This Month in Investigative Urology

Article Outline

• Early Detection of Renal Ischemia by In Situ Microdialysis
• Na,K-Adenosine Triphosphatase α1-Subunit Predicts Renal Cancer Survival
• Ex Vivo Whole Embryonic Kidney Culture
• Combined Antiangiogenic Therapy for Renal Cell Carcinoma
• Distinctive Expression of ErbB Family Receptors and Aggressive Bladder Cancer
• Copyright

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Early Detection of Renal Ischemia by In Situ Microdialysis 

Acute vascular thrombosis of the renal artery or vein is a feared and devastating complication after renal operations, especially transplantation. Keller et al (page 371) from Aarhus, Denmark evaluated microdialysis as a possible new tool for the rapid and reliable detection of renal ischemia in a porcine model. A total of 20 anesthetized pigs were randomized to experiments on the left or right kidney, and into 3 groups of arterial ischemia, venous ischemia and controls. One microdialysis catheter was inserted superficially in the renal cortex and 1 was placed outside on the renal capsule. The contralateral kidney was removed. After 2 hours of baseline measurements ischemia was introduced by clamping the renal artery or vein in the first 2 groups. Microdialysis samples were taken every 30 minutes during baseline and the following 5 hours. At 30 minutes after the introduction of arterial or venous ischemia there was a significantly increased mean change from baseline of glutamate, glycerol and lactate in the cortex and of glutamate extracapsularly. The mean change from baseline of glucose in the cortex decreased significantly 60 minutes after venous ischemia and 90 minutes after arterial ischemia. In controls these metabolites did not change significantly from baseline with time. Microdialysis from just outside the renal capsule is a reliable tool for the early detection of acute renal ischemia, and may be used to detect acute vascular complications in the first days after renal transplantation.

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Na,K-Adenosine Triphosphatase α₁-Subunit Predicts Renal Cancer Survival 

Na,K-adenosine triphosphatase (ATPase), composed of a catalytic α-subunit and a regulatory β-subunit, generates an electrochemical gradient across the plasma membrane. Previous studies demonstrated altered Na,K-ATPase subunit expression in renal clear cell carcinoma and an association of subunit levels with the prediction of recurrent bladder cancer. Seligson et al (page 338) from Los Angeles, California determined the clinical association of protein expression patterns of Na,K-ATPase α₁ and β₁-subunits in renal clear cell carcinoma using tissue microarrays with linked clinicopathological data. The protein expression of Na,K-ATPase α₁ and β₁-subunits was investigated by immunohistochemistry in 342 patients with renal clear cell carcinoma treated with radical nephrectomy, and clinical outcomes studies were performed on 317 patients. The α₁-subunit was found to be a significant and independent predictor of disease specific death from renal clear cell carcinoma on multivariate Cox proportional hazards analysis that included established prognostic factors Eastern Cooperative Oncology Group performance status, pT status, metastasis status and tumor grade. Significance was found when examining all patients with clear cell renal cell carcinoma as well as patient substrata with low or high grade tumors and localized or metastatic disease, suggesting that the Na,K-ATPase α₁-subunit could be used as a new prognosticator for disease specific death from renal clear cell carcinoma.

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Ex Vivo Whole Embryonic Kidney Culture 

Whole metanephric organ culture represents a novel investigatory approach with potential applications in many aspects of research in kidney regeneration and transplantation. Giuliani et al (page 365) from Los Angeles, California report on the current status of embryonic kidney culture, and evaluated and developed a new durable 3-dimensional organ culture system. Metanephric kidneys were microdissected from embryos of timed pregnant WT C57 mice on days 12 to 16 of gestation. Novel perfusion channels were created in the harvested embryonic kidneys before placing them in culture. Embryonic kidneys were placed on a Transwell® membrane and cultured in base medium. Histological and immunocytochemical analysis was performed to evaluate for signs of necrosis, and the structural integrity and functionality of organs during culture. The authors confirmed histologically that the organ culture system was capable of maintaining normal kidney structures significantly longer (a mean of 10 days) than previously reported standard protocols. Condensation and aggregation of the metanephric mesenchyma at the tips of the ureteral bud were observed, including the formation of well developed nephrons and glomeruli without evidence of necrosis. Organ maturation occurred in a developmentally appropriate centrifugal pattern and the expression of key regulatory factors was demonstrated. This system may represent an uncomplicated method for in vitro kidney culture.

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Combined Antiangiogenic Therapy for Renal Cell Carcinoma 

Similar to cytotoxic drugs, combination of antiangiogenic factors may lead to an improved treatment response and minimize resistance by targeting different pathways. Bartsch et al (page 326) from Ulm, Germany investigated the effects of a combination of endogenous angiogenic inhibitors using endostatin, soluble neuropilin-1 and thrombospondin-2 in a renal cell carcinoma model. Microencapsulated porcine aortic endothelial cells producing endostatin, soluble neuropilin-1 or thrombospondin-2 were tested in vitro and in a murine renal cell carcinoma alone or as a combination of all 3 factors. Renal carcinoma cells were applied subcutaneously for local therapy or injected intravenously in a metastatic model. Factors released from microbeads inhibited endothelial cell function but did not affect tumor cell proliferation in vitro. In vivo tumor growth was inhibited similarly by each angiogenic inhibitor alone. The combination of all 3 inhibitors further reduced tumor weight. In the metastatic model treatment with angiogenic inhibitors induced a significant reduction in the size and number of lung metastases with additive effects when factors were used in combination. The combination of angiogenic inhibitors was superior to single factors, suggesting additive activity. These data support the strategy of combining angiogenic inhibitors to accomplish a complete angiogenic blockade.

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Distinctive Expression of ErbB Family Receptors and Aggressive Bladder Cancer 

Expression of various members of the ErbB family (epidermal growth factor receptor [EGFR]/ErbB-1, ErbB-2, ErbB-3 and ErbB-4) is associated with disease stage and survival in patients with urothelial carcinoma. Kassouf et al (page 353) from Montreal, Canada examined the correlation of ErbB family receptor expression with the progression of urothelial carcinoma and survival. A urothelial carcinoma tissue array was constructed from 248 archival paraffin blocks and quality control studies were ascertained. The tissue microarray was stained for EGFR, ErbB-2, ErbB-3 and ErbB-4, and analyzed using an automated reader. Patient data included grade, stage, growth pattern, recurrence and survival. Kaplan-Meier estimates of 5-year overall and recurrence-free survival were 58% and 27%, respectively. Patients with high grade, invasive or nonpapillary disease had a worse prognosis than those with low grade, superficial or papillary disease. High EGFR or low ErbB-4 expression was associated with nonpapillary, high grade and invasive tumors as well as with significantly shorter recurrence-free survival and overall survival. Levels of ErbB-2 and ErbB-3 expression were not associated with overall or recurrence-free survival. The expression profiles of ErbB-4 and EGFR are prognostic in urothelial carcinoma, and may help in selecting high risk patients with bladder cancer for more aggressive therapy.