Atypical antipsychotic drug use increases risk for acute kidney injury

Nephrology_Urology

Atypical antipsychotic drug use is associated with an increased risk for acute kidney injury (AKI) and other adverse outcomes, according to a study being published in Annals of Internal Medicine.

Each year, millions of older adults are prescribed atypical antipsychotic drugs (quetiapine, risperidone, and olanzapine) to manage behavioral symptoms of dementia, which is not an approved indication. This type of off-label use has raised safety concerns, as these atypical antipsychotics are known to cause AKI. Researchers compared medical records for 97,777 adults aged 65 or older who received a new outpatient prescription for an oral atypical antipsychotic drug against a matched cohort of patients who had not received such a prescription to determine the risk for AKI and other adverse outcomes.

Persons who had received a prescription for any three atypical antipsychotic drugs in the previous 90 days had an elevated risk for hospitalization with AKI. The drugs were also associated with increased risk for hypotension, acute urinary retention, and death. The findings support current safety concerns regarding the use of these drugs in older adults.

Study: Atypical Antipsychotic Drugs and the Risk for Acute Kidney Injury and Other Adverse Outcomes in Older Adults: A Population-Based Cohort Study, Y.J. Hwang, S.N. Dixon, J.P. Reiss, R. Wald, C.R. Parikh, S. Gandhi, S.Z. Shariff, N. Pannu, D.M. Nash, F. Rehman, and A.X. Garg, Annals of Internal Medicine, doi: 10.7326/M13-2796, published 18 August 2014.

http://www.medicalnewstoday.com/releases/281206.php

 

 

Enzyme lost in 100 percent of kidney tumors analyzed

Urology_Nephrology

In an analysis of small molecules called metabolites used by the body to make fuel in normal and cancerous cells in human kidney tissue, a research team from the Perelman School of Medicine at the University of Pennsylvania identified an enzyme key to applying the brakes on tumor growth. The team found that an enzyme called FBP1 – essential for regulating metabolism – binds to a transcription factor in the nucleus of certain kidney cells and restrains energy production in the cell body. What’s more, they determined that this enzyme is missing from all kidney tumor tissue analyzed. These tumor cells without FBP1 produce energy at a much faster rate than their non-cancer cell counterparts. When FBP1 is working properly, out-of-control cell growth is kept in check.

The new study, published online this week in Nature, was led by Celeste Simon, PhD, a professor of Cell and Developmental Biology and the scientific director for the Abramson Family Cancer Research Institute at Penn.

Clear cell renal cell carcinoma (ccRCC), the most frequent form of kidney cancer, is characterized by elevated glycogen (a form of carbohydrate) and fat deposits in affected kidney cells. This over-storage of lipids causes large clear droplets to accumulate, hence the cancer’s name.

In the last decade, ccRCCs have been on the rise worldwide. However, if tumors are removed early, a patient’s prognosis for five-year survival is relatively good. If expression of the FBP1 gene is lost, patients have a worse prognosis.

“This study is the first stop in this line of research for coming up with a personalized approach for people with clear cell renal cell carcinoma-related mutations,” says Simon, also an investigator with the Howard Hughes Medical Institute.

A Series of Faulty Reactions

The aberrant storage of lipid in ccRCC results from a faulty series of biochemical reactions. These reactions, called the Kreb’s cycle, generate energy from carbohydrates, fats, and proteins in the form of ATP. However, the Kreb’s cycle is hyperactive in ccRCC, resulting in enhanced lipid production. Renal cancer cells are associated with changes in two important intracellular proteins: elevated expression of hypoxia inducible factors (HIFs) and mutations in the von Hippel-Lindau (VHL) encoded protein, pVHL. In fact, mutations in pVHL occur in 90 percent of ccRCC tumors. pVHL regulates HIFs, which in turn affect activity of the Kreb’s cycle.

Although much is already known about metabolic pathways and their role in cancer, there are still important questions to be answered. For example, kidney-specific VHL deletion in mice does not elicit clear cell-specific tumor formation, suggesting that additional mechanisms are at play. Toward answering that hunch, recent large-scale sequencing analyses have revealed the loss of several epigenetic enzymes in certain types of ccRCCs, suggesting that changes within the nucleus also account for kidney tumor progression.

To complement genetic studies revealing a role for epigenetic enzymes, the team evaluated metabolic enzymes in the 600-plus tumors they analyzed. The expression of FBP1 was lost in all kidney cancer tissue samples examined. They found FBP1 protein in the cytoplasm of normal cells, where it would be expected to be active in glucose metabolism. But, they also found FBP1 in the nucleus of these normal cells, where it binds to HIF to modulate its effects on tumor growth. In cells without FBPI, the team observed the Warburg effect – a phenomenon in which malignant, rapidly growing tumor cells go into overdrive, producing energy up to 200 times faster than their non-cancer-cell counterparts.

This unique dual function of FBP1 explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumor suppressors that are not consistently inhibited in all tumors. “And since FBP1 activity is also lost in liver cancer, which is quite prevalent, FBP1 depletion may be generally applicable to a number of human cancers,” notes Simon.

Next steps, according to the researchers, will be to identify other metabolic pathways to target, measure the abundance of metabolites in kidney and liver cancer cells to determine FBP1’s role in each, and develop a better mouse model for preclinical studies.

Picture Credit: Credit: Bo Li and Brian Keith, Perelman School of Medicine, University of Pennsylvania.

http://www.medicalnewstoday.com/releases/279893.php

 

 

 

Nanoparticles used to enhance chemotherapy

Nephrology_Urology_Radiology

University of Georgia researchers have developed a new formulation of cisplatin, a common chemotherapydrug, that significantly increases the drug’s ability to target and destroy cancerous cells.

Cisplatin may be used to treat a variety of cancers, but it is most commonly prescribed for cancer of the bladder, ovaries, cervix, testicles and lung. It is an effective drug, but many cancerous cells develop resistance to the treatment.

Shanta Dhar, assistant professor of chemistry in the UGA Franklin College of Arts and Sciences, and Rakesh Pathak, a postdoctoral researcher in Dhar’s lab, constructed a modified version of cisplatin called Platin-M, which is designed to overcome this resistance by attacking mitochondria within cancerous cells. They published their findings recently in the Proceedings of the National Academy of Sciences.

“You can think of mitochondria as a kind of powerhouse for the cell, generating the energy it needs to grow and reproduce,” said Dhar, a member of the UGA Cancer Center and principal investigator for the project. “This prodrug delivers cisplatin directly to the mitochondria in cancerous cells. Without that essential powerhouse, the cell cannot survive.”

Sean Marrache, a graduate student in Dhar’s lab, entrapped Platin-M in a specially designed nanoparticle 1,000 times finer than a human hair that seeks out the mitochondria and releases the drug. Once inside, Platin-M interferes with the mitochondria’s DNA, triggering cell death.

Dhar’s research team tested Platin-M on neuroblastoma – a cancer commonly diagnosed in children-that typically originates in the adrenal glands. In preliminary experiments using a cisplatin-resistant cell culture, Platin-M nanoparticles were 17 times more active than cisplatin alone.

“This technique could become a treatment for a number of cancers, but it may prove most useful for more aggressive forms of cancer that are resistant to current therapies,” said Pathak.

Both Dhar and Pathak caution that their experimental results are preliminary and they must do more work before Platin-M enters any clinical trials. However, their early results in mouse models are promising, and they are currently developing safety trials in larger animals.

“Cisplatin is a well-studied chemotherapy, so we hope our unique formulation will enhance its efficacy,” said Dhar, who is also a member of UGA’s Nanoscale Science and Engineering Center, Center for Drug Discovery, and Regenerative Bioscience Center. “We are excited about these early results, which look very promising.”

 

http://www.medicalnewstoday.com/releases/279303.php

Picture courtesy of www.sciencedaily.com

 

 

 

“Big data” technique improves monitoring of kidney transplant patients

Urology_Nephrology

A new data analysis technique could radically improve monitoring of kidney transplant patients, according to new research published this week in PLOS Computational Biology.

The research, carried out by a team comprising physicists, chemist and clinicians at the University of Leeds, provides a method for making sense out of the huge number of clues about a kidney transplant patient’s prognosis contained in their blood.

By applying a sophisticated “big data” analysis to the samples, scientists were able to process hundreds of thousands of variables into a single parameter to indicate how a kidney transplant was faring. This allowed them to predict poor function of a kidney after only two days in cases that may not have been previously detected as failing until weeks after transplant.

These extra few days are vital in the early stages after transplant and would give doctors a better chance to intervene to save the transplant and improve patient recovery periods. In some cases, the team were able to predict failure from patients’ blood samples taken before the transplant operation.

Dr Sergei Krivov, in the University of Leeds’ Astbury Center, said: “If you put a blood sample through Nuclear Magnetic Resonance analysis you get data down to the molecular level. You can identify chemical fingerprints left behind by specific cellular processes and you get a very large number of different parameters in those samples that vary with the outcome for a patient.

“These are vital clues. But, if you have got thousands of variables all moving in different ways in a complex system, how does a doctor bring all that information together and decide what to do? It is not possible to do this with the human mind; there are just too many variables. We have to do it with computers and find a way to weigh those variables and produce an intelligible output describing where, overall, the patient is heading.”

The study, which analysed data from daily blood samples from 18 patients immediately before and in a week-long period after kidney transplants, showed that it was possible to pick out pieces of information that varied with the overall likelihood of a patient either rejecting a kidney or recovering kidney function.

Given enough data, the technique could even be used to quantify very complex and extended processes affecting the whole population.

http://www.medicalnewstoday.com/releases/278531.php

 

 

 

Increased risk of rare, deadly condition faced by obese, older, Caucasian women on dialysis

OBGYN_Urology_Nephrology

Obese, Caucasian females over age 50 with diabetes and on dialysis because their kidneys have failed are among those at highest risk for the rare and deadly condition calciphylaxis, according to an analysis of the United States Renal Data System.

Calciphylaxis occurs when calcium and phosphorus bind to form a biological cement that blocks and inflames small blood vessels, putting patients at risk for major infection and skin ulcers as well as patches of dying skin, said Dr. Lu Huber, nephrologist at the Medical College of Georgia at Georgia Regents University.

“It’s all about balance, and our kidneys help regulate that balance,” said Huber, who scoured the national database of 2.1 million patients with failed kidneys to better define incidence and risk factors with the goal of better identifying and managing those at highest risk.

Her findings were cited as one of eight best abstracts submitted to the 51st European Renal Association – European Dialysis and Transplant Association Congress in Amsterdam.

Huber found the condition occurred in 459, or 0.02 percent, of the patients, who were mostly white, older women on traditional hemodialysis, where an external machine filters the total blood volume typically three times a week rather than the continuous efforts of healthy kidneys.

The median time from the first dialysis treatment to a diagnosis of calciphylaxis was less than four years, median survival time was 176 days, and 50 percent of deaths were within 87 days. Being over age 65, Caucasian, and diabetic are significant risk factors for death from calciphylaxis.

“We are not completely sure why calciphylaxis happens, but mostly it’s in dialysis patients,” Huber said. While dialysis is literally a lifesaver, it does not completely replace all the filtering work of the kidney, never mind other major functions, such as making the active form of vitamin D, Huber said. Vitamin D increases absorption of calcium, which is essential to strong bones and teeth as well as muscle function, including the heart.

Physicians give patients vitamin D while they are receiving dialysis to keep bone strong. Ironically, vitamin D also increases absorption of phosphorus, which, without functioning kidneys, begins to accumulate in the blood.

“In end-stage renal disease, we tend to see low calcium and high phosphorus,” Huber said. The dysregulation somehow prompts the two to bind in the blood and ‘basically make cement,” Huber said. The material deposits in small blood vessels, valves and soft tissue, contributing to the vascular complications of life on dialysis.

“When we do X-rays of patients, their small vessels actually light up because of the calcium/phosphorus deposition,” Huber said. With the calcium-phosphorus deposition, vessels quickly become stiff and narrowed, which leads to inadequate blood supply, contributing to tissue death, and paving the way for infection.

To try and balance things out, all dialysis patients take phosphorus binders before eating that grab excess phosphorus, found in high levels in animal protein and processed foods, so more will be eliminated from the gut and less absorbed into the blood. Dietitians help patients minimize phosphorus intake, and blood levels of phosphorus and calcium are regularly monitored, often as kidneys are failing and before dialysis has even begun.

However, physicians may need to be even more diligent and aggressive particularly in these high-risk populations, Huber said. This may include additional diet changes, taking more phosphorus binders, and more frequent dialysis. She notes that no prospective studies have measured the effectiveness of these current interventions.

A specific diagnostic code for calciphylaxis – currently, it shares one with multiple other conditions resulting from calcium-phosphorus abnormalities – could ease future studies of this relatively small population of patients, Huber said. This could include examining more detailed clinical information that is currently housed at countless dialysis centers across the country.

Diabetes and hypertension are major causes of kidney failure, although Huber notes that many kidney failure patients are not obese.

http://www.medicalnewstoday.com/releases/277707.php

Picture courtesy of guardianlv.com

 

 

 

 

Anxiety and depression linked to physical impairments in dialysis patients

May_Part 2_Nephrology_Urology

With the rate of chronic kidney disease on the rise among older Americans, researchers seeking to improve patients’ quality of life studied a group of adults undergoing hemodialysis and found their higher rates of depression andanxiety could be associated with their impaired physical exercise capability and reduced daily physical activity, according a new study published online by the Journal of Renal Nutrition.

The researchers studied 72 relatively healthy maintenance hemodialysis patients and compared them to 39 healthy adults who were not on dialysis. They found significantly higher rates of anxiety and depression among the dialysis patients, than among the adults who were not on dialysis. They also found the dialysis patients suffering from depression and anxiety had the greatest impairments in physical exercise performance and daily physical activity.

“Adults undergoing dialysis often have less daily physical activities than other adults, but little was known about what, if any, effect this reduced activity had on their mental state,” said Joel D. Kopple, MD, Los Angeles Biomedical Research Institute (LA BioMed) lead researcher. “Our study found an association between reduced daily physical activities and depression and anxiety. Also, the capacity to perform physical exercise was diminished in these patients. These findings provide a strong rationale for studying whether increased daily physical activity can reduce depression and anxiety among adults undergoing dialysis.”

Each person enrolled in the study took walks, climbed stairs and engaged in other physical activities so that researchers could determine their physical abilities. The researchers gauged their depression and anxiety using standardized tests and found 43% of the dialysis patients had anxiety and 33% suffered from depression. In comparison, only 2.5% of the adults who were not on dialysis had anxiety and only 5% of them suffered from depression.

Approximately one in 10 Americans has some form of chronic kidney disease, and the incidence of chronic kidney disease among people ages 65 and older more than doubled between 2000 and 2008, according to the Centers for Disease Control and Prevention.

Hemodialysis is a life-preserving treatment for hundreds of thousands of Americans with kidney failure. It is a medical procedure to remove fluid and waste products from the blood and to correct electrolyte imbalances. This is accomplished using a machine and a dialyzer, which is sometimes described as an “artificial kidney.”

“Research is important to improve the quality of life of patients undergoing dialysis,” said Dr. Kopple. “With the growing population of people undergoing dialysis, this research is growing in importance.”

http://www.medicalnewstoday.com/releases/277460.php

Picture courtesy of www.rncentral.com

 

Unplanned Visits After Urinary Stone Treatment Defined

May_Part 1_Urology

Researchers have found that, overall, 1 in 7 patients who undergo a procedure to treat urinary stones make unplanned, high-acuity, follow-up visits, defined as presentation to an emergency department or a hospital admission within 30 days of the procedure.

Charles D. Scales, MD, of Duke University in Durham, N.C., and colleagues identified 93,523 initial procedures to fragment or remove urinary stones.

Unplanned visits occur less frequently after shockwave lithotripsy (12% of cases) and occurred with similar frequency after ureteroscopy and percutaneous nephrostolithotomy (15%), the investigators reported in Surgery (2014;155:769-775). Procedures at high-volume facilities were substantially less likely to result in an unplanned visit.

http://www.renalandurologynews.com/unplanned-visits-after-urinary-stone-treatment-defined/article/345800/