Kidney Dysfunction After Liver Transplantation

Objectives

This chapter will:

1.
Present the risk factors for early postoperative acute kidney injury after orthotopic liver transplantation (OLT), including pre-OLT, intraoperative factors, and post-OLT factors.
2.
Present the factors affecting renal dysfunction in long-term survivors.
3.
Suggest strategies to reduce risk factors.

Acute kidney injury (AKI) is common immediately after orthotopic liver transplantation (OLT), whereas chronic kidney disease (CKD) and end-stage renal disease (ESRD) increase in incidence with time. The cumulative risk of developing chronic renal failure post-OLT has been described to be approximately 8%, 14%, and 18% at 12, 36, and 60 months, respectively. Therefore identifying the risk factors for AKI or progressive CKD after OLT and developing strategies to either minimize the risks for AKI or retard the progression of CKD should be an integral part in the management of OLT recipients. Assessment of renal function pre- and post-OLT and an overview of the literature on the risk factors for early postoperative AKI and those affecting progressive CKD in long-term survivors are presented. Suggested therapeutic approaches to prevent, halt, or ameliorate renal dysfunction are also discussed.

Assessment of Renal Function Before and After Liver Transplantation

Although serum creatinine (SCr) is readily accessible in routine clinical practice, assessment of renal function in patients with liver cirrhosis based on serum creatinine (SCr) or creatinine-based equations overestimates true glomerular filtration rate (GFR), particularly in those with more severe renal dysfunction or more severe liver disease. In recent years, cystatin C (CystC) has been studied extensively as an alternative endogenous marker of kidney function in cirrhotic patients because it is independent of muscle mass. In a study comparing the performance of various creatinine (creat) and CystC-based GFR-predicting equations in OLT candidates (including CKD-EPI (creat), CKD-EPI (CystC), and CKD-EPI (creat-CystC) and the 4- and 6-variable Modification of Diet in Renal Disease (MDRD) and Hoek formulas), De Souza et al. demonstrated that CystC-based had a better performance than creatinine-based equations, with CKD-EPI (CystC) equation showing the best performance regardless of the severity of ascites and in the presence of significant renal dysfunction defined as GFR less than 60 mL/min. In a small Japanese study of 14 cirrhotic patients, Adachi et al. similarly demonstrated that CystC-based GFR-estimating equations had better performances compared with creatinine-based equations in terms of bias, precision, and accuracy. However, the superior performance of CystC over creatinine in cirrhotic patients with GFR less than 80 mL/min has not been demonstrated consistently.

Similar to the cirrhotic population, CystC also has been suggested to be a more accurate filtration marker than creatinine among OLT recipients. In a study to evaluate whether the addition of CystC improves GFR estimation compared with various GFR estimating equations, Allen et al. demonstrated that CystC-based equations had superior performance in GFR estimation compared with creatinine-based equations, whereas CKD-EPI (creat-CystC) outperformed those with either marker alone. A total of 586 iothalamate-measured GFR in 401 OLT recipients were available for analysis. Of the five GFR estimation equations examined, CKD-EPI (creat-CystC) was shown to have the highest coefficient of determination (R ² of 0.83), followed by CKD-EPI (CystC) (R ² of 0.78), MDRD-6 (R ² of 0.77), and MDRD-4 and CKD-EPI (creat) (R ² of 0.76 for both). Nonetheless, the CKD-EPI (creat-CystC) formula still underestimated measured GFR by approximately 12%, particularly in low GFR groups.

Although not yet readily available in many centers, CystC-based equations may enable clinicians to more accurately assess renal function in OLT candidates and recipients. However, CystC levels may be increased in high cell turnover states (such as hyperthyroidism, steroid use, and malignancy), advanced age, gender and ethnicity, fat mass, and diabetes, among others. Although more costly and complicated, traditional studies evaluating the renal clearance of inulin or radioisotopes such as iothalamate remain the gold standard for evaluating renal function in patients with liver cirrhosis and in OLT recipients.

Risk Factors for Early Postoperative Acute Kidney Injury After Orthotopic Liver Transplantation

AKI has been reported to develop in 17% to 95% of OLT recipients, whereas severe AKI requiring perioperative renal replacement therapy occurred in 5% to 35% of patients. The broad range in the incidence reported may be due to, in part, the lack of standardized definitions of AKI among studies. In one study consisting of 424 OLT recipients, AKI within the first 3 days after transplantation occurred in 52% of patients. The former was defined as “50% increase in serum creatinine from preoperative baseline value or a 26.5 µmol/L increase from baseline within 48 hours without urine output.”

Although the risk factors for AKI are often multifactorial and difficult to establish, they can be linked to three distinct time frames in relation to the OLT: the pre-OLT, intraoperative, and post-OLT periods (discussed later in this chapter). Table 129.1 and Box 129.1 summarize suggested risk factors for early postoperative AKI and strategies to reduce risk factors.

TABLE 129.1

Risk Factors for Acute Kidney Injury in the Early Postorthotopic Liver Transplantation Period

RISK FACTORS	COMMENTS
Pretransplantation Factors Pretransplantation renal dysfunction Hepatorenal syndrome High serum bilirubin levels Hypoproteinemia Hypoalbuminemia Hyponatremia High serum lactate levels Severity of liver disease as reflected by Child-Pugh or MELD scores Viral hepatitis	Bile cast-associated AKI is thought to be due to direct bile and bilirubin toxicity and tubular obstruction Hypoalbuminemia may alter the pharmacokinetics of potentially nephrotoxic drugs, thereby increasing AKI risk High lactate levels may reflect hemodynamic instability or more severe liver disease, both of which may be associated with poor renal hemodynamics and AKI Whether undiagnosed viral glomerulonephritis plays a role in the development of AKI is speculative
Intraoperative Factors
Hemodynamic instability during anesthesia induction and anhepatic phase Intraoperative bleeding and volume of transfused blood products Standard surgical technique (with or without VVB) vs. piggyback technique (not consistently demonstrated, see comments) Conventional risk factors (see text)	The 2013 Cochrane database systematic review shows no reliable evidence that interventions during surgery provide a renoprotective effect
Postoperative Factors
Acute tubular necrosis (ATN) Delayed liver graft function or primary nonfunction Postreperfusion syndrome (ischemia-reperfusion injury) Contrast nephropathy Drug-induced tubulointerstitial nephritis Calcineurin inhibitor therapy Prolonged use of dopamine or vasopressors Perioperative volume of transfused blood products Repeat laparotomy Bacterial infection, sepsis Intraabdominal hypertension Donor liver with prolonged warm ischemia time	Factors predisposing to ATN: ischemic or toxic insults (prolonged hypotension, sustained prerenal AKI, nephrotoxic drugs), sepsis Reactive oxygen species such as superoxide anion, hydrogen peroxide, and hydroxyl radical released by donor liver with prolonged warm ischemia time may play a contributory role in the development of AKI Drug-induced tubulointerstitial nephritis generally occurs in the setting of polypharmacy (e.g., simultaneous use of multiple antibiotics) Intraabdominal hypertension from fluid accumulation, inflammation, bleed may lead to abdominal compartment syndrome with reduced renal perfusion and AKI Therapeutic drug monitoring of CNIs to minimize systemic overexposure

AKI, Acute kidney injury; CNI, calcineurin inhibitor; MELD, Model for End-stage Liver Disease; VVB, venovenous bypass.

Box 129.1

Strategies to Reduce Risk Factors

Pretransplantation

Risks and benefits of diuretics, lactulose, contrast dye exposure, nephrotoxic drugs, and NSAIDs should be weighed against the risk of precipitating HRS
Use of plasma expanders in large-volume paracentesis is recommended (particularly in patients with severe hypoalbuminemia or ascites without peripheral edema)
- In general, albumin is suggested to be more effective than artificial plasma expanders. Recommended dose: 1 g per kg body weight of 25% albumin (up to 100 g/day)
- Albumin infusion in SBP may reduce HRS risk. Recommended dose: 1.5 g/kg at diagnosis of SBP and 1 g/kg IV 48 hours later

Intraoperative

Control of bleeding during surgery
Careful attention to fluid and electrolyte management
Avoidance of hypotensive episodes

Postoperative

Bleeding and infectious complications should be sought and treated aggressively
Avoid use of contrast studies or nephrotoxic drugs if possible
Manipulation of immunosuppression:
- Early postoperative period: Consider antibody induction in patients with preexisting HRS or pretransplantation renal dysfunction (see also Table 129.6 ).
- Late postoperative period: CNI minimization or withdrawal protocols (see Table 129.6 )

CNI, calcineurin inhibitor; HRS, hepatorenal syndrome; NSAIDs, nonsteroidal antiinflammatory drugs; SBP, spontaneous bacterial peritonitis.

Pretransplantation Risk Factors

Pretransplantation renal dysfunction and hepatorenal syndrome (HRS) are well-established risk factors for posttransplantation AKI. Other suggested risk factors include higher serum bilirubin levels, hypoproteinemia, hypoalbuminemia, hyponatremia, viral hepatitis, high serum lactate levels, and severity of liver disease as reflected by the Child-Pugh or Model for End-stage Liver Disease (MELD) scores. The Organ Procurement and Transplantation Network recently has incorporated sodium into the MELD score. As of January 2016, the MELD-Na score is employed in the liver allocation system in the United States. Selected studies evaluating potential pretransplant risk factors for postoperative AKI and suggested pathogenic mechanisms are discussed.

Hyponatremia

The presence of hyponatremia, defined as a serum sodium level below 130 mEq/L at the time of transplantation, has been suggested to be associated with a high rate of complications after OLT, including neurologic disorders, infectious complications, and AKI during the first month after transplantation. It is well established that the presence of hyponatremia identifies a group of patients with cirrhosis who have severe impairment in circulatory function. The latter may act in concert with the intraoperative and perioperative hemodynamic changes to increase the risk of postoperative AKI.

In a single-center retrospective study consisting of 134 OLT recipients, AKI occurred in nearly half of patients (46.7%) in the postoperative period. Serum sodium was lower in the AKI compared with the non-AKI groups ( p = .02). Viral hepatitis, longer warm ischemia time, and high levels of serum lactate were found to be risk factors for AKI, whereas a high MELD-Na score is a predictor for hemodialysis need. A greater than eightfold increase in posttransplant hemodialysis need was observed among patients with a MELD-Na score of at least 22 (OR 8.4, 95% CI = 1.5–46.5). Among OLT recipients with viral liver disease, it is speculated that undiagnosed viral glomerulonephritis and superimposed hemodynamic instability may play a causative role in the development of AKI after OLT. In a small series of 30 OLT recipients with hepatitis C who underwent intraoperative kidney biopsy, membranoproliferative glomerulonephritis was found in 12, IgA nephropathy in 7, and mesangial glomerulonephritis in 6.

Hypoalbuminemia

A meta-analysis of observational clinical studies demonstrated that lower serum albumin was an independent predictor of AKI and death after AKI development. The odds of AKI development in association with low serum albumin were more than doubled among the six studies of surgical or intensive care unit patients and nearly tripled among studies in other hospital settings. For every 10 g/L decrement in serum albumin, the odds of developing AKI increased by 134% (CI 1.74–3.14).

The mechanisms whereby low serum albumin increases the risk of postoperative AKI remain unclear. Nonetheless, it has been suggested that hypoalbuminemia modifies Starling's forces in the systemic capillaries and results in the reduction of GFR. Hypoalbuminemia also has been suggested to alter the pharmacokinetics of potentially nephrotoxic drugs, thereby increasing the risk of AKI. In a prospective study consisting of 104 patients treated with intravenous amikacin for at least 36 hours, low serum albumin was found to be associated with amikacin accumulation in the plasma and an increased risk of nephrotoxicity. It is speculated that specific ligand-binding properties of albumin may mediate renoprotection in patients treated with nephrotoxic drugs.

Hyperbilirubinemia

The association between high serum bilirubin level and postoperative AKI has long been recognized. The spectrum of cholemic nephrosis ranges from proximal tubulopathy to bile cast nephropathy. In a clinicopathologic study of 44 jaundiced subjects (41 autopsies and 3 kidney biopsies), 18 had bile casts involving distal nephron segments and 6 had extension to proximal tubules. Eleven of 13 patients with HRS and all 10 with alcohol-related cirrhosis had tubular bile casts. A significant correlation was found between these casts and higher serum total and direct bilirubin levels ( p = .0001 and p = .003, respectively). Furthermore, a trend toward higher serum creatinine, aspartate transaminase, and alanine transaminase levels were observed among patients with bile casts compared with those without. It is suggested that bile cast–associated AKI is due to direct bile and bilirubin toxicity and tubular obstruction analogous to that observed with myeloma or myoglobin casts.

Liver Disease Severity

In a retrospective study consisting of more than 600 recipients of liver-only transplants, Sanchez et al. demonstrated that MELD scores greater than 21 were significant predictive indicators of the need for renal replacement therapy after OLT. The association between MELD score and severe AKI also was demonstrated by others. In a retrospective study consisting of 153 OLT recipients, hepatic encephalopathy, deceased donor liver transplant (compared with living donor transplant), MELD score, and intraoperative blood loss were found to be independent predictive factors for postoperative continuous renal replacement therapy. A more favorable renal outcome was observed among OLT recipients with hepatocellular carcinoma (HCC) as the indication for OLT. The study findings suggest that liver disease severity as reflected by high MELD score portends a worse renal prognosis. OLT recipients with HCC generally had preserved liver function and a lower MELD score than OLT recipients with end-stage liver disease. Similarly, living donor liver transplant recipients had a lower MELD score and a lower incidence of AKI compared with their deceased donor transplant counterparts.

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