Serum enzymes in patients with kidney failure

INTRODUCTION — The serum enzymes of patients with end-stage kidney disease (ESKD) are commonly abnormal. This is due in part to the absence of kidney excretion and to the frequent presence of multiple comorbid conditions. Since the diagnosis of many diseases is based upon the detection of elevated levels of these enzymes, the accurate clinical assessment of the patient with ESKD is hampered by a paucity of knowledge concerning the serum concentrations of different enzymes in various disease states.

The use and significance of variations in the concentrations of serum enzymes in patients on dialysis will be reviewed here. A discussion of serum cardiac enzymes in patients with kidney failure is presented separately. (See "Cardiac troponins in patients with kidney disease".)

LIVER ENZYMES — The serum enzymes most commonly used to help assess the diagnosis of hepatobiliary disease include the aminotransferases, alkaline phosphatase, and gamma-glutamyl transpeptidase (GGT).

Aminotransferases — Serum concentrations of aspartate and alanine aminotransferase (AST [SGOT] and ALT [SGPT]) are routinely measured to assess liver function in patients with and without kidney failure. The aminotransferases are normally present in the circulation in low concentrations, usually <40 int. units/L. (See "Approach to the patient with abnormal liver biochemical and function tests".)

The concentrations of serum aminotransferases in both patients on chronic dialysis and those with nondialysis chronic kidney disease most commonly fall within the lower end of the range of normal values [1-4]. Although the exact cause is unknown, possible underlying reasons may be related to pyridoxine deficiency (pyridoxal phosphate is a necessary coenzyme for ALT and AST) [5-7] and/or the presence of an inhibitory substance in the uremic milieu [1].

In one study, for example, an increase in serum AST was observed after hemodialysis, suggesting the removal of an inhibitory substance with dialysis [1]. This effect was not due to urea alone, since the addition of urea to normal serum was not associated with a decline in the activity of AST. In this observational report, serum AST also positively correlated with the level of kidney function in a transplant recipient, declining in association with rejection or the need to resume hemodialysis.

The use of standard reference values for aminotransferases to help detect liver disease is therefore less useful in patients undergoing chronic dialysis therapy. In one study of over 500 patients on dialysis, standard cutoff values for aminotransferases were found to be poor indicators of active liver disease among hepatitis C antibody-positive individuals who were undergoing liver biopsy [8].

As a result, some investigators have suggested that, to increase the sensitivity of liver function tests among patients on dialysis, lower "normal" values of aminotransferases should be adopted [9,10]. In one study, the conventional upper limit of normal of 40 int. units/L for AST and ALT was changed to 24 and 17 int. units/L, respectively. To detect liver disease resulting from hepatitis B, these altered values enhanced the sensitivity in patients undergoing peritoneal dialysis from approximately 27 to 72 percent for AST and from 18 to 64 percent for ALT. We therefore use levels of 24 and 17 int. units/L for AST and ALT, respectively, as the upper limits of normal in patients on dialysis.

Gamma-glutamyl transpeptidase — The serum concentration of GGT is usually normal in patients with end-stage kidney disease (ESKD) and the absence of liver disease. However, approximately 10 percent of patients with ESKD have unexplained elevations in serum GGT [11].

Alkaline phosphatase — Plasma alkaline phosphatase activity can originate from liver, bone, intestine, or placenta; in most patients and normals, the majority of circulating activity consists of isoenzymes derived from either liver or bone. (See "Enzymatic measures of hepatic cholestasis (alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)" and "Approach to the patient with abnormal liver biochemical and function tests".)

Serum levels of alkaline phosphatase are elevated in many patients on dialysis because of concurrent renal osteodystrophy (see "Evaluation of renal osteodystrophy"). The most reliable method of determining the tissue origin of the enzyme is polyacrylamide gel electrophoresis, a test that is not routinely performed in most clinical laboratories. Since bone-derived alkaline phosphatase is heat labile but liver derived is not, the source of elevated levels of this enzyme may be partially uncovered by the exposure of serum to elevated temperatures.

As a result, elevations in serum alkaline phosphatase alone in patients on dialysis only minimally suggest possible obstructive biliary disease. The possibility of hepatobiliary disease should be more seriously entertained if persistent elevations of this enzyme are found in conjunction with increased serum GGT or 5'-nucleotidase and if hyperparathyroidism has been excluded (see "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated alkaline phosphatase'). Retrospective studies have suggested a link between increased alkaline phosphatase and increased mortality in both peritoneal dialysis and hemodialysis populations. Possible mechanisms for this include poor bone health, increased vascular calcification, and higher levels of inflammation [12].

There are data to suggest that increased pre-ESKD alkaline phosphatase levels are linked to an increase in all-cause mortality post-ESKD when adjusted for liver disease and metabolic bone disease [13]. Increases in alkaline phosphatase in CKD stages 3 to 4 have also been shown to be associated with increases in all-cause mortality and ESKD [14]. It is unclear whether intervening to treat alkaline phosphatase levels would lead to improved outcomes in the CKD and ESKD population, and more research is warranted.

PANCREATIC ENZYMES — Marked elevations of amylase and lipase are frequently used to help diagnose pancreatitis in patients without kidney failure (see "Clinical manifestations and diagnosis of acute pancreatitis"). However, serum concentrations of pancreatic amylase and lipase are elevated in patients with end-stage kidney disease (ESKD) in the absence of acute pancreatitis [15-25]. The highest levels of amylase and lipase are noted in patients on hemodialysis, but marked elevations can also be seen in patients with chronic kidney disease and in those undergoing peritoneal dialysis. A threefold to fivefold increase in amylase and lipase levels is most commonly observed, but the absolute values do not exceed three times the upper limit of normal. The degree of elevation is roughly proportional to the degree of kidney function impairment. (See "Unique aspects of gastrointestinal disease in patients on dialysis".)

Amylase — Elevations in serum amylase among patients with kidney failure or ESKD are most likely due to impaired kidney clearance. In one study, the serum amylase began to rise only when the creatinine clearance dropped below 50 mL/min [23].

The dialysis procedure alone does not appear to alter serum amylase. In one study, for example, no change was observed in serum amylase in samples obtained pre- and postdialysis [17]. However, these observations are confounded by the failure to correlate levels of amylase with variations in dialysis membrane clearance. In this study, one patient with acute pancreatitis had an increase in the P3 isoamylase band, a finding not observed in those without acute pancreatitis.

The use of icodextrin as an oncotic ultrafiltration stimulant in peritoneal dialysis may decrease measured serum amylase activity [26,27]. Based upon competition for enzymatic cleavage, icodextrin reduced measured amylase activity by 90 percent in one study of patients on peritoneal dialysis [26]. Lipase activity, however, was not affected. The serum amylase should not be used for the diagnosis of pancreatitis among patients utilizing icodextrin in their peritoneal dialysis regimen. Icodextrin and its metabolites are essentially completely cleared from the circulation by one week after discontinuation.

Lipase — As with amylase, the elevations in serum lipase observed in patients with ESKD are most likely due to kidney function impairment. However, unlike amylase, the levels of lipase are also increased by the dialysis procedure itself [17].

The cause of increased serum lipase in postdialysis samples may be related to the use of heparin during dialysis. Consistent with this hypothesis is the observation that the postdialysis rise in serum lipase can be prevented by replacing heparin with alternate anticoagulants, nafamostat mesylate [21], and defibrotide [28].

The apparent heparin-induced postdialysis elevation in serum lipase may be attributable to the following properties of heparin:

●Lipolytic activity [17]

●Crossreactivity with lipoprotein lipase and hepatic triglyceride lipase [21]

●Ability to induce endothelial lipoprotein lipase [28]

Trypsinogen — Increased serum concentrations of trypsinogen have been observed in asymptomatic patients on dialysis or with nondialysis chronic kidney disease; it is therefore of diminished utility in these patients [20].

SERUM CREATINE PHOSPHOKINASE (CPK) — Creatine phosphokinase is degraded by the reticuloendothelial system. The level depends more on the amount of muscle damage and the half-life of the enzyme, rather than removal by the kidney.

CARDIAC ENZYMES — Levels of cardiac enzymes are utilized to help assess the presence or absence of acute myocardial injury. Abnormal elevations in the serum concentrations of these enzymes may be the key diagnostic element in determining admission to the hospital and/or coronary care units. The principal cardiac enzymes are cardiac troponin T and cardiac troponin I (see "Troponin testing: Clinical use"). Since coronary artery disease is highly prevalent in patients with end-stage kidney disease (ESKD), accurate interpretation of serum concentrations of these enzymes is extremely important.

A review of the evaluation and use of cardiac enzymes in patients with kidney failure is presented separately. (See "Cardiac troponins in patients with kidney disease".)

SUMMARY AND RECOMMENDATIONS

●Liver enzymes

•Aminotransferases – Serum aminotransferase concentrations are commonly low normal in both patients on chronic dialysis and those with nondialysis chronic kidney disease. In order to increase the sensitivity of liver function tests among patients on dialysis, we use levels of 24 and 17 int. units/L for aspartate (AST) and alanine aminotransferase (ALT), respectively, as the upper limits of normal in patients on dialysis. (See 'Liver enzymes' above.)

•Gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase – Ten percent of patients with end-stage kidney disease (ESKD) have unexplained elevations in serum GGT. Serum levels of alkaline phosphatase are elevated in many patients on dialysis because of concurrent renal osteodystrophy. Thus, isolated elevations in serum alkaline phosphatase only minimally suggests possible obstructive biliary disease in dialysis patients. Hepatobiliary disease is more strongly suggested by persistent elevations of alkaline phosphatase in conjunction with increased serum GGT or 5'-nucleotidase and if hyperparathyroidism has been excluded. (See 'Liver enzymes' above.)

●Pancreatic enzymes – Serum pancreatic amylase and lipase concentrations are elevated in patients with ESKD in the absence of acute pancreatitis. The degree of elevation is roughly proportional to the degree of kidney function impairment, but the absolute values do not exceed three times the upper limit of normal. Among patients on dialysis suspected of pancreatitis, a rise in serum amylase and/or lipase levels that is temporally associated with the onset of abdominal pain or is more than three times the upper limit of normal may be helpful. (See 'Pancreatic enzymes' above.)

●Cardiac enzymes – A review of the evaluation and use of cardiac enzymes in patients with kidney failure is presented separately. (See "Cardiac troponins in patients with kidney disease".)