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

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.

Free light chain and intact immunoglobulin abnormalities in heart transplant recipients: Two year follow-up timelines and clinical correlations.

OBJECTIVES: To assess the timelines of serum free light chain (sFLC) concentrations and the kappa/lambda light chain (K/L) ratio in heart transplant (HTX) recipients. To analyze the performance of serum protein electrophoresis (SPE), serum immunofixation (sIFE) and sFLC measurements for gammopathy detection following a HTX. METHODS: A total of 96 patients who underwent a HTX were analyzed during a two-year follow-up period. The relevant clinical data were obtained from patient medical records. SPE, sIFE and sFLC methods were used for the detection of free light chain and intact immunoglobulin gammopathies at 4 time points after HTX. RESULTS: A statistically significant decrease in sFLC K and L (a decrease of 39.1% and 27.6%, respectively, when compared to pretransplant values) was found 9months after the HTX (p<0.001, Friedman test). We detected SPE or sIFE abnormalities in 23 (8.4%) samples, and sFLC K/L ratio abnormalities in 34 (12.4%) samples. All of the K/L ratio abnormalities had normal SPE/sIFE values, and 19% of the findings were persistent. CONCLUSIONS: A significant and consistent dynamics in the sFLC concentration was found in the HTX patients during a 2-year follow-up period, which reflected changes in the immunosuppressant dosage. A remarkable number of monoclonal and polyclonal gammopathies was identified with some persistent abnormalities, using the SPE/sIFE and sFLC methods. Some of the detected abnormalities, which might possess a higher risk for PTLD if interpreted according to common practice in nonTX patients can only be detected by sFLC methods.

Rare congenital chromosomal aberration dic(X;Y)(p22.33;p11.32) in a patient with primary myelofibrosis.

BACKGROUND: Constitutional translocations between sex chromosomes are rather rare in humans with breakpoints at Xp11 and Yq11 as the most frequent. Breakpoints on the short arm of the Y chromosome form one subgroup of t(X;Y), giving rise to a derived chromosome with the centromeres of both the X and Y chromosomes, dic(X;Y). Here, we report a rare congenital chromosomal aberration, 46,X,dic(X;Y)(p22.33;p11.32)[20]/45,X[10], in an adult male. CASE PRESENTATION: Primary myelofibrosis, a malignant haematological disease, was diagnosed in a 63-year-old man following liver transplantation after hepatocellular carcinoma. By the analysis of the bone marrow sample, the karyotype 46,X,dic(X;Y)(p22.33;p11.32) was detected in all the mitoses analysed and verified with multicolour fluorescence in situ hybridization (mFISH). A cytogenetic examination of stimulated peripheral blood cells revealed the constitutional karyotype 46,X,dic(X;Y)(p22.33;p11.32)[20]/45,X[10]. The cell line 45,X was confirmed with FISH in 35 % of interphase nuclei. The SRY locus was present on the dicentric chromosome. A CGH/SNP array (Illumina) revealed a gain of 153,7 Mbp of the X chromosome and a 803-kbp microdeletion (including the SHOX gene), which were also confirmed with FISH. SHOX encodes a transcriptional factor that regulates the growth of the long bones. The deletion of the SHOX gene together with the Madelung deformity of the forearm and the short stature of the proband led to a diagnosis of Léri-Weill dyschondrosteosis (LWD). The gain of almost the whole X chromosome (153,7 Mbp) was considered a variant of Klinefelter syndrome (KS). The levels of gonadotropins and testosterone were consistent with gonadal dysfunction. A malformation of the right external ear was detected. CONCLUSIONS: We have reported a structural aberration of the sex chromosomes, dic(X;Y)(p22.33;p11.32). The related genomic imbalance is associated with two known hereditary syndromes, LWD and a KS variant, identified in our proband at an advanced age. Because the breakpoints did not involve cancer genes, we inferred that the two malignancies in the proband were not caused by this abnormality. The possible influence of SHOX haploinsufficiency on the growth regulation of auricular chondrocytes is discussed.