Higher rates of rejection in HIV-infected kidney transplant recipients on ritonavir-boosted protease inhibitors: 3-year follow-up study.

Rejection rates in HIV-infected kidney transplant (KTx) recipients are higher than HIV-negative recipients. Immunosuppression and highly active antiretroviral therapy (HAART) protocols vary with potentially significant drug-drug interactions, likely influencing outcomes. This is an IRB-approved, single-center, retrospective study of adult HIV-infected KTx patients between 5/2009 and 12/2014 with 3-year follow-up, excluding antibody-depleting induction. A total of 42 patients were included; median age was 52 years, 81% male, 50% African American, 29% Hispanic, 17% Caucasian. The most common renal failure etiology was hypertensive nephrosclerosis (50%) with 5.8 median years of pre-transplant dialysis. All patients received IL-2 receptor antagonist, were maintained on tacrolimus (76%) or cyclosporine (17%), and 40% received ritonavir-boosted PI-based HAART (rtv+) regimen. Patient and graft survival at 3 years were 93% and 90%. At 1-, 2-, and 3-year time points, median serum creatinine was 1.49, 1.35, and 1.67; treated biopsy-proven rejection was 38%, 38%, and 40.5%; and 92% of episodes were acute rejection. At these time points, rejection rates were significantly higher with boosted PI HAART regimens compared to other HAART regimens, 59% vs 24% (P = 0.029), 59% vs 24% (P = 0.029), and 68% vs 24% (P = 0.01). Despite higher rejection rates, HIV-infected KTx recipients have reasonable outcomes. Given significantly higher rejection rates using rtv+ regimens, alternative HAART regimens should be considered prior to transplantation.

Different outcomes after kidney transplantation between African Americans and Whites: A matter of income? A single-center study.

BACKGROUND: Our center has one of the largest representations of African Americans in listed and transplanted patients. We investigated if and how racial differences affect outcomes in our patient population. METHODS: We performed a retrospective analysis of all kidney transplants in African American and (non-Hispanic) White patients in our center from 1/1/2005 to 12/31/2014. Cox regression was performed to evaluate the adjusted hazard ratios for graft loss. We investigated the influence of socioeconomic status on transplant outcomes. We stratified our patients into three groups based on income: lower (<$50 000 annual household income), medium ($50 000-100 000 annual household income), and higher (>$100 000 annual household income. RESULTS: There were 1333 patients in our study, 696 Whites and 637 African Americans. The 1-, 5-, and 10-year graft survival between the two groups was 96.5% vs 91.1%, 89% vs 80.7%, and 77% vs 66.3%, respectively (P < .001 by Log Rank, Breslow and Taron-Ware). When we compared the two groups separately in each income category, we found no statistical difference between African Americans and Whites in graft survival. In the regression model, income and not race was the significant factor influencing graft survival (P < .001 vs P = .61).

Pre-liver transplant renal dysfunction and association with post-transplant end-stage renal disease: A single-center examination of updated UNOS recommendations.

Simultaneous liver-kidney allocation protocols allocate dual organs based on a sustained eGFR of 30 mL/min or less. A 2017-UNOS update includes CKD3 as dual organ candidates but only when the listing eGFR is <30 mL/min while recommending a "safety net" for prioritized kidney listing post-LT. We retrospectively reviewed adult LTs examine whether the UNOS proposal captured the LT population at highest risk for developing post-LT ESRD. Among 290 LT recipients, 67 had pre-LT CKD3, 141 had AKI, of whom 47 required dialysis (<4 weeks). During follow-up, 25 (8.62%) developed ESRD, while 70 (24.1%) died. In adjusted Cox models, CKD3 had an independent association with post-LT ESRD (adjusted HR 4.8; P = 0.001), independent of AKI. Interestingly, CKD3 with listing GFR >30 mL/min was still significantly associated with post-LT ESRD. AKI was associated with reduced post-LT survival (adjusted HR 1.9; P = 0.02), albeit only in the first-year post-LT. Severe AKI-D was associated with post-LT ESRD and mortality. The safety net would have captured only 60% of all post-LT ESRD cases in our cohort. Pre-LT CKD3 was associated with increased risk of post-LT ESRD above the recommended cutoff for listing GFR. These findings, if generalizable in larger cohorts have important implications for dual organ allocation.

Early conversion to belatacept after renal transplantation.

Belatacept is a non-nephrotoxic immunosuppressive agent, which may make it the ideal agent for patients with delayed or slow graft function on calcineurin inhibitors. There are limited data on conversion of patients to belatacept within 6 months of transplantation. Between January 2012 and December 2015, 16 patients were converted to belatacept for delayed or poor graft function (eGFR<30 mL/min/1.73 m2 , MDRD); three were HIV positive. Conversion protocols were analyzed in patients ≤4 months and 4-6 months post-transplantation. Mean serum creatinine levels after belatacept conversion were compared with preconversion levels. Patient survival was 100%, and graft survival was 88%. The mean creatinine fell from 3.9±1.82 mg/dL prebelatacept conversion to 2.1±1.1 mg/dL at 6 months and 1.9±0.47 mg/dL (median 1.8 mg/dL) at 12 months postconversion. There was no significant increased risk of rejection, infection, or malignancy. HIV parameters remained largely stable. Early conversion to belatacept in patients with DGF or slow graft function is safe and efficacious, in a single-center nonrandomized retrospective analysis.

Correlation between FDG/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia.

Richter syndrome (RS) is associated with poor outcome. The prognosis of patients with histologically aggressive chronic lymphocytic leukemia (CLL), or HAC, has not been studied. We aimed to correlate 2-deoxy-2-[(18)F]fluoroglucose/positron emission tomography (FDG/PET) data, histological diagnosis, clinical characteristics, and survival in patients with CLL. A total of 332 patients with CLL were histologically classified as: 95 RS, 117 HAC, and 120 histologically indolent CLL (HIC). HAC and RS patients had higher maximum standardized uptake value (SUVmax), more frequent constitutional symptoms, poorer performance status (PS), lower hemoglobin and platelets, and higher lactate dehydrogenase and ß-2-microglobulin. An SUVmax ≥10 strongly correlated with mortality (overall survival [OS], 56.7 vs 6.9 months in patients with SUVmax <10 vs ≥10). Survival of patients with RS and HAC was similar among patients with SUVmax <10 or ≥10. SUVmax ≥10, PS ≥2, bulky disease, and age ≥65 were independently associated with shorter OS. In patients undergoing both fine-needle aspiration and biopsy, the former proved diagnostically inadequate in 23%, 29%, and 53% of HIC, HAC, and RS, respectively. FDG/PET is a useful diagnostic tool in patients with CLL and suspected transformation. Patients with HAC show different characteristics and worse prognosis compared with those with HIC. Patients with different CLL phases, but similar SUVmax have similar outcome. Tissue biopsy should be preferred for diagnosing RS.

Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab).

Although fludarabine, cyclophosphamide, and rituximab (FCR) together are established as a standard first-line treatment of younger patients with chronic lymphocytic leukemia (CLL), there is little information to guide the management of patients with CLL refractory to, or who have relapsed after, receiving frontline FCR treatment. To define optimal salvage strategy and identify patients unsuitable for retreatment with FCR, we examined the survival and treatment outcome of 300 patients enrolled in a phase 2 study of FCR. After a median 142 months of follow-up, 156 patients developed progressive CLL, with a median survival of 51 months after disease progression. The duration of first remission (REM1) was a key determinant of survival after disease progression and first salvage. Patients with a short REM1 (<3 years) had a short survival period, irrespective of salvage therapy received; these patients have high unmet medical needs and are good candidates for investigation of novel therapies. In patients with a long REM1 (≥3 years), salvage treatment with either repeat FCR or lenalidomide-based therapy results in subsequent median survival exceeding 5 years; for these patients, FCR rechallenge represents a reasonable standard of care.

Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia.

Noncoding RNAs play a pivotal role in the pathogenesis of chronic lymphocytic leukemia (CLL). We hypothesized that microRNAs (miRs) are involved in the transition from monoclonal B-cell lymphocytosis (MBL) to CLL and tested miR-15a/16-1 cluster, miR-21, and miR-155 expression in purified B cells of normal individuals, individuals with MBL, and patients with CLL. When we analyzed 224 samples from 2 independent training and validation cohorts, we found that miR-155 was overexpressed in B cells from individuals with MBL, and even more so in B cells from patients with CLL, when compared with B cells from normal individuals. Furthermore, we were able to identify miR-155 in circulating microvesicles from both individuals with MBL and patients with CLL. Next, to examine the prognostic role of miR-155, we measured its expression level in plasma samples collected before treatment initiation in 228 patients with CLL. We found significantly higher miR-155 expression levels in patients who failed to achieve a complete response compared with those who experienced complete response. Our findings support the use of cellular and plasma levels of miR-155 as biomarkers for the risk of progression in individuals with MBL, as well as to identify patients with CLL who may not respond well to therapy.

Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study.

BACKGROUND: Ibrutinib, an orally administered covalent inhibitor of Bruton's tyrosine kinase (BTK), is an effective treatment for relapsed chronic lymphocytic leukaemia (CLL). We investigated the activity and safety of the combination of ibrutinib with the monoclonal antibody rituximab in patients with high-risk CLL. METHODS: In this single-arm phase 2 study, we enrolled adult patients with high-risk CLL at the MD Anderson Cancer Center (Houston, TX, USA). All enrolled participants had high-risk cytogenetic abnormalities (deletion 17p, TP53 mutation, or deletion 11q) or a short progression-free survival (PFS <36 months) after previous first-line chemoimmunotherapy. Patients with symptomatic disease requiring therapy received 28-day cycles of once-daily ibrutinib 420 mg together with rituximab (375 mg/m(2), intravenously, every week during cycle 1, then once per cycle until cycle 6), followed by continuous daily single-agent ibrutinib 420 mg until disease progression or until toxicities or complications precluded further treatment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov number NCT01520519, and is no longer accruing patients. FINDINGS: Between Feb 28, 2012, and Sept 11, 2012, we enrolled 40 patients with CLL with high-risk disease features, 20 of whom had deletion 17p (del[17p]) or TP53 mutations (16 previously treated, four untreated), 13 had relapsed CLL with deletion 11q (del[11q]), and seven a PFS less than 36 months after first-line chemoimmunotherapy. 18-month PFS in all patients was 78·0% (95% CI 60·6-88·5), whereas in those with a del(17p) or TP53 mutation it was 72·4% (45·6-87·6) Toxicity was mainly mild to moderate in severity (grade 1-2). Diarrhoea occurred in ten (25%) patients (grade 1 in nine patients and grade 2 in one), bleeding events in 14 (33%) patients (eight grade 1 and five grade 2), nausea or vomiting in 15 patients (38%) (ten grade 1 and five grade 2), and fatigue in seven (18%) patients (four grade 1 and three grade 2). Five patients (13%) had grade 3 infections (two lung infections, one upper respiratory tract infection, one sepsis, and one mucositis), and no grade 4 or 5 infections occurred. One patient had grade 4 neutropenia. INTERPRETATION: The encouraging safety and activity of ibrutinib and rituximab in this population of patients with high-risk CLL merits further investigation of this combination. FUNDING: Pharmacyclics Inc, Cancer Prevention and Research Institute of Texas, Leukemia and Lymphoma Society, National Cancer Institute, MD Anderson Cancer Center.

Myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: analysis of persistent and new-onset cytopenia.

BACKGROUND: The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced improved response rates and a prolonged survival in patients with chronic lymphocytic leukemia (CLL). However, its therapeutic power is counterbalanced by significant hematologic toxicity. Persistent and new-onset cytopenia after the completion of FCR raise concern about disease recurrence, the development of therapy-related myeloid malignancies (TRMM), and infections. METHODS: A total of 207 patients with CLL who achieved complete response, complete response with incomplete bone marrow recovery, or nodular partial remission were analyzed after frontline FCR therapy. RESULTS: Three months after the completion of therapy, 35% of patients had developed grade 2 to 4 cytopenia (according to Common Terminology Criteria for Adverse Events [version 4.0]). Factors found to be associated with cytopenia at 3 months after therapy were older age, advanced Rai stage disease, and lower baseline blood counts. Moreover, patients with cytopenia were less likely to have completed 6 courses of therapy with FCR. At 6 months and 9 months after therapy, the prevalence of grade 2 to 4 cytopenia was 24% and 12%, respectively. No differences in progression-free survival and overall survival were noted between cytopenic and noncytopenic patients or between patients with persistent and new-onset cytopenia. The prevalence of TRMM was 2.3% and did not differ significantly between cytopenic and noncytopenic patients or between those with persistent and new-onset disease. Late infections were more common in patients who were cytopenic at 9 months (38%) and were mostly bacterial (67%). CONCLUSIONS: Cytopenia after the completion of therapy is a common complication of frontline FCR that improves over time, particularly for new-onset cases. The presence of persistent cytopenia (lasting up to 9 months after the completion of therapy) should not raise concern about CLL recurrence of the development of TRMM, but should encourage surveillance for bacterial infections for an additional 9 months.

Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL.

Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) is dictated by patient characteristics, prior therapy, and response to prior therapy. We report the final analysis of combined fludarabine, cyclophosphamide, and rituximab (FCR) for previously treated patients with CLL and identify patients who benefit most from this therapy. We explore efficacy of FCR in patients beyond first relapse, patients with prior exposure to fludarabine and alkylating agent combinations, and patients with prior exposure to rituximab. The FCR regimen was administered to 284 previously treated patients with CLL. Patients were assessed for response and progression by 1996 National Cancer Institute-Working Group (NCI-WG) criteria for CLL and followed for survival. The overall response rate was 74%, with 30% complete remission. The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months. Subgroup analyses indicated that the following patients were most suitable for FCR treatment: patients with up to 3 prior treatments, fludarabine-sensitive patients irrespective of prior rituximab exposure, and patients without chromosome 17 abnormalities. FCR is an active and well-tolerated therapy for patients with relapsed CLL. The addition of rituximab to FC improved quality and durability of response in this patient population.

Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia.

Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes.

Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia.

Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum ß-2 microglobulin (ß2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median ß2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation.

CCL3 (MIP-1α) plasma levels and the risk for disease progression in chronic lymphocytic leukemia.

B-cell receptor (BCR) signaling has been inferred as an important mechanism for disease progression in chronic lymphocytic leukemia (CLL) and other B-cell malignancies. In response to BCR activation, CLL cells secrete the chemokine CCL3, which fosters interactions between CLL cells and the leukemia microenvironment. CCL3 secretion correlates with expression of the 70-kDa ζ-associated protein (ZAP-70) and responsiveness of the CLL clone to BCR stimulation. Here, we measured CCL3 plasma levels by enzyme-linked immunosorbent assay (ELISA) in 351 CLL patients and examined CCL3 levels for associations with established prognostic markers and time from diagnosis to initial therapy. We found that CCL3 plasma concentrations were strongly associated with established prognostic markers. In a Cox proportional hazards regression model, CCL3 as well as established prognostic markers (immunoglobulin heavy chain variable-region mutation status, CD38 or ZAP-70 cytogenetics, clinical stage) were significantly associated with time to treatment. Multivariable analysis revealed that CCL3 (hazard ratio [HR] = 2.33, P < .0001), advanced clinical stage (HR = 2.75, P = .0025), poor risk cytogenetics (del 17p, HR = 2.38; del11q, HR = 2.36, P = .001), and CD38 expression (HR = 1.43, P = .023) were independent prognostic markers. Collectively, CCL3 is a novel, robust, and independent prognostic marker in CLL that can easily and reliably be measured by ELISA. CCL3 therefore should become useful for risk assessment in patients with CLL.

Association of health-related quality of life with gender in patients with B-cell chronic lymphocytic leukemia.

PURPOSE: This analysis examined associations between gender and health-related quality of life (HRQOL) in patients with B-cell chronic lymphocytic leukemia (CLL) as they initiate therapy for CLL outside the clinical trial setting. METHODS: Baseline data were collected as part of Connect® CLL Registry, a prospective observational study initiated in community, academic, and government centers. Patient demographics and clinical characteristics were provided by clinicians. Patients reported HRQOL using the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Mean scores were analyzed, with statistical significance of differences determined by ANOVA. Multivariate analysis also considered age and line of therapy. RESULTS: Baseline HRQOL data were available for 1,140 patients: 710 (62 %) men and 430 (38 %) women from 161 centers. Patients were predominantly white (89 %) with mean age 69 ± 11 years. Women reported significantly worse global fatigue (P <0.0001), fatigue severity (P <0.0001), and fatigue-related interference (P = 0.0005) versus men (BFI). Pain/discomfort (P = 0.0077), usual activities (P = 0.0015), and anxiety/depression (P = 0.0117) were significantly worse in women than in men (EQ-5D). With women reporting a better social/family score (P = 0.0238) and men reporting a better physical score (P = 0.0002), the mean FACT-G total score did not differ by gender. However, the mean FACT-Leu total score was better among men versus women (P = 0.0223), primarily because the mean leukemia subscale score was significantly better among men (P <0.0001). Multivariate analysis qualitatively confirmed these findings. CONCLUSIONS: Connect® CLL Registry results indicate that significant differences exist in certain HRQOL domains, as women reported greater levels of fatigue and worse functioning in physical domains.

Refusal of transplant organs for non-medical reasons including COVID-19 status.

Transplant centers and physicians in the United States have limited guidance on the information which they can and cannot provide to transplant candidates regarding donors of potential organs. Patients may refuse organs for a variety of reasons ranging from pernicious requests including racism to misinformation about emerging medicine as with the COVID-19 vaccine and infection. Patient autonomy, organ stewardship, and equity are often at odds in these cases, but precedent indeed exists to help address these challenges. This work uses such cases to highlight the urgent need for uniform, national policy prohibiting informational requests unrelated to well-established risks.

The prognostic difference of monoallelic versus biallelic deletion of 13q in chronic lymphocytic leukemia.

BACKGROUND: Fluorescence in situ hybridization can detect genomic abnormalities in up to 80% of cases and provides prognostic information on patients with chronic lymphocytic leukemia (CLL). Although 13q deletion as the sole abnormality has been found to confer a favorable prognosis, there are little data as to whether there is a difference in prognostic value between monoallelic versus biallelic deletion of 13q. METHODS: The authors reviewed the electronic database for patients with CLL who carried the 13q deletion as the sole abnormality and presented to The University of Texas MD Anderson Cancer Center (MDACC). Untreated patients were separated into 2 groups: those having monoallelic versus those with biallelic deletion of 13q. Using Mann-Whitney, chi-square, and Kaplan-Meier analysis, the baseline quantitative and qualitative variables for each group, along with the time from presentation to MDACC to treatment, were compared. RESULTS: A total of 176 patients were identified; 143 patients had a monoallelic deletion of 13q, whereas 33 patients had a biallelic deletion. The only significantly different values between the groups were albumin (4.5 g/dL vs 4.4 g/dL; P = .01) and zeta-chain-associated protein kinase 70 (ZAP70) expression (1.7% vs 4.8%; P = .010). The median time from fluorescence in situ hybridization analysis to treatment in both the monoallelic and biallelic groups had not been reached (P = not significant). CONCLUSIONS: Except for inconsequential differences in albumin and ZAP70 expression, there was no difference in the baseline characteristics between patients with CLL who had monoallelic or biallelic deletion of 13q. In addition, there was no significant difference in endpoints, including time to treatment.

microRNA fingerprinting of CLL patients with chromosome 17p deletion identify a miR-21 score that stratifies early survival.

Aberrant expression of microRNAs (miRNAs) has been associated with clinical outcome in patients with chronic lymphocytic leukemia (CLL). To identify a powerful and easily assessable miRNA bio-marker of prognosis and survival, we performed quantitative reverse-transcription polymerase chain reaction (qRT-PCR) profiling in 104 CLL patients with a well-defined chromosome 17p status, and we validated our findings with miRNA microarray data from an independent cohort of 80 patients. We found that miR-15a, miR-21, miR-34a, miR-155, and miR-181b were differentially expressed between CLLs with chromosome 17p deletion and CLLs with normal 17p and normal karyotype, and that miR-181b was down-regulated in therapy-refractory cases. miR-21 expression levels were significantly higher in patients with poor prognosis and predicted overall survival (OS), and miR-181b expression levels significantly predicted treatment-free survival. We developed a 21FK score (miR-21 qRT-PCR, fluorescence in situ hybridization, Karyotype) to stratify patients according to OS and found that patients with a low score had a significantly longer OS time. When we evaluated the relative power of the 21FK score with the most used prognostic factors, the score was the most significant in both CLL cohorts. We conclude that the 21FK score represents a useful tool for distinguishing between good-prognosis and poor-prognosis CLL patients.

Effect of high-dose intravenous immunoglobulin on anti-HLA antibodies in sensitized kidney transplant candidates.

Limited data exist on the effect of intravenous immunoglobulin (IVIg) on anti-HLA antibodies as determined by solid-phase assays. We reviewed our experience treating sensitized wait-listed kidney transplant recipients with IVIg as a method for desensitization and report our results utilizing Luminex single antigen (LSA) bead assay to quantify antibody reactivity (MFI). Fifteen patients with a cPRA > 40% received 2 g/kg IVIg per month for four months or until transplanted. LSA testing was performed before and after IVIg. Median MFI for anti-class I antibodies fell in 11 (73%) and increased in 4 (27%) patients after IVIg. Similar significant changes in MFI for anti-class II antibodies were observed in 10 patients (66%). Administration of IVIg was associated with a modest decrease in reactivity to both class I and II HLA antigens (median MFI change 493 and 1110, respectively; p < 0.0001) but did not significantly alter mean cPRA (85% before IVIg vs. 80% after IVIg; p = 0.1). Our data suggest a smaller effect of IVIg on HLA antibody reactivity than previously described, leading us to question how best to measure the efficacy of a desensitization protocol in current practice.

Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation.

While studies in animal models have linked Toll-like receptor (TLR) 4 signaling to kidney injury induced by ischemia and reperfusion, the relevance of TLR4 activation to allograft injury in human kidney transplants is unknown. Here we show that TLR4 is constitutively expressed within all donor kidneys but is significantly higher in deceased-, compared with living-donor organs. Tubules from deceased- but not living-donor kidneys also stained positively for high-mobility group box-1 (HMGB1), a known endogenous TLR4 ligand. In vitro stimulation of human tubular cells with HMGB1, in a TLR4-dependent system, confirmed that HMGB1 can stimulate proinflammatory responses through TLR4. To assess the functional significance of TLR4 in human kidney transplantation, we determined whether TLR4 mutations that confer diminished affinity for HMGB1 influence intragraft gene-expression profiles and immediate graft function. Compared with kidneys expressing WT alleles, kidneys with a TLR4 loss-of-function allele contained less TNFalpha, MCP-1, and more heme oxygenase 1 (HO-1), and exhibited a higher rate of immediate graft function. These results represent previously undetected evidence that donor TLR4 contributes to graft inflammation and sterile injury following cold preservation and transplantation in humans. Targeting TLR4 signaling may have value in preventing or treating postischemic acute kidney injury after transplantation.