Pseudohypercreatininaemia in two patients caused by monoclonal IgM interference with enzymatic assay of creatinine.

INTRODUCTION Creatinine is released into the blood following non-enzymatic hydrolysis of creatine in skeletal muscle, and excreted into urine depending on glomerular filtration. The serum creatinine concentration is widely used as a marker of glomerular function because it increases in patients with decreased glomerular filtration rate (GFR). Although GFR is costly to measure, an estimated GFR (eGFR) can be calculated from the serum creatinine concentration. Since 2006, laboratories have calculated eGFR values using the isotope dilution mass spectrometry traceable modification of diet in renal disease equation. This standardisation allows direct comparison of creatinine and eGFR results from different laboratories. Reporting of eGFR is a significant advance, but it should be remembered that results are affected by interferences affecting the creatinine assay. Serum creatinine was initially measured for clinical purposes using alkaline picrate ( Jaffé reaction), but this method is affected by numerous interferents, including bilirubin, ketones, protein and non-creatinine chromogens. Enzymatic assays were later introduced, which are less susceptible to interference and more specific being unaffected by non-creatinine chromogens. However, interference has been reported from 5-fluorocytosine, ethamsylate, dopamine, dobutamine, nitromethane, creatine, sarcosine and ascorbic acid. Hummel et al reported positive interference in enzymatic creatinine measurement caused by monoclonal IgM in three patients with Waldenström’s macroglobulinaemia. IgM can precipitate and interfere in the detection step of the reaction. This interference can be avoided by ultrafiltration to remove protein before measuring creatinine. At the time of this publication, most clinical laboratories were measuring creatinine using alkaline picrate assays. However, since the introduction of eGFR, reporting the use of enzymatic assays has become more widespread. It, therefore, seems timely to illustrate this problem by describing two cases recently referred to the renal service. CASE REPORT 1 A 71-year-old female was referred by her general practitioner (GP) to a satellite nephrology outpatient clinic for investigation of a serum creatinine of 257 μmol/L (Siemens Advia enzymatic assay). She was well, and there was no significant past medical or renal history. She was not taking any prescribed medications, but did take evening primrose oil, cod liver oil, glucosamine and garlic capsules. Previous blood tests had shown normal glucose and bilirubin concentrations. Initial investigations were all normal. However, capillary electrophoresis of serum proteins (Sebia UK), showed a discrete monoclonal peak at a concentration of 9 g/L. Immunofixation (Sebia UK) showed that this was IgM kappa. Most of the IgM present was monoclonal. No monoclonal free light chains were detected in the urine. To determine the cause of the increased serum creatinine, she was invited to the central renal unit for a renal biopsy. Prebiopsy blood tests showed a serum creatinine of 73 μmol/L (Abbott Architect 3 enzymatic assay), and a second specimen analysed by the same method showed a creatinine of 70 μmol/L. The apparent decrease in creatinine concentration was initially presumed to represent an episode of acute kidney injury (AKI), of unknown cause, from which, the patient had completely recovered. She was not biopsied. Following discharge, she remained well, and after 2 weeks, attended the satellite nephrology outpatient clinic for review. The serum creatinine was again increased at 216 μmol/L (Siemens Advia enzymatic assay). To investigate the discrepancy in results, a serum specimen from the patient was sent to three different laboratories, and creatinine measured by three different methods viz Siemens Advia enzymatic assay, Abbott Architect 3 enzymatic assay and picric acid Jaffé (O’Leary) reaction. The results were as shown below in table 1. GFR was measured definitively by iohexol clearance and found to be 63 mL/min/1.73 m. At this stage, it was clear that the serum creatinine concentration, as measured by the Siemens Advia enzymatic assay, was artefactually increased.