A medication called cinacalcet—an important part of treatment to control high levels of parathyroid hormone (PTH) in patients receiving dialysis for end-stage renal disease (ESRD)—works by resetting the balance between calcium and PTH levels, according to a study in the November Journal of the American Society of Nephrology (JASN).

Cinacalcet is one of a family of drugs called calcimimetics. "In hemodialysis patients, the use of calcimimetics decreases the set point of the PTH-calcium curve, which means that PTH secretion by cells is suppressed at low or normal calcium levels," comments Mariano Rodriguez, MD, PhD, of Nephrology Service, Hospital Universitario Reina Sofia in Cordoba, Spain.

Dr. Rodriguez and colleagues studied responses to cinacalcet treatment in nine patients with ESRD receiving long-term hemodialysis to replace lost kidney function. All patients had high levels of PTH, or secondary hyperparathyroidism—a frequent complication of kidney disease that is mainly caused by low calcium levels. Hyperparathyroidism can lead to weakening of the bones and other problems, including cardiovascular disease.

The researchers assessed the "PTH-calcium curve," which reflects the way PTH levels respond to calcium levels, by comparing blood samples obtained during dialysis performed at low and high calcium levels. The study took advantage of a new test that provides more complete information on the dynamics of PTH secretion.

Treatment with cinacalcet led to significant reductions in the patients' blood phosphorus levels. Their levels of PTH before dialysis were also decreased.

Cinacalcet also led to a reduction in the set point of the PTH-calcium curve. This occurred because cinacalcet made parathyroid cells more sensitive to calcium.

The study provides important new information on how cinacalcet and other calcimimetic drugs work to reduce PTH levels. Normally, low calcium levels cause cells to increase secretion of PTH. After cinacalcet treatment, PTH secretion doesn't increase even when calcium levels are low. Cinacalcet doesn't just lower calcium and PTH levels in the short term, the new results suggest—it changes the interaction between calcium and PTH levels in the long term.

Secondary hyperparathyroidism is a common and potentially serious problem in patients with kidney disease. Calcimimetic drugs like cinacalcet provide a valuable new treatment option. "Nowadays the calcimimetics are an essential tool in the treatment of secondary hyperparathyroidism," says Dr. Rodriguez. "With these drugs, the need for surgery to remove the parathyroid gland (parathyroidectomy) is markedly decreased."

The results provide nephrologists with new insights into the way cinacalcet works to control PTH levels in ESRD patients with hyperparathyroidism. "High PTH levels and the excess of calcium in blood are easy to control with calcimimetics," Dr. Rodriguez adds.

The study was limited by the lack of data on the effects of cinacalcet in patients on peritoneal dialysis, although there are no reasons to believe that results would have been different in peritoneal dialyisis patients. In addition, the patients in the study were not taking vitamin D, another effective treatment for hyperparathyroidism. "It would have been interesting to evaluate the combined effect of calcimimetics and vitamin D on the set point of the PTH-calcium curve," says Dr. Rodriguez.

Funding was provided by Government grants from instituto Carlos III, Consejeria de Salud de la Junta de Andalucia and Fundación Nefrologica and Red de Investigación Renal. Funding for the writing was provided by Amgen Europe.

The article, entitled “Cinacalcet Reduces the Set Point of the Parathyroid Hormone -Calcium Curve in Hemodialysis Patients with Secondary Hyperparathyroidism,” will appear online at http://jasn.asnjournals.org/ on July 16, 2008, and in print in the November 2008 issue of JASN.

ASN is a not-for-profit organization of 11,000 physicians and scientists dedicated to the study of nephrology and committed to providing a forum for the promulgation of information regarding the latest research and clinical findings on kidney diseases. ASN publishes JASN, the Clinical Journal of the American Society of Nephrology (CJASN), and the Nephrology Self-Assessment Program (NephSAP). In January 2009, the Society will launch ASN Kidney News, a newsmagazine for nephrologists, scientists, allied health professionals, and staff.

A new therapy developed at Cedars-Sinai Medical Center improves transplant rates and outcomes for patients awaiting living- and deceased-donor kidney transplantation, according to a study published in the July 17 issue of the New England Journal of Medicine.

The therapy may provide an option for many patients “sensitized” to transplant antigens (human leukocyte antigens, or HLA) who previously would not have been candidates for transplantation because of their intense immune response to these HLA targets.

HLA exposure can come through blood transfusions, previous transplantation or pregnancy. Once exposed, the immune system is sensitized to those antigens and develops antibodies to fight them. If a donor organ with the antigens is later transplanted, the antibodies respond, increasing the risk of rejection and loss of the organ. Antibodies to HLA were previously considered an absolute contraindication to transplantation – the risk was too high for transplantation to be an option.

About 30 percent of the 74,000 patients on the transplant waiting lists for a deceased-donor kidney are sensitized, and those with exceptionally high antibody levels are considered especially poor candidates for transplantation. In fact, each year only 6.5 percent of highly sensitized patients receive a transplant. Most remain on dialysis indefinitely, without hope for a life-saving transplant.

“From a quality-of-life perspective, as well as from the financial standpoint, transplantation is a much better option than years of dialysis,” said Stanley C. Jordan, M.D., director of the Division of Nephrology and medical director of the Renal Transplant Program at Cedars-Sinai. The senior author of the journal article, Jordan developed high-dose intravenous immunoglobulin (IVIG) therapy to “desensitize” highly sensitized patients and increase their chances of successful transplantation. The approach became a Medicare-approved therapy in 2004 at the conclusion of a National Institutes of Health-funded multicenter study.

Cedars-Sinai is a national leader in desensitization for the highly HLA sensitized patient, offering therapy for those awaiting both living-donor and deceased-donor transplantation.

The New England Journal article describes a Phase I/II safety and limited efficacy trial of a combination of IVIG and rituximab, a monoclonal antibody – an antibody engineered to bind to a specific protein. The combination of IVIG and rituximab appears to offer superior benefits to IVIG alone, improving transplant rates to 80 percent of treated patients. The one-year patient and graft survival rates were 100 percent and 94 percent, respectively.

Based on these results, the new protocol is less costly than IVIG alone yet appears to be highly effective in reducing antibody levels and improving transplantation rates. Larger, multicenter trials are necessary to confirm these findings.

Because nearly one-third of kidney failure patients are highly sensitized and few transplant centers specialize in desensitization therapy, many potential candidates are told that a transplant simply is not possible.

“Patients who are on dialysis and those who are progressing toward renal failure should be considered for a kidney transplant. Ideally, they would be referred to a transplant center for evaluation even before they start dialysis because data show that those who get transplanted before starting dialysis do better,” Jordan said. “However, for the highly sensitized patient, transplantation is not an option unless desensitization therapies are used.”

Jordan estimates that about 40 percent of Cedars-Sinai’s kidney transplant patients are highly sensitized and are referred or self-referred to the program because of their highly sensitized state. For many patients, especially those awaiting a deceased-donor transplant, the combination of IVIG and rituximab appears to offer an alternative to ongoing dialysis.

The New England Journal of Medicine article is accompanied by an editorial written by Ron Shapiro, M.D., of the Thomas E. Starzl Transplantation Institute at the University of Pittsburgh. He concludes his comments by saying, “As the authors note, their observations need to be confirmed and validated by other centers and in larger numbers of patients and during longer periods of follow-up. However, their approach may represent a breakthrough in the care of sensitized patients awaiting transplantation and may have the potential to help thousands of patients who are languishing on waiting lists around the world.”

Citation: The New England Journal of Medicine, “Rituximab and Intravenous Immune Globulin for Desensitization during Renal Transplantation,” July 17, 2008.

Disclosure/conflicts: Study supported by Genentech and Biogen Idec, which also provided drugs used in the study. Dr. Reinsmoen received lecture fees from Cylex. Dr. Jordan receives consulting fees and grant support from Talecris and Bristol-Myers Squibb and lecture fees from Genentech. Cedars-Sinai owns a patent: “Use of IVIG in Desensitization.” No other potential conflicts of interest relevant to this article.

The articles below will be published online July 16, 2008, at 4 p.m. (ET) by the American Journal of Public Health under “First Look” at http://www.ajph.org/first_look.shmtl, and they are currently scheduled to appear in the September 2008 print issue of the Journal. “First Look” articles have undergone peer review, copyediting and approval by authors but have not yet been printed to paper or posted online by issue. The American Journal of Public Health is published by the American Public Health Association, www.apha.org, and is available at http://www.ajph.org. To stay up to date on the latest in public health research, sign up for new Journal content e-mail alerts at http://www.ajph.org/subscriptions/etoc.shtml>ck=nck.

American Journal of Public Health Highlights:

Effects on mental health assessed after devastating tsunami in Sumatra

Researchers examined the levels of post traumatic stress reactivity (PTSR) of over 20,000 adult tsunami survivors by analyzing survey data from coastal Aceh and North Sumatra, Indonesia. The findings are from the first wave of a long-term prospective longitudinal follow-up study examining the nature and course of mental health consequences and moderating influences among a population in Indonesia affected by the 2004 Indian Ocean tsunami. Survey respondents were classified into three damage zones using satellite imagery of their pre-tsunami locations of residence from before and after the disaster. Overall, 34 percent of the respondents experienced the trauma of either hearing the tsunami wave or screams about it and 6 percent watched family or friends struggle or disappear. Both exposure to traumatic events at the time of the tsunami and subsequent PTSR scores were highest for respondents from heavily damaged areas. Scores declined over time for respondents from all three damage zones. Gender and age were significant predictors of PTSR, whereas socioeconomic status before the tsunami was not.

“We expect that this 5-year study will provide important knowledge about long-term mental health outcomes after catastrophic disaster and a rationale for attention by international health organizations to sustain interventions beyond the immediate postcrisis period, and will guide the use of stratified public mental health postdisaster programs,” the study’s authors forecast. [From: “Mental Health in Sumatra After the Tsunami,” ].

Menthol in cigarettes promotes smoking among adolescents and young adults

Researchers examined U.S. cigarette brands popular among youth to determine whether or not tobacco manufacturers manipulate menthol in an effort to target young, experimental smokers. Menthol in cigarettes masks harshness and irritation for new smokers. Menthol is used as an additive in approximately 90% of cigarettes manufactured in the United States, although only about one-third of these cigarettes are explicitly marketed as mentholated. This study used data from tobacco industry documents on menthol product development, lab testing results of U.S. menthol brands, market research reports, and the 2006 National Survey on Drug Use and Health, an annual nationally representative survey among U.S. residents aged 12 years and older. The researchers found that tobacco companies control menthol in specific brands to target the sensory preferences of new or younger smokers, primarily by creating milder menthol brands, thereby easing smoking initiation. Menthol brands that have used this strategy have been most successful in attracting youth and young adult smokers and have grown in popularity.

“For decades, tobacco manufacturers have controlled levels of menthol in commercial cigarettes to promote smoking among adolescents and young adults,” the authors said. “To protect public health, tobacco products should be federally regulated and additives such as menthol should be included in that regulation.” [From: “Tobacco Industry Control of Menthol in Cigarettes and Targeting of Adolescents and Young Adults,” ].

Neighborhood psychosocial hazards connected to cardiovascular disease: Case study in Baltimore

Researchers analyzed the associations between cardiovascular disease and neighborhood psychosocial hazards, such as violent crimes, abandoned buildings, and signs of incivility, that lead to an increased sense of threat and vigilance in residents within 65 contiguous neighborhoods in Baltimore, Maryland. A total of 1,140 residents participated in this study who were aged 50 to 70 years and residents of Baltimore for at least 5 years. After adjusting for individual heart disease risk factors, researchers found that residents in neighborhoods with scores in the highest quartile of the psychosocial hazards scale had more than 4 times higher odds of a history of myocardial infarction and more than 3 times higher odds of myocardial infarction, stroke, transient ischemic attack, or intermittent claudication compared with residents living in neighborhoods scoring in the lowest quartile.

“A new wave of research is examining the health consequences of various aspects of residential neighborhoods,” the study’s author said. “Daily exposure to psychosocial hazards in the neighborhood is known to activate a physiological stress response. These findings suggest new targets for intervention and policy change.” [From: “Neighborhood Psychosocial Hazards and Cardiovascular Disease: The Baltimore Memory Study,” ].

U.S. child labor violations found in the retail and service industry

Results from this study found that a substantial proportion of U.S. adolescents working in the retail and service industry were employed in violation of the child labor laws. The Fair Labor Standards Act (FLSA) of 1938 limits the types of jobs youths ages 14 to 17 are allowed to perform, the number of hours they may devote to work, and the timing of these hours. The child labor provisions of this act were created to limit work’s interference with youths’ schooling and to minimize their health and safety risks. Contemporary studies have found that adolescents working more than 20 hours per week during the school year can experience several negative health behaviors and decrements to mental health. In addition, surveillance data show that hundreds of thousands of adolescents are injured at work as a result of performing hazardous tasks. Data for this study were obtained through a survey of a nationally representative sample of working adolescents, and the study investigated reports of select child labor violations. Approximately 37 percent of respondents reported a violation of the Hazardous Occupations Orders, and 40 percent reported a work permit violation. Less than 2 percent reported working more than the maximum weekly hours allowed during the school year, yet 11 percent reported working past the latest hour allowed on a school night, and 15 percent reported working off the clock.

“Further research on child labor violations should examine more carefully how shifts in enforcement activities over the past decade are affecting the detection of violations and the safety of young workers.” The study’s authors urge, “More-detailed research on the reasons for employer noncompliance will help inform and direct future enforcement efforts.” [From: “US Child Labor Violations in the Retail and Service Industries: Findings of a National Survey of Working Adolescents,” ].

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