Kouichi Kanagawa

Cytokine regulation of ICAM-1 expression on human renal tubular epithelial cells in vitro.

Regulation of the intercellular adhesion molecule-1 (ICAM-1) expression on human renal tubular epithelial cells in culture (hKEC-1) was investigated. A large proportion of hKEC-1 cells from the primary cultures expressed the ICAM-1 antigen. Supernatants from mixed lymphocyte reaction (MLR) of both specific and third-party combinations augmented the expression of the ICAM-1 antigen, in a dose-dependent manner. A kinetic study revealed maximal augmentation by MLR supernatant on the first day, with a gradual decrease thereafter. Among several recombinant human cytokines tested, i.e., interferon-gamma, tumor necrosis factor-alpha, interleukin 1 alpha and beta, and IL-4, IFN-γ, TNF-α, and IL-1α/β were shown to augment the expression of ICAM-1. MLR supernatants and IFN-γ were more effective in augmenting ICAM expression than TNF-α and IL-1α/β. IFN-γ upregulated ICAM-1 expression in a dose-dependent manner, and maximal augmentation was achieved on the first day. The MLR supernatants were shown to contain IFN-γ and TNF-α, and the activity of the MLR supernatant was partially inhibited by neutralizing antibody against IFN-γ. These data suggest that cytokines, especially IFN-γ, TNF-α, and IL-1α/β, released by T cells and antigen-presenting cells upon recognition of alloantigens upregulate ICAM-1 expression on renal tubular epithelial cells. This may result in an increase in the attachment of graft-infiltrating T cells to the renal tubular cells, by the ICAM-1-LFA-1 interaction.

Identification Of Icam-1-positive Cells In The Nongrafted And Transplanted Rat Kidney—an Immunohistochemical And Ultrastructural Study

Cellular localization of intercellular adhesion molecule-1 (ICAM-1) in rat nongrafted intact kidneys and in transplanted kidneys was investigated using monoclonal anti-rat ICAM-1, 1A29. The major ICAM-1-positive cells in the nongrafted and isografted kidneys were endothelial cells in the large vessels and intertubular capillaries, as observed using light microscopy. A weak, but specific expression of ICAM-1 antigen was noted in the glomeruli, but the exact localization and cell type were not clearly discernible. In the allograft, the ICAM-1-positive cells found in the nongrafted and isografted kidneys also expressed ICAM-1 antigen. In addition, tubular epithelial cells at the luminal border and some infiltrating cells in the allograft expressed IC AM-1. In the allograft, some graft-infiltrating cells were shown to be lymphocyte function-associated antigen-1 (LFA-1) -positive. As the nature of ICAM-1-positive cells in the infiltrates was unclear, we examined ICAM-1-positive cells using immunoelectron microscopy and the directimmunoperoxidase method. Glomerular endothelial cells, podocytes, and Bowmans capsular epithelial cells expressed ICAM-1 antigen in the nongrafted and transplanted kidneys. Among the infiltrating cells in the allograft, the major ICAM-1 positive cells were macrophagelike tissues, and some blastic lymphocytes also expressed ICAM-1. Only rarely did the proximal tubular cells express ICAM-1 antigen at the luminal surfaces in the intact kidney. In the allograft, the proximal, distal, and collecting ductular epithelial cells expressed ICAM-1 at the luminal surface, and in addition, the ICAM-1 antigen was also localized at the basal surfaces of some of the renal proximal tubular epithelial cells. The upregulated ICAM-1 expression in the allograft may accelerate graft rejection by augmenting adhesiveness of LFA-1-positive graft-infiltrating cells.

Experience With Revascularizing Renal Artery Aneurysms: is it Feasible, Safe and Worth Attempting?

PURPOSE We retrospectively evaluated the feasibility and efficacy of surgical revascularization for renal artery aneurysms. MATERIALS AND METHODS Beginning in 1984, 12 patients with renal artery aneurysm underwent renal revascularization regardless of clinical features. Postoperative results were analyzed regarding split renal function, patency of the revascularized arteries, blood pressure control and surgical complications. RESULTS Postoperative renal function was stable or improved in all but 1 case and patency in branched arteries was preserved in 86%. Hypertension in 8 patients was cured in 7 (88%), including 2 with renovascular hypertension, and improved in 1 (12%). Complications were minimal with only 1 ureteral stricture that required reoperation. CONCLUSIONS The majority of renal artery aneurysm cases are amenable to surgical repair. Carefully performed renal revascularization is rewarding in that high blood pressure is better controlled, renal function is improved and the potential risk of rupture is obviated.

Multicenter Phase II Trial of Combination Therapy with Meloxicam, a COX-2 Inhibitor, and Natural Interferon-α for Metastatic Renal Cell Carcinoma

OBJECTIVE We conducted a Phase II trial to investigate the efficacy of combined therapy with meloxicam, a cyclooxygenase-2 inhibitor and natural interferon (IFN)-alpha in renal cell carcinoma patients with distant metastasis. METHODS The subjects of this study were patients with untreated renal cell carcinoma who were diagnosed from the results of imaging or pathological studies and who had measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST). Patients could be enrolled in the study irrespective of whether nephrectomy had been performed. Treatment involved the subcutaneous injection of natural IFN-alpha at 3 x 10(6) or 5 x 10(6) U three times weekly plus oral administration of meloxicam at 10 mg once daily. RESULTS A total of 43 patients were enrolled in the present study, included 11 patients without nephrectomy, 23 patients with a high C-reactive protein (CRP) level and 23 patients with extrapulmonary metastasis. Four patients of complete response and 12 patients of partial response were confirmed, given an overall response rate of 37.2% (95% confidence interval, 23.0-53.3%). Stable disease for 6 months or longer was also obtained in 14 patients. The median time to progression was 14 months. Adverse events (AEs) observed were mainly flu-like symptoms due to cytokine. Although the Grade 3 or 4 AEs were fatigue, hepatic dysfunction, arthritis and gastric ulcer, all but one (gastric ulcer) were immediately improved by discontinuation of this combined therapy. CONCLUSIONS The combination of meloxicam and natural IFN-alpha is considered to be an active regimen with tolerable toxicities as a first-line treatment of metastatic renal cell carcinoma.

Is Memorial Sloan-Kettering Cancer Center risk classification appropriate for Japanese patients with metastatic renal cell carcinoma in the cytokine era?

OBJECTIVES We investigated the prognosis of Japanese patients with metastatic renal cell carcinoma (RCC), and analyzed the validity of Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification. MATERIALS AND METHODS The endpoint of the present study was overall survival. Relationships between overall survival and potential prognostic factors were assessed using the Cox proportional hazard model with a step-wise procedure. Prognostic assessment was also performed according to the MSKCC risk classification. The predictive accuracy of the MSKCC risk classification was measured employing the concordance index. RESULTS The median survival for all patients was 22 months (95% CI, 19-28 months). The eight factors were identified as independent prognostic factor; time from initial diagnosis to metastasis, low hemoglobin (Hb), lactate dehydrogenase (LDH), corrected serum calcium (cCa), C-reactive protein (CRP), and the presence or absence of liver metastasis, bone metastasis, and lymph node metastasis. When the MSKCC risk classification was applied to patients, the median overall survival was not reached and 26 and 10 months in the patients classified as favorable, intermediate, and poor risk, respectively. The c-index was 0.73. CONCLUSIONS The prognosis of Japanese metastatic renal cell carcinoma patients may be better than that of previous studies from North America or Europe. Although there are some differences in the rate of patients in the risk groups and survival time by risk group between these patients, the MSKCC risk classification may be applicable for Japanese patients with metastatic renal cell carcinoma.

MANAGEMENT AND OUTCOME OF ANTENATALLY DIAGNOSED HYDRONEPHROSIS

From March 1989 to December 1992, we encountered 25 kidneys in 21 patients with a suspicious ureteropelvic junction (UPJ) obstruction detected only on prenatal ultrasound. In all these patients other urological abnormalities were excluded by voiding cystourethrography and other radiological findings. Diuretic renography (DR) was initially performed at an age ranging from 15 days to 32 months in all patients and repeated a total of 39 times. Both the split renal function (SRF) and diuretic drainage half‐time clearance (DT1/2) of radioagent were within their normal ranges in the case of 15 (60%) of the kidneys on initial DR. In these kidneys, there were no aggravated signs on repeated DR. Decreased SRF was found in 3 kidneys (12%) on initial DR. Of these, the renal function spontaneously reverted to normal in 2 cases with bilateral hydronephrosis. Another 1 kidney revealed significant UPJ obstruction assessed by pressure flow study and continuous nephrostomy drainage had brought relief from the obstruction 1 year later. Prolonged DT1/2 with normal SRF was found in 7 (28%) kidneys. The renal function did not deteriorate and the diuretic response improved on repeat DR except for 1 kidney, whose function deteriorated and on which ultimately, pyelo‐plasty was performed at 7 months of age. Prenatally diagnosed hydronephrosis is usually asymptomatic and clinically significant UPJ obstruction should be always verified. Although even today there is still no examination which can detect a definite obstruction, we can identify one as significant by careful repeat examinations and thus avoid unnecessary surgery without causing any renal deterioration.

Kidney Transplantation in a Child with Posterior Urethral Valve from a Hepatitis B Virus-Carrier Mother

The case of a 7-year-old boy with posterior urethral valve (PUV) who underwent successful kidney transplantation for progressive renal failure is reported. He required complex reconstructive surgery for PUV-related disorders, and also specific serological preparation for hepatitis B (HB) as his living donor mother was a proven carrier. By carefully executing the principles of reconstructive surgery and with well-planned seroimmunological preparation, we have demonstrated that successful kidney transplantation can be done from an HB Ag-positive mother to an HB Ag- and HB Ab-negative son, even when his urinary tract is severely dysfunctional due to PUV.

Susceptibility of renal tubular cells to lymphokine-activated killer (LAK) cells : application of culture system using a collagen gel matrix

SummaryMonolayer cultures of renal tubular (hKEC) cells were established. These cells formed empty spheroids after 2–3 weeks of culture in a collagen gel matrix. A subcellular polarity from the apex to basement was induced in these “spheroidal” hKEC cells. The weak expression of laminin at the outer surface was evident on spheroidal but not on monolayered hKEC cells. The regulation of HLA-ABC, DR, and intercellular adhesion molecule-1 (ICAM-1) antigens on hKEC cells in the gel matrix was investigated utilizing digestion of gel matrix by collagenase. Enzymatic digestion of the collagen gel did not significantly affect the surface expression of HLA-ABC and ICAM-1, but reduced HLA-DR expression as shown by flow cytometry. The MHC and ICAM-1 molecules on both spheroid-forming and monolayered hKEC cells were upregulated by adding a supernatant of mixed lymphocyte reaction (MLR) and recombinant human interferon (IFN)-γ. HLA-DR antigen expression was inconsistently induced on the hKEC cells cultured in collagen gel without MLR supernatant or IFN-γ. In contrast, no HLA-DR expression was found on monolayered hKEC cells in the absence of MLR supernatant or IFN-γ. Spheroid-forming hKEC cells, when dispersed by enzymatic digestion, were more susceptible to cytolysis by lymphokine-activated killer (LAK) cells than were the enzymatically dispersed, monolayered cells in the51Cr-release assay. The LAK cells were seen to migrate into the collagen gel and kill the hKEC cells. Thus, LAK cells may function to favor the acceleration of graft rejection. The culture of renal tubular cells in collagen gel provides a useful in vitro system for analyzing the allogeneic response.

Immunological Analysis of Rat Renal Transplant Recipients Exhibiting Long‐term Survival Following Treatment with 15‐Deoxyspergualin in the Early Postoperative Phase

Background: We previously reported that short‐term administration of 15‐deoxyspergualin (DSG), 5 mg/kg/day on postoperative days 4 through 7, prolonged survival of rat renal allografts indefinitely. We now report the immunologic environment of DSG‐treated recipients in the early postoperative phase.

A case of neurofibromatosis associated with clitoral enlargement and hypertension

We report a case of clitoral and renovascular involvement of neurofibromatosis resulting in an enlarged phallus with juvenile hypertension. The patient was successfully treated by removal of the clitoral tumor and nephrectomy. This is the first of 15 reported cases with clitoral involvement, that showed concurrent renovascular hypertension.