Immunoglobulin abnormalities in 1677 solid organ transplant recipients. Implications for posttransplantation follow-up.

Highlights

• Immunoglobulin abnormalities are frequent after solid organ transplantation.

• Posttransplantation gammopathies are associated with high risk of PTLD, allograft loss and death.

• The combination of SPE, SIFE, UIFE and SFLC methods is optimal for gammopathy detection.

• These methods aid in identifying patients who are at risk for PTLD or allograft damage.

• As a practical application of our findings we present an algorithm for patient management and follow-up.

Abstract

Background

Posttransplant lymphoproliferative disorder (PTLD) is a severe complication of solid organ transplantation (SOT). However, there is no consensus on PTLD screening methods. Gammopathies (GP), which occur in 10–25% of SOT recipients, have been linked to subsequent development of PTLD. Therefore, GP detection methods, such as serum protein electrophoresis (SPE), serum protein immunofixation (SIFE), urine protein immunofixation (UIFE) and the quantitative measurement of serum free light chains (SFLC) are candidate methods for PTLD screening.

Objective

We aimed to assess the frequency of PTLD and GP, association of GP with subsequent PTLD, allograft loss or death and the diagnostic performance of SPE/SIFE in PTLD screening. The main objective was to explore, whether GP detection methods can be used to enhance the efficiency of PTLD screening and to formulate a concise algorithm for posttransplantation (post-Tx) follow-up.

Methods

We performed a cohort study on 1677 SOT recipients with SPE/SIFE data who underwent kidney, liver, heart, pancreas, Langerhans islets or multiple organ transplantation at the Institute of Clinical and Experimental Medicine between 1966 and 2015. The median (IQR) of follow-up time was 8.0 (4.0–12.0) years.

Results

The frequencies of PTLD and GP in SOT recipients were 2.8% and 6.4%, respectively. The frequencies of transient GP, GP of undetermined significance and malignant GP were 33%, 63% and 4% respectively. The median time between SOT and GP detection was 2.0 (interquartile range 1.0–7.0) years. GP was associated with a significantly higher risk of PTLD, allograft loss and death, with hazard ratios (95% confidence intervals) of a 6.06 (2.51–14.64), 2.61 (1.49–4.6) and 1.99 (1.2–3.3), respectively. Additionally, GP was associated with 2.98-fold increased risk of allograft loss in kidney transplant patients. SPE diagnostic sensitivity and specificity for PTLD were 14.8% and 93.9%, respectively. PTLD was diagnosed more often and earlier if SPE/SIFE was included in the post-Tx follow-up.

Conclusions

GP after SOT is associated with a high risk of PTLD, allograft loss and poor survival. The combination of SPE, SIFE, SFLC and UIFE is optimal for GP detection. These methods aid in identifying patients who are at risk for PTLD or allograft damage and should be included in regular post-Tx follow-up.

Introduction

Posttransplant lymphoproliferative disorder (PTLD) is a severe complication of solid organ transplantation (SOT) with a mortality rate of 20–70% [[1], [2], [3], [4]]. The cumulative incidence of PTLD ranges from 1% to 20% [1,[3], [4], [5], [6]], depending on various risk factors, such as Epstein Barr-virus (EBV) and Cytomegalovirus (CMV) infection, age at transplantation (Tx), the type of organ transplanted, or the type and dosage of immunosuppressive medication [[7], [8], [9], [10], [11], [12], [13], [14]].

PTLD is characterized by a heterogeneous clinical presentation, which may include late-stage organ damage but may also be limited to nonspecific symptoms (weight loss, lymphadenopathy, dyspepsia). The definitive diagnosis of PTLD relies on biopsy-based methods, which cannot be used for regular posttransplantation (post-Tx) screening. Therefore, there is an ongoing search for methods using peripheral blood samples, which possess low patient burden and offer sufficient diagnostic performance for reliable screening.

Gammopathies (GP), which occur in 10–25% of SOT recipients, have been linked to immunosuppressive treatments and the subsequent development of PTLD [5,6,[15], [16], [17], [18], [19], [20], [21], [22], [23]]. Thus, GP detection methods, serum protein electrophoresis (SPE), serum protein immunofixation (SIFE) and quantitative measurement of serum free light chains (SFLC), have already been tested as candidate PTLD screening methods. However, previously published results have displayed heterogeneity, and no clear consensus on the implementation of these methods in PTLD diagnostics has been reached so far [5,6,[15], [16], [17], [18], [19], [20],[24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]].

As a result, there is no comprehensive guideline for SPE, SIFE and SFLC use in SOT recipients. This favours ineffective ordering of tests and misinterpretation of results with incorrect management of GP patients.