Biohumoral challenge in a patient with paraproteinemia


A 69-year-old man was admitted in our Nefrology Unit for the work up of a known but cryptogenic renal failure. He is an ex smoker, affected by hypertension within 4 years, previously treated with ACE inhibitor and more recently with a beta blocker, obtaining normal values of arterial pressure. In 2014 he underwent surgery for aneurysm of the abdominal aorta. After the intervention, creatinine was 86,63 mmol/l (0,98 mg/dl). In the same year, he was operated for popliteal aneurysm; at discharge, creatinine was 88,4 mmol/l (1 mg/dl). In October 2015 he was hospitalized for viral encephalitis. On admission creatinine was 212,1 mmol/l (2,4 mg/dl), with normal BUN. A prerenal origin of the kidney injury or a drug nephrotoxicity were excluded; urinalysis was completely normal. A monoclonal gammopathy IgM kappa and lambda IgG is detected, without Bence-Jones proteinuria. RA test was negative. Total IgM were 2071 mg/dl. Renal ultrasound and Doppler ultrasound of the renal arteries resulted normal. The determination of glucose in plasma resulted always < 2,2 mmol/l (<40 mg/dl); the patient was asymptomatic and the blood glucose concentration was inversely proportional to the time that elapsed between the blood sampling and the analysis in the laboratory. The determination of glucose in capillary blood, or if performed by collecting the blood sample in a test tube containing fluoride were within normal range; physicians realized that there was an alteration in the pre-analytical and analytical phase of the measurement of plasma glucose. In January 2016 his creatinine was 256,3 mmol/l (2,9 mg/dl ), and the patient was admitted in our Unit to undergo a renal biopsy. Biohumoral analysis confirmed hypercreatininemia (274 mmol/l; 3,1 mg/dl) and showed a low C3 (31 mg/dl) and a complete consumption of C4 (0 mg/dl); determination of antinuclear antibodies (ANA) were positive (title 1/80), and Anti-neutrophil cytoplasmic antibody (ANCA) negative. Cryoglobulinemia 0,5%. Urinalysis was normal and albumin-to-creatinine ratio was 3.3 mg/g. Kappa free light chains were 164 mg/dl, lambda 17,8 mg/dl , with a k/l ratio of 9,2. Urine electrophoresis and search for Bence-Jones proteinuria were negative. BUN, LDH, PTH and complete blood count were in the normal ranges. We excluded Hepatitis B or C infection.

A chest X-ray and an electrocardiogram were performed and showed no alterations.

Renal failure remains without explanation, so we perform a kidney biopsy. While waiting for histological examination results, we hypothesized that also the measurement of creatinine was affected by a problem in the analytical phase.

Performing the determination of creatinine on a serum sample, it resulted 114,9 mmol/l (1,3 mg/dl), eGRF 56 ml/min/1,73 mq (CKD-EPI 2009).


A few days later, the result of renal biopsy became available and showed about 27 glomeruli with normal features 4/27 in scleroialin obliteration, with the presence of a lymphoid infiltrate predominantly CD20 positive is evident in the interstitium, accompanied by plasmacytic elements without light chain expression. That infiltrate extends into pericapsular adipose tissue. Immunoflurescence resulted negative for IgA, IgM, IgG, light chains kappa or lambda, fibrinogen, and C3. Electronic microscopy did not reveal any glomerular deposits. Fig. 1, 2, 3, 4.


Other biohumoral characteristics and clinical features of the patient were discordant with the supposed diagnosis of chronic kidney disease with renal failure. Alteration in glucose measurement, depending on type of test tube or anticoagulant for blood collection, made us thinking that also creatinine measurement was altered. In our laboratory an enzymatic method (AU 5008 Beckman®) is used and the blood is collected in standard tubes (Beckton-Dickinson®) with spray-coated lithium heparin.

Glucose measurement performed on blood collected with lithium heparin is altered, while dosing it on blood in sodium fluoride or serum results in normal range.

There are several previous reports that warn about the possibility of interference between paraproteinemia and clinical laboratory assays, as C-reactive protein [1], phosphorus [2] (full text), iron [3], bilirubin and cholesterol [4], glucose expecially in heparin samples [5] (full text), and creatinine, using either the Jaffe method [6] (full text) that the enzymatic one [7]. Creatinine can be overestimated or underestimated [8].

IgM interference in creatinine measurement is not well understood. It has been proposed that IgM component complexes with reagents, or causes an increased turbidity [9]; IgM it is the most common type implicated in interference due to increased sample turbidity [10]; immunoglobulins could chemically inactivate the test reagents [11], or act as antigens binding the reagents. In the case presented, monoclonal component may complex with lithium heparin.

Performing an alternative method to estimate renal function (dosing Cystatine C [12] or calculating inulin clearance) is not always possible, so, as showed in our case report, creatinine may be dosed in serum sample.

In our case, the factitious renal dysfunction has led us to perform the kidney biopsy allowing us to diagnose the lymphoid infiltrate.