Nephrology

Q) We were operating on a 58-year-old woman for a subcapital fracture of her right hip. The orthopedist mentioned that the patient had kidney disease and that it probably caused her hip fracture. I didn’t know kidney disease causes hip fractures. Is this true?

Evolving evidence suggests an association between diminishing renal function and increased risk for fracture. Here’s a look at the available data:

Atherosclerosis Risk in Communities (ARIC) Study. During a median 13 years’ follow-up of 10,955 community-based older adults, investigators identified higher albuminuria level and decreased creatinine-based estimated glomerular filtration rate (eGFR) as significant risk factors for fracture. Other risk factors included older age, race (Caucasians had the highest incidence), and sex (women were more likely than men to sustain a fracture). A nonlinear relationship was observed between eGFR and fracture diagnosis, with a graded association between fracture and albuminuria level.⁷

Cardiovascular Health Study. In this study of 4,699 older community-based adults, kidney function was assessed by measurement of serum cystatin C. During a mean follow-up of 7.1 years, higher cystatin C levels correlated to a higher risk for hip fracture in both sexes. In women, there was a significant association between diminishing renal function and hip fracture status: Those with lower eGFRs had a higher incidence of fractures. There was a similar magnitude of association among men, but it was not ­significant.⁸

Health, Aging and Body Composite Study. In 2,754 older adults, an association was noted between decreased femoral neck bone mineral density (BMD) and increased risk for fracture in those with and without CKD stage 3 to 5. With a concurrent diagnosis of osteoporosis, there was a 110% increased risk for nonspinal fracture in those with CKD and a 63% increased risk for those without CKD.⁹ In a study of 485 adult hemodialysis patients, decreased total hip and femoral neck BMD was associated with an increased risk for fractures in women with parathyroid hormone levels on the lower range of acceptable in this population (intact parathyroid hormone level [IPTH] < 204 pg/mL) and for spinal fractures in both genders.¹⁰

Bone changes associated with deterioration of renal function are complex and multifactorial. Human bone is a composite of protein fused to mineral crystals, primarily calcium and phosphate. Bone is dynamic, being broken down and rebuilt throughout adulthood, with the skeleton almost completely rebuilt every 10 years.¹¹

CKD–mineral and bone disorder (CKD–MBD) is a systemic disorder seen in those with kidney disease that affects bone and mineral metabolism. Its manifestations include abnormalities in the bone, calcifications of vascular and/or soft tissues, abnormal vitamin D metabolism, and disruptions in the phosphorus, calcium, and parathyroid hormone levels. These components, and the severity of the condition, vary by stage of CKD. One component of CKD–MBD, renal osteodystrophy, is associated with changes in bone morphology and is definitively diagnosed by bone biopsy.¹²

Care of these patients is complex and can be compounded by osteoporosis and/or loss of bone strength. Osteoporosis, like CKD, increases in incidence with age and is associated with fracture risk.¹¹

While useful for diagnosing osteoporosis and predicting fracture risk in the general population, dual-energy X-ray densitometry (DXA) has not been recommended in those with CKD due to the type of bone changes that occur with diminished renal function.¹² However, evolving evidence regarding use of DXA in these patients prompted a Kidney Disease: Improving Global Outcomes (KDIGO) “controversies” conference to recommend reexamination of the evidence regarding this recommendation.¹³ KDIGO’s 2009 clinical practice guideline on CKD–MBD (http://kdigo.org/home/mineral-bone-disorder/) can be of benefit in the assessment and care of affected patients. —CS

Cindy Smith, DNP, APRN, CNN-NP, FNP-BC
Renal Consultants, PLLC, South Charleston, West Virgina

References
7. Daya NR, Voskertchian A, Schneider ALC, et al. Kidney function and fracture risk: the Atherosclerosis Risk in Communities (ARIC) study. Am J Kidney Dis. 2016;67(2):218-226.
8. Fried LF, Biggs ML, Shlipak MG, et al. Association of kidney function with incident hip fracture in older adults. J Am Soc Nephrol. 2007;18:282-286.
9. Yenchek RH, Ix JH, Shlipak MG, et al. Bone mineral density and fracture risk in older individuals with CKD. Clin J Am Soc Nephrol. 2012;7(7):1130-1136.
10. Iimori S, Mori Y, Akita W, et al. Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients­­—a single-center cohort study. Nephrol Dial Transplant. 2012;27:345-351.
11. Office of the Surgeon General (US). Bone Health and Osteoporosis: a Report of the Surgeon General. Rockville, MD: Office of the Surgeon General; 2004.
12. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1-S130.
13. Ketteler M, Elder GJ, Evenepoel P, et al. Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference. Kidney Int. 2015;87(3):502-528.

Q) We were operating on a 58-year-old woman for a subcapital fracture of her right hip. The orthopedist mentioned that the patient had kidney disease and that it probably caused her hip fracture. I didn’t know kidney disease causes hip fractures. Is this true?

Evolving evidence suggests an association between diminishing renal function and increased risk for fracture. Here’s a look at the available data:

Atherosclerosis Risk in Communities (ARIC) Study. During a median 13 years’ follow-up of 10,955 community-based older adults, investigators identified higher albuminuria level and decreased creatinine-based estimated glomerular filtration rate (eGFR) as significant risk factors for fracture. Other risk factors included older age, race (Caucasians had the highest incidence), and sex (women were more likely than men to sustain a fracture). A nonlinear relationship was observed between eGFR and fracture diagnosis, with a graded association between fracture and albuminuria level.⁷

Cardiovascular Health Study. In this study of 4,699 older community-based adults, kidney function was assessed by measurement of serum cystatin C. During a mean follow-up of 7.1 years, higher cystatin C levels correlated to a higher risk for hip fracture in both sexes. In women, there was a significant association between diminishing renal function and hip fracture status: Those with lower eGFRs had a higher incidence of fractures. There was a similar magnitude of association among men, but it was not ­significant.⁸

Health, Aging and Body Composite Study. In 2,754 older adults, an association was noted between decreased femoral neck bone mineral density (BMD) and increased risk for fracture in those with and without CKD stage 3 to 5. With a concurrent diagnosis of osteoporosis, there was a 110% increased risk for nonspinal fracture in those with CKD and a 63% increased risk for those without CKD.⁹ In a study of 485 adult hemodialysis patients, decreased total hip and femoral neck BMD was associated with an increased risk for fractures in women with parathyroid hormone levels on the lower range of acceptable in this population (intact parathyroid hormone level [IPTH] < 204 pg/mL) and for spinal fractures in both genders.¹⁰

Bone changes associated with deterioration of renal function are complex and multifactorial. Human bone is a composite of protein fused to mineral crystals, primarily calcium and phosphate. Bone is dynamic, being broken down and rebuilt throughout adulthood, with the skeleton almost completely rebuilt every 10 years.¹¹

CKD–mineral and bone disorder (CKD–MBD) is a systemic disorder seen in those with kidney disease that affects bone and mineral metabolism. Its manifestations include abnormalities in the bone, calcifications of vascular and/or soft tissues, abnormal vitamin D metabolism, and disruptions in the phosphorus, calcium, and parathyroid hormone levels. These components, and the severity of the condition, vary by stage of CKD. One component of CKD–MBD, renal osteodystrophy, is associated with changes in bone morphology and is definitively diagnosed by bone biopsy.¹²

Care of these patients is complex and can be compounded by osteoporosis and/or loss of bone strength. Osteoporosis, like CKD, increases in incidence with age and is associated with fracture risk.¹¹

While useful for diagnosing osteoporosis and predicting fracture risk in the general population, dual-energy X-ray densitometry (DXA) has not been recommended in those with CKD due to the type of bone changes that occur with diminished renal function.¹² However, evolving evidence regarding use of DXA in these patients prompted a Kidney Disease: Improving Global Outcomes (KDIGO) “controversies” conference to recommend reexamination of the evidence regarding this recommendation.¹³ KDIGO’s 2009 clinical practice guideline on CKD–MBD (http://kdigo.org/home/mineral-bone-disorder/) can be of benefit in the assessment and care of affected patients. —CS

Cindy Smith, DNP, APRN, CNN-NP, FNP-BC
Renal Consultants, PLLC, South Charleston, West Virgina

References
7. Daya NR, Voskertchian A, Schneider ALC, et al. Kidney function and fracture risk: the Atherosclerosis Risk in Communities (ARIC) study. Am J Kidney Dis. 2016;67(2):218-226.
8. Fried LF, Biggs ML, Shlipak MG, et al. Association of kidney function with incident hip fracture in older adults. J Am Soc Nephrol. 2007;18:282-286.
9. Yenchek RH, Ix JH, Shlipak MG, et al. Bone mineral density and fracture risk in older individuals with CKD. Clin J Am Soc Nephrol. 2012;7(7):1130-1136.
10. Iimori S, Mori Y, Akita W, et al. Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients­­—a single-center cohort study. Nephrol Dial Transplant. 2012;27:345-351.
11. Office of the Surgeon General (US). Bone Health and Osteoporosis: a Report of the Surgeon General. Rockville, MD: Office of the Surgeon General; 2004.
12. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1-S130.
13. Ketteler M, Elder GJ, Evenepoel P, et al. Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference. Kidney Int. 2015;87(3):502-528.

Q) We were operating on a 58-year-old woman for a subcapital fracture of her right hip. The orthopedist mentioned that the patient had kidney disease and that it probably caused her hip fracture. I didn’t know kidney disease causes hip fractures. Is this true?

Evolving evidence suggests an association between diminishing renal function and increased risk for fracture. Here’s a look at the available data:

Atherosclerosis Risk in Communities (ARIC) Study. During a median 13 years’ follow-up of 10,955 community-based older adults, investigators identified higher albuminuria level and decreased creatinine-based estimated glomerular filtration rate (eGFR) as significant risk factors for fracture. Other risk factors included older age, race (Caucasians had the highest incidence), and sex (women were more likely than men to sustain a fracture). A nonlinear relationship was observed between eGFR and fracture diagnosis, with a graded association between fracture and albuminuria level.⁷

Cardiovascular Health Study. In this study of 4,699 older community-based adults, kidney function was assessed by measurement of serum cystatin C. During a mean follow-up of 7.1 years, higher cystatin C levels correlated to a higher risk for hip fracture in both sexes. In women, there was a significant association between diminishing renal function and hip fracture status: Those with lower eGFRs had a higher incidence of fractures. There was a similar magnitude of association among men, but it was not ­significant.⁸

Health, Aging and Body Composite Study. In 2,754 older adults, an association was noted between decreased femoral neck bone mineral density (BMD) and increased risk for fracture in those with and without CKD stage 3 to 5. With a concurrent diagnosis of osteoporosis, there was a 110% increased risk for nonspinal fracture in those with CKD and a 63% increased risk for those without CKD.⁹ In a study of 485 adult hemodialysis patients, decreased total hip and femoral neck BMD was associated with an increased risk for fractures in women with parathyroid hormone levels on the lower range of acceptable in this population (intact parathyroid hormone level [IPTH] < 204 pg/mL) and for spinal fractures in both genders.¹⁰

Bone changes associated with deterioration of renal function are complex and multifactorial. Human bone is a composite of protein fused to mineral crystals, primarily calcium and phosphate. Bone is dynamic, being broken down and rebuilt throughout adulthood, with the skeleton almost completely rebuilt every 10 years.¹¹

CKD–mineral and bone disorder (CKD–MBD) is a systemic disorder seen in those with kidney disease that affects bone and mineral metabolism. Its manifestations include abnormalities in the bone, calcifications of vascular and/or soft tissues, abnormal vitamin D metabolism, and disruptions in the phosphorus, calcium, and parathyroid hormone levels. These components, and the severity of the condition, vary by stage of CKD. One component of CKD–MBD, renal osteodystrophy, is associated with changes in bone morphology and is definitively diagnosed by bone biopsy.¹²

Care of these patients is complex and can be compounded by osteoporosis and/or loss of bone strength. Osteoporosis, like CKD, increases in incidence with age and is associated with fracture risk.¹¹

While useful for diagnosing osteoporosis and predicting fracture risk in the general population, dual-energy X-ray densitometry (DXA) has not been recommended in those with CKD due to the type of bone changes that occur with diminished renal function.¹² However, evolving evidence regarding use of DXA in these patients prompted a Kidney Disease: Improving Global Outcomes (KDIGO) “controversies” conference to recommend reexamination of the evidence regarding this recommendation.¹³ KDIGO’s 2009 clinical practice guideline on CKD–MBD (http://kdigo.org/home/mineral-bone-disorder/) can be of benefit in the assessment and care of affected patients. —CS

Cindy Smith, DNP, APRN, CNN-NP, FNP-BC
Renal Consultants, PLLC, South Charleston, West Virgina

References
7. Daya NR, Voskertchian A, Schneider ALC, et al. Kidney function and fracture risk: the Atherosclerosis Risk in Communities (ARIC) study. Am J Kidney Dis. 2016;67(2):218-226.
8. Fried LF, Biggs ML, Shlipak MG, et al. Association of kidney function with incident hip fracture in older adults. J Am Soc Nephrol. 2007;18:282-286.
9. Yenchek RH, Ix JH, Shlipak MG, et al. Bone mineral density and fracture risk in older individuals with CKD. Clin J Am Soc Nephrol. 2012;7(7):1130-1136.
10. Iimori S, Mori Y, Akita W, et al. Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients­­—a single-center cohort study. Nephrol Dial Transplant. 2012;27:345-351.
11. Office of the Surgeon General (US). Bone Health and Osteoporosis: a Report of the Surgeon General. Rockville, MD: Office of the Surgeon General; 2004.
12. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1-S130.
13. Ketteler M, Elder GJ, Evenepoel P, et al. Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference. Kidney Int. 2015;87(3):502-528.

LOS ANGELES – The equipoise between carotid stenting and endarterectomy received a further boost in 10-year results from the landmark Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) that compared the two options head-to-head.

Reported the day after results from another big trial that pitted carotid stenting against surgery, the Asymptomatic Carotid Trial (ACT I), the new long-term results from the CREST study mean that deciding among the options relies largely on patient preference although individual clinical characteristics might favor one approach or the other, experts said.

Mitchel L. Zoler/Frontline Medical News

The big remaining unknown and wild card is whether doing no procedural intervention at all and relying entirely on optimal, contemporary medical treatment works just as well as endarterectomy or carotid stenting. The role for stand-alone medical therapy against carotid surgery or stenting (on top of medical therapy) is currently undergoing a formal, direct comparison in the randomized Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2).

Taking the 5-year outcome results from ACT I and the 10-year outcome results from CREST both into account, “we now have a lot of evidence that both carotid stenting and surgery are safe and durable. The results support both options” for either patients with symptomatic carotid artery stenosis or asymptomatic patients with carotid stenosis as extensive as in the patients enrolled in these trials, said Dr. Thomas G. Brott at the International Stroke Conference.

“In routine practice, we lay out the options of endarterectomy, carotid stenting, or no intervention with just medical treatment to patients and let them decide,” noted Dr. Brott, professor of neurology and director of research at the Mayo Clinic in Jacksonville, Fla.

CREST randomized 2,502 symptomatic or asymptomatic patients with significant carotid stenosis during 2000-2008 at 117 U.S. and Canadian centers. From this group, 1,607 consented and were available for long-term follow-up, done at a median of 7.4 years and as long as 10 years after follow-up.

The study’s primary, long-term endpoint was stroke, MI, or death during the periprocedural period (30 days after treatment or 36 days after enrollment depending on when the procedural intervention occurred) plus the rate of ipsilateral stroke during up to 10 years of follow-up. This combined endpoint occurred in 10% of the patients who underwent endarterectomy and in 12% of those who had stenting, a difference that was not statistically significant, Dr. Brott reported. Concurrent with his presentation at the meeting, sponsored by the American Heart Association, the results also were published online (N Engl J Med. 2016 Feb 18. doi: 10.1056/NEJMoa1505215).

The results included a secondary endpoint that showed a significant benefit for endarterectomy. The tally of periprocedural strokes or deaths plus ipsilateral strokes during 10-year follow-up was 8% for the surgical group and 11% for those who received a stent, a 37% excess hazard with stenting.

Dr. Brott attributed this secondary difference between the two arms of the study to a statistically significant excess of stroke or death during the periprocedural period in the patients treated by stenting, and more specifically an excess of strokes. The rate of total periprocedural strokes was 4% with stenting and 2% with endarterectomy, a statistically significant difference. Although an embolic protection device was used “when feasible” during stenting, this protection can be fallible, Dr. Brott noted. In contrast, the results from the ACT I trial showed no statistically significant difference in the rate of periprocedural total strokes between the stented and endarterectomy patients.

Dr. Brott had no relevant disclosures. The CREST trial received partial funding from Abbott Vascular.

[email protected]

On Twitter @mitchelzoler

LOS ANGELES – The equipoise between carotid stenting and endarterectomy received a further boost in 10-year results from the landmark Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) that compared the two options head-to-head.

Reported the day after results from another big trial that pitted carotid stenting against surgery, the Asymptomatic Carotid Trial (ACT I), the new long-term results from the CREST study mean that deciding among the options relies largely on patient preference although individual clinical characteristics might favor one approach or the other, experts said.

Mitchel L. Zoler/Frontline Medical News

The big remaining unknown and wild card is whether doing no procedural intervention at all and relying entirely on optimal, contemporary medical treatment works just as well as endarterectomy or carotid stenting. The role for stand-alone medical therapy against carotid surgery or stenting (on top of medical therapy) is currently undergoing a formal, direct comparison in the randomized Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2).

Taking the 5-year outcome results from ACT I and the 10-year outcome results from CREST both into account, “we now have a lot of evidence that both carotid stenting and surgery are safe and durable. The results support both options” for either patients with symptomatic carotid artery stenosis or asymptomatic patients with carotid stenosis as extensive as in the patients enrolled in these trials, said Dr. Thomas G. Brott at the International Stroke Conference.

“In routine practice, we lay out the options of endarterectomy, carotid stenting, or no intervention with just medical treatment to patients and let them decide,” noted Dr. Brott, professor of neurology and director of research at the Mayo Clinic in Jacksonville, Fla.

CREST randomized 2,502 symptomatic or asymptomatic patients with significant carotid stenosis during 2000-2008 at 117 U.S. and Canadian centers. From this group, 1,607 consented and were available for long-term follow-up, done at a median of 7.4 years and as long as 10 years after follow-up.

The study’s primary, long-term endpoint was stroke, MI, or death during the periprocedural period (30 days after treatment or 36 days after enrollment depending on when the procedural intervention occurred) plus the rate of ipsilateral stroke during up to 10 years of follow-up. This combined endpoint occurred in 10% of the patients who underwent endarterectomy and in 12% of those who had stenting, a difference that was not statistically significant, Dr. Brott reported. Concurrent with his presentation at the meeting, sponsored by the American Heart Association, the results also were published online (N Engl J Med. 2016 Feb 18. doi: 10.1056/NEJMoa1505215).

The results included a secondary endpoint that showed a significant benefit for endarterectomy. The tally of periprocedural strokes or deaths plus ipsilateral strokes during 10-year follow-up was 8% for the surgical group and 11% for those who received a stent, a 37% excess hazard with stenting.

Dr. Brott attributed this secondary difference between the two arms of the study to a statistically significant excess of stroke or death during the periprocedural period in the patients treated by stenting, and more specifically an excess of strokes. The rate of total periprocedural strokes was 4% with stenting and 2% with endarterectomy, a statistically significant difference. Although an embolic protection device was used “when feasible” during stenting, this protection can be fallible, Dr. Brott noted. In contrast, the results from the ACT I trial showed no statistically significant difference in the rate of periprocedural total strokes between the stented and endarterectomy patients.

Dr. Brott had no relevant disclosures. The CREST trial received partial funding from Abbott Vascular.

[email protected]

On Twitter @mitchelzoler

LOS ANGELES – The equipoise between carotid stenting and endarterectomy received a further boost in 10-year results from the landmark Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) that compared the two options head-to-head.

Reported the day after results from another big trial that pitted carotid stenting against surgery, the Asymptomatic Carotid Trial (ACT I), the new long-term results from the CREST study mean that deciding among the options relies largely on patient preference although individual clinical characteristics might favor one approach or the other, experts said.

Mitchel L. Zoler/Frontline Medical News

The big remaining unknown and wild card is whether doing no procedural intervention at all and relying entirely on optimal, contemporary medical treatment works just as well as endarterectomy or carotid stenting. The role for stand-alone medical therapy against carotid surgery or stenting (on top of medical therapy) is currently undergoing a formal, direct comparison in the randomized Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2).

Taking the 5-year outcome results from ACT I and the 10-year outcome results from CREST both into account, “we now have a lot of evidence that both carotid stenting and surgery are safe and durable. The results support both options” for either patients with symptomatic carotid artery stenosis or asymptomatic patients with carotid stenosis as extensive as in the patients enrolled in these trials, said Dr. Thomas G. Brott at the International Stroke Conference.

“In routine practice, we lay out the options of endarterectomy, carotid stenting, or no intervention with just medical treatment to patients and let them decide,” noted Dr. Brott, professor of neurology and director of research at the Mayo Clinic in Jacksonville, Fla.

CREST randomized 2,502 symptomatic or asymptomatic patients with significant carotid stenosis during 2000-2008 at 117 U.S. and Canadian centers. From this group, 1,607 consented and were available for long-term follow-up, done at a median of 7.4 years and as long as 10 years after follow-up.

The study’s primary, long-term endpoint was stroke, MI, or death during the periprocedural period (30 days after treatment or 36 days after enrollment depending on when the procedural intervention occurred) plus the rate of ipsilateral stroke during up to 10 years of follow-up. This combined endpoint occurred in 10% of the patients who underwent endarterectomy and in 12% of those who had stenting, a difference that was not statistically significant, Dr. Brott reported. Concurrent with his presentation at the meeting, sponsored by the American Heart Association, the results also were published online (N Engl J Med. 2016 Feb 18. doi: 10.1056/NEJMoa1505215).

The results included a secondary endpoint that showed a significant benefit for endarterectomy. The tally of periprocedural strokes or deaths plus ipsilateral strokes during 10-year follow-up was 8% for the surgical group and 11% for those who received a stent, a 37% excess hazard with stenting.

Dr. Brott attributed this secondary difference between the two arms of the study to a statistically significant excess of stroke or death during the periprocedural period in the patients treated by stenting, and more specifically an excess of strokes. The rate of total periprocedural strokes was 4% with stenting and 2% with endarterectomy, a statistically significant difference. Although an embolic protection device was used “when feasible” during stenting, this protection can be fallible, Dr. Brott noted. In contrast, the results from the ACT I trial showed no statistically significant difference in the rate of periprocedural total strokes between the stented and endarterectomy patients.

Dr. Brott had no relevant disclosures. The CREST trial received partial funding from Abbott Vascular.

[email protected]

On Twitter @mitchelzoler

CHICAGO – Surgeons can expect to see more abdominal organ transplant recipients presenting with aortic aneurysms, as transplant survival rates increase along with the age of organ donors and recipients.

“The consensus is that abdominal aortic aneurysms (AAAs) have a more aggressive course post-transplant and within that context, probably need to be managed more aggressively,” Dr. Michael J. Englesbe of the University of Michigan, Ann Arbor said at the annual Northwestern Vascular Symposium.

Some 270,000 Americans are living with a functioning liver or kidney graft, and their average age has risen from 47 years to 57 years over the last decade.

Though the data isn’t great, it’s hypothesized that the immunosuppression prerequisite for successful organ transplantation promotes the progression of atherosclerosis and aneurysm growth in transplant patients, he said.

New-onset diabetes, hyperlipidemia, and hypertension are all common post-transplant due to immunosuppression therapy. Aortic aneurysms are also reported to rupture at smaller sizes in transplant recipients.

Intriguingly, the opposite effect has been observed in experimental animal models, where immunosuppression with calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors has been shown to stabilize atherosclerotic lesions and inhibit aneurysm expansion.

The reason for this disparity is unclear, but immunosuppressants likely augment other cardiovascular comorbidities such as hypertension and atherosclerosis and this may trump their anti-inflammatory effects and lead to worse aneurysm disease and faster expansion in humans, Dr. Englesbe speculated in an interview.

As for when aneurysms should be fixed, kidney transplant candidates should undergo AAA repair prior to transplantation since the risk of renal complications after aneurysm repair puts the allograft at risk, Dr. Englesbe advised. Either an open or endovascular approach can be used.

In liver transplant candidates, elective AAA repair should be avoided if possible and is contraindicated if any signs of hepatic decompensation are present such as muscle wasting, ascites, platelet count less than 50 x 10⁹/L, or encephalopathy. For well-compensated cirrhotic patients, endovascular repair is best.

One of the most important considerations for any solid-organ transplant patient undergoing aneurysm repair is perioperative management of immunosuppression, Dr. Englesbe stressed.

Transplant patients are maintained on oral calcineurin inhibitors such as cyclosporine and tacrolimus (Prograf) throughout the perioperative period to prevent organ rejection, but these drugs have nephrotoxic effects. About 10% of recipients, typically the sicker patients, will be switched to mTOR inhibitors such as everolimus (Afinitor) and sirolumus (Rapamune) as a kidney-sparing alternative.

“Part of the mechanism of these [mTOR] drugs is that they really affect fibroblast functioning, so patients that are on these medications, their wound will fall apart and they will invariably get a hernia,” Dr. Englesbe said. “You have to stop them upwards of about 6 weeks before surgical intervention, and I think this is also true for many endografts.”

He highlighted a case in which an mTOR inhibitor was started three months after liver transplant due to renal dysfunction in a patient who was fully healed, but within three weeks, “her wound fell apart, completely fell apart.” She developed several seromas underneath her incision, one of which became infected and took months to close.

“The transplant professionals – your nephrologists, your cardiologists – aren’t going to know this fact, but as a transplant surgeon it’s usually the first question we’re going to ask with respect to any post-transplant patient we’re going to operate on, so it’s something to keep in mind,” Dr. Englesbe said.

Another take-home message was the importance of maintaining kidney function in kidney recipients presenting with aortic aneurysm, as mortality in these patients is about 10-fold higher once the kidney fails, he said. A recent study reported that AAAs are significantly more common in kidney than liver transplant recipients (29.6% vs. 11.4%; P = .02), despite a similar prevalence for any aneurysm (4%) in both groups (J Vasc Surg. 2014 Mar;59;594-8).

When kidney recipients present, preoperative imaging of the aorta from the aneurysm to the kidney allograft is mandatory, he said. Endovascular repair is preferred, whenever possible.

The renal graft is typically sewn to the external iliac artery 3 cm to 10 cm from the bifurcation of the external and internal iliac arteries. Because of this, repair is challenging when aneurysmal disease involves the iliac artery, Dr. Englesbe observed. Aneurysmal dilation is less common in the external iliac, but stenting an iliac aneurysm can still compromise inflow to the transplanted kidney.

Several surgical techniques including axillofemoral bypass, aortofemoral shunt, or extracorporeal circuit have been reported to preserve renal function during open AAA repair in renal transplant recipients. These techniques are not without their own risk of complications and should be avoided in patients with low creatinine, but are appropriate in patients with marginal or impaired renal function, according to Dr. Englesbe, who reported having no relevant disclosures.

CHICAGO – Surgeons can expect to see more abdominal organ transplant recipients presenting with aortic aneurysms, as transplant survival rates increase along with the age of organ donors and recipients.

“The consensus is that abdominal aortic aneurysms (AAAs) have a more aggressive course post-transplant and within that context, probably need to be managed more aggressively,” Dr. Michael J. Englesbe of the University of Michigan, Ann Arbor said at the annual Northwestern Vascular Symposium.

Some 270,000 Americans are living with a functioning liver or kidney graft, and their average age has risen from 47 years to 57 years over the last decade.

Though the data isn’t great, it’s hypothesized that the immunosuppression prerequisite for successful organ transplantation promotes the progression of atherosclerosis and aneurysm growth in transplant patients, he said.

New-onset diabetes, hyperlipidemia, and hypertension are all common post-transplant due to immunosuppression therapy. Aortic aneurysms are also reported to rupture at smaller sizes in transplant recipients.

Intriguingly, the opposite effect has been observed in experimental animal models, where immunosuppression with calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors has been shown to stabilize atherosclerotic lesions and inhibit aneurysm expansion.

The reason for this disparity is unclear, but immunosuppressants likely augment other cardiovascular comorbidities such as hypertension and atherosclerosis and this may trump their anti-inflammatory effects and lead to worse aneurysm disease and faster expansion in humans, Dr. Englesbe speculated in an interview.

As for when aneurysms should be fixed, kidney transplant candidates should undergo AAA repair prior to transplantation since the risk of renal complications after aneurysm repair puts the allograft at risk, Dr. Englesbe advised. Either an open or endovascular approach can be used.

In liver transplant candidates, elective AAA repair should be avoided if possible and is contraindicated if any signs of hepatic decompensation are present such as muscle wasting, ascites, platelet count less than 50 x 10⁹/L, or encephalopathy. For well-compensated cirrhotic patients, endovascular repair is best.

One of the most important considerations for any solid-organ transplant patient undergoing aneurysm repair is perioperative management of immunosuppression, Dr. Englesbe stressed.

Transplant patients are maintained on oral calcineurin inhibitors such as cyclosporine and tacrolimus (Prograf) throughout the perioperative period to prevent organ rejection, but these drugs have nephrotoxic effects. About 10% of recipients, typically the sicker patients, will be switched to mTOR inhibitors such as everolimus (Afinitor) and sirolumus (Rapamune) as a kidney-sparing alternative.

“Part of the mechanism of these [mTOR] drugs is that they really affect fibroblast functioning, so patients that are on these medications, their wound will fall apart and they will invariably get a hernia,” Dr. Englesbe said. “You have to stop them upwards of about 6 weeks before surgical intervention, and I think this is also true for many endografts.”

He highlighted a case in which an mTOR inhibitor was started three months after liver transplant due to renal dysfunction in a patient who was fully healed, but within three weeks, “her wound fell apart, completely fell apart.” She developed several seromas underneath her incision, one of which became infected and took months to close.

“The transplant professionals – your nephrologists, your cardiologists – aren’t going to know this fact, but as a transplant surgeon it’s usually the first question we’re going to ask with respect to any post-transplant patient we’re going to operate on, so it’s something to keep in mind,” Dr. Englesbe said.

Another take-home message was the importance of maintaining kidney function in kidney recipients presenting with aortic aneurysm, as mortality in these patients is about 10-fold higher once the kidney fails, he said. A recent study reported that AAAs are significantly more common in kidney than liver transplant recipients (29.6% vs. 11.4%; P = .02), despite a similar prevalence for any aneurysm (4%) in both groups (J Vasc Surg. 2014 Mar;59;594-8).

When kidney recipients present, preoperative imaging of the aorta from the aneurysm to the kidney allograft is mandatory, he said. Endovascular repair is preferred, whenever possible.

The renal graft is typically sewn to the external iliac artery 3 cm to 10 cm from the bifurcation of the external and internal iliac arteries. Because of this, repair is challenging when aneurysmal disease involves the iliac artery, Dr. Englesbe observed. Aneurysmal dilation is less common in the external iliac, but stenting an iliac aneurysm can still compromise inflow to the transplanted kidney.

Several surgical techniques including axillofemoral bypass, aortofemoral shunt, or extracorporeal circuit have been reported to preserve renal function during open AAA repair in renal transplant recipients. These techniques are not without their own risk of complications and should be avoided in patients with low creatinine, but are appropriate in patients with marginal or impaired renal function, according to Dr. Englesbe, who reported having no relevant disclosures.

CHICAGO – Surgeons can expect to see more abdominal organ transplant recipients presenting with aortic aneurysms, as transplant survival rates increase along with the age of organ donors and recipients.

“The consensus is that abdominal aortic aneurysms (AAAs) have a more aggressive course post-transplant and within that context, probably need to be managed more aggressively,” Dr. Michael J. Englesbe of the University of Michigan, Ann Arbor said at the annual Northwestern Vascular Symposium.

Some 270,000 Americans are living with a functioning liver or kidney graft, and their average age has risen from 47 years to 57 years over the last decade.

Though the data isn’t great, it’s hypothesized that the immunosuppression prerequisite for successful organ transplantation promotes the progression of atherosclerosis and aneurysm growth in transplant patients, he said.

New-onset diabetes, hyperlipidemia, and hypertension are all common post-transplant due to immunosuppression therapy. Aortic aneurysms are also reported to rupture at smaller sizes in transplant recipients.

Intriguingly, the opposite effect has been observed in experimental animal models, where immunosuppression with calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors has been shown to stabilize atherosclerotic lesions and inhibit aneurysm expansion.

The reason for this disparity is unclear, but immunosuppressants likely augment other cardiovascular comorbidities such as hypertension and atherosclerosis and this may trump their anti-inflammatory effects and lead to worse aneurysm disease and faster expansion in humans, Dr. Englesbe speculated in an interview.

As for when aneurysms should be fixed, kidney transplant candidates should undergo AAA repair prior to transplantation since the risk of renal complications after aneurysm repair puts the allograft at risk, Dr. Englesbe advised. Either an open or endovascular approach can be used.

In liver transplant candidates, elective AAA repair should be avoided if possible and is contraindicated if any signs of hepatic decompensation are present such as muscle wasting, ascites, platelet count less than 50 x 10⁹/L, or encephalopathy. For well-compensated cirrhotic patients, endovascular repair is best.

One of the most important considerations for any solid-organ transplant patient undergoing aneurysm repair is perioperative management of immunosuppression, Dr. Englesbe stressed.

Transplant patients are maintained on oral calcineurin inhibitors such as cyclosporine and tacrolimus (Prograf) throughout the perioperative period to prevent organ rejection, but these drugs have nephrotoxic effects. About 10% of recipients, typically the sicker patients, will be switched to mTOR inhibitors such as everolimus (Afinitor) and sirolumus (Rapamune) as a kidney-sparing alternative.

“Part of the mechanism of these [mTOR] drugs is that they really affect fibroblast functioning, so patients that are on these medications, their wound will fall apart and they will invariably get a hernia,” Dr. Englesbe said. “You have to stop them upwards of about 6 weeks before surgical intervention, and I think this is also true for many endografts.”

He highlighted a case in which an mTOR inhibitor was started three months after liver transplant due to renal dysfunction in a patient who was fully healed, but within three weeks, “her wound fell apart, completely fell apart.” She developed several seromas underneath her incision, one of which became infected and took months to close.

“The transplant professionals – your nephrologists, your cardiologists – aren’t going to know this fact, but as a transplant surgeon it’s usually the first question we’re going to ask with respect to any post-transplant patient we’re going to operate on, so it’s something to keep in mind,” Dr. Englesbe said.

Another take-home message was the importance of maintaining kidney function in kidney recipients presenting with aortic aneurysm, as mortality in these patients is about 10-fold higher once the kidney fails, he said. A recent study reported that AAAs are significantly more common in kidney than liver transplant recipients (29.6% vs. 11.4%; P = .02), despite a similar prevalence for any aneurysm (4%) in both groups (J Vasc Surg. 2014 Mar;59;594-8).

When kidney recipients present, preoperative imaging of the aorta from the aneurysm to the kidney allograft is mandatory, he said. Endovascular repair is preferred, whenever possible.

The renal graft is typically sewn to the external iliac artery 3 cm to 10 cm from the bifurcation of the external and internal iliac arteries. Because of this, repair is challenging when aneurysmal disease involves the iliac artery, Dr. Englesbe observed. Aneurysmal dilation is less common in the external iliac, but stenting an iliac aneurysm can still compromise inflow to the transplanted kidney.

Several surgical techniques including axillofemoral bypass, aortofemoral shunt, or extracorporeal circuit have been reported to preserve renal function during open AAA repair in renal transplant recipients. These techniques are not without their own risk of complications and should be avoided in patients with low creatinine, but are appropriate in patients with marginal or impaired renal function, according to Dr. Englesbe, who reported having no relevant disclosures.

The world health community has lost ground in its fight to reduce end-stage renal disease in patients with lupus nephritis, a systematic review and meta-analysis concluded.

The risk of end-stage renal disease (ESRD) at 5 years of lupus nephritis decreased substantially from the 1970s, when it was 16%, to the mid-1990s, when it plateaued at 11%.

ESRD risks at 10 years and 15 years declined more sharply in the 1970s and 1980s but also plateaued in the mid-1990s at 17% and 22%, respectively.

This plateau was followed by a notable increase in risk in the late 2000s, particularly in the 10-year and 15-year estimates, Dr. Maria Tektonidou of the University of Athens and her coauthors reported (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39594).

“Despite extensive use of immunosuppressive medications through the 2000s, we did not find continued improvement in ESRD risks, but instead a slight increase in risks in the late 2000s,” they wrote.

The increase did not appear to be related to greater representation in recent studies of ethnic minorities, who may be more likely to develop ESRD. In the main analysis involving 148 of the 187 studies, “trends suggest this increase may have been temporary, but further follow-up will be needed to determine if this is sustained,” the investigators added.

Notably, patients with class-IV lupus nephritis had the greatest risk of ESRD during the 2000s, with a 15-year risk of 44%.

The 15-year risk of ESRD also was higher by 10 percentage points in developing countries than in developed countries during the 2000s.

The trends are worrisome because ESRD is a costly complication of lupus nephritis, which affects more than half of all patients with systemic lupus erythematosus (SLE). Patients with lupus nephritis have a 26-fold increased risk of death and estimated annual health care costs between $43,000 and $107,000 per patient, the authors noted.

The systematic review and Bayesian meta-analysis included 187 studies reporting on 18,309 adults with lupus nephritis from 1971 to 2015. The main analysis of ESRD risk included 102 studies from developed countries and 46 studies from developing countries.

Across all studies, 86% of patients were women, 32% had elevated serum creatinine levels at study entry, and proteinuria averaged 3.6 g daily. The average age was 31.2 years and mean duration of lupus nephritis was 2.7 years.

The proportion of patients treated with glucocorticoids alone in the studies declined from 54% in 1966 to 9% in 2010, while use of immunosuppressive therapies increased.

The decrease in ESRD risks early on coincided with increased use of immunosuppressives, particularly cyclophosphamide, and better control of hypertension and proteinuria. As for why those gains have stalled, Dr. Tektonidou and her colleagues said it’s possible that the limits of effectiveness of current treatments have been reached and better outcomes will require new therapies. “It is also possible that the plateau primarily reflects lack of progress in the way currently available and effective treatments are deployed,” they added. “This includes health system factors that result in delays in treatment initiation, and patient and health system factors that result in treatment interruptions and reduced adherence.”

In an accompanying editorial, Dr. Candace Feldman and Dr. Karen Costenbader, both of Brigham and Women’s Hospital in Boston, wrote, “While we have made advances over the past 50 years in our understanding of immunosuppressive medications, there have been few meaningful improvements in other domains that contribute to ESRD and to the persistent and disproportionate burden among vulnerable populations” (Ann Rheum Dis. 2016 Jan 27. doi: 10.1002/art.39593).

Despite the clear importance of medication adherence to SLE care, a recent systematic review of adherence interventions in rheumatic diseases (Ann Rheum Dis. 2015 Feb 9. doi: 10.1136/annrheumdis-2014-206593) found few SLE-specific interventions overall and none that significantly improved adherence outcomes, Dr. Feldman and Dr. Costenbader pointed out.

Dr. Tektonidou and her associates acknowledged that the new systematic review and meta-analysis were limited by the inability to estimate risks beyond 15 years and because the findings were similar only when observational studies were considered. Factors associated with ESRD, such as renal flares and uncontrolled hypertension, were not examined, and few studies were judged to be of high-quality.

Still, the results can be used to counsel patients on risks of ESRD and also will provide benchmarks to judge the effectiveness of future treatments, the authors concluded.

Dr. Feldman and Dr. Costenbader disagreed with this conclusion, citing various study limitations and the many nuanced factors that play into a patient’s risk of developing ESRD.

“This study should rather be used to provide a broad overview of our understanding of changes in SLE ESRD over time, rather than data to counsel an individual patient on his/her risks,” they wrote.

The study was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors reported having no conflicts of interest.

[email protected]

The world health community has lost ground in its fight to reduce end-stage renal disease in patients with lupus nephritis, a systematic review and meta-analysis concluded.

The risk of end-stage renal disease (ESRD) at 5 years of lupus nephritis decreased substantially from the 1970s, when it was 16%, to the mid-1990s, when it plateaued at 11%.

ESRD risks at 10 years and 15 years declined more sharply in the 1970s and 1980s but also plateaued in the mid-1990s at 17% and 22%, respectively.

This plateau was followed by a notable increase in risk in the late 2000s, particularly in the 10-year and 15-year estimates, Dr. Maria Tektonidou of the University of Athens and her coauthors reported (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39594).

“Despite extensive use of immunosuppressive medications through the 2000s, we did not find continued improvement in ESRD risks, but instead a slight increase in risks in the late 2000s,” they wrote.

The increase did not appear to be related to greater representation in recent studies of ethnic minorities, who may be more likely to develop ESRD. In the main analysis involving 148 of the 187 studies, “trends suggest this increase may have been temporary, but further follow-up will be needed to determine if this is sustained,” the investigators added.

Notably, patients with class-IV lupus nephritis had the greatest risk of ESRD during the 2000s, with a 15-year risk of 44%.

The 15-year risk of ESRD also was higher by 10 percentage points in developing countries than in developed countries during the 2000s.

The trends are worrisome because ESRD is a costly complication of lupus nephritis, which affects more than half of all patients with systemic lupus erythematosus (SLE). Patients with lupus nephritis have a 26-fold increased risk of death and estimated annual health care costs between $43,000 and $107,000 per patient, the authors noted.

The systematic review and Bayesian meta-analysis included 187 studies reporting on 18,309 adults with lupus nephritis from 1971 to 2015. The main analysis of ESRD risk included 102 studies from developed countries and 46 studies from developing countries.

Across all studies, 86% of patients were women, 32% had elevated serum creatinine levels at study entry, and proteinuria averaged 3.6 g daily. The average age was 31.2 years and mean duration of lupus nephritis was 2.7 years.

The proportion of patients treated with glucocorticoids alone in the studies declined from 54% in 1966 to 9% in 2010, while use of immunosuppressive therapies increased.

The decrease in ESRD risks early on coincided with increased use of immunosuppressives, particularly cyclophosphamide, and better control of hypertension and proteinuria. As for why those gains have stalled, Dr. Tektonidou and her colleagues said it’s possible that the limits of effectiveness of current treatments have been reached and better outcomes will require new therapies. “It is also possible that the plateau primarily reflects lack of progress in the way currently available and effective treatments are deployed,” they added. “This includes health system factors that result in delays in treatment initiation, and patient and health system factors that result in treatment interruptions and reduced adherence.”

In an accompanying editorial, Dr. Candace Feldman and Dr. Karen Costenbader, both of Brigham and Women’s Hospital in Boston, wrote, “While we have made advances over the past 50 years in our understanding of immunosuppressive medications, there have been few meaningful improvements in other domains that contribute to ESRD and to the persistent and disproportionate burden among vulnerable populations” (Ann Rheum Dis. 2016 Jan 27. doi: 10.1002/art.39593).

Despite the clear importance of medication adherence to SLE care, a recent systematic review of adherence interventions in rheumatic diseases (Ann Rheum Dis. 2015 Feb 9. doi: 10.1136/annrheumdis-2014-206593) found few SLE-specific interventions overall and none that significantly improved adherence outcomes, Dr. Feldman and Dr. Costenbader pointed out.

Dr. Tektonidou and her associates acknowledged that the new systematic review and meta-analysis were limited by the inability to estimate risks beyond 15 years and because the findings were similar only when observational studies were considered. Factors associated with ESRD, such as renal flares and uncontrolled hypertension, were not examined, and few studies were judged to be of high-quality.

Still, the results can be used to counsel patients on risks of ESRD and also will provide benchmarks to judge the effectiveness of future treatments, the authors concluded.

Dr. Feldman and Dr. Costenbader disagreed with this conclusion, citing various study limitations and the many nuanced factors that play into a patient’s risk of developing ESRD.

“This study should rather be used to provide a broad overview of our understanding of changes in SLE ESRD over time, rather than data to counsel an individual patient on his/her risks,” they wrote.

The study was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors reported having no conflicts of interest.

[email protected]

The world health community has lost ground in its fight to reduce end-stage renal disease in patients with lupus nephritis, a systematic review and meta-analysis concluded.

The risk of end-stage renal disease (ESRD) at 5 years of lupus nephritis decreased substantially from the 1970s, when it was 16%, to the mid-1990s, when it plateaued at 11%.

ESRD risks at 10 years and 15 years declined more sharply in the 1970s and 1980s but also plateaued in the mid-1990s at 17% and 22%, respectively.

This plateau was followed by a notable increase in risk in the late 2000s, particularly in the 10-year and 15-year estimates, Dr. Maria Tektonidou of the University of Athens and her coauthors reported (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39594).

“Despite extensive use of immunosuppressive medications through the 2000s, we did not find continued improvement in ESRD risks, but instead a slight increase in risks in the late 2000s,” they wrote.

The increase did not appear to be related to greater representation in recent studies of ethnic minorities, who may be more likely to develop ESRD. In the main analysis involving 148 of the 187 studies, “trends suggest this increase may have been temporary, but further follow-up will be needed to determine if this is sustained,” the investigators added.

Notably, patients with class-IV lupus nephritis had the greatest risk of ESRD during the 2000s, with a 15-year risk of 44%.

The 15-year risk of ESRD also was higher by 10 percentage points in developing countries than in developed countries during the 2000s.

The trends are worrisome because ESRD is a costly complication of lupus nephritis, which affects more than half of all patients with systemic lupus erythematosus (SLE). Patients with lupus nephritis have a 26-fold increased risk of death and estimated annual health care costs between $43,000 and $107,000 per patient, the authors noted.

The systematic review and Bayesian meta-analysis included 187 studies reporting on 18,309 adults with lupus nephritis from 1971 to 2015. The main analysis of ESRD risk included 102 studies from developed countries and 46 studies from developing countries.

Across all studies, 86% of patients were women, 32% had elevated serum creatinine levels at study entry, and proteinuria averaged 3.6 g daily. The average age was 31.2 years and mean duration of lupus nephritis was 2.7 years.

The proportion of patients treated with glucocorticoids alone in the studies declined from 54% in 1966 to 9% in 2010, while use of immunosuppressive therapies increased.

The decrease in ESRD risks early on coincided with increased use of immunosuppressives, particularly cyclophosphamide, and better control of hypertension and proteinuria. As for why those gains have stalled, Dr. Tektonidou and her colleagues said it’s possible that the limits of effectiveness of current treatments have been reached and better outcomes will require new therapies. “It is also possible that the plateau primarily reflects lack of progress in the way currently available and effective treatments are deployed,” they added. “This includes health system factors that result in delays in treatment initiation, and patient and health system factors that result in treatment interruptions and reduced adherence.”

In an accompanying editorial, Dr. Candace Feldman and Dr. Karen Costenbader, both of Brigham and Women’s Hospital in Boston, wrote, “While we have made advances over the past 50 years in our understanding of immunosuppressive medications, there have been few meaningful improvements in other domains that contribute to ESRD and to the persistent and disproportionate burden among vulnerable populations” (Ann Rheum Dis. 2016 Jan 27. doi: 10.1002/art.39593).

Despite the clear importance of medication adherence to SLE care, a recent systematic review of adherence interventions in rheumatic diseases (Ann Rheum Dis. 2015 Feb 9. doi: 10.1136/annrheumdis-2014-206593) found few SLE-specific interventions overall and none that significantly improved adherence outcomes, Dr. Feldman and Dr. Costenbader pointed out.

Dr. Tektonidou and her associates acknowledged that the new systematic review and meta-analysis were limited by the inability to estimate risks beyond 15 years and because the findings were similar only when observational studies were considered. Factors associated with ESRD, such as renal flares and uncontrolled hypertension, were not examined, and few studies were judged to be of high-quality.

Still, the results can be used to counsel patients on risks of ESRD and also will provide benchmarks to judge the effectiveness of future treatments, the authors concluded.

Dr. Feldman and Dr. Costenbader disagreed with this conclusion, citing various study limitations and the many nuanced factors that play into a patient’s risk of developing ESRD.

“This study should rather be used to provide a broad overview of our understanding of changes in SLE ESRD over time, rather than data to counsel an individual patient on his/her risks,” they wrote.

The study was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors reported having no conflicts of interest.

[email protected]

Illustrative case

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. A computed tomography scan of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.² Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine outpatient care includes oral hydration, antiemetics, and pain medications. Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.^3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.⁵ Meta-analyses of multiple randomized controlled trials (RCTs) suggest that an alpha-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.^6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk of bias.

Treatment with tamsulosin or nifedipine provided no benefits in terms of rate of kidney stone passage, time to passage, analgesic use, or pain.

STUDY SUMMARY: MET doesn’t increase the rate of stone passage

The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial¹ was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 years with a single ureteric stone measuring ≤10 mm on CT KUB, which has 98% diagnostic accuracy.⁸ (Stones >10 mm typically require surgery or lithotripsy.)

In this RCT, 1167 adults were randomized to take tamsulosin 0.4 mg/d, nifedipine 30 mg/d, or placebo for 4 weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At 4 weeks, 1136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤5 mm vs >5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21%) of participants. The mean days to stone passage was 15.9 (n=84) for placebo, 16.5 (n=79) for tamsulosin and 16.2 (n=74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, -2.9 to 3.9; P=.78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first 4 weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, -1.6 to 2.8; P=.45).

There was no difference between groups in the VAS pain score at 4 weeks. The MET vs placebo difference was 0.0 (95% CI, -0.4 to 0.4; P=.96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT'S NEW: This large RCT contradicts results from previous meta-analyses

The SUSPEND study is the first large, multi­center RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, multicenter, well-designed RCT.⁹

CAVEATS: This trial included fewer women than previous studies

The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.¹

CHALLENGES TO IMPLEMENTATION

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

Illustrative case

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. A computed tomography scan of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.² Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine outpatient care includes oral hydration, antiemetics, and pain medications. Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.^3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.⁵ Meta-analyses of multiple randomized controlled trials (RCTs) suggest that an alpha-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.^6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk of bias.

Treatment with tamsulosin or nifedipine provided no benefits in terms of rate of kidney stone passage, time to passage, analgesic use, or pain.

STUDY SUMMARY: MET doesn’t increase the rate of stone passage

The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial¹ was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 years with a single ureteric stone measuring ≤10 mm on CT KUB, which has 98% diagnostic accuracy.⁸ (Stones >10 mm typically require surgery or lithotripsy.)

In this RCT, 1167 adults were randomized to take tamsulosin 0.4 mg/d, nifedipine 30 mg/d, or placebo for 4 weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At 4 weeks, 1136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤5 mm vs >5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21%) of participants. The mean days to stone passage was 15.9 (n=84) for placebo, 16.5 (n=79) for tamsulosin and 16.2 (n=74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, -2.9 to 3.9; P=.78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first 4 weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, -1.6 to 2.8; P=.45).

There was no difference between groups in the VAS pain score at 4 weeks. The MET vs placebo difference was 0.0 (95% CI, -0.4 to 0.4; P=.96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT'S NEW: This large RCT contradicts results from previous meta-analyses

The SUSPEND study is the first large, multi­center RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, multicenter, well-designed RCT.⁹

CAVEATS: This trial included fewer women than previous studies

The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.¹

CHALLENGES TO IMPLEMENTATION

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

Illustrative case

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. A computed tomography scan of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.² Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine outpatient care includes oral hydration, antiemetics, and pain medications. Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.^3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.⁵ Meta-analyses of multiple randomized controlled trials (RCTs) suggest that an alpha-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.^6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk of bias.

Treatment with tamsulosin or nifedipine provided no benefits in terms of rate of kidney stone passage, time to passage, analgesic use, or pain.

STUDY SUMMARY: MET doesn’t increase the rate of stone passage

The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial¹ was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 years with a single ureteric stone measuring ≤10 mm on CT KUB, which has 98% diagnostic accuracy.⁸ (Stones >10 mm typically require surgery or lithotripsy.)

In this RCT, 1167 adults were randomized to take tamsulosin 0.4 mg/d, nifedipine 30 mg/d, or placebo for 4 weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At 4 weeks, 1136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤5 mm vs >5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21%) of participants. The mean days to stone passage was 15.9 (n=84) for placebo, 16.5 (n=79) for tamsulosin and 16.2 (n=74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, -2.9 to 3.9; P=.78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first 4 weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, -1.6 to 2.8; P=.45).

There was no difference between groups in the VAS pain score at 4 weeks. The MET vs placebo difference was 0.0 (95% CI, -0.4 to 0.4; P=.96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT'S NEW: This large RCT contradicts results from previous meta-analyses

The SUSPEND study is the first large, multi­center RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, multicenter, well-designed RCT.⁹

CAVEATS: This trial included fewer women than previous studies

The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.¹

CHALLENGES TO IMPLEMENTATION

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

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Incidence of newly acquired hepatitis C virus has increased recently in patients undergoing hemodialysis, according to a health advisory from the Centers for Disease Control and Prevention.

In 2014 and 2015, 36 cases of HCV infection were reported to the CDC from 19 clinics in eight states. While investigation is ongoing, HCV transmission between patients has been confirmed in at least nine facilities, and in several facilities, lapses in infection control were also identified. Better screening and awareness of HCV infection potential may also play a role in the increased disease incidence.

The CDC recommends that dialysis facilities assess current infection control practices, environmental cleaning, and disinfection practices to evaluate adherence to standards, address any gaps, screen patients for HCV, and to report all HCV infections to the CDC promptly.

“Dialysis facilities should actively assess and continuously improve their infection control, environmental cleaning and disinfection, and HCV screening practices, whether or not they are aware of infections in their clinic. Any case of new HCV infection in a patient undergoing hemodialysis is likely to be a health care–associated infection and should be reported to public health authorities in a timely manner,” the CDC said

Find the full health advisory on the CDC website.

[email protected]

Incidence of newly acquired hepatitis C virus has increased recently in patients undergoing hemodialysis, according to a health advisory from the Centers for Disease Control and Prevention.

In 2014 and 2015, 36 cases of HCV infection were reported to the CDC from 19 clinics in eight states. While investigation is ongoing, HCV transmission between patients has been confirmed in at least nine facilities, and in several facilities, lapses in infection control were also identified. Better screening and awareness of HCV infection potential may also play a role in the increased disease incidence.

The CDC recommends that dialysis facilities assess current infection control practices, environmental cleaning, and disinfection practices to evaluate adherence to standards, address any gaps, screen patients for HCV, and to report all HCV infections to the CDC promptly.

“Dialysis facilities should actively assess and continuously improve their infection control, environmental cleaning and disinfection, and HCV screening practices, whether or not they are aware of infections in their clinic. Any case of new HCV infection in a patient undergoing hemodialysis is likely to be a health care–associated infection and should be reported to public health authorities in a timely manner,” the CDC said

Find the full health advisory on the CDC website.

[email protected]

Incidence of newly acquired hepatitis C virus has increased recently in patients undergoing hemodialysis, according to a health advisory from the Centers for Disease Control and Prevention.

In 2014 and 2015, 36 cases of HCV infection were reported to the CDC from 19 clinics in eight states. While investigation is ongoing, HCV transmission between patients has been confirmed in at least nine facilities, and in several facilities, lapses in infection control were also identified. Better screening and awareness of HCV infection potential may also play a role in the increased disease incidence.

The CDC recommends that dialysis facilities assess current infection control practices, environmental cleaning, and disinfection practices to evaluate adherence to standards, address any gaps, screen patients for HCV, and to report all HCV infections to the CDC promptly.

“Dialysis facilities should actively assess and continuously improve their infection control, environmental cleaning and disinfection, and HCV screening practices, whether or not they are aware of infections in their clinic. Any case of new HCV infection in a patient undergoing hemodialysis is likely to be a health care–associated infection and should be reported to public health authorities in a timely manner,” the CDC said

Find the full health advisory on the CDC website.

[email protected]

SAN FRANCISCO – African American patients with clear-cell renal cell carcinoma may have poorer survival in part because of genomic factors that render tumors more aggressive and less sensitive to anti-angiogenic therapy, suggests a study reported at the Genitourinary Cancers Symposium.

Genomic analysis in 438 patients with metastatic disease found that African Americans were about half as likely as Caucasians to have mutations of the von Hippel–Lindau (VHL) tumor suppressor gene, reported lead investigator Dr. Tracy Lynn Rose, a hematology-oncology fellow at the University of North Carolina at Chapel Hill and Lineberger Comprehensive Cancer Center. Mutational inactivation of this gene leads to increased signaling in the vascular endothelial growth factor (VEGF) pathway.

African Americans also were more likely to have the clear cell B molecular subtype and had less up-regulation of pathways associated with hypoxia-inducible factor (HIF), which collectively suggest a less angiogenic profile and activation of non-VEGF pathways.

A companion analysis of 35,152 patients treated during a 14-year period found that African American patients with metastatic renal cell carcinoma still had a higher risk of death than white peers in the contemporary era, after introduction of multiple agents that target the VEGF pathway and similar increases in receipt of systemic therapy.

“Our findings indicate clear differences in the biology of clear-cell renal cell carcinoma between African Americans and Caucasians. These differences could suggest a larger proportion of tumors from African Americans have a HIF- and VEGF-independent propensity for aggressiveness, and they also suggest perhaps increased resistance of African Americans to VEGF-targeted therapy,” Dr. Rose said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“Overall, our data lend support to a role for tumor biology in the survival disparity observed between African American and Caucasian patients,” she said.

The study may be a step toward precision medicine, whereby race is used to guide treatment decisions, according to invited discussant Dr. Guru Sonpavde, director of the Genitourinary Malignancy Program at the University of Alabama at Birmingham. “That’s an exciting possibility,” he said.

“It is plausible that African American patients are less VEGF driven, less responsive to VEGF inhibitors, but I think the results right now are not ready for use in the clinic,” he further commented. “We need validation in a larger number of African American patients. But even more importantly, we need to focus more on molecular measures of VEGF-driven tumors, to select patients for VEGF inhibitors since we don’t have any biomarkers of this sort in the clinic today.”

“Finally, somatic differences may be driven by differences in the germline, and we may want to focus on integrating the germline and somatic alterations into a molecular panel which might be even better at predicting benefit from specific agents,” he concluded.

Previous studies have found a small but consistent elevation of the risk of death for African American patients with renal cell carcinoma, Dr. Rose noted when introducing the study. Initial hypotheses were that this disparity might be due to differences in comorbidities and use of nephrectomy.

She and her colleagues performed genomic analyses in a discovery cohort of 438 African American and Caucasian patients with metastatic clear-cell renal cell carcinoma from The Cancer Genome Atlas database.

Results indicated that African Americans in this discovery cohort were less likely to have a VHL mutation (17% vs. 50%, P = .036), a finding that was confirmed in a validation cohort of 135 similar patients (40% vs. 81%, P = .008).

African American patients were less likely to have several VEGF and HIF signatures relative to Caucasian counterparts. On the other hand, they were more likely to have the clear cell B molecular subtype (79% vs. 45%, P less than .01), which has been associated with decreased activation of angiogenic pathways and poorer prognosis.

The investigators next analyzed data from the National Cancer Database, assessing survival among 35,152 patients who received a diagnosis of metastatic clear-cell renal cell carcinoma between 1998 and 2011.

The proportion receiving systemic therapy over time was similar for African American and Caucasian patients, with both seeing a rise in 2006, corresponding to the introduction of VEGF-targeted therapies. The poorer median survival for African American versus Caucasian patients seen during 1998-2004 (6.0 vs. 7.6 months; adjusted hazard ratio, 1.07; P less than .01) was still evident in 2006-2011 (6.5 vs. 9.2 months; adjusted hazard ratio, 1.08; P less than .01).

SAN FRANCISCO – African American patients with clear-cell renal cell carcinoma may have poorer survival in part because of genomic factors that render tumors more aggressive and less sensitive to anti-angiogenic therapy, suggests a study reported at the Genitourinary Cancers Symposium.

Genomic analysis in 438 patients with metastatic disease found that African Americans were about half as likely as Caucasians to have mutations of the von Hippel–Lindau (VHL) tumor suppressor gene, reported lead investigator Dr. Tracy Lynn Rose, a hematology-oncology fellow at the University of North Carolina at Chapel Hill and Lineberger Comprehensive Cancer Center. Mutational inactivation of this gene leads to increased signaling in the vascular endothelial growth factor (VEGF) pathway.

African Americans also were more likely to have the clear cell B molecular subtype and had less up-regulation of pathways associated with hypoxia-inducible factor (HIF), which collectively suggest a less angiogenic profile and activation of non-VEGF pathways.

A companion analysis of 35,152 patients treated during a 14-year period found that African American patients with metastatic renal cell carcinoma still had a higher risk of death than white peers in the contemporary era, after introduction of multiple agents that target the VEGF pathway and similar increases in receipt of systemic therapy.

“Our findings indicate clear differences in the biology of clear-cell renal cell carcinoma between African Americans and Caucasians. These differences could suggest a larger proportion of tumors from African Americans have a HIF- and VEGF-independent propensity for aggressiveness, and they also suggest perhaps increased resistance of African Americans to VEGF-targeted therapy,” Dr. Rose said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“Overall, our data lend support to a role for tumor biology in the survival disparity observed between African American and Caucasian patients,” she said.

The study may be a step toward precision medicine, whereby race is used to guide treatment decisions, according to invited discussant Dr. Guru Sonpavde, director of the Genitourinary Malignancy Program at the University of Alabama at Birmingham. “That’s an exciting possibility,” he said.

“It is plausible that African American patients are less VEGF driven, less responsive to VEGF inhibitors, but I think the results right now are not ready for use in the clinic,” he further commented. “We need validation in a larger number of African American patients. But even more importantly, we need to focus more on molecular measures of VEGF-driven tumors, to select patients for VEGF inhibitors since we don’t have any biomarkers of this sort in the clinic today.”

“Finally, somatic differences may be driven by differences in the germline, and we may want to focus on integrating the germline and somatic alterations into a molecular panel which might be even better at predicting benefit from specific agents,” he concluded.

Previous studies have found a small but consistent elevation of the risk of death for African American patients with renal cell carcinoma, Dr. Rose noted when introducing the study. Initial hypotheses were that this disparity might be due to differences in comorbidities and use of nephrectomy.

She and her colleagues performed genomic analyses in a discovery cohort of 438 African American and Caucasian patients with metastatic clear-cell renal cell carcinoma from The Cancer Genome Atlas database.

Results indicated that African Americans in this discovery cohort were less likely to have a VHL mutation (17% vs. 50%, P = .036), a finding that was confirmed in a validation cohort of 135 similar patients (40% vs. 81%, P = .008).

African American patients were less likely to have several VEGF and HIF signatures relative to Caucasian counterparts. On the other hand, they were more likely to have the clear cell B molecular subtype (79% vs. 45%, P less than .01), which has been associated with decreased activation of angiogenic pathways and poorer prognosis.

The investigators next analyzed data from the National Cancer Database, assessing survival among 35,152 patients who received a diagnosis of metastatic clear-cell renal cell carcinoma between 1998 and 2011.

The proportion receiving systemic therapy over time was similar for African American and Caucasian patients, with both seeing a rise in 2006, corresponding to the introduction of VEGF-targeted therapies. The poorer median survival for African American versus Caucasian patients seen during 1998-2004 (6.0 vs. 7.6 months; adjusted hazard ratio, 1.07; P less than .01) was still evident in 2006-2011 (6.5 vs. 9.2 months; adjusted hazard ratio, 1.08; P less than .01).

SAN FRANCISCO – African American patients with clear-cell renal cell carcinoma may have poorer survival in part because of genomic factors that render tumors more aggressive and less sensitive to anti-angiogenic therapy, suggests a study reported at the Genitourinary Cancers Symposium.

Genomic analysis in 438 patients with metastatic disease found that African Americans were about half as likely as Caucasians to have mutations of the von Hippel–Lindau (VHL) tumor suppressor gene, reported lead investigator Dr. Tracy Lynn Rose, a hematology-oncology fellow at the University of North Carolina at Chapel Hill and Lineberger Comprehensive Cancer Center. Mutational inactivation of this gene leads to increased signaling in the vascular endothelial growth factor (VEGF) pathway.

African Americans also were more likely to have the clear cell B molecular subtype and had less up-regulation of pathways associated with hypoxia-inducible factor (HIF), which collectively suggest a less angiogenic profile and activation of non-VEGF pathways.

A companion analysis of 35,152 patients treated during a 14-year period found that African American patients with metastatic renal cell carcinoma still had a higher risk of death than white peers in the contemporary era, after introduction of multiple agents that target the VEGF pathway and similar increases in receipt of systemic therapy.

“Our findings indicate clear differences in the biology of clear-cell renal cell carcinoma between African Americans and Caucasians. These differences could suggest a larger proportion of tumors from African Americans have a HIF- and VEGF-independent propensity for aggressiveness, and they also suggest perhaps increased resistance of African Americans to VEGF-targeted therapy,” Dr. Rose said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“Overall, our data lend support to a role for tumor biology in the survival disparity observed between African American and Caucasian patients,” she said.

The study may be a step toward precision medicine, whereby race is used to guide treatment decisions, according to invited discussant Dr. Guru Sonpavde, director of the Genitourinary Malignancy Program at the University of Alabama at Birmingham. “That’s an exciting possibility,” he said.

“It is plausible that African American patients are less VEGF driven, less responsive to VEGF inhibitors, but I think the results right now are not ready for use in the clinic,” he further commented. “We need validation in a larger number of African American patients. But even more importantly, we need to focus more on molecular measures of VEGF-driven tumors, to select patients for VEGF inhibitors since we don’t have any biomarkers of this sort in the clinic today.”

“Finally, somatic differences may be driven by differences in the germline, and we may want to focus on integrating the germline and somatic alterations into a molecular panel which might be even better at predicting benefit from specific agents,” he concluded.

Previous studies have found a small but consistent elevation of the risk of death for African American patients with renal cell carcinoma, Dr. Rose noted when introducing the study. Initial hypotheses were that this disparity might be due to differences in comorbidities and use of nephrectomy.

She and her colleagues performed genomic analyses in a discovery cohort of 438 African American and Caucasian patients with metastatic clear-cell renal cell carcinoma from The Cancer Genome Atlas database.

Results indicated that African Americans in this discovery cohort were less likely to have a VHL mutation (17% vs. 50%, P = .036), a finding that was confirmed in a validation cohort of 135 similar patients (40% vs. 81%, P = .008).

African American patients were less likely to have several VEGF and HIF signatures relative to Caucasian counterparts. On the other hand, they were more likely to have the clear cell B molecular subtype (79% vs. 45%, P less than .01), which has been associated with decreased activation of angiogenic pathways and poorer prognosis.

The investigators next analyzed data from the National Cancer Database, assessing survival among 35,152 patients who received a diagnosis of metastatic clear-cell renal cell carcinoma between 1998 and 2011.

The proportion receiving systemic therapy over time was similar for African American and Caucasian patients, with both seeing a rise in 2006, corresponding to the introduction of VEGF-targeted therapies. The poorer median survival for African American versus Caucasian patients seen during 1998-2004 (6.0 vs. 7.6 months; adjusted hazard ratio, 1.07; P less than .01) was still evident in 2006-2011 (6.5 vs. 9.2 months; adjusted hazard ratio, 1.08; P less than .01).

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

See below for "Views on the News," a pro/con discussion on PPIs.

Available evidence suggests that proton pump inhibitor use is associated with an increased risk of both acute and chronic kidney disease, hypomagnesemia, Clostridium difficile infection, and osteoporotic fractures. Caution in prescribing PPIs should be used in patients at high risk for any of these conditions. Given the association with kidney disease and low magnesium levels, serum creatinine and magnesium levels probably should be monitored in patients using PPIs, especially those using high doses.

Given the evidence that PPI use is linked with a number of adverse outcomes, we recommend that patients and clinicians discuss the potential benefits and risks of PPI treatment, as well as potential alternative regimens such as histamine H₂ receptor antagonists or lifestyle changes, before PPIs are prescribed. In patients with symptomatic gastrointestinal reflux, ulcer disease, and severe dyspepsia, the benefits of PPI use likely outweigh its potential harms. For less serious symptoms, however, and for prevention of bleeding in low-risk patients, potential harms may outweigh the benefits. A large number of patients are taking PPIs for no clear reason – often remote symptoms of dyspepsia or heartburn that have since resolved. In these patients, PPIs should be stopped to determine if symptomatic treatment is needed.

Dr. Adam J. Schoenfeld and Dr. Deborah Grady are with the University of California, San Francisco. They had no disclosures. These comments were taken from their editorial (JAMA Intern Med. 2016 Jan 11. doi: 10.1001/jamainternmed.2015.7927).

Pro: When used as indicated, PPIs are good medicine

The bottom line is that PPIs should be used continually for the three specific conditions for which they are known to be beneficial – hypersecretory states, gastroesophageal reflux disease (in all its manifestations), and NSAID/aspirin prophylaxis. As with all drugs, treatment always should be at the lowest effective dose. Although it is quite appropriate to limit chronic PPI use to these groups, given the potential association (no causality identified) with various putative side effects including renal disease, in my opinion, the risks of denying PPIs when indicated are higher than the low risks of renal or other possible side effects.

Dr. David C. Metz is associate chief for clinical affairs, GI division; codirector, esophagology and swallowing program; director, acid-peptic program; codirector, neuroendocrine tumor center; and professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia.

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

See below for "Views on the News," a pro/con discussion on PPIs.

Available evidence suggests that proton pump inhibitor use is associated with an increased risk of both acute and chronic kidney disease, hypomagnesemia, Clostridium difficile infection, and osteoporotic fractures. Caution in prescribing PPIs should be used in patients at high risk for any of these conditions. Given the association with kidney disease and low magnesium levels, serum creatinine and magnesium levels probably should be monitored in patients using PPIs, especially those using high doses.

Given the evidence that PPI use is linked with a number of adverse outcomes, we recommend that patients and clinicians discuss the potential benefits and risks of PPI treatment, as well as potential alternative regimens such as histamine H₂ receptor antagonists or lifestyle changes, before PPIs are prescribed. In patients with symptomatic gastrointestinal reflux, ulcer disease, and severe dyspepsia, the benefits of PPI use likely outweigh its potential harms. For less serious symptoms, however, and for prevention of bleeding in low-risk patients, potential harms may outweigh the benefits. A large number of patients are taking PPIs for no clear reason – often remote symptoms of dyspepsia or heartburn that have since resolved. In these patients, PPIs should be stopped to determine if symptomatic treatment is needed.

Dr. Adam J. Schoenfeld and Dr. Deborah Grady are with the University of California, San Francisco. They had no disclosures. These comments were taken from their editorial (JAMA Intern Med. 2016 Jan 11. doi: 10.1001/jamainternmed.2015.7927).

Pro: When used as indicated, PPIs are good medicine

The bottom line is that PPIs should be used continually for the three specific conditions for which they are known to be beneficial – hypersecretory states, gastroesophageal reflux disease (in all its manifestations), and NSAID/aspirin prophylaxis. As with all drugs, treatment always should be at the lowest effective dose. Although it is quite appropriate to limit chronic PPI use to these groups, given the potential association (no causality identified) with various putative side effects including renal disease, in my opinion, the risks of denying PPIs when indicated are higher than the low risks of renal or other possible side effects.

Dr. David C. Metz is associate chief for clinical affairs, GI division; codirector, esophagology and swallowing program; director, acid-peptic program; codirector, neuroendocrine tumor center; and professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia.

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

See below for "Views on the News," a pro/con discussion on PPIs.

Available evidence suggests that proton pump inhibitor use is associated with an increased risk of both acute and chronic kidney disease, hypomagnesemia, Clostridium difficile infection, and osteoporotic fractures. Caution in prescribing PPIs should be used in patients at high risk for any of these conditions. Given the association with kidney disease and low magnesium levels, serum creatinine and magnesium levels probably should be monitored in patients using PPIs, especially those using high doses.

Given the evidence that PPI use is linked with a number of adverse outcomes, we recommend that patients and clinicians discuss the potential benefits and risks of PPI treatment, as well as potential alternative regimens such as histamine H₂ receptor antagonists or lifestyle changes, before PPIs are prescribed. In patients with symptomatic gastrointestinal reflux, ulcer disease, and severe dyspepsia, the benefits of PPI use likely outweigh its potential harms. For less serious symptoms, however, and for prevention of bleeding in low-risk patients, potential harms may outweigh the benefits. A large number of patients are taking PPIs for no clear reason – often remote symptoms of dyspepsia or heartburn that have since resolved. In these patients, PPIs should be stopped to determine if symptomatic treatment is needed.

Dr. Adam J. Schoenfeld and Dr. Deborah Grady are with the University of California, San Francisco. They had no disclosures. These comments were taken from their editorial (JAMA Intern Med. 2016 Jan 11. doi: 10.1001/jamainternmed.2015.7927).

Pro: When used as indicated, PPIs are good medicine

The bottom line is that PPIs should be used continually for the three specific conditions for which they are known to be beneficial – hypersecretory states, gastroesophageal reflux disease (in all its manifestations), and NSAID/aspirin prophylaxis. As with all drugs, treatment always should be at the lowest effective dose. Although it is quite appropriate to limit chronic PPI use to these groups, given the potential association (no causality identified) with various putative side effects including renal disease, in my opinion, the risks of denying PPIs when indicated are higher than the low risks of renal or other possible side effects.

Dr. David C. Metz is associate chief for clinical affairs, GI division; codirector, esophagology and swallowing program; director, acid-peptic program; codirector, neuroendocrine tumor center; and professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia.

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

SAN DIEGO – Twice-yearly denosumab effectively increased bone mineral density in kidney transplant recipients, but was associated with more frequent episodes of urinary tract infections and hypocalcemia, results from a randomized trial showed.

“Kidney transplant recipients lose bone mass and are at increased risk for fractures, more so in females than in males,” Dr. Rudolf P. Wuthrich said at Kidney Week 2015, sponsored by the American Society of Nephrology. Results from previous studies suggest that one in five patients may develop a fracture within 5 years after kidney transplantation.

Considering that current therapeutic options to prevent bone loss are limited, Dr. Wuthrich, director of the Clinic for Nephrology at University Hospital Zurich, and his associates assessed the efficacy and safety of receptor activator of nuclear factor–kappaB ligand (RANKL) inhibition with denosumab to improve bone mineralization in the first year after kidney transplantation. They recruited 108 patients from June 2011 to May 2014. Of these, 90 were randomized within 4 weeks after kidney transplant surgery in a 1:1 ratio to receive subcutaneous injections of 60 mg denosumab at baseline and after 6 months, or no treatment. The study’s primary endpoint was the percentage change in bone mineral density measured by DXA at the lumbar spine at 12 months. The study, known as Denosumab for Prevention of Osteoporosis in Renal Transplant Recipients (POSTOP), was limited to adults who had undergone kidney transplantation within 28 days and who were on standard triple immunosuppression, including a calcineurin antagonist, mycophenolate, and steroids.

Dr. Wuthrich reported results from 46 patients in the denosumab group and 44 patients in the control group. At baseline, their mean age was 50 years, 63% were male, and 96% were white. After 12 months, the total lumbar spine BMD increased by 4.6% in the denosumab group and decreased by 0.5% in the control group, for a between-group difference of 5.1% (P less than .0001). Denosumab also significantly increased BMD at the total hip by 1.9% (P = .035) over that in the control group at 12 months.

High-resolution peripheral quantitative computed tomography in a subgroup of 24 patients showed that denosumab also significantly increased BMD and cortical thickness at the distal tibia and radius (P less than .05). Two biomarkers of bone resorption in beta C-terminal telopeptide and urine deoxypyridinoline markedly decreased in the denosumab group, as did two biomarkers of bone formation in procollagen type 1 N-terminal propeptide and bone-specific alkaline phosphatase (P less than .0001).

In terms of adverse events, there were significantly more urinary tract infections in the denosumab group, compared with the control group (15% vs. 9%, respectively), as well as more episodes of diarrhea (9% vs. 5%), and transient hypocalcemia (3% vs. 0.3%). The number of serious adverse events was similar between groups, at 17% and 19%, respectively.

“We had significantly increased bone mineral density at all measured skeletal sites in response to denosumab,” Dr. Wuthrich concluded. “We had a significant increase in bone biomarkers and we can say that denosumab was generally safe in a complex population of immunosuppressed kidney transplant recipients. But it was associated with a higher incidence of urinary tract infections. At this point we have no good explanation as to why this is. We also had a few episodes of transient and asymptomatic hypocalcemia.”

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – Twice-yearly denosumab effectively increased bone mineral density in kidney transplant recipients, but was associated with more frequent episodes of urinary tract infections and hypocalcemia, results from a randomized trial showed.

“Kidney transplant recipients lose bone mass and are at increased risk for fractures, more so in females than in males,” Dr. Rudolf P. Wuthrich said at Kidney Week 2015, sponsored by the American Society of Nephrology. Results from previous studies suggest that one in five patients may develop a fracture within 5 years after kidney transplantation.

Considering that current therapeutic options to prevent bone loss are limited, Dr. Wuthrich, director of the Clinic for Nephrology at University Hospital Zurich, and his associates assessed the efficacy and safety of receptor activator of nuclear factor–kappaB ligand (RANKL) inhibition with denosumab to improve bone mineralization in the first year after kidney transplantation. They recruited 108 patients from June 2011 to May 2014. Of these, 90 were randomized within 4 weeks after kidney transplant surgery in a 1:1 ratio to receive subcutaneous injections of 60 mg denosumab at baseline and after 6 months, or no treatment. The study’s primary endpoint was the percentage change in bone mineral density measured by DXA at the lumbar spine at 12 months. The study, known as Denosumab for Prevention of Osteoporosis in Renal Transplant Recipients (POSTOP), was limited to adults who had undergone kidney transplantation within 28 days and who were on standard triple immunosuppression, including a calcineurin antagonist, mycophenolate, and steroids.

Dr. Wuthrich reported results from 46 patients in the denosumab group and 44 patients in the control group. At baseline, their mean age was 50 years, 63% were male, and 96% were white. After 12 months, the total lumbar spine BMD increased by 4.6% in the denosumab group and decreased by 0.5% in the control group, for a between-group difference of 5.1% (P less than .0001). Denosumab also significantly increased BMD at the total hip by 1.9% (P = .035) over that in the control group at 12 months.

High-resolution peripheral quantitative computed tomography in a subgroup of 24 patients showed that denosumab also significantly increased BMD and cortical thickness at the distal tibia and radius (P less than .05). Two biomarkers of bone resorption in beta C-terminal telopeptide and urine deoxypyridinoline markedly decreased in the denosumab group, as did two biomarkers of bone formation in procollagen type 1 N-terminal propeptide and bone-specific alkaline phosphatase (P less than .0001).

In terms of adverse events, there were significantly more urinary tract infections in the denosumab group, compared with the control group (15% vs. 9%, respectively), as well as more episodes of diarrhea (9% vs. 5%), and transient hypocalcemia (3% vs. 0.3%). The number of serious adverse events was similar between groups, at 17% and 19%, respectively.

“We had significantly increased bone mineral density at all measured skeletal sites in response to denosumab,” Dr. Wuthrich concluded. “We had a significant increase in bone biomarkers and we can say that denosumab was generally safe in a complex population of immunosuppressed kidney transplant recipients. But it was associated with a higher incidence of urinary tract infections. At this point we have no good explanation as to why this is. We also had a few episodes of transient and asymptomatic hypocalcemia.”

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – Twice-yearly denosumab effectively increased bone mineral density in kidney transplant recipients, but was associated with more frequent episodes of urinary tract infections and hypocalcemia, results from a randomized trial showed.

“Kidney transplant recipients lose bone mass and are at increased risk for fractures, more so in females than in males,” Dr. Rudolf P. Wuthrich said at Kidney Week 2015, sponsored by the American Society of Nephrology. Results from previous studies suggest that one in five patients may develop a fracture within 5 years after kidney transplantation.

Considering that current therapeutic options to prevent bone loss are limited, Dr. Wuthrich, director of the Clinic for Nephrology at University Hospital Zurich, and his associates assessed the efficacy and safety of receptor activator of nuclear factor–kappaB ligand (RANKL) inhibition with denosumab to improve bone mineralization in the first year after kidney transplantation. They recruited 108 patients from June 2011 to May 2014. Of these, 90 were randomized within 4 weeks after kidney transplant surgery in a 1:1 ratio to receive subcutaneous injections of 60 mg denosumab at baseline and after 6 months, or no treatment. The study’s primary endpoint was the percentage change in bone mineral density measured by DXA at the lumbar spine at 12 months. The study, known as Denosumab for Prevention of Osteoporosis in Renal Transplant Recipients (POSTOP), was limited to adults who had undergone kidney transplantation within 28 days and who were on standard triple immunosuppression, including a calcineurin antagonist, mycophenolate, and steroids.

Dr. Wuthrich reported results from 46 patients in the denosumab group and 44 patients in the control group. At baseline, their mean age was 50 years, 63% were male, and 96% were white. After 12 months, the total lumbar spine BMD increased by 4.6% in the denosumab group and decreased by 0.5% in the control group, for a between-group difference of 5.1% (P less than .0001). Denosumab also significantly increased BMD at the total hip by 1.9% (P = .035) over that in the control group at 12 months.

High-resolution peripheral quantitative computed tomography in a subgroup of 24 patients showed that denosumab also significantly increased BMD and cortical thickness at the distal tibia and radius (P less than .05). Two biomarkers of bone resorption in beta C-terminal telopeptide and urine deoxypyridinoline markedly decreased in the denosumab group, as did two biomarkers of bone formation in procollagen type 1 N-terminal propeptide and bone-specific alkaline phosphatase (P less than .0001).

In terms of adverse events, there were significantly more urinary tract infections in the denosumab group, compared with the control group (15% vs. 9%, respectively), as well as more episodes of diarrhea (9% vs. 5%), and transient hypocalcemia (3% vs. 0.3%). The number of serious adverse events was similar between groups, at 17% and 19%, respectively.

“We had significantly increased bone mineral density at all measured skeletal sites in response to denosumab,” Dr. Wuthrich concluded. “We had a significant increase in bone biomarkers and we can say that denosumab was generally safe in a complex population of immunosuppressed kidney transplant recipients. But it was associated with a higher incidence of urinary tract infections. At this point we have no good explanation as to why this is. We also had a few episodes of transient and asymptomatic hypocalcemia.”

The researchers reported having no financial disclosures.

[email protected]