AUA 2011

Evidence presented in a State-of-the-Art Lecture during yesterday’s Plenary Session indicated a strong association between the formation of kidney stones and the presence or development of the metabolic syndrome and cardiovascular disease (CVD) in patients who develop kidney stones.

In the lecture, Dean G. Assimos, M.D., Professor of Surgical Sciences-Urology at Wake Forest University School of Medicine in Winston-Salem, North Carolina, cited several studies, including a recently published analysis of data from the Coronary Artery Risk Development in Young Adults Study showing that nephrolithiasis and atherosclerosis have common systemic risk factors and that kidney stones were associated with a 60 percent increased risk of carotid atherosclerosis, even after adjusting for major atherosclerotic risk factors.

In addition, a case-controlled study of the residents of Olmsted County, Minnesota, assessed the risk of a “kidney stone former developing myocardial infarction,” Dr. Assimos said. “Despite controlling for other medical comorbidities, a stone former was at 31 percent increased risk of sustaining a myocardial infarction.”

Another case-controlled study, again done among residents of Olmsted County, revealed that kidney stone formation was a significant risk for the development of chronic kidney disease. “In this study, the hazard ratio was 1.42,” Dr. Assimos said. “It is well documented that chronic kidney disease is a significant risk factor for cardiovascular disease.”

An analysis of the National Health and Nutrition Examination Survey III (NHANES III) showed that people with the metabolic syndrome had 2 times the risk of developing a kidney stone than those without signs of the metabolic syndrome. This analysis also demonstrated a positive correlation between the prevalence of kidney stones and the components of the metabolic syndrome, including obesity, hypertension, insulin resistance, increased serum triglycerides, and low high-density lipoprotein cholesterol levels.

“A screening renal ultrasound study done on a fairly large cohort of people with the metabolic syndrome in southern Italy demonstrated that 10.3 percent of patients with the metabolic syndrome had renal stones,” Dr. Assimos added. “This is 10 times higher than rates reported from renal ultrasound screening studies of the general adult population.”

The causative factors underlying the associations between stone formation and the metabolic syndrome and CVD include low urinary pH levels. “Low urinary pH is the major driving factor for the formation of uric acid stones,” Dr. Assimos said. “Studies have demonstrated that there is a negative correlation between BMI and urinary pH, meaning that those who are obese will have lower urinary pH.”

People with the combination of obesity and low urinary pH also excrete greater amounts of calcium and oxalate, which are risk factors for the development of calcium oxalate kidney stones.

The reasons for lower urinary pH in obese individuals are not fully known, but one hypothesis is that these individuals do not produce ammonium effectively in the proximal tubule.

Dr. Assimos’ own research with his team at Wake Forest has identified a possible new pathway for the endogenous synthesis of oxalate. It involves the metabolism of the reactive dialdehyde glyoxal, which is stimulated by oxidative stress. The hypothesis behind the research is that glyoxal metabolism may be linked with increased oxalate excretion in people with obesity and diabetes.

Based on the evidence he presented, Dr. Assimos concluded: “There is strong evidence that stone formation is associated with cardiovascular disease, the metabolic syndrome, and a number of systemic disorders. We as urologists need to be cognizant of these associations and counsel our patients about these associations, as they might benefit from cardiovascular screening and lifestyle changes.”

The standard of care for upper tract transitional cell carcinoma (TCC) is on the move. Nephroureterectomy has been the preferred and often unquestioned automatic option for upper tract TCC. But clinicians today are taking a second look at laser ablation of noninvasive urothelial tumors of low metastatic potential, either in situ or using other techniques such as percutaneous resection to remove the superficial tumor while sparing the kidney.

“Just like we are not removing all bladders for all bladder urothelial tumors, maybe we should rethink the paradigm that has us removing all kidneys and ureters for all urothelial tumors of the upper urinary tract and develop a bit more sophisticated and individualized strategy,” said Anup Patel, M.D., FRCS, a consultant urological surgeon at St. Mary’s Hospital, Imperial College of Medicine, London. “Instruments and technology have evolved in the past two decades. Ureteroscopes have become smaller and more flexible, and capable of complex movements. Energy sources have also become smaller and more flexible, and we have digital imaging available in the upper urinary tract.”

Dr. Patel will examine the evolution of upper tract TCC management in the European Association of Urology Lecture, Challenging Dogma: Current Role of Endourology and Renal Preservation in Upper Tract TCC Management. His 20-minute lecture will begin at 10:40 a.m. during the Plenary Session today in Hall D of the Walter E. Washington Convention Center.

The development of smaller, more flexible ureteroscopes and accessories continues to advance practice, Dr. Patel continued. Precise digital imaging has replaced shadowy x-rays that cannot distinguish a blood clot from a tumor and have caused some kidneys to be excised needlessly. Instrumentation allows urologists to obtain material by multiple biopsies and cytology to characterize upper tract tumors more accurately. Like prostate and kidney cancers, TCCs come in a variety of shapes, sizes and danger of spread.

“The question is: Is a tumor like every other tumor, or are they all the same? Does it matter if we start treating each tumor and each patient in a slightly different and more sophisticated way? We already know that one single treatment does not fit every patient,” Dr. Patel said.

“This new paradigm is based on the accuracy of grading and staging cancers, and looking at other factors such as size and multifocality, all of which play into the risk for recurrence or a lethal outcome,” he continued. “For multifocal disease, if we take kidneys out too quickly, particularly for a nonlethal tumor, the patient is more likely to get recurrences. We would expect to see these recurrences not only in the bladder, which means a lifetime of endoscopic surveillance of the urothelium that remains, but potentially a tumor in the other kidney. Then the patient is in serious trouble, facing both kidneys being removed and dialysis. The morbidity and cost of dialysis are not insignificant.”

These changes in upper tract TCC management are following a pathway that urologists have taken in the past. New treatment data discussed in March at the EAU annual congress in Vienna showed that shock wave lithotripsy, long the standard of care for renal stones, is being replaced by ureteroscopic procedures in some countries. The treatment of bladder cancer has already shifted from radical cystectomy to more selective treatment based on individual patient and tumor characteristics. Upper tract TCC is in the early stages of a similar shift to more precise treatment based on individual patient and tumor characteristics.

“Essentially I’m talking about an individualized paradigm of natural orifice surgery rather than procedures that make new holes,” Dr. Patel said. “Cystoscopy was the first natural orifice procedure in urology, and ureterorenoscopy is merely an extension of this principle and also a natural orifice procedure. The same endo-oncology, risk stratified paradigm is developing in upper tract TCC as a result of the improvement in instrumentation, accessories and training.”

“Training is key,” he continued, “because this is a highly precise and delicate surgery that is much more challenging in the kidney since it is an organ that moves with breathing than it is in the bladder, which is a stationary target. It requires specialist or fellowship training. This is not a procedure for everybody to attempt and we need to concentrate cases in key centers in order to feed future multicenter clinical trials involving large numbers of patients. But ureterorenoscopy is the way the paradigm will evolve to facilitate both renal preservation and, beyond that, quality of life.”

For patients with polycystic kidney disease slated to undergo renal transplant for end stage renal disease, urologists are faced with the dilemma of whether to perform bilateral nephrectomy at the time of transplant or a staged nephrectomy before or after the transplant procedure.

During yesterday’s Plenary Session, two experts in urological surgery participated in a Point-Counterpoint debate over the Management of Polycystic Kidneys in Renal Transplant Patients—Concomitant or Staged Nephrectomy? Each surgeon provided strong arguments for choosing one option over the other.

“Our task this morning is to debate the timing of native nephrectomy in polycystic kidney disease patients who are candidates for transplantation,” said moderator Venkatesh Krishnamurthi, M.D., a urologist at the Cleveland Clinic.

Autosomal polycystic kidney disease (PKD) affects approximately one in 1,000 people. The renal manifestations of the condition include hypertension, kidney stones, infection, and bleeding. By age 60, nearly half of PKD patients will have advanced renal insufficiency and require dialysis or transplantation.

“Simultaneous bilateral nephrectomy should definitely be offered as an option in the setting of a need for kidney transplant with a living donor,” said the first debater, Michael Phelan, M.D., a urologist at the University of Maryland Medical Center and Assistant Professor of Surgery at the University of Maryland School of Medicine.

“So that will frame the argument: Patients are not on dialysis but need a transplant, and there is a living donor available as well as symptoms in the pulses of the kidney patient,” he continued. “The options would be to transplant the patient alone, do a staged procedure, do cystic decortication — but I would argue that the best procedure would be a simultaneous bilateral nephrectomy at the time of transplantation.”

Why not a staged procedure? That would require two anesthesias, Dr. Phelan pointed out. “If you have a pre-transplant nephrectomy, you would need hemodialysis and there are some detrimental effects of that,” he said. “If you pursue a post-transplant nephrectomy, there are wound issues you need to be concerned about. There is the potential for injury to the transplanted organ and hypotensive issues with the transplanted organ.”

Hemodialysis can be associated with activation of cytokines, T-cells, and the complement system. “There are also infectious disease issues to be concerned about,” said Dr. Phelan, noting that 12 percent of all deaths from hemodialysis are related to infectious diseases.

With post-transplant nephrectomy, there are also wound related concerns, including wound infection. “In the setting of immunosuppression, the wound infection complications are as high as 50 percent,” Dr. Phelan said.

“In conclusion, I would like to say that the simultaneous procedure can be done successfully. The risks must be outlined in informed consent, and a team approach is essential. Resuscitation is essential, and pexy of the graft is essential,” Dr. Phelan said. Patrick Luke, M.D., Co-Director of the Multiorgan Transplant Program at the London Health Sciences Centre and Associate Professor of Surgery at the University of Western Ontario, London, countered Dr. Phelan and noted that transplantation and nephrectomy are not always the best combination.

“Dr. Phelan has shown that simultaneous bilateral nephrectomy can be done, but it is really only limited to the living donor situation. The argument for transplantation alone or transplantation with cyst ablation is probably the best,” Dr. Luke said.

“Which is the primary procedure we are trying to accomplish? I think that’s the transplant. It’s life prolonging and it improves the quality of life of patients. The nephrectomy is used just to create space, for early satiety, for pain, and rarely for hematuria or infection,” Dr. Luke continued.

“It’s important when you actually add something to a procedure that has been well established for 50 years that you really don’t change the transplant procedure all that much,” he added.

“The transplant is performed with an extraperitoneal approach, so you don’t get a torsion of the kidney, and urinary leaks are kept extraperitoneal,” Dr. Luke noted. “We want to minimize the potential for complications and bleeding.”

Dr. Luke cited a study showing that 27 percent of renal transplant patients treated with a simultaneous nephrectomy had major complications while none of the study patients treated with a staged procedure experienced complications. There was also a 63 percent reoperation rate in the patients treated with the combined procedure vs. zero percent in patients who underwent the staged procedure.

Dr. Luke said he prefers post-transplant nephrectomy to pre-transplant nephrectomy because patients have restored renal and platelet function.

“Dr. Phelan has shown us that simultaneous combined kidney transplant and nephrectomy is feasible, but there is no evidence that simultaneous nephrectomy is superior,” Dr. Luke said. “There is a higher transfusion rate associated with it, a higher complication rate associated with it, and the finite risk of graft torsion. It really does jeopardize the primary procedure.”

To conclude the debate, Dr. Krishnamurthi provided a brief summary: “Probably the best approach is an individualized one,” he said. “A patient in whom you think the nephrectomy may be straightforward, may be an appropriate candidate for a simultaneous procedure. Alternatively, if the procedure is perceived to be complicated, it’s probably better to perform a staged procedure.”

A paradigm shift toward personalized medicine is under way in health care, and the trend is rapidly transforming the face of medicine, according to Daniel Theodorescu, M.D., Ph.D., who will deliver a State-of-the-Art Lecture today on Personalized Medicine in Bladder Cancer. His 20-minute presentation will begin at 8:50 a.m. during this morning’s Plenary Session in Hall D of the Walter E. Washington Convention Center.

“The purpose of my lecture is to broadly explain what personalized medicine is in the genomic era and give examples of how it may be useful in the management of bladder cancer,” said Dr. Theodorescu, the Paul Bunn Professor of Surgery and Pharmacology, and Director of the University of Colorado Comprehensive Cancer Center.

“Personalized or individualized medicine is not a new concept,” he continued. “Early examples include the use of family histories to assess the risk of tumor development. However, because not all individuals with family histories of cancer carry hereditary risk, not all such patients are at higher risk of cancer development.”

Genetic tests are available today to help determine cancer risk and the risk of tumor progression. Genetic testing and molecular markers are helping physicians determine which patients are at risk for certain cancers and which patients will respond to various treatment protocols.

“We have better tools now to stratify patients in terms of the risk of getting cancer, getting an aggressive cancer or developing metastases from the primary cancer,” Dr. Theodorescu said.

In his lab at the University of Colorado Comprehensive Cancer Center, Dr. Theodorescu and his colleagues have focused on identifying the molecular mechanisms leading to bladder cancer metastasis and the potential application of this knowledge to patients with bladder cancer. One of his accomplishments has been the identification of a new metastasis suppressor gene, RhoGDI2, in human cancer. Expression of this gene has been shown to be an independent prognostic marker for disease specific survival in patients with bladder cancer. Its mechanism of action in suppressing the spread of cancer was found to be via the immune system (J Clin Invest 2011;121(1):132-47).

“A major advance that has opened new opportunities in personalized care is the ability to manipulate and interrogate nucleic acid — DNA and RNA. Interrogating nucleic acid in some form or interrogating proteins in certain forms is the cornerstone of molecular diagnostics and prognostics,” Dr. Theodorescu said.

“In addition to physical exams, imaging studies, histologic and cytologic screening, over time the identification of DNA, RNA proteomic, micro-RNA and epigenetic biomarkers in body fluids will become more routine in detecting cancer in its nascent stages,” he said.

“We can use these new tools not only on body fluids, such as urine and blood, but also on tumor tissue and normal tissue,” he continued. “In bladder cancer, for example, normal tissue can harbor genetic mutations in urothelium damaged by a carcinogenic insult. Analyzing tumor tissue can help us determine how the tumor will respond to therapy and whether the patient needs cystectomy or can handle TURBT [transurethral resection of bladder tumor], for example.”

New tests and approaches to the diagnosis and treatment of bladder cancer are currently under investigation. One recent study used cDNA microarray technology to develop gene expression profiles from biopsies of bladder tissue from patients with invasive bladder cancer who were subsequently treated with MVAC (methotrexate, vinblastine, doxorubicin) neoadjuvant chemotherapy (Cancer Res 2009;69 (21):8302-9).

“A tectonic shift is occurring in how we will practice medicine on the economic and clinical practice levels, and on the scientific levels,” Dr. Theodorescu said. “I suspect everyday urological practice will be very different in 10 to 15 years.”

The field of genomics is having an enormous impact on the diagnosis, treatment and prevention of all types of cancer. The search is on for genes associated with prostate cancer, but such genes, if they exist, are challenging to find, according to Kathleen A. Cooney, M.D., FACP, who will give a State-ofthe- Art Lecture on Prostate Cancer Susceptibility Genes during this morning’s Plenary Session. Her 20-minute lecture will begin at 11:00 a.m. in Hall D of the Walter E. Washington Convention Center.

Dr. Cooney will provide an update on the ongoing research designed to identify genes that convey a susceptibility to prostate cancer. She will also provide some information about the technology being used to find these genes.

“I’ll address the search for genes as well as the challenges involved in this field. It is a puzzle to many clinicians and researchers why prostate cancer susceptibility genes have been so much harder to find compared to genes that contribute to hereditary breast or colon cancer,” said Dr. Cooney, Professor of Internal Medicine and Urology, Chief of Hematology/Oncology, and Associate Director for Faculty Affairs for the University of Michigan Comprehensive Cancer Center at the University of Michigan Medical School in Ann Arbor.

“I will review the impact of family history on the risk of prostate cancer and discuss what we know and also what we don’t know with regard to testing men in families with multiple cases of prostate cancer, both for establishing genetic risk and for diagnosing prostate cancer in unaffected family members,” she said.

Since 1995, Dr. Cooney has been the principal investigator for the Prostate Cancer Genetics Project (PCGP) at the University of Michigan. The purpose of this project is to determine possible genetic causes of prostate cancer through the study of men with early onset and/or a family history of prostate cancer. Candidates are individuals who have been diagnosed with prostate cancer at age 55 or younger and families with two or more living family members with prostate cancer.

“The biggest challenge in hereditary prostate cancer research is that it has been very hard to find the rare highly penetrant genes that are the equivalent of BRCA1 and BRCA2 genes for breast cancer. There has been some debate in the field as to whether these genes actually exist. I, for one, believe they do,” Dr. Cooney said.

“For our prostate cancer research project, we’ve collected DNA samples from young men with prostate cancer as well as men with a positive family history of prostate cancer, and we’ve conducted a number of research studies over the years looking for cancer susceptibility genes. We have identified a broad region on chromosome 17 containing BRCA1 that appears to be linked to prostate cancer in a subset of families with multiple cases of early onset prostate cancer,” she explained.

“Based on earlier work from the PCGP, we don’t think that BRCA1 mutations account for this linkage, and we are actively sequencing additional genes in the region to try to find what we believe would be a hereditary prostate cancer gene,” Dr. Cooney added.

Another ongoing research project she is involved with is looking into early onset prostate cancer. “Prostate cancer is a disease of older men, but about 10 percent of all cases are actually diagnosed in younger men under the age of 55, and the number of cases in young men seems to be increasing,” she said. “There is also some epidemiologic data that prostate cancer in some young men may be more clinically aggressive.”

This second project is a genome wide association study using DNA samples from nearly 1,000 men with early onset prostate cancer, and evaluating a large number of single nucleotide polymorphisms or variants to identify genes that may be associated with early onset prostate cancer. Early work from the PCGP has confirmed the hypothesis that young men diagnosed with prostate cancer have more of the common prostate cancer risk variants than older men with prostate cancer.

“If we can find novel genes that cause prostate cancer within families, these genes may provide new insights into the biology of prostate cancer,” Dr. Cooney explained. “However, there are also clinical implications for our research. If we can identify the genetic factors responsible for multiple cases of prostate cancer within families, this information can be used for genetic based risk assessment.”

The Prostate Cancer Genetics Project is still enrolling patients. For more information, call 800-723-9170 or go online to www.cancer.med.umich.edu/prevention/pcgp.shtml.