Limitations of biopsy-based transcript diagnostics to detect T cell-mediated allograft rejection.

BACKGROUND AND HYPOTHESIS: Isolated Tubulitis, Borderline Changes, and Isolated Arteritis suspicious for histologic T cell-mediated rejection (hTCMR) remain findings of uncertain significance. Although the Molecular Microscope Diagnostics System (MMDx) has not been trained on those lesions, it was suggested that MMDx might reclassify a subgroup to molecular TCMR (mTCMR). METHODS: In this single-center cohort of 326 consecutive, unselected kidney allograft biopsies assessed by histology and MMDx, we analyzed 249 cases with Isolated Tubulitis (i0, t1-3, v0; n=101), Borderline Changes (according to Banff 2022, v0; n=9), Isolated Arteritis (no borderline, v1; n=37), No Inflammation (i0, t0, v0; n=67) and a Positive Control Cohort (hTCMR, n=27; Mixed histologic Rejection, n=8; both according to Banff 2022; total n=35). The first three groups were summarized as TCMR-Suspicion (n=147). Subcategorization included the presence and absence of microvascular inflammation (MVI; g+ptc≥2). Molecular rejection rates and differentiation were investigated. RESULTS: Molecular rejection rates were 37/147 cases (25.2%; 32 with MVI) in TCMR-Suspicion, 6/67 (9%; 4 with MVI) in No Inflammation and 30/35 (85.7%; 19 with MVI) in the Positive Control Cohort. Molecular antibody-mediated rejection (mAMR) was present in 39/73 (53.4%) of cases. The presence of donor-specific antibodies (DSA) at the time of the biopsy was high (127/249, 51%). Only 3 mAMR/TCMR and no pure mTCMR cases were detected in TCMR-Suspicion and No Inflammation, compared to 12 mAMR/TCMR and 10 mTCMR cases in the Positive Control Cohort (p<0.001). Even though the TCMR-specific molecular (Classifier) score differentiated between TCMR-Suspicion and No Inflammation (p=0.005), rejection phenotype scores (R2 and R3) did not (p=0.157 and 0.121). CONCLUSIONS: MMDx did not identify pure mTCMR among Isolated Tubulitis, Borderline Changes, or Isolated Arteritis, likely due to low sensitivity for TCMR-lesions. However, it identified mAMR or mAMR/TCMR, especially in cases with MVI. Subthreshold findings remain to be further studied.

Molecular diagnosis of antibody-mediated rejection: Evaluating biopsy-based transcript diagnostics in the presence of donor-specific antibodies but without microvascular inflammation, a single-center descriptive analysis.

Biopsy-based transcript diagnostics may identify molecular antibody-mediated rejection (AMR) when microvascular inflammation (MVI) is absent. In this single-center cohort, biopsy-based transcript diagnostics were validated in 326 kidney allograft biopsies. A total of 71 histological AMR and 35 T cell-mediated rejection (TCMR) cases were identified as molecular AMR and TCMR in 55% and 63%, respectively. Among 121 cases without MVI (glomerulitis + peritubular capillaritis = 0), 45 (37%) donor-specific antibody (DSA)-positive and 76 (63%) DSA-negative cases were analyzed. Twenty-one out of the 121 (17%) cases showed borderline changes, or TCMR, while BK nephropathy was excluded. None of the 45 DSA-positive patients showed molecular AMR. Among 76 DSA-negative patients, 2 had mixed molecular AMR/TCMR. All-AMR phenotype scores (sum of R4-R6) exhibited median values of 0.13 and 0.12 for DSA-positive and DSA-negative patients, respectively (P = .84). A total of 13% (6/45) DSA-positive and 11% (8/76) DSA-negative patients showed an all-AMR phenotype score > 0.30 (P = .77). Patients with a higher all-AMR phenotype score showed 33% more histologic TCMR (P = .005). The median all-AMR phenotype scores of glomerular basement membrane double contours = 0 and glomerular basement membrane double contours > 0 biopsies were 0.12 and 0.10, respectively (P = .35). Biopsy-based transcript diagnostics did not identify molecular AMR in cases without MVI. Follow-up biopsies and outcome data should evaluate the clinical relevance of subthreshold molecular alterations.

Long-term follow-up after cardiac resynchronization therapy-optimization in a real-world setting: A single-center cohort study.

BACKGROUND: Suboptimal device programming is among the reasons for reduced response to cardiac resynchronization therapy (CRT). However, whether systematic optimization is beneficial remains unclear, particularly late after CRT implantation. The aim of this single-center cohort study was to assess the effect of systematic atrioventricular delay (AVD) optimization on echocardiographic and device parameters. METHODS: Patients undergoing CRT optimization at the University Hospital Zurich between March 2011 and January 2013, for whom a follow-up was available, were included. AVD optimization was based on 12-lead electrocardiography (ECG) and echocardiographic left ventricular inflow characteristics. Parameters were assessed at the time of CRT optimization and follow-up, and were compared between patients with AVD optimization (intervention group) and those for whom no AVD optimization was deemed necessary (control group). RESULTS: Eighty-one patients with a mean age of 64 ± 11 years were included in the analysis. In 73% of patients, AVD was deemed suboptimal and was changed accordingly. After a median follow-up time of 10.4 (IQR 6.2 to 13.2) months, the proportion of patients with sufficient biventricular pacing (> 97% pacing) was greater in the intervention group (78%) compared to controls (50%). Furthermore, AVD adaptation was associated with an improvement in interventricular mechanical delay (decrease of 6.6 ± 26.2 ms vs. increase of 4.3 ± 17.7 ms, p = 0.034) and intraventricular septal-to-lateral delay (decrease of 0.9 ± 48.1 ms vs. increase of 15.9 ± 15.7 ms, p = 0.038), as assessed by tissue Doppler imaging. Accordingly, a reduction was observed in mitral regurgitation along with a trend towards reduced left ventricular volumes. CONCLUSIONS: In this "real-world" setting systematic AVD optimization was associated with beneficial effects regarding biventricular pacing and left ventricular remodeling. These data show that AVD optimization may be advantageous in selected CRT patients.

Cluster of Leptospirosis Acquired Through River Surfing in Switzerland.

Background. In Switzerland, leptospirosis is still considered as a travel-associated disease. After the surprising diagnosis of leptospirosis in a patient who was initially suspected as having primary human immunodeficiency virus infection, we recognized that acquisition of leptospirosis occurred through recreational activities and we identified additional affected individuals. Methods. Detailed anamnesis, excluding occupational exposure, acquisition abroad, and pet contacts, enabled us to detect the source of infection and identify a cluster of leptospirosis. Convalescent sera testing was performed to confirm Leptospira infection. Microscopic agglutination tests were used to determine the infecting serovar. Results. We identified a cluster of leptospirosis in young, previously healthy persons. Acquisition of leptospirosis was traced back to a surfing spot on a river in Switzerland (Reuss, Aargau). Clinical presentation was indistinct. Two of the 3 reported cases required hospitalization, and 1 case even suffered from meningitis. Serologic tests indicated infection with the serovar Grippotyphosa in all cases. With the exception of the case with meningitis, no antibiotics were administered, because leptospirosis was diagnosed after spontaneous resolution of most symptoms. Despite a prolonged period of convalescence in 2 cases, full recovery was achieved. Recent reports on beavers suffering from leptospirosis in this region underline the possible water-borne infection of the 3 cases and raise the question of potential wildlife reservoirs. Conclusions. Insufficient awareness of caregivers, which may be promoted by the missing obligation to report human leptospirosis, combined with the multifaceted presentation of the disease result in significant underdiagnosis. More frequent consideration of leptospirosis as differential diagnosis is inevitable, particularly as veterinary data suggest re-emergence of the disease.