Graft outcomes of living donor renal transplantations in elderly recipients.

BACKGROUND: Despite the ever-lengthening renal transplant waiting lists, without more donors, living donors serve as a treatment option for patients on dialysis. In the past, patients of advanced age were not considered to be candidates for living donor renal transplantation. Therefore, this study sought to analyze whether older age affects the outcome of living donor renal transplantation. METHODS: A total of 527 primary living donor renal transplantations were performed between January 1, 1995 and January 1, 2006. The subjects were divided into 2 subgroups based on patient age at the time of transplantation. The elder group included all recipients at least 60 years vs the control group of younger patients. RESULTS: Significant differences were observed in readmission rate (elder group, 44%; young group, 31.33%; P = .031) and patient survival rate (P < .001). No significant difference was noted in graft survival rate (P = .201), acute rejection rate (elder group, 10.6%; young group, 13.3%; P = .7), serum creatinine level, or length of stay (elder group, 8.51 days; young group, 6.31 days; P = .083). CONCLUSIONS: Our results confirm that elder patients may benefit from living donor renal transplantation.

Laparoscopic radical nephrectomy in 100 patients: a single center experience from the United States.

BACKGROUND: The objective of the current study was to report a single-surgeon, single-center experience with 100 consecutive laparoscopic radical nephrectomies with intact specimen extraction, with the aim of evaluating the oncologic adequacy of the laparoscopic dissection from a technical standpoint and various parameters including the learning curve. METHODS: Of the 140 laparoscopic radical nephrectomies performed at the study institution since August 1997, the initial 100 are evaluated herein. To evaluate the technical oncologic adequacy, comparison was made with 40 contemporary open radical nephrectomy specimens with regard to detailed radiologic (computed tomography scan) and pathologic data. RESULTS: In the 100 patients studied (with a mean tumor size of 5.1 cm), the mean surgical time was 2.8 hours, the blood loss was 212 mL, the specimen weight was 554.3 g, and the hospital stay was 1.6 days. Complications occurred in 14 patients (14%) and were major in 3 (3%) and minor in 11 (11%). Two patients (2%) were converted to open surgery. There was no perioperative mortality. Over a mean follow-up of 16.1 months, there was no local or port site recurrence reported; 2 patients developed metastatic disease with 1 death occurring at 11 months. When evaluating the learning curve in the initial 50 versus the second 50 patients, a shorter surgical time (P = 0.02) appeared to be the only significant variable. On multivariate analyses, the only variables found to impact on surgical time were specimen weight (P < 0.001) and chronologic time period of surgery (P = 0.05). All laparoscopic specimens were extracted intact; surgical margins were negative for tumor in all 100 patients. All detailed radiologic and histopathologic parameters evaluated were nearly identical between the laparoscopic and open surgery groups. CONCLUSIONS: Laparoscopic radical nephrectomy with intact specimen extraction currently is a routine, effective, and efficacious treatment option for patients with T1-T3aN0M0 renal tumors. Although no long-term data were available as of last follow-up, the negative surgical margins achieved routinely in the current series provide encouraging surrogate evidence of the technical efficacy of laparoscopy from an oncologic standpoint. As such, at the study institution, laparoscopic radical nephrectomy with intact specimen extraction currently is the standard-of-care for patients with T1-3aN0M0 renal tumors measuring < or = 10-12 cm in size.

Renal outcome 25 years after donor nephrectomy.

PURPOSE: The extended outcome after kidney donation has been a particular concern ever since the recognition of hyperfiltration injury. Few published reports have examined donor renal outcome after 20 years or greater. Kidney transplantation has been performed at the Cleveland Clinic Foundation since 1963, at which there is extensive experience with live donor transplantation. We assess the impact of donor nephrectomy on renal function, urinary protein excretion and development of hypertension postoperatively to examine whether renal deterioration occurs with followup after 20 years or greater. MATERIALS AND METHODS: From 1963 to 1975, 180 live donor nephrectomies were performed at the Cleveland Clinic. We attempted to contact all patients to request participation in our study. Those 70 patients who agreed to participate in the study were mailed a package containing a 24-hour urine container (for assessment of creatinine, and total protein and albumin), a vial for blood collection (for assessment of serum creatinine) and a medical questionnaire. All specimens were returned to and processed by the Cleveland Clinic medical laboratories. Blood pressure was taken and recorded by a local physician. A 24-hour creatinine clearance and the Cockcroft-Gault formula were used to estimate renal function, and values were compared with an age adjusted glomerular filtration rate for a solitary kidney. RESULTS: Mean patient followup was 25 years. The 24-hour urinary creatinine clearance decreased to 72% of the value before donation. For the entire study cohort serum creatinine and systolic blood pressure after donation were significantly increased compared with values before, although still in the normal range. The overall incidence of hypertension was comparable to that expected in the age matched general population. There was no gender or age difference (younger or older than 50 years) for 24-hour urinary creatinine clearance, or change in serum creatinine before or after donation. Urinary protein and albumin excretion after donation was significantly higher in males compared with females. There were 13 (19%) subjects who had a 24-hour urinary protein excretion that was greater than 0.15 gm./24 hours, 5 (7%) of whom had greater than 0.8. No gender difference was noted in blood pressure, and there were no significant changes in diastolic pressure based on gender or age. CONCLUSIONS: Overall, renal function is well preserved with a mean followup of 25 years after donor nephrectomy. Males had significantly higher protein and albumin excretion than females but no other clinically significant differences in renal function, blood pressure or proteinuria were noted between them or at age of donation. Proteinuria increases with marginal significance but appears to be of no clinical consequence in most patients. Patients with mild or borderline proteinuria before donation may represent a subgroup at particular risk for the development of significant proteinuria 20 years or greater after donation. The overall incidence of proteinuria in our study is in the range of previously reported values after donor nephrectomy.

The T cell death knell: immune-mediated tumor death in renal cell carcinoma.

The antitumor effect of T cells is executed either through CD95 or Perforin (PFN)/Granzyme B (GrB) pathways. Induction of apoptosis by either mode requires activation of caspase family members. However, recent studies have suggested that cell death can proceed in the absence of caspase induction and apoptotic events. We investigated the contribution of CD95 and PFN/GrB-mediated cytotoxicity to apoptotic and necrotic mechanisms of cell death in human renal cell carcinoma. Although freshly isolated and cultured tumors expressed CD95 on their surface, they were resistant to CD95-mediated apoptosis. CD95 resistance coincided with decreased levels of FADD protein and diminished caspase-3-like activity. In contrast, we demonstrated that tumor cell death mediated by PFN/GrB can be achieved in the absence of functional caspase activity and is accompanied by a dramatic accumulation of nonapoptotic necrotic cells.

Laparoscopic radical nephrectomy.

Laparoscopic radical nephrectomy has gained in popularity as an accepted treatment modality for localized renal cell carcinoma at many centers worldwide. Laparoscopic radical nephrectomy may be performed via a transperitoneal or retroperitoneal approach. Mostly, the transperitoneal approach is used. Current indications for laparoscopic radical nephrectomy include patients with T(1)-T(3a)N(0)M(0) renal tumors. Herein, transperitoneal as well as retroperitoneal laparoscopic approaches are described. Surgical outcomes and complications from published series are reviewed with comparison to open surgery. Special related concerns as oncologic principles, organ retrieval, lymphadenectomy, and concomitant adrenalectomy are addressed. In conclusion, laparoscopic radical nephrectomy is now established with considerable advantages; decreased postoperative morbidity, decreased analgesic requirements, improved cosmesis, shorter hospital stay and convalescence. Although no long-term follow-up is available, short and intermediate follow-up results confirm the effectiveness of laparoscopic radical nephrectomy.

Nephron sparing surgery for renal tumors: indications, techniques and outcomes.

PURPOSE: A contemporary review of the indications, techniques and outcomes is presented for nephron sparing approaches to solid renal masses, emphasizing their role for the treatment of renal cell carcinoma. We also reviewed the evolving role of minimally invasive forms of parenchymal sparing renal surgery. MATERIALS AND METHODS: MEDLINE and CANCERLIT computerized literature searches, and manual bibliographic reviews were performed to identify published peer reviewed articles pertaining to nephron sparing surgery or partial nephrectomy from 1980 to 2000. Pertinent articles were collated and reviewed. RESULTS: Nephron sparing surgery is increasingly being used to treat patients with solid renal lesions. The technical success rate of nephron sparing surgery is excellent, and operative morbidity and mortality are low. For renal cell carcinoma long-term cancer-free survival is comparable to that after radical nephrectomy, particularly for low stage disease. The overall incidence of local recurrence is low at 0% to 10%. For tumors 4 cm. or less local recurrence rates are even less at 0% to 3%. The risk of local recurrence depends primarily on the initial local pathological tumor stage. The reported incidence of multifocal renal cell carcinoma is approximately 15% and it also depends on tumor size, histology and stage. The risk of multifocal disease is low at less than 5% when the maximal diameter of the primary tumor is 4 cm. or less. Recent advances in renal imaging limit the radiographic evaluation necessary when planning complex nephron sparing approaches. Three-dimensional, volume rendered computerized tomography integrates all of the necessary information previously obtained by conventional computerized tomography, angiography, venography and pyelography into a single preoperative test, allowing better operative planning with maximal preservation of unaffected parenchyma in the remnant kidney. Minimally invasive modalities of tumor resection or destruction should be reserved for highly select patients and await improvements in technology, standardization of technique and long-term outcomes data before they may be completely integrated options. CONCLUSIONS: Nephron sparing surgery provides effective therapy for patients in whom preservation of renal function is a relevant clinical consideration. The importance of meticulous operative technique for achieving acceptable oncological and functional outcomes is emphasized. Accumulating data in appropriately select patients suggest a long-term functional advantage gained by the maximal preservation of unaffected renal parenchyma without sacrificing cancer control.

Phase I and II trials of subcutaneously administered rIL-2, interferon alfa-2a, and fluorouracil in patients with metastatic renal carcinoma.

PURPOSE: A phase I followed by a phase II trial utilizing rIL-2, IFN alpha, and 5-FU were conducted in patients with unresectable and/or metastatic renal cell carcinoma. METHODS: Treatment consisted of: rIL-2 at 5.0 x 10(6) IU/m2 SQ on days 1-5 for 4 weeks, rHUIFN alpha-2a at 5.0 x 10(6) U/m2 SQ on days 1, 3, and 5 for 4 weeks, and 5-FU by IV bolus on days 1-5 during week 1. In the phase I study, patients were treated at varying doses of 5-FU: I-none, II-250 mg/m2, III-300, and IV 375. A phase II trial was then conducted utilizing the same schedule and maximum tolerated dose (MTD) for 5-FU. RESULTS: Twenty patients were entered into the phase I trial. Dose-limiting toxicity included grade III nausea and vomiting, and one sudden cardiac death. The MTD for 5-FU was determined to be 300 mg/m2. In the phase II trial, a median of two cycles of therapy was administered to 25 evaluable patients. Toxicity was moderate and consisted primarily of fevers, chills, fatigue, nausea/vomiting, and anorexia. Grade IV thrombocytopenia, consistent with ITP, developed in one patient each on the phase I and phase II trial. Seven partial responses were seen among 25 patients treated in the phase II trial for a 28% (CI 12-49%) response rate. CONCLUSIONS: The addition of 5-FU to rIL-2 and rHuIFN alpha-2a appears to increase the toxicity of this therapy. Randomized trials will be required to determine if efficacy is enhanced.

Thoracoscopic transdiaphragmatic adrenalectomy: the initial experience.

PURPOSE: We introduce the technique of thoracoscopic transdiaphragmatic adrenalectomy. MATERIALS AND METHODS: Initially in 4 human cadavers bilateral thoracoscopic nephrectomy was performed to develop the technique of diaphragmatic incision, retroperitoneal control of renal artery and vein, circumferential mobilization of the kidney and adrenal gland, and suture repair of the diaphragm. Subsequently, 3 select patients underwent thoracoscopic transdiaphragmatic adrenalectomy (2 right side and 1 left side). All 3 patients had significant prior abdominal scarring after either partial or total radical nephrectomy, thereby precluding efficient transabdominal laparoscopic access to the adrenal gland. After double lumen endotracheal intubation, a 4 port transthoracic approach without pneumo-insufflation was performed with the patient in the prone position. The diaphragm was incised under real-time laparoscopic ultrasound guidance. The adrenal gland was visualized high in the retroperitoneum, the vasculature controlled, and the specimen entrapped and extracted intact through a thoracic port site. The diaphragm was suture repaired with freehand laparoscopic suturing and intracorporeal knot tying. A chest tube was inserted in the initial 2 patients. RESULTS: There were no intraoperative or postoperative complications. Operating time was 4.5, 6.5 and 2.5 hours, and blood loss was 150, 500 and 50 cc, respectively. Mean narcotic analgesic requirement was 27 mg. morphine sulfate equivalent. Hospital stay was 2 days for all 3 patients. Pathology revealed metastatic renal cell carcinoma in 2 patients and myelolipoma in 1. CONCLUSIONS: In select patients with significant concomitant intraperitoneal and retroperitoneal scarring from prior major abdominal or renal surgery laparoscopic adrenalectomy can be safely performed with the transthoracic transdiaphragmatic approach. We present our initial experience.

Renal neoplasms in adult survivors of childhood Wilms tumor.

PURPOSE: Survivors of childhood Wilms tumor have been followed by large collaborative studies for approximately 31 years. In this time a number of second malignant neoplasms have been documented in these Wilms tumor survivors and they are at higher risk for such development compared with the general population. To our knowledge no renal neoplasms have been previously reported in patients successfully treated for Wilms tumor in childhood. MATERIALS AND METHODS: We reviewed the cases of 4 adults in whom Wilms tumor was treated in childhood by radical nephrectomy and adjuvant therapy and who presented to our institution with complex cystic or solid renal masses in the contralateral kidney. Parameters, including patient age at Wilms tumor diagnosis, Wilms tumor treatment modalities, age at second malignant neoplasm presentation and resected renal lesion pathology were outlined. A thorough literature review was performed to identify the development of renal malignancies as second malignant neoplasms in survivors of Wilms tumor in childhood. RESULTS: The International Society of Pediatric Oncology and National Wilms Tumor Study have followed patients treated for Wilms tumor for no greater than 31 years. Renal neoplasms, including 2 renal cell carcinomas, 1 oncocytoma and 1 atypical cyst, in the solitary remaining kidney of relatively young adults 34 to 50 years old who were treated for Wilms tumor greater than 31 years ago were successfully treated with partial nephrectomy at our institution. Neither the International Society of Pediatric Oncology nor National Wilms Tumor Study has identified renal cell carcinoma as a second malignant neoplasm in patients successfully treated for Wilms tumor. CONCLUSIONS: Our experience suggests that relatively young adults with a history of childhood treatment for Wilms tumor may be at increased risk for renal neoplasms at ages not yet achieved by those enrolled in large multicenter trials. This possibility should be considered when planning the long-term followup of these patients. The potential to develop this type of second malignant neoplasm again raises the clinical issue of performing a primary nephron sparing procedure in children presenting with Wilms tumor.

The Cleveland Clinic experience with papillary (chromophil) renal cell carcinoma: clinical outcome with histopathological correlation.

OBJECTIVES: A review of the Cleveland Clinic experience with papillary (chromophil) renal cell carcinoma (PRCC) is performed with emphasis on correlation of histopathologic features with prognosis. METHODS: Retrospective chart review was performed on 99 patients (85 male, 14 female) identified as having papillary renal cell carcinoma. All patients underwent renal surgery (partial or radical nephrectomy) at The Cleveland Clinic Foundation. Review of archival pathologic material was performed on all patients, and the reviewing pathologist was blinded to previous pathology reports. The reviewing pathologist evaluated tumor size, nuclear grade, TNM stage, tumor vascularity, multifocality, degree of papillary histology, macrophage infiltration, and presence of adenomata. Disease free survival data were generated via Kaplan-Meier estimates. Statistical significance was evaluated by the log rank test. RESULTS: Ninety-four (81 male, 13 female) of the original 99 patients were included in the study. Mean follow-up was 28.25 months. Most tumors were organ-confined (T1=24, T2=53, T3a=7, T3b=3, T3c=6). Histologically, most of the tumors were pure papillary histology (54.3%). Multifocality was present in 30 patients (31.9%). Overall cancer-specific survival (CSS) was 93.7% at 1 year, 89.9% at 2 years, and 78.6% at 5 years. Age (P=0.48), sex (P=0.41), tumor size (P=0.15), presence of adenomata (P=0.53), degree of pure papillary histology (P=0.73) and multifocality (P=0.93) did not significantly affect survival. Grade did not significantly affect survival (P=0.67). Low grade (Gr 1 or 2) lesions had a 5 year CSS of 75.7%, and high grade lesions had a 5 year CSS of 83.8%. Stage significantly impacted survival (P=0.017). T1-2 lesions had a 5 year CSS of 82.3%, T3a lesions 100%, T3b/T3c 66.7%. Patients with N1-2 disease (N=5) had 1 year CSS of 33.3%, and 2 year CSS of 0%. Extranodal metastases were associated with poor prognosis; 5 year CSS was 12.5% in M1 patients. CONCLUSIONS: Papillary renal cell carcinoma has a propensity to be both low grade and low stage with a less aggressive clinical course. The strongest predictor for cancer-specific survival is tumor stage. Due to the high incidence of multifocality, nephron-sparing surgery is often necessary. It is suggested that genetic differences between PRCC and other RCC variants may be exploited in the future for surgical decision making.

Tumor-induced sensitivity to apoptosis in T cells from patients with renal cell carcinoma: role of nuclear factor-kappaB suppression.

Antitumor immunity fails to adequately develop in many cancer patients, including those with renal cell carcinoma (RCC). A number of different mechanisms have been proposed to explain the immune dysfunction observed in cancer patient T cells. Here we show that T cells from RCC patients display increased sensitivity to apoptosis. Tumor-infiltrating lymphocytes (TILs) display the most profound sensitivity, because 10-15% of those cells are apoptotic when assessed by terminal deoxynucleotidyltransferase-mediated nick end labeling in situ, and the number of apoptotic TILs further increases after 24 h of culture. Peripheral blood T cells from RCC patients are not directly apoptotic, although T lymphocytes derived from 40% of those individuals undergo activation-induced cell death (AICD) upon in vitro stimulation with phorbol myristate acetate and ionomycin. This is in contrast to T cells from normal individuals, which are resistant to AICD. TILs and peripheral blood T cells from RCC patients also exhibit impaired activation of the transcription factor, nuclear factor (NF)-kappaB. Additional findings presented here indicate that the heightened sensitivity of patient T cells to apoptosis may be tumor induced, because supernatants from RCC explants sensitize, and in some instances directly induce, normal T cells to apoptosis. These same supernatants also inhibit NF-kappaB activation. RCC-derived gangliosides may represent one soluble tumor product capable of sensitizing T cells to apoptosis. Pretreatment with neuraminidase, but not proteinase K, abrogated the suppressive effects of tumor supernatants on both NF-kappaB activation and apoptosis. Additionally, gangliosides isolated from tumor supernatants not only inhibited NF-kappaB activation but also sensitized T cells to AICD. These findings demonstrate that tumor-derived soluble products, including gangliosides, may contribute to the immune dysfunction of T cells by altering their sensitivity to apoptosis.

Impaired alpha-interferon signaling in transitional cell carcinoma: lack of p48 expression in 5637 cells.

The limited success of IFN-alpha therapy for clinical treatment of transitional cell carcinoma (TCC) has prompted us to investigate the responsiveness of TCC lines to IFN-alpha. The response to IFN-alpha in terms of 561 gene induction, an IFN-stimulated response element-containing IFN-alpha/beta-inducible gene, and IFN-stimulated gene factor 3 (ISGF3) formation was normal in primary human urothelial cells. We tested the antiproliferative effects of IFN-alpha in three TCC lines as a measure of IFN-alpha responsiveness, and variable patterns of growth inhibition were observed in three TCC lines. More than 90% growth inhibition was noted in TCCSUP cells, whereas only 40% and 10% inhibition by IFN-alpha was observed in 5637 and HT1197 cells, respectively. IFN-alpha treatment formed extremely low levels of ISGF3 in electrophoretic mobility shift assays in these later two relatively insensitive cells. In addition, expression of the 561 gene was significantly reduced in these two TCC lines by Northern blots. We have further identified a low expression level of Tyk2 in HT1197 cells compared with two other TCCs. This suggests that an extremely low ISGF3 level after IFN-alpha treatment may be due to low Tyk2 expression or other unidentified defects. In 5637 cells, p48 protein expression was undetectable. This undetectable p48 expression is not due to a deletion in the coding region because the correct size protein is detected following IFN-gamma treatment. Consequently, the ISGF3 complex formation and 561 gene induction were restored by IFN-gamma pretreatment plus IFN-alpha treatment. Introduction of p48 expressing plasmid into 5637 cells was sufficient to form the ISGF3 complex by IFN-alpha treatment, suggesting the defect lies in the expression of p48 protein in 5637 cells. Detailed mechanistic understanding of the action of IFNs in bladder cancer cell lines may explain the abrogated therapeutic response of IFN-alpha in the clinical treatment of TCCs.

Quality of life and psychological adaptation after surgical treatment for localized renal cell carcinoma: impact of the amount of remaining renal tissue.

OBJECTIVES: To analyze the quality of life and psychological adjustment after surgical therapy for localized renal cell carcinoma. METHODS: Postal questionnaires including measures of quality of life (SF-36) and the impact of the stress of cancer (Impact of Events Scale) were completed by 97 patients who had undergone radical or partial nephrectomy for localized renal cell carcinoma. Data were analyzed for the group as a whole and comparing the partial nephrectomy and radical nephrectomy groups. The variables examined included the impact of the type of partial nephrectomy (elective versus mandatory) and the amount of self-reported renal tissue remaining. RESULTS: The quality of life for the group as a whole was good, with no significant differences between the sample and U.S. norms for an age and sex-matched community sample on both the mental and physical health composite scores. Having undergone a partial versus a radical nephrectomy did not influence the patients' overall quality of life. Multiple linear regression modeling demonstrated that having more remaining renal parenchyma was an independent predictor of better self-reported physical health on the SF-36 (P <0.001). The entire sample had low mean scores on both avoidance and intrusion on the Impact of Events Scale, suggesting a lack of daily anxiety about cancer. Multiple linear regression modeling showed that patients who reported having more remaining renal parenchyma had lower intrusion and avoidance scores (P = 0.002 and 0.01, respectively). Multiple logistic regression modeling also demonstrated that the patients' perception of their remaining renal parenchyma was associated with less concern about cancer recurrence (P = 0.018) and less impact of cancer on patients' overall health (P <0.001). CONCLUSIONS: Most survivors of localized kidney cancer have normal physical and mental health regardless of the type of nephrectomy performed. The quality of life is better for patients with more renal parenchyma remaining after surgery for localized renal cell carcinoma.

Giant renal oncocytoma.

We report the largest renal oncocytoma excised at the initial presentation and the second largest renal oncocytoma in published reports. Despite a tendency for renal oncocytomas to be relatively small and asymptomatic compared with renal cell carcinomas, these lesions cannot be reliably differentiated preoperatively. The variable nature of presentation and overlap of radiographic characteristics between these lesions complicates their clinical differentiation. The present case illustrates the difficulty in the preoperative diagnosis of even very large, enhancing renal masses and reinforces the inclusion of renal oncocytoma in the differential diagnosis of these lesions.