Immunosuppression Modification by Everolimus With Minimization of Calcineurin Inhibitors Recovers Kidney Graft Function Even in Patients With Very Late Conversion and Also With Poor Graft Function.

BACKGROUND: Although kidney graft survival within 5 years after transplantation is now achieved in >95% of recipients, chronic graft deterioration remains a factor limiting long-term survival. Chronic nephrotoxicity induced by calcineurin inhibitors (CNIs) is one of the major causes of chronic graft injury; thus, minimization of CNIs by administration of everolimus (EVR) is expected to relieve their toxic effects. METHODS: Fifty-six kidney transplant recipients receiving CNI-based immunosuppression (tacrolimus, n = 34; cyclosporine, n = 22) were analyzed. The average posttransplant period at conversion was 7.4 years and no less than 3 years. Conversion of immunosuppression was accomplished by reducing CNI by 40% in dose and beginning EVR at 1 or 1.5 mg. Changes in graft function were examined, and adverse effects were evaluated. RESULTS: Significant improvement in graft function was observed quickly after EVR administration, and it had persisted for 1 year after conversion as a 7% increase in estimated glomerular filtration rate. No obvious acute rejection was observed. Further analyses concerning "timing of EVR conversion" and "graft function at conversion" were performed. Graft function was significantly improved even in patients with late conversion at 2 to 10 years. The estimated glomerular filtration rate was significantly improved even in patients with poor function. CONCLUSIONS: We concluded that this modification to the immunosuppressive regimen, as expected, reduced CNI nephrotoxicity. Our results showed that even patients with very late conversion or poor graft function also benefited from EVR conversion with CNI minimization.

JunB promotes cell invasion and angiogenesis in VHL-defective renal cell carcinoma.

Inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene causes both hereditary and sporadic clear-cell renal-cell carcinoma (ccRCC). Although the best-characterized function of the VHL protein (pVHL) is regulation of hypoxia-inducible factor-α (HIFα), pVHL also controls the development of pheochromocytoma through HIF-independent pathways by regulating JunB. However, it is largely unknown how these pathways contribute to the development and progression of ccRCC. In the present study, we confirmed that JunB was upregulated in VHL-defective ccRCC specimens by immunostaining. Short-hairpin RNA (shRNA)-mediated knockdown of JunB in 786-O and A498 VHL null ccRCC cells suppressed their invasiveness. In addition, JunB knockdown significantly repressed tumor growth and microvessel density in xenograft tumor assays. Conversely, forced expression of wild-type, but not dimerization-defective, JunB in a VHL-restored 786-O subclone promoted invasion in vitro and tumor growth and vessel formation in vivo. Quantitative PCR array analysis revealed that JunB regulated multiple genes relating to tumor invasion and angiogenesis such as matrix metalloproteinase-2 (MMP-2), MMP-9 and chemokine (C-C motif) ligand-2 (CCL2) in 786-O cells. JunB knockdown in these cells reduced the proteolytic activity of both MMPs in gelatin zymography and the amount of CCL2 in the culture supernatant. Moreover, shRNA-mediated knockdown of MMP-2 or inhibition of CCL2 activity with a neutralizing antibody repressed xenograft tumor growth and angiogenesis. Collectively, these results suggest that JunB promotes tumor invasiveness and enhances angiogenesis in VHL-defective ccRCCs.

Induction of continuous ambulatory peritoneal dialysis after retroperitoneoscopic nephrectomy.

Induction of continuous ambulatory peritoneal dialysis (CAPD) as treatment of end-stage renal disease is difficult for patients requiring nephrectomy with traditional surgery, and usually hemodialysis is selected for these patients. In a 61-year-old woman with end-stage renal failure a left renal tumor was diagnosed by abdominal ultrasonography, enhanced computed tomography and magnetic resonance imaging. Following an urology consultation, we decided to perform left kidney nephrectomy. We estimated that she had to undergo dialysis permanently after nephrectomy. She desired to be treated by CAPD, however, we decided after allowing for a postoperative period for complete healing of the peritoneum to avoid complications. This is why during the interim period between surgery and induction of CAPD she underwent hemodialysis (HD) in a local outpatient HD center and in our hospital. We selected a retroperitoneoscopic approach for nephrectomy. Pathology evaluation revealed a renal cell carcinoma. 4 months after nephrectomy, CAPD catheter implantation was performed by using laparoscopy and CAPD was started. At the present time, the patient is doing well on CAPD. To our knowledge, there are no clear indications regarding initiation of peritoneal dialysis after nephrectomy. The retroperitoneoscopic approach for nephrectomy allows for initiation of peritoneal dialysis after nephrectomy within a relative short postoperative period.

Voided stain on paper method for analysis of mouse urination.

AIMS: To evaluate the usefulness of a quantification method using filter paper for analyzing minute voided urine of the mouse. METHODS: Voided stain on paper (VSOP) method; the correlation between area of stained spot on a filter paper and amount of applied liquid was calculated. Voiding behavior of the mice was analyzed by placing the animal above the same filter paper and recording voided time and area over 2 hr. The usefulness of the VSOP method was tested in analysis of the voiding behavior of five female 7-week-old ddY mice treated with cyclophosphamide (CPM, 150 mg/kg, intraperitoneally) and five control ones, in comparison with the histology of CPM-induced cystitis. Further, the voided volume of male and female ddY mouse ranging from 2 to 13 weeks was assessed. RESULTS: There was a linear correlation between liquid volume and stained area on the filter paper (y = 16.472x - 22.411, R(2) = 0.9981). Between control mice and those with histologically proven CPM cystitis, there was a significant difference in voided volume (362.7 +/- 51.9 and 127.8 +/- 100.0 microl, < 0.001) and voiding interval (10.30 +/- 3.10 and 4.47 +/- 1.70 min, < 0.001). Voided volume of ddY mice was quantifiable from as early as 2-week old, increased along with their growth and correlated well with their body weight [(voided volume: microl) = 10.8 x (body weight: g) + 32, R(2) = 0.762]. CONCLUSIONS: The VSOP method is a useful tool for evaluating voiding behavior of the mouse, including those with small bladder capacity.

[The sensitivity and clinical implications of periodical bladder biopsy following transurethral resection of superficial bladder transitional cell carcinoma].

The role of the periodical bladder biopsy after transurethral resection (TUR-Bt) of superficial bladder cancer (sBT) was evaluated. Sixty-four patients (85 TURs) with sBT who underwent TUR-Bt between 1993 and 1998 were divided into 14 (22 TURs) who had carcinoma in situ (CIS) at the first TUR (group A), and 50 (64 TURs) who had papillary tumors without concomitant CIS (group B). Post-TUR intravesical instillation was performed with bacillus Calmette-Guerin for the majority of group A, and mitomycin C for the majority of group B. The first biopsy was performed at 3 months postoperatively, and the second biopsy was done at 8 to 12 months postoperatively. The mean observation time was 4 years and 6 months. Residual cancer was detected in 7 out of 34 biopsies (20.6%) in group A, and 19 out of 94 (20.2%) in group B. Every residual lesion in group A was CIS with negative cytology. In group B, with exclusion of 11 recurrent papillary tumors, the detection rate was only 8/83 (9.6%). In both groups, even in the cases with no sign of disease in biopsies, the recurrence immediately after the termination of the biopsy protocol was common. The progression of the cancer was more frequent in group A (4 patients), than in group B (2 patients) (p < 0.01, log-rank test), and no case in group B showed local progression. The periodical biopsy may have a certain, but limited advantage over conventional examinations. A less invasive and more sensitive method in awaited.

Multivariate analysis of prognostic determinants after surgery for renal cell carcinoma at Himeji National Hospital.

A clinico-pathological study was performed retrospectively on 62 patients who underwent surgery for renal cell carcinoma between January 1992 and October 1998 at Himeji National Hospital to clarify the prognostic determinants for survival. The median follow-up period was 32 months and the cause-specific survival rates at 1, 3 and 5 years were 86.7, 81.3, 81.3%, respectively. Of the 62 patients, 11 (17.7%) patients died of renal cell carcinoma and 2 (3.2%) patients died of unrelated causes. Of the variables related to survival, presenting symptoms, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), alkaline phosphatase (ALP), tumor size, pathological tumor grade, infiltration pattern, pathological tumor stage, N classification and M classification were significant risk factors for survival by univariate analysis. However, ALP, N classification and M classification were significant for survival as determined by the step-wise procedure and M classification was the most significant factor according to Cox's proportional hazard model analysis.

[Clinical review of 39 cases with ectopic ureteroceles].

BACKGROUND: There are many controversies surrounding the management of ectopic ureteroceles (EUC). The aim of this study is to review our cases with EUCs and to show our policy of choice of treatments of EUCs. METHODS: The medical records of 39 patients with EUCs treated at Kobe. Children's Hospital from 1978 to 1998 were reviewed retrospectively. Patients' age, affected site, presentation, treatment, and postoperative course were recorded. RESULTS: The age at presentation ranged from 0 month to 13 years (mean; 6 years). The left EUCs were found in 15 patients, the right in 17 patients, and the bilateral in 7 patients. The EUCs with duplicated system of the kidney were involved in 35 cases (42 kidneys) and single system in 4 cases (4 kidneys). The most common mode of presentation was urinary tract infection (n = 24) followed by abdominal distention (n = 6) and fetal ultrasonography (n = 6). One patient presented with incontinence and in two patients EUCs were discovered incidentaly. Thirty-five cases (42 kidneys) were followed up over six months. In these cases diversion including nephrostomy and ureterostomy was performed in 5 kidneys, heminephrectomy and/or excision of the EUC and ureteral reimplantation in 8 kidneys, nephrectomy in 3 kidneys, pyeloureterostomy in 2 kidneys, excision of the EUC and ureteral reimplantation in 10 kidneys, and transurethral incision (TUI) of the EUC in 14 kidneys. After these treatments the second surgery was totally required in 15 kidneys(36%) including 7 kidneys in which TUI was performed. Furthermore, in two kidneys the third operation was performed. CONCLUSIONS: Reoperation was required in about one-third of patients with ectopic ureteroceles. It is easy to perform TUI, however the rate to reoperation is high.

Geriatric ureteropelvic junction obstruction: the possible role of an arteriosclerotic lower pole branch of renal artery: report of two cases.

An 83-year-old woman presented with left flank pain and high grade fever. After left ureteral catheterization and intensive chemotherapy with hemoperfusion, surgical exploration revealed the lower pole branches of the renal vessels were obstructing the ureteropelvic junction (UPJ), and dissection of the vessels released the obstruction. An 82-year-old man presented with right flank pain. Angiography demonstrated UPJ obstruction caused by the lower pole branch of the renal artery. Arterial dissection with dismembered pyeloplasty resulted in improvement of obstruction. In both cases, the patients had a long history of hypertension with mild to severe arteriosclerosis. Arteriosclerosis associated with fixation of the UPJ, may be one of the important factors leading to progressive hydronephrosis in geriatric patients.

[Intravesical bacillus Calmette-Guerin instillation for patients over 80 years old].

To study the efficacy and the safety of intravesical bacillus Calmette-Guerin (BCG) therapy for very elderly patients with superficial bladder cancer, we retrospectively compared patients over 80 years old who had received BCG therapy at our department between 1991 and 1996 (Group A; 10 patients 11 courses), with those below 80 years old (Group B, 17 patients 18 courses). In these patients, skin test reactivity to purified protein derivative showed a significant negative correlation with age (p = 0.016). No irreversible complications were observed in any patient. Persistence of acid-fast bacilli for more than one month after the termination of the course was observed in two patients in group A, and one in group B. A comparison of the cases undergoing eradicational BCG therapy in the two groups, grade 2 transitional cell carcinoma (TCC) was significantly more predominant than grade 3 TCC in group A (p = 0.004). (None of the tumors in group A were of grade 3) The disease-free rate was significantly lower in group A (p < 0.05), but 5 of the 10 patients in this group were finally disease-free. From these results, we conclude that intravesical BCG instillation therapy can be performed in patients over 80 years old, although a relatively lower disease-free rate is expected and special attention should be taken with regard to persistent BCG infection. The lower disease-free rate could be attributable to either diminished cellular immunity or a difference in tumor grade, although a definite conclusion could not be obtained here.

[Combination therapy of daily intramuscular injection of interferon-alpha and oral administration of fluorouracil for advanced renal cell carcinoma].

BACKGROUND: To achieve optimum drug delivery of Interferon-alpha in treatment of renal cell carcinoma, a regimen consisting of its daily intramuscular administration, in combination with oral fluorouracil, was designed and carried out. Its efficacy is examined retrospectively. METHODS: In our department 7 patients with disseminated renal cell carcinoma were treated with daily intramuscular injection of interferon-alpha (3 x 10(6) IU) and daily oral administration of fluorouracil. All patient was nehprectomized before initiation of the regimen. RESULTS: Two patients achieved complete, and three patients achieved partial response radiographically (Overall response rate 71%). Metastatic sites of responders were lung (4) and pleura (2). The time required until response was 3.9 (median 5.4) months. In two responders, new lesions appeared in other organs despite durable response in initial pulmonary metastatic sites. There were two no-responders, one patient is alive with stable disease and the other patient died for progression of the disease. In all, two patients died of disease, one died for other cause, one surviving without evidence of disease, and three are surviving with disease. No significant side effect was noted in these seven patients. CONCLUSIONS: This regimen can be carried out on outpatient basis and considerable response can be expected for pulmonary and pleural lesions.

Long-term renal function in on-heart-beating donor kidney transplantation: a single-center experience.

BACKGROUND: One of the most serious problems facing major transplant programs is the severe shortage of organs. Expansion of the donor pool to include nontraditional donors, such as non-heart-beating donors (NHBDs), would considerably expand the availability of organs. METHODS: Between 1983 and 1996, we performed a total of 125 non-heart-beating cadaveric renal transplantations under cyclosporine-based or tacrolimus-based immunosuppression. Thirty-nine recipients were females and 86 were males. Total ischemic time (TIT) and warm ischemic time (WIT) were an average of 761+/-347 min (322-2027 min) and 7.4+/-13.1 min (0-45 min), respectively. RESULTS: Of the 125 transplanted kidneys from NHBDs, 98 (78.4%) developed delayed graft function (DGF), which lasted a mean of 16+/-21 days (range 3-37 days). One hundred and eight patients (86.4%) were off dialysis by the time of discharge. Of the 125 grafts, 11 (8.8%) were primary nonfunction. The average of the nadir of serum creatinine levels, which was evaluated using 108 patients who were off dialysis by the time of discharge, was 1.4+/-0.5 mg/dl. The lowest creatinine levels (nadir) were under 2.0 mg/dl in 98 (78.4%) of the 125 patients. Acute rejection occurred in 64 (51.2%) of the 125 recipients. Patient survival rates were 90% at 5 years and 88% at 10 years. Graft survival rates were 65% at 5 years and 46% at 10 years. We tried to find the risk factors that affected graft survival. We examined the various possible risk factors, including harvesting condition (controlled versus uncontrolled), HLA-AB mismatches, HLA-DR mismatches, graft weight, donor age and sex, recipient age and sex, posttransplant DGF, acute rejection, WIT, and TIT. However, no significant risk factor was identified except acute rejection. We tried to discover the risk factors that caused primary nonfunction. Possible risk factors, including donor age, TIT, WIT, graft weight, and harvesting condition were compared, but no significant risk factor was identified. Long-term renal function was evaluated by serum creatinine levels. Serum creatinine levels at 1, 5, and 10 years were 1.76+/-0.7 mg/dl, 1.7+/-0.96 mg/dl, and 1.53-/+0.6 mg/dl, respectively. CONCLUSIONS: In conclusion, our data demonstrated that the procurement of kidneys from NHBDs leads to acceptable long-term graft survival and renal function, despite a high incidence of DGF.