Development and nationwide validation of kidney graft injury markers using urinary exosomes and microvesicles (complete English translation of the Japanese version).

BACKGROUND: Non-invasive, prompt, and proper detection tools for kidney graft injuries (KGIs) are awaited to ensure graft longevity. We screened diagnostic biomarkers for KGIs following kidney transplantation using extracellular vesicles (EVs; exosomes and microvesicles) from the urine samples of patients. METHODS: One hundred and twenty-seven kidney recipients at 11 Japanese institutions were enrolled in this study; urine samples were obtained prior to protocol/episode biopsies. EVs were isolated from urine samples, and EV RNA markers were assayed using quantitative reverse transcription polymerase chain reaction. Diagnostic performance of EV RNA markers and diagnostic formulas comprising these markers were evaluated by comparison with the corresponding pathological diagnoses. RESULTS: EV CXCL9, CXCL10, and UMOD were elevated in T-cell-mediated rejection samples compared with other KGI samples, while SPNS2 was elevated in chronic antibody-mediated rejection (cABMR) samples. A diagnostic formula developed through Sparse Logistic Regression analysis using EV RNA markers allowed us to accurately (with an area under the receiver operator characteristic curve [AUC] of 0.875) distinguish cABMR from other KGI samples. EV B4GALT1 and SPNS2 were also elevated in cABMR, and a diagnostic formula using these markers was able to distinguish between cABMR and chronic calcineurin toxicity accurately (AUC 0.886). In interstitial fibrosis and tubular atrophy (IFTA) urine samples and those with high Banff chronicity score sums (BChS), POTEM levels may reflect disease severity, and diagnostic formulas using POTEM detected IFTA (AUC 0.830) and high BChS (AUC 0.850). CONCLUSIONS: KGIs could be diagnosed with urinary EV mRNA analysis with relatively high accuracy.

Incidence and mortality of post-transplant lymphoproliferative disorders after kidney transplantation: A real-world retrospective analysis in Japan.

OBJECTIVES: Post-transplant lymphoproliferative disorder is a potentially life-threatening complication that has a greater risk of occurrence in the setting of immunosuppression and oncogenic viral infections after transplant surgery. Few studies have reported the cumulative incidence, histological subtypes and clinical outcomes of this disorder in kidney transplant recipients. METHODS: We retrospectively investigated 34 post-transplant lymphoproliferative disorder patients diagnosed out of the 1210 kidney transplant recipients who had undergone the surgery at the two largest centers in Japan between January 1983 and December 2017. RESULTS: A total of 32 patients (94.1%) developed late-onset post-transplant lymphoproliferative disorder (diagnosed 1 year after transplantation). The cumulative incidence rates were 0.76% and 1.59% at 5 and 10 years post-transplantation, respectively. The central nervous system was the most common site (35.3%, 12/34). Overall survival was similar between patients with and without central nervous system lesions (P = 0.676). Of all of the cases, 23.5% (8/34) were detected through cancer screening. Importantly, patients with screening-detected post-transplant lymphoproliferative disorder had better overall survival than those with the disorder who had been symptom detected (P = 0.0215). Overall survival was significantly reduced in patients who developed the disorder compared with those who did not (P = 0.0001). CONCLUSIONS: Post-transplant lymphoproliferative disorder was more likely to occur in the late post-transplantation period, which showed that long-term medical examination for transplant recipients is required. Based on our findings, we propose vigilant, long-term, cancer screening in kidney transplant recipients.

[A Case of Remission of Metastatic Germ Cell Tumor in an Elderly Patient by Multimodal Treatment].

There have been few reports of multimodal treatment such as chemotherapy and surgical resection for testicular tumors over 40 years old. In this case, a 64-year-old man with nonseminoma, pT2N2M1aS1, stage IIIb, IGCCC good prognosis completed induction chemotherapy, followed by retroperitoneal lymph node dissection and resection of lung metastases. Chemotherapy (4 courses of etoposide and cisplatin therapy) was completed without serious adverse events other than grade 4 neutropenia. Resection of the residual tumor confirmed no viable tumor cells. There was no evidence of recurrence or elevation of tumor markers in the following 6 months. Similar cases could increase with the increase of testicular tumors in the elderly.

[A Case of Successful Selective Arterial Embolization for Traumatic Priapism].

The first-line treatment for arterial (traumatic) priapism is follow-up, but no recommended duration has been established. We report a case of traumatic priapism that did not improve after one year of follow-up and was cured by arterial embolization. The patient was a 21-year-old male with a urethral injury caused by traffic trauma, and a urethral catheter was placed under fluoroscopic guidance. Magnetic resonance imaging (T2-weighted image) showed a low-signal area in the right penile corpus cavernosum. The urethral catheter was removed 1 month after the injury, but the erection persisted, and the patient was referred to our department 8 months after the injury. Contrast-enhanced computed tomography (CT) revealed enhancement effect of the right penile corpus cavernosum, which was diagnosed as traumatic priapism, and selective arterial embolization was performed 1 year after the injury. Angiography revealed an extravascular leak from the right patent ductus arteriosus into the cavernous sinus of the penis, and a gelatin sponge (Serescue®ï¸Ž) was injected as an embolization material into the distal portion of the right patent ductus arteriosus. Immediately after the operation, the penis became fully erect, but gradually softened. One month after embolization, priapism improved, and 6 months after embolization, contrast-enhanced CT confirmed the disappearance of the enhancement effect of the right corpus cavernosum. There has been no relapse of symptoms for 10 months after embolization. Selective arterial embolization for traumatic priapism is considered to be a useful treatment even after a certain period of follow-up.

[A Case of Urinary Incontinence Due to Ectopic Ureter with Complete Urteral Duplication Successfully Treaeted by Transcatheter Arterial Embolization (TAE)].

A 22-year-old woman who was referred to our hospital presented with a complaint of urinary incontinence since childhood. Abdominal contrast-enhanced computed tomography revealed complete duplication of the left ureter. In addition, the upper half of the left kidney showed poor contrast, accompanied by signs of hydronephrosis. Magnetic resonance urography failed to show an opening between the upper half of the left kidney and the ectopic ureter. Cystoscopy revealed two normally positioned ureteral orifices. After intravenous injection of indigo carmine, however, the dye became evident in the vagina. Thus, she was diagnosed to have urinary incontinence due to complete duplication of the left ureter and an ectopic ureteral opening into the vagina. Transcatheter arterial embolization of the upper half of the kidney, the origin of the ectopic ureter, immediately relieved the patient of urinary incontinence. At the 6-month follow-up, the patient had experienced no recurrence or complications.

[A Case of Presacral Paraganglioma Resected by Laparoscopic Surgery].

A 25-year-old woman, with chief complaints of palpitation and vomiting, was suspected of having acute myocarditis and was taken to our critical care center. She was diagnosed with Takotsubo syndrome based on the results of echocardiography, coronary angiography, and myocardial biopsy. The 24-hour urine test showed high levels of normetanephrine and noradrenaline. The abdominal computed tomographic scan showed a presacral tumor (26 mm) just below the aortic bifurcation, and ¹³¹I-meta-iodobenzylguanidine scintigraphy showed abnormal accumulation in the tumor. Finally, she was diagnosed with Takotsubo syndrome associated with presacral paraganglioma. The hemodynamics became stable with conservative treatment. Then she underwent elective laparoscopic surgery. The histopathological analysis revealed paraganglioma. The immunohistochemistry for succinate dehydrogenase was negative in the tumor cells. There has been no recurrence as of 15 months after surgery.

Efficacy of a Si-based agent against developing renal failure in a rat remnant kidney model.

Chronic renal failure is exacerbated by oxidative stress, and this condition is difficult to treat in advanced stages. Because of the lack of effective treatments, the disease is a global public health concern. We developed a Si-based agent that continuously generates hydrogen for more than 24 h by reacting with water under conditions similar to those in the gastrointestinal tract. Given the efficacy of hydrogen in the treatment of conditions associated with oxidative stress, we examined whether the Si-based agent had beneficial effects on the development of renal failure. The Si-based agent was orally administered to rats that were developing renal failure. Rats underwent 5/6 nephrectomy to establish a remnant kidney model. Specifically, on day -7, rats underwent right 2/3 nephrectomy, followed by light nephrectomy on day 0. Starting on day -3, the rats were administered a control or Si-based agent-containing diet for 8 weeks. Compared with the findings in control rats, the Si-based agent greatly suppressed the increases of both serum creatinine and urinary protein levels. All analyzed parameters of oxidative stress were significantly suppressed in the Si-based agent groups. Histopathological examination illustrated that glomerular hypertrophy was suppressed by the treatment. Quantitative real-time reverse transcription-polymerase chain reaction revealed that sirtuin 1 and heme oxygenase-1 expression was increased in the Si-based agent groups, suggesting improved antioxidant activity and reduced hypoxia. In addition, caspase-3 and interleukin-6 expression was suppressed in the Si-based agent groups, indicating the alleviation of apoptosis and inflammation. In conclusion, oral administration of a Si-based agent resulted in renoprotective effects, presumably by suppressing oxidative stress via hydrogen generation.

[A Case of 18FDG PET/CT-Positive Adrenal Adenoma Suspected of Being Adrenal Metastasis of Synchronous Triple Cancer].

A 66-year-old man was referred to our hospital because of positive fecal occult blood test. Gastric and rectal cancers were diagnosed by upper and lower endoscopic biopsy, respectively. Enhanced computed tomography (CT) indicated a pulmonary tumor and a left adrenal mass with a diameter of 15 mm presenting heterogenous enhancement. The pulmonary tumor was diagnosed as adenocarcinoma by bronchoscopic biopsy. F18 fluoro-2-deoxy D-glucose (FDG) PET/CT showed abnormal FDG accumulation (maximum standardized uptake value=26. 1) in the left adrenal mass consistent with a metastatic adrenal tumor. Although radical surgical therapy was performed for the synchronous triple cancers of gastric, colon, and lung cancer, the patient refused adrenalectomy for the left adrenal tumor. One year after surgery, CT revealed an increase in the adrenal tumor diameter to 18 mm without development of new metastases. Laparoscopic adrenalectomy was performed for the left adrenal tumor which was strongly suspected of being a metastatic tumor. Pathological diagnosis was adrenal cortical adenoma. There has been no recurrence for 5 years after surgery for simultaneous triple cancer.

Peritransplant VLA-4 blockade inhibits endogenous memory CD8 T cell infiltration into high-risk cardiac allografts and CTLA-4Ig resistant rejection.

Recipient endogenous memory CD8 T cells expressing reactivity to donor class I MHC infiltrate MHC-mismatched cardiac allografts within 24 hours after reperfusion and express effector functions mediating graft injury. The current study tested the efficacy of Very Late Antigen-4 (VLA-4) blockade to inhibit endogenous memory CD8 T cell infiltration into cardiac allografts and attenuate early posttransplant inflammation. Peritransplant anti-VLA-4 mAb given to C57BL6 (H-2b ) recipients of AJ (H-2a ) heart allografts completely inhibited endogenous memory CD4 and CD8 T cell infiltration with significant decrease in macrophage, but not neutrophil, infiltration into allografts subjected to either minimal or prolonged cold ischemic storage (CIS) prior to transplant, reduced intra-allograft IFN-γ-induced gene expression and prolonged survival of allografts subjected to prolonged CIS in CTLA-4Ig treated recipients. Anti-VLA-4 mAb also inhibited priming of donor-specific T cells producing IFN-γ until at least day 7 posttransplant. Peritransplant anti-VLA plus anti-CD154 mAb treatment similarly prolonged survival of allografts subjected to minimal or increased CIS prior to transplant. Overall, these data indicate that peritransplant anti-VLA-4 mAb inhibits early infiltration memory CD8 T cell infiltration into allografts with a marked reduction in early graft inflammation suggesting an effective strategy to attenuate negative effects of heterologous alloimmunity in recipients of higher risk grafts.

Difference in IgA1 O-glycosylation between IgA deposition donors and IgA nephropathy recipients.

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis, and disease recurrence often occurs after transplantation. On the other hands, Asymptomatic IgA deposition (IgAD) is occasionally observed in donated kidney. It is recognized that IgAD does not progress to IgAN, but the mechanism has not demonstrated yet. In IgAN, aberrant IgA1 O-glycan structure in the hinge region (HR) of serum IgA is suggested as one of the most convincing key mediators. However, little is known about IgA1 O-glycan structure in IgAD patients. Herein, we investigated the prevalence of IgAD in living renal transplant donors in our cohort. IgAD was observed in 21(13.0%) among 161 renal transplant donors and have statistically significant blood relationship with IgAN recipients (28.6% in relatives vs. 9.8% in non-relatives, respectively; p = 0.0073). Next, we evaluated the IgA1 O-glycan structure of serum IgA from IgAN recipients (n = 26), IgAD donors (n = 17), and non-IgAD helthy donors (n = 27) using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The numbers of GalNAc and Gal and the Gal/GalNAc ratio in the HR of the IgAN recipients had significantly lower comparing to the IgAD and non-IgAD healthy donors. The decreased Gal/GalNAc ratio in IgAN recipients means the increased ratio of galactose-deficient IgA1. To the best of our knowledge, this is the first report to compare the O-glycan structures in IgAN recipients and IgAD donors using MALDI-TOF MS. We concluded that IgAD was more common in IgAN related donors. Overall, decreased GalNAc and Gal contents in HR could play a material pathogenic role in IgAN.

IL-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts.

Reperfusion of organ allografts induces a potent inflammatory response that directs rapid memory T cell, neutrophil, and macrophage graft infiltration and their activation to express functions mediating graft tissue injury. The role of cardiac allograft IL-1 receptor (IL-1R) signaling in this early inflammation and the downstream primary alloimmune response was investigated. When compared with complete MHC-mismatched wild-type cardiac allografts, IL-1R(-/-) allografts had marked decreases in endogenous memory CD8 T cell and neutrophil infiltration and expression of proinflammatory mediators at early times after transplant, whereas endogenous memory CD4 T cell and macrophage infiltration was not decreased. IL-1R(-/-) allograft recipients also had marked decreases in de novo donor-reactive CD8, but not CD4, T cell development to IFN-γ-producing cells. CD8 T cell-mediated rejection of IL-1R(-/-) cardiac allografts took 3 wk longer than wild-type allografts. Cardiac allografts from reciprocal bone marrow reconstituted IL-1R(-/-)/wild-type chimeric donors indicated that IL-1R signaling on graft nonhematopoietic-derived, but not bone marrow-derived, cells is required for the potent donor-reactive memory and primary CD8 T cell alloimmune responses observed in response to wild-type allografts. These studies implicate IL-1R-mediated signals by allograft parenchymal cells in generating the stimuli-provoking development and elicitation of optimal alloimmune responses to the grafts.

[A Case of Bilateral Angiomyolipoma Accompanied by Tuberous Sclerosis Complex Successfully Treated with Transcatheter Arterial Embolization Using Functional Kidney Mapping Images Consisting of SPECT-CT and Contrast Enhanced CT Images].

Renal angiomyolipoma (AML) and aneurysm are common in tuberous sclerosis complex (TSC) and represent the main causes of morbidity in adults with TSC. Herein, we report a 22-year-old woman with TSC-associated AMLs and renal aneurysms. She was referred to our hospital for the treatment of multiple renal aneurysms larger than 5 mm in diameter. The previous hospital considered that transcatheter arterial embolization (TAE) of bilateral renal aneurysms would cause deterioration of renal function. To estimate the impact of TAE on renal function, we superimposed contrast enhanced computed tomography (CT) over single-photon emission CT (SPECT)-CT. This fusion image, referred to as functional kidney mapping image, revealed the location of renal arteries and aneurysms, and normal renal parenchyma simultaneously. Functional kidney mapping image was useful to distinguish the AML region from the normal renal parenchyma, and revealed that the planned embolization site was a non-functioning parenchyma. Therefore, TAE for her multiple renal aneurysms was successfully performed without deterioration of her renal function.

High-pressure carbon monoxide preserves rat kidney grafts from apoptosis and inflammation.

Renal ischemia-reperfusion (I/R) injury is unavoidable in kidney transplantation (KTx) and frequently influences both short- and long-term allograft survival. Carbon monoxide (CO) has attracted attention as a medical gas with anti-inflammatory and anti-apoptotic effects. We investigated a new strategy for organ preservation using ex vivo application of high-pressure CO in an experimental rat KTx model. We preserved kidney grafts using a high-pressure chamber filled with mixed gases composed of CO and O2. We found that cold I/R injury resulted in progressive deterioration of renal graft function in University of Wisconsin solution, whereas CO significantly improved renal function. We confirmed that CO decreased oxidative stress and mRNA expression of proinflammatory cytokines and inhibited tubular apoptosis in the early phases. Western blot analysis demonstrated that CO increased phosphatidylinositol-3 kinase and phosphorylation of Akt and p38 mitogen-activated protein kinase. Furthermore, CO significantly alleviated tubular injury scores and suppressed the development of interstitial fibrosis at 100 days after KTx. Thus, high-pressure mixed CO and O2 gases successfully preserved rat kidney grafts for 24 h by protecting tubular epithelial cells from apoptosis and inhibiting inflammation.

Metastatic testicular cancer presenting with liver and kidney dysfunction treated with modified BEP chemotherapy combined with continuous hemodiafiltration and rasburicase.

A 25-year-old man was admitted to our hospital complaining of right scrotal pain and upper abdominal pain. A computed tomographic scan indicated a right scrotal mass, a huge liver mass, and multiple lung masses, although there was no enlarged retroperitoneal lymph node swelling. Laboratory tests showed severe liver and kidney dysfunction and high levels of serum α-fetoprotein (11,997 ng/ml). Although needle biopsies of the testicular and liver masses were performed, the tissues were insufficient for a pathological diagnosis. As liver and kidney function worsened, we started chemotherapy with bleomycin, etoposide, and cisplatin (BEP chemotherapy), which was modified because of the liver and renal dysfunction. We also used continuous hemodiafiltration and rasburicase to prevent tumor lysis syndrome. After induction of chemotherapy, the liver and kidney dysfunction improved immediately and the high orchiectomy was performed on day 8 after chemotherapy. The pathological diagnosis was a yolk sac tumor. He underwent four courses of the BEP regimen and five courses of the TIN regimen (paclitaxel, ifosphamide, and nedaplatin), followed by the resection of liver metastases. There was no evidence of viable cells in the resected liver and no recurrence was evident at 1 year postoperatively.

[Renal Cell Carcinoma with Metastasis to the Gallbladder : A Case Report].

A 63-year-old male with a past history of left nephrectomy due to clear cell renal cell carcinoma at the age of 57 was admitted for further evaluation. Enhanced abdominal computed tomography revealed that there were several hypervascular tumors in the pancreas and a single hypervascular tumor in the gallbladder. Laparoscopic cholecystectomy was performed to obtain pathological diagnosis. Microscopically, the tumor in the gallbladder was filled with clear cells and was diagnosed as metastatic gallbladder cancer from the previous clear cell renal cell carcinoma. Metastatic renal cell carcinoma to the gallbladder is extremely rare, with reported frequencies of less than 0. 6% in 687 autopsies. We herein report a case in which cholecystectomy enabled a successful diagnosis and review the reported 22 cases in Japanese patients.

Surgical resection of primary leiomyosarcoma of retro-hepatic inferior vena cava extending from bilateral renal veins across the diaphragm.

Vascular leiomyosarcoma of the inferior vena cava is a rare malignant soft tissue tumor that requires surgical treatment to prevent tumor-related symptoms such as pulmonary embolism and Budd-Chiari syndrome. However, a treatment strategy for surgical resection of advanced cases has not yet been determined. This report describes the case of advanced leiomyosarcoma of the inferior vena cava that was successfully treated with surgery and subsequent chemotherapy. A 44-year-old man was found to have a 12 × 10 cm retroperitoneal tumor on computed tomography. The tumor originated in the inferior vena cava and extended beyond the diaphragm into the renal vein. The surgical plan was determined in joint consultation with the multidisciplinary team. It was safely resected and the inferior vena cava was closed caudal to the porta hepatis without a synthetic graft. The tumor was diagnosed as leiomyosarcoma. Doxorubicin, followed by pazopanib were administered as treatment for metastatic disease. Eighteen months after the surgery, the patient's performance status was maintained.

Mucinous cystadenoma of the renal parenchyma presenting as a Bosniak IIF complex renal cyst.

Introduction: A primary retroperitoneal mucinous cystadenoma should be surgically resected because of the risk of malignant transformation. However, mucinous cystadenoma of the renal parenchyma is very rare, and preoperative imaging mimics complicated renal cysts. Case presentation: A 72-year-old woman presented with a right renal mass on computed tomography that was followed up as a Bosniak IIF complicated renal cyst. One year later, the right renal mass gradually increased in size. Abdominal computed tomography showed an 11 × 10 cm mass in the right kidney. A laparoscopic right nephrectomy was performed because cystic carcinoma of the kidney was suspected. Pathologically, the tumor was diagnosed as mucinous cystadenoma of the renal parenchyma. Eighteen months after resection, the disease has not recurred. Conclusion: Here, we experienced a case of a renal mucinous cystadenoma as a slowly enlarging Bosniak IIF complex renal cyst.

Failure of Costimulatory Blockade-induced Regulatory T Cells to Sustain Long-term Survival of High Ischemic Allografts.

BACKGROUND: Costimulatory blockade-induced allograft tolerance has been achieved in rodent models, but these strategies do not translate well to nonhuman primate and clinical transplants. One confounder that may underlie this discrepancy is the greater ischemic inflammation imposed on the transplants. In mice, cardiac allografts subjected to prolonged cold ischemic storage (CIS) before transplant have increased ischemia-reperfusion injury, which amplifies infiltrating endogenous memory CD8 T-cell activation within hours after transplantation to mediate acute graft inflammation and cytotoxic lymphocyte-associated molecule-4 immunoglobulin-resistant rejection. This study tested strategies inhibiting memory CD8 T-cell activation within such high ischemic allografts to achieve long-term survival. METHODS: A/J (H-2 a ) hearts subjected to 0.5 or 8 h of CIS were transplanted to C57BL/6 (H-2 b ) recipients and treatment with peritransplant costimulatory blockade. At 60 d posttransplant, regulatory T cells (Treg) were depleted in recipients of high ischemic allografts with anti-CD25 monoclonal antibody (mAb) or diphtheria toxin. RESULTS: Whereas peritransplant (days 0 and +1) anti-lymphocyte function-associated antigen-1 mAb and anti-CD154 mAb prolonged survival of >60% allografts subjected to minimal CIS for >100 d, only 20% of allografts subjected to prolonged CIS survived beyond day 80 posttransplant and rejection was accompanied by high titers of donor-specific antibody. Peritransplant anti-lymphocyte function-associated antigen-1, anti-tumor necrosis factor-α, and anti-CD154 mAb plus additional anti-CD154 mAb on days 14 and 16 obviated this donor-specific antibody and promoted Treg-mediated tolerance and survival of 60% of high ischemic allografts beyond day 100 posttransplant, but all allografts failed by day 120. CONCLUSIONS: These studies indicate a strategy inducing prolonged high ischemic allograft survival through Treg-mediated tolerance that is not sustained indefinitely.

The blocking of CXCR3 and CCR5 suppresses the infiltration of T lymphocytes in rat renal ischemia reperfusion.

BACKGROUND: Recent studies have identified T cells and natural killer T (NKT) cells as important mediators in renal ischemia-reperfusion (I/R) injury. The recruitment of these cells is induced by chemotaxis factors. We investigated the effects of blocking CXCR3 and CCR5 by an antagonist (TAK) using a rat renal I/R injury model. METHODS: The Sprague-Dawley rats were either subjected to sham operation or left renal occlusion for 45 min followed by reperfusion and contralateral nephrectomy. The control or TAK groups were, respectively, injected phosphate-buffered saline or TAK at 30 min prior to clamp. Serum creatinine, tubular injury, chemokines expression and infiltrating cells were assessed. RESULTS: TAK treatment significantly suppressed the elevation in serum creatinine (sham 0.40 ± 0.05 mg/dL, control 2.86 ± 0.67 mg/dL, TAK 1.60 ± 0.73 mg/dL) and resulted in a lower tubular injury score compared with the control group (sham 0, control 4.8 ± 0.3, TAK 3.3 ± 1). The mRNA expression of chemokines that bind to CXCR3 and CCR5 in the post-ischemic kidneys was elevated at 1 h after reperfusion in each group. Moreover, the infiltration of CD4+ T cells and CD8+ NKT cells in the control group increased compared with the sham group and TAK injection significantly suppressed the number of CD4+ T cells (sham 13.5 ± 3.5 × 10(4) cells, control 28.9 ± 15.4 × 10(4) cells, TAK 11.8 ± 3.5 × 10(4) cells) and the number of CD8+ NKT cells (sham 11.7 ± 5.4 × 10(4) cells, control 30.1 ± 8.6 × 10(4) cells, TAK 11.8 ± 2.9 × 10(4) cells). CONCLUSIONS: These findings suggest that the blocking of CXCR3 and CCR5 suppress the infiltration of T cells and NKT cells and have a protective effect on kidneys that are injured by I/R.

A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney.

BACKGROUND: The tissue-protective effects of erythropoietin (EPO) have been extensively investigated, and EPO administration can raise the hemoglobin (Hb) concentration. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia-reperfusion injury as well as EPO. METHODS: To investigate the clinical applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a tubulointerstitial model rat. We randomized remnant kidney model rats to receive saline, EPO, or CEPO for 8 weeks. RESULTS: CEPO- and EPO-treated rats had improved serum creatinine levels compared with saline-treated remnant kidney model rats, although the Hb level was significantly increased in EPO-treated rats. Two-photon microscopy revealed that EPO/CEPO significantly ameliorated tubular epithelial cell damage assessed by endocytosis. In addition, CEPO or EPO protected endothelial cells with a sustained blood flow rate. EPO or CEPO suppressed the number of TUNEL-positive apoptotic cells with weak αSMA staining. Furthermore, PCR analysis demonstrated that TGF-ß and type I collagen expression was attenuated in EPO- or CEPO-treated rats, accompanied by a significant decrease in interstitial fibrosis. CONCLUSION: We established a long-term therapeutic approach to protect tubulointerstitial injury with CEPO, and thus, the therapeutic value of this approach warrants further attention and preclinical studies.