Higher Donor Age and Severe Microvascular Inflammation Are Risk Factors for Chronic Rejection After Treatment of Active Antibody-Mediated Rejection.

Recent developments in intensive desensitization protocols have enabled kidney transplantation in human leukocyte antigen (HLA)-sensitized recipients. However, cases of active antibody-mediated rejection (AABMR), when they occur, are difficult to manage, graft failure being the worst-case scenario. We aimed to assess the impact of our desensitization and AABMR treatment regimen and identify risk factors for disease progression. Among 849 patients who underwent living-donor kidney transplantation between 2014 and 2021 at our institution, 59 were diagnosed with AABMR within 1 year after transplantation. All patients received combination therapy consisting of steroid pulse therapy, intravenous immunoglobulin, rituximab, and plasmapheresis. Multivariable analysis revealed unrelated donors and preformed donor-specific antibodies as independent risk factors for AABMR. Five-year death-censored graft survival rate was not significantly different between patients with and without AABMR although 27 of 59 patients with AABMR developed chronic AABMR (CABMR) during the study period. Multivariate Cox proportional hazard regression analysis revealed that a donor age greater than 59 years and microvascular inflammation (MVI) score (g + ptc) ≥4 at AABMR diagnosis were independent risk factors for CABMR. Our combination therapy ameliorated AABMR; however, further treatment options should be considered to prevent CABMR, especially in patients with old donors and severe MVI.

Letermovir safety and efficacy for cytomegalovirus prophylaxis in adult Japanese kidney transplant recipients: a multicenter, open-label, noncomparative Phase 3 study.

BACKGROUND: Letermovir is approved for cytomegalovirus (CMV) prophylaxis in adult allogeneic hematopoietic cell transplantation recipients worldwide and is also approved in the United States for CMV prophylaxis in adult high-risk (D+/R-) kidney transplant recipients (KTRs). The safety and efficacy of letermovir for CMV prophylaxis in adult Japanese KTRs are reported here. METHODS: In this Phase 3, single-arm, open-label study, adult Japanese KTRs with CMV serostatuses D+/R-, D+/R+, and D-/R+ received letermovir 480 mg daily orally within 7 days post-transplant through Week 28. Participants were followed through Week 52. The primary objective was to evaluate letermovir safety and tolerability. Efficacy was a secondary objective, measured by CMV disease, CMV disease or infection requiring intervention, and quantifiable CMV DNAemia. All CMV disease cases were confirmed by an independent adjudication committee. RESULTS: Among 22 participants (12 were D+/R-) who received letermovir prophylaxis, 20 (90.9%) experienced ≥ 1 AE through Week 28. Most AEs were mild to moderate in severity; no deaths were reported. During the prophylaxis period through Week 28, one transient case of quantifiable CMV DNAemia was detected, but no CMV disease or infection requiring intervention was reported. Through Week 52, four D+/R- participants met the endpoint of CMV disease or infection requiring intervention, of whom two had committee-confirmed CMV syndrome; all recovered with CMV therapy. A total of 5 participants had quantifiable CMV DNAemia through Week 52. CONCLUSION: Letermovir was generally well tolerated, and the data support its use for the prevention of CMV disease/infection in adult Japanese KTRs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04129398.

Renal outcome of living kidney donors aged more than 70 years.

BACKGROUND: The number of marginal living kidney donors has increased. Medically complex donors who have hypertension, older age, or low estimated glomerular filtration rate (eGFR) have been more likely to be used. METHODS: We conducted a retrospective cohort study of living kidney donors at a single center. We analyzed 309 living donors and divided them into three groups: group with older donors (aged ≥70 years) (n = 41), middle-aged (aged 46-69 years) (n = 239), and young donors (aged <46 years) (N = 29). Donor factors associated with chronic kidney disease (CKD) stage 3b or worse within 5 years post-donation were investigated. RESULTS: Of the 309 live donors, 86 (27.8%) developed CKD stage3b or worse within 5 years post-donation. The incidence of CKD stage3b or worse within 5 years post-donation was significantly higher in older donor (p < 0.01). Cox regression models revealed that older donor ages and lower eGFR were significantly related to the development of CKD stage3b or worse, independent of comorbidities such as obesity and hypertension [hazard ratio (95% CI); 4.59 (1.02-20.6), p = 047, 0.95 (0.94-0.96), p ≤ 0.01, respectively]. However, recovery of eGFR 4-5 years after donation was noted in the middle-aged and older donor groups, whereas the level of eGFR remained unchanged in the young group. CONCLUSIONS: Older donors tend to develop CKD stage3b within 5 years post-donation but with the potential of recovery. Healthy older people (aged ≥70 years) could be candidates for living donors under careful monitoring of kidney function after donation.

Surgical and functional outcomes of repeat robot-assisted laparoscopic partial nephrectomy compared with repeat open partial nephrectomy.

OBJECTIVES: To examine the surgical and functional outcomes of patients who have undergone repeat open partial nephrectomy (reOPN) or robot-assisted laparoscopic partial nephrectomy (reRAPN). METHODS: Until May 2022, 3310 patients with renal tumors underwent nephron-sparing surgery (NSS) at affiliated institutions. Of these, 22 and 17 patients who underwent reOPN and reRAPN, respectively, were included in this study. RESULTS: No significant differences were found between the groups in terms of sex, age, comorbidities, recurrent tumor size at repeat NSS, interval from recurrence to initial NSS, and nephrometry score. ReRAPN had a shorter operative time (median: 138.0 vs. 214.0 min; p = 0.0023) and less estimated blood loss (median: 50.0 vs. 255.0 mL; p = 0.0261) than reOPN. The incidence of complications with Clavien-Dindo grade ≥ 2 was higher in the reOPN group than in the reRAPN group (31.8 vs. 5.9%; p = 0.0467). The mean decrease in the estimated glomerular filtration rate at 3 months postoperatively was not significantly different between the groups. The trifecta achievement rates in the reRAPN (64.7%) and reOPN (27.3%) groups were significantly different (p = 0.0194). On multivariate analysis, age and surgical method were significant predictors of trifecta achievement after partial nephrectomy. CONCLUSIONS: There were no differences in postoperative renal functional outcomes between reOPN and reRAPN. ReRAPN is superior to reOPN in terms of surgical burden. Therefore, ReRAPN is an important minimally invasive surgery for recurrent renal cell carcinoma.

The medical cost and outcome of desensitization protocol in kidney transplantation recipients with high immunological risks.

BACKGROUND: Kidney transplantation is a well-established alternative in renal replacement therapy. Compared with hemodialysis, low-immunological-risk kidney transplantation can reduce the medical treatment costs associated with end-stage renal disease. However, there are few reports on whether high-immunological-risk kidney transplantation reduces the financial burden on governments. We investigated the medical costs of high-immunological-risk kidney transplantation in comparison with the cost of hemodialysis in Japan. METHODS: We compared the medical costs of high-immunological-risk kidney transplantation with those of hemodialysis. 15 patients who underwent crossmatch-positive and/or donor-specific antibody-positive kidney transplantations between 2020 and 2021 were enrolled in this study. The patients received intravenous immunoglobulin, plasmapheresis, and rituximab as desensitizing therapy. RESULTS: Acute antibody-mediated rejection was detected in nine (60%) recipients, while there were no indications of graft function deterioration during the follow-up. For each patient, the transplant hospitalization cost was 38 428 ± 8789 USD. However, the cumulative costs were 59 758 ± 10 006 USD and 79 781 ± 16 366 USD, at 12 and 24 months, respectively. Compared with hemodialysis (34 286 USD per year), high-immunological-risk kidney transplantation tends to be expensive in the first year, but the cost is likely to be lower than that of hemodialysis after 3 years. CONCLUSIONS: Although kidney transplantation is initially expensive compared with hemodialysis, the medical cost becomes advantageous after 3 years even in kidney transplant recipients with high immunological risk.

Targeted expression of bgl23-D, a dominant-negative allele of ATCSLD5, affects cytokinesis of guard mother cells and exine formation of pollen in Arabidopsis thaliana.

MAIN CONCLUSION: Targeted expression of bgl23-D, a dominant-negative allele of ATCSLD5, is a useful genetic approach for functional analysis of ATCSLDs in specific cells and tissues in plants. Stomata are key cellular structures for gas and water exchange in plants and their development is influenced by several genes. We found the A. thaliana bagel23-D (bgl23-D) mutant showing abnormal bagel-shaped single guard cells. The bgl23-D was a novel dominant mutation in the A. thaliana cellulose synthase-like D5 (ATCSLD5) gene that was reported to function in the division of guard mother cells. The dominant character of bgl23-D was used to inhibit ATCSLD5 function in specific cells and tissues. Transgenic A. thaliana expressing bgl23-D cDNA with the promoter of stomata lineage genes, SDD1, MUTE, and FAMA, showed bagel-shaped stomata as observed in the bgl23-D mutant. Especially, the FAMA promoter exhibited a higher frequency of bagel-shaped stomata with severe cytokinesis defects. Expression of bgl23-D cDNA in the tapetum with SP11 promoter or in the anther with ATSP146 promoter induced defects in exine pattern and pollen shape, novel phenotypes that were not shown in the bgl23-D mutant. These results indicated that bgl23-D inhibited unknown ATCSLD(s) that exert the function of exine formation in the tapetum. Furthermore, transgenic A. thaliana expressing bgl23-D cDNA with SDD1, MUTE, and FAMA promoters showed enhanced rosette diameter and increased leaf growth. Taken together, these findings suggest that the bgl23-D mutation could be a helpful genetic tool for functional analysis of ATCSLDs and manipulating plant growth.

Comparison of BNT162b2 and mRNA1273 vaccines in solid organ transplant recipients: Post-Hoc analysis of a Japanese national prospective study.

The coronavirus disease-19 (COVID-19) vaccine efficacy and immunogenicity in the immunocompetent population are well established. However, in solid organ transplant (SOT) recipients, because of their use of immunosuppressive medication, the immunogenicity of these severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines remains suboptimal. Both BNT162b2 and mRNA1273 have been used for some time, but their immunogenicity has not been directly compared in this immunocompromised patient group. We performed a post-hoc analysis of a previous prospective cohort study. The inclusion criteria were adult SOT recipients with active grafts at least 1 month after SOT. After giving consent, participants chose to receive either BNT162b2 or mRNA1273 vaccine. Anti-spike-protein-S antibody against SARS-CoV-2 was measured. Propensity scores were calculated via logistic regression to transform the probability of having received either BNT162b2 or mRNA1273 vaccine, and a model was developed. We enrolled 623 SOT recipients. In the propensity score-matched analysis, 100 recipients were selected for BNT162b2 and 100 for mRNA1273. SARS-CoV-2 anti-spike protein antibody positivity with BNT162b2 versus mRNA1273 at 3 weeks after the first dose, 1 month after the second dose, 3 months after the second dose, and 6 months after the second dose were 10% versus 19% (P = .07), 51% versus 58% (P = .30), 74% versus 88% (P = .01), and 78% versus 87% (P = .13), respectively. We conducted a propensity score-matched comparison of BNT162b2 and mRNA1273 vaccines as the primary series of COVID-19 vaccines in SOT recipients. We found significantly better immunogenicity with the mRNA1273 vaccine than with BNT162b2.

Pregnancy Complications and Impact on Kidney Allograft After Kidney Transplantation in IgA Nephropathy.

Pregnancy in kidney transplantation (KT) recipients has been challenging because of the high risk of maternal, fetal, and renal complications. Although patients with immunoglobulin A nephropathy (IgAN)-chronic kidney disease (CKD) are at a high risk for hypertension in pregnancy (HIP), the maternal risk in KT recipients with IgAN as the etiology remains unclear. We retrospectively reviewed the medical records of pregnant KT recipients who delivered at our hospital. The incidence of maternal and fetal complications and the impact on kidney allografts between the group with IgAN as the primary kidney disease and the group with other primary diseases were compared. The analysis included 73 pregnancies in 64 KT recipients. The IgAN group had a higher incidence of HIP than the non-IgAN group (69% vs. 40%, p = 0.02). IgAN as primary kidney disease and interval from transplantation to conception were associated with HIP (OR 3.33 [1.11-9.92], p = 0.03, OR 0.83 [0.72-0.96], p < 0.01, respectively). The 20-year graft survival or prevention of CKD stage 5 in group with IgAN was lower than that in the group with other primary disease (p < 0.01). KT recipients should be informed of the risk of HIP and possibility of long-term worsening of postpartum renal function.

Association between lung immune prognostic index and survival of patients with metastatic urothelial carcinoma treated with pembrolizumab.

INTRODUCTION AND OBJECTIVE: Lung immune prognostic index score (LIPI), calculated using the derived neutrophil-lymphocyte ratio and lactate dehydrogenase level, is reported for use in numerous malignancies, while its role on metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains limited. We aimed to investigate association between LIPI and outcomes in this setting. METHODS: We retrospectively evaluated 90 patients with mUC treated with pembrolizumab at four institutions. The associations between three LIPI groups and progression-free survival (PFS), overall survival (OS), objective response rates (ORRs) or disease control rates (DCRs) were assessed. RESULTS: Based on the LIPI, good, intermediate, and poor groups were observed in 41 (45.6%), 33 (36.7%), and 16 (17.8%) patients, respectively. The PFS and OS were significantly correlated with the LIPI (median PFS: 21.2 vs. 7.0 vs. 4.0 months, p = 0.001; OS: 44.3 vs. 15.0 vs. 4.2 months, p < 0.001 in the LIPI good vs. intermediate vs. poor groups). Multivariable analysis further revealed that LIPI good (vs. intermediate or poor, hazard ratio: 0.44, p = 0.004) and performance status = 0 (p = 0.015) were independent predictors of a longer PFS. In addition, LIPI good (hazard ratio: 0.29, p < 0.001) were shown to be associated with a longer OS together with performance status = 0 (p < 0.001). The ORRs tended to be different among patients with Good LIPI compared with Poor, and DCRs were significantly different among the three groups. CONCLUSIONS: LIPI, a simple and convenient score, could be a significant prognostic biomarker of OS, PFS, and DCRs for mUC treated with pembrolizumab.

Virtual crossmatching and epitope analysis in kidney transplantation: What the physician involved in kidney transplantation should know?

Solid-phase single antigen bead (SAB) assay for detection of anti-human leukocyte antigen (HLA) antibodies and high-resolution HLA typing have enabled tremendous progress in virtual crossmatch (VXM) technology in recent years. However, misinterpretation of the SAB assay may result in detrimental consequences after kidney transplantation. Meanwhile, epitope analysis could be an effective method to estimate immunizing eplets, which may provide ancillary information for better understanding of the SAB assay. To perform epitope analysis appropriately, it is necessary to understand the basic principles related to histocompatibility testing and the characteristics of the SAB assay. Therefore, knowledge of the properties and limitations of the SAB assay is critical. In this review, we aim to describe the fundamental concepts regarding immunobiological assessment, including HLA, anti-HLA antibodies, and SAB assay, and explain epitope analysis using examples.

Long-term prolonged-release tacrolimus outcomes in living donor kidney transplantation: The Japan Academic Consortium of Kidney Transplantation study-II.

OBJECTIVES: To evaluate the 10-year efficacy and safety of a prolonged-release tacrolimus-based combination immunosuppressive regimen on longer-term outcomes in living donor kidney transplantation. METHODS: Data from Japanese living donor kidney transplant recipients (n = 410) maintained on continuous prolonged-release tacrolimus-based immunosuppression from 2009-2013 were analyzed with a median follow-up of 9.9 years. RESULTS: A prolonged-release, tacrolimus-based combination regimen provided death-censored graft failure and all-cause death rates at 10 years of 7.0% and 6.8%, respectively. In multivariable analyses, acute and chronic rejection and 'throughout' (new-onset plus preexisting) diabetes mellitus were risk factors for death-censored graft failure. Recipient age ≥ 65 years, throughout diabetes mellitus and malignancy were common risk factors for all-cause death. Throughout diabetes mellitus was the most common risk factor for both death-censored graft failure and all-cause death. Additional analyses showed 10-year cumulative rates of death-censored graft failure were 14.0% and 5.4% for recipients with or without preexisting diabetes mellitus, respectively (log-rank test: p = 0.009). All-cause death rates were 12.7% and 5.4% in the preexisting and non-diabetes mellitus groups, respectively (log-rank test: p = 0.023). CONCLUSIONS: In this real-world, retrospective, living donor kidney transplantation study, a prolonged-release tacrolimus-based immunosuppressive combination regimen provided 10-year death-censored graft failure rates of 14.0% and 5.4% in diabetes mellitus and non-diabetes mellitus patients, respectively; Similarly, 10-year all-cause death rates were 12.7% and 5.4% in diabetes mellitus and non-diabetes mellitus patients, respectively. To our knowledge, the data in this study are the first to provide 10-year transplant outcomes in living donor kidney transplant recipients under prolonged-release tacrolimus-based regimen.

Outcomes of nivolumab monotherapy for previously treated metastatic renal cell carcinoma: a real-world multi-institution data with a minimum of 2 years of follow-up.

OBJECTIVES: To investigate the long-term follow-up outcomes of nivolumab monotherapy for previously treated metastatic renal cell carcinoma, using real-world data. METHODS: A total of 121 patients were treated with nivolumab monotherapy as subsequent therapy after the failure of prior tyrosine kinase inhibitor therapy between January 2013 and December 2021 at four affiliated institutions. To evaluate the outcome after 2 years or more, we selected patients in whom nivolumab therapy was started in December 2019 or earlier because data collection was performed until the end of December 2021. RESULTS: Seventy-four patients were evaluated. During the median follow-up period of 25.8 months, 62 (84%) and 40 (54%) patients had disease progression and died, respectively. Nivolumab was administered as second-line therapy in 43 patients (58%). The median progression-free survival and overall survival were 5.52 and 31.1 months, respectively, and objective response rate was 36%. There was no difference in progression-free survival or overall survival based on the treatment line of nivolumab (P = 0.915, P = 0.559). The magnitude of tumor response and development of immune-related adverse events were significantly associated with progression-free survival (P < 0.0001, P < 0.0001, respectively) and overall survival (P < 0.0001, P = 0.0002, respectively). Treatment-related adverse events developed in 38 patients (51%), including 33 (45%) who had immune-related adverse events. Steroid administration was needed in nine patients (12%). CONCLUSIONS: The present real-world multi-institution study with long-term follow-up data demonstrates that nivolumab monotherapy is effective for previously treated metastatic renal cell carcinoma, prolonging survival, improving tumor response and has a manageable safety profile.

Surgical and functional outcomes of robot-assisted laparoscopic partial nephrectomy for renal cell carcinoma in adolescents and young adults: a propensity score matching study.

BACKGROUND: Cancer development in adolescents and young adults (AYAs) has elicited recent interest. We investigated the surgical and functional outcomes of robot-assisted laparoscopic partial nephrectomy (RAPN) for renal cell carcinoma (RCC) in AYAs. METHODS: We retrospectively reviewed the medical records of 1023 patients with clinical stage I RCC who underwent RAPN before January 2021. Patients were divided into two groups: AYAs (aged 18-39 years) and non-AYAs (aged 40-89 years). The trifecta criteria, defined as a negative surgical margin, no perioperative complications (Clavien-Dindo grade > 2), and preserved postoperative renal function (1-year postoperative estimated glomerular filtration rate > 90% of baseline), were used to compare outcomes. We performed 1:1 propensity-score matching on the patient cohort. RESULTS: There were initially 125 and 898 patients in the AYAs and non-AYAs groups, respectively, and 108 patients were included in each group after propensity score matching. There were no significant differences in surgical factors (operation time, clamping ischemia time, estimated blood loss, length of hospital stay, surgical complication rate) or renal function in the early postoperative period. The mean postoperative renal function was better (p = 0.0200) and the decrease in estimated glomerular filtration rate was lower (p = 0.0026) in AYAs than in non-AYAs 12 months postoperatively. The trifecta achievement rates in the AYAs and non-AYAs groups were significantly different (67.6% and 53.7%, respectively, p = 0.0220). CONCLUSION: Although there was no difference in surgical burden between the groups, the estimated glomerular filtration rate was better preserved in AYAs than in non-AYAs at 6 and 12 months post-RAPN.

Prognostic Impact of Trial-Eligibility Criteria in Patients with Metastatic Renal Cell Carcinoma.

OBJECTIVE: The aim of the study was to evaluate the prognostic impact of trial-eligibility criteria on outcome in real-world metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS: mRCC patients treated with TKIs as first-line systemic therapy were retrospectively evaluated. The patients were determined as trial-ineligible when they met at least 1 following trial-ineligible criteria; Karnofsky performance status score <70, hemoglobin <9.0 g/dL, creatinine >2.4 mg/dL (male) or >2.0 mg/dL (female), calcium >12.0 mg/dL, platelet <100,000 /µL, neutrophil <1,500 /µL, nonclear-cell histology, and brain metastasis. RESULTS: Of 238 patients, 101 patients (42%) were determined as trial-ineligible. Progression-free survival (PFS) and overall survival (OS) after the TKI initiation were significantly shorter in the trial-ineligible patients than in the trial-eligible patients (median PFS: 5.53 vs. 15.8 months, p < 0.0001; OS: 13.8 vs. 43.4 months, p < 0.0001). Objective response rate was also significantly lower in the trial-ineligible patients (15% vs. 37%, p = 0.0003). Multivariate analysis further showed that the trial-eligibility was an independent factor for PFS (hazard ratio [HR]: 2.46, p < 0.0001) and OS (HR: 2.39, p < 0.0001). In addition, the number of trial-ineligible factors were negatively correlated with PFS and OS. CONCLUSIONS: In real-word, the substantial number of mRCC patients did not meet the trial-eligibility criteria, and their outcome was worse than that in the trial-eligible patients. Further studies focusing on the outcome in real-world trial-ineligible patients in the immune checkpoint inhibitor era are warranted.

Robot-assisted laparoscopic versus open partial nephrectomy for renal cell carcinoma in patients with severe chronic kidney disease.

OBJECTIVES: To compare surgical and functional outcomes between robot-assisted laparoscopic partial nephrectomy and open partial nephrectomy in patients with renal cell carcinoma with stage 4 chronic kidney disease. METHODS: This was a retrospective analysis of 60 patients with stage 4 chronic kidney disease (estimated glomerular filtration rate 15-30 ml/min/1.73 m2 ) who underwent partial nephrectomy for T1 renal cell carcinoma between April 2004 and April 2020. We compared perioperative outcomes according to the surgical approach. Multivariable analysis was performed to identify predictive factors for end-stage renal disease. RESULTS: Robot-assisted laparoscopic partial nephrectomy and open partial nephrectomy were performed in 31 and 29 patients, respectively. The median age was 68 years and 17% of all patients were women. Patient and tumor characteristics did not differ between groups. The operative time (155.2 vs. 221.0 min, p < 0.0001) and the postoperative length of hospital stay (5.2 vs. 10.6 days, p = 0.0083) were significantly shorter, and the estimated blood loss was lower (53.4 vs. 363.2 ml, p = 0.0003) in the robot-assisted laparoscopic partial nephrectomy group than in the open partial nephrectomy group. Preoperative estimated glomerular filtration rate was the only significant predictor of end-stage renal disease after partial nephrectomy on multivariable analysis. CONCLUSIONS: Both procedures preserved renal function in this patient cohort, delaying the requirement for postoperative dialysis. Furthermore, robot-assisted laparoscopic partial nephrectomy was associated with shorter operative time and postoperative length of hospital stay, as well as lesser estimated blood loss than open partial nephrectomy.

Influence of a low-dose tacrolimus protocol on the appearance of de novo donor-specific antibodies during 7 years of follow-up after renal transplantation.

BACKGROUND: Tacrolimus (TAC) is a key immunosuppressant drug for kidney transplantation (KTx). However, the optimal serum trough level of TAC for good long-term outcomes remains unclear. This study aimed to investigate the relationship between the maintenance TAC trough level and the appearance of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSAs). METHODS: A total of 584 KTx recipients were enrolled in this study, of whom 164 developed dnDSAs during the follow-up period and 420 did not. RESULTS: We found no significant relationship between TAC trough level during the follow-up period and dnDSA incidence. Patients who developed dnDSAs had a significantly greater number of HLA-A/B/DR mismatches (3.4 ± 1.3 versus 2.8 ± 1.5; P < 0.001), were more likely to have preformed DSAs (48.2% versus 27.1%; P < 0.001) and showed poor allograft outcome. CONCLUSIONS: There was no clear relationship between TAC trough level and dnDSA incidence for KTx recipients whose TAC trough levels were kept within the narrow range of 4-6 ng/mL during the immunosuppression maintenance period.

Assessing improvements in metastatic renal cell carcinoma systemic treatments from the pre-cytokine to the immune checkpoint inhibitor eras: a retrospective analysis of real-world data.

OBJECTIVE: Studies assessing outcome improvements over a long period according to systemic therapy strategies for metastatic renal cell carcinoma using real-world data, including the results of the recent era of immune checkpoint inhibitors, are limited. Herein, we retrospectively evaluated patients who were diagnosed with metastatic renal cell carcinoma over a 40-year span. METHODS: Patients were classified into four groups based on when their metastases were diagnosed as follows: (i) the pre-cytokine era (1980-1986), (ii) the cytokine era (1987-2007), (iii) the molecular-targeted therapy (mTT) era (2008 to August 2016) and (iv) the immune checkpoint inhibitor era (September 2016 to 2018). The immune checkpoint inhibitor era consisted of second- or later-line nivolumab. Overall survival from the diagnoses of metastases was evaluated. RESULTS: In total, 576 patients were evaluated, including 22 (3.82%), 231 (40.1%), 253 (43.9%) and 70 (12.2%) patients from the pre-cytokine, cytokine, molecular-targeted therapy and immune checkpoint inhibitor eras, respectively. The overall survival significantly improved with each successive era (median: 13.1 vs. 24.5 vs. 44.4 months vs. not reached in pre-cytokine vs. cytokine vs. molecular-targeted therapy vs. immune checkpoint inhibitor eras, P < 0.0001). The implementation of molecular-targeted therapy improved overall survival compared with that of cytokine (cytokine vs. molecular-targeted therapy eras, P < 0.0001). Multivariate analysis demonstrated that the era was an independent factor for overall survival (P < 0.0001), together with histopathological type; metastasis status (i.e. synchronous or metachronous); systemic therapy status (i.e. absence or presence) and bone, liver or lymph node metastasis status (all, P < 0.05). CONCLUSION: This retrospective study of real-world data indicated that metastatic renal cell carcinoma outcomes improved with successive systemic therapy paradigms.

Hypopituitarism in patients with metastatic renal cell carcinoma treated with ipilimumab and nivolumab combination therapy.

OBJECTIVE: We investigated the incidence of hypopituitarism in Japanese patients with metastatic renal cell carcinoma (mRCC) who received ipilimumab and nivolumab (I-P) therapy and compared patient characteristics and survival rates between patients with hypopituitarism and those without. METHODS: Twenty-two patients with mRCC who received I-P therapy as first-line treatment were the subjects of this retrospective study. The diagnosis of hypopituitarism was based on the hormone loading test. RESULTS: Hypopituitarism occurred in 41% (9/22) patients who received I-P therapy. Median time of diagnosis was 12 weeks (IQR: 9.5-20). Clinical symptoms, such as fatigue, weakness or fever, were observed in 7 patients, while 2 patients had no clinical presentation. The following deficiency patterns were observed: isolated ACTH in 4 patients, ACTH and GH in 2 patients, ACTH and TSH in 2 patients and triple deficiency (ACTH, GH and TSH) in 1 patient. All patients with hypopituitarism were in the IMDC intermediate group, while 46% of those without hypopituitarism were in the IMDC intermediate group. Other patient characteristics were not different between the two groups. Object response rate was 33% (3/9) in patients with hypopituitarism and 23% (3/13) in those without (P = 0.5954). Progression free survival (PFS) was significantly longer in those with hypopituitarism than those without (median: 24.7 vs. 4.5 months, P = 0.0008), while overall survival did not differ (P = 0.136). CONCLUSIONS: Compared with the clinical trial, the incidence of hypopituitarism was higher than expected. Patients with hypopituitarism tended to have longer PFS, which may suggest that optimal management of hypopituitarism results in better prognosis.

Impact of sarcopenia on post-operative outcomes following nephrectomy and tumor thrombectomy for renal cell carcinoma with inferior vena cava thrombus.

OBJECTIVE: Sarcopenia is associated with oncological outcomes in various types of cancer. However, the impact of sarcopenia in renal cell carcinoma with inferior vena cava thrombus remains unclear. We herein evaluated the prognostic significance of sarcopenia for renal cell carcinoma with inferior vena cava thrombus following nephrectomy and thrombectomy. METHODS: Patients who underwent nephrectomy and thrombectomy for renal cell carcinoma with inferior vena cava thrombus at our department between 2004 and 2019 were retrospectively evaluated. Their sarcopenic status, determined by sex, body mass index and skeletal muscle index, was calculated using pre-surgical radiographic imaging. We compared the post-operative cancer-specific survival and overall survival, surgical data and duration of post-operative hospitalization of sarcopenic and non-sarcopenic patients. RESULTS: Out of 83 patients, 54 (65%) were sarcopenic. Sarcopenic patients had significantly shorter cancer-specific survival (median: 33.3 months vs. not reached, P = 0.0323) and overall survival (32.0 months vs. not reached, P = 0.0173) than non-sarcopenic patients. Furthermore, multivariate analyses showed that sarcopenia was an independent factor for cancer-specific survival (hazard ratio: 2.76, P = 0.0212) and overall survival (hazard ratio: 2.93, P = 0.014). The incidence rate of surgical complications (any grade: 35.2% vs. 27.6%, P = 0.482; grades ≥ 3: 7.4% vs. 10.3%, P = 0.648) or duration of post-operative hospitalization (median: 11 vs. 10 days, P = 0.148) was not significantly different between sarcopenic and non-sarcopenic patients. CONCLUSIONS: In conclusion, this study showed that sarcopenia was an independent prognostic factor for renal cell carcinoma with inferior vena cava thrombus after nephrectomy and tumor thrombectomy. Thus, sarcopenia evaluation can be utilized as an effective prognosticator of post-operative survival.

Prognostic impact of systemic therapy change in metastatic renal cell carcinoma treated with cytoreductive nephrectomy.

OBJECTIVE: Limited data are available regarding the effect of systemic therapy change in the post-cytokine era on survival of metastatic renal cell carcinoma (mRCC) patients undergoing cytoreductive nephrectomy (CN). METHODS: Overall, 161 patients with synchronously mRCC were retrospectively evaluated. The patients were classified into three groups based on the time of diagnosis: (i) early molecular-targeted therapy (mTT) (2008-2011), (ii) late mTT (2012-8/2016) and (iii) immune checkpoint inhibitor (ICI) eras (9/2016-2018). Overall survival (OS) after the diagnosis was compared among the eras. RESULTS: Of the 161 patients, 52 (32%), 75 (46%), and 34 patients (21%) were classified into the early mTT, late mTT and ICI eras, respectively. OS was significantly longer in the ICI and late mTT eras than that in the early mTT era (P = 0.0065 and P = 0.0010, respectively) but did not significantly differ between the ICI and late mTT eras (P = 0.389). In 112 patients undergoing CN and systemic therapy, OS was significantly longer in the ICI and late mTT eras than that in the early mTT era (P = 0.0432 and P = 0.0498, respectively) but did not significantly differ between the ICI and late mTT eras (P = 0.320). Multivariate analysis of OS in the 161 synchronous mRCC patients revealed that the era was an independent factor (P < 0.0001), together with the histopathological type (P = 0.0130), CN status (P = 0.0010), International Metastatic Renal Cell Carcinoma Database Consortium risk (P = 0.0002) and liver metastasis status (P = 0.0124). CONCLUSION: This retrospective analysis showed that systemic therapy change in the post-cytokine era improved OS of mRCC patients undergoing CN.