Nephrology

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

SAN FRANCISCO – Chronic kidney disease, even on the milder end of the spectrum, is an independent risk factor for urinary cancers and may therefore be useful for targeting screening, the results of a large observational study suggest.

In the study of nearly 1.2 million adults in the Kaiser Permanente Renal Registry, none of whom were on dialysis, the risks of urinary cancers increased in stepwise fashion with decreasing estimated glomerular filtration rate (GFR), Dr. William T. Lowrance reported at the Genitourinary Cancers Symposium.

After adjustments, patients having the lowest estimated GFRs had a more than 100% increase in the risk of renal cell cancer and a 35% increase in the risk of urothelial cancer. The risks of other types of cancers – breast, lung, prostate, and colorectal – and of cancer overall increased with decreasing estimated GFR in univariate analyses but not in multivariate analyses.

"We found an independent, graded increased risk of renal and urothelial cancer as you went to a lower estimated GFR, and this was especially true when your estimated GFR was less than 45 mL/min per 1.73 m2, in this large diverse population-based cohort," said Dr. Lowrance of the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

"Estimated GFRs may play a role in identifying patients at higher risk for renal and urothelial malignancies," he added. "Certainly, prospective studies are needed to further assess any net clinical benefit of targeted cancer screening in these patients with CKD. And we also need to try and elucidate the etiology of this mechanism: Is there some underlying biological process that explains this association?"

"As far as I could determine on a literature search, this is the largest number of patients in a study to date," commented Thomas E. Hutson, D.O., Pharm.D., of the Baylor Sammons Cancer Center in Dallas, who was invited to discuss the study.

"We are used to screening patients with end-stage renal disease already, using renal ultrasounds, looking for renal tumors," he noted. This new study suggests that "GFR may play a role in identifying patients at higher risk, and therefore we may want to use that as a potential screening mechanism," a practice that should be studied prospectively, he agreed.

End-stage renal disease is a known risk factor for cancer, according to Dr. Lowrance. And previous studies have implicated CKD generally in cancer risk, "but they are somewhat limited by their size and their ability to control for important factors that may confound the association between CKD and cancer," he maintained.

The investigators studied adults aged 40 years or older who were in the Kaiser Permanente Renal Registry and had at least one outpatient, non–emergency department measurement of serum creatinine level between 2000 and 2008. Those who had cancer or a history of dialysis or renal transplantation were excluded.

Estimated GFR values within 3 months of cancer diagnosis and incident cancers in the first 2 years of follow-up were excluded from analysis to minimize the possibility of cancer affecting kidney function.

Results were based on 1.2 million patients with a median age of 55 years. A total of 76,809 cancers were diagnosed during a median follow-up of 5.3 years.

Univariate analyses showed increasing rates of various types of common cancers and of cancer overall with decreasing GFR, which was estimated with the CKD-Epi equation.

Multivariate analysis – adjusted for numerous potential confounders, such as proteinuria, comorbidities (including diabetes), smoking status, prescription medications taken, and health care use – showed that patients having an estimated GFR of 59 mL/min per 1.73 m² or lower had a significantly increased risk of renal cell cancer, and patients having an estimated GFR of 44 mL/min per 1.73 m² or lower had a significantly increased risk of urothelial cancer – both compared with their counterparts having an estimated GFR of 60 to 89 mL/min per 1.73 m².

Those with the poorest renal function – an estimated GFR of less than 30 mL/min per 1.73 m² – had a significant 2.09-fold increased risk of renal cell cancer and a significant 1.35-fold increased risk of urothelial cancer.

"A big concern [in such a study] is potential detection bias, meaning subjects with worse renal function may be followed more closely than those with normal renal function, and as a result, we are likely to diagnose more cancers in those patients," Dr. Lowrance acknowledged. However, analyses took into account numbers of outpatient visits and hospitalizations (although not specifically hematuria tests or imaging tests), reducing this possible source of bias.

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Lowrance disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Chronic kidney disease, even on the milder end of the spectrum, is an independent risk factor for urinary cancers and may therefore be useful for targeting screening, the results of a large observational study suggest.

In the study of nearly 1.2 million adults in the Kaiser Permanente Renal Registry, none of whom were on dialysis, the risks of urinary cancers increased in stepwise fashion with decreasing estimated glomerular filtration rate (GFR), Dr. William T. Lowrance reported at the Genitourinary Cancers Symposium.

After adjustments, patients having the lowest estimated GFRs had a more than 100% increase in the risk of renal cell cancer and a 35% increase in the risk of urothelial cancer. The risks of other types of cancers – breast, lung, prostate, and colorectal – and of cancer overall increased with decreasing estimated GFR in univariate analyses but not in multivariate analyses.

"We found an independent, graded increased risk of renal and urothelial cancer as you went to a lower estimated GFR, and this was especially true when your estimated GFR was less than 45 mL/min per 1.73 m2, in this large diverse population-based cohort," said Dr. Lowrance of the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

"Estimated GFRs may play a role in identifying patients at higher risk for renal and urothelial malignancies," he added. "Certainly, prospective studies are needed to further assess any net clinical benefit of targeted cancer screening in these patients with CKD. And we also need to try and elucidate the etiology of this mechanism: Is there some underlying biological process that explains this association?"

"As far as I could determine on a literature search, this is the largest number of patients in a study to date," commented Thomas E. Hutson, D.O., Pharm.D., of the Baylor Sammons Cancer Center in Dallas, who was invited to discuss the study.

"We are used to screening patients with end-stage renal disease already, using renal ultrasounds, looking for renal tumors," he noted. This new study suggests that "GFR may play a role in identifying patients at higher risk, and therefore we may want to use that as a potential screening mechanism," a practice that should be studied prospectively, he agreed.

End-stage renal disease is a known risk factor for cancer, according to Dr. Lowrance. And previous studies have implicated CKD generally in cancer risk, "but they are somewhat limited by their size and their ability to control for important factors that may confound the association between CKD and cancer," he maintained.

The investigators studied adults aged 40 years or older who were in the Kaiser Permanente Renal Registry and had at least one outpatient, non–emergency department measurement of serum creatinine level between 2000 and 2008. Those who had cancer or a history of dialysis or renal transplantation were excluded.

Estimated GFR values within 3 months of cancer diagnosis and incident cancers in the first 2 years of follow-up were excluded from analysis to minimize the possibility of cancer affecting kidney function.

Results were based on 1.2 million patients with a median age of 55 years. A total of 76,809 cancers were diagnosed during a median follow-up of 5.3 years.

Univariate analyses showed increasing rates of various types of common cancers and of cancer overall with decreasing GFR, which was estimated with the CKD-Epi equation.

Multivariate analysis – adjusted for numerous potential confounders, such as proteinuria, comorbidities (including diabetes), smoking status, prescription medications taken, and health care use – showed that patients having an estimated GFR of 59 mL/min per 1.73 m² or lower had a significantly increased risk of renal cell cancer, and patients having an estimated GFR of 44 mL/min per 1.73 m² or lower had a significantly increased risk of urothelial cancer – both compared with their counterparts having an estimated GFR of 60 to 89 mL/min per 1.73 m².

Those with the poorest renal function – an estimated GFR of less than 30 mL/min per 1.73 m² – had a significant 2.09-fold increased risk of renal cell cancer and a significant 1.35-fold increased risk of urothelial cancer.

"A big concern [in such a study] is potential detection bias, meaning subjects with worse renal function may be followed more closely than those with normal renal function, and as a result, we are likely to diagnose more cancers in those patients," Dr. Lowrance acknowledged. However, analyses took into account numbers of outpatient visits and hospitalizations (although not specifically hematuria tests or imaging tests), reducing this possible source of bias.

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Lowrance disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Chronic kidney disease, even on the milder end of the spectrum, is an independent risk factor for urinary cancers and may therefore be useful for targeting screening, the results of a large observational study suggest.

In the study of nearly 1.2 million adults in the Kaiser Permanente Renal Registry, none of whom were on dialysis, the risks of urinary cancers increased in stepwise fashion with decreasing estimated glomerular filtration rate (GFR), Dr. William T. Lowrance reported at the Genitourinary Cancers Symposium.

After adjustments, patients having the lowest estimated GFRs had a more than 100% increase in the risk of renal cell cancer and a 35% increase in the risk of urothelial cancer. The risks of other types of cancers – breast, lung, prostate, and colorectal – and of cancer overall increased with decreasing estimated GFR in univariate analyses but not in multivariate analyses.

"We found an independent, graded increased risk of renal and urothelial cancer as you went to a lower estimated GFR, and this was especially true when your estimated GFR was less than 45 mL/min per 1.73 m2, in this large diverse population-based cohort," said Dr. Lowrance of the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

"Estimated GFRs may play a role in identifying patients at higher risk for renal and urothelial malignancies," he added. "Certainly, prospective studies are needed to further assess any net clinical benefit of targeted cancer screening in these patients with CKD. And we also need to try and elucidate the etiology of this mechanism: Is there some underlying biological process that explains this association?"

"As far as I could determine on a literature search, this is the largest number of patients in a study to date," commented Thomas E. Hutson, D.O., Pharm.D., of the Baylor Sammons Cancer Center in Dallas, who was invited to discuss the study.

"We are used to screening patients with end-stage renal disease already, using renal ultrasounds, looking for renal tumors," he noted. This new study suggests that "GFR may play a role in identifying patients at higher risk, and therefore we may want to use that as a potential screening mechanism," a practice that should be studied prospectively, he agreed.

End-stage renal disease is a known risk factor for cancer, according to Dr. Lowrance. And previous studies have implicated CKD generally in cancer risk, "but they are somewhat limited by their size and their ability to control for important factors that may confound the association between CKD and cancer," he maintained.

The investigators studied adults aged 40 years or older who were in the Kaiser Permanente Renal Registry and had at least one outpatient, non–emergency department measurement of serum creatinine level between 2000 and 2008. Those who had cancer or a history of dialysis or renal transplantation were excluded.

Estimated GFR values within 3 months of cancer diagnosis and incident cancers in the first 2 years of follow-up were excluded from analysis to minimize the possibility of cancer affecting kidney function.

Results were based on 1.2 million patients with a median age of 55 years. A total of 76,809 cancers were diagnosed during a median follow-up of 5.3 years.

Univariate analyses showed increasing rates of various types of common cancers and of cancer overall with decreasing GFR, which was estimated with the CKD-Epi equation.

Multivariate analysis – adjusted for numerous potential confounders, such as proteinuria, comorbidities (including diabetes), smoking status, prescription medications taken, and health care use – showed that patients having an estimated GFR of 59 mL/min per 1.73 m² or lower had a significantly increased risk of renal cell cancer, and patients having an estimated GFR of 44 mL/min per 1.73 m² or lower had a significantly increased risk of urothelial cancer – both compared with their counterparts having an estimated GFR of 60 to 89 mL/min per 1.73 m².

Those with the poorest renal function – an estimated GFR of less than 30 mL/min per 1.73 m² – had a significant 2.09-fold increased risk of renal cell cancer and a significant 1.35-fold increased risk of urothelial cancer.

"A big concern [in such a study] is potential detection bias, meaning subjects with worse renal function may be followed more closely than those with normal renal function, and as a result, we are likely to diagnose more cancers in those patients," Dr. Lowrance acknowledged. However, analyses took into account numbers of outpatient visits and hospitalizations (although not specifically hematuria tests or imaging tests), reducing this possible source of bias.

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Lowrance disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – MDV3100, new oral inhibitor of androgen receptor signaling, reduces the risk of death by more than a third after a failure of docetaxel chemotherapy in men with progressive castration-resistant prostate cancer, according to results of the randomized AFFIRM trial.

Interim data for the trial, which was conducted in nearly 1,200 men, showed that those given the investigational drug lived 4.8 months longer than their counterparts who had been given a placebo, corresponding to a 37% reduced risk of death, lead investigator Dr. Howard I. Scher reported at the Genitourinary Cancers Symposium. This positive finding triggered early trial closure.

Additional analyses revealed that men treated with the drug were significantly more likely to have a soft tissue response and to have at least a halving of their prostate-specific antigen (PSA) level. At the same time, there was no increase in the rate of higher-grade adverse events; seizures (a potential concern from earlier research) occurred at low frequency.

"MDV3100 now joins the list of drugs demonstrating a survival benefit in a phase III trial post docetaxel," adding to abiraterone (Zytiga) and cabazitaxel (Jevtana), Dr. Scher maintained. "The risk-benefit ratio will likely position this as the frontline agent post docetaxel therapy."

"I’m not the [Food and Drug Administration], but I would say that when you see this kind of survival benefit and safety profile – and looking at a prior drug [investigation] that I had a privilege of leading – I would say that this should be approved relatively quickly," he commented in a press briefing.

"I have only one comment: wow! That’s very impressive," said Dr. Nicholas J. Vogelzang, the moderator of the briefing and the chair and medical director of the Developmental Therapeutics Committee of US Oncology. The median survival and dramatic rates of PSA reduction seen with MDV3100 are "unprecedented. This is going to definitely change the way we take care of patients every day in the office."

"This is a landmark study," Dr. Adam S. Kibel agreed in an interview at the meeting. "I think this is a drug that will be widely used, assuming it gets FDA approved."

Initially, MDV3100 is likely to be used in the postdocetaxel space, said, Dr. Kibel, chief of urology at Brigham and Women’s Hospital and the Dana Farber Cancer Institute and a professor at Harvard Medical School, all in Boston. "I imagine that it would probably be the first-line drug because it appears to have a little less side effect profile than abiraterone and certainly lower than cabazitaxel."

"The one tripper in there is, will insurance pay for it and how much is it going to cost?" said Dr. Kibel.

MDV3100 is also being tested in patients who have not yet received docetaxel. "I will be shocked if [those data] are not positive," he commented. And should it perform well there, "it will move prior to docetaxel, because it appears to be very well tolerated from the data presented."

The AFFIRM trial enrolled 1,199 men with castration-resistant prostate cancer who had experienced progression after receiving docetaxel – a population for whom there was no standard of care at the time the trial began, Dr. Scher noted. They were assigned in 2:1 ratio to once-daily treatment with MDV3100 (manufactured by Medivation) or placebo.

The first-in-class drug has a three-pronged mechanism of action, as well as some advantages over other antiandrogen agents, according to Dr. Scher, chief of the genitourinary oncology service and D. Wayne Calloway Chair in Urologic Oncology at the Memorial Sloan-Kettering Cancer Center in New York.

It "binds more tightly [to the androgen receptor] than the currently available agents, but is also unique in that it inhibits nuclear translocation [of the receptor] as well as the association of the receptor with DNA, inducing cell death," he explained.

The patients studied had a median age of 69 years. Most (90%) had bone metastases, and the large majority (70%) also had soft tissue metastases.

Main results showed that men given MDV3100 lived 18.4 months, whereas their counterparts given the placebo lived 13.6 months (hazard ratio, 0.63; P less than .0001). Stratified analyses showed similar benefit across most patient subgroups.

Men treated with the drug also had longer median radiographic progression free survival (8.3 vs. 2.9 months; HR, 0.40) and were more likely to have a soft tissue response on imaging (29% vs. 4%) and at least a halving of their PSA level (54% vs. 2%) (all P less than .0001).

There was no increase with MDV3100 in the rate of grade 3 or higher adverse events (45% vs. 53%) or the overall rate of treatment discontinuation due to adverse events (8% vs. 10%).

Seizures occurred in 0.6% of patients given the drug, compared with none of those given the placebo. "Obviously, these cases were studied very, very carefully. In four of the five cases, there were other potential confounders," including brain metastases and receipt of intravenous lidocaine for a biopsy, Dr. Scher noted. "This is an extremely low frequency, and considering this patient population who are symptomatic post docetaxel, for us, it’s really a nonissue."

The symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Medivation Inc. sponsored the trial. Dr. Scher disclosed that he is a consultant to and receives research funding from Medivation. Dr. Vogelzang disclosed relationships with numerous companies. Dr. Kibel reported that he is a consultant to Dendreon and Sanofi-Aventis.

SAN FRANCISCO – MDV3100, new oral inhibitor of androgen receptor signaling, reduces the risk of death by more than a third after a failure of docetaxel chemotherapy in men with progressive castration-resistant prostate cancer, according to results of the randomized AFFIRM trial.

Interim data for the trial, which was conducted in nearly 1,200 men, showed that those given the investigational drug lived 4.8 months longer than their counterparts who had been given a placebo, corresponding to a 37% reduced risk of death, lead investigator Dr. Howard I. Scher reported at the Genitourinary Cancers Symposium. This positive finding triggered early trial closure.

Additional analyses revealed that men treated with the drug were significantly more likely to have a soft tissue response and to have at least a halving of their prostate-specific antigen (PSA) level. At the same time, there was no increase in the rate of higher-grade adverse events; seizures (a potential concern from earlier research) occurred at low frequency.

"MDV3100 now joins the list of drugs demonstrating a survival benefit in a phase III trial post docetaxel," adding to abiraterone (Zytiga) and cabazitaxel (Jevtana), Dr. Scher maintained. "The risk-benefit ratio will likely position this as the frontline agent post docetaxel therapy."

"I’m not the [Food and Drug Administration], but I would say that when you see this kind of survival benefit and safety profile – and looking at a prior drug [investigation] that I had a privilege of leading – I would say that this should be approved relatively quickly," he commented in a press briefing.

"I have only one comment: wow! That’s very impressive," said Dr. Nicholas J. Vogelzang, the moderator of the briefing and the chair and medical director of the Developmental Therapeutics Committee of US Oncology. The median survival and dramatic rates of PSA reduction seen with MDV3100 are "unprecedented. This is going to definitely change the way we take care of patients every day in the office."

"This is a landmark study," Dr. Adam S. Kibel agreed in an interview at the meeting. "I think this is a drug that will be widely used, assuming it gets FDA approved."

Initially, MDV3100 is likely to be used in the postdocetaxel space, said, Dr. Kibel, chief of urology at Brigham and Women’s Hospital and the Dana Farber Cancer Institute and a professor at Harvard Medical School, all in Boston. "I imagine that it would probably be the first-line drug because it appears to have a little less side effect profile than abiraterone and certainly lower than cabazitaxel."

"The one tripper in there is, will insurance pay for it and how much is it going to cost?" said Dr. Kibel.

MDV3100 is also being tested in patients who have not yet received docetaxel. "I will be shocked if [those data] are not positive," he commented. And should it perform well there, "it will move prior to docetaxel, because it appears to be very well tolerated from the data presented."

The AFFIRM trial enrolled 1,199 men with castration-resistant prostate cancer who had experienced progression after receiving docetaxel – a population for whom there was no standard of care at the time the trial began, Dr. Scher noted. They were assigned in 2:1 ratio to once-daily treatment with MDV3100 (manufactured by Medivation) or placebo.

The first-in-class drug has a three-pronged mechanism of action, as well as some advantages over other antiandrogen agents, according to Dr. Scher, chief of the genitourinary oncology service and D. Wayne Calloway Chair in Urologic Oncology at the Memorial Sloan-Kettering Cancer Center in New York.

It "binds more tightly [to the androgen receptor] than the currently available agents, but is also unique in that it inhibits nuclear translocation [of the receptor] as well as the association of the receptor with DNA, inducing cell death," he explained.

The patients studied had a median age of 69 years. Most (90%) had bone metastases, and the large majority (70%) also had soft tissue metastases.

Main results showed that men given MDV3100 lived 18.4 months, whereas their counterparts given the placebo lived 13.6 months (hazard ratio, 0.63; P less than .0001). Stratified analyses showed similar benefit across most patient subgroups.

Men treated with the drug also had longer median radiographic progression free survival (8.3 vs. 2.9 months; HR, 0.40) and were more likely to have a soft tissue response on imaging (29% vs. 4%) and at least a halving of their PSA level (54% vs. 2%) (all P less than .0001).

There was no increase with MDV3100 in the rate of grade 3 or higher adverse events (45% vs. 53%) or the overall rate of treatment discontinuation due to adverse events (8% vs. 10%).

Seizures occurred in 0.6% of patients given the drug, compared with none of those given the placebo. "Obviously, these cases were studied very, very carefully. In four of the five cases, there were other potential confounders," including brain metastases and receipt of intravenous lidocaine for a biopsy, Dr. Scher noted. "This is an extremely low frequency, and considering this patient population who are symptomatic post docetaxel, for us, it’s really a nonissue."

The symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Medivation Inc. sponsored the trial. Dr. Scher disclosed that he is a consultant to and receives research funding from Medivation. Dr. Vogelzang disclosed relationships with numerous companies. Dr. Kibel reported that he is a consultant to Dendreon and Sanofi-Aventis.

SAN FRANCISCO – MDV3100, new oral inhibitor of androgen receptor signaling, reduces the risk of death by more than a third after a failure of docetaxel chemotherapy in men with progressive castration-resistant prostate cancer, according to results of the randomized AFFIRM trial.

Interim data for the trial, which was conducted in nearly 1,200 men, showed that those given the investigational drug lived 4.8 months longer than their counterparts who had been given a placebo, corresponding to a 37% reduced risk of death, lead investigator Dr. Howard I. Scher reported at the Genitourinary Cancers Symposium. This positive finding triggered early trial closure.

Additional analyses revealed that men treated with the drug were significantly more likely to have a soft tissue response and to have at least a halving of their prostate-specific antigen (PSA) level. At the same time, there was no increase in the rate of higher-grade adverse events; seizures (a potential concern from earlier research) occurred at low frequency.

"MDV3100 now joins the list of drugs demonstrating a survival benefit in a phase III trial post docetaxel," adding to abiraterone (Zytiga) and cabazitaxel (Jevtana), Dr. Scher maintained. "The risk-benefit ratio will likely position this as the frontline agent post docetaxel therapy."

"I’m not the [Food and Drug Administration], but I would say that when you see this kind of survival benefit and safety profile – and looking at a prior drug [investigation] that I had a privilege of leading – I would say that this should be approved relatively quickly," he commented in a press briefing.

"I have only one comment: wow! That’s very impressive," said Dr. Nicholas J. Vogelzang, the moderator of the briefing and the chair and medical director of the Developmental Therapeutics Committee of US Oncology. The median survival and dramatic rates of PSA reduction seen with MDV3100 are "unprecedented. This is going to definitely change the way we take care of patients every day in the office."

"This is a landmark study," Dr. Adam S. Kibel agreed in an interview at the meeting. "I think this is a drug that will be widely used, assuming it gets FDA approved."

Initially, MDV3100 is likely to be used in the postdocetaxel space, said, Dr. Kibel, chief of urology at Brigham and Women’s Hospital and the Dana Farber Cancer Institute and a professor at Harvard Medical School, all in Boston. "I imagine that it would probably be the first-line drug because it appears to have a little less side effect profile than abiraterone and certainly lower than cabazitaxel."

"The one tripper in there is, will insurance pay for it and how much is it going to cost?" said Dr. Kibel.

MDV3100 is also being tested in patients who have not yet received docetaxel. "I will be shocked if [those data] are not positive," he commented. And should it perform well there, "it will move prior to docetaxel, because it appears to be very well tolerated from the data presented."

The AFFIRM trial enrolled 1,199 men with castration-resistant prostate cancer who had experienced progression after receiving docetaxel – a population for whom there was no standard of care at the time the trial began, Dr. Scher noted. They were assigned in 2:1 ratio to once-daily treatment with MDV3100 (manufactured by Medivation) or placebo.

The first-in-class drug has a three-pronged mechanism of action, as well as some advantages over other antiandrogen agents, according to Dr. Scher, chief of the genitourinary oncology service and D. Wayne Calloway Chair in Urologic Oncology at the Memorial Sloan-Kettering Cancer Center in New York.

It "binds more tightly [to the androgen receptor] than the currently available agents, but is also unique in that it inhibits nuclear translocation [of the receptor] as well as the association of the receptor with DNA, inducing cell death," he explained.

The patients studied had a median age of 69 years. Most (90%) had bone metastases, and the large majority (70%) also had soft tissue metastases.

Main results showed that men given MDV3100 lived 18.4 months, whereas their counterparts given the placebo lived 13.6 months (hazard ratio, 0.63; P less than .0001). Stratified analyses showed similar benefit across most patient subgroups.

Men treated with the drug also had longer median radiographic progression free survival (8.3 vs. 2.9 months; HR, 0.40) and were more likely to have a soft tissue response on imaging (29% vs. 4%) and at least a halving of their PSA level (54% vs. 2%) (all P less than .0001).

There was no increase with MDV3100 in the rate of grade 3 or higher adverse events (45% vs. 53%) or the overall rate of treatment discontinuation due to adverse events (8% vs. 10%).

Seizures occurred in 0.6% of patients given the drug, compared with none of those given the placebo. "Obviously, these cases were studied very, very carefully. In four of the five cases, there were other potential confounders," including brain metastases and receipt of intravenous lidocaine for a biopsy, Dr. Scher noted. "This is an extremely low frequency, and considering this patient population who are symptomatic post docetaxel, for us, it’s really a nonissue."

The symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Medivation Inc. sponsored the trial. Dr. Scher disclosed that he is a consultant to and receives research funding from Medivation. Dr. Vogelzang disclosed relationships with numerous companies. Dr. Kibel reported that he is a consultant to Dendreon and Sanofi-Aventis.

Kidney or urinary tract stones (whose presence is referred to as nephrolithiasis) are hard, crystalline mineral concretions that form within the kidney or the urinary tract. They are a common problem, with an estimated annual incidence of 1% and a lifetime risk of 15% to 25%; this constitutes a significant health care burden, particularly for people of working age.¹

Nephrolithiasis is currently more prevalent in men than in women (13% vs 7%, respectively), and it is three to four times more likely to present in white than nonwhite patients.² However, recent epidemiologic data suggest an alarming increase in the number of women and adolescents primarily diagnosed with stone disease.^3-6 The pattern of increasing incidence in women can be attributed in part to changes in diet and lifestyle.^4,5 Figure 1⁷ represents the prevalence of stone disease, specific to gender and race.^2,4

Due to kidney stones’ relatively common occurrence, the diagnosis, management, and prevention of stone disease have become increasingly relevant for the primary care practitioner. In the course of stone disease management, the clinician should be aware of a vital fact: Stones have a tendency to recur.¹ Indeed, evidence suggests that following an initial diagnosis of nephrolithiasis, the probability of kidney stone recurrence increases to nearly 50% after five years.⁸

Even more concerning, evidence from several studies suggests that patients with a history of stone disease have a higher probability of experiencing a significant reduction in renal function (ie, decrease in glomerular filtration rate) and hence end-stage renal disease, when compared with non–stone formers.^9-11 This accentuates the importance of early diagnosis, treatment, and initiation of steps to prevent further recurrence of this condition.

PATHOGENESIS

Stones in the urinary tract develop under specific urinary conditions, including supersaturation of the urine with stone-forming ions (ie, calcium, oxalate, uric acid, and phosphate) and deficiency of urinary stone inhibitors (citrate, magnesium, zinc, macromolecules, and pyrophosphate). Stone formation occurs in a mucoprotein matrix that attaches to the renal epithelium. Urine becomes supersaturated as a result of increasing levels of solutes (such as the stone-forming ions) and/or decreasing free water volume. When the concentration of stone-forming ions exceeds solubility in the urine (equilibrium solubility product), these ions can combine to form crystals.^12,13

Stones are typed based on the ion composition of their crystals (see Table 1^2,12).

Once crystals are formed, they can also aggregate with other crystals, developing into a calculus.¹² Urinary pH influences ion crystallization: Alkaline urine favors formation of calcium and/or phosphate stones, whereas acidic urine favors uric acid and cystine stone formation.¹³

Kidney stones can be divided into four broad types: calcium-based, struvite, uric acid, and cystine stones (see Figure 2). Among these, calcium-based stones are by far the most common, with nearly 80% of stones composed of calcium compounds (usually calcium oxalate, and rarely calcium phosphate).⁴ The etiologies of these four types are vastly different, and prevention of stone formation must be tailored to the stone type. Once stones form, however, the appropriate treatment strategies have many similarities.

RISK FACTORS

Specific risk factors for stone formation vary widely and are unique to the type of stone. A thorough history, including a family or personal history of stone disease and dietary history, must be part of the initial work-up when a patient is being evaluated for stone disease; patients with any of these risk factors should be investigated further.

The risk factors for stone disease can be broadly categorized as either individual risk factors or dietary risk factors.

Individual Risk Factors

A positive family history increases the risk for stone formation by two- to three-fold. Other individual risk factors include congenital anatomic defects, such as medullary sponge kidney, horseshoe kidney, and ureteropelvic junction obstruction (UPJ).^14-16 These can cause obstruction that leads to urinary stasis, and subsequently to stone precipitation.

Certain systemic disorders (eg, hyperparathyroidism) and situations have also been associated with stone disease and should be considered risk factors. (See Table 2^12,17).

In patients who undergo gastrointestinal bypass surgery, the development of hyperoxaluria, hypercalciuria, and decreased urinary volume are associated with an increased risk for stone formation,^18,19 and these patients should be watched for this development. Obesity and weight gain are directly proportional to nephrolithiasis risk, especially in women.^4,20

Environment plays a very important role in stone formation. Persons who live in a hot, arid climate, for example, and those who work outdoors in hot weather are at increased risk for stone formation due to excessive fluid loss from sweating.^2,4,7 (In regions where the risk for kidney stone formation is high, Romero et al⁷ predict, nephrolithiasis incidence could rise from 40% to 56% by 2050 as a result of the effects of global warming.)

Lastly, an individual’s ability (or inability) to metabolize calcium salts plays a vital role in the pathogenesis of stone disease. Intestinal calcium absorption is a major determinant of hypercalciuria, as nearly 90% of ingested calcium is absorbed in the intestines. People can broadly be divided into high or low calcium absorbers. Hypercalciuria (mean urinary calcium excretion ≥ 300 mg/d in men and ≥ 250 mg/d in women on a 1,000-mg/d calcium diet) is detected in 20% to 40% of those with calcium stones.^21-23 Hypocitraturia (mean urinary citrate excretion ≤ 320 mg/d) and hyperoxaluria (mean urinary oxalate excretion > 45 mg/d) can also increase the risk for stone formation.^12,24

Dietary Risk Factors

These are primarily related to fluid intake and dietary calcium.^7,17,25,26 Drinking less than 1 L of fluids daily is associated with an increased risk for forming stones; this risk is magnified when the urine volume is also decreased.^7,17,27 Increased dietary intake of animal protein can elevate the risk for formation of uric acid stones as a result of elevated urinary calcium and uric acid and decreased urinary citrate.¹⁷

Low dietary calcium ingestion and high oxalate consumption, resulting in increased oxalate absorption, can also exacerbate the risk for stones.^7,27 By contrast, a diet high in calcium (≥ 1,200 mg/d) reduces the risk for calcium oxalate stone recurrence,¹⁷ although the effectiveness of supplemental calcium has been questioned.^26-28

Patients who are advised to make specific dietary adjustments should later undergo repeat urine chemistries to determine the effectiveness of these changes.¹⁷

CLINICAL PRESENTATION

Nephrolithiasis typically presents with colicky flank pain, often accompanied by nausea and vomiting.²⁹ The pain radiates to the ipsilateral groin, and the patient typically has difficulty finding a comfortable position. Nephrolithiasis may also present with chronic, episodic flank pain or may even be asymptomatic.³⁰

Physical examination may reveal signs of severe pain, such as tachycardia and hypertension. Presence of fever indicates associated urinary tract infection and possibly pyelonephritis. Some larger stones can cause urinary tract obstruction; if obstruction occurs along with a preexisting urinary tract infection, it can potentially lead to pyelonephritis, pyonephrosis, and eventually urosepsis—a potentially life-threatening condition that requires immediate surgical drainage.³¹

Before a diagnosis of renal stones can be confirmed, care should be exercised to rule out the differentials, including abdominal aortic aneurysm, appendicitis, bowel obstruction, cholecystitis, drug-seeking behavior (eg, painkiller addiction), gastritis, mesenteric ischemia, musculoskeletal pain, ovarian abscess, ruptured ovarian cyst, pelvic inflammatory disease, pyelonephritis, and UPJ.^2,32,33 All patients with suspected nephrolithiasis should be carefully evaluated using laboratory and radiologic investigations.

LABORATORY EVALUATION

The goals in this two-step process are to confirm the diagnosis of nephrolithiasis, then to identify the composition of the stones formed and the associated risk factors.

Initial Evaluation

Tests include dipstick urine assessment, serum chemistries, and a complete blood count (CBC). Urine dipstick assessment may be positive for blood, protein, or leukocyte esterase, indicating stones or fragments of stones present in the urinary tract. While nearly 10% of patients with stone disease exhibit gross hematuria, nearly 90% of patients have microscopic hematuria.²

Urine osmolality should be reviewed to assess urine concentration. Serum chemistries should be ordered to evaluate kidney function. Elevated creatinine may indicate acute rather than chronic kidney disease. Electrolytes and carbon dioxide should be measured to evaluate the kidneys’ ability to concentrate urine and maintain an acid–base balance. The CBC may reveal mild leukocytosis in nephrolithiasis; presence of significant leukocytosis indicates infection.²

Secondary Evaluation

This step begins with a thorough review of the patient’s medical record and a detailed patient interview to ascertain all risk factors for stone formation (as summarized in Table 1). Specific studies to be considered are mentioned in Table 3.² This evaluation is critical to prevent formation of future stones and the associated complications. In the patient with a history of stone recurrence or stone formation of identified cause, evaluation is needed for three metabolic abnormalities—hypercalciuria, hyperuricosuria, and hypocitraturia—as these conditions predispose patients to recurrent stone formation.^1,25,34

The patient should also be encouraged to collect stones passed for further clinical evaluation. Infrared spectroscopy or quantitative wet analysis is used to identify the specific composition of the stone.^32,35

Radiologic Evaluation

Radiologic evaluation of stones is currently performed through plain x-rays, ultrasonography, and noncontrast spiral CT.^12,32,33 When a patient presents with acute signs of nephrolithiasis, a plain film x-ray of the kidneys, ureters, and bladder (KUB) is acceptable as the first imaging study, as it is inexpensive and available in most areas.³³ Plain film KUB x-rays will identify calcium oxalate, calcium phosphate, struvite, and cystine stones. However, the sensitivity of plain film x-rays has been documented between 24% and 59%, and stones that overlie a bone may be missed.^32,36 (See Figure 3.)

Hence, because of these limitations and the increasing availability of noncontrast spiral CT, noncontrast spiral CT is now the most commonly used and useful test in the diagnosis of kidney stones (sensitivity, 95% to 100%).^32,36 Spiral CT accurately defines the size as well as the location of stones, and may additionally rule out other differential diagnoses (see Figures 4a, 4b, and 4c).

Historically, IV pyelograms and urograms were considered useful in locating urinary tract stones and diagnosing related complications,¹² but these modalities carry additional risks related to IV contrast dye and radiation exposure. As a result, they have been almost completely replaced by noncontrast spiral CT because of ease of use and reduced risks.³³

Stones may also be seen on renal ultrasound—particularly uric acid stones, which are radiolucent (see Figure 5). Ultrasound is appropriate for evaluation of patients whose exposure to radiation should be limited, such as children or pregnant women. In addition to plain film x-rays, renal ultrasound may also be useful for surveillance of stones.¹²

TREATMENT

Nephrolithiasis treatment varies between acute and chronic care. Acute care for nephrolithiasis involves management of acute pain and urinary obstruction, as well as patient stabilization. Chronic care includes prevention of recurrence and management of risks.

Acute Management

Patients who present with acute nephrolithiasis most often require fluid administration, aggressive pain management, and treatment for nausea or vomiting.^31,32 Most ureteral stones measuring 5.0 mm or less will typically pass spontaneously within a few weeks,^1,29 but larger stones usually require intervention—in some cases, surgery.

Patients should be hospitalized if they require IV fluids or pain management. Isotonic IV fluids should be given to increase the urine volume and facilitate passage of stones. Care must be taken to monitor fluids, as patients with kidney stones may have a limited ability to urinate (due to urinary obstruction and/or acute or chronic renal failure). Whenever possible, all urine should be strained to collect any stones for analysis.

One new strategy to assist with stone passage is medical expulsive therapy (MET), using calcium channel blockers (eg, nifedipine) or α-blockers (eg, tamsulosin).^1,37 While there is conflicting evidence regarding the efficacy of calcium channel blockers for MET, one meta-analysis revealed a 29% improvement in stone passage with α-blockers.^1,38

Pain management can often be accomplished with NSAIDs (eg, ketorolac, diclofenac).²⁹ Since this class of medications can compromise renal function, however, they must be used with caution. Many patients require narcotic medications to control pain adequately.^39-41 Antiemetic agents (such as the H1-receptor blocker dimenhydrinate⁴²) should be administered to control nausea and vomiting.

Surgical and interventional management. Surgical intervention may be required if stones are too large to pass spontaneously (typically ≥ 8 mm); if they cause acute renal obstruction; or if they are located at a site with a potential for complications or can lead to persistent symptoms without evidence that they are passing.^1,3 Renal obstruction should be treated aggressively to preserve renal function.

The type of intervention chosen depends on the size and location of the stone, as well as the presence or absence of obstruction. Stones that measure less than 20 mm are commonly treated with extracorporeal shockwave lithotripsy (unless they overlie the sacroiliac joint), whereas patients with larger or more complex stones may require percutaneous nephrolithotomy. Nonobstructive or uncomplicated ureteral stones may be managed medically, whereas obstructive or complicated ureteral stones require placement of a stent or a nephrostomy tube until they can be removed by endoscopic surgery.^29,43

Obstruction, which may be partial or complete, is more likely when stone size exceeds 10 mm.⁴⁴ Signs of obstruction include sudden-onset, excruciating flank pain that radiates to the groin, along with nausea and vomiting (renal colic). Larger obstructive stones, such as staghorn calculi (as shown in Figures 3 and 4a), can present with symptoms of a urinary tract infection, mild flank pain, or hematuria.³³

Presence of signs of obstruction or infection mandates emergent treatment. Infections of the urinary tract (as serious as pyelonephritis or urosepsis) should be treated with antibiotics: initially with broad coverage, according to the appropriate guidelines for urinary tract infections, then tailored to the results of urine cultures. Obstruction can be relieved directly by nephrostomy tubes (and/or stents) or by interventions in which the stone is removed and normal urinary flow is restored.

Typically, endoscopy is used for direct removal of stones that cause obstruction.⁴⁴ Nephrostomy tubes and ureteral stents (see Figures 6a and 6b) are placed to relieve obstruction temporarily and provide an alternate route for drainage of urine. The goal is to prevent renal damage until the obstruction can be relieved. Stents can remain in place for several months, but nephrostomy tubes are associated with a higher risk for infection (because they are externalized), and duration of use should be limited to only a few weeks.^12,29,38

Stents are also associated with infections, but coated stents are available to reduce infection. As with any catheter material inserted into the urinary tract, ureteral stents are a prime location for development of a persistent bacterial biofilm, thus leading to infection. Recent advances in stent manufacturing have included coating stents with various biomaterials to decrease the development of this bacterial biofilm. In a preliminary study in 10 patients using a diamond-like, carbon-coated ureteral stent, Laube et al⁴⁵ demonstrated a reduction in formation of this biofilm, hence lowering the probability of stent-induced infection.

Chronic Stone Management

As previously mentioned, one of the seminal characteristics of stone disease is its ability to recur. After incidental detection of kidney stones through routine diagnostic procedures, the risk for recurrence in patients who do not receive chronic medical management is 30% to 40% within five years.^17,28 In treated patients, by comparison, this risk falls by approximately 50%.^17,26

Patients with a history of stone recurrence must be evaluated for metabolic defects that precipitate stones, since their risk for chronic kidney disease is increased.³⁴ All patients with a history of stone disease should be instructed to increase their fluid intake to maintain a daily urinary output of at least 2.5 L, unless contraindications exist.³⁴

In patients with calcium-based stones who do not benefit from conservative treatment (ie, a low-sodium diet and other dietary modifications), thiazide diuretics may help reduce urinary calcium.^1,46

Struvite stones can be prevented through use of long-term antibiotics to reduce the risk for urinary tract infection and by maintaining urinary pH levels below 6.0.^17,27,34

For patients with uric acid stones, allopurinol may be prescribed to lower uric acid levels; moreover, the solubility of uric acid is greatly increased at higher pH, so it is beneficial to treat these patients with citrate to maintain their urinary pH above 6.0.^47,34

Ensuring a high urine output (≥ 4 L/d34) and alkalinizing urine can help prevent recurrence of cystine stones.^17,33 Treatment with potassium citrate has been shown to maintain a urinary pH of 6.5 to 7.0.³⁴

CONCLUSION

The ever-increasing significance of nephrolithiasis has mandated an organized and systematic management approach. Indeed, the diagnosis and initial therapy for kidney stones have undergone considerable evolution in recent years. The basic tenets of nephrolithiasis management include early diagnosis and pertinent treatment as well as adequate prophylaxis to prevent subsequent stone recurrence.

Kidney or urinary tract stones (whose presence is referred to as nephrolithiasis) are hard, crystalline mineral concretions that form within the kidney or the urinary tract. They are a common problem, with an estimated annual incidence of 1% and a lifetime risk of 15% to 25%; this constitutes a significant health care burden, particularly for people of working age.¹

Nephrolithiasis is currently more prevalent in men than in women (13% vs 7%, respectively), and it is three to four times more likely to present in white than nonwhite patients.² However, recent epidemiologic data suggest an alarming increase in the number of women and adolescents primarily diagnosed with stone disease.^3-6 The pattern of increasing incidence in women can be attributed in part to changes in diet and lifestyle.^4,5 Figure 1⁷ represents the prevalence of stone disease, specific to gender and race.^2,4

Due to kidney stones’ relatively common occurrence, the diagnosis, management, and prevention of stone disease have become increasingly relevant for the primary care practitioner. In the course of stone disease management, the clinician should be aware of a vital fact: Stones have a tendency to recur.¹ Indeed, evidence suggests that following an initial diagnosis of nephrolithiasis, the probability of kidney stone recurrence increases to nearly 50% after five years.⁸

Even more concerning, evidence from several studies suggests that patients with a history of stone disease have a higher probability of experiencing a significant reduction in renal function (ie, decrease in glomerular filtration rate) and hence end-stage renal disease, when compared with non–stone formers.^9-11 This accentuates the importance of early diagnosis, treatment, and initiation of steps to prevent further recurrence of this condition.

PATHOGENESIS

Stones in the urinary tract develop under specific urinary conditions, including supersaturation of the urine with stone-forming ions (ie, calcium, oxalate, uric acid, and phosphate) and deficiency of urinary stone inhibitors (citrate, magnesium, zinc, macromolecules, and pyrophosphate). Stone formation occurs in a mucoprotein matrix that attaches to the renal epithelium. Urine becomes supersaturated as a result of increasing levels of solutes (such as the stone-forming ions) and/or decreasing free water volume. When the concentration of stone-forming ions exceeds solubility in the urine (equilibrium solubility product), these ions can combine to form crystals.^12,13

Stones are typed based on the ion composition of their crystals (see Table 1^2,12).

Once crystals are formed, they can also aggregate with other crystals, developing into a calculus.¹² Urinary pH influences ion crystallization: Alkaline urine favors formation of calcium and/or phosphate stones, whereas acidic urine favors uric acid and cystine stone formation.¹³

Kidney stones can be divided into four broad types: calcium-based, struvite, uric acid, and cystine stones (see Figure 2). Among these, calcium-based stones are by far the most common, with nearly 80% of stones composed of calcium compounds (usually calcium oxalate, and rarely calcium phosphate).⁴ The etiologies of these four types are vastly different, and prevention of stone formation must be tailored to the stone type. Once stones form, however, the appropriate treatment strategies have many similarities.

RISK FACTORS

Specific risk factors for stone formation vary widely and are unique to the type of stone. A thorough history, including a family or personal history of stone disease and dietary history, must be part of the initial work-up when a patient is being evaluated for stone disease; patients with any of these risk factors should be investigated further.

The risk factors for stone disease can be broadly categorized as either individual risk factors or dietary risk factors.

Individual Risk Factors

A positive family history increases the risk for stone formation by two- to three-fold. Other individual risk factors include congenital anatomic defects, such as medullary sponge kidney, horseshoe kidney, and ureteropelvic junction obstruction (UPJ).^14-16 These can cause obstruction that leads to urinary stasis, and subsequently to stone precipitation.

Certain systemic disorders (eg, hyperparathyroidism) and situations have also been associated with stone disease and should be considered risk factors. (See Table 2^12,17).

In patients who undergo gastrointestinal bypass surgery, the development of hyperoxaluria, hypercalciuria, and decreased urinary volume are associated with an increased risk for stone formation,^18,19 and these patients should be watched for this development. Obesity and weight gain are directly proportional to nephrolithiasis risk, especially in women.^4,20

Environment plays a very important role in stone formation. Persons who live in a hot, arid climate, for example, and those who work outdoors in hot weather are at increased risk for stone formation due to excessive fluid loss from sweating.^2,4,7 (In regions where the risk for kidney stone formation is high, Romero et al⁷ predict, nephrolithiasis incidence could rise from 40% to 56% by 2050 as a result of the effects of global warming.)

Lastly, an individual’s ability (or inability) to metabolize calcium salts plays a vital role in the pathogenesis of stone disease. Intestinal calcium absorption is a major determinant of hypercalciuria, as nearly 90% of ingested calcium is absorbed in the intestines. People can broadly be divided into high or low calcium absorbers. Hypercalciuria (mean urinary calcium excretion ≥ 300 mg/d in men and ≥ 250 mg/d in women on a 1,000-mg/d calcium diet) is detected in 20% to 40% of those with calcium stones.^21-23 Hypocitraturia (mean urinary citrate excretion ≤ 320 mg/d) and hyperoxaluria (mean urinary oxalate excretion > 45 mg/d) can also increase the risk for stone formation.^12,24

Dietary Risk Factors

These are primarily related to fluid intake and dietary calcium.^7,17,25,26 Drinking less than 1 L of fluids daily is associated with an increased risk for forming stones; this risk is magnified when the urine volume is also decreased.^7,17,27 Increased dietary intake of animal protein can elevate the risk for formation of uric acid stones as a result of elevated urinary calcium and uric acid and decreased urinary citrate.¹⁷

Low dietary calcium ingestion and high oxalate consumption, resulting in increased oxalate absorption, can also exacerbate the risk for stones.^7,27 By contrast, a diet high in calcium (≥ 1,200 mg/d) reduces the risk for calcium oxalate stone recurrence,¹⁷ although the effectiveness of supplemental calcium has been questioned.^26-28

Patients who are advised to make specific dietary adjustments should later undergo repeat urine chemistries to determine the effectiveness of these changes.¹⁷

CLINICAL PRESENTATION

Nephrolithiasis typically presents with colicky flank pain, often accompanied by nausea and vomiting.²⁹ The pain radiates to the ipsilateral groin, and the patient typically has difficulty finding a comfortable position. Nephrolithiasis may also present with chronic, episodic flank pain or may even be asymptomatic.³⁰

Physical examination may reveal signs of severe pain, such as tachycardia and hypertension. Presence of fever indicates associated urinary tract infection and possibly pyelonephritis. Some larger stones can cause urinary tract obstruction; if obstruction occurs along with a preexisting urinary tract infection, it can potentially lead to pyelonephritis, pyonephrosis, and eventually urosepsis—a potentially life-threatening condition that requires immediate surgical drainage.³¹

Before a diagnosis of renal stones can be confirmed, care should be exercised to rule out the differentials, including abdominal aortic aneurysm, appendicitis, bowel obstruction, cholecystitis, drug-seeking behavior (eg, painkiller addiction), gastritis, mesenteric ischemia, musculoskeletal pain, ovarian abscess, ruptured ovarian cyst, pelvic inflammatory disease, pyelonephritis, and UPJ.^2,32,33 All patients with suspected nephrolithiasis should be carefully evaluated using laboratory and radiologic investigations.

LABORATORY EVALUATION

The goals in this two-step process are to confirm the diagnosis of nephrolithiasis, then to identify the composition of the stones formed and the associated risk factors.

Initial Evaluation

Tests include dipstick urine assessment, serum chemistries, and a complete blood count (CBC). Urine dipstick assessment may be positive for blood, protein, or leukocyte esterase, indicating stones or fragments of stones present in the urinary tract. While nearly 10% of patients with stone disease exhibit gross hematuria, nearly 90% of patients have microscopic hematuria.²

Urine osmolality should be reviewed to assess urine concentration. Serum chemistries should be ordered to evaluate kidney function. Elevated creatinine may indicate acute rather than chronic kidney disease. Electrolytes and carbon dioxide should be measured to evaluate the kidneys’ ability to concentrate urine and maintain an acid–base balance. The CBC may reveal mild leukocytosis in nephrolithiasis; presence of significant leukocytosis indicates infection.²

Secondary Evaluation

This step begins with a thorough review of the patient’s medical record and a detailed patient interview to ascertain all risk factors for stone formation (as summarized in Table 1). Specific studies to be considered are mentioned in Table 3.² This evaluation is critical to prevent formation of future stones and the associated complications. In the patient with a history of stone recurrence or stone formation of identified cause, evaluation is needed for three metabolic abnormalities—hypercalciuria, hyperuricosuria, and hypocitraturia—as these conditions predispose patients to recurrent stone formation.^1,25,34

The patient should also be encouraged to collect stones passed for further clinical evaluation. Infrared spectroscopy or quantitative wet analysis is used to identify the specific composition of the stone.^32,35

Radiologic Evaluation

Radiologic evaluation of stones is currently performed through plain x-rays, ultrasonography, and noncontrast spiral CT.^12,32,33 When a patient presents with acute signs of nephrolithiasis, a plain film x-ray of the kidneys, ureters, and bladder (KUB) is acceptable as the first imaging study, as it is inexpensive and available in most areas.³³ Plain film KUB x-rays will identify calcium oxalate, calcium phosphate, struvite, and cystine stones. However, the sensitivity of plain film x-rays has been documented between 24% and 59%, and stones that overlie a bone may be missed.^32,36 (See Figure 3.)

Hence, because of these limitations and the increasing availability of noncontrast spiral CT, noncontrast spiral CT is now the most commonly used and useful test in the diagnosis of kidney stones (sensitivity, 95% to 100%).^32,36 Spiral CT accurately defines the size as well as the location of stones, and may additionally rule out other differential diagnoses (see Figures 4a, 4b, and 4c).

Historically, IV pyelograms and urograms were considered useful in locating urinary tract stones and diagnosing related complications,¹² but these modalities carry additional risks related to IV contrast dye and radiation exposure. As a result, they have been almost completely replaced by noncontrast spiral CT because of ease of use and reduced risks.³³

Stones may also be seen on renal ultrasound—particularly uric acid stones, which are radiolucent (see Figure 5). Ultrasound is appropriate for evaluation of patients whose exposure to radiation should be limited, such as children or pregnant women. In addition to plain film x-rays, renal ultrasound may also be useful for surveillance of stones.¹²

TREATMENT

Nephrolithiasis treatment varies between acute and chronic care. Acute care for nephrolithiasis involves management of acute pain and urinary obstruction, as well as patient stabilization. Chronic care includes prevention of recurrence and management of risks.

Acute Management

Patients who present with acute nephrolithiasis most often require fluid administration, aggressive pain management, and treatment for nausea or vomiting.^31,32 Most ureteral stones measuring 5.0 mm or less will typically pass spontaneously within a few weeks,^1,29 but larger stones usually require intervention—in some cases, surgery.

Patients should be hospitalized if they require IV fluids or pain management. Isotonic IV fluids should be given to increase the urine volume and facilitate passage of stones. Care must be taken to monitor fluids, as patients with kidney stones may have a limited ability to urinate (due to urinary obstruction and/or acute or chronic renal failure). Whenever possible, all urine should be strained to collect any stones for analysis.

One new strategy to assist with stone passage is medical expulsive therapy (MET), using calcium channel blockers (eg, nifedipine) or α-blockers (eg, tamsulosin).^1,37 While there is conflicting evidence regarding the efficacy of calcium channel blockers for MET, one meta-analysis revealed a 29% improvement in stone passage with α-blockers.^1,38

Pain management can often be accomplished with NSAIDs (eg, ketorolac, diclofenac).²⁹ Since this class of medications can compromise renal function, however, they must be used with caution. Many patients require narcotic medications to control pain adequately.^39-41 Antiemetic agents (such as the H1-receptor blocker dimenhydrinate⁴²) should be administered to control nausea and vomiting.

Surgical and interventional management. Surgical intervention may be required if stones are too large to pass spontaneously (typically ≥ 8 mm); if they cause acute renal obstruction; or if they are located at a site with a potential for complications or can lead to persistent symptoms without evidence that they are passing.^1,3 Renal obstruction should be treated aggressively to preserve renal function.

The type of intervention chosen depends on the size and location of the stone, as well as the presence or absence of obstruction. Stones that measure less than 20 mm are commonly treated with extracorporeal shockwave lithotripsy (unless they overlie the sacroiliac joint), whereas patients with larger or more complex stones may require percutaneous nephrolithotomy. Nonobstructive or uncomplicated ureteral stones may be managed medically, whereas obstructive or complicated ureteral stones require placement of a stent or a nephrostomy tube until they can be removed by endoscopic surgery.^29,43

Obstruction, which may be partial or complete, is more likely when stone size exceeds 10 mm.⁴⁴ Signs of obstruction include sudden-onset, excruciating flank pain that radiates to the groin, along with nausea and vomiting (renal colic). Larger obstructive stones, such as staghorn calculi (as shown in Figures 3 and 4a), can present with symptoms of a urinary tract infection, mild flank pain, or hematuria.³³

Presence of signs of obstruction or infection mandates emergent treatment. Infections of the urinary tract (as serious as pyelonephritis or urosepsis) should be treated with antibiotics: initially with broad coverage, according to the appropriate guidelines for urinary tract infections, then tailored to the results of urine cultures. Obstruction can be relieved directly by nephrostomy tubes (and/or stents) or by interventions in which the stone is removed and normal urinary flow is restored.

Typically, endoscopy is used for direct removal of stones that cause obstruction.⁴⁴ Nephrostomy tubes and ureteral stents (see Figures 6a and 6b) are placed to relieve obstruction temporarily and provide an alternate route for drainage of urine. The goal is to prevent renal damage until the obstruction can be relieved. Stents can remain in place for several months, but nephrostomy tubes are associated with a higher risk for infection (because they are externalized), and duration of use should be limited to only a few weeks.^12,29,38

Stents are also associated with infections, but coated stents are available to reduce infection. As with any catheter material inserted into the urinary tract, ureteral stents are a prime location for development of a persistent bacterial biofilm, thus leading to infection. Recent advances in stent manufacturing have included coating stents with various biomaterials to decrease the development of this bacterial biofilm. In a preliminary study in 10 patients using a diamond-like, carbon-coated ureteral stent, Laube et al⁴⁵ demonstrated a reduction in formation of this biofilm, hence lowering the probability of stent-induced infection.

Chronic Stone Management

As previously mentioned, one of the seminal characteristics of stone disease is its ability to recur. After incidental detection of kidney stones through routine diagnostic procedures, the risk for recurrence in patients who do not receive chronic medical management is 30% to 40% within five years.^17,28 In treated patients, by comparison, this risk falls by approximately 50%.^17,26

Patients with a history of stone recurrence must be evaluated for metabolic defects that precipitate stones, since their risk for chronic kidney disease is increased.³⁴ All patients with a history of stone disease should be instructed to increase their fluid intake to maintain a daily urinary output of at least 2.5 L, unless contraindications exist.³⁴

In patients with calcium-based stones who do not benefit from conservative treatment (ie, a low-sodium diet and other dietary modifications), thiazide diuretics may help reduce urinary calcium.^1,46

Struvite stones can be prevented through use of long-term antibiotics to reduce the risk for urinary tract infection and by maintaining urinary pH levels below 6.0.^17,27,34

For patients with uric acid stones, allopurinol may be prescribed to lower uric acid levels; moreover, the solubility of uric acid is greatly increased at higher pH, so it is beneficial to treat these patients with citrate to maintain their urinary pH above 6.0.^47,34

Ensuring a high urine output (≥ 4 L/d34) and alkalinizing urine can help prevent recurrence of cystine stones.^17,33 Treatment with potassium citrate has been shown to maintain a urinary pH of 6.5 to 7.0.³⁴

CONCLUSION

The ever-increasing significance of nephrolithiasis has mandated an organized and systematic management approach. Indeed, the diagnosis and initial therapy for kidney stones have undergone considerable evolution in recent years. The basic tenets of nephrolithiasis management include early diagnosis and pertinent treatment as well as adequate prophylaxis to prevent subsequent stone recurrence.

Kidney or urinary tract stones (whose presence is referred to as nephrolithiasis) are hard, crystalline mineral concretions that form within the kidney or the urinary tract. They are a common problem, with an estimated annual incidence of 1% and a lifetime risk of 15% to 25%; this constitutes a significant health care burden, particularly for people of working age.¹

Nephrolithiasis is currently more prevalent in men than in women (13% vs 7%, respectively), and it is three to four times more likely to present in white than nonwhite patients.² However, recent epidemiologic data suggest an alarming increase in the number of women and adolescents primarily diagnosed with stone disease.^3-6 The pattern of increasing incidence in women can be attributed in part to changes in diet and lifestyle.^4,5 Figure 1⁷ represents the prevalence of stone disease, specific to gender and race.^2,4

Due to kidney stones’ relatively common occurrence, the diagnosis, management, and prevention of stone disease have become increasingly relevant for the primary care practitioner. In the course of stone disease management, the clinician should be aware of a vital fact: Stones have a tendency to recur.¹ Indeed, evidence suggests that following an initial diagnosis of nephrolithiasis, the probability of kidney stone recurrence increases to nearly 50% after five years.⁸

Even more concerning, evidence from several studies suggests that patients with a history of stone disease have a higher probability of experiencing a significant reduction in renal function (ie, decrease in glomerular filtration rate) and hence end-stage renal disease, when compared with non–stone formers.^9-11 This accentuates the importance of early diagnosis, treatment, and initiation of steps to prevent further recurrence of this condition.

PATHOGENESIS

Stones in the urinary tract develop under specific urinary conditions, including supersaturation of the urine with stone-forming ions (ie, calcium, oxalate, uric acid, and phosphate) and deficiency of urinary stone inhibitors (citrate, magnesium, zinc, macromolecules, and pyrophosphate). Stone formation occurs in a mucoprotein matrix that attaches to the renal epithelium. Urine becomes supersaturated as a result of increasing levels of solutes (such as the stone-forming ions) and/or decreasing free water volume. When the concentration of stone-forming ions exceeds solubility in the urine (equilibrium solubility product), these ions can combine to form crystals.^12,13

Stones are typed based on the ion composition of their crystals (see Table 1^2,12).

Once crystals are formed, they can also aggregate with other crystals, developing into a calculus.¹² Urinary pH influences ion crystallization: Alkaline urine favors formation of calcium and/or phosphate stones, whereas acidic urine favors uric acid and cystine stone formation.¹³

Kidney stones can be divided into four broad types: calcium-based, struvite, uric acid, and cystine stones (see Figure 2). Among these, calcium-based stones are by far the most common, with nearly 80% of stones composed of calcium compounds (usually calcium oxalate, and rarely calcium phosphate).⁴ The etiologies of these four types are vastly different, and prevention of stone formation must be tailored to the stone type. Once stones form, however, the appropriate treatment strategies have many similarities.

RISK FACTORS

Specific risk factors for stone formation vary widely and are unique to the type of stone. A thorough history, including a family or personal history of stone disease and dietary history, must be part of the initial work-up when a patient is being evaluated for stone disease; patients with any of these risk factors should be investigated further.

The risk factors for stone disease can be broadly categorized as either individual risk factors or dietary risk factors.

Individual Risk Factors

A positive family history increases the risk for stone formation by two- to three-fold. Other individual risk factors include congenital anatomic defects, such as medullary sponge kidney, horseshoe kidney, and ureteropelvic junction obstruction (UPJ).^14-16 These can cause obstruction that leads to urinary stasis, and subsequently to stone precipitation.

Certain systemic disorders (eg, hyperparathyroidism) and situations have also been associated with stone disease and should be considered risk factors. (See Table 2^12,17).

In patients who undergo gastrointestinal bypass surgery, the development of hyperoxaluria, hypercalciuria, and decreased urinary volume are associated with an increased risk for stone formation,^18,19 and these patients should be watched for this development. Obesity and weight gain are directly proportional to nephrolithiasis risk, especially in women.^4,20

Environment plays a very important role in stone formation. Persons who live in a hot, arid climate, for example, and those who work outdoors in hot weather are at increased risk for stone formation due to excessive fluid loss from sweating.^2,4,7 (In regions where the risk for kidney stone formation is high, Romero et al⁷ predict, nephrolithiasis incidence could rise from 40% to 56% by 2050 as a result of the effects of global warming.)

Lastly, an individual’s ability (or inability) to metabolize calcium salts plays a vital role in the pathogenesis of stone disease. Intestinal calcium absorption is a major determinant of hypercalciuria, as nearly 90% of ingested calcium is absorbed in the intestines. People can broadly be divided into high or low calcium absorbers. Hypercalciuria (mean urinary calcium excretion ≥ 300 mg/d in men and ≥ 250 mg/d in women on a 1,000-mg/d calcium diet) is detected in 20% to 40% of those with calcium stones.^21-23 Hypocitraturia (mean urinary citrate excretion ≤ 320 mg/d) and hyperoxaluria (mean urinary oxalate excretion > 45 mg/d) can also increase the risk for stone formation.^12,24

Dietary Risk Factors

These are primarily related to fluid intake and dietary calcium.^7,17,25,26 Drinking less than 1 L of fluids daily is associated with an increased risk for forming stones; this risk is magnified when the urine volume is also decreased.^7,17,27 Increased dietary intake of animal protein can elevate the risk for formation of uric acid stones as a result of elevated urinary calcium and uric acid and decreased urinary citrate.¹⁷

Low dietary calcium ingestion and high oxalate consumption, resulting in increased oxalate absorption, can also exacerbate the risk for stones.^7,27 By contrast, a diet high in calcium (≥ 1,200 mg/d) reduces the risk for calcium oxalate stone recurrence,¹⁷ although the effectiveness of supplemental calcium has been questioned.^26-28

Patients who are advised to make specific dietary adjustments should later undergo repeat urine chemistries to determine the effectiveness of these changes.¹⁷

CLINICAL PRESENTATION

Nephrolithiasis typically presents with colicky flank pain, often accompanied by nausea and vomiting.²⁹ The pain radiates to the ipsilateral groin, and the patient typically has difficulty finding a comfortable position. Nephrolithiasis may also present with chronic, episodic flank pain or may even be asymptomatic.³⁰

Physical examination may reveal signs of severe pain, such as tachycardia and hypertension. Presence of fever indicates associated urinary tract infection and possibly pyelonephritis. Some larger stones can cause urinary tract obstruction; if obstruction occurs along with a preexisting urinary tract infection, it can potentially lead to pyelonephritis, pyonephrosis, and eventually urosepsis—a potentially life-threatening condition that requires immediate surgical drainage.³¹

Before a diagnosis of renal stones can be confirmed, care should be exercised to rule out the differentials, including abdominal aortic aneurysm, appendicitis, bowel obstruction, cholecystitis, drug-seeking behavior (eg, painkiller addiction), gastritis, mesenteric ischemia, musculoskeletal pain, ovarian abscess, ruptured ovarian cyst, pelvic inflammatory disease, pyelonephritis, and UPJ.^2,32,33 All patients with suspected nephrolithiasis should be carefully evaluated using laboratory and radiologic investigations.

LABORATORY EVALUATION

The goals in this two-step process are to confirm the diagnosis of nephrolithiasis, then to identify the composition of the stones formed and the associated risk factors.

Initial Evaluation

Tests include dipstick urine assessment, serum chemistries, and a complete blood count (CBC). Urine dipstick assessment may be positive for blood, protein, or leukocyte esterase, indicating stones or fragments of stones present in the urinary tract. While nearly 10% of patients with stone disease exhibit gross hematuria, nearly 90% of patients have microscopic hematuria.²

Urine osmolality should be reviewed to assess urine concentration. Serum chemistries should be ordered to evaluate kidney function. Elevated creatinine may indicate acute rather than chronic kidney disease. Electrolytes and carbon dioxide should be measured to evaluate the kidneys’ ability to concentrate urine and maintain an acid–base balance. The CBC may reveal mild leukocytosis in nephrolithiasis; presence of significant leukocytosis indicates infection.²

Secondary Evaluation

This step begins with a thorough review of the patient’s medical record and a detailed patient interview to ascertain all risk factors for stone formation (as summarized in Table 1). Specific studies to be considered are mentioned in Table 3.² This evaluation is critical to prevent formation of future stones and the associated complications. In the patient with a history of stone recurrence or stone formation of identified cause, evaluation is needed for three metabolic abnormalities—hypercalciuria, hyperuricosuria, and hypocitraturia—as these conditions predispose patients to recurrent stone formation.^1,25,34

The patient should also be encouraged to collect stones passed for further clinical evaluation. Infrared spectroscopy or quantitative wet analysis is used to identify the specific composition of the stone.^32,35

Radiologic Evaluation

Radiologic evaluation of stones is currently performed through plain x-rays, ultrasonography, and noncontrast spiral CT.^12,32,33 When a patient presents with acute signs of nephrolithiasis, a plain film x-ray of the kidneys, ureters, and bladder (KUB) is acceptable as the first imaging study, as it is inexpensive and available in most areas.³³ Plain film KUB x-rays will identify calcium oxalate, calcium phosphate, struvite, and cystine stones. However, the sensitivity of plain film x-rays has been documented between 24% and 59%, and stones that overlie a bone may be missed.^32,36 (See Figure 3.)

Hence, because of these limitations and the increasing availability of noncontrast spiral CT, noncontrast spiral CT is now the most commonly used and useful test in the diagnosis of kidney stones (sensitivity, 95% to 100%).^32,36 Spiral CT accurately defines the size as well as the location of stones, and may additionally rule out other differential diagnoses (see Figures 4a, 4b, and 4c).

Historically, IV pyelograms and urograms were considered useful in locating urinary tract stones and diagnosing related complications,¹² but these modalities carry additional risks related to IV contrast dye and radiation exposure. As a result, they have been almost completely replaced by noncontrast spiral CT because of ease of use and reduced risks.³³

Stones may also be seen on renal ultrasound—particularly uric acid stones, which are radiolucent (see Figure 5). Ultrasound is appropriate for evaluation of patients whose exposure to radiation should be limited, such as children or pregnant women. In addition to plain film x-rays, renal ultrasound may also be useful for surveillance of stones.¹²

TREATMENT

Nephrolithiasis treatment varies between acute and chronic care. Acute care for nephrolithiasis involves management of acute pain and urinary obstruction, as well as patient stabilization. Chronic care includes prevention of recurrence and management of risks.

Acute Management

Patients who present with acute nephrolithiasis most often require fluid administration, aggressive pain management, and treatment for nausea or vomiting.^31,32 Most ureteral stones measuring 5.0 mm or less will typically pass spontaneously within a few weeks,^1,29 but larger stones usually require intervention—in some cases, surgery.

Patients should be hospitalized if they require IV fluids or pain management. Isotonic IV fluids should be given to increase the urine volume and facilitate passage of stones. Care must be taken to monitor fluids, as patients with kidney stones may have a limited ability to urinate (due to urinary obstruction and/or acute or chronic renal failure). Whenever possible, all urine should be strained to collect any stones for analysis.

One new strategy to assist with stone passage is medical expulsive therapy (MET), using calcium channel blockers (eg, nifedipine) or α-blockers (eg, tamsulosin).^1,37 While there is conflicting evidence regarding the efficacy of calcium channel blockers for MET, one meta-analysis revealed a 29% improvement in stone passage with α-blockers.^1,38

Pain management can often be accomplished with NSAIDs (eg, ketorolac, diclofenac).²⁹ Since this class of medications can compromise renal function, however, they must be used with caution. Many patients require narcotic medications to control pain adequately.^39-41 Antiemetic agents (such as the H1-receptor blocker dimenhydrinate⁴²) should be administered to control nausea and vomiting.

Surgical and interventional management. Surgical intervention may be required if stones are too large to pass spontaneously (typically ≥ 8 mm); if they cause acute renal obstruction; or if they are located at a site with a potential for complications or can lead to persistent symptoms without evidence that they are passing.^1,3 Renal obstruction should be treated aggressively to preserve renal function.

The type of intervention chosen depends on the size and location of the stone, as well as the presence or absence of obstruction. Stones that measure less than 20 mm are commonly treated with extracorporeal shockwave lithotripsy (unless they overlie the sacroiliac joint), whereas patients with larger or more complex stones may require percutaneous nephrolithotomy. Nonobstructive or uncomplicated ureteral stones may be managed medically, whereas obstructive or complicated ureteral stones require placement of a stent or a nephrostomy tube until they can be removed by endoscopic surgery.^29,43

Obstruction, which may be partial or complete, is more likely when stone size exceeds 10 mm.⁴⁴ Signs of obstruction include sudden-onset, excruciating flank pain that radiates to the groin, along with nausea and vomiting (renal colic). Larger obstructive stones, such as staghorn calculi (as shown in Figures 3 and 4a), can present with symptoms of a urinary tract infection, mild flank pain, or hematuria.³³

Presence of signs of obstruction or infection mandates emergent treatment. Infections of the urinary tract (as serious as pyelonephritis or urosepsis) should be treated with antibiotics: initially with broad coverage, according to the appropriate guidelines for urinary tract infections, then tailored to the results of urine cultures. Obstruction can be relieved directly by nephrostomy tubes (and/or stents) or by interventions in which the stone is removed and normal urinary flow is restored.

Typically, endoscopy is used for direct removal of stones that cause obstruction.⁴⁴ Nephrostomy tubes and ureteral stents (see Figures 6a and 6b) are placed to relieve obstruction temporarily and provide an alternate route for drainage of urine. The goal is to prevent renal damage until the obstruction can be relieved. Stents can remain in place for several months, but nephrostomy tubes are associated with a higher risk for infection (because they are externalized), and duration of use should be limited to only a few weeks.^12,29,38

Stents are also associated with infections, but coated stents are available to reduce infection. As with any catheter material inserted into the urinary tract, ureteral stents are a prime location for development of a persistent bacterial biofilm, thus leading to infection. Recent advances in stent manufacturing have included coating stents with various biomaterials to decrease the development of this bacterial biofilm. In a preliminary study in 10 patients using a diamond-like, carbon-coated ureteral stent, Laube et al⁴⁵ demonstrated a reduction in formation of this biofilm, hence lowering the probability of stent-induced infection.

Chronic Stone Management

As previously mentioned, one of the seminal characteristics of stone disease is its ability to recur. After incidental detection of kidney stones through routine diagnostic procedures, the risk for recurrence in patients who do not receive chronic medical management is 30% to 40% within five years.^17,28 In treated patients, by comparison, this risk falls by approximately 50%.^17,26

Patients with a history of stone recurrence must be evaluated for metabolic defects that precipitate stones, since their risk for chronic kidney disease is increased.³⁴ All patients with a history of stone disease should be instructed to increase their fluid intake to maintain a daily urinary output of at least 2.5 L, unless contraindications exist.³⁴

In patients with calcium-based stones who do not benefit from conservative treatment (ie, a low-sodium diet and other dietary modifications), thiazide diuretics may help reduce urinary calcium.^1,46

Struvite stones can be prevented through use of long-term antibiotics to reduce the risk for urinary tract infection and by maintaining urinary pH levels below 6.0.^17,27,34

For patients with uric acid stones, allopurinol may be prescribed to lower uric acid levels; moreover, the solubility of uric acid is greatly increased at higher pH, so it is beneficial to treat these patients with citrate to maintain their urinary pH above 6.0.^47,34

Ensuring a high urine output (≥ 4 L/d34) and alkalinizing urine can help prevent recurrence of cystine stones.^17,33 Treatment with potassium citrate has been shown to maintain a urinary pH of 6.5 to 7.0.³⁴

CONCLUSION

The ever-increasing significance of nephrolithiasis has mandated an organized and systematic management approach. Indeed, the diagnosis and initial therapy for kidney stones have undergone considerable evolution in recent years. The basic tenets of nephrolithiasis management include early diagnosis and pertinent treatment as well as adequate prophylaxis to prevent subsequent stone recurrence.

All patients admitted to the hospital in noncritical care settings should have their blood glucose tested, according to a new clinical practice guideline from the Endocrine Society.

Unlike previous guidelines based largely on data from intensive care and critical care settings, the new guideline focuses on glucose management in noncritical settings, with special emphasis on systemic issues such as patient transition between hospital units and from inpatient to outpatient settings. The guidelines also include detailed guidance for creating systems and protocols to ensure optimal patient management and safety (Diabetes Care [2009;32:1119-31]).

"Management of Hyperglycemia in Hospitalized Patients in Non-Critical Care Setting: An Endocrine Society Clinical Practice Guideline" was developed by an eight-member panel with representatives from the American Diabetes Association, American Heart Association, American Association of Diabetes Educators, European Society of Endocrinology, and the Society of Hospital Medicine. The lead author was Dr. Guillermo E. Umpierrez, professor of medicine at Emory University, and chief of diabetes and endocrinology at Grady Memorial Hospital, both in Atlanta.

The guideline has eight sections, all focused on the noncritical hospital setting: diagnosis and recognition of hyperglycemia and diabetes, monitoring glycemia, glycemic targets, management of hyperglycemia, special situations, recognition and management of hypoglycemia, implementation of a glycemic control program, and patient and professional education.

The panel’s advice was characterized as "recommended" for items with strong evidence and "suggested" for items with less evidence. In the first of the guideline’s eight sections, the panel recommended all patients be assessed on admission for a history of diabetes and suggested laboratory blood glucose testing on admission for all patients, regardless of prior diagnosis of diabetes.

"There’s abundant data to show that a very large number of people … [are admitted] with undiagnosed diabetes and people also develop stress hyperglycemia" and both conditions affect patient outcomes, Dr. Richard Hellman said in an interview. Dr. Hellman is a coauthor of the guidelines and an endocrinologist who is a clinical professor of medicine at the University of Missouri–Kansas City.

<[stk -3]>While the accuracy of point-of-care testing is not optimal, the panel recommended bedside glucose testing of capillary blood because of the need to time glucose measures to the patient’s nutritional intake and medication regimens. Personal glucose meters should not be used, and continuous glucose monitors while "promising," have not been adequately tested in acute care and therefore can’t be recommended for hospital use at this time, Dr. Umpierrez and his associates wrote.<[etk]>

As in the 2009 guideline that addressed critical care patients, the glycemic targets are less than 140 mg/dL premeal and less than 180 mg/dL random for the majority of hospitalized patients with noncritical illness. Lower targets might be considered among patients who are able to achieve them without hypoglycemia, while higher targets might be appropriate for those at high risk for hypoglycemia and those with a limited life expectancy.

Medical nutrition therapy is recommended as a component of the glycemic management program for all hospitalized patients with diabetes and hyperglycemia. Meals with consistent amounts of carbohydrate are suggested to help coordinate dosing of rapid-acting insulin.

Insulin therapy is the preferred method for achieving glycemic control in all hospitalized patients with diabetes and hyperglycemia, the panel said. At admission, they suggested, oral hypoglycemic agents should be discontinued and insulin therapy should be initiated in acutely ill patients with type 2 diabetes. Oral agents are contraindicated in hospitalized patients with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, and in any patient given intravenous contrast dye, the authors noted.

<[stk -3]>For patients who are eating, the panel recommended scheduled subcutaneous basal or intermediate-acting insulin once or twice daily in combination with rapid- or short-acting insulin administered before meals. <[etk]>

Prolonged use of sliding-scale therapy should be avoided as the sole method for glycemic control, the panel wrote.

"There’s abundant data to show that a very large number of people [are admitted] with undiagnosed diabetes and people also develop stress hyperglycemia."

<[stk -3]>Two recent studies led by Dr. Umpierrez show basal-bolus insulin regimens to be superior to sliding scale insulin treatment. One of those studies was done in noncritically ill hospitalized patients with type 2 diabetes (Diabetes Care 2007;30:2181-6), and the other was done in type 2 patients undergoing general surgery (Diabetes Care 2011;34:256-61). <[etk]>

Diabetes self-management education is recommended for patients, including both short-term "survival skills" education in the hospital and referral to community sources for ongoing patient education following discharge.

At discharge, the patient’s preadmission regimen – either insulin or oral and noninsulin injectable antidiabetic drugs – can be reinstituted so long as the patient’s preadmission glycemic control was good and there are no contraindications. To assess safety and efficacy, insulin administration should be initiated at least 1 day before discharge. Patients and their caregivers should receive oral and written instructions for home glycemic management.

The guidelines also address transition from intravenous to subcutaneous insulin therapy, glycemic management of patients who are receiving enteral or parenteral nutrition, perioperative blood glucose control, and management of glucocorticoid-induced diabetes.

<[stk -3]>The panel recommended the development of protocols with specific directions for avoiding and managing hypoglycemia as well as the implementation of hospital-wide, nurse-initiated hypoglycemia treatment protocols and a system for tracking with root cause analysis the frequency of hypoglycemic events. The document lists key components of such protocols, and provides suggested nurse-initiated strategies.<[etk]>

<[stk -3]>Hospitals are advised to provide administrative support for an interdisciplinary steering committee targeting a systems approach to improve care of inpatients with hyperglycemia and diabetes. Uniform methods for collecting and evaluating point-of-care testing data and insulin use information in hospitals are recommended, as are the provision of accurate devices for glucose measurement at the bedside with ongoing staff education and competency assessments.

Dr. Hellman and Dr. Umpierrez have no financial disclosures, but three other members of the guideline panel declared relationships with manufacturers of diabetes-related products.

All patients admitted to the hospital in noncritical care settings should have their blood glucose tested, according to a new clinical practice guideline from the Endocrine Society.

Unlike previous guidelines based largely on data from intensive care and critical care settings, the new guideline focuses on glucose management in noncritical settings, with special emphasis on systemic issues such as patient transition between hospital units and from inpatient to outpatient settings. The guidelines also include detailed guidance for creating systems and protocols to ensure optimal patient management and safety (Diabetes Care [2009;32:1119-31]).

"Management of Hyperglycemia in Hospitalized Patients in Non-Critical Care Setting: An Endocrine Society Clinical Practice Guideline" was developed by an eight-member panel with representatives from the American Diabetes Association, American Heart Association, American Association of Diabetes Educators, European Society of Endocrinology, and the Society of Hospital Medicine. The lead author was Dr. Guillermo E. Umpierrez, professor of medicine at Emory University, and chief of diabetes and endocrinology at Grady Memorial Hospital, both in Atlanta.

The guideline has eight sections, all focused on the noncritical hospital setting: diagnosis and recognition of hyperglycemia and diabetes, monitoring glycemia, glycemic targets, management of hyperglycemia, special situations, recognition and management of hypoglycemia, implementation of a glycemic control program, and patient and professional education.

The panel’s advice was characterized as "recommended" for items with strong evidence and "suggested" for items with less evidence. In the first of the guideline’s eight sections, the panel recommended all patients be assessed on admission for a history of diabetes and suggested laboratory blood glucose testing on admission for all patients, regardless of prior diagnosis of diabetes.

"There’s abundant data to show that a very large number of people … [are admitted] with undiagnosed diabetes and people also develop stress hyperglycemia" and both conditions affect patient outcomes, Dr. Richard Hellman said in an interview. Dr. Hellman is a coauthor of the guidelines and an endocrinologist who is a clinical professor of medicine at the University of Missouri–Kansas City.

<[stk -3]>While the accuracy of point-of-care testing is not optimal, the panel recommended bedside glucose testing of capillary blood because of the need to time glucose measures to the patient’s nutritional intake and medication regimens. Personal glucose meters should not be used, and continuous glucose monitors while "promising," have not been adequately tested in acute care and therefore can’t be recommended for hospital use at this time, Dr. Umpierrez and his associates wrote.<[etk]>

As in the 2009 guideline that addressed critical care patients, the glycemic targets are less than 140 mg/dL premeal and less than 180 mg/dL random for the majority of hospitalized patients with noncritical illness. Lower targets might be considered among patients who are able to achieve them without hypoglycemia, while higher targets might be appropriate for those at high risk for hypoglycemia and those with a limited life expectancy.

Medical nutrition therapy is recommended as a component of the glycemic management program for all hospitalized patients with diabetes and hyperglycemia. Meals with consistent amounts of carbohydrate are suggested to help coordinate dosing of rapid-acting insulin.

Insulin therapy is the preferred method for achieving glycemic control in all hospitalized patients with diabetes and hyperglycemia, the panel said. At admission, they suggested, oral hypoglycemic agents should be discontinued and insulin therapy should be initiated in acutely ill patients with type 2 diabetes. Oral agents are contraindicated in hospitalized patients with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, and in any patient given intravenous contrast dye, the authors noted.

<[stk -3]>For patients who are eating, the panel recommended scheduled subcutaneous basal or intermediate-acting insulin once or twice daily in combination with rapid- or short-acting insulin administered before meals. <[etk]>

Prolonged use of sliding-scale therapy should be avoided as the sole method for glycemic control, the panel wrote.

"There’s abundant data to show that a very large number of people [are admitted] with undiagnosed diabetes and people also develop stress hyperglycemia."

<[stk -3]>Two recent studies led by Dr. Umpierrez show basal-bolus insulin regimens to be superior to sliding scale insulin treatment. One of those studies was done in noncritically ill hospitalized patients with type 2 diabetes (Diabetes Care 2007;30:2181-6), and the other was done in type 2 patients undergoing general surgery (Diabetes Care 2011;34:256-61). <[etk]>

Diabetes self-management education is recommended for patients, including both short-term "survival skills" education in the hospital and referral to community sources for ongoing patient education following discharge.

At discharge, the patient’s preadmission regimen – either insulin or oral and noninsulin injectable antidiabetic drugs – can be reinstituted so long as the patient’s preadmission glycemic control was good and there are no contraindications. To assess safety and efficacy, insulin administration should be initiated at least 1 day before discharge. Patients and their caregivers should receive oral and written instructions for home glycemic management.

The guidelines also address transition from intravenous to subcutaneous insulin therapy, glycemic management of patients who are receiving enteral or parenteral nutrition, perioperative blood glucose control, and management of glucocorticoid-induced diabetes.

<[stk -3]>The panel recommended the development of protocols with specific directions for avoiding and managing hypoglycemia as well as the implementation of hospital-wide, nurse-initiated hypoglycemia treatment protocols and a system for tracking with root cause analysis the frequency of hypoglycemic events. The document lists key components of such protocols, and provides suggested nurse-initiated strategies.<[etk]>

<[stk -3]>Hospitals are advised to provide administrative support for an interdisciplinary steering committee targeting a systems approach to improve care of inpatients with hyperglycemia and diabetes. Uniform methods for collecting and evaluating point-of-care testing data and insulin use information in hospitals are recommended, as are the provision of accurate devices for glucose measurement at the bedside with ongoing staff education and competency assessments.

Dr. Hellman and Dr. Umpierrez have no financial disclosures, but three other members of the guideline panel declared relationships with manufacturers of diabetes-related products.

All patients admitted to the hospital in noncritical care settings should have their blood glucose tested, according to a new clinical practice guideline from the Endocrine Society.

Unlike previous guidelines based largely on data from intensive care and critical care settings, the new guideline focuses on glucose management in noncritical settings, with special emphasis on systemic issues such as patient transition between hospital units and from inpatient to outpatient settings. The guidelines also include detailed guidance for creating systems and protocols to ensure optimal patient management and safety (Diabetes Care [2009;32:1119-31]).

"Management of Hyperglycemia in Hospitalized Patients in Non-Critical Care Setting: An Endocrine Society Clinical Practice Guideline" was developed by an eight-member panel with representatives from the American Diabetes Association, American Heart Association, American Association of Diabetes Educators, European Society of Endocrinology, and the Society of Hospital Medicine. The lead author was Dr. Guillermo E. Umpierrez, professor of medicine at Emory University, and chief of diabetes and endocrinology at Grady Memorial Hospital, both in Atlanta.

The guideline has eight sections, all focused on the noncritical hospital setting: diagnosis and recognition of hyperglycemia and diabetes, monitoring glycemia, glycemic targets, management of hyperglycemia, special situations, recognition and management of hypoglycemia, implementation of a glycemic control program, and patient and professional education.

The panel’s advice was characterized as "recommended" for items with strong evidence and "suggested" for items with less evidence. In the first of the guideline’s eight sections, the panel recommended all patients be assessed on admission for a history of diabetes and suggested laboratory blood glucose testing on admission for all patients, regardless of prior diagnosis of diabetes.

"There’s abundant data to show that a very large number of people … [are admitted] with undiagnosed diabetes and people also develop stress hyperglycemia" and both conditions affect patient outcomes, Dr. Richard Hellman said in an interview. Dr. Hellman is a coauthor of the guidelines and an endocrinologist who is a clinical professor of medicine at the University of Missouri–Kansas City.

<[stk -3]>While the accuracy of point-of-care testing is not optimal, the panel recommended bedside glucose testing of capillary blood because of the need to time glucose measures to the patient’s nutritional intake and medication regimens. Personal glucose meters should not be used, and continuous glucose monitors while "promising," have not been adequately tested in acute care and therefore can’t be recommended for hospital use at this time, Dr. Umpierrez and his associates wrote.<[etk]>

As in the 2009 guideline that addressed critical care patients, the glycemic targets are less than 140 mg/dL premeal and less than 180 mg/dL random for the majority of hospitalized patients with noncritical illness. Lower targets might be considered among patients who are able to achieve them without hypoglycemia, while higher targets might be appropriate for those at high risk for hypoglycemia and those with a limited life expectancy.

Medical nutrition therapy is recommended as a component of the glycemic management program for all hospitalized patients with diabetes and hyperglycemia. Meals with consistent amounts of carbohydrate are suggested to help coordinate dosing of rapid-acting insulin.

Insulin therapy is the preferred method for achieving glycemic control in all hospitalized patients with diabetes and hyperglycemia, the panel said. At admission, they suggested, oral hypoglycemic agents should be discontinued and insulin therapy should be initiated in acutely ill patients with type 2 diabetes. Oral agents are contraindicated in hospitalized patients with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, and in any patient given intravenous contrast dye, the authors noted.

<[stk -3]>For patients who are eating, the panel recommended scheduled subcutaneous basal or intermediate-acting insulin once or twice daily in combination with rapid- or short-acting insulin administered before meals. <[etk]>

Prolonged use of sliding-scale therapy should be avoided as the sole method for glycemic control, the panel wrote.

"There’s abundant data to show that a very large number of people [are admitted] with undiagnosed diabetes and people also develop stress hyperglycemia."

<[stk -3]>Two recent studies led by Dr. Umpierrez show basal-bolus insulin regimens to be superior to sliding scale insulin treatment. One of those studies was done in noncritically ill hospitalized patients with type 2 diabetes (Diabetes Care 2007;30:2181-6), and the other was done in type 2 patients undergoing general surgery (Diabetes Care 2011;34:256-61). <[etk]>

Diabetes self-management education is recommended for patients, including both short-term "survival skills" education in the hospital and referral to community sources for ongoing patient education following discharge.

At discharge, the patient’s preadmission regimen – either insulin or oral and noninsulin injectable antidiabetic drugs – can be reinstituted so long as the patient’s preadmission glycemic control was good and there are no contraindications. To assess safety and efficacy, insulin administration should be initiated at least 1 day before discharge. Patients and their caregivers should receive oral and written instructions for home glycemic management.

The guidelines also address transition from intravenous to subcutaneous insulin therapy, glycemic management of patients who are receiving enteral or parenteral nutrition, perioperative blood glucose control, and management of glucocorticoid-induced diabetes.

<[stk -3]>The panel recommended the development of protocols with specific directions for avoiding and managing hypoglycemia as well as the implementation of hospital-wide, nurse-initiated hypoglycemia treatment protocols and a system for tracking with root cause analysis the frequency of hypoglycemic events. The document lists key components of such protocols, and provides suggested nurse-initiated strategies.<[etk]>

<[stk -3]>Hospitals are advised to provide administrative support for an interdisciplinary steering committee targeting a systems approach to improve care of inpatients with hyperglycemia and diabetes. Uniform methods for collecting and evaluating point-of-care testing data and insulin use information in hospitals are recommended, as are the provision of accurate devices for glucose measurement at the bedside with ongoing staff education and competency assessments.

Dr. Hellman and Dr. Umpierrez have no financial disclosures, but three other members of the guideline panel declared relationships with manufacturers of diabetes-related products.

After 13 years of follow-up, men who underwent annual screening for prostate cancer were no less likely to die of prostate cancer than were men who received usual care and opportunistic screening.

Cumulative mortality rates from prostate cancer differed by a statistically insignificant rate of 0.3 deaths per 10,000 person years in the intervention and usual-care arms of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial, published online Jan. 6 in the Journal of the National Cancer Institute. Further, age, comorbidity status, and pretrial prostate-specific antigen (PSA) testing did not influence the results, wrote Dr. Gerald L. Andriole of Washington University, St. Louis, and his colleagues.

The PLCO trial randomly assigned 76,693 men, aged 55-74 years, to either 6 years of annual PSA screening in combination with 4 years of annual digital rectal examination (38,343) or to usual care (38,350), which included screening tests as recommended by physicians.

The goal was to evaluate the effect of adding annual screening and compare outcomes to the opportunistic screening already in place, the researchers said. It was expected that the impacts of earlier diagnosis and a persistent excess of cases because of annual screening in the intervention arm would exceed the impacts of opportunistic screening.

Prior to the study, 44% of all participants had undergone PSA screening. During the trial, 52% of the usual-care group, compared with the entire intervention group, underwent PSA testing.

The researchers had previously reported 7- and 10-year follow-up results. At 7 years of follow-up, yearly screening was associated with an increased incidence of prostate cancer diagnosis as compared with usual care. The rates of prostate cancer mortality and of all-cause mortality, however, were the same for both groups. Similarly, after 10 years of follow-up, no mortality benefit was observed for the intervention, the investigators reported previously (N. Engl. J. Med. 2009;360:1320-1328).

For the current study, Dr. Andriole and his associates ascertained all incident prostate cancer diagnoses and deaths through 13 years of follow-up or through December 31, 2009, and estimated relative risks as the ratio of observed rates of diagnoses and deaths in the intervention and control arms. They examined the interactions between prostate cancer mortality by trial arm and age, comorbidities, and pretrial PSA testing using Poisson regression modeling (J. Natl. Cancer Inst. 6 Jan. 2012 [doi: 10.1093/jnci/djr500]).

At 13 years, 4,250 of the 38,340 participants in the intervention arm had been diagnosed with prostate cancer, compared with 3,815 of the 38,345 control participants. "The cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10,000 person-years, respectively, resulting in a statistically significant 12% relative increase in the intervention arm," the authors wrote. Of the prostate cancer diagnoses, 401 in the intervention arm and 454 in the usual care arm were high-grade prostate cancers with Gleason scores of 8-10.

At 13 years of follow-up, there were 158 deaths in the intervention arm and 145 deaths in the usual-care arm. "The cumulative mortality rates from prostate cancer were 3.7 and 3.4 deaths per 10,000 person-years, respectively, resulting in a non-statistically significant difference between the two arms," according to the authors. The examination of mortality rates per 10,000 person-years and relative risks of prostate cancer mortality by age, comorbidity, and pretrial PSA testing produced no statistically significant interactions.

Deaths from all causes other than prostate, lung, and colorectal cancers differed by a factor of "borderline" statistical significance, with 5,783 deaths in the intervention arm and 5,982 in the usual-care arm, Dr. Andriole and his associates wrote. "Intervention and control arms showed 23% and 22% deaths, respectively, from non-PLCO cancers, and 21% and 19% deaths, respectively, from ischemic heart disease."

The authors acknowledged limitations of the study, including the possibility that a reduction in prostate cancer mortality in the analysis has somehow been masked by "the sticking diagnosis effect." In other words, more deaths were attributed to prostate cancer in the intervention arm. This possibility is supported by the statistically significant lower all-cause mortality in the intervention group as compared with the usual-care group. The percentage of deaths from other causes was higher in the intervention arm, so an error in cause of death attribution likely does not account for the excess prostate cancer deaths in the intervention group, they concluded.

The investigators plan to update the mortality findings through 15 years of follow-up, when those data become available.

Some of the study authors report relationships with Amgen, Augmenix, Bayer, Cambridge Endo, Caris, Envisioneering Medical, France Foundation, GenProbe, GlaxoSmithKline, Human Genome Sciences, Myriad Genetics, Steba Biotech, Ortho Clinical Diagnostics, and Viking Medical.

After 13 years of follow-up, men who underwent annual screening for prostate cancer were no less likely to die of prostate cancer than were men who received usual care and opportunistic screening.

Cumulative mortality rates from prostate cancer differed by a statistically insignificant rate of 0.3 deaths per 10,000 person years in the intervention and usual-care arms of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial, published online Jan. 6 in the Journal of the National Cancer Institute. Further, age, comorbidity status, and pretrial prostate-specific antigen (PSA) testing did not influence the results, wrote Dr. Gerald L. Andriole of Washington University, St. Louis, and his colleagues.

The PLCO trial randomly assigned 76,693 men, aged 55-74 years, to either 6 years of annual PSA screening in combination with 4 years of annual digital rectal examination (38,343) or to usual care (38,350), which included screening tests as recommended by physicians.

The goal was to evaluate the effect of adding annual screening and compare outcomes to the opportunistic screening already in place, the researchers said. It was expected that the impacts of earlier diagnosis and a persistent excess of cases because of annual screening in the intervention arm would exceed the impacts of opportunistic screening.

Prior to the study, 44% of all participants had undergone PSA screening. During the trial, 52% of the usual-care group, compared with the entire intervention group, underwent PSA testing.

The researchers had previously reported 7- and 10-year follow-up results. At 7 years of follow-up, yearly screening was associated with an increased incidence of prostate cancer diagnosis as compared with usual care. The rates of prostate cancer mortality and of all-cause mortality, however, were the same for both groups. Similarly, after 10 years of follow-up, no mortality benefit was observed for the intervention, the investigators reported previously (N. Engl. J. Med. 2009;360:1320-1328).

For the current study, Dr. Andriole and his associates ascertained all incident prostate cancer diagnoses and deaths through 13 years of follow-up or through December 31, 2009, and estimated relative risks as the ratio of observed rates of diagnoses and deaths in the intervention and control arms. They examined the interactions between prostate cancer mortality by trial arm and age, comorbidities, and pretrial PSA testing using Poisson regression modeling (J. Natl. Cancer Inst. 6 Jan. 2012 [doi: 10.1093/jnci/djr500]).

At 13 years, 4,250 of the 38,340 participants in the intervention arm had been diagnosed with prostate cancer, compared with 3,815 of the 38,345 control participants. "The cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10,000 person-years, respectively, resulting in a statistically significant 12% relative increase in the intervention arm," the authors wrote. Of the prostate cancer diagnoses, 401 in the intervention arm and 454 in the usual care arm were high-grade prostate cancers with Gleason scores of 8-10.

At 13 years of follow-up, there were 158 deaths in the intervention arm and 145 deaths in the usual-care arm. "The cumulative mortality rates from prostate cancer were 3.7 and 3.4 deaths per 10,000 person-years, respectively, resulting in a non-statistically significant difference between the two arms," according to the authors. The examination of mortality rates per 10,000 person-years and relative risks of prostate cancer mortality by age, comorbidity, and pretrial PSA testing produced no statistically significant interactions.

Deaths from all causes other than prostate, lung, and colorectal cancers differed by a factor of "borderline" statistical significance, with 5,783 deaths in the intervention arm and 5,982 in the usual-care arm, Dr. Andriole and his associates wrote. "Intervention and control arms showed 23% and 22% deaths, respectively, from non-PLCO cancers, and 21% and 19% deaths, respectively, from ischemic heart disease."

The authors acknowledged limitations of the study, including the possibility that a reduction in prostate cancer mortality in the analysis has somehow been masked by "the sticking diagnosis effect." In other words, more deaths were attributed to prostate cancer in the intervention arm. This possibility is supported by the statistically significant lower all-cause mortality in the intervention group as compared with the usual-care group. The percentage of deaths from other causes was higher in the intervention arm, so an error in cause of death attribution likely does not account for the excess prostate cancer deaths in the intervention group, they concluded.

The investigators plan to update the mortality findings through 15 years of follow-up, when those data become available.

Some of the study authors report relationships with Amgen, Augmenix, Bayer, Cambridge Endo, Caris, Envisioneering Medical, France Foundation, GenProbe, GlaxoSmithKline, Human Genome Sciences, Myriad Genetics, Steba Biotech, Ortho Clinical Diagnostics, and Viking Medical.

After 13 years of follow-up, men who underwent annual screening for prostate cancer were no less likely to die of prostate cancer than were men who received usual care and opportunistic screening.

Cumulative mortality rates from prostate cancer differed by a statistically insignificant rate of 0.3 deaths per 10,000 person years in the intervention and usual-care arms of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial, published online Jan. 6 in the Journal of the National Cancer Institute. Further, age, comorbidity status, and pretrial prostate-specific antigen (PSA) testing did not influence the results, wrote Dr. Gerald L. Andriole of Washington University, St. Louis, and his colleagues.

The PLCO trial randomly assigned 76,693 men, aged 55-74 years, to either 6 years of annual PSA screening in combination with 4 years of annual digital rectal examination (38,343) or to usual care (38,350), which included screening tests as recommended by physicians.

The goal was to evaluate the effect of adding annual screening and compare outcomes to the opportunistic screening already in place, the researchers said. It was expected that the impacts of earlier diagnosis and a persistent excess of cases because of annual screening in the intervention arm would exceed the impacts of opportunistic screening.

Prior to the study, 44% of all participants had undergone PSA screening. During the trial, 52% of the usual-care group, compared with the entire intervention group, underwent PSA testing.

The researchers had previously reported 7- and 10-year follow-up results. At 7 years of follow-up, yearly screening was associated with an increased incidence of prostate cancer diagnosis as compared with usual care. The rates of prostate cancer mortality and of all-cause mortality, however, were the same for both groups. Similarly, after 10 years of follow-up, no mortality benefit was observed for the intervention, the investigators reported previously (N. Engl. J. Med. 2009;360:1320-1328).

For the current study, Dr. Andriole and his associates ascertained all incident prostate cancer diagnoses and deaths through 13 years of follow-up or through December 31, 2009, and estimated relative risks as the ratio of observed rates of diagnoses and deaths in the intervention and control arms. They examined the interactions between prostate cancer mortality by trial arm and age, comorbidities, and pretrial PSA testing using Poisson regression modeling (J. Natl. Cancer Inst. 6 Jan. 2012 [doi: 10.1093/jnci/djr500]).

At 13 years, 4,250 of the 38,340 participants in the intervention arm had been diagnosed with prostate cancer, compared with 3,815 of the 38,345 control participants. "The cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10,000 person-years, respectively, resulting in a statistically significant 12% relative increase in the intervention arm," the authors wrote. Of the prostate cancer diagnoses, 401 in the intervention arm and 454 in the usual care arm were high-grade prostate cancers with Gleason scores of 8-10.

At 13 years of follow-up, there were 158 deaths in the intervention arm and 145 deaths in the usual-care arm. "The cumulative mortality rates from prostate cancer were 3.7 and 3.4 deaths per 10,000 person-years, respectively, resulting in a non-statistically significant difference between the two arms," according to the authors. The examination of mortality rates per 10,000 person-years and relative risks of prostate cancer mortality by age, comorbidity, and pretrial PSA testing produced no statistically significant interactions.

Deaths from all causes other than prostate, lung, and colorectal cancers differed by a factor of "borderline" statistical significance, with 5,783 deaths in the intervention arm and 5,982 in the usual-care arm, Dr. Andriole and his associates wrote. "Intervention and control arms showed 23% and 22% deaths, respectively, from non-PLCO cancers, and 21% and 19% deaths, respectively, from ischemic heart disease."

The authors acknowledged limitations of the study, including the possibility that a reduction in prostate cancer mortality in the analysis has somehow been masked by "the sticking diagnosis effect." In other words, more deaths were attributed to prostate cancer in the intervention arm. This possibility is supported by the statistically significant lower all-cause mortality in the intervention group as compared with the usual-care group. The percentage of deaths from other causes was higher in the intervention arm, so an error in cause of death attribution likely does not account for the excess prostate cancer deaths in the intervention group, they concluded.

The investigators plan to update the mortality findings through 15 years of follow-up, when those data become available.

Some of the study authors report relationships with Amgen, Augmenix, Bayer, Cambridge Endo, Caris, Envisioneering Medical, France Foundation, GenProbe, GlaxoSmithKline, Human Genome Sciences, Myriad Genetics, Steba Biotech, Ortho Clinical Diagnostics, and Viking Medical.