Pretransplantation Evaluation: Renal

Kidney-related complications are common sequelae of hepatic failure. These complications include electrolyte and acid-base abnormalities in addition to alterations in renal function from hemodynamic changes and parenchymal disease. Since the introduction of the Model for End-Stage Liver Disease (MELD) score in 2002, there has been a rise in the average serum creatinine level, percentage of renal replacement therapy (RRT), and use of combination liver-kidney transplant in liver transplant recipients. Proper assessment is critical for the patient undergoing evaluation for liver transplantation because these kidney-related changes influence preoperative and postoperative morbidity and mortality. Correcting metabolic abnormalities, accurately assessing renal function, appropriately using preoperative or intraoperative dialysis, and listing for combined liver-kidney transplant are valuable tools that may reduce perioperative risks. ^∗

∗ References .

Knowledge of the effects of liver disease on the kidney enables proper preoperative evaluation of liver transplant candidates.

Acid-Base Disturbances

Many metabolic abnormalities occur in the setting of hepatic failure, including disturbances in acid-base balance. Respiratory alkalosis is the most frequent acid-base abnormality, and the degree of alkalosis directly correlates with the severity of liver disease. The cause is uncertain, with progesterone and retained amines implicated as possible causes. The degree of respiratory alkalosis does not appear to be associated with ammonia (NH ₃ ) production or the development of hypoxemia. Metabolic alkalosis may develop, most commonly as a consequence of diuretic therapy or hypoalbuminemia. Metabolic alkalosis stimulates an increased formation of NH ₃ from NH ₄ ⁺ , which then more easily enters the blood-brain barrier and increases the risk for hepatic encephalopathy. Metabolic acidosis can occur in the form of hyperchloremic and dilutional acidemia in addition to lactate and renal tubular acidosis. Dilutional and hyperchloremic acidosis is a consequence of water retention because of high antidiuretic hormone levels or fluid resuscitation with excess water or chloride-containing solutions. Lactic acidosis develops in acute and chronic forms of liver disease when insufficient hepatic tissue remains to metabolize lactate or from overproduction of lactate caused by complications of infection, gastrointestinal bleeding, or hypotension. Distal (type 1) renal tubular acidosis has been reported in primary biliary cirrhosis, autoimmune hepatitis, alcoholic liver disease, and cryptogenic cirrhosis. Proximal (type 2) renal tubular acidosis is associated with Wilson’s disease, often creating a true Fanconi syndrome. Forms of hyperchloremic metabolic acidosis may develop with the use of spironolactone, lactulose, or cholestyramine. Renal dysfunction may be a source of metabolic acidosis with advanced liver disease, and in both anion gap and nonanion gap forms. Acid-base disturbances do not present a contraindication to liver transplantation, and it is not known if correction improves outcomes, but recognition is important for providing appropriate perioperative support. Mixed acid-base disturbances are common in patients with cirrhosis, and proper assessment requires measurement of levels of electrolytes (sodium, potassium, chloride, bicarbonate), serum albumin, and arterial blood gas at a minimum.

Electrolyte Abnormalities

Sodium Disturbances

Other metabolic abnormalities that occur in the setting of hepatic failure are electrolyte changes. Hyponatremia is common in patients with advanced cirrhosis, with 31% to 49% having a serum sodium concentration of less than 135 mmol/L, 22% less than 130 mmol/L, and 2.5 % to 5.7% less than 125 mmol/L. Occasionally hypovolemia (most commonly associated with diuretic use) produces hyponatremia, but most often it is caused by hemodynamic changes occurring with hepatic failure in the presence of ascites, representing a dilutional or hypervolemic state. Splanchnic vasodilation leads to a decrease in effective arterial blood volume stimulating baroreceptors, which in turn signal nonosmotic production of antidiuretic hormone forcing the kidneys to retain free water, diluting the serum sodium concentration. Side effects of hyponatremia include serious central nervous system symptoms of nausea, vomiting, lethargy, seizures, delirium, and coma. The central nervous system signs of hyponatremia may mimic those of hepatic encephalopathy, and indeed hyponatremia is recognized as a precipitating factor for hepatic encephalopathy. Injudicious correction of hyponatremia may produce devastating demyelinating complications of the brain (central pontine myelinolysis) before and after transplant. Hyponatremia is an independent predictor of mortality before and after transplant in most, but not all studies, being a more discriminating factor at low MELD scores. Whether correction of hyponatremia preoperatively improves outcomes after transplant is not clear, with one study showing liver transplant recipients with "resolved" or corrected hyponatremia more likely to be discharged at 3 weeks than uncorrected patients, although there were no differences in mortality at 180 days or other complications. A safe cutoff for preoperative sodium concentration has not been established. One opinion suggests deferring liver transplant surgery in patients with high surgical risk and a serum sodium concentration of less than 120 mmol/L. Preoperative management of hyponatremia includes fluid restriction, use of loop diuretics (to counteract urinary concentration allowing free water excretion), and vasopressin-2 receptor blockers (vaptans) as the cornerstones of therapy. ^†

† References .

Intraoperative use of fluids to avoid overcorrecting hyponatremia is described, including use of tris-hydroxymethyl aminomethane (THAM) in lieu of sodium bicarbonate.

Hypernatremia may develop as a consequence of treatment with lactulose due to free water losses through the stool. Preoperative hypernatremia is associated with higher postoperative liver transplant mortality than hyponatremia but occurs much less frequently.

Potassium Disturbances

Potassium changes also occur in patients with advanced liver disease. Hypokalemia is most commonly caused by diuretic use, gastrointestinal losses associated with lactulose, and, rarely, magnesium deficiency. Hypokalemia is a confounding factor in the development and maintenance of metabolic alkalosis and, as mentioned earlier, may therefore increase the risk for hepatic encephalopathy. Potassium supplementation and the use of potassium-sparing diuretics are effective therapies to correct hypokalemia. Renal dysfunction, β-blockers (used to prevent variceal bleeding), potassium-sparing diuretics, nonsteroidal antiinflammatory drugs (NSAIDs), and the use of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker medication may singly or in combination produce hyperkalemia. Monitoring potassium levels, particularly in patients with renal dysfunction and concomitant use of these drugs, is important to prevent life-threatening hyperkalemia. Preoperative hyperkalemia increases operative and mortality risks for the recipient. Preoperative hyperkalemia, defined as a potassium level of 4.5 mmol/L or higher, is associated with higher 1-year mortality when compared to those with a potassium level of less than 3.5 mmol/L. Higher preoperative potassium level is a risk factor for hyperkalemia during reperfusion. It is recommended that perioperative dialysis be considered for any patient with a potassium level greater than 5.5 mEq/L, particularly patients with renal dysfunction. To reduce the risk for reperfusion hyperkalemia during surgery, options include the use of insulin, β-agonists, albumin washout, and dialysis.

Assessing Renal Function

Creatinine/Cystatin C

Clinical evaluation of renal dysfunction in patients with advanced hepatic disease is challenging. Defining renal function remains important in establishing operative risk and candidacy for transplantation and may influence perioperative care, including postoperative immunosuppression. Creatinine is normally a useful marker of renal function, but in this patient population it has been found to be unreliable for several reasons. Creatine, a precursor of creatinine, is primarily synthesized by the liver and is produced at rates that are half that of healthy volunteers. This decreases the substrate available for use by the muscles and other tissue to produce creatinine. In addition, malnourishment and decreased muscle mass lead to decreased production of creatinine, with blood levels lower than one would expect for a particular given glomerular filtration rate (GFR). Increased renal tubular secretion of creatinine may further reduce blood concentrations, particularly in a setting of renal dysfunction. Analytic methods to determine creatinine concentration should be traceable to isotope dilution mass spectrometry creatinine reference measurement for standardization of different assays, although even this correction still leads to interlaboratory variations. Some analytical methods of determining creatinine concentration may underestimate true serum concentration in the presence of hyperbilirubinemia or protein-related interferences, although this appears to be laboratory dependent. In cirrhotic patients with normal serum creatinine levels, 37% of patients are reported to have a GFR of less than 50 mL/min, and 31% have a GFR between 50 and 80 mL/min. This is one of several studies confirming the poor relationship between creatinine level and GFR. Cystatin C has been proposed as an alternative marker to creatinine in estimating GFR. Production occurs in all nucleated cells, and it is eliminated by glomerular filtration with blood levels not influenced by age, sex, muscle mass, or bilirubin. Several studies have shown that cystatin C better reflects GFR than creatinine. It has not become widely used because of concerns of availability, cost, and assay variations resulting from infection and drugs such as corticosteroids or calcineurin inhibitors.

Estimation Equations

Equations estimating GFR are commonly used to assess renal function. These formulas contain varying combinations of a patient’s age, sex, weight, ethnicity, serum creatinine level, serum urea nitrogen level, and serum albumin level to predict GFR. The popular Cockcroft-Gault equation when compared to inulin clearance (the gold standard for measuring GFR) in patients with advanced liver disease is found to overestimate GFR, particularly in patients with inulin clearances less than 70 mL/min. The Modification of Diet in Renal Disease (MDRD) equation with four, five, and six (MDRD-6) variables and the Nankivell equation were evaluated before liver transplant, and the best correlation with the MDRD-6 achieved only 66% of estimates within 30% of GFR measured by ¹²⁵ I-iothalamate. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation performs better at measuring higher GFRs than the MDRD in a recent review of 12 studies, most of which did not include patients with cirrhosis. When studied in patients with liver disease, CKD-EPI offered no advantage when compared to MDRD. Cystatin C formulas have been proposed to estimate GFR better than creatinine-based equations ; however, when studied in patients with cirrhosis, mixed results were reported. Although no equation estimated GFR acceptably, a work group of members of the Acute Dialysis Quality Initiative and the International Ascites Club (IAC) recommended using the MDRD-6 formula to establish a diagnosis of chronic kidney disease with estimated GFR of less than 60 mL/min.

Glomerular Filtration Rate Measurement

Determining GFR by direct measurements is possible with several tools. As mentioned before, inulin clearance is recognized as the gold standard, but the scarcity of product, limited number of trained personnel, duration of the study, and the expense limit its use to research settings. A 24-hour urine collection for measuring creatinine clearance is a common means of determining GFR. Unfortunately, measured creatinine clearance in cirrhotic patients overestimates GFR by 13% when inulin clearance is greater than 70 mL/min, and by 96% when inulin clearance is less than 70 mL/min. These findings were confirmed in a subsequent meta-analysis. Nonetheless, measured creatinine clearance, as an estimate of GFR, is superior to creatinine or calculated creatinine clearance. Other options for determining GFR include use of isotope markers such as ¹²⁵ I-iothalamate, ^99m Tc-DTPA, and ⁵¹ Cr-EDTA, and nonisotopes like cold iothalamate and iohexol. These techniques are not widely available, and none has been validated in cirrhotic patients to determine GFR, although they may be helpful. Current expert opinion recommends using serum creatinine as the marker for renal dysfunction, although it is flawed, because of its use in MELD determination and the fact that estimation equations and direct measurement of GFR have not proved to be superior in assessment of renal function. In the future the validation of new estimation equations or the isotope and nonisotope markers for GFR listed previously in addition to integrating imaging testing and biomarkers will make the determination of renal function more precise and improve selection and care of liver transplant candidates.

Hepatorenal Disorders

Establishing a diagnosis of renal disease is predicated on finding a decreased GFR or proteinuria or abnormal urinary sediment. In the general population, definitions exist for acute kidney injury (AKI) and chronic kidney disease (CKD). Although a definition for hepatorenal syndrome (HRS) was amended in 2007 ( Table 32-1 ), defining AKI or CKD in patients with cirrhosis simply required a creatinine level of 1.5 mg/dL or higher. This lack of standardization has slowed advances in the study of renal disease in cirrhosis. Fortunately, new proposals have come forth defining these entities under the umbrella of hepatorenal disorders. Table 32-2 shows the proposed definitions for AKI, CKD, and acute on chronic kidney disease in cirrhosis. Validation of these proposals to determine their role in predicting outcomes such as mortality before and after liver transplant along with kidney function after transplant is ongoing. In one study Belcher et al demonstrated the value of the AKI definition in evaluating hospitalized patients with cirrhosis by showing that mortality rises as the stage of AKI increases and with the progression of the AKI stage. Using these proposed definitions may more accurately determine the level of dysfunction (GFR) in addition to the chronicity of disease, facilitating prediction of renal reserve (and reversibility of dysfunction) in the setting of liver transplant. The other hope is that recognition of renal disease may promote earlier treatment, thereby improving outcomes.

TABLE 32-1

International Ascites Club Criteria for Hepatorenal Syndrome Diagnosis

Modified from Salerno F, Gerbes A, Gines P, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut . 2007;56(9):1310-1318.

Cirrhosis with ascites

Serum creatinine >1.5 mg/dL

No improvement of serum creatinine (a decrease in serum creatinine <1.5 mg/dL) after 2 days off diuretics and volume expansion with albumin (1 g/kg body weight up to a maximum of 100 g/day)

Absence of shock

No current or recent treatment with nephrotoxic drugs

Absence of signs of parenchymal renal disease, as suggested by proteinuria (>500 mg/day) or hematuria (>50 red blood cells per high-power field) and/or abnormal renal ultrasonography

TABLE 32-2

Working Party Proposal for Classifying Renal Disease in Cirrhosis

Modified from Wong F, Nadim MK, Kellum JA, et al. Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. Gut . 2011;60(5):702-709.

AKI	Rise in Cr ≧ 0.3 mg/dL in <48 hr or rise of >50% from baseline Type 1 HRS regarded as a specific form of AKI
CKD	GFR <60 mL/min for >3 mo using MDRD-6 estimation equation
Acute on CKD	Rise in Cr ≧ 0.3 mg/dL in <48 hr or rise of >50% from baseline in a patient with cirrhosis whose baseline GFR <60 mL/min for >3 mo using MDRD-6 estimation equation

AKI , Acute kidney injury; CKD , chronic kidney disease; GFR , glomerular filtration rate; HRS , hepatorenal syndrome; MDRD , Modification of Diet in Renal Disease.

Acute Kidney Injury: Prerenal

AKI is the most common presentation of renal disease in patients with cirrhosis and comes in many forms. Diseases are categorized as prerenal (hypoperfusion), renal (parenchymal/intrinsic), and postrenal injuries. Prerenal injury is the most common form of AKI, mechanistically developing from reduced renal blood flow, loss of renal perfusion maintenance, and a hyperdynamic circulation that makes the kidney more susceptible to hypoperfusion changes and has been summarized in several reviews. In advanced form this prerenal physiology leads to HRS. The two disorders are differentiated by prerenal disease responding to volume expansion. Diuretic therapy, paracentesis, diarrhea secondary to lactulose, and gastrointestinal bleeding may produce volume depletion and adversely affect renal function. Although these complications are risk factors for more severe prerenal injury leading to HRS, in this setting the effect tends to be mild and transient, responding to therapy. Prevention of volume depletion in cirrhotic patients is important in maintaining renal health. Diuretic use for ascites should be limited to a maximal dose of 400 mg of spironolactone and/or 160 mg of furosemide daily in divided doses. Diuretics should be used cautiously in the setting of no edema or ascites and urine losses resulting from diuretics may exceed resorption of ascites, creating intravascular volume depletion. Potassium, blood urea nitrogen (BUN), and creatinine levels should be monitored on this therapy. The furosemide natriuresis test may help identify diuretic responders in advanced liver disease and avoid complications of diuretic use in nonresponders. Hypovolemia after large-volume paracentesis may be prevented by albumin infusion after treatment, and some studies have suggested that concomitant use of nonselective β-blockers may increase the risk for paracentesis-induced circulatory dysfunction. Lactulose-induced diarrhea used to treat hepatic encephalopathy may produce volume depletion, particularly if the patient does not ingest adequate fluid because of confusion. Gastrointestinal bleeding that produces hypotension must be aggressively treated to limit detrimental effects on renal function. Patients with subacute bacterial peritonitis should receive intravenous albumin to decrease the risk for kidney injury. Other factors that may induce prerenal injury resulting from exacerbation of vasoconstriction are NSAIDs and contrast. NSAIDs should be avoided in patients with advanced cirrhosis, and the benefit of contrast use for imaging must be balanced against the risk for kidney injury, particularly in those patients with creatinine level of 1.5 mg/dL or higher.

Acute Kidney Injury: Hepatorenal Syndrome

HRS is a prerenal or functional form of AKI that develops in patients with advanced cirrhosis or fulminant hepatic failure. The hallmark of HRS is intense renal vasoconstriction. Renal vasoconstriction starts early in the course of the liver disease, many months before renal dysfunction is clinically evident, and gradually progresses to reach its maximum intensity in HRS patients. This explains why cirrhotic patients with normal kidney function and Doppler ultrasound evidence of renal vasoconstriction are more prone to develop HRS.

Criteria

There are two types of HRS. Type 1 HRS is defined as doubling of serum creatinine to a level greater than 2.5 mg/dL in less than 2 weeks, whereas in type 2 HRS there is a gradual rise in the serum creatinine level to greater than 1.5 mg/dL. There are notable differences between type 1 and type 2 HRS that are summarized in Table 32-3 . Type 1 HRS is more acute, commonly associated with multiorgan failure, has a very grim prognosis, and can be confused with other causes of AKI, especially acute tubular necrosis (ATN). In type 1 HRS a precipitating event is identified in 50% to 70% of cases, and more than one event can occur in a single patient. Type 2 HRS is the genuine form of renal failure in cirrhotic patients as it represents the extreme expression of cirrhosis-induced circulatory failure and is heralded by refractory ascites. Renal failure in type 2 HRS is slowly progressive and parallels the degree of deterioration of liver function.

TABLE 32-3

Characteristics of Type 1 and Type 2 Hepatorenal Syndrome

	Course	Precipitating Event	History of Diuretic-Resistant Ascites	Prognosis
Type 1 HRS	Precipitous doubling of serum creatinine in <2 wk	Present in 50%-70% of cases	May or may not be present	Without therapy, 90-day survival of 10%
Type 2 HRS	Gradually progressive	Absent	Always present	Median survival, 6 mo

HRS , Hepatorenal syndrome.

The new IAC criteria for type 1 HRS diagnosis are summarized in Table 32-1 . The main points of difference between the old and new criteria for HRS are as follows:

Creatinine clearance is no longer incorporated in the diagnosis.
Ongoing bacterial infection does not exclude the diagnosis of HRS, provided septic shock is not present.
Albumin is preferred to saline for plasma volume expansion. Up to 100 g/day of albumin might need to be infused before diagnosing HRS.
Nonessential minor diagnostic criteria, including low fractional excretion of sodium and oliguria, have been omitted.

The IAC criteria, however, have been recently challenged for multiple reasons. First, these criteria are difficult to implement in clinical practice. A recent multicenter study examined the applicability of these diagnostic criteria in daily clinical practice. Of the 116 patients diagnosed with HRS, only 64% met all diagnostic criteria as outlined by the IAC while the remaining 36% with acute deterioration of serum creatinine level to above 1.5 mg/dL could not meet one or more of the diagnostic criteria because of anuria, hematuria, or proteinuria. Second, the criteria for type 2 HRS diagnosis overlap with the definition of CKD. CKD is defined as low GFR of less than 60 mL/min for more than 3 months' duration. Therefore patients with type 2 HRS with a progressive rise in serum creatinine level over 3 months or more can be misclassified as having CKD despite the absence of other CKD features such as proteinuria or hematuria. Lastly, HRS is a form of AKI; nevertheless the IAC criteria deviate from the Acute Kidney Injury Network definition of AKI in the general population as an absolute increase in serum creatinine level by 0.3 mg/dL within a 48-hour period or urine output below 0.5 mL/kg/hr for 6 hours. Cirrhotic patients who develop AKI and HRS with a rise in serum creatinine level by more than 0.3 mg/dL in less than 48 hours and whose creatinine level does not exceed 1.5 mg/dL cannot be labeled as having HRS according to the IAC criteria. This scenario is common in cirrhotic patients because of their low muscle mass. A working party proposal suggested defining AKI in cirrhotic patients as a rise in serum creatinine level by 0.3 mg/dL or more within a 48-hour period or an absolute 50% rise in serum creatinine level. Once AKI is diagnosed, all efforts should be made to differentiate organic AKI from functional HRS. Overall, the current available criteria for HRS diagnosis still need modification to align HRS diagnosis with the current AKI staging system and to clearly separate type 2 HRS from CKD.

Epidemiology

Gines et al had previously estimated the 1- and 5-year probability of HRS at 18% and 39%, respectively. However, a recent study that included 263 cirrhotic patients followed for 41 ± 3 months estimated the incidence of type-1 and type-2 HRS at 2.6% and 5%, respectively. In this study the cumulative 5-year probability of HRS development was only 11.4%. This indicates that the prevalence of HRS declined over the last 2 decades, probably reflecting better management of cirrhotic patients and the wide use of prophylactic antibiotics for spontaneous bacterial peritonitis (SBP) prevention. The prevalence of HRS increases with the progression of liver disease, and in patients with advanced cirrhosis waiting for liver transplantation the prevalence of HRS is as high as 48%. Almost 50% of cirrhotic patients with ascites will develop AKI during the course of their illness. HRS, however, constitutes a small fraction of all AKI cases that develop in cirrhotic patients. In one study HRS was responsible for the deterioration of kidney function in only 7.6% of all 129 cirrhotic patients with ascites and AKI. In another multicenter retrospective study that included 423 patients with cirrhosis and AKI, the most common cause of AKI was either ATN (35%) or prerenal failure (32%), whereas type 1 and type 2 HRS were the cause of AKI in 20% and 6.6% of cases, respectively.

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