Pretransplant donor biopsy (PTDB)‐based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the ...highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score <4 median KDPI: 87; interquartile range (IQR): 78–94 and 62 with a score = 4 median KDPI: 87; IQR: 76–93; 102 dual transplants median KDPI: 93; IQR: 86–96) and 248 single standard transplant controls (median KDPI: 36; IQR: 18–51). PTDB‐based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80–90 and of 37% for kidneys with a KDPI of 91–100. Although 1‐year estimated GFRs were significantly lower in recipients of marginal kidneys (−9.3, −17.9 and −18.8 mL/min, for dual transplants, single kidneys with PTDB score <4 and =4, respectively; p < 0.001), graft survival (median follow‐up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 95% confidence interval: 0.80–1.79; p = 0.38). In conclusion, PTDB‐based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.
This study shows that the standardized assessment of formalin‐fixed pretransplant biopsies helps recover donors with KDPI in the highest range that would be otherwise discarded, and by providing the expected graft outcomes based on KDPI and pretransplant biopsy, it guides the clinician facing the difficult decision whether to accept or reject these organs. See editorial by Gupta et al on page 2444.
The immune cell function assay (ICFA) and de novo anti‐donor‐specific HLA antibodies (DSA) have been proposed as assays for immune monitoring in renal transplantation, but longitudinal studies ...examining the modification of both parameters over time and their relation with clinical events are lacking. We prospectively measured longitudinal changes in ICFA and DSA levels in 55 kidney transplant recipients over 3‐year follow‐up (534 visits) and analyzed their relation with the risk of developing acute rejections or infections. Seven patients (12.7%) developed biopsy‐proven acute rejection, and 20 (36.4%) developed viral infections. At 3 years posttransplant, 28% of the patients had developed de novo DSA. ICFA levels peaked at 1–2 months posttransplant (p = 0.005) and leveled off thereafter. They were not associated with the risk of acute rejections, viral infections or development of de novo DSA. Instead, the incidence of de novo DSA was higher in patients who previously had viral infections (adjusted‐odds ratio of de novo DSA associated with prior infections: 6.03 95% CI, 1.64–22.06; p = 0.007). Our prospective, longitudinal study does not support using ICFA to quantify the immune risk in kidney transplantation. Further studies are needed to confirm the relationship between viral infections and the subsequent development of de novo DSA.
In this prospective longitudinal study examining an immune function assay and de novo donor‐specific alloantibodies in kidney transplant recipients, the authors find that the immune function assay was not related to the future development of rejection, infection, or donor‐specific antibodies, but that the risk of developing donorspecific antibodies was increased in patients who suffered from previous viral infection.
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The combination of essential oils (EOs) with antibiotics provides a promising strategy towards combating resistant bacteria. We have selected a mixture of 3 major components extracted ...from EOs: carvacrol (oregano oil), eugenol (clove oil) and cinnamaldehyde (cinnamon oil). These compounds were successfully encapsulated within lipid nanocapsules (LNCs). The EOs-loaded LNCs were characterised by a noticeably high drug loading of 20% and a very small particle diameter of 114nm. The in vitro interactions between EOs-loaded LNCs and doxycycline were examined via checkerboard titration and time-kill assay against 5 Gram-negative strains: Acinetobacter baumannii SAN, A. baumannii RCH, Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa. No growth inhibition interactions were found between EOs-loaded LNCs and doxycycline (FIC index between 0.7 and 1.30). However, when bactericidal effects were considered, a synergistic interaction was observed (FBC index equal to 0.5) against all tested strains. A synergistic effect was also observed in time-kill assay (a difference of at least 3 log between the combination and the most active agent alone). Scanning electron microscopy (SEM) was used to visualise the changes in the bacterial membrane. The holes in bacterial envelope and leakage of cellular contents were observed in SE micrographs after exposure to the EOs–LNCs and the doxycycline combination.
Abstract Immunological evaluation by panel-reactive antibody (PRA) and determination of anti-HLA specificity are important phases in the evaluation of patients awaiting kidney transplantation. The ...main causes of immunization are previous solid organ transplantation, hemotransfusion, and pregnancy. It is also possible that immunogenicity can be triggered by vascularized tissue grafts. Immune induction by cryopreserved bone prostheses is not yet understood. A 19-year-old patient with osteosarcoma had undergone resection of the left proximal tibia with reconstruction using human bone in 1997. The donor HLA typing was as follows: A3, A29 (19); B44 (12), Bw4; DR13 (6), DR7, DR52, DR53. The patient was subsequently enrolled onto the waiting list for cadaveric donor kidney transplantation due to chronic kidney failure caused by cisplatin toxicity. Pretransplantation immunological screening using the complement-dependent cytotoxicity (CDC) technique revealed a PRA of 63%. IgG antibody specificities were detected against class I and class II donor antigens, specifically anti-A3, B44, DR7 antibodies, using flow cytometry (Tepnel Luminex). Further immunological studies using single HLA specificity analysis (LSA Class I°–II°, Tepnel-Luminex) showed direct antibodies against all donor antigen specificities. This case showed immune induction after the implantation of bone prosthesis in a kidney transplant candidate, underlining the importance of the availability of HLA typing data of donors of a human prosthesis.
A pretransplant positive cross-match is a contraindication for kidney transplantation, unlike in liver transplantation (OLT). In combined liver kidney transplantation (LKT) it is hypothesized that ...liver can protect kidney from rejection. We report the case of a 35-year-old woman on renal replacement therapy with gastrointestinal tract compression due to a hematoma following spontaneous liver rupture (May 2004). She was affected by amyloidosis, treated with a bone marrow autotransplantation (2001). The liver rupture was surgically untreatable, so an LKT was proposed. Panel-reactive antibody was 80% to 100% (complement dependent cytotoxicity) with specific anti-HLA antibodies (enzyme-linked immunosorbent assay). A compatible donor was found (July 2004). The cross-match before LKT was positive for B and T cells (score 8): an emergency OLT was performed. Immediately after liver reperfusion the cross-match result was less positive (6) for T cells. After 6 hours it was negative for T and slightly positive for B cells (4): the kidney was transplanted. The immunosuppressive therapy was: alemtuzumab, steroids, and tacrolimus. Renal function immediately recovered. On day 7 a rejection episode was successfully treated by increasing steroids (intravenous bolus). At discharge hepatic and renal function were normal (creatinine 1 mg/dL). They are stable after 1 year. This case showed LKT efficacy even in complex immunological situations. Many immunological mechanisms, still not defined, are hypothesized about the protective role of the liver. This case confirmed experimental data that highlighted that in vivo in humans a cross-match can change from positive to negative after OLT giving highly sensitized patients the possibility for LKT.
Aims. In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator ...(CFTR) gene.
Methods. In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies.
Results. Frequencies of DRB1∗01, DQA1∗0101, DQB1∗0102 (14 vs. 8%,
p<0.05), DRB1∗16, DQA1∗0102, DQB1∗0502 (8 vs. 3%,
p<0.025) and DRB1∗04, DQA1∗03, DQB1∗0301 (10 vs. 4%,
p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1∗01, ∗1601 or ∗04 related haplotypes was significantly increased (32 vs. 14%,
p<0.00025). DRB1∗07, DQA1∗0201, DQB1∗02 haplotype frequency was significantly decreased (4 vs. 15%,
p<0.001). After removing HLA-DRB1∗01, ∗1601, ∗04 related haplotype sharing patients, HLA-DRB1∗03, DQA1∗0501, DQB1∗02 haplotype frequency was significantly increased (32 vs. 14%,
p<0.01).
TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%,
p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%,
p=0.0013).
No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased.
Conclusion. These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries.
The COL4A5 gene encodes the alpha5 (type IV) collagen chain and is defective in X-linked Alport syndrome (AS). Here, we report the first systematic analysis of all 51 exons of COL4A5 gene in a series ...of 201 Italian AS patients. We have previously reported nine major rearrangements, as well as 18 small mutations identified in the same patient series by SSCP analysis of several exons. After systematic analysis of all 51 exons of COL4A5, we have now identified 30 different mutations: 10 glycine substitutions in the triple helical domain of the protein, 9 frameshift mutations, 4 in-frame deletions, 1 start codon, 1 nonsense, and 5 splice-site mutations. These mutations were either unique or found in two unrelated families, thus excluding the presence of a common mutation in the coding part of the gene. Overall, mutations were detected in only 45% of individuals with a certain or likely diagnosis of X-linked AS. This finding suggests that mutations in noncoding segments of COL4A5 account for a high number of X-linked AS cases. An alternative hypothesis is the presence of locus heterogeneity, even within the X-linked form of the disease. A genotype/phenotype comparison enabled us to better substantiate a significant correlation between the degree of predicted disruption of the alpha5 chain and the severity of phenotype in affected male individuals. Our study has significant implications in the diagnosis and follow-up of AS patients.
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