From short‐term blood pressure variability to atherosclerosis: Relative roles of vascular stiffness and endothelial dysfunction

Both arterial blood pressure (BP) average levels and short‐term BP variability (BPV) relate to hypertension‐mediated organ damage, in particular increased carotid artery intima‐media thickness (IMT) and carotid‐femoral pulse wave velocity (PWV). Endothelial dysfunction possibly mediates such damage. The authors aimed at further investigating such role in hypertensive patients. In 189 recently diagnosed, untreated hypertensive patients the authors evaluated, in a cross‐sectional design, the relationships of BP average levels and short‐term systolic (S) BPV (standard deviation of awake SBP or of 24‐hour‐weighted SBP) with IMT and PWV, and how much these relationships are explained by endothelial function parameters—brachial artery flow‐mediated dilation (FMD) and digital reactive hyperemia index (RHI). Multivariable models assessed the strength of these relationships to derive a plausible pathogenetic sequence. Both average SBP values and our measures of SBPV were significantly related to IMT (24‐hour mean SBP: r = .156, P = .034; 24‐hour‐weighted SBPV: r = .157, P = .033) and to PWV (24‐hour mean SBP: r = .179, P = .015; 24‐hour‐weighted SBPV: r = .175; P = .018), but only poorly related to FMD or RHI (P > .05 for all). At univariable regression analysis, FMD and RHI were both related to IMT, (P < .001), but not to PWV. When FMD and RHI were added to average SBP and SBPV parameters in a multivariable model, both significantly (P < .005) contributed to predict IMT, but not PWV. Thus, endothelial dysfunction relates to IMT independently of BP parameters, but appears to play a minor role in the association between BP variability‐related variables and arterial stiffening.     

A Survey of Current Practice for Antibody‐Mediated Rejection in Heart Transplantation

No evidence based management guidelines exist for antibody mediated rejection (AMR) in heart transplantation. The International Society for Heart and Lung Transplantation (ISHLT) recently introduced standardized pathologic based diagnostic criteria for AMR (pAMR 0–3). We evaluated international practice for the management of AMR focusing on pAMR grade, donor specific antibody (DSA) and allograft function. On‐line survey data were analyzed from 184 ISHLT members (physicians‐78%, surgeons‐20%). The majority were from adult‐transplant (84%), medium‐large volume centres (transplants/year: 10–25, 61%; 25–50, 19%) across North America (60%) and Europe (26%). Irrespective of pAMR grade and DSA, 83–90% treated a drop in ejection fraction (EF ≤45% or >25% decrease). In the presence of stable EF, an increasing number elected treatment for progressively severe pAMR grade (p < 0.001) and for accompanying DSA (p < 0.05, pAMR 1–3). Intravenous steroid was the most commonly used therapy followed by intravenous immunoglobulin (IVIG) or plasmapheresis, rituximab and thymoglobulin. Plasmapheresis and rituximab were favored for positive versus negative DSA (p < 0.05). Using a threshold of ≥70% consensus among respondents, treatment for AMR may be considered for a drop in EF, asymptomatic pAMR 3 or asymptomatic pAMR 2 with DSA. Combination steroid, IVIG and plasmapheresis are suggested as initial therapies.     

Pretransplant Sensitization Against Angiotensin II Type 1 Receptor Is a Risk Factor for Acute Rejection and Graft Loss

The angiotensin II type 1 receptor (AT₁R) is an emerging target of functional non‐HLA antibodies (Ab). We examined the potential of determining the degree of presensitization against AT₁R as a risk factor for graft survival and acute rejection (AR). The study included 599 kidney recipients between 1998 and 2007. Serum samples were analyzed in a blinded fashion for anti‐AT₁R antibodies (AT₁R‐Abs) using a quantitative solid‐phase assay. A threshold of AT₁R‐Ab levels was statistically determined at 10 U based on the time to graft failure. An extended Cox model determined risk factors for occurrence of graft failure and a first AR episode. AT₁R‐Abs >10 U were detected in 283 patients (47.2%) before transplantation. Patients who had a level of AT₁R‐Abs >10 U had a 2.6‐fold higher risk of graft failure from 3 years posttransplantation onwards (p = 0.0005) and a 1.9‐fold higher risk of experiencing an AR episode within the first 4 months of transplantation (p = 0.0393). Antibody‐mediated rejection (AMR) accounted for 1/3 of AR, whereby 71.4% of them were associated with >10 U of pretransplant AT₁R‐Abs. Pretransplant anti‐AT₁R‐Abs are an independent risk factor for long‐term graft loss in association with a higher risk of early AR episodes.     

Potential Impact of Microarray Diagnosis of T Cell–Mediated Rejection in Kidney Transplants: The INTERCOM Study

We previously developed a microarray‐based test for T cell‐mediated rejection (TCMR) in a reference set of 403 biopsies. To determine the potential impact of this test in clinical practice, we undertook INTERCOM, a prospective international study of 300 indication biopsies from 264 patients ( ClinicalTrials.gov NCT01299168). Biopsies from six centers—Baltimore, Barcelona, Edmonton, Hannover, Manchester and Minneapolis—were analyzed by microarrays, assigning TCMR scores by an algorithm developed in the reference set and comparing TCMR scores to local histology assessment. The TCMR score correlated with histologic TCMR lesions—tubulitis and interstitial infiltration. The accuracy for primary histologic diagnoses (0.87) was similar to the reference set (0.89). The TCMR scores reclassified 77/300 biopsies (26%): 16 histologic TCMR were molecularly non‐TCMR; 15 histologic non‐TCMR were molecularly TCMR, including 6 with polyoma virus nephropathy; and all 46 “borderline” biopsies were reclassified as TCMR (8) or non‐TCMR (38). Like the reference set, discrepancies were primarily in situations where histology has known limitations, for example, in biopsies with scarring and inflammation/tubulitis potentially from other diseases. Neither the TCMR score nor histologic TCMR was associated with graft loss. Thus the molecular TCMR score has potential to add new insight, particularly in situations where histology is ambiguous or potentially misleading.     

Development and Application of a Loop‐mediated Isothermal Amplification Assay for Rapid Detection of Borrelia burgdorferi s. l. in Ticks

A loop‐mediated isothermal amplification (LAMP) assay was developed to detect Borrelia burgdorferi s. l. in ticks, which is a pathogen that causes Lyme disease. Cross‐reactions with Chlamydia psittaci, Mycoplasma mycoides subsp. capri and some tick‐borne pathogens were excluded. Analytical sensitivity of LAMP showed its detection limit was from 0.02 to 0.2 pg of DNA in detection of the reference samples at 65°C for 40 min. The performance of LAMP was assessed by testing 110 samples from susceptible tick species and comparing the results with conventional and nested PCR tests previously described. The results demonstrated that LAMP was significantly more sensitive than the conventional PCR (32.7% versus 15.5%, P < 0.05) and slightly more sensitive, although not significantly so, than nested PCR (32.7% versus 26.4%, P > 0.05). The assay was used to analyse a total of 1052 ticks collected from eight provinces in China. The results showed that the infection rates of B. burgdorferi s. l. varied from 12.5% to 88.9% across the different geographical sites. Selected positive samples were subjected to sequencing and sequence analysis for conformation of the accuracy of the assay. Here we report a highly sensitive, specific and easy diagnostic assay based on LAMP technology. These data indicate that LAMP is a useful approach for detecting B. burgdorferi s. l. in field‐collected ticks and has the potential as an alternative tool for the ecological and epidemiological surveillance of Lyme disease.     

Nerve ultrasound in a case of chronic inflammatory demyelinating neuropathy

Introduction: Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common acquired immune‐mediated inflammatory disorder of the peripheral nervous system. The diagnosis is based mainly on the clinical presentation and electrophysiological detection of demyelination. Methods: Several MRI studies have demonstrated hypertrophy and abnormal enhancement of spinal nerve roots or brachial plexus in CIDP, but there have been only anecdotal reports of similar sonographic findings. Results: This article reports the sonographic findings of a CIDP case and includes a review of the literature and previously reported cases. Conclusions: This case report highlights the importance of sonography in the localization and recognition of focal nerve enlargements in patients with CIDP. This method could be a helpful tool in the diagnosis of conduction block in CIDP, especially in cases where a nerve segment cannot be explored easily with the inching technique. Systematic data are needed to confirm this observation. Muscle Nerve 47:443‐446, 2013     

Antibody‐mediated rejection after ABO‐incompatible pediatric living donor liver transplantation for propionic acidemia: A case report

We herein present the case of a four‐yr‐old boy with PA who developed AMR after ABO‐incompatible LDLT despite undergoing B cell desensitization using rituximab. Although the CD19+ lymphocyte count decreased to 0.1% nine days after the administration of rituximab, he developed a high fever which was accompanied by arthralgia due to a streptococcal infection 13 days after rituximab prophylaxis. After the clearance of the infection, he underwent ABO‐incompatible LDLT 36 days after the administration of rituximab. The CD19+ lymphocyte count just prior to LDLT was 1.2%. He developed AMR five days after LDLT, and the antidonor‐type IgM and IgG antibody titers increased to 1:1024 and 1:1024, respectively. He was treated by plasma exchange, IVIG, steroid pulse therapy, and rituximab re‐administration; however, his liver dysfunction continued. Despite intensive treatment, he died due to complicated abdominal hernia, acute renal failure, and ARDS. This case suggests that a streptococcal infection may induce the activation of innate immune responses; thus, additional desensitization therapy should be considered prior to ABO‐incompatible LDLT if B cell reactivation is suspected.     

Identifying Subphenotypes of Antibody‐Mediated Rejection in Kidney Transplants

The key lesions in antibody‐mediated kidney transplant rejection (ABMR) are microcirculation inflammation (peritubular capillaritis and/or glomerulitis lesions, abbreviated “pg”) and glomerular double contours (cg lesions). We used these features to explore subphenotypes in 164 indication biopsies with ABMR‐related diagnoses: 137 ABMR (109 pure and 28 mixed with T cell–mediated rejection [TCMR]) and 27 transplant glomerulopathy (TG), identified from prospective multicenter studies. The lesions indicated three ABMR subphenotypes: pgABMR, cgABMR, and pgcgABMR. Principal component analysis confirmed these subphenotypes and showed that TG can be reclassified as pgcgABMR (n = 17) or cgABMR (n = 10). ABMR‐related biopsies included 45 pgABMR, 90 pgcgABMR, and 25 cgABMR, with four unclassifiable. Dominating all time intervals was the subphenotype pgcgABMR. The pgABMR subphenotype presented earliest (median <2 years), frequently mixed with TCMR, and was most associated with nonadherence. The cgABMR subphenotype presented late (median 9 years). Subphenotypes differed in their molecular changes, with pgABMR having the most histologic–molecular discrepancies (i.e. potential errors). Donor‐specific antibody (DSA) was not identified in 29% of pgcgABMR and 46% of cgABMR, but failure rates and molecular findings were similar to cases where DSA was known to be positive. Thus, ABMR presents distinct subphenotypes, early pg‐dominant, late cg‐dominant, and combined pgcg phenotype, differing in time, molecular features, accompanying TCMR, HLA antibody, and probability of nonadherence.     

Interferon Gamma and Contact‐dependent Cytotoxicity Are Each Rate Limiting for Natural Killer Cell–Mediated Antibody‐dependent Chronic Rejection

Natural killer (NK) cells are key components of the innate immune system. In murine cardiac transplant models, donor‐specific antibodies (DSA), in concert with NK cells, are sufficient to inflict chronic allograft vasculopathy independently of T and B cells. In this study, we aimed to determine the effector mechanism(s) required by NK cells to trigger chronic allograft vasculopathy during antibody‐mediated rejection. Specifically, we tested the relative contribution of the proinflammatory cytokine interferon gamma (IFN‐γ) versus the contact‐dependent cytotoxic mediators of perforin and the CD95/CD95L (Fas/Fas ligand [FasL]) pathway for triggering these lesions. C3H/HeJ cardiac allografts were transplanted into immune‐deficient C57BL/6 rag^?/?γc^?/? recipients, who also received monoclonal anti–major histocompatibility complex (MHC) class I DSA. The combination of DSA and wild‐type NK cell transfer triggered aggressive chronic allograft vasculopathy. However, transfer of IFN‐γ–deficient NK cells or host IFN‐γ neutralization led to amelioration of these lesions. Use of either perforin‐deficient NK cells or CD95 (Fas)–deficient donors alone did not alter development of vasculopathy, but simultaneous disruption of NK cell–derived perforin and allograft Fas expression resulted in prevention of these abnormalities. Therefore, both NK cell IFN‐γ production and contact‐dependent cytotoxic activity are rate‐limiting effector pathways that contribute to this form of antibody‐induced chronic allograft vasculopathy.     

Plasma‐Derived C1 Esterase Inhibitor for Acute Antibody‐Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double‐Blind Placebo‐Controlled Pilot Study

Antibody‐mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double‐blind randomized placebo‐controlled pilot study to evaluate the use of human plasma‐derived C1 esterase inhibitor (C1 INH) as add‐on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug‐related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six‐month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH–treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.