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Abstract Introduction Calciphylaxis occurring after kidney transplantation is rare and rarely reported. It results in chronic non-healing wounds and is associated with a poor prognosis and is often fatal. We present a case of proximal lower limb calciphylaxis that occurred early after kidney transplantation. The patient had no classic associated risk factors. He had previously had a total parathyroidectomy but had normal serum calcium-phosphate product and parathyroid hormone levels. The clinical outcome of this case was favorable and highlights some fundamental issues relating to management. Case presentation A 70-year-old British Caucasian man with end-stage renal failure secondary to IgA nephropathy presented six months post kidney transplantation with cutaneous calciphylaxis lesions involving the medial aspect of the thigh bilaterally. Conclusion To the best of our knowledge, this is the first reported case of rapid onset cutaneous calciphylaxis occurring soon after kidney transplantation that was associated with a favorable outcome. Cutaneous calciphylaxis lesions should be promptly managed with meticulous wound care, antimicrobial therapy and the correction of calcium-phosphate product where indicated.

Background: Sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) is generally associated with hematopoietic cell transplant (HCT), but little is known about this condition outside the HCT setting. This systematic review examines the burden of illness and current management approaches in non-HCT SOS/VOD., Methods: We searched Embase, Medline, and grey literature sources for non-HCT SOS/VOD studies published 2002-2023. Inclusion criteria were studies of any design reporting incidence, diagnosis, underlying disease and any ongoing treatment at the time of SOS/VOD onset, management of non-HCT SOS/VOD, clinical burden, health-related quality of life, healthcare resource use, costs, and patients' unmet needs. Studies investigating pulmonary VOD or SOS/VOD related to the ingestion of pyrrolizidine alkaloids were excluded.Two authors independently screened results, extracted data, and assessed the methodological quality of studies using the Motheral scale for retrospective studies, Newcastle-Ottawa scale for prospective studies and case control studies, the Cochrane risk of bias tool for randomized controlled trials, and the Joanna Briggs Institute critical appraisal tool for case series. Results were synthesized narratively., Results: Ninety-two studies were included; 57 % were retrospective cohort studies and 70 % were conducted in the US or Europe. The study populations included hematological and solid tumor cancers, various indications for liver transplant, Wilms' tumor, and transfusion-dependent beta thalassemia. Non-HCT SOS/VOD occurs most frequently in people with colorectal liver metastases (CRLM), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). Approximately 35 % of oxaliplatin-treated CRLM patients and 5 % of ALL and AML patients have non-HCT SOS/VOD. Diagnosis varies according to initial disease setting. Defibrotide is the most frequently reported treatment. Most studies did not clearly report their data sources or methods of outcome assessment., Conclusion: Non-HCT SOS/VOD occurs in diverse disease conditions, therefore guidelines on diagnosis and treatment are needed to optimize management in clinical practice., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lin Fan is an employee of and holds stock ownership and/or stock options in Jazz Pharmaceuticals. Fiona Stewart is employed by Cencora, which received funds from Jazz Pharmaceuticals to support this research. Kimberly Ruiz is employed by Cencora, which received funds from Jazz Pharmaceuticals to support this research. Darsh Devani was employed by Cencora, which received funds from Jazz Pharmaceuticals to support this research, during the time the study was conducted. Nicole Fusco is employed by Cencora, which received funds from Jazz Pharmaceuticals to support this research. Malia Gill is employed by Cencora, which received funds from Jazz Pharmaceuticals to support this research. Vian Amber is an employee of and holds stock ownership and/or stock options in Jazz Pharmaceuticals. Wayne Su is an employee of and holds stock ownership and/or stock options in Jazz Pharmaceuticals. Alexandra Gangi is employed by Cedars-Sinai Medical Center and has no disclosures. Raj Hanvesakul is an employee of and holds stock ownership and/or stock options in Jazz Pharmaceuticals., (© 2024 Published by Elsevier Ltd.)

Aim: Compare lurbinectedin versus other second-line (2L) small-cell lung cancer (SCLC) treatments. Methods: An unanchored matching-adjusted indirect comparison connected the platinum-sensitive SCLC cohort of a single-arm lurbinectedin trial to a network of three randomized controlled trials (oral and intravenous [IV] topotecan, and platinum re-challenge) identified by systematic literature review. Network meta-analysis methods estimated relative treatment effects. Results: In platinum-sensitive patients, lurbinectedin demonstrated a survival benefit and favorable safety profile versus oral and IV topotecan and platinum re-challenge (overall survival, hazard ratio [HR]: 0.43; 95% credible interval [CrI]: 0.27, 0.67; HR: 0.43; 95% CrI: 0.26, 0.70; HR: 0.42; 95% CrI: 0.30, 0.58 respectively). Conclusion: Lurbinectedin showed a robust survival benefit and favorable safety versus other SCLC treatments in 2L platinum-sensitive SCLC.

Background: It is proposed that chronic calcineurin inhibitor (CNI) nephrotoxicity has a central role in chronic kidney disease after nonrenal solid organ transplantation (NRSOT), although there are little data on renal histology in this setting. The aim of this study was to assess the histological features and renal outcomes of a cohort of patients with chronic kidney disease after NRSOT., Methods: Renal biopsies of 62 NRSOT recipients were evaluated for histological diagnoses. Biopsies were graded for chronic allograft damage index parameters and for arteriolar hyalinosis. The sum of all chronic allograft damage index parameters and arteriolar hyalinosis scores was called chronic damage index., Results: The biopsies were performed at a median of 4 (range: 0.3-15.9) years after NRSOT and at serum creatinine of 318±17.7 μmol/L (mean±standard deviation). Twenty-two (35.5%) biopsies showed predominant features of chronic CNI nephrotoxicity, 27 (43.5%) predominant features of hypertensive nephropathy, and 12 (19.3%) an alternative primary renal pathology. Twenty-four (38.7%) patients had progression to end-stage renal disease, at a median of 1.5 (0-10.1) years after biopsy and 6.9 (0.3-19.2) years after NRSOT. The risk of renal progression was associated with in situ damage measured by chronic damage index., Conclusions: Although CNI nephrotoxicity is an important cause of renal failure after NRSOT, many patients do not have overt histological evidence of CNI toxicity. Quantitative parameters of chronic damage can stratify renal prognosis.

Background: Although risk factors for kidney transplant failure are well described, prognostic risk scores to estimate risk in prevalent transplant recipients are limited., Study Design: Development and validation of risk-prediction instruments., Setting & Participants: The development data set included 2,763 prevalent patients more than 12 months posttransplant enrolled into the LOTESS (Long Term Efficacy and Safety Surveillance) Study. The validation data set included 731 patients who underwent transplant at a single UK center., Predictor: Estimated glomerular filtration rate (eGFR) and other risk factors were evaluated using Cox regression., Outcome: Scores for death-censored and overall transplant failure were based on the summed hazard ratios for baseline predictor variables. Predictive performance was assessed using calibration (Hosmer-Lemeshow statistic), discrimination (C statistic), and clinical reclassification (net reclassification improvement) compared with eGFR alone., Results: In the development data set, 196 patients died and another 225 experienced transplant failure. eGFR, recipient age, race, serum urea and albumin levels, declining eGFR, and prior acute rejection predicted death-censored transplant failure. eGFR, recipient age, sex, serum urea and albumin levels, and declining eGFR predicted overall transplant failure. In the validation data set, 44 patients died and another 101 experienced transplant failure. The weighted scores comprising these variables showed adequate discrimination and calibration for death-censored (C statistic, 0.83; 95% CI, 0.75-0.91; Hosmer-Lemeshow χ(2)P = 0.8) and overall (C statistic, 0.70; 95% CI, 0.64-0.77; Hosmer-Lemeshow χ(2)P = 0.5) transplant failure. However, the scores failed to reclassify risk compared with eGFR alone (net reclassification improvements of 7.6% [95% CI, -0.2 to 13.4; P = 0.09] and 4.3% [95% CI, -2.7 to 11.8; P = 0.3] for death-censored and overall transplant failure, respectively)., Limitations: Retrospective analysis of predominantly cyclosporine-treated patients; limited study size and categorization of variables may limit power to detect effect., Conclusions: Although the scores performed well regarding discrimination and calibration, clinically relevant risk reclassification over eGFR alone was not evident, emphasizing the stringent requirements for such scores. Further studies are required to develop and refine this process., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The routine assessment of cellular alloimmunity to guide therapy is of perennial interest because this limb of the immune system is the main target of current transplant immunosuppression. That this has not as yet been realized in clinical practice reflects the difficulty of developing a standardized assay that accounts for the high degree of polymorphism exhibited by histocompatibility antigens., Methods: We have investigated whether immune responses to peptides derived from nonpolymorphic regions of human leukocyte antigen arise after transplantation, in particular in those with chronic allograft dysfunction., Results: Peripheral blood mononuclear cell γ-interferon production to peptides derived from the nonpolymorphic α3 domain of class 1 human leukocyte antigen occurred more frequently in long-term renal transplant recipients than healthy controls (51/110 vs. 1/18, 46.3% vs. 5.5%; P<0.001). These responses were associated with chronic allograft dysfunction manifested by a reduced and decreasing estimated glomerular filtration rate (responders vs. nonresponders: 39.5 vs. 48.8 mL/min, P=0.015 and -4.1 vs. -1.3 mL/min/year, P=0.008). Responses occurred mostly to autologous, "cryptic self-epitopes" and arose from CD4CD25CD127 T lymphocytes, which have been previously implicated in chronic rejection., Conclusion: These findings suggest a strategy for assessing cellular immune responses to transplantation antigens with potential for generalization.

Background: HLA-C is an important ligand for killer immunoglobulin like receptors (KIR) that regulate natural killer (NK) cell function. Based on KIR specificity HLA-C molecules are allocated into two groups, HLA-C1 or HLA-C2; HLA-C2 is more inhibiting to NK cell function than HLA-C1. We studied the clinical importance of HLA-C genotypes on the long-term graft survival of 760 kidney transplants performed at our centre utilising a population based genetic study and cell culture model to define putative mechanisms., Methods and Findings: Genotyping was performed using conventional DNA PCR techniques and correlations made to clinical outcomes. We found that transplant recipients with HLA-C2 had significantly better long-term graft survival than transplant recipients with HLA-C1 (66% versus 44% at 10 years, log-rank p = 0.002, HR = 1.51, 95%CI = 1.16-1.97). In in-vitro NK and dendritic cell (DC) co-culture model we made several key observations that correlated with the population based genetic study. We observed that donor derived NK cells, on activation with IL-15, promoted differential HLA-C genotype dependent DC maturation. In NK-DC co-culture, the possession of HLA-C2 by DC was associated with anti-inflammatory cytokine production (IL-1RA/IL-6), diminished DC maturation (CD86, HLA-DR), and absent CCR7 expression. Conversely, possession of HLA-C1 by DC was associated with pro-inflammatory cytokine synthesis (TNF-α, IL-12p40/p70), enhanced DC maturation and up-regulation of CCR7 expression. By immunohistochemistry the presence of donor NK cells was confirmed in pre-transplant kidneys., Conclusions: We propose that after kidney transplantation IL-15 activated donor derived NK cells interact with recipient DC with less activation of indirect allo-reactivity in HLA-C2 positive recipients than HLA-C1 positive recipients; this has implications for long-term graft survival. Early events following kidney transplantation involving NK-DC interaction via KIR and HLA-C immune synapse may have a central role in long-term kidney transplant outcomes.

Background: Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic bone marrow transplantation (BMT) the immunopathogenesis of which is not well understood. Humoral and cellular immunity are both implicated, patients express a range of autoantibodies, but the targets of cellular immunity are not well defined. Autologous human leukocyte antigen (HLA)-derived peptides constitute a significant proportion of the repertoire., Methods: We have investigated the response to HLA-derived peptides after allogeneic BMT using gamma-interferon enzyme-linked immunospot assay (ELISPOT). We also studied the release of this gamma-interferon by flow cytometry in a subgroup of responsive patients., Results: The peripheral blood mononuclear cell response was assessed by gamma-interferon ELISPOT in 42 BMT recipients (21 with cGVHD) and 30 healthy donors. Thirteen of 21 patients diagnosed with cGVHD responded to at least one HLA-derived peptide compared with 1 of 21 patients without cGVHD (62% vs. 5%, P<10) and 1 of 30 healthy donors. In all but one patient these peptides correspond with the sequences of autologous HLA. The median single peptide-specific response in ELISPOT was 43/10 peripheral blood mononuclear cells. In a subgroup studied by flow cytometry, gamma-interferon production to individual peptides occurred in 0.04% to 0.18% of CD4 T lymphocytes., Conclusion: These observations identify HLA-derived peptides as targets of a cellular immune response in cGVHD.

Introduction: Some Indoasian (IA) patients with established renal failure travel abroad for commercial kidney transplantation. We compared the 1-year outcomes of IA patients from one UK region who received overseas transplants with IA patients receiving local living donor (LD) kidney transplantation, deceased donor (DD) transplantation, and dialysis., Methods: Between 1996 and 2006, 40 adults were transplanted overseas; 38 were IA, and follow-up data were available on 36 patients. Forty IA patients received LD transplants, and 156 patients received DD transplants locally. A cohort of 120 prospective dialysis patients was also used as a comparator group., Results: In the overseas cohort, 20 patients (56%) were not active in the UK transplant waiting list at the time of kidney transplantation overseas. One-year graft survival was 87%, and 1-year patient survival was 83%. Composite graft and patient survival was 69.5% at 1 year. In the local LD transplant recipients, patient survival was 97.5% (39 of 40; P=0.03), and graft survival was 97.5% (39 of 40; P=0.06). Composite graft and patient survival was 95% (P=0.003). In the overseas group, 42% had major infections compared with 15% in the local group (P=0.02). One-year graft survival for DD transplant was 84.6% (132 of 156), and 1-year patient survival was 93% (145 of 156; P=NS and P=0.06, respectively). In the dialysis group, 1-year patient survival was 96.7% (116 of 120; P=0.001)., Conclusion: IA patients who choose to travel overseas for kidney transplantation have poor clinical outcomes and should be counseled accordingly.

Context: Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis., Objective: To study the association of CAV1 gene variation with kidney transplant outcome, using kidney transplantation as a model of accelerated fibrosis., Design, Setting, and Patients: Candidate gene association and validation study. Genomic DNA from 785 white kidney transplant donors and their respective recipients (transplantations in Birmingham, England, between 1996 and 2006; median follow-up, 81 months) were analyzed for common variation in CAV1 using a single-nucleotide polymorphism (SNP) tagging approach. Validation of positive findings was sought in an independent kidney transplant donor-recipient cohort (transplantations in Belfast, Northern Ireland, between 1986 and 2005; n = 697; median follow-up, 69 months). Association between genotype and allograft failure was initially assessed by Kaplan-Meier analysis, then in an adjusted Cox model., Main Outcome Measure: Death-censored allograft failure, defined as a return to dialysis or retransplantation., Results: The presence of donor AA genotype for the CAV1 rs4730751 SNP was associated with increased risk of allograft failure in the Birmingham group (donor AA vs non-AA genotype in adjusted Cox model, hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.29-3.16; P = .002). No other tag SNPs showed a significant association. This finding was validated in the Belfast cohort (in adjusted Cox model, HR, 1.56; 95% CI, 1.07-2.27; P = .02). Overall graft failure rates were as follows: for the Birmingham cohort, donor genotype AA, 22 of 57 (38.6%); genotype CC, 96 of 431 (22.3%); and genotype AC, 66 of 297 (22.2%); and for the Belfast cohort, donor genotype AA, 32 of 48 (67%); genotype CC, 150 of 358 (42%); and genotype AC, 119 of 273 (44%)., Conclusion: Among kidney transplant donors, the CAV1 rs4730751 SNP was significantly associated with allograft failure in 2 independent cohorts.

'Enteric fever' is a potentially fatal, severe systemic disease, which is encountered worldwide. Traditionally, enteric fever refers to a bacteremic illness caused by members of certain Salmonella serotypes, notably: Salmonella typhi, a Gram-negative bacterium, and to a lesser extent, Salmonella paratyphi A, B and C. In addition, other non-salmonella organisms may produce a syndrome clinically indistinguishable from "enteric fever". Brucella sp., Campylobacter sp., Edwardsiella tarda, Enterobacter Cloacae, Escherichia coli, Klebsiella pneumoniae, Providencia alcalifaciens, Pseudomonas sp., Serratia marcescens, Francisella sp. and Yersinia pp have been identified in enteric fever This is, to the best of the authors' knowledge, the first case of Citrobacter to be reported presenting as enteric fever in a normal host in Thailand.

Globalization and the growth of tourism, which now includes "adventure" visits to very remote regions, has created new employment but also new problems. For example, elderly tourists break their hips where there is no competent orthopedic surgeon, a traveler gets bitten by a cobra in rural Cambodia where there is not even an "Ambu" bag to keep him oxygenated, and a tour guide develops high-altitude cerebral edema on a remote Nepalese mountain. What would we do without organizations that are capable of removing such victims rapidly and safely to a place able to provide appropriate medical care? Fortunately, several well-staffed and well-equipped air ambulance companies stand ready almost worldwide to help 24 hours a day. Medical assistance firms, which sell their own travel insurance and/or act as agents of large insurance companies, are also at hand and have offices in major cities worldwide. They have 24-hour telephone numbers and are prepared to advise a sick or injured traveler where he or she should go to obtain competent medical care. Most of these firms have regional medical advisors in strategic locations who maintain a network of contacts. They can ensure that an ill traveler is receiving appropriate care and will act as quality controllers. They are also able to advise whether medical evacuation to a higher level of care is needed and where the traveler should be evacuated to.

1. Endothelium-derived hyperpolarizing factor (EDHF) has recently been identified as potassium released from endothelial cells into the myo-endothelial space. The present study was designed to test this hypothesis. 2. In rat small mesenteric arteries, mounted in a wire myograph, relaxation to acetylcholine or potassium was not significantly changed following incubation with oxadiazolo-quinoxalin-1-one (ODQ, 4 microM) and indomethacin (10 microM, n = 9). 3. Maximal relaxations to acetylcholine occurred in all arteries, were maintained and were significantly greater (P < 0.01, n = 9) than the transient relaxations to potassium, which only occurred in 30-40% of vessels. 4. Removal of the vascular endothelium abolished relaxant responses both to potassium and acetylcholine (P < 0.005, n = 9). 5. Compared with responses in 5.5 mM potassium PSS, relaxation responses to added potassium in arteries maintained in 1.5 mM potassium PSS were more marked and were not dependent on the presence of an intact endothelium (n = 8). 6. Incubation with BaCl2 (50 microM) significantly inhibited the maximal relaxant response to potassium in the presence of an intact endothelium in 5.5 mM potassium PSS (P < 0.05, n = 4), but had no effect on relaxation of de-endothelialized preparations in 1.5 mM potassium PSS (n = 5). 7. Treatment with ouabain (0.1 mM) abolished the relaxant response to potassium in 1.5 mM potassium PSS (P < 0.001, n = 9), but only partly inhibited the maximal relaxant response to acetylcholine in 5.5 mM potassium PSS (P < 0.01, n = 5). 8. These data show that at physiological concentrations of potassium an intact endothelium is necessary for potassium-induced relaxation in rat mesenteric arteries. Furthermore, the response to potassium is clearly different to that from acetylcholine, indicating that potassium does not mimic EDHF released by acetylcholine in these arteries.