver transplants only. We therefore recommend liver transplantation alone in patients with HRS. In patients with poor renal function not thought due to HRS, we perform a preoperative or intraoperative renal biopsy to document severe intrinsic renal disease before proceeding with combined transplantation. If intrinsic renal disease is not found, we proceed with liver transplantation alone.
The patient with end-stage liver disease potentially has a variety of concomitant electrolyte and renal disorders, and the process of liver transplantation is highly likely to exacerbate these. With careful evaluation and monitoring in addition to appropriate intervention, a uniformLy good outcome may be possible even for the most complicated patients.
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