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Inhibition of Calcium Oxalate Urolithiasis in a Rat Model of Lithogenesis Using Bisphosphonates
1952
UROLITHIASIS, ENDOUROLOGY AND LAPAROSCOPIC SURGERY 1. Lugmap, H. and Pauer, W.: Self-expanding metal stents for palliative treatment of malignant ureteral obstruction. AJR, 1 5 9 1091,1992.
Risk of Urinary Tract Cancers Following Kidney or Ureter Stones W.-H. CHOW,P. LINDBLAD, G. GRIDLN,0.N&N, J. K. MCLAUGHLIN, M. S. LINET,G. A. PENNELLO, K-0.ADAMI AND J. F. FRAUMENI, JR., Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, International Epidemiology Institute, Rockville, Maryland, Department of Medical Epidemiology, Karolinska Institute, Stockholm, Department of Urology, Sundsvall Hospital, Sweden, and Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts J. Natl. Cancer Inst., 8 9 1453-1457, 1997 Background: A relationship has been suggested between kidney or ureter stones and the development of urinary tract cancers. In this study, a population-based cohort of patients hospitalized for kidney or ureter stones in Sweden was followed for up to 25 years to examine subsequent risks for developing renal cell, renal pelvidureter, or bladder cancer. Methods: Data from the national Swedish In-patient Register and the national Swedish Cancer Registry were linked to follow 61 144 patients who were hospitalized for kidney or ureter stones from 1965 through 1983. Standardized incidence ratios (SIRS) and 95% confidence intervals (CIS) were computed on the basis of nationwide cancer incidence rates, after adjustment for age, sex, and calendar year. Results: Risk of renal cell cancer was not elevated in this cohort. Significant excesses of renal pelvidureter cancer (SIR = 2.5; 95% GI = 1.8-3.3) and bladder cancer (SIR = 1.4; 95% CI = 1.3-1.6) were observed, but the SIRS for women were more than twice those for men. Risks varied little by age or duration of follow-up. Risks of renal pelvidureter cancer and bladder cancer among patients with a n associated diagnosis of urinary tract infection were more than double those among patients without such infection, although the risks were significantly elevated in both groups. Conclusions: Individuals hospitalized for kidney or ureter stones are at increased risk of developing renal pelvidureter or bladder cancer, even beyond 10 years of follow-up. Chronic irritation and infection may play a role, since kidney or ureter stones were located on the same side of the body as the tumors in most patients with renal pelvidureter cancer evaluated in our study. Editorial Comment: First, it was vasectomy and its possible association with subsequent coronary artery disease, and now it is urolithiasis leading to urothelial cancer. While the former raised a furor later calmed by additional studies, this most recent finding remains unchallenged. Although squamous cell cancer of the renal pelvis has been related to a history of urolithiasis, this study is possibly the first to link stone disease and transitional cell cancer. The data hold up even if one were to eliminate all patients with tumors discovered during the first year after a stone episode, that is concurrent disease states, or patients with tumors found only at autopsy, that is clinically silent tumors. Notably, there was no increase in renal cell or lung cancer in this patient group, suggesting that the findings cannot be attributed to a generalized renal problem or other confounding problems, such as smoking or job related risks. Also of interest, in 75% of the patients the tumor and stone were located on the same side, again invoking the argument that tumor formation was possibly due to local irritation from the stone. Lastly, the risk of urothelial tumor formation remained as long as 10 years after the initial stone event. The bottom line question is whether radiographic or cystoscopidcytology surveillance is indicated in all patients with stones to detect renal pelvidureteral or bladder tumors in 0.14 and 0.62%, respectively. This article has made me more aware but I am not planning to expand my followup of urolithiasis beyond that of urinalysis and a plain radiograph of the abdomen at routine intervals. Ralph V. Clayman, M.D.
Inhibition of Calcium Oxalate Urolithiasis in a Rat Model of Lithogenesis Using Bisphosphonates M. GUITA,0. L. TUNCAY, E. VALDERRAMA AND A. D. SMITH, Departments of Urology and Pathology, Long Island Jewish Medical Center, New Hyde Park, New York J. Endourol., 11: 1-4, 1997 Bisphosphonates bind renal calculi and inhibit calcium oxalate crystal growth in vitro. We evaluated their ability to inhibit calcium oxalate urolithiasis in a lithogenic rat model. Male Sprague-Dawley rats (four groups, eight rats each) were fed 1.0%)ethylene glycol in their drinking water for 6 weeks. All rats had implantation of a 50- to 60-mg zinc pellet in their urinary bladder at the beginning of the 6-week period. The control group received no treatment. The other three groups received six weekly intraperitoneal injections of one of three bisphosphonates: pamidronate (APD),clodronate (CLO),or methylene diphosphonate (MDP).
RENAL TUMORS, RETROPERITONEUM, URETER, AND URINARY DIVERSION AND RECONSTRUCTION
At the end of 6 weeks, the zinc pellet was retrieved and weighed; the kidneys were sectioned and stained to evaluate inflammation, tubular dilation, and crystal deposition; and blood and urine samples were analyzed for calcium and creatinine. There were no detectable biochemical differences between the control and the treatment groups. Zinc pellets removed from control animals had a significantly greater increase in weight secondary to crystal deposition than those from the treatment groups (mean 28.4% for control v 18.9%, 15.3%, and 18.6%, respectively, for animals given APD, CLO, and MDP). The control animals also had significantly higher scores for inflammation, tubular dilation, and crystal deposition than animals treated with MDP and CLO. Older and newer-generation bisphosphonates have an inhibitory effect on calcium oxalate urolithiasis that is demonstrable at relatively infrequent dosing intervals in vivo. More frequent dosing or higher doses may allow greater inhibition of stone formation. Editorial Comment: Bisphosphonates are currently part of the armamentarium of the internist in the treatment of postmenopausal osteoporosis. The possibility that this class of pharmaceuticals may also benefit patients with urolithiasis is of great interest. The mechanism of action of these drugs has yet to be elucidated, although hypotheses include inhibition of osteoclastic activity, direct renal tubular effects with regard to calcium and oxalate transport, and possible blockage of calcium oxalate and calcium phosphate crystal growth. The variation in the impact of different types of bisphosphonates on crystal deposition in this rat model is interesting. The optimal bisphosphonate and its dose have yet to be determined for clinical use, since such a great deal of work is yet to be done. Ralph V. Clayman, M.D.
RENAL TUMORS, RETROPERITONEUM, URETER, AND URINARY DIVERSION AND RECONSTRUCTION Influence of Polymorphisms of GSTMl and GS'IT1 for Risk of Renal Cell Cancer in Workers With Long-Term High Occupational Exposure to Trichloroethene T. BRUNING, M. LAMMERT, M. KEMPKES,R. THIER,K. G ~ L KAND A H. M. BOLT,Znstitut fiir Arbeitsphysiologie and der Universitat Dortmund, Dortmund, Germany Arch. Toxicol., 71: 596-599,1997 Suspected nephrocarcinogenic effects of trichloroethene (TRI) in humans are attributed to metabolites derived from the glutathione transferase (GST) pathway. The influence of polymorphisms of GSTMl and GSTTl isoenzymes on the risk of renal cell cancer in subjects having been exposed to high levels of TRI over many years was investigated. GSTMl and GSTTl genotypes were determined by internal standard controlled polymerase chain reaction. Fourty-five cases with histologically verified renal cell cancer and a history of long-term occupational exposure to high concentrations of TRI were studied. A reference group consisted of 48 workers from the same geographical region with similar histories of occupational exposures to TRI but not suffering from any cancer. Among the 45 renal cell cancer patients, 27 carried at least one functional GSTMl gene (GSTM1 +) and 18 at least one functional GSTTl gene (GS'IT1 +). Among the 48 reference workers, 17 were GSTMl + and 31 were GSTTl +. Odds ratios for renal cell cancer were 2.7 for GSTMl + individuals (95% CI, 1.18-6.33; P < 0.02) and 4.2 for GSTT1 + individuals (95% CI, 1.16-14.91; P < 0.05), respectively. The data support the present concept of the nephrocarcinogenicity of TRI. Editorial Comment: Many carcinogenic agents have been implicated in renal cell carcinoma, including petroleum products and heavy metals. Trichoroethylene is another potential carcinogenic agent. The authors investigated the mechanism of carcinogenesis of trichoroethylene induced nephrocarcinogenesis,which involves reactive metabolites generated by a glutathione dependent metabolic pathway. There was a higher risk for the development of renal cell carcinoma in trichoroethylene exposed individuals who carried the GS'IT1 or GSTMl gene. Fray F. Marshall, M.D. Human Telomerase RNA Expression and MIB-1 (Ki-67)Proliferation Index Distinguish Hemangioblastomas From Metastatic Renal Cell Carcinomas
D. F. BROWN, A. F. GAZDAR, C. L. WHITE,111, K. YASHIMA, J. W. SHAY AND E. J. RUSHING, Departments of Pathology, Cell Biology and Neuroscience, Neuropathology Laboratory, Hamon Centre for Therapeutic Oncology Research, University of Texas Southwestern Medical School, Dallas, Texas J. Neuropath. Exp. Neurol., 5 6 1349-1355, 1997 Hemangioblastomas are low-grade, capillary rich neoplasms of the cerebellum and spinal cord that can occur sporadically or in the setting of Von Hippel-Lindau syndrome. The present study analyzed the utility
1953
UROLITHIASIS, ENDOUROLOGY AND LAPAROSCOPIC SURGERY 1. Lugmap, H. and Pauer, W.: Self-expanding metal stents for palliative treatment of malignant ureteral obstruction. AJR, 1 5 9 1091,1992.
Risk of Urinary Tract Cancers Following Kidney or Ureter Stones W.-H. CHOW,P. LINDBLAD, G. GRIDLN,0.N&N, J. K. MCLAUGHLIN, M. S. LINET,G. A. PENNELLO, K-0.ADAMI AND J. F. FRAUMENI, JR., Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, International Epidemiology Institute, Rockville, Maryland, Department of Medical Epidemiology, Karolinska Institute, Stockholm, Department of Urology, Sundsvall Hospital, Sweden, and Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts J. Natl. Cancer Inst., 8 9 1453-1457, 1997 Background: A relationship has been suggested between kidney or ureter stones and the development of urinary tract cancers. In this study, a population-based cohort of patients hospitalized for kidney or ureter stones in Sweden was followed for up to 25 years to examine subsequent risks for developing renal cell, renal pelvidureter, or bladder cancer. Methods: Data from the national Swedish In-patient Register and the national Swedish Cancer Registry were linked to follow 61 144 patients who were hospitalized for kidney or ureter stones from 1965 through 1983. Standardized incidence ratios (SIRS) and 95% confidence intervals (CIS) were computed on the basis of nationwide cancer incidence rates, after adjustment for age, sex, and calendar year. Results: Risk of renal cell cancer was not elevated in this cohort. Significant excesses of renal pelvidureter cancer (SIR = 2.5; 95% GI = 1.8-3.3) and bladder cancer (SIR = 1.4; 95% CI = 1.3-1.6) were observed, but the SIRS for women were more than twice those for men. Risks varied little by age or duration of follow-up. Risks of renal pelvidureter cancer and bladder cancer among patients with a n associated diagnosis of urinary tract infection were more than double those among patients without such infection, although the risks were significantly elevated in both groups. Conclusions: Individuals hospitalized for kidney or ureter stones are at increased risk of developing renal pelvidureter or bladder cancer, even beyond 10 years of follow-up. Chronic irritation and infection may play a role, since kidney or ureter stones were located on the same side of the body as the tumors in most patients with renal pelvidureter cancer evaluated in our study. Editorial Comment: First, it was vasectomy and its possible association with subsequent coronary artery disease, and now it is urolithiasis leading to urothelial cancer. While the former raised a furor later calmed by additional studies, this most recent finding remains unchallenged. Although squamous cell cancer of the renal pelvis has been related to a history of urolithiasis, this study is possibly the first to link stone disease and transitional cell cancer. The data hold up even if one were to eliminate all patients with tumors discovered during the first year after a stone episode, that is concurrent disease states, or patients with tumors found only at autopsy, that is clinically silent tumors. Notably, there was no increase in renal cell or lung cancer in this patient group, suggesting that the findings cannot be attributed to a generalized renal problem or other confounding problems, such as smoking or job related risks. Also of interest, in 75% of the patients the tumor and stone were located on the same side, again invoking the argument that tumor formation was possibly due to local irritation from the stone. Lastly, the risk of urothelial tumor formation remained as long as 10 years after the initial stone event. The bottom line question is whether radiographic or cystoscopidcytology surveillance is indicated in all patients with stones to detect renal pelvidureteral or bladder tumors in 0.14 and 0.62%, respectively. This article has made me more aware but I am not planning to expand my followup of urolithiasis beyond that of urinalysis and a plain radiograph of the abdomen at routine intervals. Ralph V. Clayman, M.D.
Inhibition of Calcium Oxalate Urolithiasis in a Rat Model of Lithogenesis Using Bisphosphonates M. GUITA,0. L. TUNCAY, E. VALDERRAMA AND A. D. SMITH, Departments of Urology and Pathology, Long Island Jewish Medical Center, New Hyde Park, New York J. Endourol., 11: 1-4, 1997 Bisphosphonates bind renal calculi and inhibit calcium oxalate crystal growth in vitro. We evaluated their ability to inhibit calcium oxalate urolithiasis in a lithogenic rat model. Male Sprague-Dawley rats (four groups, eight rats each) were fed 1.0%)ethylene glycol in their drinking water for 6 weeks. All rats had implantation of a 50- to 60-mg zinc pellet in their urinary bladder at the beginning of the 6-week period. The control group received no treatment. The other three groups received six weekly intraperitoneal injections of one of three bisphosphonates: pamidronate (APD),clodronate (CLO),or methylene diphosphonate (MDP).
RENAL TUMORS, RETROPERITONEUM, URETER, AND URINARY DIVERSION AND RECONSTRUCTION
At the end of 6 weeks, the zinc pellet was retrieved and weighed; the kidneys were sectioned and stained to evaluate inflammation, tubular dilation, and crystal deposition; and blood and urine samples were analyzed for calcium and creatinine. There were no detectable biochemical differences between the control and the treatment groups. Zinc pellets removed from control animals had a significantly greater increase in weight secondary to crystal deposition than those from the treatment groups (mean 28.4% for control v 18.9%, 15.3%, and 18.6%, respectively, for animals given APD, CLO, and MDP). The control animals also had significantly higher scores for inflammation, tubular dilation, and crystal deposition than animals treated with MDP and CLO. Older and newer-generation bisphosphonates have an inhibitory effect on calcium oxalate urolithiasis that is demonstrable at relatively infrequent dosing intervals in vivo. More frequent dosing or higher doses may allow greater inhibition of stone formation. Editorial Comment: Bisphosphonates are currently part of the armamentarium of the internist in the treatment of postmenopausal osteoporosis. The possibility that this class of pharmaceuticals may also benefit patients with urolithiasis is of great interest. The mechanism of action of these drugs has yet to be elucidated, although hypotheses include inhibition of osteoclastic activity, direct renal tubular effects with regard to calcium and oxalate transport, and possible blockage of calcium oxalate and calcium phosphate crystal growth. The variation in the impact of different types of bisphosphonates on crystal deposition in this rat model is interesting. The optimal bisphosphonate and its dose have yet to be determined for clinical use, since such a great deal of work is yet to be done. Ralph V. Clayman, M.D.
RENAL TUMORS, RETROPERITONEUM, URETER, AND URINARY DIVERSION AND RECONSTRUCTION Influence of Polymorphisms of GSTMl and GS'IT1 for Risk of Renal Cell Cancer in Workers With Long-Term High Occupational Exposure to Trichloroethene T. BRUNING, M. LAMMERT, M. KEMPKES,R. THIER,K. G ~ L KAND A H. M. BOLT,Znstitut fiir Arbeitsphysiologie and der Universitat Dortmund, Dortmund, Germany Arch. Toxicol., 71: 596-599,1997 Suspected nephrocarcinogenic effects of trichloroethene (TRI) in humans are attributed to metabolites derived from the glutathione transferase (GST) pathway. The influence of polymorphisms of GSTMl and GSTTl isoenzymes on the risk of renal cell cancer in subjects having been exposed to high levels of TRI over many years was investigated. GSTMl and GSTTl genotypes were determined by internal standard controlled polymerase chain reaction. Fourty-five cases with histologically verified renal cell cancer and a history of long-term occupational exposure to high concentrations of TRI were studied. A reference group consisted of 48 workers from the same geographical region with similar histories of occupational exposures to TRI but not suffering from any cancer. Among the 45 renal cell cancer patients, 27 carried at least one functional GSTMl gene (GSTM1 +) and 18 at least one functional GSTTl gene (GS'IT1 +). Among the 48 reference workers, 17 were GSTMl + and 31 were GSTTl +. Odds ratios for renal cell cancer were 2.7 for GSTMl + individuals (95% CI, 1.18-6.33; P < 0.02) and 4.2 for GSTT1 + individuals (95% CI, 1.16-14.91; P < 0.05), respectively. The data support the present concept of the nephrocarcinogenicity of TRI. Editorial Comment: Many carcinogenic agents have been implicated in renal cell carcinoma, including petroleum products and heavy metals. Trichoroethylene is another potential carcinogenic agent. The authors investigated the mechanism of carcinogenesis of trichoroethylene induced nephrocarcinogenesis,which involves reactive metabolites generated by a glutathione dependent metabolic pathway. There was a higher risk for the development of renal cell carcinoma in trichoroethylene exposed individuals who carried the GS'IT1 or GSTMl gene. Fray F. Marshall, M.D. Human Telomerase RNA Expression and MIB-1 (Ki-67)Proliferation Index Distinguish Hemangioblastomas From Metastatic Renal Cell Carcinomas
D. F. BROWN, A. F. GAZDAR, C. L. WHITE,111, K. YASHIMA, J. W. SHAY AND E. J. RUSHING, Departments of Pathology, Cell Biology and Neuroscience, Neuropathology Laboratory, Hamon Centre for Therapeutic Oncology Research, University of Texas Southwestern Medical School, Dallas, Texas J. Neuropath. Exp. Neurol., 5 6 1349-1355, 1997 Hemangioblastomas are low-grade, capillary rich neoplasms of the cerebellum and spinal cord that can occur sporadically or in the setting of Von Hippel-Lindau syndrome. The present study analyzed the utility
1953