Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

OBJECTIVES: To explore the therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. PATIENTS AND METHODS: Forty-one patients with synchronous metastatic renal cell carcinoma who received nivolumab plus ipilimumab as first-line systemic therapy at our affiliated institutions were retrospectively evaluated. We focused on the prognosis, including tumor responses in primary kidney and metastatic lesions in patients treated with deferred cytoreductive nephrectomy. In addition, the overall survival according to nephrectomy status (i.e. deferred cytoreductive nephrectomy vs. upfront cytoreductive nephrectomy vs. without cytoreductive nephrectomy) was compared. RESULTS: During a median follow-up period of 12.0 months, seven (30%) patients received deferred cytoreductive nephrectomy at a median time of 10.4 months after nivolumab plus ipilimumab initiation. All the patients showed tumor shrinkage in their primary kidney lesions, including six (86%) patients with ≥30% of shrinkage. Metastatic lesions were also shrunk by ≥30% in six (86%) patients, including two (29%) obtaining complete response. At the last time of follow-up, three (43%) patients were disease-free. The overall survival rate after nivolumab plus ipilimumab initiation tended to be higher in patients with deferred cytoreductive nephrectomy compared with those with upfront cytoreductive nephrectomy (1-year survival rate: 100% vs. 72.4%, P = 0.0587) and those without cytoreductive nephrectomy (vs. 58.2%, P = 0.0613). CONCLUSIONS: The present retrospective data showed that deferred cytoreductive nephrectomy had the potential to exert a therapeutic effect in a subset of patients who obtained favorable tumor responses to nivolumab plus ipilimumab for a certain period. Prospective randomized clinical trials are needed to confirm the prognostic impact of deferred cytoreductive nephrectomy after frontline immunotherapy in synchronous metastatic renal cell carcinoma.

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.

Distribution of the CD4 Alleles in Sus scrofa Demonstrates the Genetic Profiles of Western Breeds and Miniature Pigs.

Widely used antipig CD4 monoclonal antibodies (mAbs) fail to recognize CD4 alleles characteristic of miniature pig lines such as the National Institutes of Health (NIH) miniature pigs and microminipigs. We surveyed polymorphisms in the coding sequence of the porcine CD4 gene among Western and Oriental pig breeds and Japanese wild boars and investigated their distribution. Of the 13 alleles that we identified among the 47 animals, 2 in group I and 3 in group II were found exclusively in Western breed pigs. Group IV alleles, which included mAb-nonbinding alleles, were found frequently in Oriental breed pigs, suggesting that the mAb-nonbinding allele arose from the gene pool of Oriental pigs. Group IV alleles were also found in Duroc and Large White pigs, suggesting genetic inflow from Oriental pig breeds into Western breeds. Comparison of the CD4 sequences of species in Cetartiodactyla suggested that the group IV alleles in Sus scrofa occurred before the divergence of this species from the other artiodactyls. The different antibody specificities of the various CD4 alleles may facilitate the discrimination of T-cell populations in transplantation studies using miniature pigs. The significance of the preservation of CD4 polymorphisms to immune function in pigs warrants further investigation.

Pig lacks functional NLRC4 and NAIP genes.

The NLRC4 inflammasome, which recognizes flagellin and components of the type III secretion system, plays an important role in the clearance of intracellular bacteria. Here, we examined the genomic sequences carrying two genes encoding key components of the NLRC4 inflammasome-NLR family, CARD-containing 4 (NLRC4), and NLR apoptosis inhibitory protein (NAIP)-in pigs. Pigs have a single locus encoding NLRC4 and NAIP. Comparison of the sequences thus obtained with the corresponding regions in humans revealed the deletion of intermediate exons in both pig genes. In addition, the genomic sequences of both pig genes lacked valid open reading frames encoding functional NLRC4 or NAIP protein. Additional pigs representing multiple breeds and wild boars also lacked the exons that we failed to find through genome sequencing. Furthermore, neither the NLRC4 nor the NAIP gene was expressed in pigs. These findings indicate that pigs lack the NLRC4 inflammasome, an important factor involved in monitoring bacterial proteins and contributing to the clearance of intracellular pathogens. These results also suggest that genetic polymorphisms affecting the molecular functions of TLR2, TLR4, TLR5, and other pattern recognition receptors associated with the recognition of bacteria have a more profound influence on disease resistance in pigs than in other species.

Identification of the Q969R gain-of-function polymorphism in the gene encoding porcine NLRP3 and its distribution in pigs of Asian and European origin.

The nucleotide-binding domain, leucine-rich-containing family, pyrin-domain containing-3 (NLRP3) inflammasome comprises the major components caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and NLRP3. NLRP3 plays important roles in maintaining immune homeostasis mediated by intestinal microorganisms and in the immunostimulatory properties of vaccine adjuvants used to induce an immune response. In the present study, we first cloned a complementary DNA (cDNA) encoding porcine ASC because its genomic sequence was not completely determined. The availability of the ASC cDNA enabled us to reconstitute porcine NLRP3 inflammasomes using an in vitro system that led to the identification of the immune functions of porcine NLRP3 and ASC based on the production of interleukin-1ß (IL-1ß). Further, we identified six synonymous and six nonsynonymous single-nucleotide polymorphisms (SNPs) in the coding sequence of NLRP3 of six breeds of pigs, including major commercial breeds. Among the nonsynonymous SNPs, the Q969R polymorphism is associated with an increased release of IL-1ß compared with other porcine NLRP3 variants, indicating that this polymorphism represents a gain-of-function mutation. This allele was detected in 100 % of the analyzed Chinese Jinhua and Japanese wild boars, suggesting that the allele is maintained in the major commercial native European breeds Landrace, Large White, and Berkshire. These findings represent an important contribution to our knowledge of the diversity of NLRP3 nucleotide sequences among various pig populations. Moreover, efforts to exploit the gain of function induced by the Q969R polymorphism promise to improve pig breeding and husbandry by conferring enhanced resistance to pathogens as well as contributing to vaccine efficacy.

Polymorphisms of the immune-modulating receptor dectin-1 in pigs: their functional influence and distribution in pig populations.

Dectin-1, a C-type lectin receptor that recognizes fungal ß-glucans, is involved in antifungal immunity and the regulation of intestinal immune homeostasis. Dectin-1 is involved in both synthesis and maturation of interleukin-1ß, a key pro-inflammatory cytokine in immunity. Here, we assessed the genetic diversity in the gene encoding dectin-1 (CLEC7A) within various pig populations and examined the influence of these polymorphisms on the two different signaling pathways after ligand recognition. An amino-acid polymorphism located in the carbohydrate-recognition domain, leucine to serine at position 138 (L138S), which occurred exclusively in Japanese wild boars at low frequency, significantly increased NF-κB induction but not caspase-8 activity after stimulation with zymosan. In contrast, other amino-acid polymorphisms present at comparatively high frequency in commercial pig populations had little influence on ligand recognition. These results suggest that functionally neutral polymorphisms in dectin-1 are widespread in pig populations.

Interstitial fibrosis is the critical determinant of impaired renal function in transplant glomerulopathy.

AIM: Transplant glomerulopathy (TG) is a feature of chronic antibody-mediated injury in the glomerular capillaries in renal transplant recipients. TG is generally associated with proteinuria; however, renal function at the diagnosis of TG varies. This study aimed to determine which morphological abnormalities are associated with renal function and proteinuria at the diagnosis of TG. METHODS: A total of 871 renal transplantations were performed at Tokyo Women's Medical University between 2005 and 2013. TG was diagnosed in 127 biopsies from 58 (6.7%) recipients. Renal function was evaluated by the estimated glomerular filtration rate (eGFR). Proteinuria was assessed by a dipstick test: positive for +1 and over. RESULTS: At diagnosis, of 127 biopsies, 72, 37, and 18 had mild, moderate, and severe TG (Banff cg). The severity of TG was not associated with decreased eGFR at the time of biopsy (cg1: 36.1 ± 14.8, cg2-3: 38.8 ± 14.5 mL/min per 1.73 m(2) , P = 0.25), whereas the severity of interstitial fibrosis (IF) (Banff ci) was significantly associated with decreased eGFR (ci0-1: 42.75 ± 13.32, ci2-3: 27.69 ± 11.94 mL/min per 1.73 m(2) , P < 0.0001). The multivariate analysis revealed that IF was the only independent risk factors for decreased eGFR (OR = 4.38, P = 0.0006). Meanwhile, TG was identified as the only independent risk factor for the incidence of proteinuria (OR = 2.67, P = 0.014). CONCLUSION: Interstitial fibrosis was a critical determinant of impaired renal function at the diagnosis of TG. The severity of TG was significantly associated with proteinuria, but did not contribute to renal dysfunction.

A case of recurrent focal segmental glomerulosclerosis after kidney transplantation associated with variant conversion in the Columbia classification.

Focal segmental glomerulosclerosis commonly recurs following kidney transplantation. A 33-year-old man underwent living donor kidney transplantation. Proteinuria appeared two months after transplantation, and an episode biopsy on postoperative day 66 revealed recurrent focal segmental glomerulosclerosis lesions of the cellular variant by Columbia classification. We reviewed the native kidney biopsy and confirmed collapsing variant focal segmental glomerulosclerosis. Plasma exchange therapy was performed, and his proteinuria temporarily resolved. A second allograft biopsy performed on postoperative day 200 showed no evidence of focal segmental glomerurosclerosis. He experienced incomplete remission with a proteinuria of 0.5 g/day during the subsequent three years until his urinary protein level rose to 1.3 g/day. A third biopsy performed on postoperative day 1248 showed focal segmental glomerulosclerosis cellular variant lesions. Plasma exchange was resumed in combination with additional rituximab, but his proteinuria persisted. Intermittent plasma exchange was performed 42 times in total. However, his proteinuria continued, and his renal function gradually worsened. A fourth biopsy performed on postoperative day 2540 showed focal segmental glomerulosclerosis collapsing variant lesions with severe interstitial fibrosis and tubular atrophy. He ultimately required hemodialysis seven years after transplantation. Intensive therapy with long-term intermittent plasma exchange and rituximab suppressed proteinuria and preserved graft function for seven years, at which time graft failure occurred. We here present the clinical course and histological findings from consecutive allograft biopsies.

Clinical and pathological analyses of transplant glomerulopathy cases.

AIM: Transplant glomerulopathy (TG) is included as one of the criteria of chronic active antibody-mediated rejection (c-AMR) in Banff 09 classification. In this report, we discuss the clinical and pathological analyses of cases of TG after renal transplantation. PATIENTS: TG was diagnosed in 86 renal allograft biopsy specimens (BS) obtained from 50 renal transplant patients followed up at our institute between January 2006 and October 2012. We retrospectively reviewed the data of these 86 BS and 50 patients. RESULTS: Among the 50 patients, 42 (84%) had a history of acute rejection (AR); of these, 30 (60%) had acute antibody-mediated rejection (a-AMR). Among the 86 BS of TG, the TG was mild in 35 cases (cg1 in Banff classification), moderate in 28 cases (cg2) and severe in 23 cases (cg3). Peritubular capillaritis was present in 74 BS (86%), transplant glomerulitis in 65 (76%), interstitial fibrosis and tubular atrophy (IF/TA) in 71 (83%), thickening of the peritubular capillary (PTC) basement membrane in 72 (84%), and interstitial inflammation in 40 (47%). C4d deposition in the PTC was present in 49 BS (57%); 39 of these 49 BS showed diffuse C4d deposits in the PTC (C4d3), while the remaining 10 BS showed focal deposits (C4d2). Diffuse C4d deposition in the glomerular capillaries (GC) was seen in 70 BS (81%), while focal C4d deposition in the GC was seen in 9 (11%). In the assay using plastic beads coated with HLA antigen performed in 67 serum samples obtained in the peri-biopsy period, circulating ant-HLA alloantibody was detected in 55 (82%); in 33 of the 55 (49%) samples, donor-specific antibodies (DSA) were detected. Among our study, the findings in 22 BS (26%) fully met the criteria for c-AMR in Banff '09 classification, including TG, C4d deposition in the PTC and presence of DSA, while those in 27 BS were suspicious of c-AMR. Deterioration of the renal allograft function after the biopsies was seen in 31 patients (62%), of which 11 lost their graft. CONCLUSIONS: We suggest that histopathological changes of transplant glomerulopathy might be accompanied by inflammation of the microvasculature, such as transplant glomerulitis and peritubular capillaritis, thickening of the peritubular capillary basement membrane, and circulating anti-HLA antibodies. C4d deposition in the PTC is not always present in biopsy specimens of TG. We speculated that C4d deposition in the GC, rather than that in the PTC might be a more characteristic manifestation of TG. Many of the patients with TG had a history of AR. Anti-HLA antibody Class II, particularly when the antibody was DSA Class II, appeared to be associated with the development of TG. The prognosis of grafts exhibiting TG was not too good even under the currently used immunosuppressive protocol.

Mesna, Doxorubicin, Ifosfamide and Dacarbazine (MAID) Combination Chemotherapy for Retroperitoneal Sarcoma: A Single-center Experience.

BACKGROUND/AIM: There is limited evidence regarding the systemic treatment of retroperitoneal soft-tissue sarcoma, and the current Japanese guidelines fail to make definitive suggestions. Here, we report our experience with combination chemotherapy of mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) in this population. PATIENTS AND METHODS: We retrospectively reviewed the records of eight patients (three male and five female) who received MAID for pathologically diagnosed metastatic unresectable retroperitoneal sarcoma (either leiomyosarcoma or pleomorphic sarcoma) between October 2019 and January 2022. Treatment efficacy, tolerability (need for dose reduction), and safety profiles were evaluated and summarized. RESULTS: At initiation, the median age was 56.0 years, and the body mass index was 20.0 kg/cm2 Six patients had Eastern Cooperative Oncology Group performance status scores of 0. The net clinical benefit was a partial response in three (37.5%) patients, stable disease in four (50.0%), and progressive disease in one (12.5%). During the median 90.8 weeks of follow-up, disease in five patients progressed, resulting in a median progression-free survival of 48.4 weeks, and five deaths occurred, resulting in an overall survival of 95.1 weeks. Commonly observed adverse events were neutropenia (eight patients), anemia (eight patients), and decreased platelet count (seven patients), which led to dose reduction (60-80%) in six patients. CONCLUSION: MAID combination therapy may be an acceptable option for advanced retroperitoneal sarcoma; however, its benefits must be carefully assessed owing to its not insignificant toxicity.

Structural and functional annotation of the porcine immunome.

BACKGROUND: The domestic pig is known as an excellent model for human immunology and the two species share many pathogens. Susceptibility to infectious disease is one of the major constraints on swine performance, yet the structure and function of genes comprising the pig immunome are not well-characterized. The completion of the pig genome provides the opportunity to annotate the pig immunome, and compare and contrast pig and human immune systems. RESULTS: The Immune Response Annotation Group (IRAG) used computational curation and manual annotation of the swine genome assembly 10.2 (Sscrofa10.2) to refine the currently available automated annotation of 1,369 immunity-related genes through sequence-based comparison to genes in other species. Within these genes, we annotated 3,472 transcripts. Annotation provided evidence for gene expansions in several immune response families, and identified artiodactyl-specific expansions in the cathelicidin and type 1 Interferon families. We found gene duplications for 18 genes, including 13 immune response genes and five non-immune response genes discovered in the annotation process. Manual annotation provided evidence for many new alternative splice variants and 8 gene duplications. Over 1,100 transcripts without porcine sequence evidence were detected using cross-species annotation. We used a functional approach to discover and accurately annotate porcine immune response genes. A co-expression clustering analysis of transcriptomic data from selected experimental infections or immune stimulations of blood, macrophages or lymph nodes identified a large cluster of genes that exhibited a correlated positive response upon infection across multiple pathogens or immune stimuli. Interestingly, this gene cluster (cluster 4) is enriched for known general human immune response genes, yet contains many un-annotated porcine genes. A phylogenetic analysis of the encoded proteins of cluster 4 genes showed that 15% exhibited an accelerated evolution as compared to 4.1% across the entire genome. CONCLUSIONS: This extensive annotation dramatically extends the genome-based knowledge of the molecular genetics and structure of a major portion of the porcine immunome. Our complementary functional approach using co-expression during immune response has provided new putative immune response annotation for over 500 porcine genes. Our phylogenetic analysis of this core immunome cluster confirms rapid evolutionary change in this set of genes, and that, as in other species, such genes are important components of the pig's adaptation to pathogen challenge over evolutionary time. These comprehensive and integrated analyses increase the value of the porcine genome sequence and provide important tools for global analyses and data-mining of the porcine immune response.

Effects of remote ischemic preconditioning on renal protection in patients undergoing robot-assisted laparoscopic partial nephrectomy.

We aimed to evaluate the renoprotective effects of remote ischemic preconditioning (RIPC) in patients undergoing robot-assisted laparoscopic partial nephrectomy (RAPN). Data from 59 patients with solitary renal tumors who underwent RAPN with RIPC comprising three cycles of 5-min inflation to 200 mmHg of a blood pressure cuff applied to one lower limb followed by 5-min reperfusion by cuff deflation, from 2018 to 2020 were analyzed. Patients who underwent RAPN for solitary renal tumors without RIPC between 2018 and 2020 were selected as controls. The postoperative estimated glomerular filtration rate (eGFR) at the nadir during hospitalization and the percentage change from baseline were compared using propensity score matching analysis. We performed a sensitivity analysis with imputations for missing postoperative renal function data weighted by the inverse probability of the data being observed. Of the 59 patients with RIPC and 482 patients without RIPC, 53 each were matched based on propensity scores. No significant differences in the postoperative eGFR in mL/min/1.73 m2 at nadir (mean difference 3.8; 95% confidence interval [CI] - 2.8 to 10.4) and its percentage change from baseline (mean difference 4.7; 95% CI - 1.6 to 11.1) were observed between the two groups. Sensitivity analysis also indicated no significant differences. No complications were associated with the RIPC. In conclusion, we found no significant evidence of the protective effect of RIPC against renal dysfunction after RAPN. Further research is required to determine whether specific patient subgroups benefit from RIPC.Trial registration number: UMIN000030305 (December 8, 2017).

Large-scale sequencing based on full-length-enriched cDNA libraries in pigs: contribution to annotation of the pig genome draft sequence.

BACKGROUND: Along with the draft sequencing of the pig genome, which has been completed by an international consortium, collection of the nucleotide sequences of genes expressed in various tissues and determination of entire cDNA sequences are necessary for investigations of gene function. The sequences of expressed genes are also useful for genome annotation, which is important for isolating the genes responsible for particular traits. RESULTS: We performed a large-scale expressed sequence tag (EST) analysis in pigs by using 32 full-length-enriched cDNA libraries derived from 28 kinds of tissues and cells, including seven tissues (brain, cerebellum, colon, hypothalamus, inguinal lymph node, ovary, and spleen) derived from pigs that were cloned from a sow subjected to genome sequencing. We obtained more than 330,000 EST reads from the 5'-ends of the cDNA clones. Comparison with human and bovine gene catalogs revealed that the ESTs corresponded to at least 15,000 genes. cDNA clones representing contigs and singlets generated by assembly of the EST reads were subjected to full-length determination of inserts. We have finished sequencing 31,079 cDNA clones corresponding to more than 12,000 genes. Mapping of the sequences of these cDNA clones on the draft sequence of the pig genome has indicated that the clones are derived from about 15,000 independent loci on the pig genome. CONCLUSIONS: ESTs and cDNA sequences derived from full-length-enriched libraries are valuable for annotation of the draft sequence of the pig genome. This information will also contribute to the exploration of promoter sequences on the genome and to molecular biology-based analyses in pigs.

Urinary Tract Infection in Hemodialysis-Dependent End-Stage Renal Disease Patients.

INTRODUCTION: The aim of this study was to analyze urinalysis findings and urinary bacterial culture in hemodialysis-dependent end-stage renal disease patients. The research goal was to understand the proportion, risk factors, and the causative organisms of urinary tract infection in hemodialysis-dependent end-stage renal disease patients. MATERIALS AND METHODS: Between May 2020 and June 2021, this study included 100 hemodialysis-dependent end-stage renal disease patients (50 male patients and 50 female patients). The urine underwent microscopic examination, pyuria was defined as ≥5 white blood cells per high-power field, and urinary bacterial cultures were conducted for patients with pyuria. Bacteriuria was defined as ≥104 colony-forming units/mL in men and ≥105 colony-forming units/mL in women. Daily urine output was investigated by oral listening. Postvoiding residual urine volume was measured. RESULTS: Fifty-six percent of male patients and 30% of female patients had normosthenuria, 24% of male patients and 38% of female patients had pyuria, and 20% of male patients and 32% of female patients had a urinary tract infection. A comparison of normosthenuria and urinary tract infection revealed no statistically significant difference in age, time on dialysis, daily urine output, and postvoiding residual urine volume. The proportion of female patients among those with normosthenuria was 34.8%, whereas the proportion of female patients among those with UTI was 61.5%. Urinary bacterial cultures showed that the major causative organisms were Escherichia coli (45%; 18/40 cultures) and extended spectrum beta-lactamase-producing Escherichia coli (17.5%; 7/40 cultures). CONCLUSION: The incidence of urinary tract infection was higher in female patients than in male patients. The proportion of resistant bacteria as the causative organisms was high in hemodialysis-dependent end-stage renal disease patients. Urinary bacterial culture should be checked while patients are able to void urine.

Assessment of Feasibility of Robot-assisted Radical Cystectomy in Patients With Advanced Bladder Cancer Treated With Maintenance Hemodialysis Therapy.

BACKGROUND/AIM: To clarify the perioperative and oncological outcomes of robot-assisted radical cystectomy (RARC) in advanced bladder cancer (BC) patients treated with maintenance hemodialysis (HD) therapy. PATIENTS AND METHODS: We retrospectively evaluated patients receiving HD therapy who had undergone RARC or open radical cystectomy (ORC) for BC between April 1988 and December 2021 at two affiliated institutions. We compared the surgical outcomes and survival after radical cystectomy between patients treated with RARC and those treated with ORC. RESULTS: Thirty-six patients were evaluated, and eight (22%) and 28 (78%) received RARC and ORC, respectively. RARC was more frequently conducted than ORC in elderly patients (median: 75.5 vs. 68.2 years, p<0.05). Regarding postoperative surgical outcomes, the estimated blood loss volume (median: 75 ml vs. 627 ml, p<0.05) was significantly lower in the RARC group than that in the ORC group. A lower blood transfusion rate (25% vs. 67%, p=0.170) was observed. Moreover, there were no differences in operative time (median: 255 vs. 294 min, p=0.232) or complication rate (Clavien-Dindo grade, any grade: 50% vs. 46%, p=0.858; grade 3 or more: 13% vs. 14%, p=0.897). The 11-year overall survival rate did not differ between the two groups (88% vs. 74%, p=0.365). CONCLUSION: The perioperative outcomes of RARC in patients undergoing HD therapy were comparable to those of ORC. RARC is a potentially feasible surgical option even in patients with high comorbidities.

The low dose of rituximab in ABO-incompatible kidney transplantation without a splenectomy: a single-center experience.

PURPOSE: A new protocol for ABO-incompatible (ABO-i) kidney transplantation including rituximab was introduced in January 2005 in our institute. This study reviewed the results and evaluated the use of low-dose rituximab in ABO-i kidney transplantation. MATERIAL AND METHODS: Seventy-four de novo ABO-i kidney transplantations were performed at Tokyo Women's Medical University between January 2005 and August 2010. The immunosuppressive protocol was consisting of tacrolimus, mycophenolate mofetil, and methylprednisolone. All the patients received induction therapy with basiliximab. The pre-conditioning protocol included double-filtration plasmapheresis and a single dose of rituximab. A dose of 500 mg/body rituximab was initially employed and yielded excellent results (Group I, n = 24). Afterward, the dose of rituximab was reduced to 200 mg/body in January 2007 (Group II, n = 50). RESULTS: Seventy-four de novo ABO-i recipients were treated with this protocol, and all patients underwent kidney transplantation successfully. Effective elimination of the peripheral blood CD19 cells was observed in both groups. However, the peripheral blood CD19 levels were still low in both groups at 24 months after treatment. CONCLUSION: The patients in Group II showed excellent results similar to Group I. These results suggest that the low dose of rituximab (200 mg/body) is the sufficient dose in ABO-i kidney transplantation.

De novo membranous nephropathy and antibody-mediated rejection in transplanted kidney.

BACKGROUND: The etiology of de novo membranous nephropathy (MN) after kidney transplantation is still uncertain. Immunological response to various allograft antigens is speculated to be a candidate for the etiology. METHODS: Seventeen patients with post-transplant de novo MN were studied clinically and pathologically in comparison with control post-transplant patients without MN. Double immunofluorescent staining was performed to identify the presence of donor-specific human leukocyte antigen (HLA) combined with IgG in the deposits on glomerular capillary walls. RESULTS: De novo MN occurs in relatively late period after transplantation (102.1 ± 68.3 months), presenting various degree of proteinuria. Histological findings associated with antibody-mediated rejection (AMR), such as peritubular capillaritis and C4d deposition in peritubular capillary, were more frequently observed in the patients with de novo MN than the non-MN control patients. Donor-specific antibody (DSA) was detected in five patients at the time of biopsy. In one case of de novo MN with DSA, a donor-derived HLA was identified in the subepithelial deposits on the glomerular capillary walls combined with IgG deposition. CONCLUSIONS: DSA and AMR might play some roles for the pathogenesis in some patients with de novo MN after kidney transplantation.

Efficacy of Cabozantinib in Metastatic Papillary Renal Cell Carcinoma Following Ineffective Treatment With Initial Therapy of Nivolumab and Ipilimumab.

Sunitinib is listed as first-line therapy for non clear-cell renal cell carcinoma (RCC) in several guidelines. However, in the era of immunotherapy, there is an urgent need for updated evidence for the treatment of metastatic non clear-cell RCC. Herein, we present three cases of patients with type 2 papillary RCC who were effectively treated with cabozantinib. The first case was a 48-year-old woman who underwent radical nephrectomy (pT3aN0M0). The tumor relapsed in the retroperitoneum 3 months postoperatively and was unresponsive to first-line nivolumab plus ipilimumab (NI). After the use of cabozantinib, the tumors drastically shrunk in 2 weeks, and complete response was achieved 3 months later. The second case was a 55-year-old man who underwent radical nephrectomy (pT3aN2M1). Metastatic lesions continued to grow with first-line NI, and cabozantinib was used as the second-line therapy. All metastatic lesions had shrunk by 50% after 4 months. The third case was a 36-year-old man with multiple tumors in the left solitary kidney and iliopsoas muscle metastasis. First-line therapy with NI was ineffective; subsequently, second-line axitinib was used for 5 months, and the disease was identified as progressive. Cabozantinib was started as third-line therapy. Multiple tumors shrunk in 2 weeks. There is little evidence concerning the treatment of papillary RCC. We experienced low efficacy of NI for first-line treatment of papillary RCC for three patients who were subsequently effectively treated with cabozantinib. Cabozantinib inhibits multiple tyrosine kinase receptors, which may suppress aggressive tumor progression of type 2 papillary RCC. Cabozantinib or combination with immuno-oncological drugs may be a promising treatment option for papillary RCC.

A specific promoter-type in ribonuclease L gene is associated with phagocytic activity in pigs.

We have previously generated Large White pigs with high immune competence using a selection strategy based on phagocytic activity (PA), capacity of alternative complement pathway, and antibody response after vaccination against swine erysipelas. In this study, to identify the genetic changes caused by the immune selection pressure, we compared gene expression and polymorphisms in the promoter region between pigs subjected to the immune selection (immune-selected pigs) and those that were not (non-selected pigs). After lipid A stimulation, using a microarray analysis, 37 genes related to immune function and transcription factor activity showed a greater than three-fold difference in expression between macrophages derived from immune-selected and non-selected pigs. We further performed a polymorphic analysis of the promoter region of the differentially expressed genes, and elucidated the predominant promoter-types in the immune-selected and non-selected pigs, respectively, in the genes encoding ribonuclease L (RNASEL), sterile α motif and histidine-aspartate domain containing deoxynucleoside triphosphate triphosphohydrolase 1, signal transducer and activator of transcription 3, and tripartite motif containing 21. Analysis of the association between these promoter genotypes and the immune phenotypes revealed that the immune-selected promoter-type in RNASEL was associated with increased PA and was inherited recessively. Considering that RNASEL has been reported to be involved in antimicrobial immune response of mice, it may be possible to enhance the PA of macrophages and improve disease resistance in pig populations using RNASEL promoter-type as a DNA marker for selection.