Disparities in Kidney Transplant Waitlisting Among Young Patients Without Medical Comorbidities.

Importance: Disparities in kidney transplant referral and waitlisting contribute to disparities in kidney disease outcomes. Whether these differences are rooted in population differences in comorbidity burden is unclear. Objective: To examine whether disparities in kidney transplant waitlisting were present among a young, relatively healthy cohort of patients unlikely to have medical contraindications to kidney transplant. Design, Setting, and Participants: This retrospective cohort study used the US Renal Data System Registry to identify patients with end-stage kidney disease who initiated dialysis between January 1, 2005, and December 31, 2019. Patients who were older than 40 years, received a preemptive transplant, were preemptively waitlisted, or had documented medical comorbidities other than hypertension or smoking were excluded, yielding an analytic cohort of 52 902 patients. Data were analyzed between March 1, 2022, and February 1, 2023. Main Outcome(s) and Measure(s): Kidney transplant waitlisting after dialysis initiation. Results: Of 52 902 patients (mean [SD] age, 31 [5] years; 31 132 [59%] male; 3547 [7%] Asian/Pacific Islander, 20 782 [39%] Black/African American, and 28 006 [53%] White) included in the analysis, 15 840 (30%) were waitlisted for a kidney transplant within 1 year of dialysis initiation, 11 122 (21%) were waitlisted between 1 and 5 years after dialysis initiation, and 25 940 (49%) were not waitlisted by 5 years. Patients waitlisted within 1 year of dialysis initiation were more likely to be male, to be White, to be employed full time, and to have had predialysis nephrology care. There were large state-level differences in the proportion of patients waitlisted within 1 year (median, 33%; range, 15%-58%). In competing risk regression, female sex (adjusted subhazard ratio [SHR], 0.92; 95% CI, 0.90-0.94), Hispanic ethnicity (SHR, 0.77; 95% CI, 0.75-0.80), and Black race (SHR, 0.66; 95% CI, 0.64-0.68) were all associated with lower waitlisting after dialysis initiation. Unemployment (SHR, 0.47; 95% CI, 0.45-0.48) and part-time employment (SHR, 0.74; 95% CI, 0.70-0.77) were associated with lower waitlisting compared with full-time employment, and more than 1 year of predialysis nephrology care, compared with none, was associated with greater waitlisting (SHR, 1.51; 95% CI, 1.46-1.56). Conclusions and Relevance: This retrospective cohort study found that fewer than one-third of patients without major medical comorbidities were waitlisted for a kidney transplant within 1 year of dialysis initiation, with sociodemographic disparities in waitlisting even in this cohort of young, relatively healthy patients unlikely to have a medical contraindication to transplantation. Transplant policy changes are needed to increase transparency and address structural barriers to waitlist access.

UNOS Decisions Impact Data Integrity of the OPTN Data Registry.

BACKGROUND: The Organ Procurement Transplant Network (OPTN)/United Network for Organ Sharing (UNOS) registry is an important national registry in the field of solid organ transplantation. Data collected are mission critical, given its role in organ allocation prioritization, program performance monitoring by both the OPTN and the Centers for Medicare & Medicaid Services, and countless observational analyses that helped to move the field forward. Despite the multifaceted importance of the OPTN/UNOS database, there are clear indications that investments in the database to ensure the quality and reliability of the data have been lacking. METHODS: This analysis outlines 2 examples: (1) primary diagnosis for patients who are receiving a second transplant and (2) reporting peripheral vascular disease in kidney transplantation to illustrate the extensive challenges facing the veracity and integrity of the OPTN/UNOS database today. RESULTS: Despite guidance that repeat kidney transplant patients should be coded as "retransplant/graft failure" rather than their native kidney disease, only 59% of new incident patients are coded in this manner. Peripheral vascular disease prevalence more than doubled in a 20-y span when the variable became associated with risk adjustment. CONCLUSIONS: This article summarizes critical gaps in the OPTN/UNOS database, and we bring forward ideas and proposals for consideration as a path toward improvement.

Fecal expression of Escherichia coli lysine decarboxylase (LdcC) is downregulated in E-cadherin negative lobular breast carcinoma.

Breast cancer is characterized by oncobiosis, the abnormal composition of the microbiome in neoplastic diseases. The biosynthetic capacity of the oncobiotic flora in breast cancer is suppressed, as suggested by metagenomic studies. The microbiome synthesizes a set of cytostatic and antimetastatic metabolites that are downregulated in breast cancer, including cadaverine, a microbiome metabolite with cytostatic properties. We set out to assess how the protein expression of constitutive lysine decarboxylase (LdcC), a key enzyme for cadaverine production, changes in the feces of human breast cancer patients (n = 35). We found that the fecal expression of Escherichia coli LdcC is downregulated in lobular cases as compared to invasive carcinoma of no special type (NST) cases. Lobular breast carcinoma is characterized by low or absent expression of E-cadherin. Fecal E. coli LdcC protein expression is downregulated in E-cadherin negative breast cancer cases as compared to positive ones. Receiver operating characteristic (ROC) analysis of LdcC expression in lobular and NST cases revealed that fecal E. coli LdcC protein expression might have predictive values. These data suggest that the oncobiotic transformation of the microbiome indeed leads to the downregulation of the production of cytostatic and antimetastatic metabolites. In E-cadherin negative lobular carcinoma that has a higher potential for metastasis formation, the protein levels of enzymes producing antimetastatic metabolites are downregulated. This finding represents a new route that renders lobular cases permissive for metastasis formation. Furthermore, our findings underline the role of oncobiosis in regulating metastasis formation in breast cancer.

Correlation among metallothionein expression, intratumoural macrophage infiltration and the risk of metastasis in human cutaneous malignant melanoma.

BACKGROUND: The formation of metastases and the efficacy of systemic therapies in cutaneous malignant melanoma (CMM) depend on the characteristics of the tumour cells and the host immune response. Aberrant expression of metallothionein (MT) has been observed in several types of cancers with poor prognoses. OBJECTIVE: To perform an immunohistochemical study on primary CMM comparing the MT expression of tumours without metastases (n = 23) to that of samples with haematogenous metastases (n = 23) and to examine the correlation between MT staining and immunological markers relevant in CMM progression. METHODS: The immunohistochemical labelling of different tumour sections was analysed using tissue microarrays for the evaluation of the suitability of this method in future studies. RESULTS: Our results suggest that MT overexpression is significantly more frequent in primary CMM with haematogenous metastases (P = 0.018) and that the overexpression is independent of the Breslow tumour thickness (R = 0.102, P = 0.501). Interestingly, MT overexpression of the tumour cells was correlated with the presence of tumour-infiltrating CD68(+) macrophages (P = 0.003), a known predictive factor for melanoma progression, thereby suggesting a role for MT in the development of a defective host immune response. Furthermore, the presence of CD163(+) macrophages infiltrating the tumours correlated with metastasis formation (P < 0.001), whereas the presence CD1a(+) dendritic cells surrounding the tumours was associated with a lower risk of haematogenous spread (P = 0.003). CONCLUSION: Our results demonstrate that MT may represent a suitable prognostic factor that can characterize the metastasising ability of CMM and the tumour-promoting host immune response.

Progesterone-induced blocking factor (PIBF) and trophoblast invasiveness.

Controlled trophoblast invasion is a key process during human placentation and a prerequisite for successful pregnancy. Progesterone is one of the factors to regulate trophoblast invasiveness. Progesterone-induced blocking factor (PIBF) is a progesterone-induced molecule expressed by the trophoblast, and also by tumors. The distribution of PIBF within the first-trimester decidua coincides with sites of trophoblast invasion. Another molecule that has been implicated in the control of trophoblast invasiveness is placental leptin. Leptin inhibits the secretion of progesterone by cytotrophoblast. The aim of this work was to investigate the possible interaction of PIBF and leptins in regulating trophoblast invasion. Paraffin-embedded sections from normal first-trimester placentae, partial moles, complete moles, and choriocarcinomas were reacted with PIBF, leptin, and leptin receptor specific antibodies. PIBF-deficient trophoblast cells were generated using siRNA and leptin receptor was detected on Western blot analysis. The lysates of PIBF-treated cells were used for detecting leptin expression in a protein array. PIBF was expressed in both normal first-trimester villous trophoblast and in partial mole. Compared with this, PIBF expression was markedly decreased in complete mole and absent in choriocarcinoma. Neither leptinR nor leptin were detected in partial mole, whereas both of these molecules were present in complete mole and choriocarcinoma. Leptin receptor expression was upregulated in PIBF-deficient cells, while leptin expression was decreased in PIBF-treated cells. These data suggest that PIBF affects the expression of leptin and its receptor, and that PIBF expression is inversely related to trophoblast invasiveness.

Expression of invasion-related extracellular matrix molecules in human glioblastoma versus intracerebral lung adenocarcinoma metastasis.

Tumor cell invasion into the surrounding brain tissue is mainly responsible for the failure of radical surgical resection, with tumor recurrence in the form of microdisseminated disease. Extracellular matrix (ECM)-related molecules and their receptors predominantly participate in the invasion process, including cell adhesion to the surrounding microenvironment and cell migration. The extent of infiltration of the healthy brain by malignant tumors strongly depends on the tumor cell type. Malignant gliomas show much more intensive peritumoral invasion than do metastatic tumors. In this study, the mRNA expression of 30 invasion-related molecules (twenty-one ECM components, two related receptors, and seven ECM-related enzymes) was investigated by quantitative reverse transcriptase-polymerase chain reaction. Fresh frozen human tissue samples from glioblastoma (GBM), intracerebral lung adenocarcinoma metastasis, and normal brain were evaluated. Significant differences were established for 24 of the 30 molecules. To confirm our results at the protein level, immunohistochemical analysis of seven molecules was performed (agrin, neurocan, syndecan, versican, matrix metalloproteinase 2 [MMP-2], MMP-9, and hyaluronan). Determining the differences in the levels of invasion-related molecules for tumors of different origins can help to identify the exact molecular mechanisms that facilitate peritumoral infiltration by glioblastoma cells. These results should allow the selection of target molecules for potential chemotherapeutic agents directed against highly invasive malignant gliomas.

Dehydroepiandrosterone and metformin modulate progesterone-induced blocking factor (PIBF), cyclooxygenase 2 (COX2) and cytokines in early pregnant mice.

The present study examined the mechanism by which metformin (N,N'-dimethylbiguanide) prevents embryonic resorption induced in mice by dehydroepiandrosterone (DHEA). Treatment with DHEA (60mg/kg, s.c. 24 and 48h post-implantation) induces embryo resorption of early pregnant BALB/c mice while simultaneous treatment with metformin (240mg/kg, oral 24 and 48h post-implantation) prevents it. During pregnancy progesterone-induced blocking factor (PIBF) modulates prostaglandins (PGs) and cytokine production. These findings prompted us to investigate the effect of DHEA and metformin on both PIBF and cyclooxygenase 2 (COX2) expressions at the implantation sites, as well as cytokine production. PIBF and COX2 expression were detected by immunohistochemistry from DHEA and DHEA+ metformin treated 8 days-pregnant mice and serum cytokine levels of these animals were determined by ELISA. DHEA treatment both abolished PIBF expression and increased COX2 expression. Embryo resorption correlates with the lack of PIBF expression, diminished IL-6 levels and increased IL-2 concentration while metformin was able to reverse the effect of DHEA on both PIBF and COX2 expression and IL-6 levels. We concluded that hyperandrogenization induces embryo resorption in early pregnancy diminishing PIBF in implantation sites, having a pro-inflammatory effect. Metformin is able to prevent such effects.

Progesterone-dependent immunomodulation.

The biological effects of progesterone are mediated by a 34-kDa protein named the progesterone-induced blocking factor (PIBF). PIBF, synthesized by lymphocytes of healthy pregnant women in the presence of progesterone, inhibits arachidonic acid release as well as NK activity, and modifies the cytokine balance. Within the cell the full-length PIBF is associated with the centrosome, while secretion of shorter forms is induced by activation of the cell. PIBF induces nuclear translocation of STAT6 as well as PKC phosphorylation and exerts a negative effect on STAT4 phosphorylation. The concentration of PIBF in pregnancy urine is related to the positive or negative outcome of pregnancy; furthermore, premature pregnancy termination is predictable by lower than normal pregnancy PIBF values. In vivo data suggest the biological importance of the above findings. Treatment of pregnant Balb/c mice with the antiprogesterone RU 486 results in an increased resorption rate, which is associated with the inability of spleen cells to produce PIBF. High resorption rates induced by progesterone receptor block as well as those due to high NK activity are corrected by simultaneous PIBF treatment.

The role of gamma/delta T cells in the feto-maternal relationship.

Polymorphic MHC is absent from the trophoblast, therefore, it resists NK as well as CTL-mediated lysis in vitro. Activated gamma / delta TCR positive cells are significantly enriched in the decidua as well as in peripheral blood of healthy pregnant women. Human peripheral gamma / delta lymphocytes preferentially express the V gamma 9/V delta 2 TCR, whereas those of the decidua use the V delta 1 chain. These subpopulations are functionally polarized, the former being Th1, the latter Th2. Potentially cytotoxic V delta 2+ lymphocytes recognize HLA-E on the trophoblast via the CD94/NKG2A receptor, which induces an inhibitory signal, thus potentially inhibiting Th1 type cytokine production.