CPR for ESRD Patients? It's Time to Talk… Medscape In-hospital CPR for ESRD patients is common, and it has been increasing in incidence over the years. The investigators studied the period between January 1, 2000, and December 31, 2010. The incidence of CPR for ESRD patients increased significantly ...

...

ANN ARBOR, Mich. - It started out as a treatment for arthritis. But steered by science, it could become a first new approach in two decades for treating the damage that diabetes inflicts on the kidneys of millions of people.

This past weekend, University of Michigan Medical School researchers and their colleagues presented promising results from a clinical trial of the experimental drug baricitinib in people with diabetic kidney disease. In a randomized, controlled Phase II study, it reduced a key sign of kidney damage, with higher doses producing the largest effect, few side effects, and signs of sustained impact even after patients stopped taking it.

U-M researchers not only helped conduct the clinical study - their scientific discoveries set the trial in motion. It's a fast-track example of the new treatment-development approach known as precision medicine.

The trial results presented this week at the American Diabetes Association Scientific Sessions come just three and a half years after the U-M research team linked up with the company that makes the drug, Eli Lilly & Co.

That connection resulted from the work of a team led by Matthias Kretzler, M.D. and Frank Brosius, M.D., which had worked for years to pinpoint the importance of a cell-signaling system called JAK-STAT in diabetic kidney disease.

By plowing through massive amounts of data on abnormal genetic activity in diseased human kidney tissue, and studying specially bred mice, the team showed JAK-STAT was over-active in multiple kidney cells damaged by diabetes.

But JAK-STAT also plays a key role in diseases where immune-system cells attack normal tissues - such as rheumatoid arthritis. Lilly scientists had developed baricitinib to calm the painful, inflamed joints of RA patients, and had received FDA permission to do trials that showed the drug's safety and impact.

When they learned that Kretzler was scheduled to speak about his research to another group at Lilly, they went to his talk and raised the possibility of using baricitinib against diabetic kidney disease. The international clinical trial, which enrolled 129 adult patients, began quickly -- just 14 months after that meeting.

"This is the first example of implementing precision medicine in diabetic kidney disease, which affects 8 million Americans and will surely affect more as the growing diabetes epidemic continues," says Kretzler. "It shows that the full translational research pipeline is in place, where we can study disease mechanisms, test our findings in model systems, identify drug candidates, find the right partners to take it to a clinical trial, and complete the trial - in 42 months."

The trial showed baricitinib reduced a measure of kidney dysfunction called urinary albumin/ creatinine ratio or UACR, substantially compared with placebo after six months. It also showed that patients had lower levels of two compounds in urine or blood that indicate inflammation in the kidneys, called IP-10 and sTNFR2. The only significant side effect was mild anemia in the group that received the highest dose, which was expected based on previous research.

Brosius directed the animal research studies and co-led the multi-institutional clinical trial. He notes that treatment of diabetic kidney disease costs the U.S. billions of dollars yearly. Currently, the standard approach to treating kidney damage in people with diabetes is to control blood pressure using decades-old drugs called ACE inhibitors and ARBs.

"The long-term effects of America's obesity and diabetes epidemics means that millions more kidneys are at risk. So America urgently needs new approaches to stem the damage that diabetes inflicts on kidney cells," says Brosius, who heads U-M's Division of Nephrology and the Michigan Kidney Translational Core Center that helped support this work. "So does the world, as nations like China feel the effects of obesity and diabetes epidemics."

...

A new study from The University of Texas Medical Branch at Galveston has revealed that a treatment taken daily by people who have had organ transplants to prevent organ rejection protects against Alzheimer's disease. An early online version of this paper detailing the findings has been published and is scheduled for publication in the July 7 issue of the Journal of Alzheimer's Disease.

Alzheimer's disease is the most common age-associated neurodegenerative disorder that has no cure. Compelling evidence shows that toxic protein aggregates called A? oligomers selectively target and disrupt the points of communication between brain cells, impairing memory in people suffering from the disease. Because of this, there is a large consensus that preventing this kind of toxicity would be an effective treatment strategy.

Calcineurin is an enzyme that regulates communication between brain cells and memory formation. The UTMB research team and others have shown previously that this enzyme plays a central role in the harmful effects of the A? oligomers and that elevated calcineurin is found in the nervous system of Alzheimer's patients.

Using a mouse model of Alzheimer's, the researchers earlier showed that blocking calcineurin restored memory function. However, the question of whether such a strategy would prevent the onset and progression of Alzheimer's in people is challenging because treatment with a calcineurin-blocking agent suppresses the immune system.

To bypass this issue, the UTMB team analyzed data from the medical records of 2,644 patients who received organ transplants and must take calcineurin inhibitor-based medications, such as Tacrolimus or cyclosporine, for the rest of their lives to prevent rejection of the transplanted organ. As part of the medical care for transplant recipients, any evidence of memory impairment or dementia is immediately noted and monitored, as it can limit treatment compliance among these patients.

The participants were separated into groups by age at the time of last visit or death, gender and ethnicity. Eight participants showed evidence of dementia - two were younger than 65, five were in the 65-74 years old group and one was in the 75-84 years old group.

The UTMB study data was compared with national data obtained from the 2014 Alzheimer's Association Facts and Figures dataset on age-matched patients to compare the prevalence of Alzheimer's.

Read also:

Study: Generic transplant drugs as good as brand name

"These data clearly show that the prevalence of dementia and Alzheimer's in our transplant patient group is significantly lower, in fact almost absent, when compared to national data from the general population," said senior author Luca Cicalese, professor in the department of surgery. "In patients over 65 years, 11% of the general population had dementia compared with 1.02% of the study subjects. In Americans over 75 years, 15.3% of the population had dementia compared with 0.6% of the study subjects. Among Americans over 85 years, 32% had dementia, although we did not have any patients in this age group with dementia."

Since the people involved in the study mostly come from Texas, the researchers further compared their over 65 years old group with the prevalence of Alzheimer's in the general population of the state and got similar results.

"Taken together, our findings from these people confirm the data obtained with animal models and support, for the first time in human subjects, our notion that calcineurin inhibition has a protective effect on the development and possible progression and even reversal of Alzheimer's disease," said senior author Giulio Taglialatela, Professor and Vice Chair for Research in the department of neurology and director of UTMB's Mitchell Center for Neurodegenerative Diseases. "Therefore, we are currently working on devising treatment strategies to obtain the same beneficial effects in AD humans using low doses of calcineurin inhibitors that result in minimal or no immunosuppression, thus limiting possible undesired side effects."

...

CHICAGO — Sunitinib improved radiographic PFS compared with everolimus among certain subgroups of patients with metastatic non–clear cell renal cell carcinoma, according to findings from a phase 2 trial presented at the ASCO Annual Meeting.

However, patients assigned sunitinib (Sutent, Pfizer) also demonstrated greater rates of grade 3 or worse toxicities, results showed.

This study marks the first time researchers identified an mTOR-sensitive subgroup of patients with non–clear cell renal cell carcinoma compared with VEGF inhibition in the front-line setting.

Andrew J. Armstrong, MD, ScM,an associate professor of medicine and surgery in the division of medicine-oncology at the Duke University School of Medicine, and colleagues conducted the ASPEN trial — an international, randomized trial — to compare sunitinib with everolimus (Afinitor, Novartis) in 108 patients (median age 63 years; 75% men) with metastatic non–clear cell renal cell carcinoma who had papillary (66%), chromophobe (15%) or unclassified (19%) histology and no prior systemic therapy. Most patients and intermediate-risk disease (59%), 27% had good-risk disease and 15% had poor-risk disease.

Radiographic PFS — measured using RECIST 1.1 criteria — served as the primary endpoint.

Researchers expected 90 PFS events to occur, resulting in an 83% power to detect a 38% decrease in the HR for progression or death.

Researchers stratified patients by their histology and risk group and randomly assigned them to the everolimus arm (n = 57) or sunitinib arm (n = 51).  The treatment arms were balanced at baseline.

After 87 PFS events, 53 deaths and two patients still on treatment, sunitinib met the primary endpoint by improving PFS.

Patients in the sunitinib arm achieved a median PFS of 8.3 months (80% CI, 5.8-11.1), whereas the median PFS in the everolimus arm was 5.6 months (80% CI, 5.5-6; HR = 1.41; 80% CI, 1.03-1.92).

Sunitinib specifically improved PFS compared with everolimus in patients considered good risk (14 months vs. 5.7 months; HR = 3.07; 80% CI, 1.51-6.28) or intermediate risk (6.5 months vs. 4.9 months; HR = 1.38; 80% CI, 0.96-2). Researchers also observed improved PFS with sunitinib vs. everolimus in patients with papillary (8.1 months vs. 5.5 months; HR = 1.52; 80% CI, 1.05-2.2) or unclassified histology (11.5 months vs. 5.6 months; HR = 2.55; 80% CI, 1.01-6.45).

However, everolimus improved PFS compared with sunitinib in poor-risk patients (6.1 months vs. 4 months; HR = 0.21; 80% CI, 0.06-0.69) and patients with chromophobe histology (11.4 months vs. 5.5 months; HR = 0.71; 80% CI, 0.31-1.65).

Sunitinib improved median OS compared with everolimus (31.5 months vs. 13.2 months); however, the improvement did not reach statistical significance (HR = 1.17; 95% CI, 0.65-2.14).

Although no unexpected safety signals emerged from the treatment, sunitinib did result in more grade 3 or worse treatment-related adverse events than everolimus (65% vs. 47%).

“Patients with metastatic non–clear cell renal cell carcinoma treated with sunitinib had a statistically significantly prolonged PFS duration compared with patients treated with everolimus,” Armstrong said during his presentation. “Sunitinib resulted in improved PFS both in good- and intermediate-risk patients and papillary and unclassified histologies, whereas everolimus resulted in improved PFS in both poor-risk and chromophobe subtypes.

“Future trials in this heterogeneous collection of diseases should consider these factors when designing prospective studies. Both agents resulted in short PFS times and low response rates illustrating the unmet need still in this population for better drugs to improve PFS and OS.” – by Anthony SanFilippo

Reference:Armstrong AJ, et al. Abstract 4507. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Disclosure: Armstrong reports honoraria, research funding and travel expenses from; consultant/advisory and speakers bureau roles with Astellas, Bayer, Bristol-Myers Squibb, Dendreon, ImClone Systems, Janssen Biotech, Janssen Oncology, KangLaiTe, Medivation, Novartis, Pfizer and Sanofi. See the abstract for a list of all other researchers’ relevant financial disclosures.

...